TW200835687A - Thiazole derivatives and their use as VAP-1 inhibitor - Google Patents

Thiazole derivatives and their use as VAP-1 inhibitor Download PDF

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TW200835687A
TW200835687A TW096145523A TW96145523A TW200835687A TW 200835687 A TW200835687 A TW 200835687A TW 096145523 A TW096145523 A TW 096145523A TW 96145523 A TW96145523 A TW 96145523A TW 200835687 A TW200835687 A TW 200835687A
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phenyl
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Tatsuya Matsukawa
Kazuhiro Masuzaki
Noriyuki Yamamoto
Makoto Takewaki
Hiroyuki Tanaka
Yosuke Kawai
Sumiyo Yamamoto
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R Tech Ueno Ltd
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Abstract

This invention provides a compound represented by formula (1) or pharmaceutical acceptable salt thereof, which is useful as a VAP-1 inhibitor, pharmaceutical compositions, prophylactic or therapeutic medicine of VAP-1 related disorders such as macular edema and increase in vascular permeability and the like, R1-NH-X-Y-Z (I) (wherein, each symbol has the same meaning as it defined in the specification).

Description

200835687 九、發明說明： 【發明所屬之技術領域】 本發明係有關新穎之噻唑（thiazole)衍生物（後述之 j(i)所示化合物（以下，也稱為化合物（1))及其醫藥上所 谷許之鹽，以下，也將此等總稱為本發明之化合物）。此外， 本發明係有關：含有本發明之化合物作為活性成分之血管 黏附蛋白質4抑制劑、血管黏附蛋白質4相關疾病之預防 或治療用醫藥等。 ®【先前技術】 血管黏附蛋白質-l(vascular adhesi〇n protehd) (以下簡稱為VAP-1)係大量存在於人類血漿中之胺氧化酶 (^•mine oxidase)(半卡肼（semicarbazide)敏感性胺氧化 =，SSA0) ’且在發炎部位之血管内皮及血管平滑肌中，該 蛋白質之表現顯示顯著地增加。VApq之生理作用係至今 仍尚未解明，但已於1998年選殖出VAP」基因，此外，7已 •有報告VAP-1在炎性細胞激素（cyt〇kine)表現的調控下， 調控作為黏附分子之淋巴球及NK細胞之滾動（r〇uing)及 遷移（nngration)之膜蛋白質。作為基質之胺雖係未知，但 咸認為在生物體内之任何部位所生成之甲基胺。此外也已 知起因於分子中之胺氧化酶活性而產生之過氧化氫及藤為 黏附活性之重要因子。 ，在最近之報告中已證實，血漿中之MP4酵素活性在 I型或II型之任一型之糖尿病患者中血漿中之酵素 活f生也i曰加，且此增加在罹患視網膜病變併發症之糖尿病 319771 5 200835687 患者中特別顯著（Diabetologia，42(1 999)233-237(非專 利文獻 1)，Diabetes Medicine，16(1999)514-521(非專 利文獻2))。 並且’已有報告VAP-1係與以下（1)至（6)之疾病相 關··（1)肝硬化、原發性固定性高血 stabilized hypertension)、糖尿病、動脈硬化（參照日本 特開昭61-239891號公報（專利文獻丨）及美國專利第 鲁4, 888, 283號說明書（專利文獻2)) ; (2)(糖尿病、動脈硬 化及高血壓之）内皮損傷、糖尿病及***相關之心血管疾 病、痛風及關節炎相關之疼痛、（糖尿病患者之）視網膜病 變（參照國際公開第1 993//23〇23號小冊（專利文獻3))，· (3)(結缔組織之）炎性疾病或症狀（類風濕性關節炎、僵直 生脊椎炎、乾癬性關節炎及骨關節炎或退化性關節疾病、 莱特氏（Reiter’s)症候群、修格蘭氏（Sj〇gren，s_)症候群、 貝塞特氏（Behcet’s)症候群、復發性多軟骨炎（”丨叩“叩 _ polychondritis)、全身性紅斑性狼瘡、圓盤狀紅斑性狼 瘡、、全身性硬化症、嗜酸性筋膜炎、多發性肌炎、皮肌炎、 風濕性多肌痛症、血管炎、暫時性關節炎、結節性多動脈 炎、韋格納氏（Wegener，s)肉芽腫病、混合結締組織疾病、 及幼年型類風濕性關節炎）；消化管之炎性疾病或症狀[克 隆氏（Cr〇hn，S)病、潰瘍性大腸炎、腸躁症（irritable bowel syndrome)(痙攣性結腸）、肝臟之纖維化、口腔黏膜 之發炎(口内炎)及復發性口瘡口内炎];中樞神經系統之炎 性疾病或症狀（多發性硬化症、阿滋海默αΐζΜ· 319771 6 200835687 Μ ，：狀血再灌流障礙);肺炎性疾病或 十而、呼吸君迫症候群、慢性阻塞性肺疾病）；（慢 ，之皮膚之炎性疾病或症狀（乾癖、過敏性病變、扁 癬、玫魂糠療（pityrlasis rosea)、接觸性皮膚炎、里: 性皮膚炎、毛囊性紅色糠療（pityriasis rubra[Technical Field] The present invention relates to a novel thiazole derivative (hereinafter referred to as a compound represented by j(i) (hereinafter, also referred to as a compound (1)) and a pharmaceutical thereof The salt of the glutinous rice, hereinafter, is also collectively referred to as the compound of the present invention). Further, the present invention relates to a vascular adhesion protein 4 inhibitor containing the compound of the present invention as an active ingredient, a vascular adhesion protein 4-related disease prevention or therapeutic medicine, and the like. ® [Prior Art] vascular adhesi〇n protehd (hereinafter referred to as VAP-1) is a large amount of amine oxidase (^mine oxidase) (semicarbazide) sensitive in human plasma. The amines oxidized =, SSA0) 'and the expression of the protein showed a significant increase in the vascular endothelium and vascular smooth muscle of the inflamed site. The physiological role of VApq has not yet been elucidated, but the VAP gene was selected in 1998. In addition, it has been reported that VAP-1 regulates adhesion as an inflammatory cytokine (cyt〇kine). Membrane proteins of the lymphocytes of the molecule and the rolling and nucleation of NK cells. Although the amine as a matrix is unknown, it is considered to be a methylamine formed in any part of the living body. In addition, hydrogen peroxide and rattan which are produced by the amine oxidase activity in the molecule are also important factors for adhesion activity. In recent reports, it has been confirmed that the activity of MP4 enzyme in plasma is also increased in the plasma of patients with type I or type II diabetes, and this increase in the complications of retinopathy Diabetes 319771 5 200835687 Among patients, it is particularly remarkable (Diabetologia, 42 (1 999) 233-237 (Non-Patent Document 1), Diabetes Medicine, 16 (1999) 514-521 (Non-Patent Document 2)). And 'the VAP-1 system has been reported to be related to the following diseases (1) to (6). (1) Liver cirrhosis, primary fixed blood (stabilized hypertension), diabetes, arteriosclerosis (refer to Japan Special Open Publication No. 61-239891 (Patent Document No.) and US Patent No. 4,888,283 (Patent Document 2)); (2) (Diabetes, Arteriosclerosis, and Hypertension) related to endothelial injury, diabetes, and uremia Cardiovascular disease, pain associated with gout and arthritis, retinopathy (of diabetic patients) (refer to International Publication No. 1 993//23〇23 (Patent Document 3)), (3) (Connective tissue) Inflammatory diseases or symptoms (rheumatoid arthritis, stiff vertebral inflammation, dry arthritis and osteoarthritis or degenerative joint disease, Reiter's syndrome, Sylvia (Sj〇gren, s_) Syndrome, Behcet's syndrome, recurrent polychondritis ("丨叩" polychondritis), systemic lupus erythematosus, discoid lupus erythematosus, systemic sclerosis, eosinophilic fascia Inflammation, polymyositis, Myositis, rheumatic polymyalgia, vasculitis, temporary arthritis, nodular polyarteritis, Wegener's granulomatosis, mixed connective tissue disease, and juvenile rheumatoid arthritis Inflammatory diseases or symptoms of the digestive tract [Cr〇hn (S) disease, ulcerative colitis, irritable bowel syndrome (sputum colon), fibrosis of the liver, inflammation of the oral mucosa ( Endophthalmitis) and recurrent aphthous stomatitis]; inflammatory diseases or symptoms of the central nervous system (multiple sclerosis, Azheimer's alpha 3 319771 6 200835687 Μ, : blood reperfusion disorder); pneumonia disease or Respiratory syndrome, chronic obstructive pulmonary disease); (slow, inflammatory disease or symptoms of the skin (dry, allergic disease, phlegm, pityrlasis rosea, contact dermatitis, in: Dermatitis, hair follicle red spasm (pityriasis rubra)

Pilaris));包括微血管及大血管之疾病(動脈硬化、血管 視網膜病變、視網膜病變、腎病、腎病（nephr〇sis)症候群 及神經障礙（多發性神經障礙、單一神經障礙及自律神經障 礙）、足潰瘍、關節之問題及感染風險之增加）之碳水化合 物代謝相關疾病（糖尿病及來自糖尿病之併發症）；脂肪2 胞之分化或機能或者平滑肌細胞之機能之異常相關之疾病 (動脈硬化及肥大）；血管疾病[包括動脈粥狀硬化、非動脈 粥狀硬化、心肌梗塞及周邊動脈阻塞之缺血性心臟疾病、 雷諾氏（Raynaud，s)症及雷諾氏現象、阻塞性血栓性血管炎 (柏格氏（Buerger，s)症）];慢性關節炎；炎性腸疾病；皮 φ膚病（參照國際公開第2 0 0 2 / 0 2 0 9 0號小冊（專利文獻4 )、 國際公開第2002/ 02541號小冊（專利文獻5)及美國專利 申請公開第2002/ 0173521號公報（專利文獻6)) ; (4)糖 尿病（參照國際公開第2002/38152號小冊（專利文獻 7) );以及（5) SSAO媒介併發症[糖尿病（胰島素依賴型糖 尿病（IDDM)及非胰島素依賴型糖尿病（NIDDM))及血管併發 症（心臟病發作、狹心症、中風、切除、失明及腎功能不 全）](參照國際公開第2002/38153號小冊（專利文獻 8) );( 6)血管通透性亢進疾病[老年性黃斑部退化、老年性 319771 200835687 ，盤狀黃斑部退化、囊狀黃斑部水腫、眼瞼水腫、視網臈水 腫、糖尿病性視網膜病變、脈絡視網膜病變、新生血管忡 黃斑部病變、新生血管性青光眼、葡萄膜炎、虹膜炎、視 網膜血管炎、眼内炎、全眼球炎、轉移性眼炎、脈絡膜炎、 視網膜色素上皮炎、結膜炎、睫狀體炎、鞏膜炎、上鞏膜 火、視神經炎、球後視神經炎、角膜炎、眼瞼炎、滲出性 視網膜剝離、角膜潰瘍、結膜潰瘍、慢性錢幣狀角膜炎、 塞格森氏角膜炎（Thyges〇n，s keratitis)、進行性侵蝕性 角膜潰瘍（Mooren’s ulcer)、由細菌感染或病毒感染及由 眼科手術引起之眼炎性疾病、由眼睛之物理性損傷引起之 眼炎性疾病、由包括癢、發紅、水腫及潰瘍之眼炎性疾病 引起之症狀、紅斑、多形性滲出性紅斑、結節性紅斑、環 狀紅斑、硬腫症、皮膚炎、血管神經病性水腫、咽喉水腫、 聲門水踵、聲門下咽喉炎、支氣管炎、/鼻炎、咽喉炎、鼻 竇炎及咽喉炎或中耳炎](參照國際公開第2〇〇4/〇87138 號小冊（專利文獻9))等。 在國際公開第2004/067521號小冊（專利文獻丨〇)、 國際么開第2004/087138號小冊（專利文獻9)、國際公開 第2006/01 1631號小冊（專利文獻丨丨）及國際公開第2〇〇6 /028269號小冊（專利文獻12)中係記載有具有特定構造 之噻唑衍生物，且記載有使用於黃斑部水腫和血管通透性 宄進疾病等VAP-1相關疾病之預防或治療。 在具有國際公開第2004/067521號小冊（專利文獻 10)、國際公開第2004/087138號小冊（專利文獻9)及國 319771 8 200835687 ，IV、a開第2006/028269號小冊（專利文獻12)中所記载之 特定構造之㈣衍生物中，在概念上也包含分子末端且有 胖基(山或肼基幾基之化合物。然而，關於此等分 子末而:、有肼基或肼基幾基之化合物，並無具體之揭示（實 施例）或教示，且有關SSAO抑制活性或安全性等藥理活性 等也無具體之揭示或教示。 [專利文獻1]日本特開昭61-239891號公報 鲁 [專利文獻2]美國專利第4,888, Mg號說明書 [專利文獻3]國際公開第1 993/23023號小冊 [專利文獻4]國際公開第2002/ 02090號小冊 [專利文獻5]國際公開第2002/02541號小冊 [專利文獻6]美國專利申請公開第2〇〇2/〇17352ι號 公報 [專利文獻7]國際公開第2〇〇2./38152號小冊 [專利文獻8]國際公開第2002/38153號小冊 _ [專利文獻9]國際公開第2〇〇4//〇87138號小冊 [專利文獻1〇]國際公開第2〇〇4//〇67521號小冊 [專利文獻11]國際公開第2006/ 01 1631號小冊 [專利文獻12]國際公開第2006/ 028269號小冊 [非專利文獻 l]Diabet〇i〇gia，42(1999)233-237 [非專利文獻 2]Diabetes Medicine，16(1999) 514-521 【發明内容】 (發明欲解決的課題） 9 319771 200835687 .麵 ^ 本發明係以提供有用於作為VAP-1抑制劑、yAp-i相 關疾病之預防及治療用醫藥等之新穎噻唑衍生物為目的。 (解決課題的手段） 本發明人等係致力研究後，結果發現分子末端具有特 疋S此基（肼基或肼基幾基）之σ塞嗤衍生物具有優良之 VAP-1抑制作用，且酵素選擇性優良並可排除令人擔心之 副作用，再進一步進行研究，才完成本發明。 因此，本發明係如下述。 籲（1)式（I)所示之化合物或其醫藥上所容許之鹽 R1—ΝΗ—X—Υ一ζ (I) [式中， R1係醮基； X係從可經取代之噻唑所衍生之二價殘基； - Υ 係式（111) · J—L—M (III) 式中，J係鍵結、低級伸烷基、低級伸烯基、低級伸 炔基、-(CH2)n_0-、-(CH2)n-丽-、—（CH2)n-C0-、或 -(CH2)n-S〇2-（各式中，n表示〇至6之整數）； L 係鍵結、-NH-、-C0-、或-S〇2-； Μ係鍵結、低級伸烷基、低級伸烯基、或低級伸炔基·， 惟’當 J 為-(CH2)n-〇-時，l 不為——丽-及-S〇2-， 當J為-（CH2)n-丽-時，L不為及—丽-，當J為 -（CH2)n-C0-時，L 不為-c〇-，當 J 為_(CH2)n-S〇2-時， L不為-0-及-S〇2-(各式中，n係表示與上述同義）]; 319771 10 200835687 Z係式（11) " A一B—D—E (II) {式中，A係從苯所衍生之二價殘基、或從售吩 (thiophene)所衍生之二價殘基； B 係-NR2-C0—-（CH2)n-、或-（CH2)n-C0-(各式中，r2 係氫、低級烧基、或酿基；η表示0至6之整數）； D係-NR3-(式中，R3表示氫、低級烷基、烷氧基羰基、 或醯基）； E表示可經取代之胺基]}。 (2)前述式（I)所示化合物係n-{4-[2-(4-肼基羰基苯基） 乙基]-1，3-嗟嗤-2-基}乙醯胺、 N-{4-[2-（4-肼基羰基甲基苯基）乙基]-1，3 —噻唑一2一 基}乙醯胺、 (4-{2-[4-（Ν’-曱基肼基羰基曱基）苯基]乙基}… 一1，3-噻唑-2-基）乙醯胺、 • Ν—(4Μ2-[4-(Ν-曱基肼基羰基甲基）苯基]乙基卜υ -嗟唑-2-基）乙醯胺、 ^(4一{2-[4-(1^’-乙基肼基羰基曱基）苯基]乙基}- 1，3-嗟唾—2 -基）乙醯胺、 Ν-(4〜{2 - [4-(Ν’，Ν’ -二甲基肼基羰基甲基）苯基]乙 基卜1，3-噻唑-2-基）乙醯胺、 〜[2-（4-肼基羰基甲基苯基）乙基]-5-（4-胺石黃醯 基笨甲基）-1,3-噻唑-2-基}乙醯胺、 NH{2-[4-（2-肼基羰基乙基）苯基]乙基}-1，3-噻 11 319771 200835687 哇-2-基）乙醯胺、 4-（4-{2-[2-（乙酿基胺基）-1，3-σ塞唾-4-基]乙基}苯 基）半卡肼、 Ν -（4-{2-[4-(Ν’ -乙醯基肼基羰基甲基）苯基]乙基} -1，3-噻唑-2-基）乙醯胺、 Ν -（4 - {2-[4-(Ν’ - 丁醯基肼基羰基甲基）苯基]乙基} -1，3 -嗟嗤-2-基）乙酿胺、 Ν-(4-{2-[4-（Ν’ -癸醯基肼基羰基甲基）苯基]乙基} 鲁 -1，3 -喧唾-2 -基）乙酸胺、 Ν-[4-（2-{4-[Ν’ -（3-羥基丙醯基）肼基羰基曱基]苯 基}乙基）-1，3-噻唑-2-基]乙醯胺、 1^-[4-（2-{4-[1^’-（6-羥基己醯基）肼基羰基甲基]苯 基}乙基）-1，3-噻唑-2-基]乙醯胺、 2-[(4-{2-[2-(·乙醯基胺基）-1，3-噻唑-4-基]乙基} 苯基）乙酸基]骄叛酸乙醋、 _ 2-[ (4-{2-[ 2-（乙醯基胺基）-1，3-嗟哇-4-基]乙基} 苯基）乙酸基]拼叛酸丁醋、 2-[(4-{2-[2-(乙·基胺基）-1，3-嗟嗤-4-基]乙基} 苯基）乙酿基]拼缓酸癸S旨、 2-[(4-{2-[2-(乙醯基胺基）-1，3-噻唑-4-基]乙基} 苯基）乙醯基]肼羧酸2-羥乙酯、 2-乙醯基胺基-1，3-噻唑-4-叛酸4-（肼基羰基甲基） 苯酯、 Ν-(4-{[4-(肼基羰基甲基）苯氧基]甲基卜i，3一噻唑 12 319771 200835687 - 2 -基）乙醯胺、 2-（乙醯基胺基）-N-[4-(肼基羰基曱基）苯基；μl 3一 嗟嗤-4-甲酸胺、 N-[4-（{[4-(肼基羰基甲基）苯基]胺基}甲基）-!，3一 噻唑-2-基]乙醯胺、 N - {4 - [2 -（3-肼基幾基甲基苯基）乙基]一 1，3一嗟a坐一2- 基}乙醯胺、 1^-（4-{2-[5-（肼基羰基）噻吩-2-基]乙基}一1，3-嗟唑 鲁 -2-基)乙醯胺、 N -（4-{2-[5-(肼基羰基曱基）噻吩一 2-— 噻唑-2-基）乙醯胺、 N-（4-{2-[5-(2-肼基幾基乙基）嗔吩—2-基]乙基} -1，3-噻唑-2-基）乙醯胺、 N-（4-{2-[5-(2-肼基幾基乙基）嗟吩-3-基]-乙基} -1，3_°塞峻-2-基）乙酸胺、 _ N-{4-[2-(4-肼基苯基）乙基]-1，3-噻唑一2-基}乙醯 胺、 N-（4-{2-[4-(肼基甲基）苯基]乙基卜丨，3 —噻唑—2-基） 乙酸胺、 N-（4-{2-[4-(2-肼基乙基）苯基]乙基卜1，3一噻唑-2- 基）乙醯胺、 N-(4-{2_[4-(3-肼基丙基）苯基]乙基卜1，3 —12塞嗤一2一 基）乙酿胺、 N-（4-{2-[3-(2-肼基乙基）苯基]乙基}一1，3 —嗟唾一2— 319771 13 200835687 基）乙醯胺、 N-(4-{2-[5-(2-肼基乙基）噻吩-2 —基]乙基} — ；[，3一噻 唑-2-基）乙醯胺、或 N-（4-{2-[5-(3-肼基丙基）噻吩—2-基]乙基卜丨，3一噻 唑-2-基）乙醯胺之如上述（u之化合物、或其醫藥上 所容許之鹽。 (3)前述式（I)所示之化合物係N—丨4_[2 —(4 —肼基羰基甲 基苯基）乙基]-1，3-噻唑-2-基丨乙醯胺之如上述（1) 之化合物、或其醫藥上所容5許之鹽。 (4) 作為醫藥使用之如上述（1)至（3)中任一項之化合 物、或其醫藥上所容許之鹽。 (5) 含有上述（1)至（3)中任一項之化合物或其醫藥上所 容許之鹽作為活性成分之醫藥組成物。 (6) 含有上述（1)至（3)中任一項之化合物或其醫藥上所 容許之鹽作為活性成分之VAP-1抑制劑。 _⑺$有上述⑴至⑶中任一項之化合物或其醫藥上所 容許之鹽作為活性成分之V A P -1相關疾病之預防或治 8)則述VAP-1相關疾病係黃斑部水腫（糖尿病性及非j $病黃斑部水腫）、老年性黃斑部退化、老年性盤| 更斑部退化、囊狀黃斑部水腫、眼瞼水腫、視網膜 腫、糖尿病性視網膜病冑、脈絡視網膜病變、新生 官性黃斑部病變、新生血管性青光眼、葡萄 膜炎、視網膜血管炎、眼内炎、全眼球炎、轉ς 319771 14 200835687 絡膜炎、視網膜色素上皮炎、結膜炎、目走狀體 革膜炎、上鞏膜炎、視神經炎、球後視神經炎、 角膜炎、眼臉炎、渗出性視網膜_、角膜潰瘍、& 膜：瘍、慢崎狀角膜炎、塞格森氏角膜炎、進： 2钱性角膜潰瘍、由細菌感染或病毒感染及由眼科 ::丨起之眼火性疾病、由眼睛之物理性損傷引起之 目、人生疾病、由包括瘪、發紅、水腫及潰瘍之眼炎性 疾病⑽之症狀、紅斑、多形性渗出性紅斑、結節性 ::斑广狀紅斑、硬腫症、皮膚炎(乾癬、過敏性病 扁平！癬、玫瑰糠療、接觸性皮膚炎、異位性皮 胃人毛* !·生紅色糠療）、血管神經病性水腫、咽喉 水腫、聲門水腫、聲門下咽喉炎、支氣管炎、鼻炎、、 =:!厂寶炎及，侯炎或中耳炎、肝硬化、原發性 尿病、動脈硬化、(糖尿病、動脈 硬：=厂堅之)内皮損傷、糖尿病及***相關之 痛風及關節炎相關之疼痛.、結缔組織之 火性疾病或症狀（類風濕㈣節炎、僵直性 乾癬性闕節炎及骨關節炎或退化性關節疾病、菜特氏 症候群、修袼蘭氏症候群、狀Μη/讀氏 多軟骨炎、全身性紅斑性狼瘡：“：:、群、復發性 全身性硬化症、錢㈣料、I性狼瘡、 風濕性多喻、血 =炎、拿格納氏肉芽腫病、混合結締組織 幼年型類風濕性瞻）；消化管之… 319771 15 200835687 •[克隆氏病、潰瘍性大腸炎、腸躁症（痙攣性結腸）、 肝臟之纖維化、口腔黏臈之發炎（口内炎及復發性口 瘡内人）]，中樞神經系統之炎性疾病或症狀（多發 性硬化症、阿滋海默症、及缺血性中風相關之缺血再 灌流障礙）；肺炎性疾病或症狀（氣喘、成人呼吸窘迫 症候群、慢性阻塞性肺疾病）；包括微血管及大血管 之疾病（動脈硬化、視網膜病變、腎病、腎病症候群 及神經障礙（多發性神經障礙、單一神經障礙及自律 神Μ早礙）、足潰瘍、關節之問題及感染風險之增加） 之石反水化合物代謝相關疾病（糖尿病及來自糖尿病之 併發症）’·月旨肪細胞之分化或機能或者平滑肌細胞之 機能之異常相關之疾病（動脈硬化及肥大）；血管疾病 [包括動脈粥狀硬化、非動脈粥狀硬化、心肌梗塞及 " 周邊動脈阻塞之缺血柹V、艇、t ^ 趼性u贓疾病、雷諾氏症及雷諾氏 ^象阻基性血栓性血管炎（柏格氏症慢性關節 ^炎性腸疾病；或咖媒介併發症[糖尿病（胰島 素依麵型糖尿病（1_及非胰島素依賴型糖尿病 (NI醜))及血管併發症(心臟病發作、狹心症、中風、 切除、失明及腎功能不全）]之如⑺之VMM相關疾 病之預防或治療用醫藥。 W用於製造作為VAP_w_之醫藥之如上述⑴至 中任二:之化合物、或其醫藥上所容許之鹽之使用。 、於I造VAP-1相關疾病之預防或'治療用醫藥之如上 述⑴至⑶中任一項之化合物、或其醫藥上所容許之 319771 16 200835687 鹽之使用。 (11)丽述VAP-1相關疾病係黃斑部水腫（糖尿病性及非糖 尿病黃斑部水腫）、老年性黃斑部退化、老年性盤狀 黃斑部退化、囊狀黃斑部水腫、眼瞼水腫、視網膜水 腫、糖尿病性視網膜病變、脈絡視網膜病變、新生血 管性黃斑部病變、新生血管性青光眼、葡萄膜炎、虹 膜炎、視網膜血管炎、眼内炎、全眼球炎、轉移性眼 炎、脈絡膜炎、視網膜色素上皮炎、結膜炎、睫狀體 炎:鞏膜炎、上鞏膜炎、視神經炎、球後視神經炎、 角膜炎、眼驗炎、-滲出性視網膜剝離、角膜潰癌、結 膜潰癌、慢性錢帶狀角膜炎、塞格森氏角膜炎、進: 性侵餘性角膜潰瘍、由細菌感染或病毒感染及由眼科 手術引起之眼炎性疾病、由眼睛之物理性損傷引起之 眼炎性疾病、由包括疼、.發紅、水腫及潰癌之眼炎性 疾病引起之症狀、紅斑、多形性滲出性紅斑、結節性 紅斑、環狀紅斑、硬腫症、皮膚炎（乾癬、過敏性病 變、扁平苔癬、玫魂糠疹、接觸性皮膚炎、異位性皮 膚火、毛囊性紅色糠疹）、血管神經病性水腫、咽喉 水腫、聲門水腫、聲門下咽喉炎、支氣管炎、鼻炎、、 咽喉炎、鼻竇炎及咽喉炎或中耳炎、肝硬化、原發性 固定性高血壓、糖尿病、動脈硬化、（糖尿病、動脈 硬化及高血麼之）内皮損傷、糖尿病及***相關之 心血管疾病、痛風及關節炎相關之疼痛、結締組織之 炎性疾病或症狀（類風濕性關節炎、僵直性脊椎炎、 319771 17 200835687 乾癬性關節炎及骨關節炎或退化性關節疾病、菜 =、修格蘭氏症候群、貝塞特氏症候群、復發性 夕軟骨炎、全身性紅斑性狼瘡、圓盤狀紅斑性狼瘡、 化症、嗜酸性筋膜炎、多發性肌炎、皮肌炎、 =夕肌痛症、血管炎、暫時性關節炎、結節性多 =、章格納氏肉芽腫病、混合結締組織疾病、： 年1類風濕性關節炎）；消化管之炎性疾病或症狀 克氏病、潰瘍性大腸炎、腸躁症（痙攣性結腸）、 肝臟之纖維化、Π㈣膜之發炎（口内炎及復發性口 口内炎)];中枢神經系統之炎性疾病或症狀(多發 症、阿滋海默症、及缺血性中風相關之缺血再 准4礙）’·肺炎性疾病或症狀（氣喘、成人啤吸窘迫 症候群、慢性阻塞性肺疾病）；包括微血管及大血管 之疾病(動脈硬化、-視網膜病變、腎病、腎病 障礙（多發性神經障礙、單一神經障礙及自律 子經障礙）、足潰瘍、關節之問題及感染風險之增加） 之碳水化合物代謝相關疾病（糖尿病及來自糖尿病之 :發症）；腊肪細胞之分化或機能或者平滑肌細胞之 4’月b之異系相關之疾病（動脈硬化及肥大）；血管疾病 包括動脈粥狀硬化、非㈣絲硬化、錢梗夷及 周邊動脈阻塞之缺血性心臟疾病、雷諾氏症及詩氏 ，象、、阻塞性血栓性血管炎（柏格氏症）]，·慢性關節 :，炎性腸疾病；或SSA0媒介併發症[糖尿病（姨島 素依賴型糖尿病（麵)及非胰島素依賴型糖尿病 319771 18 200835687 (NIDDM))及血管併取、广r ， UE (心臟病發作、狹心症、中風、 切除、失明及腎功能不 卜王）」之如上述（1〇)之使用。 (12) 包括將上述（1)至（3)中 吃 項之化合物、或其醫藥上 所容許之鹽之有效晋#工^ & ^又予對象之於該對象之VAP-1之 抑制方法。 (13) = :上：⑴至(3)中任—項之化合物、或其醫藥上 所谷許之鹽之有效量投予對象之於該對象之ΜΗ相 關疾病之預防或治療方法。 (14) 前述VAP-1相關旅、忘在廿 ^ 關疾病係頁斑部水腫（糖尿病性及非糖 ，病η斑#水腫）、老年性黃斑部退化、老年性盤狀 黃斑部退化、囊狀黃斑部水腫、眼驗水腫、視網膜水 腫、糖尿病性視網膜病變、脈絡視網膜病變、新生血 管性黃斑部病變、新生血管性青光眼、葡萄膜炎、虹 膜炎、視網膜血管炎、眼内炎、全眼球炎、轉移性眼 炎、脈絡膜炎、視網膜色素上皮炎、結膜炎、睫狀體 火:鞏膜炎、上鞏膜炎、視神經炎、球後視神經炎、 角膜炎、眼驗炎、滲出性視網膜剝離、角膜潰廣、結 膜潰瘍、慢性錢幣狀角膜炎、塞格森氏角膜炎、進^ 性侵钱性角膜潰瘍、由細菌感染或病毒感染及由眼科 手術引起之眼炎性疾病、由眼睛之物理性損傷引起之 眼炎性疾病、由包括癢、發紅、水腫及潰瘍之眼炎性 疾病引起之症狀、紅斑、多形性滲出性紅斑、結節性 紅斑、環狀紅斑、硬腫症、皮膚炎（乾癬、過敏性病 變、扁平苔癬、玫瑰糠疹、接觸性皮膚炎、異位性皮 319771 19 200835687 膚炎、毛囊性紅色糠療）、血管神經病性水腫、咽喉 水腫、聲門水腫、聲門下咽喉炎、支氣管炎、鼻炎、 咽喉炎、鼻竇炎及咽喉炎或中耳炎、肝硬化、:發性 固定性高血壓、糖尿病、動脈硬化、（糖尿病、動脈 硬化及高血壓之）内皮損傷、糖尿病及***相關之 血管疾病、痛風及關節炎相關之疼痛、結缔組織之 炎性疾病或症狀（類風濕性關節炎、僵直性 /、Pilaris)); diseases including microvascular and macrovascular (arteriosclerosis, vascular retinopathy, retinopathy, nephropathy, nephr〇sis syndrome and neurological disorders (multiple neurological disorders, single neurological disorders and autonomic nervous disorders), feet Carbohydrate metabolism-related diseases (diabetes and complications from diabetes); fat 2 cell differentiation or function or abnormal function of smooth muscle cells (arteriosclerosis and hypertrophy) Vascular disease [including atherosclerosis, non-atherosclerosis, ischemic heart disease with myocardial infarction and peripheral arterial occlusion, Raynaud's disease and Raynaud's phenomenon, obstructive thrombotic vasculitis (cypress (Buerger, s)]; chronic arthritis; inflammatory bowel disease; skin φ skin disease (refer to International Publication No. 2 0 0 2 0 0 0 0 0 (Patent Document 4), International Disclosure Booklet No. 2002/02541 (Patent Document 5) and US Patent Application Publication No. 2002/0173521 (Patent Document 6)); (4) Diabetes (refer to International Corporation) Volume 2002/38152 (Patent Document 7); and (5) SSAO vector complications [diabetes (insulin dependent diabetes mellitus (IDDM) and non-insulin dependent diabetes mellitus (NIDDM))) and vascular complications (heart attack) , angina, stroke, resection, blindness, and renal insufficiency)] (Refer to International Publication No. 2002/38153 (Patent Document 8)); (6) Vascular hyperreactivity disease [Degeneration of age-related macular degeneration, Senile 319771 200835687, discoid macular degeneration, cystic macular edema, orbital edema, retinal edema, diabetic retinopathy, choroidal retinopathy, neovascularization, macular degeneration, neovascular glaucoma, uveitis, Iris, retinal vasculitis, endophthalmitis, total ocular inflammation, metastatic ophthalmia, choroiditis, retinal pigment epitheliitis, conjunctivitis, ciliary body inflammation, scleritis, upper scleral fire, optic neuritis, retrobulbar optic neuritis, Keratitis, orbital inflammation, exudative retinal detachment, corneal ulcer, conjunctival ulcer, chronic coin keratitis, Szegen's keratitis (Thyges〇n, s keratitis ), Mooren's ulcer, bacterial infection or viral infection, ocular inflammatory disease caused by ophthalmic surgery, ocular inflammatory disease caused by physical damage of the eye, including itch, redness, Symptoms caused by inflammatory diseases of edema and ulcers, erythema, polymorphous exudative erythema, nodular erythema, annular erythema, scleredema, dermatitis, angioedema, edema, vocal edema, subglottic Pharyngitis, bronchitis, / rhinitis, pharyngitis, sinusitis, and pharyngitis or otitis media (refer to International Publication No. 2/4, 87, 138 (Patent Document 9)). In International Publication No. 2004/067521 (Patent Document 丨〇), International Publication No. 2004/087138 (Patent Document 9), International Publication No. 2006/01 1631 (Patent Document 丨丨) and In the pamphlet of International Publication No. 2-6/028269 (Patent Document 12), a thiazole derivative having a specific structure is described, and VAP-1 associated with macular edema and vascular hyperpermeability is described. Prevention or treatment of the disease. In International Publication No. 2004/067521 (Patent Document 10), International Publication No. 2004/087138 (Patent Document 9), and National 319771 8 200835687, IV, a, No. 2006/028269 (Patent) Among the (four) derivatives of the specific structure described in the document 12), a compound having a molecular terminal and a fat group (mountain or fluorenyl group) is conceptually included. However, with respect to these molecules, there are sulfhydryl groups. The compound of the thiol or the thiol group is not specifically disclosed (example) or teaching, and the pharmacological activity such as SSAO inhibitory activity or safety is not specifically disclosed or taught. [Patent Document 1] Japanese Patent Laid-Open No. 61 -239891 Bulletin [Patent Document 2] U.S. Patent No. 4,888, Mg Specification [Patent Document 3] International Publication No. 1 993/23023 Booklet [Patent Document 4] International Publication No. 2002/02090 Booklet [Patent Document 5] International Publication No. 2002/02541 (PATENT DOCUMENT 6) US Patent Application Publication No. 2〇〇2/〇17352ι [Publication Document 7] International Publication No. 2〇〇2./38152 Booklet [Patent Document 8] International Publication No. 2002/38153 Booklet_ [Patent Document 9] International Book 2〇〇4//〇87138 booklet [Patent Document 1〇] International Publication No. 2〇〇4//〇67521 Booklet [Patent Document 11] International Publication No. 2006/ 01 1631 Booklet [Patent Document 12] International Publication No. 2006/028269 (Non-Patent Document 1) Diabet〇i〇gia, 42 (1999) 233-237 [Non-Patent Document 2] Diabetes Medicine, 16 (1999) 514-521 [Summary Contents] (Problem to be solved by the invention) 9 319771 200835687. The present invention is intended to provide a novel thiazole derivative for use as a VAP-1 inhibitor, a yAp-i-related disease for prevention and treatment, and the like. The inventors of the present invention, after intensively researching, found that the sigma sputum derivative having a thiol group at this molecular end has excellent VAP-1 inhibitory action and enzyme selection. The present invention can be completed by further research and further investigation. The present invention is as follows. The compound represented by the formula (I) or the pharmaceutically acceptable salt thereof is claimed. —ΝΗ—X—Υ一ζ (I) [wherein, R1 is a sulfhydryl group; X is a substitutable a divalent residue derived from thiazole; - oxime (111) · J-L-M (III) wherein, a J-bond, a lower alkyl, a lower alkenyl group, a lower alkynyl group, (CH2)n_0-, -(CH2)n-Li-, -(CH2)n-C0-, or -(CH2)nS〇2- (in each formula, n represents an integer from 〇 to 6); a knot, -NH-, -C0-, or -S〇2-; a lanthanide bond, a lower alkylene group, a lower alkenyl group, or a lower alkynyl group, but when J is -(CH2)n- 〇-, l is not - Li- and -S〇2-, when J is -(CH2)n-Li-, L is not - Li-, when J is -(CH2)n-C0- When L is not -c〇-, when J is _(CH2)nS〇2-, L is not -0- and -S〇2- (in each formula, n is synonymous with the above)]; 319771 10 200835687 Z series (11) " A-B-D-E (II) {wherein, A is a divalent residue derived from benzene or a divalent residue derived from thiophene B series -NR2-C0--(CH2)n-, or -(CH2)n-C0- (in each formula, r2 is hydrogen, lower alkyl or aryl; η represents an integer from 0 to 6); D-R-NR3- (wherein R3 represents hydrogen, lower alkyl, alkoxycarbonyl, or fluorenyl); The amino may be substituted]}. (2) The compound represented by the above formula (I) is n-{4-[2-(4-mercaptocarbonylphenyl)ethyl]-1,3-indol-2-yl}acetamide, N- {4-[2-(4-Mercaptocarbonylmethylphenyl)ethyl]-1,3-thiazole-2-yl}acetamide, (4-{2-[4-(Ν'-fluorenyl) Mercaptocarbonyl fluorenyl)phenyl]ethyl}... 1,3-thiazol-2-yl)acetamide, • Ν—(4Μ2-[4-(Ν-fluorenylcarbonylcarbonyl)phenyl) Ethyl dioxime-carbazol-2-yl)acetamide, ^(4-{2-[4-(1^'-ethylmercaptocarbonylcarbonyl)phenyl]ethyl}- 1,3 - 嗟 — - 2 -yl) acetamidine, Ν-(4~{2 - [4-(Ν', Ν'-dimethylcarbonylcarbonylmethyl)phenyl]ethyl 1,3-thiazole -2-yl) acetamamine, ~[2-(4-mercaptocarbonylmethylphenyl)ethyl]-5-(4-amine fluorenylmethyl)-1,3-thiazol-2-yl }Acetamine, NH{2-[4-(2-mercaptocarbonylethyl)phenyl]ethyl}-1,3-thia 11 319771 200835687 wow-2-yl)acetamide, 4-(4 -{2-[2-(Ethylamino)-1,3-σ-Sep-4-yl]ethyl}phenyl)-semicarbazide, Ν-(4-{2-[4-(Ν '-Ethyl decylcarbonylmethyl)phenyl]ethyl}-1,3-thiazol-2-yl)B Indoleamine, Ν-(4 - {2-[4-(Ν'-butyl-decylcarbonylmethyl)phenyl]ethyl}-1,3-indol-2-yl)ethinamide, Ν-( 4-{2-[4-(Ν'-fluorenylcarbonylmethyl)phenyl]ethyl} ruthenium-1,3-indole-2-yl)acetic acid amine, Ν-[4-(2 -{4-[Ν'-(3-hydroxypropionyl)nonylcarbonylindenyl]phenyl}ethyl)-1,3-thiazol-2-yl]acetamide, 1^-[4-( 2-{4-[1^'-(6-Hydroxyhexyl)hydrazinocarbonylmethyl]phenyl}ethyl)-1,3-thiazol-2-yl]acetamide, 2-[(4 -{2-[2-(·Ethylamino)-1,3-thiazol-4-yl]ethyl}phenyl)acetic acid] arrogant acid vinegar, _ 2-[ (4-{2 -[ 2-(Ethylamino)-1,3-indolyl-4-yl]ethyl}phenyl)acetic acid] stimulating acid butyl vinegar, 2-[(4-{2-[2- (B-ylamino)-1,3-indol-4-yl]ethyl} phenyl)ethyl aryl] 拼 癸 2- 2-, 2-[(4-{2-[2-( B 2-Hydroxyethyl, 1,3-thiazol-4-yl]ethyl}phenyl)ethyl hydrazide] 2-hydroxyethyl phthalate, 2-ethyl decylamino-1,3-thiazole-4 - Retinoic acid 4-(decylcarbonylmethyl) phenyl ester, Ν-(4-{[4-(fluorenylcarbonylmethyl)phenoxy]methyl b i,3-thiazole 12 31 9771 200835687 - 2 -yl)acetamide, 2-(ethenylamino)-N-[4-(indolylcarbonylindenyl)phenyl; μl 3 -indole-4-carboxylic acid amine, N-[ 4-({[4-(indolylcarbonylmethyl)phenyl]amino}methyl)-!, 3-thiazol-2-yl]acetamide, N - {4 - [2 -(3-肼) Alkylmethylphenyl)ethyl]-1,3-indolyl sits 2-yl}acetamide, 1^-(4-{2-[5-(fluorenylcarbonyl)thiophen-2-yl Ethyl}-1,3-1,3-oxazol-2-yl)acetamide, N-(4-{2-[5-(indolylcarbonylindenyl)thiophene-2-thiazolyl-2-yl) Acetamine, N-(4-{2-[5-(2-mercaptoethyl) porphin-2-yl]ethyl}-1,3-thiazol-2-yl)acetamide, N-(4-{2-[5-(2-indolylethyl)porphin-3-yl]-ethyl}-1,3_°Shen-2-yl)acetic acid amine, _ N- {4-[2-(4-Mercaptophenyl)ethyl]-1,3-thiazole-2-yl}acetamide, N-(4-{2-[4-(fluorenylmethyl)benzene Ethyl dioxime, 3-thiazole-2-yl)acetic acid amine, N-(4-{2-[4-(2-mercaptoethyl)phenyl]ethyl b,1,3-thiazole-2 -yl) acetamidine, N-(4-{2_[4-(3-mercaptopropyl)phenyl]ethyl b, 1,3-12 thiophene-2-yl) Amine, N-(4-{2-[3-(2-mercaptoethyl)phenyl]ethyl}-1,3-indolyl 2- 219771 13 200835687 based on acetamide, N-( 4-{2-[5-(2-Mercaptoethyl)thiophen-2-yl]ethyl}-; [,3-thiazol-2-yl)acetamide, or N-(4-{2- [5-(3-Mercaptopropyl)thiophen-2-yl]ethylidene, 3-monothiazol-2-yl)acetamide as described above (u, a compound thereof, or a pharmaceutically acceptable salt thereof). (3) The compound represented by the above formula (I) is, for example, N-丨4_[2-(4-nonylcarbonylmethylphenyl)ethyl]-1,3-thiazol-2-yloximeacetamide The compound of the above (1), or a pharmaceutically acceptable salt thereof. (4) A compound according to any one of the above (1) to (3), or a pharmaceutically acceptable salt thereof, which is used as a medicine. (5) A pharmaceutical composition containing the compound of any one of the above (1) to (3) or a pharmaceutically acceptable salt thereof as an active ingredient. (6) A VAP-1 inhibitor comprising the compound of any one of the above (1) to (3) or a pharmaceutically acceptable salt thereof as an active ingredient. _(7)$Prevention or treatment of a VAP-1 related disease having the compound of any one of the above (1) to (3) or a pharmaceutically acceptable salt thereof as an active ingredient 8) VAP-1 related diseases are macular edema (diabetic And non-j $ disease macular edema), age-related macular degeneration, senile disc | more plaque degeneration, cystic macular edema, orbital edema, retinal swelling, diabetic retinopathy, choroidal retinopathy, new life Macular degeneration, neovascular glaucoma, uveitis, retinal vasculitis, endophthalmitis, total ocular inflammation, sputum 319771 14 200835687 colitis, retinal pigment epitheliitis, conjunctivitis, retinal dermatitis, upper Scleritis, optic neuritis, retrobulbar optic neuritis, keratitis, eye face inflammation, exudative retina _, corneal ulcer, & membrane: ulcer, slow stagnation keratitis, Szegen's keratitis, into: 2 money Sexual corneal ulcer, infection by bacteria or virus, and by ophthalmology:: eye disease caused by sputum, physical damage caused by the eye, life disease, eye including sputum, redness, edema and ulcer Symptoms of sexually transmitted diseases (10), erythema, polymorphous exudative erythema, nodularity: erythematous erythema, scleredema, dermatitis (dry, allergic disease flattened! 癣, rose 糠 treatment, contact dermatitis, different Position cutaneous stomach hair *! · raw red sputum treatment), vascular neuropathic edema, throat edema, glottic edema, subglottic pharyngitis, bronchitis, rhinitis, =:! Factory Baoyan and Hou Yan or otitis media, Liver cirrhosis, primary urinary disease, arteriosclerosis, (diabetes, arteriosclerosis: = factory), endothelial damage, diabetes and uremia-related gout and arthritis-related pain, connective tissue fire disease or symptoms (Rheumatoid (4) phlegm, ankylosing, dry phlegm and phlegm, and osteoarthritis or degenerative joint disease, Phytophthora syndrome, repair of Lang's syndrome, sputum 读 / Read more polychondritis, systemic lupus erythematosus: ": :, group, recurrent systemic sclerosis, money (four) material, I lupus, rheumatism, blood = inflammation, Nagnar's granulomatosis, mixed connective tissue juvenile rheumatoid); digestive tube... 319771 15 200835687 •[ Long's disease, ulcerative colitis, intestinal fistula (sputum colon), fibrosis of the liver, inflammation of the oral mucosa (endophthalmitis and recurrent aphthous ulcer)], inflammatory disease or symptom of the central nervous system (multiple Sclerosing disease, Alzheimer's disease, and ischemic stroke-related ischemia-reperfusion disorder); pneumonia disease or symptoms (asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease); including microvascular and macrovascular Diseases (arteriosclerosis, retinopathy, nephropathy, renal syndrome, and neurological disorders (multiple neurological disorders, single neurological disorders, and autonomic dysfunction), foot ulcers, joint problems, and increased risk of infection) Related diseases (diabetes and complications from diabetes)'· Diseases related to the differentiation or function of fat cells or the abnormal function of smooth muscle cells (arteriosclerosis and hypertrophy); vascular diseases [including atherosclerosis, non-atherosclerosis) Sclerosing, myocardial infarction, and "ischemic sputum V, boat, t ^ 赃 u赃 disease, Renault Syndrome and Raynaud's phlegm-based thrombotic vasculitis (Berg's disease chronic joint inflammatory bowel disease; or coffee vector complications [diabetes (insulin-dependent diabetes mellitus (1_ and non-insulin-dependent diabetes mellitus (NI Ugly)) and vascular complications (heart attack, angina, stroke, resection, blindness, and renal insufficiency)] (7) for the prevention or treatment of VMM-related diseases. W is used for the manufacture of a compound of the above-mentioned (1) to any two of the pharmaceuticals of VAP_w_, or a pharmaceutically acceptable salt thereof. The use of a compound according to any one of the above (1) to (3), or a medicinally acceptable 319771 16 200835687 salt thereof, for the prevention of VAP-1 related diseases. (11) Lishen VAP-1 related diseases are macular edema (diabetic and non-diabetic macular edema), age-related macular degeneration, senile discoid macular degeneration, cystic macular edema, orbital edema, retinal edema , diabetic retinopathy, choroidal retinopathy, neovascular macular degeneration, neovascular glaucoma, uveitis, iritis, retinal vasculitis, endophthalmitis, total ocular inflammation, metastatic ophthalmia, choroiditis, retina Pigment epitheliitis, conjunctivitis, ciliary body inflammation: scleritis, upper scleritis, optic neuritis, retrobulbar optic neuritis, keratitis, ophthalmitis, exudative retinal detachment, corneal ulceration, conjunctival ulceration, chronic money belt Keratitis, Sjogren's keratitis, progressive: sexually invasive corneal ulcer, bacterial infection or viral infection, ocular inflammatory disease caused by ophthalmic surgery, ocular inflammatory disease caused by physical damage of the eye, Symptoms caused by ocular inflammatory diseases including pain, redness, edema and ulceration, erythema, polymorphous exudative erythema, nodular erythema, annular erythema Scleredema, dermatitis (dry, allergic disease, lichen planus, prion, contact dermatitis, atopic skin fire, follicular red pityriasis), vascular neuropathic edema, throat edema, glottic edema , subglottic pharyngitis, bronchitis, rhinitis, pharyngitis, sinusitis and pharyngitis or otitis media, cirrhosis, primary fixed hypertension, diabetes, arteriosclerosis, (diabetes, arteriosclerosis and high blood) Endothelial injury, diabetes and uremia-related cardiovascular disease, pain associated with gout and arthritis, inflammatory disease or symptoms of connective tissue (rheumatoid arthritis, ankylosing spondylitis, 319771 17 200835687 Coronary arthritis and bone Arthritis or degenerative joint disease, vegetable =, repairing Gram's syndrome, Beckett's syndrome, recurrent ectopic chondritis, systemic lupus erythematosus, discoid lupus erythematosus, syndrome, eosinophilic fasciitis , polymyositis, dermatomyositis, yin muscle pain, vasculitis, temporary arthritis, nodularity =, Zhangna's granulomatosis, mixed connective tissue Disease,: 1 type of rheumatoid arthritis); inflammatory disease or symptoms of gastrointestinal tuberculosis, ulcerative colitis, intestinal fistula (sputum colon), fibrosis of the liver, sputum (four) membrane inflammation (endophthalmitis and Recurrent oral inflammation]]; inflammatory diseases or symptoms of the central nervous system (multiple, Alzheimer's, and ischemic stroke-related ischemia). · Pneumonia diseases or symptoms (asthma, Adult beer sucking distress syndrome, chronic obstructive pulmonary disease); including microvascular and macrovascular diseases (arteriosclerosis, retinopathy, nephropathy, nephrotic disorders (multiple neurological disorders, single neurological disorders and autonomic obstructive disorders), foot ulcers , joint problems and increased risk of infection) Carbohydrate metabolism-related diseases (diabetes and diabetes: hair disease); differentiation or function of waxy cells or 4' month b-related diseases of smooth muscle cells (artery Sclerosing and hypertrophy); vascular diseases include atherosclerosis, non-four-wire sclerosis, ischemic heart disease with obstruction of peripheral arteries and peripheral arteries, Raynaud's disease and , elephant, obstructive thrombophlitis (Berg's disease), · chronic joints: inflammatory bowel disease; or SSA0 vector complications [diabetes (asycholine-dependent diabetes (face) and non-insulin dependence Type 2 diabetes 319771 18 200835687 (NIDDM)) and the use of blood vessels, wide r, UE (heart attack, angina, stroke, resection, blindness and renal insufficiency)" as described above (1). (12) A method for inhibiting VAP-1 in which the compound of the above-mentioned (1) to (3), or a pharmaceutically acceptable salt thereof, is effectively administered to the subject . (13) = : Upper: The effective amount of the compound of any one of (1) to (3), or a salt thereof, which is administered to the subject, is a method for preventing or treating a disease associated with the subject. (14) The aforementioned VAP-1 related brigade, forgetting the plaque edema of the disease system (diabetic and non-sugar, disease η spot # edema), age-related macular degeneration, senile discoid macular degeneration, sac Macular edema, ophthalmologic edema, retinal edema, diabetic retinopathy, choroidal retinopathy, neovascular macular degeneration, neovascular glaucoma, uveitis, iritis, retinal vasculitis, endophthalmitis, full eyeball Inflammation, metastatic ophthalmia, choroiditis, retinal pigment epitheliitis, conjunctivitis, ciliary body fire: scleritis, upper scleritis, optic neuritis, retrobulbar optic neuritis, keratitis, ophthalmia, exudative retinal detachment, cornea Knuckle, conjunctival ulcer, chronic numismatic keratitis, Sjogson's keratitis, invasive corneal ulcer, bacterial infection or viral infection, and ocular inflammatory disease caused by ophthalmic surgery, physical condition of the eye Ocular inflammatory disease caused by injury, symptoms caused by ocular inflammatory diseases including itching, redness, edema and ulcers, erythema, polymorphous exudative erythema, nodular red , ring erythema, scleredema, dermatitis (dry, allergic disease, lichen planus, pityriasis rosea, contact dermatitis, atopic skin 319771 19 200835687 skin inflammation, hair follicle red sputum treatment), vascular neuropathy Edema, throat edema, glottic edema, subglottic pharyngitis, bronchitis, rhinitis, pharyngitis, sinusitis and pharyngitis or otitis media, cirrhosis,: fixed hypertension, diabetes, arteriosclerosis, (diabetes, arteries) Endothelial injury, vascular disease associated with diabetes and uremia, pain associated with gout and arthritis, inflammatory disease or symptom of connective tissue (rheumatoid arthritis, stiffness/,

乾癖性關節炎及骨關節炎或退化性關節疾病、萊人特氏 =群、修格蘭氏症候群、貝塞特氏症候群、復發性 多軟骨炎、全身性紅斑性狼瘡、圓盤狀紅斑性狼療、 全身性硬化症、嗜酸性筋膜炎、多發性肌炎、皮肌炎、 風濕性多肌痛症、血管炎、暫時性關節炎、結節性多 動脈炎、韋格納氏肉芽腫病、混合結締組織疾病、及 幼年型類風濕性關節炎）；消化管之炎性疾病或症狀 克隆氏病、#瘍性A腸炎、腸躁症（痙攣性結腸）、 肝臟之纖維化、口腔黏臈之發炎（口腔炎及復發性口 瘡口腔炎）];中樞神經系統之炎性疾病或症狀（多發 性魏症、阿滋海默症、及缺血財風相關之缺与 灌流F早礙），·肺炎性疾病或症狀（氣喘、成人呼吸 症候群、慢性阻塞性肺疾病）；包括微血管及大血管 之疾病（動脈硬化、視網臈病變、腎病、腎病症候 及神經障礙(多發性神經障礙、單一神經障礙及自律 相障礙）、足潰瘍1節之問題及感染風險之增加） 火艮化5物代谢相關疾病（糖尿病及來自糖尿病之 319771 20 200835687 ‘ #發症）’·脂肪細胞之分化或機能或者平滑肌細胞之 . 冑能之#常相關之疾病(動脈硬化及肥大）；血管疾病 [包括動脈粥狀硬化、非動脈粥狀硬化、心肌梗塞及 周邊動脈阻基之缺血性心臟疾病、雷諾氏症及雷諾氏 ?象：阻基性血拴性血管炎(柏格氏症)];慢性關節 炎，炎性腸疾病；或SSA0媒介併發症[糖尿病（胰島 素依賴型糖尿病⑽M)及非胰島素依賴型糖尿病 Φ (NI〇随））及血管併發症（心臟病發作、狹心症、中風、 切除、失明及腎功能不全）]如上述（13)之VAiM相關 疾病之預防或治療方法。 (發明的效果） 本發明之化合物，由於VAfM抑制活性優良，且酵素 選擇性優良並可排除作為醫藥品之不宜副作用等，故有用 於作為VAP-1抑制劑、VAfM相關疾病之預防或治療 藥等。 / _ _ 【實施方式】 在本說明書之上述以及以下之記载中，以下就本發明 所使用之用語做詳細說明。 用語「低級」，只要無其他規定，即可使用於且有卜 至6個碳原子之基，且以丨至4個碳原子為佳。 「低級烧基」可舉例如具有i至6個碳原子之直鍵或 支鏈之烷基（例如：曱基、乙基、丙基、異丙基、丁基、里 丁基、二級丁基、三級丁基、戊基、三級戊基及己基）等，、’ 其中較佳者係Ci至C4烷基。 319771 21 200835687 *或古核低、^伸^基」可舉例如具有1至6個碳原子之直鏈 :支鏈之伸烷基(例如：”基、伸乙基、三亞甲基、伸丙 基、亞乙基及亞丙基）等，其中較佳者係d ^伸烧基。 低級伸烯基」可舉例如具有2至6個碳原子之直鍵 或支鍵之伸婦基（例如：伸乙烯基、卜伸丙烯基、卜甲基+ 伸丙烯基、2-甲基+伸丙烯基、2_伸丙烯基、2_伸丁烯基、 卜伸丁烯基、3~伸丁烯基、2-伸戊浠基、卜伸戊烯基、3一 伸戊絲、、4一伸戊烯基、U-伸丁二烯基、1，3-伸戊二稀 基、2-伸戊烯-4-烯基、2_伸己蝉基、卜伸己稀基、5_伸己 稀基、3—伸己烯基、4,己烯基、3, 3-二甲基+伸丙烯基、 2一乙基一卜伸丙烯基、1，3, 5-伸己三烯、伸己二烯、 伸己二烯）等，其中較佳者係C2至C4伸烯基。 上述低級伸烯基係可分別為E體或z體。當本發明之 化口物具有低級伸烯基部分時，本發明之化合物係包含該 低級伸烯基部分為E-構造及z—構造之所有立體異構物。 「低級伸炔基」可舉例如具有i至3個三鍵之碳數2 至6之直鏈或支鏈之伸炔基（例如：伸乙炔基、卜伸丙炔 基、1-曱基-1Γ伸丙炔基、2一曱基4-伸丙炔基、2一伸丙炔 基、2-伸丁炔基、卜伸丁炔基、3-伸丁炔基、2-伸戊炔基、 卜伸戊炔基、3-伸戊炔基、4—伸戊炔基、2 —伸戊炔—4-基、 2伸己炔基、卜伸己炔基、5-伸己炔基、3-伸己炔基、4-伸己炔基、3, 3-二乙基—i —伸丙炔基、2—乙基—丨―伸丙炔 基），其中較佳者係&至C4伸炔基。 「芳基」可舉例如Ce至Ci。芳基（例如：苯基及萘基） 22 319771 200835687 取代位置係 # 1 」係可經丨至3個取代基取代 不特別限定。 「 「芳烷基」可舉例如：芳基部分具有6至1〇個碳原子 [即，芳基部分為上述「芳基 ” 」之C6至ClD方基]，且烷基 6/、有1至6個碳原子[即，烧基部分為上述「低級烧基」 之Ci至C6烷基]之芳烷基（例如：苯甲基、苯乙基、1一萘甲 基、2-,曱基、3-苯丙基、4_苯丁基及5_苯戊基)等。Dry arthritis and osteoarthritis or degenerative joint disease, Lai's group = group, repairing granule syndrome, Bethel's syndrome, recurrent polychondritis, systemic lupus erythematosus, discoid erythema Wolf therapy, systemic sclerosis, eosinophilic fasciitis, polymyositis, dermatomyositis, rheumatic polymyalgia, vasculitis, temporary arthritis, nodular polyarteritis, Wegener's granulomatosis , mixed connective tissue disease, and juvenile rheumatoid arthritis); inflammatory disease or symptom of gastrointestinal tube, Crohn's disease, enteritis (cold colon), fibrosis of the liver, oral adhesion Inflammation of sputum (stomatitis and recurrent aphthous stomatitis)]; inflammatory diseases or symptoms of the central nervous system (multiple Wei, Alzheimer's disease, and ischemic wind-related deficiency and perfusion F) , pneumonia diseases or symptoms (asthma, adult respiratory syndrome, chronic obstructive pulmonary disease); diseases including microvascular and macrovascular (arteriosclerosis, retinopathy, kidney disease, renal disease, and neurological disorders (multiple dysfunction) , single neurological disorder and self-discipline disorder), the problem of foot ulcer 1 section and the risk of infection) Firecracker 5 metabolism-related diseases (diabetes and diabetes from 319771 20 200835687 ' #发症)'·different cell differentiation Or functional or smooth muscle cells. 胄能之#Affiliated diseases (arteriosclerosis and hypertrophy); vascular diseases [including atherosclerosis, non-atherosclerosis, myocardial infarction, and ischemic heart disease of peripheral arterial resilience , Raynaud's disease and Raynaud's disease: obstructive vasospasm (Berg's disease); chronic arthritis, inflammatory bowel disease; or SSA0 vector complications [diabetes (insulin-dependent diabetes mellitus (10) M) and Non-insulin-dependent diabetes mellitus Φ (NI〇) and vascular complications (heart attack, angina, stroke, resection, blindness, and renal insufficiency)] Prevention or treatment of VAiM-related diseases as described in (13) above . (Effects of the Invention) The compound of the present invention is excellent in VAfM inhibitory activity, and has excellent enzyme selectivity and can be used as a preventive or therapeutic agent for VAP-1 inhibitors and VAfM-related diseases. Wait. [Embodiment] In the above description of the present specification and the following description, the terms used in the present invention will be described in detail below. The term "lower", as long as there are no other regulations, can be used with a base of 6 carbon atoms, preferably from 4 to 4 carbon atoms. The "lower alkyl group" may, for example, be an alkyl group having a straight bond or a branched chain of from 1 to 6 carbon atoms (for example, anthracenyl group, ethyl group, propyl group, isopropyl group, butyl group, butyl group, or secondary group). A group, a tertiary butyl group, a pentyl group, a tertiary pentyl group and a hexyl group, etc., wherein 'the preferred one is a Ci to C4 alkyl group. 319771 21 200835687 * or an ancient nucleus, such as a straight chain having 1 to 6 carbon atoms: a branched alkyl group (for example: ", a group, an ethyl group, a trimethylene group, a propylene group" a group, an ethylene group, a propylene group, etc., wherein a preferred one is a d-alkyl group. The lower alkenyl group may, for example, be a straight or a bond having 2 to 6 carbon atoms (for example, : a vinyl group, a propenyl group, a methyl group, a propenyl group, a 2-methyl group, a propenyl group, a 2-propenyl group, a 2-butenyl group, a propenyl group, a 3-butene group. , 2-extended pentamidine, b-pentenyl, 3-isopentene, 4-pentenyl, U-butadienyl, 1,3-pentylene, 2-exetene 4-alkenyl, 2-extended hexyl, diexyl, 5-extended, 3-hexenyl, 4, hexenyl, 3,3-dimethyl + propylene, 2 ethyl-ethyl-propenyl, 1,3,5-hexatriene, hexadiene, hexadiene, etc., of which C2 to C4 are alkenyl groups. The above lower alkenyl group may be an E body or a z body, respectively. When the oxime of the present invention has a lower alkenyl moiety, the compound of the present invention comprises all stereoisomers of the lower alkenyl moiety as the E-configuration and the z-configuration. The "lower alkynyl group" may, for example, be a linear or branched alkynyl group having from 2 to 6 carbon atoms of from i to 3 triple bonds (for example, an exetylene group, a propenyl group, a 1-mercapto group). 1 丙 propynyl, 2-indenyl 4-propynyl, 2-propenyl, 2-butenyl, di-butynyl, 3-butenyl, 2-exetylene, Des-pentynyl, 3-exetylene, 4-pentenyl, 2-propenyl-4-yl, 2-exexenyl, hexylene, 5-exetylene, 3 - an extenylene group, a 4-extended hexynyl group, a 3,3-diethyl-i-propanyl group, a 2-ethyl-anthracene-propenyl group, wherein the preferred one is & to C4 An alkynyl group. The "aryl group" may, for example, be Ce to Ci. Aryl group (e.g., phenyl and naphthyl) 22 319771 200835687 The substitution position system #1" may be substituted with three substituents, and is not particularly limited. The "aralkyl group" may, for example, be an aryl moiety having 6 to 1 carbon atoms [that is, a C6 to ClD group having an aryl moiety of the above "aryl group"], and an alkyl group 6/, having 1 An aralkyl group having 6 carbon atoms [i.e., a mercapto moiety which is a Ci to C6 alkyl group of the above "lower alkyl group" (for example, benzyl, phenethyl, 1-naphthylmethyl, 2-, fluorene) Base, 3-phenylpropyl, 4-phenylene and 5-phenylpentyl).

