JP4338684B2

JP4338684B2 - Benzamidine derivatives

Info

Publication number: JP4338684B2
Application number: JP2005239725A
Authority: JP
Inventors: 光一藤本; 史敏浅井; 速生松橋
Original assignee: Daiichi Sankyo Co Ltd
Current assignee: Daiichi Sankyo Co Ltd
Priority date: 1999-10-28
Filing date: 2005-08-22
Publication date: 2009-10-07
Anticipated expiration: 2020-10-27
Also published as: JP2006008702A

Description

本発明は、優れた活性化血液凝固第Ｘ因子阻害作用を有し、血液凝固性疾患の治療薬又は予防薬として有用なベンズアミジン誘導体、それらの薬理上許容される塩、及びそれらを含有する医薬に関する。 The present invention relates to a benzamidine derivative having an excellent activated blood coagulation factor X inhibitory effect and useful as a therapeutic or prophylactic agent for blood coagulation diseases, a pharmacologically acceptable salt thereof, and a medicament containing them About.

近年、人口の高齢化により、加齢に伴う循環器疾患の増加が目立っている。その中でも、脳梗塞、心筋梗塞、末梢循環障害などの血栓性疾患は、直接死因に結び付くばかりでなく、患者の予後の悪さ、生活に対する制限など個人的、社会的負担を多く強いることになる。これら血栓症に対する治療法として、抗凝固療法は今後ますます重要性が増すと考えられる。
血液の凝固は、何らかの刺激に起因して活性化される酵素反応の多段階増幅過程を経て、最終的に活性化されたトロンビンが、可溶性血漿蛋白であるフィブリノーゲンを限定分解し、フィブリンを生成することにより生じる。フィブリンは不溶性蛋白で凝塊を形成する。この過程は血液凝固カスケードとして知られ、内因系および外因系の２つの経路が有り、それぞれの経路は、血液凝固第Ｘ因子を活性化して合流する。以上のように、生成した活性化血液凝固第Ｘ因子は、血液凝固カスケードの重要な位置を占める酵素で、最終的には、２価カルシウムイオン、リン脂質及び活性化血液凝固第Ｖ因子等と複合体をつくり、プロトロンビンをトロンビンに効率良く転換し、血液凝固反応を促進させる（非特許文献１）。 In recent years, due to the aging of the population, an increase in cardiovascular diseases accompanying aging is conspicuous. Among them, thrombotic diseases such as cerebral infarction, myocardial infarction and peripheral circulation disorder are not only directly related to the cause of death, but also impose many personal and social burdens such as poor prognosis of patients and restrictions on life. Anticoagulant therapy is expected to become increasingly important as a treatment for these thrombosis.
Blood clotting goes through a multi-step amplification process of an enzymatic reaction that is activated due to some stimulus, and finally activated thrombin produces a fibrin by limited degradation of soluble plasma protein fibrinogen. Caused by Fibrin forms a clot with insoluble protein. This process is known as the blood coagulation cascade, and there are two pathways, the intrinsic system and the extrinsic system, each pathway activating and coagulating blood coagulation factor X. As described above, the generated activated blood coagulation factor X is an enzyme that occupies an important position in the blood coagulation cascade. Finally, divalent calcium ions, phospholipids, activated blood coagulation factor V, etc. A complex is formed, prothrombin is efficiently converted to thrombin, and blood coagulation reaction is promoted (Non-patent Document 1).

現在、抗凝固薬としてはワルファリンや抗トロンビン剤が知られ、使用されている。しかし、ワルファリンは経口の抗血栓薬として汎用されてはいるが、ビタミンＫ拮抗物質であり、食事や、併用薬剤との相互作用がしばしば見られるなど抗凝固能のコントロールが難しいことが知られている（非特許文献２）。また、現在の抗トロンビン剤は、薬効に伴う副作用の出血傾向が観察されることから、新たな抗凝固薬の開発が望まれている。活性化血液凝固第Ｘ因子はトロンビンの生成に直接関与し、その阻害剤は抗凝固作用を示すことが知られており、新規の抗凝固剤として可能性が示唆されている（非特許文献３）。 Currently, warfarin and antithrombin agents are known and used as anticoagulants. However, although warfarin is widely used as an oral antithrombotic drug, it is a vitamin K antagonist, and it is known that anticoagulant ability is difficult to control because it often interacts with meals and concomitant drugs. (Non-Patent Document 2). In addition, since current antithrombin agents have a tendency to bleed as a side effect associated with their efficacy, the development of new anticoagulants is desired. Activated blood coagulation factor X is directly involved in the generation of thrombin, and its inhibitor is known to exhibit an anticoagulant action, suggesting the possibility as a novel anticoagulant (Non-patent Document 3). ).

ところで、競合拮抗型の活性化血液凝固第Ｘ因子阻害剤として、特許文献１、特許文献２又は特許文献３には、芳香族アミジン誘導体又はアミジノナフチル誘導体が記載されている。また、特許文献４には、例えば、Ｎ−［４−［１−アセトイミドイル−４−ピペリジルオキシ］フェニル］−Ｎ−［２−（３−アミジノフェノキシ）エチル］スルファモイル酢酸２トリフルオロ酢酸塩等のベンズアミジン誘導体が記載されている。
Ｅ．Ｌ．スミス、Ａ．ホワイト、プリンシプルズ・オブ・バイオケミストリー：マーマリアン・バイオケミストリー，第７版（１９８３年）、マッグローヒル。クリニカル・ファーマコカイネティックス，第３０巻，第４１６頁（１９９６年）。ドラッグズ，第４９巻，第８５６頁（１９９５年）。特開平５−２０８９４６号（欧州特許出願公開第５４００５１号明細書）国際公開第９６／１６９４０号パンフレット（欧州特許出願公開第７９８２９５号明細書）国際公開第００／４７５５３号パンフレット国際公開第９８／３１６６１号パンフレット（欧州特許出願公開第９７６７２２号明細書） By the way, as competitive competitive type activated blood coagulation factor X inhibitors, Patent Document 1, Patent Document 2 or Patent Document 3 describe aromatic amidine derivatives or amidinonaphthyl derivatives. Patent Document 4 discloses, for example, N- [4- [1-acetimidoyl-4-piperidyloxy] phenyl] -N- [2- (3-amidinophenoxy) ethyl] sulfamoylacetic acid 2 trifluoroacetate salt. Benzamidine derivatives have been described.
E. L. Smith, A.M. White, Principals of Biochemistry: Marmarian Biochemistry, 7th edition (1983), McGraw Hill. Clinical Pharmacokinetics, 30, 416 (1996). Drugs, 49, 856 (1995). JP-A-5-208946 (European Patent Application Publication No. 540051) International Publication No. 96/16940 (European Patent Application Publication No. 798295) International Publication No. 00/47553 pamphlet WO 98/31661 pamphlet (European Patent Application Publication No. 976722)

本発明者等は、優れた活性化血液凝固第Ｘ因子阻害作用を有する化合物の開発を目指し、種々のベンズアミジン誘導体の薬理活性について、長年に亘り、鋭意研究を行った結果、特異な構造を有するベンズアミジン誘導体が、優れた活性化血液凝固第Ｘ因子阻害作用を有し、トリプシン阻害作用を示さないため、それに起因する副作用が無く、血液凝固性疾患の予防薬又は治療薬（特に治療薬）として有用であることを見出し、本発明を完成するに至った。 The present inventors aim to develop a compound having an excellent activated blood coagulation factor X inhibitory action, and as a result of intensive studies over many years on the pharmacological activity of various benzamidine derivatives, the present inventors have a unique structure. As benzamidine derivatives have an excellent activated blood coagulation factor X inhibitory action and do not show trypsin inhibitory action, there are no side effects resulting from it, and as a prophylactic or therapeutic agent (especially a therapeutic agent) for blood coagulation diseases It has been found useful, and the present invention has been completed.

本発明は、優れた活性化血液凝固第Ｘ因子阻害作用を有するベンズアミジン誘導体、それらの薬理上許容される塩、それらの製法、それらの合成に有用な中間体、及び血液凝固性疾患の予防薬又は治療薬として有用な、前記ベンズアミジン誘導体を含有する医薬を提供する。 The present invention relates to a benzamidine derivative having an excellent activated blood coagulation factor X inhibitory action, a pharmacologically acceptable salt thereof, a production method thereof, an intermediate useful for the synthesis thereof, and a prophylactic agent for blood coagulation diseases. Alternatively, a medicament containing the benzamidine derivative useful as a therapeutic agent is provided.

本発明は、のベンズアミジン誘導体は、一般式 In the present invention, the benzamidine derivative has the general formula

を有する。

Have

上記式中、
Ｒ¹は、水素原子、ハロゲン原子、Ｃ₁−Ｃ₆アルキル基又は水酸基を示し、
Ｒ²は、水素原子、ハロゲン原子又はＣ₁−Ｃ₆アルキル基を示し、
Ｒ³は、水素原子；Ｃ₁−Ｃ₆アルキル基；水酸基、カルボキシル基若しくは（Ｃ₁−Ｃ₆アルコキシ）カルボニル基で置換されたＣ₁−Ｃ₆アルキル基；一般式 In the above formula,
R ¹ represents a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group or a hydroxyl group,
R ² represents a hydrogen atom, a halogen atom or a C ₁ -C ₆ alkyl group,
R ³ represents a hydrogen atom; a C ₁ -C ₆ alkyl group; a C ₁ -C ₆ alkyl group substituted with a hydroxyl group, a carboxyl group or a (C ₁ -C ₆ alkoxy) carbonyl group;

（式中、Ｒ⁷は、Ｃ₁−Ｃ₆アルキル基を示し、ｍ及びｎは、同一又は異なって、１乃至６の整数を示す。）を有する基；Ｃ₇−Ｃ₁₅アラルキル基；Ｃ₁−Ｃ₆アルカノイル基；ヒドロキシＣ₂−Ｃ₆アルカノイル基；Ｃ₁−Ｃ₆アルキルスルホニル基；又は、（Ｃ₁−Ｃ₆アルコキシ）カルボニル基若しくはカルボキシル基で置換されたＣ₁−Ｃ₆アルキルスルホニル基を示し、
Ｒ⁴及びＲ⁵は、同一又は異なって、水素原子、ハロゲン原子、Ｃ₁−Ｃ₆アルキル基、ハロゲノＣ₁−Ｃ₆アルキル基、Ｃ₁−Ｃ₆アルコキシ基、カルボキシル基、（Ｃ₁−Ｃ₆アルコキシ）カルボニル基、カルバモイル基、（Ｃ₁−Ｃ₆アルキル）カルバモイル基又はジ（Ｃ₁−Ｃ₆アルキル）カルバモイル基を示し、
Ｒ⁶は、１−アセトイミドイルピロリジン−３−イル基又は１−アセトイミドイルピペリジン−４−イル基を示す。
また、本発明の医薬の有効成分は、一般式（Ｉ）を有するベンズアミジン誘導体である。

Wherein R ⁷ represents a C ₁ -C ₆ alkyl group, and m and n are the same or different and each represents an integer of 1 to 6; a C ₇ -C ₁₅ aralkyl group; ₁ -C ₆ alkanoyl group; hydroxy C ₂ -C ₆ alkanoyl group; C ₁ -C ₆ alkylsulfonyl group; or, (C ₁ -C ₆ alkoxy) C ₁ -C ₆ alkyl substituted with a carbonyl group or a carboxyl group Represents a sulfonyl group,
R ⁴ and R ⁵ are the same or different and are a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, a halogeno C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a carboxyl group, (C _1- C ₆ alkoxy) carbonyl group, carbamoyl group, (C ₁ -C ₆ alkyl) carbamoyl group or di (C ₁ -C ₆ alkyl) carbamoyl group,
R ⁶ represents a 1-acetimidoylpyrrolidin-3-yl group or a 1-acetimidoylpiperidin-4-yl group.
The active ingredient of the medicament of the present invention is a benzamidine derivative having the general formula (I).

本発明の前記一般式（Ｉ）を有するベンズアミジン誘導体は、優れた活性化血液凝固第Ｘ因子阻害作用を有し、毒性も弱いため、医薬［特に、血液凝固性疾患（例えば、脳梗塞、心筋梗塞又は末梢循環障害等の血栓性疾患）の予防薬又は治療薬（特に治療薬）］として有用である。 Since the benzamidine derivative having the above general formula (I) of the present invention has an excellent activated blood coagulation factor X inhibitory action and weak toxicity, it can be used for pharmaceuticals [particularly blood coagulation diseases (for example, cerebral infarction, myocardium). Prophylactic or therapeutic agent (especially therapeutic agent) for thrombotic diseases such as infarction or peripheral circulatory disorder)

上記一般式（Ｉ）に於て、Ｒ¹の定義に於ける「ハロゲン原子」は、例えば、弗素原子、塩素原子、臭素原子又は沃素原子であり得、好適には弗素原子、塩素原子又は臭素原子であり、更に好適には、弗素原子又は塩素原子であり、特に好適には弗素原子である。 In the general formula (I), the “halogen atom” in the definition of R ¹ can be, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and preferably a fluorine atom, a chlorine atom or a bromine atom. An atom, more preferably a fluorine atom or a chlorine atom, and particularly preferably a fluorine atom.

上記に於て、Ｒ¹の定義に於ける「Ｃ₁−Ｃ₆アルキル基」は、例えば、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓ−ブチル基、ｔ−ブチル基、ペンチル基、イソペンチル基、２−メチルブチル基、ネオペンチル基、１−エチルプロピル基、ヘキシル基、４−メチルペンチル基、３−メチルペンチル基、２−メチルペンチル基、１−メチルペンチル基、３，３−ジメチルブチル基、２，２−ジメチルブチル基、１，１−ジメチルブチル基、１，２−ジメチルブチル基、１，３−ジメチルブチル基、２，３−ジメチルブチル基又は２−エチルブチル基のような、炭素数１乃至６個の直鎖又は分枝鎖アルキル基であり、好適にはＣ₁−Ｃ₄アルキル基であり、更に好適にはメチル基又はエチル基であり、特に好適にはメチル基である。 In the above, “C ₁ -C ₆ alkyl group” in the definition of R ¹ is, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, t- Butyl group, pentyl group, isopentyl group, 2-methylbutyl group, neopentyl group, 1-ethylpropyl group, hexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group or 2- such as ethylbutyl group, a linear or branched alkyl group having 1 to 6 carbon atoms, preferably a C ₁ -C ₄ alkyl group, more preferably a methyl group or an ethyl group, especially The suitable a methyl group.

上記に於いて、Ｒ²の定義に於ける「ハロゲン原子」は、例えば、前記Ｒ¹で定義したものと同意義であり得、好適には弗素原子又は塩素原子であり、特に好適には弗素原子である。 In the above description, the “halogen atom” in the definition of R ² may have the same meaning as that defined for R ¹ , for example, preferably a fluorine atom or a chlorine atom, particularly preferably fluorine. Is an atom.

上記に於いて、Ｒ²の定義に於ける「Ｃ₁−Ｃ₆アルキル基」は、例えば、前記Ｒ¹で定義したものと同意義であり得、好適にはＣ₁−Ｃ₄アルキル基であり、更に好適にはメチル基又はエチル基であり、特に好適にはメチル基である。 In the above description, the “C ₁ -C ₆ alkyl group” in the definition of R ² can be, for example, the same as defined for R ¹ , preferably a C ₁ -C ₄ alkyl group. More preferably a methyl group or an ethyl group, and particularly preferably a methyl group.

上記に於いて、Ｒ³の定義に於ける「Ｃ₁−Ｃ₆アルキル基」及び「水酸基、カルボキシル基若しくは（Ｃ₁−Ｃ₆アルコキシ）カルボニル基で置換されたＣ₁−Ｃ₆アルキル基」の「Ｃ₁−Ｃ₆アルキル基」部分は、例えば、前記Ｒ¹で定義したものと同意義であり得、「Ｃ₁−Ｃ₆アルキル基」は、好適にはＣ₁−Ｃ₄アルキル基であり、更に好適にはメチル基、エチル基又はイソプロピル基であり、特に好適にはイソプロピル基である。他方、「水酸基、カルボキシル基若しくは（Ｃ₁−Ｃ₆アルコキシ）カルボニル基で置換されたＣ₁−Ｃ₆アルキル基」の「Ｃ₁−Ｃ₆アルキル基」部分は、好適にはＣ₁−Ｃ₄アルキル基であり、更に好適にはメチル基又はエチル基であり、特に好適にはメチル基である。 In the above, “C ₁ -C ₆ alkyl group” and “C ₁ -C ₆ alkyl group substituted with a hydroxyl group, carboxyl group or (C ₁ -C ₆ alkoxy) carbonyl group” in the definition of R ³ The “C ₁ -C ₆ alkyl group” part of the above can be, for example, the same as defined above for R ¹ , and the “C ₁ -C ₆ alkyl group” is preferably a C ₁ -C ₄ alkyl group More preferably a methyl group, an ethyl group or an isopropyl group, and particularly preferably an isopropyl group. On the other hand, "C ₁ -C ₆ alkyl group" moiety of the "hydroxyl group, C ₁ -C ₆ alkyl group substituted with a carboxyl group or a (C ₁ -C ₆ alkoxy) carbonyl group" is preferably a C ₁ -C _{4 is} an alkyl group, more preferably a methyl group or an ethyl group, and particularly preferably a methyl group.

上記に於いて、Ｒ³の定義に於ける「水酸基、カルボキシル基若しくは（Ｃ₁−Ｃ₆アルコキシ）カルボニル基で置換されたＣ₁−Ｃ₆アルキル基」の置換基及び「（Ｃ₁−Ｃ₆アルコキシ）カルボニル基若しくはカルボキシル基で置換されたＣ₁−Ｃ₆アルキルスルホニル基」の置換基の定義に於ける「（Ｃ₁−Ｃ₆アルコキシ）カルボニル基」は、例えば、メトキシカルボニル基、エトキシカルボニル基、プロポキシカルボニル基、イソプロポキシカルボニル基、ブトキシカルボニル基、イソブトキシカルボニル基、ｓ−ブトキシカルボニル基、ｔ−ブトキシカルボニル基、ペンチルオキシカルボニル基、イソペンチルオキシカルボニル基、２−メチルブトキシカルボニル基、ネオペンチルオキシカルボニル基、１−エチルプロポキシカルボニル基、ヘキシルオキシカルボニル基、４−メチルペンチルオキシカルボニル基、３−メチルペンチルオキシカルボニル基、２−メチルペンチルオキシカルボニル基、１−メチルペンチルオキシカルボニル基、３，３−ジメチルブトキシカルボニル基、２，２−ジメチルブトキシカルボニル基、１，１−ジメチルブトキシカルボニル基、１，２−ジメチルブトキシカルボニル基、１，３−ジメチルブトキシカルボニル基、２，３−ジメチルブトキシカルボニル基又は２−エチルブトキシカルボニル基のような、炭素数１乃至６個の直鎖又は分枝鎖アルコキシ基がカルボニル基に結合した基であり、好適には（Ｃ₁−Ｃ₄アルコキシ）カルボニル基であり、更に好適にはメトキシカルボニル基又はエトキシカルボニル基であり、特に好適にはエトキシカルボニル基である。 In the above, the substituent of “C ₁ -C ₆ alkyl group substituted with a hydroxyl group, carboxyl group or (C ₁ -C ₆ alkoxy) carbonyl group” in the definition of R ³ and “(C ₁ -C “(C ₁ -C ₆ alkoxy) carbonyl group” in the definition of substituent of “C ₁ -C ₆ alkylsulfonyl group substituted by ₆ alkoxy) carbonyl group or carboxyl group” means, for example, methoxycarbonyl group, ethoxy Carbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, s-butoxycarbonyl group, t-butoxycarbonyl group, pentyloxycarbonyl group, isopentyloxycarbonyl group, 2-methylbutoxycarbonyl group , Neopentyloxycarbonyl group, 1-ethylpropoxycarbo Group, hexyloxycarbonyl group, 4-methylpentyloxycarbonyl group, 3-methylpentyloxycarbonyl group, 2-methylpentyloxycarbonyl group, 1-methylpentyloxycarbonyl group, 3,3-dimethylbutoxycarbonyl group, 2 , 2-dimethylbutoxycarbonyl group, 1,1-dimethylbutoxycarbonyl group, 1,2-dimethylbutoxycarbonyl group, 1,3-dimethylbutoxycarbonyl group, 2,3-dimethylbutoxycarbonyl group or 2-ethylbutoxycarbonyl group A straight or branched alkoxy group having 1 to 6 carbon atoms bonded to a carbonyl group, preferably a (C ₁ -C ₄ alkoxy) carbonyl group, more preferably methoxy. A carbonyl group or an ethoxycarbonyl group, particularly preferably A xoxycarbonyl group;

上記に於いて、Ｒ³の定義に於ける「水酸基、カルボキシル基若しくは（Ｃ₁−Ｃ₆アルコキシ）カルボニル基で置換されたＣ₁−Ｃ₆アルキル基」は、例えば、ヒドロキシメチル基、１−ヒドロキシエチル基、２−ヒドロキシエチル基、１−ヒドロキシプロピル基、２−ヒドロキシプロピル基、３−ヒドロキシプロピル基、１−ヒドロキシブチル基、２−ヒドロキシブチル基、３−ヒドロキシブチル基、４−ヒドロキシブチル基、５−ヒドロキシペンチル基若しくは６−ヒドロキシヘキシル基、カルボキシメチル基、１−カルボキシエチル基、２−カルボキシエチル基、１−カルボキシプロピル基、２−カルボキシプロピル基、３−カルボキシプロピル基、１−カルボキシブチル基、２−カルボキシブチル基、３−カルボキシブチル基、４−カルボキシブチル基、５−カルボキシペンチル基若しくは６−カルボキシヘキシル基、メトキシカルボニルメチル基、エトキシカルボニルメチル基、プロポキシカルボニルメチル基、イソプロポキシカルボニルメチル基、ブトキシカルボニルメチル基、イソブトキシカルボニルメチル基、ｓ−ブトキシカルボニルメチル基、ｔ−ブトキシカルボニルメチル基、ペンチルオキシカルボニルメチル基、イソペンチルオキシカルボニルメチル基、２−メチルブトキシカルボニルメチル基、ネオペンチルオキシカルボニルメチル基、１−エチルプロポキシカルボニルメチル基、ヘキシルオキシカルボニルメチル基、４−メチルペンチルオキシカルボニルメチル基、３−メチルペンチルオキシカルボニルメチル基、２−メチルペンチルオキシカルボニルメチル基、１−メチルペンチルオキシカルボニルメチル基、３，３−ジメチルブトキシカルボニルメチル基、２，２−ジメチルブトキシカルボニルメチル基、１，１−ジメチルブトキシカルボニルメチル基、１，２−ジメチルブトキシカルボニルメチル基、１，３−ジメチルブトキシカルボニルメチル基、２，３−ジメチルブトキシカルボニルメチル基、２−エチルブトキシカルボニルメチル基、１−（メトキシカルボニル）エチル基、１−（エトキシカルボニル）エチル基、１−（プロポキシカルボニル）エチル基、１−（イソプロポキシカルボニル）エチル基、１−（ブトキシカルボニル）エチル基、１−（イソブトキシカルボニル）エチル基、１−（ｓ−ブトキシカルボニル）エチル基、１−（ｔ−ブトキシカルボニル）エチル基、１−（ペンチルオキシカルボニル）エチル基、１−（イソペンチルオキシカルボニル）エチル基、１−（２−メチルブトキシカルボニル）エチル基、１−（ネオペンチルオキシカルボニル）エチル基、１−（１−エチルプロポキシカルボニル）エチル基、１−（ヘキシルオキシカルボニル）エチル基、１−（４−メチルペンチルオキシカルボニル）エチル基、１−（３−メチルペンチルオキシカルボニル）エチル基、１−（２−メチルペンチルオキシカルボニル）エチル基、１−（１−メチルペンチルオキシカルボニル）エチル基、１−（３，３−ジメチルブトキシカルボニル）エチル基、１−（２，２−ジメチルブトキシカルボニル）エチル基、１−（１，１−ジメチルブトキシカルボニル）エチル基、１−（１，２−ジメチルブトキシカルボニル）エチル基、１−（１，３−ジメチルブトキシカルボニル）エチル基、１−（２，３−ジメチルブトキシカルボニル）エチル基、１−（２−エチルブトキシカルボニル）エチル基、２−（メトキシカルボニル）エチル基、２−（エトキシカルボニル）エチル基、２−（プロポキシカルボニル）エチル基、２−（イソプロポキシカルボニル）エチル基、２−（ブトキシカルボニル）エチル基、２−（イソブトキシカルボニル）エチル基、２−（ｓ−ブトキシカルボニル）エチル基、２−（ｔ−ブトキシカルボニル）エチル基、２−（ペンチルオキシカルボニル）エチル基、２−（イソペンチルオキシカルボニル）エチル基、２−（２−メチルブトキシカルボニル）エチル基、２−（ネオペンチルオキシカルボニル）エチル基、２−（１−エチルプロポキシカルボニル）エチル基、２−（ヘキシルオキシカルボニル）エチル基、２−（４−メチルペンチルオキシカルボニル）エチル基、２−（３−メチルペンチルオキシカルボニル）エチル基、２−（２−メチルペンチルオキシカルボニル）エチル基、２−（１−メチルペンチルオキシカルボニル）エチル基、２−（３，３−ジメチルブトキシカルボニル）エチル基、２−（２，２−ジメチルブトキシカルボニル）エチル基、２−（１，１−ジメチルブトキシカルボニル）エチル基、２−（１，２−ジメチルブトキシカルボニル）エチル基、２−（１，３−ジメチルブトキシカルボニル）エチル基、２−（２，３−ジメチルブトキシカルボニル）エチル基、２−（２−エチルブトキシカルボニル）エチル基、３−（メトキシカルボニル）プロピル基、３−（エトキシカルボニル）プロピル基、３−（プロポキシカルボニル）プロピル基、３−（イソプロポキシカルボニル）プロピル基、３−（ブトキシカルボニル）プロピル基、３−（イソブトキシカルボニル）プロピル基、３−（ｓ−ブトキシカルボニル）プロピル基、３−（ｔ−ブトキシカルボニル）プロピル基、３−（ペンチルオキシカルボニル）プロピル基、３−（イソペンチルオキシカルボニル）プロピル基、３−（ヘキシルオキシカルボニル）プロピル基、４−（メトキシカルボニル）ブチル基、４−（エトキシカルボニル）ブチル基、４−（プロポキシカルボニル）ブチル基、４−（イソプロポキシカルボニル）ブチル基、４−（ブトキシカルボニル）ブチル基、４−（イソブトキシカルボニル）ブチル基、４−（ｓ−ブトキシカルボニル）ブチル基、４−（ｔ−ブトキシカルボニル）ブチル基、４−（ペンチルオキシカルボニル）ブチル基、４−（イソペンチルオキシカルボニル）ブチル基、４−（ヘキシルオキシカルボニル）ブチル基、５−（メトキシカルボニル）ペンチル基、５−（エトキシカルボニル）ペンチル基、５−（プロポキシカルボニル）ペンチル基、５−（ブトキシカルボニル）ペンチル基、５−（ペンチルオキシカルボニル）ペンチル基、５−（ヘキシルオキシカルボニル）ペンチル基、６−（メトキシカルボニル）ヘキシル基、６−（エトキシカルボニル）ヘキシル基、６−（プロポキシカルボニル）ヘキシル基、６−（ブトキシカルボニル）ヘキシル基、６−（ペンチルオキシカルボニル）ヘキシル基又は６−（ヘキシルオキシカルボニル）ヘキシル基のような、水酸基、カルボキシル基若しくは前記（Ｃ₁−Ｃ₆アルコキシ）カルボニル基が、前記Ｃ₁−Ｃ₆アルキル基に結合した基であり得、好適には、ヒドロキシＣ₁−Ｃ₄アルキル基、カルボキシＣ₁−Ｃ₄アルキル基又は（Ｃ₁−Ｃ₄アルコキシ）カルボニル（Ｃ₁−Ｃ₄アルキル）基であり、更に好適には、ヒドロキシＣ₁−Ｃ₄アルキル基又は（Ｃ₁−Ｃ₄アルコキシ）カルボニルメチル基であり、より更に好適には、２−ヒドロキシエチル基、カルボキシメチル基、メトキシカルボニルメチル基、エトキシカルボニルメチル基、プロポキシカルボニルメチル基又はブトキシカルボニルメチル基であり、特に好適には、２−ヒドロキシエチル基、カルボキシメチル基、メトキシカルボニルメチル基又はエトキシカルボニルメチル基であり、最も好適には、カルボキシメチル基又はエトキシカルボニルメチル基である。 In the above, the “C ₁ -C ₆ alkyl group substituted with a hydroxyl group, a carboxyl group or a (C ₁ -C ₆ alkoxy) carbonyl group” in the definition of R ³ is, for example, a hydroxymethyl group, 1- Hydroxyethyl group, 2-hydroxyethyl group, 1-hydroxypropyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 1-hydroxybutyl group, 2-hydroxybutyl group, 3-hydroxybutyl group, 4-hydroxybutyl Group, 5-hydroxypentyl group or 6-hydroxyhexyl group, carboxymethyl group, 1-carboxyethyl group, 2-carboxyethyl group, 1-carboxypropyl group, 2-carboxypropyl group, 3-carboxypropyl group, 1- Carboxybutyl group, 2-carboxybutyl group, 3-carboxybutyl group, 4- Ruboxybutyl, 5-carboxypentyl or 6-carboxyhexyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, isopropoxycarbonylmethyl, butoxycarbonylmethyl, isobutoxycarbonylmethyl, s-butoxy Carbonylmethyl group, t-butoxycarbonylmethyl group, pentyloxycarbonylmethyl group, isopentyloxycarbonylmethyl group, 2-methylbutoxycarbonylmethyl group, neopentyloxycarbonylmethyl group, 1-ethylpropoxycarbonylmethyl group, hexyloxycarbonyl Methyl group, 4-methylpentyloxycarbonylmethyl group, 3-methylpentyloxycarbonylmethyl group, 2-methylpentyloxycarbonyl Tyl group, 1-methylpentyloxycarbonylmethyl group, 3,3-dimethylbutoxycarbonylmethyl group, 2,2-dimethylbutoxycarbonylmethyl group, 1,1-dimethylbutoxycarbonylmethyl group, 1,2-dimethylbutoxycarbonylmethyl Group, 1,3-dimethylbutoxycarbonylmethyl group, 2,3-dimethylbutoxycarbonylmethyl group, 2-ethylbutoxycarbonylmethyl group, 1- (methoxycarbonyl) ethyl group, 1- (ethoxycarbonyl) ethyl group, 1- (Propoxycarbonyl) ethyl group, 1- (isopropoxycarbonyl) ethyl group, 1- (butoxycarbonyl) ethyl group, 1- (isobutoxycarbonyl) ethyl group, 1- (s-butoxycarbonyl) ethyl group, 1- ( t-butoxycarbonyl) ethyl group, 1- (Pentyloxycarbonyl) ethyl group, 1- (isopentyloxycarbonyl) ethyl group, 1- (2-methylbutoxycarbonyl) ethyl group, 1- (neopentyloxycarbonyl) ethyl group, 1- (1-ethylpropoxycarbonyl) ) Ethyl group, 1- (hexyloxycarbonyl) ethyl group, 1- (4-methylpentyloxycarbonyl) ethyl group, 1- (3-methylpentyloxycarbonyl) ethyl group, 1- (2-methylpentyloxycarbonyl) Ethyl group, 1- (1-methylpentyloxycarbonyl) ethyl group, 1- (3,3-dimethylbutoxycarbonyl) ethyl group, 1- (2,2-dimethylbutoxycarbonyl) ethyl group, 1- (1,1 -Dimethylbutoxycarbonyl) ethyl group, 1- (1,2-dimethylbutoxycarbo) L) ethyl group, 1- (1,3-dimethylbutoxycarbonyl) ethyl group, 1- (2,3-dimethylbutoxycarbonyl) ethyl group, 1- (2-ethylbutoxycarbonyl) ethyl group, 2- (methoxycarbonyl) ) Ethyl group, 2- (ethoxycarbonyl) ethyl group, 2- (propoxycarbonyl) ethyl group, 2- (isopropoxycarbonyl) ethyl group, 2- (butoxycarbonyl) ethyl group, 2- (isobutoxycarbonyl) ethyl group 2- (s-butoxycarbonyl) ethyl group, 2- (t-butoxycarbonyl) ethyl group, 2- (pentyloxycarbonyl) ethyl group, 2- (isopentyloxycarbonyl) ethyl group, 2- (2-methyl) Butoxycarbonyl) ethyl group, 2- (neopentyloxycarbonyl) ethyl group, 2- (1-e Lupropoxycarbonyl) ethyl group, 2- (hexyloxycarbonyl) ethyl group, 2- (4-methylpentyloxycarbonyl) ethyl group, 2- (3-methylpentyloxycarbonyl) ethyl group, 2- (2-methylpentyl) Oxycarbonyl) ethyl group, 2- (1-methylpentyloxycarbonyl) ethyl group, 2- (3,3-dimethylbutoxycarbonyl) ethyl group, 2- (2,2-dimethylbutoxycarbonyl) ethyl group, 2- ( 1,1-dimethylbutoxycarbonyl) ethyl group, 2- (1,2-dimethylbutoxycarbonyl) ethyl group, 2- (1,3-dimethylbutoxycarbonyl) ethyl group, 2- (2,3-dimethylbutoxycarbonyl) Ethyl group, 2- (2-ethylbutoxycarbonyl) ethyl group, 3- (methoxycarbonyl) ) Propyl group, 3- (ethoxycarbonyl) propyl group, 3- (propoxycarbonyl) propyl group, 3- (isopropoxycarbonyl) propyl group, 3- (butoxycarbonyl) propyl group, 3- (isobutoxycarbonyl) propyl group 3- (s-butoxycarbonyl) propyl group, 3- (t-butoxycarbonyl) propyl group, 3- (pentyloxycarbonyl) propyl group, 3- (isopentyloxycarbonyl) propyl group, 3- (hexyloxycarbonyl) ) Propyl group, 4- (methoxycarbonyl) butyl group, 4- (ethoxycarbonyl) butyl group, 4- (propoxycarbonyl) butyl group, 4- (isopropoxycarbonyl) butyl group, 4- (butoxycarbonyl) butyl group, 4- (isobutoxycarbonyl) butyl group, 4 (S-butoxycarbonyl) butyl group, 4- (t-butoxycarbonyl) butyl group, 4- (pentyloxycarbonyl) butyl group, 4- (isopentyloxycarbonyl) butyl group, 4- (hexyloxycarbonyl) butyl group 5- (methoxycarbonyl) pentyl group, 5- (ethoxycarbonyl) pentyl group, 5- (propoxycarbonyl) pentyl group, 5- (butoxycarbonyl) pentyl group, 5- (pentyloxycarbonyl) pentyl group, 5- ( (Hexyloxycarbonyl) pentyl group, 6- (methoxycarbonyl) hexyl group, 6- (ethoxycarbonyl) hexyl group, 6- (propoxycarbonyl) hexyl group, 6- (butoxycarbonyl) hexyl group, 6- (pentyloxycarbonyl) Hexyl group or 6- (hexylo Aryloxycarbonyl), such as a hexyl group, a hydroxyl group, a carboxyl group or the (C ₁ -C ₆ alkoxy) carbonyl group which may be group attached to the C ₁ -C ₆ alkyl group, preferably a hydroxy C ₁ A —C ₄ alkyl group, a carboxy C ₁ -C ₄ alkyl group or a (C ₁ -C ₄ alkoxy) carbonyl (C ₁ -C ₄ alkyl) group, and more preferably a hydroxy C ₁ -C ₄ alkyl group or (C ₁ -C ₄ alkoxy) carbonylmethyl group, and more preferably 2-hydroxyethyl group, carboxymethyl group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, propoxycarbonylmethyl group or butoxycarbonylmethyl group. Particularly preferably 2-hydroxyethyl, carboxymethyl, methoxycarbonylmethyl or eth A sheet carbonyl methyl group, and most preferably a carboxymethyl group or ethoxycarbonylmethyl group.

上記一般式（ＩＩ）に於いて、Ｒ⁷の定義に於ける「Ｃ₁−Ｃ₆アルキル基」は、例えば、前記Ｒ¹で定義したものと同意義であり得、好適にはＣ₁−Ｃ₄アルキル基であり、更に好適にはメチル基又はエチル基であり、特に好適にはエチル基である。 In the above general formula (II), the “C ₁ -C ₆ alkyl group” in the definition of R ⁷ can be, for example, the same as defined for R ¹ , preferably C ₁ — A C ₄ alkyl group, more preferably a methyl group or an ethyl group, and particularly preferably an ethyl group.

上記に於いて、ｍは好適には１乃至４の整数であり、更に好適には１又は２である。 In the above, m is preferably an integer of 1 to 4, and more preferably 1 or 2.

上記に於いて、ｎは好適には１乃至４の整数であり、更に好適には１又は２である。 In the above, n is preferably an integer of 1 to 4, more preferably 1 or 2.

上記一般式（Ｉ）に於いて、Ｒ³の定義に於ける「Ｃ₇−Ｃ₁₅アラルキル基」は、例えば、ベンジル基、ナフチルメチル基、インデニルメチル基、フェナンスレニルメチル基、アントラセニルメチル基、ジフェニルメチル基、フェネチル基、ナフチルエチル基、フェニルプロピル基、ナフチルプロピル基、フェニルブチル基、ナフチルブチル基、フェニルペンチル基、ナフチルペンチル基又はフェニルヘキシル基のような、炭素数６乃至１４個の芳香族炭化水素基の１又は２個が、前記「Ｃ₁−Ｃ₆アルキル基」に結合した基であり得、好適には、ベンジル基、ナフチルメチル基、ジフェニルメチル基又はフェネチル基であり、更に好適には、ベンジル基又はフェネチル基であり、特に好適にはベンジル基である。 In the general formula (I), the “C ₇ -C ₁₅ aralkyl group” in the definition of R ³ is, for example, benzyl group, naphthylmethyl group, indenylmethyl group, phenanthrenylmethyl group, anthra 6 carbon atoms, such as senylmethyl, diphenylmethyl, phenethyl, naphthylethyl, phenylpropyl, naphthylpropyl, phenylbutyl, naphthylbutyl, phenylpentyl, naphthylpentyl or phenylhexyl 1 to 2 of 14 to 14 aromatic hydrocarbon groups may be a group bonded to the “C ₁ -C ₆ alkyl group”, preferably a benzyl group, a naphthylmethyl group, a diphenylmethyl group, or a phenethyl group. Group, more preferably a benzyl group or a phenethyl group, and particularly preferably a benzyl group.

上記に於いて、Ｒ³の定義に於ける「Ｃ₁−Ｃ₆アルカノイル基」は、例えば、ホルミル基、アセチル基、プロピオニル基、ブチリル基、イソブチリル基、ピバロイル基、バレリル基、イソバレリル基又はヘキサノイル基のような炭素数１乃至６個の直鎖又は分枝鎖のアルカノイル基であり、好適には、Ｃ₁−Ｃ₄アルカノイル基であり、更に好適には、ホルミル基又はアセチル基であり、特に好適にはアセチル基である。 In the above, the “C ₁ -C ₆ alkanoyl group” in the definition of R ³ is, for example, formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, pivaloyl group, valeryl group, isovaleryl group or hexanoyl group. A straight or branched alkanoyl group having 1 to 6 carbon atoms, such as a group, preferably a C ₁ -C ₄ alkanoyl group, more preferably a formyl group or an acetyl group, Particularly preferred is an acetyl group.

上記に於いて、Ｒ³の定義に於ける「ヒドロキシＣ₂−Ｃ₆アルカノイル基」は、例えば、ヒドロキシアセチル基、２−ヒドロキシプロピオニル基、３−ヒドロキシプロピオニル基、４−ヒドロキシブチリル基、５−ヒドロキシバレリル基又は６−ヒドロキシヘキサノイル基のような、水酸基が前記「Ｃ₁−Ｃ₆アルカノイル基」に結合した基であり得、好適にはヒドロキシアセチル基、３−ヒドロキシプロピオニル基又は４−ヒドロキシブチリル基であり、特に好適にはヒドロキシアセチル基である。 In the above, the “hydroxy C ₂ -C ₆ alkanoyl group” in the definition of R ³ is, for example, a hydroxyacetyl group, a 2-hydroxypropionyl group, a 3-hydroxypropionyl group, a 4-hydroxybutyryl group, 5 A hydroxyl group may be a group bonded to the “C ₁ -C ₆ alkanoyl group”, such as a -hydroxyvaleryl group or a 6-hydroxyhexanoyl group, preferably a hydroxyacetyl group, a 3-hydroxypropionyl group or 4 -A hydroxybutyryl group, particularly preferably a hydroxyacetyl group.

上記に於いて、Ｒ³の定義に於ける「Ｃ₁−Ｃ₆アルキルスルホニル基」は、例えば、メタンスルホニル基、エタンスルホニル基、プロパンスルホニル基、イソプロパンスルホニル基、ブタンスルホニル基、イソブタンスルホニル基、ペンタンスルホニル基、イソペンタンスルホニル基、ネオペンタンスルホニル基、ヘキサンスルホニル基又はイソヘキサンスルホニル基のような、前記「Ｃ₁−Ｃ₆アルキル基」がスルホニル基に結合した基であり得、好適にはメタンスルホニル基、エタンスルホニル基、プロパンスルホニル基、ブタンスルホニル基、ペンタンスルホニル基又はヘキサンスルホニル基であり、更に好適には、メタンスルホニル基、エタンスルホニル基又はブタンスルホニル基であり、特に好適にはエタンスルホニル基である。 In the above, “C ₁ -C ₆ alkylsulfonyl group” in the definition of R ³ is, for example, methanesulfonyl group, ethanesulfonyl group, propanesulfonyl group, isopropanesulfonyl group, butanesulfonyl group, isobutanesulfonyl group. , A pentanesulfonyl group, an isopentanesulfonyl group, a neopentanesulfonyl group, a hexanesulfonyl group, or an isohexanesulfonyl group, the “C ₁ -C ₆ alkyl group” may be a group bonded to a sulfonyl group, preferably A methanesulfonyl group, an ethanesulfonyl group, a propanesulfonyl group, a butanesulfonyl group, a pentanesulfonyl group or a hexanesulfonyl group, more preferably a methanesulfonyl group, an ethanesulfonyl group or a butanesulfonyl group, particularly preferably ethane. A sulfonyl group.

上記に於いて、Ｒ³の定義に於ける「（Ｃ₁−Ｃ₆アルコキシ）カルボニル基若しくはカルボキシル基で置換されたＣ₁−Ｃ₆アルキルスルホニル基」は、例えば、メトキシカルボニルメタンスルホニル基、エトキシカルボニルメタンスルホニル基、プロポキシカルボニルメタンスルホニル基、イソプロポキシカルボニルメタンスルホニル基、ブトキシカルボニルメタンスルホニル基、イソブトキシカルボニルメタンスルホニル基、ｓ−ブトキシカルボニルメタンスルホニル基、ｔ−ブトキシカルボニルメタンスルホニル基、ペンチルオキシカルボニルメタンスルホニル基、イソペンチルオキシカルボニルメタンスルホニル基、２−メチルブトキシカルボニルメタンスルホニル基、ネオペンチルオキシカルボニルメタンスルホニル基、１−エチルプロポキシカルボニルメタンスルホニル基、ヘキシルオキシカルボニルメタンスルホニル基、４−メチルペンチルオキシカルボニルメタンスルホニル基、３−メチルペンチルオキシカルボニルメタンスルホニル基、２−メチルペンチルオキシカルボニルメタンスルホニル基、１−メチルペンチルオキシカルボニルメタンスルホニル基、３，３−ジメチルブトキシカルボニルメタンスルホニル基、２，２−ジメチルブトキシカルボニルメタンスルホニル基、１，１−ジメチルブトキシカルボニルメタンスルホニル基、１，２−ジメチルブトキシカルボニルメタンスルホニル基、１，３−ジメチルブトキシカルボニルメタンスルホニル基、２，３−ジメチルブトキシカルボニルメタンスルホニル基、２−エチルブトキシカルボニルメタンスルホニル基、１−（メトキシカルボニル）エタンスルホニル基、１−（エトキシカルボニル）エタンスルホニル基、１−（プロポキシカルボニル）エタンスルホニル基、１−（イソプロポキシカルボニル）エタンスルホニル基、１−（ブトキシカルボニル）エタンスルホニル基、１−（イソブトキシカルボニル）エタンスルホニル基、１−（ｓ−ブトキシカルボニル）エタンスルホニル基、１−（ｔ−ブトキシカルボニル）エタンスルホニル基、１−（ペンチルオキシカルボニル）エタンスルホニル基、１−（イソペンチルオキシカルボニル）エタンスルホニル基、１−（２−メチルブトキシカルボニル）エタンスルホニル基、１−（ネオペンチルオキシカルボニル）エタンスルホニル基、１−（１−エチルプロポキシカルボニル）エタンスルホニル基、１−（ヘキシルオキシカルボニル）エタンスルホニル基、１−（４−メチルペンチルオキシカルボニル）エタンスルホニル基、１−（３−メチルペンチルオキシカルボニル）エタンスルホニル基、１−（２−メチルペンチルオキシカルボニル）エタンスルホニル基、１−（１−メチルペンチルオキシカルボニル）エタンスルホニル基、１−（３，３−ジメチルブトキシカルボニル）エタンスルホニル基、１−（２，２−ジメチルブトキシカルボニル）エタンスルホニル基、１−（１，１−ジメチルブトキシカルボニル）エタンスルホニル基、１−（１，２−ジメチルブトキシカルボニル）エタンスルホニル基、１−（１，３−ジメチルブトキシカルボニル）エタンスルホニル基、１−（２，３−ジメチルブトキシカルボニル）エタンスルホニル基、１−（２−エチルブトキシカルボニル）エタンスルホニル基、２−（メトキシカルボニル）エタンスルホニル基、２−（エトキシカルボニル）エタンスルホニル基、２−（プロポキシカルボニル）エタンスルホニル基、２−（イソプロポキシカルボニル）エタンスルホニル基、２−（ブトキシカルボニル）エタンスルホニル基、２−（イソブトキシカルボニル）エタンスルホニル基、２−（ｓ−ブトキシカルボニル）エタンスルホニル基、２−（ｔ−ブトキシカルボニル）エタンスルホニル基、２−（ペンチルオキシカルボニル）エタンスルホニル基、２−（イソペンチルオキシカルボニル）エタンスルホニル基、２−（２−メチルブトキシカルボニル）エタンスルホニル基、２−（ネオペンチルオキシカルボニル）エタンスルホニル基、２−（１−エチルプロポキシカルボニル）エタンスルホニル基、２−（ヘキシルオキシカルボニル）エタンスルホニル基、２−（４−メチルペンチルオキシカルボニル）エタンスルホニル基、２−（３−メチルペンチルオキシカルボニル）エタンスルホニル基、２−（２−メチルペンチルオキシカルボニル）エタンスルホニル基、２−（１−メチルペンチルオキシカルボニル）エタンスルホニル基、２−（３，３−ジメチルブトキシカルボニル）エタンスルホニル基、２−（２，２−ジメチルブトキシカルボニル）エタンスルホニル基、２−（１，１−ジメチルブトキシカルボニル）エタンスルホニル基、２−（１，２−ジメチルブトキシカルボニル）エタンスルホニル基、２−（１，３−ジメチルブトキシカルボニル）エタンスルホニル基、２−（２，３−ジメチルブトキシカルボニル）エタンスルホニル基、２−（２−エチルブトキシカルボニル）エタンスルホニル基、１−（メトキシカルボニル）プロパンスルホニル基、１−（エトキシカルボニル）プロパンスルホニル基、１−（プロポキシカルボニル）プロパンスルホニル基、１−（ブトキシカルボニル）プロパンスルホニル基、１−（ペンチルオキシカルボニル）プロパンスルホニル基、１−（ヘキシルオキシカルボニル）プロパンスルホニル基、２−（メトキシカルボニル）プロパンスルホニル基、２−（エトキシカルボニル）プロパンスルホニル基、２−（プロポキシカルボニル）プロパンスルホニル基、２−（ブトキシカルボニル）プロパンスルホニル基、２−（ペンチルオキシカルボニル）プロパンスルホニル基、２−（ヘキシルオキシカルボニル）プロパンスルホニル基、３−（メトキシカルボニル）プロパンスルホニル基、３−（エトキシカルボニル）プロパンスルホニル基、３−（プロポキシカルボニル）プロパンスルホニル基、３−（イソプロポキシカルボニル）プロパンスルホニル基、３−（ブトキシカルボニル）プロパンスルホニル基、３−（イソブトキシカルボニル）プロパンスルホニル基、３−（ｓ−ブトキシカルボニル）プロパンスルホニル基、３−（ｔ−ブトキシカルボニル）プロパンスルホニル基、３−（ペンチルオキシカルボニル）プロパンスルホニル基、３−（イソペンチルオキシカルボニル）プロパンスルホニル基、３−（２−メチルブトキシカルボニル）プロパンスルホニル基、３−（ネオペンチルオキシカルボニル）プロパンスルホニル基、３−（１−エチルプロポキシカルボニル）プロパンスルホニル基、３−（ヘキシルオキシカルボニル）プロパンスルホニル基、３−（４−メチルペンチルオキシカルボニル）プロパンスルホニル基、３−（３−メチルペンチルオキシカルボニル）プロパンスルホニル基、３−（２−メチルペンチルオキシカルボニル）プロパンスルホニル基、３−（１−メチルペンチルオキシカルボニル）プロパンスルホニル基、３−（３，３−ジメチルブトキシカルボニル）プロパンスルホニル基、３−（２，２−ジメチルブトキシカルボニル）プロパンスルホニル基、３−（１，１−ジメチルブトキシカルボニル）プロパンスルホニル基、３−（１，２−ジメチルブトキシカルボニル）プロパンスルホニル基、３−（１，３−ジメチルブトキシカルボニル）プロパンスルホニル基、３−（２，３−ジメチルブトキシカルボニル）プロパンスルホニル基、３−（２−エチルブトキシカルボニル）プロパンスルホニル基、２−メトキシカルボニル−１−メチルエタンスルホニル基、２−エトキシカルボニル−１−メチルエタンスルホニル基、２−プロポキシカルボニル−１−メチルエタンスルホニル基、２−ブトキシカルボニル−１−メチルエタンスルホニル基、１−（メトキシカルボニル）ブタンスルホニル基、１−（エトキシカルボニル）ブタンスルホニル基、１−（プロポキシカルボニル）ブタンスルホニル基、１−（ブトキシカルボニル）ブタンスルホニル基、１−（ペンチルオキシカルボニル）ブタンスルホニル基、１−（ヘキシルオキシカルボニル）ブタンスルホニル基、２−（メトキシカルボニル）ブタンスルホニル基、２−（エトキシカルボニル）ブタンスルホニル基、２−（プロポキシカルボニル）ブタンスルホニル基、２−（ブトキシカルボニル）ブタンスルホニル基、２−（ペンチルオキシカルボニル）ブタンスルホニル基、２−（ヘキシルオキシカルボニル）ブタンスルホニル基、３−（メトキシカルボニル）ブタンスルホニル基、３−（エトキシカルボニル）ブタンスルホニル基、３−（プロポキシカルボニル）ブタンスルホニル基、３−（ブトキシカルボニル）ブタンスルホニル基、３−（ペンチルオキシカルボニル）ブタンスルホニル基、３−（ヘキシルオキシカルボニル）ブタンスルホニル基、４−（メトキシカルボニル）ブタンスルホニル基、４−（エトキシカルボニル）ブタンスルホニル基、４−（プロポキシカルボニル）ブタンスルホニル基、４−（イソプロポキシカルボニル）ブタンスルホニル基、４−（ブトキシカルボニル）ブタンスルホニル基、４−（イソブトキシカルボニル）ブタンスルホニル基、４−（ｓ−ブトキシカルボニル）ブタンスルホニル基、４−（ｔ−ブトキシカルボニル）ブタンスルホニル基、４−（ペンチルオキシカルボニル）ブタンスルホニル基、４−（イソペンチルオキシカルボニル）ブタンスルホニル基、４−（２−メチルブトキシカルボニル）ブタンスルホニル基、４−（ネオペンチルオキシカルボニル）ブタンスルホニル基、４−（１−エチルプロポキシカルボニル）ブタンスルホニル基、４−（ヘキシルオキシカルボニル）ブタンスルホニル基、４−（４−メチルペンチルオキシカルボニル）ブタンスルホニル基、４−（３−メチルペンチルオキシカルボニル）ブタンスルホニル基、４−（２−メチルペンチルオキシカルボニル）ブタンスルホニル基、４−（１−メチルペンチルオキシカルボニル）ブタンスルホニル基、４−（３，３−ジメチルブトキシカルボニル）ブタンスルホニル基、４−（２，２−ジメチルブトキシカルボニル）ブタンスルホニル基、４−（１，１−ジメチルブトキシカルボニル）ブタンスルホニル基、４−（１，２−ジメチルブトキシカルボニル）ブタンスルホニル基、４−（１，３−ジメチルブトキシカルボニル）ブタンスルホニル基、４−（２，３−ジメチルブトキシカルボニル）ブタンスルホニル基、４−（２−エチルブトキシカルボニル）ブタンスルホニル基、３−メトキシカルボニル−２−メチルプロパンスルホニル基、３−エトキシカルボニル−２−メチルプロパンスルホニル基、５−（メトキシカルボニル）ペンタンスルホニル基、５−（エトキシカルボニル）ペンタンスルホニル基、５−（プロポキシカルボニル）ペンタンスルホニル基、５−（ブトキシカルボニル）ペンタンスルホニル基、５−（ペンチルオキシカルボニル）ペンタンスルホニル基、５−（ヘキシルオキシカルボニル）ペンタンスルホニル基、６−（メトキシカルボニル）ヘキサンスルホニル基、６−（エトキシカルボニル）ヘキサンスルホニル基、６−（プロポキシカルボニル）ヘキサンスルホニル基、６−（ブトキシカルボニル）ヘキサンスルホニル基、６−（ペンチルオキシカルボニル）ヘキサンスルホニル基、６−（ヘキシルオキシカルボニル）ヘキサンスルホニル基、カルボキシメタンスルホニル基、２−カルボキシエタンスルホニル基、３−カルボキシプロパンスルホニル基、２−カルボキシ−１−メチルエタンスルホニル基、４−カルボキシブタンスルホニル基、３−カルボキシ−２−メチルプロパンスルホニル基、５−カルボキシペンタンスルホニル基又は６−カルボキシヘキサンスルホニル基のような、前記（Ｃ₁−Ｃ₆アルコキシ）カルボニル基及びカルボキシル基からなる群より選択される一の置換基が、前記Ｃ₁−Ｃ₆アルキルスルホニル基に結合した基であり得、好適には、（Ｃ₁−Ｃ₄アルコキシ）カルボニル基又はカルボキシル基で置換されたＣ₁−Ｃ₄アルキルスルホニル基であり、更に好適には、（Ｃ₁−Ｃ₄アルコキシ）カルボニル基又はカルボキシル基で置換された、メタンスルホニル基又はエタンスルホニル基であり、より更に

好適には、メトキシカルボニルメタンスルホニル基、エトキシカルボニルメタンスルホニル基、カルボキシメタンスルホニル基、２−メトキシカルボニルエタンスルホニル基、２−エトキシカルボニルエタンスルホニル基又は２−カルボキシエタンスルホニル基であり、特に好適には、エトキシカルボニルメタンスルホニル基又はカルボキシメタンスルホニル基である。 In the above description, “(C ₁ -C ₆ alkoxy) carbonyl group or carboxyl group-substituted C ₁ -C ₆ alkylsulfonyl group” in the definition of R ³ is, for example, methoxycarbonylmethanesulfonyl group, ethoxy Carbonylmethanesulfonyl group, propoxycarbonylmethanesulfonyl group, isopropoxycarbonylmethanesulfonyl group, butoxycarbonylmethanesulfonyl group, isobutoxycarbonylmethanesulfonyl group, s-butoxycarbonylmethanesulfonyl group, t-butoxycarbonylmethanesulfonyl group, pentyloxycarbonyl Methanesulfonyl group, isopentyloxycarbonylmethanesulfonyl group, 2-methylbutoxycarbonylmethanesulfonyl group, neopentyloxycarbonylmethanesulfonyl group, 1-ethyl Propoxycarbonylmethanesulfonyl group, hexyloxycarbonylmethanesulfonyl group, 4-methylpentyloxycarbonylmethanesulfonyl group, 3-methylpentyloxycarbonylmethanesulfonyl group, 2-methylpentyloxycarbonylmethanesulfonyl group, 1-methylpentyloxycarbonylmethane Sulfonyl group, 3,3-dimethylbutoxycarbonylmethanesulfonyl group, 2,2-dimethylbutoxycarbonylmethanesulfonyl group, 1,1-dimethylbutoxycarbonylmethanesulfonyl group, 1,2-dimethylbutoxycarbonylmethanesulfonyl group, 1,3 -Dimethylbutoxycarbonylmethanesulfonyl group, 2,3-dimethylbutoxycarbonylmethanesulfonyl group, 2-ethylbutoxycarbonylmethanesulfone Group, 1- (methoxycarbonyl) ethanesulfonyl group, 1- (ethoxycarbonyl) ethanesulfonyl group, 1- (propoxycarbonyl) ethanesulfonyl group, 1- (isopropoxycarbonyl) ethanesulfonyl group, 1- (butoxycarbonyl) Ethanesulfonyl group, 1- (isobutoxycarbonyl) ethanesulfonyl group, 1- (s-butoxycarbonyl) ethanesulfonyl group, 1- (t-butoxycarbonyl) ethanesulfonyl group, 1- (pentyloxycarbonyl) ethanesulfonyl group, 1- (isopentyloxycarbonyl) ethanesulfonyl group, 1- (2-methylbutoxycarbonyl) ethanesulfonyl group, 1- (neopentyloxycarbonyl) ethanesulfonyl group, 1- (1-ethylpropoxycarbonyl) ethanesulfonyl Group, 1- (hexyloxycarbonyl) ethanesulfonyl group, 1- (4-methylpentyloxycarbonyl) ethanesulfonyl group, 1- (3-methylpentyloxycarbonyl) ethanesulfonyl group, 1- (2-methylpentyloxy) Carbonyl) ethanesulfonyl group, 1- (1-methylpentyloxycarbonyl) ethanesulfonyl group, 1- (3,3-dimethylbutoxycarbonyl) ethanesulfonyl group, 1- (2,2-dimethylbutoxycarbonyl) ethanesulfonyl group, 1- (1,1-dimethylbutoxycarbonyl) ethanesulfonyl group, 1- (1,2-dimethylbutoxycarbonyl) ethanesulfonyl group, 1- (1,3-dimethylbutoxycarbonyl) ethanesulfonyl group, 1- (2, 3-Dimethylbutoxycarbonyl) ethane Phonyl group, 1- (2-ethylbutoxycarbonyl) ethanesulfonyl group, 2- (methoxycarbonyl) ethanesulfonyl group, 2- (ethoxycarbonyl) ethanesulfonyl group, 2- (propoxycarbonyl) ethanesulfonyl group, 2- (iso Propoxycarbonyl) ethanesulfonyl group, 2- (butoxycarbonyl) ethanesulfonyl group, 2- (isobutoxycarbonyl) ethanesulfonyl group, 2- (s-butoxycarbonyl) ethanesulfonyl group, 2- (t-butoxycarbonyl) ethanesulfonyl Group, 2- (pentyloxycarbonyl) ethanesulfonyl group, 2- (isopentyloxycarbonyl) ethanesulfonyl group, 2- (2-methylbutoxycarbonyl) ethanesulfonyl group, 2- (neopentyloxycarbonyl) ethanesulfur Nyl group, 2- (1-ethylpropoxycarbonyl) ethanesulfonyl group, 2- (hexyloxycarbonyl) ethanesulfonyl group, 2- (4-methylpentyloxycarbonyl) ethanesulfonyl group, 2- (3-methylpentyloxycarbonyl) ) Ethanesulfonyl group, 2- (2-methylpentyloxycarbonyl) ethanesulfonyl group, 2- (1-methylpentyloxycarbonyl) ethanesulfonyl group, 2- (3,3-dimethylbutoxycarbonyl) ethanesulfonyl group, 2- (2,2-dimethylbutoxycarbonyl) ethanesulfonyl group, 2- (1,1-dimethylbutoxycarbonyl) ethanesulfonyl group, 2- (1,2-dimethylbutoxycarbonyl) ethanesulfonyl group, 2- (1,3- Dimethylbutoxycarbonyl) ethanesulfur Phonyl group, 2- (2,3-dimethylbutoxycarbonyl) ethanesulfonyl group, 2- (2-ethylbutoxycarbonyl) ethanesulfonyl group, 1- (methoxycarbonyl) propanesulfonyl group, 1- (ethoxycarbonyl) propanesulfonyl group 1- (propoxycarbonyl) propanesulfonyl group, 1- (butoxycarbonyl) propanesulfonyl group, 1- (pentyloxycarbonyl) propanesulfonyl group, 1- (hexyloxycarbonyl) propanesulfonyl group, 2- (methoxycarbonyl) propane Sulfonyl group, 2- (ethoxycarbonyl) propanesulfonyl group, 2- (propoxycarbonyl) propanesulfonyl group, 2- (butoxycarbonyl) propanesulfonyl group, 2- (pentyloxycarbonyl) propanths Phonyl group, 2- (hexyloxycarbonyl) propanesulfonyl group, 3- (methoxycarbonyl) propanesulfonyl group, 3- (ethoxycarbonyl) propanesulfonyl group, 3- (propoxycarbonyl) propanesulfonyl group, 3- (isopropoxycarbonyl) ) Propanesulfonyl group, 3- (butoxycarbonyl) propanesulfonyl group, 3- (isobutoxycarbonyl) propanesulfonyl group, 3- (s-butoxycarbonyl) propanesulfonyl group, 3- (t-butoxycarbonyl) propanesulfonyl group, 3- (pentyloxycarbonyl) propanesulfonyl group, 3- (isopentyloxycarbonyl) propanesulfonyl group, 3- (2-methylbutoxycarbonyl) propanesulfonyl group, 3- (neopentyloxycarbonyl) Bonyl) propanesulfonyl group, 3- (1-ethylpropoxycarbonyl) propanesulfonyl group, 3- (hexyloxycarbonyl) propanesulfonyl group, 3- (4-methylpentyloxycarbonyl) propanesulfonyl group, 3- (3-methyl Pentyloxycarbonyl) propanesulfonyl group, 3- (2-methylpentyloxycarbonyl) propanesulfonyl group, 3- (1-methylpentyloxycarbonyl) propanesulfonyl group, 3- (3,3-dimethylbutoxycarbonyl) propanesulfonyl group 3- (2,2-dimethylbutoxycarbonyl) propanesulfonyl group, 3- (1,1-dimethylbutoxycarbonyl) propanesulfonyl group, 3- (1,2-dimethylbutoxycarbonyl) propanesulfonyl group, 3- (1 , 3-dimethylbutoxycarbonyl) propanesulfonyl group, 3- (2,3-dimethylbutoxycarbonyl) propanesulfonyl group, 3- (2-ethylbutoxycarbonyl) propanesulfonyl group, 2-methoxycarbonyl-1-methylethanesulfonyl group, 2-ethoxycarbonyl-1-methylethanesulfonyl group, 2-propoxycarbonyl-1-methylethanesulfonyl group, 2-butoxycarbonyl-1-methylethanesulfonyl group, 1- (methoxycarbonyl) butanesulfonyl group, 1- (ethoxy Carbonyl) butanesulfonyl group, 1- (propoxycarbonyl) butanesulfonyl group, 1- (butoxycarbonyl) butanesulfonyl group, 1- (pentyloxycarbonyl) butanesulfonyl group, 1- (hexyloxycarbonyl) butane Sulfonyl group, 2- (methoxycarbonyl) butanesulfonyl group, 2- (ethoxycarbonyl) butanesulfonyl group, 2- (propoxycarbonyl) butanesulfonyl group, 2- (butoxycarbonyl) butanesulfonyl group, 2- (pentyloxycarbonyl) ) Butanesulfonyl group, 2- (hexyloxycarbonyl) butanesulfonyl group, 3- (methoxycarbonyl) butanesulfonyl group, 3- (ethoxycarbonyl) butanesulfonyl group, 3- (propoxycarbonyl) butanesulfonyl group, 3- (butoxy) Carbonyl) butanesulfonyl group, 3- (pentyloxycarbonyl) butanesulfonyl group, 3- (hexyloxycarbonyl) butanesulfonyl group, 4- (methoxycarbonyl) butanesulfonyl group, 4- (ethoxycarbonyl) ) Butanesulfonyl group, 4- (propoxycarbonyl) butanesulfonyl group, 4- (isopropoxycarbonyl) butanesulfonyl group, 4- (butoxycarbonyl) butanesulfonyl group, 4- (isobutoxycarbonyl) butanesulfonyl group, 4- ( s-butoxycarbonyl) butanesulfonyl group, 4- (t-butoxycarbonyl) butanesulfonyl group, 4- (pentyloxycarbonyl) butanesulfonyl group, 4- (isopentyloxycarbonyl) butanesulfonyl group, 4- (2-methyl) Butoxycarbonyl) butanesulfonyl group, 4- (neopentyloxycarbonyl) butanesulfonyl group, 4- (1-ethylpropoxycarbonyl) butanesulfonyl group, 4- (hexyloxycarbonyl) butanesulfonyl group, 4- (4-methylpepoxy) Nthyloxycarbonyl) butanesulfonyl group, 4- (3-methylpentyloxycarbonyl) butanesulfonyl group, 4- (2-methylpentyloxycarbonyl) butanesulfonyl group, 4- (1-methylpentyloxycarbonyl) butanesulfonyl group 4- (3,3-dimethylbutoxycarbonyl) butanesulfonyl group, 4- (2,2-dimethylbutoxycarbonyl) butanesulfonyl group, 4- (1,1-dimethylbutoxycarbonyl) butanesulfonyl group, 4- (1 , 2-dimethylbutoxycarbonyl) butanesulfonyl group, 4- (1,3-dimethylbutoxycarbonyl) butanesulfonyl group, 4- (2,3-dimethylbutoxycarbonyl) butanesulfonyl group, 4- (2-ethylbutoxycarbonyl) Butanesulfonyl group, 3-metho Sicarbonyl-2-methylpropanesulfonyl group, 3-ethoxycarbonyl-2-methylpropanesulfonyl group, 5- (methoxycarbonyl) pentanesulfonyl group, 5- (ethoxycarbonyl) pentanesulfonyl group, 5- (propoxycarbonyl) pentanesulfonyl Group, 5- (butoxycarbonyl) pentanesulfonyl group, 5- (pentyloxycarbonyl) pentanesulfonyl group, 5- (hexyloxycarbonyl) pentanesulfonyl group, 6- (methoxycarbonyl) hexanesulfonyl group, 6- (ethoxycarbonyl) Hexanesulfonyl group, 6- (propoxycarbonyl) hexanesulfonyl group, 6- (butoxycarbonyl) hexanesulfonyl group, 6- (pentyloxycarbonyl) hexanesulfonyl group, 6- (hexyl) Oxycarbonyl) hexanesulfonyl group, carboxymethanesulfonyl group, 2-carboxyethanesulfonyl group, 3-carboxypropanesulfonyl group, 2-carboxy-1-methylethanesulfonyl group, 4-carboxybutanesulfonyl group, 3-carboxy-2- One substituent selected from the group consisting of the (C ₁ -C ₆ alkoxy) carbonyl group and the carboxyl group, such as a methylpropanesulfonyl group, a 5-carboxypentanesulfonyl group, or a 6-carboxyhexanesulfonyl group, It may be a group bonded to a C ₁ -C ₆ alkylsulfonyl group, preferably a (C ₁ -C ₄ alkoxy) carbonyl group or a C ₁ -C ₄ alkylsulfonyl group substituted with a carboxyl group, and more preferably the, (C ₁ -C ₄ alkoxy) carbonyl or Substituted with a carboxyl group, a methanesulfonyl group or an ethanesulfonyl group, further more

Preferred is a methoxycarbonylmethanesulfonyl group, an ethoxycarbonylmethanesulfonyl group, a carboxymethanesulfonyl group, a 2-methoxycarbonylethanesulfonyl group, a 2-ethoxycarbonylethanesulfonyl group, or a 2-carboxyethanesulfonyl group, and particularly preferably. , An ethoxycarbonylmethanesulfonyl group or a carboxymethanesulfonyl group.

上記に於いて、Ｒ⁴及びＲ⁵の定義に於ける「ハロゲン原子」は、例えば、前記Ｒ¹で定義したものと同意義であり得、好適には、弗素原子、塩素原子又は臭素原子であり、更に好適には弗素原子又は塩素原子であり、特に好適には塩素原子である。 In the above, the “halogen atom” in the definition of R ⁴ and R ⁵ may have the same meaning as that defined for R ¹ , for example, preferably a fluorine atom, a chlorine atom or a bromine atom. More preferably a fluorine atom or a chlorine atom, and particularly preferably a chlorine atom.

上記に於いて、Ｒ⁴及びＲ⁵の定義に於ける「Ｃ₁−Ｃ₆アルキル基」は、例えば、前記Ｒ¹で定義したものと同意義であり得、好適には、Ｃ₁−Ｃ₄アルキル基であり、更に好適には、メチル基又はエチル基であり、特に好適にはメチル基である。 In the above description, the “C ₁ -C ₆ alkyl group” in the definition of R ⁴ and R ⁵ may have the same meaning as defined for R ¹ , for example, preferably C ₁ -C _{4 is} an alkyl group, more preferably a methyl group or an ethyl group, and particularly preferably a methyl group.

上記に於いて、Ｒ⁴及びＲ⁵の定義に於ける「ハロゲノＣ₁−Ｃ₆アルキル基」は、例えば、フルオロメチル基、ジフルオロメチル基、トリフルオロメチル基、２−フルオロエチル基、２，２−ジフルオロエチル基、２，２，２−トリフルオロエチル基、ペンタフルオロエチル基、３−フルオロプロピル基、４−フルオロブチル基、６−フルオロヘキシル基、クロロメチル基、２−クロロエチル基、３−クロロプロピル基、４−クロロブチル基、ブロモメチル基、３−ブロモプロピル基、ジブロモペンチル基、ヨードメチル基又は２−フルオロ−１−クロロエチル基のような、前記「Ｃ₁−Ｃ₆アルキル基」が１乃至５個の前記「ハロゲン原子」で置換された基であり得、好適には、弗素原子及び塩素原からなる群より、１乃至３選択されるハロゲン原子で置換されたＣ₁−Ｃ₄アルキル基であり、更に好適には、フルオロメチル基、ジフルオロメチル基、トリフルオロメチル基、２−フルオロエチル基、２，２−ジフルオロエチル基又は２，２，２−トリフルオロエチル基であり、特に好適にはトリフルオロメチル基である。 In the above, the “halogeno C ₁ -C ₆ alkyl group” in the definition of R ⁴ and R ⁵ is, for example, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, 2, 2-difluoroethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, 3-fluoropropyl group, 4-fluorobutyl group, 6-fluorohexyl group, chloromethyl group, 2-chloroethyl group, 3 The “C ₁ -C ₆ alkyl group” is 1 such as -chloropropyl group, 4-chlorobutyl group, bromomethyl group, 3-bromopropyl group, dibromopentyl group, iodomethyl group or 2-fluoro-1-chloroethyl group; Or a group substituted with 5 of the above “halogen atoms”, preferably 1 to 3 groups selected from the group consisting of a fluorine atom and a chlorine atom. A C ₁ -C ₄ alkyl group substituted with Gen atoms, more preferably, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 2,2-difluoroethyl group, or 2, A 2,2-trifluoroethyl group, particularly preferably a trifluoromethyl group.

上記に於いて、Ｒ⁴及びＲ⁵の定義に於ける「Ｃ₁−Ｃ₆アルコキシ基」は、例えは、メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、ブトキシ基、イソブトキシ基、ｓ−ブトキシ基、ｔ−ブトキシ基、ペンチルオキシ基、イソペンチルオキシ基、２−メチルブトキシ基、ネオペンチルオキシ基、１−エチルプロポキシ基、ヘキシルオキシ基、４−メチルペンチルオキシ基、３−メチルペンチルオキシ基、２−メチルペンチルオキシ基、１−メチルペンチルオキシ基、３，３−ジメチルブトキシ基、２，２−ジメチルブトキシ基、１，１−ジメチルブトキシ基、１，２−ジメチルブトキシ基、１，３−ジメチルブトキシ基、２，３−ジメチルブトキシ基又は２−エチルブトキシ基のような、前記「Ｃ₁−Ｃ₆アルキル基」が酸素原子に結合した基であり、好適にはＣ₁−Ｃ₄アルコキシ基であり、更に好適にはメトキシ基又はエトキシ基であり、特に好適にはメトキシ基である。 In the above, “C ₁ -C ₆ alkoxy group” in the definition of R ⁴ and R ⁵ is, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, s- Butoxy, t-butoxy, pentyloxy, isopentyloxy, 2-methylbutoxy, neopentyloxy, 1-ethylpropoxy, hexyloxy, 4-methylpentyloxy, 3-methylpentyloxy Group, 2-methylpentyloxy group, 1-methylpentyloxy group, 3,3-dimethylbutoxy group, 2,2-dimethylbutoxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 1, 3-dimethyl-butoxy group, 2,3-dimethylbutoxy, such as group or 2-ethylbutoxy group, wherein "C ₁ -C ₆ alkyl group" is an oxygen Hara A bonded group, preferably a C ₁ -C ₄ alkoxy group, more preferably a methoxy group or an ethoxy group, particularly preferably a methoxy group.

上記に於いて、Ｒ⁴及びＲ⁵の定義に於ける「（Ｃ₁−Ｃ₆アルコキシ）カルボニル基」は、例えば、前記Ｒ³で定義したものと同意義であり得、好適には、（Ｃ₁−Ｃ₄アルコキシ）カルボニル基であり、更に好適にはメトキシカルボニル基又はエトキシカルボニル基であり、特に好適にはエトキシカルボニル基である。 In the above description, the “(C ₁ -C ₆ alkoxy) carbonyl group” in the definitions of R ⁴ and R ⁵ may have the same meaning as defined for R ³ , for example, C ₁ -C ₄ alkoxy) carbonyl group, more preferably methoxycarbonyl group or ethoxycarbonyl group, and particularly preferably ethoxycarbonyl group.

上記に於いて、Ｒ⁴及びＲ⁵の定義に於ける「（Ｃ₁−Ｃ₆アルキル）カルバモイル基」は、例えば、メチルカルバモイル基、エチルカルバモイル基、プロピルカルバモイル基、イソプロピルカルバモイル基、ブチルカルバモイル基、イソブチルカルバモイル基、ｓ−ブチルカルバモイル基、ｔ−ブチルカルバモイル基、ペンチルカルバモイル基又はヘキシルカルバモイル基のような、前記Ｃ₁−Ｃ₆アルキル基がカルバモイル基に結合した基であり得、好適にはＣ₁−Ｃ₄アルキルカルバモイル基であり、更に好適にはメチルカルバモイル基又はエチルカルバモイル基であり、特に好適にはメチルカルバモイル基である。 In the above, “(C ₁ -C ₆ alkyl) carbamoyl group” in the definition of R ⁴ and R ⁵ is, for example, methylcarbamoyl group, ethylcarbamoyl group, propylcarbamoyl group, isopropylcarbamoyl group, butylcarbamoyl group. , An isobutylcarbamoyl group, an s-butylcarbamoyl group, a t-butylcarbamoyl group, a pentylcarbamoyl group, or a hexylcarbamoyl group, and a group in which the C ₁ -C ₆ alkyl group is bonded to a carbamoyl group, preferably A C ₁ -C ₄ alkylcarbamoyl group, more preferably a methylcarbamoyl group or an ethylcarbamoyl group, and particularly preferably a methylcarbamoyl group.

上記に於いて、Ｒ⁴及びＲ⁵の定義に於ける「ジ（Ｃ₁−Ｃ₆アルキル）カルバモイル基」は、例えば、Ｎ，Ｎ−ジメチルカルバモイル基、Ｎ−エチル−Ｎ−メチルカルバモイル基、Ｎ，Ｎ−ジエチルカルバモイル基、Ｎ，Ｎ−ジプロピルカルバモイル基、Ｎ，Ｎ−ジイソプロピルカルバモイル基、Ｎ，Ｎ−ジブチルカルバモイル基、Ｎ，Ｎ−ジイソブチルカルバモイル基、Ｎ，Ｎ−ジ−ｓ−ブチルカルバモイル基、Ｎ，Ｎ−ジ−ｔ−ブチルカルバモイル基、Ｎ，Ｎ−ジペンチルカルバモイル基又はＮ，Ｎ−ジヘキシルカルバモイル基のような、前記Ｃ₁−Ｃ₆アルキル基より、同一又は異なって選択される２個のアルキル基が、カルバモイル基に結合した基であり得、好適にはジ（Ｃ₁−Ｃ₄アルキル）カルバモイル基であり、更に好適にはＮ，Ｎ−ジメチルカルバモイル基、Ｎ−エチル−Ｎ−メチルカルバモイル基又はＮ，Ｎ−ジエチルカルバモイル基であり、特に好適にはＮ，Ｎ−ジメチルカルバモイル基である。 In the above, “di (C ₁ -C ₆ alkyl) carbamoyl group” in the definition of R ⁴ and R ⁵ is, for example, N, N-dimethylcarbamoyl group, N-ethyl-N-methylcarbamoyl group, N, N-diethylcarbamoyl group, N, N-dipropylcarbamoyl group, N, N-diisopropylcarbamoyl group, N, N-dibutylcarbamoyl group, N, N-diisobutylcarbamoyl group, N, N-di-s-butyl Selected from the above-mentioned C ₁ -C ₆ alkyl groups such as a rucarbamoyl group, N, N-di-t-butylcarbamoyl group, N, N-dipentylcarbamoyl group or N, N-dihexylcarbamoyl group. The two alkyl groups may be a group bonded to a carbamoyl group, preferably a di (C ₁ -C ₄ alkyl) carbamoyl group, and more preferably N , N-dimethylcarbamoyl group, N-ethyl-N-methylcarbamoyl group or N, N-diethylcarbamoyl group, particularly preferably N, N-dimethylcarbamoyl group.

本発明の一般式（Ｉ）を有する化合物は、常法に従って酸と処理することにより、それぞれ相当する薬理上許容される塩にすることができる。例えば、化合物（Ｉ）を溶媒中（例えばエーテル類、エステル類又はアルコール類であり得、好適にはエーテル類又はアルコール類）、相当する酸と室温で１分間乃至３０分間処理し、析出した結晶をろ取するか又は減圧下で溶媒を留去することにより得ることができる。そのような塩としては、炭酸塩；弗化水素酸塩、塩酸塩、臭化水素酸塩、沃化水素酸塩、硝酸塩、過塩素酸塩、硫酸塩又は燐酸塩等の鉱酸塩；メタンスルホン酸塩、トリフルオロメタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩又はｐ−トルエンスルホン酸塩のようなスルホン酸塩；酢酸塩、プロピオン酸塩、酪酸塩、フマール酸塩、コハク酸塩、クエン酸塩、酒石酸塩、蓚酸塩又はマレイン酸塩又は安息香酸塩等のカルボン酸塩；又はグルタミン酸塩若しくはアスパラギン酸塩のようなアミノ酸塩を挙げることができる。 The compound having the general formula (I) of the present invention can be converted into a corresponding pharmacologically acceptable salt by treating with an acid according to a conventional method. For example, the compound (I) is treated with a corresponding acid at room temperature for 1 to 30 minutes in a solvent (eg, ethers, esters or alcohols, preferably ethers or alcohols), and precipitated crystals. Can be obtained by filtering off or distilling off the solvent under reduced pressure. Such salts include: carbonates; mineral salts such as hydrofluorates, hydrochlorides, hydrobromides, hydroiodides, nitrates, perchlorates, sulfates or phosphates; methane Sulfonates such as sulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate or p-toluenesulfonate; acetate, propionate, butyrate, fumarate, succinate And carboxylic acid salts such as citrate, tartrate, oxalate or maleate or benzoate; or amino acid salts such as glutamate or aspartate.

本発明の一般式（Ｉ）を有する化合物は、Ｒ³がカルボキシル基を含む場合等、常法に従って塩基と処理することにより、それぞれ相当する薬理上許容される塩にすることができる。例えば、化合物（Ｉ）を溶媒中（例えばエーテル類、エステル類又はアルコール類であり得、好適にはアルコール類）、相当する塩基と室温で１分間乃至３０分間処理し、析出した結晶をろ取するか又は減圧下で溶媒を留去することにより得ることができる。そのような塩としては、例えば、ナトリウム塩、カリウム塩、リチウム塩のようなアルカリ金属塩、カルシウム塩、マグネシウム塩のようなアルカリ土類金属塩、アルミニウム塩、鉄塩、亜鉛塩、銅塩、ニッケル塩、コバルト塩等の金属塩；アンモニウム塩、ｔ−オクチルアミン塩、ジベンジルアミン塩、モルホリン塩、グルコサミン塩、フェニルグリシンアルキルエステル塩、エチレンジアミン塩、Ｎ−メチルグルカミン塩、グアニジン塩、ジエチルアミン塩、トリエチルアミン塩、ジシクロヘキシルアミン塩、Ｎ，Ｎ’−ジベンジルエチレンジアミン塩、クロロプロカイン塩、プロカイン塩、ジエタノールアミン塩、Ｎ−ベンジルフェネチルアミン塩、ピペラジン塩、テトラメチルアンモニウム塩、トリス（ヒドロキシメチル）アミノメタン塩のような有機アミン塩であり得、好適にはアルカリ金属塩（特にナトリウム塩又はカリウム塩）である。 The compound having the general formula (I) of the present invention can be converted into a corresponding pharmacologically acceptable salt by treating with a base according to a conventional method such as when R ³ contains a carboxyl group. For example, the compound (I) is treated with a corresponding base at room temperature for 1 to 30 minutes in a solvent (for example, ethers, esters or alcohols, preferably alcohols), and the precipitated crystals are collected by filtration. Or by distilling off the solvent under reduced pressure. Examples of such salts include alkali metal salts such as sodium salt, potassium salt and lithium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt, iron salt, zinc salt, copper salt, Metal salt such as nickel salt and cobalt salt; ammonium salt, t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine Salt, triethylamine salt, dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, tris (hydroxymethyl) aminometa It can be an organic amine salt, such as an alkali salt, and is preferably an alkali metal salt (especially sodium salt or potassium salt).

本発明の一般式（Ｉ）を有する化合物又はその薬理上許容される塩は、分子内に不斉炭素原子を有する場合、Ｒ配位、Ｓ配位である立体異性体が存在するが、その各々、或はそれらの任意の割合の化合物のいずれも本発明に包含される。そのような立体異性体は、例えば、光学分割された原料化合物を用いて化合物（Ｉ）を合成するか又は合成した化合物（Ｉ）を所望により通常の光学分割又は分離法を用いて光学分割することができる。 When the compound having the general formula (I) or the pharmacologically acceptable salt thereof has an asymmetric carbon atom in the molecule, there are stereoisomers having R-coordination and S-coordination. Any of each, or any proportion thereof, is encompassed by the present invention. For such stereoisomers, for example, compound (I) is synthesized using an optically resolved starting material compound, or the synthesized compound (I) is optically resolved using an ordinary optical resolution or separation method as desired. be able to.

本発明の一般式（Ｉ）を有する化合物又はその薬理上許容される塩は、大気中に放置したり、又は再結晶することにより、水分を吸収し、吸着水がついたり、水和物になる場合が有り、そのような水を含む化合物及び塩も本発明に包含される。 The compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof absorbs moisture by being left in the air or recrystallized, so that adsorbed water is attached, and hydrates are formed. Such water-containing compounds and salts are also encompassed by the present invention.

本発明の一般式（Ｉ）を有する化合物に於て、好適な化合物としては、例えば、
（１）Ｒ¹が、水素原子、弗素原子、塩素原子、臭素原子、Ｃ₁−Ｃ₄アルキル基又は水酸基である化合物、 In the compound having the general formula (I) of the present invention, suitable compounds include, for example,
(1) A compound in which R ¹ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a C ₁ -C ₄ alkyl group or a hydroxyl group,

（２）Ｒ¹が、水素原子、弗素原子、塩素原子、メチル基、エチル基又は水酸基である化合物、 (2) a compound wherein R ¹ is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, an ethyl group or a hydroxyl group;

（３）Ｒ¹が、水素原子、弗素原子、メチル基又は水酸基である化合物、 (3) a compound in which R ¹ is a hydrogen atom, a fluorine atom, a methyl group or a hydroxyl group;

（４）Ｒ¹が、水素原子又は水酸基である化合物、 (4) A compound in which R ¹ is a hydrogen atom or a hydroxyl group,

（５）Ｒ²が、水素原子、弗素原子、塩素原子、臭素原子又はＣ₁−Ｃ₄アルキル基である化合物、 (5) a compound wherein R ² is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or a C ₁ -C ₄ alkyl group,

（６）Ｒ²が、水素原子、弗素原子、塩素原子、メチル基又はエチル基である化合物、 (6) a compound wherein R ² is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group or an ethyl group,

（７）Ｒ²が、水素原子、弗素原子又はメチル基である化合物、 (7) A compound wherein R ² is a hydrogen atom, a fluorine atom or a methyl group,

（８）Ｒ²が、水素原子又は弗素原子である化合物、 (8) A compound in which R ² is a hydrogen atom or a fluorine atom,

（９）Ｒ²が、水素原子である化合物、 (9) the compound wherein R ² is a hydrogen atom,

（１０）Ｒ³が、水素原子；Ｃ₁−Ｃ₄アルキル基；ヒドロキシＣ₁−Ｃ₄アルキル基、カルボキシＣ₁−Ｃ₄アルキル基若しくは（Ｃ₁−Ｃ₄アルコキシ）カルボニル（Ｃ₁−Ｃ₄アルキル）基；一般式 (10) R ³ is a hydrogen atom; C ₁ -C ₄ alkyl group; hydroxy C ₁ -C ₄ alkyl group, carboxy C ₁ -C ₄ alkyl group or (C ₁ -C ₄ alkoxy) carbonyl (C ₁ -C) ₄ alkyl) group; general formula

（式中、Ｒ⁷はＣ₁−Ｃ₄アルキル基を示し、ｍ及びｎは、同一又は異なって、１乃至４の整数を示す。）を有する基；ベンジル基、ナフチルメチル基、ジフェニルメチル基若しくはフェネチル基；Ｃ₁−Ｃ₄アルカノイル基；ヒドロキシアセチル基、３−ヒドロキシプロピオニル基若しくは４−ヒドロキシブチリル基；メタンスルホニル基、エタンスルホニル基、プロパンスルホニル基、ブタンスルホニル基、ペンタンスルホニル基若しくはヘキサンスルホニル基；又は、（Ｃ₁−Ｃ₄アルコキシ）カルボニル基若しくはカルボキシル基で置換されたＣ₁−Ｃ₄アルキルスルホニル基である化合物、 Wherein R ⁷ represents a C ₁ -C ₄ alkyl group, and m and n are the same or different and each represents an integer of 1 to 4; a benzyl group, a naphthylmethyl group, a diphenylmethyl group Or phenethyl group; C ₁ -C ₄ alkanoyl group; hydroxyacetyl group, 3-hydroxypropionyl group or 4-hydroxybutyryl group; methanesulfonyl group, ethanesulfonyl group, propanesulfonyl group, butanesulfonyl group, pentanesulfonyl group or hexane sulfonyl group; or, (C ₁ -C ₄ alkoxy) compound which is C ₁ -C ₄ alkylsulfonyl group substituted with a carbonyl group or carboxyl group,

（１１）Ｒ³が、水素原子；Ｃ₁−Ｃ₄アルキル基；２−ヒドロキシエチル基、カルボキシメチル基、メトキシカルボニルメチル基、エトキシカルボニルメチル基、プロポキシカルボニルメチル基若しくはブトキシカルボニルメチル基；一般式 (11) R ³ is a hydrogen atom; C ₁ -C ₄ alkyl group; 2-hydroxyethyl group, carboxymethyl group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, propoxycarbonylmethyl group or butoxycarbonylmethyl group;

（式中、Ｒ⁷はメチル基若しくはエチル基を示し、ｍ及びｎは、同一又は異なって、１若しくは２を示す。）を有する基；ベンジル基若しくはフェネチル基；ホルミル基若しくはアセチル基；ヒドロキシアセチル基；メタンスルホニル基、エタンスルホニル基若しくはブタンスルホニル基；又は、（Ｃ₁−Ｃ₄アルコキシ）カルボニル基若しくはカルボキシル基で置換された、メタンスルホニル基若しくはエタンスルホニル基である化合物、 (Wherein R ⁷ represents a methyl group or an ethyl group, and m and n are the same or different and each represents 1 or 2); a benzyl group or a phenethyl group; a formyl group or an acetyl group; hydroxyacetyl A methanesulfonyl group, an ethanesulfonyl group or a butanesulfonyl group; or a compound which is a methanesulfonyl group or an ethanesulfonyl group substituted by a (C ₁ -C ₄ alkoxy) carbonyl group or a carboxyl group,

（１２）Ｒ³が、水素原子、メチル基、エチル基、イソプロピル基、２−ヒドロキシエチル基、カルボキシメチル基、メトキシカルボニルメチル基、エトキシカルボニルメチル基、プロポキシカルボニルメチル基、ブトキシカルボニルメチル基、アセチル基、ヒドロキシアセチル基、メタンスルホニル基、エタンスルホニル基、ブタンスルホニル基、メトキシカルボニルメタンスルホニル基、エトキシカルボニルメタンスルホニル基、カルボキシメタンスルホニル基、２−メトキシカルボニルエタンスルホニル基、２−エトキシカルボニルエタンスルホニル基又は２−カルボキシエタンスルホニル基である化合物、 (12) R ³ is a hydrogen atom, methyl group, ethyl group, isopropyl group, 2-hydroxyethyl group, carboxymethyl group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, propoxycarbonylmethyl group, butoxycarbonylmethyl group, acetyl Group, hydroxyacetyl group, methanesulfonyl group, ethanesulfonyl group, butanesulfonyl group, methoxycarbonylmethanesulfonyl group, ethoxycarbonylmethanesulfonyl group, carboxymethanesulfonyl group, 2-methoxycarbonylethanesulfonyl group, 2-ethoxycarbonylethanesulfonyl group Or a compound that is a 2-carboxyethanesulfonyl group,

（１３）Ｒ³が、イソプロピル基、２−ヒドロキシエチル基、カルボキシメチル基、メトキシカルボニルメチル基、エトキシカルボニルメチル基、エタンスルホニル基、メトキシカルボニルメタンスルホニル基、エトキシカルボニルメタンスルホニル基、カルボキシメタンスルホニル基、２−メトキシカルボニルエタンスルホニル基、２−エトキシカルボニルエタンスルホニル基又は２−カルボキシエタンスルホニル基である化合物、 (13) R ³ is isopropyl group, 2-hydroxyethyl group, carboxymethyl group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, ethanesulfonyl group, methoxycarbonylmethanesulfonyl group, ethoxycarbonylmethanesulfonyl group, carboxymethanesulfonyl group , A compound which is a 2-methoxycarbonylethanesulfonyl group, a 2-ethoxycarbonylethanesulfonyl group or a 2-carboxyethanesulfonyl group,

（１４）Ｒ³が、イソプロピル基、カルボキシメチル基、エトキシカルボニルメチル基、エトキシカルボニルメタンスルホニル基又はカルボキシメタンスルホニル基である化合物、 (14) A compound wherein R ³ is an isopropyl group, a carboxymethyl group, an ethoxycarbonylmethyl group, an ethoxycarbonylmethanesulfonyl group or a carboxymethanesulfonyl group,

（１５）Ｒ³が、エトキシカルボニルメタンスルホニル基又はカルボキシメタンスルホニル基である化合物、 (15) The compound wherein R ³ is an ethoxycarbonylmethanesulfonyl group or a carboxymethanesulfonyl group,

（１６）Ｒ⁴及びＲ⁵が、同一又は異なって、水素原子、弗素原子、塩素原子、臭素原子、Ｃ₁−Ｃ₄アルキル基、フルオロメチル基、ジフルオロメチル基、トリフルオロメチル基、２−フルオロエチル基、２，２−ジフルオロエチル基、２，２，２−トリフルオロエチル基、Ｃ₁−Ｃ₄アルコキシ基、カルボキシル基、メトキシカルボニル基、エトキシカルボニル基、カルバモイル基、メチルカルバモイル基又はＮ，Ｎ−ジメチルカルバモイル基である化合物、 (16) R ⁴ and R ⁵ are the same or different and are a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a C ₁ -C ₄ alkyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, 2- fluoroethyl, 2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, C ₁ -C ₄ alkoxy group, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a carbamoyl group, methylcarbamoyl group or N , N-dimethylcarbamoyl group,

（１７）Ｒ⁴が、水素原子、弗素原子、塩素原子又はトリフルオロメチル基であり、
Ｒ⁵が、水素原子、弗素原子、塩素原子、臭素原子、Ｃ₁−Ｃ₄アルキル基、フルオロメチル基、ジフルオロメチル基、トリフルオロメチル基、２−フルオロエチル基、２，２−ジフルオロエチル基、２，２，２−トリフルオロエチル基、Ｃ₁−Ｃ₄アルコキシ基、カルボキシル基、メトキシカルボニル基、エトキシカルボニル基、カルバモイル基、メチルカルバモイル基又はＮ，Ｎ−ジメチルカルバモイル基である化合物、 (17) R ⁴ is a hydrogen atom, a fluorine atom, a chlorine atom or a trifluoromethyl group,
R ⁵ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a C ₁ -C ₄ alkyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, or a 2,2-difluoroethyl group. , 2,2,2-trifluoroethyl group, C ₁ -C ₄ alkoxy group, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a carbamoyl group, methylcarbamoyl group or an N, compound is N- dimethylcarbamoyl group,

（１８）Ｒ⁴が、水素原子、弗素原子又は塩素原子であり、
Ｒ⁵が、水素原子、弗素原子、塩素原子、臭素原子、メチル基、エチル基、トリフルオロメチル基、メトキシ基、エトキシ基又はカルバモイル基である化合物、 (18) R ⁴ is a hydrogen atom, a fluorine atom or a chlorine atom,
A compound wherein R ⁵ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group, an ethoxy group or a carbamoyl group;

（１９）Ｒ⁴が、水素原子であり、
Ｒ⁵が、水素原子、弗素原子、塩素原子、メチル基、トリフルオロメチル基又はカルバモイル基である化合物、 (19) R ⁴ is a hydrogen atom,
A compound wherein R ⁵ is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group or a carbamoyl group;

（２０）Ｒ⁴が、水素原子であり、
Ｒ⁵が、水素原子、塩素原子、メチル基又はカルバモイル基である化合物、 (20) R ⁴ is a hydrogen atom,
A compound wherein R ⁵ is a hydrogen atom, a chlorine atom, a methyl group or a carbamoyl group,

（２１）Ｒ⁶が、１−アセトイミドイルピペリジン−４−イル基である化合物、を挙げることができ、Ｒ¹に関しては、（１）から（４）の順で好適な順位が上がり、Ｒ²に関しては、（５）から（９）の順で好適な順位が上がり、Ｒ³に関しては、（１０）から（１５）の順で好適な順位が上がり、Ｒ⁴及びＲ⁵に関しては、（１６）から（２０）の順で好適な順位が上がる。 (21) A compound in which R ⁶ is a 1-acetimidoylpiperidin-4-yl group can be mentioned. With regard to R ¹ , the preferred order increases in the order of (1) to (4). ^For ( ² ), the preferred rank increases in the order of (5) to (9), for R ³ , the suitable rank increases in the order of (10) to (15), and for R ⁴ and R ⁵ ( The preferred ranking increases in the order of 16) to (20).

また、前記一般式（Ｉ）を有する化合物としては、（１）−（４）、（５）−（９）、（１０）−（１５）、（１６）−（２０）及び（２１）からなる群より２乃至５を選択し、それらを任意に組み合わせたものを挙げることもでき、その組み合わせに於ける好適なものとしては、例えば、
（２２）Ｒ¹が、水素原子、弗素原子、塩素原子、臭素原子、Ｃ₁−Ｃ₄アルキル基又は水酸基であり、
Ｒ²が、水素原子、弗素原子、塩素原子、臭素原子又はＣ₁−Ｃ₄アルキル基であり、
Ｒ³が、水素原子；Ｃ₁−Ｃ₄アルキル基；ヒドロキシＣ₁−Ｃ₄アルキル基、カルボキシＣ₁−Ｃ₄アルキル基若しくは（Ｃ₁−Ｃ₄アルコキシ）カルボニル（Ｃ₁−Ｃ₄アルキル）基；一般式 Moreover, as a compound which has the said general formula (I), from (1)-(4), (5)-(9), (10)-(15), (16)-(20) and (21) It is also possible to select 2 to 5 from the group consisting of these and arbitrarily combine them. Examples of suitable combinations include, for example,
(22) R ¹ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a C ₁ -C ₄ alkyl group or a hydroxyl group,
R ² is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or a C ₁ -C ₄ alkyl group,
R ³ is a hydrogen atom; C ₁ -C ₄ alkyl group; hydroxy C ₁ -C ₄ alkyl group, carboxy C ₁ -C ₄ alkyl group or (C ₁ -C ₄ alkoxy) carbonyl (C ₁ -C ₄ alkyl) Group; general formula

（式中、Ｒ⁷はＣ₁−Ｃ₄アルキル基を示し、ｍ及びｎは、同一又は異なって、１乃至４の整数を示す。）を有する基；ベンジル基、ナフチルメチル基、ジフェニルメチル基若しくはフェネチル基；Ｃ₁−Ｃ₄アルカノイル基；ヒドロキシアセチル基、３−ヒドロキシプロピオニル基若しくは４−ヒドロキシブチリル基；メタンスルホニル基、エタンスルホニル基、プロパンスルホニル基、ブタンスルホニル基、ペンタンスルホニル基若しくはヘキサンスルホニル基；又は、（Ｃ₁−Ｃ₄アルコキシ）カルボニル基若しくはカルボキシル基で置換されたＣ₁−Ｃ₄アルキルスルホニル基であり、
Ｒ⁴及びＲ⁵が、同一又は異なって、水素原子、弗素原子、塩素原子、臭素原子、Ｃ₁−Ｃ₄アルキル基、フルオロメチル基、ジフルオロメチル基、トリフルオロメチル基、２−フルオロエチル基、２，２−ジフルオロエチル基、２，２，２−トリフルオロエチル基、Ｃ₁−Ｃ₄アルコキシ基、カルボキシル基、メトキシカルボニル基、エトキシカルボニル基、カルバモイル基、メチルカルバモイル基又はＮ，Ｎ−ジメチルカルバモイル基である化合物、 Wherein R ⁷ represents a C ₁ -C ₄ alkyl group, and m and n are the same or different and each represents an integer of 1 to 4; a benzyl group, a naphthylmethyl group, a diphenylmethyl group Or phenethyl group; C ₁ -C ₄ alkanoyl group; hydroxyacetyl group, 3-hydroxypropionyl group or 4-hydroxybutyryl group; methanesulfonyl group, ethanesulfonyl group, propanesulfonyl group, butanesulfonyl group, pentanesulfonyl group or hexane sulfonyl group; or a C ₁ -C ₄ alkylsulfonyl group substituted with (C ₁ -C ₄ alkoxy) carbonyl group or a carboxyl group,
R ⁴ and R ⁵ are the same or different and are a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a C ₁ -C ₄ alkyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, or a 2-fluoroethyl group. 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, C ₁ -C ₄ alkoxy group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, carbamoyl group, methylcarbamoyl group or N, N— A compound that is a dimethylcarbamoyl group,

（２３）Ｒ¹が、水素原子、弗素原子、塩素原子、メチル基、エチル基又は水酸基であり、
Ｒ²が、水素原子、弗素原子、塩素原子、メチル基又はエチル基であり、
Ｒ³が、水素原子；Ｃ₁−Ｃ₄アルキル基；２−ヒドロキシエチル基、カルボキシメチル基、メトキシカルボニルメチル基、エトキシカルボニルメチル基、プロポキシカルボニルメチル基若しくはブトキシカルボニルメチル基；一般式 (23) R ¹ is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, an ethyl group or a hydroxyl group,
R ² is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group or an ethyl group,
R ³ is a hydrogen atom; C ₁ -C ₄ alkyl group; 2-hydroxyethyl group, carboxymethyl group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, propoxycarbonylmethyl group or butoxycarbonylmethyl group;

（式中、Ｒ⁷はメチル基若しくはエチル基を示し、ｍ及びｎは、同一又は異なって、１若しくは２を示す。）を有する基；ベンジル基若しくはフェネチル基；ホルミル基若しくはアセチル基；ヒドロキシアセチル基；メタンスルホニル基、エタンスルホニル基若しくはブタンスルホニル基；又は、（Ｃ₁−Ｃ₄アルコキシ）カルボニル基若しくはカルボキシル基で置換された、メタンスルホニル基若しくはエタンスルホニル基であり、
Ｒ⁴が、水素原子、弗素原子、塩素原子又はトリフルオロメチル基であり、
Ｒ⁵が、水素原子、弗素原子、塩素原子、臭素原子、Ｃ₁−Ｃ₄アルキル基、フルオロメチル基、ジフルオロメチル基、トリフルオロメチル基、２−フルオロエチル基、２，２−ジフルオロエチル基、２，２，２−トリフルオロエチル基、Ｃ₁−Ｃ₄アルコキシ基、カルボキシル基、メトキシカルボニル基、エトキシカルボニル基、カルバモイル基、メチルカルバモイル基又はＮ，Ｎ−ジメチルカルバモイル基であり、
Ｒ⁶が、１−アセトイミドイルピペリジン−４−イル基である化合物、 (Wherein R ⁷ represents a methyl group or an ethyl group, and m and n are the same or different and each represents 1 or 2); a benzyl group or a phenethyl group; a formyl group or an acetyl group; hydroxyacetyl A methanesulfonyl group, an ethanesulfonyl group or a butanesulfonyl group; or a methanesulfonyl group or an ethanesulfonyl group substituted by a (C ₁ -C ₄ alkoxy) carbonyl group or a carboxyl group,
R ⁴ is a hydrogen atom, a fluorine atom, a chlorine atom or a trifluoromethyl group,
R ⁵ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a C ₁ -C ₄ alkyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, or a 2,2-difluoroethyl group. 2,2,2-trifluoroethyl group, C ₁ -C ₄ alkoxy group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, carbamoyl group, methylcarbamoyl group or N, N-dimethylcarbamoyl group,
A compound wherein R ⁶ is a 1-acetimidoylpiperidin-4-yl group,

（２４）Ｒ¹が、水素原子、弗素原子、メチル基又は水酸基であり、
Ｒ²が、水素原子、弗素原子又はメチル基であり、
Ｒ³が、水素原子、メチル基、エチル基、イソプロピル基、２−ヒドロキシエチル基、カルボキシメチル基、メトキシカルボニルメチル基、エトキシカルボニルメチル基、プロポキシカルボニルメチル基、ブトキシカルボニルメチル基、アセチル基、ヒドロキシアセチル基、メタンスルホニル基、エタンスルホニル基、ブタンスルホニル基、メトキシカルボニルメタンスルホニル基、エトキシカルボニルメタンスルホニル基、カルボキシメタンスルホニル基、２−メトキシカルボニルエタンスルホニル基、２−エトキシカルボニルエタンスルホニル基又は２−カルボキシエタンスルホニル基であり、
Ｒ⁴が、水素原子、弗素原子又は塩素原子であり、
Ｒ⁵が、水素原子、弗素原子、塩素原子、臭素原子、メチル基、エチル基、トリフルオロメチル基、メトキシ基、エトキシ基又はカルバモイル基であり、
Ｒ⁶が、１−アセトイミドイルピペリジン−４−イル基である化合物、 (24) R ¹ is a hydrogen atom, a fluorine atom, a methyl group or a hydroxyl group,
R ² is a hydrogen atom, a fluorine atom or a methyl group,
R ³ is a hydrogen atom, methyl group, ethyl group, isopropyl group, 2-hydroxyethyl group, carboxymethyl group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, propoxycarbonylmethyl group, butoxycarbonylmethyl group, acetyl group, hydroxy Acetyl group, methanesulfonyl group, ethanesulfonyl group, butanesulfonyl group, methoxycarbonylmethanesulfonyl group, ethoxycarbonylmethanesulfonyl group, carboxymethanesulfonyl group, 2-methoxycarbonylethanesulfonyl group, 2-ethoxycarbonylethanesulfonyl group or 2- A carboxyethanesulfonyl group,
R ⁴ is a hydrogen atom, a fluorine atom or a chlorine atom,
R ⁵ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, or a carbamoyl group,
A compound wherein R ⁶ is a 1-acetimidoylpiperidin-4-yl group,

（２５）Ｒ¹が、水素原子又は水酸基であり、
Ｒ²が、水素原子又は弗素原子であり、
Ｒ³が、イソプロピル基、２−ヒドロキシエチル基、カルボキシメチル基、メトキシカルボニルメチル基、エトキシカルボニルメチル基、エタンスルホニル基、メトキシカルボニルメタンスルホニル基、エトキシカルボニルメタンスルホニル基、カルボキシメタンスルホニル基、２−メトキシカルボニルエタンスルホニル基、２−エトキシカルボニルエタンスルホニル基又は２−カルボキシエタンスルホニル基であり、
Ｒ⁴が、水素原子であり、
Ｒ⁵が、水素原子、弗素原子、塩素原子、メチル基、トリフルオロメチル基又はカルバモイル基であり、
Ｒ⁶が、１−アセトイミドイルピペリジン−４−イル基である化合物、 (25) R ¹ is a hydrogen atom or a hydroxyl group,
R ² is a hydrogen atom or a fluorine atom,
R ³ is isopropyl, 2-hydroxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, ethanesulfonyl, methoxycarbonylmethanesulfonyl, ethoxycarbonylmethanesulfonyl, carboxymethanesulfonyl, 2- A methoxycarbonylethanesulfonyl group, a 2-ethoxycarbonylethanesulfonyl group or a 2-carboxyethanesulfonyl group,
R ⁴ is a hydrogen atom,
R ⁵ is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group or a carbamoyl group,
A compound wherein R ⁶ is a 1-acetimidoylpiperidin-4-yl group,

（２６）Ｒ¹が、水素原子又は水酸基であり、
Ｒ²が、水素原子又は弗素原子であり、
Ｒ³が、イソプロピル基、カルボキシメチル基、エトキシカルボニルメチル基、エトキシカルボニルメタンスルホニル基又はカルボキシメタンスルホニル基であり、
Ｒ⁴が、水素原子であり、
Ｒ⁵が、水素原子、塩素原子、メチル基又はカルバモイル基であり、
Ｒ⁶が、１−アセトイミドイルピペリジン−４−イル基である化合物、 (26) R ¹ is a hydrogen atom or a hydroxyl group,
R ² is a hydrogen atom or a fluorine atom,
R ³ is an isopropyl group, a carboxymethyl group, an ethoxycarbonylmethyl group, an ethoxycarbonylmethanesulfonyl group or a carboxymethanesulfonyl group,
R ⁴ is a hydrogen atom,
R ⁵ is a hydrogen atom, a chlorine atom, a methyl group or a carbamoyl group,
A compound wherein R ⁶ is a 1-acetimidoylpiperidin-4-yl group,

（２７）Ｒ¹が、水素原子又は水酸基であり、
Ｒ²が、水素原子又は弗素原子であり、
Ｒ³が、エトキシカルボニルメタンスルホニル基又はカルボキシメタンスルホニル基であり、
Ｒ⁴が、水素原子であり、
Ｒ⁵が、水素原子、塩素原子、メチル基又はカルバモイル基であり、
Ｒ⁶が、１−アセトイミドイルピペリジン−４−イル基である化合物、
を挙げることができ、上記に関しては、（２２）から（２７）の順で好適な順位が上がる。 (27) R ¹ is a hydrogen atom or a hydroxyl group,
R ² is a hydrogen atom or a fluorine atom,
R ³ is an ethoxycarbonylmethanesulfonyl group or a carboxymethanesulfonyl group,
R ⁴ is a hydrogen atom,
R ⁵ is a hydrogen atom, a chlorine atom, a methyl group or a carbamoyl group,
A compound wherein R ⁶ is a 1-acetimidoylpiperidin-4-yl group,
With regard to the above, the preferred ranking increases in the order of (22) to (27).

本発明の代表化合物としては、例えば、以下の表に記載する化合物を挙げることができるが、本発明はこれらの化合物に限定されるものではない。 As typical compounds of the present invention, for example, compounds listed in the following table can be mentioned, but the present invention is not limited to these compounds.

表中の略号は、以下の通りである。
Ａｃ : アセチル基
ＡＩ : アセトイミドイル基
１−ＡＩ−Ｐｉｐ（４） : １−アセトイミドイルピペリジン−４−イル基
１−ＡＩ−Ｐｙｒｄ（３）: １−アセトイミドイルピロリジン−３−イル基
Ｂｎ : ベンジル基
Ｂｕ : ブチル基
ｉＢｕ : イソブチル基
ｓＢｕ : セカンダリーブチル基
ｔＢｕ : ターシャリーブチル基
Ｂｙｒ : ブチリル基
Ｅｔ : エチル基
Ｈｘ : ヘキシル基
Ｍｅ : メチル基
Ｎｐ(１) : １−ナフチル基
Ｎｐ(２) : ２−ナフチル基
Ｐｈ : フェニル基
Ｐｎ : ペンチル基
Ｐｒ : プロピル基
ｉＰｒ : イソプロピル基
Ｐｒｎ : プロピオニル基
Ｖａ：バレリル基 Abbreviations in the table are as follows.
Ac: acetyl group AI: acetimidoyl group 1-AI-Pip (4): 1-acetimidoylpiperidin-4-yl group 1-AI-Pyrd (3): 1-acetimidoylpyrrolidin-3-yl group Bn: benzyl group Bu: butyl group iBu: isobutyl group sBu: secondary butyl group tBu: tertiary butyl group Byr: butyryl group Et: ethyl group Hx: hexyl group Me: methyl group Np (1): 1-naphthyl group Np ( 2): 2-naphthyl group Ph: phenyl group Pn: pentyl group Pr: propyl group iPr: isopropyl group Prn: propionyl group Va: valeryl group

(表１) (Table 1)

