TW201211028A - Fused ring pyrrolidine derivatives - Google Patents

Fused ring pyrrolidine derivatives Download PDF

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TW201211028A
TW201211028A TW100128502A TW100128502A TW201211028A TW 201211028 A TW201211028 A TW 201211028A TW 100128502 A TW100128502 A TW 100128502A TW 100128502 A TW100128502 A TW 100128502A TW 201211028 A TW201211028 A TW 201211028A
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dihydro
piperidine
oxo
carboxylic acid
indol
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TW100128502A
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Chinese (zh)
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Kentaro Takai
Takaaki Sumiyoshi
Atsushi Suwa
Yoko Takahashi
Yoshiharu Uruno
Yasuko Murata
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Dainippon Sumitomo Pharma Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Abstract

This invention provides a fused ring pyrrolidine derivative, which exhibits an effect of acting on muscarinic receptors M1, and M4 with selectivity, meanwhile decreases side effects of mediating through other muscarinic receptors or other receptors. This invention relates to a compound represented by formula (1) or pharmaceutically allowable salt thereof, a pharmaceutical composition comprising the same as active ingredient, and a prophylactic agent and/or treating agent of muscarnic receptors mediated diseases comprising the same.

Description

201211028 六、發明說明： 【發明所屬之技術領域】 本發明係關於具有蕈毒驗受體（Muscarinic receptor) 作用性之新穎縮環β比咯啶衍生物及以該等為有效成分之醫 藥組成物。本發明復提供含有該等簟毒鹼受體之媒介疾病 的預防劑及/或治療劑。 【先前技術】 0 神經傳導物質乙酿膽驗（acetylch〇l ine)受體已知有 菸鹼（nicotine)受體及簟毒鹼受體2型之膽鹼（choline) 作用性受體。蕈毒驗受體為細胞膜結合之G蛋白偶合受體 (GCPR) ’目前已知有五個亞型（subtype)(M^ 。此等m 至Ms蕈毒鹼受體係涉及中樞及末梢組織之興奮性及抑制性 的控制’而關乎諸多生理性機能，包含心搏、醒覺、認知 (cognitive)、運動調控等。 簟毒驗受體致效劑（agonist)係具有鎮痛作用、改善記 φ 憶作用、抗精神病作用、改善認知障礙作用等種種藥理作 用’而可將該等作為治療藥物使用（非專利文獻1)。然而， 以往的蕈毒驗促效劑如碳酿膽驗（carbacho 1)或毛果芸香 鹼（pilocarpine)，對於蕈毒鹼受體亞型的選擇性低，結果 發現其副作用多，故在臨床應用上受到限制。 近年來’藉由進行蕈毒鹼受體的分子選殖（molecular cloning)及對使用基因剔除小鼠（knockout Mouse)之特定 亞型於生理學上的功用進行鑑別，而提出了能將選擇性的 蕈毒鹼受體配體（ligand)作為新治療藥的可能性，並進行 4 323406 201211028 了增強效果及減少副作用所必需的選擇性資料的研究。雖 有報告稱占諾美林（xanomeline)對人類精神***症（human schi zophrenia)的陽性症狀、陰性症狀、認知障礙皆顯現 優異的臨床效杲，然使用沁及M4基因剔除小鼠進行之研 究，係提出以占諾美林之抗精神病作用為主係經由蕈毒鹼 Μι及M4受體作用性之報告。201211028 VI. Description of the Invention: [Technical Field] The present invention relates to a novel condensed β-pyrrolidine derivative having a muscarinic receptor action and a pharmaceutical composition containing the same as an active ingredient . The present invention provides a prophylactic and/or therapeutic agent for a vector disease containing such muscarinic receptors. [Prior Art] 0 The neurotransmitter (acetylch〇l ine) receptor is known to have a nicotine receptor and a choline-acting receptor of the muscarinic receptor type 2. The scorpion venom receptor is a cell membrane-bound G protein-coupled receptor (GCPR). Currently, there are five subtypes (M^. These m to Ms muscarinic systems are involved in the excitation of central and peripheral tissues. Sexual and inhibitory control' is related to many physiological functions, including heart beat, wakefulness, cognitive, motor regulation, etc. agon 验 验 agonist (agonist) has analgesic effect, improve the record φ recall These pharmacological effects such as action, antipsychotic action, and improvement of cognitive impairment can be used as therapeutic drugs (Non-Patent Document 1). However, the previous sputum test agonist such as carbocho 1 (carbacho 1) Or pilocarpine, which has low selectivity for muscarinic receptor subtypes, has been found to have many side effects, so it is limited in clinical application. In recent years, by molecular selection of muscarinic receptors (molecular Cloning) and the identification of the physiological utility of specific subtypes of knockout mice, suggesting that selective muscarinic receptor ligands can be used as new therapeutic agents. Sex, and conducted 4 323406 201211028 to study the selective data necessary to enhance the effect and reduce side effects. Although there are reports of xanomeline positive symptoms, negative symptoms, human schizophrenia (human schi zophrenia), Cognitive disorders all show excellent clinical efficacy. However, studies using sputum and M4 knockout mice have proposed a report on the antipsychotic effect of nymphalin via the muscarinic Μι and M4 receptors. .

基於以上理由，從增強效果及減低副作用之觀點來 看，創出選擇性地作用於Μι及Ms受體的藥劑，特別是作為 中樞疾病治療劑者正備受期待。 於專利文獻1，揭示例如下述式所示之α朵酮 (Oxindole)化合物。For the above reasons, from the viewpoint of enhancing the effect and reducing side effects, it is expected that a drug that selectively acts on the receptors of Μι and Ms, particularly as a therapeutic agent for central diseases, is expected. Patent Document 1 discloses an Oxindole compound represented by the following formula.

該化合物之吲哚酮環的3位碳原子係與哌啶環結合之 點，與吲哚酮環的1位氮原子與哌啶環結合之本發明化合 物為構造相異。此外，對簟毒鹼吣及M4受體作用性以及簟 毒鹼受體選擇性皆未有任何相關之具體揭示和提及。 此外，以專利文獻2中具有簟毒鹼受體作用性之化合 ^ Vl~CQ2MeThe compound of the present invention in which the 3-position carbon atom of the indolone ring of the compound is bonded to the piperidine ring is different in structure from the compound of the present invention in which the nitrogen atom at the 1-position of the indolone ring is bonded to the piperidine ring. In addition, there are no specific disclosures and references to muscarinic and M4 receptor abilities and muscarinic receptor selectivity. Further, in the patent document 2, there is a combination of muscarinic receptor action ^ Vl~CQ2Me

物而言，雖揭示例如下述式 〇 XIn terms of matter, for example, the following formula 〇 X is disclosed.

Me^'N^N 5 所示之苯並味唾琳二鲷（Benzimidazolidinone)化合物，惟Benzimidazolidinone compound represented by Me^'N^N 5

323406 S 201211028 該化合物與縮環吡咯啶化合物之本發明化合物於彳冓&上才目 異。此外，對簟毒驗Μι受體作用性亦未有任何相關之具麟 揭示和提及。 此外，專利文獻3係揭示例如下述式323406 S 201211028 This compound differs from the compound of the invention of the condensed pyrrolidine compound in oxime & In addition, there is no relevant disclosure and mention of the toxicity of 簟1 receptors. Further, Patent Document 3 discloses, for example, the following formula

所示之吲哚酮化合物，且專利文獻4係揭示例如下述式 所示之吲哚酮化合物。然而，該等化合物係於派咬環的氮 原子結合有吡咯啶環之點與本發明之化合物於構造上相 異。此外，該化合物之作用性為蕈毒驗Μι受體選擇性，選 擇性作用於簟毒驗Μι及M4兩個受體之°引π朵綱化合物在未有 任何相關之具體揭示和提及。 [先前技術文獻] [專利文獻] [專利文獻1]國際公開第 [專利文獻2]國際公開第 [專利文獻3]國際公開第 [專利文獻4]國際公開第 [非專利文獻] [非專利文獻1] Journal 99/32481號小冊 2001/27104 號小冊 2007/142585 號小冊 2009/110844 號小冊 of Medicinal Chemistry ， 6 323406 201211028 43 卷，4333 至 4353 頁（2000 年） [与g 專矛J 文獻 2] European Journal of Pharmacology， 603 卷，147 至 149 頁（2009 年） 【發明内容】 (發明欲解決之課題） 本發明係以提供一種選擇性地作用於簟毒鹼1及1\14受 體並顯現效果，同時透過其他的簟毒鹼受體或其他的受體 而減低副作用的縮環吡咯啶衍生物為課題。 ® (解決課題之手段） 本發明者等為解決上述課題而精心研究，結果發現具 有特定縮環吡咯啶構造之化合物係選擇性作用於簟毒鹼I 及Μ4，具有包含抗精神病作用、認知障礙改善作用等優異 的中樞疾病改善效果，同時透過其他的蕈毒鹼受體或其他 的受體而減低副作用，遂完成本發明。亦即，本發明係提 供： φ [1]下述式（1)所示之化合物或其藥學上容許的鹽（以下將 此等稱為化合物（I):The anthrone compound shown in the patent document 4 discloses an anthrone compound represented by the following formula. However, these compounds are structurally different from the compounds of the present invention in that the nitrogen atom of the bite ring is bonded to the pyrrolidine ring. In addition, the action of the compound is 蕈 Μ Μ 受体 受体 受体 受体 受体 受体 受体 受体 受体 受体 受体 受体 受体 受体 受体 受体 受体 受体 受体 受体 受体 受体 受体 受体 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及[Prior Art Document] [Patent Document] [Patent Document 1] International Publication [Patent Document 2] International Publication [Patent Document 3] International Publication [Patent Document 4] International Publication [Non-Patent Document] [Non-Patent Document 1] Journal 99/32481 Booklet 2001/27104 Booklet 2007/142585 Booklet 2009/110844 Booklet of Medicinal Chemistry, 6 323406 201211028 43 Volume, 4333 to 4353 (2000) [with g spear J Document 2] European Journal of Pharmacology, Vol. 603, pp. 147-149 (2009) [Disclosure] The present invention provides a selective action on muscarinic 1 and 1\14 The condensed cyclic pyrrolidine derivative in which the receptor exhibits an effect and at the same time reduces side effects through other muscarinic receptors or other receptors is a subject. ® (Means for Solving the Problem) The inventors of the present invention have intensively studied to solve the above problems, and have found that a compound having a specific condensed pyrrolidine structure selectively acts on muscarinic I and Μ4, and has an antipsychotic effect and a cognitive disorder. The present invention has been completed by improving the central disease improving effect such as an excellent effect and reducing side effects through other muscarinic receptors or other receptors. That is, the present invention provides: φ [1] a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof (hereinafter referred to as compound (I):

[式中，a、b、c及d為相同或相異，分別為CH或CR5 ; R5為鹵原子、C3-7環院基、C6-14芳基、雜芳基、C6-14芳烧基、 雜芳烧基、〇2-6烯基、〇2-6炔基、〇1-6烧氧基、氰基、〇1-6烧 7 323406 201211028 、硝基、G-6烷基磺醢 硫基、醯基、胺磺醯基、羥基、胺基 基’或可經取代的Cl_6烷基； 及R為相同或相異’分別為氣原子、可經取代的g 6烧 t =原ΡΓ M基、㈣烧基或3至7員的雜環基；或者 ^柿々互相鍵結，h ^與相鄰的碳原子一同形成Ca-7 ，，元、'或3至7員的雜環’或—起成為=cr6r7 ;[wherein, a, b, c and d are the same or different, respectively CH or CR5; R5 is a halogen atom, C3-7 ring-based, C6-14 aryl, heteroaryl, C6-14 aromatic Base, heteroarylalkyl, 〇2-6 alkenyl, 〇2-6 alkynyl, 〇1-6 alkoxy, cyano, 〇1-6 烧 7 323406 201211028, nitro, G-6 alkyl sulfonate Sulfhydryl, fluorenyl, sulfonyl, hydroxy, amino, or substituted C 6 alkyl; and R are the same or different, respectively, a gas atom, a replaceable g 6 t = the original ΡΓ M group, (4) alkyl or 3 to 7 membered heterocyclic groups; or ^ persimmons bonded to each other, h ^ together with adjacent carbon atoms to form Ca-7, meta, 'or 3 to 7 members of the miscellaneous Ring 'or - become \cr6r7;

=及R7為㈣或相異’分別為氫原子或可經取代的Ci 6烧 基’或者是R6及R7互相鍵結’尺6及R7與相鄰的碳原子一同 形成Cw環烷烴或3至7員的雜環； R3及R4為一起形成=〇或=s ; X為單鍵或伸曱基； Y及Z為相同或相異，分別為氧原子或硫原子； R為可經取代的d-e烷基、c2-6炔基或C2_6烯基； 環A為可經選自經基、齒原子、Ci 6烧基及L烧氧基所構 成群組中的1至2個取代基取代的6到7員之含氮雜環]。 ^ [2a]如上述[1]所述之化合物，其中，c為cr5。 [2] 如上述[1]或[2a]所述之化合物，其中，R5為齒原子、 C!-6烷氧基、氰基、烷基硫基、羥基、胺基、硝基、或可經 取代的Cw烷基。 [3] 如上述[1]或[2a]所述之化合物，其中，Rs為氟原子、 氯原子、漠原子、甲基、乙基、丙基、甲氧基或三氟甲基。 [4a]如上述[1]、[2a]、[2]或[3]所述之化合物，其中，環 A為下述式（2a)所示之含氮雜環·· 323406 8 201211028 (2a) ο I^N-1 或= and R7 is (d) or different from 'a hydrogen atom or a substituted Ci 6 alkyl group' or R6 and R7 are bonded to each other '6 and R7 together with adjacent carbon atoms form a Cw cycloalkane or 3 to 7-membered heterocyclic ring; R3 and R4 are taken together to form =〇 or =s; X is a single bond or a fluorene group; Y and Z are the same or different, respectively an oxygen atom or a sulfur atom; R is a replaceable Dealkyl, c2-6 alkynyl or C2_6 alkenyl; ring A is substituted by 1 to 2 substituents selected from the group consisting of a transradical, a tooth atom, a Ci 6 alkyl group and an L alkoxy group. 6 to 7 members of nitrogen-containing heterocycles]. [2a] The compound according to the above [1], wherein c is cr5. [2] The compound according to [1] or [2a] above, wherein R5 is a tooth atom, a C!-6 alkoxy group, a cyano group, an alkylthio group, a hydroxyl group, an amine group, a nitro group, or Substituted Cw alkyl. [3] The compound according to [1] or [2a] above, wherein Rs is a fluorine atom, a chlorine atom, a desert atom, a methyl group, an ethyl group, a propyl group, a methoxy group or a trifluoromethyl group. [4] The compound according to the above [1], [2a], [2] or [3] wherein the ring A is a nitrogen-containing heterocyclic ring represented by the following formula (2a) 323406 8 201211028 (2a) ) ο I^N-1 or

[式中’R8為氫原子、經基、齒原子、Ci 6烧基或Ci 6烧氧基]。 ⑸如上述[4]所述之化合物，其中，R8為氫原子、基 或Cl-6烧氧基。 ⑽如上述[1]、[2小[2]、[3]、[4小[4]或[5]所述之 化合物，其中，X為單鍵。 [6] 如上述…、^、^、^、[^、[小⑸或咖] 所述之化5物，其+，c及b為相同或相異之⑶或cr5。 [7] 如上述[1]、[2a]、[2]、[3]、[4a]、[4]、⑸或[6a][wherein R8 is a hydrogen atom, a trans group, a tooth atom, a Ci 6 alkyl group or a Ci 6 alkoxy group]. (5) The compound according to the above [4], wherein R8 is a hydrogen atom, a group or a Cl-6 alkoxy group. (10) A compound according to the above [1], [2 small [2], [3], [4 small [4] or [5], wherein X is a single bond. [6] As shown in the above, ..., ^, ^, ^, [^, [small (5) or coffee], the +, c and b are the same or different (3) or cr5. [7] As above [1], [2a], [2], [3], [4a], [4], (5) or [6a]

[4]如上述[1]、[2a]、[2]或[3]所述之化合物 A為下述式（2)所示之含氮雜環. 其中，環 (2) 〇 所述之化合物，其中，eAb其中—者為⑶，另—者為⑽。 [8] 如上述 [6]或[7]所述之化合物，其中，γ&ζ皆為氧原子。 [9] 如上述 [6]、[7]或[8]所述之化合物’其中13及1^為一起形成=〇。 [10] 如上述[i]、[2a]、m、[3]、[4a]、[4]、[5]、[6a]、 [6]、[7]、[8]或[9]所述之化合物，其中，Rl& r2為相同 或相異，分別為氫原子、氟原子、經基、或可經取代的Ch 烧基（特別是鋪基取代的Cl.道基），或者Rl& r2互相鍵 323406 9 201211028 結，R及R與相鄰的碳原子一同形成四氫娘喃環。 [11] 如上述[1]、[23]、[2]、[3]、[4刎、[4]、[5]、[6&]、 [6]、[7]、[8]、[9]或[10]中任一項所述之化合物，其中， R為可經取代的直鏈之Cm烷基。 [12] 如上述[1]所述之化合物或其藥學上容許的鹽，其係 選自： ' ’、 4-[4-(2-侧氧基-2, 3-二氫-1H-吲哚-1-基）哌啶-1-基]哌 啶-1-羧酸乙酯； 4-[4-(3-甲基-2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌啶 -1-基]哌啶-1-羧酸乙酯； 4-[4-（3, 3-二曱基-2-側氧基-2, 3-二氩-1H-吲哚-1-基）β底 啶-1-基]哌啶-1-羧酸乙酯； 4 [4-(3, 3-二乙基-2-側氧基-2, 3-二氫-1Η-σ弓卜朵-1-基）〇辰 唆-1-基]哌啶-1-羧酸乙酯； 4-[4-(3-乙基-3-甲基-2-側氧基-2, 3-二氫-1Η-吲哚-1-基） • σ底咬—1-基]哌啶-1-羧酸乙酯； 4-[4-(3, 3-二丙基-2-側氧基-2, 3-二氫-1Η-吲哚-1-基）哌 咬-1-基]哌啶-丨_羧酸乙酯； 4-{4-[2’ -側氧螺（環丙烷_13，_吲哚）_Γ (2，Η)_基]哌啶 -l-基}哌啶-1-羧酸乙酯； 4-{4-[2’ -侧氧螺（環丁烷_丨，3, _吲哚）_丨，（2, Η)-基]哌啶 -1-基辰啶-1-羧酸乙酯； 4_{4-[2’ -側氧螺（環戊烷-1，3,-吲哚）-1，（2, H)-基]哌啶 -1-基卜辰啶-1—羧酸乙酯； 10 323406 201211028 4-{4-[2’ -側氧螺（環己烷-1，3’ -吲哚）-Γ (2’ Η)-基]哌啶 -l-基}哌啶-1-羧酸乙酯； 4-{4-[2’ -側氧螺（四氫哌喃-4, 3’ -吲哚）-1’（2, Η)-基]哌 啶-1-基}哌啶-1-羧酸乙酯； 4_[4-(3，3- 二甲基-2-侧氧基-2，3_二氮-1Η-σ3|α朵-1-基）σ辰 啶-1-基]甲基哌啶-1-羧酸乙酯； 4-{4-[2’ -側氧螺（環丙烷-1，3’ -吲哚）-1’（2’ Η)-基]哌啶 -1-基丨曱基哌啶-1-羧酸乙酯； 3~[4_(3，3_二乙基-2-侧氧基-2，3_二氮-1Η-α引 °朵-1-基）σ底 啶-1-基]-8-吖雙環[3. 2. 1]辛烷-8-羧酸乙酯； 4-[4-(3, 3-二曱基-2-侧氧基-2, 3-二氩-1Η-吲哚-1-基）哌 啶-1-基]哌啶-1-羧酸曱酯； 4-[4-(3, 3-二甲基-2-侧氧基-2, 3-二氩-1Η-吲哚-1-基）哌 β定-1-基缓酸異丙酉旨； 4-[4-(2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌啶-1-基]氮 φ 雜環庚烷-1-羧酸乙酯； 4-[4-(6_ 氟-2-侧氧基-2, 3-二氫-1Η-α引 a朵- l-基）a辰咬-1-基]哌啶-1-羧酸乙酯； 4-[4-(6 -說-3，3_二曱基-2-側氧基-2，3_二氮_1Η_σ?|α朵-1 -基）哌啶-1-基]哌啶-1-羧酸乙酯； 4-[4-(5-氣-2-側氧基-2,3-二氫-111-°引11朵-1-基）1〇底唆-1-基]哌啶-1-羧酸乙酯； 4-[4-(5-氟-3, 3-二甲基-2-側氧基-2, 3-二氫-1Η-吲哚-卜 基）哌啶-1-基]哌啶-1-羧酸乙酯； 11 323406 201211028 4-[4-(5-氟-2-側氧基_2,3_二氩_1H—吲哚_丨_基）哌啶 基]旅β定基-竣酸乙醋； 4 ({3 [1-(乙氧基羰基）哌啶基_4_亞基]_6_氟_2_側氧基 2,3 —風卜辰咬_ι_基）〇底咬_ι_幾酸乙酯； 4-({3-[1-(乙氧基羰基）哌啶基_4_基]_6_氟_2_侧氧基 -2, 3-二氫-1Η-吲哚-i-基}哌啶―丨―基）哌啶_丨_羧酸乙酯； 卜乙基硫羰基-4-[4-(2-側氧基-2,3-二氫-1H-吲哚-1-基） α底咬-1 -基]α辰α定； 4-[4-(2-側氧基-2, 3-二氫-1Η-吲哚-1-基>底咬_ι_基]派 啶-1-羧酸2-氟乙酯； 4-[4-(2-侧氧基-2,3-二氫-1Η-吲哚-1-基）哌啶―丨―基]哌 唆-1-敌酸2-丙稀酯； 4-[4-(2-側氧基-2,3-二氫-1Η-吲哚-1-基）哌啶_丨_基]哌 啶-1-羧酸2-甲氧乙酯； 4-[4-(2-側氧基-2,3-二氫-1Η-吲哚-1-基）哌啶_；!_基]哌 φ 啶-1-羧酸丁酯； 1-曱基硫羰基-4-[4-(2-側氧基-2, 3-二氫-1Η-吲哚-1-基） 哌啶-1-基]哌啶； 4-[4-(2-侧氧基-2,3-二氫-111-°引嗓-1-基）旅咬_1_基]0辰 啶-1-羧酸丙酯； 4[4-(5-氟-2-側乳基-2,3-二氫-111-°引11朵-1-基）11底咬_1_ 基]氮雜環庚烧-1-羧酸乙酯； 4-[4-(3, 3-二曱基-2-側氧基-2, 3-二氫-5-氟-1Η-吲哚-1 一 基）哌啶-1-基]氮雜環庚烷-1—羧酸乙酯； 323406 12 201211028 4-[4-(3, 3-二曱基-2-硫酮基-2, 3-二氳-1H-吲哚-1-基）哌 咬_ 1 -基]B底β定_ 1-叛酸乙酉旨； 4-[4-(5-曱基-2-側氧基-2, 3-二氫-1Η-吲哚-1-基）哌啶 -1-基]哌啶-1-羧酸乙酯； 4-[4-(6-曱基-2-側氧基-2, 3-二氫-1Η-吲哚-1-基）哌啶 -1-基]哌啶-1-羧酸乙酯； 4-[4-(5-甲氧基-2-侧氧基-2, 3-二氬-1Η-吲哚-1-基）哌啶 -1-基]哌啶-1-羧酸乙酯； ® 4-[4-(5-曱氧基-2-側氧基-2, 3-二氫-1Η-吲哚-1-基）哌啶 -1-基]氮雜環庚烷-1-羧酸乙酯； 4-{4-[3,3-雙（3-曱氧基丙基）-2-側氧基-2, 3-二氫-1Η-吲 哚-1-基]哌啶-l-基}氮雜環庚烷-1-羧酸乙酯； 4-{4-[5-氟-3, 3-雙（羥基曱基）-2-側氧基-2, 3-二氫-1Η-吲哚-1-基]哌啶-l-基}哌啶-1-羧酸乙酯； 4-[4-(5-溴-2-側氧基-2, 3-二氫-1Η-吲哚-1-基）哌啶-1-φ 基]哌啶-1-羧酸乙酯； 4-[4-(5 -漠-2-側氧基-2, 3 -二氫-1Η-°引 °朵-1-基）派*1 定-1-基]氮雜環庚烷-1-羧酸乙酯； 4-[4-(5-氯-2-側氧基-2, 3-二氳-1Η-吲哚-1-基）哌啶-1-基]氮雜環庚烷-1-羧酸乙酯； 4-[4-(5-氯-2-側氧基-2, 3-二氫-1Η-吲哚-1-基）哌啶-1-基]哌啶-1-羧酸甲酯； 4-[4-(5-氟-2-側氧基-2’，3’，5’，6’ -四氳螺[吲哚-3, 4’ -哌喃]-1(2Η)-基）哌啶-1-基]哌啶-1-羧酸乙酯； 13 323406 201211028 4-[4-(5-氟-2-側氧基—2’，3,，5,，6, _四氫螺[吲哚_3, 4, _ 哌喃]-1(2H)-基）哌啶―卜基]氮雜環庚烷_丨_羧酸乙酯； 4_[4_(5’ —氣一2’ —側氧螺-[環丙烷-1，3,-吲哚]-1，（2, H)_ 基）哌啶-1~基]Π辰啶—1__羧酸乙酯； 4-[4-(5’ -氯-2’ -側氧螺_[環丙烷<，3, _吲哚]（2, H)一 基）派α定基]°辰°定-1-竣酸曱酯； 4-[4-(5 '氯-2’ -側氧螺 _[環丙烷^，3, _吲哚](2, η)一 φ 基）哌啶-1-基]氮雜環庚烷―丨―羧酸乙酯； 4-[4-(5’〜氟-2’ -侧氧螺_[環丙烷3, _吲哚](2, H)一 基）σ底咬-1-基]派咬_1_幾酸乙酯； 4-[4_(5’ ~氟-2’ -側氧螺_[環丙烷<，3’ _吲哚卜厂㈡飞）— 基）°底°定-1~基]派°定-1-竣酸甲酯； 4_[4-(5’ ~ 氟-2’ -侧氧螺_[環丙烷<，3, _吲哚]（2, Η)一 基）哌啶-1-基]氮雜環庚烷-丨―羧酸乙酯； 4 [4 (5甲基-2-側氧基一2’，3,，5’，6’ _四氫螺[吲哚 • ―3’4’-哌喃]-Κ2Η)-基）哌啶-1-基]哌啶-1-羧酸乙酯； 4 [4 (5甲基—2-側氧基_2’，3,，5’，6’ _四氫螺[吲η朵 -3’ 4’ _哌喃]—ι(2Η)-基）哌啶_丨_基；|氮雜環庚烷_丨_羧酸乙 酯； 4-[4-(5’〜甲基-2’ -側氧螺—[環丙烷<，3, _吲哚](2, Η) 基）c辰贫~1-基]u辰咬-1-幾酸乙酯； 4-[4-(5、甲基-2’ -侧氧螺—[環丙烷3, 一吲哚]—r (2, Η) -基）哌啶-1-基]氮雜環庚烷_丨-羧酸乙酯； 4-[4-(3, 3, 6-三甲基-2-側氧基-2, 3-二氫-1H-吲哚-1-基） 14 323406 201211028 派咬-1-基]哌啶-1-羧酸乙酯； 4-[4-(3, 3, 6-三甲基-2-侧氧基一2, 3-二氫-1H-吲哚-1-基） 派咬-1-基]娘咬-1-叛酸甲酯； 4-[4-(3, 3, 6-三甲基-2-側氧基-2, 3-二氫-1H-吲哚-1-基） 0辰咬-1-基]氮雜環庚烷-丨—羧酸乙酯； 4-[4-(6’ -甲基-2’ -侧氧螺-[環丙烷j，3, _吲哚卜Γ (2, H) -基）哌啶-1-基]哌啶-1-羧酸乙酯； _ 4 [4 (6 -甲基-2 _侧氧螺-[環丙烧_1，3’n朵]_1，（2, η) -基）哌啶-1-基]哌啶-1-缓酸甲酯； 4-[4-(6’ -曱基-2’ -側氧螺—[環丙烷y，3, _吲嗓]_Γ (2, H) -基）°底咬-1-基]氮雜環庚院_1_竣酸乙酯； 4 [4-(6-曱基-2-側氧基-2’，3’，5’，6’ -四氫螺[,口朵 -3, 4’ -哌喃]-1(2Η)-基）哌啶-1—基]哌啶_丨_羧酸乙酯； 4 [4-(6-甲基-2-側氧基一2’，3’，5’，6’ -四氫螺[η引〇朵 -3, 4’ -哌喃]-1(2Η)-基）哌啶-1-基]氮雜環庚烷_丨_羧酸乙 φ 酉旨； 4-[4-(6-甲基-2-侧氧基-2, 3-二氫-1Η-吲哚-1-基）哌啶 -1-基]氮雜環庚烧-1-竣酸乙酯； 4-[4-(6-曱基-2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌啶 -1-基]哌啶-1-羧酸乙酯； 4-[4-(6-曱基-2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌啶 -1-基]哌啶-1-羧酸甲酯； 4-[4-(6-甲氧基-2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌啶 -1-基]氮雜環庚烧-1-羧酸乙酯； 15 323406 201211028 (1R，5S)-3-[4-(6-甲氧基-2-侧氧基-2, 3-二氫-1H-吲哚 -1-基）派唆-1-基]-8-吖雙環[3·21]辛烷_8_羧酸乙酯； 4-{[4-(6-甲氧基-2-侧氧基-2, 3-二氫-1Η-吲哚-卜基）哌 啶-1-基]曱基}哌啶一丨一羧酸乙酯； 4 {[4 (6-曱氧基-2-側氧基一2’，3’，5’，6’_四氫螺[吲口朵 -3,4’ -哌喃]-ΐ(2Η)-基）哌啶-1—基;|哌啶_丨_羧酸乙酯； 4 {[4 (6-甲氧基-2-側氧基一2’，3’，5’，6, _四氫螺[吲哚 φ 3,4 _哌喃]_1(2H)-基）哌啶-1-基]氮雜環庚烷-1-羧酸乙 酯； (1R’ 5S)-3-[4-(6-曱氧基-2-侧氧基一2’，3’，5,，6,-四氫螺 [吲哚-3, 4,-哌喃]-l-(2H)-基）-哌啶-i_基]_8_吖雙環 [3. 2.1]辛烧-8-幾酸乙酯； 4-[4-(5-氣-6-氟-3,3-二甲基-2-側氧基-2,3-二氫-111-吲 基）哌啶-1-基]哌啶_1_羧酸乙酯； 4-[4-(3, 6-二曱基-2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌 • 咬基]哌啶-1-羧酸乙酯； 4~[4-(3, 6-二甲基-2-側氧基-2, 3-二氫-1Η-吲哚-1-基）哌 咬基]哌啶-1-羧酸甲酯； 4 [4-(3, 6-二曱基-2-侧氧基-2, 3-二氫-1Η-吲哚-1-基）n底 咬基]氮雜環庚烷-1-羧酸乙酯； 4~[4-(5-氟-3-甲基-2-側氧基-2, 3-二氫-1H-吲哚-卜基） °底啶-1-基]氮雜環庚烷-1-羧酸乙酯； 4·~{[4-(5-氟-3-曱基-2-側氧基-2, 3-二氫-1Η-吲哚-1-基） 派啶-1-基]甲基}哌啶-1-羧酸乙酯； 323406 16 201211028 4-{ [4-(3-曱基-2-側氧基-2, 3-二氬-1H-吲哚-1-基）哌啶 -1-基]曱基}哌啶-1-羧酸乙酯； 4-[4-(5-曱基-2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌啶 -1-基]氮雜環庚烷-1-羧酸乙酯； 4-{[4-(5-曱基-2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌啶 -1-基]甲基}哌啶-1-羧酸乙酯； 4-{[4-(2-側氧基-2, 3-二氩-1H-吲哚-1-基）哌啶-1-基]甲 基}哌啶-1-羧酸乙酯； ® 4-[4-(6-氟-3-曱基-2-侧氧基-2, 3-二氩-1H-吲哚-1-基） 哌啶-1-基]哌啶-1-羧酸乙酯； 4-[4-（6-氣-3-曱基-2-侧氧基-2，3 -二氮 哌啶-1-基]氮雜環庚烷-1-羧酸乙酯； 4-[4-(5-氟-2-侧氧基-2, 3-二氫-1H-吲哚-1-基）哌啶-1-基]哌啶-1-羧酸甲酯； 4-[4-（6-曱基-2-側氧基-2，3-二氫-1 Η-α弓丨B朵-1 -基）α底咬 φ -1-基]哌啶-1-羧酸曱酯； 4-[4-(6 -漠-2-侧氧基-2，3_二氮_1Η-α3Ιπ朵-1-基）°底咬_1_ 基]哌啶-1-羧酸乙酯； 4-[4-(6-';臭-2-侧氧基-2，3-二敷-111-11引11朵-1-基）旅唆-1-基]氮雜環庚烷-1-羧酸乙酯； 4_[4-(6 -臭-2-側氧基-2，3_二氫-111-°引 α朵-1 -基）11底α定-1 -基]哌啶-1-羧酸甲酯； 4-[4-(6-乙基-2-側氧基-2, 3-二氫-1Η-吲哚-卜基）哌啶 -1-基]哌啶-1-羧酸乙酯； 17 323406 201211028 4-[4-(6-乙基-2-側氧基- 2,3 -二氫-1H-吲哚-1-基）哌啶 -1-基]氮雜環庚烷-1-羧酸乙酯； 4-[4-(2 -側氧基丙基-2，3-二氮-1Η-α弓丨°朵-1~~基）旅淀 -1-基]哌啶-1-羧酸乙酯； 4-{ [4-(5-氯-2-侧氧基-2, 3-二氫嗓-1-基）π底°定-1-基）甲基}旅唆竣酸乙酯；[4] The compound A according to the above [1], [2a], [2] or [3] is a nitrogen-containing heterocyclic ring represented by the following formula (2). wherein, the ring (2) is described. A compound in which an eAb is (3) and the other is (10). [8] The compound according to the above [6] or [7] wherein γ & oxime is an oxygen atom. [9] The compound of the above [6], [7] or [8] wherein 13 and 1^ together form =〇. [10] As above [i], [2a], m, [3], [4a], [4], [5], [6a], [6], [7], [8] or [9] The compound, wherein R1 & r2 are the same or different, respectively a hydrogen atom, a fluorine atom, a trans group, or a substituted Ch group (especially a base-substituted Cl.), or Rl&; r2 mutual bond 323406 9 201211028 junction, R and R together with adjacent carbon atoms form a tetrahydro-n-anthene ring. [11] As above [1], [23], [2], [3], [4刎, [4], [5], [6&], [6], [7], [8], The compound according to any one of [10], wherein R is a linear Cm alkyl group which may be substituted. [12] The compound according to the above [1] or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of: ' ', 4-[4-(2-o-oxy-2, 3-dihydro-1H-indole) Ethyl-1-indolylpiperidin-1-yl]piperidine-1-carboxylate; 4-[4-(3-methyl-2-oxo-2,3-dihydro-1H-indole) Ethyl-1-indolylpiperidin-1-yl]piperidine-1-carboxylate; 4-[4-(3,3-dimercapto-2-yloxy-2,3-diargon- 1H-indol-1-yl)β-endridin-1-yl]piperidine-1-carboxylic acid ethyl ester; 4 [4-(3, 3-diethyl-2-oxooxy-2, 3- Dihydro-1Η-σ 卜 朵 -1--1-yl) 〇 唆 唆-1-yl] piperidine-1-carboxylic acid ethyl ester; 4-[4-(3-ethyl-3-methyl-2- Side oxy-2,3-dihydro-1Η-indol-1-yl) • σ bottom bite 1-yl]piperidine-1-carboxylic acid ethyl ester; 4-[4-(3, 3-di Propyl-2-oxo-2,3-dihydro-1Η-indol-1-yl)piperidin-1-yl]piperidine-indole-carboxylate; 4-{4-[2' -S. oxyspiro(cyclopropane_13,_吲哚)_Γ(2,Η)_yl]piperidine-1-yl}piperidine-1-carboxylic acid ethyl ester; 4-{4-[2'-side Oxyspiro(cyclobutane_丨,3, _吲哚)_丨, (2, Η)-yl]piperidin-1-ylcindine-1-carboxylic acid ethyl ester; 4_{4-[2' - Side oxo (cyclopentane-1,3,-吲哚)-1,(2,H)-yl]piperidin Ethyl-1-bryzinidine-1-carboxylate; 10 323406 201211028 4-{4-[2'-Side oxane (cyclohexane-1,3'-吲哚)-Γ (2' Η) -yl]piperidin-l-yl}piperidine-1-carboxylic acid ethyl ester; 4-{4-[2'-side oxane (tetrahydropyran-4,3'-indole)-1' ( 2, Η)-yl]piperidin-1-yl}piperidine-1-carboxylic acid ethyl ester; 4_[4-(3,3-dimethyl-2-oxo-oxy-2,3-dinitrogen- 1Η-σ3|α朵-1-yl) σ hrhen-1-yl]methylpiperidine-1-carboxylic acid ethyl ester; 4-{4-[2'-side oxyspiro (cyclopropane-1,3) '-吲哚)-1'(2' Η)-yl]piperidin-1-ylmercaptopiperidine-1-carboxylic acid ethyl ester; 3~[4_(3,3_diethyl-2- Alkyloxy-2,3-diaza-1Η-α 引等-1-yl) σ-endridin-1-yl]-8-indole bicyclo[3. 2.]octane-8-carboxylic acid B Ester; 4-[4-(3, 3-dimercapto-2-oxo-2,3-diar-ar-indol-1-yl)piperidin-1-yl]piperidine-1- Oxal carboxylate; 4-[4-(3,3-dimethyl-2-oxo-2,3-diar-arsen-1-indol-1-yl)piperidin-1-yl-acid Isopropyl hydrazine; 4-[4-(2-o-oxy-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]azepine-1 heterocycloheptane-1-carboxylate Acid ethyl ester; 4-[4-(6-fluoro-2-oxo-2,3-dihydro-1Η-α A-l-yl)achen-1-yl]piperidin-1-carboxylic acid ethyl ester; 4-[4-(6-say-3,3-didecyl-2-sidedoxy-2 , 3_dinitro-1Η_σ?|α-l-l-yl)piperidin-1-yl]piperidine-1-carboxylic acid ethyl ester; 4-[4-(5-gas-2-sideoxy-2 ,3-dihydro-111-°11-11-1-yl)1〇〇唆-1-yl]piperidine-1-carboxylic acid ethyl ester; 4-[4-(5-fluoro-3, 3- Ethyl dimethyl-2-oxo-2,3-dihydro-1Η-indole-piperidin-1-yl]piperidine-1-carboxylate; 11 323406 201211028 4-[4- (5-fluoro-2-oxo-2,3_di-argon-1H-indole-yl)piperidinyl] brigade-beta-acetic acid ethyl acetate; 4 ({3 [1-(ethoxy) Benzyl)piperidinyl_4_subunit]_6_fluoro_2_sideoxy 2,3—wind chenchen _ι_ base) 咬 bottom bite_ι_acid ethyl ester; 4-({3 -[1-(ethoxycarbonyl)piperidinyl-4-yl]-6-fluoro-2-oxoxy-2,3-dihydro-1Η-吲哚-i-yl}piperidine-hydrazine-yl Ethyl piperidine-indole-carboxylate; bethylthiocarbonyl-4-[4-(2-o-oxy-2,3-dihydro-1H-indol-1-yl) α-bottom-1 -yl α[4-(2-Sideoxy-2,3-dihydro-1Η-吲哚-1-yl)> bottom bite_ι_yl]pyridin-1-carboxylic acid 2 -fluoroethyl ester; 4-[4-(2-o-oxy-2,3-dihydro-1Η-fluoren-1-yl) Piperidine-丨-yl]piperidin-1-propionate 2-propyl ester; 4-[4-(2-o-oxy-2,3-dihydro-1Η-indol-1-yl)piperidine 2-丨-yl] piperidine-1-carboxylic acid 2-methoxyethyl ester; 4-[4-(2-o-oxy-2,3-dihydro-1Η-indol-1-yl)piperidine _ ;!_基] Piper φ pyridine-1-carboxylic acid butyl ester; 1-mercaptothiocarbonyl-4-[4-(2- oxo-2,3-dihydro-1 Η-fluoren-1-yl) Piperidin-1-yl]piperidine; 4-[4-(2-trioxy-2,3-dihydro-111-° 嗓-1-yl) brigade _1_yl]0 fen 1-carboxylic acid propyl ester; 4[4-(5-fluoro-2-sialyl-2,3-dihydro-111-°11-11-1-yl)11 bottom bite_1_yl]aza Cycloheptyl-1-carboxylic acid ethyl ester; 4-[4-(3, 3-dimercapto-2-oxo-2,3-dihydro-5-fluoro-1Η-吲哚-1-yl Ethyl piperidin-1-yl]azepane-1 -carboxylate; 323406 12 201211028 4-[4-(3,3-Dimercapto-2-thioketo-2, 3-diphenyl) -1H-吲哚-1-yl) piperidine _ 1 -yl] B-beta β- _ 1-reoxazate; 4-[4-(5-mercapto-2- oxo-2, 3- Ethyl dihydro-1Η-indol-1-ylpiperidin-1-yl]piperidine-1-carboxylate; 4-[4-(6-fluorenyl-2-yloxy-2, 3- Ethyl dihydro-1Η-indol-1-ylpiperidin-1-yl]piperidine-1-carboxylate; 4-[4-(5-methoxy-2- side Ethyloxy-2,3-diar-argon-1-indole-1-yl)piperidin-1-yl]piperidine-1-carboxylate; ® 4-[4-(5-decyloxy-2) -ethyloxy-2,3-dihydro-1Η-indol-1-yl)piperidin-1-yl]azepane-1-carboxylic acid ethyl ester; 4-{4-[3,3 - bis(3-methoxypropyl)-2-oxo-2,3-dihydro-1Η-indol-1-yl]piperidine-1-yl}azepane-1-carboxylate Acid ethyl ester; 4-{4-[5-fluoro-3,3-bis(hydroxyindenyl)-2-oxo-2,3-dihydro-1Η-indol-1-yl]piperidine- L-yl}piperidin-1-carboxylic acid ethyl ester; 4-[4-(5-bromo-2-yloxy-2,3-dihydro-1Η-indol-1-yl)piperidine-1 - φ yl] piperidine-1-carboxylic acid ethyl ester; 4-[4-(5 - desert-2-oxo-2,3-dihydro-1 Η-° 引 °-1-yl) Ethyl l-yl]azetidene-1-carboxylate; 4-[4-(5-chloro-2-oxo-2,3-diindole-1Η-吲哚-1- Ethyl piperidin-1-yl]azetidin-1-carboxylate; 4-[4-(5-chloro-2-oxo-2,3-dihydro-1Η-吲哚- Methyl 1-yl)piperidin-1-yl]piperidine-1-carboxylate; 4-[4-(5-fluoro-2-oxo-2',3',5',6'-tetra Ethyl [吲哚-3, 4'-pyrano]-1(2Η)-yl)piperidin-1-yl]piperidine-1-carboxylate; 13 323406 201211028 4-[4-(5- Fluor-2-oxo- 2',3,,5,6, _tetrahydrospiro[吲哚_3, 4, _pyrano]-1(2H)-yl)piperidinyl-p-yl]N- Heterocyclic heptane_丨_carboxylate; 4_[4_(5'-gas-2'-side oxo-[cyclopropane-1,3,-吲哚]-1,(2, H)- group Piperidine-1~yl]Π辰啶-1__carboxylic acid ethyl ester; 4-[4-(5'-chloro-2'-side oxo-[cyclopropane<,3, _吲哚]( 2, H) a group) 派α定基] ° ° 定 -1- 竣 竣 ; ;; 4-[4-(5 'chloro-2'-side oxyspiro _ [cyclopropane ^, 3, _ 吲哚(2, η)- φ yl)piperidin-1-yl]azepan-indole-carboxylate; 4-[4-(5'~fluoro-2'-side oxo-[ring] Propane 3, _吲哚] (2, H)-based) σ bottom bite-1-yl] pie bite _1_ acid ethyl ester; 4-[4_(5' ~fluoro-2'-side oxo _ [cyclopropane <, 3' _ 吲哚 厂 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( '-Side oxo-[cyclopropane<,3, _吲哚](2, Η)-yl)piperidin-1-yl]azepan-indole-carboxylate; 4 [4 ( 5 methyl-2-oxooxy-2',3,5',6'-tetrahydrospiro[吲哚• ―3'4'-pyrano]-Κ2Η)-yl)piperidin-1-yl ] piperidine-1-carboxylic acid ethyl ester; 4 [4 (5-methyl- 2- oxo-2',3,,5',6' _tetrahydro snail [吲η朵-3' 4' _ Piper]-ι(2Η)-yl) piperidine_丨-yl;|azetidine-indole-carboxylate; 4-[4-(5'~methyl-2'-side oxane - [cyclopropane <, 3, _ 吲哚] (2, Η) base) c Chen lean ~ 1-based] u Chen bite-1-acid ethyl ester; 4-[4-(5, methyl- 2'-S. oxyspiro-[cyclopropane 3, monofluorene]-r (2, fluorenyl)-ylpiperidin-1-yl]azepane-indole-carboxylic acid ethyl ester; 4-[4 -(3,3,6-trimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) 14 323406 201211028 派-1-基]piperidine-1-carboxylate Ethyl acetate; 4-[4-(3, 3, 6-trimethyl-2-oxo- 2, 3-dihydro-1H-indol-1-yl) Bite-1-restroxate methyl ester; 4-[4-(3, 3, 6-trimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) 0-bit bite -1-yl]azetidin-indole-carboxylic acid ethyl ester; 4-[4-(6'-methyl-2'-side oxo-[cyclopropane j,3, _吲哚卜Γ ( 2,H)-yl)piperidin-1-yl]piperidine-1-carboxylic acid ethyl ester; _ 4 [4 (6-methyl-2 _ oxoxane-[cyclopropanone _1,3'n _1,(2, η)-yl)piperidin-1-yl]piperidine -1--acid methyl ester; 4-[4-(6'-mercapto-2'-side oxyspiro-[cyclopropane y,3, _吲嗓]_Γ (2, H)-yl) -1-yl]azetazine _1_ethyl decanoate; 4 [4-(6-fluorenyl-2-yloxy-2',3',5',6'-tetrahydrospiro[ , oleyl-3,4'-pyrano]-1(2Η)-yl)piperidine-1-yl]piperidine-indole-carboxylic acid ethyl ester; 4 [4-(6-methyl-2- side Oxy- 2',3',5',6'-tetrahydrospiro[η引〇朵-3,4'-pyrano]-1(2Η)-yl)piperidin-1-yl]azacyclocycle Heptane_丨_carboxylic acid B φ 酉 ;; 4-[4-(6-methyl-2-oxo-2,3-dihydro-1Η-indol-1-yl)piperidin-1- 4-[4-(6-fluorenyl-2-oxo-2,3-dihydro-1H-indol-1-yl)piperidine Ethyl-1-phenyl]piperidine-1-carboxylate; 4-[4-(6-fluorenyl-2-oxo-2,3-dihydro-1H-indol-1-yl)piperidine Methyl-1-phenyl]piperidine-1-carboxylate; 4-[4-(6-methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl)piperidin Ethyl-1-yl]azetidin-1-carboxylate; 15 323406 201211028 (1R,5S)-3-[4-(6-methoxy-2- oxo-2, 3- Dihydro-1H-indol-1-yl)pyridin-1-yl]-8-indole bicyclo[3·21]octane_8_carboxylate Ethyl ester; 4-{[4-(6-methoxy-2-oxo-2,3-dihydro-1Η-indolyl)piperidin-1-yl]indolyl}piperidine Ethyl phthalate; 4 {[4(6-decyloxy-2-saloxy- 2',3',5',6'-tetrahydrospiro[吲口朵-3,4'-pipeper ]]-ΐ(2Η)-yl)piperidin-1-yl;|piperidinyl-indole-carboxylate; 4 {[4(6-methoxy-2-lateraloxy-2',3' , 5',6, _tetrahydrospiro[吲哚φ 3,4 _pyrano]_1(2H)-yl)piperidin-1-yl]azepane-1-carboxylic acid ethyl ester; (1R '5S)-3-[4-(6-oxime-2-oxooxy-2',3',5,6,-tetrahydrospiro[吲哚-3,4,-pyran]- L-(2H)-yl)-piperidine-i-yl]_8_吖bicyclo[3.2.1]octane-8-acid acid ethyl ester; 4-[4-(5-gas-6-fluoro-3) ,3-dimethyl-2-oxo-2,3-dihydro-111-fluorenylpiperidin-1-yl]piperidine-1-carboxylic acid ethyl ester; 4-[4-(3, 6-dimercapto-2-yloxy-2,3-dihydro-1H-indol-1-yl)piperidyl • octapeptide] piperidine-1-carboxylic acid ethyl ester; 4~[4-(3 , 6-dimethyl-2-oxooxy-2,3-dihydro-1Η-indol-1-yl)piperidinyl] piperidine-1-carboxylic acid methyl ester; 4 [4-(3, 6-dimercapto-2-yloxy-2,3-dihydro-1Η-indol-1-yl)n-substrate]azepane Ethyl-1-carboxylate; 4~[4-(5-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-indole-buyl) ° Ethyl azepane-1-carboxylate; 4·~{[4-(5-fluoro-3-indolyl-2-oxo-2,3-dihydro-1Η-吲哚- 1-yl)pyridin-1-yl]methyl}piperidine-1-carboxylic acid ethyl ester; 323406 16 201211028 4-{ [4-(3-mercapto-2-yloxy-2, 3-di Ethyl-1H-indol-1-ylpiperidin-1-yl]indolyl}piperidine-1-carboxylate; 4-[4-(5-fluorenyl-2-yloxy-2, Ethyl 3-dihydro-1H-indol-1-ylpiperidin-1-yl]azepane-1-carboxylate; 4-{[4-(5-mercapto-2-yloxy) Ethyl 2-, 3-dihydro-1H-indol-1-ylpiperidin-1-yl]methyl}piperidine-1-carboxylate; 4-{[4-(2-trioxy) -2,3-diar-argon-1H-indol-1-ylpiperidin-1-yl]methyl}piperidine-1-carboxylic acid ethyl ester; ® 4-[4-(6-fluoro-3- Ethyl-2-yloxy-2,3-diargon-1H-indol-1-yl)piperidin-1-yl]piperidine-1-carboxylic acid ethyl ester; 4-[4-(6- Ethyl-3-mercapto-2-oxo-2,3-diazapiperidin-1-yl]azepane-1-carboxylic acid ethyl ester; 4-[4-(5-fluoro-2) Methyl 2-oxo-2,3-dihydro-1H-indol-1-ylpiperidin-1-yl]piperidine-1-carboxylate; 4-[4-(6-fluorenyl-2 - sideoxy-2 ,3-dihydro-1 Η-α 丨B丨B-1-1-yl)α bottom bite φ-1-yl]piperidine-1-carboxylic acid oxime ester; 4-[4-(6-moin-2- Side oxy-2,3_diaza_1Η-α3Ιπ朵-1-yl) ° bottom bite _1 _ base] piperidine-1-carboxylic acid ethyl ester; 4-[4-(6-'; -Sideoxy-2,3-di---111-11-introduced 11-l-yl)t-l-yl]azetidin-1-carboxylic acid ethyl ester; 4_[4-(6 - Odor-2-sideoxy-2,3_dihydro-111-° cited α-l-yl) 11-end α-yl-yl]piperidine-1-carboxylic acid methyl ester; 4-[4- Ethyl (6-ethyl-2-oxo-2,3-dihydro-1 fluorene-hydrazinyl)piperidin-1-yl]piperidine-1-carboxylate; 17 323406 201211028 4-[ Ethyl 4-(6-ethyl-2-oxo- 2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]azepane-1-carboxylate; 4-[4-(2-oxo-propyl-propyl-2,3-diaza-1Η-α丨丨°-1~~ base) lyophilized-1-yl]piperidine-1-carboxylic acid ethyl ester 4-{[4-(5-Chloro-2-oxo-2,3-dihydroindol-1-yl)π-decyl-1-yl)methyl}methyl citrate;