「環低級烷基」彳舉例如具# 3至6個碳原子之環烷 基（例如：環丙基、環丁基、環戊基、環己基）等。< 兀 環低級烧氧基幾基」可舉例如環烧基部分具有礙數 t至6個碳原子之環烷氧基羰基（例如：環丙氧羰基、環丁 氧羰基、環戊氧羰基 '環己氧羰基）等。 ^ —雜環」可舉例如「芳香族雜環」及「非芳香族雜環」。 「芳香族雜環」可舉例如除了碳原子以外含有從氮、氧及 硫原子中選出之1至3個雜原子之5至10員芳香族雜環 等，可舉例如：噻吩、呋喃、吡咯、咪唑、吡唑、噻唑、 異喧唾、噚唑（oxazole)、異噚唑、吡啶、嗒哄 (pyridazine)、嘧啶、吡畊（pyrazine)等。「非芳香族雜環 可舉例如除了碳原子以外含有從氮、氧及硫原子中選出之 1至3個雜原子之5至1〇員非芳香族雜環等，可舉例如·· 吡咯啶（pyrrolidine)、咪唑啉（imidazoline)、吡唑啶 (pyrazolidine)、。比嗤淋（pyrazoline)、旅咬 (piperidine)、哌畊（？1?6]：&2丨116)、嗎啉、硫代嗎啉 (thi ⑽ orpholine)、二氧戊環（di〇x〇lane)、噚唑啶 319771 23 200835687 .(oxazolidine)、噻唑啶（thiaz〇lidine)、***啶 (triazolidine)等。 「酿基」包含烷基羰基、芳基羰基等。 「烷基羰基」可舉例如烷基部分具有丨至6個碳原子 [即，烷基部分為上述「低級烷基」之（^至G烷基]之烷基 羰基（例如：乙醯基、丙醯基、丁醯基、異丁醯基、戊醯基、 異戊醯基、新戊醯基（pival〇yl)、己醯基、庚醯基及癸醯 基）等。 、皿 ⑩ 「芳基羰基」可舉例如芳基部分具有6至10個碳原子 [即，芳基部分為上述「芳基」之匕至Ci。芳基]之芳基羰 基（例如：苯甲醯基、萘曱醯基）等。 「烷氧基羰基」包含烷基氧基羰基、芳烷基氧基羰基 等。 — 「烷基氧基羰基」可舉例·如烷基部分具有1至1{)個碳 原子之烷基氧基羰基（例如：曱氧羰基、乙氧羰基、丙氧羰 _基、異丙氧羰基、丁氧羰基、異丁氧羰基、二級丁氧羰基、 二級丁氧羰基、戊氧羰基、三級戊氧羰基、己氧羰基及癸 氧羰基等）等。 ' 芳烧基氧基魏基」可舉例如芳基部分具有6至1〇 個碳原子[即，芳基部分為上述「芳基」之Cs至L芳基]， 且烷基部分具有1至6個碳原子[即，烷基部分為上述「低 級烷基」之匕至C6烷基]之芳烷基氧基羰基（例如：苯甲氧 羰基、苯乙氧羰基、1一萘曱氧羰基、2一萘曱氧羰基、3一苯 丙氧羰基、4_苯丁氧羰基及5_苯戊氧羰基等）等。 319771 24 200835687 」可舉例如已在上述中 獄基係同上述之定義）等 在式（I)中以R1表示之「醯基 定義者等’且以絲料（該烧基 為佳，並以乙醯基等特佳。 在式（I)中以X表示之Γ 價殘基」則可舉例如·· 從可經取代之噻唑所衍生之二The "cyclo-lower alkyl group" is, for example, a cycloalkyl group having from 3 to 6 carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) and the like. < Anthracene ring lower alkoxy group may, for example, be a cycloalkyloxycarbonyl group having a ring-and-burn moiety having a hindrance of t to 6 carbon atoms (e.g., cyclopropoxycarbonyl, cyclobutoxycarbonyl, cyclopentyloxycarbonyl) 'Cyclohexyloxycarbonyl' and the like. ^—Heterocyclic ring”, for example, “aromatic heterocyclic ring” and “non-aromatic heterocyclic ring”. The "aromatic heterocyclic ring" may, for example, be a 5- to 10-membered aromatic heterocyclic ring containing one to three hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to a carbon atom, and examples thereof include thiophene, furan and pyrrole. , imidazole, pyrazole, thiazole, isoindole, oxazole, isoxazole, pyridine, pyridazine, pyrimidine, pyrazine, and the like. The non-aromatic heterocyclic ring may, for example, be a 5- to 1-membered non-aromatic heterocyclic ring containing one to three hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to a carbon atom, and may, for example, be pyrrolidine. (pyrrolidine), imidazoline, pyrazolidine, pyrazoline, piperididine, piperazine (?1?6:: & 2丨116), morpholine, Thiomorpholine (thi (10) orpholine), dioxolane (di〇x〇lane), oxazolidine 319771 23 200835687 . (oxazolidine), thiazidine hydrochloride, triazolidine, etc. The brewing group includes an alkylcarbonyl group, an arylcarbonyl group and the like. The "alkylcarbonyl group" may, for example, be an alkylcarbonyl group having an alkyl moiety having from 丨 to 6 carbon atoms [ie, an alkyl moiety is the above-mentioned "lower alkyl group" (^ to G alkyl group) (for example, an ethylene group, Propyl, butyl, isobutyl, pentylene, isoamyl, pivalyl, hexyl, decyl and sulfhydryl, etc., dish 10 "arylcarbonyl" For example, an arylcarbonyl group having 6 to 10 carbon atoms in the aryl moiety [that is, an aryl moiety is a hydrazine of the above "aryl group" to a Ci. aryl group (for example, a benzylidene group, a naphthyl group) The "alkoxycarbonyl group" includes an alkyloxycarbonyl group, an aralkyloxycarbonyl group, etc. - "Alkyloxycarbonyl group" is exemplified by an alkyl group having 1 to 1 {) carbon atoms in the alkyl moiety. Oxycarbonyl group (eg, oxime oxycarbonyl, ethoxycarbonyl, propoxycarbonyl-yl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, secondary butoxycarbonyl, secondary butoxycarbonyl, pentyloxycarbonyl, A tertiary pentyloxycarbonyl group, a hexyloxycarbonyl group, a fluorenyloxycarbonyl group, etc.). The 'aryl oxycarbonyl group' may, for example, have an aryl moiety having 6 to 1 Å of carbon atoms [that is, an aryl moiety is a Cs to L aryl group of the above "aryl group"), and the alkyl moiety has 1 to An aralkyloxycarbonyl group having 6 carbon atoms [ie, an alkyl moiety is a hydrazine to a C6 alkyl group of the above "lower alkyl group") (for example, benzyloxycarbonyl, phenethyloxycarbonyl, 1-naphthoquinoneoxycarbonyl) , 2-naphthoquinoneoxycarbonyl, 3-phenylpropoxycarbonyl, 4-phenylbutoxycarbonyl, 5-phenylpentyloxycarbonyl, etc.). 319771 24 200835687 "For example, the above-mentioned prison base is the same as defined above, etc.", etc., in the formula (I), the "base group definition, etc." represented by R1 and the silk material (the base is preferred, and Ethyl thiol and the like are particularly preferred. The valence residue represented by X in the formula (I) may, for example, be derived from a substituted thiazole.

、、唾唑」也可具有取代基，取代位置不特別限定。 述「可經取代之㈣」《「取代基」則可舉 下（1)至（12)之基等。 戰於 及 上 以 (1) _素（例如：氟、氯、溴）； (2) 上述所疋“之统氧基幾基（例如：乙氧幾基）； (3) 可經取代之芳基（該芳基係同上述之定義，且該芳基 係也可經-S〇2-(低級烷基）（式中，該低級烷基係同上 述之定義）等取代，取代位置不特別限定）（例如··苯 基及4-(甲磺醯基）苯基）； ⑷式：—bC0NRaRb(式巾，『係氫、低級垸基、芳基或芳烧 基R係虱、低級烧基、芳基或芳炫基，在此，該低 級烷基、芳基或芳烷基係同上述之定義）之基（例如·· N-甲基胺基羰基、N一苯基胺基羰基、N，N一二甲基胺基 羰基及N-苯甲基胺基羰基）； (5)式：-C0NH -（CH2)k-芳基[式中，k係0至6之整數；該 芳基係同上述之定義，且也可具有由—N〇2、-s〇2-(低 級烷基）（式中，該低級烷基係同上述之定義）、-CJ?3 319771 25 200835687 ，=-〇-芳基（式卜該芳基係同 尹選出之】至5個敌冲1 疋我）組成之群 基； 代基，取代位置不特別限定]之 ⑹=L(GH2)m__u 中，m 係 ^ ㈣㈣上叙定義（例如：対））之基； 該 (7)式· -C0-雜環「式中，兮雄 衣亥雜裱係同上述之定義(例如： 女°疋、派咬、娘哄、硫代嗎琳）；該雜環係也可具 —由co (低級烷基X式中，該低級烷基係同上述之 定義)—、-C0-CK低級燒基）（式中，該低級烧基係同上 γ、疋義）SO2 (低級烷基）（式中，該低級院基係同 上述之定義）、酮基（oxo)(即=0)及式：—CONRCRd(式 中，R。係氫、低級烷基、芳基或芳烷基，Rd係氫、低 級烷基、芳基或芳烷基，該低級烷基、芳基 係同上述之定義）之基組成之群中選出之取基 代基，取代位置不特別限定]之基； ⑻式：-（CH2)t-芳基[式中，t係1至6之整數；該芳基 係同上述之定義，且也可具有由—s—(低級烷基）（式 中，該低級烷基係同上述之定義）、-S〇2一（低級烷基） (式中’該低級烷基係同上述之定義）、-S〇2—nrvrw(式 中，Γ係氫、低級烷基、芳基或芳烷基，Γ係氫、低 級烧基、芳基或芳烷基，該低級烷基、芳基及芳烧基 係同上述之定義）、-C〇2-(低級烷基）（式中，該低級烷 基係同上述之定義）、-NHC0-0-(低級烷基）（式中，該 低級烷基係同上述之定義）及式：-C0NReRf(式中，Γ 26 319771 200835687 • 係氫、低級烷基、芳基或芳烷基，係氫、低級烷基、 芳基或芳院基，該低級絲、芳基及芳縣係同上述 之定義）之基組成之群中選出之丨至5個取代基，取 代位置不特別限定]之基； ⑻式：一⑽2)。-雜環[式中，〇係0至6之整數；該雜環 係同上述之定義（例如：吡咯啶、哌啶、哌哄、嗎啉、 硫代嗎啉），且也可具有由酮基（即=〇) ; _c〇_(低級 烷基）（式中，該低級烷基係同上述之定義）；_c〇_〇_ (低級烷基）（式中，該低級烷基係同上述之定義）； -S〇2_(低級烷基）（式中，該低級烷基係同上述之定 義）；-C0-(雜環）（式中，該雜環係同上述之定義（例 如比各定哌哄及嗎琳），且也可具有由低級院基（該 低級烷基係同上述之定義）及画素（例如：氟、氯、溴） 組成之群中選出之i至5個取代基，取代位置不特別 =定）；及式、C0NRf (式中，Rg係氫、低級烷基、 鲁芳基或芳烷基，Rh係氫、低級烷基、芳基或芳烷基， 該低級烷基、芳基及芳烷基係同上述之 成之群中選出之li5個取代基，取代位置= 基別且限 定]之基； (10)式·-（CHdp-NRiR][式中，p係〇至6之整數；Ri係氫、 醯基、低級烷基、芳基或芳烷基，RM系氫、醯基、低 級烷基、芳基或芳烷基，該醯基、低級烷基、芳基及 芳烷基係同上述之定義，且該低級烷基也可具有由 式：-CONRY(式中，Rk係氫、低級烷基、芳基或芳烷 319771 27 200835687 基，R1係氫'低級烷基、芳基或芳烷基，該低級烷基、 芳基及芳烧基係同上述之定義）之基組成之群中選出 之1至5個取代基，取代位置不特別限定]之美·' (11)式：-C0N(H或低級烷基）-（CHRffi)q—T[式中，q係〇至6 之整數；該低級烷基係同上述之定義；Rro係氫、已在 上述中定義之芳烧基或已在上述中定義之燒基（特別 是低級烧基）’且此等也可經由_〇IJ及—⑶丽2组成之群 中選出之1至3個取代基取代，取代位置不特別限 定；T係氫；式：-C0NRT(式中，Γ係氫、低級烷基、 芳基或芳烷基，R°係氫、低級烷基、芳基或芳烷基， 該低級烷基、芳基及芳烷基係同上述之定義）之基； (式中’ Γ係已在上述中定義之烧基或^在 上述中定義之芳烷基）之基；-NH—s〇2_(低級烷基）（式 中，竑低級烷基係同上述之定義）之基_s〇2_(低級烷 基）（式中，該低級烷基係同上述之定義）之基；—雜環 (式中，該雜環係同上述之定義（例如：吡啶、吡^二 及嗎啉），且可具有1至3個取代基（例如：酮基（即 = 〇))，取代位置不特別限定）之基；*_c〇_(雜環）（式 中，該雜環係同上述之定義（例如··哌啶及、嗎啉））之 基]之基；以及 (12)式:-(CHOr-CO-NlTr(式中 ’ r 係 j 至 6 之整數；Rt 2氫、低級烷基、芳基或芳烷基，RU係氫、低級烷基、 芳基或芳烷基，該低級烷基、芳基及芳烧基係同上述 之定義）之基。 319771 28 200835687 芳基或雜環上之取代位置係可在其任何位置，不特別 限疋。上述「可經取代之噻唑」之較佳「取代基」係甲基 磺醯基苯甲基、胺磺醯基苯f基（例如·· 4-胺磺醯基苯甲基3 專甲基& 基、胺石黃醯基等取代位置不特別限定。 在式（I)中以X表示之「從可經取代之噻唑所衍生之二 心殘基」之「從噻哇所衍生之二價殘基」部分係以Further, the "salozole" may have a substituent, and the position of substitution is not particularly limited. The words "substitutable (4)" and "substituent" can be given as the basis of (1) to (12). In the war, (1) _ prime (for example: fluorine, chlorine, bromine); (2) the above-mentioned "oxyl group (for example: ethoxy group); (3) can be substituted a base (the aryl group is as defined above, and the aryl group may also be substituted by -S〇2-(lower alkyl) (wherein the lower alkyl group is as defined above), and the substitution position is not particularly (Limited) (for example, phenyl and 4-(methylsulfonyl)phenyl); (4) Formula: -bC0NRaRb (type towel, "hydrogen, lower sulfhydryl, aryl or arylalkyl R", low grade a radical, an aryl or an aryl group, wherein the lower alkyl, aryl or aralkyl group is as defined above (for example, N-methylaminocarbonyl, N-phenylaminocarbonyl) , N,N-dimethylaminocarbonyl and N-benzylaminocarbonyl); (5) Formula: -CONH-(CH2)k-aryl [wherein k is an integer from 0 to 6; The aryl group is as defined above, and may also have -N〇2, -s〇2-(lower alkyl) (wherein the lower alkyl group is as defined above), -CJ?3 319771 25 200835687 ,=-〇-aryl (the selected aryl is the same as Yin) to 5 Enemy 1 疋 me) group group; algebra, substitution position is not particularly limited] (6) = L (GH2) m__u, m system ^ (four) (four) the definition of the above (for example: 対)); Formula -C0-heterocyclic ring "In the formula, the 兮 衣 衣 衣 裱 裱 裱 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ; ; ; ; ; ; ; ; ; ; ; Co (lower alkyl group, wherein the lower alkyl group is as defined above) -, -C0-CK lower alkyl) (wherein the lower alkyl group is the same as γ, 疋) SO2 (lower alkyl) (wherein the lower-grade home base is as defined above), keto (oxo) (ie, =0), and: -CONRCRd (wherein R is hydrogen, lower alkyl, aryl or aralkyl, Rd is a group selected from the group consisting of hydrogen, a lower alkyl group, an aryl group or an aralkyl group, and the lower alkyl group and the aryl group are the same as defined above), and the substitution position is not particularly limited; (8) Formula: -(CH2)t-aryl [wherein t is an integer from 1 to 6; the aryl group is as defined above, and may also have -s-(lower alkyl) (wherein Lower alkyl is as defined above) -S〇2-(lower alkyl) (wherein the lower alkyl group is as defined above), -S〇2-nrvrw (wherein, anthracene hydrogen, lower alkyl, aryl or aralkyl, Lanthanide hydrogen, lower alkyl, aryl or aralkyl, the lower alkyl, aryl and aryl groups are as defined above, -C〇2-(lower alkyl) (wherein the lower alkane) The base is the same as defined above), -NHC0-0-(lower alkyl) (wherein the lower alkyl group is as defined above) and the formula: -C0NReRf (in the formula, Γ 26 319771 200835687 • hydrogen, low grade An alkyl, aryl or aralkyl group selected from the group consisting of hydrogen, lower alkyl, aryl or aryl, the lower order of the filament, aryl and aryl as defined above) a substituent, the position of substitution is not particularly limited; (8) Formula: one (10) 2). a heterocyclic ring [wherein the lanthanide is an integer from 0 to 6; the heterocyclic ring is as defined above (for example: pyrrolidine, piperidine, piperidine, morpholine, thiomorpholine), and may also have a ketone a group (ie, 〇); _c〇_(lower alkyl) (wherein the lower alkyl group is as defined above); _c〇_〇_ (lower alkyl) (wherein the lower alkyl group is the same) The above definition); -S〇2_(lower alkyl) (wherein the lower alkyl group is as defined above); -C0-(heterocyclic ring) (wherein the heterocyclic ring is as defined above (for example) i to 5 selected from the group consisting of lower-grade hospital bases (the lower alkyl group is as defined above) and pixels (eg, fluorine, chlorine, bromine) a substituent, the substitution position is not particularly determined; and a formula, C0NRf (wherein Rg is hydrogen, lower alkyl, arylene or aralkyl, Rh is hydrogen, lower alkyl, aryl or aralkyl, The lower alkyl, aryl and aralkyl groups are the same as the li5 substituents selected from the above group, substituting the position = the base and defining the group; (10) Formula ·-(CHdp-NRiR) In the p system An integer of 6; Ri is hydrogen, decyl, lower alkyl, aryl or aralkyl, RM is hydrogen, decyl, lower alkyl, aryl or aralkyl, the fluorenyl, lower alkyl, aryl And the aralkyl group is the same as defined above, and the lower alkyl group may also have the formula: -CONRY (wherein Rk is hydrogen, lower alkyl, aryl or aralkyl 319771 27 200835687, R1 hydrogen is lower) 1 to 5 substituents selected from the group consisting of an alkyl group, an aryl group or an aralkyl group, the lower alkyl group, the aryl group and the aryl group are the same as defined above, and the substitution position is not particularly limited. ' (11) Formula: -C0N (H or lower alkyl)-(CHRffi)q-T [wherein q is an integer from 〇 to 6; the lower alkyl group is as defined above; Rro is hydrogen, already An aryl group as defined above or an alkyl group (especially a lower alkyl group) which has been defined above and which may also be selected from the group consisting of 〇IJ and -(3) Li 2 Substituted, the position of substitution is not particularly limited; T-hydrogen; formula: -C0NRT (wherein, hydrazine hydrogen, lower alkyl, aryl or aralkyl, R ° hydrogen, lower alkyl, aryl or aralkyl , The lower alkyl, aryl and aralkyl groups are the same as defined above; (wherein the lanthanide group has been defined in the above or the aralkyl group defined in the above); -NH —s〇 2 —(lower alkyl) (wherein the lower alkyl group is as defined above) is based on the group —s〇 2 — (lower alkyl) (wherein the lower alkyl group is as defined above) a heterocyclic ring (wherein the heterocyclic ring is as defined above (for example, pyridine, pyridinium and morpholine), and may have 1 to 3 substituents (for example, a keto group (ie, 〇)), a group in which the position of substitution is not particularly limited; *_c〇_(heterocyclic ring) (wherein the heterocyclic ring is the same as defined above (for example, piperidine and morpholine); and (12) Formula: -(CHOr-CO-NlTr (wherein 'r is an integer from j to 6; Rt 2 hydrogen, lower alkyl, aryl or aralkyl, RU is hydrogen, lower alkyl, aryl or aralkyl The group of the lower alkyl, aryl and aryl groups are as defined above. 319771 28 200835687 The substitution position on the aryl or heterocyclic ring can be anywhere, and is not particularly limited. The preferred "substituent" of the above-mentioned "substitutable thiazole" is methylsulfonylbenzyl, aminesulfonylbenzene f-based (for example, 4-aminosulfonylbenzyl 3 monomethyl & The substitution position of the group, the amine yttrium group, and the like is not particularly limited. The "two-heart residue derived from the thiazole which can be substituted" represented by X in the formula (I) "the divalent residue derived from the thioacetate" Part of

S 為佳。「從可經取代之噻唑所衍生之二價殘基」之「取代基」 係以甲基伽基苯曱基、胺磺醯基苯甲基（例如：4 _胺磁土釀 基苯甲基）等為佳。 在式（I)中以Υ表示之式（III) : J_L_M之以：及祕表 示之低級伸烷基、低級伸烯基及低級伸炔基可舉例如已在 上述中定義者等。 在式（I)中以Y表示之式（III): j_l_m之具體例可舉 ： -(CH〇n- > -(CH2)n-NH-(CH〇n- . -(CH2)n-〇-(CH2)n-. -(CH2)n-CO-〇-(CH2)n- ^ -(CH2)n-〇-C〇-(CH2)n- ^ -CCH2)n-C0-NH-(CH2)n- > -(CH2)n-NH-C0-(CH2)n- . -(CH2)n-S〇2-NH- (CH〇「或-(CH2)n_NH_s〇2_(CH2)广（各式中，n 係。至 6 之整 數）等。此等之中，以_(CH2)n_、一（Cud、正 -(CH2)n-C(MKCH2)n_、_(CH2)n_c〇,一（㈤广為佳，且以 -(cha-特佳。具體而言可舉例如：一（CH2)mc〇一、 -CH2-關-、-C0-0-、-C0-丽-等。 319771 29 200835687 示之 ，具 在f(I)中以2表示之式（II):A - B-D-E之以A表 / —斤生之一饧殘基、或從噻吩所衍生之二價殘基 體而言可舉例如：S is better. The "substituent" of the "divalent residue derived from a substituted thiazole" is methyl benzyl phenyl fluorenyl or sulfonyl benzyl (for example, 4 - amine magnetic phenyl benzyl) It is better. The formula (III) represented by Υ in the formula (I): J_L_M and the lower alkylene group, the lower alkenyl group and the lower alkynyl group represented by the above formula are, for example, those defined above. Specific examples of the formula (III) represented by Y in the formula (I): j_l_m include: -(CH〇n- > -(CH2)n-NH-(CH〇n- . -(CH2)n- 〇-(CH2)n-. -(CH2)n-CO-〇-(CH2)n- ^ -(CH2)n-〇-C〇-(CH2)n- ^ -CCH2)n-C0-NH- (CH2)n- > -(CH2)n-NH-C0-(CH2)n- . -(CH2)nS〇2-NH- (CH〇" or -(CH2)n_NH_s〇2_(CH2) wide ( In each formula, n is an integer from 6 to the like. Among these, _(CH2)n_, one (Cud, positive-(CH2)nC(MKCH2)n_, _(CH2)n_c〇, one ( (5) It is widely used, and - (cha-tejia. Specifically, for example: one (CH2) mc 〇 one, -CH2- Guan-, -C0-0-, -C0-Li-, etc. 319771 29 200835687 shows that the formula (II) represented by 2 in f(I): A-BDE is a residue of A, / or a divalent residue derived from thiophene For example:

以B表示之-NR2-C0-中之以R2表示之低級烷基、醯基 春可舉例如已在上述中定義者等。B具體而言可舉例如：鍵 結、-NH-C0-、-(CH2)n 一 c〇_(式中，n 為 〇 至 2 之整數）、 -（CH2)n-（式中，n為〇至3之整數）等。 以D表示之—NR -中之以r3表示之低級烷基、烷氧基羰 基、醯基可舉例如已在上述中定義者。〇具體而言可舉例 如：-腿―、—N(CH3)-等。 -·在以E表示之「可經取代之胺基」中係包含未取代胺 基、及經1或2個取代基取代之胺基。「可經取代之胺基_ Φ係以式-NR4R5表示。 R及R各自可舉例為氫、可為未取代或以經基等取代 之低級烧基、酿基（特別是，低級烷基羰基、羥基低級烷基 羰基）、烷氧基羰基、羥基烷氧基羰基、芳基、芳烷基、環 狀低級燒基、環狀低級烧氧基獄基、硫醯基（SUlfUryl)、 亞磺酸基（sulfinyl)、磷醯基（ph〇sphoryl)、雜環之基等。 該低級烧基、醯基（特別是，低級烷基羰基）、烷氧基羰基、 芳基、芳烷基、環狀低級烷基、環狀低級烷氧基羰基、雜 環係同上述之定義。 30 319771 200835687 R及R ’具體而言各自可皇· 甲其.^ σ目j舉例如·氣、低級烷基（例如·· 甲基、乙基等）、乙臃其、 v J ^ J ^^基 丁醯基、癸醯某、Ht<兩护1 6-羥己醯基等，己董势| 丁〆 Q皿暴3羥丙基、 乙氧縣等。 絲、癸氧羰基、2-經基 八士丌铲，、他以E表示之「可經取代之胺基」之胺基部 /刀也可依記载於"ProtectlveGr〇upsin〇rganicThe lower alkyl group or the fluorenyl group represented by R2 in -NR2-C0- represented by B may, for example, be as defined above. Specific examples of B include: bonding, -NH-C0-, -(CH2)n-c〇_ (where n is an integer from 〇 to 2), -(CH2)n- (wherein, n It is an integer of 3) and so on. The lower alkyl group, the alkoxycarbonyl group or the fluorenyl group represented by R3 in NR-, which is represented by D, may be, for example, those defined above. Specifically, for example, - leg, - N (CH3) - and the like. - "A substitutable amine group" represented by E is an unsubstituted amino group and an amine group substituted with 1 or 2 substituents. The "substituted amine group _ Φ is represented by the formula -NR4R5. Each of R and R can be exemplified by hydrogen, a lower alkyl group which may be unsubstituted or substituted by a radical or the like, and a aryl group (particularly, a lower alkylcarbonyl group) , hydroxy lower alkylcarbonyl), alkoxycarbonyl, hydroxyalkoxycarbonyl, aryl, aralkyl, cyclic lower alkyl, cyclic lower alkyloxy, thiol (SUlfUryl), sulfin a sulfinyl group, a ph〇sphoryl group, a heterocyclic group, etc. the lower alkyl group, a mercapto group (particularly, a lower alkylcarbonyl group), an alkoxycarbonyl group, an aryl group, an aralkyl group, The cyclic lower alkyl group, the cyclic lower alkoxycarbonyl group, and the heterocyclic ring are the same as defined above. 30 319771 200835687 R and R 'specifically, each of them can be augmented. Base (for example, methyl, ethyl, etc.), acetamidine, v J ^ J ^^ butyl thiol, hydrazine, Ht < two protective 1 6-hydroxyhexyl, etc., Dong Dong potential | Dilute 3 hydroxypropyl, ethoxy County, etc. Silk, oxime oxycarbonyl, 2-base octagonal shovel, the amine base / knife of the "substitutable amine group" By described in " ProtectlveGr〇upsin〇rganic

Synthesis 3rd Edition" (JohnWi ley and Sons##, 1999 年）之方誇等經保護（即取代）。r4、r5係可相同或不同。 在式（υ中以z表示之式（j ί) ·· A_B_D_E之_B_D_E部分 (分子末端）可舉例如下述之基等：β為鍵結、-簡-CO-、或 -(CH〇n-C0-(式中，η為〇至2之整數）；D為_·—或 -N(CH3)-;及e為可經取代之胺基。具體而言，u_E部 分可舉例如：-C〇-NH-NH2、-CKO-I^H-NH2、-CH2-C0-NH-NH- CH3、-CH2-C0-N(CH3)-mi2、-.CH2-C0-NH-NH-C2H5、-CH2-C0-NH-N(CH3)2> -(CH2)2-C0-NH-NH2—NH-C0-NH-NH2> -NH-NH2 > 鲁 CH2 NH 顧2、~(CH2)2-随-關2、-（CH2)3-NH-丽2、-CKO-NH- 丽-CO- CH3、-CH2-CO-丽-丽-CO-0-CH2-CH3、一CH2-CO-NH-NH-CO-0-(CH2)3-CHs、-CHrCO-丽-NH-CO-0-(CH2)2-〇H、-CH2-CO -NH- NH-CO-0-(Cfl2)9-CH3、-CH2-CO-丽-NH-CO-(CH2)2-CHs、 -CHrC0-NH-NH-CO-(CH2)5-〇H、-CH2-CO-丽-NH-C0-(CH2)8 -CH3、或者-CH2-CO-丽-匪—c〇-(CH2)rOH 等。以-（cH2)2-C0-丽-NH2、-CHrCO-丽-丽2為佳。 化合物（I)係可舉例如：N-{4_[2-(4-肼基羰基苯基） 乙基]-1，3-售嗤-2-基}乙醯胺、 31 319771 200835687 N - {4-[2-(4_肼基羰基甲基苯基）乙基]-1，3_噻唑-2-基}乙 醯胺、 N -（4 -{2-[4-(N’ -甲基肼基羰基甲基）苯基]乙基卜1，3-嗟 唑-2-基）乙醯胺、 N-（4-{2-[4-（N-甲基肼基羰基曱基）苯基]乙基}-1，3-噻唾 -2-基）乙酸胺、 N-（4-{2-[4-（Ν’ -乙基肼基羰基甲基）苯基]乙基}-1，3-,塞 唑-2-基）乙醯胺、 * Ν-(4-{2 - [4-(Ν’，Ν’ -二甲基肼基羰基甲基）苯基]乙基} ~1，3-嗔峻-2-基）乙醯胺、 Ν-{4-[2-(4-月井基獄基曱基苯基）乙基]-5-（4-胺石黃驢：基笨 甲基）-1，3-噻唑-2-基}乙醯胺、 Ν -（4-{2-[4-(2-肼基羰基乙基）苯基]乙基}-1，3-噻唑-2- 基）乙醯胺、 .. 4 -（4-{2 - [2-(乙酿基胺基）-1，3-σ塞嗤-4-基]乙基}苯基）半 •卡肼、 Ν-（4-{2-[4-〇f -乙醯基肼基羰基甲基）苯基]乙基} — ；[，3一 噻唑-2-基）乙醯胺、 N-（4-{2-[4-（Ν’ -丁醯基肼基羰基甲基）苯基]乙基} — “ 3一 噻唑-2-基）乙醯胺、 Ν -（4-{2-[4-(Ν’ -癸醯基肼基羰基甲基）苯基]乙基卜丨，3一 噻唑-2-基）乙醯胺、 Ν-[4-(2-{4-[Ν’ -（3-羥丙醯基）肼基羰基甲基]苯基丨乙基） -1，3-噻唑-2-基]乙醯胺、 319771 32 200835687 N-[4-（2-{4-[Ν’ -（6-羥己醯基）肼基羰基曱基]苯基}乙基） -1，3-噻唑-2-基]乙醯胺、 2-[(4-{2-[2-(乙醯基胺基）-1，3-噻唑-4-基]乙基}苯基） 乙酿基]耕叛酸乙醋、 2 - [(4-{2 - [2-(乙酿基胺基）-1，3 -嘆峻-4 -基]乙基}苯基） 乙酿基]耕缓酸丁 I旨、 2-[(4-{2-[2-(乙醯基胺基）-1，3-噻唑-4-基]乙基}苯基） 乙酿基]耕叛酸癸g旨、 _2-[(4-{2-[2-(乙醯基胺基）-1，3-噻唾-4-基]乙基}苯基） 乙醯基]拼緩酸2 -經乙S旨、 2-乙醯基胺基-1，3-噻唑-4-羧酸4-(肼基羰基甲基）苯酯、 N -（4-{[4-(肼基羰基曱基）苯氧基]曱基}一1，3一噻唑—2 一基） 乙醯胺、 2-（乙醯基胺基）-Ν-·[4-(肼基羰基甲基）苯基]-1，3-噻唑 -4-甲醯胺、 _ Ν-[4-({[4-（肼基羰基甲基）苯基]胺基}甲基）_1，3-噻唑 -2-基]乙醯胺、 Ν-{4-[2_(3-肼基羰基曱基苯基）乙基]—丨，3 —噻唑—2-基}乙 醯胺、 Ν-(4-{2-[5-(肼基羰基）噻吩—2-基]乙基}-1，3-噻唑-2-基） 乙酿胺、 Ν-(4-{2-[5-（肼基羰基曱基）噻吩一2一基]乙基卜1，3-噻唑 -2-基）乙醯胺、 Ν-(4-{2-[5-（2-肼基羰基乙基）噻吩一2-基]乙基丨—ι 3一噻 33 319771 200835687 唑-2-基）乙醯胺、 • N-(4-{2-[5-(2-肼基羰基乙基）噻吩-3-基]乙基卜1，3-噻 哇- 2 -基）乙酿胺、 N- {4-[2-(4-肼基苯基）乙基]-1，3-嗟嗤-2-基}乙酿胺、 N-(4-{2-[4-（肼基甲基）苯基]乙基卜1，3-噻唑-2-基）乙醯 胺、 N-（4-{2-[4-（2-肼基乙基）苯基]乙基}一；|，3一噻唑-2-基）乙 醯胺、 鲁N-（4-{2-[4-（3-肼基丙基)苯基]乙基卜n,塞哇一2一基）乙 醯胺、 N-(4-{2-[3-（2-肼基乙基）苯基]乙基丨—ι 3一噻唑一2一基）乙 隨胺、 N-（4-{2-[5-(2-肼基乙基）噻吩一2-基]乙基卜丨，3-噻唑一 基）乙酸胺、/ N-（4-{2-[5-(3-肼基丙基）噻吩—2 —基]乙基丨—丨，3 —噻唑一2一 籲基）乙醯胺等。以N-{4-[2-(4-肼基羰基曱基苯基）乙基] -1，3-噻唑-2-基}乙醯胺等為佳。 當化合物（I)在構造中具有不對稱碳原子時，本發明係 包含所有鏡像異構物及非鏡像異構物。 化合物（I)也能為醫藥上所容許之鹽。本發明中之醫藥 上所容許之鹽只要為-般醫藥上所容許之鹽且無毒性，則 無特別限制，可舉例如：與無機或有機驗之鹽、酸加成鹽 =。與無機或有機驗之鹽則可舉例如：驗金屬鹽（例如：納 里'鉀鹽等）、驗土金屬鹽（例如：齊鹽、鎂鹽等）、録鹽、 319771 34 200835687 及胺鹽（例如：三乙胺鹽、N_苯曱基_N_甲基胺鹽等）等，峻 加成鹽則可舉例如：從無機酸（例如：鹽酸、氫溴酸、氫碘 酸、磷酸、偏磷酸、硝酸及硫酸）所衍生之鹽、及從有機酸 (例如：酒石酸、醋酸 '檸檬酸、蘋果酸、乳酸、反丁烯= 酸y頓丁烯二酸、安息香酸、經乙酸、葡萄糖酸、號轴酸 及芳基磺酸（例如：對甲苯磺酸））所衍生之鹽等。 本發明之化合物係能使用後述醫藥等作為前驅藥物。 用語「前驅藥物」係包含投予後會在體内轉換成版^抑 制劑之所有化合物。該前驅藥物係可為本發明之化合物之 任何醫藥上所容許之前驅藥物。 本鲞月之化合物旎使用作為VAp— 1抑制劑、vap一 1相 關疾病之預防或治療用醫藥等醫藥之活性成分。 主「血管黏附蛋白質-1(VAIM)相關疾病」只要為疾病之 表現及/或進度與秦1相關之疾病則無特別較，包括 仗由血官通透性宄進疾病[例如：黃斑部水禮（例如：糖尿 =性及非糖尿病黃斑料腫）、老年性黃斑部·、 2狀黃斑部退化、餘黃簡水腫、《水腫、視網膜水 f、糖尿病性視網膜病變、脈絡視網膜病變、新生血管性 赚部病變、新生血管性青光眼、葡萄膜炎、紅 視 網膜血管炎、眼内炎、入咿诂火 ^ 人視 視網膜多去… 火、轉移性眼炎、脈絡膜炎、 / 、： 火、結膜炎、睫狀體炎、鞏膜炎 ::視神經炎、球後視神經炎、角膜炎、眠瞼炎、滲：： 角膜潰瘍、結膜潰瘍、慢性錢幣狀角膜炎、 林氏角膜炎、進行性侵钱性角膜潰瘍、由細菌感染或 319771 35 200835687 •病毒2染及由眼科手術引起之眼炎性疾病、由眼睛之物理 員^)W引起之眼义性疾病、由包括癢、發紅、水腫及潰瘍 =眼炎性疾病引起之症狀、紅斑、多形性滲出性紅斑、結 節性、=斑、環狀紅斑、硬腫症、皮膚炎(例如：乾癬、過敏 變、扁平苔癖、玫瑰糠疹、接觸性皮膚炎、異位性皮 f、火毛蕞性紅色糠疹）、血管神經病性水腫、咽喉水腫、 f門水腫、聲門下咽喉炎、支氣管炎、鼻炎、咽喉炎、鼻 寶炎及咽喉炎或中耳炎]、肝硬化、原發性固定性高血壓二 糖尿，、動脈硬化、（例如··糖尿病、動脈硬化及高血壓之） Μ，知^糖尿病及***相關之d管疾病、痛風及關 p人相關之疼痛、結締組織之炎性疾病或症狀（例如：類風 ^關節炎、僵直性脊椎炎、乾癬性關節炎及骨關節炎或 =化性關節疾病、萊特氏症候群、修格M氏症鱗、貝塞 =压候群、復發性多軟骨炎、全身性紅斑性狼瘡、圓盤 y、ΪΪ⑨狼瘡、全身性硬化症、嗜酸性筋膜炎、多發性肌 二炎、風濕性多肌痛症、血管炎、暫時性關節炎、 =夕動脈炎、韋格納氏肉芽腫病、混合結缔組織疾病、 年型類風濕性關節炎）；消化管之炎性疾病或症狀[例 肝臟之纖Ί“性大腸炎、腸躁症(例如:痙攣性結腸)、 臟之纖維化、Π腔黏膜之發炎（例如：口 炎神經系統之炎性疾病或症狀（例如：多發 障礙）.症肺默症、及缺血性中風相關之缺血再灌流 候群、Γ 或症狀（例如：氣喘、成人呼吸窘迫症 、_>性阻塞性肺“）；包括微㈣ 319771 36 200835687 礙脈硬、視網膜簡、腎病、腎病症候群及神經障 礙）、足生ί發性神經障礙、單一神經障礙及自律神經障 物㈣/ 關節之問題及感染風險之增加）之碳水化合 …目關疾病（例如：糖尿病及來自糖尿病之併發症）· 之分化或機能或者平滑肌細胞之機能之異;相關 ;、’丙f列如.動脈硬化及肥大）；血管疾病[例如：包括動 ::11化：非動脈粥狀硬化、心肌梗塞及周邊動脈阻塞 性血其火=臟疾病、雷諾氏症及雷諾氏現象、阻塞性血栓 二列!3 ··柏格氏症）];慢性關節炎；炎性腸疾病； =:=!症[例如:糖尿病(例如:胰島素依賴型糖尿 )及非胰島素依賴型糖尿病⑽歸)) (例如:心臟病發作、狹心症、中風、切除、失明；:二 不全)「]等組成之群中選出之疾病。 月及月功- γ「血管黏附蛋白質-UVAH).㈣疾病 係為了上述VAP]相關疾病之治療（可包 ^口療」 ★症狀之消退、進度停止及治癒)之目的，而將且有二 ^㈣之棒似竭物蝴助對象1 本發明中之醫藥、醫藥組成物、νΑρ]抑制劑m 之預防或治療用醫藥（以下，也將此等總稱為 明之商樂）之料對象係各種動物（例如：人類 : 鼠、豬m、牛等哺乳動物，特別是人類JV。 本發明之醫藥係能經由任何途徑投予。本發中 319771 37 200835687 予）、局部投予、目艮周圍投予（例如：眼球筋 ， capsule)下投予）、結膜投予、眼内投予、、—en〇n s 脈絡膜上（SUpraehQrc)i如）投予及眼球:予=下投予、 發明之醫藥之方式可依 广# °投予本 任一應用等㈣當蚊。 關以㈣或治療性地 本發明之醫藥係以哺乳動物、特別是人類之 象’在判斷為具有VAP—丨相關疾病之 '又、 性户瘃），弋本^设迅速投予（預防Synthesis 3rd Edition" (John Wiley and Sons##, 1999) is protected (ie replaced). The r4 and r5 systems may be the same or different. The _B_D_E portion (molecular end) of the formula (j ί) · A_B_D_E in the formula (υ) may be, for example, the following group: β is a bond, - Jane-CO-, or -(CH〇n) -C0- (wherein η is an integer from 〇 to 2); D is _·- or -N(CH3)-; and e is a substitutable amine group. Specifically, the u_E moiety may, for example: C〇-NH-NH2, -CKO-I^H-NH2, -CH2-C0-NH-NH-CH3, -CH2-C0-N(CH3)-mi2,-.CH2-C0-NH-NH-C2H5 , -CH2-C0-NH-N(CH3)2>-(CH2)2-C0-NH-NH2-NH-C0-NH-NH2> -NH-NH2 > Lu CH2 NH Gu 2,~(CH2) 2---off 2, -(CH2)3-NH-Li 2, -CKO-NH-Li-CO-CH3, -CH2-CO-Li-Li-CO-0-CH2-CH3, one CH2-CO -NH-NH-CO-0-(CH2)3-CHs, -CHrCO-Li-NH-CO-0-(CH2)2-〇H, -CH2-CO-NH-NH-CO-0-(Cfl2 9-CH3, -CH2-CO-Li-NH-CO-(CH2)2-CHs, -CHrC0-NH-NH-CO-(CH2)5-〇H, -CH2-CO-Li-NH-C0 -(CH2)8-CH3, or -CH2-CO-Li-匪-c〇-(CH2)rOH, etc. Preferably, -(cH2)2-C0-Li-NH2, -CHrCO-Li-Li 2 is preferred. The compound (I) is exemplified by N-{4_[2-(4-mercaptocarbonylphenyl)ethyl]-1,3-mercapto-2-yl}acetamide, 31 319771 200835687 N - { 4-[2-(4_肼基Methylphenyl)ethyl]-1,3-thiazol-2-yl}acetamide, N-(4-{2-[4-(N'-methyldecylcarbonylmethyl)phenyl] Ethyl 1,3-1,3-oxazol-2-yl)acetamide, N-(4-{2-[4-(N-methyldecylcarbonylindenyl)phenyl]ethyl}-1,3 -thiazol-2-yl)acetic acid amine, N-(4-{2-[4-(Ν'-ethylhydrazinocarbonylmethyl)phenyl]ethyl}-1,3-, pyrazole-2 -yl)acetamide, * Ν-(4-{2 - [4-(Ν',Ν'-dimethylcarbonylcarbonylmethyl)phenyl]ethyl} ~1,3-嗔峻-2 -yl)acetamide, Ν-{4-[2-(4-月井基狱基基phenyl)ethyl]-5-(4-amine scutellaria: phenylmethyl)-1, 3-thiazol-2-yl}acetamide, Ν-(4-{2-[4-(2-mercaptocarbonylethyl)phenyl]ethyl}-1,3-thiazol-2-yl) Indoleamine, .. 4 -(4-{2 - [2-(ethylamino)-1,3-σ塞嗤-4-yl]ethyl}phenyl)-half-carmine, Ν-( 4-{2-[4-〇f-ethylhydrazinylcarbonylmethyl)phenyl]ethyl} — ;[,3-thiazol-2-yl)acetamide, N-(4-{2- [4-(Ν'-Butytylcarbonylcarbonylmethyl)phenyl]ethyl} — “3-thiazol-2-yl)acetamide, Ν-(4-{2 -[4-(Ν'-fluorenylcarbonylmethyl)phenyl]ethylidene, 3-thiazole-2-yl)acetamide, Ν-[4-(2-{4-[Ν '-(3-Hydroxypropyl decyl) decylcarbonylmethyl]phenyl hydrazinoethyl)-1,3-thiazol-2-yl]acetamidamine, 319771 32 200835687 N-[4-(2-{4 -[Ν'-(6-hydroxyhexyl)decylcarbonylindenyl]phenyl}ethyl)-1,3-thiazol-2-yl]acetamide, 2-[(4-{2-[ 2-(Ethylamino)-1,3-thiazol-4-yl]ethyl}phenyl) Ethyl] cultivating acid vinegar, 2 - [(4-{2 - [2-(B Stearylamino)-1,3 - sulphate-4 -yl]ethyl}phenyl) ethoxylate] 耕 酸 酸 旨, 2-[(4-{2-[2-(ethyl fluorenyl) Amino)-1,3-thiazol-4-yl]ethyl}phenyl) ethoxylate] 耕 叛 癸 旨 旨, _2-[(4-{2-[2-(ethinylamino)) -1,3-thiasin-4-yl]ethyl}phenyl)ethyl hydrazide]2,2-ethylamino-1,3-thiazole-4-carboxylic acid 4-(decylcarbonylmethyl)phenyl ester, N-(4-{[4-(indolylcarbonylindenyl)phenoxy]indolyl}-1,3-thiazol-2-yl)acetamide, 2-(Ethylamino)-indole-·[4-(indolylcarbonylmethyl)phenyl]-1,3-thiazole-4-carboxamide _ [-[4-({[4-(indolylcarbonylmethyl)phenyl]amino}methyl)-1,3-1,3-thiazol-2-yl]acetamidine, Ν-{4-[2_(3 - mercaptocarbonylcarbonylphenyl)ethyl]-indole, 3-thiazole-2-yl}acetamide, Ν-(4-{2-[5-(fluorenylcarbonyl)thiophene-2-yl]B }}-1,3-thiazol-2-yl) Ethylamine, Ν-(4-{2-[5-(indolylcarbonylindenyl)thiophene-2-yl]ethyl 1,3-thiazole- 2-yl) acetamidine, Ν-(4-{2-[5-(2-mercaptocarbonylethyl)thiophene-2-yl]ethyl hydrazine-ι 3 monothia 33 319771 200835687 oxazol-2-yl Ethylamine, • N-(4-{2-[5-(2-mercaptocarbonylethyl)thiophen-3-yl]ethyl 1,3- thiazol-2-yl)ethinamide, N-{4-[2-(4-Mercaptophenyl)ethyl]-1,3-indol-2-yl}ethinylamine, N-(4-{2-[4-(indenyl) Phenyl]ethyl 1,3-1,3-thiazol-2-yl)acetamide, N-(4-{2-[4-(2-mercaptoethyl)phenyl]ethyl}-; , 3- thiazol-2-yl)acetamide, Lu N-(4-{2-[4-(3-mercaptopropyl)phenyl]ethyl b, Sawa 2-1-yl) Amine, N-(4-{2-[3-(2-mercaptoethyl)phenyl]ethyl hydrazine-ι 3 -thiazole-2-yl) N-(4-{2-[5-(2-Mercaptoethyl)thiophen-2-yl]ethylidene, 3-thiazole-yl)acetic acid amine, / N-(4-{2-[5 -(3-Mercaptopropyl)thiophen-2-yl]ethyl hydrazine-hydrazine, 3-thiazole 2-yl-yl acetamide, and the like. N-{4-[2-(4-fluorenylcarbonylnonylphenyl)ethyl]-1,3-thiazol-2-yl}acetamide or the like is preferred. When compound (I) has an asymmetric carbon atom in the structure, the present invention encompasses all of the image isomers and non-image isomers. Compound (I) can also be a pharmaceutically acceptable salt. The salt to be pharmaceutically acceptable in the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt and is not toxic, and examples thereof include an inorganic or organic salt and an acid addition salt. The salts with inorganic or organic tests may, for example, be metal salts (for example: Nari 'potassium salt, etc.), soil test metal salts (for example: salt, magnesium salt, etc.), salt, 319771 34 200835687 and amine salts. (for example, triethylamine salt, N-benzoinyl_N-methylamine salt, etc.), etc., for example, mineral acid (for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid) , salts derived from metaphosphoric acid, nitric acid, and sulfuric acid, and organic acids (eg, tartaric acid, acetic acid 'citric acid, malic acid, lactic acid, transbutene = acid ydonic acid, benzoic acid, acetic acid, A salt derived from gluconic acid, claric acid, and an arylsulfonic acid (for example, p-toluenesulfonic acid). As the compound of the present invention, a pharmaceutical or the like described later can be used as a prodrug. The term "precursor drug" is intended to include all compounds which are converted into a formulation in vivo after administration. The prodrug may be any pharmaceutically acceptable prodrug of the compound of the invention. The compound of this month is used as an active ingredient of a medicine such as a VAP-1 inhibitor, a prophylactic or therapeutic drug for vap-1 related diseases. The main "vascular adhesion protein-1 (VAIM)-related disease" is not particularly specific as long as the disease manifests itself and/or progresses with the disease associated with Qin 1, including sputum-passage hyperemia (eg, macular water) Ceremony (eg, diabetes = sexual and non-diabetic macular swelling), age-related macular area, 2-like macular degeneration, residual edema, "edema, retinal water f, diabetic retinopathy, choroidal retinopathy, neovascularization Sexually acquired lesions, neovascular glaucoma, uveitis, red retinitis vasculitis, endophthalmitis, sputum fire ^ people see more retinal ... fire, metastatic ophthalmia, choroiditis, /,: fire, conjunctivitis , ciliary body inflammation, scleritis: optic neuritis, retrobulbar optic neuritis, keratitis, sputum inflammation, osmosis:: corneal ulcer, conjunctival ulcer, chronic coin keratitis, Lin keratitis, progressive invasiveness Corneal ulcer, infection by bacteria or 319771 35 200835687 • Virus 2 infection and eye inflammatory disease caused by ophthalmic surgery, eye disease caused by physicists of the eye ^) W, including itching, redness, edema And ulcers = symptoms caused by ocular inflammatory diseases, erythema, polymorphous exudative erythema, nodular, = plaque, ring erythema, scleredema, dermatitis (eg dry, allergic, lichen planus, rose 糠Rash, contact dermatitis, atopic skin f, edema red pityriasis, vascular neuropathic edema, throat edema, f-edema, subglottic pharyngitis, bronchitis, rhinitis, pharyngitis, nasal fever And otitis media or otitis media], cirrhosis, primary fixed hypertension, disaccharide, arteriosclerosis, (for example, diabetes, arteriosclerosis, and hypertension), knowing diabetes and uremia-related diseases Gout, pain associated with p-person, inflammatory disease or symptoms of connective tissue (eg, wind-like arthritis, ankylosing spondylitis, dry arthritis and osteoarthritis or = joint disease, Wright's syndrome) , repairing M's scale, Bessel = pressure group, recurrent polychondritis, systemic lupus erythematosus, disc y, ΪΪ9 lupus, systemic sclerosis, eosinophilic fasciitis, multiple myocarditis Rheumatic polymyalgia , vasculitis, temporary arthritis, = ectopic arteritis, Wegener's granulomatosis, mixed connective tissue disease, type of rheumatoid arthritis); inflammatory diseases or symptoms of the digestive tract [eg liver fibrosis] "Scrotic colitis, intestinal fistula (eg, spastic colon), visceral fibrosis, inflammation of the mucosa of the sacral cavity (eg inflammatory disease or symptoms of the stomatous nervous system (eg multiple dysfunction). And ischemic stroke-related ischemia-reperfusion, sputum or symptoms (eg, asthma, adult respiratory distress, _> obstructive pulmonary); including micro (4) 319771 36 200835687 Kidney disease, renal syndrome and neurological disorders), vaginal neurological disorders, single neurological disorders and autonomic schizophrenia (4) / joint problems and increased risk of infection) carbonation...constrained diseases (eg diabetes and diabetes) Complications) · Differentiation or function or function of smooth muscle cells; related;, 'C f column such as arteriosclerosis and hypertrophy; vascular disease [eg: including:: 11: non-atherosclerotic , myocardial infarction and peripheral arterial obstructive blood fire = dirty disease, Raynaud's disease and Raynaud's phenomenon, obstructive thrombosis two! 3 · · Berg's disease)]; chronic arthritis; inflammatory bowel disease; :=! [eg diabetes (eg insulin-dependent diabetes) and non-insulin-dependent diabetes (10)) (eg heart attack, angina, stroke, resection, blindness;: incomplete) "], etc. The disease selected from the group consisting of. Month and Moon Power - γ "vascular adhesion protein - UVAH". (4) The disease system is for the treatment of the above VAP] related diseases (can be included in the treatment) ★ the symptoms are resolved, the progress is stopped and cured, and there will be two (4) A stick-like object of the present invention 1 The medicines, pharmaceutical compositions, and νΑρ] inhibitors of the present invention are used for the prevention or treatment of medicines (hereinafter, these are also collectively referred to as the business of Mingzhi). Animals (for example: humans: mammals such as rats, pigs m, cattle, etc., especially human JV. The medical system of the present invention can be administered by any route. 319771 37 200835687 in this issue), topical administration, and peripheral administration (for example: under the eyeball, capsule), conjunctival administration, intraocular administration, -en〇ns choroidal (SUpraehQrc) i, as well as eyeballs: pre-dose, invented medicine The method can be applied to any application, etc. (4) when the mosquito is used. (4) or therapeutically, the medicine of the present invention is a mammal, especially a human being, which is judged to have a VAP-丨 related disease, and is rapidly administered (prevention).