化合物 R¹ R² R³ R⁴ R⁵ R⁶
番号
1 H H H H H 1-AI-Pyrd(3)
2 H H Me H H 1-AI-Pyrd(3)
3 H H Et H H 1-AI-Pyrd(3)
4 H H iPr H H 1-AI-Pyrd(3)
5 H H iPr 3-Cl H 1-AI-Pyrd(3)
6 H H iPr 3-Me H 1-AI-Pyrd(3)
7 H H iPr 3-CONH₂ H 1-AI-Pyrd(3)
8 H H iPr 3-F 5-F 1-AI-Pyrd(3)
9 H H iPr 3-Cl 5-Cl 1-AI-Pyrd(3)
10 H H iPr 3-Me 5-Me 1-AI-Pyrd(3)
11 H H iPr 3-Cl 5-CONH₂ 1-AI-Pyrd(3)
12 H H iPr 2-Me 5-CONH₂ 1-AI-Pyrd(3)
13 H H iPr 3-Me 5-CONH₂ 1-AI-Pyrd(3)
14 H H iPr 3-CONH₂ 5-CONH₂ 1-AI-Pyrd(3)
15 6-OH H iPr H H 1-AI-Pyrd(3)
16 6-OH H iPr 3-Cl H 1-AI-Pyrd(3)
17 6-OH H iPr 3-Me H 1-AI-Pyrd(3)
18 6-OH H iPr 3-CONH₂ H 1-AI-Pyrd(3)
19 H H Bu H H 1-AI-Pyrd(3)
20 H H Pn H H 1-AI-Pyrd(3)
21 H H Hx H H 1-AI-Pyrd(3)
22 H H CH₂OH H H 1-AI-Pyrd(3)
23 H H (CH₂)₂OH H H 1-AI-Pyrd(3)
24 6-OH H (CH₂)₂OH H H 1-AI-Pyrd(3)
25 H H (CH₂)₃OH H H 1-AI-Pyrd(3)
26 H H (CH₂)₄OH H H 1-AI-Pyrd(3)
27 H H (CH₂)₅OH H H 1-AI-Pyrd(3)
28 H H (CH₂)₆OH H H 1-AI-Pyrd(3)
29 H H CH₂COOH H H 1-AI-Pyrd(3)
30 H H CH₂COOH 3-Cl H 1-AI-Pyrd(3)
31 H H CH₂COOH 3-Me H 1-AI-Pyrd(3)
32 H H CH₂COOH 3-CONH₂ H 1-AI-Pyrd(3)
33 H H CH₂COOH 3-F 5-F 1-AI-Pyrd(3)
34 H H CH₂COOH 3-Cl 5-Cl 1-AI-Pyrd(3)
35 H H CH₂COOH 3-Me 5-Me 1-AI-Pyrd(3)
36 H H CH₂COOH 3-Cl 5-CONH₂ 1-AI-Pyrd(3)
37 H H CH₂COOH 2-Me 5-CONH₂ 1-AI-Pyrd(3)
38 H H CH₂COOH 3-Me 5-CONH₂ 1-AI-Pyrd(3)
39 H H CH₂COOH 3-CONH₂ 5-CONH₂ 1-AI-Pyrd(3)
40 6-OH H CH₂COOH H H 1-AI-Pyrd(3)
41 6-OH H CH₂COOH 3-Cl H 1-AI-Pyrd(3)
42 6-OH H CH₂COOH 3-Me H 1-AI-Pyrd(3)
43 6-OH H CH₂COOH 3-CONH₂ H 1-AI-Pyrd(3)
44 H H (CH₂)₂COOH H H 1-AI-Pyrd(3)
45 H H (CH₂)₃COOH H H 1-AI-Pyrd(3)
46 H H (CH₂)₄COOH H H 1-AI-Pyrd(3)
47 H H (CH₂)₅COOH H H 1-AI-Pyrd(3)
48 H H (CH₂)₆COOH H H 1-AI-Pyrd(3)
49 H H CH₂COOMe H H 1-AI-Pyrd(3)
50 H H CH₂COOEt H H 1-AI-Pyrd(3)
51 H H CH₂COOEt 3-Cl H 1-AI-Pyrd(3)
52 H H CH₂COOEt 3-Me H 1-AI-Pyrd(3)
53 H H CH₂COOEt 3-CONH₂ H 1-AI-Pyrd(3)
54 H H CH₂COOEt 3-F 5-F 1-AI-Pyrd(3)
55 H H CH₂COOEt 3-Cl 5-Cl 1-AI-Pyrd(3)
56 H H CH₂COOEt 3-Me 5-Me 1-AI-Pyrd(3)
57 H H CH₂COOEt 3-Cl 5-CONH₂ 1-AI-Pyrd(3)
58 H H CH₂COOEt 2-Me 5-CONH₂ 1-AI-Pyrd(3)
59 H H CH₂COOEt 3-Me 5-CONH₂ 1-AI-Pyrd(3)
60 H H CH₂COOEt 3-CONH₂ 5-CONH₂ 1-AI-Pyrd(3)
61 6-OH H CH₂COOEt H H 1-AI-Pyrd(3)
62 6-OH H CH₂COOEt 3-Cl H 1-AI-Pyrd(3)
63 6-OH H CH₂COOEt 3-Me H 1-AI-Pyrd(3)
64 6-OH H CH₂COOEt 3-CONH₂ H 1-AI-Pyrd(3)
65 H H CH₂COOPr H H 1-AI-Pyrd(3)
66 H H CH₂COOBu H H 1-AI-Pyrd(3)
67 H H CH₂COOPn H H 1-AI-Pyrd(3)
68 H H CH₂COOHx H H 1-AI-Pyrd(3)
69 H H (CH₂)₂COOEt H H 1-AI-Pyrd(3)
70 H H (CH₂)₃COOMe H H 1-AI-Pyrd(3)
71 H H (CH₂)₄COOPr H H 1-AI-Pyrd(3)
72 H H (CH₂)₅COOBu H H 1-AI-Pyrd(3)
73 H H (CH₂)₆COOHx H H 1-AI-Pyrd(3)
74 H H Bn H H 1-AI-Pyrd(3)
75 H H (CH₂)₂Ph H H 1-AI-Pyrd(3)
76 H H (CH₂)₃Ph H H 1-AI-Pyrd(3)
77 H H (CH₂)₄Ph H H 1-AI-Pyrd(3)
78 H H CHO H H 1-AI-Pyrd(3)
79 H H Ac H H 1-AI-Pyrd(3)
80 H H Prn H H 1-AI-Pyrd(3)
81 H H Va H H 1-AI-Pyrd(3)
82 H H SO₂Me H H 1-AI-Pyrd(3)
83 H H SO₂Et H H 1-AI-Pyrd(3)
84 6-OH H SO₂Et H H 1-AI-Pyrd(3)
85 H H SO₂Pr H H 1-AI-Pyrd(3)
86 H H SO₂Bu H H 1-AI-Pyrd(3)
87 H H SO₂Pn H H 1-AI-Pyrd(3)
88 H H SO₂Hx H H 1-AI-Pyrd(3)
89 H H SO₂CH₂COOMe H H 1-AI-Pyrd(3)
90 H H SO₂CH₂COOEt H H 1-AI-Pyrd(3)
91 H H SO₂CH₂COOEt 3-F H 1-AI-Pyrd(3)
92 H H SO₂CH₂COOEt 2-Cl H 1-AI-Pyrd(3)
93 H H SO₂CH₂COOEt 3-Cl H 1-AI-Pyrd(3)
94 H H SO₂CH₂COOEt 2-Me H 1-AI-Pyrd(3)
95 H H SO₂CH₂COOEt 3-Me H 1-AI-Pyrd(3)
96 H H SO₂CH₂COOEt 3-Et H 1-AI-Pyrd(3)
97 H H SO₂CH₂COOEt 3-CF₃ H 1-AI-Pyrd(3)
98 H H SO₂CH₂COOEt 2-OEt H 1-AI-Pyrd(3)
99 H H SO₂CH₂COOEt 3-OMe H 1-AI-Pyrd(3)
100 H H SO₂CH₂COOEt 2-CONH₂ H 1-AI-Pyrd(3)
101 H H SO₂CH₂COOEt 3-CONH₂ H 1-AI-Pyrd(3)
102 H H SO₂CH₂COOEt 3-F 5-F 1-AI-Pyrd(3)
103 H H SO₂CH₂COOEt 3-Cl 5-Cl 1-AI-Pyrd(3)
104 H H SO₂CH₂COOEt 3-Me 5-Me 1-AI-Pyrd(3)
105 H H SO₂CH₂COOEt 3-Cl 5-CONH₂ 1-AI-Pyrd(3)
106 H H SO₂CH₂COOEt 2-Me 5-CONH₂ 1-AI-Pyrd(3)
107 H H SO₂CH₂COOEt 3-Me 5-CONH₂ 1-AI-Pyrd(3)
108 H H SO₂CH₂COOEt 3-CONH₂ 5-CONH₂ 1-AI-Pyrd(3)
109 H F SO₂CH₂COOEt H H 1-AI-Pyrd(3)
110 H Cl SO₂CH₂COOEt H H 1-AI-Pyrd(3)
111 H Me SO₂CH₂COOEt H H 1-AI-Pyrd(3)
112 H Et SO₂CH₂COOEt H H 1-AI-Pyrd(3)
113 2-F H SO₂CH₂COOEt H H 1-AI-Pyrd(3)
114 4-F H SO₂CH₂COOEt H H 1-AI-Pyrd(3)
115 5-F H SO₂CH₂COOEt H H 1-AI-Pyrd(3)
116 6-F H SO₂CH₂COOEt H H 1-AI-Pyrd(3)
117 2-Cl H SO₂CH₂COOEt H H 1-AI-Pyrd(3)
118 6-Cl H SO₂CH₂COOEt H H 1-AI-Pyrd(3)
119 4-Me H SO₂CH₂COOEt H H 1-AI-Pyrd(3)
120 6-Me H SO₂CH₂COOEt H H 1-AI-Pyrd(3)
121 5-Et H SO₂CH₂COOEt H H 1-AI-Pyrd(3)
122 6-Pr H SO₂CH₂COOEt H H 1-AI-Pyrd(3)
123 2-OH H SO₂CH₂COOEt H H 1-AI-Pyrd(3)
124 4-OH H SO₂CH₂COOEt H H 1-AI-Pyrd(3)
125 5-OH H SO₂CH₂COOEt H H 1-AI-Pyrd(3)
126 6-OH H SO₂CH₂COOEt H H 1-AI-Pyrd(3)
127 H H SO₂CH₂COOPr H H 1-AI-Pyrd(3)
128 H H SO₂CH₂COOBu H H 1-AI-Pyrd(3)
129 H H SO₂CH₂COOPn H H 1-AI-Pyrd(3)
130 H H SO₂CH₂COOHx H H 1-AI-Pyrd(3)
131 H H SO₂(CH₂)₂COOMe H H 1-AI-Pyrd(3)
132 H H SO₂(CH₂)₂COOEt H H 1-AI-Pyrd(3)
133 H H SO₂(CH₂)₂COOPr H H 1-AI-Pyrd(3)
134 H H SO₂(CH₂)₂COOBu H H 1-AI-Pyrd(3)
135 H H SO₂(CH₂)₂COOPn H H 1-AI-Pyrd(3)
136 H H SO₂(CH₂)₂COOHx H H 1-AI-Pyrd(3)
137 H H SO₂CH₂COOH H H 1-AI-Pyrd(3)
138 H H SO₂CH₂COOH 3-F H 1-AI-Pyrd(3)
139 H H SO₂CH₂COOH 2-Cl H 1-AI-Pyrd(3)
140 H H SO₂CH₂COOH 3-Cl H 1-AI-Pyrd(3)
141 H H SO₂CH₂COOH 2-Me H 1-AI-Pyrd(3)
142 H H SO₂CH₂COOH 3-Me H 1-AI-Pyrd(3)
143 H H SO₂CH₂COOH 3-Et H 1-AI-Pyrd(3)
144 H H SO₂CH₂COOH 3-CF₃ H 1-AI-Pyrd(3)
145 H H SO₂CH₂COOH 2-OMe H 1-AI-Pyrd(3)
146 H H SO₂CH₂COOH 3-OEt H 1-AI-Pyrd(3)
147 H H SO₂CH₂COOH 2-CONH₂ H 1-AI-Pyrd(3)
148 H H SO₂CH₂COOH 3-CONH₂ H 1-AI-Pyrd(3)
149 H H SO₂CH₂COOH 3-F 5-F 1-AI-Pyrd(3)
150 H H SO₂CH₂COOH 3-Cl 5-Cl 1-AI-Pyrd(3)
151 H H SO₂CH₂COOH 3-Me 5-Me 1-AI-Pyrd(3)
152 H H SO₂CH₂COOH 3-Cl 5-CONH₂ 1-AI-Pyrd(3)
153 H H SO₂CH₂COOH 2-Me 5-CONH₂ 1-AI-Pyrd(3)
154 H H SO₂CH₂COOH 3-Me 5-CONH₂ 1-AI-Pyrd(3)
155 H H SO₂CH₂COOH 3-CONH₂ 5-CONH₂ 1-AI-Pyrd(3)
156 H F SO₂CH₂COOH H H 1-AI-Pyrd(3)
157 H Cl SO₂CH₂COOH H H 1-AI-Pyrd(3)
158 H Me SO₂CH₂COOH H H 1-AI-Pyrd(3)
159 H Et SO₂CH₂COOH H H 1-AI-Pyrd(3)
160 2-F H SO₂CH₂COOH H H 1-AI-Pyrd(3)
161 4-F H SO₂CH₂COOH H H 1-AI-Pyrd(3)
162 5-F H SO₂CH₂COOH H H 1-AI-Pyrd(3)
163 6-F H SO₂CH₂COOH H H 1-AI-Pyrd(3)
164 2-Cl H SO₂CH₂COOH H H 1-AI-Pyrd(3)
165 6-Cl H SO₂CH₂COOH H H 1-AI-Pyrd(3)
166 4-Me H SO₂CH₂COOH H H 1-AI-Pyrd(3)
167 6-Me H SO₂CH₂COOH H H 1-AI-Pyrd(3)
168 5-Et H SO₂CH₂COOH H H 1-AI-Pyrd(3)
169 6-Pr H SO₂CH₂COOH H H 1-AI-Pyrd(3)
170 2-OH H SO₂CH₂COOH H H 1-AI-Pyrd(3)
171 4-OH H SO₂CH₂COOH H H 1-AI-Pyrd(3)
172 5-OH H SO₂CH₂COOH H H 1-AI-Pyrd(3)
173 6-OH H SO₂CH₂COOH H H 1-AI-Pyrd(3)
174 H H SO₂CH₂COOH H H 1-AI-Pyrd(3)
175 H H SO₂CH₂COOH H H 1-AI-Pyrd(3)
176 H H SO₂(CH₂)₂COOH H H 1-AI-Pyrd(3)
177 H H H H H 1-AI-Pip(4)
178 H H H 2-F H 1-AI-Pip(4)
179 H H H 3-F H 1-AI-Pip(4)
180 H H H 2-Cl H 1-AI-Pip(4)
181 H H H 3-Cl H 1-AI-Pip(4)
182 H H H 2-Br H 1-AI-Pip(4)
183 H H H 3-Br H 1-AI-Pip(4)
184 H H H 2-I H 1-AI-Pip(4)
185 H H H 3-I H 1-AI-Pip(4)
186 H H H 2-Me H 1-AI-Pip(4)
187 H H H 3-Me H 1-AI-Pip(4)
188 H H H 2-Et H 1-AI-Pip(4)
189 H H H 3-Et H 1-AI-Pip(4)
190 H H H 2-Pr H 1-AI-Pip(4)
191 H H H 3-Pr H 1-AI-Pip(4)
192 H H H 2-Bu H 1-AI-Pip(4)
193 H H H 3-Bu H 1-AI-Pip(4)
194 H H H 2-Pn H 1-AI-Pip(4)
195 H H H 3-Pn H 1-AI-Pip(4)
196 H H H 2-Hx H 1-AI-Pip(4)
197 H H H 3-Hx H 1-AI-Pip(4)
198 H H H 2-CF₃ H 1-AI-Pip(4)
199 H H H 3-CF₃ H 1-AI-Pip(4)
200 H H H 2-OMe H 1-AI-Pip(4)
201 H H H 3-OMe H 1-AI-Pip(4)
202 H H H 2-OEt H 1-AI-Pip(4)
203 H H H 3-OEt H 1-AI-Pip(4)
204 H H H 2-COOH H 1-AI-Pip(4)
205 H H H 3-COOH H 1-AI-Pip(4)
206 H H H 2-COOMe H 1-AI-Pip(4)
207 H H H 3-COOMe H 1-AI-Pip(4)
208 H H H 2-COOEt H 1-AI-Pip(4)
209 H H H 3-COOEt H 1-AI-Pip(4)
210 H H H 2-COOPr H 1-AI-Pip(4)
211 H H H 3-COOPr H 1-AI-Pip(4)
212 H H H 2-COOBu H 1-AI-Pip(4)
213 H H H 3-COOBu H 1-AI-Pip(4)
214 H H H 2-COOPn H 1-AI-Pip(4)
215 H H H 3-COOPn H 1-AI-Pip(4)
216 H H H 2-COOHx H 1-AI-Pip(4)
217 H H H 3-COOHx H 1-AI-Pip(4)
218 H H H 2-CONH₂ H 1-AI-Pip(4)
219 H H H 3-CONH₂ H 1-AI-Pip(4)
220 H H H 2-CONHMe H 1-AI-Pip(4)
221 H H H 3-CONHMe H 1-AI-Pip(4)
222 H H H 2-CONHEt H 1-AI-Pip(4)
223 H H H 3-CONHEt H 1-AI-Pip(4)
224 H H H 2-CON(Me)₂ H 1-AI-Pip(4)
225 H H H 3-CON(Me)₂ H 1-AI-Pip(4)
226 H H H 2-CON(Me)Et H 1-AI-Pip(4)
227 H H H 3-CON(Me)Et H 1-AI-Pip(4)
228 H H H 2-CON(Et)₂ H 1-AI-Pip(4)
229 H H H 3-CON(Et)₂ H 1-AI-Pip(4)
230 H H H 3-F 5-F 1-AI-Pip(4)
231 H H H 3-Cl 5-Cl 1-AI-Pip(4)
232 H H H 3-Me 5-Me 1-AI-Pip(4)
233 H H H 3-Cl 5-CONH₂ 1-AI-Pip(4)
234 H H H 2-Me 5-CONH₂ 1-AI-Pip(4)
235 H H H 3-Me 5-CONH₂ 1-AI-Pip(4)
236 H H H 3-CONH₂ 5-CONH₂ 1-AI-Pip(4)
237 H H Me H H 1-AI-Pip(4)
238 H H Me 2-F H 1-AI-Pip(4)
239 H H Me 3-F H 1-AI-Pip(4)
240 H H Me 2-Cl H 1-AI-Pip(4)
241 H H Me 3-Cl H 1-AI-Pip(4)
242 H H Me 2-Br H 1-AI-Pip(4)
243 H H Me 3-Br H 1-AI-Pip(4)
244 H H Me 2-I H 1-AI-Pip(4)
245 H H Me 3-I H 1-AI-Pip(4)
246 H H Me 2-Me H 1-AI-Pip(4)
247 H H Me 3-Me H 1-AI-Pip(4)
248 H H Me 2-Et H 1-AI-Pip(4)
249 H H Me 3-Et H 1-AI-Pip(4)
250 H H Me 2-Pr H 1-AI-Pip(4)
251 H H Me 3-Pr H 1-AI-Pip(4)
252 H H Me 2-Bu H 1-AI-Pip(4)
253 H H Me 3-Bu H 1-AI-Pip(4)
254 H H Me 2-Pn H 1-AI-Pip(4)
255 H H Me 3-Pn H 1-AI-Pip(4)
256 H H Me 2-Hx H 1-AI-Pip(4)
257 H H Me 3-Hx H 1-AI-Pip(4)
258 H H Me 2-CF₃ H 1-AI-Pip(4)
259 H H Me 3-CF₃ H 1-AI-Pip(4)
260 H H Me 2-OMe H 1-AI-Pip(4)
261 H H Me 3-OMe H 1-AI-Pip(4)
262 H H Me 2-OEt H 1-AI-Pip(4)
263 H H Me 3-OEt H 1-AI-Pip(4)
264 H H Me 2-COOH H 1-AI-Pip(4)
265 H H Me 3-COOH H 1-AI-Pip(4)
266 H H Me 2-COOMe H 1-AI-Pip(4)
267 H H Me 3-COOMe H 1-AI-Pip(4)
268 H H Me 2-COOEt H 1-AI-Pip(4)
269 H H Me 3-COOEt H 1-AI-Pip(4)
270 H H Me 2-COOPr H 1-AI-Pip(4)
271 H H Me 3-COOPr H 1-AI-Pip(4)
272 H H Me 2-COOBu H 1-AI-Pip(4)
273 H H Me 3-COOBu H 1-AI-Pip(4)
274 H H Me 2-COOPn H 1-AI-Pip(4)
275 H H Me 3-COOPn H 1-AI-Pip(4)
276 H H Me 2-COOHx H 1-AI-Pip(4)
277 H H Me 3-COOHx H 1-AI-Pip(4)
278 H H Me 2-CONH₂ H 1-AI-Pip(4)
279 H H Me 3-CONH₂ H 1-AI-Pip(4)
280 H H Me 2-CONHMe H 1-AI-Pip(4)
281 H H Me 3-CONHMe H 1-AI-Pip(4)
282 H H Me 2-CONHEt H 1-AI-Pip(4)
283 H H Me 3-CONHEt H 1-AI-Pip(4)
284 H H Me 2-CON(Me)₂ H 1-AI-Pip(4)
285 H H Me 3-CON(Me)₂ H 1-AI-Pip(4)
286 H H Me 2-CON(Me)Et H 1-AI-Pip(4)
287 H H Me 3-CON(Me)Et H 1-AI-Pip(4)
288 H H Me 2-CON(Et)₂ H 1-AI-Pip(4)
289 H H Me 3-CON(Et)₂ H 1-AI-Pip(4)
290 H H Me 3-F 5-F 1-AI-Pip(4)
291 H H Me 3-Cl 5-Cl 1-AI-Pip(4)
292 H H Me 3-Me 5-Me 1-AI-Pip(4)
293 H H Me 3-Cl 5-CONH₂ 1-AI-Pip(4)
294 H H Me 2-Me 5-CONH₂ 1-AI-Pip(4)
295 H H Me 3-Me 5-CONH₂ 1-AI-Pip(4)
296 H H Me 3-CONH₂ 5-CONH₂ 1-AI-Pip(4)
297 H H Et H H 1-AI-Pip(4)
298 H H Et 2-F H 1-AI-Pip(4)
299 H H Et 3-F H 1-AI-Pip(4)
300 H H Et 2-Cl H 1-AI-Pip(4)
301 H H Et 3-Cl H 1-AI-Pip(4)
302 H H Et 2-Br H 1-AI-Pip(4)
303 H H Et 3-Br H 1-AI-Pip(4)
304 H H Et 2-I H 1-AI-Pip(4)
305 H H Et 3-I H 1-AI-Pip(4)
306 H H Et 2-Me H 1-AI-Pip(4)
307 H H Et 3-Me H 1-AI-Pip(4)
308 H H Et 2-Et H 1-AI-Pip(4)
309 H H Et 3-Et H 1-AI-Pip(4)
310 H H Et 2-Pr H 1-AI-Pip(4)
311 H H Et 3-Pr H 1-AI-Pip(4)
312 H H Et 2-Bu H 1-AI-Pip(4)
313 H H Et 3-Bu H 1-AI-Pip(4)
314 H H Et 2-Pn H 1-AI-Pip(4)
315 H H Et 3-Pn H 1-AI-Pip(4)
316 H H Et 2-Hx H 1-AI-Pip(4)
317 H H Et 3-Hx H 1-AI-Pip(4)
318 H H Et 2-CF₃ H 1-AI-Pip(4)
319 H H Et 3-CF₃ H 1-AI-Pip(4)
320 H H Et 2-OMe H 1-AI-Pip(4)
321 H H Et 3-OMe H 1-AI-Pip(4)
322 H H Et 2-OEt H 1-AI-Pip(4)
323 H H Et 3-OEt H 1-AI-Pip(4)
324 H H Et 2-COOH H 1-AI-Pip(4)
325 H H Et 3-COOH H 1-AI-Pip(4)
326 H H Et 2-COOMe H 1-AI-Pip(4)
327 H H Et 3-COOMe H 1-AI-Pip(4)
328 H H Et 2-COOEt H 1-AI-Pip(4)
329 H H Et 3-COOEt H 1-AI-Pip(4)
330 H H Et 2-COOPr H 1-AI-Pip(4)
331 H H Et 3-COOPr H 1-AI-Pip(4)
332 H H Et 2-COOBu H 1-AI-Pip(4)
333 H H Et 3-COOBu H 1-AI-Pip(4)
334 H H Et 2-COOPn H 1-AI-Pip(4)
335 H H Et 3-COOPn H 1-AI-Pip(4)
336 H H Et 2-COOHx H 1-AI-Pip(4)
337 H H Et 3-COOHx H 1-AI-Pip(4)
338 H H Et 2-CONH₂ H 1-AI-Pip(4)
339 H H Et 3-CONH₂ H 1-AI-Pip(4)
340 H H Et 2-CONHMe H 1-AI-Pip(4)
341 H H Et 3-CONHMe H 1-AI-Pip(4)
342 H H Et 2-CONHEt H 1-AI-Pip(4)
343 H H Et 3-CONHEt H 1-AI-Pip(4)
344 H H Et 2-CON(Me)₂ H 1-AI-Pip(4)
345 H H Et 3-CON(Me)₂ H 1-AI-Pip(4)
346 H H Et 2-CON(Me)Et H 1-AI-Pip(4)
347 H H Et 3-CON(Me)Et H 1-AI-Pip(4)
348 H H Et 2-CON(Et)₂ H 1-AI-Pip(4)
349 H H Et 3-CON(Et)₂ H 1-AI-Pip(4)
350 H H Et 3-F F 1-AI-Pip(4)
351 H H Et 3-Cl 5-Cl 1-AI-Pip(4)
352 H H Et 3-Me 5-Me 1-AI-Pip(4)
353 H H Et 3-Cl 5-CONH₂ 1-AI-Pip(4)
354 H H Et 2-Me 5-CONH₂ 1-AI-Pip(4)
355 H H Et 3-Me 5-CONH₂ 1-AI-Pip(4)
356 H H Et 3-CONH₂ 5-CONH₂ 1-AI-Pip(4)
357 H H Pr H H 1-AI-Pip(4)
358 H H iPr H H 1-AI-Pip(4)
359 H H iPr 2-F H 1-AI-Pip(4)
360 H H iPr 3-F H 1-AI-Pip(4)
361 H H iPr 2-Cl H 1-AI-Pip(4)
362 H H iPr 3-Cl H 1-AI-Pip(4)
363 H H iPr 2-Br H 1-AI-Pip(4)
364 H H iPr 3-Br H 1-AI-Pip(4)
365 H H iPr 2-I H 1-AI-Pip(4)
366 H H iPr 3-I H 1-AI-Pip(4)
367 H H iPr 2-Me H 1-AI-Pip(4)
368 H H iPr 3-Me H 1-AI-Pip(4)
369 H H iPr 2-Et H 1-AI-Pip(4)
370 H H iPr 3-Et H 1-AI-Pip(4)
371 H H iPr 2-Pr H 1-AI-Pip(4)
372 H H iPr 3-Pr H 1-AI-Pip(4)
373 H H iPr 2-Bu H 1-AI-Pip(4)
374 H H iPr 3-Bu H 1-AI-Pip(4)
375 H H iPr 2-Pn H 1-AI-Pip(4)
376 H H iPr 3-Pn H 1-AI-Pip(4)
377 H H iPr 2-Hx H 1-AI-Pip(4)
378 H H iPr 3-Hx H 1-AI-Pip(4)
379 H H iPr 2-CF₃ H 1-AI-Pip(4)
380 H H iPr 3-CF₃ H 1-AI-Pip(4)
381 H H iPr 2-OMe H 1-AI-Pip(4)
382 H H iPr 3-OMe H 1-AI-Pip(4)
383 H H iPr 2-OEt H 1-AI-Pip(4)
384 H H iPr 3-OEt H 1-AI-Pip(4)
385 H H iPr 2-COOH H 1-AI-Pip(4)
386 H H iPr 3-COOH H 1-AI-Pip(4)
387 H H iPr 2-COOMe H 1-AI-Pip(4)
388 H H iPr 3-COOMe H 1-AI-Pip(4)
389 H H iPr 2-COOEt H 1-AI-Pip(4)
390 H H iPr 3-COOEt H 1-AI-Pip(4)
391 H H iPr 2-COOPr H 1-AI-Pip(4)
392 H H iPr 3-COOPr H 1-AI-Pip(4)
393 H H iPr 2-COOBu H 1-AI-Pip(4)
394 H H iPr 3-COOBu H 1-AI-Pip(4)
395 H H iPr 2-COOPn H 1-AI-Pip(4)
396 H H iPr 3-COOPn H 1-AI-Pip(4)
397 H H iPr 2-COOHx H 1-AI-Pip(4)
398 H H iPr 3-COOHx H 1-AI-Pip(4)
399 H H iPr 2-CONH₂ H 1-AI-Pip(4)
400 H H iPr 3-CONH₂ H 1-AI-Pip(4)
401 H H iPr 2-CONHMe H 1-AI-Pip(4)
402 H H iPr 3-CONHMe H 1-AI-Pip(4)
403 H H iPr 2-CONHEt H 1-AI-Pip(4)
404 H H iPr 3-CONHEt H 1-AI-Pip(4)
405 H H iPr 2-CON(Me)₂ H 1-AI-Pip(4)
406 H H iPr 3-CON(Me)₂ H 1-AI-Pip(4)
407 H H iPr 2-CON(Me)Et H 1-AI-Pip(4)
408 H H iPr 3-CON(Me)Et H 1-AI-Pip(4)
409 H H iPr 2-CON(Et)₂ H 1-AI-Pip(4)
410 H H iPr 3-CON(Et)₂ H 1-AI-Pip(4)
411 H H iPr 3-F 5-F 1-AI-Pip(4)
412 H H iPr 3-Cl 5-Cl 1-AI-Pip(4)
413 H H iPr 3-Me 5-Me 1-AI-Pip(4)
414 H H iPr 3-Cl 5-CONH₂ 1-AI-Pip(4)
415 H H iPr 2-Me 5-CONH₂ 1-AI-Pip(4)
416 H H iPr 3-Me 5-CONH₂ 1-AI-Pip(4)
417 H H iPr 3-CONH₂ 5-CONH₂ 1-AI-Pip(4)
418 6-OH H iPr H H 1-AI-Pip(4)
419 6-OH H iPr 2-F H 1-AI-Pip(4)
420 6-OH H iPr 3-F H 1-AI-Pip(4)
421 6-OH H iPr 2-Cl H 1-AI-Pip(4)
422 6-OH H iPr 3-Cl H 1-AI-Pip(4)
423 6-OH H iPr 2-Br H 1-AI-Pip(4)
424 6-OH H iPr 3-Br H 1-AI-Pip(4)
425 6-OH H iPr 2-I H 1-AI-Pip(4)
426 6-OH H iPr 3-I H 1-AI-Pip(4)
427 6-OH H iPr 2-Me H 1-AI-Pip(4)
428 6-OH H iPr 3-Me H 1-AI-Pip(4)
429 6-OH H iPr 2-Et H 1-AI-Pip(4)
430 6-OH H iPr 3-Et H 1-AI-Pip(4)
431 6-OH H iPr 2-Pr H 1-AI-Pip(4)
432 6-OH H iPr 3-Pr H 1-AI-Pip(4)
433 6-OH H iPr 2-Bu H 1-AI-Pip(4)
434 6-OH H iPr 3-Bu H 1-AI-Pip(4)
435 6-OH H iPr 2-Pn H 1-AI-Pip(4)
436 6-OH H iPr 3-Pn H 1-AI-Pip(4)
437 6-OH H iPr 2-Hx H 1-AI-Pip(4)
438 6-OH H iPr 3-Hx H 1-AI-Pip(4)
439 6-OH H iPr 2-CF₃ H 1-AI-Pip(4)
440 6-OH H iPr 3-CF₃ H 1-AI-Pip(4)
441 6-OH H iPr 2-OMe H 1-AI-Pip(4)
442 6-OH H iPr 3-OMe H 1-AI-Pip(4)
443 6-OH H iPr 2-OEt H 1-AI-Pip(4)
444 6-OH H iPr 3-OEt H 1-AI-Pip(4)
445 6-OH H iPr 2-COOH H 1-AI-Pip(4)
446 6-OH H iPr 3-COOH H 1-AI-Pip(4)
447 6-OH H iPr 2-COOMe H 1-AI-Pip(4)
448 6-OH H iPr 3-COOMe H 1-AI-Pip(4)
449 6-OH H iPr 2-COOEt H 1-AI-Pip(4)
450 6-OH H iPr 3-COOEt H 1-AI-Pip(4)
451 6-OH H iPr 2-COOPr H 1-AI-Pip(4)
452 6-OH H iPr 3-COOPr H 1-AI-Pip(4)
453 6-OH H iPr 2-COOBu H 1-AI-Pip(4)
454 6-OH H iPr 3-COOBu H 1-AI-Pip(4)
455 6-OH H iPr 2-COOPn H 1-AI-Pip(4)
456 6-OH H iPr 3-COOPn H 1-AI-Pip(4)
457 6-OH H iPr 2-COOHx H 1-AI-Pip(4)
458 6-OH H iPr 3-COOHx H 1-AI-Pip(4)
459 6-OH H iPr 2-CONH₂ H 1-AI-Pip(4)
460 6-OH H iPr 3-CONH₂ H 1-AI-Pip(4)
461 6-OH H iPr 2-CONHMe H 1-AI-Pip(4)
462 6-OH H iPr 3-CONHMe H 1-AI-Pip(4)
463 6-OH H iPr 2-CONHEt H 1-AI-Pip(4)
464 6-OH H iPr 3-CONHEt H 1-AI-Pip(4)
465 6-OH H iPr 2-CON(Me)₂ H 1-AI-Pip(4)
466 6-OH H iPr 3-CON(Me)₂ H 1-AI-Pip(4)
467 6-OH H iPr 2-CON(Me)Et H 1-AI-Pip(4)
468 6-OH H iPr 3-CON(Me)Et H 1-AI-Pip(4)
469 6-OH H iPr 2-CON(Et)₂ H 1-AI-Pip(4)
470 6-OH H iPr 3-CON(Et)₂ H 1-AI-Pip(4)
471 H H Bu H H 1-AI-Pip(4)
472 H H iBu H H 1-AI-Pip(4)
473 H H sBu H H 1-AI-Pip(4)
474 H H tBu H H 1-AI-Pip(4)
475 H H Pn H H 1-AI-Pip(4)
476 H H Hx H H 1-AI-Pip(4)
477 H H CH₂OH H H 1-AI-Pip(4)
478 H H (CH₂)₂OH H H 1-AI-Pip(4)
479 H H (CH₂)₂OH 2-F H 1-AI-Pip(4)
480 H H (CH₂)₂OH 3-F H 1-AI-Pip(4)
481 H H (CH₂)₂OH 2-Cl H 1-AI-Pip(4)
482 H H (CH₂)₂OH 3-Cl H 1-AI-Pip(4)
483 H H (CH₂)₂OH 2-Br H 1-AI-Pip(4)
484 H H (CH₂)₂OH 3-Br H 1-AI-Pip(4)
485 H H (CH₂)₂OH 2-I H 1-AI-Pip(4)
486 H H (CH₂)₂OH 3-I H 1-AI-Pip(4)
487 H H (CH₂)₂OH 2-Me H 1-AI-Pip(4)
488 H H (CH₂)₂OH 3-Me H 1-AI-Pip(4)
489 H H (CH₂)₂OH 2-Et H 1-AI-Pip(4)
490 H H (CH₂)₂OH 3-Et H 1-AI-Pip(4)
491 H H (CH₂)₂OH 2-Pr H 1-AI-Pip(4)
492 H H (CH₂)₂OH 3-Pr H 1-AI-Pip(4)
493 H H (CH₂)₂OH 2-Bu H 1-AI-Pip(4)
494 H H (CH₂)₂OH 3-Bu H 1-AI-Pip(4)
495 H H (CH₂)₂OH 2-Pn H 1-AI-Pip(4)
496 H H (CH₂)₂OH 3-Pn H 1-AI-Pip(4)
497 H H (CH₂)₂OH 2-Hx H 1-AI-Pip(4)
498 H H (CH₂)₂OH 3-Hx H 1-AI-Pip(4)
499 H H (CH₂)₂OH 2-CF₃ H 1-AI-Pip(4)
500 H H (CH₂)₂OH 3-CF₃ H 1-AI-Pip(4)
501 H H (CH₂)₂OH 2-OMe H 1-AI-Pip(4)
502 H H (CH₂)₂OH 3-OMe H 1-AI-Pip(4)
503 H H (CH₂)₂OH 2-OEt H 1-AI-Pip(4)
504 H H (CH₂)₂OH 3-OEt H 1-AI-Pip(4)
505 H H (CH₂)₂OH 2-COOH H 1-AI-Pip(4)
506 H H (CH₂)₂OH 3-COOH H 1-AI-Pip(4)
507 H H (CH₂)₂OH 2-COOMe H 1-AI-Pip(4)
508 H H (CH₂)₂OH 3-COOMe H 1-AI-Pip(4)
509 H H (CH₂)₂OH 2-COOEt H 1-AI-Pip(4)
510 H H (CH₂)₂OH 3-COOEt H 1-AI-Pip(4)
511 H H (CH₂)₂OH 2-COOPr H 1-AI-Pip(4)
512 H H (CH₂)₂OH 3-COOPr H 1-AI-Pip(4)
513 H H (CH₂)₂OH 2-COOBu H 1-AI-Pip(4)
514 H H (CH₂)₂OH 3-COOBu H 1-AI-Pip(4)
515 H H (CH₂)₂OH 2-COOPn H 1-AI-Pip(4)
516 H H (CH₂)₂OH 3-COOPn H 1-AI-Pip(4)
517 H H (CH₂)₂OH 2-COOHx H 1-AI-Pip(4)
518 H H (CH₂)₂OH 3-COOHx H 1-AI-Pip(4)
519 H H (CH₂)₂OH 2-CONH₂ H 1-AI-Pip(4)
520 H H (CH₂)₂OH 3-CONH₂ H 1-AI-Pip(4)
521 H H (CH₂)₂OH 2-CONHMe H 1-AI-Pip(4)
522 H H (CH₂)₂OH 3-CONHMe H 1-AI-Pip(4)
523 H H (CH₂)₂OH 2-CONHEt H 1-AI-Pip(4)
524 H H (CH₂)₂OH 3-CONHEt H 1-AI-Pip(4)
525 H H (CH₂)₂OH 2-CON(Me)₂ H 1-AI-Pip(4)
526 H H (CH₂)₂OH 3-CON(Me)₂ H 1-AI-Pip(4)
527 H H (CH₂)₂OH 2-CON(Me)Et H 1-AI-Pip(4)
528 H H (CH₂)₂OH 3-CON(Me)Et H 1-AI-Pip(4)
529 H H (CH₂)₂OH 2-CON(Et)₂ H 1-AI-Pip(4)
530 H H (CH₂)₂OH 3-CON(Et)₂ H 1-AI-Pip(4)
531 H H (CH₂)₂OH 3-F 5-F 1-AI-Pip(4)
532 H H (CH₂)₂OH 3-Cl 5-Cl 1-AI-Pip(4)
533 H H (CH₂)₂OH 3-Me 5-Me 1-AI-Pip(4)
534 H H (CH₂)₂OH 3-Cl 5-CONH₂ 1-AI-Pip(4)
535 H H (CH₂)₂OH 2-Me 5-CONH₂ 1-AI-Pip(4)
536 H H (CH₂)₂OH 3-Me 5-CONH₂ 1-AI-Pip(4)
537 H H (CH₂)₂OH 3-CONH₂ 5-CONH₂ 1-AI-Pip(4)
538 H H (CH₂)₃OH H H 1-AI-Pip(4)
539 H H (CH₂)₄OH H H 1-AI-Pip(4)
540 H H (CH₂)₅OH H H 1-AI-Pip(4)
541 H H (CH₂)₆OH H H 1-AI-Pip(4)
542 H H CH₂COOH H H 1-AI-Pip(4)
543 H H CH₂COOH 2-F H 1-AI-Pip(4)
544 H H CH₂COOH 3-F H 1-AI-Pip(4)
545 H H CH₂COOH 2-Cl H 1-AI-Pip(4)
546 H H CH₂COOH 3-Cl H 1-AI-Pip(4)
547 H H CH₂COOH 2-Br H 1-AI-Pip(4)
548 H H CH₂COOH 3-Br H 1-AI-Pip(4)
549 H H CH₂COOH 2-I H 1-AI-Pip(4)
550 H H CH₂COOH 3-I H 1-AI-Pip(4)
551 H H CH₂COOH 2-Me H 1-AI-Pip(4)
552 H H CH₂COOH 3-Me H 1-AI-Pip(4)
553 H H CH₂COOH 2-Et H 1-AI-Pip(4)
554 H H CH₂COOH 3-Et H 1-AI-Pip(4)
555 H H CH₂COOH 2-Pr H 1-AI-Pip(4)
556 H H CH₂COOH 3-Pr H 1-AI-Pip(4)
557 H H CH₂COOH 2-Bu H 1-AI-Pip(4)
558 H H CH₂COOH 3-Bu H 1-AI-Pip(4)
559 H H CH₂COOH 2-Pn H 1-AI-Pip(4)
560 H H CH₂COOH 3-Pn H 1-AI-Pip(4)
561 H H CH₂COOH 2-Hx H 1-AI-Pip(4)
562 H H CH₂COOH 3-Hx H 1-AI-Pip(4)
563 H H CH₂COOH 2-CF₃ H 1-AI-Pip(4)
564 H H CH₂COOH 3-CF₃ H 1-AI-Pip(4)
565 H H CH₂COOH 2-OMe H 1-AI-Pip(4)
566 H H CH₂COOH 3-OMe H 1-AI-Pip(4)
567 H H CH₂COOH 2-OEt H 1-AI-Pip(4)
568 H H CH₂COOH 3-OEt H 1-AI-Pip(4)
569 H H CH₂COOH 2-COOH H 1-AI-Pip(4)
570 H H CH₂COOH 3-COOH H 1-AI-Pip(4)
571 H H CH₂COOH 2-COOMe H 1-AI-Pip(4)
572 H H CH₂COOH 3-COOMe H 1-AI-Pip(4)
573 H H CH₂COOH 2-COOEt H 1-AI-Pip(4)
574 H H CH₂COOH 3-COOEt H 1-AI-Pip(4)
575 H H CH₂COOH 2-COOPr H 1-AI-Pip(4)
576 H H CH₂COOH 3-COOPr H 1-AI-Pip(4)
577 H H CH₂COOH 2-COOBu H 1-AI-Pip(4)
578 H H CH₂COOH 3-COOBu H 1-AI-Pip(4)
579 H H CH₂COOH 2-COOPn H 1-AI-Pip(4)
580 H H CH₂COOH 3-COOPn H 1-AI-Pip(4)
581 H H CH₂COOH 2-COOHx H 1-AI-Pip(4)
582 H H CH₂COOH 3-COOHx H 1-AI-Pip(4)
583 H H CH₂COOH 2-CONH₂ H 1-AI-Pip(4)
584 H H CH₂COOH 3-CONH₂ H 1-AI-Pip(4)
585 H H CH₂COOH 2-CONHMe H 1-AI-Pip(4)
586 H H CH₂COOH 3-CONHMe H 1-AI-Pip(4)
587 H H CH₂COOH 2-CONHEt H 1-AI-Pip(4)
588 H H CH₂COOH 3-CONHEt H 1-AI-Pip(4)
589 H H CH₂COOH 2-CON(Me)₂ H 1-AI-Pip(4)
590 H H CH₂COOH 3-CON(Me)₂ H 1-AI-Pip(4)
591 H H CH₂COOH 2-CON(Me)EtH 1-AI-Pip(4)
592 H H CH₂COOH 3-CON(Me)EtH 1-AI-Pip(4)
593 H H CH₂COOH 2-CON(Et)₂ H 1-AI-Pip(4)
594 H H CH₂COOH 3-CON(Et)₂ H 1-AI-Pip(4)
595 H H CH₂COOH 3-F 5-F 1-AI-Pip(4)
596 H H CH₂COOH 3-Cl 5-Cl 1-AI-Pip(4)
597 H H CH₂COOH 3-Me 5-Me 1-AI-Pip(4)
598 H H CH₂COOH 3-Cl 5-CONH₂ 1-AI-Pip(4)
599 H H CH₂COOH 2-Me 5-CONH₂ 1-AI-Pip(4)
600 H H CH₂COOH 3-Me 5-CONH₂ 1-AI-Pip(4)
601 H H CH₂COOH 3-CONH₂ 5-CONH₂ 1-AI-Pip(4)
602 6-OH H CH₂COOH H H 1-AI-Pip(4)
603 6-OH H CH₂COOH 2-F H 1-AI-Pip(4)
604 6-OH H CH₂COOH 3-F H 1-AI-Pip(4)
605 6-OH H CH₂COOH 2-Cl H 1-AI-Pip(4)
606 6-OH H CH₂COOH 3-Cl H 1-AI-Pip(4)
607 6-OH H CH₂COOH 2-Br H 1-AI-Pip(4)
608 6-OH H CH₂COOH 3-Br H 1-AI-Pip(4)
609 6-OH H CH₂COOH 2-I H 1-AI-Pip(4)
610 6-OH H CH₂COOH 3-I H 1-AI-Pip(4)
611 6-OH H CH₂COOH 2-Me H 1-AI-Pip(4)
612 6-OH H CH₂COOH 3-Me H 1-AI-Pip(4)
613 6-OH H CH₂COOH 2-Et H 1-AI-Pip(4)
614 6-OH H CH₂COOH 3-Et H 1-AI-Pip(4)
615 6-OH H CH₂COOH 2-Pr H 1-AI-Pip(4)
616 6-OH H CH₂COOH 3-Pr H 1-AI-Pip(4)
617 6-OH H CH₂COOH 2-Bu H 1-AI-Pip(4)
618 6-OH H CH₂COOH 3-Bu H 1-AI-Pip(4)
619 6-OH H CH₂COOH 2-Pn H 1-AI-Pip(4)
620 6-OH H CH₂COOH 3-Pn H 1-AI-Pip(4)
621 6-OH H CH₂COOH 2-Hx H 1-AI-Pip(4)
622 6-OH H CH₂COOH 3-Hx H 1-AI-Pip(4)
623 6-OH H CH₂COOH 2-CF₃ H 1-AI-Pip(4)
624 6-OH H CH₂COOH 3-CF₃ H 1-AI-Pip(4)
625 6-OH H CH₂COOH 2-OMe H 1-AI-Pip(4)
626 6-OH H CH₂COOH 3-OMe H 1-AI-Pip(4)
627 6-OH H CH₂COOH 2-OEt H 1-AI-Pip(4)
628 6-OH H CH₂COOH 3-OEt H 1-AI-Pip(4)
629 6-OH H CH₂COOH 2-COOH H 1-AI-Pip(4)
630 6-OH H CH₂COOH 3-COOH H 1-AI-Pip(4)
631 6-OH H CH₂COOH 2-COOMe H 1-AI-Pip(4)
632 6-OH H CH₂COOH 3-COOMe H 1-AI-Pip(4)
633 6-OH H CH₂COOH 2-COOEt H 1-AI-Pip(4)
634 6-OH H CH₂COOH 3-COOEt H 1-AI-Pip(4)
635 6-OH H CH₂COOH 2-COOPr H 1-AI-Pip(4)
636 6-OH H CH₂COOH 3-COOPr H 1-AI-Pip(4)
637 6-OH H CH₂COOH 2-COOBu H 1-AI-Pip(4)
638 6-OH H CH₂COOH 3-COOBu H 1-AI-Pip(4)
639 6-OH H CH₂COOH 2-COOPn H 1-AI-Pip(4)
640 6-OH H CH₂COOH 3-COOPn H 1-AI-Pip(4)
641 6-OH H CH₂COOH 2-COOHx H 1-AI-Pip(4)
642 6-OH H CH₂COOH 3-COOHx H 1-AI-Pip(4)
643 6-OH H CH₂COOH 2-CONH₂ H 1-AI-Pip(4)
644 6-OH H CH₂COOH 3-CONH₂ H 1-AI-Pip(4)
645 6-OH H CH₂COOH 2-CONHMe H 1-AI-Pip(4)
646 6-OH H CH₂COOH 3-CONHMe H 1-AI-Pip(4)
647 6-OH H CH₂COOH 2-CONHEt H 1-AI-Pip(4)
648 6-OH H CH₂COOH 3-CONHEt H 1-AI-Pip(4)
649 6-OH H CH₂COOH 2-CON(Me)₂ H 1-AI-Pip(4)
650 6-OH H CH₂COOH 3-CON(Me)₂ H 1-AI-Pip(4)
651 6-OH H CH₂COOH 2-CON(Me)Et H 1-AI-Pip(4)
652 6-OH H CH₂COOH 3-CON(Me)Et H 1-AI-Pip(4)
653 6-OH H CH₂COOH 2-CON(Et)₂ H 1-AI-Pip(4)
654 6-OH H CH₂COOH 3-CON(Et)₂ H 1-AI-Pip(4)
655 6-OH H CH₂COOH 3-F 5-F 1-AI-Pip(4)
656 6-OH H CH₂COOH 3-Cl 5-Cl 1-AI-Pip(4)
657 6-OH H CH₂COOH 3-Me 5-Me 1-AI-Pip(4)
658 6-OH H CH₂COOH 3-Cl 5-CONH₂ 1-AI-Pip(4)
659 6-OH H CH₂COOH 2-Me 5-CONH₂ 1-AI-Pip(4)
660 6-OH H CH₂COOH 3-Me 5-CONH₂ 1-AI-Pip(4)
661 6-OH H CH₂COOH 3-CONH₂ 5-CONH₂ 1-AI-Pip(4)
662 H H (CH₂)₂COOH H H 1-AI-Pip(4)
663 H H (CH₂)₃COOH H H 1-AI-Pip(4)
664 H H (CH₂)₄COOH H H 1-AI-Pip(4)
665 H H (CH₂)₅COOH H H 1-AI-Pip(4)
666 H H (CH₂)₆COOH H H 1-AI-Pip(4)
667 H H CH₂COOMe H H 1-AI-Pip(4)
668 H H CH₂COOEt H H 1-AI-Pip(4)
669 H H CH₂COOEt 2-F H 1-AI-Pip(4)
670 H H CH₂COOEt 3-F H 1-AI-Pip(4)
671 H H CH₂COOEt 2-Cl H 1-AI-Pip(4)
672 H H CH₂COOEt 3-Cl H 1-AI-Pip(4)
673 H H CH₂COOEt 2-Br H 1-AI-Pip(4)
674 H H CH₂COOEt 3-Br H 1-AI-Pip(4)
675 H H CH₂COOEt 2-I H 1-AI-Pip(4)
676 H H CH₂COOEt 3-I H 1-AI-Pip(4)
677 H H CH₂COOEt 2-Me H 1-AI-Pip(4)
678 H H CH₂COOEt 3-Me H 1-AI-Pip(4)
679 H H CH₂COOEt 2-Et H 1-AI-Pip(4)
680 H H CH₂COOEt 3-Et H 1-AI-Pip(4)
681 H H CH₂COOEt 2-Pr H 1-AI-Pip(4)
682 H H CH₂COOEt 3-Pr H 1-AI-Pip(4)
683 H H CH₂COOEt 2-Bu H 1-AI-Pip(4)
684 H H CH₂COOEt 3-Bu H 1-AI-Pip(4)
685 H H CH₂COOEt 2-Pn H 1-AI-Pip(4)
686 H H CH₂COOEt 3-Pn H 1-AI-Pip(4)
687 H H CH₂COOEt 2-Hx H 1-AI-Pip(4)
688 H H CH₂COOEt 3-Hx H 1-AI-Pip(4)
689 H H CH₂COOEt 2-CF₃ H 1-AI-Pip(4)
690 H H CH₂COOEt 3-CF₃ H 1-AI-Pip(4)
691 H H CH₂COOEt 2-OMe H 1-AI-Pip(4)
692 H H CH₂COOEt 3-OMe H 1-AI-Pip(4)
693 H H CH₂COOEt 2-OEt H 1-AI-Pip(4)
694 H H CH₂COOEt 3-OEt H 1-AI-Pip(4)
695 H H CH₂COOEt 2-COOH H 1-AI-Pip(4)
696 H H CH₂COOEt 3-COOH H 1-AI-Pip(4)
697 H H CH₂COOEt 2-COOMe H 1-AI-Pip(4)
698 H H CH₂COOEt 3-COOMe H 1-AI-Pip(4)
699 H H CH₂COOEt 2-COOEt H 1-AI-Pip(4)
700 H H CH₂COOEt 3-COOEt H 1-AI-Pip(4)
701 H H CH₂COOEt 2-COOPr H 1-AI-Pip(4)
702 H H CH₂COOEt 3-COOPr H 1-AI-Pip(4)
703 H H CH₂COOEt 2-COOBu H 1-AI-Pip(4)
704 H H CH₂COOEt 3-COOBu H 1-AI-Pip(4)
705 H H CH₂COOEt 2-COOPn H 1-AI-Pip(4)
706 H H CH₂COOEt 3-COOPn H 1-AI-Pip(4)
707 H H CH₂COOEt 2-COOHx H 1-AI-Pip(4)
708 H H CH₂COOEt 3-COOHx H 1-AI-Pip(4)
709 H H CH₂COOEt 2-CONH₂ H 1-AI-Pip(4)
710 H H CH₂COOEt 3-CONH₂ H 1-AI-Pip(4)
711 H H CH₂COOEt 2-CONHMe H 1-AI-Pip(4)
712 H H CH₂COOEt 3-CONHMe H 1-AI-Pip(4)
713 H H CH₂COOEt 2-CONHEt H 1-AI-Pip(4)
714 H H CH₂COOEt 3-CONHEt H 1-AI-Pip(4)
715 H H CH₂COOEt 2-CON(Me)₂ H 1-AI-Pip(4)
716 H H CH₂COOEt 3-CON(Me)₂ H 1-AI-Pip(4)
717 H H CH₂COOEt 2-CON(Me)Et H 1-AI-Pip(4)
718 H H CH₂COOEt 3-CON(Me)Et H 1-AI-Pip(4)
719 H H CH₂COOEt 2-CON(Et)₂ H 1-AI-Pip(4)
720 H H CH₂COOEt 3-CON(Et)₂ H 1-AI-Pip(4)
721 H H CH₂COOEt 3-F 5-F 1-AI-Pip(4)
722 H H CH₂COOEt 3-Cl 5-Cl 1-AI-Pip(4)
723 H H CH₂COOEt 3-Me 5-Me 1-AI-Pip(4)
724 H H CH₂COOEt 3-Cl 5-CONH₂ 1-AI-Pip(4)
725 H H CH₂COOEt 2-Me 5-CONH₂ 1-AI-Pip(4)
726 H H CH₂COOEt 3-Me 5-CONH₂ 1-AI-Pip(4)
727 H H CH₂COOEt 3-CONH₂ 5-CONH₂ 1-AI-Pip(4)
728 6-OH H CH₂COOEt H H 1-AI-Pip(4)
729 6-OH H CH₂COOEt 2-F H 1-AI-Pip(4)
730 6-OH H CH₂COOEt 3-F H 1-AI-Pip(4)
731 6-OH H CH₂COOEt 2-Cl H 1-AI-Pip(4)
732 6-OH H CH₂COOEt 3-Cl H 1-AI-Pip(4)
733 6-OH H CH₂COOEt 2-Br H 1-AI-Pip(4)
734 6-OH H CH₂COOEt 3-Br H 1-AI-Pip(4)
735 6-OH H CH₂COOEt 2-I H 1-AI-Pip(4)
736 6-OH H CH₂COOEt 3-I H 1-AI-Pip(4)
737 6-OH H CH₂COOEt 2-Me H 1-AI-Pip(4)
738 6-OH H CH₂COOEt 3-Me H 1-AI-Pip(4)
739 6-OH H CH₂COOEt 2-Et H 1-AI-Pip(4)
740 6-OH H CH₂COOEt 3-Et H 1-AI-Pip(4)
741 6-OH H CH₂COOEt 2-Pr H 1-AI-Pip(4)
742 6-OH H CH₂COOEt 3-Pr H 1-AI-Pip(4)
743 6-OH H CH₂COOEt 2-Bu H 1-AI-Pip(4)
744 6-OH H CH₂COOEt 3-Bu H 1-AI-Pip(4)
745 6-OH H CH₂COOEt 2-Pn H 1-AI-Pip(4)
746 6-OH H CH₂COOEt 3-Pn H 1-AI-Pip(4)
747 6-OH H CH₂COOEt 2-Hx H 1-AI-Pip(4)
748 6-OH H CH₂COOEt 3-Hx H 1-AI-Pip(4)
749 6-OH H CH₂COOEt 2-CF₃ H 1-AI-Pip(4)
750 6-OH H CH₂COOEt 3-CF₃ H 1-AI-Pip(4)
751 6-OH H CH₂COOEt 2-OMe H 1-AI-Pip(4)
752 6-OH H CH₂COOEt 3-OMe H 1-AI-Pip(4)
753 6-OH H CH₂COOEt 2-OEt H 1-AI-Pip(4)
754 6-OH H CH₂COOEt 3-OEt H 1-AI-Pip(4)
755 6-OH H CH₂COOEt 2-COOH H 1-AI-Pip(4)
756 6-OH H CH₂COOEt 3-COOH H 1-AI-Pip(4)
757 6-OH H CH₂COOEt 2-COOMe H 1-AI-Pip(4)
758 6-OH H CH₂COOEt 3-COOMe H 1-AI-Pip(4)
759 6-OH H CH₂COOEt 2-COOEt H 1-AI-Pip(4)
760 6-OH H CH₂COOEt 3-COOEt H 1-AI-Pip(4)
761 6-OH H CH₂COOEt 2-COOPr H 1-AI-Pip(4)
762 6-OH H CH₂COOEt 3-COOPr H 1-AI-Pip(4)
763 6-OH H CH₂COOEt 2-COOBu H 1-AI-Pip(4)
764 6-OH H CH₂COOEt 3-COOBu H 1-AI-Pip(4)
765 6-OH H CH₂COOEt 2-COOPn H 1-AI-Pip(4)
766 6-OH H CH₂COOEt 3-COOPn H 1-AI-Pip(4)
767 6-OH H CH₂COOEt 2-COOHx H 1-AI-Pip(4)
768 6-OH H CH₂COOEt 3-COOHx H 1-AI-Pip(4)
769 6-OH H CH₂COOEt 2-CONH₂ H 1-AI-Pip(4)
770 6-OH H CH₂COOEt 3-CONH₂ H 1-AI-Pip(4)
771 6-OH H CH₂COOEt 2-CONHMe H 1-AI-Pip(4)
772 6-OH H CH₂COOEt 3-CONHMe H 1-AI-Pip(4)
773 6-OH H CH₂COOEt 2-CONHEt H 1-AI-Pip(4)
774 6-OH H CH₂COOEt 3-CONHEt H 1-AI-Pip(4)
775 6-OH H CH₂COOEt 2-CON(Me)₂ H 1-AI-Pip(4)
776 6-OH H CH₂COOEt 3-CON(Me)₂ H 1-AI-Pip(4)
777 6-OH H CH₂COOEt 2-CON(Me)Et H 1-AI-Pip(4)
778 6-OH H CH₂COOEt 3-CON(Me)Et H 1-AI-Pip(4)
779 6-OH H CH₂COOEt 2-CON(Et)₂ H 1-AI-Pip(4)
780 6-OH H CH₂COOEt 3-CON(Et)₂ H 1-AI-Pip(4)
781 6-OH H CH₂COOEt 3-F 5-F 1-AI-Pip(4)
782 6-OH H CH₂COOEt 3-Cl 5-Cl 1-AI-Pip(4)
783 6-OH H CH₂COOEt 3-Me 5-Me 1-AI-Pip(4)
784 6-OH H CH₂COOEt 3-Cl 5-CONH₂ 1-AI-Pip(4)
785 6-OH H CH₂COOEt 2-Me 5-CONH₂ 1-AI-Pip(4)
786 6-OH H CH₂COOEt 3-Me 5-CONH₂ 1-AI-Pip(4)
787 6-OH H CH₂COOEt 3-CONH₂ 5-CONH₂ 1-AI-Pip(4)
788 H H CH(CH₃)COOEt H H 1-AI-Pip(4)
789 H H CH(CH₃)COOEt 2-F H 1-AI-Pip(4)
790 H H CH(CH₃)COOEt 3-F H 1-AI-Pip(4)
791 H H CH(CH₃)COOEt 2-Cl H 1-AI-Pip(4)
792 H H CH(CH₃)COOEt 3-Cl H 1-AI-Pip(4)
793 H H CH(CH₃)COOEt 2-Br H 1-AI-Pip(4)
794 H H CH(CH₃)COOEt 3-Br H 1-AI-Pip(4)
795 H H CH(CH₃)COOEt 2-I H 1-AI-Pip(4)
796 H H CH(CH₃)COOEt 3-I H 1-AI-Pip(4)
797 H H CH(CH₃)COOEt 2-Me H 1-AI-Pip(4)
798 H H CH(CH₃)COOEt 3-Me H 1-AI-Pip(4)
799 H H CH(CH₃)COOEt 2-Et H 1-AI-Pip(4)
800 H H CH(CH₃)COOEt 3-Et H 1-AI-Pip(4)
801 H H CH(CH₃)COOEt 2-Pr H 1-AI-Pip(4)
802 H H CH(CH₃)COOEt 3-Pr H 1-AI-Pip(4)
803 H H CH(CH₃)COOEt 2-Bu H 1-AI-Pip(4)
804 H H CH(CH₃)COOEt 3-Bu H 1-AI-Pip(4)
805 H H CH(CH₃)COOEt 2-Pn H 1-AI-Pip(4)
806 H H CH(CH₃)COOEt 3-Pn H 1-AI-Pip(4)
807 H H CH(CH₃)COOEt 2-Hx H 1-AI-Pip(4)
808 H H CH(CH₃)COOEt 3-Hx H 1-AI-Pip(4)
809 H H CH(CH₃)COOEt 2-CF₃ H 1-AI-Pip(4)
810 H H CH(CH₃)COOEt 3-CF₃ H 1-AI-Pip(4)
811 H H CH(CH₃)COOEt 2-OMe H 1-AI-Pip(4)
812 H H CH(CH₃)COOEt 3-OMe H 1-AI-Pip(4)
813 H H CH(CH₃)COOEt 2-OEt H 1-AI-Pip(4)
814 H H CH(CH₃)COOEt 3-OEt H 1-AI-Pip(4)
815 H H CH(CH₃)COOEt 2-COOH H 1-AI-Pip(4)
816 H H CH(CH₃)COOEt 3-COOH H 1-AI-Pip(4)
817 H H CH(CH₃)COOEt 2-COOMe H 1-AI-Pip(4)
818 H H CH(CH₃)COOEt 3-COOMe H 1-AI-Pip(4)
819 H H CH(CH₃)COOEt 2-COOEt H 1-AI-Pip(4)
820 H H CH(CH₃)COOEt 3-COOEt H 1-AI-Pip(4)
821 H H CH(CH₃)COOEt 2-COOPr H 1-AI-Pip(4)
822 H H CH(CH₃)COOEt 3-COOPr H 1-AI-Pip(4)
823 H H CH(CH₃)COOEt 2-COOBu H 1-AI-Pip(4)
824 H H CH(CH₃)COOEt 3-COOBu H 1-AI-Pip(4)
825 H H CH(CH₃)COOEt 2-COOPn H 1-AI-Pip(4)
826 H H CH(CH₃)COOEt 3-COOPn H 1-AI-Pip(4)
827 H H CH(CH₃)COOEt 2-COOHx H 1-AI-Pip(4)
828 H H CH(CH₃)COOEt 3-COOHx H 1-AI-Pip(4)
829 H H CH(CH₃)COOEt 2-CONH₂ H 1-AI-Pip(4)
830 H H CH(CH₃)COOEt 3-CONH₂ H 1-AI-Pip(4)
831 H H CH(CH₃)COOEt 2-CONHMe H 1-AI-Pip(4)
832 H H CH(CH₃)COOEt 3-CONHMe H 1-AI-Pip(4)
833 H H CH(CH₃)COOEt 2-CONHEt H 1-AI-Pip(4)
834 H H CH(CH₃)COOEt 3-CONHEt H 1-AI-Pip(4)
835 H H CH(CH₃)COOEt 2-CON(Me)₂ H 1-AI-Pip(4)
836 H H CH(CH₃)COOEt 3-CON(Me)₂ H 1-AI-Pip(4)
837 H H CH(CH₃)COOEt 2-CON(Me)Et H 1-AI-Pip(4)
838 H H CH(CH₃)COOEt 3-CON(Me)Et H 1-AI-Pip(4)
839 H H CH(CH₃)COOEt 2-CON(Et)₂ H 1-AI-Pip(4)
840 H H CH(CH₃)COOEt 3-CON(Et)₂ H 1-AI-Pip(4)
841 H H CH(CH₃)COOEt 3-F 5-F 1-AI-Pip(4)
842 H H CH(CH₃)COOEt 3-Cl 5-Cl 1-AI-Pip(4)
843 H H CH(CH₃)COOEt 3-Me 5-Me 1-AI-Pip(4)
844 H H CH(CH₃)COOEt 3-Cl 5-CONH₂ 1-AI-Pip(4)
845 H H CH(CH₃)COOEt 2-Me 5-CONH₂ 1-AI-Pip(4)
846 H H CH(CH₃)COOEt 3-Me 5-CONH₂ 1-AI-Pip(4)
847 H H CH(CH₃)COOEt 3-CONH₂ 5-CONH₂ 1-AI-Pip(4)
848 H H (CH₂)₂COOEt H H 1-AI-Pip(4)
849 H H (CH₂)₃COOEt H H 1-AI-Pip(4)
850 H H (CH₂)₄COOEt H H 1-AI-Pip(4)
851 H H (CH₂)₅COOEt H H 1-AI-Pip(4)
852 H H (CH₂)₆COOEt H H 1-AI-Pip(4)
853 H H CH₂COCH₂COOMe H H 1-AI-Pip(4)
854 H H CH₂COCH₂COOEt H H 1-AI-Pip(4)
855 H H CH₂COCH₂COOPr H H 1-AI-Pip(4)
856 H H CH₂COCH₂COOBu H H 1-AI-Pip(4)
857 H H CH₂COCH₂COOPn H H 1-AI-Pip(4)
858 H H CH₂COCH₂COOHx H H 1-AI-Pip(4)
859 H H (CH₂)₂COCH₂COOEt H H 1-AI-Pip(4)
860 H H (CH₂)₃COCH₂COOEt H H 1-AI-Pip(4)
861 H H (CH₂)₄COCH₂COOEt H H 1-AI-Pip(4)
862 H H (CH₂)₅COCH₂COOEt H H 1-AI-Pip(4)
863 H H (CH₂)₆COCH₂COOEt H H 1-AI-Pip(4)
864 H H Bn H H 1-AI-Pip(4)
865 H H Bn 2-F H 1-AI-Pip(4)
866 H H Bn 3-F H 1-AI-Pip(4)
867 H H Bn 2-Cl H 1-AI-Pip(4)
868 H H Bn 3-Cl H 1-AI-Pip(4)
869 H H Bn 2-Br H 1-AI-Pip(4)
870 H H Bn 3-Br H 1-AI-Pip(4)
871 H H Bn 2-I H 1-AI-Pip(4)
872 H H Bn 3-I H 1-AI-Pip(4)
873 H H Bn 2-Me H 1-AI-Pip(4)
874 H H Bn 3-Me H 1-AI-Pip(4)
875 H H Bn 2-Et H 1-AI-Pip(4)
876 H H Bn 3-Et H 1-AI-Pip(4)
877 H H Bn 2-Pr H 1-AI-Pip(4)
878 H H Bn 3-Pr H 1-AI-Pip(4)
879 H H Bn 2-Bu H 1-AI-Pip(4)
880 H H Bn 3-Bu H 1-AI-Pip(4)
881 H H Bn 2-Pn H 1-AI-Pip(4)
882 H H Bn 3-Pn H 1-AI-Pip(4)
883 H H Bn 2-Hx H 1-AI-Pip(4)
884 H H Bn 3-Hx H 1-AI-Pip(4)
885 H H Bn 2-CF₃ H 1-AI-Pip(4)
886 H H Bn 3-CF₃ H 1-AI-Pip(4)
887 H H Bn 2-OMe H 1-AI-Pip(4)
888 H H Bn 3-OMe H 1-AI-Pip(4)
889 H H Bn 2-OEt H 1-AI-Pip(4)
890 H H Bn 3-OEt H 1-AI-Pip(4)
891 H H Bn 2-COOH H 1-AI-Pip(4)
892 H H Bn 3-COOH H 1-AI-Pip(4)
893 H H Bn 2-COOMe H 1-AI-Pip(4)
894 H H Bn 3-COOMe H 1-AI-Pip(4)
895 H H Bn 2-COOEt H 1-AI-Pip(4)
896 H H Bn 3-COOEt H 1-AI-Pip(4)
897 H H Bn 2-COOPr H 1-AI-Pip(4)
898 H H Bn 3-COOPr H 1-AI-Pip(4)
899 H H Bn 2-COOBu H 1-AI-Pip(4)
900 H H Bn 3-COOBu H 1-AI-Pip(4)
901 H H Bn 2-COOPn H 1-AI-Pip(4)
902 H H Bn 3-COOPn H 1-AI-Pip(4)
903 H H Bn 2-COOHx H 1-AI-Pip(4)
904 H H Bn 3-COOHx H 1-AI-Pip(4)
905 H H Bn 2-CONH₂ H 1-AI-Pip(4)
906 H H Bn 3-CONH₂ H 1-AI-Pip(4)
907 H H Bn 2-CONHMe H 1-AI-Pip(4)
908 H H Bn 3-CONHMe H 1-AI-Pip(4)
909 H H Bn 2-CONHEt H 1-AI-Pip(4)
910 H H Bn 3-CONHEt H 1-AI-Pip(4)
911 H H Bn 2-CON(Me)₂ H 1-AI-Pip(4)
912 H H Bn 3-CON(Me)₂ H 1-AI-Pip(4)
913 H H Bn 2-CON(Me)Et H 1-AI-Pip(4)
914 H H Bn 3-CON(Me)Et H 1-AI-Pip(4)
915 H H Bn 2-CON(Et)₂ H 1-AI-Pip(4)
916 H H Bn 3-CON(Et)₂ H 1-AI-Pip(4)
917 H H Bn 3-F 5-F 1-AI-Pip(4)
918 H H Bn 3-Cl 5-Cl 1-AI-Pip(4)
919 H H Bn 3-Me 5-Me 1-AI-Pip(4)
920 H H Bn 3-Cl 5-CONH₂ 1-AI-Pip(4)
921 H H Bn 2-Me 5-CONH₂ 1-AI-Pip(4)
922 H H Bn 3-Me 5-CONH₂ 1-AI-Pip(4)
923 H H Bn 3-CONH₂ 5-CONH₂ 1-AI-Pip(4)
924 H H CH₂Np(1) H H 1-AI-Pip(4)
925 6-OH H CH₂Np(1) H H 1-AI-Pip(4)
926 H H CH₂Np(2) H H 1-AI-Pip(4)
927 6-OH H CH₂Np(2) H H 1-AI-Pip(4)
928 H H (CH₂)₂Ph H H 1-AI-Pip(4)
929 6-OH H (CH₂)₂Ph H H 1-AI-Pip(4)
930 H H (CH₂)₂Np(1) H H 1-AI-Pip(4)
931 6-OH H (CH₂)₂Np(1) H H 1-AI-Pip(4)
932 H H (CH₂)₂Np(2) H H 1-AI-Pip(4)
933 6-OH H (CH₂)₂Np(2) H H 1-AI-Pip(4)
934 H H (CH₂)₃Ph H H 1-AI-Pip(4)
935 6-OH H (CH₂)₃Ph H H 1-AI-Pip(4)
936 H H (CH₂)₃Np(1) H H 1-AI-Pip(4)
937 6-OH H (CH₂)₃Np(1) H H 1-AI-Pip(4)
938 H H (CH₂)₃Np(2) H H 1-AI-Pip(4)
939 6-OH H (CH₂)₃Np(2) H H 1-AI-Pip(4)
940 H H (CH₂)₄Ph H H 1-AI-Pip(4)
941 6-OH H (CH₂)₄Ph H H 1-AI-Pip(4)
942 H H (CH₂)₅Ph H H 1-AI-Pip(4)
943 6-OH H (CH₂)₅Ph H H 1-AI-Pip(4)
944 H H (CH₂)₆Ph H H 1-AI-Pip(4)
945 6-OH H (CH₂)₆Ph H H 1-AI-Pip(4)
946 H H CHO H H 1-AI-Pip(4)
947 6-OH H CHO H H 1-AI-Pip(4)
948 H H Ac H H 1-AI-Pip(4)
949 H H Ac 2-F H 1-AI-Pip(4)
950 H H Ac 3-F H 1-AI-Pip(4)
951 H H Ac 2-Cl H 1-AI-Pip(4)
952 H H Ac 3-Cl H 1-AI-Pip(4)
953 H H Ac 2-Br H 1-AI-Pip(4)
954 H H Ac 3-Br H 1-AI-Pip(4)
955 H H Ac 2-I H 1-AI-Pip(4)
956 H H Ac 3-I H 1-AI-Pip(4)
957 H H Ac 2-Me H 1-AI-Pip(4)
958 H H Ac 3-Me H 1-AI-Pip(4)
959 H H Ac 2-Et H 1-AI-Pip(4)
960 H H Ac 3-Et H 1-AI-Pip(4)
961 H H Ac 2-Pr H 1-AI-Pip(4)
962 H H Ac 3-Pr H 1-AI-Pip(4)
963 H H Ac 2-Bu H 1-AI-Pip(4)
964 H H Ac 3-Bu H 1-AI-Pip(4)
965 H H Ac 2-Pn H 1-AI-Pip(4)
966 H H Ac 3-Pn H 1-AI-Pip(4)
967 H H Ac 2-Hx H 1-AI-Pip(4)
968 H H Ac 3-Hx H 1-AI-Pip(4)
969 H H Ac 2-CF₃ H 1-AI-Pip(4)
970 H H Ac 3-CF₃ H 1-AI-Pip(4)
971 H H Ac 2-OMe H 1-AI-Pip(4)
972 H H Ac 3-OMe H 1-AI-Pip(4)
973 H H Ac 2-OEt H 1-AI-Pip(4)
974 H H Ac 3-OEt H 1-AI-Pip(4)
975 H H Ac 2-COOH H 1-AI-Pip(4)
976 H H Ac 3-COOH H 1-AI-Pip(4)
977 H H Ac 2-COOMe H 1-AI-Pip(4)
978 H H Ac 3-COOMe H 1-AI-Pip(4)
979 H H Ac 2-COOEt H 1-AI-Pip(4)
980 H H Ac 3-COOEt H 1-AI-Pip(4)
981 H H Ac 2-COOPr H 1-AI-Pip(4)
982 H H Ac 3-COOPr H 1-AI-Pip(4)
983 H H Ac 2-COOBu H 1-AI-Pip(4)
984 H H Ac 3-COOBu H 1-AI-Pip(4)
985 H H Ac 2-COOPn H 1-AI-Pip(4)
986 H H Ac 3-COOPn H 1-AI-Pip(4)
987 H H Ac 2-COOHx H 1-AI-Pip(4)
988 H H Ac 3-COOHx H 1-AI-Pip(4)
989 H H Ac 2-CONH₂ H 1-AI-Pip(4)
990 H H Ac 3-CONH₂ H 1-AI-Pip(4)
991 H H Ac 2-CONHMe H 1-AI-Pip(4)
992 H H Ac 3-CONHMe H 1-AI-Pip(4)
993 H H Ac 2-CONHEt H 1-AI-Pip(4)
994 H H Ac 3-CONHEt H 1-AI-Pip(4)
995 H H Ac 2-CON(Me)₂ H 1-AI-Pip(4)
996 H H Ac 3-CON(Me)₂ H 1-AI-Pip(4)
997 H H Ac 2-CON(Me)Et H 1-AI-Pip(4)
998 H H Ac 3-CON(Me)Et H 1-AI-Pip(4)
999 H H Ac 2-CON(Et)₂ H 1-AI-Pip(4)
1000 H H Ac 3-CON(Et)₂ H 1-AI-Pip(4)
1001 H H Ac 3-F 5-F 1-AI-Pip(4)
1002 H H Ac 3-Cl 5-Cl 1-AI-Pip(4)
1003 H H Ac 3-Me 5-Me 1-AI-Pip(4)
1004 H H Ac 3-Cl 5-CONH₂ 1-AI-Pip(4)
1005 H H Ac 2-Me 5-CONH₂ 1-AI-Pip(4)
1006 H H Ac 3-Me 5-CONH₂ 1-AI-Pip(4)
1007 H H Ac 3-CONH₂ 5-CONH₂ 1-AI-Pip(4)
1008 H H Prn H H 1-AI-Pip(4)
1009 6-OH H Prn H H 1-AI-Pip(4)
1010 H H Byr H H 1-AI-Pip(4)
1011 6-OH H Byr H H 1-AI-Pip(4)
1012 H H Va H H 1-AI-Pip(4)
1013 6-OH H Va H H 1-AI-Pip(4)
1014 H H COCH₂OH H H 1-AI-Pip(4)
1015 H H COCH₂OH 2-F H 1-AI-Pip(4)
1016 H H COCH₂OH 3-F H 1-AI-Pip(4)
1017 H H COCH₂OH 2-Cl H 1-AI-Pip(4)
1018 H H COCH₂OH 3-Cl H 1-AI-Pip(4)
1019 H H COCH₂OH 2-Br H 1-AI-Pip(4)
1020 H H COCH₂OH 3-Br H 1-AI-Pip(4)
1021 H H COCH₂OH 2-I H 1-AI-Pip(4)
1022 H H COCH₂OH 3-I H 1-AI-Pip(4)
1023 H H COCH₂OH 2-Me H 1-AI-Pip(4)
1024 H H COCH₂OH 3-Me H 1-AI-Pip(4)
1025 H H COCH₂OH 2-Et H 1-AI-Pip(4)
1026 H H COCH₂OH 3-Et H 1-AI-Pip(4)
1027 H H COCH₂OH 2-Pr H 1-AI-Pip(4)
1028 H H COCH₂OH 3-Pr H 1-AI-Pip(4)
1029 H H COCH₂OH 2-Bu H 1-AI-Pip(4)
1030 H H COCH₂OH 3-Bu H 1-AI-Pip(4)
1031 H H COCH₂OH 2-Pn H 1-AI-Pip(4)
1032 H H COCH₂OH 3-Pn H 1-AI-Pip(4)
1033 H H COCH₂OH 2-Hx H 1-AI-Pip(4)
1034 H H COCH₂OH 3-Hx H 1-AI-Pip(4)
1035 H H COCH₂OH 2-CF₃ H 1-AI-Pip(4)
1036 H H COCH₂OH 3-CF₃ H 1-AI-Pip(4)
1037 H H COCH₂OH 2-OMe H 1-AI-Pip(4)
1038 H H COCH₂OH 3-OMe H 1-AI-Pip(4)
1039 H H COCH₂OH 2-OEt H 1-AI-Pip(4)
1040 H H COCH₂OH 3-OEt H 1-AI-Pip(4)
1041 H H COCH₂OH 2-COOH H 1-AI-Pip(4)
1042 H H COCH₂OH 3-COOH H 1-AI-Pip(4)
1043 H H COCH₂OH 2-COOMe H 1-AI-Pip(4)
1044 H H COCH₂OH 3-COOMe H 1-AI-Pip(4)
1045 H H COCH₂OH 2-COOEt H 1-AI-Pip(4)
1046 H H COCH₂OH 3-COOEt H 1-AI-Pip(4)
1047 H H COCH₂OH 2-COOPr H 1-AI-Pip(4)
1048 H H COCH₂OH 3-COOPr H 1-AI-Pip(4)
1049 H H COCH₂OH 2-COOBu H 1-AI-Pip(4)
1050 H H COCH₂OH 3-COOBu H 1-AI-Pip(4)
1051 H H COCH₂OH 2-COOPn H 1-AI-Pip(4)
1052 H H COCH₂OH 3-COOPn H 1-AI-Pip(4)
1053 H H COCH₂OH 2-COOHx H 1-AI-Pip(4)
1054 H H COCH₂OH 3-COOHx H 1-AI-Pip(4)
1055 H H COCH₂OH 2-CONH₂ H 1-AI-Pip(4)
1056 H H COCH₂OH 3-CONH₂ H 1-AI-Pip(4)
1057 H H COCH₂OH 2-CONHMe H 1-AI-Pip(4)
1058 H H COCH₂OH 3-CONHMe H 1-AI-Pip(4)
1059 H H COCH₂OH 2-CONHEt H 1-AI-Pip(4)
1060 H H COCH₂OH 3-CONHEt H 1-AI-Pip(4)
1061 H H COCH₂OH 2-CON(Me)₂ H 1-AI-Pip(4)
1062 H H COCH₂OH 3-CON(Me)₂ H 1-AI-Pip(4)
1063 H H COCH₂OH 2-CON(Me)Et H 1-AI-Pip(4)
1064 H H COCH₂OH 3-CON(Me)Et H 1-AI-Pip(4)
1065 H H COCH₂OH 2-CON(Et)₂ H 1-AI-Pip(4)
1066 H H COCH₂OH 3-CON(Et)₂ H 1-AI-Pip(4)
1067 H H COCH₂OH 3-F 5-F 1-AI-Pip(4)
1068 H H COCH₂OH 3-Cl 5-Cl 1-AI-Pip(4)
1069 H H COCH₂OH 3-Me 5-Me 1-AI-Pip(4)
1070 H H COCH₂OH 3-Cl 5-CONH₂ 1-AI-Pip(4)
1071 H H COCH₂OH 2-Me 5-CONH₂ 1-AI-Pip(4)
1072 H H COCH₂OH 3-Me 5-CONH₂ 1-AI-Pip(4)
1073 H H COCH₂OH 3-CONH₂ 5-CONH₂ 1-AI-Pip(4)
1074 H H CO(CH₂)₂OH H H 1-AI-Pip(4)
1075 H H CO(CH₂)₃OH H H 1-AI-Pip(4)
1076 H H CO(CH₂)₄OH H H 1-AI-Pip(4)
1077 H H CO(CH₂)₅OH H H 1-AI-Pip(4)
1078 H H SO₂Me H H 1-AI-Pip(4)
1079 6-OH H SO₂Me H H 1-AI-Pip(4)
1080 H H SO₂Et H H 1-AI-Pip(4)
1081 H H SO₂Et 2-F H 1-AI-Pip(4)
1082 H H SO₂Et 3-F H 1-AI-Pip(4)
1083 H H SO₂Et 2-Cl H 1-AI-Pip(4)
1084 H H SO₂Et 3-Cl H 1-AI-Pip(4)
1085 H H SO₂Et 2-Br H 1-AI-Pip(4)
1086 H H SO₂Et 3-Br H 1-AI-Pip(4)
1087 H H SO₂Et 2-I H 1-AI-Pip(4)
1088 H H SO₂Et 3-I H 1-AI-Pip(4)
1089 H H SO₂Et 2-Me H 1-AI-Pip(4)
1090 H H SO₂Et 3-Me H 1-AI-Pip(4)
1091 H H SO₂Et 2-Et H 1-AI-Pip(4)
1092 H H SO₂Et 3-Et H 1-AI-Pip(4)
1093 H H SO₂Et 2-Pr H 1-AI-Pip(4)
1094 H H SO₂Et 3-Pr H 1-AI-Pip(4)
1095 H H SO₂Et 2-Bu H 1-AI-Pip(4)
1096 H H SO₂Et 3-Bu H 1-AI-Pip(4)
1097 H H SO₂Et 2-Pn H 1-AI-Pip(4)
1098 H H SO₂Et 3-Pn H 1-AI-Pip(4)
1099 H H SO₂Et 2-Hx H 1-AI-Pip(4)
1100 H H SO₂Et 3-Hx H 1-AI-Pip(4)
1101 H H SO₂Et 2-CF₃ H 1-AI-Pip(4)
1102 H H SO₂Et 3-CF₃ H 1-AI-Pip(4)
1103 H H SO₂Et 2-OMe H 1-AI-Pip(4)
1104 H H SO₂Et 3-OMe H 1-AI-Pip(4)
1105 H H SO₂Et 2-OEt H 1-AI-Pip(4)
1106 H H SO₂Et 3-OEt H 1-AI-Pip(4)
1107 H H SO₂Et 2-COOH H 1-AI-Pip(4)
1108 H H SO₂Et 3-COOH H 1-AI-Pip(4)
1109 H H SO₂Et 2-COOMe H 1-AI-Pip(4)
1110 H H SO₂Et 3-COOMe H 1-AI-Pip(4)
1111 H H SO₂Et 2-COOEt H 1-AI-Pip(4)
1112 H H SO₂Et 3-COOEt H 1-AI-Pip(4)
1113 H H SO₂Et 2-COOPr H 1-AI-Pip(4)
1114 H H SO₂Et 3-COOPr H 1-AI-Pip(4)
1115 H H SO₂Et 2-COOBu H 1-AI-Pip(4)
1116 H H SO₂Et 3-COOBu H 1-AI-Pip(4)
1117 H H SO₂Et 2-COOPn H 1-AI-Pip(4)
1118 H H SO₂Et 3-COOPn H 1-AI-Pip(4)
1119 H H SO₂Et 2-COOHx H 1-AI-Pip(4)
1120 H H SO₂Et 3-COOHx H 1-AI-Pip(4)
1121 H H SO₂Et 2-CONH₂ H 1-AI-Pip(4)
1122 H H SO₂Et 3-CONH₂ H 1-AI-Pip(4)
1123 H H SO₂Et 2-CONHMe H 1-AI-Pip(4)
1124 H H SO₂Et 3-CONHMe H 1-AI-Pip(4)
1125 H H SO₂Et 2-CONHEt H 1-AI-Pip(4)
1126 H H SO₂Et 3-CONHEt H 1-AI-Pip(4)
1127 H H SO₂Et 3-CONHPr H 1-AI-Pip(4)
1128 H H SO₂Et 3-CONHBu H 1-AI-Pip(4)
1129 H H SO₂Et 3-CONHPn H 1-AI-Pip(4)
1130 H H SO₂Et 3-CONHHx H 1-AI-Pip(4)
1131 H H SO₂Et 2-CON(Me)₂ H 1-AI-Pip(4)
1132 H H SO₂Et 3-CON(Me)₂ H 1-AI-Pip(4)
1133 H H SO₂Et 2-CON(Me)Et H 1-AI-Pip(4)
1134 H H SO₂Et 3-CON(Me)Et H 1-AI-Pip(4)
1135 H H SO₂Et 2-CON(Et)₂ H 1-AI-Pip(4)
1136 H H SO₂Et 3-CON(Et)₂ H 1-AI-Pip(4)
1137 H H SO₂Et 3-CON(Pr)₂ H 1-AI-Pip(4)
1138 H H SO₂Et 3-CON(Bu)₂ H 1-AI-Pip(4)
1139 H H SO₂Et 3-CON(Pn)₂ H 1-AI-Pip(4)
1140 H H SO₂Et 3-CON(Hx)₂ H 1-AI-Pip(4)
1141 H H SO₂Et 2-F 3-F 1-AI-Pip(4)
1142 H H SO₂Et 2-F 5-F 1-AI-Pip(4)
1143 H H SO₂Et 2-F 6-F 1-AI-Pip(4)
1144 H H SO₂Et 3-F 5-F 1-AI-Pip(4)
1145 H H SO₂Et 2-Cl 3-Cl 1-AI-Pip(4)
1146 H H SO₂Et 2-Cl 5-Cl 1-AI-Pip(4)
1147 H H SO₂Et 2-Cl 6-Cl 1-AI-Pip(4)
1148 H H SO₂Et 3-Cl 5-Cl 1-AI-Pip(4)
1149 H H SO₂Et 2-Me 3-Me 1-AI-Pip(4)
1150 H H SO₂Et 2-Me 5-Me 1-AI-Pip(4)
1151 H H SO₂Et 2-Me 6-Me 1-AI-Pip(4)
1152 H H SO₂Et 3-Me 5-Me 1-AI-Pip(4)
1153 H H SO₂Et 2-Cl 5-CONH₂ 1-AI-Pip(4)
1154 H H SO₂Et 2-Cl 6-CONH₂ 1-AI-Pip(4)
1155 H H SO₂Et 3-Cl 5-CONH₂ 1-AI-Pip(4)
1156 H H SO₂Et 2-Me 5-CONH₂ 1-AI-Pip(4)
1157 H H SO₂Et 3-Me 5-CONH₂ 1-AI-Pip(4)
1158 H H SO₂Et 2-CONH₂ 5-CONH₂ 1-AI-Pip(4)
1159 H H SO₂Et 3-CONH₂ 5-CONH₂ 1-AI-Pip(4)
1160 H F SO₂Et H H 1-AI-Pip(4)
1161 H F SO₂Et 2-F H 1-AI-Pip(4)
1162 H F SO₂Et 3-F H 1-AI-Pip(4)
1163 H F SO₂Et 2-Cl H 1-AI-Pip(4)
1164 H F SO₂Et 3-Cl H 1-AI-Pip(4)
1165 H F SO₂Et 2-Br H 1-AI-Pip(4)
1166 H F SO₂Et 3-Br H 1-AI-Pip(4)
1167 H F SO₂Et 2-I H 1-AI-Pip(4)
1168 H F SO₂Et 3-I H 1-AI-Pip(4)
1169 H F SO₂Et 2-Me H 1-AI-Pip(4)
1170 H F SO₂Et 3-Me H 1-AI-Pip(4)
1171 H F SO₂Et 2-Et H 1-AI-Pip(4)
1172 H F SO₂Et 3-Et H 1-AI-Pip(4)
1173 H F SO₂Et 2-Pr H 1-AI-Pip(4)
1174 H F SO₂Et 3-Pr H 1-AI-Pip(4)
1175 H F SO₂Et 2-Bu H 1-AI-Pip(4)
1176 H F SO₂Et 3-Bu H 1-AI-Pip(4)
1177 H F SO₂Et 2-Pn H 1-AI-Pip(4)
1178 H F SO₂Et 3-Pn H 1-AI-Pip(4)
1179 H F SO₂Et 2-Hx H 1-AI-Pip(4)
1180 H F SO₂Et 3-Hx H 1-AI-Pip(4)
1181 H F SO₂Et 2-CF₃ H 1-AI-Pip(4)
1182 H F SO₂Et 3-CF₃ H 1-AI-Pip(4)
1183 H F SO₂Et 2-OMe H 1-AI-Pip(4)
1184 H F SO₂Et 3-OMe H 1-AI-Pip(4)
1185 H F SO₂Et 2-OEt H 1-AI-Pip(4)
1186 H F SO₂Et 3-OEt H 1-AI-Pip(4)
1187 H F SO₂Et 2-COOH H 1-AI-Pip(4)
1188 H F SO₂Et 3-COOH H 1-AI-Pip(4)
1189 H F SO₂Et 2-COOMe H 1-AI-Pip(4)
1190 H F SO₂Et 3-COOMe H 1-AI-Pip(4)
1191 H F SO₂Et 2-COOEt H 1-AI-Pip(4)
1192 H F SO₂Et 3-COOEt H 1-AI-Pip(4)
1193 H F SO₂Et 2-COOPr H 1-AI-Pip(4)
1194 H F SO₂Et 3-COOPr H 1-AI-Pip(4)
1195 H F SO₂Et 2-COOBu H 1-AI-Pip(4)
1196 H F SO₂Et 3-COOBu H 1-AI-Pip(4)
1197 H F SO₂Et 2-COOPn H 1-AI-Pip(4)
1198 H F SO₂Et 3-COOPn H 1-AI-Pip(4)
1199 H F SO₂Et 2-COOHx H 1-AI-Pip(4)
1200 H F SO₂Et 3-COOHx H 1-AI-Pip(4)
1201 H F SO₂Et 2-CONH₂ H 1-AI-Pip(4)
1202 H F SO₂Et 3-CONH₂ H 1-AI-Pip(4)
1203 H F SO₂Et 2-CONHMe H 1-AI-Pip(4)
1204 H F SO₂Et 3-CONHMe H 1-AI-Pip(4)
1205 H F SO₂Et 2-CONHEt H 1-AI-Pip(4)
1206 H F SO₂Et 3-CONHEt H 1-AI-Pip(4)
1207 H F SO₂Et 2-CON(Me)₂ H 1-AI-Pip(4)
1208 H F SO₂Et 3-CON(Me)₂ H 1-AI-Pip(4)
1209 H F SO₂Et 2-CON(Me)Et H 1-AI-Pip(4)
1210 H F SO₂Et 3-CON(Me)Et H 1-AI-Pip(4)
1211 H F SO₂Et 2-CON(Et)₂ H 1-AI-Pip(4)
1212 H F SO₂Et 3-CON(Et)₂ H 1-AI-Pip(4)
1213 H F SO₂Et 3-F 5-F 1-AI-Pip(4)
1214 H F SO₂Et 3-Cl 5-Cl 1-AI-Pip(4)
1215 H F SO₂Et 3-Me 5-Me 1-AI-Pip(4)
1216 H F SO₂Et 3-Cl 5-CONH₂ 1-AI-Pip(4)
1217 H F SO₂Et 2-Me 5-CONH₂ 1-AI-Pip(4)
1218 H F SO₂Et 3-Me 5-CONH₂ 1-AI-Pip(4)
1219 H F SO₂Et 3-CONH₂ 5-CONH₂ 1-AI-Pip(4)
1220 H Me SO₂Et H H 1-AI-Pip(4)
1221 H Me SO₂Et 2-F H 1-AI-Pip(4)
1222 H Me SO₂Et 3-F H 1-AI-Pip(4)
1223 H Me SO₂Et 2-Cl H 1-AI-Pip(4)
1224 H Me SO₂Et 3-Cl H 1-AI-Pip(4)
1225 H Me SO₂Et 2-Br H 1-AI-Pip(4)
1226 H Me SO₂Et 3-Br H 1-AI-Pip(4)
1227 H Me SO₂Et 2-I H 1-AI-Pip(4)
1228 H Me SO₂Et 3-I H 1-AI-Pip(4)
1229 H Me SO₂Et 2-Me H 1-AI-Pip(4)
1230 H Me SO₂Et 3-Me H 1-AI-Pip(4)
1231 H Me SO₂Et 2-Et H 1-AI-Pip(4)
1232 H Me SO₂Et 3-Et H 1-AI-Pip(4)
1233 H Me SO₂Et 2-Pr H 1-AI-Pip(4)
1234 H Me SO₂Et 3-Pr H 1-AI-Pip(4)
1235 H Me SO₂Et 2-Bu H 1-AI-Pip(4)
1236 H Me SO₂Et 3-Bu H 1-AI-Pip(4)
1237 H Me SO₂Et 2-Pn H 1-AI-Pip(4)
1238 H Me SO₂Et 3-Pn H 1-AI-Pip(4)
1239 H Me SO₂Et 2-Hx H 1-AI-Pip(4)
1240 H Me SO₂Et 3-Hx H 1-AI-Pip(4)
1241 H Me SO₂Et 2-CF₃ H 1-AI-Pip(4)
1242 H Me SO₂Et 3-CF₃ H 1-AI-Pip(4)
1243 H Me SO₂Et 2-OMe H 1-AI-Pip(4)
1244 H Me SO₂Et 3-OMe H 1-AI-Pip(4)
1245 H Me SO₂Et 2-OEt H 1-AI-Pip(4)
1246 H Me SO₂Et 3-OEt H 1-AI-Pip(4)
1247 H Me SO₂Et 2-COOH H 1-AI-Pip(4)
1248 H Me SO₂Et 3-COOH H 1-AI-Pip(4)
1249 H Me SO₂Et 2-COOMe H 1-AI-Pip(4)
1250 H Me SO₂Et 3-COOMe H 1-AI-Pip(4)
1251 H Me SO₂Et 2-COOEt H 1-AI-Pip(4)
1252 H Me SO₂Et 3-COOEt H 1-AI-Pip(4)
1253 H Me SO₂Et 2-COOPr H 1-AI-Pip(4)
1254 H Me SO₂Et 3-COOPr H 1-AI-Pip(4)
1255 H Me SO₂Et 2-COOBu H 1-AI-Pip(4)
1256 H Me SO₂Et 3-COOBu H 1-AI-Pip(4)
1257 H Me SO₂Et 2-COOPn H 1-AI-Pip(4)
1258 H Me SO₂Et 3-COOPn H 1-AI-Pip(4)
1259 H Me SO₂Et 2-COOHx H 1-AI-Pip(4)
1260 H Me SO₂Et 3-COOHx H 1-AI-Pip(4)
1261 H Me SO₂Et 2-CONH₂ H 1-AI-Pip(4)
1262 H Me SO₂Et 3-CONH₂ H 1-AI-Pip(4)
1263 H Me SO₂Et 2-CONHMe H 1-AI-Pip(4)
1264 H Me SO₂Et 3-CONHMe H 1-AI-Pip(4)
1265 H Me SO₂Et 2-CONHEt H 1-AI-Pip(4)
1266 H Me SO₂Et 3-CONHEt H 1-AI-Pip(4)
1267 H Me SO₂Et 2-CON(Me)₂ H 1-AI-Pip(4)
1268 H Me SO₂Et 3-CON(Me)₂ H 1-AI-Pip(4)
1269 H Me SO₂Et 2-CON(Me)Et H 1-AI-Pip(4)
1270 H Me SO₂Et 3-CON(Me)Et H 1-AI-Pip(4)
1271 H Me SO₂Et 2-CON(Et)₂ H 1-AI-Pip(4)
1272 H Me SO₂Et 3-CON(Et)₂ H 1-AI-Pip(4)
1273 H Me SO₂Et 3-F 5-F 1-AI-Pip(4)
1274 H Me SO₂Et 3-Cl 5-Cl 1-AI-Pip(4)
1275 H Me SO₂Et 3-Me 5-Me 1-AI-Pip(4)
1276 H Me SO₂Et 3-Cl 5-CONH₂ 1-AI-Pip(4)
1277 H Me SO₂Et 2-Me 5-CONH₂ 1-AI-Pip(4)
1278 H Me SO₂Et 3-Me 5-CONH₂ 1-AI-Pip(4)
1279 H Me SO₂Et 3-CONH₂ 5-CONH₂ 1-AI-Pip(4)
1280 6-F H SO₂Et H H 1-AI-Pip(4)
1281 6-F H SO₂Et 2-F H 1-AI-Pip(4)
1282 6-F H SO₂Et 3-F H 1-AI-Pip(4)
1283 6-F H SO₂Et 2-Cl H 1-AI-Pip(4)
1284 6-F H SO₂Et 3-Cl H 1-AI-Pip(4)
1285 6-F H SO₂Et 2-Br H 1-AI-Pip(4)
1286 6-F H SO₂Et 3-Br H 1-AI-Pip(4)
1287 6-F H SO₂Et 2-I H 1-AI-Pip(4)
1288 6-F H SO₂Et 3-I H 1-AI-Pip(4)
1289 6-F H SO₂Et 2-Me H 1-AI-Pip(4)
1290 6-F H SO₂Et 3-Me H 1-AI-Pip(4)
1291 6-F H SO₂Et 2-Et H 1-AI-Pip(4)
1292 6-F H SO₂Et 3-Et H 1-AI-Pip(4)
1293 6-F H SO₂Et 2-Pr H 1-AI-Pip(4)
1294 6-F H SO₂Et 3-Pr H 1-AI-Pip(4)
1295 6-F H SO₂Et 2-Bu H 1-AI-Pip(4)
1296 6-F H SO₂Et 3-Bu H 1-AI-Pip(4)
1297 6-F H SO₂Et 2-Pn H 1-AI-Pip(4)
1298 6-F H SO₂Et 3-Pn H 1-AI-Pip(4)
1299 6-F H SO₂Et 2-Hx H 1-AI-Pip(4)
1300 6-F H SO₂Et 3-Hx H 1-AI-Pip(4)
1301 6-F H SO₂Et 2-CF₃ H 1-AI-Pip(4)
1302 6-F H SO₂Et 3-CF₃ H 1-AI-Pip(4)
1303 6-F H SO₂Et 2-OMe H 1-AI-Pip(4)
1304 6-F H SO₂Et 3-OMe H 1-AI-Pip(4)
1305 6-F H SO₂Et 2-OEt H 1-AI-Pip(4)
1306 6-F H SO₂Et 3-OEt H 1-AI-Pip(4)
1307 6-F H SO₂Et 2-COOH H 1-AI-Pip(4)
1308 6-F H SO₂Et 3-COOH H 1-AI-Pip(4)
1309 6-F H SO₂Et 2-COOMe H 1-AI-Pip(4)
1310 6-F H SO₂Et 3-COOMe H 1-AI-Pip(4)
1311 6-F H SO₂Et 2-COOEt H 1-AI-Pip(4)
1312 6-F H SO₂Et 3-COOEt H 1-AI-Pip(4)
1313 6-F H SO₂Et 2-COOPr H 1-AI-Pip(4)
1314 6-F H SO₂Et 3-COOPr H 1-AI-Pip(4)
1315 6-F H SO₂Et 2-COOBu H 1-AI-Pip(4)
1316 6-F H SO₂Et 3-COOBu H 1-AI-Pip(4)
1317 6-F H SO₂Et 2-COOPn H 1-AI-Pip(4)
1318 6-F H SO₂Et 3-COOPn H 1-AI-Pip(4)
1319 6-F H SO₂Et 2-COOHx H 1-AI-Pip(4)
1320 6-F H SO₂Et 3-COOHx H 1-AI-Pip(4)
1321 6-F H SO₂Et 2-CONH₂ H 1-AI-Pip(4)
1322 6-F H SO₂Et 3-CONH₂ H 1-AI-Pip(4)
1323 6-F H SO₂Et 2-CONHMe H 1-AI-Pip(4)
1324 6-F H SO₂Et 3-CONHMe H 1-AI-Pip(4)
1325 6-F H SO₂Et 2-CONHEt H 1-AI-Pip(4)
1326 6-F H SO₂Et 3-CONHEt H 1-AI-Pip(4)
1327 6-F H SO₂Et 2-CON(Me)₂ H 1-AI-Pip(4)
1328 6-F H SO₂Et 3-CON(Me)₂ H 1-AI-Pip(4)
1329 6-F H SO₂Et 2-CON(Me)Et H 1-AI-Pip(4)
1330 6-F H SO₂Et 3-CON(Me)Et H 1-AI-Pip(4)
1331 6-F H SO₂Et 2-CON(Et)₂ H 1-AI-Pip(4)
1332 6-F H SO₂Et 3-CON(Et)₂ H 1-AI-Pip(4)
1333 6-F H SO₂Et 3-F 5-F 1-AI-Pip(4)
1334 6-F H SO₂Et 3-Cl 5-Cl 1-AI-Pip(4)
1335 6-F H SO₂Et 3-Me 5-Me 1-AI-Pip(4)
1336 6-F H SO₂Et 3-Cl 5-CONH₂ 1-AI-Pip(4)
1337 6-F H SO₂Et 2-Me 5-CONH₂ 1-AI-Pip(4)
1338 6-F H SO₂Et 3-Me 5-CONH₂ 1-AI-Pip(4)
1339 6-F H SO₂Et 3-CONH₂ 5-CONH₂ 1-AI-Pip(4)
1340 6-OH H SO₂Et H H 1-AI-Pip(4)
1341 6-OH H SO₂Et 2-F H 1-AI-Pip(4)
1342 6-OH H SO₂Et 3-F H 1-AI-Pip(4)
1343 6-OH H SO₂Et 2-Cl H 1-AI-Pip(4)
1344 6-OH H SO₂Et 3-Cl H 1-AI-Pip(4)
1345 6-OH H SO₂Et 2-Br H 1-AI-Pip(4)
1346 6-OH H SO₂Et 3-Br H 1-AI-Pip(4)
1347 6-OH H SO₂Et 2-I H 1-AI-Pip(4)
1348 6-OH H SO₂Et 3-I H 1-AI-Pip(4)
1349 6-OH H SO₂Et 2-Me H 1-AI-Pip(4)
1350 6-OH H SO₂Et 3-Me H 1-AI-Pip(4)
1351 6-OH H SO₂Et 2-Et H 1-AI-Pip(4)
1352 6-OH H SO₂Et 3-Et H 1-AI-Pip(4)
1353 6-OH H SO₂Et 2-Pr H 1-AI-Pip(4)
1354 6-OH H SO₂Et 3-Pr H 1-AI-Pip(4)
1355 6-OH H SO₂Et 2-Bu H 1-AI-Pip(4)
1356 6-OH H SO₂Et 3-Bu H 1-AI-Pip(4)
1357 6-OH H SO₂Et 2-Pn H 1-AI-Pip(4)
1358 6-OH H SO₂Et 3-Pn H 1-AI-Pip(4)
1359 6-OH H SO₂Et 2-Hx H 1-AI-Pip(4)
1360 6-OH H SO₂Et 3-Hx H 1-AI-Pip(4)
1361 6-OH H SO₂Et 2-CF₃ H 1-AI-Pip(4)
1362 6-OH H SO₂Et 3-CF₃ H 1-AI-Pip(4)
1363 6-OH H SO₂Et 2-OMe H 1-AI-Pip(4)
1364 6-OH H SO₂Et 3-OMe H 1-AI-Pip(4)
1365 6-OH H SO₂Et 2-OEt H 1-AI-Pip(4)
1366 6-OH H SO₂Et 3-OEt H 1-AI-Pip(4)
1367 6-OH H SO₂Et 2-COOH H 1-AI-Pip(4)
1368 6-OH H SO₂Et 3-COOH H 1-AI-Pip(4)
1369 6-OH H SO₂Et 2-COOMe H 1-AI-Pip(4)
1370 6-OH H SO₂Et 3-COOMe H 1-AI-Pip(4)
1371 6-OH H SO₂Et 2-COOEt H 1-AI-Pip(4)
1372 6-OH H SO₂Et 3-COOEt H 1-AI-Pip(4)
1373 6-OH H SO₂Et 2-COOPr H 1-AI-Pip(4)
1374 6-OH H SO₂Et 3-COOPr H 1-AI-Pip(4)
1375 6-OH H SO₂Et 2-COOBu H 1-AI-Pip(4)
1376 6-OH H SO₂Et 3-COOBu H 1-AI-Pip(4)
1377 6-OH H SO₂Et 2-COOPn H 1-AI-Pip(4)
1378 6-OH H SO₂Et 3-COOPn H 1-AI-Pip(4)
1379 6-OH H SO₂Et 2-COOHx H 1-AI-Pip(4)
1380 6-OH H SO₂Et 3-COOHx H 1-AI-Pip(4)
1381 6-OH H SO₂Et 2-CONH₂ H 1-AI-Pip(4)
1382 6-OH H SO₂Et 3-CONH₂ H 1-AI-Pip(4)
1383 6-OH H SO₂Et 2-CONHMe H 1-AI-Pip(4)
1384 6-OH H SO₂Et 3-CONHMe H 1-AI-Pip(4)
1385 6-OH H SO₂Et 2-CONHEt H 1-AI-Pip(4)
1386 6-OH H SO₂Et 3-CONHEt H 1-AI-Pip(4)
1387 6-OH H SO₂Et 2-CON(Me)₂ H 1-AI-Pip(4)
1388 6-OH H SO₂Et 3-CON(Me)₂ H 1-AI-Pip(4)
1389 6-OH H SO₂Et 2-CON(Me)Et H 1-AI-Pip(4)
1390 6-OH H SO₂Et 3-CON(Me)Et H 1-AI-Pip(4)
1391 6-OH H SO₂Et 2-CON(Et)₂ H 1-AI-Pip(4)
1392 6-OH H SO₂Et 3-CON(Et)₂ H 1-AI-Pip(4)
1393 6-OH H SO₂Et 3-F 5-F 1-AI-Pip(4)
1394 6-OH H SO₂Et 3-Cl 5-Cl 1-AI-Pip(4)
1395 6-OH H SO₂Et 3-Me 5-Me 1-AI-Pip(4)
1396 6-OH H SO₂Et 3-Cl 5-CONH₂ 1-AI-Pip(4)
1397 6-OH H SO₂Et 2-Me 5-CONH₂ 1-AI-Pip(4)
1398 6-OH H SO₂Et 3-Me 5-CONH₂ 1-AI-Pip(4)
1399 6-OH H SO₂Et 3-CONH₂ 5-CONH₂ 1-AI-Pip(4)
1400 H H SO₂Pr H H 1-AI-Pip(4)
1401 H H SO₂ iPr H H 1-AI-Pip(4)
1402 H H SO₂Bu H H 1-AI-Pip(4)
1403 H H SO₂ sBu H H 1-AI-Pip(4)
1404 H H SO₂ iBu H H 1-AI-Pip(4)
1405 H H SO₂ tBu H H 1-AI-Pip(4)
1406 H H SO₂Pn H H 1-AI-Pip(4)
1407 H H SO₂Hx H H 1-AI-Pip(4)
1408 H H SO₂CH₂COOMe H H 1-AI-Pip(4)
1409 6-OH H SO₂CH₂COOMe H H 1-AI-Pip(4)
1410 H H SO₂CH₂COOEt H H 1-AI-Pip(4)
1411 H H SO₂CH₂COOEt 2-F H 1-AI-Pip(4)
1412 H H SO₂CH₂COOEt 3-F H 1-AI-Pip(4)
1413 H H SO₂CH₂COOEt 2-Cl H 1-AI-Pip(4)
1414 H H SO₂CH₂COOEt 3-Cl H 1-AI-Pip(4)
1415 H H SO₂CH₂COOEt 2-Br H 1-AI-Pip(4)
1416 H H SO₂CH₂COOEt 3-Br H 1-AI-Pip(4)
1417 H H SO₂CH₂COOEt 2-I H 1-AI-Pip(4)
1418 H H SO₂CH₂COOEt 3-I H 1-AI-Pip(4)
1419 H H SO₂CH₂COOEt 2-Me H 1-AI-Pip(4)
1420 H H SO₂CH₂COOEt 3-Me H 1-AI-Pip(4)
1421 H H SO₂CH₂COOEt 2-Et H 1-AI-Pip(4)
1422 H H SO₂CH₂COOEt 3-Et H 1-AI-Pip(4)
1423 H H SO₂CH₂COOEt 2-Pr H 1-AI-Pip(4)
1424 H H SO₂CH₂COOEt 3-Pr H 1-AI-Pip(4)
1425 H H SO₂CH₂COOEt 2-iPr H 1-AI-Pip(4)
1426 H H SO₂CH₂COOEt 3-iPr H 1-AI-Pip(4)
1427 H H SO₂CH₂COOEt 2-Bu H 1-AI-Pip(4)
1428 H H SO₂CH₂COOEt 3-Bu H 1-AI-Pip(4)
1429 H H SO₂CH₂COOEt 2-iBu H 1-AI-Pip(4)
1430 H H SO₂CH₂COOEt 3-iBu H 1-AI-Pip(4)
1431 H H SO₂CH₂COOEt 2-sBu H 1-AI-Pip(4)
1432 H H SO₂CH₂COOEt 3-sBu H 1-AI-Pip(4)
1433 H H SO₂CH₂COOEt 2-tBu H 1-AI-Pip(4)
1434 H H SO₂CH₂COOEt 3-tBu H 1-AI-Pip(4)
1435 H H SO₂CH₂COOEt 2-Pn H 1-AI-Pip(4)
1436 H H SO₂CH₂COOEt 3-Pn H 1-AI-Pip(4)
1437 H H SO₂CH₂COOEt 2-Hx H 1-AI-Pip(4)
1438 H H SO₂CH₂COOEt 3-Hx H 1-AI-Pip(4)
1439 H H SO₂CH₂COOEt 2-CF₃ H 1-AI-Pip(4)
1440 H H SO₂CH₂COOEt 3-CF₃ H 1-AI-Pip(4)
1441 H H SO₂CH₂COOEt 2-OMe H 1-AI-Pip(4)
1442 H H SO₂CH₂COOEt 3-OMe H 1-AI-Pip(4)
1443 H H SO₂CH₂COOEt 2-OEt H 1-AI-Pip(4)
1444 H H SO₂CH₂COOEt 3-OEt H 1-AI-Pip(4)
1445 H H SO₂CH₂COOEt 2-COOH H 1-AI-Pip(4)
1446 H H SO₂CH₂COOEt 3-COOH H 1-AI-Pip(4)
1447 H H SO₂CH₂COOEt 2-COOMe H 1-AI-Pip(4)
1448 H H SO₂CH₂COOEt 3-COOMe H 1-AI-Pip(4)
1449 H H SO₂CH₂COOEt 2-COOEt H 1-AI-Pip(4)
1450 H H SO₂CH₂COOEt 3-COOEt H 1-AI-Pip(4)
1451 H H SO₂CH₂COOEt 2-COOPr H 1-AI-Pip(4)
1452 H H SO₂CH₂COOEt 3-COOPr H 1-AI-Pip(4)
1453 H H SO₂CH₂COOEt 2-COOBu H 1-AI-Pip(4)
1454 H H SO₂CH₂COOEt 3-COOBu H 1-AI-Pip(4)
1455 H H SO₂CH₂COOEt 2-COOPn H 1-AI-Pip(4)
1456 H H SO₂CH₂COOEt 3-COOPn H 1-AI-Pip(4)
1457 H H SO₂CH₂COOEt 2-COOHx H 1-AI-Pip(4)
1458 H H SO₂CH₂COOEt 3-COOHx H 1-AI-Pip(4)
1459 H H SO₂CH₂COOEt 2-CONH₂ H 1-AI-Pip(4)
1460 H H SO₂CH₂COOEt 3-CONH₂ H 1-AI-Pip(4)
1461 H H SO₂CH₂COOEt 2-CONHMe H 1-AI-Pip(4)
1462 H H SO₂CH₂COOEt 3-CONHMe H 1-AI-Pip(4)
1463 H H SO₂CH₂COOEt 2-CONHEt H 1-AI-Pip(4)
1464 H H SO₂CH₂COOEt 3-CONHEt H 1-AI-Pip(4)
1465 H H SO₂CH₂COOEt 2-CON(Me)₂ H 1-AI-Pip(4)
1466 H H SO₂CH₂COOEt 3-CON(Me)₂ H 1-AI-Pip(4)
1467 H H SO₂CH₂COOEt 2-CON(Me)Et H 1-AI-Pip(4)
1468 H H SO₂CH₂COOEt 3-CON(Me)Et H 1-AI-Pip(4)
1469 H H SO₂CH₂COOEt 2-CON(Et)₂ H 1-AI-Pip(4)
1470 H H SO₂CH₂COOEt 3-CON(Et)₂ H 1-AI-Pip(4)
1471 H H SO₂CH₂COOEt 2-F 3-F 1-AI-Pip(4)
1472 H H SO₂CH₂COOEt 2-F 5-F 1-AI-Pip(4)
1473 H H SO₂CH₂COOEt 2-F 6-F 1-AI-Pip(4)
1474 H H SO₂CH₂COOEt 3-F 5-F 1-AI-Pip(4)
1475 H H SO₂CH₂COOEt 2-Cl 3-Cl 1-AI-Pip(4)
1476 H H SO₂CH₂COOEt 2-Cl 5-Cl 1-AI-Pip(4)
1477 H H SO₂CH₂COOEt 2-Cl 6-Cl 1-AI-Pip(4)
1478 H H SO₂CH₂COOEt 3-Cl 5-Cl 1-AI-Pip(4)
1479 H H SO₂CH₂COOEt 2-Me 3-Me 1-AI-Pip(4)
1480 H H SO₂CH₂COOEt 2-Me 5-Me 1-AI-Pip(4)
1481 H H SO₂CH₂COOEt 2-Me 6-Me 1-AI-Pip(4)
1482 H H SO₂CH₂COOEt 3-Me 5-Me 1-AI-Pip(4)
1483 H H SO₂CH₂COOEt 2-Cl 5-CONH₂ 1-AI-Pip(4)
1484 H H SO₂CH₂COOEt 3-Cl 5-CONH₂ 1-AI-Pip(4)
1485 H H SO₂CH₂COOEt 3-Cl 5-CONHMe 1-AI-Pip(4)
1486 H H SO₂CH₂COOEt 3-Cl 5-CONHEt 1-AI-Pip(4)
1487 H H SO₂CH₂COOEt 3-Cl 5-CONHPr 1-AI-Pip(4)
1488 H H SO₂CH₂COOEt 3-Cl 5-CONHBu 1-AI-Pip(4)
1489 H H SO₂CH₂COOEt 3-Cl 5-CONHPn 1-AI-Pip(4)
1490 H H SO₂CH₂COOEt 3-Cl 5-CONHHx 1-AI-Pip(4)
1491 H H SO₂CH₂COOEt 2-Me 5-CONH₂ 1-AI-Pip(4)
1492 H H SO₂CH₂COOEt 2-Me 5-CONHMe 1-AI-Pip(4)
1493 H H SO₂CH₂COOEt 2-Me 5-CONHEt 1-AI-Pip(4)
1494 H H SO₂CH₂COOEt 2-Me 5-CONHPr 1-AI-Pip(4)
1495 H H SO₂CH₂COOEt 2-Me 5-CONHBu 1-AI-Pip(4)
1496 H H SO₂CH₂COOEt 2-Me 5-CONHPn 1-AI-Pip(4)
1497 H H SO₂CH₂COOEt 2-Me 5-CONHHx 1-AI-Pip(4)
1498 H H SO₂CH₂COOEt 3-Me 5-CONH₂ 1-AI-Pip(4)
1499 H H SO₂CH₂COOEt 3-Me 5-CONHMe 1-AI-Pip(4)
1500 H H SO₂CH₂COOEt 3-Me 5-CONHEt 1-AI-Pip(4)
1501 H H SO₂CH₂COOEt 3-Me 5-CONHPr 1-AI-Pip(4)
1502 H H SO₂CH₂COOEt 3-Me 5-CONHBu 1-AI-Pip(4)
1503 H H SO₂CH₂COOEt 3-Me 5-CONHPn 1-AI-Pip(4)
1504 H H SO₂CH₂COOEt 3-Me 5-CONHHx 1-AI-Pip(4)
1505 H H SO₂CH₂COOEt 2-CONH₂ 6-CONH₂ 1-AI-Pip(4)
1506 H H SO₂CH₂COOEt 3-CONH₂ 5-CONH₂ 1-AI-Pip(4)
1507 H H SO₂CH₂COOEt 3-CONHMe 5-CONHMe 1-AI-Pip(4)
1508 H H SO₂CH₂COOEt 3-CONHEt 5-CONHEt 1-AI-Pip(4)
1509 H F SO₂CH₂COOEt H H 1-AI-Pip(4)
1510 H F SO₂CH₂COOEt 2-F H 1-AI-Pip(4)
1511 H F SO₂CH₂COOEt 3-F H 1-AI-Pip(4)
1512 H F SO₂CH₂COOEt 2-Cl H 1-AI-Pip(4)
1513 H F SO₂CH₂COOEt 3-Cl H 1-AI-Pip(4)
1514 H F SO₂CH₂COOEt 2-Br H 1-AI-Pip(4)
1515 H F SO₂CH₂COOEt 3-Br H 1-AI-Pip(4)
1516 H F SO₂CH₂COOEt 2-I H 1-AI-Pip(4)
1517 H F SO₂CH₂COOEt 3-I H 1-AI-Pip(4)
1518 H F SO₂CH₂COOEt 2-Me H 1-AI-Pip(4)
1519 H F SO₂CH₂COOEt 3-Me H 1-AI-Pip(4)
1520 H F SO₂CH₂COOEt 2-Et H 1-AI-Pip(4)
1521 H F SO₂CH₂COOEt 3-Et H 1-AI-Pip(4)
1522 H F SO₂CH₂COOEt 2-Pr H 1-AI-Pip(4)
1523 H F SO₂CH₂COOEt 3-Pr H 1-AI-Pip(4)
1524 H F SO₂CH₂COOEt 2-iPr H 1-AI-Pip(4)
1525 H F SO₂CH₂COOEt 3-iPr H 1-AI-Pip(4)
1526 H F SO₂CH₂COOEt 2-Bu H 1-AI-Pip(4)
1527 H F SO₂CH₂COOEt 3-Bu H 1-AI-Pip(4)
1528 H F SO₂CH₂COOEt 2-iBu H 1-AI-Pip(4)
1529 H F SO₂CH₂COOEt 3-iBu H 1-AI-Pip(4)
1530 H F SO₂CH₂COOEt 2-sBu H 1-AI-Pip(4)
1531 H F SO₂CH₂COOEt 3-sBu H 1-AI-Pip(4)
1532 H F SO₂CH₂COOEt 2-tBu H 1-AI-Pip(4)
1533 H F SO₂CH₂COOEt 3-tBu H 1-AI-Pip(4)
1534 H F SO₂CH₂COOEt 2-Pn H 1-AI-Pip(4)
1535 H F SO₂CH₂COOEt 3-Pn H 1-AI-Pip(4)
1536 H F SO₂CH₂COOEt 2-Hx H 1-AI-Pip(4)
1537 H F SO₂CH₂COOEt 3-Hx H 1-AI-Pip(4)
1538 H F SO₂CH₂COOEt 2-CF₃ H 1-AI-Pip(4)
1539 H F SO₂CH₂COOEt 3-CF₃ H 1-AI-Pip(4)
1540 H F SO₂CH₂COOEt 2-OMe H 1-AI-Pip(4)
1541 H F SO₂CH₂COOEt 3-OMe H 1-AI-Pip(4)
1542 H F SO₂CH₂COOEt 2-OEt H 1-AI-Pip(4)
1543 H F SO₂CH₂COOEt 3-OEt H 1-AI-Pip(4)
1544 H F SO₂CH₂COOEt 2-COOH H 1-AI-Pip(4)
1545 H F SO₂CH₂COOEt 3-COOH H 1-AI-Pip(4)
1546 H F SO₂CH₂COOEt 2-COOMe H 1-AI-Pip(4)
1547 H F SO₂CH₂COOEt 3-COOMe H 1-AI-Pip(4)
1548 H F SO₂CH₂COOEt 2-COOEt H 1-AI-Pip(4)
1549 H F SO₂CH₂COOEt 3-COOEt H 1-AI-Pip(4)
1550 H F SO₂CH₂COOEt 2-COOPr H 1-AI-Pip(4)
1551 H F SO₂CH₂COOEt 3-COOPr H 1-AI-Pip(4)
1552 H F SO₂CH₂COOEt 2-COOBu H 1-AI-Pip(4)
1553 H F SO₂CH₂COOEt 3-COOBu H 1-AI-Pip(4)
1554 H F SO₂CH₂COOEt 2-COOPn H 1-AI-Pip(4)
1555 H F SO₂CH₂COOEt 3-COOPn H 1-AI-Pip(4)
1556 H F SO₂CH₂COOEt 2-COOHx H 1-AI-Pip(4)
1557 H F SO₂CH₂COOEt 3-COOHx H 1-AI-Pip(4)
1558 H F SO₂CH₂COOEt 2-CONH₂ H 1-AI-Pip(4)
1559 H F SO₂CH₂COOEt 3-CONH₂ H 1-AI-Pip(4)
1560 H F SO₂CH₂COOEt 2-CONHMe H 1-AI-Pip(4)
1561 H F SO₂CH₂COOEt 3-CONHMe H 1-AI-Pip(4)
1562 H F SO₂CH₂COOEt 2-CONHEt H 1-AI-Pip(4)
1563 H F SO₂CH₂COOEt 3-CONHEt H 1-AI-Pip(4)
1564 H F SO₂CH₂COOEt 2-CON(Me)₂ H 1-AI-Pip(4)
1565 H F SO₂CH₂COOEt 3-CON(Me)₂ H 1-AI-Pip(4)
1566 H F SO₂CH₂COOEt 2-CON(Me)Et H 1-AI-Pip(4)
1567 H F SO₂CH₂COOEt 3-CON(Me)Et H 1-AI-Pip(4)
1568 H F SO₂CH₂COOEt 2-CON(Et)₂ H 1-AI-Pip(4)
1569 H F SO₂CH₂COOEt 3-CON(Et)₂ H 1-AI-Pip(4)
1570 H F SO₂CH₂COOEt 3-F 5-F 1-AI-Pip(4)
1571 H F SO₂CH₂COOEt 3-Cl 5-Cl 1-AI-Pip(4)
1572 H F SO₂CH₂COOEt 3-Me 5-Me 1-AI-Pip(4)
1573 H F SO₂CH₂COOEt 3-Cl 5-CONH₂ 1-AI-Pip(4)
1574 H F SO₂CH₂COOEt 2-Me 5-CONH₂ 1-AI-Pip(4)
1575 H F SO₂CH₂COOEt 3-Me 5-CONH₂ 1-AI-Pip(4)
1576 H F SO₂CH₂COOEt 3-CONH₂ 5-CONH₂ 1-AI-Pip(4)
1577 H Me SO₂CH₂COOEt H H 1-AI-Pip(4)
1578 H Me SO₂CH₂COOEt 2-F H 1-AI-Pip(4)
1579 H Me SO₂CH₂COOEt 3-F H 1-AI-Pip(4)
1580 H Me SO₂CH₂COOEt 2-Cl H 1-AI-Pip(4)
1581 H Me SO₂CH₂COOEt 3-Cl H 1-AI-Pip(4)
1582 H Me SO₂CH₂COOEt 2-Br H 1-AI-Pip(4)
1583 H Me SO₂CH₂COOEt 3-Br H 1-AI-Pip(4)
1584 H Me SO₂CH₂COOEt 2-I H 1-AI-Pip(4)
1585 H Me SO₂CH₂COOEt 3-I H 1-AI-Pip(4)
1586 H Me SO₂CH₂COOEt 2-Me H 1-AI-Pip(4)
1587 H Me SO₂CH₂COOEt 3-Me H 1-AI-Pip(4)
1588 H Me SO₂CH₂COOEt 2-Et H 1-AI-Pip(4)
1589 H Me SO₂CH₂COOEt 3-Et H 1-AI-Pip(4)
1590 H Me SO₂CH₂COOEt 2-Pr H 1-AI-Pip(4)
1591 H Me SO₂CH₂COOEt 3-Pr H 1-AI-Pip(4)
1592 H Me SO₂CH₂COOEt 2-Bu H 1-AI-Pip(4)
1593 H Me SO₂CH₂COOEt 3-Bu H 1-AI-Pip(4)
1594 H Me SO₂CH₂COOEt 2-Pn H 1-AI-Pip(4)
1595 H Me SO₂CH₂COOEt 3-Pn H 1-AI-Pip(4)
1596 H Me SO₂CH₂COOEt 2-Hx H 1-AI-Pip(4)
1597 H Me SO₂CH₂COOEt 3-Hx H 1-AI-Pip(4)
1598 H Me SO₂CH₂COOEt 2-CF₃ H 1-AI-Pip(4)
1599 H Me SO₂CH₂COOEt 3-CF₃ H 1-AI-Pip(4)
1600 H Me SO₂CH₂COOEt 2-OMe H 1-AI-Pip(4)
1601 H Me SO₂CH₂COOEt 3-OMe H 1-AI-Pip(4)
1602 H Me SO₂CH₂COOEt 2-OEt H 1-AI-Pip(4)
1603 H Me SO₂CH₂COOEt 3-OEt H 1-AI-Pip(4)
1604 H Me SO₂CH₂COOEt 2-COOH H 1-AI-Pip(4)
1605 H Me SO₂CH₂COOEt 3-COOH H 1-AI-Pip(4)
1606 H Me SO₂CH₂COOEt 2-COOMe H 1-AI-Pip(4)
1607 H Me SO₂CH₂COOEt 3-COOMe H 1-AI-Pip(4)
1608 H Me SO₂CH₂COOEt 2-COOEt H 1-AI-Pip(4)
1609 H Me SO₂CH₂COOEt 3-COOEt H 1-AI-Pip(4)
1610 H Me SO₂CH₂COOEt 2-COOPr H 1-AI-Pip(4)
1611 H Me SO₂CH₂COOEt 3-COOPr H 1-AI-Pip(4)
1612 H Me SO₂CH₂COOEt 2-COOBu H 1-AI-Pip(4)
1613 H Me SO₂CH₂COOEt 3-COOBu H 1-AI-Pip(4)
1614 H Me SO₂CH₂COOEt 2-COOPn H 1-AI-Pip(4)
1615 H Me SO₂CH₂COOEt 3-COOPn H 1-AI-Pip(4)
1616 H Me SO₂CH₂COOEt 2-COOHx H 1-AI-Pip(4)
1617 H Me SO₂CH₂COOEt 3-COOHx H 1-AI-Pip(4)
1618 H Me SO₂CH₂COOEt 2-CONH₂ H 1-AI-Pip(4)
1619 H Me SO₂CH₂COOEt 3-CONH₂ H 1-AI-Pip(4)
1620 H Me SO₂CH₂COOEt 2-CONHMe H 1-AI-Pip(4)
1621 H Me SO₂CH₂COOEt 3-CONHMe H 1-AI-Pip(4)
1622 H Me SO₂CH₂COOEt 2-CONHEt H 1-AI-Pip(4)
1623 H Me SO₂CH₂COOEt 3-CONHEt H 1-AI-Pip(4)
1624 H Me SO₂CH₂COOEt 2-CON(Me)₂ H 1-AI-Pip(4)
1625 H Me SO₂CH₂COOEt 3-CON(Me)₂ H 1-AI-Pip(4)
1626 H Me SO₂CH₂COOEt 2-CON(Me)Et H 1-AI-Pip(4)
1627 H Me SO₂CH₂COOEt 3-CON(Me)Et H 1-AI-Pip(4)
1628 H Me SO₂CH₂COOEt 2-CON(Et)₂ H 1-AI-Pip(4)
1629 H Me SO₂CH₂COOEt 3-CON(Et)₂ H 1-AI-Pip(4)
1630 H Me SO₂CH₂COOEt 3-F 5-F 1-AI-Pip(4)
1631 H Me SO₂CH₂COOEt 3-Cl 5-Cl 1-AI-Pip(4)
1632 H Me SO₂CH₂COOEt 3-Me 5-Me 1-AI-Pip(4)
1633 H Me SO₂CH₂COOEt 3-Cl 5-CONH₂ 1-AI-Pip(4)
1634 H Me SO₂CH₂COOEt 2-Me 5-CONH₂ 1-AI-Pip(4)
1635 H Me SO₂CH₂COOEt 3-Me 5-CONH₂ 1-AI-Pip(4)
1636 H Me SO₂CH₂COOEt 3-CONH₂ 5-CONH₂ 1-AI-Pip(4)
1637 2-F H SO₂CH₂COOEt H H 1-AI-Pip(4)
1638 4-F H SO₂CH₂COOEt H H 1-AI-Pip(4)
1639 4-F H SO₂CH₂COOEt 2-F H 1-AI-Pip(4)
1640 4-F H SO₂CH₂COOEt 3-F H 1-AI-Pip(4)
1641 4-F H SO₂CH₂COOEt 2-Cl H 1-AI-Pip(4)
1642 4-F H SO₂CH₂COOEt 3-Cl H 1-AI-Pip(4)
1643 4-F H SO₂CH₂COOEt 2-Br H 1-AI-Pip(4)
1644 4-F H SO₂CH₂COOEt 3-Br H 1-AI-Pip(4)
1645 4-F H SO₂CH₂COOEt 2-I H 1-AI-Pip(4)
1646 4-F H SO₂CH₂COOEt 3-I H 1-AI-Pip(4)
1647 4-F H SO₂CH₂COOEt 2-Me H 1-AI-Pip(4)
1648 4-F H SO₂CH₂COOEt 3-Me H 1-AI-Pip(4)
1649 4-F H SO₂CH₂COOEt 2-Et H 1-AI-Pip(4)
1650 4-F H SO₂CH₂COOEt 3-Et H 1-AI-Pip(4)
1651 4-F H SO₂CH₂COOEt 2-Pr H 1-AI-Pip(4)
1652 4-F H SO₂CH₂COOEt 3-Pr H 1-AI-Pip(4)
1653 4-F H SO₂CH₂COOEt 2-Bu H 1-AI-Pip(4)
1654 4-F H SO₂CH₂COOEt 3-Bu H 1-AI-Pip(4)
1655 4-F H SO₂CH₂COOEt 2-Pn H 1-AI-Pip(4)
1656 4-F H SO₂CH₂COOEt 3-Pn H 1-AI-Pip(4)
1657 4-F H SO₂CH₂COOEt 2-Hx H 1-AI-Pip(4)
1658 4-F H SO₂CH₂COOEt 3-Hx H 1-AI-Pip(4)
1659 4-F H SO₂CH₂COOEt 2-CF₃ H 1-AI-Pip(4)
1660 4-F H SO₂CH₂COOEt 3-CF₃ H 1-AI-Pip(4)
1661 4-F H SO₂CH₂COOEt 2-OMe H 1-AI-Pip(4)
1662 4-F H SO₂CH₂COOEt 3-OMe H 1-AI-Pip(4)
1663 4-F H SO₂CH₂COOEt 2-OEt H 1-AI-Pip(4)
1664 4-F H SO₂CH₂COOEt 3-OEt H 1-AI-Pip(4)
1665 4-F H SO₂CH₂COOEt 2-COOH H 1-AI-Pip(4)
1666 4-F H SO₂CH₂COOEt 3-COOH H 1-AI-Pip(4)
1667 4-F H SO₂CH₂COOEt 2-COOMe H 1-AI-Pip(4)
1668 4-F H SO₂CH₂COOEt 3-COOMe H 1-AI-Pip(4)
1669 4-F H SO₂CH₂COOEt 2-COOEt H 1-AI-Pip(4)
1670 4-F H SO₂CH₂COOEt 3-COOEt H 1-AI-Pip(4)
1671 4-F H SO₂CH₂COOEt 2-COOPr H 1-AI-Pip(4)
1672 4-F H SO₂CH₂COOEt 3-COOPr H 1-AI-Pip(4)
1673 4-F H SO₂CH₂COOEt 2-COOBu H 1-AI-Pip(4)
1674 4-F H SO₂CH₂COOEt 3-COOBu H 1-AI-Pip(4)
1675 4-F H SO₂CH₂COOEt 2-COOPn H 1-AI-Pip(4)
1676 4-F H SO₂CH₂COOEt 3-COOPn H 1-AI-Pip(4)
1677 4-F H SO₂CH₂COOEt 2-COOHx H 1-AI-Pip(4)
1678 4-F H SO₂CH₂COOEt 3-COOHx H 1-AI-Pip(4)
1679 4-F H SO₂CH₂COOEt 2-CONH₂ H 1-AI-Pip(4)
1680 4-F H SO₂CH₂COOEt 3-CONH₂ H 1-AI-Pip(4)
1681 4-F H SO₂CH₂COOEt 2-CONHMe H 1-AI-Pip(4)
1682 4-F H SO₂CH₂COOEt 3-CONHMe H 1-AI-Pip(4)
1683 4-F H SO₂CH₂COOEt 2-CONHEt H 1-AI-Pip(4)
1684 4-F H SO₂CH₂COOEt 3-CONHEt H 1-AI-Pip(4)
1685 4-F H SO₂CH₂COOEt 2-CON(Me)₂ H 1-AI-Pip(4)
1686 4-F H SO₂CH₂COOEt 3-CON(Me)₂ H 1-AI-Pip(4)
1687 4-F H SO₂CH₂COOEt 2-CON(Me)EtH 1-AI-Pip(4)
1688 4-F H SO₂CH₂COOEt 3-CON(Me)EtH 1-AI-Pip(4)
1689 4-F H SO₂CH₂COOEt 2-CON(Et)₂ H 1-AI-Pip(4)
1690 4-F H SO₂CH₂COOEt 3-CON(Et)₂ H 1-AI-Pip(4)
1691 4-F Me SO₂CH₂COOEt 3-F 5-F 1-AI-Pip(4)
1692 4-F Me SO₂CH₂COOEt 3-Cl 5-Cl 1-AI-Pip(4)
1693 4-F Me SO₂CH₂COOEt 3-Me 5-Me 1-AI-Pip(4)
1694 4-F Me SO₂CH₂COOEt 3-Cl 5-CONH₂ 1-AI-Pip(4)
1695 4-F Me SO₂CH₂COOEt 2-Me 5-CONH₂ 1-AI-Pip(4)
1696 4-F Me SO₂CH₂COOEt 3-Me 5-CONH₂ 1-AI-Pip(4)
1697 4-F Me SO₂CH₂COOEt 3-CONH₂ 5-CONH₂ 1-AI-Pip(4)
1698 5-F H SO₂CH₂COOEt H H 1-AI-Pip(4)
1699 6-F H SO₂CH₂COOEt H H 1-AI-Pip(4)
1700 2-Cl H SO₂CH₂COOEt H H 1-AI-Pip(4)
1701 4-Cl H SO₂CH₂COOEt H H 1-AI-Pip(4)
1702 5-Cl H SO₂CH₂COOEt H H 1-AI-Pip(4)
1703 6-Cl H SO₂CH₂COOEt H H 1-AI-Pip(4)
1704 2-Br H SO₂CH₂COOEt H H 1-AI-Pip(4)
1705 4-Br H SO₂CH₂COOEt H H 1-AI-Pip(4)
1706 5-Br H SO₂CH₂COOEt H H 1-AI-Pip(4)
1707 6-Br H SO₂CH₂COOEt H H 1-AI-Pip(4)
1708 2-Me H SO₂CH₂COOEt H H 1-AI-Pip(4)
1709 3-Me H SO₂CH₂COOEt H H 1-AI-Pip(4)
1710 4-Me H SO₂CH₂COOEt H H 1-AI-Pip(4)
1711 5-Me H SO₂CH₂COOEt H H 1-AI-Pip(4)
1712 5-Me H SO₂CH₂COOEt 2-F H 1-AI-Pip(4)
1713 5-Me H SO₂CH₂COOEt 3-F H 1-AI-Pip(4)
1714 5-Me H SO₂CH₂COOEt 2-Cl H 1-AI-Pip(4)
1715 5-Me H SO₂CH₂COOEt 3-Cl H 1-AI-Pip(4)
1716 5-Me H SO₂CH₂COOEt 2-Br H 1-AI-Pip(4)
1717 5-Me H SO₂CH₂COOEt 3-Br H 1-AI-Pip(4)
1718 5-Me H SO₂CH₂COOEt 2-I H 1-AI-Pip(4)
1719 5-Me H SO₂CH₂COOEt 3-I H 1-AI-Pip(4)
1720 5-Me H SO₂CH₂COOEt 2-Me H 1-AI-Pip(4)
1721 5-Me H SO₂CH₂COOEt 3-Me H 1-AI-Pip(4)
1722 5-Me H SO₂CH₂COOEt 2-Et H 1-AI-Pip(4)
1723 5-Me H SO₂CH₂COOEt 3-Et H 1-AI-Pip(4)
1724 5-Me H SO₂CH₂COOEt 2-Pr H 1-AI-Pip(4)
1725 5-Me H SO₂CH₂COOEt 3-Pr H 1-AI-Pip(4)
1726 5-Me H SO₂CH₂COOEt 2-Bu H 1-AI-Pip(4)
1727 5-Me H SO₂CH₂COOEt 3-Bu H 1-AI-Pip(4)
1728 5-Me H SO₂CH₂COOEt 2-Pn H 1-AI-Pip(4)
1729 5-Me H SO₂CH₂COOEt 3-Pn H 1-AI-Pip(4)
1730 5-Me H SO₂CH₂COOEt 2-Hx H 1-AI-Pip(4)
1731 5-Me H SO₂CH₂COOEt 3-Hx H 1-AI-Pip(4)
1732 5-Me H SO₂CH₂COOEt 2-CF₃ H 1-AI-Pip(4)
1733 5-Me H SO₂CH₂COOEt 3-CF₃ H 1-AI-Pip(4)
1734 5-Me H SO₂CH₂COOEt 2-OMe H 1-AI-Pip(4)
1735 5-Me H SO₂CH₂COOEt 3-OMe H 1-AI-Pip(4)
1736 5-Me H SO₂CH₂COOEt 2-OEt H 1-AI-Pip(4)
1737 5-Me H SO₂CH₂COOEt 3-OEt H 1-AI-Pip(4)
1738 5-Me H SO₂CH₂COOEt 2-COOH H 1-AI-Pip(4)
1739 5-Me H SO₂CH₂COOEt 3-COOH H 1-AI-Pip(4)
1740 5-Me H SO₂CH₂COOEt 2-COOMe H 1-AI-Pip(4)
1741 5-Me H SO₂CH₂COOEt 3-COOMe H 1-AI-Pip(4)
1742 5-Me H SO₂CH₂COOEt 2-COOEt H 1-AI-Pip(4)
1743 5-Me H SO₂CH₂COOEt 3-COOEt H 1-AI-Pip(4)
1744 5-Me H SO₂CH₂COOEt 2-COOPr H 1-AI-Pip(4)
1745 5-Me H SO₂CH₂COOEt 3-COOPr H 1-AI-Pip(4)
1746 5-Me H SO₂CH₂COOEt 2-COOBu H 1-AI-Pip(4)
1747 5-Me H SO₂CH₂COOEt 3-COOBu H 1-AI-Pip(4)
1748 5-Me H SO₂CH₂COOEt 2-COOPn H 1-AI-Pip(4)
1749 5-Me H SO₂CH₂COOEt 3-COOPn H 1-AI-Pip(4)
1750 5-Me H SO₂CH₂COOEt 2-COOHx H 1-AI-Pip(4)
1751 5-Me H SO₂CH₂COOEt 3-COOHx H 1-AI-Pip(4)
1752 5-Me H SO₂CH₂COOEt 2-CONH₂ H 1-AI-Pip(4)
1753 5-Me H SO₂CH₂COOEt 3-CONH₂ H 1-AI-Pip(4)
1754 5-Me H SO₂CH₂COOEt 2-CONHMe H 1-AI-Pip(4)
1755 5-Me H SO₂CH₂COOEt 3-CONHMe H 1-AI-Pip(4)
1756 5-Me H SO₂CH₂COOEt 2-CONHEt H 1-AI-Pip(4)
1757 5-Me H SO₂CH₂COOEt 3-CONHEt H 1-AI-Pip(4)
1758 5-Me H SO₂CH₂COOEt 2-CON(Me)₂ H 1-AI-Pip(4)
1759 5-Me H SO₂CH₂COOEt 3-CON(Me)₂ H 1-AI-Pip(4)
1760 5-Me H SO₂CH₂COOEt 2-CON(Me)Et H 1-AI-Pip(4)
1761 5-Me H SO₂CH₂COOEt 3-CON(Me)Et H 1-AI-Pip(4)
1762 5-Me H SO₂CH₂COOEt 2-CON(Et)₂ H 1-AI-Pip(4)
1763 5-Me H SO₂CH₂COOEt 3-CON(Et)₂ H 1-AI-Pip(4)
1764 5-Me Me SO₂CH₂COOEt 3-F 5-F 1-AI-Pip(4)
1765 5-Me Me SO₂CH₂COOEt 3-Cl 5-Cl 1-AI-Pip(4)
1766 5-Me Me SO₂CH₂COOEt 3-Me 5-Me 1-AI-Pip(4)
1767 5-Me Me SO₂CH₂COOEt 3-Cl 5-CONH₂ 1-AI-Pip(4)
1768 5-Me Me SO₂CH₂COOEt 2-Me 5-CONH₂ 1-AI-Pip(4)
1769 5-Me Me SO₂CH₂COOEt 3-Me 5-CONH₂ 1-AI-Pip(4)
1770 5-Me Me SO₂CH₂COOEt 3-CONH₂ 5-CONH₂ 1-AI-Pip(4)
1771 6-Me H SO₂CH₂COOEt H H 1-AI-Pip(4)
1772 6-Me H SO₂CH₂COOEt 2-F H 1-AI-Pip(4)
1773 6-Me H SO₂CH₂COOEt 3-F H 1-AI-Pip(4)
1774 6-Me H SO₂CH₂COOEt 2-Cl H 1-AI-Pip(4)
1775 6-Me H SO₂CH₂COOEt 3-Cl H 1-AI-Pip(4)
1776 6-Me H SO₂CH₂COOEt 2-Br H 1-AI-Pip(4)
1777 6-Me H SO₂CH₂COOEt 3-Br H 1-AI-Pip(4)
1778 6-Me H SO₂CH₂COOEt 2-I H 1-AI-Pip(4)
1779 6-Me H SO₂CH₂COOEt 3-I H 1-AI-Pip(4)
1780 6-Me H SO₂CH₂COOEt 2-Me H 1-AI-Pip(4)
1781 6-Me H SO₂CH₂COOEt 3-Me H 1-AI-Pip(4)
1782 6-Me H SO₂CH₂COOEt 2-Et H 1-AI-Pip(4)
1783 6-Me H SO₂CH₂COOEt 3-Et H 1-AI-Pip(4)
1784 6-Me H SO₂CH₂COOEt 2-Pr H 1-AI-Pip(4)
1785 6-Me H SO₂CH₂COOEt 3-Pr H 1-AI-Pip(4)
1786 6-Me H SO₂CH₂COOEt 2-Bu H 1-AI-Pip(4)
1787 6-Me H SO₂CH₂COOEt 3-Bu H 1-AI-Pip(4)
1788 6-Me H SO₂CH₂COOEt 2-Pn H 1-AI-Pip(4)
1789 6-Me H SO₂CH₂COOEt 3-Pn H 1-AI-Pip(4)
1790 6-Me H SO₂CH₂COOEt 2-Hx H 1-AI-Pip(4)
1791 6-Me H SO₂CH₂COOEt 3-Hx H 1-AI-Pip(4)
1792 6-Me H SO₂CH₂COOEt 2-CF₃ H 1-AI-Pip(4)
1793 6-Me H SO₂CH₂COOEt 3-CF₃ H 1-AI-Pip(4)
1794 6-Me H SO₂CH₂COOEt 2-OMe H 1-AI-Pip(4)
1795 6-Me H SO₂CH₂COOEt 3-OMe H 1-AI-Pip(4)
1796 6-Me H SO₂CH₂COOEt 2-OEt H 1-AI-Pip(4)
1797 6-Me H SO₂CH₂COOEt 3-OEt H 1-AI-Pip(4)
1798 6-Me H SO₂CH₂COOEt 2-COOH H 1-AI-Pip(4)
1799 6-Me H SO₂CH₂COOEt 3-COOH H 1-AI-Pip(4)
1800 6-Me H SO₂CH₂COOEt 2-COOMe H 1-AI-Pip(4)
1801 6-Me H SO₂CH₂COOEt 3-COOMe H 1-AI-Pip(4)
1802 6-Me H SO₂CH₂COOEt 2-COOEt H 1-AI-Pip(4)
1803 6-Me H SO₂CH₂COOEt 3-COOEt H 1-AI-Pip(4)
1804 6-Me H SO₂CH₂COOEt 2-COOPr H 1-AI-Pip(4)
1805 6-Me H SO₂CH₂COOEt 3-COOPr H 1-AI-Pip(4)
1806 6-Me H SO₂CH₂COOEt 2-COOBu H 1-AI-Pip(4)
1807 6-Me H SO₂CH₂COOEt 3-COOBu H 1-AI-Pip(4)
1808 6-Me H SO₂CH₂COOEt 2-COOPn H 1-AI-Pip(4)
1809 6-Me H SO₂CH₂COOEt 3-COOPn H 1-AI-Pip(4)
1810 6-Me H SO₂CH₂COOEt 2-COOHx H 1-AI-Pip(4)
1811 6-Me H SO₂CH₂COOEt 3-COOHx H 1-AI-Pip(4)
1812 6-Me H SO₂CH₂COOEt 2-CONH₂ H 1-AI-Pip(4)
1813 6-Me H SO₂CH₂COOEt 3-CONH₂ H 1-AI-Pip(4)
1814 6-Me H SO₂CH₂COOEt 2-CONHMe H 1-AI-Pip(4)
1815 6-Me H SO₂CH₂COOEt 3-CONHMe H 1-AI-Pip(4)
1816 6-Me H SO₂CH₂COOEt 2-CONHEt H 1-AI-Pip(4)
1817 6-Me H SO₂CH₂COOEt 3-CONHEt H 1-AI-Pip(4)
1818 6-Me H SO₂CH₂COOEt 2-CON(Me)₂ H 1-AI-Pip(4)
1819 6-Me H SO₂CH₂COOEt 3-CON(Me)₂ H 1-AI-Pip(4)
1820 6-Me H SO₂CH₂COOEt 2-CON(Me)Et H 1-AI-Pip(4)
1821 6-Me H SO₂CH₂COOEt 3-CON(Me)Et H 1-AI-Pip(4)
1822 6-Me H SO₂CH₂COOEt 2-CON(Et)₂ H 1-AI-Pip(4)
1823 6-Me H SO₂CH₂COOEt 3-CON(Et)₂ H 1-AI-Pip(4)
1824 6-Me Me SO₂CH₂COOEt 3-F 5-F 1-AI-Pip(4)
1825 6-Me Me SO₂CH₂COOEt 3-Cl 5-Cl 1-AI-Pip(4)
1826 6-Me Me SO₂CH₂COOEt 3-Me 5-Me 1-AI-Pip(4)
1827 6-Me Me SO₂CH₂COOEt 3-Cl 5-CONH₂ 1-AI-Pip(4)
1828 6-Me Me SO₂CH₂COOEt 2-Me 5-CONH₂ 1-AI-Pip(4)
1829 6-Me Me SO₂CH₂COOEt 3-Me 5-CONH₂ 1-AI-Pip(4)
1830 6-Me Me SO₂CH₂COOEt 3-CONH₂ 5-CONH₂ 1-AI-Pip(4)
1831 2-Et H SO₂CH₂COOEt H H 1-AI-Pip(4)
1832 4-Et H SO₂CH₂COOEt H H 1-AI-Pip(4)
1833 5-Et H SO₂CH₂COOEt H H 1-AI-Pip(4)
1834 6-Et H SO₂CH₂COOEt H H 1-AI-Pip(4)
1835 2-Pr H SO₂CH₂COOEt H H 1-AI-Pip(4)
1836 4-Bu H SO₂CH₂COOEt H H 1-AI-Pip(4)
1837 5-Pn H SO₂CH₂COOEt H H 1-AI-Pip(4)
1838 6-Hx H SO₂CH₂COOEt H H 1-AI-Pip(4)
1839 6-OH H SO₂CH₂COOEt H H 1-AI-Pip(4)
1840 6-OH H SO₂CH₂COOEt 2-F H 1-AI-Pip(4)
1841 6-OH H SO₂CH₂COOEt 3-F H 1-AI-Pip(4)
1842 6-OH H SO₂CH₂COOEt 2-Cl H 1-AI-Pip(4)
1843 6-OH H SO₂CH₂COOEt 3-Cl H 1-AI-Pip(4)
1844 6-OH H SO₂CH₂COOEt 2-Br H 1-AI-Pip(4)
1845 6-OH H SO₂CH₂COOEt 3-Br H 1-AI-Pip(4)
1846 6-OH H SO₂CH₂COOEt 2-I H 1-AI-Pip(4)
1847 6-OH H SO₂CH₂COOEt 3-I H 1-AI-Pip(4)
1848 6-OH H SO₂CH₂COOEt 2-Me H 1-AI-Pip(4)
1849 6-OH H SO₂CH₂COOEt 3-Me H 1-AI-Pip(4)
1850 6-OH H SO₂CH₂COOEt 2-Et H 1-AI-Pip(4)
1851 6-OH H SO₂CH₂COOEt 3-Et H 1-AI-Pip(4)
1852 6-OH H SO₂CH₂COOEt 2-Pr H 1-AI-Pip(4)
1853 6-OH H SO₂CH₂COOEt 3-Pr H 1-AI-Pip(4)
1854 6-OH H SO₂CH₂COOEt 2-Bu H 1-AI-Pip(4)
1855 6-OH H SO₂CH₂COOEt 3-Bu H 1-AI-Pip(4)
1856 6-OH H SO₂CH₂COOEt 2-Pn H 1-AI-Pip(4)
1857 6-OH H SO₂CH₂COOEt 3-Pn H 1-AI-Pip(4)
1858 6-OH H SO₂CH₂COOEt 2-Hx H 1-AI-Pip(4)
1859 6-OH H SO₂CH₂COOEt 3-Hx H 1-AI-Pip(4)
1860 6-OH H SO₂CH₂COOEt 2-CF₃ H 1-AI-Pip(4)
1861 6-OH H SO₂CH₂COOEt 3-CF₃ H 1-AI-Pip(4)
1862 6-OH H SO₂CH₂COOEt 2-OMe H 1-AI-Pip(4)
1863 6-OH H SO₂CH₂COOEt 3-OMe H 1-AI-Pip(4)
1864 6-OH H SO₂CH₂COOEt 2-OEt H 1-AI-Pip(4)
1865 6-OH H SO₂CH₂COOEt 3-OEt H 1-AI-Pip(4)
1866 6-OH H SO₂CH₂COOEt 2-COOH H 1-AI-Pip(4)
1867 6-OH H SO₂CH₂COOEt 3-COOH H 1-AI-Pip(4)
1868 6-OH H SO₂CH₂COOEt 2-COOMe H 1-AI-Pip(4)
1869 6-OH H SO₂CH₂COOEt 3-COOMe H 1-AI-Pip(4)
1870 6-OH H SO₂CH₂COOEt 2-COOEt H 1-AI-Pip(4)
1871 6-OH H SO₂CH₂COOEt 3-COOEt H 1-AI-Pip(4)
1872 6-OH H SO₂CH₂COOEt 2-COOPr H 1-AI-Pip(4)
1873 6-OH H SO₂CH₂COOEt 3-COOPr H 1-AI-Pip(4)
1874 6-OH H SO₂CH₂COOEt 2-COOBu H 1-AI-Pip(4)
1875 6-OH H SO₂CH₂COOEt 3-COOBu H 1-AI-Pip(4)
1876 6-OH H SO₂CH₂COOEt 2-COOPn H 1-AI-Pip(4)
1877 6-OH H SO₂CH₂COOEt 3-COOPn H 1-AI-Pip(4)
1878 6-OH H SO₂CH₂COOEt 2-COOHx H 1-AI-Pip(4)
1879 6-OH H SO₂CH₂COOEt 3-COOHx H 1-AI-Pip(4)
1880 6-OH H SO₂CH₂COOEt 2-CONH₂ H 1-AI-Pip(4)
1881 6-OH H SO₂CH₂COOEt 3-CONH₂ H 1-AI-Pip(4)
1882 6-OH H SO₂CH₂COOEt 2-CONHMe H 1-AI-Pip(4)
1883 6-OH H SO₂CH₂COOEt 3-CONHMe H 1-AI-Pip(4)
1884 6-OH H SO₂CH₂COOEt 2-CONHEt H 1-AI-Pip(4)
1885 6-OH H SO₂CH₂COOEt 3-CONHEt H 1-AI-Pip(4)
1886 6-OH H SO₂CH₂COOEt 2-CON(Me)₂ H 1-AI-Pip(4)
1887 6-OH H SO₂CH₂COOEt 3-CON(Me)₂ H 1-AI-Pip(4)
1888 6-OH H SO₂CH₂COOEt 2-CON(Me)EtH 1-AI-Pip(4)
1889 6-OH H SO₂CH₂COOEt 3-CON(Me)EtH 1-AI-Pip(4)
1890 6-OH H SO₂CH₂COOEt 2-CON(Et)₂ H 1-AI-Pip(4)
1891 6-OH H SO₂CH₂COOEt 3-CON(Et)₂ H 1-AI-Pip(4)
1892 6-OH H SO₂CH₂COOEt 2-F 3-F 1-AI-Pip(4)
1893 6-OH H SO₂CH₂COOEt 2-F 5-F 1-AI-Pip(4)
1894 6-OH H SO₂CH₂COOEt 2-F 6-F 1-AI-Pip(4)
1895 6-OH H SO₂CH₂COOEt 3-F 5-F 1-AI-Pip(4)
1896 6-OH H SO₂CH₂COOEt 2-Cl 3-Cl 1-AI-Pip(4)
1897 6-OH H SO₂CH₂COOEt 2-Cl 5-Cl 1-AI-Pip(4)
1898 6-OH H SO₂CH₂COOEt 2-Cl 6-Cl 1-AI-Pip(4)
1899 6-OH H SO₂CH₂COOEt 3-Cl 5-Cl 1-AI-Pip(4)
1900 6-OH H SO₂CH₂COOEt 2-Me 3-Me 1-AI-Pip(4)
1901 6-OH H SO₂CH₂COOEt 2-Me 5-Me 1-AI-Pip(4)
1902 6-OH H SO₂CH₂COOEt 2-Me 6-Me 1-AI-Pip(4)
1903 6-OH H SO₂CH₂COOEt 3-Me 5-Me 1-AI-Pip(4)
1904 6-OH H SO₂CH₂COOEt 2-Cl 5-CONH₂ 1-AI-Pip(4)
1905 6-OH H SO₂CH₂COOEt 3-Cl 5-CONH₂ 1-AI-Pip(4)
1906 6-OH H SO₂CH₂COOEt 3-Cl 5-CONHMe 1-AI-Pip(4)
1907 6-OH H SO₂CH₂COOEt 3-Cl 5-CONHEt 1-AI-Pip(4)
1908 6-OH H SO₂CH₂COOEt 3-Cl 5-CONHPr 1-AI-Pip(4)
1909 6-OH H SO₂CH₂COOEt 3-Cl 5-CONHBu 1-AI-Pip(4)
1910 6-OH H SO₂CH₂COOEt 3-Cl 5-CONHPn 1-AI-Pip(4)
1911 6-OH H SO₂CH₂COOEt 3-Cl 5-CONHHx 1-AI-Pip(4)
1912 6-OH H SO₂CH₂COOEt 2-Me 5-CONH₂ 1-AI-Pip(4)
1913 6-OH H SO₂CH₂COOEt 2-Me 5-CONHMe 1-AI-Pip(4)
1914 6-OH H SO₂CH₂COOEt 2-Me 5-CONHEt 1-AI-Pip(4)
1915 6-OH H SO₂CH₂COOEt 2-Me 5-CONHPr 1-AI-Pip(4)
1916 6-OH H SO₂CH₂COOEt 2-Me 5-CONHBu 1-AI-Pip(4)
1917 6-OH H SO₂CH₂COOEt 2-Me 5-CONHPn 1-AI-Pip(4)
1918 6-OH H SO₂CH₂COOEt 2-Me 5-CONHHx 1-AI-Pip(4)
1919 6-OH H SO₂CH₂COOEt 3-Me 5-CONH₂ 1-AI-Pip(4)
1920 6-OH H SO₂CH₂COOEt 3-Me 5-CONHMe 1-AI-Pip(4)
1921 6-OH H SO₂CH₂COOEt 3-Me 5-CONHEt 1-AI-Pip(4)
1922 6-OH H SO₂CH₂COOEt 3-Me 5-CONHPr 1-AI-Pip(4)
1923 6-OH H SO₂CH₂COOEt 3-Me 5-CONHBu 1-AI-Pip(4)
1924 6-OH H SO₂CH₂COOEt 3-Me 5-CONHPn 1-AI-Pip(4)
1925 6-OH H SO₂CH₂COOEt 3-Me 5-CONHHx 1-AI-Pip(4)
1926 6-OH H SO₂CH₂COOEt 2-CONH₂ 6-CONH₂ 1-AI-Pip(4)
1927 6-OH H SO₂CH₂COOEt 3-CONH₂ 5-CONH₂ 1-AI-Pip(4)
1928 6-OH H SO₂CH₂COOEt 3-CONHMe 5-CONHMe 1-AI-Pip(4)
1929 6-OH H SO₂CH₂COOEt 3-CONHEt 5-CONHEt 1-AI-Pip(4)
1930 H H SO₂CH₂COOPr H H 1-AI-Pip(4)
1931 H H SO₂CH₂COOBu H H 1-AI-Pip(4)
1932 H H SO₂CH₂COOPn H H 1-AI-Pip(4)
1933 H H SO₂CH₂COOHx H H 1-AI-Pip(4)
1934 H H SO₂(CH₂)₂COOEt H H 1-AI-Pip(4)
1935 H H SO₂(CH₂)₃COOEt H H 1-AI-Pip(4)
1936 H H SO₂(CH₂)₄COOEt H H 1-AI-Pip(4)
1937 H H SO₂(CH₂)₅COOEt H H 1-AI-Pip(4)
1938 H H SO₂(CH₂)₆COOEt H H 1-AI-Pip(4)
1939 H H SO₂CH₂COOH H H 1-AI-Pip(4)
1940 H H SO₂CH₂COOH 2-F H 1-AI-Pip(4)
1941 H H SO₂CH₂COOH 3-F H 1-AI-Pip(4)
1942 H H SO₂CH₂COOH 2-Cl H 1-AI-Pip(4)
1943 H H SO₂CH₂COOH 3-Cl H 1-AI-Pip(4)
1944 H H SO₂CH₂COOH 2-Br H 1-AI-Pip(4)
1945 H H SO₂CH₂COOH 3-Br H 1-AI-Pip(4)
1946 H H SO₂CH₂COOH 2-I H 1-AI-Pip(4)
1947 H H SO₂CH₂COOH 3-I H 1-AI-Pip(4)
1948 H H SO₂CH₂COOH 2-Me H 1-AI-Pip(4)
1949 H H SO₂CH₂COOH 3-Me H 1-AI-Pip(4)
1950 H H SO₂CH₂COOH 2-Et H 1-AI-Pip(4)
1951 H H SO₂CH₂COOH 3-Et H 1-AI-Pip(4)
1952 H H SO₂CH₂COOH 2-Pr H 1-AI-Pip(4)
1953 H H SO₂CH₂COOH 3-Pr H 1-AI-Pip(4)
1954 H H SO₂CH₂COOH 2-iPr H 1-AI-Pip(4)
1955 H H SO₂CH₂COOH 3-iPr H 1-AI-Pip(4)
1956 H H SO₂CH₂COOH 2-Bu H 1-AI-Pip(4)
1957 H H SO₂CH₂COOH 3-Bu H 1-AI-Pip(4)
1958 H H SO₂CH₂COOH 2-iBu H 1-AI-Pip(4)
1959 H H SO₂CH₂COOH 3-iBu H 1-AI-Pip(4)
1960 H H SO₂CH₂COOH 2-sBu H 1-AI-Pip(4)
1961 H H SO₂CH₂COOH 3-sBu H 1-AI-Pip(4)
1962 H H SO₂CH₂COOH 2-tBu H 1-AI-Pip(4)
1963 H H SO₂CH₂COOH 3-tBu H 1-AI-Pip(4)
1964 H H SO₂CH₂COOH 2-Pn H 1-AI-Pip(4)
1965 H H SO₂CH₂COOH 3-Pn H 1-AI-Pip(4)
1966 H H SO₂CH₂COOH 2-Hx H 1-AI-Pip(4)
1967 H H SO₂CH₂COOH 3-Hx H 1-AI-Pip(4)
1968 H H SO₂CH₂COOH 2-CF₃ H 1-AI-Pip(4)
1969 H H SO₂CH₂COOH 3-CF₃ H 1-AI-Pip(4)
1970 H H SO₂CH₂COOH 2-OMe H 1-AI-Pip(4)
1971 H H SO₂CH₂COOH 3-OMe H 1-AI-Pip(4)
1972 H H SO₂CH₂COOH 2-OEt H 1-AI-Pip(4)
1973 H H SO₂CH₂COOH 3-OEt H 1-AI-Pip(4)
1974 H H SO₂CH₂COOH 2-COOH H 1-AI-Pip(4)
1975 H H SO₂CH₂COOH 3-COOH H 1-AI-Pip(4)
1976 H H SO₂CH₂COOH 2-COOMe H 1-AI-Pip(4)
1977 H H SO₂CH₂COOH 3-COOMe H 1-AI-Pip(4)
1978 H H SO₂CH₂COOH 2-COOEt H 1-AI-Pip(4)
1979 H H SO₂CH₂COOH 3-COOEt H 1-AI-Pip(4)
1980 H H SO₂CH₂COOH 2-COOPr H 1-AI-Pip(4)
1981 H H SO₂CH₂COOH 3-COOPr H 1-AI-Pip(4)
1982 H H SO₂CH₂COOH 2-COOBu H 1-AI-Pip(4)
1983 H H SO₂CH₂COOH 3-COOBu H 1-AI-Pip(4)
1984 H H SO₂CH₂COOH 2-COOPn H 1-AI-Pip(4)
1985 H H SO₂CH₂COOH 3-COOPn H 1-AI-Pip(4)
1986 H H SO₂CH₂COOH 2-COOHx H 1-AI-Pip(4)
1987 H H SO₂CH₂COOH 3-COOHx H 1-AI-Pip(4)
1988 H H SO₂CH₂COOH 2-CONH₂ H 1-AI-Pip(4)
1989 H H SO₂CH₂COOH 3-CONH₂ H 1-AI-Pip(4)
1990 H H SO₂CH₂COOH 2-CONHMe H 1-AI-Pip(4)
1991 H H SO₂CH₂COOH 3-CONHMe H 1-AI-Pip(4)
1992 H H SO₂CH₂COOH 2-CONHEt H 1-AI-Pip(4)
1993 H H SO₂CH₂COOH 3-CONHEt H 1-AI-Pip(4)
1994 H H SO₂CH₂COOH 2-CON(Me)₂ H 1-AI-Pip(4)
1995 H H SO₂CH₂COOH 3-CON(Me)₂ H 1-AI-Pip(4)
1996 H H SO₂CH₂COOH 2-CON(Me)Et H 1-AI-Pip(4)
1997 H H SO₂CH₂COOH 3-CON(Me)Et H 1-AI-Pip(4)
1998 H H SO₂CH₂COOH 2-CON(Et)₂ H 1-AI-Pip(4)
1999 H H SO₂CH₂COOH 3-CON(Et)₂ H 1-AI-Pip(4)
2000 H H SO₂CH₂COOH 2-F 3-F 1-AI-Pip(4)
2001 H H SO₂CH₂COOH 2-F 5-F 1-AI-Pip(4)
2002 H H SO₂CH₂COOH 2-F 6-F 1-AI-Pip(4)
2003 H H SO₂CH₂COOH 3-F 5-F 1-AI-Pip(4)
2004 H H SO₂CH₂COOH 2-Cl 3-Cl 1-AI-Pip(4)
2005 H H SO₂CH₂COOH 2-Cl 5-Cl 1-AI-Pip(4)
2006 H H SO₂CH₂COOH 2-Cl 6-Cl 1-AI-Pip(4)
2007 H H SO₂CH₂COOH 3-Cl 5-Cl 1-AI-Pip(4)
2008 H H SO₂CH₂COOH 2-Me 3-Me 1-AI-Pip(4)
2009 H H SO₂CH₂COOH 2-Me 5-Me 1-AI-Pip(4)
2010 H H SO₂CH₂COOH 2-Me 6-Me 1-AI-Pip(4)
2011 H H SO₂CH₂COOH 3-Me 5-Me 1-AI-Pip(4)
2012 H H SO₂CH₂COOH 2-Cl 5-CONH₂ 1-AI-Pip(4)
2013 H H SO₂CH₂COOH 3-Cl 5-CONH₂ 1-AI-Pip(4)
2014 H H SO₂CH₂COOH 3-Cl 5-CONHMe 1-AI-Pip(4)
2015 H H SO₂CH₂COOH 3-Cl 5-CONHEt 1-AI-Pip(4)
2016 H H SO₂CH₂COOH 3-Cl 5-CONHPr 1-AI-Pip(4)
2017 H H SO₂CH₂COOH 3-Cl 5-CONHBu 1-AI-Pip(4)
2018 H H SO₂CH₂COOH 3-Cl 5-CONHPn 1-AI-Pip(4)
2019 H H SO₂CH₂COOH 3-Cl 5-CONHHx 1-AI-Pip(4)
2020 H H SO₂CH₂COOH 2-Me 5-CONH₂ 1-AI-Pip(4)
2021 H H SO₂CH₂COOH 2-Me 5-CONHMe 1-AI-Pip(4)
2022 H H SO₂CH₂COOH 2-Me 5-CONHEt 1-AI-Pip(4)
2023 H H SO₂CH₂COOH 2-Me 5-CONHPr 1-AI-Pip(4)
2024 H H SO₂CH₂COOH 2-Me 5-CONHBu 1-AI-Pip(4)
2025 H H SO₂CH₂COOH 2-Me 5-CONHPn 1-AI-Pip(4)
2026 H H SO₂CH₂COOH 2-Me 5-CONHHx 1-AI-Pip(4)
2027 H H SO₂CH₂COOH 3-Me 5-CONH₂ 1-AI-Pip(4)
2028 H H SO₂CH₂COOH 3-Me 5-CONHMe 1-AI-Pip(4)
2029 H H SO₂CH₂COOH 3-Me 5-CONHEt 1-AI-Pip(4)
2030 H H SO₂CH₂COOH 3-Me 5-CONHPr 1-AI-Pip(4)
2031 H H SO₂CH₂COOH 3-Me 5-CONHBu 1-AI-Pip(4)
2032 H H SO₂CH₂COOH 3-Me 5-CONHPn 1-AI-Pip(4)
2033 H H SO₂CH₂COOH 3-Me 5-CONHHx 1-AI-Pip(4)
2034 H H SO₂CH₂COOH 2-CONH₂ 6-CONH₂ 1-AI-Pip(4)
2035 H H SO₂CH₂COOH 3-CONH₂ 5-CONH₂ 1-AI-Pip(4)
2036 H H SO₂CH₂COOH 3-CONHMe 5-CONHMe 1-AI-Pip(4)
2037 H H SO₂CH₂COOH 3-CONHEt 5-CONHEt 1-AI-Pip(4)
2038 H F SO₂CH₂COOH H H 1-AI-Pip(4)
2039 H F SO₂CH₂COOH 2-F H 1-AI-Pip(4)
2040 H F SO₂CH₂COOH 3-F H 1-AI-Pip(4)
2041 H F SO₂CH₂COOH 2-Cl H 1-AI-Pip(4)
2042 H F SO₂CH₂COOH 3-Cl H 1-AI-Pip(4)
2043 H F SO₂CH₂COOH 2-Br H 1-AI-Pip(4)
2044 H F SO₂CH₂COOH 3-Br H 1-AI-Pip(4)
2045 H F SO₂CH₂COOH 2-I H 1-AI-Pip(4)
2046 H F SO₂CH₂COOH 3-I H 1-AI-Pip(4)
2047 H F SO₂CH₂COOH 2-Me H 1-AI-Pip(4)
2048 H F SO₂CH₂COOH 3-Me H 1-AI-Pip(4)
2049 H F SO₂CH₂COOH 2-Et H 1-AI-Pip(4)
2050 H F SO₂CH₂COOH 3-Et H 1-AI-Pip(4)
2051 H F SO₂CH₂COOH 2-Pr H 1-AI-Pip(4)
2052 H F SO₂CH₂COOH 3-Pr H 1-AI-Pip(4)
2053 H F SO₂CH₂COOH 2-iPr H 1-AI-Pip(4)
2054 H F SO₂CH₂COOH 3-iPr H 1-AI-Pip(4)
2055 H F SO₂CH₂COOH 2-Bu H 1-AI-Pip(4)
2056 H F SO₂CH₂COOH 3-Bu H 1-AI-Pip(4)
2057 H F SO₂CH₂COOH 2-iBu H 1-AI-Pip(4)
2058 H F SO₂CH₂COOH 3-iBu H 1-AI-Pip(4)
2059 H F SO₂CH₂COOH 2-sBu H 1-AI-Pip(4)
2060 H F SO₂CH₂COOH 3-sBu H 1-AI-Pip(4)
2061 H F SO₂CH₂COOH 2-tBu H 1-AI-Pip(4)
2062 H F SO₂CH₂COOH 3-tBu H 1-AI-Pip(4)
2063 H F SO₂CH₂COOH 2-Pn H 1-AI-Pip(4)
2064 H F SO₂CH₂COOH 3-Pn H 1-AI-Pip(4)
2065 H F SO₂CH₂COOH 2-Hx H 1-AI-Pip(4)
2066 H F SO₂CH₂COOH 3-Hx H 1-AI-Pip(4)
2067 H F SO₂CH₂COOH 2-CF₃ H 1-AI-Pip(4)
2068 H F SO₂CH₂COOH 3-CF₃ H 1-AI-Pip(4)
2069 H F SO₂CH₂COOH 2-OMe H 1-AI-Pip(4)
2070 H F SO₂CH₂COOH 3-OMe H 1-AI-Pip(4)
2071 H F SO₂CH₂COOH 2-OEt H 1-AI-Pip(4)
2072 H F SO₂CH₂COOH 3-OEt H 1-AI-Pip(4)
2073 H F SO₂CH₂COOH 2-COOH H 1-AI-Pip(4)
2074 H F SO₂CH₂COOH 3-COOH H 1-AI-Pip(4)
2075 H F SO₂CH₂COOH 2-COOMe H 1-AI-Pip(4)
2076 H F SO₂CH₂COOH 3-COOMe H 1-AI-Pip(4)
2077 H F SO₂CH₂COOH 2-COOEt H 1-AI-Pip(4)
2078 H F SO₂CH₂COOH 3-COOEt H 1-AI-Pip(4)
2079 H F SO₂CH₂COOH 2-COOPr H 1-AI-Pip(4)
2080 H F SO₂CH₂COOH 3-COOPr H 1-AI-Pip(4)
2081 H F SO₂CH₂COOH 2-COOBu H 1-AI-Pip(4)
2082 H F SO₂CH₂COOH 3-COOBu H 1-AI-Pip(4)
2083 H F SO₂CH₂COOH 2-COOPn H 1-AI-Pip(4)
2084 H F SO₂CH₂COOH 3-COOPn H 1-AI-Pip(4)
2085 H F SO₂CH₂COOH 2-COOHx H 1-AI-Pip(4)
2086 H F SO₂CH₂COOH 3-COOHx H 1-AI-Pip(4)
2087 H F SO₂CH₂COOH 2-CONH₂ H 1-AI-Pip(4)
2088 H F SO₂CH₂COOH 3-CONH₂ H 1-AI-Pip(4)
2089 H F SO₂CH₂COOH 2-CONHMe H 1-AI-Pip(4)
2090 H F SO₂CH₂COOH 3-CONHMe H 1-AI-Pip(4)
2091 H F SO₂CH₂COOH 2-CONHEt H 1-AI-Pip(4)
2092 H F SO₂CH₂COOH 3-CONHEt H 1-AI-Pip(4)
2093 H F SO₂CH₂COOH 2-CON(Me)₂ H 1-AI-Pip(4)
2094 H F SO₂CH₂COOH 3-CON(Me)₂ H 1-AI-Pip(4)
2095 H F SO₂CH₂COOH 2-CON(Me)EtH 1-AI-Pip(4)
2096 H F SO₂CH₂COOH 3-CON(Me)EtH 1-AI-Pip(4)
2097 H F SO₂CH₂COOH 2-CON(Et)₂ H 1-AI-Pip(4)
2098 H F SO₂CH₂COOH 3-CON(Et)₂ H 1-AI-Pip(4)
2099 H Me SO₂CH₂COOH H H 1-AI-Pip(4)
2100 H Me SO₂CH₂COOH 2-F H 1-AI-Pip(4)
2101 H Me SO₂CH₂COOH 3-F H 1-AI-Pip(4)
2102 H Me SO₂CH₂COOH 2-Cl H 1-AI-Pip(4)
2103 H Me SO₂CH₂COOH 3-Cl H 1-AI-Pip(4)
2104 H Me SO₂CH₂COOH 2-Br H 1-AI-Pip(4)
2105 H Me SO₂CH₂COOH 3-Br H 1-AI-Pip(4)
2106 H Me SO₂CH₂COOH 2-I H 1-AI-Pip(4)
2107 H Me SO₂CH₂COOH 3-I H 1-AI-Pip(4)
2108 H Me SO₂CH₂COOH 2-Me H 1-AI-Pip(4)
2109 H Me SO₂CH₂COOH 3-Me H 1-AI-Pip(4)
2110 H Me SO₂CH₂COOH 2-Et H 1-AI-Pip(4)
2111 H Me SO₂CH₂COOH 3-Et H 1-AI-Pip(4)
2112 H Me SO₂CH₂COOH 2-Pr H 1-AI-Pip(4)
2113 H Me SO₂CH₂COOH 3-Pr H 1-AI-Pip(4)
2114 H Me SO₂CH₂COOH 2-Bu H 1-AI-Pip(4)
2115 H Me SO₂CH₂COOH 3-Bu H 1-AI-Pip(4)
2116 H Me SO₂CH₂COOH 2-Pn H 1-AI-Pip(4)
2117 H Me SO₂CH₂COOH 3-Pn H 1-AI-Pip(4)
2118 H Me SO₂CH₂COOH 2-Hx H 1-AI-Pip(4)
2119 H Me SO₂CH₂COOH 3-Hx H 1-AI-Pip(4)
2120 H Me SO₂CH₂COOH 2-CF₃ H 1-AI-Pip(4)
2121 H Me SO₂CH₂COOH 3-CF₃ H 1-AI-Pip(4)
2122 H Me SO₂CH₂COOH 2-OMe H 1-AI-Pip(4)
2123 H Me SO₂CH₂COOH 3-OMe H 1-AI-Pip(4)
2124 H Me SO₂CH₂COOH 2-OEt H 1-AI-Pip(4)
2125 H Me SO₂CH₂COOH 3-OEt H 1-AI-Pip(4)
2126 H Me SO₂CH₂COOH 2-COOH H 1-AI-Pip(4)
2127 H Me SO₂CH₂COOH 3-COOH H 1-AI-Pip(4)
2128 H Me SO₂CH₂COOH 2-COOMe H 1-AI-Pip(4)
2129 H Me SO₂CH₂COOH 3-COOMe H 1-AI-Pip(4)
2130 H Me SO₂CH₂COOH 2-COOEt H 1-AI-Pip(4)
2131 H Me SO₂CH₂COOH 3-COOEt H 1-AI-Pip(4)
2132 H Me SO₂CH₂COOH 2-COOPr H 1-AI-Pip(4)
2133 H Me SO₂CH₂COOH 3-COOPr H 1-AI-Pip(4)
2134 H Me SO₂CH₂COOH 2-COOBu H 1-AI-Pip(4)
2135 H Me SO₂CH₂COOH 3-COOBu H 1-AI-Pip(4)
2136 H Me SO₂CH₂COOH 2-COOPn H 1-AI-Pip(4)
2137 H Me SO₂CH₂COOH 3-COOPn H 1-AI-Pip(4)
2138 H Me SO₂CH₂COOH 2-COOHx H 1-AI-Pip(4)
2139 H Me SO₂CH₂COOH 3-COOHx H 1-AI-Pip(4)
2140 H Me SO₂CH₂COOH 2-CONH₂ H 1-AI-Pip(4)
2141 H Me SO₂CH₂COOH 3-CONH₂ H 1-AI-Pip(4)
2142 H Me SO₂CH₂COOH 2-CONHMe H 1-AI-Pip(4)
2143 H Me SO₂CH₂COOH 3-CONHMe H 1-AI-Pip(4)
2144 H Me SO₂CH₂COOH 2-CONHEt H 1-AI-Pip(4)
2145 H Me SO₂CH₂COOH 3-CONHEt H 1-AI-Pip(4)
2146 H Me SO₂CH₂COOH 2-CON(Me)₂ H 1-AI-Pip(4)
2147 H Me SO₂CH₂COOH 3-CON(Me)₂ H 1-AI-Pip(4)
2148 H Me SO₂CH₂COOH 2-CON(Me)EtH 1-AI-Pip(4)
2149 H Me SO₂CH₂COOH 3-CON(Me)EtH 1-AI-Pip(4)
2150 H Me SO₂CH₂COOH 2-CON(Et)₂ H 1-AI-Pip(4)
2151 H Me SO₂CH₂COOH 3-CON(Et)₂ H 1-AI-Pip(4)
2152 6-F H SO₂CH₂COOH H H 1-AI-Pip(4)
2153 6-F H SO₂CH₂COOH 2-F H 1-AI-Pip(4)
2154 6-F H SO₂CH₂COOH 3-F H 1-AI-Pip(4)
2155 6-F H SO₂CH₂COOH 2-Cl H 1-AI-Pip(4)
2156 6-F H SO₂CH₂COOH 3-Cl H 1-AI-Pip(4)
2157 6-F H SO₂CH₂COOH 2-Br H 1-AI-Pip(4)
2158 6-F H SO₂CH₂COOH 3-Br H 1-AI-Pip(4)
2159 6-F H SO₂CH₂COOH 2-I H 1-AI-Pip(4)
2160 6-F H SO₂CH₂COOH 3-I H 1-AI-Pip(4)
2161 6-F H SO₂CH₂COOH 2-Me H 1-AI-Pip(4)
2162 6-F H SO₂CH₂COOH 3-Me H 1-AI-Pip(4)
2163 6-F H SO₂CH₂COOH 2-Et H 1-AI-Pip(4)
2164 6-F H SO₂CH₂COOH 3-Et H 1-AI-Pip(4)
2165 6-F H SO₂CH₂COOH 2-Pr H 1-AI-Pip(4)
2166 6-F H SO₂CH₂COOH 3-Pr H 1-AI-Pip(4)
2167 6-F H SO₂CH₂COOH 2-Bu H 1-AI-Pip(4)
2168 6-F H SO₂CH₂COOH 3-Bu H 1-AI-Pip(4)
2169 6-F H SO₂CH₂COOH 2-Pn H 1-AI-Pip(4)
2170 6-F H SO₂CH₂COOH 3-Pn H 1-AI-Pip(4)
2171 6-F H SO₂CH₂COOH 2-Hx H 1-AI-Pip(4)
2172 6-F H SO₂CH₂COOH 3-Hx H 1-AI-Pip(4)
2173 6-F H SO₂CH₂COOH 2-CF₃ H 1-AI-Pip(4)
2174 6-F H SO₂CH₂COOH 3-CF₃ H 1-AI-Pip(4)
2175 6-F H SO₂CH₂COOH 2-OMe H 1-AI-Pip(4)
2176 6-F H SO₂CH₂COOH 3-OMe H 1-AI-Pip(4)
2177 6-F H SO₂CH₂COOH 2-OEt H 1-AI-Pip(4)
2178 6-F H SO₂CH₂COOH 3-OEt H 1-AI-Pip(4)
2179 6-F H SO₂CH₂COOH 2-COOH H 1-AI-Pip(4)
2180 6-F H SO₂CH₂COOH 3-COOH H 1-AI-Pip(4)
2181 6-F H SO₂CH₂COOH 2-COOMe H 1-AI-Pip(4)
2182 6-F H SO₂CH₂COOH 3-COOMe H 1-AI-Pip(4)
2183 6-F H SO₂CH₂COOH 2-COOEt H 1-AI-Pip(4)
2184 6-F H SO₂CH₂COOH 3-COOEt H 1-AI-Pip(4)
2185 6-F H SO₂CH₂COOH 2-COOPr H 1-AI-Pip(4)
2186 6-F H SO₂CH₂COOH 3-COOPr H 1-AI-Pip(4)
2187 6-F H SO₂CH₂COOH 2-COOBu H 1-AI-Pip(4)
2188 6-F H SO₂CH₂COOH 3-COOBu H 1-AI-Pip(4)
2189 6-F H SO₂CH₂COOH 2-COOPn H 1-AI-Pip(4)
2190 6-F H SO₂CH₂COOH 3-COOPn H 1-AI-Pip(4)
2191 6-F H SO₂CH₂COOH 2-COOHx H 1-AI-Pip(4)
2192 6-F H SO₂CH₂COOH 3-COOHx H 1-AI-Pip(4)
2193 6-F H SO₂CH₂COOH 2-CONH₂ H 1-AI-Pip(4)
2194 6-F H SO₂CH₂COOH 3-CONH₂ H 1-AI-Pip(4)
2195 6-F H SO₂CH₂COOH 2-CONHMe H 1-AI-Pip(4)
2196 6-F H SO₂CH₂COOH 3-CONHMe H 1-AI-Pip(4)
2197 6-F H SO₂CH₂COOH 2-CONHEt H 1-AI-Pip(4)
2198 6-F H SO₂CH₂COOH 3-CONHEt H 1-AI-Pip(4)
2199 6-F H SO₂CH₂COOH 2-CON(Me)₂ H 1-AI-Pip(4)
2200 6-F H SO₂CH₂COOH 3-CON(Me)₂ H 1-AI-Pip(4)
2201 6-F H SO₂CH₂COOH 2-CON(Me)Et H 1-AI-Pip(4)
2202 6-F H SO₂CH₂COOH 3-CON(Me)Et H 1-AI-Pip(4)
2203 6-F H SO₂CH₂COOH 2-CON(Et)₂ H 1-AI-Pip(4)
2204 6-F H SO₂CH₂COOH 3-CON(Et)₂ H 1-AI-Pip(4)
2205 2-Me H SO₂CH₂COOH H H 1-AI-Pip(4)
2206 3-Me H SO₂CH₂COOH H H 1-AI-Pip(4)
2207 4-Me H SO₂CH₂COOH H H 1-AI-Pip(4)
2208 5-Me H SO₂CH₂COOH H H 1-AI-Pip(4)
2209 5-Me H SO₂CH₂COOH 2-F H 1-AI-Pip(4)
2210 5-Me H SO₂CH₂COOH 3-F H 1-AI-Pip(4)
2211 5-Me H SO₂CH₂COOH 2-Cl H 1-AI-Pip(4)
2212 5-Me H SO₂CH₂COOH 3-Cl H 1-AI-Pip(4)
2213 5-Me H SO₂CH₂COOH 2-Br H 1-AI-Pip(4)
2214 5-Me H SO₂CH₂COOH 3-Br H 1-AI-Pip(4)
2215 5-Me H SO₂CH₂COOH 2-I H 1-AI-Pip(4)
2216 5-Me H SO₂CH₂COOH 3-I H 1-AI-Pip(4)
2217 5-Me H SO₂CH₂COOH 2-Me H 1-AI-Pip(4)
2218 5-Me H SO₂CH₂COOH 3-Me H 1-AI-Pip(4)
2219 5-Me H SO₂CH₂COOH 2-Et H 1-AI-Pip(4)
2220 5-Me H SO₂CH₂COOH 3-Et H 1-AI-Pip(4)
2221 5-Me H SO₂CH₂COOH 2-Pr H 1-AI-Pip(4)
2222 5-Me H SO₂CH₂COOH 3-Pr H 1-AI-Pip(4)
2223 5-Me H SO₂CH₂COOH 2-Bu H 1-AI-Pip(4)
2224 5-Me H SO₂CH₂COOH 3-Bu H 1-AI-Pip(4)
2225 5-Me H SO₂CH₂COOH 2-Pn H 1-AI-Pip(4)
2226 5-Me H SO₂CH₂COOH 3-Pn H 1-AI-Pip(4)
2227 5-Me H SO₂CH₂COOH 2-Hx H 1-AI-Pip(4)
2228 5-Me H SO₂CH₂COOH 3-Hx H 1-AI-Pip(4)
2229 5-Me H SO₂CH₂COOH 2-CF₃ H 1-AI-Pip(4)
2230 5-Me H SO₂CH₂COOH 3-CF₃ H 1-AI-Pip(4)
2231 5-Me H SO₂CH₂COOH 2-OMe H 1-AI-Pip(4)
2232 5-Me H SO₂CH₂COOH 3-OMe H 1-AI-Pip(4)
2233 5-Me H SO₂CH₂COOH 2-OEt H 1-AI-Pip(4)
2234 5-Me H SO₂CH₂COOH 3-OEt H 1-AI-Pip(4)
2235 5-Me H SO₂CH₂COOH 2-COOH H 1-AI-Pip(4)
2236 5-Me H SO₂CH₂COOH 3-COOH H 1-AI-Pip(4)
2237 5-Me H SO₂CH₂COOH 2-COOMe H 1-AI-Pip(4)
2238 5-Me H SO₂CH₂COOH 3-COOMe H 1-AI-Pip(4)
2239 5-Me H SO₂CH₂COOH 2-COOEt H 1-AI-Pip(4)
2240 5-Me H SO₂CH₂COOH 3-COOEt H 1-AI-Pip(4)
2241 5-Me H SO₂CH₂COOH 2-COOPr H 1-AI-Pip(4)
2242 5-Me H SO₂CH₂COOH 3-COOPr H 1-AI-Pip(4)
2243 5-Me H SO₂CH₂COOH 2-COOBu H 1-AI-Pip(4)
2244 5-Me H SO₂CH₂COOH 3-COOBu H 1-AI-Pip(4)
2245 5-Me H SO₂CH₂COOH 2-COOPn H 1-AI-Pip(4)
2246 5-Me H SO₂CH₂COOH 3-COOPn H 1-AI-Pip(4)
2247 5-Me H SO₂CH₂COOH 2-COOHx H 1-AI-Pip(4)
2248 5-Me H SO₂CH₂COOH 3-COOHx H 1-AI-Pip(4)
2249 5-Me H SO₂CH₂COOH 2-CONH₂ H 1-AI-Pip(4)
2250 5-Me H SO₂CH₂COOH 3-CONH₂ H 1-AI-Pip(4)
2251 5-Me H SO₂CH₂COOH 2-CONHMe H 1-AI-Pip(4)
2252 5-Me H SO₂CH₂COOH 3-CONHMe H 1-AI-Pip(4)
2253 5-Me H SO₂CH₂COOH 2-CONHEt H 1-AI-Pip(4)
2254 5-Me H SO₂CH₂COOH 3-CONHEt H 1-AI-Pip(4)
2255 5-Me H SO₂CH₂COOH 2-CON(Me)₂ H 1-AI-Pip(4)
2256 5-Me H SO₂CH₂COOH 3-CON(Me)₂ H 1-AI-Pip(4)
2257 5-Me H SO₂CH₂COOH 2-CON(Me)Et H 1-AI-Pip(4)
2258 5-Me H SO₂CH₂COOH 3-CON(Me)Et H 1-AI-Pip(4)
2259 5-Me H SO₂CH₂COOH 2-CON(Et)₂ H 1-AI-Pip(4)
2260 5-Me H SO₂CH₂COOH 3-CON(Et)₂ H 1-AI-Pip(4)
2261 6-Me H SO₂CH₂COOH H H 1-AI-Pip(4)
2262 6-OH H SO₂CH₂COOH H H 1-AI-Pip(4)
2263 6-OH H SO₂CH₂COOH 2-F H 1-AI-Pip(4)
2264 6-OH H SO₂CH₂COOH 3-F H 1-AI-Pip(4)
2265 6-OH H SO₂CH₂COOH 2-Cl H 1-AI-Pip(4)
2266 6-OH H SO₂CH₂COOH 3-Cl H 1-AI-Pip(4)
2267 6-OH H SO₂CH₂COOH 2-Br H 1-AI-Pip(4)
2268 6-OH H SO₂CH₂COOH 3-Br H 1-AI-Pip(4)
2269 6-OH H SO₂CH₂COOH 2-I H 1-AI-Pip(4)
2270 6-OH H SO₂CH₂COOH 3-I H 1-AI-Pip(4)
2271 6-OH H SO₂CH₂COOH 2-Me H 1-AI-Pip(4)
2272 6-OH H SO₂CH₂COOH 3-Me H 1-AI-Pip(4)
2273 6-OH H SO₂CH₂COOH 2-Et H 1-AI-Pip(4)
2274 6-OH H SO₂CH₂COOH 3-Et H 1-AI-Pip(4)
2275 6-OH H SO₂CH₂COOH 2-Pr H 1-AI-Pip(4)
2276 6-OH H SO₂CH₂COOH 3-Pr H 1-AI-Pip(4)
2277 6-OH H SO₂CH₂COOH 2-Bu H 1-AI-Pip(4)
2278 6-OH H SO₂CH₂COOH 3-Bu H 1-AI-Pip(4)
2279 6-OH H SO₂CH₂COOH 2-Pn H 1-AI-Pip(4)
2280 6-OH H SO₂CH₂COOH 3-Pn H 1-AI-Pip(4)
2281 6-OH H SO₂CH₂COOH 2-Hx H 1-AI-Pip(4)
2282 6-OH H SO₂CH₂COOH 3-Hx H 1-AI-Pip(4)
2283 6-OH H SO₂CH₂COOH 2-CF₃ H 1-AI-Pip(4)
2284 6-OH H SO₂CH₂COOH 3-CF₃ H 1-AI-Pip(4)
2285 6-OH H SO₂CH₂COOH 2-OMe H 1-AI-Pip(4)
2286 6-OH H SO₂CH₂COOH 3-OMe H 1-AI-Pip(4)
2287 6-OH H SO₂CH₂COOH 2-OEt H 1-AI-Pip(4)
2288 6-OH H SO₂CH₂COOH 3-OEt H 1-AI-Pip(4)
2289 6-OH H SO₂CH₂COOH 2-COOH H 1-AI-Pip(4)
2290 6-OH H SO₂CH₂COOH 3-COOH H 1-AI-Pip(4)
2291 6-OH H SO₂CH₂COOH 2-COOMe H 1-AI-Pip(4)
2292 6-OH H SO₂CH₂COOH 3-COOMe H 1-AI-Pip(4)
2293 6-OH H SO₂CH₂COOH 2-COOEt H 1-AI-Pip(4)
2294 6-OH H SO₂CH₂COOH 3-COOEt H 1-AI-Pip(4)
2295 6-OH H SO₂CH₂COOH 2-COOPr H 1-AI-Pip(4)
2296 6-OH H SO₂CH₂COOH 3-COOPr H 1-AI-Pip(4)
2297 6-OH H SO₂CH₂COOH 2-COOBu H 1-AI-Pip(4)
2298 6-OH H SO₂CH₂COOH 3-COOBu H 1-AI-Pip(4)
2299 6-OH H SO₂CH₂COOH 2-COOPn H 1-AI-Pip(4)
2300 6-OH H SO₂CH₂COOH 3-COOPn H 1-AI-Pip(4)
2301 6-OH H SO₂CH₂COOH 2-COOHx H 1-AI-Pip(4)
2302 6-OH H SO₂CH₂COOH 3-COOHx H 1-AI-Pip(4)
2303 6-OH H SO₂CH₂COOH 2-CONH₂ H 1-AI-Pip(4)
2304 6-OH H SO₂CH₂COOH 3-CONH₂ H 1-AI-Pip(4)
2305 6-OH H SO₂CH₂COOH 2-CONHMe H 1-AI-Pip(4)
2306 6-OH H SO₂CH₂COOH 3-CONHMe H 1-AI-Pip(4)
2307 6-OH H SO₂CH₂COOH 2-CONHEt H 1-AI-Pip(4)
2308 6-OH H SO₂CH₂COOH 3-CONHEt H 1-AI-Pip(4)
2309 6-OH H SO₂CH₂COOH 2-CON(Me)₂ H 1-AI-Pip(4)
2310 6-OH H SO₂CH₂COOH 3-CON(Me)₂ H 1-AI-Pip(4)
2311 6-OH H SO₂CH₂COOH 2-CON(Me)EtH 1-AI-Pip(4)
2312 6-OH H SO₂CH₂COOH 3-CON(Me)EtH 1-AI-Pip(4)
2313 6-OH H SO₂CH₂COOH 2-CON(Et)₂ H 1-AI-Pip(4)
2314 6-OH H SO₂CH₂COOH 3-CON(Et)₂ H 1-AI-Pip(4)
2315 6-OH H SO₂CH₂COOH 2-F 3-F 1-AI-Pip(4)
2316 6-OH H SO₂CH₂COOH 2-F 5-F 1-AI-Pip(4)
2317 6-OH H SO₂CH₂COOH 2-F 6-F 1-AI-Pip(4)
2318 6-OH H SO₂CH₂COOH 3-F 5-F 1-AI-Pip(4)
2319 6-OH H SO₂CH₂COOH 2-Cl 3-Cl 1-AI-Pip(4)
2320 6-OH H SO₂CH₂COOH 2-Cl 5-Cl 1-AI-Pip(4)
2321 6-OH H SO₂CH₂COOH 2-Cl 6-Cl 1-AI-Pip(4)
2322 6-OH H SO₂CH₂COOH 3-Cl 5-Cl 1-AI-Pip(4)
2323 6-OH H SO₂CH₂COOH 2-Me 3-Me 1-AI-Pip(4)
2324 6-OH H SO₂CH₂COOH 2-Me 5-Me 1-AI-Pip(4)
2325 6-OH H SO₂CH₂COOH 2-Me 6-Me 1-AI-Pip(4)
2326 6-OH H SO₂CH₂COOH 3-Me 5-Me 1-AI-Pip(4)
2327 6-OH H SO₂CH₂COOH 2-Cl 5-CONH₂ 1-AI-Pip(4)
2328 6-OH H SO₂CH₂COOH 3-Cl 5-CONH₂ 1-AI-Pip(4)
2329 6-OH H SO₂CH₂COOH 3-Cl 5-CONHMe 1-AI-Pip(4)
2330 6-OH H SO₂CH₂COOH 3-Cl 5-CONHEt 1-AI-Pip(4)
2331 6-OH H SO₂CH₂COOH 3-Cl 5-CONHPr 1-AI-Pip(4)
2332 6-OH H SO₂CH₂COOH 3-Cl 5-CONHBu 1-AI-Pip(4)
2333 6-OH H SO₂CH₂COOH 3-Cl 5-CONHPn 1-AI-Pip(4)
2334 6-OH H SO₂CH₂COOH 3-Cl 5-CONHHx 1-AI-Pip(4)
2335 6-OH H SO₂CH₂COOH 2-Me 5-CONH₂ 1-AI-Pip(4)
2336 6-OH H SO₂CH₂COOH 2-Me 5-CONHMe 1-AI-Pip(4)
2337 6-OH H SO₂CH₂COOH 2-Me 5-CONHEt 1-AI-Pip(4)
2338 6-OH H SO₂CH₂COOH 2-Me 5-CONHPr 1-AI-Pip(4)
2339 6-OH H SO₂CH₂COOH 2-Me 5-CONHBu 1-AI-Pip(4)
2340 6-OH H SO₂CH₂COOH 2-Me 5-CONHPn 1-AI-Pip(4)
2341 6-OH H SO₂CH₂COOH 2-Me 5-CONHHx 1-AI-Pip(4)
2342 6-OH H SO₂CH₂COOH 3-Me 5-CONH₂ 1-AI-Pip(4)
2343 6-OH H SO₂CH₂COOH 3-Me 5-CONHMe 1-AI-Pip(4)
2344 6-OH H SO₂CH₂COOH 3-Me 5-CONHEt 1-AI-Pip(4)
2345 6-OH H SO₂CH₂COOH 3-Me 5-CONHPr 1-AI-Pip(4)
2346 6-OH H SO₂CH₂COOH 3-Me 5-CONHBu 1-AI-Pip(4)
2347 6-OH H SO₂CH₂COOH 3-Me 5-CONHPn 1-AI-Pip(4)
2348 6-OH H SO₂CH₂COOH 3-Me 5-CONHHx 1-AI-Pip(4)
2349 6-OH H SO₂CH₂COOH 2-CONH₂ 6-CONH₂ 1-AI-Pip(4)
2350 6-OH H SO₂CH₂COOH 3-CONH₂ 5-CONH₂ 1-AI-Pip(4)
2351 6-OH H SO₂CH₂COOH 3-CONHMe 5-CONHMe 1-AI-Pip(4)
2352 6-OH H SO₂CH₂COOH 3-CONHEt 5-CONHEt 1-AI-Pip(4)
2353 H H SO₂(CH₂)₂COOH H H 1-AI-Pip(4)
2354 H H SO₂(CH₂)₃COOH H H 1-AI-Pip(4)
2355 H H SO₂(CH₂)₄COOH H H 1-AI-Pip(4)
2356 H H SO₂(CH₂)₅COOH H H 1-AI-Pip(4)
2357 H H SO₂(CH₂)₆COOH H H 1-AI-Pip(4)
2358 H H SO₂CH₂COOMe 2-F H 1-AI-Pip(4)
2359 H H SO₂CH₂COOMe 3-F H 1-AI-Pip(4)
2360 H H SO₂CH₂COOMe 2-Cl H 1-AI-Pip(4)
2361 H H SO₂CH₂COOMe 3-Cl H 1-AI-Pip(4)
2362 H H SO₂CH₂COOMe 2-Br H 1-AI-Pip(4)
2363 H H SO₂CH₂COOMe 3-Br H 1-AI-Pip(4)
2364 H H SO₂CH₂COOMe 2-I H 1-AI-Pip(4)
2365 H H SO₂CH₂COOMe 3-I H 1-AI-Pip(4)
2366 H H SO₂CH₂COOMe 2-Me H 1-AI-Pip(4)
2367 H H SO₂CH₂COOMe 3-Me H 1-AI-Pip(4)
2368 H H SO₂CH₂COOMe 2-Et H 1-AI-Pip(4)
2369 H H SO₂CH₂COOMe 3-Et H 1-AI-Pip(4)
2370 H H SO₂CH₂COOMe 2-Pr H 1-AI-Pip(4)
2371 H H SO₂CH₂COOMe 3-Pr H 1-AI-Pip(4)
2372 H H SO₂CH₂COOMe 2-iPr H 1-AI-Pip(4)
2373 H H SO₂CH₂COOMe 3-iPr H 1-AI-Pip(4)
2374 H H SO₂CH₂COOMe 2-Bu H 1-AI-Pip(4)
2375 H H SO₂CH₂COOMe 3-Bu H 1-AI-Pip(4)
2376 H H SO₂CH₂COOMe 2-iBu H 1-AI-Pip(4)
2377 H H SO₂CH₂COOMe 3-iBu H 1-AI-Pip(4)
2378 H H SO₂CH₂COOMe 2-sBu H 1-AI-Pip(4)
2379 H H SO₂CH₂COOMe 3-sBu H 1-AI-Pip(4)
2380 H H SO₂CH₂COOMe 2-tBu H 1-AI-Pip(4)
2381 H H SO₂CH₂COOMe 3-tBu H 1-AI-Pip(4)
2382 H H SO₂CH₂COOMe 2-Pn H 1-AI-Pip(4)
2383 H H SO₂CH₂COOMe 3-Pn H 1-AI-Pip(4)
2384 H H SO₂CH₂COOMe 2-Hx H 1-AI-Pip(4)
2385 H H SO₂CH₂COOMe 3-Hx H 1-AI-Pip(4)
2386 H H SO₂CH₂COOMe 2-CF₃ H 1-AI-Pip(4)
2387 H H SO₂CH₂COOMe 3-CF₃ H 1-AI-Pip(4)
2388 H H SO₂CH₂COOMe 2-OMe H 1-AI-Pip(4)
2389 H H SO₂CH₂COOMe 3-OMe H 1-AI-Pip(4)
2390 H H SO₂CH₂COOMe 2-OEt H 1-AI-Pip(4)
2391 H H SO₂CH₂COOMe 3-OEt H 1-AI-Pip(4)
2392 H H SO₂CH₂COOMe 2-COOH H 1-AI-Pip(4)
2393 H H SO₂CH₂COOMe 3-COOH H 1-AI-Pip(4)
2394 H H SO₂CH₂COOMe 2-COOMe H 1-AI-Pip(4)
2395 H H SO₂CH₂COOMe 3-COOMe H 1-AI-Pip(4)
2396 H H SO₂CH₂COOMe 2-COOEt H 1-AI-Pip(4)
2397 H H SO₂CH₂COOMe 3-COOEt H 1-AI-Pip(4)
2398 H H SO₂CH₂COOMe 2-COOPr H 1-AI-Pip(4)
2399 H H SO₂CH₂COOMe 3-COOPr H 1-AI-Pip(4)
2400 H H SO₂CH₂COOMe 2-COOBu H 1-AI-Pip(4)
2401 H H SO₂CH₂COOMe 3-COOBu H 1-AI-Pip(4)
2402 H H SO₂CH₂COOMe 2-COOPn H 1-AI-Pip(4)
2403 H H SO₂CH₂COOMe 3-COOPn H 1-AI-Pip(4)
2404 H H SO₂CH₂COOMe 2-COOHx H 1-AI-Pip(4)
2405 H H SO₂CH₂COOMe 3-COOHx H 1-AI-Pip(4)
2406 H H SO₂CH₂COOMe 2-CONH₂ H 1-AI-Pip(4)
2407 H H SO₂CH₂COOMe 3-CONH₂ H 1-AI-Pip(4)
2408 H H SO₂CH₂COOMe 2-CONHMe H 1-AI-Pip(4)
2409 H H SO₂CH₂COOMe 3-CONHMe H 1-AI-Pip(4)
2410 H H SO₂CH₂COOMe 2-CONHEt H 1-AI-Pip(4)
2411 H H SO₂CH₂COOMe 3-CONHEt H 1-AI-Pip(4)
2412 H H SO₂CH₂COOMe 2-CON(Me)₂ H 1-AI-Pip(4)
2413 H H SO₂CH₂COOMe 3-CON(Me)₂ H 1-AI-Pip(4)
2414 H H SO₂CH₂COOMe 2-CON(Me)Et H 1-AI-Pip(4)
2415 H H SO₂CH₂COOMe 3-CON(Me)Et H 1-AI-Pip(4)
2416 H H SO₂CH₂COOMe 2-CON(Et)₂ H 1-AI-Pip(4)
2417 H H SO₂CH₂COOMe 3-CON(Et)₂ H 1-AI-Pip(4)
2418 H H SO₂CH₂COOMe 2-F 3-F 1-AI-Pip(4)
2419 H H SO₂CH₂COOMe 2-F 5-F 1-AI-Pip(4)
2420 H H SO₂CH₂COOMe 2-F 6-F 1-AI-Pip(4)
2421 H H SO₂CH₂COOMe 3-F 5-F 1-AI-Pip(4)
2422 H H SO₂CH₂COOMe 2-Cl 3-Cl 1-AI-Pip(4)
2423 H H SO₂CH₂COOMe 2-Cl 5-Cl 1-AI-Pip(4)
2424 H H SO₂CH₂COOMe 2-Cl 6-Cl 1-AI-Pip(4)
2425 H H SO₂CH₂COOMe 3-Cl 5-Cl 1-AI-Pip(4)
2426 H H SO₂CH₂COOMe 2-Me 3-Me 1-AI-Pip(4)
2427 H H SO₂CH₂COOMe 2-Me 5-Me 1-AI-Pip(4)
2428 H H SO₂CH₂COOMe 2-Me 6-Me 1-AI-Pip(4)
2429 H H SO₂CH₂COOMe 3-Me 5-Me 1-AI-Pip(4)
2430 H H SO₂CH₂COOMe 2-Cl 5-CONH₂ 1-AI-Pip(4)
2431 H H SO₂CH₂COOMe 3-Cl 5-CONH₂ 1-AI-Pip(4)
2432 H H SO₂CH₂COOMe 3-Cl 5-CONHMe 1-AI-Pip(4)
2433 H H SO₂CH₂COOMe 3-Cl 5-CONHEt 1-AI-Pip(4)
2434 H H SO₂CH₂COOMe 3-Cl 5-CONHPr 1-AI-Pip(4)
2435 H H SO₂CH₂COOMe 3-Cl 5-CONHBu 1-AI-Pip(4)
2436 H H SO₂CH₂COOMe 3-Cl 5-CONHPn 1-AI-Pip(4)
2437 H H SO₂CH₂COOMe 3-Cl 5-CONHHx 1-AI-Pip(4)
2438 H H SO₂CH₂COOMe 2-Me 5-CONH₂ 1-AI-Pip(4)
2439 H H SO₂CH₂COOMe 2-Me 5-CONHMe 1-AI-Pip(4)
2440 H H SO₂CH₂COOMe 2-Me 5-CONHEt 1-AI-Pip(4)
2441 H H SO₂CH₂COOMe 2-Me 5-CONHPr 1-AI-Pip(4)
2442 H H SO₂CH₂COOMe 2-Me 5-CONHBu 1-AI-Pip(4)
2443 H H SO₂CH₂COOMe 2-Me 5-CONHPn 1-AI-Pip(4)
2444 H H SO₂CH₂COOMe 2-Me 5-CONHHx 1-AI-Pip(4)
2445 H H SO₂CH₂COOMe 3-Me 5-CONH₂ 1-AI-Pip(4)
2446 H H SO₂CH₂COOMe 3-Me 5-CONHMe 1-AI-Pip(4)
2447 H H SO₂CH₂COOMe 3-Me 5-CONHEt 1-AI-Pip(4)
2448 H H SO₂CH₂COOMe 3-Me 5-CONHPr 1-AI-Pip(4)
2449 H H SO₂CH₂COOMe 3-Me 5-CONHBu 1-AI-Pip(4)
2450 H H SO₂CH₂COOMe 3-Me 5-CONHPn 1-AI-Pip(4)
2451 H H SO₂CH₂COOMe 3-Me 5-CONHHx 1-AI-Pip(4)
2452 H H SO₂CH₂COOMe 2-CONH₂ 6-CONH₂ 1-AI-Pip(4)
2453 H H SO₂CH₂COOMe 3-CONH₂ 5-CONH₂ 1-AI-Pip(4)
2454 H H SO₂CH₂COOMe 3-CONHMe 5-CONHMe 1-AI-Pip(4)
2455 H H SO₂CH₂COOMe 3-CONHEt 5-CONHEt 1-AI-Pip(4)
2456 6-OH H SO₂CH₂COOMe 2-F H 1-AI-Pip(4)
2457 6-OH H SO₂CH₂COOMe 3-F H 1-AI-Pip(4)
2458 6-OH H SO₂CH₂COOMe 2-Cl H 1-AI-Pip(4)
2459 6-OH H SO₂CH₂COOMe 3-Cl H 1-AI-Pip(4)
2460 6-OH H SO₂CH₂COOMe 2-Br H 1-AI-Pip(4)
2461 6-OH H SO₂CH₂COOMe 3-Br H 1-AI-Pip(4)
2462 6-OH H SO₂CH₂COOMe 2-I H 1-AI-Pip(4)
2463 6-OH H SO₂CH₂COOMe 3-I H 1-AI-Pip(4)
2464 6-OH H SO₂CH₂COOMe 2-Me H 1-AI-Pip(4)
2465 6-OH H SO₂CH₂COOMe 3-Me H 1-AI-Pip(4)
2466 6-OH H SO₂CH₂COOMe 2-Et H 1-AI-Pip(4)
2467 6-OH H SO₂CH₂COOMe 3-Et H 1-AI-Pip(4)
2468 6-OH H SO₂CH₂COOMe 2-Pr H 1-AI-Pip(4)
2469 6-OH H SO₂CH₂COOMe 3-Pr H 1-AI-Pip(4)
2470 6-OH H SO₂CH₂COOMe 2-iPr H 1-AI-Pip(4)
2471 6-OH H SO₂CH₂COOMe 3-iPr H 1-AI-Pip(4)
2472 6-OH H SO₂CH₂COOMe 2-Bu H 1-AI-Pip(4)
2473 6-OH H SO₂CH₂COOMe 3-Bu H 1-AI-Pip(4)
2474 6-OH H SO₂CH₂COOMe 2-iBu H 1-AI-Pip(4)
2475 6-OH H SO₂CH₂COOMe 3-iBu H 1-AI-Pip(4)
2476 6-OH H SO₂CH₂COOMe 2-sBu H 1-AI-Pip(4)
2477 6-OH H SO₂CH₂COOMe 3-sBu H 1-AI-Pip(4)
2478 6-OH H SO₂CH₂COOMe 2-tBu H 1-AI-Pip(4)
2479 6-OH H SO₂CH₂COOMe 3-tBu H 1-AI-Pip(4)
2480 6-OH H SO₂CH₂COOMe 2-Pn H 1-AI-Pip(4)
2481 6-OH H SO₂CH₂COOMe 3-Pn H 1-AI-Pip(4)
2482 6-OH H SO₂CH₂COOMe 2-Hx H 1-AI-Pip(4)
2483 6-OH H SO₂CH₂COOMe 3-Hx H 1-AI-Pip(4)
2484 6-OH H SO₂CH₂COOMe 2-CF₃ H 1-AI-Pip(4)
2485 6-OH H SO₂CH₂COOMe 3-CF₃ H 1-AI-Pip(4)
2486 6-OH H SO₂CH₂COOMe 2-OMe H 1-AI-Pip(4)
2487 6-OH H SO₂CH₂COOMe 3-OMe H 1-AI-Pip(4)
2488 6-OH H SO₂CH₂COOMe 2-OEt H 1-AI-Pip(4)
2489 6-OH H SO₂CH₂COOMe 3-OEt H 1-AI-Pip(4)
2490 6-OH H SO₂CH₂COOMe 2-COOH H 1-AI-Pip(4)
2491 6-OH H SO₂CH₂COOMe 3-COOH H 1-AI-Pip(4)
2492 6-OH H SO₂CH₂COOMe 2-COOMe H 1-AI-Pip(4)
2493 6-OH H SO₂CH₂COOMe 3-COOMe H 1-AI-Pip(4)
2494 6-OH H SO₂CH₂COOMe 2-COOEt H 1-AI-Pip(4)
2495 6-OH H SO₂CH₂COOMe 3-COOEt H 1-AI-Pip(4)
2496 6-OH H SO₂CH₂COOMe 2-COOPr H 1-AI-Pip(4)
2497 6-OH H SO₂CH₂COOMe 3-COOPr H 1-AI-Pip(4)
2498 6-OH H SO₂CH₂COOMe 2-COOBu H 1-AI-Pip(4)
2499 6-OH H SO₂CH₂COOMe 3-COOBu H 1-AI-Pip(4)
2500 6-OH H SO₂CH₂COOMe 2-COOPn H 1-AI-Pip(4)
2501 6-OH H SO₂CH₂COOMe 3-COOPn H 1-AI-Pip(4)
2502 6-OH H SO₂CH₂COOMe 2-COOHx H 1-AI-Pip(4)
2503 6-OH H SO₂CH₂COOMe 3-COOHx H 1-AI-Pip(4)
2504 6-OH H SO₂CH₂COOMe 2-CONH₂ H 1-AI-Pip(4)
2505 6-OH H SO₂CH₂COOMe 3-CONH₂ H 1-AI-Pip(4)
2506 6-OH H SO₂CH₂COOMe 2-CONHMe H 1-AI-Pip(4)
2507 6-OH H SO₂CH₂COOMe 3-CONHMe H 1-AI-Pip(4)
2508 6-OH H SO₂CH₂COOMe 2-CONHEt H 1-AI-Pip(4)
2509 6-OH H SO₂CH₂COOMe 3-CONHEt H 1-AI-Pip(4)
2510 6-OH H SO₂CH₂COOMe 2-CON(Me)₂ H 1-AI-Pip(4)
2511 6-OH H SO₂CH₂COOMe 3-CON(Me)₂ H 1-AI-Pip(4)
2512 6-OH H SO₂CH₂COOMe 2-CON(Me)Et H 1-AI-Pip(4)
2513 6-OH H SO₂CH₂COOMe 3-CON(Me)Et H 1-AI-Pip(4)
2514 6-OH H SO₂CH₂COOMe 2-CON(Et)₂ H 1-AI-Pip(4)
2515 6-OH H SO₂CH₂COOMe 3-CON(Et)₂ H 1-AI-Pip(4)
2516 6-OH H SO₂CH₂COOMe 2-F 3-F 1-AI-Pip(4)
2517 6-OH H SO₂CH₂COOMe 2-F 5-F 1-AI-Pip(4)
2518 6-OH H SO₂CH₂COOMe 2-F 6-F 1-AI-Pip(4)
2519 6-OH H SO₂CH₂COOMe 3-F 5-F 1-AI-Pip(4)
2520 6-OH H SO₂CH₂COOMe 2-Cl 3-Cl 1-AI-Pip(4)
2521 6-OH H SO₂CH₂COOMe 2-Cl 5-Cl 1-AI-Pip(4)
2522 6-OH H SO₂CH₂COOMe 2-Cl 6-Cl 1-AI-Pip(4)
2523 6-OH H SO₂CH₂COOMe 3-Cl 5-Cl 1-AI-Pip(4)
2524 6-OH H SO₂CH₂COOMe 2-Me 3-Me 1-AI-Pip(4)
2525 6-OH H SO₂CH₂COOMe 2-Me 5-Me 1-AI-Pip(4)
2526 6-OH H SO₂CH₂COOMe 2-Me 6-Me 1-AI-Pip(4)
2527 6-OH H SO₂CH₂COOMe 3-Me 5-Me 1-AI-Pip(4)
2528 6-OH H SO₂CH₂COOMe 2-Cl 5-CONH₂ 1-AI-Pip(4)
2529 6-OH H SO₂CH₂COOMe 3-Cl 5-CONH₂ 1-AI-Pip(4)
2530 6-OH H SO₂CH₂COOMe 3-Cl 5-CONHMe 1-AI-Pip(4)
2531 6-OH H SO₂CH₂COOMe 3-Cl 5-CONHEt 1-AI-Pip(4)
2532 6-OH H SO₂CH₂COOMe 3-Cl 5-CONHPr 1-AI-Pip(4)
2533 6-OH H SO₂CH₂COOMe 3-Cl 5-CONHBu 1-AI-Pip(4)
2534 6-OH H SO₂CH₂COOMe 3-Cl 5-CONHPn 1-AI-Pip(4)
2535 6-OH H SO₂CH₂COOMe 3-Cl 5-CONHHx 1-AI-Pip(4)
2536 6-OH H SO₂CH₂COOMe 2-Me 5-CONH₂ 1-AI-Pip(4)
2537 6-OH H SO₂CH₂COOMe 2-Me 5-CONHMe 1-AI-Pip(4)
2538 6-OH H SO₂CH₂COOMe 2-Me 5-CONHEt 1-AI-Pip(4)
2539 6-OH H SO₂CH₂COOMe 2-Me 5-CONHPr 1-AI-Pip(4)
2540 6-OH H SO₂CH₂COOMe 2-Me 5-CONHBu 1-AI-Pip(4)
2541 6-OH H SO₂CH₂COOMe 2-Me 5-CONHPn 1-AI-Pip(4)
2542 6-OH H SO₂CH₂COOMe 2-Me 5-CONHHx 1-AI-Pip(4)
2543 6-OH H SO₂CH₂COOMe 3-Me 5-CONH₂ 1-AI-Pip(4)
2544 6-OH H SO₂CH₂COOMe 3-Me 5-CONHMe 1-AI-Pip(4)
2545 6-OH H SO₂CH₂COOMe 3-Me 5-CONHEt 1-AI-Pip(4)
2546 6-OH H SO₂CH₂COOMe 3-Me 5-CONHPr 1-AI-Pip(4)
2547 6-OH H SO₂CH₂COOMe 3-Me 5-CONHBu 1-AI-Pip(4)
2548 6-OH H SO₂CH₂COOMe 3-Me 5-CONHPn 1-AI-Pip(4)
2549 6-OH H SO₂CH₂COOMe 3-Me 5-CONHHx 1-AI-Pip(4)
2550 6-OH H SO₂CH₂COOMe 2-CONH₂ 6-CONH₂ 1-AI-Pip(4)
2551 6-OH H SO₂CH₂COOMe 3-CONH₂ 5-CONH₂ 1-AI-Pip(4)
2552 6-OH H SO₂CH₂COOMe 3-CONHMe 5-CONHMe 1-AI-Pip(4)
2553 6-OH H SO₂CH₂COOMe 3-CONHEt 5-CONHEt 1-AI-Pip(4)

