TW200840568A - Novel diamide derivative - Google Patents

Novel diamide derivative Download PDF

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TW200840568A
TW200840568A TW097108249A TW97108249A TW200840568A TW 200840568 A TW200840568 A TW 200840568A TW 097108249 A TW097108249 A TW 097108249A TW 97108249 A TW97108249 A TW 97108249A TW 200840568 A TW200840568 A TW 200840568A
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Akiyoshi Mochizuki
Tsutomu Nagata
Hideyuki Kanno
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Daiichi Sankyo Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D333/40—Thiophene-2-carboxylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Abstract

Disclosed is a novel compound having a strong FXa inhibitory activity and exhibits quick, sufficient and lasting antithrombotic effect even by oral administration. Specifically disclosed is a compound represented by the general formula (I) below, a pharmacologically acceptable salt thereof or an FXa inhibitor containing any of them as an active ingredient. (In the formula, ring A represents a benzene ring; R represents a hydrogen atom, a halogeno group or the like; R represents a carboxy group, a carbamoyl group or the like; T represents a -C(=O)NH- group or the like; T represents a -CH2-CH2-C(=O)NH- group or the like; Q represents a tetrahydronaphthyridinyl group, a tetrahydrothiazolopyridyl group or the like; Q represents a single bond; and Q represents a phenyl group, a pyridyl group or the like.)

Description

200840568 九、發明說明： 【發明所屬之技術領域】 本i明係關於抑制活化凝血因子χ(以下，簡稱作FXa)而 顯示出強力的抗凝血作用、且可經口投予的新穎化合物； 或者含有其作為有效成分之凝血抑制劑或者血栓或栓塞之 預防及/或治療劑。 【先前技術】 不疋心紋痛、腦梗塞、腦栓塞、心肌梗塞、肺梗塞、 肺栓塞、伯格式症（Buerger，s disease)、深部靜脈血栓症 (deep vein thrombosis)、全身性血管内凝血綜合症 (disseminated intravascular coagulati〇n syndr〇me)、人工瓣 膜置換後之企栓形成、血流重建後的再閉塞及體外循環時 的血栓形成等的重要原因之一係凝血功能亢進，故而謀求 一種劑量反應性優良、具有持續性、出血之危險低、副作 用少、即使經口投予亦可立即獲得充分效果的優良之抗凝 固藥（例如，參照非專利文獻1)。 自基於各種作用機制的抗凝固藥研究中發現，Fxa抑制 藥可成為優良的抗凝固藥。凝血系統係經過多階段酶反應 所引起之擴增過程而產生大量凝血酶，從而生成不溶性的 血纖維蛋白之一系列反應。於内因系統中，於接觸因子活 化後之多階段反應後，於活化因子VIII、鈣離子之存在 下，於磷脂質膜上活化因子IX將因子X活化。又，於外因 系統中，於組織因子之存在下，活化因子VII將因子乂活 化。即，於凝固系統中將因子X活化為FXa係生成凝血酶 129677.doc 200840568 所必需的反應。於兩系統中經活化的因子x(FXa)使凝血酶 原進行有限水解而生成凝血酶。所生成的凝血酶將上游的 凝固因子活化，故而凝血酶之生成進一步擴增。如上述所 示，比FXa更上游的凝固系統劃分為内因系統、外因系 統，故而若抑制比FXa更上游的凝固系統酶則無法充分抑 弗J FXa的產生，其結果為產生凝血酶。又，凝固系統係自 身擴增反應，故而與抑制所生成的凝血酶相比，藉由抑制 位於上游的FXa則可更有效地抑制凝固系統（例如，參照非 鲁 專利文獻2)。制藥的另一優點在於，血栓模型下之 有效劑量與實驗性出血模型下之使出血時間延長的劑量之 相差較大，根據該實驗結果可認為FXa抑制藥係出血危險 較小的抗凝固藥。 作為FXa抑制藥，報告有各種化合物，但眾所周知：一 般抗凝血酶III或抗凝血酶m依賴性的五碳糖等無法抑制於 生物體内實際導致血栓形成的凝企酶原酶複合體（例如， • 參照非專利文獻1、3及4)，進而經口投予時無效。自作為 吸血動物之蜱或水蛭中所單離的蜱抗凝血肽（τΑρ)(例如， 參照非專利文獻5)及antistasin(AST)(例如，參照非專利文 獻6)亦抑制ρχα，於靜脈血栓模型至動脈血栓模型中均顯 示出抗血栓效果，但該等係高分子的肽，經口投予時無 效。由此，正在開發一種抗凝血酶ΠΙ非依賴性地直接抑制 凝固因子之可經口投予的低分子FXa抑制藥。 [非專利文獻 1] 丁 hrombosis Research，第 68卷，第 507 〜 512頁，1992年 129677.doc 200840568 [非專利文獻 2] Thrombosis Research，第 15 卷，第 617〜629頁，1979年 [非專利文獻 3] Journal of Clinical Investigation，第 71 卷，第1383〜1389頁，1983年 [非專利文獻4] Mebio，第14卷，8月號，第92〜97頁 [非專利文獻5] Science，第248卷，第593〜596頁，1990 年 [非專利文獻 6] Journal of Biological Chemistry，第 263 卷，第 10162〜10167頁，1988年 【發明内容】 [發明所欲解決之問題] 本發明之課題在於提供一種具有強力的Fxa抑制作用、 且即使經口投予亦可迅速顯示充分且持續的抗血栓效果之 新顆化合物。 [解決問題之技術手段] 本發明者等人對新穎FXa抑制藥之合成以及藥理作用進 行研究，結果發現一種顯示出較強FXa抑制作用以及較強 抗凝固作用之新穎二醯胺衍生物、其鹽、該等之溶劑合物 或其等之N-氧化物。進而發現該等化合物即使經由經口投 予亦會立即見效且持續地強力抑制FXa，顯示出強力的抗 凝固作用及抗血栓作用，故而可有效用作基於血栓·栓塞 之各種疾病之預防藥以及治療藥，從而完成本發明。 即，本發明係提供一種化合物或其藥理上容許之鹽，該 化合物係以下述通式（I)表示， 129677.doc 200840568 [化l]200840568 IX. Description of the Invention: [Technical Field of the Invention] The present invention relates to a novel compound which exhibits potent anticoagulant action and can be administered orally by inhibiting activated coagulation factor χ (hereinafter, abbreviated as FXa); Or a prophylactic and/or therapeutic agent containing a blood coagulation inhibitor or a thrombus or embolism as an active ingredient. [Prior Art] Non-sickness, cerebral infarction, cerebral embolism, myocardial infarction, pulmonary infarction, pulmonary embolism, Buerger's disease, deep vein thrombosis, systemic intravascular coagulation One of the important reasons for the syndrome (disseminated intravascular coagulati〇n syndr〇me), the formation of a thrombus after prosthetic valve replacement, reocclusion after revascularization, and thrombosis during cardiopulmonary bypass is hypercoagulability. An excellent anticoagulant which is excellent in dose-response, is persistent, has a low risk of bleeding, has few side effects, and can obtain sufficient effects immediately by oral administration (for example, refer to Non-Patent Document 1). It has been found in studies of anticoagulants based on various mechanisms of action that Fxa inhibitors can be excellent anticoagulants. The coagulation system produces a large amount of thrombin through an amplification process caused by a multi-stage enzymatic reaction, thereby producing a series of reactions of insoluble fibrin. In the internal system, factor X is activated by activating factor IX on the phospholipid membrane in the presence of activating factor VIII and calcium ions after a multi-stage reaction after activation of the contact factor. Further, in the external factor system, activated factor VII activates factor 乂 in the presence of tissue factor. That is, factor X is activated in the coagulation system to a reaction necessary for the formation of thrombin 129677.doc 200840568 by the FXa system. Prothrombin is subjected to limited hydrolysis to produce thrombin by activated factor x (FXa) in both systems. The generated thrombin activates the upstream coagulation factor, so the production of thrombin is further amplified. As described above, the coagulation system upstream of FXa is classified into an internal factor system and an external factor system. Therefore, if the coagulation system enzyme upstream of FXa is suppressed, the production of J FXa cannot be sufficiently suppressed, and as a result, thrombin is produced. Further, since the coagulation system is self-amplifying, the coagulation system can be more effectively suppressed by suppressing the FXa located upstream (see, for example, Non-Patent Document 2). Another advantage of the pharmaceutical is that the effective dose under the thrombus model differs greatly from the dose that prolongs the bleeding time under the experimental bleeding model. According to the results of the experiment, the FXa inhibits the anticoagulant with less bleeding risk. . As FXa inhibitors, various compounds have been reported, but it is well known that general antithrombin III or antithrombin m-dependent five-carbon sugars cannot inhibit the clotting enzyme complex which actually causes thrombosis in vivo. (For example, • Refer to Non-Patent Documents 1, 3 and 4), and it is invalid when administered orally. The sputum anticoagulant peptide (τΑρ) which is isolated from the sputum or leeches of the blood-sucking animal (for example, refer to Non-Patent Document 5) and the antistatsin (AST) (for example, refer to Non-Patent Document 6) also inhibit ρχα, in the vein Both the thrombus model and the arterial thrombus model showed antithrombotic effects, but these high molecular peptides were ineffective when administered orally. Thus, a low molecular FXa inhibitor which can be orally administered by anticoagulant, which directly inhibits coagulation factors, is being developed. [Non-Patent Document 1] Ding hrombosis Research, Vol. 68, pp. 507-512, 1992 129677.doc 200840568 [Non-Patent Document 2] Thrombosis Research, Vol. 15, pp. 617-629, 1979 [Non-patent Document 3] Journal of Clinical Investigation, Vol. 71, pp. 1383~1389, 1983 [Non-Patent Document 4] Mebio, Vol. 14, August, pp. 92-97 [Non-Patent Document 5] Science, Vol. 248, pp. 593-596, 1990 [Non-Patent Document 6] Journal of Biological Chemistry, Vol. 263, No. 10162 to 10167, 1988 [Invention] [Problems to be Solved by the Invention] It is to provide a novel compound which has a strong Fxa inhibitory action and which can rapidly exhibit a sufficient and sustained antithrombotic effect even by oral administration. [Technical means for solving the problem] The present inventors studied the synthesis and pharmacological action of the novel FXa inhibitor, and as a result, found a novel diamine derivative which exhibits a strong FXa inhibitory action and a strong anticoagulant effect, a salt, such a solvate or an N-oxide thereof. Further, it has been found that these compounds are effective immediately and effectively inhibit FXa even when administered orally, and exhibit potent anticoagulant action and antithrombotic action, so that they can be effectively used as a preventive for various diseases based on thrombus and embolism, and Therapeutic agents are used to complete the present invention. Namely, the present invention provides a compound or a pharmacologically acceptable salt thereof, which is represented by the following formula (I), 129677.doc 200840568 [Chem.

[式中，環A表示苯環； R1表示氫原子、鹵基、C1〜C6烷基、鹵代C1〜C6烷基或 C1〜C6烷氧基； R2表示氫原子、鹵基、C1〜C6烷基、鹵代C1〜C6烷基、 C1〜C6烷氧基、C1〜C6烷氧基C1〜C6烷基、鹵代C1〜C6烷氧 基、羧基、C1〜C6烷氧基羰基、胺甲醯基、N-單（C1〜C6烷 基）胺曱醯基或N，N-二（C1〜C6)胺曱醯基； T表不基- 此處’該基之左側的鍵表示鍵結於 Q ’ R表示氯原子或C1〜C6院基）； T2 表示基-CH2-C(R4)(R5)-C(=0)NH-、基-CH=CH-C(=0)NH-、基-CH2-0-C(=0)NH-或基-CH2-NHC(=0)NH-(此處，各基之左側的鍵表示鍵結於環A，R4及R5相同或不 同，表示氫原子、鹵基、C1〜C6烷基、羥基或C1〜C6烷氧 基）； Q1表示四氫萘啶基（該四氫萘啶基可具有C1〜C6烷基作為取 代基）、四氫噻唑并吡啶基（該四氫噻唑并吡啶基可具有選 自由C1〜C6烷基、鹵代C1〜C6烷基、C1〜C6烷氧基C1〜C6烷 基及C1〜C6烷氧基羰基所組成之群中的基作為取代基）、四 氫噻唑并噠嗪基（該四氫噻唑并噠嗪基可具有C1〜C6烷基作 129677.doc -9- 200840568 為取代基）、二氫吡喃并噻唑基、四氫噻唑并吖丁啶基（該 四氫噻唑并吖丁啶基可具有C1〜C6烷基作為取代基）、 C1〜C6烷基）哌啶-4-基、4·Ν，Ν-二（C1〜C6烷基）胺基環己 基、4-(3-氧基嗎啉-4·基)環己基或4-(3_氧基嗎啉-4-基）苯 基； Q2表示單鍵；[wherein, ring A represents a benzene ring; R1 represents a hydrogen atom, a halogen group, a C1 to C6 alkyl group, a halogenated C1 to C6 alkyl group or a C1 to C6 alkoxy group; and R2 represents a hydrogen atom, a halogen group, or a C1 to C6 group; Alkyl, halogenated C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 alkoxy C1 to C6 alkyl, halogenated C1 to C6 alkoxy, carboxyl, C1 to C6 alkoxycarbonyl, amine Mercapto, N-mono(C1~C6 alkyl)amine sulfhydryl or N,N-di(C1~C6)amine fluorenyl; T exemplified - here the bond to the left of the group represents a bond The relationship between Q ' R represents a chlorine atom or a C1~C6 yard); T2 represents a group -CH2-C(R4)(R5)-C(=0)NH-, yl-CH=CH-C(=0)NH -, -CH2-0-C(=0)NH- or yl-CH2-NHC(=0)NH- (here, the bond to the left of each group represents a bond to ring A, and R4 and R5 are the same or different , represents a hydrogen atom, a halogen group, a C1 to C6 alkyl group, a hydroxyl group or a C1 to C6 alkoxy group); Q1 represents a tetrahydronaphthyridinyl group (the tetrahydronaphthyridinyl group may have a C1 to C6 alkyl group as a substituent), Tetrahydrothiazolopyridinyl (the tetrahydrothiazolopyridyl group may have a C1 to C6 alkyl group, a halogenated C1 to C6 alkyl group, a C1 to C6 alkoxy group C1 to C6 alkyl group, and a C1 to C6 alkoxy group. Carbonyl a group in the group as a substituent), a tetrahydrothiazolopyridazinyl group (the tetrahydrothiazolopyridazinyl group may have a C1 to C6 alkyl group as a substituent of 129677.doc -9-200840568), dihydropyridyl Merylthiazolyl, tetrahydrothiazoloazetidinyl (the tetrahydrothiazoloazetidinyl group may have a C1 to C6 alkyl group as a substituent), C1 to C6 alkyl)piperidin-4-yl, 4·Ν, Ν- Di(C1-C6 alkyl)aminocyclohexyl, 4-(3-oxymorpholin-4-yl)cyclohexyl or 4-(3-methoxymorpholin-4-yl)phenyl; Q2 represents a single key;

Q3表示苯基（該苯基可具有選自由鹵基、C1〜C6烷基、_代 C1〜C6烷基及C1〜C6烷氧基所組成之群中的u個基作為取 代基）、17塞吩基、1¾代°塞吩基、π比u定基、齒代σ比咬基、噠 嗪基、i代噠嗪基、喹啉基、鹵代喹啉基、異喹啉基、自 代異喹啉基、4啉基或_代4啉基]。 又，本發明提供一種含有以上述通式⑴所表示之化合物 或其藥理上容許之鹽的醫藥，尤其是提供活化凝血因子 X(FXa)抑制劑、凝血抑制劑、血栓或栓塞之預防及/或治 療劑，進而提供腦梗塞、腦栓塞、心肌梗塞、心絞痛、肺 栓基、伯格式症、深部靜脈血栓症、全身性血管内凝血綜 合症、人工瓣膜/關節置換後的血栓形成、血流重建後的 血栓形成及再閉塞、多器官功能障礙綜合症_ds， multiple organ dysfuncti〇n syndr〇me)、體外循環時的血栓 形成或採血時的血液凝固之預防及/或治療劑。 又，本發明提供―種用以製造上述通式⑴所表示之化合 物（1)的中間體。 又，本發明提供一 理上容許之鹽的用途 種上述通式（I)所表示之化合物或其藥 ’其係用於醫藥製造。 129677.doc -10- 200840568 又，本發明提供一種上述通式⑴所表示之化合物或其藥 理上容許之鹽，其係用以預防及/或治療血栓或栓塞。 進而，本發明提供一種血栓或栓塞的治療方法，其特徵 在於投予有效量的以上述通式⑴所表示之化合物或其藥理 上容許之鹽。 本發明之新賴二醯胺衍生物顯示出強力的活化凝血因子 X(FXa)之抑制作用，故而可用作醫藥、瓜抑制劑、凝血 抑制劑、血栓或栓塞之預防及/或治療劑、血栓性疾病之 鲁預防及/或治療藥，進而可用作腦梗塞、腦检塞、心肌梗 塞、:絞痛、肺栓塞、伯格式症、深部靜脈血检症、全身 }*生血管内；旋血綜合症、人工撇腊/日日 丁口压人工瓣臈/關節置換後之血栓形 成、血流重建後之血栓形成及 ^ _ 取夂冉閉基、多器官功能障礙綜 合症（MODS)、體外循環時的血於 了 J血％形成或採血時的血液凝 固之預防及/或治療劑。 [發明之效果] 本發明之新穎二醯胺衍生物g • 了玍物即使經口投予亦顯示出強力 的活化凝血因子X(FXa)之抑制 f f j作用’故而可用於預防及/ 或治療例如腦梗塞、腦栓塞、 _ 肌梗基等血栓性或栓塞性 疾病。 【實施方式】 狀 以下，就本說明書中之取代基加以說明 (1)所謂鹵基，係指氟基 (2)所謂C1〜C6烷基， 的飽和烴形成之一價 氯基、溴基及碘基。 係扣由妷數為1〜6之直鏈狀或支鏈 基’例如可列舉：甲基、乙基、正 129677.doc 11 200840568 丙基、異丙基、正丁基、1-甲基-正丙基、2-甲基-正丙 基 第二丁基、正戊基、1-甲基-正丁基、2-甲基-正丁 基 ％甲基正丁基、1，1-二曱基-正丙基、2，2-二甲基-正 丙基1，2-一曱基-正丙基、1-乙基-正丙基、正己基、1-甲 基-正戊基、2-甲基-正戊基、3-曱基-正戊基、4—曱基-正戊 基1，1'二甲基-正丁基、2,2_二曱基-正丁基、3,3-二甲基-正丁基、1，2-二曱基-正丁基、1，3_二曱基-正丁基、2,3_二Q3 represents a phenyl group (the phenyl group may have a substituent selected from the group consisting of a halogen group, a C1 to C6 alkyl group, a _C1 to C6 alkyl group, and a C1 to C6 alkoxy group as a substituent), 17 Steenyl, 13⁄4 generation, phenanthyl, π-r, dentate, sigma, oxazinyl, i-pyridazinyl, quinolinyl, haloquinolinyl, isoquinolinyl, self-generation Isoquinolyl, 4-phenylenyl or _tetraphenyl]. Further, the present invention provides a medicament comprising the compound represented by the above formula (1) or a pharmacologically acceptable salt thereof, in particular, a prophylactic factor X (FXa) inhibitor, a blood coagulation inhibitor, a thrombus or embolism prevention and/or Or a therapeutic agent, thereby providing cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary embolism, plague, deep venous thrombosis, systemic intravascular coagulation syndrome, thrombosis after prosthetic valve/joint replacement, blood flow Thrombosis and reocclusion after reconstruction, multiple organ dysfuncti〇n syndr〇me), thrombosis during cardiopulmonary bypass, or prevention and/or treatment of blood coagulation during blood collection. Further, the present invention provides an intermediate for producing the compound (1) represented by the above formula (1). Further, the present invention provides the use of a salt which is generally acceptable. The compound represented by the above formula (I) or a drug thereof is used for pharmaceutical production. Further, the present invention provides a compound represented by the above formula (1) or a pharmacologically acceptable salt thereof for preventing and/or treating thrombus or embolism. Furthermore, the present invention provides a method for treating a thrombus or an embolism, which comprises administering an effective amount of the compound represented by the above formula (1) or a pharmacologically acceptable salt thereof. The novel lysine derivative of the present invention exhibits a strong inhibitory effect on activated factor X (FXa), and thus can be used as a prophylactic and/or therapeutic agent for medicine, melon inhibitor, blood coagulation inhibitor, thrombus or embolism, The prevention and/or treatment of thrombotic diseases can be used as cerebral infarction, brain examination, myocardial infarction,: colic, pulmonary embolism, sputum format, deep venous blood test, whole body; Thrombosis after circumcision syndrome, artificial waxing/day-day Dingkou artificial flap/joint replacement, thrombosis after blood flow reconstruction, and _ 夂冉 夂冉 、, multi-organ dysfunction syndrome (MODS) The blood at the time of cardiopulmonary bypass is a preventive and/or therapeutic agent for blood coagulation when J blood is formed or blood is collected. [Effect of the Invention] The novel diamine derivative of the present invention g • The sputum exhibits a potent inhibitory effect of activated factor X (FXa) even if administered orally, and thus can be used for prevention and/or treatment, for example. Thrombotic or embolic disease such as cerebral infarction, cerebral embolism, and musculoskeletal. [Embodiment] Hereinafter, the substituents in the present specification will be described. (1) The halogen group means a fluorine group (2), a C1 to C6 alkyl group, and a saturated hydrocarbon forms a monovalent chlorine group or a bromine group. Iodine. The fastener is a linear or branched group having a number of 1 to 6 ', for example, methyl, ethyl, and 129677.doc 11 200840568 propyl, isopropyl, n-butyl, 1-methyl- N-propyl, 2-methyl-n-propyl second butyl, n-pentyl, 1-methyl-n-butyl, 2-methyl-n-butyl-methyl-n-butyl, 1,1-di Mercapto-n-propyl, 2,2-dimethyl-n-propyl 1,2-monodecyl-n-propyl, 1-ethyl-n-propyl, n-hexyl, 1-methyl-n-pentyl , 2-methyl-n-pentyl, 3-mercapto-n-pentyl, 4-mercapto-n-pentyl 1,1'-dimethyl-n-butyl, 2,2-diindolyl-n-butyl , 3,3-dimethyl-n-butyl, 1,2-didecyl-n-butyl, 1,3-didecyl-n-butyl, 2,3_two

甲基-正丁基、i—乙基-正丁基、2_乙基-正丁基及1_(異丙 基）_正丙基等。 (3) 所謂鹵代C1〜C6烷基，係指經1〜5個鹵基取代之上述 C1 C6垸基，函基為2個以上時各齒基之種類可相同或不 同作為鹵代C1〜C 6烧基之具體例，可列舉：氟甲基、二 氟甲基、二氟曱基、1-氟乙基、2_氟乙基、2_氯乙基、2_ /臭乙基、Ο，1·二氟）乙基、（1，2-二氟）乙基、（2,2,2·三氟）乙 基、（U，2,2-四氟）乙基、（以以义五氟化基“备正丙 土 I1·一氟-正丙基、2,2·二氟·正丙基、3-氟-正丙基、 (3,3,3-三氟 >正丙基、4各正丁基、（4,4,4-三氟）-正丁 基、5 -氟-正戊基、（55,5-二蠡、^ 一亂）-正戊基、6-氟-正己基及 (6,6,6-三氟）_正己基等。 (4) 所謂C1〜C6烷氧基，係扣山丄、。 ’、寺日由上述Cl〜C6烧基與氧原子 所形成的C1〜C6烷氧基，例‘叮以淑 列如可列舉：甲氧基、乙氧基、 正丙氧基、異丙氧基、正丁ι 丁虱基、1-甲基-正丙氧基、2·甲 基-正丙氧基、第三丁氧 愚正戊虱基、1-曱基-正丁氧 土 2-甲基-正丁氧基、3、 τ丞-正丁乳基、1，1-二甲基-正 129677.doc -12- 200840568 丙氧基、2,2_二甲基-正丙氧基、二甲基·正丙氧基、^ 乙基·正丙氧基、正己氧基、“甲基-正戊氧基、2-曱基-正 戊氧基' 3-甲基-正戊氧基、4·曱基-正戊氧基、-二甲 基正丁氧基、2,2_二曱基-正丁氧基、3,3-二曱基_正丁氧 基、1，2_二曱基_正丁氧基、•二曱基-正丁氧基、2,3·二 曱基-正丁氧基、乙基_正丁氧基、2_乙基_正丁氧基及^ (異丙基）-正丙氧基等。 (5)所謂鹵RC1〜C6烷氧基，係指經1〜5個_基取代之上 述C1〜C6烷氧基，鹵基為2個以上時各鹵基之種類可相同 或不同。作為函代C1〜C6烷氧基的具體例，可列舉：氟甲 乳基、二氟甲氧基、三氟甲氧基、卜氟乙氧基、2-氟乙氧 基、2-氣乙氧基、2_演乙氧基、（u•二氣）乙氧基、以二 氣）乙氧基、（2,2,2_三幻乙氧基、〇山2,2·四氟）乙氧基、 (1，1，2,2,2-五氟)乙氧基、卜氟·正丙氧基、a二氟-正丙氧 基/2-二氟正丙氧基、3备正丙氧基、（3,3,3-三氣正 丙乳基、（2,2,3,3,3·五氟）_正丙氧基、心氣-正丁氧基、 (4’M-三氟）_正丁氧基、5氟.正戊氧基、（…三幻-正 戊乳基、6-氟-正己氧基及（6,6,6_三氣）_正己氧基等。 (6)所謂C1〜⑽氧基以〜⑽基，係指心個上述ci〜c6 燒乳基取代之C1〜⑽基，例如可列舉：甲氧基甲基、乙 :基甲基、正丙氧基甲基、異丙氧基f基、”氧基乙 ::1-乙氧基乙基、2·甲氧基乙基、2_乙氧基乙基、2_(正 基）乙基、2·異丙氧基乙基、2·(正丁氧基）乙基、第 二丁乳基）乙基、2·(正絲基）乙基、Μ己氧基）乙基、 129677.doc •13- 200840568 3_甲氧基-正丙基、2·曱氧基-2-甲基乙基、4-甲氧基·正丁 基_ 2-甲氧基-2,2-二甲基乙基、2_乙基_2_甲氧基乙基、3_ 曱氧基-3-甲基·正丙基、5_甲氧基-正戊基及6_曱氧基_正己 基等。 (7) 所謂C1〜C6燒氧基羰基，係指由上述C1〜C6烷氧基與 玻基所形成之基，例如可列舉：甲氧基羰基、乙氧基羰 基、丙氧基羰基、第三丁氧基羰基等。 (8) 所谓N-單（C1〜C6烷基）胺甲醯基，係指胺甲醯基之氮 原子上的1個氫原子經上述€：1〜(：：6烷基取代的胺甲醯基， 例如可列舉：N_曱基胺曱醯基、N_乙基胺甲醯基、(正 丙基）胺甲醯基、N-異丙基胺甲醯基、N_(正丁基）胺甲醯 基、义異丁基胺甲醯基、N_(第三丁基）胺甲醯基、N气正戊 基）胺甲醯基及N·(正己基）胺甲醯基等。 (9) 所謂N，N-二（Cl〜C6烷基）胺甲醯基，係指胺甲醯基之 氮原子上的2個氫原子經上述相同或不同的ci〜C6烷基取 代之胺甲醯基，例如可列舉：N，N-二曱基胺甲醯基、N•乙 基-队曱基胺甲醯基、N，N-二乙基胺甲醯基、沁曱基 (正丙基）胺曱醯基、N_乙基_Ν·(正丙基）胺甲醯基、N，N_: (正丙基）胺甲醯基、Ν，Ν_二（異丙基）胺甲醯基、Ν_異丙基_ Ν•甲基胺曱醯基、Ν，Ν·二（正丁基）胺甲醯基、Ν_(正戊基）_ Ν•甲基胺甲醯基及Ν-(正己基）-Ν-甲基胺甲醯基等。 (10) 所謂1_(C1〜C6烷基）哌啶_4_基，係指哌啶之u立的氯 原子經上述C1〜C6烷基取代之哌啶基，例如可列舉：丨_甲 基旅啶基、1-乙基哌啶基、1-異丙基哌啶基、^丁基派咬 129677.doc -14· 200840568 基、1 -第三丁基哌啶基等。 (11)所謂N，N-二（C1〜C6烷基）胺基環己基，係指經上述 N，N-二（C1〜C6烷基）胺基取代之環己基，例如可列舉： (N，N_二甲基胺基）環己基、（N，N-二乙基胺基）環己基、 (Ν，Νβ二（正丙基）胺基）環己基、（N，N-二（正丁基）胺基）環己 基、（N-甲基乙基胺基）環己基、（N-曱基·仏正丙基胺 基）環己基等。 以下詳細說明本發明。 就通式（I)之環 A、R1、R2、T1、T2、Qi、q2&q3加以說 明。 通式（I) [化2]Methyl-n-butyl, i-ethyl-n-butyl, 2-ethyl-n-butyl and 1-(isopropyl)-n-propyl. (3) The halogenated C1 to C6 alkyl group means the above C1 C6 fluorenyl group substituted with 1 to 5 halogen groups, and when the number of the functional groups is 2 or more, the types of the respective dentate groups may be the same or different as the halogenated C1~ Specific examples of the C 6 alkyl group include fluoromethyl, difluoromethyl, difluorodecyl, 1-fluoroethyl, 2-fluoroethyl, 2-chloroethyl, 2//odor ethyl, hydrazine. ,1·difluoro)ethyl, (1,2-difluoro)ethyl, (2,2,2·trifluoro)ethyl, (U,2,2-tetrafluoro)ethyl, Pentafluorinated "pre-properate I1·monofluoro-n-propyl, 2,2. difluoro-n-propyl, 3-fluoro-n-propyl, (3,3,3-trifluoro]> Base, 4 n-butyl, (4,4,4-trifluoro)-n-butyl, 5-fluoro-n-pentyl, (55,5-dioxin, ^1)-n-pentyl, 6- Fluorine-n-hexyl and (6,6,6-trifluoro)-n-hexyl, etc. (4) The so-called C1~C6 alkoxy group, which is deducted from the hawthorn, ', the temple is made of the above-mentioned Cl~C6 base and oxygen The C1~C6 alkoxy group formed by an atom, for example, may be exemplified by methoxy, ethoxy, n-propoxy, isopropoxy, n-butylbutanyl, 1-methyl-positive. Propoxy, 2·methyl-n-propoxy, third Oxygen, n-pentyl, 1-mercapto-n-butoxide, 2-methyl-n-butoxy, 3, τ丞-n-butyl, 1,1-dimethyl-, 129, 677.doc -12 - 200840568 Propyloxy, 2,2-dimethyl-n-propoxy, dimethyl-n-propoxy, ethyl, n-propoxy, n-hexyloxy, "methyl-n-pentyloxy, 2-mercapto-n-pentyloxy ' 3-methyl-n-pentyloxy, 4·decyl-n-pentyloxy, -dimethyl-n-butoxy, 2,2-diindolyl-n-butoxy , 3,3-diindenyl-n-butoxy, 1,2-didecyl-n-butoxy, di-n-butyl-n-butoxy, 2,3·didecyl-n-butoxy Ethyl-n-butoxy, 2-ethyl-n-butoxy and ^(isopropyl)-n-propoxy, etc. (5) The so-called halogen RC1~C6 alkoxy group means 1~5 When the number of the halogen groups is two or more, the type of each of the halogen groups may be the same or different. Specific examples of the C1 to C6 alkoxy group of the formula include a fluoromethyl group. , difluoromethoxy, trifluoromethoxy, fluoroethoxy, 2-fluoroethoxy, 2-oxoethoxy, 2- ethoxy, (u•di-)ethoxy, With two gas) ethoxy, (2, 2, 2_ three magic Oxyl, Ershan 2,2·tetrafluoro)ethoxy, (1,1,2,2,2-pentafluoro)ethoxy, fluoro-n-propoxy, a-difluoro-n-propoxy /2-Difluoro-n-propoxy, 3-pren-propoxy, (3,3,3-tri-n-propyl acrylate, (2,2,3,3,3·pentafluoro)-n-propoxy , heart-n-butoxy, (4'M-trifluoro)-n-butoxy, 5-fluoro.n-pentyloxy, (...three magic-n-pentyl lactyl, 6-fluoro-n-hexyloxy and (6 , 6, 6_ three gas) _ n-hexyloxy and the like. (6) The C1~(10)oxy group is a ～10 group, and is a C1~(10) group substituted with the above ci~c6 succinyl group, and examples thereof include a methoxymethyl group, a ethyl group, and a methyl group. Oxymethyl, isopropoxy f, "oxyethyl:: 1-ethoxyethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-(n-yl)ethyl, 2 • isopropoxyethyl, 2·(n-butoxy)ethyl, second butyl)ethyl, 2·(nextyl)ethyl, decyloxy)ethyl, 129677.doc • 13- 200840568 3_Methoxy-n-propyl, 2·decyloxy-2-methylethyl, 4-methoxy-n-butyl-2-methoxy-2,2-dimethyl Base, 2-ethyl-2-methoxyethyl, 3-methoxycarbonyl-3-methyl-n-propyl, 5-methoxy-n-pentyl and 6-methoxy-n-hexyl. 7) The C1-C6 alkoxycarbonyl group means a group formed of the above C1 to C6 alkoxy group and a glass group, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, and a third group. Butoxycarbonyl, etc. (8) The so-called N-mono(C1~C6 alkyl)amine carbenyl group refers to a hydrogen atom on the nitrogen atom of the amine carbenyl group via the above €:1~(::6 alkyl The substituted amine mercapto group may, for example, be N-decylamine fluorenyl group, N-ethylamine carbhydryl group, (n-propyl)amine carbaryl group, N-isopropylamine carbhydryl group, N_ (n-butyl)amine-carbamyl, i-isobutylamine, mercapto, N-(t-butyl)amine, mercapto, N-n-pentyl)amine, and N-(n-hexyl)amine醯基等. (9) The so-called N,N-di(Cl~C6 alkyl)aminecarbamyl group means that two hydrogen atoms on the nitrogen atom of the amine carbaryl group are the same or different ci~C6 alkane described above. The amino-substituted mercapto group may, for example, be an N,N-didecylaminocarbazinyl group, an N-ethyl- benzylamine carbhydryl group, an N,N-diethylamine fluorenyl group or an anthracene group. Mercapto (n-propyl)amine sulfhydryl, N_ethyl Ν (n-propyl)amine carbhydryl, N,N_: (n-propyl)amine carbhydryl, hydrazine, hydrazine _ two (different Propyl)amine-methyl hydrazino, hydrazine-isopropyl-methyl hydrazide, hydrazine, hydrazine, bis(n-butyl)amine, hydrazine, hydrazine Methyl hydrazino and fluorenyl-(n-hexyl)-fluorene-methylamine-methyl hydrazino group, etc. (10) The so-called 1_(C1~C6 alkyl) piperidinyl-4-yl group refers to the chlorine atom of piperidine. Through the above C1 The -C6 alkyl-substituted piperidinyl group may, for example, be a fluorene-methyl-bryridinyl group, a 1-ethylpiperidinyl group, a 1-isopropylpiperidinyl group or a butyl group 129677.doc-14. 200840568, 1 - tert-butylpiperidinyl and the like. (11) The N,N-di(C1-C6 alkyl)aminocyclohexyl group refers to the above N,N-di(C1-C6 alkyl group). The amino group-substituted cyclohexyl group may, for example, be (N,N-dimethylamino)cyclohexyl, (N,N-diethylamino)cyclohexyl, (Ν,Νβ di(n-propyl)) Amino)cyclohexyl, (N,N-di(n-butyl)amino)cyclohexyl, (N-methylethylamino)cyclohexyl, (N-fluorenyl-indenylamino) ring Heji and so on. The invention is described in detail below. Rings A, R1, R2, T1, T2, Qi, q2 & q3 of the general formula (I) will be described. General formula (I) [Chemical 2]

通式（I)之環A表示苯環； 通式（I)之R1表示氫原子、鹵基、C1〜C6烧基、鹵代 C1〜C6烷基或C1〜C6烷氧基； R1較好的是氫原子、鹵基、C1〜C4烷基、鹵代cn〜C4烷 基及C1〜C4燒氧基。 通式（I)之R2表示氫原子、画基、C1〜C6烷基、鹵代 C1〜C6烷基、C1〜C6烷氧基、C1〜C6烷氧基C1〜C6烷基、鹵 代C1〜C6燒氧基、羧基、ci〜C6烧氧基羰基、胺甲醯基、 129677.doc -15- 200840568 N-單（Cl〜C6烷基）胺曱醯基或N，N-二（Cl〜C6)胺甲醯基。 作為通式（I)之R2，較好的是氫原子、鹵基、C1〜C4烷 基、鹵代C1〜C4烷基、C1〜C4烷氧基、C1〜C4烷氧基C1〜C4 烷基、鹵代C1〜C4烷氧基、羧基、C1〜C4烷氧基羰基、胺 曱醯基、N-單（C1〜C4烷基）胺曱醯基及Ν，Ν·二（C1〜C4)胺甲 醯基。 通式（I)之Τ1表示基-C(=0)N(R3)-(此處，該基之左侧的鍵 表示鍵結於基Q2，R3表示氫原子或C1〜C6烷基）。T1較好的 是基-C(=0)N(R3)-(此處，該基之左側的鍵表示鍵結於基 Q2，R3表示氫原子或曱基），尤其好的是基-C(=0)NH-(此 處，該基之左側的鍵表示鍵結於基Q2)。 通式（I)之 T2 表示基-ch2-c(r4)(r5)-c(=o)nh-、基-CH= CH-C(=0)NH-、基-CH2-0-C(=0)NH-或基-CH2-NHC(= 0)ΝΗ-(此處，各基之左側的鍵表示鍵結於環A，R4及R5相 同或不同，表示氫原子、鹵基、Cl〜C6烷基、羥基或 C1〜C6烷氧基）； T2 較好的是基-CH2-C(R4)(R5)-C(=0)NH-、基-CH=CH-C(=0)NH-、基-CH2-0-C(=0)NH-或基-CH2-NHC(=0)NH-(此處，各基之左側的鍵表示鍵結於環A，R4表示氫原子， R5表示氫原子、鹵基、C1〜C4烷基、羥基或C1〜C4烷氧 基）。 通式⑴之T2更好的是由基-ch2-ch2-c(=o)nh-、基-ch2-CH(Me)-C(=0)NH-、基-CH2-CH(0H)-C(=0)NH-、基-CH2-CH(F)-C(=0)NH-、基-CH=CH-C(=0)NH-、基-CH2»0- 129677.doc -16- 200840568 C(=0)NH-及基-CH2-NHC(=0)NH-(此處，各基之左側的鍵 表示鍵結於環A)所表示之基； 丁2 尤其好的是以基-CH2-CH2-C(=〇)]SiH-、基 _CH2· CH(0H)-C(=0)NH_、基 _CH2_CH(F)，C(=0)NH_、基 _CH= CH-C(=0)NH-、基-CH2-〇-C(=〇)NH-及基-Ch2-NHC(= 0)ΝΗ-(此處，各基之左側的鍵表示鍵結於環a)所表示之 基。 以下，就通式（I)之基Q1加以說明。 通式（I)之Q1表示：四氫萘啶基（該四氫萘啶基可具有 C1〜C6烷基作為取代基）、四氫噻唑并吡啶基（該四氫噻唑 并吼唆基可具有選自由C1〜C6烷基、齒代ci〜C6烷基、 C1〜C6烷氧基C1〜C6烷基及C1〜C6烷氧基羰基所組成之群 中的基作為取代基）、四氫噻唑并噠嗪基（該四氫噻唑并噠 嗪基可具有C1〜C6烷基作為取代基）、二氫吼喃并噻唑基、 四氫噻唑并吖丁啶基（該四氳噻唑并吖丁啶基可具有 烷基作為取代基）、（1_C1〜C6烷基）哌啶_4•基、4_N，N_二 (C1〜C6烷基）胺基環己基、4_(3_氧基嗎啉基）環己基或仁 (3 -氧基嗎琳-4 -基）苯基。 作為Q1之四氫萘啶基，對縮合形式及形成基的位置並無 ^ 別限制，可為[1，5]、[16]、[17]、[18]、[2,6]或[2 7]蔡 啶基中之任一者；作為萘啶環之鍵結位置，可為可形成鍵 _ /中之*位，作為氫化位置，於[1，5]萘咬基體中 表示1,2,3,4_四氫體，於⑴6]萘咬基體中表示1,2,3,4-四氫 體及5,6,7,8_四氫體’於π，7]萘咬基體中表示…〆-四氫 129677.doc •17- 200840568 體及从仏四氫^於⑽萘咬基體中表示以认四氮 體’於[2,6]萘唆基體中表示^认四氫體，並且於⑽ 秦σ疋基體中表示1，2,3,4 -四氫體； 又’於四氫噻唑并吡啶基中，可為以下基團中之任一 者：4,5,6,7-嘍唑并[4,5_b]ntb啶·2_基、4,5,6,7_售唑并[七5_ b]。比咬-5-基、4,5,6,7_㈣并[4,5外比。定冬基、4,5,6,7_’嗟 嗤并[4,5咖。定_7•基、Ring A of the formula (I) represents a benzene ring; R1 of the formula (I) represents a hydrogen atom, a halogen group, a C1 to C6 alkyl group, a halogenated C1 to C6 alkyl group or a C1 to C6 alkoxy group; The hydrogen atom, the halogen group, the C1 to C4 alkyl group, the halogenated cn to C4 alkyl group, and the C1 to C4 alkoxy group. R2 of the formula (I) represents a hydrogen atom, a picture group, a C1 to C6 alkyl group, a halogenated C1 to C6 alkyl group, a C1 to C6 alkoxy group, a C1 to C6 alkoxy group C1 to C6 alkyl group, a halogenated C1 group. ~C6 alkoxy, carboxy, ci~C6 alkoxycarbonyl, amine carbaryl, 129677.doc -15- 200840568 N-mono(Cl~C6 alkyl)amine sulfhydryl or N,N-di(Cl ~C6) Aminomethyl thiol. As R2 of the formula (I), preferred are a hydrogen atom, a halogen group, a C1 to C4 alkyl group, a halogenated C1 to C4 alkyl group, a C1 to C4 alkoxy group, and a C1 to C4 alkoxy group C1 to C4 alkane. Base, halogenated C1~C4 alkoxy group, carboxyl group, C1~C4 alkoxycarbonyl group, amine fluorenyl group, N-mono(C1~C4 alkyl) amine fluorenyl group and hydrazine, Ν·2 (C1~C4 Aminomethyl thiol. The oxime 1 of the formula (I) represents a group -C(=0)N(R3)- (wherein, the bond to the left of the group represents a bond to the group Q2, and R3 represents a hydrogen atom or a C1 to C6 alkyl group). T1 is preferably a group -C(=0)N(R3)- (wherein the bond to the left of the group represents a bond to the group Q2, and R3 represents a hydrogen atom or a fluorenyl group), and particularly preferably a group-C (=0) NH- (here, the key to the left of the base indicates the bond to the base Q2). T2 of the formula (I) represents a group -ch2-c(r4)(r5)-c(=o)nh-, a group -CH=CH-C(=0)NH-, a group-CH2-0-C ( =0) NH- or yl-CH2-NHC(= 0) ΝΗ- (wherein, the bond to the left of each group indicates a bond to ring A, and R4 and R5 are the same or different, indicating a hydrogen atom, a halogen group, Cl~ C6 alkyl, hydroxy or C1~C6 alkoxy); T2 is preferably -CH2-C(R4)(R5)-C(=0)NH-, yl-CH=CH-C(=0) NH-, yl-CH2-0-C(=0)NH- or yl-CH2-NHC(=0)NH- (wherein, the bond to the left of each group represents a bond to ring A, and R4 represents a hydrogen atom, R5 represents a hydrogen atom, a halogen group, a C1 to C4 alkyl group, a hydroxyl group or a C1 to C4 alkoxy group). More preferably, T2 of the formula (1) is derived from the group -ch2-ch2-c(=o)nh-, yl-ch2-CH(Me)-C(=0)NH-, yl-CH2-CH(0H)- C(=0)NH-, yl-CH2-CH(F)-C(=0)NH-, yl-CH=CH-C(=0)NH-, yl-CH2»0-129677.doc-16 - 200840568 C(=0)NH- and yl-CH2-NHC(=0)NH- (wherein the bond to the left of each group represents the bond to ring A); -CH2-CH2-C(=〇)]SiH-, _CH2·CH(0H)-C(=0)NH_, _CH2_CH(F), C(=0)NH_, _CH=CH -C(=0)NH-, yl-CH2-〇-C(=〇)NH- and yl-Ch2-NHC(= 0)ΝΗ-(here, the bond to the left of each group indicates bonding to ring a ) the basis of the statement. Hereinafter, the base Q1 of the general formula (I) will be described. Q1 of the formula (I) represents: a tetrahydronaphthyridinyl group (the tetrahydronaphthyridinyl group may have a C1 to C6 alkyl group as a substituent), and a tetrahydrothiazolopyridinyl group (the tetrahydrothiazolofluorenyl group may have Selecting a group of a group consisting of a C1 to C6 alkyl group, a toothed ci~C6 alkyl group, a C1 to C6 alkoxy group C1 to C6 alkyl group, and a C1 to C6 alkoxycarbonyl group as a substituent), tetrahydrothiazole And pyridazinyl (the tetrahydrothiazolopyridazinyl group may have a C1 to C6 alkyl group as a substituent), dihydrofurfurylthiazolyl, tetrahydrothiazoloazetidinyl (the tetrahydrothiazoloazetidinyl group may have an alkane a substituent as a substituent), (1_C1 to C6 alkyl) piperidine-4, a 4_N,N-di(C1-C6 alkyl)aminocyclohexyl group, a 4-(3-methoxymorpholinyl)cyclohexyl group or Ren(3-oxoline-4-yl)phenyl. As the tetrahydronaphthyridinyl group of Q1, the position of the condensed form and the forming group is not limited, and may be [1, 5], [16], [17], [18], [2, 6] or [ 2 7] any of the oxaridinyl groups; as the bonding position of the naphthyridine ring, it can be a bond _ / medium * position, as a hydrogenation position, in the [1,5] naphthalene bite matrix, 1,2, 3,4_tetrahydrogen, in the (1)6]naphthalene matrix, the 1,2,3,4-tetrahydrogen and the 5,6,7,8-tetrahydrogen' are represented in the π,7]naphthalene matrix ...〆-tetrahydro 129677.doc •17- 200840568 The body and the tetrahydrogen in the (10) naphthalene matrix indicate that the tetrazide is represented in the [2,6]naphthoquinone matrix, and In the (10) Qin σ 疋 matrix, the 1,2,3,4-tetrahydrogen is represented; and in the tetrahydrothiazolopyridinyl group, it may be any of the following groups: 4, 5, 6, 7- Carbazo[4,5_b]ntb pyridine·2_yl, 4,5,6,7_ oxazolo[7-5 b]. More than bite 5-base, 4,5,6,7_(four) and [4,5 external ratio. Ding Dongji, 4,5,6,7_’嗟 嗤[4,5 coffee. _7•基,

㈣并[4,5_，（4_基、4,5,6,7_㈣并Μ♦比 啶-6-基、4,5,6,7-喧》坐并[4,5-十^定_7_基 —…、4,5一并 4,5,6,7·㈣并[5,4帅终6·基、4，M，7_心并[5,4#比 咬小基、4,5,6,7-㈣并[5,4_十比咬_2·基、Ο，？·嗟峻并 [5,4命比°定·4-基、4,5,6，H坐并[M命比唆_6_基、 4,5,6,7-噻唑并[5,4_c]吡啶·7•基； 於四氫嗟唾并嗔嗪基令，可為以下基團中之任一者· 禾 土、I2,3,4，。坐并[4,5-C]璉嗓-6-基、4,5,6,7_噻唑并 [4,5-d]噠嗪_2_基、4,5,6,7·。塞嗤并[4,5<噠嗪I基、 4夹5 =㈣并[4,5姻嗪.7_基、坐并[We]建 =:，3’4，°坐并[5，“齡4-基，^^^ [5,4-c]噠嗪-6-基； 开 於二氫°比喃并嗟哇基中，可為以下基團中之任一者. 5,6-二氫-5H-吡喃并[2,3_d]噻唑 _2_ 并[W-d]噻唾_5_基 〃 ，-一虱-H南 丞 5,6·二虱-5H-吡喃并[2,3_dpg 129677.doc -18- 200840568 基、5,6-二氫-5H-吡喃并[2,3-d]噻唑-7-基、5,6-二氫-7H-吡喃并[2,3-d]噻唑-2-基、5,6-二氫-7H·吡喃并[2,3-d]噻唑- 5- 基、5,6·二氫-7H-吡喃并[2,3-d]噻唑-6-基、5,6-二氫-7H-吡喃并[2,3-d]噻唑-7-基、5,6-二氫-5H-吡喃并[3,2-d]噻唑-2-基、5,6-二氫 _5H-吡喃并[3,2-d]噻唑-5-基、5,6-二氫-5H-吡喃并[3,2-d]噻唑-6-基、5,6-二氫-5H-吡喃并[3,2-d]噻唑-7-基、5,6-二氫-7H-吡喃并[3,2-d]噻唑-2-基、5,6-二氫-7H-吡喃并[3,2-d]噻唑-5-基、5,6-二氫-7H-吡喃并[3,2-d]噻唑- 6- 基、5,6-二氫-7H-吡喃并[3,2-d]噻唑-7·基、6,7-二氫-4H-吡喃并[3,4-d]噻唑-2-基、6,7-二氫-4H-吡喃并[3,4-d]噻唑- 4- 基、6,7-二氫-4Η^比喃并[3,4-d]噻唑-6-基、6,7-二氫-4H-吡喃并[3,4-d]噻唑-7-基、6,7-二氫-4H-吡喃并[4,3-d]噻唑-2-基、6,7-二氫-4H-。比喃并[4,3-d]噻唑-4-基、6,7-二氫-4H-吡喃并[4,3-d]噻唑-6-基、6,7-二氫-4H-吡喃并[4,3-d]噻唑- 7- 基； 又，於四氫噻唑并吖丁啶基中，可為作為4,5,6,7-四氫 體之以下基團中的任一者：噻唑并[4,5-b]吖丁啶-2-基、 4H-噻唑并[4,5-b]吖丁啶-4-基、4H-噻唑并[4,5-b]吖丁啶- 5- 基、4H-噻唑并[4,5-b]吖丁啶-6-基、4H-噻唑并[4,5-b]吖 丁啶-7-基、4H-噻唑并[4,5-b]吖丁啶-8-基、6H-噻唑并 [4,5-b]吖丁啶-2-基、6H-噻唑并[4,5-b]吖丁啶-5-基、6H-噻唑并[4,5-b]吖丁啶-6-基、6H-噻唑并[4,5-b]吖丁啶-7-基、6H-噻唑并[4,5-b]吖丁啶-8-基、8H-噻唑并[4,5-b]吖丁 啶-2-基、8H-噻唑并[4,5_b]吖丁啶-5-基、8H-噻唑并[4,5- 129677.doc -19- 200840568 b]吖丁啶-6-基、8H-噻唑并[4,5-b]吖丁啶-7-基、8H-噻唑 并[4,5-b]吖丁啶-8-基、4H-噻唑并[5,4-b]吖丁啶-2-基、 4H-噻唑并[5,4-b]吖丁啶-4-基、4H-噻唑并[5,4-b]吖丁啶- 5- 基、4H-噻唑并[5,4-b]吖丁啶-6-基、4H-噻唑并[5,4-b]吖 丁啶-7-基、4H-噻唑并[5,4-b]吖丁啶-8-基、6H_噻唑并 [5,4-b]吖丁啶-2-基、6H·噻唑并[5,4-b]吖丁啶-5·基、6H-噻唑并[5,4-b]吖丁啶-6-基、6H-噻唑并[5,4-b]吖丁啶-7-基、6H-噻唑并[5,4-b]吖丁啶-8-基、8H·噻唑并[5,4-b]吖丁 啶-2-基、8H-噻唑并[5,4-b]吖丁啶-5-基、8H-噻唑并[5,4- b] 吖丁啶-6-基、8H·噻唑并[5,4-b]吖丁啶-7-基、8H-噻唑 并[5,4-b]吖丁啶-8-基、4H-噻唑并[4,5-c]吖丁啶-2-基、 4H·噻唑并[4,5-c]吖丁啶-4-基、4H-噻唑并[4,5-c]吖丁啶- 6- 基、4H-噻唑并[4,5-c]吖丁啶-7-基、4H-噻唑并[4,5-c]吖 丁啶-8-基、6H-噻唑并[4,5-c]吖丁啶-2-基、6H-噻唑并 [4,5-c]吖丁啶-4-基、6H-噻唑并[4,5-c]吖丁啶-6-基、6H-噻唑并[4,5-c]吖丁啶-7-基、6H-噻唑并[4,5-c]吖丁啶-8-基、8H-噻唑并[4,5-c]吖丁啶-2-基、8H-噻唑并[4,5-c]吖丁 啶·4_基、8H-噻唑并[4,5_c]吖丁啶-6-基、8H·噻唑并[4,5- c] 吖丁啶-7-基、8H-噻唑并[4,5_c]吖丁啶-8-基、4H-噻唑并 [5,4-c]吖丁啶-2-基、4H·噻唑并[5,4-c]吖丁啶-4-基、4H-嗟嗅并[5,4-c]°Y 丁喘>6 -基、4H-嗟 4 并[5,4-c]4 丁唆- 7-基、4H-噻唑并[5,4-c]吖丁啶-8-基、6H-噻唑并[5,4-c]吖丁 啶-2·基、6H-噻唑并[5,4-c]吖丁啶-4-基、6H-噻唑并[5,4-c]吖丁啶-6-基、6H-噻唑并[5,4-c]吖丁啶-7-基、6H-噻唑并 129677.doc -20 - 200840568 [5,4-小丫丁咬_8_基、811_嘆唾并[5,4_小丫丁咬_2_基、紐 售哇并[5,4♦丫 丁咬_4_基、8H_喧唾并[5,4·中丫丁 ^ 基、8Η—并[5,4·。]竹Μ基、抓㈣并[Μ♦丫丁 咬冬基、4Η·㈣并[4,5♦丫丁 Μ·基、4Η·魅并[4 5 小丫 丁咬.5•基、4Η·㈣并[4,5，丁咬_7_基n坐 并w♦丫丁咬m塞。坐并[4,5_d]〇丫丁咬_2_基、 6H-^。坐并[4 5-dl11 丫丁 ·4 | 』Τ』疋4-基、6Η-噻唑并[4,5_d]% 丁啶·(4) and [4,5_,(4_base, 4,5,6,7_(four) and Μ♦ than pyridine-6-based, 4,5,6,7-喧" sit and [4,5- 十^定_ 7_基—..., 4,5 and 4,5,6,7·(4) and [5,4 handsome final 6·base, 4,M,7_heart and [5,4# than biting small base, 4 , 5,6,7-(four) and [5,4_10 than bite_2·base, Ο,?·嗟峻和[5,4 life ratio °4-base, 4,5,6,H sit And [M life is more than 唆6_yl, 4,5,6,7-thiazolo[5,4_c]pyridine·7• group; in tetrahydropurine and pyridazinyl, it can be in the following groups Either He, I2, 3, 4, Sodium [4,5-C]琏嗓-6-yl, 4,5,6,7-thiazolo[4,5-d]pyridazine_ 2_base, 4,5,6,7·. 嗤 嗤 [4,5< azine I base, 4 clamp 5 = (4) and [4,5 oxazine. 7 _ base, sit and [We] build = :, 3'4, ° sit and [5, "age 4-base, ^^^ [5,4-c]pyridazine-6-yl; open in dihydrogen than in the oxime, can be Any of the following groups: 5,6-dihydro-5H-pyrano[2,3_d]thiazole_2_ and [Wd]thiazepine-5-ylindole, -anthracene-H-anthracene 5, 6·二虱-5H-pyrano[2,3_dpg 129677.doc -18- 200840568 base, 5,6-dihydro-5H-pyrano[2,3-d]thiazole-7-yl, 5, 6-Dihydro-7H-pyrano[2,3-d]thiazol-2-yl, 5,6-dihydro-7H·pyridyl And [2,3-d]thiazole-5-yl,5,6-dihydro-7H-pyrano[2,3-d]thiazol-6-yl, 5,6-dihydro-7H-pyran And [2,3-d]thiazol-7-yl, 5,6-dihydro-5H-pyrano[3,2-d]thiazol-2-yl, 5,6-dihydro-5H-pyran And [3,2-d]thiazol-5-yl,5,6-dihydro-5H-pyrano[3,2-d]thiazol-6-yl, 5,6-dihydro-5H-pyran And [3,2-d]thiazol-7-yl, 5,6-dihydro-7H-pyrano[3,2-d]thiazol-2-yl, 5,6-dihydro-7H-pyran And [3,2-d]thiazol-5-yl,5,6-dihydro-7H-pyrano[3,2-d]thiazole-6-yl, 5,6-dihydro-7H-pyran And [3,2-d]thiazol-7-yl, 6,7-dihydro-4H-pyrano[3,4-d]thiazol-2-yl, 6,7-dihydro-4H-pyran And [3,4-d]thiazol-4-yl, 6,7-dihydro-4Η^pyrano[3,4-d]thiazol-6-yl, 6,7-dihydro-4H-pyran And [3,4-d]thiazol-7-yl, 6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl, 6,7-dihydro-4H-. Cyclo[4,3-d]thiazol-4-yl, 6,7-dihydro-4H-pyrano[4,3-d]thiazol-6-yl, 6,7-dihydro-4H-pyridyl And [4,3-d]thiazole-7-yl; and, in the tetrahydrothiazoloazetidinyl group, may be any of the following groups as a 4,5,6,7-tetrahydrogen: Thiazolo[4,5-b]azetidin-2-yl, 4H-thiazide And [4,5-b]azetidin-4-yl, 4H-thiazolo[4,5-b]azetidine-5-yl, 4H-thiazolo[4,5-b]azetidine- 6-yl, 4H-thiazolo[4,5-b]azetidin-7-yl, 4H-thiazolo[4,5-b]azetidin-8-yl,6H-thiazolo[4,5 -b]azetidin-2-yl, 6H-thiazolo[4,5-b]azetidin-5-yl, 6H-thiazolo[4,5-b]azetidin-6-yl, 6H -thiazolo[4,5-b]azetidin-7-yl, 6H-thiazolo[4,5-b]azetidin-8-yl,8H-thiazolo[4,5-b] Pyridin-2-yl, 8H-thiazolo[4,5-b]azetidin-5-yl,8H-thiazolo[4,5-129677.doc -19- 200840568 b]azetidin-6-yl, 8H -thiazolo[4,5-b]azetidin-7-yl,8H-thiazolo[4,5-b]azetidin-8-yl, 4H-thiazolo[5,4-b]indole Pyridin-2-yl, 4H-thiazolo[5,4-b]azetidin-4-yl, 4H-thiazolo[5,4-b]azetidine-5-yl, 4H-thiazolo[5 ,4-b]azetidin-6-yl, 4H-thiazolo[5,4-b]azetidin-7-yl, 4H-thiazolo[5,4-b]azetidine-8-yl , 6H_thiazolo[5,4-b]azetidin-2-yl, 6H-thiazolo[5,4-b]azetidin-5-yl,6H-thiazolo[5,4-b] Azetidin-6-yl, 6H-thiazolo[5,4-b]azetidin-7-yl, 6H-thiazolo[5,4-b]azetidin-8-yl, 8H· Zizo[5,4-b]azetidin-2-yl, 8H-thiazolo[5,4-b]azetidin-5-yl,8H-thiazolo[5,4-b]azetidine -6-yl, 8H.thiazolo[5,4-b]azetidin-7-yl, 8H-thiazolo[5,4-b]azetidin-8-yl, 4H-thiazolo[4, 5-c]azetidin-2-yl, 4H-thiazolo[4,5-c]azetidin-4-yl, 4H-thiazolo[4,5-c]azetidine-6-yl, 4H-thiazolo[4,5-c]azetidin-7-yl, 4H-thiazolo[4,5-c]azetidin-8-yl,6H-thiazolo[4,5-c]indole Butyr-2-yl, 6H-thiazolo[4,5-c]azetidin-4-yl, 6H-thiazolo[4,5-c]azetidin-6-yl, 6H-thiazolo[ 4,5-c]azetidin-7-yl, 6H-thiazolo[4,5-c]azetidin-8-yl,8H-thiazolo[4,5-c]azetidine-2- ,8H-thiazolo[4,5-c]azetidine-4-yl, 8H-thiazolo[4,5-c]azetidin-6-yl,8H-thiazolo[4,5-c]indole Butyr-7-yl, 8H-thiazolo[4,5-c]azetidin-8-yl, 4H-thiazolo[5,4-c]azetidin-2-yl, 4H-thiazolo[5, 4-c]azetidin-4-yl, 4H-oxime sniff [5,4-c]°Y Dingchuan>6-based, 4H-嗟4 and [5,4-c]4 唆- 7-yl, 4H-thiazolo[5,4-c]azetidin-8-yl, 6H-thiazolo[5,4-c]azetidin-2-yl, 6H-thiazolo[5,4 - c] azetidin-4-yl, 6H-thiazolo[5,4-c]azetidin-6-yl, 6H-thiazolo[5,4-c]azetidin-7-yl, 6H- Thiazol 129677.doc -20 - 200840568 [5,4- 丫 咬 bite _8_ base, 811_ sigh and sigh [5,4_小丫丁 bit_2_ base, Newly sold wow and [5,4 ♦ Kenting bite _4_ base, 8H_喧 并 and [5,4·中丫丁^基,8Η—and [5,4·. ]竹Μ基,抓(四)和[Μ♦丫丁丁丁基,4Η·(4) and [4,5♦丫丁Μ·基,4Η·魅和[4 5 小丫丁 bit.5•基,4Η· (d) and [4,5, biting _7_ base n sit and w♦ 丫 bite m plug. Sit and [4,5_d] 咬 bite _2_ base, 6H-^. Sit and [4 5-dl11 丫丁 ·4 | 』Τ』疋4-yl, 6Η-thiazolo[4,5_d]% butyridine

5·基、6H“塞唾并[4,5♦丫 丁咬-6·基' 6H·㈣并[4,5斗丫 丁啶-7-基、6Η·噻唑并[4,5♦丫 丁啶_8_基、8h_噻唑并 [4,5斗丫丁。定_2-基、8心塞〇坐并[45斗丫丁咬冰基、抓 嘆嗤并[4,5♦丫丁咬_5_基、8H令坐并[4,5_d]竹咬_7基 或8H-嗟嗤并[4,5斗丫丁唆_8_基；進而亦可為該等之縮合 形式及鍵結位置以外者。 作為通式⑴之基Qi，較好的是：5,6,7,8_四氯一[以]蔡咬爾 2-基、6_C1 〜C6 烷基-5,6,7,8-四氫-[ι，6]萘啶 _2-基、4 四氣嗟。坐并[5，“]…一 嘆唾并[5,4-中比咬-2-基、5-齒代C1〜C6院基-4,5,6,7-四氫 噻唑并[5,4_c]吡啶-2-基、5_C1〜C6烷氧基以〜以烷基_ 4,5,6,7-四氫噻唑并[5，‘c]吡啶-2-基、5_C1〜〇6烷氧基羰 基_4,5,6,7-四氫噻唑并[5,4_c]吡啶_2_基、6,7_二氫_411_吡 喃并[4,3，d]噻唑-2-基、5,6,7,8-四氫-4H-噻唑并[5,4-c]吖丁 口疋-2-基、5_(：1〜(：；6烷基_5,6,7,8-四氫_41^噻唑并[5,4<]吖 丁啶-2-基、5- i代C1〜C6烷基-5,6,7,8-四氫-4H-噻唑并 [5,4-c]吖丁啶-2_基或5_C1〜C6烷氧基〇1〜。6烷基_5,6，了，8_四 129677.doc -21 - 200840568 氫-4H-噻唑并[5,4-c]吖丁啶-2-基。 作為通式（I)之基Q1，進而較好的是6_C1〜C4燒基· 5,6,7,8·四氫-[1，6]萘啶基、5-C1〜C4烷基-4,5,6,7-四氯嗟 唑并[5,4-c]吡啶-2-基、6,7-二氫-4H·吡喃并[4,3，d]噻唑_2_ 基及5-C1〜C4烷基-5,6,7,8_四氫-4H-噻唑并[5,4_c]吖丁啶_ 2-基； 基(5尤其好的是6-甲基-5,6,7,8-四氫-[1，6]萘咬-2-基、5_ 甲基-4,5,6,7-四氫噻唑并[5,4-c]吡啶-2-基、5-異丙基_ • 4,5,6,7·四氫噻唑并[5,4-c]吡啶-2-基、6,7-二氫_4H-吡喃并 [4,3，d]噻唑-2-基、5·曱基胃5,6,7,8-四氫_4H_噻唑并[5,4_c] 吖丁咬-2-基及5 -異丙基-5,6,7,8 -四氫-4H_嗟唾并[5,4-c]吖 丁啶-2-基。 通式⑴之Q2表示單鍵。 通式⑴之Q3表示苯基（該苯基可具有選自由鹵基、 C1〜C6烧基、鹵代C1〜C6烧基及C1〜C6烧氧基所組成之群 籲 中的1〜2個基作為取代基）、噻吩基、鹵代噻吩基、吡啶 基、鹵代吼啶基、噠嗪基、函代噠嗪基、喹啉基、鹵代喹 啉基、異喹啉基、_代異喹啉基、4啉基或_代碎啉基。 作為基Q3,較好的是苯基（該苯基可具有選自由鹵基、 C1〜C4烧基、函代C1〜C4烷基及C1〜C4烷氧基所組成之群 中的1〜2個基作為取代基）、鹵代噻吩基、鹵代吼啶基； 基Q更好的是苯基、鹵代苯基、甲基苯基、三氟曱基苯 基、曱氧基笨基、乙氧基苯基、齒代噻吩基、鹵代σ比啶 基。 129677.doc -22· 200840568 作為通式（I)之基Q3的較好具體例，可列舉：苯基、2-氟 苯基、2 -氣苯基、2 -漠苯基、3 -氟苯基、3 -氣苯基、3 -溴 苯基、4-氣苯基、4 -氣苯基、4 ->臭苯基、3，4 -二氣苯基、 3,4 -二氣苯基、3,4-二>臭苯基、4 -氯-3-氣苯基、3 -氯-4 -氟 苯基、4 ->臭-3-氟苯基、3 -溴-4 -氟苯基、4 -溴-3 -氯苯基、3_ 溴-4-氯苯基、2,4-二氟苯基、2,4-二氯苯基、2,4-二溴苯 基、4-氣-2-氣苯基、2 -氣-4-氣苯基、4->臭-2-氣苯基、2· 溴-4-氟苯基、4-溴-2-氣苯基、2-溴-4-氯苯基、3,5-二氟苯 基、3,5-二氯苯基、3,5-二溴苯基、5-氯-3-氟苯基、3-氣-5 -氣苯基、5 -溴-3 -氟苯基、3 -漠-5 -氟苯基、5 -漠-3 -氣苯 基、3 ->臭-5 -氯苯基、2 -曱基苯基、3 -甲基苯基、4 -甲基苯 基、2-甲氧基苯基、3-甲氧基苯基、4-曱氧基苯基、4-氟-3 -曱基苯基、4 -氣-3-曱基苯基、4 ->臭-3-曱基苯基、4 -氣-2 _ 曱基苯基、4 -氯-2-曱基苯基、4 ->臭-2 -曱基苯基、 5 -塞吩-2-基、5 -氣嗟吩-2-基、5 -漠°塞吩-2-基、4,5 -二 氣11塞吩-2 -基、4，5 -二氣σ塞吩-2 -基、4，5 -二 >臭σ塞吩-2 -基、5 _ 氯-4-氟。塞吩-2-基、4 -氣-5-氣11塞吩-2-基、5 -漠-4 -氯^塞吩- 2-基、4 - >臭-5 -氯嗟吩-2 -基、5 - >臭-4 -氣σ塞吩-2 -基、4 - >臭-5 -氣 σ塞吩-2 -基、 ϋ比°定-2 -基、°比咬-3 -基、°比ϋ定-4 -基、4 -氣°比°定-2 -基、4 _ 氣°比°定-2 -基、4 -〉臭1^比^定-2 -基、4 -鼠11比°定-3 -基、4 ·氣吼咬·» 3 -基、4 - >臭°比17定-3 -基、5 -亂0比咬-2 -基、5 -鼠°比σ定-2 -基、5_ 漠吼σ定-2 -基、4，5 -二鼠吼ϋ定-2 -基、4，5 -二氯σ比咬-2 -基、 4,5-二溴吼。定-2-基、5-氯-4-Ισ比淀-2-基、4_氯-5-氣ϋ比咬· 129677.doc -23- 200840568 2-基、5- >臭-4-氣 11比咬-2-基、4- >臭-5-氯 utb。定-2-基、4 ->臭-5-氟吡啶-2-基、5-溴-4-氟吡啶-2-基、5-氟吡啶-3-基、5-氯 0比17定* 3 -基、5 - >臭σ比σ定-3 -基。 作為通式⑴之基Q3的尤其好之具體例，可列舉：4-氟苯 基、4 -氣苯基、4 ->臭苯基、3，4·二氟^苯基、3，4 -二氣苯基、 3.4 -二溴苯基、4 -氣-3-氟苯基、3 -氣-4-氣苯基、4 -漠-3 -敗 苯基、3 - >臭-4 -氣苯基、4 - >臭-3 -氣苯基、3 - >臭-4 -氯苯基、 2.4 -二氣苯基、2,4 -二氯苯基、2,4-二>臭苯基、4 -氯-2-氣苯 馨 基、2 -氯-4 -貌苯基、4 ->臭-2-氟苯基、2_溴-4-說苯基、4_ 漠-2 -氣苯基、2 -漠-4 -氯苯基、3，5 -二說苯基、4 -甲氧基苯 基、4-氣-3 -甲基苯基、4 -氯-3-甲基苯基、4 ->臭-3 -曱基苯 基、4-氣-2-甲基苯基、4 -氣-2-甲基苯基、4 ->臭-2-曱基苯 基、 5-氣σ塞吩-2-基、5-氣σ塞吩-2-基、5->臭σ塞吩-2-基、4,5 -二 敦0塞吩-2-基、4,5-二氯°塞吩-2-基、4,5-二>臭1[?塞吩-2-基、5-氯-4 -說σ塞吩-2 -基、4 -氯-5 -敗σ塞吩-2 -基、5 -漠-4 -氯σ塞吩-2 -® 基、4-溴-5-氯噻吩-2-基、5-溴-4-氟噻吩-2-基、4-溴-5-氟 σ塞吩-2 -基、 5-氣吼咬-2 -基、5 -氣ϋ比σ定-2 -基、5 · >臭°比咬· 2 -基、4，5 -二 氣σ比咬-2-基、4,5 -二氣σ比17定-2-基、4，5-二 >臭ϋ比唆-2-基、5_ 氯-4 -象ϋ比咬-2 -基、4 -氯-5 -氣。比°定-2 -基、5 - >臭-4 -氣吼°定-2 _ 基、4 - >臭-5 -氯11比咬-2 -基、4 · >臭-5 -氣17比咬-2 -基及5 - >臭-4 -氣 °比σ定-2 -基， 該等之中，最好的是4-氣苯基、4-氟苯基、4-溴苯基、 129677.doc -24- 200840568 5 -氯°比咬_2_ I . ^ 氯噻 八 土、 4臭吡啶基、5-氟吡啶_2_基、 为、土、5·溴噻吩基及5-氟噻吩_2-基。 [化^為通式⑴之環A，較好的是以下述式（II)或（in)5·基,6H“塞塞和[4,5♦丫丁乙-6·基' 6H·(四)和[4,5斗丫丁丁-7-yl, 6Η·thiazolo[4,5♦丫丁Acridine _8_ base, 8h_thiazole and [4,5 丫 丫 丁. 定_2-based, 8 heart 〇 并 and [45 丫 咬 bite ice base, sigh 嗤 嗤 [4,5 ♦ 丫Bite _5_ base, 8H to sit and [4,5_d] bamboo bite _7 base or 8H-嗟嗤 and [4,5 丫 丫 唆 _8_ base; further can also be the condensation form and bond Other than the knot position. As the base Qi of the general formula (1), it is preferred that: 5,6,7,8-tetrachloro-[in] Tsai Er 2-base, 6_C1 to C6 alkyl-5,6,7 , 8-tetrahydro-[ι,6]naphthyridin-2-yl, 4 tetrakis. Sit and [5,"]...a sigh and [5,4-to-biti-2-yl, 5- Tooth C1~C6, 4,5,6,7-tetrahydrothiazolo[5,4_c]pyridin-2-yl, 5_C1~C6 alkoxy, to alkyl-4,5,6,7 -tetrahydrothiazolo[5,'c]pyridin-2-yl, 5-C1~〇6 alkoxycarbonyl_4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine_2-yl, 6 , 7_Dihydro-411_pyrano[4,3,d]thiazol-2-yl,5,6,7,8-tetrahydro-4H-thiazolo[5,4-c]pyrene -2-yl, 5_(:1~(:;6-alkyl-5,6,7,8-tetrahydro-41^thiazolo[5,4<]azetidin-2-yl, 5-i C1~C6 alkyl-5,6,7,8-tetrahydro-4H-thiazolo[5,4-c]azetidin-2-yl or 5-C1~C6 alkoxy hydrazine 1~.6 alkyl_ 5,6,了,8_四129677.doc -21 - 200840568 Hydrogen-4H-thiazolo[5,4-c]azetidin-2-yl. As the base Q1 of the formula (I), it is further preferred Is 6_C1~C4 alkyl · 5,6,7,8·tetrahydro-[1,6]naphthyridinyl, 5-C1~C4 alkyl-4,5,6,7-tetrachlorocarbazolo[ 5,4-c]pyridin-2-yl, 6,7-dihydro-4H.pyrano[4,3,d]thiazol-2-yl and 5-C1 to C4 alkyl-5,6,7, 8_tetrahydro-4H-thiazolo[5,4_c]azetidine-2-yl; base (5 especially preferably 6-methyl-5,6,7,8-tetrahydro-[1,6] Naphthalene-2-yl, 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl, 5-isopropyl_ 4,5,6,7 · tetrahydrothiazolo[5,4-c]pyridin-2-yl, 6,7-dihydro-4H-pyrano[4,3,d]thiazol-2-yl,5·indolyl stomach 5, 6,7,8-tetrahydro_4H_thiazolo[5,4_c] 吖butyl-2-yl and 5-isopropyl-5,6,7,8-tetrahydro-4H_嗟 并[5 , 4-c] azetidin-2-yl. Q2 of the formula (1) represents a single bond. Q3 of the formula (1) represents a phenyl group (the phenyl group may have 1 to 2 groups selected from the group consisting of a halogen group, a C1 to C6 alkyl group, a halogenated C1 to C6 alkyl group, and a C1 to C6 alkoxy group). a substituent as a substituent), a thienyl group, a halogenated thienyl group, a pyridyl group, a halogenated acridinyl group, a pyridazinyl group, a functional pyridazinyl group, a quinolyl group, a halogenated quinolyl group, an isoquinolyl group, a _ generation Isoquinolyl, 4 morpholinyl or _substituted porphyrinyl. Preferred as the group Q3 is a phenyl group (the phenyl group may have 1 to 2 selected from the group consisting of a halogen group, a C1 to C4 alkyl group, a C1 to C4 alkyl group, and a C1 to C4 alkoxy group). a group as a substituent), a halogenated thienyl group, a halogenated acridinyl group; a more preferred group Q is a phenyl group, a halogenated phenyl group, a methylphenyl group, a trifluoromethylphenyl group, an anthryloxy group, Ethoxyphenyl, dentylthiophenyl, halo σ pyridine. 129677.doc -22· 200840568 Preferred examples of the group Q3 of the formula (I) include a phenyl group, a 2-fluorophenyl group, a 2-phenylphenyl group, a 2-diphenyl group, and a 3-fluorobenzene. Base, 3- gas phenyl, 3-bromophenyl, 4-phenylphenyl, 4-oxophenyl, 4-hydroxybenzene, 3,4-diphenyl, 3,4-dibenzene Base, 3,4-di> odor phenyl, 4-chloro-3-phenylphenyl, 3-chloro-4-fluorophenyl, 4-> odor-3-fluorophenyl, 3-bromo-4 -fluorophenyl, 4-bromo-3-chlorophenyl, 3-bromo-4-chlorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2,4-dibromophenyl 4- 4-Phenyl-2-phenyl, 2-air-4-phenyl, 4->odor-2-phenyl, 2·bromo-4-fluorophenyl, 4-bromo-2- gas Phenyl, 2-bromo-4-chlorophenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-dibromophenyl, 5-chloro-3-fluorophenyl, 3-a-5-oxyphenyl, 5-bromo-3-fluorophenyl, 3-di-5-fluorophenyl, 5-oxa-3-phenyl, 3 -> odor-5-chlorobenzene Base, 2-nonylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-fluoro -3 -nonylphenyl, 4-air-3-mercaptophenyl, 4 -> odor-3-mercaptophenyl 4-Gas-2 _nonylphenyl, 4-chloro-2-indolylphenyl, 4-> odor-2-nonylphenyl, 5-cephen-2-yl, 5-carbon porphine- 2-Based, 5-indesep-2-yl, 4,5-diole 11-cephen-2-yl, 4,5-digas σ-cephen-2-yl, 4,5-di> Odor σ-cetin-2-yl, 5 _ chloro-4-fluoro. Desphen-2-yl, 4-air-5-gas 11-cephen-2-yl, 5-di-4-chloro^cephen-2-yl, 4 - > odor-5-chlorophene-2 - group, 5 - > odor-4 - gas σ-cetin-2-yl, 4 - > odor-5 - gas σ-cephen-2-yl, ϋ ratio ° - 2, bp ratio - 3 - base, ° ratio -4 -4 - base, 4 - gas ° ° ° -2 - base, 4 _ gas ° ratio ° -2 - base, 4 -> odor 1 ^ ratio ^ -2 - base , 4 - mouse 11 to ° -3 - base, 4 · gas bite ·» 3 - base, 4 - > stinze ratio 17 to 3 - base, 5 - chaotic 0 to bite - 2 - base, 5 - rat ° ratio σ - 2 - base, 5 - desert 吼 定 -2 - 2 - base, 4, 5 - 吼ϋ 吼ϋ -2 - 2 - base, 4, 5 - dichloro σ ratio bite - 2 - base, 4 , 5-dibromofluorene. Ding-2-yl, 5-chloro-4-Ισ ratio -2--2-yl, 4-chloro-5-gas ϋ bit 129677.doc -23- 200840568 2-based, 5--gt; Gas 11 is more than bit-2-yl, 4-> odor-5-chloroutb. Ding-2-yl, 4 -> odor-5-fluoropyridin-2-yl, 5-bromo-4-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-chloro 0 to 17 * 3 - group, 5 - > odor σ ratio σ -3 - group. Particularly preferred specific examples of the group Q3 of the formula (1) include 4-fluorophenyl group, 4- gas phenyl group, 4-membered phenyl group, 3,4·difluorophenyl group, and 3,4. - Diphenylphenyl, 3.4-dibromophenyl, 4-ox-3-fluorophenyl, 3-air-4-phenylphenyl, 4-oxa-3-phenyl, 3 - > - gas phenyl, 4 - > odor-3 - gas phenyl, 3 - > odor-4 - chlorophenyl, 2.4 - diphenyl, 2, 4 - dichlorophenyl, 2, 4- >Smelly phenyl, 4-chloro-2- gas benzoyl, 2-chloro-4 -phenyl, 4 -> odor-2-fluorophenyl, 2-bromo-4-phenyl, 4_ -2-2 - phenyl, 2-di-4-chlorophenyl, 3,5-diphenyl, 4-methoxyphenyl, 4-a-3-methylphenyl, 4-chloro- 3-methylphenyl, 4 -> odor-3-indenyl phenyl, 4- oxa-2-methylphenyl, 4- gas-2-methylphenyl, 4 -> odor-2- Nonylphenyl, 5-gas σ-phen-2-yl, 5-gas σ-phen-2-yl, 5-> odor 塞 cephen-2-yl, 4,5-ditun 0 thiophene- 2-yl, 4,5-dichloro-sept-2-yl, 4,5-di> odor 1 [?-cephen-2-yl, 5-chloro-4 - σ sept-2-yl , 4-chloro-5-oxo-s-phenanthr-2-yl, 5-di-4-chloro-sigma-phen-2--yl, 4-bromo-5-chlorothiophen-2-yl 5-bromo-4-fluorothiophen-2-yl, 4-bromo-5-fluoroσepten-2-yl, 5-gas quinone-2-yl, 5- gas enthalpy ratio sigma-2-yl, 5 · > odor ratio bite · 2 - base, 4, 5 - two gas σ ratio bite-2-yl, 4,5 - two gas σ ratio 17 fixed-2-yl, 4,5-di > stinky Indole-2-yl, 5-chloro-4-indan is more than 2-yl-, 4-chloro-5-. Ratio ° -2 - group, 5 - > odor - 4 - gas 吼 ° - 2 _ group, 4 - > odor -5 - chloro 11 ratio bite - 2 - group, 4 · > odor - 5 - The gas 17 is more than the bite-2 - group and the 5 - > odor - 4 - gas ratio σ - 2 - group, among these, the most preferred is 4-gas phenyl, 4-fluorophenyl, 4- Bromophenyl, 129677.doc -24- 200840568 5 -Chloro ratio bite_2_ I . ^ chlorothiabate, 4 odor pyridyl, 5-fluoropyridine_2-yl, methane, 5, bromothienyl And 5-fluorothiophene-2-yl. [Chemical ^ is a ring A of the formula (1), preferably in the following formula (II) or (in)

、、、口於T ’尺及尺2表示上述所記載者)所表示之基; 環A尤其好的是以上述式（m)所表示之基。The ring is represented by the above formula (m), and the ring A is particularly preferably a group represented by the above formula (m).

通式⑴之T2最好的是基-ch2 -ch2-c(=o)nh-(此處 之左側的鍵表示鍵結於環A)。 ’各基 作為通式（I)之最好的化合物，可列舉通式⑴之環A為式 (III);且The T2 of the formula (1) is preferably a group -ch2 -ch2-c(=o)nh- (where the bond on the left side indicates bonding to the ring A). As the most preferable compound of the formula (I), the ring A of the formula (1) is represented by the formula (III);

T2為基-CH2-CH2-C(，NH.(此處，各基之左側的鍵表示 鍵結於環A)之下述通式（jy)所表示之化合物。 [化4]T2 is a compound represented by the following formula (jy) wherein the group -CH2-CH2-C (, NH. (here, the bond to the left of each group represents a bond to the ring A).

通式（I)之R1較好的是氫原子、鹵基、C1〜C4烷基、鹵代 129677.doc -25- 200840568R1 of the formula (I) is preferably a hydrogen atom, a halogen group, a C1 to C4 alkyl group, or a halogen group 129677.doc -25- 200840568

Cl〜C4烷基及ci〜C4烷氧基； 作為R1，最好的是氫原子、鹵基、三氟甲基及甲氧基。 作為通式⑴之R2，較好的是氫原子、鹵基、C1〜C4烷 基、函代C1〜C4烷基、C1〜C4烷氧基、C1〜C4烷氧基C1〜C4 烧基、_代01〜C4烷氧基、羧基、ci〜C4烷氧基羰基、胺 甲醯基、N-單（C1〜C4烷基）胺甲醯基或N，N•二（C1〜C4)胺曱 酿基； R2最好的是羧基、C1〜C4烷氧基羰基、胺曱醯基、N-甲 基胺曱醯基及N，N_二曱基胺曱醯基。 作為通式（I)之較好化合物的具體例，可列舉選自由下述 化合物所組成之群中的任一化合物或其藥理上容許之鹽： 4-〇(4·氯苯基胺甲醯基）乙基異丙基-4,5,6,7_四氫 噻唑并[5,4-c]吡啶-2-羰基）胺基]苯甲酸、4-[2-(5-氯吡啶-2-基胺甲隨基）乙基]_3·[(5-異丙基_4,5,6,7_四氫噻唑并[5，扣 ch比咬-2-羰基）胺基]苯曱酸、4-{2_[(4_氟苯基）胺甲醯基] 乙基卜3·[(5-異丙基-4,5,6,7-四氫噻唑并[5,4-c]吡啶-2-羰 基）胺基]苯曱酸、4-[2-(5-氣噻吩-2-基胺曱醯基）乙基]-5-[(5-異丙基-4,5,6,7-四氫噻唑并[5,4-c]吡啶-2-羰基）胺基]苯 甲酸、4-[2-(4-氯苯基胺甲醯基）乙基]甲基乃，6,7,8-四氫-4H-噻吐并[5,4-e]吖丁啶羰基）胺基]苯甲酸、4-[2_ (心氯苯基胺曱醯基）乙基]_3七5•異丙基—5,6,7,8-四氫_411· 噻唑并[5,4-c]吖丁啶-2-羰基）胺基]苯甲酸、3-氯-4-{2-[(4-氯苯基）胺甲醯基]乙基異丙基·4,5,6,7-四氫噻唑并 [5,4-c]吼啶-2-羰基）胺基]苯甲酸、3_氣_4_{2_[(4_氣苯基）胺 129677.doc -26- 200840568 甲醯基]乙基}-5-[(5 -甲基·4,5,6,7-四氫嗟σ坐并[5,4-c]σ比。定-2-幾基）胺基]苯曱酸、3-氯-4-{2-[(4-Ki苯基）胺曱酿基]乙 基}-5-[(5-異丙基-4,5,6,7-四氫°塞嗤并[5,4-(：]吼咬-2-幾基） 胺基]苯甲酸、4-{2-[(4-氯苯基）胺甲醯基]乙基}-3_[(5_異丙 基_4,5,6,7_四氫噻唑并[5,4-c]吡啶-2-羰基）胺基]_5·氟苯曱 酸、4-{2-[(4-氯苯基）胺甲醯基]乙基卜3_[(5_異丙基· 4,5,6,7-四氫噻唑并[5,4_c]n比啶-2_羰基）胺基]巧·甲氧基苯 甲酸、4-{2，[(4_氣苯基）胺甲醯基]乙基}-3-甲氧基-5-[(5-甲 基-4,5,6,7-四氫噻唑并[5,4_c]吡啶羰基）胺基]苯曱酸、 4_{2-[(4·氟笨基）胺曱醯基]乙基}-3-[(5-異丙基-4,5,6,7-四 ^坐并[Ή 幾基）胺基]-5-甲氧基苯曱酸及4- {2 [(4虱本基）胺甲醯基]乙基}_3-[(5-異丙基-4,5,6,7-四氫 °塞嗤并[5,4-cln比4 , 作為通式^ Λ ^丄 孕乂好化合物，可列舉選自由下述表1及表2 所組成之群中的 1Ί 化合物或其藥理上容許之鹽。Cl to C4 alkyl and ci~C4 alkoxy; as R1, a hydrogen atom, a halogen group, a trifluoromethyl group and a methoxy group are preferred. R2 of the formula (1) is preferably a hydrogen atom, a halogen group, a C1 to C4 alkyl group, a C1 to C4 alkyl group, a C1 to C4 alkoxy group, or a C1 to C4 alkoxy group C1 to C4. _01~C4 alkoxy, carboxy, ci~C4 alkoxycarbonyl, aminemethanyl, N-mono(C1~C4 alkyl)aminecarbamyl or N,N•di(C1~C4)amine The aryl group; R2 is preferably a carboxyl group, a C1 to C4 alkoxycarbonyl group, an amine fluorenyl group, an N-methylamino group and an N,N-didecylamino group. Specific examples of the preferred compound of the formula (I) include any one selected from the group consisting of the following compounds or a pharmacologically acceptable salt thereof: 4-indole (4. chlorophenylamine formazan) Ethyl isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl)amino]benzoic acid, 4-[2-(5-chloropyridine- 2-ylaminomethylmethyl)ethyl]_3·[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5, butyl ch-but-2-carbonyl)amino]phenylhydrazine Acid, 4-{2_[(4-fluorophenyl)aminemethanyl]ethyl b 3·[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c Pyridine-2-carbonyl)amino]benzoic acid, 4-[2-(5-athiophen-2-ylamine decyl)ethyl]-5-[(5-isopropyl-4,5) ,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl)amino]benzoic acid, 4-[2-(4-chlorophenylaminemethanyl)ethyl]methyl ,6,7,8-tetrahydro-4H-thexo[5,4-e]azetidinylcarbonyl)amino]benzoic acid, 4-[2_(p-chlorophenylaminoindenyl)ethyl] _3七五•isopropyl- 5,6,7,8-tetrahydro-411·thiazolo[5,4-c]azetidine-2-carbonyl)amino]benzoic acid, 3-chloro-4- {2-[(4-Chlorophenyl)amine-carbamoyl]ethylisopropyl- 4,5,6,7-tetrahydrothiazolidine [5,4-c] acridine-2-carbonyl)amino]benzoic acid, 3_gas_4_{2_[(4-hydrophenyl)amine 129677.doc -26- 200840568 formazan]ethyl} -5-[(5-methyl·4,5,6,7-tetrahydroindole σ and [5,4-c]σ ratio. sec-2-yl)amino]benzoic acid, 3- Chloro-4-{2-[(4-Kiphenyl)amine oxime]ethyl}-5-[(5-isopropyl-4,5,6,7-tetrahydro-hydrazino[5 , 4-(:] 吼 bit-2-yl) Amino]benzoic acid, 4-{2-[(4-chlorophenyl)aminemethanyl]ethyl}-3_[(5-isopropyl) _4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl)amino]_5·fluorobenzoic acid, 4-{2-[(4-chlorophenyl)amine Methyl hydrazide] ethyl bromide 3_[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4_c]n-pyridin-2-carbonyl)amino] methoxybenzene Formic acid, 4-{2,[(4-hydroxyphenyl)amine-carbamoyl]ethyl}-3-methoxy-5-[(5-methyl-4,5,6,7-tetrahydrothiazole And [5,4_c]pyridinecarbonyl)amino]benzoic acid, 4_{2-[(4.fluorophenyl)aminoindenyl]ethyl}-3-[(5-isopropyl-4,5 ,6,7-tetrazine and [Ή ))amino]-5-methoxybenzoic acid and 4-{2 [(4虱本基)胺甲甲基]ethyl}_3-[( 5-isopropyl-4,5,6,7-tetrahydro-pyrene and [5,4-cln ratio 4, as a general formula ^ Λ ^ Qe good pregnancy compounds include selected from the group of permissible 1 and 2 consisting of the free compound or a pharmacologically 1Ί following table salt.

疋羰基）胺基]-5-(三氟曱基）苯曱酸。 129677.doc -27· 200840568 ▼ fS 〜.OH WVi H l. a / W i 〇,'γ 扇 S / N 〆:.、.、〆〇 — 〇状j H [表2]Hydrazinecarbonyl)amino]-5-(trifluoromethyl)benzoic acid. 129677.doc -27· 200840568 ▼ fS ~.OH WVi H l. a / W i 〇, 'γ fan S / N 〆: ., ., 〆〇 — 〇 j j [Table 2]

本發明之以通式（I)所表示的化合物具有胺基等鹼性基 時，可視需要而製成醫藥上容許之鹽。作為上述鹽，例如 可列舉：氫氟酸鹽、鹽酸鹽、氫溴酸鹽、氫碘酸鹽等氫鹵 酸鹽；硝酸鹽、過氯酸鹽、硫酸鹽、磷酸鹽等無機酸鹽； 129677.doc -28- 200840568 甲磺酸鹽、三氟曱磺酸鹽、乙磺酸鹽等低級烷磺酸鹽；苯 石頁酸鹽、對甲苯磺酸鹽等芳磺酸鹽；乙酸、蘋果酸、反丁 烯二酸鹽、琥珀酸鹽、檸檬酸鹽、酒石酸鹽、草酸鹽、順 丁烯二酸鹽等有機酸鹽；及鳥胺酸鹽、麩胺酸鹽、天冬胺 酸鹽等胺基酸鹽；較好的是氫函酸鹽及有機酸鹽。又，以 通式（I)所表示之本發明化合物具有羧基等酸性基時，一般 可形成鹼加成鹽。作為醫藥上容許之鹽，例如可列舉：鈉When the compound represented by the formula (I) of the present invention has a basic group such as an amine group, it may be a pharmaceutically acceptable salt as needed. Examples of the salt include hydrohalide salts such as hydrofluoric acid salts, hydrochloride salts, hydrobromide salts, and hydroiodides; and inorganic acid salts such as nitrates, perchlorates, sulfates, and phosphates; 129677.doc -28- 200840568 Lower alkanesulfonate such as mesylate, trifluorosulfonate or ethanesulfonate; arylsulfonate such as benzoate or p-toluenesulfonate; acetic acid, apple Organic acid salts such as acid, fumarate, succinate, citrate, tartrate, oxalate, maleate; and aguanine, glutamate, aspartate Amino acid salts such as salts; preferred are hydrogenate salts and organic acid salts. Further, when the compound of the present invention represented by the formula (I) has an acidic group such as a carboxyl group, a base addition salt is generally formed. As a pharmaceutically acceptable salt, for example, sodium can be mentioned.

鹽、鉀鹽、鋰鹽等鹼金屬鹽；鈣鹽、鎂鹽等鹼土金屬鹽； 銨鹽等無機鹽；二苄胺鹽、嗎啉鹽、苯基甘胺酸烷基酯 鹽、乙二胺鹽、N-甲基葡糖胺鹽、二乙胺鹽、三乙胺鹽、 環己基胺鹽、二環己基胺鹽、缕二苄基乙二胺鹽、二 乙醇胺鹽、N-节基-N-(2-苯基乙氧基）胺鹽、哌嗪鹽、四曱 基鉍鹽、二（經基甲基）胺基甲烷鹽等有機胺鹽·，精胺酸鹽 等胺基酸鹽等。 又，本發明之以通式（I)所表示的化合物或其藥理上容許 之鹽亦有作為游離體或溶劑合物而存在之情形。作為溶劑 口物右為西藥上可容許者，則並無特別限制，具體而 言’較好的是水合物、乙醇合物等。又，以通式⑴所表示 之本發明化合物中存在氮原子時，可形成N_氧化物，該等 溶劑合物及N-氧化物亦包含於本發明之範圍中。 以通式（I)所表*之本發明化合物或其藥理上容許之鹽根 據取代基的種類或組合，可存在：順式體、反式體等幾何 異構物，1Η 四嗤-5 -某體、9 m , 篮 四唾_5-基體等互變異構 物；或d體、1體等光學異構物等各種異構物，且於無特別 129677.doc -29- 200840568 限制時，本發明化合物亦包含該等所有異構物、立體異構 物及任-比率的該等異構物及立體異構物混合物。 又，本發明亦包含··於生物體内之生理條件下由酶或胃 酸等之反應而轉化為本發明之醫藥组合物的有效成分即化 合物⑴的化合物1，由酶引起氧化、還原、水解等而轉 化為化合物（I)之化合物，或者利用胃酸等產生水解等而轉 化為化合物⑴的「醫藥上容許之前驅藥化合物」。An alkali metal salt such as a salt, a potassium salt or a lithium salt; an alkaline earth metal salt such as a calcium salt or a magnesium salt; an inorganic salt such as an ammonium salt; a dibenzylamine salt, a morpholine salt, an alkyl phenylglycine salt, and an ethylenediamine. Salt, N-methylglucamine salt, diethylamine salt, triethylamine salt, cyclohexylamine salt, dicyclohexylamine salt, bisdibenzylethylenediamine salt, diethanolamine salt, N-block base- N-(2-phenylethoxy)amine salt, piperazine salt, tetradecylsulfonium salt, organic amine salt such as bis(methylidenemethyl)aminomethane salt, amino acid salt such as arginine Wait. Further, the compound represented by the formula (I) or a pharmacologically acceptable salt thereof of the present invention may be present as a free form or a solvate. The solvent is not particularly limited as long as it is acceptable to the western medicine. Specifically, it is preferably a hydrate or an ethanolate. Further, when a nitrogen atom is present in the compound of the present invention represented by the formula (1), an N-oxide can be formed, and such solvates and N-oxides are also included in the scope of the present invention. The compound of the present invention represented by the formula (I) or a pharmacologically acceptable salt thereof may be present in a geometrical isomer such as a cis isomer or a trans isomer according to the kind or combination of the substituents, 1Η四嗤-5 - a tautomer such as a certain body, 9 m, a basket of tetras-_5-matrix, or an optical isomer such as a d-body or a 1-body, and when there is no special 129677.doc -29-200840568, The compounds of the invention also include all such isomers, stereoisomers and any ratio of such isomers and stereoisomer mixtures. Further, the present invention also includes the compound 1 which is an active ingredient of the pharmaceutical composition of the present invention, which is an active ingredient of the pharmaceutical composition of the present invention, which is oxidized, reduced, and hydrolyzed by an enzyme under physiological conditions in a living body. The compound which is converted into the compound (I) or the "medicinally acceptable prodrug compound" which is converted into the compound (1) by hydrolysis or the like using gastric acid or the like.

作為上述「醫藥上容許之前驅藥化合物」，於化合物⑴ 中存在胺基時，可列舉：該胺基經醯化、烷化、磷酸化之 化口物(例如，胺基經二十烷醯化、㊅胺醯化、戊基胺基 土化（5甲基氧基_丨，3-二氧雜環戊烯基）甲氧基羰 =化、四氫呋喃化、吡咯啶基甲基化、特戊醯氧甲基化、 第三丁基化之化合物等）等；於化合物⑴中存在羥基時， 可列舉·該羥基經醯化、烷化、磷酸化、硼酸化之化合物 (例如，該羥基經乙醯化、軟脂醯化、丙醯化、特戊醯 化、琥珀醯化、反丁烯二醯化、丙胺醯化、二曱基胺基曱 f羰基化之化合物等）等。又，於化合物⑴中存在羧基 k，可列舉邊叛基經能化、酸胺化之化合物（例如，該魏 基故乙_化、苯S旨化、緩基甲s旨化、：甲基胺基甲酿化、 特戊fe氧甲酯化、乙氧基羰氧基乙酯化、醯胺化或甲基醯 胺化之化合物等）等。 本發明化合物之前驅藥可利用公知方法由化合物⑴製 造。又，本發明化合物之前驅藥亦包含廣川書店1990年刊 w藥π口之開發」第7卷分子設計第ι63頁〜198頁所記載的 I29677.doc -30- 200840568 於生理條件下轉化為化合物（i)者。 以下，就本發明之二醯胺衍生物的製造方法加以說明， 但並不受該方法之任何限定。 本發明之二酸胺衍生物、其鹽及該等之溶劑合物，可藉 由已知之一般化學反應之組合而製造，以下說明代表性之 合成法。 再者’合成本發明之二醯胺衍生物之際，須要保護氮原 子、羥基、羧基等取代基時，可利用必要時可去除之通常 公知的保護基加以保護，該等保護基於必要時可藉由以下 之一般化學方法而去除。 又，為了合成本發明之二醯胺衍生物而必需的原料化合 物可藉由市售或一般合成法而獲得，代表性之原料化合物 的製造方法示於參考例中。進而，本發明之二醯胺衍生物 的原料化合物可藉由應用參考例中所例示的方法而合成。 以下，就氮原子、羥基、羧基等取代基之保護基及脫保 護方法加以闡述。 作為胺基、烷基胺基之氮原子的代表性保護基，可列 舉· fe基型保護基、芳基甲基型保護基及芳基磺醯基型保 護基。作為醯基型保護基，可列舉：乙醯基等烷醯基，苯 甲醯基等芳ϋ基’甲氧基誠、乙氧基絲、第三丁氧基 振基等烷氧基羰基，及节氧基羰基、對甲氧基苄氧基羰 基、對（或鄰）硝基苄氧基羰基等芳基甲氧基羰基等。作為 芳基甲基型保護基，可列舉··苄基、三苯基甲基等芳基甲 基’作為芳基磺醯基型保護基，可列舉：2,4_二硝基苯磺 I29677.doc -31 - 200840568 基鄰硝基笨磺酸基等芳基磺醯基。 所等保4基之脫保護方法根據所採用之保護基的化學性 貝而有所不同’例如，烷醯基、烷氧基羰基或芳醯基等醯 、1呆濩基，可藉由使用氫氧化鋰、氫氧化鈉或氫氧化鉀 等驗金屬氫氧化物等之水解而進行脫保護。又，第三丁氧 土羰基或對甲氧基节氧基羰基等取代甲氧基羰基型保護 基，可藉由使用適當之酸，例如使用乙酸、鹽酸、氫溴 ;,L ^ ^酸、二氟乙酸（TFA)、三氟甲磺酸、或者組 合使用該等酸而去除。苄氧基羰基、對甲氧基苄氧基羰 基、對（或鄰）硝基苄氧基羰基等芳基甲氧基羰基或者苄基 等方基甲基，可藉由使用鈀碳觸媒之催化還原而去除。 又，苄基亦可藉由於液氨中使用金屬鈉之伯奇還原（Birch reduction)而去除。三苯基甲基可藉由使用適當之酸，例 如使用甲酸、乙酸、鹽酸、氫溴酸、硫酸、磷酸、三氟乙 酸（TFA)、三氟甲磺酸、或組合使用該等酸而去除。又， 三苯基甲基可藉由於液氨中使用金屬鈉之伯奇還原而去 除’亦可藉由使用鈀碳觸媒之催化還原而去除。2,4_二硝 基苯磺醯基、鄰硝基苯磺醯基等芳基磺醯基可藉由與硫醇 乙酸或丙胺等一級胺進行處理而去除。 又，一級胺基可以鄰苯二甲醯基等醯亞胺型保護基加以 保護，該保護基可藉由肼、二甲基胺基丙胺等而去除。p引 0朵之氮原子可以苯石黃醯基、甲苯磺酸基、乙醯基、三氟乙 基專加以保濩’該專保護基可藉由使用氫氧化納、氫氧 化鋰、氫氧化鉀等鹼金屬氫氧化物等之水解而去除。 129677.doc -32- 200840568 作為經基之適當賴基，可列舉縣型保護基、_型伴 =基：作為代表性之醯基型保護基，可列舉乙醢基等_ 二本甲基等芳醯基，作為醚型保護基’可列舉节基等 方基甲基、第三丁基二甲基矽烷基等三烷基矽烷基、甲氧 基甲基、四氫㈣基# 1等保護基之去除根據所採用之 保。蒦基的化學性質而有所不同。例如，㈣基及芳醯基等 醯基可藉由❹氫氧化μ、氫氧仙、氫氧化鉀等驗金屬 虱乳化物等適當之鹼的水解而去除。芳基甲基型保護基可 精由使用鈀碳觸媒之催化還原而去除，第三丁基二甲基矽 院基等三㈣钱基可藉由町基氟⑽、氟化铯、;氣 酸等氟化鹽類而去除。χ，甲氧基甲基、四氫吼喃基等可 错由乙酸、鹽酸等去除。又，取代為芳基之羥基可藉由甲 基而保€，可藉由如氯化銘'三演化硼、三溴化鱗之路易 斯酸，三甲基矽烷基碘化物，溴化氫等而去除。 羧基可藉由酯化進行保護。曱酯、乙酯等可以氫氧化 氫氧化鈉、氫氧化鉀等驗金屬氫氧化物等適當之驗進 仃水解，第二丁酯可藉由以三氟乙酸（TFA)或鹽酸進行處 理而去除。又1基等芳基甲基型料藉由使用把碳觸媒 之催化還原而去除芳基曱基。 〜此外，關於保護基之選擇、保護基之導入及去除條件 尊 了參考例如 Protective Groups in Organic Synthesis (T· W. Green and P. α M. Wilts, John Wiley & Sons, Inc.5 NeWY〇rk，1991)等總論書中所記載之文獻。 以下，就本發明之衍生物⑴的製造方法加以說明。 129677.doc • 33 - 200840568 [化5]In the case of the above-mentioned "medically permissible pre-drug-removing compound", when an amine group is present in the compound (1), a sulfonate, an alkylation or a phosphorylation of the amine group is exemplified (for example, an amine group via eicosane) , hexamine deuteration, pentylamine auxamination (5-methyloxy-oxime, 3-dioxolyl) methoxycarbonyl = tetrahydrofuran, pyrrolidinyl methylation, special When a hydroxyl group is present in the compound (1), a compound in which the hydroxyl group is deuterated, alkylated, phosphorylated, or borated (for example, the hydroxyl group) may be mentioned. A compound which is acetylated, softened, softened, propylated, pentylated, amberated, butylated, propylamined, carbonylated with dimethyl hydrazine, etc.). Further, in the case where the carboxyl group k is present in the compound (1), a compound which can be subjected to acidification or acid amination can be mentioned (for example, the Wei group, the benzene group, the thiol group, and the methyl group): methyl group Amine methylation, ethoxymethyl esterification, ethoxycarbonyloxyethylation, amidation or methylammonium compound, etc.). The prodrug of the compound of the present invention can be produced from the compound (1) by a known method. In addition, the pre-drug-removing of the compound of the present invention also includes the development of the π mouth of the 1990 publication of the Guangchuan Bookstore, Volume I of the molecular design, I29677.doc -30- 200840568, which is described in the molecular design, on page 198 to page 198. i). Hereinafter, the method for producing the diamine derivative of the present invention will be described, but it is not limited to the method. The diacid amine derivative of the present invention, a salt thereof and the solvate thereof can be produced by a combination of known general chemical reactions, and a representative synthesis method will be described below. Further, when synthesizing the diamine derivative of the present invention, when it is necessary to protect a substituent such as a nitrogen atom, a hydroxyl group or a carboxyl group, it can be protected by a generally known protecting group which can be removed if necessary, and the protection can be based on necessity. It is removed by the following general chemical methods. Further, a raw material compound necessary for synthesizing the diamine derivative of the present invention can be obtained by a commercially available or general synthesis method, and a representative method of producing the raw material compound is shown in the reference example. Further, the starting compound of the diamine derivative of the present invention can be synthesized by the method exemplified in the reference example. Hereinafter, the protecting group of the substituent such as a nitrogen atom, a hydroxyl group or a carboxyl group and the deprotection method will be described. The representative protective group of the nitrogen atom of the amino group or the alkylamino group may, for example, be a fe-based protecting group, an arylmethyl-type protecting group or an arylsulfonyl-based protecting group. Examples of the fluorenyl-based protecting group include an alkoxycarbonyl group such as an acetamyl group, an alkoxycarbonyl group such as an fluorenyl group such as a fluorenyl group, a methoxy group, an ethoxy group or a third butoxy group. And an aryloxycarbonyl group such as a oxycarbonyl group, a p-methoxybenzyloxycarbonyl group or a p-(n-)nitrobenzyloxycarbonyl group. Examples of the arylmethyl group-protecting group include an arylmethyl group such as a benzyl group or a triphenylmethyl group as an arylsulfonyl group-protecting group, and examples thereof include 2,4-dinitrobenzenesulfonate I29677. .doc -31 - 200840568 An arylsulfonyl group such as a nitro-phenyl sulfonate group. The deprotection method of the protecting group is different depending on the chemical nature of the protecting group used, for example, an anthracene group, an alkoxycarbonyl group or an aryl group, and a sulfhydryl group can be used by using Deprotection by hydrolysis of a metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide. Further, a substituted methoxycarbonyl type protecting group such as a third butoxide carbonyl or a p-methoxyethoxycarbonyl group can be used by using an appropriate acid, for example, acetic acid, hydrochloric acid or hydrobromine; Difluoroacetic acid (TFA), trifluoromethanesulfonic acid, or a combination of these acids is used for removal. An arylmethoxycarbonyl group such as a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group or a p-(n-)nitrobenzyloxycarbonyl group or a benzyl group such as a benzyl group can be used by using a palladium carbon catalyst. It is removed by catalytic reduction. Further, the benzyl group can also be removed by Birch reduction using sodium metal in liquid ammonia. Triphenylmethyl can be removed by using an appropriate acid, for example, using formic acid, acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid (TFA), trifluoromethanesulfonic acid, or a combination of such acids. . Further, the triphenylmethyl group can be removed by the use of a Birch reduction of metallic sodium in liquid ammonia, and can also be removed by catalytic reduction using a palladium carbon catalyst. The arylsulfonyl group such as 2,4-dinitrobenzenesulfonyl or o-nitrophenylsulfonyl can be removed by treatment with a primary amine such as thiol acetic acid or propylamine. Further, the primary amine group may be protected by a quinone imine type protecting group such as phthalic acid, and the protecting group may be removed by hydrazine, dimethylaminopropylamine or the like. The nitrogen atom of p-derived 0 can be protected by benzathine, toluenesulfonate, ethyl sulfonate or trifluoroethyl. The specific protecting group can be used by using sodium hydroxide, lithium hydroxide, potassium hydroxide, etc. The alkali metal hydroxide or the like is removed by hydrolysis. 129677.doc -32- 200840568 As a suitable base of the base group, a county type protecting group and a _ type partner = base are mentioned: as a representative thiol type protecting group, an acetamyl group or the like can be cited. The aryl fluorenyl group, as an ether type protecting group, may be exemplified by a arylmethyl group such as a benzyl group or a trialkyl fluorenyl group such as a butyl dimethyl decyl group, a methoxymethyl group or a tetrahydro(tetra)yl group # 1 . The basis for removal is based on the insurance used. The chemical nature of sulfhydryl groups varies. For example, a thiol group such as a (tetra) group or an aryl fluorenyl group can be removed by hydrolysis of a suitable base such as hydrazine hydroxide, oxyhydroxide or potassium hydroxide. The arylmethyl type protecting group can be removed by catalytic reduction using a palladium carbon catalyst, and the third (four) money base such as the third butyl dimethyl ketone group can be obtained by the fenyl fluoride (10), cesium fluoride, gas It is removed by fluoride salts such as acids. The methoxy group, the tetrahydrofuranyl group and the like may be removed by acetic acid, hydrochloric acid or the like. Further, the hydroxyl group substituted with an aryl group can be protected by a methyl group, and can be obtained by, for example, chlorinating 'three-developed boron, tribrominated scaled Lewis acid, trimethylsulfonium alkyl iodide, hydrogen bromide, and the like. Remove. The carboxyl group can be protected by esterification. The oxime ester, ethyl ester, etc. may be hydrolyzed by an appropriate test such as sodium hydroxide or potassium hydroxide, and the second butyl ester may be removed by treatment with trifluoroacetic acid (TFA) or hydrochloric acid. . Further, an aryl group such as a aryl group removes an aryl fluorenyl group by catalytic reduction using a carbon catalyst. ~ In addition, the selection of the protecting group, the introduction of the protecting group, and the removal conditions are referred to, for example, Protective Groups in Organic Synthesis (T. W. Green and P. α M. Wilts, John Wiley & Sons, Inc. 5 NeWY〇 Rk, 1991) and other documents listed in the general book. Hereinafter, a method for producing the derivative (1) of the present invention will be described. 129677.doc • 33 - 200840568 [Chem. 5]

⑴ [製造方法1] 通式（I)之 T1 係-c(=o)-n(r3)_ 基、T2 係-ch2-c(r4)(r5)· C(=0)NH-基之下述通式（lb) [化6](1) [Production Method 1] T1 of the general formula (I) is -c(=o)-n(r3)_ group, T2 system-ch2-c(r4)(r5)·C(=0)NH-based The following general formula (lb) [Chemical 6]

Q R/ CHlR>^ 1 oneQ2-Q R/ CHlR>^ 1 oneQ2-

2 R2 R

RICRIC

b) Ib) I

Q 1 NH 所表示之化合物、其鹽、或該等之溶劑合物，例如可藉由 下述方法而製造。 • [化 7]The compound represented by Q 1 NH, a salt thereof, or a solvate thereof can be produced, for example, by the following method. • [Chem. 7]

129677.doc -34- 200840568129677.doc -34- 200840568

(式中，p2表示羧酸之保護基，x表示溴基、氯基或碘基等 画素原子，A、Ql、Q2、Q3、Rl、r2、r3、RW表：與 通式（I)相同者。）(wherein p2 represents a protecting group of a carboxylic acid, x represents a pixel atom such as a bromo group, a chloro group or an iodo group, and A, Ql, Q2, Q3, R1, r2, r3, RW are the same as the formula (I) By.)