予對象在VAP—1相關疾病開始發病後迅 ^又予u療性治療）為佳。治療計晝可依所使用之活性成 :刀之種類、投予量、投予途徑、病因、及需要及依VAIM 相關疾病之自覺程度等而適當選擇。 本發明之醫藥之投予方法能使用_般醫藥之本身已周 知之方法。投予途徑可適當選擇有效途徑，此外，能使用 或2種以上之& #。因此’上述投予途徑係僅為例示， 並非限定於此等。 • 針對包括人類之動物，特別是人類之投予對象之本發 明之醫樂之用量（投予量），只要在合理之期間内對投予對 象s足以達到所需之反應之量即可。用量可依包括所使用 之活性成分之強度、投予對象之年齡、種類、症狀或疾病 之狀態及體重以及疾病之程度之各種因子、投予途徑、時 機及次數等而適當決定。此外用量可依投予途徑、時機及 人數等而適當調整。依症狀或疾病之狀態，有時也可能必 須施予需複數次投予之長期治療。 用里及投予冲晝此依該領域中具通常知識者在一般已 319771 38 200835687 周知之範圍中所發現之技術決^。—般而言，治療或預防 係從化合物之最適用量更少之用量開始。之後，在此狀況 下逐次少量增加用量直到可得到最適效果。本發明之醫藥 (VAP_1抑制劑等）通常能以約〇. 體重/日至約 300mg/kg體重/日之用量，較宜以約q.⑽心體重 /日至j lOmg/kg體重/日之用量，每日投予單次或是投 予2至4次或持續投予。 本發明之醫藥組成物係以包括「醫藥上所容許之載 體」、及作為活性成分之足以預防性或治療性處置黏】 之量之本發明之化合物㈣抑制劑)為佳。载 f可為任何可使用作為醫藥之载體，此係除了受物理化 項目⑷如：溶解度、及對於該化合物之反應性 之人缺）及投予途徑所限定之情形外，不特別限定。 方改之本發明之化合物之量可依組成物之配 二:通常在。._至10.0重量%，且以_至5 重里％為么，以〇· 〇〇1至1重量％更佳。 本發明醫藥之投予形態不特別限定，為了達 VAP-1抑制作用能以各種型態投予。本發明 :太 ^之化合物單獨或與醫藥上所容許之载體或==本 输合而製劑化後，再經口或非經口投 :性質係依所使用之活性成分之溶解度及化學 2投予途徑及標準之藥學實務而決定。用於二4: 體形態（溶液或懸浮液）等。用於非經口投/之制劍）或液 仅卞之製劑可舉例 319771 39 200835687 如.無菌溶液或懸浮液形態之注射、點滴等。固體經口夢 劑可含有-般之賦形劑等。液體經口製劑可含有各種芳香 劑、著色劑、防腐劑、穩定劑、可溶化劑或懸浮劑等。非 經口製劑係例如：無菌之水性或非水性之溶液或懸浮液， 且可含有特定之各種防腐劑、穩定劑、緩衝劑、可溶化劑 或懸洋劑等。依需要，也可添加各種等滲透壓劑。 本發明之醫藥係只要不妨礙本發明之效果，則也可含 有其他藥學上之活性化合物。 本叙明之醫樂係只要不妨礙本發明之效果，也可同時 投予其他藥學上之活性化合物。「同時投予」係意指，將其 他樂學上之活性化合物，在投予本發明之醫藥前、同時（例 如·在同一製劑或其他製劑中）或在投予本發明之醫藥後投 予。能同時投予例如：皮質類固醇（c〇rtic〇ster〇id)、強 體松（predniSOne)、甲基強體松、***（dexamethas〇ne) 或疋曲女奈德（计1&111(^11〇1〇116 3061：01^(16)或非皮質類固 _醇抗炎性化合物（例如··伊布洛芬（ibupr〇fen)或氟比洛芬 (flurbiprofen))。同樣地，能同時投予維生素及礦物質（例 如··辞、抗氧化劑（例如··類胡蘿蔔素（例如··如葉黃素 (xanthophyll)類胡蘿蔔素之玉米黃質（zeaxanthin)或黃 體素（lutein))))以及微量營養等。 本發明之化合物係有用於製造如VAP-1抑制劑、VAP -1 相關疾病之預防或治療用醫藥之醫藥。 化合物（I)係能以以下順序製造，但並非限定於該順 序。該領域中具通常知識者係能依一般本身已周知之方法 40 319771 200835687 改變順序。化合物（i)也能以下式表示 R1—Μ Η—X—Y—Am (式中，各έ己號係與前述定義相同）。 將化合物⑴之製造方法之順序表示於下述方宰 化合物⑴可將下述方案工中所表示之部分構造之3 個化合物（1)、⑵、⑶進行化學鍵結而製 (2)、（3)也可使用其鹽。 口物（1)、 鍵結之順序係在使⑴與⑵鍵結後再與⑶鍵处 形，以及先使⑵與⑶鍵結最後與⑴鍵結之方法，月 :順序皆能製造化合物⑴。此外’依需要而進行D 護反應時’有時會轉換成t藥上所料之鹽。化合⑴、 非限定於該順序’該領域中具”知識者 係月b依一般本身已周知之方法適當改變順序 方案1 - 'It is better to give the subject a rapid therapeutic treatment after the onset of VAP-1 related diseases. The therapeutic plan can be appropriately selected depending on the type of the agent to be used, the type of the knife, the dosage, the route of administration, the cause, and the need, and the degree of self-consciousness of the VAIM-related disease. The method of administering the medicine of the present invention can be carried out by a method known per se. The route of administration can be appropriately selected, and in addition, two or more & Therefore, the above-mentioned administration route is merely an example, and is not limited thereto. • The dosage (administration amount) of the present invention for a human, especially a human, to be administered to a subject, as long as the administration of the object s is sufficient to achieve the desired response within a reasonable period of time. The amount may be appropriately determined depending on the strength of the active ingredient to be used, the age, type, symptoms, state of the disease, the state of the disease, the body weight and the degree of the disease, various factors, the route of administration, the timing and the number of times. In addition, the dosage can be adjusted according to the route of administration, timing and number of people. Depending on the state of the symptoms or disease, it may sometimes be necessary to administer a long-term treatment that requires multiple administrations. It is used in the context of the technical know-how found in the general knowledge of 319771 38 200835687. In general, treatment or prevention begins with a lower amount of the compound that is most suitable. After that, in this case, the amount is gradually increased by a small amount until the optimum effect is obtained. The medicament of the present invention (VAP_1 inhibitor, etc.) can usually be used at a dose of about 〇. body weight/day to about 300 mg/kg body weight/day, preferably about q. (10) heart weight/day to j10 mg/kg body weight/day. The dosage is administered once a day or 2 to 4 times or continuously. The pharmaceutical composition of the present invention is preferably a compound (IV) inhibitor of the present invention comprising "a pharmaceutically acceptable carrier" and an amount sufficient to prevent or therapeutically treat the adhesive as an active ingredient. The carrier f may be any carrier which can be used as a medicine, and is not particularly limited except for the case where it is limited by the physicalization item (4) such as solubility, reactivity to the compound, and the route of administration. The amount of the compound of the present invention may vary depending on the composition of the composition. ._ to 10.0% by weight, and _ to 5% by weight, more preferably 〇· 〇〇1 to 1% by weight. The administration form of the pharmaceutical of the present invention is not particularly limited, and can be administered in various forms in order to achieve VAP-1 inhibition. The present invention: the compound of the compound is prepared by oral or parenteral administration, either alone or in combination with a pharmaceutically acceptable carrier or == this conversion: the solubility and the chemical of the active ingredient used according to the nature 2 It is determined by the route of administration and the standard pharmaceutical practice. For the second 4: body form (solution or suspension) and so on. For the preparation of non-oral injection / sputum) or liquid only sputum preparation can be exemplified 319771 39 200835687 such as injection, drip, etc. in the form of sterile solution or suspension. The solid oral preparation may contain a general excipient or the like. Liquid oral preparations may contain various fragrances, coloring agents, preservatives, stabilizers, solubilizing or suspending agents, and the like. The parenteral preparation is, for example, a sterile aqueous or nonaqueous solution or suspension, and may contain specific preservatives, stabilizers, buffers, solubilizing agents or suspending agents, and the like. Various isotonizing agents may also be added as needed. The pharmaceutical system of the present invention may contain other pharmaceutically active compounds as long as it does not interfere with the effects of the present invention. The medical music of the present invention may also be administered with other pharmaceutically active compounds at the same time as long as it does not interfere with the effects of the present invention. "Simultaneous administration" means the administration of other orally active compounds prior to administration of the medicament of the present invention, simultaneously (for example, in the same preparation or other preparations) or after administration of the medicament of the present invention. . Simultaneous administration of, for example, corticosteroids (c〇rtic〇ster〇id), predniSone, methylprednisone, dexamethas〇ne or distorted female Ned (1 & 111 (^11〇1〇116 3061:01^(16) or a non-corticosteroid anti-inflammatory compound (for example, ibuprofen or flurbiprofen). Can simultaneously give vitamins and minerals (such as · rhetoric, antioxidants (such as · carotenoids (such as · xanthophyll (xanthophyll) carotenoids of zeaxanthin or lutein (lutein ())) The compound of the present invention is a medicine for the manufacture of a medicament for the prophylaxis or treatment of a VAP-1 inhibitor or a VAP-1 related disease. The compound (I) can be produced in the following order, but It is not limited to this order. Those who have ordinary knowledge in the field can change the order according to the generally known method 40 319771 200835687. Compound (i) can also represent R1 - Μ Η - X - Y - Am (where , each of which is the same as defined above.) The manufacturer of the compound (1) The order of the compound (1) can be chemically bonded to the three compounds (1), (2), and (3) of the partial structure represented by the following scheme. (2), (3) The order of the mouth (1) and the bond is the method of bonding the (1) and (2) and then the (3) bond, and first (2) and (3) bonding and finally (1) bonding. (1) In addition, when the D-protection reaction is carried out as needed, it may be converted into the salt of the t-drug. The compound (1) is not limited to the order of the knowledge in the field. The method of changing the order appropriately 1 - '

^各式中，R、X、Y、A、B、D & E係與前述定義相同。^ ^與=合物（2)之L3形成化學鍵結而形成γ之反應性官能 基。L係與化合物⑴之L2形成化學鍵結㈣成γ之反應 能基。1/係為了在化合物⑴之分子末端構築肼構造， 鉍基肼構造而與化合物（3)反應，構築β之官能基。L5孫 氫、低級烷基、烷氧基羰基、醯基或保護基）。土 ， 319771 41 200835687 化合物（1)之L2係用於與化合物⑵之l3形成化學鍵姓 而形成γ所需之反應性官能基，例如：一⑽2)『CH〇、 -(CH2)u-0H> -(CH2)u-i^ , -(CHOu-COOH^ -CCH2)u-C0-i 素、-(ch2)「nh2、-(CH2)u-S〇3H、_(CH2)u_s〇2_鹵素、或從 (CH2)u-0H 所何生之-(CH2)u_〇—醯基（例如：—（cH^u_〇_ 乙 酸基等）、-(ch2)u-石黃酸酷（例如：_(CH2)u__2CH4)、或 者從-(CH2)u-齒素等所衍生之Wittig試劑等（各式中，以系 〇至6之整數。鹵素可例示如··氯、溴、蛾），但並非限定 於此等。 化合物（1)或其鹽可為市售物，或也能依記載於國際公 開第2004/067521號等之本身已周知之方法製造。 化合物⑵之L3係用於與化合物⑴之L2形成化學鍵結 而形成Y所需之反應性官能基，例如：_(Cg2)、 -(CHOv-OH > -(CH〇v-i ^ > -(CH2)v-C00H ^ -(CH〇v-C0-i 素、-(CH2)V-NH2、-(CH2)v-S〇3H、-(C&2)v_s〇2_ ㈣、或從 Φ -(CH2)v-0H 所衍生之-(CHOv-0-酸基（例如：_(CH2)v_〇一乙 it基等）、-(ch2)4酸酯（例如：_(CH2)v—曝CH3等）、或 者從-(CH2)V-鹵素等所衍生之Wittig試劑等（各式中，V係 〇至6之整數；i素可例示如：氯U)，但並非特別 限定。L4係用於在化合物（1)之分子末端構築肼構造、醯基 肼構造而與化合物（3)反應，構築b所需之官能基，例如： -(CH2)w-CH0、-(CH2)w-0H、-(CH〇w-自素、_(CH2)w_C00H、 -(CH2)f CO-齒素、-(CH2)w-NHR2 等（各式中，w 係 〇 至 6 之 整數。鹵素可例不如.氯、溴、碘。係與前述定義相同）， 319771 42 200835687 但並非特別限定。 .化合物⑵或其鹽可為市售物，或也能依記载於國卜、 開弟2004/ 067521號、國際公開第2_/〇⑽“虎二 本身已周知之方法製造。 U、 1合物⑶係在化合物⑴之分子末端構築肼構造、酿 基肼構造用之肼等價體，可為市售物，或也能依本身已周 知之方法製造。此外，所謂L5中之保護基，係為了 必要反應之目的而導入，且直到最後步驟才去除之官能基 之情形，可舉例如：如製造例所示之（CH3)3C_〇c〇_等保蠖 基。L5中之低級烧基、烧氧基幾基、釀基係可例示如盘前 述以R3表示之低級烧基、燒氧基㈣、酿基為同樣者。 當製造Y為碳鏈之化合物（1)時，係利用反應、 H〇mer-E_〇ns反應、醛醇縮合反應、Claisen縮合、咸類 似之石炭-碳鍵結形成反應，使化合物⑴或其鹽、盘化合物 ⑺或其鹽（或者已預先使化合物⑵與⑶縮合之化合物） 進行化學鍵結，而構築含有低級伸烯基或者低級伸快基之 Y。化合物（1)及（2)之適當之鹽係可為與已例示於化合物（1〕 者相同。雖可利用各種碳-碳鍵結形成反應，但利用Wttig ^應、及其類似反應時，作為較佳例L2*_(CH2)u_CH〇，且 \為從-(CH2)V-鹵素等所衍生之鱗鹽類（Wittig試劑），或 為從-(CH2)U-鹵素等所衍生之鱗鹽類（Wittig試劑），且 L3為-(CHA-CHO為佳（各式中，u、v係與前述定義相同。 齒素可例示如：氯、溴、碘）。反應通常在如N，N-二甲基 甲醯胺、二甲基亞磲（dimethyl sulf〇xide)、四氫呋喃、 319771 43 200835687 1 及不會對反應造成不良影塑之 有機溶劑、或該等之混人必士 民以Θ之其他 & ^ y 物中，在三級丁醇鉀、氫化鈉、 虱氧化鈉等一般驗存在下 _ 下進仃。反應溫度不特別重要，反 應係在冷部下至加熱下推 ^ 颅 …仃。生成物係能藉由濃縮、在減 1下之心、溶劑萃取、結晶、再結晶 已周知之分離或精製手段而留咕士从刮 ^層析寻 于1 又而早離或精製，此外，也能轉換 成與已例示於化合物(I)之鹽同樣之鹽。 H纟1將低級伸烯基或者低級伸块基氫化而轉 換成低級伸絲。當將γ_成伸縣鍵結時，係在各種 均-糸觸媒、或不均一系觸媒存在下，依一般方法進行氫 化反應。其中尤以使用不均一系觸媒之接觸氯化為佳，且 在如鈀碳之觸媒存在下進行。 當製造γ為含有酯、醯胺或磺醯胺之基之化合物（1) 時，係使化合物⑴或其鹽、與化合物⑵或其鹽（或者已預 先使化合物⑵與⑶縮合之化合物）縮合，而難g|或醢胺 籲鍵結。此日夺，L2為-(CH2)U_0H、_(CH2)u一匪…（CH2)u_齒素 等，且 l3為-(ch2)v-cooh、-(ch2)v-co-由素、一⑽2)v_s〇3H、 -(CH2)v-S〇2-鹵素等，《l2 為-(CH2)u-C_、_(CH2)u—c〇 一齒 素、-(CH2)u-S〇3H、-(CH2)u-S〇2-鹵素等，且 L3g_(CH2)v_〇H、 -(Cii2)v-NH2、-(CH2)V-卣素等，並能按照一般有機合成手法 構築Y(各式中，u、v係與前述定義相同。鹵素可例示如： 氯、溴、碘）。反應通常在如二氯甲烷、丙酮、四氫呋喃、 ***、N，N-二甲基甲醯胺之一般溶劑、及不會對反應造成 不良影響之任何其他有機溶劑、或該等之混合物中進行。 319771 44 200835687 •，依需要’使用1-乙基—3 —(3 —二甲胺基丙基）碳二亞胺 • (carbodiimide)鹽酸鹽、N，N，-二環己基碳二亞胺、N，N，一 羰基一咪唑等縮合劑。此外，也可在如N，N-二甲基_4一胺 基比定1羥基笨并***、1-羥基琥珀醯亞胺、3, 二氫 /皂基4酮基-i，2,3-苯并三畊（benz〇triazine)之添加 刈存在下進行。反應溫度不特別重要，反應係在冷卻下至 加熱下進行。 t製造¥為含有胺之基之化合物（I)時，L2為-(CH2)u-眺或其鹽等，且L3為-(CH2)v—CH〇、_(CH〇广齒素等，或 lL2、Vcho、_(CH〇u_齒素等，且 l3為一（cH2)邊或 其鹽^，並能按照—般有機合成手法構築Y(各式中，u、v =與前，定義相同。_素可例示如··氯、溴、硬）。反應通 ㊉以四氫Π夫喃、乙基_、醇類等__般溶劑、及不會對反應 造成不良影響之任何其他有機溶劑、或該等之混合物作為 反應溶劑，錢胺與㈣合成Sehiff鹼後，再㈣氯化鋼 鲁或鼠獨氫化納等還原而構築二級胺構造。或是經由胺與齒 :化合物之縮合反應也可構築相同構造。當利用鹵化物 ^ ’係使m二異丙胺、三乙胺、碳酸鉀等驗作為反應 劑，且使用如四氫吱喃、乙腈、N，N_二甲基甲酿胺之一般 溶劑、及不會對反應造成不良影響之任何其他有機溶劑、 或該等之混合物作為反應溶劑。反應溫度不特別重要，反 應係在冷卻下至加熱下進行。生成物係也能轉換成與已例 不於化合物（I)之鹽為相同之鹽。 當製造Y為含有醚鍵結之基之化合物（1)時，係[2為 319771 45 200835687In the formulas, R, X, Y, A, B, D & E are the same as defined above. ^ ^ forms a chemical bond with L3 of the compound (2) to form a reactive functional group of γ. The L system forms a chemical bond (4) with L2 of the compound (1) to form a reaction group of γ. 1/ In order to construct a fluorene structure at the molecular end of the compound (1) and react with the compound (3), a functional group of β is constructed. L5 Sun Hydrogen, lower alkyl, alkoxycarbonyl, fluorenyl or protecting group). Soil, 319771 41 200835687 The L2 of the compound (1) is used for forming a chemical bond with the l3 of the compound (2) to form a reactive functional group required for γ, for example: one (10) 2) "CH〇, -(CH2)u-0H> -(CH2)ui^ , -(CHOu-COOH^ -CCH2)u-C0-i, -(ch2)"nh2, -(CH2)uS〇3H, _(CH2)u_s〇2_halogen, or (CH2)u-0H What is the birth of -(CH2)u_〇-醯 base (for example: - (cH^u_〇_ acetate, etc.), -(ch2)u-lithic acid cool (for example: _ (CH2)u__2CH4), or Wittig reagent derived from -(CH2)u-dentin or the like (in the formula, the formula is 整数 to an integer of 6. The halogen may be exemplified by · chlorine, bromine, moth), but The compound (1) or a salt thereof may be commercially available or may be produced by a method known per se, such as International Publication No. 2004/067521. (1) L2 forms a reactive functional group required for chemical bonding to form Y, for example: _(Cg2), -(CHOv-OH > -(CH〇vi ^ > -(CH2)v-C00H ^ -(CH 〇v-C0-i, -(CH2)V-NH2, -(CH2)vS〇3H, -(C&2)v_s〇2_ (4), or derived from Φ -(CH2)v-0H - (CHOv-0-acid group (for example: _(CH2) v_〇-ethylidyl, etc.), -(ch2)4 acid ester (for example: _(CH2)v-exposed CH3, etc.), or from - (CH2) a Wittig reagent derived from V-halogen or the like (in the formula, V is 整数 to an integer of 6; i can be exemplified by, for example, chlorine U), but is not particularly limited. L4 is used in the compound (1) The molecular end constructs a ruthenium structure and a ruthenium ruthenium structure to react with the compound (3) to construct a functional group required for b, for example: -(CH2)w-CH0, -(CH2)w-0H, -(CH〇w - Self, _(CH2)w_C00H, -(CH2)f CO-dentin, -(CH2)w-NHR2, etc. (in each formula, w is an integer from 〇 to 6. The halogen is not as good as chlorine, bromine, Iodine is the same as defined above), 319771 42 200835687 However, it is not particularly limited. The compound (2) or a salt thereof may be commercially available, or may be described in Guobu, Kaidi 2004/067521, International Publication No. 2_ / 〇 (10) "The two methods are known by the Tiger 2 itself. U, 1 compound (3) is a ruthenium structure for the structure of the ruthenium structure of the compound (1), and is commercially available, or can be Manufactured according to methods known per se. In addition, the protecting group in L5 is introduced for the purpose of the reaction, and the functional group which is removed until the last step is, for example, (CH3)3C_〇c〇_, as shown in the production example. Baoji. The lower alkyl group, the alkoxy group, and the brewing group in L5 may be, for example, a lower alkyl group represented by R3, an alkoxy group (tetra), or a brewing group. When the compound (1) in which Y is a carbon chain is produced, the compound (1) or the reaction is carried out by a reaction, a H〇mer-E_〇ns reaction, an aldol reaction, a Claisen condensation, or a salt-like carbon-carbon bond formation reaction. The salt, the disk compound (7) or a salt thereof (or a compound which has previously condensed the compound (2) and the compound (3)) is chemically bonded to form a Y containing a lower alkenyl group or a lower stretching group. The appropriate salt of the compounds (1) and (2) may be the same as those exemplified for the compound (1). Although various carbon-carbon bond formation reactions may be employed, when Wttig^ is used, and the like, As a preferred example, L2*_(CH2)u_CH〇, and \ is a scale salt derived from -(CH2)V-halogen or the like (Wittig reagent), or derived from -(CH2)U-halogen or the like. Squamous salts (Wittig reagent), and L3 is -(CHA-CHO is preferred (in each formula, u and v are the same as defined above. The dentin can be exemplified by chlorine, bromine, or iodine). The reaction is usually as in N. , N-dimethylformamide, dimethyl sulfoxixide, tetrahydrofuran, 319771 43 200835687 1 and organic solvents that do not adversely affect the reaction, or such mixed people In the other & ^ y, in the general presence of potassium butoxide, sodium hydride, sodium bismuth oxide, etc., the reaction temperature is not particularly important, the reaction system is pushed under the cold part to the heat ...仃. The product system can be retained by concentration, subtraction, solvent extraction, crystallization, recrystallization, known separation or purification means The gentleman can be separated or refined from the scratching and chromatography, and can also be converted into the same salt as the salt which has been exemplified in the compound (I). H纟1 will lower the alkenyl group or the lower stretching group. Hydrogenation and conversion into low-grade wire. When γ_成伸县 is bonded, the hydrogenation reaction is carried out according to a general method in the presence of various homo-catalysts or heterogeneous catalysts. Contact chlorination of the catalyst is preferred, and is carried out in the presence of a catalyst such as palladium carbon. When γ is a compound (1) containing a group of an ester, decylamine or sulfonamide, the compound (1) or a salt, which is condensed with the compound (2) or a salt thereof (or a compound which has previously condensed the compound (2) with (3)), and is difficult to bond with guanamine. This is a day, and L2 is -(CH2)U_0H, _(CH2) u a 匪...(CH2)u_dentin, etc., and l3 is -(ch2)v-cooh, -(ch2)v-co-yin, one (10)2)v_s〇3H, -(CH2)vS〇2- Halogen, etc., "l2 is -(CH2)u-C_, _(CH2)u-c〇-dentin, -(CH2)uS〇3H, -(CH2)uS〇2-halogen, etc., and L3g_(CH2) v_〇H, -(Cii2)v-NH2, -(CH2)V-卣素, etc., and can be organic In the formula, u and v are the same as defined above. Halogens can be exemplified by: chlorine, bromine, iodine. The reaction is usually carried out in, for example, dichloromethane, acetone, tetrahydrofuran, diethyl ether, N,N-dimethyl A general solvent for carbamide, and any other organic solvent that does not adversely affect the reaction, or a mixture of the same. 319771 44 200835687 • Use 1-ethyl-3—(3—two as needed Methylaminopropyl) carbodiimide • (carbodiimide) hydrochloride, N, N,-dicyclohexylcarbodiimide, N, N, monocarbonyl-imidazole and other condensing agents. Further, it may also be, for example, N,N-dimethyl-4-indolyl 1 hydroxy benzotriazole, 1-hydroxysuccinimide, 3, dihydro/saponyl 4-keto-i, 2, 3-benzotrit (benz〇triazine) was added in the presence of hydrazine. The reaction temperature is not particularly important, and the reaction is carried out under cooling to heating. When the compound (I) is an amine-containing group, L2 is -(CH2)u-oxime or a salt thereof, and L3 is -(CH2)v-CH〇, _(CH〇Glophone, etc. Or lL2, Vcho, _(CH〇u_ dentin, etc., and l3 is a (cH2) side or its salt ^, and can construct Y according to the general organic synthesis method (in each formula, u, v = and before, The definition is the same. The _ can be exemplified by · · chlorine, bromine, hard. The reaction is a solvent such as tetrahydrofurfuran, ethyl _, alcohol, etc., and any other solvent that does not adversely affect the reaction. An organic solvent or a mixture of the above is used as a reaction solvent, and after the synthesis of the Sehiff base by the hydroxylamine and (IV), the secondary amine structure is constructed by reduction of (4) chlorinated steel or mouse monosodium or the like, or via an amine and a tooth: a compound. The condensation reaction can also construct the same structure. When the halide is used, m diisopropylamine, triethylamine, potassium carbonate, etc. are used as reagents, and tetrahydrofuran, acetonitrile, N, N-dimethyl group are used. The general solvent of the brewing amine, and any other organic solvent that does not adversely affect the reaction, or a mixture of the same as the reaction solvent. The reaction temperature is not particularly important, It should be carried out under cooling to heating. The product system can also be converted into a salt which is the same as the salt which is not the compound (I). When Y is a compound (1) containing an ether bond group, Department [2 is 319771 45 200835687

-(CH2)u-〇H 等，且 l3A-(TH、mT 物旨等，或L、-(CH广广 ” 為（CH2)u’、~(CH〇u-鹵素、-(CH2)U-磺 ::!:且':為_鳴，等，並能按照-般有機合成手 1 各式中’u、v係與前述定義相同。鹵素可例示如： 氣、漠、埃）。使⑽結形成之方法係能依Wllliams0n法、 使用銅觸媒等之從芳族鹵化物之越合成法、光延 (，議。bu)反應、其他本身已周知之製造方法而製造。此 專反應係通常在如乙腈、二氯甲③、丙酮、四氳Μ、n，n_ -甲基甲ii胺等-般溶劑、及不會對反應造成不良影響之 ，何其他有機溶劑、或該等之混合物中進行。反應溫度不 ^別重要，反應係在冷卻下至加熱下進行。生成物係也能 軲換成與已例示於化合物（丨）之鹽為相同之鹽。 化合物（I)之分子末端係肼基羰基、或者肼基。 於化合物⑴之分子末端導人肼基幾基、或者肼基之方 法之1例如下述方案2所示 方案2 (—A—L4 (1+2)或（2) Η一ISI—Ε-(CH2)u-〇H, etc., and l3A-(TH, mT, etc., or L, -(CH Guangguang) is (CH2)u', ~(CH〇u-halogen, -(CH2)U -Sulphon::!: and ': is _ 鸣, 等等, and can be organically synthesized according to the general hand 1 '', v system is the same as defined above. Halogen can be exemplified as: gas, desert, angstrom. (10) The method of forming a knot can be carried out by a Wllliams0n method, a synthesis method using an aromatic halide such as a copper catalyst, a light extension reaction, and other well-known production methods. Usually in a solvent such as acetonitrile, dichloromethyl 3, acetone, tetraterpene, n, n-methylmethyl iiamine, etc., and other organic solvents, or mixtures thereof, which do not adversely affect the reaction. The reaction temperature is not critical, and the reaction is carried out under cooling to heating. The product system can also be replaced with the same salt as the salt of the compound (丨). The molecular end of the compound (I) A mercaptocarbonyl group or a mercapto group. The method of introducing a mercapto group or a mercapto group at the molecular end of the compound (1) is, for example, the scheme 2 shown in the following scheme 2 (-A-L4 ( 1+2) or (2) IS一ISI—Ε

(3)(3)

R1—ΝΗ—X—Υ—A—Β—D—E (各式中，R]、X、Υ、A、Β、D及Ε係與化合物⑴中之定 義相同。L4及L5係與上述定義相同）。 當製造β為-（CH2)n-C0-之化合物（！）之時，化合物（？） 319771 46 200835687 =已Γ:合物⑴與⑵鍵結之化合物)之L4係必須為R1—ΝΗ—X—Υ—A—Β—D—E (in each formula, R], X, Υ, A, Β, D, and lanthanide are the same as defined in compound (1). L4 and L5 are as defined above. the same). When a compound (!) in which β is -(CH2)n-C0- is produced, the compound (?) 319771 46 200835687 = the compound of the compound (1) and (2) bonded to the L4 system must be

^ # "，J^ ： -(CH2VC00CH- ^ --CCHO 友※’、口工中’w係與前述定義相同。齒素可例示如·· 虱、溴、碘)之構造。可從原料階段預先在化合物⑵中加 入作為羧基，也可經由對應之羧酸S旨之水解、醇之氧化等 構築為合成步驟之一部分。 、 使羧酸、羧酸酯、或者醯齒與肼（或經保護之肼）縮合 鲁而在化合物（1)之分子末端構築肼基羰基（式（ί)中，6為〇 :(Ci^-C0- :D為-NR3-、e為可經取代之胺基）（式中，w 係與前述定義相同）。反應通常在如二氯甲燒、乙腈、四氫 咬口南、N，N-二甲基甲醯胺之一般溶劑、及不會對反應造成 不良影響之任何其他有機溶劑、或該等之混合物中進行。 虽攸羧酸合成時’係使用1，1，-羰基二咪唑、N，N，-二環己 基碳二亞胺等縮合劑。此外，也可以亞硫酸氯、草醯氯等 衍生成醯函後，再進行縮合反應。此外，能依其他各種已 _周知之方法進行與肼之縮合反應。 當製造B為-NR2-C〇之化合物（丨）時，L4係必須為_NHRZ 之構造。可從原料階段預先在化合物（2)中加入作為胺基或 經保護之胺基，也可經由硝基還原等構築為合成步驟之一 部分。將胺基經由以例如：從丨，丨，_羰基二咪唑與三級丁 氧基肼基曱酸（t-butoxycarbazate)所調製之2-(1Η-咪唑 -1-基羰基）肼基曱酸三級丁酯等處理，而能構築B為_服2_ CO-、D為-NR3-、E為可經取代之胺基之分子末端構造。反 應通常在如二氯曱烷、乙腈、四氫呋喃、N，N_二甲基甲醯 319771 47 200835687 胺之-般溶劑、及不會對反 機溶劑、或該等之混合心曰之任何其他有 广l T進仃0反應溫度不牲只丨丨舌蘇 反應係在冷卻下至加熱下進行。 ^不导寸別重要， 當製造Β為-(CH2)广之化合物（ 已使化合物⑴與⑵鍵結之化合物)之L、:須=者 -CH0、-(CH2)ff-齒素或是 rrti、Λττ/ 伟义眉為-(ch2)w 義相同。i素可例示如.氣;' 切，w係與前述定 段預先在化合物⑵中力入^臭、礙）等構造。可從原料階 經基），甲酿基係經由J應之二:能基酿基二*素或者 化等，S素係對應之醇之^久酉夂，酉夂醋之遥原、醇之氧 羧酸、㈣ή化’此外’縣係經由對應之 合成丄::原、_s旨或鹵化物㈣^ s二^^^與拼類^或者經保護之拼類^合成 =„再_氫化納或㈣氫化料 是經由肼類(或者經保護之肼類)與㈣化冓= 應也可構築相同構造。反應通常在如二氯甲烷、 I:二r二甲基甲醯胺之一般溶劑、及不會對反應 I 曰之任何其他有機溶劑、或該等之混合物中進 仃。反應溫度不特別重要，反應係在冷卻下至加熱下進行。 準肼法！，也能利用光延反應作為從經基嶋 ，肼基=方法。使用作為肼等價體之（1，3-二酮基_〗，3一二 2H-異吲哚（is〇ind〇le)_2_基）胺羧酸三級丁酯，且以三 本膦、偶氮二甲酸二乙醋作為反應劑使其縮合。能經由肼 分解而去除鄰苯二甲醯亞胺部位後，再經由以酸去除三級 319771 48 200835687 丁軋碳基而在化合物（1)之分子末端構築肼基（式中，b 為-CH2-、D為—NR3_、E為可經取代之胺基）。此外，能依 其他各種已周知之有機化學方法構築肼基。 如此進行所製造之化合物（1)係能藉由結晶、再結晶、 相轉移、層析等已周知之分離或精製手段而單離或精製。 此外，能轉換成醫藥上所容許之鹽。 义 以下，藉由實施例（製造例及試驗例）進一步詳細說明 本發明，但並非限定本發明。 (實施例） 下述製造例中所使用之原料化合物係能依已周知之方 法（國際公開第2004/ 067521號、國際公開第2006/ 011631號、國際公開第2〇〇6//〇28269號）等製造。 (製造例1) N {4 [2 (4拼基％基苯基）乙基]—1，3 -π塞嗤—2 一基丨乙酿胺 之合成^ # ", J^ : -(CH2VC00CH- ^ --CCHO 友*', and the term "w" is the same as defined above. The dentate can be exemplified by structures such as 虱, bromine, and iodine. The compound (2) may be added as a carboxyl group in advance from the raw material stage, or may be a part of the synthesis step by hydrolysis of the corresponding carboxylic acid S or oxidation of an alcohol. Condensing a carboxylic acid, a carboxylic acid ester, or a dentate with a hydrazine (or a protected hydrazine) to form a fluorenylcarbonyl group at the molecular end of the compound (1) (in the formula (ί), 6 is 〇: (Ci^ -C0-: D is -NR3-, e is a substitutable amine group) (wherein w is the same as defined above). The reaction is usually carried out, for example, in the form of methylene chloride, acetonitrile, tetrahydromanganate, N, A general solvent for N-dimethylformamide, and any other organic solvent which does not adversely affect the reaction, or a mixture thereof. Although the carboxylic acid is synthesized, the 1,1,-carbonyl group is used. A condensing agent such as imidazole or N,N,-dicyclohexylcarbodiimide. Further, it may be derived from a sulfite, chloroform, or the like, and then subjected to a condensation reaction. Further, it may be known in various other forms. The method is carried out to carry out a condensation reaction with hydrazine. When the compound (B) wherein B is -NR2-C〇 is produced, the L4 system must have a structure of _NHRZ. The compound (2) can be added as an amine group or in advance from the raw material stage. The protected amine group can also be constructed as part of a synthetic step via nitro reduction, etc. The amine group is passed, for example, from , hydrazine, _ carbonyl diimidazole and tertiary (2-anthracen-1-ylcarbonyl) decyl decanoic acid ternary butyl ester prepared by t-butoxycarbazate, etc. Constructing a molecular end structure in which B is _ service 2_CO-, D is -NR3-, and E is a substituted amine group. The reaction is usually carried out in, for example, dichlorodecane, acetonitrile, tetrahydrofuran, N,N-dimethylformamidine. 319771 47 200835687 Amine-like solvents, and no other reaction to the anti-machine solvent, or any of these mixed cores, the temperature of the reaction is not the only reaction of the tongue. It is carried out. ^Indifferent is not important. When manufacturing a compound which is a compound of -(CH2) (a compound in which the compound (1) and (2) are bonded), L, : = = -CH0, -(CH2)ff-tooth Or rrti, Λττ/ weiyi eyebrows are - (ch2)w, the same meaning. i can be exemplified as qi; 'cut, w-series and the above-mentioned stipulations in the compound (2) in advance, such as odor, obstruction, etc. . It can be obtained from the base material of the raw material, and the base of the brewing base is the second one of the two: the energy base, the second base, or the chemical, etc. Oxycarboxylic acid, (4) Suihua 'In addition' county through the corresponding synthetic 丄:: original, _s or halide (four) ^ s two ^ ^ ^ and spell class ^ or protected spell class ^ synthesis = „ re_ hydride Or (iv) the hydrogenation material is via the hydrazine (or protected hydrazine) and (iv) hydrazine = the same structure may be constructed. The reaction is usually carried out in a general solvent such as dichloromethane, I: bis-dimethylcarbamamine, And does not react with any other organic solvent of the reaction I, or a mixture of the same. The reaction temperature is not particularly important, and the reaction is carried out under cooling to heating. Quasi-肼 method, can also use the light delay reaction as a slave嶋 = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = a butyl ester, which is condensed with triphosphine and azodicarboxylate as a reactant. The phthalic acid imide can be removed via hydrazine decomposition, followed by acid. The third stage 319771 48 200835687 is removed by rolling a carbon group to form a thiol group at the molecular end of the compound (1) (wherein b is -CH2-, D is -NR3_, and E is a substitutable amine group). The sulfhydryl group is constructed by various other well-known organic chemical methods. The compound (1) thus produced can be isolated or purified by well-known separation or purification means such as crystallization, recrystallization, phase transfer, and chromatography. In addition, the present invention can be further described in detail by way of examples (manufacturing examples and test examples), but the present invention is not limited thereto. (Examples) The following production examples are used. The raw material compound can be produced by a well-known method (International Publication No. 2004/067521, International Publication No. 2006/011631, International Publication No. 2/6//28269). (Manufacturing Example 1) N {4 Synthesis of [2 (4 benzyl phenyl) ethyl]-1,3 - π 嗤 嗤 2

將乙醇（25ml)、水（2· 5ml)加入至4-{2_[2-（乙醯基胺 基）-1，3-¾:口坐-4-基]乙基}安息香酸曱酯（913· Img，3. 000 mmol)而成懸浮狀態。在〇。〇加入6N氫氧化鈉水溶液（2. 5 ml，15mmol)後，在室溫攪拌24小時。冷卻至（TC後，加 入1N鹽酸（15ml)並攪拌。減壓蒸餾去除乙醇後，將水（1〇ml) 加入至殘渣並攪拌。濾取生成之固體後，以水洗淨兩次。 49 319771 200835687 ，減壓乾燥後，得到白色固體之4一{2一[2一（乙醯基胺基） -1，3-噻唑-4-基]乙基}安息香酸（51 7· 3mg，i 782匪〇卜產 率 59. 4%)。 步驟2Ethanol (25 ml) and water (2.5 ml) were added to 4-{2_[2-(ethylidenylamino)-1,3-3⁄4: orylidene-4-yl]ethyl}benzoate oxime ester ( 913· Img, 3. 000 mmol) was suspended. Here. After adding 6N aqueous sodium hydroxide solution (2.5 ml, 15 mmol), the mixture was stirred at room temperature for 24 hours. After cooling to (TC, 1N hydrochloric acid (15 ml) was added and stirred. After distilling off ethanol under reduced pressure, water (1 ml) was added to the residue and stirred. The solid formed was collected by filtration and washed twice with water. 319771 200835687, after drying under reduced pressure, gave a white solid of 4-{2-[2-(ethylamino)-1,3-thiazol-4-yl]ethyl}benzoic acid (51 7. 3 mg, i 782匪〇 yield 59.4%). Step 2

在4-{2-[ 2-(乙酿基胺基）一 1，3-嗟嗤-4-基]乙基}安 _息香酸（583· Omg，2· 008mmol)之無水N，N-二曱基甲醯胺 (5ml)溶液中加入1，1’ 一幾基二咪唾（486. 5mg，3. 00Q mmo 1)’且在5 0 C擾拌2小時。冷卻至室溫後，加入肼· 一水合物（0.49ml，lOmmol)，且在室溫攪拌6小時。加入 水（10ml )並攪拌後，濾取生成之固體。以水洗淨3次、以 醋酸·乙酯洗淨3次。減壓乾燥後，得到白色固體之標題化 合物（548· 3mg，1· 801 mmol，產率 89· 6%)。Anhydrous N,N in 4-{2-[2-(ethyl arylamino)-1,3-indol-4-yl]ethyl}an-benzoic acid (583·Omg, 2.008 mmol) To the solution of dimercaptocaramine (5 ml) was added 1,1'-single-sodium iodide (486. 5 mg, 3. 00Q mmo 1)' and spoiled at 50 C for 2 hours. After cooling to room temperature, hydrazine monohydrate (0.49 ml, 10 mmol) was added and stirred at room temperature for 6 hr. After adding water (10 ml) and stirring, the resulting solid was collected by filtration. It was washed three times with water and three times with ethyl acetate. The title compound (548·3 mg, 1· 801 mmol, yield 89.6%) was obtained as white solid.

•融點219至221°C lE-MR (200MHz, DMS0-d6)： δ (ppm)： 12.00(1H, brs), 9.68(1H, brs), 7.72 (2H，d，J=8.1Ηζ>，7·26(2Η，d, J=8-lHz)，6·73(1Η，s), 4·46(2Η, brs), 3 05-2. 81 (4H, m), 2.11(3H, s) ' i3C-NMR (50MHz, DMS0~d6) : δ (ppm): 168· 7，166· 3, 157· 9，150· 6, 145. 2, 1 31· 5, 128· 7，127· 5，108· 0, 34.8, 32· 9, 23· 0 •’ ’ (製造例2) N-{4-[2-(4-肼基幾基甲基苯基）乙基]一1，3-嗟唾—2-基}乙 醯胺之合成 319771 50 200835687• Melting point 219 to 221 ° C lE-MR (200 MHz, DMS0-d6): δ (ppm): 12.00 (1H, brs), 9.68 (1H, brs), 7.72 (2H, d, J=8.1Ηζ>, 7·26(2Η,d, J=8-lHz),6·73(1Η,s), 4·46(2Η, brs), 3 05-2. 81 (4H, m), 2.11(3H, s ) ' i3C-NMR (50MHz, DMS0~d6) : δ (ppm): 168· 7,166· 3, 157· 9,150· 6, 145. 2, 1 31· 5, 128· 7,127· 5 , 108· 0, 34.8, 32· 9, 23· 0 • ' ' (Production Example 2) N-{4-[2-(4-fluorenylmethylphenyl)ethyl]-1,3- Synthesis of hydrazine-2-yl}acetamide 319771 50 200835687

在2-(4-{2-[2-(乙醯基胺基）-丨，3 —噻唑—4一基]乙基} 苯基）醋酸（913· lmg，3· 〇〇〇m〇l)之無水N，N—二曱基甲醯胺 (7· 5ml)溶液中加入Μ，-羰基二咪唑（729. 7mg，4. 500 腿〇1) ’且在5〇 c攪拌1小時。冷卻至室溫後，加入肼· 一水合物（〇· 73ml，15mmol)，且在室溫攪拌2小時。加入 水（25ml)並授拌後，濾取生成之固體。將固體以水洗淨3 次、以醋酸乙酯洗淨3次、以四氫呋喃洗淨2次。減壓乾 燥後’得到白色固體之標題化合物（538 1mg，169〇_〇卜 產率 56, 3%)。 融點200至202它 ^-^(200^ DMS0-d6)： δ (ppm) ： 12.08(1¾ brs), 9.18(1H, brs), 7.20-7. 04(4H，m)，6·74(1Η, s), 4·21(2Η, brs), 3·40-3·25(2Η, m), 3·00-2·’80(4Η m), 2.11(3H, s) ， 13C-NMR (50MHz, DMS0-d6)： δ (ppm) ： 169.8, 168,4, 157.6, 150.5, 139.6, 13 φ 3· 9, 129.0，128.2, 107· 5, 40.3, 34. 3, 33· 0, 22.7 ’ (製造例3) N-（4-{2-[4-（Ν’ -甲基肼基幾基曱基）苯基]乙基}-1，3-嗟 唑-2-基）乙醯胺之合成 (製造例4) Ν-（4-{2-[4-（Ν-曱基肼基羰基甲基）苯基]乙基}-1，3-噻唑 -2-基）乙醯胺之合成 51 319771 200835687In 2-(4-{2-[2-(ethylideneamino)-indole, 3-thiazole-4-yl]ethyl}phenyl)acetic acid (913·lmg,3·〇〇〇m〇l To a solution of anhydrous N,N-dimercaptocaramine (7.5 ml) was added hydrazine, -carbonyldiimidazole (729. 7 mg, 4.500 leg 〇1)' and stirred at 5 ° C for 1 hour. After cooling to room temperature, hydrazine monohydrate (〇·73 ml, 15 mmol) was added and stirred at room temperature for 2 hr. After adding water (25 ml) and mixing, the resulting solid was collected by filtration. The solid was washed three times with water, three times with ethyl acetate, and twice with tetrahydrofuran. The title compound (538 1 mg, 169 〇 〇 yield 56, 3%) was obtained as white solid. Melting point 200 to 202 it ^-^(200^ DMS0-d6): δ (ppm): 12.08 (13⁄4 brs), 9.18 (1H, brs), 7.20-7. 04(4H,m),6·74( 1Η, s), 4·21(2Η, brs), 3·40-3·25(2Η, m), 3·00-2·'80(4Η m), 2.11(3H, s) , 13C-NMR (50MHz, DMS0-d6): δ (ppm): 169.8, 168,4, 157.6, 150.5, 139.6, 13 φ 3· 9, 129.0,128.2, 107· 5, 40.3, 34. 3, 33· 0, 22.7 ' (Manufacturing Example 3) N-(4-{2-[4-(Ν'-methylindolyl)phenyl]ethyl}-1,3-oxazol-2-yl)acetamidine Synthesis of Amine (Production Example 4) Ν-(4-{2-[4-(indolyl-mercaptocarbonylmethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide Synthesis 51 319771 200835687

依與製造例2類似之方法，使4-{2-[2-(乙醯基胺基） -1，3-嗟嗤-4-基]乙基}苯基醋酸（1 · 〇〇g，3· 29mmol )與甲基 肼縮合。將粗生成物以矽膠管柱層析法（Fuji Silysia 春丽-DM 2035，70g，二氯曱烷：曱醇=30 : 1)精製後，得到 2個區分（fraction)。將高極性區分減壓濃縮後，將析出 之結晶以異丙醚洗淨。將結晶乾燥後，得到白色固體之 N -（4-{2-[4-（Ν’ -甲基肼基羰基曱基）苯基]乙基卜l 3一噻 唑-2-基）乙醯胺（製造例3之標題化合物）（〇. 3〇g，（K 905 mmol，產率 27. 5%)。4-{2-[2-(Ethylamino)-1,3-indol-4-yl]ethyl}phenylacetic acid (1 · 〇〇g, in a similar manner to that in Production Example 2 3. 29 mmol) condensed with methyl hydrazine. The crude product was purified by silica gel column chromatography (Fuji Silysia - DM 2035, 70 g, dichloromethane: decyl alcohol = 30:1) to obtain two fractions. After the high polarity was concentrated under reduced pressure, the precipitated crystals were washed with isopropyl ether. After drying the crystals, N-(4-{2-[4-(Ν'-methylmercaptocarbonyl)phenyl)ethyl]l 3 -thiazol-2-yl)acetamide as a white solid was obtained. (The title compound of Production Example 3) (〇. 3〇g, (K 905 mmol, yield 27.5%).

融點179至181 °C ^ ^NMR (200MHz, DMS〇-d6): δ (ppm) ： 12.08(1¾ brs), 9.48(1H, brs), 7.20-7. 05(4H,m), 6. 74(1H, s), 4. 80(1H, brs), 3. 28(2H, s), 3. 00~2. 75 (4H,' m) 2.45-2.35(3¾ m), 2.12(3¾ s) ’ ’ 13C-NMR (50MHz，DMS0~d6〉： δ (ppm): 169· 4，168.7, 157· 9, 150· 9，139· 9, 1 34· 1, 129. 3, 128.6，107· 8, 40.8, 34. 7, 33· 3, (23. 0, 22.9) ’ (因醯胺鍵結之s-cis/s-trans異構物所以觀測到一部分 之峰***） 此外，將低極性區分減壓濃縮後，將析出之結晶以異 丙醚洗淨。將所得之結晶以四氫呋喃/異丙醚再結晶並乾 燥後’得到白色固體之N-(4-{2- [4-（N-甲基肼基幾基甲基） 苯基]乙基}-1，3-嗟峻-2-基）乙醯胺（製造例4之標題'化合 319771 52 200835687 物）（0· 14g，〇. 42mmol，產率 12· 8%)。Melting point 179 to 181 ° C ^ ^ NMR (200 MHz, DMS 〇-d6): δ (ppm): 12.08 (13⁄4 brs), 9.48 (1H, brs), 7.20-7. 05(4H, m), 6. 74(1H, s), 4. 80(1H, brs), 3. 28(2H, s), 3. 00~2. 75 (4H,' m) 2.45-2.35(33⁄4 m), 2.12(33⁄4 s ) ' ' 13C-NMR (50MHz, DMS0~d6>: δ (ppm): 169· 4,168.7, 157· 9, 150· 9,139· 9, 1 34· 1, 129. 3, 128.6,107· 8, 40.8, 34. 7, 33· 3, (23. 0, 22.9) ' (A part of the peak split is observed due to the s-cis/s-trans isomer of the indoleamine bond) After concentration and concentration under reduced pressure, the precipitated crystals were washed with isopropyl ether. The obtained crystals were recrystallized from tetrahydrofuran/isopropyl ether and dried to give a white solid N-(4-{2-[4-(N -Methylmercaptomethylmethyl)phenyl]ethyl}-1,3-yttrium-2-yl)acetamide (title of Production Example 4, Compound 319771 52 200835687) (0·14g, 〇 42 mmol, yield 12.8%).

融點173至176°C 'H-NMR (200MHz, DMS〇-d6) ： δ (ppm) ： 12.08(1¾ brs), 7.20-7.00(^ m) 6 7 5(1H, s), 4.78(2¾ s), 3.78(2¾ s), 3.0l(3H, s), 2.95-2.80(^/^)^1 1 (3H, m) > 13C~NMR (50MHz, DMSO-d6)： δ (ppm) ： 172.4, 168.4, 157.6, 150.6, 139 2 13 4.7, 129· 4，128.1, 107.5, 38. 3, 34· 4, 33.1, (22· 7，22· 6) •’ (因醯胺鍵結之s-cis/s-trans異構物所以觀測到一部分 之峰***） (製造例5) ® N-(4-{2-[4-(N’-乙基肼基羰基甲基）苯基]乙基卜^ 3_噻 唑-2-基）乙醯胺之合成Melting point 173 to 176 ° C 'H-NMR (200 MHz, DMS〇-d6) : δ (ppm) : 12.08 (13⁄4 brs), 7.20-7.00 (^ m) 6 7 5(1H, s), 4.78(23⁄4 s), 3.78 (23⁄4 s), 3.0l (3H, s), 2.95-2.80(^/^)^1 1 (3H, m) > 13C~NMR (50MHz, DMSO-d6): δ (ppm) : 172.4, 168.4, 157.6, 150.6, 139 2 13 4.7, 129· 4,128.1, 107.5, 38. 3, 34· 4, 33.1, (22· 7,22· 6) •' (due to the indole bond S-cis/s-trans isomer, so a part of the peak split was observed) (Manufacturing Example 5) ® N-(4-{2-[4-(N'-ethylmercaptocarbonylmethyl)phenyl] Synthesis of ethyl bromide 3 - thiazol-2-yl) acetamidine

Ac«N-^S 依與製造例2類似之方法，使4-{2-[2-(乙醯基胺基） -1，3-噻唑-4-基]乙基}苯基醋酸（1· 〇〇g，3 29mm〇1)與乙基 ❿肼縮合。乙基肼係將乙基肼一草酸鹽以約2 · 4當量之氫氧 化鈉處理而調製出。將粗生成物以矽膠管柱層析法（FuB Silysia 丽-DM2035 ’ 40g，二氯曱烷··甲醇=4〇 : 〇精製。 將含目標物之區分濃縮後，濾取析出之結晶，並以異丙醚 洗平。乾燥後I得到白色固體之標題化合物（129,6呢， 〇· 374mm〇卜產率 22· 8%)。Ac«N-^S 4-{2-[2-(Ethylamino)-1,3-thiazol-4-yl]ethyl}phenylacetic acid was obtained in a similar manner to that of Production Example 2. · 〇〇g, 3 29mm〇1) Condensation with ethyl hydrazine. The ethyl hydrazine system is prepared by treating ethyl hydrazine monooxalate with about 2.4 equivalents of sodium hydroxide. The crude product was purified by silica gel column chromatography (FuB Silysia 丽-DM2035 '40 g, dichloromethane, methanol = 4 〇: 〇. After concentration of the target substance was concentrated, the precipitated crystal was collected by filtration, and The title compound (129,6, 〇· 374 mm 产率 yield 22.8%) was obtained as a white solid.

融點182至186°C 319771 53 200835687 也一NMR (200MHz, DMS0-d6): δ (ppm): 12.08(1¾ brs)，9· 55-9· 41 (1H, br)，7· 20-7.05 (4H, m), 6·73(1Η, s), 4.90~4.70 (1H, m), 3. 30(2H, s), 2.98-2.79 (4H, m), 2.79-2.59 (2H, m), 2. 11(3H, s), 0.94(3H, t, J=7.1Hz) 13C-NMR(50MHz, DMS〇-d6) ： δ (ppm)： 169.5, 168.7, 157.9, 150.8, 139.9, 1 34.2, 129.3, 128.6, 107.8, 45.8, 40.6, 34.7, 33.3, (23.0, 22.9), 13.5 (因酿胺鍵結之s-cis/s-trans異構物所以觀測到一部分 之峰***）Melting point 182 to 186 ° C 319771 53 200835687 Also NMR (200MHz, DMS0-d6): δ (ppm): 12.08 (13⁄4 brs), 9· 55-9· 41 (1H, br), 7· 20-7.05 (4H, m), 6.73 (1Η, s), 4.90~4.70 (1H, m), 3. 30(2H, s), 2.98-2.79 (4H, m), 2.79-2.59 (2H, m) , 2. 11(3H, s), 0.94(3H, t, J=7.1Hz) 13C-NMR (50MHz, DMS〇-d6) : δ (ppm): 169.5, 168.7, 157.9, 150.8, 139.9, 1 34.2 , 129.3, 128.6, 107.8, 45.8, 40.6, 34.7, 33.3, (23.0, 22.9), 13.5 (A part of the peak split was observed due to the s-cis/s-trans isomer of the amine bond)

(製造例6) I N -（4-{2-[4 -（Ν’，Ν’-二曱基肼基羰基曱基）苯基]乙基} -1，3-噻唑-2-基）乙醯胺之合成(Production Example 6) IN -(4-{2-[4 -(Ν',Ν'-dimercaptocarbonylcarbonyl)phenyl]ethyl}-1,3-thiazol-2-yl)B Synthesis of guanamine

依與製造例2類似之方法’使4 - {2 - [ 2 -(乙醯基胺基） -1，3-噻唑-4-基]乙基}苯基醋酸（1· 00g，3· 29mmol)與 N，N-二曱基肼縮合。將粗生成物以石夕膠管柱層析法（Fuj i Silysia 丽-DM2035，40g，二氯曱烷：曱醇=30 : 1)精製。 _將含目標物之區分濃縮後，濾取析出之結晶，並以異丙醚 洗淨。乾燥後，得到微黃色固體之標題化合物（0. 88g， 0· 254mmol，產率77.3%)。In a similar manner to the production example 2, 4 - {2 - [2-(ethylamino)-1,3-thiazol-4-yl]ethyl}phenylacetic acid (1·00 g, 3·29 mmol) Condensation with N,N-dimercaptopurine. The crude product was purified by silica gel column chromatography (Fuj i Silysia-DM2035, 40 g, dichloromethane: decyl alcohol = 30:1). _ After the concentration of the target substance is concentrated, the precipitated crystals are collected by filtration and washed with isopropyl ether. The title compound (0. 88 g, 0·254 mmol, yield: 77.3%).