(1R，5S)-3-[4-(5-氯-2-侧氧基-2, 3-二氫-1Η- °引 π朵-1-基）-η底咬-1-基]-8-σ丫雙環[3. 2. 1]辛烧-8-致酸乙酉旨； 4-{[4-(5-氟-2-侧氧基-2,3-二氫-111-吲哚-1-基）派咬一1- 基]甲基}π底唆-1-缓酸乙醋； (1R，5S)-3-[4-(5-氣-2-側氧基-2, 3〜二氫 嗓 _卜 基W1-基]雙環[3.2.;^^紐乙^ 4-[4-(6-曱基-2-側氧基-2,3-二盡 1u !甘以 氧〜1H-吲哚-1-基）哌啶 -1-基]氣雜壞庚烧叛酸乙自旨； 4-{ [4-(6-曱基-2-側氧基-2, 3-二 A、lu 1 a： Ί m Ί 1 Η~ 0弓卜朵-1 -基）Ο底咬 -1-基]甲基}π底啶-1-叛酸乙酯； 4-{[4-(6-氟-2-側氧基-2,3-二氫 Ηΐί , «· ί α弓丨嗓_ 1_基）派咬-1 - 基]甲基}哌啶-1-羧酸乙酯； σ弓卜朵-1-基）派咬-1- 4-[4-(6-氟-2-側氧基-2, 3-二氫〜ijj 基]氮雜環庚烷-1-羧酸乙酯； 2’ 3~二氫-1Η-吲哚-1- 氣〜1Η-吲哚-1—基）哌啶 4~[4-(5-氟-3, 3-二甲基-2-硫酮基 基）哌啶-1-基]哌啶-1-羧酸乙酯； 4-[4-(6-曱氧基-2-側氧基-2, 3-二 -1-基]-4-曱基派。定一 1-緩酸乙酯； 323406 18 201211028 4-[4-(6-氟-2-侧氧基-2,3_二氫-111_吲哚-1-基）哌啶-1-基]-4-曱基哌啶-1-羧酸乙醋； 4-[4-(6-曱基-2-侧氧基_2, 3—二氫-1H-吲哚-1-基）哌啶 一卜基]—4-曱基哌啶-1-羧酸乙酯； 4-[4-(6-曱氧基-3-甲基_2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌啶-1-基]-4-曱基旅啶一 1 一羧酸乙酯； (3-内）-3-[4-(6-曱基-2-側氧基-2, 3-二氫-1H-吲哚-1-基） 派唆-1-基]-8-σ丫雙環[3. 2. 1]辛院-8-叛酸乙酉旨； _ (3-外）-3-[4-(6-曱基-2_侧氧基-2, 3-二氫-1Η-吲哚-1-基） 派0定-1-基]α丫雙環[3. 2. 1 ]辛烧-8-叛酸乙酉旨； (3-内）-3-[4-(6-氟-2_侧氧基-2, 3-二氫-1Η-σ$ °朵-1-基） 哌啶-1-基]-8-吖雙環[3· 2. 1]辛烷-8-羧酸乙酯； (3-外）-3-[4-(6-氟-2-側氧基-2, 3-二氫-1Η-π5|π朵-1-基） 派°定-1-基]-8-β丫雙環[3. 2. 1 ]辛烧-8-幾酸乙西旨； (3-内）-3-[4-(2-側氧基-2, 3-二氫-1Η-吲哚-1-基）哌啶 φ -1-基]-8-吖雙環[3. 2· 1]辛烷-8-羧酸乙酯； (3-外）-3-[4-(2-側氧基-2, 3-二氫-1Η-吲哚-1-基）哌淀 -1-基]-8-吖雙環[3. 2.1]辛烷-8-羧酸乙酯； (3-内）-3-[4-(3, 6-二甲基-2-側氧基-2, 3-二氫-1Η-吲哚 -1-基）哌啶-1-基]-8-吖雙環[3· 2. 1]辛烷-8-羧酸乙酯； (3-内）-3-[4-(6-氟-3-甲基-2-侧氧基-2, 3-二氫-1Η-σ弓卜朵 -1-基）哌啶-1-基]-8-吖雙環[3. 2. 1]辛烷-8-羧酸乙酯； (3-内）-3-[4-(5-氟-3-甲基-2-側氧基-2, 3-二氫-1Η-吲哚 -1-基）哌啶-1-基]-8-吖雙環[3. 2. 1]辛烷-8-羧酸乙酯； 323406 19 201211028 4-{4-[5-氟-2-側氧基-3-(丙烷-2-亞基）-2,3-二氫-1-11- 吲哚-1-基]哌啶-l-基}哌啶_1_羧酸乙酯； 4-U-[5-氟-2-側氧基-3-(丙烷-2-基）-2, 3-二氫-1-H-, 峰-l-基>底啶-l-基}氮雜環庚烷-1-羧酸乙酯； 4-{4-[(3Z)-3-亞乙基-5-氟-2-側氧基-2, 3-二氫-1H-吲哚 -1-基]派啶-l-基}氮雜環庚烷羧酸乙酯； 4~[4-(3-乙基-5-氟-2-侧氧基-2,3-二氫-1H-吲哚-1-基） φ °辰唆-1-基]哌啶_1_羧酸乙酯； 4-{4-[(32)-5-氟-3-(2-曱基亞丙基）-2-側氧基-2,3-二氫 ~1H~吲哚―1—基]哌啶-l-基}哌啶-1-羧酸乙酯； 4~U-[5-氟-3-0-曱基丙基）—2-側氧基-2, 3-二氫-1H-吲 木1-基]Π辰唆基卜辰咬_1一敌酸乙酯； 扣[4-(3-環戊基_5_氟_2_側氧基_2, 3_二氫_1H_吲哚_丨_基） 哌啶-1-基]哌啶羧酸乙酯； 4、{4-[(32)_5_氟_2_側氧基_3_亞丙基_2,3_二氫-1^—吲哚 _ 基>辰咬-卜基}氮雜環庚院—卜羧酸乙醋； [4 (5-氟-2-側氧基-3-丙基—2, 3-二氫-1H-吲哚-1-基） 哌啶-1-基]哌啶-丨一羧酸乙酯； 4 Q [5-氟-2-側氧基_3_(四氫_2H—哌喃_4_基）23-二氫 〜1H~吲哚基]哌啶_1-基}哌啶-1-羧酸乙酯； 4 U-[(3Z)-5-氣-3-亞乙基—2_側氧基_2, 3_二氫—1H_吲哚 1基]哌啶-1-基卜底唆羧酸乙酯； 扣丨4-[5-氟-3—(氧雜環丁烷_3_基）_2_側氧基_2,3_二氫 Η弓丨木-1-基]哌啶基}哌啶一卜羧酸乙酯； 20 323406 201211028 4-{4-[5 -氣-2-側氧基-3-(四氮α夫喃-3-基）-2，3-二氮-1H-π引°朵-1 -基]旅。定-1 -基丨旅α定-1 -叛酸乙醋； 4-{4-[3-(氧雜環丁烷-3-基）-2-側氧基-2, 3-二氫-1Η-吲 哚-1-基]哌啶-l-基}哌啶-1-羧酸乙酯； 4-{4-[3-(四氫〇丫唉-3-基）-5 -氟-2-側氧基-2, 3-二氩-1Η-吲哚-1-基]哌啶-l-基}哌啶-1-羧酸乙酯； 4-{4-[5-氟-3-(氧雜環丁烷-3-基）-2-側氧基-2, 3-二氫 -1Η- °引π朵-1 -基]α底唆-1 -基}σ底唆-1 -叛酸甲西旨； ® 4-[4-(3-環丁基-5-氟-2-侧氧基-2, 3-二氫-1Η-吲哚-1-基） 哌啶-1-基]哌啶-1-羧酸乙酯； 4-[4-（3_乙基-6_曱基-2-側氧基-2，3-二氮-111-'0弓丨'〇朵-1-基） 哌啶-1-基]哌啶-1-羧酸甲酯； 4-{4-[6-(曱基-2-側氧基-3-(丙烷-2-基）-2, 3-二氫-1Η-吲哚-l-基]。辰咬-l-基卜底咬-1-羧酸甲酯； 4-{4-[5-氟-2-側氧基-3-(丙烷-2-基）-2, 3-二氫-1Η-吲哚 φ -1-基]哌啶-l-基}哌啶-1-羧酸曱酯； 4-[4-(3-乙基-5-氟-2-侧氧基-2, 3-二氫-1Η-吲哚-1-基） 哌啶-1-基]哌啶-1-羧酸乙酯； 4-{4-[2-侧氧基-3-(丙烷-2-基）-2, 3-二氫-1Η-吲哚-1-基] 哌啶-l-基}哌啶-1-羧酸乙酯； 4-[4-(3-環丁基-2-側氧基-2, 3-二氫-1Η-吲哚-1-基）哌啶 -1-基]哌啶-1-羧酸乙酯； 4-[4-(3-環戊基-2-侧氧基-2,3-二氫-111-'1引11朵-1-基）1〇辰唆 -1-基]哌啶-1-羧酸乙酯； 21 323406 201211028 4-[4-(2-側氧基-3-丙基—2,3-二氫-1H-吲哚-1-基）哌啶 -卜基]哌啶-1-羧酸乙酯； 4-{4-[2-側氧基-3-(四氫-2H-哌喃-4-基）-2, 3-二氫-1H- °引哚-1-基]哌啶-l-基}哌啶羧酸乙酯； 4-{4-[2-側氧基-3-(戊烷-3-基）-2, 3-二氫-1H-吲哚-1-基] 0辰咬-1-基}派咬-1-致酸乙酯； 4-{4-[2-側氧基-3-（四氫呋喃-3-基曱基）-2, 3-二氫-1H- 吲哚—1-基]哌啶-l-基}哌啶-1-羧酸乙酯； 4-{4-[3-(環丙基甲基）-2-側氧基-2, 3-二氫-1H-吲哚-1-基]°底咬-1-基}派咬-1-叛酸乙酯； 4-[4-(3-乙基-2-侧氧基-2, 3-二氫-1H-吲哚-卜基）哌啶 -1-基]哌啶-1-羧酸乙酯； 4-[4-(3-乙基-2-侧氧基-2, 3-二氫-1H-吲哚-1-基）哌啶 -1-基]氮雜環庚烧-1-叛酸乙酯； 4-{4-[3-(1，3-曙嗤-2-基甲基）-2-側氧基-2, 3-二氫-1H- ^ 吲哚-1-基]派咬-1-基卜辰咬-1-敌酸乙酯； 4-{4-[2-侧氧基-3-(丙烧-2-基）-2,3-二氫-111-吲哚-1-基] 氮雜環庚烧-1-基卜底咬-1-叛酸乙酉旨； 4-[4-(2-側氧基-3-丙基-2, 3-二氫-1H-吲哚-卜基）哌咬 -1-基]氮雜環庚烷-1-羧酸乙酯； 4-{4-[2-側氧基-3-(四氫呋喃-3-基）-2, 3-二氫-lH-α弓卜朵 -1-基]旅咬-l-基}氮雜環庚院-1-叛酸乙酯； 4-{4-[3-(庚院-4-基）-2-側氧基-2,3-二氫-111-吲哚-1-基] 旅咬-l-基}氮雜環庚烧-1-致酸乙酯； 323406 22 201211028 4-{4-[2-側氧基-3-(四氫-2H-哌喃-4-基）-2, 3-二氫-1H- °引π朵-1-基]旅咬-1-基丨氣雜環庚燒_ι_緩酸乙醋； 4 - {4-[2-側氧基-3-(戊烷-3-基）-2,3-二氫-1Η-吲哚-1-基] 哌啶-l-基}氮雜環庚烷-1-羧酸乙酯； 4-{4-[2-側氧基-3-(四氫'1夫1»南-3-基）_2,3-二氫-；[1{-〇引'1朵 -1-基]哌啶-l-基}哌啶-1-羧酸乙酯； 4-[4-(3-丁基-2-侧氧基-2, 3-二氫-1Η-吲哚-1-基）哌啶 -1-基]派咬-l-竣酸乙酯； • 4-{4-[3(呋喃-3-基曱基）-2-侧氧基-2,3-二氫-111-吲哚 -1-基]哌啶-l-基}哌啶-1-羧酸乙酯； 4-{4-[3-(羥基曱基）-6-曱氧基-3-甲基-2-側氧基-2, 3-二 虱-1Η-σ弓丨嗓-1-基]u底咬-1-基卜辰咬_1—敌酸乙酉旨； 4-{4-[3-(羥基曱基）-3, 6一二曱基一2_侧氧基_2, 3_二氫 -1Η-吲哚-1-基]哌啶_ι_基卜辰啶―丨―羧酸乙酯； 4-{4-[5-氟-3-(羥基曱基）-3-甲基-2-侧氧基-2, 3-二氫 • -1Η_°弓卜朵-1-基]哌啶-l-基}氮雜環庚烷-1—羧酸乙酯； 4-{4-[3-(羥基甲基）一3_甲基-2-側氧基-2, 3-二氫-1Η-吲 D朵-1-基]0辰咬-1-基}甲基〇辰咬_1_緩酸乙酯； 4_{4-[5-氟-3-（羥基曱基）-3-曱基-2-側氧基-2, 3-二氫 -1H-。引嗓-l-基]哌啶―卜基丨曱基哌啶羧酸乙酯； 4-{4-[6-氟-3-(羥基曱基）-3_曱基一2-侧氧基_2, 3-二氫 -1Η-叫卜朵-1-基]哌啶_丨_基丨哌啶_丨_羧酸乙酯； 4-{4-[6-氟-3-(羥基曱基）一3一曱基一2-侧氧基一2, 3-二氫 -1Η-,»朵-1-基]哌啶―丨—基丨氮雜環庚烷 <—羧酸乙酯； 23 323406 201211028 4-{4-[3-(羥基甲基）一3, 6_二曱基_2_侧氧基_2, 3_二氫 -1H-吲哚-1-基]哌啶-丨_基卜底啶_丨_羧酸乙酯； 4_{4-[3_(羥基曱基）一3,6_二曱基_2一側氧基_2 3_二氫 -ΙΗ-e弓卜朵-1-基]哌啶-丨_基}氮雜環庚烷_丨_羧酸乙酯； 4-{4-[3-(羥基曱基）一3_曱基_2_側氧基_2, 3_二氫_1Η一吲 哚-1-基]派啶-l-基}哌啶-1-羧酸乙酯； (3-内）-3-{4-[6-氟-3-(羥基甲基）-3-曱基-2-側氧基 -2, 3-二氫-1Η-吲哚-1-基]哌啶-卜基卜8_吖雙環[3. 2. • 辛烷-8-羧酸乙酯； (3-内）-3-{4-[3(羥基甲基）一3, 6-二曱基-2-侧氧基-2, 3- 二氫-lH-,η朵-丨_基]哌啶_丨_基卜8_吖雙環[3. 2.丨]辛烷 -8-羧酸乙酯； 4-{4-[3-乙基-3-(羥基曱基）-2-側氧基-2, 3-二氫-1H-吲 哚-1-基>辰啶-l-基}哌啶-1 —羧酸乙酯； 4-[4-(3-乙基-3, 6-二曱基-2-側氧基-2, 3-二氳-1H-吲哚 • -1-基）哌啶-1-基]派啶-1-羧酸乙酯； 4-[4-(6-氟-2-侧氧基-2’，3,，5,，6,-四氫螺[吲哚-3, 4’ - 哌喃]-1-(2H)-基）哌啶-1-基]曱基哌啶―丨―羧酸乙酯； 4-[4-(6-曱基-2-側氧基-2’，3’，5,，6’ -四氫螺[吲哚 -3, 4’ -哌喃]-1-(2H)-基）哌啶-1-基]曱基哌啶一卜羧酸乙 酯； (3-内）-3-[4-(6-曱基-2-侧氧基-2,，3,，5’，6,-四氫螺[吲 哚-3,4’ -哌喃]-1-(2H)-基）哌啶-1-基]-8-吖雙環[3. 2. 1] 辛院-8-魏酸乙醋； 24 323406 201211028 (3-外）-3-[4-(6-氟-2-侧氧基-2’，3,，5,，6’ _四氫螺[吲哚 -3, 4’ -旅喃]-l-(2H)-基）旅咬-1 —基]_8_吖雙環[3. 2. 1 ]辛 统-8-致酸乙g旨； 4-[4-(3-羥基-2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌啶 -1-基]0底咬-1-羧酸乙酯； 4_[4-(2-侧氧基-2, 3-二氫-1H-吲哚-1-基）哌啶-1-基]哌 啶-1-羧酸丁酯-2-炔； • 4-[4-(2-侧氧基-2, 3-二氫-1H-吲哚-卜基）哌啶-1-基]哌 啶-1-羧酸2-溴乙酯； 4-[4-(2-侧氧基-2, 3-二氫-1HH °朵-1-基）旅咬-1-基]派 °定-1-羧酸2-氯乙酯； 4 [4-(2-侧氧基-2, 3-二氫-111-吲°朵-1-基）π底咬-1-基]派 °定-1-羧酸2-丙酯； 4~[4-(2-侧氧基-2,3-二氫-1H-吲哚-1-基）哌啶-1 —基]哌 啶一 1-羧酸甲酯； 參4-[4-(2-側氧基-2,3-二氫-1HH1-基）派咬-卜基]氮 雜環庚烷-1-羧酸乙酯； 4 [4-(2-側氧基-2, 3-二氫-1H-吲哚-1-基）旅啶_ι_基]氮 雜環庚烷-1-羧酸甲酯； [(2侧氧基-2, 3-—風_1Η-α引《»朵-1-基）π底咬_ι_基]氣 雜環庚烷—1-羧酸丙酯-2-炔； 4 [4 (2~侧氧基_2,3-二氫-1Η-吲哚-1-基）哌啶_丨_基]氮 雜環庚燒-1 -叛酸丁-2-醋； [(6氣-2-側軋基-2, 3-二氫-lH-°弓卜朵-1-基）旅唆-1- 323406 25 201211028 基]哌啶-1-羧酸2-氟乙酯； 4-[4-(5-氯-2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌啶-1-基]哌啶-1-羧酸2-丙酯； 4-[4-(5-氯-2-側氧基-2, 3-二氳-1H-吲哚-1-基）哌啶-1-基]哌啶-1-羧酸丙-2烯酯； 4-[4-(5 -氣-2-側氧基-2，3-二氳-1Η-α?|π朵-1-基）派唆-1-基]哌啶-1-羧酸2-甲氧乙酯； 4-[4-(6-曱基-2-側氧基-2, 3-二氳-1Η-吲哚-1-基）哌啶 ® -1-基]哌啶-1-羧酸丙-2-烯酯； 4_[4-(6-曱基-2-側氧基-2，3 -二氫-1Η-α引D朵-1-基）σ底。定 -1-基]哌啶-1-羧酸丙2-氟乙酯； 4-[4-(5-敦-2-側氧基-2，3-二氫-1Η-, π朵-1-基）派β定-1-基]哌啶-1-羧酸2-曱氧基乙酯； 4-[4-(5 -氯-2-側氧基-2, 3-二氫-1Η-, σ朵-1-基）娘咬-1-基]氮雜環庚烷-1-羧酸曱酯； 4-[4^(3，3_二氟-2-側氧基-2，3-二氮-111-0引 α朵-1 -基）π辰唆 -1-基]哌啶-1-羧酸乙酯； (1R，5S)_3_[4-(3, 3 -二氟-2-側氧基-2，3_ 二氮-1Η_° 引嗓 -1-基）_0底咬_1_基]_8-°丫雙環[3. 2. 1]辛烧-8-叛酸乙酉旨； 4_[4_(3，3_二氣-2-侧氧基-2，3_二氮-1 Η_π引π朵_ 1 _基）α底唆 -1-基]氮雜環庚烷-1-羧酸曱酯； (1R，5S)-3-{4-[3-(羥基曱基）-6-曱氧基-3-曱基-2-侧氧 基-2，3_二氮_1H_ °引π朵-1-基]-旅咬-1_基}-8_。丫雙環 [3. 2. 1]辛烷-8-羧酸乙酯； 26 323406 201211028 4-{4-[3-(羥基甲基）-6-曱氧基-3-甲基-2-側氧基-2, 3-二 氫-1H-吲哚-1-基]哌啶-i-基}氮雜環庚烷-1-羧酸乙酯； 4-{4-[5-氟-3-(羥基曱基）-3-甲基-2-侧氧基-2, 3-二氫 -1H-吲哚-1-基]哌啶-i-基}哌啶-1-羧酸乙酯； 4-[4-(6-氟-2-侧氧基-2’，3’，5’，6’ -四氫螺[吲哚-3, 4’ -哌喃]-1-(2H)-基）哌啶-1-基]氮雜環庚烷-1-羧酸乙酯； 4-[4-(6-氟-2-侧氧基-2’，3’，5’，6’ -四氫螺[吲哚-3, 4’ -$ 哌喃]-1-(2H)-基）哌啶-1-基]哌啶-1-羧酸乙酯； 4-[4-(3, 6-二甲基-2-側氧基-2, 3-二氫-吲哚-1-基）α辰 啶-1-基]氮雜環庚烷-1-羧酸乙酯； 4-[4-(6-氟-3甲基-2-側氧基-2, 3-二氫-1Η-吲哚-1-基）哌 啶-1-基]哌啶-1-羧酸乙酯； 4-[4-(6-氟-3甲基-2-侧氧基-2, 3-二氫_1Η-吲哚-1-基）哌 π定-1-基]氮雜環庚院-1-敌酸乙酯； 4~[4-(2-侧氧基-2, 3-二氫-1Η-吲哚-1-基）哌啶-1-基] % -4-曱基氮雜環庚烷-1-羧酸乙酯； 4-[4-(2-側氧基-2, 3-二氫-1Η-吲哚-1-基）哌啶-1-基] -4-曱基哌啶-1-羧酸乙酯； 4〜[4-(5-氟-2-侧氧基-2, 3-二氫-1Η-吲哚-1-基）哌啶-1-基]-4-甲基旅咬-1-竣酸乙酯； 4-[4-(5-曱基-2-側氧基-2, 3-二氫-1Η-吲哚-1-基）哌啶 -1-基]-4-甲基旅咬-1-叛酸乙酯； 444-(5-曱氧基-2-侧氧基-2, 3-二氫-1Η-吲哚-1-基）哌啶 -1-基]-4-甲基派咬-1-叛酸乙酯； 27 323406 201211028 (1R，5S)-3-{4-[5-曱基-2-側氧基-2, 3-二氫-1H-吲哚-1 一 基]-哌啶-1-基}-8_吖雙環[3 2.丨]辛烷_8_羧酸乙酯； (1R，5S)-3-{4-[5-甲氧基-2-侧氧基-2, 3-二氫-1H-吲哚 -1-基]-哌啶-1-基}-8_吖雙環[3·21]辛烷_8—羧酸乙酯； 4-[4-（3-經基-3-曱基_2_侧氧基_2,3_二氫_1Η 一吲哚_卜基） 0底唆-1-基]-4-甲基派。定-1 一敌酸乙酯； 4-[4-(3-羥基-3-曱基一 2_側氧基_2,3—二氫_1Η_吲哚基） 旅啶-1-基]-4-曱基哌啶-1—羧酸曱酯； ^ 4_[4_(3—氟—3-羥基曱基-2-側氧基-2, 3-二氫-1Η-吲哚-1- 基）0底咬-1-基]-4-曱基哌啶-1-羧酸乙酯；及 4-[4-(3-氟-3-羥基甲基-2-側氧基-2,3-二氫-1Η-吲哚-1 一 基）旅啶-1-基]-4-曱基哌啶-1-羧酸曱酯； 所構成群組之中。 [13] —種中樞疾病預防及/或治療劑，其係含有上述[丨]、 [2a]、[2]、[3]、[4a]、[4]、[5]、[6a]、[6]、[7]、[8]、 φ [9]、[l〇]、[11]或[12]所述之化合物。 [14] 如上述[13]所述之預防及/或治療劑，其中，中樞疾病 係阿兹海默症（Alzheimer’s disease)及/或精神***症 (Schizophrenia) ° [15] —種醫藥組成物，其係含有上述[1]、[2a]、[2]、[3]、 [4a] 、 [4] 、 [5] 、 [6a] 、 [6] 、 [7] 、 [8] 、 [9] 、 [1〇] 、 [11] 或[12]所述之化合物或其藥學上容許的鹽及其藥學上容許 的載體。 (發明之效果）(1R,5S)-3-[4-(5-chloro-2-oxo-2,3-dihydro-1Η- °引π朵-1-yl)-η bottom bit-1-yl]- 8-σ丫bicyclo[3.2.1]octane-8-acidic acetazone; 4-{[4-(5-fluoro-2-oxo-2,3-dihydro-111-oxime) -1-yl)-bite 1-yl]methyl}π- bottom 唆-1--acid vinegar; (1R,5S)-3-[4-(5-gas-2-sideoxy-2, 3~Dihydroindole_Buyl W1-yl]bicyclo[3.2.;^^纽乙^ 4-[4-(6-mercapto-2-yloxy-2,3-dione 1u! ~1H-indol-1-yl)piperidin-1-yl]gas sulphide sulphonic acid; 4-{[4-(6-mercapto-2- oxo-2, 3- 2A, lu 1 a: Ί m Ί 1 Η~ 0 弓 朵 1 - yl) Ο 咬 -1- yl] methyl} π pyridine -1- oxo acid ethyl ester; 4-{[4- (6-fluoro-2-oxo-2,3-dihydrofluorene, «· ί α丨嗓丨嗓_ 1_yl) pie bite-1 -yl]methyl}piperidine-1-carboxylic acid ethyl ester ; σ弓卜朵-1-yl) pie bite-1- 4-[4-(6-fluoro-2-indolyl-2,3-dihydro~ijjyl]azepane-1-carboxylate Ethyl acetate; 2' 3~ dihydro-1 Η-吲哚-1- gas ~1Η-吲哚-1-yl) piperidine 4~[4-(5-fluoro-3, 3-dimethyl-2 Ethyl thioketo)piperidin-1-yl]piperidine-1-carboxylate; 4-[4-(6-decyloxy-2- oxo-2, 3- Di-1-yl]-4-indolyl. Dimethyl-acid ethyl ester; 323406 18 201211028 4-[4-(6-fluoro-2-sidedoxy-2,3_dihydro-111_吲哚-1-yl)piperidin-1-yl]-4-mercaptopiperidine-1-carboxylic acid ethyl acetate; 4-[4-(6-fluorenyl-2-yloxy-2, 3- Ethyl dihydro-1H-indol-1-yl)piperidinyl- 4-mercaptopiperidine-1-carboxylate; 4-[4-(6-decyloxy-3-methyl_ Ethyl 2-oxo-2,3-dihydro-1H-indol-1-ylpiperidin-1-yl]-4-indolyl-l-carboxylate; (3-in)- 3-[4-(6-Mercapto-2-yloxy-2,3-dihydro-1H-indol-1-yl)pyr-1-yl]-8-σ丫bicyclo[3. 2 1]辛院-8-性酸乙酉; _ (3-Exo)-3-[4-(6-mercapto-2_sideoxy-2,3-dihydro-1Η-吲哚-1 -基) 派零定-1-基]α丫bicyclo[3. 2. 1 ]辛烧-8-- 叛 酉 ;; (3-内)-3-[4-(6-fluoro-2_ side Ethoxy-2,3-dihydro-1 Η-σ$ °-1-yl)piperidin-1-yl]-8-indole bicyclo[3·2.1]octane-8-carboxylic acid ethyl ester; (3-exo)-3-[4-(6-fluoro-2-indolyl-2,3-dihydro-1Η-π5|π朵-1-yl) 派°定-1-yl]-8 -β丫Bicyclo[3.2.1]octyl-8-acid acid; (3-in)-3-[4-(2-o-oxy-2,3-dihydro-1Η-吲哚-1-yl) piperidine φ -1-yl]-8-indole bicyclo[3. 2·1]octane-8-carboxylic acid ethyl ester; (3-exo)-3-[4-(2- oxo-2, 3- Dihydro-1Η-indol-1-yl)piperazin-1-yl]-8-indole bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester; (3-in)-3-[4- (3,6-Dimethyl-2-oxo-2,3-dihydro-1Η-indol-1-yl)piperidin-1-yl]-8-indole bicyclo[3·2.1] Ethyl octane-8-carboxylate; (3-inter)-3-[4-(6-fluoro-3-methyl-2-oxo-2,3-dihydro-1Η-σ -1-yl)piperidin-1-yl]-8-indole bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester; (3-in)-3-[4-(5-fluoro- 3-Methyl-2-oxo-2,3-dihydro-1Η-indol-1-ylpiperidin-1-yl]-8-indole bicyclo[3.2.1]octane-8 -carboxylate; 323406 19 201211028 4-{4-[5-fluoro-2-oxo-3-(propane-2-ylidene)-2,3-dihydro-1-11-indole- Ethyl 1-piperidine-l-yl}piperidine-1-carboxylate; 4-U-[5-fluoro-2-oxo-3-(propan-2-yl)-2, 3- Dihydro-1-H-, peak-l-yl group> pyridine-l-yl}azepane-1-carboxylic acid ethyl ester; 4-{4-[(3Z)-3-ethylene -5-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl]pyridin-1-yl}azepanecarboxylic acid ethyl ester; 4~[4-( 3-ethyl-5-fluoro-2-oxo-2,3-dihydro-1H -吲哚-1-yl) φ ° 唆 唆-1-yl] piperidine_1_carboxylic acid ethyl ester; 4-{4-[(32)-5-fluoro-3-(2-mercapto propylene Ethyl)-2-oxo-2,3-dihydro~1H~indole-1-yl]piperidine-1-yl}piperidine-1-carboxylic acid ethyl ester; 4~U-[5-fluoro -3-0-mercaptopropyl) 2-sideoxy-2,3-dihydro-1H-eucalyptus 1-yl] Π辰唆基卜辰 bite_1 an acid ethyl ester; buckle [4 -(3-cyclopentyl_5_fluoro_2_sideoxy-2,3_dihydro_1H_吲哚_丨-yl)piperidin-1-yl]piperidinecarboxylic acid ethyl ester; {4-[(32)_5_Fluoro-2_sideoxy_3_propylene-2,3_dihydro-1^-吲哚_ base> Chenbiti-Buji} Azaft - carboxylic acid ethyl vinegar; [4 (5-fluoro-2-oxooxy-3-propyl-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]piperidine - hydrazine monocarboxylic acid ethyl ester; 4 Q [5-fluoro-2-oxooxy_3_(tetrahydro-2H-pyran-4-yl)23-dihydro~1H~indolyl]piperidine_1 -yl}piperidin-1-carboxylic acid ethyl ester; 4 U-[(3Z)-5-gas-3-ethylene- 2_sideoxy-2,3_dihydro-1H_吲哚1 group Ethyl piperidin-1-ylpyridinium carboxylate; 4-[5-fluoro-3-(oxetane-3-yl)-2-oxo-2,3-dihydroindole Toxa-1-yl]piperidinyl}piperidine-carboxylic acid ethyl ester; 20 323406 2012110 28 4-{4-[5-Gas-2-oxo-3-(tetrazo-α-furan-3-yl)-2,3-diaza-1H-π 引度-1 -基]Brigade .定-1 - 丨 丨 α 定 定 - - - - - - - - - - 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- Ethyl 1 Η-indol-1-yl]piperidin-l-yl}piperidine-1-carboxylate; 4-{4-[3-(tetrahydroindol-3-yl)-5-fluoro- Ethyl 2-oxo-2,3-diaror-11-indol-1-yl]piperidine-1-yl}piperidine-1-carboxylate; 4-{4-[5-fluoro-3 -(oxetan-3-yl)-2-oxo-2,3-dihydro-1Η- ° π 朵-1 -yl]α bottom 唆-1 -yl}σ bottom 唆-1 - Tetrandrexate; ® 4-[4-(3-Cyclobutyl-5-fluoro-2-oxo-2,3-dihydro-1Η-indol-1-yl) piperidine-1- Ethyl piperidine-1-carboxylate; 4-[4-(3_ethyl-6-mercapto-2-yloxy-2,3-diaza-111-'0 bow 丨'〇 -1-yl)piperidin-1-yl]piperidine-1-carboxylic acid methyl ester; 4-{4-[6-(indolyl-2-oxo-3-(propan-2-yl)- 2,3-Dihydro-1Η-吲哚-l-yl]. Chenbiting-l-Kibdi bite-1-carboxylic acid methyl ester; 4-{4-[5-fluoro-2-sideoxy- 3-(propan-2-yl)-2,3-dihydro-1Η-吲哚φ-1-yl]piperidine-1-yl}piperidine-1-carboxylic acid oxime ester; 4-[4-( 3-ethyl-5-fluoro-2-oxo-2,3-dihydro-1Η-indol-1-yl)piperidin-1-yl]piperidine-1-carboxylic acid ethyl ester; 4- {4-[2-Sideoxy-3-(propane) -2-yl)-2,3-dihydro-1Η-indol-1-yl] piperidine-1-yl}piperidine-1-carboxylic acid ethyl ester; 4-[4-(3-cyclobutyl Ethyl 2-oxo-2,3-dihydro-1Η-indol-1-ylpiperidin-1-yl]piperidine-1-carboxylate; 4-[4-(3-cyclopentyl) Ethyl-2-oxo-2,3-dihydro-111-'1#11-1-yl)1〇辰唆-1-yl]piperidine-1-carboxylic acid ethyl ester; 21 323406 201211028 4 -[4-(2-Sideoxy-3-propyl-2,3-dihydro-1H-indol-1-yl)piperidin-buyl]piperidine-1-carboxylic acid ethyl ester; 4- {4-[2-Sideoxy-3-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H- ° fluoren-1-yl]piperidine-l-yl} Ethyl piperidinecarboxylate; 4-{4-[2-o-oxy-3-(pentan-3-yl)-2,3-dihydro-1H-indol-1-yl] 0-bit bite 1-yl} ketone-1-acid ethyl ester; 4-{4-[2-oxo-3-(tetrahydrofuran-3-ylindenyl)-2,3-dihydro-1H-indole- Ethyl 1-piperidine-l-yl}piperidine-1-carboxylate; 4-{4-[3-(cyclopropylmethyl)-2-oxo-2,3-dihydro- 1H-吲哚-1-yl]°Bottom--1-yl}-biting--1-reoxamate ethyl ester; 4-[4-(3-ethyl-2-yloxy-2,3-dihydrogen) -1H-indole-bu)piperidin-1-yl]piperidine-1-carboxylic acid ethyl ester; 4-[4-(3-ethyl-2-yloxy-2,3-dihydro- 1H-吲哚-1-yl Piperidin-1-yl]azepane-1-one acid; ethyl 4-{4-[3-(1,3-indol-2-ylmethyl)-2-yloxy- 2, 3-Dihydro-1H-^ 吲哚-1-yl]-biti-1-kib-butyl octazone-1-acidate ethyl ester; 4-{4-[2- oxo-3-(propyl Pyridin-2-yl)-2,3-dihydro-111-indol-1-yl]azepane-1-ylidene bite-1-retensive acid; 4-[4-(2 -ethyloxy-3-propyl-2,3-dihydro-1H-indole-buyl)piperidin-1-yl]azepane-1-carboxylic acid ethyl ester; 4-{4- [2-Sideoxy-3-(tetrahydrofuran-3-yl)-2,3-dihydro-lH-α-bend-1-yl] brigade-l-yl}azetidin-1- Oreic acid ethyl ester; 4-{4-[3-(hhenyl-4-yl)-2-yloxy-2,3-dihydro-111-indol-1-yl] brittle bite-l-yl }Azacycloheptan-1-acid ethyl ester; 323406 22 201211028 4-{4-[2-Sideoxy-3-(tetrahydro-2H-pyran-4-yl)-2, 3-di Hydrogen-1H- ° π 朵-1-yl] brigade -1- 丨 丨 杂环 庚 _ _ ι ι ι ι 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 -3-yl)-2,3-dihydro-1Η-indol-1-yl] piperidine-1-yl}azepane-1-carboxylic acid ethyl ester; 4-{4-[2- Sideoxy-3-(tetrahydro'1f1»South-3-yl)_2,3-dihydro-;[1{-〇'1-1-yl]piperidine-l-yl}peri 1-carboxylic acid ethyl ester; 4-[4-(3-butyl-2-oxo-2,3-dihydro-1Η-indol-1-yl)piperidin-1-yl] -l-ethyl decanoate; • 4-{4-[3(furan-3-ylindenyl)-2-yloxy-2,3-dihydro-111-indol-1-yl]piperidine -l-yl}ethyl piperidine-1-carboxylate; 4-{4-[3-(hydroxyindenyl)-6-decyloxy-3-methyl-2-oxo-2, 3- Diterpene-1Η-σ丨嗓丨嗓-1-yl]u bottom bite-1-kibchen bite_1-dimer acid B-type; 4-{4-[3-(hydroxyindenyl)-3, 6- Dimercapto- 2-sideoxy-2,3-dihydro-1Η-indol-1-yl]piperidine _ι_ kib- yl pyridine- oxime-carboxylic acid ethyl ester; 4-{4-[5 -fluoro-3-(hydroxyindenyl)-3-methyl-2-oxo-2,3-dihydro• -1Η_°bend-1-yl]piperidine-l-yl}nitrogen heterocycle Ethyl heptane-1 -carboxylate; 4-{4-[3-(hydroxymethyl)-3-methyl-2-oxo-2,3-dihydro-1Η-吲D--1- Base] 0 chen-1-yl}methyl 〇chen bite _1_acid ethyl ester; 4_{4-[5-fluoro-3-(hydroxyindenyl)-3-mercapto-2-yloxy -2,3-Dihydro-1H-. 4-(4-[6-fluoro-3-(hydroxyindenyl)-3-fluorenyl- 2-oxooxy group _2, 3-dihydro-1 fluorene-indole-1-yl] piperidine _ 丨 丨 丨 丨 piperidine _ 丨 carboxylic acid ethyl ester; 4-{4-[6-fluoro-3-(hydroxy 曱)) 3- methoxyl- 2- oxo- 2,3-dihydro-1 fluorene-, oxa-1-yl]piperidine-hydrazinyl-azetidinyl-ethyl carboxylate ; 23 323406 201211028 4-{4-[3-(Hydroxymethyl)-3,6-diindolyl-2-ylidene-2,3-dihydro-1H-indol-1-yl]piperidine -丨_基普底啶_丨_carboxylate; 4_{4-[3_(hydroxyindenyl)-3,6-diindenyl-2-oneoxy-2 3_dihydro-indole-e Ethyl bromide-1-yl]piperidinyl-fluorenyl-azetidine-indole-carboxylate; 4-{4-[3-(hydroxyindenyl)-3-indenyl-2-one Ethyloxy 2,3-dihydro-1-inden-1-yl]pyridin-1-yl}piperidine-1-carboxylic acid ethyl ester; (3-in)-3-{4-[6- Fluoro-3-(hydroxymethyl)-3-indolyl-2-oxo-2,3-dihydro-1Η-indol-1-yl]piperidine-bukib 8_吖bicyclo[3. 2. • Octane-8-carboxylic acid ethyl ester; (3-in)-3-{4-[3(hydroxymethyl)-3,6-dimercapto-2-yloxy-2, 3- Dihydro-lH-, η-丨-yl]piperidine _丨_基卜8_吖bicyclo[3. 2.丨]octane-8-carboxylic acid ethyl ester; 4-{4-[3-ethyl-3-(hydroxyindenyl)-2-yloxy -2,3-dihydro-1H-indol-1-yl> henidine-l-yl}piperidine-1 -carboxylic acid ethyl ester; 4-[4-(3-ethyl-3, 6- Dimethyl-2-yloxy-2,3-diindole-1H-indole-1-yl)piperidin-1-yl]pyridin-1-carboxylic acid ethyl ester; 4-[4-( 6-fluoro-2-p-oxy-2',3,,5,,6,-tetrahydrospiro[吲哚-3,4'-piperanyl]-1-(2H)-yl)piperidine-1 -yl]nonylpiperidine-oxime-carboxylate; 4-[4-(6-fluorenyl-2-oxo-2',3',5,6'-tetrahydrospiro[吲哚-3,4'-piperidol-1-(2H)-yl)piperidin-1-yl]nonylpiperidine- carboxylic acid ethyl ester; (3-in)-3-[4-(6- Mercapto-2-yloxy-2,,3,,5',6,-tetrahydrospiro[吲哚-3,4'-piperanyl]-1-(2H)-yl)piperidin-1- ]]-8-吖 bicyclo[3. 2. 1] 辛院-8-weiwei vinegar; 24 323406 201211028 (3-exo)-3-[4-(6-fluoro-2- oxo-2 ',3,,5,,6' _tetrahydrospiro[吲哚-3, 4' - britant]-l-(2H)-yl) brigade bite-1 —yl]_8_吖bicyclo[3. 2 . 1 ]Xintong-8-acidic B; 4-[4-(3-hydroxy-2-oxo-2,3-dihydro-1H-indol-1-yl)piperidine -1-yl]0 bottom bite-1-carboxylic acid ethyl ester; 4_[4-(2-o-oxy-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl] Piperidine-1-carboxylic acid butyl ester-2-yne; • 4-[4-(2-trioxy-2,3-dihydro-1H-indole-buyl)piperidin-1-yl]piperidin 2-bromoethyl pyridine-1-carboxylate; 4-[4-(2-trioxy-2,3-dihydro-1HH °dol-1-yl) travel bite-1-yl] 1-carboxylic acid 2-chloroethyl ester; 4 [4-(2-Sideoxy-2,3-dihydro-111-吲°-l-yl) π-bottom-1-yl] 1-propyl 2-carboxylate; 4~[4-(2-Sideoxy-2,3-dihydro-1H-indol-1-yl)piperidin-1 -yl]piperidine-1-carboxylate Methyl ester; benzyl 4-[4-(2-o-oxy-2,3-dihydro-1HH1-yl) ketone-buki]azepane-1-carboxylic acid ethyl ester; 4 [4 -(2-Sideoxy-2,3-dihydro-1H-indol-1-yl)-branched-yl-yl]azetidene-l-carboxylic acid methyl ester; [(2 side oxy group) -2, 3--Wind_1Η-α引《»朵-1-基)π底咬_ι_基]Heterocyclic heptane-1-carboxylic acid propyl ester-2-yne; 4 [4 (2 ~Sideoxy-2,3-dihydro-1Η-indol-1-yl) piperidine_丨_yl]azepane-1 - tartrate butyl-2-acetate; [(6 gas-2 - side rolling base-2, 3-dihydro-lH-°bend-1-yl) travel -1- 323406 25 201211028 base] piperidine 2-fluoroethyl ester of 1-carboxylic acid; 4-[4-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl] 2-propyl ester of piperidine-1-carboxylate; 4-[4-(5-chloro-2-oxo-2,3-dioxin-1H-indol-1-yl)piperidin-1-yl Piperidine-1-carboxylic acid prop-2-enyl ester; 4-[4-(5-gas-2-oxo-2,3-dioxan-1Η-α?|π朵-1-yl)唆-1-yl] piperidine-1-carboxylic acid 2-methoxyethyl ester; 4-[4-(6-mercapto-2-yloxy-2,3-diindole-1Η-吲哚-1 -yl)piperidine®-1-yl]piperidine-1-carboxylic acid prop-2-enyl ester; 4_[4-(6-mercapto-2-yloxy-2,3-dihydro-1Η- α leads to D-1-yl) σ bottom. Di-1-yl]piperidine-1-carboxylic acid propyl 2-fluoroethyl ester; 4-[4-(5-dun-2-yloxy-2,3-dihydro-1Η-, π-dot-1 -yl)pyrylene-1-yl]piperidine-1-carboxylic acid 2-methoxyethyl ester; 4-[4-(5-chloro-2-oxo-2,3-dihydro-1? -, σ多-1-yl) Nitrile-1-yl]azetidin-1-carboxylic acid oxime ester; 4-[4^(3,3-difluoro-2-indolyl-2, 3-Dinitro-111-0 引 α朵-1 -yl) π 唆 唆-1-yl] piperidine-1-carboxylic acid ethyl ester; (1R,5S)_3_[4-(3, 3-difluoro -2-Sideoxy-2,3_ Diazo-1Η_° 嗓-1-base)_0Bottom bite _1_基]_8-°丫双环 [3. 2. 1]辛烧-8-Resin 4_[4_(3,3_diox-2-oxo-2,3_diaza-1 Η_π引π朵_1 _yl)α bottom 唆-1-yl]azepane- 1-carboxylic acid oxime ester; (1R,5S)-3-{4-[3-(hydroxyindenyl)-6-methoxy-3-indol-2-yloxy-2,3-diazepine _1H_ ° π 朵-1-yl] - brigade bite -1_ base}-8_. Bis-cyclo[3.2.1]octane-8-carboxylic acid ethyl ester; 26 323406 201211028 4-{4-[3-(hydroxymethyl)-6-decyloxy-3-methyl-2-side Ethyloxy-2,3-dihydro-1H-indol-1-yl]piperidine-i-yl}azepane-1-carboxylic acid ethyl ester; 4-{4-[5-fluoro-3 -(hydroxyindenyl)-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl]piperidine-i-yl}piperidine-1-carboxylic acid ethyl ester ; 4-[4-(6-fluoro-2-indolyl-2',3',5',6'-tetrahydrospiro[吲哚-3,4'-pyranyl]-1-(2H) Ethyl-piperidin-1-yl]azepane-1-carboxylic acid ethyl ester; 4-[4-(6-fluoro-2- oxo-2',3',5',6' - tetrahydrospiro[吲哚-3, 4'-$piperan]-1-(2H)-yl)piperidin-1-yl]piperidine-1-carboxylic acid ethyl ester; 4-[4-(3 , 6-dimethyl-2-oxo-2,3-dihydro-indol-1-yl)α succin-1-yl]azepane-1-carboxylic acid ethyl ester; 4- [4-(6-Fluoro-3methyl-2-oxo-2,3-dihydro-1Η-indol-1-yl)piperidin-1-yl]piperidine-1-carboxylic acid ethyl ester ; 4-[4-(6-fluoro-3methyl-2-oxo-2,3-dihydro-1Η-indol-1-yl)piperidin-1-yl]azetidin -1-Acetate ethyl ester; 4~[4-(2-Sideoxy-2,3-dihydro-1Η-indol-1-yl)piperidin-1-yl]%-4-indolyl Ethyl heterocycloheptane-1-carboxylate; 4-[4-(2-o-oxy-2,3-dihydro-1indole-indol-1-yl)piperidin-1-yl]-4- Ethyl hydrazinidine-1-carboxylate; 4~[4-(5-fluoro-2-oxo-2,3-dihydro-1Η-indol-1-yl)piperidin-1-yl 4--4-methyl brigade 1-ethyl decanoate; 4-[4-(5-fluorenyl-2-oxo-2,3-dihydro-1Η-indol-1-yl)piperidin Pyridin-1-yl]-4-methyl brigade-1-resine ethyl ester; 444-(5-decyloxy-2-oxo-2,3-dihydro-1Η-吲哚-1- Ethyl)piperidin-1-yl]-4-methylpyrazine-1-etreic acid ethyl ester; 27 323406 201211028 (1R,5S)-3-{4-[5-mercapto-2-yloxy- 2,3-Dihydro-1H-indole-1-yl]-piperidin-1-yl}-8-indole bicyclo[3.丨]octane-8-carboxylic acid ethyl ester; (1R,5S) -3-{4-[5-Methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl]-piperidin-1-yl}-8-indole bicyclo[3 · 21] octane-8-carboxylic acid ethyl ester; 4-[4-(3-carbyl-3-indolyl-2-sideoxy-2,3_dihydro-1-indole) 0 bottom 唆-1-yl]-4-methyl group. Ding-1 an ethyl acid ester; 4-[4-(3-hydroxy-3-indolyl-2-ytoxy-2,3-dihydro-1-indenyl) benzyl-1-yl] -4-mercaptopiperidine-1 -carboxylic acid oxime ester; ^ 4_[4_(3-fluoro-3-hydroxyindole-2-yloxy-2,3-dihydro-1Η-吲哚-1- Base) a base of 1-yl]-4-mercaptopiperidine-1-carboxylate; and 4-[4-(3-fluoro-3-hydroxymethyl-2-oxo-oxy-2, 3-Dihydro-1Η-吲哚-1-yl) benzylidene-1-yl]-4-mercaptopiperidine-1-carboxylic acid decyl ester; among the constituent groups. [13] A central disease prevention and/or treatment agent comprising the above [丨], [2a], [2], [3], [4a], [4], [5], [6a], [6], [7], [8], φ [9], [l〇], [11] or [12]. [14] The prophylactic and/or therapeutic agent according to the above [13], wherein the central disease is Alzheimer's disease and/or Schizophrenia ° [15] a pharmaceutical composition , which contains the above [1], [2a], [2], [3], [4a], [4], [5], [6a], [6], [7], [8], [ The compound according to [1], [11] or [12], or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier thereof. (Effect of the invention)

S 323406 28 201211028 本發明之化合物因顯現出包含抗精神病作用、認知障 礙改善作用等優異地中樞性疾病改善效果，故作為新穎的 中樞性疾病預防及/或治療劑而言實屬有用。 【實施方式】 以下，對本說明書之用語進行說明。 關於本發明之目的，化學元素係依照元素週期表，CAS version, Handbook of Chemistry and Physics, 75th Ed 進行鑑別。而且，有機化學的一般性原理如“Organic 鲁 ChemistryM , Thomas Sorrell, University Science Books, Sausalito: 1999 及 “March’s Advanced Organic Chemistry”，5th Ed.，： Smith Μ. B. and March, J·，John Wiley &Sons，New York : 2001所記載，可參照該等之全 部内容。 受體亞型之特定接頭用語「蕈毒鹼受體」意指5種受 體亞型Μι至M5之1種以上。 結合於蕈毒鹼受體而增強蕈毒鹼活性之化合物稱為作 用劑或促效劑（a g 〇 n i s t)。使簟毒鹼受體的活性減少之化合 物稱為拮抗劑或抑制劑（Antagonist)。促效劑係與蕈毒鹼 受體互相作用後’該受體對内生性配體（Endogenous Hgand)結合產生反應，而使細胞内訊息傳導能力增加。抑 制劑係與簟毒鹼受體互相作用後，該受體上的結合部位（可 為複數）與内生性配體（可為複數）或基質競相結合，該受體 對内生性配體結合產生反應，而使細胞内訊息傳導能力減 低。 29 323406 201211028 本說明書用語中，所謂之「Ci-e烷基」意指碳數1至〔 個的直鏈狀或分枝狀的飽和烴基，可列舉例如：甲基、乙 基、正丙基、異丙基、正丁基、異丁基、第二丁基、第三 丁基、戊基、異戊基、新戊基及正己基、以及該等之結^ 異構物，其中，較佳為Cl_4烷基，更佳為甲基、乙基、°正 丙基及異丙基，特佳為甲基及乙基。S 323406 28 201211028 The compound of the present invention is useful as a novel central disease prevention and/or therapeutic agent because it exhibits an excellent central disease improving effect including an antipsychotic action and a cognitive impairment improving action. [Embodiment] Hereinafter, the terms of the present specification will be described. For the purposes of the present invention, chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Moreover, the general principles of organic chemistry are as follows: "Organic Lu ChemistryM, Thomas Sorrell, University Science Books, Sausalito: 1999 and "March's Advanced Organic Chemistry", 5th Ed.,: Smith Μ. B. and March, J., John Wiley The term "sputum receptor" as used in the receptor subtype refers to one or more of the five receptor subtypes Μι to M5, as described in <Sons, New York: 2001. A compound that binds to a muscarinic receptor to enhance muscarinic activity is referred to as a agonist or agonist (a g 〇 n i s t). A compound which reduces the activity of a muscarinic receptor is called an antagonist or an inhibitor (Antagonist). After the agonist interacts with the muscarinic receptor, the receptor reacts with endogenous Hgand binding to increase intracellular signaling capacity. After the inhibitor interacts with the muscarinic receptor, the binding site (which may be plural) on the receptor competes with the endogenous ligand (which may be a plural) or matrix, and the receptor binds to the endogenous ligand. The reaction reduces the ability of intracellular signaling. 29 323406 201211028 In the present specification, the term "Ci-e alkyl group" means a linear or branched saturated hydrocarbon group having 1 to a carbon number, and examples thereof include a methyl group, an ethyl group, and a n-propyl group. , isopropyl, n-butyl, isobutyl, t-butyl, tert-butyl, pentyl, isopentyl, neopentyl and n-hexyl, and the isomers thereof, of which Preferably, it is a C 4 alkyl group, more preferably a methyl group, an ethyl group, a n-propyl group or an isopropyl group, and particularly preferably a methyl group and an ethyl group.