羧馱（15)可藉由自_代物與丙二酸衍生物製造二酯 (14)(P為羧酸之保護基），繼而轉化為去除酯保護基之二 羧酸後，進行脫羧反應而製造。本發明之化合物（Ib)係: 由如下方式而製造：將胺（16)與羧酸（15)縮合而製造醯胺 (17)，將醯胺（17)之确基還原而製造胺（18)，再將胺叫盘 羧酸（9)縮合。 〃 一 S曰（14)(P為羧酸之保護基）例如可藉由於甲醇等溶劑 中’將於甲醇鈉等驗之存在下所生成的丙二酸醋之碳陰離 子，於-20°C〜80°CT與鹵代物（3)進行處理而製造。作為用 於本步驟中之驗’例如可列舉：碳酸鈉、碳酸鉀、乙醇 納、丁醇卸、氫氧化納、氫氧化鉀、氫化#、氫化鉀等驗 金屬或驗土金屬之碳酸鹽、鹼金屬醇氧化物、驗金屬氫氧 化物或驗金屬氫化物；正丁基鐘等燒基鐘、二異丙基醯胺 鐘等二烧基胺之有機金屬驗；如雙（三甲基㈣基）酿胺鐘 之雙(三烧基石夕烧基)胺的有機金屬㉟；或如二氮雜雙環 [5.4.0]十—7·烯（麵)之有機鹼等。作為用於本反應中之 溶劑’可列舉：甲醇、乙醇等醇系溶劑；四氫吱喘 129677.doc -35- 200840568 (THF)、1，2-二甲氧基乙院、二$烧等鱗系溶劑；苯、甲苯 等芳香族烴系溶劑；N，N•二甲基甲醯胺（dmf)、n，N-二甲 基乙醯胺(DMA)、N-甲基吡咯啶_2_酮等醯胺系溶劑，可使 用二甲基亞颯_S0)、環丁钱等亞颯系溶劑或者丙_、 甲基乙基酮等酮系溶劑等。 作為由P2為Μ之保護基的各種二s旨（14)製造p2為氯原 子之中間體的一羧酸之方法，可列舉下述（丨）〜（3)。 (j)二酯（14)(P2為羧酸之保護基）為甲g旨或乙g旨時，使用氫 氧化鐘、氫氧仙、絲化料氫氧㈣金屬等進行水解 反應。 (2)二酯（14)(P2為羧酸之保護基）為第三丁酯時，與三氟乙 酸（TFA)或鹽酸實施處理之酸處理反應。 (3)二酯（14)(P2為羧酸之保護基）為苄基等芳基甲基型酯 時，進行使用鈀碳觸媒之催化還原反應。 上述中間體之二羧酸例如可藉由於二氯甲烷等溶劑中，The carboxy oxime (15) can be subjected to a decarboxylation reaction by producing a diester (14) from a derivative and a malonic acid derivative (P is a protecting group of a carboxylic acid), followed by conversion to a dicarboxylic acid having an ester protecting group removed. Manufacturing. The compound (Ib) of the present invention is produced by condensing an amine (16) with a carboxylic acid (15) to produce a guanamine (17), and reducing the exact group of the guanamine (17) to produce an amine (18). ), the amine is condensed as a disk carboxylic acid (9). 〃 a S曰(14) (P is a protecting group for a carboxylic acid), for example, by a carbon anion of malonic acid vinegar which is formed in a solvent such as methanol in the presence of sodium methoxide or the like, at -20 ° C Manufactured by treatment with ~80°CT and halogenated material (3). As the test used in this step, for example, sodium carbonate, potassium carbonate, sodium ethoxide, butanol unloading, sodium hydroxide, potassium hydroxide, hydrogenation #, potassium hydride, or the like, or a carbonate of a soil test metal, An alkali metal alcohol oxide, a metal hydroxide or a metal hydride; an organometallic test of a dialkylamine such as a butyl clock or a diisopropyl guanamine clock; such as bis(trimethyl) An organometallic group of a amine of a bis (trivalent ruthenium) amine; or an organic base such as a diazabicyclo[5.4.0]deca-7ene (face). Examples of the solvent used in the present reaction include alcoholic solvents such as methanol and ethanol; tetrahydropyrene 129677.doc-35-200840568 (THF), 1,2-dimethoxyethane, and two calories. Squama solvent; aromatic hydrocarbon solvent such as benzene or toluene; N,N•dimethylformamide (dmf), n,N-dimethylacetamide (DMA), N-methylpyrrolidine_2 As the amide-based solvent such as ketone, a fluorene solvent such as dimethyl hydrazine _S0) or cyclobutyl ketone or a ketone solvent such as propyl or methyl ethyl ketone can be used. As a method of producing a monocarboxylic acid in which p2 is an intermediate of a chlorine atom, the following two (s) to (3) are used as a method for producing a carboxylic acid intermediate of p2. (j) When the diester (14) (P2 is a protective group of a carboxylic acid) is a g or a g, the hydrolysis reaction is carried out using a hydrogen oxidation clock, a oxyhydroquine, a silk chemical, a hydrogen (IV) metal or the like. (2) When the diester (14) (P2 is a protecting group of a carboxylic acid) is a third butyl ester, it is subjected to an acid treatment reaction with trifluoroacetic acid (TFA) or hydrochloric acid. (3) When the diester (14) (P2 is a protecting group of a carboxylic acid) is an arylmethyl type ester such as a benzyl group, a catalytic reduction reaction using a palladium carbon catalyst is carried out. The dicarboxylic acid of the above intermediate may be, for example, a solvent such as dichloromethane.

於-20°C〜80°C下，將作為第三丁酯之二酯（14)與三氟乙酸 (TFA)進行處理而製造中間體。 作為以脫羧反應而由二羧酸製造羧酸（15)之方法，可列 舉··例如於乙腈等溶劑中，於氧化銅等觸媒存在下，於 40°C〜120°C下將二羧酸加熱之方法；於吡啶中，於8〇c>c 〜130 °C下將二羧酸加熱之方法；於N，N•二甲基甲醯胺 (DMF)專溶劑中，將聚（4_乙稀基吼咬）作為觸媒而將二幾 酉文加熱之方法，將· 一魏酸加熱至15 0 °C〜2 0 0。〇之方法等。 醢胺體（17)可藉由將敌酸（15)活化，與胺（16)縮合而製 129677.doc •36- 200840568 造。 作為將羧酸(15)活化之方法’可列舉：混合酸酐、醯 齒、及活性醋等。作為製造羧酸(6)之混合酸針的方法，例 如可於鹼存在下，將羧酸（15)與氯甲酸乙醋、氯曱酸異丁 酯等氯甲酸酯類進行處理而製造。 醯鹵可藉由以亞硫醯氯、草醯氯等醯鹵對羧酸（15)進行 處理而製造。 作為羧酸（15)之活性酯，例如可藉由如下方式而製造： 使用N，N’-二環己基碳二亞胺（DCC)4丨_乙基_3_(3•二甲基 胺基丙基）碳二亞胺鹽酸鹽（EDC)等縮合劑，使羧酸（15)與 對硝基酚等酚類、1-羥基苯并***（H〇Bt)、•羥基琥珀 醯亞胺等反應。又，活性酯可藉由羧酸（15)與三氟乙酸五 氟苯酯等之反應、羧酸（6)與六氟磷酸苯并***基氧基三 0比洛烧基填之反應、紱酸（1 5 )與氰基膦酸二乙酯之反應（鹽 溶法）、叛酸（15)與三苯基膦及2,2，·二硫代聯吡啶之反應 (向山法，mukaiyama method)等而製造。 醯胺體（17)可藉由於適當之鹼存在下，於惰性溶劑中， 於-78°C〜150°C下，使上述羧酸（15)之混合酸酐、醯鹵或活 性酯與胺（16)反應而製造。作為用於本步驟中之驗，例如 可列舉：碳酸鈉、碳酸鉀、乙氧化納、丁氧化奸、氫氧化 鈉、氫氧化鉀、氫化鈉、氫化鉀等鹼金屬或鹼土金屬之碳 酸鹽、鹼金屬烷氧化物、鹼金屬氫氧化物或鹼金屬氫化 物，正丁基鋰等烷基鋰、二異丙基醯胺鋰等丄烷基胺之有 機金屬鹼；雙（三甲基矽烷基）醯胺鋰等雙（三烷基矽烷基） 129677.doc -37- 200840568 胺之有機金屬鹼，或吡啶、2,6-二甲基吡啶、三甲基吡 啶、4-(Ν，Ν·二甲基胺基）吡啶（DMAP)、三乙胺（TEA)、N-甲基嗎啉、二異丙基乙胺、二氮雜雙環[5.4.0]十一 ·7-烯 (DBU)等有機驗等。作為用於本反應中之惰性溶劑，可列 舉：二氯曱烷、氣仿、四氣化碳等鹵化烴系溶劑，四氫呋 喃（THF)、I，2-二曱氧基乙烷、二嘮烷等醚系溶劑；苯、甲 苯等芳香族烴系溶劑，Ν,Ν-二甲基甲醯胺（DMF)、N，N-二 曱基乙醯胺（DMA)、N-曱基吡咯啶-2-酮等醯胺系溶劑，亦 可使用二甲基亞砜（DMSO)、環丁砜等亞颯或磺醯基系溶 劑，丙酮、曱基乙基酮等酮系溶劑等。 R3為氫原子之化合物（18)可藉由將醯胺體（17)的硝基還 原而製造。例如，向含水N，N_二甲基甲醯胺（DMF)中添加 氯化鐵（3)及鋅粉末等金屬，於其中於25〇c〜1〇〇c>c下對醯 胺（17)進行處理，由此可製造化合物（18)(R3為氫原子）。作 為忒硝基之還原反應方法，可列舉：使用雷氏鎳、鉑、鈀 碳、釕錯合物等金屬觸媒之催化還原方法；於鈀碳等金屬 觸媒存在下以甲酸銨或肼等進行還原之方法；於酸性條件 下兵鋅或錫等金屬進行處理之方法；》巾性或驗性條件下 與鋅末等金屬進行處理之方㈣。本還原反應中，q3基為 包含®基之芳環基時，較好的是選擇該i基並不脫離之反 應條件。 R3為CK6院基之化合物（18)可藉由將上述尺3為氣原子 的化合物⑻進行㈣而製造，作為_級胺之烧化反應的表 考文獻，可列舉：實驗化學講座（第四版，趾20.日本化 129677.doc -38- 200840568 學會編，丸善股份有限公司）「有機合成π ••醇·胺，第 284〜288頁及第300〜302頁」等。 本發明之化合物（lb)可藉由將上述中所獲得之化合物 (18)與羧酸（9)的混合酸酐、醯鹵或活性酯反應而製造。化 合物（18)與羧酸（9)之反應之試劑及反應條件可適用上述羧 酸（15)與胺（16)的反應。 由此所製造之本發明化合物（〗b)可藉由公知方法，例如 萃取、沈澱、分級層析、分段結晶化、再結晶等而進行單 離、精製。又，本發明化合物的鹽可藉由通常的成鹽反應 而形成所需之鹽。 [製造方法2] 又’以下述通式（lb) [化8]An intermediate is produced by treating a diester (14) as a third butyl ester and trifluoroacetic acid (TFA) at -20 ° C to 80 ° C. The method of producing a carboxylic acid (15) from a dicarboxylic acid by a decarboxylation reaction may, for example, be a dicarboxylic acid in a solvent such as acetonitrile in the presence of a catalyst such as copper oxide at 40 ° C to 120 ° C. a method of heating an acid; heating a dicarboxylic acid in pyridine at 8 ° C > c ～130 ° C; in a special solvent of N,N•dimethylformamide (DMF), poly(4) _Ethyl-based bite) As a catalyst, the method of heating two liters is heated to a temperature of 150 ° C ~ 2 0 0. The method of squatting, etc. The guanamine body (17) can be made by activating the acid (15) and condensing with the amine (16) to make 129677.doc •36-200840568. The method of activating the carboxylic acid (15) is exemplified by a mixed acid anhydride, a tooth, and an active vinegar. The method for producing a mixed acid needle of the carboxylic acid (6) can be produced, for example, by treating a carboxylic acid (15) with a chloroformate such as ethyl chloroformate or isobutyl chloroantimonate in the presence of a base. The hydrazine halide can be produced by treating the carboxylic acid (15) with a hydrazine halide such as sulfinium chloride or hydrazine chloride. As the active ester of the carboxylic acid (15), for example, it can be produced by using N,N'-dicyclohexylcarbodiimide (DCC) 4丨_ethyl_3_(3•dimethylamino group) a condensing agent such as propyl) carbodiimide hydrochloride (EDC), such as carboxylic acid (15) and phenol such as p-nitrophenol, 1-hydroxybenzotriazole (H〇Bt), • hydroxy amber Amine reaction. Further, the active ester can be reacted by a reaction of a carboxylic acid (15) with pentafluorophenyl trifluoroacetate or the like, a carboxylic acid (6) and a benzotriazolyl hexafluorophosphate ternary alkyl group. Reaction of citric acid (15) with diethyl cyanophosphonate (salt solution method), reaction of oxalic acid (15) with triphenylphosphine and 2,2,·dithiobipyridine (to Yamaha, mukaiyama Method) and so on. The guanamine body (17) can be a mixed acid anhydride, a hydrazine halide or an active ester with an amine of the above carboxylic acid (15) in an inert solvent in the presence of a suitable base at -78 ° C to 150 ° C ( 16) Manufactured by reaction. As the test used in this step, for example, sodium carbonate, potassium carbonate, sodium ethoxide, oxidized rape, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride or the like, or an alkali earth metal carbonate, An alkali metal alkoxide, an alkali metal hydroxide or an alkali metal hydride, an alkyl metal such as n-butyllithium or an organometallic base of a mercaptoalkylamine such as lithium diisopropylguanamine; bis(trimethyldecylalkyl) Bis(trialkyldecyl) such as lithium guanamine 129677.doc -37- 200840568 Alkyl metal base, or pyridine, 2,6-lutidine, trimethylpyridine, 4-(Ν,Ν· Dimethylamino)pyridine (DMAP), triethylamine (TEA), N-methylmorpholine, diisopropylethylamine, diazabicyclo[5.4.0]undec-7-ene (DBU) Wait for an organic test. Examples of the inert solvent used in the reaction include halogenated hydrocarbon solvents such as dichloromethane, gas, and carbon tetrachloride, tetrahydrofuran (THF), 1,2-dimethoxyethane, and dioxane. Ether-based solvent; aromatic hydrocarbon solvent such as benzene or toluene, hydrazine, hydrazine-dimethylformamide (DMF), N,N-dimercaptoacetamide (DMA), N-decylpyrrolidin- A solvent such as a 2-ketone or a guanamine-based solvent may be a sulfonium-based solvent such as dimethyl sulfoxide (DMSO) or sulfolane or a ketone solvent such as acetone or mercaptoethyl ketone. The compound (18) wherein R3 is a hydrogen atom can be produced by reducing the nitro group of the guanamine body (17). For example, a metal such as iron chloride (3) and zinc powder is added to the aqueous N,N-dimethylformamide (DMF), and the indoleamine is at 25 〇c~1〇〇c>c. The treatment is carried out, whereby the compound (18) (R3 is a hydrogen atom) can be produced. Examples of the reduction reaction method of the ruthenium nitro group include a catalytic reduction method using a metal catalyst such as Raney nickel, platinum, palladium carbon or ruthenium complex; and ammonium formate or ruthenium in the presence of a metal catalyst such as palladium carbon. A method of performing reduction; a method of treating a metal such as zinc or tin under acidic conditions; and a method of treating a metal such as zinc powder under a condition of a towel or an inspection (4). In the present reduction reaction, when the q3 group is an aromatic ring group containing a yl group, it is preferred to select a reaction condition in which the i group is not detached. The compound (18) wherein R3 is a CK6-based compound can be produced by subjecting the above-mentioned compound (8) having a gas atom of 3 to (4), and as a test article for the burning reaction of the _-class amine, a lecture on experimental chemistry (fourth edition) , Toe 20. Japaneseization 129677.doc -38- 200840568 The Society, Maruzen Co., Ltd.) "Organic Synthesis of π••Alcohol Amine, pp. 284-288 and pages 300-302". The compound (lb) of the present invention can be produced by reacting the compound (18) obtained above with a mixed acid anhydride of a carboxylic acid (9), a hydrazine halide or an active ester. The reagent for reacting the compound (18) with the carboxylic acid (9) and the reaction conditions can be applied to the reaction of the above carboxylic acid (15) with the amine (16). The compound (?b) of the present invention thus produced can be isolated and purified by a known method such as extraction, precipitation, fractional chromatography, fractional crystallization, recrystallization, or the like. Further, the salt of the compound of the present invention can form a desired salt by a usual salt-forming reaction. [Manufacturing method 2] Further, the following general formula (lb) [Chemical 8]

(lb) 或該等之溶劑合物 你J如亦可藉 所表示之化合物、其鹽、 由下述方法而製造。 [化9](lb) or the solvates of these, if J can also be produced by the following compounds, their salts, by the following methods. [Chemistry 9]

129677.doc -39- 200840568129677.doc -39- 200840568

1) (EtO^OCR^COO^Bu 2) CF3COOH1) (EtO^OCR^COO^Bu 2) CF3COOH

(式中，A、Q1、Q2、Q3、Ri、R2、Rs、以及以表示與通式 (I)相同者。） 化合物（19)可藉由將化合物（2)與例如n，N-二甲基甲酸胺 二烧基縮醛等縮合而形成雙鍵後，使用過硤酸鈉等進行 石反-¾雙鍵之裂解反應而製造。本發明之化合物（Ib)可藉由 如下方式而製造：於鹼存在下，將化合物（19)與二乙基膦 酸基乙酸第三丁酯實施處理，接著去除第三丁基而製造羧 酸（20)，將羧酸（2〇)與胺（16)縮合而製造醯胺（21)，將醯胺 (21)之硝基及雙鍵同時還原而製造胺（18〇，再應用[製造 法1]，將該胺（18a)與羧酸（9)縮合。 化合物（19)可藉由如下方式而製造：例如於N，N-二甲基 曱豔胺（DMF)等溶劑中，實施於6〇。〇〜16〇乞下與二曱 基甲醯胺二甲縮駿進行加熱處理的雙鍵之形成反應後，於 含水四氫㈣（咖）等溶劑中，實施於_1(^〜5代下與過 i鈉進订處理之碳_碳雙鍵的裂解反應。作為用於雙鍵 之形成反應中的溶亦,|，# ^車乂好的是苯、甲苯等芳香族烴系溶 129677.doc 200840568 劑’ N，N-二甲基甲醯胺（DmF)、N，N-二甲基乙醯胺 (DMA)、N_甲基吡咯咬_2·酮等醯胺系溶劑。作為雙鍵之形 成反應’除了使用N，N_二曱基甲醯胺二曱縮醛之反應以 外’可列舉：於乙酸溶劑中使用福馬林-吡咯啶之方法； 或於氫氧化鉀等鹼存在下，使其與^^三噚烷或福馬林 反應後’實施將所獲得之曱醇中間體與甲基磺醯氯等試劑 進行處理之脫水反應而階段性地形成雙鍵之方法。又，作 為碳-碳雙鍵之裂解反應，可列舉··使用氯化釕（3)等觸媒 之方法；臭氧氧化之方法；及使用高錳酸鉀之方法等。 竣自欠（20)可藉由如下方式而製造：例如於四氫吱口南 (丁明等 >谷劑中，於氫化鈉等存在下，於·2〇(^下將 化合物（19)與二乙基膦酸基乙酸第三丁酯進行處理後，將 所獲得之(χ，β不飽和酯體於二氣曱烷等溶劑中，於〇它〜的 C下與二氟乙酸（TFA)進行處理。亦可使用乙酯等烷基酯 或节基S日來代替二乙基膦酸基乙酸第三丁 _，該情形時， 以氫氧化M m鈉、氫氧化㈣驗金屬氫氧化物等之 適當鹼實施水解，可製造羧酸（20)。 酿胺（21)可應用[製造方法1]所記載之方法，由胺（16)與 魏酸(2G)之混合酸酐、酸鹵或活性而製造。 、 R3為氫原子之胺（18a)可藉由例如於二料等溶劑中，使 用10%纪碳觸媒對醯胺⑵）實施常壓的催化還原而製造。 該催化還原反應中，亦可、阳搜α_ 丌了廷擇性地僅將硝基及雙鍵中之一 者還原，較好的是可同技Μ交 m N日守將兩者逛原之使用鈀碳、釕铒人 物等金屬觸媒的催化還屌古i 丄w 曰σ 延原方法。本發明之化合物（lb)可應 129677.doc •41 - 200840568 用[製造方法1]中所記載之由胺（18)與羧酸（9)製造化合物 (lb)的方法，而由胺（18a)與羧酸（9)製造。 由此所製造之本發明化合物（lb)可藉由公知方法例如萃 取、沈澱、分級層析、分段結晶化、再結晶等而進行單 離、精製。又，本發明化合物的鹽可藉由通常的成鹽反應 而形成所需之鹽。 [製造方法3] 通式⑴之T1係-C(=0)_N(R3)_基、Τ2係基_CH=CH C卜 〇)ΝΗ·之下述通式（Ic) [化 10](wherein, A, Q1, Q2, Q3, Ri, R2, Rs, and the same as those of the formula (I).) The compound (19) can be obtained by, for example, n, N-di The methyl carbamic acid dialkyl acetal or the like is condensed to form a double bond, and then produced by a cleavage reaction of a fluorenyl-tertiary double bond using sodium perrhenate or the like. The compound (Ib) of the present invention can be produced by subjecting the compound (19) to tributyl butyl phosphonate acetate in the presence of a base, followed by removing the third butyl to produce a carboxylic acid. (20) condensing a carboxylic acid (2〇) with an amine (16) to produce a guanamine (21), and simultaneously reducing a nitro group and a double bond of the guanamine (21) to produce an amine (18 〇, and then applying [manufacturing Method 1], the amine (18a) is condensed with a carboxylic acid (9). The compound (19) can be produced by, for example, a solvent such as N,N-dimethyl decylamine (DMF). After 6 〇.16~16〇乞 under the formation of a double bond with dimethyl carbazide dimethyl hydrazine, the reaction is carried out in a solvent such as aqueous tetrahydro (tetra) (caffe), in _1 (^ The cleavage reaction of the carbon-carbon double bond with the sodium treatment is carried out in the ~5th generation. As a solution for the formation reaction of the double bond, |, #^ 乂 is an aromatic hydrocarbon such as benzene or toluene. System 129677.doc 200840568 agent 'N,N-dimethylformamide (DmF), N,N-dimethylacetamide (DMA), N-methylpyrrole bite _2 ketone and other amides Solvent as a double bond In addition to the reaction of using N,N-dimercaptocaramine diacetal, a method of using a formalin-pyrrolidine in an acetic acid solvent may be mentioned; or in the presence of a base such as potassium hydroxide, After reacting with trioxane or formalin, a method of performing a dehydration reaction of a reagent obtained by treating a obtained sterol intermediate with methylsulfonium chloride to form a double bond in stages is performed. Further, as a carbon-carbon The cleavage reaction of the double bond may be exemplified by a method using a catalyst such as ruthenium chloride (3), a method of ozone oxidation, a method using potassium permanganate, etc. The enthalpy (20) can be obtained as follows Manufacture: For example, in the presence of sodium hydride, in the presence of sodium hydride, in the presence of sodium hydride (Ding Ming et al.), the compound (19) and the third butyl phosphonate acetate After the treatment, the obtained (χ, β unsaturated ester is treated with a difluoroacetic acid (TFA) in a solvent such as dioxane or a solvent such as dioxane. The ester or the radical S is replaced by the third methyl phosphinate, and in this case, the sodium oxyhydroxide, the hydrogen hydride (four) A carboxylic acid (20) can be produced by subjecting a suitable base such as a metal hydroxide to hydrolysis. The amine (21) can be a mixed acid anhydride of an amine (16) and a ferulic acid (2G) by the method described in [Production Method 1]. The amine (18a) in which R3 is a hydrogen atom can be produced by subjecting the guanamine (2) to a catalytic reduction at normal pressure using a 10% carbon catalyst, for example, in a solvent such as a second material. In the catalytic reduction reaction, it is also possible to restore only one of the nitro group and the double bond in a positive manner, and it is preferable to use the same technology to pay the mN day to keep the two. The catalysis of metal catalysts such as palladium carbon and ruthenium is also used to delay the original method. The compound (lb) of the present invention can be produced by the method for producing the compound (lb) from the amine (18) and the carboxylic acid (9) as described in [Production Method 1], and the amine (18a), which is 129677.doc •41 - 200840568. ) Manufactured with carboxylic acid (9). The compound (lb) of the present invention thus produced can be isolated and purified by a known method such as extraction, precipitation, fractional chromatography, fractional crystallization, recrystallization or the like. Further, the salt of the compound of the present invention can form a desired salt by a usual salt-forming reaction. [Production Method 3] The following general formula (Ic) of the formula (1), T1, -C(=0)_N(R3)_, Τ2, _CH=CH C, 〇)

(1C)(1C)

所表示之化合物、其鹽 述方法製造。 或該等的溶劑合物 ’例如可以下 [化 11]The compound represented by the method described above was produced. Or such solvates' can be, for example,

129677.doc -42· 200840568 (式中A Q Q、（^、^、^及^表示與通式⑴相同 者。) 本發明之化合物(Ic)可藉由如下方式而製造：將以[製造 方法2]之方法所製造的醯胺（21)的硝基選擇性地還原而製 造胺（22)，再將胺（22)與羧酸（9)縮合。129677.doc -42· 200840568 (wherein AQQ, (^, ^, ^ and ^ represent the same as in the formula (1).) The compound (Ic) of the present invention can be produced by the following method: The nitro group of the guanamine (21) produced by the method is selectively reduced to produce an amine (22), and the amine (22) is condensed with the carboxylic acid (9).

胺（22)可藉由例如於含水N，N_二甲基甲醯胺（DMF)等溶 劑中，於：代〜崎下將醯胺⑼與氯化鐵⑺及辞粉末進 打處理而製造。本反應中須要選擇不會使雙鍵還原之條 件·，較好的是於巾性錢性條件下與鋅末進行處理之方 法；或者於酸性條件下與鋅、鉄粉或錫進行處理之方法 等0 本發明之化合物（Ic)可藉由 件，由胺（22)與羧酸（9)之混 造0 應用[製造方法1]所記載的條 合酸酐、醯鹵或活性酯而製The amine (22) can be produced by, for example, treating a guanamine (9) with iron chloride (7) and a powder in a solvent such as aqueous N,N-dimethylformamide (DMF). . In the reaction, it is necessary to select a condition which does not reduce the double bond, preferably a method of treating with zinc dust under the condition of the tobacco; or a method of treating with zinc, strontium powder or tin under acidic conditions. The compound (Ic) of the present invention can be produced by mixing a mixture of an amine (22) and a carboxylic acid (9) with a strip anhydride, a hydrazine halide or an active ester as described in [Production Method 1].

由此所製造之本發明化合物⑽可藉由公知方法例如萃 取、沈澱、分級層析、分段結晶化、再結晶等而進行單 離：精製。又，本發明化合物的鹽可藉由通常的成鹽反應 而形成所需之鹽。 [製造方法4] 飞2 / T 係-CH2-〇-c(=0)NH- 通式（I)之 T1 係-C(=〇)-N(R3)-基 基之下述通式（Id) [化 12] 129677.doc -43- I!200840568 R* R] Q—Q乙 C—N R3 所表示之化合物、其鹽、或該等之 述方法製造。 [化 13] s一0 (Id) 溶劑合物，例如可以下 R' ；RR^ r〇H (23) - 1)The compound (10) of the present invention thus produced can be isolated: purified by a known method such as extraction, precipitation, fractional chromatography, fractional crystallization, recrystallization or the like. Further, the salt of the compound of the present invention can form a desired salt by a usual salt-forming reaction. [Production Method 4] Fly 2 / T system - CH 2 - 〇 - c (=0) NH - The following formula of the T 1 -C(=〇)-N(R3)- group of the formula (I) Id) 129677.doc -43- I!200840568 R* R] Q-Q B C-N R3 The compound represented by the compound, its salt, or the method described above. [Chem. 13] s-0 (Id) solvate, for example, can be R'; RR^r〇H (23) - 1)

2) Q (16) 2 〇2N 、g-〇-卜ITQ3 (24) 2 Q-Q—COOH (9) R* »^ 〇L〇2 贫 π li Q^q-c-n c-o-c~n^q^ l· 2 H (Id) c-oXn-q^ (25) r2及R3係與通式（I)相同 (式中 ’ A、Q1、Q2、Q3、r1 者。) 本發明之化合物（Id)可藉由如下方式而製造：將醇（23) 與碳酸N，N，.二破㈣亞胺等縮合劑進行處理後，與胺⑽ 進行處理而製造化合物（24)，接著將硝基還原而製造胺 (25) ’再將胺（25)與羧酸（9)縮合。 化合物（24)可藉由如下方式而製造：例如於乙腈等溶劑 中^三乙胺（TEA)等驗存在下，使用碳酸n，n，•二號拍酿 亞胺作為縮合劑’於代〜⑽下對醇⑼進行處理後’於 二亂甲貌等溶劑中’於三乙胺（tea)等驗存在下，於^ 129677.doc -44- 200840568 〜5〇°C下使其與胺（16)反應。作為可 劑’除了碳酸N，N，-二琥珀醯亞胺以 吐、碳酸二吼啶-2-基等。作為用於 (16)之反應中的溶劑，可列舉··二*2) Q (16) 2 〇2N, g-〇-卜ITQ3 (24) 2 QQ—COOH (9) R* »^ 〇L〇2 π ρ li Q^qcn coc~n^q^ l· 2 H (Id) c-oXn-q^ (25) The r2 and R3 are the same as the formula (I) (wherein A, Q1, Q2, Q3, r1.) The compound (Id) of the present invention can be used as follows Manufactured by treating a condensing agent such as an alcohol (23) with N, N, di-di(tetra)imine or the like, followed by treatment with an amine (10) to produce a compound (24), followed by reduction of the nitro group to produce an amine (25) 'The amine (25) is then condensed with the carboxylic acid (9). The compound (24) can be produced by, for example, using a solvent such as triethylamine (TEA) in a solvent such as acetonitrile, and using n, n, and 2 carbonic acid as a condensing agent. (10) After treating the alcohol (9), it is treated with an amine in a solvent such as triethylamine (tea) in the presence of triethylamine (tea), etc., at ^129677.doc -44-200840568~5〇°C. 16) Reaction. As the agent 'except for N,N,-disuccinimide carbonate, spit, diazetidine-2-yl or the like. As the solvent used in the reaction of (16), for example,

曱基甲醯胺（DMF)、N，N-二 °作為可用於本反應中之縮合 亞胺以外，可列舉羰基二咪 作為用於上述縮合反應及與胺 氯曱烷、二氯乙烷、氯 咬喃（THF)、ι，2-二曱氧基乙烷、 甲笨等芳香族烴系溶劑，N，N-二 一甲基乙醯胺（DMA)、N-曱基吡 咯啶-2-酮等醯胺系溶劑及乙腈等。 本發明之化合物（Id)可藉由如下方式而製造：與[製造方 法1]中所記載之由化合物⑺製造胺(8)，再由該胺⑻與羧 酸(9)製造化合物(Ia)的方法相同，由化合物(24)製造胺體 (25)，再將胺體（25)與羧酸（9)進行縮合反應。 由此所製造之本發明化合物（Id)可藉由公知方法例如萃 取、沈澱、分級層析、分段結晶化、再結晶等而進行單 離、精製。又，本發明化合物的鹽可藉由通常的成鹽反應 而形成所需之鹽。 [製造方法5] 通式（I)之 T1 係-C(=〇)-N(R3)-基、τ2係-CH2-NHC(=0)NH-基之下述通式（Ie) [化 14] τν2Further, mercaptocarbamide (DMF), N, N-di, as the condensed imine which can be used in the present reaction, may be exemplified by carbonyl dimer as the above condensation reaction and with an amine chlorodecane or dichloroethane. Aromatic hydrocarbon solvent such as chlorinated (THF), ι,2-dimethoxy ethane, methyl bromide, N,N-dimethylethyl decylamine (DMA), N-decylpyrrolidin-2 - a guanamine-based solvent such as a ketone or acetonitrile. The compound (Id) of the present invention can be produced by producing the amine (8) from the compound (7) and the compound (Ia) from the amine (8) and the carboxylic acid (9) as described in [Production Method 1]. The method is the same, the amine (25) is produced from the compound (24), and the amine (25) is further subjected to a condensation reaction with the carboxylic acid (9). The compound (Id) of the present invention thus produced can be isolated and purified by a known method such as extraction, precipitation, fractional chromatography, fractional crystallization, recrystallization or the like. Further, the salt of the compound of the present invention can form a desired salt by a usual salt-forming reaction. [Production Method 5] The following formula (Ie) of the formula (I), T1, -C(=〇)-N(R3)- group, τ2--CH2-NHC(=0)NH- group; 14] τν2

129677.doc •45· 200840568 或該等之溶劑合物 例如可以下 所表示之化合物、其鹽 述方法製造。 [化 15]129677.doc •45· 200840568 or such solvates can be produced, for example, by the compounds shown below and by the methods thereof. [化15]

(式中’ X表示溴基、氯基或埃基等自素原子，A、Qi、 Q、Q3、R1、R2及R3表示與通式⑴相同者。）(wherein 'X' represents a self-priming atom such as a bromo group, a chloro group or an yl group, and A, Qi, Q, Q3, R1, R2 and R3 represent the same as those of the formula (1).

本發明之化合物(Ie)可藉由如下方式而製造：由函化物 (3)製造胺（5)，使該胺（5)與異氰酸酯（26)反應後，將所獲 得之化合物（27)的硝基還原後，使胺（28)與羧酸（9)反應。 胺（5)可藉由例如向溴體（3)之曱醇溶液中添加過量的濃 氨-曱醇溶液，於室溫下使其反應而製造。作為反應溶 劑，可列舉：甲醇、乙醇等醇系溶劑，四氫呋喃（THF)、 1，2-二甲氧基乙烷、二噚烷等醚系溶劑，N，N-二甲基甲醯 胺（DMF)、N，N-二甲基乙醯胺（DMA)、N-甲基吼哈咬酮 129677.doc -46 - 200840568 等醯胺系溶劑，及水…胺(5)亦可藉由如下方式而製 造：例如向N，N-二曱基曱醯胺_F)中添加疊氣化納等疊 氮化烷基金屬鹽，於其中使溴體（3)於2〇。〇〜1〇〇。〇下反應 後將所獲付之豐氮化物與三苯基膦等有機填化合物進行 處理。The compound (Ie) of the present invention can be produced by producing an amine (5) from the compound (3) and reacting the amine (5) with an isocyanate (26) to obtain the compound (27). After the reduction of the nitro group, the amine (28) is reacted with the carboxylic acid (9). The amine (5) can be produced, for example, by adding an excess of a concentrated ammonia-sterol solution to a decyl alcohol solution of the bromine (3) and reacting it at room temperature. The reaction solvent may, for example, be an alcohol solvent such as methanol or ethanol, an ether solvent such as tetrahydrofuran (THF) or 1,2-dimethoxyethane or dioxane, or N,N-dimethylformamide ( DMF), N,N-dimethylacetamide (DMA), N-methylhaha ketone 129677.doc -46 - 200840568 and the like amide solvent, and water ... amine (5) can also be as follows Manufactured by: adding, for example, N,N-dimercaptodecylamine _F) to a sodium azide alkyl alkoxide, in which a bromine (3) is 2 Å. 〇~1〇〇. After the reaction is carried out, the obtained abundance is treated with an organic filler compound such as triphenylphosphine.

化合物（27)可藉由如下方式而製造：將胺⑺溶解於N，N ^甲基甲醯胺（DMF)、四氫呋喃（THF)、二哼烷、乙腈、Compound (27) can be produced by dissolving amine (7) in N,N^methylformamide (DMF), tetrahydrofuran (THF), dioxane, acetonitrile,

氯仿等溶劑中，％加必要量之異氰酸醋（26)，於冷卻下, 室溫下攪拌1小時〜24小時。 u R為虱原子之胺（28)可藉由將化合物（27)之硝基還原而 製k。例如，可藉由向含水队沐二甲基甲醯胺（dmf)中添 加氯化鐵（3)及辞粉末等金屬，於25。(：〜10CTC對化合物（27) 進仃處理而製造胺（28)(R3為氫原子）。作為該硝基之還原 μ方法可列舉·使用雷氏鎳、鉑、把碳、釕錯合物等 金屬觸媒之催化還原方法；於把碳等金屬觸媒存在下以甲 -文銨或肼等進行還原之方法；於酸性條件下與鋅或錫等金 屬進行處理之方法；於中性或驗性條件下與鋅末等金屬進 仃$理之方法等。本還原反應中，Q3基係包含鹵基之芳環 基較好的是選擇該_基並不脫離之反應條件。 ㈣之燒化而製造’作為—級胺之烧化反應的參考文獻， :列舉實驗化學講座（第四版，VgL 2G.日本化學會編，丸 。又伤有限公司）「有機合成Η :醇·胺第284〜288頁及第 300〜302頁」等。 R為（：1〜C6燒基之胺（28)可藉由上述R3為氫原子的胺 129677.doc •47- 200840568 本發明之化合物（le)可藉由將上述所獲得之胺（28)與魏 酸（9)之混合酸酐、酸鹵或活性酯反應而製造。胺（28)與魏 酸（9)之反應之試劑及反應條件亦可應用上述[製造方法13 所記载之反應。 由此所製造之本發明化合物（le)可藉由公知方法例如萃 取’尤炎、分級層析、分段結晶化、再結晶等而進行單 離、精製。又，本發明化合物的鹽可藉由通常的成鹽反應 而形成所需之鹽。 • 又，本發明化合物⑴或製造之中間體具有不對稱碳時， 存在光學異構物。該等光學異構物可利用與恰當之鹽進行 再釔曰曰的分段再結晶（鹽分割）或管柱層析法等常法，而將 各個異構物單離、精製。作為由消旋物分割光學異構物之 方法的參考文獻，可列舉：L㈣⑽等人之「Enanti〇mers， Racemates and Resolution. John Wiley And Sons, Inc. , 〇 本發明之二醯胺衍生物由於顯示出強力的活化凝血因子 •(殺之抑制作用’故而可用作用於包含人在内的哺乳類 $醫藥’尤其可用作FXa抑制劑、凝血抑制劑、血栓或检 :之預防及/或治療劑、血栓性疾病之預防及，或治療藥， —而可作用梗塞、腦栓塞、心肌梗塞、心絞痛、肺栓 基伯格式症、深部靜脈企栓症、全身性企管内凝血綜合 二人項膜/關節置換後之4栓形成、m建後之金 拴::及再閉塞、多器官功能障礙綜合症(MODS)、體外 : 的血权形成或採血時的血液凝固之預防及/或治療 129677.doc -48- 200840568 有通式（i)所表示之本發明化合物的醫藥組合物可根據 投予法而選擇適當之製劑，冑由通常所❹的各種製劑之 製備法進行製備。 將:乂通式(I)所表示之本發明化合物為主劑的醫藥組合物 °甫礼動物（尤其是人）投予時，可全身地或局部地經口或 非經口投予。 作為經口用醫藥之形態，可列舉：鍵劑、丸劑、散劑、 顆粒劑：膠囊劑、水劑、懸浮劑、乳劑、糖聚劑、㈣丨 等。該等形態之醫藥通常製備為：以通式⑴所表示之本發 明化合物為主劑，與作為藥學上容許之添加物的稀釋劑、x 賦：Μ或載體進行混合而形成之醫藥組合物。醫藥組合物 之衣備可使用藥學上容許之稀釋劑、賦形劑或载體，或者 除=等以夕卜，亦可使用視需要而適當選自任意適當的藥學 上容許之黏合劑、崩解劑、潤滑劑、膨潤劑、增潤劑、包 二劑、塑化劑、穩定劑、防腐劑、抗氧化劑、I色劑、助 溶劑、懸浮劑、乳化劑、甜味劑、保存劑、緩衝劑、濕潤 劑等中者，可按照常法進行。 作為非經口用之醫藥的形態，可列舉：注射劑、軟膏 :卜凝膠劑、乳劑、敷劑、黏附劑、氣霧劑、吸入劑、； 務劑、滴眼劑、滴鼻劑、栓劑、吸人劑等。該等形態之醫 藥通常製備為：以通式⑴所表示之本發明化合物為：劑： 與作為藥學上容許之添加物的稀釋劑、賦形劑或载體進行 混合而形成之醫藥組合物。醫藥組合物之製備可使用藥學 上容許之稀釋劑、賦形劑或載體，或者除該等以外，亦可 129677.doc -49- 200840568 使用視需要而選自任意適當的藥學上容許之穩定劑、防腐 d助/谷劑、保濕劑、保存劑、抗氧化劑、調味劑、膠化 剡中和劑、助溶劑、緩衝劑、等張劑、界面活性劑、著 色劑、緩衝化劑、增黏劑、濕潤劑、填充劑、促吸收劑、 懸汙劑、黏合劑等中者，可按照常法進行。To a solvent such as chloroform, % is added with a necessary amount of isocyanate (26), and the mixture is stirred at room temperature for 1 hour to 24 hours under cooling. The amine wherein the R R is a halogen atom (28) can be produced by reducing the nitro group of the compound (27). For example, a metal such as ferric chloride (3) and powder can be added to the water-containing dimethylformamide (dmf) at 25. (: ~10CTC is used to carry out the treatment of the compound (27) to produce an amine (28) (R3 is a hydrogen atom). As a method for reducing the nitro group, a method of using a nickel, a platinum, a carbon, a ruthenium complex a catalytic reduction method of a metal catalyst; a method of reducing with a metal catalyst such as carbon or a ruthenium or the like; a method of treating a metal such as zinc or tin under acidic conditions; or neutral or Under the conditions of the test, it is the same as the method of the metal such as zinc powder. In the present reduction reaction, it is preferred that the Q3 group contains an aromatic ring group of a halogen group, and the reaction condition is selected such that the base group is not separated. The manufacture of 'as a reference to the burning reaction of the amines, : a lecture on experimental chemistry (fourth edition, VgL 2G. edited by the Chemical Society of Japan, Pills and Injury Co., Ltd.) "Organic Synthesis Η: Alcohol·Amine 284 ~288 pages and pages 300-302", etc. R is (: 1 to C6 alkylamine (28) can be an amine having the above hydrogen atom by R3 129677.doc • 47- 200840568 The compound of the present invention (le) By reacting the above-obtained amine (28) with a mixed acid anhydride, acid halide or active ester of formic acid (9) The reagents and reaction conditions for the reaction of the amine (28) with the ferulic acid (9) can also be applied to the reaction described in the above [Production Method 13. The compound (le) of the present invention thus produced can be produced by a known method, for example. The extraction is carried out by analysis, fractional chromatography, fractional crystallization, recrystallization, etc., and the salt of the compound of the present invention can be formed into a desired salt by a usual salt-forming reaction. When the inventive compound (1) or the intermediate produced has an asymmetric carbon, optical isomers exist. These optical isomers can be subjected to fractional recrystallization (salt division) or column layer by re-twisting with an appropriate salt. Each of the isomers is isolated and purified by a conventional method such as an analytical method. As a reference for a method of dividing an optical isomer by a racemate, there are mentioned "Lanti", "Mother", "Enanti〇mers, Racemates and Resolution. John" Wiley And Sons, Inc., the diamine derivative of the present invention is particularly useful as a FXa inhibitor because it exhibits a potent activated blood coagulation factor (suppressed by the killing effect) and can be used as a mammal for the inclusion of humans. Agent Blood inhibitors, thrombosis or test: preventive and / or therapeutic agents, prevention of thrombotic diseases and or therapeutic drugs, - can be used for infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary embolism, deep veins In the case of sputum stagnation, systemic vascular coagulation, two-body membrane/joint replacement, 4 embolus formation, m-implantation: and reocclusion, multiple organ dysfunction syndrome (MODS), in vitro: blood rights Prevention and/or treatment of blood coagulation during blood formation or blood collection 129677.doc -48- 200840568 A pharmaceutical composition having the compound of the present invention represented by the formula (i) can be selected according to the administration method, and is usually prepared by a usual method. The preparation of various preparations of the preparations is carried out. A pharmaceutical composition containing a compound of the present invention represented by the formula (I) as a main agent can be administered systemically or locally, orally or parenterally, when administered. Examples of the form of the oral medicine include a key agent, a pill, a powder, and a granule: a capsule, a liquid, a suspending agent, an emulsion, a sugar-polymerizing agent, and (iv) hydrazine. The pharmaceutical preparation of the above-mentioned form is usually prepared by mixing a compound of the present invention represented by the formula (1) as a main component, and a diluent, a x-form, or a carrier which is a pharmaceutically acceptable additive. The pharmaceutical composition may be prepared by using a pharmaceutically acceptable diluent, excipient or carrier, or may be optionally selected from any suitable pharmaceutically acceptable binder, and may be used, if necessary. Decomposing agent, lubricant, swelling agent, humectant, two-packing agent, plasticizer, stabilizer, preservative, antioxidant, I coloring agent, solubilizing agent, suspending agent, emulsifier, sweetener, preservative, A buffering agent, a wetting agent, etc. can be carried out according to a normal method. Examples of the form of the medicine for non-oral use include an injection, an ointment: a gel, an emulsion, a dressing, an adhesive, an aerosol, an inhalant, a solution, an eye drop, a nasal drop, and a suppository. , inhalation agents, etc. The pharmaceutical preparations of the above formula are usually prepared by using the compound of the present invention represented by the formula (1) as a pharmaceutical composition which is prepared by mixing with a diluent, an excipient or a carrier which is a pharmaceutically acceptable additive. The pharmaceutical composition may be prepared by using a pharmaceutically acceptable diluent, excipient or carrier, or in addition to these, may also be selected from any suitable pharmaceutically acceptable stabilizer as required by 129677.doc -49-200840568. , anti-corrosion d help / cereal, moisturizer, preservative, antioxidant, flavoring agent, gelatinization neutralizer, cosolvent, buffer, isotonic agent, surfactant, colorant, buffering agent, viscosity-increasing The agent, the wetting agent, the filler, the absorption enhancer, the suspending agent, the binder, etc. can be carried out according to a usual method.

作為與上述藥學上容許之賦形劑相關的參考文獻，例如 牛 Handbook of Pharmaceutical Excipients, 2nd Edition, (1994)^ Edited by A. Wade and P. J. Weller j 〇 又作為與上述藥學上容許之載體或稀釋劑相關的參考 文獻例如可列舉rRemingt〇n，s pha随咖加ical Scien⑽，References relating to the above-mentioned pharmaceutically acceptable excipients, for example, Bovine Handbook of Pharmaceutical Excipients, 2nd Edition, (1994)^ Edited by A. Wade and PJ Weller j 〇 are also used as pharmaceutically acceptable carriers or dilutions as described above. Agent-related references include, for example, rRemingt〇n, s pha with coffee plus ical Scien (10),

Mack Publishing C。·（A. R· Gennaro edit. 1985)」。 以通式（I)所表不之本發明化合物、其鹽或該等之溶劑合 物的投：量根據症狀、年齡、體重、組合投予之藥劑種類 或投予^量等而有所不同，用作人體用的醫藥時，以化合物 (,υ換算量計，成人-人―次之射量為G丨賢漏叫之 範圍二較好的是1 mg〜200 mg之範圍，更好的是5叫〜1〇〇 mg之fe圍。又，動物用之投予量根據投予目的（治療或預 防）、需治療之動物的種類或大小、所感染之病原菌種 類'程度而有所不同’ Mm而言動物體重每 1 kg之投予量為〇」mg至2〇〇 mg，較好的是邮至_ mg之範圍。將該一日量，對全身或局部進行一日丨次至數 次的經口或非經口投予，或於一曰1小時〜24小時之範圍内 連續投予至靜脈内。又，視需要一日量亦可超過上述量。 含有本發明化合物之醫藥較理想的是料化合物而對成 129677.doc -50- 200840568 人1人1日投予1次至數次，且以適當間隔反覆投予。1日之 投予量為〇·5 mg〜2000 mg之範圍，較好的是3 mg〜1000 mg 之範圍，更好的是10 mg〜500 mg。 本發明中亦包含上述疾病之防止方法及/或治療方法， 其特徵在於投予本發明化合物或其鹽。 進而，本發明中亦包含本發明化合物、其鹽或該等的溶 劑合物之用途，其係用於製造上述醫藥。 [實施例] 繼而，列舉實施例來詳細說明本發明，但本發明並不限 於此。Mack Publishing C. · (A. R. Gennaro edit. 1985)". The amount of the compound of the present invention represented by the formula (I), the salt thereof or the solvate thereof may vary depending on the symptoms, age, body weight, the type of the drug to be administered, or the amount of the drug to be administered. When used as a medicine for human body, the range of 1 mg to 200 mg is better in the range of 1 mg to 200 mg, which is better for the compound (in terms of υ , , 成人 成人 成人 成人 成人 成人 成人 成人 成人 成人 较好 较好 较好 较好 较好 较好It is a total of 5 calls of ~1〇〇mg. In addition, the dosage for animals varies depending on the purpose of administration (treatment or prevention), the type or size of the animal to be treated, and the type of pathogen to be infected. 'Mm, the animal's body weight per 1 kg is 〇mg to 2〇〇mg, preferably in the range of _mg. The amount of the day, the whole body or part of the day to the next to Several times of oral or non-oral administration, or continuous administration to the vein within a range of 1 hour to 24 hours. Further, the amount may be more than the above amount as needed. The medicine containing the compound of the present invention Preferably, the compound is administered to the 129677.doc -50- 200840568 person for 1 day to 1 time, and the appropriate room The dosage for administration on the 1st is in the range of mg·5 mg to 2000 mg, preferably in the range of 3 mg to 1000 mg, more preferably 10 mg to 500 mg. The above diseases are also included in the present invention. A method for preventing and/or treating a compound of the present invention or a salt thereof. Further, the present invention also encompasses the use of the compound of the present invention, a salt thereof or a solvate thereof, which is used for the production of the above [Embodiment] The present invention will be described in detail by way of examples, but the invention is not limited thereto.

紅外光譜（IR)係使用 Hitachi 270-30 spectrometer 或 Horiba FT-720(S. T. Japan Durascope(Diamond/KRS-5)) j 以 KBr壓片法或 ATR(attenuated total reflectance，衰減全 反射）法而測定。元素分析係以Perkin-Elmer CHNS/O 2400 (II)、MITSUBISHI CHEMICAL XS-100、或 DIONEX DX-320進行測定。質譜分析（MS)係使用JEOL JMS-AX505WInfrared spectroscopy (IR) was measured by a KBr tablet method or an ATR (attenuated total reflectance) method using a Hitachi 270-30 spectrometer or a Horiba FT-720 (S. T. Japan Durascope (Diamond/KRS-5)) j. Elemental analysis was carried out by Perkin-Elmer CHNS/O 2400 (II), MITSUBISHI CHEMICAL XS-100, or DIONEX DX-320. Mass spectrometry (MS) using JEOL JMS-AX505W

(EI，FAB，Cl)、JEOL JMS-700 (EI，FAB，FD，Cl)、Agilent Technologies Agilent 1100 series LC/MSD、PE SCIEX API150EX (ESI)及 Micromass LCT (FAB)、或 JMS-T100LP AccuTOF LC-plus。溶點係使用 Yanagimoto micro溶點測定 器進行測定，值均未校正。核磁共振光譜（NMR，nuclear magnetic resonance)係使用 JEOL JNM-EX400來測定，無特 殊說明時，係指質子NMR^H-NMR)，使用四甲基矽烷作 為内部標準。又，h-NMR之多重性係指，s=singlet、 129677.doc -51 - 200840568 d=doublet、t=triplet、q=quartet、m=multiplet、及 br s=broad singlet。用於管柱層析法中之石夕膠係使用E-Merck 公司之1(^361-§6160(粒度0.060〜0.200 11[1111)。使用山善之 High Flash系統等作為快速管柱層析法系統。又，薄層層 析法（TLC，thin layer chromatography)之板係使用 E_Merck 公司製造之Kieselgel 60F254。 又，本說明書中使用以下表3及表4中所示之省略語。 [表3] AIBN 2,2’-偶氮二異丁腈 A1C13 氯化鋁 Boc20 二碳酸二第三丁酯 'BuOK 第三丁氧基鉀 GDI 羰基二咪唑 CDCI3 氘代氯仿 CD3OD 氘代甲醇 DBU 1，8-二氮雜雙環「5.4.01十一-7-烯 DCC N，N-二環己基碳二亞胺 DIEA 二異丙基乙胺 DMAP 4-(N，N-二曱基胺基)吡啶 DMA N，N-二甲基乙醯胺 DMF N，N-二甲基甲醯胺 DMSO 二曱基亞颯 DMSO-d6 氘代二甲基亞颯 IDPPA 疊氮填酸二苯酯 [表4] EDC 1 -乙基-3-(3-二甲基胺基丙基)碳二亞胺鹽酸鹽 醚 二*** HOBt 1-羥基苯并*** HPLC 高效液相層析法 IPE 異丙鍵 K2C03 碳酸鉀 LiOH 氫氧化鋰 MgS〇4 硫酸錤 129677,doc -52- 200840568(EI, FAB, Cl), JEOL JMS-700 (EI, FAB, FD, Cl), Agilent Technologies Agilent 1100 series LC/MSD, PE SCIEX API150EX (ESI) and Micromass LCT (FAB), or JMS-T100LP AccuTOF LC -plus. The melting point was measured using a Yanagimoto micro-melting point tester, and the values were uncorrected. Nuclear magnetic resonance (NMR) was measured using JEOL JNM-EX400. Unless otherwise specified, it refers to proton NMR^H-NMR, and tetramethylnonane was used as an internal standard. Further, the multiplicity of h-NMR refers to s=singlet, 129677.doc -51 - 200840568 d=doublet, t=triplet, q=quartet, m=multiplet, and br s=broad singlet. The Shishi gum used in the column chromatography method uses E-Merck Co., Ltd. 1 (^361-§6160 (particle size 0.060~0.200 11[1111). Use Shanshan's High Flash system as the rapid column chromatography method. Further, the plate of thin layer chromatography (TLC) uses Kieselgel 60F254 manufactured by E_Merck Co., Ltd. Further, the abbreviations shown in Tables 3 and 4 below are used in the present specification. [Table 3] AIBN 2,2'-azobisisobutyronitrile A1C13 aluminum chloride Boc20 dibutyl butyl dicarbonate 'BuOK potassium third potassium hydride GDI carbonyl diimidazole CDCI3 deuterated chloroform CD3OD deuterated methanol DBU 1,8-two Azabicyclo ring "5.4.01 eleven-7-ene DCC N,N-dicyclohexylcarbodiimide DIEA diisopropylethylamine DMAP 4-(N,N-didecylamino)pyridine DMA N, N-Dimethylacetamide DMF N,N-dimethylformamide DMSO Dimercaptopurine DMSO-d6 Deuterated dimethyl hydrazine IDPPA Azide-filled diphenyl ester [Table 4] EDC 1 - Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride ether diethyl ether HOBt 1-hydroxybenzotriazole HPLC high performance liquid chromatography IPE isopropyl key K2C03 potassium carbonate L iOH lithium hydroxide MgS〇4 barium sulfate 129677,doc -52- 200840568

NaCl 氯化納 Na2C03 碳酸鈉 NaHC03 碳酸氫納 NaOH 氫氧化鈉 Na2S04 硫酸鈉 NBS N-溴琥珀醯亞胺 NCS N-氯琥珀醯亞胺 TEA 三乙胺 TFA 三氟乙酸 THF 四氫呋喃 TLC 薄層層析法 [參考例1] (2-胺基吡啶-3-基甲基）胺基曱酸第三丁酯 於冰浴冷卻下，向氫化鋰鋁（330 mg)之THF(50 ml)懸浮 液中添加2-胺基菸鹼醯胺（274 mg)，於室溫下攪拌30分鐘 後，加熱回流一整夜。放置至室溫後，向反應液中依序添 加5當量NaOH水溶液、水及5當量NaOH水溶液。於室溫下 攪拌2小時後，向反應液中添加無水MgS04，將不溶物通 過氟鎂石進行過濾。於減壓下濃縮濾液，向所獲得之油狀 物質的THF(5 ml)溶液中添加Boc20(437 mg)，於室溫下授 拌2小時。於減壓下餾去溶劑，將殘渣以矽膠層析法（甲 醇：二氯甲烷=2 : 23)進行精製，獲得標題化合物（230 mg)。 iH-NMR (CDC13) δ : 1·45 (9H，s)，4.20 (2H，d，J=6.3 Hz)， 4.92 (1H，br s)，5.25 (2H，br s)，6·57 (1H，dd，J=7.3，5.6 Hz)，7·26 (1H，dd，J=7.3，1,7 Hz)，7·99 (1H，dd，J=5.6，1.7 Hz)。 MS (ESI) m/z: 224 (M+H)+。 [參考例2] {2-[(5-甲基-4,5,6,7-四氫噻唑并[5,4-c]吼啶-2-羰 基）胺基]吼啶-3-基甲基}胺基甲酸第三丁酯 129677.doc -53- 200840568 將5 -甲基·4,5,6,7 -四氫ϋ塞嗤并[5,4-c] °比咬-2-曱酸鹽酸鹽 (WO 2004/058715)(469 mg)懸浮於亞硫醯氯（10 ml)*。加 熱回流1小時後，於減壓下濃縮。於冰浴冷卻下，向所獲 得之固體添加吡啶（10 ml)及參考例1之化合物（223 mg)的 二氣甲烷（10 ml)溶液。於室溫下攪拌一整夜後，於50°c下 攪拌一整夜。向該反應液中再次追加5-甲基-4,5,6,7-四氫 嗟嗤并[5,4-c]吡啶-2-曱酸鹽酸鹽（469 mg)與由亞硫醯氣（10 ml)所製備的醯氯，於室溫下攪拌3日。於減壓下餾去溶 劑，向殘渣中添加二氯曱烷及飽和NaHC03水溶液，進行 分液。以飽和Na(M水溶液清洗，以無水Na2S04乾燥後，於 減壓下濃縮。以矽膠管柱層析法（甲醇：二氯甲烷=2 : 23) 進行精製，獲得標題化合物（211 mg)。 ^-NMR (CDC13) δ : 1.45 (9H? s), 2.60 (3H? s)? 2.96 (2H, br s)，3·05 (2H，br s)，3·86 (2H，br s)，4·34 (2H，d，J=6.1 Hz), 5·59 (1H，br s)，7·24 (1H，dd，J=7.6, 4·9 Hz)，7·91 (1H，d, J=7.6 Hz)，8.39 (1H，d，J=4.9 Hz)，9.40 (1H，br s)。 MS (ESI) m/z: 404 (M+H)+。 [參考例3] (3·胺基吡啶-4·基曱基）胺基甲酸第三丁酯 以與參考例1相同的方法，且由3_胺基異菸鹼醯胺獲得 標題化合物。 'H-NMR (CDCls) δ : 1.45 (9H? s)? 4.22 (2H, d5 J=6.6 Hz), 5·00 (1H，l>r s)，6·93 (1H，d，J=4.5 Hz)，7·92(1Η，d，J=4.5 Hz)，8·05 (1H，s) 〇 MS (ESI) m/z: 224 (M+H)+。 129677.doc -54- 200840568 [參考例4] {3-[(5-甲基-4,5,6,7-四氫噻唑并[5,4-c]吡啶-2-羰 基）胺基]吡啶-4-基甲基}胺基甲酸第三丁酯 以與參考例2相同之方法，由參考例3之化合物獲得標題 化合物。 W-NMR (CDC13) δ : 1·45 (9H，s)，2·56 (3H，s)，2,90 (2H，t， J=5.8 Ηζ)，3·01 (2Η，t，J=5.8 Ηζ)，3·80 (2Η，s)，4·34 (2Η，d， J = 6.1 Hz)，5·22 (1H，br s)，7·31 (1H，d，J=5.0 Hz)，8·46 (1H，d，J=5.0 Hz)，8·98 (1H，s)，9·47 (1H，br s)。 MS (ESI) m/z: 404 (M+H)+。 [參考例5] (3-羥基甲基。比啶-4-基)胺基甲酸第三丁酯 向（3-甲醯基吡啶-4-基）胺基甲酸第ST_(J.Med.Chem. 1988，31，2136)(603 mg)之甲醇（10 ml)溶液中添加石朋氫化 鈉（205 mg)，於室溫下攪拌1小時。於減壓下餾去溶劑， 向殘渣中添加二氣曱烷及飽和食鹽水，進行分液。將有機 層以無水Na2S04乾燥後，於減壓下濃縮。以己烷清洗所獲 得之固體，獲得標題化合物（382 mg)。 !H-NMR (CDC13) δ : 1.53 (9H，S)，4·66 (2H，s)，7·93 (1H， s)，8·08 (1Η，d，J=5.9 Ηζ)，8·28 (1Η，d，J=5.9 Ηζ)，8.32 (1H，s) 〇 MS (ESI) m/z: 225 (M+H)、 [參考例6] (3-疊氮基甲基。比啶基）胺基曱酸第三丁酯 於冰浴冷卻下，向參考例5之化合物（382 mg)的THF(5 ml)溶液中添加DPPA(732 μΐ)及DBU(509 μΐ)。於室溫下攪 拌一整夜後，於減壓下餾去溶劑。向殘渣中添加乙酸乙酯 129677.doc -55- 200840568 及水，進行分液。將所獲得之有機層以飽和睫、 < 水清洗 後，以無水MgSCU乾燥。於減壓下餾去溶劑， …將殘渣以矽 膠管柱層析法（甲醇：二氯甲烷=3 : 97)進行精製，釋得^ 題化合物（333 mg)。 i-NMR (CDC13) δ : 1.55 (9H，s)，4·36 (2H，s)，8 u (1H J=5.6 Hz)，8.36 (1H，s)，8·50 (1H，d，J=5.6 Hz)。 ’ MS (ESI) m/z: 250 (M+H)+。NaCl sodium chloride Na2C03 sodium carbonate NaHC03 sodium hydrogencarbonate sodium hydroxide sodium hydroxide Na2S04 sodium sulfate NBS N-bromosuccinimide NCS N-chloroammonium succinimide TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography [Reference Example 1] (2-Aminopyridin-3-ylmethyl)amino decanoic acid tert-butyl ester was added to a suspension of lithium aluminum hydride (330 mg) in THF (50 ml) under ice-cooling. 2-Amino nicotinamide (274 mg) was stirred at room temperature for 30 minutes and then heated to reflux overnight. After standing at room temperature, 5 equivalents of an aqueous NaOH solution, water and a 5 equivalent of aqueous NaOH solution were sequentially added to the reaction mixture. After stirring at room temperature for 2 hours, anhydrous MgS04 was added to the reaction mixture, and the insoluble matter was filtered through Florite. The filtrate was concentrated under reduced pressure. EtOAc (EtOAc) The solvent was evaporated to dryness crystals crystals crystals crystals iH-NMR (CDC13) δ : 1·45 (9H, s), 4.20 (2H, d, J = 6.3 Hz), 4.92 (1H, br s), 5.25 (2H, br s), 6·57 (1H , dd, J = 7.3, 5.6 Hz), 7.26 (1H, dd, J = 7.3, 1, 7 Hz), 7·99 (1H, dd, J = 5.6, 1.7 Hz). MS (ESI) m/z: 224 (M+H)+. [Reference Example 2] {2-[(5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]acridin-2-carbonyl)amino]anthidine-3-yl Methyl}amino carboxylic acid tert-butyl ester 129677.doc -53- 200840568 5-methyl-4,5,6,7-tetrahydro hydrazide and [5,4-c] ° ratio bite-2- The guanidate hydrochloride (WO 2004/058715) (469 mg) was suspended in sulfoxide (10 ml)*. After heating to reflux for 1 hour, it was concentrated under reduced pressure. A solution of pyridine (10 ml) and the compound of Reference Example 1 (223 mg) in dioxane (10 ml) was added to the obtained solid. After stirring overnight at room temperature, it was stirred at 50 ° C overnight. To the reaction solution, 5-methyl-4,5,6,7-tetrahydroindeno[5,4-c]pyridine-2-hydrazine hydrochloride (469 mg) was added again with sulfoxide. The hydrazine chloride prepared in gas (10 ml) was stirred at room temperature for 3 days. The solvent was distilled off under reduced pressure, and dichloromethane and a saturated aqueous NaHCO? The organic layer was washed with EtOAc (EtOAc m. -NMR (CDC13) δ : 1.45 (9H? s), 2.60 (3H? s)? 2.96 (2H, br s), 3·05 (2H, br s), 3·86 (2H, br s), 4 ·34 (2H,d,J=6.1 Hz), 5·59 (1H, br s), 7·24 (1H, dd, J=7.6, 4·9 Hz), 7·91 (1H, d, J = 7.6 Hz), 8.39 (1H, d, J = 4.9 Hz), 9.40 (1H, br s) MS (ESI) m/z: 404 (M+H)+. [Reference Example 3] (3. The title compound was obtained in the same manner as in Reference Example 1 and the title compound was obtained from 3-amino-nicotinic acid decylamine. 'H-NMR (CDCls) δ: 1.45 (9H? s)? 4.22 (2H, d5 J=6.6 Hz), 5·00 (1H, l>rs), 6.93 (1H, d, J=4.5 Hz), 7.92 (1Η, d, J=4.5 Hz), 8·05 (1H, s) 〇MS (ESI) m/z: 224 (M+H)+. 129677.doc -54- 200840568 [Reference Example 4] {3-[(5- Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl)amino]pyridin-4-ylmethyl}carbamic acid tert-butyl ester with reference example 2 identical The title compound was obtained from the compound of Reference Example 3. W-NMR (CDC13) δ: 1·45 (9H, s), 2·56 (3H, s), 2, 90 (2H, t, J = 5.8 Ηζ ), 3·01 (2Η, t, J=5.8 Ηζ), 3·80 (2Η, s), 4·34 (2Η, d, J = 6.1 Hz), 5·22 (1H, br s), 7 · 31 (1H, d, J = 5.0 Hz), 8.46 (1H, d, J = 5.0 Hz), 8·98 (1H, s), 9·47 (1H, br s) MS (ESI) m/z: 404 (M+H)+ [Reference Example 5] (3-hydroxymethyl.pyridin-4-yl)-tert-butyl carbazate to (3-methylpyridin-4-yl) To a solution of the amino acid formic acid ST_(J.Med. Chem. 1988, 31, 2136) (603 mg) in methanol (10 ml), sodium sulfonate (205 mg) was added and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and dioxane and saturated brine were added to the residue to carry out liquid separation. The organic layer was dried over anhydrous Na 2 SO 4 and evaporated. The solid obtained was washed with hexane to give the title compound (382 mg). !H-NMR (CDC13) δ : 1.53 (9H,S),4·66 (2H,s),7·93 (1H, s),8·08 (1Η,d,J=5.9 Ηζ),8· 28 (1Η,d,J=5.9 Ηζ), 8.32 (1H,s) 〇MS (ESI) m/z: 225 (M+H), [Reference Example 6] (3-azidomethyl. DP3 (732 μM) and DBU (509 μM) were added to a solution of the compound of Reference Example 5 (382 mg) in THF (5 ml). After stirring overnight at room temperature, the solvent was evaporated under reduced pressure. Ethyl acetate 129677.doc -55- 200840568 and water were added to the residue to carry out liquid separation. The obtained organic layer was washed with saturated ciliary, <water, and dried with anhydrous MgSCU. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methanol: methylene chloride = 3:97) to afford compound (333 mg). i-NMR (CDC13) δ : 1.55 (9H, s), 4·36 (2H, s), 8 u (1H J = 5.6 Hz), 8.36 (1H, s), 8.50 (1H, d, J =5.6 Hz). ' MS (ESI) m/z: 250 (M+H)+.

[參考例7] (3_{[(5-氯噻吩-2-羰基）胺基]曱基丨吡啶基）胺 基曱酸第三丁酯 向參考例6之化合物（330 mg)的乙酸乙酯（1〇 ml)溶液中 添加10%鈀-碳（含水5〇%，1〇〇 mg)。於氫氣環境下攪摔2小 時後’去除觸媒。於減壓下餾去溶劑，將殘漬溶解於 DMF(5 ml)中。向該溶液中添加％氯噻吩甲酸（215 mg)、EDC(380 mg)、及 HOBt(179 mg)，於室溫下攪拌 1 小 時。於減壓下餾去溶劑，向殘渣中添加乙酸乙酯及飽和 NaHC〇3水溶液’進行分液。將有機層以無水MgS〇4乾燥 後，於減壓下濃縮。將殘渣以矽膠管柱層析法（甲醇：二 氯甲烷=3 : 97— 1 : I9)進行精製，獲得標題化合物（338 mg)。 4-NMR (CDC13) δ : 1.57 (9H，s)，4.51 (2H，d，J=6.3 Hz)， 6·90 (1H，d，J=4.1 Hz)，7·57 (1H，d，J=4.1 Hz)，8·19·8·28 (3H，m)，8·38 (1H，d，J=6.1 Hz)，9.52 (1H，s)。 MS (ESI) m/z: 368 (M+H)+。 [參考例8] (2-經基曱基。比唆-3-基）胺基甲酸第三丁酯 129677.doc •56· 200840568 以與參考例5相同的方法，由（2_甲醯基吡啶_3_基）胺基 曱酸第三丁酯（J. Med. Chem，1988, 31，2136)獲得標題化人 物。 H-NMR (CDC13) δ : 1.53 (9H，s)，3,06-3.86 (1H，m)，4 8〇 (2H，s)，7·22 (1H，dd，J=8.5, 4·6 Hz)，7.35 (1H，br s)，§·16 (1H，d，J=4.6 Hz)，8·31 (1H，d，J=85 Hz)。 MS (ESI) m/z: 225 (M+H)+。 [參考例9] (2-疊氮基曱基吼咬_3_基）胺基曱酸第三丁酯 以與參考例6相同的方法，由參考例8之化合物獲得標題 化合物。 lH'NMR(CDCl3)S^·54^ s),4.54(2H, s),6.97(1H, br S)，7·28 (1H，dd，㈣.3, 4·8 Hz)，8·26 (1H，dd，X8, 1·6[Reference Example 7] (3_{[(5-Chlorothiophene-2-carbonyl)amino]]indolylpyridinyl)amino decanoic acid tert-butyl ester to ethyl acetate of Reference Example 6 (330 mg) (1 〇 ml) solution was added with 10% palladium-carbon (5 % by weight, 1 〇〇 mg). After stirring for 2 hours in a hydrogen atmosphere, the catalyst was removed. The solvent was evaporated under reduced pressure and the residue was dissolved in DMF (5 ml). To the solution, % chlorothiophenecarboxylic acid (215 mg), EDC (380 mg), and HOBt (179 mg) were added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and ethyl acetate and a saturated aqueous NaHC? The organic layer was dried over anhydrous MgSO 4 and evaporated. The residue was purified by silica gel column chromatography (MeOH:EtOAc:EtOAc) 4-NMR (CDC13) δ : 1.57 (9H, s), 4.51 (2H, d, J = 6.3 Hz), 6.90 (1H, d, J = 4.1 Hz), 7·57 (1H, d, J =4.1 Hz),8·19·8·28 (3H,m),8·38 (1H,d,J=6.1 Hz), 9.52 (1H, s). MS (ESI) m/z: 368 (M+H)+. [Reference Example 8] (2- mercapto group. 唆-3-yl) tert-butyl carbamic acid butyl 129677.doc • 56· 200840568 In the same manner as in Reference Example 5, from (2_methyl fluorenyl) The pyridine-3-yl)amino decanoic acid tert-butyl ester (J. Med. Chem, 1988, 31, 2136) was obtained as the titled person. H-NMR (CDC13) δ : 1.53 (9H, s), 3, 06-3.86 (1H, m), 4 8 〇 (2H, s), 7·22 (1H, dd, J=8.5, 4·6 Hz), 7.35 (1H, br s), § · 16 (1H, d, J = 4.6 Hz), 8.31 (1H, d, J = 85 Hz). MS (ESI) m/z: 225 (M+H)+. [Reference Example 9] (2-Azidofluorenyl octazone _3-yl)amino decanoic acid tert-butyl ester The title compound was obtained from the compound of Reference Example 8 in the same manner as in Reference Example 6. lH'NMR(CDCl3)S^·54^ s), 4.54(2H, s), 6.97(1H, br S), 7·28 (1H, dd, (4).3, 4·8 Hz), 8.26 (1H, dd, X8, 1·6

Hz)，8·30 (1H，dd，J=8.3，1.6 Hz)。 MS (ESI) m/z: 250 (M+H)、 [參考例10] (2-{[(5·氯嗟吩_2_羰基）胺基]甲基}吡啶基） 胺基甲酸第三丁酯 以與參考例7相同的方法，由參考例9之化合物獲得標題 化合物。 ^H-NMR (CDC13)8： 1.55 (9H, s), 4.65 (2H, d, 1=5.9 Hz), 6.87 (1H，d，J-3.9 Hz)，7·26 (1H，dd，J=8.3, 4·9 Hz)，7·34 (1H，d’ J-3.9 Hz), 8,02 (1H，t，J=5,9 Hz)，8.20 (1H，dd， J-4.9, 2·4 Hz)，8·29 (1H，dd，>8·3, } 5 hz)，8·46 (1H，s)。 MS (ESI) m/z: 368 (M+H)+ 〇 [參考例in n-(4-胺基_2•甲基喷啶_5_基甲基）_5_氣嘆吩_2_ 129677.doc -57- 200840568 曱醯胺 將4-胺基-5-胺基甲基-2-甲基嘧啶鹽酸鹽（523 mg)及5-氯 噻吩_2·曱酸（488 mg)溶解於〇“罗（15〇11)中，添加 HOBt(405 mg)、EDC(959 mg)及 ΤΕΑ(418 μΐ)，於室溫下授 拌42小時。於減壓下餾去溶劑，向殘渣中添加飽和 NaHC03水溶液及二氣甲烷。濾取不溶物，以水清洗，獲 得標題化合物（663 mg)。 !H-NMR (DMSO-d6) δ : 2·28 (3H，s)，4.20 (2H，d，J=5.9 Hz)，6·71 (2H，br s)，7·19 (1H，d，J=4.2 Hz)，7·62 (1H，d， J = 3.9 Hz)，7·91 (1H，s)，9·01 (1H，t，J二5.7 Hz)。 MS (ESI) m/z: 283 (M+H)+ 〇 [參考例12] N-(2-硝基苄基）-5-氯ϋ塞吩_2_甲醯胺 以與參考例11相同的方法，將硝基苄胺與5_氣噻吩甲 酸縮合而獲得標題化合物。 H-NMR (CDC13) δ : 4.81 (2Η，d，J=6.6 Ηζ)，6·84-6·94 (1Η， br)，6.88 (1Η，d，J=3.9 Ηζ)，7.26 (1Η，d，Ρ3·9Ηζ)，7·46-7·51 (1H，m)，7·61-7·67 (1H，m)，7.73 (1H，dd，J=7.7，1.3 Hz)，8·08 (1H，dd，J=8.3, 1·2 Hz)。 MS (ESI) m/z: 297 (M+H)+。 [多考例13] N-(2-胺基苄基）_5_氯嘆吩_2_曱醯胺 向參考例12之化合物（455 mg)的DMF(l〇 mi)、水（5 ml) '心口 ’合液中添加氯化鐵（3)(743 mg)、鋅粉末（1〇1 g)，加 :回机30刀鐘。冷卻後，添加乙酸乙酯、飽和…水 夜將不，合物通過氟鎂石而過濾去除。將濾液以飽和 129677.doc -58- 200840568Hz), 8·30 (1H, dd, J=8.3, 1.6 Hz). MS (ESI) m/z: 250 (M+H), [Reference Example 10] (2-{[(5-chlorophenphen-2-carbonyl)amino]methyl}pyridyl) Butyl ester The title compound was obtained from the compound of Reference Example 9 in the same manner as in Reference Example 7. ^H-NMR (CDC13) 8: 1.55 (9H, s), 4.65 (2H, d, 1 = 5.9 Hz), 6.87 (1H, d, J-3.9 Hz), 7·26 (1H, dd, J= 8.3, 4·9 Hz), 7·34 (1H, d' J-3.9 Hz), 8,02 (1H, t, J=5, 9 Hz), 8.20 (1H, dd, J-4.9, 2· 4 Hz), 8·29 (1H, dd, > 8·3, } 5 hz), 8.46 (1H, s). MS (ESI) m/z: 368 (M+H) + 〇 [Reference Example in n-(4-Amino-2-methylpyrazine_5_ylmethyl)_5_ annone_2_129677. Doc -57- 200840568 Hydrazine dissolves 4-amino-5-aminomethyl-2-methylpyrimidine hydrochloride (523 mg) and 5-chlorothiophene-2-decanoic acid (488 mg) in hydrazine In Luo (15〇11), HOBt (405 mg), EDC (959 mg) and hydrazine (418 μΐ) were added and mixed at room temperature for 42 hours. The solvent was distilled off under reduced pressure to add a saturated residue to the residue. An aqueous solution of NaHC03 and a mixture of methylene chloride. The residue was filtered and washed with water to give the title compound (663 mg). H-NMR (DMSO-d6) δ: 2·28 (3H, s), 4.20 (2H, d, J=5.9 Hz),6·71 (2H,br s),7·19 (1H,d,J=4.2 Hz), 7·62 (1H,d, J = 3.9 Hz), 7·91 (1H, s), 9·01 (1H, t, J 5.7 Hz) MS (ESI) m/z: 283 (M+H) + 〇 [Reference Example 12] N-(2-nitrobenzyl)-5 -Chlorobenzophene-2-carbamidine The title compound was obtained by condensing nitrobenzylamine with 5- thiophenecarboxylic acid in the same manner as in the title compound. H-NMR (CDC13) δ: 4.81 (2 Η, d , J=6.6 Ηζ), 6.84-6·94 (1Η, br), 6.88 (1Η, d, J=3.9 Ηζ), 7.26 (1Η,d,Ρ3·9Ηζ),7·46-7·51 (1H,m),7·61-7·67 (1H,m),7.73 (1H,dd,J=7.7,1.3 Hz) ,8·08 (1H, dd, J=8.3, 1·2 Hz) MS (ESI) m/z: 297 (M+H)+. [Multi-Reference 13] N-(2-Aminobenzyl) )_5_ 氯 _2 _2 曱醯 曱醯 向 向 向 743 743 743 743 743 743 743 743 743 743 743 743 743 743 743 743 743 743 743 743 743 743 743 743 743 743 743 743 743 743 743 743 743 743 743 743 743 743 743 743 Mg), zinc powder (1〇1 g), plus: return 30 knives. After cooling, add ethyl acetate, saturated... water night will not, the compound is filtered through the brucite. The filtrate is saturated 129677 .doc -58- 200840568

NaCl水溶液、水清洗後，以無水Na2S〇4乾燥。於減壓下餾 去溶劑’將殘、/查以矽膠管柱層析法（己烷：乙酸乙酯=4 : 1 —3 : 1—2 · 1)進行精製，獲得標題化合物（357 mg)。 ]H-NMR (CDC13) δ : 4.53 (2H5 d? J=6.1 Hz)? 6.23 (lH,br s)5 6·65-6·74 (2H，m)，6·87 (1H，d，J=3.9 Hz)，7·07-7·17 (2H， m)，7·22 (1H，d，J=3.9 Hz)。 MS (ESI) m/z: 267 (M+H)+。 [參考例14] 4-(3-氧基嗎啉基）苯甲酸 向4-(3·氧基嗎琳冬基）苯甲酸甲酯（w〇 2〇〇4/〇58715) (1.21 g)之二氯甲烷（4〇 ml)溶液中添加曱硫醚（5〇以）及無 水A1C13(2.06 g)，於室溫下攪拌8小時。於減壓下餾去溶 劑’向殘渔中添加冰及稀鹽酸，濾取不溶物，獲得標題化 合物（1.06 g)。 H-NMR (CDC13) δ : 3,83 (2H，t，J=5.1 Ηζ)，4·06 (2H，t， J一5·1 Hz)，4·33 (2H，s)，7·46 (2H，d，J=8.5 Hz)，8·08 (2H， d，J=8.5 Hz)，12.35 (1H，br s)。 MS (ESI) m/z: 222 (M+H)+。 [參考例15] 4-(2-氧基氮雜環庚烷-丨_基）笨甲酸曱醋 將4-碘苯甲酸甲酯（524 mg)、ε •己内醯胺（289 mg)、碘 化銅（1)(80 mg)、N，N，-二甲基乙二胺（9〇 μ1)、磷酸三鉀 (852 mg)懸浮於二哼烷（3.〇 ml)中，於封管中於n〇<t下加 熱14小時。冷卻後，以乙酸乙酯稀釋反應液後，添加水。 以乙酸乙醋萃取，以飽和NaC1水溶液清洗所合併之有機 層。以無水NkSO4乾燥後，於減壓下餾去溶劑。將殘渣以 129677.doc -59 - 200840568 :i)進 使用矽膠之快速層析法（己烷：乙酸乙醋=4: 行精製，獲得標題化合物（132 mg)。 Η - N M R (CDCI3) δ ： 1 R〇-i rq 3’ · UU 1·88 (6H，m)，2·68_2·75 (2H，m)， 3.76-3.83 (2H, m)5 3 91 Q\ n ^ ^ (3H5 s)? 7.31 (2H? d? J-8.5 Hz) 8·04 (2H，d，J=8,5 Hz)。 MS (ESI) m/z: 248 (M+H)+。 [參考例16] 4-(2-氧基氮雜環庚烷_丨_基）苯甲酸After washing with an aqueous solution of NaCl and water, it was dried over anhydrous Na 2 SO 4 . The solvent was distilled off under reduced pressure, and the residue was purified by chromatography (hexane: ethyl acetate = 4 : 1 - 3 : 1 - 2 · 1) to give the title compound (357 mg) . ]H-NMR (CDC13) δ : 4.53 (2H5 d? J=6.1 Hz)? 6.23 (lH,br s)5 6·65-6·74 (2H,m),6·87 (1H,d,J = 3.9 Hz), 7·07-7·17 (2H, m), 7·22 (1H, d, J = 3.9 Hz). MS (ESI) m/z: 266 (M+H)+. [Reference Example 14] 4-(3-Oxomorpholinyl)benzoic acid to methyl 4-(3.oxy-octenyl)-benzoic acid (w〇2〇〇4/〇58715) (1.21 g) To a solution of dichloromethane (4 ml) was added hydrazine sulfide (5 liters) and anhydrous A1C13 (2.06 g), and the mixture was stirred at room temperature for 8 hours. The solvent was distilled off under reduced pressure. To the residue was added ice and dilute hydrochloric acid, and the insoluble material was filtered to give the title compound (1.06 g). H-NMR (CDC13) δ : 3,83 (2H, t, J=5.1 Ηζ), 4·06 (2H, t, J·5·1 Hz), 4·33 (2H, s), 7.46 (2H, d, J = 8.5 Hz), 8·08 (2H, d, J = 8.5 Hz), 12.35 (1H, br s). MS (ESI) m/z: 222 (M+H)+. [Reference Example 15] 4-(2-oxyazepane-indole-yl) benzoic acid vinegar, methyl 4-iodobenzoate (524 mg), ε • caprolactam (289 mg), Copper (I) iodide (80 mg), N,N,-dimethylethylenediamine (9〇μ1), and tripotassium phosphate (852 mg) were suspended in dioxane (3.〇ml). The tube was heated at n 〇 < t for 14 hours. After cooling, the reaction solution was diluted with ethyl acetate, and then water was added. The combined organic layers were washed with a saturated aqueous solution of NaCI. After drying over anhydrous NkSO4, the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography using EtOAc (EtOAc: EtOAc: EtOAc (EtOAc: EtOAc) 1 R〇-i rq 3' · UU 1·88 (6H,m),2·68_2·75 (2H,m), 3.76-3.83 (2H, m)5 3 91 Q\ n ^ ^ (3H5 s) 7.31 (2H? d? J-8.5 Hz) 8·04 (2H, d, J=8, 5 Hz) MS (ESI) m/z: 248 (M+H)+ [Reference Example 16] 4 -(2-oxyazepane-indoleyl)benzoic acid

以與參考例14相同的方法，由參考例15之化合物獲得標 題化合物。 ^H-NMR (CDCI3) δ : 1.73-1.94 (6H? m), 2.66.2.8〇 (2H? m)? 3·72-3.89 (2H，m)，7·34 (6H，d，J=8.8 Ηζ)，8·08 (2H，d， J=8.8 Hz)。 ’ ’ MS (ESI) m/z: 234 (M+H)+。 [參考例17] 5-(第三丁氧基羰基胺基）吡啶_2_甲酸甲酯 向5-胺基吡啶-2·甲酸曱酯（1.00 g)之二氣甲烷（1〇 mi)懸 浮液中添加BoC2〇(1.5 8 g)及DMAP(8〇.3 mg)，於室溫下攪 拌4日。將反應液直接以矽膠管柱層析法（己烷：乙酸乙酯 -1 · 1)進行精製’獲得標題化合物（766 mg)。 !H-NMR (CDCIs) δ : 1.53 (9Η, s), 3.99 (3H? s), 6.81 (1H, br s)，8·11 (1H，d，J=8.5 Hz)，8.20 (1H，dd，J=8.5，1.6 Hz)， 8.48 (1H，t，J=1.6 Hz)。 MS (ESI) m/z: 253 (M+H)、 [參考例1 8] 5-(第三丁氧基幾基胺基户比α定-2-甲酸經鹽 向參考例17之化合物（252 mg)的THF(4 ml)溶液中添加水 129677.doc -60- 200840568 (1 ml)及LiOH(48.9 mg)，於室溫下攪拌2日。於減壓下餾 去溶劑，獲得粗製之標題化合物。 [參考例19] 4-甲氧基硝基苄胺 將4-曱氧基-1-甲基_2·硝基苯（5.00 g)、NBS(4.13 g)及 AIBN(173 mg)懸浮於四氯化碳（1〇〇 ml)中。將該混合物加 熱回ML —整伙後’放置至室溫。將不溶物過濾去除，將清 液於減壓下餾去溶劑。將殘渣之甲醇（5〇 ml)溶液以i小時 添加至7當量氨甲醇溶液（33瓜丨）中。於室溫下攪拌一整夜 後’於減壓下餾去溶劑。向殘渣中添加飽和NaHC〇3水溶 液及二氣曱烷，進行分液。將有機層以飽和食鹽水清洗， 以無水NaJO4乾燥後，於減壓下濃縮。以矽膠管柱層析法 (曱醇·二氯曱烧=2: 23)進行精製，獲得標題化合物（1.24 g)。 'H-NMR (CDCls) δ : 1.91 (2Η, br s), 3.87 (3H? s)? 4.03 (2H? s)，7.15 (1H，dd，J=8.5，2,8 Hz)，7·48 (1H，d，J=8.5 Hz)， 7.52 (1H，d，J=2.8 Hz) 〇 MS (ESI) m/z: 183 (M+H)+ 0 [參考例20] (3-甲基-2-硝基苯氧基）乙酸第三丁酯 向3-曱基-2-硝基酚（1,90 g)之丙酮（20 ml)溶液中添加溴 乙酸第三丁酯（2.00 ml)、K2C03(1.91 g)，於室溫下攪拌1 小時後，加熱回流17小時。冷卻後，向反應液中添加乙酸 乙酯、飽和NaCl水溶液。以乙酸乙酯萃取後，以飽和NaC1 水溶液清洗所合併之有機層，以無水Na2S〇4乾燥。於減壓 下餾去溶劑後，將殘渣以石夕膠管柱層析法（己烧··乙酸乙 129677.doc -61 - 200840568The title compound was obtained from the compound of Reference Example 15 in the same manner as in Reference Example 14. ^H-NMR (CDCI3) δ : 1.73-1.94 (6H? m), 2.66.2.8〇(2H? m)? 3·72-3.89 (2H,m),7·34 (6H,d,J=8.8 Ηζ), 8·08 (2H, d, J = 8.8 Hz). '' MS (ESI) m/z: 234 (M+H)+. [Reference Example 17] Methyl 5-(t-butoxycarbonylamino)pyridine-2-carboxylate was suspended in dioxane methane (1 〇mi) of 5-aminopyridine-2-carboxylate (1.00 g). BoC2 〇 (1.5 8 g) and DMAP (8 〇. 3 mg) were added to the solution, and the mixture was stirred at room temperature for 4 days. The reaction mixture was purified by silica gel column chromatography (hexane: ethyl acetate -1·1) to give the title compound (766 mg). !H-NMR (CDCIs) δ : 1.53 (9Η, s), 3.99 (3H? s), 6.81 (1H, br s), 8.11 (1H, d, J=8.5 Hz), 8.20 (1H, dd , J = 8.5, 1.6 Hz), 8.48 (1H, t, J = 1.6 Hz). MS (ESI) m/z: 253 (M+H), [Reference Example 1 8] 5-(t-butoxy-l- yl-amine Add 129677.doc -60-200840568 (1 ml) and LiOH (48.9 mg) to a solution of 252 mg) in THF (4 ml), and stir at room temperature for 2 days. The title compound [Reference Example 19] 4-methoxynitrobenzylamine 4-methoxy-1-phenyl-2-nitrobenzene (5.00 g), NBS (4.13 g), and AIBN (173 mg) Suspended in carbon tetrachloride (1 〇〇ml). Heat the mixture back to ML - after the whole, 'put to room temperature. Remove the insoluble matter by filtration, and distill off the solvent under reduced pressure. The methanol (5 〇ml) solution was added to 7 equivalents of ammonia methanol solution (33 guanidine) at i hour. After stirring overnight at room temperature, the solvent was distilled off under reduced pressure. Saturated NaHC 〇 3 was added to the residue. The aqueous solution and the dioxane were separated and the organic layer was washed with saturated brine, dried over anhydrous Na.sub.4, and concentrated under reduced pressure. 23) Purification to obtain the title compound (1.24 g) 'H-NMR (CDCls) δ : 1.91 (2Η, br s), 3.87 (3H? s)? 4.03 (2H? s), 7.15 (1H, dd, J=8.5, 2,8 Hz), 7·48 (1H,d,J=8.5 Hz), 7.52 (1H,d,J=2.8 Hz) 〇MS (ESI) m/z: 183 (M+H)+ 0 [Reference Example 20] (3- Adding butyl bromoacetate to a solution of 3-mercapto-2-nitrophenol (1,90 g) in acetone (20 ml) (2.00) M1), K2C03 (1.91 g), stirred at room temperature for 1 hour, and then heated to reflux for 17 hours. After cooling, ethyl acetate and a saturated aqueous solution of NaCl were added to the mixture, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with anhydrous Na2S〇4. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography (hexanes··· acetic acid 129677.doc -61 - 200840568

Ιθ =10 g) 0 〇進行精製 獲得標題化合物（3.3 2 ]H.NMR (CDCI3) δ ： 1.46 {9K s) s)，6·74 (1Η，d，片·3 ηζ)，6 2 7.30 (1Η5 m) 〇 ，2.31 (3Η，s)，4.58 (2Η， (!Η5 d? J=7.8 Ηζ)? 7.24- MS (ESI) m/z: 290 (M+Na).。 [參考例21] (3-胺基曱基_2· 月I本虱基）乙酸第三丁酯 以與參考例I9相同的方法，士办心 由參考例20之化合物獲得標 題化合物 ^-NMR (CDCI3) δ ： 1.46 (9Η) S) s)，6·83 (1H，d，J=8.3 Hz)，7 14 (1H，br t，J=8.1 Hz)。 3·84 (2H，s)，4.60 (2H， (1H，d，J=7.8 Hz)，7.39 MS (ESI) m/z: 283 (M+H)+。 [參考例22] (3-{[(5-氣噻吩_2_羰基）胺基]甲基卜2_硝基苯氧 基）乙酸第三丁酯 以與參考例11相同的方法，將參考例21之化合物與5_氣 噻吩-2-甲酸縮合而獲得標題化合物。 1H-NMR (CDC13) δ : 1·46 (9H，s)，4·54 (2H，d，J=6.1 Hz)， 4.61 (2H，s)，6·48 (1H，t，J=6.1 Hz)，6·85-6·90 (2H，m)， 7.22(lH，dd，J=7.7,0.6Hz)，7.24(lH，d，J=3.9Hz)，7.37- 7·42 (1H，m) 0 MS (ESI) m/z: 371 〇 [參考例23] (2-胺基_3-{[(5-氯噻吩-2-羰基）胺基]曱基}苯氧 基）乙酸第三丁酯 129677.doc -62- 200840568 以與參考例13相同的方法，由參考例22之化合物獲得Ιθ =10 g) 0 〇 Purification to obtain the title compound (3.3 2 ]H.NMR (CDCI3) δ : 1.46 {9K s) s),6·74 (1Η,d,片·3 ηζ),6 2 7.30 ( 1Η5 m) 〇, 2.31 (3Η, s), 4.58 (2Η, (!Η5 d? J=7.8 Ηζ)? 7.24- MS (ESI) m/z: 290 (M+Na). [Reference Example 21] (3-Aminoguanidino-2·Month I fluorenyl)acetic acid tert-butyl ester The title compound ^-NMR (CDCI3) δ was obtained from the compound of Reference Example 20 in the same manner as in Reference Example I9: 1.46 (9Η) S) s),6·83 (1H,d,J=8.3 Hz), 7 14 (1H, br t, J=8.1 Hz). 3·84 (2H, s), 4.60 (2H, (1H, d, J = 7.8 Hz), 7.39 MS (ESI) m/z: 283 (M+H)+ [Reference Example 22] (3-{ [(5-Phenylthiophene-2-carbonyl)amino]methyl-2-phenylphenoxy)acetic acid tert-butyl ester In the same manner as in Reference Example 11, the compound of Reference Example 21 and 5- thiophene were used. The title compound was obtained by condensation of -2-carboxylic acid. 1H-NMR (CDC13) δ: 1·46 (9H, s), 4·54 (2H, d, J = 6.1 Hz), 4.61 (2H, s), 6· 48 (1H, t, J = 6.1 Hz), 6.85-6·90 (2H, m), 7.22 (lH, dd, J = 7.7, 0.6 Hz), 7.24 (lH, d, J = 3.9 Hz) , 7.37- 7·42 (1H, m) 0 MS (ESI) m/z: 371 〇 [Reference Example 23] (2-Amino-3-{[(5-chlorothiophen-2-carbonyl)amino] Tert-butyl}phenoxy)acetic acid tert-butyl ester 129677.doc -62- 200840568 was obtained from the compound of Reference Example 22 in the same manner as Reference Example 13.

題化合物。 T ^NMR (CDCl3)6:1.48(9H5 s)5 4.50 (2H? s)? 4.50 (2H? d> J 5.9 Hz)’ 6·44·6·54 (1H，m)，6·57-6·67 (2H，m)，6·76 (iH dd，J-7.3，1.5 Hz)，6.84 (1H，d，K2 Hz)，7·22 (1H，d J=4.2 Hz)。 ’ ’ MS (ESI) m/z: 397 (M+H)+。 [參考例24] (4-甲基·3-硝基苯氧基）乙酸第三丁酯 以與參考例20相同的方法，由％硝基-對曱酚獲得標題 化合物。Compound. T ^ NMR (CDCl3) 6: 1.48 (9H5 s) 5 4.50 (2H? s)? 4.50 (2H? d> J 5.9 Hz)' 6·44·6·54 (1H, m), 6·57-6 · 67 (2H, m), 6.76 (iH dd, J-7.3, 1.5 Hz), 6.84 (1H, d, K2 Hz), 7.22 (1H, d J = 4.2 Hz). '' MS (ESI) m/z: 397 (M+H)+. [Reference Example 24] (4-Methyl-3-nitrophenoxy)acetic acid tert-butyl ester The title compound was obtained from nitro-p-nonylphenol in the same manner as in Reference Example 20.