融點186至189°C 'H-NMR (200MHz, DMS0~d6) ： δ (ppm) ： 12.08(1¾ brs), 8.99(lHX2/3, brs), 8. 33(lHXl/3, brs), 7·23-7·10(4Η, m), 6·73(1ΗΧ2/3, s), 6·72(1ΗΧ1/3, s), 3·61(2ΗΧ1/3), 3·22(2ΗΧ2/3, s)，3·00-2.75(4Η, m>, 2·45(6ΗΧ2/3, s), 2.4K6HX1/3, s), 2.11(3H, s) 13C~NMR(50MHz, DMS0-d6): δ (ppm) ： 173.0, 168.7, 167.9, 157.9, 150.9, 13 9.9, 139.6, 134.2, 129.7, 129.3, 128.6, 128.5, 107.8, 48.3, 46.9, 46.8, 41.0, 38.5, 34.7, 33.4, 23.0, 22.9 (觀測到醯胺鍵結之s-cis/s-trans異構物之混合物） 54 319771 200835687 (製造例7) N-{ 4-[2-(4-肼基羰基曱基苯基）乙基]—5 —(4-胺磺醯基苯 曱基）-1，3-°塞嗤-2-基}乙酿胺之合成 步驟1Melting point 186 to 189 ° C 'H-NMR (200 MHz, DMS0~d6) : δ (ppm) : 12.08 (13⁄4 brs), 8.99 (lHX2/3, brs), 8. 33 (lHXl/3, brs), 7·23-7·10(4Η, m), 6·73(1ΗΧ2/3, s), 6·72(1ΗΧ1/3, s), 3·61(2ΗΧ1/3), 3·22(2ΗΧ2/ 3, s), 3·00-2.75 (4Η, m>, 2·45(6ΗΧ2/3, s), 2.4K6HX1/3, s), 2.11(3H, s) 13C~NMR (50MHz, DMS0-d6 ): δ (ppm): 173.0, 168.7, 167.9, 157.9, 150.9, 13 9.9, 139.6, 134.2, 129.7, 129.3, 128.6, 128.5, 107.8, 48.3, 46.9, 46.8, 41.0, 38.5, 34.7, 33.4, 23.0, 22.9 (A mixture of s-cis/s-trans isomers in which a guanamine bond was observed) 54 319771 200835687 (Manufacturing Example 7) N-{ 4-[2-(4-Mercaptocarbonylcarbonylphenyl)B Synthesis of 5-(4-aminosulfonylphenyl fluorenyl)-1,3-° thiopyridin-2-yl}

AcHAcH

CISO3H CHO3CISO3H CHO3

so2ci 在〇°C在2_乙醯基胺基-5-苯甲基-1，3-噻唑-4-羧酸 鲁乙酯（10· 08g，33· 12mmol)之氯仿（200ml)溶液中滴入氯硫 酉夂（22· lml，331 mmo 1)後，在室溫攪拌17小時。將反應液 庄入冰水（4〇〇ml)中，並以四氫吱喃萃取。將水層以醋酸乙 酯萃取2次後，將混合後之有機層以飽和食鹽水洗淨、以 無水硫酸鎂乾燥。減壓濃縮，並將殘渣以矽膠管柱層析法 (Fuji Silysia BW-300SP ’ 300g，二氯甲烧：甲醇=4〇: 1)精製後’得到淡黃色固體之2-乙酿基胺基—5— (4-氯石黃醯 基苯甲基）-1，3-噻唑-4-羧酸乙酯（8· 07g，20· 〇mmo：l，產率 _ 60· 5%) 〇 步驟2So2ci in chloroform (200ml) solution of 2_acetamido-5-benzyl-1,3-thiazole-4-carboxylic acid ethyl ester (10·08g, 33·12mmol) in 〇°C After chlorinated ruthenium (22.ml, 331 mmo 1), it was stirred at room temperature for 17 hours. The reaction solution was poured into ice water (4 mL) and extracted with tetrahydrofuran. After the aqueous layer was extracted twice with ethyl acetate, the combined organic layer was washed with brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP '300 g, methylene chloride:methanol = 4 〇: 1) to give a 2-yellow amine group as a pale yellow solid. —5—(4-chlorophosphonium benzylidene)-1,3-thiazole-4-carboxylic acid ethyl ester (8·07g, 20·〇mmo:l, yield _ 60·5%) 〇Step 2

在0°C在2 -乙醯基胺基-5-(4-氯石黃醯基苯甲基）—1，3一 嗟唾-4-羧酸乙酯（8· 00g，19· 9mmol)之四氫呋喃（16〇ml) 溶液中滴入28%氨水（90· 7ml，1·34ιηο1)後，在室溫授摔2 小時。在反應液中加入飽和氯化銨水溶液後，以酷,酸乙酯 萃取。將有機層以飽和食鹽水洗淨後，以無水硫酸鎂乾燥。 319771 55 200835687 減壓濃縮後，將異丙醚（3〇〇m 1)加入至殘渣。濾取生成之固 體後，以異丙醚洗淨。減壓乾燥後，得到白色固體之2-乙 酸基胺基- 5- (4 -胺石黃酿基本曱基）-1，3 -。塞τι坐-4-缓酸乙酯 (6. 69g，17. 5mmol，產率 87· 9%)。 步驟3Tetrahydrofuran in 2-ethylaminomethyl-5-(4-chlorocalcinylbenzyl)-1,3-indolyl-4-carboxylate (8·00 g, 19.9 mmol) at 0 °C (16〇ml) After dropping 28% ammonia water (90·7ml, 1·34ιηο1) into the solution, it was dropped for 2 hours at room temperature. After adding a saturated aqueous solution of ammonium chloride to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. 319771 55 200835687 After concentration under reduced pressure, isopropyl ether (3 〇〇m 1) was added to the residue. After the resulting solid was collected by filtration, it was washed with isopropyl ether. After drying under reduced pressure, 2-ethylacetic acid 5- 5-(4-amine yellow-branched basic fluorenyl)-1,3 - was obtained as a white solid.塞τι在-4-酸酸酯 (6. 69g, 17. 5mmol, yield 87.9%). Step 3

在2 -乙酿基胺基-5-(4-胺石黃醯基苯甲基）-i，3 一嗟峻 鲁_4-羧酸乙酯（6· 5〇g，Π· Ommol)之四氫呋喃（丨95…）懸浮液 中加入蝴氫化經（4· 36g ’ 170_〇 1)後，加熱回流1 7小時。 將反應液冷卻至0°C後，滴入6N鹽酸（28· 3ml，170mmol)。 減壓?辰細至約1 / 5 I ’並加入水（210 m 1)後，以醋酸乙酉旨 萃取。將有機層以飽和食鹽水洗淨後，以無水硫酸鎮乾燥。 減壓濃縮·後，將異丙醚（30Om 1)加入至殘渣，。濾取生成之固 體後，以異丙醚洗淨。減壓乾燥後，得到黃白色固體之 _ N-[ 4-經甲基-5-（4-胺石黃酸基苯曱基）一1，3一嗟π坐一2一基]乙 醯胺（3.90g，11· 4mmol，產率67.4%)。 .步驟4In the tetrahydrofuran of 2-ethylglycosylamino-5-(4-amine fluorenylbenzyl)-i,3 嗟 鲁 鲁 _ 4-carboxylate (6·5〇g, Π·Ommol)丨95...) The butterfly hydrogenation solution (4·36g '170_〇1) was added to the suspension, and the mixture was heated under reflux for 17 hours. After cooling the reaction mixture to 0 ° C, 6N hydrochloric acid (28·3 ml, 170 mmol) was added dropwise. The pressure was reduced to about 1 / 5 I ' and water (210 m 1) was added, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sulfuric acid. After concentration under reduced pressure, isopropyl ether (30 mL) was added to the residue. After the resulting solid was collected by filtration, it was washed with isopropyl ether. After drying under reduced pressure, _N-[4-methyl-5-(4-amine-renalybdenyl phenyl fluorenyl)-1,3-嗟π-sodium 2-yl]acetamide is obtained as a yellow-white solid. (3.90 g, 11. 4 mmol, yield 67.4%). Step 4

CH2ClrMeOH 將N-[4-羥甲基-5-（4-胺磺醯基苯甲基）一i，3一噻唑 -2-基]乙醯胺（3· 38g，9· 90_〇1)溶於二氯甲烷（24〇mi)、 甲醇（12ml)之混合容劑中後，加入活化二氧化猛（33. gg， 389mmol)，且在室溫攪拌5小時。通過Celite(商品名， 319771 56 200835687 矽藻土）過濾反應液後，將濾液減壓濃縮。將二異丙醚 (100ml)加入至濃縮殘渣後，濾取析出之固體，並以異丙醚 洗淨。減壓乾燥後，得到黃白色固體之n—[4—甲酿基-5 —— 胺石黃酸基苯甲基）-1，3_°塞吐-2-基]乙酿胺（2· 39g，7. 04 mmol，產率 71. 1%)。 步驟5CH2ClrMeOH N-[4-hydroxymethyl-5-(4-aminesulfonylbenzyl)-i,3-thiazol-2-yl]acetamide (3·38 g, 9·90_〇1) After being dissolved in a mixed solvent of dichloromethane (24 〇mi) and methanol (12 ml), activated oxidized sulphur (33. gg, 389 mmol) was added, and stirred at room temperature for 5 hours. After filtering the reaction mixture through Celite (trade name, 319771 56 200835687 diatomaceous earth), the filtrate was concentrated under reduced pressure. Diisopropyl ether (100 ml) was added to the concentrated residue, and the precipitated solid was filtered and washed with isopropyl ether. After drying under reduced pressure, n-[4-bromo-5-- oleoleylbenzyl)-1,3_° sec-2-yl]ethylamine (2·39 g) , 7. 04 mmol, yield 71.1%). Step 5

在〇°C在溴化（4-羧曱基苯T基）三苯基鱗（8 859g， 18· 03mm〇l)之無水N，N-二曱基甲醯胺（80ml)溶液中加入 二級丁醇鉀（5.058g，45· 08mmol )後，在室溫攪拌3〇分。 接者’加入N - [4-甲酸基-5 -（4-胺石黃酿基苯曱基）一1，3一嗟 唑-2--基]乙醯胺（2· (Mg，6· 01 mmol)之無水n，N-二曱基曱 醯胺（30ml)溶液後，攪拌5小時。在冷卻下，加入水，並 馨以醋酸乙酯（200ml·)洗淨。將水層以in鹽酸酸化（pH5)後， 以醋酸乙酯萃取。將有機層以飽和食鹽水洗淨後，以無水 硫酸鎮乾燥。減壓濃縮後，得到黃白色固體之粗製（4—丨之一 [2-乙醢基胺基-5-（4-胺石黃隨基苯甲基）—1，3 —π塞tr坐—4—基] 乙烯基}苯基）醋酸（3. 04g) 〇Add 2 in a solution of (4-carboxymethylphenyl T-based) triphenyl scale (8 859 g, 18·03 mm〇l) in anhydrous N,N-dimercaptocaramine (80 ml) at 〇 °C After potassium butanolate (5.058 g, 45·08 mmol), it was stirred at room temperature for 3 。. Receiver 'Add N - [4-formyl-5-(4-amine fluorenylbenzoyl)-1,3-carbazol-2-yl]acetamide (2·(Mg,6· After a solution of 01 mmol) of anhydrous n,N-didecylguanamine (30 ml), stir for 5 hours. Under cooling, add water and wash with ethyl acetate (200 ml·). After acidification with hydrochloric acid (pH 5), the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Ethylamino-5-(4-amine sulphate benzyl)-1,3-π-setr-4-yl]vinyl}phenyl)acetic acid (3. 04g) 〇

319771 57 200835687 將粗製（4-{2-[2-乙醯基胺基一5-(4-胺磺醯基苯甲基） -1，3-噻唑-4-基]乙烯基}苯基）醋酸（3. 〇4g)溶於甲醇 (100ml)、四氫呋喃（ΙΟΟπιΐ)、醋酸之混合溶劑中後， 加入10%纪碳，在室溫、常壓下進行氫化。將反應液過濾、 減壓》辰縮後’將殘 >查以碎膠管柱層析法（Merck 9385，9 0g， 二氯曱烷：曱醇=5 ·· 1至1 : 1)精製。再次以矽膠管柱層 析法«61^让9385,9(^，二氯曱烷：四氫呋喃=5:1)精製 後，得到白色固體之（4-{2-[ 2-乙醯基胺基一 5-(4-胺磺醯基 苯曱基）-1，3-噻唑-4-基]乙基}苯基）醋酸（1. 7〇g，3. 59 mmol，產率 59· 7%[從步驟-5])。 步驟7319771 57 200835687 will be crude (4-{2-[2-acetamidoamino-5-(4-aminesulfonylbenzyl)-1,3-thiazol-4-yl]vinyl}phenyl) Acetic acid (3. 4 g) was dissolved in a mixed solvent of methanol (100 ml), tetrahydrofuran (ΙΟΟπιΐ), and acetic acid, and then 10% carbon was added thereto, and hydrogenation was carried out at room temperature under normal pressure. The reaction solution was filtered, decompressed, and then regenerated. The residue was purified by a gel column chromatography (Merck 9385, 90 g, dichloromethane: decyl alcohol = 5 ··1 to 1:1). After refining with a rubber column chromatography «61^, 9385, 9 (^, dichloromethane: tetrahydrofuran = 5:1), (4-{2-[2-ethylamino) 5-(4-Aminosulfonylphenylhydrazino)-1,3-thiazol-4-yl]ethyl}phenyl)acetic acid (1.7 g, 3.59 mmol, yield 59.7%) [From step -5]). Step 7

在（4-{2-[2-乙醯基胺基-5-（4-胺磺醯基苯曱基）一；[，3 _ -噻唑-4-基]乙基}苯基）醋酸（50.〇mg，〇105mm〇1)之無水 N，N-二甲基甲醯胺（imi)溶液中加入1，j，-魏基二咪嗤 (45· lmg，0· 278mmol)，且在50°C攪拌2小時。冷卻至室 /皿後，加入肼•一水合物（〇· 〇5m 1，1 · 1 mmo 1)，並攪拌17 小時。加入冰水（5ml)、飽和碳酸氫鈉水溶液（5mi)後，以 醋酸乙酯萃取。將有機層以飽和食鹽水洗淨後，以無水硫 酉欠鎮乾燥。濃縮變乾硬後’付到白色固體之標題化合物 (12· Omg，〇· 〇25mmo：l，產率 23. 4%) 〇 融點183至186T： 319771 58 200835687 W—MRteOOMHz, DMS0-d6)·· δ (ppm): 12.01 (1H, brs), 9.20(1H, brs), 7.70(2 H, d, J=7.7Hz), 7.35-6.92 (6H, m), 4.40(2H, br), 3.95(2H, s), 3.30 (2H ▲ s), 2.90-2.70 (4H,m), 2.07(3H, s) ’ 13C-NMR(50MHz, DMSO): δ (ppm) ： 169.9, 168.3, 155.4, 145.7 144.8, 142.3, 139· 6，134· 0, 129.1, 128.9, 128.4, 126.1, 123.1，115*8，34.8, 30.7, 2 2. 5 (製造例8) ^(4-{2-[4-(2-肼基羰基乙基）苯基]乙基卜1，3一噻唑-2一 基）乙醯胺之合成 步驟1(4-{2-[2-Ethylamino-5-(4-aminesulfonylphenyl)-yl][,3-thiazol-4-yl]ethyl}phenyl)acetic acid ( 50. 〇mg, 〇105mm〇1) in an anhydrous N,N-dimethylformamide (imi) solution was added 1,j,-Weiyl diimidine (45·1 mg, 0·278 mmol), and Stir at 50 ° C for 2 hours. After cooling to the chamber/dish, add hydrazine monohydrate (〇·〇5m 1,1 · 1 mmo 1) and stir for 17 hours. After adding ice water (5 ml) and a saturated aqueous sodium hydrogen carbonate solution (5m), ethyl acetate was evaporated. The organic layer was washed with saturated brine and dried over anhydrous sulphur. After concentration and drying, the title compound (12·Omg, 〇·〇 25mmo:l, yield 23.4%) was added to the white solid. 〇 183 to 186T: 319771 58 200835687 W—MRteOOMHz, DMS0-d6) ·· δ (ppm): 12.01 (1H, brs), 9.20(1H, brs), 7.70(2 H, d, J=7.7Hz), 7.35-6.92 (6H, m), 4.40(2H, br), 3.95 (2H, s), 3.30 (2H ▲ s), 2.90-2.70 (4H, m), 2.07 (3H, s) ' 13C-NMR (50MHz, DMSO): δ (ppm): 169.9, 168.3, 155.4, 145.7 144.8, 142.3, 139· 6,134· 0, 129.1, 128.9, 128.4, 126.1, 123.1, 115*8, 34.8, 30.7, 2 2. 5 (Manufacturing Example 8) ^(4-{2-[4- Synthesis of (2-mercaptocarbonylethyl)phenyl]ethyl b,1,3-thiazole-2-yl)acetamide

NBS·NBS·

CCX3H CC14 BPO BrCCX3H CC14 BPO Br

COOH 在3-(4-曱苯基）-2-丙烯酸（8· li〇g，50· 00mmol)中加 入四氯化碳（150ml )使其懸浮後，加入N-溴琥珀醯亞胺 (8· 899g，50· OOmmol)、過氧化苯甲醯（含水 25%，161. 6mg， 〇.500mmol)。加熱回流17小時後，冷卻至室溫，並減壓濃 縮。濾取所得之固體後，以醋酸乙酯洗淨2次。減壓乾燥 ⑩後，得到微褐色固體之3-[(4-溴甲基)苯基]—2一丙烯酸 (7· 777g，32· 26mmol，產率 64· 5%)。 步驟2COOH After adding carbon tetrachloride (150 ml) to 3-(4-indolyl)-2-acrylic acid (8·li〇g, 50·00 mmol), N-bromosuccinimide (8) was added. · 899 g, 50· 00 mmol), benzamidine peroxide (25% aqueous, 161.6 mg, 〇.500 mmol). After heating under reflux for 17 hours, it was cooled to room temperature and concentrated under reduced pressure. The obtained solid was collected by filtration and washed twice with ethyl acetate. After drying 10 under reduced pressure, 3-[(4-bromomethyl)phenyl]-2-acrylic acid (7· 777 g, 32·26 mmol, yield 64.5%) was obtained as a brown solid. Step 2

COOH PPh3 甲苯COOH PPh3 toluene

COOH 在3-[(4-溴曱基）苯基]-2-丙烯酸（8. 327g，34. 54 mmol)之無水曱苯（135ml)溶液中加入三苯膦（9 〇59g， 34. 54·〇1)後，加熱回流4小時。冷卻至室溫後，濾取析 出之固體’並以異丙醚洗淨3次。減壓乾燥後，得到微褐 319771 59 200835687COOH In a solution of 3-[(4-bromoindolyl)phenyl]-2-propenoic acid (8. 327 g, 34.54 mmol) in anhydrous benzene (135 ml), triphenylphosphine (9 〇 59 g, 34. 54) After 〇1), it was heated to reflux for 4 hours. After cooling to room temperature, the precipitated solid was collected by filtration and washed three times with isopropyl ether. After drying under reduced pressure, a brownish brown is obtained. 319771 59 200835687

A 色固體之>臭化{4- [2-(叛基）伸乙基]苯甲基}(三苯基）鱗 (15· 64g，31· 07mmol，產率 89· 8%)。 步驟3A color solid > stinky {4- [2-(remediate)-extended ethyl]benzyl}(triphenyl) scale (15·64 g, 31·07 mmol, yield 89·8%). Step 3

AcHI卜+ n^choAcHI Bu + n^cho

於0°C在溴化{4-[2-(羧基）伸乙基]苯甲基}(三苯基） 鎸（5.537g，11· OOmmol)之無水 N，N-二曱基曱醯胺（50ml) 溶液中加入三級丁醇鉀（3· 366g，30· OOmmol)後，在室溫擾 拌30分。加入N-( 4-曱醯基-1，3-嘆嗤-2-基）乙醯胺（1. 702 g，10. OOmmol)之無水N，N-二曱基甲醯胺（8ml)溶液，且在 室溫攪拌1小時。加入水（100ml )，並以醋酸乙酯洗淨。在 水層中加入1N鹽酸（25ml)並攪拌後，濾取析出之固體，並 以水洗淨。減壓乾燥後，得到黃色固體之3-（4- {2-[2-(乙 醯基胺基）-1，3-噻唑-4-基]乙烯基}苯基>-2-丙烯酸 - (2. 913g，9· 266mmol，產率 92· 7%)。Anhydrous N,N-didecylguanamine which is brominated {4-[2-(carboxy)exylethyl)benzyl}(triphenyl)phosphonium (5.537 g, 11.0 mmol) at 0 °C (50 ml) After adding tertiary potassium butoxide (3·366 g, 30·00 mmol) to the solution, the mixture was stirred for 30 minutes at room temperature. Adding N-(4-mercapto-1,3-indol-2-yl)acetamide (1. 702 g, 10. OOmmol) in anhydrous N,N-dimercaptocaramine (8 ml) And stirred at room temperature for 1 hour. Water (100 ml) was added and washed with ethyl acetate. After adding 1 N hydrochloric acid (25 ml) to the aqueous layer and stirring, the precipitated solid was collected by filtration and washed with water. After drying under reduced pressure, 3-(4-{2-[2-(ethylamino)-1,3-thiazol-4-yl]vinyl}phenyl>-2-acrylic acid was obtained as a yellow solid. (2. 913 g, 9·266 mmol, yield 92.7%).

COOH 使3-（4-{2-[2-（乙醯基胺基）-1，3-噻唑-4-基]乙烯 基}苯基）-2_丙烯酸（2· 913g，9· 266mmol)懸浮於四氫呋喃 (300ml)、甲醇（3〇〇ml)、醋酸（60ml)之混合溶劑中後，加 入10%鈀碳（2· 337g，含水50%)，在室溫、常壓下進行氫化 (約100小時）。通過Celite過濾反應液。將濾液減壓濃縮 60 319771 200835687 後，濾取生成之固體，並以異丙醚洗淨。減壓乾燥後，得 到白色固體。此外，將母液濃縮物以矽膠管柱層析法 SilySiaBW-300SP，75g，甲醇：二氯甲烷=1 : 2〇)精製。 收集含目標物之分液並減壓乾燥後，將生成之固體以異丙 醚洗淨，再減壓乾燥後，得到白色固體。將生成物混合後， 付到3-（4 - {2-[2-（乙醯基胺基）一1，3-嗟唾—4-基]乙基}苯 基）-2 -丙婦酸（2.383g，7· 485mmol，產率 8〇· 8%)。 步驟5COOH 3-(4-{2-[2-(Ethylamino)-1,3-thiazol-4-yl]vinyl}phenyl)-2-acrylic acid (2·913 g, 9·266 mmol) After suspending in a mixed solvent of tetrahydrofuran (300 ml), methanol (3 ml), acetic acid (60 ml), 10% palladium carbon (2·337 g, 50% aqueous) was added, and hydrogenation was carried out at room temperature under normal pressure ( About 100 hours). The reaction solution was filtered through Celite. After the filtrate was concentrated under reduced pressure of 60 3 1977 1 s, s. After drying under reduced pressure, a white solid was obtained. Further, the mother liquor concentrate was purified by silica gel column chromatography, SilySiaBW-300SP, 75 g, methanol: dichloromethane = 1: 2 Torr. After collecting the fractions containing the target and drying under reduced pressure, the obtained solid was washed with isopropyl ether and dried under reduced pressure to give a white solid. After mixing the product, it is added to 3-(4 - {2-[2-(ethylideneamino)-1,3-pyran-4-yl]ethyl}phenyl)-2-propanoic acid (2.383 g, 7·485 mmol, yield 8 〇·8%). Step 5

AcHIAcHI

CDI, DMFCDI, DMF

COOH ΝΗ2ΝΗ2Η20COOH ΝΗ2ΝΗ2Η20

AcHIAcHI

在3 (4 - {2-[2-(乙.酸基胺基）-1，3 — π塞唾-4 —基]乙基} 苯基）-2-丙烯酸（573· lmg，1· 800mmol)之無水ν，Ν-二甲基 甲酉&胺（4· 5ml)溶液中加入1，1’ —幾基二味嗤（437. gmg， 2·700ππη〇1)，且在50。(：攪拌1小時。冷卻至室溫後，加入 肼•一水合物（〇· 43ml，9· Ommol)，且在室溫攪拌2· 5小時。 加入水（10ml)並攪拌後，濾取生成之固體。以水洗淨3次、 以醋酸乙酯洗淨3次。減壓乾燥後，得到白色固體之標題 之化合物（525· 7mg，1· 581 mmol，產率 87. 9%)。In 3 (4 - {2-[2-(ethylamino)-1,3-π-supiva-4-yl]ethyl}phenyl)-2-acrylic acid (573·1 mg, 1·800 mmol To the solution of anhydrous ν, Ν-dimethylformamidine &amine (4.5 ml), 1,1'-monoaminodime (437. gmg, 2·700ππη〇1) was added, and at 50. (: stirring for 1 hour. After cooling to room temperature, hydrazine monohydrate (〇·43 ml, 9.0 mmol) was added, and stirred at room temperature for 2.5 hours. Water (10 ml) was added and stirred, and the mixture was filtered. The title compound (525·7 mg, 1· 581 mmol, yield: 87.9%) was obtained as a white solid.

融點196至198°C χΗ-ΝΜΕ(200ΜΗζ, DMS0-d6) ： δ (ppm) ： 12.06(1Η, brs), 8.93(1Η, brs), 7.17-7 02 (4Η, m〉，6·72(1Η, s), 4·14(2Η, brs), 2·90-2·78(4Η，m)，’2 75(’2Η · t · J=7.7Hz), 2.27(2¾ t, J=7.7Hz), 2.10(3¾ s) · ’ ’ 13C-NMR(50MHz, DMSO)： δ (ppm)： 17L0, 168.4, 157.6, 150.6 139 1 13« q 128.4, 128.3, 107.5, 35.3, 34.4, 33.1, 30.8, 22.4 ，⑽·1，138·9， (製造例Θ) 319771 61 200835687 4-（4-{2-[2-（乙醯基胺基）-1，3-噻唑一4-基]乙基}苯基）半 卡肼之合成 步驟1Melting point 196 to 198 ° C χΗ-ΝΜΕ (200ΜΗζ, DMS0-d6) : δ (ppm) : 12.06(1Η, brs), 8.93(1Η, brs), 7.17-7 02 (4Η, m〉,6·72 (1Η, s), 4·14(2Η, brs), 2·90-2·78(4Η,m), '2 75('2Η · t · J=7.7Hz), 2.27(23⁄4 t, J= 7.7 Hz), 2.10 (33⁄4 s) · ' ' 13C-NMR (50MHz, DMSO): δ (ppm): 17L0, 168.4, 157.6, 150.6 139 1 13« q 128.4, 128.3, 107.5, 35.3, 34.4, 33.1, 30.8, 22.4, (10)·1,138·9, (Production Example) 319771 61 200835687 4-(4-{2-[2-(Ethylamino)-1,3-thiazole-4-yl]B Synthesis of base phenyl) half-calendar

在1，1 _羰基二咪唑（810. 8mg，5. OOOmmol)之四氫呋 喃（5ml)溶液中加入三級丁氧基肼基甲酸⑽〇. 8mg，5. 〇〇〇 • mmol)，且在室溫攪拌i小時。n_{4_[2_(4_胺苯基）乙基] -1，3-嗟嗤-2-基}乙醯胺（518.7mg，2 〇〇〇mm〇1)、三乙胺 (〇.42ml，3.0賴〇1)，且在室溫攪拌17小時。加入醋酸乙 酯（40ml)、水（30ml)並攪拌，靜置後分液。將水層以醋酸 乙酯卒取。將混合後之有機層以無水硫酸鎂乾燥後，減壓 濃縮。將濃縮殘渣以矽膠管柱層析法（Fuji SHysia BW_ 300SP，45g，醋酸乙酯：己烷=7 : 3至9 : j)精製。將含 φ目標物之區分濃縮後，將析出之固體以異丙醚洗淨，並減 壓乾燥後，得到白色固體之N，_三級丁氧羰基_4_(4_{2_ [2-(乙醯基胺基）_；[，3_噻唑_4_基]乙基丨苯基）半卡肼 (663· 4mg，1· 581mmol，產率 79· 1%)。 步驟2 又 4M-HCt 在〔〇〕中 AcHN·—^To a solution of 1,1 _carbonyldiimidazole (810. 8 mg, 5. OOO mmol) in tetrahydrofuran (5 ml) was added tert-butoxycarbonylcarbazide (10) 〇. 8 mg, 5. 〇〇〇• mmol), and in the room Stir for 1 hour. N_{4_[2_(4_Aminophenyl)ethyl]-1,3-indol-2-yl}acetamide (518.7mg, 2 〇〇〇mm〇1), triethylamine (〇.42ml) , 3.0 〇 1), and stirred at room temperature for 17 hours. Ethyl acetate (40 ml) and water (30 ml) were added and stirred, and the mixture was allowed to stand for separation. The aqueous layer was drawn with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and evaporated. The concentrated residue was purified by silica gel column chromatography (Fuji SHysia BW_300SP, 45 g, ethyl acetate:hexane = 7:3 to 9: j). After the concentration of the target substance containing φ is concentrated, the precipitated solid is washed with isopropyl ether, and dried under reduced pressure to give a white solid, N, _,,,,,,,,,,,,,,,,,,,,,,,,,, Hydrazinyl)); [, 3_thiazole-4-yl]ethyl hydrazine phenyl) carbazide (663·4 mg, 1.581 mmol, yield 79·1%). Step 2 and 4M-HCt in [〇] AcHN·—^

又 ,ΝΗΖ Ν -二級丁氧幾基—4-（4-{2-[2-（乙醯基胺基）一1， 319771 62 200835687 π塞τι坐—4 一基]乙基}本基）半卡月井（629· 3mg，1· 500minol)之無 水二氯甲烷（7· 5ml)溶液中加入4M氯化氫二噚烷（di〇xane) 溶液（7· 5ml，30mmol)，且在室溫攪拌2· 5小時。減壓濃縮 後，將碳酸氫鈉水溶液（80ml)、醋酸乙酯（250ml)、四氫吱 喃（5Om 1)加入至殘、/查’靜置後分液。將水層以醋酸乙醋一 四氫呋喃混合溶液（5 : 1)萃取2次、以醋酸乙酯5次。將 混合後之有機層以無水硫酸鎂乾燥後濃縮變乾硬，得到微 桃紅色固體之標題化合物（308· 4mg，0· 966mmol，產率 * 64·3%)。Further, ΝΗΖ Ν -2 -2 -butoxy-yl- 4-(4-{2-[2-(ethionylamino)-1, 319771 62 200835687 π塞τι sitting - 4 -yl]ethyl}yl Add 4M hydrogen dioxane (di〇xane) solution (7.5 ml, 30 mmol) to a solution of half-calorie well (629·3 mg, 1500 min) in anhydrous dichloromethane (7.5 ml), and at room temperature Stir for 2 hours. After concentration under reduced pressure, a sodium hydrogencarbonate aqueous solution (80 ml), ethyl acetate (250 ml), and tetrahydrofuran (5Om 1) were added to the residue, and the mixture was allowed to stand for separation. The aqueous layer was extracted twice with a mixed solution of ethyl acetate-tetrahydrofuran (5:1) and ethyl acetate 5 times. The combined organic layer was dried with EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

融點233至236°C 'H-NMR (200MHz, DMS0~d6) ： 6 (ppm) ： 12.08(1¾ brs), 8.53(1H, brs), 7.39(2 H, d, J=8.3Hz), 7.34QH, brs), 7.04(2H, d, J=8.3Hz), 6.71(1¾ s), 4.31 (2H, brs), 2. 90-2. 78(4H, m), 2.11(3¾ s) 13C-NMR(50MHz, DMSO)： δ (ppm) ： 168.1, 157.3, 150.4, 137.7, 134.2, 128.2, 118· 1, 107.2, 33.9, 33.0, 22.3 · ’ · ’ (製造例10) - N-(4-{2-[4-（Ν’ -乙醯基肼基羰基曱基）苯基]乙基卜；[，3一 馨噻唑-2-基）乙醯胺之合成Melting point 233 to 236 ° C 'H-NMR (200 MHz, DMS0~d6): 6 (ppm): 12.08 (13⁄4 brs), 8.53 (1H, brs), 7.39 (2 H, d, J = 8.3 Hz), 7.34QH, brs), 7.04(2H, d, J=8.3Hz), 6.71(13⁄4 s), 4.31 (2H, brs), 2. 90-2. 78(4H, m), 2.11(33⁄4 s) 13C -NMR (50 MHz, DMSO): δ (ppm): 168.1, 157.3, 150.4, 137.7, 134.2, 128.2, 118·1, 107.2, 33.9, 33.0, 22.3 · ' · ' (Manufacturing Example 10) - N-(4 -{2-[4-(Ν'-Ethylmercaptocarbonylcarbonyl)phenyl]ethyl b; Synthesis of [,3-monothiazol-2-yl)acetamide

在2-(4-{2-[2-(乙酿基胺基）-1，3 -嗟峻-4_基]乙基} 苯基）醋酸（913. Img，3· OOOmol)之無水N，N-二曱基甲醯胺 (7· 5ml)>谷液中加入 1，1’ —裁基二咪哇（729· 7mg，4· 500 匪〇1)，且在50°C攪拌1小時。冷卻至室溫後，加入乙醯 基肼（acetohydrazideXI· lllg，15· OOmmol)，且在室溫攪 63 319771 200835687 拌1小時。加入水（100ml)與醋酸乙酯（5〇ml)並攪拌後，濾、 取析出之固體，並以水洗淨2次、以醋酸乙酯洗淨3次。 減壓乾餘後’仔到白色固體之標題化合物（6 3 5. 9 m g，1. 7 6 4 mmol，產率 58· 8%)。Anhydrous N in 2-(4-{2-[2-(ethylamino)-1,3-anthracepin-4-yl]ethyl}phenyl)acetic acid (913. Img, 3· OOOmol) , N-dimercaptocarhamamine (7.5 ml)> Add 1,1'-cutting kiwi (729·7 mg, 4·500 匪〇1) to the trough, and stir at 50 °C hour. After cooling to room temperature, acetaminophen (acetohydrazide XI lllg, 15.0 mmol) was added, and stirred at room temperature for 63 hrs, 1937, and 3,35,687. Water (100 ml) and ethyl acetate (5 ml) were added and stirred, and the precipitated solid was filtered, washed twice with water and three times with ethyl acetate. The title compound (6 3 5. 9 m g, 1. 7 6 4 mmol, yield 58.8%) was obtained from the white solid.

融點223至225°C 4一NMR(200MHz，DMS0-d6): δ(ρρπι): 12·07(1Η，brs)，9·95(1Η, brs), 9·78(1Η, brs), 7· 23-7· 06 (4Η, m), 6· 72(1Η, s), 3.39(2Η, s), 2.98-2.75(4Η, m),, 2-10(2H, s), 1.82(3¾ s) 13C-NMR(50MHz, DMS0-d6)： δ (ppm)： 169.5, 168.7, 168.4, 157.9, 150.8 140 〇, 133.7，129.4, 128.6, 107.8, 34· 7, 33.3, 22.9, 21,0 ’ · (製造例11) N-(4-{2-[4-(N’ -丁醯基肼基羰基甲基）苯基]乙基卜l 3一 噻唑-2-基）乙醯胺之合成 步驟1Melting point 223 to 225 ° C 4 NMR (200 MHz, DMS0-d6): δ (ρρπι): 12·07 (1Η, brs), 9·95 (1Η, brs), 9·78 (1Η, brs), 7· 23-7· 06 (4Η, m), 6·72(1Η, s), 3.39(2Η, s), 2.98-2.75(4Η, m),, 2-10(2H, s), 1.82( 33⁄4 s) 13C-NMR (50MHz, DMS0-d6): δ (ppm): 169.5, 168.7, 168.4, 157.9, 150.8 140 〇, 133.7, 129.4, 128.6, 107.8, 34· 7, 33.3, 22.9, 21,0 ' (Manufacturing Example 11) Synthesis procedure of N-(4-{2-[4-(N'-butyl-decylcarbonylmethyl)phenyl]ethyl b-l-thiazol-2-yl)acetamide 1

nh2nh2 h2o —----► MeOHNh2nh2 h2o —----► MeOH

於室溫在丁酸曱酯（4· 〇瓜1，35· 3mmol )之無水曱醇（8ml) 鲁溶液中滴入肼·一水合物（2· lml，42· 3mmol)後，攪拌18 小時。減壓濃縮後，以曱醇共沸5次去除丁酸曱酯。將濃 縮歹成 >查藉由石夕膠管柱（Sep-pak Si 1，1 Og 25cc，醋酸乙酯） 精‘後，將所得之結晶以異丙醚洗淨。減壓乾燥後，得到 白色結晶之丁酸肼（L387g，13· 56mmol，產率38_ 5%)。 步驟2After adding hydrazine monohydrate (2·1 ml, 42·3 mmol) to a solution of decyl butyrate (1·35·3 mmol) in anhydrous decyl alcohol (8 ml), stir at room temperature for 18 hours. . After concentration under reduced pressure, decyl butyrate was removed by azeotrope 5 times with decyl alcohol. The concentration was reduced to > and the crystals obtained were washed with isopropyl ether by the Shih-Pak Si 1,1 Og 25 cc (ethyl acetate). After drying under reduced pressure, yttrium succinate (L 387 g, 13.56 mmol, yield 38- 5%) was obtained as white crystals. Step 2

200835687 在2-(4-{2-[2-(乙酸基胺基）-1，3-嗟哇-4-基]乙基} 苯基）醋酸（304· 5mg，1· OOOmmol)之無水N，N-二甲基甲酿 月女（1 m 1)溶液中加入1，1 -幾基二味嗤（244· 0mg，1 · 5 0 5 mmol)，且在50°C攪拌1小時。冷卻至室溫後，加入丁酿 肼（307· lmg，3· 007mm〇l)及無水N，N-二甲基甲醯胺 (1 m 1)’且在室溫攪;拌2小時。加入水（15m 1)並擾拌後，滤 取析出之固體。將固體以水洗淨3次、以醋酸乙酯洗淨3 次。減壓乾燥後，得到淡黃色固體之標題化合物（248. 9mg， 修 0· 641 mmol，產率 64. 1%)。200835687 Anhydrous N in 2-(4-{2-[2-(Acetylamino)-1,3-indol-4-yl]ethyl}phenyl)acetic acid (304·5 mg, 1·Ommol) To the solution of N-dimethylglycolide (1 m 1), 1,1-diamino dimethane (244·0 mg, 10.55 mmol) was added, and the mixture was stirred at 50 ° C for 1 hour. After cooling to room temperature, butyl hydrazine (307·1 mg, 3·007 mm 〇l) and anhydrous N,N-dimethylformamide (1 m 1)' were added and stirred at room temperature; and mixed for 2 hours. After adding water (15 ml) and scrambling, the precipitated solid was collected by filtration. The solid was washed three times with water and three times with ethyl acetate. The title compound (248. 9 mg, m.

融點215至217°CMelting point 215 to 217 ° C

ΐ-ΝΜΟΟΟΜΗζ, DMS0-d6): δ(ρριη): 12·06(1Η, brs), 9·95(1Η，brs), 9 71(1H brs), 7.26-7.03 (4H, m), 6.72(1¾ s), 3.39(2H, s), 2.99-2.79(4h/m), 2*10(3H, s), 2.06(2H> t, J=7.1Hz), L 62-1.40(2¾ m), 0.86(3H, t, J=7 3 Hz), ,. 13C-NMR(50MHz，DMS0-d6): δ (ppm): 171· 1，169.2，168· 4, 157.6, 150.5 139· 7，133·4，129.1，128.3，107.5, 35.2, 34·4, 33· 0，22.7, 18.6, 13· 7 ·(製造例12) ·· N-(4-丨2-[4-(N’ -癸醯基肼基羰基甲基）苯基]乙基}一l 3一 鲁噻唑-2_基）乙醯胺之合成 步驟1 Λ (CH2)8CH3 nh2nh2 h2oΐ-ΝΜΟΟΟΜΗζ, DMS0-d6): δ(ρριη): 12·06(1Η, brs), 9·95(1Η,brs), 9 71(1H brs), 7.26-7.03 (4H, m), 6.72( 13⁄4 s), 3.39(2H, s), 2.99-2.79(4h/m), 2*10(3H, s), 2.06(2H> t, J=7.1Hz), L 62-1.40(23⁄4 m), 0.86(3H, t, J=7 3 Hz), ,. 13C-NMR (50MHz, DMS0-d6): δ (ppm): 171· 1,169.2,168· 4, 157.6, 150.5 139· 7,133· 4,129.1,128.3,107.5, 35.2, 34·4, 33· 0,22.7, 18.6, 13· 7 · (Manufacturing Example 12) ··· N-(4-丨2-[4-(N' -癸醯Synthesis of fluorenyl (carbonyl)methyl)phenyl]ethyl}-l-3-thiothiazol-2-yl)acetamide. Step 1 Λ (CH2)8CH3 nh2nh2 h2o

MeOHMeOH

Y 在癸酸甲酯（7· 0ml，32· 4mmol)之無水曱醇（I5ml)溶液 中滴入肼•一水合物（1· 9ml，39. 2mmol)。在室溫授拌29 小時後，減壓濃縮，並以甲醇共沸1次。將所得之固體以 己烧洗淨後’減壓乾燥’得到白色結晶之癸酿肼（2· 197g， 319771 200835687 11. 79mmol，產率 36. 1%)。 步驟2Y Toluene monohydrate (1.9 ml, 39. 2 mmol) was added dropwise to a solution of methyl decanoate (7.0 ml, 32. 4 mmol) in anhydrous methanol (1 mL). After stirring for 29 hours at room temperature, it was concentrated under reduced pressure and azeotroped with methanol. The obtained solid was washed with hexane and dried under reduced pressure to give white crystals (2. 197 g, 319771, s. Step 2

在2-(4-{2-[2-(乙醯基胺基）-1，3-噻唑-4-基]乙基} 苯基）醋酸（304. 4mg，1. OOOmmol)之無水N，N-二曱基甲醯 胺（2ml)溶液中加入1，Γ -羰基二咪唑（243· 2mg，1· 500 mmol)，且在50°C攪拌1小時。冷卻至室溫後，加入癸醯 肼（838· 3mg，4. 500mmol)，且在室溫擾拌4小時。加入水 (20ml)並攪拌後，濾取生成之固體，並以水洗淨3次、以 醋酸乙酯洗淨5次。減壓乾燥後，得到白色固體之標題化 合物（301 · 3mg，0. 638mmol，產率 63· 8%)。 融點203至205°C 一 ΐ-ΝΜΚ (200MHz, DMS(Hi6): δ (ppm): 12.06 (1H, brs), 9·94 (1H, brs), 9· 70 (1H， brs), 7.25-7.04 (4H, m), 6.72(1H, s), 3.38(2H, s), 2.97-2.76 (4H, m), φ 2.10(3¾ s), 2.07(2H, t, J=7.6Hz), 1.57~L36(2H, m), 1.36-1. 14 (12H, m), 0.84(3H, t, J=6.2Hz) 13C-NMR(50MHz, DMS0~d6): δ(ρριη): 171.2，169.2, 168· 4, 157.6，150.5, 139.7, 133.4, 129.1, 128.3, 107.5，34· 4, 33· 3, 33· 0, 29· 1, 29.0, 28.9, 28. 7, 25· 2, 22· 7，22· 3, 14· 1 (製造例13) N-[4-(2-{4-[Ν’ -（3-羥基丙醯基）肼基羰基甲基]苯基}乙 基）-1,3-噻唑-2-基]乙醯胺之合成 步驟1 | Ό ΝΗ2ΝΗ2 η2ο -^Anhydrous N in 2-(4-{2-[2-(ethionylamino)-1,3-thiazol-4-yl]ethyl}phenyl)acetic acid (304. 4 mg, 1. OOOmmol) To a solution of N-dimercaptocaramine (2 ml) was added 1, hydrazine-carbonyldiimidazole (243. 2 mg, 1.5 mmol), and stirred at 50 ° C for 1 hour. After cooling to room temperature, hydrazine (838·3 mg, 4.500 mmol) was added and the mixture was stirred at room temperature for 4 hours. After adding water (20 ml) and stirring, the resulting solid was collected by filtration, washed three times with water and five times with ethyl acetate. The title compound (301 · 3 mg, 0. 638 mmol, yield 63.8%) was obtained as white solid. Melting point 203 to 205 ° C ΐ-ΝΜΚ (200 MHz, DMS (Hi6): δ (ppm): 12.06 (1H, brs), 9·94 (1H, brs), 9·70 (1H, brs), 7.25 -7.04 (4H, m), 6.72(1H, s), 3.38(2H, s), 2.97-2.76 (4H, m), φ 2.10(33⁄4 s), 2.07(2H, t, J=7.6Hz), 1.57~L36(2H, m), 1.36-1. 14 (12H, m), 0.84(3H, t, J=6.2Hz) 13C-NMR(50MHz, DMS0~d6): δ(ρριη): 171.2,169.2 , 168· 4, 157.6, 150.5, 139.7, 133.4, 129.1, 128.3, 107.5, 34· 4, 33· 3, 33· 0, 29· 1, 29.0, 28.9, 28. 7, 25· 2, 22· 7 , 22· 3, 14· 1 (Production Example 13) N-[4-(2-{4-[Ν'-(3-hydroxypropionyl)nonylcarbonylmethyl]phenyl}ethyl)-1 , 3-thiazol-2-yl]acetamide synthesis step 1 | Ό ΝΗ2ΝΗ2 η2ο -^

MaOHMaOH

66 £t3SiCt Η η2ιγ <〇SiEt366 £t3SiCt Η η2ιγ <〇SiEt3

DMF 319771 200835687 於 0°C 在/3-丙内酯（propiolactone)(l. 5ml，23. 9 匪〇1)之無水甲醇（8ml)溶液中滴入肼•一水合物4ml， 28· 7_〇1)。升溫至室溫後’授摔7小時。減壓濃縮後，將 無水 N，N-二曱基曱酿胺（20ml)、味嗤（1. 954g，28. 70mmol) 加入至殘渣並攪拌。在〇 °C滴入三乙基氯石夕燒（4· 1，28. 7 mmol)後，升溫至室溫，並攪拌2· 5小時。加入水（10〇1111)、 醋酸乙酯（10Om 1)並攪拌，靜置後分液。將有機層以飽和氯 化錄水溶液、飽和食鹽水洗淨後，以無水硫酸鎂乾燥。減 壓濃縮’並將殘渣以矽膠管柱層析法（Fuji Silysia BW -300SP ’ 127g，醋酸乙酯）精製後，得到無色液體之3—[(三 乙基矽基）氧基]丙醯肼（1· 289g，5· 903mmol，產率24. 7%)。 步驟2DMF 319771 200835687 In a solution of /3-propiolactone (1.5 ml, 23.9 匪〇1) in anhydrous methanol (8 ml) at 0 ° C, 4 ml of hydrazine monohydrate, 28· 7_ 〇 1). After warming to room temperature, it was dropped for 7 hours. After concentration under reduced pressure, anhydrous N,N-diindenylamine (20 ml) and miso (1. 954 g, 28.70 mmol) were added to the residue and stirred. After triethyl chlorite (4·1, 28.7 mmol) was added dropwise at 〇 °C, the mixture was warmed to room temperature and stirred for 2.5 hours. Water (10〇1111) and ethyl acetate (10Om 1) were added and stirred, and the mixture was allowed to stand for liquid separation. The organic layer was washed with a saturated aqueous solution of sodium chloride and brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP '127 g, ethyl acetate) to give 3-[(triethyl-decyl)oxy]propene as a colorless liquid. (1· 289 g, 5· 903 mmol, yield 24.7%). Step 2

在2-（4-{2-[2-（乙醯基胺基3-噻唑-4-基]乙基} 笨基）醋酸（456· 5mg，1· 500mmol)之無水N，N-二曱基曱醯 胺（2ml)溶液中加入1，1，一羰基二咪唑（364. 8mg，2· 25〇 匪〇1) ’且在50°C攪拌1小時。冷卻至室溫後，加入[(三 乙基矽基）氧基]丙醯肼（982· 7mg，4· 50mmol)之無水N，N-二甲基甲醯胺（1ml)溶液，且在室溫攪拌16小時。加入水 (30ml)並攪拌後，濾取生成之固體。將固體以水洗淨2次、 以醋酸乙酯洗淨3次後，減壓乾燥，得到白色固體之一 {2-[4-(Ν’-{3-[(三乙基矽基）氧基]丙醯基丨肼基羰基曱基） 67 319771 200835687 苯基]乙基卜1，3-噻唑〜2 —基）乙醯胺（515 8mg，1〇22 mmol，產率 68. 1%)。 步驟3 .Anhydrous N,N-diindole in 2-(4-{2-[2-(ethylideneamino 3-thiazol-4-yl)ethyl} phenyl)acetic acid (456·5 mg, 1·500 mmol) 1,1,-carbonyldiimidazole (364. 8 mg, 2·25〇匪〇1)' was added to the solution of the base amide (2 ml) and stirred at 50 ° C for 1 hour. After cooling to room temperature, [[ Triethyl decyl)oxy]propanthene (982. 7 mg, 4·50 mmol) in anhydrous N,N-dimethylformamide (1 ml), and stirred at room temperature for 16 hr. After stirring, the resulting solid was collected by filtration. The solid was washed twice with water, three times with ethyl acetate, and dried under reduced pressure to give one of white solids {2-[4-(Ν'-{ 3-[(Triethyl decyl)oxy]propenyl fluorenylcarbonyl fluorenyl) 67 319771 200835687 Phenyl]ethyl 1,3- thiazole ~ 2 -yl) acetamidine (515 8 mg, 1 〇22 mmol, yield 68.1%). Step 3 .

將四氫咬喃（3ml)、水（lml)、醋酸（11111)加入至1^(4- 馨丨2—[4—(N ―丨3—[(三乙基矽基）氧基]丙醯基}肼基羰基甲基） 苯基]乙基}-1，3-噻唑—2-基）乙醯胺（5〇1.7mg，0·099 mmol) ’且在室溫攪拌1小時。減壓濃縮後，以醋酸乙酯共 >弗3次去除醋酸。將所得之固體以醋酸乙酯洗淨，並減壓 乾燥後’得到淡黃色固體之標題化合物（355. 5mg，〇. 9n mmol，產率 91. 7°/。）。 融點198至200。〇 . 2H-NMR (200MHz, DMS0-d6)： δ (ppm)： 12.07(1¾ brs), 10.00(1H, brs), 9·76(1Η, brs), 7.26-7.04 (4H, m), 6.72(1H, s), 4.58(1H, t, J=5.2Hz), W 3-66~3.53(2H, m), 3.39(2¾ s), 2.98-2.78 (4H, m), 2.26(2¾ t, J=6. 7Hz), 2.10(3¾ s) 13C-NMR(50MHz, DMSCH16): δ (ppn〇: 169.6, 169· 1, 168.4, 157· 6，150.6，139· 7，133.4，129.1，128.3，107.5, 57· 5, 37· 3，34.4，33· 4, 33· 1, 32· 4, 22· 7 (製造例14) N-[4-(2-{4-[r -(6-羥基己醯基）肼基羰基甲基]苯基}乙 基）-1，3-嗟哇-2-基]乙醯胺之合成 步驟1Add tetrahydroanion (3ml), water (lml), acetic acid (11111) to 1^(4-xin丨2-[4-(N-丨3-[(triethyldecyl)oxy]propane醯 肼 肼 羰 carbonylcarbonylmethyl) phenyl]ethyl}-1,3-thiazole-2-yl)acetamide (5 〇 1.7 mg, 0·099 mmol) and stirred at room temperature for 1 hour. After concentration under reduced pressure, acetic acid was removed three times with ethyl acetate. The obtained solid was washed with EtOAc (EtOAc m. Melting point 198 to 200. 2H-NMR (200MHz, DMS0-d6): δ (ppm): 12.07 (13⁄4 brs), 10.00 (1H, brs), 9·76 (1Η, brs), 7.26-7.04 (4H, m), 6.72 (1H, s), 4.58(1H, t, J=5.2Hz), W 3-66~3.53(2H, m), 3.39(23⁄4 s), 2.98-2.78 (4H, m), 2.26(23⁄4 t, J=6. 7Hz), 2.10(33⁄4 s) 13C-NMR (50MHz, DMSCH16): δ (ppn〇: 169.6, 169· 1, 168.4, 157·6,150.6,139·7,133.4,129.1,128.3, 107.5, 57· 5, 37· 3, 34.4, 33· 4, 33· 1, 32· 4, 22· 7 (Manufacturing Example 14) N-[4-(2-{4-[r -(6-hydroxyl) Synthesis of hexyl hydrazino) mercaptocarbonylmethyl]phenyl}ethyl)-1,3-indol-2-yl]acetamide

68 319771 200835687 於至，皿在 ε-己内酯（caprolactone)(4. 0ml，37. 9mmol) 之無水甲醇（8ml)溶液中滴入肼•-水合物（2. 2m卜45.0 咖1)。在室溫授拌3小時後，減壓濃縮。以甲醇共沸3 次後，將殘渣溶於甲醇中。冷卻至代後，遽取析出之結 晶。減壓乾燥後，得到白色結晶之6-羥基己醯肼（3. 446g , 23· 57ml，產率 62· 3%)。 步驟268 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 After stirring at room temperature for 3 hours, it was concentrated under reduced pressure. After azeotrope three times with methanol, the residue was dissolved in methanol. After cooling to the next generation, the precipitated crystals are taken. After drying under reduced pressure, 6-hydroxyhexane (3. 446 g, 23.57 ml, yield 62.3%) of white crystals was obtained. Step 2

φ H EfeSiCI Η2ΝΎ^0Η ~~ 在6-經基己醯肼（L462g，1〇· 〇〇mmol)之無水ν，Ν-二 甲基甲醯胺（l〇ml)溶液中加入咪唑（817· 4mg，12.⑽ _〇υ。在〇°c滴入三乙基氯矽烷（2.0ml，12 0_〇1)。升 〆皿至至’皿後’攪拌1· 5小時。力口入水（40ml)、酷酸乙酯（4〇mi) 亚攪拌，靜置後分液。將水層以醋酸乙酯萃取後，將混合 _後之有機層以飽和氯化銨水溶液、飽和食鹽水洗淨。以無 水硫酸鎂乾燥後，減壓濃縮。將濃縮殘渣以矽膠管柱層析 法（Fuji SilysiaBW-300SP，68g，己烷：醋酸乙酯=3 : 7 至2 : 8至1 : 9至0 : 1())精製後，得到無色液體之6—κ三 乙基石夕基）氧基]己醯肼（1.913g，7.345mmol，產率73 4%)。 步驟3 ·φ H EfeSiCI Η2ΝΎ^0Η ~~ Add imidazole (817·) to a solution of 6-pyridyl hydrazine (L462g, 1〇·〇〇mmol) in anhydrous ν, Ν-dimethylformamide (l〇ml). 4mg, 12. (10) _ 〇υ. Add triethyl chlorodecane (2.0ml, 12 0_〇1) at 〇 °c. Stir the dish until after the 'dish' for 1.5 hours. 40ml), ethyl citrate (4〇mi), sub-stirred, after standing, liquid separation. After extracting the aqueous layer with ethyl acetate, the organic layer after mixing is washed with saturated aqueous ammonium chloride solution and saturated brine. After drying over anhydrous magnesium sulfate, it was concentrated under reduced pressure. The residue was concentrated to silica gel column chromatography (Fuji Silysia BW-300SP, 68 g, hexane: ethyl acetate = 3:7 to 2:8 to 1:9 to 0) : 1 ()) After purification, 6-kappatriethylphosphonium oxy]hexanide (1.913 g, 7.345 mmol, yield: 73 4%) was obtained as a colorless liquid. Step 3 ·

319771 69 200835687 在2-(4-{2-[2-(乙醯基胺基）— ι，3-噻唑-4-基]乙基} 苯基）醋酸（305. Omg，1· 〇〇2mmol)之無水N，N-二甲基甲醯 胺（lml)溶液中加入i }，—羰基二咪唑（244· lmg，！· 5〇5 mmol) ’且在50。〇攪拌1小時。冷卻至室溫後，6-三乙基 石夕基氧基-卜己酿肼（781.4mg，3·〇〇〇_〇1)之無水N，N一二 甲基甲酿胺（〇· 5ml)溶液，且在室溫攪拌17小時。加入水 (15ml)並攪拌後，濾取析出之固體，並以水洗淨3次、以 酷酸乙醋洗淨3次。減壓乾燥後，得到白色固體之N-(4 — {2-[ 4-(N -{6-[(三乙基矽基）氧基]己醯基丨肼基羰基曱基） 苯基]乙基}-1，3-噻唑-2-基）乙醯胺（315· Omg，0· 576 mmol，產率 57· 5%)。 & 步驟4319771 69 200835687 in 2-(4-{2-[2-(ethylideneamino)-(1,3-thiazol-4-yl)ethyl}phenyl)acetic acid (305. Omg,1·〇〇2mmol To a solution of anhydrous N,N-dimethylformamide (1 ml) was added i }, carbonyl diimidazole (244·1 mg, !· 5 〇 5 mmol) ' at 50. Stir for 1 hour. After cooling to room temperature, anhydrous N,N-dimethyl ketoamine (〇·5ml) of 6-triethyl sulphate-bromo saponin (781.4mg, 3·〇〇〇_〇1) The solution was stirred at room temperature for 17 hours. After adding water (15 ml) and stirring, the precipitated solid was collected by filtration, washed with water three times, and washed three times with ethyl acetate. After drying under reduced pressure, N-(4-{2-[4-(N-{6-[(triethylsulfonyl)oxy]hexylfluorenylcarbonylcarbonyl)phenyl] was obtained as a white solid. Ethyl}-1,3-thiazol-2-yl)acetamide (315·Omg, 0·576 mmol, yield 57.5%). & Step 4

將四氫呋喃（3ml)、水（imi)、醋酸（lml)加入至n—(4一 {2-[4-(N -{6-[(二乙基矽基）氧基]己醯基丨肼基羰基曱基） 苯基]乙基卜1, 3-噻唑-2-基）乙醯胺（371. 2mg，0· 679 mmol)，且在室溫攪拌30分。減壓濃縮後，以醋酸乙酯共 沸5次去除醋酸。濾取所得之固體後，以醋酸乙酯洗淨3 次。減壓乾煉後，得到白色固體之標題化合物（286. ， 0· 661mmol，產率 97. 4%)。Add tetrahydrofuran (3 ml), water (imi), acetic acid (1 ml) to n-(4-{2-[4-(N-{6-[(diethylfluorenyl)oxy)hexanyl) Phenylcarbonyl fluorenyl)phenyl]ethylidene 1, 3-thiazol-2-yl)acetamide (371. 2 mg, 0·679 mmol), and stirred at room temperature for 30 min. After concentration under reduced pressure, acetic acid was removed by azeotrope 5 times with ethyl acetate. The obtained solid was collected by filtration and washed three times with ethyl acetate. The title compound (286., 0. 661 mmol, yield: 97. 4%).