Compound R¹  R²  R^Three                R^Four          R^Five          R⁶
number
1 H H H H H 1-AI-Pyrd (3)
2 H H Me H H 1-AI-Pyrd (3)
3 H H Et H H 1-AI-Pyrd (3)
4 H H iPr H H 1-AI-Pyrd (3)
5 H H iPr 3-Cl H 1-AI-Pyrd (3)
6 H H iPr 3-Me H 1-AI-Pyrd (3)
7 H H iPr 3-CONH₂    H 1-AI-Pyrd (3)
8 H H iPr 3-F 5-F 1-AI-Pyrd (3)
9 H H iPr 3-Cl 5-Cl 1-AI-Pyrd (3)
10 H H iPr 3-Me 5-Me 1-AI-Pyrd (3)
11 H H iPr 3-Cl 5-CONH₂    1-AI-Pyrd (3)
12 H H iPr 2-Me 5-CONH₂    1-AI-Pyrd (3)
13 H H iPr 3-Me 5-CONH₂    1-AI-Pyrd (3)
14 H H iPr 3-CONH₂    5-CONH₂    1-AI-Pyrd (3)
15 6-OH H iPr H H 1-AI-Pyrd (3)
16 6-OH H iPr 3-Cl H 1-AI-Pyrd (3)
17 6-OH H iPr 3-Me H 1-AI-Pyrd (3)
18 6-OH H iPr 3-CONH₂    H 1-AI-Pyrd (3)
19 H H Bu H H 1-AI-Pyrd (3)
20 H H Pn H H 1-AI-Pyrd (3)
21 H H Hx H H 1-AI-Pyrd (3)
22 H H CH₂OH H H 1-AI-Pyrd (3)
23 H H (CH₂)₂OH H H 1-AI-Pyrd (3)
24 6-OH H (CH₂)₂OH H H 1-AI-Pyrd (3)
25 H H (CH₂)_ThreeOH H H 1-AI-Pyrd (3)
26 H H (CH₂)_FourOH H H 1-AI-Pyrd (3)
27 H H (CH₂)_FiveOH H H 1-AI-Pyrd (3)
28 H H (CH₂)₆OH H H 1-AI-Pyrd (3)
29 H H CH₂COOH H H 1-AI-Pyrd (3)
30 H H CH₂COOH 3-Cl H 1-AI-Pyrd (3)
31 H H CH₂COOH 3-Me H 1-AI-Pyrd (3)
32 H H CH₂COOH 3-CONH₂    H 1-AI-Pyrd (3)
33 H H CH₂COOH 3-F 5-F 1-AI-Pyrd (3)
34 H H CH₂COOH 3-Cl 5-Cl 1-AI-Pyrd (3)
35 H H CH₂COOH 3-Me 5-Me 1-AI-Pyrd (3)
36 H H CH₂COOH 3-Cl 5-CONH₂    1-AI-Pyrd (3)
37 H H CH₂COOH 2-Me 5-CONH₂    1-AI-Pyrd (3)
38 H H CH₂COOH 3-Me 5-CONH₂    1-AI-Pyrd (3)
39 H H CH₂COOH 3-CONH₂    5-CONH₂    1-AI-Pyrd (3)
40 6-OH H CH₂COOH H H 1-AI-Pyrd (3)
41 6-OH H CH₂COOH 3-Cl H 1-AI-Pyrd (3)
42 6-OH H CH₂COOH 3-Me H 1-AI-Pyrd (3)
43 6-OH H CH₂COOH 3-CONH₂    H 1-AI-Pyrd (3)
44 H H (CH₂)₂COOH H H 1-AI-Pyrd (3)
45 H H (CH₂)_ThreeCOOH H H 1-AI-Pyrd (3)
46 H H (CH₂)_FourCOOH H H 1-AI-Pyrd (3)
47 H H (CH₂)_FiveCOOH H H 1-AI-Pyrd (3)
48 H H (CH₂)₆COOH H H 1-AI-Pyrd (3)
49 H H CH₂COOMe H H 1-AI-Pyrd (3)
50 H H CH₂COOEt H H 1-AI-Pyrd (3)
51 H H CH₂COOEt 3-Cl H 1-AI-Pyrd (3)
52 H H CH₂COOEt 3-Me H 1-AI-Pyrd (3)
53 H H CH₂COOEt 3-CONH₂    H 1-AI-Pyrd (3)
54 H H CH₂COOEt 3-F 5-F 1-AI-Pyrd (3)
55 H H CH₂COOEt 3-Cl 5-Cl 1-AI-Pyrd (3)
56 H H CH₂COOEt 3-Me 5-Me 1-AI-Pyrd (3)
57 H H CH₂COOEt 3-Cl 5-CONH₂    1-AI-Pyrd (3)
58 H H CH₂COOEt 2-Me 5-CONH₂    1-AI-Pyrd (3)
59 H H CH₂COOEt 3-Me 5-CONH₂    1-AI-Pyrd (3)
60 H H CH₂COOEt 3-CONH₂    5-CONH₂    1-AI-Pyrd (3)
61 6-OH H CH₂COOEt H H 1-AI-Pyrd (3)
62 6-OH H CH₂COOEt 3-Cl H 1-AI-Pyrd (3)
63 6-OH H CH₂COOEt 3-Me H 1-AI-Pyrd (3)
64 6-OH H CH₂COOEt 3-CONH₂    H 1-AI-Pyrd (3)
65 H H CH₂COOPr H H 1-AI-Pyrd (3)
66 H H CH₂COOBu H H 1-AI-Pyrd (3)
67 H H CH₂COOPn H H 1-AI-Pyrd (3)
68 H H CH₂COOHx H H 1-AI-Pyrd (3)
69 H H (CH₂)₂COOEt H H 1-AI-Pyrd (3)
70 H H (CH₂)_ThreeCOOMe H H 1-AI-Pyrd (3)
71 H H (CH₂)_FourCOOPr H H 1-AI-Pyrd (3)
72 H H (CH₂)_FiveCOOBu H H 1-AI-Pyrd (3)
73 H H (CH₂)₆COOHx H H 1-AI-Pyrd (3)
74 H H Bn H H 1-AI-Pyrd (3)
75 H H (CH₂)₂Ph H H 1-AI-Pyrd (3)
76 H H (CH₂)_ThreePh H H 1-AI-Pyrd (3)
77 H H (CH₂)_FourPh H H 1-AI-Pyrd (3)
78 H H CHO H H 1-AI-Pyrd (3)
79 H H Ac H H 1-AI-Pyrd (3)
80 H H Prn H H 1-AI-Pyrd (3)
81 H H Va H H 1-AI-Pyrd (3)
82 H H SO₂Me H H 1-AI-Pyrd (3)
83 H H SO₂Et H H 1-AI-Pyrd (3)
84 6-OH H SO₂Et H H 1-AI-Pyrd (3)
85 H H SO₂Pr H H 1-AI-Pyrd (3)
86 H H SO₂Bu H H 1-AI-Pyrd (3)
87 H H SO₂Pn H H 1-AI-Pyrd (3)
88 H H SO₂Hx H H 1-AI-Pyrd (3)
89 H H SO₂CH₂COOMe H H 1-AI-Pyrd (3)
90 H H SO₂CH₂COOEt H H 1-AI-Pyrd (3)
91 H H SO₂CH₂COOEt 3-F H 1-AI-Pyrd (3)
92 H H SO₂CH₂COOEt 2-Cl H 1-AI-Pyrd (3)
93 H H SO₂CH₂COOEt 3-Cl H 1-AI-Pyrd (3)
94 H H SO₂CH₂COOEt 2-Me H 1-AI-Pyrd (3)
95 H H SO₂CH₂COOEt 3-Me H 1-AI-Pyrd (3)
96 H H SO₂CH₂COOEt 3-Et H 1-AI-Pyrd (3)
97 H H SO₂CH₂COOEt 3-CF_Three      H 1-AI-Pyrd (3)
98 H H SO₂CH₂COOEt 2-OEt H 1-AI-Pyrd (3)
99 H H SO₂CH₂COOEt 3-OMe H 1-AI-Pyrd (3)
100 H H SO₂CH₂COOEt 2-CONH₂    H 1-AI-Pyrd (3)
101 H H SO₂CH₂COOEt 3-CONH₂    H 1-AI-Pyrd (3)
102 H H SO₂CH₂COOEt 3-F 5-F 1-AI-Pyrd (3)
103 H H SO₂CH₂COOEt 3-Cl 5-Cl 1-AI-Pyrd (3)
104 H H SO₂CH₂COOEt 3-Me 5-Me 1-AI-Pyrd (3)
105 H H SO₂CH₂COOEt 3-Cl 5-CONH₂    1-AI-Pyrd (3)
106 H H SO₂CH₂COOEt 2-Me 5-CONH₂    1-AI-Pyrd (3)
107 H H SO₂CH₂COOEt 3-Me 5-CONH₂    1-AI-Pyrd (3)
108 H H SO₂CH₂COOEt 3-CONH₂    5-CONH₂    1-AI-Pyrd (3)
109 H F SO₂CH₂COOEt H H 1-AI-Pyrd (3)
110 H Cl SO₂CH₂COOEt H H 1-AI-Pyrd (3)
111 H Me SO₂CH₂COOEt H H 1-AI-Pyrd (3)
112 H Et SO₂CH₂COOEt H H 1-AI-Pyrd (3)
113 2-F H SO₂CH₂COOEt H H 1-AI-Pyrd (3)
114 4-F H SO₂CH₂COOEt H H 1-AI-Pyrd (3)
115 5-F H SO₂CH₂COOEt H H 1-AI-Pyrd (3)
116 6-F H SO₂CH₂COOEt H H 1-AI-Pyrd (3)
117 2-Cl H SO₂CH₂COOEt H H 1-AI-Pyrd (3)
118 6-Cl H SO₂CH₂COOEt H H 1-AI-Pyrd (3)
119 4-Me H SO₂CH₂COOEt H H 1-AI-Pyrd (3)
120 6-Me H SO₂CH₂COOEt H H 1-AI-Pyrd (3)
121 5-Et H SO₂CH₂COOEt H H 1-AI-Pyrd (3)
122 6-Pr H SO₂CH₂COOEt H H 1-AI-Pyrd (3)
123 2-OH H SO₂CH₂COOEt H H 1-AI-Pyrd (3)
124 4-OH H SO₂CH₂COOEt H H 1-AI-Pyrd (3)
125 5-OH H SO₂CH₂COOEt H H 1-AI-Pyrd (3)
126 6-OH H SO₂CH₂COOEt H H 1-AI-Pyrd (3)
127 H H SO₂CH₂COOPr H H 1-AI-Pyrd (3)
128 H H SO₂CH₂COOBu H H 1-AI-Pyrd (3)
129 H H SO₂CH₂COOPn H H 1-AI-Pyrd (3)
130 H H SO₂CH₂COOHx H H 1-AI-Pyrd (3)
131 H H SO₂(CH₂)₂COOMe H H 1-AI-Pyrd (3)
132 H H SO₂(CH₂)₂COOEt H H 1-AI-Pyrd (3)
133 H H SO₂(CH₂)₂COOPr H H 1-AI-Pyrd (3)
134 H H SO₂(CH₂)₂COOBu H H 1-AI-Pyrd (3)
135 H H SO₂(CH₂)₂COOPn H H 1-AI-Pyrd (3)
136 H H SO₂(CH₂)₂COOHx H H 1-AI-Pyrd (3)
137 H H SO₂CH₂COOH H H 1-AI-Pyrd (3)
138 H H SO₂CH₂COOH 3-F H 1-AI-Pyrd (3)
139 H H SO₂CH₂COOH 2-Cl H 1-AI-Pyrd (3)
140 H H SO₂CH₂COOH 3-Cl H 1-AI-Pyrd (3)
141 H H SO₂CH₂COOH 2-Me H 1-AI-Pyrd (3)
142 H H SO₂CH₂COOH 3-Me H 1-AI-Pyrd (3)
143 H H SO₂CH₂COOH 3-Et H 1-AI-Pyrd (3)
144 H H SO₂CH₂COOH 3-CF_Three      H 1-AI-Pyrd (3)
145 H H SO₂CH₂COOH 2-OMe H 1-AI-Pyrd (3)
146 H H SO₂CH₂COOH 3-OEt H 1-AI-Pyrd (3)
147 H H SO₂CH₂COOH 2-CONH₂    H 1-AI-Pyrd (3)
148 H H SO₂CH₂COOH 3-CONH₂    H 1-AI-Pyrd (3)
149 H H SO₂CH₂COOH 3-F 5-F 1-AI-Pyrd (3)
150 H H SO₂CH₂COOH 3-Cl 5-Cl 1-AI-Pyrd (3)
151 H H SO₂CH₂COOH 3-Me 5-Me 1-AI-Pyrd (3)
152 H H SO₂CH₂COOH 3-Cl 5-CONH₂    1-AI-Pyrd (3)
153 H H SO₂CH₂COOH 2-Me 5-CONH₂    1-AI-Pyrd (3)
154 H H SO₂CH₂COOH 3-Me 5-CONH₂    1-AI-Pyrd (3)
155 H H SO₂CH₂COOH 3-CONH₂    5-CONH₂    1-AI-Pyrd (3)
156 H F SO₂CH₂COOH H H 1-AI-Pyrd (3)
157 H Cl SO₂CH₂COOH H H 1-AI-Pyrd (3)
158 H Me SO₂CH₂COOH H H 1-AI-Pyrd (3)
159 H Et SO₂CH₂COOH H H 1-AI-Pyrd (3)
160 2-F H SO₂CH₂COOH H H 1-AI-Pyrd (3)
161 4-F H SO₂CH₂COOH H H 1-AI-Pyrd (3)
162 5-F H SO₂CH₂COOH H H 1-AI-Pyrd (3)
163 6-F H SO₂CH₂COOH H H 1-AI-Pyrd (3)
164 2-Cl H SO₂CH₂COOH H H 1-AI-Pyrd (3)
165 6-Cl H SO₂CH₂COOH H H 1-AI-Pyrd (3)
166 4-Me H SO₂CH₂COOH H H 1-AI-Pyrd (3)
167 6-Me H SO₂CH₂COOH H H 1-AI-Pyrd (3)
168 5-Et H SO₂CH₂COOH H H 1-AI-Pyrd (3)
169 6-Pr H SO₂CH₂COOH H H 1-AI-Pyrd (3)
170 2-OH H SO₂CH₂COOH H H 1-AI-Pyrd (3)
171 4-OH H SO₂CH₂COOH H H 1-AI-Pyrd (3)
172 5-OH H SO₂CH₂COOH H H 1-AI-Pyrd (3)
173 6-OH H SO₂CH₂COOH H H 1-AI-Pyrd (3)
174 H H SO₂CH₂COOH H H 1-AI-Pyrd (3)
175 H H SO₂CH₂COOH H H 1-AI-Pyrd (3)
176 H H SO₂(CH₂)₂COOH H H 1-AI-Pyrd (3)
177 H H H H H 1-AI-Pip (4)
178 H H H 2-F H 1-AI-Pip (4)
179 H H H 3-F H 1-AI-Pip (4)
180 H H H 2-Cl H 1-AI-Pip (4)
181 H H H 3-Cl H 1-AI-Pip (4)
182 H H H 2-Br H 1-AI-Pip (4)
183 H H H 3-Br H 1-AI-Pip (4)
184 H H H 2-I H 1-AI-Pip (4)
185 H H H 3-I H 1-AI-Pip (4)
186 H H H 2-Me H 1-AI-Pip (4)
187 H H H 3-Me H 1-AI-Pip (4)
188 H H H 2-Et H 1-AI-Pip (4)
189 H H H 3-Et H 1-AI-Pip (4)
190 H H H 2-Pr H 1-AI-Pip (4)
191 H H H 3-Pr H 1-AI-Pip (4)
192 H H H 2-Bu H 1-AI-Pip (4)
193 H H H 3-Bu H 1-AI-Pip (4)
194 H H H 2-Pn H 1-AI-Pip (4)
195 H H H 3-Pn H 1-AI-Pip (4)
196 H H H 2-Hx H 1-AI-Pip (4)
197 H H H 3-Hx H 1-AI-Pip (4)
198 H H H 2-CF_Three      H 1-AI-Pip (4)
199 H H H 3-CF_Three      H 1-AI-Pip (4)
200 H H H 2-OMe H 1-AI-Pip (4)
201 H H H 3-OMe H 1-AI-Pip (4)
202 H H H 2-OEt H 1-AI-Pip (4)
203 H H H 3-OEt H 1-AI-Pip (4)
204 H H H 2-COOH H 1-AI-Pip (4)
205 H H H 3-COOH H 1-AI-Pip (4)
206 H H H 2-COOMe H 1-AI-Pip (4)
207 H H H 3-COOMe H 1-AI-Pip (4)
208 H H H 2-COOEt H 1-AI-Pip (4)
209 H H H 3-COOEt H 1-AI-Pip (4)
210 H H H 2-COOPr H 1-AI-Pip (4)
211 H H H 3-COOPr H 1-AI-Pip (4)
212 H H H 2-COOBu H 1-AI-Pip (4)
213 H H H 3-COOBu H 1-AI-Pip (4)
214 H H H 2-COOPn H 1-AI-Pip (4)
215 H H H 3-COOPn H 1-AI-Pip (4)
216 H H H 2-COOHx H 1-AI-Pip (4)
217 H H H 3-COOHx H 1-AI-Pip (4)
218 H H H 2-CONH₂    H 1-AI-Pip (4)
219 H H H 3-CONH₂    H 1-AI-Pip (4)
220 H H H 2-CONHMe H 1-AI-Pip (4)
221 H H H 3-CONHMe H 1-AI-Pip (4)
222 H H H 2-CONHEt H 1-AI-Pip (4)
223 H H H 3-CONHEt H 1-AI-Pip (4)
224 H H H 2-CON (Me)₂  H 1-AI-Pip (4)
225 H H H 3-CON (Me)₂  H 1-AI-Pip (4)
226 H H H 2-CON (Me) Et H 1-AI-Pip (4)
227 H H H 3-CON (Me) Et H 1-AI-Pip (4)
228 H H H 2-CON (Et)₂  H 1-AI-Pip (4)
229 H H H 3-CON (Et)₂  H 1-AI-Pip (4)
230 H H H 3-F 5-F 1-AI-Pip (4)
231 H H H 3-Cl 5-Cl 1-AI-Pip (4)
232 H H H 3-Me 5-Me 1-AI-Pip (4)
233 H H H 3-Cl 5-CONH₂    1-AI-Pip (4)
234 H H H 2-Me 5-CONH₂    1-AI-Pip (4)
235 H H H 3-Me 5-CONH₂    1-AI-Pip (4)
236 H H H 3-CONH₂    5-CONH₂    1-AI-Pip (4)
237 H H Me H H 1-AI-Pip (4)
238 H H Me 2-F H 1-AI-Pip (4)
239 H H Me 3-F H 1-AI-Pip (4)
240 H H Me 2-Cl H 1-AI-Pip (4)
241 H H Me 3-Cl H 1-AI-Pip (4)
242 H H Me 2-Br H 1-AI-Pip (4)
243 H H Me 3-Br H 1-AI-Pip (4)
244 H H Me 2-I H 1-AI-Pip (4)
245 H H Me 3-I H 1-AI-Pip (4)
246 H H Me 2-Me H 1-AI-Pip (4)
247 H H Me 3-Me H 1-AI-Pip (4)
248 H H Me 2-Et H 1-AI-Pip (4)
249 H H Me 3-Et H 1-AI-Pip (4)
250 H H Me 2-Pr H 1-AI-Pip (4)
251 H H Me 3-Pr H 1-AI-Pip (4)
252 H H Me 2-Bu H 1-AI-Pip (4)
253 H H Me 3-Bu H 1-AI-Pip (4)
254 H H Me 2-Pn H 1-AI-Pip (4)
255 H H Me 3-Pn H 1-AI-Pip (4)
256 H H Me 2-Hx H 1-AI-Pip (4)
257 H H Me 3-Hx H 1-AI-Pip (4)
258 H H Me 2-CF_Three      H 1-AI-Pip (4)
259 H H Me 3-CF_Three      H 1-AI-Pip (4)
260 H H Me 2-OMe H 1-AI-Pip (4)
261 H H Me 3-OMe H 1-AI-Pip (4)
262 H H Me 2-OEt H 1-AI-Pip (4)
263 H H Me 3-OEt H 1-AI-Pip (4)
264 H H Me 2-COOH H 1-AI-Pip (4)
265 H H Me 3-COOH H 1-AI-Pip (4)
266 H H Me 2-COOMe H 1-AI-Pip (4)
267 H H Me 3-COOMe H 1-AI-Pip (4)
268 H H Me 2-COOEt H 1-AI-Pip (4)
269 H H Me 3-COOEt H 1-AI-Pip (4)
270 H H Me 2-COOPr H 1-AI-Pip (4)
271 H H Me 3-COOPr H 1-AI-Pip (4)
272 H H Me 2-COOBu H 1-AI-Pip (4)
273 H H Me 3-COOBu H 1-AI-Pip (4)
274 H H Me 2-COOPn H 1-AI-Pip (4)
275 H H Me 3-COOPn H 1-AI-Pip (4)
276 H H Me 2-COOHx H 1-AI-Pip (4)
277 H H Me 3-COOHx H 1-AI-Pip (4)
278 H H Me 2-CONH₂    H 1-AI-Pip (4)
279 H H Me 3-CONH₂    H 1-AI-Pip (4)
280 H H Me 2-CONHMe H 1-AI-Pip (4)
281 H H Me 3-CONHMe H 1-AI-Pip (4)
282 H H Me 2-CONHEt H 1-AI-Pip (4)
283 H H Me 3-CONHEt H 1-AI-Pip (4)
284 H H Me 2-CON (Me)₂  H 1-AI-Pip (4)
285 H H Me 3-CON (Me)₂  H 1-AI-Pip (4)
286 H H Me 2-CON (Me) Et H 1-AI-Pip (4)
287 H H Me 3-CON (Me) Et H 1-AI-Pip (4)
288 H H Me 2-CON (Et)₂  H 1-AI-Pip (4)
289 H H Me 3-CON (Et)₂  H 1-AI-Pip (4)
290 H H Me 3-F 5-F 1-AI-Pip (4)
291 H H Me 3-Cl 5-Cl 1-AI-Pip (4)
292 H H Me 3-Me 5-Me 1-AI-Pip (4)
293 H H Me 3-Cl 5-CONH₂    1-AI-Pip (4)
294 H H Me 2-Me 5-CONH₂    1-AI-Pip (4)
295 H H Me 3-Me 5-CONH₂    1-AI-Pip (4)
296 H H Me 3-CONH₂    5-CONH₂    1-AI-Pip (4)
297 H H Et H H 1-AI-Pip (4)
298 H H Et 2-F H 1-AI-Pip (4)
299 H H Et 3-F H 1-AI-Pip (4)
300 H H Et 2-Cl H 1-AI-Pip (4)
301 H H Et 3-Cl H 1-AI-Pip (4)
302 H H Et 2-Br H 1-AI-Pip (4)
303 H H Et 3-Br H 1-AI-Pip (4)
304 H H Et 2-I H 1-AI-Pip (4)
305 H H Et 3-I H 1-AI-Pip (4)
306 H H Et 2-Me H 1-AI-Pip (4)
307 H H Et 3-Me H 1-AI-Pip (4)
308 H H Et 2-Et H 1-AI-Pip (4)
309 H H Et 3-Et H 1-AI-Pip (4)
310 H H Et 2-Pr H 1-AI-Pip (4)
311 H H Et 3-Pr H 1-AI-Pip (4)
312 H H Et 2-Bu H 1-AI-Pip (4)
313 H H Et 3-Bu H 1-AI-Pip (4)
314 H H Et 2-Pn H 1-AI-Pip (4)
315 H H Et 3-Pn H 1-AI-Pip (4)
316 H H Et 2-Hx H 1-AI-Pip (4)
317 H H Et 3-Hx H 1-AI-Pip (4)
318 H H Et 2-CF_Three      H 1-AI-Pip (4)
319 H H Et 3-CF_Three      H 1-AI-Pip (4)
320 H H Et 2-OMe H 1-AI-Pip (4)
321 H H Et 3-OMe H 1-AI-Pip (4)
322 H H Et 2-OEt H 1-AI-Pip (4)
323 H H Et 3-OEt H 1-AI-Pip (4)
324 H H Et 2-COOH H 1-AI-Pip (4)
325 H H Et 3-COOH H 1-AI-Pip (4)
326 H H Et 2-COOMe H 1-AI-Pip (4)
327 H H Et 3-COOMe H 1-AI-Pip (4)
328 H H Et 2-COOEt H 1-AI-Pip (4)
329 H H Et 3-COOEt H 1-AI-Pip (4)
330 H H Et 2-COOPr H 1-AI-Pip (4)
331 H H Et 3-COOPr H 1-AI-Pip (4)
332 H H Et 2-COOBu H 1-AI-Pip (4)
333 H H Et 3-COOBu H 1-AI-Pip (4)
334 H H Et 2-COOPn H 1-AI-Pip (4)
335 H H Et 3-COOPn H 1-AI-Pip (4)
336 H H Et 2-COOHx H 1-AI-Pip (4)
337 H H Et 3-COOHx H 1-AI-Pip (4)
338 H H Et 2-CONH₂    H 1-AI-Pip (4)
339 H H Et 3-CONH₂    H 1-AI-Pip (4)
340 H H Et 2-CONHMe H 1-AI-Pip (4)
341 H H Et 3-CONHMe H 1-AI-Pip (4)
342 H H Et 2-CONHEt H 1-AI-Pip (4)
343 H H Et 3-CONHEt H 1-AI-Pip (4)
344 H H Et 2-CON (Me)₂  H 1-AI-Pip (4)
345 H H Et 3-CON (Me)₂  H 1-AI-Pip (4)
346 H H Et 2-CON (Me) Et H 1-AI-Pip (4)
347 H H Et 3-CON (Me) Et H 1-AI-Pip (4)
348 H H Et 2-CON (Et)₂  H 1-AI-Pip (4)
349 H H Et 3-CON (Et)₂  H 1-AI-Pip (4)
350 H H Et 3-F F 1-AI-Pip (4)
351 H H Et 3-Cl 5-Cl 1-AI-Pip (4)
352 H H Et 3-Me 5-Me 1-AI-Pip (4)
353 H H Et 3-Cl 5-CONH₂    1-AI-Pip (4)
354 H H Et 2-Me 5-CONH₂    1-AI-Pip (4)
355 H H Et 3-Me 5-CONH₂    1-AI-Pip (4)
356 H H Et 3-CONH₂    5-CONH₂    1-AI-Pip (4)
357 H H Pr H H 1-AI-Pip (4)
358 H H iPr H H 1-AI-Pip (4)
359 H H iPr 2-F H 1-AI-Pip (4)
360 H H iPr 3-F H 1-AI-Pip (4)
361 H H iPr 2-Cl H 1-AI-Pip (4)
362 H H iPr 3-Cl H 1-AI-Pip (4)
363 H H iPr 2-Br H 1-AI-Pip (4)
364 H H iPr 3-Br H 1-AI-Pip (4)
365 H H iPr 2-I H 1-AI-Pip (4)
366 H H iPr 3-I H 1-AI-Pip (4)
367 H H iPr 2-Me H 1-AI-Pip (4)
368 H H iPr 3-Me H 1-AI-Pip (4)
369 H H iPr 2-Et H 1-AI-Pip (4)
370 H H iPr 3-Et H 1-AI-Pip (4)
371 H H iPr 2-Pr H 1-AI-Pip (4)
372 H H iPr 3-Pr H 1-AI-Pip (4)
373 H H iPr 2-Bu H 1-AI-Pip (4)
374 H H iPr 3-Bu H 1-AI-Pip (4)
375 H H iPr 2-Pn H 1-AI-Pip (4)
376 H H iPr 3-Pn H 1-AI-Pip (4)
377 H H iPr 2-Hx H 1-AI-Pip (4)
378 H H iPr 3-Hx H 1-AI-Pip (4)
379 H H iPr 2-CF_Three      H 1-AI-Pip (4)
380 H H iPr 3-CF_Three      H 1-AI-Pip (4)
381 H H iPr 2-OMe H 1-AI-Pip (4)
382 H H iPr 3-OMe H 1-AI-Pip (4)
383 H H iPr 2-OEt H 1-AI-Pip (4)
384 H H iPr 3-OEt H 1-AI-Pip (4)
385 H H iPr 2-COOH H 1-AI-Pip (4)
386 H H iPr 3-COOH H 1-AI-Pip (4)
387 H H iPr 2-COOMe H 1-AI-Pip (4)
388 H H iPr 3-COOMe H 1-AI-Pip (4)
389 H H iPr 2-COOEt H 1-AI-Pip (4)
390 H H iPr 3-COOEt H 1-AI-Pip (4)
391 H H iPr 2-COOPr H 1-AI-Pip (4)
392 H H iPr 3-COOPr H 1-AI-Pip (4)
393 H H iPr 2-COOBu H 1-AI-Pip (4)
394 H H iPr 3-COOBu H 1-AI-Pip (4)
395 H H iPr 2-COOPn H 1-AI-Pip (4)
396 H H iPr 3-COOPn H 1-AI-Pip (4)
397 H H iPr 2-COOHx H 1-AI-Pip (4)
398 H H iPr 3-COOHx H 1-AI-Pip (4)
399 H H iPr 2-CONH₂    H 1-AI-Pip (4)
400 H H iPr 3-CONH₂    H 1-AI-Pip (4)
401 H H iPr 2-CONHMe H 1-AI-Pip (4)
402 H H iPr 3-CONHMe H 1-AI-Pip (4)
403 H H iPr 2-CONHEt H 1-AI-Pip (4)
404 H H iPr 3-CONHEt H 1-AI-Pip (4)
405 H H iPr 2-CON (Me)₂  H 1-AI-Pip (4)
406 H H iPr 3-CON (Me)₂  H 1-AI-Pip (4)
407 H H iPr 2-CON (Me) Et H 1-AI-Pip (4)
408 H H iPr 3-CON (Me) Et H 1-AI-Pip (4)
409 H H iPr 2-CON (Et)₂  H 1-AI-Pip (4)
410 H H iPr 3-CON (Et)₂  H 1-AI-Pip (4)
411 H H iPr 3-F 5-F 1-AI-Pip (4)
412 H H iPr 3-Cl 5-Cl 1-AI-Pip (4)
413 H H iPr 3-Me 5-Me 1-AI-Pip (4)
414 H H iPr 3-Cl 5-CONH₂    1-AI-Pip (4)
415 H H iPr 2-Me 5-CONH₂    1-AI-Pip (4)
416 H H iPr 3-Me 5-CONH₂    1-AI-Pip (4)
417 H H iPr 3-CONH₂    5-CONH₂    1-AI-Pip (4)
418 6-OH H iPr H H 1-AI-Pip (4)
419 6-OH H iPr 2-F H 1-AI-Pip (4)
420 6-OH H iPr 3-F H 1-AI-Pip (4)
421 6-OH H iPr 2-Cl H 1-AI-Pip (4)
422 6-OH H iPr 3-Cl H 1-AI-Pip (4)
423 6-OH H iPr 2-Br H 1-AI-Pip (4)
424 6-OH H iPr 3-Br H 1-AI-Pip (4)
425 6-OH H iPr 2-I H 1-AI-Pip (4)
426 6-OH H iPr 3-I H 1-AI-Pip (4)
427 6-OH H iPr 2-Me H 1-AI-Pip (4)
428 6-OH H iPr 3-Me H 1-AI-Pip (4)
429 6-OH H iPr 2-Et H 1-AI-Pip (4)
430 6-OH H iPr 3-Et H 1-AI-Pip (4)
431 6-OH H iPr 2-Pr H 1-AI-Pip (4)
432 6-OH H iPr 3-Pr H 1-AI-Pip (4)
433 6-OH H iPr 2-Bu H 1-AI-Pip (4)
434 6-OH H iPr 3-Bu H 1-AI-Pip (4)
435 6-OH H iPr 2-Pn H 1-AI-Pip (4)
436 6-OH H iPr 3-Pn H 1-AI-Pip (4)
437 6-OH H iPr 2-Hx H 1-AI-Pip (4)
438 6-OH H iPr 3-Hx H 1-AI-Pip (4)
439 6-OH H iPr 2-CF_Three      H 1-AI-Pip (4)
440 6-OH H iPr 3-CF_Three      H 1-AI-Pip (4)
441 6-OH H iPr 2-OMe H 1-AI-Pip (4)
442 6-OH H iPr 3-OMe H 1-AI-Pip (4)
443 6-OH H iPr 2-OEt H 1-AI-Pip (4)
444 6-OH H iPr 3-OEt H 1-AI-Pip (4)
445 6-OH H iPr 2-COOH H 1-AI-Pip (4)
446 6-OH H iPr 3-COOH H 1-AI-Pip (4)
447 6-OH H iPr 2-COOMe H 1-AI-Pip (4)
448 6-OH H iPr 3-COOMe H 1-AI-Pip (4)
449 6-OH H iPr 2-COOEt H 1-AI-Pip (4)
450 6-OH H iPr 3-COOEt H 1-AI-Pip (4)
451 6-OH H iPr 2-COOPr H 1-AI-Pip (4)
452 6-OH H iPr 3-COOPr H 1-AI-Pip (4)
453 6-OH H iPr 2-COOBu H 1-AI-Pip (4)
454 6-OH H iPr 3-COOBu H 1-AI-Pip (4)
455 6-OH H iPr 2-COOPn H 1-AI-Pip (4)
456 6-OH H iPr 3-COOPn H 1-AI-Pip (4)
457 6-OH H iPr 2-COOHx H 1-AI-Pip (4)
458 6-OH H iPr 3-COOHx H 1-AI-Pip (4)
459 6-OH H iPr 2-CONH₂    H 1-AI-Pip (4)
460 6-OH H iPr 3-CONH₂    H 1-AI-Pip (4)
461 6-OH H iPr 2-CONHMe H 1-AI-Pip (4)
462 6-OH H iPr 3-CONHMe H 1-AI-Pip (4)
463 6-OH H iPr 2-CONHEt H 1-AI-Pip (4)
464 6-OH H iPr 3-CONHEt H 1-AI-Pip (4)
465 6-OH H iPr 2-CON (Me)₂  H 1-AI-Pip (4)
466 6-OH H iPr 3-CON (Me)₂  H 1-AI-Pip (4)
467 6-OH H iPr 2-CON (Me) Et H 1-AI-Pip (4)
468 6-OH H iPr 3-CON (Me) Et H 1-AI-Pip (4)
469 6-OH H iPr 2-CON (Et)₂  H 1-AI-Pip (4)
470 6-OH H iPr 3-CON (Et)₂  H 1-AI-Pip (4)
471 H H Bu H H 1-AI-Pip (4)
472 H H iBu H H 1-AI-Pip (4)
473 H H sBu H H 1-AI-Pip (4)
474 H H tBu H H 1-AI-Pip (4)
475 H H Pn H H 1-AI-Pip (4)
476 H H Hx H H 1-AI-Pip (4)
477 H H CH₂OH H H 1-AI-Pip (4)
478 H H (CH₂)₂OH H H 1-AI-Pip (4)
479 H H (CH₂)₂OH 2-F H 1-AI-Pip (4)
480 H H (CH₂)₂OH 3-F H 1-AI-Pip (4)
481 H H (CH₂)₂OH 2-Cl H 1-AI-Pip (4)
482 H H (CH₂)₂OH 3-Cl H 1-AI-Pip (4)
483 H H (CH₂)₂OH 2-Br H 1-AI-Pip (4)
484 H H (CH₂)₂OH 3-Br H 1-AI-Pip (4)
485 H H (CH₂)₂OH 2-I H 1-AI-Pip (4)
486 H H (CH₂)₂OH 3-I H 1-AI-Pip (4)
487 H H (CH₂)₂OH 2-Me H 1-AI-Pip (4)
488 H H (CH₂)₂OH 3-Me H 1-AI-Pip (4)
489 H H (CH₂)₂OH 2-Et H 1-AI-Pip (4)
490 H H (CH₂)₂OH 3-Et H 1-AI-Pip (4)
491 H H (CH₂)₂OH 2-Pr H 1-AI-Pip (4)
492 H H (CH₂)₂OH 3-Pr H 1-AI-Pip (4)
493 H H (CH₂)₂OH 2-Bu H 1-AI-Pip (4)
494 H H (CH₂)₂OH 3-Bu H 1-AI-Pip (4)
495 H H (CH₂)₂OH 2-Pn H 1-AI-Pip (4)
496 H H (CH₂)₂OH 3-Pn H 1-AI-Pip (4)
497 H H (CH₂)₂OH 2-Hx H 1-AI-Pip (4)
498 H H (CH₂)₂OH 3-Hx H 1-AI-Pip (4)
499 H H (CH₂)₂OH 2-CF_Three      H 1-AI-Pip (4)
500 H H (CH₂)₂OH 3-CF_Three      H 1-AI-Pip (4)
501 H H (CH₂)₂OH 2-OMe H 1-AI-Pip (4)
502 H H (CH₂)₂OH 3-OMe H 1-AI-Pip (4)
503 H H (CH₂)₂OH 2-OEt H 1-AI-Pip (4)
504 H H (CH₂)₂OH 3-OEt H 1-AI-Pip (4)
505 H H (CH₂)₂OH 2-COOH H 1-AI-Pip (4)
506 H H (CH₂)₂OH 3-COOH H 1-AI-Pip (4)
507 H H (CH₂)₂OH 2-COOMe H 1-AI-Pip (4)
508 H H (CH₂)₂OH 3-COOMe H 1-AI-Pip (4)
509 H H (CH₂)₂OH 2-COOEt H 1-AI-Pip (4)
510 H H (CH₂)₂OH 3-COOEt H 1-AI-Pip (4)
511 H H (CH₂)₂OH 2-COOPr H 1-AI-Pip (4)
512 H H (CH₂)₂OH 3-COOPr H 1-AI-Pip (4)
513 H H (CH₂)₂OH 2-COOBu H 1-AI-Pip (4)
514 H H (CH₂)₂OH 3-COOBu H 1-AI-Pip (4)
515 H H (CH₂)₂OH 2-COOPn H 1-AI-Pip (4)
516 H H (CH₂)₂OH 3-COOPn H 1-AI-Pip (4)
517 H H (CH₂)₂OH 2-COOHx H 1-AI-Pip (4)
518 H H (CH₂)₂OH 3-COOHx H 1-AI-Pip (4)
519 H H (CH₂)₂OH 2-CONH₂    H 1-AI-Pip (4)
520 H H (CH₂)₂OH 3-CONH₂    H 1-AI-Pip (4)
521 H H (CH₂)₂OH 2-CONHMe H 1-AI-Pip (4)
522 H H (CH₂)₂OH 3-CONHMe H 1-AI-Pip (4)
523 H H (CH₂)₂OH 2-CONHEt H 1-AI-Pip (4)
524 H H (CH₂)₂OH 3-CONHEt H 1-AI-Pip (4)
525 H H (CH₂)₂OH 2-CON (Me)₂  H 1-AI-Pip (4)
526 H H (CH₂)₂OH 3-CON (Me)₂  H 1-AI-Pip (4)
527 H H (CH₂)₂OH 2-CON (Me) Et H 1-AI-Pip (4)
528 H H (CH₂)₂OH 3-CON (Me) Et H 1-AI-Pip (4)
529 H H (CH₂)₂OH 2-CON (Et)₂  H 1-AI-Pip (4)
530 H H (CH₂)₂OH 3-CON (Et)₂  H 1-AI-Pip (4)
531 H H (CH₂)₂OH 3-F 5-F 1-AI-Pip (4)
532 H H (CH₂)₂OH 3-Cl 5-Cl 1-AI-Pip (4)
533 H H (CH₂)₂OH 3-Me 5-Me 1-AI-Pip (4)
534 H H (CH₂)₂OH 3-Cl 5-CONH₂    1-AI-Pip (4)
535 H H (CH₂)₂OH 2-Me 5-CONH₂    1-AI-Pip (4)
536 H H (CH₂)₂OH 3-Me 5-CONH₂    1-AI-Pip (4)
537 H H (CH₂)₂OH 3-CONH₂    5-CONH₂    1-AI-Pip (4)
538 H H (CH₂)_ThreeOH H H 1-AI-Pip (4)
539 H H (CH₂)_FourOH H H 1-AI-Pip (4)
540 H H (CH₂)_FiveOH H H 1-AI-Pip (4)
541 H H (CH₂)₆OH H H 1-AI-Pip (4)
542 H H CH₂COOH H H 1-AI-Pip (4)
543 H H CH₂COOH 2-F H 1-AI-Pip (4)
544 H H CH₂COOH 3-F H 1-AI-Pip (4)
545 H H CH₂COOH 2-Cl H 1-AI-Pip (4)
546 H H CH₂COOH 3-Cl H 1-AI-Pip (4)
547 H H CH₂COOH 2-Br H 1-AI-Pip (4)
548 H H CH₂COOH 3-Br H 1-AI-Pip (4)
549 H H CH₂COOH 2-I H 1-AI-Pip (4)
550 H H CH₂COOH 3-I H 1-AI-Pip (4)
551 H H CH₂COOH 2-Me H 1-AI-Pip (4)
552 H H CH₂COOH 3-Me H 1-AI-Pip (4)
553 H H CH₂COOH 2-Et H 1-AI-Pip (4)
554 H H CH₂COOH 3-Et H 1-AI-Pip (4)
555 H H CH₂COOH 2-Pr H 1-AI-Pip (4)
556 H H CH₂COOH 3-Pr H 1-AI-Pip (4)
557 H H CH₂COOH 2-Bu H 1-AI-Pip (4)
558 H H CH₂COOH 3-Bu H 1-AI-Pip (4)
559 H H CH₂COOH 2-Pn H 1-AI-Pip (4)
560 H H CH₂COOH 3-Pn H 1-AI-Pip (4)
561 H H CH₂COOH 2-Hx H 1-AI-Pip (4)
562 H H CH₂COOH 3-Hx H 1-AI-Pip (4)
563 H H CH₂COOH 2-CF_Three      H 1-AI-Pip (4)
564 H H CH₂COOH 3-CF_Three      H 1-AI-Pip (4)
565 H H CH₂COOH 2-OMe H 1-AI-Pip (4)
566 H H CH₂COOH 3-OMe H 1-AI-Pip (4)
567 H H CH₂COOH 2-OEt H 1-AI-Pip (4)
568 H H CH₂COOH 3-OEt H 1-AI-Pip (4)
569 H H CH₂COOH 2-COOH H 1-AI-Pip (4)
570 H H CH₂COOH 3-COOH H 1-AI-Pip (4)
571 H H CH₂COOH 2-COOMe H 1-AI-Pip (4)
572 H H CH₂COOH 3-COOMe H 1-AI-Pip (4)
573 H H CH₂COOH 2-COOEt H 1-AI-Pip (4)
574 H H CH₂COOH 3-COOEt H 1-AI-Pip (4)
575 H H CH₂COOH 2-COOPr H 1-AI-Pip (4)
576 H H CH₂COOH 3-COOPr H 1-AI-Pip (4)
577 H H CH₂COOH 2-COOBu H 1-AI-Pip (4)
578 H H CH₂COOH 3-COOBu H 1-AI-Pip (4)
579 H H CH₂COOH 2-COOPn H 1-AI-Pip (4)
580 H H CH₂COOH 3-COOPn H 1-AI-Pip (4)
581 H H CH₂COOH 2-COOHx H 1-AI-Pip (4)
582 H H CH₂COOH 3-COOHx H 1-AI-Pip (4)
583 H H CH₂COOH 2-CONH₂    H 1-AI-Pip (4)
584 H H CH₂COOH 3-CONH₂    H 1-AI-Pip (4)
585 H H CH₂COOH 2-CONHMe H 1-AI-Pip (4)
586 H H CH₂COOH 3-CONHMe H 1-AI-Pip (4)
587 H H CH₂COOH 2-CONHEt H 1-AI-Pip (4)
588 H H CH₂COOH 3-CONHEt H 1-AI-Pip (4)
589 H H CH₂COOH 2-CON (Me)₂  H 1-AI-Pip (4)
590 H H CH₂COOH 3-CON (Me)₂  H 1-AI-Pip (4)
591 H H CH₂COOH 2-CON (Me) EtH 1-AI-Pip (4)
592 H H CH₂COOH 3-CON (Me) EtH 1-AI-Pip (4)
593 H H CH₂COOH 2-CON (Et)₂  H 1-AI-Pip (4)
594 H H CH₂COOH 3-CON (Et)₂  H 1-AI-Pip (4)
595 H H CH₂COOH 3-F 5-F 1-AI-Pip (4)
596 H H CH₂COOH 3-Cl 5-Cl 1-AI-Pip (4)
597 H H CH₂COOH 3-Me 5-Me 1-AI-Pip (4)
598 H H CH₂COOH 3-Cl 5-CONH₂    1-AI-Pip (4)
599 H H CH₂COOH 2-Me 5-CONH₂    1-AI-Pip (4)
600 H H CH₂COOH 3-Me 5-CONH₂    1-AI-Pip (4)
601 H H CH₂COOH 3-CONH₂    5-CONH₂    1-AI-Pip (4)
602 6-OH H CH₂COOH H H 1-AI-Pip (4)
603 6-OH H CH₂COOH 2-F H 1-AI-Pip (4)
604 6-OH H CH₂COOH 3-F H 1-AI-Pip (4)
605 6-OH H CH₂COOH 2-Cl H 1-AI-Pip (4)
606 6-OH H CH₂COOH 3-Cl H 1-AI-Pip (4)
607 6-OH H CH₂COOH 2-Br H 1-AI-Pip (4)
608 6-OH H CH₂COOH 3-Br H 1-AI-Pip (4)
609 6-OH H CH₂COOH 2-I H 1-AI-Pip (4)
610 6-OH H CH₂COOH 3-I H 1-AI-Pip (4)
611 6-OH H CH₂COOH 2-Me H 1-AI-Pip (4)
612 6-OH H CH₂COOH 3-Me H 1-AI-Pip (4)
613 6-OH H CH₂COOH 2-Et H 1-AI-Pip (4)
614 6-OH H CH₂COOH 3-Et H 1-AI-Pip (4)
615 6-OH H CH₂COOH 2-Pr H 1-AI-Pip (4)
616 6-OH H CH₂COOH 3-Pr H 1-AI-Pip (4)
617 6-OH H CH₂COOH 2-Bu H 1-AI-Pip (4)
618 6-OH H CH₂COOH 3-Bu H 1-AI-Pip (4)
619 6-OH H CH₂COOH 2-Pn H 1-AI-Pip (4)
620 6-OH H CH₂COOH 3-Pn H 1-AI-Pip (4)
621 6-OH H CH₂COOH 2-Hx H 1-AI-Pip (4)
622 6-OH H CH₂COOH 3-Hx H 1-AI-Pip (4)
623 6-OH H CH₂COOH 2-CF_Three      H 1-AI-Pip (4)
624 6-OH H CH₂COOH 3-CF_Three      H 1-AI-Pip (4)
625 6-OH H CH₂COOH 2-OMe H 1-AI-Pip (4)
626 6-OH H CH₂COOH 3-OMe H 1-AI-Pip (4)
627 6-OH H CH₂COOH 2-OEt H 1-AI-Pip (4)
628 6-OH H CH₂COOH 3-OEt H 1-AI-Pip (4)
629 6-OH H CH₂COOH 2-COOH H 1-AI-Pip (4)
630 6-OH H CH₂COOH 3-COOH H 1-AI-Pip (4)
631 6-OH H CH₂COOH 2-COOMe H 1-AI-Pip (4)
632 6-OH H CH₂COOH 3-COOMe H 1-AI-Pip (4)
633 6-OH H CH₂COOH 2-COOEt H 1-AI-Pip (4)
634 6-OH H CH₂COOH 3-COOEt H 1-AI-Pip (4)
635 6-OH H CH₂COOH 2-COOPr H 1-AI-Pip (4)
636 6-OH H CH₂COOH 3-COOPr H 1-AI-Pip (4)
637 6-OH H CH₂COOH 2-COOBu H 1-AI-Pip (4)
638 6-OH H CH₂COOH 3-COOBu H 1-AI-Pip (4)
639 6-OH H CH₂COOH 2-COOPn H 1-AI-Pip (4)
640 6-OH H CH₂COOH 3-COOPn H 1-AI-Pip (4)
641 6-OH H CH₂COOH 2-COOHx H 1-AI-Pip (4)
642 6-OH H CH₂COOH 3-COOHx H 1-AI-Pip (4)
643 6-OH H CH₂COOH 2-CONH₂    H 1-AI-Pip (4)
644 6-OH H CH₂COOH 3-CONH₂    H 1-AI-Pip (4)
645 6-OH H CH₂COOH 2-CONHMe H 1-AI-Pip (4)
646 6-OH H CH₂COOH 3-CONHMe H 1-AI-Pip (4)
647 6-OH H CH₂COOH 2-CONHEt H 1-AI-Pip (4)
648 6-OH H CH₂COOH 3-CONHEt H 1-AI-Pip (4)
649 6-OH H CH₂COOH 2-CON (Me)₂  H 1-AI-Pip (4)
650 6-OH H CH₂COOH 3-CON (Me)₂  H 1-AI-Pip (4)
651 6-OH H CH₂COOH 2-CON (Me) Et H 1-AI-Pip (4)
652 6-OH H CH₂COOH 3-CON (Me) Et H 1-AI-Pip (4)
653 6-OH H CH₂COOH 2-CON (Et)₂  H 1-AI-Pip (4)
654 6-OH H CH₂COOH 3-CON (Et)₂  H 1-AI-Pip (4)
655 6-OH H CH₂COOH 3-F 5-F 1-AI-Pip (4)
656 6-OH H CH₂COOH 3-Cl 5-Cl 1-AI-Pip (4)
657 6-OH H CH₂COOH 3-Me 5-Me 1-AI-Pip (4)
658 6-OH H CH₂COOH 3-Cl 5-CONH₂    1-AI-Pip (4)
659 6-OH H CH₂COOH 2-Me 5-CONH₂    1-AI-Pip (4)
660 6-OH H CH₂COOH 3-Me 5-CONH₂    1-AI-Pip (4)
661 6-OH H CH₂COOH 3-CONH₂    5-CONH₂    1-AI-Pip (4)
662 H H (CH₂)₂COOH H H 1-AI-Pip (4)
663 H H (CH₂)_ThreeCOOH H H 1-AI-Pip (4)
664 H H (CH₂)_FourCOOH H H 1-AI-Pip (4)
665 H H (CH₂)_FiveCOOH H H 1-AI-Pip (4)
666 H H (CH₂)₆COOH H H 1-AI-Pip (4)
667 H H CH₂COOMe H H 1-AI-Pip (4)
668 H H CH₂COOEt H H 1-AI-Pip (4)
669 H H CH₂COOEt 2-F H 1-AI-Pip (4)
670 H H CH₂COOEt 3-F H 1-AI-Pip (4)
671 H H CH₂COOEt 2-Cl H 1-AI-Pip (4)
672 H H CH₂COOEt 3-Cl H 1-AI-Pip (4)
673 H H CH₂COOEt 2-Br H 1-AI-Pip (4)
674 H H CH₂COOEt 3-Br H 1-AI-Pip (4)
675 H H CH₂COOEt 2-I H 1-AI-Pip (4)
676 H H CH₂COOEt 3-I H 1-AI-Pip (4)
677 H H CH₂COOEt 2-Me H 1-AI-Pip (4)
678 H H CH₂COOEt 3-Me H 1-AI-Pip (4)
679 H H CH₂COOEt 2-Et H 1-AI-Pip (4)
680 H H CH₂COOEt 3-Et H 1-AI-Pip (4)
681 H H CH₂COOEt 2-Pr H 1-AI-Pip (4)
682 H H CH₂COOEt 3-Pr H 1-AI-Pip (4)
683 H H CH₂COOEt 2-Bu H 1-AI-Pip (4)
684 H H CH₂COOEt 3-Bu H 1-AI-Pip (4)
685 H H CH₂COOEt 2-Pn H 1-AI-Pip (4)
686 H H CH₂COOEt 3-Pn H 1-AI-Pip (4)
687 H H CH₂COOEt 2-Hx H 1-AI-Pip (4)
688 H H CH₂COOEt 3-Hx H 1-AI-Pip (4)
689 H H CH₂COOEt 2-CF_Three      H 1-AI-Pip (4)
690 H H CH₂COOEt 3-CF_Three      H 1-AI-Pip (4)
691 H H CH₂COOEt 2-OMe H 1-AI-Pip (4)
692 H H CH₂COOEt 3-OMe H 1-AI-Pip (4)
693 H H CH₂COOEt 2-OEt H 1-AI-Pip (4)
694 H H CH₂COOEt 3-OEt H 1-AI-Pip (4)
695 H H CH₂COOEt 2-COOH H 1-AI-Pip (4)
696 H H CH₂COOEt 3-COOH H 1-AI-Pip (4)
697 H H CH₂COOEt 2-COOMe H 1-AI-Pip (4)
698 H H CH₂COOEt 3-COOMe H 1-AI-Pip (4)
699 H H CH₂COOEt 2-COOEt H 1-AI-Pip (4)
700 H H CH₂COOEt 3-COOEt H 1-AI-Pip (4)
701 H H CH₂COOEt 2-COOPr H 1-AI-Pip (4)
702 H H CH₂COOEt 3-COOPr H 1-AI-Pip (4)
703 H H CH₂COOEt 2-COOBu H 1-AI-Pip (4)
704 H H CH₂COOEt 3-COOBu H 1-AI-Pip (4)
705 H H CH₂COOEt 2-COOPn H 1-AI-Pip (4)
706 H H CH₂COOEt 3-COOPn H 1-AI-Pip (4)
707 H H CH₂COOEt 2-COOHx H 1-AI-Pip (4)
708 H H CH₂COOEt 3-COOHx H 1-AI-Pip (4)
709 H H CH₂COOEt 2-CONH₂    H 1-AI-Pip (4)
710 H H CH₂COOEt 3-CONH₂    H 1-AI-Pip (4)
711 H H CH₂COOEt 2-CONHMe H 1-AI-Pip (4)
712 H H CH₂COOEt 3-CONHMe H 1-AI-Pip (4)
713 H H CH₂COOEt 2-CONHEt H 1-AI-Pip (4)
714 H H CH₂COOEt 3-CONHEt H 1-AI-Pip (4)
715 H H CH₂COOEt 2-CON (Me)₂  H 1-AI-Pip (4)
716 H H CH₂COOEt 3-CON (Me)₂  H 1-AI-Pip (4)
717 H H CH₂COOEt 2-CON (Me) Et H 1-AI-Pip (4)
718 H H CH₂COOEt 3-CON (Me) Et H 1-AI-Pip (4)
719 H H CH₂COOEt 2-CON (Et)₂  H 1-AI-Pip (4)
720 H H CH₂COOEt 3-CON (Et)₂  H 1-AI-Pip (4)
721 H H CH₂COOEt 3-F 5-F 1-AI-Pip (4)
722 H H CH₂COOEt 3-Cl 5-Cl 1-AI-Pip (4)
723 H H CH₂COOEt 3-Me 5-Me 1-AI-Pip (4)
724 H H CH₂COOEt 3-Cl 5-CONH₂    1-AI-Pip (4)
725 H H CH₂COOEt 2-Me 5-CONH₂    1-AI-Pip (4)
726 H H CH₂COOEt 3-Me 5-CONH₂    1-AI-Pip (4)
727 H H CH₂COOEt 3-CONH₂    5-CONH₂    1-AI-Pip (4)
728 6-OH H CH₂COOEt H H 1-AI-Pip (4)
729 6-OH H CH₂COOEt 2-F H 1-AI-Pip (4)
730 6-OH H CH₂COOEt 3-F H 1-AI-Pip (4)
731 6-OH H CH₂COOEt 2-Cl H 1-AI-Pip (4)
732 6-OH H CH₂COOEt 3-Cl H 1-AI-Pip (4)
733 6-OH H CH₂COOEt 2-Br H 1-AI-Pip (4)
734 6-OH H CH₂COOEt 3-Br H 1-AI-Pip (4)
735 6-OH H CH₂COOEt 2-I H 1-AI-Pip (4)
736 6-OH H CH₂COOEt 3-I H 1-AI-Pip (4)
737 6-OH H CH₂COOEt 2-Me H 1-AI-Pip (4)
738 6-OH H CH₂COOEt 3-Me H 1-AI-Pip (4)
739 6-OH H CH₂COOEt 2-Et H 1-AI-Pip (4)
740 6-OH H CH₂COOEt 3-Et H 1-AI-Pip (4)
741 6-OH H CH₂COOEt 2-Pr H 1-AI-Pip (4)
742 6-OH H CH₂COOEt 3-Pr H 1-AI-Pip (4)
743 6-OH H CH₂COOEt 2-Bu H 1-AI-Pip (4)
744 6-OH H CH₂COOEt 3-Bu H 1-AI-Pip (4)
745 6-OH H CH₂COOEt 2-Pn H 1-AI-Pip (4)
746 6-OH H CH₂COOEt 3-Pn H 1-AI-Pip (4)
747 6-OH H CH₂COOEt 2-Hx H 1-AI-Pip (4)
748 6-OH H CH₂COOEt 3-Hx H 1-AI-Pip (4)
749 6-OH H CH₂COOEt 2-CF_Three      H 1-AI-Pip (4)
750 6-OH H CH₂COOEt 3-CF_Three      H 1-AI-Pip (4)
751 6-OH H CH₂COOEt 2-OMe H 1-AI-Pip (4)
752 6-OH H CH₂COOEt 3-OMe H 1-AI-Pip (4)
753 6-OH H CH₂COOEt 2-OEt H 1-AI-Pip (4)
754 6-OH H CH₂COOEt 3-OEt H 1-AI-Pip (4)
755 6-OH H CH₂COOEt 2-COOH H 1-AI-Pip (4)
756 6-OH H CH₂COOEt 3-COOH H 1-AI-Pip (4)
757 6-OH H CH₂COOEt 2-COOMe H 1-AI-Pip (4)
758 6-OH H CH₂COOEt 3-COOMe H 1-AI-Pip (4)
759 6-OH H CH₂COOEt 2-COOEt H 1-AI-Pip (4)
760 6-OH H CH₂COOEt 3-COOEt H 1-AI-Pip (4)
761 6-OH H CH₂COOEt 2-COOPr H 1-AI-Pip (4)
762 6-OH H CH₂COOEt 3-COOPr H 1-AI-Pip (4)
763 6-OH H CH₂COOEt 2-COOBu H 1-AI-Pip (4)
764 6-OH H CH₂COOEt 3-COOBu H 1-AI-Pip (4)
765 6-OH H CH₂COOEt 2-COOPn H 1-AI-Pip (4)
766 6-OH H CH₂COOEt 3-COOPn H 1-AI-Pip (4)
767 6-OH H CH₂COOEt 2-COOHx H 1-AI-Pip (4)
768 6-OH H CH₂COOEt 3-COOHx H 1-AI-Pip (4)
769 6-OH H CH₂COOEt 2-CONH₂    H 1-AI-Pip (4)
770 6-OH H CH₂COOEt 3-CONH₂    H 1-AI-Pip (4)
771 6-OH H CH₂COOEt 2-CONHMe H 1-AI-Pip (4)
772 6-OH H CH₂COOEt 3-CONHMe H 1-AI-Pip (4)
773 6-OH H CH₂COOEt 2-CONHEt H 1-AI-Pip (4)
774 6-OH H CH₂COOEt 3-CONHEt H 1-AI-Pip (4)
775 6-OH H CH₂COOEt 2-CON (Me)₂  H 1-AI-Pip (4)
776 6-OH H CH₂COOEt 3-CON (Me)₂  H 1-AI-Pip (4)
777 6-OH H CH₂COOEt 2-CON (Me) Et H 1-AI-Pip (4)
778 6-OH H CH₂COOEt 3-CON (Me) Et H 1-AI-Pip (4)
779 6-OH H CH₂COOEt 2-CON (Et)₂  H 1-AI-Pip (4)
780 6-OH H CH₂COOEt 3-CON (Et)₂  H 1-AI-Pip (4)
781 6-OH H CH₂COOEt 3-F 5-F 1-AI-Pip (4)
782 6-OH H CH₂COOEt 3-Cl 5-Cl 1-AI-Pip (4)
783 6-OH H CH₂COOEt 3-Me 5-Me 1-AI-Pip (4)
784 6-OH H CH₂COOEt 3-Cl 5-CONH₂    1-AI-Pip (4)
785 6-OH H CH₂COOEt 2-Me 5-CONH₂    1-AI-Pip (4)
786 6-OH H CH₂COOEt 3-Me 5-CONH₂    1-AI-Pip (4)
787 6-OH H CH₂COOEt 3-CONH₂    5-CONH₂    1-AI-Pip (4)
788 H H CH (CH_ThreeCOOEt H H 1-AI-Pip (4)
789 H H CH (CH_ThreeCOOEt 2-F H 1-AI-Pip (4)
790 H H CH (CH_ThreeCOOEt 3-F H 1-AI-Pip (4)
791 H H CH (CH_ThreeCOOEt 2-Cl H 1-AI-Pip (4)
792 H H CH (CH_ThreeCOOEt 3-Cl H 1-AI-Pip (4)
793 H H CH (CH_ThreeCOOEt 2-Br H 1-AI-Pip (4)
794 H H CH (CH_ThreeCOOEt 3-Br H 1-AI-Pip (4)
795 H H CH (CH_ThreeCOOEt 2-I H 1-AI-Pip (4)
796 H H CH (CH_ThreeCOOEt 3-I H 1-AI-Pip (4)
797 H H CH (CH_ThreeCOOEt 2-Me H 1-AI-Pip (4)
798 H H CH (CH_ThreeCOOEt 3-Me H 1-AI-Pip (4)
799 H H CH (CH_ThreeCOOEt 2-Et H 1-AI-Pip (4)
800 H H CH (CH_ThreeCOOEt 3-Et H 1-AI-Pip (4)
801 H H CH (CH_ThreeCOOEt 2-Pr H 1-AI-Pip (4)
802 H H CH (CH_ThreeCOOEt 3-Pr H 1-AI-Pip (4)
803 H H CH (CH_ThreeCOOEt 2-Bu H 1-AI-Pip (4)
804 H H CH (CH_ThreeCOOEt 3-Bu H 1-AI-Pip (4)
805 H H CH (CH_Three) COOEt 2-Pn H 1-AI-Pip (4)
806 H H CH (CH_ThreeCOOEt 3-Pn H 1-AI-Pip (4)
807 H H CH (CH_Three) COOEt 2-Hx H 1-AI-Pip (4)
808 H H CH (CH_ThreeCOOEt 3-Hx H 1-AI-Pip (4)
809 H H CH (CH_ThreeCOOEt 2-CF_Three      H 1-AI-Pip (4)
810 H H CH (CH_ThreeCOOEt 3-CF_Three      H 1-AI-Pip (4)
811 H H CH (CH_ThreeCOOEt 2-OMe H 1-AI-Pip (4)
812 H H CH (CH_ThreeCOOEt 3-OMe H 1-AI-Pip (4)
813 H H CH (CH_ThreeCOOEt 2-OEt H 1-AI-Pip (4)
814 H H CH (CH_ThreeCOOEt 3-OEt H 1-AI-Pip (4)
815 H H CH (CH_ThreeCOOEt 2-COOH H 1-AI-Pip (4)
816 H H CH (CH_Three) COOEt 3-COOH H 1-AI-Pip (4)
817 H H CH (CH_ThreeCOOEt 2-COOMe H 1-AI-Pip (4)
818 H H CH (CH_ThreeCOOEt 3-COOMe H 1-AI-Pip (4)
819 H H CH (CH_ThreeCOOEt 2-COOEt H 1-AI-Pip (4)
820 H H CH (CH_Three) COOEt 3-COOEt H 1-AI-Pip (4)
821 H H CH (CH_ThreeCOOEt 2-COOPr H 1-AI-Pip (4)
822 H H CH (CH_ThreeCOOEt 3-COOPr H 1-AI-Pip (4)
823 H H CH (CH_ThreeCOOEt 2-COOBu H 1-AI-Pip (4)
824 H H CH (CH_ThreeCOOEt 3-COOBu H 1-AI-Pip (4)
825 H H CH (CH_ThreeCOOEt 2-COOPn H 1-AI-Pip (4)
826 H H CH (CH_ThreeCOOEt 3-COOPn H 1-AI-Pip (4)
827 H H CH (CH_ThreeCOOEt 2-COOHx H 1-AI-Pip (4)
828 H H CH (CH_ThreeCOOEt 3-COOHx H 1-AI-Pip (4)
829 H H CH (CH_ThreeCOOEt 2-CONH₂    H 1-AI-Pip (4)
830 H H CH (CH_ThreeCOOEt 3-CONH₂    H 1-AI-Pip (4)
831 H H CH (CH_ThreeCOOEt 2-CONHMe H 1-AI-Pip (4)
832 H H CH (CH_ThreeCOOEt 3-CONHMe H 1-AI-Pip (4)
833 H H CH (CH_ThreeCOOEt 2-CONHEt H 1-AI-Pip (4)
834 H H CH (CH_Three) COOEt 3-CONHEt H 1-AI-Pip (4)
835 H H CH (CH_ThreeCOOEt 2-CON (Me)₂  H 1-AI-Pip (4)
836 H H CH (CH_ThreeCOOEt 3-CON (Me)₂  H 1-AI-Pip (4)
837 H H CH (CH_Three) COOEt 2-CON (Me) Et H 1-AI-Pip (4)
838 H H CH (CH_Three) COOEt 3-CON (Me) Et H 1-AI-Pip (4)
839 H H CH (CH_ThreeCOOEt 2-CON (Et)₂  H 1-AI-Pip (4)
840 H H CH (CH_ThreeCOOEt 3-CON (Et)₂  H 1-AI-Pip (4)
841 H H CH (CH_ThreeCOOEt 3-F 5-F 1-AI-Pip (4)
842 H H CH (CH_Three) COOEt 3-Cl 5-Cl 1-AI-Pip (4)
843 H H CH (CH_ThreeCOOEt 3-Me 5-Me 1-AI-Pip (4)
844 H H CH (CH_ThreeCOOEt 3-Cl 5-CONH₂    1-AI-Pip (4)
845 H H CH (CH_ThreeCOOEt 2-Me 5-CONH₂    1-AI-Pip (4)
846 H H CH (CH_Three) COOEt 3-Me 5-CONH₂    1-AI-Pip (4)
847 H H CH (CH_ThreeCOOEt 3-CONH₂    5-CONH₂    1-AI-Pip (4)
848 H H (CH₂)₂COOEt H H 1-AI-Pip (4)
849 H H (CH₂)_ThreeCOOEt H H 1-AI-Pip (4)
850 H H (CH₂)_FourCOOEt H H 1-AI-Pip (4)
851 H H (CH₂)_FiveCOOEt H H 1-AI-Pip (4)
852 H H (CH₂)₆COOEt H H 1-AI-Pip (4)
853 H H CH₂COCH₂COOMe H H 1-AI-Pip (4)
854 H H CH₂COCH₂COOEt H H 1-AI-Pip (4)
855 H H CH₂COCH₂COOPr H H 1-AI-Pip (4)
856 H H CH₂COCH₂COOBu H H 1-AI-Pip (4)
857 H H CH₂COCH₂COOPn H H 1-AI-Pip (4)
858 H H CH₂COCH₂COOHx H H 1-AI-Pip (4)
859 H H (CH₂)₂COCH₂COOEt H H 1-AI-Pip (4)
860 H H (CH₂)_ThreeCOCH₂COOEt H H 1-AI-Pip (4)
861 H H (CH₂)_FourCOCH₂COOEt H H 1-AI-Pip (4)
862 H H (CH₂)_FiveCOCH₂COOEt H H 1-AI-Pip (4)
863 H H (CH₂)₆COCH₂COOEt H H 1-AI-Pip (4)
864 H H Bn H H 1-AI-Pip (4)
865 H H Bn 2-F H 1-AI-Pip (4)
866 H H Bn 3-F H 1-AI-Pip (4)
867 H H Bn 2-Cl H 1-AI-Pip (4)
868 H H Bn 3-Cl H 1-AI-Pip (4)
869 H H Bn 2-Br H 1-AI-Pip (4)
870 H H Bn 3-Br H 1-AI-Pip (4)
871 H H Bn 2-I H 1-AI-Pip (4)
872 H H Bn 3-I H 1-AI-Pip (4)
873 H H Bn 2-Me H 1-AI-Pip (4)
874 H H Bn 3-Me H 1-AI-Pip (4)
875 H H Bn 2-Et H 1-AI-Pip (4)
876 H H Bn 3-Et H 1-AI-Pip (4)
877 H H Bn 2-Pr H 1-AI-Pip (4)
878 H H Bn 3-Pr H 1-AI-Pip (4)
879 H H Bn 2-Bu H 1-AI-Pip (4)
880 H H Bn 3-Bu H 1-AI-Pip (4)
881 H H Bn 2-Pn H 1-AI-Pip (4)
882 H H Bn 3-Pn H 1-AI-Pip (4)
883 H H Bn 2-Hx H 1-AI-Pip (4)
884 H H Bn 3-Hx H 1-AI-Pip (4)
885 H H Bn 2-CF_Three      H 1-AI-Pip (4)
886 H H Bn 3-CF_Three      H 1-AI-Pip (4)
887 H H Bn 2-OMe H 1-AI-Pip (4)
888 H H Bn 3-OMe H 1-AI-Pip (4)
889 H H Bn 2-OEt H 1-AI-Pip (4)
890 H H Bn 3-OEt H 1-AI-Pip (4)
891 H H Bn 2-COOH H 1-AI-Pip (4)
892 H H Bn 3-COOH H 1-AI-Pip (4)
893 H H Bn 2-COOMe H 1-AI-Pip (4)
894 H H Bn 3-COOMe H 1-AI-Pip (4)
895 H H Bn 2-COOEt H 1-AI-Pip (4)
896 H H Bn 3-COOEt H 1-AI-Pip (4)
897 H H Bn 2-COOPr H 1-AI-Pip (4)
898 H H Bn 3-COOPr H 1-AI-Pip (4)
899 H H Bn 2-COOBu H 1-AI-Pip (4)
900 H H Bn 3-COOBu H 1-AI-Pip (4)
901 H H Bn 2-COOPn H 1-AI-Pip (4)
902 H H Bn 3-COOPn H 1-AI-Pip (4)
903 H H Bn 2-COOHx H 1-AI-Pip (4)
904 H H Bn 3-COOHx H 1-AI-Pip (4)
905 H H Bn 2-CONH₂    H 1-AI-Pip (4)
906 H H Bn 3-CONH₂    H 1-AI-Pip (4)
907 H H Bn 2-CONHMe H 1-AI-Pip (4)
908 H H Bn 3-CONHMe H 1-AI-Pip (4)
909 H H Bn 2-CONHEt H 1-AI-Pip (4)
910 H H Bn 3-CONHEt H 1-AI-Pip (4)
911 H H Bn 2-CON (Me)₂  H 1-AI-Pip (4)
912 H H Bn 3-CON (Me)₂  H 1-AI-Pip (4)
913 H H Bn 2-CON (Me) Et H 1-AI-Pip (4)
914 H H Bn 3-CON (Me) Et H 1-AI-Pip (4)
915 H H Bn 2-CON (Et)₂  H 1-AI-Pip (4)
916 H H Bn 3-CON (Et)₂  H 1-AI-Pip (4)
917 H H Bn 3-F 5-F 1-AI-Pip (4)
918 H H Bn 3-Cl 5-Cl 1-AI-Pip (4)
919 H H Bn 3-Me 5-Me 1-AI-Pip (4)
920 H H Bn 3-Cl 5-CONH₂    1-AI-Pip (4)
921 H H Bn 2-Me 5-CONH₂    1-AI-Pip (4)
922 H H Bn 3-Me 5-CONH₂    1-AI-Pip (4)
923 H H Bn 3-CONH₂    5-CONH₂    1-AI-Pip (4)
924 H H CH₂Np (1) H H 1-AI-Pip (4)
925 6-OH H CH₂Np (1) H H 1-AI-Pip (4)
926 H H CH₂Np (2) H H 1-AI-Pip (4)
927 6-OH H CH₂Np (2) H H 1-AI-Pip (4)
928 H H (CH₂)₂Ph H H 1-AI-Pip (4)
929 6-OH H (CH₂)₂Ph H H 1-AI-Pip (4)
930 H H (CH₂)₂Np (1) H H 1-AI-Pip (4)
931 6-OH H (CH₂)₂Np (1) H H 1-AI-Pip (4)
932 H H (CH₂)₂Np (2) H H 1-AI-Pip (4)
933 6-OH H (CH₂)₂Np (2) H H 1-AI-Pip (4)
934 H H (CH₂)_ThreePh H H 1-AI-Pip (4)
935 6-OH H (CH₂)_ThreePh H H 1-AI-Pip (4)
936 H H (CH₂)_ThreeNp (1) H H 1-AI-Pip (4)
937 6-OH H (CH₂)_ThreeNp (1) H H 1-AI-Pip (4)
938 H H (CH₂)_ThreeNp (2) H H 1-AI-Pip (4)
939 6-OH H (CH₂)_ThreeNp (2) H H 1-AI-Pip (4)
940 H H (CH₂)_FourPh H H 1-AI-Pip (4)
941 6-OH H (CH₂)_FourPh H H 1-AI-Pip (4)
942 H H (CH₂)_FivePh H H 1-AI-Pip (4)
943 6-OH H (CH₂)_FivePh H H 1-AI-Pip (4)
944 H H (CH₂)₆Ph H H 1-AI-Pip (4)
945 6-OH H (CH₂)₆Ph H H 1-AI-Pip (4)
946 H H CHO H H 1-AI-Pip (4)
947 6-OH H CHO H H 1-AI-Pip (4)
948 H H Ac H H 1-AI-Pip (4)
949 H H Ac 2-F H 1-AI-Pip (4)
950 H H Ac 3-F H 1-AI-Pip (4)
951 H H Ac 2-Cl H 1-AI-Pip (4)
952 H H Ac 3-Cl H 1-AI-Pip (4)
953 H H Ac 2-Br H 1-AI-Pip (4)
954 H H Ac 3-Br H 1-AI-Pip (4)
955 H H Ac 2-I H 1-AI-Pip (4)
956 H H Ac 3-I H 1-AI-Pip (4)
957 H H Ac 2-Me H 1-AI-Pip (4)
958 H H Ac 3-Me H 1-AI-Pip (4)
959 H H Ac 2-Et H 1-AI-Pip (4)
960 H H Ac 3-Et H 1-AI-Pip (4)
961 H H Ac 2-Pr H 1-AI-Pip (4)
962 H H Ac 3-Pr H 1-AI-Pip (4)
963 H H Ac 2-Bu H 1-AI-Pip (4)
964 H H Ac 3-Bu H 1-AI-Pip (4)
965 H H Ac 2-Pn H 1-AI-Pip (4)
966 H H Ac 3-Pn H 1-AI-Pip (4)
967 H H Ac 2-Hx H 1-AI-Pip (4)
968 H H Ac 3-Hx H 1-AI-Pip (4)
969 H H Ac 2-CF_Three      H 1-AI-Pip (4)
970 H H Ac 3-CF_Three      H 1-AI-Pip (4)
971 H H Ac 2-OMe H 1-AI-Pip (4)
972 H H Ac 3-OMe H 1-AI-Pip (4)
973 H H Ac 2-OEt H 1-AI-Pip (4)
974 H H Ac 3-OEt H 1-AI-Pip (4)
975 H H Ac 2-COOH H 1-AI-Pip (4)
976 H H Ac 3-COOH H 1-AI-Pip (4)
977 H H Ac 2-COOMe H 1-AI-Pip (4)
978 H H Ac 3-COOMe H 1-AI-Pip (4)
979 H H Ac 2-COOEt H 1-AI-Pip (4)
980 H H Ac 3-COOEt H 1-AI-Pip (4)
981 H H Ac 2-COOPr H 1-AI-Pip (4)
982 H H Ac 3-COOPr H 1-AI-Pip (4)
983 H H Ac 2-COOBu H 1-AI-Pip (4)
984 H H Ac 3-COOBu H 1-AI-Pip (4)
985 H H Ac 2-COOPn H 1-AI-Pip (4)
986 H H Ac 3-COOPn H 1-AI-Pip (4)
987 H H Ac 2-COOHx H 1-AI-Pip (4)
988 H H Ac 3-COOHx H 1-AI-Pip (4)
989 H H Ac 2-CONH₂    H 1-AI-Pip (4)
990 H H Ac 3-CONH₂    H 1-AI-Pip (4)
991 H H Ac 2-CONHMe H 1-AI-Pip (4)
992 H H Ac 3-CONHMe H 1-AI-Pip (4)
993 H H Ac 2-CONHEt H 1-AI-Pip (4)
994 H H Ac 3-CONHEt H 1-AI-Pip (4)
995 H H Ac 2-CON (Me)₂  H 1-AI-Pip (4)
996 H H Ac 3-CON (Me)₂  H 1-AI-Pip (4)
997 H H Ac 2-CON (Me) Et H 1-AI-Pip (4)
998 H H Ac 3-CON (Me) Et H 1-AI-Pip (4)
999 H H Ac 2-CON (Et)₂  H 1-AI-Pip (4)
1000 H H Ac 3-CON (Et)₂  H 1-AI-Pip (4)
1001 H H Ac 3-F 5-F 1-AI-Pip (4)
1002 H H Ac 3-Cl 5-Cl 1-AI-Pip (4)
1003 H H Ac 3-Me 5-Me 1-AI-Pip (4)
1004 H H Ac 3-Cl 5-CONH₂    1-AI-Pip (4)
1005 H H Ac 2-Me 5-CONH₂    1-AI-Pip (4)
1006 H H Ac 3-Me 5-CONH₂    1-AI-Pip (4)
1007 H H Ac 3-CONH₂    5-CONH₂    1-AI-Pip (4)
1008 H H Prn H H 1-AI-Pip (4)
1009 6-OH H Prn H H 1-AI-Pip (4)
1010 H H Byr H H 1-AI-Pip (4)
1011 6-OH H Byr H H 1-AI-Pip (4)
1012 H H Va H H 1-AI-Pip (4)
1013 6-OH H Va H H 1-AI-Pip (4)
1014 H H COCH₂OH H H 1-AI-Pip (4)
1015 H H COCH₂OH 2-F H 1-AI-Pip (4)
1016 H H COCH₂OH 3-F H 1-AI-Pip (4)
1017 H H COCH₂OH 2-Cl H 1-AI-Pip (4)
1018 H H COCH₂OH 3-Cl H 1-AI-Pip (4)
1019 H H COCH₂OH 2-Br H 1-AI-Pip (4)
1020 H H COCH₂OH 3-Br H 1-AI-Pip (4)
1021 H H COCH₂OH 2-I H 1-AI-Pip (4)
1022 H H COCH₂OH 3-I H 1-AI-Pip (4)
1023 H H COCH₂OH 2-Me H 1-AI-Pip (4)
1024 H H COCH₂OH 3-Me H 1-AI-Pip (4)
1025 H H COCH₂OH 2-Et H 1-AI-Pip (4)
1026 H H COCH₂OH 3-Et H 1-AI-Pip (4)
1027 H H COCH₂OH 2-Pr H 1-AI-Pip (4)
1028 H H COCH₂OH 3-Pr H 1-AI-Pip (4)
1029 H H COCH₂OH 2-Bu H 1-AI-Pip (4)
1030 H H COCH₂OH 3-Bu H 1-AI-Pip (4)
1031 H H COCH₂OH 2-Pn H 1-AI-Pip (4)
1032 H H COCH₂OH 3-Pn H 1-AI-Pip (4)
1033 H H COCH₂OH 2-Hx H 1-AI-Pip (4)
1034 H H COCH₂OH 3-Hx H 1-AI-Pip (4)
1035 H H COCH₂OH 2-CF_Three      H 1-AI-Pip (4)
1036 H H COCH₂OH 3-CF_Three      H 1-AI-Pip (4)
1037 H H COCH₂OH 2-OMe H 1-AI-Pip (4)
1038 H H COCH₂OH 3-OMe H 1-AI-Pip (4)
1039 H H COCH₂OH 2-OEt H 1-AI-Pip (4)
1040 H H COCH₂OH 3-OEt H 1-AI-Pip (4)
1041 H H COCH₂OH 2-COOH H 1-AI-Pip (4)
1042 H H COCH₂OH 3-COOH H 1-AI-Pip (4)
1043 H H COCH₂OH 2-COOMe H 1-AI-Pip (4)
1044 H H COCH₂OH 3-COOMe H 1-AI-Pip (4)
1045 H H COCH₂OH 2-COOEt H 1-AI-Pip (4)
1046 H H COCH₂OH 3-COOEt H 1-AI-Pip (4)
1047 H H COCH₂OH 2-COOPr H 1-AI-Pip (4)
1048 H H COCH₂OH 3-COOPr H 1-AI-Pip (4)
1049 H H COCH₂OH 2-COOBu H 1-AI-Pip (4)
1050 H H COCH₂OH 3-COOBu H 1-AI-Pip (4)
1051 H H COCH₂OH 2-COOPn H 1-AI-Pip (4)
1052 H H COCH₂OH 3-COOPn H 1-AI-Pip (4)
1053 H H COCH₂OH 2-COOHx H 1-AI-Pip (4)
1054 H H COCH₂OH 3-COOHx H 1-AI-Pip (4)
1055 H H COCH₂OH 2-CONH₂    H 1-AI-Pip (4)
1056 H H COCH₂OH 3-CONH₂    H 1-AI-Pip (4)
1057 H H COCH₂OH 2-CONHMe H 1-AI-Pip (4)
1058 H H COCH₂OH 3-CONHMe H 1-AI-Pip (4)
1059 H H COCH₂OH 2-CONHEt H 1-AI-Pip (4)
1060 H H COCH₂OH 3-CONHEt H 1-AI-Pip (4)
1061 H H COCH₂OH 2-CON (Me)₂  H 1-AI-Pip (4)
1062 H H COCH₂OH 3-CON (Me)₂  H 1-AI-Pip (4)
1063 H H COCH₂OH 2-CON (Me) Et H 1-AI-Pip (4)
1064 H H COCH₂OH 3-CON (Me) Et H 1-AI-Pip (4)
1065 H H COCH₂OH 2-CON (Et)₂  H 1-AI-Pip (4)
1066 H H COCH₂OH 3-CON (Et)₂  H 1-AI-Pip (4)
1067 H H COCH₂OH 3-F 5-F 1-AI-Pip (4)
1068 H H COCH₂OH 3-Cl 5-Cl 1-AI-Pip (4)
1069 H H COCH₂OH 3-Me 5-Me 1-AI-Pip (4)
1070 H H COCH₂OH 3-Cl 5-CONH₂    1-AI-Pip (4)
1071 H H COCH₂OH 2-Me 5-CONH₂    1-AI-Pip (4)
1072 H H COCH₂OH 3-Me 5-CONH₂    1-AI-Pip (4)
1073 H H COCH₂OH 3-CONH₂    5-CONH₂    1-AI-Pip (4)
1074 H H CO (CH₂)₂OH H H 1-AI-Pip (4)
1075 H H CO (CH₂)_ThreeOH H H 1-AI-Pip (4)
1076 H H CO (CH₂)_FourOH H H 1-AI-Pip (4)
1077 H H CO (CH₂)_FiveOH H H 1-AI-Pip (4)
1078 H H SO₂Me H H 1-AI-Pip (4)
1079 6-OH H SO₂Me H H 1-AI-Pip (4)
1080 H H SO₂Et H H 1-AI-Pip (4)
1081 H H SO₂Et 2-F H 1-AI-Pip (4)
1082 H H SO₂Et 3-F H 1-AI-Pip (4)
1083 H H SO₂Et 2-Cl H 1-AI-Pip (4)
1084 H H SO₂Et 3-Cl H 1-AI-Pip (4)
1085 H H SO₂Et 2-Br H 1-AI-Pip (4)
1086 H H SO₂Et 3-Br H 1-AI-Pip (4)
1087 H H SO₂Et 2-I H 1-AI-Pip (4)
1088 H H SO₂Et 3-I H 1-AI-Pip (4)
1089 H H SO₂Et 2-Me H 1-AI-Pip (4)
1090 H H SO₂Et 3-Me H 1-AI-Pip (4)
1091 H H SO₂Et 2-Et H 1-AI-Pip (4)
1092 H H SO₂Et 3-Et H 1-AI-Pip (4)
1093 H H SO₂Et 2-Pr H 1-AI-Pip (4)
1094 H H SO₂Et 3-Pr H 1-AI-Pip (4)
1095 H H SO₂Et 2-Bu H 1-AI-Pip (4)
1096 H H SO₂Et 3-Bu H 1-AI-Pip (4)
1097 H H SO₂Et 2-Pn H 1-AI-Pip (4)
1098 H H SO₂Et 3-Pn H 1-AI-Pip (4)
1099 H H SO₂Et 2-Hx H 1-AI-Pip (4)
1100 H H SO₂Et 3-Hx H 1-AI-Pip (4)
1101 H H SO₂Et 2-CF_Three      H 1-AI-Pip (4)
1102 H H SO₂Et 3-CF_Three      H 1-AI-Pip (4)
1103 H H SO₂Et 2-OMe H 1-AI-Pip (4)
1104 H H SO₂Et 3-OMe H 1-AI-Pip (4)
1105 H H SO₂Et 2-OEt H 1-AI-Pip (4)
1106 H H SO₂Et 3-OEt H 1-AI-Pip (4)
1107 H H SO₂Et 2-COOH H 1-AI-Pip (4)
1108 H H SO₂Et 3-COOH H 1-AI-Pip (4)
1109 H H SO₂Et 2-COOMe H 1-AI-Pip (4)
1110 H H SO₂Et 3-COOMe H 1-AI-Pip (4)
1111 H H SO₂Et 2-COOEt H 1-AI-Pip (4)
1112 H H SO₂Et 3-COOEt H 1-AI-Pip (4)
1113 H H SO₂Et 2-COOPr H 1-AI-Pip (4)
1114 H H SO₂Et 3-COOPr H 1-AI-Pip (4)
1115 H H SO₂Et 2-COOBu H 1-AI-Pip (4)
1116 H H SO₂Et 3-COOBu H 1-AI-Pip (4)
1117 H H SO₂Et 2-COOPn H 1-AI-Pip (4)
1118 H H SO₂Et 3-COOPn H 1-AI-Pip (4)
1119 H H SO₂Et 2-COOHx H 1-AI-Pip (4)
1120 H H SO₂Et 3-COOHx H 1-AI-Pip (4)
1121 H H SO₂Et 2-CONH₂    H 1-AI-Pip (4)
1122 H H SO₂Et 3-CONH₂    H 1-AI-Pip (4)
1123 H H SO₂Et 2-CONHMe H 1-AI-Pip (4)
1124 H H SO₂Et 3-CONHMe H 1-AI-Pip (4)
1125 H H SO₂Et 2-CONHEt H 1-AI-Pip (4)
1126 H H SO₂Et 3-CONHEt H 1-AI-Pip (4)
1127 H H SO₂Et 3-CONHPr H 1-AI-Pip (4)
1128 H H SO₂Et 3-CONHBu H 1-AI-Pip (4)
1129 H H SO₂Et 3-CONHPn H 1-AI-Pip (4)
1130 H H SO₂Et 3-CONHHx H 1-AI-Pip (4)
1131 H H SO₂Et 2-CON (Me)₂  H 1-AI-Pip (4)
1132 H H SO₂Et 3-CON (Me)₂  H 1-AI-Pip (4)
1133 H H SO₂Et 2-CON (Me) Et H 1-AI-Pip (4)
1134 H H SO₂Et 3-CON (Me) Et H 1-AI-Pip (4)
1135 H H SO₂Et 2-CON (Et)₂  H 1-AI-Pip (4)
1136 H H SO₂Et 3-CON (Et)₂  H 1-AI-Pip (4)
1137 H H SO₂Et 3-CON (Pr)₂  H 1-AI-Pip (4)
1138 H H SO₂Et 3-CON (Bu)₂  H 1-AI-Pip (4)
1139 H H SO₂Et 3-CON (Pn)₂  H 1-AI-Pip (4)
1140 H H SO₂Et 3-CON (Hx)₂  H 1-AI-Pip (4)
1141 H H SO₂Et 2-F 3-F 1-AI-Pip (4)
1142 H H SO₂Et 2-F 5-F 1-AI-Pip (4)
1143 H H SO₂Et 2-F 6-F 1-AI-Pip (4)
1144 H H SO₂Et 3-F 5-F 1-AI-Pip (4)
1145 H H SO₂Et 2-Cl 3-Cl 1-AI-Pip (4)
1146 H H SO₂Et 2-Cl 5-Cl 1-AI-Pip (4)
1147 H H SO₂Et 2-Cl 6-Cl 1-AI-Pip (4)
1148 H H SO₂Et 3-Cl 5-Cl 1-AI-Pip (4)
1149 H H SO₂Et 2-Me 3-Me 1-AI-Pip (4)
1150 H H SO₂Et 2-Me 5-Me 1-AI-Pip (4)
1151 H H SO₂Et 2-Me 6-Me 1-AI-Pip (4)
1152 H H SO₂Et 3-Me 5-Me 1-AI-Pip (4)
1153 H H SO₂Et 2-Cl 5-CONH₂    1-AI-Pip (4)
1154 H H SO₂Et 2-Cl 6-CONH₂    1-AI-Pip (4)
1155 H H SO₂Et 3-Cl 5-CONH₂    1-AI-Pip (4)
1156 H H SO₂Et 2-Me 5-CONH₂    1-AI-Pip (4)
1157 H H SO₂Et 3-Me 5-CONH₂    1-AI-Pip (4)
1158 H H SO₂Et 2-CONH₂    5-CONH₂    1-AI-Pip (4)
1159 H H SO₂Et 3-CONH₂    5-CONH₂    1-AI-Pip (4)
1160 H F SO₂Et H H 1-AI-Pip (4)
1161 H F SO₂Et 2-F H 1-AI-Pip (4)
1162 H F SO₂Et 3-F H 1-AI-Pip (4)
1163 H F SO₂Et 2-Cl H 1-AI-Pip (4)
1164 H F SO₂Et 3-Cl H 1-AI-Pip (4)
1165 H F SO₂Et 2-Br H 1-AI-Pip (4)
1166 H F SO₂Et 3-Br H 1-AI-Pip (4)
1167 H F SO₂Et 2-I H 1-AI-Pip (4)
1168 H F SO₂Et 3-I H 1-AI-Pip (4)
1169 H F SO₂Et 2-Me H 1-AI-Pip (4)
1170 H F SO₂Et 3-Me H 1-AI-Pip (4)
1171 H F SO₂Et 2-Et H 1-AI-Pip (4)
1172 H F SO₂Et 3-Et H 1-AI-Pip (4)
1173 H F SO₂Et 2-Pr H 1-AI-Pip (4)
1174 H F SO₂Et 3-Pr H 1-AI-Pip (4)
1175 H F SO₂Et 2-Bu H 1-AI-Pip (4)
1176 H F SO₂Et 3-Bu H 1-AI-Pip (4)
1177 H F SO₂Et 2-Pn H 1-AI-Pip (4)
1178 H F SO₂Et 3-Pn H 1-AI-Pip (4)
1179 H F SO₂Et 2-Hx H 1-AI-Pip (4)
1180 H F SO₂Et 3-Hx H 1-AI-Pip (4)
1181 H F SO₂Et 2-CF_Three      H 1-AI-Pip (4)
1182 H F SO₂Et 3-CF_Three      H 1-AI-Pip (4)
1183 H F SO₂Et 2-OMe H 1-AI-Pip (4)
1184 H F SO₂Et 3-OMe H 1-AI-Pip (4)
1185 H F SO₂Et 2-OEt H 1-AI-Pip (4)
1186 H F SO₂Et 3-OEt H 1-AI-Pip (4)
1187 H F SO₂Et 2-COOH H 1-AI-Pip (4)
1188 H F SO₂Et 3-COOH H 1-AI-Pip (4)
1189 H F SO₂Et 2-COOMe H 1-AI-Pip (4)
1190 H F SO₂Et 3-COOMe H 1-AI-Pip (4)
1191 H F SO₂Et 2-COOEt H 1-AI-Pip (4)
1192 H F SO₂Et 3-COOEt H 1-AI-Pip (4)
1193 H F SO₂Et 2-COOPr H 1-AI-Pip (4)
1194 H F SO₂Et 3-COOPr H 1-AI-Pip (4)
1195 H F SO₂Et 2-COOBu H 1-AI-Pip (4)
1196 H F SO₂Et 3-COOBu H 1-AI-Pip (4)
1197 H F SO₂Et 2-COOPn H 1-AI-Pip (4)
1198 H F SO₂Et 3-COOPn H 1-AI-Pip (4)
1199 H F SO₂Et 2-COOHx H 1-AI-Pip (4)
1200 H F SO₂Et 3-COOHx H 1-AI-Pip (4)
1201 H F SO₂Et 2-CONH₂    H 1-AI-Pip (4)
1202 H F SO₂Et 3-CONH₂    H 1-AI-Pip (4)
1203 H F SO₂Et 2-CONHMe H 1-AI-Pip (4)
1204 H F SO₂Et 3-CONHMe H 1-AI-Pip (4)
1205 H F SO₂Et 2-CONHEt H 1-AI-Pip (4)
1206 H F SO₂Et 3-CONHEt H 1-AI-Pip (4)
1207 H F SO₂Et 2-CON (Me)₂  H 1-AI-Pip (4)
1208 H F SO₂Et 3-CON (Me)₂  H 1-AI-Pip (4)
1209 H F SO₂Et 2-CON (Me) Et H 1-AI-Pip (4)
1210 H F SO₂Et 3-CON (Me) Et H 1-AI-Pip (4)
1211 H F SO₂Et 2-CON (Et)₂  H 1-AI-Pip (4)
1212 H F SO₂Et 3-CON (Et)₂  H 1-AI-Pip (4)
1213 H F SO₂Et 3-F 5-F 1-AI-Pip (4)
1214 H F SO₂Et 3-Cl 5-Cl 1-AI-Pip (4)
1215 H F SO₂Et 3-Me 5-Me 1-AI-Pip (4)
1216 H F SO₂Et 3-Cl 5-CONH₂    1-AI-Pip (4)
1217 H F SO₂Et 2-Me 5-CONH₂    1-AI-Pip (4)
1218 H F SO₂Et 3-Me 5-CONH₂    1-AI-Pip (4)
1219 H F SO₂Et 3-CONH₂    5-CONH₂    1-AI-Pip (4)
1220 H Me SO₂Et H H 1-AI-Pip (4)
1221 H Me SO₂Et 2-F H 1-AI-Pip (4)
1222 H Me SO₂Et 3-F H 1-AI-Pip (4)
1223 H Me SO₂Et 2-Cl H 1-AI-Pip (4)
1224 H Me SO₂Et 3-Cl H 1-AI-Pip (4)
1225 H Me SO₂Et 2-Br H 1-AI-Pip (4)
1226 H Me SO₂Et 3-Br H 1-AI-Pip (4)
1227 H Me SO₂Et 2-I H 1-AI-Pip (4)
1228 H Me SO₂Et 3-I H 1-AI-Pip (4)
1229 H Me SO₂Et 2-Me H 1-AI-Pip (4)
1230 H Me SO₂Et 3-Me H 1-AI-Pip (4)
1231 H Me SO₂Et 2-Et H 1-AI-Pip (4)
1232 H Me SO₂Et 3-Et H 1-AI-Pip (4)
1233 H Me SO₂Et 2-Pr H 1-AI-Pip (4)
1234 H Me SO₂Et 3-Pr H 1-AI-Pip (4)
1235 H Me SO₂Et 2-Bu H 1-AI-Pip (4)
1236 H Me SO₂Et 3-Bu H 1-AI-Pip (4)
1237 H Me SO₂Et 2-Pn H 1-AI-Pip (4)
1238 H Me SO₂Et 3-Pn H 1-AI-Pip (4)
1239 H Me SO₂Et 2-Hx H 1-AI-Pip (4)
1240 H Me SO₂Et 3-Hx H 1-AI-Pip (4)
1241 H Me SO₂Et 2-CF_Three      H 1-AI-Pip (4)
1242 H Me SO₂Et 3-CF_Three      H 1-AI-Pip (4)
1243 H Me SO₂Et 2-OMe H 1-AI-Pip (4)
1244 H Me SO₂Et 3-OMe H 1-AI-Pip (4)
1245 H Me SO₂Et 2-OEt H 1-AI-Pip (4)
1246 H Me SO₂Et 3-OEt H 1-AI-Pip (4)
1247 H Me SO₂Et 2-COOH H 1-AI-Pip (4)
1248 H Me SO₂Et 3-COOH H 1-AI-Pip (4)
1249 H Me SO₂Et 2-COOMe H 1-AI-Pip (4)
1250 H Me SO₂Et 3-COOMe H 1-AI-Pip (4)
1251 H Me SO₂Et 2-COOEt H 1-AI-Pip (4)
1252 H Me SO₂Et 3-COOEt H 1-AI-Pip (4)
1253 H Me SO₂Et 2-COOPr H 1-AI-Pip (4)
1254 H Me SO₂Et 3-COOPr H 1-AI-Pip (4)
1255 H Me SO₂Et 2-COOBu H 1-AI-Pip (4)
1256 H Me SO₂Et 3-COOBu H 1-AI-Pip (4)
1257 H Me SO₂Et 2-COOPn H 1-AI-Pip (4)
1258 H Me SO₂Et 3-COOPn H 1-AI-Pip (4)
1259 H Me SO₂Et 2-COOHx H 1-AI-Pip (4)
1260 H Me SO₂Et 3-COOHx H 1-AI-Pip (4)
1261 H Me SO₂Et 2-CONH₂    H 1-AI-Pip (4)
1262 H Me SO₂Et 3-CONH₂    H 1-AI-Pip (4)
1263 H Me SO₂Et 2-CONHMe H 1-AI-Pip (4)
1264 H Me SO₂Et 3-CONHMe H 1-AI-Pip (4)
1265 H Me SO₂Et 2-CONHEt H 1-AI-Pip (4)
1266 H Me SO₂Et 3-CONHEt H 1-AI-Pip (4)
1267 H Me SO₂Et 2-CON (Me)₂  H 1-AI-Pip (4)
1268 H Me SO₂Et 3-CON (Me)₂  H 1-AI-Pip (4)
1269 H Me SO₂Et 2-CON (Me) Et H 1-AI-Pip (4)
1270 H Me SO₂Et 3-CON (Me) Et H 1-AI-Pip (4)
1271 H Me SO₂Et 2-CON (Et)₂  H 1-AI-Pip (4)
1272 H Me SO₂Et 3-CON (Et)₂  H 1-AI-Pip (4)
1273 H Me SO₂Et 3-F 5-F 1-AI-Pip (4)
1274 H Me SO₂Et 3-Cl 5-Cl 1-AI-Pip (4)
1275 H Me SO₂Et 3-Me 5-Me 1-AI-Pip (4)
1276 H Me SO₂Et 3-Cl 5-CONH₂    1-AI-Pip (4)
1277 H Me SO₂Et 2-Me 5-CONH₂    1-AI-Pip (4)
1278 H Me SO₂Et 3-Me 5-CONH₂    1-AI-Pip (4)
1279 H Me SO₂Et 3-CONH₂    5-CONH₂    1-AI-Pip (4)
1280 6-F H SO₂Et H H 1-AI-Pip (4)
1281 6-F H SO₂Et 2-F H 1-AI-Pip (4)
1282 6-F H SO₂Et 3-F H 1-AI-Pip (4)
1283 6-F H SO₂Et 2-Cl H 1-AI-Pip (4)
1284 6-F H SO₂Et 3-Cl H 1-AI-Pip (4)
1285 6-F H SO₂Et 2-Br H 1-AI-Pip (4)
1286 6-F H SO₂Et 3-Br H 1-AI-Pip (4)
1287 6-F H SO₂Et 2-I H 1-AI-Pip (4)
1288 6-F H SO₂Et 3-I H 1-AI-Pip (4)
1289 6-F H SO₂Et 2-Me H 1-AI-Pip (4)
1290 6-F H SO₂Et 3-Me H 1-AI-Pip (4)
1291 6-F H SO₂Et 2-Et H 1-AI-Pip (4)
1292 6-F H SO₂Et 3-Et H 1-AI-Pip (4)
1293 6-F H SO₂Et 2-Pr H 1-AI-Pip (4)
1294 6-F H SO₂Et 3-Pr H 1-AI-Pip (4)
1295 6-F H SO₂Et 2-Bu H 1-AI-Pip (4)
1296 6-F H SO₂Et 3-Bu H 1-AI-Pip (4)
1297 6-F H SO₂Et 2-Pn H 1-AI-Pip (4)
1298 6-F H SO₂Et 3-Pn H 1-AI-Pip (4)
1299 6-F H SO₂Et 2-Hx H 1-AI-Pip (4)
1300 6-F H SO₂Et 3-Hx H 1-AI-Pip (4)
1301 6-F H SO₂Et 2-CF_Three      H 1-AI-Pip (4)
1302 6-F H SO₂Et 3-CF_Three      H 1-AI-Pip (4)
1303 6-F H SO₂Et 2-OMe H 1-AI-Pip (4)
1304 6-F H SO₂Et 3-OMe H 1-AI-Pip (4)
1305 6-F H SO₂Et 2-OEt H 1-AI-Pip (4)
1306 6-F H SO₂Et 3-OEt H 1-AI-Pip (4)
1307 6-F H SO₂Et 2-COOH H 1-AI-Pip (4)
1308 6-F H SO₂Et 3-COOH H 1-AI-Pip (4)
1309 6-F H SO₂Et 2-COOMe H 1-AI-Pip (4)
1310 6-F H SO₂Et 3-COOMe H 1-AI-Pip (4)
1311 6-F H SO₂Et 2-COOEt H 1-AI-Pip (4)
1312 6-F H SO₂Et 3-COOEt H 1-AI-Pip (4)
1313 6-F H SO₂Et 2-COOPr H 1-AI-Pip (4)
1314 6-F H SO₂Et 3-COOPr H 1-AI-Pip (4)
1315 6-F H SO₂Et 2-COOBu H 1-AI-Pip (4)
1316 6-F H SO₂Et 3-COOBu H 1-AI-Pip (4)
1317 6-F H SO₂Et 2-COOPn H 1-AI-Pip (4)
1318 6-F H SO₂Et 3-COOPn H 1-AI-Pip (4)
1319 6-F H SO₂Et 2-COOHx H 1-AI-Pip (4)
1320 6-F H SO₂Et 3-COOHx H 1-AI-Pip (4)
1321 6-F H SO₂Et 2-CONH₂    H 1-AI-Pip (4)
1322 6-F H SO₂Et 3-CONH₂    H 1-AI-Pip (4)
1323 6-F H SO₂Et 2-CONHMe H 1-AI-Pip (4)
1324 6-F H SO₂Et 3-CONHMe H 1-AI-Pip (4)
1325 6-F H SO₂Et 2-CONHEt H 1-AI-Pip (4)
1326 6-F H SO₂Et 3-CONHEt H 1-AI-Pip (4)
1327 6-F H SO₂Et 2-CON (Me)₂  H 1-AI-Pip (4)
1328 6-F H SO₂Et 3-CON (Me)₂  H 1-AI-Pip (4)
1329 6-F H SO₂Et 2-CON (Me) Et H 1-AI-Pip (4)
1330 6-F H SO₂Et 3-CON (Me) Et H 1-AI-Pip (4)
1331 6-F H SO₂Et 2-CON (Et)₂  H 1-AI-Pip (4)
1332 6-F H SO₂Et 3-CON (Et)₂  H 1-AI-Pip (4)
1333 6-F H SO₂Et 3-F 5-F 1-AI-Pip (4)
1334 6-F H SO₂Et 3-Cl 5-Cl 1-AI-Pip (4)
1335 6-F H SO₂Et 3-Me 5-Me 1-AI-Pip (4)
1336 6-F H SO₂Et 3-Cl 5-CONH₂    1-AI-Pip (4)
1337 6-F H SO₂Et 2-Me 5-CONH₂    1-AI-Pip (4)
1338 6-F H SO₂Et 3-Me 5-CONH₂    1-AI-Pip (4)
1339 6-F H SO₂Et 3-CONH₂    5-CONH₂    1-AI-Pip (4)
1340 6-OH H SO₂Et H H 1-AI-Pip (4)
1341 6-OH H SO₂Et 2-F H 1-AI-Pip (4)
1342 6-OH H SO₂Et 3-F H 1-AI-Pip (4)
1343 6-OH H SO₂Et 2-Cl H 1-AI-Pip (4)
1344 6-OH H SO₂Et 3-Cl H 1-AI-Pip (4)
1345 6-OH H SO₂Et 2-Br H 1-AI-Pip (4)
1346 6-OH H SO₂Et 3-Br H 1-AI-Pip (4)
1347 6-OH H SO₂Et 2-I H 1-AI-Pip (4)
1348 6-OH H SO₂Et 3-I H 1-AI-Pip (4)
1349 6-OH H SO₂Et 2-Me H 1-AI-Pip (4)
1350 6-OH H SO₂Et 3-Me H 1-AI-Pip (4)
1351 6-OH H SO₂Et 2-Et H 1-AI-Pip (4)
1352 6-OH H SO₂Et 3-Et H 1-AI-Pip (4)
1353 6-OH H SO₂Et 2-Pr H 1-AI-Pip (4)
1354 6-OH H SO₂Et 3-Pr H 1-AI-Pip (4)
1355 6-OH H SO₂Et 2-Bu H 1-AI-Pip (4)
1356 6-OH H SO₂Et 3-Bu H 1-AI-Pip (4)
1357 6-OH H SO₂Et 2-Pn H 1-AI-Pip (4)
1358 6-OH H SO₂Et 3-Pn H 1-AI-Pip (4)
1359 6-OH H SO₂Et 2-Hx H 1-AI-Pip (4)
1360 6-OH H SO₂Et 3-Hx H 1-AI-Pip (4)
1361 6-OH H SO₂Et 2-CF_Three      H 1-AI-Pip (4)
1362 6-OH H SO₂Et 3-CF_Three      H 1-AI-Pip (4)
1363 6-OH H SO₂Et 2-OMe H 1-AI-Pip (4)
1364 6-OH H SO₂Et 3-OMe H 1-AI-Pip (4)
1365 6-OH H SO₂Et 2-OEt H 1-AI-Pip (4)
1366 6-OH H SO₂Et 3-OEt H 1-AI-Pip (4)
1367 6-OH H SO₂Et 2-COOH H 1-AI-Pip (4)
1368 6-OH H SO₂Et 3-COOH H 1-AI-Pip (4)
1369 6-OH H SO₂Et 2-COOMe H 1-AI-Pip (4)
1370 6-OH H SO₂Et 3-COOMe H 1-AI-Pip (4)
1371 6-OH H SO₂Et 2-COOEt H 1-AI-Pip (4)
1372 6-OH H SO₂Et 3-COOEt H 1-AI-Pip (4)
1373 6-OH H SO₂Et 2-COOPr H 1-AI-Pip (4)
1374 6-OH H SO₂Et 3-COOPr H 1-AI-Pip (4)
1375 6-OH H SO₂Et 2-COOBu H 1-AI-Pip (4)
1376 6-OH H SO₂Et 3-COOBu H 1-AI-Pip (4)
1377 6-OH H SO₂Et 2-COOPn H 1-AI-Pip (4)
1378 6-OH H SO₂Et 3-COOPn H 1-AI-Pip (4)
1379 6-OH H SO₂Et 2-COOHx H 1-AI-Pip (4)
1380 6-OH H SO₂Et 3-COOHx H 1-AI-Pip (4)
1381 6-OH H SO₂Et 2-CONH₂    H 1-AI-Pip (4)
1382 6-OH H SO₂Et 3-CONH₂    H 1-AI-Pip (4)
1383 6-OH H SO₂Et 2-CONHMe H 1-AI-Pip (4)
1384 6-OH H SO₂Et 3-CONHMe H 1-AI-Pip (4)
1385 6-OH H SO₂Et 2-CONHEt H 1-AI-Pip (4)
1386 6-OH H SO₂Et 3-CONHEt H 1-AI-Pip (4)
1387 6-OH H SO₂Et 2-CON (Me)₂  H 1-AI-Pip (4)
1388 6-OH H SO₂Et 3-CON (Me)₂  H 1-AI-Pip (4)
1389 6-OH H SO₂Et 2-CON (Me) Et H 1-AI-Pip (4)
1390 6-OH H SO₂Et 3-CON (Me) Et H 1-AI-Pip (4)
1391 6-OH H SO₂Et 2-CON (Et)₂  H 1-AI-Pip (4)
1392 6-OH H SO₂Et 3-CON (Et)₂  H 1-AI-Pip (4)
1393 6-OH H SO₂Et 3-F 5-F 1-AI-Pip (4)
1394 6-OH H SO₂Et 3-Cl 5-Cl 1-AI-Pip (4)
1395 6-OH H SO₂Et 3-Me 5-Me 1-AI-Pip (4)
1396 6-OH H SO₂Et 3-Cl 5-CONH₂    1-AI-Pip (4)
1397 6-OH H SO₂Et 2-Me 5-CONH₂    1-AI-Pip (4)
1398 6-OH H SO₂Et 3-Me 5-CONH₂    1-AI-Pip (4)
1399 6-OH H SO₂Et 3-CONH₂    5-CONH₂    1-AI-Pip (4)
1400 H H SO₂Pr H H 1-AI-Pip (4)
1401 H H SO₂ iPr H H 1-AI-Pip (4)
1402 H H SO₂Bu H H 1-AI-Pip (4)
1403 H H SO₂ sBu H H 1-AI-Pip (4)
1404 H H SO₂ iBu H H 1-AI-Pip (4)
1405 H H SO₂ tBu H H 1-AI-Pip (4)
1406 H H SO₂Pn H H 1-AI-Pip (4)
1407 H H SO₂Hx H H 1-AI-Pip (4)
1408 H H SO₂CH₂COOMe H H 1-AI-Pip (4)
1409 6-OH H SO₂CH₂COOMe H H 1-AI-Pip (4)
1410 H H SO₂CH₂COOEt H H 1-AI-Pip (4)
1411 H H SO₂CH₂COOEt 2-F H 1-AI-Pip (4)
1412 H H SO₂CH₂COOEt 3-F H 1-AI-Pip (4)
1413 H H SO₂CH₂COOEt 2-Cl H 1-AI-Pip (4)
1414 H H SO₂CH₂COOEt 3-Cl H 1-AI-Pip (4)
1415 H H SO₂CH₂COOEt 2-Br H 1-AI-Pip (4)
1416 H H SO₂CH₂COOEt 3-Br H 1-AI-Pip (4)
1417 H H SO₂CH₂COOEt 2-I H 1-AI-Pip (4)
1418 H H SO₂CH₂COOEt 3-I H 1-AI-Pip (4)
1419 H H SO₂CH₂COOEt 2-Me H 1-AI-Pip (4)
1420 H H SO₂CH₂COOEt 3-Me H 1-AI-Pip (4)
1421 H H SO₂CH₂COOEt 2-Et H 1-AI-Pip (4)
1422 H H SO₂CH₂COOEt 3-Et H 1-AI-Pip (4)
1423 H H SO₂CH₂COOEt 2-Pr H 1-AI-Pip (4)
1424 H H SO₂CH₂COOEt 3-Pr H 1-AI-Pip (4)
1425 H H SO₂CH₂COOEt 2-iPr H 1-AI-Pip (4)
1426 H H SO₂CH₂COOEt 3-iPr H 1-AI-Pip (4)
1427 H H SO₂CH₂COOEt 2-Bu H 1-AI-Pip (4)
1428 H H SO₂CH₂COOEt 3-Bu H 1-AI-Pip (4)
1429 H H SO₂CH₂COOEt 2-iBu H 1-AI-Pip (4)
1430 H H SO₂CH₂COOEt 3-iBu H 1-AI-Pip (4)
1431 H H SO₂CH₂COOEt 2-sBu H 1-AI-Pip (4)
1432 H H SO₂CH₂COOEt 3-sBu H 1-AI-Pip (4)
1433 H H SO₂CH₂COOEt 2-tBu H 1-AI-Pip (4)
1434 H H SO₂CH₂COOEt 3-tBu H 1-AI-Pip (4)
1435 H H SO₂CH₂COOEt 2-Pn H 1-AI-Pip (4)
1436 H H SO₂CH₂COOEt 3-Pn H 1-AI-Pip (4)
1437 H H SO₂CH₂COOEt 2-Hx H 1-AI-Pip (4)
1438 H H SO₂CH₂COOEt 3-Hx H 1-AI-Pip (4)
1439 H H SO₂CH₂COOEt 2-CF_Three      H 1-AI-Pip (4)
1440 H H SO₂CH₂COOEt 3-CF_Three      H 1-AI-Pip (4)
1441 H H SO₂CH₂COOEt 2-OMe H 1-AI-Pip (4)
1442 H H SO₂CH₂COOEt 3-OMe H 1-AI-Pip (4)
1443 H H SO₂CH₂COOEt 2-OEt H 1-AI-Pip (4)
1444 H H SO₂CH₂COOEt 3-OEt H 1-AI-Pip (4)
1445 H H SO₂CH₂COOEt 2-COOH H 1-AI-Pip (4)
1446 H H SO₂CH₂COOEt 3-COOH H 1-AI-Pip (4)
1447 H H SO₂CH₂COOEt 2-COOMe H 1-AI-Pip (4)
1448 H H SO₂CH₂COOEt 3-COOMe H 1-AI-Pip (4)
1449 H H SO₂CH₂COOEt 2-COOEt H 1-AI-Pip (4)
1450 H H SO₂CH₂COOEt 3-COOEt H 1-AI-Pip (4)
1451 H H SO₂CH₂COOEt 2-COOPr H 1-AI-Pip (4)
1452 H H SO₂CH₂COOEt 3-COOPr H 1-AI-Pip (4)
1453 H H SO₂CH₂COOEt 2-COOBu H 1-AI-Pip (4)
1454 H H SO₂CH₂COOEt 3-COOBu H 1-AI-Pip (4)
1455 H H SO₂CH₂COOEt 2-COOPn H 1-AI-Pip (4)
1456 H H SO₂CH₂COOEt 3-COOPn H 1-AI-Pip (4)
1457 H H SO₂CH₂COOEt 2-COOHx H 1-AI-Pip (4)
1458 H H SO₂CH₂COOEt 3-COOHx H 1-AI-Pip (4)
1459 H H SO₂CH₂COOEt 2-CONH₂    H 1-AI-Pip (4)
1460 H H SO₂CH₂COOEt 3-CONH₂    H 1-AI-Pip (4)
1461 H H SO₂CH₂COOEt 2-CONHMe H 1-AI-Pip (4)
1462 H H SO₂CH₂COOEt 3-CONHMe H 1-AI-Pip (4)
1463 H H SO₂CH₂COOEt 2-CONHEt H 1-AI-Pip (4)
1464 H H SO₂CH₂COOEt 3-CONHEt H 1-AI-Pip (4)
1465 H H SO₂CH₂COOEt 2-CON (Me)₂  H 1-AI-Pip (4)
1466 H H SO₂CH₂COOEt 3-CON (Me)₂  H 1-AI-Pip (4)
1467 H H SO₂CH₂COOEt 2-CON (Me) Et H 1-AI-Pip (4)
1468 H H SO₂CH₂COOEt 3-CON (Me) Et H 1-AI-Pip (4)
1469 H H SO₂CH₂COOEt 2-CON (Et)₂  H 1-AI-Pip (4)
1470 H H SO₂CH₂COOEt 3-CON (Et)₂  H 1-AI-Pip (4)
1471 H H SO₂CH₂COOEt 2-F 3-F 1-AI-Pip (4)
1472 H H SO₂CH₂COOEt 2-F 5-F 1-AI-Pip (4)
1473 H H SO₂CH₂COOEt 2-F 6-F 1-AI-Pip (4)
1474 H H SO₂CH₂COOEt 3-F 5-F 1-AI-Pip (4)
1475 H H SO₂CH₂COOEt 2-Cl 3-Cl 1-AI-Pip (4)
1476 H H SO₂CH₂COOEt 2-Cl 5-Cl 1-AI-Pip (4)
1477 H H SO₂CH₂COOEt 2-Cl 6-Cl 1-AI-Pip (4)
1478 H H SO₂CH₂COOEt 3-Cl 5-Cl 1-AI-Pip (4)
1479 H H SO₂CH₂COOEt 2-Me 3-Me 1-AI-Pip (4)
1480 H H SO₂CH₂COOEt 2-Me 5-Me 1-AI-Pip (4)
1481 H H SO₂CH₂COOEt 2-Me 6-Me 1-AI-Pip (4)
1482 H H SO₂CH₂COOEt 3-Me 5-Me 1-AI-Pip (4)
1483 H H SO₂CH₂COOEt 2-Cl 5-CONH₂    1-AI-Pip (4)
1484 H H SO₂CH₂COOEt 3-Cl 5-CONH₂    1-AI-Pip (4)
1485 H H SO₂CH₂COOEt 3-Cl 5-CONHMe 1-AI-Pip (4)
1486 H H SO₂CH₂COOEt 3-Cl 5-CONHEt 1-AI-Pip (4)
1487 H H SO₂CH₂COOEt 3-Cl 5-CONHPr 1-AI-Pip (4)
1488 H H SO₂CH₂COOEt 3-Cl 5-CONHBu 1-AI-Pip (4)
1489 H H SO₂CH₂COOEt 3-Cl 5-CONHPn 1-AI-Pip (4)
1490 H H SO₂CH₂COOEt 3-Cl 5-CONHHx 1-AI-Pip (4)
1491 H H SO₂CH₂COOEt 2-Me 5-CONH₂    1-AI-Pip (4)
1492 H H SO₂CH₂COOEt 2-Me 5-CONHMe 1-AI-Pip (4)
1493 H H SO₂CH₂COOEt 2-Me 5-CONHEt 1-AI-Pip (4)
1494 H H SO₂CH₂COOEt 2-Me 5-CONHPr 1-AI-Pip (4)
1495 H H SO₂CH₂COOEt 2-Me 5-CONHBu 1-AI-Pip (4)
1496 H H SO₂CH₂COOEt 2-Me 5-CONHPn 1-AI-Pip (4)
1497 H H SO₂CH₂COOEt 2-Me 5-CONHHx 1-AI-Pip (4)
1498 H H SO₂CH₂COOEt 3-Me 5-CONH₂    1-AI-Pip (4)
1499 H H SO₂CH₂COOEt 3-Me 5-CONHMe 1-AI-Pip (4)
1500 H H SO₂CH₂COOEt 3-Me 5-CONHEt 1-AI-Pip (4)
1501 H H SO₂CH₂COOEt 3-Me 5-CONHPr 1-AI-Pip (4)
1502 H H SO₂CH₂COOEt 3-Me 5-CONHBu 1-AI-Pip (4)
1503 H H SO₂CH₂COOEt 3-Me 5-CONHPn 1-AI-Pip (4)
1504 H H SO₂CH₂COOEt 3-Me 5-CONHHx 1-AI-Pip (4)
1505 H H SO₂CH₂COOEt 2-CONH₂    6-CONH₂    1-AI-Pip (4)
1506 H H SO₂CH₂COOEt 3-CONH₂    5-CONH₂    1-AI-Pip (4)
1507 H H SO₂CH₂COOEt 3-CONHMe 5-CONHMe 1-AI-Pip (4)
1508 H H SO₂CH₂COOEt 3-CONHEt 5-CONHEt 1-AI-Pip (4)
1509 H F SO₂CH₂COOEt H H 1-AI-Pip (4)
1510 H F SO₂CH₂COOEt 2-F H 1-AI-Pip (4)
1511 H F SO₂CH₂COOEt 3-F H 1-AI-Pip (4)
1512 H F SO₂CH₂COOEt 2-Cl H 1-AI-Pip (4)
1513 H F SO₂CH₂COOEt 3-Cl H 1-AI-Pip (4)
1514 H F SO₂CH₂COOEt 2-Br H 1-AI-Pip (4)
1515 H F SO₂CH₂COOEt 3-Br H 1-AI-Pip (4)
1516 H F SO₂CH₂COOEt 2-I H 1-AI-Pip (4)
1517 H F SO₂CH₂COOEt 3-I H 1-AI-Pip (4)
1518 H F SO₂CH₂COOEt 2-Me H 1-AI-Pip (4)
1519 H F SO₂CH₂COOEt 3-Me H 1-AI-Pip (4)
1520 H F SO₂CH₂COOEt 2-Et H 1-AI-Pip (4)
1521 H F SO₂CH₂COOEt 3-Et H 1-AI-Pip (4)
1522 H F SO₂CH₂COOEt 2-Pr H 1-AI-Pip (4)
1523 H F SO₂CH₂COOEt 3-Pr H 1-AI-Pip (4)
1524 H F SO₂CH₂COOEt 2-iPr H 1-AI-Pip (4)
1525 H F SO₂CH₂COOEt 3-iPr H 1-AI-Pip (4)
1526 H F SO₂CH₂COOEt 2-Bu H 1-AI-Pip (4)
1527 H F SO₂CH₂COOEt 3-Bu H 1-AI-Pip (4)
1528 H F SO₂CH₂COOEt 2-iBu H 1-AI-Pip (4)
1529 H F SO₂CH₂COOEt 3-iBu H 1-AI-Pip (4)
1530 H F SO₂CH₂COOEt 2-sBu H 1-AI-Pip (4)
1531 H F SO₂CH₂COOEt 3-sBu H 1-AI-Pip (4)
1532 H F SO₂CH₂COOEt 2-tBu H 1-AI-Pip (4)
1533 H F SO₂CH₂COOEt 3-tBu H 1-AI-Pip (4)
1534 H F SO₂CH₂COOEt 2-Pn H 1-AI-Pip (4)
1535 H F SO₂CH₂COOEt 3-Pn H 1-AI-Pip (4)
1536 H F SO₂CH₂COOEt 2-Hx H 1-AI-Pip (4)
1537 H F SO₂CH₂COOEt 3-Hx H 1-AI-Pip (4)
1538 H F SO₂CH₂COOEt 2-CF_Three      H 1-AI-Pip (4)
1539 H F SO₂CH₂COOEt 3-CF_Three      H 1-AI-Pip (4)
1540 H F SO₂CH₂COOEt 2-OMe H 1-AI-Pip (4)
1541 H F SO₂CH₂COOEt 3-OMe H 1-AI-Pip (4)
1542 H F SO₂CH₂COOEt 2-OEt H 1-AI-Pip (4)
1543 H F SO₂CH₂COOEt 3-OEt H 1-AI-Pip (4)
1544 H F SO₂CH₂COOEt 2-COOH H 1-AI-Pip (4)
1545 H F SO₂CH₂COOEt 3-COOH H 1-AI-Pip (4)
1546 H F SO₂CH₂COOEt 2-COOMe H 1-AI-Pip (4)
1547 H F SO₂CH₂COOEt 3-COOMe H 1-AI-Pip (4)
1548 H F SO₂CH₂COOEt 2-COOEt H 1-AI-Pip (4)
1549 H F SO₂CH₂COOEt 3-COOEt H 1-AI-Pip (4)
1550 H F SO₂CH₂COOEt 2-COOPr H 1-AI-Pip (4)
1551 H F SO₂CH₂COOEt 3-COOPr H 1-AI-Pip (4)
1552 H F SO₂CH₂COOEt 2-COOBu H 1-AI-Pip (4)
1553 H F SO₂CH₂COOEt 3-COOBu H 1-AI-Pip (4)
1554 H F SO₂CH₂COOEt 2-COOPn H 1-AI-Pip (4)
1555 H F SO₂CH₂COOEt 3-COOPn H 1-AI-Pip (4)
1556 H F SO₂CH₂COOEt 2-COOHx H 1-AI-Pip (4)
1557 H F SO₂CH₂COOEt 3-COOHx H 1-AI-Pip (4)
1558 H F SO₂CH₂COOEt 2-CONH₂    H 1-AI-Pip (4)
1559 H F SO₂CH₂COOEt 3-CONH₂    H 1-AI-Pip (4)
1560 H F SO₂CH₂COOEt 2-CONHMe H 1-AI-Pip (4)
1561 H F SO₂CH₂COOEt 3-CONHMe H 1-AI-Pip (4)
1562 H F SO₂CH₂COOEt 2-CONHEt H 1-AI-Pip (4)
1563 H F SO₂CH₂COOEt 3-CONHEt H 1-AI-Pip (4)
1564 H F SO₂CH₂COOEt 2-CON (Me)₂  H 1-AI-Pip (4)
1565 H F SO₂CH₂COOEt 3-CON (Me)₂  H 1-AI-Pip (4)
1566 H F SO₂CH₂COOEt 2-CON (Me) Et H 1-AI-Pip (4)
1567 H F SO₂CH₂COOEt 3-CON (Me) Et H 1-AI-Pip (4)
1568 H F SO₂CH₂COOEt 2-CON (Et)₂  H 1-AI-Pip (4)
1569 H F SO₂CH₂COOEt 3-CON (Et)₂  H 1-AI-Pip (4)
1570 H F SO₂CH₂COOEt 3-F 5-F 1-AI-Pip (4)
1571 H F SO₂CH₂COOEt 3-Cl 5-Cl 1-AI-Pip (4)
1572 H F SO₂CH₂COOEt 3-Me 5-Me 1-AI-Pip (4)
1573 H F SO₂CH₂COOEt 3-Cl 5-CONH₂    1-AI-Pip (4)
1574 H F SO₂CH₂COOEt 2-Me 5-CONH₂    1-AI-Pip (4)
1575 H F SO₂CH₂COOEt 3-Me 5-CONH₂    1-AI-Pip (4)
1576 H F SO₂CH₂COOEt 3-CONH₂    5-CONH₂    1-AI-Pip (4)
1577 H Me SO₂CH₂COOEt H H 1-AI-Pip (4)
1578 H Me SO₂CH₂COOEt 2-F H 1-AI-Pip (4)
1579 H Me SO₂CH₂COOEt 3-F H 1-AI-Pip (4)
1580 H Me SO₂CH₂COOEt 2-Cl H 1-AI-Pip (4)
1581 H Me SO₂CH₂COOEt 3-Cl H 1-AI-Pip (4)
1582 H Me SO₂CH₂COOEt 2-Br H 1-AI-Pip (4)
1583 H Me SO₂CH₂COOEt 3-Br H 1-AI-Pip (4)
1584 H Me SO₂CH₂COOEt 2-I H 1-AI-Pip (4)
1585 H Me SO₂CH₂COOEt 3-I H 1-AI-Pip (4)
1586 H Me SO₂CH₂COOEt 2-Me H 1-AI-Pip (4)
1587 H Me SO₂CH₂COOEt 3-Me H 1-AI-Pip (4)
1588 H Me SO₂CH₂COOEt 2-Et H 1-AI-Pip (4)
1589 H Me SO₂CH₂COOEt 3-Et H 1-AI-Pip (4)
1590 H Me SO₂CH₂COOEt 2-Pr H 1-AI-Pip (4)
1591 H Me SO₂CH₂COOEt 3-Pr H 1-AI-Pip (4)
1592 H Me SO₂CH₂COOEt 2-Bu H 1-AI-Pip (4)
1593 H Me SO₂CH₂COOEt 3-Bu H 1-AI-Pip (4)
1594 H Me SO₂CH₂COOEt 2-Pn H 1-AI-Pip (4)
1595 H Me SO₂CH₂COOEt 3-Pn H 1-AI-Pip (4)
1596 H Me SO₂CH₂COOEt 2-Hx H 1-AI-Pip (4)
1597 H Me SO₂CH₂COOEt 3-Hx H 1-AI-Pip (4)
1598 H Me SO₂CH₂COOEt 2-CF_Three      H 1-AI-Pip (4)
1599 H Me SO₂CH₂COOEt 3-CF_Three      H 1-AI-Pip (4)
1600 H Me SO₂CH₂COOEt 2-OMe H 1-AI-Pip (4)
1601 H Me SO₂CH₂COOEt 3-OMe H 1-AI-Pip (4)
1602 H Me SO₂CH₂COOEt 2-OEt H 1-AI-Pip (4)
1603 H Me SO₂CH₂COOEt 3-OEt H 1-AI-Pip (4)
1604 H Me SO₂CH₂COOEt 2-COOH H 1-AI-Pip (4)
1605 H Me SO₂CH₂COOEt 3-COOH H 1-AI-Pip (4)
1606 H Me SO₂CH₂COOEt 2-COOMe H 1-AI-Pip (4)
1607 H Me SO₂CH₂COOEt 3-COOMe H 1-AI-Pip (4)
1608 H Me SO₂CH₂COOEt 2-COOEt H 1-AI-Pip (4)
1609 H Me SO₂CH₂COOEt 3-COOEt H 1-AI-Pip (4)
1610 H Me SO₂CH₂COOEt 2-COOPr H 1-AI-Pip (4)
1611 H Me SO₂CH₂COOEt 3-COOPr H 1-AI-Pip (4)
1612 H Me SO₂CH₂COOEt 2-COOBu H 1-AI-Pip (4)
1613 H Me SO₂CH₂COOEt 3-COOBu H 1-AI-Pip (4)
1614 H Me SO₂CH₂COOEt 2-COOPn H 1-AI-Pip (4)
1615 H Me SO₂CH₂COOEt 3-COOPn H 1-AI-Pip (4)
1616 H Me SO₂CH₂COOEt 2-COOHx H 1-AI-Pip (4)
1617 H Me SO₂CH₂COOEt 3-COOHx H 1-AI-Pip (4)
1618 H Me SO₂CH₂COOEt 2-CONH₂    H 1-AI-Pip (4)
1619 H Me SO₂CH₂COOEt 3-CONH₂    H 1-AI-Pip (4)
1620 H Me SO₂CH₂COOEt 2-CONHMe H 1-AI-Pip (4)
1621 H Me SO₂CH₂COOEt 3-CONHMe H 1-AI-Pip (4)
1622 H Me SO₂CH₂COOEt 2-CONHEt H 1-AI-Pip (4)
1623 H Me SO₂CH₂COOEt 3-CONHEt H 1-AI-Pip (4)
1624 H Me SO₂CH₂COOEt 2-CON (Me)₂  H 1-AI-Pip (4)
1625 H Me SO₂CH₂COOEt 3-CON (Me)₂  H 1-AI-Pip (4)
1626 H Me SO₂CH₂COOEt 2-CON (Me) Et H 1-AI-Pip (4)
1627 H Me SO₂CH₂COOEt 3-CON (Me) Et H 1-AI-Pip (4)
1628 H Me SO₂CH₂COOEt 2-CON (Et)₂  H 1-AI-Pip (4)
1629 H Me SO₂CH₂COOEt 3-CON (Et)₂  H 1-AI-Pip (4)
1630 H Me SO₂CH₂COOEt 3-F 5-F 1-AI-Pip (4)
1631 H Me SO₂CH₂COOEt 3-Cl 5-Cl 1-AI-Pip (4)
1632 H Me SO₂CH₂COOEt 3-Me 5-Me 1-AI-Pip (4)
1633 H Me SO₂CH₂COOEt 3-Cl 5-CONH₂    1-AI-Pip (4)
1634 H Me SO₂CH₂COOEt 2-Me 5-CONH₂    1-AI-Pip (4)
1635 H Me SO₂CH₂COOEt 3-Me 5-CONH₂    1-AI-Pip (4)
1636 H Me SO₂CH₂COOEt 3-CONH₂    5-CONH₂    1-AI-Pip (4)
1637 2-F H SO₂CH₂COOEt H H 1-AI-Pip (4)
1638 4-F H SO₂CH₂COOEt H H 1-AI-Pip (4)
1639 4-F H SO₂CH₂COOEt 2-F H 1-AI-Pip (4)
1640 4-F H SO₂CH₂COOEt 3-F H 1-AI-Pip (4)
1641 4-F H SO₂CH₂COOEt 2-Cl H 1-AI-Pip (4)
1642 4-F H SO₂CH₂COOEt 3-Cl H 1-AI-Pip (4)
1643 4-F H SO₂CH₂COOEt 2-Br H 1-AI-Pip (4)
1644 4-F H SO₂CH₂COOEt 3-Br H 1-AI-Pip (4)
1645 4-F H SO₂CH₂COOEt 2-I H 1-AI-Pip (4)
1646 4-F H SO₂CH₂COOEt 3-I H 1-AI-Pip (4)
1647 4-F H SO₂CH₂COOEt 2-Me H 1-AI-Pip (4)
1648 4-F H SO₂CH₂COOEt 3-Me H 1-AI-Pip (4)
1649 4-F H SO₂CH₂COOEt 2-Et H 1-AI-Pip (4)
1650 4-F H SO₂CH₂COOEt 3-Et H 1-AI-Pip (4)
1651 4-F H SO₂CH₂COOEt 2-Pr H 1-AI-Pip (4)
1652 4-F H SO₂CH₂COOEt 3-Pr H 1-AI-Pip (4)
1653 4-F H SO₂CH₂COOEt 2-Bu H 1-AI-Pip (4)
1654 4-F H SO₂CH₂COOEt 3-Bu H 1-AI-Pip (4)
1655 4-F H SO₂CH₂COOEt 2-Pn H 1-AI-Pip (4)
1656 4-F H SO₂CH₂COOEt 3-Pn H 1-AI-Pip (4)
1657 4-F H SO₂CH₂COOEt 2-Hx H 1-AI-Pip (4)
1658 4-F H SO₂CH₂COOEt 3-Hx H 1-AI-Pip (4)
1659 4-F H SO₂CH₂COOEt 2-CF_Three      H 1-AI-Pip (4)
1660 4-F H SO₂CH₂COOEt 3-CF_Three      H 1-AI-Pip (4)
1661 4-F H SO₂CH₂COOEt 2-OMe H 1-AI-Pip (4)
1662 4-F H SO₂CH₂COOEt 3-OMe H 1-AI-Pip (4)
1663 4-F H SO₂CH₂COOEt 2-OEt H 1-AI-Pip (4)
1664 4-F H SO₂CH₂COOEt 3-OEt H 1-AI-Pip (4)
1665 4-F H SO₂CH₂COOEt 2-COOH H 1-AI-Pip (4)
1666 4-F H SO₂CH₂COOEt 3-COOH H 1-AI-Pip (4)
1667 4-F H SO₂CH₂COOEt 2-COOMe H 1-AI-Pip (4)
1668 4-F H SO₂CH₂COOEt 3-COOMe H 1-AI-Pip (4)
1669 4-F H SO₂CH₂COOEt 2-COOEt H 1-AI-Pip (4)
1670 4-F H SO₂CH₂COOEt 3-COOEt H 1-AI-Pip (4)
1671 4-F H SO₂CH₂COOEt 2-COOPr H 1-AI-Pip (4)
1672 4-F H SO₂CH₂COOEt 3-COOPr H 1-AI-Pip (4)
1673 4-F H SO₂CH₂COOEt 2-COOBu H 1-AI-Pip (4)
1674 4-F H SO₂CH₂COOEt 3-COOBu H 1-AI-Pip (4)
1675 4-F H SO₂CH₂COOEt 2-COOPn H 1-AI-Pip (4)
1676 4-F H SO₂CH₂COOEt 3-COOPn H 1-AI-Pip (4)
1677 4-F H SO₂CH₂COOEt 2-COOHx H 1-AI-Pip (4)
1678 4-F H SO₂CH₂COOEt 3-COOHx H 1-AI-Pip (4)
1679 4-F H SO₂CH₂COOEt 2-CONH₂    H 1-AI-Pip (4)
1680 4-F H SO₂CH₂COOEt 3-CONH₂    H 1-AI-Pip (4)
1681 4-F H SO₂CH₂COOEt 2-CONHMe H 1-AI-Pip (4)
1682 4-F H SO₂CH₂COOEt 3-CONHMe H 1-AI-Pip (4)
1683 4-F H SO₂CH₂COOEt 2-CONHEt H 1-AI-Pip (4)
1684 4-F H SO₂CH₂COOEt 3-CONHEt H 1-AI-Pip (4)
1685 4-F H SO₂CH₂COOEt 2-CON (Me)₂  H 1-AI-Pip (4)
1686 4-F H SO₂CH₂COOEt 3-CON (Me)₂  H 1-AI-Pip (4)
1687 4-F H SO₂CH₂COOEt 2-CON (Me) EtH 1-AI-Pip (4)
1688 4-F H SO₂CH₂COOEt 3-CON (Me) EtH 1-AI-Pip (4)
1689 4-F H SO₂CH₂COOEt 2-CON (Et)₂  H 1-AI-Pip (4)
1690 4-F H SO₂CH₂COOEt 3-CON (Et)₂  H 1-AI-Pip (4)
1691 4-F Me SO₂CH₂COOEt 3-F 5-F 1-AI-Pip (4)
1692 4-F Me SO₂CH₂COOEt 3-Cl 5-Cl 1-AI-Pip (4)
1693 4-F Me SO₂CH₂COOEt 3-Me 5-Me 1-AI-Pip (4)
1694 4-F Me SO₂CH₂COOEt 3-Cl 5-CONH₂    1-AI-Pip (4)
1695 4-F Me SO₂CH₂COOEt 2-Me 5-CONH₂    1-AI-Pip (4)
1696 4-F Me SO₂CH₂COOEt 3-Me 5-CONH₂    1-AI-Pip (4)
1697 4-F Me SO₂CH₂COOEt 3-CONH₂    5-CONH₂    1-AI-Pip (4)
1698 5-F H SO₂CH₂COOEt H H 1-AI-Pip (4)
1699 6-F H SO₂CH₂COOEt H H 1-AI-Pip (4)
1700 2-Cl H SO₂CH₂COOEt H H 1-AI-Pip (4)
1701 4-Cl H SO₂CH₂COOEt H H 1-AI-Pip (4)
1702 5-Cl H SO₂CH₂COOEt H H 1-AI-Pip (4)
1703 6-Cl H SO₂CH₂COOEt H H 1-AI-Pip (4)
1704 2-Br H SO₂CH₂COOEt H H 1-AI-Pip (4)
1705 4-Br H SO₂CH₂COOEt H H 1-AI-Pip (4)
1706 5-Br H SO₂CH₂COOEt H H 1-AI-Pip (4)
1707 6-Br H SO₂CH₂COOEt H H 1-AI-Pip (4)
1708 2-Me H SO₂CH₂COOEt H H 1-AI-Pip (4)
1709 3-Me H SO₂CH₂COOEt H H 1-AI-Pip (4)
1710 4-Me H SO₂CH₂COOEt H H 1-AI-Pip (4)
1711 5-Me H SO₂CH₂COOEt H H 1-AI-Pip (4)
1712 5-Me H SO₂CH₂COOEt 2-F H 1-AI-Pip (4)
1713 5-Me H SO₂CH₂COOEt 3-F H 1-AI-Pip (4)
1714 5-Me H SO₂CH₂COOEt 2-Cl H 1-AI-Pip (4)
1715 5-Me H SO₂CH₂COOEt 3-Cl H 1-AI-Pip (4)
1716 5-Me H SO₂CH₂COOEt 2-Br H 1-AI-Pip (4)
1717 5-Me H SO₂CH₂COOEt 3-Br H 1-AI-Pip (4)
1718 5-Me H SO₂CH₂COOEt 2-I H 1-AI-Pip (4)
1719 5-Me H SO₂CH₂COOEt 3-I H 1-AI-Pip (4)
1720 5-Me H SO₂CH₂COOEt 2-Me H 1-AI-Pip (4)
1721 5-Me H SO₂CH₂COOEt 3-Me H 1-AI-Pip (4)
1722 5-Me H SO₂CH₂COOEt 2-Et H 1-AI-Pip (4)
1723 5-Me H SO₂CH₂COOEt 3-Et H 1-AI-Pip (4)
1724 5-Me H SO₂CH₂COOEt 2-Pr H 1-AI-Pip (4)
1725 5-Me H SO₂CH₂COOEt 3-Pr H 1-AI-Pip (4)
1726 5-Me H SO₂CH₂COOEt 2-Bu H 1-AI-Pip (4)
1727 5-Me H SO₂CH₂COOEt 3-Bu H 1-AI-Pip (4)
1728 5-Me H SO₂CH₂COOEt 2-Pn H 1-AI-Pip (4)
1729 5-Me H SO₂CH₂COOEt 3-Pn H 1-AI-Pip (4)
1730 5-Me H SO₂CH₂COOEt 2-Hx H 1-AI-Pip (4)
1731 5-Me H SO₂CH₂COOEt 3-Hx H 1-AI-Pip (4)
1732 5-Me H SO₂CH₂COOEt 2-CF_Three      H 1-AI-Pip (4)
1733 5-Me H SO₂CH₂COOEt 3-CF_Three      H 1-AI-Pip (4)
1734 5-Me H SO₂CH₂COOEt 2-OMe H 1-AI-Pip (4)
1735 5-Me H SO₂CH₂COOEt 3-OMe H 1-AI-Pip (4)
1736 5-Me H SO₂CH₂COOEt 2-OEt H 1-AI-Pip (4)
1737 5-Me H SO₂CH₂COOEt 3-OEt H 1-AI-Pip (4)
1738 5-Me H SO₂CH₂COOEt 2-COOH H 1-AI-Pip (4)
1739 5-Me H SO₂CH₂COOEt 3-COOH H 1-AI-Pip (4)
1740 5-Me H SO₂CH₂COOEt 2-COOMe H 1-AI-Pip (4)
1741 5-Me H SO₂CH₂COOEt 3-COOMe H 1-AI-Pip (4)
1742 5-Me H SO₂CH₂COOEt 2-COOEt H 1-AI-Pip (4)
1743 5-Me H SO₂CH₂COOEt 3-COOEt H 1-AI-Pip (4)
1744 5-Me H SO₂CH₂COOEt 2-COOPr H 1-AI-Pip (4)
1745 5-Me H SO₂CH₂COOEt 3-COOPr H 1-AI-Pip (4)
1746 5-Me H SO₂CH₂COOEt 2-COOBu H 1-AI-Pip (4)
1747 5-Me H SO₂CH₂COOEt 3-COOBu H 1-AI-Pip (4)
1748 5-Me H SO₂CH₂COOEt 2-COOPn H 1-AI-Pip (4)
1749 5-Me H SO₂CH₂COOEt 3-COOPn H 1-AI-Pip (4)
1750 5-Me H SO₂CH₂COOEt 2-COOHx H 1-AI-Pip (4)
1751 5-Me H SO₂CH₂COOEt 3-COOHx H 1-AI-Pip (4)
1752 5-Me H SO₂CH₂COOEt 2-CONH₂    H 1-AI-Pip (4)
1753 5-Me H SO₂CH₂COOEt 3-CONH₂    H 1-AI-Pip (4)
1754 5-Me H SO₂CH₂COOEt 2-CONHMe H 1-AI-Pip (4)
1755 5-Me H SO₂CH₂COOEt 3-CONHMe H 1-AI-Pip (4)
1756 5-Me H SO₂CH₂COOEt 2-CONHEt H 1-AI-Pip (4)
1757 5-Me H SO₂CH₂COOEt 3-CONHEt H 1-AI-Pip (4)
1758 5-Me H SO₂CH₂COOEt 2-CON (Me)₂  H 1-AI-Pip (4)
1759 5-Me H SO₂CH₂COOEt 3-CON (Me)₂  H 1-AI-Pip (4)
1760 5-Me H SO₂CH₂COOEt 2-CON (Me) Et H 1-AI-Pip (4)
1761 5-Me H SO₂CH₂COOEt 3-CON (Me) Et H 1-AI-Pip (4)
1762 5-Me H SO₂CH₂COOEt 2-CON (Et)₂  H 1-AI-Pip (4)
1763 5-Me H SO₂CH₂COOEt 3-CON (Et)₂  H 1-AI-Pip (4)
1764 5-Me Me SO₂CH₂COOEt 3-F 5-F 1-AI-Pip (4)
1765 5-Me Me SO₂CH₂COOEt 3-Cl 5-Cl 1-AI-Pip (4)
1766 5-Me Me SO₂CH₂COOEt 3-Me 5-Me 1-AI-Pip (4)
1767 5-Me Me SO₂CH₂COOEt 3-Cl 5-CONH₂    1-AI-Pip (4)
1768 5-Me Me SO₂CH₂COOEt 2-Me 5-CONH₂    1-AI-Pip (4)
1769 5-Me Me SO₂CH₂COOEt 3-Me 5-CONH₂    1-AI-Pip (4)
1770 5-Me Me SO₂CH₂COOEt 3-CONH₂    5-CONH₂    1-AI-Pip (4)
1771 6-Me H SO₂CH₂COOEt H H 1-AI-Pip (4)
1772 6-Me H SO₂CH₂COOEt 2-F H 1-AI-Pip (4)
1773 6-Me H SO₂CH₂COOEt 3-F H 1-AI-Pip (4)
1774 6-Me H SO₂CH₂COOEt 2-Cl H 1-AI-Pip (4)
1775 6-Me H SO₂CH₂COOEt 3-Cl H 1-AI-Pip (4)
1776 6-Me H SO₂CH₂COOEt 2-Br H 1-AI-Pip (4)
1777 6-Me H SO₂CH₂COOEt 3-Br H 1-AI-Pip (4)
1778 6-Me H SO₂CH₂COOEt 2-I H 1-AI-Pip (4)
1779 6-Me H SO₂CH₂COOEt 3-I H 1-AI-Pip (4)
1780 6-Me H SO₂CH₂COOEt 2-Me H 1-AI-Pip (4)
1781 6-Me H SO₂CH₂COOEt 3-Me H 1-AI-Pip (4)
1782 6-Me H SO₂CH₂COOEt 2-Et H 1-AI-Pip (4)
1783 6-Me H SO₂CH₂COOEt 3-Et H 1-AI-Pip (4)
1784 6-Me H SO₂CH₂COOEt 2-Pr H 1-AI-Pip (4)
1785 6-Me H SO₂CH₂COOEt 3-Pr H 1-AI-Pip (4)
1786 6-Me H SO₂CH₂COOEt 2-Bu H 1-AI-Pip (4)
1787 6-Me H SO₂CH₂COOEt 3-Bu H 1-AI-Pip (4)
1788 6-Me H SO₂CH₂COOEt 2-Pn H 1-AI-Pip (4)
1789 6-Me H SO₂CH₂COOEt 3-Pn H 1-AI-Pip (4)
1790 6-Me H SO₂CH₂COOEt 2-Hx H 1-AI-Pip (4)
1791 6-Me H SO₂CH₂COOEt 3-Hx H 1-AI-Pip (4)
1792 6-Me H SO₂CH₂COOEt 2-CF_Three      H 1-AI-Pip (4)
1793 6-Me H SO₂CH₂COOEt 3-CF_Three      H 1-AI-Pip (4)
1794 6-Me H SO₂CH₂COOEt 2-OMe H 1-AI-Pip (4)
1795 6-Me H SO₂CH₂COOEt 3-OMe H 1-AI-Pip (4)
1796 6-Me H SO₂CH₂COOEt 2-OEt H 1-AI-Pip (4)
1797 6-Me H SO₂CH₂COOEt 3-OEt H 1-AI-Pip (4)
1798 6-Me H SO₂CH₂COOEt 2-COOH H 1-AI-Pip (4)
1799 6-Me H SO₂CH₂COOEt 3-COOH H 1-AI-Pip (4)
1800 6-Me H SO₂CH₂COOEt 2-COOMe H 1-AI-Pip (4)
1801 6-Me H SO₂CH₂COOEt 3-COOMe H 1-AI-Pip (4)
1802 6-Me H SO₂CH₂COOEt 2-COOEt H 1-AI-Pip (4)
1803 6-Me H SO₂CH₂COOEt 3-COOEt H 1-AI-Pip (4)
1804 6-Me H SO₂CH₂COOEt 2-COOPr H 1-AI-Pip (4)
1805 6-Me H SO₂CH₂COOEt 3-COOPr H 1-AI-Pip (4)
1806 6-Me H SO₂CH₂COOEt 2-COOBu H 1-AI-Pip (4)
1807 6-Me H SO₂CH₂COOEt 3-COOBu H 1-AI-Pip (4)
1808 6-Me H SO₂CH₂COOEt 2-COOPn H 1-AI-Pip (4)
1809 6-Me H SO₂CH₂COOEt 3-COOPn H 1-AI-Pip (4)
1810 6-Me H SO₂CH₂COOEt 2-COOHx H 1-AI-Pip (4)
1811 6-Me H SO₂CH₂COOEt 3-COOHx H 1-AI-Pip (4)
1812 6-Me H SO₂CH₂COOEt 2-CONH₂    H 1-AI-Pip (4)
1813 6-Me H SO₂CH₂COOEt 3-CONH₂    H 1-AI-Pip (4)
1814 6-Me H SO₂CH₂COOEt 2-CONHMe H 1-AI-Pip (4)
1815 6-Me H SO₂CH₂COOEt 3-CONHMe H 1-AI-Pip (4)
1816 6-Me H SO₂CH₂COOEt 2-CONHEt H 1-AI-Pip (4)
1817 6-Me H SO₂CH₂COOEt 3-CONHEt H 1-AI-Pip (4)
1818 6-Me H SO₂CH₂COOEt 2-CON (Me)₂  H 1-AI-Pip (4)
1819 6-Me H SO₂CH₂COOEt 3-CON (Me)₂  H 1-AI-Pip (4)
1820 6-Me H SO₂CH₂COOEt 2-CON (Me) Et H 1-AI-Pip (4)
1821 6-Me H SO₂CH₂COOEt 3-CON (Me) Et H 1-AI-Pip (4)
1822 6-Me H SO₂CH₂COOEt 2-CON (Et)₂  H 1-AI-Pip (4)
1823 6-Me H SO₂CH₂COOEt 3-CON (Et)₂  H 1-AI-Pip (4)
1824 6-Me Me SO₂CH₂COOEt 3-F 5-F 1-AI-Pip (4)
1825 6-Me Me SO₂CH₂COOEt 3-Cl 5-Cl 1-AI-Pip (4)
1826 6-Me Me SO₂CH₂COOEt 3-Me 5-Me 1-AI-Pip (4)
1827 6-Me Me SO₂CH₂COOEt 3-Cl 5-CONH₂    1-AI-Pip (4)
1828 6-Me Me SO₂CH₂COOEt 2-Me 5-CONH₂    1-AI-Pip (4)
1829 6-Me Me SO₂CH₂COOEt 3-Me 5-CONH₂    1-AI-Pip (4)
1830 6-Me Me SO₂CH₂COOEt 3-CONH₂    5-CONH₂    1-AI-Pip (4)
1831 2-Et H SO₂CH₂COOEt H H 1-AI-Pip (4)
1832 4-Et H SO₂CH₂COOEt H H 1-AI-Pip (4)
1833 5-Et H SO₂CH₂COOEt H H 1-AI-Pip (4)
1834 6-Et H SO₂CH₂COOEt H H 1-AI-Pip (4)
1835 2-Pr H SO₂CH₂COOEt H H 1-AI-Pip (4)
1836 4-Bu H SO₂CH₂COOEt H H 1-AI-Pip (4)
1837 5-Pn H SO₂CH₂COOEt H H 1-AI-Pip (4)
1838 6-Hx H SO₂CH₂COOEt H H 1-AI-Pip (4)
1839 6-OH H SO₂CH₂COOEt H H 1-AI-Pip (4)
1840 6-OH H SO₂CH₂COOEt 2-F H 1-AI-Pip (4)
1841 6-OH H SO₂CH₂COOEt 3-F H 1-AI-Pip (4)
1842 6-OH H SO₂CH₂COOEt 2-Cl H 1-AI-Pip (4)
1843 6-OH H SO₂CH₂COOEt 3-Cl H 1-AI-Pip (4)
1844 6-OH H SO₂CH₂COOEt 2-Br H 1-AI-Pip (4)
1845 6-OH H SO₂CH₂COOEt 3-Br H 1-AI-Pip (4)
1846 6-OH H SO₂CH₂COOEt 2-I H 1-AI-Pip (4)
1847 6-OH H SO₂CH₂COOEt 3-I H 1-AI-Pip (4)
1848 6-OH H SO₂CH₂COOEt 2-Me H 1-AI-Pip (4)
1849 6-OH H SO₂CH₂COOEt 3-Me H 1-AI-Pip (4)
1850 6-OH H SO₂CH₂COOEt 2-Et H 1-AI-Pip (4)
1851 6-OH H SO₂CH₂COOEt 3-Et H 1-AI-Pip (4)
1852 6-OH H SO₂CH₂COOEt 2-Pr H 1-AI-Pip (4)
1853 6-OH H SO₂CH₂COOEt 3-Pr H 1-AI-Pip (4)
1854 6-OH H SO₂CH₂COOEt 2-Bu H 1-AI-Pip (4)
1855 6-OH H SO₂CH₂COOEt 3-Bu H 1-AI-Pip (4)
1856 6-OH H SO₂CH₂COOEt 2-Pn H 1-AI-Pip (4)
1857 6-OH H SO₂CH₂COOEt 3-Pn H 1-AI-Pip (4)
1858 6-OH H SO₂CH₂COOEt 2-Hx H 1-AI-Pip (4)
1859 6-OH H SO₂CH₂COOEt 3-Hx H 1-AI-Pip (4)
1860 6-OH H SO₂CH₂COOEt 2-CF_Three      H 1-AI-Pip (4)
1861 6-OH H SO₂CH₂COOEt 3-CF_Three      H 1-AI-Pip (4)
1862 6-OH H SO₂CH₂COOEt 2-OMe H 1-AI-Pip (4)
1863 6-OH H SO₂CH₂COOEt 3-OMe H 1-AI-Pip (4)
1864 6-OH H SO₂CH₂COOEt 2-OEt H 1-AI-Pip (4)
1865 6-OH H SO₂CH₂COOEt 3-OEt H 1-AI-Pip (4)
1866 6-OH H SO₂CH₂COOEt 2-COOH H 1-AI-Pip (4)
1867 6-OH H SO₂CH₂COOEt 3-COOH H 1-AI-Pip (4)
1868 6-OH H SO₂CH₂COOEt 2-COOMe H 1-AI-Pip (4)
1869 6-OH H SO₂CH₂COOEt 3-COOMe H 1-AI-Pip (4)
1870 6-OH H SO₂CH₂COOEt 2-COOEt H 1-AI-Pip (4)
1871 6-OH H SO₂CH₂COOEt 3-COOEt H 1-AI-Pip (4)
1872 6-OH H SO₂CH₂COOEt 2-COOPr H 1-AI-Pip (4)
1873 6-OH H SO₂CH₂COOEt 3-COOPr H 1-AI-Pip (4)
1874 6-OH H SO₂CH₂COOEt 2-COOBu H 1-AI-Pip (4)
1875 6-OH H SO₂CH₂COOEt 3-COOBu H 1-AI-Pip (4)
1876 6-OH H SO₂CH₂COOEt 2-COOPn H 1-AI-Pip (4)
1877 6-OH H SO₂CH₂COOEt 3-COOPn H 1-AI-Pip (4)
1878 6-OH H SO₂CH₂COOEt 2-COOHx H 1-AI-Pip (4)
1879 6-OH H SO₂CH₂COOEt 3-COOHx H 1-AI-Pip (4)
1880 6-OH H SO₂CH₂COOEt 2-CONH₂    H 1-AI-Pip (4)
1881 6-OH H SO₂CH₂COOEt 3-CONH₂    H 1-AI-Pip (4)
1882 6-OH H SO₂CH₂COOEt 2-CONHMe H 1-AI-Pip (4)
1883 6-OH H SO₂CH₂COOEt 3-CONHMe H 1-AI-Pip (4)
1884 6-OH H SO₂CH₂COOEt 2-CONHEt H 1-AI-Pip (4)
1885 6-OH H SO₂CH₂COOEt 3-CONHEt H 1-AI-Pip (4)
1886 6-OH H SO₂CH₂COOEt 2-CON (Me)₂  H 1-AI-Pip (4)
1887 6-OH H SO₂CH₂COOEt 3-CON (Me)₂  H 1-AI-Pip (4)
1888 6-OH H SO₂CH₂COOEt 2-CON (Me) EtH 1-AI-Pip (4)
1889 6-OH H SO₂CH₂COOEt 3-CON (Me) EtH 1-AI-Pip (4)
1890 6-OH H SO₂CH₂COOEt 2-CON (Et)₂  H 1-AI-Pip (4)
1891 6-OH H SO₂CH₂COOEt 3-CON (Et)₂  H 1-AI-Pip (4)
1892 6-OH H SO₂CH₂COOEt 2-F 3-F 1-AI-Pip (4)
1893 6-OH H SO₂CH₂COOEt 2-F 5-F 1-AI-Pip (4)
1894 6-OH H SO₂CH₂COOEt 2-F 6-F 1-AI-Pip (4)
1895 6-OH H SO₂CH₂COOEt 3-F 5-F 1-AI-Pip (4)
1896 6-OH H SO₂CH₂COOEt 2-Cl 3-Cl 1-AI-Pip (4)
1897 6-OH H SO₂CH₂COOEt 2-Cl 5-Cl 1-AI-Pip (4)
1898 6-OH H SO₂CH₂COOEt 2-Cl 6-Cl 1-AI-Pip (4)
1899 6-OH H SO₂CH₂COOEt 3-Cl 5-Cl 1-AI-Pip (4)
1900 6-OH H SO₂CH₂COOEt 2-Me 3-Me 1-AI-Pip (4)
1901 6-OH H SO₂CH₂COOEt 2-Me 5-Me 1-AI-Pip (4)
1902 6-OH H SO₂CH₂COOEt 2-Me 6-Me 1-AI-Pip (4)
1903 6-OH H SO₂CH₂COOEt 3-Me 5-Me 1-AI-Pip (4)
1904 6-OH H SO₂CH₂COOEt 2-Cl 5-CONH₂    1-AI-Pip (4)
1905 6-OH H SO₂CH₂COOEt 3-Cl 5-CONH₂    1-AI-Pip (4)
1906 6-OH H SO₂CH₂COOEt 3-Cl 5-CONHMe 1-AI-Pip (4)
1907 6-OH H SO₂CH₂COOEt 3-Cl 5-CONHEt 1-AI-Pip (4)
1908 6-OH H SO₂CH₂COOEt 3-Cl 5-CONHPr 1-AI-Pip (4)
1909 6-OH H SO₂CH₂COOEt 3-Cl 5-CONHBu 1-AI-Pip (4)
1910 6-OH H SO₂CH₂COOEt 3-Cl 5-CONHPn 1-AI-Pip (4)
1911 6-OH H SO₂CH₂COOEt 3-Cl 5-CONHHx 1-AI-Pip (4)
1912 6-OH H SO₂CH₂COOEt 2-Me 5-CONH₂    1-AI-Pip (4)
1913 6-OH H SO₂CH₂COOEt 2-Me 5-CONHMe 1-AI-Pip (4)
1914 6-OH H SO₂CH₂COOEt 2-Me 5-CONHEt 1-AI-Pip (4)
1915 6-OH H SO₂CH₂COOEt 2-Me 5-CONHPr 1-AI-Pip (4)
1916 6-OH H SO₂CH₂COOEt 2-Me 5-CONHBu 1-AI-Pip (4)
1917 6-OH H SO₂CH₂COOEt 2-Me 5-CONHPn 1-AI-Pip (4)
1918 6-OH H SO₂CH₂COOEt 2-Me 5-CONHHx 1-AI-Pip (4)
1919 6-OH H SO₂CH₂COOEt 3-Me 5-CONH₂    1-AI-Pip (4)
1920 6-OH H SO₂CH₂COOEt 3-Me 5-CONHMe 1-AI-Pip (4)
1921 6-OH H SO₂CH₂COOEt 3-Me 5-CONHEt 1-AI-Pip (4)
1922 6-OH H SO₂CH₂COOEt 3-Me 5-CONHPr 1-AI-Pip (4)
1923 6-OH H SO₂CH₂COOEt 3-Me 5-CONHBu 1-AI-Pip (4)
1924 6-OH H SO₂CH₂COOEt 3-Me 5-CONHPn 1-AI-Pip (4)
1925 6-OH H SO₂CH₂COOEt 3-Me 5-CONHHx 1-AI-Pip (4)
1926 6-OH H SO₂CH₂COOEt 2-CONH₂    6-CONH₂    1-AI-Pip (4)
1927 6-OH H SO₂CH₂COOEt 3-CONH₂    5-CONH₂    1-AI-Pip (4)
1928 6-OH H SO₂CH₂COOEt 3-CONHMe 5-CONHMe 1-AI-Pip (4)
1929 6-OH H SO₂CH₂COOEt 3-CONHEt 5-CONHEt 1-AI-Pip (4)
1930 H H SO₂CH₂COOPr H H 1-AI-Pip (4)
1931 H H SO₂CH₂COOBu H H 1-AI-Pip (4)
1932 H H SO₂CH₂COOPn H H 1-AI-Pip (4)
1933 H H SO₂CH₂COOHx H H 1-AI-Pip (4)
1934 H H SO₂(CH₂)₂COOEt H H 1-AI-Pip (4)
1935 H H SO₂(CH₂)_ThreeCOOEt H H 1-AI-Pip (4)
1936 H H SO₂(CH₂)_FourCOOEt H H 1-AI-Pip (4)
1937 H H SO₂(CH₂)_FiveCOOEt H H 1-AI-Pip (4)
1938 H H SO₂(CH₂)₆COOEt H H 1-AI-Pip (4)
1939 H H SO₂CH₂COOH H H 1-AI-Pip (4)
1940 H H SO₂CH₂COOH 2-F H 1-AI-Pip (4)
1941 H H SO₂CH₂COOH 3-F H 1-AI-Pip (4)
1942 H H SO₂CH₂COOH 2-Cl H 1-AI-Pip (4)
1943 H H SO₂CH₂COOH 3-Cl H 1-AI-Pip (4)
1944 H H SO₂CH₂COOH 2-Br H 1-AI-Pip (4)
1945 H H SO₂CH₂COOH 3-Br H 1-AI-Pip (4)
1946 H H SO₂CH₂COOH 2-I H 1-AI-Pip (4)
1947 H H SO₂CH₂COOH 3-I H 1-AI-Pip (4)
1948 H H SO₂CH₂COOH 2-Me H 1-AI-Pip (4)
1949 H H SO₂CH₂COOH 3-Me H 1-AI-Pip (4)
1950 H H SO₂CH₂COOH 2-Et H 1-AI-Pip (4)
1951 H H SO₂CH₂COOH 3-Et H 1-AI-Pip (4)
1952 H H SO₂CH₂COOH 2-Pr H 1-AI-Pip (4)
1953 H H SO₂CH₂COOH 3-Pr H 1-AI-Pip (4)
1954 H H SO₂CH₂COOH 2-iPr H 1-AI-Pip (4)
1955 H H SO₂CH₂COOH 3-iPr H 1-AI-Pip (4)
1956 H H SO₂CH₂COOH 2-Bu H 1-AI-Pip (4)
1957 H H SO₂CH₂COOH 3-Bu H 1-AI-Pip (4)
1958 H H SO₂CH₂COOH 2-iBu H 1-AI-Pip (4)
1959 H H SO₂CH₂COOH 3-iBu H 1-AI-Pip (4)
1960 H H SO₂CH₂COOH 2-sBu H 1-AI-Pip (4)
1961 H H SO₂CH₂COOH 3-sBu H 1-AI-Pip (4)
1962 H H SO₂CH₂COOH 2-tBu H 1-AI-Pip (4)
1963 H H SO₂CH₂COOH 3-tBu H 1-AI-Pip (4)
1964 H H SO₂CH₂COOH 2-Pn H 1-AI-Pip (4)
1965 H H SO₂CH₂COOH 3-Pn H 1-AI-Pip (4)
1966 H H SO₂CH₂COOH 2-Hx H 1-AI-Pip (4)
1967 H H SO₂CH₂COOH 3-Hx H 1-AI-Pip (4)
1968 H H SO₂CH₂COOH 2-CF_Three      H 1-AI-Pip (4)
1969 H H SO₂CH₂COOH 3-CF_Three      H 1-AI-Pip (4)
1970 H H SO₂CH₂COOH 2-OMe H 1-AI-Pip (4)
1971 H H SO₂CH₂COOH 3-OMe H 1-AI-Pip (4)
1972 H H SO₂CH₂COOH 2-OEt H 1-AI-Pip (4)
1973 H H SO₂CH₂COOH 3-OEt H 1-AI-Pip (4)
1974 H H SO₂CH₂COOH 2-COOH H 1-AI-Pip (4)
1975 H H SO₂CH₂COOH 3-COOH H 1-AI-Pip (4)
1976 H H SO₂CH₂COOH 2-COOMe H 1-AI-Pip (4)
1977 H H SO₂CH₂COOH 3-COOMe H 1-AI-Pip (4)
1978 H H SO₂CH₂COOH 2-COOEt H 1-AI-Pip (4)
1979 H H SO₂CH₂COOH 3-COOEt H 1-AI-Pip (4)
1980 H H SO₂CH₂COOH 2-COOPr H 1-AI-Pip (4)
1981 H H SO₂CH₂COOH 3-COOPr H 1-AI-Pip (4)
1982 H H SO₂CH₂COOH 2-COOBu H 1-AI-Pip (4)
1983 H H SO₂CH₂COOH 3-COOBu H 1-AI-Pip (4)
1984 H H SO₂CH₂COOH 2-COOPn H 1-AI-Pip (4)
1985 H H SO₂CH₂COOH 3-COOPn H 1-AI-Pip (4)
1986 H H SO₂CH₂COOH 2-COOHx H 1-AI-Pip (4)
1987 H H SO₂CH₂COOH 3-COOHx H 1-AI-Pip (4)
1988 H H SO₂CH₂COOH 2-CONH₂    H 1-AI-Pip (4)
1989 H H SO₂CH₂COOH 3-CONH₂    H 1-AI-Pip (4)
1990 H H SO₂CH₂COOH 2-CONHMe H 1-AI-Pip (4)
1991 H H SO₂CH₂COOH 3-CONHMe H 1-AI-Pip (4)
1992 H H SO₂CH₂COOH 2-CONHEt H 1-AI-Pip (4)
1993 H H SO₂CH₂COOH 3-CONHEt H 1-AI-Pip (4)
1994 H H SO₂CH₂COOH 2-CON (Me)₂  H 1-AI-Pip (4)
1995 H H SO₂CH₂COOH 3-CON (Me)₂  H 1-AI-Pip (4)
1996 H H SO₂CH₂COOH 2-CON (Me) Et H 1-AI-Pip (4)
1997 H H SO₂CH₂COOH 3-CON (Me) Et H 1-AI-Pip (4)
1998 H H SO₂CH₂COOH 2-CON (Et)₂  H 1-AI-Pip (4)
1999 H H SO₂CH₂COOH 3-CON (Et)₂  H 1-AI-Pip (4)
2000 H H SO₂CH₂COOH 2-F 3-F 1-AI-Pip (4)
2001 H H SO₂CH₂COOH 2-F 5-F 1-AI-Pip (4)
2002 H H SO₂CH₂COOH 2-F 6-F 1-AI-Pip (4)
2003 H H SO₂CH₂COOH 3-F 5-F 1-AI-Pip (4)
2004 H H SO₂CH₂COOH 2-Cl 3-Cl 1-AI-Pip (4)
2005 H H SO₂CH₂COOH 2-Cl 5-Cl 1-AI-Pip (4)
2006 H H SO₂CH₂COOH 2-Cl 6-Cl 1-AI-Pip (4)
2007 H H SO₂CH₂COOH 3-Cl 5-Cl 1-AI-Pip (4)
2008 H H SO₂CH₂COOH 2-Me 3-Me 1-AI-Pip (4)
2009 H H SO₂CH₂COOH 2-Me 5-Me 1-AI-Pip (4)
2010 H H SO₂CH₂COOH 2-Me 6-Me 1-AI-Pip (4)
2011 H H SO₂CH₂COOH 3-Me 5-Me 1-AI-Pip (4)
2012 H H SO₂CH₂COOH 2-Cl 5-CONH₂    1-AI-Pip (4)
2013 H H SO₂CH₂COOH 3-Cl 5-CONH₂    1-AI-Pip (4)
2014 H H SO₂CH₂COOH 3-Cl 5-CONHMe 1-AI-Pip (4)
2015 H H SO₂CH₂COOH 3-Cl 5-CONHEt 1-AI-Pip (4)
2016 H H SO₂CH₂COOH 3-Cl 5-CONHPr 1-AI-Pip (4)
2017 H H SO₂CH₂COOH 3-Cl 5-CONHBu 1-AI-Pip (4)
2018 H H SO₂CH₂COOH 3-Cl 5-CONHPn 1-AI-Pip (4)
2019 H H SO₂CH₂COOH 3-Cl 5-CONHHx 1-AI-Pip (4)
2020 H H SO₂CH₂COOH 2-Me 5-CONH₂    1-AI-Pip (4)
2021 H H SO₂CH₂COOH 2-Me 5-CONHMe 1-AI-Pip (4)
2022 H H SO₂CH₂COOH 2-Me 5-CONHEt 1-AI-Pip (4)
2023 H H SO₂CH₂COOH 2-Me 5-CONHPr 1-AI-Pip (4)
2024 H H SO₂CH₂COOH 2-Me 5-CONHBu 1-AI-Pip (4)
2025 H H SO₂CH₂COOH 2-Me 5-CONHPn 1-AI-Pip (4)
2026 H H SO₂CH₂COOH 2-Me 5-CONHHx 1-AI-Pip (4)
2027 H H SO₂CH₂COOH 3-Me 5-CONH₂    1-AI-Pip (4)
2028 H H SO₂CH₂COOH 3-Me 5-CONHMe 1-AI-Pip (4)
2029 H H SO₂CH₂COOH 3-Me 5-CONHEt 1-AI-Pip (4)
2030 H H SO₂CH₂COOH 3-Me 5-CONHPr 1-AI-Pip (4)
2031 H H SO₂CH₂COOH 3-Me 5-CONHBu 1-AI-Pip (4)
2032 H H SO₂CH₂COOH 3-Me 5-CONHPn 1-AI-Pip (4)
2033 H H SO₂CH₂COOH 3-Me 5-CONHHx 1-AI-Pip (4)
2034 H H SO₂CH₂COOH 2-CONH₂    6-CONH₂    1-AI-Pip (4)
2035 H H SO₂CH₂COOH 3-CONH₂    5-CONH₂    1-AI-Pip (4)
2036 H H SO₂CH₂COOH 3-CONHMe 5-CONHMe 1-AI-Pip (4)
2037 H H SO₂CH₂COOH 3-CONHEt 5-CONHEt 1-AI-Pip (4)
2038 H F SO₂CH₂COOH H H 1-AI-Pip (4)
2039 H F SO₂CH₂COOH 2-F H 1-AI-Pip (4)
2040 H F SO₂CH₂COOH 3-F H 1-AI-Pip (4)
2041 H F SO₂CH₂COOH 2-Cl H 1-AI-Pip (4)
2042 H F SO₂CH₂COOH 3-Cl H 1-AI-Pip (4)
2043 H F SO₂CH₂COOH 2-Br H 1-AI-Pip (4)
2044 H F SO₂CH₂COOH 3-Br H 1-AI-Pip (4)
2045 H F SO₂CH₂COOH 2-I H 1-AI-Pip (4)
2046 H F SO₂CH₂COOH 3-I H 1-AI-Pip (4)
2047 H F SO₂CH₂COOH 2-Me H 1-AI-Pip (4)
2048 H F SO₂CH₂COOH 3-Me H 1-AI-Pip (4)
2049 H F SO₂CH₂COOH 2-Et H 1-AI-Pip (4)
2050 H F SO₂CH₂COOH 3-Et H 1-AI-Pip (4)
2051 H F SO₂CH₂COOH 2-Pr H 1-AI-Pip (4)
2052 H F SO₂CH₂COOH 3-Pr H 1-AI-Pip (4)
2053 H F SO₂CH₂COOH 2-iPr H 1-AI-Pip (4)
2054 H F SO₂CH₂COOH 3-iPr H 1-AI-Pip (4)
2055 H F SO₂CH₂COOH 2-Bu H 1-AI-Pip (4)
2056 H F SO₂CH₂COOH 3-Bu H 1-AI-Pip (4)
2057 H F SO₂CH₂COOH 2-iBu H 1-AI-Pip (4)
2058 H F SO₂CH₂COOH 3-iBu H 1-AI-Pip (4)
2059 H F SO₂CH₂COOH 2-sBu H 1-AI-Pip (4)
2060 H F SO₂CH₂COOH 3-sBu H 1-AI-Pip (4)
2061 H F SO₂CH₂COOH 2-tBu H 1-AI-Pip (4)
2062 H F SO₂CH₂COOH 3-tBu H 1-AI-Pip (4)
2063 H F SO₂CH₂COOH 2-Pn H 1-AI-Pip (4)
2064 H F SO₂CH₂COOH 3-Pn H 1-AI-Pip (4)
2065 H F SO₂CH₂COOH 2-Hx H 1-AI-Pip (4)
2066 H F SO₂CH₂COOH 3-Hx H 1-AI-Pip (4)
2067 H F SO₂CH₂COOH 2-CF_Three      H 1-AI-Pip (4)
2068 H F SO₂CH₂COOH 3-CF_Three      H 1-AI-Pip (4)
2069 H F SO₂CH₂COOH 2-OMe H 1-AI-Pip (4)
2070 H F SO₂CH₂COOH 3-OMe H 1-AI-Pip (4)
2071 H F SO₂CH₂COOH 2-OEt H 1-AI-Pip (4)
2072 H F SO₂CH₂COOH 3-OEt H 1-AI-Pip (4)
2073 H F SO₂CH₂COOH 2-COOH H 1-AI-Pip (4)
2074 H F SO₂CH₂COOH 3-COOH H 1-AI-Pip (4)
2075 H F SO₂CH₂COOH 2-COOMe H 1-AI-Pip (4)
2076 H F SO₂CH₂COOH 3-COOMe H 1-AI-Pip (4)
2077 H F SO₂CH₂COOH 2-COOEt H 1-AI-Pip (4)
2078 H F SO₂CH₂COOH 3-COOEt H 1-AI-Pip (4)
2079 H F SO₂CH₂COOH 2-COOPr H 1-AI-Pip (4)
2080 H F SO₂CH₂COOH 3-COOPr H 1-AI-Pip (4)
2081 H F SO₂CH₂COOH 2-COOBu H 1-AI-Pip (4)
2082 H F SO₂CH₂COOH 3-COOBu H 1-AI-Pip (4)
2083 H F SO₂CH₂COOH 2-COOPn H 1-AI-Pip (4)
2084 H F SO₂CH₂COOH 3-COOPn H 1-AI-Pip (4)
2085 H F SO₂CH₂COOH 2-COOHx H 1-AI-Pip (4)
2086 H F SO₂CH₂COOH 3-COOHx H 1-AI-Pip (4)
2087 H F SO₂CH₂COOH 2-CONH₂    H 1-AI-Pip (4)
2088 H F SO₂CH₂COOH 3-CONH₂    H 1-AI-Pip (4)
2089 H F SO₂CH₂COOH 2-CONHMe H 1-AI-Pip (4)
2090 H F SO₂CH₂COOH 3-CONHMe H 1-AI-Pip (4)
2091 H F SO₂CH₂COOH 2-CONHEt H 1-AI-Pip (4)
2092 H F SO₂CH₂COOH 3-CONHEt H 1-AI-Pip (4)
2093 H F SO₂CH₂COOH 2-CON (Me)₂  H 1-AI-Pip (4)
2094 H F SO₂CH₂COOH 3-CON (Me)₂  H 1-AI-Pip (4)
2095 H F SO₂CH₂COOH 2-CON (Me) EtH 1-AI-Pip (4)
2096 H F SO₂CH₂COOH 3-CON (Me) EtH 1-AI-Pip (4)
2097 H F SO₂CH₂COOH 2-CON (Et)₂  H 1-AI-Pip (4)
2098 H F SO₂CH₂COOH 3-CON (Et)₂  H 1-AI-Pip (4)
2099 H Me SO₂CH₂COOH H H 1-AI-Pip (4)
2100 H Me SO₂CH₂COOH 2-F H 1-AI-Pip (4)
2101 H Me SO₂CH₂COOH 3-F H 1-AI-Pip (4)
2102 H Me SO₂CH₂COOH 2-Cl H 1-AI-Pip (4)
2103 H Me SO₂CH₂COOH 3-Cl H 1-AI-Pip (4)
2104 H Me SO₂CH₂COOH 2-Br H 1-AI-Pip (4)
2105 H Me SO₂CH₂COOH 3-Br H 1-AI-Pip (4)
2106 H Me SO₂CH₂COOH 2-I H 1-AI-Pip (4)
2107 H Me SO₂CH₂COOH 3-I H 1-AI-Pip (4)
2108 H Me SO₂CH₂COOH 2-Me H 1-AI-Pip (4)
2109 H Me SO₂CH₂COOH 3-Me H 1-AI-Pip (4)
2110 H Me SO₂CH₂COOH 2-Et H 1-AI-Pip (4)
2111 H Me SO₂CH₂COOH 3-Et H 1-AI-Pip (4)
2112 H Me SO₂CH₂COOH 2-Pr H 1-AI-Pip (4)
2113 H Me SO₂CH₂COOH 3-Pr H 1-AI-Pip (4)
2114 H Me SO₂CH₂COOH 2-Bu H 1-AI-Pip (4)
2115 H Me SO₂CH₂COOH 3-Bu H 1-AI-Pip (4)
2116 H Me SO₂CH₂COOH 2-Pn H 1-AI-Pip (4)
2117 H Me SO₂CH₂COOH 3-Pn H 1-AI-Pip (4)
2118 H Me SO₂CH₂COOH 2-Hx H 1-AI-Pip (4)
2119 H Me SO₂CH₂COOH 3-Hx H 1-AI-Pip (4)
2120 H Me SO₂CH₂COOH 2-CF_Three      H 1-AI-Pip (4)
2121 H Me SO₂CH₂COOH 3-CF_Three      H 1-AI-Pip (4)
2122 H Me SO₂CH₂COOH 2-OMe H 1-AI-Pip (4)
2123 H Me SO₂CH₂COOH 3-OMe H 1-AI-Pip (4)
2124 H Me SO₂CH₂COOH 2-OEt H 1-AI-Pip (4)
2125 H Me SO₂CH₂COOH 3-OEt H 1-AI-Pip (4)
2126 H Me SO₂CH₂COOH 2-COOH H 1-AI-Pip (4)
2127 H Me SO₂CH₂COOH 3-COOH H 1-AI-Pip (4)
2128 H Me SO₂CH₂COOH 2-COOMe H 1-AI-Pip (4)
2129 H Me SO₂CH₂COOH 3-COOMe H 1-AI-Pip (4)
2130 H Me SO₂CH₂COOH 2-COOEt H 1-AI-Pip (4)
2131 H Me SO₂CH₂COOH 3-COOEt H 1-AI-Pip (4)
2132 H Me SO₂CH₂COOH 2-COOPr H 1-AI-Pip (4)
2133 H Me SO₂CH₂COOH 3-COOPr H 1-AI-Pip (4)
2134 H Me SO₂CH₂COOH 2-COOBu H 1-AI-Pip (4)
2135 H Me SO₂CH₂COOH 3-COOBu H 1-AI-Pip (4)
2136 H Me SO₂CH₂COOH 2-COOPn H 1-AI-Pip (4)
2137 H Me SO₂CH₂COOH 3-COOPn H 1-AI-Pip (4)
2138 H Me SO₂CH₂COOH 2-COOHx H 1-AI-Pip (4)
2139 H Me SO₂CH₂COOH 3-COOHx H 1-AI-Pip (4)
2140 H Me SO₂CH₂COOH 2-CONH₂    H 1-AI-Pip (4)
2141 H Me SO₂CH₂COOH 3-CONH₂    H 1-AI-Pip (4)
2142 H Me SO₂CH₂COOH 2-CONHMe H 1-AI-Pip (4)
2143 H Me SO₂CH₂COOH 3-CONHMe H 1-AI-Pip (4)
2144 H Me SO₂CH₂COOH 2-CONHEt H 1-AI-Pip (4)
2145 H Me SO₂CH₂COOH 3-CONHEt H 1-AI-Pip (4)
2146 H Me SO₂CH₂COOH 2-CON (Me)₂  H 1-AI-Pip (4)
2147 H Me SO₂CH₂COOH 3-CON (Me)₂  H 1-AI-Pip (4)
2148 H Me SO₂CH₂COOH 2-CON (Me) EtH 1-AI-Pip (4)
2149 H Me SO₂CH₂COOH 3-CON (Me) EtH 1-AI-Pip (4)
2150 H Me SO₂CH₂COOH 2-CON (Et)₂  H 1-AI-Pip (4)
2151 H Me SO₂CH₂COOH 3-CON (Et)₂  H 1-AI-Pip (4)
2152 6-F H SO₂CH₂COOH H H 1-AI-Pip (4)
2153 6-F H SO₂CH₂COOH 2-F H 1-AI-Pip (4)
2154 6-F H SO₂CH₂COOH 3-F H 1-AI-Pip (4)
2155 6-F H SO₂CH₂COOH 2-Cl H 1-AI-Pip (4)
2156 6-F H SO₂CH₂COOH 3-Cl H 1-AI-Pip (4)
2157 6-F H SO₂CH₂COOH 2-Br H 1-AI-Pip (4)
2158 6-F H SO₂CH₂COOH 3-Br H 1-AI-Pip (4)
2159 6-F H SO₂CH₂COOH 2-I H 1-AI-Pip (4)
2160 6-F H SO₂CH₂COOH 3-I H 1-AI-Pip (4)
2161 6-F H SO₂CH₂COOH 2-Me H 1-AI-Pip (4)
2162 6-F H SO₂CH₂COOH 3-Me H 1-AI-Pip (4)
2163 6-F H SO₂CH₂COOH 2-Et H 1-AI-Pip (4)
2164 6-F H SO₂CH₂COOH 3-Et H 1-AI-Pip (4)
2165 6-F H SO₂CH₂COOH 2-Pr H 1-AI-Pip (4)
2166 6-F H SO₂CH₂COOH 3-Pr H 1-AI-Pip (4)
2167 6-F H SO₂CH₂COOH 2-Bu H 1-AI-Pip (4)
2168 6-F H SO₂CH₂COOH 3-Bu H 1-AI-Pip (4)
2169 6-F H SO₂CH₂COOH 2-Pn H 1-AI-Pip (4)
2170 6-F H SO₂CH₂COOH 3-Pn H 1-AI-Pip (4)
2171 6-F H SO₂CH₂COOH 2-Hx H 1-AI-Pip (4)
2172 6-F H SO₂CH₂COOH 3-Hx H 1-AI-Pip (4)
2173 6-F H SO₂CH₂COOH 2-CF_Three      H 1-AI-Pip (4)
2174 6-F H SO₂CH₂COOH 3-CF_Three      H 1-AI-Pip (4)
2175 6-F H SO₂CH₂COOH 2-OMe H 1-AI-Pip (4)
2176 6-F H SO₂CH₂COOH 3-OMe H 1-AI-Pip (4)
2177 6-F H SO₂CH₂COOH 2-OEt H 1-AI-Pip (4)
2178 6-F H SO₂CH₂COOH 3-OEt H 1-AI-Pip (4)
2179 6-F H SO₂CH₂COOH 2-COOH H 1-AI-Pip (4)
2180 6-F H SO₂CH₂COOH 3-COOH H 1-AI-Pip (4)
2181 6-F H SO₂CH₂COOH 2-COOMe H 1-AI-Pip (4)
2182 6-F H SO₂CH₂COOH 3-COOMe H 1-AI-Pip (4)
2183 6-F H SO₂CH₂COOH 2-COOEt H 1-AI-Pip (4)
2184 6-F H SO₂CH₂COOH 3-COOEt H 1-AI-Pip (4)
2185 6-F H SO₂CH₂COOH 2-COOPr H 1-AI-Pip (4)
2186 6-F H SO₂CH₂COOH 3-COOPr H 1-AI-Pip (4)
2187 6-F H SO₂CH₂COOH 2-COOBu H 1-AI-Pip (4)
2188 6-F H SO₂CH₂COOH 3-COOBu H 1-AI-Pip (4)
2189 6-F H SO₂CH₂COOH 2-COOPn H 1-AI-Pip (4)
2190 6-F H SO₂CH₂COOH 3-COOPn H 1-AI-Pip (4)
2191 6-F H SO₂CH₂COOH 2-COOHx H 1-AI-Pip (4)
2192 6-F H SO₂CH₂COOH 3-COOHx H 1-AI-Pip (4)
2193 6-F H SO₂CH₂COOH 2-CONH₂    H 1-AI-Pip (4)
2194 6-F H SO₂CH₂COOH 3-CONH₂    H 1-AI-Pip (4)
2195 6-F H SO₂CH₂COOH 2-CONHMe H 1-AI-Pip (4)
2196 6-F H SO₂CH₂COOH 3-CONHMe H 1-AI-Pip (4)
2197 6-F H SO₂CH₂COOH 2-CONHEt H 1-AI-Pip (4)
2198 6-F H SO₂CH₂COOH 3-CONHEt H 1-AI-Pip (4)
2199 6-F H SO₂CH₂COOH 2-CON (Me)₂  H 1-AI-Pip (4)
2200 6-F H SO₂CH₂COOH 3-CON (Me)₂  H 1-AI-Pip (4)
2201 6-F H SO₂CH₂COOH 2-CON (Me) Et H 1-AI-Pip (4)
2202 6-F H SO₂CH₂COOH 3-CON (Me) Et H 1-AI-Pip (4)
2203 6-F H SO₂CH₂COOH 2-CON (Et)₂  H 1-AI-Pip (4)
2204 6-F H SO₂CH₂COOH 3-CON (Et)₂  H 1-AI-Pip (4)
2205 2-Me H SO₂CH₂COOH H H 1-AI-Pip (4)
2206 3-Me H SO₂CH₂COOH H H 1-AI-Pip (4)
2207 4-Me H SO₂CH₂COOH H H 1-AI-Pip (4)
2208 5-Me H SO₂CH₂COOH H H 1-AI-Pip (4)
2209 5-Me H SO₂CH₂COOH 2-F H 1-AI-Pip (4)
2210 5-Me H SO₂CH₂COOH 3-F H 1-AI-Pip (4)
2211 5-Me H SO₂CH₂COOH 2-Cl H 1-AI-Pip (4)
2212 5-Me H SO₂CH₂COOH 3-Cl H 1-AI-Pip (4)
2213 5-Me H SO₂CH₂COOH 2-Br H 1-AI-Pip (4)
2214 5-Me H SO₂CH₂COOH 3-Br H 1-AI-Pip (4)
2215 5-Me H SO₂CH₂COOH 2-I H 1-AI-Pip (4)
2216 5-Me H SO₂CH₂COOH 3-I H 1-AI-Pip (4)
2217 5-Me H SO₂CH₂COOH 2-Me H 1-AI-Pip (4)
2218 5-Me H SO₂CH₂COOH 3-Me H 1-AI-Pip (4)
2219 5-Me H SO₂CH₂COOH 2-Et H 1-AI-Pip (4)
2220 5-Me H SO₂CH₂COOH 3-Et H 1-AI-Pip (4)
2221 5-Me H SO₂CH₂COOH 2-Pr H 1-AI-Pip (4)
2222 5-Me H SO₂CH₂COOH 3-Pr H 1-AI-Pip (4)
2223 5-Me H SO₂CH₂COOH 2-Bu H 1-AI-Pip (4)
2224 5-Me H SO₂CH₂COOH 3-Bu H 1-AI-Pip (4)
2225 5-Me H SO₂CH₂COOH 2-Pn H 1-AI-Pip (4)
2226 5-Me H SO₂CH₂COOH 3-Pn H 1-AI-Pip (4)
2227 5-Me H SO₂CH₂COOH 2-Hx H 1-AI-Pip (4)
2228 5-Me H SO₂CH₂COOH 3-Hx H 1-AI-Pip (4)
2229 5-Me H SO₂CH₂COOH 2-CF_Three      H 1-AI-Pip (4)
2230 5-Me H SO₂CH₂COOH 3-CF_Three      H 1-AI-Pip (4)
2231 5-Me H SO₂CH₂COOH 2-OMe H 1-AI-Pip (4)
2232 5-Me H SO₂CH₂COOH 3-OMe H 1-AI-Pip (4)
2233 5-Me H SO₂CH₂COOH 2-OEt H 1-AI-Pip (4)
2234 5-Me H SO₂CH₂COOH 3-OEt H 1-AI-Pip (4)
2235 5-Me H SO₂CH₂COOH 2-COOH H 1-AI-Pip (4)
2236 5-Me H SO₂CH₂COOH 3-COOH H 1-AI-Pip (4)
2237 5-Me H SO₂CH₂COOH 2-COOMe H 1-AI-Pip (4)
2238 5-Me H SO₂CH₂COOH 3-COOMe H 1-AI-Pip (4)
2239 5-Me H SO₂CH₂COOH 2-COOEt H 1-AI-Pip (4)
2240 5-Me H SO₂CH₂COOH 3-COOEt H 1-AI-Pip (4)
2241 5-Me H SO₂CH₂COOH 2-COOPr H 1-AI-Pip (4)
2242 5-Me H SO₂CH₂COOH 3-COOPr H 1-AI-Pip (4)
2243 5-Me H SO₂CH₂COOH 2-COOBu H 1-AI-Pip (4)
2244 5-Me H SO₂CH₂COOH 3-COOBu H 1-AI-Pip (4)
2245 5-Me H SO₂CH₂COOH 2-COOPn H 1-AI-Pip (4)
2246 5-Me H SO₂CH₂COOH 3-COOPn H 1-AI-Pip (4)
2247 5-Me H SO₂CH₂COOH 2-COOHx H 1-AI-Pip (4)
2248 5-Me H SO₂CH₂COOH 3-COOHx H 1-AI-Pip (4)
2249 5-Me H SO₂CH₂COOH 2-CONH₂    H 1-AI-Pip (4)
2250 5-Me H SO₂CH₂COOH 3-CONH₂    H 1-AI-Pip (4)
2251 5-Me H SO₂CH₂COOH 2-CONHMe H 1-AI-Pip (4)
2252 5-Me H SO₂CH₂COOH 3-CONHMe H 1-AI-Pip (4)
2253 5-Me H SO₂CH₂COOH 2-CONHEt H 1-AI-Pip (4)
2254 5-Me H SO₂CH₂COOH 3-CONHEt H 1-AI-Pip (4)
2255 5-Me H SO₂CH₂COOH 2-CON (Me)₂  H 1-AI-Pip (4)
2256 5-Me H SO₂CH₂COOH 3-CON (Me)₂  H 1-AI-Pip (4)
2257 5-Me H SO₂CH₂COOH 2-CON (Me) Et H 1-AI-Pip (4)
2258 5-Me H SO₂CH₂COOH 3-CON (Me) Et H 1-AI-Pip (4)
2259 5-Me H SO₂CH₂COOH 2-CON (Et)₂  H 1-AI-Pip (4)
2260 5-Me H SO₂CH₂COOH 3-CON (Et)₂  H 1-AI-Pip (4)
2261 6-Me H SO₂CH₂COOH H H 1-AI-Pip (4)
2262 6-OH H SO₂CH₂COOH H H 1-AI-Pip (4)
2263 6-OH H SO₂CH₂COOH 2-F H 1-AI-Pip (4)
2264 6-OH H SO₂CH₂COOH 3-F H 1-AI-Pip (4)
2265 6-OH H SO₂CH₂COOH 2-Cl H 1-AI-Pip (4)
2266 6-OH H SO₂CH₂COOH 3-Cl H 1-AI-Pip (4)
2267 6-OH H SO₂CH₂COOH 2-Br H 1-AI-Pip (4)
2268 6-OH H SO₂CH₂COOH 3-Br H 1-AI-Pip (4)
2269 6-OH H SO₂CH₂COOH 2-I H 1-AI-Pip (4)
2270 6-OH H SO₂CH₂COOH 3-I H 1-AI-Pip (4)
2271 6-OH H SO₂CH₂COOH 2-Me H 1-AI-Pip (4)
2272 6-OH H SO₂CH₂COOH 3-Me H 1-AI-Pip (4)
2273 6-OH H SO₂CH₂COOH 2-Et H 1-AI-Pip (4)
2274 6-OH H SO₂CH₂COOH 3-Et H 1-AI-Pip (4)
2275 6-OH H SO₂CH₂COOH 2-Pr H 1-AI-Pip (4)
2276 6-OH H SO₂CH₂COOH 3-Pr H 1-AI-Pip (4)
2277 6-OH H SO₂CH₂COOH 2-Bu H 1-AI-Pip (4)
2278 6-OH H SO₂CH₂COOH 3-Bu H 1-AI-Pip (4)
2279 6-OH H SO₂CH₂COOH 2-Pn H 1-AI-Pip (4)
2280 6-OH H SO₂CH₂COOH 3-Pn H 1-AI-Pip (4)
2281 6-OH H SO₂CH₂COOH 2-Hx H 1-AI-Pip (4)
2282 6-OH H SO₂CH₂COOH 3-Hx H 1-AI-Pip (4)
2283 6-OH H SO₂CH₂COOH 2-CF_Three      H 1-AI-Pip (4)
2284 6-OH H SO₂CH₂COOH 3-CF_Three      H 1-AI-Pip (4)
2285 6-OH H SO₂CH₂COOH 2-OMe H 1-AI-Pip (4)
2286 6-OH H SO₂CH₂COOH 3-OMe H 1-AI-Pip (4)
2287 6-OH H SO₂CH₂COOH 2-OEt H 1-AI-Pip (4)
2288 6-OH H SO₂CH₂COOH 3-OEt H 1-AI-Pip (4)
2289 6-OH H SO₂CH₂COOH 2-COOH H 1-AI-Pip (4)
2290 6-OH H SO₂CH₂COOH 3-COOH H 1-AI-Pip (4)
2291 6-OH H SO₂CH₂COOH 2-COOMe H 1-AI-Pip (4)
2292 6-OH H SO₂CH₂COOH 3-COOMe H 1-AI-Pip (4)
2293 6-OH H SO₂CH₂COOH 2-COOEt H 1-AI-Pip (4)
2294 6-OH H SO₂CH₂COOH 3-COOEt H 1-AI-Pip (4)
2295 6-OH H SO₂CH₂COOH 2-COOPr H 1-AI-Pip (4)
2296 6-OH H SO₂CH₂COOH 3-COOPr H 1-AI-Pip (4)
2297 6-OH H SO₂CH₂COOH 2-COOBu H 1-AI-Pip (4)
2298 6-OH H SO₂CH₂COOH 3-COOBu H 1-AI-Pip (4)
2299 6-OH H SO₂CH₂COOH 2-COOPn H 1-AI-Pip (4)
2300 6-OH H SO₂CH₂COOH 3-COOPn H 1-AI-Pip (4)
2301 6-OH H SO₂CH₂COOH 2-COOHx H 1-AI-Pip (4)
2302 6-OH H SO₂CH₂COOH 3-COOHx H 1-AI-Pip (4)
2303 6-OH H SO₂CH₂COOH 2-CONH₂    H 1-AI-Pip (4)
2304 6-OH H SO₂CH₂COOH 3-CONH₂    H 1-AI-Pip (4)
2305 6-OH H SO₂CH₂COOH 2-CONHMe H 1-AI-Pip (4)
2306 6-OH H SO₂CH₂COOH 3-CONHMe H 1-AI-Pip (4)
2307 6-OH H SO₂CH₂COOH 2-CONHEt H 1-AI-Pip (4)
2308 6-OH H SO₂CH₂COOH 3-CONHEt H 1-AI-Pip (4)
2309 6-OH H SO₂CH₂COOH 2-CON (Me)₂  H 1-AI-Pip (4)
2310 6-OH H SO₂CH₂COOH 3-CON (Me)₂  H 1-AI-Pip (4)
2311 6-OH H SO₂CH₂COOH 2-CON (Me) EtH 1-AI-Pip (4)
2312 6-OH H SO₂CH₂COOH 3-CON (Me) EtH 1-AI-Pip (4)
2313 6-OH H SO₂CH₂COOH 2-CON (Et)₂  H 1-AI-Pip (4)
2314 6-OH H SO₂CH₂COOH 3-CON (Et)₂  H 1-AI-Pip (4)
2315 6-OH H SO₂CH₂COOH 2-F 3-F 1-AI-Pip (4)
2316 6-OH H SO₂CH₂COOH 2-F 5-F 1-AI-Pip (4)
2317 6-OH H SO₂CH₂COOH 2-F 6-F 1-AI-Pip (4)
2318 6-OH H SO₂CH₂COOH 3-F 5-F 1-AI-Pip (4)
2319 6-OH H SO₂CH₂COOH 2-Cl 3-Cl 1-AI-Pip (4)
2320 6-OH H SO₂CH₂COOH 2-Cl 5-Cl 1-AI-Pip (4)
2321 6-OH H SO₂CH₂COOH 2-Cl 6-Cl 1-AI-Pip (4)
2322 6-OH H SO₂CH₂COOH 3-Cl 5-Cl 1-AI-Pip (4)
2323 6-OH H SO₂CH₂COOH 2-Me 3-Me 1-AI-Pip (4)
2324 6-OH H SO₂CH₂COOH 2-Me 5-Me 1-AI-Pip (4)
2325 6-OH H SO₂CH₂COOH 2-Me 6-Me 1-AI-Pip (4)
2326 6-OH H SO₂CH₂COOH 3-Me 5-Me 1-AI-Pip (4)
2327 6-OH H SO₂CH₂COOH 2-Cl 5-CONH₂    1-AI-Pip (4)
2328 6-OH H SO₂CH₂COOH 3-Cl 5-CONH₂    1-AI-Pip (4)
2329 6-OH H SO₂CH₂COOH 3-Cl 5-CONHMe 1-AI-Pip (4)
2330 6-OH H SO₂CH₂COOH 3-Cl 5-CONHEt 1-AI-Pip (4)
2331 6-OH H SO₂CH₂COOH 3-Cl 5-CONHPr 1-AI-Pip (4)
2332 6-OH H SO₂CH₂COOH 3-Cl 5-CONHBu 1-AI-Pip (4)
2333 6-OH H SO₂CH₂COOH 3-Cl 5-CONHPn 1-AI-Pip (4)
2334 6-OH H SO₂CH₂COOH 3-Cl 5-CONHHx 1-AI-Pip (4)
2335 6-OH H SO₂CH₂COOH 2-Me 5-CONH₂    1-AI-Pip (4)
2336 6-OH H SO₂CH₂COOH 2-Me 5-CONHMe 1-AI-Pip (4)
2337 6-OH H SO₂CH₂COOH 2-Me 5-CONHEt 1-AI-Pip (4)
2338 6-OH H SO₂CH₂COOH 2-Me 5-CONHPr 1-AI-Pip (4)
2339 6-OH H SO₂CH₂COOH 2-Me 5-CONHBu 1-AI-Pip (4)
2340 6-OH H SO₂CH₂COOH 2-Me 5-CONHPn 1-AI-Pip (4)
2341 6-OH H SO₂CH₂COOH 2-Me 5-CONHHx 1-AI-Pip (4)
2342 6-OH H SO₂CH₂COOH 3-Me 5-CONH₂    1-AI-Pip (4)
2343 6-OH H SO₂CH₂COOH 3-Me 5-CONHMe 1-AI-Pip (4)
2344 6-OH H SO₂CH₂COOH 3-Me 5-CONHEt 1-AI-Pip (4)
2345 6-OH H SO₂CH₂COOH 3-Me 5-CONHPr 1-AI-Pip (4)
2346 6-OH H SO₂CH₂COOH 3-Me 5-CONHBu 1-AI-Pip (4)
2347 6-OH H SO₂CH₂COOH 3-Me 5-CONHPn 1-AI-Pip (4)
2348 6-OH H SO₂CH₂COOH 3-Me 5-CONHHx 1-AI-Pip (4)
2349 6-OH H SO₂CH₂COOH 2-CONH₂    6-CONH₂    1-AI-Pip (4)
2350 6-OH H SO₂CH₂COOH 3-CONH₂    5-CONH₂    1-AI-Pip (4)
2351 6-OH H SO₂CH₂COOH 3-CONHMe 5-CONHMe 1-AI-Pip (4)
2352 6-OH H SO₂CH₂COOH 3-CONHEt 5-CONHEt 1-AI-Pip (4)
2353 H H SO₂(CH₂)₂COOH H H 1-AI-Pip (4)
2354 H H SO₂(CH₂)_ThreeCOOH H H 1-AI-Pip (4)
2355 H H SO₂(CH₂)_FourCOOH H H 1-AI-Pip (4)
2356 H H SO₂(CH₂)_FiveCOOH H H 1-AI-Pip (4)
2357 H H SO₂(CH₂)₆COOH H H 1-AI-Pip (4)
2358 H H SO₂CH₂COOMe 2-F H 1-AI-Pip (4)
2359 H H SO₂CH₂COOMe 3-F H 1-AI-Pip (4)
2360 H H SO₂CH₂COOMe 2-Cl H 1-AI-Pip (4)
2361 H H SO₂CH₂COOMe 3-Cl H 1-AI-Pip (4)
2362 H H SO₂CH₂COOMe 2-Br H 1-AI-Pip (4)
2363 H H SO₂CH₂COOMe 3-Br H 1-AI-Pip (4)
2364 H H SO₂CH₂COOMe 2-I H 1-AI-Pip (4)
2365 H H SO₂CH₂COOMe 3-I H 1-AI-Pip (4)
2366 H H SO₂CH₂COOMe 2-Me H 1-AI-Pip (4)
2367 H H SO₂CH₂COOMe 3-Me H 1-AI-Pip (4)
2368 H H SO₂CH₂COOMe 2-Et H 1-AI-Pip (4)
2369 H H SO₂CH₂COOMe 3-Et H 1-AI-Pip (4)
2370 H H SO₂CH₂COOMe 2-Pr H 1-AI-Pip (4)
2371 H H SO₂CH₂COOMe 3-Pr H 1-AI-Pip (4)
2372 H H SO₂CH₂COOMe 2-iPr H 1-AI-Pip (4)
2373 H H SO₂CH₂COOMe 3-iPr H 1-AI-Pip (4)
2374 H H SO₂CH₂COOMe 2-Bu H 1-AI-Pip (4)
2375 H H SO₂CH₂COOMe 3-Bu H 1-AI-Pip (4)
2376 H H SO₂CH₂COOMe 2-iBu H 1-AI-Pip (4)
2377 H H SO₂CH₂COOMe 3-iBu H 1-AI-Pip (4)
2378 H H SO₂CH₂COOMe 2-sBu H 1-AI-Pip (4)
2379 H H SO₂CH₂COOMe 3-sBu H 1-AI-Pip (4)
2380 H H SO₂CH₂COOMe 2-tBu H 1-AI-Pip (4)
2381 H H SO₂CH₂COOMe 3-tBu H 1-AI-Pip (4)
2382 H H SO₂CH₂COOMe 2-Pn H 1-AI-Pip (4)
2383 H H SO₂CH₂COOMe 3-Pn H 1-AI-Pip (4)
2384 H H SO₂CH₂COOMe 2-Hx H 1-AI-Pip (4)
2385 H H SO₂CH₂COOMe 3-Hx H 1-AI-Pip (4)
2386 H H SO₂CH₂COOMe 2-CF_Three      H 1-AI-Pip (4)
2387 H H SO₂CH₂COOMe 3-CF_Three      H 1-AI-Pip (4)
2388 H H SO₂CH₂COOMe 2-OMe H 1-AI-Pip (4)
2389 H H SO₂CH₂COOMe 3-OMe H 1-AI-Pip (4)
2390 H H SO₂CH₂COOMe 2-OEt H 1-AI-Pip (4)
2391 H H SO₂CH₂COOMe 3-OEt H 1-AI-Pip (4)
2392 H H SO₂CH₂COOMe 2-COOH H 1-AI-Pip (4)
2393 H H SO₂CH₂COOMe 3-COOH H 1-AI-Pip (4)
2394 H H SO₂CH₂COOMe 2-COOMe H 1-AI-Pip (4)
2395 H H SO₂CH₂COOMe 3-COOMe H 1-AI-Pip (4)
2396 H H SO₂CH₂COOMe 2-COOEt H 1-AI-Pip (4)
2397 H H SO₂CH₂COOMe 3-COOEt H 1-AI-Pip (4)
2398 H H SO₂CH₂COOMe 2-COOPr H 1-AI-Pip (4)
2399 H H SO₂CH₂COOMe 3-COOPr H 1-AI-Pip (4)
2400 H H SO₂CH₂COOMe 2-COOBu H 1-AI-Pip (4)
2401 H H SO₂CH₂COOMe 3-COOBu H 1-AI-Pip (4)
2402 H H SO₂CH₂COOMe 2-COOPn H 1-AI-Pip (4)
2403 H H SO₂CH₂COOMe 3-COOPn H 1-AI-Pip (4)
2404 H H SO₂CH₂COOMe 2-COOHx H 1-AI-Pip (4)
2405 H H SO₂CH₂COOMe 3-COOHx H 1-AI-Pip (4)
2406 H H SO₂CH₂COOMe 2-CONH₂    H 1-AI-Pip (4)
2407 H H SO₂CH₂COOMe 3-CONH₂    H 1-AI-Pip (4)
2408 H H SO₂CH₂COOMe 2-CONHMe H 1-AI-Pip (4)
2409 H H SO₂CH₂COOMe 3-CONHMe H 1-AI-Pip (4)
2410 H H SO₂CH₂COOMe 2-CONHEt H 1-AI-Pip (4)
2411 H H SO₂CH₂COOMe 3-CONHEt H 1-AI-Pip (4)
2412 H H SO₂CH₂COOMe 2-CON (Me)₂  H 1-AI-Pip (4)
2413 H H SO₂CH₂COOMe 3-CON (Me)₂  H 1-AI-Pip (4)
2414 H H SO₂CH₂COOMe 2-CON (Me) Et H 1-AI-Pip (4)
2415 H H SO₂CH₂COOMe 3-CON (Me) Et H 1-AI-Pip (4)
2416 H H SO₂CH₂COOMe 2-CON (Et)₂  H 1-AI-Pip (4)
2417 H H SO₂CH₂COOMe 3-CON (Et)₂  H 1-AI-Pip (4)
2418 H H SO₂CH₂COOMe 2-F 3-F 1-AI-Pip (4)
2419 H H SO₂CH₂COOMe 2-F 5-F 1-AI-Pip (4)
2420 H H SO₂CH₂COOMe 2-F 6-F 1-AI-Pip (4)
2421 H H SO₂CH₂COOMe 3-F 5-F 1-AI-Pip (4)
2422 H H SO₂CH₂COOMe 2-Cl 3-Cl 1-AI-Pip (4)
2423 H H SO₂CH₂COOMe 2-Cl 5-Cl 1-AI-Pip (4)
2424 H H SO₂CH₂COOMe 2-Cl 6-Cl 1-AI-Pip (4)
2425 H H SO₂CH₂COOMe 3-Cl 5-Cl 1-AI-Pip (4)
2426 H H SO₂CH₂COOMe 2-Me 3-Me 1-AI-Pip (4)
2427 H H SO₂CH₂COOMe 2-Me 5-Me 1-AI-Pip (4)
2428 H H SO₂CH₂COOMe 2-Me 6-Me 1-AI-Pip (4)
2429 H H SO₂CH₂COOMe 3-Me 5-Me 1-AI-Pip (4)
2430 H H SO₂CH₂COOMe 2-Cl 5-CONH₂    1-AI-Pip (4)
2431 H H SO₂CH₂COOMe 3-Cl 5-CONH₂    1-AI-Pip (4)
2432 H H SO₂CH₂COOMe 3-Cl 5-CONHMe 1-AI-Pip (4)
2433 H H SO₂CH₂COOMe 3-Cl 5-CONHEt 1-AI-Pip (4)
2434 H H SO₂CH₂COOMe 3-Cl 5-CONHPr 1-AI-Pip (4)
2435 H H SO₂CH₂COOMe 3-Cl 5-CONHBu 1-AI-Pip (4)
2436 H H SO₂CH₂COOMe 3-Cl 5-CONHPn 1-AI-Pip (4)
2437 H H SO₂CH₂COOMe 3-Cl 5-CONHHx 1-AI-Pip (4)
2438 H H SO₂CH₂COOMe 2-Me 5-CONH₂    1-AI-Pip (4)
2439 H H SO₂CH₂COOMe 2-Me 5-CONHMe 1-AI-Pip (4)
2440 H H SO₂CH₂COOMe 2-Me 5-CONHEt 1-AI-Pip (4)
2441 H H SO₂CH₂COOMe 2-Me 5-CONHPr 1-AI-Pip (4)
2442 H H SO₂CH₂COOMe 2-Me 5-CONHBu 1-AI-Pip (4)
2443 H H SO₂CH₂COOMe 2-Me 5-CONHPn 1-AI-Pip (4)
2444 H H SO₂CH₂COOMe 2-Me 5-CONHHx 1-AI-Pip (4)
2445 H H SO₂CH₂COOMe 3-Me 5-CONH₂    1-AI-Pip (4)
2446 H H SO₂CH₂COOMe 3-Me 5-CONHMe 1-AI-Pip (4)
2447 H H SO₂CH₂COOMe 3-Me 5-CONHEt 1-AI-Pip (4)
2448 H H SO₂CH₂COOMe 3-Me 5-CONHPr 1-AI-Pip (4)
2449 H H SO₂CH₂COOMe 3-Me 5-CONHBu 1-AI-Pip (4)
2450 H H SO₂CH₂COOMe 3-Me 5-CONHPn 1-AI-Pip (4)
2451 H H SO₂CH₂COOMe 3-Me 5-CONHHx 1-AI-Pip (4)
2452 H H SO₂CH₂COOMe 2-CONH₂    6-CONH₂    1-AI-Pip (4)
2453 H H SO₂CH₂COOMe 3-CONH₂    5-CONH₂    1-AI-Pip (4)
2454 H H SO₂CH₂COOMe 3-CONHMe 5-CONHMe 1-AI-Pip (4)
2455 H H SO₂CH₂COOMe 3-CONHEt 5-CONHEt 1-AI-Pip (4)
2456 6-OH H SO₂CH₂COOMe 2-F H 1-AI-Pip (4)
2457 6-OH H SO₂CH₂COOMe 3-F H 1-AI-Pip (4)
2458 6-OH H SO₂CH₂COOMe 2-Cl H 1-AI-Pip (4)
2459 6-OH H SO₂CH₂COOMe 3-Cl H 1-AI-Pip (4)
2460 6-OH H SO₂CH₂COOMe 2-Br H 1-AI-Pip (4)
2461 6-OH H SO₂CH₂COOMe 3-Br H 1-AI-Pip (4)
2462 6-OH H SO₂CH₂COOMe 2-I H 1-AI-Pip (4)
2463 6-OH H SO₂CH₂COOMe 3-I H 1-AI-Pip (4)
2464 6-OH H SO₂CH₂COOMe 2-Me H 1-AI-Pip (4)
2465 6-OH H SO₂CH₂COOMe 3-Me H 1-AI-Pip (4)
2466 6-OH H SO₂CH₂COOMe 2-Et H 1-AI-Pip (4)
2467 6-OH H SO₂CH₂COOMe 3-Et H 1-AI-Pip (4)
2468 6-OH H SO₂CH₂COOMe 2-Pr H 1-AI-Pip (4)
2469 6-OH H SO₂CH₂COOMe 3-Pr H 1-AI-Pip (4)
2470 6-OH H SO₂CH₂COOMe 2-iPr H 1-AI-Pip (4)
2471 6-OH H SO₂CH₂COOMe 3-iPr H 1-AI-Pip (4)
2472 6-OH H SO₂CH₂COOMe 2-Bu H 1-AI-Pip (4)
2473 6-OH H SO₂CH₂COOMe 3-Bu H 1-AI-Pip (4)
2474 6-OH H SO₂CH₂COOMe 2-iBu H 1-AI-Pip (4)
2475 6-OH H SO₂CH₂COOMe 3-iBu H 1-AI-Pip (4)
2476 6-OH H SO₂CH₂COOMe 2-sBu H 1-AI-Pip (4)
2477 6-OH H SO₂CH₂COOMe 3-sBu H 1-AI-Pip (4)
2478 6-OH H SO₂CH₂COOMe 2-tBu H 1-AI-Pip (4)
2479 6-OH H SO₂CH₂COOMe 3-tBu H 1-AI-Pip (4)
2480 6-OH H SO₂CH₂COOMe 2-Pn H 1-AI-Pip (4)
2481 6-OH H SO₂CH₂COOMe 3-Pn H 1-AI-Pip (4)
2482 6-OH H SO₂CH₂COOMe 2-Hx H 1-AI-Pip (4)
2483 6-OH H SO₂CH₂COOMe 3-Hx H 1-AI-Pip (4)
2484 6-OH H SO₂CH₂COOMe 2-CF_Three      H 1-AI-Pip (4)
2485 6-OH H SO₂CH₂COOMe 3-CF_Three      H 1-AI-Pip (4)
2486 6-OH H SO₂CH₂COOMe 2-OMe H 1-AI-Pip (4)
2487 6-OH H SO₂CH₂COOMe 3-OMe H 1-AI-Pip (4)
2488 6-OH H SO₂CH₂COOMe 2-OEt H 1-AI-Pip (4)
2489 6-OH H SO₂CH₂COOMe 3-OEt H 1-AI-Pip (4)
2490 6-OH H SO₂CH₂COOMe 2-COOH H 1-AI-Pip (4)
2491 6-OH H SO₂CH₂COOMe 3-COOH H 1-AI-Pip (4)
2492 6-OH H SO₂CH₂COOMe 2-COOMe H 1-AI-Pip (4)
2493 6-OH H SO₂CH₂COOMe 3-COOMe H 1-AI-Pip (4)
2494 6-OH H SO₂CH₂COOMe 2-COOEt H 1-AI-Pip (4)
2495 6-OH H SO₂CH₂COOMe 3-COOEt H 1-AI-Pip (4)
2496 6-OH H SO₂CH₂COOMe 2-COOPr H 1-AI-Pip (4)
2497 6-OH H SO₂CH₂COOMe 3-COOPr H 1-AI-Pip (4)
2498 6-OH H SO₂CH₂COOMe 2-COOBu H 1-AI-Pip (4)
2499 6-OH H SO₂CH₂COOMe 3-COOBu H 1-AI-Pip (4)
2500 6-OH H SO₂CH₂COOMe 2-COOPn H 1-AI-Pip (4)
2501 6-OH H SO₂CH₂COOMe 3-COOPn H 1-AI-Pip (4)
2502 6-OH H SO₂CH₂COOMe 2-COOHx H 1-AI-Pip (4)
2503 6-OH H SO₂CH₂COOMe 3-COOHx H 1-AI-Pip (4)
2504 6-OH H SO₂CH₂COOMe 2-CONH₂    H 1-AI-Pip (4)
2505 6-OH H SO₂CH₂COOMe 3-CONH₂    H 1-AI-Pip (4)
2506 6-OH H SO₂CH₂COOMe 2-CONHMe H 1-AI-Pip (4)
2507 6-OH H SO₂CH₂COOMe 3-CONHMe H 1-AI-Pip (4)
2508 6-OH H SO₂CH₂COOMe 2-CONHEt H 1-AI-Pip (4)
2509 6-OH H SO₂CH₂COOMe 3-CONHEt H 1-AI-Pip (4)
2510 6-OH H SO₂CH₂COOMe 2-CON (Me)₂  H 1-AI-Pip (4)
2511 6-OH H SO₂CH₂COOMe 3-CON (Me)₂  H 1-AI-Pip (4)
2512 6-OH H SO₂CH₂COOMe 2-CON (Me) Et H 1-AI-Pip (4)
2513 6-OH H SO₂CH₂COOMe 3-CON (Me) Et H 1-AI-Pip (4)
2514 6-OH H SO₂CH₂COOMe 2-CON (Et)₂  H 1-AI-Pip (4)
2515 6-OH H SO₂CH₂COOMe 3-CON (Et)₂  H 1-AI-Pip (4)
2516 6-OH H SO₂CH₂COOMe 2-F 3-F 1-AI-Pip (4)
2517 6-OH H SO₂CH₂COOMe 2-F 5-F 1-AI-Pip (4)
2518 6-OH H SO₂CH₂COOMe 2-F 6-F 1-AI-Pip (4)
2519 6-OH H SO₂CH₂COOMe 3-F 5-F 1-AI-Pip (4)
2520 6-OH H SO₂CH₂COOMe 2-Cl 3-Cl 1-AI-Pip (4)
2521 6-OH H SO₂CH₂COOMe 2-Cl 5-Cl 1-AI-Pip (4)
2522 6-OH H SO₂CH₂COOMe 2-Cl 6-Cl 1-AI-Pip (4)
2523 6-OH H SO₂CH₂COOMe 3-Cl 5-Cl 1-AI-Pip (4)
2524 6-OH H SO₂CH₂COOMe 2-Me 3-Me 1-AI-Pip (4)
2525 6-OH H SO₂CH₂COOMe 2-Me 5-Me 1-AI-Pip (4)
2526 6-OH H SO₂CH₂COOMe 2-Me 6-Me 1-AI-Pip (4)
2527 6-OH H SO₂CH₂COOMe 3-Me 5-Me 1-AI-Pip (4)
2528 6-OH H SO₂CH₂COOMe 2-Cl 5-CONH₂    1-AI-Pip (4)
2529 6-OH H SO₂CH₂COOMe 3-Cl 5-CONH₂    1-AI-Pip (4)
2530 6-OH H SO₂CH₂COOMe 3-Cl 5-CONHMe 1-AI-Pip (4)
2531 6-OH H SO₂CH₂COOMe 3-Cl 5-CONHEt 1-AI-Pip (4)
2532 6-OH H SO₂CH₂COOMe 3-Cl 5-CONHPr 1-AI-Pip (4)
2533 6-OH H SO₂CH₂COOMe 3-Cl 5-CONHBu 1-AI-Pip (4)
2534 6-OH H SO₂CH₂COOMe 3-Cl 5-CONHPn 1-AI-Pip (4)
2535 6-OH H SO₂CH₂COOMe 3-Cl 5-CONHHx 1-AI-Pip (4)
2536 6-OH H SO₂CH₂COOMe 2-Me 5-CONH₂    1-AI-Pip (4)
2537 6-OH H SO₂CH₂COOMe 2-Me 5-CONHMe 1-AI-Pip (4)
2538 6-OH H SO₂CH₂COOMe 2-Me 5-CONHEt 1-AI-Pip (4)
2539 6-OH H SO₂CH₂COOMe 2-Me 5-CONHPr 1-AI-Pip (4)
2540 6-OH H SO₂CH₂COOMe 2-Me 5-CONHBu 1-AI-Pip (4)
2541 6-OH H SO₂CH₂COOMe 2-Me 5-CONHPn 1-AI-Pip (4)
2542 6-OH H SO₂CH₂COOMe 2-Me 5-CONHHx 1-AI-Pip (4)
2543 6-OH H SO₂CH₂COOMe 3-Me 5-CONH₂    1-AI-Pip (4)
2544 6-OH H SO₂CH₂COOMe 3-Me 5-CONHMe 1-AI-Pip (4)
2545 6-OH H SO₂CH₂COOMe 3-Me 5-CONHEt 1-AI-Pip (4)
2546 6-OH H SO₂CH₂COOMe 3-Me 5-CONHPr 1-AI-Pip (4)
2547 6-OH H SO₂CH₂COOMe 3-Me 5-CONHBu 1-AI-Pip (4)
2548 6-OH H SO₂CH₂COOMe 3-Me 5-CONHPn 1-AI-Pip (4)
2549 6-OH H SO₂CH₂COOMe 3-Me 5-CONHHx 1-AI-Pip (4)
2550 6-OH H SO₂CH₂COOMe 2-CONH₂    6-CONH₂    1-AI-Pip (4)
2551 6-OH H SO₂CH₂COOMe 3-CONH₂    5-CONH₂    1-AI-Pip (4)
2552 6-OH H SO₂CH₂COOMe 3-CONHMe 5-CONHMe 1-AI-Pip (4)
2553 6-OH H SO₂CH₂COOMe 3-CONHEt 5-CONHEt 1-AI-Pip (4)