H-NMR (CDC13) δ : 1.50 (9Η, s), 2.54 (3H, s), 4.55 (2H s), 7.10 (1H, dd, J=8.5, 2.7 Hz), 7.25 (1H, d, J=8.5 Hz)! 7·49 (1H，d，J=2.7 Hz)。 ’ MS (ESI) m/z: 290 (M+Na)+。 [參考例25] (4-胺基甲基-3-硝基苯氧基）乙酸第三丁酯 以與參考例19相同的方法，由參考例24之化合物獲得標 題化合物。 H-NMR (CDC13) δ : 1.50 (9H，s)，ι·85_2 27 (2H，br)，4.04 (2H，s)，4·57 (2H，s)，7.17 (1H，dd，J=8.5，2.7 Ηζ)，7·49 (1H，d，J=8.5 Hz)，7·50 (1H，d，J=2.7 Hz)。 MS (ESI) m/z: 283 (M+H)、 [參考例26] (4-{[(5-氯嗔吩-2-羰基）胺基]甲基卜3_硝基苯氧 基）乙酸第三丁酯 以與參考例11相同的方法，將參考例25之化合物與5_氯 129677.doc -63- 200840568 嗟吩-2-甲酸縮合而獲得標題化合物。 ]H-NMR (CDCI3) δ : 1.50 (9H? s)5 4.57 (2H? s)? 4.73 (2H? d3 J = 6.3 Hz)，6·83 (1H，t，J=6.1 Hz)，6.88 (1H, d，J=3.9 Hz)， 7·15 (1H，dd，J=8.5，2·7 Hz)，7·24 (1H，d，J=3.9 Hz)，7·57 (1H，d，J=2.7 Hz)，7·65 (1H，d，J=8.5 Hz)。 MS (ESI) m/z: 371 (M-tBu)+ 〇 [參考例27] (3-胺基-4-{[(5-氯噻吩-2-羰基）胺基]甲基}苯氧 基）乙酸第三丁酯 向參考例26之化合物（707 mg)的乙醇（20 ml)溶液中添加 雷氏鎳（727 mg)，於氫條件下，於室溫下攪拌24小時。使 用玻璃過濾器將觸媒過濾分離後，於減壓下餾去溶劑。將 殘渣以使用石夕膠之快速層析法（己烧··乙酸乙酯=4 : 1 — 3 : 1)進行精製，於室溫下以真空泵乾燥，獲得標題化合 物（612 mg) 〇 H-NMR (CDC13) δ : 1·49 (9H，s)，4·45 (2H，s)，4·46 (2H，d， J=6.8 Hz)，6.14-6.26 (3H，m)，6.87 (1H，d，J=3,9 Ηζ)，6·99 (1H，d，J=7.8 Hz)，7.22 (1H，d，J=39 Hz)。 MS (ESI) m/z: 397 (M+H)+ 〇 [參考例28] 3-甲基-2·硝基苯曱酸第三丁醋 將3-甲基-2-硝基苯甲酸（ι·8ι g)、2_第三丁基-二異 丙基異脲（2.80 g)及曱苯（1 〇 mi)的混合物於6〇。〇下攪拌2小 時。向反應混合物中追加2-第三丁基十％二異丙基異脲 (2.80 g)後，於60 C下攪拌2小時。於減壓下館去溶劑，向 殘渣中添加醚。過濾去除不溶物，對所獲得之濾液於減壓 129677.doc -64- 200840568 下餾去溶劑。以矽膠層析法（己烷：乙酸乙酯=4 : 1)進行 精製，獲得標題化合物（1.99 。 'H-NMR (CDC13) δ : 1.54 (9H5 s)5 2.34 (3H, s), 7.40-7.46 (2H，m)，7·77-7·82 (1H，m)。 MS (ESI) m/z: 182 (M-tBu)+。 [參考例29] 3-胺基甲基-2-硝基苯甲酸第三丁酯 以與參考例19相同的方法，由參考例28之化合物獲得標 題化合物。 H-NMR (CDCI3) δ : 1·54 (9H，s)，1.78 (2H，br s)，3·86 (2H， s)，7·54 (1H，t，J=7.8 ΗΖ)，7·72 (1H，dd，J=7,8，1·2 ϋζ)， 7·85 (1H，dd，J=7.8，1.2 Hz)。 MS (ESI) m/z: 253 (M+H)+。 [參考例30] 3-{[(5-氣噻吩_2_羰基）胺基]曱基卜2_硝基笨甲 酸第三丁酯 以與參考例11相同的方法’將參考例29之化合物與5_氣 噻吩-2-甲酸縮合而獲得標題化合物。 'h-nmr (cdci^m.ss^ s)j4 54 (2H5 d&gt; J=6 3 Hz)&gt; 6.57 (1H, t, J=6.3 Hz), 6.89 (1H, d, J=3.9 Hz), 7.27 (lH, ^ J 3.9 Hz)’ 7.54 (1H，t，J=7.7 Hz)，7 79 (1H, dd，J = 7 7，丄 3 Hz)，7·87 (1H，dd，J=7.7, 1.3 Hz)。 MS (ESI) m/z: 419 (M+Na)+。 U考例31] 2-胺基-3][(5_氣嗟吩I幾基）胺基]甲基}H-NMR (CDC13) δ : 1.50 (9Η, s), 2.54 (3H, s), 4.55 (2H s), 7.10 (1H, dd, J=8.5, 2.7 Hz), 7.25 (1H, d, J= 8.5 Hz)! 7·49 (1H, d, J = 2.7 Hz). ' MS (ESI) m/z: 290 (M+Na)+. [Reference Example 25] (4-Aminomethyl-3-nitrophenoxy)acetic acid tert-butyl ester The title compound was obtained from the compound of Reference Example 24 in the same manner as in Reference Example 19. H-NMR (CDC13) δ : 1.50 (9H, s), ι·85_2 27 (2H, br), 4.04 (2H, s), 4·57 (2H, s), 7.17 (1H, dd, J=8.5 , 2.7 Ηζ), 7·49 (1H, d, J = 8.5 Hz), 7·50 (1H, d, J = 2.7 Hz). MS (ESI) m/z: 283 (M+H), [Ref. 26] (4-{[(5-chloro phenphen-2- yl)amino)] The title compound was obtained by condensing the compound of Reference Example 25 with 5-chloro-129677.doc-63-200840568 porphin-2-carboxylic acid in the same manner as in Reference Example 11. ]H-NMR (CDCI3) δ : 1.50 (9H? s)5 4.57 (2H? s)? 4.73 (2H? d3 J = 6.3 Hz), 6.83 (1H, t, J = 6.1 Hz), 6.88 ( 1H, d, J=3.9 Hz), 7·15 (1H, dd, J=8.5, 2·7 Hz), 7·24 (1H, d, J=3.9 Hz), 7·57 (1H, d, J = 2.7 Hz), 7·65 (1H, d, J = 8.5 Hz). MS (ESI) m/z: 372 (M-tBu) + 〇 [Reference 27] (3-amino-4-{[(5-chlorothiophen-2-carbonyl)amino]methyl}phenoxy To a solution of the compound of Reference Example 26 (707 mg) in ethanol (20 ml), EtOAc (EtOAc) (EtOAc) The catalyst was separated by filtration using a glass filter, and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (hexanes ethyl acetate = 4:1 - 3 : 1) eluted with EtOAc (EtOAc) NMR (CDC13) δ : 1·49 (9H, s), 4·45 (2H, s), 4·46 (2H, d, J = 6.8 Hz), 6.14-6.26 (3H, m), 6.87 (1H , d, J = 3, 9 Ηζ), 6.99 (1H, d, J = 7.8 Hz), 7.22 (1H, d, J = 39 Hz). MS (ESI) m/z: 397 (M+H)+ 〇 [Reference Example 28] 3-methyl-2·nitrobenzoic acid terpene vinegar 3-methyl-2-nitrobenzoic acid ( Mixture of ι·8ι g), 2_t-butyl-diisopropylisourea (2.80 g) and toluene (1 〇mi) at 6 〇. Stir under the arm for 2 hours. After adding 2-t-butyl decene diisopropylisourea (2.80 g) to the reaction mixture, the mixture was stirred at 60 C for 2 hours. The solvent was removed under reduced pressure, and ether was added to the residue. The insoluble matter was removed by filtration, and the obtained filtrate was evaporated under reduced pressure 129677.doc -64 - 200840568. Purification by silica gel chromatography (hexane: ethyl acetate = 4: 1) toield of the title compound (1.99..H-NMR (CDC13) δ: 1.54 (9H5 s)5 2.34 (3H, s), 7.40- 7.46 (2H,m),7·77-7·82 (1H,m) MS (ESI) m/z: 182 (M-tBu)+. [Reference Example 29] 3-aminomethyl-2- The title compound was obtained from the compound of the compound of Example 28 in the same manner as the compound of the title compound. H-NMR (CDCI3) δ: 1·54 (9H, s), 1.78 (2H, br s ),3·86 (2H, s),7·54 (1H,t,J=7.8 ΗΖ),7·72 (1H,dd,J=7,8,1·2 ϋζ), 7·85 (1H , dd, J = 7.8, 1.2 Hz) MS (ESI) m/z: 253 (M+H)+. [Reference Example 30] 3-{[(5- thiophene-2-carbonyl)amino] The title compound was obtained by condensing the compound of Reference Example 29 with 5-hydroxythiophene-2-carboxylic acid in the same manner as in Reference Example 11. 'h-nmr (cdci^m) .ss^ s)j4 54 (2H5 d&gt; J=6 3 Hz)&gt; 6.57 (1H, t, J=6.3 Hz), 6.89 (1H, d, J=3.9 Hz), 7.27 (lH, ^ J 3.9 Hz)' 7.54 (1H, t, J = 7.7 Hz), 7 79 (1H, dd, J = 7 7, 丄 3 Hz), 7·87 (1H, dd, J=7.7, 1.3 Hz) MS (ESI) m/z: 419 (M+Na)+. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt;

酸第三丁酯 T 以與參考例27相同的方法，由參考例默化合物獲得標 129677.doc •65· 200840568 題化合物。 ]Η.ΝΜΚ (CDC13) δ : 1.57 (9Η? s)5 4.56 (2Η5 d? J=6.l Ηζ)5 6·07·6·11 (1Η，m)，6.57 (1Η，t，&gt;7·7 Ηζ)，6·87_6·88 (1Η， m)，7.21-7.26 (2Η，m)，7.84 (1Η，dd，J=8.2，1·6 Hz)。 MS (ESI) m/z: 367 (M+H)、 [參考例32] 5-異丙基-4,5,6,7-四氫噻唑并[5,4_c]吡啶·：甲 酸鹽酸鹽 向2-溴-5-異丙基-4,5,6,7-四氫噻唑并[5,4_c]吡啶曱笨碏 酸鹽（WO 2003/000680)(11.3幻之喊懸浮液中添加飽和 NaHC〇3水溶液，進行分液，以無水MgS〇4乾燥有機層。 於減壓下餾去溶劑，將所獲得之油狀物質溶解於乾燥醚 (150爪1)中。於-781下以10分鐘向該溶液中添加正丁基鋰 (1.54 Μ己烷溶液，16.7 ml)。攪拌丨小時後，吹入二氧化 奴氣體（約5 1)，於-7 8 C下攪拌2小時。於室溫下攪拌3 〇分 鐘後，於減壓下餾去溶劑。向殘渣中添加乙醇（5〇 〇11)及1 當量鹽酸乙醇溶液（55 ml)。濾取所析出之粉末，進行乾燥 而獲得標題化合物（5.42 g)。 H-NMR (DMSO-d6) δ : 1.36 (6H，d，J=6.6 Hz)，3.00-3.52 (3H, m), 3.60-3.81 (2H, m), 4.35-4.83 (2H，m)。 MS (ESI) m/z: 227 (M+H)、 [參考例33]2-溴_5-異丙基-5,6,7,8-四氫_4{|-嗟嗤并[5,4-(：] 吖丁啶 使5,6,7,8 -四氫-4Η-σ塞峻并[5,4-c] σ丫 丁咬-2_胺氬漠酸鹽 (WO 2004/058715)(2.10 g)溶解於丙酮（5〇 ml)及曱醇（5〇 129677.doc -66- 200840568 中’添加ΤΈΑ(1,77 ml)及乙酸（350 μΐ)，冷卻至〇°c，添加 氰基硼氫化鈉（400 mg)，於室溫下攪拌3小時。向反應液 中添加飽和NaHC〇3水溶液，進行分液，以氯仿萃取水層5 次。合併有機層，以無水NazSO4乾燥，濃縮而獲得粗製之 5-異丙基-5,6,7,8-四氫-411-17塞吐并[5,4-(：]17丫丁咬-2-胺（1.36 g)。使其懸浮於水（10 ml)中，於〇°C下謹慎地滴下47%氫演 酸水溶液（7 ml)及亞硝酸鈉（570 mg)的水（5 ml)溶液。4小 時後’向反應液中添加飽和NaHC03水溶液及氯仿後，以 氟鎂石過濾去除不溶物。對濾液進行分液，將有機層以無 水NajO4水溶液乾燥，進行濃縮。向殘渣中添加IpE而去 除不溶物後，以矽膠層析法（氯仿：甲醇=98 : 2)進行精 製，獲得標題化合物（343 mg)。 H-NMR (CDC13) δ : 1.07 (6H5 d5 J=6.3 Hz), 1.74-1.80 (2H, m)，2.85-2.95 (1H，m)，2.99-3.02 (2H，m)，3·09·3·07 (2H， m)，3·84 (2H，s)。 MS (ESI) m/z: 275 (M+H)+。 [參考例34] 5-異丙基_5,6,7,8_四氫_4H_噻唑并[5,4_c]吖丁 啶-2-甲酸鋰鹽 於-7S°C下，向參考例33之化合物（343 mg)的醚（1〇ml)溶 液中滴下正丁基鋰（1·57 M己烷溶液，8〇〇 ，攪拌 時。向反應液中吹入二氧化碳氣體（約1 1)，升溫至室溫， 擾拌5小時。濾取析出#，獲得標題化合物（253 mg)。 4遍化(DMS〇-d6) δ : 〇·98 (6H，d，J=6.4 Hz)，1.63-1.68 (2H，m)，2·75·2·82 (1Ii，m)，2.84-2.87 (2H，m)，2·95-2·98 129677.doc -67- 200840568 (2H，m)，3.79 (2H，s) 〇 MS (ESI) m/z: 247 (M+H)+。 [參考例35] 6,7-二氫_4H-吼喃并[4,3-d]嗟σ坐-2 -甲酸 向6,7-二氫-4Η- σ比鳴并[4,3-d]嗟。坐_2-曱酸鐘鹽 (W02004/058715)(1.19 g)中添加 1當量鹽酸（12 ml)，於室 溫下攪拌。濾取所析出之固體，獲得標題化合物（754 mg) 〇 W-NMR (DMSO-d6) δ : 2.88 (2H，t，J=5.6 Hz)，3.97 (2H，t， J = 5.6 Hz)，4.85 (2H，s)。 MS (ESI) m/z: 186 (M+H)+ 〇 [參考例35 a] N-(2-胺基曱基-6-甲氧基苯基）_5_甲基_4,5,6,7_ 四氫噻唑并[5,4-c]吡啶-2-曱醯胺鹽酸鹽 將{3-甲氧基-2-[(5-甲基-4,5,6,7_四氫噻唑并[5,4-c]吡啶- 2-羰基）胺基]苄基}胺基甲酸第三丁酯（7〇〇 mg)溶解於二氯 曱烷（10 ml)中，添加4當量鹽酸二噚烷溶液（1() ml)。於室 溫下攪拌1小時後，於減壓下餾去溶劑。向殘渣中添加乙 酸乙酯，濾取固體，獲得標題化合物（593 mg)。 ^H-NMR (DMS〇.d6) δ ： 2.93 (3Η5 s)? 3.10-3.42 (2Η, m)? 3.44-3.74 (2Η，m)，3·89-3·97 (2Η，m)，4.35-4.87 (2Η，m)， 7.16 (2H? d? J^8.3 HZ), 7.41 (1H&gt; ^ br s)，10.08 (1H，S)，11.86 (lH，brs)。 MS (ESI) m/z: 333 (M+H)+。 [參考例36]5,6,7,8-四氫-『]61#+/^〇3办。;&gt; 从U，6]萘啶_2_甲酸甲g旨鹽酸鹽 以與參考例35a相同的方法 丄q。 卜 J万去，由7,8·二氫-5H-[1，6]萘啶-129677.doc '68- 200840568 2,6-二甲酸 6-第三丁酯 2-曱酯（J· Med· Chem. 2004, 47 (21)， 5167·)獲得標題化合物。 〗H，NMR (DMSO-d6) δ : 3·16 (2H，t，J=6.2 Hz)，3.45-3.51 (2H，m)5 3·87 (3H，s)，4.38 (2H，t，J=4.6 Hz)，7.86 (1H，d， J=8.1 Hz)，7.93 (1H，d，J=7.8 Hz)，9·82 (2H，br s)。 MS (ESI) m/z: 193 (M+H)+ 〇 [參考例37] 6-甲基-5,6,7,8_四氫-[1，6]萘啶-2-甲酸甲酯 向參考例36之化合物（1.00 g)的二氯甲烷（2〇 ml)-THF(25Acid T-butyl ester T The compound of the title compound 129677.doc • 65· 200840568 was obtained from the reference example compound in the same manner as in Reference Example 27. ]Η.ΝΜΚ (CDC13) δ : 1.57 (9Η? s)5 4.56 (2Η5 d? J=6.l Ηζ)5 6·07·6·11 (1Η,m), 6.57 (1Η,t,&gt; 7·7 Ηζ),6·87_6·88 (1Η, m), 7.21-7.26 (2Η,m), 7.84 (1Η, dd, J=8.2,1.66 Hz). MS (ESI) m/z: 367 (M+H), [Ref. 32] 5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4_c]pyridine: Addition of salt to 2-bromo-5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4_c]pyridinium sulphonate (WO 2003/000680) (11.3 phantom shout suspension) The aqueous NaHC 3 solution was saturated, and the organic layer was dried over anhydrous MgSO4. The solvent was evaporated under reduced pressure, and the obtained oily material was dissolved in dry ether (150 C). To the solution was added n-butyllithium (1.54 hexane solution, 16.7 ml) over 10 minutes. After stirring for a few hours, a sulphur dioxide gas (about 5 1) was blown in, and stirred at -7 8 C for 2 hours. After stirring at room temperature for 3 minutes, the solvent was evaporated under reduced pressure. To the residue was added ethanol (5 〇〇 11) and 1 eq. hydrochloric acid (55 ml). The precipitated powder was filtered and dried. The title compound (5.42 g) H-NMR (DMSO-d6) δ: 1.36 (6H, d, J = 6.6 Hz), 3.00-3.52 (3H, m), 3.60-3.81 (2H, m), 4.35-4.83 (2H, m) MS (ESI) m/z: 227 (M+H), [Ref. 33] 2-bromo-5-isopropyl-5,6,7,8-tetrahydro_4{| -嗟嗤[5,4-(:] Azetidine makes 5,6,7,8-tetrahydro-4Η-σ stopper and [5,4-c] σ丫丁咬-2_amine argonate (WO 2004/058715) (2.10 g) Dissolved in acetone (5 〇ml) and decyl alcohol (5 〇 129677.doc -66- 200840568 'add hydrazine (1,77 ml) and acetic acid (350 μ ΐ), cool to 〇 °c, add sodium cyanoborohydride (400 mg), the mixture was stirred at room temperature for 3 hours, and a saturated aqueous solution of NaHC 3 was added to the mixture, and the aqueous layer was separated, and the aqueous layer was extracted 5 times with chloroform. 5-isopropyl-5,6,7,8-tetrahydro-411-17 spit and [5,4-(:]17-butan-2-amine (1.36 g). suspended in water ( In 10 ml), a solution of 47% aqueous hydrogen acid solution (7 ml) and sodium nitrite (570 mg) in water (5 ml) was carefully dripped at 〇 ° C. After 4 hours, saturated NaHC03 was added to the reaction solution. After the aqueous solution and chloroform, the insoluble matter was removed by filtration with fluorite. The filtrate was separated, and the organic layer was dried over anhydrous NajO4 aqueous solution to concentrate. IpE was added to the residue to remove the insoluble matter, followed by silica gel chromatography (chloroform). :Methanol = 98 : 2) Refined to obtain the title Compound (343 mg). H-NMR (CDC13) δ : 1.07 (6H5 d5 J=6.3 Hz), 1.74-1.80 (2H, m), 2.85-2.95 (1H, m), 2.99-3.02 (2H, m), 3·09·3 · 07 (2H, m), 3.84 (2H, s). MS (ESI) m/z: 275 (M+H)+. [Reference Example 34] 5-isopropyl-5,6,7,8-tetrahydro-4H-thiazolo[5,4-c]azetidine-2-carboxylic acid lithium salt at -7 S ° C, to a reference example To a solution of 33 compound (343 mg) in ether (1 ml), n-butyllithium (1·57 M hexane solution, 8 Torr, while stirring, carbon dioxide gas (about 1 1) was blown into the reaction solution. The temperature was raised to room temperature, and the mixture was stirred for 5 hours. The title compound (253 mg) was obtained by filtration. 4D (DMS 〇-d6) δ: 〇·98 (6H, d, J = 6.4 Hz), 1.63 -1.68 (2H,m),2·75·2·82 (1Ii,m),2.84-2.87 (2H,m),2·95-2·98 129677.doc -67- 200840568 (2H,m), 3.79 (2H, s) 〇MS (ESI) m/z: 247 (M+H)+. [Reference 35] 6,7-dihydro-4H-indole[4,3-d]嗟σ -2 - Formic acid to 6,7-dihydro-4 Η-σ 鸣 and [4,3-d] 嗟. Sitrate _2- citrate clock salt (W02004/058715) (1.19 g) with 1 equivalent of hydrochloric acid ( 12 ml), stirred at room temperature. The solid was crystallized to give the title compound (754 mg) </RTI> NMR (DMSO-d6) δ: 2.88 (2H, t, J = 5.6 Hz), 3.97 (2H , t, J = 5.6 Hz), 4.85 (2H, s) MS (ESI) m/z: 186 (M+H) + 〇 [Reference Example 35 a] N-(2-amine曱-yl-6-methoxyphenyl)_5_methyl_4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-indoleamine hydrochloride {3- Oxy-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl)amino]benzyl}aminocarbamic acid tert-butyl ester (7 〇〇 mg) was dissolved in dichloromethane (10 ml), and 4 ml of a dioxane hydrochloride solution (1 ml) was added. After stirring at room temperature for 1 hour, the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, and the solid was filtered to give the title compound ( 593 mg). NMR (DMS 〇.d6) δ: 2.93 (3Η5 s)? 3.10-3.42 (2Η, m)? 3.44-3.74 (2Η,m),3·89-3·97 (2Η,m), 4.35-4.87 (2Η,m), 7.16 (2H?d? J^8.3 HZ), 7.41 (1H&gt; ^ br s), 10.08 (1H, S), 11.86 (lH, brs). MS (ESI) m/z: 333 (M+H)+. [Reference Example 36] 5,6,7,8-tetrahydro-"]61#+/^〇3. ;&gt; From U,6] naphthyridine_2_carboxylic acid methyl chlorate hydrochloride The same procedure as in Reference Example 35a 丄q. Bu Jwan, from 7,8. dihydro-5H-[1,6]naphthyridine-129677.doc '68- 200840568 2,6-dicarboxylic acid 6-tert-butyl ester 2-decyl ester (J· Med · Chem. 2004, 47 (21), 5167·) obtained the title compound. H, NMR (DMSO-d6) δ : 3·16 (2H, t, J = 6.2 Hz), 3.45-3.51 (2H, m) 5 3·87 (3H, s), 4.38 (2H, t, J =4.6 Hz), 7.86 (1H, d, J = 8.1 Hz), 7.93 (1H, d, J = 7.8 Hz), 9·82 (2H, br s). MS (ESI) m / z: 193 (M+H) + 〇 [Reference Example 37] 6-methyl-5,6,7,8-tetrahydro-[1,6]naphthyridine-2-carboxylic acid methyl ester To the compound of Reference Example 36 (1.00 g) in dichloromethane (2 mL)-THF (25

ml)懸浮液中添加ΤΕΑ(609 μΐ)、乙酸（480 μΐ)、37%福馬林 水溶液（657 μΐ)及三乙醯氧基硼氫化鈉（185 g)，攪拌2〇小 時。向反應液中追加37%福馬林水溶液（328 μ丨）、三乙醯氧 基侧氫化鈉（G.93G g)，進而授拌7小時。添加飽和祕叫 水溶液而成為驗性後’以二氯甲烧萃取，以無水MgS〇4乾 燥。於減壓下餾去溶劑，釋徂挪日石&amp;人&quot; 又知才示通化合物（688 mg) 〇 iH-NMR (CDC13) δ ·· 2·49 、、 (Η，s)，2.82 (2Η，t，J=6.〇 Hz) 3.18 (2H，t，J=6.1 Hz)，3.65 ( ’， (2H，s)，3·99 (3H，s)，7.47 (lH d，J=8.1Hz)，7.92(lH，d，h8 lHz)。 、^ MS (ESI) m/z: 207 (M+H)+ 〇 [參考例38] 6-甲基_5,6,7,8 四H-[l，6]萘啶-2·甲酸鋰_ 以與參考例1 8相同的方法 ^ 万去，由參考例37之化合物獲楫扭 題化合物。 ^件標 s)，2·65 (2H， ，s)，7·54 (1H， t，J&gt;6.〇 d，j&gt;7.8 ]H-NMR (DMSO-d6) δ ； 2 34 (3¾ Hz), 2.77 (2H, t, J=5.7Hz), 3 51 (2h Ηζ)，7·72 (1H，d，J=7』hz) 0 129677.doc -69 * 200840568M) The suspension was mixed with hydrazine (609 μΐ), acetic acid (480 μΐ), 37% aqueous solution of formalin (657 μΐ) and sodium triethoxysulfonate (185 g), and stirred for 2 hours. To the reaction liquid, a 37% aqueous solution of Formalin (328 μM) and sodium hydride (G.93 G g) were added, and the mixture was further mixed for 7 hours. After adding a saturated aqueous solution to the test, it was extracted with methylene chloride and dried with anhydrous MgS 4 . The solvent was distilled off under reduced pressure, and the product was released. The compound (688 mg) 〇iH-NMR (CDC13) δ ·· 2·49 , (Η, s), 2.82 (2Η,t,J=6.〇Hz) 3.18 (2H,t,J=6.1 Hz), 3.65 ( ', (2H, s), 3·99 (3H, s), 7.47 (lH d, J= 8.1 Hz), 7.92 (lH, d, h8 lHz), ^ MS (ESI) m/z: 207 (M+H) + 〇 [Reference Example 38] 6-Methyl_5,6,7,8 IV H-[l,6]naphthyridine-2·formic acid lithium _ was obtained in the same manner as in Reference Example 18, and the compound of Reference Example 37 was obtained as a tow compound. ^ s), 2·65 ( 2H, , s),7·54 (1H, t, J&gt;6.〇d,j&gt;7.8]H-NMR (DMSO-d6) δ ; 2 34 (33⁄4 Hz), 2.77 (2H, t, J= 5.7 Hz), 3 51 (2h Ηζ), 7·72 (1H, d, J=7』hz) 0 129677.doc -69 * 200840568

Ms (ESI) m/z: 193 (M+H)+。Ms (ESI) m/z: 193 (M+H)+.

[參考例39] 6-異丙基-5,6,7,8-四氫-[1，6]萘啶-2-甲酸甲酉旨 向參考例36之化合物（l.oo g)的THF(50 ml)懸浮液中添加 ΤΕΑ(609 μΐ)、乙酸（480 μ1)、丙酮（963 μΐ)及三乙醯氧基蝴 氫化鈉（1.85 g)。於5小時後、9小時後及19小時後向反應 液中分別追加丙酮（963 μΐ)、三乙醯氧基硼氫化鈉（〇.93 g)，進而攪拌24小時。添加飽和NaHC〇3水溶液而成為鹼 性後，以二氯曱烷萃取，以無水MgS〇4乾燥。於減壓下餾 去洛劑’獲得標題化合物（784 mg)。 *H-NMR (CDC13) δ : 1.15 (6Η, d, J=6.6 Hz), 2.89 (2H, t J = 6.0Hz), 2.91-3.02 (1H, m), 3.15(2H, t, J=6.〇 Hz), 3.80 (2H，s)，3·99 (3H，s)，7·48 (1H，d，J=8.〇 Hz)，7·91 (iH d J = 7,8 Hz) 〇 MS (ESI) m/z: 235 (M+H)+。 以與參考例1 8相同的方法 題化合物。 [參考例40] 6·異丙基·5,6,7,8-四氫·萘咬·2_甲酸鐘鹽 由參考例39之化合物獲得標 6·6 Hz)，2·74 (4H， (1H，d，J=7.8 Hz)， !H.NMR (DMSO-d6) δ : 1.04 (6H? d5 s)，2.81-2.92 (1H，m)，3.65 (2H，s)，7·55 7·71 (1H，d，J=7.8 Hz)。 MS (ESI) m/z: 221(M+H)+。 -c]utb ^ -6« ψ [參考例41] 2-異丙基-2,3-二氫-iH_吡略并[3 * 酸甲酉旨 氧· 1H- °比嘻并[3，4_ 以與參考例39相同的方法，由2,3_二 129677.doc -70- 200840568 C]吡啶-6-甲酸甲酯鹽酸鹽（W02004/058728)獲得標題化合 物。 'H-NMR (CDC13) δ : 1.21 (6H? d? J=6.3 Hz)? 2.77-2.88 (1H5 m)，4·01 (3H，s)，4·01-4·07 (4H，m)，8.02 (1H，s)，8·59 (1H， s) 〇 MS (ESI) m/z: 221 (M+H)+。 [參考例42] 2-異丙基-2,3 -二氣比口各并[3,4-c]11比σ定-6-甲 酸鹽酸鹽 將參考例41之化合物（281 mg)溶解於THF(4 ml)及水（1 ml)的混合溶劑中。向該溶液中添加Li〇H(34,3 mg)，於室 溫下擾拌2小時。於減壓下鶴去溶劑，向殘渣中添加1當量 鹽酸（3 ml)。於減壓下餾去溶劑，向殘渣中添加乙醇。濾 取固體，獲得標題化合物（204 mg)。 】H-NMR (DMSO-d6) δ ·· 1.36 (6H，d，J=6.3 Hz)，3.66-3.78 (1H，m)，4·57-4·94 (4H，m)，8.09 (1H，s)，8·72 (1H，s)， 12.15 (1H，br s)。 MS (ESI) m/z: 207 (M+H)+。 [參考例43] 2-溴-5-(2-氟-1-甲基乙基）-4,5,6,7-四氫噻唑并 [5,4-c]ab 咬 以與參考例39相同的方法，由2-溴-4,5,6,7-四氫噻唑并 [5,4-c]吡啶TFA鹽（W02003/000680)與氟丙酮獲得標題化合 物。 1H-NMR (CDC13) δ : 1.17 (3H，dd，J=6.9, 1·5 Ηζ)，2.84·2·89 (2H，m)，2·96 (2H，t，J=5.5 Hz)，3·08-3·21 (1H，m)，3·78- 129677.doc •71 - 200840568 3.86 (2H，m)，4.40-4.59 (2H，m)。 MS (ESI) m/z: 280 [(M+H)+，8lBr]。 [參考例44]5_(2_氣·r甲基乙基）_4,5,6,7_四氫嘆嗅并p叫 吡啶_2_甲酸鋰鹽 以與參考例34㈣的方法’由參考例43之化合物獲得標 題化合物。 W-NMR (DMSO-d6) δ : 1·〇4 (3H d τ “ … d, J=6.4 Hz), 2.67 (2H t J = 5.1 Hz)，2.82-2.90 (2H m) 1 a/ι， ’[Reference Example 39] 6-isopropyl-5,6,7,8-tetrahydro-[1,6]naphthyridine-2-carboxylic acid formazan THF to the compound of Reference 36 (l.oo g) (50 ml) suspension was added with cesium (609 μΐ), acetic acid (480 μl), acetone (963 μΐ) and triethylphosphonium hydrogen hydride (1.85 g). After 5 hours, 9 hours, and 19 hours, acetone (963 μM) and sodium triethoxysulfonate (〇.93 g) were added to the reaction mixture, followed by stirring for 24 hours. After adding a saturated aqueous solution of NaHC〇3 to alkalinity, it was extracted with dichloromethane and dried over anhydrous Mg??. The extract was removed under reduced pressure to give the title compound (784 mg). *H-NMR (CDC13) δ : 1.15 (6Η, d, J=6.6 Hz), 2.89 (2H, t J = 6.0Hz), 2.91-3.02 (1H, m), 3.15(2H, t, J=6 .〇Hz), 3.80 (2H, s), 3·99 (3H, s), 7·48 (1H, d, J=8.〇Hz), 7·91 (iH d J = 7,8 Hz) 〇MS (ESI) m/z: 235 (M+H)+. The compound was obtained in the same manner as in Reference Example 18. [Reference Example 40] 6·Isopropyl·5,6,7,8-tetrahydro·naphthalene bite·2—carboxylic acid citrate was obtained from the compound of Reference Example 39 by 6·6 Hz), 2.74 (4H, (1H, d, J = 7.8 Hz), !H.NMR (DMSO-d6) δ : 1.04 (6H? d5 s), 2.81-2.92 (1H, m), 3.65 (2H, s), 7·55 7 · 71 (1H, d, J = 7.8 Hz) MS (ESI) m/z: 221 (M+H) + -c]utb ^ -6« ψ [Reference Example 41] 2-isopropyl-2 , 3-dihydro-iH_pyrrolo[3* acid methyl hydrazine-1H-° 嘻[3,4_ in the same manner as in Reference Example 39, from 2,3_two 129677.doc -70 - 200840568 C] Pyridine-6-carboxylic acid methyl ester hydrochloride (W02004/058728) gave the title compound. 'H-NMR (CDC13) δ: 1.21 (6H? d? J=6.3 Hz)? 2.77-2.88 (1H5 m ),4·01 (3H,s),4·01-4·07 (4H,m),8.02 (1H,s),8·59 (1H, s) 〇MS (ESI) m/z: 221 ( M+H)+ [Reference Example 42] 2-isopropyl-2,3-dialdehyde ratio each [3,4-c]11 ratio sigma-6-formate hydrochloride Reference Example 41 The compound (281 mg) was dissolved in a mixed solvent of THF (4 ml) and water (1 ml). To the solution was added Li〇H (34, 3 mg), and the mixture was stirred at room temperature for 2 hours. Press the crane to remove the solvent and into the residue After adding 1 N of hydrochloric acid (3 ml), the solvent was evaporated to dryness, and the residue was evaporated to ethylamine. ,d,J=6.3 Hz),3.66-3.78 (1H,m),4·57-4·94 (4H,m),8.09 (1H,s),8·72 (1H,s), 12.15 (1H , s s) MS (ESI) m/z: 207 (M+H)+. [Ref. 43] 2-bromo-5-(2-fluoro-1-methylethyl)-4,5,6 , 7-tetrahydrothiazolo[5,4-c]ab was bitten in the same manner as in Reference Example 39, from 2-bromo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine The title compound was obtained from the TFA salt (W02003/000680) and fluoroacetone. 1H-NMR (CDC13) δ: 1.17 (3H, dd, J=6.9, 1·5 Ηζ), 2.84·2·89 (2H, m), 2 ·96 (2H,t,J=5.5 Hz),3·08-3·21 (1H,m),3·78- 129677.doc •71 - 200840568 3.86 (2H,m),4.40-4.59 (2H, m). MS (ESI) m/z: 280 [ (M+H)+, 8lBr]. [Reference Example 44] 5_(2_gas·rmethylethyl)_4,5,6,7-tetrahydrosole and p-pyridyl 2-carboxylic acid lithium salt as in the method of Reference Example 34 (IV) 'by reference example The compound of 43 obtained the title compound. W-NMR (DMSO-d6) δ : 1·〇4 (3H d τ “ ... d, J=6.4 Hz), 2.67 (2H t J = 5.1 Hz), 2.82-2.90 (2H m) 1 a/ι, '

、，m)，3·04·3·13 (1H，m)，3·79 (2H， d，J=30.6 Hz)，4.36-4.58 (2H，m)。 ’ MS (ESI) m/z: 244 (M+H)+。 [參考例45] 2-溴-5-(2-氟-l-氟甲其7甘、1 &lt; π 甲基乙基）-4,5,6,7 -四氫嗟唾 并[5,4-〇]0比σ定 以與參考例39相同的方法，由 田溴-4,5,6,7-四氧π塞唾并 [5,4-c]吼咬TFA鹽與：氟丙s同獲得標題化合物。 W-NMR (CDC13) δ : 2,87 (2H t τ c ⑽，t，&gt;5·6 Hz)，3.08 (2H t &gt;5.9 Hz)，3.17-3.33 (1H，m)，3 93 加、… ，， 乂，(2H，s)，4.70 (4H，dd J=47.4, 5.1 Hz)。 cid， MS (ESI) m/z: 297 (M+H)、 乙基）·4,5,6,7-四氫噻唑并 由參考例45之化合物獲得標 [參考例46] 5-(2-敗-i-氟曱基 [5,4-c]°比咬-2-甲酸經鹽 以與參考例34相同的方法， 題化合物。 :2·68 (2H，t， (1H，m)，3·87 W-NMR (DMSO-d6) δ J-5.6 Hz)? 3.20-3.37 J-5.9 Hz)5 2.98 (2H, t5(2H，s)，4·66 (4H，dd， 129677.doc -72- 200840568 J=47.3, 5·1 Hz) 〇 MS (ESI) m/z: 263 (M+H)+。 [參考例47] 2-溴-5-(2-甲氧基曱基乙基）_4,5,6,7_四氫噻 °坐并[5,4-〇]°比唆 以與芩考例39相同的方法，由孓溴_4,5,6,7_四氫噻唑并 [5,4-c]吼啶TFA鹽與曱氧基丙酮獲得標題化合物。 ^H^NMR (CDC13) δ : 1.12 (3H) d5 J=6.6 Hz), 2.83-2.89 (2H, m)，2.93 (2H，t，卜5.1 Hz)，3·〇1_3·1〇 (1H，m)，3 35 (3H，s)， 3.38 (1H，dd，J=9.8, 5.1 Hz)，3·52 (1H，dd，J=9 8, 6 4 Hz)， 3·75-3·84 (2H，m)。 MS (ESI) m/z: 293 [(M+H)+，81Br]。 [參考例48] 5-(2-甲氧基+甲基乙基）·4,5,6,7_四氫嗟唾并 [5,4-c]吡啶-2-甲酸鋰鹽 以與參考例34相同的方法，由參考例〜之化合物獲得標 題化合物。 • lH-NMR (DMS〇-d6) δ : 101 ⑽，d，&gt;6.6 Hz)，2_65 (2H，t， J=5.6 HZ)，2_82 (2H，t，卜5.8 HZ)，2.92_3.〇() (1H，m)，3.28 H, dd, J-9.8, 6.1 Hz), 3.32 (3H, s), 3.46 (1H, dd, J=9.8, ^•9 Hz), 3.70 (1H, d, 1=15.2 Hz), 3.75 (1H, d, 1=15.2 Hz) 〇, m), 3·04·3·13 (1H, m), 3.79 (2H, d, J = 30.6 Hz), 4.36-4.58 (2H, m). ' MS (ESI) m/z: 244 (M+H)+. [Reference Example 45] 2-bromo-5-(2-fluoro-l-fluoromethyl 7-glycol, 1 &lt; π-methylethyl)-4,5,6,7-tetrahydroindole[5, 4-〇]0 σ is determined in the same manner as in Reference Example 39, from the field of bromo-4,5,6,7-tetraoxo π-sal[5,4-c] bite TFA salt with: fluoropropane s The title compound was obtained. W-NMR (CDC13) δ : 2,87 (2H t τ c (10), t, &gt; 5·6 Hz), 3.08 (2H t &gt; 5.9 Hz), 3.17-3.33 (1H, m), 3 93 plus ,... ,, 乂, (2H, s), 4.70 (4H, dd J=47.4, 5.1 Hz). Cid, MS (ESI) m/z: 297 (M+H), ethyl) 4,5,6,7-tetrahydrothiazole and obtained from the compound of Reference Example 45 [Reference Example 46] 5-(2) -----fluoroindolyl [5,4-c]° than the bite-2-carboxylic acid salt in the same manner as in Reference Example 34, the title compound: 2·68 (2H, t, (1H, m) ,3·87 W-NMR (DMSO-d6) δ J-5.6 Hz)? 3.20-3.37 J-5.9 Hz)5 2.98 (2H, t5(2H,s),4·66 (4H,dd, 129677.doc -72- 200840568 J=47.3, 5·1 Hz) 〇MS (ESI) m/z: 263 (M+H)+ [Ref. 47] 2-bromo-5-(2-methoxyindenyl )4,5,6,7_tetrahydrothiophene[5,4-〇]° 唆 in the same manner as in Test Example 39, from 孓 孓 4,5,6,7_tetrahydrogen The title compound was obtained from the thiazolo[5,4-c]acridine TFA salt and decyloxyacetone. ^H^NMR (CDC13) δ: 1.12 (3H) d5 J=6.6 Hz), 2.83-2.89 (2H, m) , 2.93 (2H, t, 5.2 Hz), 3·〇1_3·1〇(1H,m), 3 35 (3H,s), 3.38 (1H,dd,J=9.8, 5.1 Hz),3·52 (1H, dd, J = 9 8, 6 4 Hz), 3·75-3·84 (2H, m). MS (ESI) m/z: 293 [ (M+H)+, 81Br]. [Reference Example 48] 5-(2-methoxy+methylethyl)·4,5,6,7-tetrahydroindole[5,4-c]pyridine-2-carboxylic acid lithium salt with reference In the same manner as in Example 34, the title compound was obtained. • lH-NMR (DMS〇-d6) δ : 101 (10), d, &gt; 6.6 Hz), 2_65 (2H, t, J = 5.6 HZ), 2_82 (2H, t, 4.8 HZ), 2.92_3.〇 () (1H, m), 3.28 H, dd, J-9.8, 6.1 Hz), 3.32 (3H, s), 3.46 (1H, dd, J=9.8, ^•9 Hz), 3.70 (1H, d, 1=15.2 Hz), 3.75 (1H, d, 1=15.2 Hz) 〇

Ms (ESI) m/z: 257 (M+H)+。 [參考例49] 4-演甲基_2_甲氧基_5_石肖基苯甲酸甲醋 將2-甲氧基-4_ ▼基·5·硝基苯甲酸甲酯（186 及 NBS(1.76 g)懸洋於四氯化破（5〇 _中。肖該懸浮液中添 加過氧化苯甲醯（含水25〇/O,〇.l3g)，加熱回流一整夜。過 129677.doc •73· 200840568 遽去除不溶物後，將浦德、、曲μ ，愿液，辰縮。將殘渣以矽膠層析法（己 烷：乙酸乙酯=9 : 1)進行籍制 ^ ^ ^ β 仃積製，獲得標題化合物（174g)。 W-NMR (CDC13) δ : 3 、 (3Η，s)，4·04 (3Η，s)，4.90 (2Η， s)，7.13 (1H，s)，8·65 (1H，s)。 [參考例50]3-[2-(第三丁氡基《胺基）苯基]丙酸乙酉旨Ms (ESI) m/z: 257 (M+H)+. [Reference Example 49] 4-Methyl-2_methoxy_5_Cishyl benzoic acid methyl acetonate 2-methoxy-4_\yl·5·nitrobenzoic acid methyl ester (186 and NBS (1.76 g) Suspended in tetrachlorinated (5 〇 _. Add benzoyl peroxide (25 〇 / O, 〇.l3g) to the suspension, and heat to reflux overnight. 129677.doc • 73· 200840568 遽 After removing the insoluble matter, Puer, 曲μ, 愿液, 缩 。. The residue was chromatographed (hexane: ethyl acetate = 9: 1) for the system ^ ^ ^ β 仃 accumulation system The title compound (174g) was obtained. W-NMR (CDC13) δ: 3, (3Η, s), 4·04 (3Η, s), 4.90 (2Η, s), 7.13 (1H, s), 8.65 (1H, s) [Reference Example 50] 3-[2-(Tertidinyl "amino)phenyl]propanoic acid

向⑹-3-(2_硝基苯基）丙稀酸乙酉旨0 .24 g)之乙酸乙醋（20 ml)溶液中添加B〇C2〇(i.90 ml) ' 1〇%鈀碳觸媒（55呵），於 氫氣環境下且於室溫下攪拌3日。將觸媒過濾分離後，於 減壓下餾去溶劑。將殘渣以矽膠管柱層析法（己烷：乙酸 乙酯=8 : 1—7 : 1—6 : 1)進行精製，獲得標題化合物（1 42 g) 〇 H-NMR (CDC13) δ : 1.23 (3H，t，J=7.1 Hz)，1.53 (9H，s)， 2·67 (2H，t，J=7.1 Hz)，2.89 (2H，t，J=7.1 Hz)，4·12 (2H，q， J = 7.1 Hz)，7·02-7·08 (1H5 m)，7.11-7.16 (1H，m), 7·17-7·24 (2H, m)，7·69，7·71 (total 1H，each br s) 〇 MS (ESI) m/z: 316 (M+Na)+ 〇 [參考例51] (2-{2-[N-(4-氯苯基）胺甲醯基]乙基}苯基）胺基 曱酸第三丁酯 向參考例50之化合物（975 mg)的二崎烧（9 ml)溶液中添 加LiOH(82 mg)、水（2 ml)，於室溫下攪拌28小時，且於50 °C下攪拌1小時。向反應液中添加LiOH(26 mg)、水（3 ml)、二咩烷（2 ml)，於50°C下攪拌17·5小時。向反應液中 添加LiOH(28 mg)、甲醇（2 ml)，於50°C下攪拌7.5小時。 將反應液於減壓下濃縮。向殘渣之DMF(20 ml)溶液中添加 129677.doc -74- 200840568 4-氯苯胺（508 mg)、HOBt(406 mg)、EDC(760 mg)，於室 溫下攪拌3日。將反應液於減壓下濃縮後，添加乙酸乙 酯、5%檸檬酸水溶液。以乙酸乙酯萃取後，以飽和 NaHCCb水溶液、飽和NaCl水溶液清洗所合併之有機層， 以無水NajO4乾燥，於減壓下餾去溶劑。向殘渣中添加己 烷-乙酸乙酯之混合溶液，濾取不溶物，獲得標題化合物 (7 1 9 mg) 〇 1H-NMR (CDC13) δ ·· 1·54 (9H，s)，2·67 (2H，t，J=6.7 Hz) 3.00 (2H, t, J—6.7 Hz), 7.03-7.09 (1H? m), 7.12-7.24 (5JJ m)，7·32 (2H，d，J=8.8 Hz)，7.48-7.59 (2H，m)。 MS (ESI) m/z: 397 (M+Na)+ 〇 [參考例52] 3-曱基-2-硝基苯甲酸曱酯 向3-甲基-2-硝基苯甲酸（15·0 g)之甲醇（150 ml)溶液中添 加濃硫酸（1.50 ml)，加熱回流2日。將反應液冷卻後，於 減壓下濃縮為一半左右的量，添加乙酸乙酯、飽和 NaHCCb水溶液。以乙酸乙酯萃取後，以飽*NaC1水溶液 清洗所合併之有機層。以無水Na2S〇4乾燥後，於減壓下麵 去〉谷劑’獲得標題化合物（14. 〇 g)。 iH-NMR (CDC13) δ : 2·36 (3H，s)，3.9G (3H，S)，7,40-7.53 (2Η，m)，7·79-7·89 (1Η，m)。 MS (ESI) m/z: 218 (M+Na)+。 [參考例53] 3-((E)-2-二甲基胺基乙烯基）-2-硝基苯甲酸甲 酉旨 向參考例52之化合物（14.0 g)的DMF(72 ml)溶液中添加 129677.doc -75- 200840568 N，N-二曱基曱醯胺二曱縮醛（12·5 ml)，於14〇〇c下攪拌24 小日寸。將反應液於減壓下濃縮後，向殘渣中添加甲醇，濾 取固體’獲得標題化合物（8.54 g)。 i-NMR (CDC13) δ : 2·85 (6H，s)，3·87 (3H，s)，4·92 (1H，d， J = 13.4 Hz)，6.85 (1H，d，J=13.4 Hz)，7·27-7·33 (1H，m)， 7.52 (1H，dd，J=7.6, 1.2 Hz)，7·55 (1H，dd，J=8.1，1.2 Hz)。 [參考例54] 3-曱醯基硝基苯曱酸曱酯 於冰浴冷卻下，向參考例53之化合物（8.51 g)的THF(100 ml)、水（100 ml)的混合溶液中添加過碘酸鈉（2〇 9 g)，於 室溫下攪拌2.5小時。將沈澱物過濾分離後，向濾液中添 加飽和NaHC〇3水溶液。將所析出之結晶再次過濾分離 後，以乙酸乙酯萃取，以飽和NaHC〇3水溶液清洗所合併 之有機層。以無水NaJ〇4乾燥後，於減壓下顧去溶劑。將 殘渣以矽膠管柱層析法（己烷：乙酸乙酯: 1 -&gt; 4 : 1 — 2 ·· 1)進行精製。向粗精製物的乙酸乙酯（3〇 ^1)溶液中添 加己烷（40 ml)，於室溫下攪拌13小時。濾取固體，獲得標 題化合物（3.73 g)。 iH-NMR (CDC13) δ : 3.95 (3H，S)，7·77 (1H，t，J=7.8 Hz)， 8·18 (1H，dd，J=7.8，1·5 Hz)，8·28 (1H，dd，J=7.8, 1·5 Hz)， 9.98 (1H，s)。 [參考例55] 3-((E)-2-第三丁氧基羰基乙烯基）_2_硝基苯甲 酸曱酯 於0°C下’向二乙基膦酸基乙酸第三丁酯（4·21 g)的 THF (3 5 ml)溶液中添加55%氫化鈉（675 mg)，於0°C下授掉 129677.doc -76- 200840568 30分鐘。向反應液中添加參考例54之化合物（2 97幻的 THF(40 ml)、DMF(3 ml)混合溶液，於〇°C下攪拌3〇分鐘， 且於室溫下攪拌3 0分鐘。向反應液中添加飽和NaCi水溶 液、乙酸乙酯。以乙酸乙酯萃取後，以飽和Naci水溶液清 洗所合併之有機層。以無水NaJO4乾燥後，於減壓下餾去 溶劑。將殘渣以矽膠管柱層析法（己烷：乙酸乙酯=5 : 1 — 4 : 1—3 : 1)進行精製，獲得標題化合物（3.70 g)。 】H-NMR (CDC13) δ : 1.52 (9H，s)，3.92 (3H，s)，6.42 (1H，d， J=15.9 Hz)，7.45 (1H，d，J=15.9 Hz)，7.55-7.62 (1H，m)， 7·84 (1H，dd，J=8.1，1·2 Hz)，8·02 (1H，dd，J=7.7, 1.2 Hz)。 MS (ESI) m/z: 330 (M+Na)+。 [參考例56] 3-((E)-2-第三丁氧基羰基乙烯基)_2_硝基苯 曱酸 向參考例55之化合物（3·65 g)的二氯甲烷（20 ml)溶液中 添加TFA(10 ml)，於室溫下攪拌16小時。濾取所析出之固 體，以己烷清洗，獲得標題化合物（2.82 g)。 iH-NMR (CD3OD) δ : 3·89 (3H，s)，6.65 (1H，d，J=15.9 Hz)， 7.46 (1H，d，J=15.9 Hz)，7·68-7·75 (1H，m)，8·07 〇H，dd， 卜7.7，1.3 Hz)，8·13 (1H，dd，J=8.0，1·3 Hz)。 MS (ESI) m/z: 250 (M-H)\ [參考例57] 3-{(E)-2-[(4-氣苯基）胺曱醯基]乙烯基卜2_硝基 苯曱酸曱酯 向參考例56之化合物（601 mg)中添加亞硫醯氯（6.0 、 DMF(約〇·〇2 ml) ’加熱回流3小時。將反應液於減壓下濃 129677.doc •77- 200840568 縮後，將殘潰製成THF(6 ml)溶液，添加4_氯笨胺（353 mg)、ΤΕΑ(500 μΐ)，於室溫下攪拌4小時。濾取所析出之 固體。將濾液濃縮後，以二氣甲烷清洗殘渣，且與濾取之 固體一併於曱醇中攪拌丨4小時。濾取不溶物，獲得標題化 合物（701 mg)。 iH-NMR (DMSO-d6) δ : 3·87 (3H，s)，6·96 (1H，d，J=i5 4Add B〇C2〇(i.90 ml) '1〇% palladium carbon to a solution of (6)-3-(2-nitrophenyl)propanoic acid ethyl acetate (0.4 g) in ethyl acetate (20 ml) The catalyst (55 °) was stirred under a hydrogen atmosphere at room temperature for 3 days. After the catalyst was separated by filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=8:1-7:1 - 6:1) to give the title compound (1 42 g) 〇H-NMR (CDC13) δ: 1.23 (3H, t, J = 7.1 Hz), 1.53 (9H, s), 2·67 (2H, t, J = 7.1 Hz), 2.89 (2H, t, J = 7.1 Hz), 4·12 (2H, q, J = 7.1 Hz), 7·02-7·08 (1H5 m), 7.11-7.16 (1H, m), 7·17-7·24 (2H, m), 7·69, 7·71 ( Total 1H,each br s) 〇MS (ESI) m/z: 316 (M+Na)+ 〇 [Reference Example 51] (2-{2-[N-(4-chlorophenyl)aminemethanyl] To the solution of the compound of Reference Example 50 (975 mg) in bisaki (9 ml) was added LiOH (82 mg), water (2 ml) at room temperature. It was stirred for 28 hours and stirred at 50 ° C for 1 hour. LiOH (26 mg), water (3 ml), and dioxane (2 ml) were added to the reaction mixture, and the mixture was stirred at 50 ° C for 17.5 hours. LiOH (28 mg) and methanol (2 ml) were added to the reaction mixture, and the mixture was stirred at 50 ° C for 7.5 hours. The reaction solution was concentrated under reduced pressure. 129677.doc -74- 200840568 4-chloroaniline (508 mg), HOBt (406 mg), EDC (760 mg) was added to a solution of the residue in DMF (20 ml), and stirred at room temperature for 3 days. After the reaction mixture was concentrated under reduced pressure, ethyl acetate and 5% aqueous citric acid were added. After extracting with ethyl acetate, the combined organic layer was washed with saturated aqueous NaH. A mixed solution of hexane-ethyl acetate was added to the residue, and the insoluble material was filtered to give the title compound (7 1 9 mg) 〇1H-NMR (CDC13) δ ··1·54 (9H, s), 2.67 (2H, t, J = 6.7 Hz) 3.00 (2H, t, J-6.7 Hz), 7.03-7.09 (1H? m), 7.12-7.24 (5JJ m), 7·32 (2H, d, J=8.8 Hz), 7.48-7.59 (2H, m). MS (ESI) m/z: 397 (M+Na) + 〇 [Ref. 52] 3-decyl-2-nitrobenzoic acid decyl ester to 3-methyl-2-nitrobenzoic acid (15·0 To a solution of methanol (150 ml), concentrated sulfuric acid (1.50 ml) was added and heated to reflux for 2 days. After cooling the reaction mixture, the mixture was concentrated to a half amount under reduced pressure, and ethyl acetate and a saturated aqueous NaHCCb solution were added. After extracting with ethyl acetate, the combined organic layers were washed with a saturated aqueous solution of NaCI. After drying over anhydrous Na 2 S 〇 4, the title compound (14. iH-NMR (CDC13) δ : 2·36 (3H, s), 3.9G (3H, S), 7, 40-7.53 (2Η, m), 7·79-7·89 (1Η, m). MS (ESI) m/z: 218 (M+Na)+. [Reference Example 53] 3-((E)-2-Dimethylaminovinyl)-2-nitrobenzoic acid methyl hydrazide To a solution of the compound of Example 52 (14.0 g) in DMF (72 ml) Add 129677.doc -75- 200840568 N,N-dimercaptodecyl diacetal (12. 5 ml), stir at 24 ° C for 24 hours. The reaction mixture was concentrated under reduced pressure. i-NMR (CDC13) δ : 2·85 (6H, s), 3·87 (3H, s), 4.92 (1H, d, J = 13.4 Hz), 6.85 (1H, d, J = 13.4 Hz) ), 7·27-7·33 (1H, m), 7.52 (1H, dd, J=7.6, 1.2 Hz), 7·55 (1H, dd, J=8.1, 1.2 Hz). [Reference Example 54] 3-decyl nitrophenyl decanoate was added to a mixed solution of the compound of Reference Example 53 (8.51 g) in THF (100 ml), water (100 ml). Sodium periodate (2〇9 g) was stirred at room temperature for 2.5 hours. After the precipitate was separated by filtration, a saturated aqueous solution of NaHC 3 was added to the filtrate. The precipitated crystals were again separated by filtration, and then extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous NaHC. After drying over anhydrous NaJ® 4, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate: 1 -&gt; 4:1 - 2 ··1). Hexane (40 ml) was added to a solution of ethyl acetate (3 mL), and the mixture was stirred at room temperature for 13 hr. The solid was collected by filtration to give the title compound (3.73 g). iH-NMR (CDC13) δ : 3.95 (3H,S),7·77 (1H,t,J=7.8 Hz), 8·18 (1H,dd,J=7.8,1·5 Hz),8·28 (1H, dd, J = 7.8, 1·5 Hz), 9.98 (1H, s). [Reference Example 55] 3-((E)-2-Tertoxycarbonylvinyl)-2-nitrobenzoate decyl ester at 0 ° C 'to diethylphosphonic acid tert-butyl ester ( 4·21 g) of THF (3 5 ml) was added 55% sodium hydride (675 mg), and 129677.doc-76-200840568 was dispensed at 0 °C for 30 minutes. A mixed solution of the compound of Reference Example 54 (2 97 Magic THF (40 ml), DMF (3 ml) was added to the reaction mixture, and the mixture was stirred at 〇 ° C for 3 hr, and stirred at room temperature for 30 minutes. A saturated aqueous solution of NaCi and ethyl acetate were added to the mixture, and the mixture was extracted with ethyl acetate, and the combined organic layer was washed with saturated aqueous NaCI, dried over anhydrous Na.sub.4, and the solvent was evaporated under reduced pressure. Purification by chromatography (hexane: ethyl acetate = 5:1 - 4 : 1 - 3 : 1) to give the title compound (3.70 g). H-NMR (CDC13) δ: 1.52 (9H, s), 3.92 (3H, s), 6.42 (1H, d, J = 15.9 Hz), 7.45 (1H, d, J = 15.9 Hz), 7.55-7.62 (1H, m), 7·84 (1H, dd, J= 8.1,1·2 Hz), 8·02 (1H, dd, J=7.7, 1.2 Hz) MS (ESI) m/z: 330 (M+Na)+ [Reference Example 56] 3-((E To a solution of the compound of Example 55 (3·65 g) in dichloromethane (20 ml) The mixture was stirred at room temperature for 16 hr. CD3OD) δ : 3·89 (3H, s), 6.65 (1H, d, J = 15.9 Hz), 7.46 (1H, d, J = 15.9 Hz), 7·68-7·75 (1H, m), 8·07 〇H, dd, Bu 7.7, 1.3 Hz), 8·13 (1H, dd, J=8.0, 1.3·Hz). MS (ESI) m/z: 250 (MH)\ [Reference 57] 3-{(E)-2-[(4-Phenylphenyl)aminoindenyl] vinyl b-2-nitrobenzoic acid To the compound of Reference Example 56 (601 mg), hydrazine chloride (6.0, DMF (about 〇·〇 2 ml)' was heated and refluxed for 3 hours. The reaction mixture was concentrated under reduced pressure 129 677.doc. After the shrinkage was carried out, the mixture was poured into a THF (6 ml) solution, and 4-chloromethaneamine (353 mg) and hydrazine (500 μM) were added thereto, and the mixture was stirred at room temperature for 4 hours. The precipitated solid was collected by filtration. After concentrating, the residue was washed with methylene chloride (methanol) (m.) 3·87 (3H, s), 6.96 (1H, d, J=i5 4

Hz)5 7.34 (1H, d5 J-15.4 Hz), 7.41 (2H, d, J=9.〇 Hz)5 7.72 (2H，d，卜9·0 Hz)，7·86 (1H，t，J=7.8 Hz)，8·〇9 (ih，dd J = 7.8，1·1 Hz)，8·14 (1H，dd，J=7.8，1·1 Hz)，ΐ〇·56 (1H， s) o MS (ESI) m/z: 361 (M+H)+。 [參考例58] 2-胺基-3-{2-[(4-氯苯基）胺曱醯基]乙基}苯甲 酸甲酯 向參考例57之化合物（628 mg)的二，号烷（65 ml)·浮液中 添加10%鈀碳觸媒（75 mg)，於氫條件下且於室溫下攪拌15 小時。將觸媒過濾分離後，將濾液於減壓下濃縮。將殘渣 製成DMF(6.0 ml)、水（2·〇 ml)混合溶液，添加氣化鐵 (3)(808 mg)、鋅粉末（1·19 g)，於8(rc下加熱攪拌$分鐘。 冷卻後，向反應液中添加乙酸乙酯，過濾分離不溶物。向 濾液中添加飽和NaHCCh水溶液，過濾分離不溶物後，以 乙酸乙酯萃取。以飽和NaCl水溶液清洗所合併之有機層 後，以無水NaJO4乾燥，於減壓下餾去溶劑。將殘渣以矽 膠管柱層析法（己烷：乙酸乙酯: 3 : 2 ·〗）進― 精製，獲得標題化合物(337 mg)。 129677.doc •78· 200840568 W-NMR (CDC13) δ : 2·67 (2H，t，J=7.2 Ηζ)，2·96 (2H，t， J=7.2 Hz)? 3.87 (3H5 s)5 6.00-6.21 (2H, br)? 6.57-6.65 (1H5 m)，7·14 (1H，br s)，7.20 (1H，br d，J=7.3 Hz)，7·26 (2H，d， J=8.8 Hz)，7·39 (2H，d，Hz)，7·80 (1H，dd，J=8.1，1·5Hz)5 7.34 (1H, d5 J-15.4 Hz), 7.41 (2H, d, J=9.〇Hz)5 7.72 (2H,d,b 9·0 Hz),7·86 (1H,t,J =7.8 Hz),8·〇9 (ih,dd J = 7.8,1·1 Hz),8·14 (1H,dd,J=7.8,1·1 Hz),ΐ〇·56 (1H, s) o MS (ESI) m/z: 361 (M+H)+. [Reference Example 58] 2-Amino-3-{2-[(4-chlorophenyl)aminoindenyl]ethyl}benzoic acid methyl ester to the compound of Reference Example 57 (628 mg) (65 ml). A 10% palladium carbon catalyst (75 mg) was added to the float, and the mixture was stirred under a hydrogen atmosphere at room temperature for 15 hours. After separating the catalyst by filtration, the filtrate was concentrated under reduced pressure. The residue was made into a mixed solution of DMF (6.0 ml) and water (2·〇ml), and iron (3) (808 mg) and zinc powder (1·19 g) were added, and the mixture was heated and stirred at 8 (rc) for 8 minutes. After cooling, ethyl acetate was added to the reaction mixture, and the insoluble material was separated by filtration. The saturated NaHCCh aqueous solution was added to the filtrate, and the insoluble material was separated by filtration and then extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous NaCl solution. The title compound (337 mg) was obtained from EtOAc EtOAc (EtOAc). Doc •78· 200840568 W-NMR (CDC13) δ : 2·67 (2H,t,J=7.2 Ηζ), 2·96 (2H,t, J=7.2 Hz)? 3.87 (3H5 s)5 6.00-6.21 (2H, br)? 6.57-6.65 (1H5 m), 7·14 (1H, br s), 7.20 (1H, br d, J=7.3 Hz), 7·26 (2H, d, J=8.8 Hz) ,7·39 (2H,d,Hz),7·80 (1H,dd,J=8.1,1·5

Hz) 〇 MS (ESI) m/z: 333 (M+H)+。 [參考例59] 4-((E)-2-第三丁氧基羰基乙烯基»硝基苯甲 酸甲酯Hz) 〇 MS (ESI) m/z: 333 (M+H)+. [Reference Example 59] 4-((E)-2-Tertoxycarbonylvinyl»methyl nitrobenzoate

以與參考例55相同的方法，由4_甲醯基硝基苯曱酸甲 酯獲得標題化合物。 ^H-NMR (CDC13)5:1.55(9H5 s)5 3.99 (3H? s)? 6.37 (1H? d, 1=15.9 Hz), 7.72 (1H, d, J=8.3 Hz), 8.01 (1H, d, J=15.9The title compound was obtained from methyl 4-methylmercaptonitrobenzoate in the same manner as in the title compound. ^H-NMR (CDC13) 5:1.55(9H5 s)5 3.99 (3H?s)? 6.37 (1H?d, 1=15.9 Hz), 7.72 (1H, d, J=8.3 Hz), 8.01 (1H, d, J=15.9

Hz), 8·26 (1H，dd，J=8.3, 1.7 Hz), 8.65 (1H，d, J=i.7 Hz)。 MS (ESI) m/z: 330 (M+Na)+。 [參考例6G]4-{⑻-2_[(4_氣笨基）胺甲醯基]乙稀基卜3•硝基 苯甲酸甲酯 以與參考例S6及參考例57 相冋的方法，由參考例59之化 合物獲得標題化合物。 !H-NMR (DMSO-d6) δ ： 3.93 (，s)，6·88 (1Η，d，J=15.6Hz), 8·26 (1H, dd, J=8.3, 1.7 Hz), 8.65 (1H, d, J=i.7 Hz). MS (ESI) m/z: 330 (M+Na)+. [Reference Example 6G] 4-{(8)-2_[(4_ oxa)aminomercapto]ethylidene 3 nitrobenzoic acid methyl ester in a method contrary to Reference Example S6 and Reference Example 57, The title compound was obtained from the compound of Reference Example 59. !H-NMR (DMSO-d6) δ : 3.93 (,s),6·88 (1Η,d,J=15.6)

Hz)，7·42 (2H，d，J=8,8 Hz) 7 mHz), 7·42 (2H, d, J=8, 8 Hz) 7 m

），7·73 (2H，d5 Ju Hz)，7·92 (1H，d，J=15.6 Hz)，7.97 (ih y T 打，d，J吶·3 Hz)， dd 卜8.3, 1·7 Ηζ)，8·52 (1H，d，J==1 7 u ·(，， U Hz)，10.55 (1H MS (ESI) m/z: 361 (M+H)+。 ’ [參考例61] 3-胺基-4-(24(4^贫甘、 虱本基）胺甲醯基]乙基}苯甲 129677.doc -79. 200840568 酸甲酯 向參考例60之化合物（540 mg)的THF(20 ml)、DMF(3.〇 ml)混合懸浮液中添加ι〇%鈀碳觸媒（51 mg)，於氫條件下 且於室溫下攪拌3小時。以玻璃過濾器過濾分離觸媒後， 於減壓下餾去溶劑，放置3日。將殘渣以使用矽膠之快速 層析法（二氯曱烷：甲醇=50 : 1)進行精製，獲得粗製之標 題化合物（230 mg)。 iH-NMR (CD3〇D) δ : 2.66 (2H，t，J=7.6 Hz)，2.93 (2H，t， _ J = 7.6 Hz)5 3.83 (3H, s)? 7.10 (1H? d5 J=7.8 Hz), 7.23-7.31 (3H，m)，7·37 (1H，d，J=1.5 Hz)，7·51 (2H，d，J=8.8 Hz)。 MS (ESI) m/z: 333 (M+H)+ 〇 [參考例62] 4-[(E)-2-(5-氯吼啶-2·基胺曱醯基）乙烯基]_3•硝 基苯曱酸甲酯 以與參考例56及參考例57相同的方法，將由參考例59之 化合物所衍生之醯氣與2-胺基-5-氯吡啶縮合，獲得標題化 合物。 H-NMR (DMSO-d6) δ : 3.93 (3Η, s)5 7.08 (1H, d, J-15.4 Hz)，7·92 (1H，d，J=8.1 Hz)，7·94-8·〇〇 (2H，m)，8 28 (1H，d J=9.0 Hz), 8.34 (1H5 dd5 1=8.1, 1.5 Hz)? 8.42 (1H? d5), 7·73 (2H, d5 Ju Hz), 7.92 (1H, d, J = 15.6 Hz), 7.97 (ih y T, d, J呐·3 Hz), dd 8.3, 1·7 Ηζ),8·52 (1H,d,J==1 7 u ·(,, U Hz), 10.55 (1H MS (ESI) m/z: 361 (M+H)+. ' [Reference Example 61] 3-Amino-4-(24(4^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Add ι〇% palladium carbon catalyst (51 mg) to a mixed suspension of THF (20 ml) and DMF (3. 〇ml), and stir under hydrogen for 3 hours at room temperature. After the solvent, the solvent was evaporated to dryness crystals crystals crystals crystals crystalssssssssssssssssssssssssss iH-NMR (CD3〇D) δ : 2.66 (2H, t, J = 7.6 Hz), 2.93 (2H, t, _ J = 7.6 Hz) 5 3.83 (3H, s)? 7.10 (1H? d5 J=7.8 Hz), 7.23-7.31 (3H, m), 7.37 (1H, d, J = 1.5 Hz), 7·51 (2H, d, J = 8.8 Hz) MS (ESI) m/z: 333 ( M+H)+ 〇 [Reference Example 62] 4-[(E)-2-(5-Chloroacridin-2-ylamino)vinyl]_3 • Nitrobenzoic acid methyl ester The helium gas derived from the compound of Reference Example 59 was condensed with 2-amino-5-chloropyridine in the same manner as in Reference Example 56 and Reference Example 57 to give the title compound. NMR (DMSO-d6) δ : 3.93 (3Η, s)5 7.08 (1H, d, J-15.4 Hz), 7.92 (1H, d, J=8.1 Hz), 7·94-8·〇〇 ( 2H,m),8 28 (1H,d J=9.0 Hz), 8.34 (1H5 dd5 1=8.1, 1.5 Hz)? 8.42 (1H? d5

Hz)，8·52 (1H，d，J=1.5 Hz)，11.08 (1H，s)。 MS (ESI) m/z: 362(M+H)+ 〇 [參考例63] 3-胺基·4-[2-(5-氣吼啶_2•基胺甲醯基）乙基]笨 曱酸甲酯 1 以與參考例61相同的方法，由參考例似化合物獲得標 129677.doc -80- 200840568 題化合物。 】H-NMR (CD3OD) δ : 2·74 (2H，t，J=7.6 Hz)，2.94 (2H，t， J = 7.6 Hz)，3·84 (3H，s)，7·12 (1H，d，J=7.8 Hz)，7·27 (1H， dd，J=7.8，1.7 Hz)，7.37 (1H，d，J=1.7 Hz)，7.75 (1H，dd， J = 8.8，2.0 Hz)，8.12 (1H，d，J=8.8 Hz)，8·23 (1H，d，J=2,〇 Hz)。 MS (ESI) m/z: 334 (M+H)+。 [參考例64] 3-胺基-4-[2-(第三丁氧基幾基）乙基]苯甲酸 ⑩ 甲酉旨 以與參考例61相同的方法，由參考例59之化合物獲得標 題化合物。 !H-NMR (CDC13) δ : 1.43 (9H，S)，2·57 (2H，t，J=7.4 Hz)， 2.82 (2H，t，卜7·4 Hz)，3·87 (3H，s)，3·89-4·02 (2H，br)， 7·〇8 (1H，d，J=7.8 Hz)，7·34 (1H，br s)，7·38 (1H，dd，J=7.8, 1·1 Hz)。 MS (ESI) m/z: 280 (M+H)、 馨 [參考例65] 4-[2-(第三丁氧基羰基）乙基]_3_[(5_異丙基_ 4,5,6,7-四氫噻唑并[5,4-〇]吡啶-2-羰基）胺基]苯曱酸曱酯 向參考例32之化合物（ΐ·21 g)的二氯曱烷（2〇 ml)懸浮液 中添加DMF(0.20 ml)、草醯氣（600 μΐ)，於室溫下攪拌3〇 分鐘。向反應液中追加草醯氯（300 μΐ)，於室溫下攪拌2〇 分鐘。將反應液於減壓下濃縮乾固，向殘渣之二氯曱烧 (30 ml)懸浮液中添加參考例64之化合物（996 mg)的二氯曱 烷（1〇1111)溶液、丁£八(3.〇1111)，於室溫下攪拌14小時。以 129677.doc -81 - 200840568 二氣甲烷稀釋反應液後，添加飽和NaCl水溶液。以二氯甲 烧萃取後，以無水Na2S04乾燥，於減壓下餾去溶劑。將殘 渣以矽膠管柱層析法（己烷：乙酸乙酯=3 : I·» 2 : 1-M : 1 —1 : 2)、及使用石夕膠之快速層析法（己院：乙酸乙酯二2 : l) 進行精製，獲得標題化合物（1.06 g)。Hz), 8·52 (1H, d, J = 1.5 Hz), 11.08 (1H, s). MS (ESI) m/z: 362 (M+H) + 〇 [Ref. 63] 3-amino- 4-[2-(5-azeridin-2-ylaminomethyl)ethyl] Methyl decanoate 1 In the same manner as in Reference Example 61, a compound of the title 129677.doc-80-200840568 was obtained from a reference compound. H-NMR (CD3OD) δ : 2·74 (2H, t, J = 7.6 Hz), 2.94 (2H, t, J = 7.6 Hz), 3.84 (3H, s), 7·12 (1H, d, J = 7.8 Hz), 7·27 (1H, dd, J = 7.8, 1.7 Hz), 7.37 (1H, d, J = 1.7 Hz), 7.75 (1H, dd, J = 8.8, 2.0 Hz), 8.12 (1H, d, J = 8.8 Hz), 8.23 (1H, d, J = 2, 〇 Hz). MS (ESI) m/z: 334 (M+H)+. [Reference Example 64] 3-Amino-4-[2-(t-butoxymethyl)ethyl]benzoic acid 10 methyl hydrazide The title was obtained from the compound of Reference Example 59 in the same manner as in Reference Example 61. Compound. !H-NMR (CDC13) δ : 1.43 (9H,S),2·57 (2H,t,J=7.4 Hz), 2.82 (2H,t,b 7·4 Hz),3·87 (3H,s ),3·89-4·02 (2H,br), 7·〇8 (1H,d,J=7.8 Hz),7·34 (1H,br s),7·38 (1H,dd,J= 7.8, 1·1 Hz). MS (ESI) m/z: 280 (M+H), s. [Ref. 65] 4-[2-(T-butoxycarbonyl)ethyl]_3_[(5-isopropyl-4,5, 6,7-Tetrahydrothiazolo[5,4-indole]pyridine-2-carbonyl)amino]benzoic acid decyl ester to the compound of Reference Example 32 (ΐ·21 g) of dichloromethane (2 〇ml) DMF (0.20 ml) and grasshopper gas (600 μM) were added to the suspension, and the mixture was stirred at room temperature for 3 minutes. Grassy chlorine (300 μM) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 minutes. The reaction solution was concentrated to dryness under reduced pressure. EtOAc (jjjjjjj (3.〇1111), stirred at room temperature for 14 hours. After diluting the reaction solution with 129677.doc -81 - 200840568 di-methane, a saturated aqueous solution of NaCl was added. After extracting with methylene chloride, the mixture was dried over anhydrous Na2SO. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 3: I·» 2 : 1-M : 1 -1 : 2), and flash chromatography using Ethyl ester 2: 1) Purification gave the title compound (1.06 g).

iH-NMR (CDC13) δ : 1·17 (6H，d，J=6.6 Hz)，1.40 (9H，s) 2·65 (2H，t，J=7.2 Hz)，2.80-3.07 (7H，m)，3.86-3.90 (2H m) ，3.90 (3H，s)，7·31 (1H，d，J=8.0 Hz)，7.83 (1H，ddiH-NMR (CDC13) δ : 1·17 (6H, d, J = 6.6 Hz), 1.40 (9H, s) 2·65 (2H, t, J = 7.2 Hz), 2.80-3.07 (7H, m) , 3.86-3.90 (2H m) , 3.90 (3H, s), 7·31 (1H, d, J = 8.0 Hz), 7.83 (1H, dd

J = 8.0, 1·5 Hz)，8·63 (1H, d，卜 1.5 Hz)，9.51 (1H，s)。 MS (ESI) m/z: 488 (M+H)、 [參考例66] 4-(2-羧基乙基）-3-[(5-異丙基_4,5,6,7-四氣。笑^坐 并[5，4-c]吼啶-2-羰基）胺基]苯曱酸甲酯鹽酸鹽 向參考例65之化合物（1·38 g)的二氣甲烷（2〇 ml)溶夜中 添加4當量鹽酸二噚烷溶液（20 ml)，於室溫下授掉^ 時。將反應液於減壓下濃縮後，以水、乙酸乙鴨此、、弗 於 室溫下以真空泵乾燥，獲得標題化合物（1.00 g)。 ^-NMR (DMSO-d6) δ : 1.37 (3H? d? 1=6.3 Hz), i.39J = 8.0, 1·5 Hz), 8·63 (1H, d, 卜 1.5 Hz), 9.51 (1H, s). MS (ESI) m/z: 488 (M+H), [Ref. 66] 4-(2-carboxyethyl)-3-[(5-isopropyl-4,5,6,7-tetra笑^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Add 4 equivalents of dioxane hydrochloride solution (20 ml) to the solution overnight, and then give it at room temperature. The reaction mixture was concentrated under reduced pressure. ^-NMR (DMSO-d6) δ : 1.37 (3H? d? 1 = 6.3 Hz), i.39

Hz)， 4.48. J=6.6 Hz)，2·59 (2H，t，J=7.4 Hz)，2.90 (2H，t，j&gt;7 4 3·11-3·54 (3H，m)，3·61-3·85 (2H，m)，3·85 (3H，s) ㈣ 1 HZ)， Ήζ)，10.65 4.61 (1H，m)，4.68-4.79 (1H，m)，7·49 (1H，d， 7·81 (1H，dd，J=8.1，1.7 Hz), 8.01 (1H，d，J=l.7 (1H，s)，11.07-11.23 (1H，b〇 〇 MS (ESI) m/z: 432 (M+H)、 [參考例67] 4-溴曱基—3_硝基苯甲酸第三丁酯 129677.doc -82- 200840568 向MgSO^.i g)中添加二氯甲烧（2〇〇叫、濃硫酸（3〇 ml)，於室溫下攪拌30分鐘後’添加第三丁醇（28瓜丨）、4_ 漠甲基〜肖基苯甲酸（9.75 g)，㈣3日。將不溶物過滤分 離後，向飽和NaHC〇3水溶液中添加濾液。以二氯甲烷萃 取，以飽和NaCl水溶液清洗所合併之有機層。以無水 NaJO4水溶液乾燥後，於減壓下餾去溶劑。將殘渣以矽膠 管柱層析法（己烷：乙酸乙酯=1〇 : 8 :丨）進行精製，獲 得標題化合物（10.5 g)。Hz), 4.48. J=6.6 Hz), 2·59 (2H, t, J=7.4 Hz), 2.90 (2H, t, j&gt; 7 4 3·11-3·54 (3H, m), 3· 61-3·85 (2H,m),3·85 (3H,s) (4) 1 HZ), Ήζ), 10.65 4.61 (1H,m), 4.68-4.79 (1H,m),7·49 (1H, d, 7·81 (1H, dd, J=8.1, 1.7 Hz), 8.01 (1H,d,J=l.7 (1H,s),11.07-11.23 (1H,b〇〇MS (ESI) m/ z: 432 (M+H), [Reference Example 67] 4-bromodecyl-3-nitrobenzoic acid tert-butyl ester 129677.doc -82- 200840568 Add chloroformate to MgSO^.ig) 2 bark, concentrated sulfuric acid (3 〇 ml), stirred at room temperature for 30 minutes, then added 't-butanol (28 guanidine), 4_ dimethyl- to octyl benzoic acid (9.75 g), (iv) 3 days. After the insoluble material was separated by filtration, the filtrate was added to a saturated aqueous solution of NaHCO3, and extracted with dichloromethane, and the combined organic layer was washed with saturated aqueous NaCI. The residue was purified by silica gel column chromatography (hexane: ethyl acetate

^-NMR (CDC13) δ : 1.61 (9H? s), 4.84 (2H, s)5 7.64 (1H, d, J-8.0 Hz)5 8.19 (1H5 dd5 J=8.〇, 1.7 Hz), 8.58 (1H) d,^-NMR (CDC13) δ : 1.61 (9H? s), 4.84 (2H, s)5 7.64 (1H, d, J-8.0 Hz)5 8.19 (1H5 dd5 J=8.〇, 1.7 Hz), 8.58 ( 1H) d,

Hz)。 MS (ESI) m/z: 316 (M+H)+ 〇 [參考例 68] 2-[4-(t 於〇°C下，向55%氫化納（1,7〇 g)之THF(2〇〇 mi)懸浮液中 添加丙二酸二乙酯（6.〇 ml)，於〇它下攪拌i〇分鐘。向反應 液中追加丙二酸二乙醋(0.60 ml)，於室溫下攪拌1〇分鐘’: 以20分鐘向反應液中滴下參考例”之化合物（ι〇 5幻的 THF(50 ml)溶液後，於室溫下攪拌3〇分鐘。向反應液中添 加飽和氯化錄水溶液、乙酸乙醋。以乙酸乙醋萃取後，以 飽和NaCM水溶液清洗所合併之有機層。以無水ν_〇4乾燥 後’於減壓下餾去溶劑。向粗精製物中添加己烷-乙酸乙 酯’濾取固體，獲得標題化合物（丨〇 . 3 。 Ή-NMR (CDC13) ：1·23 (6H, t, J=7.1 Hz), 1.60 (9H, s), 3.54 (2H, d, J=7.6 Hz), 3.85 (1H, t5 J=7.6 Hz), 4.10-4.24 129677.doc -83- 200840568 (4H，m)，7.47 (1H, d，J=7.8 Hz)，8.11 (1H，dd，J=7.8，1.7 Hz)，8·54 (1H，d，J=L7 Hz)。 MS (ESI) m/z: 396 (M+H)+。 [參考例69] 4-(2-羧基乙基）_3_硝基苯甲酸第三丁酯 於-5C下’向參考例68之化合物（5.21 g)的THF(150 ml) &gt;谷液中滴下1當量NaOH水溶液（26·5 ml)，於- 5°C下授拌40 小時。向反應液中追加1當量NaOH水溶液（5.0 ml)，於0°C 下攪拌5小時。向反應液中添加1當量鹽酸（3 1 ml)，於減壓 下餾去有機溶劑。向殘渣中添加二氯甲烷，進行萃取，以 無水Na^SO4乾燥。於減壓下顧去溶劑後，將殘潰製成乙腈 (5 0 ml)溶液，添加氧化銅（i)(2〇i mg)，於7〇〜8(rc下攪拌5 小時。冷卻後過濾分離不溶物，將濾液於減壓下濃縮。向 殘渣中添加乙酸乙酯，以0.3 N之NaOH水溶液萃取3次。 向所合併之水層中添加1當量鹽酸而成為酸性，以乙酸乙 酯萃取2次。以飽和NaCl水溶液清洗所合併之有機層後， 以無水NaJCU乾燥。於減壓下餾去溶劑後，將殘渣以石夕膠 管柱層析法（二氣甲烷：曱醇=1〇〇 ·· 1^50 ·· 1}及使用石夕膠 之快速層析法（二氣曱烷··甲醇=1〇〇 ·· 1：)進行精製，獲得 標題化合物（1 ·73 g)。 iH-NMR (CDC13) δ : 1·61 (9H，S)，2·80 (2H，t，J=7.6 Hz) 3·27 (2H，t，J=7.6 Hz)，7·49 (1H，d，ρ8·0 Hz)，8·14 (1H dd，J=8.0, 1·7 Hz)，8·51 (1H，d，J=1.7 Hz)。 ’ MS (ESI) m/z: 318 (M+Na)+。 [參考例70] 4-[2-(5-氣噻吩-2-基胺曱醯基）乙基]_3_硝基笨 129677.doc -84- 200840568 甲酸第三丁酯 向參考例69之化合物（196 mg)的二氯曱烷（20 溶液中 添加草醯氯（115 μΐ)、DMF(0.02 ml)，於室溫下授拌3小 時。向反應液中追加草醯氯（10 μΐ)，於減壓下濃縮，獲得 粗製之4-(2-氯羰基乙基）-3-硝基苯曱酸第三丁酯。 向（5-氣噻吩-2-基）胺基曱酸第三丁酯（參照wo 2003/000680中所記載之方法）（220 mg)的二口号烷（2 ml)溶液 中添加4當量鹽酸二嘮烷溶液（2 ml)，於室溫下攪拌19小 # 時。將反應液於減壓下濃縮後，向殘渣中添加DMF(1 ml)、粗製之4-(2 -氣緣基乙基）-3 -硝基苯曱酸第三丁自旨的二 氯甲烷（5 ml)溶液，於室溫下攪拌20分鐘。向反應液中添 加NaHC〇3(l〇8 mg)，於室溫下攪拌18小時。將反應液於減 壓下濃縮後，向殘渣中添加乙酸乙酯、0·5 N鹽酸。以乙 酸乙酯萃取後，以飽和NaCl水溶液及水清洗所合併之有機 層。以無水Na2S〇4乾燥後，於減壓下餾去溶劑。將殘渣以 使用矽膠之快速層析法（己烷：乙酸乙酯=6 : 1 — 2 : 1)進 鲁 行精製，獲得標題化合物（II6 mg)。 W-NMR (CDC13) δ : 1.60 (9H，s)，2.79 (2H，t，J二7·4 Hz)， 3·32 (2H，t，J=7.4 Hz), 6·36 (1H，d，J=4.2 Hz)，6·63 (1H，d， J=4,2 Hz)，7·50 (1H，d，J=8.1 Hz)，8.10 (1H，dd，J=8.1，ι·7 Hz)，8·47 (1H，d，J=1.7 Hz)，8·66 (1H，s)。 MS (ESI) m/z: 411 (M+H)+。 [參考例71] 3-胺基-4-[2_(5-氣噻吩基胺甲醯基)乙基]-3-硝基苯甲酸第三丁 _ 129677.doc -85 - 200840568 以與參考例13相同的方法，由參考例7〇之化合物獲得標 題化合物。 H-NMR (CDC13) δ ·· 1·56 (9H，s)，2.68 (2H，t，J=7.2 Hz)， 2·92 (2H，t，J=7.2 Hz)，3.32-4.47 (2H，br)，6.31 (1H5 d， J = 4.1 Hz)，6.63 (1H，d，J=4.1 Hz)，7·00 (1H，d，J=7.8 Hz)， 7·25 (1H，d，J=l，5 Hz)，7.29 (1H，dd，J=7.8，1·5 Hz)，8·74 (1H，br s) 〇 MS (ESI) m/z: 381 (M+H)+。 ® [參考例72] (7_氯畤啉-3-基）胺基甲酸第三丁酯 向 7-氯 4 啉-3-曱酸（W02004/058715)(250 mg)的乙腈（6 ml)溶液中添加ΤΕΑ(174 μΐ)及DPPA(310 μΐ)，於室溫下加 熱20分鐘，且於7〇°C下加熱50分鐘。將反應液放冷，過濾 去除不溶物。向濾液中添加乙酸乙酯，水洗後，以無水 MgS〇4乾燥。於減壓下鶴去溶劑，向殘渣的甲苯（〗〇如）溶 液中添加第三丁醇（3 ml)及TEA(1 ml)，M10(rC下加熱授 拌5小時。於減壓下餾去溶劑後，將殘渣以石夕膠層析法（一 籲 氯曱烷—二氯甲烷··乙酸乙酯=19 : 1)進行精製，獲得標 題化合物（125 mg)。 'H-NMR (CDC13) δ : 1.58 (9H? s), 7.60 (1H? dd5 J-8.9, 2 1Hz). MS (ESI) m/z: 316 (M+H) + 〇 [Ref. 68] 2-[4-(t at 〇 ° C, to 55% hydride (1,7 〇g) of THF (2) 〇〇mi) Add diethyl malonate (6. 〇ml) to the suspension, stir it for 〇 minutes. Add malonic acid diethyl vinegar (0.60 ml) to the reaction solution at room temperature. Stirring for 1 hr.': The reference compound "( THF (50 ml)) was added dropwise to the reaction mixture over 20 minutes, and then stirred at room temperature for 3 Torr. Adding saturated chlorination to the reaction mixture The aqueous solution and ethyl acetate were taken. After extraction with ethyl acetate, the combined organic layer was washed with saturated aqueous NaCI solution. After drying with anhydrous ν 〇 4, the solvent was distilled off under reduced pressure. - Ethyl acetate - filtered to give the title compound (3. NMR: NMR (CDC13):1·23 (6H, t, J=7.1 Hz), 1.60 (9H, s), 3.54 (2H, d, J=7.6 Hz), 3.85 (1H, t5 J=7.6 Hz), 4.10-4.24 129677.doc -83- 200840568 (4H,m), 7.47 (1H, d,J=7.8 Hz), 8.11 (1H , dd, J = 7.8, 1.7 Hz), 8.54 (1H, d, J = L7 Hz) MS (ESI) m/z: 396 (M+H)+ [Reference 69] 4-(2 -carboxyl To a solution of the compound of Reference Example 68 (5.21 g) in THF (150 ml) &gt; a solution of NaOH (1·5 ml) The mixture was stirred for 40 hours at -5 ° C. One equivalent of NaOH aqueous solution (5.0 ml) was added to the reaction mixture, and the mixture was stirred at 0 ° C for 5 hours, and 1 equivalent of hydrochloric acid (3 1 ml) was added to the reaction mixture. The organic solvent was distilled off under reduced pressure, dichloromethane was added to the residue, and the mixture was extracted and dried over anhydrous Na?SO?. After solvent was removed under reduced pressure, the residue was dissolved in acetonitrile (50 ml) and oxidized. Copper (i) (2 〇 i mg) was stirred at 7 〇 8 8 (rc for 5 hours. After cooling, the insoluble material was separated by filtration, and the filtrate was concentrated under reduced pressure. The aqueous solution of NaOH was extracted three times. To the combined aqueous layer was added 1 N hydrochloric acid to be acidic, and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCI and dried over anhydrous NaJ. After distilling off the solvent, the residue was chromatographed on a Shixi gum column (di-methane: decyl alcohol = 1 〇〇 · · 1^50 ··1} and using Shishijiao Flash chromatography (two gas Yue dioxane ·· ·· 1〇〇 methanol = 1 :) purified to obtain the title compound (1 · 73 g). iH-NMR (CDC13) δ : 1·61 (9H, S), 2·80 (2H, t, J = 7.6 Hz) 3·27 (2H, t, J = 7.6 Hz), 7·49 (1H, d, ρ8·0 Hz), 8·14 (1H dd, J=8.0, 1·7 Hz), 8·51 (1H, d, J=1.7 Hz). ' MS (ESI) m/z: 318 (M+Na)+. [Reference Example 70] 4-[2-(5-Acethiophen-2-ylaminoindolyl)ethyl]_3_nitroso stupid 129677.doc -84- 200840568 tert-butyl formate to the compound of Reference Example 69 (196 mg) of dichloromethane (20 μg of oxalic acid chloride (115 μΐ) and DMF (0.02 ml) were added to the solution for 3 hours at room temperature. Grassy chlorine (10 μM) was added to the reaction solution. Concentration under reduced pressure afforded crude 3-(2-chlorocarbonylethyl)-3-nitrobenzoic acid tert-butyl ester. To (5- thiophen-2-yl)amino decanoic acid tributyl To a solution of the ester (220 mg) in dioxane (2 ml) was added 4 ml of a dioxane hydrochloride solution (2 ml), and stirred at room temperature for 19 hours. After the reaction mixture was concentrated under reduced pressure, DMF (1 ml) and crude 4-(2-carboylethyl)-3-nitrobenzoic acid tributylmethane was added to the residue. (5 ml) The solution was stirred at room temperature for 20 minutes. NaHC〇3 (10 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and then evaporated. Add ethyl acetate, 0.5 N hydrochloric acid, extract with ethyl acetate, and saturate The combined organic layer was washed with aq. EtOAc (aq. EtOAc). : 1) Refined to the title compound (II6 mg). W-NMR (CDC13) δ: 1.60 (9H, s), 2.79 (2H, t, J 27.4 Hz), 3·32 (2H ,t,J=7.4 Hz), 6·36 (1H,d,J=4.2 Hz),6·63 (1H,d, J=4,2 Hz),7·50 (1H,d,J=8.1 Hz), 8.10 (1H, dd, J=8.1, ι·7 Hz), 8·47 (1H, d, J=1.7 Hz), 8.66 (1H, s) MS (ESI) m/z: 411 (M+H)+ [Reference Example 71] 3-Amino-4-[2-(5-athiophenylaminocarbamoyl)ethyl]-3-nitrobenzoic acid teridine _ 129677.doc -85 - 200840568 The title compound was obtained from the compound of the compound of Example 7 in the same manner as the the the the the the the the the the the the the the the the the the the the the 7.2 Hz), 2·92 (2H, t, J=7.2 Hz), 3.32-4.47 (2H, br), 6.31 (1H5 d, J = 4.1 Hz), 6.63 (1H, d, J = 4.1 Hz), 7·00 (1H, d, J=7.8 Hz), 7·25 (1H, d, J=l, 5 Hz), 7.29 (1H, dd, J=7.8, 1·5 Hz), 8·74 (1H, br s) 〇 MS (ESI) m/z: 381 (M+H)+. ® [Reference Example 72] (7-Chloropiperidin-3-yl)carbamic acid tert-butyl ester to 7-chlorotetralin-3-decanoic acid (W02004/058715) (250 mg) in acetonitrile (6 ml) ΤΕΑ (174 μΐ) and DPPA (310 μΐ) were added to the solution, heated at room temperature for 20 minutes, and heated at 7 ° C for 50 minutes. The reaction solution was allowed to cool and filtered to remove insolubles. Ethyl acetate was added to the filtrate, washed with water and dried over anhydrous Mg??. The solvent was removed under reduced pressure, and a solution of toluene (3 ml) and TEA (1 ml) was added to the toluene solution of the residue, and M10 (heated under rC for 5 hours). After the solvent was removed, the residue was purified by chromatography eluting elut elut elut elut elut elut elut elut elut elut δ : 1.58 (9H? s), 7.60 (1H? dd5 J-8.9, 2 1

Hz)，7·73 (1H，d，J=8.8 Hz)，7.91 (1H，br s)，8·39 (1H，s) 8·48 (1H，s)。 MS (ESI) m/z: 457 (M+H)+。 [參考例73] 7-氯4啉-3-基胺 向參考例72之化合物（163 mg)的二氯甲烷（4 ^1)溶液中 129677.doc -86- 200840568 添加4當量鹽酸-二π号院（4 ml)，於室温下授拌21小時。向 反應液中添加飽和NaHC03水而成為鹼性後，以二氯甲烷 萃取。以無水MgS04乾燥萃取液，於減壓下餾去溶劑。以 己烷清洗殘渣，獲得標題化合物（76 mg)。 W-NMR (CDC13) δ : 4·87 (2H，br s)，6·92 (1H，s)，7·47 (1H， dd，J=9,〇, 2·0 Ηζ)，7·52 (1Η，d，J=8.8 Ηζ)，8·29 (1Η，s)。 [參考例74] 4-[2-(7-氯4啉-3-基胺曱醯基）乙基]硝基苯 曱酸第三丁酯 向參考例69之化合物（221 mg)的二氣甲烷（1〇瓜丨）溶液中 添加草醯氣（143 μΐ)、DMF(2滴），於室溫下攪拌2小時。將 反應液於減壓下濃縮後，將殘〉查的^ ^氣甲烧（3 m 1)溶液添 加至參考例73之化合物（106 mg)、ΤΕΑ(209 μΐ)的二氣甲烧 (5 ml)溶液中，攪拌2小時。向反應液中添加甲醇（2 ml)， 進而攪拌30分鐘後，於減壓下餾去溶劑。將殘渣以石夕膠層 析法進行精製，獲得標題化合物（107 mg)。 iH-NMR (CDC13) δ : 1·54 (9H，s)，3·02 (2H，t，J=7.4 Hz)， 3·43 (2H，t，J=7.4 Hz)，7·57 (1H，d，J=8.3 Hz)，7·65 (1H， dd，J = 8.8, 2·0 Hz)，7,79 (1H，d，J=8.8 Hz)，8·15 (1H，dd， J=7.8，1·5 Hz)，8·39 (1H，s)，8·54 (1H，d，Hz)，8 78 (1H，s)，8·86 (1H，br s)。 MS (ESI) m/z: 457 (M+H)+ 〇 [參考例75] 2-{2-[2-(第三丁氧基羰基）乙基；]·%(甲氧基幾 基）苯基胺甲醯基卜6,7·二氫-4H-噻唑并[5,4_c]吡咬_5_甲酸 弟三丁酉旨 129677.doc -87- 200840568 以與參考例Μ相同的方法’將由6,7 -二氫-4H- σ塞嗤并 [5,4-。]°比咬-2,5-二甲酸 5·第三丁酯 2-鐘鹽（w〇2 00 4/05 8715) 所衍生之醯氣與參考例64的化合物縮合而獲得標題化合 物。 'H-NMR (CDCls) δ : 1.40 (9Ή? s)5 1.51 (9H, s), 2.66 (2H, t, J=7.0 Hz)，2.87-3.06 (4H，m)，3.70-3.87 (2H，m)，3.91 (3H， s)，4.65-4.79 (2H，m)，7·32 (1H，d，J=8.1 Hz)，7·85 (1H，dd， J = 8.1，1·5 Hz)，8·61 (1H，d，J=l.5 Hz)，9.53-9.70 (1H，br)。 MS (ESI) m/z: 546 (M+H)+。 [參考例76] 2-(N-{2-[2-(第三丁氧基羰基）乙基]_%(曱氧基 羰基）苯基}-N-甲基胺甲醯基）-6,7-二氫-4H-噻唑并[5,4-c] 吡啶-5-甲酸第三丁酯 於冰浴冷卻下’向參考例75之化合物（3 3 4 mg)的DMF(4 ml)溶液中添加55%氫化納（33 mg)，於室溫下攪拌25分 鐘。於冰浴冷卻下，向反應液中添加碘曱烷（5〇 μι)，於室 溫下攪拌2日。以乙酸乙酯稀釋反應液後，添加水。以乙 酸乙醋萃取後，以飽和NaCl水溶液清洗所合併之有機層。 以無水NaaSO4乾燥，於減壓下餾去溶劑。將殘渣以使用石夕 膠之快速層析法（己烧：乙酸乙酯=6 : 1 4 : 1)進行精 氣。於冰洛冷卻下’向包含目標物之混合物（212 nig)的 THF(8 ml)溶液中添加55%氫化鈉（7 mg)，於室溫下攪拌5 分鐘。於冰浴冷卻下，向反應液中添加埃甲烧（2〇 μ 1)，於 室溫下攪拌7小時。向反應液中添加飽和氣化銨水溶液、 乙酸乙酯。以乙酸乙酯萃取後，以飽和NaCl水溶液清洗所 129677.doc -88- 200840568 合併之有機層。以無水NazSCU乾燥，於減壓下餾去溶劑。 將殘渣以使用矽膠之快速層析法（己烷··乙酸乙酯=6 : 1 — 4 : 1)進行精製，獲得標題化合物（159 mg)。 'H-NMR (CDC13) δ : 1.39 (1.6H? s)? 1.41 (6.4H? s), I.45 (6·4Η，s)，1·51 (1·6Η，s)，2·39·2·71 (3.5H，m)，2·79·3·〇5 (2.5H，m)，3·42 (2·4Η，s)，3.54-3.66 (1.5H，m)，3.75-3.86 (〇·5Η，m)，3·89 (3H，s)，3.90 (0.6H，s)，4·57 (1·5Η，br s)， 4·72 (〇·5Η，br s)，7·35 (0·8Η，d，J=8.1 Hz)，7·41 (0.2H，d， J=8.1HZ)，7.73(0.8H，d，J=1.5Hz)，7.91(0.2H，brs)，7.92- 8·00 (1H，m)。 MS (ESI) m/z: 560 (M+H)+ 〇 [參考例77] 2-{N-[2-(2-羧基乙基）-5-(曱氧基羰基）苯基]_冰 甲基胺甲酿基}-6,7 -二氫-411-嗟。坐并[5,4-c]°比咬-5-甲酸第 三丁酯 向參考例76之化合物（159 mg)的乙酸乙酯（3 ml)溶液中 添加4當量鹽酸二嘮烷溶液（2.0 ml)，於室溫下攪拌23小 時。將反應液於減壓下濃縮後，向殘渣中添加二氯甲烷 ml)、ΤΕΑ(3 00 μΐ)、Boc2O(140 mg)，於室溫下揽拌 2 小 時。以二氯甲烧稀釋反應液後，添加10%檸檬酸水。以二 氯甲烷萃取後，以飽和NaCl水溶液清洗所合併之有機層。 以無水Na2S〇4乾燥，於減壓下餾去溶劑。將殘渣以使用石夕 膠之快速層析法（二氣曱烷：曱醇=50 : 1)進行精製，獲得 標題化合物（93 mg)。 ^-NMR (CDCI3) δ : 1.45, 1.51 (total 9H, eachs), 2.39-2.58 129677.doc •89- 200840568 (1.6H，m)，2.60-2.80 (2H，m)，2.87-3.05 (2.4H，m)，3.41 (2·4Η，s)，3,59 (1·6Η，t，J=5.4 Hz)，3·73-3·96 (4H，m)，4·58 (1.6H，s)，4.72 (0·4Η，s)，7·37 (0.8H，d，J=8.i Hz)，7·42 (0.2H，d，J = 8.3 Hz)，7·72 (0.8H，d，J=1.2 Hz)，7·91 (〇·2Η， s)，7.94-8.00 (1H，m) 〇 MS (ESI) m/z: 504 (M+H)+ 〇 [參考例78] 4-甲基-3-硝基苯甲酸第三丁酉旨 以與參考例67相同的方法，由4-甲基-3-硝基苯曱酸獲得 標題化合物。 W-NMR (CDC13) δ: 1·61 (9H，s)，2·65 (3H，s)，7.40 (1H，d， J二7·8 Ηζ)，8·09 (1Η，dd，J=7.8, 1.7 Ηζ)，8·52 (1Η，d，J=l,7Hz), 7.73 (1H, d, J = 8.8 Hz), 7.91 (1H, br s), 8.39 (1H, s) 8·48 (1H, s). MS (ESI) m/z: 457 (M+H)+. [Reference Example 73] 7-Chloropipelin-3-ylamine to a solution of the compound of Reference Example 72 (163 mg) in methylene chloride (4^1) 129677.doc -86 - 200840568 The hospital (4 ml) was mixed for 21 hours at room temperature. Saturated NaHC03 water was added to the reaction mixture to make a basic solution, followed by extraction with dichloromethane. The extract was dried over anhydrous MgS04, and the solvent was evaporated under reduced pressure. The residue was washed with hexane toiel W-NMR (CDC13) δ : 4·87 (2H, br s), 6.92 (1H, s), 7·47 (1H, dd, J=9, 〇, 2·0 Ηζ), 7·52 (1Η,d,J=8.8 Ηζ), 8·29 (1Η, s). [Reference Example 74] Dihydrogenation of tert-butyl 4-[2-(7-chlorotetralin-3-ylaminoindolyl)ethyl]nitrobenzoate to the compound of Reference Example 69 (221 mg) Grass methane (143 μM) and DMF (2 drops) were added to the methane (1 guanidine) solution, and the mixture was stirred at room temperature for 2 hours. After concentrating the reaction solution under reduced pressure, a solution of the gas (3 m 1) of the residue was added to the compound of Reference Example 73 (106 mg) and hydrazine (209 μΐ). In ml), stir for 2 hours. Methanol (2 ml) was added to the reaction mixture, and the mixture was further stirred for 30 minutes, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (107 mg). iH-NMR (CDC13) δ : 1·54 (9H, s), 3·02 (2H, t, J = 7.4 Hz), 3·43 (2H, t, J = 7.4 Hz), 7·57 (1H ,d,J=8.3 Hz),7·65 (1H, dd, J = 8.8, 2·0 Hz), 7,79 (1H,d,J=8.8 Hz),8·15 (1H,dd,J = 7.8, 1·5 Hz), 8·39 (1H, s), 8·54 (1H, d, Hz), 8 78 (1H, s), 8·86 (1H, br s). MS (ESI) m/z: 457 (M+H) + 〇 [Ref. 75] 2-{2-[2-(T-butoxycarbonyl)ethyl;]·% (methoxy) Phenylamine-mercaptopurine 6,7·dihydro-4H-thiazolo[5,4_c]pyrodo_5_carboxylic acid triterpenoid 129677.doc -87- 200840568 In the same way as the reference example 将6,7-Dihydro-4H- σ 嗤 嗤 [5,4-. The ratio of the helium to the -2,5-dicarboxylic acid 5·t-butyl ester 2-ring salt (w〇2 00 4/05 8715) The helium gas derived was condensed with the compound of Reference Example 64 to give the title compound. 'H-NMR (CDCls) δ : 1.40 (9Ή? s)5 1.51 (9H, s), 2.66 (2H, t, J=7.0 Hz), 2.87-3.06 (4H, m), 3.70-3.87 (2H, m), 3.91 (3H, s), 4.65-4.79 (2H, m), 7·32 (1H, d, J = 8.1 Hz), 7·85 (1H, dd, J = 8.1, 1·5 Hz) , 8.61 (1H, d, J = 1. 5 Hz), 9.53-9.70 (1H, br). MS (ESI) m/z: 546 (M+H)+. [Reference Example 76] 2-(N-{2-[2-(Tertidinoxycarbonyl)ethyl]-%(decyloxycarbonyl)phenyl}-N-methylaminecarbamyl)-6 , 7-Dihydro-4H-thiazolo[5,4-c]pyridin-5-carboxylic acid tert-butyl ester under ice-cooling 'To the compound of Reference Example 75 (3 3 4 mg) in DMF (4 ml) 55% sodium hydride (33 mg) was added to the solution, and the mixture was stirred at room temperature for 25 minutes. Under ice cooling, iodonane (5 μm) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 days. After the reaction mixture was diluted with ethyl acetate, water was added. After extracting with ethyl acetate, the combined organic layers were washed with a saturated aqueous solution of NaCl. It was dried over anhydrous NaaSO4, and the solvent was evaporated under reduced pressure. The residue was subjected to flash chromatography using flash chromatography (hexane: ethyl acetate = 6 : 1 4 : 1). To a solution of the mixture (212 nig) in THF (8 ml) was added 55% sodium hydride (7 mg), and the mixture was stirred at room temperature for 5 minutes. After cooling in an ice bath, toluene (2 〇 μ 1 ) was added to the reaction mixture, and the mixture was stirred at room temperature for 7 hours. A saturated aqueous solution of ammonium sulfate and ethyl acetate were added to the reaction mixture. After extraction with ethyl acetate, the combined organic layers of 129677.doc-88-200840568 were washed with a saturated aqueous solution of NaCl. It was dried over anhydrous NazSCU, and the solvent was evaporated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc) 'H-NMR (CDC13) δ : 1.39 (1.6H? s)? 1.41 (6.4H? s), I.45 (6·4Η, s), 1.51 (1·6Η, s), 2.39 ·2·71 (3.5H, m), 2·79·3·〇5 (2.5H, m), 3·42 (2·4Η, s), 3.54-3.66 (1.5H, m), 3.75-3.86 (〇·5Η,m),3·89 (3H,s),3.90 (0.6H,s),4·57 (1·5Η,br s), 4·72 (〇·5Η,br s),7 ·35 (0·8Η, d, J=8.1 Hz), 7.41 (0.2H, d, J=8.1HZ), 7.73 (0.8H, d, J=1.5Hz), 7.91 (0.2H, brs) , 7.92 - 8·00 (1H, m). MS (ESI) m/z: 560 (M+H) + 〇 [Reference 77] 2-{N-[2-(2-carboxyethyl)-5-(decyloxycarbonyl)phenyl] Methylamine methyl}-6,7-dihydro-411-oxime. Sit and [5,4-c]° to a solution of the compound of Reference Example 76 (159 mg) in ethyl acetate (3 ml). Ml), stirred at room temperature for 23 hours. After the reaction mixture was concentrated under reduced pressure, dichloromethane (m.sub.3), EtOAc (3 00 ΐ), and EtOAc (140 mg) were added to the residue, and the mixture was stirred at room temperature for 2 hours. After diluting the reaction mixture with methylene chloride, 10% citric acid water was added. After extraction with methylene chloride, the combined organic layers were washed with saturated aqueous NaCl. It was dried over anhydrous Na 2 S 4 and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (dHHHHHHH) ^-NMR (CDCI3) δ : 1.45, 1.51 (total 9H, eachs), 2.39-2.58 129677.doc •89- 200840568 (1.6H,m), 2.60-2.80 (2H,m),2.87-3.05 (2.4H , m), 3.41 (2·4Η, s), 3, 59 (1·6Η, t, J=5.4 Hz), 3·73-3·96 (4H, m), 4·58 (1.6H, s ), 4.72 (0·4Η, s), 7.37 (0.8H, d, J=8.i Hz), 7.42 (0.2H, d, J = 8.3 Hz), 7.72 (0.8H, d, J = 1.2 Hz), 7·91 (〇·2Η, s), 7.94-8.00 (1H, m) 〇MS (ESI) m/z: 504 (M+H)+ 〇 [Reference Example 78] 4 -Methyl-3-nitrobenzoic acid tributyl sulfonate The title compound was obtained from 4-methyl-3-nitrobenzoic acid in the same manner as in the title compound 67. W-NMR (CDC13) δ: 1·61 (9H, s), 2·65 (3H, s), 7.40 (1H, d, J 2·7 Ηζ), 8·09 (1Η, dd, J= 7.8, 1.7 Ηζ), 8·52 (1Η, d, J=l, 7

Hz)。 [參考例79] 4-(2 -乙氧基幾基-2-經基乙基）-3-確基苯甲酸第 三丁酯 向參考例78之化合物（2.37 g)的THF(20 ml)溶液中添加草 酸二乙酯（2.04 1111)及屯11〇尺（1.80 g)，攪拌25分鐘。向反應 液中添加10%擰檬酸水溶液，以乙酸乙酯萃取。以無水 NajO4乾燦萃取液後，於減壓下餾去溶劑。將殘渣以矽膠 層析法（乙酸乙酯：己烷=1 : 9» 3 : 22 — 3 : 17)進行精 製，獲得粗製之4-(2-乙氧基羰基-2-氧基乙基）-3-硝基苯曱 酸第三丁酉旨（742 mg)。 向粗製之4_(2_乙氧基羰基-2-氧基乙基）-3_硝基苯甲酸第 三丁酯（742 mg)的THF(1 5 ml)溶液中添加硼氫化鈉（Μ mg)，攪拌15分鐘。向反應液中添加0.1當量鹽酸，以乙酸 129677.doc -90- 200840568 乙醋萃取。以無水NkSO4乾燥萃取液後，於減壓下館去溶 劑。將殘渣以矽膠層析法（乙酸乙酯· Ρ ρ , ' 転·己烷=1 ·· 4)進行精 製，獲得標題化合物（5 12 mg)。 Ή-NMR (CDC13) 5:1.30 (3H, t, J=7.1 Hz), !.60 (9H, s), 2·90 (1H，d，卜5·4 Hz)，3·25 (1H，dd，J=i3 9, 8] Hz) 3 58Hz). [Reference Example 79] tert-butyl 4-(2-ethoxylated-2-ylethylethyl)-3-decylbenzoate To a compound of Reference Example 78 (2.37 g) THF (20 ml) Diethyl oxalate (2.04 1111) and 屯11〇 (1.80 g) were added to the solution and stirred for 25 minutes. A 10% aqueous solution of citric acid was added to the reaction mixture, followed by extraction with ethyl acetate. After drying the extract with anhydrous NajO4, the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:hexane = 1 : 9 : 3 : 22 - 3 : 17) to give crude 4-(2-ethoxycarbonyl-2- oxyethyl) -3-nitrobenzoic acid tributyl sulfonate (742 mg). To a solution of crude 4_(2-ethoxycarbonyl-2-oxoethyl)-3-nitrobenzoic acid tert-butyl ester (742 mg) in THF (15 mL) ), stirring for 15 minutes. 0.1N hydrochloric acid was added to the reaction mixture, and extracted with acetic acid 129677.doc -90-200840568. After the extract was dried over anhydrous NkSO4, the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate EtOAc EtOAc EtOAc Ή-NMR (CDC13) 5:1.30 (3H, t, J=7.1 Hz), !.60 (9H, s), 2·90 (1H, d, Bu 5·4 Hz), 3·25 (1H, Dd,J=i3 9, 8] Hz) 3 58