融點174至178°C 319771 70 200835687 ΐ-ΝΜβΟΟΜΗζ, DMS0-d6): δ(ρρπ〇: 12·07(1Η, brs), 9·96(1Η，brs)，9·71(1Η, brs), 7·28-7·01(4Η, m), 6·72(1Η, s), 4·33(1Η, t, J=5.1Hz>, 3·48-3·32(4Η, m), 2.97-2·78(4Η, m), 2·10(3Η, s), 2.08(2Η, t，J=7.5Hz), 1.60-1.12 細，m) 13C-NMR(50MHz, DMS0-d6)： 6(ppm): 171.2, 169.2, 168.4, 157.6, 150.5, 139.7, 133.5, 129.1, 128.3, 107· 5, 60.8，34· 4, 33· 4，33· 0，32.4，25.3, 25.2, 22.7 (製造例15) 2-[(4-{2-[2-(乙醯基胺基）-1，3-噻唑-4-基]乙基}苯基） 乙醯基]肼羧酸乙酯之合成Melting point 174 to 178 ° C 319771 70 200835687 ΐ-ΝΜβΟΟΜΗζ, DMS0-d6): δ(ρρπ〇: 12·07(1Η, brs), 9·96(1Η,brs),9·71(1Η, brs) , 7·28-7·01(4Η, m), 6·72(1Η, s), 4·33(1Η, t, J=5.1Hz>, 3·48-3·32(4Η, m), 2.97-2·78(4Η, m), 2·10(3Η, s), 2.08(2Η, t, J=7.5Hz), 1.60-1.12 Fine, m) 13C-NMR (50MHz, DMS0-d6): 6 (ppm): 171.2, 169.2, 168.4, 157.6, 150.5, 139.7, 133.5, 129.1, 128.3, 107· 5, 60.8, 34· 4, 33· 4, 33· 0, 32.4, 25.3, 25.2, 22.7 (manufactured Example 15) Synthesis of ethyl 2-[(4-{2-[2-(ethylideneamino)-1,3-thiazol-4-yl]ethyl}phenyl)ethyl) ruthenium carboxylate

在2-(4-{2-[2-(乙酸基胺基）-1，3-嗟唾-4-基]乙基} 苯基）醋酸（304· 4mg，1· OOOmmol )之無水N，N-二曱基甲醯 胺（3ml)溶液中加入1，Γ-羰基二咪唑（243. 2mg，1. 500 _〇 1) ’且在5 Q C擾摔1小時。冷卻/至室溫後，加入骄叛 酸乙酯（312· 3mg，3· OOOmmol)，且在室溫攪拌2. 5小時。 _加入水（10ml)並攪拌後，濾取析出之固體。以醋酸乙酯洗 淨3次後，減壓乾燥，得到淡黃色固體之標題化合物 (261 · 5mg，0· 670mmol，產率 67· 0%)。 融點176至178°C 2H-NMR (200MHz, DMS0-d6)： δ (ppm): 12.08(1H, brs), 9.85(1H, brs), 8.99(1H, L25一7·?6 (4H; ‘ 6·73(1Η,s〉，4·01(2Η, q,风《,3·36 伽， s), 2. 99-2. 76 (4H, m), 2.10 (3H, s), 1.16 (3H, t, J=6. 9Hz) C NMR (50MHz, DMSO—d6) · 5(ppm) ^ 170,0, 168.4, 157 6 15fi 4- 150 5 139.8, 133· 3, 129.1, 128.3, 107· 5, 60.6, 34· 3, 33.3/22U ί4· Γ (製造例16) 2-[(4-{2-[2-(乙醯基胺基）-1，3-噻唑一4-基]乙基}苯基） 71 319771 200835687 乙酿基]肼幾酸丁酯之合成 步驟1Anhydrous N in 2-(4-{2-[2-(acetamidoamino)-1,3-ylidene-4-yl]ethyl}phenyl)acetic acid (304·4 mg, 1·. To a solution of N-dimercaptocaramine (3 ml) was added 1, hydrazine-carbonyldiimidazole (243. 2 mg, 1.500 _〇1)' and was disturbed for 1 hour at 5 QC. 5小时。 After cooling / to room temperature, the addition of ethic acid ethyl ester (312. 3mg, 3, OOOmmol), and stirred at room temperature for 2.5 hours. After adding water (10 ml) and stirring, the precipitated solid was collected by filtration. After washing three times with ethyl acetate, the title compound (261·5··········· Melting point 176 to 178 ° C 2H-NMR (200MHz, DMS0-d6): δ (ppm): 12.08 (1H, brs), 9.85 (1H, brs), 8.99 (1H, L25-7:6 (4H; '6·73(1Η,s〉,4·01(2Η, q, wind“,3·36 gamma, s), 2. 99-2. 76 (4H, m), 2.10 (3H, s), 1.16 (3H, t, J=6. 9Hz) C NMR (50MHz, DMSO-d6) · 5(ppm) ^ 170,0, 168.4, 157 6 15fi 4- 150 5 139.8, 133· 3, 129.1, 128.3, 107 · 5, 60.6, 34· 3, 33.3/22U ί4· Γ (Production Example 16) 2-[(4-{2-[2-(Ethylamino)-1,3-thiazole-4-yl] Ethyl}phenyl) 71 319771 200835687 Synthesis of butyl phthalate

νη2νη2η2ο ο 使肼• 一水合物（1· 5mi，30· 9mmol)懸浮於四氫呋喃 (20ml)中後’在〇。〇滴入氯甲酸丁酯（j. 〇ml，7. 7_〇1)。 升溫至室溫後，攪拌16小時。減壓濃縮後，將水加入至殘 渣，並以醋酸乙酯萃取2次。將混合後之有機層以飽和食 鹽水洗淨後，以無水硫酸鎂乾燥。減壓濃縮，並將殘渣依 矽膠管柱層析法（Fuji Silysia BW-300SP，36g，己烧：醋 酸乙酯=1 : 1至1 : 3)精製後，得到白色固體之肼羧酸丁 酯（869. 5mg，6· 579mmol，產率 85· 5%)。 步驟2Νη2νη2η2ο ο 肼• monohydrate (1·5mi, 30·9mmol) was suspended in tetrahydrofuran (20ml) and then ’. The butyl chloroformate (j. 〇ml, 7.7_〇1) was added dropwise. After warming to room temperature, it was stirred for 16 hours. After concentration under reduced pressure, water was added to residue and extracted twice with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure, and the residue was purified by hexane column chromatography (Fuji Silysia BW-300SP, 36 g, hexanes: ethyl acetate = 1:1 to 1:3) to give butyl carboxylic acid as a white solid. (869. 5 mg, 6. 579 mmol, yield 85.5%). Step 2

ΑοΗΗ-ζ 在2-(4_{2-[2-(乙基胺基）一 ι，3 —嗔σ坐一 4 一基]乙基} 苯基）醋酸（304· 8mg，1· OOlmmol)之無水ν，Ν一二曱基甲醯 胺（11111)溶液中加入1，1’-幾基二咪啤（243.611^，1502 mmo 1)’且在5 0 C擾拌1小時。冷卻至室溫後，加入肼竣 酸丁酯（264· 8mg，2. 004mmol)，且在室溫攪拌24小時。加 入水（20ml)、醋酸乙酯（20ml)並攪拌，靜置後分液。將水 層以酷酸乙i旨萃取後’將混合後之有機層以水洗淨2次、 以飽和食鹽水洗淨1次。以無水硫酸鎂乾燥後，減壓濃縮。 319771 72 200835687 使濃縮殘渣懸浮於醋酸乙酯中後過濾。將所得之固體以醋 /酸乙酯洗淨3次後，減壓乾燥，得到淡黃色固體之標題化 合物（295· 4mg，0· 706mmol，產率 70· 5%)。ΑοΗΗ-ζ in 2-(4_{2-[2-(ethylamino)-I,3 -嗔σ sit a 4-yl]ethyl}phenyl)acetic acid (304·8mg, 1·OOlmmol) To the solution of anhydrous ν, indoleylcarbendazim (11111), 1,1'-diaminodimer (243.611^, 1502 mmo 1) was added and the mixture was stirred at 50 °C for 1 hour. After cooling to room temperature, butyl phthalate (264·8 mg, 2.004 mmol) was added and stirred at room temperature for 24 hours. Water (20 ml) and ethyl acetate (20 ml) were added and stirred, and the mixture was allowed to stand for liquid separation. After the aqueous layer was extracted with a cool acid, the organic layer after mixing was washed twice with water and once with saturated brine. After drying over anhydrous magnesium sulfate, it was concentrated. 319771 72 200835687 The concentrated residue was suspended in ethyl acetate and filtered. The obtained solid was washed with EtOAc / EtOAc EtOAc (EtOAc)EtOAc.

融點120至122°C 'H-NMR (200MHz, CDC13) ： δ (ppm)： 10.27(1¾ brs), 8.66 (1¾ brs), 7.86(1¾ brs), 7.18-6.95(4H, m), 6.5〇(lH, s), 4.13(1H, t, J=6.6Hz), 3.57(2¾ s), 2. 91-2. 83 (4H, m), 2.25(3H, s), 1.68-1. 5〇(2H, m), 1.44-1.23(2¾ m), ’ 0.90(3H, t, J=7.2Hz) 13C-NMR(50MHz, CDC13): δ (ppm〉： 171·7, 168.6, 158·8, 157.7，150·0, 14〇·3， 131·5, 129.0，128·8，107.7, 66·1, 40·9, 34.8, 33.0，22·8, 18·9, 13.6 ’ (製造例17) 馨2-[(4-{2-[2-(乙醯基胺基）-1，3-噻唑-4-基]乙基}苯基） 乙醯基]肼羧酸癸酯之合成 步驟1Melting point 120 to 122 ° C 'H-NMR (200 MHz, CDC13) : δ (ppm): 10.27 (13⁄4 brs), 8.66 (13⁄4 brs), 7.86 (13⁄4 brs), 7.18-6.95 (4H, m), 6.5 〇(lH, s), 4.13(1H, t, J=6.6Hz), 3.57(23⁄4 s), 2. 91-2. 83 (4H, m), 2.25(3H, s), 1.68-1. 5 〇(2H, m), 1.44-1.23(23⁄4 m), '0.90(3H, t, J=7.2Hz) 13C-NMR(50MHz, CDC13): δ (ppm>: 171·7, 168.6, 158·8 , 157.7, 150·0, 14〇·3, 131·5, 129.0, 128·8, 107.7, 66·1, 40·9, 34.8, 33.0, 22·8, 18·9, 13.6 ' (Manufacturing example 17 Synthesis step of 2-(4-{2-[2-(ethylideneamino)-1,3-thiazol-4-yl]ethyl}phenyl)ethinyl]indenyl carboxylate 1

CI Η2Ν^γ〇(〇Η2)9〇Η3 丫 〇(CH2)0CH3 nh2nh2 h2o -^CI Η2Ν^γ〇(〇Η2)9〇Η3 丫 〇(CH2)0CH3 nh2nh2 h2o -^

THF 使肼•一水合物（1· 27ml，26· 1 mmol)懸浮於無水四氫 呋喃（20ml)中後，在0°C滴入氯曱酸癸酯（1. 50ml，6. 52 _ mmol)。升溫至室溫後，攪拌16小時。減壓濃縮後，加入 水（20ml )，並以醋酸乙酯萃取2次。將混合後之有機層以 飽和食鹽水洗淨後，以無水硫酸鎂乾燥。減壓濃縮，並將 殘渣依矽膠管柱層析法（Fuji SilysiaBW-300SP，3〇g，己 烧·酷酸乙酯=2 : 1至1 : 2)精製後，得到白色固體之肼 緩酸癸輯（1· 222g，5· 649_〇1，產率 86. 7%)。 步驟2 73 319771 200835687After THF was dissolved in anhydrous tetrahydrofuran (20 ml), EtOAc (1.50 ml, 6.52 _ mmol) was added dropwise at 0 °C. After warming to room temperature, it was stirred for 16 hours. After concentration under reduced pressure, water (20 ml) was evaporated and evaporated. The organic layer after washing was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by column chromatography (Fuji Silysia BW-300SP, 3 〇g, hexane, ethyl acetate = 2:1 to 1: 2) to give a white solid.癸(1· 222g, 5·649_〇1, yield 86.7%). Step 2 73 319771 200835687

CDI, DMF n-C10H2i〇CONHNH2CDI, DMF n-C10H2i〇CONHNH2

,0(CH2)9CH3 在2-(4-{2-[2-(乙醯基胺基）-1，3-噻唑-4-基]乙基} 苯基）錯酸（304. 4mg，1 · OOOmmol)之無水N，N-二曱基甲酿 胺（lml)溶液中加入1，Γ-羰基二咪唑（243. 6mg，1. 500 mmol)，且在50°C攪拌1小時。冷卻至室溫後，加入肼羧 酸癸S曰（64 9 · 0mg ’ 3 · 0 0 0πΗπο 1) ’且在室溫擾摔2 2小時。加 _入水（5〇ml)、飽和食鹽水（50ml)、醋酸乙酯（50ml)並攪拌， 靜置後分液。將有機層以飽和食鹽水洗淨後，以無水硫酸 鎂乾燥。減壓濃縮，並將殘渣以矽膠管柱層析法精製2次 (Fuji Silysia BW-300SP，30g 及 20g，己烷：醋酸乙酯= 3 : 7)後，得到白色固體之標題化合物（391. Img，0. 778 mmol，產率 77. 8%)。， - 融點128至130t： A 'H-NMR (200MHz, CDC13) ： δ (ppm)： 10. 72(1H, brs), 9.23(1H, brs), 8.36(1H, w brs), 7.17-6.89 (4H, m), 6.47(1H, s), 4.10(2H, t, J=6.7Hz), 3.54(2H, s), 2.93-2.77 (4H, m), 2,22(3H, s), 1.78-1.50(4«, m), L 39-L 17(12¾ m)9 0.87(3H, t, J=6.4Hz) 13C-NMR(50MHz, CDC13)： 5(ppm) ： 171.7, 168.5, 158.8, 157.7, 150.0, 140.3, 131· 5, 129· 0, 128· 8，107. 7, 66· 5, 40· 9，34. 9，33. 0, 31· 9, 29· 5, 29· 3， 29.2, 28.7, 25.7, 22.9, 22.6, 14.1 (製造例18) 2-[(4-{2-[2-(乙醯基胺基）-1，3-噻唑-4-基]乙基}苯基） 乙醯基]肼羧酸2-羥基乙酯之合成 步驟1 74 319771 200835687, 0(CH2)9CH3 in 2-(4-{2-[2-(ethylideneamino)-1,3-thiazol-4-yl]ethyl}phenyl) tyrosine (304. 4mg, 1 To a solution of anhydrous, N,N-dimercaptoamine (1 ml), hydrazine-carbonyldiimidazole (243. 6 mg, 1.500 mmol) was added and stirred at 50 ° C for 1 hour. After cooling to room temperature, hydrazine hydrazide S 曰 (64 9 · 0 mg ' 3 · 0 0 0 π Η π ο 1) was added and spattered for 22 hours at room temperature. _Into water (5 〇ml), saturated saline (50 ml), and ethyl acetate (50 ml) were added and stirred, and the mixture was allowed to stand for separation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, and the residue was purified by EtOAc EtOAc (EtOAc) Img, 0. 778 mmol, yield 77.8%). , - Melting point 128 to 130t: A 'H-NMR (200MHz, CDC13) : δ (ppm): 10. 72(1H, brs), 9.23(1H, brs), 8.36(1H, w brs), 7.17- 6.89 (4H, m), 6.47(1H, s), 4.10(2H, t, J=6.7Hz), 3.54(2H, s), 2.93-2.77 (4H, m), 2,22(3H, s) , 1.78-1.50(4«, m), L 39-L 17(123⁄4 m)9 0.87(3H, t, J=6.4Hz) 13C-NMR(50MHz, CDC13): 5(ppm) : 171.7, 168.5, 158.8, 157.7, 150.0, 140.3, 131· 5, 129· 0, 128· 8,107. 7, 66· 5, 40· 9,34. 9,33. 0, 31· 9, 29· 5, 29· 3, 29.2, 28.7, 25.7, 22.9, 22.6, 14.1 (Production Example 18) 2-[(4-{2-[2-(Ethylamino)-1,3-thiazol-4-yl]ethyl }Phenyl) Ethyl mercapto] carboxylic acid 2-hydroxyethyl ester synthesis step 1 74 319771 200835687

AA

MeOH nh2nh2 h2o -MeOH nh2nh2 h2o -

nh2 在碳酸伸乙酯（2· 600g，29. 53mmol)之無水曱醇（5ml) 溶液中滴入肼•一水合物（1· 7ml，35· 〇mm〇1)。在室溫攪拌 2小時後，減壓濃縮。加熱溶解於2-丙醇（3〇ml)中後冷卻， 並濾取析出之結晶。將結晶以2-丙醇洗淨3次、以醋酸乙 醋洗淨2次。減壓乾燥後，得到白色結晶之肼羧酸2—羥基 乙酉日（1· 745g，14· 53mmol，產率 49· 2%)。 _步驟2 HOs nh5Nh2 Into a solution of ethyl acetate (2·600 g, 29.53 mmol) in anhydrous decyl alcohol (5 ml) was added dropwise hydrazine monohydrate (1.7 ml, 35·〇mm〇1). After stirring at room temperature for 2 hours, it was concentrated under reduced pressure. The mixture was dissolved in 2-propanol (3 〇 ml) by heating, cooled, and the precipitated crystals were collected by filtration. The crystals were washed three times with 2-propanol and twice with acetic acid. After drying under reduced pressure, a white crystalline bismuth carboxylic acid 2-hydroxyethyl hydrazide (1· 745 g, 14.53 mmol, yield: 49. 2%) was obtained. _Step 2 HOs nh5

EtaSiC!EtaSiC!

DMFDMF

Et3SiOs^| 在肼羧酸2-羥基乙酯（360.9mg , 3 005mm〇1)之無水 N，N-一甲基甲醯胺（lml)溶液中加入咪唑（245. ，3. mm〇U。在0。〇滴入三乙基氯矽烷（〇. 6〇mi，& 6〇丽〇1)後 擾=30分。升溫至室溫後，擾拌2. 5小時。加入水、醋圈 乙醋並授拌，靜置後分液。將水層以醋酸乙S旨萃取後，廣 ^合後=有機層以飽和氯化銨水溶液洗淨2次、以飽和養 孤水洗淨1次。以無水硫酸鎂乾燥後，減壓濃縮。將濃紹 殘渣以梦膠管柱層析法精製2次（第H:Fuji Sllysia BW-300SP’ 20g，二氯甲垸：甲醇=2〇 : i ;第 2 次 士]] Silysia NH-DM1G2G，18g，二氯曱烧：甲醇=4() : })後， 得到淡黃色液體之肼叛酸2-[(三乙基梦基）氧基]乙酉旨 (531· 9mg，2. 269mmol，產率 75. 6%)。 319771 75 200835687 步驟3Et3SiOs^| Add imidazole (245., 3. mm〇U) to a solution of 2-hydroxyethyl hydrazinecarboxylate (360.9 mg, 3 005 mm 〇1) in anhydrous N,N-monomethylformamide (1 ml). 5小时。 After dripping into the triethyl chlorodecane (〇. 6〇mi, & 6 〇 〇 ) 1) after the disturbance = 30 minutes. After warming to room temperature, disturbed 2. 5 hours. Add water, vinegar circle Ethyl vinegar and mixing, after standing, liquid separation. After extracting the water layer with ethyl acetate, after widening, the organic layer is washed twice with saturated aqueous ammonium chloride solution and once with saturated sow water. After drying over anhydrous magnesium sulfate, the residue was concentrated under reduced pressure. The residue was purified twice by EtOAc EtOAc (H. 2nd sect]] Silysia NH-DM1G2G, 18g, dichlorohydrazine: methanol = 4 () : }), after obtaining a pale yellow liquid, 肼 酸 2- 2-[(Triethylmethyl) oxy] oxime Purpose (531·9mg, 2. 269mmol, yield 75.6%). 319771 75 200835687 Step 3

在2-(4-{2-[2-（乙醯基胺基）一；[，3-噻哇—4一基]乙基} 苯基）酷酸（608· 7mg，2· OOOmmol)之無水N，N-二甲基甲醯 ⑩胺（2ml)溶液中加入1，1，—羰基二咪唑（486. 5mg，3· mmo 1)’且在5 0 C攪拌1小時。冷卻至室溫後，加入肼幾 酉欠2 [(一乙基砍基）氧基]乙酯（i.466g，6. OOOmmol)，且 在室溫攪拌28小時。加入水（2〇mi)、醋酸乙酯（4〇mi)、飽 和艮鹽水（20m 1)並授拌’靜置後分液。將水層以醋酸乙酯 萃取後，將混合後之有機層以飽和食鹽水洗淨。以無水硫 酸鎂乾燥後，減壓濃縮。將殘渣依矽膠管柱層析法 _ Silysia BW - 300SP，l〇〇g，己烷：醋酸乙酯=3: 7 至 2: 8)精製後，得到2-[(4-{2-[2-(乙醯基胺基）4, 3 —噻唑一4一 基]乙基}苯基）乙醯基]肼羧酸2-[(三乙基矽基）氧基]乙 酯（809. 5mg，1· 555mmo卜產率 77· 7%)。 步驟4In the form of 2-(4-{2-[2-(ethionylamino)-;[,3-thiazol-4-yl]ethyl}phenyl)hydrous acid (608·7 mg, 2······· To a solution of anhydrous N,N-dimethylformamidine 10 amine (2 ml) was added 1,1,-carbonyldiimidazole (486. 5 mg, 3·mmo 1)' and stirred at 50 C for 1 hour. After cooling to room temperature, hydrazine 2 [(ethylcyano)oxy]ethyl ester (i.466 g, 6. OMmmol) was added and stirred at room temperature for 28 hours. Water (2 〇 mi), ethyl acetate (4 〇 mi), saturated hydrazine brine (20 ml) were added and the mixture was allowed to stand for separation. After the aqueous layer was extracted with ethyl acetate, the combined organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, it was concentrated under reduced pressure. The residue was purified by column chromatography _Silysia BW-300SP, l〇〇g, hexane:ethyl acetate=3:7 to 2:8) to give 2-[(4-{2-[2 -(Ethylamino) 4,3-thiazole-4-yl]ethyl}phenyl)ethinyl]hydrazinecarboxylic acid 2-[(triethylsulfonyl)oxy]ethyl ester (809. 5mg , 1· 555mmo yield 77.7%). Step 4

319771 76 200835687 四氫呋喃（4ml)、水（4ml)、醋酸（12ml)加入至2-[(4- {2 - [2-（乙醯基胺基）-1，3-噻唑-4-基]乙基}苯基）乙醯基] 肼羧酸2-[(三乙基矽基）氧基]乙酯（765· 5mg，L 47〇 丽〇1)’且在室溫攪拌15分。減壓濃縮後，以醋酸乙酯共 彿5次去除醋酸。將濃縮殘渣以水洗淨3次、以醋酸乙酯 洗淨3次。減壓乾燥後，得到白色固體之標題化合物（453. ^ mg，1· 115 mmol，產率 75. 8%)。319771 76 200835687 Tetrahydrofuran (4ml), water (4ml), acetic acid (12ml) was added to 2-[(4- {2 - [2-(ethylamino)-1,3-thiazol-4-yl] 2-phenyl(ethenyl) hydrazine carboxylic acid 2-[(triethylhydrazino)oxy]ethyl ester (765·5 mg, L 47 〇 〇 1)' and stirred at room temperature for 15 minutes. After concentration under reduced pressure, acetic acid was removed 5 times with ethyl acetate. The concentrated residue was washed three times with water and three times with ethyl acetate. The title compound (453.^ mg, 1.115 mmol, yield: 75.

融點176至179°C 'H-NMR (200MHz, DMS0-d6) ： δ (ppm): 12.07(1Η, brs), 9.85(1Η, brs), 9.05(1Η, brs), 7.24-7.03 (4Η, m), 6.73(1H, s), 4.76 (1H, br), 3.98(2¾ t, ’ 3-60'3*47(4H^ 3-37(2H, s), 2.98-2.79 (4H, m), 2.10(3¾ s) "C-NMR(50MHz, DMS0-d6)： 5(ppm)： 170.0, 168.4, 157.6, 156.5, 150.5, 139· 7，133· 2，129· 1，128· 3，107. 5’ 66· 5, 59· 4, 34.4，33· 0, 22· 6 (製造例19) 2-乙醯基胺基-1，3-噻唑-4-羧酸4-(肼基羰基曱基）苯酯 鹽酸鹽之合成 - 步驟1Melting point 176 to 179 ° C 'H-NMR (200 MHz, DMS0-d6) : δ (ppm): 12.07 (1Η, brs), 9.85 (1Η, brs), 9.05 (1Η, brs), 7.24-7.03 (4Η , m), 6.73(1H, s), 4.76 (1H, br), 3.98(23⁄4 t, ' 3-60'3*47(4H^ 3-37(2H, s), 2.98-2.79 (4H, m ), 2.10(33⁄4 s) "C-NMR(50MHz, DMS0-d6): 5(ppm): 170.0, 168.4, 157.6, 156.5, 150.5, 139· 7,133· 2,129· 1,128· 3 ,107. 5' 66· 5, 59· 4, 34.4, 33· 0, 22· 6 (Manufacturing Example 19) 2-Ethylamino-1,3-thiazole-4-carboxylic acid 4-(fluorenyl) Synthesis of carbonyl fluorenyl) phenyl ester hydrochloride - Step 1

於-78°C在1M肼/四氫呋喃溶液（8〇.〇ml，80.0mmol) 中加入（4-羥基）苯基醋酸甲酯（3· 323g，20· OOmmol)之四氫 呋喃（20ml)溶液。緩緩升溫至室溫，且在室溫攪拌i7小 時。濾取析出之結晶，並以異丙醚洗淨3次。減壓乾燥後， 得到白色固體之2-(4-羥基苯基）乙醯基肼（2. 187g，13. 16 mmol，產率 65. 8%)。 77 319771 200835687 *步驟2A solution of methyl (4-hydroxy)phenylacetate (3·323 g, 20.0 mmol) in tetrahydrofuran (20 ml) was added to a solution of EtOAc (EtOAc). Slowly warm to room temperature and stir for i7 hours at room temperature. The precipitated crystals were collected by filtration and washed three times with isopropyl ether. After drying under reduced pressure, 2-(4-hydroxyphenyl)ethylhydrazinium (2. 187 g, 13.16 mmol, yield: 65.8%). 77 319771 200835687 *Step 2

(B〇C>2〇 i2ithf(B〇C>2〇 i2ithf

於0°C在2-(4-羥基苯基）乙醯基肼（2. 15〇g，12. 94 mmol)、二碳酸二（三級丁酯）（3」〇6g，14·23ππη〇1)、四氫 呋喃（5ml)之混合物中加入蛾（164· 〇mg，1· 298mmol)。升溫 至室溫後，攪拌3小時。在反應液中加入四氫σ夫喃（3〇mi)， ⑩再攪拌8· 5小時。將反應液通過矽膠墊（pad)(Fuji SUysia BW-300SP，100g)過濾後，以醋酸乙酯/己烷（2 :丨）混合溶 劑洗淨。將濾液濃縮變乾硬後，加入醋酸乙酯（5〇m 1)。濾 取生成之固體，並以醋酸乙酯洗淨1次、以異丙醚洗淨5 次。減壓乾燥後，得到白色固體之2—[ (4—羥基苯基）乙醯 基]‘肼緩酸二級丁 S旨（2_ 301g，8.639mmo 1，產率 66· 8%)。 從母液濃縮物回收二次結晶（529.7mg，1.989mmol，產率 φ I5· 4%)。（初級結晶、二次結晶合計產率82. 2%) 步驟32-(4-hydroxyphenyl)ethylhydrazine ruthenium (2.15 〇g, 12.94 mmol), di(tertiary butyl dicarbonate) (3 〇6 g, 14·23ππη〇) at 0 °C 1) A mixture of tetrahydrofuran (5 ml) was added with moth (164·mg, 1.298 mmol). After warming to room temperature, it was stirred for 3 hours. Tetrahydro-p-amyl (3 〇mi) was added to the reaction solution, and 10 was further stirred for 8.5 hours. The reaction solution was filtered through a pad (Fuji SUysia BW-300SP, 100 g), and then washed with a solvent mixture of ethyl acetate/hexane (2:?). After the filtrate was concentrated to dryness, ethyl acetate (5 〇m 1) was added. The resulting solid was filtered, washed once with ethyl acetate and 5 times with isopropyl ether. After drying under reduced pressure, 2-[(4-hydroxyphenyl)ethylidene]-supplemented acid secondary succinate (2_ 301 g, 8.639 mm, 1, yield 66.8%) was obtained as a white solid. Secondary crystals (529.7 mg, 1.989 mmol, yield φ I5·4%) were recovered from the mother liquor concentrate. (primary crystallization, secondary crystallization total yield 82.2%) Step 3

在2-（乙酸基胺基）-1，3-嗟嗤-4-曱酸（750. 0mg， 4· 028mmol)之無水N，N-二甲基甲醯胺（9ml)溶液中加入 1，1’ -羰基二咪唾（751· 4mg，4· 634mmol)，且在 50°C 攪拌1 78 319771 200835687 小時。冷卻至室溫後，加入2_[(4—羥基苯基）乙醯基]肼羧 酸二級丁酯（1. 394g，5· 234mm〇l)、N，N-二甲基-4-胺基吡 口疋（24· 6 mg，0· 20mmol)。在5〇°C攪拌8小時後，冷卻至 室溫，並注入經冰冷之飽和碳酸氫鈉水溶液（25〇ml)中。以 醋酸乙酯卒取3次後，將混合後之有機層以飽和碳酸氫鈉 水溶液、飽和氯化銨水溶液、飽和食鹽水洗淨。通過矽膠 墊（Fuji Silysia BW-300SP，50g)過濾後，以醋酸乙酯洗 淨。將濾液減壓濃縮後，將殘渣溶於醋酸乙酯（25ml)中。 在室溫滴入異丙醚（l〇〇ml)後，攪拌1小時。濾取析出物， 並以異丙醚洗淨3次。減壓乾燥後，得到白色固體之2-（乙 醯基胺基）-1，3-噻唑-4-羧酸4-{2-[2-(三級丁氧基羰基） 肼基]羰基曱基}苯酯（l、539g，3.542mmol，產率87.9%)。 步驟4Add 1 to a solution of 2-(acetamido)-1,3-indole-4-decanoic acid (750. 0 mg, 4·028 mmol) in anhydrous N,N-dimethylformamide (9 ml). 1'-Carbo-dimethine (751·4 mg, 4·634 mmol), and stirred at 50 ° C for 1 78 319771 200835687 hours. After cooling to room temperature, 2 -[(4-hydroxyphenyl)ethinyl]hydrazinecarboxylic acid secondary butyl ester (1.394g, 5 · 234mm〇l), N,N-dimethyl-4-amine was added. Kisperidin (24·6 mg, 0·20 mmol). After stirring at 5 ° C for 8 hours, it was cooled to room temperature and poured into ice-cooled saturated aqueous sodium hydrogen carbonate (25 mL). After the mixture was taken up three times with ethyl acetate, the mixed organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, a saturated aqueous solution of ammonium chloride and brine. After filtration through a silicone pad (Fuji Silysia BW-300SP, 50 g), it was washed with ethyl acetate. After the filtrate was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (25 ml). After dropping isopropyl ether (10 ml) at room temperature, it was stirred for 1 hour. The precipitate was collected by filtration and washed three times with isopropyl ether. After drying under reduced pressure, 4-(2-[2-(tert-butoxycarbonyl)indenyl]carbonyl ruthenium 2-(ethoxymethylamino)-1,3-thiazole-4-carboxylic acid was obtained as a white solid. Phenyl ester (1, 539 g, 3.542 mmol, yield 87.9%). Step 4

將2-(乙醯基胺基）-1，3-噻唑-4-羧酸4-{2-[2-(三級 丁氧基幾基）肼基]羰基曱基}苯醋（565. Omg，1. 300mmol) 懸浮於二噚烷（5· 7ml)中後，加入4M氯化氫二噚烷溶液 (22· 6ml，90· 4mmol)。在室溫攪拌2小時後，加入二氯曱 烷（45ml)並攪拌30分。濾取析出物後，以二氯甲烷洗淨3 次。減壓乾燥後，得到白色固體之標題化合物（477. 6mg， 1 · 288 ππη〇 1 ’ 產率 99.1%)。2-{2-[Ethylamino)-1,3-thiazole-4-carboxylic acid 4-{2-[2-(tertiarybutoxy)phenyl]carbonylcarbonyl}benzene vinegar (565. Omg, 1. 300 mmol) was suspended in dioxane (5.7 ml), and then a solution of 4M hydrogen chloride in dioxane (22.6 ml, 9.0 mmol) was added. After stirring at room temperature for 2 hours, dichloromethane (45 ml) was added and stirred for 30 minutes. The precipitate was collected by filtration and washed three times with dichloromethane. The title compound (477. 6 mg, 1 · 288 ππη 〇 1 ' yield 99.1%) was obtained as white solid.

融點205至209°C 79 319771 200835687 ^-NMR (200MHz, DMSO~d6) ： δ (ppm)： 12.58(1¾ brs), 11.44(1H, brs), 11.00-9.90(2H, br), 8.29(1H, s), 7.38(2H, d, J=8.4Hz), 7.21(2¾ d, J=8.4^iz), • 3.63(2H, s), 2·16(3Η, s) 13C-NMR(50MHz, DMS0~d6) ： 6(ppm) ： 169.7, 169.4, 159. 7, 158· 6, 149.5, 139.9, 132.7, 130.5, 124.8, 121. 9, 22.7 (製造例20) N-(4-{[4-（肼基幾基曱基）苯氧基]曱基}-1，3-°塞嗤-2-基） 乙醯胺之合成Melting point 205 to 209 ° C 79 319771 200835687 ^-NMR (200MHz, DMSO~d6) : δ (ppm): 12.58 (13⁄4 brs), 11.44 (1H, brs), 11.00-9.90 (2H, br), 8.29 ( 1H, s), 7.38 (2H, d, J=8.4Hz), 7.21(23⁄4 d, J=8.4^iz), • 3.63(2H, s), 2·16(3Η, s) 13C-NMR (50MHz , DMS0~d6) : 6(ppm) : 169.7, 169.4, 159. 7, 158· 6, 149.5, 139.9, 132.7, 130.5, 124.8, 121. 9, 22.7 (manufacturing example 20) N-(4-{[ 4-(indolyl yl) phenoxy] fluorenyl}-1,3-° thiophene-2-yl) Synthesis of acetamidine

步驟1step 1

MeCN tPr2NEt, K1 -MeCN tPr2NEt, K1 -

在N-(4-氯曱基-1，3-噻唑-2-基）乙醯胺（4. OOOg， 20· 98mmol)、（4-經基苯基）酷酸曱酯（6· 972g，41. 96mniol) 之無水乙腈（80ml)溶液中加入N，N-二異丙基乙基胺 (8· 135g，62. 94mmol)、埃化鉀（696· 5mg，4· 196mmol)。在 70°C攪拌36小時後，冷卻-至室温。減壓濃縮後，將IN鹽 酸（100ml)加入至殘渣，並以醋酸乙酯萃取3次。將混合後 _之有機層以1N鹽酸、飽和碳酸鈉水溶液、飽和食鹽水洗 淨。以無水硫酸鎂乾燥後，減壓濃縮。將殘渣以矽膠管柱 層析法（Fuji Silysia BW-300SP，200g，醋酸乙酯：己烷 =2 : 3至3 : 2)精製後，得到白色固體（1. 631 g)。將*** (100ml)加入至此固體使其懸浮後，加入己烷（5〇ml)。濾取 生成之固體後，以20%***/己烷混合溶劑洗淨。減壓乾 燥後，得到白色固體之{4-[(2-乙醯基胺基-1，3-噻唑-4- 基）曱氧基]苯基}醋酸甲酯d. 385g，4· 327mmol，產率 20.6%)。 80 319771 200835687 "步驟2N-(4-chloroindolyl-1,3-thiazol-2-yl)acetamide (4. OOOg, 20·98 mmol), (4-phenylphenyl) decanoate (6·972 g, 41. 96mniol) Anhydrous acetonitrile (80 ml) was added N,N-diisopropylethylamine (8·135 g, 62.94 mmol), potassium hydride (696·5 mg, 4.196 mmol). After stirring at 70 ° C for 36 hours, it was cooled to room temperature. After concentration under reduced pressure, IN hydrochloric acid (100 ml) was added to the residue, and the mixture was extracted three times with ethyl acetate. The organic layer after mixing was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium carbonate and brine. After drying over anhydrous magnesium sulfate, it was concentrated. The residue was purified by silica gel column chromatography (yield: EtOAc, EtOAc (EtOAc: EtOAc) After adding diethyl ether (100 ml) to this solid to suspend it, hexane (5 〇ml) was added. The resulting solid was collected by filtration and washed with a mixture of 20% diethyl ether/hexane. After drying under reduced pressure, m-[4-[(2-ethylamino)-1,3-thiazol-4-yl) decyloxy]phenyl}acetate methyl ester d. 385 g, 4· 327 mmol, The yield was 20.6%). 80 319771 200835687 "Step 2

在〇°C在{4-[(2-乙醯基胺基-1，3-噻唑-4-基）甲氧基] 本基}醋酸曱酯（800. 〇mg，2· 500mm〇l)之二口琴烧（8ml)溶液 中滴入1N氫氧化鈉水溶液（6· 25ml，6· 25丽〇1)。升溫至室 溫後，攪拌30分。將反應液減壓濃縮後，加入水（2〇ml)。 在0 C滴入1N鹽酸（9. Om 1，9· Ommo 1)[鹽酸滴入中，追加 投入水（30ml)]。在攪拌30分後，濾取析出物，並以 冰水洗淨。充分去除母液後，以己烷洗淨。減壓乾燥後， 得到白色固體之{4-[(2-乙醯基胺基-1，3-噻唑-4-基）甲氧 基]苯基}醋酸（728· 3mg，2· 377mmol，產率 95· 1%)。 步驟3 ， /In the 〇 ° C in {4-[(2-acetamidoamino-1,3-thiazol-4-yl)methoxy] benzyl} decyl acetate (800. 〇mg, 2 · 500mm〇l) A 2N aqueous solution of sodium hydroxide (6·25 ml, 6.2 〇1) was added dropwise to the solution of the two harmonica (8 ml). After warming to room temperature, stir for 30 minutes. After the reaction mixture was concentrated under reduced pressure, water (2 mL) was added. 1N hydrochloric acid (9. Om 1,9· Ommo 1) was added dropwise at 0 C [in the dropwise addition of hydrochloric acid, additional water (30 ml) was added]. After stirring for 30 minutes, the precipitate was collected by filtration and washed with ice water. After the mother liquor was sufficiently removed, it was washed with hexane. After drying under reduced pressure, <RTI ID=0.0>#</RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Rate 95·1%). Step 3, /

{4-[(2-乙醯基胺基-1，3-噻唑-4-基）甲氧基]苯基}醋 酸（720· Omg，2· 350mmol)之無水 N，N-二曱基曱酸胺（5. 5ml) 溶液中加入1，Γ -羰基二咪唑（571. 6mg，3. 525mmol)，且 在5 0 C授拌1小時。冷卻至-2 5 °C後，加入肼•一水合物 (〇·57πι1 ’ 11· 8ππηο 1) ’並缓缓升溫至室溫後，擾拌3〇分。 冷卻至0°C後，加入水（90ml)。在0°C攪拌20分後，濾取 析出物，並以水诜淨4次、以醋酸乙酯洗淨2次。減壓乾 319771 81 200835687 _ 餘後’得到微帶黃色固體之標題化合物（662. 5mg，2. 068 mmol，產率 88. 〇%)。 [再結晶] 將N，N-二曱基曱醯胺（4 〇mi)加入至微帶黃色固體 (640· Omg，1. 998mmol)後，以約60°C加熱溶解。冷卻至室 溫後，滴入醋酸乙酯（160ml)。在室溫攪拌1小時後，濾取 析出之結晶’並以酷酸乙酯洗淨3次。減壓乾燥後，得到 白色固體之標題化合物（549· 7mg，1· 716mmol，回收率 • 85. 9%) 〇{4-[(2-Ethylamino-1,3-thiazol-4-yl)methoxy]phenyl}acetic acid (720·Omg, 2·350 mmol) of anhydrous N,N-diindenylhydrazine To the solution of the acid amine (5.5 ml) was added 1, hydrazine-carbonyldiimidazole (57. 6 mg, 3.525 mmol), and the mixture was stirred at 50 C for 1 hour. After cooling to -2 5 °C, hydrazine monohydrate (〇·57πι1 '11·8ππηο 1)' was added and the temperature was gradually raised to room temperature, and then scrambled for 3 minutes. After cooling to 0 ° C, water (90 ml) was added. After stirring at 0 ° C for 20 minutes, the precipitate was collected by filtration, washed twice with water and twice with ethyl acetate. The title compound (662. 5 mg, 2.068 mmol, yield: 88.%) was obtained. [Recrystallization] N,N-dimercaptoguanamine (4 〇mi) was added to a microstrip yellow solid (640·Omg, 1.998 mmol), and dissolved by heating at about 60 °C. After cooling to room temperature, ethyl acetate (160 ml) was added dropwise. After stirring at room temperature for 1 hour, the precipitated crystals were collected by filtration and washed three times with ethyl succinate. The title compound (549·7 mg, 1·716 mmol, recovery: 85.9%)

融點216至219°C 'H-NMR (200MHz, DMS〇-d6) ： δ(ρρπι) ： 12.15(1H, brs), 9·15(1Η, brs), 7,16(1¾ s), 7.14 (2H, d, J=8.6Hz), 6. 91 (2H, d, J=8. 6Hz), 5. 00 (2H, s), 4. 25 (2H, brs), 3.25(2H, s), 2.11 (3H, s) 13C-NMR (50MHz, DMSO-d6): δ (ppm) : 170.0, 168.6, 158.3, 157.0, 146.6, 130· 1, 128. 6, 114 6, 111· 5, 65· 6, 22· 6 ’ (製造例21) - - 2-（乙酿基胺基）-N-[4_(肼基獄基曱基）苯基]-1，3-嗟嗤 籲-4-曱醯胺鹽酸鹽之合成 步驟1 /Melting point 216 to 219 °C 'H-NMR (200MHz, DMS〇-d6) : δ(ρρπι) : 12.15(1H, brs), 9·15(1Η, brs), 7,16(13⁄4 s), 7.14 (2H, d, J=8.6Hz), 6. 91 (2H, d, J=8. 6Hz), 5. 00 (2H, s), 4. 25 (2H, brs), 3.25(2H, s) , 2.11 (3H, s) 13C-NMR (50MHz, DMSO-d6): δ (ppm) : 170.0, 168.6, 158.3, 157.0, 146.6, 130· 1, 128. 6, 114 6, 111· 5, 65· 6, 22· 6 ' (Manufacturing Example 21) - - 2-(Ethylamino)-N-[4_(肼基狱基曱)phenyl]-1,3-嗟嗤--4-曱Synthesis step of indoleamine hydrochloride 1 /

在2-(乙醯基胺基）-1，3-噻唑-4-羧酸（183. 2mg， 1 · OOOmmol)之無水N，N-二曱基曱酸胺（3. 0ml)溶液中加入 1，Γ -羰基二咪唑（243. 2mg，1· 500mmol)，且在 45°C 攪拌 1. 5小時。冷卻至室温後，加入2 - [(4 -胺基苯基）乙酿基] 82 319771 200835687 胼竣二級丁酯（530. 6mg，2· OOOmmol )並授拌1小時。在 451攪拌2· 5小時後，冷卻至室溫。加入水（2〇mi)後，濾 取生成之固體，並以醋酸乙酯洗淨2次。減壓乾燥後，得 到被褐色固體之2 -{[4-（{[2-(乙驢基胺基）一1，3-嗟嗤-4-基]羰基丨胺基）苯基]乙醯基}肼羧酸三級丁酯（291 5mg， 〇· 672mmol，產率 67. 2%)。 步驟2Add to a solution of 2-(ethoxymethylamino)-1,3-thiazole-4-carboxylic acid (183. 2 mg, 1 · 00 mmol) in anhydrous N,N-didecyl decanoate (3.0 ml) 5小时。 1. Γ - carbonyl diimidazole (243. 2mg, 1. 500mmol), and stirred at 45 ° C for 1. 5 hours. After cooling to room temperature, 2-[(4-aminophenyl)ethyl] 82 319771 200835687 胼竣 butyl butyl ester (530. 6 mg, 2.0 mmol) was added and stirred for 1 hour. After stirring at 451 for 2.5 hours, it was cooled to room temperature. After adding water (2 〇mi), the resulting solid was filtered and washed twice with ethyl acetate. After drying under reduced pressure, 2-{[4-({[2-(ethyl)amino)-1,3-indol-4-yl]carbonylindenyl)phenyl]acetamidine was obtained as a brown solid. Base 肼 carboxylic acid tertiary butyl ester (291 5 mg, 〇·672 mmol, yield 67. 2%). Step 2

在2-{ [4-({[2-(乙醯基胺基）-1，3-嗟峻-4-基]幾基} 胺基）苯基]乙醯基}肼羧酸三級丁酯（260. lmg，0. 600mmol) 之無水二氯曱烧（3m 1)溶液中加入4M氯化氫二噚院溶液 (3· Oml，3. Ommol)，且在室溫攪拌4小時。將反應液減壓 、/辰細後’以醋酸乙i旨共沸3次。使殘渣懸浮於酷酸乙醋中 ⑩後濾取，並以醋酸乙酯洗淨2次。減壓乾燥後，得到白色 固體之標題化合物（185· Omg，0· 500mmo 1，產率83· 4%)。 融點248至255t： 'H-NMR (200MHz, DMS〇-d6) ： δ (ppm)： 12.27(1¾ brs), 11.29(1H, brs), 10.18(2H, brs), 9.68(1¾ brs), 7.85(1¾ s), 7.59(2¾ d, J=8.4Hz), 7.17(2H, d, J=8.4Hz), 3.46(2¾ s), 2.08(3H, s) 13C-NMR(50MHz, DMSO-d6)： δ (ppm)： 168. 1, 167.6, 157.7, 156.3, 142.7, 135· 6, 128· 4，127· 9，118.3，116.7，20· 9 (製造例22) N-[4-（{[4-（肼基羰基甲基）苯基]胺基}曱基）-1，3-噻唑 -2-基]乙醯胺二鹽酸鹽之合成 83 319771 2008356873-{[4-({[2-(Ethylamino))-1,3-yttrium-4-yl]yl}amino)phenyl]ethenyl} carboxylic acid tert-butyl To a solution of the ester (260. lmg, 0. 600 mmol) in anhydrous dichloropyrene (3m1) was added 4M hydrogen chloride dioxane solution (3·Oml, 3.0 mmol), and stirred at room temperature for 4 hours. The reaction solution was depressurized and then fined to azeotrope three times with acetic acid. The residue was suspended in citric acid ethyl acetate 10 and filtered, and washed twice with ethyl acetate. The title compound (185·Omg, 0········· Melting point 248 to 255t: 'H-NMR (200MHz, DMS〇-d6) : δ (ppm): 12.27(13⁄4 brs), 11.29(1H, brs), 10.18(2H, brs), 9.68(13⁄4 brs), 7.85 (13⁄4 s), 7.59 (23⁄4 d, J=8.4 Hz), 7.17 (2H, d, J=8.4 Hz), 3.46 (23⁄4 s), 2.08 (3H, s) 13C-NMR (50 MHz, DMSO-d6) ): δ (ppm): 168. 1, 167.6, 157.7, 156.3, 142.7, 135· 6, 128· 4, 127· 9, 118.3, 116.7, 20· 9 (Manufacturing example 22) N-[4-({ Synthesis of [4-(decylcarbonylmethyl)phenyl]amino}indenyl)-1,3-thiazol-2-yl]acetamide dihydrochloride 83 319771 200835687

步驟iStep i

BocNHNH2 在4-硝基苯基醋酸（3· 623g，20· OOmmol)之無水四氫 呋喃（70ml)溶液中加入1，Γ -羰基二咪唑（4· 865g，30. 00 mmol)，在室溫攪拌30分。加入肼基甲酸三級丁酯（6. 608 g，50· OOmmol)後，攪拌1小時。減壓蒸餾去除溶劑後，加 入醋酸乙酯（250ml)、0.5N鹽酸（180ml)並攪拌。靜置後分 液’並將有機層以餘和碳酸氫納水溶液、飽和食鹽水洗淨， 以無水硫酸鎂乾燥。減壓濃縮後，將殘渣以矽膠管柱層析 法（Fuji Silysia BW-300SP，300g，己烷：醋酸乙酯=1 : 1)精製後，得到白色固體之2-[ (4-硝基苯基）乙醯基]肼羧 酸三級丁酯（4· 566g，15· 46mmol，產率 77. 3%)。 步驟2 / ，To a solution of 4-nitrophenylacetic acid (3·623 g, 00 mmol) in anhydrous tetrahydrofuran (70 ml), hydrazine-carbonyldiimidazole (4· 865 g, 30. 00 mmol) was stirred at room temperature 30 Minute. After the addition of butyl carbazate (6. 608 g, 50· 00 mmol), it was stirred for 1 hour. After the solvent was distilled off under reduced pressure, ethyl acetate (250 ml) and 0.5N hydrochloric acid (180 ml) were added and stirred. After standing, the mixture was separated and the organic layer was washed with aq. sodium hydrogencarbonate and brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP, 300 g, hexane: ethyl acetate = 1: 1) to give 2-[4-nitrobenzene as a white solid. Ethyl mercapto] carboxylic acid tert-butyl butyl ester (4·566 g, 15.46 mmol, yield 77.3%). Step 2 / ,

2-[(4-硝基苯基）乙醯基]肼羧酸三級丁酯（4. ， 15.22mmol)溶於醋酸乙酯（90ml)中後，加入1〇%鈀碳 (〇· 899g)，在室溫進行氫化12小時。通過celite墊過濾 後，將濾液減壓濃縮。使生成之固體懸浮於三級丁基甲基 醚中後過濾。減壓乾燥。得到白色固體之2—[(4_胺基苯基） 乙醯基]肼羧酸三級丁酯a 666g, 13.59mm〇1，產率 89· 3%)。 步驟3 319771 84 200835687 Η2&quot;〇Λ2-[(4-Nitrophenyl)ethinyl]hydrazinecarboxylic acid tert-butyl butyl ester (4. , 15.22 mmol) was dissolved in ethyl acetate (90 ml), then 1% palladium on carbon (〇· 899 g) ), hydrogenation was carried out at room temperature for 12 hours. After filtration through a celite pad, the filtrate was concentrated under reduced pressure. The resulting solid was suspended in tributyl butyl ether and filtered. Dry under reduced pressure. 2-[(4-Aminophenyl)ethinyl]hydrazinecarboxylic acid tert-butyl butyl a 666 g, 13.59 mm 〇1, yield 89·3%) was obtained as a white solid. Step 3 319771 84 200835687 Η2&quot;〇Λ

Vy：Vy:

AcHN·AcHN·

CHOCHO

THF 將N-（4-曱醯基-1，3-噻唑-2-基）乙醯胺（510· 6mg， 3· 00Ommol)與2-[(4-胺基苯基）乙驢基]肼叛酸三級丁酯 (795. 9mg，3· OOOmmol)溶於無水四氫呋喃（5〇ml)中後，加 熱回流2小時。蒸餾去除溶劑後，加入醋酸乙酯（5ml)、三 級丁基甲基醚（50ml)至殘渣，並濾取析出之固體。減壓乾 燥後，得到白色固體之2-{[4-（{[2-(乙醯基胺基）-1，3-噻 唑-4-基]次曱基}胺基）苯基]乙醯基丨肼缓酸三級丁酯 (1· 233g，2· 953mmol，產率 98· 5%)。 步驟4THF N-(4-mercapto-1,3-thiazol-2-yl)acetamide (510·6 mg, 3.000 mmol) and 2-[(4-aminophenyl)ethenyl]fluorene The acid-reacting tertiary butyl ester (795. 9 mg, 3·0.000 mmol) was dissolved in anhydrous tetrahydrofuran (5 〇ml) and heated to reflux for 2 hours. After distilling off the solvent, ethyl acetate (5 ml) and tris-butyl methyl ether (50 ml) were added to the residue, and the precipitated solid was collected by filtration. After drying under reduced pressure, 2-{[4-({[2-(ethyl)amino)-1,3-thiazol-4-yl] decyl}amino)phenyl] oxime was obtained as a white solid. Base acid succinic acid tert-butyl ester (1·233g, 2·953mmol, yield 98·5%). Step 4

AcHN·AcHN·

NaBH4NaBH4

MeOH 將2-{[4-（{ [2-（乙醯基胺基）一1，3-嗟唾—4-基]次曱 基}胺基）苯基]乙醯基丨肼羧酸三級丁酯（918. 5mg，2. 2〇〇 mmol)溶解於無水甲醇（25ml)中後，冷卻至〇。〇。加入硼氫 化鈉（83.2mg，2·20ππη〇1)，且在〇t：攪拌4〇分。加入醋酸 (0· 5ml)並攪拌30分。減壓蒸餾去除溶劑後，加入醋酸乙 酯（100ml)、甲醇（5〇ml)，並過濾不溶物。將濾液減壓濃縮 後’將殘渣以矽膠管柱層析法（Fuji silysia BW-300SP， 60g ’二氯甲烷：甲醇=20 : 1至10 : 1)精製。將含目標物 之區分濃縮，且使所得之固體懸浮於醋酸乙酯（2〇ml)中後 85 319771 200835687 濾取。減壓乾燥後，得到白色固體之2-{[4-（{ [2-（乙醯基 胺基）-1，3-噻唑-4-基]曱基}胺基）苯基]乙醯基}肼羧酸三 級丁酯（640· lmg，1· 526mmol，產率 69· 4%)。 步驟5MeOH 2-{[4-({ [2-(ethinylamino)-1,3-1,3-indol-4-yl]-indenyl}amino)phenyl]ethenylhydrazinecarboxylic acid The butyl ester (918. 5 mg, 2.2 mmol) was dissolved in anhydrous methanol (25 ml) and cooled to hydr. Hey. Sodium borohydride (83.2 mg, 2·20ππη〇1) was added, and the mixture was stirred at 4 Torr. Add acetic acid (0.5 ml) and stir for 30 minutes. After the solvent was distilled off under reduced pressure, ethyl acetate (100 ml) and methanol (5 ml) were added, and insoluble materials were filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji silysia BW-300SP, 60 g 'methylene chloride:methanol = 20:1 to 10:1). The fractions containing the target were concentrated, and the obtained solid was suspended in ethyl acetate (2 mL) and then filtered. After drying under reduced pressure, 2-{[4-({[2-(ethyl)amino)-1,3-thiazol-4-yl] decyl}amino)phenyl]ethenyl) was obtained as a white solid. } Terpene carboxylic acid tert-butyl ester (640·1 mg, 1. 526 mmol, yield 69. 4%). Step 5

CH2Cl2 hci在二噚烷中 ---CH2Cl2 hci in dioxane ---

4之2 {[4 ({[2-(乙酉&amp;基胺基）一 1，3 -嗟σ坐- 4 -基]甲基} 鲁胺基）苯基]乙醯基}肼羧酸三級丁酯（320· 〇mg，〇· 763mmol) 懸浮於無水二氯曱烷（5· 7ml)中後，加入4M氯化氫二噚烷 溶液（5· 7ml)，且在室溫攪拌3小時。將反應液減壓濃縮 後，以醋酸乙酯共沸3次。使所得之固體懸浮於醋酸乙酯 中後滤、取’並以醋&quot;酸乙S旨洗淨2次。減壓乾燥後，得到白4 of 2 {[4 ({[2-(Ethyl)amine-1,3-嗟σ sita-4-yl]methyl}lumino)phenyl]ethenyl}anthracenecarboxylic acid The butyl ester (320· 〇mg, 763· 763 mmol) was suspended in anhydrous dichloromethane (5·7 ml), then 4M hydrogen chloride in dioxane (5·7 ml) was added and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and then evaporated to ethyl ether. The obtained solid was suspended in ethyl acetate, filtered, taken and washed twice with vinegar &quot;acid B. After drying under reduced pressure, white is obtained.