本說明書用語中，所謂之「C2_6婦基」意指具有ι個以 j鍵之碳數2至6個的錢狀或分枝狀料飽和 =美Γ!例如：乙稀基、丙稀基、巴豆基、丁婦基、、 雙鍵i位:了ί:以及該等之結構異構物或幾何異構物。 =鍵的位置可為城上之任意位置。其中，較佳為&歸 本說明書用語中，所士田「 上三鍵之碳數2至6個^ 2—6块基」意指具有1個以 烴基，可列舉例如··乙枝狀的不飽和脂肪族 之任意位置。其中，= 參鍵的位置可為碳鍵上 罕乂 4土為C2-4炔基。 本忒明書用語中，所謂之「 、 子構成的3至7員之飽# 3—7辰炫基」思指僅以碳原 環燒基」之具不制，旨職碳環基。該「C3-7 環戊稀基、環戊二_、= ·環丙基、環丁基、環戊基、 烯基、1，4-環己二婦其 基、裱己烯基、環己二 埽基、1，3-環庚二歸^、、環庚基L環庚烯基、丨，2—環庚二 為Cw環烷基。此外，^丨，衣庚二烯基，其中，較佳 。Gw環烷基」在不產生芳香族疋 323406 30 201211028 電子系之情況下，可具有任 且亦可與（v14芳煙（arene)進1個以上的不飽和鏠結， 本說明書用語中，所謂 <端合。 原子、硫原子及氮原子所構㈣基」意指包含選自氣 作為環構成原子之3至？員^^中的1個以上的雜原= 該「雜環基」在不產生芳香族飽和或不飽和脂肪埃環基。 任意之1個以上的不飽和鍵^電子系之情況下，可具有 進行縮合H以環構 且f可與芳煙或雜壤 硫，，該雜環基亦可包::如可的 t環i?的=硫醯?胺、環狀胺甲酸醋等環狀基δ:該 雇* C二r:°位置可在雜原子上亦可在碳原子上，二 方烴或雜環之縮合體時，亦可於^芳煙或雜; δ雜衣基」之具體例可列舉例如：四氮硫旅淹基、 价派喃基、四氫料基、w基、卜乙氧基絲錢基、 卜乙氧基羰基哌啶烯基 (1 ethoxyearbonylpiperidylidenyl)、1，3-二氧雜環己烯 基、1’3-二氧雜環己基、1>4一二氧雜環己烯基、1>4_二氧 雜環己基、㈣基、H氧雜硫雜環己烧基、氧雜硫 雜環乙稀、1,4-氧硫雜環己烧基、四氫_ι，4_嘆二嗤基、 2Η-1，2-噚畊基、馬來醯亞胺基、琥珀醯亞胺基、二側氧哌 畊基、乙内醯脲基、二氫尿嘧啶、Ν_嗎啉基、六氫_丨，3, 5_ 彡畊基、四氫噻吩基、四氫呋喃基、二氫呋喃基、氧雜環 丁基、吡咯啉基、吡咯啶基、吡咯烷酮基、吡咯二酮基、 31 323406 201211028 吡唑啉基、吡唑啶基、咪唑啉基、咪唑啶基、丨^一 環戊稀基、1，3-二氧雜環錢基、丨，3_二硫雜環戊^其雜 1，3-二硫雜環戊烷基、異噚唑啉基、異噚唑 土、 =3絲、嗟唾琳基、嗟錢基及13_氧雜· 基（Oxathiolanyl)。 ”衣戊In the terminology of this specification, the term "C2_6 women's base" means that there are ι of 2 to 6 carbon numbers or branched materials with j-keys saturated = Γ! For example: ethylene, acryl, Crotonyl, butyl group, and double bond i position: ί: and such structural isomers or geometric isomers. The position of the = key can be anywhere in the city. In the terminology of the specification, "the carbon number of the upper three bonds is 2 to 6 ^ 2 - 6 blocks" means that one has a hydrocarbon group, and for example, an ethylene branch is mentioned. Any position of unsaturated aliphatic. Wherein, the position of the = bond can be a carbon bond, and the soil is C2-4 alkynyl. In the language of this book, the so-called "3 to 7 members of the sub-composition of the 3 to 7 Chen Xingji" refers to the carbon-based ring-burning base. The "C3-7 cyclopentyl, cyclopentane, = cyclopropyl, cyclobutyl, cyclopentyl, alkenyl, 1,4-cyclohexanyl, hexenyl, cyclohexyl Dimercapto, 1,3-cycloheptanyl, cycloheptyl L-cycloheptenyl, anthracene, 2-cycloheptyl are Cw cycloalkyl. In addition, oxime, hexahedenyl, Preferably, the Gw cycloalkyl group may have any one or more unsaturated groups in the case of the (v14 aromatic) 323406 30 201211028 electronic system. In the above, the term "terminal". The atom (four) group of the atom, the sulfur atom and the nitrogen atom means one or more kinds of impurities including 3 to the member of the ring. In the case where no aromatic saturated or unsaturated aliphatic ring group is produced. In the case of any one or more unsaturated bonds, it may have a condensation H and a ring structure and f may be combined with aromatic or heterogenous sulfur. , the heterocyclic group may also be:: such as t ring i? = thiopurine amine, cyclic amine formate vinegar and other cyclic groups δ: the employment * C two r: ° position can be on the hetero atom Also on carbon atoms, dihydrocarbons or In the case of a condensate of a heterocyclic ring, a specific example of the aryl group or the δ cleavage group may be exemplified by a tetrazolude brigade, a valence group, a tetrahydro group, a w group, and an ethoxy group. 1, ethoxyearbonylpiperidylidenyl, 1,3-dioxanylene, 1'3-dioxahexyl, 1> 4-dioxane Alkenyl, 1>4-dioxahexyl, (tetra)yl, Hoxathiacyclohexyl, oxathiazepine, 1,4-oxothiocycloalkyl, tetrahydro- , 4_ 嗤 嗤 、, 2Η-1, 2-噚 基, 马 醯 imine, amber quinone imine, two-side oxyperpine, beta-ureganyl, dihydrouracil, hydrazine _ morpholinyl, hexahydro-indole, 3, 5_ hydrazine, tetrahydrothiophenyl, tetrahydrofuranyl, dihydrofuranyl, oxetanyl, pyrrolinyl, pyrrolidinyl, pyrrolidinyl, pyrrolidin , 31 323406 201211028 pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, oxime-cyclopentyl, 1,3-dioxe, hydrazine, 3-dithiolan ^hetero1,3-dithiolanyl, isoxazolinyl, Isoxazole soil, =3 silk, 嗟 琳 琳 嗟, 嗟 money base and 13 oxa ethoxy group (Oxathiolanyl).

本說明書用語中，所謂之rC6_u芳基」意 14的芳香族碳環基。該「Cei4芳基」可與至少丄個 烴或c”環院烴進行縮合。以該「Ce i4芳基」之具體例^_方 了列舉例如：苯基、萘基、菲基、葱基、隸、四氫蔡^、 茚基及二氫茚基，其中，較佳為苯基及萘基，特佳芏^。 /該「C6-14芳基」係可具有選自齒原子、經基、‘胺f 氰基、硝基、C,-6烧基-胺甲酿基、醯基、Ci 6烧氧基^經 取代的Ch烧基、單或二Cl_6烧基胺基、Ci 6燒基硫基、Ci 6 烷基亞磺醯基、CH烷基磺醯基、胺磺醯基及三氟甲基所構 成群組中之1似上的任意取代基，較料具有相同或相 異之1個或2個以上取代基之苯基。以Ce i4芳基的代表例 而s，可列舉如：苯基、經_原子取代的苯基（例如：於3 位或4位經函原子取代的苯基）、3_羥基苯基、4_羥基苯 基、3-胺基苯基、4-胺基笨基、3一甲基苯基、4_曱基苯基、 3-曱氧基笨基、4_甲氧基苯基、3一氰基苯基、4_氰基苯基、 3,4-~=·甲基苯基、萘基、1-羥基萘基、4_(羥基曱基）苯基 及4-(三氟曱基）苯基，惟不侷限此等者。 ^本說明書用語中，所謂之「C6-u芳烷基」意指經 芳基取代的匕-6烷基。 32 323406 201211028 本說明書用語中’所謂之「雜芳基」意指包含選自氣 原子、硫原子及氮原子所構成群組中的1個以上的雜原子 作為環構成原子之5至10員的芳香族環基。以「雜芳基」 之具體例而言’可列舉例如：σ夫喃基、苯并D夫喃基、嘆吩 基、苯並嘆吩基、11比11各基、°比咬基、4丨D朵基、嗜嗤基、笨 並噚唑基、異噚唑基、苯並異噚唑基、噻唑基、苯並嘆唾 基、異垄β坐基、味峻基、苯並_峻基、〇比》坐基、叫丨嗤基、 四唑基、呋吖基、1，2, 3-噚二唑基、1，2, 3-噻二唑基、1, 2, 4-π塞二β坐基、1，2, 3-三唾基、1，2, 4-三峻基、苯並三唾基、 喹啉基、異喹啉基、嗒畊基、嘧啶基、嘌呤基、吡哄基、 嗓咬基、啡曙11坐基、苯並吧嗤基、喧哄基、。曾琳基；、吹 畊基、喹唑啉基及喹噚啉基，其中較佳為5員及6員之雜 芳基。該「雜芳基」可與至少一個之Ce-H芳烴或雜環進行 縮合。 該雜务基」係可具有選自鹵原子、經基、胺基、氰 • 基、硝基、Cl-6烷基-胺甲醯基、醯基、d-6烷氧基、可經取 代的Ci-6烧基、早或一 Ci-6燒基胺基、Ci-e烧基硫基、Q 6产 基亞磺醯基、Cl-6烷基磺醯基、胺磺醯基及三氟曱基所構成 群組中之1個以上的取代基，較佳亦可為具有相同或相異 之1個或2個以上取代基。最為典型的取代基，可舉如了 鹵原子、羥基、氰基、硝基、Cl — 6烷氧基及可經取代的Cl 6 烧基。 本說明書用語中，所謂之「雜芳烷基」意指經雜芳基 取代的Ch烷基。 土 323406 33 201211028 本說明書用語中，所謂之「Cm烷氧基」意指鍵結有In the terminology of the specification, the term "rC6_u aryl" means an aromatic carbocyclic group. The "Cei4 aryl group" may be condensed with at least one hydrocarbon or a c" ring hydrocarbon. Specific examples of the "Ce i4 aryl group" include, for example, a phenyl group, a naphthyl group, a phenanthryl group, and an onion group. , Lithium, tetrahydroxanthene, fluorenyl and dihydroindenyl, of which phenyl and naphthyl are preferred. / The "C6-14 aryl" group may have a substituent selected from a tooth atom, a trans group, an 'amine f cyano group, a nitro group, a C, -6 alkyl group-amine aryl group, a fluorenyl group, a Ci 6 alkoxy group ^ The substituted Ch alkyl group, mono or diCl 6 alkylamino group, Ci 6 alkylthio group, Ci 6 alkylsulfinyl group, CH alkylsulfonyl group, amine sulfonyl group and trifluoromethyl group Any substituent on the 1st in the group is similar to a phenyl group having the same or different one or more substituents. Representative examples of the Ce i4 aryl group include, for example, a phenyl group, a phenyl group substituted with a _ atom (for example, a phenyl group substituted with a functional atom at the 3- or 4-position), a 3-hydroxyphenyl group, and 4 _hydroxyphenyl, 3-aminophenyl, 4-aminophenyl, 3-methylphenyl, 4-nonylphenyl, 3-decyloxy, 4-methoxyphenyl, 3 Monocyanophenyl, 4-cyanophenyl, 3,4-~=methylphenyl, naphthyl, 1-hydroxynaphthyl, 4-(hydroxyindenyl)phenyl and 4-(trifluoromethyl) Phenyl, but not limited to these. In the phrase of the specification, the term "C6-u aralkyl" means an 匕-6 alkyl group substituted with an aryl group. 32 323406 201211028 The term "heteroaryl" as used in the specification means 5 or 10 members including one or more hetero atoms selected from the group consisting of a gas atom, a sulfur atom and a nitrogen atom. Aromatic ring group. Specific examples of the "heteroaryl group" include, for example, a sigma-based group, a benzo-D-f-butyl group, a stilbene group, a benzophenantyl group, an 11-to-11 group, a ratio of a bite base, and 4丨D-based, eosinophilic, stupid and carbazolyl, isoxazolyl, benzoisoxazolyl, thiazolyl, benzo-salt, hetero-salt β-sodium, succinyl, benzo-jun Base, 〇 ratio, sit-based, sulfhydryl, tetrazolyl, furazyl, 1,2,3-oxadiazolyl, 1,2,3-thiadiazolyl, 1, 2, 4-π Dipyridyl β, 1,2,3-trisal, 1,2,4-trisyl, benzotrisal, quinolyl, isoquinolyl, hydrazine, pyrimidinyl, fluorenyl , pyridyl, acetophenone, benzoquinone, benzoyl, fluorenyl, fluorenyl. Zeng Linji; Plowing base, quinazolinyl and quinoxalinyl, of which 5 and 6 heteroaryl groups are preferred. The "heteroaryl" can be condensed with at least one Ce-H aromatic hydrocarbon or heterocyclic ring. The hydroxy group may have a halogen atom, a trans group, an amine group, a cyano group, a nitro group, a Cl-6 alkyl group, an amino group, a fluorenyl group, a d-6 alkoxy group, and may be substituted. Ci-6 alkyl, early or a Ci-6 alkylamino group, Ci-e alkylthio group, Q 6 sulfinyl group, Cl-6 alkylsulfonyl group, amine sulfonyl group and three One or more substituents in the group consisting of fluoroindenyl groups are preferably one or two or more substituents having the same or different. The most typical substituents may, for example, be a halogen atom, a hydroxyl group, a cyano group, a nitro group, a C1-6 alkoxy group or a substituted C6 alkyl group. In the phrase of the specification, the term "heteroaralkyl" means a heteroalkyl-substituted Ch alkyl group.土 323406 33 201211028 In the language of this specification, the term "Cm alkoxy" means that there is a bond

Cm烧基經鍵結’具體而言’可列舉例如：甲氧基、乙 氧基、正丙氧基、異丙氧基、正丁氧基、異丁氧基、第二 丁氧基、第三丁氧基、戊氧基、異戊氧基、新戊氧基及己 氧基’其中，較佳為C,_3烷氧基，特佳為甲氧基及乙氧基。 本說明書用語中，所謂之「鹵原子」意指氟原子、氣 原子、溴原子和碘原子，其中，較佳為氟原子、溴原子及 氯原子。 本說明書用語中，所謂之「C1_6燒基硫基」意指C16烷 基經鍵結-S-，可列舉例如：甲基硫基、乙基硫基、丙基硫 基、丁基硫基、戊基硫基（亦即戊烷基硫基）、己基硫基、 異丙基硫基、異丁基硫基、第二丁基硫基、第三丁基硫基、 異戊基硫基、新戊基硫基及第三戊基硫基，其中，較佳為 Cm烷基硫基、特佳為曱基硫基及乙基硫基。 ，山本說明書用語中，所謂之「醯基」可舉如：「Ci6烧基一 鲁羰基」（Cl—6烷基經鍵結-C0-，例如：乙醯基、丙醯基、丁 酿基、異丁醯基、戊醯基、三曱基乙酿基、己酿基及庚酿 基）、「Ce-u芳基-羰基」（(V,4芳基經鍵結〜c〇_，例如：苯甲 酸基、萘甲醯基）及「C6_14芳基烧基，基」（C614芳基烧基 經鍵結-C0-，例如：苯甲基錢、2_苯基乙基縣及3_苯 基丙基幾基），其中，較佳為乙醯基、㈣基及苯甲酿基。 該「醯基」中的苯環及萘環亦可具有選自齒原子、烷基、 硝基、氰基、經基及Cl_6烧氧基所構成群組中的！至5個 取代基’取代位置並無特別限定。 323406 34 201211028 本說明書用語中’所謂之「胺基」為胺基及具有Cl-6 烷基的二級或三級胺基。可舉例如：胺基、及單或二Cl_6 烷基胺基（曱基胺基、二甲基胺基、乙基胺基、二乙基胺基、 丙基胺基、二丙基胺基、丁基胺基、二丁基胺基等），其中， 較佳為胺基、及單或二-G-3烷基胺基，特佳為胺基、曱基 胺基及二甲基胺基。 本說明書用語中’所謂之「Cm烷基磺醯基」意指Ci-6 烷基經鍵結-S〇2_。可舉例如：甲基磺醯基、乙基續酿基、 丙基磺醯基及異丙基續醯基’其中’較佳為CN3燒基續醯 基，特佳為甲基磺醯基及乙基磺醯基。 本說明書用語中’所謂之「Cw烷基亞磺醯基」意指 Ch烷基經鍵結-so-。可舉例如：曱基亞磺醯基、乙基亞磺 醯基、丙基亞磺醯基及異丙基亞磺醯基，其中，較佳為C13 烧基亞績醯基。 本說明書用語中，所謂「胺磺醯基」意指胺磺醯基 • (-SOWH2-)及胺磺醯基之氮原子上的1個或2個氫原子取代 為Ch烷基之基，可舉例如：胺磺醯基、及單或二—^ 6烷基 胺磺醯基（例如：甲基胺磺醢基、二甲基胺磺醯基、乙基胺 續醯基、二乙基胺續醯基、丙基胺續醢基、二兩基胺續醯 基、丁基胺磺醯基及二丁基胺磺醯基），其中，較佳為胺橫 醯基及單或二-Cm烷基胺磺醯基，特佳為胺基、甲基胺磺 醯基及二甲基胺磺醯基。 本說明書用語中，所謂之「含氮雜環」意指至少包含 一個氮原子作為環構成原子之6至7員的飽和脂肪族環， 323406 35 201211028 且以作為環構成原子而言，亦·^ a ,, kJ含有選自氧原子及硫原子 個之Ce-u芳烴、C3-i 之1個以上的雜原子，亦可_ i,丨、 環烷烴或3至7員的雜環進行縮人 該「含氮雜環」之具體例可 氧雜氮雜環庚烷）、硫雜氮雜環 J Γ列舉如：哌啶、哌畊、氮 雜環庚烷、二氮雜環庚烷、 庚烷、嗎啉及硫嗎啉。 本說明書用語中，所謂之「1 可經取代的0-6烷基」意 指在可被取代的位置可經選自 子m基、Cl-6絲硫基、齒原 于妝丞τ醞暴胺甲醯基、氰其、坊糞r # Γ, , 1¾ ^ ^ ^ ^ 氘I、硫基、Cl-6 烷虱基、 -衣烷基及雜％基所構成群組中 取代之C4基。、_ 彳原子絲代基 如.二翁田I ^ 代的Cl-6烷基」之具體例可列舉 如· 一亂曱基、氣曱基、2~ϋ 7 « m其"土基、曱氧基乙基、羥基甲 基、裱丙基曱基、呋喃某甲放 甲某。 土、亏唑基曱基及四氫呋喃基 所谓之「Ce-H芳烴」意指對應「c6The Cm alkyl group may be exemplified by a bond 'specifically': methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, second butoxy group, Among them, a tributyloxy group, a pentyloxy group, an isopentyloxy group, a neopentyloxy group and a hexyloxy group are preferred, and a C, _3 alkoxy group is particularly preferred as a methoxy group and an ethoxy group. In the phrase of the specification, the "halogen atom" means a fluorine atom, a gas atom, a bromine atom and an iodine atom, and among them, a fluorine atom, a bromine atom and a chlorine atom are preferred. In the phrase of the specification, the term "C1_6 alkylthio group" means a C16 alkyl group bonded to -S-, and examples thereof include a methylthio group, an ethylthio group, a propylthio group, a butylthio group, and the like. Butylthio (also known as pentylthio), hexylthio, isopropylthio, isobutylthio, t-butylthio, tert-butylthio, isopentylthio, The neopentylthio group and the third amylthio group are preferably a Cm alkylthio group, particularly preferably a mercaptothio group and an ethylthio group. In the language of Yamamoto, the so-called "mercapto" can be referred to as "Ci6 alkyl-l-carbonyl" (Cl-6 alkyl bonded-C0-, for example: ethyl thiol, propyl sulfhydryl, butyl , isobutyl fluorenyl, amyl sulfhydryl, triterpene ethyl aryl, hexyl and heptyl), "Ce-u aryl-carbonyl" ((V, 4 aryl via bonded ~c〇_, for example: Benzoic acid, naphthylmethyl) and "C6_14 arylalkyl, benzyl" (C614 arylalkyl bonded-C0-, for example: benzylic, 2-phenylethyl and 3-benzene a propyl group, wherein the benzyl group, the (tetra) group and the benzoyl group are preferred. The benzene ring and the naphthalene ring in the "fluorenyl group" may also be selected from a tooth atom, an alkyl group, a nitro group, The position of the substitution to the five substituents in the group consisting of a cyano group, a trans group and a Cl_6 alkoxy group is not particularly limited. 323406 34 201211028 The term "amino group" in the specification is an amine group and has Cl. a secondary or tertiary amine group of a -6 alkyl group, for example, an amine group, and a mono or diCl 6 alkylamino group (mercaptoamine group, dimethylamino group, ethylamino group, diethylamine) Base, propylamino, dipropylamine And a butylamino group, a dibutylamino group or the like, wherein an amine group and a mono- or di-G-3 alkylamino group are preferred, and an amine group, a mercaptoamine group and a dimethylamine are particularly preferred. The term "Cm alkylsulfonyl" as used in the specification means a Ci-6 alkyl-bonded-S〇2_. For example, methylsulfonyl, ethyl continuation, propyl Sulfonyl and isopropyl sulfhydryl 'wherein' is preferably a CN3 alkyl group, particularly preferably a methylsulfonyl group and an ethylsulfonyl group. The term "so-called "Cw alkyl amide" is used in the specification. Sulfoalkyl means that the Ch alkyl group is bonded to -so-, and examples thereof include a mercaptosulfinyl group, an ethylsulfinyl group, a propylsulfinyl group, and an isopropylsulfinyl group. Preferably, it is a C13 alkyl group. In the terms of this specification, the term "amine sulfonyl" means 1 or 2 of the nitrogen atom of the aminesulfonyl group (-SOWH2-) and the amine sulfonyl group. The hydrogen atom is substituted with a group of a Ch alkyl group, and examples thereof include an amine sulfonyl group, and a mono- or di- 6 alkylamine sulfonyl group (for example, methylamine sulfonyl group, dimethylamine sulfonyl group). , ethylamine thiol, diethylamine hydrazino, propyl Further, an anthracenyl group, a diamylamine hydrazino group, a butylamine sulfonyl group and a dibutylamine sulfonyl group, wherein an amine fluorenyl group and a mono- or di-Cm alkylamine sulfonyl group are preferred. Particularly preferred are amine groups, methylamine sulfonyl groups and dimethylamine sulfonyl groups. In the present specification, the term "nitrogen-containing heterocyclic ring" means 6 to 7 members having at least one nitrogen atom as a ring-constituting atom. The saturated aliphatic ring, 323406 35 201211028, and as a ring-constituting atom, also contains a Ce-u aromatic hydrocarbon selected from an oxygen atom and a sulfur atom, and one or more hetero atoms of C3-i. Further, _i, hydrazine, cycloalkane or a heterocyclic ring of 3 to 7 members may be used for the specific example of the "nitrogen-containing heterocyclic ring", and the thiazepine heterocyclic ring is exemplified. : piperidine, piperazine, azepane, diazepane, heptane, morpholine and thiomorpholine. In the phrase used in the specification, the term "1 substituted alkyl group 0-6" means that the position which can be substituted may be selected from the group consisting of a m group, a Cl-6 thio group, and a tooth. Aminomethyl thiol, cyanamide, sulphate r # Γ, , 13⁄4 ^ ^ ^ ^ 氘I, thiol, Cl-6 alkyl fluorenyl, -yl-alkyl and hetero-l-group substituted C4 groups . Specific examples of _ 彳 彳 丝 如 如 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体 具体Alkoxyethyl, hydroxymethyl, propylpropyl sulfhydryl, furan a certain armor. Soil, oxazolylhydrazyl and tetrahydrofuranyl The so-called "Ce-H aromatic hydrocarbon" means corresponding to "c6"

本說明書用語中 芳基」的環。 雜環基」 本說明書用語中，所謂之「雜環」意指對應 的環。 本說明書用語中，所謂之rC3 7環烧」意指對應 環烧基」的環。 用語中，所謂之「鹽」意指藉由將胺等官能基的鹼型 以適當的酸，例如以無機酸[例如鹵化氫酸（例如：鹽酸、 氫溴酸、氫氟酸、氫碘酸）或硫酸、硝酸、磷酸等]或是有 機酸[例如·乙酸、丙酸、氫乙酸（hydr〇aCetiCaCU)、2 36 3234〇6 201211028 羥基丙酸、2-側氧基丙酸、乙二酸、丙二酸、丁二酸、（ζ)ι〜 丁烯二酸、（E)-丁烯二酸、2__羥基丁二酸、2, 3_二羥基丁 二酸、2-羥基丙烷-丨，2, 3_三綾酸、曱磺酸、乙磺酸、笨崎 酸、4-甲基苯確酸、環己胺續酸、2經基安息香酸、4〜胺^ 基-2-羥基安息香酸及本發明所屬技術領域中之通常知熾 者所知之其他有機酸]進行處理而可得之於藥學上容許的 酸加成鹽。 為了將前述通式（1)所示之本發明的化合物進行更加 具體的揭示’式⑴所用之各種代號列舉其合適之具^ 例’以進行更為詳細的說明。 本發明之通式（1)的化合物因其取代基之態樣而有光 學異構物、非鏡像（Diastereo)異構物、幾何異構物等立體 異構物存在之情形’惟此等之全部的立體異構物及該等之 混合物皆包含於本發明之通式（1)的化合物内。 前，通式（1)之a、b、c及d為相同或相異，分別為 _ CH或CR5，較佳為a及d皆為CH，且b及c為相同或相異*、、， 係CH或CR5。c為cr5時，蕈毒鹼Μι及M4受體的、担 升’此外’藥物動力有改善之傾向。 者為^佳為皆為CH，且Wc之任一者為CH，另一 前述通式（1)中，R5為鹵原子、C3_7環烷基、c 广土 Ce—14芳烷基、雜芳烷基、C2-6烯基> c2-6炔基、Ci -氧基氰基、Cl-6烧基硫基、醯基、胺績酿基、經其、〜 基、硝基、Cm烷基磺醯基或可經取代的Ci_e烷基。土 323406 37 201211028 R5較佳為鹵原子、C2-6烯基、C2-6炔基、Cw烷氧基、氰 基、Cl-6烷基硫基、醯基、胺磺醯基、羥基、胺基、硝基、 Cl-6烧基績酿基或可經取代的Cl-6烧基（較佳亦可為經選自 羥基、Cl-6烷基硫基、齒原子、氰基、硝基及曱氧基所構成 群組中之1至4個取代基取代），The term "aryl" in the terminology of this specification. Heterocyclic group In the phrase of the specification, the term "heterocyclic ring" means the corresponding ring. In the terminology of the specification, the term "rC3 7 ring-burning" means a ring corresponding to a cycloalkyl group. In the phrase, "salt" means a basic acid of a functional group such as an amine to a suitable acid, for example, a mineral acid [for example, a hydrogen halide (for example, hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid). ) or sulfuric acid, nitric acid, phosphoric acid, etc. or organic acids [eg acetic acid, propionic acid, hydroacetic acid (hydr〇aCetiCaCU), 2 36 3234〇6 201211028 hydroxypropionic acid, 2-oxopropionic acid, oxalic acid , malonic acid, succinic acid, (ζ)ι~ butenedioic acid, (E)-butenedioic acid, 2-hydroxybutyric acid, 2,3-dihydroxysuccinic acid, 2-hydroxypropane-丨, 2, 3_ tridecanoic acid, sulfonic acid, ethanesulfonic acid, stupid acid, 4-methyl benzoic acid, cyclohexylamine acid, 2 benzoic acid, 4 〜 amine yl-2- A pharmaceutically acceptable acid addition salt can be obtained by treatment with hydroxybenzoic acid and other organic acids known to those of ordinary skill in the art to which the present invention pertains. In order to more specifically disclose the compound of the present invention represented by the above formula (1), the various codes used in the formula (1) are listed as appropriate examples for further explanation. The compound of the formula (1) of the present invention has a stereoisomer such as an optical isomer, a diastereo isomer or a geometric isomer due to the form of its substituent. All stereoisomers and mixtures thereof are included in the compounds of formula (1) of the present invention. Before, a, b, c and d of the formula (1) are the same or different, respectively _CH or CR5, preferably a and d are both CH, and b and c are the same or different*, , is CH or CR5. When c is cr5, the muscarinic Μι and M4 receptors have a tendency to improve the drug's kinetics. Any one of them is CH, and any of Wc is CH. In the other formula (1), R5 is a halogen atom, a C3_7 cycloalkyl group, a c-cetyl Ce-14 aralkyl group, and a heteroaryl group. Alkyl, C2-6 alkenyl> c2-6 alkynyl, Ci-oxycyano, Cl-6 alkylthio, decyl, amine, via, benzyl, nitro, Cm A sulfonyl group or a substituted Ci_e alkyl group. 323406 37 201211028 R5 is preferably a halogen atom, a C2-6 alkenyl group, a C2-6 alkynyl group, a Cw alkoxy group, a cyano group, a C1-6 alkylthio group, a decyl group, an amine sulfonyl group, a hydroxyl group, an amine. a base, a nitro group, a Cl-6 alkyl group or a substituted C1-6 alkyl group (preferably also selected from the group consisting of a hydroxyl group, a C1-6 alkylthio group, a tooth atom, a cyano group, a nitro group) And 1 to 4 substituents in the group consisting of decyloxy groups),

更佳為鹵原子、Cl-6烧氧基、氛基、Cl-6烧基硫基、經基、 胺基、硝基、或可經取代的Cl-6烷基（較佳亦可為經選自羥 基、Cm烷基硫基、齒原子、氰基、硝基及甲氧基所構成群 組中之1至4個取代基取代）， 又更佳為齒原子、曱基、乙基、丙基、氰基、羥基、甲氧 基、或三氟曱基， 特佳為氟原子、氯原子、溴原子、甲基、乙基、丙基、甲 氧基、或三氟甲基， 3為》^原子、氣原子、㈣、子、甲基、乙基、丙基、或 甲氣基。 前述通式（1)中，R2為相同或相異 子、可經取代的Cl_6烷基、齒原子、經 ^原 至7員的雜環基，或是RjR2為互_ 燒基或3 =原子-同形成k環烧或3至？員 ，鄰 起形成=cr6r7。 及考疋一More preferably, it is a halogen atom, a Cl-6 alkoxy group, an aryl group, a Cl-6 alkylthio group, a trans group, an amine group, a nitro group, or a substituted C1-6 alkyl group (preferably also a One to four substituents selected from the group consisting of a hydroxyl group, a Cm alkylthio group, a tooth atom, a cyano group, a nitro group and a methoxy group, and more preferably a tooth atom, a fluorenyl group, an ethyl group, a propyl group, a cyano group, a hydroxyl group, a methoxy group, or a trifluoromethyl group, particularly preferably a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, a propyl group, a methoxy group, or a trifluoromethyl group, 3 It is a ^ atom, a gas atom, a (tetra), a sub, a methyl group, an ethyl group, a propyl group, or a methyl group. In the above formula (1), R2 is the same or a heterologous, a substituted Cl-6 alkyl group, a tooth atom, a heterocyclic group via a 7-membered group, or RjR2 is an exo group or a 3 = atom. - Same as forming k ring burning or 3 to? Member, neighboring formation =cr6r7. And test one

a久R苟相同或相異，分別為氯 =的^基，或者是⑴7為互相 相碳原子1形成‘祕或3至7員 及R hR2較佳為相同或相異，分別為氫原子衣可 323406 38 201211028 子、羥基、C3-7環烷基或3至7員的雜環 二：疋s 、為互相鍵結，Rl及R2與相鄰的碳原子-同 ==喊或3至7 s的雜環，或者是—起形成=cr6r7， 齒;^目^相異，分別為氫原子、可經取代的Cl禮基、 R1及R2盘或C3,7環燒基’或是以R2為互相鍵結， 與相鄰的碳原子—同形成一環院或3至7員的雜 =為=或相異，分別為氫原子、氟原子、氣原 原子、羥基、或可經取代的 兴 鍵結或是R及R2為互相 員的雜環， 的碳原子—同形成^魏或3至7 :寺佳= 同或相異，分別為氣原子、氣原 是可經歸取代的4 _成3疋至7?為互相鍵結，以R2與相鄰的碳原子-成3至7員的雜環， 相同或相異’分別為氫原子、氟原子、經 是ί及二互T基(特別是可經經基取代的Ci-3燒基)，:戈 氣^環為互相鍵結’hR2與相鄰的破原子-同形成四 最佳為相同或相異，分別為氫原子、氟原 f經基取代的C1-6燒基（特別是經甲基），或是r‘r2^ 具趙而言：一Γ—環》 ⑴氫原子、 為相同或相異，分別為: 323406 39 201211028 (2) 可經選自 (a) 經基、 (b) Cm烷氧基（例如曱氧基）、 (c) 3至7員的雜環基（例如：呋喃基、 呋喃基）、及 虱 (d) Cw環烷基（例如環丙基） 異丙基、丁基、異丁基、1-乙基丙基 2構成群財之1至4個取代絲代的“絲（例如：甲 基、乙基、丙基、田“ τ 卜丙基丁基）、 (3) 齒原子(例如：氟原子、氣原子、溴原子）、 (4) 經基、 ⑸C3-7環貌基（例如：環丁基、環戊基）、或是 乂至7員的雜環基(例如：氮雜環丁基、四氫哌喃美 四虱呋喃基、氧雜環丁基），或是 土 =及R2為^相鍵結，R1及R2與相鄰的碳原子—同 (1) c3-7環烷（例如：環 y 或 衣j沉J衣戊燒、環己烧） ⑵3至7員的雜環(例如：四氫哌喃）， 或者是R1及R2係一起形成=cr6r7( 別為氫原子或基（例如基、乙^目同或相異4 及R7與相鄰的碳原子1形成可丙基），石 如：乙氧基幾基)取代的3至 ;^基-幾基（命 (_佳為相同或相異員 (〇風原子、 323406 40 201211028 (2) 可經選自 (a) 羥基、 (b) Cm烷氧基（例如曱氧基）、 (c) 3至7員的雜環基（例如：呋喃基、噚唑基、四氫 呋喃基）、及 (d) G—7環烷基（例如環丙基） 所構成群組中之1至4個取代基取代的C,-道基（例如：f 基、乙基、丙基、異丙基、丁基、異丁基、卜乙基丙基、 1-丙基丁基）、 (3) 齒原子（例如：氟原子、氯原子、漠原子）、 (4) 經基、 ⑸C”環院基（例如：環丁基、環戊基）、或是 ⑻3至7員的雜環基(例如：氮雜環丁基、 四氫料基、氧雜環丁基），或是 Λ辰南基 R及R為互相鍵結，r2 ⑴7環烧（例如··環丙尸與原子一同形成 或 衣丙坑、壞丁炫、環戊烧、環己烧）、 I2) U7員的雜環（例如：四氫娘嚼），a long-term R 苟 is the same or different, respectively, is chlorine = ^, or (1) 7 is a mutual carbon atom 1 forming 'secret or 3 to 7 members and R hR2 are preferably the same or different, respectively, hydrogen atomic clothing 323406 38 201211028 Sub, hydroxy, C3-7 cycloalkyl or 3 to 7 membered heterocyclic two: 疋s, bonded to each other, R1 and R2 with adjacent carbon atoms - same == shout or 3 to 7 The heterocyclic ring of s, or the formation of =cr6r7, the tooth; the difference of ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Bonded to each other, with adjacent carbon atoms - forming a ring or 3 to 7 members of the impurity = = or different, respectively, a hydrogen atom, a fluorine atom, a gas atom, a hydroxyl group, or a replaceable Bonding or R and R2 are mutually heterocyclic rings, and the carbon atoms are formed together with ^Wei or 3 to 7: Temple Jia = the same or different, respectively, the gas atom, the gas source is replaced by the 4 _ 3疋 to 7? are bonded to each other, R2 and adjacent carbon atoms - 3 to 7 members of the heterocyclic ring, the same or different 'respectively hydrogen atom, fluorine atom, ί and dico-T base (especially Ci-3 base which can be substituted by a base) :Ge gas ^ ring is a bond to each other 'hR2 and adjacent broken atom - the same as the formation of four is the same or different, respectively, a hydrogen atom, a fluorine atom f substituted by a C1-6 alkyl group (especially Methyl), or r'r2^ with Zhao: one Γ-ring" (1) hydrogen atoms, which are the same or different, respectively: 323406 39 201211028 (2) can be selected from (a) ketone, (b) Cm alkoxy (e.g., decyloxy), (c) 3- to 7-membered heterocyclic (e.g., furyl, furyl), and hydrazine (d) Cw cycloalkyl (e.g., cyclopropyl) isopropyl , butyl, isobutyl, 1-ethylpropyl 2 constitutes one to four substituted filaments of the group (for example: methyl, ethyl, propyl, and "taubupropyl"), 3) a tooth atom (for example: fluorine atom, gas atom, bromine atom), (4) a meridine, (5) a C3-7 ring-like group (for example, cyclobutyl, cyclopentyl), or a heterocyclic ring of up to 7 members. a group (for example: azetidinyl, tetrahydropentanyltetrahydrofuranyl, oxetanyl), or soil = and R2 is a phase bond, R1 and R2 are adjacent to a carbon atom (1) c3-7 naphthenic (for example: ring y or clothing j sinking J Cyclohexene) (2) a heterocyclic ring of 3 to 7 members (for example, tetrahydropyran), or R1 and R2 together form =cr6r7 (other than a hydrogen atom or a group (for example, a group, an identical or a different 4) R7 forms an propyl group with an adjacent carbon atom 1, and a metal such as an ethoxy group has a 3 to a group of a group of a group of ethoxy groups. 40 201211028 (2) A heterocyclic group (e.g., furyl, carbazolyl, tetrahydrofuran) selected from (a) hydroxy, (b) Cm alkoxy (e.g., decyloxy), (c) 3 to 7 member a C,-diyl group substituted with 1 to 4 substituents in the group consisting of G-7 cyclyl groups (eg, cyclopropyl) (eg, f group, ethyl group, propyl group, Isopropyl, butyl, isobutyl, ethylidenepropyl, 1-propylbutyl), (3) tooth atom (eg fluorine atom, chlorine atom, desert atom), (4) meridine, (5) C" ring a hospital base (eg, cyclobutyl, cyclopentyl), or (8) a 3 to 7 membered heterocyclic group (eg, azetidinyl, tetrahydrocarbyl, oxetanyl), or Λchennan The bases R and R are bonded to each other, and the r2 (1) 7 ring is burned (for example, ····· Together with the atoms or pit prop clothing, Hyun bad butyl, cyclopentyl burn, burn cyclohexyl), I2) U7-membered heterocycle (e.g.: Mother tetrahydro chewing),

’者是r1 m起形成=CR 別為氫原子或Cl_6^An 尺為相同或相異’分' is the formation of r1 m = CR is a hydrogen atom or Cl_6^An ruler is the same or different'

及·^與相鄰的^子基(=，基、乙基、異丙基W 如：乙氧基幾基）取代的3° '可.經CM炫氧基_幾基（例 R1及R2更較佳/貞的雜環(例如哌啶基))。 及K更車又佳為相同或 (1)氫原子、 J馮 323406 201211028 (2) 可經選自 (a) 經基、 (b) G-6烷氧基（例如曱氧基）、 (c) 3至7員的雜環基（例如：呋喃基、噚唑基、四氫 吱喃基）、及 (d) C3-7環烧基（例如環丙基） 所構成群組中之1至4個取代基取代的G-6烷基（例如：甲 基、乙基、丙基、異丙基、丁基、異丁基、1-乙基丙基、 • 1-丙基丁基)、 (3) 鹵原子（例如：氟原子、氯原子、溴原子）、 (4) 經基、或 (5) Cw環烷基（例如：環丁基、環戊基），或是 R1及R2為互相鍵結，R1及R2與相鄰的碳原子一同形成 (1) Cw環烷（例如：環丙烷、環丁烷、環戊烷、環己烷）、 或 φ (2) 3至7員的雜環（例如：四氫旅喃）。 R1及R2又更佳為相同或相異，分別為 (1) 氫原子、 (2) 可經選自 (a) 羥基、 (b) G-6烷氧基（例如甲氧基）、 (c) 3至7員的雜環基（例如：呋喃基、噚唑基、四氫 °夫喃基）、及 (d) C3-7環烧基（例如：環丙基） 42 323406 201211028 所構成群”之1至4録代絲代的基（例如：f =基;、基、異丙基、丁基、異丁基一 (3) 氟原子、氯原子或溴原子、 (4) 羥基、 鍵結，R1及R2與相鄰的碳原子一同形成 ••環丙烷、環丁烷、環戊烷、環己烷）、And ^^ with the adjacent ^ group (=, base, ethyl, isopropyl W such as: ethoxy group) substituted 3 ° ' can be CM methoxy group _ a few bases (example R1 and R2 More preferably, a heterocyclic ring (e.g., piperidinyl)). And K is more preferably the same or (1) hydrogen atom, J von 323406 201211028 (2) can be selected from (a) thiol, (b) G-6 alkoxy (such as decyloxy), (c a group of 3 to 7 membered heterocyclic groups (for example, furyl, carbazolyl, tetrahydrofuranyl), and (d) C3-7 cycloalkyl (for example, cyclopropyl) 4 substituent-substituted G-6 alkyl groups (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1-ethylpropyl, • 1-propylbutyl), (3) a halogen atom (for example, a fluorine atom, a chlorine atom or a bromine atom), (4) a mesogenic group, or a (5) Cw cycloalkyl group (for example, a cyclobutyl group or a cyclopentyl group), or R1 and R2 are Bonded to each other, R1 and R2 together with adjacent carbon atoms form (1) Cw naphthenes (eg cyclopropane, cyclobutane, cyclopentane, cyclohexane), or φ (2) 3 to 7 members Heterocycle (for example: tetrahydrogen). R1 and R2 are more preferably the same or different, respectively (1) a hydrogen atom, (2) may be selected from (a) a hydroxyl group, (b) a G-6 alkoxy group (e.g., a methoxy group), (c) a heterocyclic group of 3 to 7 members (for example, furyl, carbazolyl, tetrahydrofuranyl), and (d) a C3-7 cycloalkyl group (for example, cyclopropyl) 42 323406 201211028 "1 to 4 records the base of the silky generation (for example: f = group; base, isopropyl, butyl, isobutyl-(3) fluorine atom, chlorine atom or bromine atom, (4) hydroxyl group, bond a knot, R1 and R2 form together with an adjacent carbon atom • • cyclopropane, cyclobutane, cyclopentane, cyclohexane),

或是R1及R2為互相 (1) ¢3-7¾燒（例如 或 (丨2) 3至7員的雜環（例如：四氫哌喃）。 R及R特佳為相同或相異，分別為 (1) 氫原子、 (2) 可經選自 (a) 羥基、 (b) Ci-6燒氧基（例如甲氧基）、 (c) 3至7員的雜環基（例如：呋喃基、噚唑基、 呋喃基）、及 (d) G-7環烷基（例如環丙基） ^構成群組中之1至4個取代基取代的C,禮基（例如：甲 Γ二基I丙基、異丙基、丁基、異丁基、卜乙基丙基、 土 T 土 ’ Μ為ei_道基）（特佳為可軸基取代的^ 現基）、 (3) 氟原子或氯原子、或 (4) 經基， 或是R1及R2為互相鍵結，RlAR>相鄰的碳原子—同形成 323406 43 201211028 3至7員的雜環（例如：四氫哌喃）。 R及R2又特佳為相同或相異，分別為 (1)氫原子、 (2) 可經選自 (a) 經基、 (b) Cw烷氧基（例如曱氧基）、 (c) 3至7員的雜環基（例如：呋喃基、曙β坐基、四氫 呋喃基）、及 (d) C3—7環烷基（例如環丙基） 所構成群組中之1至4個取代基取代的Ci 6院基（例如··甲 基、乙基、丙基、異丙基、丁基、異丁基、1-乙基丙基、 1丙基丁基’較佳為L道基）（特佳為可經經基取代的k 烷基）、 (3) 氟原子、或 (4) 羥基， 或疋R及R為互相鍵結，尺1及r2與相鄰的碳原子一同形成 四氫派喃環。 R1及R2最佳為相同或相異，分別為 (1)氣原子、 ⑵可經經基取代的Cl_3炫基（例如··甲基、乙基、丙基、 異丙基，較佳為f基）（特佳為羥尹基）、 (3) 氟原子、或 (4) 經基， 或是^R2為互相鍵結，R1W與相鄰的碳原子-同形成 323406 44 201211028 四氫旅喃環。 又，當R1及R2皆係氫原子以外之情形時，則為有改善 hERG抑制的傾向。 前述通式（1)中，環A係可經選自羥基、鹵原子、G-6 烷基及Cw烷氧基所構成群組中之1至2個取代基取代的6 至7員含氮雜環。 環A較佳為可經1至2個Cw烷基取代的6至7員含 氮雜環（該2個Ch烷基可鍵結形成雙環）， 更佳為下述式（2):Or R1 and R2 are mutually (1) ¢3-73⁄4 calcined (for example or (丨2) 3 to 7 membered heterocyclic ring (for example: tetrahydropyran). R and R are preferably the same or different, respectively And (2) a heterocyclic group (for example, furan) which may be selected from (a) a hydroxyl group, (b) a Ci-6 alkoxy group (for example, a methoxy group), (c) 3 to 7 members. Base, carbazolyl, furyl), and (d) G-7 cycloalkyl (eg cyclopropyl) ^ constitutes one to four substituents in the group substituted by C, ritual (eg: formazan) Base I propyl, isopropyl, butyl, isobutyl, puethyl propyl, soil T soil ' Μ is ei                   Or a chlorine atom, or (4) a meridine, or R1 and R2 are bonded to each other, and an adjacent carbon atom of RlAR> forms a heterocyclic ring (for example, tetrahydropyran) of 323406 43 201211028 3 to 7 members. R and R2 are particularly preferably the same or different and are respectively (1) a hydrogen atom, (2) may be selected from (a) a trans group, (b) a Cw alkoxy group (e.g., a decyloxy group), (c) a heterocyclic group of 3 to 7 members (for example, a furyl group, a fluorene-based group, a tetrahydrofuranyl group), and (d) a C3-7 cycloalkyl group ( a Ci 6 courtyard group substituted with 1 to 4 substituents in the group consisting of cyclopropyl) (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1-B) a propyl group, a 1-propylbutyl group is preferably a L-based group (particularly a k-alkyl group which may be substituted by a trans group), (3) a fluorine atom, or a (4) hydroxyl group, or 疋R and R are Bonding to each other, the scales 1 and r2 together with the adjacent carbon atoms form a tetrahydropyran ring. R1 and R2 are preferably the same or different, respectively (1) a gas atom, (2) a Cl_3 which can be substituted by a base group. a group (for example, methyl, ethyl, propyl, isopropyl, preferably f group) (excellently hydroxyxy), (3) fluorine atom, or (4) thiol, or ^R2 In order to bond to each other, R1W and the adjacent carbon atoms form the same 323406 44 201211028 tetrahydrourethane ring. Further, when both R1 and R2 are hydrogen atoms, there is a tendency to improve hERG inhibition. In the formula (1), the ring A is a 6 to 7 member nitrogen-containing heterocyclic ring which may be substituted with 1 to 2 substituents selected from the group consisting of a hydroxyl group, a halogen atom, a G-6 alkyl group and a Cw alkoxy group. Ring A is preferably 6 to 7 which may be substituted by 1 to 2 Cw alkyl groups. Nitrogen-containing heterocyclic (Ch 2 which may be bonded to form a bicyclic alkyl group), more preferably represented by the following formula (2):

所示之含氮雜環。 前述式（2)中，R8為氳原子、羥基、鹵原子、G-6烷基 或Cl-6烧氧基。 R8較佳為氫原子、羥基、氟原子、曱基、乙基、丙基、 • 甲氧基或乙氧基，更佳為氫原子、羥基、氟原子、曱基、 乙基、曱氧基，又更佳為氫原子、曱基。 特佳之環A為：The nitrogen-containing heterocycle shown. In the above formula (2), R8 is a halogen atom, a hydroxyl group, a halogen atom, a G-6 alkyl group or a Cl-6 alkoxy group. R8 is preferably a hydrogen atom, a hydroxyl group, a fluorine atom, a decyl group, an ethyl group, a propyl group, a methoxy group or an ethoxy group, more preferably a hydrogen atom, a hydroxyl group, a fluorine atom, a decyl group, an ethyl group or a decyloxy group. More preferably, it is a hydrogen atom or a sulfhydryl group. The best ring A is:

所示之含氮雜環。 45 323406 201211028 前述通式⑴中，以The nitrogen-containing heterocycle shown. 45 323406 201211028 In the above formula (1),

RiR較佳係-糾成為=G。蛛0或=S。 前述通式⑴中，x為單鍵或伸甲基。 前述通式⑴中，YAZ為相 或硫原子。 一異，为別為氧原子 Y較佳為氧原子。 Z較佳為氧原子。 前述通式⑴中，R為可經取代的c c2-6烯基。 6況基、c2-6炔基或 R較佳為可峰代的Gi 6烧基（較佳為可 =燒氧基所構成群組中之…個取代基取代者二子 炔基或C2-6埽基， ）C2-6 更佳為可經取代的k燒基（較佳為可 烧氧基所構成敎中之丨至4個取代基取代者）原子及k 為可，取代的直鏈之&烷基(較佳為可經選自齒原 ^ 1-6烷氧基所構成群組中之1至4個取代基取代者）， =又更佳為可經取代的直鏈之&道基（較佳為可經選自自 '、子及匕-6烷氧基所構成群組中之i至4個取代基取 再又更佳為可經取代的直鏈之烷基， 特佳為甲基或乙基。 人物以較佳之本發明的化合物而言，可列舉例如以下之化 [化合物A] a 為 CH， 46 323406 201211028 b為CH或CR5(R5與前述同義）， c為CR (R5與前述同義）， d 為 CH， R及R為相同或相異，分別為氫原子、可經取代的& 6炫 基、鹵原子或C”環烷基，或是R2為互相鍵結，以 ^與相4鄰的碳原子一同形成C3_7環烷或3至7員的雜環， R3及R4為一起形成=0或=s， _ X為單鍵， Y為氧原子或硫原子， z為氧原子或硫原子， R為可經取代的Ch烷基（較佳可為經選自鹵原子及Ci 6烷氧 基所構成群組中之1至4個取代基取代），且 環A為可經1至2個Cl_6烧基取代的6至7員之含氮雜環（該 2個C,-6烷基可鍵結形成雙環）（較佳為哌啶或氮雜環庚烷）， 之化合物或其藥學上容許的鹽。 ^ [化合物B] a 為 CH， b為CH或CR5(R5與前述同義）， c為CR5(R5為鹵原子、Cl_6烧氧基、氣基、Ci 6烧基硫基、羥 基、胺基、龜、或可齡代的一絲（較佳可為經選自 羥基、Ch烧基硫基、鹵原子、氰基、硝基、及甲氧基所構 成群組中之1至4個取代基取代））， d 為 CH，RiR is better-corrected to =G. Spider 0 or =S. In the above formula (1), x is a single bond or a methyl group. In the above formula (1), YAZ is a phase or a sulfur atom. A different one is an oxygen atom. Y is preferably an oxygen atom. Z is preferably an oxygen atom. In the above formula (1), R is a substitutable c c2-6 alkenyl group. The 6-form, c2-6 alkynyl or R is preferably a Gi6 alkyl group which may be a peak (preferably, a group of substituents which may be alkoxy groups), a substituent substituent, a di-alkynyl group or a C2-6 group. Further, a C2-6 group is preferably a substitutable k-alkyl group (preferably a oxime-forming oxime to a 4-substituent substituent) atom and k is a replaceable linear chain. & alkyl (preferably substituted with from 1 to 4 substituents selected from the group consisting of dentate 1-6 alkoxy), = more preferably a linear & a sulfhydryl group (preferably, a linear alkyl group which may be further substituted by i to 4 substituents selected from the group consisting of ', and 匕-6 alkoxy groups, Particularly preferred is a methyl group or an ethyl group. The preferred compound of the present invention may, for example, be a compound [Compound A] a is CH, 46 323406 201211028 b is CH or CR5 (R5 is synonymous with the foregoing), c Is CR (R5 is synonymous with the above), d is CH, R and R are the same or different, respectively a hydrogen atom, a substituted & 6 hexyl group, a halogen atom or a C" cycloalkyl group, or R2 is Bonded to each other, with a carbon atom adjacent to the phase 4 With the formation of a C3_7 cycloalkane or a 3 to 7 membered heterocyclic ring, R3 and R4 together form =0 or = s, _X is a single bond, Y is an oxygen atom or a sulfur atom, z is an oxygen atom or a sulfur atom, and R is a substituted C alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a Ci 6 alkoxy group), and the ring A is flammable via 1 to 2 Cl 6 a substituted nitrogen-containing heterocyclic ring of 6 to 7 members (the 2 C, -6 alkyl groups may be bonded to form a bicyclic ring) (preferably piperidine or azepane), or a pharmaceutically acceptable compound thereof ^ [Compound B] a is CH, b is CH or CR5 (R5 is synonymous with the above), and c is CR5 (R5 is a halogen atom, Cl_6 alkoxy group, gas group, Ci 6 alkylthio group, hydroxyl group, amine a filament of a base, a turtle, or an ageing group (preferably 1 to 4 substituents selected from the group consisting of a hydroxyl group, a thiol group, a halogen atom, a cyano group, a nitro group, and a methoxy group) Base substitution)), d is CH,

R1及R2為相同或相異，分別為氫原子、或可經取代的L 323406 47 201211028 烷基， R3及R4為一起形成=0， X為單鍵， Y為氧原子， Z為氧原子， R為可經取代的直鏈之Cm烷基（較佳可為經選自函原子及 匕-6烷氧基所構成群組中之1至4個取代基取代），且 環A為下述式（2a): 所示之含氮雜環， 之化合物或其藥學上容許的鹽。 [化合物C] a 為 CH， • b 為 CH ， c為CR5(R5為氟原子、氯原子、溴原子、曱基、曱氧基、或 三氟曱基，較佳為氟原子、氯原子、溴原子、曱基或曱氧 基）， d 為 CH， R1及R2為相同或相異，分別為氫原子、或Cm烷基（較佳為 Cl-3烧基）， R3及R4為一起形成=0， X為單鍵， 48 323406 201211028 Y為氧原子， ζ為氧原子， R為可經取代的直鏈之α3烧基（較佳可為經選自 C古-6烧氧基所構鱗財之丨^ 4錄代絲代 直鏈之Cm烷基），且 較佳為 環A為下述式（2a):R1 and R2 are the same or different and each are a hydrogen atom or a substituted L 323406 47 201211028 alkyl group, R 3 and R 4 are taken together to form =0, X is a single bond, Y is an oxygen atom, and Z is an oxygen atom. R is a linear Cm alkyl group which may be substituted (preferably substituted with 1 to 4 substituents selected from the group consisting of a functional atom and a fluorenyl-6 alkoxy group), and ring A is as follows Formula (2a): A nitrogen-containing heterocyclic ring, a compound thereof or a pharmaceutically acceptable salt thereof. [Compound C] a is CH, • b is CH, and c is CR5 (R5 is a fluorine atom, a chlorine atom, a bromine atom, a fluorenyl group, a decyloxy group, or a trifluoromethyl group, preferably a fluorine atom or a chlorine atom, a bromine atom, a fluorenyl group or a decyloxy group), d is CH, and R1 and R2 are the same or different, each being a hydrogen atom or a Cm alkyl group (preferably a Cl-3 alkyl group), and R3 and R4 are formed together. =0, X is a single bond, 48 323406 201211028 Y is an oxygen atom, ζ is an oxygen atom, and R is a linear α3 alkyl group which may be substituted (preferably, it may be selected from a C--6 alkoxy group)鳞 丨 丨 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4

所示之含氮雜環， 之化合物或其藥學上容許的鹽。 [化合物D] a 為 CH，A nitrogen-containing heterocyclic ring, a compound thereof, or a pharmaceutically acceptable salt thereof. [Compound D] a is CH,

C為相_相異mGR5(為氟原子、氣原子 Γ為CH甲基、乙基、丙基、，氧基、或三氣甲基。）， ^為相同或相異，分別為氫原子、可經取代的G 6院 基^原子、或C3-7環燒基， 二7^及R為互相鍵結，K丨及R2與相鄰的碳原子-同形成 C3—7裱烷或3至7員的雜環， R3及R4為-起形成=0或=5， X為草鍵或伸尹基， Y為氧原子或硫原子， z為氧原子或硫原子， 49 323406 201211028 R為可趣取代的Cw烷基（較佳可為經選自齒原子及c】-6烧氧 基所構成群組中之1至4個取代基取代）’且 ^八為可趣選自羥基、函原子、Cw烷基及Ch烷氧基所構 成群組中的1至2個取代基取代的6至7員之含氮雜環， 之化合物或其藥學上容許的鹽。 [化合物E] a 為 CH，C is a phase _ distinct mGR5 (a fluorine atom, a gas atom Γ is a CH methyl group, an ethyl group, a propyl group, an oxy group, or a trimethyl group.), ^ is the same or different, respectively, a hydrogen atom, a substituted G 6 compound atom or a C 3-7 cycloalkyl group, 2 7 and R are mutually bonded, and K 丨 and R 2 together with an adjacent carbon atom form a C 3-7 decane or 3 to a heterocyclic ring of 7 members, R3 and R4 are -formed = 0 or =5, X is a grass bond or a thiophene group, Y is an oxygen atom or a sulfur atom, and z is an oxygen atom or a sulfur atom, 49 323406 201211028 R is An interesting substituted Cw alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a tooth atom and a c-6 oxy group)) and the octyl group is selected from a hydroxyl group. A nitrogen-containing heterocyclic ring of 6 to 7 members substituted with 1 to 2 substituents in the group consisting of an atom, a Cw alkyl group and a Ch alkoxy group, or a pharmaceutically acceptable salt thereof. [Compound E] a is CH,

b及c為相同或相異，係Ch或CR5(為氟原子、氣原子、溴 原子、曱基、乙基、丙基、甲氧基、或三氟甲基）， d 為 CH， R1及R2為相同或相異，分別為氫原子、氟原子、羥基、或 可經取代的Ci e烷基（特別是可經羥基取代的Ci a烷基），^ 是R1及R2為互相鍵結，R1及R2與相鄰的碳原子一 艺 氫哌喃環， 门开/成四 R及R4為一起形成=〇或=s， X為單鍵， Y為氣原子， z為氧原子， R為可經取代的直鏈之Ci-6烷基（較佳可為經選自鹵b and c are the same or different and are Ch or CR5 (which is a fluorine atom, a gas atom, a bromine atom, a decyl group, an ethyl group, a propyl group, a methoxy group, or a trifluoromethyl group), and d is CH, R1 and R2 is the same or different and is respectively a hydrogen atom, a fluorine atom, a hydroxyl group, or a substituted Ci e alkyl group (especially a Ci a alkyl group which may be substituted by a hydroxyl group), and ^ is a bond of R1 and R2, R1 and R2 are bonded to an adjacent carbon atom, and the ring is opened to form four R and R4 together to form =〇 or =s, X is a single bond, Y is a gas atom, z is an oxygen atom, and R is a substituted straight chain Ci-6 alkyl group (preferably which may be selected from a halogen

Cl~6烷氧基所構成群組中之1至4個取代基取代），原子及 環A為下述式（2): 且 所示之含氮雜環， ' 3234〇6 50 201211028 R8為氫原子、羥基、鹵原子、Cw烷基或G-6烷氧基， 之化合物或其藥學上容許的鹽。 [化合物F ] a 為 CH， b 為 CH， c為CR5(為氟原子、氯原子、溴原子、曱基、乙基、丙基、 曱氧基、或三氟曱基。）， d 為 CH， ® R1及R2為相同或相異，分別為氫原子、氟原子、羥基、或 可經取代的G-6烷基（特別是可經羥基取代的G-3烷基），或 是R1及R2為互相鍵結，R1及R2與相鄰的碳原子一同形成四 氫派喃環， R3及R4為一起形成=0， X為單鍵， Y為氧原子， ^ Z為氧原子， R為可經取代的直鏈之Ch烷基（較佳可為經選自鹵原子及 G-6烷氧基所構成群組中之1至4個取代基取代）（較佳為直 鏈之Cl_3烧基），且 環A為下述式（2): 丨办、叮或KD-，⑺ 所示之含氮雜環， R8為氫原子、羥基、氟原子、甲基、乙基、曱氧基， 51 323406 201211028 之化合物或其藥學上容許的鹽。 [化合物G] a 為 CH， b為CR5(為氟原子、氣原子、溴原子、曱基、乙基、丙基、 曱氧基、或三氟甲基）， c 為 CH， d 為 CH， R1及R2為相同或相異，分別為氩原子、氟原子、羥基、或 可經取代的Ch烷基（特別是可經羥基取代的Cw烷基），或 是R1及R2為互相鍵結，R1及R2與相鄰的碳原子一同形成四 氫α底喃環， R3及R4為一起形成=0， X為單鍵， Υ為氧原子， Ζ為氧原子， ^ R為可經取代的直鏈之Cl-3烧基（較佳可為經選自鹵原子及 匕-6烷氧基所構成群組中之1至4個取代基取代）（較佳為直 鏈之Cl-3烧基），且 環A為下述式（2): 所示之含氮雜環， R8為氫原子、羥基、氟原子、曱基、乙基、甲氧基， 之化合物或其藥學上容許的鹽。 52 323406 201211028 [化合物Η] a 為 CH， b及c為相同或相異，為CH或CR5(為氟原子、氣原子、溴 原子、曱基、乙基、丙基、甲氧基、或三氟甲基）， d 為 CH， R1及R2為相同或相異，分別為氫原子、氟原子、羥基、或 可經取代的Cw烷基（特別是可經羥基取代的匕-3烷基），或 是R1及R2為互相鍵結，R1及R2與相鄰的碳原子一同形成四 氬旅喃環， R3及R4為一起形成二0， X為亞曱基， Y為氧原子， Z為氧原子， R為可經取代的直鏈之G-6烷基（較佳可為經選自鹵原子及 匕-6烷氧基所構成群組中之1至4個取代基取代），且 φ 環A為下述式（2): 丨^〇十^0'KD-·（2) 所示之含氮雜環， R8為氮原子、經基、鹵原子、Cl-6烧基或Cl-6烧氧基》 之化合物或其藥學上容許的鹽。 [化合物I ] a 為 CH， b及c為相同或相異，為CH或CR5(為氟原子、氣原子、溴 53 323406 201211028 原子、曱基、乙基、丙基、曱氧基、或三氟曱基）， d 為 CH， R1及R2為相同或相異，分別為氫原子、氟原子、羥基、或 可經取代的Ch烷基（特別是可經羥基取代的G-3烷基），或 是R1及R2為互相鍵結，R1及R2與相鄰的碳原子一同形成四 氬D底喃環， R3及R4為一起形成=0， X為單鍵， • Y為氧原子， Z為氧原子， R為可經取代的直鏈之Cl-6烧基（較佳可為經選自鹵原子及 Ch烷氧基所構成群組中之1至4個取代基取代），且 環A為下述式（3):1 to 4 substituents in the group consisting of Cl~6 alkoxy groups), the atom and ring A are the following formula (2): and the nitrogen-containing heterocycle shown, '3234〇6 50 201211028 R8 is A compound of a hydrogen atom, a hydroxyl group, a halogen atom, a Cw alkyl group or a G-6 alkoxy group, or a pharmaceutically acceptable salt thereof. [Compound F] a is CH, b is CH, and c is CR5 (which is a fluorine atom, a chlorine atom, a bromine atom, a decyl group, an ethyl group, a propyl group, a decyloxy group, or a trifluoromethyl group), and d is CH. , R1 and R2 are the same or different and are each a hydrogen atom, a fluorine atom, a hydroxyl group, or a substituted G-6 alkyl group (especially a G-3 alkyl group which may be substituted by a hydroxyl group), or R1 and R2 is bonded to each other, R1 and R2 together with adjacent carbon atoms form a tetrahydropyran ring, R3 and R4 form together = 0, X is a single bond, Y is an oxygen atom, ^ Z is an oxygen atom, and R is a substituted straight chain Ch alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a G-6 alkoxy group) (preferably a linear Cl_3 burn) And the ring A is a nitrogen-containing heterocyclic ring represented by the following formula (2): hydrazine, hydrazine or KD-, (7), and R8 is a hydrogen atom, a hydroxyl group, a fluorine atom, a methyl group, an ethyl group, a decyloxy group. , 51 323406 201211028 A compound or a pharmaceutically acceptable salt thereof. [Compound G] a is CH, b is CR5 (a fluorine atom, a gas atom, a bromine atom, a decyl group, an ethyl group, a propyl group, a decyloxy group, or a trifluoromethyl group), c is CH, and d is CH, R1 and R2 are the same or different and are respectively an argon atom, a fluorine atom, a hydroxyl group, or a substituted Ch alkyl group (particularly a Cw alkyl group which may be substituted by a hydroxyl group), or R1 and R2 are bonded to each other, R1 and R2 together with adjacent carbon atoms form a tetrahydro-α-decane ring, R3 and R4 are taken together to form =0, X is a single bond, Υ is an oxygen atom, Ζ is an oxygen atom, and ^ R is a replaceable straight a Cl-3 alkyl group of the chain (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a fluorenyl-6 alkoxy group) (preferably a linear Cl-3 alkyl group) And ring A is a nitrogen-containing heterocyclic ring represented by the following formula (2): R8 is a hydrogen atom, a hydroxyl group, a fluorine atom, a decyl group, an ethyl group, a methoxy group, or a pharmaceutically acceptable salt thereof . 52 323406 201211028 [Compound Η] a is CH, b and c are the same or different and are CH or CR5 (which is a fluorine atom, a gas atom, a bromine atom, a thiol group, an ethyl group, a propyl group, a methoxy group, or a triple Fluoromethyl), d is CH, R1 and R2 are the same or different and are each a hydrogen atom, a fluorine atom, a hydroxyl group, or a Cw alkyl group which may be substituted (particularly a hydrazone-3 group which may be substituted by a hydroxy group) , or R1 and R2 are mutually bonded, R1 and R2 together with adjacent carbon atoms form a tetraral argon ring, R3 and R4 together form 20,000, X is a fluorenylene group, Y is an oxygen atom, and Z is An oxygen atom, R is a linear C-6 alkyl group which may be substituted (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a fluorenyl-6 alkoxy group), and φ Ring A is a nitrogen-containing heterocyclic ring represented by the following formula (2): 丨^〇10^0'KD-·(2), R8 is a nitrogen atom, a trans group, a halogen atom, a Cl-6 alkyl group or Cl a compound of -6 alkoxylate or a pharmaceutically acceptable salt thereof. [Compound I] a is CH, and b and c are the same or different and are CH or CR5 (a fluorine atom, a gas atom, a bromine 53 323406 201211028 atom, a fluorenyl group, an ethyl group, a propyl group, a decyloxy group, or a third group). Fluorinyl), d is CH, and R1 and R2 are the same or different and each is a hydrogen atom, a fluorine atom, a hydroxyl group, or a substituted C-alkyl group (especially a G-3 alkyl group which may be substituted by a hydroxyl group) , or R1 and R2 are mutually bonded, R1 and R2 together with adjacent carbon atoms form a tetra-argon D-bottom ring, R3 and R4 together form =0, X is a single bond, • Y is an oxygen atom, Z Is an oxygen atom, R is a linear C-6 alkyl group which may be substituted (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a Ch alkoxy group), and a ring A is the following formula (3):

所示之含氮雜環， 之化合物或其藥學上容許的鹽。 [化合物J] a 為 CH， b及c為相同或相異，為CH或CR5(為氟原子、氯原子、溴 原子、曱基、乙基、丙基、曱氧基、或三氟曱基）， d 為 CH， R1及R2為相同或相異，分別為氫原子、氟原子、羥基、或 可經取代的Ci-6烷基（特別是可經羥基取代的C!-3烷基），或 54 323406 201211028 同形成四 是R及R2為互相鍵結，R1及R2與相鄰的碳原子一 氫旅喃環， R及R4為一起形成=〇, X為单鍵， Y為氧原子， z為氧原子， R為可經取代的直鏈之Ch烷基（較佳可為經選自齒原子及 φ Cl—6烧氧基所構成群組中之1至4個取代基取代），且 環A為下述式（4): KQh⑷ 所示之含氮雜環， 之化合物或其藥學上容許的鹽。 本發明之化合物較佳為： 4 [4 (2侧氧基-2，3_二氮-1Η-ι^Ιπ朵_1_基）娘唆-1-基]派 φ 啶-1-羧酸乙酯； 4-[4-(3-甲基-2-侧氧基-2, 3-二氫-1Η-吲哚-1-基）旅咬 -1-基]哌啶-1-羧酸乙酯； 4-[4-(3, 3-二曱基-2-侧氧基-2, 3-二氫-1Η-吲哚-1-基）哌 唆-1-基>底啶-1-叛酸乙酯； 4-[4-(3, 3-二乙基-2-侧氧基-2, 3-二氫-1Η-吲哚-1-基）哌 咬-1-基]派啶-1-羧酸乙酯； 4-[4-(3-乙基-3-曱基-2-侧氧基-2, 3-二氫-1H-吲哚-1-基） 哌啶-1-基]哌啶-1-羧酸乙酯； 55 323406 201211028 4-[4-(3, 3-二丙基-2-側氧基-2, 3-二氩-1H-吲哚-1-基）哌 啶-1-基]哌啶-1-羧酸乙酯； 4-{4-[2’ -侧氧螺（環丙烷-1，3’ -吲哚）-1’（2’ H)-基]哌啶 -l-基}哌啶-1-羧酸乙酯； 4-{4-[2’ -侧氧螺（環丁烷-1，3’ -吲哚）-1’（2’ H)-基]哌啶 -l-基}哌啶-1-羧酸乙酯； 4-{4-[2’ -側氧螺（環戊烷-1，3’ -吲哚）-1’（2’ H)-基]哌啶 -l-基}哌啶-1-羧酸乙酯； # 4-{4-[2’ -侧氧螺（環己烷-1，3’ -吲哚）-1’（2’ H)-基]哌啶 -1-基}哌啶-1-羧酸乙酯； 4-{4-[2’ -側氧螺（四氫α底喃-4, 3’ -°引π朵）_1 ’（2’ H)-基]派 啶-l-基}哌啶-1-羧酸乙酯； 4-[4-(3, 3-二曱基-2-侧氧基-2, 3-二氫-1Η-吲哚-1-基）哌 啶-1-基]甲基哌啶-1-羧酸乙酯； 4-{4-[2’ -側氧螺（環丙烷-1，3’ -吲哚）-1’（2’ Η)-基]哌啶 φ -l-基}曱基哌啶-1-羧酸乙酯； 3- [4-(3, 3-二乙基-2-侧氧基-2, 3-二氫-1Η-吲哚-1-基）哌 〇定_1_基]_8-°丫雙環[3. 2. 1]辛炫-8-叛酸乙酉旨； 4- [4-（3，3-二曱基-2-側氧基-2，3-二氫-1Η-α引°朵-1-基）派 α定-1 ·'基]派。定_ 1_缓酸甲酉旨； 4-[4-(3, 3-二曱基-2-側氧基-2, 3-二氫-1Η-吲哚-1-基）哌 啶-1-基]哌啶-1-羧酸異丙酯； 4-[4-(2-側氧基-2, 3-二氩-1Η-吲哚-1-基）哌啶-1-基] 氮雜環庚烷-1-羧酸乙酯； 56 323406 201211028 4-[4-(6-氟-2-側氧基_2,3-二氫-1H-吲哚_卜基）哌啶-i- 基]派°定-1-繞酸乙酯； 4-[4-(6-氟-3,3-二甲基-2-侧氧基-2,3-二氫-lH-吲哚-l- 基）α底啶-l-基]哌啶-l_羧酸乙酯； 4-[4-(5-氯-2-侧氧基—2,3-二氫-1H-吲哚-1-基）哌啶-1 一 基]旅°定-1-緩酸乙酯； 4-[4-(5-氟-3, 3-二甲基-2-側氧基-2,3-二氫-1H-吲哚-1- φ 基）派咬_1_基]哌啶-1-羧酸乙酯； 4-[4-(5-氟-2-侧氧基-2,3-二氫-1H-吲哚-1-基）哌啶-1一 基]派唆基-敌酸乙醋； 4-({3-[1-(乙氧基羰基）哌啶基_4_亞基]_6_氟_2_侧氧基 -2, 3-—氫-1H-吲哚—1—基丨哌啶_ι_基）派啶羧酸乙酯； 4-({3-[1-(乙氧基羰基）哌啶基_4_基]_6_氟_2_侧氧基 -2,3-二氫-111-吲哚-1-基}哌啶_1_基）哌啶_1_羧酸乙酯； 1-乙基硫羰基-4-[4-(2-侧氧基-2, 3-二氫-1H-吲哚-1-基） ^ 派咬-1 _基]°辰b定； 4-[4-(2-侧氧基-2, 3-二氫-1H-吲哚-1-基）哌啶_ι_基]哌 啶-1-羧酸2-氟乙酯； 4-[4-(2-侧氧基-2,3_二氫_1H—吲哚_丨_基）哌啶_丨_基]哌 啶-1-羧酸2-丙烯酯； 4-[4-(2-侧氧基-2,3_二氫_1H_吲哚基）哌啶_丨_基]哌 咬-1-缓酸2-甲氧乙酯； 4-[4-(2-侧氧基-2, 3-二氫-1H-吲哚-1-基）哌啶_丨_基]哌 啶-1-羧酸丁酯； 323406 57 201211028 1-曱基硫羰基-4-[4-(2-側氧基-2,3-二氫-1H-吲哚―丨―基） 哌啶-1-基]哌啶； α 4-[4-(2-侧氧基-2,3-二氫-1H-吲哚基）哌啶_丨_基]哌 啶-1-羧酸丙酯； 4-[4-(5-氟-2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌啶一卜 基]氣雜環庚院-1-竣酸乙醋； 4-[4-(3,3-二曱基-2-側氧基一2, 3一二氫_5一氟—1H_吲哚—卜 φ 基）哌啶基]氮雜環庚烷-1-羧酸乙酯； 4-[4-(3,3-二甲基-2-硫酮基-2, 3一二氫一1H_吲哚―卜基）哌 啶-1-基]哌啶-1-鲮酸乙酯； 4 [4-(5-甲基-2-侧氧基_2, 3_二氫一1H_吲哚一卜基）哌啶 -1-基]哌啶-1-羧酸乙酯； [4 (6曱基2-側氧基_2,3-二氫-1H-吲哚-1-基）0辰咬 - 1-基]°底啶-1-綾酸乙酯； 4一[4_(5一甲氧基—2-側氧基_2, 3-二氫-1H-吲哚-1-基）哌啶 Φ -1-基]派啶-1—羧酸乙酯； 4一[4_(5—甲氧基~2-側氧基—2, 3-二氫-1H-十朵-卜基）旅啶 一1_基]氮雜環庚烷-1-羧酸乙酯； 4:{4-[3,3-雙（3—甲氧基丙基）_2_侧氧基_2,3_二氫_ih一吲 哚基]哌啶―1—基丨氮雜環庚烷-1-羧酸乙酯； 4-氟-3’ 3-雙（經基甲基）_2_側氧基_2, 3-二氫-1H- 引朵1基]哌啶-1_基}哌啶羧酸乙酯； 4 [4 (5肩-2-側氧基_2,3-二氫-1H-吲哚-1 —基）哌啶一卜 基 >辰啶-1-鲮酸乙酯； 58 323406 201211028 4-[4-(5-溴-2-側氧基-2, 3-二氫-1H-吲哚-卜基）娘咬-1_ 基]氮雜環庚烧-1-竣酸乙酯； 4-[4-(5-氯-2-側氧基-2, 3-二氫-1H-吲哚基）派咬一1一 基]氣雜環庚烧-1-缓酸乙酯； 4-[4-(5-氯-2-側氧基-2, 3-二氫-1H-吲哚-卜基）哌啶一1_ 基]哌啶-1-羧酸曱酯； 4一[4-(5-氟-2-側氧基-2,，3’，5,，6,-四氫螺[吲哚 _3’ 4 _ φ 哌喃]-1(2H)-基）哌啶-1-基]哌啶_卜羧酸乙酯； 4-[4-(5-氟-2-側氧基-2,，3,，5,，6,-四氮螺[吲哚 4 _ 哌喃]-1(2H)-基）哌啶-1-基]氮雜環庚烷-1-羧酸乙酯； 4-[4-(5’ -氯-2’ -側氧螺—[環丙烷-1，3’ -吲哚]―1’（2’ H)一 基）旅咬-1-基]旅咬-1-致酸乙酯； 4-[4-(5,-氣-2’ -側氧螺-[環丙烷-1，3,-吲哚]-1’（2’ H)-基）D辰变基]0底咬-1-竣酸甲酯； 4-[4-(5’ -氯-2’ -側氧螺—[環丙烷—1，3,-吲哚]-Γ (2’ H)-• 基>底咬-1-基]氮雜環庚烷_丨_羧酸乙酯； 4一[4-(5’ -氟-2’ -侧氧螺-[環丙烷_丨，3’ —吲哚]-1，（2, H)-基）D辰啶-1-基]哌啶—1_羧酸乙酯； 4~[4-(5’ -氟-2’ -側氧螺—[環丙烷μ，3, _吲哚]—r (2, h)-基）D辰啶-1-基]哌啶一 羧酸甲酯； 4一[4-(5’ -氟-2’ -側氧螺_[環丙烷_丨，3, _吲哚卜r (2, H)_ 基）。辰咬-1-基]氮雜環庚烷_丨_羧酸乙酯； 4 [4 (5曱基-2-侧氧基_2’，3’，5’，6’ _四氫螺[吲口朵 -3’4’-哌喃]-1(2H)-基）哌啶-1-基]哌啶<一羧酸乙酯； 323406 59 201211028 4_[4气5—甲基一2~側氧基-2,，3,，5,，6,-四氫螺[吲哚 3’4哌喃]_1(2H)-基）哌啶-1-基]氮雜環庚烷-1-羧酸乙 酯； 4_[4_(5 ~曱基一2’ -側氧螺-[環丙烷-1，3, -吲哚]-Γ (2, H) -基）哌啶-1-基]哌啶_丨_羧酸乙酯； 4_[4一（5 ~甲基一2’ —側氧螺-[環丙烷-1, 3,-吲哚]-1，（2, H) 一基）°底°定―1—基]氮雜環庚烷-1-羧酸乙酯； φ 4一[4一（3, 3, 6~三甲基—2-侧氧基-2, 3-二氫-1H-吲哚-卜基） 哌啶_1~基]哌啶-1-羧酸乙酯； 4-[4-(3’ 3’ 6-三曱基-2-侧氧基_2, 3-二氫-1H-吲哚-1-基） 哌啶-1-基]哌啶-1-羧酸甲酯； 4-[4-(3, 3, 6-三甲基-2-侧氧基—2, 3-二氫-1H-吲哚-1-基） 旅啶-1-基]氮雜環庚烧-1-羧酸乙酯； 4-[4-(6’ _曱基-2’ -侧氧螺-[環丙烷 — i，3, _吲哚卜Γ (2, H) -基）。底咬-1-基]派咬-1-幾酸乙酯； φ 4一[4_(6’ _甲基_2’ 一侧氧螺-[環丙烷-1，3,-吲哚]-Γ (2，H) -基）旅唆-1-基]旅咬-1-幾酸甲酯； 4_[4-(6’ -甲基-2’ -侧氧螺-[環丙烷q，3,—吲哚]_Γ (2, H) -基）°辰11 定-1-基]氮雜環庚院-1—敌酸乙酯； 4-[4-(6-甲基-2-側氧基-2,，3,，5,，6,-四氫螺[吲哚 -3,4’-哌喃]-1(21〇-基）哌啶-1—基]哌啶_1_鲮酸乙酯； 4-[4_(6-曱基-2-侧氧基-2,，3,，5,，6, _四氫螺[吲哚 -3,4’-哌喃]-1(21〇-基）哌啶-1-基；1氮雜環庚烷_1_羧酸乙 酯； 323406 60 201211028 氣〜1H〜吲哚-1-基）哌啶A nitrogen-containing heterocyclic ring, a compound thereof, or a pharmaceutically acceptable salt thereof. [Compound J] a is CH, and b and c are the same or different and are CH or CR5 (which is a fluorine atom, a chlorine atom, a bromine atom, a decyl group, an ethyl group, a propyl group, a decyloxy group, or a trifluoromethyl group). ), d is CH, and R1 and R2 are the same or different and each is a hydrogen atom, a fluorine atom, a hydroxyl group, or a substituted Ci-6 alkyl group (especially a C!-3 alkyl group which may be substituted by a hydroxyl group) , or 54 323406 201211028 with the formation of four is R and R2 are mutually bonded, R1 and R2 and the adjacent carbon atom-hydrogen bridging ring, R and R4 together form = 〇, X is a single bond, Y is an oxygen atom z is an oxygen atom, and R is a linear C chain which may be substituted (preferably substituted with 1 to 4 substituents selected from the group consisting of a tooth atom and a φ Cl-6 alkoxy group) And ring A is a nitrogen-containing heterocyclic ring represented by the following formula (4): KQh(4), or a pharmaceutically acceptable salt thereof. Preferably, the compound of the present invention is: 4 [4 (2 oxo-2,3-diaza-1 Η-ι^Ιπ多_1_yl) 唆-1-yl] pi pyridine-1-carboxylic acid Ethyl ester; 4-[4-(3-methyl-2-oxo-2,3-dihydro-1Η-indol-1-yl) brigade-1-yl]piperidine-1-carboxylic acid Ethyl ester; 4-[4-(3,3-dimercapto-2-oxo-2,3-dihydro-1Η-indol-1-yl)piperazin-1-yl] 1-oleic acid ethyl ester; 4-[4-(3, 3-diethyl-2-oxo-2,3-dihydro-1Η-indol-1-yl)piperidin-1-yl] Ethyl pyridin-1-carboxylate; 4-[4-(3-ethyl-3-indolyl-2-oxo-2,3-dihydro-1H-indol-1-yl)piperidine Ethyl-1-yl]piperidine-1-carboxylate; 55 323406 201211028 4-[4-(3,3-dipropyl-2-yloxy-2,3-diar-argon-1H-indole- Ethyl 1-phenyl)piperidin-1-yl]piperidine-1-carboxylate; 4-{4-[2'-side oxyspiro(cyclopropane-1,3'-indole)-1' (2 'H)-yl]piperidin-l-yl}piperidine-1-carboxylic acid ethyl ester; 4-{4-[2'-side oxoxane (cyclobutane-1,3'-吲哚)-1 '(2' H)-yl] piperidine-l-yl}piperidine-1-carboxylic acid ethyl ester; 4-{4-[2'-side oxo[cyclopentane-1,3'-吲哚-1 '(2' H)-yl] piperidine-l-yl}piperidine-1-carboxylic acid ethyl ester; # 4-{4-[2'-Sideoxyspiro(cyclohexane-1,3'-indole)-1'(2'H)-yl]piperidin-1-yl}piperidine-1-carboxylic acid Ethyl ester; 4-{4-[2'-side oxyspiro (tetrahydro-α-pyran-4, 3'-° π 朵)_1 '(2' H)-yl]pyridinyl-l-yl} Ethyl pyridine-1-carboxylate; 4-[4-(3,3-dimercapto-2-oxo-2,3-dihydro-1Η-indol-1-yl)piperidin-1- Ethyl methyl piperidine-1-carboxylate; 4-{4-[2'-side oxo (cyclopropane-1,3'-indole)-1'(2' Η)-yl]piperidin Ethyl pyridine φ-l-yl}nonylpiperidine-1-carboxylate; 3-[4-(3, 3-diethyl-2-oxo-2,3-dihydro-1 fluorene-fluorene -1-yl)piperidine_1_yl]_8-°丫bicyclo[3. 2. 1]Xinxuan-8-Resinic acid; 4-[4-(3,3-didecyl-2 - Side oxy-2,3-dihydro-1 Η-α 引 °-1-yl) 派 α定-1 · '基基派. _ 1_ 酸酸甲酉; 4-[4-(3, 3-Dimercapto-2-oxo-2,3-dihydro-1Η-indol-1-yl)piperidine-1 -yl]piperidine-1-carboxylic acid isopropyl ester; 4-[4-(2-o-oxy-2,3-diar-ar-indol-indol-1-yl)piperidin-1-yl] nitrogen Ethyl heterocycloheptane-1-carboxylate; 56 323406 201211028 4-[4-(6-fluoro-2-indolyl 2,3-dihydro-1H-indole-diyl)piperidine-i -基]派定定-1-Acetate ethyl ester; 4-[4-(6-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-lH-indole- L-yl)α-pyridinyl-l-yl]piperidine-l-carboxylate; 4-[4-(5-chloro-2-oxo- 2,3-dihydro-1H-indole- 1-yl)piperidin-1-yl]-t-butyl-1-acidic ethyl ester; 4-[4-(5-fluoro-3,3-dimethyl-2-oxo-2,3- Dihydro-1H-indol-1- φ group) bite _1 yl] piperidine-1-carboxylic acid ethyl ester; 4-[4-(5-fluoro-2- oxo-2,3- Dihydro-1H-indol-1-yl)piperidine-1-yl]pyrazine-dicarboxylic acid ethyl acetate; 4-({3-[1-(ethoxycarbonyl)piperidinyl_4_ya Base]_6_fluoro_2_sideoxy-2, 3-hydrogen-1H-indole-1-ylpiperidinyl-yl)pyridinium carboxylate; 4-({3-[1 -(ethoxycarbonyl)piperidinyl-4-yl]-6-fluoro-2-oxo-2,3-dihydro-111-indol-1-yl}piperidine-1-yl Ethyl piperidine_1-carboxylate; 1-ethylthiocarbonyl-4-[4-(2-o-oxy-2,3-dihydro-1H-indol-1-yl)^ _基]°辰乙定; 4-[4-(2-Sideoxy-2,3-dihydro-1H-indol-1-yl)piperidinyl-yl]piperidine-1-carboxylic acid 2-fluoroethyl ester; 4-[4-(2-o-oxy-2,3-dihydro-1H-indole-indolyl) piperidine-indolyl]piperidine-1-carboxylic acid 2- Propylene ester; 4-[4-(2-o-oxy-2,3-dihydro-1H-indenyl) piperidine-yl-yl]piperidone-1-hypoacid 2-methoxyethyl ester; 4 -[4-(2-Sideoxy-2,3-dihydro-1H-indol-1-yl)piperidine-indolyl]piperidine-1-carboxylic acid butyl ester; 323406 57 201211028 1-曱Thiocarbonyl-4-[4-(2-o-oxy-2,3-dihydro-1H-indole-yl)piperidin-1-yl]piperidine; α 4-[4-(2 -Phenoxy-2,3-dihydro-1H-indenyl) piperidine-yl-yl]piperidine-1-carboxylic acid propyl ester; 4-[4-(5-fluoro-2-oxooxyl) -2,3-dihydro-1H-indol-1-yl)piperidine-diyl]-cyclohexane-glycine-1-acetic acid ethyl acetate; 4-[4-(3,3-didecyl- 2-sided oxy-2,3-dihydro-5-fluoro-1H_吲哚-bu φ-)piperidinyl]azepane-1-carboxylic acid ethyl ester; 4-[4-(3 ,3-dimethyl-2-thioketo-2,3-dihydro- 1H_吲哚-Buji) Ethyl-1-yl]piperidine-1-decanoate; 4 [4-(5-Methyl-2-oxo-2,3-dihydro-1H-indenyl)piperidine- Ethyl 1-piperidine-l-carboxylate; [4 (6-mercapto 2-oxo-2,3-dihydro-1H-indol-1-yl) 0-bite- 1-yl]底 啶 绫 绫 绫 绫 绫 ; ;; 4 -[4_(5-methoxy-2-sideoxy-2, 3-dihydro-1H-indol-1-yl)piperidine Φ -1- Ethyl pyridyl-1 -carboxylic acid ethyl ester; 4 -[4_(5-methoxy~2-o-oxy-2,3-dihydro-1H-decadet-bu)) Azideheptane-1-carboxylic acid ethyl ester; 4: {4-[3,3-bis(3-methoxypropyl)_2_sideoxy-2,3_dihydro-ih- 吲Ethyl]piperidin-1-ylhydrazin-1-carboxylate; 4-fluoro-3' 3-bis(transmethyl)_2_sideoxy-2, 3-dihydro -1H- 引一基基]piperidin-1_yl}piperidinecarboxylic acid ethyl ester; 4 [4 (5 shoulder-2-sided oxy-2,3-dihydro-1H-indole-1 -yl) Piperidine-diyl> henidine-1-decanoic acid ethyl ester; 58 323406 201211028 4-[4-(5-bromo-2-yloxy-2,3-dihydro-1H-indole-b Base) Ninjabita-1_yl]azetidinyl-1-acetate; 4-[4-(5-chloro-2-oxo-2,3-dihydro-1H-indenyl) Pie bite one base one] Cycloheptyl-1-acid acid ethyl ester; 4-[4-(5-chloro-2-oxo-2,3-dihydro-1H-indole-buyl)piperidine-1-yl]piperidine -1-carboxylic acid oxime ester; 4-[4-(5-fluoro-2-oxo-2,3',5,6,-tetrahydrospiro[吲哚_3' 4 _ φ pentane Ethyl 1-(2H)-yl)piperidin-1-yl]piperidine-carboxylate; 4-[4-(5-fluoro-2-oxo-2,3,5,, 6, 4-tetrazirospiro[吲哚4 _piperan]-1(2H)-yl)piperidin-1-yl]azepane-1-carboxylic acid ethyl ester; 4-[4-(5' -Chloro-2'-side oxo-[cyclopropane-1,3'-吲哚]-1'(2'H)-yl)) Bite-1-yl] Bistamine-1-acid ethyl ester; 4-[4-(5,-Gas-2'-side oxo-[cyclopropane-1,3,-吲哚]-1'(2' H)-yl)D hen cleavage]0 bottom bite- Methyl 1-decanoate; 4-[4-(5'-chloro-2'-side oxo-[cyclopropane-1,3,-吲哚]-Γ(2' H)-• base>Ethyl-1-yl]azepane-indole-carboxylate; 4-[4-(5'-fluoro-2'-side oxo-[cyclopropane_丨,3'-吲哚]- 1,(2,H)-yl)D-Cyridin-1-yl]piperidine-1-carboxylic acid ethyl ester; 4~[4-(5'-fluoro-2'-side oxyspiro-[cyclopropane μ ,3, _吲哚]-r (2, h)-yl)D-Cyridin-1-yl]piperidine monocarboxylic acid Ester; a 4 [4- (5 '- fluoro-2' - _ side oxo spiro [cyclopropane Shu _, 3, _ indol-Bu r (2, H) _ yl). Erythryl-1-yl]azetidin-indole-carboxylate; 4 [4 (5-mercapto-2-oxo-2',3',5',6'-tetrahydrospiro[吲口多-3'4'-Peranid]-1(2H)-yl)piperidin-1-yl]piperidine<monocarboxylate; 323406 59 201211028 4_[4 gas 5-methyl-2 ~Sideoxy-2,,3,,5,,6,-tetrahydrospiro[吲哚3'4piperan]_1(2H)-yl)piperidin-1-yl]azepane-1 -Carboxylic acid ethyl ester; 4_[4_(5~曱-yl 2'-side oxyspiro-[cyclopropane-1,3, -吲哚]-fluorene (2,H)-yl)piperidin-1-yl ] piperidine _ 丨 carboxylic acid ethyl ester; 4_[4 - (5 ~ methyl - 2' - side oxo-[cyclopropane-1, 3, - 吲哚]-1, (2, H)-based ° 底 一 定 定 氮 氮 ; ; ; 一 一 一 一 一 一 一 一 一 一 一 一 一 一 一 一 一 一 一 一 一 一 一 一 一 一 一 一 一 一 一Dihydro-1H-indole-buyl) piperidine-1-yl]piperidine-1-carboxylic acid ethyl ester; 4-[4-(3' 3' 6-tridecyl-2-yloxy) Methyl 2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]piperidine-1-carboxylate; 4-[4-(3,3,6-trimethyl-2 - oxy- 2, 3-dihydro-1H-indol-1-yl) benzylidene-1-yl]azetidin-1-carboxylic acid ethyl ester; 4-[4-(6' _ Mercapto-2'-side oxo-[cyclopropyl] - i, 3, _ indol-Bu Γ (2, H) - yl). Bottom--1-yl]-biting 1-carboxylic acid ethyl ester; φ 4-[4_(6' _methyl-2' oxo-[cyclopropane-1,3,-吲哚]-Γ (2,H)-yl) Tour-1-yl]Break-But-1-carboxylic acid methyl ester; 4_[4-(6'-methyl-2'-side oxo-[cyclopropane q,3, —吲哚]_Γ(2, H)-yl)°辰11 定-1-yl]azetidin-1-diethyl acid; 4-[4-(6-methyl-2-sideoxy) Base-2,,3,,5,6,-tetrahydrospiro[吲哚-3,4'-pyrano]-1(21〇-yl)piperidin-1-yl]piperidine_1_鲮Ethyl acetate; 4-[4_(6-fluorenyl-2-oxo-2,3,5,6, _tetrahydrospiro[吲哚-3,4'-pyranyl]-1 ( 21〇-yl)piperidin-1-yl; 1 azepan-1-ylcarboxylate; 323406 60 201211028 gas ~1H~吲哚-1-yl)piperidine

°弓1π朵-1 -基）β辰π定 4-[4-(6-曱基-2-侧氧基-2, 3-二 -1-基]氮雜環庚烷-1-羧酸乙酯； 4-[4-(6-曱基-2-侧氧基-2,3-二 -1-基]哌啶-1-羧酸乙酯； 1Η〜吲哚-1-基）哌啶 3_ 氫 4-[4-(6-曱基-2-側氧基一： -1-基]哌啶-1-羧酸曱酯；°1π朵-1 -yl)β辰π定4-[4-(6-Mercapto-2-oxo-2,3-di-1-yl)azepane-1-carboxylic acid Ethyl ester; 4-[4-(6-fluorenyl-2-oxo-2,3-di-1-yl]piperidine-1-carboxylic acid ethyl ester; 1Η~吲哚-1-yl)piperidin Pyridinium 3-hydrogen 4-[4-(6-fluorenyl-2-oxo-1:-1-yl]piperidine-1-carboxylic acid decyl ester;