(1H, dd? 1^13.9, 4.4 Hz)? 4.19-4.32 (2H, m)? 4.46-4.5^ (lH m)，7,51 (1H，d，Hz)，8.13 (1H，机 J=8丄 i 7 Hz)’ 8·47 (1H，d，J=1.7 Hz)。 ’ • MS (ESI) m/z: 340 (M+H)+。 [參考例79a] 4-胺基_ 3 _硝基苯甲酸曱酉旨 使4-胺基-3-硝基苯甲酸（2.0 g)懸浮於曱醇（2〇 mi)中，添 加亞硫醯氯（4 ml)，加熱回流3小時。將反應液冷卻至〇 °C，添加IPE(30 ml)，進行攪拌。濾取析出物，獲得標題 化合物（1.66 g)。 TH.NMR (CDCls) δ: 3.90 (3Η, d5 1=3.2 Hz)? 6.42 (2H5 br s)5 6.83 (1H? d, J=8.8 Hz)? 8.00 (1H? dd5 J=：8.8? 2.0 Hz)? 8.85 • (1H, d? J=2.0 Hz) 〇 [參考例79b] 4-[(弟二丁氧基幾基）胺基]硝基苯甲酸甲酉旨 使參考例79a之化合物（4.22g)懸浮於THF(1〇〇ml)中，冷 卻至0°C後，添加55%氫化鈉（2.35 g)，攪拌3〇分鐘。接 著，添加Βο〇2〇(11_7 g)，於室溫下攪拌2小時後，添加 水，以乙酸乙酯萃取。將有機層以無水NajO*乾燥，進行 濃縮後，添加IPE，濾取析出物，獲得標題化合物（4.41 g) ° 129677.doc -91 - 200840568 !H-NMR (CDC13) δ : 1·56 (9H，S)，3·95 (3H，S)，8·23 (1H， dd，J=8.9，2.0 Hz)，8.69 (1H，d，J=8.9 Hz)，8·88 (1H，d， J=2.0 Hz)，9·88 (1H，s)。 MS (ESI) m/z: 593 (2M+H)+ [參考例79c] 4_[(第三丁氧基羰基）胺基]-3-硝基苯曱酸 使參考例79b之化合物（1·〇 g)溶解於THF(20 ml)及水（2 ml)中，添加LiOH(80 mg)，於室溫下攪拌8小時。向反應 液中添加1當量鹽酸水溶液（6 ml)，以乙酸乙酯萃取後，以 無水Na2S〇4乾燥有機層。將其濃縮，向殘渣中添加乙酸乙 酯、己烷，進行濾取，獲得標題化合物（846 mg)。 !H-NMR (CDC13) δ : 1·57 (9H，S)，8·29 (1H，dd，J=9.0, 2.2 Hz)，8.75 (1H，d，J=9.0 Hz)，8.96 (1H，d，J=2.2 Hz)，9.94 (1H，s)。 MS (ESI) m/z: 565 (2M+H)+ [參考例80] 4-(2-羧基-2-羥基乙基&gt;3_硝基苯甲酸第三丁酯 以與參考例79c相同的方法，由參考例79之化合物獲得 標題化合物。 ]H-NMR (CDC13) δ : 1.61 (9H5 s)5 2.50-3.25 (1H5 br)5 3.30 (1H，dd，J=14」，8·0 Hz)，3.67 (1H，dd，J=13.9，4.4 Hz)， 4·61 (1H, dd，J=8.0, 4.4 Hz)，7·53 (1H，d，J=8.0 Hz)，8.16 (1H，dd，1.8 Hz)，8·49 (1H，d，J=1.7 Hz)。 [參考例81] 4-[2-(4-氯笨基胺曱醯基）_2-羥基乙基；|-3_硝基 苯曱酸第三丁酯 向參考例80之化合物（260 mg)的DMF(8 ml)溶液中添加 129677.doc -92- 200840568 4-氯苯胺（105 mg)、HOBt(m mg)、及 EDC(315 mg)，於 室溫下攪拌18小時。於減壓下餾去溶劑，向殘渣中添加飽 和NaHCCb水溶液，以二氯甲烷萃取。以無水Na2S〇4乾燥 萃取液後’於減壓下餾去溶劑。將殘渣以矽膠層析法（乙 酸乙酯：己烷=1 : 9— 1 : 4)進行精製，獲得標題化合物 (257 mg) 〇 'H-NMR (CDCls) δ : 1.60 (9Η5 s), 3.37 (1Η? dd5 J=13.9, 7.1 Ηζ)，3.55 (1Η，d，J=4.6 Ηζ)，3·69 (1Η，dd，J=13.9, 4·4 Ηζ)， 4.56-4.62 (1H，m)，7·31 (2H，d，J=8.8 Hz)，7·52 (2H，d， J = 9.0 Hz)，7·55 (1H，d，J=8.0 Hz)，8·14 (1H，dd，J=8.0, 1.7 Hz)，8·39 (1H，s)，8.49 (1H，d，J=1.7 Hz)。 MS (ESI) m/z: 421 (M+H)+ 〇 [參考例82] 3-胺基·4_[2·(4_氣苯基胺甲醯基）_2-羥基乙基] 苯曱酸第三丁酯 以與參考例13相同的方法，由參考例8丨之化合物獲得標 題化合物。 ]H-NMR (CDCls) δ : 1.57 (9H3 s)? 1.58-1.65 (2H5 m)5 3.11 (1H，dd，J=14.6，7·3 Hz)，3·32 (1H，dd，J=14.5，3.8 Hz)， 3.85-4.15 (1H，br)，4.51 (1H，dd，J=7.4，3.8 Hz)，7·17 (1H， d，J=7.8 Hz)，7·28 (2H，d，J=9.〇 Hz)，7·38 (1H，d，J=1.5 Hz)，7·43 (1H，dd，J=7.7，1.6 Hz)，7·48 (2H，d，J=8.8 Hz)， 8·54 (1H，s)。 MS (ESI) m/z: 391 (M+H)+。 [參考例83] 4-[(2-乙氧基羰基）丙基]_3_硝基苯甲酸第三丁 129677.doc -93- 200840568(1H, dd? 1^13.9, 4.4 Hz)? 4.19-4.32 (2H, m)? 4.46-4.5^ (lH m), 7, 51 (1H, d, Hz), 8.13 (1H, machine J=8丄i 7 Hz)' 8·47 (1H, d, J = 1.7 Hz). ' MS (ESI) m/z: 340 (M+H)+. [Reference Example 79a] 4-Amino-3_nitrobenzoic acid hydrazine To suspend 4-amino-3-nitrobenzoic acid (2.0 g) in decyl alcohol (2 〇mi), add sulfoxide Chlorine (4 ml) was heated to reflux for 3 hours. The reaction solution was cooled to 〇 ° C, and IPE (30 ml) was added and stirred. The precipitate was filtered to give the title compound (1.66 g). TH.NMR (CDCls) δ: 3.90 (3Η, d5 1=3.2 Hz)? 6.42 (2H5 br s)5 6.83 (1H? d, J=8.8 Hz)? 8.00 (1H? dd5 J=:8.8? 2.0 Hz 8.85 • (1H, d? J=2.0 Hz) 〇 [Reference Example 79b] 4-[(Di-dioxyoxy)amino]nitrobenzoic acid formazan The compound of Reference Example 79a (4.22) g) Suspension in THF (1 〇〇ml), after cooling to 0 ° C, 55% sodium hydride (2.35 g) was added and stirred for 3 hr. Then, Βο〇2〇 (11_7 g) was added, and after stirring at room temperature for 2 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous NajO*, and then concentrated, and then ethylamine was added, and the precipitate was collected to give the title compound (4.41 g) 129677.doc -91 - 200840568 !H-NMR (CDC13) δ : 1·56 (9H ,S),3·95 (3H,S),8·23 (1H, dd,J=8.9,2.0 Hz), 8.69 (1H,d,J=8.9 Hz),8·88 (1H,d,J =2.0 Hz), 9·88 (1H, s). MS (ESI) m/z: 592 (2M+H) + [JJJJJJJJJJJJJJJJJJJJJJJJJJJJ 〇g) was dissolved in THF (20 ml) and water (2 ml). LiOH (80 mg) was added and stirred at room temperature for 8 hours. After a 1N aqueous solution of hydrochloric acid (6 ml) was added to the mixture, ethyl acetate was evaporated, and the organic layer was dried over anhydrous Na? This was concentrated, and ethyl acetate and hexane were added to the residue, and filtered to give the title compound (846 mg). !H-NMR (CDC13) δ : 1·57 (9H,S),8·29 (1H,dd,J=9.0, 2.2 Hz), 8.75 (1H,d,J=9.0 Hz), 8.96 (1H, d, J = 2.2 Hz), 9.94 (1H, s). MS (ESI) m/z: 565 (2M+H) + [Reference Example 80] 4-(2-carboxy-2-hydroxyethyl) 3 - nitrobenzoic acid tert-butyl ester was the same as in Reference Example 79c The title compound was obtained from the compound of Reference Example 79.]H-NMR (CDC13) δ: 1.61 (9H5 s)5 2.50-3.25 (1H5 br)5 3.30 (1H,dd,J=14",8·0 Hz), 3.67 (1H, dd, J=13.9, 4.4 Hz), 4·61 (1H, dd, J=8.0, 4.4 Hz), 7·53 (1H, d, J=8.0 Hz), 8.16 (1H , dd, 1.8 Hz), 8.49 (1H, d, J = 1.7 Hz) [Reference Example 81] 4-[2-(4-Chlorophenylaminoindenyl)_2-hydroxyethyl;|- To the solution of the compound of Reference Example 80 (260 mg) in DMF (8 ml), 129677.doc-92-200840568 4-chloroaniline (105 mg), HOBt (m mg) And EDC (315 mg), and stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure. EtOAc m. The solvent was evaporated under reduced pressure.yield crystals eluted elute 1.60 (9Η5 s), 3.37 (1Η? dd5 J=13.9, 7.1 Ηζ), 3.55 (1Η,d,J=4.6 Ηζ),3·69 (1Η,dd,J=13.9, 4·4 Ηζ), 4.56 -4.62 (1H,m),7·31 (2H,d,J=8.8 Hz),7·52 (2H,d, J = 9.0 Hz),7·55 (1H,d,J=8.0 Hz), 8·14 (1H, dd, J=8.0, 1.7 Hz), 8.39 (1H, s), 8.49 (1H, d, J = 1.7 Hz) MS (ESI) m/z: 421 (M+H + 〇 [Reference Example 82] 3-amino group 4_[2·(4_ phenylphenylcarbamoyl)_2-hydroxyethyl]benzoic acid tert-butyl ester in the same manner as in Reference Example 13, The title compound was obtained from the compound of the compound of Example 8:]H-NMR (CDCls) δ: 1.57 (9H3 s)? 1.58-1.65 (2H5 m)5 3.11 (1H,dd,J=14.6,7·3 Hz), 3·32 (1H, dd, J=14.5, 3.8 Hz), 3.85-4.15 (1H, br), 4.51 (1H, dd, J=7.4, 3.8 Hz), 7·17 (1H, d, J=7.8 Hz), 7·28 (2H, d, J=9.〇Hz), 7·38 (1H, d, J=1.5 Hz), 7·43 (1H, dd, J=7.7, 1.6 Hz), 7 · 48 (2H, d, J = 8.8 Hz), 8·54 (1H, s). MS (ESI) m/z: 391 (M+H)+. [Reference Example 83] 4-[(2-ethoxycarbonyl)propyl]_3_nitrobenzoic acid tributyl 129677.doc -93- 200840568

向參考例67之化合物（1.58 g)的乙醇（30 ml)溶液中添加 2_甲基乙酿乙酸乙酯（778 μΐ)及20%乙醇鈉·乙醇溶液（2.55 ml) ° 50分鐘後，向反應液中追加20%乙醇鈉-乙醇溶液 (1·〇〇 ml)，進而攪拌4〇分鐘。向反應液中添加1當量鹽酸一 乙醇溶液（4 ml)，於減壓下餾去溶劑。向殘渣中添加乙酸 乙_ ’水洗後，以無水NkSO4乾燥。於減壓下餾去溶劑， 將殘渣以矽膠管柱層析法（乙酸乙酯：己烷=3 : 47)進行精 製’獲得標題化合物（734 mg)。 'H-NMR (CDC13) δ : 1.17 (3Η? J=7.1 Ηζ)5 1.25 (3Η5 d5 J=7.1 Ηζ)，1·60 (9Η，s)，2.80-2.90 (1Η，m)，3·09 (1Η，dd， J=13.5, 6.0 Hz)，3.27 (1H，dd，J=13.5, 8·7 Hz)，4.01-4.12 (2H，m)，7.42 (1H，d，J=8.0 Hz)，8.09 (1H，dd，J=8.0, 2·〇 Hz)，8·49 (1H，d，J=1.7 Hz)。 MS (ESI) m/z: 338 (M+H)+。 [參考例84] 4-(2-魏基丙基）-3-石肖基苯甲酸第三丁醋 以與參考例79c相同的方法，由參考例83之化合物獲得 標題化合物。 ]H-NMR (CDC13) δ : 1.30 (3Η, d, J=7.1 Hz)? 1.60 (9H? s)5 2.88-2.98 (1H，m)，3·10 (1H，dd，J=13.4, 6·1 Hz)，3·33 (1H， dd，J=13.7，8.3 Hz)，7.45 (1H，d，J=7.8 Hz), 8.12 (1H，dd5 J=8.0，1·7 Hz)，8·51 (1H，d，J=2.0 Hz)。 MS (ESI) m/z: 310 (M+H)+。 [參考例85] 4-[2-(4-氯苯基胺甲醯基）丙基]-3-硝基苯曱酸 129677.doc -94- 200840568 第三丁酯 以與參考例8 1相同的方法，將參考例84之化合物與4_氯 苯胺縮合而獲得標題化合物。To a solution of the compound of Reference Example 67 (1.58 g) in ethanol (30 ml), ethyl 2-ethylacetate ethyl acetate (778 μM) and 20% sodium ethoxide/ethanol solution (2.55 ml) for 50 minutes, A 20% sodium ethoxide-ethanol solution (1·ml) was added to the reaction mixture, and the mixture was further stirred for 4 minutes. A 1 N hydrochloric acid-ethanol solution (4 ml) was added to the reaction mixture, and the solvent was evaporated. After adding acetic acid to the residue, the mixture was washed with water and dried over anhydrous NkSO4. The solvent was evaporated to dryness crystals crystals crystals crystals crystals 'H-NMR (CDC13) δ : 1.17 (3Η? J=7.1 Ηζ)5 1.25 (3Η5 d5 J=7.1 Ηζ),1·60 (9Η, s), 2.80-2.90 (1Η,m),3·09 (1Η, dd, J=13.5, 6.0 Hz), 3.27 (1H, dd, J=13.5, 8·7 Hz), 4.01-4.12 (2H, m), 7.42 (1H, d, J=8.0 Hz), 8.09 (1H, dd, J=8.0, 2·〇Hz), 8.49 (1H, d, J = 1.7 Hz). MS (ESI) m/z: 338 (M+H)+. [Reference Example 84] 4-(2-Wylicylpropyl)-3-stone sulfonylbenzoic acid terpene succinate The title compound was obtained from the compound of the compound of the titled compound. ]H-NMR (CDC13) δ : 1.30 (3Η, d, J=7.1 Hz)? 1.60 (9H? s)5 2.88-2.98 (1H,m),3·10 (1H,dd,J=13.4, 6 · 1 Hz), 3·33 (1H, dd, J=13.7, 8.3 Hz), 7.45 (1H, d, J = 7.8 Hz), 8.12 (1H, dd5 J=8.0, 1·7 Hz), 8· 51 (1H, d, J = 2.0 Hz). MS (ESI) m/z: 310 (M+H)+. [Reference Example 85] 4-[2-(4-Chlorophenylaminomethane)propyl]-3-nitrobenzoic acid 129677.doc -94- 200840568 The third butyl ester is the same as Reference Example 81 The title compound was obtained by condensing the compound of Reference Example 84 with 4-chloroaniline.

h-NMR (CDC13) δ : 1·31 (3H，d，Hz)，1.60 (9H，s) 2.72-2.81 (1H，m)，3.02 (1H，dd，J=13.3, 6.2 Hz)，3·4〇 (1H dd，J=13.2，7·6 Hz)，7·11 (1H，s)，7·26 (2H，d，J=8.5 hz) 7.41 (2H，d，J=9.0 Hz)，7.46 (1H，d，J=7.8 Hz)，8.09 (1H dd，J=8.1，1.7 Hz)，8·54 (1H，s)。 ’ MS (ESI) m/z: 419 (M+H)+。 [參考例86] 3-胺基-4-[2-(4-氣苯基胺曱醯基）丙基]苯甲酸 第三丁酯 以與參考例13相同的方法，由參考例85之化合物獲得伊、 題化合物。 'H-NMR (CDC13) δ : 1.35 (3H? d? J=6.8 Hz), 1.56 (9H) s) 2·60-2·72 (2H，m)，3.00-3.13 (1H，m)，3·94 (2H，br s)，6 98 (1H，s)，7,06 (1H，d，J=7.8 Hz)，7·23 (2H，d，J，〇Hz) 7·28 (2H，d，J = 9.0 Hz)，7.30-7.33 (2H，m)。 MS (ESI) m/z: 389 (M+H)+ 〇 [參考例87] 2-(4-第三丁氧基羰基-2-硝基苄基）_2-氟丙二酸 二乙酉旨 向參考例67之化合物（500 mg)的乙醇（10 ml)溶液中添加 2 -氣丙^一酸二乙1旨（281 mg)及20%乙畔納-乙醇溶液（5 82 μΐ)。7小時後，向反應液中追加2-氟丙二酸二乙酯μ1) 及20%乙醇鈉-乙醇溶液（2〇〇 μΐ)，進而攪拌3曰。於減壓下 129677.doc -95- 200840568 餾去溶劑，向殘渣中添加乙酸乙酯，水洗後，以無水 NajO4乾燥。於減壓下餾去溶劑，將殘渣以矽膠管柱層析 法（乙酸乙酯：己烷=1 : 19—2 : 23)進行精製，獲得標題 化合物（3 60 mg)。 1H-NMR (CDC13) δ ·· 1.27 (6H，t，J=7.1 Ηζ)，1·60 (9H，s)， 3·98 (2H，d，J=23.2 Hz)，4.21-4.29 (4H，m)，7.53 (1H，d， J = 8.0 Hz)，8·12 (1H，dd，J=8.0，1.7 Hz)，8.44 (1H，d，J=1.7h-NMR (CDC13) δ : 1·31 (3H, d, Hz), 1.60 (9H, s) 2.72-2.81 (1H, m), 3.02 (1H, dd, J = 13.3, 6.2 Hz), 3· 4〇(1H dd, J=13.2,7·6 Hz), 7·11 (1H, s), 7·26 (2H, d, J=8.5 hz) 7.41 (2H, d, J=9.0 Hz), 7.46 (1H,d,J=7.8 Hz), 8.09 (1H dd, J=8.1, 1.7 Hz), 8.54 (1H, s). ' MS (ESI) m/z: 419 (M+H)+. [Reference Example 86] 3-Amino-4-[2-(4-phenylphenylindenyl)propyl]benzoic acid tert-butyl ester In the same manner as in Reference Example 13, the compound of Reference Example 85 Obtained the compound of Iraq and the title. 'H-NMR (CDC13) δ : 1.35 (3H? d? J=6.8 Hz), 1.56 (9H) s) 2·60-2·72 (2H, m), 3.00-3.13 (1H, m), 3 ·94 (2H, br s), 6 98 (1H, s), 7, 06 (1H, d, J = 7.8 Hz), 7·23 (2H, d, J, 〇 Hz) 7·28 (2H, d, J = 9.0 Hz), 7.30-7.33 (2H, m). MS (ESI) m/z: 389 (M+H) + 〇 [Reference Example 87] 2-(4-t-butoxycarbonyl-2-nitrobenzyl)_2-fluoromalonic acid diethyl hydrazine A solution of the compound of Example 67 (500 mg) in ethanol (10 ml) was added to a mixture of 2-dichloropropanediethyldichloride (281 mg) and 20% of ethylamine-ethanol (5 82 μM). After 7 hours, diethyl 2-fluoromalonate μ1) and a 20% sodium ethoxide-ethanol solution (2 μM) were added to the reaction mixture, and the mixture was further stirred for 3 Torr. Under reduced pressure 129677.doc -95- 200840568 The solvent was evaporated, ethyl acetate was added to the residue, and washed with water and dried over anhydrous Naj. The solvent was evaporated under reduced pressure, and the residue was purified mjjjjjjjjjjj 1H-NMR (CDC13) δ ·· 1.27 (6H, t, J=7.1 Ηζ), 1·60 (9H, s), 3·98 (2H, d, J=23.2 Hz), 4.21-4.29 (4H, m), 7.53 (1H, d, J = 8.0 Hz), 8·12 (1H, dd, J=8.0, 1.7 Hz), 8.44 (1H, d, J=1.7

Hz) 〇 [參考例88] 4-(2-叛基-2-氟乙基）-3-硝基_苯曱酸第三丁酯 以與參考例69相同的方法，由參考例87之化合物獲得標 題化合物。 lH.NMR (CDC13) δ : 1.61 (PH, s)? 3.39-3.54 (1H? m), 3.72- 3.90 (1H5 m)? 5.21-5.45 (1H5 m)5 7.49-7.54 (1H? m), 8.18 (1H，d，J二6·6 Hz)，8·57 (1H，d，J=i.5 Ήζ) o [參考例89] 4-[2-(4-氯苯基胺甲醯基）_2_氟乙基]_3_硝基笨 甲酸第三丁酯 以與參考例81相同的方法，將參考例88之化合物與4_氯 苯胺縮合而獲得標題化合物。 lH-NMR (CDCI3) δ : 1.61 (9Η5 ，s)，3·59 (1Η，ddd，J=21.3,Hz) 参考 [Reference Example 88] 4-(2-Resyl-2-fluoroethyl)-3-nitro-benzoic acid tert-butyl ester In the same manner as in Reference Example 69, the compound of Reference Example 87 The title compound was obtained. lH.NMR (CDC13) δ : 1.61 (PH, s)? 3.39-3.54 (1H? m), 3.72- 3.90 (1H5 m)? 5.21-5.45 (1H5 m)5 7.49-7.54 (1H? m), 8.18 (1H, d, J 2 6. 6 Hz), 8.57 (1H, d, J = i.5 Ήζ) o [Reference Example 89] 4-[2-(4-Chlorophenylaminecarbamyl) _2_Fluoroethyl]_3_nitrobenzoic acid tert-butyl ester The title compound was obtained by condensing the compound of Reference Example 88 with 4-chloroaniline in the same manner as in the the the the lH-NMR (CDCI3) δ : 1.61 (9Η5 , s), 3·59 (1Η, ddd, J=21.3,

Hz) 〇 129677.doc -96 - 200840568 MS (ESI) m/z: 423 (M+H)+。 [參考例90] 3-胺基-4-[2-(4-氯笨基胺甲醯基）_2_氣乙 甲酸第三丁酯 4 ]笨 以與參考例丨3相同的方法，由參考例的之化合物獲γ迅 題化合物。 &amp;件檫 ^H-NMR (CDC13) δ : 1.57 (9H?S)5 3.20-3.40 (2H5m) 39 (2H，br s)，5·32 (1H，ddd，J=49.5, 5 6, 3 7 Hz)，7 i5 ⑽，·:Hz) 129 129677.doc -96 - 200840568 MS (ESI) m/z: 423 (M+H)+. [Reference Example 90] 3-Amino-4-[2-(4-chlorophenylaminocarbamimidyl)_2-glycolic acid tert-butyl ester 4] is the same as in Reference Example 3, by reference The compound of the example is obtained as a γ-sound compound. &amp; 檫^H-NMR (CDC13) δ : 1.57 (9H?S)5 3.20-3.40 (2H5m) 39 (2H,br s),5·32 (1H,ddd,J=49.5, 5 6, 3 7 Hz), 7 i5 (10), ·:

J=7.8 Hz)，7·30 (2H，d，J=8.8 Hz)，7 3〇 (1H，d，— 7 知’ 7.34 (1H，dd，J=7.8, 17 Hz)，7·43 (2H，d，卜8·8 Hz)，^)， (1H，d，J=6.6 Hz)。 ’ · 3 MS (ESI) m/z: 393 (M+H)、 [參考例91] 3-胺基-4-{(Ε)·2-[(4-氯苯基）胺甲醯基]乙烯基} 苯甲酸第三丁酯 &amp; 以與參考例13相同的方法，由參考例6〇之化合物獲得標 題化合物。 Η-NMR (CDC13) δ : 1·59 (9H，s)，3.92-4.23 (2H，br)，6,50 (1H，d，J=15.1 Ηζ)，7·29-7·41 (6H，m)，7.57 (2H，d，JuJ = 7.8 Hz), 7·30 (2H, d, J = 8.8 Hz), 7 3 〇 (1H, d, - 7 know ' 7.34 (1H, dd, J = 7.8, 17 Hz), 7·43 ( 2H, d, Bu 8·8 Hz), ^), (1H, d, J = 6.6 Hz). ' · 3 MS (ESI) m/z: 393 (M+H), [Ref. 91] 3-amino-4-{(Ε)·2-[(4-chlorophenyl)aminemethanyl] Vinyl} benzoic acid tert-butyl ester &amp; The title compound was obtained from the compound of Reference Example 6 in the same manner as in the the the Η-NMR (CDC13) δ : 1·59 (9H, s), 3.92-4.23 (2H, br), 6, 50 (1H, d, J = 15.1 Ηζ), 7·29-7·41 (6H, m), 7.57 (2H, d, Ju

Hz)，7·88 (1H，d，J=15.1 Hz)。 MS (ESI) m/z: 373 (M+H)+ 〇 [芩考例92] 4-{(E)-2_[(5·氯吼啶基）胺甲醯基]乙烯基卜3· 硝基苯甲酸第三丁酯 以與參考例74相同的方法，使由心（⑻_2_叛基乙稀基 3_硝基苯甲酸第三丁 所衍生之醯氯與2_胺基·5_氯吼咬反 應而獲得標題化合物。 I29677.doc 97 - 200840568 H-NMR (CDC13)5: 1.63 (9H, s), 6.52 (1H, d, J=15.4h 7.69 (1H, d, 1=8.5 Hz), 7.72 (1H, dd, J=8.8, 2.6 He), (1H’ d’ J=15’4 Hz)’ 8·21-8·28 (3H，m)，8.34 (1H，（Hz), 7·88 (1H, d, J = 15.1 Hz). MS (ESI) m/z: 373 (M+H) + 〇 [芩例92] 4-{(E)-2_[(5·chloroacridinyl)aminemethanyl]vinyl bromide 3· The third butyl benzoate was subjected to the same method as in Reference Example 74 to give hydrazine and 2-amino-5-chlorobenzene derived from the heart ((8)_2- ethidyl 3-nitrobenzoic acid tert-butyl) The title compound was obtained by a bite reaction. I29677.doc 97 - 200840568 H-NMR (CDC13) 5: 1.63 (9H, s), 6.52 (1H, d, J = 15.4h 7.69 (1H, d, 1 = 8.5 Hz) , 7.72 (1H, dd, J=8.8, 2.6 He), (1H' d' J=15'4 Hz)' 8·21-8·28 (3H,m), 8.34 (1H,(

Hz), 8.60 (1H，d，J=1.5 Hz)。 .8 MS (ESI) m/z: 404 (M+H)+ 〇 [參考例93] 3-胺基-4-{(E)-2-[(5H定-2-基）胺甲酿義飞 烯基}苯曱酸第三丁酯Hz), 8.60 (1H, d, J = 1.5 Hz). .8 MS (ESI) m/z: 404 (M+H) + 〇 [Ref. 93] 3-amino-4-{(E)-2-[(5H-di-2-yl)amine Feltenyl}benzoic acid tert-butyl ester

以與參考例13相同的方法’由參考靜之化In the same way as in Reference Example 13

^-NMR (CDC13) δ : 1.59 (9Η, s)? 4.07 (2H5 br s)? 6.52 (lH d，J-15·4 Hz)，7·32-7·44 (3H，m)，7.70 (1H，dd，J=9 〇，^-NMR (CDC13) δ : 1.59 (9Η, s)? 4.07 (2H5 br s)? 6.52 (lH d, J-15·4 Hz), 7·32-7·44 (3H, m), 7.70 ( 1H, dd, J=9 〇,

Hz)，7·91 (1H，d，J=15.4 Hz)，8·15 (1H，br s)，8·25 (1H J=2.7 Hz)，8·33 (1H，d，卜9.0 Hz)。 ，’ MS (ESI) m/z: 374 (M+H)+。 [參考例94]4-漠甲基_3_氯_5_硝基苯甲酸甲醋 以與參考例49相同的方法，由3-氯-4-甲基·5-硝基苯甲 酸甲酯獲得標題化合物。 ^-NMR (CDC13) δ 00 3” · 3·99 (3Η，s)，4·88 (2Η，s)，8·32 (1Η d J=1.7 Hz), 8.47 (1Η, d, J=1.7Hz)〇 ’ ’ MS (ESI) m/z: 308 (M+H)+。 [參考例95] 2_[2'教田&amp; /、 （曱氣基幾基）-6-硝基节基]丙二酸二 第三丁酯 以與參考例68相同的方法 例94之化合物獲得標題化合物 由丙二酸二第三丁酯與參考 129677.doc -98、 200840568 】H-NMR (CDC13) δ : 1·41 (18H，s)，3·58 (1H，dd，J = 8.3, 6·8 Hz)，3·68 (2H，br· d，J=7.1 Hz)，3·97 (3H，s)，8·26 (1H，d， J=1.7 Hz)，8.37 (1H，d，J=1.7 Hz)。 MS (ESI) m/z: 466 (M+Na)+。 [參考例96] 4-(2-羧基乙基）-3-氯-5-硝基苯甲酸曱酯 向筝考例95之化合物（1.18 g)的二噚烷（5 ml)溶液中添加 4當量鹽酸二呤烷溶液（8 ml)，於室溫下攪拌14小時。向反 應液中添加二氯曱烷（5 ml)、4當量鹽酸二噚烷溶液（5 ml)、水（1 ml)，攪拌7日。將反應液於減壓下濃縮後，向 殘渣中添加二吟烧（8 ml)、4當量鹽酸二吟烧溶液（1〇 ml)， 於室溫下攪拌3日。將反應液於減壓下濃縮後，向殘渣中 添加二氯甲烷（8 ml)、TFA(6 ml)，於室溫下攪拌2小時。 將反應液於減壓下濃縮，將殘渣製成乙腈（20 ml)溶液，添 加氧化銅（1)(90 mg)，於80°C下攪拌16小時。冷卻後將不 溶物過濾分離，將濾液於減壓下濃縮。將殘渣以使用矽膠 之快速層析法（二氣曱烷：曱醇=30 : 1)進行精製。向粗精 製物中添加己烷-乙酸乙酯（20/1)混合液，濾取固體，獲得 標題化合物（645 mg)。 ^-NMR (CDCI3) δ : 2.83 (2Η, t? 1=7.4 Hz)5 3.29 (2H5 t, J=7.4 Hz)，3·98 (3H，s)，8·28 (1H，d，J=1.7 Hz)，8.36 (1H， d，J=1.7 Hz)。 MS (ESI) m/z: 310 (M+Na)+ 〇 [參考例97] 3-氣-4-{2-[(4-氣苯基）胺甲醯基]乙基卜5-硝基 苯曱酸甲酉旨 129677.doc -99- 200840568 以與參考例81相同的方、本 ^ ^ 决’將參考例96之化合物與4-氣 苯胺縮合而獲得標題化合物。 'H^NMR (CDCls) δ ： 2.77 (oxr ·&quot; (2H，t，J=8.1 Ηζ)，3·33 (2H，t， J = 8.1 Hz)，3·97 (3H，s) 7 9ς ,οττ /.25 (2H5 d, J=8.8 Hz), 7.46 (2H, d，J=8·8 Hz)，7·56 (1Η 〇 〇c J 、 ，s)，8·25 (1H，d，J=1.5 Hz)，8.34 (1H，d5 J=1.5 Hz) 〇 MS (ESI) m/z: 397 (M+H)+。 [芩考例98]3-胺基-5-氯·4_{2-[(4-氯笨基）胺甲 醯基]乙基}苯Hz),7·91 (1H,d,J=15.4 Hz),8·15 (1H,br s),8·25 (1H J=2.7 Hz),8·33 (1H,d,Bu 9.0 Hz) . , ' MS (ESI) m/z: 374 (M+H)+. [Reference Example 94] 4-Methylmethyl_3_chloro-5-nitrobenzoic acid methyl ketone In the same manner as Reference Example 49, methyl 3-chloro-4-methyl-5-nitrobenzoate The title compound was obtained. ^-NMR (CDC13) δ 00 3" · 3·99 (3Η, s), 4·88 (2Η, s), 8·32 (1Η d J=1.7 Hz), 8.47 (1Η, d, J=1.7 Hz)〇' ' MS (ESI) m/z: 308 (M+H)+ [Reference Example 95] 2_[2'Teaching &amp; /, (曱气基基)-6-nitro-knot ]Dibutyl tert-butyl acrylate. The title compound was obtained from the compound of Example 94 in the same manner as the compound of Example 68, m.p. : 1·41 (18H, s), 3·58 (1H, dd, J = 8.3, 6·8 Hz), 3·68 (2H, br·d, J=7.1 Hz), 3·97 (3H, s), 8.26 (1H, d, J = 1.7 Hz), 8.37 (1H, d, J = 1.7 Hz) MS (ESI) m/z: 466 (M+Na) + [Reference Example 96] 4-(2-Carboxyethyl)-3-chloro-5-nitrobenzoic acid oxime ester To a solution of the compound of Example 65 (1.18 g) in dioxane (5 ml) was added 4 eq. The solution (8 ml) was stirred at room temperature for 14 hours. To the reaction mixture was added dichloromethane (5 ml), 4 eq. of dioxane hydrochloride (5 ml) and water (1 ml). After concentrating the reaction mixture under reduced pressure, dioxane (8 ml) and 4 equivalents of salt were added to the residue. The bismuth sulphate solution (1 ml) was stirred at room temperature for 3 days. After the reaction mixture was concentrated under reduced pressure, dichloromethane (8 ml) and TFA (6 ml). The mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was evaporated to ethyl acetate (20 ml). The mixture was separated by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (dichlorohexane: decyl alcohol = 30: 1). 20/1) mixture, the solid was filtered, crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 3·98 (3H, s), 8·28 (1H, d, J = 1.7 Hz), 8.36 (1H, d, J = 1.7 Hz) MS (ESI) m/z: 310 (M+Na)+ 〇 [Reference Example 97] 3-Gas-4-{2-[(4-Phenylphenyl)amine-carbamoyl]ethyl b 5-nitrobenzoic acid formazan 129677.doc -99- 200840568 The title compound was obtained by condensing the compound of Reference Example 96 with 4- aniline. 'H^NMR (CDCls) δ : 2.77 (oxr ·&quot; (2H,t,J=8.1 Ηζ),3·33 (2H,t, J = 8.1 Hz),3·97 (3H,s) 7 9ς , οττ /.25 (2H5 d, J=8.8 Hz), 7.46 (2H, d, J=8·8 Hz), 7·56 (1Η 〇〇c J , , s), 8·25 (1H,d , J=1.5 Hz), 8.34 (1H, d5 J=1.5 Hz) 〇MS (ESI) m/z: 397 (M+H)+ [ [Test Example 98] 3-Amino-5-chloro·4_ {2-[(4-chlorophenyl)aminemethanyl]ethyl}benzene

曱酸甲酯 以與參考例13相同的方法，由參考例97之化合物獲得標 題化合物。 ^-NMR (CDCI3) δ : 2.77 (2H? t, J=6.6 Hz)? 3.13 (2H? t9 J=6.6 Hz)，3·87 (3H, s)，4·52 (2H，br s)，7.19 (1H，br s)， 7.21 (1H, d，J=1.7 Hz)，7·27 (2H，d，J=8.8 Hz)，7·39 (2H，d， J = 8.8 Hz)，7.43 (1H，d，J=1.7 Hz) 〇 MS (ESI) m/z: 367 (M+H)+。 [參考例99] 3 -氣-4-{2-[(4 -氟苯基）胺甲醢基]乙基卜5_石肖基 苯甲酸甲酯 以與參考例81相同的方法，將參考例96之化合物與4-氟 苯胺縮合而獲得標題化合物。 &quot;H-NMR (CDCI3) δ : 2.78 (2H? t? J-g.2 Hz), 3.36 (2H5 t, J = 8.2 Hz)，3·98 (3H，s)，6.99-7.06 (2H，m)，7·23 (1H，br s)， 7·48 (2H，dd，J=8.9, 4.8 Hz)，8·28 (1H，d，J=1.5 Hz)，8.37 (1H，d，J=1.5 Hz)。 129677.doc -100- 200840568 MS (ESI) m/z: 381 (M+H)+ 〇 [參，考例100] 3_胺基-5-氯-4_(2 rr/1〆 KM，泼苯基）胺甲醯基]乙基 本甲酸甲S旨 i 以與參考例13相同的方法 ά 由參考例99之化合物獲得 題化合物。 行私 !H-NMR (CDC13) δ ： 2.76 (2Η t 1 ，％ J=6·6 Ηζ)，3.14 (2Η t J = 6.6 Ηζ)，3·87 (3Η，s)，4·53 (2Η κ 、 ，， (2Η，br s)，6.96-7.04 (2Η， 7·20 (1H，br s)，7·21 (1H，d，J…H Λ ”Methyl decanoate The title compound was obtained from the compound of Reference Example 97 in the same manner as in Reference Example 13. ^-NMR (CDCI3) δ : 2.77 (2H? t, J=6.6 Hz)? 3.13 (2H? t9 J=6.6 Hz), 3·87 (3H, s), 4·52 (2H, br s), 7.19 (1H, br s), 7.21 (1H, d, J = 1.7 Hz), 7·27 (2H, d, J = 8.8 Hz), 7·39 (2H, d, J = 8.8 Hz), 7.43 ( 1H,d,J=1.7 Hz) 〇MS (ESI) m/z: 367 (M+H)+. [Reference Example 99] 3-Hydroxy-4-{2-[(4-fluorophenyl)amine-carbamoyl]ethyl bromide 5-methylsuccinylbenzoic acid methyl ester In the same manner as in Reference Example 81, Reference Example 96 The compound was condensed with 4-fluoroaniline to give the title compound. &quot;H-NMR (CDCI3) δ : 2.78 (2H? t? Jg.2 Hz), 3.36 (2H5 t, J = 8.2 Hz), 3·98 (3H, s), 6.99-7.06 (2H, m) ,7·23 (1H,br s), 7·48 (2H,dd,J=8.9, 4.8 Hz),8·28 (1H,d,J=1.5 Hz), 8.37 (1H,d,J=1.5 Hz). 129677.doc -100- 200840568 MS (ESI) m/z: 381 (M+H)+ 〇 [Ref., Test 100] 3_Amino-5-chloro-4_(2 rr/1〆KM, phenylene The title compound was obtained from the compound of Reference Example 99. Private! H-NMR (CDC13) δ : 2.76 (2Η t 1 ,% J=6·6 Ηζ), 3.14 (2Η t J = 6.6 Ηζ), 3·87 (3Η, s), 4·53 (2Η κ , ,, (2Η,br s),6.96-7.04 (2Η, 7·20 (1H,br s),7·21 (1H,d,J...H Λ ”

，J l·5 Hz)，7·35_7·42 (2H 7·42 (1H，d，J=1.5 Hz)。 ni)， MS (ESI) m/z: 351 (M+H)+ 〇 [參考例101] 4-[2-(4-氯苯基胺甲醯基）乙基]_2_ 第三丁酯 &amp; 以與參考例8 1相同的方法，將 胂參考例69之化合物與4_氣 苯胺縮合而獲得標題化合物。 ' W-NMR (CDC13) δ : 1·60 (9H，s) V ，J，厶76 (2H，t，J=7.5 Hz)， 3·34 (2H，t，J=7.5 Hz)，7.14 (1H，s) 7 28 H T n ， Λ /·28 (2H，d，J=9.1 Hz)， 7.44 (2H，d，J=8.6 Hz)，7·54 (1H d T—r 1 u、 ， V ，d，J —8.1 Hz)，8·12 (1H， dd，J = 8.0，1·6 Hz)，8·51 (1H，s)。 ’ MS (ESI) m/z: 405 (M+H)、 [參考例102] 3-胺基-4-[2-(4-氯苯基胺甲醯基）乙基]苯甲酸 第三丁酯 以與參考例丨3相同的方法，由參考例ι〇ι之化合物獲得 標題化合物。 ^H-NMR (CDC13) δ : 1.57 (9Η, s), 2.69 (2H) t) J=71Hz)} 129677.doc -101 - 200840568 2·97 (2H，t，J二7·4 Ηζ)，4·02 (2H，s)，7.08 (1H，d，j=7.8 Hz)， 7·14 (1H，br s)，7·26 (2H，d，P8.8 HZ)，7 29 (1H，d，J==1 5, J l·5 Hz), 7·35_7·42 (2H 7·42 (1H, d, J=1.5 Hz). ni), MS (ESI) m/z: 351 (M+H)+ 〇 [Reference Example 101] 4-[2-(4-Chlorophenylaminocarbamimidyl)ethyl]_2_ tert-butyl ester &amp; In the same manner as in Reference Example 81, the compound of Example 69 was reacted with 4_gas. The aniline was condensed to give the title compound. ' W-NMR (CDC13) δ : 1·60 (9H, s) V , J, 厶 76 (2H, t, J = 7.5 Hz), 3·34 (2H, t, J = 7.5 Hz), 7.14 ( 1H,s) 7 28 HT n , Λ /·28 (2H,d,J=9.1 Hz), 7.44 (2H,d,J=8.6 Hz),7·54 (1H d T—r 1 u, , V , d, J — 8.1 Hz), 8·12 (1H, dd, J = 8.0, 1·6 Hz), 8·51 (1H, s). ' MS (ESI) m/z: 405 (M+H), [Ref. 102] 3-amino-4-[2-(4-chlorophenylamine-carbamoyl)ethyl]benzoic acid tributyl The title compound was obtained from the title compound of the title compound. ^H-NMR (CDC13) δ : 1.57 (9Η, s), 2.69 (2H) t) J=71Hz)} 129677.doc -101 - 200840568 2·97 (2H,t,J 2:7 Ηζ), 4·02 (2H, s), 7.08 (1H, d, j = 7.8 Hz), 7·14 (1H, br s), 7·26 (2H, d, P8.8 HZ), 7 29 (1H, d, J==1 5

Hz)，7·34 (1H，dd，J=7.8, 1.5 Hz), 7·39 (2H，d，J=8.8 Hz)。 MS (ESI) m/z: 375 (M+H)+。 [參考例102a] 2-氟-4-曱基-5-硝基苯甲酸 以冰-食鹽將2-氟-4-曱基苯曱酸（5 ·2〇 g)冷卻後，添加濃 硫酸（90 ml)及發煙硝酸（2.24 ml)，攪拌3小時。將反應液 注入冰浴冷卻水（500 ml)中，濾取所析出之固體。將所獲 得之固體水洗後，於減壓下乾燥，獲得標題化合物（5.73 g)。 】H-NMR (CDC13) δ : 2·71 (3H，s)，7.19 (iH，d，J=10.7 Hz)， 8.74 (1H，d，J=6.6 Hz) o MS (ESI) m/z: 200 (M+H)+。 [參考例102b] 2-氟-4-甲基-5-硝基苯甲酸甲酯 將參考例l〇2a之化合物（5·98 g)溶解於甲醇（5〇 ml)中， 添加亞硫醯氯（1 ml)，加熱回流3小時。於減壓下顧去溶 劑’向所獲得之殘渣中添加水，濾取所析出之固體，獲得 標題化合物（6,3 1 g)。 】H-NMR (CDC13) δ : 2.68 (3H，s)，3·97 (3H，S)，7.14 (1H，d， J=10.5 Ηζ)，8·66 (1H，d，J=6.8 Hz)。 MS (ESI) m/z: 214 (M+H)+ 〇 [參考例102c] 2-甲氧基-4-甲基苯甲酸甲酯 向55%氫化鈉（1.83 g)之DMF(50 ml)懸浮液中添加2·羥 基-4-甲基苯曱酸（3.〇4 g)及碘甲烷（2 61如），於室溫下授 129677.doc -102- 200840568 拌4小時。向反應液中添加IPE及水，進行分液後，以飽和 食鹽水清洗有機層。以無水MgS〇4乾燥後，於減壓下餾去 溶劑，獲得標題化合物（3.23 g)。 】H-NMR (CDC13) δ : 2·38 (3H，s)，3.87 (3H，s)，3.89 (3H， s)，6·76-6·81 (2Η，m)，7·72 (1Η，d，J=8.3 Hz)。 MS (ESI) m/z: 181 (M+H)+。 [參考例102d] 2-曱氧基-4-曱基-5-硝基苯甲酸曱酯 以冰-食鹽冷卻下，向參考例102c之化合物（3.23 g)中添 加濃硫酸（19· 1 ml)及發煙硝酸（0.67 ml)，擾拌2小時。將 反應液注入冰水中，添加乙酸乙酯進行分液。以飽和食鹽 水及飽和NaHC03水溶液清洗有機層。以無水MgS04乾燥 後，於減壓下餾去溶劑。向殘渣中添加IPE，濾取所析出 之固體，獲得標題化合物（1.86 g)。 ^-NMR (CDC13) δ : 2.71 (3Η, s)? 3.91 (3H, s), 4.00 (3H? s)，6·86 (1H，s)，8.63 (1H，s)。 MS (ESI) m/z: 226 (M+H)+。 [參考例102e] 4-溴曱基-2-曱氧基-5-硝基苯甲酸甲酯 將參考例102d之化合物（1,86 g)及NBS(1.76 g)懸浮於四 氯化碳（50 ml)中。向該懸浮液中添加過氧化苯曱醯（含水 25%，〇· 13 g)，加熱回流一整夜。過濾去除不溶物後，將 濾、液濃縮。將殘渣以；ς夕膠層析法（己貌··乙酸乙酯=9 : 1) 進行精製，獲得標題化合物（174 g)。 H-NMR (CDC13) δ: 3·93 (3H，s)，4.04 (3H，s)，4·90 (2H，s)， 7·13 (1Η，s)，8·65 (1Η，s) 〇 129677.doc -103- 200840568 [參考例102ee] 4-胺基曱基-2-甲氧基_5-硝基苯甲酸甲酯 於室溫下，以10分鐘向7當量氨-曱醇溶液（16.4 ml)中滴 下參考例102e之化合物（1.74 g)的二氯曱烷（50 ml)溶液。 攪拌4小時後，於減壓下餾去溶劑，向殘渣中添加二氣甲 烷、1當量鹽酸（20 ml)及水，進行分液。向所獲得之水層 中添加飽和NaHCCb水溶液，以二氯曱烷萃取。將萃取液 以無水Na2S04乾燥後，於減壓下餾去溶劑，獲得標題化合 物（663 mg) 〇 'H-NMR (CDC13) δ : 1.61 (2H9 br s)5 3.92 (3H? s)? 4.05 (3H, s)，4·25 (2H，s)，7·35 (1H，s)，8·65 (1H，s)。 MS (ESI) m/z: 241 (M+H)、 [參考例102f] 4-甲基-3,5-二硝基苯甲酸曱酯 以與參考例102b相同的方法，由4-甲基-3，5-二硝基苯甲 酸獲得標題化合物。 W-NMR (CDC13) δ : 2·64 (3H，s)，4.01 (3H，s)，8·60 (2H， s) 〇 MS (ESI) m/z: 239 (M-H)、 [參考例102g] 3-胺基-4-曱基-5-硝基苯甲酸曱酯 將參考例102f之化合物（16.0 g)溶解於曱醇（200 ml)及二 口号烷（100 ml)中。向該溶液中添加濃鹽酸（40 ml)及鐵粉 (11.9 g)，加熱回流一整夜。放置至室溫後，向反應液中 添加飽和NaHC03水溶液及乙酸乙酯。將不溶物通過氟鎂 石而過濾去除，對濾液進行分液。以無水MgSCU乾燥有機 層，於減壓下餾去溶劑。向殘渣中添加甲醇，濾取固體， 129677.doc -104- 200840568 獲得標題化合物（7.07 g&gt;。 •H-NMRCCDCI^^.^ph, s),3.92 (3H, s)&gt; 4.03 (2H, br s), 7.52 (1H, d, J=1.5 Hz), 7.81 (1H, d, J=1.5 Hz) 〇 MS (ESI) m/z: 211 (M+H)+。 [參考例102h] 3-氟-4-甲基-5-硝基笨甲酸甲酯 將參考例H)2g之化合物（6.00 §)、水（2〇 _及濃鹽酸⑽ ml)的混合物冷卻至内溫代。以約1〇分鐘向該混合液中予 加包含亞硝酸納（2.07 g)的水溶液（2㈣後，於内溫〇〜； 下攪拌30分鐘。添加48%四氟硼酸水溶液（3 73，攪拌工 小時後，慮取所析出之固體，以乙酸乙g旨清洗。將所獲得 之固體加熱至15〇。(：後，放置至室溫。添加乙酸乙酯及飽 和NaHC〇3水溶液’進行分液後，以無水乾燥有機 .層。於減壓下餾去溶劑後，將殘渣以矽膠層析法（己烷： 乙酸乙酯=9: 1)進行精製，獲得標題化合物（1 54g)。 ^-NMR (CDC13) δ : 2.53 (3Η, d, J=2.2 Hz), 3.97 (3H, s), 7.94 (1H，dd，J=9.2, 1.6 Hz)，8·38 (1H，br s)。 [參考例102i] 4-&gt;臭甲基-3-氟-5-硝基笨甲酸甲酯 以與參考例102e相同的方法，由參考例1〇2h之化合物獲 得標題化合物。 ^-NMR (CDCI3) δ : 3.99 (3Η, s), 4.83 (2H, d, J=2.〇 Hz), 8.03 (1H, dd, J=9.3, 1.7 Hz), 8.49 (1H, t, J=1.7 Hz) 〇 [參考例102j] 4-胺基甲基-3-氟-5-硝基笨曱酸甲酯 以與參考例102e相同的方法，由參考例1〇2i的化合物獲 得標題化合物。 129677.doc -105 - 200840568 H-NMR (CDC13) δ : ι·68 (2H, s)，3 98 (3H，s)，4 〇8 (2H，d， J-1.7 Hz)，7·99 (1H，dd，㈣.3, 1.6 Hz)，8·38 (1H，t，J=1.6Hz), 7·34 (1H, dd, J=7.8, 1.5 Hz), 7·39 (2H, d, J=8.8 Hz). MS (ESI) m/z: 375 (M+H)+. [Reference Example 102a] 2-Fluoro-4-indolyl-5-nitrobenzoic acid was cooled with 2-fluoro-4-mercaptobenzoic acid (5·2 〇g) in ice-salt, and then concentrated sulfuric acid was added ( 90 ml) and fuming nitric acid (2.24 ml), stirred for 3 hours. The reaction solution was poured into ice-cold cooling water (500 ml), and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried under reduced pressure to yield the title compound (5.73 g). H-NMR (CDC13) δ : 2·71 (3H, s), 7.19 (iH, d, J = 10.7 Hz), 8.74 (1H, d, J = 6.6 Hz) o MS (ESI) m/z: 200 (M+H)+. [Reference Example 102b] Methyl 2-fluoro-4-methyl-5-nitrobenzoate The compound of Reference Example 1 2a (5·98 g) was dissolved in methanol (5 〇ml), and sulfinium was added. Chlorine (1 ml) was heated to reflux for 3 hours. The solvent was added under reduced pressure. Water was added to the residue obtained, and the precipitated solid was filtered to give the title compound (6, 3 1 g). H-NMR (CDC13) δ : 2.68 (3H, s), 3.97 (3H, S), 7.14 (1H, d, J = 10.5 Ηζ), 8.66 (1H, d, J = 6.8 Hz) . MS (ESI) m/z: </RTI> </RTI> </RTI> </RTI> </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> 2·Hydroxy-4-methylbenzoic acid (3.〇4 g) and methyl iodide (2 61) were added to the suspension, and 129677.doc -102-200840568 was mixed at room temperature for 4 hours. IPE and water were added to the reaction mixture, and the mixture was separated, and the organic layer was washed with saturated brine. After drying over anhydrous MgSO.sub.4, the solvent was evaporated. H-NMR (CDC13) δ : 2·38 (3H, s), 3.87 (3H, s), 3.89 (3H, s), 6·76-6·81 (2Η, m), 7·72 (1Η) , d, J = 8.3 Hz). MS (ESI) m/z: 181 (M+H)+. [Reference Example 102d] 2-decyloxy-4-mercapto-5-nitrobenzoic acid decyl ester was added to a compound of Reference Example 102c (3.23 g) under concentrated ice-salt (19·1 ml). ) and fuming nitric acid (0.67 ml), disturbed for 2 hours. The reaction solution was poured into ice water, and ethyl acetate was added thereto to carry out liquid separation. The organic layer was washed with saturated brine and a saturated aqueous solution of NaHCO. After drying over anhydrous MgS04, the solvent was evaporated under reduced pressure. IPE was added to the residue, and the precipitated solid was filtered to give the title compound (1.86 g). ^-NMR (CDC13) δ : 2.71 (3Η, s)? 3.91 (3H, s), 4.00 (3H? s), 6·86 (1H, s), 8.63 (1H, s). MS (ESI) m/z: 226 (M+H)+. [Reference Example 102e] 4-bromodecyl-2-decyloxy-5-nitrobenzoic acid methyl ester The compound of Reference Example 102d (1, 86 g) and NBS (1.76 g) were suspended in carbon tetrachloride ( 50 ml). To the suspension was added benzoquinone (25% aqueous solution, 13 g), and the mixture was heated under reflux overnight. After insoluble matter was removed by filtration, the filtrate and liquid were concentrated. The residue was purified by chromatography (yield: ethyl acetate = 9:1) to afford the title compound (174 g). H-NMR (CDC13) δ: 3·93 (3H, s), 4.04 (3H, s), 4·90 (2H, s), 7·13 (1Η, s), 8·65 (1Η, s) 〇129677.doc -103- 200840568 [Reference Example 102ee] Methyl 4-aminomercapto-2-methoxy-5-nitrobenzoate to 7 equivalents of ammonia-nonanol solution at room temperature for 10 minutes A solution of the compound of Reference Example 102e (1.74 g) in dichloromethane (50 ml). After stirring for 4 hours, the solvent was evaporated under reduced pressure, and dichloromethane (1 ml) and water (1 ml) and water were added to the residue to carry out liquid separation. A saturated aqueous solution of NaHCCb was added to the obtained aqueous layer, and extracted with dichloromethane. The extract was dried over anhydrous Na.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.ssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss 3H, s), 4·25 (2H, s), 7·35 (1H, s), 8.65 (1H, s). MS (ESI) m/z: 241 (M+H), [Nv. </ RTI> </ RTI> </ RTI> 4-methyl-3,5-dinitrobenzoic acid decyl ester in the same manner as in Reference Example 102b, from 4-methyl The title compound was obtained from -3,5-dinitrobenzoic acid. NMR (ESI) m/z: ] 3-Amino-4-mercapto-5-nitrobenzoic acid oxime ester The compound of Reference Example 102f (16.0 g) was dissolved in decyl alcohol (200 ml) and di- hexane (100 ml). Concentrated hydrochloric acid (40 ml) and iron powder (11.9 g) were added to the solution, and the mixture was heated to reflux overnight. After standing at room temperature, a saturated aqueous solution of NaHCO 3 and ethyl acetate were added to the mixture. The insoluble matter was filtered off through the fluorite, and the filtrate was subjected to liquid separation. The organic layer was dried over anhydrous MgSO.sub. Methanol was added to the residue, and the solid was filtered. 129 677. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Br s), 7.52 (1H, d, J=1.5 Hz), 7.81 (1H, d, J=1.5 Hz) 〇MS (ESI) m/z: 211 (M+H)+. [Reference Example 102h] 3-Fluoro-4-methyl-5-nitrobenzoic acid methyl ester The mixture of the compound of Example H) 2g (6.00 §), water (2 〇 _ and concentrated hydrochloric acid (10) ml) was cooled to Internal temperature generation. An aqueous solution containing sodium nitrite (2.07 g) (2 (4)) was added to the mixture for about 1 minute, and then stirred at an internal temperature for 30 minutes. A 48% aqueous solution of tetrafluoroboric acid (3 73, a blender was added. After an hour, the precipitated solid was taken into consideration and washed with acetic acid. The obtained solid was heated to 15 Torr. (:, then allowed to stand at room temperature. Ethyl acetate and saturated NaHC〇3 aqueous solution were added to carry out liquid separation. After that, the organic layer was dried (mjjjjjjjjjjjjjjjjjj NMR (CDC13) δ : 2.53 (3Η, d, J = 2.2 Hz), 3.97 (3H, s), 7.94 (1H, dd, J=9.2, 1.6 Hz), 8.38 (1H, br s). Reference Example 102i] 4-&gt;Smelly Methyl-3-fluoro-5-nitrobenzoic acid methyl ester The title compound was obtained from the compound of Reference Example 1 2h in the same manner as in the the the the ) δ : 3.99 (3Η, s), 4.83 (2H, d, J=2.〇Hz), 8.03 (1H, dd, J=9.3, 1.7 Hz), 8.49 (1H, t, J=1.7 Hz) 〇 [Reference Example 102j] 4-Aminomethyl-3-fluoro-5-nitroindoleic acid methyl ester In the same manner as in Test Example 102e, the title compound was obtained from the compound of Reference Example 1 〇 2i. 129677.doc -105 - 200840568 H-NMR (CDC13) δ : ι·68 (2H, s), 3 98 (3H, s) , 4 〇 8 (2H, d, J-1.7 Hz), 7·99 (1H, dd, (4).3, 1.6 Hz), 8.38 (1H, t, J=1.6

Hz) 〇 MS (ESI) m/z: 229 (Μ+Η)+。 [參考例1〇2k] 4_{[(5_氯噻吩-2-羰基）胺基]甲基卜3-氟_5-硝 基苯甲酸曱酯 以與參考例11相同的方法，將參考例丨〇幻之化合物與5_ 氯噻吩-2-甲酸縮合而獲得標題化合物。 # ，H-NMR ^CDC1^ δ : 3.98 (3Η, s), 4.92 (2H, dd, J=6.3, l.〇 Hz)? 6.64 (1H? t9 J-6.3 Hz), 6.88 (1H, d, J=4.0 Hz), 7.23 (1H，d，J=4.0 Hz)，8.04 (1H，dd，J=9.0，1.5 Hz)，8.46-8.48 (1H，m) 〇 MS (ESI) m/z: 373 (M+H)+ 〇 [麥考例l〇2l] 3·胺基_4_{[(5_氯噻吩_2_羰基）胺基]甲基 氟苯曱酸甲酯 以與參考例13相同的方法，由參考例l〇2k之化合物獲得 標題化合物。 ^-NMR (CDC13) δ : 3.88 (3H? s), 4.58 (2H, dd? J=6.65 2.〇Hz) 〇 MS (ESI) m/z: 229 (Μ+Η)+. [Reference Example 1〇2k] 4_{[(5-chlorothiophene-2-carbonyl)amino]methyl-3-fluoro-5-nitrobenzoic acid decyl ester In the same manner as in Reference Example 11, reference examples were given. The title compound was obtained by condensation of the phantom compound with 5-chlorothiophene-2-carboxylic acid. # ,H-NMR ^CDC1^ δ : 3.98 (3Η, s), 4.92 (2H, dd, J=6.3, l.〇Hz)? 6.64 (1H? t9 J-6.3 Hz), 6.88 (1H, d, J=4.0 Hz), 7.23 (1H, d, J=4.0 Hz), 8.04 (1H, dd, J=9.0, 1.5 Hz), 8.46-8.48 (1H, m) 〇MS (ESI) m/z: 373 (M+H)+ 〇[麦考例1〇2l] 3·Amino_4_{[(5-chlorothiophene-2-carbonyl)amino]methylfluorobenzoic acid methyl ester is the same as Reference Example 13 The title compound was obtained from the compound of Reference Example 1 2k. ^-NMR (CDC13) δ : 3.88 (3H? s), 4.58 (2H, dd? J=6.65 2.〇

Hz)，4·94 (2H，br s)，6·38 (1H，t，&gt;6·6 Hz)，6·90 (1H，d， J=4.0 Hz)，7·05 (1H，dd，J=i〇,〇，！ 5 HZ)，7.13 (1H，br 7.26 (1H，d，J=4.0 Hz)。 ’ MS (ESI) m/z: 343 (M+H)+。 [參考例102m] 3_經基甲基_5_硝基苯甲酸 將參考例l〇2g之化合物（3·〇〇 g)、水（1〇 ml)及濃硫峻 129677.doc -106- 200840568 (3 0.4 ml)的混合物冷卻至内溫〇 C。以約i 〇分鐘向該反應 液中添加包含亞硝酸鈉（1·97 g)的水溶液（10 ml)。於内溫 〇〜5°C下將所獲得之混合物攪拌40分鐘後，加熱回流3小 時。放置至室溫後，將水添加至反應液中，濾取所析出之 固體，獲得標題化合物（1.78 g)。 !H-NMR (DMSO-d6) δ : 2·28 (3H，S)，7·65 (1H，d，J=1 6 Hz)，7.79 (1H，d，J=1.6 Hz)，10,76 (1H，s)。 [參考例1 02n] 3 -甲氧基-4-曱基-5-硝基苯曱酸甲酉旨 ⑩ 於0°C下，向參考例l〇2m之化合物（1·93 g)的THF(5〇㈣ 溶液中添加55%氫化鈉（858 mg)、碘甲烷（1·5〇 m〇，於室 溫下攪拌1小時。向反應液中添加DMFO0 ml)，於室溫下 攪拌17小時。於減壓下餾去溶劑後，向殘渣中添加乙酸乙 酯、水。以乙酸乙酯萃取後，以飽*NaC1水溶液、水清洗 所合併之有機層。以無ANhSO4乾燥後，於減壓下餾去溶 劑。將殘渣以矽膠管柱層析法（己烷：乙酸乙酯=8 : i — φ 4 : 1_&gt;3 ··丨）進行精製，獲得標題化合物（I.82 g)。 ^H.NMR (CDCI3) δ ： 2.41 (3Η, s)? 3.95 (3H, s)? 3.96 (3H, s)，7.69 (1H，br s)，8.07 (1H，d，J=1.2 Hz)。 [參考例102o] 4-溴甲基_3_甲氧基_5_硝基笨甲酸曱酯 以與參考例102e相同的方法，由參考例1〇2n之化合物獲 得標題化合物。 Ή-NMR (CDCl3)5:3.98(3H, s), 4.05 (3H, s), 4.82 (2H, s): 7.80 (1H, d, 1=1.2 Hz), 8.19 (1H, d, J = 1.5 Hz) 〇 [參考例甲氧基叛基）_6_硝基节基]丙二酸二 129677.doc 200840568 第三丁酯 以與參考例68相同的方法，由丙二酸二第三丁酯與參考 例102i的化合物獲得標題化合物。 】H-NMR (CDC13) δ ·· 1.42 (18H，s)，3·49-3·59 (3H，m)，3·97 (3H，s)，7·95 (1H，dd，J=9.5, 1·7 Hz)，8·40-8·42 (1H，m)。 MS (ESI) m/z: 450 (M+Na)+。 [參考例104] 4-(2-羧基乙基）-3 _氟巧_硝基苯甲酸甲酯 向參考例103之化合物（738 mg)的二氯甲烷（5 mi)溶液中 添加TFA(5.0 ml)，於室溫下攪拌6小時。將反應液於減壓 下》辰縮後，以二氯甲院於減壓下共沸3次。向殘渣之乙腈 (15 ml)溶液中添加氧化銅（i)(85 mg)，加熱回流ι5小時。 冷卻後將不溶物過濾分離，將濾液於減壓下濃縮。將殘渣 以使用矽膠之2次快速層析法（二氣甲烧：甲醇=i 〇〇 :丨)進 行精製。於室溫下以真空泵乾燥4小時，獲得標題化合物 (335 mg) 〇 'H-NMR (CDC13) δ : 2.78 (2Η, t5 J = 7.1 Hz)? 3.26 (2H? t, J = 7.1 Hz)，3·98 (3H，s)，7·97 (1H，dd，J = 9.3, 1·5 HZ)，8.37 (1H，br s)。 MS (ESI) m/z: 272 (M+H)、 [參考例105] 4-{2-[(4-氯苯基）胺曱醯基]乙基卜3-氟-5-硝基 苯甲酸甲酯 以與參考例81相同的方法，將參考例1〇4之化合物與4-氯苯胺縮合而獲得標題化合物。 !H-NMR (CDC13) δ : 2·75 (2H，t，J二8·0 Hz)，3、33 (2H，t， 129677.doc -108- 200840568 J=7.2 Ηζ)，3·97 (3H，d，J=7.4 Ηζ)，7·20-7·33 (3H，m)，7·46 (2H，d，J=8.6 Hz)，7·97 (1H，d，J=9.3 Hz)，8·39 (1H，s)。 MS (ESI) m/z·· 381 (M+H).。 [參考例106] 3-胺基-4-{2-[(4·氣苯基）胺甲醯基]乙基卜5_氟 苯甲酸甲酯 以與參考例13相同的方法，由參考例丨〇5之化合物獲得 標題化合物。 ^-NMR (CDC13) δ : 2.72 (2Η, t, J=6.5 Hz), 3.01 (2H, t5 J=6.5 Hz), 3.87 (3H, s), 4.46 (2H, br s), 7.08 (1H, dd, J=10.1, 1.3 Hz), 7.12 (1H, br s), 7.13-7.19 (1H, br), 7.26 (2H，d，J=8.8 Hz)，7.39 (2H，d，J=8.8 Hz)。 MS (ESI) m/z: 351 (M+H)+。 [參考例1〇7]2-[2-甲氧基-4_(甲氧基幾基）_6_硝基节基]丙二 酸二第三丁酯Hz), 4·94 (2H, br s), 6.38 (1H, t, &gt; 6·6 Hz), 6.90 (1H, d, J = 4.0 Hz), 7·05 (1H, dd , J=i〇, 〇,! 5 HZ), 7.13 (1H, br 7.26 (1H, d, J=4.0 Hz). ' MS (ESI) m/z: 343 (M+H)+. [Reference example 102m] 3_transmethylmethyl_5-nitrobenzoic acid Reference compound 1〇2g of compound (3·〇〇g), water (1〇ml) and concentrated sulfur 129677.doc -106- 200840568 (3 0.4 ml) of the mixture was cooled to an internal temperature 〇 C. An aqueous solution (10 ml) containing sodium nitrite (1.97 g) was added to the reaction solution over about 1 〇 minutes, at an internal temperature of ～5 ° C. After the mixture was stirred for 40 minutes, it was heated to reflux for 3 hours. After standing to room temperature, water was added to the reaction mixture, and the precipitated solid was filtered to give the title compound (1.78 g). D6) δ : 2·28 (3H, S), 7·65 (1H, d, J = 16 Hz), 7.79 (1H, d, J = 1.6 Hz), 10, 76 (1H, s). Reference Example 1 02n] 3 -Methoxy-4-indolyl-5-nitrobenzoic acid formazan 10 To a reference compound (1·93 g) of THF at 0 ° C ( 5〇(4) Add 55% sodium hydride (858 mg) and methyl iodide to the solution ( After stirring for 1 hour at room temperature, DMFO (0 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 17 hours. After the solvent was evaporated under reduced pressure, ethyl acetate and water were added to the residue. After extracting with ethyl acetate, the combined organic layers were washed with aq. NaH.sub.1 and water. After drying over anhydrous NahSO4, solvent was evaporated under reduced pressure. The residue was purified by column chromatography (hexane: acetic acid Ethyl ester = 8 : i - φ 4 : 1_&gt; 3 ··丨) Purified to give the title compound (I.82 g). ^H.NMR (CDCI3) δ : 2.41 (3Η, s)? 3.95 (3H, s)? 3.96 (3H, s), 7.69 (1H, br s), 8.07 (1H, d, J = 1.2 Hz) [Reference Example 102o] 4-Bromomethyl_3_methoxy_5_Nitrate The title compound was obtained from the compound of Reference Example 1 2 2n. 2H, s): 7.80 (1H, d, 1 = 1.2 Hz), 8.19 (1H, d, J = 1.5 Hz) 〇 [Reference example methoxy thiol) _6_nitro] glutamic acid II 129677 .doc 200840568 Tert-butyl ester in the same manner as Reference Example 68, from dibutyl succinate and reference Compound 102i to obtain the title compound. H-NMR (CDC13) δ ·· 1.42 (18H,s),3·49-3·59 (3H,m),3·97 (3H,s),7·95 (1H,dd,J=9.5 , 1·7 Hz), 8·40-8·42 (1H, m). MS (ESI) m/z: 450 (M+Na)+. [Reference Example 104] 4-(2-Carboxyethyl)-3-fluoro fluoro-nitrobenzoic acid methyl ester To a solution of the compound of Example 103 (738 mg) in dichloromethane (5 mi) Ml), stirred at room temperature for 6 hours. The reaction solution was condensed under reduced pressure, and then azeotroped three times under reduced pressure in a dichlorocarbyl plant. Copper oxide (i) (85 mg) was added to a solution of the residue in acetonitrile (15 ml) and heated to reflux for 5 hours. After cooling, the insoluble material was separated by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by two-time flash chromatography (two gas compression: methanol = i 〇〇 : 丨) using silica gel. Drying at room temperature for 4 hours with a vacuum pump gave the title compound (335 mg) 〇'H-NMR (CDC13) δ: 2.78 (2 Η, t5 J = 7.1 Hz)? 3.26 (2H? t, J = 7.1 Hz), 3·98 (3H, s), 7.97 (1H, dd, J = 9.3, 1·5 HZ), 8.37 (1H, br s). MS (ESI) m/z: 272 (M+H), [Ref. 105] 4-{2-[(4-chlorophenyl)amine fluorenyl]ethyl-ethyl 3-fluoro-5-nitrobenzene Methyl formate The title compound was obtained by condensing the compound of Reference Example 1-4 with 4-chloroaniline in the same manner as in the title compound. !H-NMR (CDC13) δ : 2·75 (2H, t, J 2 8.0 Hz), 3, 33 (2H, t, 129677.doc -108- 200840568 J=7.2 Ηζ), 3.97 ( 3H,d,J=7.4 Ηζ),7·20-7·33 (3H,m),7·46 (2H,d,J=8.6 Hz),7·97 (1H,d,J=9.3 Hz) , 8.39 (1H, s). MS (ESI) m/z·· 381 (M+H). [Reference Example 106] 3-Amino-4-{2-[(4.sup.phenyl)aminocarbazyl]ethyl bromide-5-fluorobenzoic acid methyl ester in the same manner as in Reference Example 13, from Reference Example The title compound was obtained as a compound of 丨〇5. ^-NMR (CDC13) δ : 2.72 (2Η, t, J=6.5 Hz), 3.01 (2H, t5 J=6.5 Hz), 3.87 (3H, s), 4.46 (2H, br s), 7.08 (1H, Dd, J = 10.1, 1.3 Hz), 7.12 (1H, br s), 7.13-7.19 (1H, br), 7.26 (2H, d, J = 8.8 Hz), 7.39 (2H, d, J = 8.8 Hz) . MS (ESI) m/z: 351 (M+H)+. [Reference Example 1〇7] 2-[2-Methoxy-4-((methoxymethyl)-6-nitro]pyranyldipropionate

以與參考例68相同的方法，由丙二酸二第三丁 _與參考 例102〇的化合物獲得標題化合物。 ]H.NMR (CDCI3) δ : 1.395 (9Η ^ 1 PH，s)，1·398 (9H，s)，3·47 (2H， d，J=8.l Ηζ)，3·61 (ΙΗ，t，㈣ I Μ、。 ’ ，6·1 Ηζ)，3·96 (6Η，s)，7.71 (1Η， br s)，8·07 (1Η，s) 〇 ’ MS (ESI) m/z: 462 (M+Na)+ 〇 [參考例108] 4_(2-羧基乙基）_弘曱 以與參考例104相同的方法 標題化合物。 氧基-5-硝基苯甲酸甲酯 由參考例107之化合物獲得 'H-NMR (CDCI3) δ : 2.74 (2Η5 ^ J^7.9 Hz)? 3·14 (2H，t， 129677.doc •109· 200840568 J=7.9 Hz), 3.96 (3H, s), 3.97 (3H, s), 7.73 (1H, d, J=i.5 Hz)，8.07 (1H，d，J=1.5 Hz)。 MS (ESI) m/z: 284 (M+H)+。 [參考例109] 4-{2-[(4-氯苯基）胺甲醯基]乙基}·3_曱氧基巧_ 硝基苯甲酸曱酯 以與參考例81相同的方法，將參考例1 〇8之化合物與‘ 氯苯胺縮合而獲得標題化合物。 !H.NMR (CDCls) δ : 2.70 (2Η, t, J-8.1 Hz)? 3.21 (2H, t _ 1 = 8.1 Hz), 3.95 (3H? s)5 3.96 (3H? s), 7.27 (2H, d9 J=8.8In the same manner as in Reference Example 68, the title compound was obtained from m. H.NMR (CDCI3) δ : 1.395 (9Η ^ 1 PH, s), 1·398 (9H, s), 3·47 (2H, d, J=8.l Ηζ), 3.61 (ΙΗ, t, (4) I Μ, . ' , 6·1 Ηζ), 3·96 (6Η, s), 7.71 (1Η, br s), 8·07 (1Η, s) 〇' MS (ESI) m/z: 462 (M+Na) + 〇 [Reference Example 108] 4-(2-carboxyethyl) Methyl oxy-5-nitrobenzoate was obtained from the compound of Reference Example 107 as 'H-NMR (CDCI3) δ: 2.74 (2Η5^J^7.9 Hz)? 3·14 (2H,t, 129677.doc •109 · 200840568 J=7.9 Hz), 3.96 (3H, s), 3.97 (3H, s), 7.73 (1H, d, J=i.5 Hz), 8.07 (1H, d, J=1.5 Hz). MS (ESI) m/z: 284 (M+H)+. [Reference Example 109] 4-{2-[(4-Chlorophenyl)amine-carbamoyl]ethyl}·3_fluorenyloxy- nitro benzoate oxime ester in the same manner as in Reference Example 81, Reference Example 1 The compound of 〇8 was condensed with 'chloroaniline to give the title compound. !H.NMR (CDCls) δ : 2.70 (2Η, t, J-8.1 Hz)? 3.21 (2H, t _ 1 = 8.1 Hz), 3.95 (3H? s)5 3.96 (3H? s), 7.27 (2H , d9 J=8.8

Hz)，7·36 (1H，br s)，7·48 (2H，d，J = 8.8 Hz)，7·72 (1H，d, J=1.5 Hz)，8.08 (1H，d，J=1.5 Hz)。 MS (ESI) m/z: 393 (M+H)、 [參考例110] 3-胺基-4-{2-[(4-氣苯基）胺甲醯基]乙基}_%曱 氧基苯甲酸曱酯 以與參考例13相同的方法，由參考例1 〇9的化合物獲得 標題化合物。 ^•NMR (CDC13) δ : 2.68 (2H，t，J=6.6 Hz)，2.97 (2H，t， J = 6.6 Hz)? 3.747, 3.752 (total 3H5 s)? 3.88 (3H, s), 4.07-4.50 (2H，b〇, 6·92 (1H，bf s)，7.02 (1H，d，J=l,5 Hz)，7.24 (2H，d，J=8.8 Hz)，7.38 (2H，d，J=8.8 Hz)，7.41-7.50 (1H， br) 〇 MS (ESI) m/z: 363 (M+H)+。 [參考例111] 4-{2-[(4-氟苯基）胺甲醯基]乙基}-3-曱氧基-5- 硝基苯甲酸曱酯 129677.doc -110- 200840568 以與參考例81相同的方法，將參考例108之化合物與4-氟苯胺縮合而獲得標題化合物。 !H-NMR (CDC13) δ : 2.70 (2H? t? J=8.2 Hz), 3.22 (2H5 t? JD Hz)，3.96 (3H，s)，3·97 (3H，s)，6·98-7·05 (2H，m)， 7·26 (1H，br s)，7·48 (2H，dd，J=9.0，4·9 Hz)，7·73 (1H，d， J=1.2 Hz)，8.09 (1H，d，J=1.2 Hz)。 MS (ESI) m/z: 377 (M+H)+。 [參考例112] 3-胺基-4_{2-[(4-氟苯基）胺曱醯基]乙基卜5-曱 氧基苯甲酸甲酯 以與參考例13相同的方法，由參考例111之化合物獲得 標題化合物。 1H-NMR (CDC13) δ : 2·68 (2H，t，J=6.6 Ηζ)，2·99 (2H，t， J=6.6Hz)，3.82(3H，s)，3.88(3H，s)，4.28(2H，brs)，6.94-7.02 (3H，m)，7·03 (1H，d，J=1.5 Hz)，7.19-7.24 (1H，br)， 7.33-7.41 (2H，m) 〇 MS (ESI) m/z: 347 (M+H)+ o [參考例113] 4-甲基-3-硝基-5-(三氟甲基）苯甲酸 於冰浴冷卻下，向硫酸（15 ml)中添加4-曱基-3-(三氟甲 基）苯甲酸（2.04 g)、硝酸（3.0 mi)，於室溫下授拌15分鐘 後’於80〜100C下攪拌1·5小時。將反應液冷卻後，於冰 浴冷卻下添加冰。於室溫下攪拌30分鐘後，濾取所析出之 固體，以水清洗。以真空泵乾燥，獲得標題化合物（2 38 g)。 H-NMR (CDC13) δ ： 2.66 (3H5 br s)? 8.55-8.57 (1H5 m) -Ill - 129677.doc 200840568 8·60 (1H，d，J=l,7 Hz)。 MS (ESI) m/z: 271 (M+Na)+。 [參考例114] 4-甲基-3-硝基-5-(三氟甲基）苯曱酸甲酉旨 以與參考例52相同的方法，由參考例i丨3之化合物獲得 標題化合物。 H-NMR (CDC13) δ : 2.63 (3H，q，HZ)，3·99 (3H，s)， 8·51 (1H，br s)，8·53 (1H，d，J=1.2 Hz)。 [參考例11 5] 4-溴甲基-3-石肖基-5-(三氟甲基）苯甲酸甲酯 _ 以與參考例49相同的方法，由參考例！ 14的化合物獲得 標題化合物。 H-NMR (CDC13) δ : 4·02 (3H，s)，4·94 (2H，s)，8·56 (1H，d， J=1.5 Ηζ)，8·66 (1H，d，J=1.5 Hz)。 [參考例116] 2-[4-(曱氧基羰基）-2_硝基(三氟曱基）苄基] 丙二酸二第三丁酯 以與參考例68相同的方法，由丙二酸二第三丁酯與參考 例115之化合物獲得標題化合物。 ^-NMR (CDCls) δ : 1.40 (18Η, s), 3.40 (1H, t, J=7.6 Hz), 3.74 (2H, d, J=7.6 Hz), 4.00 (3H, s), g.54 (2H, d, J=i 7 Hz)，8.61 (2H，d，J=1.7 Hz)。 MS (ESI) m/z: 478 (M+H)+ 〇 [參考例U7] 4-(2-叛基乙基）_3-石肖基_5_(三氟甲基）苯甲 酯 以與參考例1〇4相同的方法’由參考例ιι6之化合物獲^ 標題化合物。 X ^ 129677.doc -112· 200840568 ^H.NMR (CDC13) δ : 2.76.2.84 (2H, m)5 3.32 (2H? t5 1=8.2Hz),7·36 (1H,br s),7·48 (2H,d,J = 8.8 Hz),7·72 (1H,d, J=1.5 Hz),8.08 (1H,d,J=1.5 Hz). MS (ESI) m/z: 393 (M+H), [Res. 110] 3-amino-4-{2-[(4-phenylphenyl)amine-carbamoyl]ethyl}_% The title compound was obtained from the compound of Reference Example 1-9 in the same manner as in the title compound. ^•NMR (CDC13) δ : 2.68 (2H,t,J=6.6 Hz), 2.97 (2H,t, J = 6.6 Hz)? 3.747, 3.752 (total 3H5 s)? 3.88 (3H, s), 4.07- 4.50 (2H, b〇, 6·92 (1H, bf s), 7.02 (1H, d, J=l, 5 Hz), 7.24 (2H, d, J=8.8 Hz), 7.38 (2H, d, J = 8.8 Hz), 7.41-7.50 (1H, br) 〇MS (ESI) m/z: 363 (M+H)+. [Reference Example 111] 4-{2-[(4-fluorophenyl)amine A Ethyl]ethyl}-3-decyloxy-5-nitrobenzoic acid decyl ester 129677.doc -110- 200840568 The compound of Reference Example 108 was condensed with 4-fluoroaniline in the same manner as Reference Example 81. The title compound was obtained. !H-NMR (CDC13) δ: 2.70 (2H? t? J = 8.2 Hz), 3.22 (2H5 t? JD Hz), 3.96 (3H, s), 3·97 (3H, s), 6·98-7·05 (2H,m), 7·26 (1H,br s),7·48 (2H,dd,J=9.0,4·9 Hz),7·73 (1H,d,J = 1.2 Hz), 8.09 (1H, d, J = 1.2 Hz) MS (ESI) m/z: 377 (M+H)+. [Reference 112] 3-amino-4_{2-[(4 -Fluorophenyl)aminoindenyl]ethyl bromide-5-nonyloxybenzoic acid methyl ester The title compound was obtained from the compound of the titled compound 111. ·68 ( 2H,t,J=6.6 Ηζ),2·99 (2H,t, J=6.6Hz), 3.82(3H,s),3.88(3H,s), 4.28(2H,brs),6.94-7.02 (3H ,m),7·03 (1H,d,J=1.5 Hz), 7.19-7.24 (1H,br), 7.33-7.41 (2H,m) 〇MS (ESI) m/z: 347 (M+H) + o [Reference Example 113] 4-Methyl-3-nitro-5-(trifluoromethyl)benzoic acid was added to a solution of sulfuric acid (15 ml). Fluoromethyl)benzoic acid (2.04 g) and nitric acid (3.0 mi) were stirred at room temperature for 15 minutes and then stirred at 80 to 100 C for 1.5 hours. After cooling the reaction solution, it was added under ice cooling. After stirring at room temperature for 30 minutes, the precipitated solid was collected by filtration and washed with water. Drying with a vacuum pump gave the title compound (2 38 g). H-NMR (CDC13) δ: 2.66 (3H5 br s)? 8.55-8.57 (1H5 m) -Ill - 129677.doc 200840568 8·60 (1H, d, J=l, 7 Hz). MS (ESI) m/z: 271 (M+Na)+. [Reference Example 114] 4-Methyl-3-nitro-5-(trifluoromethyl)benzoic acid methyl hydrazide The title compound was obtained from the compound of the compound of Example i. H-NMR (CDC13) δ: 2.63 (3H, q, HZ), 3·99 (3H, s), 8·51 (1H, br s), 8.53 (1H, d, J = 1.2 Hz). [Reference Example 11 5] 4-Bromomethyl-3-stone-succinyl-5-(trifluoromethyl)benzoic acid methyl ester _ In the same manner as in Reference Example 49, by reference example! The compound of 14 obtained the title compound. H-NMR (CDC13) δ : 4·02 (3H, s), 4·94 (2H, s), 8.56 (1H, d, J = 1.5 Ηζ), 8.66 (1H, d, J= 1.5 Hz). [Reference Example 116] 2-[4-(decyloxycarbonyl)-2-nitro(trifluoromethyl)benzyl]malonate di-t-butyl ester in the same manner as in Reference Example 68, from C The di-tert-butyl acid ester and the compound of Reference Example 115 gave the title compound. ^-NMR (CDCls) δ : 1.40 (18Η, s), 3.40 (1H, t, J=7.6 Hz), 3.74 (2H, d, J=7.6 Hz), 4.00 (3H, s), g.54 ( 2H, d, J=i 7 Hz), 8.61 (2H, d, J = 1.7 Hz). MS (ESI) m/z: 478 (M+H) + 〇 [Reference Example U7] 4-(2-Resylethyl)_3-Shisokyl-5-(trifluoromethyl)phenylmethyl ester with Reference Example 1相同 4 the same method 'obtained from the compound of Reference Example ι^^. X ^ 129677.doc -112· 200840568 ^H.NMR (CDC13) δ : 2.76.2.84 (2H, m)5 3.32 (2H? t5 1=8.2

Hz)，4.01 (3H，s)，8.56 (1H，d，J=i·? Hz)，8·59 (1H，d， J=1.7 Hz) 〇 MS (ESI) m/z: 322 (M+H)、 [參考例118] 4-{2-[(4-氣苯基）胺曱醯基]乙基卜％硝基_5_ (三氟曱基）苯甲酸甲酯 以與參考例81相同的方法，將參考例117之化合物與4_ 氯苯胺縮合而獲得標題化合物。 h-NMR (CDCl3) δ : 2.75 (2H，t，J=8 2 Hz)，3 39 (2H，丈， 1=8.3 Hz), 4.01 (3H, s), 7.24 〇H, br s)? y.28 (2H&gt; ^ J=g g Hz)，7.47 (2H，d，J=8.8 Hz)，8.56 〇H，&amp; s)，8 58 (ih，&amp; S) 〇 MS (ESI) m/z: 431 (M+H)+。 甲醯基]乙基}-5- [參考例119] 3-胺基-4-{2-[(4_氯笨基）胺 (三氟甲基）苯甲酸曱酯Hz), 4.01 (3H, s), 8.56 (1H, d, J=i·? Hz), 8·59 (1H, d, J=1.7 Hz) 〇MS (ESI) m/z: 322 (M+ H), [Reference Example 118] 4-{2-[(4-Phenylphenyl)amine fluorenyl]ethyl bromo nitro _5_(trifluoromethyl)benzoic acid methyl ester was the same as Reference Example 81 The title compound was obtained by condensing the compound of Reference Example 117 with 4-chloroaniline. h-NMR (CDCl3) δ : 2.75 (2H, t, J = 8 2 Hz), 3 39 (2H, zhang, 1 = 8.3 Hz), 4.01 (3H, s), 7.24 〇H, br s)? y .28 (2H&gt; ^ J=gg Hz), 7.47 (2H, d, J = 8.8 Hz), 8.56 〇H, &amp; s), 8 58 (ih, &amp; S) 〇MS (ESI) m/z : 431 (M+H)+. Methyl hydrazide] ethyl}-5- [Reference Example 119] 3-Amino-4-{2-[(4-chlorophenyl)amine (trifluoromethyl)benzoate decyl ester

以與參考例13相同的方法， 標題化合物。 由參考例11 8之化合物獲得 J=7.3 Hz)，3·14 (2H，t， br S), 7.21 (1H5 br s)5 J=8.8 Hz)，7.50 (1H，d， h-NMR (CDC13) δ : 2·63 (2H，t 卜7·1 Ηζ)，3·91 (3H，s)，4.55 (2H， 7·30 (2H，d，J=8.8 Hz)，7.45 (2H，d J=1.5 Hz)，7.70 (1H，d，J=1.5 Hz)。 MS (ESI) m/z: 401 (M+H)+ 〇 [參考例120] 3-((E)-2_第三丁 酸甲酯 氧基羰基乙烯基）-4-硝基笨 甲 129677.doc 113 - 200840568 以與參考例55相同的方法，由3_甲醯基_4_《肖基苯甲酸甲 酿獲得標題化合物。 】H-NMR (CDCI3) δ : 1 55 iQH e、q / ； ^ (9H，s)，3·99 (3H，s)，6·42 (1H，d， J—15.9 Hz)，7·95 (1H，d，J=15,9 Hz)，8·04 (1H，d，J=8.3In the same manner as Reference Example 13, the title compound. From the compound of Reference Example 81, J = 7.3 Hz), 3·14 (2H, t, br S), 7.21 (1H5 br s) 5 J = 8.8 Hz), 7.50 (1H, d, h-NMR (CDC13) δ : 2·63 (2H, t 卜 7·1 Ηζ), 3·91 (3H, s), 4.55 (2H, 7·30 (2H, d, J=8.8 Hz), 7.45 (2H, d J = 1.5 Hz), 7.70 (1H, d, J = 1.5 Hz) MS (ESI) m/z: 401 (M+H) + 〇 [Reference Example 120] 3-((E)-2_Third Methyl ester oxycarbonylvinyl)-4-nitro-p-methyl 129677.doc 113 - 200840568 The title compound was obtained from 3-methylmercapto-4-yl_Schottylbenzoic acid in the same manner as in Reference Example 55. H-NMR (CDCI3) δ : 1 55 iQH e, q / ; ^ (9H, s), 3·99 (3H, s), 6·42 (1H, d, J-15.9 Hz), 7.95 (1H,d,J=15,9 Hz),8·04 (1H,d,J=8.3

Hz)，8·15 (1H，dd，J=8.3, 2.0 Hz)，8 31 (m，d，J=2 〇 Hz)。 MS (ESI) m/z: 330 (M+Na)+。 [麥考例121] 3-((E)-2-羧基乙烯基）_4_硝基苯曱酸甲酯 以與參考例56相同的方法，由參考例12〇之化合物獲得 _ 標題化合物。 ^-NMR (CDCI3) δ : 4.01 (3Η? s)5 6.51 (1H5 d5 1=15.9 Hz), 8.10 (1H，d，J=8.3 Hz)，8·18 (1H，d，J=15.9 Hz)，8.21 (1H， dd，J=8.3, 1·7 Hz)，8.35 (1H，d，J=1.7 Hz)。 MS (ESI) m/z: 274 (M+Na)+。 [參考例122] 3-{(E)-2-[(4-氯苯基）胺甲醯基]乙烯基}_4-硝 基苯甲酸甲酯 鲁 以與參考例81相同的方法，將參考例121之化合物與4_ 氣本fee細合而獲得標題化合物。 iH-NMR (DMSO-d6) δ : 3.95 (3H，s)，6,94 (1H，d，J=15.6 Hz)，7·42 (2H，d，J=8.8 Hz)，7.73 (2H，d，J=8.8 Hz)，7.84 (1H，d，J=15.6 Hz)，8·16 (1H，dd，J=8.5, 1.5 Hz)，8·21 (1H， d，J=8.5 Hz)，8.32 (1H, d，J=1.5 Hz)，1〇·52 (1H，s)。 MS (ESI) m/z: 361 (M+H)+。 [參考例123] 4-胺基-3-{2-[(4-氯苯基）胺甲醯基]乙基）苯曱 酸甲酯 129677.doc llyl 200840568 以與參考例6 1相同的方法，由參考例1 22之化合物獲得 標題化合物。 1H-NMR (CDC13) δ : 2.69 (2H，t，J = 7,0 Ηζ)，2·93 (2H，t， Hz)，3.84 (3H，s)，4·25-4·65 (2H，m)，6·62 (1H，d， 卜8.3 Hz)，7·26 (2H，d，J=8.8 Hz)，7·33 (1H，br s)，7·41 (2H，d，J=8.8 Hz), 7·71 (1H，dd，J=8.3, 2·0 Hz)，7·74 (1H， d，J=2.0 Hz) 〇 MS (ESI) m/z: 333 (M+H)+。 [參考例124] 4-乙醯氧曱基-3-硝基苯曱酸 向4-羥基甲基-3-硝基苯曱酸（986 mg)之二氣甲烷（30 ml) 溶液中添加ΤΕΑ(2·79 ml)及乙酸酐（1 · 18 ml)，於室温下攪 拌8小時。向反應液中添加水，放置一晚後，添加濃鹽 酸’將有機層分離，以無水MgS04乾燥。於減壓下餾去溶 劑’向殘渣中添加乙酸乙酯（5 ml)及己烷（60 ml)，充分攪 拌後，進行傾析而去除溶劑。將固體於減壓下乾燥，獲得 標題化合物（923 mg)。 W-NMR (CDC13) δ ·· 2.20 (3H，s)，5·59 (2H，s)，7·75 (1H，d， J = 8.1 Ηζ)，8·36 (1Η，dd，J=8.1，1·7 Ηζ)，8·81 (1Η，d，J=l.7Hz), 8·15 (1H, dd, J=8.3, 2.0 Hz), 8 31 (m, d, J=2 〇 Hz). MS (ESI) m/z: 330 (M+Na)+. [Mexicotest Example 121] 3-((E)-2-Carboxyvinyl)_4-nitrobenzoic acid methyl ester The title compound was obtained from the compound of the compound of Example 12 in the same manner as the compound of the compound. ^-NMR (CDCI3) δ : 4.01 (3Η? s)5 6.51 (1H5 d5 1=15.9 Hz), 8.10 (1H,d,J=8.3 Hz),8·18 (1H,d,J=15.9 Hz) , 8.21 (1H, dd, J=8.3, 1·7 Hz), 8.35 (1H, d, J = 1.7 Hz). MS (ESI) m/z: 274 (M+Na)+. [Reference Example 122] 3-{(E)-2-[(4-Chlorophenyl)amine-carbamoyl]vinyl}- 4-nitrobenzoic acid methyl ester was used in the same manner as in Reference Example 81, and reference was made. The compound of Example 121 was combined with 4_ gas-fee to give the title compound. iH-NMR (DMSO-d6) δ : 3.95 (3H, s), 6, 94 (1H, d, J = 15.6 Hz), 7.42 (2H, d, J = 8.8 Hz), 7.73 (2H, d , J=8.8 Hz), 7.84 (1H, d, J = 15.6 Hz), 8·16 (1H, dd, J=8.5, 1.5 Hz), 8.21 (1H, d, J=8.5 Hz), 8.32 (1H, d, J = 1.5 Hz), 1 〇 · 52 (1H, s). MS (ESI) m/z: 361 (M+H)+. [Reference Example 123] 4-Amino-3-{2-[(4-chlorophenyl)amine-carbamoyl]ethyl)benzoic acid methyl ester 129677.doc llyl 200840568 In the same manner as in Reference Example 61 The title compound was obtained from the compound of the title compound. 1H-NMR (CDC13) δ : 2.69 (2H, t, J = 7,0 Ηζ), 2·93 (2H, t, Hz), 3.84 (3H, s), 4·25-4·65 (2H, m),6·62 (1H,d, 8.3 Hz),7·26 (2H,d,J=8.8 Hz),7·33 (1H,br s),7·41 (2H,d,J= 8.8 Hz), 7·71 (1H, dd, J=8.3, 2·0 Hz), 7·74 (1H, d, J=2.0 Hz) 〇MS (ESI) m/z: 333 (M+H) +. [Reference Example 124] 4-Ethyloxyindol-3-nitrobenzoic acid was added to a solution of 4-hydroxymethyl-3-nitrobenzoic acid (986 mg) in di-methane (30 ml). (2.79 ml) and acetic anhydride (1 · 18 ml) were stirred at room temperature for 8 hours. Water was added to the reaction mixture, and after standing overnight, concentrated hydrochloric acid was added. The organic layer was separated and dried over anhydrous MgSO. The solvent was distilled off under reduced pressure. ethyl acetate (5 ml) and hexane (60 ml) were added to the residue, and the mixture was thoroughly stirred and then decanted to remove solvent. The solid was dried under reduced pressure toiel W-NMR (CDC13) δ ·· 2.20 (3H,s),5·59 (2H,s),7·75 (1H,d, J = 8.1 Ηζ),8·36 (1Η,dd,J=8.1 ,1·7 Ηζ),8·81 (1Η,d,J=l.7

Hz) 〇 MS (ESI) m/z: 240 (M+H)+。 [參考例125] 4-羥基曱基硝基苯甲酸第三丁酯 向無水MgS〇4(3.91 g)的二氣甲烷（40 mi)中添加濃硫酸 (0.43 ml) ’於室溫下攪拌5分鐘。向該混合物中添加參考 例124之化合物（2·03 g)，於室溫下攪拌1〇分鐘後，添加第 129677.doc 115 200840568 過濾去除不 進行分液。 三丁醇（3·89 ml)且塞嚴，於室溫下攪拌3曰。 溶物後’向滤液中添加飽和NaHC〇3水溶液， 以無水NazSO4乾燥有機層後，於減壓下餾去溶劑。兔、 之THF(2〇 ml)溶液中添加1當量Na〇H(9 ml)。搜掉3小日士 後’以乙酸乙S曰萃取’以無水Na2S〇4乾燥。於減壓下餘去 溶劑，將殘渣以矽膠管柱層析法（二氯甲烧—曱醇：一扣 甲烷=1 : 99)進行精製，獲得標題化合物（97〇 mg)。Hz) 〇 MS (ESI) m/z: 240 (M+H)+. [Reference Example 125] 3-butylmercaptonitrobenzoic acid tert-butyl ester To a dry MgS〇4 (3.91 g) of di-methane (40 mi) was added concentrated sulfuric acid (0.43 ml). minute. The compound of Reference Example 124 (2.03 g) was added to the mixture, and the mixture was stirred at room temperature for 1 hr, and then added to 129 677.doc 115 200840568 to remove the liquid. Tributyl alcohol (3·89 ml) was stoppered and stirred at room temperature for 3 Torr. After the solution was added, a saturated aqueous solution of NaHC 3 was added to the filtrate, and the organic layer was dried over anhydrous NazSO4. One equivalent of Na〇H (9 ml) was added to a solution of rabbit, THF (2 ml). After 3 hours of search, the product was extracted with ethyl acetate (sodium acetate) and dried over anhydrous Na2S〇4. The solvent was evaporated under reduced pressure, and the residue was purified mjjjjjlilililililililililililililili

1H-NMR (CDC13) δ : 1.62 (9H，s)，2.39 (1H, t，J=6.3 Hz)1H-NMR (CDC13) δ : 1.62 (9H, s), 2.39 (1H, t, J = 6.3 Hz)

5·06 (2H，d，J=6.3 Hz)，7.86 (1H，d，J = 8,0 Hz)，8.26 (1H dd，J = 8.3, 1·7 Hz)，8·66 (1H，d，J=1.7 Hz)。 MS (ESI) m/z: 254 (M+H)+ 〇 [參考例126] 4-[(4-氯苯基胺甲醢基）氧基甲基]硝基苯甲 酸第三丁酯 向參考例125之化合物（122 mg)的乙腈（3 nU)溶液中添加 碳酸N，N·-二琥珀醯亞胺（25 8 mg)及TEA(251μl)，於室溫 下攪拌2小時。於減壓下餾去溶劑，向殘渣中添加乙酸乙 酯後’以飽和NaHC〇3水溶液清洗。以無水他2§〇4乾燥有 機層後，於減壓下餾去溶劑。向殘渣之二氯甲烷溶液中添 加4_氣苯胺（57.4 mg)及ΤΕΑ(251 μΐ)，攪拌70分鐘。向反應 液中添加乙醯氣（42.6 μΐ)，攪拌15小時。向反應液中添加 飽和NaHC〇3水溶液後，將有機層分離，以無水]^28〇4乾 燥。於減壓下餾去溶劑，將殘渣以矽膠管柱層析法（乙酸 乙酉旨··己烷=1 ·· 9)進行精製，獲得標題化合物（162 mg)。 'H_NMR (CDC13) δ : 1·62 (9H，S)，5·65 (2H，s)，6·75 (1H，br 129677.doc -116- 200840568 s)，7.29 (2H，d，J一8·8 Hz)，7.35 (2H，d，J=8.6 Hz)，7.70 (1H，d，J=8.1 Hz)，8·25 (1H，dd，J=8.1，1.5 Hz)，8.66 (1H， d，J=1.7 Hz)。 MS (ESI) m/z: 338 (M+H)+ 〇 [參考例127]3-胺基-4-[(4-氣苯基胺甲醯基）氧基甲基]苯曱 酸第三丁酯 以與參考例13相同的方法，由參考例126之化合物獲得 標題化合物。5·06 (2H,d,J=6.3 Hz), 7.86 (1H,d,J = 8,0 Hz), 8.26 (1H dd, J = 8.3, 1·7 Hz), 8.66 (1H,d , J = 1.7 Hz). MS (ESI) m / z: 254 (M+H) + 〇 [Ref. 126] 4-[(4-chlorophenylamine-carbamoyl)oxymethyl]nitrobenzoic acid tert-butyl ester N,N--disuccinimide (25 8 mg) and TEA (251 μl) of a compound of Example 125 (122 mg) in acetonitrile (3 nM) were stirred at room temperature for 2 hr. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue, and then washed with saturated aqueous NaHC? After drying the organic layer with anhydrous 2 § 4, the solvent was evaporated under reduced pressure. To the dichloromethane solution of the residue was added 4_gas aniline (57.4 mg) and hydrazine (251 μΐ), and the mixture was stirred for 70 minutes. Ethylene gas (42.6 μM) was added to the reaction mixture, and the mixture was stirred for 15 hours. After a saturated aqueous solution of NaHC〇3 was added to the reaction mixture, the organic layer was separated and dried over anhydrous EtOAc. The solvent was evaporated under reduced pressure, and the residue was purified eluted eluted elut elut elut elut elut elut elut elut 'H_NMR (CDC13) δ : 1·62 (9H, S), 5·65 (2H, s), 6.75 (1H, br 129677.doc -116- 200840568 s), 7.29 (2H, d, J 8·8 Hz), 7.35 (2H, d, J=8.6 Hz), 7.70 (1H, d, J=8.1 Hz), 8·25 (1H, dd, J=8.1, 1.5 Hz), 8.66 (1H, d, J = 1.7 Hz). MS (ESI) m/z: 338 (M+H) + 〇 [Reference 127] 3-amino-4-[(4-phenylphenylaminomethylamino)oxymethyl]benzoic acid The title compound was obtained from the compound of Reference Example 126.

^NMR(CDCl3)8：1.57(9H5 s)? 4.23 (2H, br s), 5.19 (2H? s)，6·83 (1H，br s)，7·24 (1H，d，J==7 6 Hz)，7】（2H，d， J-9.0 Hz)? 7.30-7.36 (4H? m) 〇 [參考例128] 4-[(5'氣吡啶·2_其脫田於# p 4 ^ 甲醯基）氧基曱基]-3-硝基 苯甲酸第三丁酯 以與參考例12 6相同的方法 ,. * 由參考例125之化合物與2- 胺基-5-氯吡啶獲得標題化合物。 ^-NMR (CDCI3) δ : 1.62 (οΜ 、 、s)，5·68 (2Η，s)，7·66 (1Η， dd? J=9.0? 2.4 Hz), 7.69^7 73 • J m)，7.93 (m，d，J=9.0^NMR(CDCl3)8:1.57(9H5 s)? 4.23 (2H, br s), 5.19 (2H? s),6·83 (1H,br s),7·24 (1H,d,J==7 6 Hz), 7] (2H, d, J-9.0 Hz)? 7.30-7.36 (4H? m) 〇 [Reference Example 128] 4-[(5' gas pyridine · 2 _ 脱 田 in # p 4 ^ The title compound was the same as that of Reference Example 126. The title was obtained from the compound of Reference Example 125 and 2-amino-5-chloropyridine. Compound. ^-NMR (CDCI3) δ : 1.62 (οΜ , s), 5·68 (2Η, s), 7.66 (1Η, dd? J=9.0? 2.4 Hz), 7.69^7 73 • J m), 7.93 (m,d,J=9.0

Hz)，8·22 (1H，d，J=2.4 Q … ’，S·26 (1H，dd，J=8.1，1·5 Hz)， 8·68 (1H，d，J=1.5 Hz)。Hz), 8·22 (1H, d, J=2.4 Q ... ', S·26 (1H, dd, J=8.1, 1. 5 Hz), 8·68 (1H, d, J=1.5 Hz).

[參考例129] 3_胺基_4](夂翕L ^ ^ 乳％°定，I基胺曱醯基）氧基曱基] 苯甲酸第三丁酯 以與參考例13相同的方、本 搞,人t ’ ’由參考例128之化合物獲得 標題化合物。 W-NMR (CDC13) δ : 1·57 (9 打，s)，4.19 (2Η，br s)，5·22 (2Η， 129677.doc -117. 200840568 S)，7.27 (1H，d，J=7.8 Ηζ)，7·33 (1H，d，J=1.5 Ηζ)，7·37 (1H，dd，J=7.8，1·7 Hz)，7.64 (1H，dd，J=8.8, 2·5 Hz)，7.95 (1H，d，J=8.6 Hz)，8·17 (1H，d，J=2.5 Hz)，8·41 (1H，br s)。 [參考例129a]4-胺基甲基-3_硝基苯甲酸第三丁酯 向無水MgS〇4(46.3 g)的二氣曱烷（400 ml)懸浮液中添加 硫酸（5.12 ml)，於室溫下攪拌15分鐘。向該混合物中添加 4-溴甲基-3-硝基苯甲酸（25.0 g)，於室溫下攪拌15分鐘 後’添加第三丁醇（46 ml)且塞嚴，於室溫下攪拌一整夜。 _ 過濾去除不溶物後，向濾液中添加飽和NaHC03水溶液， 進行分液。將有機層以飽和食鹽水清洗後，以無水Na2S04 乾燥。過濾去除不溶物後，以2小時將所獲得之濾液滴下 至7當量氨-曱醇溶液（137 mi)中。於減壓下餾去溶劑，向 殘渣中添加二氣甲烷及飽和NaHC〇3水溶液，進行分液。 以無水NasSO4乾燥有機層後，於減壓下餾去溶劑。以石夕膠 層析法（二氯甲烧—曱醇：二氯曱烧=1 : 19)進行精製，辦 得標題化合物（13·〇 g)。 〗H-NMR (CDC13) δ ·· 1.62 (9H，s)，4·17 (2H，S)，7·71 (1H，d， J=8.1 Hz)，8·20 (1H，dd，J=7.9, 1·8 Hz)，8·54 (1H，d，J=i 8[Reference Example 129] 3_Amino group_4](夂翕L^^乳%°, I-aminoamido)oxyindenyl] tert-butyl benzoate was the same as in Reference Example 13, The title compound was obtained from the compound of Reference Example 128. W-NMR (CDC13) δ : 1·57 (9 dozen, s), 4.19 (2Η, br s), 5·22 (2Η, 129677.doc -117. 200840568 S), 7.27 (1H, d, J= 7.8 Ηζ),7·33 (1H,d,J=1.5 Ηζ),7·37 (1H,dd,J=7.8,1·7 Hz), 7.64 (1H, dd, J=8.8, 2·5 Hz ), 7.95 (1H, d, J = 8.6 Hz), 8.17 (1H, d, J = 2.5 Hz), 8.41 (1H, br s). [Reference 129a] 4-Aminomethyl-3-nitrobenzoic acid tert-butyl ester To a suspension of anhydrous MgS 4 (46.3 g) in dioxane (400 ml) was added sulfuric acid (5.12 ml), Stir at room temperature for 15 minutes. To the mixture was added 4-bromomethyl-3-nitrobenzoic acid (25.0 g), and the mixture was stirred at room temperature for 15 minutes, then thricol (46 ml) was added and stoppered, and stirred at room temperature. All night. _ After removing the insoluble matter by filtration, a saturated aqueous solution of NaHCO 3 was added to the filtrate to carry out liquid separation. The organic layer was washed with brine and dried over anhydrous Na2SO. After insoluble matter was removed by filtration, the obtained filtrate was dropped to 7 equivalents of an ammonia-decanol solution (137 mi) over 2 hours. The solvent was distilled off under reduced pressure, and a mixture of di-methane and saturated NaHC? After drying the organic layer with anhydrous NasSO4, the solvent was evaporated under reduced pressure. The title compound (13·〇 g) was purified by chromatography on silica gel chromatography (dichloromethane-decanol:dichloromethane = 1 : 19). H-NMR (CDC13) δ ·· 1.62 (9H, s), 4·17 (2H, S), 7·71 (1H, d, J=8.1 Hz), 8·20 (1H, dd, J= 7.9, 1·8 Hz), 8.54 (1H, d, J=i 8

Hz)。Hz).

Ms (ESI) m/z: 253 (M+H)+。 [參考例130] 4-[3-(4-氯苯基）脲基甲基]-3-硝基苯甲酸第二 丁酯 向參考例l29a之化合物（321 mg)的THF(l〇 ml)溶液中添 加4 -氣本基異策酸|旨（215 mg)’於室溫下擾拌分梦 、 王 129677.doc -118- 200840568 減壓下餾去溶劑，向殘潰中添加醚/己烷（1/1)，濾取不溶 物，獲得標題化合物（490 mg)。 'H-NMR (CDC13) δ : 1·61 (9H，S)，4·70 (2H，d，J=6.1 Hz)， 5·54 (1H，t，J = 6.4 Hz)，6·33 (1H，s)5 7.23-7.25 (4H，m)， 7.78 (1H，d，J=8.1 Hz)，8.19 (1H，dd，1.7 Hz)，8·60 (1H，d，J=1.5 Hz)。 MS (ESI) m/z: 406 (m+H)+。Ms (ESI) m/z: 253 (M+H)+. [Reference Example 130] 4-[3-(4-Chlorophenyl)ureidomethyl]-3-nitrobenzoic acid, the second butyl ester to the compound of the compound of the formula Add 4-oxo-isomethic acid to the solution|(215 mg)' to disturb the dream at room temperature, Wang 129677.doc -118- 200840568 Distillate the solvent under reduced pressure, add ether/hexane to the residue The title compound (490 mg) was obtained. 'H-NMR (CDC13) δ : 1·61 (9H,S), 4·70 (2H,d,J=6.1 Hz), 5·54 (1H,t,J = 6.4 Hz),6·33 ( 1H, s) 5 7.23-7.25 (4H, m), 7.78 (1H, d, J = 8.1 Hz), 8.19 (1H, dd, 1.7 Hz), 8.60 (1H, d, J = 1.5 Hz). MS (ESI) m/z: 406 (m+H)+.