-色固體之標題化合物（297· 3mg，0· 758mmol，產率99· 3%)。 融點162至165°C _ ^hNMRGOOMHz, DMS0-d6): δ(ρριη): 12·06(1Η，brs), 11·17(1Η, brs), 擊 10·40(3Η, brs), 7.04(2¾ d, J=8.2Hz)，6· 90(1¾ s) , 6· 69 (2Η, d, J=8.2Hz), 4·25(2Η, s), 3·41 (2H, s), 2·11(3Η, s) 13C-NMR(50MHz, DMS0-d6)： δ (ppm) ： 169.6, 169.0, 158*3, 143*3, 137. 7, 132.7，130· 4, 121.2, 113.2, 48· 2，39.0, 22· 7 ,(製造例23) 1^-{4-[2-（3-肼基羰基曱基苯基）乙基]一1，3一嗟唾一2一基}乙 醯胺之合成 步驟1The title compound (297·3 mg, 0·758 mmol, yield 99.3%). Melting point 162 to 165 ° C _ ^hNMRGOOMHz, DMS0-d6): δ(ρριη): 12·06(1Η,brs), 11·17(1Η, brs), hit 10·40(3Η, brs), 7.04 (23⁄4 d, J=8.2Hz), 6·90(13⁄4 s) , 6· 69 (2Η, d, J=8.2Hz), 4·25(2Η, s), 3·41 (2H, s), 2·11(3Η, s) 13C-NMR (50MHz, DMS0-d6): δ (ppm): 169.6, 169.0, 158*3, 143*3, 137. 7, 132.7,130· 4, 121.2, 113.2, 48· 2,39.0, 22· 7 , (Production Example 23) 1^-{4-[2-(3-indolylcarbonylmercaptophenyl)ethyl]-1,3-indolyl-2-yl} Synthesis of acetaminophen step 1

NBS CCI4 319771 86 200835687 在間甲笨基醋酸（25· 〇〇g，166· 5mm〇l)之無水四氯化碳 (200ml)溶液中加入N—溴琥珀醯亞胺（3〇· 〇〇g，168. 6匪〇ι) 後緩緩升/JBL至沸點。加熱回流5 · 5小時後，冷卻至室溫。 將反應液過濾去除不溶物後，以四氯化碳（100ml)將不溶物 洗淨2 -人。將濾液濃縮後，將四氣化碳（6⑽1)加入至殘渣， 並以約70°C加熱溶解。冷卻至約4〇r後，滴入己烷（3〇〇 ml)。在室溫攪拌30分後，過濾析出之結晶，並以己烷洗 淨。減壓乾燥後，得到白色固體之（3-溴甲基苯基）醋酸 籲（22· 80g，99. 53mmol，產率 59· 8%)。 步驟2NBS CCI4 319771 86 200835687 Add N-bromosuccinimide (3〇·〇〇g) to a solution of m-chloroacetic acid (25·〇〇g, 166·5mm〇l) in anhydrous carbon tetrachloride (200ml) , 168. 6匪〇ι) slowly rise / JBL to the boiling point. After heating to reflux for 5 · 5 hours, it was cooled to room temperature. After the reaction solution was filtered to remove insoluble matters, the insoluble material was washed with carbon tetrachloride (100 ml) for 2 - human. After the filtrate was concentrated, carbon tetrachloride (6(10)1) was added to the residue, and dissolved by heating at about 70 °C. After cooling to about 4 Torr, hexane (3 〇〇 ml) was added dropwise. After stirring at room temperature for 30 minutes, the precipitated crystals were filtered and washed with hexane. After drying under reduced pressure, (3-bromomethylphenyl)acetic acid (22. 80 g, 99.53 mmol, yield: 59.8%). Step 2

將（3-溴甲基苯基）醋酸（22· 〇〇g，96· 04mmol)、三苯膦 (30. 23g’ 115. 2mmol)之無水乙腈（3〇〇ml)溶液加熱回流 小時。冷卻至室溫後，減壓濃縮至約l〇〇g。加入***（2〇〇 ❿ml) ’且在室溫攪拌1小時。濾取析出之結晶，並以***洗 淨。減壓乾燥後，得到白色固體之溴化[(3 一羰基曱基）苯甲 基](二本基）鱗（43· 60g，88· 7 3 mmol，產率 92.4%)。 步驟3A solution of (3-bromomethylphenyl)acetic acid (22 〇〇g, 96·04 mmol) and triphenylphosphine (30.23 g' 115. 2 mmol) in anhydrous acetonitrile (3 mL) was heated under reflux. After cooling to room temperature, it was concentrated to about 10 g under reduced pressure. Diethyl ether (2 〇〇 ❿ ml) was added and stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration and washed with diethyl ether. After drying under reduced pressure, a brominated [(3-carbonylcarbonyl) benzyl] (di-based) scale (43·60 g, 88·3 3 mmol, yield: 92.4%) was obtained as a white solid. Step 3

於Ot：在溴化[(3-羰甲基）苯曱基](三苯基）鱗（9. 529 g，19.39mmol)之無水N，N-二曱基曱醯胺（85ml)懸浮液中 逐次少量加入三級丁醇鉀（5· 935g，52· 89匪〇1)。在室溫攪 87 319771 200835687 拌30分後，加入（4-甲醯基—1，3-噻唑-2-基）乙醯胺（3. 〇〇〇 .g，17· 63mmol)，再攪拌3小時。冷卻至（TC後，加入水 (200ml)，並以醋酸乙酯（l〇〇mi)洗淨2次。於（TC在水層 中滴入6N鹽酸調整成pH3後，攪拌30分。濾取析出物後， 以水洗淨3次、以異丙醚洗淨2次。減壓乾燥後，得到白 色固體之3-{2-[2-(乙酿基胺基）—1，3 -嗟唾-4 -基]乙烯基} 苯基醋酸（4· 625g，15· 30mmol，產率 86. 8%)。 步驟4Ot: a suspension of [(3-carbonylmethyl)phenylhydrazolyl](triphenyl) scale (9. 529 g, 19.39 mmol) in anhydrous N,N-didecylguanamine (85 ml) A small amount of potassium butoxide (5·935g, 52·89匪〇1) was added in small portions. After stirring at room temperature for 87 319771 200835687, add (4-carbamimido-1,3-thiazol-2-yl)acetamide (3. 〇〇〇.g, 17·63 mmol), and stir 3 hour. After cooling to (TC, water (200 ml) was added, and the mixture was washed twice with ethyl acetate (l?mi). (TC was added dropwise 6N hydrochloric acid to pH 3 in the aqueous layer, and then stirred for 30 minutes. After the precipitates were washed three times with water and twice with isopropyl ether. After drying under reduced pressure, 3-{2-[2-(ethyl-bromoamino)-1,3-indole as a white solid. Saliva-4-yl]vinyl}phenylacetic acid (4·625 g, 15·30 mmol, yield 86.8%). Step 4

H2t Pd-C THF-MeOH 將3-{2-[2-(乙醯基胺基）-1，3-噻唑-4-基]乙稀基} 苯基醋酸（4· 500g，14· 88mmol)溶於四氫呋喃（225ml)、甲 醇（90ml)之混合溶齊丨中後，加入20%鈀碳（含水50%，]；. 800 g)。在室溫至30°C、4大氣壓下進行氫化。反應結束後， ⑩通過Ce 1 i te過濾反應液，並將濾液濃縮。將乙趟（1 〇〇m 1) 加入至殘渣，並濾取析出物。以***洗淨3次後，減壓乾 燥，得到白色固體之3-{2-[2-(乙醯基胺基）-1，3-售唑-4- 基]乙基}苯基酷酸（4· 152g，13· 64mmol，產率91. 7%)。 步驟5H2t Pd-C THF-MeOH 3-{2-[2-(Ethylamino)-1,3-thiazol-4-yl]ethenyl}phenylacetic acid (4·500 g, 14·88 mmol) After dissolving in a mixed solution of tetrahydrofuran (225 ml) and methanol (90 ml), 20% palladium on carbon (50% aqueous;); 800 g) was added. The hydrogenation was carried out at room temperature to 30 ° C under 4 atm. After completion of the reaction, 10 was filtered through Cel 1 i te, and the filtrate was concentrated. Acetate (1 〇〇m 1) was added to the residue, and the precipitate was collected by filtration. After washing three times with diethyl ether, it was dried under reduced pressure to give 3-{2-[2-(ethylamino)-l-(y-y-ylidene) (4· 152 g, 13·64 mmol, yield 91.7%). Step 5

在3-{2-[2-（乙醯基胺基）-1，3-噻唑-4-基]乙基}苯 基酷酸（l.OOOg，3· 286mmol)之無水N，N-二甲基曱醯胺 319771 88 200835687 (9ml)溶液中加入1，Γ -羰基二咪唑（799· lmg，4. 928 • mmol)，並在50°C攪拌1小時。冷卻至—15。〇後，加入肼· 一水合物（0.80ml，16.4mmol)，並緩緩升溫至5t：。在〇 °C加入水（150ml)，並以醋酸乙酯萃取3次。將混合後之有 機層以飽和食鹽水洗淨，以無水硫酸鎂乾燥。減壓濃縮後， 得到淡黃色固體之粗生成物（968mg)。將粗生成物溶於二氯 曱烧/甲醇（85 : 15)混合溶劑中後，通過化學修飾矽膠 (Fuji Silysia匪-DM2035，40g)過濾，以二氯曱烷/甲醇 馨（10 · 1)混合溶劑洗淨。將濾液減壓濃縮後，使殘渣懸浮於 酉a酉文乙酉曰中後濾、取。以醋酸乙酯洗淨3次後，減壓乾燥， 仔到白色固體之;f示遞化合物（848· 5mg，2· 665mmol，產率 81. 1¾) 〇Anhydrous N,N-di in 3-{2-[2-(ethionylamino)-1,3-thiazol-4-yl]ethyl}phenyl succinic acid (1.00 g, 3.286 mmol) To the solution of methyl decylamine 319771 88 200835687 (9 ml) was added 1, hydrazine-carbonyldiimidazole (799·1 mg, 4.928 • mmol), and stirred at 50 ° C for 1 hour. Cool to -15. After hydrazine, hydrazine monohydrate (0.80 ml, 16.4 mmol) was added and the temperature was slowly raised to 5t:. Water (150 ml) was added at 〇 ° C, and extracted with ethyl acetate three times. The mixed organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, a crude product (968 mg) was obtained. After dissolving the crude product in a mixed solvent of dichlorohydrin/methanol (85:15), it was filtered through a chemically modified silicone (Fuji Silysia®-DM2035, 40 g) to dichloromethane/methanol (10 · 1). Wash with a mixed solvent. After the filtrate was concentrated under reduced pressure, the residue was suspended in 酉a酉 酉曰 酉曰 后 and filtered. After washing with ethyl acetate for 3 times, it was dried under reduced pressure and taken to a white solid; </ br> compound (848·5 mg, 2· 665 mmol, yield 81. 13⁄4) 〇

融點179至181°C 'H-NMR (200MHz, DMS〇-d6)i δ (ppm)： 12.07(1¾ brs), 9.17(1¾ brs), 7.22--7.01(4H, m), 6.74(1H, s), 4.20(2H, brs), 3.3〇(2H, s), 2.95-2 80 (4H m) 2.10(3¾ s) ’ ’ 13C-NMR(50MHz, DMS0-d6)： 5(ppm)： 169.7, 168.4, 157.6, 150.5, 141.5, φ 136· 4，129· 1，128· 3, 126· 7, 126· 5，107· 5，40. 6，34· 8，33_ 〇,’ 22· 6 ’ (製造例24) N-（4-{2-[5-(肼基幾基）嗟吩-2-基]乙基}-l，3-嗟it坐—2-基） 乙醯胺之合成 步驟1Melting point 179 to 181 ° C 'H-NMR (200 MHz, DMS〇-d6) i δ (ppm): 12.07 (13⁄4 brs), 9.17 (13⁄4 brs), 7.22--7.01 (4H, m), 6.74 (1H , s), 4.20(2H, brs), 3.3〇(2H, s), 2.95-2 80 (4H m) 2.10(33⁄4 s) ' '13C-NMR(50MHz, DMS0-d6): 5(ppm): 169.7, 168.4, 157.6, 150.5, 141.5, φ 136· 4,129· 1,128· 3, 126· 7, 126· 5,107· 5,40. 6,34· 8,33_ 〇,' 22· 6 ' (Manufacturing Example 24) N-(4-{2-[5-(indolyl) porphin-2-yl]ethyl}-l,3-嗟it sitting-2-yl) acetamide Synthesis step 1

Ph3PPh3P

MeGNMeGN

在N -（4-氯甲基-1，3-喧11 坐-2-基）乙醯胺（4. OOOg， 20· 98mmol)之無水乙腈（i〇〇mi)溶液中加入三苯膦（7· 703 89 319771 200835687 g，29· 37mmol)後，加熱回流15小時。冷卻至室溫後，蒸 餾去除溶劑至約一半量。濾取析出之結晶，並以異丙醚洗 淨。減壓乾燥後，得到白色固體之氯化{[ 2-(乙醯基胺基） 一1，3-噻唑 一4-基]曱基}(三苯基）鱗（9· 251g，20. 42 _〇：[， 產率 97. 3%)。 步驟2Addition of triphenylphosphine to a solution of N-(4-chloromethyl-1,3-indole-11-yl)acetamide (4. OOOg, 20·98 mmol) in anhydrous acetonitrile (i〇〇mi) After 7· 703 89 319771 200835687 g, 29·37 mmol), the mixture was heated under reflux for 15 hours. After cooling to room temperature, the solvent was distilled off to about half the amount. The precipitated crystals were collected by filtration and washed with isopropyl ether. After drying under reduced pressure, chloro[{2-(ethinylamino)-1,3-thiazole-4-yl]indenyl}(triphenyl) sulphate (9·251 g, 20.42) was obtained as a white solid. _〇: [, yield 97.3%). Step 2

於〇C在氣化{[2 -（乙酿基胺基）—1，3-嗟σ坐-4-基]甲 基}(三苯基）鱗（3.771g，8· 325mmol)之無水Ν，Ν-二曱基甲 酿胺（35ml)溶液中加入三級丁醇鉀（2.515g，22.41mmol) 後’攪拌15分。逐次少量加入5-曱酸基嗟吩一2-甲酸 (1· OOOg，6· 404mmol)，且在〇°c攪拌30分。升溫至室溫 並攪拌2小詩後，將反應液注入冰水（300ml)中。授掉3〇 分後，以醋酸乙酯洗淨2次。將水層冷卻至〇°c後，滴入 ⑩6N鹽酸調整成PH3。在0至5t：攪拌2小時後，濾取析出 之結晶’並以水洗淨3次、以異丙洗淨2次。減壓乾燥 後，得到土黃色固體之5-{2-[2-(乙醯基胺基）一1，3-噻唾 -4-基]乙烯基}噻吩-2-甲酸（1· l〇4g，3· 751mmo卜產率 58·6%)。 步驟3〇C is in the gasification of {[2-(ethylamino)-1,3-pyridin-4-yl]methyl}(triphenyl) scale (3.771 g, 8·325 mmol) of anhydrous hydrazine After adding a potassium tert-butoxide (2.515 g, 22.41 mmol) to a solution of hydrazine-dimercaptoacetamide (35 ml), it was stirred for 15 minutes. 5-decanoic acid porphin-2-carboxylic acid (1· OOOg, 6·404 mmol) was added in small portions, and stirred at 〇 °c for 30 minutes. After warming to room temperature and stirring for 2 hours, the reaction solution was poured into ice water (300 ml). After 3 minutes, 3 times of washing with ethyl acetate. After the aqueous layer was cooled to 〇 °c, 106 N hydrochloric acid was added dropwise to adjust to pH 3. After stirring for 2 hours at 0 to 5t, the precipitated crystals were collected by filtration and washed three times with water and twice with isopropyl. After drying under reduced pressure, 5-{2-[2-(ethionylamino)-1,3-1,3-thiasin-4-yl]vinyl}thiophene-2-carboxylic acid (1·l〇) was obtained as a yellow solid. 4g, 3 · 751mmo yield 58.6%). Step 3

H2i Pd-C THF, ΜβΟΗH2i Pd-C THF, ΜβΟΗ

將5-{2-[2-(乙酸基胺基）-1，3-嗟嗤-4-基]乙稀基 319771 90 200835687 嗟吩-2-甲酸（900. Omg，3· 058mm〇l)溶於四氳吱喃（250 m 1)、曱醇（1 0 0 m 1)之混合溶劑中。加入2 〇 % I巴石炭，在室溫、 4大氣壓下進行氫化。反應結束後，通過Ce 1 i 過濾反應 液’並將濾'液減壓》辰縮。將乙鍵（1 〇 q m 1)加入至濃縮殘涫 後，濾取析出物，並以***洗淨。減壓乾燥後，得到灰白 色固體之5-{2-[2-(乙醯基胺基）-1，3-嗟嗤-4-基]乙基} 噻吩-2-曱酸（738· lmg，2. 490mmol，產率 81. 4%)。 步驟45-{2-[2-(Acetylamino)-1,3-indol-4-yl]ethenyl 319771 90 200835687 porphin-2-carboxylic acid (900. Omg, 3·058mm〇l) It is dissolved in a mixed solvent of tetrafuran (250 m 1) and decyl alcohol (100 m 1). 2 〇 % I barnacle charcoal was added and hydrogenation was carried out at room temperature under 4 atm. After completion of the reaction, the reaction solution was filtered through Ce 1 i and the filtrate was depressurized. After the ethyl bond (1 〇 q m 1) was added to the concentrated residue, the precipitate was collected by filtration and washed with diethyl ether. After drying under reduced pressure, 5-{2-[2-(ethylamino)-1,3-indol-4-yl]ethyl}thiophen-2-pyruic acid (738·1 mg, 2. 490 mmol, yield 81. 4%). Step 4

在5 {2-[2 -（乙基胺基）-1，3-ϋ塞唾-4-基]乙基}嗟 吩-2-曱酸（350· Omg，1· 181mmol)之無水Ν，Ν-二甲基甲酿 胺（3ml)溶液中加入1，1’ -羰基二咪唑（287. 2mg，1. 771 mmol) 1且在50。〇攪拌1小時。冷卻至室溫後，滴入異丙 醚（15ml)。攪拌5分後，濾取析出物，並以異丙醚洗淨2 馨次、以醋酸乙酯洗淨3次。減壓乾燥後，得到黃色固體之 N-（4-{2-[5-(咪唑-1-羰基）噻吩-2-基]乙基}-1，3 -噻唑 -2-基）乙醯胺（346· 2mg，0· 999mmol，產率 84· 6%)。 步驟5Anhydrous hydrazine in 5 {2-[2-(ethylamino)-1,3-indole-4-yl]ethyl} porphin-2-furic acid (350·Omg, 1·181 mmol), To a solution of hydrazine-dimethylacetamide (3 ml) was added 1,1'-carbonyldiimidazole (287. 2 mg, 1.771 mmol) 1 and at 50. Stir for 1 hour. After cooling to room temperature, isopropyl ether (15 ml) was added dropwise. After stirring for 5 minutes, the precipitate was collected by filtration, washed twice with isopropyl ether and three times with ethyl acetate. After drying under reduced pressure, N-(4-{2-[5-(imidazol-1-carbonyl)thiophen-2-yl]ethyl}-1,3-thiazol-2-yl)acetamide as a yellow solid. (346· 2 mg, 0·999 mmol, yield 84·6%). Step 5

AcHNAcHN

nh2nh2 -^ THFNh2nh2 -^ THF

AcHN—^AcHN—^

於〇°C在1M肼/四氫呋味溶液（4· 76ml，4· 76mmol)中 滴入N- (4- {2-[5-( 口米嗤-1-獄基）σ塞吩-2-基]乙基}-1，3〜 σ塞嗤-2-基）乙醯胺（330· Omg，0· 953mmol)之無水四氳咬喃 91 319771 200835687 (15m 1)懸浮液。在〇°C擾拌1小時，且在室溫授拌3〇分。 、在〇°C加入水（2ml)後，減壓濃縮。將水（33ml)加入至殘 渣，且在0°C攪拌20分。濾取生成之固體，並以水洗淨5 次、以醋酸乙酯洗淨2次。減壓乾燥後，得到灰白色固體 之標題化合物（278· 6mg，0· 898mmol，產率 94 2%)。N-(4-{2-[5-( 口米嗤-1-)) sigma- instilled in 1M 肼/tetrahydrofuran solution (4·76 ml, 4.76 mmol) at 〇 °C 2-Alkyl]ethyl}-1,3~ σ嗤嗤-2-yl)acetamidamine (330·Omg, 0·953 mmol) of anhydrous tetrahydroanthrene 91 319771 200835687 (15m 1) suspension. The mixture was stirred for 1 hour at 〇 °C, and 3 〇 was mixed at room temperature. After adding water (2 ml) at 〇 ° C, it was concentrated under reduced pressure. Water (33 ml) was added to the residue and stirred at 0 ° C for 20 minutes. The resulting solid was collected by filtration, washed with water 5 times and twice with ethyl acetate. The title compound (278·6 mg, 0··········

融點193至196°C 'H-NMR (200MHz, DMSCHd6) ： δ (ppm)： 12.06(1¾ brs), 9.61(1H, brs) 7 48(1H d, J=3.6Hz), 6.82(1H, d, J=3.6Hz), 6.76(1H, s), 4.39(2H, brs)| 3* 14(2H d，&gt;7·1Ηζ), 2·91(2Η，d, J=7.1Hz), 2.49(3¾ s) ’ · ’ A 13C~NMR(50MHz, DMS0~d6)： δ (ppm)： 168.7, 161.7, 158.0, 149.8, 149 〇 響 136· 3，127· 8, 126· 1，108.5，33.2, 29.4, 23· 0 ’ •’ (製造例25) N-（4-{2-[5-（肼基羰基甲基）噻吩一2-基]乙基卜^ 3-噻唑 -2-基）乙醯胺之合成Melting point 193 to 196 ° C 'H-NMR (200 MHz, DMSCHd6) : δ (ppm): 12.06 (13⁄4 brs), 9.61 (1H, brs) 7 48 (1H d, J = 3.6 Hz), 6.82 (1H, d, J=3.6Hz), 6.76(1H, s), 4.39(2H, brs)| 3* 14(2H d,&gt;7·1Ηζ), 2·91(2Η,d, J=7.1Hz), 2.49(33⁄4 s) ' · ' A 13C~NMR (50MHz, DMS0~d6): δ (ppm): 168.7, 161.7, 158.0, 149.8, 149 136 136· 3,127· 8, 126· 1,108.5, 33.2, 29.4, 2· 0 ' • (Production Example 25) N-(4-{2-[5-(indolylcarbonylmethyl)thiophene-2-yl]ethylidene-3-thiazol-2-yl ) Synthesis of acetamide

CD!, DMF S、 -- ACHN-&lt;N 1 Η NH2NH2H20 N^^X_V^YN^H2 ν~^ Ο 在3 (5-{2-[2-(乙酿基胺基）-1，3 -嗟唾-4-基]乙基} _噻吩-2-基）醋酸（3〇〇.〇mg，〇.967腿〇1)之無水ν，Ν-二甲基 曱酿胺（3ml)溶液中加入1，1’ -羰基二咪唑（235· 〇mg， 1.449mm〇l)，且在50。(：攪拌1小時。冷卻至◦。◦後，加入 水（50ml)並攪拌。濾取析出之固體，並以水洗淨5次。減 壓乾燥後，得到淡黃色固體（2〇6· 7mg)。將此固體以矽膠管 柱層析法（Fuji Silysia FL-60D，100g，二氯曱烧：甲醇 =85 : 15)精製。再次以矽膠管柱層析法（Fuji si iysia 關-DM2035，80g，二氯曱烷：甲醇=ι〇 ·· d精製。將含目 標物之區分減壓濃縮，並將所得之固體以醋酸乙酯洗淨3 92 319771 200835687 次、減壓乾煉後’得到微帶黃白色固體之標題化合物（144. 7 rag，0· 446ππηο1，產率 46· 1%)。CD!, DMF S, -- ACHN-&lt;N 1 Η NH2NH2H20 N^^X_V^YN^H2 ν~^ Ο at 3 (5-{2-[2-(ethyl arylamino)-1,3 -嗟 -4--4-yl]ethyl} _thiophen-2-yl)acetic acid (3 〇〇.〇mg, 〇.967 leg 〇 1) of anhydrous ν, Ν-dimethyl hydrazine (3 ml) solution 1,1 '-carbonyldiimidazole (235·〇mg, 1.449 mm〇l) was added, and was at 50. (: stirring for 1 hour. After cooling to hydrazine. After addition, water (50 ml) was added and stirred. The precipitated solid was collected by filtration and washed with water 5 times. After drying under reduced pressure, a pale yellow solid (2 〇 6·7 mg) The solid was purified by silica gel column chromatography (Fuji Silysia FL-60D, 100 g, dichlorohydrazine: methanol = 85: 15), and again by silica gel column chromatography (Fuji si iysia off-DM2035, 80g, methylene chloride: methanol = ι〇·· d refined. The target substance is separated and concentrated under reduced pressure, and the obtained solid is washed with ethyl acetate 3 92 319771 200835687 times, and dried under reduced pressure. The title compound (144. 7 rag, 0·446ππηο1, yield 46·1%) of the yellowish white solid.

融點202至205°CMelting point 202 to 205 ° C

'H-NMR (200MHz, DMS〇-d6) ： δ (ppm): 12.08(1H, brs), 9. 18(1H, brs), 6.78(1¾ s), 6. 66 (1H, d, J-3.4Hz), 6.63 (1H, d, J=3. 4Hz), 4. 22 (2H, brs), 3. 46 (2H s)，3.08(2H, t, J=7.1Hz), 2.88(2¾ t, J=7.1Hz), 2.11 (3H, s) , 13C-NMR(50MHz, DMS0~d6)： δ (ppm) ： 168.4, 168.1, 157.4, 149.6, 142.5, 135.1, 125.4, 123.8, 107.6, 34.8, 32.9, 28*7, 22.4 ’ (製造例26) N -（4 - {2-[5-(2-肼基羰基乙基）噻吩一 2 一基]乙基卜l 3一噻 _唑-2-基）乙醯胺之合成'H-NMR (200MHz, DMS〇-d6) : δ (ppm): 12.08(1H, brs), 9. 18(1H, brs), 6.78(13⁄4 s), 6. 66 (1H, d, J- 3.4 Hz), 6.63 (1H, d, J=3. 4Hz), 4. 22 (2H, brs), 3. 46 (2H s), 3.08 (2H, t, J=7.1Hz), 2.88(23⁄4 t , J=7.1Hz), 2.11 (3H, s), 13C-NMR (50MHz, DMS0~d6): δ (ppm): 168.4, 168.1, 157.4, 149.6, 142.5, 135.1, 125.4, 123.8, 107.6, 34.8, 32.9, 28*7, 22.4 ' (Manufacturing Example 26) N -(4 - {2-[5-(2-mercaptocarbonylethyl)thiophene-2-yl]ethyl b 1 thiazole-2 -based) synthesis of acetamide

OHOH

CDI/DMFCDI/DMF

NH2NH2 H2ONH2NH2 H2O

在3-(5-{2-[2-(乙醯基胺基）-1，3-噻唑-4-基]乙基} 噻吩-2-基）丙酸（840· Omg，2· 589mmol)之無水N，N-二甲基 -甲醯胺（6· 5ml)溶液中加入1，Γ -羰基二咪唑（629. 8mg， 3· 884mmol)，且在50°C攪拌1小時。冷卻至-l〇°c後，加 馨入肼•一水合物（〇· 63ml，13· Ommol)，且在室溫擾拌2 5 小時。冷卻至0°C後，加入水（2Om 1)並攪拌。濾取析出之 固體，並以水洗淨5次、以醋酸乙酯洗淨4次。減壓乾燥 後，得到白色固體之標題化合物（731· 7mg，2· 162mmol，產 率 83.5%)。 融點188至191°C ΐ-ΝΜ (200MHz, DMS0-d6)： δ (ppm)： 12.00(1H, brs), 9.00(1¾ brs), 6.78(1H, s), 6.6K2H, s), 4.19(2H, br), 3.12-3.00 (2H, m), 2.98-2.82 (4H, m), 2·32(2Η, t，J=7.6Hz), 2·11(3Η, s) 13C-NMR (50MHz, DMS0-d6)： δ (ppm) ： 170. 5, 168.4, 157.7, 149.9, 14L 8, 141· 5, 1213, 124· 2, 107. 9，35· 3，33· 2, 29· 1, 25· 5, 22· 6 93 319771 200835687 4 (製造例27) ' N-(4-{2-[5-(2-肼基羰基乙基）噻吩-3-基]乙基}-1，3-噻 唑-2-基）乙醯胺之合成 步驟13-(5-{2-[2-(Ethylamino)-1,3-thiazol-4-yl]ethyl}thiophen-2-yl)propanoic acid (840·Omg, 2.589 mmol) To a solution of anhydrous N,N-dimethyl-carbamide (6.5 ml) was added 1, hydrazine-carbonyldiimidazole (629. 8 mg, 3. 884 mmol), and stirred at 50 ° C for 1 hour. After cooling to -l 〇 °c, add hydrazine monohydrate (〇·63 ml, 13·Ommol) and stir for 25 hours at room temperature. After cooling to 0 ° C, water (2Om 1) was added and stirred. The precipitated solid was collected by filtration, washed 5 times with water and 4 times with ethyl acetate. The title compound (731·7 mg, 2·162 mmol, yield 83.5%) was obtained as white solid. Melting point 188 to 191 ° C ΐ-ΝΜ (200 MHz, DMS0-d6): δ (ppm): 12.00 (1H, brs), 9.00 (13⁄4 brs), 6.78 (1H, s), 6.6K2H, s), 4.19 (2H, br), 3.12-3.00 (2H, m), 2.98-2.82 (4H, m), 2·32 (2Η, t, J=7.6Hz), 2·11(3Η, s) 13C-NMR ( 50MHz, DMS0-d6): δ (ppm): 170. 5, 168.4, 157.7, 149.9, 14L 8, 141· 5, 1213, 124· 2, 107. 9,35· 3,33· 2, 29· 1 , 25· 5, 22· 6 93 319771 200835687 4 (Production Example 27) 'N-(4-{2-[5-(2-Mercaptocarbonylethyl)thiophen-3-yl]ethyl}-1, Synthesis of 3-thiazol-2-yl)acetamide Step 1

hoch2ch2oh PTSA, PhMeHoch2ch2oh PTSA, PhMe

在噻吩-3-曱醛（25· 00g，222· 9mmol)之曱苯（250ml) ⑩溶液中加入乙二醇（69· 18g，1115mmol)、對甲苯磺酸（424· 0 mg ’ 2· 229mmol)。一面在分水器（Dean-Stark trap)中分離 生成之水，同時加熱回流4小時。冷卻至〇°c後，加入飽 和碳酸氳鈉水溶液（5Oml)並攪拌，靜置後分液。將水層以 醋酸乙醋举取2次後’將混合後之有機層以水、飽和食鹽 水洗淨後，以無水硫酸鎂乾燥。減壓濃縮後，通過矽膠墊― (Fuji SilysiaBW-300SP，l〇〇g)過濾殘渣，並以醋酸乙酯 _/己烷混合溶劑（1 : 2，1 000ml)洗淨。將濾液減壓濃縮後， 得到黃色油狀物之2-(噻吩-3-基）~1，3-二氧戊環（33. 40 g，213· 8mmol，產率 95· 9%)。 步驟2Add ethylene glycol (69·18g, 1115mmol) and p-toluenesulfonic acid (424· 0 mg ' 2· 229mmol) to a solution of thiophene-3-furaldehyde (25·00g, 222.9mmol) in benzene (250ml) 10 ). The resulting water was separated in a Dean-Stark trap while heating to reflux for 4 hours. After cooling to 〇 °c, a saturated aqueous sodium carbonate solution (5Oml) was added and stirred, and the mixture was allowed to stand for separation. After the aqueous layer was extracted twice with ethyl acetate, the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the residue was filtered through a pad of EtOAc (EtOAc, EtOAc, EtOAc, EtOAc) The filtrate was concentrated under reduced pressure to give 2-(thiophen-3-yl)~ 1,3-dioxolane (33.40 g, 213·8 mmol, yield 95.9%). Step 2

將 2-(噻吩-3-基）-1，3-二氧戊環（1〇.⑽g，64. 〇2mm〇1) 之無水四氫呋喃（50ml)溶液在乾冰-甲醇浴内冷卻，且在使 319771 94 200835687 •反應液溫度不超過-55下滴入正丁鋰己烷溶液（i. 59M， 44· 3ml ’ 70· 4mmol)。擾拌1小時後，在使反應液溫度不超 過-60(3下滴入二甲基氣梦烧（8.941111，70.4111111〇1)。在—78 至- 60C撥摔30分後’歷時30分升溫至〇。〇，且在〇。〇擾 拌1小時。再次將反應液以乾冰-甲醇浴冷卻，且在使反應 液溫度不超過-60°C下滴入正丁鐘己烧溶液（i.59M，46 3 ml，73· 6mmol)。在-78至-60°C攪拌1小時後，滴入n，N- 二曱基曱醯胺（12· 4nd，160mmol)，再攪拌1小時。費時工 ⑩小時升溫至0°C後，加入飽和氯化銨水溶液（1 〇〇mi)。以酷 酸乙酯洗淨3次後，將混合後之有機層以〇· 2N鹽酸洗淨2 次、以飽和食鹽水洗淨1次。在有機層中加入無水硫酸鎂 與活性碳並揽摔5分後過遽。將濾、液減壓濃縮後，得到橙 色油狀物之4 -（ 1，3 - -一乳戍- 2 -基）-5 -（三甲基砍基）π塞 吩-2-甲醛（16· 09g，，62· 76mmol，產率 98· 0%)。 · 步驟3A solution of 2-(thiophen-3-yl)-1,3-dioxolane (1 〇. (10) g, 64. 〇 2 mm 〇 1) in anhydrous tetrahydrofuran (50 ml) was cooled in a dry ice-methanol bath and 319771 94 200835687 • The reaction solution temperature was not more than -55, and the n-butyl lithium hexane solution (i. 59M, 44·3ml '70·4mmol) was added dropwise. After 1 hour of stirring, the temperature of the reaction solution should not exceed -60 (3 drops of dimethyl gas dream (8.941111, 70.4111111〇1). After -78 to -60C drop 30 points, it will heat up for 30 minutes. 〇 〇 〇 且 且 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 拌 拌 拌 拌 拌 拌 拌 拌 拌 拌 拌 拌 拌 拌 拌 拌 拌 拌 拌 拌 拌 拌 拌 拌 拌 拌 拌 拌 拌 拌 拌 拌 拌 拌 拌 拌59 M, 46 3 ml, 73·6 mmol). After stirring at -78 to -60 ° C for 1 hour, n,N-didecylguanamine (12·4nd, 160 mmol) was added dropwise and stirred for 1 hour. After heating to 0 ° C for 10 hours, a saturated aqueous solution of ammonium chloride (1 〇〇mi) was added. After washing with ethyl acrylate for 3 times, the mixed organic layer was washed twice with 〇 2N hydrochloric acid. The mixture was washed once with saturated brine, and anhydrous magnesium sulfate and activated carbon were added to the organic layer, and the mixture was shaken for 5 minutes, and then filtered. The filtrate and the mixture were concentrated under reduced pressure to give an orange oil. - - chylo - 2 -yl)-5 - (trimethyl decyl) π cephene-2-carbaldehyde (16·09 g, 62·76 mmol, yield 98·0%) · Step 3

於0°C在4-（1，3-二氧戊環-2-基）-5-(三曱基矽基）噻 吩-2-甲醛（12· 82g，50· OOmmol)之氯仿（128ml)溶液中逐次 少量加入（三苯基亞填酸基（phosphanyl idene))酷酸甲酯 (Π· 55g，52· 50mmol)。在0°C攪拌1小時後，在室溫攪拌 12小時。將反應液減壓濃縮後，加入***（20 0m 1)至殘渣 並攪拌。過濾去除不溶物（主要為氧化三苯膦）後，以*** 95 319771 200835687 Λ (50ml)洗淨4次。將濾液減壓濃縮，並將濃縮殘渣以矽膠 ‘管柱層析法（Fu j i Si lysia BW-300SP，450g，醋酸乙酯： 己烷: 6)精製後，得到淡黃色油狀物之（2E)-3-[4 -(1，3 -二氧戊環-2-基）-5-(三曱基石夕基）嗟吩-2-基]丙烯酸 曱酯（13· 76g，44· 04mmol，產率 88· 1%)。 步驟4Chloroform (128 ml) at 4-(1,3-dioxolan-2-yl)-5-(tridecylsulfenyl)thiophene-2-carbaldehyde (12·82 g, 50· 00 mmol) at 0 °C A small amount of (phosphoryl idene) carboxylic acid methyl ester (Π·55 g, 52·50 mmol) was added in small portions in the solution. After stirring at 0 ° C for 1 hour, it was stirred at room temperature for 12 hours. After the reaction mixture was concentrated under reduced pressure, diethyl ether (20m) was evaporated. After insoluble matter (mainly triphenylphosphine oxide) was removed by filtration, it was washed 4 times with diethyl ether 95 319771 200835687 Λ (50 ml). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc EtOAc EtOAc EtOAc EtOAc )-3-[4-(1,3-dioxolan-2-yl)-5-(trimethylsulfanyl)porphin-2-yl]decyl acrylate (13·76 g, 44·04 mmol, Yield 88·1%). Step 4

在（2E)-3-[4-（1，3-二氧戊環-2-基）-5-（三曱基石夕基） 噻吩-2-基]丙烯酸甲酯（4· 〇〇〇g，12· 80mmol)之四氫呋喃 (20ml)溶液中加入水（〇· 2ml)後，冷卻至（Tc。加入氟化四 丁基銨四氫呋喃溶液（1M，13.4ml，13.4mmol)，在〇°C攪 拌5分、在室溫攪拌1〇分。冷卻至〇艺後，加入飽和氯化 銨水溶液（40ml)，並以醋酸乙酯萃取3次。將混合後之有 ⑩機層以飽和食鹽水洗淨後，以無水硫酸鎂乾燥。減壓濃縮 後，將殘渣以矽膠管柱層析法（Fuji Silysia BW-300.SP， 200g，醋酸乙酯：己烷=丨：3)精製後，得到無色油狀物之 (2E)-3- [4-（1，3-二氧戊環一2一基）σ塞吩一2 —基]丙烯酸甲酯 (3. 065 g，12. 76腿〇1，產率 99· 7%)。 步驟5Methyl (2E)-3-[4-(1,3-dioxolan-2-yl)-5-(trimethylsulfanyl)thiophen-2-yl]acrylate (4·〇〇〇g After adding water (〇·2 ml) to a solution of 12·80 mmol) in tetrahydrofuran (20 ml), it was cooled to (Tc). A solution of tetrabutylammonium fluoride tetrahydrofuran (1 M, 13.4 ml, 13.4 mmol) was added and stirred at 〇 ° C. 5 minutes, stirring at room temperature for 1 〇. After cooling to the turmeric, a saturated aqueous solution of ammonium chloride (40 ml) was added and extracted with ethyl acetate three times. After mixing, 10 layers were washed with saturated brine. After drying over anhydrous magnesium sulfate, the residue was purified by silica gel column chromatography (EtOAc, EtOAc, EtOAc: EtOAc: (2E)-3-[4-(1,3-dioxolan-2-yl)σ-sept-2-yl]methyl acrylate (3. 065 g, 12.76 leg 〇1, Yield 99·7%). Step 5

319771 96 200835687 在（2E)-3-[4-(1，3-二氧戊環-2-基）噻吩-2-基]丙稀 酸甲酯（3. 05Og，12· 69mmol)之四氫呋喃（l〇ml)溶液中加入 醋酸（30ml)、水（l〇ml)，且在50°C攪拌2小時。冷卻至室 溫後，減壓濃縮，並將水（30ml)加入至殘渣。以醋酸乙酯 卒取3次後’將混合後之有機層以飽和食鹽水洗淨。以無 水硫酸鎂乾燥後，減壓濃縮至約50ml，並加入己烷（2〇〇 ml)。再次減壓濃縮至約50ml後，濾取析出物。以己烷洗 淨3次後，減壓乾燥，得到白色固體之（2E)-3-[4-甲醯基 •噻吩-2-基]丙浠酸甲酯（2. 213g，11. 28mmol，88. 9%)。 步驟6 0|Θ319771 96 200835687 Tetrahydrofuran of (2E)-3-[4-(1,3-dioxolan-2-yl)thiophen-2-yl]acrylic acid methyl ester (3.05Og, 12.69mmol) To the solution, acetic acid (30 ml) and water (10 ml) were added, and the mixture was stirred at 50 ° C for 2 hours. After cooling to room temperature, it was concentrated under reduced pressure and water (30 ml) was added to the residue. After the mixture was taken three times with ethyl acetate, the mixed organic layer was washed with a saturated saline solution. After drying over anhydrous magnesium sulfate, it was concentrated under reduced pressure to about 50 ml, and hexane (2 〇〇 ml) was added. After concentration under reduced pressure to about 50 ml again, the precipitate was collected by filtration. After washing three times with hexane, EtOAc (2. 88. 9%). Step 6 0|Θ

將無水N，N-二甲基曱醯胺（30ml)加入至氯化{[2-（乙 醯基胺基)一1，3-噻唑-4-基]甲基}(三苯基）鱗（6· 6〇 2g， 14· 58mmol)後，冷卻至〇°c。加入三級丁醇_ (3. I46g， _ 28· 03 mmol)，且在〇它攪拌15分。滴入（2£)-3-[4-曱醯 基嚷吩-2-基]丙細酸曱醋（2. 200g，11· 21 mmol)之無水 N，N-二甲基甲醯胺（30ml)溶液，且在〇。〇攪拌1小時。將 反應液注入經冰冷之稀鹽酸（6〇〇ml，含有15丽〇1之HC1) 中。加入食鹽（10g)後，以醋酸乙酯萃取3次。將混合後之 有機層以飽和食鹽水洗淨後，以無水硫酸鎂乾燥、減壓濃 縮。將殘渣以矽膠管柱層析法（Fuji Silysia BW-300SP， 500g，醋酸乙酯：己烷=ί : i)精製後，得到黃白色固體之 (2Ε)-3-(4- {2-[2-(乙醯基胺基）—1，3-噻唑-4-基]乙烯基} 97 319771 200835687 口塞吩-2-基）丙稀酸甲酯（3.〇90g’ 9. 241mm〇l，82· 4%)。 步驟7Anhydrous N,N-dimethyldecylamine (30 ml) was added to the {[2-(ethionylamino)-1,3-thiazol-4-yl]methyl}(triphenyl) scale (6·6〇2g, 14·58mmol), cooled to 〇°c. Add tertiary butanol _ (3. I46g, _ 28· 03 mmol) and stir it for 15 minutes. Anhydrous N,N-dimethylformamide (2 £)-3-[4-mercaptophenen-2-yl]propionic acid vinegar (2.200 g, 11. 21 mmol) was added dropwise. 30 ml) solution, and in hydrazine. Stir for 1 hour. The reaction solution was poured into ice-cold diluted hydrochloric acid (6 〇〇ml, HC1 containing 15 〇1). After adding salt (10 g), it was extracted three times with ethyl acetate. The organic layer after washing was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP, 500 g, ethyl acetate:hexane = ί: i) to give (2 Ε)-3-(4- {2-[ 2-(Ethylamino)-1,3-thiazol-4-yl]vinyl} 97 319771 200835687 Methyl phenoxy-2-yl) acrylate (3. 〇90g' 9. 241mm〇l , 82· 4%). Step 7

將醋酸乙酯（400ml)、醋酸（100ml)加入至（2Ε) - 3-(4-{2-[2-(乙酸基胺基）-1，3-σ塞ϋ坐-4-基]乙烯基}嗟吩-2 -基） 丙烯酸甲酯（3· 000g，8· 971mmol )且使其溶解。加入20%名巴 碳，在常壓、室溫下進行氫化。反應結束後，過濾去除觸 _媒，並將濾液減壓濃縮。將殘渣以矽膠管柱層析法（FujiEthyl acetate (400 ml) and acetic acid (100 ml) were added to (2Ε)-3-(4-{2-[2-(acetamidoamino)-1,3-σϋϋ-4-yl]ethylene Methyl phenoxy-2-(methyl acrylate) (3 000 g, 8 · 971 mmol) was dissolved. Hydrogenation was carried out at normal pressure and room temperature by adding 20% of a bar of carbon. After completion of the reaction, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was chromatographic column chromatography (Fuji

Si lysia BW-300SP，100g，醋酸乙酯：己烷=2 : 3)精製後， 得到淡黃色固體之3-（4-{2-[2-（乙醯基胺基）-1，3-噻唑 -4-基]乙基}噻吩一2-基）丙酸曱酯（2· 521g，7· 449mmo：l，產 率 83· 0%)。 步驟Si lysia BW-300SP, 100 g, ethyl acetate: hexane = 2: 3) After purification, 3-(4-{2-[2-(ethylideneamino)-1,3- Thiazol-4-yl]ethyl}thiophene-2-yl)propanoate (2·521 g, 7·449 mmo: l, yield 83. 0%). step

1N-NaOH 二噚烷1N-NaOH dioxane

於〇°C在3-(4-{2-[2-(乙醯基胺基）-1，3-噻唑—4-基] 乙基卜塞吩-2-基）丙酸甲酯（1· 〇〇〇g，2· 955mm〇1)之二曙烷 (1〇ml)溶液中滴入1N氫氧化鈉水溶液（7· 39ml，7· 39 _〇1)。在室溫攪拌1小時後，將反應液減壓濃縮。將水 (20ml)加入至殘渣，並冷卻至〇。〇後，滴入in鹽酸u ml，10.5mmol)。在〇〇c攪拌3〇分後，濾取析出物，並以 士洗’Γ10久、以***洗淨3次、以二氯甲烷洗淨3次。減 壓乾燥後’得到微黃色固體之3-(4-{2-[2-(乙醯基胺基） 319771 98 200835687 -1，3-嘆唾-4-基]乙基卜塞吩-2-基）丙酸（934· 5 mg，2· 881 mmol，產率 97. 5%)。 步驟9Methyl 3-(4-{2-[2-(ethylideneamino)-1,3-thiazole-4-yl]ethyl bexephen-2-yl)propanoate (1) at 〇 °C · A solution of 1 N sodium hydroxide (7·39 ml, 7·39 _〇1) was added dropwise to a solution of 〇〇〇g, 2·955 mm〇1) in dioxane (1 〇ml). After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure. Water (20 ml) was added to the residue and cooled to hydrazine. After mashing, in ml of hydrochloric acid u ml, 10.5 mmol) was added dropwise. After stirring for 3 minutes in 〇〇c, the precipitate was collected by filtration, washed with EtOAc EtOAc (EtOAc) EtOAc (EtOAc) After drying under reduced pressure, '(4-{2-[2-(ethyl)amino) 319771 98 200835687 -1,3-sept-4-yl]ethylbexene-2 was obtained as a yellowish solid. -yl)propionic acid (934. 5 mg, 2.881 mmol, yield 97.5%). Step 9

在3-(4-{2-[2-(乙醯基胺基）-1，3-噻唑-4-基]乙基} 噻吩-2-基）丙酸（8〇〇· 〇mg，2· 466_〇1)之無水N，N-二曱基 曱醯胺（6ml)溶液中加入1，1，—羰基二咪唑（599. 8mg， 3· 699mmol)，且在50°C攪拌1小時。冷卻至-2〇°C後，加 入肼•一水合物（〇· 6〇ml，12· 3mmol)，且在室溫擾拌2小 時。冷卻至〇°C後，加入水（90ml)並擾拌30分後，濾取析 出之固體。以水洗淨5次、以醋酸乙酯洗淨3次後，減壓 乾燥’得到白色固體之標題化合物（763. 3mg，2. 255mmol， 產率 91 · 5%)。3-(4-{2-[2-(Ethylamino)-1,3-thiazol-4-yl]ethyl}thiophen-2-yl)propanoic acid (8〇〇· 〇mg, 2 · 466_〇1) A solution of anhydrous N,N-didecylguanamine (6 ml) was added with 1,1,-carbonyldiimidazole (599. 8 mg, 3.699 mmol), and stirred at 50 ° C for 1 hour. . After cooling to -2 °C, hydrazine monohydrate (〇·6〇ml, 12·3 mmol) was added and the mixture was stirred at room temperature for 2 hours. After cooling to 〇 ° C, water (90 ml) was added and the mixture was stirred for 30 minutes, and the precipitated solid was collected by filtration. After washing with water for 5 times and ethyl acetate for 3 times, the title compound (763. 3 mg, 2. 255 mmol, yield 91 5%) was obtained as white solid.

融點174至177°C 屯-腿(200脈，DMS0-d6): δ(ρρπι): 12·05(1Η, brs)，9·00(1Η, brs)，6·90(1Η, s)，6·74(1Η, s)，6·70(1Η, s), 4·17(2Η，br&gt;, 2·95(2Η, t, J=7.5Hz), 2.90-2.70 (4H, m), 2.33(2H, t, J=7.5Hz), 2.10(3H, s) wC-NMR(50MHz, DMS0-d6): δ (ppm) : 170.4, 168· 4, 157.6, 150.6, 143.7, * 141.5, 126· 0，118· 5, 107.4, 35· 3, 32.0, 29· 6，25· 6，22.7 (製造例28) N-{4-[2-(4-肼基苯基）乙基]-1，3-噻唑-2-基}乙醯胺鹽酸 鹽之合成Melting point 174 to 177 ° C 屯-legs (200 pulses, DMS0-d6): δ (ρρπι): 12·05 (1Η, brs), 9·00 (1Η, brs), 6·90 (1Η, s) ,6·74(1Η, s),6·70(1Η, s), 4·17(2Η,br&gt;, 2·95(2Η, t, J=7.5Hz), 2.90-2.70 (4H, m) , 2.33 (2H, t, J = 7.5 Hz), 2.10 (3H, s) wC-NMR (50 MHz, DMS0-d6): δ (ppm): 170.4, 168·4, 157.6, 150.6, 143.7, * 141.5, 126· 0,118· 5, 107.4, 35· 3, 32.0, 29· 6, 25· 6, 22.7 (Production Example 28) N-{4-[2-(4-mercaptophenyl)ethyl]- Synthesis of 1,3-thiazol-2-yl}acetamide hydrochloride

AcHN-&lt;\ 1AcHN-&lt;\ 1

NaN〇2NaN〇2

Na2S〇3 HCINa2S〇3 HCI

99 319771 200835687 在N-{4-[2_(4-胺基苯基）乙基]—1，3-°塞唾—2-基}乙 .醯胺（525· 3mg，2· OlOmmol)之水（15ml)懸浮液中加入6N 鹽酸（1· 0ml，6· Ommol )、冰（lg)、亞硝酸鈉（i4〇mg，2. OOmmol) 之水（lml)溶液，且在0°C攪拌45分。在〇°C加入亞硝酸鈉 (1. 267g，10· 05mmol)之水（7ml)溶液後，升溫至 65°C。加 入濃鹽酸（0 · 4 m 1)並搜摔4小時後，冷卻至〇 。濾取析出 之固體，並以水洗淨、減壓乾燥後，得到黃色固體之標題 化合物（492· 3mg，1· 574mmol，產率 78. 3%)。99 319771 200835687 Water in N-{4-[2_(4-aminophenyl)ethyl]-1,3-°-sodium-2-yl}acetamide (525·3 mg, 2· OlOmmol) (15 ml) A solution of 6N hydrochloric acid (1.0 ml, 6·Ommol), ice (lg), sodium nitrite (i4 〇mg, 2.0 mmol) in water (1 ml) was added to the suspension, and stirred at 0 ° C. Minute. After adding a solution of sodium nitrite (1.267 g, 10.05 mmol) in water (7 ml) at 〇 ° C, the mixture was heated to 65 ° C. Add concentrated hydrochloric acid (0 · 4 m 1) and collect for 4 hours, then cool to 〇. The precipitated solid was filtered, washed with water and dried then evaporated.

⑩融點143至146°C 出一NMR(200MHz, DMS0-d6): δ (ppm): 12.11 (1H, brs), 7·65(2H, d, J=8.1Hz)， 7.39 (2H, d, J=8.1Hz), 6.76(1H, s), 4.07(4H, brs), 3. 10-2.78 (4H, m),' 2.12(3¾ s) 13C-NMR(50MHz, DMSO)： δ (ppm) ： 168.5, 157.8, 150.0, 148.9, 146. 0, 129.6, 122.8，107.8, 34.6, 32· 5, 22.7 ’ (製造例29) -· N-(4-{2-[4-（肼基曱基）苯基}乙基卜i，3 —噻唑一2-基）乙醯 胺二鹽酸鹽之合成 馨步驟110 melting point 143 to 146 ° C. NMR (200 MHz, DMS0-d6): δ (ppm): 12.11 (1H, brs), 7·65 (2H, d, J = 8.1 Hz), 7.39 (2H, d , J=8.1Hz), 6.76(1H, s), 4.07(4H, brs), 3. 10-2.78 (4H, m), ' 2.12(33⁄4 s) 13C-NMR (50MHz, DMSO): δ (ppm) ) : 168.5, 157.8, 150.0, 148.9, 146. 0, 129.6, 122.8, 107.8, 34.6, 32· 5, 22.7 ' (Manufacturing Example 29) -· N-(4-{2-[4-(肼基曱) Synthesis of phenyl)ethyl}ethyl i,3-thiazole-2-yl)acetamide dihydrochloride

Mn〇2Mn〇2

CH2CIv MeOH 將N-（4-{2-[4-（羥基曱基）苯基]乙基}一1，3一噻唑一2- 基）乙醯胺（2· 581g，9· 340mmol)溶於二氯甲烷（200ml)、甲 醇（10ml)之混合溶劑中。加入活化二氧化錳（16. 24g, 186. 7 mmo 1) ’且在室溫攪拌5小時。通過Ce 1 ite過濾後，將濾 液減壓濃縮。將異丙醚加入至殘渣後，濾取生成之固體。 100 319771 200835687 減Μ乾餘後’付到白色固體之N-{4-[2-(4~~曱酿基苯基）乙 基]-1，3-噻唑-2-基}乙醯胺（2· 373mg，8· 650mmol，產率 92· 6«。 步驟2CH2CIv MeOH Dissolve N-(4-{2-[4-(hydroxyindenyl)phenyl]ethyl}-1,3-thiazole-2-yl)acetamide (2·581g, 9·340mmol) A mixed solvent of dichloromethane (200 ml) and methanol (10 ml). Activated manganese dioxide (16.24g, 186.7 mmo 1) was added and stirred at room temperature for 5 hours. After filtration through Ce 1 ite, the filtrate was concentrated under reduced pressure. After adding isopropyl ether to the residue, the resulting solid was collected by filtration. 100 319771 200835687 N-{4-[2-(4~~ 基-phenyl)ethyl]-1,3-thiazol-2-yl}acetamide (after a reduction in dryness) 2· 373mg, 8· 650mmol, yield 92· 6«. Step 2

在N-{4-[2-（4-曱醯基苯基）乙基]-1，3-噻唑-2-基} 馨乙醯胺（863· 5mg，3· 148mmol)之無水四氫吱喃（10ml)溶液 中加入肼基曱酸三級丁酯（1· 249g，9.451mmol)，且在室溫 攪拌2小時。另外再加入肼基曱酸三級丁酯（1. 25〇g，9. 458 mmo 1)’且在室溫攪拌4小時。減壓濃縮後，將異丙醚加入 至歹义 &gt;查，並濾取生成之固體。減壓乾燥後，得到白色固體 之4-{2-[2-(乙酿基胺基）一ι，3-嗟嗤- 4-基]乙基}-2 -苯亞 甲基（benzylidene)肼羧酸三級丁酯（977· 5mg，2. 516 ⑩ mmol，產率 79· 9%)。 步驟3Anhydrous tetrahydroanthracene in N-{4-[2-(4-mercaptophenyl)ethyl]-1,3-thiazol-2-yl} ocamperamine (863·5 mg, 3·148 mmol) To the solution (10 ml) was added tert-butyl decyl decanoate (1·249 g, 9.451 mmol), and stirred at room temperature for 2 hr. Further, a tertiary butyl decyl citrate (1.25 gram, 9.458 mmo 1) was added and stirred at room temperature for 4 hours. After concentration under reduced pressure, isopropyl ether was added to &lt;&quot;&gt;&gt; and the resulting solid was filtered. After drying under reduced pressure, 4-{2-[2-(ethylamino)-, 3-indol-4-yl]ethyl}-2-benzylidene oxime was obtained as a white solid. Tributyl carboxylic acid ester (977. 5 mg, 2. 516 10 mmol, yield 79.9%). Step 3

在4-{2 -[2-（乙酸基胺基）一1，3 -嗟σ坐一4-基]乙基}一2-本亞甲基肼叛酸二級丁 g旨（3· 〇51g，7· 854mmol)之無水四氫 呋喃（80ml)溶液中加入氰硼氫化鈉（986. 6mg，π. 7〇 mmol)、對甲苯磺酸一水合物（;L 493g，7.849mm〇1)之四氫 101 319771 200835687 咬喃（20ml)溶液，且在室溫攪拌3小時。另外再加入氰硼 氳化納（246· 6mg，3· 924mmol)與對甲苯磺酸一水合物 (373· 3mg，1· 962mmol)之四氫呋喃（5ml)溶液，且在室溫攪 拌2小時。加入醋酸乙酯（8〇ml)、水（8〇ml)、飽和食鹽水 (80ml)並攪拌，靜置後分液。將有機層以飽和碳酸氫鈉水 溶液及飽和食鹽水洗淨、以無水硫酸鎂乾燥。減壓濃縮後， 將異丙醚/醋酸乙酯混合溶劑（3 :丨）加入至濃縮殘渣，並 濾取生成之固體。將固體以二氯甲烷洗淨後，減壓乾燥， 馨得到白色固體之2-(4-{2-[2-(乙醯基胺基）—1，3-噻嗤一4-基]乙基}苯曱基）肼羧酸三級丁酯（1· 33〇g，3· 4〇6_〇1，產 率 43. 4%) 〇 步驟44-{2 -[2-(Acetylamino)-1,3 -嗟σ sits a 4-yl]ethyl}- 2-methyleneidene oxalic acid secondary butyl g (3· 〇 51 g, 7· 854 mmol) of anhydrous tetrahydrofuran (80 ml) was added with sodium cyanoborohydride (986. 6 mg, π. 7 〇 mmol), p-toluenesulfonic acid monohydrate (L 493 g, 7.849 mm 〇 1) Hydrogen 101 319771 200835687 The solution was whispered (20 ml) and stirred at room temperature for 3 hours. Further, a solution of cyanoborohydride (246. 6 mg, 3. 924 mmol) and p-toluenesulfonic acid monohydrate (373·3 mg, 1.962 mmol) in tetrahydrofuran (5 ml) was added, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate (8 〇 ml), water (8 〇 ml), and saturated brine (80 ml) were added and stirred, and the mixture was allowed to stand for separation. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, a mixed solvent of isopropyl ether/ethyl acetate (3: EtOAc) was added to the residue, and the solid formed was collected by filtration. After washing the solid with dichloromethane, it was dried under reduced pressure to give 2-(4-{2-[2-(ethylamino)- 1,3- thiazol-4-yl] Tertiary benzyl benzoate carboxylic acid tert-butyl butyl ester (1·33〇g, 3·4〇6_〇1, yield 43.4%) 〇Step 4

在2-(4-{2-[2-(乙醯基胺基）—1，3 —嗟峻―4—基]乙基}In 2-(4-{2-[2-(ethylideneamino)-1,3-anthracene 4-yl]ethyl}

物（918· 4mg，2· 528mmol，產率 60. 8%)。 融點194至196°C 、後，得到白色固體之標題化合 產率 60· 8%)。 319771 102 200835687 ^-NMR (200MHz, DMS0~d6): δ (ppm) ： 12. 07(1H, brs), 7. 30(2H, d, J=8.1Hz), 7.21(2H, d, J=8. 1Hz), 6. 72(1H, s), 4.00(2H, s), 3.01-2.80 (4H, m), 2.1 0(3¾ s) 13C-NMR(50MHz, DMSO)： δ (ppm) ： 168.4, 157.7, 150.2, 14L 7, 13L 3, 129.7, 128.6, 107.6, 53.7, 34.4, 32.8, 22.7 (製造例30) N-(4-{2-[4-(2-肼基乙基）苯基]乙基} — i，3一噻唑—2-基）乙 酸胺二鹽酸鹽之合成 步驟1(918·4 mg, 2·528 mmol, yield 60.8%). The melting point was 194 to 196 ° C, and the title compound was obtained as a white solid (yield: 60.8%). 319771 102 200835687 ^-NMR (200MHz, DMS0~d6): δ (ppm): 12. 07(1H, brs), 7. 30(2H, d, J=8.1Hz), 7.21(2H, d, J= 8. 1 Hz), 6. 72 (1H, s), 4.00 (2H, s), 3.01-2.80 (4H, m), 2.1 0 (33⁄4 s) 13C-NMR (50MHz, DMSO): δ (ppm): 168.4, 157.7, 150.2, 14L 7, 13L 3, 129.7, 128.6, 107.6, 53.7, 34.4, 32.8, 22.7 (manufacturing example 30) N-(4-{2-[4-(2-mercaptoethyl)benzene Synthesis of alkyl]ethyl}-i,3-thiazolyl-2-yl)acetic acid amine dihydrochloride

於0°C在N-(4-{2-[4-(2-經基乙基）苯基]乙基卜塞嗤 -2-基）乙醯胺（1· 800g，6· 199mmol)、（1，3-二酮基-1，3-二氫-2H-異吲哚-2-基）胺曱酸三級丁酯（2. 〇32g” 7. 749 mmol )、三苯膦（2.520义，9.608111111〇1)之無水四氫吱喃（15〇1111) ⑩溶液中滴入偶氮二羧酸二乙酯（已從2. 2M曱苯溶液4. 23ml ?备德去除&gt;谷劑者’ 9· 31 πππο 1)之無水四氮咬σ^(15πι1)溶液。 在室溫攪拌16小時後，減壓濃縮。將濃縮殘渣以矽膠管柱 層析法（Fuji Silysia BW-300SP，170g，醋酸乙酯：己烷 =1 : 1)精製後，得到白色固體之（2-{4-[2-（2-乙醯基胺基 -1，3-噻唑-4-基）乙基]苯基}乙基）-(1，3-二酮基-1，3-二 氫-2H-異吲哚-2-基）胺甲酸三級丁酯（2. 449g，4. 581 mmol，產率 73· 9%)。 步驟2 103 319771 200835687N-(4-{2-[4-(2-P-ethyl)phenyl]ethylbexin-2-yl)acetamide (1·800 g, 6·199 mmol) at 0 ° C, (1,3-Diketo-1,3-dihydro-2H-isoindol-2-yl)amine decanoic acid tert-butyl butyl ester (2. 〇32g) 7. 749 mmol ), triphenylphosphine (2.520)义,9.608111111〇1) of anhydrous tetrahydrofuran (15〇1111) 10 solution was added dropwise diethyl azodicarboxylate (has been removed from 2. 2M benzene solution 4. 23ml? The solution of '93·πππο1) of anhydrous tetrazolium σ^(15πι1) was stirred at room temperature for 16 hours, and concentrated under reduced pressure. The residue was concentrated to silica gel column chromatography (Fuji Silysia BW-300SP, 170 g) , ethyl acetate: hexane = 1: 1) After purification, (2-{4-[2-(2-ethylamino)-1,3-thiazol-4-yl)ethyl] Phenyl}ethyl)-(1,3-diketo-1,3-dihydro-2H-isoindol-2-yl)aminecarboxylic acid tert-butyl butyl ester (2. 449 g, 4. 581 mmol, produced Rate 73·9%). Step 2 103 319771 200835687

於-20°C在（2-{4-[2-(2-乙醯基胺基-1，3-噻唑-4-基） 乙基]本基}乙基）-（1，3-二嗣基-1，3 -二氮異口引°朵-2-基）胺 甲酸三級丁酯（2. 134g，3. 992mmol)之無水四氫呋喃（32ml) 溶液中滴入曱基肼（〇.32ml，6.00mmol)。在室溫攪拌15 小時後，過濾反應液，並將濾液減壓濃縮。將濃縮殘渣以 修石夕膠管柱層析法（Fu j i Si lysia BW-300SP，50g，二氯甲烧: 曱醇=30 : 1)精製後，得到白色固體之N-（2-{4-[2-(2-乙 醯基胺基-1，3-噻唑-4-基）乙基]苯基}乙基）肼羧酸三級丁 酯（1 · 481g，3· 661mmol，產率 91 · 7%)。 步驟3(2-{4-[2-(2-Ethylamino-1,3-thiazol-4-yl)ethyl]benyl}ethyl)-(1,3-di) at -20 °C A solution of fluorenyl-1,3-diaza-iso-butyl-tert-butyl-2-ylaminocarbamic acid tert-butyl ester (2. 134 g, 3.992 mmol) in anhydrous tetrahydrofuran (32 ml) was added dropwise to the hydrazino group (〇. 32 ml, 6.00 mmol). After stirring at room temperature for 15 hours, the reaction solution was filtered, and the filtrate was evaporated. The concentrated residue was purified by silica gel column chromatography (Fuji Si lysia BW-300SP, 50 g, methylene chloride: decyl alcohol = 30:1) to give a white solid N-(2-{4- [2-(2-Ethylamino-1,3-1,3-thiazol-4-yl)ethyl]phenyl}ethyl) decanoic acid tert-butyl butyl ester (1 · 481 g, 3 · 661 mmol, yield 91 · 7%). Step 3

將N-(2-{4-[2-(2-乙醯基胺基-1，3-噻唑-4-基）乙基] 苯基}乙基）肼羧酸三級丁酯（1· 363g，3· 369mmol)溶於二氯 曱烧（10ml)、曱醇（20ml)之混合溶劑中。滴入1M氯化氫乙 鱗溶液（50· 5m：l，50· 5mmol)，並在室溫攪拌15小時後，減 壓濃縮。將***（30ml)加入至濃縮殘渣後，再次減壓濃縮。 重複此操作3次，去除過量之氯化氫。將***（5〇mi)加入 至殘渣後過濾。將所得之固體以***洗淨3次、以靡酸乙 酯洗淨2次。減壓乾燥後，得到灰白色固體之標題化合物 319771 104 200835687 ‘ （1· 260g，3· 340mmol，產率 99. 1%)。N-(2-{4-[2-(2-Ethylamino)-1,3-thiazol-4-yl)ethyl]phenyl}ethyl)hydrazinecarboxylic acid tert-butyl butyl ester (1· 363 g, 3·369 mmol) was dissolved in a mixed solvent of dichlorohydrin (10 ml) and decyl alcohol (20 ml). A 1 M hydrogen chloride solution (50·5 m: 1, 50·5 mmol) was added dropwise, and the mixture was stirred at room temperature for 15 hr and then concentrated under reduced pressure. Diethyl ether (30 ml) was added to a concentrated residue and then evaporated. This operation was repeated 3 times to remove excess hydrogen chloride. Diethyl ether (5 〇mi) was added to the residue and filtered. The obtained solid was washed three times with diethyl ether and twice with ethyl acetate. The title compound was obtained as a white solid (3:1, 260 g, 3.34 mmol, yield: 99.1%).