4-[4-(6-曱氧基一2-側氧基_2, 3_二氫 -卜基]氮雜環庚烧-1-叛自曼乙醋； ^ 1基 (1R, 5S)-3-[4-(6-曱氧基-2-侧氧基^ +基)派咬-1-基]-8-。丫雙環[3. 2.1]辛p 一氫1H吲口木 4_胸-甲氧基+側氧基_2,3_二氫，，朵+基)娘 啶-1-基]甲基}哌啶-1-羧酸乙酯； 4-{[4-（6-甲氧基一 2 一側氧基_2，，3’，5，，6，_四氮螺[十朵 -3, 4’-哌喃]-ΐ(2Η)-基）哌啶-1-基]哌啶-卜鲮酸乙酯； 4-{[4-(6-甲氧基-2-侧氧基-2，，3，，5，，6’_四氫螺[吲哚 -3,4 底喃]-i(2H)-基）派咬-1-基]氮雜環庚烧_ι_緩酸乙 酯； (1R，5S)-3-[4-(6-曱氧基-2-侧氧基-2’，3’，5’，6’ -四氫螺 [σ弓丨**朵-3, 4’ -派喃]-l-(2H)-基）-派淀-1-基]-8-。丫雙環 [3.2. 1]辛烧-8-叛酸乙酉旨； 4-[4-(5-氯-6-氟-3, 3-二曱基-2-侧氧基-2, 3-二氫-1Η-吲 哚-1-基）哌啶-1-基]哌啶-1—羧酸乙酯； 4 [4-(3, 6-一曱基_2-侧氧基-2, 3-二氫-1Η-σ引°朵-1-基）派 °定-1-基]派咬-1-竣酸乙酯； 61 323406 201211028 4-[4-（3，6-二曱基-2-側氧基-2，3-二氮_1Η-α引°朵-1_基）派 啶-1-基]哌啶-1-羧酸甲酯； 4-[4-(3, 6-二曱基-2-側氧基-2, 3-二氫-1Η-吲哚-1-基）哌 啶-1-基]氮雜環庚烷-1-羧酸乙酯； 4-[4-(5-氟-3-曱基-2-側氧基-2, 3-二氫-1Η-吲哚-1-基） 哌啶-1-基]氮雜環庚烷-1-羧酸乙酯； 4-{ [4-(5_ 氟-3-曱基-2-側氧基-2, 二氫-1Η-α引 α朵-1-基） 哌啶-1-基]甲基}哌啶-1-羧酸乙酯； 4-{[4-(3-曱基-2-側氧基-2, 3-二氫-1Η-σ引嗓_1 -基）旅咬 -1-基]曱基}哌啶-1-羧酸乙酯； 4- [ 4-(5-曱基-2-側氧基-2，3_二氮-1Η- °弓丨π朵-1_基）α底咬 -1-基]氮雜環庚烷-1-羧酸乙酯； 4-{[4-(5-曱基-2-側氧基-2, 3-二氫-1Η-吲哚-1-基）哌啶 -1-基]曱基}哌啶-1-羧酸乙酯； 4-{[4-(2-侧氧基-2, 3-二氫-1Η-吲哚-1-基）哌啶-1-基]曱 φ 基}哌啶-1-羧酸乙酯； 4-[4-(6-氟-3-曱基-2-側氧基-2, 3-二氫-1Η-吲哚-1-基） 哌啶-1-基]哌啶-1-羧酸乙酯； 4-[4-(6-氟-3-甲基-2-側氧基-2, 3-二氫-1Η-吲哚-1-基） 哌啶-1-基]氮雜環庚烷-1-羧酸乙酯； 4-[4-(5-氟-2-侧氧基-2,3-二氫-111-17引11朵_1-基）旅唆-1-基]哌啶-1-羧酸甲酯； 4-[4-(6-曱基-2-側氧基-2, 3-二氫-1Η-吲哚-1-基）哌啶 -1-基]哌啶-1-羧酸曱酯； 62 323406 201211028 4-[4-(6-溴-2-側氧基-2, 3-二氫-1H-吲哚-卜基）哌啶-1-基]哌啶-1-羧酸乙酯； 4-[4-(6-溴-2-側氧基-2, 3-二氳-1H-吲哚-卜基）哌啶-1-基]氮雜環庚烷-1-羧酸乙酯； 4-[4-(6-溴-2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌啶-1-基]哌啶-1-羧酸曱酯； 4-[4-(6-乙基-2-侧氧基-2, 3-二氩-1H-吲哚-1-基）哌啶 -1-基]哌啶-1-羧酸乙酯； ® 4-[4-(6-乙基-2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌啶 -1-基]氮雜環庚烧_1_叛酸乙酉旨·； 4-[4-(2-側氧基-6-丙基-2, 3-二氫-1H-吲哚-1-基）哌啶 -卜基]哌啶-1-羧酸乙酯； 4-{[4-(5-氯-2-侧氧基-2, 3-二氫-1H-吲哚-1-基）哌啶-1-基]甲基}哌啶-1-羧酸乙酯； (1R，5S)-3-[4-(5-氯-2-侧氧基-2, 3-二氫-1H-吲哚-1-基） φ -哌啶-1-基]-8-吖雙環[3. 2. 1]辛烷-8-羧酸乙酯； 4-{[4-(5_氟-2-侧氧基-2，3-二氮_111-11引11朵_1_基）。底咬_1_ 基]曱基}哌啶-1-羧酸乙酯； (1R, 5S)-3-[4-(5 -氣-2-側氧基-2，3-二氮-1Η-σ引 π朵-1-基） -哌啶-1-基]-8-吖雙環[3. 2. 1]辛烷-8-羧酸乙酯； 4-[4-(6-甲基-2-側氧基-2, 3-二氫-1Η-吲哚-1-基）哌啶 _ι_基]氮雜環庚烧_ι_叛酸乙s旨； 4-{[4-(6-曱基-2-侧氧基-2, 3_二氫_1Η-σ引α朵_1-基）α底唆 _1_基]甲基}0辰。定_1_叛酸乙酉旨； 63 323406 201211028 4-{[4-(6-氟-2-側氧基-2, 3-二氩-1H-吲哚-1-基）哌啶-1-基]甲基}哌啶-1-羧酸乙酯； 4-[4-(6 -氟-2-側氧基-2, 3-二氮-1Η-σ5|π朵_l_S)n底咬-1_ 基]氮雜環庚烷-1-羧酸乙酯； 4-[4-(5-氟-3, 3-二曱基-2-硫酮基-2, 3-二氫-1H-吲哚-1-基）哌啶-1-基]哌啶-1-羧酸乙酯； 4-[4-(6-曱氧基-2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌啶 -卜基]-4-曱基哌啶-1-羧酸乙酯； 4-[4-(6-氟-2-側氧基-2, 3-二氳-1H-吲哚-1-基）哌啶-1-基]-4-曱基哌啶-1-羧酸乙酯； 4-[4-(6-曱基-2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌啶 _1_基]-4-曱基10辰咬_1_竣酸乙酉旨； 4-[4-(6-曱氧基-3-曱基-2-侧氧基-2, 3-二氬-1Η-吲哚-1-基）哌啶-1-基]-4-甲基哌啶-1-羧酸乙酯； (3-内）-3-[4-(6-曱基-2-侧氧基-2, 3-二氫-1Η-吲哚-1-基） • 哌啶-1-基]-8-吖雙環[3. 2. 1]辛烷-8-羧酸乙酯； (3-外）-3-[4-(6-曱基-2-側氧基-2, 3-二氫-1Η-吲哚-1-基） 哌啶-1-基]-8-吖雙環[3. 2. 1]辛烷-8-羧酸乙酯； (3-内）-3-[4-(6-氟-2-側氧基-2, 3-二氩-1Η-吲哚-1-基） 哌啶-1-基]-8-吖雙環[3. 2. 1]辛烷-8-羧酸乙酯； (3 -外）-3-[4-(6 -氟-2-側氧基-2, 3 -二版- D朵 _1-基） 哌啶-1-基]-8-吖雙環[3. 2.1]辛烷-8-羧酸乙酯； (3-内）-3-[4-(2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌啶 -卜基]-8-吖雙環[3. 2.1]辛烷-8-羧酸乙酯； 64 323406 201211028 (3-外）-3-[4-(2-侧氧基-2, 3-二氫-1H-吲哚-1-基）哌啶 -1-基]-8-吖雙環[3. 2.1]辛烷-8-羧酸乙酯； (3-内）-3-[4-(3, 6-二曱基-2-侧氧基-2, 3-二氫-1H-吲哚 -1-基）痕啶-1-基]-8-吖雙環[3. 2. 1]辛烷-8-羧酸乙酯； (3-内）-3-[4-(6-氟-3-曱基-2-側氧基-2, 3-二氫-1H-吲哚 _1-基）°底咬-1-基]-8-σ丫雙環[3. 2. 1]辛烧-8-缓酸乙g旨； (3-内）-3-[4-(5-氟-3-曱基-2-側氧基-2, 3-二氫-1H-吲哚 φ 基）哌啶-1-基]-8-吖雙環[3.2. 1]辛烷-8-羧酸乙酯； 4-{4-[5-氟-2-側氧基-3-(丙烷-2-亞基）-2,3-二氫-1-H- °引°朵-1-基]派咬-1—基卜辰咬_丨_竣酸乙酯； 4-{4-[5-氟-2-側氧基-3-(丙烧-2-基）-2,3-二氫-1-11-'1引 °木-1-基]旅啶-l-基}氮雜環庚烷_1_羧酸乙酯； 4 {4-[(3Z)-3-亞乙基-5-氟-2-側氧基-2, 3-二氫-1H-吲哚 -1-基]哌啶-l-基}氮雜環庚烷_丨_羧酸乙酯； 4-[4-(3-乙基-5-氟-2-側氧基—2,3_二氫_1H_吲哚基） # 哌啶-1-基]哌啶-1_羧酸乙酯； 4 {4 [(3Z)-5-氣-3-(2-甲基亞丙基）_2_側氧基_2,3_二氫4-[4-(6-decyloxy-2-oxo-2,3-dihydro-buyl]azepane-1-rebate to Ethylacetate; ^1 base (1R, 5S) -3-[4-(6-oxime-2-oneoxy^^yl) ketone-1-yl]-8-. 丫bicyclo[3. 2.1] octyl p-hydrogen 1H gargle 4_ Chest-methoxy + pendant oxy 2,3-dihydro, dioxin-1-yl]methyl}piperidine-1-carboxylic acid ethyl ester; 4-{[4-(6 -Methoxy-2o-oxy-2,,3',5,6,-tetrazospiro[deca--3,4'-pyrano]-indole (2Η)-yl)piperidine-1 -yl]piperidinyl-bromide; 4-{[4-(6-methoxy-2-oxo-2,3,5,6'-tetrahydrospiro[吲哚- 3,4 喃]]i(2H)-yl) ketone-1-yl]azepane __ι_ 酸酸ethyl; (1R,5S)-3-[4-(6-oxime Benzyl-2-oxo-2',3',5',6'-tetrahydrospiro[σ弓丨**,3,4'-Pan]-l-(2H)-yl)- -1--1-yl]-8-.丫Bicyclo[3.2. 1]octane-8-rebel acid; 4-[4-(5-chloro-6-fluoro-3,3-dimercapto-2-yloxy-2, 3-di Ethyl hydrogen hydrochloride-1Η-indol-1-ylpiperidin-1-yl]piperidine-1 -carboxylate; 4 [4-(3,6-indolyl-2-sideoxy-2, 3 -Dihydro-1 Η-σ 引 °-1-yl) 派定定-1-基]派咬-1-竣酸酯; 61 323406 201211028 4-[4-(3,6-二曱基- 2-sided oxy-2,3-diaza_1Η-α 引一-1_yl)pyridin-1-yl]piperidine-1-carboxylic acid methyl ester; 4-[4-(3, 6 -dimercapto-2-oxo-2,3-dihydro-1Η-indol-1-yl)piperidin-1-yl]azepane-1-carboxylic acid ethyl ester; 4-[ 4-(5-fluoro-3-indolyl-2-oxo-2,3-dihydro-1indole-indol-1-yl)piperidin-1-yl]azepane-1-carboxylate Acid ethyl ester; 4-{[4-(5-fluoro-3-indolyl-2-oxo-2, dihydro-1Η-α cited α-l-yl) piperidin-1-yl]methyl } piperidine-1-carboxylic acid ethyl ester; 4-{[4-(3-mercapto-2-oxo-2,3-dihydro-1Η-σ嗓嗓_1-yl) brigade bite-1 -yl] fluorenyl}piperidin-1-carboxylic acid ethyl ester; 4-[4-(5-mercapto-2-yloxy-2,3-diaza-1Η- °丨丨π朵-1_ Ethyl)-[beta]-yl]azetidin-1-carboxylic acid ethyl ester; 4-{[4-(5-mercapto-2-yloxy-2, Ethyl 3-dihydro-1Η-indol-1-ylpiperidin-1-yl]fluorenyl}piperidine-1-carboxylate; 4-{[4-(2-trioxy-2, 3 -dihydro-1Η-indol-1-yl)piperidin-1-yl]oxime yl}piperidin-1-carboxylic acid ethyl ester; 4-[4-(6-fluoro-3-indolyl-2 -ethyloxy-2,3-dihydro-1indole-indol-1-yl)piperidin-1-yl]piperidine-1-carboxylic acid ethyl ester; 4-[4-(6-fluoro-3- Ethyl methyl-2-oxo-2,3-dihydro-1Η-indol-1-yl)piperidin-1-yl]azepane-1-carboxylate; 4-[4- (5-fluoro-2-oxo-2,3-dihydro-111-17 cited 11-_1-yl) 唆-1-yl] piperidine-1-carboxylic acid methyl ester; 4-[4 -(6-Mercapto-2-yloxy-2,3-dihydro-1indole-indol-1-yl)piperidin-1-yl]piperidine-1-carboxylic acid decyl ester; 62 323406 201211028 4 -[4-(6-Bromo-2-oxo-2,3-dihydro-1H-indole-buyl)piperidin-1-yl]piperidine-1-carboxylic acid ethyl ester; 4-[ Ethyl 4-(6-bromo-2-oxo-2,3-diindole-1H-indolyl)piperidin-1-yl]azepane-1-carboxylate; 4- [4-(6-Bromo-2-oxo-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]piperidine-1-carboxylic acid oxime ester; 4-[ Ethyl 4-(6-ethyl-2-oxo-2,3-diaro-1H-indol-1-yl)piperidin-1-yl]piperidine-1-carboxylate; ® 4- [4-(6-B -2-Sideoxy-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]azepane _1_rebel acid · ;; 4-[4-( Ethyl 2-oxo-6-propyl-2,3-dihydro-1H-indol-1-yl)piperidine-diyl]piperidine-1-carboxylate; 4-{[4-( Ethyl 5-chloro-2-oxo-2,3-dihydro-1H-indol-1-ylpiperidin-1-yl]methyl}piperidine-1-carboxylate; (1R, 5S )-3-[4-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) φ-piperidin-1-yl]-8-indole bicyclo[3 2. 1] octane-8-carboxylic acid ethyl ester; 4-{[4-(5-fluoro-2-sided oxy-2,3-diaza_111-11 cited 11-pin_1_yl) . Bottom bite _1_yl] fluorenyl} piperidine-1-carboxylic acid ethyl ester; (1R, 5S)-3-[4-(5-gas-2-oxooxy-2,3-diaza-1Η- σ引ππ朵-1-yl)-piperidin-1-yl]-8-indole bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester; 4-[4-(6-methyl- 2-sided oxy-2, 3-dihydro-1 fluorenyl-inden-1-yl) piperidine _ι-yl] azepine _ _ 叛 叛 4- 4-; 4-{[4-( 6-mercapto-2-yloxy-2,3_dihydro_1Η-σ cited α-dot-1-yl)α bottom 唆_1_yl]methyl}0 辰. _1 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Ethyl]methyl}piperidine-1-carboxylic acid ethyl ester; 4-[4-(6-fluoro-2-oxo-2,3-diaza-1Η-σ5|π朵_l_S)n bottom bite -1_yl]azetidene-1-carboxylic acid ethyl ester; 4-[4-(5-fluoro-3,3-dimercapto-2-thioketo-2,3-dihydro-1H- Ethyl-1-indolylpiperidin-1-yl]piperidine-1-carboxylate; 4-[4-(6-decyloxy-2-oxo-2,3-dihydro-1H -吲哚-1-yl)piperidin-buki]-4-mercaptopiperidine-1-carboxylic acid ethyl ester; 4-[4-(6-fluoro-2-sided oxy-2, 3-di Ethyl-1H-indol-1-ylpiperidin-1-yl]-4-mercaptopiperidine-1-carboxylate; 4-[4-(6-fluorenyl-2-yloxy)- 2,3-Dihydro-1H-indol-1-yl)piperidin-1-yl]-4-indenyl 10 chen _1_ decanoic acid; 4-[4-(6-decyloxy) Ethyl -3-mercapto-2-oxo-2,3-diar-argon-1-indole-1-yl)piperidin-1-yl]-4-methylpiperidine-1-carboxylate; (3-in)-3-[4-(6-fluorenyl-2-oxo-2,3-dihydro-1Η-indol-1-yl) •piperidin-1-yl]-8-吖Bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester; (3-exo)-3-[4-(6-fluorenyl-2-yloxy-2,3-dihydro-1Η -吲哚-1-yl) piperidine -1-yl]-8-fluorene bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester; (3-inter)-3-[4-(6-fluoro-2-sidedoxy-2 , 3-diar-argon-1Η-indol-1-yl)piperidin-1-yl]-8-indole bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester; (3 -external)- 3-[4-(6-fluoro-2-indolyl-2,3-di-di-D-l-yl)piperidin-1-yl]-8-indole bicyclo[3. 2.1]octane- 8-carboxylic acid ethyl ester; (3-inter)-3-[4-(2-o-oxy-2,3-dihydro-1H-indol-1-yl)piperidinyl-yl]-8- Bis-cyclo[3.2.1]octane-8-carboxylic acid ethyl ester; 64 323406 201211028 (3-exo)-3-[4-(2-o-oxy-2,3-dihydro-1H-indole- 1-yl)piperidin-1-yl]-8-indole bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester; (3-in)-3-[4-(3,6-didecyl) -2-Sideoxy-2,3-dihydro-1H-indol-1-yl)trin-1-yl]-8-indolebicyclo[3.2.1]octane-8-carboxylic acid Ester; (3-inter)-3-[4-(6-fluoro-3-indolyl-2-oxo-2,3-dihydro-1H-indole-1-yl) ° bottom bite-1 -yl]-8-σ丫bicyclo[3.2.1]octane-8-supplemented acid g; (3-in)-3-[4-(5-fluoro-3-indolyl-2- Ethyloxy-2,3-dihydro-1H-indolyl)piperidin-1-yl]-8-indole bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester; 4-{4- [5-fluoro-2-oxo-3- (propane-2-arylene) )-2,3-dihydro-1-H- ° 引等-1-基]派咬-1—基卜辰咬_丨_竣酸酯; 4-{4-[5-fluoro-2 -Sideoxy-3-(propan-2-yl)-2,3-dihydro-1-11-'1 hexan-1-yl] bromo-l-yl}azepane_ 1-carboxylic acid ethyl ester; 4 {4-[(3Z)-3-ethylidene-5-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl]piperidine -l-yl}azetidinyl-indole-carboxylate; 4-[4-(3-ethyl-5-fluoro-2-oxo- 2,3-dihydro-1H_吲哚#) piperidin-1-yl]piperidine-1_carboxylic acid ethyl ester; 4 {4 [(3Z)-5-gas-3-(2-methylpropylidene)_2_sideoxy-2 , 3_ dihydrogen

广签厂取欠羧酸乙酯； 4 [4-(3-環戊基_5_氟_2_侧氧基_2, 3_二氫一^ 哌啶-1-基]哌啶_丨—羧酸乙酯； 4 {4-[(3Z)-5-氟-2-側氧基 + 亞丙基_2,3_二 基]辰°定-1-基}氮雜環庚燒_1_ _2，3-二氣-1H-口引 -1Η-π弓卜朵-1-基） 二氫-1Η-β引嗓 -羧酸乙酯； 323406 65 201211028 4-[4-(5-氟-2-側氧基_3_丙基_2,3_二氫_1H_吲哚—丨_基） 口底啶-1-基]哌啶-1-羧酸乙酯； 土 4-{4-[5-氟-2-側氧基_3_(四氫—2H_哌喃_4—基）_23—二氫 -1H-吲哚-1-基]哌啶一卜基}哌啶羧酸乙酯； 巫 4-{4-[(3Z)-5-氯-3-亞乙基-2-側氧基-2, 3~二氫-1Η_Π引哚 -1-基]β辰°定-1-基卜辰咬_1_幾酸乙酯； ’、The labeling plant takes the ethyl carboxylate; 4 [4-(3-cyclopentyl_5_fluoro_2_sideoxy-2,3_dihydro-[piperidin-1-yl]piperidine 丨—Carboxylic acid ethyl ester; 4 {4-[(3Z)-5-fluoro-2-sidedoxy + propylene-2,3_diyl] ° 定 -1- yl} aziridine _ 1_ _2,3-digas-1H-oral 引-1Η-π 弓 -1--1-yl) dihydro-1Η-β 嗓-carboxylate; 323406 65 201211028 4-[4-(5-fluoro -2-Sideoxy_3_propyl-2,3_dihydro_1H_吲哚-丨-yl) ethyl benzoyl-1-yl]piperidine-1-carboxylate; soil 4-{ 4-[5-fluoro-2-indolyl_3_(tetrahydro-2H-pyran-4-yl)_23-dihydro-1H-indol-1-yl]piperidine-diyl}piperidinecarboxylate Acid ethyl ester; Wu 4-{4-[(3Z)-5-chloro-3-ethylidene-2-oxo-2,3~dihydro-1Η_Π 哚-1-yl]β辰° -1- kibchen bite _1_ acid ethyl ester; ',

4-{4-[5-氟-3~(氧雜環丁烷_3_基）_2_側氧基_2,3_二氫 一1Η—吲哚-1_基]哌啶一1-基}哌啶-1-羧酸乙酯； 里 4一U-[5-氟-2-侧氧基-3-(四氫呋喃-3-基）_2, 3-二氫-1Η_ 吲哚-1-基]哌啶-l-基}哌啶_丨_羧酸乙酯； 4—ί4-[3-(氧雜環丁烷_3_基）_2_側氧基_2,3_二氫_11}_吲 °木·~1-基]η辰唆基丨哌啶_丨_羧酸乙酯； 4-{4-[3-(四氫吖唉-3_基）_5_氟_2_側氧基_2, 3_二氫_1H_ 弓卜木-1-基]哌啶-1_基}哌啶羧酸乙酯； 4~H-[5-氟-3-(氧雜環丁烷_3_基）_2—側氧基-2, 3-二氫 吲哚一 1-基]哌啶基丨哌啶一卜羧酸曱酯； 咎[4-(3-環丁基-5—氟_2_侧氧基_2, 3_二氫— 〖Η-吲哚-1-基） 哌啶-1-基]哌啶_1_羧酸乙酯； ^[4-(3-乙基-6-甲基-2-側氧基-2,3-二氫-1肜吲哚-1_基） 哌啶-1-基]哌啶-丨―羧酸甲酯； 扣{4-[6-(甲基-2-側氧基_3_(丙烷_2_基）-2, 3-二氮—1Η一 引哚-1-基]哌啶-1 一基}哌啶羧酸甲酯； 4~{4-[5-氟-2-側氧基-3-(丙烷-2-基）-2, 3-二氫-1Η-吲哚 1 一基]哌啶一 1-基}哌啶-1-羧酸甲酯； 323406 66 201211028 4-[4-(3-乙基-5-氟-2-侧氧基-2, 3-二氫-1H-吲哚-1-基） 旅咬-1-基]旅咬-1-羧酸乙醋； 4-{4-[2-侧氧基-3-(丙烷-2-基）-2, 3-二氫-1H-吲哚-1-基] 派咬-1-基}派咬-1-幾_酸乙酯； 4-[4-(3-環丁基-2-侧氧基-2, 3-二氫-1H-吲哚-1-基）哌啶 -1-基]哌啶-1-羧酸乙酯； 4-[4-(3-環戊基-2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌啶 基]α辰咬-1-叛酸乙酉旨； 4-[4-(2-側氧基-3-丙基-2, 3-二氫-1Η-吲哚-1-基）哌啶 卜基]派啶-1-羧酸乙酯； 4-{4-[2-側氧基-3-(四氫-2Η-哌喃-4-基）-2, 3-二氫-1Η- 吲哚-1 -基]α辰咬-l-基} η辰咬-1-叛酸乙酯； 4-{4-[2-側氧基-3-(戊烷-3-基）-2, 3-二氫-1Η-吲哚-1-基] 哌啶-l-基}哌啶-1-羧酸乙酯； 4-{4-[2-側氧基-3-(四氫呋喃-3-基甲基）-2, 3-二氫-1Η-• π引哚-1-基]哌啶-1-基}哌啶-1-羧酸乙酯； 4-{4-[3-(環丙基曱基）-2-側氧基-2, 3-二氫-1Η-吲哚-卜 基]哌啶-l-基}哌啶—1-羧酸乙酯； 4 [4 (3_乙基-2-側氧基-2，3-二氮-1Η_α引〇朵-1_基）旅咬 -1-基]哌啶-1-羧酸乙酯； 4- [ 4-(3-乙基-2-側氧基-2, 3-二氫-1Η-吲哚-1 -基）哌啶 基]氮雜環庚烷-1-羧酸乙酯； 4~{4-[3-(1，3-噚唑-2-基曱基）-2-侧氧基-2, 3-二氬-1Η- D弓卜朵-1-基]哌啶-1_基}哌啶_1_羧酸乙酯； 67 323406 201211028 4-{4-[2-侧氧基-3-(丙烧-2-基）-2,3-二氫-111-1 2 3 4 5 6 7 8弓卜朵-1-基] 氮雜環庚烷-l-基}哌啶-1-羧酸乙酯； 4-[4-(2-側氧基-3-丙基-2, 3-二氫-1H-吲哚-1-基）哌啶 -1-基]氮雜環庚烷-1-羧酸乙酯； 4-{4-[2-側氧基-3-(四氫0夫喃-3-基）-2, 3-二氫-1 Η-, π朵 -卜基]哌啶-1-基丨氮雜環庚烷-1-羧酸乙酯； 4~{4-[3-(庚烷-4-基）-2-侧氧基-2, 3-二氫-1H-吲哚-1-基] 呢·σ疋基}氣雜環庚烧_1_敌酸乙醋； 4~{4-[2-侧氧基-3-(四氫-211-哌喃-4-基）-2,3-二氫-111- °引°朵-1-基]哌啶-l-基}氮雜環庚烷-1_羧酸乙酯.； 扣{4-[2-側氧基-3-(戊烷-3-基）-2,3-二氫-1Η-吲哚-1-基] °辰啶-1-基}氮雜環庚烷_1_羧酸乙酯； 4-{4-[2-側氧基-3-(四氫呋喃-3-基）-2, 3-二氫-1Η-吲哚 —1-基]哌啶-l-基}哌啶-1—羧酸乙酯； 4、[4-(3-丁基-2-侧氧基-2, 3-二氫-1Η-吲哚-卜基）哌啶 基]哌啶-1-羧酸乙酯； 68 323406 1 、U-[3(呋喃-3-基甲基）-2-側氧基-2, 3-二氫-1Η-吲哚 2 基]哌啶-l-基}哌啶-1—羧酸乙酯； 3 羥基▼基）-6一曱氧基_3_甲基_2一侧氧基一2,3一二 4 哚-1-基]哌啶_ι_基丨哌啶_丨_羧酸乙酯； 5 4〜ί4-[3-(經基曱基）一3,6_二甲基一2_侧氧基_2,3_二氫 6 ΙΗ-叫卜朵-卜基]^1 底啶_ι_基丨哌咬_丨_羧酸乙醋； 7 氟-3-(羥基甲基）-3_τ基_2_侧氧基_2, 3-二氫 8 朵_丨_基]哌啶基丨氮雜環庚烷羧酸乙酯； 201211028 4-{4-[3-(經基甲基）-3-曱基-2-侧氧基一2, 3-二氫-iH-n引 °朵-1-基]°底咬-l-基}甲基旅《定-1-叛酸乙酯； 4-{4-[5-氟-3-(羥基曱基）-3-甲基-2-側氧基-2, 3-二氫 -1Η-吲哚-1-基]哌啶-l-基}曱基哌啶一卜羧酸乙酯； 4-{4-[6-氟-3-(羥基曱基）-3-甲基-2-側氧基_2, 3-二氫 -1H-吲哚-1-基]哌啶-i-基}哌啶_ι_羧酸乙酯； 4-{4-[6-氟-3-（羥基甲基）-3-甲基-2-侧氧基一2,3一二氫 吲哚-1-基]派咬-l-基}氮雜環庚烧-1-羰酸乙酯； 4-{4-[3-(羥基甲基）-3,6-二甲基-2-侧氧基-2,3-二氫 -1H-吲哚-1-基]哌啶-i-基}哌啶_丨_羧酸乙酯； 4-{4-[3-(羥基甲基）-3, 6一二甲基_2_側氧基_2, 3_二氫 -1H-吲哚-1-基]哌啶基卜氮雜環庚烷羧酸乙酯； 4-{4-[3-(羥基曱基）一3一曱基_2_侧氧基—2, 3一二氫_1H—吲 %-1-基]旅咬-1-基丨_α辰咬_1_叛酸乙酯； (3-内）-3-{4-[6-氟-3(羥基曱基）-3-甲基-2-側氧基-2,3- • 二氫-1Η-吲哚-卜基]哌啶-1-基}-8-吖雙環[3.2· 1]辛烷 -8-羧酸乙酯； (3-内）-3-{4-[3(羥基甲基）-3, 6-二甲基-2-侧氧基-2, 3- 二氫_1Η_吲哚-卜基]哌啶-1-基}-8-吖雙環[3.2. 1]辛烷 -8-羧酸乙酯； 4-{4-[3-乙基-3-(羥基甲基）一2-側氧基-2, 3-二氫-1Η-吲 °朵一卜基]娘啶-丨-基}哌啶-1-羧酸乙酯； 4~[4-(3-乙基-3, 6-二甲基-2-側氧基-2, 3-二氫-1Η-吲哚 ~1-基）η辰咬-1-基]哌啶_1_羧酸乙酯； 69 323406 201211028 4-[4-(6-氟-2-側氧基-2，3’，5’，6’ -四氫螺[巧。朵_3, 4, _ 哌喃]-1-(2H)-基）哌啶-1-基]甲基哌啶_丨—鲮酸乙酯； 4-[4-(6-曱基-2-侧氧基-2,，3,，5,，6,-四氫螺卜引哚 -3’ 4’ -哌喃]-1-(2H)-基）哌啶-1-基]甲基哌啶羧酸乙 酯； (3-内）-3-[4-(6-甲基-2-側氧基-2,，3,，5,，6,-四氫螺[吲 哚-3, 4’ -哌喃]-1-(2H)-基）哌啶-1-基]-8-吖雙環[3. 2 1 ] ^ 辛烧-8-缓酸乙g旨； (3-外）-3-[4-(6-氟-2-側氧基-2,，3,，5’，6,-四氳螺[吲哚 3,4 底喃]-1-(2H)-基）旅.唆-1-基]_8_σ丫雙環[3 2 1]辛 烷-8-羧酸乙酯； 4-[4-(3-羥基-2-側氧基-2, 3-二氫-1Η-吲哚-1-基）哌啶 -1-基]哌啶-1-羧酸乙酯； 4-[4-(2-側氧基-2,3-二氫-1Η-吲哚-1-基）哌啶_丨_基]哌 啶-1-羧酸丁酯-2-炔； • 4-[4-(2-側氧基_2, 3_二氫-1H-吲哚-1-基）哌啶-丨-基]哌 啶-1-羧酸2-溴乙酯； 4 [4 (2側氧基-2, 3-一虱_1Η-α弓丨嗓-1-基）α辰咬_ι_基]派 啶-1-羧酸2-氯乙酯； 4 [4-(2-側氧基-2, 3-二氫-1Η-吲哚-1-基）派咬基]派 啶-1-羧酸2-丙酯； 4-[4-(2-側氧基-2,3-二氫-1Η-吲哚-1-基）哌啶—丨_基]哌 啶-1-羧酸甲酯； 4 [4-(2-側氧基-2, 3-二氫-1Η-, η朵基）派咬—基]氮 323406 70 201211028 雜環庚烷-1-羧酸乙酯； 4-[4-(2-侧氧基-2, 3-二氫-1H-吲哚-1-基）哌啶-1-基]氮 雜環庚烷-1-羧酸曱酯； 4-[4-(2-侧氧基-2, 3-二氫π朵-1-基）α底咬-1-基]It 雜環庚烷-1-羧酸丙酯-2-炔； 4-[4-(2-侧氧基-2，3-二氮α朵-1-基定_1_基]氮 雜環庚烷-1-羧酸丁酯-2-炔； 4-[4-(6-氯-2-側氧基-2, 3-二氫-1Η-吲哚-1-基）哌啶-1-基]哌啶-1-羧酸-2氟乙酯； 4-[4-(5 -氯-2-側氧基-2，3-二氳-1Η-α引 σ朵一1_基）σ辰咬_1_ 基]哌啶-1-羧酸2-丙酯； 4_[4-(5_氯-2-側氧基-2，3 -二氮α朵-1_基）α底咬_1-基]哌啶-1-羧酸丙-2-烯酯； 4-[4-(5-氯-2-侧氧基-2，3-二氫-111-'〇引'〇朵-1_基）旅咬-1_ 基]哌啶-1-羧酸2-曱氧乙酯； 4- [ 4_(6-曱基_2_側氧基-2，3-二氣-1Η- °引π朵-1_基）π辰咬 -1-基]哌啶-1-羧酸丙-2-烯酯； 4_[4-（6_曱基-2-側氧基-2，3_二氮_1 Η_α引π朵_ 1 -基）〇底咬 -卜基]哌啶-1-羧酸2-氟乙基酯； 4-[4-(5-敦-2-侧氧基-2，3-二氩-111-'0弓丨11朵-1-基）。底唆_1_ 基]哌啶-1-羧酸2-曱氧基乙基酯； 4-[4-(5-氯-2-侧氧基-2, 3-二氫-1Η-吲哚-卜基）哌啶-1-基]氮雜環庚烷-1-羧酸曱酯； 4-[4-(3, 3-二氟-2-側氧基-2, 3-二氫-111-0引σ朵-1-基）旅°定 71 323406 201211028 -1-基]α辰唆-1-竣酸乙酯； (1R’ 5S)-3-[4-(3, 3-二氟-2-侧氧基-2, 3~ 二氫-1Η- η弓| *»朵 -1-基）哌啶-1-基]-8-吖雙環[3. 2· 1]辛烷-8~羧酸乙酯； 4-[4-(3, 3-—氣-2-侧氧基-2, 3-二氫-1Η-°引π朵_ι_基）派咬 -1-基]氮雜環庚烷-1-羧酸甲酯； (1R，5S)-3-{4-[3-(羥基甲基）-6-甲氧基-3-曱基-2-侧氧 基3-一乳_111-11引β朵-1-基]派咬-1-基丨-8〜α丫雙環[3 2 1 ] 辛烧-8-竣酸乙醋； 4-U-[3-(羥基曱基）-6-曱氧基-3-曱基-2~側氧基_2,3_二 氫-1Η-吲哚-1-基]哌啶-丨_基丨氮雜環庚烷―丨―羧酸乙酯； 4-{4-[5-氟-3-(羥基曱基）-3_曱基-2-側氧基_2, 3_二氫 -1Η-吲哚-1-基]哌啶_ι_基}哌啶_丨_羧酸乙酯； 444-(6-氟-2-側氧基-2,，3,，5,，6,-四氫螺[吲哚_3, 4, 一 哌喃]-1-(2Η)-基）哌啶-1-基]氮雜環庚烷—丨―羧酸乙酯； 4 [4-(6-氟-2-側氧基-2’，3’，5’，6,-四氫螺[α引 Β朵 _3, 4, - 哌喃：Η-(2Η)-基）哌啶-1-基]哌啶-丨-羧酸乙酯； 扣[4-(3,6-二曱基-2-側氧基一2,3-二氫-1Η-吲哚-1 一基）哌 咬基]氮雜環庚烧-1-叛酸乙酯； 4~[4-(6-氟-3-曱基-2-侧氧基-2, 3-二氫-1Η-吲哚-1-基） 派啶-l-基]哌啶_1_羧酸乙酯； 4〜[4-(6-氟-3-曱基-2-側氧基-2, 3-二氫-1Η-吲哚-1-基） 底咳· 1基]氮雜環庚烧_1_叛酸乙.酉旨； 4 [4-(2-侧氧基-2, 3-二氫-lH-n引η朵-i-基）α底咬_ι—基] 〜甲基氮雜環庚烷—丨一羧酸乙酯； 72 323406 201211028 4-[4-(2-側氧基—2, 3-二氫-1H-吲哚-1-基）哌啶-卜基] -4-曱基哌啶-1-羧酸乙酯； 4 [4 (5 氟-2-側氧基-2,3-二氫-1Η-α3|π朵-1-基）派咬一1一 基]-4-甲基哌啶-丨_羧酸乙酯； 4 [4 (5甲基-2-侧氧基_2,3-二氫-1Η-π引°朵-1-基）〇底π定 -1-基]-4-甲基哌啶-1-羧酸乙酯； 4 [4 (5甲氧基-2-側氧基_2,3_二氫-111-〇弓卜朵-1-基）π辰淀 ^ _1_基]甲基哌啶-1-羧酸乙酯； (1R’ 5S)-3-{4-[5-曱基-2-側氧基-2, 3-二氫-1Η-吲哚-1- 基]°辰°定-1-基}-8-吖雙環[3. 2. 1]辛烷-8-羧酸乙酯； (1R，5S)-3-{4-[5-甲氧基-2-侧氧基-2, 3-二氫-1H-吲哚 -1-基>辰咬-1-基卜8_吖雙環[3. 2.丨]辛烷_8_羧酸乙酯； 4-[4-(3-經基-3-曱基—2-侧氧基-2, 3-二氫-1H-吲哚-1-基） 〇底咬一基]一4-曱基哌啶-1-羧酸乙酯； 4 一 [4 一（3一經基一 3-曱基-2-侧氧基-2,3-二氫-1H-吲哚-1-基） # 派咬-1~基]—4一曱基哌啶-1-羧酸甲酯； 4-[4-(3-氟-3-羥基甲基_2一侧氧基一2, 3_二氫一 1H_吲哚一卜 基）派°定-1_基]-4-甲基哌啶-1-羧酸乙酯；及 4-[4-(3-氟-3-羥基曱基一2-側氧基_2, 3-二氫-1H-吲哚-1- 基）°辰咬-1-基]_4-甲基哌啶_ι_羧酸曱酯； 等。 接下來’於以下對本發明的化合物之製造法進行說 明。通式（1)所示之本發明的化合物係可藉由以下方法製 造。 73 323406 201211028 製法1 :製造前述式⑴的方法，其係使下述式⑸4-{4-[5-fluoro-3~(oxetan-3-yl)_2_sideoxy-2,3_dihydro-1Η-吲哚-1_yl]piperidine 1- Ethyl piperidine-1-carboxylic acid ethyl ester; ali 4-U-[5-fluoro-2-oxo-3-(tetrahydrofuran-3-yl)_2,3-dihydro-1Η_ 吲哚-1- Ethyl]piperidinyl-l-yl}piperidine-hydrazine-carboxylate; 4-—(4-(4-oxo-oxetane-3-yl)-2-oxetyl-2,3-dihydro- 11}_吲°木·~1-基]η辰唆基丨piperidine_丨_carboxylate; 4-{4-[3-(tetrahydroindol-3-yl)_5_fluoro_2 _Sideoxy_2, 3_Dihydro_1H_ 弓木-1-yl]piperidin-1_yl}piperidinecarboxylic acid ethyl ester; 4~H-[5-fluoro-3-(oxo-heterocyclic ring) Butane_3_yl)_2-oxo-2,3-dihydroindole-1-yl]piperidinylpiperidinyl-p-carboxylate; 咎[4-(3-cyclobutyl- 5-fluoro-2-oxoxy-2,3_dihydro-[Η-indol-1-yl)piperidin-1-yl]piperidine-1-carboxylic acid ethyl ester; ^[4-(3 -ethyl-6-methyl-2-oxo-2,3-dihydro-1肜吲哚-1-yl)piperidin-1-yl]piperidine-oxime-carboxylic acid methyl ester; 4-[6-(methyl-2-yloxy_3_(propan-2-yl)-2,3-diaza-1Η-indol-1-yl]piperidine-1-yl}piperidinecarboxylate Methyl ester; 4~{4-[5-fluoro-2-oxo-3-(propan-2-yl)-2, 3- Hydrogen-1Η-吲哚1-yl]piperidine-1-yl}piperidine-1-carboxylic acid methyl ester; 323406 66 201211028 4-[4-(3-ethyl-5-fluoro-2-sidedoxy -2,3-dihydro-1H-indol-1-yl) brigade-1-yl] travel bite-1-carboxylic acid ethyl acetate; 4-{4-[2-o-oxy-3-(propane -2-yl)-2,3-dihydro-1H-indol-1-yl] ketone-1-yl} ketone-1-diethyl ester; 4-[4-(3-cyclobutene) Ethyl 2-oxo-2,3-dihydro-1H-indol-1-ylpiperidin-1-yl]piperidine-1-carboxylate; 4-[4-(3-ring pentyl-2-yloxy-2,3-dihydro-1H-indol-1-yl)piperidinyl]α-bite-1-reoacetate; 4-[4-(2-side oxygen Ethyl-3-propyl-2,3-dihydro-1Η-indol-1-yl)piperidinyl]pyridin-1-carboxylic acid ethyl ester; 4-{4-[2-sideoxy- 3-(tetrahydro-2Η-piperazin-4-yl)-2,3-dihydro-1Η-吲哚-1 -yl]α辰咬-l-yl} 4-{4-[2-Sideoxy-3-(pentan-3-yl)-2,3-dihydro-1Η-indol-1-yl]piperidine-1-yl}piperidine- 1-carboxylic acid ethyl ester; 4-{4-[2-oxo-3-(tetrahydrofuran-3-ylmethyl)-2,3-dihydro-1Η-• π-indol-1-yl]piperidin Ethyl pyridine-1-yl}piperidine-1-carboxylate; 4-{4-[3-(cyclopropylindolyl)-2-yloxy-2,3-dihydro-1?-indole -buki]piperidin-l-yl}piperidine-1-carboxylate; 4 [4 (3-ethyl-2-oxo-2,3-diaza-1Η_α引〇朵-1_) Ethyl bromide-1-yl]piperidin-1-carboxylic acid ethyl ester; 4-[4-(3-ethyl-2-yloxy-2,3-dihydro-1Η-吲哚-1 - Ethyl piperidinyl]azepane-1-carboxylic acid ethyl ester; 4~{4-[3-(1,3-oxazol-2-ylindenyl)-2-yloxy-2, Ethyl 3-dihydro-1Η-D-bend-1-yl]piperidine-1_yl}piperidine-1-carboxylate; 67 323406 201211028 4-{4-[2-Sideoxy-3- (propen-2-yl)-2,3-dihydro-111-1 2 3 4 5 6 7 8-bend-1-yl]azepane-l-yl}piperidine-1-carboxylate Ethyl acetate; 4-[4-(2-o-oxy-3-propyl-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]azepane- 1-carboxylic acid ethyl ester; 4-{4-[2-o-oxy-3-(tetrahydro-O-furan-3-yl)-2,3-dihydro-1 fluorene-, π-d-bu] Ethyl piperidin-1-ylindole heptane-1-carboxylate; 4~{4-[3-(heptan-4-yl)-2-yloxy-2,3-dihydro- 1H-吲哚-1-yl] σ σ } } 气 气 } } 气 _ _ _ _ _ _ 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4-yl)-2,3-dihydro-111- ° 引-1-yl]piperidine-1-yl}azepane-1_carboxylic acid .;{4-[2-Sideoxy-3-(pentan-3-yl)-2,3-dihydro-1Η-indol-1-yl] ° 啶 -1--1-yl} aza Ethyl cycloheptane_1-carboxylate; 4-{4-[2-o-oxy-3-(tetrahydrofuran-3-yl)-2,3-dihydro-1Η-吲哚-1-yl]piperidin Ethyl pyridine-l-yl}piperidine-1-carboxylate; 4. [4-(3-butyl-2-oxo-2,3-dihydro-1Η-indole-bu)piperidine Ethyl piperidine-1-carboxylate; 68 323406 1 , U-[3(furan-3-ylmethyl)-2-oxo-2,3-dihydro-1Η-吲哚2 base] Ethyl piperidine-l-yl}piperidine-1-carboxylate; 3 hydroxyheptyl)-6-methoxy-_3_methyl-2-oneoxy-2,3-12 哚-1- Ethyl] piperidine_ι_yl piperidine_丨_carboxylate; 5 4~ί4-[3-(via fluorenyl)-3,6-dimethyl- 2_sideoxy-2, 3_Dihydro 6 ΙΗ-called 卜朵-卜基]^1 啶 __ι_基丨 Piper _丨_carboxylic acid vinegar; 7 fluoro-3-(hydroxymethyl)-3_τ base_2_ side Ethoxy 2,3-dihydro 8 丨 丨 基 ] 哌 哌 哌 ; ; ; 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 -2-Sideoxy-2,3-dihydro-iH-n 引等-1-yl]° bottom bite-l-yl}methyl brigade "definite-1-deoxyethyl ester; 4-{4 -[5-fluoro-3-(hydroxyindenyl) Ethyl 3-methyl-2-oxo-2,3-dihydro-1Η-indol-1-yl]piperidine-1-yl}hydrazinopiperidine-carboxylate; 4-{ 4-[6-fluoro-3-(hydroxyindenyl)-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl]piperidine-i-yl}piperidin Alkyl carboxylic acid; 4-{4-[6-fluoro-3-(hydroxymethyl)-3-methyl-2-oxo- 2,3-dihydroindole-1-yl ]]-[1-(3-(hydroxymethyl)-3,6-dimethyl-2-oxo-2) ,3-dihydro-1H-indol-1-yl]piperidine-i-yl}piperidine-hydrazine-carboxylate; 4-{4-[3-(hydroxymethyl)-3, 6- Ethyl 2-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl]piperidinyl azepanecarboxylate; 4-{4-[3-(hydroxyl)曱基)一三一曱基_2_sideoxy-2,3-dihydro-1H-吲%-1-yl] travel bite-1-ylindole_α辰咬_1_ oleic acid ethyl ester; (3-in)-3-{4-[6-fluoro-3(hydroxyindenyl)-3-methyl-2-oxo-2,3- • dihydro-1Η-吲哚-buji] Piperidin-1-yl}-8-indole bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester; (3-in)-3-{4-[3(hydroxymethyl)-3, 6- Dimethyl-2-oxo-2,3-dihydro_1Η_吲哚-buyl]piperidin-1-yl}-8-indole bicyclo [3.2. 1] ethyl octane-8-carboxylate; 4-{4-[3-ethyl-3-(hydroxymethyl)- 2-oxo-2,3-dihydro-1Η-吲° Ethyl bromide-1-carboxylate; 4~[4-(3-ethyl-3, 6-dimethyl-2-oxo-2, 3-di Hydrogen-1Η-吲哚~1-yl)n-n-yl-1-yl]piperidine-1-carboxylic acid ethyl ester; 69 323406 201211028 4-[4-(6-fluoro-2-sided oxy-2, 3',5',6'-tetrahydro snail [could. _3, 4, _piperid]-1-(2H)-yl)piperidin-1-yl]methylpiperidine oxime-capric acid ethyl ester; 4-[4-(6-mercapto-2 -Sideoxy-2,,3,,5,6,-tetrahydrospiro-indole-3' 4'-pyrano]-1-(2H)-yl)piperidin-1-yl]methyl Ethyl piperidinecarboxylate; (3-inter)-3-[4-(6-methyl-2-oxo-2,3,5,6,4-tetrahydrospiro[吲哚-3 , 4'-pyrano]-1-(2H)-yl)piperidin-1-yl]-8-indole bicyclo[3. 2 1 ] ^ 辛烧-8-慢酸乙格; (3-外)-3-[4-(6-fluoro-2-indolyl-2,,3,,5',6,-tetraspiro[吲哚3,4 carboxy]-1-(2H)-yl旅.唆-1-yl]_8_σ丫bicyclo[3 2 1]octane-8-carboxylic acid ethyl ester; 4-[4-(3-hydroxy-2-yloxy-2,3-dihydro- Ethyl 1 Η-吲哚-1-yl)piperidin-1-yl]piperidine-1-carboxylate; 4-[4-(2-trioxy-2,3-dihydro-1Η-吲哚- 1-yl) piperidine-yl-yl]piperidine-1-carboxylic acid butyl ester-2-yne; • 4-[4-(2-trioxy-2,3-dihydro-1H-indole- 1-bromopiperidinyl-p-yl]piperidine-1-carboxylic acid 2-bromoethyl ester; 4 [4 (2 oxo-2, 3- 虱_1Η-α-bend-1-yl) )α辰咬_ι_基]Pyridin-1-carboxylic acid 2-chloroethyl ester; 4 [4-(2-Sideoxy-2,3-dihydro-1Η-吲哚-1-yl) Biting base] 1-propyl 2-carboxylate; 4-[4-(2-o-oxy-2,3-dihydro-1Η-indol-1-yl)piperidine-indolyl]piperidine-1-carboxylate Methyl ester; 4 [4-(2-Sideoxy-2,3-dihydro-1Η-, η-moleyl) ketone-yl]nitrogen 323406 70 201211028 Ethyl heterocycloheptane-1-carboxylate; 4-[4-(2-Sideoxy-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]azepane-1-carboxylic acid decyl ester; 4- [4-(2-Sideoxy-2,3-dihydroπ-l-yl)α-bottom-1-yl]It heterocycloheptane-1-carboxylic acid propyl ester-2-yne; 4- [4-(2-Sideoxy-2,3-diaza α-l-butyl-1-yl]azetidin-1-carboxylic acid butyl ester-2-yne; 4-[4- (6-Chloro-2-oxo-2,3-dihydro-1Η-indol-1-yl)piperidin-1-yl]piperidine-1-carboxylic acid-2-fluoroethyl ester; 4-[ 4-(5-chloro-2-oxo-2,3-dioxan-1Η-α-inducing σ-a 1-yl) σchen _1_ yl] piperidine-1-carboxylic acid 2-propyl ester; 4-(4-(5-chloro-2-oxo-2,3-diaza-alpha-1-yl)α-bottom-1-yl]piperidine-1-carboxylic acid prop-2-enyl ester; 4-[4-(5-Chloro-2-oxo-2,3-dihydro-111-' 〇 〇 '〇朵-1_基)Brigade bite-1_ ki]piperidine-1-carboxylic acid 2 - oxime ethyl ester; 4- [ 4_(6-fluorenyl_2_sideoxy-2,3-digas-1Η- °引π朵-1_ base) πchen bite -1-yl]piperidine-1-carboxylic acid prop-2-enyl ester; 4_[4-(6-mercapto-2-epoxy-2,3_diaza_1Η_α引π朵_ 1 - Base 〇 咬 卜 卜 卜 ] ] ] 哌 哌 哌 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- Bow 丨 11 -1- base). Bottom 唆_1_yl] piperidine-1-carboxylic acid 2-methoxyethyl ester; 4-[4-(5-chloro-2-oxo-2,3-dihydro-1Η-吲哚- Ethyl p-piperidin-1-yl]azepane-1-carboxylate; 4-[4-(3,3-difluoro-2-oxo-2,3-dihydro-111 -0引σ朵-1-基)Brigade ° 71 323406 201211028 -1-based]α辰唆-1-decanoic acid ethyl ester; (1R' 5S)-3-[4-(3, 3-difluoro -2-Sideoxy-2,3~ Dihydro-1Η- η bow | *»多-1-yl)piperidin-1-yl]-8-indole bicyclo[3. 2·1]octane-8 ~Carboxylic acid ethyl ester; 4-[4-(3, 3-Gas-2-oxo-2,3-dihydro-1Η-°引π朵_ι_基) Piebit-1-yl] Methyl azacycloheptane-1-carboxylate; (1R,5S)-3-{4-[3-(hydroxymethyl)-6-methoxy-3-indolyl-2-oxooxy 3 -一乳_111-11引β朵-1-基]派咬-1-基丨-8~α丫双环[3 2 1 ]辛烧-8-竣酸乙醋; 4-U-[3- (hydroxyindenyl)-6-methoxy-3-indolyl-2-butoxy 2,3-dihydro-1Η-indol-1-yl]piperidine-indole-ylindole Alkenyl-indole-carboxylate; 4-{4-[5-fluoro-3-(hydroxyindenyl)-3-mercapto-2-yloxy-2,3-dihydro-1Η-吲哚- 1-yl]piperidinyl-yl-yl}piperidinyl-indole-carboxylate; 444-(6-fluoro-2-oxo-2,3, 5,6,-tetrahydrospiro[吲哚_3,4,monomethane]-1-(2Η)-yl)piperidin-1-yl]azepan-indole-carboxylate; 4 [4-(6-fluoro-2-indolyl-2',3',5',6,-tetrahydrospiro[α引Β_3, 4, -pyran: Η-(2Η)- Ethyl)piperidin-1-yl]piperidine-indole-carboxylate; [4-(3,6-dimercapto-2-oxo- 2,3-dihydro-1Η-吲哚- 1-yl) piperidine] azepan-pyrene-1-ethylate; 4~[4-(6-fluoro-3-indolyl-2-yloxy-2,3-dihydro-1Η -吲哚-1-yl)p-pyridyl-l-yl]piperidine-1-carboxylic acid ethyl ester; 4~[4-(6-fluoro-3-indolyl-2-yloxy-2, 3- Dihydro-1 Η-吲哚-1-yl) 咳 · · 1 yl] azepine _1 叛 叛 乙 ; 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 -lH-n ηη-i-yl)α bottom bite_ι-基]~methylazepane-indole monocarboxylate; 72 323406 201211028 4-[4-(2-sideoxy —2,3-dihydro-1H-indol-1-yl)piperidinyl-diyl]-4-mercaptopiperidine-1-carboxylic acid ethyl ester; 4 [4 (5 fluoro-2-oxooxy) -2,3-dihydro-1 Η-α3|π朵-1-yl) ketone-1-yl]-4-methylpiperidine-indole-carboxylate; 4 [4 (5 methyl-2) - sideoxy 2,3-dihydro-1 Η-π 引 °-1-yl) Ethyl π-1-yl]-4-methylpiperidine-1-carboxylate; 4 [4 (5-methoxy-2-oxo-2,3-dihydro-111-indole) -1--1-yl) π辰盐^ _1_yl]ethyl piperidine-1-carboxylate; (1R' 5S)-3-{4-[5-mercapto-2-yloxy-2 , 3-dihydro-1Η-吲哚-1-yl] ° ° 定-1-yl}-8-fluorene bicyclo [3. 2. 1] octane-8-carboxylic acid ethyl ester; (1R, 5S )-3-{4-[5-methoxy-2-indolyl-2,3-dihydro-1H-indol-1-yl]> Chen ken-1-kib 8_吖bicyclo[3 2. 丨]octane _8_carboxylic acid ethyl ester; 4-[4-(3-carbyl-3-indolyl-2-etheroxy-2,3-dihydro-1H-indole-1 - base) 〇 咬 基 ] ] 一 一 一 一 一 一 一 一 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 Hydrogen-1H-indol-1-yl) #派咬-1~基]-4 methyl hydrazinyl-1-carboxylate; 4-[4-(3-fluoro-3-hydroxymethyl) 2-side oxy- 2,3-dihydro- 1H-indole-based)-ethyl--4-methylpiperidine-1-carboxylic acid ethyl ester; and 4-[4- (3-Fluoro-3-hydroxyindolyl- 2-oxooxy-2,3-dihydro-1H-indol-1-yl) °chen-1-yl]_4-methylpiperidine_ι_ An carboxylic acid oxime ester; Next, the production method of the compound of the present invention will be described below. The compound of the present invention represented by the formula (1) can be produced by the following method. 73 323406 201211028 Method 1: The method of the above formula (1) is produced by the following formula (5)