下述表5〜表12中表示 物的結構。[表5] [參考例1]〜[參考例 130]之標題化合The structures shown in Tables 5 to 12 below are shown. [Table 5] [Reference Example 1] ~ [Reference Example 130] Title Combination

129677.doc -119- 200840568129677.doc -119- 200840568

[參考例1 6J (y/〇H [參考例1 7] 乂 λχ/〆 Κ [參考例1 8] [參考例19] \〇2 [參考例2 0] !:參考例2 1 ] 〇;Λ^ SvlL[Reference Example 1 6J (y/〇H [Reference Example 1 7] 乂λχ/〆Κ [Reference Example 1 8] [Reference Example 19] \〇2 [Reference Example 2 0] !: Reference Example 2 1 ] 〇; Λ^ SvlL

[表6][Table 6]

129677.doc 120- 200840568 [參考例3 6 ] 0 [參考例3 7】 0 〔參考例3 8 ] 〇 rYNY^〇〆 广 lt [表7] [參考例3 9 ] 丫CO1。/ 〔參考例4 0] 丫00^。、 ί參考例4 1 ] κχ^ [參考例4 2] χο1。3 [參考例4 3〕 F&gt;&lt;^ [參考例4 4] [篸考例4 5] ：&gt;^ [參考例4 6] [參考例4 7] /0&gt;^ [參考例4 8〕 、。&gt;#“ [參考例4 9] 。丫 〇、 。々 [參考例5 0 ] [參考例5 1 ] ^〇is%Nxrcl Η [參考例5 2 ] ,Qr~ 〇-\H〇^ [參考例5 3] \ OH no2 [參考例5 4] [參考例3 5〕 [參考例5 6 ] N 令2 OH [參考例5 7] [參考例5 8] [參考例5 9] N〇2 129677.doc 121 - 200840568 [表8]129677.doc 120- 200840568 [Reference Example 3 6 ] 0 [Reference Example 3 7] 0 [Reference Example 3 8 ] 〇 rYNY^〇〆 广 [Table 7] [Reference Example 3 9 ] 丫CO1. / [Reference Example 4 0] 丫00^. Reference example 4 1 ] κχ^ [Reference Example 4 2] χο1. 3 [Reference Example 4 3] F&gt;&lt;^ [Reference Example 4 4] [Reference Example 4 5] :&gt;^ [Reference Example 4 6] [Reference Example 4 7] /0&gt;^ [Reference Example 4 8], . &gt;#" [Reference Example 4 9]. 丫〇, 々 [Reference Example 5 0 ] [Reference Example 5 1 ] ^〇is%Nxrcl Η [Reference Example 5 2 ], Qr~ 〇-\H〇^ [ Reference Example 5 3] \ OH no2 [Reference Example 5 4] [Reference Example 3 5] [Reference Example 5 6 ] N Let 2 OH [Reference Example 5 7] [Reference Example 5 8] [Reference Example 5 9] N〇 2 129677.doc 121 - 200840568 [Table 8]

I29677.doc 122- 200840568 [表9]I29677.doc 122- 200840568 [Table 9]

129677.doc 123· 200840568129677.doc 123· 200840568

[表 10][Table 10]

129677.doc 124- 200840568 [表 11]129677.doc 124- 200840568 [Table 11]

129677.doc 125- 200840568 [表 12]129677.doc 125- 200840568 [Table 12]

[實施例1] N-(3-{[(5·氣嗟吩-2·幾基）胺基]曱基}吼咬基）_ 5 -甲基-4,5,6,7-四氫噻唑并[5,4-c]吡啶-2-曱醯胺鹽酸鹽 向參考例7之化合物（238 mg)的二氣曱烷（5 mi)溶液中添 加4當量鹽酸二哼烷溶液（5 ml)，於室溫下攪拌丨小時。= 減壓下餾去溶劑後，向殘渣之DMF(5 ml)溶液中添加5_甲 129677.doc -126- 200840568 基-4,5,6,7-四氫噻唑并[5,4-c]吡啶-2_甲酸鹽酸鹽（182 mg)、HOBt(87.4 mg)、EDC(186 mg)及 ΤΕΑ(271 μΐ)，於室 溫下攪拌一整夜。於減壓下餾去溶劑後，向殘渣中添加二 氣甲烷及NaHC〇3水溶液，進行分液，以無水]^化!§〇4乾燥 有機層。於減壓下餾去溶劑，以矽膠層析法（曱醇：二氣 甲烷=2 ·· 23)將所獲得之殘渣純化。向所獲得之標題化合 物的自由體中添加1當量鹽酸乙醇溶液，進行濃縮。以乙 酸乙酯清洗所獲得之固體，獲得標題化合物（52 9 mg)。 W-NMR (DMSO-d6) : 2.93 (3H，s)，3·08-3·94 (4H，m)， 4·43-4·58 (1H，m)，4.63 (2H，d，J=5.2 Hz)，4·69-4·86 (1H， m)，7·21 (1H，d，J=4.1 Hz)，7·75 (1H，d，J=4.1 Hz)，8.35 (1H，d，J=6.2 Hz)，8·74 (1H，d，J=6.2 Hz)，8·80 (1H，s)， 9·57 (1H，t，J=5.2 Hz)，11.14 (1H，s)，1 1.53-1 1.85 (1H， m) o MS (ESI) m/z: 448 (M+H)+。 [實施例2] N-(2-{[(5-氣噻吩-2-羰基）胺基]甲基}苯基）_；μ異 丙基旅咬-4-甲醯胺鹽酸鹽 將1·異丙基哌啶_4_甲酸鋰鹽（116 mg)及參考例13之化合 物（150 mg)溶解於 DMF(15 ml)t，添加 H〇m(676 mg)、 EDC(194 mg)，於室溫下攪拌3日。於減壓下餾去溶劑，向 殘渣中添加飽和NaHC〇3水溶液，以二氣甲烷萃取，以無 水NajO4乾燥。以矽膠管柱層析法（二氯甲烷：甲醇=49 : 1-&gt;47 · 3)進行精製，向所獲得之標題化合物的自由體（81 mg)中添加1當量鹽酸乙醇（21〇…），於減壓下餾去溶劑。 129677.doc -127· 200840568 向殘渣中添加乙醇及水’於減壓下顧去溶劑，獲得標題化 合物（75 mg)。 ]H-NMR (DMSO-d6) δ : 1.27 (6H? d5 J=6.6 Hz)? 1.91-2.17 (4H，m)，2.69-2.78 (1H，m)，2·92-3·04 (2H，m)，3.42-3.49 (3H，m)，4.39(2H，d，J=6，lHz)，7，14-7.21(2H，m)，7,23-7.32 (2H，m)，7.48 (1H，d，J=7.8 Hz)，7·74 (1H，d，J=4.2 Hz)，9.30 (1H，t，J=6.0 Hz)，9.43 (1H，s)，9.85 (1H，s)。 MS (ESI) m/z: 420 (M+H)+ 〇 ® [實施例3] {3-{[(5_氯噻吩-2-羰基）胺基]甲基卜2_[(5 -甲基_ 4,5,6,7-四氫噻唑并[5,4-c]吼啶-2-羰基）胺基]苯氧基}乙酸 第三丁酯 向參考例23之化合物（118 mg)的DMF(4 ml)溶液中添加5-曱基-4,5,6,7-四氫嗟唑并[5,4-c]吡唆-2-甲酸鹽酸鹽（95 mg)、HOBt(54 mg)、EDC(83 mg)、ΤΕΑ(120 μΐ)，於室溫 下攪拌3 9小時。於減壓下餾去溶劑後，向殘渣中添加乙酸 乙酉曰、飽和N a H C Ο 3水〉谷液。以乙酸乙S旨卒取後，以飽和 m[Example 1] N-(3-{[(5 嗟 -2 -2 · · )))]]]]}}}}}} Thiazolo[5,4-c]pyridin-2-indanamine hydrochloride To a solution of the compound of Reference Example 7 (238 mg) in dioxane (5 mi) was added 4 eq. Ml), stir at room temperature for 丨 hours. = After distilling off the solvent under reduced pressure, add 5_A 129677.doc -126- 200840568 base-4,5,6,7-tetrahydrothiazolo[5,4-c to the residue in DMF (5 ml). Pyridine-2_formate (182 mg), HOBt (87.4 mg), EDC (186 mg) and hydrazine (271 ΐ) were stirred overnight at room temperature. After distilling off the solvent under reduced pressure, a mixture of methylene methane and aqueous NaHCI 3 was added to the residue to carry out liquid separation, and the organic layer was dried. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (methanol: methane = 2 · 23). To the free body of the title compound obtained, 1 equivalent of a hydrochloric acid ethanol solution was added and concentrated. The solid obtained was washed with ethyl acetate to give the title compound (52. W-NMR (DMSO-d6): 2.93 (3H, s), 3·08-3·94 (4H, m), 4·43-4·58 (1H, m), 4.63 (2H, d, J= 5.2 Hz), 4·69-4·86 (1H, m), 7·21 (1H, d, J=4.1 Hz), 7·75 (1H, d, J=4.1 Hz), 8.35 (1H, d , J=6.2 Hz), 8.74 (1H, d, J=6.2 Hz), 8·80 (1H, s), 9·57 (1H, t, J=5.2 Hz), 11.14 (1H, s) , 1 1.53-1 1.85 (1H, m) o MS (ESI) m/z: 448 (M+H)+. [Example 2] N-(2-{[(5-athiophen-2-yl)amino]methyl}phenyl)_; μ isopropyl brigade-4-carboxamide hydrochloride 1 · Isopropylpiperidine _4-formic acid lithium salt (116 mg) and the compound of Reference Example 13 (150 mg) were dissolved in DMF (15 ml) t, H 〇m (676 mg), EDC (194 mg), Stir at room temperature for 3 days. The solvent was evaporated under reduced pressure, and a saturated aqueous NaHC? Purification by gel column chromatography (dichloromethane: methanol = 49: 1-&gt; 47 · 3), and adding 1 equivalent of hydrochloric acid to ethanol (81 mg) of the obtained title compound (21 mg). The solvent was distilled off under reduced pressure. 129677.doc -127· 200840568 Ethyl alcohol and water were added to the residue. The solvent was evaporated to give the title compound (75 mg). H-NMR (DMSO-d6) δ : 1.27 (6H? d5 J=6.6 Hz)? 1.91-2.17 (4H,m), 2.69-2.78 (1H,m),2·92-3·04 (2H, m), 3.42-3.49 (3H, m), 4.39 (2H, d, J=6, lHz), 7, 14-7.21 (2H, m), 7, 23-7.32 (2H, m), 7.48 (1H , d, J = 7.8 Hz), 7.74 (1H, d, J = 4.2 Hz), 9.30 (1H, t, J = 6.0 Hz), 9.43 (1H, s), 9.85 (1H, s). MS (ESI) m/z: 420 (M+H) + 〇® [Example 3] {3-{[(5-chlorothiophene-2-carbonyl)amino]methyl b 2_[(5-methyl) _ 4,5,6,7-Tetrahydrothiazolo[5,4-c]acridin-2-carbonyl)amino]phenoxy}acetic acid tert-butyl ester to the compound of Reference Example 23 (118 mg) Add 5-mercapto-4,5,6,7-tetrahydrocarbazol[5,4-c]pyridin-2-carboxylic acid hydrochloride (95 mg) to HOFt in DMF (4 ml) solution. 54 mg), EDC (83 mg), hydrazine (120 μM), stirred at room temperature for 39 hours. After distilling off the solvent under reduced pressure, acetic acid acetonitrile and saturated NaH.sub.3 s. After the stroke of acetic acid B, it is saturated with m

NaC 1水溶液清洗所合併之有機層。以無水Na2S〇4乾燥後， 於減壓下餾去溶劑。將殘渣以矽膠管柱層析法（二氯甲 烷：曱醇=50 : 1— 30 : 1—20 : 1)進行精製，獲得標題化 合物（1 32 mg)。 W-NMR (CDC13) δ ·· 1·46 (9H，s)，2·53 (3H，s)，2.86 (2H，t， J=5.9 Ηζ)，3.00 (2Η，t，J=5.9 Ηζ)，3·76 (2Η，s)，4·54 (2Η, d， J=6.1 Ηζ)，4·57 (2Η，s)，6·78-6·84 (1Η，m)，6·86 (1Η，d， J=3.9 Ηζ)，7.21-7.27 (2Η，m)，7·31 (1Η，d，J=3,9 Ηζ)，7·79 129677.doc -128- 200840568 (1H，t，J=6，l Hz)，9.33 (1H，s)。 MS (ESI) m/z: 577 (M+H)+。 [實施例4] 2-( {[2-(第三丁氧基羰基）-6- {[(5-氣噻吩-2-羰基） 胺基]甲基}苯基]胺基}羰基）-4,5,6,7-四氫嗟唑并[5,4-c]口比 啶-5-甲酸第三丁酯 使5-(第三丁氧基幾基）-4,5,6,7-四氫嗟唾并[5,4-c] °比σ定-2-甲酸鋰鹽（J· Med_ Chem· 2004，47，5167)(791 mg)懸浮於 二氣甲烧（10 ml)及吡啶（1 ml)中，於〇°c下添加亞硫醯氯 ⑩ （294 μΐ)及DMF(1滴），於室溫下攪拌2小時。將反應液再次 冷卻至0〇’添加參考例31之化合物（5〇〇111§)及〇]\4八？（45.8 mg) ’於室溫下攪拌1 8小時。向反應液中添加飽和NaHC〇3 水溶液，以氯仿萃取後，將有機層以無水Na2s〇yK溶液乾 燥，進行濃縮。將殘渣以矽膠層析法（己烷··乙酸乙酯 =6 : 4)進行精製，獲得標題化合物（88〇 mg)。 'H-NMR (CDC13) δ : 1.51 (9Η, s)? 1.57 (9H5 s)5 2.98-3.02 籲（2H，m)，3.79-3.84 (2H，m)，4·55 (2H，d，J=6.1 Hz)，4.75 (2H，s)，6.89 (1H，d，J=3.9 Hz)，7.30 (1H，d，J=3.9 Hz)， 7.33 (1H，d，J=7.7 Hz)，7.69-7.66 (1H，m)，7·77 (1H，dd， J — 7.7，1.6 Hz)，7·87 (1H，dd，J=7.7，1.6 Hz)，10.52 (1H， s)。 MS (ESI) m/z: 633 (M+H)+。 [實施例5] 3_{[(5-氯噻吩-2-羰基）胺基]甲基}-2-[(5-異丙基-4,5,6,7-四氫噻唑并[5,4&lt;]吡啶-2-羰基）胺基]苯甲酸第三 丁酯 129677.doc -129- 200840568 向實施例4之化合物（880 mg)的二氯曱烷（15 ml)懸浮液 中添加TFA(1.5 ml)，於(TC下攪拌5小時。向反應溶液中添 加飽和NaHCCh水溶液，以氣仿萃取後，將有機層以無水 NajO4乾燥，進行濃縮，獲得粗製之氯噻吩_2•羰 基）胺基]甲基}-2-[(4,5,6,7-四氫噻唑并[5,4-c]吡啶_2·羰基） 胺基]苯曱酸第三丁酯（712 mg)。使其溶解於二氯甲烷（5 ml)及丙酮（5 ml)中，添加乙酸（5〇 μ1)及三乙醯氧基硼氫化 鈉（425 mg)，於室溫下攪拌丨小時。向反應液中添加飽和 • NaHC〇3水溶液，以氣仿萃取後，將有機層以無水Na2S〇4 乾餘，進行濃縮。以矽膠層析法（氯仿：甲醇=99 :丨）將所 獲得之殘渣精製，獲得標題化合物（5〇4mg)。 ^-NMR (CDCI3) δ : 1.17 (6H? d, J=6.6 Hz), 1.56 (9H? s)? 2.92-2.95 (2H，m)，2.99-3.06 (3H，m)，3·88 (2H，s)，4,56 (2H，d，J=6.1 Hz)，6.88 (1H，d，J=4.1 Hz)，7.30 (1H，d J=4.1 Hz)，7.32 (1H，t，J=7.8 Hz)，7.73 (1H，t，J=5.9 Hz) 7·76 (1H，dd，J=7.8, 1·7 Hz)，7.85 (1H，dd，J=7.8, 1 7 如 • 1〇·47(1Η，δ)。 ’ ）， MS (ESI) m/z: 575 (M+H)+ 〇 [實施例6] N-(2-{2-[(4-氯苯基）胺甲醯基]乙基}苯基）_5•甲 基-4,5,6,7-四氫噻唑并[5,4-c]吡啶-2-曱醯胺鹽酸鹽 以與實施例1相同的方法，由參考例5丨之化合物獲得標 題化合物。 ^H-NMR (DMSO-d6) δ : 2.67 (2Η, t&gt; J=7.6 Hz), 2.81 (3h, s)，2.91 (2H，t，J=7,6 Hz)，3.08-3.18 (2H，m)，3.21-3·51 129677.doc •130- 200840568 (2H，m)，4.25-4.51 (2H，br)，7.20-7.28 (2H，m)，7.30-7.37 (3H，m)，7.40-7.46 (1H，m)，7·58 (2H，d，J=9.0 Hz)，10.13 (1H，s)，10.51 (1H，s)。 MS (ESI) m/z: 455 (M+H)+。 [實施例7] N-(2-{2-[(4-氯苯基）胺甲醯基]乙基}苯基）·卜異 丙基哌啶-4·甲醯胺鹽酸鹽 以與實施例1相同的方法，將參考例5丨之化合物進行酸 處理後，與1 -異丙基哌啶-4-甲酸鋰鹽縮合而獲得標題化合 ⑩ 物。 H-NMR (DMSO-d6) δ : 1.23, 1.27 (total 6H? each d? J=6.8 Hz)，1.93-2.22 (4H，m)，2·61 (2H，t，J=7.8 Hz)，2.66-2.81 (lH，m)，2.88(2H，t，J=7.8Hz)，2.91-3,02(2H，m)，3,17-3.53(3H，m)，7.12-7.23(2H，m)，7.25-7.39 (4H，m)，7.61-7.68 (2H，m)，9.62, 9.71 (total 2H，each br s)，10.26, 10.28 (total 1H，each br s) 〇 MS (ESI) m/z: 428 (M+H)+。 φ [實施例8] 3-[2-(4-氯苯基胺甲醯基）乙基卜2-[(5-異丙基-4,5,6,7-四氫噻唑并[5,4-c]吼啶-2-羰基）胺基]苯曱酸甲酯 向參考例32之化合物（250 mg)的二氣甲烷（5 ml)懸浮液 中依序添加草醯氯（166 μΐ)、DMF(約〇.〇2 ml)，於室溫下 攪拌3小時。將溶劑於減壓下濃縮後，以真空泵於室溫下 乾燥3小時。將殘渣製成二氣曱烷（5·〇 ^1)懸浮液，添加參 考例58之化合物（I% mg)的二氣甲烷（5 ml)溶液、ΤΈΑ(500 μΐ)，於室溫下攪拌2日。以二氣曱烷稀釋反應液後，添加 129677.doc -131 - 200840568 飽和NaHC〇3水溶液。以二氯曱烷萃取後，以飽和NaCl水 溶液清洗所合併之有機層。以無水Na2s〇4乾燥後，於減壓 下餾去溶劑。將殘渣以使用矽膠之快速層析法（己烷：乙 酸乙酯=4 : 1~&gt;2 : 1— 1 : 1，二氯甲烷··甲醇=50 : 1)進行 精製，獲得標題化合物（116 mg)。 ]H-NMR (CDC13) δ : 1.16 (6H5 d5 J=6.3 Hz)5 2.72 (2H, t? J = 7.6 Hz)，2.85-3.10 (7H，m)，3·83 (3H，s)，3·85 (2H，s)， 7.09 (2H，d，J=8.8 Hz)，7.26 (1H，t，J=7.7 Hz)，7.39 (2H，d， 鲁 J = 8.8 Hz), 7.47 (1H5 d, J=7.7 Hz)? 7.85 (1H5 d, J=7.7 Hz), 8.43 (1H，s)，10.12 (1H，s) 〇 MS (ESI) m/z: 541 (M+H)、 [實施例9] 3-[2-(4-氣苯基胺甲醯基）乙基]_2-[(5-異丙基-4,5,6,7-四氫噻唑并[5,4-c]吼啶-2-羰基）胺基]苯甲酸 向實施例8之化合物（200 mg)的THF(3 ml)溶液中添加 LiOH(ll mg)、水（ΐ·〇 mi)，於室溫下攪拌4日。向反應液 中添加1當量鹽酸（460 μΐ)後，於減壓下濃縮。將殘渣以製 _ 備用TLC進行精製，獲得標題化合物（154 mg)。 ^-NMR (DMSO-d6) δ : 1.08 (6Η, d, J=6.3 Hz)? 2.63 (2H, t? J = 7.6 Hz), 2.86 (4H? br s)? 2.89-3.03 (3H, m), 3.83 (2H, br s)，7·27-7·34 (3H，m)，7.50 (1H，d，J=7,7 Hz)，7·55 (2H，d， J = 8.8 Hz)，7·70 (1H，dd，J=7.7，1.6 Hz)，10.02 (1H，s)， 10.75-1 1.06 (1H，br) 〇 MS (ESI) m/z: 527 (M+H)+。 [實施例10] 4-[2-(4_氯苯基胺曱醯基）乙基]_3_[(5_異丙基_ 129677.doc -132- 200840568 4,5,6,7_四氫噻唑并[5,4-c]吡啶-2-羰基）胺基]苯甲酸甲酯 以與實施例3相同的方法，將參考例6丨之化合物與參考 例3 2之化合物合而獲得標題化合物。 W-NMR (CDC13) δ : 1.17 (6H，d，J=6.6 Ηζ)，2·72 (2H，t， J = 7.2 Hz)，2,86-3.06 (5H，m)，3·12 (2H，t，J=7.2 Hz)，3·88 (2H，br s)，3.89 (3H，s)，7·21 (2H，d J=8.8 Hz)，7·34 (1H，d J=8.0 Hz)，7·38 (2H，d，J=8.8 Hz)，7·61 (1H，s)，7.84 (1H， dd，J-8.0，1·5 Hz)，8·35 (1H，d，J=1.5 Hz)，9·37 (1H，s)。 • MS (ESI) m/z: 541 (M+H)+。 [實施例11] 4-[2-(4-氣苯基胺曱醯基）乙基]-3_[(5_異丙基_ 4,5,6,7-四氫噻唑并[5,4&lt;]吡啶-2-羰基）胺基]苯甲酸 向實施例10之化合物（137 mg)的二ρ号烧（5 ml)懸浮液中 添加1當量LiOH水溶液（278 μΐ)，於室溫下擾拌14小時。添 加水（1 ml)，於40°C下攪拌23小時。向反應液中追加1當量 LiOH水溶液（125 μΐ)，於40°C下攪拌24小時。添加1當量鹽 酸（403 μΐ)後，於減壓下濃縮。將殘渣以製備用TLC進行精 W 製後，添加乙醇（2 ml)，濾取不溶物，以真空泵乾燥，獲 得標題化合物（73 mg)。 W-NMR (DMSO-d6) δ : 1·08 (6H，d，J=6，l Ηζ)，2·69 (2H，t， J=7.2 Hz)，2·85 (4H，br s)，2.92-3,04 (3H，m)，3·83 (2H，s)， 7·32 (2H，d，J=8.1 Hz)，7.46 (1H，d，J=8.1 Hz)，7.56 (2H，d， J=8.1 Hz)，7·77 (1H，d，J=8.1 Hz)，8.03，8·05 (total 1H， each s)，10.06 (1H，s)，10.46 (1H，s)，12.84-13.03 (1H， br) 〇 129677.doc -133- 200840568 MS (ESI) m/z: 527 (M+H)+ 〇 [實施例12] 4-[2-(4·氯苯基胺甲醯基）乙基]_3-[(5·曱基· 4,5,6,7-四氫噻唑并[5,4-(：]吡啶-2-羰基）胺基]苯甲酸甲酯 以與實施例3相同的方法，將參考例61之化合物與5-甲 基-4,5,6,7-四氫噻唑并[5,4-c]吼啶-2-甲酸鹽酸鹽縮合而獲 得標題化合物。 lH-NMR (CDC13) δ : 2.53 (3H? s)5 2.71 (2H? t? J=7.1 Hz)5 2.79-2.88 (2H，m)，2.92-3,00 (2H，m)，3.08 (2H，t，J”」The combined organic layer was washed with a NaC 1 aqueous solution. After drying over anhydrous Na 2 S 4 , the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography ( methylene chloride: EtOAc: EtOAc: EtOAc: EtOAc) W-NMR (CDC13) δ ·· 1·46 (9H, s), 2·53 (3H, s), 2.86 (2H, t, J=5.9 Ηζ), 3.00 (2Η, t, J=5.9 Ηζ) ,3·76 (2Η, s), 4·54 (2Η, d, J=6.1 Ηζ), 4·57 (2Η, s), 6·78-6·84 (1Η, m), 6·86 ( 1Η,d, J=3.9 Ηζ), 7.21-7.27 (2Η,m),7·31 (1Η,d,J=3,9 Ηζ),7·79 129677.doc -128- 200840568 (1H,t, J=6, l Hz), 9.33 (1H, s). MS (ESI) m/z: 577 (M+H)+. [Example 4] 2-( {[2-(T-butoxycarbonyl)-6- {[(5-athiophen-2-yl)amino]methyl}phenyl]amino}carbonyl)- 4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-5-carboxylic acid tert-butyl ester gives 5-(t-butoxymethyl)-4,5,6, 7-Tetrahydropurine and [5,4-c] ° lithium salt of sigmaidine-2-carboxylate (J· Med_Chem. 2004, 47, 5167) (791 mg) suspended in digas (10 ml) In pyridine (1 ml), sulfoxide 10 (294 μM) and DMF (1 drop) were added at 〇 ° C, and the mixture was stirred at room temperature for 2 hours. The reaction solution was again cooled to 0 〇'. Add the compound of Reference Example 31 (5〇〇111§) and 〇]\4? (45.8 mg) was stirred at room temperature for 18 hours. A saturated aqueous solution of NaHC〇3 was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous Na?s? The residue was purified by EtOAc (EtOAc:EtOAc) 'H-NMR (CDC13) δ : 1.51 (9Η, s)? 1.57 (9H5 s)5 2.98-3.02 (2H, m), 3.79-3.84 (2H, m), 4·55 (2H, d, J =6.1 Hz), 4.75 (2H, s), 6.89 (1H, d, J = 3.9 Hz), 7.30 (1H, d, J = 3.9 Hz), 7.33 (1H, d, J = 7.7 Hz), 7.69- 7.66 (1H, m), 7·77 (1H, dd, J — 7.7, 1.6 Hz), 7·87 (1H, dd, J=7.7, 1.6 Hz), 10.52 (1H, s). MS (ESI) m/z: 633 (M+H)+. [Example 5] 3_{[(5-chlorothiophene-2-carbonyl)amino]methyl}-2-[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5, 4&lt;]pyridine-2-carbonyl)amino]benzoic acid tert-butyl ester 129677.doc -129- 200840568 To a suspension of the compound of Example 4 (880 mg) in dichloromethane (15 ml) was added TFA ( 1.5 ml), and stirred for 5 hours under TC. A saturated aqueous solution of NaHCCh was added to the reaction solution, and the organic layer was dried over anhydrous NajO4 and concentrated to give a crude chlorothiophene-2-carbonyl group. Methyl}-2-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine_2.carbonyl)amino]benzoic acid tert-butyl ester (712 mg). This was dissolved in dichloromethane (5 ml) and acetone (5 ml), and acetic acid (5 〇 μ1) and sodium triethoxy hydride hydride (425 mg) were added thereto, and the mixture was stirred at room temperature for hr. Saturated • NaHC〇3 aqueous solution was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous Na? The residue obtained was purified by EtOAc (EtOAc:MeOH:MeOH: ^-NMR (CDCI3) δ : 1.17 (6H? d, J=6.6 Hz), 1.56 (9H? s)? 2.92-2.95 (2H, m), 2.99-3.06 (3H, m), 3.88 (2H , s), 4, 56 (2H, d, J = 6.1 Hz), 6.88 (1H, d, J = 4.1 Hz), 7.30 (1H, d J = 4.1 Hz), 7.32 (1H, t, J = 7.8) Hz), 7.73 (1H, t, J=5.9 Hz) 7.76 (1H, dd, J=7.8, 1·7 Hz), 7.85 (1H, dd, J=7.8, 1 7 eg • 1〇·47 (1Η, δ). ' ), MS (ESI) m/z: 575 (M+H) + 〇 [Example 6] N-(2-{2-[(4-chlorophenyl)aminecarboxamide ]ethyl}phenyl)_5•methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-indoleamine hydrochloride in the same manner as in Example 1, The title compound was obtained from the compound of the title compound. ^H-NMR (DMSO-d6) δ : 2.67 (2Η, t&gt; J=7.6 Hz), 2.81 (3h, s), 2.91 (2H, t, J=7,6 Hz), 3.08-3.18 (2H, m), 3.21-3·51 129677.doc •130- 200840568 (2H,m), 4.25-4.51 (2H,br), 7.20-7.28 (2H,m),7.30-7.37 (3H,m),7.40- 7.46 (1H, m), 7.58 (2H, d, J = 9.0 Hz), 10.13 (1H, s), 10.51 (1H, s). MS (ESI) m/z: 455 (M+H)+. [Example 7] N-(2-{2-[(4-chlorophenyl)aminemethanyl]ethyl}phenyl)·iisopropylpiperidine-4·carbamide hydrochloride In the same manner as in Example 1, the compound of Reference Example 5 was subjected to an acid treatment, and then condensed with lithium salt of 1-isopropylpiperidine-4-carboxylate to obtain the title compound. H-NMR (DMSO-d6) δ: 1.23, 1.27 (total 6H? each d? J=6.8 Hz), 1.93-2.22 (4H, m), 2.61 (2H, t, J = 7.8 Hz), 2.66 -2.81 (lH,m),2.88(2H,t,J=7.8Hz),2.91-3,02(2H,m),3,17-3.53(3H,m),7.12-7.23(2H,m) , 7.25-7.39 (4H,m), 7.61-7.68 (2H,m), 9.62, 9.71 (total 2H,each br s),10.26, 10.28 (total 1H,each br s) 〇MS (ESI) m/z : 428 (M+H)+. φ [Example 8] 3-[2-(4-Chlorophenylaminocarbamimidyl)ethyl b 2-[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5, 4-c]Acridine-2-carbonyl)amino]benzonic acid methyl ester To a suspension of the compound of Reference Example 32 (250 mg) in di-methane (5 ml), oxalyl chloride (166 μM) was added sequentially. DMF (about 〇. 2 ml) was stirred at room temperature for 3 hours. The solvent was concentrated under reduced pressure and dried with a vacuum pump at room temperature for 3 hr. The residue was made into a suspension of dioxane (5·〇^1), and a solution of the compound of Example 58 (I% mg) in di-methane (5 ml), hydrazine (500 μM) was stirred at room temperature. 2nd. After diluting the reaction mixture with dioxane, a 129677.doc -131 - 200840568 saturated NaHC〇3 aqueous solution was added. After extraction with dichloromethane, the combined organic layers were washed with a saturated aqueous solution of NaCl. After drying over anhydrous Na 2 〇 4 , the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (hexane: ethyl acetate = 4 : 1 to &gt; 2 : 1 - 1 : 1, methylene chloride, methanol = 50: 1) to give the title compound ( 116 mg). ]H-NMR (CDC13) δ : 1.16 (6H5 d5 J=6.3 Hz) 5 2.72 (2H, t? J = 7.6 Hz), 2.85-3.10 (7H, m), 3·83 (3H, s), 3 ·85 (2H, s), 7.09 (2H, d, J = 8.8 Hz), 7.26 (1H, t, J = 7.7 Hz), 7.39 (2H, d, Lu J = 8.8 Hz), 7.47 (1H5 d, J=7.7 Hz)? 7.85 (1H5 d, J=7.7 Hz), 8.43 (1H, s), 10.12 (1H, s) 〇MS (ESI) m/z: 541 (M+H), [Example 9 3-[2-(4-Phenylaminocarbamoyl)ethyl]_2-[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]indole] To a solution of the compound of Example 8 (200 mg) in THF (3 ml), LiOH (ll mg), water ( ΐ·〇mi), and stirred at room temperature 4 day. After adding 1 equivalent of hydrochloric acid (460 μM) to the reaction mixture, the mixture was concentrated under reduced pressure. The residue was purified by preparative EtOAc (EtOAc) ^-NMR (DMSO-d6) δ : 1.08 (6Η, d, J=6.3 Hz)? 2.63 (2H, t? J = 7.6 Hz), 2.86 (4H? br s)? 2.89-3.03 (3H, m) , 3.83 (2H, br s), 7·27-7·34 (3H, m), 7.50 (1H, d, J=7, 7 Hz), 7·55 (2H, d, J = 8.8 Hz), 7·70 (1H, dd, J=7.7, 1.6 Hz), 10.02 (1H, s), 10.75-1 1.06 (1H, br) 〇MS (ESI) m/z: 527 (M+H)+. [Example 10] 4-[2-(4-Chlorophenylaminoindenyl)ethyl]_3_[(5-isopropyl-129677.doc-132- 200840568 4,5,6,7-tetrahydrogen The thiazolo[5,4-c]pyridine-2-carbonyl)amino]benzoic acid methyl ester was combined with the compound of Reference Example 3 2 in the same manner as in Example 3 to give the title compound. . W-NMR (CDC13) δ : 1.17 (6H,d,J=6.6 Ηζ), 2·72 (2H,t, J = 7.2 Hz), 2,86-3.06 (5H,m),3·12 (2H ,t,J=7.2 Hz),3·88 (2H,br s),3.89 (3H,s),7·21 (2H,d J=8.8 Hz),7·34 (1H,d J=8.0 Hz ),7·38 (2H,d,J=8.8 Hz),7·61 (1H,s),7.84 (1H, dd,J-8.0,1·5 Hz),8·35 (1H,d,J =1.5 Hz), 9·37 (1H, s). • MS (ESI) m/z: 541 (M+H)+. [Example 11] 4-[2-(4-Phenylaminoindenyl)ethyl]-3_[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4&lt;;] Pyridin-2-carbonyl)amino]benzoic acid To a suspension of the compound of Example 10 (137 mg) in a mixture of 2 g (5 ml) was added 1 eq. Mix for 14 hours. Water (1 ml) was added and stirred at 40 ° C for 23 hours. One equivalent of a LiOH aqueous solution (125 μM) was added to the reaction mixture, and the mixture was stirred at 40 ° C for 24 hours. After adding 1 equivalent of hydrochloric acid (403 μM), it was concentrated under reduced pressure. After the residue was purified by TLC, ethyl alcohol (2 ml) was added, and the insoluble material was filtered, and dried to give the title compound (73 mg). W-NMR (DMSO-d6) δ : 1·08 (6H, d, J=6, l Ηζ), 2·69 (2H, t, J = 7.2 Hz), 2·85 (4H, br s), 2.92-3,04 (3H,m),3·83 (2H,s), 7·32 (2H,d,J=8.1 Hz), 7.46 (1H,d,J=8.1 Hz), 7.56 (2H, d, J=8.1 Hz), 7·77 (1H, d, J=8.1 Hz), 8.03, 8·05 (total 1H, each s), 10.06 (1H, s), 10.46 (1H, s), 12.84 -13.03 (1H, br) 〇 129677.doc -133- 200840568 MS (ESI) m/z: 527 (M+H) + 〇 [Example 12] 4-[2-(4·Chlorophenylaminecarboxamide) Ethyl]ethyl]_3-[(5·decyl·4,5,6,7-tetrahydrothiazolo[5,4-(:]pyridine-2-carbonyl)amino]benzoic acid methyl ester In the same manner as in Example 3, the compound of Reference Example 61 was condensed with 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]acridin-2-carboxylate. The title compound. lH-NMR (CDC13) δ: 2.53 (3H? s)5 2.71 (2H? t? J=7.1 Hz)5 2.79-2.88 (2H,m), 2.92-3,00 (2H,m), 3.08 (2H,t,J""

Hz)，3·73 (2H，br s)，3·86 (3H，s)，7·19 (2H，d，J=8.8 Hz)， 7·28 (1H，d，J=8.1 Hz)，7·39 (2H，d，Hz)，7·79 (iH， dd，J = 8.1，1.5 Hz)，8.06-8.12 (1H，br)，8·37 (1H，d，5 Hz)，9·59 (1H，s)。 MS (ESI) m/z: 513 (M+H)+。 [實施例13] 4-[2-(4-氣苯基胺曱醯基）乙基]-3-[(5、甲基 4,5，6,7-四氫噻唑并[5，4-c]吼啶-2-羰基）胺基]苯甲酸 以與實施例9相同的方法，由實施例12之化合物獲得榜、 題化合物。 λ W-NMR (DMSO-d6) δ : 2·41 (3Η，s)，2.69 (2Η，t，2Hz),3·73 (2H,br s),3·86 (3H,s),7·19 (2H,d,J=8.8 Hz), 7·28 (1H,d,J=8.1 Hz), 7·39 (2H, d, Hz), 7.79 (iH, dd, J = 8.1, 1.5 Hz), 8.06-8.12 (1H, br), 8.37 (1H, d, 5 Hz), 9· 59 (1H, s). MS (ESI) m/z: 513 (M+H)+. [Example 13] 4-[2-(4-Acetylaminoindenyl)ethyl]-3-[(5,methyl 4,5,6,7-tetrahydrothiazolo[5,4- c] acridine-2-carbonyl)amino]benzoic acid The title compound was obtained from the compound of Example 12 in the same manner as in Example 9. λ W-NMR (DMSO-d6) δ : 2·41 (3Η, s), 2.69 (2Η, t, 2

Hz)，2·77 (2H，t，J=5.7 Hz)，2.89 (2H，t，J=5.7 Hz)，2 97 (2H，t，J=7.2 Hz)，3.70 (2H，s)，7·32 (2H，d，J=8.8 Hz、1 Λ Λ43 (1H，d，J=8.1 Hz)，7·57 (2H，d，J = 8,8 Hz)，7·76 J=8.1，1·7 Hz)，7.98-8.03 (1H，m)，10·09 (1H，s)，1〇·48 ’ s)。 H’ MS (ESI) m/z: 499 (M+H)+ 0 129677.doc -134- 200840568 [實施例 14] 4_[2_(5_氯。 ^.4 5 6 7 ® ^ 疋-2·基胺甲醯基）乙基]-3-[(5_甲 丞5，：)，0，’-四虱噻唑并 g, ， e]°比咬-2-羰基）胺基]苯甲酸曱 以與實施例3相同的方法， 基-4,5,6,7-四氫噻唑并[5,4叫 得標題化合物。 將參考例6 3之化合物與5 -曱 0比啶-2_甲酸鹽酸鹽縮合而獲 ^-NMR (CDC13) δ * 2 54 • ·54 (3Η，s)，2.78-2.89 (4Η，m)，2·99 (2H? t, 1=5.6 Hz). 3 14 fjijHz), 2·77 (2H, t, J = 5.7 Hz), 2.89 (2H, t, J = 5.7 Hz), 2 97 (2H, t, J = 7.2 Hz), 3.70 (2H, s), 7 ·32 (2H,d,J=8.8 Hz, 1 Λ Λ43 (1H,d,J=8.1 Hz),7·57 (2H,d,J=8,8 Hz),7·76 J=8.1,1 · 7 Hz), 7.98-8.03 (1H, m), 10·09 (1H, s), 1〇·48 's). H' MS (ESI) m/z: 499 (M+H) + 0 129677.doc -134 - 200840568 [Example 14] 4_[2_(5_chloro. ^.4 5 6 7 ® ^ 疋-2·胺 醯 ) ) ) 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 咬 咬 咬 咬 咬 咬 咬 咬 咬 -2- 羰 羰 羰 羰 羰 羰 羰 羰 羰 羰 羰 羰 羰 羰 羰 羰 羰 羰 羰In the same manner as in Example 3, the group - 4,5,6,7-tetrahydrothiazolo[5,4 was obtained as the title compound. The compound of Reference Example 63 was condensed with 5-indole-2-pyridin-2-formate to obtain ^-NMR (CDC13) δ * 2 54 • · 54 (3 Η, s), 2.78-2.89 (4 Η, m), 2·99 (2H? t, 1=5.6 Hz). 3 14 fjij

• 4 (2H，t，J=7.2 Hz)，3.76 (2H，s)，3.89 (3H, s)? 7.34 (in； d5 J-g.l Hz)5 7.63 (1H9 dd? J-8.8, 2.7 HZ)，7·85 (1H，dd，J:8·1，！·5 Hz)，7.96 (1H，br s)，8.15 (1H， d? J=8.8 Hz)? 8.18 (1H5 d5 J=2.7 Hz)? 8.49 (1H, d, J^i.5 Hz)，9·58 (1H，s)。 MS (ESI) m/z: 514 (M+H)+。 [實施例15] 4-[2-(5_氯吡啶·2·基胺甲醯基）乙基]_3_[(5_甲 基-4,5,6,7-四氫噻唑并[5,4-cp比啶羰基）胺基]苯曱酸 以與實施例9相同的方法，由實施例14之化合物獲得標 題化合物。 iH-NMR (DMSO-d6) δ ·· 2.41 (3H，s)，2·72-2·81 (4H，m)， 2·85-2·92 (2H，m)，2.96 (2H，t，J=7.3 Hz)，3.70 (2H, s)， 7.39 (1H，d，J=8.0 Hz)，7.76 (1H，d，J=8.0 Hz)，7·86 (1H， dd，J=9.〇, 2·7 Hz)，7·98 (1H，br s)，8.07 (1H，d，J=9.0 Hz)， 8·32 (1H，d，J=2,7 Hz)，10.41 (1H，s)，10.68 (1H，s)。 MS (ESI) m/z: 500 (M+H)+。 [實施例16]4-[2-(5-氣1?比'{7定-2-基胺曱&amp;1&amp;基）乙基]-3*-[(5-異丙 129677.doc -135- 200840568 基-4,5,6,7-四 酯 氫嗟唾 开[5,4&lt;]吼啶羰基）胺基]苯曱酸甲 以與實施例3相同的方沐 时— ^ 去’將參考例63之化合物與參考 例32之化合物縮合而獲得標題化合物。 'H-NMR (CDCls) δ ； 1 17 ^ ίΛΊ (6Η, d? 1=6.6 Hz)5 2.81 (2H? t? 风2Hz)，2.86-3.07 (5H，m) 3l3(2H，t，j=72Hz) 388 (2H, br s), 3.89 (3H, s), 7.34 (1H? d? J=8.1 Hz), 7.63 (1H,• 4 (2H, t, J = 7.2 Hz), 3.76 (2H, s), 3.89 (3H, s)? 7.34 (in; d5 Jg.l Hz) 5 7.63 (1H9 dd? J-8.8, 2.7 HZ) ,7·85 (1H,dd,J:8·1,!·5 Hz), 7.96 (1H, br s), 8.15 (1H, d? J=8.8 Hz)? 8.18 (1H5 d5 J=2.7 Hz) 8.49 (1H, d, J^i.5 Hz), 9·58 (1H, s). MS (ESI) m/z: 514 (M+H)+. [Example 15] 4-[2-(5-chloropyridine·2.ylaminocarbamoyl)ethyl]_3_[(5-methyl-4,5,6,7-tetrahydrothiazolo[5, 4-cp-pyridylcarbonyl)amino]benzoic acid The title compound was obtained from the compound of Example 14 in the same manner as in Example 9. iH-NMR (DMSO-d6) δ ·· 2.41 (3H, s), 2·72-2·81 (4H, m), 2·85-2·92 (2H, m), 2.96 (2H, t, J=7.3 Hz), 3.70 (2H, s), 7.39 (1H, d, J=8.0 Hz), 7.76 (1H, d, J=8.0 Hz), 7·86 (1H, dd, J=9.〇 , 2·7 Hz), 7·98 (1H, br s), 8.07 (1H, d, J=9.0 Hz), 8·32 (1H, d, J=2, 7 Hz), 10.41 (1H, s ), 10.68 (1H, s). MS (ESI) m/z: 500 (M+H)+. [Example 16] 4-[2-(5-gas 1? ratio '{7-di-2-amine oxime &amp;1&amp;yl)ethyl]-3*-[(5-isopropyl 129677.doc - 135- 200840568 yl-4,5,6,7-tetraester hydroquinone saliva [5,4&lt;] acridinecarbonyl)amino]benzoic acid A in the same manner as in Example 3 - ^ go ' The compound of Reference Example 63 was condensed with the compound of Reference Example 32 to give the title compound. 'H-NMR (CDCls) δ ; 1 17 ^ ΛΊ (6Η, d? 1 = 6.6 Hz) 5 2.81 (2H? t? wind 2Hz), 2.86-3.07 (5H, m) 3l3 (2H, t, j= 72Hz) 388 (2H, br s), 3.89 (3H, s), 7.34 (1H? d? J=8.1 Hz), 7.63 (1H,

dd，J-9.0, 2.4 Hz)，7·85 (1H，dd，J=8.1，1·7 Hz)，7·99 (1H， s)，8.15 (1H，d，J=9.〇 Hz)，8·18 (1H，d，J=2.4 Hz)，8.50 (1H，d，J=1.7 Hz)，9·56 (1H，s)。 MS (ESI) m/z: 542 (M+H)+ 〇 [實施例17] 4_[2_(5-氣吡啶-2-基胺甲醯基）乙基]-3-[(5_異丙 基-4,5,6,7-四氫噻唑并[5,4-c]吡啶-2-羰基）胺基]苯甲酸 以與實施例9相同的方法，由實施例16之化合物獲得標 題化合物。 W-NMR (DMSO-d6) δ ·· 1·〇7 (6H，d，J=6.3 Hz)，2.76 (2H，t， J = 7.3 Hz)，2·84 (4H，br s)，2.91-3.02 (3H，m)，3·82 (2H，s)， 7·42 (1H, d，J=8.1 Hz)，7.76 (1H，d，J=8.1 Hz)，7·86 (1H， dd，J=9.0，2.7 Hz)，8.01 (1H，s)，8.06 (1H，d，J=9.〇 Hz)， 8·32 (1H，d，J=2.7 Hz)，10.41 (1H，s)，10·67 (1H，s)。 MS (ESI) m/z: 528 (M+H)+。 [實施例18] 4-{2-[(4-氟苯基）胺甲醯基]乙基卜3-[(5_異丙 基-4,5,6,7-四氫嗟嗤并[5,4-〇]11比咬-2-羧基）胺基]笨甲酸 曱酯 129677.doc -136- 200840568 向參考例66之化合物（123 mg)的DMF(5 ml)懸浮液中、、泰 加HOBt(36 mg)、EDC(99 mg)，於60°C下攪拌3分鐘。向反 應液中添加4-氟苯胺（48 μΐ)，於60°C下攪拌16小時。將反 應液於減壓下濃縮後，向殘渣中添加二氣甲烷、飽和 NaHCC^水溶液。以二氯甲烷萃取後，以飽和NaCl/Jc溶液 清洗所合併之有機層。以無水Na2S〇4乾燥後，於減壓下館 去溶劑。將殘渣以使用矽膠之快速層析法（二氣甲烷：甲 醇=100 : 1— 50 : 1— 30 : 1)進行精製，獲得標題化合物 (76 mg) 〇 'H-NMR (CDC13) δ : 1.17 (6H，d，J=6,6 Ηζ)，2·71 (2H，t， J=7.1 Hz)，2·87-3·08 (5H，m)，3·11 (2H，t，J=7.1 Hz)，3·87 (2H，s)，3.88 (3H，s)，6.90-6.99 (2H，m)，7.33 (1H，d，J=8.1 Hz)，7·34-7·42 (2H，m)，7·73 (1H，br s)，7.83 (1H，dd， J=8.1，1.5 Hz)，8·38 (1H，d，J=1.5 Hz)，9.45 (1H，s)。 MS (ESI) m/z: 525 (M+H)+。 [實施例19] 4-{2-[(4-氟苯基）胺甲醯基]乙基卜3_[(5-異丙 基-4,5,6,7-四氫噻唑并[5,4-cp比啶-2-羰基）胺基]苯甲酸鹽 酸鹽 以與實施例9相同的方法，由實施例1 8之化合物’獲得 標題化合物。 ^-NMR (DMS〇-d6) δ : 1.38 (6Η, br s)9 2.70 (2H, t? J=7.〇Dd, J-9.0, 2.4 Hz), 7.85 (1H, dd, J=8.1, 1·7 Hz), 7·99 (1H, s), 8.15 (1H, d, J=9.〇Hz) , 8.18 (1H, d, J = 2.4 Hz), 8.50 (1H, d, J = 1.7 Hz), 9.56 (1H, s). MS (ESI) m/z: 542 (M+H) + 〇 [EXAMPLE 17] 4_[2_(5-apyridin-2-ylaminemethanyl)ethyl]-3-[(5-isopropyl Base-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl)amino]benzoic acid The title compound was obtained from the compound of Example 16 in the same manner as in Example 9. . W-NMR (DMSO-d6) δ ·· 1·〇7 (6H,d,J=6.3 Hz), 2.76 (2H, t, J = 7.3 Hz), 2·84 (4H, br s), 2.91 3.02 (3H,m),3·82 (2H,s), 7·42 (1H, d,J=8.1 Hz), 7.76 (1H,d,J=8.1 Hz),7·86 (1H, dd, J=9.0, 2.7 Hz), 8.01 (1H, s), 8.06 (1H, d, J=9.〇Hz), 8·32 (1H, d, J=2.7 Hz), 10.41 (1H, s), 10.67 (1H, s). MS (ESI) m/z: 528 (M+H)+. [Example 18] 4-{2-[(4-fluorophenyl)aminemethanyl]ethyl b-3-[(5-isopropyl-4,5,6,7-tetrahydroindole[ 5,4-〇]11-bito-2-carboxy)amino] benzoic acid oxime ester 129677.doc -136- 200840568 To a suspension of reference compound 66 (123 mg) in DMF (5 ml), HOBt (36 mg) and EDC (99 mg) were added and stirred at 60 ° C for 3 minutes. 4-Fluoroaniline (48 μM) was added to the reaction mixture, and the mixture was stirred at 60 ° C for 16 hours. After the reaction mixture was concentrated under reduced pressure, a mixture of di-methane and saturated NaHCC^ was added to the residue. After extracting with dichloromethane, the combined organic layers were washed with a saturated NaCl/Jc solution. After drying with anhydrous Na2S〇4, the solvent was removed under reduced pressure. The residue was purified by flash chromatography (dichloromethane: methanol = 100 : 1 - 50 : 1 - 30 : 1) to give the title compound (76 mg) 〇 'H-NMR (CDC13) δ: 1.17 (6H,d,J=6,6 Ηζ), 2·71 (2H,t, J=7.1 Hz), 2·87-3·08 (5H,m),3·11 (2H,t,J= 7.1 Hz), 3·87 (2H, s), 3.88 (3H, s), 6.90-6.99 (2H, m), 7.33 (1H, d, J = 8.1 Hz), 7·34-7·42 (2H , m), 7.73 (1H, br s), 7.83 (1H, dd, J = 8.1, 1.5 Hz), 8.38 (1H, d, J = 1.5 Hz), 9.45 (1H, s). MS (ESI) m/z: 525 (M+H)+. [Example 19] 4-{2-[(4-Fluorophenyl)amine-carbamoyl]ethyl b- 3-[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5, 4-cpbipyridin-2-carbonyl)amino]benzoic acid hydrochloride The title compound was obtained from the compound of Example 18 in the same manner as in Example 9. ^-NMR (DMS〇-d6) δ : 1.38 (6Η, br s)9 2.70 (2H, t? J=7.〇

Hz)，2·98 (2H，t，J=7.3 Hz)，3.05-3.53 (3H，m)，3.59-3.88 (2H，m)，4·4(Μ·82 (2H，m)，7,07-7·16 (2H，m)5 7·48 (1H，d5 J=8,0 Hz)，7.53-7.62 (2H，m)，7.79 (1H，dd，J=8.2, 1_6 Hz)， 129677.doc -137- 200840568 8.02 (1H，d，J=l，7 Hz), 10.06-10.27 (1H，m)，10.69 (1H，s)， 1 1.46-1 1.67 (1H，br)，12·83-13·14 (1H，b〇。 MS (ESI) m/z: 511 (M+H)+。 [實施例20] 4-{2-[(4-溴苯基）胺甲醯基]乙基卜3-[(5-異丙 基-4,5,6,7-四氫噻唑并[5,4-〇]吡啶-2-羰基）胺基]苯曱酸甲 以與實施例1 8相同的方法，將參考例66之化合物與4-溴 苯胺縮合而獲得標題化合物。Hz), 2·98 (2H, t, J = 7.3 Hz), 3.05-3.53 (3H, m), 3.59-3.88 (2H, m), 4·4 (Μ·82 (2H, m), 7, 07-7·16 (2H,m)5 7·48 (1H,d5 J=8,0 Hz), 7.53-7.62 (2H,m), 7.79 (1H,dd,J=8.2, 1_6 Hz), 129677 .doc -137- 200840568 8.02 (1H,d,J=l,7 Hz), 10.06-10.27 (1H,m),10.69 (1H,s), 1 1.46-1 1.67 (1H,br),12·83 -13·14 (1H, b. MS (ESI) m/z: 511 (M+H)+. [EXAMPLE 20] 4-{2-[(4-bromophenyl)aminemethanyl] Keb 3-[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-indolyl]pyridine-2-carbonyl)amino]benzoic acid A and Example 18 In the same manner, the compound of Reference Example 66 was condensed with 4-bromoaniline to give the title compound.

]H-NMR (CDC13) δ : 1.16 (6H5 d? J=6.6 Hz)5 2.70 (2H? t5]H-NMR (CDC13) δ : 1.16 (6H5 d? J=6.6 Hz) 5 2.70 (2H? t5

J=7.1 Hz)，2·85-3·12 (7H，m)，3·85 (2H，br s)，3·86 (3H，s) 7.27 (1H，d，J=8.1 Hz)，7·33 (4H，s)，7·78 (1H，dd，㈣·1 1.5 Hz)，8·11 (1H，br s)，8.37 (1H，d，J=1.5 Hz)，9.52 (1H s) 0 MS (ESI) m/z: 585 (M+H)+ 0 [實施例21] 4-{2-[(4-溴苯基）胺甲醯基]乙基卜3·[(5_異丙 基-4,5,6,7-四氫噻唑并[5,4-e]吡啶-2-羰基）胺基]笨甲酸_ 酸鹽 以與實施例9相同的方法，由實施例20之化合物獲得脊、 題化合物。 ^-NMR (DMSO-d6) δ : 1.38 (3H5 d? J=6.6 Hz), I.39 UH，d，J=7.1 Hz), 2·85-3·12 (7H, m), 3·85 (2H, br s), 3·86 (3H, s) 7.27 (1H, d, J=8.1 Hz), 7 · 33 (4H, s), 7·78 (1H, dd, (4)·1 1.5 Hz), 8·11 (1H, br s), 8.37 (1H, d, J = 1.5 Hz), 9.52 (1H s) 0 MS (ESI) m/z: 585 (M+H) + 0 [EXAMPLE 21] 4-{2-[(4-bromophenyl)aminemethanyl]ethyl b. Propyl-4,5,6,7-tetrahydrothiazolo[5,4-e]pyridine-2-carbonyl)amino]benzoic acid _ acid salt in the same manner as in Example 9, from Example 20 The compound acquires a ridge, a compound. ^-NMR (DMSO-d6) δ : 1.38 (3H5 d? J = 6.6 Hz), I.39 UH,d,

J=6.3 Hz)，2·72 (2H，t，J=7.2 Hz)，2.98 (2H，t，J&gt;7 0 T 』Hz)， 3·06-3·22 (1H，m)，3.25-3.50 (2H，m)，3.61-3.84 ㈣，m)， 4·45·4,60 (1H，m)，4·63-4·78 (1H，m)，7·45 (2H，d5 j、8 Hz)，7.48 (1H，d，J=8.0 Hz)，7.55 (2H，br d，J=8.8 Hz) 7 ? 129677.doc -138· 200840568 (1H，dd，J=8.0, 1·7 Hz)，8.02 (1H，d，卜 1·7 Ηζ)，ΐ〇·19_ 10.34 (1H, br)? 10.67 (1H5 s)5 11.43^11.84 (1H? br), 12.82^ 13.13 (1H，br)。 MS (ESI) m/z: 571 (M+H)+。 [實施例22] 4-{2-[(4-氯-3-氟苯基）胺甲醯基]乙基卜3_[(5_異 丙基-4,5,6,7-四氫噻唑并[5,4_c]吡啶羰基）胺基]苯甲酸 甲酯 以與實施例18相同的方法，將參考例66之化合物與‘ 氯-3-氟苯胺縮合而獲得標題化合物。 ^-NMR (CDC13) δ : 1.17 (6H5 d5 J^6.6 Hz)? 2.71 (2H? J-7.1 Hz)? 2.89-3.07 (5H, m), 3.10 (2H5 t5 1=7.1 Hz)? 3.89 (5H，s)，6.97-7.04 (1H，m)，7,19-7.25 (1H，m)，7·32 (1H，d， J=7.8 Hz)，7·55 (1H，dd，J=ll.〇，2·2 Hz)，7·83 (1H，dd， J=8.15 1.7 Hz), 7.88 (1H, br s)5 8.30 (1H5 d, J=1.2 Hz), 9.35 (1H，s) 〇 MS (ESI) m/z: 559 (M+H)+。 [實施例23] 4-{2-[(4-氣-3-氟苯基）胺甲醯基]乙基卜3-[(5_異 丙基-4,5,6,7·四氫噻唑并[5,4_c]吡啶·羰基）胺基]苯曱酸 鹽酸鹽 以與實施例9相同的方法，由實施例22之化合物獲得標 題化合物。 H—NMR (DMS〇-d6) δ : 1.34-1.43 (6H，m)，2.73 (2H，t， J-7.2Hz)，2.99(2H，t5J=7,3Hz)，3.08-3,52(3H，m)，3.62-3·85 (2H，m)，4·46-4·61 (1H，m)，4.64-4.79 (1H，m)，7.28-129677.doc -139- 200840568 7·35 (1H，m)，7.45-7.52 (2H，m)5 7.75-7.83 (2H，m)，8,01 (1H，d，卜 1.7 Hz)，10.44-10,56 ⑽，⑷，1〇 67 (1H，s)， 11.31-11.66 (1H，b〇, 12.85-13.17 (1H，br)。 MS (ESI) m/z: 545 (M+H)+ 〇 [實施例24] 4-{2-[(4-溴-3-氟苯基）胺甲醯基]乙基卜3_[(5_異 丙基-4,5,6,7-四氫噻唑并[5,4-c]吡啶_2_羰基）胺基]苯曱酸 甲酯 以與實施例18相同的方法，將參考例66之化合物與4_ 溴-3-氟苯胺縮合而獲得標題化合物。 lH-NMR (CDC13) δ : 1.17 (6H5 d, J^6.6 Hz)5 2.71 (2H5 t5 J = 7.1Hz)，2.87-3.08 (5H，m)，3.11(2H，t，J = 6.8Hz)，3.86-3·91 (2H，m)，3.89 (3H，s)，6·97 (1H，dd，J=8.3，1.7 Hz)， 7·28_7·41 (2H，m)，7.54 (1H，dd，J=l〇.6, 2·1 Hz)，7·84 (1H， dd，卜7·9，1·8 Hz)，7·96 (1H，br s)，8.30 (1H，s)，9·35 (1H， s) 0 MS (ESI) m/z: 603 (M+H)+。 [實施例25] 4-{2-[(4-溴_3-氟苯基）胺甲酿基]乙基卜3 _[(%異 丙基-4,5,6,7-四氫嗟峻并[5,4-c]吼啶-2-羰基）胺基]苯甲酸 鹽酸鹽 以與實施例9相同的方法，由實施例24之化合物獲得標 題化合物。 ^-NMR (DMSO-d6) δ : 1.39 (6H? br s), 2.69-2.78 (2H5 m)5 2·99 (2H，t，J-7,3 Hz)5 3·06,3·57 (3H，m)，3,58-3,87 (2H， m)，4·41-4·81 (2H，m)，7.30 (1H，dd，J=8.8，2·0 Hz)，7.49 129677.doc -140- 200840568J = 6.3 Hz), 2·72 (2H, t, J = 7.2 Hz), 2.98 (2H, t, J &gt; 7 0 T Hz), 3·06-3·22 (1H, m), 3.25- 3.50 (2H, m), 3.61-3.84 (iv), m), 4·45·4, 60 (1H, m), 4·63-4·78 (1H, m), 7·45 (2H, d5 j, 8 Hz), 7.48 (1H, d, J = 8.0 Hz), 7.55 (2H, br d, J = 8.8 Hz) 7 ? 129677.doc -138· 200840568 (1H, dd, J=8.0, 1·7 Hz ), 8.02 (1H, d, Bu 1·7 Ηζ), ΐ〇·19_ 10.34 (1H, br)? 10.67 (1H5 s)5 11.43^11.84 (1H? br), 12.82^ 13.13 (1H, br). MS (ESI) m/z: 571 (M+H)+. [Example 22] 4-{2-[(4-chloro-3-fluorophenyl)aminemethanyl]ethyl b 3_[(5-isopropyl-4,5,6,7-tetrahydrothiazole) And [5,4-c]pyridinecarbonyl)amino]benzoic acid methyl ester The title compound was obtained by condensing the compound of the reference compound 66 with chloro-3-fluoroaniline in the same manner as in Example 18. ^-NMR (CDC13) δ : 1.17 (6H5 d5 J^6.6 Hz)? 2.71 (2H? J-7.1 Hz)? 2.89-3.07 (5H, m), 3.10 (2H5 t5 1=7.1 Hz)? 3.89 (5H , s), 6.97-7.04 (1H, m), 7, 19-7.25 (1H, m), 7.32 (1H, d, J = 7.8 Hz), 7·55 (1H, dd, J=ll. 〇, 2·2 Hz), 7·83 (1H, dd, J=8.15 1.7 Hz), 7.88 (1H, br s)5 8.30 (1H5 d, J=1.2 Hz), 9.35 (1H, s) 〇MS (ESI) m/z: 559 (M+H)+. [Example 23] 4-{2-[(4-Gayl-3-fluorophenyl)aminemethanyl]ethylidene 3-[(5-isopropyl-4,5,6,7·tetrahydro) The title compound was obtained from the compound of Example 22 in the same manner as in Example 9 H-NMR (DMS〇-d6) δ : 1.34-1.43 (6H, m), 2.73 (2H, t, J-7.2Hz), 2.99 (2H, t5J=7,3Hz), 3.08-3,52 (3H , m), 3.62-3·85 (2H, m), 4·46-4·61 (1H, m), 4.64-4.79 (1H, m), 7.28-129677.doc -139- 200840568 7·35 ( 1H,m), 7.45-7.52 (2H,m)5 7.75-7.83 (2H,m),8,01 (1H,d,Bu 1.7 Hz), 10.44-10,56 (10),(4),1〇67 (1H , s), 11.31-11.66 (1H, b〇, 12.85-13.17 (1H, br) MS (ESI) m/z: 545 (M+H) + 〇 [Example 24] 4-{2-[( 4-bromo-3-fluorophenyl)amine-mercapto]ethylidene 3_[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine_2_ Carbonyl)amino]benzoic acid methyl ester The title compound was obtained by condensing the compound of Reference 66 with 4-bromo-3-fluoroaniline in the same manner as in Example 18. lH-NMR (CDC13) δ: 1.17 (6H5 d, J^6.6 Hz)5 2.71 (2H5 t5 J = 7.1Hz), 2.87-3.08 (5H, m), 3.11 (2H, t, J = 6.8Hz), 3.86-3·91 (2H, m), 3.89 (3H, s), 6.97 (1H, dd, J=8.3, 1.7 Hz), 7·28_7·41 (2H, m), 7.54 (1H, dd, J=l〇.6, 2·1 Hz), 7.84 (1H, dd, Bu 7·9, 1·8 Hz), 7·96 (1H, br s) 8.30 (1H, s), 9·35 (1H, s) 0 MS (ESI) m/z: 603 (M+H)+. [Example 25] 4-{2-[(4-bromo-3- Fluorophenyl)amine methyl]ethyl b 3 _[(% isopropyl-4,5,6,7-tetrahydroindenyl[5,4-c]acridin-2-carbonyl)amino The title compound was obtained from the compound of Example 24 in the same manner as in Example 9. NMR (DMSO-d6) δ: 1.39 (6H? br s), 2.69-2.78 (2H5 m ) 5 2·99 (2H, t, J-7, 3 Hz) 5 3·06, 3·57 (3H, m), 3, 58-3, 87 (2H, m), 4·41-4· 81 (2H,m), 7.30 (1H,dd,J=8.8,2·0 Hz),7.49 129677.doc -140- 200840568

(1H，d，J=8.3 Ηζ)，7·56-7·62 (1H，m)，7·74-7·82 (2H 8·01 (1H，d，J=1.7 Hz)，1〇·63 (1H，s)，10·66 (m，s)，u 利’ 11·96 (1H，br)，12.77-13.19 (1H，br) 〇 MS (ESI) iii/z: 589 (M+H)+。 [貫施例26] 4-[2-(5-氣^塞吩-2胃基胺甲酿基）乙基]_3_[(5、芩丙 基·4,5,6,7-四氫噻唑并[5,4-C]吡啶-2·羰基）胺基]苯甲醆第 三丁酯 以與實施例8相同的方法，使由參考例32之化合物所行 生之醯氯與參考例71之化合物反應而獲得標題化合物。何 ^-NMR (CDC13) δ : 1.16 (6Η, d, J=6.3 Hz), 1.56 (9H, s) 2.69 (2H, t, J=7.l Hz), 2.83-3.14 (7H, m), 3.86 (2^ ^ 6.27 (1H, d, J=3.9 Hz), 6.58 (1H, d, J=3.9 Hz), 7.24 (lH, d J = 8.1 Hz), 7.76 (1H, dd, J=8.1, 1.5 Hz), 8.20 (1H, d,(1H, d, J=8.3 Ηζ), 7·56-7·62 (1H, m), 7·74-7·82 (2H 8·01 (1H, d, J=1.7 Hz), 1〇· 63 (1H,s),10·66 (m,s),u 利' 11·96 (1H,br),12.77-13.19 (1H,br) 〇MS (ESI) iii/z: 589 (M+H +) [Example 26] 4-[2-(5-Gas^ephen-2-gastriamine)ethyl]_3_[(5, 芩propyl·4,5,6,7- Tetrahydrothiazolo[5,4-C]pyridine-2.carbonyl)amino]benzilidine tert-butyl ester In the same manner as in Example 8, the chlorine derived from the compound of Reference Example 32 was used. The title compound was obtained by the reaction of the compound of Example 71. NMR (CDC13) δ: 1.16 (6 Η, d, J = 6.3 Hz), 1.56 (9H, s) 2.69 (2H, t, J = 7.l Hz ), 2.83-3.14 (7H, m), 3.86 (2^^ 6.27 (1H, d, J=3.9 Hz), 6.58 (1H, d, J=3.9 Hz), 7.24 (lH, d J = 8.1 Hz) , 7.76 (1H, dd, J=8.1, 1.5 Hz), 8.20 (1H, d,

Hz)，9.32 (1H，br s)，9·34 (1H，s)。 MS (ESI) m/z: 589 (M+H)+。 [實靶例27]4-[2-(5-氣噻吩_2-基胺甲醯基）乙基]-5-[(5_異丙 基-4,5,6,7-四氫噻唑并[5,4_c]吡啶_2_羰基）胺基]苯甲酸鹽 酸鹽 1 向實施例26之化合物（97 mg)的二氯甲烷（1⑹）溶液中添 加4田里鹽g夂一％烷溶液（2.〇 mi)，於室溫下攪拌3日。將 反應液於減麼下濃縮後，向㈣中添加乙酸乙酉旨，濟取固 體。以使用石夕膠之快速層灰幻二氯甲烧：甲醇=2〇: h 1 0 : 1 8 : 1)進行精製 由體中添加水（3 ml)、 ’獲得標題化合物之自由體。向自 1當量鹽酸（4〇0 μΐ)、乙酸乙酯（3 129677.doc -141 . 200840568 ml)，於減壓下濃縮，獲得標題化合物（56 mg)。 W-NMR (DMSO-d6) δ : 1·38 (6H，d，J==5」Hz)，2 71 (2H，、 J = 7.3 Hz)? 2.80-3.60 (5H? m)5 3.62-3.87 (2H? m)? 4.43-4.81 (2H，m)，6·43 (1H，d，Χ2 Hz)，6·84 (1H，d，J=4.2 Hz)， 7.47 (1H, d? J=8.1 Hz)? 7.80 (1H5 dd5 J=8.l, 1.5 Hz), 7.98 (1H，d，J=1.5 Hz)，1〇·65 (1H，s)，1ΐ·〇5-η·35 (1H，卜)， 11.55，11.56 (total 1H，each s)。 MS (ESI) m/z: 533 (M+H)+ 〇 [實施例28] 4-[2-(7-氯4啉_3_基胺曱醯基）乙基]_3_[(5_甲 基-4,5,6,7-四氫噻唑并[5，‘c]吡啶羰基）胺基]苯曱酸第 三丁醋 向參考例74之化合物（1〇7 mg)的DMF(6 ml)溶液中依序 添加水（1 ml)、無水氣化鐵（3)(114 mg)、鋅末（153 mg)， 於室溫下攪拌25分鐘，且於5〇°C下攪拌5分鐘。向反應液 中添加乙酸乙酯，藉由使用氟鎂石進行過濾而過濾去除不 溶物。以乙酸乙酯清洗不溶物，將濾液之有機層分離。將 有機層以水清洗5次，以無水Na2S〇4乾燥。於減壓下顧去 溶劑，獲得粗製之胺。向5-甲基-4,5,6,7-四氫噻唑并[5冬 Μ吼啶-2-甲酸鹽酸鹽（82.4 mg)的二氣甲烷（5 ml)懸浮液中 添加草醯氯（66·7 μΐ)、DMF(1滴），於室溫下攪拌4小時。 將反應液於減壓下濃縮，向殘渣之二氣甲烷（5 ml)溶液中 添加.製之胺的二氯甲烷（3 ml)溶液、ΤΕΑ(49 μΐ)，於室 級下攪:拌3小時。向反應液中添加飽和NaHC〇3水溶液，以 二氯甲烷萃取後，以無水NajO4乾燥。於減壓下餾去溶 129677.doc 142· 200840568 劑，將殘渣以石夕膠管柱層析法(二氯甲烧：甲醇=99… 197 . 3— 489 . 11)進仃精製，獲得粗製之標題化合物。將 其以製備訂LC(二氯甲醇=24:…獲得標題化合 物（9.0 mg)。 Ή-NMR (CDCl3)5:1.57(9H, s), 2.52 (3H, s), 2.84 (2H, t, J=5.9 Hz), 2.94-3.03 (4H, m)} 3.2〇 (2H, t, J=7.2 Hz), 3 75 (2H，s)’ 7.39 (1H，d，Hz)，7 64 (1H，仉 j=8* i 8Hz), 9.32 (1H, br s), 9·34 (1H, s). MS (ESI) m/z: 589 (M+H)+. [Target Example 27] 4-[2-(5-Arothiophene-2-ylaminemethanyl)ethyl]-5-[(5-isopropyl-4,5,6,7-tetrahydrothiazole) And [5,4_c]pyridine-2-ylcarbonyl)amino]benzoic acid hydrochloride 1 To a solution of the compound of Example 26 (97 mg) in dichloromethane (1 (6)), 4 The alkane solution (2. 〇mi) was stirred at room temperature for 3 days. After the reaction solution was concentrated under reduced conditions, ethyl acetate was added to (d) to obtain a solid. In order to obtain a free form of the title compound, water (3 ml) was added to the body to obtain a free compound of the title compound. The title compound (56 mg) was obtained from EtOAcjjjjjjj W-NMR (DMSO-d6) δ : 1·38 (6H,d,J==5”Hz), 2 71 (2H,, J = 7.3 Hz)? 2.80-3.60 (5H? m)5 3.62-3.87 (2H? m)? 4.43-4.81 (2H,m),6·43 (1H,d,Χ2 Hz),6·84 (1H,d,J=4.2 Hz), 7.47 (1H, d? J=8.1 Hz)? 7.80 (1H5 dd5 J=8.l, 1.5 Hz), 7.98 (1H, d, J=1.5 Hz), 1〇·65 (1H, s), 1ΐ·〇5-η·35 (1H, Bu), 11.55, 11.56 (total 1H, each s). MS (ESI) m/z: 533 (M+H) + 〇 [EXAMPLE 28] 4-[2-(7-chlorotetralin-3-ylaminomethyl)ethyl]_3_[(5_A Base-4,5,6,7-tetrahydrothiazolo[5,'c]pyridinecarbonyl)amino]benzoic acid tert-butyl vinegar To the compound of Reference Example 74 (1〇7 mg) in DMF (6 ml Water (1 ml), anhydrous iron (3) (114 mg), and zinc dust (153 mg) were added to the solution, and the mixture was stirred at room temperature for 25 minutes and at 5 ° C for 5 minutes. Ethyl acetate was added to the reaction mixture, and the insoluble matter was removed by filtration using a solution of the fluorite. The insoluble material was washed with ethyl acetate, and the organic layer of the filtrate was separated. The organic layer was washed 5 times with water and dried over anhydrous Na.sub.2. The solvent was removed under reduced pressure to give a crude amine. Adding grass to a suspension of 5-methyl-4,5,6,7-tetrahydrothiazolo[5 winter acridine-2-formate (82.4 mg) in di-methane (5 ml) Chlorine (66·7 μΐ) and DMF (1 drop) were stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure. EtOAc (3 ml). hour. A saturated aqueous NaHC 3 solution was added to the reaction mixture, extracted with dichloromethane and dried over anhydrous Naj. The 129677.doc 142·200840568 agent was distilled off under reduced pressure, and the residue was purified by Shixi rubber column chromatography (dichloromethane: methanol = 99...197. 489.11) to obtain a crude product. Title compound. The title compound (9.0 mg) was obtained by preparative LC (dichloromethanol = 24: </ RTI> NMR (CDCl3) 5: 1.57 (9H, s), 2.52 (3H, s), 2.84 (2H, t, J=5.9 Hz), 2.94-3.03 (4H, m)} 3.2〇(2H, t, J=7.2 Hz), 3 75 (2H,s)' 7.39 (1H,d,Hz),7 64 (1H,仉j=8* i 8

Hz), 7.77 (1H, d, J=9.1 Hz), 7.83 (1H, dd, J=8.1, l η Hz) 8.36 (1H, d, J=1.7Hz),8.38(1H, s), 8.76 (1H, s), 8.96 〇H s), 9.44 (1H，s)。 ’ MS (ESI) m/z: 607 (M+H)+ 〇 [實施例29] 4-[2-(7-氣啐啉_3_基胺甲醯基）乙基]_3_[(%甲 基-4’5,6,7-四氫嗟唾并[5,4外比^炭基）胺基]笨甲酸鹽 酸鹽 1 以與實施例27相同的方法，由實施例28之化合物獲得桿 題化合物。 Λ iH-NMR (DMSO-d6) δ : 2·89 (2Η，t，J=7.6 Ηζ)，2.95 (3Η s), 3.05 (2H, t? J=7.2 Hz)5 3.1 3-3.26 (2H, m)? 3.67.3 77 (2H，m)，4·46 (1H，d，J=l5.9 Hz)，4.76 (1H，d，J=i5 9 Hz)Hz), 7.77 (1H, d, J=9.1 Hz), 7.83 (1H, dd, J=8.1, l η Hz) 8.36 (1H, d, J=1.7Hz), 8.38(1H, s), 8.76 ( 1H, s), 8.96 〇H s), 9.44 (1H, s). ' MS (ESI) m/z: 607 (M+H) + 〇 [Example 29] 4-[2-(7-Gaxoporphyrin_3_ylaminemethanyl)ethyl]_3_[(%A Base-4'5,6,7-tetrahydroindole[5,4-exo-carbomethoxy)amino] hydrazide hydrochloride 1 In the same manner as in Example 27, the compound of Example 28 Get the title compound. Λ iH-NMR (DMSO-d6) δ : 2·89 (2Η, t, J=7.6 Ηζ), 2.95 (3Η s), 3.05 (2H, t? J=7.2 Hz) 5 3.1 3-3.26 (2H, m)? 3.67.3 77 (2H,m),4·46 (1H,d,J=l5.9 Hz), 4.76 (1H,d,J=i5 9 Hz)

7.51 (1H, d5 1=8.1 Hz)? 7.78-7.83 (2H, m)? 7.97 (iH?V J=1.2 Hz)? 8.10 (1H5 d? J-9.1 Hz)5 8.46 (1H, s)? 8.74 (1H s), 10,63 (1H, s), 11.16 (1H，br s)，11.54 (1H，s)。 MS (ESI) m/z: 551 (M+H)+ 〇 [實施例30] 4_[2-(4-氯苯基胺甲醯基）乙基卜3_{[5_(2•氟1 129677.doc -143 - 200840568 曱基乙基）-4,5,6,7_四氫 曱酸第三丁酯 噻唑并[5,4-c]吡啶_2_羰基]胺基}苯7.51 (1H, d5 1=8.1 Hz)? 7.78-7.83 (2H, m)? 7.97 (iH?VJ=1.2 Hz)? 8.10 (1H5 d? J-9.1 Hz)5 8.46 (1H, s)? 8.74 ( 1H s), 10,63 (1H, s), 11.16 (1H, br s), 11.54 (1H, s). MS (ESI) m/z: 551 (M+H) + 〇 [EXAMPLE 30] 4_[2-(4-chlorophenylaminemethanyl)ethyl b. 3_{[5_(2•Fluor 1 129677. Doc -143 - 200840568 decylethyl)-4,5,6,7_tetrahydrofurfuric acid tert-butyl ester thiazolo[5,4-c]pyridine_2-carbonyl]amino}benzene

以與實施例2相同的方法 ^ 將參考例44之化合物盥灸者 例102之化合物縮合而獲得標題化合物。 ^ &gt; 】H-NMR (CDC13) δ: 1 20 加… 20 OH, d, J=6.9 Hz), 1.57 (9H s) 2.70 (2H，t，J=7.2 Hz), 2.96 ( ’ ’， ^付，t，J—5·1 Hz)，3·03 (2H t J=5.5 Hz)，3.10 (2H，t 卜7 i u、， ’ l，t，J—7」Hz)，3.16_3.26 (1H，蚧 4 〇〇 (2H，S)，4.44 — 4.63 (2H，^7.21(2H，d，i=8,6Hz) 73i (m，d，】=8.丨 Hz)，7.37 (2H，d，㈣ 8 Hz)，7 7.79(m，d，J=8.1Hz)，8.21(1H s) 9 28 (iH s)。，）’ MS (ESI) m/z: 601 (M+H)+ 〇 [實施例31] 4-[2-(4-氯笨基胺曱醯基）乙基]_3_{[5·(^氟i 甲基乙基）-4,5,6,7-四氫嘍唾并[5,4_c]Dm幾基]胺基 甲酸鹽酸鹽 1 I 以與實施例2 7相同的方法 題化合物。 由實施例30之化合物獲得標The compound of the compound of the reference example 44 was condensed in the same manner as in Example 2 to obtain the title compound. ^ &gt; 】H-NMR (CDC13) δ: 1 20 plus... 20 OH, d, J=6.9 Hz), 1.57 (9H s) 2.70 (2H, t, J=7.2 Hz), 2.96 ( ' ', ^ Pay, t, J—5·1 Hz), 3·03 (2H t J=5.5 Hz), 3.10 (2H, t 卜 7 iu,, ' l, t, J-7 Hz), 3.16_3.26 (1H, 蚧4 〇〇(2H,S), 4.44 — 4.63 (2H,^7.21(2H,d,i=8,6Hz) 73i (m,d,]=8.丨Hz), 7.37 (2H, d, (iv) 8 Hz), 7 7.79 (m, d, J = 8.1 Hz), 8.21 (1H s) 9 28 (iH s).,) ' MS (ESI) m/z: 601 (M+H)+ 〇 [Example 31] 4-[2-(4-Chlorophenylaminoindolyl)ethyl]_3_{[5·(^fluoroimethylethyl)-4,5,6,7-tetrahydro The compound was titled the compound of Example 30.

^-NMR (DMSO-d6) δ : 1.41 (3Η, br s)5 2.69 Hz)，2.97 (2H，t，J=7.4 Hz)，3.16-3.41 (5H (4H，m)，7·32 (2H，d，J=8.8 Hz), 7.47 (lj*j 7·57 (2H，d，J=8.8 Hz)，7·79 (1H，dd，】=7·8 (1H，d，J=1.5 Hz)，10.14 (1H，s)，10·67 (1H， br s) 〇 (2H，t，J==7 4m)，4.58-5.09 d，J二8.1 Hz), K5 Hz), 8.00 s)，11.24 (1H， MS (ESI) m/z: 545 (M+H)+。 [實施例32] 4-[2-(4-氣苯基胺曱醯基）乙基]^ &amp; 129677.doc -144- 200840568 鼠甲基乙基）-4,5,6,7 -四氯σ塞吐并[5,4-c]°比唆-2-碳基]胺基} 苯甲酸第三丁酯 以與實施例2相同的方法，將參考例46之化合物與參考 例102之化合物縮合而獲得標題化合物。 ^H.NMR (CDCl3)6: !.57 (9H? s)} 2 71 (2Hj t5 J=? 4 Hz)j 2.96 (2H，t，J=5.5 Hz)，3 1〇 (2h，t，j=6 9 Hz)，3 i5 (2h，％ J = 5.6 Hz)，3.22-3.38 (1H，m)，4 u (2H，s)，4 73 (4h，叫^-NMR (DMSO-d6) δ : 1.41 (3Η, br s)5 2.69 Hz), 2.97 (2H, t, J=7.4 Hz), 3.16-3.41 (5H (4H, m), 7·32 (2H ,d,J=8.8 Hz), 7.47 (lj*j 7·57 (2H,d,J=8.8 Hz),7·79 (1H,dd,]=7·8 (1H,d,J=1.5 Hz ), 10.14 (1H, s), 10.67 (1H, br s) 〇 (2H, t, J == 7 4m), 4.58-5.09 d, J 2 8.1 Hz), K5 Hz), 8.00 s), 11.24 (1H, MS (ESI) m/z: 545 (M+H)+. [Example 32] 4-[2-(4-phenylphenylaminomethyl)ethyl]^ &amp; 129677.doc -144- 200840568 Methylmethylethyl)-4,5,6,7-tetrachloro-sigma-[5,4-c]° 唆-2-carbyl]amino}-tert-butyl benzoate The compound of Reference Example 46 was condensed with the compound of Reference Example 102 in the same manner as in Example 2 to give the title compound. ^H.NMR (CDCl3)6: !.57 (9H? s)} 2 71 (2Hj t5 J=? 4 Hz)j 2.96 (2H,t,J=5.5 Hz), 3 1〇(2h,t, j=6 9 Hz), 3 i5 (2h, % J = 5.6 Hz), 3.22-3.38 (1H, m), 4 u (2H, s), 4 73 (4h, called

J-47.6, 5.1 Hz)，7.21 (2H，d，J=8 8 Hz)，7.31 (1H，d，J=7.7J-47.6, 5.1 Hz), 7.21 (2H, d, J=8 8 Hz), 7.31 (1H, d, J=7.7

Hz), 7.37 (2H, d, J=8.6 Hz), 7.56 (1H, s), 7.80 (1H, dd, J = 8.1，1.7 Hz)，8.21 (1H，d，J=1.2 Hz)，9 29 (1H，s)。， MS (ESI) m/z: 619 (M+H)+ 〇 [實施例33] 4-[2-(4-氣笨基胺甲醯基）乙基]_3_{[5_(2•氟 氟甲基乙基）-4,5,6,7-四氫嗟4并[5,心比咬-2_幾基]胺基} 苯甲酸鹽酸鹽 以與實施例27相同的方法，由實施例32之化合物獲得標 題化合物。 H-NMR (DMSO-d6) δ : 2·69 (2H，t，J=7.4 Hz), 2.97 (2H，t J-7·4 Hz)，3·06-3·19 (2H，m)，3·44-3·62 (2H，m)，3.78'〇〇 (1H，m)，4.44-4.62 (2H，m)，4·94 (4H，d，卜46 3 Hz)，7 3i (2H，d，J=8.8 Hz)，7·47 (1H，d，J=8.1 Hz)，7·57 (2H，d J=8.8 Hz)，7·78 (1H，dd，J=7.8, &quot; Hz)，8 01 (ih，d，㈣ 7 Hz)，10.14 (1H，s)，10.61 (1H，s) 〇 MS (ESI) m/z: 563 (M+H)+ 〇 [實施例34] 4-[2-(4-氣苯基胺甲醯基）乙基卜3_q5_(2_甲氧 129677.doc •145- 200840568 基-l-曱基乙基）-4,5,6,7_四氫嘆唾并[5,4々比咬_2_叛基]胺 基}苯甲酸第三丁酯 以與實施例2相同的方法，將參考例48之化合物與參考 例102之化合物縮合而獲得標題化合物。 ^-NMR (CDC13) δ : 1.15 (3Η, d&gt; J=6.6 Hz), 1.57 (9H, s),Hz), 7.37 (2H, d, J=8.6 Hz), 7.56 (1H, s), 7.80 (1H, dd, J = 8.1, 1.7 Hz), 8.21 (1H, d, J = 1.2 Hz), 9 29 (1H, s). , MS (ESI) m/z: 619 (M+H) + 〇 [EXAMPLE 33] 4-[2-(4-Azylaminocarbamoyl)ethyl]_3_{[5_(2•Fluorofluoro Methyl ethyl)-4,5,6,7-tetrahydroindole 4 and [5, heart ratio bit-2-yl]amino} benzoate hydrochloride in the same manner as in Example 27, The compound of Example 32 gave the title compound. H-NMR (DMSO-d6) δ : 2·69 (2H, t, J = 7.4 Hz), 2.97 (2H, t J-7·4 Hz), 3·06-3·19 (2H, m), 3·44-3·62 (2H,m), 3.78'〇〇(1H,m),4.44-4.62 (2H,m),4·94 (4H,d,Bu 46 3 Hz),7 3i (2H ,d,J=8.8 Hz),7·47 (1H,d,J=8.1 Hz),7·57 (2H,d J=8.8 Hz),7·78 (1H,dd,J=7.8, &quot; Hz), 8 01 (ih, d, (iv) 7 Hz), 10.14 (1H, s), 10.61 (1H, s) 〇MS (ESI) m/z: 563 (M+H)+ 〇 [Example 34] 4-[2-(4-Phenylaminocarbamoyl)ethyl b 3_q5_(2_methoxy 129677.doc •145- 200840568 ke-l-decylethyl)-4,5,6,7_ Tetrahydro-suppressed and condensed with the compound of Reference Example 102 in the same manner as in Example 2, except that the compound of Reference Example 48 was condensed with the compound of Reference Example 102. The title compound was obtained. ^-NMR (CDC13) δ : 1.15 (3Η, d&gt; J=6.6 Hz), 1.57 (9H, s),

2.70 (2H, t, J=7.2 Hz), 2.91-3.02 (4H, m), 3.10 (3H J J = 7.2 Hz), 3.37 (3H, s), 3.41 (lH, dd, J=9.9, 4.8 Hz), s.si (1H, dd, J=9.8, 6.6 Hz), 3.99 (2H, s), 7.21 (2H, d, J=8.62.70 (2H, t, J=7.2 Hz), 2.91-3.02 (4H, m), 3.10 (3H JJ = 7.2 Hz), 3.37 (3H, s), 3.41 (lH, dd, J=9.9, 4.8 Hz) , s.si (1H, dd, J=9.8, 6.6 Hz), 3.99 (2H, s), 7.21 (2H, d, J=8.6

Hz), 7.31 (1H, d, J=8.1 Hz), 7.36 (2H, d, J=8.6 Hz), 7.61 (1H, s), 7.79 (1H, dd, J=8.1, 1.5 Hz), 8.20 (1H, s), 9.23 (lH，s)。 ，· MS (ESI) m/z: 613 (M+H)+。 [實施例35] 4-[2-(4-氯苯基胺曱醯基）乙基]_3·{[5_(2·曱氧 基-1-甲基乙基）-4,5,6,7_四氫噻唑并[5,4&lt;]吡啶羰基]胺 基}苯甲酸鹽酸鹽 以與實施例27相同的方法，由實施例34之化合物獲得標 題化合物。 iH-NMR (DMS0-d6) δ : 134 (1 5H，d，J=6 4 Ηζ)，！ 4〇 (1.5Η，d，J=5.9 Ηζ)，2·69 (2Η，t，J=7,6 Ηζ)，2·97 (2Η，t， J-7.2 Ηζ)，3.11-3.23 (1Η，m)，3.34 (3Η，s)，3·45-3·59 (2Η， m)，3·62-3·88 (4H，m)，4.61-4.80 (2H，m)，7·32 (2H，d， J = 8.8 Hz)，7·47 (1H，d，JU Hz)，7·56 (2H，d，J=8 8 Hz)， 7.79 (1H? d? J=8.1 Hz)? g.OO (1H3 s)5 10.14 (1H? s)5 l〇.63 (1H，br s)，10.67 (1H，s)，12·97 (1H，s)。 129677.doc -146- 200840568 MS (ESI) m/z: 557 (M+H)+ 〇 [實施例36] 4-[2-(4-氯苯基胺曱酿基）乙基]·3_[(5_甲基_ 5.6.7.8- 四氫-4Η-嗟嗤并[5,4-c：K 丁啶羰基）胺基]苯曱酸 第三丁酯 以與實施例2相同的方法’將5-甲基_5,6,7,8-四氫-4H·嗟 峻并[5,4-c]吖丁咬-2-曱酸經鹽（參照wq2〇〇4/〇58715記載 之方法）與參考例102之化合物縮合而獲得標題化合物。 ^-NMR (CDCls) δ : 1.57 (9Η, s), 1.80-1.86 (2H? m)5 2.41 (3H，s)，2·71 (2H，t，J=7.2 Hz)，3,06-3·11 (6H，m)，3·95 (2H，s)，7.21 (2H，d，J=8.8 Hz)，7.30 (1H，d，J=8.1 Hz)， 7.38 (2H，d，J=8.8 Hz)，7.70 (1H，s)，7·79 (1H，cid，J=7.8, 1.7 Hz)，8.21 (1H，s)，9·31 (1H，s) o MS (ESI) m/z: 569 (M+H)+。 [實施例37] 4-[2-(4-氣苯基胺曱醯基）乙基]-3_[(5-曱基- 5.6.7.8- 四氫-4H-噻唑并[5,4_c]吖丁啶_2_羰基）胺基]苯甲酸 鹽酸鹽 以與實施例27相同的方法，由實施例36之化合物獲得標 題化合物。 ^-NMR (DMSO^d6) δ ： ^97-2.12 (2H, m), 2.71 (2H, t, J=7.5 Hz)，2·79 (3H，s)，2,97 (2H，t，Hz)，3·15 (2H，br s)，3·42-3·56 (1H，in)，3 57·3 7〇 (iH，in)，4.63-4.74 (1H， m)，4·75-4·87 (1H，m)，7 32 (2H，d，J = 8.8 Hz)，7·47 (1H，d， J=8，l Hz)，7,58 (2H，d5 J=8.8 Hz)，7·78 (1H，dd，J二7.8, 1.5 Hz)，8.01 (1H，d，j：=：i 5 hz)，ι〇·ΐ9 (1H，s)，10.61 (1H，s)， 129677.doc -147- 200840568 11·04 (1H，br s)，12·96 (1H，s)。 MS (ESI) m/z: 513 (M+H)+。 [實施例38] 4-[2_(4-氯苯基胺曱醯基乙基]-3-[(5-異丙基- 5.6.7.8- 四氫-4H-噻唑并[5,4-c]吖丁啶-2-羰基）胺基]-苯甲 酸第三丁酯 以與實施例2相同的方法，將參考例34之化合物與參考 例102之化合物縮合而獲得標題化合物。 W-NMR (CDC13) δ : 1·1〇 (6H，d，J=6.4 Hz)，1.57 (9H，s)， 1·79-1·86 (2H，m)，2.70 (2H，t，J=7.2 Hz)，2.85-2.95 (1H， m)，3.06-3.17 (6H，m)，4·〇〇 (2H，s)，7.21 (2H，d，J=8.8 Hz)， 7.31 (1H，d，J = 8.1 Hz)，7·37 (2H, d，J=8.8 Hz)，7.64 (1H， s)，7·79 (1H，dd，J=8.1，1.7 Hz)，8 18 (1H，s)，9 24 (1H， s) 〇 MS (ESI) m/z: 597 (M+H)+ 〇 [實施例39] 4-[2-(4-氯苯基胺曱醯基）乙基]異丙基_ 5.6.7.8- 四氫-4Η-噻唑并[5,4〜c]吖丁啶羰基）胺基]苯甲酸 鹽酸鹽 以與實施例27相同的方法，由實施例38之化合物獲得標 題化合物。 H-NMR (DMSO-d6) δ : ι·3〇 (3H，d，J=5,6 Hz)，1.31 (3H，d， J=5.6 Hz)，1.99-2.20 (2H，m)，2.65-2.67 (1H，m)，2·70 (2H， t，J=7.4 Hz)，2·96 (2H，t，J=7.2 Hz)，3·46-3·46 (2H，m)， 3·53-3·65 (2H，m)，4.69-4.87 (2H，m)，7·32 (2H，d，J = 8,8Hz), 7.31 (1H, d, J=8.1 Hz), 7.36 (2H, d, J=8.6 Hz), 7.61 (1H, s), 7.79 (1H, dd, J=8.1, 1.5 Hz), 8.20 ( 1H, s), 9.23 (lH, s). , MS (ESI) m/z: 613 (M+H)+. [Example 35] 4-[2-(4-Chlorophenylaminoindenyl)ethyl]_3·{[5_(2·曱oxy-1-methylethyl)-4,5,6, 7_Tetrathiathiazolo[5,4&lt;]pyridinecarbonyl]amino}benzoate hydrochloride The title compound was obtained from the compound of Example 34. iH-NMR (DMS0-d6) δ : 134 (1 5H, d, J = 6 4 Ηζ),! 4〇(1.5Η,d,J=5.9 Ηζ), 2·69 (2Η,t,J=7,6 Ηζ), 2·97 (2Η,t, J-7.2 Ηζ), 3.11-3.23 (1Η, m), 3.34 (3Η, s), 3·45-3·59 (2Η, m), 3·62-3·88 (4H, m), 4.61-4.80 (2H, m), 7·32 (2H ,d, J = 8.8 Hz),7·47 (1H,d,JU Hz),7·56 (2H,d,J=8 8 Hz), 7.79 (1H? d? J=8.1 Hz)? g. OO (1H3 s)5 10.14 (1H? s)5 l〇.63 (1H, br s), 10.67 (1H, s), 12·97 (1H, s). 129677.doc -146- 200840568 MS (ESI) m/z: 557 (M+H) + 〇 [Example 36] 4-[2-(4-chlorophenylamine oxime)ethyl]·3_[ (5-Methyl_5.6.7.8-tetrahydro-4Η-indolo[5,4-c:K-butylidenecarbonyl)amino]benzoic acid tert-butyl ester in the same manner as in Example 2 5-methyl_5,6,7,8-tetrahydro-4H·嗟君[5,4-c]吖丁咬-2-曱酸 via salt (refer to wq2〇〇4/〇58715) Condensation with the compound of Reference Example 102 gave the title compound. ^-NMR (CDCls) δ : 1.57 (9Η, s), 1.80-1.86 (2H? m)5 2.41 (3H, s), 2·71 (2H, t, J = 7.2 Hz), 3, 06-3 ·11 (6H,m),3·95 (2H,s), 7.21 (2H,d,J=8.8 Hz), 7.30 (1H,d,J=8.1 Hz), 7.38 (2H,d,J=8.8 Hz), 7.70 (1H, s), 7·79 (1H, cid, J=7.8, 1.7 Hz), 8.21 (1H, s), 9·31 (1H, s) o MS (ESI) m/z: 569 (M+H)+. [Example 37] 4-[2-(4-Phenylaminoindenyl)ethyl]-3_[(5-fluorenyl-5.6.7.8-tetrahydro-4H-thiazolo[5,4_c]indole Butyl-2-(carbonyl)amino]benzoic acid hydrochloride The title compound was obtained from the compound of Example 36. ^-NMR (DMSO^d6) δ : ^97-2.12 (2H, m), 2.71 (2H, t, J=7.5 Hz), 2·79 (3H, s), 2,97 (2H, t, Hz ),3·15 (2H,br s),3·42-3·56 (1H,in),3 57·3 7〇(iH,in),4.63-4.74 (1H, m),4·75- 4·87 (1H,m),7 32 (2H,d,J = 8.8 Hz), 7·47 (1H,d, J=8,l Hz), 7,58 (2H, d5 J=8.8 Hz) ,7·78 (1H,dd,J two 7.8, 1.5 Hz), 8.01 (1H,d,j:=:i 5 hz), ι〇·ΐ9 (1H, s), 10.61 (1H, s), 129677 .doc -147- 200840568 11·04 (1H, br s), 12·96 (1H, s). MS (ESI) m/z: 513 (M+H)+. [Example 38] 4-[2_(4-Chlorophenylaminoindenyl)-3-[(5-isopropyl-5.6.7.8-tetrahydro-4H-thiazolo[5,4-c] Azetidine-2-carbonyl)amino]-benzoic acid tert-butyl ester The title compound was obtained by condensing the compound of Reference Example 34 with the compound of Reference Example 102 in the same manner as in Example 2. W-NMR ( CDC13) δ : 1·1〇(6H,d,J=6.4 Hz), 1.57 (9H,s), 1·79-1·86 (2H,m), 2.70 (2H,t,J=7.2 Hz) , 2.85-2.95 (1H, m), 3.06-3.17 (6H, m), 4·〇〇(2H, s), 7.21 (2H, d, J=8.8 Hz), 7.31 (1H,d,J = 8.1 Hz),7·37 (2H, d, J=8.8 Hz), 7.64 (1H, s), 7.79 (1H, dd, J=8.1, 1.7 Hz), 8 18 (1H, s), 9 24 (1H, s) 〇MS (ESI) m/z: 597 (M+H) + 〇 [Example 39] 4-[2-(4-chlorophenylaminoindenyl)ethyl]isopropyl 5.6.7.8-Tetrahydro-4-indole-thiazolo[5,4~c]azetidinylcarbonyl)amino]benzoic acid hydrochloride The title compound was obtained from the compound of Example 38 in the same manner as in Example 27 . H-NMR (DMSO-d6) δ : ι·3〇 (3H, d, J=5, 6 Hz), 1.31 (3H, d, J = 5.6 Hz), 1.99-2.20 (2H, m), 2.65- 2.67 (1H, m), 2·70 (2H, t, J = 7.4 Hz), 2·96 (2H, t, J = 7.2 Hz), 3·46-3·46 (2H, m), 3· 53-3·65 (2H,m),4.69-4.87 (2H,m),7·32 (2H,d,J = 8,8

Hz)，7·47 (1H，d，J=8.1 Hz)，7.57 (2H，d，J=8.8 Hz)，7·79 129677.doc •148. 200840568 (1H，dd，J=8.0, 1·6 Ηζ)，8·00 (1H，d，J=1.5 Hz), 10,09 (1H， br s)，10·16 (1H，s)，10.62 (1H，s)，12·96 (1H，s)。 MS (ESI) m/z: 541 (M+H)+。 [實施例40] 4-[2-(4-氯苯基胺甲醯基）乙基卜異丙基_ 5,6,7,8-四氫[1，6]奈。定_2_羰基）胺基]苯甲酸第三丁酯 以與實施例2相同的方法，將參考例4〇之化合物與參考 例102之化合物縮合而獲得標題化合物。 W-NMR (CDC13) δ : 1·π (6H，d，J=6.4 Hz)，1.58 (9H，s)， 2·68 (2H，t，J=7.2 Hz)，2·88 (2H，t，J=5,9 Hz)，2.95-3.04 (1H，m)，3.07 (2H，t，J=5.4 Hz)，3·13 (2H，t，J=7.4 Hz)， 3.81 (2H，s)，7.20 (2H，d，J=8.6 Hz)，7.30 (1H，d，J=7.4 Hz)，7·36 (2H，d，J=8.8 Hz)，7·56 (1H，d，J=7.8 Hz)，7·77 (1H，dd，J=8.1，1·7 Hz)，7.79 (1H，br s)，8·04 (1H，d，J=8.1Hz),7·47 (1H,d,J=8.1 Hz), 7.57 (2H,d,J=8.8 Hz),7·79 129677.doc •148.200840568 (1H,dd,J=8.0, 1· 6 Ηζ), 8·00 (1H, d, J=1.5 Hz), 10,09 (1H, br s), 10·16 (1H, s), 10.62 (1H, s), 12·96 (1H, s). MS (ESI) m/z: 541 (M+H)+. [Example 40] 4-[2-(4-Chlorophenylaminocarbamimidyl)ethylbuisopropyl_5,6,7,8-tetrahydro[1,6]na. The title compound was obtained by condensing the compound of Reference Example 4 with the compound of Reference Example 102 in the same manner as in Example 2. W-NMR (CDC13) δ : 1·π (6H, d, J = 6.4 Hz), 1.58 (9H, s), 2·68 (2H, t, J = 7.2 Hz), 2·88 (2H, t , J=5,9 Hz), 2.95-3.04 (1H, m), 3.07 (2H, t, J=5.4 Hz), 3·13 (2H, t, J=7.4 Hz), 3.81 (2H, s) , 7.20 (2H, d, J = 8.6 Hz), 7.30 (1H, d, J = 7.4 Hz), 7·36 (2H, d, J = 8.8 Hz), 7·56 (1H, d, J = 7.8) Hz),7·77 (1H,dd,J=8.1,1·7 Hz), 7.79 (1H,br s),8·04 (1H,d,J=8.1

Hz)，8·28 (1H，s)，10·ΐ〇 (ih，s)。 MS (ESI) m/z: 577 (M+H)+。 [實施例41] 4-[2-(4-氯苯基胺甲醢基）乙基]_3 —[(6-異丙基-5,6,7,8-四氫[1，6]萘啶_2-羰基）胺基]苯甲酸鹽酸鹽 以與實施例27相同的方法，由實施例40之化合物獲得標 題化合物。 iH-NMR (DMSO-d6) δ : ι·37 (3H，d，J=5.9 Ηζ)，1·38 (3H，d， J —5.9 Hz), 2.75 (2Hj t, J=7.1 Hz), 3.01 (2H? t, J=7.4 Hz)? 3.15-3.26 (1H，m)，3.41-3.50 (2H，m)，3.64-3.80 (2H，m)， 4.48-4.60 (2H，m)，7,33 (2H，d，Hz)，7·47 (1H，d， J=8，l Hz)，7.58 (2H，d，J=8.8 Hz)，7·74 (1H，dd，J=7.8，1.7 129677.doc -149- 200840568 Ηζ)，7·93 (1H，d，J=7.8 Ηζ)，8·06 (1H，d，J=7.8 Ηζ)，8·37 (1H，s)，10.16 (1H，s)，10.72 (2H，s)，12.93 (1H，br s)。 MS (ESI) m/z: 521 (M+H)+。 [實施例42] 2-[N-(2-{2-[(4-氯苯基）胺甲醯基]乙基-5-(甲氧 基羰基）苯基甲基胺甲醯基]-6,7-二氫-4H-噻唑并[5,4-c]吡啶-5-曱酸第三丁酯 以與實施例1 8相同的方法，將參考例77之化合物與4-氯 苯胺縮合而獲得標題化合物。 h-NMR (CDC13) δ : 1.44, 1.51 (total 9H，each s)，2.31-2.69 (3H，m)，2.91-3.11 (3H，m)，3·42 (1·5Η，s)，3·46-3·62 (1H， m)，3.73-3.87 (1H，m)，3.89 (1·5Η，s)，3.90 (3H，s)，4.57 (1H，br s)，4·74 (1H，br s)，7.10-7.37 (5H，m)，7.58-8.00 (2.5H，m)，8·18 (0.5H，br s)。 MS (ESI) m/z: 613 (M+H)+ 〇 [實施例43] 4-{2-[(4-氣苯基）胺曱酸基]乙基}·3-[Ν-(5·異丙 基-4,5,6,7-四氫噻唑并[5,4-c]吡啶-2-羰基）-Ν-甲基胺基]苯 曱酸甲酯 以與實施例5相同的方法，由實施例42之化合物獲得標 題化合物。 iH-NMR (CDC13) δ ·· 1·07 (3Η，d，J=6.3 Ηζ)，1·17 (3Η，d， J=6.6 Hz)，2,30-2·75 (4H，m)，2·80·3·15 (4·5Η，m)，3.41 (1.8H，s)，3·61-3·79 (1·7Η，m)，3·89 (3H，s)，3,90 (2H, s)， 7.06-7.36 (5H，m)，7·64-7·97 (2.5H, m)，8.16-8.27 (〇·5Η， m) 〇 129677.doc 150- 200840568 MS (ESI) m/z: 535 (M+H)+。 [實施例44]4-{2-[(4·氣苯基）胺曱醯基]乙基卜3_[N_(5_異丙 基·4,5,6,7-四氫噻唑并[5,4-(：]吡啶_2_羰基）^_甲基胺基]苯 甲酸鹽酸鹽 以與實施例9相同的方法，由實施例43之化合物獲得標 題化合物。 H-NMR (DMSO-d6) 6 : 1.18-1.46 (6H, m), 2.18-3.89 (12H, m)，4·24-4·75 (2H，m)，7.32 (2H，d，J = 8.3 Hz)，7.45-7.96 (5H，m)，10.31-10.73(lH，m)，1 1.06-1 1.53 (lH，m)，11.70-12·03 (1H，br) ° MS (ESI) m/z: 541 (M+H)+。 [實施例45] 4-[2-(4-氯苯基胺甲醯基）-2-羥基乙基]-3-[(5-異 丙基-4,5,6,7-四氫噻唑并[5,4&lt;]吡啶_2_羰基）胺基]苯甲酸 第三丁酯 以與實施例3相同的方法，將參考例3 2之化合物與參考 例82之化合物縮合而獲得標題化合物。 iH-NMR (CDC13) δ : 1.15 (6H，d，J=6.6 Ηζ)，1·58 (9H，S)， 2·90 (4H，br s)，2.96-3.05 (1H，m)，3·17 (1H，dd，J=14.4, 8.3Hz)，3.36(m，dd，J：=14、3,4.0Hz)，3.86(2H，s)，4.54-4·61 (1H，m)，5·20-5·26 (1H，m)，7·28 (2H，d，Ρ8·5 Hz)， 7·45 (1H，d，J=8.1 Hz)，7·50 (2H，d，J=8.5 Hz)，7·84 (1H， dd，J=7.9，1.8 Hz)，8·16 (1H，d，J=1.7 Hz)，8·74 (1H，s)， 9·49 (1H，s) 〇 MS (ESI) m/z: 599 (M+H)+ 〇 I29677.doc -151 · 200840568 [實施例46] 4-[2-(4-氣苯基胺曱醯基羥基乙基]_3_[(5·異 丙基-4,5,6,7_四氫噻唑并[5,4-c]。比啶_2_羰基）胺基]苯曱酸 鹽酸鹽 以與實施例27相同的方法，由實施例45之化合物獲得標 題化合物。 4-NMR (DMSO-d6) δ : 1·35 (3H，d，J=5.4 Hz)，135 (3H，d， J = 5.1 Hz)，2.96-3.06 (1H，m)，3·1〇、3·26 (2H，m)，3·3(Μ.51 (2H，m)，3·67-3·84 (2H，m)，4.38-4.45 (1H，m)，4.51-4.63 (1H，m)，4.71-4.79 (1H，m)，6·46-6·54 (1H，m)，7.33 (2H，d， J=9.0 Hz)，7.44 (1H，d，J=8.3 Hz)，7·66 (2H，d，卜9.〇 Hz)， 7·73 (1H，d，&gt;8·3 Hz)，8·19 (1H，s)，9·88 (1H，s)，10.50-ι〇·6ΐ (ih，m)，10·71 (1H, d，Hu Hz)，12 98 (1H，s)。 MS (ESI) m/z: 543 (M+H)+。 [實施例47] 4-[2-(4-氣苯基胺甲醯基）丙基]_3一[(5_異丙基_ 4,5,6,7-四氫噻唑并[5,4_c]吡啶-2_羰基）胺基]苯曱酸第三 丁酯 以與實施例3相同的方法，將參考例32之化合物與參考 例86之化合物縮合而獲得標題化合物。 H-NMR (CDC13) δ : 1·17 (6H，d，J=6.6 Hz)，1.29 (3H，d， J=6.6 Hz)，1.56 (9H，s)，2·60-2·70 (1H，m)，2.86-3.07 (7H， m)，3·89 (2H，s)，7·15 (2H，d，J=9.4 Hz)，7.22-7.26 (3H，m)， 7.70-7·73 (2H，m)，8·16 (1H，d，J=1.7 Hz), 9.05 (1H，s)。 MS (ESI) m/z: 597 (M+H)+。 [實施例48] 4-[2-(4-氯苯基胺甲醯基）丙基]-3-[(5-異丙基_ 129677.doc -152- 200840568 4,5’6,7_四氫嘆嗤并[5,4·中炭基）胺基]苯甲酸鹽峻邊 以與實施例27相同的方法，由實施例47之化合物獲得標 題化合物。 $ H-NMR (DMSO-d6) δ : i 12 (3H，d，j=6」Hz)，1.37 (6H，t， J=5.7 Hz)，2·72-2·88 (2H，m)，2·98-3·07 (1H，m)，3·1〇-3·52 (3H5 m)5 3.67-3.83 (2H? m), 4.51-4.61 (1H? m), 4.70^4.79 (1H，m)，7·30 (2H，d，J = 8 8 hz)，7·44 (1H，d，J=8.3 Hz)， 7.53 (2H，d，J=8.5 Hz)，7.75 〇H，dd，J=8 〇, 2 〇 Hz)，8 〇4 ® (1H，S)，1()·03 (1H，br s)，10·51 (1H，d，J=4,6 Hz), 10.68 (1H, br s)，12.96 (1H，s) 〇 MS (ESI) m/z: 541 (M+H)+。 [實施例49] 4-[2-(4-氯苯基胺甲醯基）_2_氟乙基]_3-[(5-異丙 基-4,5,6,7-四氫噻唑并[5,4_c]吡啶_2•羰基）胺基]苯曱酸第 三丁酯 以與實施例3相同的方法，將參考例32之化合物與參考 例90之化合物縮合而獲得標題化合物。 H-NMR (CDC13) δ : 1·17 (6H，d，J=6.6 Ηζ)，1·58 (9H，s)， 2.85-3.06 (6H，m)，3.34-3.55 (1H，m)，3·88 (2H，s)，5.36 (1H，ddd，J=49.3, 5.9, 4·1 Hz)，7·28 (2H，d，㈣·〇 Hz)，7·39 (1H，d，J=8.0 Hz)，7·41 (2H，d，Hz)，7·80 (1H，dd， J = 7.8，1.8 Hz)，7·88 (1H，d，J=5 9 hz)，8.39 (1H，d，J=1.7Hz), 8·28 (1H, s), 10·ΐ〇 (ih, s). MS (ESI) m/z: 577 (M+H)+. [Example 41] 4-[2-(4-Chlorophenylaminocarbamimidyl)ethyl]_3 -[(6-isopropyl-5,6,7,8-tetrahydro[1,6]naphthalene The title compound was obtained from the compound of Example 40 in the same manner as in Example 27. iH-NMR (DMSO-d6) δ : ι·37 (3H,d,J=5.9 Ηζ),1·38 (3H,d, J —5.9 Hz), 2.75 (2Hj t, J=7.1 Hz), 3.01 (2H?t, J=7.4 Hz)? 3.15-3.26 (1H,m), 3.41-3.50 (2H,m), 3.64-3.80 (2H,m), 4.48-4.60 (2H,m),7,33 (2H,d,Hz),7·47 (1H,d, J=8,l Hz), 7.58 (2H,d,J=8.8 Hz),7·74 (1H,dd,J=7.8,1.7 129677 .doc -149- 200840568 Ηζ),7·93 (1H,d,J=7.8 Ηζ),8·06 (1H,d,J=7.8 Ηζ),8·37 (1H,s),10.16 (1H, s), 10.72 (2H, s), 12.93 (1H, br s). MS (ESI) m/z: 521 (M+H)+. [Example 42] 2-[N-(2-{2-[(4-Chlorophenyl)aminemethanyl]ethyl-5-(methoxycarbonyl)phenylmethylaminecarbamyl]- 6,7-Dihydro-4H-thiazolo[5,4-c]pyridine-5-decanoic acid tert-butyl ester. The compound of Reference Example 77 was condensed with 4-chloroaniline in the same manner as in Example 18. The title compound was obtained. h-NMR (CDC13) δ: 1.44, 1.51 (total 9H, each s), 2.31-2.69 (3H, m), 2.91-3.11 (3H, m), 3·42 (1·5Η, s),3·46-3·62 (1H, m), 3.73-3.87 (1H, m), 3.89 (1·5Η, s), 3.90 (3H, s), 4.57 (1H, br s), 4 · 74 (1H, br s), 7.10-7.37 (5H, m), 7.58-8.00 (2.5H, m), 8.18 (0.5H, br s) MS (ESI) m/z: 613 (M +H)+ 〇 [Example 43] 4-{2-[(4-Phenylphenyl)amine decanoic acid]ethyl}·3-[Ν-(5·isopropyl-4,5,6, 7-Tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl)-indole-methylamino]benzoic acid methyl ester The title compound was obtained from the compound of Example 42 in the same manner as in Example 5. iH-NMR (CDC13) δ ·· 1·07 (3Η,d,J=6.3 Ηζ),1·17 (3Η,d, J=6.6 Hz), 2,30-2·75 (4H,m) , 2·80·3·15 (4·5Η, m), 3.41 (1.8H s),3·61-3·79 (1·7Η,m),3·89 (3H,s),3,90 (2H, s), 7.06-7.36 (5H,m),7·64-7 · 97 (2.5H, m), 8.16-8.27 (〇·5Η, m) 〇129677.doc 150- 200840568 MS (ESI) m/z: 535 (M+H)+. [Example 44] 4-{ 2-[(4·Phenylphenyl)amine oxime]ethyl b 3_[N_(5_isopropyl·4,5,6,7-tetrahydrothiazolo[5,4-(:]pyridine_ 2-carbonyl)^-methylamino]benzoic acid hydrochloride The title compound was obtained from the compound of Example 43 in the same manner as in Example 9. H-NMR (DMSO-d6) 6 : 1.18-1.46 ( 6H, m), 2.18-3.89 (12H, m), 4·24-4·75 (2H, m), 7.32 (2H, d, J = 8.3 Hz), 7.45-7.96 (5H, m), 10.31- 10.73 (lH, m), 1 1.06-1 1.53 (lH, m), 11.70-12·03 (1H, br), MS (ESI) m/z: 541 (M+H)+. [Example 45] 4-[2-(4-Chlorophenylaminocarbamimidyl)-2-hydroxyethyl]-3-[(5-isopropyl-4,5,6,7-tetrahydrothiazole) And [5,4 <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; iH-NMR (CDC13) δ : 1.15 (6H,d,J=6.6 Ηζ),1·58 (9H,S), 2·90 (4H,br s),2.96-3.05 (1H,m),3· 17 (1H, dd, J = 14.4, 8.3 Hz), 3.36 (m, dd, J: = 14, 3, 4.0 Hz), 3.86 (2H, s), 4.54-4·61 (1H, m), 5 ·20-5·26 (1H,m),7·28 (2H,d,Ρ8·5 Hz), 7·45 (1H,d,J=8.1 Hz), 7·50 (2H,d,J= 8.5 Hz), 7.84 (1H, dd, J=7.9, 1.8 Hz), 8·16 (1H, d, J=1.7 Hz), 8.74 (1H, s), 9·49 (1H, s 〇MS (ESI) m/z: 599 (M+H)+ 〇I29677.doc -151 · 200840568 [Example 46] 4-[2-(4-Phenylphenylaminodecylhydroxyethyl)_3_ [(5·isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c].pyridin-2-carbonyl)amino]benzoquinone hydrochloride was the same as in Example 27. The title compound was obtained from the compound of Example 45. 4-NMR (DMSO-d6) δ: 1·35 (3H, d, J = 5.4 Hz), 135 (3H, d, J = 5.1 Hz), 2.96 -3.06 (1H,m),3·1〇,3·26 (2H,m),3·3(Μ.51 (2H,m),3·67-3·84 (2H,m),4.38- 4.45 (1H, m), 4.51-4.63 (1H, m), 4.71-4.79 (1H, m), 6·46-6·54 (1H, m), 7.33 (2H, d, J=9.0 Hz), 7.44 (1H, d, J = 8.3 Hz), 7.66 (2H, d, Bu 9. Hz), 7·73 (1H, d, &gt; 8·3 Hz), 8·19 ( 1H, s), 9·88 (1H, s), 10.50-ι〇·6ΐ (ih, m), 10·71 (1H, d, Hu Hz), 12 98 (1H, s) MS (ESI) m/z: 543 (M+H) +. [EXAMPLE 47] 4-[2-(4-phenylphenylcarbamoyl)propyl]-3-[(5-isopropyl-4,5, 6,7-Tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl)amino]benzoic acid tert-butyl ester In the same manner as in Example 3, the compound of Reference Example 32 and the compound of Reference Example 86 were used. The title compound was obtained by condensation. H-NMR (CDC13) δ : 1·17 (6H, d, J = 6.6 Hz), 1.29 (3H, d, J = 6.6 Hz), 1.56 (9H, s), 2·60-2·70 (1H , m), 2.86-3.07 (7H, m), 3·89 (2H, s), 7·15 (2H, d, J = 9.4 Hz), 7.22-7.26 (3H, m), 7.70-7·73 (2H,m),8·16 (1H,d,J=1.7 Hz), 9.05 (1H, s). MS (ESI) m/z: 597 (M+H)+. [Example 48] 4-[2-(4-Chlorophenylaminocarbamimidyl)propyl]-3-[(5-isopropyl- 129677.doc-152- 200840568 4,5'6,7_ The title compound was obtained from the compound of Example 47 in the same manner as in Example 27. </ RTI> </ RTI> <RTIgt; 2·98-3·07 (1H,m),3·1〇-3·52 (3H5 m)5 3.67-3.83 (2H? m), 4.51-4.61 (1H? m), 4.70^4.79 (1H, m), 7·30 (2H, d, J = 8 8 hz), 7.44 (1H, d, J = 8.3 Hz), 7.53 (2H, d, J = 8.5 Hz), 7.75 〇H, dd, J=8 〇, 2 〇Hz),8 〇4 ® (1H,S),1()·03 (1H,br s),10·51 (1H,d,J=4,6 Hz), 10.68 ( 1H, br s), 12.96 (1H, s) 〇MS (ESI) m/z: 541 (M+H)+. [Example 49] 4-[2-(4-Chlorophenylaminocarbamimidyl)_2-fluoroethyl]_3-[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[ 5,4_c]pyridine-2-carboxycarbonyl]amino]benzoic acid tert-butyl ester The compound of Reference Example 32 was condensed with the compound of Reference Example 90 in the same manner as in Example 3 to give the title compound. H-NMR (CDC13) δ : 1·17 (6H,d,J=6.6 Ηζ),1·58 (9H,s), 2.85-3.06 (6H,m),3.34-3.55 (1H,m),3 ·88 (2H, s), 5.36 (1H, ddd, J=49.3, 5.9, 4·1 Hz), 7·28 (2H, d, (4)·〇Hz), 7·39 (1H, d, J= 8.0 Hz), 7·41 (2H, d, Hz), 7·80 (1H, dd, J = 7.8, 1.8 Hz), 7.88 (1H, d, J = 5 9 hz), 8.39 (1H, d, J=1.7