本発明の一般式（Ｉ）を有するベンズアミジン誘導体に於て、好適な化合物としては、例示化合物番号83、90、93、101、137、140、142、148、177、237、297、358、478、542、663、668、788、849、864、948、1014、1080、1220、1280、1408、1410、1411、1412、1413、1414、1415、1416、1419、1420、1422、1424、1426、1434、1440、1442、1448、1450、1460、1462、1466、1474、1478、1482、1484、1492、1498、1509、1513、1539、1638、1711、1771、1839、1843、1849、1881、1939、1941、1943、1945、1949、1951、1955、1963、1969、1971、1975、1977、1979、1989、1991、1995、2003、2007、2011、2013、2027、2038、2040、2042、2044、2048、2054、2068、2070、2076、2078、2088、2094、2109、2208、2262、2266、2272、2304又は2353を挙げることができ、 In the benzamidine derivative having the general formula (I) of the present invention, preferred compounds include Exemplified Compound Nos. 83, 90, 93, 101, 137, 140, 142, 148, 177, 237, 297, 358, 478 , 542, 663, 668, 788, 849, 864, 948, 1014, 1080, 1220, 1280, 1408, 1410, 1411, 1412, 1413, 1414, 1415, 1416, 1419, 1420, 1422, 1424, 1426, 1434 , 1440, 1442, 1448, 1450, 1460, 1462, 1466, 1474, 1478, 1482, 1484, 1492, 1498, 1509, 1513, 1539, 1638, 1711, 1771, 1839, 1843, 1849, 1881, 1939, 1941 , 1943, 1945, 1949, 1951, 1955, 1963, 1969, 1971, 1975, 1977, 1979, 1989, 1991, 1995, 2003, 2007, 2011, 2013, 2027, 2038, 2040, 2042, 2044, 2048, 2054 , 2068, 2070, 2076, 2078, 2088, 2094, 2109, 2208, 2262, 2266, 2272, 2304 or 2353,

更に好適には、例示化合物番号90、137、177、237、297、358、478、542、663、668、788、849、864、948、1014、1080、1408、1410、1412、1414、1416、1419、1420、1426、1440、1442、1450、1460、1462、1466、1474、1478、1482、1484、1492、1498、1509、1513、1638、1711、1771、1839、1843、1849、1881、1939、1941、1943、1945、1949、1951、1955、1969、1971、1975、1979、1989、1991、1995、2003、2007、2011、2013、2027、2038、2040、2042、2094、2208、2262、2266、2272又は2304を挙げることができ、 More preferably, exemplified compound numbers 90, 137, 177, 237, 297, 358, 478, 542, 663, 668, 788, 849, 864, 948, 1014, 1080, 1408, 1410, 1412, 1414, 1416, 1419, 1420, 1426, 1440, 1442, 1450, 1460, 1462, 1466, 1474, 1478, 1482, 1484, 1492, 1498, 1509, 1513, 1638, 1711, 1771, 1839, 1843, 1849, 1881, 1939, 1941, 1943, 1945, 1949, 1951, 1955, 1969, 1971, 1975, 1979, 1989, 1991, 1995, 2003, 2007, 2011, 2013, 2027, 2038, 2040, 2042, 2094, 2208, 2262, 2266, 2272 or 2304,

より更に好適には、例示化合物番号668、849、1014、1410、1412、1414、1420、1426、1440、1442、1450、1460、1462、1466、1474、1478、1482、1484、1498、1509、1839、1843、1939、1941、1943、1945、1949、1955、1969、1971、1975、1979、1989、1991、1995、2003、2007、2011、2013、2027又は2038を挙げることができ、 More preferably, exemplified compound numbers 668, 849, 1014, 1410, 1412, 1414, 1420, 1426, 1440, 1442, 1450, 1460, 1462, 1466, 1474, 1478, 1482, 1484, 1498, 1509, 1839 , 1843, 1939, 1941, 1943, 1945, 1949, 1955, 1969, 1971, 1975, 1979, 1989, 1991, 1995, 2003, 2007, 2011, 2013, 2027 or 2038,

特に好適には、
例示化合物番号1410：Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル、
例示化合物番号1414：Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−クロロフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル、
例示化合物番号1420：Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−メチルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル、
例示化合物番号1460：Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−カルバモイルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル、
例示化合物番号1939：Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸、
例示化合物番号1941：Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−フルオロフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸、
例示化合物番号1943：Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−クロロフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸、
例示化合物番号1949：Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−メチルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸、
例示化合物番号1969：Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−トリフルオロメチルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸、
例示化合物番号1989：Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−カルバモイルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸、
例示化合物番号2003：Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３，５−ジクロロフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル、
例示化合物番号2007：Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３，５−ジクロロフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸、又は、
例示化合物番号2038：Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−フルオロ−２−（Ｚ）−プロペニル］スルファモイル酢酸を挙げることができる。
Particularly preferably,
Illustrative compound number 1410: N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl acetate,
Illustrative compound number 1414: N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-chlorophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoylacetic acid ethyl,
Illustrative compound number 1420: N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-methylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl Ethyl acetate,
Illustrative compound number 1460: N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-carbamoylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl Ethyl acetate,
Illustrative compound number 1939: N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoylacetic acid,
Illustrative compound number 1941: N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-fluorophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl Acetic acid,
Illustrative compound number 1943: N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-chlorophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoylacetic acid ,
Illustrative compound number 1949: N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-methylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl Acetic acid,
Illustrative compound number 1969: N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-trifluoromethylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl ] Sulfamoyl acetic acid,
Illustrative compound number 1989: N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-carbamoylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl Acetic acid,
Illustrative compound number 2003: N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-dichlorophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] Ethyl sulfamoyl acetate,
Illustrative compound number 2007: N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-dichlorophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] Sulfamoyl acetic acid, or
Illustrative compound number 2038: N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2-fluoro-2- (Z) -propenyl] sulfamoyl Mention may be made of acetic acid.

本発明の一般式（Ｉ）を有する化合物は、以下の方法に従い容易に製造することができる。 The compound having the general formula (I) of the present invention can be easily produced according to the following method.

上記に於いて、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵及びＲ⁶は、前述したものと同意義を示し、
Ｒ³aは、水素原子を示し、
Ｒ³bは、Ｃ₁−Ｃ₆アルキル基；保護された水酸基若しくは（Ｃ₁−Ｃ₆アルコキシ）カルボニル基で置換されたＣ₁−Ｃ₆アルキル基；一般式 In the above, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the same meaning as described above,
R ³ a represents a hydrogen atom,
R ³ b represents a C ₁ -C ₆ alkyl group; a C ₁ -C ₆ alkyl group substituted with a protected hydroxyl group or a (C ₁ -C ₆ alkoxy) carbonyl group;

（式中、Ｒ⁷、ｍ及びｎは、前述したものと同意義を示す。）を有する基；Ｃ₇−Ｃ₁₅アラルキル基；Ｃ₁−Ｃ₆アルキルスルホニル基；又は、（Ｃ₁−Ｃ₆アルコキシ）カルボニル基で置換されたＣ₁−Ｃ₆アルキルスルホニル基を示し、
Ｒ³cは、Ｃ₁−Ｃ₆アルキル基又はＣ₇−Ｃ₁₅アラルキル基を示し、
Ｒ³dは、Ｃ₁−Ｃ₆アルカノイル基又は保護された水酸基で置換されたＣ₂−Ｃ₆アルカノイル基を示し、
Ｒ⁸は、アミノ基が保護されている他はＲ⁶と同意義を示し、
Ｒ⁹は、Ｃ₁−Ｃ₅アルキル基、Ｃ₆−Ｃ₁₄アリール基又はＣ₇−Ｃ₁₄アラルキル基を示し、
Ｒ¹⁰は、Ｃ₁−Ｃ₆アルカノイル基；又は、保護された水酸基で置換されたＣ₂−Ｃ₆アルカノイル基を示し、
Ｒ¹¹は、Ｃ₁−Ｃ₆アルキル基を示し、
Ｒ¹²は、水酸基の保護基を示し、
Ｒ¹³は、水酸基が保護されている他は、Ｒ¹と同意義を示し、
Ｘは、ハロゲン原子を示す。 (Wherein R ⁷ , m and n are as defined above); a C ₇ -C ₁₅ aralkyl group; a C ₁ -C ₆ alkylsulfonyl group; or (C ₁ -C ₆ alkoxy) represents a C ₁ -C ₆ alkyl sulfonyl group substituted with a carbonyl group,
R ³ c represents a C ₁ -C ₆ alkyl group or a C ₇ -C ₁₅ aralkyl group,
R ³ d represents a C ₁ -C ₆ alkanoyl group or a C ₂ -C ₆ alkanoyl group substituted with a protected hydroxyl group;
R ⁸ has the same meaning as R ⁶ except that the amino group is protected,
R ⁹ represents a C ₁ -C ₅ alkyl group, a C ₆ -C ₁₄ aryl group or a C ₇ -C ₁₄ aralkyl group,
R ¹⁰ represents a C ₁ -C ₆ alkanoyl group; or a C ₂ -C ₆ alkanoyl group substituted with a protected hydroxyl group,
R ¹¹ represents a C ₁ -C ₆ alkyl group,
R ¹² represents a hydroxyl-protecting group,
R ¹³ has the same meaning as R ¹ except that the hydroxyl group is protected,
X represents a halogen atom.

上記に於いて、Ｒ³bの定義に於ける、「Ｃ₁−Ｃ₆アルキル基」、「（Ｃ₁−Ｃ₆アルコキシ）カルボニル基で置換されたＣ₁−Ｃ₆アルキル基」、「一般式 In the above, in the definition of R ³ b, "C ₁ -C ₆ alkyl group", "(C ₁ -C ₆ alkoxy) C ₁ -C ₆ alkyl group substituted with a carbonyl group", "General formula

（式中、Ｒ⁷、ｍ及びｎは、前述したものと同意義を示す。）を有する基」、「Ｃ₇−Ｃ₁₅アラルキル基」、「Ｃ₁−Ｃ₆アルキルスルホニル基」、「（Ｃ₁−Ｃ₆アルコキシ）カルボニル基で置換されたＣ₁−Ｃ₆アルキルスルホニル基」；Ｒ³cの定義に於ける「Ｃ₁−Ｃ₆アルキル基」、「Ｃ₇−Ｃ₁₅アラルキル基」；及び、Ｒ³dの定義に於ける、「Ｃ₁−Ｃ₆アルカノイル基」は、各々、Ｒ³で定義したものと同意義を示す。 (Wherein R ⁷ , m and n are as defined above), “C ₇ -C ₁₅ aralkyl group”, “C ₁ -C ₆ alkylsulfonyl group”, “( C ₁ -C ₆ alkoxy) carbonyl substituted C ₁ -C ₆ alkylsulfonyl group ”;“ C ₁ -C ₆ alkyl group ”and“ C ₇ -C ₁₅ aralkyl group ”in the definition of R ³ c And “C ₁ -C ₆ alkanoyl group” in the definition of R ³ d has the same meaning as defined for R ³ .

上記に於いて、Ｒ³bの定義に於ける「保護された水酸基で置換されたＣ₁−Ｃ₆アルキル基」は、水酸基が保護されている他は、Ｒ³で定義されたものと同意義を示す。 In the above, R ³ b "C ₁ -C ₆ alkyl group substituted with a protected hydroxyl group" in the definition of the other hydroxyl groups are protected, the as defined by R ³ Show significance.

上記に於いて、Ｒ³dの定義に於ける「保護された水酸基で置換されたＣ₂−Ｃ₆アルカノイル基」は、水酸基が保護されている他は、Ｒ³で定義された「ヒドロキシＣ₂−Ｃ₆アルカノイル基」と同意義を示す。 In the above, the “C ₂ -C ₆ alkanoyl group substituted with a protected hydroxyl group” in the definition of R ³ d is the same as “hydroxy C” defined in R ³ except that the hydroxyl group is protected. It has the same meaning as “ _2- C ₆ alkanoyl group”.

上記に於いて、Ｒ³bの定義に於ける「保護された水酸基で置換されたＣ₁−Ｃ₆アルキル基」の「水酸基の保護基」、Ｒ³d及びＲ¹⁰の定義に於ける「保護された水酸基で置換されたＣ₂−Ｃ₆アルカノイル基」の「水酸基の保護基」、Ｒ¹²の定義に於ける「水酸基の保護基」、Ｒ¹³に含まれる「水酸基の保護基」は、一般に水酸基の保護基として使用される基であれば、特に限定はなく用いることができるが、例えば、ホルミル基、アセチル基、プロピオニル基、ブチリル基、イソブチリル基、ペンタノイル基、ピバロイル基、バレリル基、イソバレリル基、オクタノイル基、ノナノイル基、デカノイル基、３−メチルノナノイル基、８−メチルノナノイル基、３−エチルオクタノイル基、３，７−ジメチルオクタノイル基、ウンデカノイル基、ドデカノイル基、トリデカノイル基、テトラデカノイル基、ペンタデカノイル基、ヘキサデカノイル基、１−メチルペンタデカノイル基、１４−メチルペンタデカノイル基、１３，１３−ジメチルテトラデカノイル基、ヘプタデカノイル基、１５−メチルヘキサデカノイル基、オクタデカノイル基、１−メチルヘプタデカノイル基、ノナデカノイル基、アイコサノイル基又はヘナイコサノイル基のようなアルカノイル類；スクシノイル基、グルタロイル基又はアジポイル基のようなカルボキシ化アルカノイル類；クロロアセチル基、ジクロロアセチル基、トリクロロアセチル基又はトリフルオロアセチル基のようなハロゲノアルカノイル類；メトキシアセチル基のようなアルコキシアルカノイル類；（Ｅ）−２−メチル−２−ブテノイル基のような不飽和アルカノイル類；ベンゾイル基、α−ナフトイル基又はβ−ナフトイル基のようなアリールカルボニル類；２−ブロモベンゾイル基又は４−クロロベンゾイル基のようなハロゲノアリールカルボニル類；２，４，６−トリメチルベンゾイル基又は４−トルオイル基のようなアルキル化アリールカルボニル類；４−アニソイル基のようなアルコキシ化アリールカルボニル類；２−カルボキシベンゾイル基、３−カルボキシベンゾイル基又は４−カルボキシベンゾイル基のようなカルボキシ化アリールカルボニル類；４−ニトロベンゾイル基又は２−ニトロベンゾイル基のようなニトロ化アリールカルボニル類；２−（メトキシカルボニル）ベンゾイル基のようなアルコキシカルボニル化アリールカルボニル類；４−フェニルベンゾイル基のようなアリール化アリールカルボニル類；テトラヒドロピラン−２−イル基、３−ブロモテトラヒドロピラン−２−イル基、４−メトキシテトラヒドロピラン−４−イル基、テトラヒドロチオピラン−２−イル基又は４−メトキシテトラヒドロチオピラン−４−イル基のようなテトラヒドロピラニル類又はテトラヒドロチオピラニル類；テトラヒドロフラン−２−イル基又はテトラヒドロチオフラン−２−イル基のようなテトラヒドロフラニル類又はテトラヒドロチオフラニル類；メトキシメチル基、１，１−ジメチル−１−メトキシメチル基、エトキシメチル基、プロポキシメチル基、イソプロポキシメチル基、ブトキシメチル基又はｔ−ブトキシメチル基のようなアルコキシメチル類；２−メトキシエトキシメチル基のようなアルコキシ化アルコキシメチル類；２，２，２−トリクロロエトキシメチル基又はビス（２−クロロエトキシ）メチル基のようなハロゲノアルコキシメチル類；１−エトキシエチル基又は１−（イソプロポキシ）エチル基のようなアルコキシ化エチル類；２，２，２−トリクロロエチル基のようなハロゲン化エチル類；ベンジル基、α−ナフチルメチル基、β−ナフチルメチル基、ジフェニルメチル基、トリフェニルメチル基、α−ナフチルジフェニルメチル基又は９−アンスリルメチル基のような１乃至３個のアリール基で置換されたアラルキル類；４−メチルベンジル基、２，４，６−トリメチルベンジル基、３，４，５−トリメチルベンジル基、４−メトキシベンジル基、４−メトキシフェニルジフェニルメチル基、２−ニトロベンジル基、４−ニトロベンジル基、４−クロロベンジル基、４−ブロモベンジル基又は４−シアノベンジル基のような、アルキル、アルコキシ、ハロゲン又はシアノ基でアリール環が置換されたアラルキル類；メトキシカルボニル基、エトキシカルボニル基、ｔ−ブトキシカルボニル基若しくはイソブトキシカルボニル基のようなアルコキシカルボニル類又は２，２，２−トリクロロエトキシカルボニル基ような、ハロゲン化アルコキシカルボニル類；ビニルオキシカルボニル基又はアリルオキシカルボニル基のようなアルケニルオキシカルボニル類；或は、ベンジルオキシカルボニル基、４−メトキシベンジルオキシカルボニル基、３，４−ジメトキシベンジルオキシカルボニル基、２−ニトロベンジルオキシカルボニル基又は４−ニトロベンジルオキシカルボニル基のような、１又は２個のアルコキシ若しくはニトロ基でアリール環が置換されていてもよいアラルキルオキシカルボニル類；トリメチルシリル基、トリエチルシリル基、イソプロピルジメチルシリル基、ｔ−ブチルジメチルシリル基、メチルジイソプロピルシリル基、メチルジ−ｔ−ブチルシリル基、トリイソプロピルシリル基、ジフェニルメチルシリル基、ジフェニルブチルシリル基、ジフェニルイソプロピルシリル基又はフェニルジイソプロピルシリル基のようなシリル類であり得、Ｒ³bの定義に於ける「保護された水酸基で置換されたＣ₁−Ｃ₆アルキル基」の「水酸基の保護基」、Ｒ³d及びＲ¹⁰の定義に於ける「保護された水酸基で置換されたＣ₂−Ｃ₆アルカノイル基」の「水酸基の保護基」は、好適にはアルカノイル類であり、特に好適にはアセチル基である。他方、Ｒ¹²の定義に於ける「水酸基の保護基」及びＲ¹³に含まれる「水酸基の保護基」は、好適にはアルコキシ化アルコキシメチル類であり、特に好適にはメトキシメチル基である。 In the above, “hydroxyl-protecting group” of “C ₁ -C ₆ alkyl group substituted with protected hydroxyl group” in the definition of R ³ b, “in the definition of R ³ d and R ¹⁰ ” protected hydroxy C ₂ -C ₆ alkanoyl group substituted by "a" hydroxyl protecting group ", in" hydroxyl protecting group in the definition of R ¹² ", the protecting group of" the hydroxyl group contained in R ¹³ 'is As long as it is a group that is generally used as a protective group for a hydroxyl group, it can be used without any particular limitation. , Isovaleryl group, octanoyl group, nonanoyl group, decanoyl group, 3-methylnonanoyl group, 8-methylnonanoyl group, 3-ethyloctanoyl group, 3,7-dimethyloctanoyl group, undecanoyl , Dodecanoyl group, tridecanoyl group, tetradecanoyl group, pentadecanoyl group, hexadecanoyl group, 1-methylpentadecanoyl group, 14-methylpentadecanoyl group, 13,13-dimethyltetradecanoyl group, heptadecanoyl group , Alkanoyls such as 15-methylhexadecanoyl group, octadecanoyl group, 1-methylheptadecanoyl group, nonadecanoyl group, icosanoyl group or heinaicosanoyl group; carboxylated alkanoyl such as succinoyl group, glutaroyl group or adipoyl group Halogenoalkanoyls such as chloroacetyl group, dichloroacetyl group, trichloroacetyl group or trifluoroacetyl group; alkoxyalkanoyls such as methoxyacetyl group; (E) -2-methyl-2-butenoyl Unsaturated alkanoyls such as: arylcarbonyls such as benzoyl, α-naphthoyl or β-naphthoyl; halogenoarylcarbonyls such as 2-bromobenzoyl or 4-chlorobenzoyl; Alkylated arylcarbonyls such as 6-trimethylbenzoyl group or 4-toluoyl group; alkoxylated arylcarbonyls such as 4-anisoyl group; 2-carboxybenzoyl group, 3-carboxybenzoyl group or 4-carboxybenzoyl group Carboxylated arylcarbonyls such as 4-nitrobenzoyl or 2-nitrobenzoyl groups nitrated arylcarbonyls such as 2- (methoxycarbonyl) benzoyl groups; Arylated arylcarbonyls such as yl group; tetrahydropyran-2-yl group, 3-bromotetrahydropyran-2-yl group, 4-methoxytetrahydropyran-4-yl group, tetrahydrothiopyran-2-yl group or Tetrahydropyranyls or tetrahydrothiopyranyls such as 4-methoxytetrahydrothiopyran-4-yl group; Tetrahydrofuranyls or tetrahydrothiofuran such as tetrahydrofuran-2-yl group or tetrahydrothiofuran-2-yl group Nyls; alkoxymethyls such as methoxymethyl group, 1,1-dimethyl-1-methoxymethyl group, ethoxymethyl group, propoxymethyl group, isopropoxymethyl group, butoxymethyl group or t-butoxymethyl group; Such as methoxyethoxymethyl group Lucoxylated alkoxymethyls; halogenoalkoxymethyls such as 2,2,2-trichloroethoxymethyl group or bis (2-chloroethoxy) methyl group; such as 1-ethoxyethyl group or 1- (isopropoxy) ethyl group Alkoxylated ethyls; ethyl halides such as 2,2,2-trichloroethyl group; benzyl group, α-naphthylmethyl group, β-naphthylmethyl group, diphenylmethyl group, triphenylmethyl group, α-naphthyl Aralkyls substituted with 1 to 3 aryl groups such as diphenylmethyl group or 9-anthrylmethyl group; 4-methylbenzyl group, 2,4,6-trimethylbenzyl group, 3,4,5-trimethyl Benzyl group, 4-methoxybenzyl group, 4-methoxyphenyldiphenylmethyl group, 2-nitrobenzyl group Aralkyls in which the aryl ring is substituted with an alkyl, alkoxy, halogen or cyano group, such as 4-nitrobenzyl group, 4-chlorobenzyl group, 4-bromobenzyl group or 4-cyanobenzyl group; methoxycarbonyl group, ethoxy Alkoxycarbonyls such as carbonyl group, t-butoxycarbonyl group or isobutoxycarbonyl group or halogenated alkoxycarbonyls such as 2,2,2-trichloroethoxycarbonyl group; such as vinyloxycarbonyl group or allyloxycarbonyl group Or benzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, 3,4-dimethoxybenzyloxycarbonyl group, 2-nitrobenzyloxycarbonyl group or 4-nitrobenzyl Aralkyloxycarbonyls in which the aryl ring may be substituted with one or two alkoxy or nitro groups, such as a xycarbonyl group; a trimethylsilyl group, a triethylsilyl group, an isopropyldimethylsilyl group, a t-butyldimethylsilyl group, It may be a silyl such as methyldiisopropylsilyl group, methyldi-t-butylsilyl group, triisopropylsilyl group, diphenylmethylsilyl group, diphenylbutylsilyl group, diphenylisopropylsilyl group or phenyldiisopropylsilyl group, and the definition of R ³ b "C substituted with protected hydroxy ₁ -C ₆ alkyl group" in the "hydroxyl protecting group" of, R ³ d and C ₂ substituted by at "protected hydroxy group in the definition of R ¹⁰ The “hydroxyl protecting group” of —C ₆ alkanoyl group ”is preferably Noyls, particularly preferably an acetyl group. On the other hand, the “hydroxyl-protecting group” in the definition of R ^{12 and} the “hydroxyl-protecting group” contained in R ¹³ are preferably alkoxylated alkoxymethyls, particularly preferably methoxymethyl groups.

上記に於いて、Ｒ⁸の「アミノ基の保護基」は、一般にアミノ基の保護基として使用される基であれば、特に限定はなく用いることができるが、例えば、ホルミル基、アセチル基、プロピオニル基、ブチリル基、イソブチリル基、ペンタノイル基、ピバロイル基、バレリル基、イソバレリル基又はヘキサノイル基のようなＣ₁−Ｃ₆アルカノイル基；クロロアセチル基、ジクロロアセチル基、トリクロロアセチル基、トリフルオロアセチル基、３−フルオロプロピオニル基、４，４−ジクロロブチリル基、メトキシアセチル基、ブトキシアセチル基、エトキシプロピオニル基又はプロポキシブチリル基のような、ハロゲン若しくはＣ₁−Ｃ₄アルコキシで置換されたＣ₁−Ｃ₄アルカノイル基；アクリロイル基、プロピオロイル基、メタクリロイル基、クロトノイル基又はイソクロトノイル基のような不飽和Ｃ₁−Ｃ₄アルカノイル基；ベンゾイル基、α−ナフトイル基、β−ナフトイル基、２−フルオロベンゾイル基、２−ブロモベンゾイル基、２，４−ジクロロベンゾイル基、６−クロロ−α−ナフトイル基、４−トルオイル基、４−プロピルベンゾイル基、４−ｔ−ブチルベンゾイル基、２，４，６−トリメチルベンゾイル基、６−エチル−α−ナフトイル基、４−アニソイル基、４−プロポキシベンゾイル基、４−ｔ−ブトキシベンゾイル基、６−エトキシ−α−ナフトイル基、２−エトキシカルボニルベンゾイル基、４−ｔ−ブトキシカルボニルベンゾイル基、６−メトキシカルボニル−α−ナフトイル基、４−フェニルベンゾイル基、４−フェニル−α−ナフトイル基、６−α−ナフチルベンゾイル基、４−ニトロベンゾイル基、２−ニトロベンゾイル基又は６−ニトロ−α−ナフトイル基のような、ハロゲン、Ｃ₁−Ｃ₄アルキル、Ｃ₁−Ｃ₄アルコキシ、Ｃ₁−Ｃ₄アルコキシカルボニル、Ｃ₆−Ｃ₁₀アリ−ル又はニトロで置換されてもよいＣ₆−Ｃ₁₀アリ−ルカルボニル基；メトキシカルボニル基、エトキシカルボニル基、プロポキシカルボニル基、イソプロポキシカルボニル基、ブトキシカルボニル基、イソブトキシカルボニル基、ｓ−ブトキシカルボニル基、ｔ−ブトキシカルボニル基、クロロメトキシカルボニル基、２，２，２−トリクロロエトキシカルボニル基、２−フルオロプロポキシカルボニル基、２−ブロモ−ｔ−ブトキシカルボニル基、２，２−ジブロモ−ｔ−ブトキシカルボニル基、トリエチルシリルメトキシカルボニル基、２−トリメチルシリルエトキシカルボニル基、４−トリプロピルシリルブトキシカルボニル基又はｔ−ブチルジメチルシリルプロポキシカルボニル基のような、ハロゲン又はトリＣ₁−Ｃ₄アルキルシリルで置換されてもよいＣ₁−Ｃ₄アルコキシカルボニル基；ビニルオキシカルボニル基、アリルオキシカルボニル基、１，３−ブタジエニルオキシカルボニル基又は２−ペンテニルオキシカルボニル基のようなＣ₂−Ｃ₅アルケニルオキシカルボニル基；フタロイル基のようなアリールジカルボニル基；ベンジル基、フェネチル基、３−フェニルプロピル基、４−フェニルブチル基、α−ナフチルメチル基、β−ナフチルメチル基、ジフェニルメチル基、トリフェニルメチル基、α−ナフチルジフェニルメチル基又は９−アンスリルメチル基のようなアラルキル基；或はベンジルオキシカルボニル基、（１−フェニル）ベンジルオキシカルボニル基、α−ナフチルメチルオキシカルボニル基、β−ナフチルメチルオキシカルボニル基、９−アンスリルメチルオキシカルボニル基、ｐ−メトキシベンジルオキシカルボニル基又はｐ−ニトロベンジルオキシカルボニル基のような、メトキシ又はニトロで置換されてもよいＣ₇−Ｃ₁₅アラルキルオキシカルボニル基であり得、好適には、Ｃ₁−Ｃ₄アルカノイル基；トリフルオロアセチル基；メトキシアセチル基；ベンゾイル基；α−ナフトイル基；β−ナフトイル基；アニソイル基；ニトロベンゾイル基；Ｃ₁−Ｃ₄アルコキシカルボニル基；２，２，２−トリクロロエトキシカルボニル基；トリエチルシリルメトキシカルボニル基；２−トリメチルシリルエトキシカルボニル基；ビニルオキシカルボニル基；アリルオキシカルボニル基；フタロイル基；ベンジル基；ベンジルオキシカルボニル基；又はニトロベンジルオキシカルボニル基であり、更に好適には、ホルミル基、アセチル基、ベンゾイル基、４−アニソイル基、４−ニトロベンゾイル基、メトキシカルボニル基、エトキシカルボニル基、ブトキシカルボニル基、ｔ−ブトキシカルボニル基、フタロイル基、ベンジル基、ベンジルオキシカルボニル基又はｐ−ニトロベンジルオキシカルボニル基であり、特に好適にはｔ−ブトキシカルボニル基である。 In the above, the “amino-protecting group” for R ⁸ can be used without particular limitation as long as it is a group generally used as an amino-protecting group. For example, a formyl group, an acetyl group, C ₁ -C ₆ alkanoyl groups such as propionyl group, butyryl group, isobutyryl group, pentanoyl group, pivaloyl group, valeryl group, isovaleryl group or hexanoyl group; chloroacetyl group, dichloroacetyl group, trichloroacetyl group, trifluoroacetyl group 3-fluoro propionyl group, 4,4-dichloro-butyryl group, methoxyacetyl group, butoxy acetyl group, ethoxy propionyl, such as group or propoxy butyryl group, C ₁ substituted with halogen or C ₁ -C ₄ alkoxy -C ₄ alkanoyl group; an acryloyl group, propioloyl group, methacrylonitrile Group, unsaturated C ₁ -C ₄ alkanoyl group such as crotonoyl or isocrotonoyl groups; benzoyl group, alpha-naphthoyl group, beta-naphthoyl, 2-fluorobenzoyl group, 2-bromobenzoyl group, 2,4 Dichlorobenzoyl group, 6-chloro-α-naphthoyl group, 4-toluoyl group, 4-propylbenzoyl group, 4-t-butylbenzoyl group, 2,4,6-trimethylbenzoyl group, 6-ethyl-α-naphthoyl group 4-anisoyl group, 4-propoxybenzoyl group, 4-t-butoxybenzoyl group, 6-ethoxy-α-naphthoyl group, 2-ethoxycarbonylbenzoyl group, 4-t-butoxycarbonylbenzoyl group, 6-methoxycarbonyl- α-naphthoyl group, 4-phenylbenzoyl group, 4-phenyl-α-naphthoyl group, 6-α- Halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkoxy, such as naphthylbenzoyl group, 4-nitrobenzoyl group, 2-nitrobenzoyl group or 6-nitro-α-naphthoyl group carbonyl, C ₆ -C ₁₀ ants - le or nitro that is substituted C ₆ -C ₁₀ optionally Ari - nyl group; a methoxycarbonyl group, an ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, Isobutoxycarbonyl group, s-butoxycarbonyl group, t-butoxycarbonyl group, chloromethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, 2-fluoropropoxycarbonyl group, 2-bromo-t-butoxycarbonyl group, 2,2-dibromo-t-butoxycarbonyl group, triethyl Lil methoxycarbonyl group, 2-trimethylsilyl ethoxycarbonyl group, such as 4-tripropylsilyl butoxycarbonyl group or t- butyldimethylsilyl propoxycarbonyl group, optionally substituted by halogen or tri C ₁ -C ₄ alkylsilyl C ₁ -C ₄ alkoxycarbonyl group; a vinyl oxycarbonyl group, allyloxycarbonyl group, 1,3-butadienyl oxycarbonyl group or a 2-C ₂ -C ₅ alkenyloxycarbonyl group such as pentenyl oxycarbonyl group; phthaloyl group Aryldicarbonyl groups such as: benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyl Diphenylmethyl group Is an aralkyl group such as 9-anthrylmethyl group; or benzyloxycarbonyl group, (1-phenyl) benzyloxycarbonyl group, α-naphthylmethyloxycarbonyl group, β-naphthylmethyloxycarbonyl group, 9-anthryl It may be a C ₇ -C ₁₅ aralkyloxycarbonyl group which may be substituted with methoxy or nitro, such as a methyloxycarbonyl group, p-methoxybenzyloxycarbonyl group or p-nitrobenzyloxycarbonyl group, preferably C ₁ -C ₄ alkanoyl group; a trifluoroacetyl group; methoxyacetyl group; a benzoyl group; alpha-naphthoyl group; beta-naphthoyl group; anisoyl group; nitrobenzoyl group; C ₁ -C ₄ alkoxycarbonyl group; 2,2, 2-trichloroethoxycarbonyl group; triethylsilyl group 2-trimethylsilylethoxycarbonyl group; vinyloxycarbonyl group; allyloxycarbonyl group; phthaloyl group; benzyl group; benzyloxycarbonyl group; or nitrobenzyloxycarbonyl group, more preferably formyl group, acetyl group Group, benzoyl group, 4-anisoyl group, 4-nitrobenzoyl group, methoxycarbonyl group, ethoxycarbonyl group, butoxycarbonyl group, t-butoxycarbonyl group, phthaloyl group, benzyl group, benzyloxycarbonyl group or p-nitrobenzyloxy A carbonyl group, particularly preferably a t-butoxycarbonyl group.

上記に於いて、Ｒ⁹の定義に於ける「Ｃ₁−Ｃ₅アルキル基」は、例えば、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓ−ブチル基、ｔ−ブチル基、ペンチル基、イソペンチル基、２−メチルブチル基、ネオペンチル基又は１−エチルプロピル基のような、炭素数１乃至５個の直鎖又は分枝鎖アルキル基であり得、好適にはＣ₁−Ｃ₃アルキル基であり、更に好適にはメチル基、エチル基又はイソプロピル基である。 In the above, “C ₁ -C ₅ alkyl group” in the definition of R ⁹ is, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, t- It may be a linear or branched alkyl group having 1 to 5 carbon atoms such as butyl group, pentyl group, isopentyl group, 2-methylbutyl group, neopentyl group or 1-ethylpropyl group, preferably C ₁ -C is ₃ alkyl group, more preferably a methyl group, an ethyl group or an isopropyl group.

上記に於いて、Ｒ⁹の定義に於ける「Ｃ₆−Ｃ₁₄アリール基」は、例えば、フェニル基、インデニル基、ナフチル基、フェナンスレニル基又はアントラセニル基のような炭素数６乃至１４個の芳香族炭化水素基であり得、好適にはフェニル基又はナフチル基であり、更に好適にはフェニル基である。 In the above, the “C ₆ -C ₁₄ aryl group” in the definition of R ⁹ is an aromatic group having 6 to 14 carbon atoms such as a phenyl group, an indenyl group, a naphthyl group, a phenanthrenyl group or an anthracenyl group. It may be an aromatic hydrocarbon group, preferably a phenyl group or a naphthyl group, and more preferably a phenyl group.

上記に於いて、Ｒ⁹の定義に於ける「Ｃ₇−Ｃ₁₄アラルキル基」は、例えば、ベンジル基、α−ナフチルメチル基、インデニルメチル基、ジフェニルメチル基、２−フェネチル基、２−α−ナフチルエチル基、３−フェニルプロピル基、３−α−ナフチルプロピル基、フェニルブチル基、４−α−ナフチルブチル基又は５−フェニルペンチル基のような、炭素数６乃至１４個の芳香族炭化水素基の１又は２個が、「Ｃ₁−Ｃ₅アルキル基」に結合した基であり得、好適には、ベンジル基、α−ナフチルメチル基、ジフェニルメチル基又は２−フェネチル基であり、更に好適には、ベンジル基又は２−フェネチル基であり、特に好適にはベンジル基である。 In the above, “C ₇ -C ₁₄ aralkyl group” in the definition of R ⁹ is, for example, benzyl group, α-naphthylmethyl group, indenylmethyl group, diphenylmethyl group, 2-phenethyl group, 2- Aromatic compounds having 6 to 14 carbon atoms such as α-naphthylethyl group, 3-phenylpropyl group, 3-α-naphthylpropyl group, phenylbutyl group, 4-α-naphthylbutyl group or 5-phenylpentyl group One or two of the hydrocarbon groups may be a group bonded to a “C ₁ -C ₅ alkyl group”, preferably a benzyl group, an α-naphthylmethyl group, a diphenylmethyl group or a 2-phenethyl group. More preferably, it is a benzyl group or a 2-phenethyl group, and particularly preferably a benzyl group.

上記に於いて、Ｒ¹⁰の定義に於ける「Ｃ₁−Ｃ₆アルカノイル基」は、例えば、ホルミル基、アセチル基、プロピオニル基、ブチリル基、イソブチリル基、ピバロイル基、バレリル基、イソバレリル基又はヘキサノイル基のような炭素数１乃至６個の直鎖又は分枝鎖のアルカノイル基であり、好適には、Ｃ₁−Ｃ₄アルカノイル基であり、特に好適にはアセチル基である。 In the above, “C ₁ -C ₆ alkanoyl” in the definition of R ¹⁰ is, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl, isovaleryl or hexanoyl. A straight-chain or branched alkanoyl group having 1 to 6 carbon atoms, such as a group, preferably a C ₁ -C ₄ alkanoyl group, and particularly preferably an acetyl group.

上記に於いて、Ｒ¹⁰の定義に於ける「保護された水酸基で置換されたＣ₂−Ｃ₆アルカノイル基」の「Ｃ₂−Ｃ₆アルカノイル基」部分は、上記「Ｃ₁−Ｃ₆アルカノイル基」に於いて、炭素数２乃至６個の直鎖又は分枝鎖のアルカノイル基であり、好適にはＣ₂−Ｃ₄アルカノイル基であり、更に好適にはアセチル基である。 In the above, "C ₂ -C ₆ alkanoyl group" portion of the at "substituted with a protected hydroxy group the C ₂ -C ₆ alkanoyl group" in the definition of R ¹⁰ is the "C ₁ -C ₆ alkanoyl In the “group”, it is a straight chain or branched alkanoyl group having 2 to 6 carbon atoms, preferably a C ₂ -C ₄ alkanoyl group, and more preferably an acetyl group.

上記に於いて、Ｒ¹¹の定義に於ける「Ｃ₁−Ｃ₆アルキル基」は、例えば、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓ−ブチル基、ｔ−ブチル基、ペンチル基、イソペンチル基、２−メチルブチル基、ネオペンチル基、１−エチルプロピル基、ヘキシル基、４−メチルペンチル基、３−メチルペンチル基、２−メチルペンチル基、１−メチルペンチル基、３，３−ジメチルブチル基、２，２−ジメチルブチル基、１，１−ジメチルブチル基、１，２−ジメチルブチル基、１，３−ジメチルブチル基、２，３−ジメチルブチル基又は２−エチルブチル基のような、炭素数１乃至６個の直鎖又は分枝鎖アルキル基であり得、好適にはＣ₁−Ｃ₄アルキル基であり、更に好適にはメチル基又はエチル基であり、特に好適にはエチル基である。 In the above, the “C ₁ -C ₆ alkyl group” in the definition of R ¹¹ is, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, t- Butyl group, pentyl group, isopentyl group, 2-methylbutyl group, neopentyl group, 1-ethylpropyl group, hexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group or 2- such as ethylbutyl group which may be straight or branched chain alkyl group having 1 to 6 carbon atoms, preferably a C ₁ -C ₄ alkyl group, more preferably a methyl group or an ethyl group, Particularly preferred is an ethyl group.

上記に於いて、Ｘの定義に於ける「ハロゲン原子」は、例えば、弗素原子、塩素原子、臭素原子又は沃素原子である。 In the above, the “halogen atom” in the definition of X is, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

Ａ法は、一般式（Ｉ）を有する化合物を製造する方法である。 Method A is a method for producing a compound having the general formula (I).

第Ａ１工程は、一般式（Ｖ）を有する化合物を製造する工程であり、一般式（ＩＩＩ）を有する化合物を、不活性溶媒中、ホスフィン類及びアゾ化合物存在下、一般式（ＩＶ）を有する化合物と縮合させることにより達成される。 Step A1 is a step of producing a compound having the general formula (V). The compound having the general formula (III) has the general formula (IV) in the presence of a phosphine and an azo compound in an inert solvent. This is accomplished by condensation with a compound.

使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えばヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジクロロメタン、クロロホルム、四塩化炭素、ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；或はジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類であり得、好適には脂肪族炭化水素類、芳香族炭化水素類、ハロゲン化炭化水素類又はエーテル類であり、更に好適には、ハロゲン化炭化水素類（ジクロロメタン）或いはエーテル類（特にジエチルエーテル又はテトラヒドロフラン）である。
使用されるホスフィン類は、例えば、トリメチルホスフィン、トリエチルホスフィン、トリプロピルホスフィン、トリブチルホスフィン、トリペンチルホスフィン又はトリヘキシルホスフィン等のトリＣ₁−Ｃ₆アルキルホスフィン；トリフェニルホスフィン、トリインデニルホスフィン又はトリナフチルホスフィン等のトリＣ₆−Ｃ₁₀アリールホスフィン；或はトリルジフェニルホスフィン、トリトリルホスフィン、トリメシチルホスフィン、トリブチルフェニルホスフィン又はトリ−６−エチル−２−ナフチルホスフィン等の、Ｃ₁−Ｃ₄アルキルを置換基として有してもよいトリＣ₆−Ｃ₁₀アリールホスフィンであり得、好適にはトリＣ₁−Ｃ₆アルキルホスフィン類（特にトリメチルホスフィン、トリエチルホスフィン、トリプロピルホスフィン又はトリブチルホスフィン、）又はトリＣ₆−Ｃ₁₀アリールホスフィン（特にトリフェニルホスフィン、トリインデニルホスフィン又はトリナフチルホスフィン）であり、更に好適には、トリブチルホスフィン又はトリフェニルホスフィンである。
使用されるアゾ化合物は、例えば、アゾジカルボニルジピペリジン或いはアゾジカルボン酸ジメチル、アゾジカルボン酸ジエチル、アゾジカルボン酸ジプロピル又はアゾジカルボン酸ジブチルのようなアゾジカルボン酸ジ−Ｃ₁−Ｃ₄アルキルであり得、好適には、アゾジカルボニルジピペリジン、アゾジカルボン酸ジメチル又はアゾジカルボン酸ジエチルである。
反応温度は原料化合物、試薬等によって変化するが、通常−５０℃乃至１００℃であり、好適には０℃乃至６０℃である。
反応時間は原料化合物、試薬、反応温度によって変化するが、通常５分乃至２４時間であり、好適には１０分乃至６時間である。
反応終了後、本工程の目的化合物は、常法に従って反応混合物から採取される。例えば、反応終了後、不溶物が存在する場合にはそれをろ去し、溶媒を留去することにより、或いは、反応終了後、溶媒を留去し、得られる残渣に水を注ぎ、水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル等）を加え抽出した後、抽出液を水洗し、有機層を無水硫酸マグネシウム等で乾燥させた後、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱又はクロマトグラフィー等によって更に精製できる。 The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; benzene, toluene or Aromatic hydrocarbons such as xylene; Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; or diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether Ethers, preferably aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons or ethers, more preferably halogenated hydrocarbons (dichloromethane) or ethers Kind (special Diethyl ether or tetrahydrofuran).
The phosphines used are, for example, tri-C ₁ -C ₆ alkyl phosphines such as trimethylphosphine, triethylphosphine, tripropylphosphine, tributylphosphine, tripentylphosphine or trihexylphosphine; triphenylphosphine, triindenylphosphine or triphenylphosphine. tri C ₆ -C ₁₀ arylphosphine such as naphthyl phosphine; or tolyl diphenyl phosphine, tritolylphosphine, trimesitylphosphine phosphine, such tributyl triphenylphosphine or tri-6-ethyl-2-naphthyl phosphine, C ₁ -C ₄ alkyl the can be a good tri C ₆ -C ₁₀ arylphosphine which may have a substituent, preferably tri C ₁ -C ₆ alkyl phosphines (especially trimethylphosphine, triethylphosphine, tri-propyl Sufin or tributylphosphine) is or tri C ₆ -C ₁₀ arylphosphine (particularly triphenylphosphine, tri indenyl phosphine or trinaphthylphosphine), more preferably a tributylphosphine or triphenylphosphine.
Azo compounds used are, for example, azodicarbonyldipiperidine or azodicarboxylic acid dimethyl, diethyl azodicarboxylate, be azodicarboxylate di -C ₁ -C ₄ alkyl such as azodicarboxylate dipropyl or azodicarboxylic dibutyl Preferred is azodicarbonyldipiperidine, dimethyl azodicarboxylate or diethyl azodicarboxylate.
While the reaction temperature varies depending on the raw material compound, reagent and the like, it is generally −50 ° C. to 100 ° C., preferably 0 ° C. to 60 ° C.
While the reaction time varies depending on the raw material compound, reagent, and reaction temperature, it is generally 5 minutes to 24 hours, preferably 10 minutes to 6 hours.
After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, if insoluble matter is present, it is filtered off and the solvent is distilled off, or after the reaction is completed, the solvent is distilled off, and water is poured into the resulting residue. Extraction is performed by adding an immiscible solvent (for example, benzene, ether, ethyl acetate, etc.), the extract is washed with water, the organic layer is dried over anhydrous magnesium sulfate, and the solvent is distilled off to obtain the target compound. . If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

第Ａ２工程は、一般式（Ｉ）を有する化合物を製造する工程であり、
（ａ）シアノ基をアミジノ基へと変換させる反応、
（ｂ）保護されたアミノ基の保護基を除去する反応、
（ｃ）アミノ基のアセトイミドイル化反応、
所望により、
（ｄ）エステルの加水分解反応、
（ｅ）保護された水酸基の保護基を除去する反応
を、適宜順序を変えて、組み合わせることにより達成される。 Step A2 is a step of producing a compound having the general formula (I),
(A) a reaction for converting a cyano group into an amidino group,
(B) a reaction to remove the protecting group of the protected amino group,
(C) Acetimidylation reaction of amino group,
If desired
(D) ester hydrolysis reaction,
(E) The reaction for removing the protecting group of the protected hydroxyl group can be achieved by combining the reactions in appropriate order.

必須の反応（ａ）である「シアノ基をアミジノ基へと変換させる反応」は、一般にこの分野の技術に於て周知の方法に従い、
（１）原料化合物を、不活性溶媒中又は溶媒不存在下（好適には不活性溶媒中）、酸存在下、アルコール類と反応させ、中間体として生じるイミノエーテル化合物をアンモノリシスさせるか、又は、
（２）原料化合物を、不活性溶媒中、塩基存在下又は不存在下、ヒドロキシルアミンと反応させ、中間体として生じるアミドオキシム化合物を加水素分解することにより達成される。 The essential reaction (a) “reaction for converting a cyano group into an amidino group” is generally performed according to a method well known in the art of this field.
(1) The raw material compound is reacted with an alcohol in an inert solvent or in the absence of a solvent (preferably in an inert solvent) in the presence of an acid, and the resulting imino ether compound is subjected to ammonolysis, or
(2) It is achieved by reacting a raw material compound with hydroxylamine in an inert solvent in the presence or absence of a base, and hydrogenolysis of the resulting amide oxime compound.

反応（ａ）（１）は２段階からなる反応である。先ず、第１段階は、酸の存在下、ニトリル基をアルコールと反応させ、イミノエーテル化合物を得る反応である。
使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ヘキサン、シクロヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジクロロメタン、クロロホルム、四塩化炭素、１，２−ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類；アセトン又はメチルエチルケトンのようなケトン類；酢酸メチル又は酢酸エチルのようなエステル類；ニトロメタンのようなニトロ化合物類；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又はＮ−メチル−２−ピロリジノンのようなアミド類；ジメチルスルホキシド又はスルホランのようなスルホキシド類；或は上記有機溶媒の混合溶媒であり得、好適には、芳香族炭化水素類（特にベンゼン）又はハロゲン化炭化水素類（特にジクロロメタンであり、特に好適にはハロゲン化炭化水素類（特にジクロロメタン）である。
また、本反応は、溶媒も兼ねて、過剰のアルコール類中（例えば、メタノール、エタノール、プロパノール、２−プロパノール、ブタノール又はイソブタノール等であり得、好適には、メタノール又はエタノールである。）で行うことができ、また、通常、支障がないかぎりアルコール中で反応が行われる。
使用される酸は、例えば、塩化水素、塩酸、臭化水素酸、沃化水素酸、硝酸、過塩素酸、硫酸又は燐酸等の鉱酸；メタンスルホン酸、トリフルオロメタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸又はｐ−トルエンスルホン酸のようなスルホン酸；或は、三弗化ホウ素、塩化アルミニウム、塩化鉄（ＩＩＩ）、塩化亜鉛、塩化水銀（ＩＩ）等のルイス酸であり得、好適には鉱酸又はルイス酸であり、特に好適には塩化水素である。
反応温度は、原料化合物、試薬等によって異なるが、通常−１０℃乃至１００℃であり、好適には０℃乃至５０℃である。
反応時間は、原料化合物、試薬、反応温度によって異なるが、通常１０分間乃至４８時間であり、好適には１時間乃至１５時間である。
反応終了後、本反応の目的化合物は、常法（例えば、溶媒を留去する方法）に従って反応混合物から採取されるが、特に単離・精製することなく次の反応に用いることもできる。 Reaction (a) (1) is a reaction consisting of two stages. First, the first stage is a reaction for reacting a nitrile group with an alcohol in the presence of an acid to obtain an imino ether compound.
The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin or petroleum ether; benzene Aromatic hydrocarbons such as toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, Ethers such as dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone or methyl ethyl ketone; esters such as methyl acetate or ethyl acetate; nitro compounds such as nitromethane; formamide, N Amides such as N-dimethylformamide, N, N-dimethylacetamide or N-methyl-2-pyrrolidinone; sulfoxides such as dimethyl sulfoxide or sulfolane; or a mixed solvent of the above organic solvents, preferably Aromatic hydrocarbons (particularly benzene) or halogenated hydrocarbons (particularly dichloromethane), particularly preferably halogenated hydrocarbons (particularly dichloromethane).
In addition, this reaction also serves as a solvent and is in an excess of alcohols (for example, methanol, ethanol, propanol, 2-propanol, butanol, isobutanol, etc., preferably methanol or ethanol). In general, the reaction is carried out in alcohol as long as there is no hindrance.
The acid used is, for example, a mineral acid such as hydrogen chloride, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, A sulfonic acid such as benzene sulfonic acid or p-toluene sulfonic acid; or a Lewis acid such as boron trifluoride, aluminum chloride, iron (III) chloride, zinc chloride, mercury (II) chloride, preferably Is a mineral acid or Lewis acid, particularly preferably hydrogen chloride.
While the reaction temperature varies depending on the raw material compound, reagent and the like, it is generally −10 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C.
While the reaction time varies depending on the raw material compound, reagent, and reaction temperature, it is generally 10 minutes to 48 hours, preferably 1 hour to 15 hours.
After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method (for example, a method of distilling off the solvent), but can also be used in the next reaction without being isolated or purified.

反応（ａ）（１）の第２段階は、第１段階で生成したイミノエーテル化合物を、加アンモニア分解させる反応である。この反応は、通常、不活性溶媒中、アンモニウムイオンの存在下に行われる。
使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、メタノール、エタノール、プロパノール、２−プロパノール、ブタノール又はイソブタノールのようなアルコール類；水；或いはアルコール類と水の混合溶媒であり得、好適には、メタノール、エタノール、水、含水メタノール又は含水エタノールであり、特に好適には、含水メタノール又は含水エタノールである。
使用されるアンモニウムイオンのアンモニウム源としては、例えば、アンモニア水、塩化アンモニウム、炭酸アンモニウム又はそれらの混合物であり得、好適には、塩化アンモニウムである。
反応に於けるｐＨは、中性乃至弱塩基性であり、好適には、アンモニア水及び塩酸を用いて、ｐＨ７乃至９である。
反応温度は、原料化合物、試薬等によって異なるが、通常−１０℃乃至１００℃であり、好適には０℃乃至５０℃である。
反応時間は、原料化合物、試薬、反応温度によって異なるが、通常１０分間乃至４８時間であり、好適には１時間乃至１５時間である。
反応終了後、本反応の目的化合物は、常法に従って反応混合物から採取される。例えば、反応終了後、溶媒を留去することにより、或は、反応終了後、反応液に水を加え、水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル等）を加えて目的化合物を抽出した後、抽出した有機層を水洗し、無水硫酸マグネシウム等を用いて乾燥させた後、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱、クロマトグラフィーにより更に精製できる。 The second stage of the reaction (a) (1) is a reaction in which the imino ether compound produced in the first stage is subjected to ammonia decomposition. This reaction is usually performed in an inert solvent in the presence of ammonium ions.
The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, alcohols such as methanol, ethanol, propanol, 2-propanol, butanol or isobutanol; Water; or a mixed solvent of alcohols and water, preferably methanol, ethanol, water, water-containing methanol or water-containing ethanol, particularly preferably water-containing methanol or water-containing ethanol.
The ammonium source used may be, for example, aqueous ammonia, ammonium chloride, ammonium carbonate, or a mixture thereof, and is preferably ammonium chloride.
The pH in the reaction is neutral to weakly basic, and preferably 7 to 9 using aqueous ammonia and hydrochloric acid.
While the reaction temperature varies depending on the raw material compound, reagent and the like, it is generally −10 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C.
While the reaction time varies depending on the raw material compound, reagent, and reaction temperature, it is generally 10 minutes to 48 hours, preferably 1 hour to 15 hours.
After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, by distilling off the solvent after completion of the reaction, or after completion of the reaction, water is added to the reaction solution, and a solvent immiscible with water (eg benzene, ether, ethyl acetate, etc.) is added to extract the target compound. After that, the extracted organic layer is washed with water, dried using anhydrous magnesium sulfate and the like, and then the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

反応（ａ）（２）は２段階からなる反応である。先ず、第１段階は、不活性溶媒中、所望に応じて塩基存在下、ニトリル基をヒドロキシルアミンと反応させ、アミドオキシム化合物を得る反応である。
使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ヘキサン、シクロヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジクロロメタン、クロロホルム、四塩化炭素、１，２−ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類；アセトン又はメチルエチルケトンのようなケトン類；ニトロメタンのようなニトロ化合物類；アセトニトリル又はイソブチロニトリルのようなニトリル類；メタノール、エタノール、プロパノール、２−プロパノール、ブタノール又はイソブタノールのようなアルコール類；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又はＮ−メチル−２−ピロリジノンのようなアミド類；ジメチルスルホキシド又はスルホランのようなスルホキシド類；或いは水であり得、好適には、アルコール類（特にメタノール又はエタノール）である。
使用されるヒドロキシルアミンの供給源としては、ヒドロキシルアミンの水溶液、有機溶媒の溶液又は酸との塩を挙げることができる。
使用される塩基は、ヒドロキシルアミンの酸との塩を使用する場合に、それを中和し得るものであれば特に限定はないが（また、ヒドロキシルアミンの溶液を直接用いる場合は、必ずしも必要としない。）、例えば、炭酸ナトリウム、炭酸カリウム又は炭酸リチウムのようなアルカリ金属炭酸塩類；炭酸水素ナトリウム、炭酸水素カリウム又は炭酸水素リチウムのようなアルカリ金属重炭酸塩類；酢酸ナトリウムのようなアルカリ金属酢酸塩類；水酸化ナトリウム、水酸化カリウム又は水酸化リチウムのようなアルカリ金属水酸化物類；ナトリウムメトキシド、ナトリウムエトキシド、カリウムｔ−ブトキシド又はリチウムメトキシドのようなアルカリ金属アルコキシド類；或いは、トリエチルアミン、トリブチルアミン、ジイソプロピルエチルアミン、Ｎ−メチルモルホリン、ピリジン、４−（Ｎ，Ｎ−ジメチルアミノ）ピリジン、Ｎ，Ｎ−ジメチルアニリン、Ｎ，Ｎ−ジエチルアニリン、１，５−ジアザビシクロ［４．３．０］ノナ−５−エン、１，４−ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ）又は１，８−ジアザビシクロ［５．４．０］ウンデク−７−エン（ＤＢＵ）のような有機塩基類であり得、好適には、アルカリ金属炭酸塩類（特に炭酸ナトリウム）又はアルカリ金属アルコキシド類（特にカリウムｔ−ブトキシド）である。
反応温度は、原料化合物、試薬等によって異なるが、通常０℃乃至１５０℃であり、好適には５０℃乃至１００℃である。
反応時間は、原料化合物、試薬、反応温度によって異なるが、通常、１時間乃至２４時間であり、好適には５時間乃至１２時間である。
反応終了後、本反応の目的化合物は常法（例えば、溶媒を留去する方法）に従って反応混合物から採取されるが、特に単離・精製することなく、次反応に用いることもできる。 Reaction (a) (2) is a reaction consisting of two stages. First, the first stage is a reaction in which an amide oxime compound is obtained by reacting a nitrile group with hydroxylamine in an inert solvent in the presence of a base as desired.
The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin or petroleum ether; benzene Aromatic hydrocarbons such as toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, Ethers such as dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone or methyl ethyl ketone; nitro compounds such as nitromethane; nitriles such as acetonitrile or isobutyronitrile; Alcohols such as ethanol, propanol, 2-propanol, butanol or isobutanol; amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide or N-methyl-2-pyrrolidinone; Sulfoxides such as dimethyl sulfoxide or sulfolane; or water, preferably alcohols (especially methanol or ethanol).
The source of hydroxylamine used can include an aqueous solution of hydroxylamine, a solution of an organic solvent, or a salt with an acid.
The base used is not particularly limited as long as it can neutralize a salt of hydroxylamine with an acid (and is not necessarily required when a solution of hydroxylamine is used directly). For example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; alkali metal acetic acid such as sodium acetate Salts; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; or triethylamine , Tributylamine, diisopropyl ether Ruamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] nona-5 Organic bases such as -ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU); Preferred are alkali metal carbonates (particularly sodium carbonate) or alkali metal alkoxides (particularly potassium t-butoxide).
While the reaction temperature varies depending on the raw material compound, reagent and the like, it is generally 0 ° C. to 150 ° C., preferably 50 ° C. to 100 ° C.
While the reaction time varies depending on the raw material compound, reagent, and reaction temperature, it is generally 1 hour to 24 hours, preferably 5 hours to 12 hours.
After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method (for example, a method of distilling off the solvent).

反応（ａ）（２）の第２段階は、第１段階で生成したアミドオキシム化合物を加水素分解する反応である。
通常、加水素分解に先立ち、水酸基を脱離性の基で修飾するが、簡便にアセチル基が常用される。アセチル化は、通常、酢酸中、無水酢酸を用いて行われるが、必要に応じて溶媒中で行うこともできる。
アセチル化に使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ヘキサン、シクロヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジクロロメタン、クロロホルム、四塩化炭素、１，２−ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類；アセトン又はメチルエチルケトンのようなケトン類；ニトロメタンのようなニトロ化合物類；或いは、アセトニトリル又はイソブチロニトリルのようなニトリル類であり得、好適には、ハロゲン化炭化水素類（特にジクロロメタン）又はエーテル類（特にテトラヒドロフラン）である。
アセチル化の反応温度は、原料化合物、試薬等によって異なるが、通常０℃乃至１５０℃であり、好適には１０℃乃至５０℃である。
アセチル化の反応時間は、原料化合物、試薬、反応温度によって異なるが、通常、１時間乃至２４時間であり、好適には５時間乃至１２時間である。
反応終了後、本反応の目的化合物は常法（例えば、反応終了後、溶媒を留去する方法）に従って反応混合物から採取されるが、特に単離・生成することなく次の反応に用いることもできる。 The second stage of the reaction (a) (2) is a reaction for hydrogenolysis of the amide oxime compound produced in the first stage.
Usually, prior to hydrogenolysis, the hydroxyl group is modified with a leaving group, but an acetyl group is commonly used for convenience. Acetylation is usually carried out in acetic acid using acetic anhydride, but can also be carried out in a solvent if necessary.
The solvent used for the acetylation is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, an aliphatic hydrocarbon such as hexane, cyclohexane, heptane, ligroin or petroleum ether. Aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran Ethers such as dioxane, dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone or methyl ethyl ketone; nitro compounds such as nitromethane; or acetonitrile or isobutyronitrile. Obtained is a nitrile, preferably a halogenated hydrocarbon (particularly dichloromethane) or an ether (particularly tetrahydrofuran).
The reaction temperature for acetylation varies depending on the raw material compounds, reagents and the like, but is usually 0 ° C. to 150 ° C., preferably 10 ° C. to 50 ° C.
The reaction time for acetylation varies depending on the raw material compound, the reagent, and the reaction temperature, but is usually 1 to 24 hours, preferably 5 to 12 hours.
After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method (for example, a method of distilling off the solvent after completion of the reaction), but it can also be used in the next reaction without isolation or formation. it can.

アミドオキシム化合物の加水素分解（水酸基をアセチル化した場合は、脱アセトキシ化）は、通常、反応溶媒を変えず、引き続いて行われる。また、所望により、一度、溶媒を留去し、得られる残渣を再度、不活性溶媒に溶解させ行うこともできる。
使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ヘキサン、シクロヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジクロロメタン、クロロホルム、四塩化炭素、１，２−ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類；アセトン又はメチルエチルケトンのようなケトン類；ニトロメタンのようなニトロ化合物類；アセトニトリル又はイソブチロニトリルのようなニトリル類；メタノール、エタノール、プロパノール、２−プロパノール、ブタノール又はイソブタノールのようなアルコール類；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又はＮ−メチル−２−ピロリジノンのようなアミド類；ジメチルスルホキシド又はスルホランのようなスルホキシド類；蟻酸又は酢酸のようなカルボン酸類；水；或いは、上記溶媒の混合溶媒であり得、好適には、アルコール類（特にメタノール又はエタノール）、酢酸、或いはそれらの混合溶媒である。
加水素分解に於て使用される触媒は、通常の接触還元反応に使用されるものであれば、特に限定はないが、例えば、パラジウム黒、パラジウム−炭素、水酸化パラジウム、水酸化パラジウム−炭素、ラネーニッケル、ロジウム−酸化アルミニウム、パラジウム−硫酸バリウム、酸化白金又は白金黒であり得、好適には、パラジウム−炭素である。
反応温度は、原料化合物、試薬等によって異なるが、通常−１０℃乃至１００℃であり、好適には０℃乃至８０℃である。
反応時間は、原料化合物、試薬、反応温度によって異なるが、通常、１時間乃至２４時間であり、好適には５時間乃至１２時間である。
反応終了後、本反応の目的化合物は常法に従って反応混合物から採取される。例えば、反応終了後、触媒をろ去した後、溶媒を留去するか、或は、反応終了後、触媒をろ去した後、反応液に水を加え、水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル等）を加えて目的化合物を抽出した後、抽出した有機層を水洗し、無水硫酸マグネシウム等を用いて乾燥させた後、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱、クロマトグラフィーにより更に精製できる。 Hydrogenolysis of the amide oxime compound (deacetoxylation when the hydroxyl group is acetylated) is usually carried out continuously without changing the reaction solvent. If desired, the solvent can be once distilled off, and the resulting residue can be dissolved again in an inert solvent.
The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin or petroleum ether; benzene Aromatic hydrocarbons such as toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, Ethers such as dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone or methyl ethyl ketone; nitro compounds such as nitromethane; nitriles such as acetonitrile or isobutyronitrile; Alcohols such as ethanol, propanol, 2-propanol, butanol or isobutanol; amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide or N-methyl-2-pyrrolidinone; Sulfoxides such as dimethyl sulfoxide or sulfolane; carboxylic acids such as formic acid or acetic acid; water; or a mixed solvent of the above solvents, preferably alcohols (particularly methanol or ethanol), acetic acid, or their It is a mixed solvent.
The catalyst used in the hydrogenolysis is not particularly limited as long as it is used in a normal catalytic reduction reaction. For example, palladium black, palladium-carbon, palladium hydroxide, palladium hydroxide-carbon. Raney nickel, rhodium-aluminum oxide, palladium-barium sulfate, platinum oxide or platinum black, preferably palladium-carbon.
While the reaction temperature varies depending on the raw material compound, reagent and the like, it is generally −10 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.
While the reaction time varies depending on the raw material compound, reagent, and reaction temperature, it is generally 1 hour to 24 hours, preferably 5 hours to 12 hours.
After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the catalyst is filtered off, and then the solvent is distilled off, or after the reaction is completed, the catalyst is filtered off, and then water is added to the reaction solution, and a solvent immiscible with water (eg, benzene, The target compound is extracted by adding ether, ethyl acetate, etc., and then the extracted organic layer is washed with water and dried using anhydrous magnesium sulfate, and then the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

必須の反応（ｂ）である「保護されたアミノ基の保護基を除去する反応」は、一般に有機合成化学の技術において周知の方法に従い、以下の様に実施される。 The essential reaction (b) “reaction for removing the protecting group of the protected amino group” is generally carried out as follows according to a method well known in the art of organic synthetic chemistry.

アミノ基の保護基が、ホルミル基、アセチル基、ベンゾイル基、メトキシカルボニル基、エトキシカルボニル基、ｔ−ブトキシカルボニル基、２−トリメチルシリルエトキシカルボニル基、２−ブロモ−ｔ−ブトキシカルボニル基、２，２−ジブロモ−ｔ−ブトキシカルボニル基、ビニルオキシカルボニル基、ベンジルオキシカルボニル基、（１−フェニル）ベンジルオキシカルボニル基、９−アンスリルメチルオキシカルボニル基、ｐ−メトキシベンジルオキシカルボニル基又はｐ−ニトロベンジルオキシカルボニル基である場合には、不活性溶媒中又は水性溶媒中で酸で処理することにより除去することができる。尚、その際に、目的化合物を塩として得ることもできる。
使用される酸は、例えば、塩酸、硫酸、リン酸、臭化水素酸又はトリフルオロ酢酸であり得、好適には、塩酸、硫酸、臭化水素酸又はトリフルオロ酢酸である。
使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジクロロメタン、クロロホルム、四塩化炭素、ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類；酢酸メチル又は酢酸エチルのようなエステル類；メタノール、エタノール、プロパノール、２−プロパノール又はブタノールのようなアルコール類；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又はヘキサメチルリン酸トリアミドのようなアミド類；ジメチルスルホキシド又はスルホランのようなスルホキシド類；蟻酸又は酢酸のような脂肪酸類；或は水又は水と上記溶媒との混合溶媒を挙げることができるが、好適には、ハロゲン化炭化水素類、エーテル類、アルコール類、脂肪酸類又は水と上記溶媒との混合溶媒であり、さらに好適にはハロゲン化炭化水素類（特にジクロロメタン）、エーテル類（特にテトラヒドロフラン又はジオキサン）、脂肪酸類（特に酢酸）、アルコール類（特にメタノール又はエタノール）、或は、水又は水と上記溶媒との混合溶媒である。
反応温度は、原料化合物、溶媒又は使用される酸によって変化するが、通常−１０℃乃至１５０℃であり、好適には０℃乃至１００℃である。
反応時間は、原料化合物、溶媒又は使用される酸によって変化するが、通常５分乃至４８時間であり、好適には１０分乃至１５時間である。
反応終了後、本反応の目的化合物は常法に従って反応混合物から採取される。例えば、反応液中に析出した目的化合物をろ取するか、必要に応じ、適宜中和して、溶媒を留去し、乾燥させるか、又は、反応液を水に注いだり、必要に応じ適宜中和して、水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル等）を加え抽出し、目的化合物を含む有機層を水洗後、無水硫酸マグネシウム等を用いて乾燥させ、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱又はクロマトグラフィー等によって更に精製できる。 The protecting group of amino group is formyl group, acetyl group, benzoyl group, methoxycarbonyl group, ethoxycarbonyl group, t-butoxycarbonyl group, 2-trimethylsilylethoxycarbonyl group, 2-bromo-t-butoxycarbonyl group, 2,2 -Dibromo-t-butoxycarbonyl group, vinyloxycarbonyl group, benzyloxycarbonyl group, (1-phenyl) benzyloxycarbonyl group, 9-anthrylmethyloxycarbonyl group, p-methoxybenzyloxycarbonyl group or p-nitrobenzyl In the case of an oxycarbonyl group, it can be removed by treatment with an acid in an inert solvent or an aqueous solvent. In this case, the target compound can also be obtained as a salt.
The acid used can be, for example, hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid or trifluoroacetic acid, preferably hydrochloric acid, sulfuric acid, hydrobromic acid or trifluoroacetic acid.
The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; benzene, toluene Or aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether Ethers such as methyl acetate or esters such as ethyl acetate; alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; formamide, N, N-dimethylform Amides such as amide, N, N-dimethylacetamide or hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide or sulfolane; fatty acids such as formic acid or acetic acid; or water or a mixture of water and the above solvent Examples of the solvent include halogenated hydrocarbons, ethers, alcohols, fatty acids or a mixed solvent of water and the above solvent, and more preferable are halogenated hydrocarbons (particularly dichloromethane). ), Ethers (especially tetrahydrofuran or dioxane), fatty acids (especially acetic acid), alcohols (especially methanol or ethanol), or water or a mixed solvent of water and the above solvent.
While the reaction temperature varies depending on the raw material compound, the solvent or the acid used, it is generally −10 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C.
While the reaction time varies depending on the raw material compound, the solvent or the acid used, it is generally 5 min to 48 hr, preferably 10 min to 15 hr.
After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the target compound precipitated in the reaction solution is collected by filtration, or neutralized as necessary, and the solvent is distilled off and dried, or the reaction solution is poured into water as needed. Neutralize, extract by adding a solvent immiscible with water (eg benzene, ether, ethyl acetate, etc.), wash the organic layer containing the target compound with water, dry with anhydrous magnesium sulfate, etc., and evaporate the solvent. This gives the target compound. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

アミノ基の保護基がアルカノイル類、アリールカルボニル類、アルコキシカルボニル類、アルケニルオキシカルボニル類、アリールジカルボニル類、アラルキル類又はアラルキルオキシカルボニル類である場合には、不活性溶媒中又は水性溶媒中で塩基で処理することにより除去することができる。
使用される塩基は、例えば、炭酸ナトリウム、炭酸カリウム又は炭酸リチウムのようなアルカリ金属炭酸塩類；炭酸水素ナトリウム、炭酸水素カリウム又は炭酸水素リチウムのようなアルカリ金属重炭酸塩類；水素化リチウム、水素化ナトリウム又は水素化カリウムのようなアルカリ金属水素化物類；水酸化ナトリウム、水酸化カリウム又は水酸化リチウムのようなアルカリ金属水酸化物類；ナトリウムメトキシド、ナトリウムエトキシド、カリウムｔ−ブトキシド又はリチウムメトキシドのようなアルカリ金属アルコキシド類；メチルメルカプタンナトリウム又はエチルメルカプタンナトリウムのようなメルカプタンアルカリ金属類；ヒドラジン、メチルアミン、ジメチルアミン、エチルアミン、トリエチルアミン、トリブチルアミン、ジイソプロピルエチルアミン、Ｎ−メチルモルホリン、ピリジン、４−（Ｎ，Ｎ−ジメチルアミノ）ピリジン、Ｎ，Ｎ−ジメチルアニリン、Ｎ，Ｎ−ジエチルアニリン、１，５−ジアザビシクロ［４．３．０］ノナ−５−エン、１，４−ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ）又は１，８−ジアザビシクロ［５．４．０］ウンデク−７−エン（ＤＢＵ）のような有機塩基類であり得、好適には、アルカリ金属炭酸塩類（特に炭酸ナトリウム又は炭酸カリウム）、アルカリ金属水酸化物類（特に水酸化ナトリウム又は水酸化カリウム）、アルカリ金属アルコキシド類（特にナトリウムメトキシド、ナトリウムエトキシド又はカリウム−ｔ−ブトキシド）或は有機塩基類（特にヒドラジン又はメチルアミン）である。
使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジクロロメタン、クロロホルム、四塩化炭素、ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類；メタノール、エタノール、プロパノール、２−プロパノール又はブタノールのようなアルコール類；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又はヘキサメチルリン酸トリアミドのようなアミド類；ジメチルスルホキシド又はスルホランのようなスルホキシド類；又は水と上記溶媒との混合溶媒であり得、好適には、ハロゲン化炭化水素類、エーテル類、アルコール類、又は水と上記溶媒との混合溶媒であり、さらに好適にはエーテル類（特にテトラヒドロフラン又はジオキサン）、アルコール類（特にメタノール、エタノール）、又は水と上記溶媒との混合溶媒である。
反応温度は、原料化合物、溶媒又は使用される塩基によって変化するが、通常−１０℃乃至５０℃であり、好適には−５℃乃至１０℃である。
反応時間は、原料化合物、溶媒又は使用される塩基によって変化するが、通常５分間乃至２０時間であり、好適には１０分間乃至３時間である。
反応終了後、本反応の目的化合物は常法に従って反応混合物から採取される。例えば、反応液中に析出した目的化合物をろ取するか、又は必要に応じて酸で中和した後溶媒を留去し、或いは、反応液に水を注ぎ、水層のｐＨを調整して生じた析出物をろ取するか、又は水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル等）を加え抽出し、目的化合物を含む有機層を水洗後、無水硫酸マグネシウム等で乾燥し、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱又はクロマトグラフィー等によって更に精製できる。 When the protecting group of the amino group is alkanoyls, arylcarbonyls, alkoxycarbonyls, alkenyloxycarbonyls, aryldicarbonyls, aralkyls or aralkyloxycarbonyls, a base in an inert solvent or an aqueous solvent It can be removed by processing.
Bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; lithium hydride, hydrogenated Alkali metal hydrides such as sodium or potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxy Alkali metal alkoxides such as methyl mercaptan sodium or mercaptan alkali metals such as sodium ethyl mercaptan; hydrazine, methylamine, dimethylamine, ethylamine, triethylamine, tributylamine, dialkyl Sopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] nona Organic bases such as -5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) Preferably, alkali metal carbonates (especially sodium carbonate or potassium carbonate), alkali metal hydroxides (especially sodium hydroxide or potassium hydroxide), alkali metal alkoxides (especially sodium methoxide, sodium ethoxide or Potassium-t-butoxide) or organic bases (especially hydrazine or methylamine).
The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; benzene, toluene Or aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether Such ethers; alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; formamide, N, N-dimethylformamide, N, N-dimethylacetamide or Amides such as samethyl phosphate triamide; sulfoxides such as dimethyl sulfoxide or sulfolane; or a mixed solvent of water and the above solvent, preferably halogenated hydrocarbons, ethers, alcohols, or water And a mixed solvent of water and the above solvent, more preferably ethers (particularly tetrahydrofuran or dioxane), alcohols (particularly methanol, ethanol), or a mixed solvent of water and the above solvent.
While the reaction temperature varies depending on the raw material compound, the solvent or the base used, it is generally −10 ° C. to 50 ° C., preferably −5 ° C. to 10 ° C.
While the reaction time varies depending on the raw material compound, the solvent or the base used, it is generally 5 minutes to 20 hours, preferably 10 minutes to 3 hours.
After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the target compound precipitated in the reaction solution is collected by filtration, or neutralized with an acid as necessary, and then the solvent is distilled off, or water is poured into the reaction solution, and the pH of the aqueous layer is adjusted. The resulting precipitate is filtered or extracted by adding a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.), and the organic layer containing the target compound is washed with water and dried over anhydrous magnesium sulfate. Is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

尚、アミノ基の保護基がｔ−ブトキシカルボニル基の場合には、特に不活性溶媒中で、シリル化合物又はルイス酸と処理することによっても除去することもできる。
使用されるシリル化合物としては、例えば、トリメチルシリルクロリド、トリメチルシリルイオダイド又はトリメチルシリルトリフルオロメタンスルホネートを挙げることができ、使用されるルイス酸としては、例えば塩化アルミニウム等を挙げることができる。
使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ジクロロメタン、クロロホルム又は四塩化炭素のようなハロゲン化炭化水素類；ジエチルエ−テル、テトラヒドロフラン又はジオキサンのようなエ−テル類；或いは、アセトニトリルのようなニトリル類であり得、好適には、ハロゲン化炭化水素類（特にジクロロメタン又はクロロホルム）或いはニトリル類（特にアセトニトリル）である。
反応温度は、原料化合物、試薬又は溶媒等によって変化するが、通常−２０℃乃至１００℃であり、好適には０℃乃至５０℃である。
反応時間は、原料化合物、試薬、溶媒又は反応温度等によって変化するが、通常１０分乃至１０時間であり、好適には３０分乃至３時間である。
反応終了後、本反応の目的化合物は常法に従って反応混合物から採取される。例えば、溶媒を留去し、反応液に水を注ぎ、水層をアルカリ性にして析出物をろ取するか、又は水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル等）を加え抽出し、目的化合物を含む有機層を水洗後、無水硫酸マグネシウム等で乾燥し、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱又はクロマトグラフィー等によって更に精製できる。 When the amino-protecting group is a t-butoxycarbonyl group, it can also be removed by treatment with a silyl compound or a Lewis acid, particularly in an inert solvent.
Examples of the silyl compound used include trimethylsilyl chloride, trimethylsilyl iodide, and trimethylsilyl trifluoromethanesulfonate. Examples of the Lewis acid used include aluminum chloride.
The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, halogenated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride; diethyl ether, Ethers such as tetrahydrofuran or dioxane; or nitriles such as acetonitrile, preferably halogenated hydrocarbons (especially dichloromethane or chloroform) or nitriles (especially acetonitrile).
While the reaction temperature varies depending on the raw material compound, reagent, solvent, etc., it is generally −20 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C.
While the reaction time varies depending on the raw material compound, reagent, solvent, reaction temperature and the like, it is usually 10 minutes to 10 hours, preferably 30 minutes to 3 hours.
After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the solvent is distilled off, water is poured into the reaction solution, the aqueous layer is made alkaline and the precipitate is collected by filtration, or extracted with a solvent immiscible with water (eg benzene, ether, ethyl acetate, etc.), The organic layer containing the target compound is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

尚、アミノ基の保護基がアリルオキシカルボニル基の場合は、特に、アラルキル基等の場合の接触還元反応による除去方法と同様に除去することができる。即ちパラジウム、及びトリフェニルホスフィン又はニッケルテトラカルボニルを使用して除去することができる。 When the amino-protecting group is an allyloxycarbonyl group, it can be removed in the same manner as in the removal method using a catalytic reduction reaction in the case of an aralkyl group or the like. That is, it can be removed using palladium and triphenylphosphine or nickel tetracarbonyl.

アミノ基の保護基が、アラルキル基又はＣ₇−Ｃ₁₁アラルキルオキシカルボニル基である場合には、通常、不活性溶媒中で、還元剤と接触（好適には、触媒存在下に接触還元）させることにより除去する方法又は酸化剤を用いて除去する方法を挙げることができる。
接触還元による保護基の除去反応の場合に於て、使用される溶媒は、本反応に関与しないものであれば特に限定はないが、例えば、ヘキサン又はシクロヘキサンのような脂肪族炭化水素類；トルエン、ベンゼン又はキシレンのような芳香族炭化水素類；ジエチルエーテル、テトラヒドロフラン又はジオキサンのようなエーテル類；酢酸エチル又は酢酸プロピルのようなエステル類；メタノール、エタノール又は２−プロパノールのようなアルコール類；蟻酸又は酢酸のような脂肪酸類；或いは、これらの有機溶媒と水との混合溶媒であり得、好適には、脂肪族炭化水素類、芳香族炭化水素類、エーテル類、エステル類、アルコール類、脂肪酸類又はこれらの有機溶媒と水との混合溶媒であり、更に好適には、アルコール類（特にメタノール又はエタノール）、脂肪酸類（特に蟻酸又は酢酸）或いはこれらの有機溶媒と水との混合溶媒である。
使用される触媒は、通常の接触還元反応に使用されるものであれば、特に限定はないが、例えば、パラジウム−炭素、ラネ−ニッケル、ロジウム−酸化アルミニウム又はパラジウム−硫酸バリウムを挙げることができるが、好適には、パラジウム−炭素又はラネ−ニッケルである。
圧力は、特に限定はないが、通常１乃至１０気圧で行なわれ、好適には１気圧である。
反応温度は、原料化合物、溶媒又は使用される還元剤等によって変化するが、通常０℃乃至１００℃であり、好適には１０℃乃至５０℃である。
反応時間は、原料化合物、溶媒、使用される還元剤又は反応温度等によって変化するが、通常１５分乃至２４時間であり、好適には３０分乃至１２時間である。
反応終了後、本反応の目的化合物は常法に従って反応混合物から採取される。例えば、触媒をろ去した後溶媒を留去し、反応液に水を注ぎ、水層をアルカリ性にして析出物をろ取するか、又は水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル等）を加え抽出し、目的化合物を含む有機層を水洗後、無水硫酸マグネシウム等で乾燥し、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱又はクロマトグラフィー等によって更に精製できる。 When the amino-protecting group is an aralkyl group or a C ₇ -C ₁₁ aralkyloxycarbonyl group, it is usually contacted with a reducing agent (preferably catalytic reduction in the presence of a catalyst) in an inert solvent. And a method of removing using an oxidizing agent.
In the case of the reaction for removing the protecting group by catalytic reduction, the solvent used is not particularly limited as long as it does not participate in this reaction. For example, aliphatic hydrocarbons such as hexane or cyclohexane; toluene Aromatic hydrocarbons such as benzene or xylene; ethers such as diethyl ether, tetrahydrofuran or dioxane; esters such as ethyl acetate or propyl acetate; alcohols such as methanol, ethanol or 2-propanol; formic acid Or fatty acids such as acetic acid; or a mixed solvent of these organic solvents and water, preferably aliphatic hydrocarbons, aromatic hydrocarbons, ethers, esters, alcohols, fatty acids Or a mixed solvent of these organic solvents and water, and more preferably alcohols (especially methanol or Ethanol), a mixed solvent of fatty acids (particularly formic acid or acetic acid), or these organic solvents and water.
The catalyst used is not particularly limited as long as it is used for a normal catalytic reduction reaction, and examples thereof include palladium-carbon, rane-nickel, rhodium-aluminum oxide, and palladium-barium sulfate. Is preferably palladium-carbon or Raney-nickel.
The pressure is not particularly limited, but is usually 1 to 10 atm, and preferably 1 atm.
While the reaction temperature varies depending on the raw material compound, the solvent, the reducing agent used and the like, it is generally 0 ° C. to 100 ° C., preferably 10 ° C. to 50 ° C.
While the reaction time varies depending on the raw material compound, the solvent, the reducing agent used, the reaction temperature and the like, it is usually 15 minutes to 24 hours, preferably 30 minutes to 12 hours.
After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the catalyst is removed by filtration, the solvent is distilled off, water is poured into the reaction solution, the aqueous layer is made alkaline, and the precipitate is collected by filtration, or is immiscible with water (for example, benzene, ether, ethyl acetate, etc.) The organic layer containing the target compound is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

酸化による除去において使用される溶媒は、本反応に関与しないものであれば特に限定はないが、例えば、アセトンのようなケトン類；ジクロロメタン、クロロホルム又は四塩化炭素のようなハロゲン化炭化水素類；アセトニトリルのようなニトリル類；ジエチルエーテル、テトラヒドロフラン又はジオキサンのようなエーテル類；Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド又はヘキサメチルホスホロトリアミドのようなアミド類；ジメチルスルホキシドのようなスルホキシド類；或いは、これらの有機溶媒と水との混合溶媒であり得、好適には、ケトン類、ハロゲン化炭化水素類、ニトリル類、エーテル類、アミド類、スルホキシド類或いはこれらの有機溶媒と水との混合溶媒であり、更に好適には、ケトン類（特にアセトン）、ハロゲン化炭化水素類（特にジクロロメタン）、ニトリル類（特にアセトニトリル）、アミド類（特にヘキサメチルホスホロトリアミド）、スルホキシド類（特にジメチルスルホキシド）或いはこれらの有機溶媒と水との混合溶媒である。
使用される酸化剤は、例えば、過硫酸カリウム、過硫酸ナトリウム、アンモニウムセリウムナイトレイト（ＣＡＮ）又は２，３−ジクロロ−５，６−ジシアノ−ｐ−ベンゾキノン（ＤＤＱ）であり得、好適には、ＣＡＮ又はＤＤＱである。
反応温度は、原料化合物、溶媒又は使用される酸化剤等によって変化するが、通常０℃乃至１５０℃であり、好適には１０℃乃至５０℃である。
反応時間は、化合物、溶媒又は使用される酸化剤等によって変化するが、通常１５分乃至２４時間であり、好適には３０分乃至１２時間である。
反応終了後、本反応の目的化合物は常法に従って反応混合物から採取される。例えば、酸化剤をろ去した後溶媒を留去し、反応液に水を注ぎ、水層をアルカリ性にして析出物をろ取するか、又は水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル等）を加え抽出し、目的化合物を含む有機層を水洗後、無水硫酸マグネシウム等で乾燥し、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱又はクロマトグラフィー等によって更に精製できる。 The solvent used in the removal by oxidation is not particularly limited as long as it does not participate in this reaction. For example, ketones such as acetone; halogenated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride; Nitriles such as acetonitrile; ethers such as diethyl ether, tetrahydrofuran or dioxane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide or hexamethylphosphorotriamide; sulfoxide such as dimethyl sulfoxide Or a mixed solvent of these organic solvents and water, preferably ketones, halogenated hydrocarbons, nitriles, ethers, amides, sulfoxides or organic solvents thereof and water. More preferably, ketones (particularly, SETON), halogenated hydrocarbons (especially dichloromethane), nitriles (especially acetonitrile), amides (especially hexamethylphosphorotriamide), sulfoxides (especially dimethyl sulfoxide) or a mixed solvent of these organic solvents and water. is there.
The oxidizing agent used can be, for example, potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN) or 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), preferably , CAN or DDQ.
While the reaction temperature varies depending on the raw material compound, the solvent, the oxidizing agent used and the like, it is generally 0 ° C. to 150 ° C., preferably 10 ° C. to 50 ° C.
While the reaction time varies depending on the compound, solvent, oxidizing agent used and the like, it is generally 15 min to 24 hr, preferably 30 min to 12 hr.
After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after removing the oxidizing agent by filtration, the solvent is distilled off, water is poured into the reaction solution, the aqueous layer is made alkaline, and the precipitate is collected by filtration, or a solvent immiscible with water (for example, benzene, ether, ethyl acetate). And the like, and the organic layer containing the target compound is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

必須の反応（ｃ）である「アミノ基のアセトイミドイル化」は、原料化合物を、不活性溶媒中、塩基存在下又は不存在下（好適には、塩基存在下）、エチルアセトイミデート又はエチルアセトイミデート塩酸塩（好適にはエチルアセトイミデート塩酸塩）と反応させることにより達成される。
反応（ｃ）で使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ヘキサン、シクロヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジクロロメタン、クロロホルム、四塩化炭素、１，２−ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類；アセトン又はメチルエチルケトンのようなケトン類；ニトロメタンのようなニトロ化合物類；アセトニトリル又はイソブチロニトリルのようなニトリル類；メタノール、エタノール、プロパノール、２−プロパノール、ブタノール又はイソブタノールのようなアルコール類；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又はＮ−メチル−２−ピロリジノンのようなアミド類；或いは、ジメチルスルホキシド又はスルホランのようなスルホキシド類であり得、好適には、アルコール類（特にエタノール）である。
反応（ｃ）で使用される塩基は、例えば、炭酸ナトリウム、炭酸カリウム又は炭酸リチウムのようなアルカリ金属炭酸塩類；炭酸水素ナトリウム、炭酸水素カリウム又は炭酸水素リチウムのようなアルカリ金属重炭酸塩類；水酸化ナトリウム、水酸化カリウム又は水酸化リチウムのようなアルカリ金属水酸化物類；或いは、トリエチルアミン、トリブチルアミン、ジイソプロピルエチルアミン、Ｎ−メチルモルホリン、ピリジン、４−（Ｎ，Ｎ−ジメチルアミノ）ピリジン、Ｎ，Ｎ−ジメチルアニリン、Ｎ，Ｎ−ジエチルアニリン、１，５−ジアザビシクロ［４．３．０］ノナ−５−エン、１，４−ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ）又は１，８−ジアザビシクロ［５．４．０］ウンデク−７−エン（ＤＢＵ）のような有機塩基類であり得、好適には、アルカリ金属炭酸塩類（炭酸ナトリウム又は炭酸カリウム）或いは有機塩基類（特にトリエチルアミン）である。
反応温度は、原料化合物、試薬等によって異なるが、通常−１０℃乃至１００℃であり、好適には０℃乃至５０℃である。
反応時間は、原料化合物、試薬、反応温度によって異なるが、通常１時間乃至４８時間であり、好適には５時間乃至１５時間である。
反応終了後、本反応の目的化合物は常法に従って反応混合物から採取される。例えば、反応終了後、溶媒を留去することにより、或は、反応終了後、反応液に水を加え、水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル等）を加えて目的化合物を抽出した後、抽出した有機層を水洗し、無水硫酸マグネシウム等を用いて乾燥させた後、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱、クロマトグラフィーにより更に精製できる。 The essential reaction (c) “acetoimidoylation of amino group” is a method in which a raw material compound is prepared in an inert solvent in the presence or absence of a base (preferably in the presence of a base), ethylacetimidate or This is accomplished by reacting with ethyl acetimidate hydrochloride (preferably ethyl acetimidate hydrochloride).
The solvent used in the reaction (c) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, an aliphatic such as hexane, cyclohexane, heptane, ligroin or petroleum ether. Hydrocarbons; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether Ethers such as tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone or methyl ethyl ketone; nitro compounds such as nitromethane; nitro compounds such as acetonitrile or isobutyronitrile Alcohols such as methanol, ethanol, propanol, 2-propanol, butanol or isobutanol; amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide or N-methyl-2-pyrrolidinone Or sulfoxides such as dimethyl sulfoxide or sulfolane, preferably alcohols (especially ethanol).
The base used in reaction (c) is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal bicarbonate such as sodium bicarbonate, potassium bicarbonate or lithium bicarbonate; water Alkali metal hydroxides such as sodium oxide, potassium hydroxide or lithium hydroxide; or triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N , N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1, Such as 8-diazabicyclo [5.4.0] undec-7-ene (DBU). Obtained are bases, preferably an alkali metal carbonates (sodium carbonate or potassium carbonate) or organic bases (particularly triethylamine).
While the reaction temperature varies depending on the raw material compound, reagent and the like, it is generally −10 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C.
While the reaction time varies depending on the raw material compound, reagent, and reaction temperature, it is generally 1 hour to 48 hours, preferably 5 hours to 15 hours.
After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, by distilling off the solvent after completion of the reaction, or after completion of the reaction, water is added to the reaction solution, and a solvent immiscible with water (eg benzene, ether, ethyl acetate, etc.) is added to extract the target compound. After that, the extracted organic layer is washed with water, dried using anhydrous magnesium sulfate and the like, and then the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

所望の反応（ｄ）である「エステルの加水分解反応」は、一般に有機合成化学の技術において周知の方法に従い、原料化合物を、不活性溶媒中又は溶媒不存在下、酸又は塩基存在下、加水分解することにより達成されるが、酸による加水分解がより好ましい。
使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、メタノール、エタノール、プロパノール、２−プロパノール、ブタノール又はイソブタノールのようなアルコール類及び水の混合溶媒であり得、好適には含水メタノール又は含水エタノールである。
使用される酸は、例えば、塩酸、臭化水素酸、沃化水素酸、硝酸、過塩素酸、硫酸又は燐酸等の鉱酸；メタンスルホン酸、トリフルオロメタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸又はｐ−トルエンスルホン酸のようなスルホン酸；或は、フマール酸、コハク酸、クエン酸、酒石酸、蓚酸又はマレイン酸等のカルボン酸塩であり得、好適には鉱酸（特に塩酸）である。
使用される塩基は、例えば、炭酸ナトリウム、炭酸カリウム又は炭酸リチウムのようなアルカリ金属炭酸塩類；炭酸水素ナトリウム、炭酸水素カリウム又は炭酸水素リチウムのようなアルカリ金属重炭酸塩類；或は、水酸化ナトリウム、水酸化カリウム又は水酸化リチウムのようなアルカリ金属水酸化物類であり得、好適には水酸化ナトリウムである。
反応温度は、原料化合物、試薬等によって異なるが、酸を用いた反応では、通常、０℃乃至１５０℃（好適には５０℃乃至１００℃）であり、塩基を用いた反応では、通常、−１０℃乃至５０℃（好適には−５℃乃至１０℃）である。
反応時間は、原料化合物、試薬、反応温度によって異なるが、酸を用いた反応では、通常、通常３０分間乃至４８時間（好適には３時間乃至１０時間）であり、塩基を用いた反応では、通常５分間乃至１０時間（好適には１０分間乃至３時間）である。
反応終了後、本工程の目的化合物は常法に従って反応混合物から採取される。例えば、反応終了後、溶媒を留去することにより、或いは、反応終了後、酸（例えば塩酸）を用いて反応液を酸性とし、析出する目的化合物をろ取するか、又は水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル等）を加えて目的化合物を抽出し、抽出した有機層を水洗し、無水硫酸マグネシウム等を用いて乾燥させた後、溶媒を留去することによって目的化合物が得られる。尚、反応終了後、水性溶媒中、炭酸ガスを通じるか或いは炭酸ナトリウム又は炭酸カリウムを加えることにより、目的化合物の炭酸塩を得ることもできる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱、クロマトグラフィーにより更に精製することができる。 The desired reaction (d), “ester hydrolysis reaction” is generally carried out according to a method well known in the art of organic synthetic chemistry, in which a raw material compound is hydrolyzed in an inert solvent or in the absence of a solvent in the presence of an acid or a base. Although it is achieved by decomposing, acid hydrolysis is more preferred.
The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, alcohols such as methanol, ethanol, propanol, 2-propanol, butanol or isobutanol and It can be a mixed solvent of water, and is preferably water-containing methanol or water-containing ethanol.
Examples of the acid used include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid Or a sulfonic acid such as p-toluenesulfonic acid; or a carboxylic acid salt such as fumaric acid, succinic acid, citric acid, tartaric acid, succinic acid or maleic acid, preferably a mineral acid (especially hydrochloric acid). .
Bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; or sodium hydroxide , Alkali metal hydroxides such as potassium hydroxide or lithium hydroxide, preferably sodium hydroxide.
The reaction temperature varies depending on the raw material compound, reagent, and the like, but is usually 0 ° C. to 150 ° C. (preferably 50 ° C. to 100 ° C.) in the reaction using an acid, and usually − It is 10 ° C. to 50 ° C. (preferably −5 ° C. to 10 ° C.).
The reaction time varies depending on the raw material compound, reagent, and reaction temperature, but is usually 30 minutes to 48 hours (preferably 3 hours to 10 hours) in a reaction using an acid, and in a reaction using a base, Usually 5 minutes to 10 hours (preferably 10 minutes to 3 hours).
After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, by distilling off the solvent after completion of the reaction, or after completion of the reaction, the reaction solution is acidified using an acid (for example, hydrochloric acid), and the target compound to be precipitated is collected by filtration or is not miscible with water. (For example, benzene, ether, ethyl acetate, etc.) are added to extract the target compound. The extracted organic layer is washed with water and dried using anhydrous magnesium sulfate, and then the solvent is distilled off to obtain the target compound. It is done. In addition, after completion | finish of reaction, the carbonate of a target compound can also be obtained by passing a carbon dioxide gas or adding sodium carbonate or potassium carbonate in an aqueous solvent. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation, or chromatography.

所望の反応（ｅ）である「保護された水酸基の保護基を除去する反応」は、例えば、プロテクティブ・グループス・イン・オーガニック・シンセシス，第３版，Ｔ．Ｗ．グリーン・アンド・Ｐ．Ｇ．Ｍ．ワッツ, ジョン・ワイリー・アンド・サンズ・インク［Protective Groups in Organic Synthesis, 3rd edition, T.W.Greene & P.G.M.Wuts; John Wiley & Sons,Inc.］に記載される方法に従い行うことができる。 The desired reaction (e) “reaction for removing a protecting group of a protected hydroxyl group” is described in, for example, Protective Groups in Organic Synthesis, 3rd Edition, T.A. W. Green & P. G. M.M. It can be performed according to the method described in Watts, John Wiley & Sons, Inc. [Protective Groups in Organic Synthesis, 3rd edition, T.W.Greene &P.G.M.Wuts; John Wiley & Sons, Inc.].

水酸基の保護基が、ホルミル基、アセチル基、ベンゾイル基、テトラヒドロピラン−２−イル基、３−ブロモテトラヒドロピラン−２−イル基、４−メトキシテトラヒドロピラン−４−イル基、テトラヒドロチオピラン−２−イル基、４−メトキシテトラヒドロチオピラン−４−イル基、テトラヒドロフラン−２−イル基、テトラヒドロチオフラン−２−イル基、メトキシメチル基、１，１−ジメチル−１−メトキシメチル基、エトキシメチル基、プロポキシメチル基、イソプロポキシメチル基、ブトキシメチル基、ｔ−ブトキシメチル基、２−メトキシエトキシメチル基、２，２，２−トリクロロエトキシメチル基、ビス（２−クロロエトキシ）メチル基、１−エトキシエチル基、１−（イソプロポキシ）エチル基、メトキシカルボニル基、エトキシカルボニル基、ｔ−ブトキシカルボニル基、２−トリメチルシリルエトキシカルボニル基、２−ブロモ−ｔ−ブトキシカルボニル基、２，２−ジブロモ−ｔ−ブトキシカルボニル基、ビニルオキシカルボニル基、ベンジルオキシカルボニル基、（１−フェニル）ベンジルオキシカルボニル基、９−アンスリルメチルオキシカルボニル基、ｐ−メトキシベンジルオキシカルボニル基又はｐ−ニトロベンジルオキシカルボニル基である場合には、不活性溶媒中又は水性溶媒中で酸で処理することにより除去することができる。
使用される酸は、例えば、塩酸、硫酸、リン酸、臭化水素酸又はトリフルオロ酢酸のような酸であり得、好適には、塩酸、硫酸、臭化水素酸又はトリフルオロ酢酸である。
使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジクロロメタン、クロロホルム、四塩化炭素、ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類；酢酸メチル又は酢酸エチルのようなエステル類；メタノール、エタノール、プロパノール、２−プロパノール又はブタノールのようなアルコール類；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又はヘキサメチルリン酸トリアミドのようなアミド類；ジメチルスルホキシド又はスルホランのようなスルホキシド類；蟻酸又は酢酸のような脂肪酸類；或は水又は水と上記溶媒との混合溶媒であり得、好適には、ハロゲン化炭化水素類、エーテル類、エステル類、アルコール類、脂肪酸類又は水と上記溶媒との混合溶媒であり、さらに好適にはハロゲン化炭化水素類（特にジクロロメタン）、エーテル類（特にテトラヒドロフラン又はジオキサン）、エステル類（特に酢酸エチル）、脂肪酸類（特に酢酸）或は水又は水と上記溶媒との混合溶媒である。
反応温度は原料化合物、溶媒又は使用される酸によって変化するが、通常−１０℃乃至１５０℃であり、好適には０℃乃至６０℃である。
反応時間は原料化合物、溶媒又は使用される酸によって変化するが、通常５分乃至２０時間であり、好適には１０分乃至１２時間である。
反応終了後、本工程の目的化合物は常法に従って反応混合物から採取される。例えば、反応終了後、反応液を適宜中和し、溶媒を留去し、反応液に水を注ぎ、水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル等）を加え抽出した後、目的化合物を含む有機層を水洗し、無水硫酸マグネシウム等を用いて乾燥させた後、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱又はクロマトグラフィー等によって更に精製できる。 The protective group for hydroxyl group is formyl group, acetyl group, benzoyl group, tetrahydropyran-2-yl group, 3-bromotetrahydropyran-2-yl group, 4-methoxytetrahydropyran-4-yl group, tetrahydrothiopyran-2 -Yl group, 4-methoxytetrahydrothiopyran-4-yl group, tetrahydrofuran-2-yl group, tetrahydrothiofuran-2-yl group, methoxymethyl group, 1,1-dimethyl-1-methoxymethyl group, ethoxymethyl Group, propoxymethyl group, isopropoxymethyl group, butoxymethyl group, t-butoxymethyl group, 2-methoxyethoxymethyl group, 2,2,2-trichloroethoxymethyl group, bis (2-chloroethoxy) methyl group, 1 -Ethoxyethyl group, 1- (isopropoxy) ethyl group, methoxycarbonyl group Ethoxycarbonyl group, t-butoxycarbonyl group, 2-trimethylsilylethoxycarbonyl group, 2-bromo-t-butoxycarbonyl group, 2,2-dibromo-t-butoxycarbonyl group, vinyloxycarbonyl group, benzyloxycarbonyl group, In the case of 1-phenyl) benzyloxycarbonyl group, 9-anthrylmethyloxycarbonyl group, p-methoxybenzyloxycarbonyl group or p-nitrobenzyloxycarbonyl group, an acid is used in an inert solvent or an aqueous solvent. It can be removed by processing.
The acid used can be, for example, an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid or trifluoroacetic acid, preferably hydrochloric acid, sulfuric acid, hydrobromic acid or trifluoroacetic acid.
The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; benzene, toluene Or aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether Ethers such as methyl acetate or esters such as ethyl acetate; alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; formamide, N, N-dimethylform Amides such as amide, N, N-dimethylacetamide or hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide or sulfolane; fatty acids such as formic acid or acetic acid; or water or a mixture of water and the above solvent It can be a solvent, preferably a halogenated hydrocarbon, ether, ester, alcohol, fatty acid or a mixed solvent of water and the above solvent, more preferably a halogenated hydrocarbon (especially dichloromethane). ), Ethers (especially tetrahydrofuran or dioxane), esters (especially ethyl acetate), fatty acids (especially acetic acid), or water or a mixed solvent of water and the above solvent.
While the reaction temperature varies depending on the raw material compound, the solvent or the acid used, it is generally −10 ° C. to 150 ° C., preferably 0 ° C. to 60 ° C.
While the reaction time varies depending on the raw material compound, the solvent or the acid used, it is generally 5 minutes to 20 hours, preferably 10 minutes to 12 hours.
After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the reaction solution is appropriately neutralized, the solvent is distilled off, water is poured into the reaction solution, a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added and extracted, and then the target compound The organic layer containing is washed with water, dried using anhydrous magnesium sulfate and the like, and then the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

水酸基の保護基がアルカノイル類、カルボキシ化アルカノイル類、ハロゲノアルカノイル類、アルコキシアルカノイル類、不飽和アルカノイル類、アリールカルボニル類、ハロゲノアリールカルボニル類、アルキル化アリールカルボニル類、カルボキシ化アリールカルボニル類、ニトロ化アリールカルボニル類、アルコキシカルボニル化アリールカルボニル類又はアリール化アリールカルボニル類である場合には、不活性溶媒中又は水性溶媒中で塩基で処理することにより除去することができる。
使用される塩基は、例えば、炭酸ナトリウム、炭酸カリウム又は炭酸リチウムのようなアルカリ金属炭酸塩類；炭酸水素ナトリウム、炭酸水素カリウム又は炭酸水素リチウムのようなアルカリ金属重炭酸塩類；水素化リチウム、水素化ナトリウム又は水素化カリウムのようなアルカリ金属水素化物類；水酸化ナトリウム、水酸化カリウム又は水酸化リチウムのようなアルカリ金属水酸化物類；ナトリウムメトキシド、ナトリウムエトキシド、カリウムｔ−ブトキシド又はリチウムメトキシドのようなアルカリ金属アルコキシド類；メチルメルカプタンナトリウム又はエチルメルカプタンナトリウムのようなメルカプタンアルカリ金属類；ヒドラジン、メチルアミン、ジメチルアミン、エチルアミン、トリエチルアミン、トリブチルアミン、ジイソプロピルエチルアミン、Ｎ−メチルモルホリン、ピリジン、４−（Ｎ，Ｎ−ジメチルアミノ）ピリジン、Ｎ，Ｎ−ジメチルアニリン、Ｎ，Ｎ−ジエチルアニリン、１，５−ジアザビシクロ［４．３．０］ノナ−５−エン、１，４−ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ）又は１，８−ジアザビシクロ［５．４．０］ウンデク−７−エン（ＤＢＵ）のような有機塩基類であり得、好適には、アルカリ金属炭酸塩類（特に炭酸ナトリウム又は炭酸カリウム）、アルカリ金属水酸化物類（特に水酸化ナトリウム又は水酸化カリウム）、アルカリ金属アルコキシド類（特にナトリウムメトキシド、ナトリウムエトキシド又はカリウム−ｔ−ブトキシド）或は有機塩基類（特にヒドラジン又はメチルアミン）である。
使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジクロロメタン、クロロホルム、四塩化炭素、ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類；メタノール、エタノール、プロパノール、２−プロパノール又はブタノールのようなアルコール類；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又はヘキサメチルリン酸トリアミドのようなアミド類；ジメチルスルホキシド又はスルホランのようなスルホキシド類；又は水と上記溶媒との混合溶媒であり得、好適には、ハロゲン化炭化水素類、エーテル類、アルコール類、又は水と上記溶媒との混合溶媒であり、さらに好適にはエーテル類（特にテトラヒドロフラン又はジオキサン）、アルコール類（特にメタノール、エタノール）、又は水と上記溶媒との混合溶媒である。
反応温度は原料化合物、溶媒又は使用される塩基によって変化するが、通常−１０℃乃至１５０℃であり、好適には０℃乃至５０℃である。
反応時間は原料化合物、溶媒又は使用される塩基によって変化するが、通常５０分間乃至２０時間であり、好適には１０分間乃至５時間である。
反応終了後、本工程の目的化合物は常法に従って反応混合物から採取される。例えば、反応終了後、溶媒を留去し、反応液に水を注いだ後、水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル等）を加え抽出し、目的化合物を含む有機層を水洗した後、無水硫酸マグネシウム等を用いて乾燥させ、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱又はクロマトグラフィー等によって更に精製できる。 Hydroxyl protecting groups are alkanoyls, carboxylated alkanoyls, halogenoalkanoyls, alkoxyalkanoyls, unsaturated alkanoyls, arylcarbonyls, halogenoarylcarbonyls, alkylated arylcarbonyls, carboxylated arylcarbonyls, nitrated aryls In the case of carbonyls, alkoxycarbonylated arylcarbonyls or arylated arylcarbonyls, they can be removed by treatment with a base in an inert solvent or an aqueous solvent.
Bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; lithium hydride, hydrogenated Alkali metal hydrides such as sodium or potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxy Alkali metal alkoxides such as methyl mercaptan sodium or mercaptan alkali metals such as sodium ethyl mercaptan; hydrazine, methylamine, dimethylamine, ethylamine, triethylamine, tributylamine, dialkyl Sopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] nona Organic bases such as -5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) Preferably, alkali metal carbonates (especially sodium carbonate or potassium carbonate), alkali metal hydroxides (especially sodium hydroxide or potassium hydroxide), alkali metal alkoxides (especially sodium methoxide, sodium ethoxide or Potassium-t-butoxide) or organic bases (especially hydrazine or methylamine).
The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; benzene, toluene Or aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether Such ethers; alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; formamide, N, N-dimethylformamide, N, N-dimethylacetamide or Amides such as samethyl phosphate triamide; sulfoxides such as dimethyl sulfoxide or sulfolane; or a mixed solvent of water and the above solvent, preferably halogenated hydrocarbons, ethers, alcohols, or water And a mixed solvent of water and the above solvent, more preferably ethers (particularly tetrahydrofuran or dioxane), alcohols (particularly methanol, ethanol), or a mixed solvent of water and the above solvent.
While the reaction temperature varies depending on the raw material compound, the solvent or the base used, it is generally −10 ° C. to 150 ° C., preferably 0 ° C. to 50 ° C.
While the reaction time varies depending on the raw material compound, the solvent or the base used, it is generally 50 minutes to 20 hours, preferably 10 minutes to 5 hours.
After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, water is poured into the reaction solution, a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added and extracted, and the organic layer containing the target compound is washed with water. Thereafter, the desired compound is obtained by drying using anhydrous magnesium sulfate and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

水酸基の保護基が、アラルキル基又はアラルキルオキシカルボニル基である場合には、通常、不活性溶媒中で、還元剤と接触（好適には、触媒存在下に接触還元）させることにより除去する方法又は酸化剤を用いて除去する方法が好適である。
接触還元による保護基の除去反応の場合において、使用される溶媒は、本反応に関与しないものであれば特に限定はないが、例えば、ヘキサン又はシクロヘキサンのような脂肪族炭化水素類；トルエン、ベンゼン又はキシレンのような芳香族炭化水素類；ジエチルエーテル、テトラヒドロフラン又はジオキサンのようなエーテル類；酢酸エチル又は酢酸プロピルのようなエステル類；メタノール、エタノール又は２−プロパノールのようなアルコール類；蟻酸又は酢酸のような脂肪酸類；或いは、これらの有機溶媒と水との混合溶媒であり得、好適には、脂肪族炭化水素類、芳香族炭化水素類、エーテル類、エステル類、アルコール類、脂肪酸類又はこれらの有機溶媒と水との混合溶媒であり、更に好適には、アルコール類（特にメタノール又はエタノール）、脂肪酸類（特に蟻酸又は酢酸）、又はこれらの有機溶媒と水との混合溶媒である。
使用される触媒は、通常の接触還元反応に使用されるものであれば、特に限定はないが、例えば、パラジウム−炭素、ラネ−ニッケル、ロジウム−酸化アルミニウム又はパラジウム−硫酸バリウムであり得、好適には、パラジウム−炭素又はラネ−ニッケルである。
圧力は、特に限定はないが、通常１乃至１０気圧で行なわれ、好適には１気圧である。
反応温度は、原料化合物、溶媒又は使用される還元剤等によって変化するが、通常０℃乃至１００℃であり、好適には１０℃乃至５０℃である。
反応時間は、原料化合物、溶媒、使用される還元剤又は反応温度等によって変化するが、通常１５分乃至１０時間であり、好適には３０分乃至３時間である。
反応終了後、本工程の目的化合物は常法に従って反応混合物から採取される。例えば、触媒をろ去した後溶媒を留去し、水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル等）を加え抽出し、目的化合物を含む有機層を水洗した後、無水硫酸マグネシウム等を用いて乾燥させ、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱又はクロマトグラフィー等によって更に精製できる。 When the protective group for the hydroxyl group is an aralkyl group or an aralkyloxycarbonyl group, it is usually removed by contact with a reducing agent (preferably catalytic reduction in the presence of a catalyst) in an inert solvent or A removal method using an oxidizing agent is preferred.
In the case of the reaction for removing the protective group by catalytic reduction, the solvent used is not particularly limited as long as it does not participate in this reaction. For example, aliphatic hydrocarbons such as hexane or cyclohexane; toluene, benzene Or aromatic hydrocarbons such as xylene; ethers such as diethyl ether, tetrahydrofuran or dioxane; esters such as ethyl acetate or propyl acetate; alcohols such as methanol, ethanol or 2-propanol; formic acid or acetic acid Or a mixed solvent of these organic solvents and water, preferably aliphatic hydrocarbons, aromatic hydrocarbons, ethers, esters, alcohols, fatty acids or A mixed solvent of these organic solvents and water, more preferably alcohols (especially methanol). Ethanol), fatty acids (particularly formic acid or acetic acid), or a mixed solvent of these organic solvents and water.
The catalyst used is not particularly limited as long as it is used for a normal catalytic reduction reaction, and may be, for example, palladium-carbon, Raney-nickel, rhodium-aluminum oxide or palladium-barium sulfate, and is suitable. Is palladium-carbon or Raney-nickel.
The pressure is not particularly limited, but is usually 1 to 10 atm, and preferably 1 atm.
While the reaction temperature varies depending on the raw material compound, the solvent, the reducing agent used and the like, it is generally 0 ° C. to 100 ° C., preferably 10 ° C. to 50 ° C.
While the reaction time varies depending on the raw material compound, the solvent, the reducing agent used, the reaction temperature and the like, it is usually 15 minutes to 10 hours, preferably 30 minutes to 3 hours.
After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after removing the catalyst by filtration, the solvent is distilled off, a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added and extracted, the organic layer containing the target compound is washed with water, and anhydrous magnesium sulfate is then added. And the target compound is obtained by evaporating the solvent. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

酸化による除去において使用される溶媒は、本反応に関与しないものであれば特に限定はないが、例えば、アセトンのようなケトン類；ジクロロメタン、クロロホルム又は四塩化炭素のようなハロゲン化炭化水素類；アセトニトリルのようなニトリル類；ジエチルエーテル、テトラヒドロフラン又はジオキサンのようなエ−テル類；Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド又はヘキサメチルホスホロトリアミドのようなアミド類；ジメチルスルホキシドのようなスルホキシド類；又はこれらの有機溶媒と水との混合溶媒であり得、好適には、ケトン類、ハロゲン化炭化水素類、ニトリル類、エーテル類、アミド類、スルホキシド類、又はこれらの有機溶媒と水との混合溶媒であり、更に好適には、ケトン類（特にアセトン）、ハロゲン化炭化水素類（特にジクロロメタン）、ニトリル類（特にアセトニトリル）、アミド類（特にヘキサメチルホスホロトリアミド）、スルホキシド類（特にジメチルスルホキシド）又はこれらの有機溶媒と水との混合溶媒である。
使用される酸化剤は、例えば、過硫酸カリウム、過硫酸ナトリウム、アンモニウムセリウムナイトレイト（ＣＡＮ）又は２，３−ジクロロ−５，６−ジシアノ−ｐ−ベンゾキノン（ＤＤＱ）であり得、好適には、ＣＡＮ又はＤＤＱである。
反応温度は原料化合物、溶媒又は使用される酸化剤等によって変化するが、通常０℃乃至１５０℃であり、好適には１０℃乃至５０℃である。
反応時間は化合物、溶媒又は使用される酸化剤等によって変化するが、通常１５分乃至２４時間であり、好適には３０分乃至５時間である。
反応終了後、本工程の目的化合物は常法に従って反応混合物から採取される。例えば、酸化剤をろ去した後溶媒を留去し、水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル等）を加え抽出し、目的化合物を含む有機層を水洗した後、無水硫酸マグネシウム等を用いて乾燥させ、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱又はクロマトグラフィー等によって更に精製できる。 The solvent used in the removal by oxidation is not particularly limited as long as it does not participate in this reaction. For example, ketones such as acetone; halogenated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride; Nitriles such as acetonitrile; ethers such as diethyl ether, tetrahydrofuran or dioxane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide or hexamethylphosphorotriamide; dimethyl sulfoxide Sulfoxides; or a mixed solvent of these organic solvents and water, preferably ketones, halogenated hydrocarbons, nitriles, ethers, amides, sulfoxides, or organic solvents thereof. A mixed solvent with water, more preferably ketones (especially ), Halogenated hydrocarbons (especially dichloromethane), nitriles (especially acetonitrile), amides (especially hexamethylphosphorotriamide), sulfoxides (especially dimethyl sulfoxide) or a mixed solvent of these organic solvents and water. is there.
The oxidizing agent used can be, for example, potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN) or 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), preferably , CAN or DDQ.
While the reaction temperature varies depending on the raw material compound, the solvent, the oxidizing agent used and the like, it is generally 0 ° C. to 150 ° C., preferably 10 ° C. to 50 ° C.
While the reaction time varies depending on the compound, solvent, oxidizing agent used and the like, it is generally 15 min to 24 hr, preferably 30 min to 5 hr.
After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after removing the oxidant by filtration, the solvent is distilled off, a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added and extracted, and the organic layer containing the target compound is washed with water, then anhydrous magnesium sulfate, etc. And the target compound is obtained by distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

水酸基の保護基が、シリル類である場合には、通常、不活性溶媒中で、弗素アニオンを生成する化合物と反応させさせることにより除去する方法が好適である。
使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ヘキサン、シクロヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジクロロメタン、クロロホルム、四塩化炭素、１，２−ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；或は、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類であり得、好適にはエーテル類（好適にはテトラヒドロフラン）である。
使用される弗素アニオンを生成する化合物は、例えば、弗化テトラブチルアンモニウム、弗化水素酸、弗化水素酸−ピリジン又は弗化カリウムであり得、好適には弗化テトラブチルアンモニウムである。
反応温度は原料化合物、試薬等によって異なるが、通常−５０℃乃至１００℃であり、好適には−１０℃乃至５０℃である。
反応時間は原料化合物、試薬、反応温度によって異なるが、通常５分間乃至１２時間であり、好適には１０分間乃至１時間である。
反応終了後、本工程の目的化合物は常法に従って反応混合物から採取される。例えば、反応終了後、反応液に水を加え、水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル等）を加えて目的化合物を抽出した後、抽出した有機層を水洗し、無水硫酸マグネシウム等を用いて乾燥させた後、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱、クロマトグラフィーにより更に精製できる。 When the hydroxyl-protecting group is a silyl compound, a method of removing it by reacting with a compound that generates a fluorine anion in an inert solvent is usually preferred.
The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin or petroleum ether; benzene Aromatic hydrocarbons such as toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; or diethyl ether, diisopropyl ether, tetrahydrofuran , Ethers such as dioxane, dimethoxyethane or diethylene glycol dimethyl ether, preferably ethers (preferably tetrahydrofuran).
The compound that forms the fluorine anion used can be, for example, tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine or potassium fluoride, preferably tetrabutylammonium fluoride.
While the reaction temperature varies depending on the raw material compound, reagent and the like, it is generally −50 ° C. to 100 ° C., preferably −10 ° C. to 50 ° C.
While the reaction time varies depending on the raw material compound, reagent, and reaction temperature, it is generally 5 minutes to 12 hours, preferably 10 minutes to 1 hour.
After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, water is added to the reaction solution, a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and then the extracted organic layer is washed with water, anhydrous magnesium sulfate, etc. Then, the target compound is obtained by distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

Ｂ法は、Ａ法に於ける中間体化合物である、一般式（Ｖａ）、（Ｖｂ）、（Ｖｃ）又は（Ｖｄ）を有する化合物を、別途製造する方法である。 Method B is a method for separately producing a compound having the general formula (Va), (Vb), (Vc) or (Vd), which is an intermediate compound in Method A.

第Ｂ１工程は、化合物（Ｖ）に於いてＲ³が水素原子である、一般式（Ｖａ）を有する化合物を製造する工程であり、一般式（ＶＩ）を有する化合物を、
（１）不活性溶媒中、モレキュラーシーブス（好適には粉末モレキュラーシーブス５Ａ）存在下又は不存在下（好適には存在下）、一般式（ＩＶａ）を有する化合物と縮合させた後、
（２）得られた中間体化合物を、不活性溶媒中、還元剤を用いて還元させることにより達成される。 Step B1 is a step of producing a compound having the general formula (Va) in which R ³ is a hydrogen atom in the compound (V).
(1) After condensation with a compound having the general formula (IVa) in the presence or absence (preferably in the presence) of molecular sieves (preferably powder molecular sieve 5A) in an inert solvent,
(2) This is achieved by reducing the obtained intermediate compound with a reducing agent in an inert solvent.

第Ｂ１（１）工程で使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジクロロメタン、クロロホルム、四塩化炭素、ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類；酢酸メチル又は酢酸エチルのようなエステル類；メタノール、エタノール、プロパノール、２−プロパノール又はブタノールのようなアルコール類；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又はヘキサメチルリン酸トリアミドのようなアミド類；ジメチルスルホキシド又はスルホランのようなスルホキシド類であり得、好適には、ハロゲン化炭化水素類、エーテル類又は芳香族炭化水素類であり、更に好適には、エーテル類又は芳香族炭化水素類であり、より更に好適には、芳香族炭化水素類（特にベンゼン又はトルエン）である。
反応温度は原料化合物、溶媒又は使用される酸によって変化するが、通常０℃乃至１５０℃であり、好適には５０℃乃至１００℃である。
反応時間は原料化合物、溶媒又は使用される酸によって変化するが、通常５分乃至２０時間であり、好適には１０分乃至１２時間である。
反応終了後、本工程の目的化合物は常法に従って反応混合物から採取される。例えば、反応終了後、溶媒を留去し、反応液に水を注いだ後、水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル等）を加えて目的化合物を抽出し、抽出液を水洗した後、無水硫酸マグネシウム等を用いて乾燥させ、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱又はクロマトグラフィー等によって更に精製できる。尚、本工程により得られる中間体化合物は、特に精製することなく次工程に用いることもできる。 The solvent used in Step B1 (1) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, an aliphatic such as hexane, heptane, ligroin or petroleum ether. Hydrocarbons; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane Ethers such as dimethoxyethane or diethylene glycol dimethyl ether; esters such as methyl acetate or ethyl acetate; alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; formamide, N Amides such as N-dimethylformamide, N, N-dimethylacetamide or hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide or sulfolane, preferably halogenated hydrocarbons, ethers or aromatics Group hydrocarbons, more preferably ethers or aromatic hydrocarbons, and even more preferably aromatic hydrocarbons (particularly benzene or toluene).
While the reaction temperature varies depending on the raw material compound, the solvent or the acid used, it is generally 0 ° C. to 150 ° C., preferably 50 ° C. to 100 ° C.
While the reaction time varies depending on the raw material compound, the solvent or the acid used, it is generally 5 minutes to 20 hours, preferably 10 minutes to 12 hours.
After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, water is poured into the reaction solution, a solvent immiscible with water (eg benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extract is washed with water. Thereafter, the desired compound is obtained by drying using anhydrous magnesium sulfate and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography. In addition, the intermediate compound obtained by this process can also be used for the next process, without refine | purifying in particular.

第Ｂ１（２）工程で使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジクロロメタン、クロロホルム、四塩化炭素、ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類；メタノール、エタノール、プロパノール、２−プロパノール又はブタノールのようなアルコール類；或いは上記溶媒の混合溶媒であり得、好適には、ハロゲン化炭化水素類、エーテル類、アルコール類又はそれらの混合溶媒であり、更に好適にはアルコール類（特に、メタノール又はエタノール）である。
使用される還元剤は、水素化リチウムアルミニウム若しくは水素化ジイソブチルアルミニウム等のような水素化アルミニウム化合物、水素化硼素ナトリウム又はジボラン等であり得、好適には水素化硼素ナトリウムである。尚、還元剤として水素化硼素ナトリウムを用いる場合、塩化セリウムを触媒として用いることができる。
反応温度は原料化合物、溶媒又は使用される酸によって変化するが、通常−５０℃乃至５０℃であり、好適には０℃乃至３０℃である。
反応時間は原料化合物、溶媒又は使用される酸によって変化するが、通常５分乃至２０時間であり、好適には１０分乃至１２時間である。
反応終了後、本工程の目的化合物は常法に従って反応混合物から採取される。例えば、反応終了後、溶媒を留去したり、反応液を氷水に注いだ後、水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル等）を加えて抽出し、抽出液を水洗した後、無水硫酸マグネシウム等を用いて乾燥させ、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱又はクロマトグラフィー等によって更に精製できる。 The solvent used in Step B1 (2) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, an aliphatic such as hexane, heptane, ligroin or petroleum ether. Hydrocarbons; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane Ethers such as dimethoxyethane or diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; or a mixed solvent of the above solvents, preferably halogenated hydrocarbons S, ethers, and alcohols or a mixed solvent thereof is more preferably an alcohol (particularly methanol or ethanol).
The reducing agent used may be an aluminum hydride compound such as lithium aluminum hydride or diisobutylaluminum hydride, sodium borohydride or diborane, preferably sodium borohydride. When sodium borohydride is used as the reducing agent, cerium chloride can be used as a catalyst.
While the reaction temperature varies depending on the raw material compound, the solvent or the acid used, it is generally −50 ° C. to 50 ° C., preferably 0 ° C. to 30 ° C.
While the reaction time varies depending on the raw material compound, the solvent or the acid used, it is generally 5 minutes to 20 hours, preferably 10 minutes to 12 hours.
After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off or the reaction solution is poured into ice water, and then extracted by adding a solvent immiscible with water (eg benzene, ether, ethyl acetate, etc.), and the extract is washed with water. The desired compound is obtained by drying with anhydrous magnesium sulfate and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

第Ｂ２工程は、化合物（Ｖ）に於いて、Ｒ³が、Ｃ₁−Ｃ₆アルキル基；保護された水酸基若しくは（Ｃ₁−Ｃ₆アルコキシ）カルボニル基で置換されたＣ₁−Ｃ₆アルキル基；一般式 In step B2, in the compound (V), R ³ is a C ₁ -C ₆ alkyl group; a C ₁ -C ₆ alkyl substituted with a protected hydroxyl group or a (C ₁ -C ₆ alkoxy) carbonyl group. Group; general formula

（式中、Ｒ⁷、ｍ及びｎは、前述したものと同意義を示す。）を有する基；Ｃ₇−Ｃ₁₅アラルキル基；Ｃ₁−Ｃ₆アルキルスルホニル基；又は、（Ｃ₁−Ｃ₆アルコキシ）カルボニル基で置換されたＣ₁−Ｃ₆アルキルスルホニル基である、一般式（Ｖｂ）を有する化合物を製造する工程であり、化合物（Ｖａ）を、不活性溶媒中、塩基存在下又は不存在下（好適には塩基存在下）、一般式（ＶＩＩ）を有する化合物と反応させることにより達成される。 (Wherein R ⁷ , m and n are as defined above); a C ₇ -C ₁₅ aralkyl group; a C ₁ -C ₆ alkylsulfonyl group; or (C ₁ -C ₆ alkoxy) a process for producing a compound having the general formula (Vb) which is a C ₁ -C ₆ alkylsulfonyl group substituted by a carbonyl group, wherein the compound (Va) is reacted in an inert solvent in the presence of a base or It is achieved by reacting with a compound having the general formula (VII) in the absence (preferably in the presence of a base).

使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ヘキサン、シクロヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジクロロメタン、クロロホルム、四塩化炭素、１，２−ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類；アセトン又はメチルエチルケトンのようなケトン類；ニトロメタンのようなニトロ化合物類；アセトニトリル又はイソブチロニトリルのようなニトリル類；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又はＮ−メチル−２−ピロリジノンのようなアミド類；或いは、ジメチルスルホキシド又はスルホランのようなスルホキシド類であり得、好適には、ハロゲン化炭化水素類（特にジクロロメタン）、エーテル類（ジエチルエーテル若しくはテトラヒドロフラン）又はアミド類（特にＮ，Ｎ−ジメチルホルムアミド）である。
使用される塩基は、例えば、炭酸ナトリウム、炭酸カリウム又は炭酸リチウムのようなアルカリ金属炭酸塩類；炭酸水素ナトリウム、炭酸水素カリウム又は炭酸水素リチウムのようなアルカリ金属重炭酸塩類；水素化リチウム、水素化ナトリウム又は水素化カリウムのようなアルカリ金属水素化物類；水酸化ナトリウム、水酸化カリウム又は水酸化リチウムのようなアルカリ金属水酸化物類；ナトリウムメトキシド、ナトリウムエトキシド、カリウムｔ−ブトキシド又はリチウムメトキシドのようなアルカリ金属アルコキシド類；メチルアミン、ジメチルアミン、エチルアミン、トリエチルアミン、トリブチルアミン、ジイソプロピルエチルアミン、Ｎ−メチルモルホリン、ピリジン、４−（Ｎ，Ｎ−ジメチルアミノ）ピリジン、Ｎ，Ｎ−ジメチルアニリン、Ｎ，Ｎ−ジエチルアニリン、１，５−ジアザビシクロ［４．３．０］ノナ−５−エン、１，４−ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ）又は１，８−ジアザビシクロ［５．４．０］ウンデク−７−エン（ＤＢＵ）のような有機塩基類であり得、好適には、アルカリ金属炭酸塩類（特に炭酸ナトリウム又は炭酸カリウム）、アルカリ金属重炭酸塩類（特に炭酸水素ナトリウム又は炭酸水素カリウム）或いはアルカリ金属水素化物類（特に水素化リチウム又は水素化ナトリウム）である。
反応温度は原料化合物、試薬等によって異なるが、通常−１０℃乃至１００℃であり、好適には０℃乃至５０℃である。
反応時間は原料化合物、試薬、反応温度によって異なるが、通常１０分間乃至２４時間であり、好適には１時間乃至１２時間である。
反応終了後、本工程の目的化合物は常法に従って反応混合物から採取される。例えば、反応終了後、反応液に水を加え、水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル等）を加えて目的化合物を抽出した後、抽出した有機層を水洗し、無水硫酸マグネシウム等を用いて乾燥させた後、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱、クロマトグラフィーにより更に精製できる。 The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin or petroleum ether; benzene Aromatic hydrocarbons such as toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, Ethers such as dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone or methyl ethyl ketone; nitro compounds such as nitromethane; nitriles such as acetonitrile or isobutyronitrile; Amides such as amides, N, N-dimethylformamide, N, N-dimethylacetamide or N-methyl-2-pyrrolidinone; or sulfoxides such as dimethyl sulfoxide or sulfolane, preferably halogenated Hydrocarbons (especially dichloromethane), ethers (diethyl ether or tetrahydrofuran) or amides (especially N, N-dimethylformamide).
Bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; lithium hydride, hydrogenated Alkali metal hydrides such as sodium or potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxy Alkali metal alkoxides such as methylamine, dimethylamine, ethylamine, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-di Tylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [ 5.4.0] Organic bases such as undec-7-ene (DBU), preferably alkali metal carbonates (especially sodium carbonate or potassium carbonate), alkali metal bicarbonates (especially bicarbonate) Sodium or potassium hydrogen carbonate) or alkali metal hydrides (especially lithium hydride or sodium hydride).
While the reaction temperature varies depending on the raw material compound, reagent and the like, it is generally −10 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C.
While the reaction time varies depending on the raw material compound, reagent, and reaction temperature, it is generally 10 min to 24 hr, preferably 1 hr to 12 hr.
After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, water is added to the reaction solution, a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and then the extracted organic layer is washed with water, anhydrous magnesium sulfate, etc. Then, the target compound is obtained by distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

第Ｂ３工程は、化合物（Ｖ）に於いて、Ｒ³が、Ｃ₁−Ｃ₆アルキル基又はＣ₇−Ｃ₁₅アラルキル基である、一般式（Ｖｃ）を有する化合物を製造する工程であり、化合物（Ｖａ）を、不活性溶媒中、酢酸及びシアン化３水素化ホウ素ナトリウム又は水素化トリアセトキシホウ素ナトリウム存在下、一般式（ＶＩＩＩ）を有する化合物と反応させることにより達成される。 Step B3 is a step of producing a compound having the general formula (Vc) in which R ³ is a C ₁ -C ₆ alkyl group or a C ₇ -C ₁₅ aralkyl group in the compound (V), It is achieved by reacting compound (Va) with a compound having general formula (VIII) in the presence of acetic acid and sodium tricyanoborohydride or sodium triacetoxyborohydride in an inert solvent.

使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ヘキサン、シクロヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジクロロメタン、クロロホルム、四塩化炭素、１，２−ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類；メタノール、エタノール、プロパノール、２−プロパノール、ブタノール又はイソブタノールのようなアルコール類；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又はＮ−メチル−２−ピロリジノンのようなアミド類；ジメチルスルホキシド又はスルホランのようなスルホキシド類；或は上記有機溶媒の混合溶媒であり得、好適には、ハロゲン化炭化水素類（特にジクロロメタン）、アルコール類（メタノール又はエタノール）或いはそれらの混合溶媒（特にジクロロメタン及びメタノールの混合溶媒）である。
反応温度は原料化合物、試薬等によって異なるが、通常−１０℃乃至１５０℃であり、好適には０℃乃至１００℃である。
反応時間は原料化合物、試薬、反応温度によって異なるが、通常１０分間乃至２４時間であり、好適には１時間乃至１２時間である。
反応終了後、本工程の目的化合物は常法に従って反応混合物から採取される。例えば、反応終了後、反応液に水を加え、水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル等）を加えて目的化合物を抽出した後、抽出した有機層を水洗し、無水硫酸マグネシウム等を用いて乾燥させた後、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱、クロマトグラフィーにより更に精製できる。 The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin or petroleum ether; benzene Aromatic hydrocarbons such as toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, Ethers such as dimethoxyethane or diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, propanol, 2-propanol, butanol or isobutanol; formamide, N, N-dimethylformua Amides such as N, N-dimethylacetamide or N-methyl-2-pyrrolidinone; sulfoxides such as dimethyl sulfoxide or sulfolane; or a mixed solvent of the above organic solvents, preferably halogenated It is a hydrocarbon (especially dichloromethane), an alcohol (methanol or ethanol) or a mixed solvent thereof (especially a mixed solvent of dichloromethane and methanol).
While the reaction temperature varies depending on the raw material compound, reagent and the like, it is generally −10 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C.
While the reaction time varies depending on the raw material compound, reagent, and reaction temperature, it is generally 10 min to 24 hr, preferably 1 hr to 12 hr.
After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, water is added to the reaction solution, a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and then the extracted organic layer is washed with water, anhydrous magnesium sulfate, etc. Then, the target compound is obtained by distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

第Ｂ４工程は、化合物（Ｖ）に於いてＲ³がＣ₁−Ｃ₆アルカノイル基又は保護された水酸基で置換されたＣ₂−Ｃ₆アルカノイル基である、一般式（Ｖｄ）を有する化合物を製造する工程であり、化合物（Ｖａ）を、
（１）不活性溶媒中、塩基存在下又は不存在下（好適には塩基存在下）、一般式（ＩＸ）又は（Ｘ）を有する化合物と反応させた後、
所望に応じて、
（２）上記（１）で得られた化合物の、水酸基の保護基を除去することにより達成される。 Step B4 is a compound having the general formula (Vd) in which R ³ in the compound (V) is a C ₁ -C ₆ alkanoyl group or a C ₂ -C ₆ alkanoyl group substituted with a protected hydroxyl group. A step of producing a compound (Va),
(1) After reacting with a compound having the general formula (IX) or (X) in an inert solvent in the presence or absence of a base (preferably in the presence of a base),
As desired
(2) This is achieved by removing the hydroxyl protecting group of the compound obtained in (1) above.

第Ｂ４（１）工程に於いて使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ヘキサン、シクロヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジクロロメタン、クロロホルム、四塩化炭素、１，２−ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類；アセトン又はメチルエチルケトンのようなケトン類；ニトロメタンのようなニトロ化合物類；アセトニトリル又はイソブチロニトリルのようなニトリル類；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又はＮ−メチル−２−ピロリジノンのようなアミド類；或いは、ジメチルスルホキシド又はスルホランのようなスルホキシド類であり得、好適には、ハロゲン化炭化水素類（特にジクロロメタン）又はエーテル類（ジエチルエーテル若しくはテトラヒドロフラン）である。
使用される塩基は、例えば、炭酸ナトリウム、炭酸カリウム又は炭酸リチウムのようなアルカリ金属炭酸塩類；炭酸水素ナトリウム、炭酸水素カリウム又は炭酸水素リチウムのようなアルカリ金属重炭酸塩類；水酸化ナトリウム、水酸化カリウム又は水酸化リチウムのようなアルカリ金属水酸化物類；メチルアミン、ジメチルアミン、エチルアミン、トリエチルアミン、トリブチルアミン、ジイソプロピルエチルアミン、Ｎ−メチルモルホリン、ピリジン、４−（Ｎ，Ｎ−ジメチルアミノ）ピリジン、Ｎ，Ｎ−ジメチルアニリン、Ｎ，Ｎ−ジエチルアニリン、１，５−ジアザビシクロ［４．３．０］ノナ−５−エン、１，４−ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ）又は１，８−ジアザビシクロ［５．４．０］ウンデク−７−エン（ＤＢＵ）のような有機塩基類であり得、好適には、アルカリ金属炭酸塩類（特に炭酸ナトリウム又は炭酸カリウム）、アルカリ金属重炭酸塩類（特に炭酸水素ナトリウム又は炭酸水素カリウム）或いは有機塩基類（特に、トリエチルアミン、ピリジン又は４−（Ｎ，Ｎ−ジメチルアミノ）ピリジン）である。
反応温度は原料化合物、試薬等によって異なるが、通常−１０℃乃至１００℃であり、好適には０℃乃至５０℃である。
反応時間は原料化合物、試薬、反応温度によって異なるが、通常１０分間乃至２４時間であり、好適には１時間乃至１２時間である。
反応終了後、本工程の目的化合物は常法に従って反応混合物から採取される。例えば、反応終了後、反応液に水を加え、水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル等）を加えて目的化合物を抽出した後、抽出した有機層を水洗し、無水硫酸マグネシウム等を用いて乾燥させた後、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱、クロマトグラフィーにより更に精製できる。 The solvent used in Step B4 (1) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, hexane, cyclohexane, heptane, ligroin or petroleum ether Aliphatic hydrocarbons such as; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; Ethers such as ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone or methyl ethyl ketone; nitro compounds such as nitromethane; acetonitrile or isobutyronitrile Nitriles such as; amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide or N-methyl-2-pyrrolidinone; or sulfoxides such as dimethyl sulfoxide or sulfolane, preferred Are halogenated hydrocarbons (especially dichloromethane) or ethers (diethyl ether or tetrahydrofuran).
Bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; sodium hydroxide, hydroxide Alkali metal hydroxides such as potassium or lithium hydroxide; methylamine, dimethylamine, ethylamine, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1 , 8-Diazabicyclo [5.4.0] undec-7- And organic bases such as alkali metal carbonates (particularly sodium carbonate or potassium carbonate), alkali metal bicarbonates (particularly sodium bicarbonate or potassium bicarbonate) or organic bases. (Especially triethylamine, pyridine or 4- (N, N-dimethylamino) pyridine).
While the reaction temperature varies depending on the raw material compound, reagent and the like, it is generally −10 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C.
While the reaction time varies depending on the raw material compound, reagent, and reaction temperature, it is generally 10 min to 24 hr, preferably 1 hr to 12 hr.
After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, water is added to the reaction solution, a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and then the extracted organic layer is washed with water, anhydrous magnesium sulfate, etc. Then, the target compound is obtained by distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

第Ｂ４（２）工程に於いて、水酸基の保護基の除去については、第Ａ２工程の反応（ｅ）と同様の条件下で行うことができる。 In step B4 (2), removal of the hydroxyl-protecting group can be carried out under the same conditions as in reaction (e) in step A2.

Ｃ法は、Ａ法に於ける中間体化合物である、化合物（Ｖ）を、別途製造する方法である。 Method C is a method for separately producing compound (V), which is an intermediate compound in Method A.

第Ｃ１工程は、化合物（Ｖ）を製造する工程であり、一般式（ＸＩ）を有する化合物を、不活性溶媒中、パラジウム触媒及びホスフィン類存在下、化合物（ＩＶ）と縮合させることにより達成される。 Step C1 is a step of producing compound (V) and is achieved by condensing compound having general formula (XI) with compound (IV) in the presence of a palladium catalyst and phosphines in an inert solvent. The

使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ヘキサン、シクロヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジクロロメタン、クロロホルム、四塩化炭素、１，２−ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類；或いは、アセトニトリル又はイソブチロニトリルのようなニトリル類であり得、好適にはエーテル類（特にテトラヒドロフラン）である。
使用されるパラジウム触媒は、例えば、トリス（ジベンジリデンアセトン）ジパラジウムクロロホルム錯体、ビス（ジベンジリデンアセトン）パラジウム、酢酸パラジウム又はパイアリルパラジウムクロリド２量体であり得、好適には、トリス（ジベンジリデンアセトン）ジパラジウムクロロホルム錯体である。
使用されるホスフィン類は、例えば、トリメチルホスフィン、トリエチルホスフィン、トリプロピルホスフィン、トリブチルホスフィン、トリペンチルホスフィン又はトリヘキシルホスフィン等のトリＣ₁−Ｃ₆アルキルホスフィン；トリフェニルホスフィン、トリインデニルホスフィン又はトリナフチルホスフィン等のトリＣ₆−Ｃ₁₀アリールホスフィン；或はトリルジフェニルホスフィン、トリトリルホスフィン、トリメシチルホスフィン、トリブチルフェニルホスフィン又はトリ−６−エチル−２−ナフチルホスフィン等の、Ｃ₁−Ｃ₄アルキルを置換基として有してもよいトリＣ₆−Ｃ₁₀アリールホスフィンであり得、好適にはトリＣ₁−Ｃ₆アルキルホスフィン類（特にトリメチルホスフィン、トリエチルホスフィン、トリプロピルホスフィン又はトリブチルホスフィン、）又はトリＣ₆−Ｃ₁₀アリールホスフィン（特にトリフェニルホスフィン、トリインデニルホスフィン又はトリナフチルホスフィン）であり、更に好適には、トリブチルホスフィン又はトリフェニルホスフィンであり、特に好適にはトリフェニルホスフィンである。
反応温度は原料化合物、試薬等によって異なるが、通常−１０℃乃至１００℃であり、好適には０℃乃至５０℃である。
反応時間は原料化合物、試薬、反応温度によって異なるが、通常１０分間乃至１０時間であり、好適には３０分間乃至５時間である。
反応終了後、本工程の目的化合物は常法に従って反応混合物から採取される。例えば、反応終了後、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱、クロマトグラフィーにより更に精製できる。 The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin or petroleum ether; benzene Aromatic hydrocarbons such as toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, Ethers such as dimethoxyethane or diethylene glycol dimethyl ether; or nitriles such as acetonitrile or isobutyronitrile, preferably ethers (especially tetrahydrofuran).
The palladium catalyst used can be, for example, tris (dibenzylideneacetone) dipalladium chloroform complex, bis (dibenzylideneacetone) palladium, palladium acetate or pyaryl palladium chloride dimer, preferably tris (dibenzylidene). Acetone) dipalladium chloroform complex.
The phosphines used are, for example, tri-C ₁ -C ₆ alkyl phosphines such as trimethylphosphine, triethylphosphine, tripropylphosphine, tributylphosphine, tripentylphosphine or trihexylphosphine; triphenylphosphine, triindenylphosphine or triphenylphosphine. tri C ₆ -C ₁₀ arylphosphine such as naphthyl phosphine; or tolyl diphenyl phosphine, tritolylphosphine, trimesitylphosphine phosphine, such tributyl triphenylphosphine or tri-6-ethyl-2-naphthyl phosphine, C ₁ -C ₄ alkyl the can be a good tri C ₆ -C ₁₀ arylphosphine which may have a substituent, preferably tri C ₁ -C ₆ alkyl phosphines (especially trimethylphosphine, triethylphosphine, tri-propyl Sufin or tributylphosphine) or tri C ₆ -C ₁₀ arylphosphine (particularly triphenylphosphine, a tri-indenyl phosphine or trinaphthylphosphine), more preferably a tributylphosphine or triphenylphosphine, particularly preferably Is triphenylphosphine.
While the reaction temperature varies depending on the raw material compound, reagent and the like, it is generally −10 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C.
While the reaction time varies depending on the raw material compound, reagent, and reaction temperature, it is generally 10 minutes to 10 hours, preferably 30 minutes to 5 hours.
After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, the target compound is obtained by distilling off the solvent after completion of the reaction. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

Ｄ法は、Ａ法に於ける中間体化合物である、化合物（Ｖ）を、別途製造する方法である。 Method D is a method for separately producing compound (V), which is an intermediate compound in Method A.

第Ｄ１工程は、一般式（ＸＩＩＩ）を有する化合物を製造する工程であり、化合物（ＩＩＩ）を、不活性溶媒中、ホスフィン類及びアゾ化合物存在下、一般式（ＸＩＩ）を有する化合物と縮合させることにより達成され、第Ａ１工程と同様の条件下で行なわれる。 Step D1 is a step of producing a compound having the general formula (XIII), and the compound (III) is condensed with a compound having the general formula (XII) in the presence of a phosphine and an azo compound in an inert solvent. This is achieved under the same conditions as in Step A1.

第Ｄ２工程は、一般式（ＸＩＶ）を有する化合物を製造する工程であり、化合物（ＸＩＩＩ）の水酸基の保護基を除去することにより達成され、第Ａ２工程の反応（ｅ）と同様の条件下で行うことができる。 Step D2 is a step for producing a compound having the general formula (XIV), and is achieved by removing the hydroxyl-protecting group of compound (XIII) under the same conditions as in reaction (e) in Step A2. Can be done.

第Ｄ３工程は、化合物（Ｖ）を製造する工程であり、化合物（ＸＩＶ）を、不活性溶媒中、ホスフィン類及びアゾ化合物存在下、一般式（ＸＶ）を有する化合物と縮合させることにより達成され、第Ａ１工程と同様の条件下で行なわれる。 Step D3 is a step for producing compound (V), and is achieved by condensing compound (XIV) with a compound having the general formula (XV) in the presence of a phosphine and an azo compound in an inert solvent. The reaction is performed under the same conditions as in Step A1.

本発明の原料化合物である、化合物（ＩＩＩ）、（ＩＶ）、（ＩＶａ）、（ＶＩ）、（ＸＩ）又は（ＸＩＩ）は、例えば、以下の方法に従い、容易に製造することができる。 The compound (III), (IV), (IVa), (VI), (XI) or (XII), which is a raw material compound of the present invention, can be easily produced, for example, according to the following method.

上記に於いて、Ｒ¹、Ｒ²、Ｒ³、Ｒ³a、Ｒ³b、Ｒ³c、Ｒ³d、Ｒ⁴、Ｒ⁵、Ｒ⁶、
Ｒ⁸、Ｒ⁹、Ｒ¹⁰、Ｒ¹¹、Ｒ¹²、Ｒ¹³及びＸは、前述したものと同意義を示し、
Ｒ²aは、水素原子を示し、
Ｒ⁵aは、カルボキシル基を示し、
Ｒ⁵bは、（Ｃ₁−Ｃ₆アルコキシ）カルボニル基を示し、
Ｒ⁵cは、カルバモイル基、（Ｃ₁−Ｃ₆アルキル）カルバモイル基又はジ（Ｃ₁−Ｃ₆アルキル）カルバモイル基を示し、
Ｚは、水酸基又は脱離基を示す。 In the ^{^{above, R 1, R 2, R}} 3, R 3 a, R 3 b, R 3 c, R 3 d, R 4, R 5, R 6,
R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and X are as defined above,
R ² a represents a hydrogen atom,
R ⁵ a represents a carboxyl group,
R ⁵ b represents a (C ₁ -C ₆ alkoxy) carbonyl group,
R ⁵ c represents a carbamoyl group, a (C ₁ -C ₆ alkyl) carbamoyl group or a di (C ₁ -C ₆ alkyl) carbamoyl group,
Z represents a hydroxyl group or a leaving group.

上記に於いて、Ｒ⁵bの定義に於ける「（Ｃ₁−Ｃ₆アルコキシ）カルボニル基」、Ｒ⁵cの定義に於ける「（Ｃ₁−Ｃ₆アルキル）カルバモイル基」及び「ジ（Ｃ₁−Ｃ₆アルキル）カルバモイル基」は、各々、Ｒ⁵で定義したものと同意義を示す。 In the above, R ⁵ b in the definition of "(C ₁ -C ₆ alkoxy) carbonyl group" in the definition of R ⁵ c "(C ₁ -C ₆ alkyl) carbamoyl group" and "di ( The “C ₁ -C ₆ alkyl) carbamoyl group” has the same meaning as defined for R ⁵ .

Ｚの定義に於ける「脱離基」は、通常、求核性残基として脱離する基であれば特に限定はないが、例えば、塩素原子、臭素原子又は沃素原子のようなハロゲン原子；メタンスルホニルオキシ基、エタンスルホニルオキシ基、プロパンスルホニルオキシ基又はブタンスルホニルオキシ基のようなＣ₁−Ｃ₄アルカンスルホニルオキシ基；トリフルオロメタンスルホニルオキシ基、２，２，２−トリクロロエタンスルホニルオキシ基、３，３，３−トリブロモプロパンスルホニルオキシ基又は、４，４，４−トリフルオロブタンスルホニルオキシ基のような、ハロゲノＣ₁−Ｃ₄アルカンスルホニルオキシ基；或は、ベンゼンスルホニルオキシ基、α−ナフチルスルホニルオキシ基、β−ナフチルスルホニルオキシ基、ｐ−トルエンスルホニルオキシ基、４−ｔ−ブチルベンゼンスルホニルオキシ基、メシチレンスルホニルオキシ基又は６−エチル−α−ナフチルスルホニルオキシ基のような、Ｃ₁−Ｃ₄アルキルを１乃至３個有してもよいＣ₆−Ｃ₁₀アリ−ルスルホニルオキシ基であり得、好適には、ハロゲン原子、メタンスルホニルオキシ基、エタンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基、２，２，２−トリクロロエタンスルホニルオキシ基、ベンゼンスルホニルオキシ基、トルエンスルホニルオキシ基又はメシチレンスルホニルオキシ基であり、更に好適には、ハロゲン原子、メタンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基、ベンゼンスルホニルオキシ基、ｐ−トルエンスルホニルオキシ基又はメシチレンスルホニルオキシ基であり、より更に好適には、ハロゲン原子であり、特に好適には、弗素原子又は塩素原子である。 The “leaving group” in the definition of Z is not particularly limited as long as it is usually a group capable of leaving as a nucleophilic residue. For example, a halogen atom such as a chlorine atom, a bromine atom or an iodine atom; C ₁ -C ₄ alkanesulfonyloxy group such as methanesulfonyloxy group, ethanesulfonyloxy group, propanesulfonyloxy group or butanesulfonyloxy group; trifluoromethanesulfonyloxy group, 2,2,2-trichloroethanesulfonyloxy group, 3 , 3,3-tribromopropane sulfonyloxy group or 4,4,4 such as trifluoroacetic butane sulfonyloxy group, halogeno C ₁ -C ₄ alkanesulfonyloxy group; or a benzene sulfonyloxy group, alpha- Naphthylsulfonyloxy group, β-naphthylsulfonyloxy group, p-toluenesulfonyloxy Group, 4-t-butylbenzene sulfonyloxy groups, such as mesitylene sulfonyloxy group or a 6-ethyl -α- naphthylsulfonyl group, C ₁ -C ₄ alkyl which may have 1 to 3 C ₆ - C ₁₀ Ali - be a Le sulfonyloxy group, preferably a halogen atom, a methanesulfonyloxy group, ethanesulfonyloxy group, trifluoromethanesulfonyloxy group, 2,2,2-trichloroethane sulfonyloxy group, benzenesulfonyloxy group , A toluenesulfonyloxy group or a mesitylenesulfonyloxy group, and more preferably a halogen atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a benzenesulfonyloxy group, a p-toluenesulfonyloxy group or a mesitylenesulfonyloxy group. , Yo More preferably a halogen atom, particularly preferably a fluorine atom or a chlorine atom.