之化合物或其鹽與下述式（6)a compound or a salt thereof and the following formula (6)

或下述式（7)Or the following formula (7)

所示之化合物進行反應而成者。 式（5)之化合物或其鹽與样得的式（6)之化合物或式 ⑺之化合物的反應係可使㈣氫化納、氰㈣氫化鈉、三 乙醯氧基硼酸鈉、吡啶硼烷、2-甲基比唆棚炫專被廣為使 用的還原性胺化試劑進行。 式（5)之化合物或其鹽與式（6)之化合物或式（？）之化 φ 合物的反應係可於適當的溶媒中進行。使用之溶媒可列舉 如：二氯曱烧、四氫吱喃、二曱氧基乙烧、二乙基醚、二 甲基甲醯胺、曱醇、乙醇、乙酸乙酯等，此等之反應係可 單獨或將2種以上混合後使用。本反應係因應所需而於酸 或鹼存在下進行，可舉例如：以乙酸作為酸；以三乙胺、 二異丙基乙胺等作為鹼。且可因應所需而併用四異丙基氧 化鈦等縮合劑。此外，反應溫度通常為-78Ϊ至1〇〇。(：。 刖述式（5)之化合物或其鹽係可依照下述方案 ⑽酸）1進行合成⑻及R4為-起形成=0之式（1-4)的化 323406 74 201211028 合物）。 方案1 :The compound shown is reacted. The reaction of the compound of the formula (5) or a salt thereof with the compound of the formula (6) or the compound of the formula (7) may be (4) sodium hydride, sodium cyano(tetra) hydride, sodium triethoxy borohydride, pyridine borane, 2-Methyl is more widely used as a reductive aminating reagent. The reaction of the compound of the formula (5) or a salt thereof with the compound of the formula (6) or the compound of the formula (?) can be carried out in a suitable solvent. The solvent to be used may, for example, be dichloropyrene, tetrahydrofuran, dimethoxyethane, diethyl ether, dimethylformamide, decyl alcohol, ethanol, ethyl acetate, etc., and the like. These may be used alone or in combination of two or more. The reaction is carried out in the presence of an acid or a base as required, and examples thereof include acetic acid as an acid and triethylamine, diisopropylethylamine and the like as a base. Further, a condensing agent such as tetraisopropyl titanium oxide may be used in combination as needed. Further, the reaction temperature is usually -78 Torr to 1 Torr. (: The compound of the formula (5) or a salt thereof can be synthesized according to the following scheme (10) acid) 1 (8) and R4 is a compound of the formula (1-4): 323406 74 201211028) . plan 1 :

(式中，Prot表示胺基的保護基，其他代號之意義與前述 相同。） 胺基的保護基之具體例可列舉例如：第三丁氧羰基、 苯曱氧基羰基等胺基與胺曱酸酯類形成的基，或是苯曱基 或三苯曱基等胺基與苯甲胺類形成的基。 步驟1 : 式（1-2)的化合物係可依照慣常方法將式（1-1)化合物 之胺基的保護基進行脫保護而製造。 步驟2 : 式（1-3)的化合物係可將式（1-1)化合物與對應R1及R2 之胺基的鹵化劑或烷化劑等於鹼存在下，在惰性溶媒中進 行反應而製造。以驗而言，可列舉例如：氫化納、氫化鉀、 碳酸鈉、碳酸鉀、碳酸鉋、三乙胺、二異丙基乙胺、曱氧 化鈉、乙氧化鈉、第三丁氧化鉀、六曱基二矽胺化鋰、六 曱基二矽胺化鉀等。惰性溶媒可列舉例如：四氩呋喃、二 噚烷、苯、曱苯、二曱苯、二曱基甲醯胺、二曱亞颯、氯 75 323406 201211028 仿、二氯甲烷、二氣乙烷等，可單獨或將2種以上混合後 使用。進行時反應溫度通常為-78°C至140°C，較佳為-78 °C 至 100°C。 步驟3 : 本步驟係以與本方案之工程1相同的方法進行。 前述式（1-1)的化合物或其鹽係可依照下述方案2、3、 4或5而進行合成。 方案2 : farN〇2 —► raYN〇2 —► 人步驟1 步驟2(In the formula, Prot represents a protecting group of an amine group, and the other symbols have the same meanings as described above.) Specific examples of the protecting group of the amine group include, for example, an amine group such as a third butoxycarbonyl group or a benzoquinoneoxycarbonyl group; The group formed by the acid ester is a group formed by an amine group such as a benzoinyl group or a triphenylfluorenyl group and a benzylamine. Step 1: The compound of the formula (1-2) can be produced by subjecting a protective group of an amine group of the compound of the formula (1-1) to deprotection according to a usual method. Step 2: A compound of the formula (1-3) can be produced by reacting a compound of the formula (1-1) with a halogenating agent or an alkylating agent corresponding to an amine group of R1 and R2 in the presence of a base in an inert solvent. For the purposes of the test, for example, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, carbonic acid planing, triethylamine, diisopropylethylamine, sodium ruthenium oxide, sodium ethoxide, potassium third potassium hydride, and the like Lithium decyl diamide, lithium hexamethyldiamide, and the like. Examples of the inert solvent include tetrahydrofuran, dioxane, benzene, toluene, dinonylbenzene, dimercaptomethylamine, diterpenoid, chlorine 75 323406 201211028 imitation, dichloromethane, di-hexane, and the like. They may be used alone or in combination of two or more. The reaction temperature during the reaction is usually -78 ° C to 140 ° C, preferably -78 ° C to 100 ° C. Step 3: This step is carried out in the same manner as the work 1 of the present scheme. The compound of the above formula (1-1) or a salt thereof can be synthesized according to the following scheme 2, 3, 4 or 5. Option 2: farN〇2 —► raYN〇2 —► person step 1 step 2

丫叫 Jk^C02R， (2-1) P-2} (2-3)Howling Jk^C02R, (2-1) P-2} (2-3)

〇=aCN -Prot r\ (2^4) ^ 步驟3〇=aCN -Prot r\ (2^4) ^ Step 3

<1-1) (式中，R’表示Ci-6烷基，其他代號之意義與前述相同。） 步驟1 : 式（2-2)的化合物係可藉由使可取得的式（2-1)的化合 物於氩氧化鈉或碳酸鉋等鹼存在下與烷基鹵化物進行反應 而製造。以使用的溶媒而言，可列舉例如：二甲基曱醯胺、 四氫呋喃、二氯甲烷等，可單獨或將2種以上混合後使用。 反應通常為-40°C至40°C，較佳為-10°C至10°C。 步驟2 : 式（2-3)的化合物係可將式（2-2)化合物於氫環境下使 用鈀等金屬觸媒進行接觸還原而製造。所使用之溶媒可列 舉例如：四氫呋喃、乙醇、曱醇、乙酸、乙酸乙酯、二氯 甲烷等，可單獨或將2種以上混合後使用。 步驟3 : 76 323406 201211028<1-1) (wherein R' represents a Ci-6 alkyl group, and the other symbols have the same meanings as described above.) Step 1: The compound of the formula (2-2) can be obtained by making the formula (2) The compound of -1) is produced by reacting an alkyl halide with a base such as sodium argon or carbonate. The solvent to be used may, for example, be dimethyl decylamine, tetrahydrofuran or dichloromethane, and may be used singly or in combination of two or more. The reaction is usually -40 ° C to 40 ° C, preferably -10 ° C to 10 ° C. Step 2: The compound of the formula (2-3) can be produced by subjecting the compound of the formula (2-2) to contact reduction with a metal catalyst such as palladium under a hydrogen atmosphere. The solvent to be used may, for example, be tetrahydrofuran, ethanol, decyl alcohol, acetic acid, ethyl acetate or methylene chloride, and may be used singly or in combination of two or more. Step 3: 76 323406 201211028

式（1-1)的化合物係可藉由使式（2-3)的化合物與可取 得的式（2-4)的化合物進行反應而製造。該反應係可依據上 述之還原性胺化的條件進行。以試劑而言，可列舉例如： 硼風化鈉、氰基硼氫化鈉、三乙醯氧基棚酸納、D比咬硼烧、 2-甲基吼啶硼烷等被廣為使用的試劑。以使用的溶媒而 言，可列舉例如：曱苯、二氯曱烷、四氫呋喃、二甲氧基 乙烧、二乙基趟、二曱基甲醯胺、曱醇、乙醇、乙酸乙酯 等’可單獨或將2種以上混合後使用。本反應係因應所需 而於酸或鹼存在下進行，以酸而言，例如：醋酸；以鹼而 言’可舉例如：三乙胺、二異丙基乙胺等。且可因應所需 而併用四異丙氧化鈦等縮合劑。此外，反應溫度通常為-20 。(：至 100°C，較佳為（TC 至 8(TC。 方案3 :The compound of the formula (1-1) can be produced by reacting a compound of the formula (2-3) with a compound of the formula (2-4) which can be obtained. This reaction can be carried out in accordance with the conditions of the reductive amination described above. Examples of the reagent include widely used reagents such as boron weathering sodium, sodium cyanoborohydride, sodium triacetoxy sulphate, D boring, and 2-methyl acridine borane. Examples of the solvent to be used include guanidine, dichloromethane, tetrahydrofuran, dimethoxyethane, diethyl hydrazine, dimercaptomethylamine, decyl alcohol, ethanol, ethyl acetate, and the like. These may be used alone or in combination of two or more. The reaction is carried out in the presence of an acid or a base as required. The acid is, for example, acetic acid; and the base is, for example, triethylamine or diisopropylethylamine. Further, a condensing agent such as titanium tetraisopropoxide may be used in combination as needed. Further, the reaction temperature is usually -20. (: to 100 ° C, preferably (TC to 8 (TC. Scheme 3:

ProtProt

0 (1-1) (式中’ X1表示鹵原子，其他代號之意義與前述相同。） 步驟1 : 式（3-2)的化合物係可藉由將可取得的式（34)的2-鹵 化硝基芳基於氫氧化鈉或碳酸铯等鹼存在下使與兩二酸二 酯進行反應而製造。以使用的溶媒而言，可列舉例如：二 77 323406 201211028 甲基？醯胺、四氫呋喃、乙腈、二氯甲烷等，可單獨或將 2種以上混合後使用。反應溫度通常為曹^ 15代，較 佳為o°c至loot。 步驟2 : 式（3-3)的化合物係可藉由將式（3_2)的化合物於氯環 境下使用域料金屬觸騎接_原而製I以使用 的溶媒而言’可列舉例如：四氫呋喃、乙醇、甲醇、乙酸、 乙酸乙酯、二氯甲烧等’可單獨或將2種以上混合後使用。 步驟3 : 本步驟係以與方案2記載之步驟3相同的方法進行。 步驟4 : 式（1-3)的化合物係可將式（3_4)化合物於酸存在下進 行加熱獅而製造。以酸而言，可列舉例如：⑽、硫酸、 彻夂對甲、4-乙基苯4酸等，較佳可舉如對甲苯 續酸、4-乙基苯俩等。以溶媒而言，可列舉例如：二甲0 (1-1) (wherein X1 represents a halogen atom, and the other symbols have the same meaning as described above.) Step 1: The compound of the formula (3-2) can be obtained by the formula (34) 2- The halogenated nitroaryl is produced by reacting with a diacid diester in the presence of a base such as sodium hydroxide or cesium carbonate. For the solvent to be used, for example, two 77 323406 201211028 methyl group? The guanamine, tetrahydrofuran, acetonitrile, dichloromethane, etc. may be used alone or in combination of two or more. The reaction temperature is usually Cao 15 generation, preferably from o ° c to loot. Step 2: The compound of the formula (3-3) can be prepared by using a compound of the formula (3-2) in a chlorine environment using a domain metal, and the solvent is used. For example, tetrahydrofuran can be cited. Ethanol, methanol, acetic acid, ethyl acetate, methylene chloride, etc. may be used alone or in combination of two or more. Step 3: This step is carried out in the same manner as in Step 3 described in Scheme 2. Step 4: A compound of the formula (1-3) can be produced by heating a lion in the presence of an acid of the compound of the formula (3-4). The acid may, for example, be (10), sulfuric acid, ruthenium or 4-ethylbenzenetetracarboxylic acid, and the like, preferably p-toluene or 4-ethylbenzene. In the case of a solvent, for example, dimethyl

基甲醯胺、四氫呋喃、二氯甲烷、苯、甲苯、二甲苯等， 較佳可舉如苯、^等。且可單獨或將2㈣I混合後使 用。反應通常以ot至職進行，較佳為阶至14〇。。。 方案4 :The carbamide, tetrahydrofuran, dichloromethane, benzene, toluene, xylene, etc. are preferably benzene, or the like. It can be used alone or in combination with 2 (four) I. The reaction is usually carried out in ot, preferably in the order of 14 Torr. . . Option 4:

_ (1-1) (式中’ X2表示i原子’其他代號之㈣與前述相同） 323406 78 201211028 式（4-1)的化合物係可藉由使可取得的2-鹵化乙酸與 亞硫醯氯或草醯二氯反應而製造。以使用的溶媒而言，可 列舉例如：二曱基甲醯胺、四氫呋喃、氣仿、二氯甲烷等， 可單獨或將2種以上混合後使用。 步驟1 :_ (1-1) (wherein X2 represents an i atom; the other code (4) is the same as the above) 323406 78 201211028 The compound of the formula (4-1) can be obtained by making 2-halogenated acetic acid and sulfoxide Manufactured by reacting chlorine or grass mash dichloride. The solvent to be used may, for example, be dimercaptomethylamine, tetrahydrofuran, gas, methylene chloride or the like, and may be used singly or in combination of two or more. step 1 :

式（4-3)的化合物係可藉由使式（4-1)的化合物與可取 得的式（4-2)的化合物於鹼存在下反應而製造。以使用的鹼 而言，可列舉例如：氫氧化納、氫氧化鉀、碳酸納、碳酸 鉀、碳酸鉋、三乙胺、二異丙基乙胺等。以溶媒而言，可 列舉例如：二曱基甲醯胺、四氳呋喃、乙腈、苯、曱苯、 二氣甲烷等，較佳可舉如二曱基曱醯胺、乙腈、二氣曱烷 等。且可單獨或將2種以上混合後使用。反應通常於-20 它至120°C進行，較佳為0°C至70°C。 步驟2 : 式（1-1)的化合物係可藉由使式（4-3)的化合物於鈀等 金屬觸媒存在下反應而製造。亦即可藉由Tetrahedron Lett.，45，8535-8537(2004)等記載的方法或是依照該者 進行的方法而製造。 方案5 :The compound of the formula (4-3) can be produced by reacting a compound of the formula (4-1) with a compound of the formula (4-2) which can be obtained in the presence of a base. The base to be used may, for example, be sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, carbonic acid planer, triethylamine or diisopropylethylamine. Examples of the solvent include dimercaptocarbamide, tetrahydrofuran, acetonitrile, benzene, toluene, dihalomethane, and the like, and preferably dimethyl decylamine, acetonitrile, and dioxane. Wait. Further, it may be used alone or in combination of two or more. The reaction is usually carried out at -20 to 120 ° C, preferably 0 ° C to 70 ° C. Step 2: The compound of the formula (1-1) can be produced by reacting a compound of the formula (4-3) in the presence of a metal catalyst such as palladium. Alternatively, it can be produced by the method described in Tetrahedron Lett., 45, 8535-8537 (2004) or the like. Option 5:

Pr〇t PratPr〇t Prat

(5-2) (5-3) (1-1) (式中各代號之意義與前述相同。） 79 323406 201211028 步驟1 : 式（5-2)的化合物係可藉由將可取得之式（5-1)的苯胺 衍生物與式（2-4)化合物以與方案2記載之步驟3相同的方 法而製造。 步驟2 : 式（5-3)的化合物係可藉由使式（5-2)的化合物與氣乙 醯氯於鹼存在下反應而製造。以鹼而言，可列舉例如··氫 氧化鈉、氫氧化鉀、碳酸鈉、碳酸鉀、碳酸铯、三乙胺、 二異丙基乙胺、吡啶等。以溶媒而言，可列舉例如：二曱 基甲醯胺、四氫呋喃、乙腈、乙酸乙酯、苯、甲苯、二曱 苯、氯仿、二氣曱烷等，可單獨或將2種以上混合後使用。 反應通常於-20°C至140°C進行，較佳為20°C至100°C。 步驟3 : 式（1-1)的化合物係可藉由使式（5-3)的化合物於路易 斯酸存在下，在惰性溶媒中或者是在無溶媒中反應而製 φ 造。以路易斯酸而言，可舉如：氣化鋅、氣化鋁等。以惰 性溶媒而言，可列舉例如：苯、曱苯、二曱苯、氯苯、氣 仿、二氯甲烷、二甲基甲醯胺、二甲亞砜等，此等係可單 獨或將2種以上混合後使用。反應通常為-20°C至220°C進 行，較佳為20°C至200°C。 前述式（3)之化合物或其鹽係可依照下述方案6進行 合成（R3及R4為一起形成=S之式（6-1)的化合物）。 方案6 : 80 323406 201211028(5-2) (5-3) (1-1) (The meaning of each code in the formula is the same as above.) 79 323406 201211028 Step 1: The compound of formula (5-2) can be obtained by The aniline derivative of (5-1) and the compound of the formula (2-4) are produced in the same manner as in the step 3 described in Scheme 2. Step 2: A compound of the formula (5-3) can be produced by reacting a compound of the formula (5-2) with methylene chloride in the presence of a base. The base may, for example, be sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine or pyridine. Examples of the solvent include dimercaptomethylamine, tetrahydrofuran, acetonitrile, ethyl acetate, benzene, toluene, diphenylbenzene, chloroform, and dioxane. These may be used alone or in combination of two or more. . The reaction is usually carried out at -20 ° C to 140 ° C, preferably 20 ° C to 100 ° C. Step 3: The compound of the formula (1-1) can be produced by reacting a compound of the formula (5-3) in the presence of a Lewis acid in an inert solvent or in a solvent-free medium. Examples of the Lewis acid include zinc vapor, vaporized aluminum, and the like. Examples of the inert solvent include benzene, toluene, diphenylbenzene, chlorobenzene, gas, dichloromethane, dimethylformamide, dimethyl sulfoxide, etc., which may be used alone or in combination. The above is mixed and used. The reaction is usually carried out at -20 ° C to 220 ° C, preferably 20 ° C to 200 ° C. The compound of the above formula (3) or a salt thereof can be synthesized according to the following scheme 6 (R3 and R4 together form a compound of the formula (6-1) = S). Option 6: 80 323406 201211028

步驟1 :step 1 :

式（6-1)的化合物係可藉由將式（卜4)的化合物進行硫 醯胺化而製造。硫醯胺化所使用的試劑可舉例如：Lawess〇n 試劑、五硫化碟等。歧應可無溶媒或於適當的溶媒中進 行。以使用的溶媒而言，可列舉例如：氣仿、二氯甲烧、 甲苯、苯、二甲苯等，係可將此等之2種以上混合後使用。 I Z-R (8) 前述式（7)的化合物係可藉由將可取得的下述式（8) 的化合物以公知的方法，例如新實驗化學講座15卷（丸 善，1978年）所§己載的方法或是依照該者進行氧化而製造。 製法2 :於下述式（9)The compound of the formula (6-1) can be produced by subjecting a compound of the formula (B) to thiolation. The reagent to be used for the sulfhydrylation may, for example, be a Lawess〇n reagent or a sulphuric acid disc. The reaction can be carried out without a solvent or in a suitable solvent. Examples of the solvent to be used include, for example, a gas, a methylene chloride, a toluene, a benzene, a xylene, and the like. These two or more types may be used in combination. I ZR (8) The compound of the above formula (7) can be obtained by a known method, for example, a new experimental chemistry lecture 15 (Maruzen, 1978) by a compound of the following formula (8). The method is either made according to the oxidation of the person. System 2: in the following formula (9)

之化合物與對應R1及R2之烷化劑等於鹼存在下，使於惰性 溶媒中反應而成之前述式（丨）之化合物的製造方法。 以驗而言’可列舉例如：氫化鈉、氫化鉀、碳酸鈉、 碳酸鉀 '碳酸鎚、三乙胺、二異丙基乙胺、甲氧基氧化納、 第二丁氧基氧化鉀等。惰性溶媒可列舉例如··四氫呋喃、 81 323406 201211028 二曙烧、苯、曱苯、二甲苯、二曱基曱酿胺、二甲亞石風、 氯仿、二氣甲烷、二氣乙烷等，係可將此等之2種以上混 合後使用。反應通常於-20°C至14(TC進行，較佳為別^至 10(TC。 製法3 :依照下述方案7 方案7 :A method for producing a compound of the above formula (丨) obtained by reacting a compound with an alkylating agent corresponding to R1 and R2 in the presence of a base in an inert solvent. For the test, for example, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, carbonic acid hammer, triethylamine, diisopropylethylamine, methoxy oxidized sodium, potassium second butoxide or the like can be mentioned. Examples of the inert solvent include tetrahydrofuran, 81 323406 201211028 diterpene, benzene, toluene, xylene, dimercaptoamine, dimethyl sulphur, chloroform, di-methane, di-ethane, and the like. These two or more types may be mixed and used. The reaction is usually carried out at -20 ° C to 14 (TC, preferably from 0 to 10 (TC. Process 3: according to Scheme 7 below) Scheme 7:

c^^C02R ~ co2r (7-1)c^^C02R ~ co2r (7-1)

(式中代號之意義與前述相同 以製造前述式（1)的方法。 步驟1 : 式（7-3)的化合物係可藉由使製法i、方案3記載的步 驟1及步驟2的方法所合成的式（7_ι)的化合物與式（7_2) 的化合物進行反應而製造。該反應係藉由與製法丨、方案2 記載的步驟3之相同方法進行。 步驟2 : 式（7-4)的化合物係可將式（7_3)的化合物與對應^之 烷化劑於鹼存在下，使於惰性溶媒中進行反應而製造。 82 323406 201211028 以驗而言，可列舉例如：氫化納、氳氧化鉀、碳酸納、 碳酸鉀、碳酸鉋、三乙胺、二異丙基乙胺、六曱基二矽氮 鋰、六甲基二矽氮鈉等。惰性溶媒可列舉例如：二甲基曱 醯胺、四氫呋喃、乙腈、苯、曱苯、二氯曱烷等，亦可將 此等之2種以上混合後使用。反應通常於-20°C至120°C進 行，較佳為0°C至120°C。 步驟3 : 本步驟係以與方案3記載之步驟4相同的方法進行。 步驟4 : 式（1)之化合物係可使式（7-5)的化合物之對應於R2之 烷化劑以本方案記載之步驟1相同的方法進行反應而製造。 下述式（7-2)(The meaning of the code in the formula is the same as described above to produce the method of the above formula (1). Step 1: The compound of the formula (7-3) can be obtained by the methods of the steps 1 and 2 described in the production methods i and 3 The synthesized compound of the formula (7_ι) is produced by reacting a compound of the formula (7-2) with a compound of the formula (7-2). The reaction is carried out in the same manner as in the method of the method described in Scheme 2, Step 2. Step 2: Formula (7-4) The compound can be produced by reacting a compound of the formula (7-3) with a corresponding alkylating agent in the presence of a base in an inert solvent. 82 323406 201211028 For example, sodium hydride or potassium hydride can be cited. , sodium carbonate, potassium carbonate, carbonic acid planing, triethylamine, diisopropylethylamine, hexamethylene diazoxide, sodium hexamethyldiazoxide, etc. Examples of the inert solvent include dimethyl decylamine. And tetrahydrofuran, acetonitrile, benzene, toluene, dichloromethane, etc., may be used after mixing two or more of these. The reaction is usually carried out at -20 ° C to 120 ° C, preferably 0 ° C to 120 ° ° C. Step 3: This step is carried out in the same manner as in step 4 described in Scheme 3. Step 4: The compound of the formula (1) can be produced by reacting an alkylating agent corresponding to R2 of the compound of the formula (7-5) in the same manner as in the first step described in the above scheme. The following formula (7-2)

係可依照下述方案8或9而合成。 方案8 : 步驟1It can be synthesized according to the following scheme 8 or 9. Option 8: Step 1

(8-2) 〇=〇-x~GK_r (7-2) 〇=CN~/ (8-1) (式中代號之意義與前述相同。） 步驟1 : 式（8-2)之化合物係可藉由使可取得之式（8-1)的化合 物之N-乙基-4-哌啶酮於無溶媒或者是在適當溶媒中與烷 基鹵化物反應，以作為4級銨鹽而製造。以烷基鹵化物而 83 323406 201211028 言，可舉如：甲基碘、乙基碘、甲基溴、乙基溴等，較佳 為甲基蛾。以使用之溶媒而言，可列舉例如：丙_、尹苯、 氣仿、二氯f烷、乙醆乙酯、己烷等，係可將此等之2種 以上混合後使用。反應溫度通常於―別乞至14(rc進行，較 佳為0°C至50°C。 步驟2 : 式（7-2)之化合物係可藉由使式（8_2)之化合物與可取 得之式（8-3)的胺於在適當溶媒中、於鹼存在下進行反應而 製造。以鹼而言’可列舉例如：氫化鈉、氫氧化鉀、碳酸 鈉、破酸鉀、碳酸鉋。所使用之溶媒可列舉例如：水、乙 醇、甲醇、2-丙醇等，亦可將此等之2種以上混合後使用。 反應通常於〇°C至140°C進行，較佳為2(TC至l〇〇°C。 方案9 : NH + 0=( A N-Boc -^ N-VA N-Boc (9-1) (9-2) (9-3)(8-2) 〇=〇-x~GK_r (7-2) 〇=CN~/ (8-1) (The meaning of the code in the formula is the same as above.) Step 1: Compound of formula (8-2) The N-ethyl-4-piperidone of the compound of the formula (8-1) can be produced as a quaternary ammonium salt by reacting the alkyl halide with a solvent or a suitable solvent in a suitable solvent. . As the alkyl halide, 83 323406 201211028, for example, methyl iodide, ethyl iodide, methyl bromide, ethyl bromide or the like may be mentioned, and methyl moth is preferred. The solvent to be used may, for example, be a mixture of two or more kinds of these, which may be used in the form of a mixture of two or more of them. The reaction temperature is usually carried out at a temperature of from 14 to rc (preferably from 0 ° C to 50 ° C. Step 2: The compound of the formula (7-2) can be obtained by making the compound of the formula (8-2) The amine of the formula (8-3) is produced by reacting in a suitable solvent in the presence of a base. Examples of the base include, for example, sodium hydride, potassium hydroxide, sodium carbonate, potassium bromate, and carbonic acid planer. The solvent to be used may, for example, be water, ethanol, methanol or 2-propanol, or may be used in combination of two or more kinds thereof. The reaction is usually carried out at 〇 ° C to 140 ° C, preferably 2 (TC). To l〇〇°C. Scheme 9: NH + 0=( A N-Boc -^ N-VA N-Boc (9-1) (9-2) (9-3)

(9-6) (9·7) (式中，L表示脫離基，其他代號之意義與前述相同。） 步驟1 : 式（9-3)之化合物係可藉由使式（9-1)之化合物與式 323406 84 201211028 (9-2)的化合物與具有脫離基的親核劑進行反應而製造。以 親核劑而言，可列舉例如：氰化鈉（s〇dium cyanide)、氰 化鉀、三峻、四嗤、二甲基氰化鋁等。所使用之溶媒可列 舉例如：甲苯、二甲笨、四氫呋喃、丨，4一二噚烷、乙腈、 二曱基乙烧等’亦可將此等之2種以上混合後使用。反應 溫度通常於0°C至200°c進行，較佳為加艽至16〇〇c。 步驟2 : 式（9-4)之化合物係可藉由使式（9_3)之化合物與對應 於R8之烷化劑進行反應而製造。以烷化劑而言，可列舉例 如：對應於R8之烷基鋰、烷基氯化鎂、烷基溴化鎂等。所 使用之溶媒可列舉例如：二甲基曱醯胺、四氫呋喃、h 4-一％烧、乙腈、本、甲苯、氯仿、二氯曱烧等，亦可將此 等之2種以上混合後使用。反應通常於_2〇。(3至100°C進 行，較佳為0°C至80°C。 步驟3 : 式（9-5)之化合物係可藉由將式（9-4)之化合物之Boc 基於酸存在下進彳于脫保遵而製造。以酸而言，可列舉例如： 三氟醋酸、鹽酸、硫酸。所使用之溶媒可列舉例如：四氫 呋喃、1,4-二噚烷、乙腈、苯、曱笨、氣仿、二氯甲烷等。 反應通常於-20C至l〇〇C進行，較佳為〇。〇至8〇。匚。 步驟4 : 式（9-6)之化合物係可藉由使式（9〜5)之化合物於鹼存 在下與對應之Y、Z及R之碳醯氣或是硫碳醯二氯進行反應 而製造。以鹼而言，可列舉例如：氫化鈉、氫氧化鉀、碳 323406 85 201211028 酸鈉、碳酸鉀、碳酸铯、三乙胺、二異丙基乙胺、六甲基 一矽氮鋰、六甲基二矽氮鈉等。以溶媒而言可列舉例如： 二曱基曱醯胺、四氫呋喃、乙腈、苯、甲苯、二氯甲烷等。 亦可將此等之2種以上混合後使用。反應通常於_2〇«>c至 120°C進行’較佳為〇°c至i2(TC。 步驟5 : 式（9-7)之化合物係可藉由使式（9_6)之化合物之縮醛 φ 部分於酸存在下進行脫保護而製造。以酸而言，可列舉例 如：三氟醋酸、鹽酸、硫酸等。所使用之溶媒可列舉例如： 四氫呋喃、1,4-二噚烷、乙腈、苯、甲苯、氣仿、二氯甲 烷等。反應通常於-2(TC至16(TC進行，較佳為〇。(：至120 〇C。 製法4 :依照下述方案1〇 , 方案10 :(9-6) (9·7) (wherein, L represents a leaving group, and the meanings of the other symbols are the same as described above.) Step 1: The compound of the formula (9-3) can be obtained by making the formula (9-1) The compound is produced by reacting a compound of the formula 323406 84 201211028 (9-2) with a nucleophilic agent having a leaving group. Examples of the nucleophilic agent include sodium sulfonate (cyanide), potassium cyanide, saponin, tetraterpene, and dimethyl aluminum cyanide. For the solvent to be used, for example, toluene, dimethyl benzene, tetrahydrofuran, hydrazine, 4 dioxane, acetonitrile, dimethyl ketone or the like can be used, and two or more of these may be used in combination. The reaction temperature is usually carried out at 0 ° C to 200 ° C, preferably to 16 ° C. Step 2: A compound of the formula (9-4) can be produced by reacting a compound of the formula (9-3) with an alkylating agent corresponding to R8. The alkylating agent may, for example, be an alkyl lithium corresponding to R8, an alkyl magnesium chloride or an alkyl magnesium bromide. The solvent to be used may, for example, be dimethyl decylamine, tetrahydrofuran, h 4-monohydrin, acetonitrile, benzoyl, chloroform or chloranil, or may be used in combination of two or more kinds thereof. . The reaction is usually at _2 〇. (3 to 100 ° C, preferably 0 ° C to 80 ° C. Step 3: The compound of the formula (9-5) can be obtained by subjecting the Boc of the compound of the formula (9-4) to the presence of an acid The acid may be produced by deprotection, and examples thereof include trifluoroacetic acid, hydrochloric acid, and sulfuric acid. Examples of the solvent to be used include tetrahydrofuran, 1,4-dioxane, acetonitrile, benzene, and hydrazine. Gas imitation, dichloromethane, etc. The reaction is usually carried out at -20C to 1〇〇C, preferably 〇.〇 to 8〇.匚 Step 4: The compound of formula (9-6) can be obtained by The compound of 9 to 5) is produced by reacting a carbon helium gas or a sulphur-carbonium dichloride of the corresponding Y, Z and R in the presence of a base. Examples of the base include sodium hydride and potassium hydroxide. Carbon 323406 85 201211028 Sodium, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, hexamethyl-niobium hydride, hexamethyldiazoxide sodium, etc. Examples of the solvent include: Hydrylamine, tetrahydrofuran, acetonitrile, benzene, toluene, dichloromethane, etc. These two or more kinds may be used in combination, and the reaction is usually carried out at _2〇«>c to 120 °C. 'preferably 〇cc to i2 (TC. Step 5: The compound of the formula (9-7) can be produced by deprotecting the acetal φ moiety of the compound of the formula (9-6) in the presence of an acid. Examples of the acid include trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. Examples of the solvent to be used include tetrahydrofuran, 1,4-dioxane, acetonitrile, benzene, toluene, gas, dichloromethane, and the like. Usually at -2 (TC to 16 (TC, preferably 〇. (: to 120 〇C. Process 4: according to the following scheme 1), Scheme 10:

(式中代號之意義與前述相同。） 86 323406 201211028 以製造前述式（1)的方法。 步驟1 : 式（10-2)之化合物係可藉由對可依照製法1的方法合 成之式（1-1)之化合物而可取得的式（10-1)的化合物進行 脫水縮合而製造。 本步驟係可因應所需而於酸存在下進行，以酸而言， 可列舉例如：醋酸、硫酸、鹽酸、氯化鋅、氯化鋁、氣化 鈦、四異丙基氧化鈦等。此外，可無溶媒或於適當的溶媒 ^ 中進行，所使用之溶媒可列舉例如：苯、曱苯、二曱苯、 氣仿、二氯曱烷、四氫呋喃、二乙基醚、1，4-二卩琴院等， 亦可將此等之2種以上混合後使用。反應溫度通常於-20 °(：至200°C進行，較佳為20°C至140°C。 步驟2 : 式（10-3)之化合物係可依照與製法1、方案1所記載 之步驟1相同的方法，對式（10-2)之化合物之胺基的保護 φ 基進行脫保護而製造。 步驟3 : 式（10-4)之化合物係可藉由對式（10-3)之化合物依照 與製法1、方案2所記載之步驟3相同的方法，進行還原 胺化反應而製造。 步驟4 : 式（1)之化合物係可藉由對（10-4)之化合物於氫環境 存在下使用鈀或铑等金屬觸媒進行接觸還原而製造。所使 用之溶媒可列舉例如：四氫呋喃、乙醇、甲醇、乙酸、乙 87 323406 201211028 酸乙酯、氯仿、二氯曱烷等，亦可單獨或將2種以上混合 後使用。反應溫度通常於0°C至100°C進行，較佳為20°C 至 60°C。 製法5 :依照下述方案11 方案11 :(The meaning of the code in the formula is the same as the above.) 86 323406 201211028 The method of the above formula (1) is manufactured. Step 1: The compound of the formula (10-2) can be produced by dehydrating condensation of a compound of the formula (10-1) which can be obtained by a compound of the formula (1-1) which can be obtained by the method of Process 1. This step can be carried out in the presence of an acid as required. Examples of the acid include acetic acid, sulfuric acid, hydrochloric acid, zinc chloride, aluminum chloride, titanium oxide, and tetraisopropyl titanium oxide. Further, it may be carried out without a solvent or in a suitable solvent. Examples of the solvent to be used include benzene, toluene, diphenylbenzene, gas, dichloromethane, tetrahydrofuran, diethyl ether, and 1,4-. Two or more of the two pianos can be used together. The reaction temperature is usually carried out at -20 ° (: to 200 ° C, preferably 20 ° C to 140 ° C. Step 2: The compound of the formula (10-3) can be in accordance with the procedures described in Process 1, Scheme 1. The same method is carried out by deprotecting the protective φ group of the amine group of the compound of the formula (10-2). Step 3: The compound of the formula (10-4) can be obtained by the formula (10-3) The compound is produced by a reductive amination reaction in the same manner as in the third step described in Process 1 and Scheme 2. Step 4: The compound of the formula (1) can be present in a hydrogen environment by the compound of (10-4). It is produced by contact reduction using a metal catalyst such as palladium or ruthenium. Examples of the solvent to be used include tetrahydrofuran, ethanol, methanol, acetic acid, ethyl 87 323406 201211028 acid ethyl ester, chloroform, dichloromethane, and the like. Further, two or more kinds may be used after mixing. The reaction temperature is usually from 0 ° C to 100 ° C, preferably from 20 ° C to 60 ° C. Process 5: According to the following scheme 11 Scheme 11:

步称3 HO oeCN-x-〇^ Z-R (7-2) 步驟1 i-f dV=/*Step 3 HO oeCN-x-〇^ Z-R (7-2) Step 1 i-f dV=/*

Z-R (1) (式中代號之意義與前述相同。） 以製造前述式（1)的方法。 步驟1 : 式（11-2)之化合物係可藉由將可取得之式（11-1)之化 合物之苯胺衍生物與式（7-2)的化合物依照與製法1、方案 2所記載之步驟3相同的方法而製造。 步驟2 : 式（11-3)之化合物係可藉由使式（11-2)之化合物與草 醯二氯於在適當溶媒中、於酸存在下進行反應而製造。以 酸而言，可列舉例如：三氯化铭、三氣化辞、三氯化鈦等。 以溶媒而言，可列舉例如：苯、曱苯、氯仿、二氯曱烷、 二氯乙烷等，此等係可單獨或將2種以上混合後使用。反 應溫度通常於-20°C至200°C進行，較佳為0°C至120°C。 步驟3 : 88 323406 201211028 式（1)之化合物係可 讲 ^㈣之化合物的心進行:原：適當、= g ’可列舉例如：侧翁 以還原沖J而 ’虱化納、硼氫化知 ^ 使用之溶媒可列舉例如. 。、氧化鋰鋁等。所 四氫呋喃、二乙基醚等.二醇、乙醇、氣仿、二氯甲烷、 反應通常於-20°C至ι〇η> 種以上混合後使用。 也丨、 〇〇C進行，較佳為0。广$ 製法6 :依照下述方案12 至8 0 C。 方案12 :Z-R (1) (The meaning of the code in the formula is the same as described above.) The method of the above formula (1) is produced. Step 1: The compound of the formula (11-2) can be obtained by the aniline derivative of the compound of the formula (11-1) and the compound of the formula (7-2) according to the method 1 and the scheme 2; Step 3 is manufactured in the same manner. Step 2: A compound of the formula (11-3) can be produced by reacting a compound of the formula (11-2) with gadolinium dichloride in a suitable solvent in the presence of an acid. Examples of the acid include, for example, trichlorinated, trigastric, and titanium trichloride. Examples of the solvent include benzene, toluene, chloroform, dichloromethane, dichloroethane, and the like. These may be used alone or in combination of two or more. The reaction temperature is usually carried out at -20 ° C to 200 ° C, preferably 0 ° C to 120 ° C. Step 3: 88 323406 201211028 The compound of the formula (1) can be carried out by the heart of the compound of the formula (4): the original: appropriate, = g ' can be enumerated, for example, the side of the genus to reduce the rushing J and the 虱 纳 、, borohydride know ^ The solvent to be used may, for example, be . , lithium aluminum oxide and the like. The tetrahydrofuran, diethyl ether or the like. diol, ethanol, gas, methylene chloride, and the reaction are usually used after mixing at -20 ° C to ι η >. Also, 〇〇C, preferably 0. Wide $ Method 6: According to the following scheme 12 to 80 C. Option 12:

2-R (1) (式中代號之意義與前述相同。） 以製造前述式（1)的方法。 步驟1 : 式（12 2)之彳物係可藉由將可以市售或本發明所屬 技術領域巾之通料料所公知时法合紅式UH)化 合物的t朵衍生物還原為，琳而製造。以還原劑而言， 係可將《還原為，料者即無特別限定，可使用例如氮 基爛氫化#3。所制之溶媒係可使驗本反應者即無特別 限定，可列舉例如：二氯甲燒或二氯乙㈣。反應溫度通 常於-20C至100C進行，較佳為〇它至8〇<>c。 步驟2 : 89 323406 201211028 式（12-3)之化合物係可藉由式G2-2)之化合物與式 (12)的化合物進行還原性胺化反應而製造。本反應係可依 照與製法1相同之條件而實施。 步驟3 : 式（12-4)之化合物係可藉由適當的氧化劑使式（12-3) 之化合物於溶媒中進行氧化而製造。以氧化劑而言，可舉 例如：二氧化錳等。溶媒可列舉例如：氯仿、二氯甲烷等， 亦可將此等之2種以上混合後使用。反應溫度通常於-20 °C至100°C進行，較佳為〇。〇至80。〇。 步驟4 : 式（1)之化合物係可藉由適當的氧化劑使式（12-4)之 化合物於溶媒中進行氧化而製造。氧化劑係可將烯烴進行 氧化之一般氧化劑即無特別限定，可舉例如：2-碘醯基安 息香酸（IBX ; 2-Iodoxybenzoic acid)。溶媒可列舉例如： 乙腈、水等’此等可單獨或將2種以上混合後使用。以添 加劑而言’可使用氣化鈽等。反應溫度通常於-2(TC至1〇〇 °C進行，較佳為0°c至8(TC 製法7 :依照下述方案13 方案13 : —2-R (1) (The meaning of the code in the formula is the same as described above.) The method of the above formula (1) is produced. Step 1: The oxime of the formula (12 2) can be reduced to a t derivative of a compound of the formula UH) which is commercially available or known in the art of the present invention. Manufacturing. In the case of the reducing agent, the reduction to the material is not particularly limited, and for example, nitrogen-based hydrogenation #3 can be used. The solvent to be prepared is not particularly limited, and examples thereof include dichloromethane or dichloroethane (tetra). The reaction temperature is usually carried out at -20C to 100C, preferably 〇 to 8〇<>c. Step 2: 89 323406 201211028 The compound of the formula (12-3) can be produced by a reductive amination reaction of a compound of the formula G2-2) with a compound of the formula (12). This reaction can be carried out under the same conditions as in Process 1. Step 3: The compound of the formula (12-4) can be produced by oxidizing a compound of the formula (12-3) in a solvent by a suitable oxidizing agent. The oxidizing agent may, for example, be manganese dioxide or the like. For the solvent, for example, chloroform, dichloromethane, or the like may be mentioned, and two or more of these may be used in combination. The reaction temperature is usually carried out at -20 ° C to 100 ° C, preferably hydrazine. 〇 to 80. Hey. Step 4: The compound of the formula (1) can be produced by oxidizing a compound of the formula (12-4) in a solvent with a suitable oxidizing agent. The oxidizing agent is not particularly limited as long as it is a general oxidizing agent capable of oxidizing an olefin, and examples thereof include 2-iodooxybenzoic acid (IBX; 2-Iodoxybenzoic acid). The solvent may, for example, be acetonitrile, water or the like. These may be used alone or in combination of two or more. In the case of an additive, vaporized hydrazine or the like can be used. The reaction temperature is usually carried out at -2 (TC to 1 ° C, preferably 0 ° C to 8 (TC method 7: according to Scheme 13 below: Scheme 13: -

(13*2) (1M) 步驊3 90 323406 (1) 201211028 (式中代號之意義與前述相同。） 以製造前述式（1)的方法。 步驟1 :(13*2) (1M) Step 3 90 323406 (1) 201211028 (The meaning of the code in the formula is the same as described above.) The method of the above formula (1) is manufactured. step 1 :