Hz)，9·25 (1H，s)。 MS (ESI) m/z: 602 (M+H)+。 [實施例50] 4-[2-(4-氯苯基胺甲醯基）氟乙基卜3_[(5-異丙 129677.doc -153- 200840568 基_4,5,6,7_四氫嗟唾并[5,4_小比咬_2_幾基）胺基]苯甲 酸鹽 欠&lt; 以與實施例27相同的方法，由實施例49之化合物獲 題化合物。 a于標 ^H-NMR (DMS〇.d6) δ ： ^35 (3H? d5 1^6.1 Hz)? 1.37 (3^ d J-6.1 Hz), 3·12-3·49 (5H，m)，3.65-3.82 (2H，m)，4.48-4 59 (1H5 m)? 4.73 (1H? d? J=15.〇 Hz)? 5.30-5.48 (1H5 m) 7 % (2H，d，J=8.8 Hz)，7·54 (1H，d，J=8.1 Hz)，7·64 (2H d 鲁 J = 8.8 Hz), 7.82 (1H, d? J=8.l Hz), 8.01 (1H? s), l〇.33 {m s)，10.57 (1H，br s)，1〇·85 (1H，br s)，13 〇6 (1H，w s)。 ’ MS (ESI) m/z: 545 (M+H)、 [實施例51] 4-{(Ε)-2·[(‘氯苯基）胺曱醯基]乙烯基卜3、[(5 異丙基-4,5,6,7-四氫噻唑并[5,4-c]吡啶-2-羰基）胺基]笨甲 酸第三丁酯 以與實施例8相同的方法，使由參考例3 2之化合物所行 生之醯氯與參考例91之化合物反應而獲得標題化合物。 ⑩ ]H-NMR (CDCI3) δ : 1.17 (6Η, d? J=6.6 Hz), 1.60 (9H5 s) 2.88-2.98 (4H，m)，2.98-3.06 (1H，m)，3.87 (2H，s)，6 58 (1H，d，J=15.4 Hz)，7·29 (2H，d，J=8,8 Hz), 7·52·7·6〇 (3H m)，7·66-7·73 (1H，m)，7.83 (1H，dd，J=8.3，1·5 Hz)，7 89 (1H，d，J=15.4 Hz)，8·50 (1H，d，J=1.5 Hz)，9·18 (1H，br s) 0 MS (ESI) m/z: 581 (M+H)+。 [實施例52] 4-{(E)-2-[(4-氯苯基）胺甲醯基]乙烯基卜3-[(5_ 129677.doc -154· 200840568 唑并[5，tc],比啶_2_羰基）胺基]苯甲 以與實施例27相同的方 題化合物。 由汽施例51之化合物獲得標 JH-NMR (DMSO-d6) δ · j 3r „„ 、 · 138 d, J=5.9 Hz), 3.16-3.57 (3H，m)，3.65-3.88 (2H m、^ ⑽、 （H，^ 4.49-4.65 UH，m)，4·68·4.82 (1H，m)，6.94 (1H，d，J=15 z)&gt; 7·39 (2H, d, J=8.8 Hz), 7.71 (1H5 d, J=15.7 Hz) η J2 (ouHz), 9·25 (1H, s). MS (ESI) m/z: 602 (M+H)+. [Example 50] 4-[2-(4-Chlorophenylaminocarbamimidyl)fluoroethyl b 3_[(5-isopropyl 129677.doc -153- 200840568 base_4,5,6,7_four Hydroquinone [5,4 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ a Yu^H-NMR (DMS〇.d6) δ : ^35 (3H? d5 1^6.1 Hz)? 1.37 (3^ d J-6.1 Hz), 3·12-3·49 (5H, m) , 3.65-3.82 (2H, m), 4.48-4 59 (1H5 m)? 4.73 (1H? d? J=15.〇Hz)? 5.30-5.48 (1H5 m) 7 % (2H,d,J=8.8 Hz),7·54 (1H,d,J=8.1 Hz), 7·64 (2H d Lu J = 8.8 Hz), 7.82 (1H, d? J=8.l Hz), 8.01 (1H? s) , l〇.33 {ms), 10.57 (1H, br s), 1〇·85 (1H, br s), 13 〇 6 (1H, ws). ' MS (ESI) m/z: 545 (M+H), [Example 51] 4-{(Ε)-2·[('Chlorophenyl)amine fluorenyl]vinyl bromide 3, [(5 Isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl)amino]benzoic acid tert-butyl ester in the same manner as in Example 8, The chlorobenzene of the compound of Example 3 was reacted with the compound of Reference 91 to give the title compound. 10 ]H-NMR (CDCI3) δ : 1.17 (6Η, d? J=6.6 Hz), 1.60 (9H5 s) 2.88-2.98 (4H,m), 2.98-3.06 (1H,m),3.87 (2H,s ),6 58 (1H,d,J=15.4 Hz),7·29 (2H,d,J=8,8 Hz), 7·52·7·6〇(3H m),7·66-7· 73 (1H,m), 7.83 (1H,dd,J=8.3,1·5 Hz), 7 89 (1H,d,J=15.4 Hz), 8·50 (1H,d,J=1.5 Hz), 9·18 (1H, br s) 0 MS (ESI) m/z: 581 (M+H)+. [Example 52] 4-{(E)-2-[(4-chlorophenyl)aminemethanyl]vinyl b-3-[(5_129677.doc-154· 200840568 oxazolo[5,tc], Bisidine-2-carbonyl(amino)amino]benz was the same compound as in Example 27. The standard JH-NMR (DMSO-d6) δ · j 3r „„ , · 138 d, J=5.9 Hz), 3.16-3.57 (3H, m), 3.65-3.88 (2H m, obtained from the compound of the gas example 51). ^ (10), (H,^ 4.49-4.65 UH,m),4·68·4.82 (1H,m), 6.94 (1H,d,J=15 z)&gt; 7·39 (2H, d, J=8.8 Hz), 7.71 (1H5 d, J=15.7 Hz) η J2 (ou

^ 7·72 (2H, d, J=8.8 Hz), 7.85 (1H, d, J=8.3 Hz), 7.93 (iH，dd j 8·3，1.7 Hz)，8.01 (1H，d， J=1.7 Hz)? 10.59 (1H 10 qa i ，s)，10.94_u 〇9 (1H u s)，13.05-13.37 (1H，br)。 MS (ESI) m/z: 525 (M+H)+。 [實施例53]4-{(E)-2-[(5-氣口比吩9甘、a U乳疋基）胺甲醯基]乙烯基卜3- [(5_異丙基-4,5,6,7-四氫σ塞峻^「ς _ 辽巷主开[5,4-c]吡啶_2_羰基）胺基]苯 甲酸第三丁酯^ 7·72 (2H, d, J=8.8 Hz), 7.85 (1H, d, J=8.3 Hz), 7.93 (iH, dd j 8·3, 1.7 Hz), 8.01 (1H, d, J=1.7 Hz)? 10.59 (1H 10 qa i , s), 10.94_u 〇9 (1H us), 13.05-13.37 (1H, br). MS (ESI) m/z: 525 (M+H)+. [Example 53] 4-{(E)-2-[(5-air-port ratio -9g, a U nipyl)-aminomethyl hydrazino] vinyl b 3- [(5-isopropyl-4, 5,6,7-tetrahydro σ 塞 ^ ^ "ς _ Liaoxiang main open [5,4-c]pyridine_2_carbonyl) amino] benzoic acid tert-butyl ester

異丙基_4,5,6,7-四氫〇塞 酸鹽酸鹽 以與實施例8相同的方法，使由參考例32之化合物所衍 生之醯氯與參考例93之化合物反應而獲得標題化合物。 !H-NMR (CDC13) δ : 1·17 (6H，d，j=6.6 Ηζ)，1·61 (9H，S)， 2·82-3·08 (5H，m)，3.88 (2H，s)，6.64 (1H，d，J=15,6 Hz)， 7·62 (1H，d，J=8.1 Hz)，7·69 (1H，dd，J=8.9，2.6 Hz)，7.87 (1H，dd，J=8.1，1.5 Hz)，7·96 (1H，d，J=i5、6 Hz)，8·12 (1H， s)，8·24 (1H，d，J=2.6 Hz)，8·31 (1H，d，J=8.9 Hz)，8·55 (1H，d，J=L5 Hz)，9.17 (1H，s)。 MS (ESI) m/z: 582 (M+H)+。 129677.doc -155- 200840568 [實施例54] 4-{(E)-2-[(5-氯吼啶-2-基）胺甲醯基]乙烯基}-3_ [(5-異丙基-4,5,6,7-四氫噻唑并[5,4-c]吡啶-2-羰基）胺基]苯 甲酸鹽酸鹽 以與實施例27相同的方法，由實施例53之化合物獲得標 題化合物。 i-NMR (DMSO-d6) δ : 1.38 (3H，d，J=6.8 Hz)，1.40 (3H，d J = 6,8 Hz)，3·10-3·27 (1H，m)，3,30-3.54 (2H，m)，3.58-3.85 (2H，m)，4·28-4·86 (2H，m)，7.12 (1H，d，J=15,6 Hz)，7·77 (1H，d，J=15.6 Hz)，7.82 (1H，d，J=8.3 Hz)，7·89-7·97 (2H m)，8·01 (1H，s)，8·24 (1H，d，J=9.0 Hz)，8·41 (1H，d，J=2.4Isopropyl-4,5,6,7-tetrahydrophosphonate hydrochloride was obtained by reacting the ruthenium chloride derived from the compound of Reference Example 32 with the compound of Reference Example 93 in the same manner as in Example 8. Title compound. !H-NMR (CDC13) δ : 1·17 (6H,d,j=6.6 Ηζ),1·61 (9H,S), 2·82-3·08 (5H,m),3.88 (2H,s ), 6.64 (1H, d, J=15, 6 Hz), 7·62 (1H, d, J=8.1 Hz), 7·69 (1H, dd, J=8.9, 2.6 Hz), 7.87 (1H, Dd, J=8.1, 1.5 Hz), 7.96 (1H, d, J=i5, 6 Hz), 8·12 (1H, s), 8·24 (1H, d, J=2.6 Hz), 8 · 31 (1H, d, J = 8.9 Hz), 8·55 (1H, d, J = L5 Hz), 9.17 (1H, s). MS (ESI) m/z: 582 (M+H)+. 129677.doc -155- 200840568 [Example 54] 4-{(E)-2-[(5-chloroacridin-2-yl)aminemethanyl]vinyl}-3_ [(5-isopropyl) -4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-carbonyl)amino]benzoic acid hydrochloride The compound of Example 53 was obtained in the same manner as in Example 27 The title compound was obtained. i-NMR (DMSO-d6) δ : 1.38 (3H, d, J = 6.8 Hz), 1.40 (3H, d J = 6,8 Hz), 3·10-3·27 (1H, m), 3, 30-3.54 (2H,m), 3.58-3.85 (2H,m),4·28-4·86 (2H,m),7.12 (1H,d,J=15,6 Hz),7·77 (1H ,d,J=15.6 Hz),7.82 (1H,d,J=8.3 Hz),7·89-7·97 (2H m),8·01 (1H,s),8·24 (1H,d, J=9.0 Hz), 8.41 (1H, d, J=2.4

Hz)，11.01 (2H，s)，11·28-11·61 (1H，br)。 MS (ESI) m/z: 526 (M+H)+。 [實施例55]3·氯-4-{2-[(4-氯苯基）胺甲醯基]乙基卜5_[(5_異 丙基-4,5,6,7-四氫噻唑并[5,4-c]吡啶-2-羰基）胺基]苯甲峻 甲酯 以與實施例8相同的方法，使由參考例3 2之化合物所街 生之醯氯與參考例98之化合物反應而獲得標題化合物。 ^-NMR (CDC13) δ : 1.17 (6Η, d5 J=6.6 Hz), 2.86-3.08 (7H5 m)，3.22 (2H, t，J-6.5 Hz)，3,88 (2H，br s)，3.89 (3H，s) 7·24 (2H, d，J=8.8 Hz), 7.33 (1H，br s)，7·44 (2H，d，g Hz)，7·91 (1H，d，Hz)，8.38 (1H，d5 J=1.7 Hz)，1〇·5〇 (1H，br s) 〇 MS (ESI) m/z: 575 (M+H)+。 [實施例56] 3·氯·4-{2·[(4-氣苯基）胺甲醯基]乙基卜5_[(5·異 129677.doc -156- 200840568 丙基-4,5,6,7-四氫噻唑并[5,4-C]吡啶-2-羰基）胺基]苯甲駿 鹽酸鹽 以與實施例9相同的方法，由實施例55之化合物獲得襟 題化合物。 'H-NMR (DMS〇-d6) δ : 1.38 (6H5 br s)? 2.71-2.85 (2H5 m) 3·00-3·54 (5H，m)，3.61-3.87 (2H，m)，4·46-4·63 (1H，m)， 4.65-4.81 (1H，m)，7.34 (2H，d，J=9.0 Hz)，7·58 (2H, d， J=9.0 Hz)，7.85 (1H，d，J=1.7 Hz)，8.04 (1H，d，J=1.7 Hz)， 10.24 (1H? br s)5 11.01-11.19 (1H, br)? 11.07 (1H5 s)5 13.37 (1H，br s) o MS (ESI) m/z: 561 (M+H)+。 [實施例57] 3-氣-4-{2-[(4·氣苯基）胺甲醯基]乙基卜5-[(5-曱 基-4,5,6,7-四氫噻唑并[5,4-c]。比啶-2-羰基）胺基]笨甲酸甲 酯 以與實施例3相同的方法，將參考例98之化合物與5-甲 基-4,5,6,7-四氫噻唑并[5,4-c]吡啶-2-甲酸鹽酸鹽縮合而獲 得標題化合物。 1H-NMR (CDC13) δ : 2·52 (3H，s)，2·84 (2H，t，J=5.5 Hz)， 2·89 (2H，t，J=6.6 Hz)，2.98 (2H，t，J=4.9 Hz)，3·16 (2H，t， J = 6.2 Hz)，3.73 (2H，s)，3·85 (3H，s)，7.18 (2H，d，J=8.8 Hz), 7.46 (2H? d? J=8.8 Hz)? 7.83 (1H? d? J=1.5 Hz), 8.35 (1H，d，J=1.5 Hz)，8·44 (1H，s)，1〇·82 (1H，s)。 MS (ESI) m/z: 547 (M+H)+。 [實施例58] 3-氣-4-{2·[(4-氣苯基）胺甲醯基]乙基卜5-[(5-曱 129677.doc -157- 200840568 基-4,5’6,7-四氫噻唑并[5,4-c]吡啶·2_羰基）胺基]苯曱酸鹽 酸鹽 以與貝施例9相同的方法，由實施例$ 7之化合物獲得標 題化合物。 h-NMR (DMS〇-d6) δ : 2.79 (2Η，t，J=7.1 Ηζ)，2·88 (3Η， s)，3·09 (2H，t，J=7.1 Hz)，3.13-3.69 (4H，m)，4·31-4·75 (2H，br)，7.34 (2H，d，J=8.8 Hz)，7.60 (2H，d，卜8·8 Hz)， 7·84 (1H，d，J=1.7 Hz)，8.04 (1H，d，J=1.7 Hz)，10.36 (1H， Φ s)，11.07 (1H，s)。 MS (ESI) m/z: 533 (M+H)、 [實施例59] 3 -氯- 4-{2-[(4 -氟苯基）胺甲醢基]乙基}·5_[(%異 丙基-4,5,6,7-四氫噻唑并[5,4-c]吡啶-2-羰基）胺基]苯甲酸 曱酯 以與實施例8相同的方法，使由參考例32之化合物所衍 生之醯氯與參考例100之化合物反應而獲得標題化合物。 'H-NMR (CDC13) δ : 1.17 (6Η, d, J=6.6 Hz)3 2.86-3.07 (7H, ^ m)，3·23 (2H，t，J=6.5 Hz)，3·88 (2H，br s)，3·90 (3H，s)， 6·94-7·02 (3H，m)，7.41-7.48 (2H，m)，7·92 (1H，d，J=1.7 Hz)，8·39 (1H，d，J=1.7 Hz)，10·53 (1H，s)。 MS (ESI) m/z: 559 (M+H)+。 [實施例60] 3-氯-4-{2-[(4-氟苯基）胺曱醯基]乙基}-5-[(5-異 丙基-4,5,6,7-四氫噻唑并[5,4-c]吡啶-2-羰基）胺基]苯曱酸 鹽酸鹽 以與實施例9相同的方法，由實施例59之化合物獲得標 129677.doc -158- 200840568 題化合物。 ^-NMR (DMSO-d6) δ : 1.38 (6Η, d, J=6.3 Hz), 2.78 (2H, t, J = 6.7 Hz), 2.98-3.89 (7H, m), 4.40-4.82 (2H, m), 7.13 (2H, t, J=9.0 Hz), 7.59 (2H, dd, J=9.〇, 5.1 Hz), 7.85 (1H, d, J = 1.7 Hz), 8.05 (1H, d, J=1.7 Hz), l〇.27 (1H, s), 11.11 (lH, s)，11.50-12,01 (1H，br)，13.08-13.68 (1H，br)。 MS (ESI) m/z: 545 (M+H)+ 〇 [實施例61] 4-{2-[(4-氯苯基）胺甲醯基]乙基}_3_[(5異丙 • 基·4,5,6,7-四氫噻唑并[5,4_c]吡啶-2-羰基）胺基]-5-氟苯甲 酸曱酯 以與實施例8相同的方法，使由參考例π之化合物所衍 生之酿氣與參考例106之化合物反應而獲得標題化合物。 ]H-NMR (CDCI3) δ : 1.17 (6H? d5 J = 6.6 Hz), 2.83 (2H, t? J = 6.6 Hz)，2.88-3.07 (5H，m)，3·11 (2H，t，J=5.6 Hz)，3,88 (2H，br s)，3.89 (3H，s)，7·24 (2H，d，J=8.8 Hz)，7.41 (1H， br s)，7·44 (2H，d，J=8.8 Hz)，7·56 (1H，dd，J=10.0, 1.5 Hz)， 響 8.31 (1H, s)5 10.30 (1H, s) 〇 MS (ESI) m/z: 559 (M+H)、 [實施例62] 4-{2·[(4-氯笨基）胺甲醯基]乙基}-3-[(5-異丙 基·4,5,6,7-四氫噻唑并[5,4-c]吡啶-2-羰基）胺基]-5-氟苯甲 酸鹽酸鹽 以與實施例9相同的方法，由實施例61之化合物獲得標 題化合物。 !H-NMR (DMSO-d6) δ : 1.38 (6H9 d? J=6.1 Hz)? 2.76 (2H? t? 129677.doc -159- 200840568 4.85 J = 6.8 Hz)，2.92-3.04 (2H，m)，3,04-3.87 (5H，m)，4.36 (2H，m)，7·33 (2H，d，J=9.0 Hz)，7,56 (1H，dd，J=l〇,〇 'U &gt; 1 s)，Hz), 11.01 (2H, s), 11·28-11·61 (1H, br). MS (ESI) m/z: 526 (M+H)+. [Example 55] 3·Chloro-4-{2-[(4-chlorophenyl)aminemethanyl]ethyl b 5_[(5-isopropyl-4,5,6,7-tetrahydrothiazole And [5,4-c]pyridine-2-carbonyl)amino]benzil methyl ester was subjected to the same procedure as in Example 8 to give the chlorobenzene which was produced by the compound of Reference Example 32 and Reference Example 98. The compound is reacted to give the title compound. ^-NMR (CDC13) δ : 1.17 (6Η, d5 J=6.6 Hz), 2.86-3.08 (7H5 m), 3.22 (2H, t, J-6.5 Hz), 3,88 (2H, br s), 3.89 (3H, s) 7·24 (2H, d, J=8.8 Hz), 7.33 (1H, br s), 7·44 (2H, d, g Hz), 7·91 (1H, d, Hz), 8.38 (1H, d5 J=1.7 Hz), 1〇·5〇(1H, br s) 〇MS (ESI) m/z: 575 (M+H)+. [Example 56] 3·Chloro·4-{2·[(4-phenylphenyl)aminemethanyl]ethyl b 5_[(5·iso 129677.doc -156- 200840568 propyl-4,5, 6,7-Tetrathiathiazolo[5,4-C]pyridine-2-carbonyl)amino]benzamide hydrochloride The title compound was obtained from the compound of Example 55 in the same manner as in Example 9. 'H-NMR (DMS〇-d6) δ : 1.38 (6H5 br s)? 2.71-2.85 (2H5 m) 3·00-3·54 (5H, m), 3.61-3.87 (2H, m), 4· 46-4·63 (1H,m), 4.65-4.81 (1H,m), 7.34 (2H,d,J=9.0 Hz),7·58 (2H, d, J=9.0 Hz), 7.85 (1H, d, J=1.7 Hz), 8.04 (1H, d, J=1.7 Hz), 10.24 (1H? br s)5 11.01-11.19 (1H, br)? 11.07 (1H5 s)5 13.37 (1H, br s) o MS (ESI) m/z: 561 (M+H)+. [Example 57] 3-ox-4-{2-[(4·gasphenyl)aminemethanyl]ethyl b- 5-[(5-fluorenyl-4,5,6,7-tetrahydrothiazole) And [5,4-c].pyridin-2-carbonyl)amino]benzoic acid methyl ester. In the same manner as in Example 3, the compound of Reference Example 98 and 5-methyl-4,5,6, Condensation of 7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate gave the title compound. 1H-NMR (CDC13) δ : 2·52 (3H, s), 2·84 (2H, t, J = 5.5 Hz), 2·89 (2H, t, J = 6.6 Hz), 2.98 (2H, t , J=4.9 Hz), 3·16 (2H, t, J = 6.2 Hz), 3.73 (2H, s), 3·85 (3H, s), 7.18 (2H, d, J = 8.8 Hz), 7.46 (2H? d? J=8.8 Hz)? 7.83 (1H? d? J=1.5 Hz), 8.35 (1H, d, J=1.5 Hz), 8.44 (1H, s), 1〇·82 (1H , s). MS (ESI) m/z: 547 (M+H)+. [Example 58] 3-Ga-4-{2·[(4-Phenylphenyl)aminemethanyl]ethyl b 5-[(5-曱129677.doc -157- 200840568 base-4,5' 6,7-Tetrathiathiazolo[5,4-c]pyridine-2-ylcarbonyl)amino]phenylhydrazine hydrochloride The title compound was obtained from the compound of Example 7 in the same manner as in Example 9 . h-NMR (DMS〇-d6) δ : 2.79 (2Η,t,J=7.1 Ηζ), 2·88 (3Η, s),3·09 (2H,t,J=7.1 Hz),3.13-3.69 ( 4H,m),4·31-4·75 (2H,br),7.34 (2H,d,J=8.8 Hz), 7.60 (2H,d,b 8·8 Hz), 7·84 (1H,d , J = 1.7 Hz), 8.04 (1H, d, J = 1.7 Hz), 10.36 (1H, Φ s), 11.07 (1H, s). MS (ESI) m/z: 533 (M+H), [ </ RTI> </ RTI> </ RTI> 3- chloro-4-{2-[(4-fluorophenyl)amine carbamoyl]ethyl}·5_[(% Isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl)amino]benzoic acid oxime ester was obtained in the same manner as in Example 8 by reference example 32 The hydrazine chloride derived from the compound was reacted with the compound of Reference Example 100 to give the title compound. 'H-NMR (CDC13) δ : 1.17 (6Η, d, J=6.6 Hz)3 2.86-3.07 (7H, ^ m), 3·23 (2H, t, J=6.5 Hz), 3·88 (2H , br s), 3·90 (3H, s), 6·94-7·02 (3H, m), 7.41-7.48 (2H, m), 7.92 (1H, d, J = 1.7 Hz), 8·39 (1H, d, J = 1.7 Hz), 10.53 (1H, s). MS (ESI) m/z: 559 (M+H)+. [Example 60] 3-Chloro-4-{2-[(4-fluorophenyl)amine fluorenyl]ethyl}-5-[(5-isopropyl-4,5,6,7-tetra Hydrothiazolo[5,4-c]pyridine-2-carbonyl)amino]benzoquinone hydrochloride The title compound 129677.doc-158-200840568 was obtained from the compound of Example 59 in the same manner as in Example 9. Compound. ^-NMR (DMSO-d6) δ : 1.38 (6Η, d, J = 6.3 Hz), 2.78 (2H, t, J = 6.7 Hz), 2.98-3.89 (7H, m), 4.40-4.82 (2H, m ), 7.13 (2H, t, J=9.0 Hz), 7.59 (2H, dd, J=9.〇, 5.1 Hz), 7.85 (1H, d, J = 1.7 Hz), 8.05 (1H, d, J= 1.7 Hz), l〇.27 (1H, s), 11.11 (lH, s), 11.50-12, 01 (1H, br), 13.08-13.68 (1H, br). MS (ESI) m/z: 545 (M+H) + 〇 [Example 61] 4-{2-[(4-chlorophenyl)amine-carbamoyl]ethyl}_3_[(5 isopropyl) · 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl)amino]-5-fluorobenzoic acid oxime ester in the same manner as in Example 8, by reference example π The brewer gas derived from the compound was reacted with the compound of Reference Example 106 to give the title compound. ]H-NMR (CDCI3) δ : 1.17 (6H? d5 J = 6.6 Hz), 2.83 (2H, t? J = 6.6 Hz), 2.88-3.07 (5H, m), 3·11 (2H, t, J =5.6 Hz),3,88 (2H,br s),3.89 (3H,s),7·24 (2H,d,J=8.8 Hz), 7.41 (1H, br s), 7·44 (2H, d, J = 8.8 Hz), 7·56 (1H, dd, J = 10.0, 1.5 Hz), 8.31 (1H, s)5 10.30 (1H, s) 〇MS (ESI) m/z: 559 (M +H), [Example 62] 4-{2·[(4-chlorophenyl)aminemethanyl]ethyl}-3-[(5-isopropyl-4,5,6,7-tetra Hydrothiathiazolo[5,4-c]pyridin-2-carbonyl)amino]-5-fluorobenzoic acid hydrochloride The title compound was obtained from the compound of Example 61. !H-NMR (DMSO-d6) δ : 1.38 (6H9 d? J=6.1 Hz)? 2.76 (2H? t? 129677.doc -159- 200840568 4.85 J = 6.8 Hz), 2.92-3.04 (2H, m) ,3,04-3.87 (5H,m),4.36 (2H,m),7·33 (2H,d,J=9.0 Hz),7,56 (1H,dd,J=l〇,〇'U &gt ; 1 s),

Hz)，7·60 (2H，d，J=9.0 Hz)，7·98 (1H，br s)，10.35 10.97 (1H，s)，11·57-12·00 (1H，br)。 MS (ESI) m/z: 545 (M+H)+ 〇 [實施例63] 4-{2-[(4-氯苯基）胺曱醯基]乙基卜3·[(5、異 基-4,5,6,7-四氫噻唑并[5,4-c；h比啶-2-羰基）胺基]_5_甲^ 氣基 苯曱酸甲酯Hz), 7·60 (2H, d, J=9.0 Hz), 7·98 (1H, br s), 10.35 10.97 (1H, s), 11·57-12·00 (1H, br). MS (ESI) m/z: 545 (M+H) + 〇 [EXAMPLE 63] 4-{2-[(4-chlorophenyl)amine fluorenyl]ethyl b. -4,5,6,7-tetrahydrothiazolo[5,4-c;h-pyridyl-2-carbonyl)amino]_5_methylsulfonate

以與實施例8相同的方法，使由參考例32之化合铷&amp; 生之醯氣與參考例110之化合物反應而獲得標題化合物。 ]H-NMR (CDC13) δ ： 1.17 (6H? d? J=6.6 Hz), 2.78 (2tl ，15 J = 6.6 Hz)，2.84-3.11 (7H，m)，3.84 (3H，s)，3·88 (2H，br s) 3·89 (3H，s)，7.23 (2H，d，J=8,8 Hz)，7·38 (1H，d，jy 5 Hz)，7·43 (2H，d，J=8.8 Hz)，7·48 (1H，br s)，8.08 (1H，s)， 10.09 (1H，s)。 MS (ESI) m/z: 571 (M+H)+。 [實施例64] 4-{2-[(4-氯苯基）胺甲薩基]乙基}-3-[(5 -異丙 基-4,5,6,7-四氫噻唑并[5,4-c]吡啶-2-羰基）胺基甲氧基 苯甲酸鹽酸鹽 以與實施例9相同的方法，由實施例63之化合物獲得標 題化合物。 W-NMR (DMSO-d6) δ : 1·38 (6H，br s)，2·69-2·77 (2H，m)， 2.85-2,95 (2H，m)，3.05-3.52 (3H，m)，3.60-3.85 (2H，m)， 3·91 (3H，s)，4.43-4.81 (2H，m)，7·33 (2H，d，Hz)， 129677.doc •160- 200840568 7.40 (1H，br s)，7.59 (2H，d，J=8.8 Hz)，7.76 (1H，d，J=i.〇In the same manner as in Example 8, the title compound was obtained by reacting the hydrazine of &lt;&apos;&gt; ]H-NMR (CDC13) δ : 1.17 (6H? d? J=6.6 Hz), 2.78 (2tl, 15 J = 6.6 Hz), 2.84-3.11 (7H, m), 3.84 (3H, s), 3· 88 (2H, br s) 3·89 (3H, s), 7.23 (2H, d, J=8, 8 Hz), 7·38 (1H, d, jy 5 Hz), 7·43 (2H, d , J = 8.8 Hz), 7.48 (1H, br s), 8.08 (1H, s), 10.09 (1H, s). MS (ESI) m/z: 571 (M+H)+. [Example 64] 4-{2-[(4-Chlorophenyl)amine mesatyl]ethyl}-3-[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[ 5,4-c]pyridine-2-carbonyl)aminomethoxybenzoic acid hydrochloride The title compound was obtained from the compound from m. W-NMR (DMSO-d6) δ : 1·38 (6H, br s), 2·69-2·77 (2H, m), 2.85-2, 95 (2H, m), 3.05-3.52 (3H, m), 3.60-3.85 (2H, m), 3·91 (3H, s), 4.43-4.81 (2H, m), 7·33 (2H, d, Hz), 129677.doc • 160- 200840568 7.40 ( 1H, br s), 7.59 (2H, d, J = 8.8 Hz), 7.76 (1H, d, J = i.〇

Hz)? 10.20 (1H5 S)5 10.91 (1H? s)? 11.23-11.56 (1H5 br)? 12.63-13.22 (1H，br)。 MS (ESI) m/z: 557 (M+H)、 [實施例65] 4-{2-[(4-氯苯基）胺曱醯基]乙基卜3-甲氧基巧· [(5-甲基-4,5,6,7-四氫噻唑并[5,4-c]吼啶-2-羰基）胺基]笨甲 酸甲ϊ旨 以與實施例3相同的方法，將參考例丨丨〇之化合物與％甲 _ 基_4,5,6,7-四氫噻唑并[5,4-c]吡啶-2-甲酸鹽酸鹽縮合而獲 得標題化合物。 ]H-NMR (CDC13) δ : 2.54 (3H5 s)5 2.81 (2H? t? J=6.6 Hz)? 2·86 (2H，t，J=5.7 Hz)，3·00 (2H，t，J=5.7 Hz)，3·07 (2H，t J=6.6 Hz)，3·76 (2H，br s)，3.82 (3H，s)，3·89 (3H，s)，7·23 (2H，d，J=8.8 Hz)，7·37 (1H，d，J=1.2 Hz)，7·41-7·49 (3H m)，8.09 (1H，s)，10.21 (1H，s)。 MS (ESI) m/z: 543 (M+H)+。 [實施例66] 4-{2-[(4-氯苯基）胺甲醯基]乙基卜3-甲氧基_5_ [(5 -甲基-4,5，6,7-四氫嗟唑并[5，4-c]吼唆-2-羰基）胺基]笨甲 酸鹽酸鹽 以與實施例9相同的方法，由實施例65之化合物獲得_ 題化合物。 】H-NMR (DMSO-d6) δ : 2·74 (2H，t，J=6.8 Hz), 2.86-2 95 (5H，m)，3·12-3·68 (4H，m)，3·90 (3H，s)，4·44·4,7〇 (2jj m)，7.33 (2H，d，J=9.0 Hz)，7·39 (1H，d，J=l.2 Hz)，7 61 129677.doc -161 - 200840568 10.29 (ih，s)， (2H, d, J=9.0 Hz), 7.76 〇H, d, J=1.2 Hz)? 10·92 (1H，s)，11.73-12.17 (1H，br)。 MS (ESI) m/z: 529 (M+H)+ 〇 [實施例67] 4-{2·[(4_氟苯基）胺甲酿基]乙基}_3你異两 基-4,5,6,7-四氫嗟唾并[5,4外比咬-2-幾基）胺基甲氧式 苯曱酸甲酯 1 以與實施例3相同的方法，將參考例ιΐ2之化合物與表考 例32之化合物縮合而獲得標題化合物。Hz)? 10.20 (1H5 S)5 10.91 (1H? s)? 11.23-11.56 (1H5 br)? 12.63-13.22 (1H, br). MS (ESI) m/z: 557 (M+H), [EXAMPLE 65] 4-{2-[(4-chlorophenyl)amine fluorenyl]ethyl b. 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]acridin-2-carbonyl)amino]benzoic acid formazan is used in the same manner as in Example 3, and will be referred to. The title compound was obtained by condensation of a compound of the title compound with a </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; ]H-NMR (CDC13) δ : 2.54 (3H5 s)5 2.81 (2H? t? J=6.6 Hz)? 2·86 (2H, t, J=5.7 Hz), 3·00 (2H, t, J =5.7 Hz),3·07 (2H,t J=6.6 Hz),3·76 (2H,br s),3.82 (3H,s),3·89 (3H,s),7·23 (2H, d, J = 8.8 Hz), 7.37 (1H, d, J = 1.2 Hz), 7·41-7·49 (3H m), 8.09 (1H, s), 10.21 (1H, s). MS (ESI) m/z: 543 (M+H)+. [Example 66] 4-{2-[(4-Chlorophenyl)aminecarbamyl]ethyl b 3-methoxy_5_ [(5-methyl-4,5,6,7-tetrahydro) The oxazo[5,4-c]indole-2-carbonyl)amino] hydrazide hydrochloride was obtained from the compound of Example 65 in the same manner as in Example 9. H-NMR (DMSO-d6) δ : 2·74 (2H, t, J = 6.8 Hz), 2.86-2 95 (5H, m), 3·12-3·68 (4H, m), 3· 90 (3H, s), 4·44·4, 7〇 (2jj m), 7.33 (2H, d, J=9.0 Hz), 7·39 (1H, d, J=l.2 Hz), 7 61 129677.doc -161 - 200840568 10.29 (ih,s), (2H, d, J=9.0 Hz), 7.76 〇H, d, J=1.2 Hz)? 10·92 (1H, s), 11.73-12.17 ( 1H, br). MS (ESI) m/z: 529 (M+H)+ 〇 [Example 67] 4-{2·[(4-fluorophenyl)amine]]]}}} 5,6,7-tetrahydroindolizine [5,4 exo-2-mercapto)methylaminomethoxybenzoate 1 In the same manner as in Example 3, the compound of Reference Example ι 2 was used. Condensation with the compound of Table 32 gave the title compound.

•H.NMR (CDC13) δ: 1.16 (6H, d, J=6 6 Hz)&gt; 2 ?9 (2H t 1=6.5 Hz)，2.86-3,09 (7H，m)，3 % (3H, s), 3 87 (2h，w， 3·89 (3H，s)，6/90-6.99 (2H，m)，7·34 (1H，d，J=i.2 Hz) 7.40-7.48 (2H，m)，7.69 (1H，br s)，8·ι〇 (1H，d，J=i.2 10.25 (1H，s)。 Z)， MS (ESI) m/z: 555 (M+H)、 [實施例68] 4-{2-[(4-氟苯基）胺甲醯基]乙基卜夂[(^異 基·4,5,6,7-四氫噻唑并[5,4-c]吡啶-2-羰基）胺基甲氧義 苯甲酸鹽酸鹽 &amp; 以與實施例9相同的方法， 題化合物。 由實施例67之化合物獲得秩 'H-NMR (DMSO-d6) δ : 1.38 (6H? br s) 2 72 (2H t Hz)? 2.84-2.96 (2H, m), 3.03-3.50 (3H5 m)? 3.58^3.84 (2h m)，3.91 (3H，s)，4·38-4·81 (2H，m)，7.12 (2H，t，Jq 〇 ’• H. NMR (CDC13) δ: 1.16 (6H, d, J=6 6 Hz)&gt; 2 ?9 (2H t 1 = 6.5 Hz), 2.86-3, 09 (7H, m), 3 % (3H , s), 3 87 (2h, w, 3·89 (3H, s), 6/90-6.99 (2H, m), 7·34 (1H, d, J=i.2 Hz) 7.40-7.48 ( 2H,m), 7.69 (1H,br s),8·ι〇(1H,d,J=i.2 10.25 (1H,s). Z), MS (ESI) m/z: 555 (M+H ), [Example 68] 4-{2-[(4-Fluorophenyl)aminemethanyl]ethylidene [(^isoyl·4,5,6,7-tetrahydrothiazolo[5, 4-c]pyridine-2-carbonyl)aminomethoxybenzoic acid hydrochloride &amp; Compound was obtained in the same manner as in Example 9. The title 'H-NMR (DMSO- D6) δ : 1.38 (6H? br s) 2 72 (2H t Hz)? 2.84-2.96 (2H, m), 3.03-3.50 (3H5 m)? 3.58^3.84 (2h m), 3.91 (3H, s) ,4·38-4·81 (2H,m),7.12 (2H,t,Jq 〇'

Hz) 7·39 (1H，d，Ρ1·2 Hz)，7·59 (2H，dd，J=8.9 5 1 M、 ， ’ z)&gt; 7.77 (1H，d，Ρ1·2 Hz)，1〇·18 (1H，s)，1〇·94 〇H，s)，u 5i ^ ^ 129677.doc -162- 200840568 (1H，br)，12.81-13.25 (1H，br)。 MS (ESI) m/z: 541 (M+H)+。 [實施例69] 4-{2-[(4-氣苯基）胺曱基]乙基卜 基-4,5,6,7-四氫噻唑并[5,4_c]吡啶-2-羰基）胺基]-5-(三氣甲 基）苯甲酸甲酯 以與實施例8相同的方法，使由參考例3 2之化合物所&amp; 生之醯氣與參考例119之化合物反應而獲得標題化合物。 iH-NMR (CDC13) δ : 1.17 (6H，d，J=6.6 Hz)，2.47-3.09 (7¾ _ m)，3.33 (2H，t，J=7.2 Hz)，3.87 (2H，s)，3.93 (3H，s)5 7·2ι 7.28 (3H，m)，7·43 (2H，d，J=8,8 Hz)，8·22 (1H，d，㈣ 2 Hz)，8·75 (1H，d，J=1.2 Hz)，10.01 (1H，s)。 MS (ESI) m/z: 609 (M+H)+。 [實施例70] 4-{2-[(4-氯笨基）胺甲醯基]乙基}-3_[(5_異丙 基-4,5,6,7-四氫噻唑并[5,4-c]吼啶-2-羰基）胺基]·5_(三氟甲 基）苯甲酸鹽酸鹽 以與實施例9相同的方法，由實施例69之化合物獲得標 ®題化合物。 'H-NMR (DMSO-d6) δ : 1.36 (6H? d5 J=6.3 Hz), 2.50-2.63 (2H，m)，3.01-3.56 (5H，m)5 3·59-3·86 (2H，m)，4·40-4·83 (2H，m)，7.34 (2H，d，J=9.0 Hz)，7·55 (2H，d，J=9.0 Hz)， 8.14 (1H，s)，8.25 (1H，s)，10.15 (1H，s)，10.96 (1H，s)， 10·97-11·18 (1H，br)。 MS (ESI) m/z: 595 (M+H)+。 [實施例71] 4-{2-[(4-氯苯基）胺甲酿基]乙基-甲基_ 129677.doc -163- 200840568 C]吡啶-2-羰基）胺基]-5-(三氟甲基） 4,5,6,7-四氫ϋ塞吐并[5,4 苯曱酸甲酯 以與實施例3相同的 方法’將參考例119之化合物與5 _甲 基-4,5,6,7·四氫噻唑其 王开15,4-C]吡啶_2_曱酸鹽酸鹽縮合而 得標題化合物。 &amp; H NMR (CDC13) δ : 2·53 (3H，s)，2,74 (2H，t,】=7·2 HZ)， 2.82 (2H，t，J-5.9 Hz)，2.90-2.96 (2H，m)，3·34 (2H，t，Hz) 7·39 (1H, d, Ρ1·2 Hz), 7·59 (2H, dd, J=8.9 5 1 M, , 'z)&gt; 7.77 (1H, d, Ρ1·2 Hz), 1 〇·18 (1H, s), 1〇·94 〇H, s), u 5i ^ ^ 129677.doc -162- 200840568 (1H, br), 12.81-13.25 (1H, br). MS (ESI) m/z: 541 (M+H)+. [Example 69] 4-{2-[(4-Phenylphenyl)aminoindenyl]ethylidyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl) Amino]-5-(trimethylmethyl)benzoic acid methyl ester The title compound was obtained by reacting the compound of Reference Example 32 with the compound of Reference Example 119 in the same manner as in Example 8 to obtain the title. Compound. iH-NMR (CDC13) δ : 1.17 (6H, d, J = 6.6 Hz), 2.47-3.09 (73⁄4 _ m), 3.33 (2H, t, J = 7.2 Hz), 3.87 (2H, s), 3.93 ( 3H,s)5 7·2ι 7.28 (3H,m),7·43 (2H,d,J=8,8 Hz),8·22 (1H,d,(iv) 2 Hz),8·75 (1H, d, J = 1.2 Hz), 10.01 (1H, s). MS (ESI) m/z: 609 (M+H)+. [Example 70] 4-{2-[(4-Chlorophenyl)aminemethanyl]ethyl}-3_[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5] , 4-c] acridine-2-carbonyl)amino]-5-(trifluoromethyl)benzoic acid hydrochloride The title compound was obtained from the compound of Example 69 in the same manner as in Example 9. 'H-NMR (DMSO-d6) δ : 1.36 (6H? d5 J=6.3 Hz), 2.50-2.63 (2H, m), 3.01-3.56 (5H, m) 5 3·59-3·86 (2H, m),4·40-4·83 (2H,m), 7.34 (2H,d,J=9.0 Hz),7·55 (2H,d,J=9.0 Hz), 8.14 (1H,s), 8.25 (1H, s), 10.15 (1H, s), 10.96 (1H, s), 10·97-11·18 (1H, br). MS (ESI) m/z: 595 (M+H)+. [Example 71] 4-{2-[(4-Chlorophenyl)amine-methanol]ethyl-methyl- 129677.doc -163- 200840568 C]pyridine-2-carbonyl)amino]-5- (Trifluoromethyl) 4,5,6,7-tetrahydromethane oxime [5,4 benzophenone methyl ester in the same manner as in Example 3] The compound of Reference Example 119 and 5 _methyl- 4,5,6,7-tetrahydrothiazole, the title compound was obtained by condensation of 15,4-C]pyridine-2-hydrazine hydrochloride. &amp; H NMR (CDC13) δ : 2·53 (3H, s), 2, 74 (2H, t, 】=7·2 HZ), 2.82 (2H, t, J-5.9 Hz), 2.90-2.96 ( 2H,m),3·34 (2H,t,

J 7.2 Hz), 3.74 (2H5 s)5 3.93 (3H? s), 7.23 (1H? br s), 7.26 (2H, d? J=8.8 Hz)? 7.44 (2H5 d3 J=8.8 Hz)5 8.22 〇Η d 卜1.5HZ)，8.74(1H，d，&gt;l5Hz)，1()()7(iH，s)。 ， MS (ESI) m/z: 581 (M+H)+ 〇 [實施例72] 4-{2-[(4-氯苯基）胺甲醯基]乙基卜3_[(5_甲基· 4,5,6,7-四氫噻唑并[5,4-c]咄啶羰基）胺基]_5_(三氟甲基） 苯曱酸鹽酸鹽 以與實施例9相同的方法，由實施例7丨之化合物獲得標 題化合物。 h-NMR (DMSO-d6) δ : 2.55-2.65 (2H，m)，2.91 (3H，s) 2.98-3.79 (6H，m)，4·36-4·84 (2H，m)，7·34 (2H，d，J=8.8 Hz)，7·61 (2H，d，J=8.8 Hz)，8·12 (1H，s)，8.25 (1H，s)， 10·41 (1H，s)，10,98 (1H，s)，12.05-12.38 (1H，br)。 MS (ESI) m/z: 567 (M+H)+。 [實施例73] 3-[2-(4-氯苯基胺甲醯基）乙基;μ4-[(5_異丙基_ 4,5,6,7-四氫噻唑并[5,4-c]吼啶-2-羰基）胺基]苯甲酸甲酉旨 以與實施例8相同的方法，使由參考例32之化合物所衍 129677.doc -J64- 200840568 生之醯氣與參考例123之化合物反應而獲撂拆 又化合物。 'H-NMR (CDC13) δ : 1.17 (6H? d5 J=6.3 Hz) 2 77 J=7.1 Hz)，2.88-2.98 (4H，m)，2.98-3.06 (m 、 ’ (1H，m)，3·13 ⑽ t，J=7.1 Hz)，3·87 (2H，br s)，3.90 (3H s、7 % ，s)，7.24 (2H，d， 1=8.8 Hz), 7.38-7.45 (3H? m), 7.90-7 96 Ou 、J 7.2 Hz), 3.74 (2H5 s)5 3.93 (3H? s), 7.23 (1H? br s), 7.26 (2H, d? J=8.8 Hz)? 7.44 (2H5 d3 J=8.8 Hz)5 8.22 〇 Η d 卜 1.5HZ), 8.74 (1H, d, &gt; l5Hz), 1()()7(iH, s). , MS (ESI) m/z: 581 (M+H)+ 〇 [Example 72] 4-{2-[(4-chlorophenyl)amine-carbamoyl]ethyl b- 3-[(5-methyl) · 4,5,6,7-tetrahydrothiazolo[5,4-c]acridinylcarbonyl)amino]-5-(trifluoromethyl)benzoquinone hydrochloride in the same manner as in Example 9, The compound of Example 7 was obtained as the title compound. h-NMR (DMSO-d6) δ : 2.55-2.65 (2H, m), 2.91 (3H, s) 2.98-3.79 (6H, m), 4·36-4·84 (2H, m), 7.34 (2H,d,J=8.8 Hz),7·61 (2H,d,J=8.8 Hz),8·12 (1H,s), 8.25 (1H,s), 10·41 (1H,s), 10,98 (1H, s), 12.05-12.38 (1H, br). MS (ESI) m/z: 564 (M+H)+. [Example 73] 3-[2-(4-Chlorophenylaminocarbamimidyl)ethyl; μ4-[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4 -c] acridine-2-carbonyl)amino]benzoic acid formazan. In the same manner as in Example 8, the oxime produced by the compound of Reference Example 32, 129677.doc-J64-200840568, and the reference example were obtained. The compound of 123 is reacted to obtain a compound. 'H-NMR (CDC13) δ : 1.17 (6H? d5 J=6.3 Hz) 2 77 J=7.1 Hz), 2.88-2.98 (4H, m), 2.98-3.06 (m , ' (1H, m), 3 ·13 (10) t, J=7.1 Hz), 3·87 (2H, br s), 3.90 (3H s, 7 %, s), 7.24 (2H, d, 1 = 8.8 Hz), 7.38-7.45 (3H? m), 7.90-7 96 Ou,

• Ό m)5 8.08 (1H d5 J=8.3 Hz)，9·77 (1H，bi: s)。 ， MS (ESI) m/z: 541 (M+H)、 [實施例74] 3·[2·(4_氣苯基胺甲醯基）乙基]里 以與實施例9相同的方法，由實施例73之化合物;; &gt;H-NMR(DMSO-d6) δ ^.37(3^^1=6.3 Hz) 1 39 (3H d ；=6.1Ηζ), 2.73 (2H, , J=7.3 Hz), 2.99 (2H&gt; t&gt; J=? 3 r ? 3.10-3.23 (1H, m)s 3.25-3.53 (2H, m), 3.64-3.86 (2H, m)； 4.48-4.62 (1H，m)，4.68-4.80 (1H，m)，7 33 (2h，d 卜8 8 HZ)，7.5M2H，d，J=8.8 Hz)，7.67 (1H，^ j=8 3 叫，7μ (1H，dd，J=8.3，1·7 Hz) 7 Mu i ^7·95(1Η, d, J=1.7 Hz), 10.17 (1H, s)，10.70 (1H，s)，10.90-u 〇5 n (1H，br)，12.73-13.08 (1H， br)。 ， MS (ESI) m/z: 527 (M+H)+ 〇 [實施例75]4_[(4_氯苯基）胺甲酿基]氧基甲基-3-[(5-異丙 基-4’5’Μ·四氫以并[⑷]m幾基）胺基]苯曱酸第 三丁酯 以與實施例3相同的方法， 將參考例32之化合物與參考 129677.doc •165、 200840568 例127之化合物縮合而獲得標題化合物。 i-NMR (CDC13) δ : 1·15 (6H，d，J=6.6 Ηζ)，ΐ·55 (9H s) 2·79-2·88 (4H，m)，2.96-3.05 (1H，m)，3·86 (2H，s) 5 ” (2H，s)，6.97 (1H，br s)，7.20 (1H，br s)，7·27 (2H，d，J=10 〇• Ό m)5 8.08 (1H d5 J=8.3 Hz), 9·77 (1H, bi: s). , MS (ESI) m/z: 541 (M+H), [Example 74] 3·[2·(4-(p-phenylphenylmethylamino)ethyl), in the same manner as in Example 9, Compound of Example 73;; &gt; H-NMR (DMSO-d6) δ ^.37 (3^^1 = 6.3 Hz) 1 39 (3H d ;=6.1Ηζ), 2.73 (2H, , J=7.3 Hz), 2.99 (2H&gt;t&gt; J=? 3 r ? 3.10-3.23 (1H, m)s 3.25-3.53 (2H, m), 3.64-3.86 (2H, m); 4.48-4.62 (1H, m) , 4.68-4.80 (1H, m), 7 33 (2h, d Bu 8 8 HZ), 7.5M2H, d, J=8.8 Hz), 7.67 (1H, ^ j=8 3 call, 7μ (1H, dd, J=8.3,1·7 Hz) 7 Mu i ^7·95(1Η, d, J=1.7 Hz), 10.17 (1H, s), 10.70 (1H, s), 10.90-u 〇5 n (1H, Br), 12.73-13.08 (1H, br)., MS (ESI) m/z: 527 (M+H) + 〇 [Example 75] 4_[(4-chlorophenyl)amine] Methyl-3-[(5-isopropyl-4'5'Μ·tetrahydrofuro[(4)]m))amino]benzoic acid tert-butyl ester in the same manner as in Example 3, The compound of Reference Example 32 was condensed with a compound of Reference 129677.doc • 165, 200840568 Example 127 to give the title compound: i-NMR (CDC13) δ: 1·15 (6H, d, J = 6.6 Ηζ), ΐ·55 ( 9H s) 2·79-2· 88 (4H, m), 2.96-3.05 (1H, m), 3·86 (2H, s) 5 ” (2H, s), 6.97 (1H, br s), 7.20 (1H, br s), 7· 27 (2H,d,J=10 〇

Hz)，7·33 (2H，d，J=8.8 Hz)，7·43 (1H，d，】=7·8 Hz) ? (1H，dd，J=7.8, 1.7 Hz)，8.73 (1H，d，J=1.7 HZ)，9·8ι (1H s) ° MS (ESI) m/z: 580 (M+H)+。 _ [實施例76] 4-[(4-氣苯基）胺甲醯基]氧基曱基_3七5_異丙 基-4,5,6,7-四氫噻嗅并[5,4-c]。比啶-2-羰基）胺基]苯甲酸趟 酸鹽 以與實施例27相同的方法，由實施例75之化合物獲得桿 題化合物。 ^NMR (DMSO-d6) δ : 1.36 (6H，t，J=6、0 Hz)，3.06-3 14 (1H，m)，3·20-3·47 (2H，m)，3.66-3.80 (2H，m)，4·48_4 59 (1H，m)，4.70-4.78 (1H，m)，5·24 (1H，d，J=13.4 Hz)，5·28 (1H，d，J=13.4 Hz)，7·33 (2H，d，J=8.8 Hz)，7·45 (2H d J = 8.8 Hz)，7·63 (1H，d，Hz)，7·88 (1H，dd，J=8.3, 1.7Hz),7·33 (2H,d,J=8.8 Hz),7·43 (1H,d,]=7·8 Hz) ? (1H,dd,J=7.8, 1.7 Hz), 8.73 (1H, d, J = 1.7 HZ), 9·8ι (1H s) ° MS (ESI) m/z: 580 (M+H)+. _ [Example 76] 4-[(4-Phenylphenyl)aminemethanyl]oxyindenyl_3-7-5-isopropyl-4,5,6,7-tetrahydrothiazolidine [5, 4-c]. Pyridin-2-carbonyl)amino]benzoic acid oximeate The title compound was obtained from the compound of Example 75 in the same manner as in Example 27. ^NMR (DMSO-d6) δ : 1.36 (6H, t, J = 6, 0 Hz), 3.06-3 14 (1H, m), 3·20-3·47 (2H, m), 3.66-3.80 ( 2H,m),4·48_4 59 (1H,m), 4.70-4.78 (1H,m),5·24 (1H,d,J=13.4 Hz),5·28 (1H,d,J=13.4 Hz ), 7·33 (2H, d, J=8.8 Hz), 7·45 (2H d J = 8.8 Hz), 7·63 (1H, d, Hz), 7·88 (1H, dd, J=8.3 , 1.7

Hz)，8·10 (1H，d，J=1.5 HZ)，lo.oo (1H，s)，1〇 69 (1H, s)， 10.75 (1H，br s)，13·13 (1H，s)。 MS (ESI) m/z: 529 (M+H)+。 [實施例77] 4-[(5-氯咏啶-2-基）胺甲醯基]氧基甲基_3_[(5-異丙基-4,5,6,7-四氫噻嗤并[5,4-c]吨啶-2-羰基）胺基]苯曱 酸第三丁酯 129677.doc 166 - 200840568 以與貝施例3相同的方法，將參考例32之化合物與參考 例129之化合物縮合而獲得標題化合物。 Η-NMR (CDC13) δ : 1.16 (6H，d，j=6 6 Ηζ)，1·54 (9Ή，s)， 2.89 (4H，s)，2·96-3·〇5 (1H，m)，3』7 (2H，s)，5.36 (2H，s)， 7.44 (1H，d，J=7.8 Hz)，7.67 (1H，br s)，7_65 (1H，dd，J=9-0, 2·4 Hz)，7·82 (1H，dd，j=8.1，1·7 Hz)，7.93 (1H，d，J=8.5 Hz)，8.19 (1H，d，J = 2.4 Hz)，8·74 (1H，d，J=1.7 Hz)，9.84 (1H，s) 〇 MS (ESI) m/z: 586 (M+H)+。 [實施例78] 4-[(5-氣。比啶基)胺曱醯基]氧基甲基-3-[(5-異丙基-4,5，6,7-四氫噻唑并[5，4_c]吡啶羰基）胺基]苯甲 酸鹽酸鹽 以與實施例27相同的方法，由實施例77之化合物獲得標 題化合物。 W-NMR (DMSO-d6) δ : 1·36 (3H，d，J = 6.1 Ηζ)，1·37 (3H，d， J=6.1 Hz)，3.06-3.15 (1H，m)，3.23-3.35 (1H，m)，3·37-3·47 (1H，m)，3·65-3·80 (2H，rn)，4,48-4.58 (1H，m)，4·73 (1H，d， J=15.1 Hz)，5·29 (2H，s)，7.66 (1H，d，J=8.1 Hz)，7·80 (1H， d，J=8.8 Hz)，7.85-7.91 (2H，m)，8.10 (1H，s)，8.31 (1H，s)， 10·58 (1H，s)，10.67 (1H，s)，1〇·99 (1H，s)。 MS (ESI) m/z: 530 (M+H). 〇 [實施例79] 4-[3-(4-氯苯基）脲基甲基]-3-[(5-異丙基-4,5,6,7-四氫°塞嗤并[5,4-〇]°比。定-2-羰基）胺基]苯甲酸第三 丁酯 129677.doc -167- 200840568 向參考例130之化合物（490 1^)的〇1^?(12 m〇溶液中依 序添加水（4 ml)、無水氯化鐵（3)(642 mg)、鋅末（863 mg) ’攪拌3 0分鐘。向反應液中添加乙酸乙酯，藉由使用 敦鎭石進行過濾而過濾去除不溶物。以乙酸乙醋清洗不溶 物，將濾液之有機層分離。將有機層以水清洗5次，以無 水NhSCU乾燥。於減壓下餾去溶劑，獲得粗製之3_胺基 [3-(4-氣苯基）脲基曱基]苯曱酸第三丁酯（4h 。 向參考例32之化合物（260 mg)的二氣甲烷（5 mi)懸浮液 _ 中添加草醯氣（277 P1)及DMF(1滴），於室溫下檀拌1⑽分 鐘。於減壓下餾去溶劑，將殘渣之二氣甲烷（15 ml)溶液添 加至粗製之3-胺基-4-[3-(4-氯苯基）脲基甲基]苯曱酸第三 丁酯（435 mg)與ΤΕΑ(212 μΐ)的二氯曱烷（3〇 ml)溶液中。攪 拌15分鐘後，向反應液中添加飽和NaHC〇3水溶液，將有 機層分離。以無水NajO4乾燥後，於減壓下餾去溶劑。將 殘渣以矽膠層析法（二氣甲烷：乙酸乙酯=1 : 1—丨：2)進 行精製後，添加醚進行濾取，獲得標題化合物（125 mg)。 Ή-NMR (CDC13) δ: 1·15 (6H，d，J=6.4 Ηζ)，1·58 (9H，s) 2·86 (4H，s)，2·96-3·06 (1H, m)，3.83 (2H，s)，4.47 (2H，d J=5.6 Hz)，5·53 (1H，s)，6·74 (1H，s)，7·22 (2H，d，J = 8,8 Hz)，7·30 (2H，d，J=8.8 Hz)，7·44 (1H，d，J=8.1 Hz)，7.80 (1H，d，J=8.1 Hz)，8·24 (1H，s)，9·50 (1H，s) 〇 MS (ESI) m/z: 584 (M+H)+ 〇 [實施例80] 4-[3-(4-氣苯基）脲基甲基]_3_[(5_異丙基· 4,5，6,7-四氫嗟。坐并[5,4-c]11比唆-2-幾基）胺基]苯甲酸鹽酸鹽 129677.doc -168- 200840568 以與實施例27相同的方法，由實施例77之化合物獲得標 題化合物。 lH-NMR (DMSO-d6) δ ： ι.35 (3Η, d? J=5.6 Hz)5 1.37 (3H5 d5 J=5.6 Hz), 3.10-3.51 (3H) m)? 3.66-3.82 (2H5 m)5 4.35 (2H5 d，J=5.9 Hz)，4.50-4.60 (ih，m)，4·70·4·78 (1H, m)，6.86 (1H, t, J=5.6 Hz), 7.26 (2H5 d5 J=8.8 Hz)? 7.42 (2H5 d, J = 8.6 Hz)，7·51 (1H，d，J=7.8 Hz)，7·82 (1H，d，K3 Hz)， 8.08 (1H，s)，9.01 (1H，s)，10.69 (1H，br s)，10.91 (1H，s)， 13.03 (1H，s)。 MS (ESI) m/z: 528 (M+H)+。 [實施例81] 4-{2_[(4-氣苯基）胺甲醯基]乙基卜3_乙氧基_5_ [(5-異丙基-4,5,6,7,氫噻唑并[5，“]σ比啶_2_基頂基胺基] 苯甲酸鹽酸鹽 (步驟a)3-經基-4-甲基-5-硝基苯甲酸甲g旨 向3_經基-4·甲基硝基笨甲酸（2刺g)之曱醇⑽ml) 溶液中添加硝酸（市售）（1.0 ml)，加熱回流24小時。添加 麗⑽而中和後，於減壓下顧去溶劑。向殘渣中添加二 氯甲烧、飽和NaC1水溶液。以m萃取後，以飽和 ㈣水溶液清洗所合併之有機層。以無水Na2s〇4乾燥後， 於減壓：顧去溶劑。將殘潰以石夕膠管柱層析法(二氯甲 烧.甲醇=100:卜50: ^30: υ進行精製，於室溫下以 真空果乾燥1小時，獲得標題化合物⑽4mg)。 一 仏 2.46 (3H，s)，3 97 (3h，S)，6。7 (ih S)，7·80 (1H，d)，8·07 (1H，d)。 129677.doc -169. 200840568 MS (ESI) m/z: 212 (M+H)+。 (步驟b) 3-乙氧基-4·甲基-5-硝基苯甲酸甲酯 向3-¾基-4-甲基-5-硝基苯曱酸曱酯（1.034 g)的丙酮（1〇 ml)溶液中添加k2C03(市售）（853 mg)、碘乙烷（523 μ1)，於 室溫下攪拌5小時。追加碘乙烷（2〇〇 μι)後，加熱回流4小 時，進而於室溫下攪拌14小時。以乙酸乙酯稀釋反應液 後’添加飽和NaCl水溶液。以乙酸乙酯萃取後，以飽和 NaCl水溶液清洗所合併之有機層。以無ANa2S〇4乾燥後， 鲁 於減壓下餾去溶劑，於室溫下以真空泵乾燥1小時，獲得 標題化合物（1149 mg)。 W-NMR (CDC13) δ : 1·49 (3H，t)，2·42 (3H，s)，3.95 (3H， s)，4·15 (2H，q)，7·66 (1H，s)，8·05 (1H，s)。 MS (ESI) m/z: 240 (M+H)+ 〇 (步驟c) 4-溴甲基-3-乙氧基_5_硝基苯甲酸甲酯 向3-乙氧基-4-甲基-5-硝基苯甲酸甲酯（1·135 g)的四氣化 春 石反（3〇 ml)洛液中添加NBS(252〇 mg)、過氧化苯甲醯25〇/0 水（62 mg)，加熱回流16小時。冷卻後，將不溶物過濾分 離，以己烷-乙酸乙酯混合液（己烷：乙酸乙酯=4 ··丨）清洗 後，將洗液、濾液於減壓下濃縮。向殘渣中添加乙酸乙 酯、飽和NaHC〇3水溶液。以乙酸乙酯萃取後，以飽和 NaCl水溶液清洗所合併之有機層。以無水]^^§〇4乾燥後， 於減壓下餾去溶劑。將殘渣利用以矽膠為載體之快速層析 法（己烷：乙酸乙酯勺〇 ·· 1}進行精製，於室溫下以真空泵 乾燥14小時，獲得標題化合物（1219 mg)。 129677.doc •170- 200840568 ]H-NMR (CDCi3) δ : 1.54 (3H? t)5 3.97 (3H? s)? 4,26 (2H? q)，4·83 (2H，s)，7·77 (1H，d)，8.16 (1H，d)。 (步驟d) 2-[2-乙氧基-4-(甲氧基羰基硝基苄基]丙二酸二 第三丁酯 於冰浴冷卻下，向丙二酸二第三丁酯（115〇 ml)的 THF(20 ml)溶液中添加氫化鈉（55%)(2〇7 mg)，於冰浴冷卻 下授拌10分鐘，且於室溫下攪拌1小時。向反應液中滴下 4-演甲基-3-乙氧基-5-硝基苯曱酸甲酯（n98 mg)的THF( 15 ⑩ ml)溶液’於室溫下攪拌20小時。以乙酸乙酯稀釋反應 液，添加飽和NaCl水溶液。以乙酸乙酯萃取後，以飽和Hz),8·10 (1H,d,J=1.5 HZ),lo.oo (1H,s),1〇69 (1H, s), 10.75 (1H,br s),13·13 (1H,s ). MS (ESI) m/z: 529 (M+H)+. [Example 77] 4-[(5-Chloroacridin-2-yl)aminemethanyl]oxymethyl_3_[(5-isopropyl-4,5,6,7-tetrahydrothiazide) [5,4-c] oxaridin-2-carbonyl)amino]benzoic acid tert-butyl ester 129677.doc 166 - 200840568 In the same manner as the shell example 3, the compound of Reference Example 32 and the reference example The compound of 129 was condensed to give the title compound. Η-NMR (CDC13) δ : 1.16 (6H,d,j=6 6 Ηζ),1·54 (9Ή,s), 2.89 (4H,s),2·96-3·〇5 (1H,m) ,3』7 (2H,s), 5.36 (2H,s), 7.44 (1H,d,J=7.8 Hz), 7.67 (1H,br s),7_65 (1H,dd,J=9-0, 2 · 4 Hz), 7·82 (1H, dd, j=8.1, 1·7 Hz), 7.93 (1H, d, J=8.5 Hz), 8.19 (1H, d, J = 2.4 Hz), 8.74 (1H,d,J=1.7 Hz), 9.84 (1H, s) 〇MS (ESI) m/z: 586 (M+H)+. [Example 78] 4-[(5-Gas.pyridyl)aminoindolyl]oxymethyl-3-[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[ 5,4_c]pyridinecarbonyl)amino]benzoic acid hydrochloride The title compound was obtained from the compound of Example 77. W-NMR (DMSO-d6) δ : 1·36 (3H,d,J = 6.1 Ηζ), 1.37 (3H,d, J=6.1 Hz), 3.06-3.15 (1H,m),3.23-3.35 (1H,m),3·37-3·47 (1H,m),3·65-3.80 (2H,rn),4,48-4.58 (1H,m),4·73 (1H,d , J=15.1 Hz), 5·29 (2H, s), 7.66 (1H, d, J=8.1 Hz), 7·80 (1H, d, J=8.8 Hz), 7.85-7.91 (2H, m) , 8.10 (1H, s), 8.31 (1H, s), 10·58 (1H, s), 10.67 (1H, s), 1〇·99 (1H, s). MS (ESI) m/z: 530 (M+H). </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> 4-[3-(4-chlorophenyl)ureidomethyl]-3-[(5-isopropyl-4) , 5,6,7-tetrahydrogen oxime and [5,4-〇]° ratio. Benz-2-carbonyl)amino]benzoic acid tert-butyl ester 129677.doc -167- 200840568 to reference example 130化合物1^? of the compound (490 1^) (water (4 ml), anhydrous ferric chloride (3) (642 mg), and zinc dust (863 mg) were added to the 12 m 〇 solution for 30 minutes. Ethyl acetate was added to the reaction mixture, and the insoluble matter was removed by filtration using Dunhuang stone. The insoluble material was washed with ethyl acetate, and the organic layer of the filtrate was separated. The organic layer was washed 5 times with water to dry NhSCU. The solvent was evaporated under reduced pressure to give a crude 3-(3-(4-phenylphenyl)ureidomethyl]benzoic acid tert-butyl ester (4 h). Mg) of di-methane (5 mi) suspension _ add grasshopper gas (277 P1) and DMF (1 drop), and mix at room temperature for 1 (10) minutes. Distill the solvent under reduced pressure to remove the residue. A solution of methane (15 ml) was added to the crude tert-butyl 3-amino-4-[3-(4-chlorophenyl)ureidomethyl]benzoate (435 m) g) with hydrazine (212 μΐ) in dichloromethane (3 〇ml). After stirring for 15 minutes, a saturated aqueous solution of NaHC〇3 was added to the reaction mixture to separate the organic layer. After drying with anhydrous NajO4, The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (dichloromethane: ethyl acetate = 1:1 to hexane: 2) to give the title compound (125 mg). NMR (CDC13) δ: 1·15 (6H,d,J=6.4 Ηζ),1·58 (9H,s) 2·86 (4H,s),2·96-3·06 (1H, m), 3.83 (2H, s), 4.47 (2H, d J = 5.6 Hz), 5·53 (1H, s), 6.74 (1H, s), 7·22 (2H, d, J = 8,8 Hz ), 7·30 (2H, d, J = 8.8 Hz), 7.44 (1H, d, J = 8.1 Hz), 7.80 (1H, d, J = 8.1 Hz), 8·24 (1H, s) , 9·50 (1H, s) 〇MS (ESI) m/z: 584 (M+H) + 〇 [Example 80] 4-[3-(4-Phenylphenyl)ureidomethyl]_3_[ (5-isopropyl-4,5,6,7-tetrahydroindole. Sodium [5,4-c]11-indol-2-yl)amino]benzoic acid hydrochloride 129677.doc - 166-200840568 The title compound was obtained from the compound of Example 77. lH-NMR (DMSO-d6) δ : ι.35 (3Η, d? J=5.6 Hz)5 1.37 (3H5 d5 J=5.6 Hz), 3.10-3.51 (3H) m)? 3.66-3.82 (2H5 m) 5 4.35 (2H5 d, J=5.9 Hz), 4.50-4.60 (ih,m), 4·70·4·78 (1H, m), 6.86 (1H, t, J=5.6 Hz), 7.26 (2H5 d5) J=8.8 Hz)? 7.42 (2H5 d, J = 8.6 Hz), 7·51 (1H, d, J=7.8 Hz), 7·82 (1H, d, K3 Hz), 8.08 (1H, s), 9.01 (1H, s), 10.69 (1H, br s), 10.91 (1H, s), 13.03 (1H, s). MS (ESI) m/z: 528 (M+H)+. [Example 81] 4-{2_[(4-Phenylphenyl)aminemethanyl]ethyl b 3_ethoxy_5_ [(5-isopropyl-4,5,6,7,hydrothiazole) And [5, "] σ-pyridin-2-ylidylamino] benzoic acid hydrochloride (step a) 3-pyridyl-4-methyl-5-nitrobenzoic acid methyl g aim 3_ Nitric acid (commercially available) (1.0 ml) was added to the solution of benzyl alcohol (10 mM g) in methanol (10 ml), and heated under reflux for 24 hours. After adding Li (10) and neutralizing, decompression was carried out. The solvent was removed. To the residue was added methylene chloride and saturated aqueous Na.sub.1, and then extracted with m. The residue was purified by silica gel column chromatography (m.c. 2.46 (3H, s), 3 97 (3h, S), 6. 7 (ih S), 7·80 (1H, d), 8.07 (1H, d). 129677.doc -169. 200840568 MS ( ESI) m/z: 212 (M+H) + (Step b) Methyl 3-ethoxy-4·methyl-5-nitrobenzoate to 3-3⁄4yl-4-methyl-5- Niobium benzophenate (1.034 g) K2C03 (commercially available) (853 mg) and ethyl iodide (523 μl) were added to a solution of acetone (1 ml), and the mixture was stirred at room temperature for 5 hours. After adding ethyl iodide (2 μm), the mixture was heated under reflux. The mixture was stirred at room temperature for 14 hours. After the reaction mixture was diluted with ethyl acetate, a saturated aqueous solution of NaCl was added. After extraction with ethyl acetate, the combined organic layers were washed with a saturated aqueous solution of NaCI. The solvent was evaporated under reduced pressure, and then evaporated to dryness tolululululululululululululululululululululululululululululululululu , s), 3.95 (3H, s), 4·15 (2H, q), 7.66 (1H, s), 8·05 (1H, s) MS (ESI) m/z: 240 (M+ H) + 〇 (Step c) Methyl 4-bromomethyl-3-ethoxy-5-nitrobenzoate to methyl 3-ethoxy-4-methyl-5-nitrobenzoate (1 · 135 g) of four gasification Chunshi anti (3 〇 ml) Lok solution was added NBS (252 〇 mg), benzamidine peroxide 25 〇 / 0 water (62 mg), heated to reflux for 16 hours. After cooling, The insoluble material was separated by filtration and purified with a hexane-ethyl acetate mixture (hexane: ethyl acetate = 4 ···) After the washings, the filtrate was concentrated under reduced pressure. Ethyl acetate and a saturated aqueous solution of NaHC〇3 were added to the residue. After extracting with ethyl acetate, the combined organic layers were washed with a saturated aqueous solution of sodium chloride. After drying over anhydrous water, the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (hexane: ethyl acetate EtOAc) eluting with EtOAc (EtOAc: EtOAc) 170- 200840568 ]H-NMR (CDCi3) δ : 1.54 (3H? t)5 3.97 (3H? s)? 4,26 (2H? q), 4·83 (2H, s), 7·77 (1H, d), 8.16 (1H, d) (Step d) 2-[2-ethoxy-4-(methoxycarbonylnitrobenzyl)malonate di-t-butyl ester under ice cooling, Add sodium hydride (55%) (2〇7 mg) to a solution of di-tert-butyl malonate (115 ml) in THF (20 ml), and mix for 10 minutes under ice-cooling and at room temperature After stirring for 1 hour, a solution of methyl 4-methyl-3-ethoxy-5-nitrobenzoate (n98 mg) in THF (15 10 ml) was added dropwise to the reaction mixture and stirred at room temperature for 20 hours. The reaction solution was diluted with ethyl acetate, and a saturated aqueous solution of NaCl was added.

NaCl水溶液清洗所合併之有機層。以無水Na2S〇4乾燥後， 於減壓下餾去溶劑。利用以矽膠為載體之快速層析法（己 烷：乙酸乙酯=10: 1—6: 1)進行精製，於室溫下以真空 栗乾燥1小時’獲得標題化合物（148 8 mg)。 i-NMR (CDC13) δ·· 1·40 (18H，s)，1·49 (3H，t)，3.49 (2H， br· d)，3·61 (1Η，dd)，3·95 (3Η，s)，4.18 (2Η，q)，7·68 (1Η， 響 d)，8·05 (1H，d)。 MS (ESI) m/z: 476 (M+Na)+。 (步驟e) 4-(2-魏基乙基）_3_乙氧基_5_硝基苯甲酸曱酯 向2-[2 -乙氧基- 4-(甲氧基戴基）-6-梢基节基]丙二酸二第 三丁酉1 (1.447 g)的二氯甲烷（8.〇 ml)溶液中添加TFA(4 〇 ml) ’於室溫下擾拌17小時。將反應液於減壓下濃縮後， 以真空泵於室溫下乾燥3小時。向殘渣中添加乙腈（3〇 ml)、氧化銅（1)(市售）（72 mg)，加熱回流3小時。冷卻後， 129677.doc -171 - 200840568 ，將濾液、洗液於 之快速層析法進行 ’獲彳于標題化合物 將不溶物過濾分離，以二氯甲燒^丨青洗後^ 減壓下濃縮。將殘渣利用以矽膠為載體 精製，以真空泵於室溫下乾燥6小時 (622 mg) 〇 3.07-br s)， ^H-NMR (CDC13) δ : 1.49 (3Η, t)? 2.65-2.90 (2H5 br)5 3.24 (2H5 br),3.95 (3H, s)5 4.18(2H5 q)5 7.70(1^ 8.05 (1H，br s) 〇 ’ MS (ESI) m/z: 320 (M+Na)+，296 (M-H)·。 ® (步驟f) 4-{2-[(4_氣苯基）胺曱醯基]乙基卜3_乙氧基_5_硝基 苯甲酸甲酯 向4-(2-魏基乙基）-3 -乙氧基-5-硝基苯甲酸甲酯（2 94 mg) 的二氯曱烷（7.0 ml)溶液中添加4-氣苯胺（161 mg)、 HOBt(131 mg)、EDC(245 mg)、TEA(市售）（179 μΐ)，於室 溫下攪拌4日。向反應液中添加二氯甲烷、〇·5 n鹽酸。以 二氣甲烷萃取後，以飽和NaHC03水溶液、飽和NaCl水溶 液清洗所合併之有機層。以無水Na2S04乾燥後，於減壓下 餾去溶劑。將殘渣利用以矽膠為載體之快速層析法（己 烷：乙酸乙酯=4 : 1)進行精製後，由乙酸乙酯-己烷加以 固化，濾取固體。以真空泵於室溫下乾燥1小時，獲得標 題化合物（309 mg)。 h-NMR (CDC13) δ: 1,47 (3H，t)，2.70 (2H，t)，3.21 (2H，〇, 3·96 (3H，s)，4.17 (2H，q)，7·27 (2H，d)，7·31 (1H，br s)， 7.48 (2H，d)，7.70 (1H，d)，8.07 (1H，d)。 MS (ESI) m/z: 407 [(M+H)+，35C1]，409 [(M+H)+，37C1]，429 129677.doc • 172_ 200840568 [(M+Na)' 35C1]，431 [(M+Na)+，37C1]。 (步驟g) 3-胺基-4-{2-[(4·氯苯基）胺甲醯基]乙基卜5_乙氧基 苯甲酸甲酯 向4-{2-[(4-氣苯基）胺曱醯基]乙基}·3_乙氧基_5_硝基苯 曱酸曱酯（303 mg)的DMF(7.0 ml)溶液中添加水（ι·5 ml)、 氯化鐵（111)(362 mg)、鋅（487 mg)，於80〜90°C下攪拌30分 鐘。冷卻後，以乙酸乙酯稀釋後，添加飽和NaHC〇s水溶 液，將不溶物過濾分離。以乙酸乙酯萃取，以飽和NaCbK _ 溶液、水清洗所合併之有機層後，以無水Na2S04乾燥，於 減壓下鶴去溶劑。將殘渣利用以矽膠為載體之快速層析法 (己烷：乙酸乙酯=4 : 1)進行精製後，以真空泵於室溫下 乾餘1小時’獲付標題化合物（141 mg)。 W-NMR (CDC13) δ : 1·37 (3H，t)，2·71 (2H，〇, 2·98 (2H，t)， 3·28-3·77 (2Η，m)，3.87 (3Η，s)，3·95 (2Η，q)，6.91 (1Η，br s)，7.01 (1H，d)，7.24 (2H，d)，7.38 (2H，d)，7·41 (1H，br s) ° 鲁 MS (ESI) m/z: 377 [(M+H)V5C1]，379 [(M+H)+，37C1]。 (步驟h) 4-{2·[(4·氣苯基）胺甲醯基]乙基卜3_乙氧基_5-[(5_ 異丙基-4,5,6,7-四氫噻唑并[5,4-c]吡啶-2-基）羰基胺基]苯 曱酸甲酯 向參考例32之化合物（267 mg)的DMF(5.〇 ml)溶液中添加 HOBt(140 mg)、EDC(211 mg)，於室溫下攪拌2小時。向反 應液中添加3-胺基-4-{2-[(4-氯苯基）胺甲醯基]乙基}_5_乙 氧基本甲酸甲i曰（13 7 mg)的DMF(5 ·0 ml)，於室溫下擾摔4 129677.doc -173· 200840568 日。將反應液於減壓下濃縮後，向殘渣中添加二氯甲烧、 飽和NaHC03水溶液。以二氯甲烷萃取後’以飽和NaC1水 溶液清洗所合併之有機層。以無水Na2S〇4乾燥後’於減壓 下餾去溶劑。將殘渣利用以矽膠為載體之快速層析法（二 氯甲烷：甲醇=100 : 1)進行精製，獲得標題化合物（62 mg)。The combined organic layers were washed with an aqueous solution of NaCl. After drying over anhydrous Na 2 S 4 , the solvent was evaporated under reduced pressure. Purification by flash chromatography (hexane: ethyl acetate = 10:1 - 6:1) eluted with EtOAc (EtOAc: EtOAc) i-NMR (CDC13) δ·· 1·40 (18H, s), 1·49 (3H, t), 3.49 (2H, br·d), 3.61 (1Η, dd), 3·95 (3Η) , s), 4.18 (2Η, q), 7.68 (1Η, ring d), 8·05 (1H, d). MS (ESI) m/z: 476 (M+Na)+. (Step e) 4-(2-Wylylethyl)_3_ethoxy_5-nitrobenzoate oxime to 2-[2-ethoxy-4-(methoxy-l-yl)-6-) To the solution of methylene chloride (3,47 ml) in methylene chloride (8. 〇ml), TFA (4 〇ml) was added and the mixture was stirred at room temperature for 17 hours. The reaction solution was concentrated under reduced pressure, and then dried at room temperature for 3 hr. Acetonitrile (3 〇 ml) and copper oxide (1) (commercially available) (72 mg) were added to the residue, and the mixture was heated under reflux for 3 hours. After cooling, 129677.doc -171 - 200840568, the filtrate and the washing solution were subjected to flash chromatography to obtain the title compound, and the insoluble matter was separated by filtration, washed with dichloromethane, washed with chloroform, and concentrated under reduced pressure. . The residue was purified by using a silicone resin as a carrier, and dried by a vacuum pump at room temperature for 6 hours (622 mg) 〇3.07-br s), ^H-NMR (CDC13) δ: 1.49 (3Η, t)? 2.65-2.90 (2H5) Br)5 3.24 (2H5 br), 3.95 (3H, s)5 4.18(2H5 q)5 7.70(1^ 8.05 (1H,br s) 〇' MS (ESI) m/z: 320 (M+Na)+ ,296 (MH)·. ® (Step f) 4-{2-[(4_Phenylphenyl)amine fluorenyl]ethyl b 3_ethoxy_5-nitrobenzoic acid methyl ester to 4- 4-(Vinylethyl)-3-ethoxy-5-nitrobenzoic acid methyl ester (2 94 mg) in dichlorodecane (7.0 ml) was added with 4- aniline (161 mg), HOBt (131) Mg), EDC (245 mg), TEA (commercially available) (179 μΐ), stirred at room temperature for 4 days. To the reaction mixture were added dichloromethane, 〇·5 n hydrochloric acid, and extracted with di-methane. The combined organic layer was washed with aq. EtOAc (aq. 1) After purification, it was solidified with ethyl acetate-hexane, and the solid was collected by filtration, and dried at room temperature for 1 hour with a vacuum pump. The title compound (309 mg) was obtained. h-NMR (CDC13) δ: 1, 47 (3H, t), 2.70 (2H, t), 3.21. (2H, 〇, 3·96 (3H, s), 4.17 (2H , q),7·27 (2H,d),7·31 (1H,br s), 7.48 (2H,d), 7.70 (1H,d),8.07 (1H,d) MS (ESI) m/ z: 407 [(M+H)+, 35C1], 409 [(M+H)+, 37C1], 429 129677.doc • 172_ 200840568 [(M+Na)' 35C1], 431 [(M+Na) +,37C1]. (Step g) 3-Amino-4-{2-[(4.chlorophenyl)amine-carbamoyl]ethyl b-ethyl 5-ethoxybenzoate to 4-{2- Add water to a solution of [(4-phenylphenyl)aminoindenyl]ethyl}·3_ethoxy_5-nitrophenyl decanoate (303 mg) in DMF (7.0 ml) Ml), ferric chloride (111) (362 mg), zinc (487 mg), stirred at 80-90 ° C for 30 minutes. After cooling, dilute with ethyl acetate, add saturated NaHC〇s aqueous solution, insoluble The material was separated by filtration. After extracting with ethyl acetate, the combined organic layer was washed with saturated NaHbK _ solution and water, and dried over anhydrous Na2SO. The residue was purified by flash chromatography (hexane: ethyl acetate = 4:1) eluted with EtOAc. W-NMR (CDC13) δ : 1·37 (3H, t), 2·71 (2H, 〇, 2·98 (2H, t), 3·28-3·77 (2Η, m), 3.87 (3Η ,s),3·95 (2Η,q),6.91 (1Η,br s),7.01 (1H,d),7.24 (2H,d),7.38 (2H,d),7·41 (1H,br s ° Lu MS (ESI) m/z: 377 [(M+H)V5C1], 379 [(M+H)+, 37C1]. (Step h) 4-{2·[(4·Phenylphenyl) Aminomethyl]ethylidene 3_ethoxy_5-[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonylamine To a solution of the compound of Example 32 (267 mg) in DMF (5. EtOAc), EtOAc (EtOAc) Add 3-Amino-4-{2-[(4-chlorophenyl)amine-carbamoyl]ethyl}_5_ethoxybenzate formic acid (13 7 mg) to DMF (5 ·0 ml) ), disturbed at room temperature 4 129677.doc -173· 200840568. After the reaction solution was concentrated under reduced pressure, a solution of methylene chloride and saturated aqueous NaHC03 was added to the residue. The combined organic layer was washed with a NaC1 aqueous solution. After drying over anhydrous Na.sub.2.sub.4, the solvent was distilled off under reduced pressure. Purified to obtain the title compound (62 mg) as a vector of flash chromatography (1 dichloromethane: methanol: = 100).