Ｅ法は、化合物（ＶＩ）、（ＩＩＩ）又は（ＸＩ）を製造する方法である。 Method E is a method for producing compound (VI), (III) or (XI).

第Ｅ１工程は、化合物（ＶＩ）を製造する工程であり、一般式（ＸＶＩ）を有する化合物を、不活性溶媒中、一般式（ＸＶＩＩ）を有する化合物と反応させることにより達成される。 Step E1 is a step for producing compound (VI) and is achieved by reacting a compound having the general formula (XVI) with a compound having the general formula (XVII) in an inert solvent.

使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ヘキサン、シクロヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジクロロメタン、クロロホルム、四塩化炭素、１，２−ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類；或いは、アセトニトリル、プロピオニトリル又はブチロニトリルのようなニトリル類であり得、好適には、芳香族炭化水素類（特にベンゼン又はトルエン）である。
反応温度は原料化合物、試薬等によって異なるが、通常０℃乃至１５０℃であり、好適には３０℃乃至１００℃である。
反応時間は原料化合物、試薬、反応温度によって異なるが、通常１０分間乃至１０時間であり、好適には３０分間乃至５時間である。
反応終了後、本工程の目的化合物は常法に従って反応混合物から採取される。例えば、反応終了後、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱、クロマトグラフィーにより更に精製できる。 The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin or petroleum ether; benzene Aromatic hydrocarbons such as toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, Ethers such as dimethoxyethane or diethylene glycol dimethyl ether; or nitriles such as acetonitrile, propionitrile or butyronitrile, preferably aromatic hydrocarbons (especially benzene or toluene). .
While the reaction temperature varies depending on the raw material compounds, reagents and the like, it is generally 0 ° C. to 150 ° C., preferably 30 ° C. to 100 ° C.
While the reaction time varies depending on the raw material compound, reagent, and reaction temperature, it is generally 10 minutes to 10 hours, preferably 30 minutes to 5 hours.
After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, the target compound is obtained by distilling off the solvent after completion of the reaction. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

第Ｅ２工程は、化合物（ＩＩＩ）を製造する工程であり、化合物（ＶＩ）を、不活性溶媒中、還元剤存在下、還元することにより達成される。 Step E2 is a step for producing compound (III), and is achieved by reducing compound (VI) in the presence of a reducing agent in an inert solvent.

使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ヘキサン、シクロヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジクロロメタン、クロロホルム、四塩化炭素、１，２−ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類；メタノール、エタノール、プロパノール、２−プロパノール、ブタノール又はイソブタノールのようなアルコール類；或いは、上記溶媒の混合溶媒であり得、還元剤が水素化アルミニウム類又はジボランの場合には、脂肪族炭化水素類（特にヘキサン又はシクロヘキサン）、芳香族炭化水素類（特にベンゼン、トルエン又はキシレン）或はエーテル類（特にジエチルエーテル、テトラヒドロフラン又はジオキサン）であり、還元剤が水素化硼素ナトリウムの場合にはアルコール類（特にメタノール又はエタノール）又はハロゲン化炭化水素類及びアルコール類の混合溶媒（特にジクロロメタン及びエタノールの混合溶媒）である。
使用される還元剤は、水素化リチウムアルミニウム若しくは水素化ジイソブチルアルミニウム等のような水素化アルミニウム化合物、水素化硼素ナトリウム又はジボラン等であり得、好適には水素化硼素ナトリウムである。尚、還元剤として水素化硼素ナトリウムを用いる場合、塩化セリウムを触媒として用いることができる。
反応温度は原料化合物、試薬等によって異なるが、通常−７８℃乃至１００℃であり、好適には０℃乃至５０℃である。
反応時間は原料化合物、試薬、反応温度によって異なるが、通常１０分間乃至１２時間であり、好適には３０分間乃至５時間である。
反応終了後、本工程の目的化合物は常法に従って反応混合物から採取される。例えば、反応終了後、溶媒を留去し、得られる残渣に水を加えた後、水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル等）を加えて目的化合物を抽出した後、抽出した有機層を水洗し、無水硫酸マグネシウム等を用いて乾燥させた後、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱、クロマトグラフィーにより更に精製できる。 The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin or petroleum ether; benzene Aromatic hydrocarbons such as toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, Ethers such as dimethoxyethane or diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, propanol, 2-propanol, butanol or isobutanol; or a mixed solvent of the above solvents, When the agent is an aluminum hydride or diborane, an aliphatic hydrocarbon (especially hexane or cyclohexane), an aromatic hydrocarbon (especially benzene, toluene or xylene) or an ether (especially diethyl ether, tetrahydrofuran or dioxane) And when the reducing agent is sodium borohydride, it is an alcohol (especially methanol or ethanol) or a mixed solvent of halogenated hydrocarbons and alcohols (especially a mixed solvent of dichloromethane and ethanol).
The reducing agent used may be an aluminum hydride compound such as lithium aluminum hydride or diisobutylaluminum hydride, sodium borohydride or diborane, preferably sodium borohydride. When sodium borohydride is used as the reducing agent, cerium chloride can be used as a catalyst.
While the reaction temperature varies depending on the raw material compound, reagent and the like, it is generally −78 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C.
While the reaction time varies depending on the raw material compound, reagent, and reaction temperature, it is generally 10 minutes to 12 hours, preferably 30 minutes to 5 hours.
After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, water is added to the resulting residue, a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extracted organic The layer is washed with water, dried using anhydrous magnesium sulfate and the like, and then the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

第Ｅ３工程は、化合物（ＸＩ）を製造する工程であり、化合物（ＩＩＩ）を、不活性溶媒中、塩基存在下又は不存在下（好適には塩基存在下）、一般式（ＸＶＩＩＩ）を有する化合物と反応させることにより達成される。 Step E3 is a step for producing compound (XI). Compound (III) is represented by the general formula (XVIII) in an inert solvent in the presence or absence of a base (preferably in the presence of a base). This is accomplished by reacting with a compound.

使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ヘキサン、シクロヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジクロロメタン、クロロホルム、四塩化炭素、１，２−ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類；アセトン又はメチルエチルケトンのようなケトン類；ニトロメタンのようなニトロ化合物類；アセトニトリル又はイソブチロニトリルのようなニトリル類；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又はＮ−メチル−２−ピロリジノンのようなアミド類；或いは、ジメチルスルホキシド又はスルホランのようなスルホキシド類であり得、好適には、ハロゲン化炭化水素類（特にジクロロメタン）又はエーテル類（特にジエチルエーテル又はテトラヒドロフラン）である。
使用される塩基は、例えば、炭酸ナトリウム、炭酸カリウム又は炭酸リチウムのようなアルカリ金属炭酸塩類；炭酸水素ナトリウム、炭酸水素カリウム又は炭酸水素リチウムのようなアルカリ金属重炭酸塩類；或いは、トリエチルアミン、トリブチルアミン、ジイソプロピルエチルアミン、Ｎ−メチルモルホリン、ピリジン、４−（Ｎ，Ｎ−ジメチルアミノ）ピリジン、Ｎ，Ｎ−ジメチルアニリン、Ｎ，Ｎ−ジエチルアニリン、１，５−ジアザビシクロ［４．３．０］ノナ−５−エン、１，４−ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ）又は１，８−ジアザビシクロ［５．４．０］ウンデク−７−エン（ＤＢＵ）のような有機アミン類であり得、好適には、有機アミン類（特にトリエチルアミン又はピリジン）である。
反応温度は原料化合物、試薬等によって異なるが、通常−５０℃乃至８０℃であり、好適には−２０℃乃至５０℃である。
反応時間は原料化合物、試薬、反応温度によって異なるが、通常１０分間乃至１０時間であり、好適には３０分間乃至５時間である。
反応終了後、本工程の目的化合物は常法に従って反応混合物から採取される。例えば、反応終了後、反応液に水を加え、水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル等）を加えて目的化合物を抽出した後、抽出した有機層を水洗し、無水硫酸マグネシウム等を用いて乾燥させた後、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱、クロマトグラフィーにより更に精製できる。 The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin or petroleum ether; benzene Aromatic hydrocarbons such as toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, Ethers such as dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone or methyl ethyl ketone; nitro compounds such as nitromethane; nitriles such as acetonitrile or isobutyronitrile; Amides such as amide, N, N-dimethylformamide, N, N-dimethylacetamide or N-methyl-2-pyrrolidinone; or sulfoxides such as dimethyl sulfoxide or sulfolane, preferably halogenated Hydrocarbons (especially dichloromethane) or ethers (especially diethyl ether or tetrahydrofuran).
Bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; or triethylamine, tributylamine , Diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] nona Organic amines such as -5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) Obtained and preferably organic amines (particularly triethylamine or pyridine).
While the reaction temperature varies depending on the raw material compound, reagent and the like, it is generally −50 ° C. to 80 ° C., preferably −20 ° C. to 50 ° C.
While the reaction time varies depending on the raw material compound, reagent, and reaction temperature, it is generally 10 minutes to 10 hours, preferably 30 minutes to 5 hours.
After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, water is added to the reaction solution, a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and then the extracted organic layer is washed with water, anhydrous magnesium sulfate, etc. Then, the target compound is obtained by distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

Ｇ法は、化合物（ＩＩＩ）に於いて、Ｒ²が水素原子である、一般式（ＩＩＩａ）を有する化合物を別途製造する方法である。 Method G is a method for separately producing a compound having the general formula (IIIa) in which R ² is a hydrogen atom in the compound (III).

第Ｇ１工程は、一般式（ＸＸＩＶ）を有する化合物を製造する工程であり、一般式（ＸＸＩＩ）を有する化合物を、
（１）不活性溶媒中又は溶媒不存在下（好適には、溶媒不存在下）、カテコールボランと反応させた後、
（２）得られた中間体化合物を、不活性溶媒中、パラジウム触媒及び塩基存在下、一般式（ＸＸＩＩＩ）を有する化合物と反応させることにより達成される。 Step G1 is a step of producing a compound having the general formula (XXIV), and the compound having the general formula (XXII)
(1) After reacting with catecholborane in an inert solvent or in the absence of a solvent (preferably in the absence of a solvent),
(2) This is achieved by reacting the obtained intermediate compound with a compound having the general formula (XXIII) in an inert solvent in the presence of a palladium catalyst and a base.

第Ｇ１（１）工程で使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ヘキサン、シクロヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジクロロメタン、クロロホルム、四塩化炭素、１，２−ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；或いは、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類であり得、好適には、脂肪族炭化水素類（特に、ヘキサン又は石油エーテル）又は芳香族炭化水素類（特にトルエン）である。
第Ｇ１（１）工程の反応温度は原料化合物、試薬等によって異なるが、通常−１０℃乃至１００℃であり、好適には３０℃乃至８０℃である。
第Ｇ１（１）工程の反応時間は原料化合物、試薬、反応温度によって異なるが、通常１０分間乃至１０時間であり、好適には３０分間乃至５時間である。
反応終了後、第Ｇ１（１）工程の目的化合物は常法に従って反応混合物から採取される。例えば、反応終了後、溶媒を留去することによって目的化合物が得られる。尚、特に精製することなく次工程に用いることもできる。 The solvent used in the G1 (1) step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, hexane, cyclohexane, heptane, ligroin or petroleum ether Aliphatic hydrocarbons; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; or diethyl It can be an ether such as ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, preferably aliphatic hydrocarbons (especially hexane or petroleum ether) or aromatic hydrocarbons (especially toluene). It is.
The reaction temperature in Step G1 (1) varies depending on the raw material compounds, reagents and the like, but is usually −10 ° C. to 100 ° C., preferably 30 ° C. to 80 ° C.
The reaction time in the G1 (1) step varies depending on the raw material compound, reagent, and reaction temperature, but is usually 10 minutes to 10 hours, preferably 30 minutes to 5 hours.
After completion of the reaction, the target compound of Step G1 (1) is collected from the reaction mixture according to a conventional method. For example, the target compound is obtained by distilling off the solvent after completion of the reaction. In addition, it can also be used in the next step without particular purification.

第Ｇ１（２）工程で使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ヘキサン、シクロヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジクロロメタン、クロロホルム、四塩化炭素、１，２−ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類；メタノール、エタノール、プロパノール、２−プロパノール、ブタノール又はイソブタノールのようなアルコール類；或は上記有機溶媒の混合溶媒であり得、好適には、芳香族炭化水素類（特にトルエン）である。
第Ｇ１（２）工程で使用されるパラジウム触媒は、例えば、テトラキス（トリフェニルホスフィン）パラジウム、塩化パラジウムビス（トリフェニルホスフィン）錯体、塩化パラジウムビス（ジフェニルホスフィノフェロセン）錯体又は酢酸パラジウムビス（トリフェニルホスフィン）等のパラジウムホスフィン錯体；或いは、トリス（ジベンジリデンアセトン）ジパラジウムクロロホルム錯体、ビス（ジベンジリデンアセトン）パラジウム、酢酸パラジウム又はパイアリルパラジウムクロリド２量体であり得、好適には、テトラキス（トリフェニルホスフィン）パラジウム、塩化パラジウムビス（トリフェニルホスフィン）錯体又は塩化パラジウムビス（ジフェニルホスフィノフェロセン）錯体であり、更に好適にはテトラキス（トリフェニルホスフィン）パラジウムである。
第Ｇ１（２）工程で使用される塩基は、例えば、炭酸ナトリウム、炭酸カリウム又は炭酸リチウムのようなアルカリ金属炭酸塩類；炭酸水素ナトリウム、炭酸水素カリウム又は炭酸水素リチウムのようなアルカリ金属重炭酸塩類；ナトリウムメトキシド、ナトリウムエトキシド、カリウムｔ−ブトキシド又はリチウムメトキシドのようなアルカリ金属アルコキシド類；或いは、トリエチルアミン、トリブチルアミン、ジイソプロピルエチルアミン、Ｎ−メチルモルホリン、ピリジン、４−（Ｎ，Ｎ−ジメチルアミノ）ピリジン、Ｎ，Ｎ−ジメチルアニリン、Ｎ，Ｎ−ジエチルアニリン、１，５−ジアザビシクロ［４．３．０］ノナ−５−エン、１，４−ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ）又は１，８−ジアザビシクロ［５．４．０］ウンデク−７−エン（ＤＢＵ）のような有機アミン類であり得、好適には、アルカリ金属アルコキシド類（特にナトリウムエトキシド）である。
第Ｇ１（２）工程の反応温度は原料化合物、試薬等によって異なるが、通常０℃乃至１５０℃であり、好適には５０℃乃至１２０℃である。
第Ｇ１（２）工程の反応時間は原料化合物、試薬、反応温度によって異なるが、通常１０分間乃至１０時間であり、好適には３０分間乃至５時間である。
反応終了後、第Ｇ１（２）工程の目的化合物は常法に従って反応混合物から採取される。例えば、反応終了後、反応液に水を加え、水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル等）を加えて目的化合物を抽出した後、抽出した有機層を水洗し、無水硫酸マグネシウム等を用いて乾燥させた後、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱、クロマトグラフィーにより更に精製できる。 The solvent used in Step G1 (2) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, hexane, cyclohexane, heptane, ligroin or petroleum ether can be used. Aliphatic hydrocarbons; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether; Ethers such as diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, propanol, 2-propanol, butanol or isobutanol; or a mixture of the above organic solvents It is a solvent, preferably an aromatic hydrocarbon (particularly toluene).
The palladium catalyst used in the G1 (2) step is, for example, tetrakis (triphenylphosphine) palladium, palladium chloride bis (triphenylphosphine) complex, palladium chloride bis (diphenylphosphinoferrocene) complex or palladium acetate bis (tri A palladium phosphine complex such as phenylphosphine); or tris (dibenzylideneacetone) dipalladium chloroform complex, bis (dibenzylideneacetone) palladium, palladium acetate or piaryl palladium chloride dimer, preferably tetrakis ( Triphenylphosphine) palladium, palladium chloride bis (triphenylphosphine) complex or palladium chloride bis (diphenylphosphinoferrocene) complex, and more preferably tetrakis (triphenylphosphine). Le phosphine) palladium.
The base used in Step G1 (2) is, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate. Alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; or triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethyl) Amino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane ( DABCO) or 1,8-diazabicyclo [5 4.0] undec-7-ene (DBU) to give an organic amines such as, preferably, alkali metal alkoxides (particularly sodium ethoxide).
The reaction temperature in Step G1 (2) varies depending on the raw material compounds, reagents and the like, but is usually 0 ° C. to 150 ° C., preferably 50 ° C. to 120 ° C.
The reaction time in the G1 (2) step varies depending on the raw material compounds, reagents and reaction temperature, but is usually 10 minutes to 10 hours, preferably 30 minutes to 5 hours.
After completion of the reaction, the target compound in Step G1 (2) is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, water is added to the reaction solution, a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and then the extracted organic layer is washed with water, anhydrous magnesium sulfate, etc. Then, the target compound is obtained by distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

第Ｇ２工程は、化合物（ＩＩＩａ）を製造する工程であり、化合物（ＸＸＩＶ）の水酸基の保護基を除去することにより達成され、第Ａ２工程の反応（ｅ）と同様の条件下で行うことができる。 Step G2 is a step for producing compound (IIIa), which is achieved by removing the protecting group for the hydroxyl group of compound (XXIV), and can be carried out under the same conditions as in reaction (e) in Step A2. it can.

Ｈ法は、一般式（ＩＶａ）、（ＩＶｂ）、（ＩＶｃ）又は（ＩＶｄ）を有する化合物を製造する方法である。 Method H is a method for producing a compound having the general formula (IVa), (IVb), (IVc) or (IVd).

第Ｈ１工程は、一般式（ＸＸＶＩ）を有する化合物を製造する工程であり、一般式（ＸＸＶ）を有する化合物に於いて、Ｚが脱離基を示す場合、
（１）化合物（ＸＸＶ）を、不活性溶媒中、塩基存在下、化合物（ＸＶ）と反応させるか、
又は、化合物（ＸＸＶ）に於いて、Ｚが水酸基を示す場合、
（２）化合物（ＸＸＶ）を、不活性溶媒中で、ホスフィン類とアゾ化合物の存在下、化合物（ＸＶ）と脱水縮合させることにより達成される。 Step H1 is a step of producing a compound having the general formula (XXVI). In the compound having the general formula (XXV), when Z represents a leaving group,
(1) reacting compound (XXV) with compound (XV) in the presence of a base in an inert solvent,
Or, in the compound (XXV), when Z represents a hydroxyl group,
(2) It is achieved by subjecting compound (XXV) to dehydration condensation with compound (XV) in the presence of a phosphine and an azo compound in an inert solvent.

第Ｈ１（１）工程で使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ヘキサン、シクロヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジクロロメタン、クロロホルム、四塩化炭素、１，２−ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類；ニトロメタンのようなニトロ化合物類；アセトニトリル又はイソブチロニトリルのようなニトリル類；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又はＮ−メチル−２−ピロリジノンのようなアミド類；或いは、ジメチルスルホキシド又はスルホランのようなスルホキシド類であり得、好適にはアミド類（特に、Ｎ，Ｎ−ジメチルホルムアミド又はＮ，Ｎ−ジメチルアセトアミド）である。
第Ｈ１（１）工程で使用される塩基は、例えば、炭酸ナトリウム、炭酸カリウム又は炭酸リチウムのようなアルカリ金属炭酸塩類；炭酸水素ナトリウム、炭酸水素カリウム又は炭酸水素リチウムのようなアルカリ金属重炭酸塩類；酢酸ナトリウムのようなアルカリ金属酢酸塩類；水素化リチウム、水素化ナトリウム又は水素化カリウムのようなアルカリ金属水素化物類；水酸化ナトリウム、水酸化カリウム又は水酸化リチウムのようなアルカリ金属水酸化物類；ナトリウムメトキシド、ナトリウムエトキシド、カリウムｔ−ブトキシド又はリチウムメトキシドのようなアルカリ金属アルコキシド類；トリエチルアミン、トリブチルアミン、ジイソプロピルエチルアミン、Ｎ−メチルモルホリン、ピリジン、４−（Ｎ，Ｎ−ジメチルアミノ）ピリジン、Ｎ，Ｎ−ジメチルアニリン、Ｎ，Ｎ−ジエチルアニリン、１，５−ジアザビシクロ［４．３．０］ノナ−５−エン、１，４−ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ）又は１，８−ジアザビシクロ［５．４．０］ウンデク−７−エン（ＤＢＵ）のような有機塩基類；メチルリチウム、エチルリチウム又はブチルリチウムのようなアルキルリチウム類；或いは、リチウムジイソプロピルアミド又はリチウムジシクロヘキシルアミドのようなリチウムアルキルアミド類であり得、好適にはアルカリ金属水素化物類（特に水素化リチウム若しくは水素化ナトリウム）、金属アルコキシド類（特にナトリウムメトキシド）又はアルキルリチウム類（特にブチルリチウム）である。
第Ｈ１（１）工程の反応温度は、原料化合物、試薬等によって異なるが、通常−１０℃乃至１００℃であり、好適には−５℃乃至５０℃である。
第Ｈ１（１）工程の反応時間は、原料化合物、試薬、反応温度によって異なるが、通常５分間乃至２４時間であり、好適には１０分間乃至１２時間である。
反応終了後、第Ｈ１（１）工程の目的化合物は常法に従って反応混合物から採取される。例えば、反応終了後、反応液に水を加えた後、水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル等）を加えて目的化合物を抽出した後、抽出した有機層を水洗し、無水硫酸マグネシウム等を用いて乾燥させた後、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱、クロマトグラフィーにより更に精製できる。 The solvent used in Step H1 (1) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, hexane, cyclohexane, heptane, ligroin or petroleum ether can be used. Aliphatic hydrocarbons; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether; Ethers such as diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; nitro compounds such as nitromethane; nitriles such as acetonitrile or isobutyronitrile; formamide, N, N-dimethylform Amides such as amide, N, N-dimethylacetamide or N-methyl-2-pyrrolidinone; or sulfoxides such as dimethyl sulfoxide or sulfolane, preferably amides (especially N, N-dimethyl Formamide or N, N-dimethylacetamide).
The base used in Step H1 (1) is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate, or lithium carbonate; an alkali metal bicarbonate such as sodium bicarbonate, potassium bicarbonate, or lithium bicarbonate. Alkali metal acetates such as sodium acetate; alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide Alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) ) Gin, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) Or organic bases such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU); alkyllithiums such as methyllithium, ethyllithium or butyllithium; or lithium diisopropylamide or lithium Lithium alkylamides such as dicyclohexylamide can be used, preferably alkali metal hydrides (especially lithium hydride or sodium hydride), metal alkoxides (especially sodium methoxide) or alkyllithiums (especially butyllithium). It is.
The reaction temperature in Step H1 (1) varies depending on the raw material compounds, reagents and the like, but is usually −10 ° C. to 100 ° C., preferably −5 ° C. to 50 ° C.
The reaction time in the H1 (1) step varies depending on the raw material compounds, reagents and reaction temperature, but is usually 5 minutes to 24 hours, preferably 10 minutes to 12 hours.
After completion of the reaction, the target compound in Step H1 (1) is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, water is added to the reaction solution, a solvent immiscible with water (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, the extracted organic layer is washed with water, and sulfuric anhydride is added. After drying using magnesium or the like, the target compound is obtained by distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

第Ｈ１（２）工程で使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えばヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジクロロメタン、クロロホルム、四塩化炭素、ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；或はジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類であり得、好適には、脂肪族炭化水素類、芳香族炭化水素類、ハロゲン化炭化水素類又はエーテル類であり、更に好適には、ハロゲン化炭化水素類（特にジクロロメタン）又はエーテル類（特にジエチルエーテル又はテトラヒドロフラン）である。
第Ｈ１（２）工程で使用されるホスフィン類は、例えば、トリメチルホスフィン、トリエチルホスフィン、トリプロピルホスフィン、トリブチルホスフィン、トリペンチルホスフィン又はトリヘキシルホスフィン等のトリＣ₁−Ｃ₆アルキルホスフィン；トリフェニルホスフィン、トリインデニルホスフィン又はトリナフチルホスフィン等のトリＣ₆−Ｃ₁₀アリールホスフィン；或はトリルジフェニルホスフィン、トリトリルホスフィン、トリメシチルホスフィン、トリブチルフェニルホスフィン又はトリ−６−エチル−２−ナフチルホスフィン等の、Ｃ₁−Ｃ₄アルキルを置換基として有してもよいトリＣ₆−Ｃ₁₀アリールホスフィンであり得、好適にはトリＣ₁−Ｃ₆アルキルホスフィン類（特にトリメチルホスフィン、トリエチルホスフィン、トリプロピルホスフィン又はトリブチルホスフィン）又はトリＣ₆−Ｃ₁₀アリールホスフィン（特にトリフェニルホスフィン、トリインデニルホスフィン又はトリナフチルホスフィン）であり、更に好適には、トリブチルホスフィン又はトリフェニルホスフィンである。
第Ｈ１（２）工程で使用されるアゾ化合物は、例えば、アゾジカルボニルジピペリジン、アゾジカルボン酸ジメチル、アゾジカルボン酸ジエチル、アゾジカルボン酸ジプロピル又はアゾジカルボン酸ジブチルのようなアゾジカルボン酸ジ−Ｃ₁−Ｃ₄アルキルであり得、好適にはアゾジカルボン酸ジメチル又はアゾジカルボン酸ジエチルである。
第Ｈ１（２）工程の反応温度は、原料化合物、試薬等によって変化するが、通常−２０℃乃至１００℃であり、好適には−１０℃乃至５０℃である。
第Ｈ１（２）工程の反応時間は、原料化合物、試薬、反応温度によって変化するが、通常１５分乃至４８時間であり、好適には３０分乃至２４時間である。
反応終了後、第Ｈ１（２）工程の目的化合物は、常法に従って反応混合物から採取される。例えば、不溶物が存在する場合にはそれをろ去し、溶剤を留去すること、又は溶剤を留去した残渣に水を注ぎ、水と混和しない溶剤（例えばベンゼン、エーテル、酢酸エチル等）を加え抽出した後、水洗し、無水硫酸マグネシウム等で乾燥後、溶剤を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱又はクロマトグラフィー等によって更に精製できる。 The solvent used in Step H1 (2) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic carbonization such as hexane, heptane, ligroin or petroleum ether. Hydrogens; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; or diethyl ether, diisopropyl ether, tetrahydrofuran, It can be ethers such as dioxane, dimethoxyethane or diethylene glycol dimethyl ether, preferably aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons or ethers, more preferably halogenated Hydrocarbons (especially dichlorometa ) Or ethers (in particular diethyl ether or tetrahydrofuran).
The phosphines used in Step H1 (2) are, for example, tri-C ₁ -C ₆ alkyl phosphines such as trimethyl phosphine, triethyl phosphine, tripropyl phosphine, tributyl phosphine, tripentyl phosphine or trihexyl phosphine; , tri C ₆ -C ₁₀ arylphosphine such as tri indenyl phosphine or trinaphthylphosphine; or tolyl diphenyl phosphine, tritolylphosphine, trimesitylphosphine phosphine, tributyl triphenylphosphine or tri-6-ethyl-2-naphthyl phosphines such as , C ₁ -C ₄ can also be a good tri C ₆ -C ₁₀ arylphosphine have alkyl as a substituent, preferably tri C ₁ -C ₆ alkyl phosphines (particularly trimethylphosphine, triethylphosphine phosphine Emissions, tripropylphosphine or tributylphosphine) or tri C ₆ -C ₁₀ arylphosphine (particularly triphenylphosphine, a tri-indenyl phosphine or trinaphthylphosphine), more preferably a tributylphosphine or triphenylphosphine.
The azo compound used in Step H1 (2) is, for example, azodicarboxylic acid di-C such as azodicarbonyldipiperidine, dimethyl azodicarboxylate, diethyl azodicarboxylate, dipropyl azodicarboxylate or dibutyl azodicarboxylate. it is a ₁ -C ₄ alkyl, preferably a azodicarboxylic acid dimethyl or diethyl azodicarboxylate.
The reaction temperature in Step H1 (2) varies depending on the raw material compounds, reagents and the like, but is usually −20 ° C. to 100 ° C., preferably −10 ° C. to 50 ° C.
The reaction time in Step H1 (2) varies depending on the raw material compounds, reagents and reaction temperature, but is usually 15 minutes to 48 hours, preferably 30 minutes to 24 hours.
After completion of the reaction, the target compound of Step H1 (2) is collected from the reaction mixture according to a conventional method. For example, if insolubles are present, filter them off, distill off the solvent, or pour water into the residue from which the solvent has been distilled off, and a solvent that is immiscible with water (eg benzene, ether, ethyl acetate, etc.) After extraction, the product is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

第Ｈ２工程は、化合物（ＩＶａ）を製造する工程であり、化合物（ＸＸＶＩ）を、
（１）不活性溶媒中、１気圧乃至５気圧の水素雰囲気下（好適には１気圧）、接触還元触媒を用いて還元するか、或いは、
（２）金属粉存在下、酢酸中で攪拌する等により、通常、有機化学的に既知なニトロ基のアミノ基への還元法を適用することにより達成される。 Step H2 is a step of producing compound (IVa). Compound (XXVI) is converted into
(1) Reduction with a catalytic reduction catalyst in an inert solvent under a hydrogen atmosphere of 1 to 5 atm (preferably 1 atm), or
(2) It is usually achieved by applying a method of reducing organically known nitro groups to amino groups by stirring in acetic acid in the presence of metal powder.

接触還元に於て使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ヘキサン、シクロヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジクロロメタン、クロロホルム、四塩化炭素、１，２−ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類；メタノール、エタノール、プロパノール、２−プロパノール、ブタノール又はイソブタノールのようなアルコール類；或いは、それらの混合溶媒であり得、好適にはアルコール類（特にメタノール）又はエーテル類及びアルコール類の混合溶媒（特にテトラヒドロフラン及びメタノール又はエタノールの混合溶媒）である。
使用される接触還元触媒は、通常の接触還元反応に使用されるものであれば、特に限定はないが、例えば、パラジウム黒、パラジウム−炭素、水酸化パラジウム、水酸化パラジウム−炭素、ラネーニッケル、ロジウム−酸化アルミニウム、パラジウム−硫酸バリウム、酸化白金又は白金黒であり得、好適には、パラジウム−炭素である。
反応温度は、原料化合物、試薬等によって異なるが、通常−１０℃乃至１００℃であり、好適には０℃乃至５０℃である。
反応時間は原料化合物、試薬、反応温度によって異なるが、通常１０分間乃至１０時間であり、好適には３０分間乃至６時間である。
反応終了後、本工程の目的化合物は常法に従って反応混合物から採取される。例えば、反応終了後、触媒をろ去した後、ろ液を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱、クロマトグラフィーにより更に精製できる。 The solvent used in the catalytic reduction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, aliphatic solvents such as hexane, cyclohexane, heptane, ligroin or petroleum ether. Hydrocarbons; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether , Tetrahydrofuran, dioxane, dimethoxyethane or ethers such as diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, propanol, 2-propanol, butanol or isobutanol; or a mixed solvent thereof There obtained, preferably alcohols (particularly methanol) or a mixture of ethers and alcohols (particularly a mixed solvent of tetrahydrofuran and methanol or ethanol).
The catalytic reduction catalyst used is not particularly limited as long as it is used in a normal catalytic reduction reaction. For example, palladium black, palladium-carbon, palladium hydroxide, palladium hydroxide-carbon, Raney nickel, rhodium -Aluminum oxide, palladium-barium sulfate, platinum oxide or platinum black, preferably palladium-carbon.
While the reaction temperature varies depending on the raw material compound, reagent and the like, it is generally −10 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C.
While the reaction time varies depending on the raw material compound, reagent, and reaction temperature, it is generally 10 minutes to 10 hours, preferably 30 minutes to 6 hours.
After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the catalyst is filtered off, and then the filtrate is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

また、金属粉を用いた還元に於て使用される溶媒は、酢酸、塩酸水、水、アルコール又は水に溶解する有機溶媒との混合物であり得、好適には酢酸である。
使用される金属粉は、例えば、亜鉛粉、錫粉又は鉄粉であり得、好適には亜鉛粉又は錫粉である。
反応温度は、原料化合物、試薬等によって異なるが、通常−１０℃乃至１００℃であり、好適には０℃乃至５０℃である。
反応時間は原料化合物、試薬、反応温度によって異なるが、通常１０分間乃至１０時間であり、好適には３０分間乃至３時間である。
反応終了後、本工程の目的化合物は常法に従って反応混合物から採取される。例えば、反応終了後、不溶物をろ去した後、ろ液を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱、クロマトグラフィーにより更に精製できる。 The solvent used in the reduction using the metal powder can be acetic acid, aqueous hydrochloric acid, water, alcohol or a mixture with an organic solvent dissolved in water, and is preferably acetic acid.
The metal powder used can be, for example, zinc powder, tin powder or iron powder, preferably zinc powder or tin powder.
While the reaction temperature varies depending on the raw material compound, reagent and the like, it is generally −10 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C.
While the reaction time varies depending on the raw material compound, reagent, and reaction temperature, it is generally 10 minutes to 10 hours, preferably 30 minutes to 3 hours.
After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the insoluble matter is removed by filtration, and then the filtrate is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

第Ｈ３工程は、一般式（ＩＶｂ）を有する化合物を製造する工程であり、化合物（ＩＶａ）を、不活性溶媒中、塩基存在下又は不存在下（好適には塩基存在下）、化合物（ＶＩＩ）と反応させることにより達成され、第Ｂ２工程と同様の条件下で行なうことができる。 Step H3 is a step of producing a compound having the general formula (IVb). The compound (IVa) is compounded with compound (VII) in an inert solvent in the presence or absence of a base (preferably in the presence of a base). And can be carried out under the same conditions as in Step B2.

第Ｈ４工程は、一般式（ＩＶｃ）を有する化合物を製造する工程であり、化合物（ＩＶａ）を、不活性溶媒中、酢酸及びシアン化３水素化ホウ素ナトリウム存在下、化合物（ＶＩＩＩ）と反応させることにより達成され、第Ｂ３工程と同様の条件下で行なうことができる。 Step H4 is a step for producing a compound having the general formula (IVc), and reacting compound (IVa) with compound (VIII) in the presence of acetic acid and sodium tricyanoborohydride in an inert solvent. Can be carried out under the same conditions as in Step B3.

第Ｈ５工程は、一般式（ＩＶｄ）を有する化合物を製造する工程であり、化合物（ＩＶａ）を、
（１）不活性溶媒中、塩基存在下又は不存在下（好適には塩基存在下）、化合物（ＩＸ）又は（Ｘ）と反応させた後、
所望に応じて、
（２）上記（１）で得られた化合物の、水酸基の保護基を除去することにより達成され、各々、第Ｂ４（１）工程又は第Ａ２工程の反応（ｅ）と同様の条件下で行うことができる。 Step H5 is a step of producing a compound having the general formula (IVd), and the compound (IVa)
(1) After reacting with compound (IX) or (X) in an inert solvent in the presence or absence of a base (preferably in the presence of a base),
As desired
(2) The compound obtained in (1) above is achieved by removing the hydroxyl-protecting group, and each is carried out under the same conditions as in step B4 (1) or reaction (e) in step A2. be able to.

Ｊ法は、一般式（ＸＩＩａ）、（ＸＩＩｂ）、（ＸＩＩｃ）又は（ＸＩＩｄ）を有する化合物を製造する方法である。 Method J is a method for producing a compound having the general formula (XIIa), (XIIb), (XIIc) or (XIId).

第Ｊ１工程は、一般式（ＸＸＶＩＩ）を有する化合物を製造する工程であり、化合物（ＸＸＶ）に於いて、Ｚが水酸基である、一般式（ＸＸＶａ）を有する化合物を、
（１）不活性溶媒中、塩基存在下又は不存在下（好適には塩基存在下）、一般式Ｒ¹²−Ｚa 有する化合物（式中、Ｒ¹²は、前述したものと同意義を示し、Ｚaは、脱離基を示す他はＺと同意義を示す。）又は一般式Ｒ¹²a−Ｏ−Ｒ¹²aを有する化合物（式中、Ｒ¹²aは、アシル基を示す他はＲ¹²と同意義を示す。）と反応させるか、
（２）不活性溶媒中、縮合剤及び塩基存在下又は不存在下（好適には塩基存在下）一般式Ｒ¹²a−ＯＨを有する化合物（式中、Ｒ¹²aは、前記と同意義を示す。）と反応させるか、
（３）不活性溶媒中、塩化燐酸ジエチルのようなハロゲン化燐酸ジアルキルエステル類及び塩基存在下、一般式Ｒ¹²a−ＯＨを有する化合物（Ｒ¹²aは、前記と同意義を示す。）と反応させるか、又は
（４）不活性溶媒中、酸存在下又は不存在下（好適には酸存在下）、ジヒドロフラン若しくはジヒドロピラン類と反応させることにより達成される。 Step J1 is a step of producing a compound having the general formula (XXVII). In the compound (XXV), a compound having the general formula (XXVa), wherein Z is a hydroxyl group,
(1) A compound having the general formula R ¹² -Za in an inert solvent, in the presence or absence of a base (preferably in the presence of a base) (wherein R ¹² is as defined above, Za Represents the same as Z except that it represents a leaving group.) Or a compound having the general formula R ¹² a—O—R ¹² a (wherein R ¹² a represents an acyl group, and R ¹² represents Show the same meaning.)
(2) In an inert solvent, in the presence or absence of a condensing agent and a base (preferably in the presence of a base), a compound having the general formula R ¹² a-OH (wherein R ¹² a is as defined above). Or show)
(3) a compound having the general formula R ¹² a-OH in the presence of a halogenated phosphoric acid dialkyl ester such as diethyl chlorophosphate and a base in an inert solvent (R ¹² a is as defined above); (4) It is achieved by reacting with dihydrofuran or dihydropyrans in an inert solvent in the presence or absence of an acid (preferably in the presence of an acid).

第Ｊ１（１）工程に於いて使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ヘキサン、シクロヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジクロロメタン、クロロホルム、四塩化炭素、１，２−ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類；蟻酸エチル、酢酸エチル、酢酸プロピル、酢酸ブチル又は炭酸ジエチルのようなエステル類；アセトン又はメチルエチルケトンのようなケトン類；ニトロメタンのようなニトロ化合物類；アセトニトリル又はイソブチロニトリルのようなニトリル類；メタノール、エタノール、プロパノール、２−プロパノール、ブタノール又はイソブタノールのようなアルコール類；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又はＮ−メチル−２−ピロリジノンのようなアミド類；或いは、ジメチルスルホキシド又はスルホランのようなスルホキシド類であり得、好適には、ハロゲン化炭化水素類（特にジクロロメタン）、エーテル類（特にジエチルエーテル又はテトラヒドロフラン）或いはアミド類（特にＮ，Ｎ−ジメチルホルムアミド）である。
第Ｊ１（１）工程で使用される塩基は、例えば、炭酸ナトリウム、炭酸カリウム又は炭酸リチウムのようなアルカリ金属炭酸塩類；炭酸水素ナトリウム、炭酸水素カリウム又は炭酸水素リチウムのようなアルカリ金属重炭酸塩類；水素化リチウム、水素化ナトリウム又は水素化カリウムのようなアルカリ金属水素化物類；ナトリウムメトキシド、ナトリウムエトキシド、カリウムｔ−ブトキシド又はリチウムメトキシドのようなアルカリ金属アルコキシド類；或いは、トリエチルアミン、トリブチルアミン、ジイソプロピルエチルアミン、Ｎ−メチルモルホリン、ピリジン、４−（Ｎ，Ｎ−ジメチルアミノ）ピリジン、Ｎ，Ｎ−ジメチルアニリン、Ｎ，Ｎ−ジエチルアニリン、１，５−ジアザビシクロ［４．３．０］ノナ−５−エン、１，４−ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ）又は１，８−ジアザビシクロ［５．４．０］ウンデク−７−エン（ＤＢＵ）のような有機アミン類であり得、好適には、アルカリ金属水素化物類（特に水素化ナトリウム）、アルカリ金属アルコキシド類（特にカリウムｔ−ブトキシド）或いは有機アミン類（特にトリエチルアミン又はピリジン）である。
尚、４−（Ｎ，Ｎ−ジメチルアミノ）ピリジン、４−ピロリジノピリジンは、他の塩基と組み合わせて、触媒量を用いることもでき、又、反応を効果的に行わせるために、ベンジルトリエチルアンモニウムクロリド、テトラブチルアンモニウムクロリドのような第４級アンモニウム塩類、ジベンゾ−１８−クラウン−６のようなクラウンエーテル類等を添加することもできる。
第Ｊ１（１）工程の反応温度は、原料化合物、試薬等によって異なるが、通常−２０℃乃至１００℃であり、好適には０℃乃至５０℃である。
第Ｊ１（１）工程の反応時間は、原料化合物、試薬、反応温度によって異なるが、通常１０分間乃至２４時間であり、好適には３０分間乃至１２時間である。
一般式Ｒ¹²−Ｚa を有する化合物の具体例としては、例えば、アセチルクロリド、プロピオニルクロリド、ブチリルブロミド、バレリルクロリド、ヘキサノイルクロリド、メトキシカルボニルクロリド、メトキシカルボニルブロミド、エトキシカルボニルクロリド、プロポキシカルボニルクロリド、ブトキシカルボニルクロリド、ヘキシルオキシカルボニルクロリド、ベンゾイルクロリド、ベンゾイルブロミド又はナフトイルクロリドのようなアシルハライド類；ｔ−ブチルジメチルシリルクロリド、トリメチルシリルクロリド、トリエチルシリルクロリド、トリエチルシリルブロミド、トリイソプロピルシリルクロリド、ジメチルイソプロピルシリルクロリド、ジエチルイソプロピルシリルクロリド、ｔ−ブチルジフェニルシリルクロリド、ジフェニルメチルシリルクロリド、トリフェニルシリルクロリドのようなシリルハライド類又は対応するシリルトリフルオロメタンスルホネート類；ベンジルクロリド、ベンジルブロミドのようなアラルキルハライド類；或いは、メトキシメチルクロリド、エトキシメチルクロリド、ピバロイルオキシメチルクロリド、エトキシカルボニルオキシメチルクロリドのようなアルキルハライド類を挙げることができ、好適にはアルキルハライド類（特にメトキシメチルクロリド）である。
一般式Ｒ¹²a−Ｏ−Ｒ¹²a を有する化合物の具体例としては、例えば、無水酢酸、無水プロピオン酸、無水バレリル酸、無水ヘキサン酸のような脂肪族カルボン酸無水物を挙げることができ、更に、ギ酸と酢酸のような混合酸無水物を使用することもできる。 The solvent used in Step J1 (1) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, hexane, cyclohexane, heptane, ligroin or petroleum ether Aliphatic hydrocarbons such as; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; Ethers such as ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate; like acetone or methyl ethyl ketone Ketones; nitro compounds such as nitromethane; nitriles such as acetonitrile or isobutyronitrile; alcohols such as methanol, ethanol, propanol, 2-propanol, butanol or isobutanol; formamide, N, N-dimethyl Amides such as formamide, N, N-dimethylacetamide or N-methyl-2-pyrrolidinone; or sulfoxides such as dimethyl sulfoxide or sulfolane, preferably halogenated hydrocarbons (especially dichloromethane) Ethers (particularly diethyl ether or tetrahydrofuran) or amides (particularly N, N-dimethylformamide).
The base used in Step J1 (1) is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate, or lithium carbonate; an alkali metal bicarbonate such as sodium bicarbonate, potassium bicarbonate, or lithium bicarbonate. Alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; or triethylamine, Butylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] Non-5-ene, 1,4 It can be an organic amine such as diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), preferably an alkali metal hydrogen Compounds (especially sodium hydride), alkali metal alkoxides (especially potassium t-butoxide) or organic amines (especially triethylamine or pyridine).
Incidentally, 4- (N, N-dimethylamino) pyridine and 4-pyrrolidinopyridine can be used in combination with other bases in a catalytic amount. In order to carry out the reaction effectively, benzyltriethyl Quaternary ammonium salts such as ammonium chloride and tetrabutylammonium chloride, crown ethers such as dibenzo-18-crown-6, and the like can also be added.
The reaction temperature in Step J1 (1) varies depending on the raw material compounds, reagents and the like, but is usually −20 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C.
The reaction time in Step J1 (1) varies depending on the raw material compounds, reagents and reaction temperature, but is usually 10 minutes to 24 hours, preferably 30 minutes to 12 hours.
Specific examples of the compound having the general formula R ¹² -Za include, for example, acetyl chloride, propionyl chloride, butyryl bromide, valeryl chloride, hexanoyl chloride, methoxycarbonyl chloride, methoxycarbonyl bromide, ethoxycarbonyl chloride, propoxycarbonyl chloride, butoxy Acyl halides such as carbonyl chloride, hexyloxycarbonyl chloride, benzoyl chloride, benzoyl bromide or naphthoyl chloride; t-butyldimethylsilyl chloride, trimethylsilyl chloride, triethylsilyl chloride, triethylsilyl bromide, triisopropylsilyl chloride, dimethylisopropylsilyl Chloride, diethylisopropylsilyl chloride, t-butyldiphenylsilyl chloride Silyl halides such as diphenylmethylsilyl chloride, triphenylsilyl chloride or the corresponding silyl trifluoromethanesulfonates; aralkyl halides such as benzyl chloride, benzyl bromide; or methoxymethyl chloride, ethoxymethyl chloride, pivaloyl Examples include alkyl halides such as oxymethyl chloride and ethoxycarbonyloxymethyl chloride, and alkyl halides (particularly methoxymethyl chloride) are preferred.
Specific examples of the compound having the general formula R ¹² a—O—R ¹² a include aliphatic carboxylic acid anhydrides such as acetic anhydride, propionic anhydride, valeric acid anhydride, and hexanoic anhydride. Furthermore, mixed acid anhydrides such as formic acid and acetic acid can also be used.

第Ｊ１（２）工程に於いて使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ヘキサン、シクロヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジクロロメタン、クロロホルム、四塩化炭素、１，２−ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類；アセトン又はメチルエチルケトンのようなケトン類；ニトロメタンのようなニトロ化合物類；アセトニトリル又はイソブチロニトリルのようなニトリル類；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又はＮ−メチル−２−ピロリジノンのようなアミド類；或いは、ジメチルスルホキシド又はスルホランのようなスルホキシド類であり得、好適には、エーテル類（特にジエチルエーテル又はテトラヒドロフラン）或いはアミド類（特にＮ，Ｎ−ジメチルアセトアミド又はＮ−メチル−２−ピロリジノン）である。
第Ｊ１（２）工程に於いて使用される縮合剤は、例えば、ジシクロヘキシルカルボジイミド、カルボニルジイミダゾール又は１−メチル−２−クロロ−ピリジニウムヨージド−トリエチルアミンであり得、好適にはジシクロヘキシルカルボジイミドである。
第Ｊ１（２）工程において使用される塩基は、第Ｊ１（１）工程に於いて使用されるものと同様のものを挙げることができる。
第Ｊ１（２）工程の反応温度は原料化合物、試薬等によって異なるが、通常−２０℃乃至１００℃であり、好適には０℃乃至５０℃である。
第Ｊ１（２）工程の反応時間は原料化合物、試薬、反応温度によって異なるが、通常１０分間乃至２４時間であり、好適には３０分間乃至１２時間である。 The solvent used in Step J1 (2) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, hexane, cyclohexane, heptane, ligroin or petroleum ether Aliphatic hydrocarbons such as; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; Ethers such as ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone or methyl ethyl ketone; nitro compounds such as nitromethane; acetonitrile or isobutyronitrile Nitriles such as; amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide or N-methyl-2-pyrrolidinone; or sulfoxides such as dimethyl sulfoxide or sulfolane, which are preferred Are ethers (especially diethyl ether or tetrahydrofuran) or amides (especially N, N-dimethylacetamide or N-methyl-2-pyrrolidinone).
The condensing agent used in Step J1 (2) can be, for example, dicyclohexylcarbodiimide, carbonyldiimidazole or 1-methyl-2-chloro-pyridinium iodide-triethylamine, and is preferably dicyclohexylcarbodiimide.
Examples of the base used in the J1 (2) step include the same bases as used in the J1 (1) step.
The reaction temperature in Step J1 (2) varies depending on the raw material compounds, reagents and the like, but is usually −20 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C.
The reaction time in the J1 (2) step varies depending on the raw material compounds, reagents, and reaction temperature, but is usually 10 minutes to 24 hours, preferably 30 minutes to 12 hours.

第Ｊ１（３）工程に於いて使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ヘキサン、シクロヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジクロロメタン、クロロホルム、四塩化炭素、１，２−ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類；アセトン又はメチルエチルケトンのようなケトン類；蟻酸エチル、酢酸エチル、酢酸プロピル、酢酸ブチル、炭酸ジエチルのようなエステル類；ニトロメタンのようなニトロ化合物類；アセトニトリル又はイソブチロニトリルのようなニトリル類；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又はＮ−メチル−２−ピロリジノンのようなアミド類；或いは、ジメチルスルホキシド又はスルホランのようなスルホキシド類であり得、好適には、エーテル類（特にジエチルエーテル又はテトラヒドロフラン）である。
第Ｊ１（３）工程に於いて使用される塩基は、第Ｊ１（１）工程に於いて使用されるものと同様のものを挙げることができる。
第Ｊ１（３）工程の反応温度は原料化合物、試薬等によって異なるが、通常−２０℃乃至１００℃であり、好適には０℃乃至５０℃である。
第Ｊ１（３）工程の反応時間は原料化合物、試薬、反応温度によって異なるが、通常１０分間乃至２４時間であり、好適には３０分間乃至１２時間である。 The solvent used in Step J1 (3) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, hexane, cyclohexane, heptane, ligroin or petroleum ether Aliphatic hydrocarbons such as; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; Ethers such as ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; ketones such as acetone or methyl ethyl ketone; ethers such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate Nitro compounds such as nitromethane; nitriles such as acetonitrile or isobutyronitrile; amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide or N-methyl-2-pyrrolidinone Or sulfoxides such as dimethyl sulfoxide or sulfolane, preferably ethers (especially diethyl ether or tetrahydrofuran).
Examples of the base used in the J1 (3) step can be the same as those used in the J1 (1) step.
The reaction temperature in Step J1 (3) varies depending on the raw material compounds, reagents and the like, but is usually −20 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C.
The reaction time in the J1 (3) step varies depending on the raw material compounds, reagents and reaction temperature, but is usually 10 minutes to 24 hours, preferably 30 minutes to 12 hours.

第Ｊ１（４）工程に於いて使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ヘキサン、シクロヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジクロロメタン、クロロホルム、四塩化炭素、１，２−ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類；蟻酸エチル、酢酸エチル、酢酸プロピル、酢酸ブチル又は炭酸ジエチルのようなエステル類；ニトロメタンのようなニトロ化合物類；或いは、アセトニトリル又はイソブチロニトリルのようなニトリル類であり得、好適には、ハロゲン化炭化水素類（特にジクロロメタン）又はエーテル類（特にジエチルエーテル若しくはテトラヒドロフラン）である。
第Ｊ１（４）工程で使用される酸は、例えば、弗化水素酸、塩酸、臭化水素酸、沃化水素酸、硝酸、過塩素酸、硫酸又は燐酸等の鉱酸；メタンスルホン酸、トリフルオロメタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸又はｐ−トルエンスルホン酸のようなスルホン酸；或いは、酢酸、プロピオン酸、酪酸、フマール酸、コハク酸、クエン酸、酒石酸、蓚酸、マレイン酸又は安息香酸等のカルボン酸であり得、好適にはスルホン酸（特にｐ−トルエンスルホン酸）である。
第Ｊ１（４）工程の反応温度は、原料化合物、試薬等によって異なるが、通常−２０℃乃至１００℃であり、好適には０℃乃至５０℃である。
第Ｊ１（４）工程の反応時間は、原料化合物、試薬、反応温度によって異なるが、通常１０分間乃至２４時間であり、好適には３０分間乃至１２時間である。
反応終了後、第Ｊ１工程の各反応の目的化合物は、常法に従って反応混合物から採取される。例えば、反応終了後、反応液に水を加え、水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル等）を加えて目的化合物を抽出した後、抽出した有機層を水洗し、無水硫酸マグネシウム等を用いて乾燥させた後、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱、クロマトグラフィーにより更に精製できる。 The solvent used in Step J1 (4) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, hexane, cyclohexane, heptane, ligroin or petroleum ether Aliphatic hydrocarbons such as; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; Ethers such as ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate; nitro compounds such as nitromethane; There is obtained a nitrile such as acetonitrile or isobutyronitrile, preferably a halogenated hydrocarbon (particularly dichloromethane) or an ether (particularly diethyl ether or tetrahydrofuran).
Examples of the acid used in Step J1 (4) include mineral acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; methanesulfonic acid, Sulfonic acids such as trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid; or acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, citric acid, tartaric acid, succinic acid, maleic acid or benzoic acid It can be a carboxylic acid such as an acid, and is preferably a sulfonic acid (particularly p-toluenesulfonic acid).
The reaction temperature in Step J1 (4) varies depending on the raw material compounds, reagents and the like, but is usually −20 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C.
The reaction time in Step J1 (4) varies depending on the raw material compounds, reagents, and reaction temperature, but is usually 10 minutes to 24 hours, preferably 30 minutes to 12 hours.
After completion of the reaction, the target compound of each reaction in Step J1 is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, water is added to the reaction solution, a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and then the extracted organic layer is washed with water, anhydrous magnesium sulfate, etc. Then, the target compound is obtained by distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

第Ｊ２工程は、化合物（ＸＩＩａ）を製造する工程であり、化合物（ＸＸＶＩＩ）を、
（１）不活性溶媒中、１気圧乃至５気圧の水素雰囲気下（好適には１気圧）、接触還元触媒を用いて還元するか、或いは、
（２）金属粉存在下、酢酸中で攪拌する等により、通常、有機化学的に既知なニトロ基のアミノ基への還元法を適用することにより達成され、第Ｈ２工程と同様の条件下で行なうことができる。 Step J2 is a step of producing compound (XIIa), wherein compound (XXVII)
(1) Reduction with a catalytic reduction catalyst in an inert solvent under a hydrogen atmosphere of 1 to 5 atm (preferably 1 atm), or
(2) Usually achieved by applying a method of reducing organically known nitro groups to amino groups by stirring in acetic acid in the presence of metal powder, under the same conditions as in Step H2. Can be done.

第Ｊ３工程は、一般式（ＸＩＩｂ）を有する化合物を製造する工程であり、化合物（ＸＩＩａ）を、不活性溶媒中、塩基存在下又は不存在下（好適には塩基存在下）、化合物（ＶＩＩ）と反応させることにより達成され、第Ｂ２工程と同様の条件下で行なうことができる。 Step J3 is a step of producing a compound having the general formula (XIIb). The compound (XIIa) is compounded with the compound (VII) in an inert solvent in the presence or absence of a base (preferably in the presence of a base). And can be carried out under the same conditions as in Step B2.

第Ｊ４工程は、一般式（ＸＩＩｃ）を有する化合物を製造する工程であり、化合物（ＸＩＩａ）を、不活性溶媒中、酢酸及びシアン化３水素化ホウ素ナトリウム存在下、化合物（ＶＩＩＩ）と反応させることにより達成され、第Ｂ３工程と同様の条件下で行なうことができる。 Step J4 is a step of producing a compound having the general formula (XIIc), and reacting compound (XIIa) with compound (VIII) in the presence of acetic acid and sodium tricyanoborohydride in an inert solvent. Can be carried out under the same conditions as in Step B3.

第Ｊ５工程は、一般式（ＸＩＩｄ）を有する化合物を製造する工程であり、化合物（ＸＩＩａ）を、
（１）不活性溶媒中、塩基存在下又は不存在下（好適には塩基存在下）、化合物（ＩＸ）又は（Ｘ）と反応させた後、
所望に応じて、
（２）上記（１）で得られた化合物の、水酸基の保護基を除去することにより達成され、各々、第Ｂ４（１）工程又は第Ａ２工程の反応（ｅ）と同様の条件下で行うことができる。 Step J5 is a step of producing a compound having the general formula (XIId), and the compound (XIIa)
(1) After reacting with compound (IX) or (X) in an inert solvent in the presence or absence of a base (preferably in the presence of a base),
As desired
(2) The compound obtained in (1) above is achieved by removing the hydroxyl-protecting group, and each is carried out under the same conditions as in step B4 (1) or reaction (e) in step A2. be able to.

Ｋ法は、一般式（ＸＸＶｃ）又は（ＸＸＶｄ）を有する化合物を製造する方法である。 Method K is a method for producing a compound having the general formula (XXVc) or (XXVd).

第Ｋ１工程は、化合物（ＸＸＶｃ）を製造する工程であり、化合物（ＸＸＶｂ）を、
（１）不活性溶媒中、エステル化剤存在下、アルコールと反応させるか、
（２）不活性溶媒中、活性エステル化剤と反応させ、活性エステルを製造した後、不活性溶媒中、アルコールと反応させるか、
（３）不活性溶媒中、ハロゲン化剤と反応させ、酸ハライドを製造した後、不活性溶媒中、アルコールと反応させるか、又は、
（４）不活性溶媒中又は溶媒不存在下（好適には溶媒不存在下）、酸存在下、アルコールと反応させることにより達成される。 Step K1 is a step of producing compound (XXVc), and compound (XXVb)
(1) react with an alcohol in the presence of an esterifying agent in an inert solvent,
(2) After reacting with an active esterifying agent in an inert solvent to produce an active ester, reacting with an alcohol in an inert solvent,
(3) After reacting with a halogenating agent in an inert solvent to produce an acid halide, react with an alcohol in an inert solvent, or
(4) It is achieved by reacting with an alcohol in the presence of an acid in an inert solvent or in the absence of a solvent (preferably in the absence of a solvent).

第Ｋ１（１）工程に於て使用されるエステル化剤は、一般に有機合成化学の技術に於て通常用いられるものであれば特に限定はないが、例えば、ジアゾアルカン又はトリアルキルシリルジアゾアルカンであり得、好適には、ジアゾメタン、ジアゾエタン、ジアゾプロパン、ジアゾブタン、ジアゾペンタン又はジアゾヘキサンのようなＣ₁−Ｃ₆ジアゾアルカン或はトリメチルシリルジアゾメタンであり、更に好適にはＣ₁−Ｃ₄ジアゾアルカン又はトリメチルシリルジアゾメタンであり、特に好適にはジアゾメタンである。
ジアゾＣ₁−Ｃ₆アルカンを用いた反応に於て使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；メチレンクロリド、クロロホルム、四塩化炭素、ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類；酢酸メチル又は酢酸エチルのようなエステル類；或いは、上記溶媒の混合溶媒であり得、好適にはハロゲン化炭化水素類、エーテル類、エステル類又は上記溶媒の混合溶媒であり、更に好適にはエーテル類（特にジエチルエーテル）、エステル類（特に酢酸エチル）又は上記溶媒の混合溶媒である。
トリメチルシリルジアゾメタンを用いた反応に於て使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、メタノール、エタノール、プロパノール、２−プロパノール、ブタノール、イソブタノール、ｔ−ブタノール、ペンタノール又はヘキサノールのようなアルコ−ル類；或は、ヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；メチレンクロリド、クロロホルム、四塩化炭素、ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類；及び酢酸メチル又は酢酸エチルのようなエステル類からなる群より選択される溶媒と前記アルコ−ル類との混合溶媒であり得、好適にはアルコ−ル類（特にメタノール）又は芳香族炭化水素類（特にベンゼン）及びアルコ−ル類（特にメタノール）との混合溶媒である。
第Ｋ１（１）工程の反応温度は原料化合物、試薬等によって変化するが、通常−１０℃乃至１００℃であり、好適には１０℃乃至５０℃である。
第Ｋ１（１）工程の反応時間は原料化合物、試薬、反応温度によって変化するが、通常１０分乃至１０時間であり、好適には１５分乃至２時間である。
反応終了後、第Ｋ１（１）工程の目的化合物は常法に従って反応混合物から採取される。例えば、反応終了後、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱又はクロマトグラフィー等によって更に精製できる。 The esterifying agent used in the K1 (1) step is not particularly limited as long as it is generally used in organic synthetic chemistry techniques. For example, diazoalkane or trialkylsilyldiazoalkane is used. C ₁ -C ₆ diazoalkanes such as diazomethane, diazoethane, diazopropane, diazobutane, diazopentane or diazohexane or trimethylsilyldiazomethane, more preferably C ₁ -C ₄ diazoalkane or Trimethylsilyldiazomethane, particularly preferably diazomethane.
The solvent used in the reaction using diazo C ₁ -C ₆ alkane is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, hexane, heptane, ligroin or Aliphatic hydrocarbons such as petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl Ethers such as ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; esters such as methyl acetate or ethyl acetate; or a mixed solvent of the above solvents, preferably halogenated hydrocarbons , Ethers, An ethers or a mixed solvent of the above solvents, more preferably ethers (particularly diethyl ether), esters (particularly ethyl acetate) or a mixed solvent of the above solvents.
The solvent used in the reaction using trimethylsilyldiazomethane is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, methanol, ethanol, propanol, 2-propanol, butanol , Alcohols such as isobutanol, t-butanol, pentanol or hexanol; or aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatics such as benzene, toluene or xylene Hydrocarbons; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol Ethers such as methyl ether; and a solvent selected from the group consisting of esters such as methyl acetate or ethyl acetate and the above alcohols, preferably alcohols (especially Methanol) or a mixed solvent with aromatic hydrocarbons (especially benzene) and alcohols (especially methanol).
The reaction temperature in the K1 (1) step varies depending on the raw material compounds, reagents and the like, but is usually −10 ° C. to 100 ° C., preferably 10 ° C. to 50 ° C.
The reaction time in the K1 (1) step varies depending on the raw material compound, the reagent and the reaction temperature, but is usually 10 minutes to 10 hours, preferably 15 minutes to 2 hours.
After completion of the reaction, the target compound of Step K1 (1) is collected from the reaction mixture according to a conventional method. For example, the target compound is obtained by distilling off the solvent after completion of the reaction. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

第Ｋ１（２）工程に於て使用される活性エステル化剤は、一般に有機合成化学の技術に於て通常用いられるものであれば特に限定はないが、例えば、クロロギ酸エチル、Ｎ−ヒドロキシサクシンイミド、１−ヒドロキシベンゾトリアゾール又はＮ−ヒドロキシ−５−ノルボルネン−２，３−ジカルボキシイミドのようなＮ−ヒドロキシ化合物或はジピリジルジスルフィドのようなジスルフィド化合物であり得、活性エステル化反応は、ジシクロヘキシルカルボジイミド、カルボニルジイミダゾール又はトリフェニルホスフィンのような縮合剤の存在下に好適に行われる。
第Ｋ１（２）工程の両反応に於て使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、メチレンクロリド、クロロホルム、四塩化炭素、ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類；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又はヘキサメチルリン酸トリアミドのようなアミド類；或は、アセトニトリルのようなニトリル類であり得、好適にはエーテル類（特にテトラヒドロフラン）又はアミド類（特にＮ，Ｎ−ジメチルホルムアミド）である。
第Ｋ１（２）工程の反応温度は、原料化合物、試薬等によって変化するが、通常、活性エステル化反応では、−７０℃乃至１５０℃（好適には−１０℃乃至１００℃）であり、活性エステル化合物とアルコールとの反応では、−２０℃乃至１００℃（好適には０℃乃至５０℃）である。
第Ｋ１（２）工程の反応時間は、原料化合物、試薬、反応温度によって変化するが、両反応ともに、通常、３０分乃至８０時間（好適には１時間乃至４８時間）である。
反応終了後、第Ｋ１（２）工程の目的化合物は常法に従って反応混合物から採取される。例えば、反応終了後、溶媒を留去すること、又は溶媒を留去した残渣に水を注ぎ、水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル等）を加えて目的化合物を抽出し、抽出した有機層を水洗後、無水硫酸マグネシウム等で乾燥し、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱又はクロマトグラフィー等によって更に精製できる。 The active esterifying agent used in the K1 (2) step is not particularly limited as long as it is generally used in the organic synthetic chemistry technology. For example, ethyl chloroformate, N-hydroxysuccin It can be an N-hydroxy compound such as imide, 1-hydroxybenzotriazole or N-hydroxy-5-norbornene-2,3-dicarboximide or a disulfide compound such as dipyridyl disulfide. It is preferably carried out in the presence of a condensing agent such as carbodiimide, carbonyldiimidazole or triphenylphosphine.
The solvent used in both reactions of the K1 (2) step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, methylene chloride, chloroform, carbon tetrachloride Halogenated hydrocarbons such as dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; formamide, N, N-dimethylformamide, N, N- Amides such as dimethylacetamide or hexamethylphosphoric triamide; or nitriles such as acetonitrile, preferably ethers (especially tetrahydrofuran) or amides (especially N, N-dimethylformamide) That.
The reaction temperature in step K1 (2) varies depending on the raw material compounds, reagents, etc., but is usually -70 ° C to 150 ° C (preferably -10 ° C to 100 ° C) in the active esterification reaction, and active In the reaction between the ester compound and the alcohol, the temperature is -20 ° C to 100 ° C (preferably 0 ° C to 50 ° C).
The reaction time in the K1 (2) step varies depending on the raw material compound, the reagent, and the reaction temperature, but both reactions are usually 30 minutes to 80 hours (preferably 1 hour to 48 hours).
After completion of the reaction, the target compound of Step K1 (2) is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, or water is poured into the residue from which the solvent has been distilled off, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound and extraction The obtained organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

第Ｋ１（３）工程に於て使用されるハロゲン化剤は、一般に有機合成化学の技術に於て通常用いられるものであれば特に限定はないが、例えば、オキザリルクロリド、チオニルクロリド、オキシ塩化リン又は五塩化リンである。
第Ｋ１（３）工程の両反応に於て使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；メチレンクロリド、クロロホルム、四塩化炭素、ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；或はジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類であり得、好適にはエーテル類（特にテトラヒドロフラン）である。
第Ｋ１（３）工程の反応温度は、原料化合物、試薬等によって変化するが、通常、酸ハライド化反応では、−７０℃乃至１５０℃（好適には−１０℃乃至１００℃）であり、酸ハライドとアルコールとの反応では−２０℃乃至１００℃（好適には０℃乃至５０℃）である。
第Ｋ１（３）工程の反応時間は、原料化合物、試薬、反応温度によって変化するが、両反応ともに、通常、３０分乃至８０時間（好適には１時間乃至４８時間）である。
反応終了後、第Ｋ１（３）工程の目的化合物は常法に従って反応混合物から採取される。例えば、反応終了後、溶媒を留去すること、又は溶媒を留去した残渣に水を注ぎ、水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル等）を加えて目的化合物を抽出し、抽出した有機層を水洗後、無水硫酸マグネシウム等で乾燥し、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱又はクロマトグラフィー等によって更に精製できる。 The halogenating agent used in Step K1 (3) is not particularly limited as long as it is generally used in organic synthetic chemistry techniques. For example, oxalyl chloride, thionyl chloride, oxychloride Phosphorus or phosphorus pentachloride.
The solvent used in both reactions of the K1 (3) step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, benzene, toluene, xylene, etc. Aromatic hydrocarbons; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; or such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether Ethers can be used, and ethers (particularly tetrahydrofuran) are preferred.
The reaction temperature in step K1 (3) varies depending on the raw material compounds, reagents, etc., but is usually −70 ° C. to 150 ° C. (preferably −10 ° C. to 100 ° C.) in the acid halide reaction. In the reaction between halide and alcohol, the temperature is -20 ° C to 100 ° C (preferably 0 ° C to 50 ° C).
The reaction time in the K1 (3) step varies depending on the raw material compound, the reagent, and the reaction temperature, but both reactions are usually 30 minutes to 80 hours (preferably 1 hour to 48 hours).
After completion of the reaction, the target compound of Step K1 (3) is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, or water is poured into the residue from which the solvent has been distilled off, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound and extraction The obtained organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

第Ｋ１（４）工程に於いて使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、メチレンクロリド、クロロホルム、四塩化炭素、ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類；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又はヘキサメチルリン酸トリアミドのようなアミド類；或は、アセトニトリルのようなニトリル類であり得、好適にはエーテル類（特に、ジエチルエーテル又はテトラヒドロフラン）である。
第Ｋ１（４）工程で使用される酸は、例えば、弗化水素酸、塩酸、臭化水素酸、沃化水素酸、硝酸、過塩素酸、硫酸又は燐酸等の鉱酸；メタンスルホン酸、トリフルオロメタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸又はｐ−トルエンスルホン酸のようなスルホン酸；或いは、酢酸、プロピオン酸、酪酸、フマール酸、コハク酸、クエン酸、酒石酸、蓚酸、マレイン酸又は安息香酸等のカルボン酸であり得、好適には鉱酸（特に塩酸又は硫酸）である。
第Ｋ１（４）工程の反応温度は、原料化合物、試薬等によって変化するが、通常、０℃乃至１５０℃（好適には３０℃乃至１００℃）である。
第Ｋ１（４）工程の反応時間は、原料化合物、試薬、反応温度によって変化するが、通常、３０分乃至８０時間（好適には１時間乃至４８時間）である。
反応終了後、第Ｋ１（４）工程の目的化合物は常法に従って反応混合物から採取される。例えば、反応終了後、溶媒を留去すること、又は溶媒を留去した残渣に水を注ぎ、水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル等）を加えて目的化合物を抽出し、抽出した有機層を水洗後、無水硫酸マグネシウム等で乾燥し、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱又はクロマトグラフィー等によって更に精製できる。 The solvent used in the K1 (4) step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, methylene chloride, chloroform, carbon tetrachloride, dichloroethane, Halogenated hydrocarbons such as chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; formamide, N, N-dimethylformamide, N, N-dimethylacetamide or Amides such as hexamethylphosphoric triamide; or nitriles such as acetonitrile, preferably ethers (especially diethyl ether or tetrahydrofuran).
Examples of the acid used in the K1 (4) step include mineral acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; methanesulfonic acid, Sulfonic acids such as trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid; or acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, citric acid, tartaric acid, succinic acid, maleic acid or benzoic acid It can be a carboxylic acid such as an acid, preferably a mineral acid (especially hydrochloric acid or sulfuric acid).
The reaction temperature in the K1 (4) step varies depending on the raw material compounds, reagents and the like, but is usually 0 ° C. to 150 ° C. (preferably 30 ° C. to 100 ° C.).
The reaction time in the K1 (4) step varies depending on the raw material compound, the reagent, and the reaction temperature, but is usually 30 minutes to 80 hours (preferably 1 hour to 48 hours).
After completion of the reaction, the target compound of Step K1 (4) is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, or water is poured into the residue from which the solvent has been distilled off, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound and extraction The obtained organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

第Ｋ２工程は、化合物（ＸＸＶｄ）を製造する工程であり、化合物（ＸＸＶｃ）を、不活性溶媒中、塩基存在下又は不存在下（好適には塩基存在下）、アンモニア類、Ｃ₁−Ｃ₆アルキルアミン又はジ（Ｃ₁−Ｃ₆アルキル）アミンと反応させることにより達成される。 Step K2 is a step for producing compound (XXVd). Compound (XXVc) is converted to ammonia, C ₁ -C in an inert solvent in the presence or absence of a base (preferably in the presence of a base). _This is accomplished by reacting with ₆ alkylamine or di (C ₁ -C ₆ alkyl) amine.

使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；メチレンクロリド、クロロホルム、四塩化炭素、ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類；メタノール、エタノール、プロパノール、２−プロパノール、ブタノール又はイソブタノールのようなアルコール類；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、ヘキサメチルリン酸トリアミド又はヘキサメチル亜りん酸トリアミドのようなアミド類；或は、ジメチルスルホキシド又はスルホランのようなスルホキシド類であり得、好適には、ハロゲン化炭化水素類又はエーテル類であり、更に好適にはエーテル類（特にテトラヒドロフラン）である。
使用される塩基は、例えば、炭酸ナトリウム、炭酸カリウム又は炭酸リチウムのようなアルカリ金属炭酸塩類；炭酸水素ナトリウム、炭酸水素カリウム又は炭酸水素リチウムのようなアルカリ金属重炭酸塩類；水酸化ナトリウム、水酸化カリウム又は水酸化リチウムのようなアルカリ金属水酸化物類であり得、好適にはアルカリ金属炭酸塩類（特に炭酸ナトリウム又は炭酸カリウム）である。
使用されるアンモニア類は、例えば、アンモニアガス又は濃アンモニア水であり得、好適にはアンモニア水である。
使用されるＣ₁−Ｃ₆アルキルアミンは、例えば、メチルアミン、エチルアミン、プロピルアミン、イソプロピルアミン、ブチルアミン、イソブチルアミン、ｓ−ブチルアミン、ｔ−ブチルアミン、ペンチルアミン又はヘキシルアミンである。
使用されるジ（Ｃ₁−Ｃ₆アルキル）アミンは、例えば、Ｎ，Ｎ−ジメチルアミン、Ｎ−エチル−Ｎ−メチルアミン、Ｎ，Ｎ−ジエチルアミン、Ｎ，Ｎ−ジプロピルアミン、Ｎ，Ｎ−ジイソプロピルアミン、Ｎ，Ｎ−ジブチルアミン、Ｎ，Ｎ−ジイソブチルアミン、Ｎ，Ｎ−ジ−ｓ−ブチルアミン、Ｎ，Ｎ−ジ−ｔ−ブチルアミン、Ｎ，Ｎ−ジペンチルアミン又はＮ，Ｎ−ジヘキシルアミンである。
反応温度は原料化合物、試薬等によって変化するが、通常−１０℃乃至１００℃であり、好適には０℃乃至５０℃である。
反応時間は原料化合物、試薬、反応温度によって変化するが、通常１０分乃至１０時間であり、好適には３０分乃至３時間である。
反応終了後、本工程の目的化合物は常法に従って反応混合物から採取される。例えば、反応終了後、溶媒を留去すること、又は溶媒を留去した残渣に水を注ぎ、水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル等）を加えて目的化合物を抽出し、抽出した有機層を水洗後、無水硫酸マグネシウム等で乾燥し、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱又はクロマトグラフィー等によって更に精製できる。 The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; benzene, toluene Or aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether Ethers such as: alcohols such as methanol, ethanol, propanol, 2-propanol, butanol or isobutanol; formamide, N, N-dimethylformamide, N, N-dimethyl Amides such as cetamide, hexamethylphosphoric triamide or hexamethylphosphorous triamide; or sulfoxides such as dimethyl sulfoxide or sulfolane, preferably halogenated hydrocarbons or ethers; More preferred are ethers (particularly tetrahydrofuran).
Bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; sodium hydroxide, hydroxide It can be an alkali metal hydroxide such as potassium or lithium hydroxide, preferably an alkali metal carbonate (especially sodium carbonate or potassium carbonate).
The ammonia used can be, for example, ammonia gas or concentrated aqueous ammonia, preferably aqueous ammonia.
The C ₁ -C ₆ alkylamine used is, for example, methylamine, ethylamine, propylamine, isopropylamine, butylamine, isobutylamine, s-butylamine, t-butylamine, pentylamine or hexylamine.
The di (C ₁ -C ₆ alkyl) amine used is, for example, N, N-dimethylamine, N-ethyl-N-methylamine, N, N-diethylamine, N, N-dipropylamine, N, N -Diisopropylamine, N, N-dibutylamine, N, N-diisobutylamine, N, N-di-s-butylamine, N, N-di-t-butylamine, N, N-dipentylamine or N, N-dihexyl It is an amine.
While the reaction temperature varies depending on the raw material compound, reagent and the like, it is generally −10 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C.
While the reaction time varies depending on the raw material compound, reagent, and reaction temperature, it is generally 10 minutes to 10 hours, preferably 30 minutes to 3 hours.
After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, or water is poured into the residue from which the solvent has been distilled off, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound and extraction The obtained organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

第Ｋ３工程は、化合物（ＸＸＶｄ）を別途製造する工程であり、有機合成化学で周知の方法により行われ、例えば、化合物（ＸＸＶｂ）を、ペプチド合成法における常法［例えば、アジド法、活性エステル法、混合酸無水物法又は縮合法（好適には混合酸無水物法）］に従い、不活性溶媒中、アンモニア類、Ｃ₁−Ｃ₆アルキルアミン又はジ（Ｃ₁−Ｃ₆アルキル）アミンと反応させることにより達成される。 Step K3 is a step for separately producing compound (XXVd), and is performed by a well-known method in organic synthetic chemistry. For example, compound (XXVb) is synthesized by a conventional method in peptide synthesis [eg, azide method, active ester Method, mixed acid anhydride method or condensation method (preferably mixed acid anhydride method)] with ammonia, C ₁ -C ₆ alkylamine or di (C ₁ -C ₆ alkyl) amine in an inert solvent. This is achieved by reacting.

上記方法に於いて、アジド法は、不活性溶媒中（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又はヘキサメチルリン酸トリアミドのようなアミド類であり、好適にはＮ，Ｎ−ジメチルホルムアミド）、ヒドラジンと、−１０℃乃至１００℃（好適には０℃乃至５０℃）で反応させることによって得られるヒドラジドを亜硝酸化合物と反応させアジド化合物に変換した後、アンモニア類、Ｃ₁−Ｃ₆アルキルアミン又はジ（Ｃ₁−Ｃ₆アルキル）アミンと処理することにより行われる。
使用される亜硝酸化合物は、例えば亜硝酸ナトリウムのようなアルカリ金属亜硝酸塩又は亜硝酸イソアミルのような亜硝酸アルキルである。
反応は、好適には不活性溶媒中で行われ、使用される溶媒は、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又はヘキサメチルリン酸トリアミドのようなアミド類；ジメチルスルホキシド又はスルホランのようなスルホキシド類；或はＮ−メチル−２−ピロリジノンのようなピロリドン類であり得、好適にはアミド類（特にＮ，Ｎ−ジメチルホルムアミド）である。
又、本反応の２つの工程［アジド化及びアンモニア類、Ｃ₁−Ｃ₆アルキルアミン又はジ（Ｃ₁−Ｃ₆アルキル）アミンとの反応］は、通常１つの反応液中で行われる。
反応温度は、原料化合物、試薬等によって変化するが、通常、アジド化の工程は−７０℃乃至５０℃（好適には−５０℃乃至０℃）であり、アンモニア類等との反応は−７０℃乃至５０℃（好適には−１０℃乃至１０℃）である。
反応に要する時間は、原料化合物、試薬、反応温度によって変化するが、通常、アジド化の工程は５分乃至３時間（好適には１０分乃至１時間）であり、アンモニア類等との反応は５時間乃至７日間（好適には１０時間乃至５日間）である。
反応終了後、本反応の目的化合物は常法に従って反応混合物から採取される。例えば、反応終了後、溶媒を留去すること、又は溶媒を留去した残渣に水を注ぎ、水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル等）を加えて目的化合物を抽出し、抽出した有機層を水洗後、無水硫酸マグネシウム等で乾燥し、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱又はクロマトグラフィー等によって更に精製できる。 In the above method, the azide method is an amide such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide or hexamethylphosphoric triamide in an inert solvent, preferably N, N-dimethylformamide), hydrazine, and hydrazide obtained by reacting at −10 ° C. to 100 ° C. (preferably 0 ° C. to 50 ° C.) with a nitrite compound to convert it to an azide compound, ammonia, It is carried out by treatment with C ₁ -C ₆ alkylamine or di (C ₁ -C ₆ alkyl) amine.
The nitrite compound used is, for example, an alkali metal nitrite such as sodium nitrite or an alkyl nitrite such as isoamyl nitrite.
The reaction is preferably carried out in an inert solvent, the solvent used being for example an amide such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide or hexamethylphosphoric triamide; dimethyl sulfoxide Or sulfoxides such as sulfolane; or pyrrolidones such as N-methyl-2-pyrrolidinone, preferably amides (especially N, N-dimethylformamide).
In addition, the two steps of this reaction [azidation and reaction with ammonia, C ₁ -C ₆ alkylamine or di (C ₁ -C ₆ alkyl) amine] are usually carried out in one reaction solution.
The reaction temperature varies depending on the raw material compounds, reagents, etc., but usually the azidation step is -70 ° C to 50 ° C (preferably -50 ° C to 0 ° C), and the reaction with ammonia and the like is -70 ° C. ° C to 50 ° C (preferably -10 ° C to 10 ° C).
The time required for the reaction varies depending on the raw material compound, reagent, and reaction temperature. Usually, the azidation step is 5 minutes to 3 hours (preferably 10 minutes to 1 hour), and the reaction with ammonia or the like is performed. 5 hours to 7 days (preferably 10 hours to 5 days).
After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, or water is poured into the residue from which the solvent has been distilled off, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound and extraction The obtained organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

活性エステル法は、不活性溶媒中、活性エステル化剤と反応させ、活性エステルを製造した後、不活性溶媒中、アンモニア類、Ｃ₁−Ｃ₆アルキルアミン又はジ（Ｃ₁−Ｃ₆アルキル）アミンと反応させることによって行われる。
両反応に於て使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、メチレンクロリド、クロロホルム、四塩化炭素、ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類；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又はヘキサメチルリン酸トリアミドのようなアミド類；或はアセトニトリルのようなニトリル類であり得、好適にはエーテル類（特にテトラヒドロフラン）又はアミド類（特にＮ，Ｎ−ジメチルホルムアミド）である。
使用される活性エステル化剤は、例えば、Ｎ−ヒドロキシサクシンイミド、１−ヒドロキシベンゾトリアゾール又はＮ−ヒドロキシ−５−ノルボルネン−２，３−ジカルボキシイミドのようなＮ−ヒドロキシ化合物或はジピリジルジスルフィドのようなジスルフィド化合物であり得、活性エステル化反応は、ジシクロヘキシルカルボジイミド、カルボニルジイミダゾール又はトリフェニルホスフィンのような縮合剤の存在下に好適に行われる。
反応温度は、原料化合物、試薬等によって変化するが、通常、活性エステル化反応では、−７０℃乃至１５０℃（好適には−１０℃乃至１００℃）であり、活性エステル化合物とアンモニア類等との反応では−２０℃乃至１００℃（好適には０℃乃至５０℃）である。
反応に要する時間は原料化合物、試薬、反応温度によって変化するが、両反応ともに、通常、３０分乃至８０時間（好適には１時間乃至４８時間）である。
反応終了後、本反応の目的化合物は常法に従って反応混合物から採取される。例えば、反応終了後、溶媒を留去すること、又は溶媒を留去した残渣に水を注ぎ、水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル等）を加えて目的化合物を抽出し、抽出した有機層を水洗後、無水硫酸マグネシウム等で乾燥し、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱又はクロマトグラフィー等によって更に精製できる。 In the active ester method, after reacting with an active esterifying agent in an inert solvent to produce an active ester, ammonia, C ₁ -C ₆ alkylamine or di (C ₁ -C ₆ alkyl) in the inert solvent This is done by reacting with an amine.
The solvent used in both reactions is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene. Halogenated hydrocarbons such as: ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; formamide, N, N-dimethylformamide, N, N-dimethylacetamide or hexamethylphosphoric acid Amides such as triamide; or nitriles such as acetonitrile, preferably ethers (particularly tetrahydrofuran) or amides (particularly N, N-dimethylformamide).
The active esterifying agents used are, for example, N-hydroxy compounds such as N-hydroxysuccinimide, 1-hydroxybenzotriazole or N-hydroxy-5-norbornene-2,3-dicarboximide or dipyridyl disulfides. The active esterification reaction is suitably performed in the presence of a condensing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole or triphenylphosphine.
The reaction temperature varies depending on the raw material compound, reagent, etc., but is usually −70 ° C. to 150 ° C. (preferably −10 ° C. to 100 ° C.) in the active esterification reaction. In the reaction of -20 ° C to 100 ° C (preferably 0 ° C to 50 ° C).
The time required for the reaction varies depending on the raw material compound, the reagent, and the reaction temperature, but both reactions are usually 30 minutes to 80 hours (preferably 1 hour to 48 hours).
After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, or water is poured into the residue from which the solvent has been distilled off, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound and extraction The obtained organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

混合酸無水物法は、不活性溶媒中、塩基存在下、混合酸無水物化剤を反応させ、混合酸無水物を製造した後、不活性溶媒中、混合酸無水物とアンモニア類、Ｃ₁−Ｃ₆アルキルアミン又はジ（Ｃ₁−Ｃ₆アルキル）アミンを反応させることにより行われる。
混合酸無水物を製造する反応に於て使用される溶媒は、反応を阻害せず、出発物質をある程度溶解する物であれば特に限定はないが、例えば、メチレンクロリド、クロロホルム、四塩化炭素、ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類；或は、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又はヘキサメチルリン酸トリアミドのようなアミド類であり得、好適にはエーテル類（特にテトラヒドロフラン）である。
混合酸無水物化剤は、例えば、クロロギ酸エチル又はクロロギ酸イソブチルのようなハロゲノギ酸Ｃ₁−Ｃ₄アルキル、ピバロイルクロリドのようなＣ₁−Ｃ₅アルカノイルハライド或はジエチルシアノリン酸又はジフェニルシアノリン酸のようなＣ₁−Ｃ₄アルキル若しくはジＣ₆−Ｃ₁₄アリールシアノリン酸であり得、好適には、ハロゲノギ酸Ｃ₁−Ｃ₄アルキル（特にクロロギ酸エチル）である。
使用される塩基は、例えば、炭酸ナトリウム、炭酸カリウム又は炭酸リチウムのようなアルカリ金属炭酸塩類；或はトリエチルアミン、トリブチルアミン、ジイソプロピルエチルアミン、Ｎ−メチルモルホリン、ピリジン、４−（Ｎ，Ｎ−ジメチルアミノ）ピリジン、Ｎ，Ｎ−ジメチルアニリン、Ｎ，Ｎ−ジエチルアニリン、１，５−ジアザビシクロ［４．３．０］ノナ−５−エン、１，４−ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ）又は１，８−ジアザビシクロ［５．４．０］ウンデク−７−エン（ＤＢＵ）のような有機アミン類であり得、好適には有機アミン類（特にトリエチルアミン）である。
混合酸無水物を製造する反応に於ける反応温度は、原料化合物、試薬等によって変化するが、通常−５０℃乃至１００℃（好適には−１０℃乃至５０℃）である。
混合酸無水物を製造する反応に於ける反応時間は、原料化合物、試薬、反応温度によって変化するが、通常５分乃至２０時間（好適には１０分乃至１０時間）である。
混合酸無水物とアンモニア類等の反応に於て使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類或はホルムアミド、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド又はヘキサメチルリン酸トリアミドのようなアミド類であり得、好適にはエーテル類（特にテトラヒドロフラン）である。
混合酸無水物とアンモニア類等の反応に於ける反応温度は、原料化合物、試薬等によって変化するが、通常−３０℃乃至１００℃（好適には０℃乃至８０℃）である。
混合酸無水物とアンモニア類等の反応に於ける反応時間は、原料化合物、試薬、反応温度によって変化するが、通常５分乃至２４時間（好適には１０分乃至５時間）である。
反応終了後、本反応の目的化合物は常法に従って反応混合物から採取される。例えば、反応終了後、溶媒を留去すること、又は溶媒を留去した残渣に水を注ぎ、水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル等）を加えて目的化合物を抽出し、抽出した有機層を水洗後、無水硫酸マグネシウム等で乾燥し、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱又はクロマトグラフィー等によって更に精製できる。 In the mixed acid anhydride method, a mixed acid anhydride agent is reacted in an inert solvent in the presence of a base to produce a mixed acid anhydride, and then the mixed acid anhydride and ammonia, C ₁ − It carried out by reacting the C ₆ alkylamine or a di (C ₁ -C ₆ alkyl) amine.
The solvent used in the reaction for producing the mixed acid anhydride is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, methylene chloride, chloroform, carbon tetrachloride, Halogenated hydrocarbons such as dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; or formamide, N, N-dimethylformamide, N, Amides such as N-dimethylacetamide or hexamethylphosphoric triamide are preferred, and ethers (particularly tetrahydrofuran) are preferred.
Mixed acid anhydride agent, for example, Harogenogi acid C ₁ -C ₄ alkyl, such as ethyl chloroformate or isobutyl chloroformate, C ₁ -C ₅ alkanoyl halide or diethyl cyano phosphate or diphenyl, such as pivaloyl chloride be a C ₁ -C ₄ alkyl or di-C ₆ -C ₁₄ aryl cyanophosphate such as cyanophosphonate, preferably a Harogenogi acid C ₁ -C ₄ alkyl (especially ethyl chloroformate).
Bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; or triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino). ) Pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO ) Or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), preferably organic amines (particularly triethylamine).
The reaction temperature in the reaction for producing the mixed acid anhydride varies depending on the raw material compounds, reagents and the like, but is usually −50 ° C. to 100 ° C. (preferably −10 ° C. to 50 ° C.).
The reaction time in the reaction for producing the mixed acid anhydride varies depending on the raw material compound, the reagent, and the reaction temperature, but is usually 5 minutes to 20 hours (preferably 10 minutes to 10 hours).
The solvent used in the reaction of the mixed acid anhydride and ammonia is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, diethyl ether, diisopropyl ether, tetrahydrofuran , Ethers such as dioxane, dimethoxyethane or diethylene glycol dimethyl ether or amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide or hexamethylphosphoric triamide, preferably ethers (Especially tetrahydrofuran).
The reaction temperature in the reaction of the mixed acid anhydride with ammonia or the like varies depending on the raw material compounds, reagents and the like, but is usually −30 ° C. to 100 ° C. (preferably 0 ° C. to 80 ° C.).
The reaction time in the reaction of the mixed acid anhydride with ammonia or the like varies depending on the raw material compound, the reagent, and the reaction temperature, but is usually 5 minutes to 24 hours (preferably 10 minutes to 5 hours).
After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, or water is poured into the residue from which the solvent has been distilled off, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound and extraction The obtained organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

縮合法は、不活性溶媒中、縮合剤存在下、アンモニア類、Ｃ₁−Ｃ₆アルキルアミン又はジ（Ｃ₁−Ｃ₆アルキル）アミンと直接反応させることによって行われる。
使用される縮合剤は、例えば、ジシクロヘキシルカルボジイミド、カルボニルジイミダゾール又は１−メチル−２−クロロ−ピリジニウムヨージド−トリエチルアミンであり得、好適にはジシクロヘキシルカルボジイミドである。
本反応は、前記の活性エステルを製造する反応と同様の条件下で行うことができる。
反応終了後、本反応の目的化合物は常法に従って反応混合物から採取される。例えば、反応終了後、溶媒を留去すること、又は溶媒を留去した残渣に水を注ぎ、水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル等）を加えて目的化合物を抽出し、抽出した有機層を水洗後、無水硫酸マグネシウム等で乾燥し、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱又はクロマトグラフィー等によって更に精製できる。 The condensation method is carried out by directly reacting with ammonia, C ₁ -C ₆ alkylamine or di (C ₁ -C ₆ alkyl) amine in an inert solvent in the presence of a condensing agent.
The condensing agent used can be, for example, dicyclohexylcarbodiimide, carbonyldiimidazole or 1-methyl-2-chloro-pyridinium iodide-triethylamine, preferably dicyclohexylcarbodiimide.
This reaction can be performed under the same conditions as in the reaction for producing the active ester.
After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, or water is poured into the residue from which the solvent has been distilled off, and a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound and extraction The obtained organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

Ｌ法は、一般式（ＸＸＶＩｂ）又は（ＸＸＶＩｃ）を有する化合物を製造する方法である。 Method L is a method for producing a compound having the general formula (XXVIb) or (XXVIc).

第Ｌ１工程は、化合物（ＸＸＶＩｂ）を製造する工程であり、一般に有機合成化学の技術において周知の方法に従い、一般式（ＸＸＶＩａ）を有する化合物を、不活性溶媒中又は溶媒不存在下、酸又は塩基存在下、加水分解することにより達成され、第Ａ２工程の反応（ｄ）と同様の条件下で行なうことができる。 Step L1 is a step of producing compound (XXVIb). In general, according to a method well known in the art of organic synthetic chemistry, a compound having the general formula (XXVIa) is converted into an acid or an inert solvent or in the absence of a solvent. This is achieved by hydrolysis in the presence of a base, and can be carried out under the same conditions as in the reaction (d) in Step A2.

第Ｌ２工程は、化合物（ＸＸＶＩｃ）を製造する工程であり、一般に有機合成化学の技術に於いて周知の方法に従い、例えば、化合物（ＸＸＶＩｂ）を、ペプチド合成法における常法［例えば、アジド法、活性エステル法、混合酸無水物法又は縮合法（好適には混合酸無水物法）］に従い、不活性溶媒中、アンモニア類、Ｃ₁−Ｃ₆アルキルアミン又はジ（Ｃ₁−Ｃ₆アルキル）アミンと反応させることにより達成され、第Ｋ３工程と同様の条件下で行なうことができる。 Step L2 is a step for producing compound (XXVIc). Generally, according to a method well known in the art of organic synthetic chemistry, for example, compound (XXVIb) is converted into a conventional method in peptide synthesis [eg, azide method, active ester method, in accordance with a mixed acid anhydride method or condensation (preferably mixed acid anhydride method to)], in an inert solvent, ammonia compounds, C ₁ -C ₆ alkylamine or a di (C ₁ -C ₆ alkyl) This is achieved by reacting with an amine and can be carried out under the same conditions as in Step K3.

Ｍ法は、一般式（ＸＶＩ）を有する化合物又は一般式（ＸＸＩＩＩ）を有する化合物を製造する方法である。 Method M is a method for producing a compound having the general formula (XVI) or a compound having the general formula (XXIII).

第Ｍ１工程は、化合物（ＸＶＩ）又は化合物（ＸＸＩＩＩ）を製造する工程であり、一般式（ＸＸＶＩＩＩ）を有する化合物又は一般式（ＸＸＩＸ）を有する化合物を、
（１）不活性溶媒中、塩基存在下又は不存在下（好適には塩基存在下）、一般式Ｒ¹²−Ｚa 有する化合物（式中、Ｒ¹²及びＺaは、前述したものと同意義を示す。）又は一般式Ｒ¹²a−Ｏ−Ｒ¹²aを有する化合物（式中、Ｒ¹²aは、前述したものと同意義を示す。）と反応させるか、
（２）不活性溶媒中、縮合剤及び塩基存在下又は不存在下（好適には塩基存在下）一般式Ｒ¹²a−ＯＨを有する化合物（式中、Ｒ¹²aは、前述したものと同意義を示す。）と反応させるか、
（３）不活性溶媒中、塩化燐酸ジエチルのようなハロゲン化燐酸ジアルキルエステル類及び塩基存在下、一般式Ｒ¹²a−ＯＨを有する化合物（Ｒ¹²aは、前述したものと同意義を示す。）と反応させるか、又は
（４）不活性溶媒中、酸存在下又は不存在下（好適には酸存在下）、ジヒドロフラン若しくはジヒドロピラン類と反応させることにより達成され、第Ｊ１工程と同様の条件下で行うことができる。 Step M1 is a step of producing compound (XVI) or compound (XXIII). A compound having the general formula (XXVIII) or a compound having the general formula (XXIX)
(1) A compound having the general formula R ¹² -Za in an inert solvent in the presence or absence of a base (preferably in the presence of a base) (wherein R ¹² and Za are as defined above). Or a compound having the general formula R ¹² a—O—R ¹² a (wherein R ¹² a is as defined above), or
(2) In an inert solvent, in the presence or absence of a condensing agent and a base (preferably in the presence of a base), a compound having the general formula R ¹² a-OH (wherein R ¹² a is the same as described above) Or show significance)
(3) an inert solvent, halogenated dialkyl phosphoric acid esters and the presence of a base such as chloride phosphodiesterase, compounds having the general formula ^{^{R 12 a-OH (R 12}} a have the same meanings as those described above. Or (4) in an inert solvent in the presence or absence of an acid (preferably in the presence of an acid) and reaction with dihydrofuran or dihydropyrans, as in Step J1 Can be carried out under the following conditions.

Ｎ法は、一般式（ＩＩＩ）を有する化合物を別途製造する方法である。 Method N is a method for separately producing a compound having the general formula (III).

第Ｎ１工程は、一般式（ＸＸＸＩ）を有する化合物を製造する工程であり、一般式（ＸＸＸ）を有する化合物を、不活性溶媒中又は溶媒不存在下、酸又は塩基存在下、加水分解することにより達成され、第Ａ２工程の反応（ｄ）と同様の条件下で行うことができる。 Step N1 is a step of producing a compound having the general formula (XXXI), and hydrolyzing the compound having the general formula (XXX) in an inert solvent or in the absence of a solvent in the presence of an acid or a base. And can be carried out under the same conditions as in the reaction (d) in the step A2.

第Ｎ２工程は、一般式（ＸＸＸＩＩ）を有する化合物を製造する工程であり、化合物（ＸＸＸＩ）を、不活性溶媒中、塩基存在下、一般式（ＸＶＩ）を有する化合物と反応させることにより達成される。 Step N2 is a step of producing a compound having the general formula (XXXII), and is achieved by reacting the compound (XXXI) with a compound having the general formula (XVI) in the presence of a base in an inert solvent. The

使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ヘキサン、シクロヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジクロロメタン、クロロホルム、四塩化炭素、１，２−ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類；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又はＮ−メチル−２−ピロリジノンのようなアミド類；或いは、ジメチルスルホキシド又はスルホランのようなスルホキシド類であり得、好適には、エーテル類（特にジエチルエーテル又はテトラヒドロフラン）である。
使用される塩基は、例えば、炭酸ナトリウム、炭酸カリウム又は炭酸リチウムのようなアルカリ金属炭酸塩類；炭酸水素ナトリウム、炭酸水素カリウム又は炭酸水素リチウムのようなアルカリ金属重炭酸塩類；水素化リチウム、水素化ナトリウム又は水素化カリウムのようなアルカリ金属水素化物類；水酸化ナトリウム、水酸化カリウム又は水酸化リチウムのようなアルカリ金属水酸化物類；ナトリウムメトキシド、ナトリウムエトキシド、カリウムｔ−ブトキシド又はリチウムメトキシドのようなアルカリ金属アルコキシド類；トリエチルアミン、トリブチルアミン、ジイソプロピルエチルアミン、Ｎ−メチルモルホリン、ピリジン、４−（Ｎ，Ｎ−ジメチルアミノ）ピリジン、Ｎ，Ｎ−ジメチルアニリン、Ｎ，Ｎ−ジエチルアニリン、１，５−ジアザビシクロ［４．３．０］ノナ−５−エン、１，４−ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ）又は１，８−ジアザビシクロ［５．４．０］ウンデク−７−エン（ＤＢＵ）のような有機アミン類；メチルリチウム、エチルリチウム又はブチルリチウムのようなアルキルリチウム類；リチウムジイソプロピルアミド又はリチウムジシクロヘキシルアミドのようなリチウムアルキルアミド類；或いは、カリウムヘキサメチルジシラジド又はナトリウムヘキサメチルジシラジドのようなアルカリ金属ヘキサメチルジシラジド類であり得、好適には、アルキルリチウム類（特にブチルリチウム）又はリチウムアルキルアミド類（特にリチウムジイソプロピルアミド）である。
反応温度は原料化合物、試薬等によって異なるが、通常−１５０℃乃至５０℃であり、好適には−１００℃乃至０℃である。
反応時間は原料化合物、試薬、反応温度によって異なるが、通常１０分間乃至１０時間であり、好適には３０分間乃至５時間である。
反応終了後、本工程の目的化合物は常法に従って反応混合物から採取される。例えば、反応終了後、反応液に水を加え目的化合物を抽出した後、酸（例えば、塩酸等）を用いて抽出した水層のｐＨを酸性に調整し、水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル又はジクロロメタン等）を加えて目的化合物を抽出した後、抽出した有機層を水洗し、無水硫酸マグネシウム等を用いて乾燥させた後、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱、クロマトグラフィーにより更に精製できる。 The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin or petroleum ether; benzene Aromatic hydrocarbons such as toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, Ethers such as dimethoxyethane or diethylene glycol dimethyl ether; amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide or N-methyl-2-pyrrolidinone; It obtained a glucoside or sulfoxides such as sulfolane, suitably from ethers (particularly diethyl ether or tetrahydrofuran).
Bases used are, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; lithium hydride, hydrogenated Alkali metal hydrides such as sodium or potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxy Alkali metal alkoxides such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1 5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.0] undec-7-ene Organic amines such as (DBU); alkyllithiums such as methyllithium, ethyllithium or butyllithium; lithium alkylamides such as lithium diisopropylamide or lithium dicyclohexylamide; or potassium hexamethyldisilazide or sodium Alkali metal hexamethyldisilazides such as hexamethyldisilazide can be used, preferably alkyllithiums (especially butyllithium) or lithium alkylamides (especially lithium diisopropylamide).
While the reaction temperature varies depending on the raw material compound, reagent and the like, it is generally −150 ° C. to 50 ° C., preferably −100 ° C. to 0 ° C.
While the reaction time varies depending on the raw material compound, reagent, and reaction temperature, it is generally 10 minutes to 10 hours, preferably 30 minutes to 5 hours.
After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, water is added to the reaction solution to extract the target compound, and then the pH of the aqueous layer extracted with an acid (for example, hydrochloric acid) is adjusted to acidic, and a solvent immiscible with water (for example, benzene, Ether, ethyl acetate or dichloromethane) is added to extract the target compound, and the extracted organic layer is washed with water, dried using anhydrous magnesium sulfate and the like, and then the solvent is distilled off to obtain the target compound. . If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

第Ｎ３工程は、化合物（ＩＩＩ）を製造する工程であり、
（１）化合物（ＸＸＸＩＩ）を、不活性溶媒中、塩基存在下、ハロゲノ炭酸Ｃ₁−Ｃ₆アルキルと反応させた後、
（２）得られた中間体化合物を、不活性溶媒中、水素化ホウ素ナトリウムと反応させることにより達成される。 Step N3 is a step of producing compound (III),
(1) Compound (XXXII) is reacted with halogenated carbonic acid C ₁ -C ₆ alkyl in the presence of a base in an inert solvent,
(2) Achieved by reacting the resulting intermediate compound with sodium borohydride in an inert solvent.

第Ｎ３（１）工程で使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ヘキサン、シクロヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジクロロメタン、クロロホルム、四塩化炭素、１，２−ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；或いは、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類であり得、好適には、ハロゲン化炭化水素類（特にジクロロメタン）又はエーテル類（特にジエチルエーテル又はテトラヒドロフラン）である。
第Ｎ３（１）工程で使用される塩基は、例えば、炭酸ナトリウム、炭酸カリウム又は炭酸リチウムのようなアルカリ金属炭酸塩類；炭酸水素ナトリウム、炭酸水素カリウム又は炭酸水素リチウムのようなアルカリ金属重炭酸塩類；水酸化ナトリウム、水酸化カリウム又は水酸化リチウムのようなアルカリ金属水酸化物類；メチルアミン、ジメチルアミン、エチルアミン、トリエチルアミン、トリブチルアミン、ジイソプロピルエチルアミン、Ｎ−メチルモルホリン、ピリジン、４−（Ｎ，Ｎ−ジメチルアミノ）ピリジン、Ｎ，Ｎ−ジメチルアニリン、Ｎ，Ｎ−ジエチルアニリン、１，５−ジアザビシクロ［４．３．０］ノナ−５−エン、１，４−ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ）又は１，８−ジアザビシクロ［５．４．０］ウンデク−７−エン（ＤＢＵ）のような有機塩基類であり得、好適には有機塩基類（特にトリエチルアミン）である。
第Ｎ３（１）工程で使用される「ハロゲノ炭酸Ｃ₁−Ｃ₆アルキル」は、例えば、フルオロ炭酸メチル、クロロ炭酸メチル、ブロモ炭酸メチル、ヨード炭酸メチル、フルオロ炭酸エチル、クロロ炭酸エチル、ブロモ炭酸エチル、ヨード炭酸エチル、フルオロ炭酸プロピル、クロロ炭酸ブチル、ブロモ炭酸ペンチル又はヨード炭酸ヘキシルであり得、好適にはクロロ炭酸メチル又はクロロ炭酸エチルである。
反応温度は原料化合物、試薬等によって異なるが、通常−１０℃乃至１５０℃であり、好適には０℃乃至１００℃である。
反応時間は原料化合物、試薬、反応温度によって異なるが、通常５分間乃至１２時間であり、好適には１０分間乃至６時間である。
反応終了後、本工程の目的化合物は常法に従って反応混合物から採取される。例えば、反応終了後、所望に応じて不溶物をろ去した後、溶媒を留去することにより、或いは、反応終了後、反応液に水を加え、水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル等）を加えて目的化合物を抽出した後、抽出した有機層を水洗し、無水硫酸マグネシウム等を用いて乾燥させた後、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱、クロマトグラフィーにより更に精製できる。 The solvent used in the N3 (1) step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, hexane, cyclohexane, heptane, ligroin or petroleum ether can be used. Aliphatic hydrocarbons; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; or diethyl It can be an ether such as ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, preferably halogenated hydrocarbons (especially dichloromethane) or ethers (especially diethyl ether or tetrahydrofuran). It is.
The base used in the N3 (1) step is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate, or lithium carbonate; an alkali metal bicarbonate such as sodium bicarbonate, potassium bicarbonate, or lithium bicarbonate. Alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; methylamine, dimethylamine, ethylamine, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2 ] Octane (DABCO) or 1,8-diazabicyclo [5.4. ] Undec-7-ene to give an organic base, such as (DBU), preferably an organic base such (especially triethylamine).
“Halogenocarbonic acid C ₁ -C ₆ alkyl” used in the N3 (1) step is, for example, methyl fluorocarbonate, methyl chlorocarbonate, methyl bromocarbonate, methyl iodocarbonate, ethyl fluorocarbonate, ethyl chlorocarbonate, bromocarbonic acid. It can be ethyl, ethyl iodocarbonate, propyl fluorocarbonate, butyl chlorocarbonate, pentyl bromocarbonate or hexyl iodocarbonate, preferably methyl chlorocarbonate or ethyl chlorocarbonate.
While the reaction temperature varies depending on the raw material compound, reagent and the like, it is generally −10 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C.
While the reaction time varies depending on the raw material compound, reagent, and reaction temperature, it is generally 5 minutes to 12 hours, and preferably 10 minutes to 6 hours.
After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, insoluble matters are filtered off as desired, and then the solvent is distilled off, or after completion of the reaction, water is added to the reaction solution and a solvent immiscible with water (for example, benzene, ether, The target compound is extracted by adding ethyl acetate and the like, and the extracted organic layer is washed with water, dried using anhydrous magnesium sulfate and the like, and then the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

第Ｎ３（２）工程で使用される溶媒は、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ヘキサン、シクロヘキサン、ヘプタン、リグロイン又は石油エーテルのような脂肪族炭化水素類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジクロロメタン、クロロホルム、四塩化炭素、１，２−ジクロロエタン、クロロベンゼン又はジクロロベンゼンのようなハロゲン化炭化水素類；或いは、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン又はジエチレングリコールジメチルエーテルのようなエーテル類であり得、好適にはエーテル類（特にジエチルエーテル又はテトラヒドロフラン）である。
反応温度は原料化合物、試薬等によって異なるが、通常−１０℃乃至１５０℃であり、好適には０℃乃至１００℃である。
反応時間は原料化合物、試薬、反応温度によって異なるが、通常１時間乃至４８時間であり、好適には６時間乃至２４時間である。
反応終了後、本工程の目的化合物は常法に従って反応混合物から採取される。例えば、反応終了後反応液に水を加え、水と混和しない溶媒（例えばベンゼン、エーテル、酢酸エチル等）を加えて目的化合物を抽出した後、抽出した有機層を水洗し、無水硫酸マグネシウム等を用いて乾燥させた後、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱、クロマトグラフィーにより更に精製できる。 The solvent used in the N3 (2) step is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, hexane, cyclohexane, heptane, ligroin or petroleum ether can be used. Aliphatic hydrocarbons; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; or diethyl It can be an ether such as ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, preferably ethers (especially diethyl ether or tetrahydrofuran).
While the reaction temperature varies depending on the raw material compound, reagent and the like, it is generally −10 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C.
While the reaction time varies depending on the raw material compound, reagent, and reaction temperature, it is generally 1 hour to 48 hours, preferably 6 hours to 24 hours.
After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, water is added to the reaction solution, a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, the extracted organic layer is washed with water, anhydrous magnesium sulfate, etc. After use and drying, the target compound is obtained by distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

Ｏ法は、Ｍ法の原料化合物である一般式（ＸＸＶＩＩＩ）を有する化合物を製造する方法である。 Method O is a method for producing a compound having the general formula (XXVIII), which is a raw material compound of Method M.

第Ｏ１工程は、化合物（ＸＸＶＩＩＩ）を製造する工程であり、一般式（ＸＸＸＩＩＩ）を有する化合物を、トリフルオロ酢酸中、ヘキサメチレンテトラミンと反応させることにより達成される。 Step O1 is a step for producing compound (XXVIII) and is achieved by reacting a compound having the general formula (XXXIII) with hexamethylenetetramine in trifluoroacetic acid.

反応温度は原料化合物、試薬等によって異なるが、ヘキサメチレンテトラミンとの反応は、通常、０℃乃至１５０℃であり、好適には５０℃乃至１２０℃であり、硫酸との反応は、通常、−２０℃乃至１００℃であり、好適には０℃乃至５０℃である。
反応時間は原料化合物、試薬、反応温度によって異なるが、ヘキサメチレンテトラミンとの反応は、通常、１時間乃至２４時間であり、好適には６時間乃至１２時間である。
反応終了後、本工程の目的化合物は、常法に従って反応混合物から採取される。例えば、反応終了後、溶媒を留去することにより、或いは、反応終了後、溶媒を留去し、得られる残渣に水を注ぎ、水と混和しない溶媒（例えばベンゼン、ジエチルエーテル又は酢酸エチル等）を加え抽出した後、抽出液を水洗し、有機層を無水硫酸マグネシウム等で乾燥させた後、溶媒を留去することによって目的化合物が得られる。得られる目的化合物は必要ならば、常法、例えば再結晶、再沈澱又はクロマトグラフィー等によって更に精製できる。 The reaction temperature varies depending on the raw material compound, reagent, etc., but the reaction with hexamethylenetetramine is usually 0 ° C. to 150 ° C., preferably 50 ° C. to 120 ° C., and the reaction with sulfuric acid is usually − It is 20 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C.
Although the reaction time varies depending on the raw material compound, reagent, and reaction temperature, the reaction with hexamethylenetetramine is usually 1 hour to 24 hours, preferably 6 hours to 12 hours.
After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, by distilling off the solvent, or after completion of the reaction, the solvent is distilled off, water is poured into the resulting residue, and a solvent immiscible with water (for example, benzene, diethyl ether or ethyl acetate) After extraction, the extract is washed with water, the organic layer is dried over anhydrous magnesium sulfate and the like, and then the solvent is distilled off to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation or chromatography.

本発明の原料化合物（ＶＩＩ）、（ＶＩＩＩ）、（ＩＸ）、（Ｘ）、（ＸＶ）、（ＸＶＩ）、（ＸＶＩＩ）、（ＸＶＩＩＩ）、（ＸＩＸ）、（ＸＸＩＩ）、（ＸＸＩＩＩ）、（ＸＸＶ）、（ＸＸＶＩＩＩ）、（ＸＸＩＸ）、（ＸＸＸ）及び（ＸＸＸＩＩＩ）等は、公知であるか又は公知の方法に従って容易に製造される。｛例えば、バイオオーガニック・アンド・メディシナル・ケミストリー・レターズ，第８巻，第２７７頁（１９９８年）[Bioorg. Med. Chem. Lett., 8, 277 (1998)]、テトラヘドロン・レターズ，第３７巻，第６４３９頁（１９９６年）[Tetrahedron Letters, 37, 6439 (1996)]等｝。 Raw material compounds (VII), (VIII), (IX), (X), (XV), (XVI), (XVII), (XVIII), (XIX), (XXII), (XXIII), ( XXV), (XXVIII), (XXIX), (XXX), (XXXIII) and the like are known or easily produced according to known methods. {For example, Bioorganic and Medicinal Chemistry Letters, Vol. 8, 277 (1998) [Bioorg. Med. Chem. Lett., 8, 277 (1998)], Tetrahedron Letters, 37 Volume, p. 6439 (1996) [Tetrahedron Letters, 37, 6439 (1996)] etc.}.

本発明の前記一般式（Ｉ）を有する化合物又はその薬理上許容される塩は、優れた活性化血液凝固第Ｘ因子阻害作用を有し、毒性も弱いため、医薬［特に、血液凝固性疾患（例えば、脳梗塞、心筋梗塞又は末梢循環障害等の血栓性疾患）の予防薬又は治療薬（特に治療薬）］として有用である。 The compound having the above general formula (I) or a pharmacologically acceptable salt thereof of the present invention has an excellent activated blood coagulation factor X inhibitory action and weak toxicity, so (For example, prophylactic or therapeutic agent (especially therapeutic agent) for thrombotic diseases such as cerebral infarction, myocardial infarction or peripheral circulation disorder).

本発明の一般式（Ｉ）を有する化合物又はその薬理上許容される塩類を、上記疾患の治療薬又は予防薬として使用する場合には、それ自体あるいは適宜の薬理学的に許容される、賦形剤、希釈剤等と混合し、錠剤、カプセル剤、顆粒剤、散剤若しくはシロップ剤等による経口的又は注射剤若しくは坐剤等による非経口的に投与することができる。
これらの製剤は、賦形剤（例えば、乳糖、白糖、葡萄糖、マンニトール、ソルビトールのような糖誘導体；トウモロコシデンプン、バレイショデンプン、α澱粉、デキストリンのような澱粉誘導体；結晶セルロースのようなセルロース誘導体；アラビアゴム；デキストラン；プルランのような有機系賦形剤；及び、軽質無水珪酸、合成珪酸アルミニウム、珪酸カルシウム、メタ珪酸アルミン酸マグネシウムのような珪酸塩誘導体；燐酸水素カルシウムのような燐酸塩；炭酸カルシウムのような炭酸塩；硫酸カルシウムのような硫酸塩等の無機系賦形剤を挙げることができる。）、滑沢剤（例えば、ステアリン酸、ステアリン酸カルシウム、ステアリン酸マグネシウムのようなステアリン酸金属塩；タルク；コロイドシリカ；ビーズワックス、ゲイ蝋のようなワックス類；硼酸；アジピン酸；硫酸ナトリウムのような硫酸塩；グリコール；フマル酸；安息香酸ナトリウム；ＤＬロイシン；ラウリル硫酸ナトリウム、ラウリル硫酸マグネシウムのようなラウリル硫酸塩；無水珪酸、珪酸水和物のような珪酸類；及び、上記澱粉誘導体を挙げることができる。）、結合剤（例えば、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、マクロゴール、及び、前記賦形剤と同様の化合物を挙げることができる。）、崩壊剤（例えば、低置換度ヒドロキシプロピルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、内部架橋カルボキシメチルセルロースナトリウムのようなセルロース誘導体；カルボキシメチルスターチ、カルボキシメチルスターチナトリウム、架橋ポリビニルピロリドンのような化学修飾されたデンプン・セルロース類を挙げることができる。）、乳化剤（例えば、ベントナイト、ビーガムのようなコロイド性粘土；水酸化マグネシウム、水酸化アルミニウムのような金属水酸化物；ラウリル硫酸ナトリウム、ステアリン酸カルシウムのような陰イオン界面活性剤；塩化ベンザルコニウムのような陽イオン界面活性剤；及び、ポリオキシエチレンアルキルエーテル、ポリオキシエチレンソルビタン脂肪酸エステル、ショ糖脂肪酸エステルのような非イオン界面活性剤を挙げることができる。）、安定剤（メチルパラベン、プロピルパラベンのようなパラオキシ安息香酸エステル類；クロロブタノール、ベンジルアルコール、フェニルエチルアルコールのようなアルコール類；塩化ベンザルコニウム；フェノール、クレゾールのようなフェノール類；チメロサール；デヒドロ酢酸；及び、ソルビン酸を挙げることができる。）、矯味矯臭剤（例えば、通常使用される、甘味料、酸味料、香料等を挙げることができる。）、希釈剤等の添加剤を用いて周知の方法で製造される。
その使用量は症状、年齢等により異なるが、経口投与の場合には、１回当り下限１mg（好適には、１０mg）、上限１０００mg（好適には、５００mg）を、静脈内投与の場合には、１回当り下限０．５mg（好適には、５mg）、上限５００mg（好適には、２５０mg）を成人に対して、１日当り１乃至６回症状に応じて投与することが望ましい。 When the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is used as a therapeutic or prophylactic agent for the above-mentioned diseases, the compound itself or an appropriate pharmacologically acceptable It can be mixed with a dosage form, diluent, etc., and can be administered orally by tablets, capsules, granules, powders, syrups, etc. or parenterally by injections or suppositories.
These formulations include excipients (eg sugar derivatives such as lactose, sucrose, sucrose, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, alpha starch, dextrin; cellulose derivatives such as crystalline cellulose; Gum arabic; dextran; organic excipients such as pullulan; and silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium magnesium aluminosilicate; phosphates such as calcium hydrogen phosphate; Carbonates such as calcium; inorganic excipients such as sulfates such as calcium sulfate; and lubricants (eg, stearic acid, calcium stearate, metal stearate such as magnesium stearate) Salt; talc; colloidal silica; bead wax; Waxes such as wax; boric acid; adipic acid; sulfate such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; lauryl sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; Silicic acids such as silicic acid hydrate; and the above-mentioned starch derivatives), binders (for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and the same as the above-mentioned excipients) And disintegrants (for example, cellulose derivatives such as low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally crosslinked sodium carboxymethylcellulose; And starch, celluloses chemically modified such as sodium carboxymethyl starch and cross-linked polyvinyl pyrrolidone), emulsifiers (eg, colloidal clays such as bentonite and bee gum; magnesium hydroxide, hydroxylated Metal hydroxides such as aluminum; anionic surfactants such as sodium lauryl sulfate and calcium stearate; cationic surfactants such as benzalkonium chloride; and polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acids Nonionic surfactants such as esters and sucrose fatty acid esters), stabilizers (paraoxybenzoates such as methylparaben and propylparaben; chlorobutanol, benzyl alcohol, phenylethyl) Alcohols such as alcohol; benzalkonium chloride; phenols, phenols such as cresol; thimerosal; dehydroacetic acid; and sorbic acid and the. ), Flavoring agents (for example, commonly used sweeteners, acidulants, fragrances and the like), and additives such as diluents, and the like.
The amount used varies depending on symptoms, age, etc. In the case of oral administration, the lower limit is 1 mg (preferably 10 mg), the upper limit is 1000 mg (preferably 500 mg), and in the case of intravenous administration It is desirable to administer a lower limit of 0.5 mg (preferably 5 mg) and an upper limit of 500 mg (preferably 250 mg) to an adult 1 to 6 times per day depending on symptoms.

以下に、実施例及び製剤例を示し、本発明をさらに詳細に説明するが、本発明の範囲は、これらに限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to examples and formulation examples, but the scope of the present invention is not limited thereto.

尚、ＮＭＲスペクトルは、内部標準にテトラメチルシランを用い、δ値をｐｐｍで示し、結合定数はＪ値（Ｈｚ）で示した（０．５Ｈｚ単位に近似した）。カップリング・パターンは、
ｄ：ダブレット、
ｄｄ：ダブルダブレット、
ｄｄｄ：ダブルダブルダブレット、
ｄｔ：ダブルトリプレット、
ｔ：トリプレット、
ｑ：カルテット、
ｍ：マルチプレット、
ｓ：シングレット、
ｂｓ：幅広、または形の崩れたシングレット様に観測されたシグナル、と略した。 The NMR spectrum used tetramethylsilane as an internal standard, the δ value was expressed in ppm, and the coupling constant was expressed in J value (Hz) (approximate to 0.5 Hz unit). The coupling pattern is
d: Doublet,
dd: double doublet,
ddd: double doublet,
dt: double triplet,
t: triplet,
q: quartet,
m: multiplet,
s: singlet,
bs: Abbreviated as a signal observed as a singlet with a wide or broken shape.

実施例１
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］エタンスルホンアミド２塩酸塩（例示化合物番号：１０８０） Example 1
N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] ethanesulfonamide dihydrochloride (Exemplary compound number) : 1080)

（ａ）Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］エタンスルホンアミド２塩酸塩
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］エタンスルホンアミド（９５５ｍｇ）を、ジクロロメタン（４０ｍｌ）及びエタノール（２０ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１時間通じた後、密栓をして室温で９時間撹拌した。反応液を減圧下濃縮した後、残渣をエタノール（３０ｍｌ）に溶解させ、塩化アンモニウム水溶液（１９３ｍｇを水１０ｍｌに溶解）及び２８％アンモニア水（０．３７５ｍｌ）を加えた後、室温で１２時間放置した。減圧下溶媒を留去し、残渣をメタノール（２０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（２ｍｌ）を加えた後、減圧下濃縮した。残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１５％アセトニトリル／水）にて精製した後、得られた無定形固体をメタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（１ｍｌ）を加えた後、これを減圧下濃縮乾固させた。得られた無定形固体を水（約１０ｍｌ）に溶解させた後、凍結乾燥に付すことにより、表記化合物３５４ｍｇ（収率４４％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.27 (3H, t, J=7.0), 1.83 (2H, m), 2.09 (2H, m), 3.03 (2H, m), 3.17 (2H, q, J=7.0), 3.19 (2H, m), 4.45 (2H, d, J=6.0), 4.64 (1H, m), 6.45 (1H, dt, J=16.0, 6.0), 6.55 (1H, d, J=16.0), 7.00 (2H, d, J=9.0), 7.37 (2H, d, J=9.0), 7.54 (1H, t, J=8.0), 7.70 (2H, m), 7.89 (1H, s) ;
MS (FAB) m/z = 443 (M+H)⁺. (A) N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [4- (piperidin-4-yloxy) phenyl] ethanesulfonamide dihydrochloride N- [4- ( 1-tert-Butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] ethanesulfonamide (955 mg) was added to dichloromethane (40 ml) and ethanol ( 20 ml) was dissolved in a mixed solvent, and hydrogen chloride was passed through for 1 hour under ice-cooling. After sealing, the mixture was sealed and stirred at room temperature for 9 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (30 ml), an aqueous ammonium chloride solution (193 mg dissolved in 10 ml of water) and 28% aqueous ammonia (0.375 ml) were added, and then left at room temperature for 12 hours. did. The solvent was evaporated under reduced pressure, the residue was dissolved in methanol (20 ml), 4M hydrogen chloride dioxane solution (2 ml) was added, and the mixture was concentrated under reduced pressure. After the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 15% acetonitrile / water), the obtained amorphous solid was dissolved in methanol (10 ml), and 4M hydrogen chloride dioxane solution (1 ml) was obtained. After that, it was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml) and then freeze-dried to obtain 354 mg (yield 44%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.27 (3H, t, J = 7.0), 1.83 (2H, m), 2.09 (2H, m), 3.03 (2H, m), 3.17 (2H, q , J = 7.0), 3.19 (2H, m), 4.45 (2H, d, J = 6.0), 4.64 (1H, m), 6.45 (1H, dt, J = 16.0, 6.0), 6.55 (1H, d, J = 16.0), 7.00 (2H, d, J = 9.0), 7.37 (2H, d, J = 9.0), 7.54 (1H, t, J = 8.0), 7.70 (2H, m), 7.89 (1H, s );
MS (FAB) m / z = 443 (M + H) ⁺ .

（ｂ）Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］エタンスルホンアミド２塩酸塩
Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］エタンスルホンアミド２塩酸塩（３１１ｍｇ）を、エタノール（１０ｍｌ）に溶解させ、エチルアセトイミデート塩酸塩（２６０ｍｇ）及びトリエチルアミン（０．５００ｍｌ）を加えた後、室温で１２時間撹拌した。反応液に４Ｍ塩化水素ジオキサン溶液（１ｍｌ）を加えた後、減圧下濃縮した。残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２０％アセトニトリル／水）にて精製した後、得られた無定形固体をメタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．５ｍｌ）を加えた後、減圧下濃縮乾固させた。得られた無定形固体を水（約１０ｍｌ）に溶解させた後、凍結乾燥に付すことにより、表記化合物２４３ｍｇ（収率６２％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.27 (3H, t, J=7.0), 1.72 (2H, m), 2.04 (2H, m), 2.30 (3H, s), 3.18 (2H, q, J=7.0), 3.50-3.59 (2H, m), 3.72 (1H, m), 3.84 (1H, m), 4.45 (2H, d, J=6.0), 4.70 (1H, m), 6.46 (1H, dt, J=15.5, 6.0), 6.55 (1H, d, J=15.5), 7.01 (2H, d, J=9.0), 7.37 (2H, d, J=9.0), 7.54 (1H, t, J=8.0), 7.71 (2H, m), 7.91 (1H, s) ;
IR (KBr, cm^-1) : 1674, 1625. (B) N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] ethanesulfonamide dihydrochloride N -[3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [4- (piperidin-4-yloxy) phenyl] ethanesulfonamide dihydrochloride (311 mg) in ethanol (10 ml) After dissolution, ethylacetimidate hydrochloride (260 mg) and triethylamine (0.500 ml) were added and stirred at room temperature for 12 hours. A 4M hydrogen chloride dioxane solution (1 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. After the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water), the obtained amorphous solid was dissolved in methanol (10 ml), and 4M hydrogen chloride dioxane solution (0. 5 ml) and then concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml) and then freeze-dried to obtain 243 mg (yield 62%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.27 (3H, t, J = 7.0), 1.72 (2H, m), 2.04 (2H, m), 2.30 (3H, s), 3.18 (2H, q , J = 7.0), 3.50-3.59 (2H, m), 3.72 (1H, m), 3.84 (1H, m), 4.45 (2H, d, J = 6.0), 4.70 (1H, m), 6.46 (1H , dt, J = 15.5, 6.0), 6.55 (1H, d, J = 15.5), 7.01 (2H, d, J = 9.0), 7.37 (2H, d, J = 9.0), 7.54 (1H, t, J = 8.0), 7.71 (2H, m), 7.91 (1H, s);
IR (KBr, cm ^-1 ): 1674, 1625.

実施例２
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−メチル−２−（Ｅ）−プロペニル］エタンスルホンアミド２塩酸塩（例示化合物番号：１２２０） Example 2
N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2-methyl-2- (E) -propenyl] ethanesulfonamide dihydrochloride (Exemplary compound number: 1220)

（ａ）Ｎ−［３−（３−アミジノフェニル）−２−メチル−２−（Ｅ）−プロペニル］−Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］エタンスルホンアミド２塩酸塩
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−シアノフェニル）−２−メチル−２−（Ｅ）−プロペニル］エタンスルホンアミド（８３９ｍｇ）を、ジクロロメタン（４０ｍｌ）及びエタノール（２０ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１時間通じた後、密栓をして室温で８時間撹拌した。反応液を減圧下濃縮した後、残渣をエタノール（３０ｍｌ）に溶解させ、塩化アンモニウム水溶液（１６６ｍｇを水１０ｍｌに溶解）及び２８％アンモニア水（０．３２０ｍｌ）を加えた後、室温で１２時間放置した。減圧下溶媒を留去した後、残渣をメタノール（２０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（１ｍｌ）を加えた後、減圧下濃縮した。残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒１５％アセトニトリル／水）にて精製した後、得られた無定形固体をメタノール（２０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（１ｍｌ）を加えた後、これを減圧下濃縮乾固させた。得られた無定形固体を水（約１０ｍｌ）に溶解させた後、凍結乾燥に付すことにより、表記化合物５１４ｍｇ（収率６３％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.27 (3H, t, J=7.0), 1.84 (2H, m), 1.87 (3H, s), 2.09 (2H, m), 3.04 (2H, m), 3.16 (2H, q, J=7.0), 3.20 (2H, m), 4.39 (2H, s), 4.64 (1H, m), 6.35 (1H, s), 7.01 (2H, d, J=9.5), 7.39 (2H, d, J=9.5), 7.47 (1H, d, J=8.0), 7.55 (2H, m), 7.64 (1H, d, J=8.0) ;
IR (KBr, cm^-1) : 1675. (A) N- [3- (3-Amidinophenyl) -2-methyl-2- (E) -propenyl] -N- [4- (piperidin-4-yloxy) phenyl] ethanesulfonamide dihydrochloride N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2-methyl-2- (E) -propenyl] ethanesulfonamide (839 mg) , Dissolved in a mixed solvent of dichloromethane (40 ml) and ethanol (20 ml), passed through hydrogen chloride for 1 hour under ice cooling, then sealed and stirred at room temperature for 8 hours. After concentrating the reaction solution under reduced pressure, the residue was dissolved in ethanol (30 ml), aqueous ammonium chloride solution (166 mg dissolved in 10 ml of water) and 28% aqueous ammonia (0.320 ml) were added, and then allowed to stand at room temperature for 12 hours. did. After evaporating the solvent under reduced pressure, the residue was dissolved in methanol (20 ml), 4M hydrogen chloride dioxane solution (1 ml) was added, and the mixture was concentrated under reduced pressure. After the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent 15% acetonitrile / water), the obtained amorphous solid was dissolved in methanol (20 ml), and 4M hydrogen chloride dioxane solution (1 ml) was added. After the addition, it was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml) and then freeze-dried to obtain 514 mg (yield 63%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.27 (3H, t, J = 7.0), 1.84 (2H, m), 1.87 (3H, s), 2.09 (2H, m), 3.04 (2H, m ), 3.16 (2H, q, J = 7.0), 3.20 (2H, m), 4.39 (2H, s), 4.64 (1H, m), 6.35 (1H, s), 7.01 (2H, d, J = 9.5 ), 7.39 (2H, d, J = 9.5), 7.47 (1H, d, J = 8.0), 7.55 (2H, m), 7.64 (1H, d, J = 8.0);
IR (KBr, cm ^-1 ): 1675.

（ｂ）Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−メチル−２−（Ｅ）−プロペニル］エタンスルホンアミド２塩酸塩
Ｎ−［３−（３−アミジノフェニル）−２−メチル−２−（Ｅ）−プロペニル］−Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］エタンスルホンアミド２塩酸塩（３０３ｍｇ）を、エタノール（１０ｍｌ）に溶解させ、エチルアセトイミデート塩酸塩（２４６ｍｇ）及びトリエチルアミン（０．４６０ｍｌ）を加え、室温で１２時間撹拌した。反応液に４Ｍ塩化水素ジオキサン溶液（０．９ｍｌ）を加えた後、減圧下濃縮した。残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２０％アセトニトリル／水）にて精製した後、得られた無定形固体をメタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．４ｍｌ）を加えた後、これを減圧下濃縮乾固させた。得られた無定形固体を水（約１０ｍｌ）に溶解させた後、凍結乾燥に付すことにより、表記化合物１７０ｍｇ（収率４５％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.27 (3H, t, J=7.0), 1.71 (2H, m), 1.87 (3H, s), 2.04 (2H, m), 2.30 (3H, s), 3.17 (2H, q, J=7.0), 3.53 (2H, m), 3.72 (1H, m), 3.83 (1H, m), 4.39 (2H, s), 4.70 (1H, m), 6.35 (1H, s),
7.01 (2H, d, J=9.0), 7.39 (2H, d, J=9.0), 7.47 (1H, d, J=8.0), 7.55 (1H, s), 7.55 (1H, t, J=8.0), 7.65 (1H, d, J=8.0) ;
IR (KBr, cm^-1) : 1673, 1626. (B) N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2-methyl-2- (E) -propenyl] ethanesulfonamide Dihydrochloride N- [3- (3-Amidinophenyl) -2-methyl-2- (E) -propenyl] -N- [4- (piperidin-4-yloxy) phenyl] ethanesulfonamide dihydrochloride (303 mg ) Was dissolved in ethanol (10 ml), ethylacetimidate hydrochloride (246 mg) and triethylamine (0.460 ml) were added, and the mixture was stirred at room temperature for 12 hours. A 4M hydrogen chloride dioxane solution (0.9 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. After the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water), the obtained amorphous solid was dissolved in methanol (10 ml), and 4M hydrogen chloride dioxane solution (0. 4 ml) was added, and this was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml) and then freeze-dried to obtain 170 mg (yield 45%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.27 (3H, t, J = 7.0), 1.71 (2H, m), 1.87 (3H, s), 2.04 (2H, m), 2.30 (3H, s ), 3.17 (2H, q, J = 7.0), 3.53 (2H, m), 3.72 (1H, m), 3.83 (1H, m), 4.39 (2H, s), 4.70 (1H, m), 6.35 ( 1H, s),
7.01 (2H, d, J = 9.0), 7.39 (2H, d, J = 9.0), 7.47 (1H, d, J = 8.0), 7.55 (1H, s), 7.55 (1H, t, J = 8.0) , 7.65 (1H, d, J = 8.0);
IR (KBr, cm ^-1 ): 1673, 1626.

実施例３
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩（例示化合物番号：１４１０） Example 3
N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl acetate dihydrochloride (Exemplary Compound No. : 1410)

（ａ）Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル（１．４６ｇ）を、ジクロロメタン（５０ｍｌ）及びエタノール（２５ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１時間通じた後、密栓をして室温で８時間撹拌した。反応液を減圧下濃縮し、残渣をエタノール（４０ｍｌ）に溶解させた後、塩化アンモニウム水溶液（０．３０ｇを水１５ｍｌに溶解）及び２８％アンモニア水（０．５８ｍｌ）を加え、室温で１２時間放置した。反応液に４Ｍ塩化水素ジオキサン溶液（２ｍｌ）を加えた後、減圧下濃縮した。残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１５％アセトニトリル／水）にて精製することにより、表記化合物０．９８ｇ（収率６８％）を淡黄色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.23 (3H, t, J=7.0), 1.83 (2H, m), 2.10 (2H, m), 3.05 (2H, m), 3.19 (2H, m), 4.20 (2H, q, J=7.0), 4.34 (2H, s), 4.45 (2H, d, J=6.0), 4.66 (1H, m), 6.45 (1H, dt, J=16.0, 6.0), 6.55 (1H, d, J=16.0), 7.04 (2H, d, J=8.5), 7.39 (2H, d, J=8.5), 7.55 (1H, t, J=8.0), 7.69 (1H, d, J=8.0), 7.72 (1H, d, J=8.0), 7.89 (1H, s) ;
IR (KBr, cm^-1) : 1737, 1675. (A) N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [4- (piperidin-4-yloxy) phenyl] sulfamoyl acetate ethyl dihydrochloride N- [4- ( 1-t-Butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl acetate (1.46 g) in dichloromethane (50 ml) and The mixture was dissolved in a mixed solvent of ethanol (25 ml), passed through hydrogen chloride for 1 hour under ice-cooling, sealed, and stirred at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethanol (40 ml). Then, an aqueous ammonium chloride solution (0.30 g dissolved in 15 ml of water) and 28% aqueous ammonia (0.58 ml) were added, and the mixture was stirred at room temperature for 12 hours. I left it alone. A 4M hydrogen chloride dioxane solution (2 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 15% acetonitrile / water) to obtain 0.98 g (yield 68%) of the title compound as a pale yellow amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.0), 1.83 (2H, m), 2.10 (2H, m), 3.05 (2H, m), 3.19 (2H, m ), 4.20 (2H, q, J = 7.0), 4.34 (2H, s), 4.45 (2H, d, J = 6.0), 4.66 (1H, m), 6.45 (1H, dt, J = 16.0, 6.0) , 6.55 (1H, d, J = 16.0), 7.04 (2H, d, J = 8.5), 7.39 (2H, d, J = 8.5), 7.55 (1H, t, J = 8.0), 7.69 (1H, d , J = 8.0), 7.72 (1H, d, J = 8.0), 7.89 (1H, s);
IR (KBr, cm ^-1 ): 1737, 1675.

（ｂ）Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩（１０９０ｍｇ）を、エタノール（４０ｍｌ）に溶解させ、エチルアセトイミデート塩酸塩（７０５ｍｇ）及びトリエチルアミン（１．３０ｍｌ）を加えた後、室温で６時間撹拌した。反応液を減圧下濃縮乾固させ、残渣をメタノール（１５ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（２ｍｌ）を加えた後、減圧下濃縮した。残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２０％アセトニトリル／水）にて精製した後、得られた無定形固体をメタノール（１５ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（１ｍｌ）を加えた後、これを減圧下濃縮乾固させることにより、表記化合物８１２ｍｇ（収率７０％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.23 (3H, t, J=7.0), 1.67-1.79 (2H, m), 2.04 (2H, m), 2.29 (3H, s), 3.50 (2H, m), 3.72 (1H, m), 3.81 (1H, m),
4.19 (2H, q, J=7.0), 4.34 (2H, s), 4.44 (2H, d, J=6.0), 4.70 (1H, m), 6.45 (1H, dt, J=16.5, 6.0), 6.55 (1H, d, J=16.5), 7.04 (2H, d, J=9.5), 7.39 (2H, d, J=9.5), 7.54 (1H, t, J=8.0), 7.69 (1H, d, J=8.0), 7.71 (1H, d, J=8.0), 7.88 (1H, s) ;
IR (KBr, cm^-1) : 1738, 1673, 1626. (B) N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl acetate dihydrochloride N -[3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [4- (piperidin-4-yloxy) phenyl] sulfamoyl acetate ethyl dihydrochloride (1090 mg) in ethanol (40 ml) After dissolution, ethylacetimidate hydrochloride (705 mg) and triethylamine (1.30 ml) were added and stirred at room temperature for 6 hours. The reaction mixture was concentrated to dryness under reduced pressure, the residue was dissolved in methanol (15 ml), 4M hydrogen chloride dioxane solution (2 ml) was added, and the mixture was concentrated under reduced pressure. After the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water), the obtained amorphous solid was dissolved in methanol (15 ml), and 4M hydrogen chloride dioxane solution (1 ml) was obtained. Then, this was concentrated to dryness under reduced pressure to obtain 812 mg (yield 70%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.0), 1.67-1.79 (2H, m), 2.04 (2H, m), 2.29 (3H, s), 3.50 (2H , m), 3.72 (1H, m), 3.81 (1H, m),
4.19 (2H, q, J = 7.0), 4.34 (2H, s), 4.44 (2H, d, J = 6.0), 4.70 (1H, m), 6.45 (1H, dt, J = 16.5, 6.0), 6.55 (1H, d, J = 16.5), 7.04 (2H, d, J = 9.5), 7.39 (2H, d, J = 9.5), 7.54 (1H, t, J = 8.0), 7.69 (1H, d, J = 8.0), 7.71 (1H, d, J = 8.0), 7.88 (1H, s);
IR (KBr, cm ^-1 ): 1738, 1673, 1626.

実施例４
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸２塩酸塩（例示化合物番号：１９３９）
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩（４４０ｍｇ）を、３Ｍ塩酸（３０ｍｌ）に溶解させ、８０℃で３時間撹拌した。反応液を室温まで冷却させた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１５％アセトニトリル／水）にて精製した後、得られた無定形固体をメタノール（１５ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（１ｍｌ）を加えた後、減圧下濃縮乾固させた。残渣を水（約１５ｍｌ）に溶解させた後、凍結乾燥に付すことにより、表記化合物３３１ｍｇ（収率７８％）を得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.73 (2H, m), 2.04 (2H, m), 2.29 (3H,
s), 3.51 (2H, m), 3.72 (1H, m), 3.80 (1H, m), 4.18 (2H, s), 4.45 (2H, d, J=6.0), 4.70 (1H, m), 6.44 (1H, dt, J=16.5, 6.0), 6.55 (1H, d, J=16.5), 7.03 (2H, d, J=8.5), 7.40 (2H, d, J=8.5), 7.54 (1H, t, J=8.0), 7.68 (1H, d, J=8.0), 7.71 (1H, d, J=8.0), 7.87 (1H, s) ;
IR (KBr, cm^-1) : 1733, 1673, 1627. Example 4
N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoylacetic acid dihydrochloride (Exemplary compound number: 1939)
N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl ethyl acetate dihydrochloride (440 mg) It was dissolved in 3M hydrochloric acid (30 ml) and stirred at 80 ° C. for 3 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 15% acetonitrile / water), and then the resulting amorphous solid was treated with methanol. (15 ml), 4M hydrogen chloride dioxane solution (1 ml) was added, and the mixture was concentrated to dryness under reduced pressure. The residue was dissolved in water (about 15 ml) and then freeze-dried to obtain 331 mg (yield 78%) of the title compound.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.73 (2H, m), 2.04 (2H, m), 2.29 (3H,
s), 3.51 (2H, m), 3.72 (1H, m), 3.80 (1H, m), 4.18 (2H, s), 4.45 (2H, d, J = 6.0), 4.70 (1H, m), 6.44 (1H, dt, J = 16.5, 6.0), 6.55 (1H, d, J = 16.5), 7.03 (2H, d, J = 8.5), 7.40 (2H, d, J = 8.5), 7.54 (1H, t , J = 8.0), 7.68 (1H, d, J = 8.0), 7.71 (1H, d, J = 8.0), 7.87 (1H, s);
IR (KBr, cm ^-1 ): 1733, 1673, 1627.

実施例５
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（５−アミジノ−２−フルオロフェニル）−２−（Ｅ）−プロペニル］エタンスルホンアミド２塩酸塩（例示化合物番号：１２８０） Example 5
N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (5-amidino-2-fluorophenyl) -2- (E) -propenyl] ethanesulfonamide dihydrochloride (Exemplary compound number: 1280)

（ａ）Ｎ−［３−（５−アミジノ−２−フルオロフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］エタンスルホンアミド２塩酸塩
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（５−シアノ−２−フルオロフェニル）−２−（Ｅ）−プロペニル］エタンスルホンアミド（２．００ｇ）を、ジクロロメタン（６０ｍｌ）及びエタノール（４０ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１時間通じた後、密栓をして室温で７時間撹拌した。反応液を減圧下濃縮した後、残渣をエタノール（５０ｍｌ）に溶解させ、塩化アンモニウム水溶液（０．３９ｇを水２５ｍｌに溶解）及び２８％アンモニア水（０．７６ｍｌ）を加えた後、室温で１２時間放置した。反応液を減圧下濃縮し、残渣をメタノール（２０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（２ｍｌ）を加えた後、減圧下濃縮した。残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２０％アセトニトリル／水）にて精製し、得られた無定形固体をメタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（１ｍｌ）を加えた後、減圧下濃縮乾固させた。得られた無定形固体を水（約１０ｍｌ）に溶解させた後、凍結乾燥に付すことにより、表記化合物１．２０ｇ（収率６１％）を淡褐色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.27 (3H, t, J=7.0), 1.82 (2H, m), 2.09 (2H, m), 3.04 (2H, m), 3.17 (2H, q, J=7.0), 3.18 (2H, m), 4.49 (2H, d, J=6.0), 4.64 (1H, m), 6.55 (1H, dt, J=16.0, 6.0), 6.61 (1H, d, J=16.0), 7.01 (2H, d, J=8.5), 7.37 (2H, d, J=8.5), 7.45 (1H, m), 7.78 (1H, m), 8.11 (1H, m) ;
IR (KBr, cm^-1) : 3056, 1676. (A) N- [3- (5-Amidino-2-fluorophenyl) -2- (E) -propenyl] -N- [4- (piperidin-4-yloxy) phenyl] ethanesulfonamide dihydrochloride N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3- (5-cyano-2-fluorophenyl) -2- (E) -propenyl] ethanesulfonamide (2.00 g ) Was dissolved in a mixed solvent of dichloromethane (60 ml) and ethanol (40 ml), hydrogen chloride was passed through for 1 hour under ice-cooling, and the mixture was sealed and stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (50 ml), aqueous ammonium chloride solution (0.39 g dissolved in 25 ml water) and 28% aqueous ammonia (0.76 ml) were added, Left for hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol (20 ml), 4M hydrogen chloride dioxane solution (2 ml) was added, and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water), the obtained amorphous solid was dissolved in methanol (10 ml), and 4M hydrogen chloride dioxane solution (1 ml) was added. After the addition, the mixture was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml) and then freeze-dried to obtain 1.20 g (yield 61%) of the title compound as a light brown amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.27 (3H, t, J = 7.0), 1.82 (2H, m), 2.09 (2H, m), 3.04 (2H, m), 3.17 (2H, q , J = 7.0), 3.18 (2H, m), 4.49 (2H, d, J = 6.0), 4.64 (1H, m), 6.55 (1H, dt, J = 16.0, 6.0), 6.61 (1H, d, J = 16.0), 7.01 (2H, d, J = 8.5), 7.37 (2H, d, J = 8.5), 7.45 (1H, m), 7.78 (1H, m), 8.11 (1H, m);
IR (KBr, cm ^-1 ): 3056, 1676.

（ｂ）Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（５−アミジノ−２−フルオロフェニル）−２−（Ｅ）−プロペニル］エタンスルホンアミド２塩酸塩
Ｎ−［３−（５−アミジノ−２−フルオロフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］エタンスルホンアミド２塩酸塩（５３４ｍｇ）を、エタノール（２０ｍｌ）に溶解させ、エチルアセトイミデート塩酸塩（３７１ｍｇ）及びトリエチルアミン（０．７０ｍｌ）を室温で加えた後、同温で１２時間撹拌した。反応液に４Ｍ塩化水素ジオキサン溶液（２ｍｌ）を加えた後、減圧下濃縮した。残渣を分取ＨＰＬＣ（YMC-Pack ODS
YMC、溶出溶媒：２０％アセトニトリル／水）にて精製した後、得られた無定形固体をメタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．５ｍｌ）を加えた後、これを減圧下濃縮乾固させた。得られた無定形固体を水（約１０ｍｌ）に溶解させた後、凍結乾燥に付すことにより、表記化合物４１５ｍｇ（収率７５％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.28 (3H, t, J=7.0), 1.74 (2H, m), 2.05 (2H, m), 2.30 (3H, s), 3.18 (2H, q, J=7.0), 3.52 (2H, m), 3.72 (1H, m), 3.81 (1H, m), 4.50 (2H, d, J=6.0), 4.70 (1H, m), 6.56 (1H, dt, J=16.5, 6.0), 6.62 (1H, d, J=16.5), 7.02 (2H, d, J=9.0),7.37 (2H, d, J=9.0), 7.46 (1H, m), 7.78 (1H, m), 8.12 (1H, m) ;
IR (KBr, cm^-1) : 3113, 1674, 1625. (B) N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (5-amidino-2-fluorophenyl) -2- (E) -propenyl] ethanesulfonamide Dihydrochloride N- [3- (5-amidino-2-fluorophenyl) -2- (E) -propenyl] -N- [4- (piperidin-4-yloxy) phenyl] ethanesulfonamide dihydrochloride (534 mg ) Was dissolved in ethanol (20 ml), ethylacetimidate hydrochloride (371 mg) and triethylamine (0.70 ml) were added at room temperature, and the mixture was stirred at the same temperature for 12 hours. A 4M hydrogen chloride dioxane solution (2 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Preparative HPLC (YMC-Pack ODS
After purification with YMC, elution solvent: 20% acetonitrile / water, the obtained amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and this was reduced in pressure. Concentrated to dryness. The obtained amorphous solid was dissolved in water (about 10 ml) and then freeze-dried to obtain 415 mg (yield 75%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.28 (3H, t, J = 7.0), 1.74 (2H, m), 2.05 (2H, m), 2.30 (3H, s), 3.18 (2H, q , J = 7.0), 3.52 (2H, m), 3.72 (1H, m), 3.81 (1H, m), 4.50 (2H, d, J = 6.0), 4.70 (1H, m), 6.56 (1H, dt , J = 16.5, 6.0), 6.62 (1H, d, J = 16.5), 7.02 (2H, d, J = 9.0), 7.37 (2H, d, J = 9.0), 7.46 (1H, m), 7.78 ( 1H, m), 8.12 (1H, m);
IR (KBr, cm ^-1 ): 3113, 1674, 1625.

実施例６
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−２−メチルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩（例示化合物番号：１４１９） Example 6
N- [4- (1-acetimidoylpiperidin-4-yloxy) -2-methylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl acetate dihydrochloride (Exemplary compound number: 1419)

（ａ）Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［２−メチル−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−２−メチルフェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル（１．８０ｇ）を、ジクロロメタン（６０ｍｌ）及びエタノール（４０ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１時間通じた後、密栓をして室温で６時間撹拌した。反応液を減圧下濃縮し、残渣をエタノール（５０ｍｌ）に溶解させ、塩化アンモニウム水溶液（０．３２ｇを水２５ｍｌに溶解）及び２８％アンモニア水（０．６２ｍｌ）を加えた後、室温で１２時間放置した。反応液を減圧下濃縮し、残渣をメタノール（３０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（２ｍｌ）を加えた後、減圧下濃縮した。残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２０％アセトニトリル／水）にて精製することにより、表記化合物０．７８ｇ（収率４５％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.23 (3H, t, J=7.0), 1.73 (2H, m), 2.04 (2H, m), 2.27 (3H, s), 3.00 (2H, m), 3.18 (2H, m), 4.20 (2H, q, J=7.0), 4.25 (1H, m), 4.33 (1H, d, J=14.5), 4.45 (1H, m), 4.46 (1H, d, J=14.5), 4.59 (1H, m), 6.46 (2H, s), 6.88 (1H, d, J=9.0), 6.90 (1H, s), 7.39 (1H, d, J=9.0), 7.55 (1H, t, J=8.0), 7.67 (1H, d, J=8.0), 7.71 (1H, d, J=8.0), 7.81 (1H, s) ;
IR (KBr, cm^-1) : 1737, 1676. (A) N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [2-methyl-4- (piperidin-4-yloxy) phenyl] sulfamoyl acetate ethyl dihydrochloride N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -2-methylphenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl ethyl acetate (1.80 g ) Was dissolved in a mixed solvent of dichloromethane (60 ml) and ethanol (40 ml), hydrogen chloride was passed through for 1 hour under ice-cooling, and the mixture was sealed and stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (50 ml), aqueous ammonium chloride solution (0.32 g dissolved in 25 ml water) and 28% aqueous ammonia (0.62 ml) were added, and then at room temperature for 12 hours. I left it alone. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol (30 ml), 4M hydrogen chloride dioxane solution (2 ml) was added, and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water) to obtain 0.78 g (yield 45%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.0), 1.73 (2H, m), 2.04 (2H, m), 2.27 (3H, s), 3.00 (2H, m ), 3.18 (2H, m), 4.20 (2H, q, J = 7.0), 4.25 (1H, m), 4.33 (1H, d, J = 14.5), 4.45 (1H, m), 4.46 (1H, d , J = 14.5), 4.59 (1H, m), 6.46 (2H, s), 6.88 (1H, d, J = 9.0), 6.90 (1H, s), 7.39 (1H, d, J = 9.0), 7.55 (1H, t, J = 8.0), 7.67 (1H, d, J = 8.0), 7.71 (1H, d, J = 8.0), 7.81 (1H, s);
IR (KBr, cm ^-1 ): 1737, 1676.

（ｂ）Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−２−メチルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［２−メチル−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩（６３１ｍｇ）を、エタノール（３０ｍｌ）に溶解させ、エチルアセトイミデート塩酸塩（３９７ｍｇ）及びトリエチルアミン（０．７５ｍｌ）を加えた後、室温で６４時間撹拌した。４Ｍ塩化水素ジオキサン溶液（２ｍｌ）を加えた後、反応液を減圧下濃縮した。残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２４％アセトニトリル／水）にて精製した後、得られた無定形固体をメタノール（２０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（１ｍｌ）を加えた後、これを減圧下濃縮乾固させた。得られた無定形固体を水（約１５ｍｌ）に溶解させた後、凍結乾燥に付すことにより、表記化合物４２３ｍｇ（収率６０％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.24 (3H, t, J=6.5), 1.65-1.79 (2H, m), 2.04 (2H, m), 2.28 (3H, s), 2.31 (3H, s), 3.48-3.59 (2H, m), 3.72 (1H, m), 3.85 (1H, m), 4.21 (2H, q, J=6.5), 4.28 (1H, dd, J=14.5, 6.0), 4.34 (1H, d, J=15.0), 4.43 (1H, dd, J=14.5, 4.5), 4.49 (1H, d, J=15.0), 4.70 (1H, m), 6.46 (1H, d, J=15.5), 6.49 (1H, m), 6.90 (1H, dd, J=9.0, 3.0), 6.93 (1H, d, J=3.0), 7.41 (1H, d, J=9.0), 7.55 (1H, t, J=8.0), 7.72 (2H, m), 7.88 (1H, s) ;
IR (KBr, cm^-1) : 1738, 1673, 1624. (B) ethyl N- [4- (1-acetimidoylpiperidin-4-yloxy) -2-methylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl acetate Dihydrochloride N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [2-methyl-4- (piperidin-4-yloxy) phenyl] sulfamoyl ethyl acetate dihydrochloride (631 mg ) Was dissolved in ethanol (30 ml), ethylacetoimidate hydrochloride (397 mg) and triethylamine (0.75 ml) were added, and the mixture was stirred at room temperature for 64 hours. After adding 4M hydrogen chloride dioxane solution (2 ml), the reaction solution was concentrated under reduced pressure. After the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 24% acetonitrile / water), the obtained amorphous solid was dissolved in methanol (20 ml), and 4M hydrogen chloride dioxane solution (1 ml) was obtained. This was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 15 ml) and then freeze-dried to obtain 423 mg (yield 60%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.24 (3H, t, J = 6.5), 1.65-1.79 (2H, m), 2.04 (2H, m), 2.28 (3H, s), 2.31 (3H , s), 3.48-3.59 (2H, m), 3.72 (1H, m), 3.85 (1H, m), 4.21 (2H, q, J = 6.5), 4.28 (1H, dd, J = 14.5, 6.0) , 4.34 (1H, d, J = 15.0), 4.43 (1H, dd, J = 14.5, 4.5), 4.49 (1H, d, J = 15.0), 4.70 (1H, m), 6.46 (1H, d, J = 15.5), 6.49 (1H, m), 6.90 (1H, dd, J = 9.0, 3.0), 6.93 (1H, d, J = 3.0), 7.41 (1H, d, J = 9.0), 7.55 (1H, t, J = 8.0), 7.72 (2H, m), 7.88 (1H, s);
IR (KBr, cm ^-1 ): 1738, 1673, 1624.

実施例７
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−メトキシフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩（例示化合物番号：１４４２） Example 7
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-methoxyphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl acetate dihydrochloride (Exemplary compound number: 1442)

（ａ）Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［３−メトキシ−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−メトキシフェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル（９８５ｍｇ）をジクロロメタン（３０ｍｌ）及びエタノール（１５ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を４０分間通じた後、密栓をして室温で６時間撹拌した。反応液を減圧下濃縮した後、残渣をエタノール（２０ｍｌ）に溶解させ、塩化アンモニウム水溶液（１７２ｍｇを水１０ｍｌに溶解）及び２８％アンモニア水（０．３３ｍｌ）を加えた後、室温で１３時間放置した。反応液を減圧下濃縮し、残渣をメタノール（２０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（１．５ｍｌ）を加えた後、減圧下濃縮した。残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１７％アセトニトリル／水）にて精製し、得られた無定形固体をメタノール（２０ｍｌ）及び４Ｍ塩化水素ジオキサン溶液（０．４ｍｌ）に溶解させた後、これを濃縮乾固することにより、表記化合物５６０ｍｇ（収率５８％）を淡黄色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.24 (3H, t, J=7.0), 1.84 (2H, m), 2.05 (2H, m), 3.03 (2H, m), 3.19 (2H, m), 3.79 (3H, s), 4.21 (2H, q, J=7.0), 4.38 (2H, s), 4.46 (2H, d, J=6.0), 4.56 (1H, m), 6.46 (1H, dt, J=15.5, 6.0), 6.57 (1H, d, J=15.5), 6.98 (1H, dd, J=9.0, 2.0), 7.08 (1H, d, J=9.0), 7.11 (1H, d, J=2.0), 7.55 (1H, t, J=7.5), 7.69 (1H, d, J=7.5), 7.73 (1H, d, J=7.5), 7.90 (1H, s) ;
IR (KBr, cm^-1) : 1737, 1675. (A) N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-methoxy-4- (piperidin-4-yloxy) phenyl] sulfamoyl acetate ethyl dihydrochloride N- Ethyl [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-methoxyphenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl acetate (985 mg) The mixture was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), passed through hydrogen chloride for 40 minutes under ice-cooling, sealed, and stirred at room temperature for 6 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), an aqueous ammonium chloride solution (172 mg dissolved in 10 ml of water) and 28% aqueous ammonia (0.33 ml) were added, and then left at room temperature for 13 hours. did. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol (20 ml), 4M hydrogen chloride dioxane solution (1.5 ml) was added, and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 17% acetonitrile / water), and the resulting amorphous solid was dissolved in methanol (20 ml) and 4M hydrogen chloride dioxane solution (0.4 ml). This was concentrated and dried to obtain 560 mg (yield 58%) of the title compound as a pale yellow amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.24 (3H, t, J = 7.0), 1.84 (2H, m), 2.05 (2H, m), 3.03 (2H, m), 3.19 (2H, m ), 3.79 (3H, s), 4.21 (2H, q, J = 7.0), 4.38 (2H, s), 4.46 (2H, d, J = 6.0), 4.56 (1H, m), 6.46 (1H, dt , J = 15.5, 6.0), 6.57 (1H, d, J = 15.5), 6.98 (1H, dd, J = 9.0, 2.0), 7.08 (1H, d, J = 9.0), 7.11 (1H, d, J = 2.0), 7.55 (1H, t, J = 7.5), 7.69 (1H, d, J = 7.5), 7.73 (1H, d, J = 7.5), 7.90 (1H, s);
IR (KBr, cm ^-1 ): 1737, 1675.

（ｂ）Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−メトキシフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［３−メトキシ−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩（３９２ｍｇ）を、エタノール（２０ｍｌ）に溶解させ、エチルアセトイミデート塩酸塩（２４１ｍｇ）及びトリエチルアミン（０．４５２ｍｌ）を加えた後、室温で３８時間撹拌した。反応液に４Ｍ塩化水素ジオキサン溶液（０．８ｍｌ）を加えた後、減圧下濃縮した。残渣を分取ＨＰＬＣ（YMC-Pack
ODS YMC、溶出溶媒：２０％アセトニトリル／水）にて精製した後、得られた無定形固体をメタノール（２０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．３ｍｌ）を加えた後、これを減圧下濃縮乾固させた。得られた無定形固体を水（約１０ｍｌ）に溶解させた後、凍結乾燥に付すことにより、表記化合物３１７ｍｇ（収率７６％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.24 (3H, t, J=7.0), 1.66-1.80 (2H, m), 2.01 (2H, m), 2.30 (3H, s), 3.47-3.59 (2H, m), 3.72 (1H, m), 3.78 (3H, s), 3.82 (1H, m), 4.21 (2H, q, J=7.0), 4.39 (2H, s), 4.47 (2H, d, J=5.5), 4.62 (1H, m), 6.47 (1H, dt, J=15.5, 5.5), 6.57 (1H, d, J=15.5), 6.99
(1H, dd, J=9.0, 3.0), 7.11 (2H, m), 7.55 (1H, t, J=8.0), 7.71 (1H, d, J=8.0), 7.73 (1H, d, J=8.0), 7.91 (1H, s) ;
IR (KBr, cm^-1) : 1738, 1674, 1625. (B) ethyl N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-methoxyphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl acetate Dihydrochloride N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-methoxy-4- (piperidin-4-yloxy) phenyl] sulfamoyl ethyl acetate dihydrochloride (392 mg ) Was dissolved in ethanol (20 ml), ethylacetoimidate hydrochloride (241 mg) and triethylamine (0.452 ml) were added, and the mixture was stirred at room temperature for 38 hours. A 4M hydrogen chloride dioxane solution (0.8 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Preparative HPLC (YMC-Pack
After purification with ODS YMC, elution solvent: 20% acetonitrile / water, the obtained amorphous solid was dissolved in methanol (20 ml), and 4M hydrogen chloride dioxane solution (0.3 ml) was added. Concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml) and then freeze-dried to obtain 317 mg (yield 76%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.24 (3H, t, J = 7.0), 1.66-1.80 (2H, m), 2.01 (2H, m), 2.30 (3H, s), 3.47-3.59 (2H, m), 3.72 (1H, m), 3.78 (3H, s), 3.82 (1H, m), 4.21 (2H, q, J = 7.0), 4.39 (2H, s), 4.47 (2H, d , J = 5.5), 4.62 (1H, m), 6.47 (1H, dt, J = 15.5, 5.5), 6.57 (1H, d, J = 15.5), 6.99
(1H, dd, J = 9.0, 3.0), 7.11 (2H, m), 7.55 (1H, t, J = 8.0), 7.71 (1H, d, J = 8.0), 7.73 (1H, d, J = 8.0 ), 7.91 (1H, s);
IR (KBr, cm ^-1 ): 1738, 1674, 1625.

実施例８
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−クロロフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩（例示化合物番号：１４１４） Example 8
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-chlorophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl acetate dihydrochloride ( Illustrative compound number: 1414)

（ａ）Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［３−クロロ−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−クロロフェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル（１２００ｍｇ）を、ジクロロメタン（３０ｍｌ）及びエタノール（２０ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を２時間通じた後、密栓をして室温で４時間撹拌した。反応液を減圧下濃縮した後、残渣をエタノール（２０ｍｌ）に溶解させ、塩化アンモニウム水溶液（２０８ｍｇを水１０ｍｌに溶解）及び２８％アンモニア水（０．４０ｍｌ）を加えた後、室温で１３時間放置した。反応液を減圧下濃縮し、残渣をメタノール（２５ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（１．６ｍｌ）を加えた後、減圧下濃縮した。残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２０％アセトニトリル／水）にて精製し、得られた無定形固体をメタノール（２０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．５ｍｌ）を加えた後、これを濃縮乾固させ、無定形固体を得た。これを水に溶解させた後、凍結乾燥に付すことにより、表記化合物６６２ｍｇ（収率５６％）を淡黄色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.23 (3H, t, J=7.0), 1.88 (2H, m), 2.10 (2H, m), 3.08 (2H, m), 3.17 (2H, m), 4.19 (2H, q, J=7.0), 4.41 (2H, s), 4.47 (2H, d, J=6.5), 4.78 (1H, m), 6.44 (1H, dt, J=16.0, 6.5), 6.57 (1H, d, J=16.0), 7.30 (1H, d, J=9.5), 7.41 (1H, dd, J=9.5, 2.5), 7.55 (1H, t, J=8.0), 7.59 (1H, d, J=2.5), 7.69 (1H, d, J=8.0), 7.73 (1H, d, J=8.0), 7.88 (1H, s) ;
IR (KBr, cm^-1) : 1737, 1675. (A) N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- (piperidin-4-yloxy) phenyl] sulfamoyl acetate ethyl dihydrochloride N- Ethyl [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-chlorophenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl acetate (1200 mg) After dissolving in a mixed solvent of dichloromethane (30 ml) and ethanol (20 ml) and passing through hydrogen chloride for 2 hours under ice cooling, the mixture was sealed and stirred at room temperature for 4 hours. After concentrating the reaction solution under reduced pressure, the residue was dissolved in ethanol (20 ml), aqueous ammonium chloride solution (208 mg dissolved in 10 ml of water) and 28% aqueous ammonia (0.40 ml) were added, and then allowed to stand at room temperature for 13 hours. did. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol (25 ml), 4M hydrogen chloride dioxane solution (1.6 ml) was added, and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water). The obtained amorphous solid was dissolved in methanol (20 ml), and 4M hydrogen chloride dioxane solution (0.5 ml) was obtained. ) Was added and concentrated to dryness to give an amorphous solid. This was dissolved in water and then freeze-dried to obtain 662 mg (yield 56%) of the title compound as a pale yellow amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.0), 1.88 (2H, m), 2.10 (2H, m), 3.08 (2H, m), 3.17 (2H, m ), 4.19 (2H, q, J = 7.0), 4.41 (2H, s), 4.47 (2H, d, J = 6.5), 4.78 (1H, m), 6.44 (1H, dt, J = 16.0, 6.5) , 6.57 (1H, d, J = 16.0), 7.30 (1H, d, J = 9.5), 7.41 (1H, dd, J = 9.5, 2.5), 7.55 (1H, t, J = 8.0), 7.59 (1H , d, J = 2.5), 7.69 (1H, d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.88 (1H, s);
IR (KBr, cm ^-1 ): 1737, 1675.

（ｂ）Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−クロロフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［３−クロロ−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩（３８７ｍｇ）を、エタノール（１０ｍｌ）に溶解させ、エチルアセトイミデート塩酸塩（２３２ｍｇ）及びトリエチルアミン（０．４４０ｍｌ）を加えた後、室温で５時間撹拌した。４Ｍ塩化水素ジオキサン溶液（１ｍｌ）を加えた後、反応液を減圧下濃縮した。残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２２％アセトニトリル／水）にて精製した後、得られた無定形固体をメタノール（２０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．２５ｍｌ）を加えた後、これを減圧下濃縮乾固させた。得られた無定形固体を水（約１５ｍｌ）に溶解させた後、凍結乾燥に付すことにより、表記化合物２６８ｍｇ（収率６６％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.23 (3H, t, J=7.0), 1.80 (2H, m), 2.05 (2H, m), 2.30 (3H, s), 3.55 - 3.78 (4H, m), 4.19 (2H, q, J=7.0), 4.42
(2H, s), 4.47 (2H, d, J=6.0), 4.84 (1H, m), 6.45 (1H, dt, J=15.5, 6.0),
6.58 (1H, d, J=15.5), 7.33 (1H, d, J=9.0), 7.41 (1H, dd, J=9.0, 3.0), 7.55 (1H, t, J=8.0), 7.59 (1H, d, J=3.0), 7.70 (1H, d, J=8.0), 7.73 (1H, d, J=8.0), 7.90 (1H, s) ;
IR (KBr, cm^-1) : 1738, 1673, 1623. (B) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-chlorophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl ethyl acetate 2 Hydrochloride N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-chloro-4- (piperidin-4-yloxy) phenyl] sulfamoyl ethyl acetate dihydrochloride (387 mg) Was dissolved in ethanol (10 ml), ethylacetoimidate hydrochloride (232 mg) and triethylamine (0.440 ml) were added, and the mixture was stirred at room temperature for 5 hr. After adding 4M hydrogen chloride dioxane solution (1 ml), the reaction solution was concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 22% acetonitrile / water). 25 ml), and then concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 15 ml) and then freeze-dried to obtain 268 mg (yield 66%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.0), 1.80 (2H, m), 2.05 (2H, m), 2.30 (3H, s), 3.55-3.78 (4H , m), 4.19 (2H, q, J = 7.0), 4.42
(2H, s), 4.47 (2H, d, J = 6.0), 4.84 (1H, m), 6.45 (1H, dt, J = 15.5, 6.0),
6.58 (1H, d, J = 15.5), 7.33 (1H, d, J = 9.0), 7.41 (1H, dd, J = 9.0, 3.0), 7.55 (1H, t, J = 8.0), 7.59 (1H, d, J = 3.0), 7.70 (1H, d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.90 (1H, s);
IR (KBr, cm ^-1 ): 1738, 1673, 1623.

実施例９
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−クロロフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸２塩酸塩（例示化合物番号：１９４３）
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−クロロフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩（１８７ｍｇ）を３Ｍ塩酸（７ｍｌ）に溶解させ、これを８０℃で２時間撹拌した。反応液を室温まで冷却させた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１５％アセトニトリル／水）にて精製し、得られた無定形固体をメタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．２ｍｌ）を加えた後、減圧下濃縮乾固させた。これを水（約１０ｍｌ）に溶解させた後、凍結乾燥に付すことにより、表記化合物１４７ｍｇ（収率８２％）を得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.79 (2H, m), 2.05 (2H, m), 2.29 (3H,
s), 3.54-3.75 (4H, m), 4.23 (2H, s), 4.47 (2H, d, J=6.0), 4.83 (1H, m),
6.45 (1H, dt, J=16.0, 6.0), 6.57 (1H, d, J=16.0), 7.32 (1H, d, J=9.0), 7.41 (1H, m), 7.55 (1H, t, J=8.0), 7.60 (1H, m), 7.68 (1H, d, J=8.0), 7.73 (1H, d, J=8.0), 7.88 (1H, s) ;
IR (KBr, cm^-1) : 1734, 1673, 1625. Example 9
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-chlorophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoylacetic acid dihydrochloride (Exemplary Compound number: 1943)
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-chlorophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl ethyl acetate dihydrochloride ( 187 mg) was dissolved in 3M hydrochloric acid (7 ml) and stirred at 80 ° C. for 2 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 15% acetonitrile / water), and the resulting amorphous solid was methanol ( 10 ml), 4M hydrogen chloride dioxane solution (0.2 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water (about 10 ml) and then freeze-dried to obtain 147 mg (yield 82%) of the title compound.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.79 (2H, m), 2.05 (2H, m), 2.29 (3H,
s), 3.54-3.75 (4H, m), 4.23 (2H, s), 4.47 (2H, d, J = 6.0), 4.83 (1H, m),
6.45 (1H, dt, J = 16.0, 6.0), 6.57 (1H, d, J = 16.0), 7.32 (1H, d, J = 9.0), 7.41 (1H, m), 7.55 (1H, t, J = 8.0), 7.60 (1H, m), 7.68 (1H, d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.88 (1H, s);
IR (KBr, cm ^-1 ): 1734, 1673, 1625.

実施例１０
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−フルオロフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩（例示化合物番号：１４１２） Example 10
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-fluorophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl ethyl acetate dihydrochloride (Exemplary compound number: 1412)

（ａ）Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［３−フルオロ−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−フルオロフェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル（１２１０ｍｇ）をジクロロメタン（３０ｍｌ）及びエタノール（２０ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１時間通じた後、密栓をして室温で６時間撹拌した。反応液を減圧下濃縮し、残渣をエタノール（２０ｍｌ）に溶解させた後、塩化アンモニウム水溶液（２１５ｍｇを水１０ｍｌに溶解）及び２８％アンモニア水（０．４１ｍｌ）を加え、室温で１７時間放置した。反応液を減圧下濃縮し、残渣をメタノール（２０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（２ｍｌ）を加えた後、減圧下濃縮した。残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１７％アセトニトリル／水）にて精製し、得られた無定形固体をメタノール（１５ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．３ｍｌ）を加えた後、これを減圧下濃縮乾固させることにより、表記化合物７９８ｍｇ（収率６７％）を淡黄色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.23 (3H, t, J=7.0), 1.85 (2H, m), 2.09 (2H, m), 3.06 (2H, m), 3.19 (2H, m), 4.19 (2H, q, J=7.0), 4.40 (2H, s), 4.47 (2H, d, J=7.0), 4.68 (1H, m), 6.43 (1H, m), 6.58 (1H, d, J=16.0), 7.25 (1H, dd, J=9.0, 2.5), 7.31 (1H, t, J=9.0), 7.43 (1H, dd, J=12.5, 2.5), 7.55 (1H, t, J=8.0), 7.68 (1H, m), 7.73 (1H, d, J=8.0), 7.88 (1H, bs) ;
IR (KBr, cm^-1) : 1737, 1675. (A) N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-fluoro-4- (piperidin-4-yloxy) phenyl] sulfamoyl acetate dihydrochloride N- Ethyl [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-fluorophenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl acetate (1210 mg) The mixture was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (20 ml), and hydrogen chloride was passed through for 1 hour under ice-cooling. The solution was sealed and stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethanol (20 ml). Aqueous ammonium chloride (215 mg dissolved in 10 ml of water) and 28% aqueous ammonia (0.41 ml) were added, and the mixture was allowed to stand at room temperature for 17 hours. . The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol (20 ml), 4M hydrogen chloride dioxane solution (2 ml) was added, and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 17% acetonitrile / water). The obtained amorphous solid was dissolved in methanol (15 ml), and 4M hydrogen chloride dioxane solution (0.3 ml) was obtained. ) Was added and concentrated to dryness under reduced pressure to obtain 798 mg (yield 67%) of the title compound as a pale yellow amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.0), 1.85 (2H, m), 2.09 (2H, m), 3.06 (2H, m), 3.19 (2H, m ), 4.19 (2H, q, J = 7.0), 4.40 (2H, s), 4.47 (2H, d, J = 7.0), 4.68 (1H, m), 6.43 (1H, m), 6.58 (1H, d , J = 16.0), 7.25 (1H, dd, J = 9.0, 2.5), 7.31 (1H, t, J = 9.0), 7.43 (1H, dd, J = 12.5, 2.5), 7.55 (1H, t, J = 8.0), 7.68 (1H, m), 7.73 (1H, d, J = 8.0), 7.88 (1H, bs);
IR (KBr, cm ^-1 ): 1737, 1675.

（ｂ）Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−フルオロフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［３−フルオロ−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩（４６７ｍｇ）を、エタノール（２５ｍｌ）に溶解させ、エチルアセトイミデート塩酸塩（２９３ｍｇ）及びトリエチルアミン（０．５５０ｍｌ）を加えた後、室温で６６時間撹拌した。反応液に４Ｍ塩化水素ジオキサン溶液（１．５ｍｌ）を加えた後、減圧下濃縮した。残渣を分取ＨＰＬＣ（YMC-Pack
ODS YMC、溶出溶媒：２２％アセトニトリル／水）にて精製した後、得られた無定形固体をメタノール（１５ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．３ｍｌ）を加えた後、これを減圧下濃縮乾固させた。得られた無定形固体を水（約１５ｍｌ）に溶解させた後、凍結乾燥に付すことにより、表記化合物２８４ｍｇ（収率５７％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.22 (3H, t, J=7.0), 1.68-1.82 (2H, m), 2.06 (2H, m), 2.31 (3H, s), 3.51 (1H, m), 3.59 (1H, m), 3.71 (1H, m),
3.86 (1H, m), 4.19 (2H, q, J=7.0), 4.42 (2H, s), 4.47 (2H, d, J=6.0), 4.76 (1H, m), 6.46 (1H, dt, J=15.5, 6.0), 6.57 (1H, d, J=15.5), 7.26 (1H,
d, J=9.0), 7.35 (1H, t, J=9.0), 7.43 (1H, dd, J=12.0, 2.5), 7.54 (1H, t, J=8.0), 7.73 (2H, m), 7.95 (1H, s) ;
IR (KBr, cm^-1) : 1738, 1673, 1623. (B) ethyl N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-fluorophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl acetate Dihydrochloride N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-fluoro-4- (piperidin-4-yloxy) phenyl] sulfamoyl ethyl acetate dihydrochloride (467 mg ) Was dissolved in ethanol (25 ml), ethylacetoimidate hydrochloride (293 mg) and triethylamine (0.550 ml) were added, and the mixture was stirred at room temperature for 66 hours. A 4M hydrogen chloride dioxane solution (1.5 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Preparative HPLC (YMC-Pack
After purification with ODS YMC, elution solvent: 22% acetonitrile / water, the obtained amorphous solid was dissolved in methanol (15 ml), and 4M hydrogen chloride dioxane solution (0.3 ml) was added. Concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 15 ml) and then freeze-dried to obtain 284 mg (yield 57%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.22 (3H, t, J = 7.0), 1.68-1.82 (2H, m), 2.06 (2H, m), 2.31 (3H, s), 3.51 (1H , m), 3.59 (1H, m), 3.71 (1H, m),
3.86 (1H, m), 4.19 (2H, q, J = 7.0), 4.42 (2H, s), 4.47 (2H, d, J = 6.0), 4.76 (1H, m), 6.46 (1H, dt, J = 15.5, 6.0), 6.57 (1H, d, J = 15.5), 7.26 (1H,
d, J = 9.0), 7.35 (1H, t, J = 9.0), 7.43 (1H, dd, J = 12.0, 2.5), 7.54 (1H, t, J = 8.0), 7.73 (2H, m), 7.95 (1H, s);
IR (KBr, cm ^-1 ): 1738, 1673, 1623.