式（13-2)之化合物係可藉由使依照方案7可合成之式 (13-1)之化合物於鹼存在下與鹵化甲酸烷酯進行反應而製 造。以鹼而言，係可使用於本反應者即無特別限定，可舉 例如：二異丙基胺基醯胺基鋰（LDA)。所使用之溶媒可列舉 例如：二乙基醚或四氫呋喃等。反應溫度通常於—8〇它至 1〇〇°C進行’較佳為_8(Tc至5(TC。 步驟2 : 式（13-3)之化合物係可依照參考例93的方法，可於鹼 =在下以一般的氟化劑使式（13-2)之化合物進行反應而製 造。以反應條件而言，較合適之條件，係於碳酸鉀存在下 於THF中與N-氟苯續酿亞胺以& 5『c進行反應。 步驟3 : ' 式⑴之化合物係可藉由將式（13_3)之化合物進行還 =製造。還原㈣可僅將脂進行還原者即無特別限定， :二例如.爛氫化鋰。溶媒可列舉例如：四氫吱喃、二乙 ΐ 醇、^醇等，此等可單獨或將2種以上混合後使 I反應溫度通常於-机至i⑽。c進行，較佳為酿5〇 取、造方法得到的式⑴之化合物以如萃 &柱層析、再結晶、再沉澱之慣常方 以萃取溶媒而言 々了早離/精I。 —乙基醚、乙酸乙酯、氯仿、 323406 91 201211028 二氯甲烷、甲苯等。以管柱層析進行之精製，係使用酸性、 驗性、或是經各種化學處理之石夕膠或氧化銘（Alumina)，以 展開溶媒而言，可列舉例如：己烧/乙酸乙醋、己烧/氯仿、 乙酸乙酯/曱醇、氣仿/曱醇、乙腈/水、曱醇/水等。 式（1)之化合物為消旋（Racem i c)體時，係使用光學活 性管柱進行管柱層析，以光學活性的酸以及合成手性分離 劑等而依照光學離析方法、優先結晶法、非鏡像異構物法 等慣常方法，而可將各別之對掌體進行分離/精製。 具有羥基之式（1)之化合物，係可依照慣常方法而於上 述所示之製造方法中安插適當之羥基的保護步驟與脫保護 步驟以進行製造。 式（1)之化合物雖依構造式中所存在的官能基的種 類、原料化合物的選定、反應處理條件，而得為游離鹼或 酸加成鹽之形式，惟可依照慣常方法而變換為式（1)之化合 物。另一方面，式（1)之化合物係可依照慣常方法，藉由各 種酸進行處理而導為酸加成鹽。 式（1)之化合物之對掌體之分離係藉由例如：使用光學 活性酸而依照慣常方法使形成非鏡像異構鹽後，分離2種 非鏡像異構鹽，接著使此等變換為游離鹼而進行。以可作 為分離劑之光學活性酸而言，可列舉例如：（+)-或（-)-樟 腦酸、（lS)-( + )-或（lR)-(-)-棒腦-1〇-續酸、L_( + )_ 或 〇-(-)-酒石酸、（+ )-或（-)-杏仁酸、（8)-(-)-或（尺）-(+)-蘋果酸、L-焦麩胺酸、（S)-(+)-或（ί〇-(-)-1，Γ-聯萘基 -2,2’-二基、（+ )-二（苯甲醯基）-0-酒石酸或（-)-二（苯曱 92 323406 ii〇28 醯基酒石酸等。 本發明化人私 對於簟毒鹼Ml^Ml簟毒鹼M2、吣及Ms受體亞型相比較， 用之選擇性篁 4叉體有高選擇性及親和性，而可作為有 本發明化=:M4作用劑進行作用。 顯示效果， 、；經由蕈毒鹼Μι及…受體媒介之疾病 是作為發揮優異I為中樞性疾病預防及/或治療劑，特別 而且，因、的抗精神病作用之抗精神病劑。 其他受體之選擇丨月之化合物係具有對於蕈毒驗受體以及 少且安全的中生故可期待使用作為較以往藥劑副作用 輩毒驗ItT之簡及/或治療劑。 例如：吻4 之相關障礙的典型為精神障礙，可列棄 ,δΛίί知障礙、梯亡 干 視覺缺損、憂#、疚；！、料、喪失記憶、注意力缺損、 +:疼痛、睡眠障礙、精神病等。 纟，¥毒驗Μ,受體之相關障礙不僅限於精神障礙， 1如眼球内壓上升亦與^體有關。因此，本發明之目標 障礙亦包含非精神障礙。 蕈毒驗Μ4受體之相關障礙的典型為精神障礙，可列舉 例如·錯亂、注意力缺損、疼痛、睡眠障礙、精神***症 等。 因此’以本發明之化合物或醫藥組成物之目標障礙而 言，可列舉例如：神經退化性疾病、阿兹海默症、帕金森 氏病症、精神***症、亨汁頓氏舞蹈症、富來德瑞克氏運 動失調症（Friedreichataxia)、妥瑞氏症候群、唐氏症侯 群、疼痛、匹克氏病（plck’ S disease)、癡呆、臨床性抑 323406 93 201211028 鬱、老化性（Age-associated)認知機能低落、注意力缺損 障礙、嬰兒猝死症、青光眼、認知障礙、健忘、錯亂、喪 失記憶、視覺缺損、憂鬱、睡眠障礙、精神病等，較佳為 神經退化性疾病、注意力缺損障礙、疼痛、阿兹海默症、 精神***症、認知障礙；特佳為精神***症、阿茲海默症、 認知障礙。 本發明化合物之投予途徑可為口服投予、非口服投予 _或直腸投予中之任一者，其一日投予量係因化合物的種 類、投予方法、患者的症狀/年齡等而有所不同，例如：口 服投予時，通常人或哺乳動物每公斤體重投予約〇 〇1至 1〇〇呢’更佳為可分為！至數次而以約〇」至1〇呢投予。 靜脈注射等非口服投予時，通常為例如：人或哺乳動物每 公斤體重為投予約lyg至1〇mg，更佳為可投予約1〇以这 至Img。此處所謂之非口服投予係包含投予至靜脈内、肌 肉内、皮下、鼻腔内、皮内、滴眼、腦内、直腸内、*** ^ 内及腹腔内等。 則述醫藥製劑之投予時間及間隔，乃因應各種狀況而 有所變更而由醫師的判斷作即時判斷者，係有分次投予、 連續投予、間歇投予、短期大量投予、反複投予等方法。 例如當口服投予時，期望於丨日中分為i至數次（特別是i 日2至3次）進行投予。此外，亦可作為緩釋性製劑進行投 予或耗費長時間以點滴進行靜脈注射。 本發明之化合物在使用於如上述之醫藥用途時，通常 係與製劑用載體混合而調製成製劑的形式投予。以製劑用 94 323406 201211028 載體而言，係可使用製劑領域常用、且不與本發明之化合 物反應之無毒性物質。具體而言，可列舉如：檸檬酸、麩 胺酸、甘胺酸、乳糖、肌醇、葡萄糖、甘露醇、葡聚糖、 山梨醇、環糊精、澱粉、部分α化鎂、合成矽酸鋁、結晶 纖維素、羧曱基纖維素鈉、羥丙基澱粉、羧曱基纖維素鈣、 離子交換樹脂、曱基纖維素、明膠、***膠、聚三葡萄 糖（pullulan)、羥丙基纖維素、低取代度之經丙基纖維素、 羥丙基甲基纖維素、聚乙烯吡咯啶酮、聚乙烯醇、海藻酸、 ® 海藻酸鈉、輕質無水矽酸、硬脂酸鎂、滑石、紫雲英樹膠、 膨土、VEE GUM、羧基乙烯聚合物、氧化鈦、山梨醇酐脂肪 酸醋、月桂基硫酸納、甘油、脂肪酸甘油S旨、精製羊毛脂、 甘油明膠、聚山梨糖醇S旨、MACR0G0L (聚乙二醇）、植物油、 蠟、丙二醇、乙醇、苯曱醇、氯化鈉、氫氧化鈉、鹽酸、 水等。 以劑型而言，可列舉如：錠劑、膠囊劑、顆粒劑、粉 ^ 劑、液劑、漿_(Syrup)劑、懸浮劑、注射劑、栓劑、滴眼劑、 軟膏劑、塗布劑、貼劑、吸入劑等。此等製劑係可依照慣 常方法進行調製。而當使用液體製劑時，係可為溶解或懸 浮於水或是其他適當的介質中之形式。此外，亦可以周知 的方法將錠劑及顆粒劑進行包覆。而製造非口服製劑，例 如製造注射劑時，係可適當調配水性溶劑（例如：蒸餾水、 生理食鹽水、林格氏液（Ringer’s solution))、等張化劑 (例如：匍萄糖、D-山梨醉、D-甘露鮮、氯化納等）、安定 劑（例如：人類血清白蛋白等）、防腐劑（例如：苯甲醇、氣 95 323406 201211028 丁醇、對羥基安息香酸曱酯、對羥基苯甲酸丙酯、酚等）、 緩衝劑（例如：磷酸鹽緩衝劑、醋酸鈉緩衝劑等）、舒緩劑（例 如：氯化苯二甲烴鍵（Benzalkonium chloride)、鹽酸普羅 卡因等）。而且，此等製劑亦可含有具有醫療價值之其他成 分。 本發明之醫藥製劑係可依照慣常方法製造，製劑中之 本發明化合物的含有比例通常為0. 01至50%(w/w)。具體 例係如以下所示。 (1) 錠劑、粉劑、顆粒劑、膠囊劑：於本發明之化合物 添加例如：賦形劑、崩解劑、黏結劑或潤滑劑等並進行壓 縮成型，接著可因應所需進行以掩味、腸溶性或持續性為 目的之包覆而製造。 例如為旋劑時，可藉由將實施例1之化合物2 Omg、乳 糖lOOmg、結晶纖維素25mg及硬脂酸鎮lmg進行混合，將 所得到的混合物進行打鍵而製造。 (2) 注射劑：可藉由將本發明之化合物與例如：分散 劑、保存劑、等張化劑等一同成為水性注射劑，或者是將 本發明之化合物溶解、懸浮或乳化於例如：撖欖油、芝麻 油、綿軒油、玉米油等植物油；丙二醇，成為油性注射劑 而製造。 (3) 栓劑：可藉由將本發明之化合物成為油性或水性的 固狀、半固狀或是液狀之組成物而製造。以用於如此之組 成物之油性基劑而言，可列舉例如：高級脂肪酸的三酸甘 油酯（例如：可可脂、Witepsol類（Witepsol為註冊商標） 96 323406 201211028 等）、中級脂肪酸（例如：MIGLY0L類（MIGLY0L為註冊商標） 等）、或植物油（例如：芝麻油、大豆油、綿籽油等）。以水 性凝膠基劑而言，可列舉例如：天然橡膠類、纖維素衍生 物、乙烯系聚合物、丙烯酸聚合物等。 (實施例） 以下列舉參考例、實施例及試驗例對本發明進行更為 具體的說明，惟本發明不限定為此等者。化合物之鑑別係 使用質子核磁共振吸收光譜GH-NMR)、LC-MS等進行。又， ® 參考例及實施例之胺矽膠管柱層析係使用山善股份公司製 之胺矽膠管柱。LC-MS係使用以2010EV與2010HT構成之 系統（島津製作所）或LC10ATVP(島津製作所）與API150EX (Perkin Elmer)構成之系統。LC-MS之移動相係使用乙腈 (1至99°/〇與0. 05%三氟乙酸水溶液或是曱醇（10至99%)與 0. 05%三氟乙酸水溶液。滯留時間（R. T.)係表示LC-MS測定 之質譜峰顯現的時間。 φ LC-MS係以各種條件進行測定，該等係詳細記於以下。 條件A : LCMS :島津 LCMS-2010EV 管柱：Shiseido CAPCELL 溶媒： A 液：MeOH，B 液：0. 05% 梯度條件： 0· 0 至 1. 0 分鐘；A/B=30 1. 0 至 7. 0 分鐘；A/B=99 PAK C18 MGII(4.6mmx50mm) TFA/H2O 70 97 323406 201211028 7. 1 至 12. 0 分鐘；A/B=30 : 70 流速：2. 8mL/min UV ： 220nm 管柱溫度：40°C 條件B : 檢測機器：API系列用Agi lent 1100系列（Applied Biosystems 公司製） HPLC : API150EX LC/MS 系統（Applied Biosystems 公司製） 鲁 管柱：YMC CombiScreen 0DS-A(S-5 a M，12nm，4. 6x50mm) 溶媒： A 液：0·05% TFA/H2〇 ， B 液：0.035% TFA/MeOH 梯度條件： 0. 0 至 0. 5 分鐘；A/B=90 : 10 0. 5 至 4. 2 分鐘；A/B=l : 99 4. 2 至 4. 4 分鐘；A/B=99 : 1 ^ 流速：1. 8mL/min UV : 220nm 條件C :The compound of the formula (13-2) can be produced by reacting a compound of the formula (13-1) which can be synthesized according to the scheme 7 with an alkyl halide. The base to be used in the present reaction is not particularly limited, and examples thereof include diisopropylaminophosphonium amide (LDA). The solvent to be used may, for example, be diethyl ether or tetrahydrofuran. The reaction temperature is usually -8 Torr to 1 ° C to carry out 'preferably _8 (Tc to 5 (TC. Step 2: the compound of the formula (13-3)) can be obtained according to the method of Reference Example 93, The base is produced by reacting a compound of the formula (13-2) with a general fluorinating agent. In terms of reaction conditions, it is suitable for N-fluorobenzene in THF in the presence of potassium carbonate under suitable conditions. The imine is reacted with & 5 <c. Step 3: 'The compound of the formula (1) can be produced by subjecting the compound of the formula (13-3) to the same. The reduction (iv) can be carried out only by reducing the fat, and is not particularly limited, For example, the lithium ruthenium hydride may be, for example, tetrahydrofuran, diethyl hydroxide or hydric alcohol, and these may be used singly or in combination of two or more kinds, and the reaction temperature is usually from - to i (10). Preferably, the compound of the formula (1) obtained by the method of extracting and extracting is subjected to a conventional method such as extraction and chromatography, recrystallization, and reprecipitation, in the case of extracting the solvent, and is separated from the fine I. Ether, ethyl acetate, chloroform, 323406 91 201211028 dichloromethane, toluene, etc. Purification by column chromatography, using acidity, test For the development of the solvent, for example, hexane/acetic acid ethyl acetate, hexane/chloroform, ethyl acetate/nonanol, gas imitation, etc. / sterol, acetonitrile / water, sterol / water, etc. When the compound of formula (1) is a racemic ic, it is an optically active column for column chromatography, with optically active acid and synthetic hands. Separating and purifying each of the palms according to a conventional method such as an optical separation method, a preferential crystallization method, or a non-image mirror method, such as a sex separating agent, etc. The compound of the formula (1) having a hydroxyl group can be used. The protective step and the deprotection step of inserting an appropriate hydroxyl group in the above-described production method according to a conventional method are carried out for production. The compound of the formula (1) is selected according to the kind of the functional group present in the structural formula and the starting compound. And the reaction treatment conditions are obtained in the form of a free base or an acid addition salt, but can be converted into a compound of the formula (1) according to a conventional method. On the other hand, the compound of the formula (1) can be borrowed according to a conventional method. Treated by various acids The acid addition salt is formed. The separation of the compound of the formula (1) by the palm body is carried out, for example, by using an optically active acid to form a non-imagewise isomerized salt according to a conventional method, and separating the two non-image salt isomers. Then, the conversion to the free base is carried out. Examples of the optically active acid which can be used as a separating agent include (+)- or (-)-camphoric acid, (lS)-(+)- or ( lR)-(-)-Bell brain-1〇-continued acid, L_( + )_ or 〇-(-)-tartaric acid, (+)- or (-)-mandelic acid, (8)-(-)- Or (foot)-(+)-malic acid, L-pyroglutamic acid, (S)-(+)- or (ί〇-(-)-1, Γ-binaphtyl-2,2'- Base, (+)-bis(benzylidene)-0-tartaric acid or (-)-bis(benzoquinone 92 323406 ii〇28 decyl tartaric acid, etc. Compared with the scorpion Ml^Ml muscarinic M2, 吣 and Ms receptor subtypes, the selective 篁4-fork has high selectivity and affinity, and can be used as the invention. =: M4 agent acts. A disease which is an antipsychotic agent which exhibits an excellent anti-psychotic effect, which is a central disease prevention and/or therapeutic agent, and which is excellent in the cause of the disease. Selection of other receptors The compound of the month has a simple and safe medium for the detection of sputum, and it is expected to be used as a simpler and/or therapeutic agent for the side effects of the conventional drug. For example, the typical obstacles related to Kiss 4 are mental disorders, which can be discarded, δΛίί 障碍 、 、 梯 梯 梯 梯 梯 梯 视觉 ! ! ! ! ! ! ! ! ! ! ! ! , material, loss of memory, attention deficit, +: pain, sleep disorders, mental illness, etc. Hey, the drug test, the receptor-related disorders are not limited to mental disorders, 1 such as the increase in intraocular pressure is also related to the body. Therefore, the target obstacle of the present invention also includes non-mental disorders. The disorder associated with the scorpion venom 4 receptor is typically a mental disorder, and examples thereof include dislocation, attention deficit, pain, sleep disorder, and schizophrenia. Therefore, the target disorder of the compound or the pharmaceutical composition of the present invention may, for example, be a neurodegenerative disease, Alzheimer's disease, Parkinson's disease, schizophrenia, Hendrick's disease, Fulai Friedreichataxia, Tourette's syndrome, Down's syndrome, pain, plck's disease, dementia, clinical depression 323406 93 201211028 、, aging (Age-associated Cognitive hypofunction, attention deficit disorder, sudden infant death, glaucoma, cognitive impairment, forgetfulness, confusion, loss of memory, visual impairment, depression, sleep disorders, mental illness, etc., preferably neurodegenerative diseases, attention deficit disorder, Pain, Alzheimer's disease, schizophrenia, cognitive impairment; especially good for schizophrenia, Alzheimer's disease, cognitive impairment. The administration route of the compound of the present invention may be any one of oral administration, parenteral administration, or rectal administration, and the amount of the compound to be administered per day is the type of the compound, the administration method, the symptom/age of the patient, and the like. However, when administered orally, usually humans or mammals are given about 1 to 1 ounce per kilogram of body weight. 'Better is divided into! It will be given several times to approximately one to one. In the case of parenteral administration such as intravenous injection, it is usually, for example, that human or mammal is administered from about lyg to about 1 mg per kg of body weight, and more preferably about 1 〇 to about 1 mg. The non-oral administration herein includes administration to intravenous, intramuscular, subcutaneous, intranasal, intradermal, intraocular, intracerebral, intrarectal, intravaginal, and intraperitoneal. The time and interval of administration of the pharmaceutical preparations are determined by the judgment of the physician in light of various conditions, and are determined by the doctors in a divided manner, continuous administration, intermittent administration, short-term large-scale administration, and repeated Casting and other methods. For example, when administered orally, it is desirable to carry out the administration in the next day, divided into i to several times (especially 2 to 3 times on i day). Further, it may be administered as a sustained-release preparation or may be intravenously administered in a small amount for a long period of time. When the compound of the present invention is used in the pharmaceutical use as described above, it is usually administered in the form of a preparation prepared by mixing with a carrier for preparation. In the case of the formulation 94 323406 201211028 carrier, a non-toxic substance which is commonly used in the field of formulation and which does not react with the compound of the present invention can be used. Specific examples thereof include citric acid, glutamic acid, glycine, lactose, inositol, glucose, mannitol, dextran, sorbitol, cyclodextrin, starch, partially magnesium citrate, and synthetic citric acid. Aluminum, crystalline cellulose, sodium carboxymethyl cellulose, hydroxypropyl starch, calcium carboxymethyl cellulose, ion exchange resin, mercapto cellulose, gelatin, gum arabic, pullulan, hydroxypropyl fiber , low-substituted propyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, alginic acid, ® sodium alginate, light anhydrous citric acid, magnesium stearate, talc , Astragalus gum, bentonite, VEE GUM, carboxyvinyl polymer, titanium oxide, sorbitan fatty acid vinegar, sodium lauryl sulfate, glycerin, fatty acid glycerin S, refined lanolin, glycerin gelatin, polysorbate S, MACR0G0L (polyethylene glycol), vegetable oil, wax, propylene glycol, ethanol, benzoquinone, sodium chloride, sodium hydroxide, hydrochloric acid, water, and the like. The dosage form may, for example, be a tablet, a capsule, a granule, a powder, a liquid, a syrup (Syrup), a suspension, an injection, a suppository, an eye drop, an ointment, a coating agent, or a sticker. Agent, inhalant, etc. These formulations can be prepared according to conventional methods. When a liquid preparation is used, it may be in the form of dissolved or suspended in water or other suitable medium. Further, the tablets and granules may be coated by a known method. For the preparation of parenteral preparations, for example, when preparing injections, aqueous solvents (for example, distilled water, physiological saline, Ringer's solution), isotonic agents (for example, glucosamine, D-sorbus) can be suitably formulated. Drunk, D-mannose, sodium chloride, etc., tranquilizers (eg human serum albumin, etc.), preservatives (eg benzyl alcohol, gas 95 323406 201211028 butanol, p-hydroxybenzoic acid decyl ester, p-hydroxybenzene A propyl formate, a phenol, etc.), a buffer (for example, a phosphate buffer, a sodium acetate buffer, etc.), a soothing agent (for example, Benzalkonium chloride, procaine hydrochloride, etc.). Moreover, such formulations may also contain other ingredients of medical value. 01至50百分比(w/w) The content of the compound of the present invention is usually from 0.01 to 50% (w/w). The specific examples are as follows. (1) Lozenges, powders, granules, capsules: Adding, for example, an excipient, a disintegrating agent, a binder or a lubricant to the compound of the present invention, and performing compression molding, and then performing the taste-masking as needed It is manufactured by coating for the purpose of enteric or persistence. For example, when it is a spinning agent, the obtained mixture can be produced by mixing 2 mg of the compound of Example 1, 100 mg of lactose, 25 mg of crystalline cellulose, and 1 mg of stearic acid. (2) Injection: The compound of the present invention can be used as an aqueous injection together with, for example, a dispersing agent, a preservative, an isotonic agent, or the like, or the compound of the present invention can be dissolved, suspended or emulsified in, for example, eucalyptus oil. , vegetable oil such as sesame oil, Mianxuan oil, corn oil; propylene glycol, manufactured as an oily injection. (3) Suppository: It can be produced by forming the compound of the present invention into an oily or aqueous solid, semisolid or liquid composition. Examples of the oily base used in such a composition include triglycerides of higher fatty acids (for example, cocoa butter, Witepsol (Witepsol is a registered trademark) 96 323406 201211028, etc.), and intermediate fatty acids (for example: MIGLY0L (MIGLY0L is a registered trademark), etc., or vegetable oil (for example, sesame oil, soybean oil, cottonseed oil, etc.). The aqueous gel base may, for example, be a natural rubber, a cellulose derivative, a vinyl polymer or an acrylic polymer. (Examples) Hereinafter, the present invention will be more specifically described by reference to Examples, Examples and Test Examples, but the present invention is not limited thereto. The identification of the compound was carried out by proton nuclear magnetic resonance absorption spectroscopy (GH-NMR), LC-MS or the like. Further, the amine oxime column chromatography of the reference examples and the examples used an amine ruthenium rubber column manufactured by Shanshan Co., Ltd. LC-MS uses a system consisting of a system composed of 2010EV and 2010HT (Shimadzu Corporation) or LC10ATVP (Shimadzu Corporation) and API150EX (Perkin Elmer). The mobile phase of LC-MS is acetonitrile (1 to 99 ° / 〇 and 0. 05% aqueous solution of trifluoroacetic acid or decyl alcohol (10 to 99%) and 0. 05% aqueous solution of trifluoroacetic acid. Retention time (RT) The time at which the mass spectrum peak of the LC-MS measurement appears is shown. φ LC-MS is measured under various conditions, and these are described in detail below. Condition A: LCMS: Shimadzu LCMS-2010EV Column: Shiseido CAPCELL Solvent: A solution : MeOH, B solution: 0. 05% Gradient conditions: 0·0 to 1. 0 minutes; A/B=30 1. 0 to 7. 0 minutes; A/B=99 PAK C18 MGII (4.6mmx50mm) TFA/ H2O 70 97 323406 201211028 7. 1 to 12. 0 minutes; A/B=30 : 70 Flow rate: 2. 8mL/min UV : 220nm Column temperature: 40°C Condition B: Testing machine: API series with Agi lent 1100 Series (Applied Biosystems) HPLC : API150EX LC/MS system (Applied Biosystems) Lu column: YMC CombiScreen 0DS-A (S-5 a M, 12nm, 4. 6x50mm) Solvent: A solution: 0·05 % TFA/H2〇, B solution: 0.035% TFA/MeOH Gradient conditions: 0. 0 to 0. 5 minutes; A/B=90: 10 0. 5 to 4. 2 minutes; A/B=l: 99 4 2 to 4. 4 minutes; A/B=99: 1 ^ Flow rate: 1. 8 mL/min UV: 220 nm Condition C:

LCMS:島津 LCMS-2010EV 管柱：Ximate C18 3. 0//m 2. Iramx30mm 溶媒： A 液：0. 019% TFA/H2〇，B 液：0. 038% TFA/CH3CN 梯度條件： 0.分鐘；A/B=90 : 10 98 323406 201211028 0. 0 至 1. 35 分鐘；A/B=20 : 80 1. 35 至 2. 25 分鐘；A/B=20 : 80 2. 25 至 2. 26 分鐘；A/B=90 : 10 2. 26 至 3. 00 分鐘；A/B=90 : 10LCMS: Shimadzu LCMS-2010EV Column: Ximate C18 3. 0//m 2. Iramx30mm Solvent: A solution: 0. 019% TFA/H2〇, B solution: 0. 038% TFA/CH3CN Gradient conditions: 0. ;A/B=90 : 10 98 323406 201211028 0. 0 to 1.35 minutes; A/B=20 : 80 1. 35 to 2.25 minutes; A/B=20 : 80 2. 25 to 2.26 Minutes; A/B=90 : 10 2. 26 to 3. 00 minutes; A/B=90 : 10

流速：0. 8mL/min UV : 220nm 管枉溫度：50°C 當實驗項目無特別記載時，係使用條件A。 ® 此外，為將說明書中之記述簡略化而亦於參考例、實 施例及表中使用如下所示之代號。 以取代基之代號而言，Me意指甲基、Et意指乙基、tBu 意指第三丁基、Boc意指第三丁氧羰基。 以NMR使用之代號而言，s表示單峰、d表示雙峰、dd 表示雙雙峰、t表示三重峰、td表示三雙峰、q表示四重 峰、m表示多重峰、br表示寬峰、brd表示寬雙峰、brt表 φ 示寬三重峰，以及J意指偶合常數。 參考例1 2-硝基苯乙酸曱酯 CC〇rMe 於室溫，將2-硝基苯乙酸（200g)之曱醇（1.3L)溶液滴 至硫酸（15mL)。於加熱回流下將反應液攪拌16小時。冷卻 為室溫後，以30%碳酸氫鈉水溶液（500mL)中和後，進行減 壓濃縮。以乙酸乙酯萃取殘渣，以飽和食鹽水進行洗淨。 99 323406 201211028 以無水硫酸鈉乾燥後，進行減壓濃縮而得到目的物（150g， 70%) 〇 參考例2 2-胺基笨乙酸甲酯Flow rate: 0. 8 mL/min UV: 220 nm Tube temperature: 50 ° C When the experimental item is not specifically described, Condition A is used. In addition, in order to simplify the description in the specification, the following symbols are used in the reference examples, examples and tables. In the case of the substituent code, Me means methyl, Et means ethyl, tBu means tributyl, and Boc means third butoxycarbonyl. In the code used for NMR, s represents a single peak, d represents a doublet, dd represents a doublet, t represents a triplet, td represents a triplet, q represents a quadruple, m represents a multiplet, br represents a broad peak, Brd represents a broad bimodal, brt table φ shows a broad triplet, and J means a coupling constant. Reference Example 1 Ethyl 2-nitrophenylacetate CC〇rMe A solution of 2-nitrophenylacetic acid (200 g) in methanol (1.3 L) was added dropwise to sulfuric acid (15 mL). The reaction solution was stirred under heating and reflux for 16 hours. After cooling to room temperature, it was neutralized with a 30% aqueous sodium hydrogencarbonate solution (500 mL), and concentrated under reduced pressure. The residue was extracted with ethyl acetate and washed with brine. 99 323406 201211028 After drying with anhydrous sodium sulfate, concentration under reduced pressure gave the title compound (150 g, 70%) 〇 Reference Example 2 2-Amino-benzylacetate

於參考例1之化合物（100g)的曱醇（1.5L)溶液中加入 絶•碳（12g)。將反應容器進行氫置換，並於室溫徹夜攪拌。 以石夕藻土濾除纪-碳，得到減壓濃縮目的物（73g, 86%)。 參考例3 4-(2-侧氧基-2, 3-二氫吲哚-1-基）哌啶-1-綾酸第三丁酯 〇To a solution of the compound (100 g) of Reference Example 1 in decyl alcohol (1.5 L) was added carbon (12 g). The reaction vessel was replaced with hydrogen and stirred overnight at room temperature. The celite-carbon was filtered off with Shixia, and the objective substance (73 g, 86%) was concentrated under reduced pressure. Reference Example 3 4-(2-Sideoxy-2,3-dihydroindol-1-yl)piperidine-1-furic acid tert-butyl ester 〇

將參考例2之化合物（150g)溶解於二氯曱烷（2.5L)， 於室溫加入1-第三丁氧羰基—4-哌啶酮（217. 5g)。攪拌2 • 小時後’冷卻為5至10°C，加入三乙醯氧基硼氫化納 (320g)，於室溫下攪拌72小時。反應液中加入冰水 (500mL) ’以30%碳酸氫納水溶液使pH成為11後，以曱苯 進行萃取。以飽和食鹽水將有機層洗淨，以無水硫酸鈉乾 燥後’進行減壓濃縮。以矽膠管柱層析（石油醚/乙酸乙酯 -20/1)精製得到的殘渣，得到目的物（i25g，43%)。 參考例4 4 (2侧氧基~2，3~二氮-1-基）旅咬 100 323406 201211028The compound of Reference Example 2 (150 g) was dissolved in dichloromethane (2.5 L), and 1-t-butoxycarbonyl-4-piperidinone (217. 5 g) was added at room temperature. After stirring for 2 hours, the mixture was cooled to 5 to 10 ° C, and triethyloxyborohydride (320 g) was added thereto, and the mixture was stirred at room temperature for 72 hours. Ice water (500 mL) was added to the reaction mixture to adjust the pH to 11 with a 30% aqueous sodium hydrogencarbonate solution, followed by extraction with benzene. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained was purified by silica gel column chromatography ( petroleum ether / ethyl acetate - 20/1) to afford the object (i25g, 43%). Reference Example 4 4 (2-sided oxy~2,3~diazin-1-yl) brigade bite 100 323406 201211028

將參考例3之化合物（2. 0g)溶解於二氯甲烷（25ml)， 於冰浴下加入三氟乙酸（4. 0ml)。徐緩升溫後，於室溫徹夜 擾拌。於反應液中加入4mol/L之NaOH水溶液，以氯仿進 行萃取。以無水硫酸鈉將有機層乾燥後，進行減壓濃縮， 得到標題之化合物（1. 35g)。 參考例5 4-(3, 3-二甲基-2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌啶 -1-羧酸第三丁酯The compound of Reference Example 3 (2.0 g) was dissolved in dichloromethane (25 ml). After slowly warming up, disturb at room temperature overnight. A 4 mol/L aqueous NaOH solution was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium Reference Example 5 4-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

使參考例3得到的化合物（316mg)溶解於二曱基曱醯 胺（5mL)，進行氮置換後冰冷之。擾拌5分鐘後，逐次少量 加入氫化納（55%，105mg)。於不再泡出氣泡時將甲基蛾 • (341mg)滴下。於室溫攪拌2小時後，加入飽和氣化銨水溶 液（5mL)。以飽和食鹽水將以乙酸乙酯萃取的有機層洗淨。 以無水硫酸鈉乾燥後，將減壓濃縮後得到的殘渣以矽膠管 柱層析（己烧/乙酸乙S旨=9/1至4/1)進行精製，得到目的物 (350mg)。 參考例6 4-(3, 3-二曱基-2-侧氧基-2, 3-二氫-1H-吲哚-1-基）哌啶 基 101 323406 201211028The compound (316 mg) obtained in Reference Example 3 was dissolved in dimethyl hydrazide (5 mL), and subjected to nitrogen substitution, followed by ice-cooling. After 5 minutes of scramble, a small amount of sodium hydride (55%, 105 mg) was added in small portions. Methyl moth (341 mg) was dropped when bubbles were no longer bubbled out. After stirring at room temperature for 2 hours, a saturated aqueous solution of ammonium sulfate (5 mL) was added. The organic layer extracted with ethyl acetate was washed with saturated brine. After drying over anhydrous sodium sulfate, the residue obtained by concentrating under reduced pressure was purified by silica gel column chromatography (hexanes / ethyl acetate / / / / / / / / / / / / / / / / / / / Reference Example 6 4-(3,3-Dimercapto-2-oxo-2,3-dihydro-1H-indol-1-yl)piperidinyl 101 323406 201211028

使用參考例5之化合物，依照與參考例4相同的方法 而得到標題化合物。 參考例7 4-(3, 3-二乙基-2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌啶 -1-羧酸第三丁酯Using the compound of Reference Example 5, the title compound was obtained according Reference Example 7 4-(3,3-Diethyl-2-oxo-2,3-dihydro-1H-indol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

使參考例3得到的化合物（40g)溶解於二曱基甲醯胺 (320mL)，進行氮置換後冰冷之。攪拌5分鐘後，逐次少量 加入氳化納（55%，6g)。於不再泡出氣泡時將乙基破（25. 2g) 滴下。於室溫攪拌2小時後，加入飽和氯化銨水溶液。以 飽和食鹽水將以乙酸乙酯萃取的有機層洗淨。以無水硫酸 鈉乾燥後，將減壓濃縮後得到的殘渣以矽膠管柱層析（石油 # 醚/乙酸乙酯=5(^1至20/1)進行精製，得到目的物（6. 5g， 29%)。 參考例8 4-(3-乙基-2-侧氧基-2, 3-二氫-1H-吲哚-1-基）哌啶-1-羧 酸第三丁酯The compound (40 g) obtained in Reference Example 3 was dissolved in dimercaptocaramine (320 mL), and then subjected to nitrogen substitution and then ice-cooled. After stirring for 5 minutes, sodium hydride (55%, 6 g) was added in small portions. The ethyl group (25. 2g) was dropped when the bubble was no longer bubbled out. After stirring at room temperature for 2 hours, a saturated aqueous solution of ammonium chloride was added. The organic layer extracted with ethyl acetate was washed with saturated brine. After drying with anhydrous sodium sulfate, the residue obtained by concentrating under reduced pressure was purified by silica gel column chromatography (ethyl ether / ethyl acetate = 5 (^1 to 20/1) 29%). Reference Example 8 4-(3-Ethyl-2-oxo-2,3-dihydro-1H-indol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

係作為參考例7之副生成物而得到（5. 4g，25%)。 102 323406 201211028 參考例9 4-(3-乙基-3-曱基-2-側氧基-2，3-二氳-1 Η-, α朵-1-基）0底 啶-1-羧酸第三丁酯The product was obtained as a by-product of Reference Example 7 (5.4 g, 25%). 102 323406 201211028 Reference Example 9 4-(3-Ethyl-3-indolyl-2-yloxy-2,3-diindole-1 Η-, α-l-yl)0-acridin-1-carboxylate Tert-butyl acid

於參考例8之化合物（llg)之二曱基曱醯胺（50mL)溶 液進行氮置換後冰冷之。攪拌10分鐘後，逐次少量加入氩 化鈉（55%，2g)。於不再泡出氣泡時將曱基碘（7. 05g)滴下。 於室溫攪拌2小時後，加入飽和氯化銨水溶液。以飽和食 鹽水將以乙酸乙酯萃取的有機層洗淨。以無水硫酸鈉乾燥 後，進行減壓濃縮而得到目的物（10. 5g)。 參考例10 4-(3-乙基-3-曱基-2-侧氧基-2, 3-二氫 啶The solution of the compound (llg) in dimethyl decylamine (50 mL) of Reference Example 8 was replaced with nitrogen and then ice-cooled. After stirring for 10 minutes, sodium hydride (55%, 2 g) was added in small portions. The thiol iodine (7.55 g) was dropped while the bubble was no longer bubbled out. After stirring at room temperature for 2 hours, a saturated aqueous solution of ammonium chloride was added. The organic layer extracted with ethyl acetate was washed with saturated brine. After drying over anhydrous sodium sulfate, the title compound (10.5 g) was obtained. Reference Example 10 4-(3-Ethyl-3-indolyl-2-oxo-2,3-dihydropyridine

使用參考例9之化合物，依照與參考例4相同的方法 而得到標題化合物。 參考例11 4-(2-側氧基-3, 3-二丙基-2, 3-二氫-1Η-σ3 °朵-1-基）派咬 -1-羧酸第三丁酯Using the compound of Reference Example 9, the title compound was obtained in the same manner as in the title compound. Reference Example 11 4-(2-Sideoxy-3,3-dipropyl-2,3-dihydro-1Η-σ3 °-1-yl)-bite 1-carboxylic acid tert-butyl ester

103 323406 201211028 使用參考例3之化合物，並使用丙基蛾以取代甲其 蛾，依照與參考例5相同的方法而得到標題化合物。土 參考例12 4-（2-侧氧基-3,3-二丙基一2 3--翁111?丨；^1 Me、 · 叼丞一虱-1H-吲哚-1-基）哌啶103 323406 201211028 Using the compound of Reference Example 3, and using a propyl moth to replace the methyl moth, the title compound was obtained in the same manner as in Reference Example 5. Soil Reference Example 12 4-(2-Sideoxy-3,3-dipropyl- 2 3--ion 111?丨; ^1 Me, ·叼丞一虱-1H-吲哚-1-yl) Piper Pyridine

广N-HWide N-H

使用參考例11之化合物’依照與參考例4相同的方法 而得到標題化合物。 參考例13 4~[2’ -側氧螺（環丙烷—1，3’ -羧酸第三丁酯 °弓卜朵）-1’（2,+The title compound was obtained by the same procedure as that of Reference Example 4 using the compound of the title compound. Reference Example 13 4~[2'-side oxo (cyclopropane-1,3'-carboxylic acid tert-butyl ester °bendo)-1' (2,+

Boc 使用參考例3之化合物，並使用〗9 ^Boc uses the compound of Reference Example 3 and uses 〖9^

田# 1文用12-二溴乙烷以取代 甲基碘，依照與參考例5相同的方沐；π μ (81%) 〇 』刃万去而得到標題化合物 參考例14 4~[2’-側氧螺（環丙烷-1,3’Tian #1 text uses 12-dibromoethane to replace methyl iodide, according to the same formula as in Reference Example 5; π μ (81%) 〇 刃 万 去 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题- side oxo (cyclopropane-1,3'

，朵）-Γ(2’Η)-基]派咬 使用參考例13之化合物，依照與參考你! 4相同的方法 而得到標題化合物。 323406 104 201211028 參考例15 4-[2’ -側氧螺（環丙烷-i，3’ 羧酸第三丁酯； -吲哚)-Γ(2，Η)-基]哌啶+, (), Γ (2' Η)-based cations. Using the compound of Reference Example 13, the title compound was obtained in the same manner as in Reference 4! 323406 104 201211028 Reference Example 15 4-[2'-Side oxane (cyclopropane-i, 3' carboxylic acid tert-butyl ester; - hydrazine)-hydrazine (2, fluorene)-yl] piperidine +

使用參考例3之化合物’並使们，卜二討烧 甲基蛾’依職參相5相同的方法叫顺題化合來 (71%) ° 參考例16 4-[2’ -側氧螺（環丙烷_丨，3, 〇Using the compound of Reference Example 3 and letting them, the two methods of the sputum-burning methyl moths are called the same method (71%) ° Reference Example 16 4-[2'-side oxane ( Cyclopropane _ 丨, 3, 〇

Η 吲哚）-1’（2，1〇-基]哌啶 使用參考例15之化合物，依照與參考例4 而得到標題化合物。 參考例17 相同的方法 4-[2’-侧氧螺（環己烷-υ，Η 吲哚)-1'(2,1〇-yl)piperidine The compound of Reference Example 15 was used, and the title compound was obtained according to Reference Example 4. Reference Example 17 The same procedure 4-[2'-S. Cyclohexane-hydrazine,

一基]哌啶-1- 使用參考例3之化合物， 甲基碘，依照與參考例5相 (82%) 〇 1>5Ί戊院以取代 同的方法而㈣標題化合物 323406 105 201211028 參考例181-Based] Piperidine-1- Using the compound of Reference Example 3, methyl iodide, in accordance with Reference Example 5 (82%) 〇 1 > 5 Ί 院 instead of the same method (4) title compound 323406 105 201211028 Reference Example 18

4一[2n-側氧螺（環己烷-1，3, °引嗓）-1’（2, η)-基]哌啶 使用參考例17之化合物，依昭伽 而得到標触合物。 依雄參相4相同的方法 參考例19 4 [2侧氧螺（四氩哌喃_4,3，—吲哚）_ι，（2，η) 基]派淀 卜竣酸第三4-[2n-S. oxyspiro(cyclohexane-1,3, ° 嗓)-1'(2, η)-yl] piperidine using the compound of Reference Example 17 to obtain a conjugated compound . The same method as Yixiong ginseng 4 Reference Example 19 4 [2 Side Oxygen (tetrahydropyran-4-4,3,-吲哚)_ι, (2,η)-based] Diethyl citrate

• Boc 酉旨 :用參考例3之化合物，並使用雙㈣乙基)醚以取 =基峨，依照與參考例5相同的方法而得到 合物。 參考例20 [2 〇側氧螺（四氳U底喃_4, 3’ -Π弓丨η朵）_1，（2, "9 J^n-h• Boc: The compound of Reference Example 3 was used, and bis(tetra)ethyl)ether was used to give a base, and the compound was obtained in the same manner as in Reference Example 5. Reference Example 20 [2 〇 氧 snail (four 氲 U 喃 _4, 3' - Π 丨 丨 ) _1), (2, "9 J^n-h

Η)-基]派咬 使用參考例19之化合物，2,依照與參相4相同的 方法而得到標題化合物。 參考例21 甲基—2_侧氧基_2,3_二氫餐°引°朵+基）㈣+叛 酸第三丁酯 323406 106 201211028 ΟThe title compound was obtained by the same method as that of the the same. Reference Example 21 Methyl-2_sideoxy-2,3_dihydrogen meal °#+) (4)+3rd butyl acid 323406 106 201211028 Ο

Ο B〇c 於參考例3之化合物（40g)之四氫呋喃（1L)溶液加入 六曱基磷酸三醯胺，於氮環境下冷卻為-78°C。滴下六甲基 一矽氮鋰胺之四氫呋喃溶液（1等量）並攪拌2小時後，加 入曱基碘（1.2等量）攪拌5小時。加入飽和氯化銨水溶液 後，水層以乙酸乙酯萃取。以飽和食鹽水將有機層洗淨。 1，水硫酸鈉乾燥。將減壓濃縮所得到的油狀物質進行矽 膠官柱層析(石油醚/乙酸乙酯=50/1至20/1)，得到作為目 的物之白色固體（13. 5g)。 參考例22 4 (3甲基2侧氧基_2,3-二氫-iH-n引d朵-1-基）旅咬 使用參考例21之化合物，依照與參考例4相同的方法 而得到標題化合物。 參考例23Ο B〇c A solution of the compound of Example 3 (40 g) in tetrahydrofuran (1 L) was added to the tridecylamine hexamethylamine and the mixture was cooled to -78 ° C under nitrogen. A solution of hexamethyl-nitrilolithamine in tetrahydrofuran (1 equivalent) was added dropwise and stirred for 2 hours, and then thiol iodide (1.2 equivalent) was added thereto and stirred for 5 hours. After adding a saturated aqueous solution of ammonium chloride, the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine. 1. Dry with sodium sulfate. The oily substance obtained by concentrating under reduced pressure was subjected to silica gel column chromatography ( petroleum ether / ethyl acetate = 50/1 to 20/1) to give a white solid (13.5 g). Reference Example 22 4 (3 methyl 2-o-oxy-2,3-dihydro-iH-n-indol-1-yl) brittle bite The compound of Reference Example 21 was used in the same manner as in Reference Example 4. Title compound. Reference example 23

4_{[(2_>臭-4-氣本）乙酿基]胺基}u辰唆-1—叛酸第三丁g旨. 於2-溴-4-氟笨基乙酸（2.〇g，8.58mmol)加入亞硫醯 氯（10ml)，於80°C攪拌5小時。將反應液減壓濃縮後，加 入乙腈（30ml)、故酸卸（1.42g，1〇. 3〇mmol)、4-胺基-卜4_{[(2_> 臭-4-气本)Ethyl]Amine}uchen唆-1-Resinic acid third butyl g. In 2-bromo-4-fluorophenyl acetic acid (2.〇g , 8.58 mmol) was added with sulfoxide (10 ml) and stirred at 80 ° C for 5 hours. After the reaction mixture was concentrated under reduced pressure, acetonitrile (30 ml) was added, and then acid was removed (1.42 g, 1 〇. 3 〇mmol), 4-amino-b

S 323406 107 201211028 第三丁氧基羰基哌啶（1.89g，9.44賴ol)，於室溫徹夜擾 拌。於反應液加入水，以乙酸乙酯萃取，以飽和食鹽水將 有機層洗淨。以無水硫酸鎂乾燥後，以矽藻土過濾，將濾 液進行減壓濃縮。以乙酸乙酯洗淨所得到的固體，得到標 題化合物（2. 67g，75%)。 !H-NMR (CDCh, 400MHz) ^ 1. 19-1. 29 (m, 2H), 1.44(s, 9H), 1.82-1.90 (d, J=12. 7Hz, 2H), 2.77-2.90 (br, 2H), 3.64 (s, 2H), 3.88-4.03 (br, 2H), 5.27-5.33 (br, 1H), 7.02-7.08 (td, J=8. 3, 2. 7Hz, 1H), 7.30-7.36 (m, 2H). LC-MS ： R.T. 8.3 min., m/z 361. O(M-tBu), 參考例24 4_(6_氟-2-側氧基-2，3-二氫°朵-1-基）α底咬-l-敌酸 第三丁酯S 323406 107 201211028 Third butoxycarbonylpiperidine (1.89 g, 9.44 Å) was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the mixture was filtered over Celite, and filtered. The obtained solid was washed with ethyl acetate to give title compound (2. 67 g, 75%). !H-NMR (CDCh, 400MHz) ^ 1. 19-1. 29 (m, 2H), 1.44(s, 9H), 1.82-1.90 (d, J=12. 7Hz, 2H), 2.77-2.90 (br , 2H), 3.64 (s, 2H), 3.88-4.03 (br, 2H), 5.27-5.33 (br, 1H), 7.02-7.08 (td, J=8. 3, 2. 7Hz, 1H), 7.30- 7.36 (m, 2H). LC-MS: RT 8.3 min., m/z 361. O (M-tBu), Reference Example 24 4_(6-Fluoro-2-oxo-2,3-dihydro -1--1-yl)α bottom bite-l-dibasic acid tert-butyl ester

將參考例23之化合物（1. 0g，2. 41mmol)溶解於第三丁 醇（24mL)後，於之加入乙酸把（27mg，0. 12mmol)、苯删酸 (29mg，〇.24mmol)、X-Phos(114mg，0.24mmol)、碳酸鉀 (883ing，6. 〇3mm〇i)，於氮環境下以85°C攪拌2小時。於 反應液加入水，以乙酸乙酯萃取，以水、飽和食鹽水將有 機層洗淨。有機層以無水硫酸鎂乾燥後，以矽藻土過濾， 將濾液進行減壓濃縮。以矽膠管柱層析精製所得到的殘渣 1 ’得到標題化合物（237mg，35%)。 108 323406 201211028 參考例25 4-(6_氣-2~*側氧基-2，3_二氮_1Η-°引 ηψ 〇 〇Η 'After the compound of Reference Example 23 (1. 0 g, 2.41 mmol) was dissolved in toluene (24 mL), acetic acid (27 mg, 0.12 mmol), benzene acid (29 mg, 〇.24 mmol), X-Phos (114 mg, 0.24 mmol), potassium carbonate (883 ing, 6. 〇 3 mm 〇i) was stirred at 85 ° C for 2 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered over Celite. The residue obtained was purified by silica gel column chromatography to give the title compound (237 mg, 35%). 108 323406 201211028 Reference Example 25 4-(6_Gas-2~*sideoxy-2,3_diaza_1Η-° ηψ 〇 〇Η '

F 基）哌啶F group) piperidine

使用參考例24之化合物’依照與參考例4 而得到標題化合物（86%)。 目同的方法 參考例26 4-(6-氣-3, 3-二甲基-2-側氧基_2,3_n α底啶-1-羧酸第三丁酯 /、 基） FThe title compound (86%) was obtained according The same method Reference Example 26 4-(6-Gas-3, 3-dimethyl-2-oxooxy-2,3_n α-endridin-1-carboxylic acid tert-butyl ester /, base) F

使用參考例24之化合物，依照與參相5相 而得到標題化合物（33%)。 ' 參考例27 4一（6-氟-3, 3-二甲基-2-側氧基-2, 3~二 α辰啶 氫-1Η-吲哚-1-基）Using the compound of Reference Example 24, the title compound (33%) was obtained. 'Reference Example 27 4-(6-fluoro-3,3-dimethyl-2-oxo-2,3~di-α-------------

使用參考例26之化合物，依照與參考例4相同的方法 而得到標題化合物。 參考例28 (5-氣-2-石肖苯基）-1，3-丙二酸二第三丁酉旨 323406 109 201211028 C02tBu 丫Y^C02iBu ^N02Using the compound of Reference Example 26, the title compound was obtained according Reference Example 28 (5-Gas-2-stone phenyl)-1,3-malonic acid 2-3 butyl 323406 109 201211028 C02tBu 丫Y^C02iBu ^N02

使氫化鈉（於油中55%，634mg，14. 54mmol)懸浮於二 甲基甲醯胺（20mL)中，於冰浴下加入丙二酸二第三丁酯 (2. 10ml，9. 40mmol)且擾拌40分鐘。於之加入4-氯-2-氣 石肖苯（1.5g, 8. 55mmol)之二曱基曱驢胺（10ml)溶液，徐缓 昇溫至室溫後，徹夜進行攪拌。於反應液加入水，以乙酸 乙酯萃取，以水、飽和食鹽水將有機層洗淨。以無水硫酸 鈉將有機層乾燥後，以矽藻土過濾，將濾液進行減壓濃縮。 以矽膠管柱層析精製所得到的殘渣，得到標題化合物 (3.30g)。 參考例29 2-(2_胺基_5_氯苯）-1，3 -丙二酸二第三丁酉旨The sodium hydride (55% in oil, 634 mg, 14.54 mmol) was suspended in dimethylformamide (20 mL), and dibutyl succinate (2.10 ml, 9.40 mmol) was added to the ice bath. ) and disturbed for 40 minutes. A solution of 4-chloro-2-methane benzene (1.5 g, 8.55 mmol) in dimercaptoamine (10 ml) was added thereto, and the mixture was warmed to room temperature and then stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered over Celite. The residue was purified by silica gel column chromatography toiel Reference Example 29 2-(2-Amino-5-chlorophenyl)-1,3-malonic acid di-t-butyl

將參考例28之化合物（3. 300g)溶解於乙醇（30mL) 後，加入10%錄碳（Rhodium Carbon)(3. Og)，於氫環境下 攪拌4小時。過濾反應液後，進行減壓濃縮而得到標題化 合物（2. 72g)。 參考例30 2(2-{[1-(第三丁氧幾基）α辰唆基]胺基}-5-氯苯丙烧） -1，3-二酸二第三丁酯 110 323406 201211028After dissolving the compound of Reference Example 28 (3. 300 g) in ethanol (30 mL), 10% of Rhodium Carbon (3.0 g) was added, and the mixture was stirred under hydrogen atmosphere for 4 hours. The reaction mixture was filtered, and then evaporated. Reference Example 30 2(2-{[1-(Tertidinoxy)yl)-amino]amino}-5-chloropropanone]-1,3-diacid di-t-butyl ester 110 323406 201211028

C02tBu 將參考例29之化合物（UOg，4.39咖1)溶解於二氯 甲烧（2GmL)後’加入卜第三丁氧幾基_4_旅咬嗣⑺⑽， UW)、乙酸⑽mg，8.78職〇1)、三乙醯氧基爛氫化 納（1.86g，U8mmol) ’於室溫下徹賴拌。於反應液加入 2mol/L氫减納水溶液，以·萃取後，以飽和食鹽水將 有機層洗淨。以無水硫_賴後，叫藻土過濾，將浦 液進行減壓濃縮。以㈣管柱層析精製所得到的殘潰，得 到標題化合物（1. l〇g，489〇。 參考例31 4(5-氣-2-側氧基-2 3-二氫~ΐΗ~·αζ|πη_、^ 第三丁醋 -心丨…)錢领酸C02tBu The compound of Reference Example 29 (UOg, 4.39 coffee 1) was dissolved in dichloromethane (2GmL) and then added to the third butanoxy group _4_Broaden sputum (7) (10), UW), acetic acid (10) mg, 8.78 〇 1), triethyl decyloxy hydride (1.86 g, U8 mmol) 'mix thoroughly at room temperature. After adding 2 mol/L of a hydrogen-reducing aqueous solution to the reaction solution, the organic layer was washed with a saturated saline solution after extraction. After the anhydrous sulfur was used, it was filtered by algae, and the liquid was concentrated under reduced pressure. The residue obtained by (4) column chromatography was purified to give the title compound (1. l〇g, 489 〇. Reference Example 31 4 (5-gas-2-oxooxy-2 3-dihydro~ΐΗ~· ζ ζ | πη_, ^ third vinegar - heart 丨 ...) money collar acid

广、Ν - B〇c 將^例30之化合物（1.1Qg，2肩圓υ溶解於甲笨 二=，加入對乙綱酸(3,邮2〇·95_〇ι)，以 140 C攪拌5小時。將反應液減壓濃 + +/1C /屣縮’於冰浴下加入四氫 吱鳴（耐）、三乙胺（3.2ml，22 99in 二 碳酸酯（912mg，4.l8mmol)，攪拌 一丞一 9mnl/T . . 愰仵2小時。於反應液加入 虱魏納水溶液，以氯仿進行萃取，以飽和食鹽水 323406 111 201211028 將有機層洗淨。以無水硫酸鈉乾燥後，以矽藻土過濾，將 濾液進行減壓濃縮。以矽膠管柱層析精製所得到的殘渣， 得到標題化合物（435mg，59%)。 參考例32 4(5-氯-2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌啶广, Ν - B〇c The compound of Example 30 (1.1Qg, 2 shoulder υ υ dissolved in 甲笨二 =, added to bis-acid (3, post 2〇·95_〇ι), stirred with 140 C 5 hours. The reaction solution was dehydrated to a concentration of + + / 1 C / condensed. Under ice bath, tetrahydrofuran (resistant), triethylamine (3.2 ml, 22 99 in dicarbonate (912 mg, 4.18 mmol), After stirring for 9 hours, the mixture was stirred for 2 hours. The reaction mixture was added with a solution of 虱Weina, extracted with chloroform, and the organic layer was washed with saturated brine 323406 111 201211028. The celite was filtered, and the filtrate was evaporated to dryness. 3-dihydro-1H-indol-1-yl)piperidine

使用參考例31之化合物，依照與參考例4相同的方法 而得到標題化合物。 參考例33 4(5-氟-2-侧氧基-2, 3-二氫-1H-吲哚-1-基）哌啶-1-羧酸 第三丁酯Using the compound of Reference Example 31, the title compound was obtained according Reference Example 33 4(5-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

使用2,4-二敗硝苯以取代4-氯-2-氟硝苯，依照與參 考例28至31相同的方法而得到標題化合物。 參考例34 4(5-氟-2-侧氧基-2, 3-二氫-1H-吲哚-1-基）哌啶The title compound was obtained in the same manner as in References 28 to 31 using 2,4-di-n-n-n-n-benzene. Reference Example 34 4(5-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl)piperidine

使用參考例33之化合物，依照與參考例4相同的方法 112 323406 201211028 而得到標題化合物。 參考例35 4-(5-氟-3, 3-二曱基-2-侧氧基-2, 3-二氫-1H-吲哚-1-基）Using the compound of Reference Example 33, the title compound was obtained according to the same procedure as that of Reference Example 4 112 323406 201211028. Reference Example 35 4-(5-Fluoro-3, 3-dimercapto-2-yloxy-2,3-dihydro-1H-inden-1-yl)

使用參考例33之化合物，依照與參考例5及參考例4 相同的方法而合成標題化合物。 參考例36 3，3-二曱基-1-(派°定-4-基）-1, 3-二氮_2H-D引σ朵-2-硫酉同The title compound was synthesized in the same manner as in Reference Example 5 and Reference Example 4 using the compound of Reference Example 33. Reference Example 36 3,3-Dimercapto-1-(Pytidine-4-yl)-1,3-diaza_2H-D-introduced σ-spin-2-thioindole

將參考例6之化合物（162mg)、Lawesson試劑（804mg) φ 溶解於曱苯（7ml)後，於120°C攪拌6小時。以矽藻土過濾 反應液後，進行減壓濃縮。以矽膠管柱層析精製所得到的 殘渣，得到標題化合物（216mg)。 參考例37 4-(5-曱基-2-側氧基-2, 3-二氩-1H-吲哚-1-基）哌啶The compound of Reference Example 6 (162 mg) and Lawesson's reagent (804 mg) φ were dissolved in toluene (7 ml), and stirred at 120 ° C for 6 hours. The reaction mixture was filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography toiel Reference Example 37 4-(5-Mercapto-2-oxo-2,3-diar-argon-1H-indol-1-yl)piperidine

使用2-氟-4-曱基石肖苯以取代4-氯-2-氟石肖苯，依照與 113 323406 201211028 參考例28至31相同的方法而得到標題化合物。 參考例38 4-(5-甲基-2-側氧基-2, 3-二氫-1H-吲11 朵一1_基）旅啶The title compound was obtained by the same method as that of 113 323406 201211028, Reference Examples 28 to 31, using 2-fluoro-4-indolyl benzene. Reference Example 38 4-(5-Methyl-2-oxo-2,3-dihydro-1H-indole 11-indolyl)

MeO 使用2-氟-4-甲氧基硝苯以取代4-氟氟硝笨’依照 與參考例28至31相同的方法而得到標題化合物。MeO was used in the same manner as Reference Examples 28 to 31 using 2-fluoro-4-methoxynitrobenzene in place of 4-fluorofluoronitrobenzene.