W-NMR (CDC13) δ : 1·16 (6H，d)，1·31 (3H，t)，2.81 (2H， t)，2.85-3.10 (7Η，m)，3·79-3·88 (4Η，m)，3.88 (3Η，s)，7·20 (2H，d)，7.26 (lH，br s)，7·45 (2H，d)，7.96 (1H，br s)，8·08 (1H，br s)，10·32 (1H，br s)。 MS (ESI) m/z: 585 [(M+H)+，35C1]，587 [(M+H)+，37C1]。 (步驟i) 4-{2-[(4-氯苯基）胺甲醯基]乙基}-3-乙氧基-5-[(5-異丙基-4,5,6,7-四氫噻唑并[5,4-c]吡啶-2-基）羰基胺基]苯 甲酸鹽酸鹽 向Μ2-[(4-氣苯基）胺甲醯基]乙基卜3-乙氧基_5_[(5-異丙 基-4,5,6,7-四氫噻唑并[5,4-c]吼啶-2-基）羰基胺基]苯甲酸 甲酯（103 mg)的THF(5.0 ml)溶液中添加u〇h(11 mg)、水 (1·5 ml)，於室溫下攪拌23小時。追加THF(5.0 ml)、水（1.〇 ml)，於室溫下攪拌3日。向反應液中添加1當量鹽酸（5〇〇 μΐ)後，於減壓下濃縮。將殘渣利用以矽膠為載體之快速 層析法（二氯甲f甲醇=20: h10:⑽行精製，獲得 標題化合物的自由體（55 mg)〇向自由體（55 mg)*添加乙 酸乙酯（6.0 ml)、4當量鹽酸/乙酸乙酯溶液（1〇〇 ，於室 溫下料30分鐘後，照射超聲波3分鐘。將溶劑於減壓下 129677.doc -174- 200840568 濃縮後’以乙酸乙酯（5 ·0 ml)共沸。以真空果於40 °C下乾 燦26小時’獲得標題化合物（59 mg)。 i-NMR (DMSO_d6) δ : 1.32-1.44 (9H，m)，2·75 (2H，t)， 2.90(2H，t)，3.09-3.23 (lH，m)，3.23-3.52 (2H，m)，3.64-3·84 (2H，m)，4.15 (2H，q)，4·48-4·62 (1H，m)，4·67-4·80 (1H，m)，7·33 (2H，d)，7·37 (1H，d)，7.59 (2H，d)，7·75 (1H， s)，10.16 (1H，br· d)，10.74-11.25 (1H，br)，10.94 (1H，s)， 12.88-13.17 (1H，br) 〇 Φ MS (ESI) m/z: 571 [(M+H)+，35C1]，573 [(M+H)+，37C1]。 [實施例82] 4-{2-[(4-氣苯基）胺甲醯基]乙基卜3_異丙氧基-5-[(5-異丙基-4,5,6,7-四氫噻唑并[5,4_小比咬-2-基）魏基胺 基]苯曱酸鹽酸鹽 (步驟a) 3-異丙氧基-4-甲基-5-硝基苯曱酸曱酯 向3_經基甲基硝基苯甲酸甲酯（825 mg)的丙酮（10 ml)溶液中添加2_溴丙烷（563 μΐ)、K2C03(853 mg)，加熱回 • 流7小時。追加2-溴丙烷（500 μΐ)、K2C〇3(625 mg)後，加熱 回流7小時。向反應液中追加丙酮（6 〇 ，進而加熱回流 23小時。以乙酸乙酯稀釋反應液後，添加飽和NaC1水溶 液。以乙酸乙酯萃取後，以飽和NaC1水溶液清洗所合併之 有機層。以無水NajO4乾燥後，於減壓下餾去溶劑。將殘 ，查利用以石夕膠為载體之快速層析法（己烧：乙酸乙酯=1 〇 : 1 — 4 : 1)進行精製，於室溫下以真空泵乾燥2小時，獲得 標題化合物（665 mg)。 ^-NMR (CDC13) δ ： Κ36-1.46 (6Η, m)5 2.39 (3H, s), 3.95 129677.doc •175- 200840568 (3H，s)，4·63-4·74 (1H，m)，7·68 (1H，d)，8·02 (1H，d)。 MS (ESI) m/z: 254 (M+H)+。 (步驟b) 4-溴曱基-3-異丙氧基-5-硝基苯甲酸甲酯 向3-異丙氧基-4-曱基-5-硝基苯甲酸曱酯（643 mg)的四氯 化碳（20 ml)溶液中添加;NBS( 1368 mg)、過氧化苯甲酿（含 水25%，38 mg)，加熱回流23小時。冷卻後，將不溶物過 濾分離，以己烷-乙酸乙酯混合液（己烷：乙酸乙酯=5 : 1) 清洗後，將洗液、濾液於減壓下濃縮。向殘渣中添加乙酸 乙酯、飽和NaHC03水溶液。以乙酸乙酯萃取後，以飽和 NaCl水溶液清洗所合併之有機層。以無水Na2S04乾燥後， 於減壓下餾去溶劑。將殘渣利用以矽膠為載體之快速層析 法（己烧：乙酸乙酯=2〇 ·· 1)進行兩次精製，於室溫下以真 空泵乾燥2小時，獲得標題化合物（863 mg)。 lH-NMR (CDC13) δ : L45 (6H5 d)5 3.97 (3H5 s), 4.75-4.85 (3H，m)，7·77 (1H，d)，8.13 (1H，d)。 (步驟c) 2_[2-異丙氧基-4-(曱氧基羰基）-6-硝基苄基]丙二酸 二第三丁酯 於冰浴冷卻下，向丙二酸二第三丁酯（900 μΐ)的THF(20 ml)溶液中添加氫化納（55%)(162 mg)，於室溫下攪拌1 ·5小 時。向反應液中滴下4_溴曱基-3-異丙氧基-5-硝基苯曱酸 甲酯（860 mg)的THF( 15 ml)溶液，於室溫下攪拌6·5小時。 以乙酸乙酯稀釋反應液，添加飽和NaCl水溶液。以乙酸乙 酯萃取後，以飽和NaCl水溶液清洗所合併之有機層。以無 水NaJO4乾燥後，於減壓下餾去溶劑。利用以矽膠為載體 129677.doc -176 - 200840568 之决速層析法（己$元·乙酸乙酿=2 0 : 1 4 1 〇 : 1)進行精 製，於室溫下以真空泵乾燥3小時，獲得標題化合物（836 mg) 〇 H-NMR (CDCI3) δ : 1·40 (18H，s)，1·41 (6H，d)，3·46 (2H， br. d)，3·59 (1Η，dd)，3.94 (3Η，s)，4·68、4·79 (1Η，m)，7·68 (1H，d)，8.01 (1H，d)。 MS (ESI) m/z: 490 (M+Na)+ 〇 (步驟d) 4-(2-羧基乙基）-3-異丙氧基-5-硝基苯甲酸甲酯 _ 向2-[2-異丙氧基-4-(甲氧基羰基）-6-硝基苄基]丙二酸二 第三丁酯（825 mg)的二氯甲烷（6·〇 ml)溶液中添加tfa(3.〇 ml)，於室溫下攪拌1 5小時。將反應液於減壓下濃縮後， 以真空泵於室溫下乾燥4小時。向殘渣中添加乙腈（3〇 ml)、氧化銅（1)(60 mg)，加熱回流4小時。冷卻後，將不 溶物過濾分離，以二氣甲烷清洗後，將濾液、洗液於減壓 下濃縮。將殘渣利用以矽膠為載體之快速層析法（二氯甲 烧：曱醇=40 : 1)進行精製，以真空泵於室溫下乾燥2小 •日夺’獲得標題化合物(427 mg)。 W-NMR (CDC13) δ : 1·41 (6H，d)，2·73 (2H，t)，3·11 (2H， t)，3·95 (3H，s)，4.69-4.80 (1H，m)，7·70 (1H，d)，8.02 (1H， d) 〇 MS (ESI) m/z: 334 (M+Na)+，310 (M-H)、 (步驟e) 4-{2_[(4-氯苯基）胺甲醯基]乙基}-3-異丙氧基-5-硝 基苯甲酸曱酯 向4-(2-羧基乙基）-3-異丙氧基-5-硝基苯甲酸曱酯（288 129677.doc -177- 200840568 mg)的二氯甲烷（8.0 ml)溶液中添加4-氯苯胺（142 mg)、 HOBt(125 mg)、EDC(194 mg)、ΤΕΑ(140 μΐ)，於室溫下攪 拌5日。向反應液中添加二氯甲烷、1 N鹽酸。以二氯甲烷 萃取後，以飽和NaHC〇3水溶液、飽和NaCl水溶液清洗所 合併之有機層。以無水Na2S04乾燥後，於減壓下餾去溶 劑。將殘渣利用以矽膠為載體之快速層析法（己烷：乙酸 乙酯=6 ·· 1 — 4 ·· 1)進行精製。以真空泵於室溫下乾燥1小 時，獲得標題化合物（296 mg)。 _ ]H-NMR (CDC13) δ : 1.40 (6Η, d)5 2.69 (2H? t), 3.19 (2H? t)，3·96 (3H，s)，4·68-4·79 (1H，m)，7.23 (1H，br s)，7·28 (2H，d)，7·49 (2H，d)，7·71 (1H，br s)，8·05 (1H，d)。 MS (ESI) m/z: 421 [(M+H)+，35C1]，423 [(M+H)+，37C1]，443 [(M+Na)V5Cl]，445 [(M+Na)V7Cl]。 (步驟f) 3-胺基-4-{2-[(4-氯苯基）胺曱醯基]乙基}_5_異丙氧 基苯曱酸甲酯 向4_{2_[(4-氯苯基）胺曱醯基]乙基}-3-異丙氧基-5-硝基 苯曱酸曱酯（292 mg)的DMF(3.0 ml)溶液中添加水（1〇 ml)、氯化鐵（III)(338 mg)、鋅（市售）（471 mg)，於室溫下 攪拌2小時。以乙酸乙酯稀釋後，添加飽和ν&amp;η(：〇3水溶 液將不洛物過渡分離。以乙酸乙g旨萃取，將所合併之有 機層以飽和NaCl水溶液、水清洗後，以無水Na2S〇4乾燥， 於減麼下镏去溶劑。將殘逢利用以石夕膠為載體之快速層析 法（己烧：乙酸乙醋=6 :卜4 : 進行精製後，以真空泉 於室溫下乾燥1小時，獲得標題化合物（203 mg)。 129677.doc -178- 200840568 !H-NMR (CDC13) δ : 1.34 (6H5 d)? 2.69 (2H? t), 2.97 (2H, t)，3.87(3H，s)，4.23(2H，br.s)，4.57-4.68 (lH，m)，6.96· 7·00 (2H，m)，7.14 (1H，br· s)，7·25 (2H，d)，7.37 (2H，d)。 MS (ESI) m/z: 391 [(M+H)+，35C1]，393 [(M+H)+，37C1]。 (步驟g) 4-{2-[(4-氣苯基）胺甲酿基]乙基}-3 -異丙乳基- 5· [(5-異丙基-4,5,6,7-四氫噻唑并[5,4&lt;]吡啶_2-基）羰基胺基] 苯曱酸甲酯 向3-胺基-4-{2-[(4-氣苯基）胺甲醯基]乙基卜5-異丙氧基 Φ 苯甲酸甲酯（200 mg)的DMF(4.0 ml)溶液中添加參考例32之 化合物（200 mg)、HOBt(104 mg)、EDC(156 mg)、TEA(220 μΐ)，於室溫下攪拌2日。將反應液於減壓下濃縮後，向殘 渣中添加二氯甲烷、飽和NaHC03水溶液。以二氯甲烷萃 取後，以飽和NaCl水溶液清洗所合併之有機層。以無水 Na2S04乾燥後，於減壓下餾去溶劑。將殘渣利用以矽膠為 載體之快速層析法（二氯甲烷··甲醇=100 ·· 1 — 50 ·· 1)進行 精製，於室溫下以真空泵乾燥2小時，獲得標題化合物 ® (278 mg)。 h-NMR (CDC13) δ : 1.17 (6H，d)，1·36 (6H，d)，2·78 (2H， t)，2.84-3.10(7H，m)，3.83-3.88 (2H，m)，3.88(3H，s)，4.62-4·74 (1H，m)，7·23 (2H，d)，7·40 (2H，br s)，7,44 (2H，d)， 8.03 (1H，s)，10.06 (1H，s)。 MS (ESI) m/z: 599 [(M+H)V5C1]，601 [(M+H)+，37C1]。 (步驟h) 4-{2-[(4-氯苯基）胺曱醯基]乙基異丙氧基 [(5-異丙基-4,5,6,7-四氫嗟哇并[5,4-c]吼咬-2-基）幾基胺基] 129677.doc -179- 200840568 苯甲酸鹽酸鹽 向4-{2-[(4-氯苯基）胺甲醯基]乙基}_3-異丙氧基_5-[(5-異 丙基-4,5,6,7-四氫噻唑并[5,4-(：]吡啶-2-基）羰基胺基]苯甲 酸曱酯（273 mg)的 THF(7.〇 ml)溶液中添加Li〇H(22 mg)、 水（1 ·5 ml) ’於室溫下檟;拌2日。追加Li〇H(8 mg)，於室溫 下攪拌4小時。向反應液中添加1當量鹽酸（15〇〇 μ1)後，於 減壓下濃縮。將殘渣利用以矽膠為載體之快速層析法（二 氯曱烧：甲醇=5 0: 1—30: 1—10: 1)進行精製， _ 獲得標題化合物的自由體（202 mg)。向自由體（202 mg)中 添加乙酸乙酯（6·0 ml)、4當量鹽酸乙酸乙酯溶液（3〇〇 μ 1) ’照射超聲波5分鐘。將溶劑於減壓下濃縮後，添加乙 酸乙酯（5·0 ml)進行清洗，濾取固體。以真空泵乾燥，獲 得標題化合物（187 mg)。 lH-NMR (DMSO-d6) δ : 1.34 (6H? d)5 1.38 (6H? d)5 2.76 (2H，t)，2.83-2.93 (2H，m)，2.99-3.84 (5H，m)，4.43-4.81 φ (3H，m)，7·34 (2H，d)，7·37 (1H，s)，7·61 (2H，d)，7·73 (1H， s)，1〇·24 (1H，s)，10·95 (1H，s)，11·28·11·79 (1H，m)， 12.74-13.28 (1H，m)。 MS (ESI) m/z: 585 [(M+H)+，35C1]，587 [(M+H)+，37C1]。 [實施例83]4-{2-[(4-溴苯基）胺曱醯基]乙基卜3-氣_5_[(5-異 丙基-4,5,6,7-四氫噻唑并[5,4-c]吡啶-2-基）羰基胺基]苯甲 酸鹽酸鹽 (步驟a) 4-{2-[(4-溴苯基）胺甲醯基]乙基卜3-氯硝基苯甲 酸甲酯 129677.doc -180- 200840568 向參考例96之化合物（301 mg)的二氣曱烷（3,0 ml)溶液中 添加 4-溴苯胺（200 mg)、HOBt(147 mg)、EDC(233 mg)、 TEA(168 μΐ)，於室溫下擾拌3日。向反應液中添加二氯甲 院、飽和NaHC〇3水溶液。以二氯甲烧萃取後，以〇·5 Ν鹽 酸、飽和NaCl水溶液清洗所合併之有機層。以無水Na2S04 乾燥後，於減壓下I留去溶劑。向殘渣中添加乙酸乙酯（5.〇 ml)、己烷（5.0 ml)，進行超聲波清洗後，濾取固體。將濾 液於減壓下濃縮後，向殘渣中添加乙酸乙酯（2·〇 ml)、己 火完（2·0 ml)，進行超聲波清洗後，再次濾取固體。將所獲 得之固體合併，以真空泵於室溫下乾燥2小時，獲得標題 化合物（382 mg)。 W-NMR (CDC13) δ : 2.73-2.83 (2H，m)，3·30-3·40 (2H，m)， 3·98 (3Η，s)，7·23 (1Η，br s)，7·43 (4Η，s)，8·28 (1Η, d)， 8.37 (1H，d)。 MS (ESI) m/z: 441 (M+H)+。 (步驟b) 3-胺基-4-{2-[(4-溴苯基）胺甲醯基]乙基}_5•氣苯甲 酸甲酯 於〇°C下，向3-氯-4-{2-[(4-氟苯基）胺曱醯基]乙基卜5_硝 基苯甲酸甲酯（376 mg)的DMF(7.0 ml)溶液中添加水（1〇 ml)、氣化鐵（111)(483 mg)、鋅（611 mg)，於室溫下擾拌2〇 小時。添加乙酸乙酯、飽和NaHC〇3水溶液，將不溶物過 濾分離。以乙酸乙酯萃取，以飽和NaCl水溶液、水清洗所 合併之有機層。以無水NajO4乾無後’於減壓下德去溶 劑。向殘渣中添加己烧-乙酸乙酯混合液進行清洗後，濟 129677.doc -181 - 200840568 取固體。將濾液濃縮後，利用以矽膠為載體之快速層析法 (己烷：乙酸乙酯=5 : 1)進行精製，與濾取之固體合併， 以真空泵於室溫下乾燥2小時，獲得標題化合物（33 8 mg)。 】H-NMR (CDC13) δ : 2·76 (2H，t)，3·13 (2H，t)，3.87 (3H，s)， 4·51 (2H，br s)，7·17 (1H，br s)，7.21 (1H，d)，7.34 (2H，d)， 7.42 (2H，d)，7·43 (1H，br s)。 MS (ESI) m/z: 411 (M+H)+ 〇 _ (步驟c) 4-{2_[(4-溴苯基）胺曱醯基]乙基卜3_氯_5_[(5_異丙 基-4,5,6,7-四氫噻唑并[5，4-c]吡啶-2-基）羰基胺基]苯甲酸 曱酯 向參考例32的化合物（4〇5 mg)之二氯甲烷（4 〇 ml)懸浮液 中添加DMF(0.02 ml)、草醯氯（260 μΐ)，於室溫下攪拌2小 時。將反應液於減壓下濃縮後，以真空泵於室溫下乾燥4 小時。向殘渣中添加二氣甲烧（10 ml)、3-胺基-4-{2-[(4-';臭 苯基）胺甲醯基]乙基}-5-氣苯甲酸曱酯（318 mg)的二氣甲烷 馨 （30 ml)溶液、TEA( 1.0 ml)，於室溫下攪拌5.5小時。以二 氯甲烷稀釋反應液後，添加飽和NaHC03水溶液。以二氣 曱烧萃取後，以飽和NaCl水溶液清洗所合併之有機層。以 無水Na2S〇4乾燥後，於減壓下餾去溶劑。將殘渣利用以矽 膠為載體之快速層析法（二氯甲烷：甲醇= 100 : 1— 50 : 1) 進行兩次精製，於室溫下以真空泵乾燥1小時，獲得標題 化合物（199 mg)。 ]H-NMR (CDC13) δ : 1.17 (6Η, d)? 2.86-3.07 (7H5 m)? 3.22 129677.doc -182- 200840568 (2H，t)，3.87-3.89 (2H，m)，3,89 (3H，s)，7·39 (5H，s)，7·9〇 (1H，d)，8_38 (1H，d)，10.49 (1H，s)。 MS (ESI) m/z: 619 (M+H)+。 (步驟d) 4-{2-[(4-溴苯基）胺曱醯基]乙基卜3_氯·5_[(5_異丙 基-4,5,6,7·四氫噻唑并[5,4-c]吡啶-2-基）羰基胺基]苯曱酸 鹽酸鹽 向4-{2-[(4-溴苯基）胺曱醯基]乙基}_3_氯_5_[(5-異丙基_ 4,5,6,7-四氫噻唑并[5,4-c]吡啶-2-基）羰基胺基]苯曱酸甲酯 籲（196 mg)的 THF(5.0 ml)溶液中添加 Li〇H(16 mg)、水（ι·〇 ml) ’於至/JEL下攪拌23小時。追加Li〇H( 11 mg)，於室溫下 攪拌30小時。向反應液中添加！當量鹽酸（2 〇 後，於減 壓下濃縮。將殘潰利用以矽膠為載體之快速層析法（二氯 曱烧：甲醇=30 : 1— 20 : 1— 1〇 :1)進行精製後，添加乙 酸乙酯加以清洗，進行濾取。將剩餘之固體製成乙酸乙酯 (3.0 ml)懸浮液，添加4當量鹽酸乙酸乙酯溶液（1〇〇 μ1)， 照射超聲波3分鐘。將溶劑於減壓下濃縮後，向殘渣中添 加乙酸乙酯（3.0 ml)進行清洗，濾取固體。以真空泵於4〇 °C下加以乾燥，獲得標題化合物（142 mg)。 iH-NMR (DMSO-d6) δ : 1·36 (6H，d)，2.78 (2H，t)，3.09 (2H，t)，3·12-3·81 (5H，m)，4·39-4·75 (2H，m)，7·46 (2H，d)， 7·54 (2H，d)，7·85 (1H，d)，8·04 (1H, d)，10.26 (1H，s)， 11 ·04 (1H，br s)。 MS (ESI) m/z: 605 (M+H)+。 [實施例84] 4-{2-[(4-氯苯基）胺曱醯基]乙基卜3_乙氧基 129677.doc -183- 200840568 [(5-甲基-4,5,6,7-四氫噻唑并[5,4-c]/比啶_2_基）羰基胺基]笨 曱酸鹽酸鹽 (步驟a) 4-{2-[(4-氯苯基）胺甲醯基]乙基}-3-乙氧基-5-[(5-曱基-4,5,6,7-四氫噻唑并[5,4-(^比啶-2-基）羰基胺基]苯曱 酸曱醋 向3-胺基-4-{2_[(4_氣苯基）胺曱醯基]乙基}_5_乙氧基笨 甲酸甲酯（164 mg)的DMF(3.0 ml)溶液中添加5-甲基-4,5,6,7-四氫噻唑并[5,4-c]吡啶-2-甲酸鹽酸鹽（141 mg)、 HOBt(63 mg)、EDC(117 mg)、ΤΕΑ(168 μΐ)，於室溫下搜 拌4曰。於減壓下餾去溶劑後，向殘渣中添加二氯曱烷、 飽和NaHC03水溶液。以二氣甲烷萃取後，以飽和NaCl水 溶液清洗所合併之有機層。以無水Na2S04乾燥後，於減壓 下顧去溶劑。將殘渣利用以矽膠為載體之快速層析法（二 氯甲烧··申醇=1〇〇 ·· 1— 50 : 1— 30 : 1)進行精製，於室溫 下以真空泵乾燥30分鐘，獲得標題化合物（224 mg)。 lR&quot;NMR (CDCI3) δ : 1.40 (3Η, t), 2.53 (3H5 s)5 2.81 (2H5 t)5 2·85 (2H，t)，3.00 (2H，t)，3.08 (2H，t)，3·75 (2H，s)，3·89 (3H，s)，4·01 (2H，q)，7.22 (2H，d)，7·34 (1H，d)，7·44 (2H， d)，7·51 (1H，br s)，8·07 (1H，d)，10.18 (1H，s)。 MS (ESI) m/z: 557 [(M+H)+，35C1]，559 [(M+H)+，37C1]。 (步驟b) 4_(2-[(4-氯苯基）胺甲醯基]乙基卜3-乙氧基-5-[(5-甲基-4,5,6,7-四氫嗟。坐并[5,4-c]吼咬-2-基）羰基胺基]苯甲 酸鹽酸鹽 向4-{2-[(4-氣苯基）胺曱醯基]乙基卜3_乙氧基-5-[(5·甲 129677.doc -184- 200840568 基·4,5,6,7-四氫噻唑并[5,4&lt;]咄啶_2_基）羰基胺基]苯甲酸 曱酯（218 mg)的THF(6.0 ml)溶液中mg)、水 (1.0 ml)，於室溫下攪拌4日。向反應液中追加u〇H(8 mg)，於40 C下攪拌1日。向反應液中添加i當量鹽酸（2 〇 ml)後’於減壓下濃縮。將殘渣利用以矽膠為載體之快速 層析法（二氣甲烷··甲醇=30 ·· 1 一 20 ·· 1— 1〇 ·· 1)進行精 製’獲得}示通化合物的自由體。向自由體中添加乙酸乙酯 (3·0 ml)、4當量鹽酸乙酸乙酯溶液（15〇 μ1)，照射超聲波5 籲 分知。將溶劑於減壓下濃縮後，添加乙酸乙酯（5 .〇 ml)， 濾取不溶物。以真空泵於40°C下乾燥24小時，獲得標題化 合物（227 mg)。 'H-NMR (DMSO&gt;d6) δ : 1.40 (3H? t), 2.78 (2H5 t), 2.90 (5H? br s)，3.10-3.72 (4H，m)，4.15 (2H，q)，4.39-4.72 (2H，m)， 7·33 (2H，d)，7.36 (1H，s)，7·64 (2H，d)，7·76 (1H，s)，1〇·41 (1H，s)，10.94 (1H，s)，12·00-12·40 (1H，br)，12.76-13,26 (1H，br) 〇 馨 MS (ESI) m/z: 543 [(M+H)+，35C1]，545 [(M+H)V7C1]。 [實施例85] 4-{2-[(4-氣苯基）胺甲醯基]乙基}-3-[(6,7-二氫_ 4H·-比喃并[4,3-d]噻唑-2-基）羰基胺基]-5-甲氧基苯甲酸 (步驟a) 4-{2-[(4-氯苯基）胺曱醯基]乙基}-3-[(6,7-二氫-4H-吼喃并[4,3-d]噻唑-2-基）羰基胺基]-5-甲氧基苯甲酸曱酯 向參考例110之化合物（100 mg)的DMF(2.〇 ml)溶液中添 加參考例 135 的化合物（78 mg)、HOBt(55 mg)、EDC(86 mg)、TEA(63 μΐ)，於室溫下攪拌2日。於減壓下餾去溶劑 129677.doc -185- 200840568 後，向殘潰中添加二氣甲烧、飽和NaHC03水溶液。以二 氯甲烷萃取後，以飽*NaCi水溶液、水清洗所合併之有機 層。以無水NajO4乾燥後，於減壓下餾去溶劑。向殘渣中 添加己院-乙酸乙醋混合液’藉由超聲波照射而進行清 洗。濾取固體，於室溫下以真空泵乾燥14小時，獲得標題 化合物（122 mg)。W-NMR (CDC13) δ : 1·16 (6H,d),1·31 (3H,t),2.81 (2H, t), 2.85-3.10 (7Η,m),3·79-3·88 ( 4Η,m),3.88 (3Η,s),7·20 (2H,d), 7.26 (lH,br s),7·45 (2H,d),7.96 (1H,br s),8·08 ( 1H, br s), 10·32 (1H, br s). MS (ESI) m/z: 585 [(M+H)+, 35C1], 587 [(M+H)+, 37C1]. (Step i) 4-{2-[(4-Chlorophenyl)amine-carbamoyl]ethyl}-3-ethoxy-5-[(5-isopropyl-4,5,6,7- Tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonylamino]benzoic acid hydrochloride to Μ2-[(4-phenylphenyl)aminemethanyl]ethyl b-3-ethoxy Methyl 5-[5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]acridin-2-yl)carbonylamino]benzoic acid methyl ester (103 mg) In a solution of THF (5.0 ml), u〇h (11 mg) and water (1·5 ml) were added, and the mixture was stirred at room temperature for 23 hours. THF (5.0 ml) and water (1. 〇 ml) were added, and the mixture was stirred at room temperature for 3 days. After adding 1 equivalent of hydrochloric acid (5 μM) to the reaction mixture, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography using silica gel as a solvent (dichloromethyl-methanol = 20: h10: (10) to give the title compound as a free compound (55 mg) to free (55 mg). (6.0 ml), 4 N hydrochloric acid / ethyl acetate solution (1 Torr, after 30 minutes at room temperature, irradiated with ultrasonic for 3 minutes. The solvent was concentrated under reduced pressure 129677.doc -174-200840568 after concentration to acetic acid Ethyl ester (5·0 ml) was azeotroped. The title compound (59 mg) was obtained from EtOAc EtOAc EtOAc EtOAc ·75 (2H,t), 2.90(2H,t),3.09-3.23 (lH,m),3.23-3.52 (2H,m),3.64-3.84 (2H,m),4.15 (2H,q) ,4·48-4·62 (1H,m),4·67-4·80 (1H,m),7·33 (2H,d),7·37 (1H,d),7.59 (2H,d ),7·75 (1H, s), 10.16 (1H, br·d), 10.74-11.25 (1H, br), 10.94 (1H, s), 12.88-13.17 (1H, br) 〇Φ MS (ESI) m/z: 571 [(M+H)+, 35C1], 573 [(M+H)+, 37C1]. [Example 82] 4-{2-[(4-Phenylphenyl)amine Ethyl b 3_isopropoxy-5-[(5-isopropyl-4,5,6,7-tetrahydrothiazole) [5,4_small-biti-2-yl)-weilkylamino]benzoquinone hydrochloride (step a) 3-isopropoxy-4-methyl-5-nitrobenzoic acid oxime ester Add 3-bromopropane (563 μΐ) and K2C03 (853 mg) to a solution of methyl nitrobenzoate (825 mg) in acetone (10 ml), heat back to flow for 7 hours. Bromopropane (500 μM) and K2C 3 (625 mg) were heated under reflux for 7 hours. Acetone (6 Torr) was added to the reaction mixture, and the mixture was further heated under reflux for 23 hours. After the reaction mixture was diluted with ethyl acetate, a saturated aqueous solution of Na. After extracting with ethyl acetate, the combined organic layer was washed with saturated aqueous NaH.sub.1. (Calcination: ethyl acetate = 1 hydrazine: 1 - 4 : 1), and the residue was purified by vacuum pumping at room temperature for 2 hours to give the title compound (665 mg). NMR (CDC13) δ: Κ36-1.46 ( 6Η, m)5 2.39 (3H, s), 3.95 129677.doc •175- 200840568 (3H,s),4·63-4·74 (1H,m),7·68 (1H,d),8· 02 (1H, d). MS (ESI) m/z: 254 (M+H)+. (Step b) Methyl 4-bromomethyl-3-isopropoxy-5-nitrobenzoate to decyl 3-isopropoxy-4-indolyl-5-nitrobenzoate (643 mg) Add in a solution of carbon tetrachloride (20 ml); NBS (1368 mg), benzoyl peroxide (25% aqueous, 38 mg), and reflux under heating for 23 hours. After cooling, the insoluble material was separated by filtration and washed with hexane-ethyl acetate mixture (hexane: ethyl acetate = 5:1), and the filtrate and filtrate were concentrated under reduced pressure. Ethyl acetate and a saturated aqueous solution of NaHCO03 were added to the residue. After extracting with ethyl acetate, the combined organic layers were washed with a saturated aqueous solution of sodium chloride. After drying over anhydrous Na 2 SO 4 , the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (hexanes: ethyl acetate = 2 hexanes··············· lH-NMR (CDC13) δ : L45 (6H5 d) 5 3.97 (3H5 s), 4.75-4.85 (3H, m), 7.77 (1H, d), 8.13 (1H, d). (Step c) 2_[2-Isopropoxy-4-(decyloxycarbonyl)-6-nitrobenzyl]malonic acid di-t-butyl ester, cooled to an ice bath, to a third of malonic acid Sodium hydride (55%) (162 mg) was added to a solution of butyl ester (900 μl) in THF (20 ml) and stirred at room temperature for 1.5 hours. A solution of methyl 4-bromoindolyl-3-isopropoxy-5-nitrobenzoate (860 mg) in THF (15 ml) was evaporated. The reaction solution was diluted with ethyl acetate and a saturated aqueous NaCI solution was added. After extraction with ethyl acetate, the combined organic layers were washed with a saturated aqueous solution of NaCl. After drying with anhydrous NaJO4, the solvent was evaporated under reduced pressure. Purification was carried out by using a silica gel as a carrier 129677.doc -176 - 200840568 by means of a fast-speed chromatography method ($$·acetic acid ethyl acetate = 2 0: 1 4 1 〇: 1), and dried by vacuum pumping at room temperature for 3 hours. Obtained the title compound (836 mg) 〇H-NMR (CDCI3) δ: 1·40 (18H, s), 1·41 (6H, d), 3·46 (2H, br. d), 3·59 (1Η , dd), 3.94 (3Η, s), 4.68, 4.79 (1Η, m), 7.68 (1H, d), 8.01 (1H, d). MS (ESI) m/z: 490 (M+Na) + 〇 (Step d) 4-(2-carboxyethyl)-3-isopropoxy-5-nitrobenzoic acid methyl ester _ to 2-[ Add tfa to a solution of diisobutyloxy-2-(methoxycarbonyl)-6-nitrobenzyl]malonic acid di-tert-butyl ester (825 mg) in dichloromethane (6·〇ml) 3. 〇ml), stir at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure and dried at room temperature for 4 hr. Acetonitrile (3 〇 ml) and copper oxide (1) (60 mg) were added to the residue, and the mixture was heated under reflux for 4 hours. After cooling, the insoluble material was separated by filtration, washed with di-methane, and the filtrate and washings were concentrated under reduced pressure. The residue was purified by flash chromatography (dichloromethane: decyl alcohol = 40:1) using silica gel as a solvent, and dried under a vacuum pump at room temperature for 2 hours to obtain the title compound (427 mg). W-NMR (CDC13) δ : 1·41 (6H, d), 2·73 (2H, t), 3·11 (2H, t), 3·95 (3H, s), 4.69-4.80 (1H, m),7·70 (1H,d),8.02 (1H, d) 〇MS (ESI) m/z: 334 (M+Na)+,310 (MH), (step e) 4-{2_[( 4-chlorophenyl)amine-mercapto]ethyl}-3-isopropoxy-5-nitrobenzoate oxime to 4-(2-carboxyethyl)-3-isopropoxy-5- Add 4-chloroaniline (142 mg), HOBt (125 mg), EDC (194 mg), hydrazine to a solution of dimethyl nitrobenzoate (288 129677.doc -177- 200840568 mg) in dichloromethane (8.0 ml). (140 μΐ), stir at room temperature for 5 days. Methylene chloride and 1 N hydrochloric acid were added to the reaction liquid. After extracting with methylene chloride, the combined organic layers were washed with saturated aqueous NaHCO3 and saturated aqueous NaCl. After drying over anhydrous Na 2 SO 4 , the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (hexane: ethyl acetate = 6 ··1 - 4 ··1) using a silica gel as a carrier. Drying at room temperature for 1 hour with a vacuum pump gave the title compound (296 mg). _ ]H-NMR (CDC13) δ : 1.40 (6Η, d)5 2.69 (2H? t), 3.19 (2H? t), 3·96 (3H, s), 4·68-4·79 (1H, m), 7.23 (1H, br s), 7·28 (2H, d), 7·49 (2H, d), 7·71 (1H, br s), 8.05 (1H, d). MS (ESI) m/z: 421 [(M+H)+, 35C1], 423 [(M+H)+, 37C1], 443 [(M+Na)V5Cl], 445 [(M+Na)V7Cl ]. (Step f) methyl 3-amino-4-{2-[(4-chlorophenyl)amine decyl]ethyl}_5-isopropoxy benzoate to 4_{2_[(4-chloro Add water (1〇ml), chlorination to a solution of phenyl)aminoindenyl]ethyl}-3-isopropoxy-5-nitrobenzoate (292 mg) in DMF (3.0 ml) Iron (III) (338 mg) and zinc (commercially available) (471 mg) were stirred at room temperature for 2 hours. After diluting with ethyl acetate, a saturated ν &amp; η (: 〇 3 aqueous solution was added to separate the lovastate. The extraction was carried out with ethyl acetate, and the combined organic layers were washed with a saturated aqueous solution of NaCl and water, followed by anhydrous Na2S. 4 Dry, remove the solvent after subtraction. Use the rapid chromatography method using Shishijiao as the carrier (cooked: acetic acid ethyl acetate = 6: Bu 4: after refining, vacuum spring at room temperature After drying for 1 hour, the title compound (203 mg) was obtained. 129677.doc -178 - 200840568 !H-NMR (CDC13) δ : 1.34 (6H5 d)? 2.69 (2H? t), 2.97 (2H, t), 3.87 ( 3H, s), 4.23 (2H, br.s), 4.57-4.68 (lH, m), 6.96·7·00 (2H, m), 7.14 (1H, br·s), 7·25 (2H, d ), 7.37 (2H, d) MS (ESI) m/z: 391 [(M+H)+, 35C1], 393 [(M+H)+, 37C1] (Step g) 4-{2- [(4-Phenylphenyl)amine-branched]Ethyl}-3-isopropyllacyl- 5· [(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4&lt;;]pyridine-2-yl)carbonylamino]methyl benzoate to 3-amino-4-{2-[(4-phenylphenyl)amine-carbamoyl]ethyl b-isopropoxy Add reference to Φ methyl benzoate (200 mg) in DMF (4.0 ml) The compound of Example 32 (200 mg), HOBt (104 mg), EDC (156 mg), and TEA (220 μΐ) were stirred at room temperature for 2 days. The reaction solution was concentrated under reduced pressure and then added to the residue. After the mixture was extracted with dichloromethane, the combined organic layer was washed with saturated aqueous Na.sub.2Cl. The residue was purified by a vacuum pump at room temperature for 2 hours to give the title compound (278 mg). h-NMR (CDC13) δ: 1.17 (6H,d),1·36 (6H,d),2·78 (2H, t), 2.84-3.10(7H,m),3.83-3.88 (2H,m),3.88(3H,s),4.62 -4·74 (1H,m),7·23 (2H,d),7·40 (2H,br s),7,44 (2H,d), 8.03 (1H,s),10.06 (1H,s MS (ESI) m/z: 599 [(M+H)V5C1], 601 [(M+H)+, 37C1]. (Step h) 4-{2-[(4-Chlorophenyl)aminoindenyl]ethylisopropoxy[(5-isopropyl-4,5,6,7-tetrahydroanthracene [ 5,4-c] 吼-2-yl) arylamino] 129677.doc -179- 200840568 benzoate to 4-{2-[(4-chlorophenyl)amine carbhydryl] Ethyl}_3-isopropoxy[5-[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-(:]pyridin-2-yl)carbonylamino]] To a solution of decyl benzoate (273 mg) in THF (7. 〇ml), add Li〇H (22 mg) and water (1·5 ml) to 室温 at room temperature; mix for 2 days. Add Li〇H ( 8 mg), stirred at room temperature for 4 hours. After adding 1 eq. of hydrochloric acid (15 〇〇μ1) to the reaction mixture, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography using silica gel. Calcination: Methanol = 5 0: 1 - 30: 1 - 10: 1) Purification, _ Obtained the title compound (202 mg). Add ethyl acetate (6·0 ml) to free (202 mg) 4 hours of ethyl acetate solution (3 〇〇μ1) 'Ion the ultrasonic wave for 5 minutes. After concentrating the solvent under reduced pressure, ethyl acetate (5.0 ml) was added and washed, and the solid was collected by filtration. , get the title combination (187 mg). lH-NMR (DMSO-d6) δ: 1.34 (6H?d)5 1.38 (6H?d)5 2.76 (2H,t),2.83-2.93 (2H,m),2.99-3.84 (5H ,m),4.43-4.81 φ (3H,m),7·34 (2H,d),7·37 (1H,s),7·61 (2H,d),7·73 (1H, s), 1〇·24 (1H, s), 10·95 (1H, s), 11·28·11·79 (1H, m), 12.74-13.28 (1H, m) MS (ESI) m/z: 585 [(M+H)+, 35C1], 587 [(M+H)+, 37C1] [Example 83] 4-{2-[(4-bromophenyl)amine fluorenyl]ethyl b 3 - gas_5_[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonylamino]benzoic acid hydrochloride (step a 4-{2-[(4-bromophenyl)amine-carbamoyl]ethyl bromide 3-chloronitrobenzoic acid methyl ester 129677.doc -180- 200840568 to reference compound 96 (301 mg) 4-bromoaniline (200 mg), HOBt (147 mg), EDC (233 mg), TEA (168 μΐ) were added to the gas decane (3,0 ml) solution, and the mixture was stirred at room temperature for 3 days. To the reaction liquid, a solution of dichloromethane or saturated NaHC〇3 was added. After extraction with methylene chloride, the combined organic layers were washed with 〇·5 Ν hydrochloric acid and saturated aqueous NaCl. After drying over anhydrous Na 2 SO 4 , the solvent was left under reduced pressure. Ethyl acetate (5. 〇 ml) and hexane (5.0 ml) were added to the residue, and the mixture was subjected to ultrasonic cleaning. After the filtrate was concentrated under reduced pressure, ethyl acetate (2··················· The obtained solids were combined and dried under a vacuum vacuum oven for 2 hr to give the title compound (382 mg). W-NMR (CDC13) δ : 2.73-2.83 (2H, m), 3·30-3·40 (2H, m), 3·98 (3Η, s), 7·23 (1Η, br s), 7 · 43 (4Η, s), 8·28 (1Η, d), 8.37 (1H, d). MS (ESI) m/z: 441 (M+H)+. (Step b) 3-Amino-4-{2-[(4-bromophenyl)amine-carbamoyl]ethyl}_5• benzoic acid methyl ester at 〇°C to 3-chloro-4- Add water (1〇ml), gasified iron to a solution of {2-[(4-fluorophenyl)aminoindenyl]ethyl bromide-5-nitrobenzoic acid methyl ester (376 mg) in DMF (7.0 ml) (111) (483 mg), zinc (611 mg), stir on for 2 hours at room temperature. Ethyl acetate and a saturated aqueous NaHC 3 solution were added, and the insoluble material was separated by filtration. The combined organic layers were washed with aq. EtOAc and water. After drying in anhydrous NajO4, the solvent was removed under reduced pressure. After the hexane-ethyl acetate mixture was added to the residue for washing, 129677.doc -181 - 200840568 was taken as a solid. After concentrating the filtrate, it was purified by flash chromatography (hexane: ethyl acetate = 5:1) using a silica gel, and the solid was collected by filtration and dried at room temperature for 2 hours to obtain the title compound. (33 8 mg). H-NMR (CDC13) δ : 2·76 (2H, t), 3·13 (2H, t), 3.87 (3H, s), 4·51 (2H, br s), 7·17 (1H, Br s), 7.21 (1H, d), 7.34 (2H, d), 7.42 (2H, d), 7·43 (1H, br s). MS (ESI) m/z: 411 (M+H) + 〇 _ (Step c) 4-{2_[(4-bromophenyl)amine fluorenyl]ethyl b3_chloro_5_[(5_ Isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonylamino]benzoic acid oxime ester to the compound of Reference Example 32 (4〇5 mg) DMF (0.02 ml) and grass chloroform (260 μM) were added to a suspension of dichloromethane (4 〇ml), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and then dried at room temperature for 4 hr. To the residue was added dimethyl ketone (10 ml), 3-amino-4-{2-[(4-'; odor phenyl) carbamoyl]ethyl}-5- benzoic acid oxime ( A solution of 318 mg) of dioxomethane (30 ml), TEA (1.0 ml) was stirred at room temperature for 5.5 hours. After diluting the reaction mixture with methylene chloride, a saturated aqueous solution of NaHCO? After extraction by two gas simmering, the combined organic layers were washed with a saturated aqueous solution of NaCl. After drying over anhydrous Na 2 S 4 , the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (dichloromethane:methanol = 100:1 - 50:1) using EtOAc (m. ]H-NMR (CDC13) δ : 1.17 (6Η, d)? 2.86-3.07 (7H5 m)? 3.22 129677.doc -182- 200840568 (2H,t),3.87-3.89 (2H,m),3,89 (3H, s), 7·39 (5H, s), 7·9 〇 (1H, d), 8_38 (1H, d), 10.49 (1H, s). MS (ESI) m/z: 619 (M+H)+. (Step d) 4-{2-[(4-Bromophenyl)aminoindenyl]ethyl b 3_chloro·5_[(5-isopropyl-4,5,6,7-tetrahydrothiazolidine [5,4-c]pyridin-2-yl)carbonylamino]benzoic acid hydrochloride to 4-{2-[(4-bromophenyl)amine fluorenyl]ethyl}_3_chloro_5_ [(5-Isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonylamino]benzoic acid methyl ester (196 mg) in THF (196 mg) 5.0 ml) Add Li〇H (16 mg) and water (ι·〇ml) to the solution and stir for 23 hours at /JEL. Further, Li〇H (11 mg) was added, and the mixture was stirred at room temperature for 30 hours. Add to the reaction solution! Equivalent hydrochloric acid (2 〇, concentrated under reduced pressure. The residue was purified by flash chromatography using silica gel as a carrier (dichlorohydrazine: methanol = 30: 1-20: 1-1 〇:1). Ethyl acetate was added and washed, and the mixture was filtered. The remaining solid was made into a suspension of ethyl acetate (3.0 ml), and 4 eq. of ethyl acetate (1 〇〇μ1) was added thereto, and the mixture was irradiated with ultrasonic waves for 3 minutes. After concentrating under reduced pressure, ethyl acetate (3 mL) was evaporated. D6) δ : 1·36 (6H, d), 2.78 (2H, t), 3.09 (2H, t), 3·12-3·81 (5H, m), 4·39-4·75 (2H, m),7·46 (2H,d), 7·54 (2H,d),7·85 (1H,d),8·04 (1H,d),10.26 (1H,s), 11 ·04 ( 1H, br s) MS (ESI) m/z: 605 (M+H)+. [Example 84] 4-{2-[(4-chlorophenyl)aminoindolyl]ethyl b. Ethoxy 129677.doc -183- 200840568 [(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]/pyridin-2-yl)carbonylamino] alum Acidate (step a) 4-{2-[(4- Phenyl)amine-mercapto]ethyl}-3-ethoxy-5-[(5-mercapto-4,5,6,7-tetrahydrothiazolo[5,4-(^-pyridin-2) -yl)carbonylamino]benzoic acid hydrazine vinegar to 3-amino-4-{2_[(4-hydrophenyl)aminoindenyl]ethyl}_5-ethoxy acetonate methyl ester (164 mg To a solution of DMF (3.0 ml), 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (141 mg), HOBt ( 63 mg), EDC (117 mg), and cesium (168 μΐ) were mixed at room temperature for 4 Torr. After distilling off the solvent under reduced pressure, dichloromethane and saturated aqueous NaHC03 were added to the residue. After the extraction of the methane, the combined organic layer was washed with a saturated aqueous solution of Na.sub.2, and dried over anhydrous Na.sub.2SO.sub.sub.sub.sub. =1 〇〇·· 1 - 50 : 1 - 30 : 1) Purification was carried out by vacuum pumping at room temperature for 30 minutes to obtain the title compound (224 mg). l &quot;NMR (CDCI3) δ: 1.40 (3 Η, t ), 2.53 (3H5 s)5 2.81 (2H5 t)5 2·85 (2H,t), 3.00 (2H,t), 3.08 (2H,t),3·75 (2H,s),3·89 ( 3H, s), 4·01 (2H, q), 7.2 2 (2H,d),7·34 (1H,d),7·44 (2H, d),7·51 (1H,br s),8·07 (1H,d),10.18 (1H,s) . MS (ESI) m/z: 555 [ (M+H)+, 35C1], 559 [(M+H)+, 37C1]. (Step b) 4_(2-[(4-Chlorophenyl)aminemethanyl]ethyl b 3-ethoxy-5-[(5-methyl-4,5,6,7-tetrahydroindole) Sit and [5,4-c] bite-2-yl)carbonylamino]benzoic acid hydrochloride to 4-{2-[(4-phenylphenyl)amine fluorenyl]ethyl b 3 _Ethoxy-5-[(5·甲129677.doc -184- 200840568 ·4,5,6,7-tetrahydrothiazolo[5,4&lt;] acridine-2-yl)carbonylamino] To a solution of decyl benzoate (218 mg) in THF (6.0 ml), water (1.0 ml) was stirred at room temperature for 4 days. U〇H (8 mg) was added to the reaction mixture, and the mixture was stirred at 40 C for 1 day. After adding i equivalent of hydrochloric acid (2 〇 ml) to the reaction mixture, the mixture was concentrated under reduced pressure. The residue was subjected to rapid chromatography (diqi methane··methanol = 30 ··1 - 20 ··1 - 1 〇 ··1) using a silica gel as a carrier to carry out the purification of the free compound of the compound. Ethyl acetate (3.0 ml) and 4 equivalents of ethyl acetate in ethyl acetate (15 〇 μ1) were added to the free body, and ultrasonic waves were applied to the laser. After the solvent was concentrated under reduced pressure, ethyl acetate (5.m.) was added, and insoluble matter was filtered. Drying at 40 ° C for 24 hours with a vacuum pump gave the title compound (227 mg). 'H-NMR (DMSO&gt;d6) δ : 1.40 (3H? t), 2.78 (2H5 t), 2.90 (5H? br s), 3.10-3.72 (4H, m), 4.15 (2H, q), 4.39- 4.72 (2H,m), 7·33 (2H,d), 7.36 (1H,s),7·64 (2H,d),7·76 (1H,s),1〇·41 (1H,s) , 10.94 (1H, s), 12·00-12·40 (1H, br), 12.76-13, 26 (1H, br) 〇 MS (ESI) m/z: 543 [(M+H)+, 35C1], 545 [(M+H)V7C1]. [Example 85] 4-{2-[(4-Phenylphenyl)aminemethanyl]ethyl}-3-[(6,7-dihydro-4H·-pyrano[4,3-d] ]thiazol-2-yl)carbonylamino]-5-methoxybenzoic acid (step a) 4-{2-[(4-chlorophenyl)amineindolyl]ethyl}-3-[(6 , 7-Dihydro-4H-indolo[4,3-d]thiazol-2-yl)carbonylamino]-5-methoxybenzoate oxime to DMF of the compound of Reference Example 110 (100 mg) (2. 〇ml) The compound of Reference Example 135 (78 mg), HOBt (55 mg), EDC (86 mg), and TEA (63 μM) were added to the solution and stirred at room temperature for 2 days. After distilling off the solvent 129677.doc -185-200840568 under reduced pressure, a two-gas-fired, saturated aqueous NaHC03 solution was added to the residue. After extraction with methylene chloride, the combined organic layers were washed with a saturated aqueous solution of NaCI. After drying over anhydrous NajO4, the solvent was evaporated under reduced pressure. To the residue, a mixture of hexanes and ethyl acetate was added, and the mixture was washed by ultrasonic irradiation. The solid was collected by filtration and dried under vacuum EtOAc (EtOAc)

i-NMR (CDC13) δ : 2.82 (2H，t)，3·01 (2H，t)，3.08 (2H，〇, 3.88 (3H，s), 3·90 (3H，s)，4·07 (2H，t)，4·92 (2H，s)，7·23 (2H，d)，7.30 (1H，br s)，7·41 (1H，d)，7·43 (2H，d)，8·1〇 (1H，br· s)，10.26 (1H，s)。 MS (ESI) m/z: 530 [(M+H)+，35C1]，532 [(M+H)+，37C1]。 (步驟b) 4-{2-[(4-氣苯基）胺甲醯基]乙基}_3-[(6,7-二氫-4H-口比喃并[4,3-d]噻唑-2-基）羰基胺基]-5-曱氧基苯曱酸 向4-{2-[(4-氯苯基）胺曱醯基]乙基卜3-[(6,7_二氫-4H-。比 喃并[4,3-d]噻唑-2-基）羰基胺基]-5-甲氧基苯甲酸甲酯（118 mg)的 THF(6.0 ml)溶液中添加 LiOH(19 mg)、水（1 ·〇 mi)， 於室溫下攪拌24小時。向反應液中添加1當量鹽酸、二氣 曱烷。以二氣曱烷萃取後，以飽和NaCl水溶液清洗所合併 之有機層。以無水NajO4乾燥後，於減壓下濃縮。將殘洁 利用以矽膠為载體之快速層析法（二氯曱烷··甲醇二1() —7 : 1)進行精製後，以二氣曱烷加以清洗，進行途取。 以真空泵於室溫下乾燥14小時，獲得標題化合物（ι〇ι mg)。 m)， !H-NMR (DMSO-d6) δ : 2.70 (2H5 t)5 2.86-2.96 (4^ 129677.doc -186· 200840568 3.90 (3H，s)，3,99 (2H，t)，4·88 (2H，s)，7·32 (2H，d)，7.39 (1H，d)，7·56 (2H，d)，7·75 (1H，d)，10·07 (1H，s)，10.77 (1H，s)，12.91-13.17 (1H，br)。 MS (ESI) m/z: 516 [(M+H)+，35C1]，518 [(M+H)+，37C1]。 [實施例86]3-氟-4-{2-[(4-氟苯基）胺甲醯基]乙基卜5_|^5_異 丙基-4,5,6,7-四氫噻唑并[5,4-c]吡啶-2-基）羰基胺基]苯甲 酸鹽酸鹽 (步驟a) 3-氟-4-{2-[(4-氟苯基）胺甲醯基]乙基硝基苯曱 酸甲酯 向參考例104之化合物（11〇 mg)的二氯甲院（2· 〇 ml)溶液 中添加 4-氟苯胺（50 μΐ)、HOBt(58 mg)、EDC(95 mg)、 TEA(68 μΐ)，於室溫下攪拌i9日。向反應液中添加二氣曱 烧、飽和NaHC〇3水溶液。以二氣甲烷萃取後，以〇1當量 鹽酸水溶液、飽和NaCl水溶液清洗所合併之有機層。以無 水NadO4乾燥後’於減壓下餾去溶劑。向殘渣中添加乙酸 乙酿-己烧混合液進行清洗後，濾取固體。以真空泵於室 溫下乾燥1小時，獲得標題化合物（丨25 mg)。 H-NMR (CDC13) δ ： 2.70-2.78 (2H5 m)? 3.28-3.37 (2H? m)? 3·98 (3H，s)，6·97·7·〇4 (2H，m)，7·25 (1H，s)，7.41-7.49 (2H，m)，7.96 (1H，d)，8.38 (1H，s)。 MS (ESI) m/z: 365 (M+H)+。 (步驟b) 3-胺基-5-氟-4_{2_[(4_氟苯基）胺曱醯基]乙基}苯甲 酸甲酯 向3-氟-4-{2·[(‘氟苯基）胺甲醯基]乙基卜5-硝基苯甲酸 129677.doc •187- 200840568 甲酯（120 mg)的DMF(5.0 ml)溶液中添加水（ΐ·〇 mi)、氯化 鐵（111)( 190 mg)、鋅（284 mg)，於室溫下攪拌5小時。添加 乙酸乙酯、飽和NaHC〇3水溶液，將不溶物過濾分離，以 乙酸乙酯萃取。將所合併之有機層以飽和NaCl水溶液、水 清洗後，以無水Na2S〇4乾燥。於減壓下餾去溶劑後，向殘 渣中添加乙酸乙酯，將不溶物過濾分離後，將濾液於減壓 下濃縮。以真空泵於室溫下乾燥2小時，獲得標題化合物 (111 mg) 〇 W-NMR (CDC13) δ : 2.72 (2H，t)，2·98-3·04 (2H，m)，3.87i-NMR (CDC13) δ : 2.82 (2H, t), 3·01 (2H, t), 3.08 (2H, 〇, 3.88 (3H, s), 3·90 (3H, s), 4·07 ( 2H,t),4·92 (2H,s),7·23 (2H,d), 7.30 (1H,br s),7·41 (1H,d),7·43 (2H,d),8 1〇(1H, br· s), 10.26 (1H, s) MS (ESI) m/z: 530 [(M+H)+, 35C1], 532 [(M+H)+, 37C1]. (Step b) 4-{2-[(4-Phenylphenyl)amine-carbamoyl]ethyl}_3-[(6,7-dihydro-4H-oral bromo[4,3-d]thiazole -2-yl)carbonylamino]-5-nonyloxybenzoic acid to 4-{2-[(4-chlorophenyl)amine fluorenyl]ethyl b 3-[(6,7-dihydrogen) -4H-. Adding LiOH (19) to a solution of methyl [4,3-d]thiazol-2-yl)carbonylamino]-5-methoxybenzoate (118 mg) in THF (6.0 ml) (mg), water (1 · 〇mi), stirred at room temperature for 24 hours. Add 1 equivalent of hydrochloric acid and dioxane to the reaction solution. After extraction with dioxane, the combined organics were washed with saturated aqueous NaCl solution. The layer was dried over anhydrous NajO4, and concentrated under reduced pressure. The residue was purified by flash chromatography using silica gel as a carrier (dichloromethane·methanol (1) to 7:1). Dioxane The mixture was washed with a vacuum pump at room temperature for 14 hours to obtain the title compound (m.p.m.) m), ?H-NMR (DMSO-d6) δ: 2.70 (2H5 t)5 2.86-2.96 ( 4^ 129677.doc -186· 200840568 3.90 (3H,s),3,99 (2H,t),4·88 (2H,s),7·32 (2H,d),7.39 (1H,d), 7·56 (2H,d),7·75 (1H,d),10·07 (1H,s), 10.77 (1H,s),12.91-13.17 (1H,br) MS (ESI) m/z : 516 [(M+H)+, 35C1], 518 [(M+H)+, 37C1] [Example 86] 3-fluoro-4-{2-[(4-fluorophenyl)aminecarboxamide Ethyl bromide 5_|^5_isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonylamino]benzoic acid hydrochloride Step a) 3-Fluoro-4-{2-[(4-fluorophenyl)amine-carbamoyl]ethylnitrophenyl decanoate to the compound of Reference Example 104 (11 〇mg) (2· 〇ml) 4-Fluoroaniline (50 μM), HOBt (58 mg), EDC (95 mg), TEA (68 μM) were added to the solution, and the mixture was stirred at room temperature for 9 days. A two-gas agitated, saturated NaHC〇3 aqueous solution was added to the reaction liquid. After extraction with di-methane, the combined organic layers were washed with 1N aqueous hydrochloric acid and saturated aqueous NaCl. After drying with anhydrous NadO4, the solvent was evaporated under reduced pressure. After adding acetic acid to the residue, the mixture was washed, and the solid was collected by filtration. Drying at room temperature for 1 hour with a vacuum pump gave the title compound (? 25 mg). H-NMR (CDC13) δ : 2.70-2.78 (2H5 m)? 3.28-3.37 (2H? m)? 3·98 (3H, s), 6·97·7·〇4 (2H, m), 7· 25 (1H, s), 7.41-7.49 (2H, m), 7.96 (1H, d), 8.38 (1H, s). MS (ESI) m/z: 365 (M+H)+. (Step b) 3-Amino-5-fluoro-4_{2_[(4-fluorophenyl)aminoindenyl]ethyl}benzoic acid methyl ester to 3-fluoro-4-{2·[('fluorine Phenyl)amine-methylmercapto]ethylidene 5-nitrobenzoic acid 129677.doc •187- 200840568 Add methyl (ΐ·〇mi), ferric chloride to a solution of methyl ester (120 mg) in DMF (5.0 ml) (111) (190 mg), zinc (284 mg), stirred at room temperature for 5 hours. Ethyl acetate and a saturated aqueous NaHCO3 solution were added, and the insoluble material was separated by filtration and ethyl acetate. The combined organic layers were washed with saturated aqueous NaCI and water and dried over anhydrous Na? After distilling off the solvent under reduced pressure, ethyl acetate was added to the residue, and the insoluble material was separated by filtration, and the filtrate was concentrated under reduced pressure. Drying at room temperature for 2 hours with a vacuum pump gave the title compound (111 mg) 〇 W-NMR (CDC13) δ: 2.72 (2H, t), 2·98-3·04 (2H, m), 3.87

(3H，s)，4·48 (2H，br s)，6.96-7.03 (2H，m)，7.06-7.15 (3H m)5 7.35-7.41 (2H，m)。 MS (ESI) m/z: 335 (M+H)+ 〇 (步驟e) 3-氟- 4- {2-[(4 -氣笨基）胺甲醯基]乙基卜5_[(異兩基_ 4,5,6,7-四氫噻唑并[5,4-c]吡啶-2·基）羰基胺基]苯甲酸甲g旨 向參考例32之化合物（186 mg)的二氯甲烷（4·0 ml)懸浮液 中添加DMF(0.04 ml)、草醯氯（121 μΐ)，於室溫下擾拌i小 時。將反應液於減壓下濃縮後，以真空泵於室溫下乾燥6 小時。向殘渣中添加3 -胺基-5-氟-4-{2-[(4-氟苯基）胺曱酿 基]乙基}苯曱酸曱酯（110 mg)的二氯甲烷（5.0 ml)溶液、 TEA( 1.0 ml)、二氯曱烷（10 ml)，於室溫下攪拌3日。以二 氯甲烧稀釋反應液後’添加飽和NaHC〇3水溶液。以二氯 甲烷萃取後，以飽*NaC〗水溶液清洗所合併之有機層。以 無水Na2S04乾燥後，於減壓下餾去溶劑。將殘渣利用以石夕 膠為載體之快速層析法（己烷：乙酸乙酯=5:1^&gt;2:1-&gt;二 129677.doc -188- 200840568 氯曱烧·甲醇=50: 1—30: 1—20: 1)進行精製，於室溫 下以真空泵乾燥2小時，獲得標題化合物37 mg)。 W-NMR (CDC13) δ : 1·16 (6H，d)，2·81 (2H，t)，2·86-3,10 (7H，m)，3.86 (5H，s)，6.87-6.96 (2H，m)，7·40-7·48 (2H， m)，7·50 (1H，dd)，8.15 (1H，s)，8·31 (1H, s)，10.58 (1H， s)。 MS (ESI) m/z: 543 (M+H)+。 (步驟d) 3-a-4-{2-[(4-氟笨基）胺曱醯基]乙基卜異丙 基-4,5,6,7·四氫噻唑并[5,4_c]吡啶_2_基）羰基胺基]苯曱酸 鹽酸鹽 向3-氟·4-{2-[(4-氟苯基）胺甲醯基]乙基卜5·[(5_異丙基_ 4,5,6,7-四氫噻唑并[5,4_cp比啶_2_基）羰基胺基]苯曱酸甲酯 (136 mg)的 THF(5.0 如）溶液中添加水（1 〇 、u〇H(11(3H, s), 4·48 (2H, br s), 6.96-7.03 (2H, m), 7.06-7.15 (3H m)5 7.35-7.41 (2H, m). MS (ESI) m/z: 335 (M+H) + 〇 (Step e) 3-Fluoro-4-(2-[(4-(-)))) Methyl 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonylamino]benzoic acid methyl chloroformate as a reference compound of Example 32 (186 mg) (4·0 ml) DMF (0.04 ml) and grass chlorophyll (121 μΐ) were added to the suspension, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and then dried at room temperature for 6 hr. To the residue was added dichloromethane (10 ml) of 3-amino-5-fluoro-4-{2-[(4-fluorophenyl)amine decyl]ethyl}benzoate (110 mg). The solution, TEA (1.0 ml) and dichloromethane (10 ml) were stirred at room temperature for 3 days. After diluting the reaction mixture with methylene chloride, a saturated aqueous solution of NaHC 3 was added. After extraction with methylene chloride, the combined organic layers were washed with a saturated aqueous solution of NaCI. After drying over anhydrous Na 2 SO 4 , the solvent was evaporated under reduced pressure. The residue was subjected to flash chromatography using saponin as a carrier (hexane: ethyl acetate = 5:1^&gt; 2:1 -> 129,677.doc -188 - 200840568 chlorpyrifos methanol = 50: 1-30: 1-20: 1) The residue was purified by vacuum pumping at room temperature for 2 hours to obtain the title compound (37 mg). W-NMR (CDC13) δ : 1·16 (6H, d), 2·81 (2H, t), 2·86-3, 10 (7H, m), 3.86 (5H, s), 6.87-6.96 ( 2H, m), 7·40-7·48 (2H, m), 7·50 (1H, dd), 8.15 (1H, s), 8.31 (1H, s), 10.58 (1H, s). MS (ESI) m/z: 543 (M+H)+. (Step d) 3-a-4-{2-[(4-Fluoro)aminoindolyl]ethylidene-4,5,6,7-tetrahydrothiazolo[5,4_c] Pyridin-2-yl)carbonylamino]benzoic acid hydrochloride to 3-fluoro-4-(2-[(4-fluorophenyl)aminemethanyl]ethyl b 5·[(5_isopropyl Add water to a solution of methyl 4,5,6,7-tetrahydrothiazolo[5,4_cp-pyridin-2-yl)carbonylamino]benzoic acid methyl ester (136 mg) in THF (5.0) 〇, u〇H (11

mg)，於至溫下攪拌3日。向反應液中添加i當量鹽酸（5〇〇 μΐ)後’於減壓下H將殘潰利用膠為載體之快速 層析法（二氣甲烧··甲醇=3〇 ··卜2〇 : ·· ^進行精 製’獲得標題化合物的白士鱗。 的自由體（139 mg)。向自由體（139 mg)中添加乙酸乙酯（4 〇】 ^ V ·ϋ ml)、4當1鹽酸乙酸乙酯溶液（7〇 μΐ)，照射超聲波20分鏟。於、資w ~ l 、里於減壓下顧去溶劑後，以真空 泵於40°C下乾燥14小時，獾γA ^ 时，獲侍標題化合物（13〇 mg)。 ]H-NMR (DMSO-d6) δ · ι i , . 1.34-1.44 (6H5 m)5 2.69-2.82 (2H, m)? 2.90-3.07 (2H, ^ 91 . ’ -21-3.60 (2H? m), 3.61-3.84 (2H? ni), 4,44-4.61 (2H m\ λ λ nf\ )，4.63-4.79 (1H，m)，7.12 (2H，t)， 7·52-7·63 (3H，m)，7 9q η μ 、 Λ *y9 OH, s), 10.22 (1H, s)? 10.99 (1H? 129677.doc 200840568 S)，11·66 (1H，br s)，13·03-13·51 (1H，br)。 MS (ESI) m/z: 529 (M+H)+ 〇 [實施例87] N-{5-胺甲醯基-2-[2-(4-氟苯基胺曱醯基）乙基；μ 3 -曱氧基苯基}-5 -甲基-4,5,6,7-四氫°塞嗤并[5,4-c]吼唆_2- 曱醯胺鹽酸鹽 (步驟a) 4-{2-[(4-氟苯基）胺甲醯基]乙基}-3·曱氧基_5-[(5_ 甲基-4,5,6,7-四氫噻唑并[5,4-c]吡啶-2-基）羰基胺基]苯甲 酸甲酉旨 鲁 向參考例II2之化合物（439 mg}的DMF(6.0 ml)溶液中添 加5-曱基-4,5,6,7-四氫噻嗤并[5,4-c] °比咬-2-甲酸鹽酸鹽 (354 mg)、HOBt(203 mg)、EDC(302 mg)、ΤΕΑ(434 μΐ)， 於室溫下攪拌4日。將反應液於減壓下濃縮後，向殘渣中 添加二氣甲烷、飽和NaHC〇3水溶液，濾取不溶物。將濾 液以二氣甲烧萃取後’以飽和NaCl水溶液清洗所合併之有 機層。以無水NazSO4乾燥後，於減壓下餾去溶劑。向殘渣 中添加乙酸乙酯加以清洗後’進行濾取。與分液前所濾取 之固體合併，以真空泵乾燥，獲得標題化合物（548 mg)。 ]H-NMR (DMSO-d6) δ : 2·40 (3H，s)，2.70 (2H，t)，2.77 (2H，t)，2.83-2.95 (4H，m)，3·7〇 (2H，br s)，3·86 (3H，s)， 3·91 (3H, s)，7.06-7.14 (2H，m)，7·38 (1H，d)，7 51-7.58 (2H，m)，7.80 (1H，d)，10·00 (1H，s)，1Q 77 (ih，s)。 MS (ESI) m/z: 527 (M+H)+ 〇 (步驟b) 4-{2-[(4·亂本基）胺甲酿基]乙基卜3_甲氧基_5_[(5_ 曱基-4,5,6,7-四氫嚷唾并[5,44]吡啶_2-基）羰基胺基]苯甲 129677.doc -190- 200840568Mg), stirred at room temperature for 3 days. After adding i equivalent of hydrochloric acid (5 〇〇μΐ) to the reaction solution, 'H under reduced pressure will be used for rapid chromatography using a gel as a carrier (two gas combustion · methanol = 3 〇 · · 卜 2 〇: ·· ^ Purification of the free title of the title compound of the white scale (139 mg). Add ethyl acetate (4 〇) ^ V · ϋ ml) to the free body (139 mg), 4 when 1 hydrochloric acid acetic acid Ethyl ester solution (7〇μΐ), irradiated with ultrasonic wave for 20 minutes. After removing the solvent under reduced pressure, it was dried by vacuum pump at 40 °C for 14 hours, 獾γA ^ The title compound (13 〇 mg).]H-NMR (DMSO-d6) δ · ι i , . 1.34-1.44 (6H5 m)5 2.69-2.82 (2H, m)? 2.90-3.07 (2H, ^ 91 . ' -21-3.60 (2H? m), 3.61-3.84 (2H? ni), 4,44-4.61 (2H m\ λ λ nf\ ), 4.63-4.79 (1H,m), 7.12 (2H,t), 7·52-7·63 (3H,m),7 9q η μ , Λ *y9 OH, s), 10.22 (1H, s)? 10.99 (1H? 129677.doc 200840568 S),11·66 (1H, Br s), 13·03-13·51 (1H, br) MS (ESI) m/z: 529 (M+H) + 〇 [Example 87] N-{5-amine-carbazin-2- [2-(4-fluorophenylaminoindenyl)ethyl; μ 3 -oxime Phenyl}-5-methyl-4,5,6,7-tetrahydro-[5,4-c]indole-2-decylamine hydrochloride (step a) 4-{2- [(4-Fluorophenyl)amine-methylmethyl]ethyl}-3·decyloxy_5-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c] Pyridin-2-yl)carbonylamino]benzoic acid methyl hydrazide To a solution of the compound of Reference Example II2 (439 mg} in DMF (6.0 ml) was added 5-mercapto-4,5,6,7-tetrahydrogen Thiazolo[5,4-c] ° ratio 2-formate hydrochloride (354 mg), HOBt (203 mg), EDC (302 mg), cesium (434 μΐ), stirred at room temperature 4 After the reaction solution was concentrated under reduced pressure, a mixture of di-methane and saturated aqueous NaHC 3 was added to the residue, and the insoluble material was collected by filtration. The filtrate was extracted with a methane and then washed with saturated aqueous NaCl. After drying over anhydrous NazSO4, the solvent was evaporated under reduced pressure. ethyl acetate was added to the residue and washed, and then filtered, and the mixture was collected by filtration. 548 mg). H-NMR (DMSO-d6) δ : 2·40 (3H, s), 2.70 (2H, t), 2.77 (2H, t), 2.83-2.95 (4H, m), 3·7〇 (2H, Br s),3·86 (3H,s), 3·91 (3H, s),7.06-7.14 (2H,m),7·38 (1H,d),7 51-7.58 (2H,m), 7.80 (1H, d), 10·00 (1H, s), 1Q 77 (ih, s). MS (ESI) m/z: 527 (M+H) + 〇 (Step b) 4-{2-[(4·乱基基) Aminomethyl]ethyl b 3_methoxy_5_[( 5_ Mercapto-4,5,6,7-tetrahydroindole[5,44]pyridin-2-yl)carbonylamino]benzil 129677.doc -190- 200840568

向4-{2-[(4-氟苯基）胺甲醯基]乙基卜3_曱氧基曱 基-4,5,6,7-四氫噻唑并〇cp比啶-2-基）羰基胺基]苯甲酸 甲醋（548 mg)的二号：(:完（20 ml)溶液中添加水（3.0 ml)、 LiOH(31 mg)，於室溫下攪拌7日。於40°C下攪拌24小時 後，添加LiOH(7 mg)，於40°C下攪拌49小時。冷卻後，向 反應液中添加1當量鹽酸（1600 μΐ)後，於減壓下濃縮。向 殘渣中添加水（30 ml)實施超聲波照射後，濾取固體，以乙 酸乙酯（5.0 ml)清洗。以真空泵於4〇。(：下乾燥3日，獲得標 題化合物（466 mg)。 ]H-NMR (DMSO-d6) δ : 2.48 (3Η, s)? 2.69 (2H5 t)? 2.83- 2·97 (6H，m)，3.83 (2H，br s)，3·90 (3H，s)，7·05-7·15 (2H, m)，7.39 (1H，d)，7·55 (2H，dd)，7·76 (1H，d)，10.00 (1H，s)， 1〇·76 (1H，s)。未觀測到 COOH。 MS (ESI) m/z: 513 (M+H)+。 (步驟c) N-{5-胺甲酿基-2-[2-(4 -敗苯基胺曱酿基）乙基]·3· 曱氧基苯基卜5 -曱基-4,5,6,7_四氫嗟°坐并[5,4-c]吼u定-2-曱 醯胺鹽酸鹽 於冰浴冷卻下，向4-{2-[(4-氟苯基）胺甲醯基]乙基卜3_ 曱氧基_5-[(5-甲基·4,5,6,7-四氩噻唑并[5,4-c]吡啶基）魏 基胺基]苯甲酸（140 mg)的THF (5.0 ml)懸浮液中添加氯甲 酸乙醋（38 μ1)、ΤΕΑ(56μ1)’於〇C下授掉1小時。向反應 液中添加28%氨水（120 μΐ)，於室温下攪拌16小時。將溶劑 於減壓下濃縮後，向殘渣中添加二氣甲烷、甲醇、水。以 129677.doc -191 - 200840568 二氣曱烷曱醇混合液萃取後，以i 7{c M 。 …、^Na2S〇4乾燥。將溶劑 於減壓下濃縮後，將殘渣利用以石夕腿或 膠為载體之快速層析法 (二氯甲烷：曱醇=30 : 1~&gt;20 : I— . η 10 . 1)進行精製，獲得 標題化合物的自由體(77 mg)。向自由體(77叫)中添加乙 醇（5 mi)、i當量鹽酸乙醇溶液（15〇 μ1)，將溶劑於減壓下 濃縮。以乙醇共沸-次後’以真空泵乾燥2〇小時，獲得標 題化合物（79 mg)。To 4-{2-[(4-fluorophenyl)amine-carbamoyl]ethyl b- 3 - fluorenyl fluorenyl-4,5,6,7-tetrahydrothiazolidine cp pyridine-2-yl ) carbonylamino] benzoic acid methyl vinegar (548 mg) No. 2: (: (20 ml) solution was added with water (3.0 ml), LiOH (31 mg), and stirred at room temperature for 7 days at 40 ° After stirring for 24 hours at C, LiOH (7 mg) was added, and the mixture was stirred at 40 ° C for 49 hours. After cooling, 1N hydrochloric acid (1600 μM) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. After the water (30 ml) was subjected to ultrasonic irradiation, the solid was filtered, and washed with ethyl acetate (5.0 ml). DMSO-d6) δ : 2.48 (3Η, s)? 2.69 (2H5 t)? 2.83- 2·97 (6H,m), 3.83 (2H,br s),3·90 (3H,s),7·05 -7·15 (2H, m), 7.39 (1H, d), 7·55 (2H, dd), 7·76 (1H, d), 10.00 (1H, s), 1〇·76 (1H, s No COOH was observed MS (ESI) m/z: 513 (M+H) + (Step c) N-{5-Amino-mercapto-2-[2-(4- phenylene hydrazide) Styrene) ethyl]·3· 曱oxyphenyl b-5-mercapto-4,5,6,7_tetrahydroindole °[5,4-c]吼u 曱醯-2-decylamine hydrochloride under ice-cooling, to 4-{2-[(4-fluorophenyl)amine carbhydryl]ethyl b 3 曱 oxy _5-[(5 Add methyl chloroformate to a suspension of methyl 4-,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl]weirylamido]benzoic acid (140 mg) in THF (5.0 ml) Vinegar (38 μl) and hydrazine (56 μl) were allowed to stand for 1 hour at 〇C. 28% aqueous ammonia (120 μM) was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. Dihydromethane, methanol and water were added to the residue, and after extracting with a mixture of 129677.doc -191 - 200840568 dioxane sterol, it was dried with i 7{c M . . . , Na2S〇4. After concentration, the residue was purified by flash chromatography (dichloromethane: decyl alcohol = 30:1~&gt;20:I-. η 10.1) using Shixi leg or gum as a carrier. Free form of the compound (77 mg). Add ethanol (5 mi), i equivalent of hydrochloric acid in ethanol (15 μl) to the free body (77), and concentrate the solvent under reduced pressure. Drying with a vacuum pump for 2 hrs gave the title compound (79 mg).

]H.NMR (DMSO-d6) δ : 2.68 (2H? t), 2.86 (2H5 t)? 2.93 (3H? s)，3·06-3·81 (4H，m)，3·89 (3H，s)，4.27-4.93 (2H，m)，7·ι〇 (2H，t)，7·35 (1H，br s)，7·40 (1H，s)，7.56 (2H，dd), 7·64 (1H，s)，7·98 (1H，br s)，10.07 (1H，s)，10.85 (1H，s)，1139-11.67 (1H, br) 〇 MS (ESI) m/z: 512 (M+H)+。 [實施例88] N-{2-[2-(4 -氟苯基胺曱醯基）乙基]曱氧基_5-(曱基胺甲醯基）苯基}_5 -甲基-4,5,6,7-四氫嗟哇并[5,4-c]吼 啶-2-甲醯胺鹽酸鹽 於冰浴冷卻下，向實施例87之（步驟b)的標題化合物（14〇 mg)的THF(5.0 ml)懸浮液中添加氯甲酸乙酯（38 μΐ)、 ΤΕΑ(56 μΐ)，於0 °C下攪拌1小時。向反應液中添加 ΤΕΑ(140 μΐ)、甲胺鹽酸鹽（70 mg)，於室溫下攪拌19小 時。將溶劑於減壓下濃縮後，向殘渣中添加二氯甲烷、甲 醇、飽和NaCl水溶液。以二氯甲烷萃取後，以無水Na2S04 乾燥。將溶劑於減壓下濃縮後，將殘渣利用以矽膠為載體 之快速層析法（二氣曱烷：甲醇=50 : 30 : 1)進行精 129677.doc -192- 200840568 裝，獲得標題化合物的自由體（94 mg)。向自由體（94 mg) 中添加乙醇（5 ml)、1當量鹽酸乙醇溶液（200 μΐ)，將溶劑 於減壓下濃縮。以乙醇共沸一次後，以真空泵乾燥19小 時，獲得標題化合物（1〇2 mg)。 H-NMR (DMSO-d6) δ : 2·69 (2H，t)，2·78 (3H，d)，2·87 (2H，d)，2.95(3H，s)，3.07-3.85 (4H，m)，3.91(3H，s)，4.36-4·89 (2H，m)，7·η (2H，t)，7·38 (1H，s)，7·57 (2H，dd)，7.62 (1H，s)，8.43-8.51 (1H，m)，10.08 (1H，s)，1〇·87 (1H，s)， 11·38-11·69 (1H，br)。 MS (ESI) m/z: 526 (M+H)+ 〇 [實施例89] N-{5-(二曱基胺甲醯基）-2-[2_(4_氟苯基胺甲醯 基）乙基]-3-曱氧基苯基卜5 -甲基-4,5，6,7-四氫噻唑并[5，4-c] 吡啶-2·甲醯胺鹽酸鹽 於冰浴冷卻下，向4-{2-[(4-氟苯基）胺甲醯基]乙基}_3_ 甲氧基-5-[(5_甲基-4,5,6,7-四氫噻唑并[5,4-〇]吡啶-2-基）羰 基胺基]苯甲酸（140 mg)的THF(5.〇 mi)懸浮液中添加氣甲 酸乙醋（38 μΐ)、ΤΕΑ(56 μΐ)，於〇°C下攪拌1小時。向反應 液中添加ΤΕΑ(140 μΐ)、二曱胺鹽酸鹽mg)，於室溫下 攪拌24小時。將溶劑於減壓下濃縮後，向殘渣中添加二氣 曱烷、甲醇、飽和NaCl水溶液。以二氣甲烷萃取後，以無 水NaJO4乾燥。將溶劑於減壓下濃縮後，將殘渣利用以矽 膠為載體之快速層析法（二氯甲烧：甲醇=3〇: 1)進行精 製’獲得標題化合物的自由體（58 mg)。向自由體（58 mg) 中添加乙醇（5 ml)、1當量鹽酸乙醇溶液（12〇〆），將溶劑 129677.doc -193- 200840568 於減壓下濃縮。以乙醇共沸一次後，以真空泵乾燥18小 時，獲得標題化合物（60 mg)。 'H-NMR (DMSO-d6) δ : 2.72 (2H? t)? 2.87 (2H, t), 2.90-3.01 (9H，m)，3·06-3·82 (4H，m)，3·87 (3H，s), 4.36-4.87 (2H， m)，6.92 (1H，s)，7·12 (2H，t)，7·18 (1H，s)，7·58 (2H，dd)， 10.09 (1H，s)，10.90 (1H，s)，11·63-11·48 (1H，b〇。 MS (ESI) m/z: 540 (M+H)+。 [實施例90] 3-溴-4-{2-[(4-氣苯基）胺甲醯基]乙基}-5-[(5-異 丙基-4,5,6,7-四氫嘆嗤并[5,4-c]吼咬-2-基）羰基胺基]苯曱 酸鹽酸鹽 (步驟a) 3-溴-4-甲基-5-硝基苯甲酸甲酯 向溴化銅（11)(4.04 g)的乙腈（1〇〇 ml)溶液中添加亞硝酸 第三丁酯（2.16 ml)、參考例l〇2g的化合物（3.026 g)，於室 溫下攪拌5分鐘。於90°C下攪拌1小時後，冷卻至室溫。以 乙酸乙酯稀釋反應液後，添加1 〇%檸檬酸水溶液。以乙酸 乙酯萃取後，以飽和NaHC〇3水溶液、飽和NaCl水溶液清 洗所合併之有機層。以無水Na2S〇4乾燥後，於減壓下餾去 溶劑。將殘渣利用以矽膠為載體之快速層析法（己烷：乙 酸乙酯=10 : 1)進行精製，獲得標題化合物（2.847 g)。 iH-NMR (CDC13) δ : 2.62 (3H，s)，3.96 (3H，S)，8.35 (1H， d)，8.43 (1Η，d)。 (步驟b ) 3 -漠-4 -漠曱基-5 -确基苯甲酸甲酉旨 向3-溴-4-甲基-5-硝基苯曱酸甲酯（2·807 g)的四氯化碳 (60 ml)溶液中添加NBS(5.535 g)、過氧化苯曱醯（含水 129677.doc -194- 200840568 25%，110 mg)，加熱回流22小時。冷卻後，將不溶物過濾 分離，以己烷-乙酸乙酯混合液（己烷/乙酸乙酯=2/1)清洗 後，將洗液、濾液合併，於減壓下濃縮。將殘渣利用以矽 膠為載體之快速層析法（己烷：乙酸乙酯=丨〇 :丨）進行精 製，於室溫下以真空泵乾燥1小時，獲得標題化合物（3.439 g)。 H-NMR (CDC13) δ :爻99 (3H，s)，4.89 (2H，s)，8·48 (1H， d)，8.49 (1Η，d) 〇 (步驟e) 2-[2-溴-4-(甲氧基羰基）硝基苄基]丙二酸二第三 丁酯H. NMR (DMSO-d6) δ : 2.68 (2H? t), 2.86 (2H5 t)? 2.93 (3H? s), 3·06-3·81 (4H, m), 3·89 (3H, s), 4.27-4.93 (2H, m), 7·ι〇(2H, t), 7·35 (1H, br s), 7·40 (1H, s), 7.56 (2H, dd), 7· 64 (1H, s), 7·98 (1H, br s), 10.07 (1H, s), 10.85 (1H, s), 1139-11.67 (1H, br) 〇MS (ESI) m/z: 512 ( M+H)+. [Example 88] N-{2-[2-(4-fluorophenylaminoindenyl)ethyl]decyloxy_5-(decylamine-carbenyl)phenyl}_5-methyl-4 , 5,6,7-tetrahydrofuran [5,4-c] acridine-2-carboxamide hydrochloride, the title compound (Step b) of Example 87 (14) Ethyl chloroformate (38 μM) and hydrazine (56 μM) were added to a suspension of THF (5.0 ml) and stirred at 0 ° C for 1 hour. To the reaction mixture, hydrazine (140 μM) and methylamine hydrochloride (70 mg) were added, and the mixture was stirred at room temperature for 19 hours. After the solvent was concentrated under reduced pressure, dichloromethane, methanol and a saturated aqueous solution of NaCl were added to the residue. After extracting with dichloromethane, it was dried over anhydrous Na 2 SO 4 . After concentrating the solvent under reduced pressure, the residue was purified by flash chromatography (dichlorohexane:methanol: 50:30:1) Free body (94 mg). To a free body (94 mg) was added ethanol (5 ml), 1N aqueous hydrochloric acid (200 μM), and the solvent was concentrated under reduced pressure. After azeotropy with ethanol, it was dried with a vacuum pump for 19 hours to obtain the title compound (1 〇 2 mg). H-NMR (DMSO-d6) δ : 2·69 (2H, t), 2·78 (3H, d), 2·87 (2H, d), 2.95 (3H, s), 3.07-3.85 (4H, m), 3.91 (3H, s), 4.36-4·89 (2H, m), 7·η (2H, t), 7·38 (1H, s), 7·57 (2H, dd), 7.62 ( 1H, s), 8.43-8.51 (1H, m), 10.08 (1H, s), 1〇·87 (1H, s), 11·38-11·69 (1H, br). MS (ESI) m/z: 526 (M+H) + 〇 [Example 89] N-{5-(didecylaminocarbamoyl)-2-[2_(4-fluorophenylaminecarbazinyl) Ethyl]-3-decyloxyphenyl 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2·carbenamide hydrochloride in ice bath 4-{2-[(4-Fluorophenyl)amine-carbamoyl]ethyl}_3_methoxy-5-[(5-methyl-4,5,6,7-tetrahydrothiazole) under cooling And [5,4-〇]pyridin-2-yl)carbonylamino]benzoic acid (140 mg) in THF (5. 〇mi) suspension was added with ethane formate (38 μΐ), ΤΕΑ (56 μΐ) Stir at 〇 ° C for 1 hour. To the reaction solution, hydrazine (140 μM) and diammonium hydrochloride (mg) were added, and the mixture was stirred at room temperature for 24 hours. After the solvent was concentrated under reduced pressure, dioxane, methanol and a saturated aqueous solution of NaCl were added to the residue. After extraction with digas methane, it was dried with anhydrous NaJO4. After the solvent was concentrated under reduced pressure, the residue was purified by flash chromatography (dichloromethane:methanol:m. To a free body (58 mg) was added ethanol (5 ml), 1N aqueous solution of hydrochloric acid (12 EtOAc), and solvent 129677. doc - 193 - 200840568 was concentrated under reduced pressure. After azeotropy with ethanol, it was dried under vacuum for 18 hours to give the title compound (60 mg). 'H-NMR (DMSO-d6) δ : 2.72 (2H? t)? 2.87 (2H, t), 2.90-3.01 (9H, m), 3·06-3·82 (4H, m), 3.87 (3H, s), 4.36-4.87 (2H, m), 6.92 (1H, s), 7·12 (2H, t), 7·18 (1H, s), 7·58 (2H, dd), 10.09 (1H, s), 10.90 (1H, s), 11·63-11·48 (1H, b. MS (ESI) m/z: 540 (M+H)+. [Example 90] 3-bromo -4-{2-[(4-Phenylphenyl)aminemethanyl]ethyl}-5-[(5-isopropyl-4,5,6,7-tetrahydroindenyl[5,4 -c]bite-2-yl)carbonylamino]benzoquinone hydrochloride (step a) methyl 3-bromo-4-methyl-5-nitrobenzoate to copper bromide (11) (4.04 g) acetonitrile (1 〇〇ml) solution was added with butyl trinitrate (2.16 ml), reference compound (3.026 g), and stirred at room temperature for 5 minutes. Stir at 90 ° C After 1 hour, it was cooled to room temperature. After the reaction mixture was diluted with ethyl acetate, a 1% aqueous solution of citric acid was added. After extraction with ethyl acetate, the combined organic layers were washed with saturated aqueous NaHCI3 and saturated aqueous NaCl. After drying over anhydrous Na 2 S 〇 4, the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography using silica gel. The title compound (2.847 g) was obtained. ), 8.43 (1Η, d). (Step b) 3 - Desert-4 - Molybdenum-5-Acidylbenzoic acid formazan to 3-bromo-4-methyl-5-nitrobenzoic acid Add NBS (5.535 g), benzoquinone peroxide (hydrated 129677.doc -194-200840568 25%, 110 mg) to a solution of ester (2·807 g) in carbon tetrachloride (60 ml), and heat to reflux for 22 hours. After cooling, the insoluble material was separated by filtration and washed with a hexane-ethyl acetate mixture (hexane/ethyl acetate = 2/1), and the mixture and the filtrate were combined and concentrated under reduced pressure. Purification by flash chromatography (hexane: ethyl acetate = EtOAc: EtOAc): EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH :爻99 (3H,s),4.89 (2H,s),8·48 (1H, d),8.49 (1Η,d) 〇(Step e) 2-[2-Bromo-4-(methoxycarbonyl) Nitrobenzyl]malonic acid di-t-butyl ester

於冰浴冷卻下’向丙二酸二第三丁酯（3 ·21 ml)的THF (50.0 ml)溶液中添加氫化鈉（55〇/〇)(545 mg)，於0°C下攪拌 3 0分鐘。於室溫下攪拌30分鐘後，於〇。〇下向反應液中滴 下3-溴-4-溴曱基-5-硝基苯甲酸曱酯（3·381 g)的thF(20 ml) 溶液後，於室溫下攪拌2小時。以乙酸乙酯稀釋反應液， 添加飽和NaCl水溶液。以乙酸乙酯萃取後，以飽和Naci水 溶液清洗所合併之有機層。以無水Na2S〇4乾燥後，於減壓 下餾去溶劑。將殘渣利用以矽膠為載體之快速層析法（己 烧：乙酸乙酯=10 : 1— 6 : 1)進行精製，以真空泵於4〇°C 下乾燥1小時，獲得標題化合物（3.3 89 g)。 'H-NMR (CDC13) δ : 1.41 (18Η, s)? 3.60 (1H? dd)? 3.71 (2H? br· d)，3.97 (3H，s)，8.40 (1H，d)，8.44 (1H，d)。 MS (ESI) m/z: 510 [(M+Na)+，79Br]，512 [(M+Na)+，81Bf]。 (步驟d) 3 -漠-4-(2 -叛基乙基）-5 -硝基苯甲酸甲g旨 129677.doc •195- 200840568 向2-[2-溴-4-(甲氧基羰基）-6-硝基苄基]丙二酸二第三丁 酯（3.360 g)的二氯甲烷（6.〇 ml)溶液中添加TFA(6.〇 ml)， 於室溫下攪拌20小時。將反應液於減壓下濃縮後，向殘渣 中添加乙腈（20 ml)、氧化銅（1)(110 mg)，加熱回流4小 時。將反應液冷卻至室溫後，將不溶物過濾分離。將濾液 於減壓下濃縮後，將殘渣利用以矽膠為載體之快速層析法 (二氯甲烷：甲醇=100 : 1)進行精製，以真空泵乾燥2小 時，獲得標題化合物（2.073 g)。 ^-NMR (CDC13) δ : 2.80-2.89 (2Η, m)? 3.25-3.32 (2H, m)5 3·97 (3H，s)，8,39 (1H，d)，8·45 (1H，d)。 MS (ESI) m/z: 332 [(M+Na)+，79Br]，334 [(M+Na)+，81Br]。 (步驟e) 3-溴-4-{2-[(4-氯苯基）胺甲醯基]乙基-硝基苯甲 酸甲酯 向3-溴-4-(2-羧基乙基）-5-硝基苯甲酸甲酯（355 mg)的二 氣甲烧（10 ml) &gt;谷液中添加4 -氣苯胺（165 mg)、HOBt( 149 mg)、EDC(256 mg)、ΤΕΑ(182 μΐ)，於室溫下攪拌 23 小 時。向反應液中添加二氯曱烷、丨當量鹽酸。以二氣曱烷 萃取後，以飽和NaHC〇3水溶液、飽和NaC1水溶液清洗所 合併之有機層。以無水NaeCU乾燥後，於減壓下餾去溶 劑。以甲醇清洗殘渣，渡取不溶物。將渡液於減壓下濃縮 後，以甲醇清洗殘渣，濾取不溶物。將所獲得之固體合 併，以真空泵於室溫下乾燥1小時’獲得標題化合物（344 mg)。 4-NMR (DMSO-d6) δ : 2·72 (2H，t)，3.21 (2H，t)，3·91 (3H， 129677.doc -196- 200840568 s)，7·35 (2H，d)，7·59 (2H，d)，8·37 (1H，d)，8·39 (1H，d)， 10·10 (1H，s)。 MS (ESI) m/z: 441 (M+H)+。 (步驟f) 3-胺基-5-溴-4-{2-[(4-氯苯基)胺甲醯基]乙基}苯曱 酸曱酯 於〇°C下，向3-溴-4·{2·[(4-氣苯基）胺甲醯基]乙基卜5_硝 基苯甲酸甲酯（337 mg)的DMF(9.0 ml)水（1.5 ml)混合液中 添加氣化鐵（111)(382 mg)、鋅（494 mg)，於室溫下攪拌40 小時。添加乙酸乙酯、飽和NaHC03水溶液，將不溶物過 濾分離，以乙酸乙酯萃取。將所合併之有機層以飽和NaC1 水溶液、水清洗後，以無水Na2S04乾燥，於減壓下餾去溶 劑。添加乙酸乙自曰-己烧混合液（己烧/乙酸乙g旨=4 /1)( 1 〇 ml)清洗殘渣，濾取固體。將所獲得之固體溶解於二氣甲 烧曱醇中，將不溶物過濾分離後，將濾液於減壓下濃縮。 以真空泵於室溫下乾燥4小時，獲得標題化合物（285 mg)。 ]H-NMR (CDCI3) δ : 2.77 (2H? t), 3.16 (2H? t)? 3.87 (3H, s), 4.53 (2H，s)，7·12 (1H，br s)，7·25 (1H，d)，7·27 (2H，d)， 7·40 (2H，d)，7.61 (1H，d)。 MS (ESI) m/z: 411 (M+H)、 (步驟g) 3-溴-4-{2-[(4·氯苯基）胺甲醯基]乙基}·5…[(5一異丙 基-4,5,6,7-四氫噻唑并[5,4-〇]吡啶-2-基）羰基胺基]苯甲酸 曱酯 向苓考例32之化合物（210 mg)的二氯曱烧（5.0 ml)懸浮液 129677.doc -197- 200840568 中添加DMF(0.02 ml)、草醯氣（137 μΐ)，於室溫下攪拌lj、 時。將反應液於減壓下濃縮後，以真空泵乾燥。向殘渣中 添加二氯曱烷（5.0 ml)而製成懸浮液，添加3·胺基-5-溴-4_ {2-[(4-氣苯基）胺曱醯基]乙基}苯曱酸甲酯（145 mg)的二氯 甲烷（15 ml)溶液、ΤΕΑ(1·0 ml)，於室溫下攪拌7日。以二 氯甲烧稀釋反應液後，添加飽和NaHC〇3水溶液。以二氣 甲烷萃取後，以飽和NaCl水溶液清洗所合併之有機層。以 無水Na2S04乾燥後，於減壓下餾去溶劑。將殘渣利用以石夕 膠為載體之快速層析法（二氣甲烷：甲醇=1〇〇 : 1— 50 : 1) 進行精製，於室溫下以真空泵乾燦1小時，獲得標題化合 物（135 mg) 〇 lH-NMR (CDC13) δ : 1.17 (6H5 d)5 2.84-3.10 (7H5 m)? 3.24 (2H，t)，3·89 (5H，s)，7.25 (2H，d)，7·33 (1H，s)，7·45 (2H， d)，8.10 (1H，d)，8.42 (1H，d)，10.49 (1H，s)。 MS (ESI) m/z: 619 (M+H)+。 (步驟h) 3-溴-4-{2-[(4-氯苯基）胺曱醯基]乙基}-5-[(5-異丙 基-4,5,6,7-四氫噻唑并[5，4-c]吼啶-2-基）羰基胺基]苯曱酸 鹽酸鹽 向3-溴-4-{2-[(4-氯苯基）胺甲醯基]乙基}-5-[(5-異丙基-4,5,6,7-四氫噻唑并[5,4-(：]吡啶-2-基）羰基胺基]苯甲酸甲酯 (135 mg)的THF(5.0 ml)溶液中添加1當量NaOH水溶液（300 μΐ)，於室溫下攪拌3日。向反應液中追加1當量NaOH水溶 液（100 μΐ)，於室溫下攪拌2日。向反應液中添加1當量鹽 酸（400 μ〇後，於減壓下濃縮。將殘渣利用以矽膠為載體 129677.doc -198- 200840568 之快速層析法（二氯曱烷：曱醇=3〇 : : ι〇 : 〇進 行精製，獲得標題化合物的自由體（88 mg)。向自由體（88 mg)中添加乙酸乙酯（5 mi)、4當量鹽酸乙酸乙酯溶液〇㈧ μ 1)，照射超聲波。於減壓下濃縮後，以真空泵乾燥，獲 得標題化合物（94 mg)。 ]H-NMR (DMSO-d6) δ : 1.34 (6H? d), 2.77 (2H5 t)5 2.94- 3·83 (7H，m)，4.38-4.77 (2H，m)，7·34 (2H，d)，7·59 (2H，d)， 8·〇1 (1H，d)，8·06 (1H，d)，1〇·26 (1H，s)，11.06 (1H，s)。 MS (ESI) m/z: 605 (M+H)十。 [實施例91] 3-氯-4-{2-[(4-氣苯基）胺甲醯基]乙基}_5_[4_(3_ 氧基嗎琳-4-基）苯甲醢基胺基]苯甲酸 (步驟a) 3-氣-4-{2-[(4-氣苯基)胺甲醯基]乙基卜5_[(‘硝基 本甲&amp;&amp;基）胺基]苯曱酸甲酉旨 向參考例98之化合物（200 mg)的二氯甲烷（3·〇 ml)懸浮液 中添加4-硝基苯甲醯氣（143 mg)、ΤΕΑ(226 μΐ)，於室溫下 授拌1 7小。以二氣甲烧稀釋後，添加1當量鹽酸。以二 氯甲院萃取後，以飽和NaHC〇3水溶液、飽和NaCl水溶液 清洗所合併之有機層。以無水Naecu乾燥後，將溶劑於減 壓下濃縮。向殘渣中添加甲醇，進行清洗濾取，獲得標題 化合物（247 mg)。 iH-NMR (DMSO-d6) δ : 2·78 (2H，t)，3.18 (2H，t)，3·91 (3H， s)，7·36 (2H，d)，7.58 (2H，d)，7.92 (1H，s)，8·14 (1H，s) 8.28 (2H，d)，8·43 (2H，d)，10·25 (1H，s)，10.83 (1H，S)。 MS (ESI) m/z: 516 (M+H)、 129677.doc -199- 200840568 (步驟b) 3-[(4-胺基苯曱醯基）胺基]氯_4_{2_[(4-氯苯基） 胺曱醯基]乙基}苯曱酸甲酯 向3-氯-4-{2-[(4-氯苯基）胺甲醯基]乙基}_5-[(4-硝基苯甲 醯基）胺基]苯曱酸甲酯（242 mg)的DMF(5.0 ml)溶液中添加 水（0.5〇1111)、氣化鐵（111)六水合物（37〇1^)、鋅（3 3〇11^)， 於室溫下檀拌1 8小時。以乙酸乙酯稀釋後，添加飽和Add sodium hydride (55 〇 / 〇) (545 mg) to a solution of di-tert-butyl malonate (3 · 21 ml) in THF (50.0 ml) under ice-cooling and stir at 0 ° C. 0 minutes. After stirring at room temperature for 30 minutes, it was simmered. A solution of 3-bromo-4-bromoindol-5-nitrobenzoate (3·381 g) in thF (20 ml) was added dropwise to the mixture, and the mixture was stirred at room temperature for 2 hr. The reaction solution was diluted with ethyl acetate, and a saturated aqueous solution of NaCl was added. After extraction with ethyl acetate, the combined organic layers were washed with saturated aqueous NaCI. After drying over anhydrous Na 2 S 4 , the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (hexane: ethyl acetate = 10:1 - 6 : 1) using silica gel as a solvent, and dried under vacuum at 4 ° C for 1 hour to give the title compound (3.3 89 g). ). 'H-NMR (CDC13) δ : 1.41 (18Η, s)? 3.60 (1H? dd)? 3.71 (2H? br·d), 3.97 (3H, s), 8.40 (1H, d), 8.44 (1H, d). MS (ESI) m/z: 510 [(M+Na)+, 79Br], 512 [(M+Na)+, 81Bf]. (Step d) 3 - Desert-4-(2- ethylethyl)-5-nitrobenzoic acid methylg 129677.doc •195- 200840568 to 2-[2-bromo-4-(methoxycarbonyl) To a solution of di-tert-butyl 3-aminobenzyl]malonate (3.360 g) in dichloromethane (6. 〇ml) was added TFA (6. 〇ml) and stirred at room temperature for 20 hr. After concentrating the reaction mixture under reduced pressure, acetonitrile (20 ml) and copper oxide (1) (110 mg) were added to the residue, and the mixture was refluxed for 4 hours. After cooling the reaction solution to room temperature, the insoluble matter was separated by filtration. After the filtrate was concentrated under reduced pressure, the residue was purified by flash chromatography (dichloromethanol:methanol = 100:1). ^-NMR (CDC13) δ : 2.80-2.89 (2Η, m)? 3.25-3.32 (2H, m)5 3·97 (3H,s),8,39 (1H,d),8·45 (1H, d). MS (ESI) m/z: 332 [(M+Na)+, 79Br], 334 [(M+Na)+, 81Br]. (Step e) 3-bromo-4-{2-[(4-chlorophenyl)amine-carbamoyl]ethyl-nitrobenzoate to 3-bromo-4-(2-carboxyethyl)- Methyl 5-nitrobenzoate (355 mg) in two gas (10 ml) &gt; 4 - aniline (165 mg), HOBt (149 mg), EDC (256 mg), hydrazine () 182 μΐ), stirred at room temperature for 23 hours. Dichlorosilane and hydrazine hydrochloride were added to the reaction liquid. After extraction with dioxane, the combined organic layers were washed with a saturated aqueous solution of NaHC? After drying in anhydrous NaeCU, the solvent was evaporated under reduced pressure. The residue was washed with methanol to obtain insoluble matter. After the liquid was concentrated under reduced pressure, the residue was washed with methanol, and the insoluble material was filtered. The obtained solid was combined and dried under a vacuum pump at room temperature for 1 hour to give the title compound (344 mg). 4-NMR (DMSO-d6) δ : 2·72 (2H, t), 3.21 (2H, t), 3.91 (3H, 129677.doc -196- 200840568 s), 7·35 (2H, d) , 7·59 (2H, d), 8.37 (1H, d), 8. 39 (1H, d), 10·10 (1H, s). MS (ESI) m/z: 441 (M+H)+. (Step f) 3-Amino-5-bromo-4-{2-[(4-chlorophenyl)amine-carbamoyl]ethyl}benzoate decyl ester at 〇 ° C to 3-bromo- 4·{2·[(4-Phenylphenyl)amine-carbamoyl]ethyl bromide 5-nitrobenzoic acid methyl ester (337 mg) in a mixture of DMF (9.0 ml) water (1.5 ml) Iron (111) (382 mg) and zinc (494 mg) were stirred at room temperature for 40 hours. Ethyl acetate and a saturated aqueous NaHCO 3 solution were added, and the insoluble material was separated by filtration and ethyl acetate. The combined organic layer was washed with saturated aqueous NaH.sub.1, water, dried over anhydrous Na? The residue was washed with a mixture of ethyl acetate-hexanes (hexane/acetic acid ethyl acetate = 4 /1) (1 〇 ml), and the solid was collected by filtration. The obtained solid was dissolved in dimethyl decyl alcohol, and the insoluble matter was separated by filtration, and the filtrate was concentrated under reduced pressure. Drying at room temperature for 4 hours with a vacuum pump gave the title compound (285 mg). H-NMR (CDCI3) δ : 2.77 (2H? t), 3.16 (2H? t)? 3.87 (3H, s), 4.53 (2H, s), 7·12 (1H, br s), 7.25 (1H, d), 7.27 (2H, d), 7·40 (2H, d), 7.61 (1H, d). MS (ESI) m / z: 411 (M+H), (Step g) 3-bromo-4-{2-[(4-chlorophenyl)aminemethanyl]ethyl}·5...[(5 Monomethyl isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-indolylpyridin-2-yl)carbonylamino]benzoate to the compound of Example 32 (210 mg) Dichlorohydrazine (5.0 ml) suspension 129677.doc -197- 200840568 DMF (0.02 ml) and grass cockroach (137 μΐ) were added and stirred at room temperature for lj. The reaction solution was concentrated under reduced pressure and dried with a vacuum. Dichloromethane (5.0 ml) was added to the residue to prepare a suspension, and 3·amino-5-bromo-4_ {2-[(4-phenylphenyl)aminoindenyl]ethyl}benzoquinone was added. A solution of methyl ester (145 mg) in dichloromethane (15 ml) and EtOAc (1·0 ml) was stirred at room temperature for 7 days. After diluting the reaction mixture with methylene chloride, a saturated aqueous solution of NaHC〇3 was added. After extraction with dioxane, the combined organic layers were washed with a saturated aqueous solution of NaCl. After drying over anhydrous Na 2 SO 4 , the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (dihydromethane: methanol = 1 〇〇: 1 - 50: 1) using the saponin as a carrier, and dried under vacuum at room temperature for 1 hour to obtain the title compound (135). Mg) 〇lH-NMR (CDC13) δ : 1.17 (6H5 d)5 2.84-3.10 (7H5 m)? 3.24 (2H,t),3·89 (5H,s), 7.25 (2H,d),7· 33 (1H, s), 7.45 (2H, d), 8.10 (1H, d), 8.42 (1H, d), 10.49 (1H, s). MS (ESI) m/z: 619 (M+H)+. (Step h) 3-bromo-4-{2-[(4-chlorophenyl)amine fluorenyl]ethyl}-5-[(5-isopropyl-4,5,6,7-tetrahydro) Thiazolo[5,4-c]acridin-2-yl)carbonylamino]benzoquinone hydrochloride to 3-bromo-4-{2-[(4-chlorophenyl)aminemethanyl]B Methyl}-5-[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-(:]pyridin-2-yl)carbonylamino]benzoic acid methyl ester (135 mg 1 NaOH aqueous solution (300 μM) was added to a solution of THF (5.0 ml), and the mixture was stirred at room temperature for 3 days, and 1 NaOH aqueous solution (100 μM) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 days. After adding 1 equivalent of hydrochloric acid (400 μM) to the reaction mixture, the residue was concentrated under reduced pressure. The residue was purified by flash chromatography using EtOAc 129677.doc-198-200840568 (dichloromethane: oxime = 3 〇: : ι〇: 〇 Purification to obtain the title compound as a free form (88 mg). To a free body (88 mg), ethyl acetate (5 mi), 4 eq. ethyl acetate solution (8) μ 1), Ultrasonic. After concentration under reduced pressure, the title compound (94 mg) was obtained from EtOAc EtOAc (EtOAc: EtOAc) (7H m), 4.38-4.77 (2H, m), 7·34 (2H, d), 7·59 (2H, d), 8·〇1 (1H, d), 8·06 (1H, d), 1 〇·26 (1H, s), 11.06 (1H, s) MS (ESI) m/z: 605 (M+H) s. [EX.91] 3-chloro-4-{2-[(4- Gas phenyl)amine methylmercapto]ethyl}_5_[4_(3-oxymorphin-4-yl)benzimidino]benzoic acid (step a) 3- gas-4-{2-[( 4-oxophenyl)amine-methylmercapto]ethylidene 5-[('nitro-methyl&amp;&amp;&gt;))amino]benzonic acid methyl hydrazide to the compound of Reference Example 98 (200 mg) in dichloromethane (3·〇ml) Add 4-nitrobenzhydrazide (143 mg) and cesium (226 μΐ) to the suspension, and mix at room temperature for 7 hours. After diluting with two gas, add 1 equivalent. After the extraction with chloroform, the combined organic layer was washed with a saturated aqueous solution of NaHC 3 and saturated aqueous NaCI, and dried over anhydrous Naecu, and the solvent was concentrated under reduced pressure. The title compound (247 mg) was obtained. iH-NMR (DMSO-d6) δ: 2·78 (2H, t), 3.18 (2H, t), 3·91 (3H, s), 7·36 (2H ,d), 7.58 (2H,d), 7.92 (1H,s),8·14 (1H s) 8.28 (2H, d), 8 · 43 (2H, d), 10 · 25 (1H, s), 10.83 (1H, S). MS (ESI) m/z: 516 (M+H), 129677.doc -199 - 200840568 (Step b) 3-[(4-Aminophenylphenyl)amino]Chloro_4_{2_[(4 -Chlorophenyl)methylamino]ethyl}benzoate methyl ester to 3-chloro-4-{2-[(4-chlorophenyl)aminemethanyl]ethyl}_5-[(4- To a solution of methyl nitrobenzhydryl)amino]benzoate (242 mg) in DMF (5.0 ml), water (0.5〇1111), iron (111) hexahydrate (37〇1^) Zinc (3 3〇11^), sandalwood at room temperature for 18 hours. After diluting with ethyl acetate, add saturation

NaHC03水溶液’將不溶物過濾分離。對濾液進行分液操 作’以乙酸乙酯萃取。將所合併之有機層以飽和Naci水溶 液、水清洗後，以無水NazSO4乾燥，於減壓下餾去溶劑。 向殘渣中添加二氯曱烷、甲醇，將不溶物過濾分離，於減 壓下濃縮。以真空泵於室溫下乾燥1小時，獲得標題化合 物（179 mg)。 ]H-NMR (DMSO-d6) δ : 2.82 (2H5 t)? 3.11 (2H5 t)5 3.86 (3H5 s)，5·84 (2H，s)，6.63 (2H，d)，7.35 (2H，d)，7·57 (2H，d)， 7·76-7·83 (3H，m)，8.13 (1H，d)，10.17 (1H，s)，10.26 (1H， s) o MS (ESI) m/z: 486 (M+H)+。 (步驟c) 3-氣-5-{4-[2-(2-氣乙氧基）乙醯基胺基]苯甲醯基胺 基}-4-[2-(4-氯苯基胺甲醯基）乙基]苯甲酸甲酉旨 向（2_氯乙氧基）乙酸（92 mg)的二氯甲燒（2·〇 mi)溶液中 添加DMF(0.02 ml)、草醯氣（60 μΐ)，於室溫下授拌分 鐘。進而，追加草醯氣（60 μΐ)，於室溫下攪拌i小時。將 反應液於減壓下濃縮後，將殘渣製成二氯甲烷（5〇 ml)溶 液，將其滴下至3-[(4-胺基苯甲醯基）胺基；μ5_氣-4_{2_[(4_ 129677.doc -200 - 200840568 氯苯基）胺曱醯基]乙基丨笨曱酸甲酯（165 mg)中。添加二氣 甲烷（10.0 ml)、ΤΕΑ(420 μΐ)，於室溫下攪拌6小時。以二 氯曱烷稀釋反應液後，添加飽和NaHC〇3水溶液。以二氣 甲烷萃取後，將所合併之有機層以飽和NaC1水溶液清洗 後，以無水NajO4乾燥。將溶劑於減壓下濃縮後，將殘渣 利用以矽膠為載體之快速層析法（二氯甲烷 :甲醇=100 : 1 —50 ·· 1)進行精製，獲得標題化合物（153 mg)。 ]H-NMR (CDC13) δ : 2.95-3.05 (2H? m)5 3.13-3.22 (2H? m), 3.77-3.83 (2H，m)，3.87 (3H，s)，3.91-3.96 (2H，m)，4.19 (2H，s)，7·27 (2H，d)，7.41 (2H，d)，7·52 (1H，s)，7.78 (2H， d)，7·85 (1H，d)，8·23 (2H，d)，8·40 (1H，d)，8·71 (1H，s)， 10.65 (1H，s) 〇 (步驟d) 3-氯-4-{2-[(4-氣苯基）胺曱醯基]乙基卜5 — [4_(3_氧 基嗎琳-4-基）苯曱酸基胺基]苯曱酸 於冰浴冷卻下，向3_氯-5_{4_[2_(2-氯乙氧基）乙醯基胺 基]苯曱醯基胺基卜4-[2-(4-氣苯基胺曱醯基）乙基]苯甲酸 曱酯（151 mg)的 THF(5.〇 ml)溶液中添加 tBu〇K(27 mg)，於 冰冷冷卻下攪拌15分鐘。追加tgu〇K(28 mg)，於室溫下攪 拌1小時。進而，追加t；Bu〇K(27 mg)，於室溫下攪拌i小 時。以二氣甲烷稀釋後，添加〇.丨當量鹽酸溶液。以二氯 曱烧萃取後’將所合併之有機層以飽和NaC1水溶液清洗， 以無水NazSCU乾燥。於減壓下濃縮，將殘渣利用以矽膠為 載體之快速層析法（二氯曱烷：甲醇=5〇 ·· 3〇 : 2〇 ·· 1 10 · 1)進行精製’獲得標題化合物（74 mg)。又，作為 129677.doc -201 - 200840568 副產物，獲得3-氯-4-{2-[(4-氣苯基）胺甲醯基]乙基}_5-[4-(3-氧基嗎琳-4 -基）苯曱酿基胺基]苯曱酸甲@旨（46 mg)。 ^-NMR (DMSO-d6) δ : 2·78 (2H，t)，3·13 (2H，t)，3·83 (2H， t)，4·01 (2Η，t)，4·25 (2Η，s)，7·34 (2Η，d)，7·56 (2Η，d)， 7·63 (2Η，d)，7.83 (1Η，s)，8.05-8.10 (3Η，m)，10.23 (1Η，s)， 10.55 (1H，s)，13·35 (1H，s)。 MS (ESI) m/z: 556 (M+H)+ 〇 [實施例92] 3-溴-4-{2-[(4-氯苯基）胺甲醯基]乙基}_5_[(5_甲 基-4,5,6,7-四氫噻唑并[5,4-c]吼啶-2-基）羰基胺基]苯甲酸 鹽酸鹽 (步驟a) 3-溴-4-{2-[(4-氯苯基）胺甲醯基]乙基甲基_ 4,5，6,7-四氫噻唑并[5,4-c]吡啶-2-基）羰基胺基]苯甲酸甲酯 向5 -甲基- 4,5,6,7 -四氫。塞唾并[5,4-〇]。比。定-2-甲酸鹽酸鹽 (309 mg)的二氣甲烷（5·〇 ml)懸浮液中添加DMF(0.04 ml)、 草醯氯（452 μΐ)，於室温下攪拌i小時。將反應液於減壓下 濃縮後，以二氣甲烧共沸一次，以真空泵乾燥。向殘渣中 添加實施例90之（步驟f)的標題化合物（271 mg)的二氯甲烷 (30 ml)溶液、ΤΕΑ( 1400 μΐ)，於室溫下攪拌4曰。以二氣 甲烧稀釋反應液後，添加飽和NaHC〇3水溶液。以二氣曱 烷萃取後’以飽和NaCl水溶液清洗所合併之有機層。以無 水NazSO4乾燥後，於減壓下餾去溶劑。將殘渣利用以矽膠 為載體之快速層析法（二氣甲烷：甲醇=1〇〇 : 5〇 : 1 — 3〇 : 1)進行精製，於室溫下以真空泵乾燥1小時，獲得標 題化合物（118 mg)。 129677.doc -202- 200840568 W-NMR (CDC13) δ : 2·54 (3H，s)，2·86 (2H，t)，2·91 (2H，t)， 2·98 (2H，t)，3·19 (2H，t)，3·75 (2H，s)，3.86 (3H，s)，7·2〇 (2H，d)，7,45 (2H，d)，7-96 (1H，s)，8·04 (1H，d)，8·38 (1H， d)，10,76 (1H，s)。 MS (ESI) m/z: 591 (M+H)+。 (步驟b) 3-溴-4-{2-[(4-氯苯基）胺甲醯基]乙基卜5-[(5-甲基_ 4,5,6,7-四鼠0塞嗅弁[5,4_〇]17比咬-2-基）|£反基胺基]苯曱酸鹽酸 mThe aqueous NaHC03 solution was separated by filtration. The filtrate was subjected to a liquid separation operation 'extracted with ethyl acetate. The combined organic layer was washed with a saturated aqueous NaCI solution and water, dried over anhydrous NazSO? Dichlorosilane and methanol were added to the residue, and the insoluble material was separated by filtration and concentrated under reduced pressure. Drying at room temperature for 1 hour with a vacuum pump gave the title compound (179 mg). H-NMR (DMSO-d6) δ : 2.82 (2H5 t)? 3.11 (2H5 t)5 3.86 (3H5 s), 5.84 (2H, s), 6.63 (2H, d), 7.35 (2H, d ),7·57 (2H,d), 7·76-7·83 (3H,m),8.13 (1H,d),10.17 (1H,s),10.26 (1H, s) o MS (ESI) m /z: 486 (M+H)+. (Step c) 3-Ga-5-{4-[2-(2-Gasethoxy)ethenylamino]benzimidyl}-4-[2-(4-chlorophenylamine) Methyl hydrazide)ethyl]benzoic acid formazan is added to a solution of (2-chloroethoxy)acetic acid (92 mg) in dichloromethane (2·〇mi) with DMF (0.02 ml) and oxalate ( 60 μΐ), mixing at room temperature for a minute. Further, grasshopper gas (60 μM) was added thereto, and the mixture was stirred at room temperature for 1 hour. After the reaction mixture was concentrated under reduced pressure, the residue was taken to methylene chloride (5 mL), which was then dropped to 3-[(4-aminobenzhydryl)amine; 2_[(4_ 129677.doc -200 - 200840568 chlorophenyl)amine hydrazino]ethyl hydrazide methyl ester (165 mg). Dioxane (10.0 ml) and hydrazine (420 μΐ) were added and stirred at room temperature for 6 hours. After diluting the reaction mixture with dichloromethane, a saturated aqueous solution of NaHC 3 was added. After extraction with dioxane, the combined organic layers were washed with a saturated aqueous NaCI solution and dried over anhydrous Naj. After the solvent was concentrated under reduced pressure, the residue was purified eluted eluted elut elut elut elut elut elut elut ]H-NMR (CDC13) δ : 2.95-3.05 (2H? m)5 3.13-3.22 (2H? m), 3.77-3.83 (2H, m), 3.87 (3H, s), 3.91-3.96 (2H, m ), 4.19 (2H, s), 7·27 (2H, d), 7.41 (2H, d), 7·52 (1H, s), 7.78 (2H, d), 7·85 (1H, d), 8·23 (2H,d),8·40 (1H,d),8·71 (1H,s), 10.65 (1H,s) 〇(step d) 3-chloro-4-{2-[(4 - gas phenyl)amine hydrazino]ethyl b 5 - [4_(3_ oxymorphin-4-yl)benzoylamino]benzoic acid under ice cooling, to 3-chloro- 5_{4_[2_(2-chloroethoxy)ethinylamino]phenylhydrazinyl- 4-[2-(4-cyclophenylaminoindenyl)ethyl]benzoate oxime ( To a solution of 151 mg) in THF (5. Tgu〇K (28 mg) was added and stirred at room temperature for 1 hour. Further, t; Bu〇K (27 mg) was added, and the mixture was stirred at room temperature for 1 hour. After diluting with di-methane, a solution of hydrazine was added. After extraction with dichlorohydrazine, the combined organic layers were washed with a saturated aqueous NaCI solution and dried over anhydrous NazSCU. The residue was concentrated under reduced pressure, and the residue was purified by flash chromatography (dichloromethane:methanol = 5 〇·· 3 〇: 2 〇·· 1 10 · 1) to obtain the title compound (74). Mg). Further, as a by-product of 129677.doc -201 - 200840568, is obtained 3-chloro-4-{2-[(4-phenylphenyl)amine-carbamoyl]ethyl}_5-[4-(3-oxy? Lin-4-yl)benzoylamino]benzoic acid A@46 (46 mg). ^-NMR (DMSO-d6) δ : 2·78 (2H, t), 3·13 (2H, t), 3·83 (2H, t), 4·01 (2Η, t), 4·25 ( 2Η,s),7·34 (2Η,d),7·56 (2Η,d), 7·63 (2Η,d),7.83 (1Η,s),8.05-8.10 (3Η,m),10.23 ( 1Η, s), 10.55 (1H, s), 13·35 (1H, s). MS (ESI) m/z: 556 (M+H) + 〇 [Example 92] 3-bromo-4-{2-[(4-chlorophenyl)aminecarbazyl]ethyl}_5_[(5 _Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]acridin-2-yl)carbonylamino]benzoic acid hydrochloride (step a) 3-bromo-4- {2-[(4-Chlorophenyl)aminemethanyl]ethylmethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonylamino] Methyl benzoate to 5-methyl-4,5,6,7-tetrahydrogen. Sputum and [5,4-〇]. ratio. DMF (0.04 ml) and oxalic acid chloride (452 μM) were added to a suspension of dioxane (309 mg) in dioxane (5·〇 ml), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and then azeotroped with a second gas and dried by a vacuum pump. A solution of the title compound (271 mg) in m.p. After diluting the reaction mixture with a second gas, a saturated aqueous solution of NaHC〇3 was added. After extraction with dioxane, the combined organic layers were washed with a saturated aqueous solution of NaCl. After drying in anhydrous NazSO4, the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (dihydromethane: methanol = 1 〇〇: 5 〇: 1 - 3 〇: 1) using hydrazine as a carrier, and dried under vacuum at room temperature for 1 hour to obtain the title compound ( 118 mg). 129677.doc -202- 200840568 W-NMR (CDC13) δ : 2·54 (3H, s), 2·86 (2H, t), 2·91 (2H, t), 2·98 (2H, t) ,3·19 (2H,t),3·75 (2H,s),3.86 (3H,s),7·2〇(2H,d),7,45 (2H,d),7-96 (1H , s), 8·04 (1H, d), 8.38 (1H, d), 10, 76 (1H, s). MS (ESI) m/z: 591 (M+H)+. (Step b) 3-bromo-4-{2-[(4-chlorophenyl)amine-carbamoyl]ethyl b- 5-[(5-methyl-4,5,6,7-tetrazine 0 stopper Olfactory 弁[5,4_〇]17 than bit-2-yl)|£反基基基]benzoate acid m