実施例１１
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−フルオロフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸２塩酸塩（例示化合物番号：１９４１）
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−フルオロフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩（１９９ｍｇ）を３Ｍ塩酸（７ｍｌ）に溶解させ、８０℃で２時間撹拌した。反応液を室温まで冷却させた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１５％アセトニトリル／水）にて精製し、得られた無定形固体をメタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．２ｍｌ）を加えた後、減圧下濃縮乾固させた。これを水（約１０ｍｌ）に溶解させた後、凍結乾燥に付すことにより、表記化合物１６３ｍｇ（収率８６％）を得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.77 (2H, m), 2.05 (2H, m), 2.29 (3H,
s), 3.52 (2H, m), 3.71 (1H, m), 3.80 (1H, m), 4.23 (2H, s), 4.47 (2H, d, J=6.0), 4.73 (1H, m), 6.44 (1H, dt, J=16.0, 6.0), 6.57 (1H, d, J=16.0), 7.26 (1H, m), 7.32 (1H, t, J=8.5), 7.43 (1H, dd, J=13.0, 2.0), 7.55 (1H, t, J=8.0), 7.68 (1H, d, J=8.0), 7.72 (1H, d, J=8.0), 7.88 (1H, s) ;
IR (KBr, cm^-1) : 3295, 1733, 1673, 1624. Example 11
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-fluorophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoylacetic acid dihydrochloride ( Exemplified compound number: 1941)
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-fluorophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl ethyl acetate dihydrochloride (199 mg) was dissolved in 3M hydrochloric acid (7 ml) and stirred at 80 ° C. for 2 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 15% acetonitrile / water), and the resulting amorphous solid was methanol ( 10 ml), 4M hydrogen chloride dioxane solution (0.2 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water (about 10 ml) and then freeze-dried to obtain 163 mg (yield 86%) of the title compound.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.77 (2H, m), 2.05 (2H, m), 2.29 (3H,
s), 3.52 (2H, m), 3.71 (1H, m), 3.80 (1H, m), 4.23 (2H, s), 4.47 (2H, d, J = 6.0), 4.73 (1H, m), 6.44 (1H, dt, J = 16.0, 6.0), 6.57 (1H, d, J = 16.0), 7.26 (1H, m), 7.32 (1H, t, J = 8.5), 7.43 (1H, dd, J = 13.0 , 2.0), 7.55 (1H, t, J = 8.0), 7.68 (1H, d, J = 8.0), 7.72 (1H, d, J = 8.0), 7.88 (1H, s);
IR (KBr, cm ^-1 ): 3295, 1733, 1673, 1624.

実施例１２
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（５−アミジノ−２−メチルフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩（例示化合物番号：１７７１） Example 12
N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (5-amidino-2-methylphenyl) -2- (E) -propenyl] sulfamoyl ethyl acetate dihydrochloride (Exemplary compound number: 1771)

（ａ）Ｎ−［３−（５−アミジノ−２−メチルフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（５−シアノ−２−メチルフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル（２．０３ｇ）を、ジクロロメタン（４０ｍｌ）及びエタノール（４０ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１時間通じた後、密栓をして室温で６時間撹拌した。反応液を減圧下濃縮した後、残渣をエタノール（４５ｍｌ）に溶解させ、塩化アンモニウム水溶液（０．３６ｇを水１５ｍｌに溶解）及び２８％アンモニア水（０．６８ｍｌ）を加えた後、室温で１２時間放置した。反応液を減圧下濃縮し、残渣をメタノール（３０ｍｌ）に溶解させ、４Ｍ塩化水素酢酸エチル溶液（２ｍｌ）を加えた後、減圧下濃縮した。残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２０％アセトニトリル／水）にて精製し、得られた無定形固体をメタノール（２０ｍｌ）に溶解させ、４Ｍ塩化水素酢酸エチル溶液（１ｍｌ）を加えた後、これを減圧下濃縮乾固させることにより、表記化合物１．４９ｇ（収率７５％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.23 (3H, t, J=7.0), 1.82 (2H, m), 2.09 (2H, m), 2.22 (3H, s), 3.05 (2H, m), 3.21 (2H, m), 4.19 (2H, q, J=7.0), 4.34 (2H, s), 4.46 (2H, d, J=6.5), 4.66 (1H, m), 6.30 (1H, dt, J=16.0, 6.5), 6.66 (1H, d, J=16.0), 7.05 (2H, d, J=9.5), 7.37 (1H, d, J=7.5), 7.38 (2H, d, J=9.5), 7.61 (1H, dd, J=7.5, 2.0), 7.86 (1H, d, J=2.0) ;
IR (KBr, cm^-1) : 1738, 1674. (A) N- [3- (5-Amidino-2-methylphenyl) -2- (E) -propenyl] -N- [4- (piperidin-4-yloxy) phenyl] sulfamoyl acetate ethyl dihydrochloride N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3- (5-cyano-2-methylphenyl) -2- (E) -propenyl] sulfamoyl ethyl acetate (2.03 g ) Was dissolved in a mixed solvent of dichloromethane (40 ml) and ethanol (40 ml), hydrogen chloride was passed through for 1 hour under ice-cooling, and the mixture was sealed and stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (45 ml), aqueous ammonium chloride solution (0.36 g dissolved in 15 ml water) and 28% aqueous ammonia (0.68 ml) were added, Left for hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol (30 ml), 4M hydrogen chloride ethyl acetate solution (2 ml) was added, and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water), the obtained amorphous solid was dissolved in methanol (20 ml), and 4M hydrogen chloride ethyl acetate solution (1 ml). Then, this was concentrated to dryness under reduced pressure to obtain 1.49 g (yield 75%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.0), 1.82 (2H, m), 2.09 (2H, m), 2.22 (3H, s), 3.05 (2H, m ), 3.21 (2H, m), 4.19 (2H, q, J = 7.0), 4.34 (2H, s), 4.46 (2H, d, J = 6.5), 4.66 (1H, m), 6.30 (1H, dt , J = 16.0, 6.5), 6.66 (1H, d, J = 16.0), 7.05 (2H, d, J = 9.5), 7.37 (1H, d, J = 7.5), 7.38 (2H, d, J = 9.5 ), 7.61 (1H, dd, J = 7.5, 2.0), 7.86 (1H, d, J = 2.0);
IR (KBr, cm ^-1 ): 1738, 1674.

（ｂ）Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（５−アミジノ−２−メチルフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［３−（５−アミジノ−２−メチルフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩（１．４３ｇ）を、エタノール（４０ｍｌ）に溶解させ、エチルアセトイミデート塩酸塩（０．６０ｇ）及びトリエチルアミン（１．４ｍｌ）を加えた後、室温で１３時間撹拌した。反応液に４Ｍ塩化水素酢酸エチル溶液（２ｍｌ）を加えた後、減圧下濃縮した。残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２５％アセトニトリル／水）にて精製した後、得られた無定形固体をメタノール（２０ｍｌ）に溶解させ、４Ｍ塩化水素酢酸エチル溶液（０．８ｍｌ）を加えた後、これを減圧下濃縮乾固させることにより、表記化合物１．１８ｇ（収率７７％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.23 (3H, t, J=7.0), 1.67-1.80 (2H, m), 2.05 (2H, m), 2.22 (3H, s), 2.30 (3H, s), 3.49 - 3.61 (2H, m), 3.72 (1H, m), 3.83 (1H, m), 4.19 (2H, q, J=7.0), 4.35 (2H, s), 4.46 (2H, d, J=6.0), 4.72 (1H, m), 6.32 (1H, dt, J=16.0, 6.0), 6.66 (1H, d, J=16.0), 7.06 (2H, d, J=9.5), 7.38 (1H, d, J=9.0), 7.39 (2H, d, J=9.5), 7.64 (1H, dd, J=9.0, 2.0), 7.88 (1H, d, J=2.0) ;
IR (KBr, cm^-1) : 1738, 1675, 1626. (B) ethyl N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (5-amidino-2-methylphenyl) -2- (E) -propenyl] sulfamoyl acetate Dihydrochloride N- [3- (5-Amidino-2-methylphenyl) -2- (E) -propenyl] -N- [4- (piperidin-4-yloxy) phenyl] sulfamoyl acetate ethyl acetate dihydrochloride (1 .43 g) was dissolved in ethanol (40 ml), ethylacetimidate hydrochloride (0.60 g) and triethylamine (1.4 ml) were added, and the mixture was stirred at room temperature for 13 hours. A 4M hydrogen chloride ethyl acetate solution (2 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. After the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 25% acetonitrile / water), the obtained amorphous solid was dissolved in methanol (20 ml), and 4M hydrogen chloride ethyl acetate solution (0 .8 ml) was added and then concentrated to dryness under reduced pressure to obtain 1.18 g (yield 77%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.0), 1.67-1.80 (2H, m), 2.05 (2H, m), 2.22 (3H, s), 2.30 (3H , s), 3.49-3.61 (2H, m), 3.72 (1H, m), 3.83 (1H, m), 4.19 (2H, q, J = 7.0), 4.35 (2H, s), 4.46 (2H, d , J = 6.0), 4.72 (1H, m), 6.32 (1H, dt, J = 16.0, 6.0), 6.66 (1H, d, J = 16.0), 7.06 (2H, d, J = 9.5), 7.38 ( 1H, d, J = 9.0), 7.39 (2H, d, J = 9.5), 7.64 (1H, dd, J = 9.0, 2.0), 7.88 (1H, d, J = 2.0);
IR (KBr, cm ^-1 ): 1738, 1675, 1626.

実施例１３
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−トリフルオロメチルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩
（例示化合物番号：１４４０） Example 13
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-trifluoromethylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl ethyl acetate 2 Hydrochloride (Exemplary Compound Number: 1440)

（ａ）Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［４−（ピペリジン−４−イルオキシ）−３−トリフルオロメチルフェニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−トリフルオロメチルフェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル（２．０６ｇ）を、ジクロロメタン（５０ｍｌ）及びエタノール（２５ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１時間通じた後、密栓をして室温で６時間撹拌した。反応液を減圧下濃縮した後、残渣をエタノール（４５ｍｌ）に溶解させ、塩化アンモニウム水溶液（０．３４ｇを水１５ｍｌに溶解）及び２８％アンモニア水（０．６３ｍｌ）を加えた後、室温で１２時間放置した。反応液を減圧下濃縮し、残渣をメタノール（３０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（２．５ｍｌ）を加えた後、減圧下濃縮した。残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２５％アセトニトリル／水）にて精製し、得られた無定形固体をメタノール（２０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．５ｍｌ）を加えた後、これを減圧下濃縮乾固させることにより、表記化合物１．２１ｇ（収率６０％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.22 (3H, t, J=7.0), 1.87 (2H, m), 2.08 (2H, m), 3.11 (2H, m), 3.33 (2H, m), 4.18 (2H, q, J=7.0), 4.44 (2H, s), 4.50 (2H, d, J=6.5), 4.89 (1H, m), 6.44 (1H, dt, J=16.0, 6.5), 6.57 (1H, d, J=16.0), 7.39 (1H, d, J=9.0), 7.55 (1H, t, J=8.0), 7.66-7.73 (4H,
m), 7.85 (1H, s) ;
IR (KBr, cm^-1) : 1738, 1676. (A) N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [4- (piperidin-4-yloxy) -3-trifluoromethylphenyl] sulfamoyl acetate ethyl dihydrochloride N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3-trifluoromethylphenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl acetate ethyl (2.06 g) was dissolved in a mixed solvent of dichloromethane (50 ml) and ethanol (25 ml), and hydrogen chloride was passed through for 1 hour under ice-cooling. The mixture was sealed and stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (45 ml), aqueous ammonium chloride solution (0.34 g dissolved in 15 ml water) and 28% aqueous ammonia (0.63 ml) were added, Left for hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol (30 ml), 4M hydrogen chloride dioxane solution (2.5 ml) was added, and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 25% acetonitrile / water). The obtained amorphous solid was dissolved in methanol (20 ml), and 4M hydrogen chloride dioxane solution (0.5 ml) was obtained. ) Was added and concentrated to dryness under reduced pressure to give 1.21 g (yield 60%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.22 (3H, t, J = 7.0), 1.87 (2H, m), 2.08 (2H, m), 3.11 (2H, m), 3.33 (2H, m ), 4.18 (2H, q, J = 7.0), 4.44 (2H, s), 4.50 (2H, d, J = 6.5), 4.89 (1H, m), 6.44 (1H, dt, J = 16.0, 6.5) , 6.57 (1H, d, J = 16.0), 7.39 (1H, d, J = 9.0), 7.55 (1H, t, J = 8.0), 7.66-7.73 (4H,
m), 7.85 (1H, s);
IR (KBr, cm ^-1 ): 1738, 1676.

（ｂ）Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−トリフルオロメチルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［４−（ピペリジン−４−イルオキシ）−３−トリフルオロメチルフェニル］スルファモイル酢酸エチル２塩酸塩（１．１３ｇ）を、エタノール（２０ｍｌ）に溶解させ、エチルアセトイミデート塩酸塩（０．６５ｇ）及びトリエチルアミン（１．２０ｍｌ）を加えた後、室温で１３時間撹拌した。反応液に４Ｍ塩化水素ジオキサン溶液（２ｍｌ）を加えた後、減圧下濃縮した。残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：３０％アセトニトリル／水）にて精製した後、得られた無定形固体をメタノール（２０ｍｌ）に溶解させ、４Ｍ塩化水素酢酸エチル溶液（０．５ｍｌ）を加えた後、これを減圧下濃縮乾固させることにより、表記化合物１．０４ｇ（収率８７％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.22 (3H, t, J=7.0), 1.81 (2H, m), 2.07 (2H, m), 2.30 (3H, s), 3.59-3.73 (4H, m), 4.19 (2H, q, J=7.0), 4.46 (2H, s), 4.50 (2H, d, J=6.5), 4.96 (1H, m), 6.47 (1H, dt, J=16.5, 6.5), 6.58 (1H, d, J=16.5), 7.44 (1H, d, J=9.5), 7.56 (1H, t, J=8.0), 7.71 (4H,
m), 7.90 (1H, s) ;
IR (KBr, cm^-1) : 1739, 1673, 1618. (B) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-trifluoromethylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl Ethyl acetate dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- (piperidin-4-yloxy) -3-trifluoromethylphenyl] sulfamoyl ethyl acetate 2 Hydrochloride (1.13 g) was dissolved in ethanol (20 ml), ethylacetimidate hydrochloride (0.65 g) and triethylamine (1.20 ml) were added, and the mixture was stirred at room temperature for 13 hours. A 4M hydrogen chloride dioxane solution (2 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. After the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 30% acetonitrile / water), the obtained amorphous solid was dissolved in methanol (20 ml), and 4M hydrogen chloride ethyl acetate solution (0 0.5 ml) and concentrated to dryness under reduced pressure to obtain 1.04 g (yield 87%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.22 (3H, t, J = 7.0), 1.81 (2H, m), 2.07 (2H, m), 2.30 (3H, s), 3.59-3.73 (4H , m), 4.19 (2H, q, J = 7.0), 4.46 (2H, s), 4.50 (2H, d, J = 6.5), 4.96 (1H, m), 6.47 (1H, dt, J = 16.5, 6.5), 6.58 (1H, d, J = 16.5), 7.44 (1H, d, J = 9.5), 7.56 (1H, t, J = 8.0), 7.71 (4H,
m), 7.90 (1H, s);
IR (KBr, cm ^-1 ): 1739, 1673, 1618.

実施例１４
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−メチルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩（例示化合物番号：１４２０） Example 14
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-methylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl ethyl acetate dihydrochloride (Exemplary compound number: 1420)

（ａ）Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［３−メチル−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−メチルフェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル（１．９０ｇ）を、ジクロロメタン（４０ｍｌ）及びエタノール（４０ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１時間通じた後、密栓をして室温で５時間撹拌した。反応液を減圧下濃縮した後、残渣をエタノール（４５ｍｌ）に溶解させ、塩化アンモニウム水溶液（０．３４ｇを水１５ｍｌに溶解）及び２８％アンモニア水（０．６４ｍｌ）を加えた後、室温で１３時間放置した。反応液を減圧下濃縮し、残渣をメタノール（２０ｍｌ）に溶解させ、４Ｍ塩化水素酢酸エチル溶液（２ｍｌ）を加えた後、減圧下濃縮した。残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２０％アセトニトリル／水）にて精製した後、得られた無定形固体をメタノール（２０ｍｌ）に溶解させ、４Ｍ塩化水素酢酸エチル溶液（１ｍｌ）を加えた後、これを減圧下濃縮乾固させることにより、表記化合物１．３６ｇ（収率７３％）を無色無定形固体として得た。
¹H NMR (400MHz, DMSO-d₆) δppm : 1.23 (3H, t, J=7.0), 1.87 (2H, m), 2.10 (2H, m), 2.17 (3H, s), 3.07 (2H, m), 3.17 (2H, m), 4.20 (2H, q, J=7.0), 4.33 (2H, s), 4.44 (2H, d, J=6.0), 4.65 (1H, m), 6.44 (1H, dt, J=16.0, 6.0), 6.56 (1H, d, J=16.0), 7.05 (1H, d, J=9.0), 7.24 (1H, dd, J=9.0, 2.5), 7.29 (1H, d, J=2.5), 7.54 (1H, t, J=8.0), 7.71 (2H, m), 7.90 (1H, s) ;
IR (KBr, cm^-1) : 1738, 1675. (A) N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-methyl-4- (piperidin-4-yloxy) phenyl] sulfamoyl acetate ethyl dihydrochloride N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3-methylphenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl ethyl acetate (1.90 g) ) Was dissolved in a mixed solvent of dichloromethane (40 ml) and ethanol (40 ml), hydrogen chloride was passed through for 1 hour under ice-cooling, and the mixture was sealed and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (45 ml), aqueous ammonium chloride solution (0.34 g dissolved in 15 ml water) and 28% aqueous ammonia (0.64 ml) were added, and Left for hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol (20 ml), 4M hydrogen chloride ethyl acetate solution (2 ml) was added, and the mixture was concentrated under reduced pressure. After the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water), the obtained amorphous solid was dissolved in methanol (20 ml), and 4M hydrogen chloride ethyl acetate solution (1 ml) was obtained. ) Was added and concentrated to dryness under reduced pressure to obtain 1.36 g (yield 73%) of the title compound as a colorless amorphous solid.
¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.0), 1.87 (2H, m), 2.10 (2H, m), 2.17 (3H, s), 3.07 (2H, m ), 3.17 (2H, m), 4.20 (2H, q, J = 7.0), 4.33 (2H, s), 4.44 (2H, d, J = 6.0), 4.65 (1H, m), 6.44 (1H, dt , J = 16.0, 6.0), 6.56 (1H, d, J = 16.0), 7.05 (1H, d, J = 9.0), 7.24 (1H, dd, J = 9.0, 2.5), 7.29 (1H, d, J = 2.5), 7.54 (1H, t, J = 8.0), 7.71 (2H, m), 7.90 (1H, s);
IR (KBr, cm ^-1 ): 1738, 1675.

（ｂ）Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−メチルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［３−メチル−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩（１．２３ｇ）を、エタノール（４０ｍｌ）に溶解させ、エチルアセトイミデート塩酸塩（０．５２ｇ）及びトリエチルアミン（１．２０ｍｌ）を加えた後、室温で１３時間撹拌した。反応液に４Ｍ塩化水素ジオキサン溶液（２ｍｌ）を加えた後、減圧下濃縮した。残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２２％アセトニトリル／水）にて精製した後、得られた無定形固体をメタノール（２０ｍｌ）に溶解させ、４Ｍ塩化水素酢酸エチル溶液（０．６ｍｌ）を加えた後、これを減圧下濃縮乾固させることにより、表記化合物１．１０ｇ（収率８４％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.24 (3H, t, J=7.0), 1.77 (2H, m), 2.03 (2H, m), 2.16 (3H, s), 2.30 (3H, s), 3.60 - 3.80 (4H, m), 4.20 (2H, q, J=7.0), 4.33 (2H, s), 4.44 (2H, d, J=6.0), 4.73 (1H, m), 6.45 (1H, dt,
J=16.0, 6.0), 6.56 (1H, d, J=16.0), 7.06 (1H, d, J=9.0), 7.25 (1H, dd, J=9.0, 2.5), 7.29 (1H, d, J=2.5), 7.55 (1H, t, J=8.0), 7.71 (2H, m), 7.91 (1H, s) ;
IR (KBr, cm^-1) : 1738, 1672, 1624. (B) ethyl N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-methylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl acetate Dihydrochloride N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-methyl-4- (piperidin-4-yloxy) phenyl] sulfamoyl ethyl acetate dihydrochloride (1 .23 g) was dissolved in ethanol (40 ml), ethylacetimidate hydrochloride (0.52 g) and triethylamine (1.20 ml) were added, and the mixture was stirred at room temperature for 13 hours. A 4M hydrogen chloride dioxane solution (2 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. After the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 22% acetonitrile / water), the obtained amorphous solid was dissolved in methanol (20 ml), and 4M hydrogen chloride ethyl acetate solution (0 .
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.24 (3H, t, J = 7.0), 1.77 (2H, m), 2.03 (2H, m), 2.16 (3H, s), 2.30 (3H, s ), 3.60-3.80 (4H, m), 4.20 (2H, q, J = 7.0), 4.33 (2H, s), 4.44 (2H, d, J = 6.0), 4.73 (1H, m), 6.45 (1H , dt,
J = 16.0, 6.0), 6.56 (1H, d, J = 16.0), 7.06 (1H, d, J = 9.0), 7.25 (1H, dd, J = 9.0, 2.5), 7.29 (1H, d, J = 2.5), 7.55 (1H, t, J = 8.0), 7.71 (2H, m), 7.91 (1H, s);
IR (KBr, cm ^-1 ): 1738, 1672, 1624.

実施例１５
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−アミジノ−５−メチルフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩（例示化合物番号：１７１１） Example 15
N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidino-5-methylphenyl) -2- (E) -propenyl] sulfamoyl acetate dihydrochloride (Exemplary compound number: 1711)

（ａ）Ｎ−［３−（３−アミジノ−５−メチルフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−シアノ−５−メチルフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル（１．５９ｇ）を、ジクロロメタン（１５ｍｌ）及びエタノール（１５ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１時間通じた後、密栓をして室温で４時間撹拌した。反応液を減圧下濃縮した後、残渣をエタノール（２０ｍｌ）に溶解させ、塩化アンモニウム水溶液（０．２１ｇを水４ｍｌに溶解）及び２８％アンモニア水（０．５３ｍｌ）を加えた後、室温で終夜放置した。反応液を減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２０％アセトニトリル／水）にて精製することにより、表記化合物１．１０ｇ（収率８０％）を無色無定形固体として得た。
¹H NMR (270MHz, DMSO-d₆) δppm : 1.23 (3H, t, J=7.0), 1.85 (2H, m), 2.10 (2H, m), 2.36 (3H, s), 3.06 (2H, m), 3.18 (2H, m), 4.19 (2H, q, J=7.0), 4.33 (2H, s), 4.44 (2H, d, J=5.5), 4.66 (1H, m), 6.41 (1H, dt, J=16.0, 5.5), 6.51 (1H, d, J=16.0), 7.04 (2H, d, J=9.0), 7.38 (2H, d, J=9.0), 7.54 (1H, s), 7.58 (1H, s), 7.68 (1H, s) ;
IR (KBr, cm^-1) : 1737, 1674. (A) N- [3- (3-Amidino-5-methylphenyl) -2- (E) -propenyl] -N- [4- (piperidin-4-yloxy) phenyl] sulfamoyl acetate ethyl dihydrochloride N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3- (3-cyano-5-methylphenyl) -2- (E) -propenyl] sulfamoyl ethyl acetate (1.59 g ) Was dissolved in a mixed solvent of dichloromethane (15 ml) and ethanol (15 ml), hydrogen chloride was passed through for 1 hour under ice-cooling, and the mixture was sealed and stirred at room temperature for 4 hours. After concentrating the reaction solution under reduced pressure, the residue was dissolved in ethanol (20 ml), aqueous ammonium chloride solution (0.21 g dissolved in 4 ml of water) and 28% aqueous ammonia (0.53 ml) were added, and then at room temperature overnight. I left it alone. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water) to give 1.10 g (yield 80%) of the title compound colorless. Obtained as a regular solid.
¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.0), 1.85 (2H, m), 2.10 (2H, m), 2.36 (3H, s), 3.06 (2H, m ), 3.18 (2H, m), 4.19 (2H, q, J = 7.0), 4.33 (2H, s), 4.44 (2H, d, J = 5.5), 4.66 (1H, m), 6.41 (1H, dt , J = 16.0, 5.5), 6.51 (1H, d, J = 16.0), 7.04 (2H, d, J = 9.0), 7.38 (2H, d, J = 9.0), 7.54 (1H, s), 7.58 ( 1H, s), 7.68 (1H, s);
IR (KBr, cm ^-1 ): 1737, 1674.

（ｂ）Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−アミジノ−５−メチルフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［３−（３−アミジノ−５−メチルフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩（８００ｍｇ）を、エタノール（２５ｍｌ）に溶解させ、エチルアセトイミデート塩酸塩（１４００ｍｇ）及びトリエチルアミン（２．２ｍｌ）を加えた後、室温で２７時間撹拌した。反応液を減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２０％アセトニトリル／水）にて精製した後、得られた無定形固体をエタノール（２０ｍｌ）に溶解させ、４Ｍ塩化水素酢酸エチル溶液（１ｍｌ）を加えた後、減圧下濃縮乾固させた。得られた無定形固体を酢酸エチルに懸濁させた後、ろ取することにより、表記化合物４００ｍｇ（収率４１％）を無色無定形固体として得た。
¹H NMR (270MHz, DMSO-d₆) δppm : 1.23 (3H, t, J=7.0), 1.70 (2H, m), 2.05 (2H, m), 2.30 (3H, s), 2.36 (3H, s), 3.45-3.65 (2H, m), 3.65-3.95 (2H, m), 4.19 (2H, q, J=7.0), 4.34 (2H, s), 4.44 (2H, d, J=5.5), 4.71 (1H, m), 6.41 (1H, dt, J=16.0, 5.5), 6.51 (1H, d, J=16.0), 7.04 (2H, d, J=9.0), 7.39 (2H, d, J=9.0), 7.56 (2H, ２本のs重複), 7.70 (1H, s) ;
IR (KBr, cm^-1) : 1738, 1672, 1625. (B) ethyl N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidino-5-methylphenyl) -2- (E) -propenyl] sulfamoyl acetate Dihydrochloride N- [3- (3-Amidino-5-methylphenyl) -2- (E) -propenyl] -N- [4- (piperidin-4-yloxy) phenyl] sulfamoyl ethyl acetate dihydrochloride (800 mg ) Was dissolved in ethanol (25 ml), ethylacetimidate hydrochloride (1400 mg) and triethylamine (2.2 ml) were added, and the mixture was stirred at room temperature for 27 hours. The reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water), and the obtained amorphous solid was dissolved in ethanol (20 ml). A 4M hydrogen chloride ethyl acetate solution (1 ml) was added, and the mixture was concentrated to dryness under reduced pressure. The obtained amorphous solid was suspended in ethyl acetate and collected by filtration to obtain 400 mg (yield 41%) of the title compound as a colorless amorphous solid.
¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.0), 1.70 (2H, m), 2.05 (2H, m), 2.30 (3H, s), 2.36 (3H, s ), 3.45-3.65 (2H, m), 3.65-3.95 (2H, m), 4.19 (2H, q, J = 7.0), 4.34 (2H, s), 4.44 (2H, d, J = 5.5), 4.71 (1H, m), 6.41 (1H, dt, J = 16.0, 5.5), 6.51 (1H, d, J = 16.0), 7.04 (2H, d, J = 9.0), 7.39 (2H, d, J = 9.0 ), 7.56 (2H, 2 s overlap), 7.70 (1H, s);
IR (KBr, cm ^-1 ): 1738, 1672, 1625.

実施例１６
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−アミジノ−５−メチルフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸２塩酸塩（例示化合物番号：２２０８）
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−アミジノ−５−メチルフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩（２００ｍｇ）を、１Ｍ塩酸（８ｍｌ）に溶解させ、８０℃で８時間撹拌した。反応液を減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２０％アセトニトリル／水）にて精製した後、得られた無定形固体を水に溶解させ、４Ｍ塩化水素酢酸エチル溶液（０．２ｍｌ）を加えた後、これを減圧下濃縮乾固させることにより、表記化合物１１０ｍｇ（収率５７％）を無色無定形固体として得た。
¹H NMR (270MHz, DMSO-d₆) δppm : 1.60-1.85 (2H, m), 2.05 (2H, m), 2.30
(3H, s), 2.36 (3H, s), 3.40-3.65 (2H, m), 3.65-3.95 (2H, m), 4.20 (2H, s), 4.44 (2H, d, J=5.0), 4.70 (1H, m), 6.41 (1H, dt, J=16.0, 5.0), 6.51 (1H, d, J=16.0), 7.04 (2H, d, J=9.0), 7.39 (2H, d, J=9.0), 7.55 (2H, ２本のs重複), 7.69 (1H, s) ;
MS (FAB) m/z = 528 (M+H)⁺. Example 16
N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidino-5-methylphenyl) -2- (E) -propenyl] sulfamoylacetic acid dihydrochloride ( Exemplified compound number: 2208)
N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidino-5-methylphenyl) -2- (E) -propenyl] sulfamoyl acetate dihydrochloride (200 mg) was dissolved in 1M hydrochloric acid (8 ml) and stirred at 80 ° C. for 8 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water), and then the resulting amorphous solid was dissolved in water, and 4M hydrogen chloride. After adding an ethyl acetate solution (0.2 ml), this was concentrated to dryness under reduced pressure to obtain 110 mg (yield 57%) of the title compound as a colorless amorphous solid.
¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.60-1.85 (2H, m), 2.05 (2H, m), 2.30
(3H, s), 2.36 (3H, s), 3.40-3.65 (2H, m), 3.65-3.95 (2H, m), 4.20 (2H, s), 4.44 (2H, d, J = 5.0), 4.70 (1H, m), 6.41 (1H, dt, J = 16.0, 5.0), 6.51 (1H, d, J = 16.0), 7.04 (2H, d, J = 9.0), 7.39 (2H, d, J = 9.0 ), 7.55 (2H, 2 s overlap), 7.69 (1H, s);
MS (FAB) m / z = 528 (M + H) ⁺ .

実施例１７
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−アミジノ−４−フルオロフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩（例示化合物番号：１６３８） Example 17
N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidino-4-fluorophenyl) -2- (E) -propenyl] sulfamoyl acetate ethyl dihydrochloride (Exemplary compound number: 1638)

（ａ）Ｎ−［３−（３−アミジノ−４−フルオロフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−シアノ−４−フルオロフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル（１５３０ｍｇ）を、ジクロロメタン（１５ｍｌ）及びエタノール（１５ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１．２５時間通じた後、密栓をして室温で４時間撹拌した。反応液を減圧下濃縮した後、残渣をエタノール（２０ｍｌ）に溶解させ、塩化アンモニウム水溶液（２００ｍｇを水４ｍｌに溶解）及び２８％アンモニア水（０．５０ｍｌ）を加えた後、室温で終夜放置した。反応液を減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２０％アセトニトリル／水）にて精製することにより、表記化合物５５０ｍｇ（収率４１％）を無色無定形固体として得た。
¹H NMR (270MHz, DMSO-d₆) δppm : 1.23 (3H, t, J=7.0), 1.75-1.95 (2H, m), 2.00-2.20 (2H, m), 2.95-3.15 (2H, m), 3.15-3.30 (2H, m), 4.19 (2H, q,
J=7.0), 4.33 (2H, s), 4.42 (2H, d, J=6.0), 4.65 (1H, m), 6.35 (1H, dt, J=16.0, 6.0), 6.53 (1H, d, J=16.0), 7.03 (2H, d, J=9.0), 7.38 (2H, d, J=9.0), 7.42 (1H, m), 7.73 (2H, m) ;
IR (KBr, cm^-1) : 1737, 1677. (A) N- [3- (3-Amidino-4-fluorophenyl) -2- (E) -propenyl] -N- [4- (piperidin-4-yloxy) phenyl] sulfamoyl acetate dihydrochloride N- Ethyl [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3- (3-cyano-4-fluorophenyl) -2- (E) -propenyl] sulfamoyl acetate (1530 mg) , Dissolved in a mixed solvent of dichloromethane (15 ml) and ethanol (15 ml), passed through hydrogen chloride for 1.25 hours under ice cooling, then sealed and stirred at room temperature for 4 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), an aqueous ammonium chloride solution (200 mg dissolved in 4 ml of water) and 28% aqueous ammonia (0.50 ml) were added, and the mixture was allowed to stand overnight at room temperature. . The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water) to give 550 mg (yield 41%) of the title compound as a colorless amorphous solid. Got as.
¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.0), 1.75-1.95 (2H, m), 2.00-2.20 (2H, m), 2.95-3.15 (2H, m) , 3.15-3.30 (2H, m), 4.19 (2H, q,
J = 7.0), 4.33 (2H, s), 4.42 (2H, d, J = 6.0), 4.65 (1H, m), 6.35 (1H, dt, J = 16.0, 6.0), 6.53 (1H, d, J = 16.0), 7.03 (2H, d, J = 9.0), 7.38 (2H, d, J = 9.0), 7.42 (1H, m), 7.73 (2H, m);
IR (KBr, cm ^-1 ): 1737, 1677.

（ｂ）Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−アミジノ−４−フルオロフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［３−（３−アミジノ−４−フルオロフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩（３５０ｍｇ）を、エタノール（１４ｍｌ）に溶解させ、エチルアセトイミデート塩酸塩（１６０ｍｇ）及びトリエチルアミン（０．３６ｍｌ）を加えた後、室温で６時間撹拌した。反応液を減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２０％アセトニトリル／水）にて精製した後、得られた無定形固体をエタノール（８ｍｌ）に溶解させ、４Ｍ塩化水素酢酸エチル溶液（０．５ｍｌ）を加えた後、これを減圧下濃縮乾固させることにより、表記化合物２７９ｍｇ（収率６５％）を無色無定形固体として得た。
¹H NMR (270MHz, DMSO-d₆) δppm : 1.23 (3H, t, J=7.0), 1.73 (2H, m), 2.05 (2H, m), 2.29 (3H, s), 3.40-3.65 (2H, m), 3.65-3.90 (2H, m), 4.19 (2H, q, J=7.0), 4.33 (2H, s), 4.42 (2H, d, J=5.5), 4.71 (1H, m), 6.35 (1H, dt, J=16.0, 5.5), 6.54 (1H, d, J=16.0), 7.04 (2H, d, J=9.0), 7.38 (2H, d, J=9.0), 7.40 (1H, m), 7.73 (2H, m) ;
IR (KBr, cm^-1) : 1738, 1675, 1618. (B) ethyl N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidino-4-fluorophenyl) -2- (E) -propenyl] sulfamoyl acetate Dihydrochloride N- [3- (3-Amidino-4-fluorophenyl) -2- (E) -propenyl] -N- [4- (piperidin-4-yloxy) phenyl] sulfamoyl ethyl acetate dihydrochloride (350 mg ) Was dissolved in ethanol (14 ml), ethylacetimidate hydrochloride (160 mg) and triethylamine (0.36 ml) were added, and the mixture was stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water), and the obtained amorphous solid was dissolved in ethanol (8 ml). 4M Hydrogen chloride ethyl acetate solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give the title compound (279 mg, yield 65%) as a colorless amorphous solid.
¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.0), 1.73 (2H, m), 2.05 (2H, m), 2.29 (3H, s), 3.40-3.65 (2H , m), 3.65-3.90 (2H, m), 4.19 (2H, q, J = 7.0), 4.33 (2H, s), 4.42 (2H, d, J = 5.5), 4.71 (1H, m), 6.35 (1H, dt, J = 16.0, 5.5), 6.54 (1H, d, J = 16.0), 7.04 (2H, d, J = 9.0), 7.38 (2H, d, J = 9.0), 7.40 (1H, m ), 7.73 (2H, m);
IR (KBr, cm ^-1 ): 1738, 1675, 1618.

実施例１８
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］アセトアミド２塩酸塩（例示化合物番号：９４８） Example 18
N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] acetamide dihydrochloride (Exemplified compound number: 948) )

（ａ）Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］アセトアミド２塩酸塩
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］アセトアミド（１２０３ｍｇ）を、ジクロロメタン（６０ｍｌ）及びエタノール（３０ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１時間通じた後、密栓をして室温で７時間撹拌した。反応液を減圧下濃縮した後、残渣をエタノール（５０ｍｌ）に溶解させ、塩化アンモニウム水溶液（２７１ｍｇを水２５ｍｌに溶解）及び２８％アンモニア水（０．５１ｍｌ）を加えた後、室温で１２時間放置した。反応液に４Ｍ塩化水素ジオキサン溶液（１．５ｍｌ）を加え、減圧下濃縮した。残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１３％アセトニトリル／水）にて精製した後、得られた無定形固体をメタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（１．５ｍｌ）を加えた後、これを減圧下濃縮乾固させた。得られた無定形固体を水（約１０ｍｌ）に溶解させた後、凍結乾燥に付すことにより、表記化合物８５３ｍｇ（収率７２％）を淡黄色無定形固体として得た。
¹H NMR (270MHz, DMSO-d₆) δppm : 1.78 (3H, s), 1.83 (2H, m), 2.11 (2H,
m), 2.90-3.30 (4H, m), 4.39 (2H, m), 4.50-4.80 (1H, m), 6.40-6.60 (2H, m), 7.04 (2H, d, J=9.0), 7.28 (2H, d, J=9.0), 7.55 (1H, t, J=7.5), 7.71 (1H, d, J=7.5), 7.73 (1H, d, J=7.5), 7.94 (1H, s) ;
IR (KBr, cm^-1) : 1675, 1626. (A) N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [4- (piperidin-4-yloxy) phenyl] acetamide dihydrochloride N- [4- (1- t-Butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] acetamide (1203 mg) was mixed with dichloromethane (60 ml) and ethanol (30 ml). After dissolving in a solvent and passing through hydrogen chloride for 1 hour under ice cooling, the solution was sealed and stirred at room temperature for 7 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (50 ml), an aqueous ammonium chloride solution (271 mg dissolved in 25 ml of water) and 28% aqueous ammonia (0.51 ml) were added, and the mixture was allowed to stand at room temperature for 12 hours. did. A 4M hydrogen chloride dioxane solution (1.5 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. After the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 13% acetonitrile / water), the obtained amorphous solid was dissolved in methanol (10 ml), and 4M hydrogen chloride dioxane solution (1. 5 ml), and then concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml) and then freeze-dried to obtain 853 mg (yield 72%) of the title compound as a pale yellow amorphous solid.
¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.78 (3H, s), 1.83 (2H, m), 2.11 (2H,
m), 2.90-3.30 (4H, m), 4.39 (2H, m), 4.50-4.80 (1H, m), 6.40-6.60 (2H, m), 7.04 (2H, d, J = 9.0), 7.28 ( 2H, d, J = 9.0), 7.55 (1H, t, J = 7.5), 7.71 (1H, d, J = 7.5), 7.73 (1H, d, J = 7.5), 7.94 (1H, s);
IR (KBr, cm ^-1 ): 1675, 1626.

（ｂ）Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］アセトアミド２塩酸塩
Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］アセトアミド２塩酸塩（４００ｍｇ）を、メタノール（２０ｍｌ）に溶解させ、エチルアセトイミデート塩酸塩（３２０ｍｇ）及びトリエチルアミン（０．６０ｍｌ）を室温で加えた後、同温で１２時間撹拌した。反応液に４Ｍ塩化水素ジオキサン溶液（１ｍｌ）を加えた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１５％アセトニトリル／水）にて精製した後、得られた無定形固体をメタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．５ｍｌ）を加えた後、これを減圧下濃縮乾固させた。得られた無定形固体を水（約１０ｍｌ）に溶解させた後、凍結乾燥に付すことにより、表記化合物３４２ｍｇ（収率７９％）を無色無定形固体として得た。
¹H NMR (270MHz, DMSO-d₆) δppm : 1.74 (2H, m), 1.78 (3H, s), 2.04 (2H,
m), 2.31 (3H, s), 3.45-3.95 (4H, m), 4.39 (2H, m), 4.60-4.80 (1H, m), 6.40-6.60 (2H, m), 7.05 (2H, d, J=8.5), 7.28 (2H, d, J=8.5), 7.55 (1H, t,
J=7.5), 7.65-7.80 (2H, m), 7.95 (1H, s) ;
IR (KBr, cm^-1) : 1672, 1624. (B) N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] acetamide dihydrochloride N- [ 3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [4- (piperidin-4-yloxy) phenyl] acetamide dihydrochloride (400 mg) was dissolved in methanol (20 ml) and ethyl Acetimidate hydrochloride (320 mg) and triethylamine (0.60 ml) were added at room temperature, followed by stirring at the same temperature for 12 hours. A 4M hydrogen chloride dioxane solution (1 ml) was added to the reaction solution, followed by concentration under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 15% acetonitrile / water) and then obtained. The amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml) and then freeze-dried to obtain 342 mg (yield 79%) of the title compound as a colorless amorphous solid.
¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.74 (2H, m), 1.78 (3H, s), 2.04 (2H,
m), 2.31 (3H, s), 3.45-3.95 (4H, m), 4.39 (2H, m), 4.60-4.80 (1H, m), 6.40-6.60 (2H, m), 7.05 (2H, d, J = 8.5), 7.28 (2H, d, J = 8.5), 7.55 (1H, t,
J = 7.5), 7.65-7.80 (2H, m), 7.95 (1H, s);
IR (KBr, cm ^-1 ): 1672, 1624.

実施例１９
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−２−ヒドロキシアセトアミド２塩酸塩（例示化合物番号：１０１４） Example 19
N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] -2-hydroxyacetamide dihydrochloride (Exemplary Compound number: 1014)

（ａ）Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］−２−ヒドロキシアセトアミド２塩酸塩
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］−２−ヒドロキシアセトアミド（９７７ｍｇ）を、ジクロロメタン（３０ｍｌ）及びエタノール（１５ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１時間通じた後、密栓をして室温で７時間撹拌した。反応液を減圧下濃縮した後、残渣をエタノール（２０ｍｌ）に溶解させ、塩化アンモニウム水溶液（２１３ｍｇを水１０ｍｌに溶解）及び２８％アンモニア水（０．４０ｍｌ）を加えた後、室温で１２時間放置した。反応液に４Ｍ塩化水素ジオキサン溶液（１ｍｌ）を加えた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１１％アセトニトリル／水）にて精製した後、得られた無定形固体をメタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．５ｍｌ）を加えた後、これを減圧下濃縮乾固させた。得られた無定形固体を水（約１０ｍｌ）に溶解させた後、凍結乾燥に付すことにより、表記化合物６８５ｍｇ（収率７２％）を無色無定形固体として得た。
¹H NMR (270MHz, DMSO-d₆) δppm : 1.84 (2H, m), 2.10 (2H, m), 2.90-3.80
(6H, m), 4.36 (2H, m), 4.65 (1H, m), 6.50 (2H, m), 7.03 (2H, d, J=8.5),
7.28 (2H, d, J=8.5), 7.55 (1H, t, J=7.5), 7.65-7.80 (2H, m), 7.92 (1H, s) ;
IR (KBr, cm^-1) : 1673. (A) N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [4- (piperidin-4-yloxy) phenyl] -2-hydroxyacetamide dihydrochloride N- [4 -(1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] -2-hydroxyacetamide (977 mg) was added to dichloromethane (30 ml). ) And ethanol (15 ml), and after passing through hydrogen chloride for 1 hour under ice cooling, the mixture was sealed and stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethanol (20 ml). Aqueous ammonium chloride (213 mg dissolved in 10 ml of water) and 28% aqueous ammonia (0.40 ml) were added, and the mixture was allowed to stand at room temperature for 12 hours. did. A 4M hydrogen chloride dioxane solution (1 ml) was added to the reaction solution, followed by concentration under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 11% acetonitrile / water), and then obtained. The amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml) and then freeze-dried to obtain 685 mg (yield 72%) of the title compound as a colorless amorphous solid.
¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.84 (2H, m), 2.10 (2H, m), 2.90-3.80
(6H, m), 4.36 (2H, m), 4.65 (1H, m), 6.50 (2H, m), 7.03 (2H, d, J = 8.5),
7.28 (2H, d, J = 8.5), 7.55 (1H, t, J = 7.5), 7.65-7.80 (2H, m), 7.92 (1H, s);
IR (KBr, cm ^-1 ): 1673.

（ｂ）Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−２−ヒドロキシアセトアミド２塩酸塩
Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］−２−ヒドロキシアセトアミド２塩酸塩（３８５ｍｇ）を、メタノール（２０ｍｌ）に溶解させ、エチルアセトイミデート塩酸塩（３００ｍｇ）及びトリエチルアミン（０．５６ｍｌ）を室温で加えた後、同温で１２時間撹拌した。反応液に４Ｍ塩化水素ジオキサン溶液（１ｍｌ）を加えた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１４％アセトニトリル／水）にて精製した後、得られた無定形固体をメタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．５ｍｌ）を加えた後、これを減圧下濃縮乾固させた。得られた無定形固体を水（約１０ｍｌ）に溶解させた後、凍結乾燥に付すことにより、表記化合物３３６ｍｇ（収率８０％）を無色無定形固体として得た。
¹H NMR (270MHz, DMSO-d₆) δppm : 1.73 (2H, m), 2.05 (2H, m), 2.30 (3H,
s), 3.30-3.90 (6H, m), 4.39 (2H, m), 4.69 (1H, m), 6.40-6.60 (2H, m), 7.04 (2H, d, J=9.0), 7.28 (2H, d, J=9.0), 7.55 (1H, t, J=8.0), 7.65-7.80 (2H, m), 7.93 (1H, s) ;
IR (KBr, cm^-1) : 1671. (B) N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] -2-hydroxyacetamide dihydrochloride Salt N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [4- (piperidin-4-yloxy) phenyl] -2-hydroxyacetamide dihydrochloride (385 mg) was dissolved in methanol. (20 ml), ethylacetoimidate hydrochloride (300 mg) and triethylamine (0.56 ml) were added at room temperature, and the mixture was stirred at the same temperature for 12 hours. A 4M hydrogen chloride dioxane solution (1 ml) was added to the reaction solution, followed by concentration under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 14% acetonitrile / water), and then obtained. The amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml) and then freeze-dried to obtain 336 mg (yield 80%) of the title compound as a colorless amorphous solid.
¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.73 (2H, m), 2.05 (2H, m), 2.30 (3H,
s), 3.30-3.90 (6H, m), 4.39 (2H, m), 4.69 (1H, m), 6.40-6.60 (2H, m), 7.04 (2H, d, J = 9.0), 7.28 (2H, d, J = 9.0), 7.55 (1H, t, J = 8.0), 7.65-7.80 (2H, m), 7.93 (1H, s);
IR (KBr, cm ^-1 ): 1671.

実施例２０
３−［３−［Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−ベンジルアミノ］−１−（Ｅ）−プロペニル］ベンズアミジン３塩酸塩（例示化合物番号：８６４） Example 20
3- [3- [N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N-benzylamino] -1- (E) -propenyl] benzamidine trihydrochloride (Exemplary compound number: 864 )

（ａ）３−［３−［Ｎ−ベンジル−Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］アミノ］−１−（Ｅ）−プロペニル］ベンズアミジン３塩酸塩
３−［３−［Ｎ−ベンジル−Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］アミノ］−１−（Ｅ）−プロペニル］ベンゾニトリル（９１６ｍｇ）を、ジクロロメタン（３０ｍｌ）及びエタノール（１５ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１時間通じた後、密栓をして室温で７時間撹拌した。反応液を減圧下濃縮した後、残渣をエタノール（２０ｍｌ）に溶解させ、塩化アンモニウム水溶液（１８７ｍｇを水１０ｍｌに溶解）及び２８％アンモニア水（０．４６ｍｌ）を加えた後、室温で１２時間放置した。反応液に４Ｍ塩化水素ジオキサン溶液（１ｍｌ）を加えた後、減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィ−［Cosmosil（登録商標）75C18 - PREP
; Nacalai Tesque、溶出溶媒：５％アセトニトリル／水）にて精製した後、得られた無定形固体をメタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．５ｍｌ）を加えた後、これを減圧下濃縮乾固させた。得られた無定形固体を水（約１０ｍｌ）に溶解させた後、凍結乾燥に付すことにより、表記化合物５８１ｍｇ（収率６０％）を淡褐色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.78 (2H, m), 2.03 (2H, m), 2.98 (2H,
m), 3.15 (2H, m), 4.35 (2H, m), 4.50 (1H, m), 4.76 (2H, m), 6.61 (1H, dt, J=16.0, 6.5), 6.70 (1H, d, J=16.0), 6.93 (2H, m), 7.20-7.35 (3H, m), 7.35-7.50 (4H, m), 7.57 (1H, t, J=8.0), 7.70 (1H, d, J=8.0), 7.73 (1H, d, J=8.0), 7.89 (1H, s) ;
IR (KBr, cm^-1) : 1675. (A) 3- [3- [N-Benzyl-N- [4- (piperidin-4-yloxy) phenyl] amino] -1- (E) -propenyl] benzamidine trihydrochloride 3- [3- [N- Benzyl-N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] amino] -1- (E) -propenyl] benzonitrile (916 mg) was added in dichloromethane (30 ml) and ethanol (15 ml). After dissolving in a mixed solvent and passing through hydrogen chloride for 1 hour under ice cooling, the mixture was sealed and stirred at room temperature for 7 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), an aqueous ammonium chloride solution (187 mg dissolved in 10 ml of water) and 28% aqueous ammonia (0.46 ml) were added, and then left at room temperature for 12 hours. did. A 4M hydrogen chloride dioxane solution (1 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [Cosmosil® 75C18-PREP.
After purification with Nacalai Tesque, elution solvent: 5% acetonitrile / water), the obtained amorphous solid was dissolved in methanol (10 ml), and 4M hydrogen chloride dioxane solution (0.5 ml) was added. Was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml) and then freeze-dried to obtain 581 mg (yield 60%) of the title compound as a light brown amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.78 (2H, m), 2.03 (2H, m), 2.98 (2H,
m), 3.15 (2H, m), 4.35 (2H, m), 4.50 (1H, m), 4.76 (2H, m), 6.61 (1H, dt, J = 16.0, 6.5), 6.70 (1H, d, J = 16.0), 6.93 (2H, m), 7.20-7.35 (3H, m), 7.35-7.50 (4H, m), 7.57 (1H, t, J = 8.0), 7.70 (1H, d, J = 8.0 ), 7.73 (1H, d, J = 8.0), 7.89 (1H, s);
IR (KBr, cm ^-1 ): 1675.

（ｂ）３−［３−［Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−ベンジルアミノ］−１−（Ｅ）−プロペニル］ベンズアミジン３塩酸塩
３−［３−［Ｎ−ベンジル−Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］アミノ］−１−（Ｅ）−プロペニル］ベンズアミジン３塩酸塩（３３５ｍｇ）を、メタノール（２０ｍｌ）に溶解させ、エチルアセトイミデート塩酸塩（２３０ｍｇ）及びトリエチルアミン（０．５１ｍｌ）を室温で加えた後、同温で１２時間撹拌した。反応液に４Ｍ塩化水素ジオキサン溶液（１ｍｌ）を加えた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：３０％アセトニトリル／水）にて精製した後、得られた無定形固体をメタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．５ｍｌ）を加えた後、これを減圧下濃縮乾固させた。得られた無定形固体を水（約１０ｍｌ）に溶解させた後、凍結乾燥に付すことにより、表記化合物２５２ｍｇ（収率７０％）を無色無定形固体として得た。
¹H NMR (270MHz, DMSO-d₆) δppm : 1.50-1.75 (2H, m), 1.96 (2H, m), 2.29
(3H, s), 3.40 -3.90 (4H, m), 4.40 (2H, m), 4.50-4.90 (3H, m), 6.63 (1H,
dt, J=16.0, 6.0), 6.74 (1H, d, J=16.0), 6.97 (2H, d, J=8.5), 7.15-7.30 (3H, m), 7.40-7.60 (4H, m), 7.56 (1H, t, J=7.5), 7.66 (1H, d, J=7.5), 7.77 (1H, d, J=7.5), 7.92 (1H, s) ;
IR (KBr, cm^-1) : 1672, 1624. (B) 3- [3- [N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N-benzylamino] -1- (E) -propenyl] benzamidine trihydrochloride 3- [ 3- [N-Benzyl-N- [4- (piperidin-4-yloxy) phenyl] amino] -1- (E) -propenyl] benzamidine trihydrochloride (335 mg) was dissolved in methanol (20 ml) and dissolved in ethyl. Acetimidate hydrochloride (230 mg) and triethylamine (0.51 ml) were added at room temperature, followed by stirring at the same temperature for 12 hours. A 4M hydrogen chloride dioxane solution (1 ml) was added to the reaction solution, followed by concentration under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 30% acetonitrile / water), and then obtained The amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml) and then freeze-dried to obtain 252 mg (yield 70%) of the title compound as a colorless amorphous solid.
¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.50-1.75 (2H, m), 1.96 (2H, m), 2.29
(3H, s), 3.40 -3.90 (4H, m), 4.40 (2H, m), 4.50-4.90 (3H, m), 6.63 (1H,
dt, J = 16.0, 6.0), 6.74 (1H, d, J = 16.0), 6.97 (2H, d, J = 8.5), 7.15-7.30 (3H, m), 7.40-7.60 (4H, m), 7.56 (1H, t, J = 7.5), 7.66 (1H, d, J = 7.5), 7.77 (1H, d, J = 7.5), 7.92 (1H, s);
IR (KBr, cm ^-1 ): 1672, 1624.

実施例２１
３−［３−［Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］アミノ］−１−（Ｅ）−プロペニル］ベンズアミジン３塩酸塩
（例示化合物番号：１７７） Example 21
3- [3- [N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] amino] -1- (E) -propenyl] benzamidine trihydrochloride (Exemplary Compound No. 177)

（ａ）３−［３−［Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］アミノ］−１−（Ｅ）−プロペニル］ベンズアミジン３塩酸塩
３−［３−［Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］アミノ］−１−（Ｅ）−プロペニル］ベンゾニトリル（９００ｍｇ）を、ジクロロメタン（３０ｍｌ）及びエタノール（１５ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１時間通じた後、密栓をして室温で７時間撹拌した。反応液を減圧下濃縮した後、残渣をエタノール（２０ｍｌ）に溶解させ、塩化アンモニウム水溶液（２２２ｍｇを水１０ｍｌに溶解）及び２８％アンモニア水（０．５４ｍｌ）を加えた後、室温で１２時間放置した。反応液に４Ｍ塩化水素ジオキサン溶液（１ｍｌ）を加えた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１５％アセトニトリル／水）にて精製した後、得られた無定形固体をメタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．５ｍｌ）を加えた後、これを減圧下濃縮乾固させることにより、表記化合物７３５ｍｇ（収率７７％）を黄色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.82 (2H, m), 2.05 (2H, m), 3.03 (2H,
m), 3.20 (2H, m), 3.95-4.10 (2H, m), 4.50-4.65 (1H, m), 6.55 (1H, dt, J=16.0, 6.5), 6.79 (1H, d, J=16.0), 7.05 (2H, m), 7.20-7.45 (2H, m), 7.61
(1H, t, J=8.0), 7.70-7.80 (2H, m), 7.87 (1H, s) ;
IR (KBr, cm^-1) : 1675. (A) 3- [3- [N- [4- (Piperidin-4-yloxy) phenyl] amino] -1- (E) -propenyl] benzamidine trihydrochloride 3- [3- [N- [4- ( 1-t-Butoxycarbonylpiperidin-4-yloxy) phenyl] amino] -1- (E) -propenyl] benzonitrile (900 mg) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml) and ice-cooled. Then, hydrogen chloride was allowed to pass through for 1 hour, and then sealed and stirred at room temperature for 7 hours. After concentrating the reaction solution under reduced pressure, the residue was dissolved in ethanol (20 ml), aqueous ammonium chloride solution (222 mg dissolved in 10 ml of water) and 28% aqueous ammonia (0.54 ml) were added, and then allowed to stand at room temperature for 12 hours. did. A 4M hydrogen chloride dioxane solution (1 ml) was added to the reaction solution, followed by concentration under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 15% acetonitrile / water), and then obtained. The amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 735 mg (yield 77%) of the title compound as yellow. Obtained as an amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.82 (2H, m), 2.05 (2H, m), 3.03 (2H,
m), 3.20 (2H, m), 3.95-4.10 (2H, m), 4.50-4.65 (1H, m), 6.55 (1H, dt, J = 16.0, 6.5), 6.79 (1H, d, J = 16.0 ), 7.05 (2H, m), 7.20-7.45 (2H, m), 7.61
(1H, t, J = 8.0), 7.70-7.80 (2H, m), 7.87 (1H, s);
IR (KBr, cm ^-1 ): 1675.

（ｂ）３−［３−［Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］アミノ］−１−（Ｅ）−プロペニル］ベンズアミジン３塩酸塩
３−［３−［Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］アミノ］−１−（Ｅ）−プロペニル］ベンズアミジン３塩酸塩（３４５ｍｇ）を、メタノール（２０ｍｌ）に溶解させ、エチルアセトイミデート塩酸塩（１８５ｍｇ）及びトリエチルアミン（０．５２ｍｌ）を室温で加えた後、同温で１２時間撹拌した。反応液に４Ｍ塩化水素ジオキサン溶液（１ｍｌ）を加えた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：３０％アセトニトリル／水）にて精製した後、得られた無定形固体をメタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．５ｍｌ）を加えた後、これを減圧下濃縮乾固させた。得られた無定形固体を水（約１０ｍｌ）に溶解させた後、凍結乾燥に付すことにより、表記化合物２７２ｍｇ（収率７２％）を黄色無定形固体として得た。
¹H NMR (270MHz, DMSO-d₆) δppm : 1.73 (2H, m), 2.05 (2H, m), 2.30 (S, 3H), 3.40-3.95 (4H, m), 4.06 (2H, d, J=6.5), 4.69 (1H, m), 6.56 (1H, dt,
J=16.0, 6.5), 6.80 (1H, d, J=16.0), 7.10 (2H, d, J=9.0), 7.35-7.55 (2H,
m), 7.60 (1H, t, J=8.0), 7.70-7.80(2H, m), 7.87 (1H, s) ;
IR (KBr, cm^-1) : 1672, 1625. (B) 3- [3- [N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] amino] -1- (E) -propenyl] benzamidine trihydrochloride 3- [3- [N -[4- (Piperidin-4-yloxy) phenyl] amino] -1- (E) -propenyl] benzamidine trihydrochloride (345 mg) was dissolved in methanol (20 ml) and ethylacetimidate hydrochloride (185 mg) And triethylamine (0.52 ml) was added at room temperature, followed by stirring at the same temperature for 12 hours. A 4M hydrogen chloride dioxane solution (1 ml) was added to the reaction solution, followed by concentration under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 30% acetonitrile / water), and then obtained The amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml) and then freeze-dried to obtain 272 mg (yield 72%) of the title compound as a yellow amorphous solid.
¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.73 (2H, m), 2.05 (2H, m), 2.30 (S, 3H), 3.40-3.95 (4H, m), 4.06 (2H, d, J = 6.5), 4.69 (1H, m), 6.56 (1H, dt,
J = 16.0, 6.5), 6.80 (1H, d, J = 16.0), 7.10 (2H, d, J = 9.0), 7.35-7.55 (2H,
m), 7.60 (1H, t, J = 8.0), 7.70-7.80 (2H, m), 7.87 (1H, s);
IR (KBr, cm ^-1 ): 1672, 1625.

実施例２２
３−［３−［Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−イソプロピルアミノ］−１−（Ｅ）−プロペニル］ベンズアミジン３塩酸塩（例示化合物番号：３５８） Example 22
3- [3- [N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N-isopropylamino] -1- (E) -propenyl] benzamidine trihydrochloride (Exemplary Compound Number: 358 )

（ａ）３−［３−［Ｎ−イソプロピル−Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］アミノ］−１−（Ｅ）−プロペニル］ベンズアミジン３塩酸塩
３−［３−［Ｎ−４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル−Ｎ−イソプロピルアミノ］−１−（Ｅ）−プロペニル］ベンゾニトリル（７０５ｍｇ）を、ジクロロメタン（３０ｍｌ）及びエタノール（１５ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１時間通じた後、密栓をして室温で７時間撹拌した。反応液を減圧下濃縮した後、残渣をエタノール（２０ｍｌ）に溶解させ、塩化アンモニウム水溶液（１５９ｍｇを水１０ｍｌに溶解）及び２８％アンモニア水（０．３９ｍｌ）を加えた後、室温で１２時間放置した。反応液に４Ｍ塩化水素ジオキサン溶液（１ｍｌ）を加えた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１５％アセトニトリル／水）にて精製した後、得られた無定形固体をメタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．５ｍｌ）を加えた後、これを減圧下濃縮乾固させた。得られた無定形固体を水（約１０ｍｌ）に溶解させた後、凍結乾燥に付すことにより、表記化合物５７０ｍｇ（収率７０％）を淡褐色無定形固体として得た。
¹H NMR (270MHz, DMSO-d₆) δppm : 1.16 (3H, m), 1.40 (3H, m), 1.82 (2H,
m), 2.07 (2H, m), 3.03 (2H, m), 3.18 (2H, m), 3.98 (1H, m), 4.41 (2H, m), 4.68(1H, m), 6.40 (1H, m), 6.72 (1H, d, J=16.0), 7.13 (2H, m), 7.50-7.65 (2H, m), 7.70-7.85 (4H, m) ;
IR (KBr, cm^-1) : 1675. (A) 3- [3- [N-isopropyl-N- [4- (piperidin-4-yloxy) phenyl] amino] -1- (E) -propenyl] benzamidine trihydrochloride 3- [3- [N- 4- (1-t-Butoxycarbonylpiperidin-4-yloxy) phenyl-N-isopropylamino] -1- (E) -propenyl] benzonitrile (705 mg) in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml) After dissolving in water and passing through hydrogen chloride for 1 hour under ice cooling, the mixture was sealed and stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethanol (20 ml). Aqueous ammonium chloride (159 mg dissolved in 10 ml of water) and 28% aqueous ammonia (0.39 ml) were added, and the mixture was allowed to stand at room temperature for 12 hours. did. A 4M hydrogen chloride dioxane solution (1 ml) was added to the reaction solution, followed by concentration under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 15% acetonitrile / water) and then obtained. The amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml) and then freeze-dried to obtain 570 mg (yield 70%) of the title compound as a light brown amorphous solid.
¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.16 (3H, m), 1.40 (3H, m), 1.82 (2H,
m), 2.07 (2H, m), 3.03 (2H, m), 3.18 (2H, m), 3.98 (1H, m), 4.41 (2H, m), 4.68 (1H, m), 6.40 (1H, m ), 6.72 (1H, d, J = 16.0), 7.13 (2H, m), 7.50-7.65 (2H, m), 7.70-7.85 (4H, m);
IR (KBr, cm ^-1 ): 1675.

（ｂ）３−［３−［Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−イソプロピルアミノ］−１−（Ｅ）−プロペニル］ベンズアミジン３塩酸塩
３−［３−［Ｎ−イソプロピル−Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］アミノ］−１−（Ｅ）−プロペニル］ベンズアミジン３塩酸塩（３１０ｍｇ）を、メタノール（２０ｍｌ）に溶解させ、エチルアセトイミデート塩酸塩（２２９ｍｇ）及びトリエチルアミン（０．５２ｍｌ）を室温で加えた後、同温で１２時間撹拌した。反応液に４Ｍ塩化水素ジオキサン溶液（１ｍｌ）を加えた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１５％アセトニトリル／水）にて精製した後、得られた無定形固体をメタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．５ｍｌ）を加えた後、これを減圧下濃縮乾固させた。得られた無定形固体を水（約１０ｍｌ）に溶解させた後、凍結乾燥に付すことにより、表記化合物２５９ｍｇ（収率７７％）を淡褐色無定形固体として得た。
¹H NMR (270MHz, DMSO-d₆) δppm : 1.17 (3H, d, J=6.0), 1.43 (3H, d, J=6.0), 1.70 (2H, m), 2.04 (2H, m), 2.31 (3H, s), 3.45-4.05 (5H, m), 4.41 (2H, m), 4.74 (1H, m), 6.42 (1H, dt, J=16.0, 7.0), 6.73 (1H, d, J=16.0), 7.15 (2H, d, J=8.5), 7.50-7.65 (2H, m), 7.70-7.90 (4H, m) ;
IR (KBr, cm^-1) : 1672, 1623. (B) 3- [3- [N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N-isopropylamino] -1- (E) -propenyl] benzamidine trihydrochloride 3- [ 3- [N-isopropyl-N- [4- (piperidin-4-yloxy) phenyl] amino] -1- (E) -propenyl] benzamidine trihydrochloride (310 mg) was dissolved in methanol (20 ml) and ethyl Acetimidate hydrochloride (229 mg) and triethylamine (0.52 ml) were added at room temperature, followed by stirring at the same temperature for 12 hours. A 4M hydrogen chloride dioxane solution (1 ml) was added to the reaction solution, followed by concentration under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 15% acetonitrile / water) and then obtained. The amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml) and then freeze-dried to obtain 259 mg (yield 77%) of the title compound as a light brown amorphous solid.
¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.17 (3H, d, J = 6.0), 1.43 (3H, d, J = 6.0), 1.70 (2H, m), 2.04 (2H, m), 2.31 (3H, s), 3.45-4.05 (5H, m), 4.41 (2H, m), 4.74 (1H, m), 6.42 (1H, dt, J = 16.0, 7.0), 6.73 (1H, d, J = 16.0), 7.15 (2H, d, J = 8.5), 7.50-7.65 (2H, m), 7.70-7.90 (4H, m);
IR (KBr, cm ^-1 ): 1672, 1623.

実施例２３
２−［Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］アミノ］酢酸エチル３塩酸塩（例示化合物番号：６６８） Example 23
2- [N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] amino] ethyl acetate trihydrochloride (Exemplary compound number: 668)

（ａ）２−［Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］アミノ］酢酸エチル３塩酸塩
２−［Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］アミノ］酢酸エチル（１３０５ｍｇ）を、ジクロロメタン（３０ｍｌ）及びエタノール（１５ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１時間通じた後、密栓をして室温で７時間撹拌した。反応液を減圧下濃縮した後、残渣をエタノール（２０ｍｌ）に溶解させ、塩化アンモニウム水溶液（２６９ｍｇを水１０ｍｌに溶解）及び２８％アンモニア水（０．６６ｍｌ）を加えた後、室温で１２時間放置した。反応液に４Ｍ塩化水素ジオキサン溶液（１ｍｌ）を加えた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２０％アセトニトリル／水）にて精製した後、得られた無定形固体をメタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．５ｍｌ）を加えた後、これを減圧下濃縮乾固させた。得られた無定形固体を水（約１０ｍｌ）に溶解させた後、凍結乾燥に付すことにより、表記化合物６５２ｍｇ（収率４８％）を淡黄色無定形固体として得た。
¹H NMR (270MHz, DMSO-d₆) δppm : 1.18 (3H, t, J=7.0), 1.80 (2H, m), 2.04 (2H, m), 3.00 (2H, m), 3.17 (2H, m), 4.11 (2H, q, J=7.0), 4.10-4.20 (4H, m), 4.42 (1H, m), 6.55 (1H, dt, J=16.0, 5.0), 6.65 (2H, d, J=9.0), 6.67 (1H, d, J=16.0), 6.87 (2H, d, J=9.0), 7.56 (1H, t, J=7.5), 7.65-7.80
(2H, m), 7.91 (1H, s) ;
IR (KBr, cm^-1) : 1747, 1675. (A) 2- [N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- (piperidin-4-yloxy) phenyl] amino] ethyl acetate trihydrochloride 2- [N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] amino] ethyl acetate (1305 mg) , Dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), passed through hydrogen chloride for 1 hour under ice cooling, then sealed and stirred at room temperature for 7 hours. After concentrating the reaction solution under reduced pressure, the residue was dissolved in ethanol (20 ml), aqueous ammonium chloride solution (269 mg dissolved in 10 ml of water) and 28% aqueous ammonia (0.66 ml) were added, and then allowed to stand at room temperature for 12 hours. did. A 4M hydrogen chloride dioxane solution (1 ml) was added to the reaction solution, followed by concentration under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water), and then obtained. The amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml) and then freeze-dried to obtain 652 mg (yield 48%) of the title compound as a pale yellow amorphous solid.
¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.18 (3H, t, J = 7.0), 1.80 (2H, m), 2.04 (2H, m), 3.00 (2H, m), 3.17 (2H, m ), 4.11 (2H, q, J = 7.0), 4.10-4.20 (4H, m), 4.42 (1H, m), 6.55 (1H, dt, J = 16.0, 5.0), 6.65 (2H, d, J = 9.0), 6.67 (1H, d, J = 16.0), 6.87 (2H, d, J = 9.0), 7.56 (1H, t, J = 7.5), 7.65-7.80
(2H, m), 7.91 (1H, s);
IR (KBr, cm ^-1 ): 1747, 1675.

（ｂ）２−［Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］アミノ］酢酸エチル３塩酸塩
２−［Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］アミノ］酢酸エチル３塩酸塩（４００ｍｇ）を、メタノール（２０ｍｌ）に溶解させ、エチルアセトイミデート塩酸塩（２７０ｍｇ）及びトリエチルアミン（０．６１ｍｌ）を室温で加えた後、同温で１２時間撹拌した。反応液に４Ｍ塩化水素ジオキサン溶液（１ｍｌ）を加えた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２４％アセトニトリル／水）にて精製した後、得られた無定形固体をメタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．５ｍｌ）を加えた後、これを減圧下濃縮乾固させた。得られた無定形固体を水（約１０ｍｌ）に溶解させた後、凍結乾燥に付すことにより、表記化合物３５０ｍｇ（収率８１％）を淡黄色無定形固体として得た。
¹H NMR (270MHz, DMSO-d₆) δppm : 1.18 (3H, t, J=7.0), 1.70 (2H, m), 1.99 (2H, m), 2.31 (3H, s), 3.45-3.85 (4H, m), 4.11 (2H, q, J=7.0), 4.15-4.25 (4H, m), 4.48 (1H, m), 6.56 (1H, dt, J=16.0, 4.5), 6.66 (2H, d, J=9.0), 6.67 (1H, d, J=16.0), 6.88 (2H, d, J=9.0), 7.56 (1H, t, J=8.0), 7.65-7.80 (2H, m), 7.92 (1H, s) ;
IR (KBr, cm^-1) : 1747, 1672, 1623. (B) 2- [N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] amino] ethyl acetate Trihydrochloride 2- [N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [4- (piperidin-4-yloxy) phenyl] amino] ethyl acetate trihydrochloride (400 mg ) Was dissolved in methanol (20 ml), ethylacetoimidate hydrochloride (270 mg) and triethylamine (0.61 ml) were added at room temperature, and the mixture was stirred at the same temperature for 12 hours. A 4M hydrogen chloride dioxane solution (1 ml) was added to the reaction solution, followed by concentration under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 24% acetonitrile / water), and then obtained. The amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml) and then freeze-dried to obtain 350 mg (yield 81%) of the title compound as a pale yellow amorphous solid.
¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.18 (3H, t, J = 7.0), 1.70 (2H, m), 1.99 (2H, m), 2.31 (3H, s), 3.45-3.85 (4H , m), 4.11 (2H, q, J = 7.0), 4.15-4.25 (4H, m), 4.48 (1H, m), 6.56 (1H, dt, J = 16.0, 4.5), 6.66 (2H, d, J = 9.0), 6.67 (1H, d, J = 16.0), 6.88 (2H, d, J = 9.0), 7.56 (1H, t, J = 8.0), 7.65-7.80 (2H, m), 7.92 (1H , s);
IR (KBr, cm ^-1 ): 1747, 1672, 1623.

実施例２４
３−［３−［Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−エチルアミノ］−１−（Ｅ）−プロペニル］ベンズアミジン３塩酸塩（例示化合物番号：２９７） Example 24
3- [3- [N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N-ethylamino] -1- (E) -propenyl] benzamidine trihydrochloride (Exemplary Compound Number: 297 )

（ａ）３−［３−［Ｎ−エチル−Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］アミノ］−１−（Ｅ）−プロペニル］ベンズアミジン３塩酸塩
３−［３−［Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］−Ｎ−エチルアミノ］−１−（Ｅ）−プロペニル］ベンゾニトリル（７７０ｍｇ）を、ジクロロメタン（３０ｍｌ）及びエタノール（１５ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１時間通じた後、密栓をして室温で７時間撹拌した。反応液を減圧下濃縮した後、残渣をエタノール（２０ｍｌ）に溶解させ、塩化アンモニウム水溶液（１７８ｍｇを水１０ｍｌに溶解）及び２８％アンモニア水（０．４４ｍｌ）を加えた後、室温で１２時間放置した。反応液に４Ｍ塩化水素ジオキサン溶液（１ｍｌ）を加えた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２０％アセトニトリル／水）にて精製した後、得られた無定形固体をメタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．５ｍｌ）を加えた後、これを減圧下濃縮乾固させた。得られた無定形固体を水（約１０ｍｌ）に溶解させた後、凍結乾燥に付すことにより、表記化合物５７０ｍｇ（収率７０％）を無色無定形固体として得た。
¹H NMR (270MHz, DMSO-d₆) δppm : 1.07 (3H, t, J=7.0), 1.83 (2H, m), 2.10 (2H, m), 2.95-3.25 (4H, m), 3.60 (2H, m), 4.30 (2H, m), 4.69 (1H, m),
6.48 (1H, dt, J=16.0, 7.0), 6.72 (1H, d, J=16.0), 7.15 (2H, d, J=8.5), 7.56 (1H, t, J=7.5), 7.66 (1H, d, J=7.5), 7.70-8.00 (4H, m) ;
IR (KBr, cm^-1) : 1675. (A) 3- [3- [N-ethyl-N- [4- (piperidin-4-yloxy) phenyl] amino] -1- (E) -propenyl] benzamidine trihydrochloride 3- [3- [N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) phenyl] -N-ethylamino] -1- (E) -propenyl] benzonitrile (770 mg) was added to dichloromethane (30 ml) and ethanol (15 ml). After dissolving in a mixed solvent and passing through hydrogen chloride for 1 hour under ice cooling, the mixture was sealed and stirred at room temperature for 7 hours. After concentrating the reaction solution under reduced pressure, the residue was dissolved in ethanol (20 ml), aqueous ammonium chloride solution (178 mg dissolved in 10 ml of water) and 28% aqueous ammonia (0.44 ml) were added, and then left at room temperature for 12 hours. did. A 4M hydrogen chloride dioxane solution (1 ml) was added to the reaction solution, followed by concentration under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water), and then obtained. The amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml) and then freeze-dried to obtain 570 mg (yield 70%) of the title compound as a colorless amorphous solid.
¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.07 (3H, t, J = 7.0), 1.83 (2H, m), 2.10 (2H, m), 2.95-3.25 (4H, m), 3.60 (2H , m), 4.30 (2H, m), 4.69 (1H, m),
6.48 (1H, dt, J = 16.0, 7.0), 6.72 (1H, d, J = 16.0), 7.15 (2H, d, J = 8.5), 7.56 (1H, t, J = 7.5), 7.66 (1H, d, J = 7.5), 7.70-8.00 (4H, m);
IR (KBr, cm ^-1 ): 1675.

（ｂ）３−［３−［Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−エチルアミノ］−１−（Ｅ）−プロペニル］ベンズアミジン３塩酸塩
３−［３−［Ｎ−エチル−Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］アミノ］−１−（Ｅ）−プロペニル］ベンズアミジン３塩酸塩（４２０ｍｇ）を、メタノール（２０ｍｌ）に溶解させ、エチルアセトイミデート塩酸塩（３１９ｍｇ）及びトリエチルアミン（０．７２ｍｌ）を室温で加えた後、同温で１２時間撹拌した。反応液に４Ｍ塩化水素ジオキサン溶液（１ｍｌ）を加えた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２０％アセトニトリル／水）にて精製した後、得られた無定形固体をメタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．５ｍｌ）を加えた後、これを減圧下濃縮乾固させた。得られた無定形固体を水（約１０ｍｌ）に溶解させた後、凍結乾燥に付すことにより、表記化合物２８７ｍｇ（収率６３％）を無色無定形固体として得た。
¹H NMR (270MHz, DMSO-d₆) δppm : 1.09 (3H, t, J=7.0), 1.71 (2H, m), 2.03 (2H, m), 2.32 (3H, s), 3.50-3.95 (6H, m), 4.30 (2H, m), 4.75 (1H, m),
6.49 (1H, dt, J=16.0, 6.5), 6.73 (1H, d, J=16.0), 7.00-7.30 (2H, m), 7.58 (1H, t, J=7.5), 7.67 (1H, d, J=7.5), 7.75-7.90 (4H, m) ;
IR (KBr, cm^-1) : 1673, 1623. (B) 3- [3- [N- [4- (1-Acetimidylpiperidin-4-yloxy) phenyl] -N-ethylamino] -1- (E) -propenyl] benzamidine trihydrochloride 3- [ 3- [N-ethyl-N- [4- (piperidin-4-yloxy) phenyl] amino] -1- (E) -propenyl] benzamidine trihydrochloride (420 mg) was dissolved in methanol (20 ml) and ethyl was added. Acetimidate hydrochloride (319 mg) and triethylamine (0.72 ml) were added at room temperature, followed by stirring at the same temperature for 12 hours. A 4M hydrogen chloride dioxane solution (1 ml) was added to the reaction solution, followed by concentration under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water), and then obtained. The amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml) and then freeze-dried to obtain 287 mg (yield 63%) of the title compound as a colorless amorphous solid.
¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.09 (3H, t, J = 7.0), 1.71 (2H, m), 2.03 (2H, m), 2.32 (3H, s), 3.50-3.95 (6H , m), 4.30 (2H, m), 4.75 (1H, m),
6.49 (1H, dt, J = 16.0, 6.5), 6.73 (1H, d, J = 16.0), 7.00-7.30 (2H, m), 7.58 (1H, t, J = 7.5), 7.67 (1H, d, J = 7.5), 7.75-7.90 (4H, m);
IR (KBr, cm ^-1 ): 1673, 1623.

実施例２５
Ｎ−［４−（１−アセトイミドイルピロリジン−３−イルオキシ）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩（例示化合物番号：９０） Example 25
N- [4- (1-acetimidoylpyrrolidin-3-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl acetate dihydrochloride (Exemplary Compound Number) : 90)

（ａ）Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［４−（ピロリジン−３−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［４−（１−ｔ−ブトキシカルボニルピロリジン−３−イルオキシ）フェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル（２３４９ｍｇ）を、ジクロロメタン（６０ｍｌ）及びエタノール（３０ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１時間通じた後、密栓をして室温で７時間撹拌した。反応液を減圧下濃縮した後、残渣をエタノール（１００ｍｌ）に溶解させ、塩化アンモニウム水溶液（４４０ｍｇを水５０ｍｌに溶解）及び２８％アンモニア水（０．８３ｍｌ）を加えた後、室温で１２時間放置した。反応液に４Ｍ塩化水素ジオキサン溶液（２ｍｌ）を加えた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１８％アセトニトリル／水）にて精製した。得られた無定形固体をメタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．５ｍｌ）を加えた後、これを減圧下濃縮乾固させることにより、表記化合物２７２ｍｇ（収率１２％）を無色無定形固体として得た。
¹H NMR (270MHz, DMSO-d₆) δppm : 1.23 (3H, t, J=7.0), 2.05-2.25 (2H, m), 3.15-3.50 (4H, m), 4.20 (2H, q, J=7.0), 4.34 (2H, s), 4.45 (2H, d, J=5.5), 5.12 (1H, m), 6.44 (1H, dt, J=16.0, 5.5), 6.56 (1H, d, J=16.0), 7.01 (2H, d, J=9.0), 7.42 (2H, d, J=9.0), 7.54 (1H, t, J=8.0), 7.65-7.75 (2H, m), 7.90 (1H, s) ;
IR (KBr, cm^-1) : 1737, 1675. (A) N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [4- (pyrrolidin-3-yloxy) phenyl] sulfamoyl acetate ethyl dihydrochloride N- [4- ( 1-t-butoxycarbonylpyrrolidin-3-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl ethyl acetate (2349 mg) was added to dichloromethane (60 ml) and ethanol ( 30 ml), and the mixture was passed through hydrogen chloride for 1 hour under ice-cooling, then sealed and stirred at room temperature for 7 hours. After concentrating the reaction solution under reduced pressure, the residue was dissolved in ethanol (100 ml), aqueous ammonium chloride solution (440 mg dissolved in 50 ml of water) and 28% aqueous ammonia (0.83 ml) were added, and then allowed to stand at room temperature for 12 hours. did. A 4M hydrogen chloride dioxane solution (2 ml) was added to the reaction solution, followed by concentration under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 18% acetonitrile / water). The obtained amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 272 mg (yield 12%) of the title compound. Was obtained as a colorless amorphous solid.
¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.0), 2.05-2.25 (2H, m), 3.15-3.50 (4H, m), 4.20 (2H, q, J = 7.0), 4.34 (2H, s), 4.45 (2H, d, J = 5.5), 5.12 (1H, m), 6.44 (1H, dt, J = 16.0, 5.5), 6.56 (1H, d, J = 16.0 ), 7.01 (2H, d, J = 9.0), 7.42 (2H, d, J = 9.0), 7.54 (1H, t, J = 8.0), 7.65-7.75 (2H, m), 7.90 (1H, s) ;
IR (KBr, cm ^-1 ): 1737, 1675.

（ｂ）Ｎ−［４−（１−アセトイミドイルピロリジン−３−イルオキシ）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［４−（ピロリジン−３−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩（４００ｍｇ）を、メタノール（２０ｍｌ）に溶解させ、エチルアセトイミデート塩酸塩（３５０ｍｇ）及びトリエチルアミン（０．５０ｍｌ）を室温で加えた後、同温で１２時間撹拌した。反応液に４Ｍ塩化水素ジオキサン溶液（１ｍｌ）を加えた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２０％アセトニトリル／水）にて精製した後、得られた無定形固体をメタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．５ｍｌ）を加えた後、これを減圧下濃縮乾固させた。得られた無定形固体を水（約１０ｍｌ）に溶解させた後、凍結乾燥に付すことにより、表記化合物２５５ｍｇ（収率５９％）を無色無定形固体として得た。
¹H NMR (270MHz, DMSO-d₆) δppm : 1.23 (3H, t, J=7.0), 2.10-2.30 (2H, m), 2.26及び2.29 (合計3H, 各s), 3.40-4.05 (4H, m), 4.19 (2H, q, J=7.0), 4.34 (2H, s), 4.45 (2H, d, J=5.5), 5.10-5.30 (1H, m), 6.44 (1H, dt, J=16.0, 5.5), 6.56 (1H, d, J=16.0), 7.01及び7.02 (合計2H, 各d, J=9.0), 7.42及び7.43 (合計2H, 各d, J=9.0), 7.54 (1H, t, J=7.5), 7.65-7.75 (2H, m), 7.91 (1H, s) ;
IR (KBr, cm^-1) : 1738, 1672, 1629. (B) N- [4- (1-acetimidoylpyrrolidin-3-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl ethyl acetate dihydrochloride N -[3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [4- (pyrrolidin-3-yloxy) phenyl] sulfamoyl acetate dihydrochloride (400 mg) in methanol (20 ml). After dissolution, ethylacetimidate hydrochloride (350 mg) and triethylamine (0.50 ml) were added at room temperature, and the mixture was stirred at the same temperature for 12 hours. A 4M hydrogen chloride dioxane solution (1 ml) was added to the reaction solution, followed by concentration under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water), and then obtained. The amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml) and then freeze-dried to obtain 255 mg (yield 59%) of the title compound as a colorless amorphous solid.
¹ H NMR (270 MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.0), 2.10-2.30 (2H, m), 2.26 and 2.29 (total 3H, each s), 3.40-4.05 (4H, m), 4.19 (2H, q, J = 7.0), 4.34 (2H, s), 4.45 (2H, d, J = 5.5), 5.10-5.30 (1H, m), 6.44 (1H, dt, J = 16.0 , 5.5), 6.56 (1H, d, J = 16.0), 7.01 and 7.02 (total 2H, each d, J = 9.0), 7.42 and 7.43 (total 2H, each d, J = 9.0), 7.54 (1H, t , J = 7.5), 7.65-7.75 (2H, m), 7.91 (1H, s);
IR (KBr, cm ^-1 ): 1738, 1672, 1629.

実施例２６
２−［Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］アミノ］プロピオン酸エチル３塩酸塩（例示化合物番号：７８８） Example 26
2- [N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] amino] ethyl propionate 3 hydrochloric acid Salt (Exemplary compound number: 788)

（ａ）２−［Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］アミノ］プロピオン酸エチル３塩酸塩
２−［Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］アミノ］プロピオン酸エチル（８８２ｍｇ）を、ジクロロメタン（３０ｍｌ）及びエタノール（１５ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１時間通じた後、密栓をして室温で７時間撹拌した。反応液を減圧下濃縮した後、残渣をエタノール（２０ｍｌ）に溶解させ、塩化アンモニウム水溶液（１７７ｍｇを水１０ｍｌに溶解）及び２８％アンモニア水（０．４３ｍｌ）を加えた後、室温で１２時間放置した。反応液に４Ｍ塩化水素ジオキサン溶液（１ｍｌ）を加えた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２５％アセトニトリル／水）にて精製した。得られた無定形固体をメタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．５ｍｌ）を加えた後、これを減圧下濃縮乾固させることにより、表記化合物３８４ｍｇ及び純度の低い表記化合物２００ｍｇ（収率４１％以上）をそれぞれ褐色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.16 (3H, t, J=7.0), 1.44 (3H, d, J=7.0), 1.78 (2H, m), 2.04 (2H, m), 3.01 (2H, m), 3.18 (2H, m), 4.09 (2H, q, J=7.0), 3.96-4.15 (2H, m), 4.42 (1H, m), 4.55 (1H, q, J=7.0), 6.55 (1H, dt, J=16.0, 4.5), 6.64 (1H, d, J=16.0), 6.72 (2H, d, J=8.5), 6.86 (2H,
d, J=8.5), 7.54 (1H, t, J=8.0), 7.67 (1H, d, J=8.0), 7.73 (1H, d, J=8.0), 7.86 (1H, s) ;
IR (KBr, cm^-1) : 1745, 1681. (A) 2- [N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [4- (piperidin-4-yloxy) phenyl] amino] ethyl propionate trihydrochloride 2 -[N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] amino] ethyl propionate (882 mg ) Was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), hydrogen chloride was passed through for 1 hour under ice-cooling, and the mixture was sealed and stirred at room temperature for 7 hours. After concentrating the reaction solution under reduced pressure, the residue was dissolved in ethanol (20 ml), aqueous ammonium chloride solution (177 mg dissolved in 10 ml of water) and 28% aqueous ammonia (0.43 ml) were added, and then allowed to stand at room temperature for 12 hours. did. A 4M hydrogen chloride dioxane solution (1 ml) was added to the reaction solution, followed by concentration under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 25% acetonitrile / water). The obtained amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and then this was concentrated to dryness under reduced pressure to give 384 mg of the title compound and a lower purity title compound. 200 mg (yield 41% or more) was obtained as a brown amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.16 (3H, t, J = 7.0), 1.44 (3H, d, J = 7.0), 1.78 (2H, m), 2.04 (2H, m), 3.01 (2H, m), 3.18 (2H, m), 4.09 (2H, q, J = 7.0), 3.96-4.15 (2H, m), 4.42 (1H, m), 4.55 (1H, q, J = 7.0) , 6.55 (1H, dt, J = 16.0, 4.5), 6.64 (1H, d, J = 16.0), 6.72 (2H, d, J = 8.5), 6.86 (2H,
d, J = 8.5), 7.54 (1H, t, J = 8.0), 7.67 (1H, d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.86 (1H, s);
IR (KBr, cm ^-1 ): 1745, 1681.

（ｂ）２−［Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］アミノ］プロピオン酸エチル３塩酸塩
２−［Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］アミノ］プロピオン酸エチルを含む混合物（５４４ｍｇ）を、メタノール（３０ｍｌ）に溶解させ、エチルアセトイミデート塩酸塩（３６０ｍｇ）及びトリエチルアミン（０．８１ｍｌ）を室温で加えた後、同温で１２時間撹拌した。反応液に４Ｍ塩化水素ジオキサン溶液（１ｍｌ）を加えた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS
YMC、溶出溶媒：２５％アセトニトリル／水）にて精製した後、得られた無定形固体をメタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．５ｍｌ）を加えた後、これを減圧下濃縮乾固させた。得られた無定形固体を水（約１０ｍｌ）に溶解させた後、凍結乾燥に付すことにより、表記化合物４６８ｍｇ（収率２行程４７％）を淡褐色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.15 (3H, t, J=7.0), 1.45 (3H, d, J=7.0), 1.68 (2H, m), 1.98 (2H, m), 2.29 (3H, s), 3.45-3.60 (2H, m), 3.65-3.85 (2H, m), 4.09 (2H, q, J=7.0), 3.95-4.20 (2H, m), 4.49 (1H, m), 4.56 (1H, q, J=7.0), 6.56 (1H, dt, J=16.0, 4.5), 6.64 (1H, d, J=16.0), 6.76 (2H, d, J=9.0), 6.87 (2H, d, J=9.0), 7.54 (1H, t, J=8.0), 7.70 (1H, d, J=8.0), 7.73 (1H, d, J=8.0), 7.89 (1H, s) ;
IR (KBr, cm^-1) : 1745, 1673, 1623. (B) 2- [N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] amino] propionic acid Ethyl trihydrochloride A mixture comprising ethyl 2- [N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [4- (piperidin-4-yloxy) phenyl] amino] propionate (544 mg) was dissolved in methanol (30 ml), ethylacetoimidate hydrochloride (360 mg) and triethylamine (0.81 ml) were added at room temperature, and the mixture was stirred at the same temperature for 12 hours. A 4M hydrogen chloride dioxane solution (1 ml) was added to the reaction solution, followed by concentration under reduced pressure. The residue was subjected to preparative HPLC (YMC-Pack ODS).
YMC, elution solvent: 25% acetonitrile / water) After purification, the obtained amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and this was reduced in pressure. Concentrated to dryness. The obtained amorphous solid was dissolved in water (about 10 ml) and then freeze-dried to obtain 468 mg (yield 2 steps 47%) of the title compound as a light brown amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.15 (3H, t, J = 7.0), 1.45 (3H, d, J = 7.0), 1.68 (2H, m), 1.98 (2H, m), 2.29 (3H, s), 3.45-3.60 (2H, m), 3.65-3.85 (2H, m), 4.09 (2H, q, J = 7.0), 3.95-4.20 (2H, m), 4.49 (1H, m) , 4.56 (1H, q, J = 7.0), 6.56 (1H, dt, J = 16.0, 4.5), 6.64 (1H, d, J = 16.0), 6.76 (2H, d, J = 9.0), 6.87 (2H , d, J = 9.0), 7.54 (1H, t, J = 8.0), 7.70 (1H, d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.89 (1H, s);
IR (KBr, cm ^-1 ): 1745, 1673, 1623.

実施例２７
３−［３−［Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−メチルアミノ］−１−（Ｅ）−プロペニル］ベンズアミジン３塩酸塩（例示化合物番号：２３７） Example 27
3- [3- [N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N-methylamino] -1- (E) -propenyl] benzamidine trihydrochloride (Exemplary Compound Number: 237 )

（ａ）３−［３−［Ｎ−メチル−Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］アミノ］−１−（Ｅ）−プロペニル］ベンズアミジン３塩酸塩
３−［３−［Ｎ−４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル−Ｎ−メチルアミノ］−１−（Ｅ）−プロペニル］ベンゾニトリル（７６１ｍｇ）を、ジクロロメタン（３０ｍｌ）及びエタノール（１５ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１時間通じた後、密栓をして室温で７時間撹拌した。反応液を減圧下濃縮した後、残渣をエタノール（２０ｍｌ）に溶解させ、塩化アンモニウム水溶液（１８１ｍｇを水１０ｍｌに溶解）及び２８％アンモニア水（０．４４ｍｌ）を加えた後、室温で１２時間放置した。反応液に４Ｍ塩化水素ジオキサン溶液（１ｍｌ）を加えた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：８％アセトニトリル／水）にて精製した。得られた無定形固体をメタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．５ｍｌ）を加えた後、これを減圧下濃縮乾固させることにより、表記化合物４０１ｍｇ（収率５０％）を黄色無定形固体として得た。
¹H NMR (270MHz, DMSO-d₆) δppm : 1.83 (2H, m), 2.08 (2H, m), 2.95-3.25
(7H, m), 4.22 (2H, m), 4.60 (1H, m), 6.49 (1H, dt, J=16.0, 6.5), 6.71 (1H, d, J=16.0), 6.90-7.90 (8H, m) ;
IR (KBr, cm^-1) : 1675. (A) 3- [3- [N-methyl-N- [4- (piperidin-4-yloxy) phenyl] amino] -1- (E) -propenyl] benzamidine trihydrochloride 3- [3- [N- 4- (1-t-Butoxycarbonylpiperidin-4-yloxy) phenyl-N-methylamino] -1- (E) -propenyl] benzonitrile (761 mg) was mixed with dichloromethane (30 ml) and ethanol (15 ml). Then, the mixture was passed through hydrogen chloride for 1 hour under ice-cooling, sealed, and stirred at room temperature for 7 hours. After concentrating the reaction solution under reduced pressure, the residue was dissolved in ethanol (20 ml), aqueous ammonium chloride solution (181 mg dissolved in 10 ml of water) and 28% aqueous ammonia (0.44 ml) were added, and then allowed to stand at room temperature for 12 hours. did. A 4M hydrogen chloride dioxane solution (1 ml) was added to the reaction solution, followed by concentration under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 8% acetonitrile / water). The obtained amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and then this was concentrated to dryness under reduced pressure to give 401 mg of the title compound (yield 50%). Was obtained as a yellow amorphous solid.
¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.83 (2H, m), 2.08 (2H, m), 2.95-3.25
(7H, m), 4.22 (2H, m), 4.60 (1H, m), 6.49 (1H, dt, J = 16.0, 6.5), 6.71 (1H, d, J = 16.0), 6.90-7.90 (8H, m);
IR (KBr, cm ^-1 ): 1675.

（ｂ）３−［３−［Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−メチルアミノ］−１−（Ｅ）−プロペニル］ベンズアミジン３塩酸塩
３−［３−［Ｎ−メチル−Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］アミノ］−１−（Ｅ）−プロペニル］ベンズアミジン３塩酸塩（３６８ｍｇ）を、メタノール（２０ｍｌ）に溶解させ、エチルアセトイミデート塩酸塩（２９０ｍｇ）及びトリエチルアミン（０．６５ｍｌ）を室温で加えた後、同温で１２時間撹拌した。反応液に４Ｍ塩化水素ジオキサン溶液（１ｍｌ）を加えた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１０％アセトニトリル／水）にて精製した後、得られた無定形固体をメタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．５ｍｌ）を加えた後、これを減圧下濃縮乾固させた。得られた無定形固体を水（約１０ｍｌ）に溶解させた後、凍結乾燥に付すことにより、表記化合物２８８ｍｇ（収率７２％）を淡褐色無定形固体として得た。
¹H NMR (270MHz, DMSO-d₆) δppm : 1.71 (2H, m), 2.02(2H, m), 2.31 (3H, s), 3.13 (3H, s), 3.40-3.70 (4H, m), 4.29 (2H, d, J=7.0), 4.75 (1H, m), 6.50 (1H, dt, J=16.0, 7.0), 6.76 (1H, d, J=16.0), 7.15 (2H, d, J=9.0), 7.58 (1H, t, J=7.5), 7.69 (1H, d, J=7.5), 7.70-7.85 (3H, m), 7.92 (1H, s)
;
IR (KBr, cm^-1) : 1672, 1625. (B) 3- [3- [N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N-methylamino] -1- (E) -propenyl] benzamidine trihydrochloride 3- [ 3- [N-methyl-N- [4- (piperidin-4-yloxy) phenyl] amino] -1- (E) -propenyl] benzamidine trihydrochloride (368 mg) was dissolved in methanol (20 ml) and ethyl Acetimidate hydrochloride (290 mg) and triethylamine (0.65 ml) were added at room temperature, followed by stirring at the same temperature for 12 hours. A 4M hydrogen chloride dioxane solution (1 ml) was added to the reaction solution, followed by concentration under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 10% acetonitrile / water), and then obtained. The amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml) and then freeze-dried to obtain 288 mg (yield 72%) of the title compound as a light brown amorphous solid.
¹ H NMR (270MHz, DMSO-d ₆ ) δppm: 1.71 (2H, m), 2.02 (2H, m), 2.31 (3H, s), 3.13 (3H, s), 3.40-3.70 (4H, m), 4.29 (2H, d, J = 7.0), 4.75 (1H, m), 6.50 (1H, dt, J = 16.0, 7.0), 6.76 (1H, d, J = 16.0), 7.15 (2H, d, J = 9.0), 7.58 (1H, t, J = 7.5), 7.69 (1H, d, J = 7.5), 7.70-7.85 (3H, m), 7.92 (1H, s)
;
IR (KBr, cm ^-1 ): 1672, 1625.

実施例２８
３−［３−［Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−（２−ヒドロキシエチル）アミノ］−１−（Ｅ）−プロペニル］ベンズアミジン３塩酸塩（例示化合物番号：４７８） Example 28
3- [3- [N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- (2-hydroxyethyl) amino] -1- (E) -propenyl] benzamidine trihydrochloride ( Exemplified compound number: 478)

（ａ）３−［３−［Ｎ−（２−ヒドロキシエチル）−Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］アミノ］−１−（Ｅ）−プロペニル］ベンズアミジン３塩酸塩
３−［３−［Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］−Ｎ−（２−ヒドロキシエチル）アミノ］−１−（Ｅ）−プロペニル］ベンゾニトリル（１０９８ｍｇ）を、ジクロロメタン（３０ｍｌ）及びエタノール（１５ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１時間通じた後、密栓をして室温で６時間撹拌した。反応液を減圧下濃縮した後、残渣をエタノール（２０ｍｌ）に溶解させ、塩化アンモニウム水溶液（２４６ｍｇを水１０ｍｌに溶解）及び２８％アンモニア水（０．６０ｍｌ）を加えた後、室温で１２時間放置した。反応液に４Ｍ塩化水素ジオキサン溶液（１ｍｌ）を加えた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１２％アセトニトリル／水）にて精製した後、得られた無定形固体をメタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．５ｍｌ）を加えた後、これを減圧下濃縮乾固させた。得られた無定形固体を水（約１０ｍｌ）に溶解させた後、凍結乾燥に付すことにより、表記化合物５５５ｍｇ（収率４８％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.82 (2H, m), 2.07 (2H, m), 3.03 (2H,
m), 3.18 (2H, m), 3.54 (2H, m), 3.60 (2H, m), 4.31 (2H, m), 4.62 (1H, m), 6.48 (1H, dt, J=16.0, 6.5), 6.69 (1H, d, J=16.0), 7.08 (2H, m), 7.50 (2H, m), 7.58 (1H, t, J=8.0), 7.70 (1H, d, J=8.0), 7.73 (1H, d, J=8.0), 7.86 (1H, s) ;
IR (KBr, cm^-1) : 1676. (A) 3- [3- [N- (2-hydroxyethyl) -N- [4- (piperidin-4-yloxy) phenyl] amino] -1- (E) -propenyl] benzamidine trihydrochloride 3- [ 3- [N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) phenyl] -N- (2-hydroxyethyl) amino] -1- (E) -propenyl] benzonitrile (1098 mg) The mixture was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), and hydrogen chloride was passed through for 1 hour under ice-cooling. The solution was sealed and stirred at room temperature for 6 hours. After concentrating the reaction solution under reduced pressure, the residue was dissolved in ethanol (20 ml), aqueous ammonium chloride solution (246 mg dissolved in 10 ml of water) and 28% aqueous ammonia (0.60 ml) were added, and then allowed to stand at room temperature for 12 hours. did. A 4M hydrogen chloride dioxane solution (1 ml) was added to the reaction solution, followed by concentration under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 12% acetonitrile / water), and then obtained. The amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml) and then freeze-dried to obtain 555 mg (yield 48%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.82 (2H, m), 2.07 (2H, m), 3.03 (2H,
m), 3.18 (2H, m), 3.54 (2H, m), 3.60 (2H, m), 4.31 (2H, m), 4.62 (1H, m), 6.48 (1H, dt, J = 16.0, 6.5) , 6.69 (1H, d, J = 16.0), 7.08 (2H, m), 7.50 (2H, m), 7.58 (1H, t, J = 8.0), 7.70 (1H, d, J = 8.0), 7.73 ( 1H, d, J = 8.0), 7.86 (1H, s);
IR (KBr, cm ^-1 ): 1676.

（ｂ）３−［３−［Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−（２−ヒドロキシエチル）アミノ］−１−（Ｅ）−プロペニル］ベンズアミジン３塩酸塩
３−［３−［Ｎ−（２−ヒドロキシエチル）−Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］アミノ］−１−（Ｅ）−プロペニル］ベンズアミジン３塩酸塩（２９５ｍｇ）を、メタノール（２０ｍｌ）に溶解させ、エチルアセトイミデート塩酸塩（３６２ｍｇ）及びトリエチルアミン（０．４１ｍｌ）を室温で加えた後、同温で２時間撹拌した。反応液に４Ｍ塩化水素ジオキサン溶液（１ｍｌ）を加えた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１６％アセトニトリル／水）にて精製した後、得られた無定形固体をメタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．５ｍｌ）を加えた後、これを減圧下濃縮乾固させた。得られた無定形固体を水（約１０ｍｌ）に溶解させた後、凍結乾燥に付すことにより、表記化合物１７５ｍｇ（収率５５％）を薄黄色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.71 (2H, m), 2.03 (2H, m), 2.31 (3H,
s), 3.40-4.00 (8H, m), 4.32 (2H, m), 4.67 (1H, m), 6.50 (1H, dt, J=16.0, 6.5), 6.70 (1H, d, J=16.0), 7.08 (2H, m), 7.50 (2H, m), 7.58 (1H, t, J=8.0), 7.70 (1H, d, J=8.0), 7.75 (1H, d, J=8.0), 7.89 (1H, s) ;
IR (KBr, cm^-1) : 1673, 1626. (B) 3- [3- [N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- (2-hydroxyethyl) amino] -1- (E) -propenyl] benzamidine 3 Hydrochloride 3- [3- [N- (2-hydroxyethyl) -N- [4- (piperidin-4-yloxy) phenyl] amino] -1- (E) -propenyl] benzamidine trihydrochloride (295 mg) , Dissolved in methanol (20 ml), ethylacetimidate hydrochloride (362 mg) and triethylamine (0.41 ml) were added at room temperature, followed by stirring at the same temperature for 2 hours. A 4M hydrogen chloride dioxane solution (1 ml) was added to the reaction solution, followed by concentration under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 16% acetonitrile / water), and then obtained. The amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 10 ml) and then freeze-dried to obtain 175 mg (yield 55%) of the title compound as a pale yellow amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.71 (2H, m), 2.03 (2H, m), 2.31 (3H,
s), 3.40-4.00 (8H, m), 4.32 (2H, m), 4.67 (1H, m), 6.50 (1H, dt, J = 16.0, 6.5), 6.70 (1H, d, J = 16.0), 7.08 (2H, m), 7.50 (2H, m), 7.58 (1H, t, J = 8.0), 7.70 (1H, d, J = 8.0), 7.75 (1H, d, J = 8.0), 7.89 (1H , s);
IR (KBr, cm ^-1 ): 1673, 1626.

実施例２９
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−エトキシカルボニルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩
（例示化合物番号：１４５０） Example 29
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-ethoxycarbonylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl ethyl acetate dihydrochloride Salt (Exemplary compound number: 1450)

（ａ）Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［３−エトキシカルボニル−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−エトキシカルボニルフェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル（２．４５ｇ）をジクロロメタン（２５ｍｌ）及びエタノール（２５ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１．５時間通じた後、密栓をして室温で４．５時間撹拌した。反応液を減圧下濃縮した後、残渣をエタノール（２０ｍｌ）に溶解させ、塩化アンモニウム水溶液（０．４４ｇを水５ｍｌに溶解）及び２８％アンモニア水（１．００ｍｌ）を加えた後、反応液を室温で０．５時間撹拌し、次いで１３時間放置した。反応液を減圧下濃縮した後、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２２％アセトニトリル／水）にて精製し、得られた無定形固体をエタノール（２０ｍｌ）に溶解させ、４Ｍ塩化水素酢酸エチル溶液（１．９０ｍｌ）を加えた後、これを減圧下濃縮乾固することにより、表記化合物１．４１ｇ（収率５８％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.23 (3H, t, J=7.0), 1.29 (3H, t, J=7.0), 1.85-1.95 (2H, m), 2.05-2.15 (2H, m), 3.05-3.40 (4H, m), 4.19 (2H, q, J=7.0), 4.28 (2H, q, J=7.0), 4.41 (2H, s), 4.47 (2H, d, J=6.0), 4.86 (1H, m), 6.45 (1H, dt, J=16.0, 6.0), 6.57 (1H, d, J=16.0), 7.30 (1H, m),
7.55 (1H, m), 7.61 (1H, m), 7.65-7.80 (3H, m), 7.89 (1H, m);
IR (KBr, cm^-1) : 1729, 1676. (A) N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-ethoxycarbonyl-4- (piperidin-4-yloxy) phenyl] sulfamoyl acetate dihydrochloride N -[4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3-ethoxycarbonylphenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl ethyl acetate (2 .45 g) was dissolved in a mixed solvent of dichloromethane (25 ml) and ethanol (25 ml), hydrogen chloride was passed through for 1.5 hours under ice-cooling, and the mixture was sealed and stirred at room temperature for 4.5 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), aqueous ammonium chloride solution (0.44 g dissolved in 5 ml water) and 28% aqueous ammonia (1.00 ml) were added, and then the reaction mixture was dissolved. Stir at room temperature for 0.5 hour and then let stand for 13 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 22% acetonitrile / water), and the obtained amorphous solid was dissolved in ethanol (20 ml). A 4M hydrogen chloride ethyl acetate solution (1.90 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 1.41 g (yield 58%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.0), 1.29 (3H, t, J = 7.0), 1.85-1.95 (2H, m), 2.05-2.15 (2H, m), 3.05-3.40 (4H, m), 4.19 (2H, q, J = 7.0), 4.28 (2H, q, J = 7.0), 4.41 (2H, s), 4.47 (2H, d, J = 6.0 ), 4.86 (1H, m), 6.45 (1H, dt, J = 16.0, 6.0), 6.57 (1H, d, J = 16.0), 7.30 (1H, m),
7.55 (1H, m), 7.61 (1H, m), 7.65-7.80 (3H, m), 7.89 (1H, m);
IR (KBr, cm ^-1 ): 1729, 1676.

（ｂ）Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−エトキシカルボニルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［３−エトキシカルボニル−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩（１．２４ｇ）をエタノール（２０ｍｌ）に溶解させ、氷冷下、エチルアセトイミデート塩酸塩（０．７２ｇ）及びトリエチルアミン（１．７０ｍｌ）を加え、室温で０．５時間撹拌した後、１５時間放置した。反応液を減圧下濃縮した後、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２２％アセトニトリル／水）にて精製し、得られた無定形固体をエタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素酢酸エチル溶液（１．３０ｍｌ）を加えた後、これを減圧下濃縮乾固することにより、表記化合物１．０１ｇ（収率７６％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.23 (3H, t, J=7.0), 1.27 (3H, t, J=7.0), 1.75-1.90 (2H, m), 1.95-2.10 (2H, m), 2.31 (3H, s), 3.60-3.70 (3H, m), 3.70-3.80 (1H, m), 4.19 (2H, q, J=7.0), 4.26 (2H, q, J=7.0), 4.41 (2H, s), 4.47 (2H, d, J=6.0), 4.90 (1H, m), 6.45 (1H, dt, J=16.0, 6.0), 6.58 (1H, d, J=16.0), 7.32 (1H, m), 7.55 (1H, m), 7.62 (1H, m), 7.65-7.70 (3H, m), 7.90 (1H, m);
IR (KBr, cm^-1) : 1730, 1673, 1624. (B) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-ethoxycarbonylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl acetic acid Ethyl dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-ethoxycarbonyl-4- (piperidin-4-yloxy) phenyl] sulfamoyl acetate ethyl dihydrochloride (1.24 g) was dissolved in ethanol (20 ml), ethylacetimidate hydrochloride (0.72 g) and triethylamine (1.70 ml) were added under ice-cooling, and the mixture was stirred at room temperature for 0.5 hour, then 15 Left for hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 22% acetonitrile / water), and the obtained amorphous solid was dissolved in ethanol (10 ml). 4M Hydrogen chloride ethyl acetate solution (1.30 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 1.01 g (yield 76%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.0), 1.27 (3H, t, J = 7.0), 1.75-1.90 (2H, m), 1.95-2.10 (2H, m), 2.31 (3H, s), 3.60-3.70 (3H, m), 3.70-3.80 (1H, m), 4.19 (2H, q, J = 7.0), 4.26 (2H, q, J = 7.0), 4.41 (2H, s), 4.47 (2H, d, J = 6.0), 4.90 (1H, m), 6.45 (1H, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.32 (1H, m), 7.55 (1H, m), 7.62 (1H, m), 7.65-7.70 (3H, m), 7.90 (1H, m);
IR (KBr, cm ^-1 ): 1730, 1673, 1624.

実施例３０
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−カルボキシフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸２塩酸塩（例示化合物番号：１９７５）
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−エトキシカルボニルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩（０．３０ｇ）を３Ｍ塩酸（６ｍｌ）に溶解させ、８０℃で２時間撹拌した。反応液を室温まで冷却させた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１０％アセトニトリル／水）にて精製し、得られた無定形固体を１Ｍ塩酸（１．１０ｍｌ）に溶解させた後、これを減圧下濃縮乾固することにより、表記化合物０．２２ｇ（収率７９％）を無色無定形固体として得た。
1H NMR (500MHz, DMSO-d₆) δppm : 1.75-1.90 (2H, m), 1.90-2.10 (2H, m),
2.29 (3H, s), 3.55-3.75 (4H, m), 4.26 (2H, s), 4.47 (2H, d, J=6.0), 4.87 (1H, m), 6.44 (1H, dt, J=16.0, 6.0), 6.57 (1H, d, J=16.0), 7.28 (1H, m), 7.50-7.65 (2H, m), 7.65-7.80 (3H, m), 7.86 (1H, m);
IR (KBr, cm^-1) : 1726, 1673, 1627. Example 30
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-carboxyphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoylacetic acid dihydrochloride ( Exemplified compound number: 1975)
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-ethoxycarbonylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl ethyl acetate dihydrochloride The salt (0.30 g) was dissolved in 3M hydrochloric acid (6 ml) and stirred at 80 ° C. for 2 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 10% acetonitrile / water), and the resulting amorphous solid was converted to 1M hydrochloric acid. After being dissolved in (1.10 ml), this was concentrated to dryness under reduced pressure to obtain 0.22 g (yield 79%) of the title compound as a colorless amorphous solid.
1H NMR (500MHz, DMSO-d ₆ ) δppm: 1.75-1.90 (2H, m), 1.90-2.10 (2H, m),
2.29 (3H, s), 3.55-3.75 (4H, m), 4.26 (2H, s), 4.47 (2H, d, J = 6.0), 4.87 (1H, m), 6.44 (1H, dt, J = 16.0 , 6.0), 6.57 (1H, d, J = 16.0), 7.28 (1H, m), 7.50-7.65 (2H, m), 7.65-7.80 (3H, m), 7.86 (1H, m);
IR (KBr, cm ^-1 ): 1726, 1673, 1627.

実施例３１
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−ブロモフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩（例示化合物番号：１４１６） Example 31
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-bromophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl acetate dihydrochloride (Exemplary compound number: 1416)

（ａ）Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［３−ブロモ−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［３−ブロモ−４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル（２．２０ｇ）をジクロロメタン（２５ｍｌ）及びエタノール（２５ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１．５時間通じた後、密栓をして室温にて５時間撹拌した。反応液を減圧下濃縮した後、残渣をエタノール（２０ｍｌ）に溶解させ、塩化アンモニウム水溶液（０．４０ｇを水５ｍｌに溶解）及び２８％アンモニア水（０．９０ｍｌ）を加え、室温で０．５時間撹拌した後、１５時間放置した。反応液を減圧下濃縮した後、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２２％アセトニトリル／水）にて精製し、得られた無定形固体をエタノール（２０ｍｌ）に溶解させ、４Ｍ塩化水素酢酸エチル溶液（１．７０ｍｌ）を加えた後、これを減圧下濃縮乾固することにより、表記化合物１．３４ｇ（収率６１％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.23 (3H, t, J=7.0), 1.85-1.95 (2H, m), 2.05-2.15 (2H, m), 3.05-3.20 (4H, m), 4.20 (2H, q, J=7.0), 4.42 (2H, s), 4.47 (2H, d, J=6.0), 4.80 (1H, m), 6.44 (1H, dt, J=16.0, 6.0), 6.58 (1H, d, J=16.0), 7.27 (1H, m), 7.45 (1H, m), 7.55 (1H, m), 7.65-7.80 (3H, m), 7.90 (1H, m);
IR (KBr, cm^-1) : 1737, 1675. (A) N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-bromo-4- (piperidin-4-yloxy) phenyl] sulfamoyl acetate ethyl dihydrochloride N- [3-Bromo-4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl ethyl acetate (2.20 g ) Was dissolved in a mixed solvent of dichloromethane (25 ml) and ethanol (25 ml). Under ice-cooling, hydrogen chloride was passed through for 1.5 hours, and the bottle was sealed and stirred at room temperature for 5 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), aqueous ammonium chloride solution (0.40 g dissolved in 5 ml of water) and 28% aqueous ammonia (0.90 ml) were added, and 0.5% at room temperature was added. After stirring for an hour, it was left for 15 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 22% acetonitrile / water), and the resulting amorphous solid was dissolved in ethanol (20 ml). 4M Hydrogen chloride ethyl acetate solution (1.70 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 1.34 g (yield 61%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.0), 1.85-1.95 (2H, m), 2.05-2.15 (2H, m), 3.05-3.20 (4H, m) , 4.20 (2H, q, J = 7.0), 4.42 (2H, s), 4.47 (2H, d, J = 6.0), 4.80 (1H, m), 6.44 (1H, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.27 (1H, m), 7.45 (1H, m), 7.55 (1H, m), 7.65-7.80 (3H, m), 7.90 (1H, m);
IR (KBr, cm ^-1 ): 1737, 1675.

（ｂ）Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−ブロモフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［３−ブロモ−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩（１．１７ｇ）をエタノール（３０ｍｌ）に溶解させ、氷冷下、エチルアセトイミデート塩酸塩（０．６７ｇ）及びトリエチルアミン（１．５０ｍｌ）を加え、室温で２時間撹拌した後、１４時間放置した。反応液を減圧下濃縮した後、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２２％アセトニトリル／水）にて精製し、得られた無定形固体をエタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素酢酸エチル溶液（１．２０ｍｌ）を加えた後、これを減圧下濃縮乾固することにより、表記化合物０．９７ｇ（収率７７％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.23 (3H, t, J=7.0), 1.70-1.90 (2H, m), 1.95-2.15 (2H, m), 2.30 (3H, s), 3.55-3.75 (4H, m), 4.19 (2H, q, J=7.0), 4.42 (2H, s), 4.47 (2H, d, J=6.0), 4.85 (1H, m), 6.44 (1H, dt, J=16.0, 6.0), 6.58 (1H, d, J=16.0), 7.29 (1H, m), 7.45 (1H, m), 7.55 (1H, m),
7.65-7.80 (3H, m), 7.90 (1H, m);
IR (KBr, cm^-1) : 1738, 1674, 1625. (B) ethyl N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-bromophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl acetate Dihydrochloride N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-bromo-4- (piperidin-4-yloxy) phenyl] sulfamoyl ethyl acetate dihydrochloride (1 .17 g) was dissolved in ethanol (30 ml), ethylacetimidate hydrochloride (0.67 g) and triethylamine (1.50 ml) were added under ice cooling, and the mixture was stirred at room temperature for 2 hours and then allowed to stand for 14 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 22% acetonitrile / water), and the obtained amorphous solid was dissolved in ethanol (10 ml). A 4M hydrogen chloride ethyl acetate solution (1.20 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 0.97 g (yield 77%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.0), 1.70-1.90 (2H, m), 1.95-2.15 (2H, m), 2.30 (3H, s), 3.55 -3.75 (4H, m), 4.19 (2H, q, J = 7.0), 4.42 (2H, s), 4.47 (2H, d, J = 6.0), 4.85 (1H, m), 6.44 (1H, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.29 (1H, m), 7.45 (1H, m), 7.55 (1H, m),
7.65-7.80 (3H, m), 7.90 (1H, m);
IR (KBr, cm ^-1 ): 1738, 1674, 1625.

実施例３２
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−ブロモフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸２塩酸塩（例示化合物番号：１９４５）
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−ブロモフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩（０．８０ｇ）を３Ｍ塩酸（１５ｍｌ）に溶解させ、９０℃で２時間撹拌した。反応液を室温まで冷却させた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２２％アセトニトリル／水）で精製し、得られた無定形固体をエタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素酢酸エチル溶液（０．５０ｍｌ）を加えた後、これを減圧下濃縮乾固することにより、表記化合物０．３７ｇ（収率４８％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.70-1.85 (2H, m), 1.95-2.10 (2H, m),
2.30 (3H, s), 3.55-3.75 (4H, m), 4.26 (2H, s), 4.47 (2H, d, J=6.0), 4.85 (1H, m), 6.45 (1H, dt, J=16.0, 6.0), 6.58 (1H, d, J=16.0), 7.29 (1H, m), 7.46 (1H, m), 7.55 (1H, m), 7.65-7.75 (3H, m), 7.89 (1H, m);
IR (KBr, cm^-1) : 1732, 1672, 1626. Example 32
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-bromophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoylacetic acid dihydrochloride ( Exemplified compound number: 1945)
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-bromophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl ethyl acetate dihydrochloride (0.80 g) was dissolved in 3M hydrochloric acid (15 ml) and stirred at 90 ° C. for 2 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 22% acetonitrile / water), and the resulting amorphous solid was ethanol (10 ml). 4M hydrogen chloride ethyl acetate solution (0.50 ml) was added, and then this was concentrated to dryness under reduced pressure to give 0.37 g (yield 48%) of the title compound as a colorless amorphous solid. It was.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.70-1.85 (2H, m), 1.95-2.10 (2H, m),
2.30 (3H, s), 3.55-3.75 (4H, m), 4.26 (2H, s), 4.47 (2H, d, J = 6.0), 4.85 (1H, m), 6.45 (1H, dt, J = 16.0 , 6.0), 6.58 (1H, d, J = 16.0), 7.29 (1H, m), 7.46 (1H, m), 7.55 (1H, m), 7.65-7.75 (3H, m), 7.89 (1H, m );
IR (KBr, cm ^-1 ): 1732, 1672, 1626.

実施例３３
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−イソプロピルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩（例示化合物番号：１４２６） Example 33
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-isopropylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl ethyl acetate dihydrochloride (Exemplary compound number: 1426)

（ａ）Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［３−イソプロピル−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−イソプロピルフェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル（１．８２ｇ）をジクロロメタン（３０ｍｌ）及びエタノール（３０ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１．５時間通じた後、密栓をして室温で２時間撹拌した。反応液を減圧下濃縮した後、残渣をエタノール（２０ｍｌ）に溶解させ、塩化アンモニウム水溶液（０．３５ｇを水５ｍｌに溶解）及び２８％アンモニア水（０．８０ｍｌ）を加え、室温で０．５時間撹拌した後、１３時間放置した。反応液を減圧下濃縮した後、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２５％アセトニトリル／水）にて精製し、得られた無定形固体をエタノール（２０ｍｌ）に溶解させ、４Ｍ塩化水素酢酸エチル溶液（１．４０ｍｌ）を加えた後、これを減圧下濃縮乾固することにより、表記化合物０．９２ｇ（収率５１％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.15 (6H, d, J=7.0), 1.24 (3H, t, J=7.0), 1.80-1.95 (2H, m), 2.05-2.20 (2H, m), 3.00-3.20 (4H, m), 3.21 (1H, m), 4.21 (2H, q, J=7.0), 4.33 (2H, s), 4.43 (2H, d, J=6.0), 4.68 (1H, m), 6.45 (1H, dt, J=16.0, 6.0), 6.55 (1H, d, J=16.0), 7.04 (1H, d, J=9.0),
7.23 (1H, dd, J=9.0, 3.0), 7.29 (1H, d, J=3.0), 7.54 (1H, m), 7.65-7.75
(2H, m), 7.89 (1H, m);
IR (KBr, cm^-1) : 1738, 1676. (A) N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-isopropyl-4- (piperidin-4-yloxy) phenyl] sulfamoyl acetate dihydrochloride N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3-isopropylphenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl ethyl acetate (1.82 g ) Was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (30 ml), and hydrogen chloride was passed through for 1.5 hours under ice-cooling, then sealed and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), aqueous ammonium chloride solution (0.35 g dissolved in 5 ml water) and 28% aqueous ammonia (0.80 ml) were added, and 0.5% at room temperature was added. After stirring for an hour, it was left for 13 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 25% acetonitrile / water), and the obtained amorphous solid was dissolved in ethanol (20 ml). A 4M hydrogen chloride ethyl acetate solution (1.40 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 0.92 g (yield 51%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.15 (6H, d, J = 7.0), 1.24 (3H, t, J = 7.0), 1.80-1.95 (2H, m), 2.05-2.20 (2H, m), 3.00-3.20 (4H, m), 3.21 (1H, m), 4.21 (2H, q, J = 7.0), 4.33 (2H, s), 4.43 (2H, d, J = 6.0), 4.68 ( 1H, m), 6.45 (1H, dt, J = 16.0, 6.0), 6.55 (1H, d, J = 16.0), 7.04 (1H, d, J = 9.0),
7.23 (1H, dd, J = 9.0, 3.0), 7.29 (1H, d, J = 3.0), 7.54 (1H, m), 7.65-7.75
(2H, m), 7.89 (1H, m);
IR (KBr, cm ^-1 ): 1738, 1676.

（ｂ）Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−イソプロピルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［３−イソプロピル−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩（０．７８ｇ）をエタノール（３０ｍｌ）に溶解させ、氷冷下、エチルアセトイミデート塩酸塩（０．５０ｇ）及びトリエチルアミン（１．１０ｍｌ）を加え、室温で７時間撹拌した後、１２時間放置した。反応液を減圧下濃縮した後、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２５％アセトニトリル／水）で精製し、得られた無定形固体をエタノール（２０ｍｌ）に溶解させ、４Ｍ塩化水素酢酸エチル溶液（０．９０ｍｌ）を加えた後、これを減圧下濃縮乾固することにより、表記化合物０．６７ｇ（収率８０％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.14 (6H, d, J=7.0), 1.24 (3H, t, J=7.0), 1.70-1.85 (2H, m), 1.95-2.10 (2H, m), 2.30 (3H, s), 3.22 (1H, m), 3.50-3.60 (1H, m), 3.60-3.70 (2H, m), 3.70-3.80 (1H, m), 4.21 (2H, q, J=7.0), 4.33 (2H, s), 4.43 (2H, d, J=6.0), 4.74 (1H, m), 6.45 (1H, dt, J=16.0, 6.0), 6.55 (1H, d, J=16.0), 7.07 (1H, d, J=9.0), 7.23 (1H, dd, J=9.0, 3.0), 7.28 (1H, d, J=3.0), 7.55 (1H, m), 7.71 (2H, m), 7.90 (1H, m);
IR (KBr, cm^-1) : 1739, 1673, 1623. (B) ethyl N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-isopropylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl acetate Dihydrochloride N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-isopropyl-4- (piperidin-4-yloxy) phenyl] sulfamoyl ethyl acetate dihydrochloride (0 .78 g) was dissolved in ethanol (30 ml), ethylacetimidate hydrochloride (0.50 g) and triethylamine (1.10 ml) were added under ice cooling, and the mixture was stirred at room temperature for 7 hours and then allowed to stand for 12 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 25% acetonitrile / water), and the resulting amorphous solid was dissolved in ethanol (20 ml), and 4M A hydrogen chloride ethyl acetate solution (0.90 ml) was added, and the mixture was concentrated to dryness under reduced pressure to obtain 0.67 g (yield 80%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.14 (6H, d, J = 7.0), 1.24 (3H, t, J = 7.0), 1.70-1.85 (2H, m), 1.95-2.10 (2H, m), 2.30 (3H, s), 3.22 (1H, m), 3.50-3.60 (1H, m), 3.60-3.70 (2H, m), 3.70-3.80 (1H, m), 4.21 (2H, q, J = 7.0), 4.33 (2H, s), 4.43 (2H, d, J = 6.0), 4.74 (1H, m), 6.45 (1H, dt, J = 16.0, 6.0), 6.55 (1H, d, J = 16.0), 7.07 (1H, d, J = 9.0), 7.23 (1H, dd, J = 9.0, 3.0), 7.28 (1H, d, J = 3.0), 7.55 (1H, m), 7.71 (2H, m), 7.90 (1H, m);
IR (KBr, cm ^-1 ): 1739, 1673, 1623.

実施例３４
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−イソプロピルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸２塩酸塩（例示化合物番号：１９５５）
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−イソプロピルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩（０．５１ｇ）を３Ｍ塩酸（２０ｍｌ）に溶解させ、９０℃で２時間撹拌した。反応液を室温まで冷却させた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２５％アセトニトリル／水）で精製し、得られた無定形固体を１Ｍ塩酸（１．７０ｍｌ）に溶解させ、これを減圧下濃縮乾固することにより、表記化合物０．３３ｇ（収率６６％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.14 (6H, d, J=7.0), 1.70-1.85 (2H, m), 1.95-2.10 (2H, m), 2.30 (3H, s), 3.21 (1H, m), 3.50-3.60 (1H, m), 3.60-3.70 (2H, m), 3.70-3.80 (1H, m), 4.21 (2H, s), 4.44 (2H, d, J=6.0), 4.73 (1H, m), 6.46 (1H, dt, J=16.0, 6.0), 6.54 (1H, d, J=16.0), 7.06 (1H, d, J=9.0), 7.24 (1H, dd, J=9.0, 3.0), 7.29 (1H, d, J=3.0), 7.54 (1H, m),
7.71 (2H, m), 7.90 (1H, m);
IR (KBr, cm^-1) : 1733, 1673, 1625. Example 34
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-isopropylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoylacetic acid dihydrochloride ( Exemplified compound number: 1955)
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-isopropylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl ethyl acetate dihydrochloride (0.51 g) was dissolved in 3M hydrochloric acid (20 ml) and stirred at 90 ° C. for 2 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 25% acetonitrile / water), and the resulting amorphous solid was converted to 1M hydrochloric acid ( 1.70 ml), and this was concentrated to dryness under reduced pressure to obtain 0.33 g (yield 66%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.14 (6H, d, J = 7.0), 1.70-1.85 (2H, m), 1.95-2.10 (2H, m), 2.30 (3H, s), 3.21 (1H, m), 3.50-3.60 (1H, m), 3.60-3.70 (2H, m), 3.70-3.80 (1H, m), 4.21 (2H, s), 4.44 (2H, d, J = 6.0) , 4.73 (1H, m), 6.46 (1H, dt, J = 16.0, 6.0), 6.54 (1H, d, J = 16.0), 7.06 (1H, d, J = 9.0), 7.24 (1H, dd, J = 9.0, 3.0), 7.29 (1H, d, J = 3.0), 7.54 (1H, m),
7.71 (2H, m), 7.90 (1H, m);
IR (KBr, cm ^-1 ): 1733, 1673, 1625.

実施例３５
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−カルバモイルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩（例示化合物番号：１４６０） Example 35
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-carbamoylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl acetate ethyl dihydrochloride (Exemplary compound number: 1460)

（ａ）Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［３−カルバモイル−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−カルバモイルフェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル（２．４０ｇ）をジクロロメタン（２０ｍｌ）及びエタノール（２０ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を２．５時間通じた後、密栓をして室温で６時間撹拌した。反応液を減圧下濃縮した後、残渣をエタノール（２０ｍｌ）に溶解させ、塩化アンモニウム水溶液（０．５０ｇを水５ｍｌに溶解）及び２８％アンモニア水（１．１０ｍｌ）を加え、反応液を室温で０．５時間撹拌した後、１３時間放置した。反応液を減圧下濃縮した後、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１５％アセトニトリル／水）で精製し、得られた無定形固体をエタノール（２０ｍｌ）に溶解させ、４Ｍ塩化水素酢酸エチル溶液（０．９０ｍｌ）を加えた後、これを減圧下濃縮乾固することにより、表記化合物０．６０ｇ（収率２５％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.23 (3H, t, J=7.0), 1.85-2.00 (2H, m), 2.05-2.20 (2H, m), 3.00-3.10 (2H, m), 3.15-3.25 (2H, m), 4.20 (2H, q,
J=7.0), 4.38 (2H, s), 4.47 (2H, d, J=6.0), 4.80 (1H, m), 6.45 (1H, dt, J=16.0, 6.0), 6.57 (1H, d, J=16.0), 7.24 (1H, m), 7.50 (1H, m), 7.54 (1H, m), 7.65-7.75 (3H, m), 7.90 (1H, m);
IR (KBr, cm^-1) : 1736, 1671, 1658. (A) N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-carbamoyl-4- (piperidin-4-yloxy) phenyl] sulfamoyl acetate ethyl dihydrochloride N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3-carbamoylphenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl acetate (2.40 g) ) Was dissolved in a mixed solvent of dichloromethane (20 ml) and ethanol (20 ml), and hydrogen chloride was passed through for 2.5 hours under ice-cooling, then sealed and stirred at room temperature for 6 hours. After concentrating the reaction solution under reduced pressure, the residue was dissolved in ethanol (20 ml), aqueous ammonium chloride solution (0.50 g dissolved in 5 ml of water) and 28% aqueous ammonia (1.10 ml) were added, and the reaction solution was stirred at room temperature. After stirring for 0.5 hour, it was left for 13 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 15% acetonitrile / water), and the resulting amorphous solid was dissolved in ethanol (20 ml), and 4M A hydrogen chloride ethyl acetate solution (0.90 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give the title compound (0.60 g, yield 25%) as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.0), 1.85-2.00 (2H, m), 2.05-2.20 (2H, m), 3.00-3.10 (2H, m) , 3.15-3.25 (2H, m), 4.20 (2H, q,
J = 7.0), 4.38 (2H, s), 4.47 (2H, d, J = 6.0), 4.80 (1H, m), 6.45 (1H, dt, J = 16.0, 6.0), 6.57 (1H, d, J = 16.0), 7.24 (1H, m), 7.50 (1H, m), 7.54 (1H, m), 7.65-7.75 (3H, m), 7.90 (1H, m);
IR (KBr, cm ^-1 ): 1736, 1671, 1658.

（ｂ）Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−カルバモイルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［３−カルバモイル−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩（０．４４ｇ）をエタノール（２０ｍｌ）に溶解させ、氷冷下、エチルアセトイミデート塩酸塩（０．２７ｇ）及びトリエチルアミン（０．６０ｍｌ）を加え、室温で０．５時間撹拌した後、１４時間放置した。反応液を減圧下濃縮した後、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１５％アセトニトリル／水）で精製し、得られた無定形固体をエタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素酢酸エチル溶液（０．５０ｍｌ）を加えた後、これを減圧下濃縮乾固することにより、表記化合物０．３７ｇ（収率７８％）を無色無定形固体として得た。
¹H NMR (400MHz, DMSO-d₆) δppm : 1.24 (3H, t, J=7.0), 1.80-1.95 (2H, m), 2.00-2.15 (2H, m), 2.29 (3H, s), 3.45-3.65 (2H, m), 3.65-3.85 (2H, m), 4.20 (2H, q, J=7.0), 4.37 (2H, s), 4.47 (2H, d, J=6.0), 4.86 (1H, m), 6.44 (1H, dt, J=16.0, 6.0), 6.58 (1H, d, J=16.0), 7.28 (1H, m), 7.45-7.60 (2H, m), 7.70 (2H, m), 7.78 (1H, m),7.88 (1H, m);
IR (KBr, cm^-1) : 1737, 1672. (B) N- [4- (1-Acetimidoylpiperidin-4-yloxy) -3-carbamoylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl acetate ethyl Dihydrochloride N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-carbamoyl-4- (piperidin-4-yloxy) phenyl] sulfamoyl ethyl acetate dihydrochloride (0 .44 g) was dissolved in ethanol (20 ml), ethylacetimidate hydrochloride (0.27 g) and triethylamine (0.60 ml) were added under ice-cooling, and the mixture was stirred at room temperature for 0.5 hours and then allowed to stand for 14 hours. did. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 15% acetonitrile / water), and the resulting amorphous solid was dissolved in ethanol (10 ml), and 4M A hydrogen chloride ethyl acetate solution (0.50 ml) was added, and the mixture was concentrated to dryness under reduced pressure to obtain 0.37 g (yield 78%) of the title compound as a colorless amorphous solid.
¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.24 (3H, t, J = 7.0), 1.80-1.95 (2H, m), 2.00-2.15 (2H, m), 2.29 (3H, s), 3.45 -3.65 (2H, m), 3.65-3.85 (2H, m), 4.20 (2H, q, J = 7.0), 4.37 (2H, s), 4.47 (2H, d, J = 6.0), 4.86 (1H, m), 6.44 (1H, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.28 (1H, m), 7.45-7.60 (2H, m), 7.70 (2H, m), 7.78 (1H, m), 7.88 (1H, m);
IR (KBr, cm ^-1 ): 1737, 1672.

実施例３６
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−カルバモイルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸２塩酸塩（例示化合物番号：１９８９）
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−カルバモイルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩（０．２０ｇ）を１．５Ｍ塩酸（２０ｍｌ）に溶解させ、６０℃で６時間撹拌した。反応液を室温まで冷却させた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１５％アセトニトリル／水）で精製し、得られた無定形固体を１Ｍ塩酸（０．７５ｍｌ）に溶解させ、これを減圧下濃縮乾固することにより、表記化合物０．１４ｇ（収率７１％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.75-1.95 (2H, m), 2.00-2.15 (2H, m),
2.29 (3H, s), 3.45-3.65 (2H, m), 3.65-3.85 (2H, m), 4.24 (2H, s), 4.47 (2H, d, J=6.0), 4.85 (1H, m), 6.45 (1H, dt, J=16.0, 6.0), 6.57 (1H, d, J=16.0), 7.27 (1H, m), 7.45-7.60 (2H, m), 7.70 (2H, m), 7.77 (1H, m), 7.88 (1H, m);
IR (KBr, cm^-1) : 1729, 1672. Example 36
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-carbamoylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoylacetic acid dihydrochloride ( Exemplified compound number: 1989)
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-carbamoylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl acetate ethyl dihydrochloride (0.20 g) was dissolved in 1.5 M hydrochloric acid (20 ml) and stirred at 60 ° C. for 6 hours. The reaction solution was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 15% acetonitrile / water), and the resulting amorphous solid was treated with 1M hydrochloric acid ( 0.75 ml) and concentrated to dryness under reduced pressure to obtain 0.14 g (yield 71%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.75-1.95 (2H, m), 2.00-2.15 (2H, m),
2.29 (3H, s), 3.45-3.65 (2H, m), 3.65-3.85 (2H, m), 4.24 (2H, s), 4.47 (2H, d, J = 6.0), 4.85 (1H, m), 6.45 (1H, dt, J = 16.0, 6.0), 6.57 (1H, d, J = 16.0), 7.27 (1H, m), 7.45-7.60 (2H, m), 7.70 (2H, m), 7.77 (1H , m), 7.88 (1H, m);
IR (KBr, cm ^-1 ): 1729, 1672.

実施例３７
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−（Ｎ’−メチルカルバモイル）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩
（例示化合物番号：１４６２） Example 37
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3- (N′-methylcarbamoyl) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] Sulfamoyl ethyl acetate dihydrochloride (Exemplary Compound No .: 1462)

（ａ）Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［３−（Ｎ’−メチルカルバモイル）−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−（Ｎ’−メチルカルバモイル）フェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル（１．５０ｇ）をジクロロメタン（２０ｍｌ）及びエタノール（２０ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１．５時間通じた後、密栓をして室温で３．５時間撹拌した。反応液を減圧下濃縮し、残渣をエタノール（２０ｍｌ）に溶解させた後、塩化アンモニウム水溶液（０．２９ｇを水５ｍｌに溶解）及び２８％アンモニア水（０．６６ｍｌ）を加え、室温で２時間撹拌した後、１５時間放置した。反応液を減圧下濃縮した後、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１５％アセトニトリル／水）で精製し、得られた無定形固体をエタノール（２０ｍｌ）に溶解させ、４Ｍ塩化水素酢酸エチル溶液（１．５５ｍｌ）を加えた後、これを減圧下濃縮乾固することにより、表記化合物１．１４ｇ（収率７３％）を無色無定形固体として得た。
¹H NMR (400MHz, DMSO-d₆) δppm : 1.23 (3H, t, J=7.0), 1.85-1.95 (2H, m), 2.05-2.15 (2H, m), 2.79 (3H, m), 2.95-3.10 (2H, m), 3.10-3.25 (2H, m), 4.20 (2H, q, J=7.0), 4.38 (2H, s), 4.47 (2H, d, J=6.0), 4.79 (1H, m), 6.45 (1H, dt, J=16.0, 6.0), 6.58 (1H, d, J=16.0), 7.24 (1H, m), 7.48 (1H, m), 7.54 (1H, m), 7.62 (1H, m), 7.12 (2H, m), 7.92 (1H, m);
IR (KBr, cm^-1) : 1737, 1676, 1641. (A) N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3- (N′-methylcarbamoyl) -4- (piperidin-4-yloxy) phenyl] sulfamoyl acetic acid Ethyl dihydrochloride N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3- (N′-methylcarbamoyl) phenyl] -N- [3- (3-cyanophenyl) -2- ( E) -propenyl] sulfamoyl ethyl acetate (1.50 g) was dissolved in a mixed solvent of dichloromethane (20 ml) and ethanol (20 ml), hydrogen chloride was passed through for 1.5 hours under ice-cooling, and the bottle was sealed and sealed at room temperature. For 3.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethanol (20 ml). Aqueous ammonium chloride (0.29 g dissolved in 5 ml of water) and 28% aqueous ammonia (0.66 ml) were added, and the mixture was stirred at room temperature for 2 hours. After stirring, it was left for 15 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 15% acetonitrile / water), and the obtained amorphous solid was dissolved in ethanol (20 ml), and 4M A hydrogen chloride ethyl acetate solution (1.55 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 1.14 g (yield 73%) of the title compound as a colorless amorphous solid.
¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.0), 1.85-1.95 (2H, m), 2.05-2.15 (2H, m), 2.79 (3H, m), 2.95 -3.10 (2H, m), 3.10-3.25 (2H, m), 4.20 (2H, q, J = 7.0), 4.38 (2H, s), 4.47 (2H, d, J = 6.0), 4.79 (1H, m), 6.45 (1H, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.24 (1H, m), 7.48 (1H, m), 7.54 (1H, m), 7.62 ( 1H, m), 7.12 (2H, m), 7.92 (1H, m);
IR (KBr, cm ^-1 ): 1737, 1676, 1641.

（ｂ）Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−（Ｎ’−メチルカルバモイル）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［３−（Ｎ’−メチルカルバモイル）−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩（１．００ｇ）をエタノール（３０ｍｌ）に溶解させ、氷冷下、エチルアセトイミデート塩酸塩（０．６０ｇ）及びトリエチルアミン（１．３５ｍｌ）を加え、室温で８時間撹拌した。反応液を減圧下濃縮した後、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１５％アセトニトリル／水）で精製し、得られた無定形固体をエタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素酢酸エチル溶液（１．００ｍｌ）を加えた後、これを減圧下濃縮乾固することにより、表記化合物０．７９ｇ（収率７４％）を無色無定形固体として得た。
¹H NMR (400MHz, DMSO-d₆) δppm : 1.23 (3H, t, J=7.0), 1.75-1.90 (2H, m), 1.95-2.10 (2H, m), 2.30 (3H, s), 2.78 (3H, s), 3.50-3.80 (4H, m), 4.20 (2H, q, J=7.0), 4.37 (2H, s), 4.47 (2H, d, J=6.0), 4.84 (1H, m), 6.44 (1H, dt, J=16.0, 6.0), 6.58 (1H, d, J=16.0), 7.27 (1H, m), 7.50 (1H, m),
7.55 (1H, m), 7.65-7.75 (3H, m), 7.90 (1H, m);
IR (KBr, cm^-1) : 1738, 1673, 1633. (B) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3- (N′-methylcarbamoyl) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -Propenyl] sulfamoyl ethyl acetate dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3- (N'-methylcarbamoyl) -4- (piperidine-4- [Iloxy) phenyl] sulfamoylacetic acid ethyl dihydrochloride (1.00 g) was dissolved in ethanol (30 ml), and under ice cooling, ethylacetimidate hydrochloride (0.60 g) and triethylamine (1.35 ml) were added. For 8 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 15% acetonitrile / water), and the resulting amorphous solid was dissolved in ethanol (10 ml), and 4M After adding a hydrogen chloride ethyl acetate solution (1.00 ml), this was concentrated to dryness under reduced pressure to obtain 0.79 g (yield 74%) of the title compound as a colorless amorphous solid.
¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.0), 1.75-1.90 (2H, m), 1.95-2.10 (2H, m), 2.30 (3H, s), 2.78 (3H, s), 3.50-3.80 (4H, m), 4.20 (2H, q, J = 7.0), 4.37 (2H, s), 4.47 (2H, d, J = 6.0), 4.84 (1H, m) , 6.44 (1H, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.27 (1H, m), 7.50 (1H, m),
7.55 (1H, m), 7.65-7.75 (3H, m), 7.90 (1H, m);
IR (KBr, cm ^-1 ): 1738, 1673, 1633.

実施例３８
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−（Ｎ’−メチルカルバモイル）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸２塩酸塩
（例示化合物番号：１９９１）
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−（Ｎ’−メチルカルバモイル）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩（０．５３ｇ）を１．５Ｍ塩酸（３０ｍｌ）に溶解させ、６０℃で８時間撹拌した。反応液を室温まで冷却させた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１５％アセトニトリル／水）で精製し、得られた無定形固体を１Ｍ塩酸（２．２０ｍｌ）に溶解させ、これを減圧下濃縮乾固することにより、表記化合物０．４２ｇ（収率８２％）を無色無定形固体として得た。
¹H NMR (400MHz, DMSO-d₆) δppm : 1.75-1.90 (2H, m), 1.95-2.10 (2H, m),
2.30 (3H, s), 2.78 (3H, s), 3.50-3.85 (4H, m), 4.25 (2H, s), 4.47 (2H, d, J=6.0), 4.84 (1H, m), 6.45 (1H, dt, J=16.0, 6.0), 6.57 (1H, d, J=16.0), 7.27 (1H, m), 7.45-7.60 (2H, m), 7.65-7.75 (3H, m), 7.90 (1H, m);
IR (KBr, cm^-1) : 1732, 1673, 1628. Example 38
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3- (N′-methylcarbamoyl) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] Sulfamoyl acetic acid dihydrochloride (Exemplified compound number: 1991)
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3- (N′-methylcarbamoyl) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] Sulfamoyl ethyl acetate dihydrochloride (0.53 g) was dissolved in 1.5 M hydrochloric acid (30 ml) and stirred at 60 ° C. for 8 hours. The reaction solution was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 15% acetonitrile / water), and the resulting amorphous solid was treated with 1M hydrochloric acid ( 2.20 ml), and this was concentrated to dryness under reduced pressure to obtain 0.42 g (yield 82%) of the title compound as a colorless amorphous solid.
¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.75-1.90 (2H, m), 1.95-2.10 (2H, m),
2.30 (3H, s), 2.78 (3H, s), 3.50-3.85 (4H, m), 4.25 (2H, s), 4.47 (2H, d, J = 6.0), 4.84 (1H, m), 6.45 ( 1H, dt, J = 16.0, 6.0), 6.57 (1H, d, J = 16.0), 7.27 (1H, m), 7.45-7.60 (2H, m), 7.65-7.75 (3H, m), 7.90 (1H , m);
IR (KBr, cm ^-1 ): 1732, 1673, 1628.

実施例３９
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−（Ｎ’，Ｎ’−ジメチルカルバモイル）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩
（例示化合物番号：１４６６） Example 39
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3- (N ′, N′-dimethylcarbamoyl) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -Propenyl] ethyl sulfamoyl acetate dihydrochloride (Exemplified Compound No. 1466)

（ａ）Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［３−（Ｎ’，Ｎ’−ジメチルカルバモイル）−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−（Ｎ’，Ｎ’−ジメチルカルバモイル）フェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル（１．７０ｇ）をジクロロメタン（２０ｍｌ）及びエタノール（２０ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１．５時間通じた後、密栓をして室温で３．５時間撹拌した。反応液を減圧下濃縮し、残渣をエタノール（２０ｍｌ）に溶解させ、塩化アンモニウム水溶液（０．３０ｇを水５ｍｌに溶解）及び２８％アンモニア水（０．７０ｍｌ）を加え、室温で５時間撹拌した後、１３時間放置した。反応液を減圧下濃縮した後、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１５％アセトニトリル／水）で精製し、得られた無定形固体をエタノール（２０ｍｌ）に溶解させ、４Ｍ塩化水素酢酸エチル溶液（１．００ｍｌ）を加えた後、これを減圧下濃縮乾固することにより、表記化合物０．７５ｇ（収率４４％）を無色無定形固体として得た。
¹H NMR (400MHz, DMSO-d₆) δppm : 1.22 (3H, t, J=7.0), 1.75-1.95 (2H, m), 1.95-2.15 (2H, m), 2.69 (3H, s), 2.97 (3H, s), 2.95-3.15 (4H, m), 4.19 (2H, q, J=7.0), 4.38 (2H, s), 4.35-4.55 (2H, m), 4.75 (1H, m), 6.43 (1H, dt, J=16.0, 6.0), 6.55 (1H, d, J=16.0), 7.22 (1H, d, J=9.0), 7.30 (1H, d, J=3.0), 7.45 (1H, dd, J=9.0, 3.0), 7.54 (1H, t, J=8.0), 7.70 (2H, d, J=8.0), 7.88 (1H, s);
IR (KBr, cm^-1) : 1738, 1676, 1618. (A) N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3- (N ′, N′-dimethylcarbamoyl) -4- (piperidin-4-yloxy) phenyl Ethyl sulfamoyl acetate dihydrochloride N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3- (N ′, N′-dimethylcarbamoyl) phenyl] -N- [3- (3-cyano Phenyl) -2- (E) -propenyl] sulfamoyl acetate (1.70 g) was dissolved in a mixed solvent of dichloromethane (20 ml) and ethanol (20 ml), and hydrogen chloride was passed for 1.5 hours under ice cooling. The bottle was sealed and stirred at room temperature for 3.5 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), aqueous ammonium chloride solution (0.30 g dissolved in 5 ml of water) and 28% aqueous ammonia (0.70 ml) were added, and the mixture was stirred at room temperature for 5 hours. Then, it was left for 13 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 15% acetonitrile / water), and the obtained amorphous solid was dissolved in ethanol (20 ml), and 4M A hydrogen chloride ethyl acetate solution (1.00 ml) was added, and the mixture was concentrated to dryness under reduced pressure to obtain 0.75 g (yield 44%) of the title compound as a colorless amorphous solid.
¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.22 (3H, t, J = 7.0), 1.75-1.95 (2H, m), 1.95-2.15 (2H, m), 2.69 (3H, s), 2.97 (3H, s), 2.95-3.15 (4H, m), 4.19 (2H, q, J = 7.0), 4.38 (2H, s), 4.35-4.55 (2H, m), 4.75 (1H, m), 6.43 (1H, dt, J = 16.0, 6.0), 6.55 (1H, d, J = 16.0), 7.22 (1H, d, J = 9.0), 7.30 (1H, d, J = 3.0), 7.45 (1H, dd , J = 9.0, 3.0), 7.54 (1H, t, J = 8.0), 7.70 (2H, d, J = 8.0), 7.88 (1H, s);
IR (KBr, cm ^-1 ): 1738, 1676, 1618.

（ｂ）Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−（Ｎ’，Ｎ’−ジメチルカルバモイル）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［３−（Ｎ’，Ｎ’−ジメチルカルバモイル）−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩（０．６０ｇ）をエタノール（２０ｍｌ）に溶解させ、氷冷下、エチルアセトイミデート塩酸塩（０．３５ｇ）及びトリエチルアミン（０．８０ｍｌ）を加え、室温で０．５時間撹拌した後、１２時間放置した。反応液を減圧下濃縮した後、残渣を分取ＨＰＬＣ（YMC-Pack
ODS YMC、溶出溶媒：２０％アセトニトリル／水）で精製し、得られた無定形固体をエタノール（２０ｍｌ）に溶解させ、４Ｍ塩化水素酢酸エチル溶液（０．６０ｍｌ）を加えた後、これを減圧下濃縮乾固することにより、表記化合物０．４７ｇ（収率７３％）を無色無定形固体として得た。
¹H NMR (400MHz, DMSO-d₆) δppm : 1.22 (3H, t, J=7.0), 1.60-1.85 (2H, m), 1.85-2.10 (2H, m), 2.29 (3H, s), 2.69 (3H, s), 2.95 (3H, s), 3.50-3.70 (4H, m), 4.19 (2H, q, J=7.0), 4.35-4.55 (2H, m), 4.39 (2H, s), 4.79 (1H, m), 6.44 (1H, dt, J=16.0, 6.0), 6.55 (1H, d, J=16.0), 7.25 (1H, d, J=9.0), 7.29 (1H, d, J=3.0), 7.45 (1H, dd, J=9.0, 3.0), 7.54 (1H, m), 7.65-7.75 (2H, m), 7.90 (1H, s);
IR (KBr, cm^-1) : 1738, 1673, 1618. (B) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3- (N ′, N′-dimethylcarbamoyl) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl acetate ethyl dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3- (N ′, N′-dimethylcarbamoyl) -4 -(Piperidin-4-yloxy) phenyl] sulfamoyl ethyl acetate dihydrochloride (0.60 g) was dissolved in ethanol (20 ml), and ethylacetimidate hydrochloride (0.35 g) and triethylamine (0. 80 ml) was added, and the mixture was stirred at room temperature for 0.5 hour and then allowed to stand for 12 hours. After the reaction solution was concentrated under reduced pressure, the residue was subjected to preparative HPLC (YMC-Pack
ODS YMC, elution solvent: 20% acetonitrile / water) The resulting amorphous solid was dissolved in ethanol (20 ml), 4M hydrogen chloride ethyl acetate solution (0.60 ml) was added, Concentration and solidification under reduced pressure afforded 0.47 g (yield 73%) of the title compound as a colorless amorphous solid.
¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.22 (3H, t, J = 7.0), 1.60-1.85 (2H, m), 1.85-2.10 (2H, m), 2.29 (3H, s), 2.69 (3H, s), 2.95 (3H, s), 3.50-3.70 (4H, m), 4.19 (2H, q, J = 7.0), 4.35-4.55 (2H, m), 4.39 (2H, s), 4.79 (1H, m), 6.44 (1H, dt, J = 16.0, 6.0), 6.55 (1H, d, J = 16.0), 7.25 (1H, d, J = 9.0), 7.29 (1H, d, J = 3.0 ), 7.45 (1H, dd, J = 9.0, 3.0), 7.54 (1H, m), 7.65-7.75 (2H, m), 7.90 (1H, s);
IR (KBr, cm ^-1 ): 1738, 1673, 1618.

実施例４０
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−（Ｎ’，Ｎ’−ジメチルカルバモイル）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸２塩酸塩
（例示化合物番号：１９９５）
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−（Ｎ’，Ｎ’−ジメチルカルバモイル）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩（０．３０ｇ）を１．５Ｍ塩酸（１０ｍｌ）に溶解させ、６０℃で９．５時間撹拌した。反応液を室温まで冷却させた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack
ODS YMC、溶出溶媒：１０％アセトニトリル／水）で精製し、得られた無定形固体を１Ｍ塩酸（１．２０ｍｌ）に溶解させ、これを減圧下濃縮乾固することにより、表記化合物０．２４ｇ（収率８３％）を無色無定形固体として得た。
¹H NMR (400MHz, DMSO-d₆) δppm : 1.65-1.85 (2H, m), 1.90-2.10 (2H, m),
2.28 (3H, s), 2.69 (3H, s), 2.95 (3H, s), 3.50-3.70 (4H, m), 4.25 (2H, s), 4.35-4.55 (2H, m), 4.78 (1H, m), 6.43 (1H, dt, J=16.0, 6.0), 6.55 (1H, d, J=16.0), 7.24 (1H, d, J=9.0), 7.29 (1H, d, J=3.0), 7.46 (1H, dd, J=9.0, 3.0), 7.54 (1H, m), 7.65-7.75 (2H, m), 7.88 (1H, s);
IR (KBr, cm^-1) : 1733, 1672, 1614. Example 40
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3- (N ′, N′-dimethylcarbamoyl) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -Propenyl] sulfamoyl acetic acid dihydrochloride (Exemplary Compound Number: 1995)
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3- (N ′, N′-dimethylcarbamoyl) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -Propenyl] sulfamoyl ethyl acetate dihydrochloride (0.30 g) was dissolved in 1.5 M hydrochloric acid (10 ml) and stirred at 60 ° C. for 9.5 hours. The reaction solution was allowed to cool to room temperature and then concentrated under reduced pressure, and the residue was subjected to preparative HPLC (YMC-Pack
ODS YMC, elution solvent: 10% acetonitrile / water) The obtained amorphous solid was dissolved in 1M hydrochloric acid (1.20 ml), and this was concentrated to dryness under reduced pressure to give 0.24 g of the title compound. (Yield 83%) was obtained as a colorless amorphous solid.
¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.65-1.85 (2H, m), 1.90-2.10 (2H, m),
2.28 (3H, s), 2.69 (3H, s), 2.95 (3H, s), 3.50-3.70 (4H, m), 4.25 (2H, s), 4.35-4.55 (2H, m), 4.78 (1H, m), 6.43 (1H, dt, J = 16.0, 6.0), 6.55 (1H, d, J = 16.0), 7.24 (1H, d, J = 9.0), 7.29 (1H, d, J = 3.0), 7.46 (1H, dd, J = 9.0, 3.0), 7.54 (1H, m), 7.65-7.75 (2H, m), 7.88 (1H, s);
IR (KBr, cm ^-1 ): 1733, 1672, 1614.

実施例４１
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−クロロフェニル］−Ｎ−［３−（５−アミジノ−２−ヒドロキシフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩
（例示化合物番号：１８４３） Example 41
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-chlorophenyl] -N- [3- (5-amidino-2-hydroxyphenyl) -2- (E) -propenyl] sulfamoyl acetate ethyl Dihydrochloride (Exemplary Compound Number: 1843)

（ａ）Ｎ−［３−（５−アミジノ−２−ヒドロキシフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［３−クロロ−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−クロロフェニル］−Ｎ−［３−（５−シアノ−２−メトキシメトキシフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル（１．４ｇ）をジクロロメタン（２０ｍｌ）及びエタノール（２０ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１．５時間通じた後、密栓をして室温で２時間撹拌した。反応液を減圧下濃縮した後、残渣をエタノール（４０ｍｌ）に溶解させ、塩化アンモニウム水溶液（０．２ｇを水１０ｍｌに溶解）及び２８％アンモニア水（０．５ｍｌ）を加え、室温で０．５時間撹拌した後、１２時間放置した。反応液を減圧下濃縮した後、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１５％アセトニトリル／水）で精製し、これを減圧下濃縮乾固することにより、表記化合物０．１ｇ（収率４％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.23 (3H, t, J=7.0), 1.85-1.95 (2H, m), 2.05-2.15 (2H, m), 3.05-3.15 (2H, m), 3.15-3.25 (2H, m), 4.19 (2H, q,
J=7.0), 4.40 (2H, s), 4.45 (2H, d, J=6.0), 4.78 (1H, m), 6.38 (1H, dt, J=16.0, 6.0), 6.66 (1H, d, J=16.0), 7.04 (1H, d, J=9.0), 7.31 (1H, d, J=9.0), 7.38 (1H, dd, J=9.0, 3.0), 7.56 (1H, d, J=3.0), 7.62 (1H, dd, J=9.0, 2.0), 7.94 (1H, d, J=2.0). (A) N- [3- (5-amidino-2-hydroxyphenyl) -2- (E) -propenyl] -N- [3-chloro-4- (piperidin-4-yloxy) phenyl] sulfamoyl acetate ethyl N -[4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3-chlorophenyl] -N- [3- (5-cyano-2-methoxymethoxyphenyl) -2- (E) -propenyl] sulfamoylacetic acid Ethyl (1.4 g) was dissolved in a mixed solvent of dichloromethane (20 ml) and ethanol (20 ml), and hydrogen chloride was passed through for 1.5 hours under ice-cooling, then sealed and stirred at room temperature for 2 hours. After concentrating the reaction solution under reduced pressure, the residue was dissolved in ethanol (40 ml), aqueous ammonium chloride solution (0.2 g dissolved in 10 ml water) and 28% aqueous ammonia (0.5 ml) were added, and 0.5% at room temperature was added. After stirring for an hour, it was left for 12 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 15% acetonitrile / water), and this was concentrated to dryness under reduced pressure to give 0.1 g of the title compound. (Yield 4%) was obtained as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.0), 1.85-1.95 (2H, m), 2.05-2.15 (2H, m), 3.05-3.15 (2H, m) , 3.15-3.25 (2H, m), 4.19 (2H, q,
J = 7.0), 4.40 (2H, s), 4.45 (2H, d, J = 6.0), 4.78 (1H, m), 6.38 (1H, dt, J = 16.0, 6.0), 6.66 (1H, d, J = 16.0), 7.04 (1H, d, J = 9.0), 7.31 (1H, d, J = 9.0), 7.38 (1H, dd, J = 9.0, 3.0), 7.56 (1H, d, J = 3.0), 7.62 (1H, dd, J = 9.0, 2.0), 7.94 (1H, d, J = 2.0).

（ｂ）Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−クロロフェニル］−Ｎ−［３−（５−アミジノ−２−ヒドロキシフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［３−（５−アミジノ−２−ヒドロキシフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［３−クロロ−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル（０．０５ｇ）をエタノール（１０ｍｌ）に溶解させ、氷冷下、エチルアセトイミデート塩酸塩（０．０４ｇ）及びトリエチルアミン（０．０８ｍｌ）を加え、室温で５時間撹拌した後、１３時間放置した。反応液を減圧下濃縮した後、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２０％アセトニトリル／水）で精製し、得られた無定形固体をエタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素酢酸エチル溶液（０，０５ｍｌ）を加えた後、これを減圧下濃縮乾固することにより、表記化合物０．０４ｇ（収率５９％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.23 (3H, t, J=7.0), 1.70-1.85 (2H, m), 2.00-2.15 (2H, m), 2.30 (3H, s), 3.50-3.80 (4H, m), 4.19 (2H, q, J=7.0), 4.41 (2H, s), 4.45 (2H, d, J=6.0), 4.84 (1H, m), 6.39 (1H, dt, J=16.0, 6.0), 6.65 (1H, d, J=16.0), 7.08 (1H, d, J=9.0), 7.33 (1H, d, J=9.0),
7.38 (1H, dd, J=9.0, 2.0), 7.56 (1H, d, J=2.0), 7.63 (1H, dd, J=9.0, 2.0), 7.95 (1H, d, J=2.0);
IR (KBr, cm^-1) : 1738, 1671. (B) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-chlorophenyl] -N- [3- (5-amidino-2-hydroxyphenyl) -2- (E) -propenyl] Ethyl sulfamoyl acetate dihydrochloride N- [3- (5-amidino-2-hydroxyphenyl) -2- (E) -propenyl] -N- [3-chloro-4- (piperidin-4-yloxy) phenyl] sulfamoyl Ethyl acetate (0.05 g) was dissolved in ethanol (10 ml), ethylacetimidate hydrochloride (0.04 g) and triethylamine (0.08 ml) were added under ice cooling, and the mixture was stirred at room temperature for 5 hours. Left for hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water), and the obtained amorphous solid was dissolved in ethanol (10 ml), and 4M A hydrogen chloride ethyl acetate solution (0.05 ml) was added, and the mixture was concentrated to dryness under reduced pressure to obtain 0.04 g (yield 59%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.0), 1.70-1.85 (2H, m), 2.00-2.15 (2H, m), 2.30 (3H, s), 3.50 -3.80 (4H, m), 4.19 (2H, q, J = 7.0), 4.41 (2H, s), 4.45 (2H, d, J = 6.0), 4.84 (1H, m), 6.39 (1H, dt, J = 16.0, 6.0), 6.65 (1H, d, J = 16.0), 7.08 (1H, d, J = 9.0), 7.33 (1H, d, J = 9.0),
7.38 (1H, dd, J = 9.0, 2.0), 7.56 (1H, d, J = 2.0), 7.63 (1H, dd, J = 9.0, 2.0), 7.95 (1H, d, J = 2.0);
IR (KBr, cm ^-1 ): 1738, 1671.

実施例４２
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−５−カルバモイル−３−クロロフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩
（例示化合物番号：１４８４） Example 42
N- [4- (1-Acetimidylpiperidin-4-yloxy) -5-carbamoyl-3-chlorophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl acetate ethyl Dihydrochloride (Exemplary Compound Number: 1484)

（ａ）Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［５−カルバモイル−３−クロロ−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−５−カルバモイル−３−クロロフェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル（１．５０ｇ）をジクロロメタン（２０ｍｌ）及びエタノール（２０ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１．５時間通じた後、密栓をして室温で４時間撹拌した。反応液を減圧下濃縮した後、残渣をエタノール（２０ｍｌ）に溶解させ、塩化アンモニウム水溶液（０．２６ｇを水５ｍｌに溶解）及び２８％アンモニア水（０．６０ｍｌ）を加え、室温で４時間撹拌した後、１２時間放置した。反応液を減圧下濃縮した後、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２０％アセトニトリル／水）で精製し、得られた無定形固体を１Ｍ塩酸に溶解させ、これを減圧下濃縮乾固することにより、表記化合物０．５５ｇ（収率３７％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.23 (3H, t, J=7.0), 1.90-2.00 (2H, m), 2.00-2.10 (2H, m), 2.95-3.05 (2H, m), 3.20-3.30 (2H, m), 4.19 (2H, q,
J=7.0), 4.35 (1H, m), 4.48 (2H, s), 4.51 (2H, d, J=6.0), 6.44 (1H, dt, J=16.0, 6.0), 6.62 (1H, d, J=16.0), 7.50-7.60 (2H, m), 7.65-7.80 (3H, m), 7.88 (1H, m);
IR (KBr, cm^-1) : 1737, 1672. (A) N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [5-carbamoyl-3-chloro-4- (piperidin-4-yloxy) phenyl] sulfamoyl acetate ethyl 2 Hydrochloride N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-carbamoyl-3-chlorophenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] Ethyl sulfamoyl acetate (1.50 g) was dissolved in a mixed solvent of dichloromethane (20 ml) and ethanol (20 ml), and hydrogen chloride was passed through for 1.5 hours under ice-cooling, then sealed and stirred at room temperature for 4 hours. . The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethanol (20 ml). Aqueous ammonium chloride (0.26 g dissolved in 5 ml of water) and 28% aqueous ammonia (0.60 ml) were added, and the mixture was stirred at room temperature for 4 hours. And left for 12 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water), and the resulting amorphous solid was dissolved in 1M hydrochloric acid, and this was reduced in pressure. By concentrating to dryness, 0.55 g (yield 37%) of the title compound was obtained as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.0), 1.90-2.00 (2H, m), 2.00-2.10 (2H, m), 2.95-3.05 (2H, m) , 3.20-3.30 (2H, m), 4.19 (2H, q,
J = 7.0), 4.35 (1H, m), 4.48 (2H, s), 4.51 (2H, d, J = 6.0), 6.44 (1H, dt, J = 16.0, 6.0), 6.62 (1H, d, J = 16.0), 7.50-7.60 (2H, m), 7.65-7.80 (3H, m), 7.88 (1H, m);
IR (KBr, cm ^-1 ): 1737, 1672.

（ｂ）Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−５−カルバモイル−３−クロロフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［５−カルバモイル−３−クロロ−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩（０．５１ｇ）をエタノール（２５ｍｌ）に溶解させ、氷冷下、エチルアセトイミデート塩酸塩（０．３０ｇ）及びトリエチルアミン（０．７０ｍｌ）を加え、室温で１時間撹拌した後、１２時間放置した。反応液を減圧下濃縮した後、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２０％アセトニトリル／水）で精製し、得られた無定形固体をエタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素酢酸エチル溶液（０．５０ｍｌ）を加えた後、これを減圧下濃縮乾固することにより、表記化合物０．３６ｇ（収率６６％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.23 (3H, t, J=7.0), 1.75-1.90 (2H, m), 1.90-2.05 (2H, m), 2.29 (3H, s), 3.40-3.55 (2H, m), 3.75-3.90 (2H, m), 4.20 (2H, q, J=7.0), 4.42 (1H, m), 4.48 (2H, s), 4.52 (2H, d, J=6.0), 6.44 (1H, dt, J=16.0, 6.0), 6.62 (1H, d, J=16.0), 7.50-7.60 (2H, m), 7.65-7.80 (3H, m), 7.89 (1H, m);
IR (KBr, cm^-1) : 1738, 1671, 1622. (B) N- [4- (1-acetimidoylpiperidin-4-yloxy) -5-carbamoyl-3-chlorophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] Sulfamoyl ethyl acetate dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [5-carbamoyl-3-chloro-4- (piperidin-4-yloxy) phenyl] sulfamoyl Ethyl acetate dihydrochloride (0.51 g) was dissolved in ethanol (25 ml), ethylacetimidate hydrochloride (0.30 g) and triethylamine (0.70 ml) were added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Then, it was left for 12 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water), and the resulting amorphous solid was dissolved in ethanol (10 ml), and 4M A hydrogen chloride ethyl acetate solution (0.50 ml) was added, and the mixture was concentrated to dryness under reduced pressure to obtain 0.36 g (yield 66%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.0), 1.75-1.90 (2H, m), 1.90-2.05 (2H, m), 2.29 (3H, s), 3.40 -3.55 (2H, m), 3.75-3.90 (2H, m), 4.20 (2H, q, J = 7.0), 4.42 (1H, m), 4.48 (2H, s), 4.52 (2H, d, J = 6.0), 6.44 (1H, dt, J = 16.0, 6.0), 6.62 (1H, d, J = 16.0), 7.50-7.60 (2H, m), 7.65-7.80 (3H, m), 7.89 (1H, m );
IR (KBr, cm ^-1 ): 1738, 1671, 1622.

実施例４３
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−５−カルバモイル−３−クロロフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸２塩酸塩
（例示化合物番号：２０１３）
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−５−カルバモイル−３−クロロフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩（０．２０ｇ）を３Ｍ塩酸（２０ｍｌ）に溶解させ、７０℃で１．５時間撹拌した。反応液を室温まで冷却させた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１５％アセトニトリル／水）で精製し、得られた無定形固体を１Ｍ塩酸（０．８０ｍｌ）に溶解させ、これを減圧下濃縮乾固することにより、表記化合物０．１６ｇ（収率８３％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.75-1.90 (2H, m), 1.90-2.05 (2H, m),
2.28 (3H, s), 3.40-3.55 (2H, m), 3.75-3.90 (2H, m), 4.35 (2H, s), 4.42 (1H, m), 4.51 (2H, d, J=6.0), 6.44 (1H, dt, J=16.0, 6.0), 6.61 (1H, d, J=16.0), 7.50-7.60 (2H, m), 7.65-7.80 (3H, m), 7.87 (1H, m);
IR (KBr, cm^-1) : 1730, 1671, 1628. Example 43
N- [4- (1-acetimidoylpiperidin-4-yloxy) -5-carbamoyl-3-chlorophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoylacetic acid 2 Hydrochloride (Exemplary Compound Number: 2013)
N- [4- (1-Acetimidoylpiperidin-4-yloxy) -5-carbamoyl-3-chlorophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl acetate ethyl Dihydrochloride (0.20 g) was dissolved in 3M hydrochloric acid (20 ml) and stirred at 70 ° C. for 1.5 hours. The reaction solution was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 15% acetonitrile / water), and the resulting amorphous solid was treated with 1M hydrochloric acid ( This was dissolved in 0.80 ml and concentrated to dryness under reduced pressure to obtain 0.16 g (yield 83%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.75-1.90 (2H, m), 1.90-2.05 (2H, m),
2.28 (3H, s), 3.40-3.55 (2H, m), 3.75-3.90 (2H, m), 4.35 (2H, s), 4.42 (1H, m), 4.51 (2H, d, J = 6.0), 6.44 (1H, dt, J = 16.0, 6.0), 6.61 (1H, d, J = 16.0), 7.50-7.60 (2H, m), 7.65-7.80 (3H, m), 7.87 (1H, m);
IR (KBr, cm ^-1 ): 1730, 1671, 1628.

実施例４４
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−カルバモイル−５−メチルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩
（例示化合物番号：１４９８） Example 44
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-carbamoyl-5-methylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl acetic acid Ethyl dihydrochloride (Exemplified compound number: 1498)

（ａ）Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［３−カルバモイル−５−メチル−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−カルバモイル−５−メチルフェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル（３．２０ｇ）をジクロロメタン（３０ｍｌ）及びエタノール（３０ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１．５時間通じた後、密栓をして室温で２．５時間撹拌した。反応液を減圧下濃縮した後、残渣をエタノール（３０ｍｌ）に溶解させ、塩化アンモニウム水溶液（０．５９ｇを水８ｍｌに溶解）及び２８％アンモニア水（１．３４ｍｌ）を加え、室温で０．５時間撹拌した後、１５時間放置した。反応液を減圧下濃縮した後、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２０％アセトニトリル／水）で精製し、得られた無定形固体をエタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（３．００ｍｌ）を加えた後、これを減圧下濃縮乾固することにより、表記化合物２．８５ｇ（収率９０％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.23 (3H, t, J=7.0), 1.85-1.95 (2H, m), 1.95-2.05 (2H, m), 2.26 (3H, s), 2.90-3.00 (2H, m), 3.20-3.30 (2H, m), 4.15-4.20 (1H, m), 4.20 (2H, q, J=7.0), 4.39 (2H, s), 4.47 (2H, d, J=6.0), 6.43 (1H, dt, J=16.0, 6.0), 6.60 (1H, d, J=16.0), 7.54 (2H, m), 7.57 (1H, m), 7.68 (1H, m), 7,73 (1H, m), 7.87 (1H, m);
IR (KBr, cm^-1) : 1737, 1672. (A) N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3-carbamoyl-5-methyl-4- (piperidin-4-yloxy) phenyl] sulfamoyl acetate ethyl 2 Hydrochloride N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carbamoyl-5-methylphenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl Ethyl sulfamoyl acetate (3.20 g) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (30 ml), and hydrogen chloride was passed through for 1.5 hours under ice-cooling. Stir for hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (30 ml), an aqueous ammonium chloride solution (0.59 g dissolved in 8 ml of water) and 28% aqueous ammonia (1.34 ml) were added, and 0.5% at room temperature was added. After stirring for an hour, it was left for 15 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water), and the resulting amorphous solid was dissolved in ethanol (10 ml), and 4M A hydrogen chloride dioxane solution (3.00 ml) was added, and the mixture was concentrated to dryness under reduced pressure to obtain 2.85 g (yield 90%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.0), 1.85-1.95 (2H, m), 1.95-2.05 (2H, m), 2.26 (3H, s), 2.90 -3.00 (2H, m), 3.20-3.30 (2H, m), 4.15-4.20 (1H, m), 4.20 (2H, q, J = 7.0), 4.39 (2H, s), 4.47 (2H, d, J = 6.0), 6.43 (1H, dt, J = 16.0, 6.0), 6.60 (1H, d, J = 16.0), 7.54 (2H, m), 7.57 (1H, m), 7.68 (1H, m), 7,73 (1H, m), 7.87 (1H, m);
IR (KBr, cm ^-1 ): 1737, 1672.