‘融點142至144°C 'H-NMR (200MHz, DMS〇-d6) ： δ (ppm)： 12.10(1H, brs), 7.28-7.08 (4H, m), 6. 74(1¾ s), 3.69(2H, t, J=7. 0Hz), 2.95-2.72(6H, m), 2. 10(3H, s) 13C-NMR (50MHz, DMSO)： δ (ppm) ： 168.5, 157.7, 153.1, 150.3, 135,6, 129. 1，128· 5, 107· 6, 49. 9, 34· 3, 33· 0, 32· 8, 22. 7 (製造例31) N-(4-{2-[4-（3-肼基丙基）苯基]乙基卜i, 3-噻唑-2-基）乙 醯胺之二鹽酸鹽之合成 步驟1'melting point 142 to 144 ° C 'H-NMR (200 MHz, DMS 〇-d6) : δ (ppm): 12.10 (1H, brs), 7.28-7.08 (4H, m), 6. 74 (13⁄4 s), 3.69(2H, t, J=7. 0Hz), 2.95-2.72(6H, m), 2. 10(3H, s) 13C-NMR (50MHz, DMSO): δ (ppm): 168.5, 157.7, 153.1, 150.3, 135, 6, 129. 1,128· 5, 107· 6, 49. 9, 34· 3, 33· 0, 32· 8, 22. 7 (Manufacturing Example 31) N-(4-{2- Synthesis of [4-(3-mercaptopropyl)phenyl]ethyl i, 3-thiazol-2-yl)acetamide dihydrochloride Step 1

在3 -（4-{2-[2-(乙酿基胺基）-1，3 -嗟σ坐-4-基]乙基} 苯基）丙酸（1. 019g，3· 200mmol)之無水Ν，Ν-二甲基甲醯胺 (8ml)溶液中加入1，1，一羰基二咪唑（7T8. 3mg，4. 800 mmol) ’且在50°C授拌1小時。加入曱醇（2. 6ml，64mmol)， ❿且在5 0 C攪拌3小時。冷卻至室溫後，加入水（24m 1)並擾 拌’濾取生成之固體，並以水洗淨3次。減壓乾燥後，得 到白色固體之3-(4-{2-[2-(乙醯基胺基）_1，3-噻唑-4-基] 乙基}苯基）丙酸甲酯（943.6mg，2.839mmol，產率88.7%)。 步驟2In the presence of 3-(4-{2-[2-(ethylamino)-1,3-indolyl-4-yl]ethyl}phenyl)propanoic acid (1. 019 g, 3·200 mmol) To a solution of hydrazine hydrate and hydrazine-dimethylformamide (8 ml) was added 1,1,monocarbonyldiimidazole (7T8.3 mg, 4.800 mmol) and was stirred at 50 ° C for 1 hour. Hydroxide (2.6 ml, 64 mmol) was added, and stirred at 50 C for 3 h. After cooling to room temperature, water (24 ml) was added and the resulting solid was filtered off and washed three times with water. After drying under reduced pressure, methyl 3-(4-{2-[2-(ethionylamino)-1,3-thiazol-4-yl]ethyl}phenyl)propanoate as a white solid (94. , 2.839 mmol, yield 88.7%). Step 2

Η 於-78C 在 3-(4-{2-[2-(乙醯基胺基）-1，3-^^-4-基]乙基}苯基）丙酸曱酯（997· 3mg，3· OOOmmol)之無水四氫 105 319771 200835687 *呋喃（20ml)溶液中滴入ι·5Μ氫化二異丁基鋁（6.0ml，9·〇 —mmol)。在-78°C攪拌30分後，歷時1小時升溫至室溫，且 在室溫擾拌1小時。冷卻至〇 t後，加入水（1. 5m 1)/四氫 吱喃（15ml)混合液，且在室溫攪拌1小時。加入無水硫酸 鎂後’再攪拌30分。將不溶物過濾去除後，將濾液減壓乾 燥。將殘 &gt;查依石夕膠管柱層析法Silysia BW-300SP， 40g，酷酸乙酯：己烷=ι :丨）精製後，得到白色固體之 N-(4-{2-[4-(3-羥基丙基）苯基]乙基卜1，3-噻唑一2-基）乙 •醯胺（645· 6mg，2· 122mmo：l，產率 70. 7%)。 步驟3Η-78C in 3-(4-{2-[2-(ethinylamino)-1,3-^^-4-yl]ethyl}phenyl)propanoate (99 g, 3· OOOmmol) of anhydrous tetrahydrogen 105 319771 200835687 *In a solution of furan (20 ml), 1 m of diisobutylaluminum hydride (6.0 ml, 9·〇-mmol) was added dropwise. After stirring at -78 ° C for 30 minutes, the temperature was raised to room temperature over 1 hour, and the mixture was stirred at room temperature for 1 hour. After cooling to 〇t, a mixture of water (1.5 m 1) / tetrahydrofuran (15 ml) was added and stirred at room temperature for 1 hour. After adding anhydrous magnesium sulfate, the mixture was stirred for another 30 minutes. After the insoluble matter was removed by filtration, the filtrate was dried under reduced pressure. After refining &gt; Chayi Shixi gum column chromatography Silysia BW-300SP, 40g, ethyl acrylate: hexane = ι: 丨), N-(4-{2-[4- (3-hydroxypropyl)phenyl]ethyl 1,3-thiazole-2-yl)ethyl decylamine (645·6 mg, 2.122 mmo: l, yield 70.7%). Step 3

- 在N—(4—丨2—[4-(3-羥基丙基）苯基]乙基}一1，3-噻唑 -2-基）乙醯胺（643· 7mg，2· 115mmol)之無水四氫呋喃（5〇ml) ⑩/谷液中加入（1，3 -二酮基—1，3-二氫-2H-異〇弓卜朵—2 一基）胺曱 酸二級丁酯（693· 2mg，2· 643mmol)、三苯膦（857· 8mg， 3· 270mmol)。冷卻至〇°c後’滴入2. 2M偶氮二甲酸二乙酯 曱笨溶液（1· 44mL· 3· 17mmol)。在室溫攪拌14小時後，減 壓濃縮。將濃縮殘渣依矽膠管柱層析法（第1次：Fuji Silysia BW-300SP，l〇〇g，醋酸乙酯：己烷=4 : 6 ;第 2 人· Fuji Silysia BW-300SP，50g，醋酸乙酯：己烧=4 : 6)精製後，得到白色固體之[3一（4—{2—[2 —(乙醯基胺基） 一L 3 —嗟哇—4—基]乙基}苯基）丙基](1，3-二酮基-1，3-二氫 319771 106 200835687 2H-異吲哚-2-基）胺曱酸三級丁酯（776· 9mg，1. 416mmol， ’產率 67· 0%) 步驟4- in N-(4- 丨2-[4-(3-hydroxypropyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (643·7 mg, 2.115 mmol) Add (1,3 -diketo-1,3-dihydro-2H-isoindole) to a solution of anhydrous hexahydrofuran (5 〇ml) 10 / glutamic acid (693) 2 mg, 2·643 mmol), triphenylphosphine (857·8 mg, 3·270 mmol). After cooling to 〇 °c, the amount of diethyl azodicarboxylate (1·44 mL·3·17 mmol) was dropped. After stirring at room temperature for 14 hours, it was concentrated under reduced pressure. The concentrated residue was subjected to a rubber column chromatography (1st time: Fuji Silysia BW-300SP, l〇〇g, ethyl acetate: hexane = 4:6; 2nd person, Fuji Silysia BW-300SP, 50 g, acetic acid Ethyl ester: hexane = 4: 6) After purification, a white solid is obtained [3 -(4-{2-[2-(ethylamino)-L---ww- 4-yl]ethyl} Phenyl)propyl](1,3-diketo-1,3-dihydro319771 106 200835687 2H-isoindol-2-yl)amine decanoic acid tert-butyl ester (776·9 mg, 1.416 mmol, 'Yield 67· 0%') Step 4

m«nhnh2 achnH 於-15 C在[3-（4-{2-[2-(乙酿基胺基）-1，3 -π塞嗤-4-基]乙基}本基）丙基](1，3 -二ί同基-1，3-二氮-2Η -異〇引。朵 修-2-基）胺甲酸三級丁酯（760· 5mg，1 · 386mmol)之無水四氫 呋喃（10ml)溶液中加入甲基肼（92# 1，1.7mmol)。歷時1 小時升溫至室溫’且在室溫擾拌6小時。加入酷酸乙酯 (l〇ml)，並濾除生成之固體後，將濾液減壓濃縮。將殘渣 依石夕膠管柱層析法（Fu j i Si lysia BW-300SP，20g，醋酸乙 '酯：己烷=4 : 6至5 : 5至6 : 4)精製後，得到白色固體之 N-[3- (4-{2-[2-(乙醯基胺基）—1，3-噻唑-4-基]乙基}苯 籲基）丙基]肼羧酸三級丁酯（544· 6mg，1· 301mmol，產率 93· 9%)。 步驟5m«nhnh2 achnH at -15 C in [3-(4-{2-[2-(ethyl arylamino)-1,3 -π嗤嗤-4-yl]ethyl}benzyl)propyl] (1,3 - bis-iso-yl-1,3-diaza-2Η-isoindole. oxime-2-yl) dimethyl butyl carbamate (760·5mg, 1 · 386mmol) in anhydrous tetrahydrofuran (10ml To the solution was added methyl hydrazine (92# 1, 1.7 mmol). The temperature was raised to room temperature over 1 hour and spoiled for 6 hours at room temperature. After adding ethyl oleate (10 ml) and filtering off the resulting solid, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fu ji Si lysia BW-300SP, 20 g, ethyl acetate: hexane = 4:6 to 5:5 to 6:4) to give a white solid N- [3-(4-{2-[2-(Ethylamino)-1,3-thiazol-4-yl]ethyl}phenyl)phenyl) hydrazincarboxylic acid tert-butyl butyl ester (544· 6 mg, 1 · 301 mmol, yield 93.9%). Step 5

在N-[3-(4-{2-[2-（乙酸基胺基）-1，3-嗟峻-4-基]乙 基}苯基）丙基]肼羧酸三級丁酯（449· Img，1· 〇73mmol)之甲 醇（10ml)溶液中加入4M氯化氫二Df烷溶液（ι〇· 7ml，42. s 107 319771 200835687 mmo 1) ’且在室溫擾拌18小時。減遷濃縮後，將醋酸乙酯 加入殘渣且洗淨，並濾取固體。將固體溶於曱醇（10ml)中 後，加入醋酸乙酯（80ml)並濾取結晶。重複再結晶2次後， 付到白色固體之標題化合物（369· lmg，〇· 943mmol，產率 87· 9%)。 融點133至136它 ^-NMR (200MHz, DMS〇-d6) ： δ (ppm) ： 12.10(1Η, brs), 7.69 (5Η, brs), 7.18-7. 04 (4Η, m), 6.72(1¾ s), 2.96-2.78(6¾ m), 2.58(2¾ t, J=7.3Hz), 2.11 (3H, s), L 92-1.74(2¾ m) 13C-NMR(50MHz, DMSO)： δ (ppm) ： 168.4, 157.7, 150,4, 139.2, 138.6, 128.5, 響 1〇7· 6, 50· 1，34.4, 33· 0, 31· 8, 26.6, 22.7 (製造例32) N-（4-{2-[3-(2-肼基乙基）苯基]乙基} —1，3 —噻唑—2 —基）乙 醯胺鹽酸鹽之合成 步驟1Tertiary butyl ester of N-[3-(4-{2-[2-(acetoxyamino)-1,3-indol-4-yl]ethyl}phenyl)propyl]indolecarboxylic acid ( A solution of 449·1 mg, 1· 〇 73 mmol) in methanol (10 ml) was added 4M hydrogen chloride in di- D-hexane (m.sub.sup.7ml, 42. s 107 319771 200835. After the concentration was reduced, ethyl acetate was added to the residue and washed, and the solid was collected by filtration. After dissolving the solid in decyl alcohol (10 ml), ethyl acetate (80 ml) was added and the crystals were collected by filtration. The title compound (369·1 mg, 〇·943 mmol, yield 87.9%) was obtained as white solid. Melting point 133 to 136 which is ^-NMR (200MHz, DMS〇-d6): δ (ppm): 12.10(1Η, brs), 7.69 (5Η, brs), 7.18-7. 04 (4Η, m), 6.72( 13⁄4 s), 2.96-2.78 (63⁄4 m), 2.58 (23⁄4 t, J=7.3Hz), 2.11 (3H, s), L 92-1.74 (23⁄4 m) 13C-NMR (50MHz, DMSO): δ (ppm) ) : 168.4, 157.7, 150, 4, 139.2, 138.6, 128.5, Ring 1〇7· 6, 50· 1, 34.4, 33· 0, 31· 8, 26.6, 22.7 (Manufacturing Example 32) N-(4- Synthesis of {2-[3-(2-mercaptoethyl)phenyl]ethyl}-1,3-thiazolyl-2-ylacetamide hydrochloride Step 1

3-{2-[2-(乙醯基胺基）-1，3-噻唑-4-基]乙基}苯基醋 酸（1. OOOg，3· 286mmol)之無水 N，N-二甲基甲醯胺（4. 5ml) 溶液中加入1，1，-羰基二咪唑（799· lmg，4· 928mmol)，且 在50°C攪拌1小時。冷卻至〇°c後，加入甲醇（4. 〇mi，99 mmo 1)。在室溫擾拌5小時後，加入水（20〇1111)，並以酷酸 乙酉旨萃取3次。將混合後之有機層以飽和食鹽水洗淨、以 無水硫酸鎂乾燥後，減壓濃縮。將濃縮殘渔以石夕膠管柱層 析法（Fu j· i Si lysia BW-300SP，100g，醋酸乙酯：己燒=2 ·· 3)精製後，得到白色固體之3-{2-[2-(乙醯基胺基）一i，3- 108 319771 200835687 噻唑-4-基]乙基}苯基醋酸曱酯（949.5mg，2.982mmol，產 率 90. 8%)。 步驟23-{2-[2-(Ethylamino)-1,3-thiazol-4-yl]ethyl}phenylacetic acid (1. OOOg, 3·286 mmol) of anhydrous N,N-dimethyl 1,1,-Carbonyldiimidazole (799·1 mg, 4.928 mmol) was added to the solution of formazan (4.5 ml), and stirred at 50 ° C for 1 hour. After cooling to 〇 °c, methanol (4. 〇mi, 99 mmo 1) was added. After 5 hours of stirring at room temperature, water (20〇1111) was added and extracted 3 times with a cool acid. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The concentrated residue was purified by Shixi rubber column chromatography (Fu j· i Si lysia BW-300SP, 100 g, ethyl acetate: hexane = 2 ··3) to obtain 3-{2-[ 2-(Ethylamino)-i,3-108 319771 200835687 Isoazyl-4-yl]ethyl}phenylacetate (949.5 mg, 2.982 mmol, yield 90.8%). Step 2

於-78°C在3-{2-[2-（乙g藍基胺基）-1，3-嘆唾-4-基] 乙基}苯基醋酸曱酯（900· Omg，2· 827mmol)之無水四氫π夫喃 (20ml)溶液中滴入1· 5M氫化二異丁基鋁甲苯溶液（5. 65 鲁ml ’ 8. 48mmol)。一面攪拌同時歷時3小時從-78°C緩緩升 溫至0C。在0°C滴入水（1.51111)與四氫吱喃（151111)之混合 溶液。升溫至室溫後，攪;拌3 0分。加入無水硫酸鎂（5 g)， 再攪拌3 0分。過濾後，將殘渔以酷酸乙酯洗淨，並將濾液 減壓》辰縮。將濃縮殘、/查以梦膠管柱層析法（F u j i g丨1 y s i a BW-300SP，l〇〇g，醋酸乙酯：己烷=2 : 1)精製後，得到白 色固體之N-(4-{2-[3-（2-羥基乙基）苯基]乙基卜丨，3一噻 籲唑-2-基）乙醯胺（577· 3mg，1· 988mmol，產率 70· 3%)。 步驟33-{2-[2-(ethylglylamylamino)-1,3-sept-4-yl]ethyl}phenylacetate (900·Omg, 2·827 mmol) at -78 °C A solution of 1.5 M hydrogenated diisobutylaluminum toluene (5. 65 ru ml ' 8. 48 mmol) was added dropwise to a solution of anhydrous tetrahydro π-propanol (20 ml). While stirring for 3 hours, slowly warmed from -78 °C to 0C. A mixed solution of water (1.51111) and tetrahydrofuran (151111) was added dropwise at 0 °C. After warming to room temperature, stir; mix 30 minutes. Anhydrous magnesium sulfate (5 g) was added, and the mixture was stirred for 30 minutes. After filtration, the residual fish was washed with ethyl acrylate, and the filtrate was depressurized. The concentrated residue was purified by a gel column chromatography (F ujig丨1 ysia BW-300SP, l〇〇g, ethyl acetate:hexane = 2:1) to give a white solid N-(4 -{2-[3-(2-Hydroxyethyl)phenyl]ethylidene, 3-monothiazol-2-yl)acetamide (577·3 mg, 1·988 mmol, yield 70·3%) ). Step 3

於〇°C在N-(4-{2-[3-（2-羥基乙基）苯基]乙基}一1，3-口奉嗤一2-基）乙酸胺（57〇.〇mg，1· 963mmol)、（1，3-二酉同基 -1，3-二氫-2H-異吲哚-2-基）胺甲酸三級丁酯（643. 5mg， 2· 454 mmol )、二本膦（798.0 mg，3· 04 3mmol)之無水四氫口夫 109 319771 200835687 喃（50ml)溶液中滴入偶氮二羧酸二乙酯（已從2·2Μ曱苯溶 液1· 34ml蒸餾去除溶劑者，2· 95mm〇1)之無水四氫呋喃 (3ml)溶液。在室溫攪拌13·5小時後，減壓濃縮。將濃縮 殘渣以矽膠官柱層析法（Fuji Silysia bw-300SP，120g， 醋酸乙酯：己烷=1 : υ精製後，得到無色油狀物之（2一 {4-[3-（2-乙醯基胺基—1，3-噻唑-4-基）乙基]苯基}乙基） (1，3-二酮基-1，3-二氫-2Η-異吲哚-2-基）胺曱酸三級丁酯 (784· 4mg，1· 400 mmol，產率 71. 3%) •步驟4N-(4-{2-[3-(2-hydroxyethyl)phenyl]ethyl}-1,3-phenanthene-2-yl)acetic acid amine (57〇.〇mg) , 1· 963 mmol), (1,3-diindolyl-1,3-dihydro-2H-isoindol-2-yl)aminecarboxylic acid tert-butyl butyl ester (643. 5 mg, 2·454 mmol), Di-phosphine (798.0 mg, 3·04 3 mmol) of anhydrous tetrahydrogen husband 109 319771 200835687 Ethyl (50 ml) solution was added dropwise diethyl azodicarboxylate (distilled from 2. 2 benzene solution 1 · 34 ml) A solvent-free solution of 2.95 mm 〇1) in anhydrous tetrahydrofuran (3 ml) was added. After stirring at room temperature for 13.5 hours, it was concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (Fuji Silysia bw-300SP, 120 g, ethyl acetate:hexane = 1: hydrazine to give a colorless oil (2 -{4-[3-(2- Ethylamino-1,3-thiazol-4-yl)ethyl]phenyl}ethyl) (1,3-dione-1,3-dihydro-2Η-isoindol-2-yl) Acetylate tertiary butyl ester (784·4 mg, 1.400 mmol, yield 71.3%) • Step 4

MeNHNH THF 於-201：在（2-{4-[ 3-（2-乙醯基胺基-1，3-噻唑-4-基） 乙基]苯基}乙基）（1，3-二酮基-1，3-二氫-2H-異吲哚-2-基） 胺曱酸二級丁酯（730· 8mg，1· 367mmol)之無水四氫咬口南 ⑩（10ml)溶液中滴入曱基肼（〇· 〇9ml，1· 7腿〇1)。升溫至室溫 後，攪拌14小時。將反應液減壓濃縮後，加入乙_(1 〇 〇 ml)，並濾取不溶物。將不溶物以***洗淨，並將濾液濃縮。— 將濃縮殘渣以矽膠管柱層析法（Fuji Silysia BW-300SP， l〇〇g，二氯甲烷：甲醇=10 ·· 1)精製後，得到白色固體之 N-(2 - {4-[3 -（2 -乙酿基胺基-1，3-嗔嗤-4-基）乙基]苯基} 乙基）肼羧酸三級丁酯（由1H-NMR得到之純度分析值：約 93%，包含2-曱基-2,3-二氫酜哄（&lt;11]17(11&quot;(^111:11&amp;1&amp;21116) -1，4-二酮，570· 2mg，純度成分 530mg，1· 31mmol，產率 no 319771 200835687 • 95.8%)。 ‘步驟5 HC丨在Et20中 將N-(2-{4-[3-(2-乙醯基胺基-1，3-噻唑-4-基）乙基] 苯基}乙基）肼幾酸三級丁酯（純度93%，5〇〇. 〇mg，純度成 分1· 148mmol)溶於二氯甲烷（3· 5ml)、曱醇（7ml)之混合溶 劑中。加入1M氯化氫***溶液（173ml，ι7·3_〇1)，且在 室溫攪拌17小時後，減壓濃縮。將***（2〇m〇加入至濃縮 殘渣後，再次減壓濃縮，去除氯化氫。將***（2〇ml)加入 至殘渔後過濾，並將所得之固體以***洗淨3次、以二氯 曱烷洗淨5次。減壓乾燥後，得到白色固體之標題化合物MeNHNH THF at -201: in (2-{4-[ 3-(2-Ethylamino-1,3-thiazol-4-yl)ethyl]phenyl}ethyl)(1,3-di) Keto-1,3-dihydro-2H-isoindol-2-yl) butyl phthalate (730·8 mg, 1·367 mmol) in anhydrous tetrahydromanganate 10 (10 ml) Enter the base (〇·〇9ml, 1.7 leg 〇1). After warming to room temperature, it was stirred for 14 hours. After the reaction mixture was concentrated under reduced pressure, ethyl acetate (1 〇 〇 ml) was added, and insolubles were collected by filtration. The insoluble material was washed with diethyl ether and the filtrate was concentrated. - The concentrated residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP, l〇〇g, methylene chloride:methanol = 10 ··1) to give N-(2 - {4-[ 3-(2-Ethylamino-1,3-indol-4-yl)ethyl]phenyl}ethyl)hydrazinecarboxylic acid tert-butyl butyl ester (purity analysis value by 1H-NMR: approx. 93%, containing 2-mercapto-2,3-dihydroanthracene (&lt;11]17(11&quot;(^111:11&amp;1&amp;21116)-1,4-dione, 570·2mg, purity component 530 mg, 1. 31 mmol, yield no 319771 200835687 • 95.8%). 'Step 5 HC丨N-(2-{4-[3-(2-Ethylamino-1,3-thiazole) in Et20 -4-yl)ethyl]phenyl}ethyl) decanoic acid tert-butyl ester (purity 93%, 5 〇〇. 〇mg, purity component 1 · 148 mmol) dissolved in dichloromethane (3.5 ml), To a mixed solvent of decyl alcohol (7 ml), 1 M hydrogen chloride diethyl ether (173 ml, ι 7·3_〇1) was added, and the mixture was stirred at room temperature for 17 hours, then concentrated under reduced pressure. Et. After that, it was concentrated under reduced pressure again to remove hydrogen chloride. Diethyl ether (2 mL) was added to the residue and filtered, and the obtained solid was washed with diethyl ether. After 3 times, it was washed 5 times with dichloromethane.

MeOH，CHAMeOH, CHA

(369· 4mg ” 1. 〇84mmol，產率 94· 4%)。 融點10 5至118。〇 (融點不甚明確） H~Nm(200ffiz, D20, DSS=0ppm)： δ (ppm)： 7.40-7.25(¾ m), 7.25-7. 10 (3H, m), 6..91(1¾ s), 3.40(2¾ t, J=7.5Hz), 3.15-2.90 (6H m) 2 38(3H s) Ζ^Ρη)： 5(PPm)： 174·3· 139.6, 32· 0，131· 6，130.1，129.5, 112· 6, 54.7，36.1, 33· 3, 3ΐ·7, 25· 0 (製造例33) N-(4_{2-[5-(2-肼基乙基）噻吩—2-基]乙基卜i，3 —噻唑一2一 基）乙醯胺順丁烯二酸鹽之合成 步驟1(369·4mg ” 1. 〇84mmol, yield 94·4%) Melting point 10 5 to 118. 〇 (melting point is not clear) H~Nm (200ffiz, D20, DSS=0ppm): δ (ppm) : 7.40-7.25(3⁄4 m), 7.25-7. 10 (3H, m), 6..91(13⁄4 s), 3.40(23⁄4 t, J=7.5Hz), 3.15-2.90 (6H m) 2 38( 3H s) Ζ^Ρη): 5(PPm): 174·3· 139.6, 32· 0,131· 6,130.1,129.5, 112· 6, 54.7,36.1, 33· 3, 3ΐ·7, 25· 0 (Production Example 33) N-(4_{2-[5-(2-mercaptoethyl)thiophene-2-yl]ethylid i,3-thiazole-2-yl)acetamide maleic acid Salt synthesis step 1

POCb PhNMeCHOPOCb PhNMeCHO

在惰性氣體中’在N-曱基甲醯苯胺（28.67g，212. 1 319771 111 200835687 * mmol)中加入磷醯氯（32.53g，212.lmm〇1)後，在室溫放置 .30分。一面攪拌同時滴入乙酸2_噻吩—2 —基乙酯（36. ， 212· 1 mmo 1)，且在室溫攪拌14小時。將已混合n一甲基甲 醯胺苯（1.4348，1〇.61111111〇1)與磷醯氯（1.6278，1〇.61111111〇1) 並靜置30分者加入反應液中。在室溫攪拌6小時後，將反 應液庄入冰水中，並以***萃取。將有機層以1N鹽酸、飽 和碳酸氫鈉水溶液、飽和食鹽水洗淨，並以無水硫酸鎂乾 爍。減壓濃縮後，將殘渣以;5夕膠管柱層析法（Fu j i S i 1 y s i a ⑩BW-300SP，600g，醋酸乙酯：己烷=1 : 3)精製後，得到淡 黃色油狀物之乙酸2-(5-曱醯基噻吩-2-基）乙酯（41. 63 g，210· Ommol，產率 99· 0%)。 步驟2After adding phosphonium chloride (32.53 g, 212.lmm〇1) to N-mercaptomethylaniline (28.67 g, 212.1 119771 111 200835687 * mmol) in an inert atmosphere, place at room temperature. 30 minutes . 2_Thien-2-ylethyl acetate (36., 212·1 mmo 1) was added dropwise while stirring, and stirred at room temperature for 14 hours. The n-methylformamide benzene (1.4348, 1〇.61111111〇1) and phosphonium chloride (1.6278, 1〇.61111111〇1) were mixed and allowed to stand for 30 minutes, and added to the reaction liquid. After stirring at room temperature for 6 hours, the reaction solution was poured into ice water and extracted with diethyl ether. The organic layer was washed with 1N aqueous HCl, aq. sodium hydrogen carbonate and brine, and dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the residue was purified by EtOAc EtOAc (EtOAc EtOAc EtOAc EtOAc 2-(5-Mercaptothiophen-2-yl)ethyl acetate (41.63 g, 210·Ommol, yield 99. 0%). Step 2

NaBH4 ΤΗΜΛβΟΗNaBH4 ΤΗΜΛβΟΗ

將乙酸2-（5-曱醯基噻吩一2-基）乙酯（4〇· 〇〇g，201. 8 馨mmol )&gt;谷解於20%曱醇/四氫tr夫喃混合溶劑（4〇〇mi)中。冷 卻至-25°C後，加入硼氫化鈉（3· 〇53g，80· 71mmol)，且在 -25至0 C攪拌1 · 5小時。將反應液注入經冰冷之2N鹽酸 (200 m 1)中後’加入食鹽（5g)，並以醋酸乙酯萃取。將有 機層以飽和食鹽水、飽和碳酸氫鈉水溶液、飽和氯化銨水 溶液、飽和食鹽水洗淨。加入無水硫酸鎂、活性;5炭並攪拌 後過濾。將濾液減壓濃縮後，得到無色油狀物之乙酸2- (5-羥基曱基嘆吩-2-基）乙酯（39· 91g，199· 3mmol，產率 98·80/〇)〇 112 319771 200835687 •步驟3 ho&quot;^lT^〇Ac —Cr^y^c2-(5-Mercaptothiophen-2-yl)ethyl acetate (4〇·〇〇g, 201.8 mol mmol) &gt; glutamic solution in a 20% decyl alcohol / tetrahydrotruffane mixed solvent ( 4〇〇mi). After cooling to -25 ° C, sodium borohydride (3· 〇 53 g, 80·71 mmol) was added, and stirred at -25 to 0 C for 1.5 hours. After the reaction solution was poured into ice-cold 2N hydrochloric acid (200 m1), salt (5 g) was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, saturated aqueous sodium hydrogencarbonate solution, saturated aqueous ammonium chloride solution and brine. Anhydrous magnesium sulfate was added, and the activity was carried out; 5 charcoal was stirred and filtered. The filtrate was concentrated under reduced pressure to give ethyl 2-(5-hydroxypurpurin-2-yl)ethyl acetate (39·91 g, 199·3 mmol, yield 98·80 / 〇) 〇 112 as a colorless oil. 319771 200835687 • Step 3 ho&quot;^lT^〇Ac —Cr^y^c

EI3N，。《2〇2 U 在乙酸2-（5-羥基甲基噻吩一2一基）乙酯（39. 6〇g， 197· 8mmol)之無水一氯甲院（200ml)溶液中加入三乙基胺 (21· Olg，207· 6mmol)後，在 〇°c 滴入亞硫醯氯（24· 7〇g， 207· 6腿〇1)。在0°C攪拌5小時後，將反應液注入冰水（2〇〇g) 中’並以***萃取。將有機層以飽和食鹽水溶液、飽和碳 酸氫鈉水溶液、飽和氯化銨水溶液、飽和食鹽水洗淨。加 入無水硫酸鎂、活性碳並攪拌後過濾。將濾液減壓濃縮後， 知到橙色油狀物之乙酸2-(5-氯甲基售吩-2-基）乙g旨 (42· 12g，192· 6 mmol，產率 97. 4%)。 步驟4EI3N,. Adding triethylamine to a solution of 2-(5-hydroxymethylthiophene-2-yl)ethyl acetate (39.6 〇g, 197·8 mmol) in anhydrous monochloromethane (200 ml) (21· Olg, 207·6 mmol), thiol chloride (24·7〇g, 207·6 leg 〇1) was added dropwise at 〇°c. After stirring at 0 ° C for 5 hours, the reaction solution was poured into ice water (2 g) and extracted with diethyl ether. The organic layer was washed with a saturated aqueous salt solution, a saturated aqueous solution of sodium hydrogencarbonate, a saturated aqueous ammonium chloride solution and brine. Anhydrous magnesium sulfate, activated carbon was added thereto, and the mixture was stirred and filtered. After the filtrate was concentrated under reduced pressure, ethyl acetate (yield: 2-(5-chloromethyl) . Step 4

在乙酸2-（5-氯甲基嗟吩—2-基）乙酯（42. 00g，192. 0 mmol)之無水乙腈（210ml)溶液中加入三苯膦（5〇· 37g， 192· Ommo 1)。在80°C攪拌6小時後，冷卻至室溫。滴入異 丙醚（420ml)後，攪拌1小時。濾取析出之結晶，並以異丙 _洗淨。減壓乾燥後，得到白色固體之氯化[5-(2-乙酿氧 基乙基）噻吩-2-基甲基]三苯基鱗（72· 09g，149· 9mmol，產 率 78. 1%)。 步驟5 113 319771 200835687Add triphenylphosphine (5〇·37g, 192· Ommo) to a solution of 2-(5-chloromethyl porphin-2-yl)ethyl acetate (42. 00g, 192.0 mmol) in anhydrous acetonitrile (210 ml) 1). After stirring at 80 ° C for 6 hours, it was cooled to room temperature. After dropping isopropyl ether (420 ml), the mixture was stirred for 1 hour. The precipitated crystals were collected by filtration and washed with isopropyl. After drying under reduced pressure, chloro[5-(2-ethyloxyethyl)thiophen-2-ylmethyl]triphenyl scale (72·09 g, 149·9 mmol, yield 78. 1 %). Step 5 113 319771 200835687

%uOK%uOK

THF-DMFTHF-DMF

在25 C在氣化[5-(2 -乙Si&amp;氧基乙基）π塞吩一 2-基甲基] 三苯基鱗（19· 68g，40. 91mmol)之無水四氫呋喃（2〇ml)懸浮 液中滴入三級丁醇鈉四氫呋喃溶液（丨Μ，4〇. 〇mi，40. 〇 ππηο 1)。授掉30分後’加入N-(4-甲酿基—1，3-嗟σ坐-2-基） 乙醯胺（6.330g，37· 19mmol)之無水Ν，Ν-二曱基甲醯胺 (35ml)，再攪拌20分。歷時2小時升溫至〇t：後，將反應 ⑩液注入冰水（200ml)中。以醋酸乙酯萃取後，以飽和碳酸氫 鈉水溶液、飽和氯化銨水溶液、飽和食鹽水洗淨。加入硫 酸鎂與活性碳並攪拌。過濾後，將濾液減壓濃縮。將殘渣 以石夕膠管柱層析法（Fuji Silysia BW-300SP，600g，醋酸 乙S曰·己:ί元一 2 · 3)精製後’得到淡黃色油狀物之乙酸 2 - {5-[2-(2-乙醯基胺基-1，3。嗟唾-4-基）乙烯基]σ塞吩-2-基}乙酯（8.53 9g，25.38 mmol，產率 68· 2%)。 0步驟6Anhydrous tetrahydrofuran (2〇ml) was gasified at 25 C in [5-(2-ethyl-Si&amp;oxyethyl)π-cephen-2-ylmethyl]triphenyl scale (19·68 g, 40.91 mmol) A suspension of sodium butoxide sodium tetrahydrofuran (丨Μ, 4〇. 〇mi, 40. 〇ππηο 1) was added dropwise to the suspension. After adding 30 minutes, 'add N-(4-methyl aryl-1,3-嗟σ sitting-2-yl) acetamidine (6.330g, 37·19mmol) of anhydrous hydrazine, Ν-dimercaptomethyl hydrazine Amine (35 ml), stir for another 20 minutes. After heating to 〇t: for 2 hours, the reaction solution 10 was poured into ice water (200 ml). After extracting with ethyl acetate, it was washed with a saturated aqueous solution of sodium hydrogencarbonate, a saturated aqueous solution of ammonium chloride and brine. Magnesium sulfate is added to the activated carbon and stirred. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Shixi rubber column chromatography (Fuji Silysia BW-300SP, 600 g, acetic acid ethyl acetate: hexane: 2-1) to obtain acetic acid 2 - {5-[ 2-(2-Ethylamino-1,3. oxime-4-yl)vinyl]σ-phen-2-yl}ethyl ester (8.53 9 g, 25.38 mmol, yield 68. 2%). 0 step 6

AcOE^AcOH H2f Pd^AcOE^AcOH H2f Pd^

在乙酸2-(5-{2-[2-(乙醯基胺基）-1，3-噻唑-4-基] 乙烯基}嗟吩—2-基）乙酯（9· 795g，29· 11 mmol)之if酸乙酯 (20〇1111)溶液中加入醋酸（5〇1111)、1〇%鈀碳（3918&amp;)，在常 溫、常壓下進行氫化。將反應液過濾後，將濾液減壓濃縮。 將殘渣溶於醋酸乙酯（3〇〇mi)中後，以飽和碳酸氫鈉水溶 液、飽和氯化銨水溶液、飽和食鹽水洗淨。以無水硫酸鎂 114 319771 200835687 乾燥後’濃縮變乾硬，得到微帶黃白色之固體之乙酸2-( {2-[2-(乙醯基胺基）—丨，3-噻唑一 4_基]乙基丨噻吩一2-基）乙 酯（9. 320g，27· 54mmol，產率 94· 6%)。 步驟72-(5-{2-[2-(Ethylamino)-1,3-thiazol-4-yl]vinyl} porphin-2-yl)ethyl acetate (9·795g, 29·) To a solution of 11 mmol) of ethyl orthoacetate (20〇1111), acetic acid (5〇1111) and 1% by weight of palladium carbon (3918&amp;) were added, and hydrogenation was carried out at normal temperature and normal pressure. After filtering the reaction mixture, the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (3 〇〇mi), and washed with a saturated aqueous sodium hydrogen carbonate solution, a saturated aqueous ammonium chloride solution and brine. After drying with anhydrous magnesium sulfate 114 319771 200835687, it is concentrated and dried to obtain 2-( {2-[2-(ethylideneamino)-hydrazine, 3-thiazole- 4-yl group as a solid yellow-white solid. Ethyl thiophene-2-yl)ethyl ester (9. 320 g, 27.54 mmol, yield 94.6%). Step 7

在乙酸2-(5-{2-[2-（乙醯基胺基）-1，3-σ塞嗤-4-基] 乙基}σ塞吩-2-基）乙酯（9.300g，27. 48mmol)之無水甲醇 鲁（250 ml)溶液中加入經乾燥之碳酸鉀（3·798δ，27·48_〇1) 後’攪拌2小時。加入錯酸（1 · 65g，27· 5mmol)後，減壓濃 知百。將水（15 〇 m 1)加入至殘渣後，以酷酸乙酯萃取。將有機 層以飽和食鹽水、飽和碳酸氫鈉水溶液、飽和氯化銨水溶 液、飽和食鹽水依序洗淨。加入無水硫酸鎂、活性碳並授 拌後過濾。將濾液濃縮至約75ml後，滴入異丙醚（2〇〇ml) 授拌30分後，濾取析出之結晶。將結晶以異丙醚洗淨、減 _壓乾燥後，得到白色結晶之N-(4-{2-[5-(2-羥基乙基）喧 吩-2-基]乙基}噻唑-2-基）乙醯胺（7· 684g，25· 92mmol，產 率 94.3%) 〇 步驟82-(5-{2-[2-(Ethylamino)-1,3-σ塞嗤-4-yl]ethyl}σ-cephen-2-yl)ethyl acetate (9.300 g, 27. 48 mmol) of anhydrous methanol (250 ml) was added to dry potassium carbonate (3·798δ, 27.48_〇1) and stirred for 2 hours. After adding the wrong acid (1 · 65 g, 27.5 mmol), it was concentrated under reduced pressure. Water (15 〇 m 1) was added to the residue and extracted with ethyl acrylate. The organic layer was washed successively with saturated brine, saturated aqueous sodium hydrogen carbonate solution, saturated aqueous ammonium chloride solution and brine. Anhydrous magnesium sulfate, activated carbon was added and the mixture was filtered and filtered. After the filtrate was concentrated to about 75 ml, isopropyl ether (2 〇〇 ml) was added dropwise, and after 30 minutes of mixing, the precipitated crystals were collected by filtration. The crystals are washed with isopropyl ether and dried under reduced pressure to give N-(4-{2-[5-(2-hydroxyethyl)nonphen-2-yl]ethyl}thiazole-2 as a white crystal. -yl)acetamide (7·684g, 25.92mmol, yield 94.3%) 〇Step 8

於〇°C在N-(4-{2-[5-(2_羥基乙基）噻吩-2-基]乙基} 噻唑-基）乙醯胺（1· 200g，4· 048mmol)、（1，3-二酮基 319771 115 200835687 -1，3-—氫-2H-異吲哚-2-基）胺f酸三級丁酯（i. 327g， ，5.060 mmol)、三苯膦（h 646g，6〇72mm〇1)之無水四氬呋 喃（1 00ml)溶液中滴入偶氮二羧酸二乙酯（已從2· 2M甲苯 溶液2.76ml蒸餾去除溶劑者，6·〇7ππη〇1)之無水四氫呋喃 (5ml)溶液。一面從〇。〇緩緩升溫至室溫，同時攪拌15小 時。將反應液減壓濃縮後，將殘渣以矽膠管柱層析法（Fu〕· 土 SilysiaBW-300SP，350g，醋酸乙酯··己烷=1 ·· 1)精製後， 得到白色固體之[2-（5-{2-[2-（乙醯基胺基）—1，3-噻唑一4-❿基]乙基}嘆吩-2-基）乙基]-（1，3-二酮基一1，3-二氫一2H-異 吲哚-2-基）胺甲酸三級丁酯（1571§，2·9〇5_〇1，產率 71·8%)。 步驟9In N-(4-{2-[5-(2-hydroxyethyl)thiophen-2-yl]ethyl}thiazol-yl)acetamide (1·200 g, 4·048 mmol), ( 1,3-diketo group 319771 115 200835687 -1,3-1,3-hydrogen-2H-isoindol-2-yl)amine tri-butyl butylate (i. 327g, 5.060 mmol), triphenylphosphine (h 646g, 6〇72mm〇1) anhydrous tetrahydrofuran (100ml) solution was added dropwise diethyl azodicarboxylate (distilled from 2. 2ml of 2. 2M toluene solution to remove solvent, 6·〇7ππη〇1 A solution of anhydrous tetrahydrofuran (5 ml). One side from the embarrassment. 〇 Slowly warm to room temperature while stirring for 15 hours. After the reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (fu), soil, Silysia BW-300SP, 350 g, ethyl acetate·hexane = 1 · 1) to give a white solid. -(5-{2-[2-(ethinylamino)-1,3-thiazole- 4-indolyl]ethyl}indol-2-yl)ethyl]-(1,3-dione Base 1,3-dihydro-2H-isoindol-2-yl)carbamic acid tert-butyl butyl ester (1571 §, 2·9〇5_〇1, yield 71.8%). Step 9

⑩ 於—20 c在[2 —(5-{2-[2-(乙醯基胺基）-1，3-噻唑-4-基]乙基}噻吩-2-基）乙基]— (1，3 —二酮基q，3 —二氫一2Η一異 引0^ 2基）胺曱酸二級丁酯（i.57〇g，2· 904mmol )之無水四 氫呋喃（20ml)溶液中滴入甲基肼（〇· 19ml，3· 6匪〇1)。一面 從-20°C緩緩升溫至室溫同時攪拌7小時。將反應液減壓濃 縮後，將殘渣溶於二氯甲燒（3〇m 1)中，並過濾去除不溶物。 將濾液減壓濃縮後，將殘渣以矽膠管柱層析法（Fu j i10 at -20 c in [2 -(5-{2-[2-(ethylideneamino)-1,3-thiazol-4-yl]ethyl}thiophen-2-yl)ethyl]- ( 1,3 -dione-based q,3-dihydro- 2 Η-iso-doped 0^ 2 group) Amino phthalic acid secondary butyl ester (i.57〇g, 2·904mmol) in anhydrous tetrahydrofuran (20ml) Into methyl hydrazine (〇·19ml, 3. 6匪〇1). The temperature was gradually raised from -20 ° C to room temperature while stirring for 7 hours. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in methylene chloride (3 m) and filtered to remove insolubles. After the filtrate was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (Fu j i

Si lysia BW-300SP ’ 200g，醋酸乙酯：己烧=3: 2 至 2: 1)精製。將含目標物之區分減壓濃縮後，將殘渣溶於醋酸 116 319771 200835687 乙酯（50ml)中。將不溶物過濾去除後，將濾液濃縮，得到 白色固體之N-[2-(5-{2-[2-(乙醯基胺基）-1，3-噻唑-4-基]乙基}噻吩-2-基）乙基]肼羧酸三級丁酯（1· 〇68g，2· 601 mmol，產率 89. 6%)。 步驟1 0Si lysia BW-300SP '200g, ethyl acetate: hexane = 3: 2 to 2: 1) refined. After the concentration of the target substance was concentrated under reduced pressure, the residue was dissolved in ethyl acetate &lt;RTIgt;&lt;/RTI&gt; After the insoluble material was removed by filtration, the filtrate was concentrated to give N-[2-(5-{2-[2-(ethylamino)-1,3-thiazol-4-yl]ethyl} as a white solid. Thiophen-2-yl)ethyl]indolecarboxylic acid tert-butyl butyl ester (1·〇68 g, 2·601 mmol, yield 89.6%). Step 1 0

將N-[2-(5-{2-[2-(乙醯基胺基）一 1，3-噻唑-4-基]乙 基}嗟吩-2-基）乙基]肼羧酸三級丁酯（996· lmg, 2· 426mm〇1) 溶解於無水甲醇（15mi)、無水二氯甲烷（7. 5ml)之混合溶劑 中加入1M氯化氲乙^|溶液（364ml，36· 4mmo 1)，且在室 溫攪拌22小時。減壓濃縮後，將殘渣懸浮於無水***（50ml) 中。濾取析出物，並以無水***與醋酸乙酯洗淨。減壓乾 煉後，得到灰白色固體之粗鹽酸鹽（923· 9nig)。將粗鹽酸鹽 籲/合於水，谷液（25 ml)中後，加入飽和碳酸氳鈉水溶液（25 ml)加入艮鹽（7g)後，以醋酸乙酯萃取。將有機層通過活 性碳、無水硫酸鎂、CeUte過濾。將濾液注入順丁烯二酸 (1 9· 6mg 5· 338mmol)之醋酸乙酯（5mi )溶液中後，減壓濃 縮。將濃縮殘渣溶於無水甲醇(15ml)中後，加入***(2〇〇 ml)。濾取析出之結晶，並以***與醋酸乙酯洗淨後，減壓 乾燥。將結晶再次溶解於無水甲醇（15πι1)中後，加入醋酸 乙醋（20〇ml)。濾取析出之結晶，並以無水***與醋酸乙醋 洗淨。減壓乾職，得到淡黃色固體之標題化合物（糊.δ 319771 117 200835687 、mg，1· 080mmol，產率 44· 5%)。N-[2-(5-{2-[2-(Ethylamino)-1,3-thiazol-4-yl]ethyl}porphen-2-yl)ethyl]indolecarboxylic acid Butyl butyl ester (996·1mg, 2· 426mm〇1) was dissolved in a mixture of anhydrous methanol (15mi) and anhydrous dichloromethane (7.5ml). Add 1M cesium chloride solution (364ml, 36·4mmo) 1) and stirred at room temperature for 22 hours. After concentration under reduced pressure, the residue was crystallised from ethyl ether The precipitate was collected by filtration and washed with diethyl ether and ethyl acetate. After drying under reduced pressure, a crude white salt (yield: 923. After the crude hydrochloride salt was added to water and EtOAc (25 ml), EtOAc (EtOAc) The organic layer was filtered through activated carbon, anhydrous magnesium sulfate and EtOAc. The filtrate was poured into a solution of maleic acid (19.6 g of 5·338 mmol) in ethyl acetate (5 mi), followed by concentration under reduced pressure. After the concentrated residue was dissolved in anhydrous methanol (15 ml), diethyl ether The precipitated crystals were collected by filtration and washed with diethyl ether and ethyl acetate. After the crystals were redissolved in anhydrous methanol (15 π1), ethyl acetate (20 〇ml) was added. The precipitated crystals were collected by filtration and washed with diethyl ether and ethyl acetate. The title compound (paste: δ 319771 117 200835687, mg, 1.080 mmol, yield 44.5%) was obtained as a pale yellow solid.