向3 -溴-4-{2-[(4-氯苯基）胺甲醯基]乙基卜％[(5_甲基· 4,5,6,7-四氫噻嗤并[5,4-c]咄啶_2_基）羰基胺基]苯甲酸曱酿 (155 mg)的THF(6.0 ml)溶液中添加LiOH—水合物（17 mg)、水（1.0 ml)，於室溫下攪拌17小時。添加u〇H一水合 物（15 mg)，於室溫下攪拌2日。向反應液中添加〗當量鹽 酸（1.50 ml)後，於減壓下濃縮。將殘渣利用以矽膠為載體 之快速層析法（二氯甲烷：甲醇=5〇 : l43〇 : — 10 : :1)進行精製。添加二噚烷（10 ml)、4當量鹽酸 乙酸乙酯溶液（125 μΐ)、水（4·〇 ml)，照射超聲波。於減壓 下濃，縮後，以水共沸，以真空泵乾燥，獲得標題化合物 (181 mg) 〇 h-NMR (DMS〇-d6) δ : 2.62_4.32 (9H，m)，4 37 4 84 (4H， m), 7.34 (2H, d), 7.71 (2H, d), 8.〇〇 (1H, s), 8.07 (1H&gt; s), 9·12 (0·4Η，s)，10.89 (1H i i \ f： ίΛΎΎ 、 、，s)’ U·16 (1H，s)，11.93-12.48 (1,6H，m)。 MS (ESI) m/z: 577 (M+H)+。 129677.doc -203 - 200840568 [實施例93] 3-溴-4-{2-[(4-氟苯基）胺曱醯基]乙基卜5-[(5-異 丙基-4,5,6,7-四氫噻唑并[5,4-c]吡啶-2-基）羰基胺基]苯甲 酸曱酯鹽酸鹽 (步驟a) 3-溴-4-{2-[(4-氟苯基）胺甲醯基]乙基}-5-硝基苯曱 酸曱酯 向實施例90之（步驟d)的標題化合物（643 mg)的二氣甲烧 (8.0 ml)懸浮液中添加4-氟苯胺（223 μΐ)、HOBt(294 mg)、 EDC(445 mg)、ΤΕΑ(235 μΐ)，於室溫下攪拌24小時。向反 應液中添加二氣甲烷、1當量鹽酸。以二氯曱烷萃取後， 以飽和NaHC〇3水溶液、飽和NaCl水溶液清洗所合併之有 機層。以無水Na2S〇4乾燥後，於減壓下餾去溶劑。以乙酸 乙酯（6 ml)-己烷（6 ml)混合液清洗殘渣，濾取固體。將遽 液減壓下濃縮後，利用以矽膠為載體之快速層析法（二氯 曱烷：甲醇=1〇〇: 1)進行精製。與先前所濾取的固體合 併，以真空泵於室溫下乾燥1小時，獲得標題化合物（73 j mg) 〇 b-NMR (CDC13) δ : 2·82 (2H，t)，3·39 (2H，t)，4·01 (3H，s)， 7·02-7·09 (2Η，m)，7·23 (1Η，s)，7·52 (2Η，dd)，8·43 (1Η，s)， 8·49 (1H，s) 〇 MS (ESI) m/z: 423 (M+H)、 (步驟b) 3-胺基-5-溴-4-{2-[(4-氟苯基）胺曱醯基]乙基}苯甲 酸曱酯 於〇 C下向3-溴-4-{2-[(4·氟苯基）胺曱醯基]乙基卜5-硝基 苯甲酸甲酯（720 mg)的DMF(5.0 ml)、水（0.5 ml)混合液中 129677.doc -204- 200840568 添加氣化鐵（III)六水合物（1350 mg)、鋅（114〇11^)，於室 溫下攪拌22小時。添加乙酸乙酯、飽和NaHC03水溶液， 將不溶物過濾分離，以乙酸乙酯萃取。將所合併之有機層 以飽和NaCl水溶液、水清洗後，以無水Na2S04乾燥，於減 壓下顧去溶劑。向殘渣中添加甲醇進行清洗後，漉取固 體。將濾液於減壓下濃縮後，利用以矽膠為載體之快速層 析法（二氣曱烷：曱醇=1 〇〇 : 1)進行精製。與先前所濾取 的固體合併，以真空泵於室溫下乾燥丨小時，獲得標題化 合物（63 8 mg)。 h-NMR (DMSO-d6) δ : 2·98 (2H，t)，3.29-3.34 (2H，m)， 3·80 (3H，s)，5.70 (2H，br s)，7·11-7·17 (2H，m)，7.27 (1H， s)，7.28 (1H，s)，7.60 (2H，dd)，10.01 (ih，s) 0 MS (ESI) m/z: 395 (M+H)+。 (步驟c)3-溴-4-{2-[(4-氟苯基）胺曱醯基]乙基}·5_[(5-異丙 基-4,5,6,7-四氫嗟唾并[5,4-cp比啶·2-基）羰基胺基]苯曱酸 甲酯鹽酸鹽 向參考例32之化合物（554 mg)的二氯甲烷（5 〇 ml)懸浮液 中添加DMF(0.04 ml)、草醯氯（181 μ1),於室溫下攪拌15 分鐘。追加草醯氣（181 μΐ)，於室溫下攪拌45分鐘。將反 應液於減壓下濃縮後，以真空泵乾燥25小時。將殘渣與 二氣甲烷（20 ml)—併添加至3-胺基_5_溴_4_{2_[(4_氟苯基） 胺甲醯基]乙基}苯甲酸曱酯（440 mg)的二氯曱烷（5〇 ml). 浮液中。向混合液中添加TEA((K7〇 ml)，於室溫下擾摔2〇 小時。將反應液於減壓下濃縮後，向殘渣中添加二氯甲 129677.doc -205 - 200840568 烧、餘和NaCl水溶液。以二氣甲烷萃取後，將所合併之有 機層以無水NaaSCU乾燥，於減壓下濃縮。將殘渣利用以矽 膠為載體之快速層析法（二氣甲烷：甲醇=5〇 : 〇進行精 製，獲得粗精製物（5丨4 mg)。以甲醇清洗粗精製物，濾取 固體。將濾液於減壓下濃縮後，利用以矽膠為載體之快速 層析法（一氣甲烷：甲醇H00: 1—5〇: i)進行精製。與先 前所濾取的固體合併、以甲醇（2 ml)清洗後，於二氯曱烷 甲醇混合液中將不溶物過濾分離，以真空泵於室溫下乾燥 1小k ’獲付標題化合物（422 mg)。 ^-NMR (CDC13) δ : 1.16 (6Η, d), 2.87-3.06 (7H, m), 3.25 (2H, t), 3.87 (2H, s), 3.89 (3H, s), 6.95-7.01 (2H, m), 7&gt;2? (1H, br s), 7.45 (2H, dd), 8.10 (1H, s), 8.43 (1s), 1 〇.56 (1H，br s) 0 向標題化合物之自由體（220 mg)的甲妒Λ 妁甲.（8·〇 ml)懸浮液中 添加4當量鹽酸二噚烷溶液（150 μ1) I成洛液後，於減壓 下鶴去溶劑。以水共沸，以真空i# 泵乾輛，獲得標題化合物 (237 mg)。 切 W-NMR (DMSO-d6) δ : 1·38 (3H d、η ? d)^ !·40 (3Η? d), 2.70. 2.85 (2Η，m)，3·03-3·21 (3Η，m)，3 , c • ·3·50(2Η，πι)，3.59- 3·84 (2H，m)，3·87 (3H，s)，4.47-4 60 屬（1H，m)，4.6“ (1H，m)，7.07-7.18 (2H，m)，7.58 心、To 3-bromo-4-{2-[(4-chlorophenyl)aminemethanyl]ethyl b%[(5-methyl·4,5,6,7-tetrahydrothiazepine [5, To a solution of 4-c] acridine-2-yl)carbonylamino]benzoic acid (155 mg) in THF (6.0 ml), LiOH-hydrate (17 mg), water (1.0 ml) Stir for 17 hours. U 〇 H monohydrate (15 mg) was added and stirred at room temperature for 2 days. After adding the equivalent of hydrochloric acid (1.50 ml) to the reaction mixture, it was concentrated under reduced pressure. The residue was purified by a flash chromatography (dichloromethane:methanol:methanol:m. Dioxane (10 ml), 4 equivalents of an ethyl acetate solution (125 μM), and water (4·ml) were added, and the mixture was irradiated with ultrasonic waves. Concentrated under reduced pressure, and the mixture was evaporated to dryness with water and evaporated to give the title compound (181 mg) 〇h-NMR (DMS 〇-d6) δ: 2.62_4.32 (9H, m), 4 37 4 84 (4H, m), 7.34 (2H, d), 7.71 (2H, d), 8.〇〇(1H, s), 8.07 (1H&gt; s), 9·12 (0·4Η, s), 10.89 (1H ii \ f: ίΛΎΎ , , , s) ' U·16 (1H, s), 11.93-12.48 (1,6H, m). MS (ESI) m/z: 577 (M+H)+. 129677.doc -203 - 200840568 [Example 93] 3-bromo-4-{2-[(4-fluorophenyl)amine fluorenyl]ethyl b-[-(5-isopropyl-4,5 ,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonylamino]benzoic acid oxime ester hydrochloride (step a) 3-bromo-4-{2-[(4- To a suspension of the title compound (643 mg) of Example 90 (Step d) in dimethylacetone (8.0 ml), EtOAc. 4-Fluoroaniline (223 μΐ), HOBt (294 mg), EDC (445 mg), hydrazine (235 μΐ) were added, and the mixture was stirred at room temperature for 24 hours. Dioxane methane and 1 equivalent of hydrochloric acid were added to the reaction solution. After extraction with methylene chloride, the combined organic layers were washed with a saturated aqueous solution of NaHC 3 and a saturated aqueous solution of NaCl. After drying over anhydrous Na 2 S 4 , the solvent was evaporated under reduced pressure. The residue was washed with a mixture of ethyl acetate (6 ml) and hexane (6 ml). The hydrazine was concentrated under reduced pressure, and then purified by flash chromatography (dichloromethane:methanol = 1 : 1) using hydrazine as a carrier. The title compound (73 j mg) 〇b-NMR (CDC13) δ: 2·82 (2H, t), 3·39 (2H) was combined with the previously collected solid. ,t),4·01 (3H,s), 7·02-7·09 (2Η,m),7·23 (1Η,s),7·52 (2Η,dd),8·43 (1Η, s), 8·49 (1H, s) 〇MS (ESI) m/z: 423 (M+H), (step b) 3-amino-5-bromo-4-{2-[(4-fluoro Phenyl)aminoindenyl]ethyl}benzoate oxime ester to 溴C to 3-bromo-4-{2-[(4.fluorophenyl)amine fluorenyl]ethyl b-nitrobenzene Methyl formate (720 mg) in a mixture of DMF (5.0 ml) and water (0.5 ml) 129677.doc -204- 200840568 Addition of iron (III) hexahydrate (1350 mg), zinc (114〇11^) ), stirring at room temperature for 22 hours. Ethyl acetate and a saturated aqueous NaHC03 solution were added, and the insoluble material was separated by filtration and ethyl acetate. The combined organic layers were washed with aq. sat. aq. After the methanol was added to the residue for washing, the solid was taken. The filtrate was concentrated under reduced pressure, and then purified by a rapid layer chromatography (dioxane: dec. The title compound (63 8 mg) was obtained from the title compound. h-NMR (DMSO-d6) δ : 2·98 (2H, t), 3.29-3.34 (2H, m), 3·80 (3H, s), 5.70 (2H, br s), 7·11-7 · 17 (2H, m), 7.27 (1H, s), 7.28 (1H, s), 7.60 (2H, dd), 10.01 (ih, s) 0 MS (ESI) m/z: 395 (M+H) +. (Step c) 3-bromo-4-{2-[(4-fluorophenyl)amine fluorenyl]ethyl}·5_[(5-isopropyl-4,5,6,7-tetrahydroindole) Salivation of [5,4-cp-pyridyl-2-yl)carbonylamino]benzoic acid methyl ester hydrochloride to a suspension of the compound of Example 32 (554 mg) in dichloromethane (5 mL) DMF (0.04 ml) and grass chloroform (181 μl) were stirred at room temperature for 15 minutes. Additional grass cockroach (181 μΐ) was added and stirred at room temperature for 45 minutes. The reaction solution was concentrated under reduced pressure and dried with a vacuum pump for 25 hours. The residue was combined with di-methane (20 ml) and added to 3-amino-5-bromo-4_{2_[(4-fluorophenyl)amine-carbamoyl]ethyl}benzoate (440 mg) Chlorodioxane (5 〇 ml). In the float. TEA ((K7〇ml) was added to the mixture, and the mixture was shaken at room temperature for 2 hours. After the reaction solution was concentrated under reduced pressure, the residue was added with dichloromethyl 129677.doc -205 - 200840568. After the extraction with di-methane, the combined organic layers were dried over anhydrous NaaSCU and concentrated under reduced pressure. The residue was purified by flash chromatography using methylene chloride (methane: methanol = 5 〇: The hydrazine was purified to obtain a crude product (5 丨 4 mg). The crude product was washed with methanol, and the solid was collected by filtration. The filtrate was concentrated under reduced pressure, and then purified by flash chromatography (methane methane: methanol) H00: 1 - 5 〇: i) Refining. Combine with the previously collected solids, wash with methanol (2 ml), and filter the insolubles in a mixture of dichloromethane and methanol to vacuum at room temperature. The title compound (422 mg) was obtained after drying 1 h. <-NMR (CDC13) δ: 1.16 (6 Η, d), 2.87-3.06 (7H, m), 3.25 (2H, t), 3.87 (2H, s), 3.89 (3H, s), 6.95-7.01 (2H, m), 7&gt;2? (1H, br s), 7.45 (2H, dd), 8.10 (1H, s), 8.43 (1s), 1 〇.56 (1H, br s) 0 Add 4 equivalents of a solution of dioxane hydrochloride (150 μl) I to the suspension of the free compound (220 mg) of the title compound (220 mg), and then remove the crane under reduced pressure. The solvent was azeotroped with water and dried in vacuo to give the title compound (237 mg). </ RTI> NMR (DMSO-d6) δ: 1·38 (3H d, η ? d)^ !·40 ( 3Η? d), 2.70. 2.85 (2Η,m),3·03-3·21 (3Η,m),3 , c • ·3·50(2Η,πι),3.59- 3·84 (2H,m ), 3·87 (3H, s), 4.47-4 60 genus (1H, m), 4.6" (1H, m), 7.07-7.18 (2H, m), 7.58 heart,

dd), 8.04 (1H 8·11 (1H，s)，10·22 (1H，s)，11.16 (1H Q、i ，Dd), 8.04 (1H 8·11 (1H, s), 10.22 (1H, s), 11.16 (1H Q, i,

s)，11·40·11·53 (1H br)。 ， MS (ESI) m/z: 603 (M+H)+。 129677.doc -206- 200840568 [實施例94] 3-溴-4-{2-[(4-氟苯基）胺甲醯基]乙基}-5-[(5-異 丙基-4,5,6,7-四氫噻唑并[5,4-c]吼啶-2-基）羰基胺基]苯甲 酸鹽酸鹽 向實施例93之化合物（197 mg)的THF(8.0 ml)溶液中添加 LiOH —水合物（18.0 mg)、水（1.0 mi)，於室溫下攪拌2曰。 向反應液中追加LiOH—水合物（8·〇 mg)，於室溫下攪拌4 日。向反應液中添加1當量鹽酸（800 μ 1)，於減壓下濃縮。 向殘渣中添加水，加以清洗後進行濾取，以二氣曱烷清洗 所獲得之白色固體，獲得標題化合物的自由體（176 mg)。 向自由體（176 mg)中添加二崎烧（1 〇 ml)、4當量鹽酸二号 院溶液（100 μΐ) ’照射超聲波。添加水（1 ·〇 ml)而製成溶 液，將不溶物過濾分離。於減壓下濃縮後，以真空泵乾 燥’獲得標題化合物（1 86 mg)。 ]H-NMR (DMSO-d6) δ ： 1.37 (6Η, d)5 2.77 (2H? t)? 2.94-3.86 (ΤΗ, m), 4.36-4.81 (2H, m), 7.08-7.18 (2H, m), 7.52- 7·63 (2H，m)，8.02 (1H，d)，8·07 (1H，d)，1〇·2〇 (1H，s)， 11.12 (1H，s)，11·15-11·63 (1H，br) 〇 MS (ESI) m/z: 589 (M+H)+ 〇 [實施例95] 4-{2-[(4-氣苯基）胺甲醯基]乙基}_3_[(i_異丙基 旅17疋-4-基）魏基胺基]-5 -甲氧基苯甲酸鹽酸鹽 (步驟a)-{2-[(4-氯苯基）胺曱醯基]乙基}_3_[(1_異丙基哌啶- 4-基）魏基胺基]-5 -甲氧基苯甲酸甲酯 向1-異丙基哌啶-4-甲酸鋰鹽（198 mg)的二氯甲烷〇 ml)懸浮液中添加吡啶（426 μ1)。於冰浴冷卻下向混合液中 129677.doc -207- 200840568 添加亞硫醯氯（93 μΐ)，於冰浴冷卻下攪拌3小時。向反應 液中追加亞硫醯氯（30 μ 1)，於冰浴冷卻下授掉丨小時。白 反應液中添加參考例110之化合物（21 7 mg)，於室溫下授摔 1 5小k。以一氣甲烧稀釋後’添加飽和NaHC03水溶液而 成為兩層。以二氯甲烧萃取後，將所合併之有機層以飽和 NaCl水溶液清洗，以無水NadO4乾燥。於減壓下餾去溶劑 後，將殘渣利用以矽膠為載體之快速層析法（二氣甲烧： 甲醇=10: 1—8: 1—6: 1)進行精製，於室溫下以真空泵 乾餘2小時’獲得標題化合物（1 〇 4 m g)。 ^-NMR (CDC13) δ : 1.11 (6Η, d)5 1.88-2.23 (4H? m), 2.27-2.57 (3H? m)5 2.76-2.90 (3H, m)5 2.90-2.98 (2H, m), 2.98- 3.10 (2H，m)，3·64 (3H，s)，3·86 (3H，s)，7·19 (1H，br s) 7·23 (2H，d)，7.40 (2H，d)，8·00 (1H，br s)，8,04 (1H，d) 9·63 (1H，br s) 〇 MS (ESI) m/z: 516 [(M+H)+，35C1], 518 [(M+H)+，37C1]。 (步驟b) 4-{2-[(4-氣苯基）胺甲醯基]乙基卜3_[(1-異丙基旅 咬-4-基）羰基胺基]-5 -甲氧基苯曱酸鹽酸鹽 向4-{2-[(4 -鼠本基曱酿基]乙基異丙基。辰。定_4_ 基）羰基胺基]-5-甲氧基苯曱酸甲酯（1〇1 mg)的THF(4.0 ml) 溶液中添加LiOH—水合物（10 mg)、水（0.50 ml)，於室溫 下攪拌3日。向反應液中添加1當量鹽酸（260 μΐ)後，於減 壓下濃縮。將殘渣以製備用TLC(2 mm)進行精製，獲得標 題化合物的自由體（107 mg)。向自由體（1〇7 mg)中添加二 噚烷（4·0 ml)、4當量鹽酸乙酸乙酯溶液（75 μ1)、水（4 〇 129677.doc -208- 200840568 ml) °將溶劑於減壓下濃縮後，以水於減壓下共沸1次。以 真二泵乾燥’獲得標題化合物（1 mg)。 ^-NMR (DMSO-d6) δ : 1,28 (6Η, d)? 1.92-2.28 (4H5 m)? 2.60 (2H，t)，2·71-2·85 (1H，m)，2·89 (2H，t)，291-3.06 (2H， m)，3.14-3.37 (1H，m)，3·37-3·51 (2H，m)，3.87 (3H，s)， 7.33 (1H5 s)? 7.35 (2H, d)? 7.63 (2H5 d)? 7.66 (1H? s)? 9.57- 9.98 (1H，br)，9·85 (1H，s)，10.31 (1H，s)，12·84-13·10 (1H， br)。 MS (ESI) m/z: 502(M+H)、 [實施例96] 3-氯-4-{2胃[(4-氟苯基）胺甲醯基]乙基}_5-[(5_異 丙基-4,5,6,7-四氫噻唑并[5,4-c]吡啶-2-基）羰基胺基]苯甲 酸乙酯 (步驟a) 3-氣-4-甲基-5-硝基苯甲酸 向3-氣-4-甲基-5-石肖基苯甲酸甲醋（3·281 g)的ΤΉΡ(60·0 ml)溶液中添加水（15·〇 ml)、u〇H一水合物（652 mg)，於 室溫下攪拌3日。向反應液中添加丨當量鹽酸（21〇 ml)，使 液性成為酸性後，添加乙酸乙酯。以乙酸乙酯及以二氯甲 烷萃取，以飽和NaCl清洗後，以無水Na2S04乾燥。於減壓 下餾去溶劑，以真空泵乾燥，獲得標題化合物（2 97 g)。 ^-NMR (CDC13) δ : 2.63 (3Η, s)? 8.32 (1H, s)? 8.41 (1H5 s) 0 MS (ESI) m/z: 214 [(M_H)·，35C1]，216 [(m_h)' ”C1]。 (步驟b) 3 -氯-4-甲基-5-石肖基苯甲酸乙酉旨 向3-氯_4_甲基-5-硝基苯甲酸（3·14 g)的乙醇（4〇 溶液中 129677.doc •209- 200840568 &quot;j、、加/辰H(l.〇 ml)，加熱回流6小時。添加NaHC〇3粉末 加X中和將，谷劑於減壓下濃縮。向殘渣中添加乙酸乙 酉曰、水。U乙酸乙酿萃取後，將所合併之有機層以飽和 、、、夜π洗，以無水^“8〇4乾燥。將殘渣利用以石夕膠 為載體之快速層析法（己烧：乙酸乙_=1G : 1)進行精製， 於至’孤下以真空泵乾燥3小時，獲得標題化合物7 mg)。 lH&quot;NMR (CDC13) δ ： 1.42 (3H? t)5 2.60 (3Η5 s)? 4.42 (2Η? 馨 q)，8·25 (出，s)，8·33 (1Η，s)。 (步驟c) 4_溴甲基_3_氯_5_硝基苯甲酸乙酯 向3_氯-4_曱基硝基苯甲酸乙酯（3·287 g)的四氯化碳 (60 ml)溶液中添加nbs(72 16 mg)、過氧化苯甲醯（58 mg) ’加熱回流2日。冷卻後，將不溶物過濾分離，以己 烷-乙酸乙酯混合液清洗後，將洗液、濾液合併，於減壓 下濃縮。將殘渣利用以矽膠管柱為載體之快速層析法（己 肇 烧··乙酸乙醋=10 ·· 1)進行精製，於室溫下以真空泵乾燥2 小時’獲得標題化合物（3817 mg)。 'H-NMR (CDC13) δ : 1·43 (3H，t)，4·44 (2H，q)，4·88 (2H， s)，8·32 (1H，d)，8·46 (1H，d)。 (步驟d) 2-[2-氯-4-(乙氧基羰基）-6-硝基苄基]丙二酸二第三 丁酯 於冰浴冷卻下，向丙二酸二第三丁酯（3,〇〇 g)的丁 HF(50 ml)溶液中添加氫化鈉（約63%)(5〇2 mg)，於0°C下攪拌1〇分 鐘，於室溫下攪拌30分鐘。向反應液中滴下4-溴甲基_3_ 129677.doc -210- 200840568 氣·5·硝基苯甲酸乙酯（187〇 mi)溶液，於室 溫下攪拌5小時。以乙酸乙酯稀釋反應液，添加飽和NaC1 水溶液。以乙酸乙酯萃取後，以飽*NaCbX溶液清洗所合 併之有機層。以無水NajCU乾燥後，於減壓下餾去溶劑。 將殘渣利用以石夕膠為載體之快速層析法（己烧：乙酸乙酯 =20 : 1)進行精製，於室溫下以真空泵乾燥4小時，獲得標 題化合物（3.74 g)。 1h_NMR (CDC13) δ : 1·4(Μ·44 (21H，m)，3.59 (1H，t)， • 3·68 (2H，d)，4·42 (2H，q)，8·25 (1H，d)，8.37 (1H，d)。 MS (ESI) m/z: 346。 (步驟e) 4-(2-魏基乙基）-3-氯-5-硝基苯曱酸乙酯 向2-[2 -氣- 4- (乙氧基_厌基）-6-硝基节基]丙二酸二第三丁 酯（3.69 g)的二吟烷（15.0 ml)溶液中添加4當量鹽酸二α号烧 溶液（15.0 ml)，於室溫下攪拌23小時。將反應液於減壓下 濃縮後，向殘渣中添加二氯甲烷（6.0 ml)、TFA(8.0 ml)， 於室溫下攪拌2小時。將反應液於減壓下濃縮後，以二氯 ⑩ 曱烷使其共沸一次。將殘渣製成乙腈（50 ml)溶液，添加氧 化銅（1)(125 mg)，加熱回流30分鐘。向反應液中添加氧化 銅（1)(84 mg)，加熱回流2·5小時。冷卻後，將反應液於減 壓下濃縮。將殘渣利用以石夕膠為載體之快速層析法（二氣 甲烷：甲醇漏100 : 1)進行精製。向粗精製物中添加己烷_ 乙酸乙酯混合液，加以清洗後進行濾取。以真空泵乾燥3〇 分鐘，獲得標題化合物（2469 mg)。 ]H-NMR (CDC13) δ : 1.42 (3H? t), 2.83 (2H, t), 3.28 (2H? t)5 129677.doc -211 - 200840568 4·43 (2H，q)，8.27 (1H，d)，8·36 (1H，d)。 MS (ESI) m/z: 300 [(M_H)+] 〇 (步驟f) 3 -氯- 4-{2-[(4-氟苯基）胺甲醯基]乙基}_5_琐基苯曱 酸乙酯 向4-(2-羧基乙基）-3-氣-5-硝基苯甲酸乙酯（677 mg)的二 氯甲烷（10.0 ml)溶液中添加4_氟苯胺（258 μΐ)、HOBt(342 mg)、EDC(5 16 mg)、ΤΕΑ(3 73 μΐ)，於室溫下攪拌 4 日。向 反應液中添加二氣曱烧、1當量鹽酸。以二氣曱烧萃取 後，以飽和NaHC〇3水溶液、飽和NaCl水溶液清洗所合併 之有機層。以無水NaJO4乾燥後，於減壓下餾去溶劑。添 加己烷-乙酸乙酯混合液，藉由照射超聲波而清洗殘渣。 濾取固體，以己烷-乙酸乙酯混合液清洗後，以真空泵於 室溫下乾炼4小時’獲得標題化合物（68〇 mg)。 ]H-NMR (CDCls) δ : 1.42 (3H5 t)? 2.78 (2H, t)5 3.36 (2H9 t)5 4·43 (2H，q)，7.03 (2H，t)，7.20 (1H，s)，7·48 (2H，dd)，8.28 (1H，s)，8.37 (1H，s)。 MS (ESI) m/z: 395 (M+H)+，417 (M+Na)+。 (步驟g) 3-胺基-5-氣-4-{2-[(4-氟苯基）胺甲醯基]乙基丨苯甲 酸乙酯 向3 -氯-4-{2-[(4-氟苯基)胺曱醯基]乙基卜5-硝基苯甲酸 乙酯（657 mg)的DMF(14,0 ml)溶液中添加水（2.0 ml)、氯化 鐵（III)六水合物（MOO mg)、鋅（ll4〇 mg)，於室溫下搜掉 24小時。向反應液中添加乙酸乙酯、飽和NaHC〇3水溶 液，將不溶物過濾分離。以乙酸乙酯萃取，將所合併之有 129677.doc -212- 200840568 機層以飽和NaCl水溶液、水清洗後，以無水!^4〇4乾燥， 於減壓下餾去溶劑。添加己烷-乙酸乙酯混合液，且藉由 起4波知、射而清洗殘渣。濾取固體，於乙酸乙酯中將不溶 物過濾分離。將乙酸乙酯溶液於減壓下濃縮，以真空泵於 室溫下乾燥1小時，獲得標題化合物（543 mg)。 H-NMR (CDC13) δ ·· 1.36 (3H，t)，2·75 (2H，t)，3.13 (2H，t)， 4·33 (2H，q)，4·52 (2H，s)，6.96-7.02 (2H，m)，7·21 (1H，s)， 7·25 (1H，br· s)，7·39 (2H，dd)，7.42 (1H，s)。 MS (ESI) m/z: 365 [(M+H).，35C1]，367 [(m+h)+，37ci]。 (步驟h) 3-氣-4-{2-[(4-氟苯基）胺曱醯基]乙基卜5_[(5_異丙 基_4,5,6,7-四氫噻唑并[5,4-c]吡啶基）羰基胺基]苯曱酸 乙酯 向苓考例32之化合物（291 mg)的二氯曱烷（5 〇 ml)懸浮液 中添加dmf(0.04 ml)、草醯氯（95 μι)，於室溫下攪拌15分 釦。追加草醯氯（95 μΐ)，於室溫下攪拌15分鐘。進而追加 草醯氯（30 μΐ)，於室溫下攪拌3〇分鐘。將反應液於減壓下 濃縮後，以真空泵於室溫下乾燥2小時。向殘渣中添加弘 胺基-5-氯-4-{2-[(4-氟苯基）胺甲醯基]乙基丨苯曱酸乙酯 (270 mg)的二氣甲烷（25 ml)溶液、tea(280 μ1)，於室溫下 攪拌16小時。以二氯甲烷稀釋反應液後，添加飽和 NaHC〇3水溶液。以二氯甲烷萃取後，以飽和Naci水溶液 清洗所合併之有機層。以無水^^七8〇4乾燥後，於減壓下餾 去溶劑。將殘渣利用以矽膠為載體之快速層析法（二氯曱 烷：甲醇=100: 1—50 : 1)進行精製，獲得標題化合物的 129677.doc -213- 200840568 自由體（421 mg)。 Ή-NMR (CDC13) δ : 1.16 (6H, d),1.34 (3Η, t), 2.82-3.06 (7H，m)，3·17 (2H，t)，3·86 (2H，s)，4·33 (2H，q)，6 88&lt; % (2H5 m), 7.43 (2H? dd)? 7.85 (1H, s)? 7.95 (1H? s)5 8.3 5 (iH s)，10.68 (1H，s)。 ’ MS (ESI) m/z: 573 (M+H)+ 〇 以乙醇清洗標題化合物的自由體（421 mg)後，進行濾 取。將所獲得之固體懸浮於乙醇（15叫中，添加4當量/鹽 酸乙酸乙醋溶液（650 μ1)。於減壓下濃縮後，以乙醇、2 各共沸一次，以真空泵於室溫下乾燥7小時，獲得作為白 色固體之標題化合物（379 mg)。 H-NMR (DMSO-d6) δ : 1.32 (3H，t)，1.37 (3H，d)，ι·38 (3Η，d)，2·77 (2Η，t)，3·03-3·22 (3Η，m)，3.26-3.52 (2Η，m)， 3.66-3.85 (2H，m)，4.33(2H，q)，4.51-4.61(lH，m)，4.70-4·80 (1H，m)，7.10-7.16 (2H，m)，7·56 (2H，dd)，7·88 (1H， s)，8.07 (1H，s)，10.15 (1H，s)，10,82-10,95 (1H，br)，11.12 (1H，s) 〇 MS (ESI) m/z: 573 [(M+H)+，35C1]，575 [(M+H)V7C1]。 [實施例97] 4-[2-(4-氯苯基胺甲醯基）乙基]-3-甲氧基_5_ {[4-(3-氧基嗎啉-4-基）環己基]羰基胺基}苯甲酸 (步驟a) 3-{[反- 4- (第三丁氧基羰基胺基）環己烧-1-基]戴基 胺基}-4-{2-[(4_氣苯基）胺曱醯基]乙基}-5-甲氧基苯甲酸甲s), 11·40·11·53 (1H br). , MS (ESI) m/z: 603 (M+H)+. 129677.doc -206- 200840568 [Example 94] 3-Bromo-4-{2-[(4-fluorophenyl)amine-carbamoyl]ethyl}-5-[(5-isopropyl-4, 5,6,7-Tetrathiathiazolo[5,4-c]acridin-2-yl)carbonylamino]benzoic acid hydrochloride to the compound of Example 93 (197 mg) THF (8.0 ml) LiOH-hydrate (18.0 mg) and water (1.0 mi) were added to the solution, and the mixture was stirred at room temperature for 2 Torr. LiOH-hydrate (8·〇 mg) was added to the reaction liquid, and the mixture was stirred at room temperature for 4 days. 1N hydrochloric acid (800 μl) was added to the reaction liquid, and the mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was washed and filtered, and the obtained white solid was washed with dioxane to afford the title compound (176 mg). Ultrasonic (1 〇 ml) and 4 equivalents of hydrochloric acid No. 2 (100 μΐ) were irradiated to the free body (176 mg). Water (1 · 〇 ml) was added to prepare a solution, and the insoluble matter was separated by filtration. After concentration under reduced pressure, the title compound (1, 86 mg) was obtained. ]H-NMR (DMSO-d6) δ : 1.37 (6Η, d)5 2.77 (2H? t)? 2.94-3.86 (ΤΗ, m), 4.36-4.81 (2H, m), 7.08-7.18 (2H, m ), 7.52- 7·63 (2H,m), 8.02 (1H,d),8·07 (1H,d),1〇·2〇(1H,s), 11.12 (1H,s),11·15 -11·63 (1H, br) 〇MS (ESI) m/z: 589 (M+H)+ 〇 [Example 95] 4-{2-[(4-Phenylphenyl)aminemethanyl]B Base}_3_[(i_isopropylidene 17疋-4-yl)-Wittylamino]-5-methoxybenzoic acid hydrochloride (step a)-{2-[(4-chlorophenyl) Aminomethyl]ethyl}_3_[(1-isopropylpiperidin-4-yl)weirylamino]-5-methoxybenzoic acid methyl ester to 1-isopropylpiperidine-4- Pyridine (426 μl) was added to a suspension of lithium formate (198 mg) in dichloromethane (ml). To the mixture was cooled in an ice bath 129677.doc - 207 - 200840568. Thionite chloride (93 μM) was added and stirred for 3 hours under ice cooling. Thionite chloride (30 μl) was added to the reaction solution, and the mixture was allowed to cool for an hour while cooling in an ice bath. The compound of Reference Example 110 (21 7 mg) was added to the white reaction mixture, and was dropped at room temperature for 15 min. After diluting with a gas-fired product, a saturated NaHC03 aqueous solution was added to form two layers. After extraction with methylene chloride, the combined organic layers were washed with saturated aqueous NaCI and dried over anhydrous Nad. After distilling off the solvent under reduced pressure, the residue was purified by flash chromatography using silica gel as a carrier (two gas: methanol = 10:1-8:1 - 6:1), and a vacuum pump at room temperature. The title compound (1 〇 4 mg) was obtained after 2 hours of dryness. ^-NMR (CDC13) δ : 1.11 (6Η, d)5 1.88-2.23 (4H? m), 2.27-2.57 (3H? m)5 2.76-2.90 (3H, m)5 2.90-2.98 (2H, m) , 2.98- 3.10 (2H,m),3·64 (3H,s),3·86 (3H,s),7·19 (1H,br s) 7·23 (2H,d), 7.40 (2H, d),8·00 (1H,br s),8,04 (1H,d) 9·63 (1H,br s) 〇MS (ESI) m/z: 516 [(M+H)+,35C1] , 518 [(M+H)+, 37C1]. (Step b) 4-{2-[(4-Phenylphenyl)amine-carbamoyl]ethyl b- 3-[(1-isopropyl-bran-4-yl)carbonylamino]-5-methoxy Benzoate hydrochloride to 4-{2-[(4-murine-based aryl) ethyl isopropyl. 。. _4_ yl)carbonylamino]-5-methoxybenzoic acid LiOH-hydrate (10 mg) and water (0.50 ml) were added to a solution of the ester (1 ml) in THF (4.0 ml), and stirred at room temperature for 3 days. After adding 1 equivalent of hydrochloric acid (260 μM) to the reaction mixture, the mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (2 mm) to afford the title compound (107 mg). Add free dioxane (4·0 ml), 4 equivalents of ethyl acetate (75 μl), water (4 〇 129677.doc -208- 200840568 ml) to the free body (1〇7 mg). After concentration under reduced pressure, the mixture was azeotroped with water under reduced pressure. The title compound (1 mg) was obtained by drying in a true second pump. ^-NMR (DMSO-d6) δ : 1,28 (6Η, d)? 1.92-2.28 (4H5 m)? 2.60 (2H,t),2·71-2·85 (1H,m),2·89 (2H,t),291-3.06 (2H,m),3.14-3.37 (1H,m),3·37-3·51 (2H,m),3.87 (3H,s), 7.33 (1H5 s)? 7.35 (2H, d)? 7.63 (2H5 d)? 7.66 (1H? s)? 9.57- 9.98 (1H, br), 9·85 (1H, s), 10.31 (1H, s), 12·84-13 · 10 (1H, br). MS (ESI) m/z: 502 (M+H), [EXAMPLE 96] 3-chloro-4-{2 stomach [(4-fluorophenyl)aminemethanyl]ethyl}_5-[(5 -Isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonylamino]benzoic acid ethyl ester (step a) 3-ox-4-methyl -5-Nitrobenzoic acid To a solution of hydrazine (60·0 ml) of 3-gas-4-methyl-5-shidocylbenzoic acid methyl vinegar (3·281 g), water (15·ml), u 〇H monohydrate (652 mg) was stirred at room temperature for 3 days. Ethyl acetate (21 〇 ml) was added to the reaction mixture to make the liquid acidic, and then ethyl acetate was added. After extraction with ethyl acetate and methylene chloride, washed with saturated NaCI and dried over anhydrous Na? The solvent was evaporated under reduced pressure. ^-NMR (CDC13) δ : 2.63 (3Η, s)? 8.32 (1H, s)? 8.41 (1H5 s) 0 MS (ESI) m/z: 214 [(M_H)·,35C1],216 [(m_h ) ' ” C1]. (Step b) 3-Chloro-4-methyl-5-stone succinyl benzoate for the 3-chloro-4-methyl-5-nitrobenzoic acid (3·14 g) of ethanol (4〇 solution 129677.doc •209- 200840568 &quot;j, plus / Chen H (l. 〇ml), heated reflux for 6 hours. Add NaHC〇3 powder plus X neutralization, the trough is under reduced pressure Concentration. Add ethyl acetate and water to the residue. After extraction with U-acetic acid, the combined organic layer is washed with saturated, night, π, dried with anhydrous ^8〇4. The residue is used as Shiqijiao. Purification by flash chromatography (hexane: acetic acid _ = 1 G: 1) was carried out, and dried under vacuum for 3 hours to give the title compound 7 mg. lH&quot;NMR (CDC13) δ : 1.42 (3H? t)5 2.60 (3Η5 s)? 4.42 (2Η? Xin q), 8·25 (out, s), 8.33 (1Η, s). (Step c) 4_Bromomethyl_3_chloro-5_nitrobenzoate to ethyl 3-chloro-4-indolyl nitrobenzoate (3·287 g) of carbon tetrachloride (60 Mb) Add nbs (72 16 mg) and benzamidine peroxide (58 mg) to the solution and heat to reflux for 2 days. After cooling, the insoluble material was separated by filtration and washed with a mixture of hexane and ethyl acetate. The mixture and filtrate were combined and concentrated under reduced pressure. The residue was purified by a flash chromatography (m.p., ethyl acetate, ethyl acetate = 10··1), which was purified by a vacuum pump at room temperature for 2 hours to give the title compound (3817 mg). 'H-NMR (CDC13) δ : 1·43 (3H, t), 4·44 (2H, q), 4·88 (2H, s), 8·32 (1H, d), 8.46 (1H , d). (Step d) 2-[2-Chloro-4-(ethoxycarbonyl)-6-nitrobenzyl]malonic acid di-t-butyl ester under ice-cooling to di-tert-butyl malonate Sodium hydride (about 63%) (5 〇 2 mg) was added to a solution of (3, 〇〇g) in butyl HF (50 ml), stirred at 0 ° C for 1 hr and stirred at room temperature for 30 min. A solution of 4-bromomethyl_3_129677.doc-210-200840568 gas·5·nitrobenzoate (187〇 mi) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 5 hours. The reaction solution was diluted with ethyl acetate and a saturated aqueous NaCI solution was added. After extracting with ethyl acetate, the combined organic layers were washed with a saturated solution of NaCbX. After drying with anhydrous NajCU, the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (hexanes: ethyl acetate = 20:1) eluted with EtOAc (yield: ethyl acetate = 20:1) and dried in vacuo for 4 hours at room temperature to afford title compound (3.74 g). 1h_NMR (CDC13) δ : 1·4 (Μ·44 (21H, m), 3.59 (1H, t), • 3.68 (2H, d), 4·42 (2H, q), 8·25 (1H , d), 8.37 (1H, d) MS (ESI) m/z: 346. (Step e) 4-(2-Wilylethyl)-3-chloro-5-nitrobenzoic acid ethyl ester 2- [2-Gas-4-(Ethoxy- ary)-6-nitro]ylmalonate dibutyl acrylate (3.69 g) in dioxane (15.0 ml) was added with 4 equivalents of hydrochloric acid The α-calcined solution (15.0 ml) was stirred at room temperature for 23 hours. After the reaction mixture was concentrated under reduced pressure, dichloromethane (6.0 ml), TFA (8.0 ml) After 2 hours, the reaction solution was concentrated under reduced pressure, and then azeotroped with dichloro 10 decane. The residue was made into acetonitrile (50 ml) solution, copper oxide (1) (125 mg) was added and heated to reflux 30 Copper oxide (1) (84 mg) was added to the reaction solution, and the mixture was heated under reflux for 2.5 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography using (di-gas methane: methanol leakage 100: 1) is purified. Add hexane-ethyl acetate mixture to the crude product and wash it. Filtration was carried out, and dried by a vacuum pump for 3 minutes to give the title compound (2469 mg).]H-NMR (CDC13) δ: 1.42 (3H? t), 2.83 (2H, t), 3.28 (2H? t)5 129677 .doc -211 - 200840568 4·43 (2H,q), 8.27 (1H,d),8·36 (1H,d) MS (ESI) m/z: 300 [(M_H)+] 〇(step f 3 -Chloro 4-{2-[(4-fluorophenyl)amine-carbamoyl]ethyl}_5_triethyl benzoate to 4-(2-carboxyethyl)-3- gas- Add 4-fluoroaniline (258 μΐ), HOBt (342 mg), EDC (5 16 mg), ΤΕΑ (3 73 μΐ) to a solution of ethyl 5-nitrobenzoate (677 mg) in dichloromethane (10.0 ml). The mixture was stirred at room temperature for 4 days, and a mixture of two gas and 1 liter of hydrochloric acid was added to the reaction mixture, and the mixture was extracted with a gas mixture, and the combined organic layer was washed with a saturated aqueous solution of NaHC 3 and saturated aqueous NaCl. After drying anhydrous NaJO4, the solvent was evaporated under reduced pressure, and a mixture of hexane-ethyl acetate was added, and the residue was washed by irradiation with an ultrasonic wave. The solid was collected by filtration, washed with a hexane-ethyl acetate mixture, and then vacuum pumped. Drying for 4 hours at room temperature gave the title compound (68 mg). ]H-NMR (CDCls) δ : 1.42 (3H5 t)? 2.78 (2H, t)5 3.36 (2H9 t)5 4·43 (2H,q),7.03 (2H,t), 7.20 (1H,s) , 7.48 (2H, dd), 8.28 (1H, s), 8.37 (1H, s). MS (ESI) m/z: 395 (M+H)+, 417 (M+Na)+. (Step g) 3-Amino-5-gas-4-{2-[(4-fluorophenyl)amine-carbamoyl]ethyl phthalic acid ethyl ester to 3-chloro-4-{2-[( 4-Fluorophenyl)amine fluorenyl]ethyl bromide ethyl 5-hydroxybenzoate (657 mg) in DMF (14,0 ml) was added water (2.0 ml), ferric chloride (III) Hydrate (MOO mg), zinc (ll4 〇 mg), and searched for 24 hours at room temperature. Ethyl acetate and a saturated NaHC〇3 aqueous solution were added to the reaction mixture, and the insoluble material was separated by filtration. After extracting with ethyl acetate, the combined organic layer of 129677.doc-212-200840568 was washed with a saturated aqueous solution of NaCl and water, and dried over anhydrous EtOAc. A hexane-ethyl acetate mixture was added, and the residue was washed by 4 waves of radiation. The solid was collected by filtration, and the insoluble material was separated by filtration from ethyl acetate. The ethyl acetate solution was concentrated under reduced pressure. H-NMR (CDC13) δ ·· 1.36 (3H,t),2·75 (2H,t),3.13 (2H,t), 4·33 (2H,q),4·52 (2H,s), 6.96-7.02 (2H, m), 7·21 (1H, s), 7·25 (1H, br·s), 7·39 (2H, dd), 7.42 (1H, s). MS (ESI) m/z: 366 [(M+H)., 35C1], 367 [(m+h)+, 37 ci]. (Step h) 3-Ga-4-{2-[(4-Fluorophenyl)amine fluorenyl]ethyl b 5_[(5-isopropyl-4,5,6,7-tetrahydrothiazole [5,4-c]pyridyl)carbonylamino]benzoic acid ethyl ester To a suspension of the compound of Example 32 (291 mg) in dichloromethane (5 〇ml) was added dmf (0.04 ml), The grass was chlorinated (95 μm) and stirred at room temperature for 15 minutes. Additional grass chloroform (95 μM) was added and stirred at room temperature for 15 minutes. Further, grass chloroform (30 μM) was added, and the mixture was stirred at room temperature for 3 minutes. The reaction solution was concentrated under reduced pressure and dried at room temperature for 2 hr. To the residue was added dihydromethane (25 ml) of urethane-5-chloro-4-{2-[(4-fluorophenyl)amine-carbamoyl]ethyl phthalic acid ethyl ester (270 mg). The solution, tea (280 μl), was stirred at room temperature for 16 hours. After diluting the reaction mixture with dichloromethane, a saturated aqueous solution of NaHC 3 was added. After extraction with dichloromethane, the combined organic layers were washed with a saturated aqueous NaCI. After drying over anhydrous MgSO4, the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (methylene chloride:methanol:methanol: 100:1 - 50:1) to afford the title compound 129677.doc - 213 - 200840568 free (421 mg). Ή-NMR (CDC13) δ : 1.16 (6H, d), 1.34 (3Η, t), 2.82-3.06 (7H, m), 3·17 (2H, t), 3·86 (2H, s), 4 ·33 (2H,q),6 88&lt; % (2H5 m), 7.43 (2H? dd)? 7.85 (1H, s)? 7.95 (1H? s)5 8.3 5 (iH s), 10.68 (1H, s ). ' MS (ESI) m/z: 573 (M+H) + ??? The title compound (421 mg) was washed with ethanol and filtered. The obtained solid was suspended in ethanol (15 liters, 4 equivalents / hydrochloric acid ethyl acetate solution (650 μl) was added. After concentration under reduced pressure, the mixture was azeotroped with ethanol and 2, and dried by vacuum pump at room temperature. The title compound (379 mg) was obtained as a white solid. H-NMR (DMSO-d6) δ: 1.32 (3H,t), 1.37 (3H,d), ι·38 (3Η,d),2· 77 (2Η,t),3·03-3·22 (3Η,m), 3.26-3.52 (2Η,m), 3.66-3.85 (2H,m),4.33(2H,q),4.51-4.61(lH , m), 4.70-4·80 (1H, m), 7.10-7.16 (2H, m), 7.56 (2H, dd), 7.88 (1H, s), 8.07 (1H, s), 10.15 (1H, s), 10, 82-10, 95 (1H, br), 11.12 (1H, s) 〇MS (ESI) m/z: 573 [(M+H)+,35C1],575 [(M +H)V7C1]. [Example 97] 4-[2-(4-Chlorophenylaminocarbamimidyl)ethyl]-3-methoxy_5_ {[4-(3-oxymorpholine- 4-yl)cyclohexyl]carbonylamino}benzoic acid (step a) 3-{[trans-4-((t-butoxycarbonylamino)cyclohexan-1-yl)-ylamino}-4 -{2-[(4_Phenylphenyl)aminoindolyl]ethyl}-5-methoxybenzoic acid

II 向反-4-[(第三丁氧基羰基）胺基]環己烷曱酸（198 mg)的 129677.doc -214- 200840568 二氯甲炫（5·〇 ml)溶液中添加吡啶（285 μι)、亞硫醯氯（65 μ 1)，於室溫下攪拌3小時。向反應液中添加參考例丨丨〇之化 合物（13 9 mg)，於室溫下攪拌丨4小時。以二氯甲烷稀釋 後，添加〇·5當量鹽酸而成為兩層。以二氯曱烧萃取後， 將所合併之有機層以飽和NaHC〇3水溶液清洗，以無水 NadCU乾餘。於減壓下顧去溶劑後，將殘渣利用以石夕膠為 載體之快速層析法（二氯甲完：甲醇=10(): 1)進行精製， 獲得標題化合物（1 09 mg)。 !H-NMR (DMSO-d6) δ : 1.11-1.32 (2H? m), 1.38 (9H, s)? 1.40-1.55 (2H，m)，1.75-1.97 (4H，m)，2·27·2·39 (1H，m)， 2·58 (2H，t)，2.89 (2H，t)，3.12-3.30 (1H，m)，3·84 (3H，s)， 3·87 (3H，s)，6.75 (1H，d)，7.30 (1H，s)，7·35 (2H, d)，7.59 (2H，d)，7·74 (1H，s)，9.56 (1H，s)，1〇·〇9 (1H，s)。 MS (ESI) m/z: 588 (M+H)+。 (步驟b) 3-( {反-4-[2-(2-氣乙氧基）乙醯基胺基]環己基）羰基 胺基：)_4-[2-(4-氯苯基胺甲醯基）乙基]_5_甲氧基苯甲酸甲酉旨 向3-{[反-4-(第三丁氧基羰基胺基）環己烷-丨·基]羰基胺 基}-4-{2-[(4-氯苯基）胺甲醯基]乙基卜5_甲氧基苯甲酸甲酯 (106 mg)的二氯甲烷（5.0 ml)溶液中添加tfa(2.5 ml)，於 室溫下攪拌5小時。將反應液於減壓下濃縮後，向殘渣中 添加二氣甲烧、飽和NaHC〇3水溶液。以二氯甲烧萃取 後，以飽和NaCl水溶液清洗所合併之有機層。以無水 NaJO4乾燥後，於減壓下餾去溶劑，以真空泵乾燥，獲得 3-[(反-4-胺基環己烷-1-基）羰基胺基]_4-{2-[(4-氯苯基）胺 129677.doc -215- 200840568 曱醯基]乙基}-5-甲氧基苯曱酸甲酯。 向（2-氣乙氧基）乙酸（67 mg)的二氣甲烷（3.0 ml)溶液中 添加DMF(0.02 ml)、草醯氣（市售）（40 μΐ)，於室溫下攪拌 15分鐘。向反應液中追加草醯氯（市售）(20 μΐ)後，於減壓 下濃縮。以真空泵乾燥後，向所獲得之殘渣中添加二氯甲 烷（8.0 ml)、3-[(反-4-胺基環己烷-1-基）羰基胺基]_4_{2_ [(4-氯苯基）胺曱酿基]乙基}-5 -甲氧基苯曱酸曱酿的二氯甲 燒（10 ml)懸浮液、TEA(市售）(300 μΐ)，於室溫下攪拌4小 時。以二氣甲烷稀釋後，添加〇·5當量鹽酸。以二氯曱烧 萃取後，以飽和NaHC〇3水溶液、飽和NaCl水溶液清洗所 合併之有機層。以無水NajCU乾燥後，於減壓下餾去溶 劑，以真空泵乾燥，獲得標題化合物（73 mg)。 !H-NMR (CDC13) δ ： 1.30-1.42 (2Η, m), 1.75-1.88 (2H? m), 2.10-2.22 (4H，m)，2.38-2,48 (1H，m)，2.77-2.86 (2H，m)， 2.91-3.00(2H，m)，3.69-3.73(5H，m)，3.81(2H，t)，3.84-3·94 (1H，m)，3·87 (3H，s)，4·01 (2H，s)，6.64 (1H，d)，7.23 (1H，s)，7·25 (2H，d)，7.38 (2H，d)，7.68 (1H，s)，8.09 (1H, s)，9·62 (1H，s) 〇 MS (ESI) m/z: 608 (M+H)+。 (步驟c) 4-[2-(4-氯苯基胺甲醯基）乙基]-3_甲氧基_5_{[反_4_ (3-氧基嗎啉-4-基）環己基]羰基胺基}苯甲酸 向3-({反-4-[2-(2-氯乙氧基）乙醯基胺基]環己基）羰基胺 基）-4_[2-(4-氯苯基胺甲醯基）乙基]_5_甲氧基苯曱酸甲酯 (70 mg)的 ΤΗΤ(5·0 ml)溶液中添加 tBu〇K(33 mg)，於室溫 129677.doc -216- 200840568 下攪拌2小時。向反應液中添加DMF(〇.5 ml)、tBu〇K(16 mg)，於室溫下攪拌6小時。添加DMF(2.5 ml)，攪拌6曰。 追加BuOK(45 mg)，於室溫下攪拌24小時後，進而追加 tBuOKGS mg)，於室溫下攪拌4日。以二氣甲烷稀釋反應 液後，添加0.1當量鹽酸水溶液。以二氣曱烷萃取，以飽 和NaCl水溶液清洗所合併之二氯甲烷層。以無水1^七8〇4乾 综後’將溶劑於減壓下濃縮。將殘渣利用以矽膠為載體之 快速層析法（一氣甲烧：曱醇=5〇: J)進行Adding pyridine to a solution of 129677.doc -214-200840568 dichloromethane (5·〇ml) of trans-4-[(t-butoxycarbonyl)amino]cyclohexane decanoic acid (198 mg) 285 μM), sulfoxide (65 μl), stirred at room temperature for 3 hours. The compound of the reference example (13 9 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 4 hours. After diluting with dichloromethane, 〇·5 equivalent of hydrochloric acid was added to form two layers. After extraction with dichlorohydrazine, the combined organic layers were washed with a saturated aqueous solution of NaHC.sub.3 and dried over anhydrous Nad. After the solvent was removed under reduced pressure, the residue was purified by flash chromatography eluting elut elut elut elut elut elut !H-NMR (DMSO-d6) δ : 1.11-1.32 (2H? m), 1.38 (9H, s)? 1.40-1.55 (2H, m), 1.75-1.97 (4H, m), 2·27·2 ·39 (1H,m), 2·58 (2H,t),2.89 (2H,t),3.12-3.30 (1H,m),3·84 (3H,s), 3·87 (3H,s) , 6.75 (1H, d), 7.30 (1H, s), 7.35 (2H, d), 7.59 (2H, d), 7.74 (1H, s), 9.56 (1H, s), 1〇· 〇9 (1H, s). MS (ESI) m/z: 592 (M+H)+. (Step b) 3-( {trans-4-[2-(2-Gasethoxy)ethylamino)cyclohexyl)carbonylamino:) 4-[2-(4-chlorophenylamine A Indole)ethyl]_5-methoxybenzoic acid formazan to 3-{[trans-4-(t-butoxycarbonylamino)cyclohexane-fluorenyl]carbonylamino}-4- Add tfa (2.5 ml) to a solution of methyl 2-((4-chlorophenyl)amine-carbamoyl)ethyl bromide (106 mg) in dichloromethane (5.0 ml) Stir at room temperature for 5 hours. After the reaction mixture was concentrated under reduced pressure, a methylene chloride and saturated aqueous NaHC? After extraction with methylene chloride, the combined organic layers were washed with a saturated aqueous solution of NaCl. After drying over anhydrous NaJO4, the solvent was evaporated under reduced pressure and dried in vacuo to give 3-[(4- 4-aminocyclohexane-1-yl)carbonylamino]- 4-{2-[(4- Chlorophenyl)amine 129677.doc -215- 200840568 Methyl]ethyl}-5-methoxybenzoic acid methyl ester. To a solution of (2-glyoxy)acetic acid (67 mg) in di-methane (3.0 ml), DMF (0.02 ml), sorghum (commercial) (40 μM) was stirred at room temperature for 15 min. . After adding grassy chlorine (commercially available) (20 μM) to the reaction mixture, the mixture was concentrated under reduced pressure. After drying with a vacuum pump, dichloromethane (8.0 ml), 3-[(trans-4-aminocyclohexane-1-yl)carbonylamino]_4_{2_[(4-chloro) was added to the obtained residue. Phenyl)amine oxime]ethyl}-5-methoxybenzoic acid brothed dichloromethane (10 ml) suspension, TEA (commercially available) (300 μΐ), stirred at room temperature 4 hour. After diluting with di-methane, 〇·5 equivalent of hydrochloric acid was added. After extraction with dichlorohydrazine, the combined organic layers were washed with a saturated aqueous solution of NaHC 3 and a saturated aqueous solution of NaCl. After drying over anhydrous NajCU, the solvent was evaporated. !H-NMR (CDC13) δ : 1.30-1.42 (2Η, m), 1.75-1.88 (2H? m), 2.10-2.22 (4H, m), 2.38-2,48 (1H, m), 2.77-2.86 (2H,m), 2.91-3.00(2H,m),3.69-3.73(5H,m),3.81(2H,t),3.84-3.94 (1H,m),3·87 (3H,s) , 4·01 (2H, s), 6.64 (1H, d), 7.23 (1H, s), 7·25 (2H, d), 7.38 (2H, d), 7.68 (1H, s), 8.09 (1H , s), 9·62 (1H, s) 〇MS (ESI) m/z: 608 (M+H)+. (Step c) 4-[2-(4-Chlorophenylaminomethane)ethyl]-3_methoxy_5_{[trans_4_(3-oxymorpholin-4-yl)cyclohexyl ]carbonylamino}benzoic acid to 3-({trans-4-[2-(2-chloroethoxy)ethoxymethylamino]cyclohexyl)carbonylamino)-4_[2-(4-chlorobenzene) Add tBu〇K (33 mg) to a solution of methyl hydrazinyl)ethyl]_5-methoxybenzoate (70 mg) in hydrazine (5. 0 ml) at room temperature 129677.doc -216 - Stirring for 2 hours under 200840568. DMF (〇. 5 ml) and tBu〇K (16 mg) were added to the reaction mixture, and the mixture was stirred at room temperature for 6 hours. DMF (2.5 ml) was added and stirred for 6 Torr. After adding BuOK (45 mg), the mixture was stirred at room temperature for 24 hours, and then tBuOKGS mg) was added thereto, and the mixture was stirred at room temperature for 4 days. After diluting the reaction mixture with di-methane, 0.1% aqueous hydrochloric acid solution was added. The mixture was extracted with dioxane, and the combined dichloromethane layers were washed with a saturated aqueous solution of NaCl. After drying in anhydrous 1^7-8 〇4, the solvent was concentrated under reduced pressure. The residue was subjected to flash chromatography (one gas-fired: decyl alcohol = 5 〇: J) using ruthenium as a carrier.

精製後’自乙醇（2.0 ml)、水（ι·〇 ml)混合液中於減壓下餾 去溶劑，以真空泵乾燥，獲得標題化合物（6() mg)。 】H-NMR (DMSO-d6) δ : 1.52-1.74 (6H，m)，1.95-2,10 (2H， m)，2.30-2.44 (1H，m)，2.62 (2H，t)，2·89 (2H，t)，3.28 (2H， t)，3·82 (2H，t)，3·86 (3H，s)，4.03 (2H，s)，4.18-4.33 (1H， m)，7.30 (2H，d)，7,31 (1H，s)，7.60 (2H，d)，7.71 (1H，s)， 9.60 (1H，s)，10.11 (ih，s) 〇 MS (FAB) m/z: 558 (M+H)+，580 (M+Na)+。 [實施例98]4-[斤)-2-(4-氣苯基胺甲醯基）乙烯基]-3-[(5-異 丙基·4,5,6,7·四氫噻唑并[5,4-c]吡啶羰基）胺基卜5_甲基 苯甲酸鹽酸鹽 (步驟a) 4-溴-3-甲基-5-硝基苯甲酸甲酯 將4-溴-3-甲基苯甲酸甲酯〇 〇1 g)溶解於濃硫酸（12〇 ^1) 中。於冰浴冷卻下，向該反應液中添加TFA( 15 ml)及硝酸 納（3.95 g) ’於室溫下攪拌一整夜。將反應液釋放至冰水 中’添加乙酸乙酯（3〇〇 ml)進行分液。以飽和食鹽水及飽 129677.doc -217- 200840568 和NaHC〇3水洛液清洗有機層。以無水乾燥後，於 減壓下鶴去浴劑。向所獲得之殘逢中添加己烧，濾取固形 物，進行乾燥，獲得標題化合物（3.71g)。 H-NMR (CDCh) δ : 2.55 (3H，S)，3·94 (3H，S)，8·07 (1H， d)，8·13 (1Η，d)。 (步驟b) 4·((Ε)-2-第三丁氧基羰基乙烯基）_3_甲基_5_硝基苯 甲酸甲酯 向4-溴·3-甲基-5-硝基苯甲酸甲酯（3·71 g)與丙烯酸第三 丁酯（5.20 g)的混合物中添加乙酸鈀（2)(〇15 g)及三苯基膦 (0.3 6 g)，於1〇〇 ◦下攪拌12小時。放置至室溫後，於減壓 下餾去溶劑。利用以矽膠為載體之快速層析法（己烷：乙 酸乙酯=4 ·· 1)進行精製，獲得標題化合物（〇 624 g)。 H-NMR (CDC13) δ : 1·50 (9H，s)，2.41 (3H，s)，3·93 (3H， s)，5·89 (1Η，d)，7.72 (1Η，d)，8·09 (1Η，br s)，8·33 (1Η，br s)。 (步驟c) 4-((E)-2-第三丁氧基羰基乙烯基）·3_[(5•異丙基_ 4,5,6,7-四氫噻唑并[5,4-c]n比啶_2-羰基）胺基卜5-甲基苯甲 酸甲酯 將4-((Ε)·2-第三丁氧基羰基乙烯基甲基-5-硝基苯甲 酸甲酯（500 mg)懸浮於乙酸乙酯（5〇 ^1)中，添加10%鈀-碳 (含水5 0% ’ 200 mg)。於氫氣環境下，於室溫下擾拌4小時 後，去除觸媒。對濾液於減壓下餾去溶劑，獲得3-胺基 ((E)-2-第三丁氧基羰基乙烯基）巧_甲基苯曱酸甲酯的粗精 製物。 129677.doc -218- 200840568 向參考例32之化合物（819 mg)的二氯甲燒（5叫懸浮液 中添加DMF(0.04 mI)、草醯氯（544吣，於室溫下擾掉4小 時。將反應液於減麼下濃縮後，向所獲得之殘逢中添加以 上述方法所獲得之3_胺基·4鲁2·第三丁氧基羰基乙烯 基）-5-甲基苯甲酸甲s|之粗精製物的二氯甲燒溶液（ι〇叫 及TEA(1.74 ml)，於室溫下授拌一整夜。以二氣甲院稀釋 反應液後，添加飽和NaHC〇3水溶液。以二氯甲烷萃取 後，以飽和NaCl水溶液清洗所合併之有機層。以無水 ♦ Na2S04乾燥後’於減麼下館去溶劑。利用以石夕膠為載體之 快速層析法（己烧：乙酸乙醋=1 : υ進行精製，獲得標題 化合物（105 mg)。 *H-NMR (CDC13)5:1.15(6H, d), 1.54 (9H, s), 2.36 (3H, s), 2.89 (4H, br s), 2.95-3.06 (1H, m), 3.85 (2H, br s), 3.90 (3H, s), 6.21 (1H, d), 7.64-7.70 (2Hj m), 8.88 (1H, br s), 9.40 (1H，br s)。 ’ MS (ESI) m/z: 500 (M+H)+，498 (M+H)、 馨（步驟d) 4-[(E)-2_(4·氣苯基胺甲醯基）乙烯基]_3-[(5_異丙 基-4,5,6,7-四氫噻唑并[5,4-c]咄啶羰基）胺基卜弘曱基苯 曱酸曱酯 將4-((E)-2-第三丁氧基羰基乙烯基）_3一[(5_異丙基- 4,5,6,7·四氫噻嗤并[5,4-c]吡啶-2-羰基）胺基]-5-曱基苯甲 酸甲酯（105 mg)溶解於二氯曱烷（3 ml)中。向該反應液中 添加TFA(3 ml)，於室溫下攪拌2小時。於減壓下餾去溶 劑，向殘渣中添加4-氯苯胺（29.5 mg)、HOBt(28.4 mg)、 129677.doc -219· 200840568 EDC(6〇.5mg)、TEA(59nl)，於室溫下攪拌3日。向反應液 中添加二氯曱烧、飽和NaHCCb水溶液。以二氯甲烧萃取 後’以飽和NaCl水溶液清洗所合併之有機層。以無水 NaJO4乾燥後，於減壓下儒去溶劑。利用以石夕膠為載體之 快速層析法（二氯曱烷··甲醇=97 : 3)進行精製，獲得標題 化合物（21.9 mg)。 'H-NMR (DMSO-d6) δ: 1.05 (6H? d), 2.42 (3Η, br s)5 2.72- 2.83 (4H，m)，2.88-2.98 (1H，m)，3,81 (2H，br s)，3.88 (3H， br s)，6·53 (1H，d)，7.39 (2H，d)，7·65-7·79 (4H，m)，8.15 (1H，br s)，10.37-10.39 (2H，m)。 MS (ESI) m/z: 553 [(M+H)+，35C1]，555 [(M+H)' 37C1]。 (步驟e) 4-[(Ε)·2-(4-氣笨基胺曱醯基）乙烯基]-3-[(5-異丙 基-4,5,6,7-四氫噻唑并[5,4-c]吼啶-2-羰基）胺基]-5-甲基苯 曱酸鹽酸鹽 向4-[(E)-2-(4-氣苯基胺曱醯基）乙烯基]-3-[(5-異丙基-4,5,6,7-四氫噻唑并[5,4-c]吡啶-2-羰基）胺基]-5-甲基苯曱 酸曱酯（21.9 mg)的THF(4 ml)溶液中添加水（1·〇 ml)、Li〇H 一水合物（5,0 mg)，於室溫下攪拌一整夜。於減壓下餾去 溶劑，添加1當量鹽酸（2 ml)。於減壓下濃縮，以水清洗所 獲得之固體，獲得標題化合物（11.5 mg)。 ^-NMR (DMSO-d6) δ : 1.31 (6H9 br s)9 2.42 (3H, s)? 2.94- 3.49 (3H，m)，3.51-3.81 (2H，m)，4·38-4·81 (2H，m)，6.55 (1H，d)，7·37 (2H，d)，7·65 (1H，d)，7·69 (2H，d)，7·76 (1H， br s)，7·98 (1H，br s)5 10.46 (1H，br s)，1〇·56 (1H，br s)， 129677.doc -220- 200840568 10.68-10.91 (1H，m)，12.96-13.21 (1H，m)。 MS (ESI) m/z: 539 (M+H)+。 [實施例99] 4-[2-(4 -氣苯基胺甲酿基）乙基]-3-[(5 -異丙基_ 4,5,6,7-四氫噻唑并[5,4-c]吡啶-2-羰基）胺基]甲基笨甲 酸曱酉旨 (步驟a) 4-(2-第三丁氧基羰基乙基）-3-[(5-異丙基·4,5,6,7_ 四氫噻唑并[5，4-c]吡啶-2-羰基）胺基]-5 -曱基苯甲酸曱酉旨 將實施例98之（步驟b)的標題化合物（124 mg)懸浮於甲醇 (10 ml)中’添加10%委巴-碳（含水50%，40 mg)。於氫氣環境 下，於室溫下攪拌7小時後，去除觸媒。於減壓下德去溶 劑，獲得固體。 向參考例32之化合物（222 mg)的二氣甲烷（5 ^1)懸浮液 中添加DMF(0.04 ml)、草酸氣（148 μ 1)，於室溫下攪拌2小 時。將反應液於減壓下濃縮後，向所獲得之殘渣中添加以 上述方法所獲得之固體、二氣甲烷（1〇 ml)及ΤΕΑ(〇 471 ml)，於室溫下攪拌一整夜。以二氯曱烷稀釋反應液後， 添加飽和NaHC〇3水溶液。以二氯曱烷萃取後，以飽和After the purification, the solvent was evaporated under reduced pressure from ethyl acetate (yield: EtOAc) (m. H-NMR (DMSO-d6) δ : 1.52-1.74 (6H, m), 1.95-2,10 (2H, m), 2.30-2.44 (1H, m), 2.62 (2H, t), 2·89 (2H,t), 3.28 (2H, t), 3·82 (2H, t), 3·86 (3H, s), 4.03 (2H, s), 4.18-4.33 (1H, m), 7.30 (2H ,d),7,31 (1H,s), 7.60 (2H,d),7.71 (1H,s), 9.60 (1H,s),10.11 (ih,s) 〇MS (FAB) m/z: 558 (M+H)+, 580 (M+Na)+. [Example 98] 4-[6]-2-(4-phenylphenylcarbamoyl)vinyl]-3-[(5-isopropyl-4,5,6,7-tetrahydrothiazole [5,4-c]pyridinecarbonyl)aminopurine 5-methylbenzoic acid hydrochloride (step a) 4-bromo-3-methyl-5-nitrobenzoic acid methyl ester 4-bromo-3 Methyl-methylbenzoate 〇〇 1 g) was dissolved in concentrated sulfuric acid (12 〇 ^ 1). Under ice cooling, TFA (15 ml) and sodium nitrate (3.95 g) were added to the mixture and stirred at room temperature overnight. The reaction solution was released into ice water, and ethyl acetate (3 ml) was added for liquid separation. The organic layer was washed with saturated brine and saturated 129677.doc -217-200840568 and NaHC〇3 aqueous solution. After drying in anhydrous form, the mixture was removed under reduced pressure. The obtained residue was added to the obtained residue, and the solid was filtered, and dried to give the title compound (3.71 g). H-NMR (CDCh) δ : 2.55 (3H, S), 3·94 (3H, S), 8.07 (1H, d), 8·13 (1Η, d). (Step b) 4·((Ε)-2-Tertoxycarbonylvinyl)_3_methyl_5-nitrobenzoic acid methyl ester to 4-bromo-3-methyl-5-nitrobenzene Palladium acetate (2) (〇15 g) and triphenylphosphine (0.36 g) were added to a mixture of methyl formate (3·71 g) and tributyl acrylate (5.20 g) at 1〇〇◦ Stir for 12 hours. After standing at room temperature, the solvent was evaporated under reduced pressure. Purification by flash chromatography (hexane: ethyl acetate = 4 ···) H-NMR (CDC13) δ : 1·50 (9H, s), 2.41 (3H, s), 3·93 (3H, s), 5·89 (1Η, d), 7.72 (1Η, d), 8 · 09 (1Η, br s), 8·33 (1Η, br s). (Step c) 4-((E)-2-Tertoxycarbonylvinyl)·3_[(5•isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c Methyl 4-((Ε)·2-t-butoxycarbonylvinylmethyl-5-nitrobenzoate (n-pyridyl 2-carbonyl)-amino-5-methylbenzoate 500 mg) was suspended in ethyl acetate (5 〇^1), and 10% palladium-carbon (aqueous 50% '200 mg) was added. After stirring for 4 hours at room temperature under hydrogen atmosphere, the catalyst was removed. The solvent was distilled off under reduced pressure to give a crude product of 3-amino ((E)-2-t-butoxycarbonylvinyl)-methyl benzoic acid methyl ester. 129677.doc - 218- 200840568 To the compound of Reference Example 32 (819 mg) of methylene chloride (5-fold suspension was added DMF (0.04 mI), and chlorophyll chloride (544 吣, disturbed at room temperature for 4 hours. After concentration under reduced concentration, the obtained 3_amino-4-ru 2·t-butoxycarbonylvinyl)-5-methylbenzoic acid methyl s obtained by the above method is added to the obtained residue. The crude purified product of dichloromethane (Iso and TEA (1.74 ml) was mixed overnight at room temperature. After diluting the reaction solution with the second gas, add The aqueous solution of saturated NaHC〇3 was saturated. After extracting with dichloromethane, the combined organic layer was washed with a saturated aqueous solution of NaCI. (Heat-fired: ethyl acetate = 1 : hydrazine to give the title compound (105 mg). *H-NMR (CDC13) 5: 1.15 (6H, d), 1.54 (9H, s), 2.36 (3H, s ), 2.89 (4H, br s), 2.95-3.06 (1H, m), 3.85 (2H, br s), 3.90 (3H, s), 6.21 (1H, d), 7.64-7.70 (2Hj m), 8.88 (1H, br s), 9.40 (1H, br s). ' MS (ESI) m/z: 500 (M+H)+, 498 (M+H), 馨 (Step d) 4-[(E) -2_(4·Phenylaminocarbamyl)vinyl]_3-[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]acridinylcarbonyl)amine基 曱 曱 曱 将 将 将 4-((E)-2-Tertoxycarbonylvinyl)_3-[(5-isopropyl-4,5,6,7·tetrahydrothiophene) Methyl [5,4-c]pyridine-2-carbonyl)amino]-5-mercaptobenzoate (105 mg) was dissolved in dichloromethane (3 ml). TFA was added to the mixture. (3 ml), stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and 4-chloroaniline (29.5 mg), HOBt (28.4 mg), 129677. doc - 219, 200840568 EDC (6 〇. 5 mg), TEA (59 nl) were added to the residue at room temperature. Stir for 3 days. Dichlorohydrazine and a saturated aqueous solution of NaHCCb were added to the reaction mixture. After extraction with methylene chloride, the combined organic layers were washed with a saturated aqueous solution of NaCl. After drying with anhydrous NaJO4, the solvent was removed under reduced pressure. The title compound (21.9 mg) was obtained by purified by flash chromatography eluting elution elution elution 'H-NMR (DMSO-d6) δ: 1.05 (6H?d), 2.42 (3Η, br s)5 2.72- 2.83 (4H,m),2.88-2.98 (1H,m),3,81 (2H, Br s), 3.88 (3H, br s), 6.53 (1H, d), 7.39 (2H, d), 7·65-7·79 (4H, m), 8.15 (1H, br s), 10.37 -10.39 (2H, m). MS (ESI) m/z: 553 [(M+H)+, 35C1], 555 [(M+H) '37C1]. (Step e) 4-[(Ε)·2-(4-Astylaminomethyl)vinyl]-3-[(5-isopropyl-4,5,6,7-tetrahydrothiazole [5,4-c]Acridine-2-carbonyl)amino]-5-methylphenylhydrazine hydrochloride to 4-[(E)-2-(4-cyclophenylaminoindenyl)ethylene ]]-3-[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl)amino]-5-methylbenzoate To a solution of the ester (21.9 mg) in THF (4 ml), water (1············ The solvent was evaporated under reduced pressure and 1N hydrochloric acid (2 ml) was added. The extract was concentrated under reduced pressure. ^-NMR (DMSO-d6) δ : 1.31 (6H9 br s)9 2.42 (3H, s)? 2.94- 3.49 (3H,m), 3.51-3.81 (2H,m),4·38-4·81 ( 2H,m),6.55 (1H,d),7·37 (2H,d),7·65 (1H,d),7·69 (2H,d),7·76 (1H, br s),7 ·98 (1H, br s) 5 10.46 (1H, br s), 1〇·56 (1H, br s), 129677.doc -220- 200840568 10.68-10.91 (1H, m), 12.96-13.21 (1H, m). MS (ESI) m/z: 539 (M+H)+. [Example 99] 4-[2-(4-Phenylaminomethyl)ethyl]-3-[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5, 4-c]pyridine-2-carbonyl)amino]methyl benzoic acid hydrazine (step a) 4-(2-t-butoxycarbonylethyl)-3-[(5-isopropyl-4) , 5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl)amino]-5-mercaptobenzoic acid hydrazine the title compound of Example 98 (Step b) Mg) Suspension in methanol (10 ml) 'Add 10% Ciba-carbon (50% aqueous, 40 mg). After stirring at room temperature for 7 hours under a hydrogen atmosphere, the catalyst was removed. The solvent was removed under reduced pressure to give a solid. DMF (0.04 ml) and oxalic acid gas (148 μl) were added to a suspension of the compound of Example 32 (222 mg) in di-methane (5^1), and stirred at room temperature for 2 hours. After the reaction mixture was concentrated under reduced pressure, the obtained solid, methylene chloride (1 ml) and yt. After diluting the reaction mixture with dichloromethane, a saturated aqueous solution of NaHC〇3 was added. After being extracted with dichloromethane, to saturate

NaCl水溶液清洗所合併之有機層。以無水Na2S04乾燥後， 於減壓下餾去溶劑。利用以矽膠為載體之快速層析法（己 烷.乙酸乙酯=3 : 1)進行精製，獲得標題化合物（146 mg)。 Η-NMR (CDC13) δ: 1.14 (6H，d)，1·40 (9H，s)，2·38 (3H，s)， 2.54 (2Η, t)5 2.86-3.04 (7Η5 m)5 3.84-3.90 (5Η, m)? 7.71 (1H，d)，8·38 (1H，d)，9·79 (1H，br s)。 129677.doc -221 - 200840568 MS (ESI) m/z: 502 (M+H)+。 (步驟b) 4-[2-(4-氯苯基胺曱醯基）乙基]_3_[(5_異丙基_ 4,5,6,7-四氫噻唑并[5,4-c]吡啶_2·羰基）胺基]-5 -甲基苯曱 酸曱酯 將4-(2-第二丁氧基羰基乙基）_3_[(5-異丙基_4,5,6,7_四氫 噻唑并[5,4-c]吡啶_2_羰基）胺基]巧—甲基苯甲酸甲酯（146 mg)溶解於一氣曱烷（3 ml)中。向該反應液中添加4當量鹽 酸二’院溶液（3 ml)，於室溫下攪拌一整夜。於減壓下餾 _ 去溶劑，向所獲得之殘渣中添加4-氯苯胺（40.8 mg)、 HOBt(3 9.3 mg)、EDC(83.7 mg)、TEA(8 1 · 1 μΐ)，於室溫下 攪拌7日。向反應液中添加二氣甲烷、飽和NaHc〇3水溶 液。以二氯曱烧萃取後，以飽和NaCl水溶液清洗所合併之 有機層。以無水NajO4乾燥後，於減壓下餾去溶劑。利用 以石夕膠為載體之快速層析法（山善SI-40W-2L ;二氣甲燒： 甲醇=97 : 3)進行精製，獲得標題化合物（6.6 mg)。 b-NMR (CDC13) δ: 1·15 (6H，d)，2·39 (3H，s)，2.62 (2H，t)， 馨 2.87-2.93(4H，m)，2.96-3.05 (lH，m)，3.12(2H，t)，3.84- 3,88 (5H，m)，7.20 (2H，d)，7·36 (2H，d)，7·58 (1H，br s)， 7·73 (1H，br s)，8.15 (1H，br s)，9.47 (1H，br s)。 MS (ESI) m/z: 555 (M+H)+。 下述表13〜26表示[實施例1]〜[實施例99]之標題化合物的 結構。 129677.doc -222- 200840568 [表 13] [實施例1 ] [實施例2] 〇V?l Vt&gt;a [實施例3] [實施例4〕 O^VVa [實施例5] I ? [實施例6] /N-/ — [實施例7] [實施例8] 〇 γΟ%〆 'm〇^YS r^t〇i,Oa &lt; Vs Η H-y 〔實施例9] X [實施例1 0] (X 〇 m^〇 -fN’ ΗThe combined organic layers were washed with an aqueous solution of NaCl. After drying over anhydrous Na 2 SO 4 , the solvent was evaporated under reduced pressure. Purification was carried out by flash chromatography (hexanes: ethyl acetate = 3:1). Η-NMR (CDC13) δ: 1.14 (6H,d),1·40 (9H,s),2·38 (3H,s), 2.54 (2Η, t)5 2.86-3.04 (7Η5 m)5 3.84- 3.90 (5Η, m)? 7.71 (1H,d),8·38 (1H,d),9·79 (1H,br s). 129677.doc -221 - 200840568 MS (ESI) m/z: 502 (M+H)+. (Step b) 4-[2-(4-Chlorophenylaminoindenyl)ethyl]_3_[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c Pyridine-2·carbonyl)amino]-5-methylbenzoic acid decyl ester 4-(2-second-butoxycarbonylethyl)_3_[(5-isopropyl-4,5,6, 7_Tetrathiathiazolo[5,4-c]pyridine_2-carbonyl)amino]methyl-methylbenzoate (146 mg) was dissolved in monooxane (3 ml). To the reaction mixture was added 4 equivalents of a hydrochloric acid solution (3 ml), and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and 4-chloroaniline (40.8 mg), HOBt (3 9.3 mg), EDC (83.7 mg), and TEA (8 1 · 1 μΐ) were added to the obtained residue at room temperature. Stir under 7 days. A two-gas methane and a saturated NaHc 3 aqueous solution were added to the reaction liquid. After extraction with dichlorohydrazine, the combined organic layers were washed with a saturated aqueous solution of NaCl. After drying over anhydrous NajO4, the solvent was evaporated under reduced pressure. Purification by flash chromatography (Shanshan SI-40W-2L; methane: methanol = 97:3) using b-NMR (CDC13) δ: 1·15 (6H, d), 2·39 (3H, s), 2.62 (2H, t), scent 2.87-2.93 (4H, m), 2.96-3.05 (lH, m ), 3.12(2H,t),3.84- 3,88 (5H,m), 7.20 (2H,d),7·36 (2H,d),7·58 (1H,br s), 7·73 ( 1H, br s), 8.15 (1H, br s), 9.47 (1H, br s). MS (ESI) m/z: 555 (M+H)+. Tables 13 to 26 below show the structures of the title compounds of [Example 1] to [Example 99]. 129677.doc -222- 200840568 [Table 13] [Example 1] [Example 2] 〇V?l Vt&gt;a [Example 3] [Example 4] O^VVa [Example 5] I ? Example 6] /N-/ - [Example 7] [Example 8] 〇γΟ%〆'm〇^YS r^t〇i, Oa &lt; Vs Η Hy [Example 9] X [Example 1 0 ] (X 〇m^〇-fN' Η

223 - 129677.doc 200840568223 - 129677.doc 200840568

[表 14][Table 14]

129677.doc 224- 200840568 [表 15]129677.doc 224- 200840568 [Table 15]

129677.doc 225 - 200840568129677.doc 225 - 200840568

[表 16][Table 16]

129677.doc 226- 200840568 [表 17] [實施例4 7] [實施例4 8] OyOM [實施例4 9] 〇·ν〇νζ [實施例5 0 ] ΟγΟΗ [實施例5 1 ] [實施例5 2 ·] °rV O ΟγΟΗ 0 ijAx Η ct [實施例3 3] [實施例5 4〕 &gt;^Λτ ct 〇工㈡^^ Ο^ΌΗ V^/ηΎ C1 [實施例5 5 ] 0γ0、 [實施例5 6 ] cyoH &gt;^v Η 227- 129677.doc 200840568 [表 18]129677.doc 226- 200840568 [Table 17] [Example 4 7] [Example 4 8] OyOM [Example 4 9] 〇·ν〇νζ [Example 5 0 ] ΟγΟΗ [Example 5 1 ] [Examples 5 2 ·°rV O ΟγΟΗ 0 ijAx Η ct [Embodiment 3 3] [Embodiment 5 4] &gt;^Λτ ct Completion (2)^^ Ο^ΌΗ V^/ηΎ C1 [Embodiment 5 5] 0γ0, [Example 5 6 ] cyoH &gt;^v Η 227- 129677.doc 200840568 [Table 18]

129677.doc 228- 200840568 [表 19]129677.doc 228- 200840568 [Table 19]

129677.doc 229- 200840568 [表 20]129677.doc 229- 200840568 [Table 20]

129677.doc 230- 200840568 [表 21]129677.doc 230- 200840568 [Table 21]

129677.doc 231 - 200840568 [表 22]129677.doc 231 - 200840568 [Table 22]

129677.doc 232- 200840568 [表 23]129677.doc 232- 200840568 [Table 23]

129677.doc 233 - 200840568 [表 24]129677.doc 233 - 200840568 [Table 24]

129677.doc 234- 200840568 [表 25]129677.doc 234- 200840568 [Table 25]

129677.doc 235 - 200840568 [表 26]129677.doc 235 - 200840568 [Table 26]

[試驗例1]人體FXa抑制作用（IC5〇值）的測定 向96孔（well)微孔板的各孔中，添加10 μΐ的對濃度進行 適宜階段性設定之被試驗物質5% DMSO溶液、40 μΐ之三 經甲基胺基曱烧緩衝液（tris buffer)(100 mM三經曱基胺基 甲烧、200 mM 氣化卸、0·2〇/〇 之 BSA(bovine serum albumin，牛血清白蛋白）、pH值 7.4)、1 0 μΐ之 0.0625 U/ml 129677.doc -236- 200840568 的人體FXa(Enzyme.Research.Labolatories，Inc，，於三_ 甲基胺基甲烷緩衝液中溶解及稀釋）後，添加40 μ1&lt;75() μΜ的S-2222水溶液（Chromogenix公司），於室溫下以ι〇分 鐘測定405 nm下之吸光度，求得吸光度的增加 鐘）。為了進行對照而使用三羥曱基胺基甲烷緩衝液來替 代被試驗物質。 分別將由下式所求得的被試驗物質的各最終濃度之抑制 率（％)作為對數機率紙的縱軸，將被試驗物質的最終濃後 ❿ 作為橫軸而作圖，求得50%抑制濃度（ic50值）。 抑制率被試驗物質的△〇!)/分鐘+對照物Δ〇Ε)/分麵）k 100 (結果）表27表示本發明化合物具有強力之FXa抑制作 用。 [表 27][Test Example 1] Measurement of human FXa inhibition (IC5 〇 value) To each well of a 96-well microplate, 10 μM of a 5% DMSO solution of a test substance which was appropriately set in a concentration was added, 40 μΐ of trimethylamine-based tris buffer (100 mM tris-hydrazinocarbazide, 200 mM gasification, 0·2〇/〇 BSA (bovine serum albumin, bovine serum) FX (Enzyme. Research.Labolatories, Inc., dissolved in tris-methylaminomethane buffer) After dilution, 40 μl of &lt;75 () μΜ of S-2222 aqueous solution (Chromogenix) was added, and the absorbance at 405 nm was measured at room temperature for 1 minute to obtain an increase in absorbance. For the control, a trihydroxydecylaminomethane buffer was used instead of the test substance. The inhibition rate (%) of each final concentration of the test substance obtained by the following formula was taken as the vertical axis of the logarithmic probability paper, and the final concentrated enthalpy of the test substance was plotted as the horizontal axis to obtain 50% suppression. Concentration (ic50 value). The inhibition rate of the test substance was Δ〇!)/min + control Δ〇Ε) / facet) k 100 (Result) Table 27 shows that the compound of the present invention has potent FXa inhibitory action. [Table 27]

化合物 實i例11— 實施例27 實施例37 實施例56 人體FXa抑制作用 (IC5〇值）：njyj 人體FXa抑 (IC50值）： 化合物Compound Example 11 - Example 27 Example 37 Example 56 Inhibition of human FXa (IC5 〇 value): njyj Human FXa (IC50 value): Compound

實施例17 實施例31 ^施例瓦Example 17 Example 31 ^Example tile

[試驗例2]經口投予後的猴子血漿濃度之測定 將被試驗物質以成為以自由體 量之方式溶解或懸浮於〇·5〇/〇甲基 換算為1 mg/2 mL/kg之劑 纖維素溶液中，將其經口 129677.doc -237. 200840568 投予給斷'15小時以上的猴子。於被試驗物質投予前及投 予後0’5 1、2、4、8、24小時之時，以相對於1份之 3 ·13%柃板酸二鈉^水合物，^液為9份％比例進行採血 (合计1 ml)。將採集血液進行離心分離（3〇⑼卬瓜、1〇分 鐘、4。〇,製備血漿。對所製備之血漿進行前處理後，以 HPLC/MS/MS進行測定，由内部標準物質與各srm (selected reaction monitoring，選擇反應監測）層析圖峰面 積比’且使用校正曲線，算出金漿濃度。 (結果）實施例11、17、27、39及56顯示出較高之經口吸 收性。[Test Example 2] Measurement of plasma concentration of monkeys after oral administration The test substance was dissolved or suspended in a free volume to a dose of 1 mg/2 mL/kg in terms of 〇·5〇/〇 methyl group. In the cellulose solution, it was administered to a monkey that was broken for more than 15 hours by oral 129677.doc - 237. 200840568. Before the test substance is administered and at 0'5, 1, 2, 4, 8 and 24 hours after the administration, it is 9 parts relative to 1 part of 3·13% disodium silicate acid hydrate. Blood was collected in % ratio (total 1 ml). The collected blood was centrifuged (3 〇(9) 卬 melon, 1 〇 minute, 4 〇, and plasma was prepared. After the prepared plasma was pretreated, it was measured by HPLC/MS/MS, and the internal standard substance and each srm were determined. (Selected reaction monitoring) The chromatogram peak area ratio 'and the calibration curve was used to calculate the gold paste concentration. (Results) Examples 11, 17, 27, 39 and 56 showed higher oral absorbency.

129677.doc -238·129677.doc -238·

Claims (1)

200840568 十、申請專利範圍： 1 · 一種化合物或其藥理上容許之鹽’該化合物係以下述通 式（I)表示： [化1]200840568 X. Patent application scope: 1 · A compound or a pharmacologically acceptable salt thereof] The compound is represented by the following general formula (I): [Chemical Formula 1] [式中，環A表示苯環； R1表示氫原子、鹵基、C1〜C6烧基、鹵代C1〜C6烧基 或C1〜C6烷氧基； R2表示氫原子、鹵基、C1〜C6院基、鹵代C1〜C6烧 基、C1〜C6烷氧基、C1〜C6烷氧基C1〜C6烷基、齒代 C1〜C6烷氧基、羧基、C1〜C6烷氧基羰基、胺甲醯基、 N-單（C1〜C6烷基）胺甲醯基或n，N-二（C1〜C6)胺甲醯基； T1表示基-C( = 0)N(R3)-(此處，該基之左側的鍵表示鍵 結於Q2，R3表示氫原子或C1〜C6烷基）； T2 表示基-CH2_C(R4)(R5)-C(=0)NH-、基-CH=CH-C(=0)NH-、基-CH2-〇-C(=〇)NH-或基-CH2-NHC(=0)NH- (此處’各基之左側的鍵表示鍵結於環A，化4及尺5相同或 不同’表示氫原子、鹵基、C1〜C6烷基、羥基或C1〜C6 烷氧基）； Q表不四氫萘唆基（該四氫萘啶基可具有C1〜C6烷基作 為取代基）、四氫噻唑并吡啶基（該四氫噻唑并吡啶基可 具有選自由C1〜C6烷基、鹵代C1〜C6烷基、ci〜C6烷氧基 129677.doc 200840568 Cl〜C6烷基及Cl〜C6烷氧基羰基所組成之群中的基作為 取代基）、四氫噻唑并噠嗪基（該四氫嗟唑并嚏嗪基可具 有C1〜C6烧基作為取代基）、二氫吼喃并嘆σ坐基、四氫售 唑并吖丁啶基（該四氫噻唑并吖丁啶基可具有Cl〜C6烧基 作為取代基）、（1-C1〜C6烧基）旅咬-4-基、4-Ν，Ν-二 (C1〜C6烷基）胺基環己基、4-(3-氧基嗎啉-4_基）環己基或 4- (3-氧基嗎啉-4-基）苯基； Q2表示單鍵； ® Q3表示苯基（該苯基可具有選自由鹵基、Cl〜C6烷基、 鹵代C1〜C6烷基及C1〜C6烷氧基所組成之群中的1〜2個基 作為取代基）、噻吩基、函代噻吩基、吡啶基、鹵代吼啶 基、噠嗪基、i代噠嗪基、喹啉基、i代喹啉基、異喹 琳基、_代異唾琳基、峰琳基或鹵代n辛琳基。] 2·如請求項1之化合物或其藥理上容許之鹽，其中通式⑴ 中的基Qi係：5,6,7,8-四氫-[1，6]萘啶-2-基、6-C1〜C6烷 基-5,6,7,8-四氫-[1，6]萘啶-2·基、4,5,6,7-四氫嚙ϋ坐并 [5,4-(：]吡啶-2-基、5-0：1〜€6烷基-4,5,6,7-四氫噻唑并[5,4-c]吡啶_2-基、5-鹵代C1〜C6烷基-4,5,6,7-四氫噻唑并[5,4· c]吡啶-2-基、5-C1〜C6烷氧基C1〜C6烷基-4,5,6,7-四氫噻 唑并[5,4-c]吡啶-2-基、5-C1〜C6烷氧基羰基-4,5,6,7_四氫 噻唑并[5,4_c]吡啶·2·基、6,7-二氫-4Η-吡喃并[4,3，d]噻 唑-2-基、5,6,7,8·四氫-4H-噻唑并[5,4-c]吖丁啶-2-基、5- C1〜C6烷基-5,6,7,8_四氫-4H-噻唑并[5,4-c]吖丁啶基、 5- 鹵代C1〜C6烷基-5,6,7,8-四氫-4H-噻唑并[5,4-c]吖丁 &quot;定- 129677.doc -2- 200840568 基或5-C1〜C6烷氧基Cl〜C6烷基-5,6,7,8-四氫-4H-噻唑并 [5，‘c]吖丁啶 _2·基。 3.如凊求項1之化合物或其藥理上容許之鹽，其中通式⑴ 中的環Α係以下述式（π)或（111)所表示之基： [化2][wherein, ring A represents a benzene ring; R1 represents a hydrogen atom, a halogen group, a C1 to C6 alkyl group, a halogenated C1 to C6 alkyl group or a C1 to C6 alkoxy group; and R2 represents a hydrogen atom, a halogen group, or a C1 to C6 group; Affiliation, halogenated C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 alkoxy C1 to C6 alkyl, dentate C1 to C6 alkoxy, carboxyl, C1 to C6 alkoxycarbonyl, amine Mercapto, N-mono(C1~C6 alkyl)amine carbenyl or n,N-di(C1~C6)amine carbenyl; T1 represents yl-C(=0)N(R3)-(this Wherein, the bond to the left of the group indicates bonding to Q2, R3 represents a hydrogen atom or a C1 to C6 alkyl group; T2 represents a group -CH2_C(R4)(R5)-C(=0)NH-, a group-CH= CH-C(=0)NH-, yl-CH2-〇-C(=〇)NH- or yl-CH2-NHC(=0)NH- (wherein the bond to the left of each group represents a bond to the ring A, 4 and 5 are the same or different 'representing a hydrogen atom, a halogen group, a C1 to C6 alkyl group, a hydroxyl group or a C1 to C6 alkoxy group); Q represents a tetrahydronaphthyl group (the tetrahydronaphthyridinyl group can be used) Having a C1~C6 alkyl group as a substituent), a tetrahydrothiazolopyridinyl group (the tetrahydrothiazolopyridinyl group may have a C1 to C6 alkyl group, a halogenated C1 to C6 alkyl group, a ci~C6 alkoxy group 129677) .doc 200840568 Cl~C6 alkyl and a group of Cl~C6 alkoxycarbonyl groups as a substituent), tetrahydrothiazolopyridazinyl (the tetrahydrooxazolopyridazinyl group may have a C1 to C6 alkyl group) As a substituent), a dihydrofuran and a succinyl group, a tetrahydro-s-oxazolo-azetidinyl group (the tetrahydrothiazoloazetidinyl group may have a Cl~C6 alkyl group as a substituent), (1-C1 to C6 alkyl group) ) BTS 4-yl, 4-anthracene, fluoren-di(C1-C6 alkyl)aminocyclohexyl, 4-(3-oxymorpholin-4-yl)cyclohexyl or 4-(3-oxo) Benzalolin-4-yl)phenyl; Q2 represents a single bond; ® Q3 represents a phenyl group (the phenyl group may have a group selected from a halogen group, a C1 to C6 alkyl group, a halogenated C1 to C6 alkyl group, and a C1 to C6 alkyl group). 1 to 2 groups in the group consisting of oxy groups as a substituent), thienyl group, functional thienyl group, pyridyl group, haloacridinyl group, pyridazinyl group, i-pyridazinyl group, quinolyl group, i a quinolinyl group, an isoquinolinyl group, a y-iso-indolyl group, a peak-linyl group or a halogenated n-in-line group. The compound of claim 1 or a pharmacologically acceptable salt thereof, wherein the group Qi in the formula (1) is: 5,6,7,8-tetrahydro-[1,6]naphthyridin-2-yl, 6-C1~C6 alkyl-5,6,7,8-tetrahydro-[1,6]naphthyridin-2yl, 4,5,6,7-tetrahydroindolizine [5,4- (:]pyridin-2-yl, 5-0:1~€6 alkyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-yl, 5-halogen C1 ~C6 alkyl-4,5,6,7-tetrahydrothiazolo[5,4·c]pyridin-2-yl, 5-C1~C6 alkoxy C1~C6 alkyl-4,5,6, 7-Tetrathiathiazolo[5,4-c]pyridin-2-yl, 5-C1-C6 alkoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4_c]pyridine·2· 6,6-Dihydro-4Η-pyrano[4,3,d]thiazol-2-yl,5,6,7,8·tetrahydro-4H-thiazolo[5,4-c]indole Butyr-2-yl, 5-C1-C6 alkyl-5,6,7,8-tetrahydro-4H-thiazolo[5,4-c]azetidinyl, 5-halo C1~C6 alkyl- 5,6,7,8-tetrahydro-4H-thiazolo[5,4-c]吖丁-quot; 129677.doc -2- 200840568 base or 5-C1~C6 alkoxy Cl~C6 alkyl -5,6,7,8-tetrahydro-4H-thiazolo[5,'c]azetidin-2-yl. 3. A compound of claim 1 or a pharmacologically acceptable salt thereof, wherein The ring 中 in (1) is as follows [pi]) or (111) represented by the group: [Formula 2] 鍵結於基T2，R1及R2表示如請求項1所記載者）。 4·如請求項3之化合物或其藥理上容許之鹽，其中環a係以 式（ΠΙ)所表示之基。 5·如請求項1之化合物或其藥理上容許之鹽，其中通式⑴ 中的R1係氫原子、鹵基、C1〜C6烧氧基、ci〜C6烧基或 i代C1〜C6烷基。 6·如請求項1之化合物或其藥理上容許之鹽，其中通式⑴ 中的R2係氫原子、鹵基、C1〜C6烷氧基、C1〜C6烷基、 綾基、C1〜C6烷氧基羰基、胺曱醯基、N-單（C1〜C6烷基） 胺甲醯基或N，N-二（cn〜C6烷基）胺甲醯基。 7·如請求項1之化合物或其藥理上容許之鹽，其中通式⑴ 中的R2係羧基、C卜C6烷氧基羰基、胺甲醯基、N—單 (C1〜C6烷基）胺甲醯基或N，N-二（C1〜C6烷基）胺甲醯基。 129677.doc 200840568 8，如請求項1之化合物或其藥理上容許之鹽，其中通式（i) 中的T1係基_c(=0)NH-(此處，該基之左側的鍵表示鍵結 於基Q2)。 9·如請求項1之化合物或其藥理上容許之鹽，其中通式（I) 中的基T2係基- CH2-CH2-C(=0)NH-(此處，左側之鍵表示 鍵結於環A)。 10.如請求項1之化合物或其藥理上容許之鹽，其中通式⑴ 中的基Q3係4-氯苯基、4-1苯基、4-漠苯基、5 -氣吼咬-2-基、5-溴吼。定-2-基、5_氟吼。定-2-基、5-氯嗟吩-2-基、 5 - &gt;臭σ塞吩· 2 -基或5 -氣ϋ塞吩-2 -基。 11 · 一種化合物或其藥理上容許之鹽，該化合物係選自由下 述化合物所組成之群中的任一者：4-[2-(4-氯苯基胺甲醯 基）乙基]_3-[(5-異丙基-4,5,6,7-四氫嗟嗤并[5,4-c]吼咬-2-羰基）胺基]苯甲酸、4-[2-(5-氣吼咬-2-基胺甲醯基）乙基]_ -異丙基-4,5,6,7 -四氫嘆唾并[5,4-c]吼咬_2·毅基）胺 基]苯曱酸、4-{2-[(4-氟苯基）胺曱醯基]乙基卜3_[(5_異丙 基-4,5,6,7-四氫噻唑并[5,4-c]吡啶-2-羰基）胺基]苯甲 酸、4-[2-(5-氣噻吩-2-基胺甲醯基）乙基]_5_[(5_異丙基_ 4,5,6,7-四氫噻唑并[5,4-(：]吡啶-2-羰基）胺基]苯甲酸、4_ [2-(4-氯苯基胺甲醢基）乙基]-3-[(5-甲基-5,6,7,8-四氫_ 411-°塞嗤并[5,4-〇]1[3丫丁唆_2-魏基）胺基]苯甲酸、4-[2-(4&quot;· 裁I苯基胺甲醯基）乙基]-3-[(5 -異丙基-5,6,7,8 -四氫-4Ή-嗔 唑并[5,4-c]吖丁啶-2·羰基）胺基]苯甲酸、3_氯_心{2_[(心 氯苯基）胺甲醯基]乙基}-5-[(5-異丙基-4,5,6,7_四氫嗟吐 129677.doc 200840568 并[5,4-c]吼啶-2-羰基）胺基]苯甲酸、3_氣-4_{2_[(4·氯苯 基）胺甲&amp;&amp;基]乙基}-5-[(5-甲基-4,5,6,7-四氫嗟唾并[5,4_ c]吼啶-2-羰基)胺基]苯甲酸、弘氯_4_{2_[(4_氟苯基）胺甲 醯基]乙基卜5-[(5-異丙基_4,5,6，八四氫噻唑并[5,4_c]吡 啶-2-羰基）胺基]苯甲酸、‘{2-[(4_氯苯基）胺甲醯基]乙 基}-3-[(5-異丙基-4,5,6,7-四氫噻唑并[5,4-c]吡啶-2-羰基） 胺基]-5-氟苯曱酸、4_{2_[(4—氯苯基）胺甲醯基]乙基卜％ [(5-異丙基-4,5,6,7-四氫噻唑并[5,4-e]吡啶_2_羰基）胺基卜 5-曱氧基苯甲酸、4-{2-[(4-氣苯基）胺甲醯基]乙基卜3_曱 氧基_5-[(5_甲基-4,5,6,7-四氫噻唑并[5,4-c]吡啶_2_羰基） 胺基]苯甲酸、4-{2·[(4-氟苯基）胺甲醯基]乙基卜3_[(5_異 丙基-4,5,6,7-四氫噻唑并[5,4_c]吡啶羰基）胺基]_5_甲 氧基苯甲酸及4-{2-[(4-氣苯基）胺曱醯基]乙基卜3_[(5_異 丙基-4,5,6,7·四氫噻唑并[5,4-c]吡啶_2_羰基）胺基]_5_(三 氟甲基)苯甲酸。 12· —種醫藥組合物，其含有如請求項一項之化 合物或其藥理上容許之鹽。 13· —種活化凝血因子χ抑制劑組合物，其含有如請求項工至 11中任一項之化合物或其藥理上容許之鹽。 14· 一種凝血抑制劑組合物，其含有如請求項丨至丨〗中任一 項之化合物或其藥理上容許之鹽。 15· —種血栓或栓塞之預防及/或治療劑組合物，其含有如請 求項1至11中任一項之化合物或其藥理上容許之鹽。 1 6·種腦梗基、腦栓基、心肌梗塞、心絞痛、肺栓塞、伯 129677.doc 200840568 才°式症、深部靜脈血栓症、全身性血管内凝血綜合症、 人工瓣膜/關節置換後之血栓形成、血流重建後之血栓形 成及再閉塞、多器官功能障礙綜合症（MODS)、體外循 壞時的血栓形成或採i時的血液凝固之預防劑及/或治療 劑組合物，其含有如請求項1至丨丨中任一項之化合物或 其藥理上容許之鹽。 129677.doc 200840568 七、指定代表圖： (一) 本案指定代表圖為：（無） (二) 本代表圖之元件符號簡單說明： 八、本案若有化學式時，請揭示最能顯示發明特徵的化學式：The bond is at the base T2, and R1 and R2 are as indicated in claim 1. 4. The compound of claim 3, wherein the ring a is a group represented by the formula (ΠΙ), or a pharmacologically acceptable salt thereof. The compound of claim 1 or a pharmacologically acceptable salt thereof, wherein R1 in the formula (1) is a hydrogen atom, a halogen group, a C1 to C6 alkoxy group, a ci~C6 alkyl group or an i generation C1 to C6 alkyl group. . 6. The compound of claim 1, or a pharmacologically acceptable salt thereof, wherein R2 in the formula (1) is a hydrogen atom, a halogen group, a C1 to C6 alkoxy group, a C1 to C6 alkyl group, a decyl group, a C1 to C6 alkoxy group. A carbonyl group, an amine fluorenyl group, an N-mono(C1-C6 alkyl)aminocarboxamyl group or an N,N-di(cn~C6 alkyl)aminecarbamyl group. The compound of claim 1, or a pharmacologically acceptable salt thereof, wherein R2 is a carboxyl group, a CbC6 alkoxycarbonyl group, an amine formazan group or an N-mono(C1 to C6 alkyl)amine in the formula (1) Mercapto or N,N-di(C1-C6 alkyl)aminecarbamyl. The compound of claim 1 or a pharmacologically acceptable salt thereof, wherein the T1 group in the formula (i) is _c(=0)NH- (wherein the bond on the left side of the group is represented by Bonded to the base Q2). A compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein the base T2 group in the formula (I) is -CH2-CH2-C(=0)NH- (wherein the bond on the left side represents a bond) In the ring A). 10. The compound of claim 1, or a pharmacologically acceptable salt thereof, wherein the group Q3 in the formula (1) is 4-chlorophenyl, 4-1 phenyl, 4-oxaphenyl, 5-gasbiti-2 - group, 5-bromoindole. Ding-2-yl, 5-fluoroindene. Din-2-yl, 5-chloroindol-2-yl, 5-(&gt; oxazepine-2-yl or 5- gas oxenophen-2-yl. A compound or a pharmacologically acceptable salt thereof, which is selected from any one of the group consisting of 4-[2-(4-chlorophenylaminomethane)ethyl]_3 -[(5-isopropyl-4,5,6,7-tetrahydroindeno[5,4-c]bite-2-carbonyl)amino]benzoic acid, 4-[2-(5- Gasoline bit-2-ylamine-mercapto)ethyl]_-isopropyl-4,5,6,7-tetrahydrosine[5,4-c]bitone_2·yiyl)amine Benzoic acid, 4-{2-[(4-fluorophenyl)amine fluorenyl]ethyl b 3_[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5 , 4-c]pyridine-2-carbonyl)amino]benzoic acid, 4-[2-(5-athiophen-2-ylaminemethylindenyl)ethyl]_5_[(5-isopropyl-4, 5,6,7-tetrahydrothiazolo[5,4-(:]pyridine-2-carbonyl)amino]benzoic acid, 4-[2-(4-chlorophenylaminemethanyl)ethyl]-3 -[(5-methyl-5,6,7,8-tetrahydro- 411-° thiazepine [5,4-〇]1[3丫丁唆_2-weiki)amino]benzoic acid, 4-[2-(4&quot;· cleavage I phenylamine-mercapto)ethyl]-3-[(5-isopropyl-5,6,7,8-tetrahydro-4Ή-carbazolo[5 ,4-c]azetidine-2·carbonyl)amino]benzoic acid, 3_chloro-heart {2_[(cardochlorophenyl)amine-methylmethyl]ethyl}-5-[(5-isopropyl Base-4,5,6,7_four Hydroquinone 129677.doc 200840568 and [5,4-c] acridine-2-carbonyl)amino]benzoic acid, 3_gas-4_{2_[(4·chlorophenyl)amine A &amp;&amp; Ethyl}-5-[(5-methyl-4,5,6,7-tetrahydroindole[5,4_c]acridin-2-carbonyl)amino]benzoic acid, prochlorinated _4_ {2_[(4-fluorophenyl)amine-carbamoyl]ethyl b- 5-[(5-isopropyl-4,5,6, octahydrothiazolo[5,4-c]pyridine-2-carbonyl) Amino]benzoic acid, '{2-[(4-chlorophenyl)aminemethanyl]ethyl}-3-[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[ 5,4-c]pyridine-2-carbonyl)amino]-5-fluorobenzoic acid, 4_{2_[(4-chlorophenyl)aminemethanyl]ethyl b% [(5-isopropyl) -4,5,6,7-tetrahydrothiazolo[5,4-e]pyridine_2-carbonyl)aminopur-5-decyloxybenzoic acid, 4-{2-[(4-phenylene) Aminomethyl]ethylidene-3-yloxy_5-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl) Amino Benzoic acid, 4-{2·[(4-fluorophenyl)aminemethanyl]ethyl b 3_[(5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4_c Pyridinecarbonyl)amino]_5-methoxybenzoic acid and 4-{2-[(4-phenylphenyl)amine hydrazino]ethyl b 3_[(5-isopropyl-4,5,6 ,7·tetrahydrothiazolo[5,4-c Pyridine-2-carbonyl)amino]_5_(trifluoromethyl)benzoic acid. A pharmaceutical composition comprising a compound according to claim 1 or a pharmacologically acceptable salt thereof. An active clotting factor χ inhibitor composition comprising a compound according to any one of claims 1 to 11, or a pharmacologically acceptable salt thereof. A coagulation inhibitor composition comprising a compound according to any one of claims 丨 to 或其 or a pharmacologically acceptable salt thereof. A preventive and/or therapeutic composition for thrombus or embolism, which comprises a compound according to any one of claims 1 to 11 or a pharmacologically acceptable salt thereof. 1 6 · cerebral infarction, cerebral infarction, myocardial infarction, angina pectoris, pulmonary embolism, Bo 129677.doc 200840568 syndrome, deep vein thrombosis, systemic intravascular coagulation syndrome, prosthetic valve / joint replacement Thrombosis, thrombosis and reocclusion after revascularization, multiple organ dysfunction syndrome (MODS), thrombosis during in vitro circulation, or prophylactic and/or therapeutic composition of blood coagulation A compound according to any one of claims 1 to 3, or a pharmacologically acceptable salt thereof. 129677.doc 200840568 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please reveal the best indication of the characteristics of the invention. Chemical formula: 129677.doc129677.doc
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