（ｂ）Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−カルバモイル−５−メチルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［３−カルバモイル−５−メチル−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩（２．６８ｇ）をエタノール（４０ｍｌ）に溶解させ、氷冷下、エチルアセトイミデート塩酸塩（１．５８ｇ）及びトリエチルアミン（３．５５ｍｌ）を加え、室温で１時間撹拌した後、１３時間放置した。反応液を減圧下濃縮した後、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２０％アセトニトリル／水）で精製し、得られた無定形固体をエタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．４４ｍｌ）を加えた後、これを減圧下濃縮乾固することにより、表記化合物０．３８ｇ（収率１３％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.23 (3H, t, J=7.0), 1.70-1.90 (2H, m), 1.90-2.00 (2H, m), 2.27 (3H, s), 2.29 (3H, s), 3.35-3.45 (2H, m), 3.75-3.95 (2H, m), 4.20 (2H, q, J=7.0), 4.25 (1H, m), 4.40 (2H, s), 4.48 (2H, d, J=6.0), 6.43 (1H, dt, J=16.0, 6.0), 6.60 (1H, d, J=16.0), 7.43 (2H, m), 7.55 (1H, m), 7.69 (1H, m), 7.73 (1H, m), 7.88 (1H, m);
IR (KBr, cm^-1) : 1738, 1672, 1625. (B) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-carbamoyl-5-methylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl ] Ethyl sulfamoyl acetate dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3-carbamoyl-5-methyl-4- (piperidin-4-yloxy) phenyl] Dissolve ethyl sulfamoyl acetate dihydrochloride (2.68 g) in ethanol (40 ml), add ethylacetimidate hydrochloride (1.58 g) and triethylamine (3.55 ml) under ice cooling, and stir at room temperature for 1 hour. And left for 13 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water), and the resulting amorphous solid was dissolved in ethanol (10 ml), and 4M A hydrogen chloride dioxane solution (0.44 ml) was added and then concentrated to dryness under reduced pressure to obtain 0.38 g (yield 13%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.0), 1.70-1.90 (2H, m), 1.90-2.00 (2H, m), 2.27 (3H, s), 2.29 (3H, s), 3.35-3.45 (2H, m), 3.75-3.95 (2H, m), 4.20 (2H, q, J = 7.0), 4.25 (1H, m), 4.40 (2H, s), 4.48 (2H, d, J = 6.0), 6.43 (1H, dt, J = 16.0, 6.0), 6.60 (1H, d, J = 16.0), 7.43 (2H, m), 7.55 (1H, m), 7.69 ( 1H, m), 7.73 (1H, m), 7.88 (1H, m);
IR (KBr, cm ^-1 ): 1738, 1672, 1625.

実施例４５
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−カルバモイル−５−メチルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸２塩酸塩
（例示化合物番号：２０２７）
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−カルバモイル−５−メチルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩（０．２４ｇ）を３Ｍ塩酸（２０ｍｌ）に溶解させ、７０℃で２．５時間撹拌した。反応液を室温まで冷却させた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１５％アセトニトリル／水）で精製し、得られた無定形固体を１Ｍ塩酸（１．００ｍｌ）に溶解させ、これを減圧下濃縮乾固することにより、表記化合物０．１８ｇ（収率７８％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.70-1.85 (2H, m), 1.90-2.00 (2H, m),
2.27 (3H, s), 2.29 (3H, s), 3.30-3.45 (2H, m), 3.75-3.90 (2H, m), 4.25 (1H, m), 4.27 (2H, s), 4.48 (2H, d, J=6.0), 6.43 (1H, dt, J=16.0, 6.0), 6.60 (1H, d, J=16.0), 7.43 (2H, m), 7.55 (1H, m), 7.67 (1H, m), 7.72 (1H, m), 7.86 (1H, m);
IR (KBr, cm^-1) : 1731, 1672. Example 45
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-carbamoyl-5-methylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl acetic acid Dihydrochloride (Exemplified compound number: 2027)
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-carbamoyl-5-methylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl acetic acid Ethyl dihydrochloride (0.24 g) was dissolved in 3M hydrochloric acid (20 ml) and stirred at 70 ° C. for 2.5 hours. The reaction solution was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 15% acetonitrile / water), and the resulting amorphous solid was treated with 1M hydrochloric acid ( 1.00 ml), and this was concentrated to dryness under reduced pressure to obtain 0.18 g (yield 78%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.70-1.85 (2H, m), 1.90-2.00 (2H, m),
2.27 (3H, s), 2.29 (3H, s), 3.30-3.45 (2H, m), 3.75-3.90 (2H, m), 4.25 (1H, m), 4.27 (2H, s), 4.48 (2H, d, J = 6.0), 6.43 (1H, dt, J = 16.0, 6.0), 6.60 (1H, d, J = 16.0), 7.43 (2H, m), 7.55 (1H, m), 7.67 (1H, m ), 7.72 (1H, m), 7.86 (1H, m);
IR (KBr, cm ^-1 ): 1731, 1672.

実施例４６
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３，５−ジフルオロフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩
（例示化合物番号：１４７４） Example 46
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-difluorophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl ethyl acetate 2 Hydrochloride (Exemplary Compound Number: 1474)

（ａ）Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［３，５−ジフルオロ−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３，５−ジフルオロフェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル（１８２３ｍｇ）をジクロロメタン（３０ｍｌ）及びエタノール（１５ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１時間通じた後、密栓をして室温で５．５時間撹拌した。反応液を減圧下濃縮した後、残渣をエタノール（２０ｍｌ）に溶解させ、塩化アンモニウム水溶液（３１５ｍｇを水１０ｍｌに溶解）及び２８％アンモニア水（０．５９ｍｌ）を加えた後、室温で１５時間放置した。反応液に４Ｍ塩化水素ジオキサン溶液（１ｍｌ）を加え、減圧下濃縮した後、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２０％アセトニトリル／水）で精製した。得られた無定形固体をエタノール（２０ｍｌ）に溶解させ、１Ｍ塩酸（２ｍｌ）を加えた後、減圧下濃縮乾固することにより、表記化合物１２１４ｍｇ（収率６８％）を無色無定形固体として得た。
¹H NMR (400MHz, DMSO-d₆) δppm : 1.21 (3H, t, J=7.0), 1.85-1.91 (2H, m), 2.04-2.10 (2H, m), 2.99-3.05 (2H, m), 3.18-3.24 (2H, m), 4.18 (2H, q,
J=7.0), 4.37 (1H, m), 4.50 (2H, s), 4.51 (2H, d, J=6.0), 6.42 (1H, dt, J=16.0, 6.0), 6.62 (1H, d, J=16.0), 7.39 (2H, m), 7.55 (1H, t, J=8.0), 7.68 (1H, d, J=8.0), 7.74 (1H, d, J=8.0), 7.88 (1H, s);
IR (KBr, cm^-1) : 1738, 1676. (A) N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3,5-difluoro-4- (piperidin-4-yloxy) phenyl] sulfamoyl acetate ethyl dihydrochloride N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3,5-difluorophenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl acetate ethyl (1823 mg) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), and hydrogen chloride was passed through for 1 hour under ice-cooling. The mixture was sealed and stirred at room temperature for 5.5 hours. After concentrating the reaction solution under reduced pressure, the residue was dissolved in ethanol (20 ml), aqueous ammonium chloride solution (315 mg dissolved in 10 ml of water) and 28% aqueous ammonia (0.59 ml) were added, and then left at room temperature for 15 hours. did. A 4M hydrogen chloride dioxane solution (1 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water). The obtained amorphous solid was dissolved in ethanol (20 ml), 1M hydrochloric acid (2 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 1214 mg (yield 68%) of the title compound as a colorless amorphous solid. It was.
¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.21 (3H, t, J = 7.0), 1.85-1.91 (2H, m), 2.04-2.10 (2H, m), 2.99-3.05 (2H, m) , 3.18-3.24 (2H, m), 4.18 (2H, q,
J = 7.0), 4.37 (1H, m), 4.50 (2H, s), 4.51 (2H, d, J = 6.0), 6.42 (1H, dt, J = 16.0, 6.0), 6.62 (1H, d, J = 16.0), 7.39 (2H, m), 7.55 (1H, t, J = 8.0), 7.68 (1H, d, J = 8.0), 7.74 (1H, d, J = 8.0), 7.88 (1H, s) ;
IR (KBr, cm ^-1 ): 1738, 1676.

（ｂ）Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３，５−ジフルオロフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［３，５−ジフルオロ−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩（１０２０ｍｇ）をエタノール（３０ｍｌ）に溶解させ、エチルアセトイミデート塩酸塩（６２０ｍｇ）及びトリエチルアミン（１．１７ｍｌ）を加えた後、室温で１５時間撹拌した。反応液に４Ｍ塩化水素ジオキサン溶液（１．０ｍｌ）を加え、減圧下濃縮した後、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２２％アセトニトリル／水）で精製した。得られた無定形固体をエタノール（１５ｍｌ）に溶解させ、１Ｍ塩酸（１．０ｍｌ）を加えた後、減圧下濃縮乾固させた。これを水（約２０ｍｌ）に溶解させ、凍結乾燥に付すことにより、表記化合物を８５１ｍｇ（収率７８％）を無色無定形固体として得た。
¹H NMR (400MHz, DMSO-d₆) δppm : 1.22 (3H, t, J=7.0), 1.76-1.83 (2H, m), 1.98-2.03 (2H, m), 2.30 (3H, s), 3.52 (2H, m), 3.78 (2H, m), 4.18 (2H, q, J=7.0), 4.46 (1H, m), 4.51 (2H, s), 4.52 (2H, d, J=6.0), 6.43 (1H, dt, J=16.0, 6.0), 6.62 (1H, d, J=16.0), 7.39 (2H, m), 7.55 (1H, t, J=8.0), 7.70 (1H, d, J=8.0), 7.73 (1H, d, J=8.0), 7.91 (1H, s);
IR (KBr, cm^-1) : 1739, 1673, 1624. (B) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-difluorophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl Ethyl acetate dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3,5-difluoro-4- (piperidin-4-yloxy) phenyl] sulfamoyl ethyl acetate 2 Hydrochloride (1020 mg) was dissolved in ethanol (30 ml), ethylacetoimidate hydrochloride (620 mg) and triethylamine (1.17 ml) were added, and the mixture was stirred at room temperature for 15 hr. A 4M hydrogen chloride dioxane solution (1.0 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 22% acetonitrile / water). The obtained amorphous solid was dissolved in ethanol (15 ml), 1M hydrochloric acid (1.0 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water (about 20 ml) and freeze-dried to obtain 851 mg (yield 78%) of the title compound as a colorless amorphous solid.
¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.22 (3H, t, J = 7.0), 1.76-1.83 (2H, m), 1.98-2.03 (2H, m), 2.30 (3H, s), 3.52 (2H, m), 3.78 (2H, m), 4.18 (2H, q, J = 7.0), 4.46 (1H, m), 4.51 (2H, s), 4.52 (2H, d, J = 6.0), 6.43 (1H, dt, J = 16.0, 6.0), 6.62 (1H, d, J = 16.0), 7.39 (2H, m), 7.55 (1H, t, J = 8.0), 7.70 (1H, d, J = 8.0 ), 7.73 (1H, d, J = 8.0), 7.91 (1H, s);
IR (KBr, cm ^-1 ): 1739, 1673, 1624.

実施例４７
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３，５−ジフルオロフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸２塩酸塩（例示化合物番号：２００３）
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３，５−ジフルオロフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩（４１５ｍｇ）を２Ｍ塩酸（２０ｍｌ）に溶解させ、６０℃で５時間撹拌した。反応液を室温まで冷却させた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１５％アセトニトリル／水）で精製した。得られた無定形固体を１５％アセトニトリル／水（２０ｍｌ）に溶解させ、１Ｍ塩酸（１．０ｍｌ）を加え、減圧下濃縮乾固させた。得られた無定形固体を水（約２０ｍｌ）に溶解させ、凍結乾燥に付すことにより表記化合物３１９ｍｇ（収率８０％）を無色無定形固体として得た。
¹H NMR (400MHz, DMSO-d₆) δppm : 1.70-1.90 (2H, m), 1.95-2.10 (2H, m),
2.29 (3H, s), 3.40-3.60 (2H, m), 3.78 (2H, m), 4.37 (2H, s), 4.46 (1H, m), 4.52 (2H, d, J=6.0), 6.43 (1H, dt, J=16.0, 6.0), 6.62 (1H, d, J=16.0), 7.38 (2H, m), 7.55 (1H, t, J=8.0), 7.69 (1H, d, J=8.0), 7.74 (1H, d, J=8.0), 7.89 (1H, s);
IR (KBr, cm^-1) : 3123, 1733, 1674, 1626. Example 47
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-difluorophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoylacetic acid dihydrochloride Salt (Exemplary compound number: 2003)
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-difluorophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl ethyl acetate 2 Hydrochloride (415 mg) was dissolved in 2M hydrochloric acid (20 ml) and stirred at 60 ° C. for 5 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 15% acetonitrile / water). The obtained amorphous solid was dissolved in 15% acetonitrile / water (20 ml), 1M hydrochloric acid (1.0 ml) was added, and the mixture was concentrated to dryness under reduced pressure. The obtained amorphous solid was dissolved in water (about 20 ml) and freeze-dried to obtain 319 mg (yield 80%) of the title compound as a colorless amorphous solid.
¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.70-1.90 (2H, m), 1.95-2.10 (2H, m),
2.29 (3H, s), 3.40-3.60 (2H, m), 3.78 (2H, m), 4.37 (2H, s), 4.46 (1H, m), 4.52 (2H, d, J = 6.0), 6.43 ( 1H, dt, J = 16.0, 6.0), 6.62 (1H, d, J = 16.0), 7.38 (2H, m), 7.55 (1H, t, J = 8.0), 7.69 (1H, d, J = 8.0) , 7.74 (1H, d, J = 8.0), 7.89 (1H, s);
IR (KBr, cm ^-1 ): 3123, 1733, 1674, 1626.

実施例４８
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３，５−ジクロロフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩（例示化合物番号：１４７８） Example 48
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-dichlorophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl ethyl acetate dihydrochloride Salt (Exemplified compound number: 1478)

（ａ）Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［３，５−ジクロロ−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３，５−ジクロロフェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル（２０５７ｍｇ）をジクロロメタン（３０ｍｌ）及びエタノール（１５ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１時間通じた後、密栓をして室温で６時間撹拌した。反応液を減圧下濃縮した後、残渣をエタノール（４０ｍｌ）に溶解させ、塩化アンモニウム水溶液（３３７ｍｇを水２０ｍｌに溶解）及び２８％アンモニア水（０．６３ｍｌ）を加え、室温で１５時間放置した。反応液に４Ｍ塩化水素ジオキサン溶液（２．０ｍｌ）を加え、減圧下濃縮した後、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２３％アセトニトリル／水）にて精製した。得られた無定形固体をエタノール（２０ｍｌ）に溶解させ、１Ｍ塩酸（１．０ｍｌ）を加えた後、これを減圧下濃縮乾固することにより、表記化合物１００２ｍｇ（収率４９％）を無色無定形固体として得た。
¹H NMR (400MHz, DMSO-d₆) δppm : 1.21 (3H, t, J=7.0), 1.95-2.15 (4H, m), 2.95-3.10 (2H, m), 3.20-3.35 (2H, m), 4.18 (2H, q, J=7.0), 4.46 (1H, m), 4.53 (4H, m), 6.43 (1H, dt, J=16.0, 6.0), 6.62 (1H, d, J=16.0), 7.55
(1H, t, J=7.5), 7.67 (2H, s), 7.68 (1H, d, J=7.5), 7.74 (1H, d, J=7.5),
7.88 (1H, s);
IR (KBr, cm^-1) : 1738, 1676. (A) N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3,5-dichloro-4- (piperidin-4-yloxy) phenyl] sulfamoyl acetate ethyl dihydrochloride N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3,5-dichlorophenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl acetate ( 2057 mg) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), and hydrogen chloride was passed through for 1 hour under ice-cooling. After sealing, the mixture was sealed and stirred at room temperature for 6 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (40 ml), aqueous ammonium chloride solution (337 mg dissolved in 20 ml of water) and 28% aqueous ammonia (0.63 ml) were added, and the mixture was allowed to stand at room temperature for 15 hours. A 4M hydrogen chloride dioxane solution (2.0 ml) was added to the reaction solution and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 23% acetonitrile / water). The obtained amorphous solid was dissolved in ethanol (20 ml), 1M hydrochloric acid (1.0 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 1002 mg (yield 49%) of the title compound colorless and colorless. Obtained as a regular solid.
¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.21 (3H, t, J = 7.0), 1.95-2.15 (4H, m), 2.95-3.10 (2H, m), 3.20-3.35 (2H, m) , 4.18 (2H, q, J = 7.0), 4.46 (1H, m), 4.53 (4H, m), 6.43 (1H, dt, J = 16.0, 6.0), 6.62 (1H, d, J = 16.0), 7.55
(1H, t, J = 7.5), 7.67 (2H, s), 7.68 (1H, d, J = 7.5), 7.74 (1H, d, J = 7.5),
7.88 (1H, s);
IR (KBr, cm ^-1 ): 1738, 1676.

（ｂ）Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３，５−ジクロロフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［３，５−ジクロロ−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩（８００ｍｇ）をエタノール（３０ｍｌ）に溶解させ、エチルアセトイミデート塩酸塩（４６２ｍｇ）及びトリエチルアミン（０．８７ｍｌ）を加え、室温で１５時間撹拌した。反応液に４Ｍ塩化水素ジオキサン溶液（１ｍｌ）を加え、減圧下濃縮した後、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２５％アセトニトリル／水）で精製した。得られた無定形固体をエタノール（２０ｍｌ）に溶解させ、１Ｍ塩酸（１．０ｍｌ）を加えた後、減圧下濃縮乾固させた。これを水（約２０ｍｌ）に溶解させ、凍結乾燥に付すことにより、表記化合物７２２ｍｇ（収率８５％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.22 (3H, t, J=7.0), 1.80-2.00 (2H, m), 2.00-2.10 (2H, m), 2.29 (3H, s), 3.40-3.55 (2H, m), 3.80-4.00 (2H, m), 4.18 (2H, q, J=7.0), 4.53 (5H, m), 6.43 (1H, dt, J=16.0, 6.0), 6.63 (1H, d, J=16.0), 7.56 (1H, t, J=8.0), 7.67 (2H, s), 7.68 (1H, d, J=8.0), 7.74 (1H, d, J=8.0), 7.88 (1H, s);
IR (KBr, cm^-1) : 1739, 1674, 1624. (B) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-dichlorophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl acetic acid Ethyl dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3,5-dichloro-4- (piperidin-4-yloxy) phenyl] sulfamoyl ethyl acetate dihydrochloride The salt (800 mg) was dissolved in ethanol (30 ml), ethylacetoimidate hydrochloride (462 mg) and triethylamine (0.87 ml) were added, and the mixture was stirred at room temperature for 15 hours. A 4M hydrogen chloride dioxane solution (1 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 25% acetonitrile / water). The obtained amorphous solid was dissolved in ethanol (20 ml), 1M hydrochloric acid (1.0 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water (about 20 ml) and freeze-dried to obtain 722 mg (yield 85%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.22 (3H, t, J = 7.0), 1.80-2.00 (2H, m), 2.00-2.10 (2H, m), 2.29 (3H, s), 3.40 -3.55 (2H, m), 3.80-4.00 (2H, m), 4.18 (2H, q, J = 7.0), 4.53 (5H, m), 6.43 (1H, dt, J = 16.0, 6.0), 6.63 ( 1H, d, J = 16.0), 7.56 (1H, t, J = 8.0), 7.67 (2H, s), 7.68 (1H, d, J = 8.0), 7.74 (1H, d, J = 8.0), 7.88 (1H, s);
IR (KBr, cm ^-1 ): 1739, 1674, 1624.

実施例４９
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３，５−ジクロロフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸２塩酸塩（例示化合物番号：２００７）
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３，５−ジクロロフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩（３００ｍｇ）を２Ｍ塩酸（２０ｍｌ）に溶解させ、６０℃で６時間撹拌した。反応液を室温まで冷却させた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１８％アセトニトリル／水）で精製した。得られた無定形固体を１８％アセトニトリル／水（２０ｍｌ）に溶解させ、１Ｍ塩酸（１．０ｍｌ）を加えた後、減圧下濃縮乾固させた。これを水（約２０ｍｌ）に溶解させ、凍結乾燥に付すことにより、表記化合物２３３ｍｇ（収率８１％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.80-2.00 (2H, m), 2.00-2.10 (2H, m),
2.30 (3H, s), 3.40-3.55 (2H, m), 3.80-4.00 (2H, m), 4.39 (2H, s), 4.53 (2H, d, J=6.0), 4.53 (1H, m), 6.44 (1H, dt, J=16.0, 6.0), 6.62 (1H, d, J=16.0), 7.56 (1H, t, J=8.0), 7.67 (2H, s), 7.70 (1H, d, J=8.0), 7.74 (1H, d, J=8.0), 7.90 (1H, s);
IR (KBr, cm^-1) : 3127, 1733, 1673, 1625. Example 49
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-dichlorophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoylacetic acid dihydrochloride (Exemplary compound number: 2007)
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-dichlorophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl ethyl acetate dihydrochloride The salt (300 mg) was dissolved in 2M hydrochloric acid (20 ml) and stirred at 60 ° C. for 6 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 18% acetonitrile / water). The obtained amorphous solid was dissolved in 18% acetonitrile / water (20 ml), 1M hydrochloric acid (1.0 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water (about 20 ml) and freeze-dried to obtain 233 mg (yield 81%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.80-2.00 (2H, m), 2.00-2.10 (2H, m),
2.30 (3H, s), 3.40-3.55 (2H, m), 3.80-4.00 (2H, m), 4.39 (2H, s), 4.53 (2H, d, J = 6.0), 4.53 (1H, m), 6.44 (1H, dt, J = 16.0, 6.0), 6.62 (1H, d, J = 16.0), 7.56 (1H, t, J = 8.0), 7.67 (2H, s), 7.70 (1H, d, J = 8.0), 7.74 (1H, d, J = 8.0), 7.90 (1H, s);
IR (KBr, cm ^-1 ): 3127, 1733, 1673, 1625.

実施例５０
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３，５−ジメチルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸メチル２塩酸塩（例示化合物番号：２４２９） Example 50
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-dimethylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl acetate methyl 2 Hydrochloride (Exemplified compound number: 2429)

（ａ）Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［３，５−ジメチル−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３，５−ジメチルフェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル（１．７５ｇ）をジクロロメタン（３０ｍｌ）及びエタノール（１５ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１時間通じた後、密栓をして室温で６時間撹拌した。反応液を減圧下濃縮した後、残渣をエタノール（３０ｍｌ）に溶解させ、塩化アンモニウム水溶液（０．３１ｇを水１５ｍｌに溶解）及び２８％アンモニア水（０．５７ｍｌ）を加え、室温で１４時間放置した。反応液に４Ｍ塩化水素ジオキサン溶液（１ｍｌ）を加えた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２０％アセトニトリル／水）にて精製した。得られた無定形固体をエタノール（２０ｍｌ）に溶解させ、１Ｍ塩酸（１ｍｌ）を加えた後、これを減圧下濃縮乾固することにより、表記化合物１．２１ｇ（収率７０％）を無色無定形固体として得た。
¹H NMR (400MHz, DMSO-d₆) δppm : 1.23 (3H, t, J=7.0), 1.80-1.95 (2H, m), 2.00-2.10 (2H, m), 2.22 (6H, s), 2.94 (2H, m), 3.26 (2H, m), 4.12 (1H, m), 4.19 (2H, q, J=7.0), 4.35 (2H, s), 4.44 (2H, d, J=6.0), 6.43 (1H, dt, J=16.0, 6.0), 6.59 (1H, d, J=16.0), 7.17 (2H, s), 7.55 (1H, t, J=8.0), 7.68 (1H, d, J=8.0), 7.73 (1H, d, J=8.0), 7.88 (1H, s);
IR (KBr, cm^-1) : 1738, 1676. (A) N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3,5-dimethyl-4- (piperidin-4-yloxy) phenyl] sulfamoyl acetate ethyl dihydrochloride N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3,5-dimethylphenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl acetate ethyl (1.75 g) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), and hydrogen chloride was passed through for 1 hour under ice-cooling. The mixture was sealed and stirred at room temperature for 6 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethanol (30 ml), aqueous ammonium chloride solution (0.31 g dissolved in 15 ml water) and 28% aqueous ammonia (0.57 ml) were added, and the mixture was allowed to stand at room temperature for 14 hours. did. A 4M hydrogen chloride dioxane solution (1 ml) was added to the reaction solution, followed by concentration under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water). The obtained amorphous solid was dissolved in ethanol (20 ml), 1M hydrochloric acid (1 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 1.21 g (yield 70%) of the title compound as colorless solid. Obtained as a regular solid.
¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.23 (3H, t, J = 7.0), 1.80-1.95 (2H, m), 2.00-2.10 (2H, m), 2.22 (6H, s), 2.94 (2H, m), 3.26 (2H, m), 4.12 (1H, m), 4.19 (2H, q, J = 7.0), 4.35 (2H, s), 4.44 (2H, d, J = 6.0), 6.43 (1H, dt, J = 16.0, 6.0), 6.59 (1H, d, J = 16.0), 7.17 (2H, s), 7.55 (1H, t, J = 8.0), 7.68 (1H, d, J = 8.0 ), 7.73 (1H, d, J = 8.0), 7.88 (1H, s);
IR (KBr, cm ^-1 ): 1738, 1676.

（ｂ）Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３，５−ジメチルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸メチル２塩酸塩
Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［３，５−ジメチル−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩（１．００ｇ）をメタノール（３０ｍｌ）に溶解させ、エチルアセトイミデート塩酸塩（０．６２ｇ）及びトリエチルアミン（１．１６ｍｌ）を加え、室温で１４時間撹拌した。反応液に４Ｍ塩化水素ジオキサン溶液（２ｍｌ）を加えた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２０％アセトニトリル／水）で精製した。得られた無定形固体をメタノール（２０ｍｌ）に溶解させ、１Ｍ塩酸（１．０ｍｌ）を加えた後、減圧下濃縮乾固させた。これを水（約２０ｍｌ）に溶解させ、凍結乾燥に付すことにより、表記化合物０．８１ｇ（収率７８％）を無色無定形固体として得た。
¹H NMR (400MHz, DMSO-d₆) δppm : 1.75 (2H, m), 1.98 (2H, m), 2.23 (6H,
s), 2.29 (3H, s), 3.25-3.35 (2H, m), 3.73 (3H, s), 3.85 (1H, m), 4.02 (1H, m), 4.18 (1H, m), 4.38 (2H, s), 4.44 (2H, d, J=6.0), 6.42 (1H, dt, J=16.0, 6.0), 6.59 (1H, d, J=16.0), 7.16 (2H, s), 7.55 (1H, t, J=8.0), 7.68 (1H, d, J=8.0), 7.73 (1H, d, J=8.0), 7.88 (1H, s);
IR (KBr, cm^-1) : 1743, 1673, 1626. (B) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-dimethylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl Methyl acetate dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3,5-dimethyl-4- (piperidin-4-yloxy) phenyl] sulfamoyl ethyl acetate 2 Hydrochloride (1.00 g) was dissolved in methanol (30 ml), ethylacetimidate hydrochloride (0.62 g) and triethylamine (1.16 ml) were added, and the mixture was stirred at room temperature for 14 hours. A 4M hydrogen chloride dioxane solution (2 ml) was added to the reaction solution, followed by concentration under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water). The obtained amorphous solid was dissolved in methanol (20 ml), 1M hydrochloric acid (1.0 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water (about 20 ml) and subjected to lyophilization to obtain 0.81 g (yield 78%) of the title compound as a colorless amorphous solid.
¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.75 (2H, m), 1.98 (2H, m), 2.23 (6H,
s), 2.29 (3H, s), 3.25-3.35 (2H, m), 3.73 (3H, s), 3.85 (1H, m), 4.02 (1H, m), 4.18 (1H, m), 4.38 (2H , s), 4.44 (2H, d, J = 6.0), 6.42 (1H, dt, J = 16.0, 6.0), 6.59 (1H, d, J = 16.0), 7.16 (2H, s), 7.55 (1H, t, J = 8.0), 7.68 (1H, d, J = 8.0), 7.73 (1H, d, J = 8.0), 7.88 (1H, s);
IR (KBr, cm ^-1 ): 1743, 1673, 1626.

実施例５１
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３，５−ジメチルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸２塩酸塩（例示化合物番号：２０１１）
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３，５−ジメチルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸メチル２塩酸塩（６２０ｍｇ）を２Ｍ塩酸（２０ｍｌ）に溶解させ、６０℃で５時間撹拌した。反応液を室温まで冷却させた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１８％アセトニトリル／水）で精製した。得られた無定形固体を１８％アセトニトリル／水（２０ｍｌ）に溶解させ、１Ｍ塩酸（１．０ｍｌ）を加え、減圧下濃縮乾固させた。これを水（約２０ｍｌ）に溶解させ、凍結乾燥に付すことにより、表記化合物２２０ｍｇ（収率５７％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.75 (2H, m), 1.98 (2H, m), 2.23 (6H,
s), 2.29 (3H, s), 3.25-3.40 (2H, m), 3.85 (1H, m), 4.02 (1H, m), 4.17 (1H, m), 4.22 (2H, s), 4.44 (2H, d, J=6.0), 6.43 (1H, dt, J=16.0, 6.0), 6.58 (1H, d, J=16.0), 7.17 (2H, s), 7.55 (1H, t, J=8.0), 7.69 (1H, d, J=8.0), 7.72 (1H, d, J=8.0), 7.88 (1H, s);
IR (KBr, cm^-1) : 3131, 1733, 1673, 1626. Example 51
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-dimethylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoylacetic acid dihydrochloride Salt (Exemplary compound number: 2011)
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-dimethylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl acetate methyl 2 Hydrochloride (620 mg) was dissolved in 2M hydrochloric acid (20 ml) and stirred at 60 ° C. for 5 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 18% acetonitrile / water). The obtained amorphous solid was dissolved in 18% acetonitrile / water (20 ml), 1M hydrochloric acid (1.0 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water (about 20 ml) and subjected to lyophilization to obtain 220 mg (yield 57%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.75 (2H, m), 1.98 (2H, m), 2.23 (6H,
s), 2.29 (3H, s), 3.25-3.40 (2H, m), 3.85 (1H, m), 4.02 (1H, m), 4.17 (1H, m), 4.22 (2H, s), 4.44 (2H , d, J = 6.0), 6.43 (1H, dt, J = 16.0, 6.0), 6.58 (1H, d, J = 16.0), 7.17 (2H, s), 7.55 (1H, t, J = 8.0), 7.69 (1H, d, J = 8.0), 7.72 (1H, d, J = 8.0), 7.88 (1H, s);
IR (KBr, cm ^-1 ): 3131, 1733, 1673, 1626.

実施例５２
４−［Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］アミノ］酪酸エチル３塩酸塩（例示化合物番号：８４９） Example 52
4- [N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] amino] ethyl butyrate trihydrochloride (Exemplary compound number: 849)

（ａ）４−［Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−［Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］アミノ］酪酸エチル３塩酸塩
４−［Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］アミノ］酪酸エチル（２．１９ｇ）をジクロロメタン（３０ｍｌ）及びエタノール（１５ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１時間通じた後、密栓をして室温で５．５時間撹拌した。反応液を減圧下濃縮した後、残渣をエタノール（２０ｍｌ）に溶解させ、塩化アンモニウム水溶液（０．４３ｇを水１０ｍｌに溶解）及び２８％アンモニア水（１．０４ｍｌ）を加えた後、室温で１４時間放置した。これに４Ｍ塩化水素ジオキサン溶液（１ｍｌ）を加え、減圧下濃縮した後、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２５％アセトニトリル／水）で精製した。得られた無定形固体をエタノール（２０ｍｌ）に溶解させ、１Ｍ塩酸（１．０ｍｌ）を加えた後、減圧下濃縮乾固させた。これを水（約１０ｍｌ）に溶解させた後、凍結乾燥に付すことにより、表記化合物１．５２ｇ（収率６６％）を淡黄色無定形固体として得た。
¹H NMR (400MHz, DMSO-d₆) δppm : 1.19 (3H, t, J=7.0), 1.70-1.95 (4H, m), 2.00-2.15 (2H, m), 2.39 (2H, m), 3.00-3.15 (2H, m), 3.15-3.30 (2H, m), 3.30-3.40 (2H, m), 4.07 (2H, q, J=7.0), 4.00-4.20 (2H, m), 4.43 (1H, m), 6.52 (1H, dt, J=16.0, 5.5), 6.55-7.00 (5H, m), 7.59 (1H, t, J=8.0), 7.65-7.80 (2H, m), 7.88 (1H, s);
IR (KBr, cm^-1): : 1728, 1674. (A) Ethyl 4- [N- [3- (3-amidinophenyl) -2- (E) -propenyl]-[N- [4- (piperidin-4-yloxy) phenyl] amino] butyric acid trihydrochloride 4 -[N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] amino] ethyl butyrate (2. 19 g) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (15 ml), and hydrogen chloride was passed through for 1 hour under ice-cooling. The mixture was sealed and stirred at room temperature for 5.5 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (20 ml), aqueous ammonium chloride solution (0.43 g dissolved in 10 ml of water) and 28% aqueous ammonia (1.04 ml) were added, Left for hours. A 4M hydrogen chloride dioxane solution (1 ml) was added thereto, and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 25% acetonitrile / water). The obtained amorphous solid was dissolved in ethanol (20 ml), 1M hydrochloric acid (1.0 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water (about 10 ml) and then freeze-dried to obtain 1.52 g (yield 66%) of the title compound as a pale yellow amorphous solid.
¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.19 (3H, t, J = 7.0), 1.70-1.95 (4H, m), 2.00-2.15 (2H, m), 2.39 (2H, m), 3.00 -3.15 (2H, m), 3.15-3.30 (2H, m), 3.30-3.40 (2H, m), 4.07 (2H, q, J = 7.0), 4.00-4.20 (2H, m), 4.43 (1H, m), 6.52 (1H, dt, J = 16.0, 5.5), 6.55-7.00 (5H, m), 7.59 (1H, t, J = 8.0), 7.65-7.80 (2H, m), 7.88 (1H, s );
IR (KBr, cm ^-1 ):: 1728, 1674.

（ｂ）４−［Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］アミノ］酪酸エチル３塩酸塩
４−［Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−［Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］アミノ］酪酸エチル３塩酸塩（１３７８ｍｇ）をエタノール（２０ｍｌ）に溶解させ、エチルアセトイミデート塩酸塩（８９０ｍｇ）及びトリエチルアミン（２．０１ｍｌ）を加えた後、室温で４時間撹拌した。反応液に４Ｍ塩化水素ジオキサン溶液（１ｍｌ）を加え、減圧下濃縮した後、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２５％アセトニトリル／水）で精製した。得られた無定形固体をエタノール（２０ｍｌ）に溶解させ、１Ｍ塩酸（１．０ｍｌ）を加えた後、減圧下濃縮乾固させた。これを水（約２０ｍｌ）に溶解させた後、凍結乾燥に付すことにより、表記化合物１０７２ｍｇ（収率７３％）を淡黄色無定形固体として得た。
¹H NMR (400MHz, DMSO-d₆) δppm : 1.16 (3H, t, J=7.0), 1.60-1.90 (4H, m), 1.90-2.10 (2H, m), 2.29 (3H, s), 2.30-2.40 (2H, m), 3.20-3.40 (2H, m), 3.45-3.60 (2H, m), 3.70-3.85 (2H, m), 4.04 (2H, q, J=7.0), 4.00-4.10 (2H, m), 4.40-4.55 (1H, m), 6.49 (1H, dt, J=16.0, 6.0), 6.55-6.95 (5H, m), 7.57 (1H, t, J=7.5), 7.65-7.75 (2H, m), 7.85 (1H, s);
IR (KBr, cm^-1) : 1727, 1673, 1624. (B) Ethyl 4- [N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] amino] butyrate Trihydrochloride 4- [N- [3- (3-Amidinophenyl) -2- (E) -propenyl]-[N- [4- (piperidin-4-yloxy) phenyl] amino] ethyl butyrate trihydrochloride ( 1378 mg) was dissolved in ethanol (20 ml), ethylacetimidate hydrochloride (890 mg) and triethylamine (2.01 ml) were added, and the mixture was stirred at room temperature for 4 hours. A 4M hydrogen chloride dioxane solution (1 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 25% acetonitrile / water). The obtained amorphous solid was dissolved in ethanol (20 ml), 1M hydrochloric acid (1.0 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water (about 20 ml) and then freeze-dried to obtain 1072 mg (yield 73%) of the title compound as a pale yellow amorphous solid.
¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.16 (3H, t, J = 7.0), 1.60-1.90 (4H, m), 1.90-2.10 (2H, m), 2.29 (3H, s), 2.30 -2.40 (2H, m), 3.20-3.40 (2H, m), 3.45-3.60 (2H, m), 3.70-3.85 (2H, m), 4.04 (2H, q, J = 7.0), 4.00-4.10 ( 2H, m), 4.40-4.55 (1H, m), 6.49 (1H, dt, J = 16.0, 6.0), 6.55-6.95 (5H, m), 7.57 (1H, t, J = 7.5), 7.65-7.75 (2H, m), 7.85 (1H, s);
IR (KBr, cm ^-1 ): 1727, 1673, 1624.

実施例５３
４−［Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］アミノ］酪酸３塩酸塩（例示化合物番号：６６３）
４−［Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］アミノ］酪酸エチル３塩酸塩（５７２ｍｇ）を２Ｍ塩酸（２０ｍｌ）に溶解させ、室温で２時間攪拌した後、５０℃で２時間撹拌した。反応液を室温まで冷却させた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１８％アセトニトリル／水）で精製した。得られた無定形固体を１８％アセトニトリル／水（２０ｍｌ）及び１Ｍ塩酸（１．０ｍｌ）に溶解させ、減圧下濃縮乾固させた。これを水（約２０ｍｌ）に溶解させ、凍結乾燥に付すことにより、表記化合物３３３ｍｇ（収率６１％）を淡褐色無定形固体として得た。
¹H NMR (400MHz, DMSO-d₆) δppm : 1.40-1.95 (4H, m), 1.95-2.10 (2H, m),
2.30 (3H, s), 2.25-2.35 (2H, m), 3.45-4.40 (8H, m), 4.65-4.80 (1H, m), 6.50 (1H, dt, J=15.5, 6.5), 6.55-7.30 (5H, m), 7.58 (1H, t, J=7.5), 7.65-7.75 (2H, m), 7.85 (1H, s);
IR (KBr, cm^-1) : 3119, 1726, 1673, 1625. Example 53
4- [N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] amino] butyric acid trihydrochloride ( Illustrative compound number: 663)
4- [N- [4- (1-Acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] amino] ethyl butyrate trihydrochloride (572 mg) was dissolved in 2M hydrochloric acid (20 ml), stirred at room temperature for 2 hours, and then stirred at 50 ° C. for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 18% acetonitrile / water). The obtained amorphous solid was dissolved in 18% acetonitrile / water (20 ml) and 1M hydrochloric acid (1.0 ml), and concentrated to dryness under reduced pressure. This was dissolved in water (about 20 ml) and subjected to lyophilization to obtain 333 mg (yield 61%) of the title compound as a light brown amorphous solid.
¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 1.40-1.95 (4H, m), 1.95-2.10 (2H, m),
2.30 (3H, s), 2.25-2.35 (2H, m), 3.45-4.40 (8H, m), 4.65-4.80 (1H, m), 6.50 (1H, dt, J = 15.5, 6.5), 6.55-7.30 (5H, m), 7.58 (1H, t, J = 7.5), 7.65-7.75 (2H, m), 7.85 (1H, s);
IR (KBr, cm ^-1 ): 3119, 1726, 1673, 1625.

実施例５４
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−トリフルオロメチルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸２塩酸塩
（例示化合物番号：１９６９）
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−トリフルオロメチルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩（３２１ｍｇ）を３Ｍ塩酸（１５ｍｌ）に溶解させ、８０℃で３時間撹拌した。反応液を室温まで冷却させた後、減圧下溶媒を留去し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２０％アセトニトリル／水）にて精製した後、得られた無定形固体をメタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．５ｍｌ）を加えた後、減圧下濃縮乾固させた。これを水（約１５ｍｌ）に溶解させた後、凍結乾燥に付すことにより、表記化合物２３１ｍｇ（収率７５％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.79 (2H, m), 2.05 (2H, m), 2.31 (3H,
s), 3.40-3.75 (4H, m), 4.32 (2H, s), 4.50 (2H, d, J=6.5), 4.96 (1H, m),
6.47 (1H, dt, J=17.0, 6.5), 6.57 (1H, d, J=17.0), 7.43 (1H, d, J=10.0),
7.54 (1H, d, J=7.5), 7.71 (4H, m), 7.92 (1H, s);
IR (KBr, cm^-1) : 3102, 1734, 1675, 1617. Example 54
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-trifluoromethylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoylacetic acid dihydrochloride Salt (Exemplary compound number: 1969)
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-trifluoromethylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl ethyl acetate 2 Hydrochloride (321 mg) was dissolved in 3M hydrochloric acid (15 ml) and stirred at 80 ° C. for 3 hours. The reaction solution was allowed to cool to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water), and the resulting amorphous product was obtained. The solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water (about 15 ml) and then freeze-dried to obtain 231 mg (yield 75%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.79 (2H, m), 2.05 (2H, m), 2.31 (3H,
s), 3.40-3.75 (4H, m), 4.32 (2H, s), 4.50 (2H, d, J = 6.5), 4.96 (1H, m),
6.47 (1H, dt, J = 17.0, 6.5), 6.57 (1H, d, J = 17.0), 7.43 (1H, d, J = 10.0),
7.54 (1H, d, J = 7.5), 7.71 (4H, m), 7.92 (1H, s);
IR (KBr, cm ^-1 ): 3102, 1734, 1675, 1617.

実施例５５
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−メチルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸２塩酸塩（例示化合物番号：１９４９）
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３−メチルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩（４８０ｍｇ）を３Ｍ塩酸（１５ｍｌ）に溶解させ、８０℃で３時間撹拌した。反応液を室温まで冷却させた後、減圧下溶媒を留去し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２０％アセトニトリル／水）で精製した。得られた無定形固体をメタノール（１５ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．５ｍｌ）を加えた後、減圧下濃縮乾固させることにより、表記化合物３１５ｍｇ（収率６９％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.78 (2H, m), 2.02 (2H, m), 2.14 (3H,
s), 2.29 (3H, s), 3.62 (4H, m), 3.71 (2H, s), 4.12 (1H, m), 4.46 (2H, d, J=6.0), 4.70 (1H, m), 6.45 (1H, dt, J=16.0, 6.0), 6.50 (1H, d, J=16.0), 7.02 (1H, d, J=8.5), 7.36 (1H, s), 7.37 (1H, d, J=8.5), 7.52 (1H, d, J=8.0), 7.67 (1H, d, J=7.5), 7.69 (1H, d, J=8.0), 7.86 (1H, s);
IR (KBr, cm^-1) : 3067, 1678, 1608, 1497. Example 55
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-methylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoylacetic acid dihydrochloride ( Exemplified compound number: 1949)
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-methylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl ethyl acetate dihydrochloride (480 mg) was dissolved in 3M hydrochloric acid (15 ml) and stirred at 80 ° C. for 3 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water). The obtained amorphous solid was dissolved in methanol (15 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 315 mg (yield 69%) of the title compound as colorless. Obtained as an amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.78 (2H, m), 2.02 (2H, m), 2.14 (3H,
s), 2.29 (3H, s), 3.62 (4H, m), 3.71 (2H, s), 4.12 (1H, m), 4.46 (2H, d, J = 6.0), 4.70 (1H, m), 6.45 (1H, dt, J = 16.0, 6.0), 6.50 (1H, d, J = 16.0), 7.02 (1H, d, J = 8.5), 7.36 (1H, s), 7.37 (1H, d, J = 8.5 ), 7.52 (1H, d, J = 8.0), 7.67 (1H, d, J = 7.5), 7.69 (1H, d, J = 8.0), 7.86 (1H, s);
IR (KBr, cm ^-1 ): 3067, 1678, 1608, 1497.

実施例５６
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−フルオロ−２−（Ｚ）−プロペニル］スルファモイル酢酸エチル２塩酸塩（例示化合物番号：１５０９） Example 56
N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2-fluoro-2- (Z) -propenyl] sulfamoyl ethyl acetate dihydrochloride (Exemplary compound number: 1509)

（ａ）Ｎ−［３−（３−アミジノフェニル）−２−フルオロ−２−（Ｚ）−プロペニル］−Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−シアノフェニル）−２−フルオロ−２−（Ｚ）−プロペニル］スルファモイル酢酸エチル（１．４１ｇ）をジクロロメタン（２５ｍｌ）及びエタノール（２５ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１時間通じた後、密栓をして室温で１０時間撹拌した。反応液を減圧下濃縮し、残渣をエタノール（３０ｍｌ）に溶解させた後、塩化アンモニウム水溶液（０．２５ｇを水１０ｍｌに溶解）及び２８％アンモニア水（０．４７ｍｌ）を加え、室温で８時間放置した。４Ｍ塩化水素ジオキサン溶液（２．０ｍｌ）を加え、溶媒を留去した後、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２０％アセトニトリル／水）で精製した。得られた無定形固体をメタノール（１５ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．５ｍｌ）を加えた後、これを減圧下濃縮乾固することにより、表記化合物１．００ｇ（収率７５％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.24 (3H, t, J=7.0), 1.81 (2H, m), 2.08 (2H, m), 3.06 (2H, m), 3.22 (2H, m), 4.20 (2H, q, J=7.0), 4.36 (2H, s), 4.56 (2H, d, J=16.5), 4.65 (1H, m), 5.94 (1H, d, J=39.0), 7.05 (2H, d, J=9.5), 7.40 (2H, d, J=9.5), 7.56 (1H, d, J=8.0), 7.74 (2H, m), 7.81 (1H, s);
IR (KBr, cm^-1) : 3061, 2985, 1737, 1676, 1507. (A) N- [3- (3-Amidinophenyl) -2-fluoro-2- (Z) -propenyl] -N- [4- (piperidin-4-yloxy) phenyl] sulfamoyl acetate ethyl dihydrochloride N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2-fluoro-2- (Z) -propenyl] sulfamoyl ethyl acetate (1.41 g ) Was dissolved in a mixed solvent of dichloromethane (25 ml) and ethanol (25 ml), hydrogen chloride was passed through for 1 hour under ice-cooling, and the mixture was sealed and stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethanol (30 ml). Aqueous ammonium chloride (0.25 g dissolved in 10 ml of water) and 28% aqueous ammonia (0.47 ml) were added, and the mixture was stirred at room temperature for 8 hours. I left it. A 4M hydrogen chloride dioxane solution (2.0 ml) was added and the solvent was distilled off. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water). The obtained amorphous solid was dissolved in methanol (15 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 1.00 g of the title compound (yield 75). %) As a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.24 (3H, t, J = 7.0), 1.81 (2H, m), 2.08 (2H, m), 3.06 (2H, m), 3.22 (2H, m ), 4.20 (2H, q, J = 7.0), 4.36 (2H, s), 4.56 (2H, d, J = 16.5), 4.65 (1H, m), 5.94 (1H, d, J = 39.0), 7.05 (2H, d, J = 9.5), 7.40 (2H, d, J = 9.5), 7.56 (1H, d, J = 8.0), 7.74 (2H, m), 7.81 (1H, s);
IR (KBr, cm ^-1 ): 3061, 2985, 1737, 1676, 1507.

（ｂ）Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−フルオロ−２−（Ｚ）−プロペニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［３−（３−アミジノフェニル）−２−フルオロ−２−（Ｚ）−プロペニル］−Ｎ−［４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩（８００ｍｇ）をエタノール（２０ｍｌ）に溶解させ、エチルアセトイミデート塩酸塩（５１５ｍｇ）及びトリエチルアミン（０．９７ｍｌ）を加え、室温で４時間撹拌した。反応液に４Ｍ塩化水素ジオキサン溶液（２ｍｌ）を加えた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２５％アセトニトリル／水）で精製した。得られた無定形固体をメタノール（１５ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．５ｍｌ）を加えた後、これを減圧下濃縮乾固させることにより、表記化合物４５８ｍｇ（収率５４％）を淡黄色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.24 (3H, t, J=7.0), 1.74 (2H, m), 2.05 (2H, m), 2.28 (3H, s), 3.52 (2H, m), 3.72 (1H, m), 3.78 (1H, m), 4.20
(2H, q, J=7.0), 4.36 (2H, s), 4.59 (2H, d, J=15.5), 4.71 (1H, m), 5.96 (1H, d, J=39.0), 7.05 (2H, d, J=9.5), 7.41 (2H, d, J=9.5), 7.59 (1H, t, J=7.5), 7.67 (1H, d, J=7.5), 7.76 (1H, d, J=7.5), 7.80 (1H, s);
IR (KBr, cm^-1) : 3103, 1738, 1673, 1627, 1606. (B) N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2-fluoro-2- (Z) -propenyl] sulfamoyl ethyl acetate Dihydrochloride N- [3- (3-Amidinophenyl) -2-fluoro-2- (Z) -propenyl] -N- [4- (piperidin-4-yloxy) phenyl] sulfamoyl ethyl acetate dihydrochloride (800 mg ) Was dissolved in ethanol (20 ml), ethylacetimidate hydrochloride (515 mg) and triethylamine (0.97 ml) were added, and the mixture was stirred at room temperature for 4 hours. A 4M hydrogen chloride dioxane solution (2 ml) was added to the reaction solution, followed by concentration under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 25% acetonitrile / water). The obtained amorphous solid was dissolved in methanol (15 ml), 4M hydrogen chloride dioxane solution (0.5 ml) was added, and the mixture was concentrated to dryness under reduced pressure to give 458 mg (yield 54%) of the title compound. Was obtained as a pale yellow amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.24 (3H, t, J = 7.0), 1.74 (2H, m), 2.05 (2H, m), 2.28 (3H, s), 3.52 (2H, m ), 3.72 (1H, m), 3.78 (1H, m), 4.20
(2H, q, J = 7.0), 4.36 (2H, s), 4.59 (2H, d, J = 15.5), 4.71 (1H, m), 5.96 (1H, d, J = 39.0), 7.05 (2H, d, J = 9.5), 7.41 (2H, d, J = 9.5), 7.59 (1H, t, J = 7.5), 7.67 (1H, d, J = 7.5), 7.76 (1H, d, J = 7.5) , 7.80 (1H, s);
IR (KBr, cm ^-1 ): 3103, 1738, 1673, 1627, 1606.

実施例５７
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−フルオロ−２−（Ｚ）−プロペニル］スルファモイル酢酸２塩酸塩（例示化合物番号：２０３８）
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−アミジノフェニル）−２−フルオロ−２−（Ｚ）−プロペニル］スルファモイル酢酸エチル２塩酸塩（２６５ｍｇ）を３Ｍ塩酸（１５ｍｌ）に溶解させ、８０℃で２時間撹拌した。反応液を室温まで冷却させた後、減圧下溶媒を留去し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１５％アセトニトリル／水）で精製した。得られた無定形固体をメタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．２ｍｌ）を加えた後、減圧下濃縮乾固させた。これを水（約１５ｍｌ）に溶解させた後、凍結乾燥に付すことにより、表記化合物２１８ｍｇ（収率８６％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.74 (2H, m), 2.05 (2H, m), 2.29 (3H,
s), 3.52 (2H, m), 3.72 (1H, m), 3.82 (1H, m), 4.20 (2H, s), 4.59 (2H, d, J=15.5), 4.71 (1H, m), 5.95 (1H, d, J=38.0), 7.06 (2H, d, J=9.0), 7.42
(2H, d, J=9.0), 7.59 (1H, t, J=8.0), 7.68 (1H, d, J=8.0), 7.76 (1H, d, J=8.0), 7.81 (1H, s);
IR (KBr, cm^-1) : 1734, 1673, 1627. Example 57
N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2-fluoro-2- (Z) -propenyl] sulfamoylacetic acid dihydrochloride ( Exemplified compound number: 2038)
N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2-fluoro-2- (Z) -propenyl] sulfamoyl ethyl acetate dihydrochloride (265 mg) was dissolved in 3M hydrochloric acid (15 ml) and stirred at 80 ° C. for 2 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 15% acetonitrile / water). The obtained amorphous solid was dissolved in methanol (10 ml), 4M hydrogen chloride dioxane solution (0.2 ml) was added, and the mixture was concentrated to dryness under reduced pressure. This was dissolved in water (about 15 ml) and then freeze-dried to obtain 218 mg (yield 86%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.74 (2H, m), 2.05 (2H, m), 2.29 (3H,
s), 3.52 (2H, m), 3.72 (1H, m), 3.82 (1H, m), 4.20 (2H, s), 4.59 (2H, d, J = 15.5), 4.71 (1H, m), 5.95 (1H, d, J = 38.0), 7.06 (2H, d, J = 9.0), 7.42
(2H, d, J = 9.0), 7.59 (1H, t, J = 8.0), 7.68 (1H, d, J = 8.0), 7.76 (1H, d, J = 8.0), 7.81 (1H, s);
IR (KBr, cm ^-1 ): 1734, 1673, 1627.

実施例５８
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３，５−ジカルバモイルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩
（例示化合物番号：１５０６） Example 58
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-dicarbamoylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl ethyl acetate Dihydrochloride (Exemplified compound number: 1506)

（ａ）Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［３，５−ジカルバモイル−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３，５−ジカルバモイルフェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル（０．８４ｇ）をジクロロメタン（２５ｍｌ）及びエタノール（２５ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１．５時間通じた後、密栓をして室温で３時間撹拌した。反応液を減圧下濃縮した後、残渣をエタノール（２５ｍｌ）に溶解させ、塩化アンモニウム水溶液（０．１５ｇを水５ｍｌに溶解）及び２８％アンモニア水（０．３５ｍｌ）を加え、室温で２．５時間撹拌した後、１２時間放置した。反応液を減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１７．５％アセトニトリル／水）にて精製した後、得られた無定形固体をエタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．２０ｍｌ）を加えた後、これを減圧下濃縮乾固することにより、表記化合物０．１７ｇ（収率２０％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.24 (3H, t, J=7.0), 1.85-2.00 (4H, m), 2.95-3.05 (2H, m), 3.20-3.30 (2H, m), 4.20 (2H, q, J=7.0), 4.25-4.35 (1H, m), 4.45 (2H, s), 4.50 (2H, d, J=6.0), 6.45 (1H, dt, J=16.0, 6.0), 6.61 (1H, d, J=16.0), 7.55 (1H, t, J=8.0), 7.61 (2H, s), 7.67 (1H, d, J=8.0), 7.72 (1H, d, J=8.0), 7.88 (1H, s);
MASS (FAB, m/z) : 587 [M+H]. (A) N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [3,5-dicarbamoyl-4- (piperidin-4-yloxy) phenyl] sulfamoyl acetate ethyl dihydrochloride Salt N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3,5-dicarbamoylphenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl Ethyl acetate (0.84 g) was dissolved in a mixed solvent of dichloromethane (25 ml) and ethanol (25 ml), and hydrogen chloride was passed through for 1.5 hours under ice-cooling, then the container was sealed and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (25 ml), aqueous ammonium chloride solution (0.15 g dissolved in 5 ml water) and 28% aqueous ammonia (0.35 ml) were added, and the mixture was stirred at room temperature for 2.5. After stirring for an hour, it was left for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 17.5% acetonitrile / water), and the obtained amorphous solid was dissolved in ethanol (10 ml). After adding 4M hydrogen chloride dioxane solution (0.20 ml), this was concentrated to dryness under reduced pressure to obtain 0.17 g (yield 20%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.24 (3H, t, J = 7.0), 1.85-2.00 (4H, m), 2.95-3.05 (2H, m), 3.20-3.30 (2H, m) , 4.20 (2H, q, J = 7.0), 4.25-4.35 (1H, m), 4.45 (2H, s), 4.50 (2H, d, J = 6.0), 6.45 (1H, dt, J = 16.0, 6.0 ), 6.61 (1H, d, J = 16.0), 7.55 (1H, t, J = 8.0), 7.61 (2H, s), 7.67 (1H, d, J = 8.0), 7.72 (1H, d, J = 8.0), 7.88 (1H, s);
MASS (FAB, m / z): 587 [M + H].

（ｂ）Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３，５−ジカルバモイルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［３，５−ジカルバモイル−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩（０．１７ｇ）をエタノール（２０ｍｌ）に溶解させ、エチルアセトイミデート塩酸塩（１．６７ｇ）及びトリエチルアミン（１．６８ｍｌ）を加え、室温で５．５時間撹拌した。反応液を減圧下濃縮した後、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１７．５％アセトニトリル／水）にて精製した後、得られた無定形固体をエタノール（５ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（０．１０ｍｌ）を加えた後、これを減圧下濃縮乾固することにより、表記化合物０．０８ｇ（収率４３％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.24 (3H, t, J=7.0), 1.75-2.00 (4H, m), 2.28 (3H, s), 3.45-3.55 (2H, m), 3.70-3.80 (2H, m), 4.20 (2H, q, J=7.0), 4.30-4.40 (1H, m), 4.45 (2H, s), 4.51 (2H, d, J=6.0), 6.44 (1H, dt, J=16.0, 6.0), 6.61 (1H, d, J=16.0), 7.55 (1H, t, J=8.0), 7.64 (2H, s), 7.68 (1H, d, J=8.0), 7.72 (1H, d, J=8.0), 7.88 (1H, s);
MASS (FAB, m/z) : 628 [M+H]. (B) N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-dicarbamoylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] Ethyl sulfamoyl acetate dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [3,5-dicarbamoyl-4- (piperidin-4-yloxy) phenyl] sulfamoyl acetic acid Ethyl dihydrochloride (0.17 g) was dissolved in ethanol (20 ml), ethylacetimidate hydrochloride (1.67 g) and triethylamine (1.68 ml) were added, and the mixture was stirred at room temperature for 5.5 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 17.5% acetonitrile / water), and the resulting amorphous solid was then added to ethanol (5 ml). After dissolution, 4M hydrogen chloride dioxane solution (0.10 ml) was added, and this was concentrated to dryness under reduced pressure to obtain 0.08 g (yield 43%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.24 (3H, t, J = 7.0), 1.75-2.00 (4H, m), 2.28 (3H, s), 3.45-3.55 (2H, m), 3.70 -3.80 (2H, m), 4.20 (2H, q, J = 7.0), 4.30-4.40 (1H, m), 4.45 (2H, s), 4.51 (2H, d, J = 6.0), 6.44 (1H, dt, J = 16.0, 6.0), 6.61 (1H, d, J = 16.0), 7.55 (1H, t, J = 8.0), 7.64 (2H, s), 7.68 (1H, d, J = 8.0), 7.72 (1H, d, J = 8.0), 7.88 (1H, s);
MASS (FAB, m / z): 628 [M + H].

実施例５９
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３，５−ジカルバモイルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸２塩酸塩（例示化合物番号：２０３５）
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−３，５−ジカルバモイルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩（０．０７ｇ）を３Ｍ塩酸（１０ｍｌ）に溶解させ、７０℃で２時間撹拌した。反応液を室温まで冷却させた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１０％アセトニトリル／水）にて精製した後、得られた無定形固体を１Ｍ塩酸（０．３０ｍｌ）に溶解させ、これを減圧下濃縮乾固することにより、表記化合物０．０５ｇ（収率６９％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.75-2.00 (4H, m), 2.27 (3H, s), 3.45-3.55 (2H, m), 3.70-3.80 (2H, m), 4.32 (2H, s), 4.35-4.40 (1H, m), 4.51 (2H, d, J=6.0), 6.45 (1H, dt, J=16.0, 6.0), 6.60 (1H, d, J=16.0), 7.55 (1H, t, J=8.0), 7.63 (2H, s), 7.67 (1H, d, J=8.0), 7.72 (1H, d, J=8.0), 7.87 (1H, s);
IR (KBr, cm^-1) : 1729, 1668. Example 59
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-dicarbamoylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoylacetic acid 2 Hydrochloride (Exemplified Compound Number: 2035)
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-dicarbamoylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl ethyl acetate Dihydrochloride (0.07 g) was dissolved in 3M hydrochloric acid (10 ml) and stirred at 70 ° C. for 2 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 10% acetonitrile / water), and the resulting amorphous solid was treated with 1M. This was dissolved in hydrochloric acid (0.30 ml) and concentrated to dryness under reduced pressure to obtain 0.05 g (yield 69%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.75-2.00 (4H, m), 2.27 (3H, s), 3.45-3.55 (2H, m), 3.70-3.80 (2H, m), 4.32 (2H , s), 4.35-4.40 (1H, m), 4.51 (2H, d, J = 6.0), 6.45 (1H, dt, J = 16.0, 6.0), 6.60 (1H, d, J = 16.0), 7.55 ( 1H, t, J = 8.0), 7.63 (2H, s), 7.67 (1H, d, J = 8.0), 7.72 (1H, d, J = 8.0), 7.87 (1H, s);
IR (KBr, cm ^-1 ): 1729, 1668.

実施例６０
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−５−カルバモイル−２−メチルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩
（例示化合物番号：１４９１） Example 60
N- [4- (1-acetimidoylpiperidin-4-yloxy) -5-carbamoyl-2-methylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl acetic acid Ethyl dihydrochloride (Exemplified compound number: 1491)

（ａ）Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［５−カルバモイル−２−メチル−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−５−カルバモイル−２−メチルフェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル（２．１０ｇ）をジクロロメタン（２５ｍｌ）及びエタノール（２５ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化水素を１時間通じた後、密栓をして室温で３時間撹拌した。反応液を減圧下濃縮した後、残渣をエタノール（２５ｍｌ）に溶解させ、塩化アンモニウム水溶液（０．５９ｇを水５ｍｌに溶解）及び２８％アンモニア水（１．３４ｍｌ）を加え、室温で７時間撹拌した後、１２時間放置した。反応液を減圧下濃縮した後、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１７．５％アセトニトリル／水）にて精製し、得られた無定形固体をエタノール（２０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（１．４０ｍｌ）を加えた後、これを減圧下濃縮乾固することにより、表記化合物１．１８ｇ（収率５７％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.24 (3H, t, J=7.0), 1.85-1.95 (2H, m), 2.10-2.20 (2H, m), 2.33 (3H, s), 3.05-3.15 (2H, m), 3.20-3.30 (2H, m), 4.21 (2H, q, J=7.0), 4.25-4.30 (1H, m), 4.36 (1H, d, J=14.0), 4.45-4.50 (1H, m), 4.51 (1H, d, J=14.0), 4.80 (1H, m), 6.40-6.55 (2H, m), 6.48 (1H, s), 7.55 (1H, t, J=8.0), 7.69 (1H, d, J=8.0), 7.72 (1H, d, J=8.0), 7,77 (1H, s), 7.83 (1H, s);
IR (KBr, cm^-1) : 1737, 1673, 1657. (A) N- [3- (3-Amidinophenyl) -2- (E) -propenyl] -N- [5-carbamoyl-2-methyl-4- (piperidin-4-yloxy) phenyl] sulfamoyl ethyl acetate 2 Hydrochloride N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-carbamoyl-2-methylphenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl ] Ethyl sulfamoyl acetate (2.10 g) was dissolved in a mixed solvent of dichloromethane (25 ml) and ethanol (25 ml). Under ice-cooling, hydrogen chloride was passed through for 1 hour, and the bottle was sealed and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (25 ml), aqueous ammonium chloride solution (0.59 g dissolved in 5 ml of water) and 28% aqueous ammonia (1.34 ml) were added, and the mixture was stirred at room temperature for 7 hours. And left for 12 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 17.5% acetonitrile / water), and the resulting amorphous solid was dissolved in ethanol (20 ml). After adding a 4M hydrogen chloride dioxane solution (1.40 ml), this was concentrated to dryness under reduced pressure to obtain 1.18 g (yield 57%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.24 (3H, t, J = 7.0), 1.85-1.95 (2H, m), 2.10-2.20 (2H, m), 2.33 (3H, s), 3.05 -3.15 (2H, m), 3.20-3.30 (2H, m), 4.21 (2H, q, J = 7.0), 4.25-4.30 (1H, m), 4.36 (1H, d, J = 14.0), 4.45- 4.50 (1H, m), 4.51 (1H, d, J = 14.0), 4.80 (1H, m), 6.40-6.55 (2H, m), 6.48 (1H, s), 7.55 (1H, t, J = 8.0 ), 7.69 (1H, d, J = 8.0), 7.72 (1H, d, J = 8.0), 7,77 (1H, s), 7.83 (1H, s);
IR (KBr, cm ^-1 ): 1737, 1673, 1657.

（ｂ）Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−５−カルバモイル−２−メチルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩
Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−［５−カルバモイル−２−メチル−４−（ピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル２塩酸塩（１．００ｇ）をエタノール（５０ｍｌ）に溶解させ、エチルアセトイミデート塩酸塩（０．５９ｇ）及びトリエチルアミン（１．３３ｍｌ）を加え、室温で１時間撹拌した後、１４時間放置した。反応液を減圧下濃縮した後、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：２０％アセトニトリル／水）にて精製し、得られた無定形固体をエタノール（１０ｍｌ）に溶解させ、４Ｍ塩化水素ジオキサン溶液（１．００ｍｌ）を加えた後、これを減圧下濃縮乾固することにより、表記化合物０．９８ｇ（収率９２％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.24 (3H, t, J=7.0), 1.75-1.90 (2H, m), 2.00-2.15 (2H, m), 2.30 (3H, s), 2.34 (3H, s), 3.50-3.60 (2H, m), 3.70-3.80 (1H, m), 3.80-3.90 (1H, m), 4.21 (2H, q, J=7.0), 4.25-4.30 (1H, m), 4.36 (1H, d, J=14.0), 4.45-4.50 (1H, m), 4.51 (1H, d, J=14.0), 4.87 (1H, m), 6.40-6.55 (2H, m), 7.19 (1H, s), 7.56 (1H, t, J=8.0), 7.70 (1H, d, J=8.0), 7.72 (1H, d, J=8.0), 7,82 (1H, s), 7.84 (1H, s);
IR (KBr, cm^-1) : 1737, 1672, 1622. (B) N- [4- (1-acetimidoylpiperidin-4-yloxy) -5-carbamoyl-2-methylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl ] Sulfamoyl ethyl acetate dihydrochloride N- [3- (3-amidinophenyl) -2- (E) -propenyl] -N- [5-carbamoyl-2-methyl-4- (piperidin-4-yloxy) phenyl] Ethyl sulfamoyl acetate dihydrochloride (1.00 g) was dissolved in ethanol (50 ml), ethylacetimidate hydrochloride (0.59 g) and triethylamine (1.33 ml) were added, and the mixture was stirred at room temperature for 1 hour. Left for hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 20% acetonitrile / water), and the resulting amorphous solid was dissolved in ethanol (10 ml). A 4M hydrogen chloride dioxane solution (1.00 ml) was added, and the mixture was concentrated to dryness under reduced pressure to obtain 0.98 g (yield 92%) of the title compound as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.24 (3H, t, J = 7.0), 1.75-1.90 (2H, m), 2.00-2.15 (2H, m), 2.30 (3H, s), 2.34 (3H, s), 3.50-3.60 (2H, m), 3.70-3.80 (1H, m), 3.80-3.90 (1H, m), 4.21 (2H, q, J = 7.0), 4.25-4.30 (1H, m), 4.36 (1H, d, J = 14.0), 4.45-4.50 (1H, m), 4.51 (1H, d, J = 14.0), 4.87 (1H, m), 6.40-6.55 (2H, m), 7.19 (1H, s), 7.56 (1H, t, J = 8.0), 7.70 (1H, d, J = 8.0), 7.72 (1H, d, J = 8.0), 7,82 (1H, s), 7.84 (1H, s);
IR (KBr, cm ^-1 ): 1737, 1672, 1622.

実施例６１
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−５−カルバモイル−２−メチルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸２塩酸塩
（例示化合物番号：２０２０）
Ｎ−［４−（１−アセトイミドイルピペリジン−４−イルオキシ）−５−カルバモイル−２−メチルフェニル］−Ｎ−［３−（３−アミジノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル２塩酸塩（０．８０ｇ）を３Ｍ塩酸（４０ｍｌ）に溶解させ、７０℃で１．５時間撹拌した。反応液を室温まで冷却させた後、減圧下濃縮し、残渣を分取ＨＰＬＣ（YMC-Pack ODS YMC、溶出溶媒：１２．５％アセトニトリル／水）にて精製し、得られた無定形固体を１Ｍ塩酸（３．００ｍｌ）に溶解させ、これを減圧下濃縮乾固することにより、表記化合物０．７１ｇ（収率９２％）を無色無定形固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.75-1.90 (2H, m), 2.00-2.15 (2H, m),
2.30 (3H, s), 2.34 (3H, s), 3.45-3.55 (1H, m), 3.55-3.65 (1H, m), 3.65-3.80 (1H, m), 3.80-3.95 (1H, m), 4.20-4.30 (1H, m), 4.22 (1H, d, J=15.0), 4.41 (1H, d, J=15.0), 4.45-4.55 (1H, m), 4.86 (1H, m), 6.40-6.55 (2H, m), 7.18 (1H, s), 7.55 (1H, t, J=7.0), 7.70 (1H, d, J=7.0), 7.72 (1H, d,
J=7.0), 7,83 (1H, s), 7.84 (1H, s);
IR (KBr, cm^-1) : 1730, 1672. Example 61
N- [4- (1-acetimidoylpiperidin-4-yloxy) -5-carbamoyl-2-methylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl acetic acid Dihydrochloride (Exemplary Compound Number: 2020)
N- [4- (1-acetimidoylpiperidin-4-yloxy) -5-carbamoyl-2-methylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl acetic acid Ethyl dihydrochloride (0.80 g) was dissolved in 3M hydrochloric acid (40 ml) and stirred at 70 ° C. for 1.5 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS YMC, elution solvent: 12.5% acetonitrile / water), and the resulting amorphous solid was purified. By dissolving in 1M hydrochloric acid (3.00 ml) and concentrating to dryness under reduced pressure, 0.71 g (yield 92%) of the title compound was obtained as a colorless amorphous solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.75-1.90 (2H, m), 2.00-2.15 (2H, m),
2.30 (3H, s), 2.34 (3H, s), 3.45-3.55 (1H, m), 3.55-3.65 (1H, m), 3.65-3.80 (1H, m), 3.80-3.95 (1H, m), 4.20-4.30 (1H, m), 4.22 (1H, d, J = 15.0), 4.41 (1H, d, J = 15.0), 4.45-4.55 (1H, m), 4.86 (1H, m), 6.40-6.55 (2H, m), 7.18 (1H, s), 7.55 (1H, t, J = 7.0), 7.70 (1H, d, J = 7.0), 7.72 (1H, d,
J = 7.0), 7,83 (1H, s), 7.84 (1H, s);
IR (KBr, cm ^-1 ): 1730, 1672.

参考例１
３−シアノ桂皮アルデヒド
３−シアノベンズアルデヒド（４．５ｇ）をトルエン（２００ｍｌ）に溶解させ、トリフェニルホスホラニリデンアセトアルデヒド（１３．６ｇ）を加えた後、反応液を７０℃で４時間撹拌した。反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン）にて精製した後、さらにトルエン及びヘキサンから再結晶化させることにより、表記化合物３．０９ｇ（収率５７％）を淡黄色針状晶として得た。
¹H NMR (500MHz, CDCl₃) δppm : 6.76 (1H, dd, J=16.0, 7.5), 7.46 (1H, d, J=16.0), 7.58 (1H, t, J=8.0), 7.73 (1H, d, J=8.0), 7.80 (1H, d, J=8.0), 7.84 (1H, s), 9.75 (1H, d, J=7.5). Reference example 1
3-Cyanocinnaldehyde 3-Cyanobenzaldehyde (4.5 g) was dissolved in toluene (200 ml), triphenylphosphoranylideneacetaldehyde (13.6 g) was added, and the reaction solution was stirred at 70 ° C. for 4 hours. The reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: dichloromethane), and then recrystallized from toluene and hexane to obtain 3.09 g (yield 57%) of the title compound. Obtained as pale yellow needles.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 6.76 (1H, dd, J = 16.0, 7.5), 7.46 (1H, d, J = 16.0), 7.58 (1H, t, J = 8.0), 7.73 (1H, d, J = 8.0), 7.80 (1H, d, J = 8.0), 7.84 (1H, s), 9.75 (1H, d, J = 7.5).

参考例２
３−（３−シアノフェニル）−２−（Ｅ）−プロペン−１−オール
３−シアノ桂皮アルデヒド（３．００ｇ）をジクロロメタン（３０ｍｌ）及びエタノール（７０ｍｌ）の混合溶媒に溶解させ、氷冷下、水素化ホウ素ナトリウム（１．３２ｇ）及び塩化セリウム（２．４９ｇ）を加えた後、同温で１．５時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加えた後、ジクロロメタンで３回抽出し、抽出液を飽和食塩水で洗浄した後、有機層を無水硫酸ナトリウムを用いて乾燥させた。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝３／２）にて精製することにより、表記化合物３．２７ｇ（収率定量的）を淡黄色油状物質として得た。
¹H NMR (500MHz, CDCl₃) δppm : 4.37 (2H, m), 6.43 (1H, dt, J=16.0, 5.0), 6.62 (1H, d, J=16.0), 7.43 (1H, t, J=8.0), 7.52 (1H, d, J=8.0), 7.60 (1H, d, J=8.0), 7.65 (1H, s). Reference example 2
3- (3-Cyanophenyl) -2- (E) -propen-1-ol 3-Cyanocinnaldehyde (3.00 g) was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (70 ml), and ice-cooled. , Sodium borohydride (1.32 g) and cerium chloride (2.49 g) were added, followed by stirring at the same temperature for 1.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction three times with dichloromethane. The extract was washed with saturated brine, and then the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/2) to give 3.27 g (quantitative yield) of the title compound as a pale yellow oily substance. Got as.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 4.37 (2H, m), 6.43 (1H, dt, J = 16.0, 5.0), 6.62 (1H, d, J = 16.0), 7.43 (1H, t, J = 8.0), 7.52 (1H, d, J = 8.0), 7.60 (1H, d, J = 8.0), 7.65 (1H, s).

参考例３
炭酸［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］エチル
３−（３−シアノフェニル）−２−（Ｅ）−プロペン−１−オール（４０３ｍｇ）をジクロロメタン（６ｍｌ）に溶解させ、ピリジン（１ｍｌ）を加えた後、氷冷下、クロロギ酸エチル（０．３８ｍｌ）を滴下し、同温で２時間撹拌した。反応液に塩化アンモニウム水溶液を加えた後、酢酸エチルで抽出し、抽出液を水、飽和食塩水で洗浄した後、有機層を無水硫酸ナトリウムを用いて乾燥させた。ろ過した後減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝４／１）にて精製することにより、表記化合物４９２ｍｇ（収率８４％）を無色油状物質として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.34 (3H, t, J=7.0), 4.24 (2H, q, J=7.0), 4.80 (2H, d, J=5.5), 6.36 (1H, dt, J=16.0, 5.5), 6.67 (1H, d, J=16.0), 7.44 (1H, t, J=8.0), 7.55 (1H, d, J=8.0), 7.61 (1H, d, J=8.0), 7.66 (1H, s). Reference example 3
[3- (3-Cyanophenyl) -2- (E) -propenyl] ethyl carbonate 3- (3-cyanophenyl) -2- (E) -propen-1-ol (403 mg) dissolved in dichloromethane (6 ml) After adding pyridine (1 ml), ethyl chloroformate (0.38 ml) was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 2 hours. An aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with water and saturated brine, and then the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 4/1) to give 492 mg (yield 84%) of the title compound as a colorless oily substance. Got as.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.34 (3H, t, J = 7.0), 4.24 (2H, q, J = 7.0), 4.80 (2H, d, J = 5.5), 6.36 (1H, dt, J = 16.0, 5.5), 6.67 (1H, d, J = 16.0), 7.44 (1H, t, J = 8.0), 7.55 (1H, d, J = 8.0), 7.61 (1H, d, J = 8.0) , 7.66 (1H, s).

参考例４
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）ニトロベンゼン
水素化ナトリウム（２．２ｇ）をヘキサンで洗浄し、Ｎ，Ｎ−ジメチルアセトアミド（１５０ｍｌ）に懸濁させた後、氷冷下、１−ｔ−ブトキシカルボニル−４−ヒドロキシピペリジン（１０．１ｇ）を加え、室温で２時間撹拌した。次いで、反応液に４−フルオロニトロベンゼンを２０分間かけて加えた後、濃褐色の反応液を４時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加えて反応を停止させた後、ｔ−ブチルメチルエーテルで３回抽出し、抽出液を水、飽和食塩水で洗浄した後、有機層を無水硫酸ナトリウムを用いて乾燥させた。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝２／１）にて精製することにより、表記化合物１１．９ｇ（収率７４％）を淡黄色固体として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.43 (9H, s), 1.76 (2H, m), 1.91 (2H, m), 3.34 (2H, m), 3.65 (2H, m), 4.56 (1H, m), 6.91 (2H, d, J=9.0), 8.15 (2H, d, J=9.0). Reference example 4
4- (1-t-Butoxycarbonylpiperidin-4-yloxy) nitrobenzene Sodium hydride (2.2 g) was washed with hexane and suspended in N, N-dimethylacetamide (150 ml). 1-t-Butoxycarbonyl-4-hydroxypiperidine (10.1 g) was added, and the mixture was stirred at room temperature for 2 hours. Subsequently, 4-fluoronitrobenzene was added to the reaction solution over 20 minutes, and then the dark brown reaction solution was stirred for 4 hours. Saturated aqueous ammonium chloride solution was added to the reaction solution to stop the reaction, followed by extraction three times with t-butyl methyl ether. The extract was washed with water and saturated brine, and the organic layer was then washed with anhydrous sodium sulfate. Dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to give 11.9 g (yield 74%) of the title compound as a pale yellow solid. Obtained.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.43 (9H, s), 1.76 (2H, m), 1.91 (2H, m), 3.34 (2H, m), 3.65 (2H, m), 4.56 (1H, m), 6.91 (2H, d, J = 9.0), 8.15 (2H, d, J = 9.0).

参考例５
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）アニリン
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）ニトロベンゼン（１１．９ｇ）をメタノール（１００ｍｌ）に溶解させ、パラジウム−炭素触媒（１．９ｇ）を加えた後、水素雰囲気下、室温で４時間撹拌した。反応液をろ過した後、ろ液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／１）にて精製することにより、表記化合物１０．７ｇ（収率９９％）を淡赤色固体として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.46 (9H, s), 1.71 (2H, m), 1.87 (2H, m), 3.27 (2H, m), 3.71 (2H, m), 4.26 (1H, m), 6.63 (2H, d,
J=8.5), 6.76 (2H, d, J=8.5). Reference Example 5
4- (1-t-Butoxycarbonylpiperidin-4-yloxy) aniline 4- (1-t-Butoxycarbonylpiperidin-4-yloxy) nitrobenzene (11.9 g) is dissolved in methanol (100 ml) to prepare a palladium-carbon catalyst. (1.9 g) was added, followed by stirring at room temperature for 4 hours under a hydrogen atmosphere. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to give 10.7 g of the title compound (yield 99). %) As a pale red solid.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.46 (9H, s), 1.71 (2H, m), 1.87 (2H, m), 3.27 (2H, m), 3.71 (2H, m), 4.26 (1H, m), 6.63 (2H, d,
J = 8.5), 6.76 (2H, d, J = 8.5).

参考例６
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］エタンスルホンアミド
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）アニリン（１０．６ｇ）及びピリジン（８ｍｌ）をジクロロメタン（７５ｍｌ）に溶解させ、氷冷下、エタンスルホニルクロリド（４．１ｍｌ）を滴下した後、室温で５時間撹拌した。反応液にメタノール（１ｍｌ）を加えた後、減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝３／２）にて精製することにより、表記化合物１１．７ｇ（収率８４％）を淡桃色固体として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.38 (3H, t, J=8.0), 1.47 (9H, s), 1.74
(2H, m), 1.90 (2H, m), 3.07 (2H, q, J=8.0), 3.34 (2H, m), 3.69 (2H, m),
4.42 (1H, m), 6.88 (2H, d, J=9.0), 7.17 (2H, d, J=9.0). Reference Example 6
N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] ethanesulfonamide 4- (1-t-butoxycarbonylpiperidin-4-yloxy) aniline (10.6 g) and pyridine (8 ml) After dissolving in dichloromethane (75 ml) and adding ethanesulfonyl chloride (4.1 ml) dropwise under ice cooling, the mixture was stirred at room temperature for 5 hours. Methanol (1 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/2) to give 11.7 g (yield) of the title compound. 84%) was obtained as a pale pink solid.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.38 (3H, t, J = 8.0), 1.47 (9H, s), 1.74
(2H, m), 1.90 (2H, m), 3.07 (2H, q, J = 8.0), 3.34 (2H, m), 3.69 (2H, m),
4.42 (1H, m), 6.88 (2H, d, J = 9.0), 7.17 (2H, d, J = 9.0).

参考例７
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］エタンスルホンアミド
炭酸［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］エチル（１．０４ｇ）及びＮ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］エタンスルホンアミド（１．１５ｇ）をテトラヒドロフラン（９ｍｌ）に懸濁させ、トリス（ジベンジリデンアセトン）パラジウムクロロホルム錯体（０．０７７ｇ）及びトリフェニルホスフィン（０．０３９ｇ）を加えた後、室温で３時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／酢酸エチル＝８／１）にて精製することにより、表記化合物１．５７ｇ（収率定量的）を淡黄色油状物質として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.42 (3H, t, J=7.0), 1.47 (9H, s), 1.74
(2H, m), 1.90 (2H, m), 3.06 (2H, q, J=7.0), 3.34 (2H, m), 3.68 (2H, m),
4.42 (2H, d, J=7.0), 4.44 (1H, m), 6.28 (1H, dt, J=15.5, 7.0), 6.42 (1H, d, J=15.5), 6.89 (2H, d, J=9.0), 7.26 (2H, d, J=9.0), 7.40 (1H, t, J=7.5), 7.52 (2H, m), 7.56 (1H, s). Reference Example 7
N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] ethanesulfonamide Carbonate [3- (3 -Cyanophenyl) -2- (E) -propenyl] ethyl (1.04 g) and N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] ethanesulfonamide (1.15 g) in tetrahydrofuran (9 ml), tris (dibenzylideneacetone) palladium chloroform complex (0.077 g) and triphenylphosphine (0.039 g) were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 8/1) to give 1.57 g of the title compound (quantitative yield) as a pale yellow oil. Obtained as material.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.42 (3H, t, J = 7.0), 1.47 (9H, s), 1.74
(2H, m), 1.90 (2H, m), 3.06 (2H, q, J = 7.0), 3.34 (2H, m), 3.68 (2H, m),
4.42 (2H, d, J = 7.0), 4.44 (1H, m), 6.28 (1H, dt, J = 15.5, 7.0), 6.42 (1H, d, J = 15.5), 6.89 (2H, d, J = 9.0), 7.26 (2H, d, J = 9.0), 7.40 (1H, t, J = 7.5), 7.52 (2H, m), 7.56 (1H, s).

参考例８
３−（３−シアノフェニル）−２−メチル−２−（Ｅ）−プロペナール
３−シアノベンズアルデヒド（２．６２ｇ）をトルエン（９０ｍｌ）に溶解させ、２−トリフェニルホスホラニリデンプロピオンアルデヒド（８．２８ｇ）を加えた後、７０℃で１１時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン）にて精製することにより、表記化合物２．６１ｇ（収率７６％）を淡黄色針状晶として得た。
¹H NMR (500MHz, CDCl₃) δppm : 2.07 (3H, s), 7.25 (1H, bs), 7.59 (1H, t, J=8.0), 7.68 (1H, d, J=8.0), 7.74 (1H, d, J=8.0), 7.79 (1H, s), 9.63 (1H, s). Reference Example 8
3- (3-Cyanophenyl) -2-methyl-2- (E) -propenal 3-Cyanobenzaldehyde (2.62 g) was dissolved in toluene (90 ml) and 2-triphenylphosphoranylidenepropionaldehyde (8. 28 g) was added and stirred at 70 ° C. for 11 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane) to give 2.61 g (yield 76%) of the title compound as pale yellow needles.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 2.07 (3H, s), 7.25 (1H, bs), 7.59 (1H, t, J = 8.0), 7.68 (1H, d, J = 8.0), 7.74 (1H , d, J = 8.0), 7.79 (1H, s), 9.63 (1H, s).

参考例９
３−（３−シアノフェニル）−２−メチル−２−（Ｅ）−プロペン−１−オール
３−（３−シアノフェニル）−２−メチル−２−（Ｅ）−プロペナール（２．００ｇ）をジクロロメタン（３０ｍｌ）及びエタノール（６０ｍｌ）の混合溶媒に溶解させ、氷冷下、水素化ホウ素ナトリウム（０．８３ｇ）及び塩化セリウム（１．３０ｇ）を加えた後、同温で３時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加えた後、ジクロロメタンで３回抽出し、抽出液を水及び飽和食塩水で洗浄した後、有機層を無水硫酸ナトリウムを用いて乾燥させた。ろ過した後、減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／１）にて精製することにより、表記化合物２．０５ｇ（収率定量的）を淡黄色油状物質として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.87 (3H, s), 4.22 (2H, m), 6.52
(1H, bs), 7.42 - 7.52 (3H, m), 7.55 (1H, s). Reference Example 9
3- (3-cyanophenyl) -2-methyl-2- (E) -propen-1-ol 3- (3-cyanophenyl) -2-methyl-2- (E) -propenal (2.00 g) The mixture was dissolved in a mixed solvent of dichloromethane (30 ml) and ethanol (60 ml), and sodium borohydride (0.83 g) and cerium chloride (1.30 g) were added under ice cooling, followed by stirring at the same temperature for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction three times with dichloromethane. The extract was washed with water and saturated brine, and then the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/1) to give 2.05 g of the title compound (quantitative yield). Obtained as a pale yellow oil.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.87 (3H, s), 4.22 (2H, m), 6.52
(1H, bs), 7.42-7.52 (3H, m), 7.55 (1H, s).

参考例１０
炭酸［３−（３−シアノフェニル）−２−メチル−２−（Ｅ）−プロペニル］エチル
３−（３−シアノフェニル）−２−メチル−２−（Ｅ）−プロペン−１−オール（２．００ｇ）をジクロロメタン（２０ｍｌ）に溶解させ、ピリジン（３ｍｌ）を加えた後、氷冷下、クロロギ酸エチル（１．３０ｍｌ）を滴下し、室温で１２時間撹拌した。反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝４／１）にて精製することにより、表記化合物２．４６ｇ（収率８７％）を無色油状物質として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.34 (3H, t, J=7.0), 1.90 (3H, s), 4.25
(2H, q, J=7.0), 4.70 (2H, s), 6.53 (1H, bs), 7.43 - 7.55 (4H, m). Reference Example 10
[3- (3-Cyanophenyl) -2-methyl-2- (E) -propenyl] ethyl carbonate 3- (3-cyanophenyl) -2-methyl-2- (E) -propen-1-ol (2 0.000 g) was dissolved in dichloromethane (20 ml), pyridine (3 ml) was added, and then ethyl chloroformate (1.30 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to give 2.46 g (yield 87%) of the title compound as a colorless oil. Obtained.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.34 (3H, t, J = 7.0), 1.90 (3H, s), 4.25
(2H, q, J = 7.0), 4.70 (2H, s), 6.53 (1H, bs), 7.43-7.55 (4H, m).

参考例１１
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−シアノフェニル）−２−メチル−２−（Ｅ）−プロペニル］エタンスルホンアミド
炭酸［３−（３−シアノフェニル）−２−メチル−２−（Ｅ）−プロペニル］エチル（１．１０ｇ）及びＮ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］エタンスルホンアミド（１．１５ｇ）をテトラヒドロフラン（９ｍｌ）に懸濁させ、トリス（ジベンジリデンアセトン）パラジウムクロロホルム錯体（７８ｍｇ）及びトリフェニルホスフィン（３９ｍｇ）を加えた後、室温で１６時間撹拌した。反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／酢酸エチル＝１２／１）にて精製することにより、表記化合物０．５８ｇ（収率３６％）を無色無定形固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.42 (3H, t, J=7.5), 1.47 (9H, s), 1.75
(2H, m), 1.89 (3H, s), 1.91 (2H, m), 3.07 (2H, q, J=7.5), 3.34 (2H, m),
3.69 (2H, m), 4.37 (2H, s), 4.45 (1H, m), 6.21 (1H, s), 6.89 (2H, d, J=9.0), 7.26 (2H, d, J=9.0), 7.32 (1H, d, J=8.0), 7.35 (1H, s), 7.38 (1H, t, J=8.0), 7.48 (1H, d, J=8.0). Reference Example 11
N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2-methyl-2- (E) -propenyl] ethanesulfonamide Carbonate [ 3- (3-Cyanophenyl) -2-methyl-2- (E) -propenyl] ethyl (1.10 g) and N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] ethanesulfone Amide (1.15 g) was suspended in tetrahydrofuran (9 ml), tris (dibenzylideneacetone) palladium chloroform complex (78 mg) and triphenylphosphine (39 mg) were added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 12/1) to give 0.58 g (36% yield) of the title compound as a colorless amorphous solid. Got as.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.42 (3H, t, J = 7.5), 1.47 (9H, s), 1.75
(2H, m), 1.89 (3H, s), 1.91 (2H, m), 3.07 (2H, q, J = 7.5), 3.34 (2H, m),
3.69 (2H, m), 4.37 (2H, s), 4.45 (1H, m), 6.21 (1H, s), 6.89 (2H, d, J = 9.0), 7.26 (2H, d, J = 9.0), 7.32 (1H, d, J = 8.0), 7.35 (1H, s), 7.38 (1H, t, J = 8.0), 7.48 (1H, d, J = 8.0).

参考例１２
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）アニリン（４．３９ｇ）及びピリジン（２．４ｍｌ）をジクロロメタン（３０ｍｌ）に溶解させ、氷冷下、クロロスルホニル酢酸エチル（２．４ｍｌ）を滴下した後、室温で１３時間撹拌した。反応液にメタノール（０．５ｍｌ）を加えた後、減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝３／２）にて精製することにより、表記化合物４．９６ｇ（収率７５％）を淡赤色油状物質として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.33 (3H, t, J=7.0), 1.47 (9H, s), 1.75
(2H, m), 1.90 (2H, m), 3.34 (2H, m), 3.69 (2H, m), 3.89 (2H, s), 4.29 (2H, q, J=7.0), 4.44 (1H, m), 6.89 (2H, d, J=8.5), 7.27 (2H, d, J=8.5). Reference Example 12
N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] sulfamoyl acetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) aniline (4.39 g) and pyridine (2.4 ml) ) Was dissolved in dichloromethane (30 ml), and ethyl chlorosulfonyl acetate (2.4 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 13 hours. Methanol (0.5 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/2) to give 4.96 g of the title compound. (75% yield) was obtained as a pale red oil.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.33 (3H, t, J = 7.0), 1.47 (9H, s), 1.75
(2H, m), 1.90 (2H, m), 3.34 (2H, m), 3.69 (2H, m), 3.89 (2H, s), 4.29 (2H, q, J = 7.0), 4.44 (1H, m ), 6.89 (2H, d, J = 8.5), 7.27 (2H, d, J = 8.5).

参考例１３
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル
３−（３−シアノフェニル）−２−（Ｅ）−プロペン−１−オール（０．８０ｇ）、Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル（２．２１ｇ）及びトリフェニルホスフィン（１．７０ｇ）を、ジクロロメタン（４０ｍｌ）に溶解させ、氷冷下、アゾジカルボン酸ジエチル（１．０ｍｌ）を滴下した後、同温で２時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／酢酸エチル＝１０／１）にて精製することにより、表記化合物２．１５ｇ（収率７４％）を無色油状物質として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.35 (3H, t, J=7.0), 1.47 (9H, s), 1.75
(2H, m), 1.90 (2H, m), 3.34 (2H, m), 3.68 (2H, m), 3.98 (2H, s), 4.30 (2H, q, J=7.0), 4.45 (1H, m), 4.47 (2H, d, J=6.0), 6.24 (1H, dt, J=15.5, 6.0), 6.40 (1H, d, J=15.5), 6.90 (2H, d, J=8.5), 7.39 (3H, m), 7.51 (2H,
m), 7.55 (1H, s). Reference Example 13
N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl acetate ethyl 3- (3-cyano Phenyl) -2- (E) -propen-1-ol (0.80 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] sulfamoyl ethyl acetate (2.21 g) and tri Phenylphosphine (1.70 g) was dissolved in dichloromethane (40 ml), and diethyl azodicarboxylate (1.0 ml) was added dropwise under ice cooling, followed by stirring at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 10/1) to give 2.15 g (yield 74%) of the title compound as a colorless oily substance. Got as.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.35 (3H, t, J = 7.0), 1.47 (9H, s), 1.75
(2H, m), 1.90 (2H, m), 3.34 (2H, m), 3.68 (2H, m), 3.98 (2H, s), 4.30 (2H, q, J = 7.0), 4.45 (1H, m ), 4.47 (2H, d, J = 6.0), 6.24 (1H, dt, J = 15.5, 6.0), 6.40 (1H, d, J = 15.5), 6.90 (2H, d, J = 8.5), 7.39 ( 3H, m), 7.51 (2H,
m), 7.55 (1H, s).

参考例１４
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−２−メチルニトロベンゼン
１−ｔ−ブトキシカルボニル−４−ヒドロキシピペリジン（６．０４ｇ）、３−メチル−４−ニトロフェノール（４．５９ｇ）及びトリフェニルホスフィン（１０．２０ｇ）を、ジクロロメタン（１００ｍｌ）に溶解させ、氷冷下、アゾジカルボン酸ジエチル（６．１ｍｌ）を滴下した後、室温で６時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝３／１）にて精製することにより、表記化合物６．０４ｇ（収率６０％）を淡黄色固体として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.48 (9H, s), 1.78 (2H, m), 1.94 (2H, m), 2.62 (3H, s), 3.38 (2H, m), 3.69 (2H, m), 4.58 (1H, m), 6.80 (2H, m),
8.08 (1H, d, J=9.5). Reference Example 14
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -2-methylnitrobenzene 1-t-butoxycarbonyl-4-hydroxypiperidine (6.04 g), 3-methyl-4-nitrophenol (4.59 g) And triphenylphosphine (10.20 g) were dissolved in dichloromethane (100 ml), and diethyl azodicarboxylate (6.1 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/1) to give 6.04 g (yield 60%) of the title compound as a pale yellow solid. Got as.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.48 (9H, s), 1.78 (2H, m), 1.94 (2H, m), 2.62 (3H, s), 3.38 (2H, m), 3.69 (2H, m), 4.58 (1H, m), 6.80 (2H, m),
8.08 (1H, d, J = 9.5).

参考例１５
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−２−メチルアニリン
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−２−メチルニトロベンゼン（３．２３ｇ）をメタノール（３０ｍｌ）に溶解させ、パラジウム−炭素触媒（０．２１ｇ）を加えた後、水素雰囲気下、室温で４時間撹拌した。反応液をろ過した後、ろ液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／１）にて精製することにより、表記化合物３．０２ｇ（収率９９％）を淡赤色油状物質として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.47 (9H, s), 1.70 (2H, m), 1.87 (2H, m), 2.12 (3H, s), 3.27 (2H, m), 3.71 (2H, m), 4.26 (1H, m), 6.59-6.69 (3H, m). Reference Example 15
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -2-methylaniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -2-methylnitrobenzene (3.23 g) in methanol (30 ml) After adding palladium-carbon catalyst (0.21 g), the mixture was stirred at room temperature for 4 hours in a hydrogen atmosphere. After filtration of the reaction solution, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/1) to give 3.02 g of the title compound (yield 99). %) As a pale red oil.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.70 (2H, m), 1.87 (2H, m), 2.12 (3H, s), 3.27 (2H, m), 3.71 (2H, m), 4.26 (1H, m), 6.59-6.69 (3H, m).

参考例１６
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−２−メチルフェニル］スルファモイル酢酸エチル
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−２−メチルアニリン（３．００ｇ）及びピリジン（１．６ｍｌ）をジクロロメタン（２０ｍｌ）に溶解させ、氷冷下、クロロスルホニル酢酸エチル（１．６ｍｌ）を滴下した後、室温で１３時間撹拌した。反応液にメタノール（１ｍｌ）を加えた後、減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝３／２）にて精製することにより、表記化合物２．３５ｇ（収率５３％）を淡黄色固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.33 (3H, t, J=7.0), 1.47 (9H, s), 1.74
(2H, m), 1.90 (2H, m), 2.38 (3H, s), 3.34 (2H, m), 3.68 (2H, m), 4.01 (2H, s), 4.29 (2H, q, J=7.0), 4.43 (1H, m), 6.73 (1H, dd, J=8.5, 3.0), 6.80 (1H, d, J=3.0), 7.34 (1H, d, J=8.0). Reference Example 16
N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -2-methylphenyl] sulfamoyl acetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -2-methylaniline (3. 00 g) and pyridine (1.6 ml) were dissolved in dichloromethane (20 ml), and ethyl chlorosulfonylacetate (1.6 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 13 hours. Methanol (1 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/2) to give 2.35 g (yield) of the title compound. 53%) was obtained as a pale yellow solid.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.33 (3H, t, J = 7.0), 1.47 (9H, s), 1.74
(2H, m), 1.90 (2H, m), 2.38 (3H, s), 3.34 (2H, m), 3.68 (2H, m), 4.01 (2H, s), 4.29 (2H, q, J = 7.0 ), 4.43 (1H, m), 6.73 (1H, dd, J = 8.5, 3.0), 6.80 (1H, d, J = 3.0), 7.34 (1H, d, J = 8.0).

参考例１７
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−２−メチルフェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル
３−（３−シアノフェニル）−２−（Ｅ）−プロペン−１−オール（０．４８ｇ）、Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−２−メチルフェニル］スルファモイル酢酸エチル（１．３７ｇ）及びトリフェニルホスフィン（０．９４ｇ）を、ジクロロメタン（２０ｍｌ）に溶解させ、氷冷下、アゾジカルボン酸ジエチル（０．５７ｍｌ）を滴下した後、同温で１時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／酢酸エチル＝１１／１）にて精製することにより、表記化合物１．８０ｇ（収率定量的）を淡黄色無定形固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.36 (3H, t, J=7.0), 1.47 (9H, s), 1.74
(2H, m), 1.90 (2H, m), 2.35 (3H, s), 3.34 (2H, m), 3.68 (2H, m), 3.99 (1H, d, J=15.0), 4.12 (1H, d, J=15.0), 4.27 (1H, dd, J=15.0, 6.0), 4.31 (2H, m), 4.44 (1H, m), 4.50 (1H, dd, J=15.0, 6.0), 6.28 (1H, dt, J=16.5, 6.0), 6.32 (1H, d, J=16.5), 6.76 (1H, dd, J=9.0, 3.0), 6.79 (1H, d, J=3.0), 7.39 (1H, d, J=9.0), 7.41 (1H, d, J=7.5), 7.52 (3H, m). Reference Example 17
N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -2-methylphenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl acetate 3- (3-Cyanophenyl) -2- (E) -propen-1-ol (0.48 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -2-methylphenyl] sulfamoyl acetic acid Ethyl (1.37 g) and triphenylphosphine (0.94 g) were dissolved in dichloromethane (20 ml), and diethyl azodicarboxylate (0.57 ml) was added dropwise under ice cooling, followed by stirring at the same temperature for 1 hour. . The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 11/1) to give 1.80 g (quantitative yield) of the title compound as pale yellow. Obtained as a regular solid.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.0), 1.47 (9H, s), 1.74
(2H, m), 1.90 (2H, m), 2.35 (3H, s), 3.34 (2H, m), 3.68 (2H, m), 3.99 (1H, d, J = 15.0), 4.12 (1H, d , J = 15.0), 4.27 (1H, dd, J = 15.0, 6.0), 4.31 (2H, m), 4.44 (1H, m), 4.50 (1H, dd, J = 15.0, 6.0), 6.28 (1H, dt, J = 16.5, 6.0), 6.32 (1H, d, J = 16.5), 6.76 (1H, dd, J = 9.0, 3.0), 6.79 (1H, d, J = 3.0), 7.39 (1H, d, J = 9.0), 7.41 (1H, d, J = 7.5), 7.52 (3H, m).

参考例１８
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−メトキシニトロベンゼン
１−ｔ−ブトキシカルボニル−４−ヒドロキシピペリジン（３．０２ｇ）、２−メトキシ−４−ニトロフェノール（２．５４ｇ）及びトリフェニルホスフィン（１０．２０ｇ）を、ジクロロメタン（６０ｍｌ）に溶解させ、氷冷下、アゾジカルボン酸ジエチル（３．１ｍｌ）を滴下した後、室温で２０時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝５／２）にて精製することにより、表記化合物４．３６ｇ（収率８２％）を淡黄色油状物質として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.47 (9H, s), 1.83 (2H, m), 1.96 (2H, m), 3.33 (2H, m), 3.77 (2H, m), 3.94 (3H, s), 4.61 (1H, m), 6.94 (1H, d, J=9.0), 7.76 (1H, d, J=2.0), 7.87 (1H, dd, J=9.0, 2.0). Reference Example 18
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-methoxynitrobenzene 1-t-butoxycarbonyl-4-hydroxypiperidine (3.02 g), 2-methoxy-4-nitrophenol (2.54 g) And triphenylphosphine (10.20 g) were dissolved in dichloromethane (60 ml), and diethyl azodicarboxylate (3.1 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 5/2) to give 4.36 g (yield 82%) of the title compound as a pale yellow oil. Obtained as material.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.83 (2H, m), 1.96 (2H, m), 3.33 (2H, m), 3.77 (2H, m), 3.94 (3H, s), 4.61 (1H, m), 6.94 (1H, d, J = 9.0), 7.76 (1H, d, J = 2.0), 7.87 (1H, dd, J = 9.0, 2.0).

参考例１９
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−メトキシアニリン
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−メトキシニトロベンゼン（４．３６ｇ）をメタノール（６０ｍｌ）に溶解させ、パラジウム−炭素触媒（０．２５ｇ）を加えた後、水素雰囲気下、室温で６５時間撹拌した。反応液をろ過した後、ろ液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／１）にて精製することにより、表記化合物２．０３ｇ（収率５１％）を淡赤色油状物質として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.46 (9H, s), 1.71 (2H, m), 1.87 (2H, m), 3.18 (2H, m), 3.78 (2H, m), 3.80 (3H, s), 4.15 (1H, m), 6.19 (1H, dd,
J=8.5, 3.0), 6.29 (1H, d, J=3.0), 6.76 (1H, d, J=8.5). Reference Example 19
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-methoxyaniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-methoxynitrobenzene (4.36 g) in methanol (60 ml) After adding palladium-carbon catalyst (0.25 g), the mixture was stirred at room temperature for 65 hours in a hydrogen atmosphere. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/1) to give 2.03 g (yield 51) of the title compound. %) As a pale red oil.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.46 (9H, s), 1.71 (2H, m), 1.87 (2H, m), 3.18 (2H, m), 3.78 (2H, m), 3.80 (3H, s), 4.15 (1H, m), 6.19 (1H, dd,
J = 8.5, 3.0), 6.29 (1H, d, J = 3.0), 6.76 (1H, d, J = 8.5).

参考例２０
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−メトキシフェニル］スルファモイル酢酸エチル
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−メトキシアニリン（２．００ｇ）及びピリジン（１．０ｍｌ）をジクロロメタン（４０ｍｌ）に溶解させ、氷冷下、クロロスルホニル酢酸エチル（１．０ｍｌ）を滴下し、同温で２時間、続いて室温で５時間撹拌した。反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝２／１）にて精製することにより、表記化合物２．５６ｇ（収率８７％）を淡赤色油状物質として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.32 (3H, t, J=7.0), 1.47 (9H, s), 1.76
(2H, m), 1.90 (2H, m), 3.25 (2H, m), 3.78 (2H, m), 3.85 (3H, s), 3.92 (2H, s), 4.29 (2H, q, J=7.0), 4.36 (1H, m), 6.82 (1H, dd, J=9.0, 2.5), 6.88 (1H, d, J=9.0), 6.96 (1H, d, J=2.5). Reference Example 20
N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3-methoxyphenyl] sulfamoyl acetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-methoxyaniline (2. 00 g) and pyridine (1.0 ml) were dissolved in dichloromethane (40 ml), and ethyl chlorosulfonylacetate (1.0 ml) was added dropwise under ice cooling, followed by stirring at the same temperature for 2 hours and then at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to give 2.56 g (yield 87%) of the title compound as a pale red oily substance. Got as.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.32 (3H, t, J = 7.0), 1.47 (9H, s), 1.76
(2H, m), 1.90 (2H, m), 3.25 (2H, m), 3.78 (2H, m), 3.85 (3H, s), 3.92 (2H, s), 4.29 (2H, q, J = 7.0 ), 4.36 (1H, m), 6.82 (1H, dd, J = 9.0, 2.5), 6.88 (1H, d, J = 9.0), 6.96 (1H, d, J = 2.5).

参考例２１
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−メトキシフェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル
３−（３−シアノフェニル）−２−（Ｅ）−プロペン−１−オール（３３８ｍｇ）、Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−メトキシフェニル］スルファモイル酢酸エチル（８２３ｍｇ）及びトリフェニルホスフィン（１０００ｍｇ）を、ジクロロメタン（２０ｍｌ）に溶解させ、氷冷下、アゾジカルボン酸ジエチル（０．４３ｍｌ）を滴下した後、同温で１時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／酢酸エチル＝１２／１）にて精製することにより、表記化合物９８５ｍｇ（収率７６％）を無色無定形固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.37 (3H, t, J=7.0), 1.48 (9H, s), 1.78
(2H, m), 1.93 (2H, m), 3.27 (2H, m), 3.80 (2H, m), 3.84 (3H, s), 4.02 (2H, s), 4.32 (2H, q, J=7.0), 4.43 (1H, m), 4.50 (2H, d, J=7.0), 6.27 (1H, dt, J=15.5, 7.0), 6.42 (1H, d, J=15.5), 6.92 (1H, d, J=8.0), 7.03 (1H,
dd, J=8.0, 3.0), 7.05 (1H, d, J=3.0), 7.42 (1H, t, J=8.0), 7.53 (2H, m), 7.58 (1H, s). Reference Example 21
N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3-methoxyphenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl acetate 3- (3-Cyanophenyl) -2- (E) -propen-1-ol (338 mg), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-methoxyphenyl] sulfamoyl acetate ( 823 mg) and triphenylphosphine (1000 mg) were dissolved in dichloromethane (20 ml), and diethyl azodicarboxylate (0.43 ml) was added dropwise under ice cooling, followed by stirring at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate = 12/1) to give 985 mg (yield 76%) of the title compound as a colorless amorphous solid. Obtained.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.37 (3H, t, J = 7.0), 1.48 (9H, s), 1.78
(2H, m), 1.93 (2H, m), 3.27 (2H, m), 3.80 (2H, m), 3.84 (3H, s), 4.02 (2H, s), 4.32 (2H, q, J = 7.0 ), 4.43 (1H, m), 4.50 (2H, d, J = 7.0), 6.27 (1H, dt, J = 15.5, 7.0), 6.42 (1H, d, J = 15.5), 6.92 (1H, d, J = 8.0), 7.03 (1H,
dd, J = 8.0, 3.0), 7.05 (1H, d, J = 3.0), 7.42 (1H, t, J = 8.0), 7.53 (2H, m), 7.58 (1H, s).

参考例２２
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−フルオロニトロベンゼン
１−ｔ−ブトキシカルボニル−４−ヒドロキシピペリジン（３．０２ｇ）、２−フルオロ−４−ニトロフェノール（２．３６ｇ）及びトリフェニルホスフィン（５．１１ｇ）を、ジクロロメタン（６０ｍｌ）に溶解させ、氷冷下、アゾジカルボン酸ジエチル（３．１ｍｌ）を滴下した後、室温で１４時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝５／２）にて精製することにより、表記化合物３．７１ｇ（収率７３％）を淡黄色固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.48 (9H, s), 1.84 (2H, m), 1.97 (2H, m), 3.41 (2H, m), 3.71 (2H, m), 4.66 (1H, m), 7.05 (1H, m), 8.04 (2H, m). Reference Example 22
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-fluoronitrobenzene 1-t-butoxycarbonyl-4-hydroxypiperidine (3.02 g), 2-fluoro-4-nitrophenol (2.36 g) And triphenylphosphine (5.11 g) were dissolved in dichloromethane (60 ml), and diethyl azodicarboxylate (3.1 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 5/2) to give 3.71 g (yield 73%) of the title compound as a pale yellow solid. Got as.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.48 (9H, s), 1.84 (2H, m), 1.97 (2H, m), 3.41 (2H, m), 3.71 (2H, m), 4.66 (1H, m), 7.05 (1H, m), 8.04 (2H, m).

参考例２３
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−フルオロアニリン
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−フルオロニトロベンゼン（３．７１ｇ）をメタノール（５０ｍｌ）に溶解させ、パラジウム−炭素触媒（０．３０ｇ）を加えた後、水素雰囲気下、室温で４時間撹拌した。反応液をろ過した後、ろ液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／１）にて精製することにより、表記化合物３．２７ｇ（収率９７％）を淡赤色固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.46 (9H, s), 1.72 (2H, m), 1.86 (2H, m), 3.23 (2H, m), 3.75 (2H, m), 4.17 (1H, m), 6.35 (1H, dd, J=8.5, 3.0), 6.44 (1H, dd, J=12.5, 3.0), 6.82 (1H, dd, J=9.0, 8.5). Reference Example 23
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-fluoroaniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-fluoronitrobenzene (3.71 g) in methanol (50 ml) After adding palladium-carbon catalyst (0.30 g), the mixture was stirred at room temperature for 4 hours in a hydrogen atmosphere. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/1) to give 3.27 g (yield 97) of the title compound. %) As a pale red solid.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.46 (9H, s), 1.72 (2H, m), 1.86 (2H, m), 3.23 (2H, m), 3.75 (2H, m), 4.17 (1H, m), 6.35 (1H, dd, J = 8.5, 3.0), 6.44 (1H, dd, J = 12.5, 3.0), 6.82 (1H, dd, J = 9.0, 8.5).

参考例２４
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−フルオロフェニル］スルファモイル酢酸エチル
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−フルオロアニリン（１．４９ｇ）及びピリジン（０．７７ｍｌ）をジクロロメタン（３０ｍｌ）に溶解させ、氷冷下、クロロスルホニル酢酸エチル（０．７７ｍｌ）を滴下した後、室温で７時間撹拌した。反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝３／２）にて精製することにより、表記化合物１．５８ｇ（収率７１％）を淡赤色油状物質として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.33 (3H, t, J=7.0), 1.47 (9H, s), 1.77
(2H, m), 1.90 (2H, m), 3.32 (2H, m), 3.72 (2H, m), 3.92 (2H, s), 4.29 (2H, q, J=7.0), 4.42 (1H, m), 6.97 (1H, dd, J=9.0, 8.5), 7.04 (1H, dd, J=9.0, 3.0), 7.17 (1H, dd, J=11.5, 3.0). Reference Example 24
Ethyl N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-fluorophenyl] sulfamoyl acetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-fluoroaniline (1. 49 g) and pyridine (0.77 ml) were dissolved in dichloromethane (30 ml), and ethyl chlorosulfonylacetate (0.77 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/2) to give 1.58 g (yield 71%) of the title compound as a pale red oily substance. Got as.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.33 (3H, t, J = 7.0), 1.47 (9H, s), 1.77
(2H, m), 1.90 (2H, m), 3.32 (2H, m), 3.72 (2H, m), 3.92 (2H, s), 4.29 (2H, q, J = 7.0), 4.42 (1H, m ), 6.97 (1H, dd, J = 9.0, 8.5), 7.04 (1H, dd, J = 9.0, 3.0), 7.17 (1H, dd, J = 11.5, 3.0).

参考例２５
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−フルオロフェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル
３−（３−シアノフェニル）−２−（Ｅ）−プロペン−１−オール（０．４０ｇ）、Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−フルオロフェニル］スルファモイル酢酸エチル（１．１５ｇ）及びトリフェニルホスフィン（０．８５ｇ）を、ジクロロメタン（２０ｍｌ）に溶解させ、氷冷下、アゾジカルボン酸ジエチル（０．５１ｍｌ）を滴下した後、同温で３時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／酢酸エチル＝１０／１）にて精製することにより、表記化合物１．２１ｇ（収率８１％）を淡黄色無定形固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.35 (3H, t, J=7.0), 1.47 (9H, s), 1.77
(2H, m), 1.91 (2H, m), 3.34 (2H, m), 3.70 (2H, m), 3.98 (2H, s), 4.31 (2H, q, J=7.0), 4.46 (1H, m), 4.47 (2H, d, J=7.0), 6.22 (1H, dt, J=16.0, 7.0), 6.41 (1H, d, J=16.0), 6.98 (1H, dd, J=9.0, 8.5), 7.20 (1H, dd, J=8.5, 2.0), 7.27 (1H, m), 7.40 (1H, dd, J=8.0, 7.0), 7.52 (1H, d, J=7.0), 7.53 (1H, d, J=8.0), 7.56 (1H, s). Reference Example 25
N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3-fluorophenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl acetate 3- (3-Cyanophenyl) -2- (E) -propen-1-ol (0.40 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-fluorophenyl] sulfamoyl acetic acid Ethyl (1.15 g) and triphenylphosphine (0.85 g) were dissolved in dichloromethane (20 ml), and diethyl azodicarboxylate (0.51 ml) was added dropwise under ice cooling, followed by stirring at the same temperature for 3 hours. . The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 10/1) to give 1.21 g (yield 81%) of the title compound as a pale yellow solid. Obtained as a regular solid.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.35 (3H, t, J = 7.0), 1.47 (9H, s), 1.77
(2H, m), 1.91 (2H, m), 3.34 (2H, m), 3.70 (2H, m), 3.98 (2H, s), 4.31 (2H, q, J = 7.0), 4.46 (1H, m ), 4.47 (2H, d, J = 7.0), 6.22 (1H, dt, J = 16.0, 7.0), 6.41 (1H, d, J = 16.0), 6.98 (1H, dd, J = 9.0, 8.5), 7.20 (1H, dd, J = 8.5, 2.0), 7.27 (1H, m), 7.40 (1H, dd, J = 8.0, 7.0), 7.52 (1H, d, J = 7.0), 7.53 (1H, d, J = 8.0), 7.56 (1H, s).

参考例２６
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−クロロニトロベンゼン
１−ｔ−ブトキシカルボニル−４−ヒドロキシピペリジン（３．３２ｇ）、２−クロロ−４−ニトロフェノール（２．３６ｇ）及びトリフェニルホスフィン（５．１１ｇ）を、ジクロロメタン（６０ｍｌ）に溶解させ、氷冷下、アゾジカルボン酸ジエチル（３．１ｍｌ）を滴下した後、室温で１８時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝５／２）にて精製することにより、表記化合物３．９０ｇ（収率７６％）を淡黄色固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.48 (9H, s), 1.84-1.98 (4H, m) 3.54 (2H, m), 3.62 (2H, m), 4.73 (1H, m), 7.00 (1H, d, J=9.0), 8.14 (1H, dd, J=9.0, 3.0), 8.31 (1H, d, J=3.0). Reference Example 26
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-chloronitrobenzene 1-t-butoxycarbonyl-4-hydroxypiperidine (3.32 g), 2-chloro-4-nitrophenol (2.36 g) Then, triphenylphosphine (5.11 g) was dissolved in dichloromethane (60 ml), and diethyl azodicarboxylate (3.1 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 5/2) to give 3.90 g (yield 76%) of the title compound as a pale yellow solid. Got as.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.48 (9H, s), 1.84-1.98 (4H, m) 3.54 (2H, m), 3.62 (2H, m), 4.73 (1H, m), 7.00 (1H , d, J = 9.0), 8.14 (1H, dd, J = 9.0, 3.0), 8.31 (1H, d, J = 3.0).

参考例２７
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−クロロアニリン
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−クロロニトロベンゼン（２．４０ｇ）を酢酸（５０ｍｌ）に溶解させ、室温で亜鉛粉末（５．６０ｇ）を４回に分けて加え、２時間撹拌した。反応液をろ過した後、ろ液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／１）にて精製することにより、表記化合物１．９９ｇ（収率８７％）を橙色油状物質として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.47 (9H, s), 1.77 (2H, m), 1.87 (2H, m), 3.31 (2H, m), 3.72 (2H, m), 4.26 (1H, m), 6.52 (1H, dd, J=9.0, 3.0), 6.73 (1H, d, J=3.0), 6.80 (1H, d, J=9.0). Reference Example 27
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-chloroaniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-chloronitrobenzene (2.40 g) in acetic acid (50 ml) Zinc powder (5.60 g) was added in four portions at room temperature and stirred for 2 hours. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/1) to give 1.99 g (yield 87) of the title compound. %) As an orange oil.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.77 (2H, m), 1.87 (2H, m), 3.31 (2H, m), 3.72 (2H, m), 4.26 (1H, m), 6.52 (1H, dd, J = 9.0, 3.0), 6.73 (1H, d, J = 3.0), 6.80 (1H, d, J = 9.0).

参考例２８
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−クロロフェニル］スルファモイル酢酸エチル
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−クロロアニリン（１．５０ｇ）及びピリジン（０．５６ｍｌ）をジクロロメタン（２０ｍｌ）に溶解させ、氷冷下、クロロスルホニル酢酸エチル（０．７４ｍｌ）を滴下した後、室温で５時間撹拌した。反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝３／２）にて精製することにより、表記化合物１．１９ｇ（収率５４％）を淡赤色油状物質として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.34 (3H, t, J=7.0), 1.47 (9H, s), 1.79-1.92 (4H, m), 3.46 (2H, m), 3.64 (2H, m), 3.92 (2H, s), 4.30 (2H, q, J=7.0), 4.52 (1H, m), 6.94 (1H, d, J=9.0), 7.22 (1H, dd, J=9.0, 2.5), 7.40
(1H, d, J=2.5). Reference Example 28
N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3-chlorophenyl] sulfamoyl acetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-chloroaniline (1.50 g) ) And pyridine (0.56 ml) were dissolved in dichloromethane (20 ml), and ethyl chlorosulfonyl acetate (0.74 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/2) to give 1.19 g (yield 54%) of the title compound as a pale red oily substance. Got as.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.34 (3H, t, J = 7.0), 1.47 (9H, s), 1.79-1.92 (4H, m), 3.46 (2H, m), 3.64 (2H, m ), 3.92 (2H, s), 4.30 (2H, q, J = 7.0), 4.52 (1H, m), 6.94 (1H, d, J = 9.0), 7.22 (1H, dd, J = 9.0, 2.5) , 7.40
(1H, d, J = 2.5).

参考例２９
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−クロロフェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル
３−（３−シアノフェニル）−２−（Ｅ）−プロペン−１−オール（０．４０ｇ）、Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−クロロフェニル］スルファモイル酢酸エチル（１．１９ｇ）及びトリフェニルホスフィン（０．７９ｇ）を、ジクロロメタン（２０ｍｌ）に溶解させ、氷冷下、アゾジカルボン酸ジエチル（０．５０ｍｌ）を滴下した後、同温で２．５時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／酢酸エチル＝１０／１）にて精製することにより、表記化合物１．２０ｇ（収率７８％）を淡赤色無定形固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.36 (3H, t, J=7.0), 1.47 (9H, s), 1.79-1.92 (4H, m), 3.47 (2H, m), 3.62 (2H, m), 3.99 (2H, s), 4.31 (2H, q, J=7.0), 4.47 (2H, d, J=6.5), 4.55 (1H, m), 6.23 (1H, dt, J=16.0, 6.5), 6.41 (1H, d, J=16.0), 6.94 (1H, d, J=9.0), 7.32 (1H, dd, J=9.0, 3.0), 7.41 (1H, t, J=7.5), 7.50-7.58 (4H, m). Reference Example 29
N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3-chlorophenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl ethyl acetate 3- ( 3-cyanophenyl) -2- (E) -propen-1-ol (0.40 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-chlorophenyl] sulfamoyl acetate ( 1.19 g) and triphenylphosphine (0.79 g) were dissolved in dichloromethane (20 ml), and diethyl azodicarboxylate (0.50 ml) was added dropwise under ice cooling, followed by stirring at the same temperature for 2.5 hours. . The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 10/1) to give 1.20 g (yield 78%) of the title compound as a pale red solid. Obtained as a regular solid.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.0), 1.47 (9H, s), 1.79-1.92 (4H, m), 3.47 (2H, m), 3.62 (2H, m ), 3.99 (2H, s), 4.31 (2H, q, J = 7.0), 4.47 (2H, d, J = 6.5), 4.55 (1H, m), 6.23 (1H, dt, J = 16.0, 6.5) , 6.41 (1H, d, J = 16.0), 6.94 (1H, d, J = 9.0), 7.32 (1H, dd, J = 9.0, 3.0), 7.41 (1H, t, J = 7.5), 7.50-7.58 (4H, m).

参考例３０
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−トリフルオロメチルニトロベンゼン
１−ｔ−ブトキシカルボニル−４−ヒドロキシピペリジン（１．４５ｇ）、ジャーナル・オブ・オーガニック・ケミストリー．，第６３巻，第４１９９頁（１９９８年）[J. Org. Chem., 63, 4199 (1998)]に記載の方法に従い３−トリフルオロメチルニトロベンゼンより合成された２−トリフルオロメチル−４−ニトロフェノール（１．３８ｇ）及びトリフェニルホスフィン（２．２７ｇ）を、ジクロロメタン（６５ｍｌ）に溶解させ、氷冷下、アゾジカルボン酸ジエチル（１．４ｍｌ）を滴下した後、室温で２４時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン）にて精製することにより、表記化合物２．２８ｇ（収率８８％）を淡黄色油状物質として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.49 (9H, s), 1.88-1.99 (4H, m), 3.51 (2H, m), 3.64 (2H, m), 4.83 (1H, m), 7.09 (1H, d, J=9.0), 8.41 (1H, dd, J=9.0, 3.0), 8.53 (1H, d, J=3.0). Reference Example 30
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-trifluoromethylnitrobenzene 1-t-butoxycarbonyl-4-hydroxypiperidine (1.45 g), Journal of Organic Chemistry. 63, 4199 (1998) [ J. Org. Chem. , 63 , 4199 (1998)], synthesized from 3-trifluoromethylnitrobenzene according to 2-trifluoromethyl-4- Nitrophenol (1.38 g) and triphenylphosphine (2.27 g) were dissolved in dichloromethane (65 ml), and diethyl azodicarboxylate (1.4 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 24 hours. . The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane) to give the title compound (2.28 g, yield 88%) as a pale yellow oil.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.49 (9H, s), 1.88-1.99 (4H, m), 3.51 (2H, m), 3.64 (2H, m), 4.83 (1H, m), 7.09 ( 1H, d, J = 9.0), 8.41 (1H, dd, J = 9.0, 3.0), 8.53 (1H, d, J = 3.0).

参考例３１
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−トリフルオロメチルアニリン
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−トリフルオロメチルニトロベンゼン（２．２８ｇ）を、メタノール（５０ｍｌ）に溶解させ、パラジウム−炭素触媒（０．２０ｇ）を加えた後、水素雰囲気下、室温で５時間撹拌した。反応液をろ過した後、ろ液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝３／２）にて精製することにより、表記化合物１．６９ｇ（収率８０％）を淡赤色油状物質として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.47 (9H, s), 1.76-1.88 (4H, m), 3.43 (2H, m), 3.59 (2H, m), 4.46 (1H, m), 6.78 (1H, dd, J=9.0, 3.0), 6.83 (1H,
d, J=9.0), 6.91 (1H, d, J=3.0). Reference Example 31
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-trifluoromethylaniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-trifluoromethylnitrobenzene (2.28 g) After dissolving in methanol (50 ml) and adding a palladium-carbon catalyst (0.20 g), the mixture was stirred at room temperature for 5 hours in a hydrogen atmosphere. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/2) to give 1.69 g (yield 80) of the title compound. %) As a pale red oil.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.76-1.88 (4H, m), 3.43 (2H, m), 3.59 (2H, m), 4.46 (1H, m), 6.78 ( 1H, dd, J = 9.0, 3.0), 6.83 (1H,
d, J = 9.0), 6.91 (1H, d, J = 3.0).

参考例３２
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−トリフルオロメチルフェニル］スルファモイル酢酸エチル
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−トリフルオロメチルアニリン（１．６９ｇ）及びピリジン（０．４９ｍｌ）をジクロロメタン（２０ｍｌ）に溶解させ、氷冷下、クロロスルホニル酢酸エチル（０．７６ｍｌ）を滴下した後、室温で３時間撹拌した。反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝３／２）にて精製することにより、表記化合物１．７４ｇ（収率７３％）を淡赤色油状物質として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.34 (3H, t, J=7.0), 1.48 (9H, s), 1.83-1.94 (4H, m), 3.48-3.60 (4H, m), 3.91 (2H, s), 4.31 (2H, q, J=7.0), 4.65 (1H, m), 6.99 (1H, d, J=9.0), 7.52 (1H, dd, J=9.0, 2.5),
7.56 (1H, d, J=2.5). Reference Example 32
N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3-trifluoromethylphenyl] sulfamoyl acetate ethyl 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-trifluoromethyl Aniline (1.69 g) and pyridine (0.49 ml) were dissolved in dichloromethane (20 ml), and ethyl chlorosulfonylacetate (0.76 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/2) to give 1.74 g (yield 73%) of the title compound as a pale red oily substance. Got as.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.34 (3H, t, J = 7.0), 1.48 (9H, s), 1.83-1.94 (4H, m), 3.48-3.60 (4H, m), 3.91 (2H , s), 4.31 (2H, q, J = 7.0), 4.65 (1H, m), 6.99 (1H, d, J = 9.0), 7.52 (1H, dd, J = 9.0, 2.5),
7.56 (1H, d, J = 2.5).

参考例３３
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−トリフルオロメチルフェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル
３−（３−シアノフェニル）−２−（Ｅ）−プロペン−１−オール（０．５７ｇ）、Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−トリフルオロメチルフェニル］スルファモイル酢酸エチル（１．７４ｇ）及びトリフェニルホスフィン（１．０７ｇ）を、ジクロロメタン（２７ｍｌ）に溶解させ、氷冷下、アゾジカルボン酸ジエチル（０．６５ｍｌ）を滴下した後、同温で３時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／酢酸エチル＝１２／１）にて精製することにより、表記化合物２．０６ｇ（収率９３％）を無色無定形固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.35 (3H, t, J=7.0), 1.47 (9H, s), 1.82-1.92 (4H, m), 3.46-3.62 (4H, m), 3.98 (2H, s), 4.31 (2H, q, J=7.0), 4.48 (2H, d, J=6.5), 4.66 (1H, m), 6.22 (1H, dt, J=16.0, 6.5), 6.41 (1H, d,
J=16.0), 6.98 (1H, d, J=7.5), 7.41 (1H, dd, J=8.0, 7.5), 7.52 (2H, m), 7.57 (1H, s), 7.58 (1H, dd, J=9.0, 2.0), 7.72 (1H, d, J=2.0). Reference Example 33
N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3-trifluoromethylphenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl acetate ethyl 3- (3-Cyanophenyl) -2- (E) -propen-1-ol (0.57 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-trifluoromethyl Phenyl] sulfamoyl acetate (1.74 g) and triphenylphosphine (1.07 g) were dissolved in dichloromethane (27 ml), and diethyl azodicarboxylate (0.65 ml) was added dropwise under ice-cooling. Stir for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 12/1) to give 2.06 g (yield 93%) of the title compound as colorless amorphous. Obtained as a solid.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.35 (3H, t, J = 7.0), 1.47 (9H, s), 1.82-1.92 (4H, m), 3.46-3.62 (4H, m), 3.98 (2H , s), 4.31 (2H, q, J = 7.0), 4.48 (2H, d, J = 6.5), 4.66 (1H, m), 6.22 (1H, dt, J = 16.0, 6.5), 6.41 (1H, d,
J = 16.0), 6.98 (1H, d, J = 7.5), 7.41 (1H, dd, J = 8.0, 7.5), 7.52 (2H, m), 7.57 (1H, s), 7.58 (1H, dd, J = 9.0, 2.0), 7.72 (1H, d, J = 2.0).

参考例３４
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−メチルニトロベンゼン
１−ｔ−ブトキシカルボニル−４−ヒドロキシピペリジン（３．６２ｇ）、２−メチル−４−ニトロフェノール（２．５５ｇ）及びトリフェニルホスフィン（５．２５ｇ）を、ジクロロメタン（１００ｍｌ）に溶解させ、氷冷下、アゾジカルボン酸ジエチル（３．２ｍｌ）を滴下した後、室温で１８時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン）にて精製することにより、表記化合物４．０７ｇを淡黄色油状物質の不純物混入物として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.48 (9H, s), 1.84 (2H, m), 1.95 (2H, m), 2.29 (3H, s), 3.49 (2H, m), 3.62 (2H, m), 4.66 (1H, m), 6.86 (1H, d, J=8.5), 8.07 (2H, m). Reference Example 34
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-methylnitrobenzene 1-t-butoxycarbonyl-4-hydroxypiperidine (3.62 g), 2-methyl-4-nitrophenol (2.55 g) And triphenylphosphine (5.25 g) was dissolved in dichloromethane (100 ml), and diethyl azodicarboxylate (3.2 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane) to give 4.07 g of the title compound as a light yellow oily contaminant.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.48 (9H, s), 1.84 (2H, m), 1.95 (2H, m), 2.29 (3H, s), 3.49 (2H, m), 3.62 (2H, m), 4.66 (1H, m), 6.86 (1H, d, J = 8.5), 8.07 (2H, m).

参考例３５
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−メチルアニリン
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−メチルニトロベンゼン（４．０７ｇ）を、メタノール（４０ｍｌ）に溶解させ、パラジウム−炭素触媒（０．４１ｇ）を加えた後、水素雰囲気下、室温で４時間撹拌した。反応液をろ過した後、ろ液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝３／２）にて精製することにより、表記化合物２．７３ｇ（収率参考例４１より２工程で５３％）を淡赤色油状物質として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.47 (9H, s), 1.74 (2H, m), 1.87 (2H, m), 2.17 (3H, s), 3.30 (2H, m), 3.68 (2H, m), 4.25 (1H, m), 6.47 (1H, dd,
J=8.5, 2.5), 6.53 (1H, d, J=2.5), 6.68 (1H, d, J=8.5). Reference Example 35
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-methylaniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-methylnitrobenzene (4.07 g) was added to methanol (40 ml). ), Palladium-carbon catalyst (0.41 g) was added, and the mixture was stirred at room temperature for 4 hours in a hydrogen atmosphere. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/2) to give 2.73 g of the title compound (yield reference). From Example 41, 53%) was obtained as a pale red oily substance in two steps.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.74 (2H, m), 1.87 (2H, m), 2.17 (3H, s), 3.30 (2H, m), 3.68 (2H, m), 4.25 (1H, m), 6.47 (1H, dd,
J = 8.5, 2.5), 6.53 (1H, d, J = 2.5), 6.68 (1H, d, J = 8.5).

参考例３６
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−メチルフェニル］スルファモイル酢酸エチル
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−メチルアニリン（１．６３ｇ）及びピリジン（０．８１ｍｌ）をジクロロメタン（３０ｍｌ）に溶解させ、氷冷下、クロロスルホニル酢酸エチル（０．８６ｍｌ）を滴下した後、室温で５時間撹拌した。反応液にメタノール（０．５ｍｌ）を加えた後、減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝３／２）にて精製することにより、表記化合物１．８４ｇ（収率７６％）を淡褐色無定形固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.34 (3H, t, J=7.0), 1.47 (9H, s), 1.78
(2H, m), 1.89 (2H, m), 2.22 (3H, s), 3.43 (2H, m), 3.62 (2H, m), 3.90 (2H, s), 4.29 (2H, q, J=7.0), 4.48 (1H, m), 6.79 (1H, d, J=8.0), 7.12 (2H, m). Reference Example 36
N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3-methylphenyl] sulfamoyl acetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-methylaniline (1. 63 g) and pyridine (0.81 ml) were dissolved in dichloromethane (30 ml), and ethyl chlorosulfonylacetate (0.86 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 5 hours. After adding methanol (0.5 ml) to the reaction solution, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/2) to give the title compound. 1.84 g (76% yield) was obtained as a light brown amorphous solid.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.34 (3H, t, J = 7.0), 1.47 (9H, s), 1.78
(2H, m), 1.89 (2H, m), 2.22 (3H, s), 3.43 (2H, m), 3.62 (2H, m), 3.90 (2H, s), 4.29 (2H, q, J = 7.0 ), 4.48 (1H, m), 6.79 (1H, d, J = 8.0), 7.12 (2H, m).

参考例３７
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−メチルフェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル
３−（３−シアノフェニル）−２−（Ｅ）−プロペン−１−オール（０．６４ｇ）、Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−メチルフェニル］スルファモイル酢酸エチル（１．８４ｇ）及びトリフェニルホスフィン（１．２６ｇ）を、ジクロロメタン（４０ｍｌ）に溶解させ、氷冷下、アゾジカルボン酸ジエチル（０．７６ｍｌ）を滴下した後、同温で１時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／酢酸エチル＝１２／１）にて精製することにより、表記化合物１．９０ｇ（収率７９％）を無色無定形固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.36 (3H, t, J=7.0), 1.47 (9H, s), 1.78
(2H, m), 1.89 (2H, m), 2.21 (3H, s), 3.44 (2H, m), 3.60 (2H, m), 3.99 (2H, s), 4.31 (2H, q, J=7.0), 4.46 (2H, d, J=6.5), 4.50 (1H, m), 6.24 (1H, dt, J=16.0, 6.5), 6.41 (1H, d, J=16.0), 6.80 (1H, d, J=8.0), 7.24 (2H,
m), 7.40 (1H, t, J=8.0), 7.50 (1H, d, J=7.5), 7.52 (1H, d, J=8.0), 7.56
(1H, s). Reference Example 37
N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3-methylphenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl acetate 3- (3-Cyanophenyl) -2- (E) -propen-1-ol (0.64 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-methylphenyl] sulfamoyl acetic acid Ethyl (1.84 g) and triphenylphosphine (1.26 g) were dissolved in dichloromethane (40 ml), and diethyl azodicarboxylate (0.76 ml) was added dropwise under ice cooling, followed by stirring at the same temperature for 1 hour. . The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 12/1) to give 1.90 g (yield 79%) of the title compound as colorless amorphous. Obtained as a solid.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.0), 1.47 (9H, s), 1.78
(2H, m), 1.89 (2H, m), 2.21 (3H, s), 3.44 (2H, m), 3.60 (2H, m), 3.99 (2H, s), 4.31 (2H, q, J = 7.0 ), 4.46 (2H, d, J = 6.5), 4.50 (1H, m), 6.24 (1H, dt, J = 16.0, 6.5), 6.41 (1H, d, J = 16.0), 6.80 (1H, d, J = 8.0), 7.24 (2H,
m), 7.40 (1H, t, J = 8.0), 7.50 (1H, d, J = 7.5), 7.52 (1H, d, J = 8.0), 7.56
(1H, s).

参考例３８
３−ブロモ−５−シアノトルエン
３，５−ジブロモトルエン（１０．００ｇ）を１−メチル−２−ピロリドン（７０ｍｌ）に溶解させ、シアン化銅（Ｉ）（５．２０ｇ）を加えた後、２００℃で１．５時間撹拌した。反応液を室温まで冷却させた後、水を加えて酢酸エチルで抽出し、抽出液を１Ｍ塩酸、水、飽和食塩水で順次洗浄した後、有機層を無水硫酸マグネシウムを用いて乾燥させた。減圧下溶媒を留去し、残渣をヘキサン及び酢酸エチルの混合溶媒（９／１）に懸濁させた後、ろ過した。ろ液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝９／１）にて精製することにより、表記化合物１．７０ｇ（収率２１％）を得た。
¹H NMR (270MHz, CDCl₃) δppm : 2.39 (3H, s), 7.40 (1H, s), 7.57 (1H, s), 7.60 (1H, s). Reference Example 38
3-bromo-5-cyanotoluene 3,5-dibromotoluene (10.00 g) was dissolved in 1-methyl-2-pyrrolidone (70 ml), and after adding copper (I) cyanide (5.20 g), Stir at 200 ° C. for 1.5 hours. The reaction solution was allowed to cool to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed successively with 1M hydrochloric acid, water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was suspended in a mixed solvent of hexane and ethyl acetate (9/1), followed by filtration. After the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 9/1) to obtain 1.70 g (yield 21%) of the title compound.
¹ H NMR (270MHz, CDCl ₃ ) δppm: 2.39 (3H, s), 7.40 (1H, s), 7.57 (1H, s), 7.60 (1H, s).

参考例３９
３−（３−シアノ−５−メチルフェニル）−２−（Ｅ）−プロペン−１−オール
１−ｔ−ブチルジメチルシロキシ−２−プロピン（１．７０ｇ）にカテコールボラン（１．０７ｍｌ）を加え、６０℃で３時間撹拌した。反応液を室温まで冷却させた後、トルエン（２０ｍｌ）で希釈し、３−ブロモ−５−シアノトルエン（１．４０ｇ）、テトラキス（トリフェニルホスフィン）パラジウム錯体（０．４２ｇ）、及びナトリウムエトキシド２０％エタノール溶液（３．４０ｍｌ）を加えた後、１００℃で３時間撹拌した。反応液に水を加えた後、エーテルで抽出し、抽出液を１Ｍ水酸化ナトリウム水溶液、水、飽和食塩水で順次洗浄した後、有機層を無水硫酸ナトリウムを用いて乾燥させた。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１９／１）にて精製することにより、シリルエーテル体１．５０ｇを得た。
次ぎに、得られたシリルエーテル体をテトラヒドロフラン（３０ｍｌ）に溶解させ、氷冷下、１Ｍフッ化テトラブチルアンモニウム／テトラヒドロフラン溶液（７ｍｌ）を加えた後、同温で１時間撹拌した。反応液に水を加えた後、酢酸エチルで抽出し、抽出液を水、飽和食塩水で洗浄した後、有機層を無水硫酸マグネシウムを用いて乾燥させた。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝３／２）にて精製することにより、表記化合物０．５４ｇ（収率２工程４３％）を黄色油状物質として得た。
¹H NMR (270MHz, CDCl₃) δppm : 2.38 (3H, s), 4.35 (2H, d, J=5.0), 6.40
(1H, dt, J=16.0, 5.0), 6.58 (1H, d, J=16.0), 7.33 (1H, s), 7.40 (1H, s), 7.46 (1H, s). Reference Example 39
Catecholborane (1.07 ml) was added to 3- (3-cyano-5-methylphenyl) -2- (E) -propen-1-ol 1-t-butyldimethylsiloxy-2-propyne (1.70 g) , And stirred at 60 ° C. for 3 hours. The reaction solution was allowed to cool to room temperature, diluted with toluene (20 ml), 3-bromo-5-cyanotoluene (1.40 g), tetrakis (triphenylphosphine) palladium complex (0.42 g), and sodium ethoxide. After adding a 20% ethanol solution (3.40 ml), the mixture was stirred at 100 ° C. for 3 hours. Water was added to the reaction solution, followed by extraction with ether. The extract was washed successively with 1M aqueous sodium hydroxide solution, water and saturated brine, and then the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 19/1) to obtain 1.50 g of a silyl ether form.
Next, the obtained silyl ether form was dissolved in tetrahydrofuran (30 ml), and 1M tetrabutylammonium fluoride / tetrahydrofuran solution (7 ml) was added under ice cooling, followed by stirring at the same temperature for 1 hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with water and saturated brine, and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/2) to give 0.54 g of the title compound (yield 2 steps 43%) as a yellow oil. Obtained as material.
¹ H NMR (270MHz, CDCl ₃ ) δppm: 2.38 (3H, s), 4.35 (2H, d, J = 5.0), 6.40
(1H, dt, J = 16.0, 5.0), 6.58 (1H, d, J = 16.0), 7.33 (1H, s), 7.40 (1H, s), 7.46 (1H, s).

参考例４０
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−シアノ−５−メチルフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル
３−（３−シアノ−５−メチルフェニル）−２−（Ｅ）−プロペン−１−オール（０．５４ｇ）、Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル（１．５０ｇ）及びトリフェニルホスフィン（１．１０ｇ）を、ジクロロメタン（３０ｍｌ）に溶解させ、氷冷下、アゾジカルボン酸ジエチル（０．６６ｍｌ）を滴下した後、室温で４．５時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／酢酸エチル＝１９／１）にて精製することにより、表記化合物１．７０ｇ（収率９１％）を無定形固体として得た。
¹H NMR (270MHz, CDCl₃) δppm : 1.35 (3H, t, J=7.0), 1.47 (9H, s), 1.65-1.80 (2H, m), 1.85-2.00 (2H, m), 2.36 (3H, s), 3.25-3.40 (2H, m), 3.60-3.75 (2H, m), 3.98 (2H, s), 4.30 (2H, q, J=7.0), 4.40-4.50 (3H, m), 6.21
(1H, dt, J=16.0, 6.0), 6.36 (1H, d, J=16.0), 6.90 (2H, m), 7.30-7.45 (5H, m). Reference Example 40
N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3- (3-cyano-5-methylphenyl) -2- (E) -propenyl] sulfamoyl acetate 3- (3-Cyano-5-methylphenyl) -2- (E) -propen-1-ol (0.54 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] sulfamoyl acetic acid Ethyl (1.50 g) and triphenylphosphine (1.10 g) were dissolved in dichloromethane (30 ml), and diethyl azodicarboxylate (0.66 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 4.5 hours. did. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 19/1) to give 1.70 g (yield 91%) of the title compound as an amorphous solid. Got as.
¹ H NMR (270MHz, CDCl ₃ ) δppm: 1.35 (3H, t, J = 7.0), 1.47 (9H, s), 1.65-1.80 (2H, m), 1.85-2.00 (2H, m), 2.36 (3H , s), 3.25-3.40 (2H, m), 3.60-3.75 (2H, m), 3.98 (2H, s), 4.30 (2H, q, J = 7.0), 4.40-4.50 (3H, m), 6.21
(1H, dt, J = 16.0, 6.0), 6.36 (1H, d, J = 16.0), 6.90 (2H, m), 7.30-7.45 (5H, m).

参考例４１
３−（３−シアノ−４−フルオロフェニル）−２−（Ｅ）−プロペン−１−オール
１−ｔ−ブチルジメチルシロキシ−２−プロピン（１．７０ｇ）にカテコールボラン（１．０７ｍｌ）を加え、６０℃で４時間撹拌した。反応液を室温まで冷却させた後、トルエン（２０ｍｌ）で希釈し、５−ブロモ−２−フルオロベンゾニトリル（１．４３ｇ）、テトラキス（トリフェニルホスフィン）パラジウム錯体（０．４２ｇ）及びナトリウムエトキシド２０％エタノール溶液（３．４ｍｌ）を加えた後、１００℃で４時間撹拌した。反応液に水を加えた後、エーテルで抽出し、抽出液を１Ｍ水酸化ナトリウム水溶液、水、飽和食塩水で順次洗浄した後、有機層を無水硫酸ナトリウムを用いて乾燥させた。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１９／１）にて精製することにより、シリルエーテル体１．３３ｇを得た。
次いで、得られたシリルエーテル体をテトラヒドロフラン（２０ｍｌ）に溶解させ、氷冷下、１Ｍフッ化テトラブチルアンモニウム／テトラヒドロフラン溶液（６ｍｌ）を加えた後、同温で１時間撹拌した。反応液に水を加えた後、酢酸エチルで抽出し、抽出液を水、飽和食塩水で洗浄した後、有機層を無水硫酸マグネシウムを用いて乾燥させた。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝３／２−１／１）にて精製することにより、表記化合物０．４８ｇ（収率２工程３７％）を黄色油状物質として得た。
¹H NMR (270MHz, CDCl₃) δppm : 4.30-4.40 (2H, m), 6.35 (1H, dt, J=16.0, 5.0), 6.59 (1H, d, J=16.0), 7.18 (1H, m), 7.55-7.65 (2H, m). Reference Example 41
Catecholborane (1.07 ml) was added to 3- (3-cyano-4-fluorophenyl) -2- (E) -propen-1-ol 1-tert-butyldimethylsiloxy-2-propyne (1.70 g) And stirred at 60 ° C. for 4 hours. The reaction solution was allowed to cool to room temperature, diluted with toluene (20 ml), 5-bromo-2-fluorobenzonitrile (1.43 g), tetrakis (triphenylphosphine) palladium complex (0.42 g) and sodium ethoxide. After adding a 20% ethanol solution (3.4 ml), the mixture was stirred at 100 ° C. for 4 hours. Water was added to the reaction solution, followed by extraction with ether. The extract was washed successively with 1M aqueous sodium hydroxide solution, water and saturated brine, and then the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 19/1) to obtain 1.33 g of a silyl ether compound.
Next, the obtained silyl ether was dissolved in tetrahydrofuran (20 ml), and 1M tetrabutylammonium fluoride / tetrahydrofuran solution (6 ml) was added under ice cooling, followed by stirring at the same temperature for 1 hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with water and saturated brine, and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3 / 2-1 / 1) to give 0.48 g of the title compound (yield: 37% for 2 steps). ) Was obtained as a yellow oil.
¹ H NMR (270MHz, CDCl ₃ ) δppm: 4.30-4.40 (2H, m), 6.35 (1H, dt, J = 16.0, 5.0), 6.59 (1H, d, J = 16.0), 7.18 (1H, m) , 7.55-7.65 (2H, m).

参考例４２
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−シアノ−４−フルオロフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル
３−（３−シアノ−４−フルオロフェニル）−２−（Ｅ）−プロペン−１−オール（０．４８ｇ）、Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル（１．３０ｇ）及びトリフェニルホスフィン（１．００ｇ）を、ジクロロメタン（３０ｍｌ）に溶解させ、氷冷下、アゾジカルボン酸ジエチル（０．６０ｍｌ）を滴下した後、室温で１時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／酢酸エチル＝１９／１）にて精製することにより、表記化合物１．５３ｇ（収率９３％）を無定形固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.35 (3H, t, J=7.0), 1.47 (9H, s), 1.70-1.80 (2H, m), 1.85-1.95 (2H, m), 3.30-3.40 (2H, m), 3.65-3.75 (2H, m), 3.97 (2H, s), 4.30 (2H, q, J=7.0), 4.40-4.50 (3H, m), 6.16 (1H, dt, J=16.0, 6.0), 6.37 (1H, d, J=16.0), 6.91 (2H, d, J=9.0), 7.14 (1H, m), 7.38 (2H, d, J=9.0), 7.45-7.55 (2H, m). Reference Example 42
N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3- (3-cyano-4-fluorophenyl) -2- (E) -propenyl] sulfamoyl acetate 3- (3-Cyano-4-fluorophenyl) -2- (E) -propen-1-ol (0.48 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] sulfamoyl acetic acid Ethyl (1.30 g) and triphenylphosphine (1.00 g) were dissolved in dichloromethane (30 ml), and diethyl azodicarboxylate (0.60 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 19/1) to give 1.53 g (yield 93%) of the title compound as an amorphous solid. Got as.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.35 (3H, t, J = 7.0), 1.47 (9H, s), 1.70-1.80 (2H, m), 1.85-1.95 (2H, m), 3.30-3.40 (2H, m), 3.65-3.75 (2H, m), 3.97 (2H, s), 4.30 (2H, q, J = 7.0), 4.40-4.50 (3H, m), 6.16 (1H, dt, J = 16.0, 6.0), 6.37 (1H, d, J = 16.0), 6.91 (2H, d, J = 9.0), 7.14 (1H, m), 7.38 (2H, d, J = 9.0), 7.45-7.55 (2H , m).

参考例４３
３−［３−［Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］アミノ］−１−（Ｅ）−プロペニル］ベンゾニトリル
３−シアノ桂皮アルデヒド（６．０ｇ）、４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）アニリン（１１．３ｇ）及び粉末モレキュラーシーブス５Ａ（１５．０ｇ）を、トルエン（３０ｍｌ）に懸濁させ、２時間加熱還流させた。反応液をセライトを用いてろ過した後、ろ液を減圧下濃縮し、残渣をジクロロメタン及びエーテルを用いて再結晶化させることにより、イミン体（１２．９ｇ）を得た。
次いで、得られたイミン体を、エタノール（２００ｍｌ）に懸濁させ、触媒量の塩化セリウムを加えた後、氷冷下、水素化ホウ素ナトリウム（１．１ｇ）を加え、同温で撹拌した。反応液を減圧下濃縮し、残渣に水を加えた後、酢酸エチルで抽出し、抽出液を飽和食塩水で洗浄した後、有機層を無水硫酸マグネシウムを用いて乾燥させた。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝３／２）にて精製した後、得られた黄色固体をジイソプロピルエーテルで洗浄することにより、表記化合物１０．０ｇ（収率６０％）を淡黄色結晶として得た。
¹H NMR (270MHz, CDCl₃) δppm : 1.46 (9H, s), 1.60 - 1.80 (2H, m), 1.80
- 1.95 (2H, m), 3.20 - 3.35 (2H, m), 3.65 - 3.80 (2H, m), 3.93 (2H, dd,
J=5.5, 1.0), 4.28 (1H, m), 6.39 (1H, dt, J=16.0, 5.5), 6.61 (1H, d, J=16.0), 6.61 (2H, d, J=9.0), 6.81 (2H, d, J=9.0), 7.41 (1H, t, J=7.5), 7.51 (1H, d, J=7.5), 7.57 (1H, d, J=7.5), 7.63 (1H, s). Reference Example 43
3- [3- [N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] amino] -1- (E) -propenyl] benzonitrile 3-cyanocinnaldehyde (6.0 g), 4- (1-t-Butoxycarbonylpiperidin-4-yloxy) aniline (11.3 g) and powder molecular sieve 5A (15.0 g) were suspended in toluene (30 ml) and heated to reflux for 2 hours. The reaction solution was filtered using Celite, the filtrate was concentrated under reduced pressure, and the residue was recrystallized using dichloromethane and ether to obtain an imine compound (12.9 g).
Next, the obtained imine was suspended in ethanol (200 ml), a catalytic amount of cerium chloride was added, sodium borohydride (1.1 g) was added under ice cooling, and the mixture was stirred at the same temperature. The reaction mixture was concentrated 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 the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/2), and the resulting yellow solid was washed with diisopropyl ether to give the title compound 10 0.0 g (60% yield) was obtained as pale yellow crystals.
¹ H NMR (270MHz, CDCl ₃ ) δppm: 1.46 (9H, s), 1.60-1.80 (2H, m), 1.80
-1.95 (2H, m), 3.20-3.35 (2H, m), 3.65-3.80 (2H, m), 3.93 (2H, dd,
J = 5.5, 1.0), 4.28 (1H, m), 6.39 (1H, dt, J = 16.0, 5.5), 6.61 (1H, d, J = 16.0), 6.61 (2H, d, J = 9.0), 6.81 (2H, d, J = 9.0), 7.41 (1H, t, J = 7.5), 7.51 (1H, d, J = 7.5), 7.57 (1H, d, J = 7.5), 7.63 (1H, s).

参考例４４
３−［３−［Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］−Ｎ−メチルアミノ］−１−（Ｅ）−プロペニル］ベンゾニトリル
３−［３−［Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］アミノ］−１−（Ｅ）−プロペニル］ベンゾニトリル（１０００ｍｇ）及びパラホルムアルデヒド（１３８ｍｇ）を、ジクロロメタン（２０ｍｌ）に懸濁させ、氷冷下、酢酸（０．２６ｍｌ）及びシアン化３水素化ホウ素ナトリウム（１４４ｍｇ）を加えた後、室温で終夜撹拌した。反応液にメタノール（２０ｍｌ）を加えた後、３０℃で５時間撹拌し、水を加えた後、酢酸エチルで抽出し、抽出液を飽和食塩水で洗浄した後、有機層を無水硫酸マグネシウムを用いて乾燥させた。ろ過した後減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝３／２）にて精製することにより、表記化合物７６１ｍｇ（収率７４％）を黄色油状物質として得た。
¹H NMR (270MHz, CDCl₃) δppm : 1.47 (9H, s), 1.72 (2H, m), 1.87 (2H, m), 2.92 (3H, s), 3.28 (2H, m), 3.71 (2H, m), 4.02 (2H, d, J=5.0), 4.29 (1H, m), 6.32 (1H, dt, J=16.0, 5.0), 6.51 (1H, d, J=16.0), 6.72 (2H, d, J=9.0), 6.86 (2H, d, J=9.0), 7.39 (1H, t, J=7.5), 7.49 (1H, d, J=7.5), 7.56 (1H, d, J=7.5), 7.62 (1H, s). Reference Example 44
3- [3- [N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) phenyl] -N-methylamino] -1- (E) -propenyl] benzonitrile 3- [3- [N -[4- (1-t-Butoxycarbonylpiperidin-4-yloxy) phenyl] amino] -1- (E) -propenyl] benzonitrile (1000 mg) and paraformaldehyde (138 mg) suspended in dichloromethane (20 ml) Under ice-cooling, acetic acid (0.26 ml) and sodium tricyanoborohydride (144 mg) were added, and the mixture was stirred overnight at room temperature. Methanol (20 ml) was added to the reaction solution, and the mixture was stirred at 30 ° C. for 5 hours. After adding water, the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and the organic layer was washed with anhydrous magnesium sulfate. Used to dry. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/2) to give 761 mg (yield 74%) of the title compound as a yellow oily substance. Got as.
¹ H NMR (270MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.72 (2H, m), 1.87 (2H, m), 2.92 (3H, s), 3.28 (2H, m), 3.71 (2H, m), 4.02 (2H, d, J = 5.0), 4.29 (1H, m), 6.32 (1H, dt, J = 16.0, 5.0), 6.51 (1H, d, J = 16.0), 6.72 (2H, d , J = 9.0), 6.86 (2H, d, J = 9.0), 7.39 (1H, t, J = 7.5), 7.49 (1H, d, J = 7.5), 7.56 (1H, d, J = 7.5), 7.62 (1H, s).

参考例４５
３−［３−［Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］−Ｎ−エチルアミノ］−１−（Ｅ）−プロペニル］ベンゾニトリル
３−［３−［Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］アミノ］−１−（Ｅ）−プロペニル］ベンゾニトリル（１０００ｍｇ）及びアセトアルデヒド（０．５２ｍｌ）を、ジクロロメタン（１０ｍｌ）及びメタノール（２０ｍｌ）の混合溶媒に溶解させ、氷冷下、酢酸（０．２６ｍｌ）及びシアン化３水素化ホウ素ナトリウム（１４４ｍｇ）を加え、同温で２時間撹拌した後、室温で終夜撹拌した。反応液に水を加えた後、酢酸エチルで抽出し、抽出液を飽和食塩水で洗浄した後、有機層を無水硫酸マグネシウムを用いて乾燥させた。ろ過した後減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝４／１−２／１）にて精製することにより、表記化合物６６１ｍｇ（収率６２％）を黄色油状物質として得た。
¹H NMR (270MHz, CDCl₃) δppm : 1.16 (3H, t, J=7.0), 1.46 (9H, s), 1.72
(2H, m), 1.87 (2H, m), 3.25 (2H, m), 3.36 (2H, q, J=7.0), 3.71 (2H, m),
4.01 (2H, d, J=5.0), 4.26 (1H, m), 6.31 (1H, dt, J=16.0, 5.0), 6.50 (1H, d, J=16.0), 6.69 (2H, d, J=9.0), 6.84 (2H, d, J=9.0), 7.39 (1H, t, J=7.5), 7.49 (1H, d, J=7.5), 7.55 (1H, d, J=7.5), 7.61 (1H, s). Reference Example 45
3- [3- [N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) phenyl] -N-ethylamino] -1- (E) -propenyl] benzonitrile 3- [3- [N -[4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] amino] -1- (E) -propenyl] benzonitrile (1000 mg) and acetaldehyde (0.52 ml), dichloromethane (10 ml) and methanol (20 ml) was dissolved in a mixed solvent, acetic acid (0.26 ml) and sodium tricyanoborohydride (144 mg) were added under ice cooling, and the mixture was stirred at the same temperature for 2 hours and then stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 4 / 1-2 / 1) to give 661 mg of the title compound (yield 62%). Was obtained as a yellow oil.
¹ H NMR (270MHz, CDCl ₃ ) δppm: 1.16 (3H, t, J = 7.0), 1.46 (9H, s), 1.72
(2H, m), 1.87 (2H, m), 3.25 (2H, m), 3.36 (2H, q, J = 7.0), 3.71 (2H, m),
4.01 (2H, d, J = 5.0), 4.26 (1H, m), 6.31 (1H, dt, J = 16.0, 5.0), 6.50 (1H, d, J = 16.0), 6.69 (2H, d, J = 9.0), 6.84 (2H, d, J = 9.0), 7.39 (1H, t, J = 7.5), 7.49 (1H, d, J = 7.5), 7.55 (1H, d, J = 7.5), 7.61 (1H , s).

参考例４６
３−［３−［Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］−Ｎ−イソプロピルアミノ］−１−（Ｅ）−プロペニル］ベンゾニトリル
３−［３−［Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］アミノ］−１−（Ｅ）−プロペニル］ベンゾニトリル（１５００ｍｇ）をアセトン（２０ｍｌ）に溶解させ、氷冷下、酢酸（０．２０ｍｌ）及びシアン化３水素化ホウ素ナトリウム（２１４ｍｇ）を加え、室温で終夜撹拌した後、８時間加熱還流させた。反応液に水を加えた後、酢酸エチルで抽出し、抽出液を飽和食塩水で洗浄した後、有機層を無水硫酸マグネシウムを用いて乾燥させた。ろ過した後減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒ヘキサン−酢酸エチル＝４：１）にて精製することにより、表記化合物５８３ｍｇ（収率３５％）を淡黄色油状物質として得た。
¹H NMR (270MHz, CDCl₃) δppm : 1.18 (6H, d, J=6.5), 1.46 (9H, s), 1.60
- 1.80 (2H, m), 1.80 - 1.95 (2H, m), 3.26 (2H, m), 3.71 (2H, m), 3.91 (2H, d, J=4.5), 4.00 (1H, m), 4.26 (1H, m), 6.33 (1H, dt, J=16.0, 4.5), 6.53 (1H, d, J=16.0), 6.73 (2H, d, J=9.0), 6.82 (2H, d, J=9.0), 7.38 (1H,
t, J=7.5), 7.47 (1H, d, J=7.5), 7.53 (1H, d, J=7.5), 7.60 (1H, s). Reference Example 46
3- [3- [N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) phenyl] -N-isopropylamino] -1- (E) -propenyl] benzonitrile 3- [3- [N -[4- (1-t-Butoxycarbonylpiperidin-4-yloxy) phenyl] amino] -1- (E) -propenyl] benzonitrile (1500 mg) was dissolved in acetone (20 ml), and acetic acid ( 0.20 ml) and sodium tricyanoborohydride (214 mg) were added, and the mixture was stirred at room temperature overnight and then heated to reflux for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent hexane-ethyl acetate = 4: 1) to give 583 mg (yield 35%) of the title compound as a pale yellow oily substance. Got as.
¹ H NMR (270MHz, CDCl ₃ ) δppm: 1.18 (6H, d, J = 6.5), 1.46 (9H, s), 1.60
-1.80 (2H, m), 1.80-1.95 (2H, m), 3.26 (2H, m), 3.71 (2H, m), 3.91 (2H, d, J = 4.5), 4.00 (1H, m), 4.26 (1H, m), 6.33 (1H, dt, J = 16.0, 4.5), 6.53 (1H, d, J = 16.0), 6.73 (2H, d, J = 9.0), 6.82 (2H, d, J = 9.0 ), 7.38 (1H,
t, J = 7.5), 7.47 (1H, d, J = 7.5), 7.53 (1H, d, J = 7.5), 7.60 (1H, s).

参考例４７
３−［３−［Ｎ−ベンジル−Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］アミノ］−１−（Ｅ）−プロペニル］ベンゾニトリル
３−［３−［Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］アミノ］−１−（Ｅ）−プロペニル］ベンゾニトリル（１０００ｍｇ）及びベンズアルデヒド（０．５２ｍｌ）を、ジクロロメタン（１０ｍｌ）及びメタノール（２０ｍｌ）の混合溶媒に溶解させ、氷冷下、酢酸（０．２６ｍｌ）及びシアン化３水素化ホウ素ナトリウム（１４４ｍｇ）を加えた後、１０時間加熱還流させた。反応液に水を加えた後、酢酸エチルで抽出し、抽出液を飽和食塩水で洗浄した後、有機層を無水硫酸マグネシウムを用いて乾燥させた。ろ過した後減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝４／１−２／１）にて精製することにより、表記化合物９２４ｍｇ（収率７６％）を黄色油状物質として得た。
¹H NMR (270MHz, CDCl₃) δppm : 1.46 (9H, s), 1.70 (2H, m), 1.87 (2H, m), 3.26 (2H, m), 3.69 (2H, m), 4.11 (2H, d, J=5.0), 4.26 (1H, m), 4.52 (2H, s), 6.32 (1H, dt, J=16.0, 5.0), 6.48 (1H, d, J=16.0), 6.71 (2H, d, J=9.0), 6.81 (2H, d, J=9.0), 7.20 - 7.60 (9H, m). Reference Example 47
3- [3- [N-Benzyl-N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] amino] -1- (E) -propenyl] benzonitrile 3- [3- [N -[4- (1-t-Butoxycarbonylpiperidin-4-yloxy) phenyl] amino] -1- (E) -propenyl] benzonitrile (1000 mg) and benzaldehyde (0.52 ml), dichloromethane (10 ml) and methanol (20 ml) was dissolved in a mixed solvent, and acetic acid (0.26 ml) and sodium tricyanoborohydride (144 mg) were added under ice cooling, followed by heating to reflux for 10 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 4 / 1-2 / 1) to give 924 mg (76% yield) of the title compound. Was obtained as a yellow oil.
¹ H NMR (270MHz, CDCl ₃ ) δppm: 1.46 (9H, s), 1.70 (2H, m), 1.87 (2H, m), 3.26 (2H, m), 3.69 (2H, m), 4.11 (2H, d, J = 5.0), 4.26 (1H, m), 4.52 (2H, s), 6.32 (1H, dt, J = 16.0, 5.0), 6.48 (1H, d, J = 16.0), 6.71 (2H, d , J = 9.0), 6.81 (2H, d, J = 9.0), 7.20-7.60 (9H, m).

参考例４８
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］アセトアミド
３−［３−［Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］アミノ］−１−（Ｅ）−プロペニル］ベンゾニトリル（５０３ｍｇ）及びピリジン（０．１４ｍｌ）をジクロロメタン（１０ｍｌ）に溶解させ、氷冷下、無水酢酸（０．１３ｍｌ）を加え、室温で１時間撹拌した。反応液に水を加えた後、酢酸エチルで抽出し、抽出液を飽和食塩水で洗浄した後、有機層を無水硫酸マグネシウムを用いて乾燥させた。ろ過した後減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／１−酢酸エチル）で精製した後、得られた黄色結晶をジイソプロピルエーテルで洗浄することにより、表記化合物４０３ｍｇ（収率５０％）を淡黄色結晶として得た。
¹H NMR (270MHz, CDCl₃) δppm : 1.47 (9H, s), 1.88 (3H, s), 1.70 - 1.95
(4H, m), 3.33 (2H, m), 3.70 (2H, m), 4.41 (2H, d, J=5.5), 4.47 (1H, m),
6.32 (1H, dt, J=16.0, 5.5), 6.38 (1H, d, J=16.0), 6.91 (2H, d, J=9.0), 7.07 (2H, d, J=9.0), 7.40 (1H, t, J=8.0), 7.51 (1H, d, J=8.0), 7.55 (1H,
d, J=8.0), 7.58 (1H, s). Reference Example 48
N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] acetamide 3- [3- [N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) phenyl] amino] -1- (E) -propenyl] benzonitrile (503 mg) and pyridine (0.14 ml) were dissolved in dichloromethane (10 ml), Acetic anhydride (0.13 ml) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1 / 1-ethyl acetate), and then the resulting yellow crystals were washed with diisopropyl ether. Gave 403 mg (yield 50%) of the title compound as pale yellow crystals.
¹ H NMR (270MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.88 (3H, s), 1.70-1.95
(4H, m), 3.33 (2H, m), 3.70 (2H, m), 4.41 (2H, d, J = 5.5), 4.47 (1H, m),
6.32 (1H, dt, J = 16.0, 5.5), 6.38 (1H, d, J = 16.0), 6.91 (2H, d, J = 9.0), 7.07 (2H, d, J = 9.0), 7.40 (1H, t, J = 8.0), 7.51 (1H, d, J = 8.0), 7.55 (1H,
d, J = 8.0), 7.58 (1H, s).

参考例４９
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］−２−ヒドロキシアセトアミド
３−［３−［Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］アミノ］−１−（Ｅ）−プロペニル］ベンゾニトリル（１０００ｍｇ）及びピリジン（０．２８ｍｌ）をジクロロメタン（２０ｍｌ）に溶解させ、氷冷下、アセトキシアセチルクロリド（０．２７ｍｌ）を加え、同温で１時間撹拌した。反応液に水を加えた後、酢酸エチルで抽出し、抽出液を飽和食塩水で洗浄した後、有機層を無水硫酸マグネシウムを用いて乾燥させた。ろ過した後減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝２／３）にて精製することにより、中間体化合物１２３２ｍｇを無色無定形固体として得た。
次いで、得られた中間体化合物をメタノール（２０ｍｌ）に溶解させ、炭酸カリウム（６４０ｍｇ）を加え、室温で１時間撹拌した。反応液に水を加えた後、酢酸エチルで抽出し、抽出液を飽和食塩水で洗浄した後、有機層を無水硫酸マグネシウムを用いて乾燥させた。ろ過した後減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／２）にて精製することにより、表記化合物９７７ｍｇ（収率８６％）を無色無定形固体として得た。
¹H NMR (270MHz, CDCl₃) δppm : 1.47 (9H, s), 1.76 (2H, m), 1.93 (2H, m), 3.28 - 3.40 (2H, m), 3.60 - 3.80 (2H, m), 3.81 (2H, d, J=4.5), 4.46 (2H, d, J=6.5), 4.47 (1H, m), 6.30 (1H, dt, J=16.0, 6.5), 6.44 (1H, d, J=16.0), 6.93 (2H, d, J=9.0), 7.07 (2H, d, J=9.0), 7.42 (1H, t, J=7.5), 7.53 (1H, d, J=7.5), 7.56 (1H, d, J=7.5), 7.59 (1H, s). Reference Example 49
N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] -2-hydroxyacetamide 3- [3 -[N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] amino] -1- (E) -propenyl] benzonitrile (1000 mg) and pyridine (0.28 ml) in dichloromethane (20 ml) Acetoxyacetyl chloride (0.27 ml) was added under ice cooling, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2/3) to obtain 1232 mg of an intermediate compound as a colorless amorphous solid.
Next, the obtained intermediate compound was dissolved in methanol (20 ml), potassium carbonate (640 mg) was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/2), whereby 977 mg (yield 86%) of the title compound was colorless and amorphous. Obtained as a solid.
¹ H NMR (270MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.76 (2H, m), 1.93 (2H, m), 3.28-3.40 (2H, m), 3.60-3.80 (2H, m), 3.81 (2H, d, J = 4.5), 4.46 (2H, d, J = 6.5), 4.47 (1H, m), 6.30 (1H, dt, J = 16.0, 6.5), 6.44 (1H, d, J = 16.0), 6.93 (2H, d, J = 9.0), 7.07 (2H, d, J = 9.0), 7.42 (1H, t, J = 7.5), 7.53 (1H, d, J = 7.5), 7.56 (1H , d, J = 7.5), 7.59 (1H, s).

参考例５０
２−［Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］アミノ］酢酸エチル
３−［３−［Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］アミノ］−１−（Ｅ）−プロペニル］ベンゾニトリル（１．００ｇ）を、Ｎ，Ｎ−ジメチルホルムアミド（２０ｍｌ）に溶解させ、炭酸カリウム（０．９６ｇ）及びブロモ酢酸エチル（０．６２ｍｌ）を加え、７０℃で９時間撹拌した。反応液に水を加えた後、酢酸エチルで抽出し、抽出液を飽和食塩水で洗浄した後、有機層を無水硫酸マグネシウムを用いて乾燥させた。ろ過した後減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝２／１）にて精製することにより、表記化合物１．３１ｇ（収率定量的）を黄色油状物質として得た。
¹H NMR (270MHz, CDCl₃) δppm : 1.26 (3H, t, J=7.0), 1.46 (9H, s), 1.71
(2H, m), 1.88 (2H, m), 3.27 (2H, m), 3.71 (2H, m), 4.03 (2H, m), 4.15 -
4.35 (5H, m), 6.36 (1H, dt, J=16.0, 5.0), 6.57 (1H, d, J=16.0), 6.65 (2H, d, J=9.0), 6.83 (2H, d, J=9.0), 7.40 (1H, t, J=7.5), 7.50 (1H, d, J=7.5), 7.57 (1H, d, J=7.5), 7.63 (1H, s). Reference Example 50
2- [N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] amino] ethyl acetate 3- [3- [N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) phenyl] amino] -1- (E) -propenyl] benzonitrile (1.00 g) was converted to N, N-dimethylformamide. (20 ml), potassium carbonate (0.96 g) and ethyl bromoacetate (0.62 ml) were added, and the mixture was stirred at 70 ° C. for 9 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2/1) to give 1.31 g (quantitative yield) of the title compound as yellow. Obtained as an oil.
¹ H NMR (270MHz, CDCl ₃ ) δppm: 1.26 (3H, t, J = 7.0), 1.46 (9H, s), 1.71
(2H, m), 1.88 (2H, m), 3.27 (2H, m), 3.71 (2H, m), 4.03 (2H, m), 4.15-
4.35 (5H, m), 6.36 (1H, dt, J = 16.0, 5.0), 6.57 (1H, d, J = 16.0), 6.65 (2H, d, J = 9.0), 6.83 (2H, d, J = 9.0), 7.40 (1H, t, J = 7.5), 7.50 (1H, d, J = 7.5), 7.57 (1H, d, J = 7.5), 7.63 (1H, s).

参考例５１
２−［Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］アミノ］プロピオン酸エチル
３−［３−［Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］アミノ］−１−（Ｅ）−プロペニル］ベンゾニトリル（１２００ｍｇ）を、Ｎ，Ｎ−ジメチルホルムアミド（２０ｍｌ）に溶解させ、炭酸カリウム（１７１０ｍｇ）及び２−ブロモプロピオン酸エチル（１．５ｍｌ）を加えた後、１００℃で１２時間撹拌した。反応液に水を加えた後、酢酸エチルで抽出し、抽出液を飽和食塩水で洗浄した後、有機層を無水硫酸マグネシウムを用いて乾燥させた。ろ過した後減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝２／１）にて精製することにより、表記化合物８８２ｍｇ（収率６０％）を黄色油状物質として得た。
¹H NMR (270MHz, CDCl₃) δppm : 1.24 (3H, t, J=7.0), 1.46 (9H, s), 1.50
(3H, d, J=7.0), 1.71 (2H, m), 1.87 (2H, m), 3.27 (2H, m), 3.70 (2H, m),
4.17 (2H, q, J=7.0), 4.01 - 4.32 (3H, m), 4.38 (1H, q, J=7.0), 6.36 (1H, dt, J=16.0, 4.5), 6.57 (1H, d, J=16.0), 6.73 (2H, d, J=9.0), 6.82 (2H,
d, J=9.0), 7.39 (1H, t, J=8.0), 7.49 (1H, d, J=8.0), 7.55 (1H, d, J=8.0), 7.61 (1H, s). Reference Example 51
2- [N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] amino] ethyl propionate 3 -[3- [N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) phenyl] amino] -1- (E) -propenyl] benzonitrile (1200 mg) was added to N, N-dimethylformamide (1200 mg). 20 ml), potassium carbonate (1710 mg) and ethyl 2-bromopropionate (1.5 ml) were added, and the mixture was stirred at 100 ° C. for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2/1) to give 882 mg (yield 60%) of the title compound as a yellow oily substance. Got as.
¹ H NMR (270MHz, CDCl ₃ ) δppm: 1.24 (3H, t, J = 7.0), 1.46 (9H, s), 1.50
(3H, d, J = 7.0), 1.71 (2H, m), 1.87 (2H, m), 3.27 (2H, m), 3.70 (2H, m),
4.17 (2H, q, J = 7.0), 4.01-4.32 (3H, m), 4.38 (1H, q, J = 7.0), 6.36 (1H, dt, J = 16.0, 4.5), 6.57 (1H, d, J = 16.0), 6.73 (2H, d, J = 9.0), 6.82 (2H,
d, J = 9.0), 7.39 (1H, t, J = 8.0), 7.49 (1H, d, J = 8.0), 7.55 (1H, d, J = 8.0), 7.61 (1H, s).

参考例５２
Ｎ−（４−メトキシメトキシフェニル）スルファモイル酢酸エチル
４−メトキシメトキシアニリン（２０．９ｇ）及びピリジン（３３ｍｌ）をジクロロメタン（４００ｍｌ）に溶解させ、氷冷下、クロロスルホニル酢酸エチル（１８．０ｍｌ）を滴下し、室温で終夜撹拌した。反応液に水を加えた後、酢酸エチルで抽出し、抽出液を飽和食塩水で洗浄した後、有機層を無水硫酸マグネシウムを用いて乾燥させた。ろ過した後減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝３／２）にて精製することにより、表記化合物２８．０ｇ（収率６７％）を褐色油状物質として得た。
¹H NMR (270MHz, CDCl₃) δppm : 1.33 (3H, t, J=7.0), 3.48 (3H, s), 3.90
(2H, s), 4.29 (2H, q, J=7.0), 5.16 (2H, s), 7.03 (2H, d, J=9.0), 7.28 (2H, d, J=9.0). Reference Example 52
N- (4-methoxymethoxyphenyl) sulfamoyl acetate ethyl 4-methoxymethoxyaniline (20.9 g) and pyridine (33 ml) were dissolved in dichloromethane (400 ml), and ethyl chlorosulfonylacetate (18.0 ml) was added under ice cooling. The solution was added dropwise and stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/2) to give 28.0 g (yield 67%) of the title compound as brown. Obtained as an oil.
¹ H NMR (270MHz, CDCl ₃ ) δppm: 1.33 (3H, t, J = 7.0), 3.48 (3H, s), 3.90
(2H, s), 4.29 (2H, q, J = 7.0), 5.16 (2H, s), 7.03 (2H, d, J = 9.0), 7.28 (2H, d, J = 9.0).