'融點 13 5. 5 至 13 8 °C -NMR(200MHz, D20): δ(ρρπ〇: 6·77(2Η, d, J=3.5Hz), 6·70(1Η，s)，6·67 (2H, d, J=3.5Hz)，6·30(2Η, s)，3_36(2H, t-like), 3·13(4Η，t, J=6.9Hz), 2·96(2Η, t，J=6.9Hz), 2·25(3Η, s) 13C-NMR(50MHz, D20/DMS0-d6) ： δ (ppm) ： 173. 1, 172· 2, 160.0, 151· 5, 145· 3， 138· 3, 136· 7，127· 9, 126.7, 111.0, 53.5，33· 9, 30.3, 27· 0，23· 9 (製造例34) [(4-{2-[5-(3-肼基丙基）噻吩-2-基]乙基}-1，3-噻唑-2-基）乙醯胺鹽酸鹽之合成 _步驟1'melting point 13 5. 5 to 13 8 °C - NMR (200MHz, D20): δ(ρρπ〇: 6·77(2Η, d, J=3.5Hz), 6·70(1Η, s), 6· 67 (2H, d, J=3.5Hz), 6·30(2Η, s), 3_36(2H, t-like), 3·13(4Η,t, J=6.9Hz), 2·96(2Η, t, J=6.9 Hz), 2·25(3Η, s) 13C-NMR (50MHz, D20/DMS0-d6) : δ (ppm) : 173. 1, 172· 2, 160.0, 151· 5, 145· 3, 138· 3, 136· 7,127· 9, 126.7, 111.0, 53.5, 33· 9, 30.3, 27· 0, 23· 9 (Manufacturing Example 34) [(4-{2-[5-(3) -Mercaptopropyl)thiophen-2-yl]ethyl}-1,3-thiazol-2-yl)acetamide hydrochloride synthesis_Step 1

於0°C在N-(4-{2-[5-(3-羥基丙基）噻吩-2-基]乙基} -1，3-噻唑--2-基）乙醯胺（710· 〇mg，2· 287mmol)、（1，3-二 酮基-1，3-二氳-2H-異、。引哚-2-基）胺曱酸三級丁酯（750. 0 ⑩ mg，2.859mmol)、三苯膦（929.8mg，3· 545mmol)之無水四 氫吱喃（50ml)溶液中滴入偶氮二羧酸二乙酯（已從2·2Μ曱 苯溶液1.56ml蒸餾去除溶劑者，3· 43mm〇1)之無水四氫呋 喃（3· 0ml)溶液。在室溫攪拌14小時後，減壓濃縮。將濃 縮殘渣以石夕膠管柱層析法（j?u以lysia bw-300SP，130g， 醋酸乙酯·己烧=1 : 1)精製後，得到白色固體之（丨5一 [2-（2-乙醯基胺基—；[，3-噻唑-4一基）乙基]噻吩-2一基丨丙基） (1，3-二酮基-1，3-二氫-2H-異吲哚-2-基）胺甲酸三級丁酯 (871. 3mg，1· 571mmol，產率 68· 7%)。 319771 118 200835687 /步驟2N-(4-{2-[5-(3-hydroxypropyl)thiophen-2-yl]ethyl}-1,3-thiazol-2-yl)acetamide at 0 ° C (710· 〇mg, 2· 287mmol), (1,3-diketo-1,3-dioxin-2H-iso, fluoren-2-yl) aminate butyl citrate (750. 0 10 mg, 2.859 mmol), triphenylphosphine (929.8 mg, 3·545 mmol) in anhydrous tetrahydrofuran (50 ml) was added dropwise diethyl azodicarboxylate (distilled solvent from 1.56 ml of 2,2 benzene solution) A solution of 3·43 mm〇1) of anhydrous tetrahydrofuran (3.0 ml). After stirring at room temperature for 14 hours, it was concentrated under reduced pressure. The concentrated residue was purified by Shixi rubber column chromatography (j?u with lysia bw-300SP, 130 g, ethyl acetate·hexane = 1 : 1) to give a white solid (丨5一[2-(2) -Ethylamino--[,3-thiazol-4-yl)ethyl]thiophene-2-yl propyl) (1,3-dione-1,3-dihydro-2H-isoindole) Indole-2-ylamine carboxylic acid tert-butyl ester (871. 3 mg, 1.571 mmol, yield 68.7%). 319771 118 200835687 / Step 2

MeNHNH2 THFMeNHNH2 THF

iS 於-20 C在（3-{5-[2-(2-乙驢基胺基-1，3-σ塞峻-4-基） 乙基]嗟吩-2-基}丙基）（1，3-二酮基-1，3-二氳-211-異吲12朵 -2-基）胺甲酸三級丁酯（860· Omg，1· 550mmol)之無水四氫 吱喃（10ml)溶液中滴入曱基肼（〇· 1 1 · 9mmo 1)。升溫至 鲁室溫後，攪拌17小時。將反應液減壓濃縮後，加入*** (100ml)，並濾取不溶物。將不溶物以***洗淨後，將濾液 濃縮。將醋酸乙酯（30ml)加入至濃縮殘渣，並濾取不溶物。 將不溶物以醋酸乙酯洗淨後，將濾液濃縮。將濃縮殘渣以 矽膠管柱層析法（Fuji Silysia FL-60D，100g，醋酸乙酯： 己烷=1 : 1)精製後，得到白色結晶之-N-(3-{5-[2- (2-乙 醯基胺基-1，3-噻唑-4-基）乙基]噻吩-2-基}丙基）肼羧酸 •三級丁酯（由1H-NMR得到之純度分析值：約95· 3%，包含 2-曱基-2, 3-二氫酞畊-1，4-二酮，613. 8mg，純度成分 585mg，1· 38mmol，產率 88· 9%)。 步驟3iS is at -20 C in (3-{5-[2-(2-ethylamino)-1,3-σ-Shen-4-yl)ethyl] phenylphen-2-yl}propyl) ( Anhydrous tetrahydrofuran (10 ml) of 1,3-diketo-1,3-dioxin-211-isoindole 12-2-yl)carbamic acid tert-butyl butyl ester (860·Omg, 1·550 mmol) Indole hydrazine (〇·1 1 · 9mmo 1) was added dropwise to the solution. After warming to room temperature, it was stirred for 17 hours. After the reaction mixture was concentrated under reduced pressure, diethyl ether (100 ml) was added, and the insoluble material was filtered. After the insoluble material was washed with diethyl ether, the filtrate was concentrated. Ethyl acetate (30 ml) was added to a concentrated residue, and the insoluble material was filtered. After the insoluble matter was washed with ethyl acetate, the filtrate was concentrated. The concentrated residue was purified by silica gel column chromatography (Fuji Silysia FL-60D, 100 g, ethyl acetate:hexane = 1 : 1) to give white crystals of -N-(3-{5-[2- ( 2-Ethylamino-1,3-1,3-thiazol-4-yl)ethyl]thiophen-2-yl}propyl)indolecarboxylic acid • Tertiary butyl ester (purity analysis by 1H-NMR: approx. 95·3%, containing 2-mercapto-2,3-dihydroindole-1,4-dione, 613. 8 mg, purity component 585 mg, 1.38 mmol, yield 88·9%). Step 3

將N-(3-{5_[2-（2 -乙酿基胺基-1，3 -ϋ塞σ坐-4-基）乙基] 噻吩-2-基}丙基）肼羧酸三級丁酯（純度95. 3%，58(K Omg， 119 319771 200835687 純度成分1.30mmol)溶解於二氯甲烷（4mi)、曱醇（gml)之 混合溶劑中。加入1M氯化氳***溶液（19. 2ml，19. 2 匪〇1)，且在室溫攪拌1〇· 5小時後，減壓濃縮。將***（2〇ml) 加入至濃縮殘渣後，再次減壓濃縮，去除氯化氫。將*** (2Ora 1)加入至殘渣後過濾，並將所得之固體以乙_洗淨5 次。減壓乾燥後，得到白色固體之標題化合物（43〇.5mg， 1· 193mmol，產率 91· 6%)。 融點8 0至10 5 °C (融點不甚明確） •屯一NMR (200MHz, D20，DSS=Oppm): δ (ppm〉： 6·98(1Η，s), 6·74(1Η, d, J=3.4Hz)，6·71(1Η, d, J=3.4Hz), 3·25-3·05(6Η, m), 2·89(2Η, t, J=7.4Hz), 2.38(3H，s), 2·01(2Η, quintet, J=7.6Hz) 13C-NMR (50MHz, D20, DSS=Oppm) ： δ (ppm) : 174.3, 163.4, 144. 7, 143. 7, 127.9, 127.6, 112.9, 53.0, 32.1, 30.6, 28.8, 25.0, 21.8, 17.7 (試驗例1 ) 對於人類及大鼠之VAP-1酵素（SSAO)之酵素活性抑制效果 -關於在製造例中所得之本發明之化合物，以下述方 法，調查對於人類及大鼠之VAP—i酵素（SSA〇)之酵素活性 肇抑制效果。 在人類及大鼠兩者之VAP-1酵素（SSA0)活性係使用 C-本曱基胺作為人工基質經由放射化學-酵素檢驗測 定。從cDNA資料庫（library)純株化人類及大鼠VAP-1， 並將經表現之細胞萃取液與被驗化合物溶液（最終濃度1 χ 10 7 至 Ixl O—nmol/L)同時在室溫預培養（preincubate)2() 分。接著，添加14C-苯甲基胺（最終濃度lxl0-5mol/L)後， 以最終體積200 /z L，在37。〇培養2小時。加入2mol/L(200 #L)檸檬酸使酵素反應結束。將氧化產物萃取至lmL甲苯 319771 120 200835687 &gt; /醋酸乙酯（i : l)中，且以液體閃爍計數器測定其放射活 性。結果如表1及2所示。 如表1及2所示，本發明之化合物係顯著地抑制人類 及大鼠SSA0之酵素活性。N-(3-{5_[2-(2-Ethylamino-1,3-indole s-yt-4-yl)ethyl] thiophen-2-yl}propyl) ruthenium carboxylic acid Butyl ester (purity: 95.3%, 58 (K Omg, 119 319771 200835687 purity component 1.30 mmol) was dissolved in a mixed solvent of dichloromethane (4 mi) and decyl alcohol (gml). 2 ml, 19.2 匪〇1), and stirred at room temperature for 1 〇 5 hours, and concentrated under reduced pressure. diethyl ether (2 mL) was added to concentrated residue and then concentrated under reduced pressure to remove hydrogen chloride. (2Ora 1) was added to the residue and the residue was evaporated,jjjjjjjjjjjjjjjjjj Melting point 80 to 10 5 °C (melting point is not clear) • NMR (200MHz, D20, DSS=Oppm): δ (ppm>: 6·98 (1Η, s), 6.74 ( 1Η, d, J=3.4Hz),6·71(1Η, d, J=3.4Hz), 3·25-3·05(6Η, m), 2·89(2Η, t, J=7.4Hz) , 2.38(3H, s), 2·01(2Η, quintet, J=7.6Hz) 13C-NMR (50MHz, D20, DSS=Oppm) : δ (ppm) : 174.3, 163.4, 144. 7, 143. 7 , 127.9, 127.6, 112.9, 53.0, 32.1, 30 .6, 28.8, 25.0, 21.8, 17.7 (Test Example 1) Inhibitory effect on the enzyme activity of VAP-1 enzyme (SSAO) in humans and rats - the compound of the present invention obtained in the production example is as follows, Investigate the inhibitory effect on the enzyme activity of VAP-i enzyme (SSA〇) in humans and rats. The VAP-1 enzyme (SSA0) activity in both human and rat uses C-benzamide as an artificial substrate. Radiochemical-enzyme assay. Pure humanized human and rat VAP-1 from a cDNA library, and the expressed cell extract and test compound solution (final concentration 1 χ 10 7 to Ixl O-nmol) /L) Preincubate 2() at room temperature. Then, after adding 14C-benzylamine (final concentration lxl0-5mol/L), the final volume is 200 /z L, at 37. 2 hours. Add 2 mol/L (200 #L) citric acid to complete the reaction of the enzyme. The oxidation product was extracted into 1 mL of toluene 319771 120 200835687 &gt; / ethyl acetate (i: l), and its emission was measured by liquid scintillation counter. active. The results are shown in Tables 1 and 2. As shown in Tables 1 and 2, the compounds of the present invention significantly inhibited the enzyme activity of human and rat SSA0.

121 319771 200835687 [表1] •試管内試驗中之人類、大鼠SSA0(VAP-1)抑制活性 化合物 製造例“號 化學構造 ic50(&quot;m) 人類 大鼠 1 AcHN-&lt;l 0.1427 0,0716 2 AcHN-nfl Η 0.0016 0.0001 7 achn^jCMT 0.0038 0.0223 8 AcHN-^ 1 0 0.0035 0.0020 9 0 Ι^ΛνΑν.νη2 H - H 0.0511 0.0020 19 AcHNHSl Λ _ HCl NY〇V 0.0424 0.0010 20 0.0147 0.0002 21 achh-4 1 Η πα M i XXlr 0.0334 0.0011 22 AdiN—4S*ll H 2HCI n&quot;^nY^i 0 1Ι^Λ^Λ^ΝΗ2 0,0243 0.0026 23 0.0450 0.0015 122 319771 200835687 [表2] 試管内試驗中之人類、大鼠SSAO(VAP-1)抑制活性 化合物 製造例編號 化學構造 IC5〇(/iM) 人類 大鼠 24 0.0155 0.0280 25 0.0045 0.0001 26 0.0050 0.0011 27 0.0026 0.0004 29 ACHN^I 2HC, 0.0015 0.0010 30 0.0015 0Ό004 31 AcHN—2HCI ^XX^j、NH2 0.0050 0.0004 32 0.0016 0.0002 33 〔議 0.0011 0.0002 34 HCI 0.0090 0.0006 123 319771 200835687 (試驗例2) β對於大鼠之視網膜中MP-!酵素（SSA〇)之酵素活性抑制效 果 ^ 關於在製造例中所得之本發明之化合物及比較例，以 下述方法，調查對於大鼠之視網膜中VAP-1酵素（SSA〇)之 酵素活性抑制效果。 在斷食約20小時後，經由靜脈内注射在2_〇1/乙_ 檬酸緩衝液（PH4.5)中之50mg/mL/kg之鏈佐黴素 丁 • (Strept〇z〇t(^in)(STZ)誘發大鼠之糖尿病。依己酶激酶 (hexokinase)法檢查血漿葡萄糖濃度。在STZ處理後第3 天，診斷出大鼠為顯示血漿葡萄糖濃度在35〇mg/dl以上 之糖尿病。 在STZ處理後第7天，將被驗化合物溶液Umg/m〇 在大鼠後眼部做結膜下注射（〇〇5mg/eye)。在投予3小時 後採集視網膜，使用苯甲基胺（最終濃度ixi〇_5m〇i/L) ❿作為基質，經由放射化學—酵素檢驗測定視網膜中之 活性。結果如表3所示。 如表3所示，因投予本發明之化合物，而可觀疚到相 對於介質對照群，有效抑制視網膜中·酵素活性丁、。 319771 124 200835687 [表3] ’視網膜中SSA0活性 群 視網膜中SSAO活性 (pmol/min/mg protein) 介質對照 (比較例） Η (國際公開第2006/01 1 631 -製造例25) 1· 654 ± 〇. 199 製造例2 AeHN-&lt;Sl 〇 ULa严 Η 〇· 473 ± 〇· 204*氺 製造例29 AcHN-^fl 2Hci l 419 ± 〇·030氺 值係3隻大鼠之平均±s. E. M· ° 馨* * :表示由Dunnett檢試之藏著差異（P &lt; 〇· 〇 1對介質對照群之 對應值）。 * :表示由Dunnett檢試之顯著差異（P &lt; 〇· 05對介質對照群之對 應值）。 (試驗例3) 對於人類早胺氣化酶（ΜΑ0-Α及MAO-B)之酵素活性抑制六文 果 &quot; 關於在製造例中所得之本發明之化合物，以下述方 319771 125 200835687 法，調查對於人類單胺氧化酶（MAO-A及MAO-B)之酵素活性 '抑制效果。 基因重組之人類ΜΑ0-Α及ΜΑ0-Β酵素係取得自121 319771 200835687 [Table 1] • Human and rat SSA0 (VAP-1) inhibitory active compound production example in in-vitro test "No. chemical structure ic50 (&quot;m) human rat 1 AcHN-&lt;l 0.1427 0, 0716 2 AcHN-nfl Η 0.0016 0.0001 7 achn^jCMT 0.0038 0.0223 8 AcHN-^ 1 0 0.0035 0.0020 9 0 Ι^ΛνΑν.νη2 H - H 0.0511 0.0020 19 AcHNHSl Λ _ HCl NY〇V 0.0424 0.0010 20 0.0147 0.0002 21 achh- 4 1 Η πα M i XXlr 0.0334 0.0011 22 AdiN—4S*ll H 2HCI n&quot;^nY^i 0 1Ι^Λ^Λ^ΝΗ2 0,0243 0.0026 23 0.0450 0.0015 122 319771 200835687 [Table 2] In-tube test Human, rat SSAO (VAP-1) inhibitory active compound manufacturing example number chemical structure IC5〇(/iM) human rat 24 0.0155 0.0280 25 0.0045 0.0001 26 0.0050 0.0011 27 0.0026 0.0004 29 ACHN^I 2HC, 0.0015 0.0010 30 0.0015 0Ό004 31 AcHN—2HCI ^XX^j, NH2 0.0050 0.0004 32 0.0016 0.0002 33 [Consultation 0.0011 0.0002 34 HCI 0.0090 0.0006 123 319771 200835687 (Test Example 2) β Enzyme activity of MP-! enzyme (SSA〇) in rat retina In the compound of the present invention and a comparative example obtained in the production example, the inhibitory effect on the activity of the VAP-1 enzyme (SSA〇) in the retina of the rat was examined by the following method. After about 20 hours of fasting Intravenous injection of 50 mg/mL/kg of streptomycin butyl• (Strept〇z〇t(^in)(STZ) in 2_〇1/ citrate buffer (pH 4.5) Diabetes in rats. Plasma glucose concentrations were examined by the hexokinase method. On day 3 after STZ treatment, rats were diagnosed as having diabetes with a plasma glucose concentration of 35 〇 mg/dl or more. On the 7th day after the STZ treatment, the test compound solution Umg/m〇 was subconjunctival injection (〇〇5 mg/eye) in the posterior eye of the rat. The retina was collected 3 hours after the administration, and the activity in the retina was measured by a radiochemical-enzyme test using benzylamine (final concentration ixi 〇 5 m 〇 i / L) as a substrate. The results are shown in Table 3. As shown in Table 3, by administering the compound of the present invention, it was possible to effectively inhibit the activity of the enzyme in the retina by the relative control group. 319771 124 200835687 [Table 3] 'SSAO activity in the retina of the SSA0 active group in the retina (pmol/min/mg protein) Medium control (Comparative Example) Η (International Publication No. 2006/01 1 631 - Production Example 25) 1· 654 ± 199. 199 Production Example 2 AeHN-&lt;Sl 〇ULa strict 〇· 473 ± 〇· 204*氺 Manufacturing Example 29 AcHN-^fl 2Hci l 419 ± 〇·030氺 is the average ± s of 3 rats. E. M· ° 馨* * : Indicates the difference between the test by Dunnett (P &lt; 〇· 〇1 corresponds to the media control group). * : indicates a significant difference by the Dunnett test (P &lt; 〇 · 05 for the corresponding value of the media control group). (Test Example 3) Enzyme activity inhibition of human early amine gasification enzymes (ΜΑ0-Α and MAO-B). The compound of the present invention obtained in the production example was subjected to the following method 319771 125 200835687, The inhibitory effect on the enzyme activity of human monoamine oxidase (MAO-A and MAO-B) was investigated. Recombinant human ΜΑ0-Α and ΜΑ0-Β enzymes were obtained from

Sigma。人類 ΜΑ0-Α 及 ΜΑ0-Β 活性係使用 MAO DetectionSigma. Human ΜΑ0-Α and ΜΑ0-Β active systems use MAO Detection

Kit(Fluoro MAO，Cell Technology Inc·)測定。檢驗係在 96孔盤内實施。在各孔中添加ixReacti〇n buffer 4〇// L， 並且添加50# L之MAO-A或MAO-B。接著添加被驗化合物 溶液（最終濃度 lxHT5 至 lxl〇-i〇mol/L)1〇//L，在 37。(：培 ⑩養20分。添加Reacti〇ri cocktai 1 100 // L後，以最終體 積200 // L ’在37 C培養2小時。之後，使用Mul tispectralKit (Fluoro MAO, Cell Technology Inc.) measurement. The test was performed in a 96-well plate. Add ixReacti〇n buffer 4〇// L to each well and add 50# L of MAO-A or MAO-B. Next, the test compound solution (final concentration lxHT5 to lxl〇-i〇mol/L) was added at 1 〇//L at 37. (: Pei 10 raises 20 points. After adding Reacti〇ri cocktai 1 100 // L, it is incubated for 2 hours at 37 C with a final volume of 200 // L '. After that, use Mul tispectral

Microplate Reader (Varioskan ^ Thermo FisherMicroplate Reader (Varioskan ^ Thermo Fisher

Scienti f ic) ’以激發光57〇顏，偵測59Q·之螢光。結果 如表4所示。 胃如表4所示，本發明之化合物對於人類Μ〇—Μ〇-β ^ ”属不頌著之抑制作用。因實際上不會對其它單胺氧化酶 ⑩1不抑制作用’故得知本發明之化合物對SSA0顯示有選擇 特異性之抑制作用。 126 319771 200835687 [表4] 、對於人類單胺氧化酶（MAO-A及ΜΑ0-Β)之酵素活性抑制*文Scienti f ic) ' Detects the light of 57, and detects the fluorescence of 59Q·. The results are shown in Table 4. As shown in Table 4, the compound of the present invention has an inhibitory effect on human Μ〇-Μ〇-β ^ ”. Since it does not actually inhibit other monoamine oxidase 101, the compound of the present invention is known. SSA0 showed selective inhibition of specificity. 126 319771 200835687 [Table 4], inhibition of enzyme activity of human monoamine oxidase (MAO-A and ΜΑ0-Β)

一本發明係提供有用於作為VAP-1抑制劑之如式 不之化合物或其醫藥上所容許之鹽、醫藥組成物、龙）所 水廬及通透性宄進疾病等VAP-1相關疾病之=部 療用醫藥等 員防或治The present invention provides a VAP-1 related disease such as a compound of a VAP-1 inhibitor or a pharmaceutically acceptable salt thereof, a pharmaceutical composition, a dragon, and a hypertonic permeable disease. = partial treatment, medical treatment, etc.

Rf—ΝΗ—Χϋ (|》 (式中，各記號係同上述之定義）。 [相關申請案] 127 319771 200835687 本申請案係以在曰本所申請之專利申請案2 0 0 6 -325061號為基礎，其内容係皆包含於本說明書中。 【圖式簡單說明】 無 【主要元件符號說明】 無Rf—ΝΗ—Χϋ (|》 (where the symbols are the same as defined above). [Related application] 127 319771 200835687 This application is based on the patent application No. 2 0 06-325061 Based on the contents, the contents are included in this manual. [Simple description of the diagram] No [Main component symbol description] None

128 319771128 319771

Claims (1)

200835687 十、申請專利範圍： L 一種化合物或其醫藥上所容許之鹽，其係如式（丨）所厂、 者 不 R1 —-NH—X~γ—2 (|) {式中， Ri係醯基； X係從可經取代之噻唑所衍生之二價殘基； Y係式（111) J——L—M (III) [式中，J係鍵結、低級伸烧基、低級伸稀基、低級伸 炔基、-（CH2)n-〇-、-（CH2)n-NH-、-（CH2)n-C0-、或 -（CH2)n-S〇2-(各式中，n表示〇至β之整數）； L 係鍵結、—丽-、-C0-、或-S〇2-； Μ係鍵結、低級伸烷基、低級/伸烯基、或低級伸炔基； 惟’當 J 為-（CH2)n-0-時，L 不為—丽-及-S〇2-， 當J為-(CH2)n-NH-時，L不為-及—NH-，當j為 -（CH2)n-CO-時，L 不為-C0-，當 J 為—（CH2)n—s〇2-時，L 不為-〇-及-S〇2-(各式中，η表示與上述同義）]; Ζ係式（II) A~B——D—E ⑴） [式中，A係從苯所衍生之二價殘基、或從噻吩所衍生 之二價殘基； β 係-NR2-C0-、-（CH2)n-、或-(CH2)n〜C0-(各式中，R2 係 氫、低級烧基、或醢基；η表示〇至6之整數）； 319771 129 200835687 D係-NR3-(式中，R3表示氫、低級燒基、垸氧基幾基、 或酿基）； E表示可經取代之胺基]}。 2·如申請專利範圍第1項之化合物或其醫藥上所容許之 鹽，其中，該式（I)所示之化合物係N-{4-[2-(4-耕基 幾基苯基）乙基]-1，3 -嗟嗤-2-基}乙酿胺、 N-{4 - [2-(4-肼基幾基甲基苯基）乙基]-1，3-π塞。坐一 2 一基} 乙醯胺、 Ν-（4-{2-[4-(Ν’ -曱基肼基羰基甲基）苯基]乙基} —l 3一 噻唑-2-基）乙醯胺、 Ν-(4 - {2 - [4 -（Ν-甲基肼基羰基曱基）苯基]乙基卜l 3一 噻唑-2-基）乙醯胺、 Ν-（4- {2-[4 -（Ν’ -乙基肼基藏基甲基）苯基]乙基卜1，3一 ϋ塞π坐—2-基）乙醢胺、 -· Ν-（4- {2 - [4-（Ν’，Ν’ -二曱基肼基獄基曱基）苯基]乙基} -1，3-1?塞°坐-2-基）乙酿胺、 Ν-{ 4-[2-（4-耕基幾基甲基苯基）乙基]- 5 -（4-胺石黃酸基 苯曱基）-1，3-噻唑-2-基}乙醯胺、 Ν-（4-{2-[4_(2-肼基羰基乙基）苯基]乙基}-1，3-噻哇 -2-基）乙醯胺、 4-（4-{2-[2-(乙醯基胺基）-1，3-噻唑-4-基]乙基}苯基） 半卡肼、 Ν-(4-{2-[4-(Ν’ -乙醯基肼基羰基曱基）苯基]乙基} -1，3 - °塞σ坐-2 -基）乙酿胺、 130 319771 200835687 N -（4-{2-[4-(N’ -丁醯基肼基羰基曱基）苯基]乙基} -1，3-噻唑-2-基）乙醯胺、 N -（4-{2-[4-（Ν’ -癸醯基肼基羰基曱基）苯基]乙基} -1，3-噻唑-2-基）乙醯胺、 Ν-[4-（2-{4-[Ν’ -（3-羥丙醯基）肼基羰基曱基]苯基}乙 基）-1，3-噻唑-2-基]乙醯胺、 Ν-[ 4-（2-{4-[Ν’ -(6-羥己醯基）肼基羰基曱基]苯基}乙 基）-1，3-嘆唾-2-基]乙醯胺、 2-[(4 - {2 - [2-(乙醯基胺基）-1，3-嘆唾-4-基]乙基}苯 基）乙醯基]肼羧酸乙酯、 2-[(4-{2-[2-(乙醯基胺基）-1，3-噻哇-4-基]乙基}笨 基）乙醯基]肼羧酸丁酯、 2-[ (4-{2-[2-（乙醯基胺基）-1，3-售嗤-4-基]乙基}笨 基）乙酿基]耕叛酸癸酯、 -· 2-[(4-{2-[2-(乙醯基胺基）-1，3-噻唑-4-基]乙基}苯 基）乙酿基]拼叛酸2 -經乙醋、 2-乙醯基胺基-1，3-噻唑-4-羧酸4-(肼基羰基甲基）苯 酯、 Ν -（4-{[4-（肼基羰基曱基）苯氧基]曱基卜；[，3一嗔唾〜2一 基）乙醯胺、 2-（乙醢基胺基）- Ν- [4-（肼基幾基甲基）苯基]一；唉 唑-4-曱醯胺、 Ν-[4-（{[4-（肼基羰基甲基）苯基]胺基}曱基）一！，3 —嗟 唑-2-基]乙醯胺、 319771 131 200835687 N-{4-[2-（3-肼基羰基甲基苯基）乙基]一i，3 —噻唑—2-基} 乙醯胺、 N-（4-{2-[5-(肼基羰基）噻吩-2-基]乙基}一1，3-噻唑 -2-基）乙醯胺、 N-(4-{2-[5-（肼基羰基甲基）噻吩一2-基]乙基}一1，3一嗟 唑-2-基）乙醯胺、 N-(4-{2-[5-(2-肼基羰基乙基）嗟吩—2-基]乙基}一1，3-噻唑-2-基）乙醯胺、 _ ^(4-{2-[5-(2-肼基魏基乙基）嗟吩一3-基]乙基}一1，3一 嗟嗤-2 -基）乙醯胺、 N - {4-[2 -（4 -朋1基苯基）乙基]-1，3 -嗟嗤- 2-基}乙酿胺、 N-（4- {2 - [4-（肼基曱基）苯基]乙基}-1，3-嗟唾一2-基） 乙醯胺、 / N-(4-{2-[4-(2-肼基乙基）苯基]乙基} —ι，3~π塞峻一2 —基） 乙酿胺、 φ Ν-(4-{2-[4-(3-肼基丙基）苯基]乙基} —1，3-嘆唾一 2-基） 乙醯胺、 Ν-（4-{2-[3-(2-肼基乙基）苯基]乙基} — !，3-嘆唾-2-基） 乙醢胺、 Ν-（4-{2-[5-(2-肼基乙基）嗟吩-2-基]乙基}-1，3-嗟嗤 -2-基）乙醯胺、或 Ν-(4-{2-[5-(3-肼基丙基）噻吩-2-基]乙基}-1，3-噻唑 -2-基）乙醢胺。 3·如申請專利範圍第1項之化合物或其醫藥上所容許之 132 319771 200835687 鹽，其中，該式⑴所示之化合物係Ν-{4-[2-(4-肼美 幾基甲基苯基）乙基]~1，3-嗟唾-2-基}乙醯胺。^ 4.如申請專利範圍第！項至第3項中任一項之化合物或並 醫藥上所容許之鹽，其係作為醫藥使用。 5·種面‘組成物’其係含有申請專利範圍帛！項至第3 員中任貞之化合物或其醫藥上所容許之鹽作為活性 成分。 6· .種VAP 1抑制劑’其係含有申請專利範圍第工項至第 3項中任-項之化合物或其醫藥上所容許之鹽作為活 性成分。 7. 種VAP-1相關疾病之預防或治療用醫藥，其係含有申 請專利範圍第i項至第3項中任—項之化合物或1醫率 上所容許之鹽作為活性成分。 ’、 8. 如=專利範圍第7項之VAIM相關疾病之預防或治療 用醫樂，其中，該VAP-1相關疾病係黃斑部水腫（糖尿 病性及非糖尿病黃斑部水腫）、老年性黃斑部退化、老 年性盤狀黃斑部退化、囊狀黃斑部水腫、眼驗水腫、視 、、：尺腫糖尿病性視網膜病變、脈絡視網膜病變、新 生=管性黃斑部病變、新生血管性青光目艮、葡萄臈炎、 虹膜火、視網臈血管炎、眼内炎、全眼球炎、轉移性眼 ^、^絡膜炎、i網膜色素上皮炎、結膜炎、睫狀體炎、 革，炎、上鞏膜炎、視神經炎、球後視神經炎、角膜炎、 眼知炎、苓出性視網膜剝離、角膜潰瘍、結膜潰瘍、斤 性錢幣狀角膜炎、塞格森氏角膜炎、進行性侵㈣角^ 319771 133 200835687 潰瘍、由細菌感染或病毒感染及由眼科手術引起之眼炎 性疾病、由目艮睛之物理性損傷引起之眼炎性疾病、由包 括瘩、發紅、水腫及潰瘍之眼炎性疾病引起之症狀、紅 斑、多形性滲出性紅斑、結節性紅斑、環狀紅斑、硬腫 症、皮膚炎（乾癬、過敏性病變、扁平苔癬、玫瑰糠疹、 接觸性皮膚炎、異位性皮膚炎、毛囊性紅色糠療）、血 管神經病性水腫、咽喉水腫、聲門水腫、聲門下咽喉炎、 支氣管炎、鼻炎、咽喉炎、鼻竇炎及咽喉炎或中耳炎、 肝硬化、原發性固定性高血麗、糖尿病、動脈硬化、（糖 尿病、動脈硬化及高血壓之）内皮損傷、糖尿病及尿毒 症相關之心血管疾病、痛風及關節炎相關之疼痛、結締 組織之炎性疾病或症狀（類風濕性關節炎、僵直性脊椎 炎、乾癬性關節炎及骨關節炎或退化性關節疾病、萊特 =候群、修格蘭氏症候群、貝塞特氏症候群、復發性 多軟骨炎、全身性紅斑性狼瘡、圓盤狀紅斑性狼瘡、全 _身性硬化症、嗜酸性筋膜炎、多發性肌炎、皮肌炎、風 ^性^肌痛症、血管炎、暫時性關節炎、結節性多動脈 炎、韋格納氏肉芽腫病、混合結締組織疾病及幼年型類 =濕性關節炎消化管之炎性疾病或症狀[克隆氏病、、 &gt;貝瘍性大腸炎、腸躁症（痙攣性結腸）、肝臟之纖維化、 口腔黏膜之發炎（口内炎及復發性口瘡口内炎）];中樞 神經系統之炎性疾病或症狀（多發性硬化症、阿滋海默 症、、及缺血性中風相關之缺血再灌流障礙）；肺炎性疾 病或症狀（氣喘、成人呼吸窘迫症候群、慢性阻塞性肺 319771 134 200835687 疾=);包括微血管及大血管之疾病（動脈硬化、視網膜 病又、月病、腎病症候群及神經障礙（多發性神經障礙、 單-神經障礙及自律神經障礙）、足潰瘍、關節之問題 及感染風險之增加）之碳水化合物代謝相關疾病（糖尿 病及來自糖尿病之併發症）；月旨肪細胞之分化或機能或 者平滑肌—細胞之機能之異常相關之疾病（動脈硬化及肥 大），血管疾病[包括動脈粥狀硬化、非動脈粥狀硬化、 心肌梗塞及周邊動脈阻塞之缺血性心臟疾病、雷諾氏症 及雷，氏現象、阻塞性血栓性血管炎（柏格氏症慢 性關筇久’ x性腸疾病，或SSA〇媒介併發症[糖尿病（胰 島素依賴型糖尿病（IDDM)及非胰島素依賴型糖尿病 (NI_))及血管併發症(心臟病發作、狹心症、中風、 切除、失明及腎功能不全）]。 9. 一種巾請專利範圍第1項至第3項中任—項之化合物或 其醫藥上所容許之鹽之使用，其係用於製造作為VApq _ 抑制劑之醫藥。 1〇·-種巾請專利範圍第1項至第3項中任—項之化合物或 其醫藥上所容許之鹽之使用，其係用於製造咐]相關 疾病之預防或治療用醫藥。 U.如申請專利範圍第10項之使用’其中，該ΜΗ相關 疾病係黃斑部水腫（糖尿病性及非糖尿病黃斑部水 腫老年性黃斑部退化、老年性盤狀黃斑部退化、囊 狀黃斑部水腫、眼驗水腫、視賴水腫、糖尿病性視網 臊病變、脈絡視網膜病變、新生血管性黃斑部病變、新 319771 135 200835687 生血T性青光眼、葡萄膜炎、虹膜炎、視網膜血管炎、 ::炎：全眼球炎、轉移性眼炎、脈絡膜炎、視：：色 [、皮炎、結膜炎、睫狀體炎、鞏膜炎、上鞏膜炎、、 :f f、球後視神經炎'角膜炎、眼瞼炎、滲出：視： 、j離、角膜潰瘍、結膜潰瘍、慢性錢幣狀角膜炎、夷 ^，角膜炎、進行性侵姓性角膜潰瘍、由細菌感染或 力毋，染及由眼科手術引起之眼炎性疾病、由眼睛之物 =性損傷引起之眼炎性疾病、*包括癢、發紅、水腫及 ’貝瘍之目:炎性疾病引起之症狀、紅斑、多形性滲出性紅 、、、Q即性紅斑、環狀紅斑、硬腫症、皮膚炎（乾癖、 匕破性病變、扁平苔癖、玫瑰糠疹、接觸性皮膚炎、異 (生皮膚夂、毛囊性紅色糠疹）、血管神經病性水腫、 。口侯水腫、聲門水腫、聲門下咽喉炎、支氣管炎、鼻炎、 =f、鼻竇炎及咽喉炎或中耳炎、肝硬化、原發性固 、糖尿病、動脈硬化、（糖尿病、動脈硬化 回血麗之）内皮損傷、糖尿病及***相關之心血管 =病、痛風及關節炎相關之疼痛、結缔組織之炎性疾病 :症狀（類風濕性關節炎、僵直性脊椎炎、乾癬性關節 =及骨關節炎m性㈣疾病、料氏症候群、修格 闌氏症候群、貝塞特氏症候群、復發性多軟骨炎、全身 =紅斑性祕、圓盤狀紅斑性狼瘡、全身性硬化症、嗜 筋膜炎、多發性肌炎、皮肌炎、風濕性多肌痛症、 =炎、暫時性關節炎、結節性多動脈炎、韋格納氏肉 牙病、混合結締組織疾病及幼年型類風濕性關節 319771 136 200835687 炎）；消化管之炎性疾病或症狀[克隆氏病、潰瘍性大腸 炎、腸踪症（痙攣性結腸）、肝臟之纖維化、口腔黏膜之 發炎（口内炎及復發性口瘡口内炎）];中柩神經系統之 炎性疾病或症狀（多發性硬化症、阿滋海默症、及缺血 性中風相關之缺血再灌流障礙）；肺炎性疾病或症狀'(氣 喘、成人呼吸窘迫症候群、慢性阻塞性肺疾病）；包括 u血f及大血管之疾病（動脈硬化、視網膜病變、腎病、 腎病症候群及神經障礙（多發性神經障礙、單一神經障 礙及自律神經障礙）潰瘍、，之問題及感染驗 之增加）之碳水化合物代謝相關疾病（糖尿病及來自糖 尿病之併發症）；脂肪細胞之分化或機能或者平滑肌細 胞之機能之異常相關之疾病（動脈硬化及肥大）；血管疾 病[包括動脈粥狀硬化、非動脈粥狀硬化、心肌梗塞及 周政動脈阻基之缺血性心臟疾病、雷諾氏症及雷諾氏現 象阻基性血栓性血管炎（柏格氏症）];慢性關節炎； 火性腸疾病；或SSA0媒介併發症[糖尿病（胰島素依賴 唐尿病（IDDM)及非胰島素依賴型糖尿病⑻麵乃及 血f併么症(〜臟病發作、狹心症、中風、切除、失明 及腎功能不全）]。 12·斤種，對對象之VAIM之抑制方法，係包括將申請專利 車巳圍弟1項至第3項中任一項之化合物或其醫藥上所容 許之鹽之有效量投予該對象。 •種、'十對對象之相關疾病之預防或治療方法，僞 包括將申請專利範圍第1項至第3項中任一項之化合物 319771 137 200835687 或其醫藥上所容許之鹽之有效量投予該對象。 14.如申請專利範園第！ 3項之v A p 相關疾病之預防或治 療方法，其中，該VAfMw關疾病係黃斑部水腫（糖尿 病性及非糖尿病黃斑部水腫）、老年性黃斑部退化、老 树盤狀黃斑部m狀黃斑部水腫、⑽水腫、視 網膜水腫、糖尿病性視網膜病變、脈絡視網膜病變、新 生血管性黃斑部病變、新生血管性青光眼、葡萄膜炎、 虹膜炎、視網膜血管炎、眼内炎、全眼球炎、轉移性眼 炎、脈絡膜炎、視網膜色素上皮炎、結膜炎、睫狀體炎、 鞏膜炎、上鞏膜炎、視神經炎、球後視神經炎、角膜炎、 眼驗炎、滲出性視網膜剝離、角膜潰瘍、結膜潰癌、慢 =錢瞥狀角膜炎、塞格森氏角膜炎、進行性侵錄角膜 /貝瘍由細菌感染或病毒感染及由眼科手術引起之眼炎 性疾病、由眼睛之物理性損傷引起之眼炎性疾病、由包 括癢、發紅、水腫及潰瘍之眼炎性疾病引起之症狀、紅 斑、多形性參出性紅斑、結節性紅斑、環狀紅斑、硬腫 症、皮膚炎（乾癬、過敏性病變、扁平苔癬、玫瑰糠疹、 ，觸性皮膚炎、異位性皮膚炎、毛囊性紅色縣）、血 管神經病性水腫、咽喉水腫、聲門水腫、聲門下咽喉炎、 支氣管炎、鼻炎、咽喉炎、鼻竇炎及咽喉炎或中耳炎、 肝硬化、原發性固定性高血壓、糖尿病、動脈硬化、（糖 尿病、動脈硬化及高血壓之）内皮損傷、糖尿病及尿毒 症相關之心血管疾病、痛風及關節炎相關之疼痛、結締 組織之炎性疾病或症狀（類風濕性關節炎、僵直性脊椎 138 319771 200835687 y 火、乾癬性關節炎及骨關節炎或退化性關節疾病、菜特 , ^症候群、修格蘭氏症候群、貝塞特氏症候群、復發性 夕車人月义、王身性紅斑性狼瘡、圓盤狀紅斑性狼瘡、全 身性硬化症、嗜酸性筋膜炎、多發性肌炎、皮肌炎、風 濕性多肌痛症、血管炎、暫時性關節炎、結節性多動脈 炎、韋格納氏肉芽腫病、混合結缔組織疾病、及幼年型 類風濕性關節炎）；消化管之炎性疾病或症狀[克隆氏 病、頃瘍性大腸炎、腸躁症（痙攣性結腸）、肝臟之纖維 ⑩化、口腔黏膜之發炎（口内炎及復發性口瘡口内炎）]; 中樞神經系統之炎性疾病或症狀（多發性硬化症、阿滋 海默症、及缺血性中風相關之缺血再灌流障礙）；肺炎 性疾病或症狀（氣喘、成人呼吸窘迫症候群、慢性阻塞 性肺疾病）；包括微血管及大血管之疾病（動脈硬化、視 /網膜病變、腎病、腎病症候群及神經障礙（多發性神經 障礙、單一神經障礙及自律神經障礙）、足潰瘍、關節 # 之問題及感染風險之增加）之碳水化合物代謝相關疾病 (糖尿病及來自糖尿病之併發症）；脂肪細胞之分化或機 能或者平滑肌細胞之機能之異常相關之疾病（動脈硬化 及肥大）；血管疾病[包括動脈粥狀硬化、非動脈粥狀硬 化、心肌梗塞及周邊動脈阻塞之缺血性心臟疾病、雷諾 氏症及雷祐氏現象、阻塞性血栓性血管炎（柏格氏 症）];慢性關節炎；炎性腸疾病；或SSA〇媒介併發症[糖 尿病（胰島素依賴型糖尿病（IDDM)及非胰島素依賴型糖 尿病（NIDDM))及血管併發症（心臟病發作、狹心症、中 319771 139 200835687 i 風、切除、失明及腎功能不全）]。200835687 X. Patent application scope: L A compound or a pharmaceutically acceptable salt thereof, which is a plant of the formula (丨), not R1 —-NH—X~γ—2 (|) {wherein, Ri醯 base; X is a divalent residue derived from a substituted thiazole; Y is a formula (111) J——L—M (III) [wherein, J-bonding, low-stretching, low-level stretching Dilute, lower alkynyl, -(CH2)n-〇-, -(CH2)n-NH-, -(CH2)n-C0-, or -(CH2)nS〇2- (in each formula, n An integer of 〇 to β); an L-bond, a ——, a —C0-, or a —S〇2-; a lanthanide linkage, a lower alkylene group, a lower/alkenyl group, or a lower alkynyl group; However, when J is -(CH2)n-0-, L is not -Li- and -S〇2-, when J is -(CH2)n-NH-, L is not - and -NH-, When j is -(CH2)n-CO-, L is not -C0-, and when J is -(CH2)n-s〇2-, L is not -〇- and -S〇2-(various Wherein, η means synonymous with the above); lanthanide (II) A~B——D-E (1)) [wherein, A is a divalent residue derived from benzene or a divalent derived from thiophene Residue; β-NR2-C0-, -(CH2)n-, Or -(CH2)n~C0- (in each formula, R2 is hydrogen, lower alkyl or fluorenyl; η represents an integer from 〇 to 6); 319771 129 200835687 D-NR3-(wherein R3 represents hydrogen , a lower alkyl group, a decyloxy group, or a aryl group; E represents a substituted amino group]}. 2. A compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (I) is N-{4-[4-(4-peptidylphenyl)B Base]-1,3-indol-2-yl}ethinylamine, N-{4-[2-(4-mercaptomethylphenyl)ethyl]-1,3-π. Sodium 2-yl} acetamidine, Ν-(4-{2-[4-(Ν'-fluorenylcarbonylcarbonylmethyl)phenyl]ethyl}-l 3-thiazol-2-yl) Indoleamine, Ν-(4 - {2 - [4 -(Ν-methylhydrazinocarbonyl)phenyl]ethyl]l 3 -thiazol-2-yl)acetamide, Ν-(4- { 2-[4 -(Ν'-ethyl-hydrazinomethyl)phenyl]ethyl bromide, 1,3-anthracene π-sodium 2-yl acetamide, -· Ν-(4- {2 - [4-(Ν',Ν'-二曱基肼基基基基)phenyl]ethyl} -1,3-1????-2-yl)Ethylamine, Ν-{ 4 -[2-(4-Trynylmethylphenyl)ethyl]-5-(4-amine-carhenylbenzoyl)-1,3-thiazol-2-yl}acetamide, hydrazine- (4-{2-[4_(2-mercaptocarbonylethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide, 4-(4-{2-[2- (Ethylamino)-1,3-thiazol-4-yl]ethyl}phenyl) Semicarbazone, Ν-(4-{2-[4-(Ν'-ethylhydrazinocarbonylcarbonylhydrazine) Base) phenyl]ethyl} -1,3 - ° sigma -2 -yl) ethanoamine, 130 319771 200835687 N -(4-{2-[4-(N'-butenyl fluorenylcarbonyl) Phenyl]ethyl}-1,3-thiazol-2-yl)acetamide, N -(4-{2-[4-(Ν'-indolylcarbonylcarbonyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide, Ν-[4- (2-{4-[Ν(-hydroxypropionyl)nonylcarbonylindenyl]phenyl}ethyl)-1,3-thiazol-2-yl]acetamide, Ν-[ 4- (2-{4-[Ν-(6-hydroxyhexyl)hydrazinocarbonylindenyl]phenyl}ethyl)-1,3-snex-2-yl]acetamidamine, 2-[( 4-{2-[2-(Ethylamino)-1,3-suppur-4-yl]ethyl}phenyl)ethinyl]hydrazinecarboxylate, 2-[(4-{ 2-[2-(Ethylamino)-1,3-thiazol-4-yl]ethyl}phenyl)ethyl hydrazide] butyl carboxylic acid, 2-[ (4-{2-[ 2-(Ethylamino)-1,3-(indolyl-4-yl)ethyl}indolyl]-branched oleic acid ester, -· 2-[(4-{2-[2 -(Ethylamino)-1,3-thiazol-4-yl]ethyl}phenyl)ethyl]dithioresin 2 - acetonitrile, 2-ethylhydrazino-1,3- 4-(indolylcarbonylmethyl)phenyl ester of thiazole-4-carboxylic acid, Ν-(4-{[4-(fluorenylcarbonylfluorenyl)phenoxy]indolyl; [, 3 嗔 〜~2 Alkylamine, 2-(ethenylamino)-indole-[4-(indolylmethyl)phenyl]- oxazol-4-indole Amine, Ν- [4 - ({[4- (hydrazino carbonyl) phenyl] amino} Yue-yl) a! , 3 —oxazol-2-yl]acetamide, 319771 131 200835687 N-{4-[2-(3-mercaptocarbonylmethylphenyl)ethyl]-i,3-thiazole-2-yl} Acetamine, N-(4-{2-[5-(fluorenylcarbonyl)thiophen-2-yl]ethyl}-1,3-thiazol-2-yl)acetamide, N-(4-{ 2-[5-(indolylcarbonylmethyl)thiophene-2-yl]ethyl}-1,3-azoxazol-2-yl)acetamide, N-(4-{2-[5-(2) - mercaptocarbonylethyl) porphin-2-yl]ethyl}-1,3-thiazol-2-yl)acetamide, _ ^(4-{2-[5-(2-mercapto-Weiylethyl)嗟-3-yl]ethyl}- 1,3-indol-2-yl)acetamidamine, N-{4-[2-(4-p-phenylphenyl)ethyl]-1, 3 -嗟嗤- 2-yl}ethinylamine, N-(4-{2 -[4-(indolyl)phenyl]ethyl}-1,3-indolyl-2-yl)acetamidine Amine, / N-(4-{2-[4-(2-mercaptoethyl)phenyl]ethyl} - ι, 3~π 塞 一 2 - yl) Ethylamine, φ Ν-(4 -{2-[4-(3-Mercaptopropyl)phenyl]ethyl}-1,3-suppressyl-2-yl) acetamidine, Ν-(4-{2-[3-(2 -mercaptoethyl)phenyl]ethyl} — !,3-suppressin-2-yl) acetamidine, Ν-(4-{2-[5-(2-mercaptoethyl)嗟-phen-2-yl]ethyl}-1,3-indol-2-yl)acetamide, or Ν-(4-{2-[5-(3-mercaptopropyl)thiophene-2- Ethyl]ethyl}-1,3-thiazol-2-yl)acetamide. 3. The compound of claim 1 or the pharmaceutically acceptable 132 319771 200835687 salt thereof, wherein the compound represented by the formula (1) is Ν-{4-[2-(4-carbamicidylmethyl) Phenyl)ethyl]~1,3-indole-2-yl}acetamide. ^ 4. If you apply for a patent scope! A compound or a pharmaceutically acceptable salt thereof according to any one of the items 3 to 3, which is used as a medicine. 5. The type of ‘composition’ contains the scope of the patent application! The compound to the third member of the present invention or a pharmaceutically acceptable salt thereof is used as an active ingredient. 6. A VAP 1 inhibitor which is a compound containing a compound of any one of the claims to the third aspect of the invention, or a pharmaceutically acceptable salt thereof, as an active ingredient. A medicament for the prophylaxis or treatment of a VAP-1-related disease, which comprises a compound of any one of items i to 3 of the patent application or a salt permissible at a therapeutic rate as an active ingredient. ', 8. For the prevention or treatment of VAIM-related diseases according to item 7 of the patent scope, the VAP-1 related diseases are macular edema (diabetic and non-diabetic macular edema), senile macular area Degenerative, senile discoid macular degeneration, cystic macular edema, ophthalmologic edema, visual, ulnar edema, diabetic retinopathy, choroidal retinopathy, neonatal = ductal macular degeneration, neovascular glaucoma , grape sputum inflammation, iris fire, retinal vasculitis, endophthalmitis, total ocular inflammation, metastatic eye ^, ^ colitis, i omental pigment epitheliitis, conjunctivitis, ciliary body inflammation, leather, inflammation, upper Scleritis, optic neuritis, retrobulbar optic neuritis, keratitis, ophthalmia, purulent retinal detachment, corneal ulcer, conjunctival ulcer, sputum keratitis, Sengex's keratitis, progressive invasion (four) angle ^ 319771 133 200835687 Ulcer, infection by a bacterium or virus, ocular inflammatory disease caused by ophthalmic surgery, ocular inflammatory disease caused by physical damage caused by eyesight, including sputum, redness, edema and ulceration Symptoms caused by inflammatory diseases of the eye, erythema, polymorphous exudative erythema, nodular erythema, ring erythema, scleredema, dermatitis (dryness, allergic disease, lichen planus, pityriasis rosea, contact skin) Inflammation, atopic dermatitis, follicular red sputum), vascular neuropathic edema, sore throat, glottic edema, subglottic pharyngitis, bronchitis, rhinitis, pharyngitis, sinusitis and pharyngitis or otitis media, cirrhosis, Primary fixed hypercholemia, diabetes, arteriosclerosis, endothelial damage (diabetes, arteriosclerosis and hypertension), cardiovascular disease associated with diabetes and uremia, pain associated with gout and arthritis, inflammation of connective tissue Disease or symptom (rheumatoid arthritis, ankylosing spondylitis, dry arthritis and osteoarthritis or degenerative joint disease, Wright = group, repairing Gram's syndrome, Beckett's syndrome, recurrent multi-cartilage Inflammation, systemic lupus erythematosus, discoid lupus erythematosus, all-body sclerosis, eosinophilic fasciitis, polymyositis, dermatomyositis, wind Muscular pain, vasculitis, temporary arthritis, nodular polyarteritis, Wegener's granulomatosis, mixed connective tissue disease and juvenile type = inflammatory disease or symptoms of digestive tract of wet arthritis [Clone Disease, &gt; benign colitis, intestinal fistula (sputum colon), fibrosis of the liver, inflammation of the oral mucosa (endophthalmitis and recurrent aphthous stomatitis)]; inflammatory disease or symptom of the central nervous system (multiple Sclerosing disease, Alzheimer's disease, and ischemic stroke-related ischemia-reperfusion disorder); pneumonia disease or symptom (asthma, adult respiratory distress syndrome, chronic obstructive pulmonary 319771 134 200835687 disease =); Microvascular and macrovascular diseases (arteriosclerosis, retinopathy, monthly disease, renal disease and neurological disorders (multiple neurological disorders, mono-neuropathic and autonomic neurological disorders), foot ulcers, joint problems and increased risk of infection) Carbohydrate metabolism-related diseases (diabetes and complications from diabetes); differentiation or function of the fat cells or smooth muscle-cells Abnormally related diseases (arteriosclerosis and hypertrophy), vascular diseases [including atherosclerosis, non-atherosclerosis, ischemic heart disease with myocardial infarction and peripheral arterial occlusion, Raynaud's disease and Ray's phenomenon, Obstructive thrombotic vasculitis (Berg's disease chronic Guanjiu's bowel disease, or SSA〇 vector complications [diabetes (insulin dependent diabetes mellitus (IDDM) and non-insulin dependent diabetes mellitus (NI_))) and vascular complications ( Heart attack, angina, stroke, resection, blindness and renal insufficiency)]. 9. A use of a compound according to any one of items 1 to 3 of the patent or a pharmaceutically acceptable salt thereof for the manufacture of a medicament as a VApq _ inhibitor. 1〇·--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- U. For use in the scope of claim 10, where the sputum-related diseases are macular edema (diabetic and non-diabetic macular edema, age-related macular degeneration, senile discoid macular degeneration, cystic macular edema) Ophthalmology, edema, edema, diabetic retinopathy, choroidal retinopathy, neovascular macular degeneration, new 319771 135 200835687 T-glaucoma, uveitis, iritis, retinal vasculitis, :: inflammation : total ocular inflammation, metastatic ophthalmia, choroiditis, visual:: color [, dermatitis, conjunctivitis, ciliary body inflammation, scleritis, upper scleritis, : ff, retrobulbar optic neuritis keratitis, orbital inflammation, Exudation: visual:, j, corneal ulcer, conjunctival ulcer, chronic coin keratitis, sputum, keratitis, progressive invasion of the cornea, infection by bacteria or sputum, infection and ophthalmia caused by ophthalmic surgery Sexual diseases, ocular inflammatory diseases caused by eye damage = sexual injury, *including itching, redness, edema, and 'beauty of the beasts: symptoms caused by inflammatory diseases, erythema, polymorphic exudation Red,,, Q, sexual erythema, ring erythema, scleredema, dermatitis (dry, smashed lesions, lichen planus, pityriasis rosea, contact dermatitis, different (skin sputum, hair follicle red) Pityriasis, vascular neuropathic edema, oral edema, glottic edema, subglottic pharyngitis, bronchitis, rhinitis, =f, sinusitis and pharyngitis or otitis media, cirrhosis, primary solid, diabetes, arteriosclerosis (diabetes, arteriosclerosis, blood stasis) endothelial damage, diabetes and uremia-related cardiovascular = disease, gout and arthritis-related pain, connective tissue inflammatory disease: symptoms (rheumatoid arthritis, stiffness) Spondylitis, Coronary Joints = and Osteoarthritis m (4) Diseases, Disease Syndrome, Strain Syndrome, Bethel's Syndrome, Recurrent Polychondritis, Whole Body = Erythema, Discoid Lupus , systemic sclerosis, fasciitis, polymyositis, dermatomyositis, rheumatic polymyalgia, = inflammation, temporary arthritis, nodular polyarteritis, Wegener's disease, mixed connective organization Disease and juvenile rheumatoid joints 319771 136 200835687 inflammation); inflammatory diseases or symptoms of the digestive tract [Clone's disease, ulcerative colitis, intestinal tract (sputum colon), fibrosis of the liver, inflammation of the oral mucosa (Endophthalmitis and recurrent aphthous stomatitis)]; inflammatory disease or symptom of the middle sacral nervous system (multiple sclerosis, Alzheimer's disease, and ischemic stroke-related ischemia-reperfusion disorder); pneumonia disease or Symptoms '(asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease); diseases including u blood and large blood vessels (arteriosclerosis, retinopathy, kidney disease, renal disease and neurological disorders (multiple neurological disorders, single neurological disorders and Carbohydrate-related diseases (diabetes and complications from diabetes); diseases of differentiation or function of fat cells or abnormalities of smooth muscle cells (arteriosclerosis) And hypertrophy); vascular disease [including atherosclerosis, non-atherosclerosis, Ischemic heart disease with muscular infarction and Zhouzheng arterial block, Raynaud's disease and Raynaud's phenomenon of thrombotic vasculitis (Berg's disease); chronic arthritis; fire intestinal disease; or SSA0 media Symptoms [diabetes (insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (8) face and blood f and disease (~ visceral attack, angina, stroke, resection, blindness and renal insufficiency)]. 12. The method of suppressing the VAIM of the subject comprises administering an effective amount of the compound of any one of the patents of the applicant to the corpora, or a pharmaceutically acceptable salt thereof, to the subject. • The prevention or treatment of the disease associated with the ten pairs of subjects, including the effective amount of the compound 319771 137 200835687 or its pharmaceutically acceptable salt, which will apply for any of the scopes of the patents 1 to 3 To the subject. 14. If you apply for a patent Fanyuan! 3 cases of prevention or treatment of v A p related diseases, wherein the VAfMw is a macular edema (diabetic and non-diabetic macular edema), senile macular degeneration, and an o-shaped macula of the old tree discoid macular Edema, (10) edema, retinal edema, diabetic retinopathy, choroidal retinopathy, neovascular macular degeneration, neovascular glaucoma, uveitis, iritis, retinal vasculitis, endophthalmitis, total ocular inflammation, metastasis Ophthalmitis, choroiditis, retinal pigment epitheliitis, conjunctivitis, ciliary body inflammation, scleritis, upper scleritis, optic neuritis, retrobulbar optic neuritis, keratitis, ophthalmia, exudative retinal detachment, corneal ulcer, conjunctiva Cancer, slow = sputum keratitis, Sjogson's keratitis, progressive invasion of the cornea / shell ulcer by bacterial or viral infections and ocular inflammatory diseases caused by ophthalmic surgery, caused by physical damage to the eye Ocular inflammatory disease, symptoms caused by ocular inflammatory diseases including itching, redness, edema and ulcers, erythema, polymorphic erythema, Ganglion erythema, ring erythema, scleredema, dermatitis (cognac, allergic disease, lichen planus, pityriasis rosea, contact dermatitis, atopic dermatitis, follicular red county), vascular neuropathy Edema, throat edema, glottic edema, subglottic pharyngitis, bronchitis, rhinitis, pharyngitis, sinusitis and pharyngitis or otitis media, cirrhosis, primary fixed hypertension, diabetes, arteriosclerosis, (diabetes, arteriosclerosis) And hypertension, cardiovascular disease associated with diabetes and uremia, pain associated with gout and arthritis, inflammatory disease or symptoms of connective tissue (rheumatoid arthritis, anastomotic spine 138 319771 200835687 y fire, Dry arthritis and osteoarthritis or degenerative joint disease, Phytophthora, syndrome, repair granule syndrome, Bethel's syndrome, recurrent sedans, cerebral erythematosus, discoid Lupus erythematosus, systemic sclerosis, eosinophilic fasciitis, polymyositis, dermatomyositis, rheumatic polymyalgia, vasculitis, temporary joints , nodular polyarteritis, Wegener's granulomatosis, mixed connective tissue disease, and juvenile rheumatoid arthritis); inflammatory diseases or symptoms of the digestive tract [Clone's disease, colitis, bowel Hysteria (sputum colon), fibrosis of the liver, inflammation of the oral mucosa (endophthalmitis and recurrent aphthous stomatitis)]; inflammatory diseases or symptoms of the central nervous system (multiple sclerosis, Alzheimer's disease, and Ischemic stroke-related ischemia-reperfusion disorder); pneumonia disease or symptoms (asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease); diseases including microvascular and macrovascular disease (arteriosclerosis, optic retinopathy, nephropathy) Carbohydrate metabolism-related diseases (diabetes and complications from diabetes), renal disorders and neurological disorders (polyneuropathy, single neurological disorders and autonomic neurological disorders), foot ulcers, joint # problems and increased risk of infection); A disease associated with abnormal differentiation or function of fat cells or abnormal function of smooth muscle cells (arteriosclerosis and hypertrophy); Tube diseases [including atherosclerosis, non-atherosclerosis, ischemic heart disease with myocardial infarction and peripheral arterial occlusion, Raynaud's disease and Ray's phenomenon, obstructive thrombotic vasculitis (Berg's disease)] Chronic arthritis; inflammatory bowel disease; or SSA〇 vector complications [diabetes (insulin dependent diabetes mellitus (IDDM) and non-insulin dependent diabetes mellitus (NIDDM)) and vascular complications (heart attack, angina, middle) 319771 139 200835687 i Wind, resection, blindness and renal insufficiency)]. 140 319771 200835687 冬 * 七、指定代表圖：無 \· (一） 本案指定代表圖為：第（）圖。 (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： R1—NH—X—Y——Z (I) 4 319771140 319771 200835687 Winter * VII. Designated representative map: None \· (1) The representative representative of the case is: (). (2) A brief description of the symbol of the representative figure: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: R1—NH—X—Y—Z (I) 4 319771
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