参考例５３
Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−（４−メトキシメトキシフェニル）スルファモイル酢酸エチル
３−（３−シアノフェニル）−２−（Ｅ）−プロペン−１−オール（０．５２５ｇ）、Ｎ−（４−メトキシメトキシフェニル）スルファモイル酢酸エチル（１．００ｇ）及びトリフェニルホスフィン（１．１２ｇ）を、ジクロロメタン（３０ｍｌ）に溶解させ、アゾジカルボン酸ジエチル（０．６６ｍｌ）を滴下した後、室温で３．５時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝３／２）にて精製することにより、表記化合物１．３８ｇ（収率９４％）を黄色油状物質として得た。
¹H NMR (270MHz, CDCl₃) δppm : 1.37 (3H, t, J=7.0), 3.48 (3H, s), 3.99
(2H, s), 4.32 (2H, q, J=7.0), 4.49 (2H, d, J=6.0), 5.18 (2H, s), 6.25 (1H, dt, J=16.0, 6.0), 6.42 (1H, d, J=16.0), 7.06 (2H, d, J=9.0), 7.40 (1H, t, J=7.0), 7.41 (2H, d, J=9.0), 7.52 (1H, d, J=7.0), 7.54 (1H, d, J=7.0), 7.56 (1H, s). Reference Example 53
N- [3- (3-cyanophenyl) -2- (E) -propenyl] -N- (4-methoxymethoxyphenyl) sulfamoyl acetate ethyl 3- (3-cyanophenyl) -2- (E) -propene- 1-ol (0.525 g), N- (4-methoxymethoxyphenyl) sulfamoyl acetate (1.00 g) and triphenylphosphine (1.12 g) were dissolved in dichloromethane (30 ml), and diethyl azodicarboxylate ( 0.66 ml) was added dropwise, followed by stirring at room temperature for 3.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/2) to give 1.38 g (yield 94%) of the title compound as a yellow oily substance. Got as.
¹ H NMR (270MHz, CDCl ₃ ) δppm: 1.37 (3H, t, J = 7.0), 3.48 (3H, s), 3.99
(2H, s), 4.32 (2H, q, J = 7.0), 4.49 (2H, d, J = 6.0), 5.18 (2H, s), 6.25 (1H, dt, J = 16.0, 6.0), 6.42 ( 1H, d, J = 16.0), 7.06 (2H, d, J = 9.0), 7.40 (1H, t, J = 7.0), 7.41 (2H, d, J = 9.0), 7.52 (1H, d, J = 7.0), 7.54 (1H, d, J = 7.0), 7.56 (1H, s).

参考例５４
Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−（４−ヒドロキシフェニル）スルファモイル酢酸エチル
Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−（４−メトキシメトキシフェニル）スルファモイル酢酸エチル（１０．７ｇ）を、酢酸エチル（１２０ｍｌ）に溶解させ、氷冷下、４Ｍ塩化水素酢酸エチル溶液（８０ｍｌ）を加えた後、室温で４時間撹拌した。反応液を減圧下濃縮し、残渣に水を加えた後、酢酸エチルで抽出し、抽出液を飽和食塩水で洗浄した後、有機層を無水硫酸マグネシウムを用いて乾燥させた。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／１）にて精製することにより、表記化合物９．１ｇ（収率９５％）を黄色油状物質として得た。
¹H NMR (270MHz, CDCl₃) δppm : 1.35 (3H, t, J=7.0), 3.98 (2H, s), 4.30
(2H, q, J=7.0), 4.46 (2H, d, J=6.0), 6.23 (1H, dt, J=16.0, 6.0), 6.39 (1H, d, J=16.0), 6.84 (2H, d, J=9.0), 7.34 (2H, d, J=9.0), 7.39 (1H, t, J=7.5), 7.50 (2H, m), 7.54 (1H, s). Reference Example 54
N- [3- (3-Cyanophenyl) -2- (E) -propenyl] -N- (4-hydroxyphenyl) sulfamoyl acetate ethyl N- [3- (3-cyanophenyl) -2- (E)- Propenyl] -N- (4-methoxymethoxyphenyl) sulfamoyl ethyl acetate (10.7 g) was dissolved in ethyl acetate (120 ml), and 4M hydrogen chloride ethyl acetate solution (80 ml) was added under ice-cooling. For 4 hours. The reaction mixture was concentrated 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 the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/1) to give 9.1 g (yield 95%) of the title compound as a yellow oily substance. Obtained.
¹ H NMR (270MHz, CDCl ₃ ) δppm: 1.35 (3H, t, J = 7.0), 3.98 (2H, s), 4.30
(2H, q, J = 7.0), 4.46 (2H, d, J = 6.0), 6.23 (1H, dt, J = 16.0, 6.0), 6.39 (1H, d, J = 16.0), 6.84 (2H, d , J = 9.0), 7.34 (2H, d, J = 9.0), 7.39 (1H, t, J = 7.5), 7.50 (2H, m), 7.54 (1H, s).

参考例５５
Ｎ−［４−（１−ｔ−ブトキシカルボニルピロリジン−３−イルオキシ）フェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル
Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］−Ｎ−（４−ヒドロキシフェニル）スルファモイル酢酸エチル（８００ｍｇ）、１−ｔ−ブトキシカルボニル−３−ヒドロキシピロリジン（４５０ｍｇ）及びトリフェニルホスフィン（６８０ｍｇ）を、テトラヒドロフラン（２０ｍｌ）に溶解させ、アゾジカルボン酸ジエチル（０．６８ｍｌ）を加えた後、室温で終夜撹拌した。反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／酢酸エチル＝１０／１）にて精製することにより、表記化合物９００ｍｇ（収率７９％）を無色無定形固体として得た。
¹H NMR (270MHz, CDCl₃) δppm : 1.36 (3H, t, J=7.0), 1.46 (9H, s), 2.00
- 2.25 (2H, m), 3.40 - 3.70 (4H, m), 3.98 (2H, s), 4.31 (2H, q, J=7.0),
4.48 (2H, d, J=6.5), 4.85 (1H, m), 6.24 (1H, dt, J=16.0, 6.5), 6.41 (1H, d, J=16.0), 6.87 (2H, d, J=9.0), 7.35-7.45 (3H, m), 7.45-7.60 (3H, m). Reference Example 55
N- [4- (1-t-Butoxycarbonylpyrrolidin-3-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl acetate ethyl N- [3- ( 3-cyanophenyl) -2- (E) -propenyl] -N- (4-hydroxyphenyl) sulfamoyl acetate (800 mg), 1-t-butoxycarbonyl-3-hydroxypyrrolidine (450 mg) and triphenylphosphine (680 mg) ) Was dissolved in tetrahydrofuran (20 ml), diethyl azodicarboxylate (0.68 ml) was added, and the mixture was stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 10/1) to give 900 mg (yield 79%) of the title compound as a colorless amorphous solid. It was.
¹ H NMR (270MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.0), 1.46 (9H, s), 2.00
-2.25 (2H, m), 3.40-3.70 (4H, m), 3.98 (2H, s), 4.31 (2H, q, J = 7.0),
4.48 (2H, d, J = 6.5), 4.85 (1H, m), 6.24 (1H, dt, J = 16.0, 6.5), 6.41 (1H, d, J = 16.0), 6.87 (2H, d, J = 9.0), 7.35-7.45 (3H, m), 7.45-7.60 (3H, m).

参考例５６
３−［３−［Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］−Ｎ−（２−ヒドロキシエチル）アミノ］−１−（Ｅ）−プロペニル］ベンゾニトリル
３−［３−［Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］アミノ］−１−（Ｅ）−プロペニル］ベンゾニトリル（１０００ｍｇ）及びグリコールアルデヒド２量体（２７７ｍｇ）を、ジクロロメタン（２０ｍｌ）に溶解させ、氷冷下、酢酸（０．１３ｍｌ）及びシアン化３水素化ホウ素ナトリウム（７２ｍｇ）を加え、同温で５時間撹拌した後、室温で４時間撹拌した。反応液に水を加えた後、酢酸エチルで抽出し、抽出液を飽和食塩水で洗浄した後、有機層を無水硫酸マグネシウムを用いて乾燥させた。ろ過した後減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝４／３）で精製することにより、表記化合物１１００ｍｇ（収率５０％）を黄色油状物質として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.46 (9H, s), 1.72 (2H, m), 1.89 (2H, m), 3.28 (2H, m), 3.45 (2H, t, J=5.5), 3.71 (2H, m), 3.79 (2H, m), 4.07 (2H, m), 4.30 (1H, m), 6.31 (1H, dt, J=16.0, 5.5), 6.48 (1H, d, J=16.0), 6.80 (2H, d, J=9.0), 6.84 (2H, d, J=9.0), 7.39 (1H, t, J=8.0), 7.49 (1H,
d, J=8.0), 7.54 (1H, d, J=8.0), 7.60 (1H, s). Reference Example 56
3- [3- [N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) phenyl] -N- (2-hydroxyethyl) amino] -1- (E) -propenyl] benzonitrile 3- [3- [N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) phenyl] amino] -1- (E) -propenyl] benzonitrile (1000 mg) and glycolaldehyde dimer (277 mg) The mixture was dissolved in dichloromethane (20 ml), acetic acid (0.13 ml) and sodium tricyanoborohydride (72 mg) were added under ice-cooling, and the mixture was stirred at the same temperature for 5 hours, and then stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 4/3) to give 1100 mg (yield 50%) of the title compound as a yellow oily substance. Obtained.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.46 (9H, s), 1.72 (2H, m), 1.89 (2H, m), 3.28 (2H, m), 3.45 (2H, t, J = 5.5), 3.71 (2H, m), 3.79 (2H, m), 4.07 (2H, m), 4.30 (1H, m), 6.31 (1H, dt, J = 16.0, 5.5), 6.48 (1H, d, J = 16.0 ), 6.80 (2H, d, J = 9.0), 6.84 (2H, d, J = 9.0), 7.39 (1H, t, J = 8.0), 7.49 (1H,
d, J = 8.0), 7.54 (1H, d, J = 8.0), 7.60 (1H, s).

参考例５７
５−ニトロサリチル酸エチル
５−ニトロサリチル酸（１０．８ｇ）をエタノール（１００ｍｌ）に溶解させ、室温で濃硫酸（９２．０ｇ）加えた後、７．５時間加熱還流させた。反応液に水酸化ナトリウム水溶液を加え中和した後、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、０．５Ｍ塩酸及び飽和食塩水で順次洗浄した後、有機層を無水硫酸マグネシウムを用いて乾燥させた。ろ過した後、減圧下溶媒を留去し、表記化合物１０．７ｇ（収率８５％）を淡黄色固体として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.47 (3H, t, J=7.0), 4.49 (2H, q, J=7.0), 7.09 (1H, d, J=9.0), 8.33 (1H, dd, J=9.0, 3.0), 8.79 (1H, d, J=3.0). Reference Example 57
Ethyl 5-nitrosalicylate 5-Nitrosalicylate (10.8 g) was dissolved in ethanol (100 ml), concentrated sulfuric acid (92.0 g) was added at room temperature, and the mixture was heated to reflux for 7.5 hours. The reaction solution was neutralized with an aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium bicarbonate, 0.5 M hydrochloric acid and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. Used to dry. After filtration, the solvent was distilled off under reduced pressure to obtain 10.7 g (yield 85%) of the title compound as a pale yellow solid.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.47 (3H, t, J = 7.0), 4.49 (2H, q, J = 7.0), 7.09 (1H, d, J = 9.0), 8.33 (1H, dd, J = 9.0, 3.0), 8.79 (1H, d, J = 3.0).

参考例５８
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−エトキシカルボニルニトロベンゼン
１−ｔ−ブトキシカルボニル−４−ヒドロキシピペリジン（１０．２ｇ）、５−ニトロサリチル酸エチル（１０．７ｇ）及びトリフェニルホスフィン（１７．３ｇ）をジクロロメタン（２００ｍｌ）に溶解させ、氷冷下、アゾジカルボン酸ジエチル（１０．４ｍｌ）を滴下した後、室温で４時間撹拌した。反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝３／１）で精製し、得られた黄色固体にヘキサンを加えてろ取することにより、表記化合物１２．３ｇ（収率６１％）を白色固体として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.40 (3H, t, J=7.0), 1.47 (9H, s), 1.91
(4H, m), 3.58 (4H, m), 4.39 (2H, q, J=7.0), 4.79 (1H, m), 7.04 (1H, d, J=9.0), 8.32 (1H, dd, J=9.0, 3.0), 8.69 (1H, d, J=3.0). Reference Example 58
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-ethoxycarbonylnitrobenzene 1-t-butoxycarbonyl-4-hydroxypiperidine (10.2 g), ethyl 5-nitrosalicylate (10.7 g) and tri Phenylphosphine (17.3 g) was dissolved in dichloromethane (200 ml), and diethyl azodicarboxylate (10.4 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 4 hours. The reaction mixture is concentrated under reduced pressure, the residue is purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/1), and hexane is added to the resulting yellow solid and collected by filtration to give the title compound 12. 3 g (61% yield) was obtained as a white solid.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.40 (3H, t, J = 7.0), 1.47 (9H, s), 1.91
(4H, m), 3.58 (4H, m), 4.39 (2H, q, J = 7.0), 4.79 (1H, m), 7.04 (1H, d, J = 9.0), 8.32 (1H, dd, J = 9.0, 3.0), 8.69 (1H, d, J = 3.0).

参考例５９
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−エトキシカルボニルアニリン
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−エトキシカルボニルニトロベンゼン（５．０ｇ）をメタノール（７５ｍｌ）に溶解させ、パラジウム−炭素触媒（０．５ｇ）を加えた後、水素雰囲気下、室温で２．５時間撹拌した。反応液をろ過した後、ろ液を減圧下濃縮し、表記化合物４．６ｇ（収率９９％）を灰色油状物質として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.37 (3H, t, J=7.0), 1.46 (9H, s), 1.70-1.95 (4H, m), 3.25-3.40 (2H, m), 3.60-3.75 (2H, m), 4.30-4.40 (1H, m), 4.34 (2H, q, J=7.0), 6.77 (1H, dd, J=9.0, 3.0), 6.83 (1H, d, J=9.0), 7.12 (1H, d, J=3.0). Reference Example 59
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-ethoxycarbonylaniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-ethoxycarbonylnitrobenzene (5.0 g) in methanol ( 75 ml), palladium-carbon catalyst (0.5 g) was added, and the mixture was stirred at room temperature for 2.5 hours under a hydrogen atmosphere. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure to obtain 4.6 g (yield 99%) of the title compound as a gray oily substance.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.37 (3H, t, J = 7.0), 1.46 (9H, s), 1.70-1.95 (4H, m), 3.25-3.40 (2H, m), 3.60-3.75 (2H, m), 4.30-4.40 (1H, m), 4.34 (2H, q, J = 7.0), 6.77 (1H, dd, J = 9.0, 3.0), 6.83 (1H, d, J = 9.0), 7.12 (1H, d, J = 3.0).

参考例６０
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−エトキシカルボニルフェニル］スルファモイル酢酸エチル
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−エトキシカルボニルアニリン（４．６ｇ）及びピリジン（２．０ｍｌ）をジクロロメタン（７０ｍｌ）に溶解させ、氷冷下、クロロスルホニル酢酸エチル（２．５ｍｌ）を滴下し、室温で６時間撹拌した。反応液を減圧下濃縮し、不溶物をろ過（ヘキサン−酢酸エチル＝１：１）した後、ろ液をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／１）で精製することにより、表記化合物５．９ｇ（収率９０％）を橙色無定形固体として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.34 (3H, t, J=7.0), 1.37 (3H, t, J=7.0), 1.47 (9H, s), 1.75-1.95 (4H, m), 3.45-3.55 (2H, m), 3.55-3.65 (2H, m), 3.91 (2H, s), 4.30 (2H, q, J=7.0), 4.35 (2H, q, J=7.0), 4.59 (1H, m), 6.97 (1H, d, J=9.0), 7.47 (1H, dd, J=9.0, 3.0), 7.70 (1H, d, J=3.0). Reference Example 60
N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-ethoxycarbonylphenyl] sulfamoyl acetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-ethoxycarbonylaniline ( 4.6 g) and pyridine (2.0 ml) were dissolved in dichloromethane (70 ml), and ethyl chlorosulfonylacetate (2.5 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure, the insoluble material was filtered (hexane-ethyl acetate = 1: 1), and the filtrate was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/1). 5.9 g (yield 90%) of the title compound was obtained as an orange amorphous solid.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.34 (3H, t, J = 7.0), 1.37 (3H, t, J = 7.0), 1.47 (9H, s), 1.75-1.95 (4H, m), 3.45 -3.55 (2H, m), 3.55-3.65 (2H, m), 3.91 (2H, s), 4.30 (2H, q, J = 7.0), 4.35 (2H, q, J = 7.0), 4.59 (1H, m), 6.97 (1H, d, J = 9.0), 7.47 (1H, dd, J = 9.0, 3.0), 7.70 (1H, d, J = 3.0).

参考例６１
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−エトキシカルボニルフェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル
３−（３−シアノフェニル）−２−（Ｅ）−プロペン−１−オール（１．７ｇ）、Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−エトキシカルボニルフェニル］スルファモイル酢酸エチル（５．９ｇ）及びトリフェニルホスフィン（４．５ｇ）をジクロロメタン（１００ｍｌ）に溶解させ、アゾジカルボン酸ジエチル（２．７ｍｌ）を滴下した後、室温で３時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝２／１）で精製することにより、表記化合物５．７ｇ（収率８１％）を黄色無定形固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.35 (3H, t, J=7.0), 1.36 (3H, t, J=7.0), 1.46 (9H, s), 1.75-1.95 (4H, m), 3.45-3.65 (4H, m), 3.99 (2H, s), 4.31 (2H, q, J=7.0), 4.35 (2H, q, J=7.0), 4.49 (2H, d, J=7.0), 4.62 (1H, m), 6.23 (1H, dt, J=16.0, 7.0), 6.41 (1H, d, J=16.0), 6.97 (1H, m), 7.40 (1H, m), 7.45-7.60 (4H, m), 7.89 (1H, m). Reference Example 61
N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3-ethoxycarbonylphenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl acetate 3 -(3-Cyanophenyl) -2- (E) -propen-1-ol (1.7 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-ethoxycarbonylphenyl] Ethyl sulfamoyl acetate (5.9 g) and triphenylphosphine (4.5 g) were dissolved in dichloromethane (100 ml), diethyl azodicarboxylate (2.7 ml) was added dropwise, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to give 5.7 g (yield 81%) of the title compound as a yellow amorphous solid. Got as.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.35 (3H, t, J = 7.0), 1.36 (3H, t, J = 7.0), 1.46 (9H, s), 1.75-1.95 (4H, m), 3.45 -3.65 (4H, m), 3.99 (2H, s), 4.31 (2H, q, J = 7.0), 4.35 (2H, q, J = 7.0), 4.49 (2H, d, J = 7.0), 4.62 ( 1H, m), 6.23 (1H, dt, J = 16.0, 7.0), 6.41 (1H, d, J = 16.0), 6.97 (1H, m), 7.40 (1H, m), 7.45-7.60 (4H, m ), 7.89 (1H, m).

参考例６２
３−ブロモ−４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）ニトロベンゼン
１−ｔ−ブトキシカルボニル−４−ヒドロキシピペリジン（２．７ｇ）、ジャーナル・オブ・オーガニック・ケミストリー．，第６３巻，第４１９９頁（１９９８年）[J. Org. Chem., 63, 4199 (1998)]に記載の方法に従い３−ブロモニトロベンゼンより合成された３−ブロモ−４−ヒドロキシニトロベンゼン（１．９ｇ）及びトリフェニルホスフィン（４．４ｇ）をジクロロメタン（５０ｍｌ）に溶解させ、アゾジカルボン酸ジエチル（２．７ｍｌ）を滴下した後、室温で１１．５時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝２／１）で精製することにより、表記化合物３．１ｇ（収率９１％）を黄色油状物質として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.48 (9H, s), 1.91 (4H, m), 3.59 (4H, m), 4.75 (1H, m), 6.96 (1H, d, J=9.0), 8.19 (1H, dd, J=9.0, 3.0), 8.48 (1H, d, J=3.0). Reference Example 62
3-Bromo-4- (1-t-butoxycarbonylpiperidin-4-yloxy) nitrobenzene 1-t-butoxycarbonyl-4-hydroxypiperidine (2.7 g), Journal of Organic Chemistry. 63, 4199 (1998) [ J. Org. Chem. , 63 , 4199 (1998)], synthesized from 3-bromonitrobenzene (1-bromo-4-hydroxynitrobenzene (1) 0.9 g) and triphenylphosphine (4.4 g) were dissolved in dichloromethane (50 ml), and diethyl azodicarboxylate (2.7 ml) was added dropwise, followed by stirring at room temperature for 11.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to give 3.1 g (yield 91%) of the title compound as a yellow oil. Obtained.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.48 (9H, s), 1.91 (4H, m), 3.59 (4H, m), 4.75 (1H, m), 6.96 (1H, d, J = 9.0), 8.19 (1H, dd, J = 9.0, 3.0), 8.48 (1H, d, J = 3.0).

参考例６３
３−ブロモ−４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）アニリン
３−ブロモ−４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）ニトロベンゼン（３．１ｇ）を酢酸（４０ｍｌ）に溶解させ、亜鉛粉（１０．０ｇ）を１０回に分けて加えた後、室温で５時間撹拌した。反応液をセライト（登録商標）を用いてろ過した後、ろ液を酢酸エチルで抽出し、抽出液を飽和炭酸カリウム水溶液、水及び飽和食塩水で順次洗浄した後、有機層を無水硫酸マグネシウムを用いて乾燥させた。ろ過した後、減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／１）で精製することにより、表記化合物２．０ｇ（収率６９％）を茶色無定形固体として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.47 (9H, s), 1.70-1.90 (4H, m), 3.30-3.40 (2H, m), 3.65-3.75 (2H, m), 4.30 (1H, m), 6.57 (1H, dd, J=9.0, 3.0),
6.78 (1H, d, J=9.0), 6.91 (1H, d, J=3.0). Reference Example 63
3-Bromo-4- (1-t-butoxycarbonylpiperidin-4-yloxy) aniline 3-Bromo-4- (1-t-butoxycarbonylpiperidin-4-yloxy) nitrobenzene (3.1 g) in acetic acid (40 ml) After adding zinc powder (10.0 g) in 10 portions, the mixture was stirred at room temperature for 5 hours. The reaction solution was filtered using Celite (registered trademark), and then the filtrate was extracted with ethyl acetate. The extract was washed successively with saturated aqueous potassium carbonate solution, water and saturated brine, and then the organic layer was washed with anhydrous magnesium sulfate. Used to dry. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/1) to give 2.0 g (yield 69%) of the title compound as brown. Obtained as an amorphous solid.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.70-1.90 (4H, m), 3.30-3.40 (2H, m), 3.65-3.75 (2H, m), 4.30 (1H, m ), 6.57 (1H, dd, J = 9.0, 3.0),
6.78 (1H, d, J = 9.0), 6.91 (1H, d, J = 3.0).

参考例６４
Ｎ−［３−ブロモ−４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル
３−ブロモ−４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）アニリン（２．０ｇ）及びピリジン（０．９ｍｌ）をジクロロメタン（６０ｍｌ）に溶解させ、氷冷下、クロロスルホニル酢酸エチル（０．９ｍｌ）を滴下し、室温で２時間撹拌した。反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／１）で精製することにより、表記化合物２．１ｇ（収率７４％）を黄色無定形固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.34 (3H, t, J=7.0), 1.47 (9H, s), 1.75-1.95 (4H, m), 3.45-3.55 (2H, m), 3.55-3.65 (2H, m), 3.92 (2H, s), 4.29 (2H, q, J=7.0), 4.55 (1H, m), 6.85-6.95 (2H, m), 7.56 (1H, m). Reference Example 64
N- [3-Bromo-4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] sulfamoyl acetate ethyl 3-bromo-4- (1-t-butoxycarbonylpiperidin-4-yloxy) aniline (2. 0 g) and pyridine (0.9 ml) were dissolved in dichloromethane (60 ml), and ethyl chlorosulfonylacetate (0.9 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 2 hours. The reaction solution is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to give 2.1 g (yield 74%) of the title compound as a yellow amorphous solid. Obtained.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.34 (3H, t, J = 7.0), 1.47 (9H, s), 1.75-1.95 (4H, m), 3.45-3.55 (2H, m), 3.55-3.65 (2H, m), 3.92 (2H, s), 4.29 (2H, q, J = 7.0), 4.55 (1H, m), 6.85-6.95 (2H, m), 7.56 (1H, m).

参考例６５
Ｎ−［３−ブロモ−４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル
３−（３−シアノフェニル）−２−（Ｅ）−プロペン−１−オール（０．７ｇ）、Ｎ−［３−ブロモ−４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル（２．１ｇ）及びトリフェニルホスフィン（１．４ｇ）をジクロロメタン（３０ｍｌ）に溶解させ、アゾジカルボン酸ジエチル（０．９ｍｌ）を滴下した後、室温で６時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／酢酸エチル＝１９／１）で精製することにより、表記化合物２．２ｇ（収率８２％）を無色無定形固体として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.36 (3H, t, J=7.0), 1.47 (9H, s), 1.75-1.95 (4H, m), 3.45-3.65 (4H, m), 3.99 (2H, s), 4.31 (2H, q, J=7.0), 4.46 (2H, d, J=6.0), 4.58 (1H, m), 6.22 (1H, dt, J=16.0, 6.0), 6.42 (1H, d,
J=16.0), 6.90 (1H, m), 7.37 (1H, m), 7.42 (1H, m), 7.45-7.60 (3H, m), 7.71 (1H, m). Reference Example 65
N- [3-Bromo-4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl acetate 3- (3-Cyanophenyl) -2- (E) -propen-1-ol (0.7 g), N- [3-bromo-4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] sulfamoylacetic acid Ethyl (2.1 g) and triphenylphosphine (1.4 g) were dissolved in dichloromethane (30 ml), and diethyl azodicarboxylate (0.9 ml) was added dropwise, followed by stirring at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 19/1) to give 2.2 g (yield 82%) of the title compound as a colorless amorphous solid. Got as.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.0), 1.47 (9H, s), 1.75-1.95 (4H, m), 3.45-3.65 (4H, m), 3.99 (2H , s), 4.31 (2H, q, J = 7.0), 4.46 (2H, d, J = 6.0), 4.58 (1H, m), 6.22 (1H, dt, J = 16.0, 6.0), 6.42 (1H, d,
J = 16.0), 6.90 (1H, m), 7.37 (1H, m), 7.42 (1H, m), 7.45-7.60 (3H, m), 7.71 (1H, m).

参考例６６
２−イソプロピル−４−ニトロフェノール
２−イソプロピルフェノール（４．１ｍｌ）を酢酸（３０ｍｌ）に溶解させ、氷冷下、６９％硝酸（４ｍｌ）を加え、同温で３０分間攪拌した。反応液を氷水に注いだ後、ｔ−ブチルメチルエーテルで抽出し、抽出液を水及び飽和食塩水で順次洗浄した後、有機層を無水硫酸ナトリウムを用いて乾燥させた。ろ過した後、減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝４／１）で精製することにより、表記化合物２．６６ｇ（収率４９％）を黄色固体として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.30 (6H, d, J=7.0), 3.25 (1H, m), 6.82
(1H, d, J=9.0), 8.01 (1H, dd, J=9.0, 2.5), 8.13 (1H, d, J=2.5). Reference Example 66
2-Isopropyl-4-nitrophenol 2-Isopropylphenol (4.1 ml) was dissolved in acetic acid (30 ml), 69% nitric acid (4 ml) was added under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was poured into ice water and extracted with t-butyl methyl ether. The extract was washed with water and saturated brine successively, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 4/1) to give 2.66 g (yield 49%) of the title compound as yellow. Obtained as a solid.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.30 (6H, d, J = 7.0), 3.25 (1H, m), 6.82
(1H, d, J = 9.0), 8.01 (1H, dd, J = 9.0, 2.5), 8.13 (1H, d, J = 2.5).

参考例６７
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−イソプロピルニトロベンゼン
１−ｔ−ブトキシカルボニル−４−ヒドロキシピペリジン（２．９６ｇ）、２−イソプロピル−４−ニトロフェノール（２．６６ｇ）及びトリフェニルホスフィン（５．００ｇ）をジクロロメタン（８０ｍｌ）に溶解させ、アゾジカルボン酸ジエチル（３．０ｍｌ）を加えた後、室温で２時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン）で精製することにより、表記化合物４．０７ｇ（収率７６％）を茶色固体として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.26 (6H, d, J=7.0),1.48 (9H, s), 1.80-1.90 (2H, m), 1.90-2.05 (2H, m), 3.33 (1H, m), 352 (2H, m), 3.62 (2H, m), 4.67 (1H, m), 6.87 (1H, d, J=9.0), 8.08 (1H, dd, J=9.0, 3.0), 8.12 (1H, d, J=3.0). Reference Example 67
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-isopropylnitrobenzene 1-t-butoxycarbonyl-4-hydroxypiperidine (2.96 g), 2-isopropyl-4-nitrophenol (2.66 g) And triphenylphosphine (5.00 g) were dissolved in dichloromethane (80 ml), diethyl azodicarboxylate (3.0 ml) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane) to give 4.07 g (yield 76%) of the title compound as a brown solid.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.26 (6H, d, J = 7.0), 1.48 (9H, s), 1.80-1.90 (2H, m), 1.90-2.05 (2H, m), 3.33 (1H , m), 352 (2H, m), 3.62 (2H, m), 4.67 (1H, m), 6.87 (1H, d, J = 9.0), 8.08 (1H, dd, J = 9.0, 3.0), 8.12 (1H, d, J = 3.0).

参考例６８
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−イソプロピルアニリン
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−イソプロピルニトロベンゼン（４．１ｇ）をメタノール（７０ｍｌ）に溶解させ、パラジウム−炭素触媒（０．４ｇ）を加え、水素雰囲気下、室温で３時間撹拌した。反応液をろ過した後、ろ液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝３／２）で精製することにより、表記化合物２．８ｇ（収率７４％）を赤色油状物質として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.18 (6H, d, J=7.0), 1.47 (9H, s), 1.70-1.80 (2H, m), 1.85-1.95 (2H, m), 3.20-3.40 (3H, m), 3.60-3.75 (2H, m), 4.29 (1H, m), 6.47 (1H, dd, J=9.0, 3.0), 6.60 (1H, d, J=3.0), 6.68 (1H, d, J=9.0). Reference Example 68
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-isopropylaniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-isopropylnitrobenzene (4.1 g) in methanol (70 ml) Into the solution, palladium-carbon catalyst (0.4 g) was added, and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/2) to give 2.8 g (yield 74%) of the title compound. ) Was obtained as a red oil.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.18 (6H, d, J = 7.0), 1.47 (9H, s), 1.70-1.80 (2H, m), 1.85-1.95 (2H, m), 3.20-3.40 (3H, m), 3.60-3.75 (2H, m), 4.29 (1H, m), 6.47 (1H, dd, J = 9.0, 3.0), 6.60 (1H, d, J = 3.0), 6.68 (1H, d, J = 9.0).

参考例６９
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−イソプロピルフェニル］スルファモイル酢酸エチル
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−イソプロピルアニリン（２．８ｇ）及びピリジン（１．４ｍｌ）をジクロロメタン（８０ｍｌ）に溶解させ、氷冷下、クロロスルホニル酢酸エチル（１．５ｍｌ）を滴下した後、室温で４時間撹拌した。反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／酢酸エチル＝１９／１）で精製することにより、表記化合物３．３ｇ（収率８０％）を黄色無定形固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.20 (6H, d, J=7.0), 1.37 (3H, t, J=7.0), 1.48 (9H, s), 1.75-1.85 (2H, m), 1.85-1.95 (2H, m), 3.30 (1H, m), 3.40-3.50 (2H, m), 3.55-3.65 (2H, m), 3.90 (2H, s), 4.30 (2H, q, J=7.0), 4.50 (1H, m), 6.80 (1H, d, J=9.0), 7.13 (1H, dd, J=9.0, 3.0), 7.17 (1H, d,
J=3.0). Reference Example 69
N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3-isopropylphenyl] sulfamoyl acetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-isopropylaniline (2. 8 g) and pyridine (1.4 ml) were dissolved in dichloromethane (80 ml), and ethyl chlorosulfonylacetate (1.5 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 4 hours. The reaction mixture is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate = 19/1) to give 3.3 g (yield 80%) of the title compound as a yellow amorphous solid. Obtained.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.20 (6H, d, J = 7.0), 1.37 (3H, t, J = 7.0), 1.48 (9H, s), 1.75-1.85 (2H, m), 1.85 -1.95 (2H, m), 3.30 (1H, m), 3.40-3.50 (2H, m), 3.55-3.65 (2H, m), 3.90 (2H, s), 4.30 (2H, q, J = 7.0) , 4.50 (1H, m), 6.80 (1H, d, J = 9.0), 7.13 (1H, dd, J = 9.0, 3.0), 7.17 (1H, d,
J = 3.0).

参考例７０
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−イソプロピルフェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル
３−（３−シアノフェニル）−２−（Ｅ）−プロペン−１−オール（０．５ｇ）、Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−イソプロピルフェニル］スルファモイル酢酸エチル（１．５ｇ）及びトリフェニルホスフィン（１．１ｇ）をジクロロメタン（５０ｍｌ）に溶解させ、氷冷下、アゾジカルボン酸ジエチル（０．７ｍｌ）を滴下した後、室温で４時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／酢酸エチル＝１９／１）で精製することにより、表記化合物１．８ｇ（収率９６％）を黄色無定形固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.18 (6H, d, J=7.0), 1.36 (3H, t, J=7.0), 1.47 (9H, s), 1.75-1.85 (2H, m), 1.85-1.95 (2H, m), 3.29 (1H, m), 3.40-3.50 (2H, m), 3.55-3.65 (2H, m), 3.99 (2H, s), 4.31 (2H, q, J=7.0), 4.46 (2H, d, J=6.0), 4.52 (1H, m), 6.25 (1H, dt, J=16.0, 6.0), 6.40 (1H, d, J=16.0), 6.81 (1H, d, J=9.0), 7.22 (1H, dd, J=9.0, 3.0), 7.31 (1H, d, J=3.0), 7.40 (1H, m), 7.45-7.60 (3H, m). Reference Example 70
N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3-isopropylphenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl acetate 3- (3-Cyanophenyl) -2- (E) -propen-1-ol (0.5 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-isopropylphenyl] sulfamoyl acetic acid Ethyl (1.5 g) and triphenylphosphine (1.1 g) were dissolved in dichloromethane (50 ml), and diethyl azodicarboxylate (0.7 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 19/1) to give 1.8 g (yield 96%) of the title compound as a yellow amorphous solid. Got as.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.18 (6H, d, J = 7.0), 1.36 (3H, t, J = 7.0), 1.47 (9H, s), 1.75-1.85 (2H, m), 1.85 -1.95 (2H, m), 3.29 (1H, m), 3.40-3.50 (2H, m), 3.55-3.65 (2H, m), 3.99 (2H, s), 4.31 (2H, q, J = 7.0) , 4.46 (2H, d, J = 6.0), 4.52 (1H, m), 6.25 (1H, dt, J = 16.0, 6.0), 6.40 (1H, d, J = 16.0), 6.81 (1H, d, J = 9.0), 7.22 (1H, dd, J = 9.0, 3.0), 7.31 (1H, d, J = 3.0), 7.40 (1H, m), 7.45-7.60 (3H, m).

参考例７１
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−カルボキシニトロベンゼン
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−エトキシカルボニルニトロベンゼン（１．０ｇ）をエタノール（１０ｍｌ）に溶解させ、水酸化カリウム（０．２ｇ）水溶液（０．５ｍｌ）を加えた後、２時間加熱還流させた。反応液に１Ｍ塩酸を加え中和した後、酢酸エチルで抽出し、抽出液を水及び飽和食塩水で順次洗浄した後、有機層を無水硫酸マグネシウムを用いて乾燥させた。ろ過した後、減圧下溶媒を留去し、表記化合物０．９ｇ（収率９６％）を淡黄色固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.48 (9H, s), 1.85-1.95 (2H, m), 2.00-2.10 (2H, m), 3.45-3.55 (2H, m), 3.65-3.75 (2H, m), 4.87 (1H, m), 7.13 (1H, d, J=9.0), 8.39 (1H, dd, J=9.0, 3.0), 8.93 (1H, d, J=3.0). Reference Example 71
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carboxynitrobenzene 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-ethoxycarbonylnitrobenzene (1.0 g) in ethanol (10 ml) ), Potassium hydroxide (0.2 g) aqueous solution (0.5 ml) was added, and the mixture was heated to reflux for 2 hours. The reaction solution was neutralized with 1M hydrochloric acid, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 0.9 g (yield 96%) of the title compound as a pale yellow solid.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.48 (9H, s), 1.85-1.95 (2H, m), 2.00-2.10 (2H, m), 3.45-3.55 (2H, m), 3.65-3.75 (2H , m), 4.87 (1H, m), 7.13 (1H, d, J = 9.0), 8.39 (1H, dd, J = 9.0, 3.0), 8.93 (1H, d, J = 3.0).

参考例７２
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−カルバモイルニトロベンゼン
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−カルボキシニトロベンゼン（０．９ｇ）をジクロロメタン（２０ｍｌ）に溶解させ、氷冷下、クロロギ酸イソブチル（０．３ｍｌ）及びトリエチルアミン（０．４ｍｌ）を加え、同温で１時間撹拌した後、２８％アンモニア水（０．２ｍｌ）を加え、室温で１時間撹拌した。反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／メタノール＝１９／１）で精製することにより、表記化合物０．９ｇ（収率９８％）を淡黄色無定形固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.48 (9H, s), 1.80-1.90 (2H, m), 2.05-2.20 (2H, m), 3.30-3.40 (2H, m), 3.75-3.90 (2H, m), 4.81 (1H, m), 7.11 (1H, d, J=9.0), 8.33 (1H, dd, J=9.0, 3.0), 9.09 (1H, d, J=3.0). Reference Example 72
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carbamoylnitrobenzene 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carboxynitrobenzene (0.9 g) in dichloromethane (20 ml) In an ice bath, isobutyl chloroformate (0.3 ml) and triethylamine (0.4 ml) were added, and the mixture was stirred at the same temperature for 1 hour, followed by addition of 28% aqueous ammonia (0.2 ml) and 1 at room temperature. Stir for hours. The reaction solution is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (elution solvent: dichloromethane / methanol = 19/1) to give 0.9 g (yield 98%) of the title compound as a pale yellow amorphous solid. Obtained.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.48 (9H, s), 1.80-1.90 (2H, m), 2.05-2.20 (2H, m), 3.30-3.40 (2H, m), 3.75-3.90 (2H , m), 4.81 (1H, m), 7.11 (1H, d, J = 9.0), 8.33 (1H, dd, J = 9.0, 3.0), 9.09 (1H, d, J = 3.0).

参考例７３
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−カルバモイルアニリン
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−カルバモイルニトロベンゼン（５．７ｇ）をメタノール（８０ｍｌ）に溶解させ、パラジウム−炭素触媒（０．６ｇ）を加え、水素雰囲気下、室温で２．５時間撹拌した。反応液をろ過した後、ろ液をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／メタノール＝１９／１）で精製することにより、表記化合物４．８ｇ（収率９１％）を淡黄色無定形固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.47 (9H, s), 1.65-1.80 (2H, m), 1.95-2.05 (2H, m), 3.19 (2H, m), 3.75-3.85 (2H, m), 4.44 (1H, m), 6.78 (1H, dd, J=9.0, 3.0), 6.84 (1H, d, J=9.0), 7.50 (1H, d, J=3.0). Reference Example 73
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carbamoylaniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carbamoylnitrobenzene (5.7 g) in methanol (80 ml) And palladium-carbon catalyst (0.6 g) was added thereto, followed by stirring at room temperature for 2.5 hours under a hydrogen atmosphere. After the reaction solution was filtered, the filtrate was purified by silica gel column chromatography (elution solvent: dichloromethane / methanol = 19/1) to give 4.8 g (yield 91%) of the title compound as a pale yellow amorphous solid. Obtained.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.65-1.80 (2H, m), 1.95-2.05 (2H, m), 3.19 (2H, m), 3.75-3.85 (2H, m ), 4.44 (1H, m), 6.78 (1H, dd, J = 9.0, 3.0), 6.84 (1H, d, J = 9.0), 7.50 (1H, d, J = 3.0).

参考例７４
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−カルバモイルフェニル］スルファモイル酢酸エチル
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−カルバモイルアニリン（４．８ｇ）及びピリジン（２．３ｍｌ）をジクロロメタン（８０ｍｌ）に溶解させ、氷冷下、クロロスルホニル酢酸エチル（２．５ｍｌ）を滴下し、室温で６時間撹拌した。反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／メタノール＝１９／１）で精製し、得られた橙色固体にエーテルを加えた後、ろ取することにより、表記化合物３．７ｇ（収率５３％）を淡黄色固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.32 (3H, t, J=7.0), 1.47 (9H, s), 1.70-1.85 (2H, m), 2.00-2.15 (2H, m), 3.27 (2H, m), 3.75-3.85 (2H, m), 3.94 (2H, s), 4.28 (2H, q, J=7.0), 4.65 (1H, m), 7.02 (1H, d, J=9.0), 7.59 (1H, dd, J=9.0, 3.0), 8.12 (1H, d, J=3.0). Reference Example 74
N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carbamoylphenyl] sulfamoyl acetate ethyl 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carbamoylaniline (4. 8 g) and pyridine (2.3 ml) were dissolved in dichloromethane (80 ml), and ethyl chlorosulfonylacetate (2.5 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 6 hours. The reaction solution is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (elution solvent: dichloromethane / methanol = 19/1). Ether is added to the resulting orange solid, followed by filtration to give the title compound. 3.7 g (yield 53%) was obtained as a pale yellow solid.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.32 (3H, t, J = 7.0), 1.47 (9H, s), 1.70-1.85 (2H, m), 2.00-2.15 (2H, m), 3.27 (2H , m), 3.75-3.85 (2H, m), 3.94 (2H, s), 4.28 (2H, q, J = 7.0), 4.65 (1H, m), 7.02 (1H, d, J = 9.0), 7.59 (1H, dd, J = 9.0, 3.0), 8.12 (1H, d, J = 3.0).

参考例７５
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−カルバモイルフェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル
３−（３−シアノフェニル）−２−（Ｅ）−プロペン−１−オール（０．７ｇ）、Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−カルバモイルフェニル］スルファモイル酢酸エチル（２．０ｇ）及びトリフェニルホスフィン（１．５ｇ）をジクロロメタン（３０ｍｌ）に溶解させ、アゾジカルボン酸ジエチル（０．９ｍｌ）を滴下した後、室温で８時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／２）で精製することにより、表記化合物２．５ｇ（収率９４％）を黄色無定形固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.36 (3H, t, J=7.0), 1.47 (9H, s), 1.75-1.85 (2H, m), 2.00-2.10 (2H, m), 3.27 (2H, m), 3.75-3.85 (2H, m), 3.99 (2H, s), 4.31 (2H, q, J=7.0), 4.53 (2H, d, J=7.0), 4.66 (1H, m), 6.22 (1H, dt, J=16.0, 7.0), 6.42 (1H, d, J=16.0), 7.01 (1H, m), 7.39 (1H, m), 7.45-7.60 (2H, m), 7.65-7.75 (2H, m), 8.32 (1H, m). Reference Example 75
N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carbamoylphenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl acetate 3- (3-Cyanophenyl) -2- (E) -propen-1-ol (0.7 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carbamoylphenyl] sulfamoyl acetic acid Ethyl (2.0 g) and triphenylphosphine (1.5 g) were dissolved in dichloromethane (30 ml), and diethyl azodicarboxylate (0.9 ml) was added dropwise, followed by stirring at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/2) to give 2.5 g (yield 94%) of the title compound as a yellow amorphous solid. Got as.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.0), 1.47 (9H, s), 1.75-1.85 (2H, m), 2.00-2.10 (2H, m), 3.27 (2H , m), 3.75-3.85 (2H, m), 3.99 (2H, s), 4.31 (2H, q, J = 7.0), 4.53 (2H, d, J = 7.0), 4.66 (1H, m), 6.22 (1H, dt, J = 16.0, 7.0), 6.42 (1H, d, J = 16.0), 7.01 (1H, m), 7.39 (1H, m), 7.45-7.60 (2H, m), 7.65-7.75 ( 2H, m), 8.32 (1H, m).

参考例７６
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−（Ｎ−メチルカルバモイル）ニトロベンゼン
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−カルボキシニトロベンゼン（３．３ｇ）をジクロロメタン（５０ｍｌ）に溶解させ、氷冷下、クロロギ酸イソブチル（１．４ｍｌ）及びトリエチルアミン（１．４ｍｌ）を加え、同温で０．５時間撹拌した後、４０％メチルアミン水溶液（１．１ｍｌ）を加え、室温で３時間撹拌した。反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／メタノール＝１９／１）で精製することにより、表記化合物３．５ｇ（収率定量的）を黄色無定形固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.48 (9H, s), 1.80-1.90 (2H, m), 2.05-2.15 (2H, m), 3.04 (3H, m), 3.30-3.40 (2H, m), 3.75-3.85 (2H, m), 4.79 (1H, m), 7.08 (1H, d, J=9.0), 8.29 (1H, dd, J=9.0, 3.0), 9.07 (1H, d, J=3.0). Reference Example 76
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3- (N-methylcarbamoyl) nitrobenzene 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carboxynitrobenzene (3.3 g) Was dissolved in dichloromethane (50 ml), isobutyl chloroformate (1.4 ml) and triethylamine (1.4 ml) were added under ice-cooling, and the mixture was stirred at the same temperature for 0.5 hour, and then 40% aqueous methylamine solution (1. 1 ml) was added and stirred at room temperature for 3 hours. The reaction mixture is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: dichloromethane / methanol = 19/1) to give 3.5 g (quantitative yield) of the title compound as a yellow amorphous solid. It was.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.48 (9H, s), 1.80-1.90 (2H, m), 2.05-2.15 (2H, m), 3.04 (3H, m), 3.30-3.40 (2H, m ), 3.75-3.85 (2H, m), 4.79 (1H, m), 7.08 (1H, d, J = 9.0), 8.29 (1H, dd, J = 9.0, 3.0), 9.07 (1H, d, J = 3.0).

参考例７７
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−（Ｎ−メチルカルバモイル）アニリン
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−（Ｎ−メチルカルバモイル）ニトロベンゼン（３．５ｇ）をメタノール（５０ｍｌ）に溶解させ、パラジウム−炭素触媒（０．４ｇ）を加え、水素雰囲気下、室温で１時間撹拌した。反応液をろ過した後、ろ液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／メタノール＝１９／１）で精製することにより、表記化合物２．９ｇ（収率９２％）を黄色無定形固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.47 (9H, s), 1.65-1.75 (2H, m), 1.95-2.05 (2H, m), 2.99 (3H, m), 3.20 (2H, m), 3.75-3.85 (2H, m), 4.40 (1H, m), 6.74 (1H, dd, J=9.0, 3.0), 6.81 (1H, d, J=9.0), 7.50 (1H, d, J=3.0). Reference Example 77
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3- (N-methylcarbamoyl) aniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3- (N-methylcarbamoyl) nitrobenzene (3.5 g) was dissolved in methanol (50 ml), palladium-carbon catalyst (0.4 g) was added, and the mixture was stirred at room temperature for 1 hour in a hydrogen atmosphere. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / methanol = 19/1) to give 2.9 g of the title compound (yield 92%). Was obtained as a yellow amorphous solid.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.65-1.75 (2H, m), 1.95-2.05 (2H, m), 2.99 (3H, m), 3.20 (2H, m), 3.75-3.85 (2H, m), 4.40 (1H, m), 6.74 (1H, dd, J = 9.0, 3.0), 6.81 (1H, d, J = 9.0), 7.50 (1H, d, J = 3.0) .

参考例７８
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−（Ｎ’−メチルカルバモイル）フェニル］スルファモイル酢酸エチル
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−（Ｎ−メチルカルバモイル）アニリン（２．９ｇ）及びピリジン（０．８ｍｌ）をジクロロメタン（５０ｍｌ）に溶解させ、氷冷下、クロロスルホニル酢酸エチル（１．３ｍｌ）を滴下し、室温で１時間撹拌した。反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／酢酸エチル＝２／１）で精製することにより、表記化合物３．０ｇ（収率７２％）を淡黄色固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.28 (3H, t, J=7.0), 1.48 (9H, s), 1.70-1.85 (2H, m), 2.00-2.15 (2H, m), 3.05 (3H, m), 3.29 (2H, m), 3.70-3.85 (2H, m), 3.95 (2H, s), 4.22 (2H, q, J=7.0), 4.63 (1H, m), 7.00 (1H, d, J=9.0), 7.61 (1H, dd, J=9.0, 3.0), 8.27 (1H, d, J=3.0). Reference Example 78
N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3- (N′-methylcarbamoyl) phenyl] sulfamoyl acetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3 -(N-methylcarbamoyl) aniline (2.9 g) and pyridine (0.8 ml) were dissolved in dichloromethane (50 ml), and ethyl chlorosulfonylacetate (1.3 ml) was added dropwise under ice-cooling. Stir. The reaction mixture is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 2/1) to give the title compound (3.0 g, yield 72%) as a pale yellow solid. It was.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.28 (3H, t, J = 7.0), 1.48 (9H, s), 1.70-1.85 (2H, m), 2.00-2.15 (2H, m), 3.05 (3H , m), 3.29 (2H, m), 3.70-3.85 (2H, m), 3.95 (2H, s), 4.22 (2H, q, J = 7.0), 4.63 (1H, m), 7.00 (1H, d , J = 9.0), 7.61 (1H, dd, J = 9.0, 3.0), 8.27 (1H, d, J = 3.0).

参考例７９
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−（Ｎ’−メチルカルバモイル）フェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル
３−（３−シアノフェニル）−２−（Ｅ）−プロペン−１−オール（０．５ｇ）、Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−（Ｎ’−メチルカルバモイル）フェニル］スルファモイル酢酸エチル（１．５ｇ）及びトリフェニルホスフィン（１．０ｇ）をジクロロメタン（４０ｍｌ）に溶解させ、氷冷下、アゾジカルボン酸ジエチル（０．６ｍｌ）を滴下した後、室温で３時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／２）で精製することにより、表記化合物１．５ｇ（収率７７％）を無色無定形固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.36 (3H, t, J=7.0), 1.47 (9H, s), 1.75-1.85 (2H, m), 2.00-2.10 (2H, m), 3.01 (3H, m), 3.30 (2H, m), 3.70-3.80 (2H, m), 3.99 (2H, s), 4.32 (2H, q, J=7.0), 4.53 (2H, d, J=7.0), 4.64 (1H, m), 6.22 (1H, dt, J=16.0, 7.0), 6.42 (1H, d, J=16.0), 6.98 (1H, m), 7.35-7.45 (1H, m), 7.45-7.55 (4H, m), 8.33 (1H, m). Reference Example 79
N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3- (N′-methylcarbamoyl) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl ] Ethyl sulfamoyl acetate 3- (3-cyanophenyl) -2- (E) -propen-1-ol (0.5 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3 -(N'-methylcarbamoyl) phenyl] sulfamoyl ethyl acetate (1.5 g) and triphenylphosphine (1.0 g) were dissolved in dichloromethane (40 ml), and diethyl azodicarboxylate (0.6 ml) was added under ice cooling. After dropping, the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/2) to give 1.5 g (yield 77%) of the title compound as a colorless amorphous solid. Got as.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.0), 1.47 (9H, s), 1.75-1.85 (2H, m), 2.00-2.10 (2H, m), 3.01 (3H , m), 3.30 (2H, m), 3.70-3.80 (2H, m), 3.99 (2H, s), 4.32 (2H, q, J = 7.0), 4.53 (2H, d, J = 7.0), 4.64 (1H, m), 6.22 (1H, dt, J = 16.0, 7.0), 6.42 (1H, d, J = 16.0), 6.98 (1H, m), 7.35-7.45 (1H, m), 7.45-7.55 ( 4H, m), 8.33 (1H, m).

参考例８０
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−（Ｎ，Ｎ−ジメチルカルバモイル）ニトロベンゼン
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−カルボキシニトロベンゼン（３．４ｇ）をジクロロメタン（６０ｍｌ）に溶解させ、氷冷下、クロロギ酸イソブチル（１．４ｍｌ）及びトリエチルアミン（１．５ｍｌ）を加え、同温で０．５時間撹拌した後、５０％ジメチルアミン水溶液（１．１ｍｌ）を加え、室温で２時間撹拌した。反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／メタノール＝１９／１）で精製することにより、表記化合物３．１ｇ（収率８３％）を淡黄色無定形固体として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.47 (9H, s), 1.75-2.10 (4H, m), 2.89 (3H, s), 3.14 (3H, s), 3.35-3.65 (4H, m), 4.69 (1H, m), 7.00 (1H, d, J=9.0), 8.20 (1H, d, J=3.0), 8.25 (1H, dd, J=9.0, 3.0). Reference Example 80
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3- (N, N-dimethylcarbamoyl) nitrobenzene 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carboxynitrobenzene (3. 4 g) was dissolved in dichloromethane (60 ml), isobutyl chloroformate (1.4 ml) and triethylamine (1.5 ml) were added under ice cooling, and the mixture was stirred at the same temperature for 0.5 hour, and then 50% dimethylamine aqueous solution ( 1.1 ml) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / methanol = 19/1) to give 3.1 g (yield 83%) of the title compound as a pale yellow amorphous solid. Obtained.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.75-2.10 (4H, m), 2.89 (3H, s), 3.14 (3H, s), 3.35-3.65 (4H, m), 4.69 (1H, m), 7.00 (1H, d, J = 9.0), 8.20 (1H, d, J = 3.0), 8.25 (1H, dd, J = 9.0, 3.0).

参考例８１
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−（Ｎ，Ｎ−ジメチルカルバモイル）アニリン
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−（Ｎ，Ｎ−ジメチルカルバモイル）ニトロベンゼン（３．１ｇ）をメタノール（３０ｍｌ）に溶解させ、パラジウム−炭素触媒（０．３ｇ）を加え、水素雰囲気下、室温で１時間撹拌した。反応液をろ過した後、ろ液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／メタノール＝１９／１）で精製することにより、表記化合物２．８ｇ（収率９９％）を黄色無定形固体として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.45 (9H, s), 1.55-1.95 (4H, m), 2.89 (3H, s), 3.09 (3H, s), 3.25-3.40 (2H, m), 3.50-3.65 (2H, m), 4.20-4.30 (1H, m), 6.61 (1H, d, J=3.0), 6.64 (1H, dd, J=9.0, 3.0), 6.76 (1H, d, J=9.0). Reference Example 81
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3- (N, N-dimethylcarbamoyl) aniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3- (N, N- Dimethylcarbamoyl) nitrobenzene (3.1 g) was dissolved in methanol (30 ml), palladium-carbon catalyst (0.3 g) was added, and the mixture was stirred at room temperature for 1 hour in a hydrogen atmosphere. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / methanol = 19/1) to give 2.8 g of the title compound (yield 99%). Was obtained as a yellow amorphous solid.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.45 (9H, s), 1.55-1.95 (4H, m), 2.89 (3H, s), 3.09 (3H, s), 3.25-3.40 (2H, m), 3.50-3.65 (2H, m), 4.20-4.30 (1H, m), 6.61 (1H, d, J = 3.0), 6.64 (1H, dd, J = 9.0, 3.0), 6.76 (1H, d, J = 9.0).

参考例８２
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−（Ｎ’，Ｎ’−ジメチルカルバモイル）フェニル］スルファモイル酢酸エチル
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−（Ｎ，Ｎ−ジメチルカルバモイル）アニリン（２．８ｇ）及びピリジン（０．７ｍｌ）をジクロロメタン（３０ｍｌ）に溶解させ、氷冷下、クロロスルホニル酢酸エチル（１．２ｍｌ）を滴下し、室温で１時間撹拌した。反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／酢酸エチル＝１／１）で精製することにより、表記化合物３．３ｇ（収率７９％）を黄色無定形固体として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.32 (3H, t, J=7.0), 1.46 (9H, s), 1.70-2.00 (4H, m), 2.87 (3H, s), 3.10 (3H, s), 3.30-3.50 (2H, m), 3.50-3.60 (2H, m), 3.93 (2H, s), 4.28 (2H, q, J=7.0), 4.48 (1H, m), 6.91 (1H, d, J=9.0), 7.22 (1H, d, J=3.0), 7.34 (1H, dd, J=9.0, 3.0). Reference Example 82
N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3- (N ′, N′-dimethylcarbamoyl) phenyl] sulfamoyl acetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) ) -3- (N, N-dimethylcarbamoyl) aniline (2.8 g) and pyridine (0.7 ml) were dissolved in dichloromethane (30 ml), and ethyl chlorosulfonylacetate (1.2 ml) was added dropwise under ice cooling. And stirred at room temperature for 1 hour. The reaction solution is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate = 1/1) to give 3.3 g (yield 79%) of the title compound as a yellow amorphous solid. Obtained.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.32 (3H, t, J = 7.0), 1.46 (9H, s), 1.70-2.00 (4H, m), 2.87 (3H, s), 3.10 (3H, s ), 3.30-3.50 (2H, m), 3.50-3.60 (2H, m), 3.93 (2H, s), 4.28 (2H, q, J = 7.0), 4.48 (1H, m), 6.91 (1H, d , J = 9.0), 7.22 (1H, d, J = 3.0), 7.34 (1H, dd, J = 9.0, 3.0).

参考例８３
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−（Ｎ’，Ｎ’−ジメチルカルバモイル）フェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル
３−（３−シアノフェニル）−２−（Ｅ）−プロペン−１−オール（０．５ｇ）、Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−（Ｎ’，Ｎ’−ジメチルカルバモイル）フェニル］スルファモイル酢酸エチル（１．５ｇ）及びトリフェニルホスフィン（１．０ｇ）をジクロロメタン（３０ｍｌ）に溶解させ、氷冷下、アゾジカルボン酸ジエチル（０．６ｍｌ）を滴下し、室温で３時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／２）で精製することにより、表記化合物１．７ｇ（収率８８％）を無色無定形固体として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.34 (3H, t, J=7.0), 1.46 (9H, s), 1.75-2.00 (4H, m), 2.83 (3H, s), 3.10 (3H, s), 3.30-3.60 (4H, m), 3.95-4.05 (2H, m), 4.30 (2H, q, J=7.0), 4.47 (2H, d, J=7.0), 4.52 (1H, m), 6.23 (1H, dt, J=16.0, 7.0), 6.42 (1H, d, J=16.0), 6.92 (1H, m), 7.35-7.55 (6H, m). Reference Example 83
N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3- (N ′, N′-dimethylcarbamoyl) phenyl] -N- [3- (3-cyanophenyl) -2- (E ) -Propenyl] ethyl sulfamoyl acetate 3- (3-cyanophenyl) -2- (E) -propen-1-ol (0.5 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) ) -3- (N ′, N′-dimethylcarbamoyl) phenyl] sulfamoyl ethyl acetate (1.5 g) and triphenylphosphine (1.0 g) were dissolved in dichloromethane (30 ml), and diethyl azodicarboxylate was cooled with ice. (0.6 ml) was added dropwise and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/2) to give 1.7 g (yield 88%) of the title compound as a colorless amorphous solid. Got as.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.34 (3H, t, J = 7.0), 1.46 (9H, s), 1.75-2.00 (4H, m), 2.83 (3H, s), 3.10 (3H, s ), 3.30-3.60 (4H, m), 3.95-4.05 (2H, m), 4.30 (2H, q, J = 7.0), 4.47 (2H, d, J = 7.0), 4.52 (1H, m), 6.23 (1H, dt, J = 16.0, 7.0), 6.42 (1H, d, J = 16.0), 6.92 (1H, m), 7.35-7.55 (6H, m).

参考例８４
５−シアノ−２−ヒドロキシベンズアルデヒド
４−シアノフェノール（２５．０ｇ）をトリフルオロ酢酸（１５０ｍｌ）に溶解させ、ヘキサメチレンテトラミン（５０．０ｇ）を加え、１００℃で９時間攪拌した。反応液を室温まで冷却させた後、硫酸（５０ｍｌ）及び水（３００ｍｌ）を加え、室温で１時間攪拌した。反応液をジクロロメタンで抽出し、抽出液を水及び飽和食塩水で順次洗浄した後、有機層を無水硫酸マグネシウムを用いて乾燥させた。ろ過した後、減圧下溶媒を留去し、得られた残渣をシリカゲルクロマトグラフィー（溶出溶媒：酢酸エチル／ジクロロメタン＝１／１９）で精製することにより、表記化合物４．３ｇ（収率１３％）を無色固体として得た。
¹H NMR (400MHz, CDCl₃) δppm : 7.11 (1H, d, J=9.0), 7.78 (1H, dd, J=9.0, 2.0), 7.94 (1H, d, J=2.0), 9.93 (1H, s). Reference Example 84
5-Cyano-2-hydroxybenzaldehyde 4-Cyanophenol (25.0 g) was dissolved in trifluoroacetic acid (150 ml), hexamethylenetetramine (50.0 g) was added, and the mixture was stirred at 100 ° C. for 9 hours. The reaction solution was cooled to room temperature, sulfuric acid (50 ml) and water (300 ml) were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was extracted with dichloromethane, and the extract was washed successively with water and saturated brine, and then the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (elution solvent: ethyl acetate / dichloromethane = 1/19) to give 4.3 g of the title compound (yield 13%). Was obtained as a colorless solid.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 7.11 (1H, d, J = 9.0), 7.78 (1H, dd, J = 9.0, 2.0), 7.94 (1H, d, J = 2.0), 9.93 (1H, s).

参考例８５
５−シアノ−２−ヒドロキシ桂皮アルデヒド
５−シアノ−２−ヒドロキシベンズアルデヒド（４．３ｇ）及びトリフェニルホスホラニリデンアセトアルデヒド（９．４ｇ）をトルエン（１５０ｍｌ）に溶解させ、７０℃で２時間攪拌した。反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ジクロロメタン＝１／３）で精製し、標記化合物２．３ｇ（収率４４％）を無色固体として得た。
¹H NMR (400MHz, DMSO-d₆) δppm : 6.98 (1H, dd, J=16.0, 8.0), 7.08 (1H,
d, J=9.0), 7.73 (1H, d, J=9.0), 7.83 (1H, d, J=16.0), 8.22 (1H, s), 9.67 (1H, d, J=8.0). Reference Example 85
5-Cyano-2-hydroxycinnamic aldehyde 5-Cyano-2-hydroxybenzaldehyde (4.3 g) and triphenylphosphoranylideneacetaldehyde (9.4 g) were dissolved in toluene (150 ml) and stirred at 70 ° C. for 2 hours. . The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / dichloromethane = 1/3) to obtain 2.3 g (yield 44%) of the title compound as a colorless solid.
¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 6.98 (1H, dd, J = 16.0, 8.0), 7.08 (1H,
d, J = 9.0), 7.73 (1H, d, J = 9.0), 7.83 (1H, d, J = 16.0), 8.22 (1H, s), 9.67 (1H, d, J = 8.0).

参考例８６
５−シアノ−２−メトキシメトキシ桂皮アルデヒド
５−シアノ−２−ヒドロキシ桂皮アルデヒド（２．３ｇ）をＮ，Ｎ−ジメチルホルムアミド（２５ｍｌ）に溶解させ、氷冷下、メトキシメトキシクロリド（１．５ｍｌ）及びトリエチルアミン（２．８ｍｌ）を加え、室温で１時間攪拌した。反応液を酢酸エチルで抽出し、抽出液を飽和食塩水で洗浄した後、有機層を無水硫酸マグネシウムを用いて乾燥させた。ろ過した後、減圧下溶媒を留去することにより、表記化合物（２．８ｇ）（収率９８％）を無色固体として得た。
¹H NMR (400MHz, CDCl₃) δppm : 3.52 (3H, s), 5.36 (2H, s), 6.80 (1H, dd, J=16.0, 8.0), 7.30 (1H, d, J=9.0), 7.66 (1H, dd, J=9.0, 2.0), 7.75 (1H, d, J=16.0), 7.84 (1H, d, J=2.0), 9.74 (1H, d, J=8.0). Reference Example 86
5-Cyano-2-methoxymethoxycinnamic aldehyde 5-Cyano-2-hydroxycinnamic aldehyde (2.3 g) was dissolved in N, N-dimethylformamide (25 ml), and methoxymethoxy chloride (1.5 ml) was cooled with ice. And triethylamine (2.8 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate, and the extract was washed with saturated brine, and then the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain the title compound (2.8 g) (yield 98%) as a colorless solid.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 3.52 (3H, s), 5.36 (2H, s), 6.80 (1H, dd, J = 16.0, 8.0), 7.30 (1H, d, J = 9.0), 7.66 (1H, dd, J = 9.0, 2.0), 7.75 (1H, d, J = 16.0), 7.84 (1H, d, J = 2.0), 9.74 (1H, d, J = 8.0).

参考例８７
３−（５―シアノ−２−メトキシメトキシフェニル）−２−（Ｅ）−プロペン−１−オール
５−シアノ−２−メトキシメトキシ桂皮アルデヒド（２．８ｇ）をジクロロメタン（２０ｍｌ）及びエタノール（４０ｍｌ）の混合溶媒に溶解させ、氷冷下、塩化セリウム（１．７ｇ）を加え、同温で０．５時間撹拌した後、水素化ホウ素ナトリウム（０．９ｇ）を加え、さらに同温で２時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加えた後、ジクロロメタンで抽出し、抽出液を水及び飽和食塩水で順次洗浄した後、有機層を無水硫酸マグネシウムを用いて乾燥させた。ろ過した後、減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒ヘキサン／酢酸エチル＝１／１）で精製することにより、表記化合物２．６ｇ（収率９３％）を黄色油状物質として得た。
¹H NMR (500MHz, CDCl₃) δppm : 3.49 (3H, s), 4.37 (2H, d, J=5.0), 5.27
(2H, s), 6.41 (1H, dt, J=16.0, 5.0), 6.90 (1H, d, J=16.0), 7.18 (1H, d,
J=9.0), 7.49 (1H, dd, J=9.0, 2.0), 7.72 (1H, d, J=2.0). Reference Example 87
3- (5-Cyano-2-methoxymethoxyphenyl) -2- (E) -propen-1-ol 5-cyano-2-methoxymethoxycinnaldehyde (2.8 g) in dichloromethane (20 ml) and ethanol (40 ml) After adding cerium chloride (1.7 g) under ice-cooling and stirring at the same temperature for 0.5 hour, sodium borohydride (0.9 g) was added, and further at the same temperature for 2 hours. Stir. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with dichloromethane. The extract was washed successively with water and saturated brine, and then the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent hexane / ethyl acetate = 1/1) to give 2.6 g (yield 93%) of the title compound as a yellow oil. Obtained as material.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 3.49 (3H, s), 4.37 (2H, d, J = 5.0), 5.27
(2H, s), 6.41 (1H, dt, J = 16.0, 5.0), 6.90 (1H, d, J = 16.0), 7.18 (1H, d,
J = 9.0), 7.49 (1H, dd, J = 9.0, 2.0), 7.72 (1H, d, J = 2.0).

参考例８８
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−クロロフェニル］−Ｎ−［３−（５−シアノ−２−メトキシメトキシフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル
３−（５−シアノ−２−メトキシメトキシフェニル）−２−（Ｅ）−プロペン−１−オール（０．６ｇ）、Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−クロロフェニル］スルファモイル酢酸エチル（１．３ｇ）及びトリフェニルホスフィン（０．９ｇ）をジクロロメタン（４０ｍｌ）に溶解させ、氷冷下、アゾジカルボン酸ジエチル（０．６ｍｌ）を加え、室温で１．５時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／酢酸エチル＝９／１）で精製することにより、表記化合物１．４ｇ（収率７４％）を黄色無定形固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.36 (3H, t, J=7.0), 1.47 (9H, s), 1.75-1.85 (2H, m), 1.85-1.95 (2H, m), 3.40-3.50 (2H, m), 3.44 (3H, s), 3.55-3.65 (2H, m), 3.99 (2H, s), 4.31 (2H, q, J=7.0), 4.48 (2H, d, J=7.0), 4.55 (1H, m), 5.23 (2H, s), 6.17 (1H, dt, J=16.0, 7.0), 6.70 (1H, d, J=16.0), 6.94 (1H, d, J=9.0), 7.13 (1H, d, J=9.0), 7.34 (1H, dd, J=9.0, 3.0),
7.47 (1H, dd, J=9.0, 2.0), 7.55 (1H, d, J=3.0), 7.61 (1H, d, J=2.0). Reference Example 88
N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3-chlorophenyl] -N- [3- (5-cyano-2-methoxymethoxyphenyl) -2- (E) -propenyl] sulfamoyl Ethyl acetate 3- (5-cyano-2-methoxymethoxyphenyl) -2- (E) -propen-1-ol (0.6 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) ) -3-Chlorophenyl] sulfamoyl ethyl acetate (1.3 g) and triphenylphosphine (0.9 g) were dissolved in dichloromethane (40 ml), and diethyl azodicarboxylate (0.6 ml) was added under ice-cooling at room temperature. Stir for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 9/1) to give 1.4 g (yield 74%) of the title compound as a yellow amorphous solid. Got as.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.0), 1.47 (9H, s), 1.75-1.85 (2H, m), 1.85-1.95 (2H, m), 3.40-3.50 (2H, m), 3.44 (3H, s), 3.55-3.65 (2H, m), 3.99 (2H, s), 4.31 (2H, q, J = 7.0), 4.48 (2H, d, J = 7.0) , 4.55 (1H, m), 5.23 (2H, s), 6.17 (1H, dt, J = 16.0, 7.0), 6.70 (1H, d, J = 16.0), 6.94 (1H, d, J = 9.0), 7.13 (1H, d, J = 9.0), 7.34 (1H, dd, J = 9.0, 3.0),
7.47 (1H, dd, J = 9.0, 2.0), 7.55 (1H, d, J = 3.0), 7.61 (1H, d, J = 2.0).

参考例８９
３−クロロ−５−ニトロサリチル酸メチル
３−クロロサリチル酸（４．５ｇ）をメタノール（１０ｍｌ）及びベンゼン（４０ｍｌ）の混合溶媒に溶解させ、氷冷下、２Ｍトリメチルシリルジアゾメタン／ヘキサン溶液（２０．０ｍｌ）を加え、室温で２時間撹拌した。反応液を減圧下濃縮し、得られた無色油状物質を、６９％硝酸（１５ｍｌ）及び濃硫酸（１５ｍｌ）の混合液に加えた後、室温で０．５時間撹拌した。反応液を氷水に注ぎ、酢酸エチルで抽出した後、抽出液を水及び飽和食塩水で順次洗浄し、有機層を無水硫酸マグネシウムを用いて乾燥させた。ろ過した後、減圧下溶媒を留去し、得られた黄色固体にヘキサンを加えた後、ろ取することにより、表記化合物２．４ｇ（収率３９％）を黄色固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 4.07 (3H, s), 8.47 (1H, d, J=3.0), 8.72
(1H, d, J=3.0). Reference Example 89
Methyl 3-chloro-5-nitrosalicylate 3-chlorosalicylic acid (4.5 g) was dissolved in a mixed solvent of methanol (10 ml) and benzene (40 ml), and 2M trimethylsilyldiazomethane / hexane solution (20.0 ml) under ice-cooling. And stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting colorless oily substance was added to a mixture of 69% nitric acid (15 ml) and concentrated sulfuric acid (15 ml), and then stirred at room temperature for 0.5 hour. The reaction solution was poured into ice water and extracted with ethyl acetate, and then the extract was washed successively with water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and hexane was added to the resulting yellow solid, followed by filtration to obtain 2.4 g (yield 39%) of the title compound as a yellow solid.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 4.07 (3H, s), 8.47 (1H, d, J = 3.0), 8.72
(1H, d, J = 3.0).

参考例９０
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−クロロ−５−メトキシカルボニルニトロベンゼン
１−ｔ−ブトキシカルボニル−４−ヒドロキシピペリジン（６．３ｇ）、３−クロロ−５−ニトロサリチル酸メチル（２．４ｇ）及びトリフェニルホスフィン（１０．８ｇ）をジクロロメタン（１００ｍｌ）に溶解させ、アゾジカルボン酸ジエチル（６．６ｍｌ）を加え、室温で４時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝４／１）で精製することにより、表記化合物３．４ｇ（収率７９％）を桃色固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.47 (9H, s), 1.75-1.85 (2H, m), 1.85-1.95 (2H, m), 3.11 (2H, m), 3.85-3.95 (2H, m), 3.97 (3H, s), 4.44 (1H, m), 8.43 (1H, d, J=3.0), 8.56 (1H, d, J=3.0). Reference Example 90
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-chloro-5-methoxycarbonylnitrobenzene 1-t-butoxycarbonyl-4-hydroxypiperidine (6.3 g), 3-chloro-5-nitrosalicylic acid Methyl (2.4 g) and triphenylphosphine (10.8 g) were dissolved in dichloromethane (100 ml), diethyl azodicarboxylate (6.6 ml) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to give 3.4 g (yield 79%) of the title compound as a pink solid. It was.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.75-1.85 (2H, m), 1.85-1.95 (2H, m), 3.11 (2H, m), 3.85-3.95 (2H, m ), 3.97 (3H, s), 4.44 (1H, m), 8.43 (1H, d, J = 3.0), 8.56 (1H, d, J = 3.0).

参考例９１
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−５−カルボキシ−３−クロロニトロベンゼン
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−クロロ−５−メトキシカルボニルニトロベンゼン（３．４ｇ）を濃塩酸（３０ｍｌ）に溶解させ、７５℃で１６時間撹拌した。反応液を減圧下濃縮し、得られた無色固体を、水（１５ｍｌ）及びアセトン（１５ｍｌ）の混合溶媒に溶解させ、氷冷下、炭酸水素ナトリウム（１．６ｇ）及びジ−ｔ−ブチルジカーボネート（２．２ｇ）加えた後、４０℃で１時間撹拌した。反応液を酢酸エチルで抽出し、抽出液を０．５Ｍ塩酸、水及び飽和食塩水で順次洗浄した後、有機層を無水硫酸マグネシウムを用いて乾燥させた。ろ過した後、減圧下溶媒を留去し、得られた淡黄色固体にヘキサンを加えた後、ろ取することにより、表記化合物２．６ｇ（収率７９％）を淡黄色固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.48 (9H, s), 1.85-1.95 (2H, m), 1.95-2.05 (2H, m), 3.16 (2H, m), 3.90-4.00 (2H, m), 4.54 (1H, m), 8.45 (1H, d,
J=3.0), 8.70 (1H, d, J=3.0). Reference Example 91
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-carboxy-3-chloronitrobenzene 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-chloro-5-methoxycarbonylnitrobenzene ( 3.4 g) was dissolved in concentrated hydrochloric acid (30 ml) and stirred at 75 ° C. for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting colorless solid was dissolved in a mixed solvent of water (15 ml) and acetone (15 ml). Under ice-cooling, sodium hydrogen carbonate (1.6 g) and di-t-butyldioxide were dissolved. After adding carbonate (2.2 g), the mixture was stirred at 40 ° C. for 1 hour. The reaction solution was extracted with ethyl acetate, and the extract was washed successively with 0.5M hydrochloric acid, water and saturated brine, and then the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and hexane was added to the obtained pale yellow solid, followed by filtration to obtain 2.6 g (yield 79%) of the title compound as a pale yellow solid.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.48 (9H, s), 1.85-1.95 (2H, m), 1.95-2.05 (2H, m), 3.16 (2H, m), 3.90-4.00 (2H, m ), 4.54 (1H, m), 8.45 (1H, d,
J = 3.0), 8.70 (1H, d, J = 3.0).

参考例９２
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−５−カルバモイル−３−クロロニトロベンゼン
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−５−カルボキシ−３−クロロニトロベンゼン（２．６ｇ）をジクロロメタン（８０ｍｌ）に溶解させ、氷冷下、クロロギ酸イソブチル（１．０ｍｌ）及びトリエチルアミン（１．１ｍｌ）を加え、同温で０．５時間撹拌した後、２８％アンモニア水（０．５ｍｌ）を加え、室温で１時間撹拌した。反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／メタノール＝１９／１）で精製することにより、表記化合物２．２ｇ（収率８４％）を淡黄色無定形固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.47 (9H, s), 1.75-1.85 (2H, m), 2.00-2.10 (2H, m), 2.85 (2H, m), 4.05-4.15 (2H, m), 4.51 (1H, m), 8.42 (1H, d,
J=3.0), 8.79 (1H, d, J=3.0). Reference Example 92
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-carbamoyl-3-chloronitrobenzene 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-carboxy-3-chloronitrobenzene (2 .6 g) was dissolved in dichloromethane (80 ml), isobutyl chloroformate (1.0 ml) and triethylamine (1.1 ml) were added under ice-cooling, and the mixture was stirred at the same temperature for 0.5 hour, followed by 28% aqueous ammonia ( 0.5 ml) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / methanol = 19/1) to give 2.2 g (yield 84%) of the title compound as a pale yellow amorphous solid. Obtained.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.75-1.85 (2H, m), 2.00-2.10 (2H, m), 2.85 (2H, m), 4.05-4.15 (2H, m ), 4.51 (1H, m), 8.42 (1H, d,
J = 3.0), 8.79 (1H, d, J = 3.0).

参考例９３
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−５−カルバモイル−３−クロロアニリン
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−５−カルバモイル−３−クロロニトロベンゼン（２．２ｇ）を酢酸（１００ｍｌ）に溶解させ、錫粉（９．９ｇ）を加えた後、室温で１１時間撹拌した。反応液をセライト（登録商標）を用いてろ過した後、ろ液を減圧下濃縮し、得られた淡黄色固体を炭酸カリウム水溶液に溶解させた後、酢酸エチルで抽出し、抽出液を水及び飽和食塩水で順次洗浄した後、有機層を無水硫酸マグネシウムを用いて乾燥させた。ろ過した後、減圧下溶媒を留去することにより、表記化合物１．７ｇ（収率８３％）を黄色無定形固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.46 (9H, s), 1.65-1.75 (2H, m), 1.95-2.05 (2H, m), 2.77 (2H, m), 3.70-3.80 (2H, m), 4.17 (1H, m), 6.84 (1H, d,
J=3.0), 7.19 (1H, d, J=3.0). Reference Example 93
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-carbamoyl-3-chloroaniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-carbamoyl-3-chloronitrobenzene (2 0.2 g) was dissolved in acetic acid (100 ml), tin powder (9.9 g) was added, and the mixture was stirred at room temperature for 11 hours. After the reaction solution was filtered using Celite (registered trademark), the filtrate was concentrated under reduced pressure, and the resulting pale yellow solid was dissolved in an aqueous potassium carbonate solution, and then extracted with ethyl acetate. After sequentially washing with saturated brine, the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 1.7 g (yield 83%) of the title compound as a yellow amorphous solid.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.46 (9H, s), 1.65-1.75 (2H, m), 1.95-2.05 (2H, m), 2.77 (2H, m), 3.70-3.80 (2H, m ), 4.17 (1H, m), 6.84 (1H, d,
J = 3.0), 7.19 (1H, d, J = 3.0).

参考例９４
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−５−カルバモイル−３−クロロフェニル］スルファモイル酢酸エチル
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−５−カルバモイル−３−クロロアニリン（１．７ｇ）をジクロロメタン（３０ｍｌ）に溶解させ、ピリジン（０．７ｍｌ）を加えた後、氷冷下、クロロスルホニル酢酸エチル（０．７ｍｌ）を滴下し、室温で１時間撹拌した。反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／メタノール＝１／１）で精製することにより、表記化合物１．２ｇ（収率４８％）を淡黄色固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.17 (3H, t, J=7.0), 1.40 (9H, s), 1.55-1.65 (2H, m), 1.80-1.90 (2H, m), 2.95-3.05 (2H, m), 3.70-3.80 (2H, m), 4.10 (2H, q, J=7.0), 4.21 (1H, m), 4.27 (2H, s), 7.28 (1H, d, J=3.0), 7.36 (1H, d, J=3.0). Reference Example 94
N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -5-carbamoyl-3-chlorophenyl] sulfamoyl acetate ethyl 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-carbamoyl- 3-Chloroaniline (1.7 g) was dissolved in dichloromethane (30 ml), pyridine (0.7 ml) was added, ethyl chlorosulfonylacetate (0.7 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. Stir. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 1/1) to give 1.2 g (yield 48%) of the title compound as a pale yellow solid. .
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.17 (3H, t, J = 7.0), 1.40 (9H, s), 1.55-1.65 (2H, m), 1.80-1.90 (2H, m), 2.95 -3.05 (2H, m), 3.70-3.80 (2H, m), 4.10 (2H, q, J = 7.0), 4.21 (1H, m), 4.27 (2H, s), 7.28 (1H, d, J = 3.0), 7.36 (1H, d, J = 3.0).

参考例９５
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−５−カルバモイル−３−クロロフェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル
３−（３−シアノフェニル）−２−（Ｅ）−プロペン−１−オール（０．４ｇ）、Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−５−カルバモイル−３−クロロフェニル］スルファモイル酢酸エチル（１．２ｇ）及びトリフェニルホスフィン（０．８ｇ）を、ジクロロメタン（５０ｍｌ）及びテトラヒドロフラン（２０ｍｌ）の混合溶媒に溶解させ、氷冷下、アゾジカルボン酸ジエチル（０．５ｍｌ）を加え、室温で１時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／酢酸エチル＝３／２）で精製することにより、表記化合物１．５ｇ（収率定量的）を黄色無定形固体として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.35 (3H, t, J=7.0), 1.46 (9H, s), 1.65-1.80 (2H, m), 1.95-2.05 (2H, m), 2.79 (2H, m), 4.00 (2H, s), 4.00-4.15 (2H, m), 4.31 (2H, q, J=7.0), 4.38 (1H, m), 4.53 (2H, d, J=7.0), 6.21 (1H, dt, J=16.0, 7.0), 6.46 (1H, d, J=16.0), 7.23 (1H, m), 7.41 (1H, m), 7.50-7.60 (3H, m), 8.03 (1H, m). Reference Example 95
N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-carbamoyl-3-chlorophenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoylacetic acid Ethyl 3- (3-cyanophenyl) -2- (E) -propen-1-ol (0.4 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-carbamoyl- 3-Chlorophenyl] sulfamoylethyl acetate (1.2 g) and triphenylphosphine (0.8 g) were dissolved in a mixed solvent of dichloromethane (50 ml) and tetrahydrofuran (20 ml), and diethyl azodicarboxylate (0. 5 ml) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 3/2) to give 1.5 g of the title compound (quantitative yield) as a yellow amorphous solid. Got as.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.35 (3H, t, J = 7.0), 1.46 (9H, s), 1.65-1.80 (2H, m), 1.95-2.05 (2H, m), 2.79 (2H , m), 4.00 (2H, s), 4.00-4.15 (2H, m), 4.31 (2H, q, J = 7.0), 4.38 (1H, m), 4.53 (2H, d, J = 7.0), 6.21 (1H, dt, J = 16.0, 7.0), 6.46 (1H, d, J = 16.0), 7.23 (1H, m), 7.41 (1H, m), 7.50-7.60 (3H, m), 8.03 (1H, m).

参考例９６
３−メチル−５−ニトロサリチル酸メチル
３−メチルサリチル酸（５．１ｇ）をメタノール（１０ｍｌ）及びベンゼン（４０ｍｌ）の混合溶媒に溶解させ、氷冷下、２Ｍトリメチルシリルジアゾメタン／ヘキサン溶液（２５．０ｍｌ）を加えた後、室温で１時間撹拌した。反応液を減圧下濃縮し、得られた無色油状物質を、６９％硝酸（１５ｍｌ）及び濃硫酸（１５ｍｌ）の混合液に加え、室温で１時間撹拌した。反応液を氷水に注ぎ、酢酸エチルで抽出した後、抽出液を水及び飽和食塩水で順次洗浄し、有機層を無水硫酸マグネシウムを用いて乾燥させた。ろ過した後、減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝２／１）で精製し、得られた黄色固体にヘキサンを加えた後、ろ取することにより、表記化合物１．８ｇ（収率２５％）を淡黄色固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 2.35 (3H, s), 4.03 (3H, s), 8.21 (1H, d, J=3.0), 8.66 (1H, d, J=3.0). Reference Example 96
3-methyl-5-nitrosalicylic acid methyl 3-methylsalicylic acid (5.1 g) was dissolved in a mixed solvent of methanol (10 ml) and benzene (40 ml), and 2M trimethylsilyldiazomethane / hexane solution (25.0 ml) under ice cooling After stirring, the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting colorless oily substance was added to a mixture of 69% nitric acid (15 ml) and concentrated sulfuric acid (15 ml), and stirred at room temperature for 1 hour. The reaction solution was poured into ice water and extracted with ethyl acetate, and then the extract was washed successively with water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2/1), and hexane was added to the resulting yellow solid, followed by filtration. This gave 1.8 g (yield 25%) of the title compound as a pale yellow solid.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 2.35 (3H, s), 4.03 (3H, s), 8.21 (1H, d, J = 3.0), 8.66 (1H, d, J = 3.0).

参考例９７
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−メトキシカルボニル−５−メチルニトロベンゼン
１−ｔ−ブトキシカルボニル−４−ヒドロキシピペリジン（４．２ｇ）、３−メチル−５−ニトロサリチル酸メチル（１．８ｇ）及びトリフェニルホスフィン（６．８ｇ）をジクロロメタン（１００ｍｌ）に溶解させ、アゾジカルボン酸ジエチル（４．１ｍｌ）を加え、室温で３時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝４／１）で精製することにより、表記化合物３．１ｇ（収率９１％）を桃色油状物質として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.47 (9H, s), 1.65-1.75 (2H, m), 1.85-1.95 (2H, m), 2.39 (3H, s), 2.97 (2H, m), 3.90-4.00 (2H, m), 3.95 (3H, s), 4.16 (1H, m), 8.22 (1H, d, J=3.0), 8.52 (1H, d, J=3.0). Reference Example 97
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-methoxycarbonyl-5-methylnitrobenzene 1-t-butoxycarbonyl-4-hydroxypiperidine (4.2 g), 3-methyl-5-nitrosalicylic acid Methyl (1.8 g) and triphenylphosphine (6.8 g) were dissolved in dichloromethane (100 ml), diethyl azodicarboxylate (4.1 ml) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to give 3.1 g (yield 91%) of the title compound as a pink oily substance. Obtained.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.65-1.75 (2H, m), 1.85-1.95 (2H, m), 2.39 (3H, s), 2.97 (2H, m), 3.90-4.00 (2H, m), 3.95 (3H, s), 4.16 (1H, m), 8.22 (1H, d, J = 3.0), 8.52 (1H, d, J = 3.0).

参考例９８
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−カルボキシ−５−メチルニトロベンゼン
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−メトキシカルボニル−５−メチルニトロベンゼン（４．０ｇ）を濃塩酸（４０ｍｌ）に溶解させ、７５℃で７時間撹拌した。反応液を減圧下濃縮し、得られた白色固体を、水（２０ｍｌ）及びアセトン（２０ｍｌ）の混合溶媒に溶解させ、氷冷下、炭酸水素ナトリウム（１．９ｇ）及びジ−ｔ−ブチルジカーボネート（２．７ｇ）加えた後、４０℃で２時間撹拌した。反応液を酢酸エチルで抽出し、抽出液を０．５Ｍ塩酸、水及び飽和食塩水で順次洗浄した後、有機層を無水硫酸マグネシウムを用いて乾燥させた。ろ過した後、減圧下溶媒を留去し、得られた淡黄色固体にヘキサンを加えた後、ろ取することにより、表記化合物３．６ｇ（収率７９％）を淡黄色固体として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.47 (9H, s), 1.70-1.85 (2H, m), 1.90-2.05 (2H, m), 2.43 (3H, s), 2.95 (2H, m), 4.00-4.10 (2H, m), 4.26 (1H, m), 8.26 (1H, d, J=3.0), 8.69 (1H, d, J=3.0). Reference Example 98
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carboxy-5-methylnitrobenzene 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-methoxycarbonyl-5-methylnitrobenzene ( 4.0 g) was dissolved in concentrated hydrochloric acid (40 ml) and stirred at 75 ° C. for 7 hours. The reaction mixture was concentrated under reduced pressure, and the resulting white solid was dissolved in a mixed solvent of water (20 ml) and acetone (20 ml). Under ice-cooling, sodium hydrogen carbonate (1.9 g) and di-t-butyldioxide were dissolved. After adding carbonate (2.7 g), the mixture was stirred at 40 ° C. for 2 hours. The reaction solution was extracted with ethyl acetate, and the extract was washed successively with 0.5M hydrochloric acid, water and saturated brine, and then the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and hexane was added to the obtained pale yellow solid, followed by filtration to obtain 3.6 g (yield 79%) of the title compound as a pale yellow solid.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.70-1.85 (2H, m), 1.90-2.05 (2H, m), 2.43 (3H, s), 2.95 (2H, m), 4.00-4.10 (2H, m), 4.26 (1H, m), 8.26 (1H, d, J = 3.0), 8.69 (1H, d, J = 3.0).

参考例９９
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−カルバモイル−５−メチルニトロベンゼン
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−カルボキシ−５−メチルニトロベンゼン（３．６ｇ）をジクロロメタン（６０ｍｌ）に溶解させ、氷冷下、クロロギ酸イソブチル（１．４ｍｌ）及びトリエチルアミン（１．６ｍｌ）を加え、同温で０．５時間撹拌した後、２８％アンモニア水（０．７ｍｌ）を加え、室温で１．５時間撹拌した。反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／メタノール＝１９／１）で精製することにより、表記化合物３．９ｇ（収率定量的）を黄色油状物質として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.46 (9H, s), 1.70-1.80 (2H, m), 1.90-2.00 (2H, m), 2.43 (3H, s), 2.79 (2H, m), 4.05-4.15 (2H, m), 4.17 (1H, m), 8.20 (1H, d, J=3.0), 8.66 (1H, d, J=3.0). Reference Example 99
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carbamoyl-5-methylnitrobenzene 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carboxy-5-methylnitrobenzene (3 .6 g) was dissolved in dichloromethane (60 ml), isobutyl chloroformate (1.4 ml) and triethylamine (1.6 ml) were added under ice cooling, and the mixture was stirred at the same temperature for 0.5 hour, and then 28% aqueous ammonia ( 0.7 ml) was added and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 19/1) to give 3.9 g (quantitative yield) of the title compound as a yellow oil. .
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.46 (9H, s), 1.70-1.80 (2H, m), 1.90-2.00 (2H, m), 2.43 (3H, s), 2.79 (2H, m), 4.05-4.15 (2H, m), 4.17 (1H, m), 8.20 (1H, d, J = 3.0), 8.66 (1H, d, J = 3.0).

参考例１００
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−カルバモイル−５−メチルアニリン
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−カルバモイル−５−メチルニトロベンゼン（３．９ｇ）をメタノール（１００ｍｌ）に溶解させ、パラジウム−炭素触媒（０．５ｇ）を加え、水素雰囲気下、室温で１．５時間撹拌した。反応液をろ過した後、ろ液を減圧下濃縮することにより、表記化合物３．５ｇ（収率９７％）を黒緑色無定形固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.46 (9H, s), 1.60-1.70 (2H, m), 1.90-2.00 (2H, m), 2.23 (3H, s), 2.71 (2H, m), 3.62 (2H, m), 3.80-3.90 (1H, m), 6.65 (1H, d, J=3.0), 7.11 (1H, d, J=3.0). Reference Example 100
4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3-carbamoyl-5-methylaniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carbamoyl-5-methylnitrobenzene (3 .9 g) was dissolved in methanol (100 ml), palladium-carbon catalyst (0.5 g) was added, and the mixture was stirred at room temperature for 1.5 hours in a hydrogen atmosphere. After filtering the reaction solution, the filtrate was concentrated under reduced pressure to obtain 3.5 g (yield 97%) of the title compound as a black-green amorphous solid.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.46 (9H, s), 1.60-1.70 (2H, m), 1.90-2.00 (2H, m), 2.23 (3H, s), 2.71 (2H, m), 3.62 (2H, m), 3.80-3.90 (1H, m), 6.65 (1H, d, J = 3.0), 7.11 (1H, d, J = 3.0).

参考例１０１
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−カルバモイル−５−メチルフェニル］スルファモイル酢酸エチル
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−カルバモイル−５−メチルアニリン（３．５ｇ）及びピリジン（１．０ｍｌ）をジクロロメタン（８０ｍｌ）に溶解させ、氷冷下、クロロスルホニル酢酸エチル（１．６ｍｌ）を滴下し、室温で０．５時間撹拌した。反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／メタノール＝１９／１）で精製することにより、表記化合物２．６ｇ（収率５１％）を淡黄色固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.31 (3H, t, J=7.0), 1.46 (9H, s), 1.65-1.75 (2H, m), 1.90-2.00 (2H, m), 2.33 (3H, s), 2.74 (2H, m), 3.90-4.00 (1H, m), 3.97 (2H, s), 4.00-4.15 (2H, m), 4.27 (2H, q, J=7.0), 7.44 (1H,
d, J=3.0), 7.72 (1H, d, J=3.0). Reference Example 101
N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3-carbamoyl-5-methylphenyl] sulfamoyl acetate ethyl 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carbamoyl -5-Methylaniline (3.5 g) and pyridine (1.0 ml) were dissolved in dichloromethane (80 ml), ethyl chlorosulfonylacetate (1.6 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 0.5 hour. did. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 19/1) to give 2.6 g (yield 51%) of the title compound as a pale yellow solid. .
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.31 (3H, t, J = 7.0), 1.46 (9H, s), 1.65-1.75 (2H, m), 1.90-2.00 (2H, m), 2.33 (3H , s), 2.74 (2H, m), 3.90-4.00 (1H, m), 3.97 (2H, s), 4.00-4.15 (2H, m), 4.27 (2H, q, J = 7.0), 7.44 (1H ,
d, J = 3.0), 7.72 (1H, d, J = 3.0).

参考例１０２
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−カルバモイル−５−メチルフェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル
３−（３−シアノフェニル）−２−（Ｅ）−プロペン−１−オール（０．８ｇ）、Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３−カルバモイル−５−メチルフェニル］スルファモイル酢酸エチル（２．６ｇ）及びトリフェニルホスフィン（１．７ｇ）を、ジクロロメタン（５０ｍｌ）及びテトラヒドロフラン（５０ｍｌ）の混合溶媒に溶解させ、氷冷下、アゾジカルボン酸ジエチル（１．０ｍｌ）を加え、室温で１．５時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／２）で精製することにより、表記化合物３．２ｇ（収率９６％）を黄色無定形固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.35 (3H, t, J=7.0), 1.46 (9H, s), 1.65-1.75 (2H, m), 1.85-1.95 (2H, m), 2.32 (3H, s), 2.73 (2H, m), 3.95-4.05 (1H, m), 4.00 (2H, s), 4.05-4.15 (2H, m), 4.31 (2H, q, J=7.0), 4.52 (2H,
d, J=7.0), 6.22 (1H, dt, J=16.0, 7.0), 6.44 (1H, d, J=16.0), 7.22 (1H, m), 7.40 (1H, m), 7.50-7.60 (3H, m), 7.91 (1H, m). Reference Example 102
N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3-carbamoyl-5-methylphenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl Ethyl acetate 3- (3-cyanophenyl) -2- (E) -propen-1-ol (0.8 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3-carbamoyl -5-Methylphenyl] sulfamoyl ethyl acetate (2.6 g) and triphenylphosphine (1.7 g) were dissolved in a mixed solvent of dichloromethane (50 ml) and tetrahydrofuran (50 ml), and diethyl azodicarboxylate ( 1.0 ml) was added and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/2) to give 3.2 g (yield 96%) of the title compound as a yellow amorphous solid. Got as.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.35 (3H, t, J = 7.0), 1.46 (9H, s), 1.65-1.75 (2H, m), 1.85-1.95 (2H, m), 2.32 (3H , s), 2.73 (2H, m), 3.95-4.05 (1H, m), 4.00 (2H, s), 4.05-4.15 (2H, m), 4.31 (2H, q, J = 7.0), 4.52 (2H ,
d, J = 7.0), 6.22 (1H, dt, J = 16.0, 7.0), 6.44 (1H, d, J = 16.0), 7.22 (1H, m), 7.40 (1H, m), 7.50-7.60 (3H , m), 7.91 (1H, m).

参考例１０３
２，６−ジフルオロ−４−ニトロフェノール
２，６−ジフルオロフェノール（２．００ｇ）を酢酸（２０ｍｌ）に溶解させ、氷冷下、６０％硝酸（１．２０ｍｌ）を滴下した後、室温で１時間攪拌した。反応液を氷水中に注いだ後、酢酸エチルを加えて抽出し、抽出液を飽和食塩水で洗浄した後、有機層を無水硫酸マグネシウムを用いて乾燥させた。ろ過した後、減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝３／１〜２／１）で精製することにより、表記化合物１．３７ｇ（収率５１％）を淡黄色固体として得た。
¹H NMR (400MHz, CDCl₃) δppm : 7.95 (2H, m). Reference Example 103
2,6-difluoro-4-nitrophenol 2,6-difluorophenol (2.00 g) was dissolved in acetic acid (20 ml), and 60% nitric acid (1.20 ml) was added dropwise under ice cooling. Stir for hours. The reaction solution was poured into ice water, extracted with ethyl acetate, the extract was washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/1 to 2/1) to give 1.37 g (yield 51) of the title compound. %) As a pale yellow solid.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 7.95 (2H, m).

参考例１０４
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３，５−ジフルオロニトロベンゼン
１−ｔ−ブトキシカルボニル−４−ヒドロキシピペリジン（１．７３ｇ）、２，６−ジフルオロ−４−ニトロフェノール（１．３７ｇ）及びトリフェニルホスフィン（２．６７ｇ）をジクロロメタン（３０ｍｌ）に溶解させ、氷冷下、アゾジカルボン酸ジエチル（１．５７ｍｌ）を滴下した後、室温で９時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝６／１）で精製することにより、表記化合物２．１３ｇ（収率７６％）を淡黄色固体として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.47 (9H, s), 1.77-1.85 (2H, m), 1.89-1.96 (2H, m), 3.35 (2H, m), 3.72 (2H, m), 4.62 (1H, m), 7.87 (2H, m). Reference Example 104
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-difluoronitrobenzene 1-t-butoxycarbonyl-4-hydroxypiperidine (1.73 g), 2,6-difluoro-4-nitrophenol ( 1.37 g) and triphenylphosphine (2.67 g) were dissolved in dichloromethane (30 ml), and diethyl azodicarboxylate (1.57 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 9 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 6/1) to give 2.13 g (yield 76%) of the title compound as a pale yellow solid. Obtained.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.77-1.85 (2H, m), 1.89-1.96 (2H, m), 3.35 (2H, m), 3.72 (2H, m), 4.62 (1H, m), 7.87 (2H, m).

参考例１０５
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３，５−ジフルオロアニリン
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３，５−ジフルオロニトロベンゼン（２．１３ｇ）をエタノール（４０ｍｌ）に溶解させ、パラジウム−炭素触媒（０．２０ｇ）を加え、水素雰囲気下、室温で１時間撹拌した。反応液をろ過した後、ろ液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝２／１）で精製することにより、表記化合物１．７０ｇ（収率８７％）を無色固体として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.46 (9H, s), 1.72-1.78 (2H, m), 1.83-1.89 (2H, m), 3.23 (2H, m), 3.77 (2H, m), 4.11 (1H, m), 6.21 (2H, m). Reference Example 105
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-difluoroaniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-difluoronitrobenzene (2.13 g) It was dissolved in ethanol (40 ml), palladium-carbon catalyst (0.20 g) was added, and the mixture was stirred at room temperature for 1 hour in a hydrogen atmosphere. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2/1) to give 1.70 g of the title compound (yield 87%). ) Was obtained as a colorless solid.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.46 (9H, s), 1.72-1.78 (2H, m), 1.83-1.89 (2H, m), 3.23 (2H, m), 3.77 (2H, m), 4.11 (1H, m), 6.21 (2H, m).

参考例１０６
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３，５−ジフルオロフェニル］スルファモイル酢酸エチル
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３，５−ジフルオロアニリン（１．７０ｇ）及びピリジン（０．８４ｍｌ）をジクロロメタン（３０ｍｌ）に溶解させ、氷冷下、クロロスルホニル酢酸エチル（０．７６ｍｌ）を滴下し、室温で１．５時間撹拌した。反応液に水を加え、酢酸エチルで抽出した後、抽出液を飽和食塩水で洗浄し、有機層を無水硫酸マグネシウムを用いて乾燥させた。ろ過した後、減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝２／１）で精製することにより、表記化合物２．４８ｇ（定量的）を黄色油状物質として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.34 (3H, t, J=7.0), 1.47 (9H, s), 1.72-1.82 (2H, m), 1.83-1.93 (2H, m), 3.28 (2H, m), 3.75 (2H, m), 3.95 (2H, s), 4.30 (2H, q, J=7.0), 4.31 (1H, m), 6.95 (2H, m). Reference Example 106
N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-difluorophenyl] sulfamoyl acetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-difluoro Aniline (1.70 g) and pyridine (0.84 ml) were dissolved in dichloromethane (30 ml), ethyl chlorosulfonylacetate (0.76 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2/1) to give 2.48 g (quantitative) of the title compound as a yellow oily substance. Got as.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.34 (3H, t, J = 7.0), 1.47 (9H, s), 1.72-1.82 (2H, m), 1.83-1.93 (2H, m), 3.28 (2H , m), 3.75 (2H, m), 3.95 (2H, s), 4.30 (2H, q, J = 7.0), 4.31 (1H, m), 6.95 (2H, m).

参考例１０７
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３，５−ジフルオロフェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル
３−（３−シアノフェニル）−２−（Ｅ）−プロペン−１−オール（０．５２ｇ）、Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３，５−ジフルオロフェニル］スルファモイル酢酸エチル（１．５５ｇ）及びトリフェニルホスフィン（１．０２ｇ）をジクロロメタン（３０ｍｌ）に溶解させ、氷冷下、アゾジカルボン酸ジエチル（０．６０ｍｌ）を滴下した後、同温で１時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝２／１）で精製することにより、表記化合物１．８２ｇ（収率９１％）を無色無定形固体として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.36 (3H, t, J=7.0), 1.46 (9H, s), 1.72-1.82 (2H, m), 1.83-1.93 (2H, m), 3.29 (2H, m), 3.73 (2H, m), 3.99 (2H, s), 4.31 (2H, q, J=7.0), 4.37 (1H, m), 4.47 (2H, d, J=6.5), 6.20 (1H, dt, J=16.0, 6.5), 6.43 (1H, d, J=16.0), 7.12 (2H, m), 7.41 (1H, t, J=7.5),
7.53 (1H, d, J=7.5), 7.54 (1H, d, J=7.5), 7.57 (1H, s). Reference Example 107
N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3,5-difluorophenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl acetate ethyl 3- (3-Cyanophenyl) -2- (E) -propen-1-ol (0.52 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-difluoro Phenyl] sulfamoyl ethyl acetate (1.55 g) and triphenylphosphine (1.02 g) were dissolved in dichloromethane (30 ml), and diethyl azodicarboxylate (0.60 ml) was added dropwise under ice cooling. Stir for hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to give 1.82 g (yield 91%) of the title compound as a colorless amorphous solid. Got as.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.0), 1.46 (9H, s), 1.72-1.82 (2H, m), 1.83-1.93 (2H, m), 3.29 (2H , m), 3.73 (2H, m), 3.99 (2H, s), 4.31 (2H, q, J = 7.0), 4.37 (1H, m), 4.47 (2H, d, J = 6.5), 6.20 (1H , dt, J = 16.0, 6.5), 6.43 (1H, d, J = 16.0), 7.12 (2H, m), 7.41 (1H, t, J = 7.5),
7.53 (1H, d, J = 7.5), 7.54 (1H, d, J = 7.5), 7.57 (1H, s).

参考例１０８
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３，５−ジクロロニトロベンゼン
１−ｔ−ブトキシカルボニル−４−ヒドロキシピペリジン（６７７ｍｇ）、２，６−ジクロロ−４−ニトロフェノール（７００ｍｇ）及びトリフェニルホスフィン（１１５０ｍｇ）をジクロロメタン（４０ｍｌ）に溶解させ、氷冷下、アゾジカルボン酸ジエチル（０．６７ｍｌ）を滴下し、室温で２時間撹拌した。反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝６／１）で精製することにより、表記化合物９５０ｍｇ（収率７２％）を無色固体として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.48 (9H, s), 1.85-2.00 (4H, m), 3.20 (2H, m), 3.91 (2H, m), 4.59 (1H, m), 8.23 (2H, s). Reference Example 108
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-dichloronitrobenzene 1-t-butoxycarbonyl-4-hydroxypiperidine (677 mg), 2,6-dichloro-4-nitrophenol (700 mg) And triphenylphosphine (1150 mg) were dissolved in dichloromethane (40 ml), and diethyl azodicarboxylate (0.67 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 6/1) to give the title compound (950 mg, yield 72%) as a colorless solid.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.48 (9H, s), 1.85-2.00 (4H, m), 3.20 (2H, m), 3.91 (2H, m), 4.59 (1H, m), 8.23 ( 2H, s).

参考例１０９
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３，５−ジクロロアニリン
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３，５−ジクロロニトロベンゼン（１．９５ｇ）を酢酸（５０ｍｌ）に溶解させ、室温で亜鉛粉末（１１．１０ｇ）を５回に分けて加えた後、５０℃で６時間撹拌した。反応液をろ過し、ろ液を減圧下濃縮した後、残渣に酢酸エチル及び水を加えて抽出し、抽出液を飽和食塩水で洗浄した後、有機層を無水硫酸マグネシウムを用いて乾燥させた。ろ過した後、減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝３／１）で精製することにより、表記化合物１．４０ｇ（収率７８％）を無色固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.47 (9H, s), 1.80-1.95 (4H, m), 3.09 (2H, m), 3.92 (2H, m), 4.22 (1H, m), 6.61 (2H, s). Reference Example 109
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-dichloroaniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-dichloronitrobenzene (1.95 g) After dissolving in acetic acid (50 ml) and adding zinc powder (11.10 g) in 5 portions at room temperature, the mixture was stirred at 50 ° C. for 6 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate and water, and the extract was washed with saturated brine, and then the organic layer was dried over anhydrous magnesium sulfate. . After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/1) to give 1.40 g (yield 78%) of the title compound. ) Was obtained as a colorless solid.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.80-1.95 (4H, m), 3.09 (2H, m), 3.92 (2H, m), 4.22 (1H, m), 6.61 ( 2H, s).

参考例１１０
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン―４−イルオキシ）−３，５−ジクロロフェニル］スルファモイル酢酸エチル
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３，５−ジクロロアニリン（１．４０ｇ）及びピリジン（０．６３ｍｌ）をジクロロメタン（３０ｍｌ）に溶解させ、氷冷下、クロロスルホニル酢酸エチル（０．５７ｍｌ）を滴下し、室温で１．５時間撹拌した。反応液に酢酸エチル及び水を加えて抽出し、抽出液を飽和食塩水で洗浄した後、有機層を無水硫酸マグネシウムを用いて乾燥させた。ろ過した後、減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝２／１）で精製することにより、表記化合物１．８９ｇ（収率９５％）を淡黄色無定形固体として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.34 (3H, t, J=7.0), 1.47 (9H, s), 1.80-2.00 (4H, m), 3.14 (2H, m), 3.92 (2H, m), 3.96 (2H, s), 4.30 (2H, q, J=7.0), 4.37 (1H, m), 7.33 (2H, s). Reference Example 110
N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-dichlorophenyl] sulfamoyl acetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-dichloroaniline (1.40 g) and pyridine (0.63 ml) were dissolved in dichloromethane (30 ml), and ethyl chlorosulfonylacetate (0.57 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 1.5 hours. Ethyl acetate and water were added to the reaction solution for extraction, and the extract was washed with saturated brine, and then the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2/1) to give 1.89 g (yield 95%) of the title compound. ) Was obtained as a pale yellow amorphous solid.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.34 (3H, t, J = 7.0), 1.47 (9H, s), 1.80-2.00 (4H, m), 3.14 (2H, m), 3.92 (2H, m ), 3.96 (2H, s), 4.30 (2H, q, J = 7.0), 4.37 (1H, m), 7.33 (2H, s).

参考例１１１
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３，５−ジクロロフェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル
３−（３−シアノフェニル）−２−（Ｅ）−プロペン−１−オール（０．５９ｇ）、Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３，５−ジクロロフェニル］スルファモイル酢酸エチル（１．８９ｇ）及びトリフェニルホスフィン（１．１６ｇ）をジクロロメタン（３０ｍｌ）に溶解させ、氷冷下、アゾジカルボン酸ジエチル（０．６８ｍｌ）を滴下し、同温で４時間撹拌した。反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝３／１）で精製することにより、表記化合物２．０６ｇ（収率８６％）を無色無定形固体として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.36 (3H, t, J=7.0), 1.47 (9H, s), 1.80-2.00 (4H, m), 3.15 (2H, m), 3.90 (2H, m), 4.00 (2H, s), 4.31 (2H, q, J=7.0), 4.41 (1H, m), 4.47 (2H, d, J=6.5), 6.20 (1H, dt, J=16.0, 6.5), 6.44 (1H, d, J=16.0), 7.42 (1H, t, J=8.0), 7.47 (2H, s), 7.53 (2H, m), 7.58
(1H, s). Reference Example 111
N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-dichlorophenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl acetate 3 -(3-Cyanophenyl) -2- (E) -propen-1-ol (0.59 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-dichlorophenyl] Ethyl sulfamoyl acetate (1.89 g) and triphenylphosphine (1.16 g) were dissolved in dichloromethane (30 ml), and diethyl azodicarboxylate (0.68 ml) was added dropwise under ice cooling, followed by stirring at the same temperature for 4 hours. . The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/1) to give 2.06 g (yield 86%) of the title compound as a colorless amorphous solid. Obtained.
^{_{1 H NMR (400MHz, CDCl 3}} ) δppm: 1.36 (3H, t, J = 7.0), 1.47 (9H, s), 1.80-2.00 (4H, m), 3.15 (2H, m), 3.90 (2H, m ), 4.00 (2H, s), 4.31 (2H, q, J = 7.0), 4.41 (1H, m), 4.47 (2H, d, J = 6.5), 6.20 (1H, dt, J = 16.0, 6.5) , 6.44 (1H, d, J = 16.0), 7.42 (1H, t, J = 8.0), 7.47 (2H, s), 7.53 (2H, m), 7.58
(1H, s).

参考例１１２
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３，５−ジメチルニトロベンゼン
１−ｔ−ブトキシカルボニル−４−ヒドロキシピペリジン（２．４０ｇ）、２，６−ジメチル−４−ニトロフェノール（１．５０ｇ）及びトリフェニルホスフィン（３．０６ｇ）をジクロロメタン（６０ｍｌ）に溶解させ、氷冷下、アゾジカルボン酸ジエチル（１．８０ｍｌ）を滴下し、室温で１９時間撹拌した。反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝５／１）で精製することにより、表記化合物２．２５ｇ（収率７１％）を無色固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.48 (9H, s), 1.73 (2H, m), 1.93 (2H, m), 2.35 (6H, s), 2.93 (2H, m), 4.00-4.10 (3H, m), 7.92 (2H, s). Reference Example 112
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-dimethylnitrobenzene 1-t-butoxycarbonyl-4-hydroxypiperidine (2.40 g), 2,6-dimethyl-4-nitrophenol ( 1.50 g) and triphenylphosphine (3.06 g) were dissolved in dichloromethane (60 ml), and diethyl azodicarboxylate (1.80 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 19 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 5/1) to give the title compound (2.25 g, yield 71%) as a colorless solid. .
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.48 (9H, s), 1.73 (2H, m), 1.93 (2H, m), 2.35 (6H, s), 2.93 (2H, m), 4.00-4.10 ( 3H, m), 7.92 (2H, s).

参考例１１３
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３，５−ジメチルアニリン
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３，５−ジメチルニトロベンゼン（２．２４ｇ）をエタノール（３０ｍｌ）及びテトラヒドロフラン（１０ｍｌ）の混合溶媒に溶解させ、パラジウム−炭素触媒（０．２０ｇ）を加え、水素雰囲気下、室温で１時間撹拌した。反応液をろ過した後、ろ液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝２／１）で精製することにより、表記化合物１．９４ｇ（収率９５％）を淡桃色固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.47 (9H, s), 1.66 (2H, m), 1.92 (2H, m), 2.19 (6H, s), 2.86 (2H, m), 3.79 (1H, m), 4.02 (2H, m), 6.36 (2H, s). Reference Example 113
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-dimethylaniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-dimethylnitrobenzene (2.24 g) The mixture was dissolved in a mixed solvent of ethanol (30 ml) and tetrahydrofuran (10 ml), palladium-carbon catalyst (0.20 g) was added, and the mixture was stirred at room temperature for 1 hour in a hydrogen atmosphere. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2/1) to give 1.94 g of the title compound (yield 95%). ) Was obtained as a pale pink solid.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.66 (2H, m), 1.92 (2H, m), 2.19 (6H, s), 2.86 (2H, m), 3.79 (1H, m), 4.02 (2H, m), 6.36 (2H, s).

参考例１１４
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３，５−ジメチルフェニル］スルファモイル酢酸エチル
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３，５−ジメチルアニリン（１．９４ｇ）及びピリジン（０．９８ｍｌ）をジクロロメタン（３０ｍｌ）に溶解させ、氷冷下、クロロスルホニル酢酸エチル（０．９７ｍｌ）を滴下し、室温で１４時間撹拌した。反応液に酢酸エチル及び水を加えて抽出し、抽出液を飽和食塩水で洗浄した後、有機層を無水硫酸マグネシウムを用いて乾燥させた。ろ過した後、ろ液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝２／１）で精製することにより、表記化合物２．００ｇ（収率７０％）を淡黄色固体として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.33 (3H, t, J=7.0), 1.47 (9H, s), 1.69
(2H, m), 1.91 (2H, m), 2.26 (6H, s), 2.89 (2H, m), 3.90 (1H, m), 3.93 (2H, s), 4.03 (2H, m), 4.29 (2H, q, J=7.0), 6.98 (2H, s). Reference Example 114
N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-dimethylphenyl] sulfamoyl acetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-dimethyl Aniline (1.94 g) and pyridine (0.98 ml) were dissolved in dichloromethane (30 ml), and ethyl chlorosulfonylacetate (0.97 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 14 hours. Ethyl acetate and water were added to the reaction solution for extraction, and the extract was washed with saturated brine, and then the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to give 2.00 g (yield 70%) of the title compound as a pale salt. Obtained as a yellow solid.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.33 (3H, t, J = 7.0), 1.47 (9H, s), 1.69
(2H, m), 1.91 (2H, m), 2.26 (6H, s), 2.89 (2H, m), 3.90 (1H, m), 3.93 (2H, s), 4.03 (2H, m), 4.29 ( 2H, q, J = 7.0), 6.98 (2H, s).

参考例１１５
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３，５−ジメチルフェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル
３−（３−シアノフェニル）−２−（Ｅ）−プロペン−１−オール（０．５５ｇ）、Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３，５−ジメチルフェニル］スルファモイル酢酸エチル（１．５０ｇ）及びトリフェニルホスフィン（１．０８ｇ）をジクロロメタン（２０ｍｌ）に溶解させ、氷冷下、アゾジカルボン酸ジエチル（０．６３ｍｌ）を滴下し、同温で１．５時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝２／１）で精製することにより、表記化合物１．７５ｇ（収率９０％）を無色無定形固体として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.36 (3H, t, J=7.0), 1.47 (9H, s), 1.70
(2H, m), 1.91 (2H, m), 2.26 (6H, s), 2.90 (2H, m), 3.93 (1H, m), 3.99 (2H, s), 4.00 (2H, m), 4.30 (2H, q, J=7.0), 4.47 (2H, d, J=6.5), 6.23 (1H, dt, J=16.0, 6.5), 6.42 (1H, d, J=16.0), 7.11 (2H, s), 7.40 (1H, t, J=8.0), 7.52 (2H, m), 7.56 (1H, s). Reference Example 115
N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3,5-dimethylphenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl acetate ethyl 3- (3-Cyanophenyl) -2- (E) -propen-1-ol (0.55 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-dimethyl Phenyl] sulfamoyl ethyl acetate (1.50 g) and triphenylphosphine (1.08 g) were dissolved in dichloromethane (20 ml), and diethyl azodicarboxylate (0.63 ml) was added dropwise under ice cooling. Stir for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to give 1.75 g (yield 90%) of the title compound as a colorless amorphous solid. Got as.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.0), 1.47 (9H, s), 1.70
(2H, m), 1.91 (2H, m), 2.26 (6H, s), 2.90 (2H, m), 3.93 (1H, m), 3.99 (2H, s), 4.00 (2H, m), 4.30 ( 2H, q, J = 7.0), 4.47 (2H, d, J = 6.5), 6.23 (1H, dt, J = 16.0, 6.5), 6.42 (1H, d, J = 16.0), 7.11 (2H, s) , 7.40 (1H, t, J = 8.0), 7.52 (2H, m), 7.56 (1H, s).

参考例１１６
４−［Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］アミノ］酪酸エチル
３−［３−［Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニルアミノ］−１−（Ｅ）−プロペニル］ベンゾニトリル（２．００ｇ）をＮ，Ｎ−ジメチルホルムアミド（４０ｍｌ）に溶解させ、炭酸カリウム（６．５０ｇ）及びブロモ酪酸エチル（５．００ｍｌ）を５回に分けて加え、１４０℃で１６時間撹拌した。反応液に水を加えた後、酢酸エチルで抽出し、抽出液を飽和食塩水で洗浄した後、有機層を無水硫酸マグネシウムを用いて乾燥させた。ろ過した後、減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝２／１）で精製することにより、表記化合物１．２０ｇ（収率４８％）を黄色油状物質として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.25 (3H, t, J=7.0), 1.46 (9H, s), 1.65-1.75 (2H, m), 1.80-2.00 (4H, m), 2.36 (2H, t, J=7.0), 3.20-3.35 (4H, m), 3.65-3.75 (2H, m), 4.02 (2H, d, J=5.0), 4.13 (2H, q, J=7.0), 4.27 (1H,
m), 6.29 (1H, dt, J=16.0, 5.0), 6.47 (1H, d, J=16.0), 6.70 (2H, d, J=9.0), 6.84 (2H, d, J=9.0), 7.39 (1H, t, J=8.0), 7.49 (1H, d, J=8.0), 7.54 (1H, d, J=8.0), 7.61 (1H, s). Reference Example 116
4- [N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] amino] ethyl butyrate 3- [3- [N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) phenylamino] -1- (E) -propenyl] benzonitrile (2.00 g) was added to N, N-dimethylformamide (40 ml). ), Potassium carbonate (6.50 g) and ethyl bromobutyrate (5.00 ml) were added in 5 portions and stirred at 140 ° C. for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2/1) to give 1.20 g (yield 48%) of the title compound as yellow. Obtained as an oil.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.25 (3H, t, J = 7.0), 1.46 (9H, s), 1.65-1.75 (2H, m), 1.80-2.00 (4H, m), 2.36 (2H , t, J = 7.0), 3.20-3.35 (4H, m), 3.65-3.75 (2H, m), 4.02 (2H, d, J = 5.0), 4.13 (2H, q, J = 7.0), 4.27 ( 1H,
m), 6.29 (1H, dt, J = 16.0, 5.0), 6.47 (1H, d, J = 16.0), 6.70 (2H, d, J = 9.0), 6.84 (2H, d, J = 9.0), 7.39 (1H, t, J = 8.0), 7.49 (1H, d, J = 8.0), 7.54 (1H, d, J = 8.0), 7.61 (1H, s).

参考例１１７
３−（３−シアノフェニル）−２−フルオロ−２−（Ｚ）−プロペン−１−オール
ジャーナル・オブ・オーガノメタリック・ケミストリー，第３３２巻，第１頁（１９８７）[J. Organomet. Chem., 332, 1 (1987)]に記載の方法に従い合成された２−ジエチルホスホノ−２−フルオロ酢酸（４．３５ｇ）を、テトラヒドロフラン（９０ｍｌ）に溶解させ、−７８℃で攪拌下、１．６Ｍブチルリチウムヘキサン溶液（２８ｍｌ）を滴下し、同温で１時間撹拌した。反応液に３−シアノベンズアルデヒド（２．６６ｇ）のテトラヒドロフラン（１０ｍｌ）溶液を１０分間で滴下し、−７８℃で３時間撹拌した後、０℃に昇温させた。反応液に水（４０ｍｌ）を加えた後、水層を分離させ、有機層を飽和炭酸水素ナトリウム水溶液で２回抽出した。全ての水層を合わせた後、濃塩酸を用いて溶液のｐＨを４に調整し、ｔ−ブチルメチルエーテルで５回抽出した後、抽出液を無水硫酸ナトリウムを用いて乾燥させた。ろ過した後、ろ液を減圧下濃縮することにより、中間体化合物（３．４７ｇ）を白色固体として得た。
次いで、得られた中間体化合物（１．１５ｇ）及びトリエチルアミン（０．９２ｍｌ）をジクロロメタン（１０ｍｌ）に溶解させ、氷冷攪拌下、クロロ炭酸エチル（０．６３ｍｌ）を加え、室温で１５分間撹拌した。減圧下溶媒を留去し、残渣に酢酸エチル（１０ｍｌ）を加え不溶物をろ去した後、ろ液を減圧下濃縮した。残渣をテトラヒドロフラン（１０ｍｌ）に溶解させ、氷冷攪拌下、水素化ホウ素ナトリウム水溶液（０．４５ｇを水５ｍｌに溶解）を加え、室温で１８時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加えた後、ｔ−ブチルメチルエーテルで３回抽出し、抽出液を飽和塩化ナトリウム水溶液で洗浄した後、有機層を無水硫酸ナトリウムを用いて乾燥させた。ろ過した後、減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝３／２）で精製することにより、表記化合物０．３３ｇ（収率３１％）を無色固体として得た。
¹H NMR (500MHz, CDCl₃) δppm :4.32 (2H, dd, J=12.5, 5.5), 5.82 (1H, d,
J=37.5), 7.45 (1H, t, J=8.0), 7.53 (1H, d, J=8.0), 7.70 (1H, d, J=8.0),
7.81 (1H, s). Reference Example 117
3- (3-Cyanophenyl) -2-fluoro-2- (Z) -propen-1-ol Journal of Organometallic Chemistry, Vol. 332, page 1 (1987) [ J. Organomet. Chem ., 332, 1 (1987)] are 2-diethylphosphono-2-fluoro-acid synthesis according to the method described in (4.35 g), was dissolved in tetrahydrofuran (90 ml), under stirring at -78 ° C., 1 A 6M butyllithium hexane solution (28 ml) was added dropwise and stirred at the same temperature for 1 hour. A solution of 3-cyanobenzaldehyde (2.66 g) in tetrahydrofuran (10 ml) was added dropwise to the reaction solution over 10 minutes, and the mixture was stirred at -78 ° C for 3 hours, and then heated to 0 ° C. Water (40 ml) was added to the reaction solution, the aqueous layer was separated, and the organic layer was extracted twice with a saturated aqueous sodium hydrogen carbonate solution. After all the aqueous layers were combined, the pH of the solution was adjusted to 4 using concentrated hydrochloric acid, extracted 5 times with t-butyl methyl ether, and then the extract was dried using anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain an intermediate compound (3.47 g) as a white solid.
Next, the obtained intermediate compound (1.15 g) and triethylamine (0.92 ml) were dissolved in dichloromethane (10 ml), ethyl chlorocarbonate (0.63 ml) was added with ice-cooling and stirring, and the mixture was stirred at room temperature for 15 minutes. did. The solvent was evaporated under reduced pressure, ethyl acetate (10 ml) was added to the residue, insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 ml), an aqueous sodium borohydride solution (0.45 g dissolved in 5 ml of water) was added with stirring under ice cooling, and the mixture was stirred at room temperature for 18 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction three times with t-butyl methyl ether. The extract was washed with a saturated aqueous sodium chloride solution, and then the organic layer was dried using anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/2) to give 0.33 g (yield 31%) of the title compound colorless. Obtained as a solid.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 4.32 (2H, dd, J = 12.5, 5.5), 5.82 (1H, d,
J = 37.5), 7.45 (1H, t, J = 8.0), 7.53 (1H, d, J = 8.0), 7.70 (1H, d, J = 8.0),
7.81 (1H, s).

参考例１１８
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（３−シアノフェニル）−２−フルオロ−２−（Ｚ）−プロペニル］スルファモイル酢酸エチル
３−（３−シアノフェニル）−２−フルオロ−２−（Ｚ）−プロペン−１−オール（０．４５ｇ）、Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル（１．１２ｇ）及びトリフェニルホスフィン（０．８０ｇ）をジクロロメタン（２０ｍｌ）に溶解させ、氷冷下、アゾジカルボン酸ジエチル（０．４８ｍｌ）を滴下し、同温で２時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／酢酸エチル＝１５／１）で精製することにより、表記化合物１．４０ｇ（収率９２％）を無色油状物質として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.35 (3H, t, J=7.0), 1.47 (9H, s), 1.74
(2H, m), 1.90 (2H, m), 3.34 (2H, m), 3.68 (2H, m), 4.00 (2H, s), 4.30 (2H, q, J=7.0), 4.46 (1H, m), 4.54 (2H, d, J=15.0), 5.62 (1H, d, J=36.5),
6.92 (2H, d, J=9.5), 7.42 (3H, m), 7.51 (1H, d, J=7.0), 7.63 (1H, d, J=8.0), 7.71 (1H, s). Reference Example 118
N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3- (3-cyanophenyl) -2-fluoro-2- (Z) -propenyl] sulfamoyl acetate 3- (3-Cyanophenyl) -2-fluoro-2- (Z) -propen-1-ol (0.45 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] sulfamoyl acetic acid Ethyl (1.12 g) and triphenylphosphine (0.80 g) were dissolved in dichloromethane (20 ml), and diethyl azodicarboxylate (0.48 ml) was added dropwise under ice cooling, followed by stirring at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 15/1) to give 1.40 g (yield 92%) of the title compound as a colorless oil. Obtained.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.35 (3H, t, J = 7.0), 1.47 (9H, s), 1.74
(2H, m), 1.90 (2H, m), 3.34 (2H, m), 3.68 (2H, m), 4.00 (2H, s), 4.30 (2H, q, J = 7.0), 4.46 (1H, m ), 4.54 (2H, d, J = 15.0), 5.62 (1H, d, J = 36.5),
6.92 (2H, d, J = 9.5), 7.42 (3H, m), 7.51 (1H, d, J = 7.0), 7.63 (1H, d, J = 8.0), 7.71 (1H, s).

参考例１１９
２−ヒドロキシイソフタル酸
２−メトキシイソフタル酸（１．０ｇ）を５５％ヨウ化水素酸（１０ｍｌ）に溶解させ、８０℃で１時間撹拌した。反応液を氷水に加え、析出した沈殿物をろ取することにより、表記化合物０．９ｇ（収率９５％）を淡黄色固体として得た。
¹H NMR (400MHz, DMSO-d₆) δppm : 6.93 (1H, t, J=8.0), 7.96 (2H, d, J=8.0). Reference Example 119
2-Hydroxyisophthalic acid 2-Methoxyisophthalic acid (1.0 g) was dissolved in 55% hydroiodic acid (10 ml) and stirred at 80 ° C. for 1 hour. The reaction mixture was added to ice water, and the deposited precipitate was collected by filtration to obtain 0.9 g (yield 95%) of the title compound as a pale yellow solid.
¹ H NMR (400MHz, DMSO-d ₆ ) δppm: 6.93 (1H, t, J = 8.0), 7.96 (2H, d, J = 8.0).

参考例１２０
２−ヒドロキシイソフタル酸ジメチル
２−ヒドロキシイソフタル酸（１．９ｇ）をメタノール（２０ｍｌ）に溶解させ、氷冷下、塩化チオニル（１．５ｍｌ）を加え、７０℃で４時間撹拌した。反応液を減圧下濃縮することにより、表記化合物１．５ｇ（６８％）を白色固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 3.96 (6H, s), 6.94 (1H, t, J=8.0), 8.06
(2H, d, J=8.0). Reference Example 120
Dimethyl 2-hydroxyisophthalate 2-hydroxyisophthalic acid (1.9 g) was dissolved in methanol (20 ml), thionyl chloride (1.5 ml) was added under ice cooling, and the mixture was stirred at 70 ° C. for 4 hours. The reaction solution was concentrated under reduced pressure to obtain 1.5 g (68%) of the title compound as a white solid.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 3.96 (6H, s), 6.94 (1H, t, J = 8.0), 8.06
(2H, d, J = 8.0).

参考例１２１
２−ヒドロキシ−５−ニトロイソフタル酸ジメチル
２−ヒドロキシイソフタル酸ジメチル（１．５ｇ）を、６９％硝酸（５ｍｌ）及び濃硫酸（５ｍｌ）の混合液に加え、氷冷下、０．５時間撹拌した。反応液を氷水に注ぎ、酢酸エチルで抽出し、抽出液を水及び飽和食塩水で順次洗浄した後、有機層を無水硫酸マグネシウムを用いて乾燥させた。ろ過した後、減圧下溶媒を留去し、得られた黄色固体をヘキサンを加えてろ取することにより、表記化合物１．６ｇ（収率８９％）を黄色固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 4.03 (6H, s), 8.94 (2H, s). Reference Example 121
Dimethyl 2-hydroxy-5-nitroisophthalate Dimethyl 2-hydroxyisophthalate (1.5 g) is added to a mixture of 69% nitric acid (5 ml) and concentrated sulfuric acid (5 ml), and the mixture is stirred for 0.5 hour under ice cooling. did. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and then the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting yellow solid was filtered by adding hexane to obtain 1.6 g (yield 89%) of the title compound as a yellow solid.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 4.03 (6H, s), 8.94 (2H, s).

参考例１２２
２−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−５−ニトロイソフタル酸ジメチル
１−ｔ−ブトキシカルボニル−４−ヒドロキシピペリジン（２．６ｇ）、２−ヒドロキシ−５−ニトロイソフタル酸ジメチル（１．６ｇ）及びトリフェニルホスフィン（４．４ｇ）をジクロロメタン（４０ｍｌ）及びテトラヒドロフラン（２０ｍｌ）の混合溶媒に溶解させ、アゾジカルボン酸ジエチル（２．６ｍｌ）を加え、室温で４時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／酢酸エチル＝１９／１）で精製し、得られた黄色固体をヘキサン及び酢酸エチル（４／１）を加えてろ取することにより、表記化合物２．２ｇ（収率７８％）を白色固体として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.46 (9H, s), 1.70-1.80 (2H, m), 1.85-1.95 (2H, m), 3.05 (2H, m), 3.80-3.95 (2H, m), 3.97 (6H, s), 4.29 (1H, m), 8.74 (2H, s). Reference Example 122
2- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-nitroisophthalate dimethyl 1-t-butoxycarbonyl-4-hydroxypiperidine (2.6 g), dimethyl 2-hydroxy-5-nitroisophthalate ( 1.6 g) and triphenylphosphine (4.4 g) were dissolved in a mixed solvent of dichloromethane (40 ml) and tetrahydrofuran (20 ml), diethyl azodicarboxylate (2.6 ml) was added, and the mixture was stirred at room temperature for 4 hours. After concentrating the reaction solution under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate = 19/1), and the resulting yellow solid was filtered with hexane and ethyl acetate (4/1). By taking 2.2 g (yield 78%) of the title compound as a white solid.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.46 (9H, s), 1.70-1.80 (2H, m), 1.85-1.95 (2H, m), 3.05 (2H, m), 3.80-3.95 (2H, m ), 3.97 (6H, s), 4.29 (1H, m), 8.74 (2H, s).

参考例１２３
２−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−５−ニトロイソフタル酸
２−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−５−ニトロイソフタル酸ジメチル（１０．７ｇ）を濃塩酸（１００ｍｌ）に溶解させ、８０℃で１０時間撹拌した。反応液を減圧下濃縮した後、残渣にヘキサンを加え、白色固体をろ取した。次いで、得られた固体を水（５０ｍｌ）及びアセトン（５０ｍｌ）の混合溶媒に溶解させ、室温で炭酸水素ナトリウム（４．６ｇ）及びジ−ｔ−ブチルジカーボネート（５．９ｇ）加え、４０℃で１時間撹拌した。反応液を酢酸エチルで抽出し、抽出液を飽和食塩水で洗浄した後、有機層を無水硫酸マグネシウムを用いて乾燥させた。ろ過した後、減圧下溶媒を留去し、残渣にヘキサンを加えた後、ろ取することにより、表記化合物４．１ｇ（収率４０％）を淡黄色固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.40 (9H, s), 1.55-1.65 (2H, m), 1.75-1.85 (2H, m), 3.05-3.15 (2H, m), 3.55-3.65 (2H, m), 4.40 (1H, m), 8.54 (2H, s). Reference Example 123
2- (1-t-Butoxycarbonylpiperidin-4-yloxy) -5-nitroisophthalic acid Dimethyl 2- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-nitroisophthalate (10.7 g) was concentrated. It was dissolved in hydrochloric acid (100 ml) and stirred at 80 ° C. for 10 hours. The reaction mixture was concentrated under reduced pressure, hexane was added to the residue, and a white solid was collected by filtration. Next, the obtained solid was dissolved in a mixed solvent of water (50 ml) and acetone (50 ml), sodium hydrogen carbonate (4.6 g) and di-t-butyl dicarbonate (5.9 g) were added at room temperature, For 1 hour. The reaction solution was extracted with ethyl acetate, and the extract was washed with saturated brine, and then the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and hexane was added to the residue, followed by filtration to obtain 4.1 g (yield 40%) of the title compound as a pale yellow solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.40 (9H, s), 1.55-1.65 (2H, m), 1.75-1.85 (2H, m), 3.05-3.15 (2H, m), 3.55-3.65 (2H, m), 4.40 (1H, m), 8.54 (2H, s).

参考例１２４
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３，５−ジカルバモイルニトロベンゼン
２−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−５−ニトロイソフタル酸（４．６ｇ）をジクロロメタン（１５０ｍｌ）に溶解させ、氷冷下、クロロギ酸イソブチル（４．３ｍｌ）及びトリエチルアミン（４．８ｍｌ）を加え、同温で０．５時間撹拌した後、２８％アンモニア水（１．９ｍｌ）を加え、さらに室温で１時間撹拌した。析出した沈殿物をろ取することにより、表記化合物３．０ｇ（収率６４％）を淡黄色固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.40 (9H, s), 1.60-1.70 (2H, m), 1.75-1.85 (2H, m), 3.05-3.15 (2H, m), 3.55-3.65 (2H, m), 4.48 (1H, m), 8.31 (2H, s). Reference Example 124
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-dicarbamoylnitrobenzene 2- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-nitroisophthalic acid (4.6 g) Dissolve in dichloromethane (150 ml), add isobutyl chloroformate (4.3 ml) and triethylamine (4.8 ml) under ice-cooling, stir at the same temperature for 0.5 hours, and then 28% aqueous ammonia (1.9 ml). And further stirred at room temperature for 1 hour. The deposited precipitate was collected by filtration to obtain 3.0 g (yield 64%) of the title compound as a pale yellow solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.40 (9H, s), 1.60-1.70 (2H, m), 1.75-1.85 (2H, m), 3.05-3.15 (2H, m), 3.55-3.65 (2H, m), 4.48 (1H, m), 8.31 (2H, s).

参考例１２５
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３，５−ジカルバモイルアニリン
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３，５−ジカルバモイルニトロベンゼン（３．０ｇ）をメタノール（６０ｍｌ）に溶解させ、パラジウム−炭素触媒（０．３ｇ）を加え、水素雰囲気下、室温で１時間撹拌した。反応液をろ過した後、ろ液を減圧下濃縮することにより、表記化合物２．８ｇ（収率定量的）を黄色固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.45 (9H, s), 1.55-1.70 (2H, m), 1.85-2.00 (2H, m), 2.67 (2H, m), 3.80-3.90 (2H, m), 4.02 (1H, m), 7.34 (2H, s). Reference Example 125
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-dicarbamoylaniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-dicarbamoylnitrobenzene (3.0 g ) Was dissolved in methanol (60 ml), palladium-carbon catalyst (0.3 g) was added, and the mixture was stirred at room temperature for 1 hour in a hydrogen atmosphere. After filtering the reaction solution, the filtrate was concentrated under reduced pressure to obtain 2.8 g (quantitative yield) of the title compound as a yellow solid.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.45 (9H, s), 1.55-1.70 (2H, m), 1.85-2.00 (2H, m), 2.67 (2H, m), 3.80-3.90 (2H, m ), 4.02 (1H, m), 7.34 (2H, s).

参考例１２６
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３，５−ジカルバモイルフェニル］スルファモイル酢酸エチル
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３，５−ジカルバモイルアニリン（２．８ｇ）をジクロロメタン（８０ｍｌ）に溶解させ、ピリジン（１．４ｍｌ）を加えた後、氷冷下、クロロスルホニル酢酸エチル（２．４ｍｌ）を滴下し、室温で２時間撹拌した。反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／メタノール＝４／１）で精製することにより、表記化合物０．９ｇ（収率２３％）を淡黄色固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.18 (3H, t, J=7.0), 1.40 (9H, s), 1.50-1.60 (2H, m), 1.75-1.85 (2H, m), 2.90-3.00 (2H, m), 3.30 (2H, s), 3.65-3.75 (2H, m), 4.10 (2H, q, J=7.0), 4.15-4.20 (1H, m), 7.43 (2H, s). Reference Example 126
N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -3,5-dicarbamoylphenyl] sulfamoyl acetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5- Dicarbamoylaniline (2.8 g) was dissolved in dichloromethane (80 ml), pyridine (1.4 ml) was added, and then ethyl chlorosulfonylacetate (2.4 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 2 hours. did. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 4/1) to give 0.9 g (yield 23%) of the title compound as a pale yellow solid. .
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.18 (3H, t, J = 7.0), 1.40 (9H, s), 1.50-1.60 (2H, m), 1.75-1.85 (2H, m), 2.90 -3.00 (2H, m), 3.30 (2H, s), 3.65-3.75 (2H, m), 4.10 (2H, q, J = 7.0), 4.15-4.20 (1H, m), 7.43 (2H, s) .

参考例１２７
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３，５−ジカルバモイルフェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル
３−（３−シアノフェニル）−２−（Ｅ）−プロペン−１−オール（０．９ｇ）、Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−３，５−ジカルバモイルフェニル］スルファモイル酢酸エチル（０．９ｇ）及びトリフェニルホスフィン（１．８ｇ）をジクロロメタン（３０ｍｌ）及びテトラヒドロフラン（３０ｍｌ）の混合溶媒に溶解させ、氷冷下、アゾジカルボン酸ジエチル（１．１ｍｌ）を加え、室温で１時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／酢酸エチル＝１／２）で精製することにより、表記化合物０．８ｇ（収率７３％）を黄色無定形固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.26 (3H, t, J=7.0), 1.45 (9H, s), 1.60-1.75 (2H, m), 1.85-2.00 (2H, m), 2.60-2.75 (2H, m), 4.00-4.15 (2H, m), 4.03 (2H, s), 4.15-4.25 (1H, m), 4.31 (2H, q, J=7.0), 4.55 (2H, d, J=7.0), 6.22 (1H, dt, J=16.0, 7.0), 6.46 (1H, d, J=16.0), 7.35-7.45 (2H, m), 7.50-7.60 (3H, m), 8.16 (1H, m). Reference Example 127
N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5-dicarbamoylphenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl acetic acid Ethyl 3- (3-cyanophenyl) -2- (E) -propen-1-ol (0.9 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -3,5- Dicarbamoylphenyl] ethyl sulfamoylacetate (0.9 g) and triphenylphosphine (1.8 g) were dissolved in a mixed solvent of dichloromethane (30 ml) and tetrahydrofuran (30 ml). Under ice-cooling, diethyl azodicarboxylate (1.1 ml) ) And stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 1/2) to give 0.8 g (yield 73%) of the title compound as a yellow amorphous solid. Got as.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.26 (3H, t, J = 7.0), 1.45 (9H, s), 1.60-1.75 (2H, m), 1.85-2.00 (2H, m), 2.60-2.75 (2H, m), 4.00-4.15 (2H, m), 4.03 (2H, s), 4.15-4.25 (1H, m), 4.31 (2H, q, J = 7.0), 4.55 (2H, d, J = 7.0), 6.22 (1H, dt, J = 16.0, 7.0), 6.46 (1H, d, J = 16.0), 7.35-7.45 (2H, m), 7.50-7.60 (3H, m), 8.16 (1H, m ).

参考例１２８
４−メチル−５−ニトロサリチル酸メチル
４−メチルサリチル酸（３．５ｇ）をメタノール（８ｍｌ）及びベンゼン（３２ｍｌ）の混合溶媒に溶解させ、氷冷下、２．０Ｍトリメチルシリルジアゾメタンヘキサン溶液（１５．０ｍｌ）を加え、室温で０．５時間撹拌した。反応液を減圧下濃縮し、得られた黄色油状物質を、氷冷下、６９％硝酸（２０ｍｌ）に加え、同温で２時間撹拌した。反応液を氷水に注ぎ、酢酸エチルで抽出した後、抽出液を水及び飽和食塩水で順次洗浄し、有機層を無水硫酸マグネシウムを用いて乾燥させた。ろ過した後、減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝４／１）で精製することにより、表記化合物１．３ｇ（収率２１％）を淡黄色固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 2.66 (3H, s), 4.01 (3H, s), 6.92 (1H, s), 8.66 (1H, s). Reference Example 128
4-methyl-5-nitrosalicylic acid methyl 4-methylsalicylic acid (3.5 g) was dissolved in a mixed solvent of methanol (8 ml) and benzene (32 ml), and 2.0M trimethylsilyldiazomethanehexane solution (15.0 ml) was cooled with ice. ) And stirred at room temperature for 0.5 hour. The reaction solution was concentrated under reduced pressure, and the resulting yellow oily substance was added to 69% nitric acid (20 ml) under ice cooling, followed by stirring at the same temperature for 2 hours. The reaction solution was poured into ice water and extracted with ethyl acetate, and then the extract was washed successively with water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 4/1) to give 1.3 g (yield 21%) of the title compound as a pale compound. Obtained as a yellow solid.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 2.66 (3H, s), 4.01 (3H, s), 6.92 (1H, s), 8.66 (1H, s).

参考例１２９
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−５−メトキシカルボニル−２−メチルニトロベンゼン
１−ｔ−ブトキシカルボニル−４−ヒドロキシピペリジン（５．４ｇ）、４−メチル−５−ニトロサリチル酸メチル（２．８ｇ）及びトリフェニルホスフィン（９．０ｇ）をジクロロメタン（１００ｍｌ）に溶解させ、アゾジカルボン酸ジエチル（５．４ｍｌ）を加え、室温で９時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝４／１）で精製することにより、表記化合物４．９ｇ（収率９３％）を黄色油状物質として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.47 (9H, s), 1.85-1.95 (4H, m), 2.68 (3H, s), 3.50-3.65 (4H, m), 3.91 (3H, s), 4.78 (1H, m), 6.84 (1H, s), 8.63 (1H, s). Reference Example 129
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-methoxycarbonyl-2-methylnitrobenzene 1-t-butoxycarbonyl-4-hydroxypiperidine (5.4 g), 4-methyl-5-nitrosalicylic acid Methyl (2.8 g) and triphenylphosphine (9.0 g) were dissolved in dichloromethane (100 ml), diethyl azodicarboxylate (5.4 ml) was added, and the mixture was stirred at room temperature for 9 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to give 4.9 g (yield 93%) of the title compound as a yellow oil. Obtained.
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.85-1.95 (4H, m), 2.68 (3H, s), 3.50-3.65 (4H, m), 3.91 (3H, s), 4.78 (1H, m), 6.84 (1H, s), 8.63 (1H, s).

参考例１３０
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−５−カルボキシ−２−メチルニトロベンゼン
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−５−メトキシカルボニル−２−メチルニトロベンゼン（４．９ｇ）を濃塩酸（１００ｍｌ）に溶解させ、８０℃で５時間撹拌した。反応液を減圧下濃縮し、得られた白色固体を、水（３０ｍｌ）及びアセトン（３０ｍｌ）の混合溶媒に溶解させ、室温で、炭酸水素ナトリウム（２．３ｇ）及びジ−ｔ−ブチルジカーボネート（３．３ｇ）加え、４０℃で１時間撹拌した。反応液を酢酸エチルで抽出し、抽出液を飽和食塩水で洗浄した後、有機層を無水硫酸マグネシウムを用いて乾燥させた。ろ過した後、減圧下溶媒を留去することにより、表記化合物４．８ｇ（収率定量的）を黄色無定形固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.48 (9H, s), 1.85-1.95 (2H, m), 2.05-2.15 (2H, m), 2.71 (3H, s), 3.35-3.45 (2H, m), 3.70-3.80 (2H, m), 4.85 (1H, m), 6.93 (1H, s), 8.84 (1H, s). Reference Example 130
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-carboxy-2-methylnitrobenzene 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-methoxycarbonyl-2-methylnitrobenzene ( 4.9 g) was dissolved in concentrated hydrochloric acid (100 ml) and stirred at 80 ° C. for 5 hours. The reaction solution was concentrated under reduced pressure, and the resulting white solid was dissolved in a mixed solvent of water (30 ml) and acetone (30 ml), and at room temperature, sodium hydrogen carbonate (2.3 g) and di-t-butyl dicarbonate. (3.3 g) was added and the mixture was stirred at 40 ° C. for 1 hour. The reaction solution was extracted with ethyl acetate, and the extract was washed with saturated brine, and then the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 4.8 g (quantitative yield) of the title compound as a yellow amorphous solid.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.48 (9H, s), 1.85-1.95 (2H, m), 2.05-2.15 (2H, m), 2.71 (3H, s), 3.35-3.45 (2H, m ), 3.70-3.80 (2H, m), 4.85 (1H, m), 6.93 (1H, s), 8.84 (1H, s).

参考例１３１
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−５−カルバモイル−２−メチルニトロベンゼン
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−５−カルボキシ−２−メチルニトロベンゼン（４．８ｇ）をジクロロメタン（１００ｍｌ）に溶解させ、氷冷下、クロロギ酸イソブチル（１．７ｍｌ）及びトリエチルアミン（１．８ｍｌ）を加え、同温で１時間撹拌した後、２８％アンモニア水（０．８ｍｌ）を加え、さらに２時間撹拌した。反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／メタノール＝１９／１）で精製することにより、表記化合物４．７ｇ（収率９７％）を白色固体として得た。
¹H NMR (500MHz, DMSO-d₆) δppm : 1.41 (9H, s), 1.75-1.85 (2H, m), 1.90-2.00 (2H, m), 2.61 (3H, s), 3.20-3.30 (2H, m), 3.60-3.70 (2H, m), 4.93 (1H, m), 7.35 (1H, s), 8.42 (1H, s). Reference Example 131
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-carbamoyl-2-methylnitrobenzene 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-carboxy-2-methylnitrobenzene (4 0.8 g) was dissolved in dichloromethane (100 ml), isobutyl chloroformate (1.7 ml) and triethylamine (1.8 ml) were added under ice cooling, and the mixture was stirred at the same temperature for 1 hour, followed by 28% aqueous ammonia (0. 8 ml) was added and stirred for another 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 19/1) to give 4.7 g (yield 97%) of the title compound as a white solid.
¹ H NMR (500MHz, DMSO-d ₆ ) δppm: 1.41 (9H, s), 1.75-1.85 (2H, m), 1.90-2.00 (2H, m), 2.61 (3H, s), 3.20-3.30 (2H , m), 3.60-3.70 (2H, m), 4.93 (1H, m), 7.35 (1H, s), 8.42 (1H, s).

参考例１３２
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−５−カルバモイル−２−メチルアニリン
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−５−カルバモイル−２−メチルニトロベンゼン（４．７ｇ）をメタノール（１２０ｍｌ）に溶解させ、パラジウム−炭素触媒（０．５ｇ）を加え、水素雰囲気下、室温で２時間撹拌した。反応液をろ過した後、ろ液を減圧下濃縮することにより、表記化合物４．０ｇ（収率９３％）を黄色無定形固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.47 (9H, s), 1.65-1.75 (2H, m), 1.95-2.05 (2H, m), 2.20 (3H, s), 3.18 (2H, m), 3.75-3.85 (2H, m), 4.45 (1H, m), 6.74 (1H, s), 7.47 (1H, s). Reference Example 132
4- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-carbamoyl-2-methylaniline 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-carbamoyl-2-methylnitrobenzene (4 0.7 g) was dissolved in methanol (120 ml), palladium-carbon catalyst (0.5 g) was added, and the mixture was stirred at room temperature for 2 hours in a hydrogen atmosphere. After filtering the reaction solution, the filtrate was concentrated under reduced pressure to obtain 4.0 g (yield 93%) of the title compound as a yellow amorphous solid.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.47 (9H, s), 1.65-1.75 (2H, m), 1.95-2.05 (2H, m), 2.20 (3H, s), 3.18 (2H, m), 3.75-3.85 (2H, m), 4.45 (1H, m), 6.74 (1H, s), 7.47 (1H, s).

参考例１３３
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−５−カルバモイル−２−メチルフェニル］スルファモイル酢酸エチル
４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−５−カルバモイル−２−メチルアニリン（４．０ｇ）をジクロロメタン（６０ｍｌ）に溶解させ、ピリジン（１．２ｍｌ）を加えた後、氷冷下、クロロスルホニル酢酸エチル（１．９ｍｌ）を滴下し、室温で０．５時間撹拌した。反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／メタノール＝１９／１）で精製することにより、表記化合物２．８ｇ（収率４８％）を淡黄色固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.35 (3H, t, J=7.0), 1.48 (9H, s), 1.75-1.85 (2H, m), 2.00-2.10 (2H, m), 2.49 (3H, s), 3.29 (2H, m), 3.75-3.85 (2H, m), 4.06 (2H, s), 4.33 (2H, q, J=7.0), 4.66 (1H, m), 6.90 (1H, s), 8.16 (1H, s). Reference Example 133
N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-carbamoyl-2-methylphenyl] sulfamoyl acetate 4- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-carbamoyl 2-Methylaniline (4.0 g) was dissolved in dichloromethane (60 ml), pyridine (1.2 ml) was added, and then ethyl chlorosulfonylacetate (1.9 ml) was added dropwise under ice cooling. Stir for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 19/1) to give 2.8 g (yield 48%) of the title compound as a pale yellow solid. .
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.35 (3H, t, J = 7.0), 1.48 (9H, s), 1.75-1.85 (2H, m), 2.00-2.10 (2H, m), 2.49 (3H , s), 3.29 (2H, m), 3.75-3.85 (2H, m), 4.06 (2H, s), 4.33 (2H, q, J = 7.0), 4.66 (1H, m), 6.90 (1H, s ), 8.16 (1H, s).

参考例１３４
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−５−カルバモイル−２−メチルフェニル］−Ｎ−［３−（３−シアノフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル
３−（３−シアノフェニル）−２−（Ｅ）−プロペン−１−オール（０．９ｇ）、Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）−５−カルバモイル−２−メチルフェニル］スルファモイル酢酸エチル（２．８ｇ）及びトリフェニルホスフィン（２．０ｇ）をジクロロメタン（１００ｍｌ）に溶解させ、氷冷下、アゾジカルボン酸ジエチル（１．２ｍｌ）を加え、室温で３時間撹拌した。反応液を減圧下濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／４）で精製することにより、表記化合物２．１ｇ（収率５８％）を黄色無定形固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.37 (3H, t, J=7.0), 1.47 (9H, s), 1.75-1.85 (2H, m), 2.00-2.10 (2H, m), 2.41 (3H, s), 3.25-3.35 (2H, m), 3.75-3.85 (2H, m), 4.02 (1H, d, J=14.0), 4.16 (1H, d, J=14.0), 4.20-4.25 (1H,
m), 4.30-4.40 (2H, m), 4.65-4.75 (2H, m), 6.20-6.30 (1H, m), 6.35 (1H, d, J=16.0), 6.88 (1H, s), 7.41 (1H, m), 7.50-7.55 (3H, m), 8.30 (1H, s). Reference Example 134
N- [4- (1-t-Butoxycarbonylpiperidin-4-yloxy) -5-carbamoyl-2-methylphenyl] -N- [3- (3-cyanophenyl) -2- (E) -propenyl] sulfamoyl Ethyl acetate 3- (3-cyanophenyl) -2- (E) -propen-1-ol (0.9 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) -5-carbamoyl 2-Methylphenyl] sulfamoyl ethyl acetate (2.8 g) and triphenylphosphine (2.0 g) were dissolved in dichloromethane (100 ml), and diethyl azodicarboxylate (1.2 ml) was added under ice-cooling at room temperature. Stir for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/4) to give 2.1 g (yield 58%) of the title compound as a yellow amorphous solid. Got as.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.37 (3H, t, J = 7.0), 1.47 (9H, s), 1.75-1.85 (2H, m), 2.00-2.10 (2H, m), 2.41 (3H , s), 3.25-3.35 (2H, m), 3.75-3.85 (2H, m), 4.02 (1H, d, J = 14.0), 4.16 (1H, d, J = 14.0), 4.20-4.25 (1H,
m), 4.30-4.40 (2H, m), 4.65-4.75 (2H, m), 6.20-6.30 (1H, m), 6.35 (1H, d, J = 16.0), 6.88 (1H, s), 7.41 ( 1H, m), 7.50-7.55 (3H, m), 8.30 (1H, s).

参考例１３５
３−（５−シアノ−２−メチルフェニル）−２−（Ｅ）−プロペン−１−オール
１−ｔ−ブチルジメチルシロキシ−２−プロピン（２．４５ｇ）にカテコールボラン（１．５ｍｌ）を加え、６０℃で４時間撹拌した。反応液を室温まで冷却させた後、トルエン（４０ｍｌ）で希釈し、３−ブロモ−４−メチルベンゾニトリル（２．０２ｇ）、テトラキス（トリフェニルホスフィン）パラジウム錯体（０．５８ｇ）及びナトリウムエトキシド２０％エタノール溶液（５．０ｍｌ）を加え、９０℃で４時間撹拌した。反応液に水を加えた後、酢酸エチルで抽出し、抽出液を１Ｍ水酸化ナトリウム水溶液、水及び飽和食塩水で順次洗浄した後、有機層を無水硫酸ナトリウムを用いて乾燥させた。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝８／１）にて精製することにより、中間体化合物（２．２３ｇ）を得た。
次いで、得られた中間体化合物をテトラヒドロフラン（６０ｍｌ）に溶解させ、氷冷下、１Ｍ弗化テトラブチルアンモニウム／テトラヒドロフラン溶液（１２ｍｌ）を加えた後、同温で１時間撹拌した。反応液に水を加えた後、ｔ−ブチルメチルエーテルで抽出し、抽出液を水及び飽和食塩水で順次洗浄した後、有機層を無水硫酸ナトリウムを用いて乾燥させた。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝３／２）にて精製することにより、表記化合物０．６４ｇ（収率２工程３６％）を無色固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 2.41 (3H, s), 4.39 (2H, bs), 6.30 (1H, dt, J=16.0, 5.5), 6.80 (1H, d, J=16.0), 7.25 (1H, d, J=8.0), 7.43 (1H, dd, J=8.0, 2.0), 7.70 (1H, d, J=2.0). Reference Example 135
Catecholborane (1.5 ml) was added to 3- (5-cyano-2-methylphenyl) -2- (E) -propen-1-ol 1-t-butyldimethylsiloxy-2-propyne (2.45 g) , And stirred at 60 ° C. for 4 hours. The reaction solution was allowed to cool to room temperature, diluted with toluene (40 ml), 3-bromo-4-methylbenzonitrile (2.02 g), tetrakis (triphenylphosphine) palladium complex (0.58 g) and sodium ethoxide. A 20% ethanol solution (5.0 ml) was added, and the mixture was stirred at 90 ° C. for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1M aqueous sodium hydroxide solution, water and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 8/1) to obtain an intermediate compound (2.23 g).
Next, the obtained intermediate compound was dissolved in tetrahydrofuran (60 ml), and 1M tetrabutylammonium fluoride / tetrahydrofuran solution (12 ml) was added under ice cooling, followed by stirring at the same temperature for 1 hour. Water was added to the reaction solution, followed by extraction with t-butyl methyl ether. The extract was washed successively with water and saturated brine, and then the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/2) to give 0.64 g of the title compound (yield: 2 steps 36%) as a colorless solid. Got as.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 2.41 (3H, s), 4.39 (2H, bs), 6.30 (1H, dt, J = 16.0, 5.5), 6.80 (1H, d, J = 16.0), 7.25 (1H, d, J = 8.0), 7.43 (1H, dd, J = 8.0, 2.0), 7.70 (1H, d, J = 2.0).

参考例１３６
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（５−シアノ−２−メチルフェニル）−２−（Ｅ）−プロペニル］スルファモイル酢酸エチル
３−（５−シアノ−２−メチルフェニル）−２−（Ｅ）−プロペン−１−オール（０．６４ｇ）、Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］スルファモイル酢酸エチル（１．６２ｇ）及びトリフェニルホスフィン（１．１６ｇ）をジクロロメタン（３０ｍｌ）に溶解させ、氷冷下、アゾジカルボン酸ジエチル（０．７０ｍｌ）を滴下した後、同温で２時間撹拌した。反応液を濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／酢酸エチル＝１２／１）で精製することにより、表記化合物２．０３ｇ（収率９２％）を無色無定形固体として得た。
¹H NMR (500MHz, CDCl₃) δppm : 1.36 (3H, t, J=7.0), 1.47 (9H, s), 1.75
(2H, m), 1.91 (2H, m), 2.25 (3H, s), 3.43 (2H, m), 3.69 (2H, m), 3.98 (2H, s), 4.31 (2H, q, J=7.0), 4.47 (1H, m), 4.49 (2H, d, J=6.5), 6.05 (1H, dt, J=15.5, 6.5), 6.56 (1H, d, J=15.5), 6.92 (2H, d, J=10.0), 7.19 (1H, d, J=7.5), 7.40 (3H, m), 7.55 (1H, s). Reference Example 136
N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3- (5-cyano-2-methylphenyl) -2- (E) -propenyl] sulfamoyl acetate 3- (5-Cyano-2-methylphenyl) -2- (E) -propen-1-ol (0.64 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] sulfamoyl acetic acid Ethyl (1.62 g) and triphenylphosphine (1.16 g) were dissolved in dichloromethane (30 ml), and diethyl azodicarboxylate (0.70 ml) was added dropwise under ice cooling, followed by stirring at the same temperature for 2 hours. After concentrating the reaction solution, the residue was purified by silica gel column chromatography (elution solvent: dichloromethane / ethyl acetate = 12/1) to obtain 2.03 g (yield 92%) of the title compound as a colorless amorphous solid. It was.
¹ H NMR (500MHz, CDCl ₃ ) δppm: 1.36 (3H, t, J = 7.0), 1.47 (9H, s), 1.75
(2H, m), 1.91 (2H, m), 2.25 (3H, s), 3.43 (2H, m), 3.69 (2H, m), 3.98 (2H, s), 4.31 (2H, q, J = 7.0 ), 4.47 (1H, m), 4.49 (2H, d, J = 6.5), 6.05 (1H, dt, J = 15.5, 6.5), 6.56 (1H, d, J = 15.5), 6.92 (2H, d, J = 10.0), 7.19 (1H, d, J = 7.5), 7.40 (3H, m), 7.55 (1H, s).

参考例１３７
３−（５−シアノ−２−フルオロフェニル）−２−（Ｅ）−プロペン−１−オール
１−ｔ−ブチルジメチルシロキシ−２−プロピン（１．７０ｇ）にカテコールボラン（１．０７ｍｌ）を加え、６０℃で３時間撹拌した。反応液を室温まで冷却させた後、トルエン（２０ｍｌ）で希釈し、３−ブロモ−４−フルオロベンゾニトリル（１．４０ｇ）、テトラキス（トリフェニルホスフィン）パラジウム錯体（０．４１ｇ）及びナトリウムエトキシド２０％エタノール溶液（３．４ｍｌ）を加えた後、１００℃で６時間撹拌した。反応液に１Ｍ水酸化ナトリウム水溶液を加えた後、エーテル抽出し、抽出液を１Ｍ水酸化ナトリウム水溶液、水及び飽和食塩水で順次洗浄した後、有機層を無水硫酸ナトリウムを用いて乾燥させた。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１０／１）にて精製することにより、中間体化合物（１．２９ｇ）を得た。
次いで、得られた中間体化合物をテトラヒドロフラン（１０ｍｌ）に溶解させ、氷冷下、１Ｍフッ化テトラブチルアンモニウム／テトラヒドロフラン溶液（５．３０ｍｌ）を加えた後、同温で１．５時間撹拌した。反応液に水を加えた後、酢酸エチルで抽出し、抽出液を水及び食塩水で順次洗浄した後、有機層を無水硫酸マグネシウムを用いて乾燥させた。反応液を濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／１）にて精製することにより、表記化合物０．４６ｇ（収率２工程３７％）を無色固体として得た。
¹H NMR (400MHz, CDCl₃) δppm : 4.40 (2H, m), 6.52 (1H, dt, J=16.5, 5.0), 6.75 (1H, d, J=16.5), 7.16 (1H, dd, J=10.0, 8.5), 7.53 (1H, ddd, J=8.5, 5.0, 2.0), 7.70 (1H, dd, J=7.0, 2.0). Reference Example 137
Catecholborane (1.07 ml) was added to 3- (5-cyano-2-fluorophenyl) -2- (E) -propen-1-ol 1-tert-butyldimethylsiloxy-2-propyne (1.70 g) , And stirred at 60 ° C. for 3 hours. The reaction solution was allowed to cool to room temperature, diluted with toluene (20 ml), 3-bromo-4-fluorobenzonitrile (1.40 g), tetrakis (triphenylphosphine) palladium complex (0.41 g) and sodium ethoxide. After adding 20% ethanol solution (3.4 ml), the mixture was stirred at 100 ° C. for 6 hours. A 1M aqueous sodium hydroxide solution was added to the reaction solution, followed by ether extraction. The extract was washed with a 1M aqueous sodium hydroxide solution, water and saturated brine successively, and then the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 10/1) to obtain an intermediate compound (1.29 g).
Next, the obtained intermediate compound was dissolved in tetrahydrofuran (10 ml), and 1M tetrabutylammonium fluoride / tetrahydrofuran solution (5.30 ml) was added under ice cooling, followed by stirring at the same temperature for 1.5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed successively with water and brine, and then the organic layer was dried over anhydrous magnesium sulfate. After concentrating the reaction solution, the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/1) to give 0.46 g (yield: 2 steps 37%) of the title compound as a colorless solid. Obtained.
^{_{1 H NMR (400MHz, CDCl 3}} ) δppm: 4.40 (2H, m), 6.52 (1H, dt, J = 16.5, 5.0), 6.75 (1H, d, J = 16.5), 7.16 (1H, dd, J = 10.0, 8.5), 7.53 (1H, ddd, J = 8.5, 5.0, 2.0), 7.70 (1H, dd, J = 7.0, 2.0).

参考例１３８
Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］−Ｎ−［３−（５−シアノ−２−フルオロフェニル）−２−（Ｅ）−プロペニル］エタンスルホンアミド
３−（５−シアノ−２−フルオロフェニル）−２−（Ｅ）−プロペン−１−オール（０．７２ｇ）、Ｎ−［４−（１−ｔ−ブトキシカルボニルピペリジン−４−イルオキシ）フェニル］エタンスルホンアミド（１．６３ｇ）及びトリフェニルホスフィン（１．３７ｇ）をジクロロメタン（４０ｍｌ）に溶解させ、氷冷下、アゾジカルボン酸ジエチル（０．８３ｍｌ）を滴下した後、室温で２時間撹拌した。反応液を濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ジクロロメタン／酢酸エチル＝１０／１）で精製することにより、表記化合物２．００ｇ（収率９１％）を無色油状物質として得た。
¹H NMR (400MHz, CDCl₃) δppm : 1.42 (3H, t, J=7.5), 1.47 (9H, s), 1.74
(2H, m), 1.90 (2H, m), 3.06 (2H, q, J=7.5), 3.33 (2H, m), 3.68 (2H, m),
4.45 (3H, m), 6.34 (1H, dt, J=16.0, 6.0), 6.54 (1H, d, J=16.0), 6.90 (2H, d, J=9.0), 7.12 (1H, dd, J=10.5, 9.0), 7.27 (2H, d, J=9.0), 7.51 (1H,
ddd, J=9.0, 5.0, 2.0), 7.68 (1H, dd, J=6.5, 2.0). Reference Example 138
N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] -N- [3- (5-cyano-2-fluorophenyl) -2- (E) -propenyl] ethanesulfonamide 3- (5-Cyano-2-fluorophenyl) -2- (E) -propen-1-ol (0.72 g), N- [4- (1-t-butoxycarbonylpiperidin-4-yloxy) phenyl] ethanesulfone Amide (1.63 g) and triphenylphosphine (1.37 g) were dissolved in dichloromethane (40 ml), and diethyl azodicarboxylate (0.83 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 10/1) to give the title compound (2.00 g, yield 91%) as a colorless oil. .
¹ H NMR (400MHz, CDCl ₃ ) δppm: 1.42 (3H, t, J = 7.5), 1.47 (9H, s), 1.74
(2H, m), 1.90 (2H, m), 3.06 (2H, q, J = 7.5), 3.33 (2H, m), 3.68 (2H, m),
4.45 (3H, m), 6.34 (1H, dt, J = 16.0, 6.0), 6.54 (1H, d, J = 16.0), 6.90 (2H, d, J = 9.0), 7.12 (1H, dd, J = 10.5, 9.0), 7.27 (2H, d, J = 9.0), 7.51 (1H,
ddd, J = 9.0, 5.0, 2.0), 7.68 (1H, dd, J = 6.5, 2.0).

試験例１
抗ファクターXa活性の測定
抗ファクターXa活性の測定は、Haraらの方法［トロンボシス・アンド・ヘモスタシス，第７１巻，第３１４頁（１９９４年）[Thromb. Haemost., 71, 314 (1994)]］を一部改変して行った。０．９％塩化ナトリウム、０．４mMの発色基質S-2222（第一化学薬品）および被検化合物を含む５０mMのTris塩酸緩衝液（ｐＨ８．４）を混和し、０．２５unit/mlのヒトファクターＸａ（コスモバイオ）を添加することにより反応を開始した。コントロール群においては、被験化合物の代わりに蒸留水を緩衝液に加えた。反応溶液（総容量０．１ml）は、室温で5分間インキュベーションした。４０５nmの吸光度を９６ウェルマイクロプレートリーダー（モデル５５０、バイオラッド）で持続的に測定し、５分間の吸光度の増加をファクターＸａ活性の指標として算出した。被験化合物の抗ファクターＸａ活性を評価するために、被験化合物がファクターＸａ活性を５０％阻害する濃度（ＩＣ₅₀値）を求めた。
その結果、本発明の前記一般式（Ｉ）を有するベンズアミジン誘導体が、優れた活性化血液凝固第Ｘ因子阻害作用を有することがわかった。ＩＣ₅₀が１０nM以下の化合物を、表２に示す。尚、表中、化合物Ａは、ＷＯ９８／３１６６１（ＥＰ９７６７２２）に記載の、Ｎ−［４−［１−アセトイミドイル−４−ピペリジルオキシ］フェニル］−Ｎ−［２−（３−アミジノフェノキシ）エチル］スルファモイル酢酸の２塩酸塩を示す。 Test example 1
Measurement of anti-factor Xa activity Anti-factor Xa activity was measured by the method of Hara et al. [Thrombosis and hemostasis, 71, 314 (1994) [ Thromb. Haemost. , 71 , 314 (1994)]]. Was carried out with some modifications. 0.9% sodium chloride, 0.4 mM chromogenic substrate S-2222 (Daiichi Kagaku) and 50 mM Tris hydrochloric acid buffer (pH 8.4) containing the test compound are mixed, and 0.25 unit / ml human is mixed. The reaction was started by adding Factor Xa (Cosmo Bio). In the control group, distilled water was added to the buffer instead of the test compound. The reaction solution (total volume 0.1 ml) was incubated at room temperature for 5 minutes. Absorbance at 405 nm was continuously measured with a 96-well microplate reader (Model 550, Bio-Rad), and an increase in absorbance for 5 minutes was calculated as an indicator of factor Xa activity. In order to evaluate the anti-factor Xa activity of the test compound, the concentration at which the test compound inhibits factor Xa activity by 50% (IC ₅₀ value) was determined.
As a result, it was found that the benzamidine derivative having the general formula (I) of the present invention has an excellent activated blood coagulation factor X inhibitory action. Table 2 shows compounds having an IC ₅₀ of 10 nM or less. In the table, compound A is N- [4- [1-acetimidoyl-4-piperidyloxy] phenyl] -N- [2- (3-amidinophenoxy) described in WO98 / 31661 (EP976722). Ethyl] sulfamoyl acetic acid dihydrochloride.

(表２)
──────────────────────
実施例化合物ファクターXa阻害活性
番号 [IC₅₀ (nM)]
──────────────────────
実施例３８．６
実施例４６．４
実施例８４．５
実施例９７．４
実施例１０４．６
実施例１１８．１
実施例２２８．３
実施例２３８．３
実施例２８９．０
実施例２９９．０
実施例３１１０．０
実施例３４１０．０
実施例３６７．１
実施例３８８．７
実施例４１７．５
実施例４６６．８
実施例４７３．７
実施例４９９．８
実施例５４４．６
実施例５５５．０
実施例５６１０．０
実施例５７９．３
──────────────────────
化合物Ａ１３０
────────────────────── (Table 2)
──────────────────────
Example Compound Factor Xa inhibitory activity No. [IC ₅₀ (nM)]
──────────────────────
Example 3 8.6
Example 4 6.4
Example 8 4.5
Example 9 7.4
Example 10 4.6
Example 11 8.1
Example 22 8.3
Example 23 8.3
Example 28 9.0
Example 29 9.0
Example 31 10.0
Example 34 10.0
Example 36 7.1
Example 38 8.7
Example 41 7.5
Example 46 6.8
Example 47 3.7
Example 49 9.8
Example 54 4.6
Example 555.0
Example 56 10.0
Example 57 9.3
──────────────────────
Compound A 130
──────────────────────

試験例２
抗トリプシン活性の測定
抗トリプシン活性の測定は、Taniuchiらの方法［トロンボシス・アンド・ヘモスタシス，第７９巻，第５４３頁（１９９８年）[Thromb. Haemost., 79, 543 (1998)]］を一部改変して行った。０．９％塩化ナトリウムを含む５０mM Ｔｒｉｓ塩酸緩衝液８５μl（ｐＨ８．４）、５μlの発色基質Ｓ−２２２２（終濃度０．４mM、第一化学薬品）、および被検化合物５μlを混和し、５μlのウシ・トリプシン（終濃度０．２５μg-protein/ml、シグマ）を添加することにより反応を開始した。コントロール群においては、被検化合物の代わりに蒸留水を緩衝液に添加した。反応溶液（総容量０．１ml）は室温でインキュベーションした。４０５nmの吸光度を９６ウェルマイクロプレートリーダー（モデル５５０、バイオラッド）にて連続測定して、５分間の吸光度の増加をトリプシン活性の指標として算出した。被検化合物の抗トリプシン活性を評価するために、被検化合物がトリプシン活性を５０％抑制するに要する濃度（ＩＣ₅₀値）を求めた。結果を表３に示す。 Test example 2
The Measurement of antitrypsin activity of anti-trypsin activity, Taniuchi et al method [Toronboshisu And Hemosutashisu, 79, pp. 543 (1998) [Thromb. Haemost., 79 , 543 (1998)]] an This was done with partial modification. Mix 85 μl of 50 mM Tris HCl buffer solution (pH 8.4) containing 0.9% sodium chloride, 5 μl of chromogenic substrate S-2222 (final concentration 0.4 mM, Daiichi Kagaku), and 5 μl of the test compound. The reaction was started by adding bovine trypsin (final concentration 0.25 μg-protein / ml, sigma). In the control group, distilled water was added to the buffer instead of the test compound. The reaction solution (total volume 0.1 ml) was incubated at room temperature. Absorbance at 405 nm was continuously measured with a 96-well microplate reader (Model 550, Bio-Rad), and the increase in absorbance for 5 minutes was calculated as an index of trypsin activity. In order to evaluate the antitrypsin activity of the test compound, the concentration (IC ₅₀ value) required for the test compound to suppress trypsin activity by 50% was determined. The results are shown in Table 3.

(表３)
──────────────────────
実施例化合物抗トリプシン活性
番号 [IC₅₀ (nM)]
──────────────────────
実施例９５２０
実施例１１８４０
────────────────────── (Table 3)
──────────────────────
Example Compound antitrypsin activity number [IC ₅₀ (nM)]
──────────────────────
Example 9 520
Example 11 840
──────────────────────

製剤例１
ハードカプセル剤
５０mgの粉末状の実施例９の化合物、１２８．７mgのラクトース、７０mgのセルロース及び１．３mgのステアリン酸マグネシウムを混合し、６０メッシュのふるいを通した後、この粉末を２５０mgの３号ゼラチンカプセルに入れ、カプセル剤とする。 Formulation Example 1
Hard Capsules 50 mg of the powdered compound of Example 9, 128.7 mg lactose, 70 mg cellulose and 1.3 mg magnesium stearate were mixed and passed through a 60 mesh sieve, then the powder was 250 mg of No. 3 Put into a gelatin capsule to make a capsule.

製剤例２
錠剤
５０mgの粉末状の実施例９の化合物、１２４mgのラクトース、２５mgのセルロース及び１mgのステアリン酸マグネシウムを混合し、打錠機により打錠して、１錠２００mgの錠剤とする。この錠剤は必要に応じて糖衣を施すことができる。 Formulation Example 2
Tablet 50 mg of the powdered compound of Example 9, 124 mg lactose, 25 mg cellulose and 1 mg magnesium stearate are mixed and compressed by a tableting machine to make one tablet of 200 mg. This tablet can be sugar-coated if necessary.

製剤例３
注射剤
１．５重量％の実施例９の化合物を、１０容量％のプロピレングリコール中で攪拌し、次いで、注射用水で一定容量に調整した後、滅菌して注射剤とする。 Formulation Example 3
Injection: 1.5% by weight of the compound of Example 9 is stirred in 10% by volume of propylene glycol, adjusted to a constant volume with water for injection, and then sterilized to give an injection.

Claims

Any one compound selected from the following or a pharmacologically acceptable salt thereof:
N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl acetate,
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-chlorophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl ethyl acetate,
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-methylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl ethyl acetate,
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-carbamoylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl ethyl acetate,
N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoylacetic acid,
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-fluorophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoylacetic acid,
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-chlorophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoylacetic acid,
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-methylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoylacetic acid,
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-trifluoromethylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoylacetic acid,
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-carbamoylphenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoylacetic acid,
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-dichlorophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoyl acetate,
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3,5-dichlorophenyl] -N- [3- (3-amidinophenyl) -2- (E) -propenyl] sulfamoylacetic acid,
N- [4- (1- acetimidoyl piperidin-4-yloxy) phenyl] -N- [3- (3- amidinophenyl) -2-fluoro-2- (Z) - propenyl] sulfamoyl acetic acid,
N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-carbamoylphenyl] -N- [3- (3-amidinophenyl) -2-fluoro-2- (Z) -propenyl] sulfamoylacetic acid ,as well as,
N- [4- (1-acetimidoylpiperidin-4-yloxy) phenyl] -N- [3- (3-amidinophenyl) -2-methyl-2- (E) -propenyl] sulfamoylacetic acid.