實施例1 4[4-(3-曱基-2-侧氧基-2, 3-二氫-1H-吲c朵—'基）哌啶-1- 基]哌啶-1-羧酸乙酯 將參考例22之化合物（69mg, 0. 3mm〇l)溶解於二氯曱Example 1 4[4-(3-Mercapto-2-oxo-2,3-dihydro-1H-indolyl-'yl)piperidin-1-yl]piperidine-1-carboxylic acid The ester of the compound of Reference Example 22 (69 mg, 0.3 mm 〇l) was dissolved in dichloropurine.

烷（3mL)後，於室溫加入乙酸（36mg)、l-乙氧基艘基哌啶-4-嗣（57mg)、四異丙氧化鈦（427mg)。擾拌1〇分鐘後加入三 乙醯氧基硼氫化鈉（127mg)，於加熱回流下橄夜攪拌。冷卻 至室溫後，加入25%氨水溶液使pH為10。將經矽藻土過濾 之濾液進行分液，以氣仿萃取水層。與有機層合併，以飽 和食鹽水洗淨。以無水硫酸鈉水溶液進行乾燥後，將減壓 濃縮所得之殘渣進行胺矽膠管柱層析（己烷/乙酸乙酯= 9/1至乙酸乙酯），得到為油狀物質之目的物（81mg/70%)。 使溶於乙醇，加入延胡索酸（24mg)後進行滅壓濃縮。將所 114 323406 201211028 得到的固體以二異丙基醚進行研製（triturate)後濾除，得 到標題化合物之延胡索酸鹽（90mg)。 !H-NMR (300MHz, CD3〇D)(5 1.26 (3H, t, J=7. 1Hz), 1.42 (3H, d, J=7. 7Hz), 1.55-1.75 (2H, in), 1.9-2.0 (2H, m), 2.05-2.15 (2H, in), 2.7-2.95 (4H, m), 3.09 (2H, t, J=12Hz), 3.46 (lH,m), 3.5-3.6 (2H, m), 4.12 (2H, q, J=7. 1Hz), 4.25-4.45 (3H, m), 6.72 (2H, s), 7.07 (1H, t, J=7.4Hz), 7.18 (1H, m), 7.29 (2H, m) LC-MS:R.T. 6.4 min, m/z 386.2 (M+l). 實施例2 4[4-(3, 3-二曱基-2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌 啶-1-基]哌啶-1-羧酸乙酯After alkane (3 mL), acetic acid (36 mg), 1-ethoxyphenylpiperidine-4-indole (57 mg), and titanium tetraisopropoxide (427 mg) were added at room temperature. After stirring for 1 minute, sodium triethoxysulfonium borohydride (127 mg) was added, and stirred under reflux with stirring under stirring. After cooling to room temperature, a 25% aqueous ammonia solution was added to bring the pH to 10. The filtrate filtered through diatomaceous earth was subjected to liquid separation, and the aqueous layer was extracted with a gas pattern. Combine with the organic layer and wash with saturated saline. After drying over anhydrous sodium sulfate aqueous solution, the residue obtained by concentration under reduced pressure was subjected to ethylamine chromatography (hexane/ethyl acetate = 9/1 to ethyl acetate) to give an oily substance (81 mg). /70%). It was dissolved in ethanol, and fumaric acid (24 mg) was added, followed by concentration under reduced pressure. The solid obtained in 114 323406 201211028 was triturated with diisopropyl ether and filtered to give the title compound of the fumarate (90 mg). !H-NMR (300MHz, CD3〇D) (5 1.26 (3H, t, J=7. 1Hz), 1.42 (3H, d, J=7. 7Hz), 1.55-1.75 (2H, in), 1.9- 2.0 (2H, m), 2.05-2.15 (2H, in), 2.7-2.95 (4H, m), 3.09 (2H, t, J=12Hz), 3.46 (lH,m), 3.5-3.6 (2H, m ), 4.12 (2H, q, J=7. 1Hz), 4.25-4.45 (3H, m), 6.72 (2H, s), 7.07 (1H, t, J=7.4Hz), 7.18 (1H, m), 7.29 (2H, m) LC-MS: RT 6.4 min, m/z 386.2 (M+l). Example 2 4[4-(3, 3- bis decyl </ br> Ethyl dihydro-1H-indol-1-ylpiperidin-1-yl]piperidine-1-carboxylate

使用參考例6之化合物，依照與實施例2相同的方法 而得到為鹽酸鹽之標題化合物（344mg)。 LC-MS ： R. T. 1.2 min, m/z 400.4 (M+l). 實施例3 4[4-(3-乙基-3-甲基-2-侧氧基-2, 3-二氫-1H-吲哚-1〜基） 0底咬-1-基]旅咬-1-叛酸乙醋The title compound (344 mg) was obtained from the title compound. LC-MS: RT 1.2 min, m/z 400.4 (M+l). Example 3 4[4-(3-ethyl-3-methyl-2- s s s -吲哚-1~base) 0 bottom bite-1-base] brigade bite-1-rebel acid vinegar

115 3234〇6 201211028 使用參考例10之化合物’依照與實施例1相同的方法 而得到為三氟乙酸鹽之標題化合物（17mg)。 LC-MS ： R. T. 4.8 rain, m/z 414.8 (M+l). 實施例4 4[4-(3, 3-二丙基-2-側氧基-2, 3-二氫-1H-吲哚-I —基）0底 啶-1-基]哌啶-1-羧酸乙酯115 3234 〇 6 201211028 Using the compound of Reference Example 10 The title compound (17 mg) was obtained. LC-MS: RT 4.8 min, m/z 414.8 (M+l). Example 4 4[4-(3, 3-dipropyl-2- oxo-2, 3-dihydro-1H-indole)哚-I —yl) 0-endridin-1-yl]piperidine-1-carboxylic acid ethyl ester

使用參考例12之化合物’依照與實施例1相同的方法 而得到標題化合物（8. 6mg)。 LC-MS ： R. T. 4.1 rain, m/z 456.6 (M+l). 實施例5 4{4-[2’ -側氧螺（環丙烷-1，3’ -吲哚）-Γ (2, Η)-基]哌啶 -l-基}哌啶-1-羧酸乙酯The title compound (8.6 mg) was obtained. LC-MS: RT 4.1 min, m/z 456.6 (M+l). Example 5 4{4-[2'-S. snail (cyclopropane-1,3'-indole)-indole (2, Η Ethyl-piperidinyl-l-yl}piperidine-1-carboxylate

使用參考例14之化合物，依照與實施例1相同的方法 而得到為延胡索酸鹽之標題化合物。 'H-NMR (300MHz, CDsOD) 5 1.25(3H, t, J = 7. 1Hz), 1.45-1. 75 (6H, m), 1. 96-2.18 (5H, m), 2. 8-2. 95 (5H, m), 3. 19 (2H, t, J = 12Hz), 3.31 (2H, m), 3.45 (1H, m), 3.64 (2H, d, J = 12Hz), 4.12 (2H, q, J = 7.1Hz), 4.2-4.35 116 323406 201211028 (3H, m), 4. 57 (1H, m), 6. 73 (2H, s), 6. 95 (1H, m), 7. 03 (1H, t, J = 7.4Hz), 7.29 (2H, in). LC-MS R. T. 6.3 min, m/z 398. 2 (M+l). 實施例6 4{4-[2’ -侧氧螺（環丁烧-1，3’ 弓丨嗓）-Γ (2’ H)-基]π辰咬 -l-基}哌啶-1-羧酸乙酯Using the compound of Reference Example 14, the title compound as the fumarate was obtained in the same manner as in Example 1. 'H-NMR (300MHz, CDsOD) 5 1.25(3H, t, J = 7. 1Hz), 1.45-1. 75 (6H, m), 1. 96-2.18 (5H, m), 2. 8-2 . 95 (5H, m), 3. 19 (2H, t, J = 12Hz), 3.31 (2H, m), 3.45 (1H, m), 3.64 (2H, d, J = 12Hz), 4.12 (2H, q, J = 7.1Hz), 4.2-4.35 116 323406 201211028 (3H, m), 4. 57 (1H, m), 6. 73 (2H, s), 6. 95 (1H, m), 7. 03 (1H, t, J = 7.4 Hz), 7.29 (2H, in). LC-MS RT 6.3 min, m/z 398. 2 (M+l). Example 6 4{4-[2' - side oxygen Snail (cyclobutanol-1,3' 丨嗓)-Γ(2' H)-yl]π辰咬-l-yl}ethylpiperidine-1-carboxylate

步驟1 使用參考例4之化合物（436mg，2. 02mmol)，依照與實 施例1相同的方法而得到油狀物質（547mg，85%)。 步驟2 將步驟1所得到的化合物（547mg，1. 47mmol)溶解於二 甲基曱酿胺（8mL)後’加入碳酸铯（1. 19g，3. 68mmol)於室 # 溫授拌3分鐘。於之加入1，3-二溴丙烷（164/z 1，1.62mmol)， 於7(TC攪拌3小時。於反應液加入水、4m〇1/L氫氧化鈉水 溶液，以氯仿萃取後，以水將有機層洗淨。以硫酸鈉乾燥 後，以矽藻土過濾，將濾液進行減壓濃縮。以矽膠管柱層 析精製所得到的殘渣’得到標題化合物（6〇mg， H-NMR (CDCh, 400MHz) (5 1. 22-1. 30 (t, J=7. 1Hz, 3H), 1.63-1. 7 (m, 2H), 1.85-1.96 (br, 2H), 2.10-2.2.40 (ra, 6H), 2.54-2.66 (m, 2H), 2.71-2.89 (br, 2H), 2.90-3.09 (br, 4H), 3.40-3.51 (br, 1H), 3.66 (s, 2H), 4.08-4.16 323406 117 201211028 (q，J=7.1Hz，2H), 4. 22-4.44 (br，2H)，4.61-4.73 (br， 1H) 7.07-7. 12 (t, J=7. 7Hz, 1H), 7. 22-7. 26 (t, J=7. 7Hz, 1H), 7.33-7.36 (d, J=8.0Hz, 1H), 7.43-7.52 (d, J=6.4Hz, 1H). LC-MS：R. T. 6.8 min., ra/z 412.2CM+1). 實施例7 4{4-[2’ -側氧螺（環戊烷-1，3’ -吲哚）-Γ (2’ h)-基]B底咬 -l-基}哌啶-1-羧酸乙酯The oily substance (547 mg, 85%) was obtained by the same procedure as in Example 1, using the compound of Example 4 (436 mg, 0.02 mmol). Step 2 The compound obtained in Step 1 (547 mg, 1.47 mmol) was dissolved in dimethylamine (8 mL), and then yttrium carbonate (1. 19 g, 3.68 mmol) was added and stirred at room temperature for 3 minutes. Add 1,3-dibromopropane (164/z 1,1.62 mmol), and stir at 7 (TC for 3 hours. Add water, 4 m〇l/L sodium hydroxide solution to the reaction solution, and extract with chloroform to The organic layer was washed with water, dried over sodium sulfate, and filtered over Celite, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give the title compound (6 mg, H-NMR ( CDCh, 400MHz) (5 1. 22-1. 30 (t, J=7. 1Hz, 3H), 1.63-1. 7 (m, 2H), 1.85-1.96 (br, 2H), 2.10-2.2.40 (ra, 6H), 2.54-2.66 (m, 2H), 2.71-2.89 (br, 2H), 2.90-3.09 (br, 4H), 3.40-3.51 (br, 1H), 3.66 (s, 2H), 4.08 -4.16 323406 117 201211028 (q, J=7.1Hz, 2H), 4. 22-4.44 (br, 2H), 4.61-4.73 (br, 1H) 7.07-7. 12 (t, J=7. 7Hz, 1H ), 7. 22-7. 26 (t, J=7. 7Hz, 1H), 7.33-7.36 (d, J=8.0Hz, 1H), 7.43-7.52 (d, J=6.4Hz, 1H). LC -MS: RT 6.8 min., ra/z 412.2 CM +1). Example 7 4{4-[2'-Side oxo (cyclopentane-1,3'-吲哚)-Γ (2' h )-based] B bottom bite-l-yl}piperidin-1-carboxylic acid ethyl ester

將參考例16的化合物（108mg)溶解於二氯甲烧（2mL) 及二曱氧乙烷（2mL)後，於室溫加入卜乙氧基羰基娘咬_4_ 酮（86mg)、四異丙氧化鈦（568mg) ’於室溫擾拌3日後，加 入25%氨水溶液使pH為10。以矽藻土過濾並進行分液後， 以氯仿萃取水層。將有機層合併，以飽和食鹽水洗淨。以 無水硫酸鈉水溶液進行乾燥後，將減壓濃縮所得之殘渣進 行胺矽膠管柱層析（己烷/乙酸乙酯=9/1至乙酸乙酯），得 到為油狀物質之目的物（58mg)。使溶於乙醇，加入延胡索 酸（16mg)後進行減壓濃縮。將所得到的固體以二異丙基醚 進行研製後濾除，得到標題化合物之延胡索酸鹽（60mg)。 LC-MS ： R. T. 2.5 min, m/z 426.6(M+1). 實施例8 4{4-[2’ -側氧螺（環己烷-1，3’ -吲哚）-Γ (2, Η)-基]哌啶 118 323406 201211028 -1-基丨哌啶-1-羧酸乙酯After dissolving the compound of Reference Example 16 (108 mg) in dichloromethane (2 mL) and dioxirane (2 mL), ethoxyethyl carbonyl benzophenone (86 mg), tetraisopropyl Titanium oxide (568 mg) ' After 3 days of stirring at room temperature, a 25% aqueous ammonia solution was added to bring the pH to 10. After filtering with diatomaceous earth and separating the layers, the aqueous layer was extracted with chloroform. The organic layers were combined and washed with saturated brine. After drying over anhydrous sodium sulfate aqueous solution, the residue obtained by concentration under reduced pressure was subjected to ethylamine chromatography (hexane/ethyl acetate = 9/1 to ethyl acetate) to give the object as an oily substance (58 mg) ). This was dissolved in ethanol, and fumaric acid (16 mg) was added, followed by concentration under reduced pressure. The obtained solid was triturated with diisopropyl ether and filtered to give the title compound (60 mg). LC-MS: RT 2.5 min, m/z 426.6 (M + 1). Example 8 4{4-[2'-S. snail (cyclohexane-1,3'-indole)-indole (2, Η)-yl]piperidine 118 323406 201211028 -1-ylpiperidin-1-carboxylic acid ethyl ester

使用參考例18之化合物，依照與實施例9相同的方法 而得到標題化合物（58mg)。 LC-MS R.T. 3.4 min, m/z 440.5 (M+l). 實施例9 • 4{4-[2’ -側氧螺（四氫呋喃-4, 3’ -吲哚）-Γ (2’ Η)-基]哌啶 -l-基}哌啶-1-羧酸乙酯The title compound (58 mg) was obtained. LC-MS RT 3.4 min, m/z 440.5 (M+l). Example 9: 4{4-[2'-S. snail (tetrahydrofuran-4, 3'- 吲哚)- Γ (2' Η) -yl]piperidin-l-yl}piperidine-1-carboxylic acid ethyl ester

使用參考例20之化合物，依照與實施例9相同的方法 而得到標題化合物（105mg)。 LC-MS：R. T. 4. 2 rain., ra/z 442.5(M+1). 實施例10 4[4-[3, 3-二曱基-2-側氧基-2, 3-二氳-1H-吲哚-1-基]哌 啶-1-基]哌啶-1-羧酸甲酯The title compound (105 mg) was obtained. LC-MS: RT 4. 2 min., m/z 44. (M+l). Example 10 4[4-[3, 3-didecyl-2-yloxy-2, 3-diindole- Methyl 1H-indol-1-ylpiperidin-1-yl]piperidine-1-carboxylate

步驟1 將參考例6的化合物（244mg)、卜第三丁氧基羰基-4-旅咬酮（239mg)及乙酸（0. 5mL)溶解於甲醇（4. 5mL)後，於室 119 323406 201211028 溫加入2-甲基。比咬硼烧（i〇7mg)。以室溫徹夜搜拌後，進 行減壓濃縮。將殘渣進行矽膠管柱層析（氯仿至氯仿/曱醇 =9/1) ’付到為油狀物質（43〇mg)。 步驟2 將步驟1得到的化合物（210mg)於冰冷下溶解於4mol/ L·之鹽酸-二嗎燒溶液（5mL)後，進行授拌1小時。將反應 液減壓濃縮而得到油狀物質（l〇〇mg)。 步驟3 將步驟2得到的化合物（5〇mg)及三乙胺溶解於四氫呋 喃（5mL)後’於冰冷下滴下氯甲酸甲酯。升溫為室溫，徹夜 攪拌後加入水。以25%氨水溶液使pH為10。將經氣仿萃取 之有機層以飽和食鹽水洗淨後，以無水硫酸鈉水溶液進行 乾燥後，進行減壓濃縮。將所得之殘渣進行矽膠管柱層析 (氯仿至氣仿/曱醇=9/1 )，得到為油狀物質之目的物 (21mg)。 φ LC-MS：R.T. 0.7min, m/z 386.5(M+1). 實施例11 4-({3-[1-(乙氧基羰基）哌啶-4-吲哚]-6-氟-2-側氧基 -2, 3-二氫-1H-吲哚-l-基}哌啶-1-基）哌啶-1-羧酸乙酯Step 1 After dissolving the compound of Reference Example 6 (244 mg), butylbutoxycarbonyl-4-cingosterone (239 mg) and acetic acid (0.5 mL) in methanol (4.5 mL), in a chamber 119 323406 201211028 Add 2-methyl at room temperature. Boiled with boron (i〇7mg). After mixing at room temperature overnight, it was concentrated under reduced pressure. The residue was subjected to a gel column chromatography (chloroform to chloroform / decyl alcohol = 9 / 1) to afford an oily substance (43 〇mg). Step 2 The compound obtained in the step 1 (210 mg) was dissolved in 4 mol/L············ The reaction solution was concentrated under reduced pressure to give an oily material (1 mg). Step 3 After dissolving the compound obtained in Step 2 (5 mg) and triethylamine in tetrahydrofuran (5 mL), methyl chloroformate was dropped under ice cooling. The temperature was raised to room temperature, and water was added after stirring overnight. The pH was made 10 with a 25% aqueous ammonia solution. The organic layer obtained by the gas chromatography was washed with saturated brine, dried over anhydrous sodium sulfate aqueous solution, and concentrated under reduced pressure. The obtained residue was subjected to chromatography on silica gel column chromatography (chloroform tomethanol / decyl alcohol = 9/1) to afford the title compound (21 mg). φ LC-MS: RT 0.7 min, m/z 386.5 (M + 1). Example 11 4-({3-[1-(ethoxycarbonyl)piperidine-4-indole]-6-fluoro- Ethyl 2-oxo-2,3-dihydro-1H-indole-l-yl}piperidin-1-yl)piperidine-1-carboxylate

使用參考例25之化合物（436mg，2. 02mmol)，依照與實 120 323406 201211028 施例1相同的反應而得到標題化合物（37mg)。 !H-NMR (CDCh, 400MHz) ^ 1. 16-1. 31 (m, 6H), 1.62-1.74 (br, 2H), 1.82-1.91 (d, J=11.5Hz, 2H), 2.10-2.29 (br, 2H), 2.75-3.22 (m, 9H), 3. 35-3. 78 (m, 10H), 4.03-4.21 (m, 4H), 4.74-4.89 (br, 1H), 6.95-7.04 (m, 1H), 7.21-7.23 (m, 1H), 7.53(s, 1H). LC-MS ： R.T. 7.2 rain., m/z 565.2(M+Na). 實施例12 4 ({3 [1-(乙氧基幾基）娘咬基_4-基]-6-氟^ -2-側氧基 -2, 3-二氫-1H-吲哚-1-基}哌啶-1-基）哌啶-1-羧酸乙酯The title compound (37 mg) was obtained from m. m. !H-NMR (CDCh, 400MHz) ^ 1. 16-1. 31 (m, 6H), 1.62-1.74 (br, 2H), 1.82-1.91 (d, J=11.5Hz, 2H), 2.10-2.29 ( Br, 2H), 2.75-3.22 (m, 9H), 3. 35-3. 78 (m, 10H), 4.03-4.21 (m, 4H), 4.74-4.89 (br, 1H), 6.95-7.04 (m , 1H), 7.21-7.23 (m, 1H), 7.53 (s, 1H). LC-MS: RT 7.2 min., m/z 565.2 (M+Na). Example 12 4 ({3 [1-( Ethoxyl group) Nitrile _4-yl]-6-fluoro^-2-oxooxy-2,3-dihydro-1H-indol-1-yl}piperidin-1-yl)per Ethyl pyridine-1-carboxylate

將實施例11的化合物（18mg)溶解於乙醇（1.5ml)後， 加入10% Pd/C(l〇〇mg)後，於氫環境下攪拌5小時。以矽 藻土過濾反應液後，將經減壓濃縮之殘渣進行胺矽膠管柱 層析’得到為油狀物質之標題化合物（2mg)。 LC-MS：R.T. 7.1 rain., πι/ζ 567.2(M+Na). 實施例13 4-[4-（6-氟-3, 3-二甲基-2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌啶-1-基]哌啶—1—羧酸乙酯After dissolving the compound of Example 11 (18 mg) in ethanol (1.5 ml), 10% Pd/C (10 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 5 hours. After the reaction mixture was filtered through EtOAc (EtOAc)EtOAc. LC-MS: RT 7.1 min., πι / ζ 567.2 (M+Na). Example 13 4-[4-(6-fluoro-3, 3-dimethyl-2-oxooxy-2, 3- Ethyl dihydro-1H-indol-1-ylpiperidin-1-yl]piperidine-1carboxylate

F 121 323406 201211028 使用參考例27之化合物，依照與實施例1相同的方法 而得到標題化合物（25mg)。 'H-NMR (CDCls, 400MHz) (5 1. 21-1. 28 (t, J=7. 1Hz, 3H), 1.33 (s, 6H), 1.65-1.87 (m, 6H), 2.29-2.44 (m, 4H), 2.47-2.58 (m, 1H), 2.71-2.82 (m, 2H), 2.99-3.10 (m&gt; 2H)，4.09-4. 14 (q, J=7.1Hz，2H), 4. 17-4.32 (br, 3H)， 6.67-6.74 (td, J=9. 6, 2.1Hz, 1H), 6.91-6.94 J=9.6，2.2Hz，1H), 7.07-7.14(dd，J=8.3, 5.6Hz, 1H). LC-MS ： R. T. 6.7 min., m/z 418. 2(M+1). 實施例14 4~[4-(5-氟-3,3-二甲基-2-側氧基-2,3-二氫-111-吲哚、1、 基）哌啶-卜基]哌啶-1-羧酸乙酯F 121 323406 201211028 The title compound (25 mg) was obtained. 'H-NMR (CDCls, 400MHz) (5 1. 21-1. 28 (t, J=7. 1Hz, 3H), 1.33 (s, 6H), 1.65-1.87 (m, 6H), 2.29-2.44 ( m, 4H), 2.47-2.58 (m, 1H), 2.71-2.82 (m, 2H), 2.99-3.10 (m&gt; 2H), 4.09-4. 14 (q, J=7.1Hz, 2H), 4. 17-4.32 (br, 3H), 6.67-6.74 (td, J=9. 6, 2.1Hz, 1H), 6.91-6.94 J=9.6, 2.2Hz, 1H), 7.07-7.14 (dd, J=8.3, 5.6 Hz, 1H). LC-MS: RT 6.7 min., m/z 418. 2 (M+1). Example 14 4~[4-(5-fluoro-3,3-dimethyl-2- Ethyloxy-2,3-dihydro-111-indole, 1, yl) piperidine-diyl] piperidine-1-carboxylic acid ethyl ester

使用參考例35之化合物，依照與實施例1相同的方法 而得到標題化合物（40mg)。 'H-NMR (CDCh, 400MHz) (5 1.20-1.25 (t, J=7. 1Hz, 3H)&gt; 1.33 (s，6H)，1.6卜 1.79 (br，2H)，1.80-1·91 (br，2H)， 2.19-2.42 (br, 2H), 2.71-2.87 (br, 2H), 2. 88-3. 〇〇 (br&gt; 2H)，3.21-3.41 (br, 3H), 3.52-3.62 (br, 2H), 4.〇8、 4. 13 (q, J=7. 1Hz, 2H), 4. 24-4. 45 (br, 2H), 4. 62-4. 73 (br, 1H)，6.88-6.92. (dd，J=7.8，2.4Hz, 1H), 6.99、 122 323406 201211028 7.05 (br, 1H), 7.77-7.83 (br, 1H). LC-MS：R. T. 6. 8 min. , m/z 418. 2(M+1). 實施例15 4-[4-(2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌啶-1-基]氮 雜環庚烷-1-羧酸乙酯The title compound (40 mg) was obtained. 'H-NMR (CDCh, 400MHz) (5 1.20-1.25 (t, J=7. 1Hz, 3H)&gt; 1.33 (s, 6H), 1.6, 1.79 (br, 2H), 1.80-1·91 (br , 2H), 2.19-2.42 (br, 2H), 2.71-2.87 (br, 2H), 2. 88-3. 〇〇 (br &gt; 2H), 3.21-3.41 (br, 3H), 3.52-3.62 (br , 2H), 4.〇8, 4. 13 (q, J=7. 1Hz, 2H), 4. 24-4. 45 (br, 2H), 4. 62-4. 73 (br, 1H), 6.88-6.92. (dd, J=7.8, 2.4 Hz, 1H), 6.99, 122 323406 201211028 7.05 (br, 1H), 7.77-7.83 (br, 1H). LC-MS: RT 6. 8 min. , m /z 418. 2(M+1). Example 15 4-[4-(2-Sideoxy-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]nitrogen Heterocyclic heptane-1-carboxylic acid ethyl ester

將參考例3的化合物（200mg)溶解於曱醇（9mL)後，於 室溫加入卜乙氧基羰基氮雜環庚烷-4-酮（154mg)、四異丙 氧化鈦（392mg)、乙酸（66mg)。擾拌10分鐘後加入三乙酿 氧基硼氫化鈉（234mg)，加熱攪拌2小時。冷卻至室溫後， 加入25%氨水溶液使pH為10。以矽藻土過濾並進行分液 後，以氣仿萃取水層。將有機層合併，以飽和食鹽水洗淨。 以無水硫酸鈉水溶液進行乾燥後，將減壓濃縮所得之殘渣 進行胺矽膠管柱層析（己烷/乙酸乙酯=9/1至乙酸乙酯）， 得到為油狀物質之目的物（152mg)。使溶於乙醇，加入延胡 索酸（45mg)後進行減壓濃縮。將所得到的固體以二乙基醚 進行研製後濾除，得到標題化合物之延胡索酸鹽（194mg)。 ^-NMR (DMSO-de, 400MHz) (5 1. 14-1. 19 (td, J=7. 1, 3. 4Hz, 3H), 1.37-1.52 (br, 2H), 1.56-1.68 (br, 3H), 1.74-1.99 (m, 3H), 2.30-2.42 (br, 2H), 2.43-2.58 (in, 2H), 2.63-2.72 (br, 1H), 2. 91-3. 01 (br, 2H), 3.18-3.29 (br, 2H), 3.33-3.53 (m, 4H), 3.98-4.07 (q, J=7. 1Hz, 2H), 123 323406 201211028 4. 10-4.22 (br，1H)，6.58 (s，2H，fumaric acid (延相 索酸）），6.93-7.00 (t，J=7.3Hz，1H)，7.12-7.25 (IQ， 3H). LC-MS：R. T. 6.0 min., m/z 386. 3(M+1). 實施例16 1-乙基硫基羰基-4[4-(2-侧氧基-2, 3-二氳-1H-吲哚~1、基） π底β定_ 1_基]娘咬 〇After dissolving the compound of Reference Example 3 (200 mg) in methanol (9 mL), ethoxyethoxycarbonyl azepan-4-one (154 mg), titanium tetraisopropoxide (392 mg), acetic acid were added at room temperature. (66 mg). After stirring for 10 minutes, sodium triethyloxyborohydride (234 mg) was added, and the mixture was stirred under heating for 2 hours. After cooling to room temperature, a 25% aqueous ammonia solution was added to bring the pH to 10. After filtering with diatomaceous earth and liquid separation, the aqueous layer was extracted with a gas pattern. The organic layers were combined and washed with saturated brine. After drying over anhydrous sodium sulfate aqueous solution, the residue obtained by concentration under reduced pressure was subjected to ethylamine chromatography (hexane/ethyl acetate=9/1 to ethyl acetate) to give the object of oily substance (152 mg) ). This was dissolved in ethanol, and fumaric acid (45 mg) was added, followed by concentration under reduced pressure. The obtained solid was triturated with diethyl ether and filtered to give the title compound ( 194 mg). ^-NMR (DMSO-de, 400MHz) (5 1. 14-1. 19 (td, J=7. 1, 3. 4Hz, 3H), 1.37-1.52 (br, 2H), 1.56-1.68 (br, 3H), 1.74-1.99 (m, 3H), 2.30-2.42 (br, 2H), 2.43-2.58 (in, 2H), 2.63-2.72 (br, 1H), 2. 91-3. 01 (br, 2H ), 3.18-3.29 (br, 2H), 3.33-3.53 (m, 4H), 3.98-4.07 (q, J=7. 1Hz, 2H), 123 323406 201211028 4. 10-4.22 (br,1H), 6.58 (s, 2H, fumaric acid), 6.93-7.00 (t, J = 7.3 Hz, 1H), 7.12-7.25 (IQ, 3H). LC-MS: RT 6.0 min., m/z 386. 3(M+1). Example 16 1-Ethylthiocarbonyl-4[4-(2-trioxy-2,3-dioxan-1H-indole-1, yl) π-bottom β定_1_基] Niang Bite

步驟1 將參考例3的化合物（2. 9g，13mmol)、1-第三丁氧基 幾基-4-〇底》定酮（2.7gm, 13ramol)、乙酸（3.1ml，54mm〇l) 及四異丙氧化欽（20ml, 67mmol)溶解於二氯甲烧（5〇ml) 後，於室溫逐次少量加入三乙醯氧基硼氫化鈉（5. 7g， 籲 27mmol)。以5(TC攪拌4小時後，加入25%氨水溶液，以石夕 藻土過濾後，以乙酸乙酯進行萃取。以水及飽和食鹽水進 行洗淨後’以無水硫酸鈉乾燥，進行減壓濃縮。將殘渣進 行胺矽膠管柱層析（己烷/乙酸乙酯=1〇/〇至〇/1〇)，得到目 的物（3. 4g，64%)。 步驟2 將步驟1得到的化合物（3.4g，86mmol)溶解於4mol/L 之鹽酸-二卩萼烷溶液（llnil)後，於室溫進行徹夜攪拌。將反 323406 124 201211028 應液進行減壓濃縮而得到目的物，直接將粗生成物用於步 驟3。 步驟3 使步驟2得到的化合物（50mg，0.13mmol)懸浮於二氣 甲烧（1.51111)中，加入〇比唆（0.0541111，0.67111111〇1)後，逐次 少量加入乙基硫隸氣（0.021ml, 0. 20mmol)。於室溫徹夜擾 拌後，加入氯仿，並以水洗淨。將有機層進行減壓濃縮， 將所得之殘渣進行逆相高效能液體管柱層析（0. 035%三氟 ® 乙酸-乙腈/0. 05%三氣乙酸-水=1%至95%)，得到為油狀物 質之目的物（6. lmg)。 LC-MS：R. T. 2.8min, m/z 388.5(M+1). 實施例17 4-[4-(2-側氧基-2, 3-二氮-1Η-Π引D朵-1 -基）旅唆_1_基]0底 啶-1-羧酸2-氟乙酯Step 1 The compound of Reference Example 3 (2.9 g, 13 mmol), 1-t-butoxy-based ketone ketone (2.7 gm, 13 ramol), acetic acid (3.1 ml, 54 mm 〇l) and After the tetraisopropoxy oxime (20 ml, 67 mmol) was dissolved in dichloromethane (5 mL), sodium triethyl sulfoxyborohydride (5.7 g, 27 mmol) was added in small portions at room temperature. After stirring for 5 hours, the mixture was stirred for 5 hours, and then added with a 25% aqueous ammonia solution, filtered through celite, and extracted with ethyl acetate. After washing with water and saturated brine, dried over anhydrous sodium sulfate and then evaporated. Concentration. The residue was subjected to an amine hydrazine column chromatography (hexane / ethyl acetate = 1 / / / / / / / / / / / (3.4 g, 86 mmol) was dissolved in 4 mol/L hydrochloric acid-dioxane solution (llnil), and stirred overnight at room temperature. The anti-323406 124 201211028 solution was concentrated under reduced pressure to obtain the desired product. The product was used in the step 3. Step 3 The compound obtained in the step 2 (50 mg, 0.13 mmol) was suspended in a methane (1.51111), and after the addition of hydrazine (0.0541111, 0.67111111〇1), a small amount of ethyl was added in small portions. Sulphur gas (0.021 ml, 0.20 mmol). After stirring overnight at room temperature, chloroform was added and washed with water. The organic layer was concentrated under reduced pressure, and the residue was subjected to reverse phase high performance liquid column layer. Analysis (0. 035% trifluoro-acetic acid-acetonitrile / 0. 05% tri-acetic acid - water = 1% to 95%), obtained For the object of the oily substance (6. lmg). LC-MS: RT 2.8 min, m/z 388.5 (M + 1). Example 17 4-[4-(2-s. Diazo-1Η-Π引D朵-1 -yl) Tourism _1_基]0 base pyridine-1-carboxylic acid 2-fluoroethyl ester

使用參考例3之化合物，並使用氯曱酸2-氟甲酯以取 代乙基硫羰氯，依照與實施例16相同的方法而得到標題化 合物（17mg)。 LC-MS · R. T. 2. 6min., m/z 390.5(M+1). 實施例18 4_[4-(2-側氧基-2，3-二氮-111_11引π朵_1_基）旅咬_1_基]派 125 323406 201211028 啶-1-羧酸2-丙烯酯The title compound (17 mg) was obtained according to the procedure of the the the the LC-MS · RT 2. 6 min., m/z 390.5 (M + 1). Example 18 4_[4-(2- </ RTI> </ RTI> </ RTI> <RTIgt; Travel bite_1_基]派125 323406 201211028 pyridine-1-carboxylic acid 2-propenyl ester

將參考例3的化合物（50mg，0.23mmol)、1-烯丙氧基 幾基-4-派咬酮（0.042gm，0.23mmol)、乙酸（0.()53ml， 0. 93mmol)及四異丙氧化鈦（0. 34ml，1. 2mmol)溶解於二氯 φ 曱烷（2ml)後，於室溫逐次少量加入三乙醯氧基硼氫化鈉 (98mg，0. 46mmol)。以50°C擾拌5小時後，加入28%氨水 溶液、氯仿，以矽藻土過濾後，去除水層。以水進行洗淨 後，進行減壓濃縮。將殘渣進行逆相高效能液體管柱層析 (0. 035%三氟乙酸-乙腈/0. 05%三氟乙酸-水=1%至95%)，得 到為油狀物質之目的物（17mg，19%)。 LC-MS：R. T. 2.8 rain, ra/z 384. 5(M+1). 實施例19 4-[4-(2-側氧基-2，3-二氫-111-11引11朵-1-基）51底咬-1-基]旅 啶-1-羧酸2-曱氧乙酯The compound of Reference Example 3 (50 mg, 0.23 mmol), 1-allyloxymethyl-4-ketone (0.042 gm, 0.23 mmol), acetic acid (0. () 53 ml, 0.93 mmol), and four different After dissolving the titanium oxychloride (0.34 ml, 1.2 mmol) in dichlorocyclodecane (2 ml), sodium triethyloxyborohydride (98 mg, 0.446 mmol) was added in small portions at room temperature. After 5 hours of soaking at 50 ° C, 28% aqueous ammonia solution and chloroform were added, and the mixture was filtered through diatomaceous earth to remove the aqueous layer. After washing with water, it was concentrated under reduced pressure. The residue was subjected to reverse phase high performance liquid column chromatography (0. 035% trifluoroacetic acid-acetonitrile/0. 05% trifluoroacetic acid-water = 1% to 95%) to obtain the object of oily substance (17 mg). , 19%). LC-MS: RT 2.8 min, m/z 384. 5 (M +1). Example 19 4-[4-(2- </RTI> </ RTI> </ RTI> - base) 51 bottom bite-1-yl] bridone-1-carboxylic acid 2-oxime ethyl ester

使用參考例3之化合物，並使用氯曱酸2-甲氧乙酯以 取代乙基硫羰氯，依照與實施例16相同的方法而得到標題 化合物（3. 8mg)。 126 323406 201211028 LC-MS:R. T. 2.5min.，m/z 402. 6(M+1). 實施例20 1-甲基硫基幾基-4-[4-(2-侧氧基-2, 3-二氫-iH-i B朵-1_ 基）哌啶-1-基]哌啶The title compound (3.8 mg) was obtained from the title compound. 126 323406 201211028 LC-MS: RT 2.5 min., m/z 402. 6 (M + 1). Example 20 1-methylthio-l-yl-4-[4-(2- </RTI> 3-dihydro-iH-i B-to-1-1-ylpiperidin-1-yl]piperidine

使用參考例3之化合物，並使用曱基硫羰氣以取代乙 基硫幾氣，依照與實施例16相同的方法而得到標題化合物 (19mg)。 LC-MS：R.T. 2. 6rain, m/z 374. 5(M+1). 實施例21 4-[4-(2-侧氧基-2, 3-二氫-111-°引n朵-1-基）u辰e定-i-基]b底 啶-1-羧酸丙酯The title compound (19 mg) was obtained. LC-MS: RT 2. 6 min, m/z 374. 5 (M +1). Example 21 4-[4-(2- </ RTI> </ RTI> </ RTI> 1-yl)uchene-i-yl]b- pyridine-1-carboxylate

使用參考例3之化合物，並使用氣甲酸丙酯以取代乙 基硫羰氯，依照與實施例16相同的方法而得到標題化合物 (15mg)。 LC-MS：R. T. 2.8min., m/z 386.6(M+1). 實施例22 4_[4-(5-|L_2-側氧基-2, 3 -二氫-1Η-α引 α朵-1-基）痕咬-i- 127 323406 201211028 基]氮雜環庚烷-1-羧酸乙酯The title compound (15 mg) was obtained from the title compound (m. LC-MS: RT 2.8 min., m/z 38 </RTI> (M +1). Example 22 4 _[4-(5-|L_2- </ RTI> </ RTI> </ RTI> 1-base) bite-i- 127 323406 201211028 base] azepane-1-carboxylic acid ethyl ester

使用參考例34之化合物，依照與實施例15相同的方 法而得到標題化合物之延胡索酸鹽（86mg)。 ^-NMR (DMSO-de, 400MHz) (5 1. 12-1. 20 (td, J=7. 1, 3. 4Hz, φ 3H), 1.38-1.51 (m, 2H), 1.58-1.69 (m, 3H), 1.78-2.01 (m, 3H), 2.32-2.44 (m, 2H), 2.50-2.62 (m, 2H), 2.70-2.78(br, 1H), 2. 95-3. 04 (br, 2H), 3. 18-3. 30 (br, 2H), 3.39-3.50 (m, 2H), 3. 55 (s, 2H), 4. 00-4. 09 (q, J=7. 1Hz, 2H), 4.13-4.23 (br, 1H), 7.11-7.20 (m, 2H). LC-MS：R. T. 6.1 rain., m/z 404. 2(M+1). 實施例23 4-[4-(3, 3-二曱基-2-側氧基-2, 3-二氫-5-氟-1H-吲哚-1-φ 基）派咬-1-基]氣雜環庚烧_1-緩酸乙酉旨The title compound of the fumarate (86 mg) was obtained in the same manner as in Example 15 using the title compound. ^-NMR (DMSO-de, 400MHz) (5 1. 12-1. 20 (td, J=7. 1, 3. 4Hz, φ 3H), 1.38-1.51 (m, 2H), 1.58-1.69 (m , 3H), 1.78-2.01 (m, 3H), 2.32-2.44 (m, 2H), 2.50-2.62 (m, 2H), 2.70-2.78 (br, 1H), 2. 95-3. 04 (br, 2H), 3. 18-3. 30 (br, 2H), 3.39-3.50 (m, 2H), 3. 55 (s, 2H), 4. 00-4. 09 (q, J=7. 1Hz, 2H), 4.13-4.23 (br, 1H), 7.11-7.20 (m, 2H). LC-MS: RT 6.1 min., m/z 404. 2 (M+1). Example 23 4-[4- (3, 3-dimercapto-2-yloxy-2,3-dihydro-5-fluoro-1H-indol-1-yl) ketone-1-yl] heterocycloheptane _1 - Slow acid

使用參考例35之化合物，依照與實施例15相同的方 法而得到標題化合物之延胡索酸鹽（156rag)。 !H-NMR (DMSO-de, 400MHz)5 1. 13-1. 19 (td, J=7. 1, 3. 2Hz, 3H), 1.24 (s, 6H), 1.37-1.51 (br, 2H), 1.57-1.68 (d, 128 323406 201211028 J=ll.〇Hz，3H)，1.76-2. 00 (m，3H)，2.29-2.41 (br，2H)， 2.50-2.60 (m, 2H), 2.68-2.75 (br, 1H), 2.94-3.03 (m, 2H), 3.18-3.29 (br, 2H), 3.40-3.52 (s, 2H), 4. 〇〇_4. 〇7 Cq» J=7. 1Hz, 2H), 4.11-4.22 (br, 1H), 6.58 (s, 2H, fumaric acid), 7.00-8.3, 2. 7Hz. 1H). LC-MS：R.T. 6. 9 min., m/z 432. 2(M+1). 實施例24 4-[4-(3,3-二曱基-2-硫酮基-2,3-二氫-111-°弓卜朵〜1_基）11底 啶-1-基]哌啶-1-羧酸乙酯Using the compound of Reference Example 35, the title compound of the fumarate (156rag) was obtained in the same manner as in Example 15. !H-NMR (DMSO-de, 400MHz) 5 1. 13-1. 19 (td, J=7. 1, 3. 2Hz, 3H), 1.24 (s, 6H), 1.37-1.51 (br, 2H) , 1.57-1.68 (d, 128 323406 201211028 J=ll.〇Hz, 3H), 1.76-2. 00 (m, 3H), 2.29-2.41 (br, 2H), 2.50-2.60 (m, 2H), 2.68 -2.75 (br, 1H), 2.94-3.03 (m, 2H), 3.18-3.29 (br, 2H), 3.40-3.52 (s, 2H), 4. 〇〇_4. 〇7 Cq» J=7. 1Hz, 2H), 4.11-4.22 (br, 1H), 6.58 (s, 2H, fumaric acid), 7.00-8.3, 2. 7Hz. 1H). LC-MS: RT 6. 9 min., m/z 432 2(M+1). Example 24 4-[4-(3,3-Dimercapto-2-thioketo-2,3-dihydro-111-°bendo~1_yl) 11 Ethylpyridin-1-yl]piperidine-1-carboxylic acid ethyl ester

使用參考例36之化合物，依照與實施例1相同的方法 而得到標題化合物（lmg)。 LC-MS ： R. T. 7. 12 min., m/z 416. 3(M+1). 實施例25 4~[4-(5-曱基-2-侧氧基-2, 3-二氫- 弓卜朵~1-基）派唆 ~l-基]哌啶-1-羧酸乙酯 Μβ^ 使用參考例37之化合物，依照與實施例1相同的方法 而得到標題化合物（149mg)。 'H-NMR (DMSO-d6, 400MHz)(5 1.12-1.21 (t, J=7.1Hz, 3H), 129 323406 201211028 1.21-1.38 (m, 2H), 1.54-1.51 (s, 2H), 1.68-1.77 (d, J=11.2Hz, 2H), 2.21-2.32 (m, 2H), 2.43-2.54 (m, 5H), 2.64-2.83 (br, 2H), 2.89-3.00 (d, J=6. 4Hz, 2H), 3.32 (s, 1H), 3.46 (s, 2H), 3.95-4.10 (m, 5H), 6.97-7.10 (m, 3H). LC-MS:R.T. 6.2 min.，m/z 386. 2(M+1). 實施例26 4-[4-(5-曱氧基-2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌啶 —1-基]哌啶-1-羧酸乙酯Using the compound of Reference Example 36, the title compound (1 mg) was obtained. LC-MS: RT 7. 12 min., m/z 416. 3 (M +1). Example 25 4~[4-(5-decyl-2-yloxy-2, 3-dihydro- The title compound (149 mg) was obtained according to the same procedure as in Example 1 to the title compound (149 mg). 'H-NMR (DMSO-d6, 400MHz) (5 1.12-1.21 (t, J=7.1Hz, 3H), 129 323406 201211028 1.21-1.38 (m, 2H), 1.54-1.51 (s, 2H), 1.68- 1.77 (d, J=11.2Hz, 2H), 2.21-2.32 (m, 2H), 2.43-2.54 (m, 5H), 2.64-2.83 (br, 2H), 2.89-3.00 (d, J=6. 4Hz , 2H), 3.32 (s, 1H), 3.46 (s, 2H), 3.95-4.10 (m, 5H), 6.97-7.10 (m, 3H). LC-MS: RT 6.2 min., m/z 386. 2(M+1). Example 26 4-[4-(5-Methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl)piperidine-1-yl Piperidine-1-carboxylic acid ethyl ester

使用參考例38之化合物，依照與實施例1相同的方法 而得到標題化合物之延胡索酸鹽（160mg)。 ^-NMR (DMSO-de, 400MHz) 5 1. 12-1. 20 (td, J=7. 1, 2. 2Hz, 3H), 1, 31-1, 43 (m, 2H), 1.56-1.62 (m, 2H), 1.75-1.84 (d, J=11.4Hz, 2H), 2.30-2.63 (m, 4H), 2.64-2.82 (m, 3H), 3. 02-3. 11 (d, J=10.7Hz, 2H), 3. 49 (s, 2H), 3. 69 (s, 3H), 3. 96-4. 08 (q, J=7. 1Hz, 4H), 4.09-4.21 (m, 1H), 6. 59 (s, 2H, fumaric acid), 6.75-6.80 (d, J=8. 1Hz, 1H). LC-MS：R. T. 5. 7min., m/z 402.2(M+1). 實施例27 4~[4-(5-曱氧基-2-側氧基-2, 3-二氫-1H-吲哚-1-基）派咬 130 323406 201211028 -1-基]氮雜環庚烷-1-羧酸乙酯The title compound of the fumarate (160 mg) was obtained by the same procedure as in Example 1 using the title compound. ^-NMR (DMSO-de, 400MHz) 5 1. 12-1. 20 (td, J=7. 1, 2. 2Hz, 3H), 1, 31-1, 43 (m, 2H), 1.56-1.62 (m, 2H), 1.75-1.84 (d, J=11.4Hz, 2H), 2.30-2.63 (m, 4H), 2.64-2.82 (m, 3H), 3. 02-3. 11 (d, J= 10.7Hz, 2H), 3. 49 (s, 2H), 3. 69 (s, 3H), 3. 96-4. 08 (q, J=7. 1Hz, 4H), 4.09-4.21 (m, 1H ), 6. 59 (s, 2H, fumaric acid), 6.75-6.80 (d, J=8.11Hz, 1H). LC-MS: RT 5. 7min., m/z 402.2(M+1). Example 27 4~[4-(5-decyloxy-2-oxo-2,3-dihydro-1H-indol-1-yl)-doping 130 323406 201211028 -1-yl]azepane Ethyl-1-carboxylic acid ethyl ester

使用參考例38之化合物，依照與實施例15相同的方 法而得到標題化合物之延胡索酸鹽（131mg)。 !H-NMR (DMSO-de, 400MHz) (5 1. 13-1.20 (td, J=7. 1, 3. 4Hz, φ 3H), 1.39-1.50 (m, 2H), 1.52-1.70 (m, 3H), 1.73-1.88 (m, 1H), 1.89-2.03 (m, 2H), 2.31-2.42 (m, 2H), 2.55-2.69 (in, 2H), 2.71-2.80 (in, 1H), 2.96-3.05 (m, 2H), 3.17-3.30 (br, 2H), 3.39-3.52 (m, 4H), 3.69 (s, 3H), 4.00-4.06 (q, J=7. 1Hz, 2H), 4.16-4.27 (m, 1H), 6.58 (s, 2H, fumaric acid), 6.73-6.78 (d, J=8. 1Hz. 1H) 6.90 (s, 1H), 7.08-7.12 (d, J=8. 1Hz, 1H). LC-MS:R.T. 5.9 min.，m/z 438.2(M+Na). _實施例28 4-[4-(5-氯-2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌咬 基]哌啶-1-羧酸乙酯The title compound of the fumarate (131 mg) was obtained in the same manner as in Example 15 using the title compound. !H-NMR (DMSO-de, 400MHz) (5 1. 13-1.20 (td, J=7. 1, 3. 4Hz, φ 3H), 1.39-1.50 (m, 2H), 1.52-1.70 (m, 3H), 1.73-1.88 (m, 1H), 1.89-2.03 (m, 2H), 2.31-2.42 (m, 2H), 2.55-2.69 (in, 2H), 2.71-2.80 (in, 1H), 2.96- 3.05 (m, 2H), 3.17-3.30 (br, 2H), 3.39-3.52 (m, 4H), 3.69 (s, 3H), 4.00-4.06 (q, J=7. 1Hz, 2H), 4.16-4.27 (m, 1H), 6.58 (s, 2H, fumaric acid), 6.73-6.78 (d, J=8. 1Hz. 1H) 6.90 (s, 1H), 7.08-7.12 (d, J=8. 1Hz, 1H LC-MS: RT 5.9 min., m/z 438.2 (M+Na). </RTI> Example 28 4-[4-(5-chloro-2- </RTI>吲哚-1-yl) piperidine] piperidine-1-carboxylic acid ethyl ester

而得到為延胡索酸鹽之標題化合物（73mg)。 使用參考例32之化合物，依照與實施例1相同的方去 323406 131 201211028 !H-NMR (CDC13, 400MHz) 5 1.22-1.29 (t, J=7.1Hz, 3H), 1.65-1.77 (m, 2H), 1.90-1.98 (d, J=12. 0Hz, 2H), 2.13-2.28 (br, 2H), 2.76-2.90 (br, 2H), 2.93-3.08 (br, 2H), 3.09-3.21 (m, 2H), 3.38-3.48 (m, 1H), 3.56 (s, 2H), 3.61-3.70 (d, J=10.5Hz, 2H), 4. 10-4. 18 (q, J=7.1Hz, 2H), 4. 30-4.45 (br, 2H), 4. 69-4. 81 (m, 1H), 7. 20-7. 25 (m, 1H), 7.26-7.32 (d, J=8. 3Hz, 1H), 7. 54-7. 58 (d, J=8. 3Hz, 1H). LC-MS : R. T. 6. 6 min.，m/z 406. 1(M+1). 實施例29 4-[4-(5-氟-2-侧氧基-2,3-二氫-1H-吲哚-1-基）哌啶一1 一 基]哌啶-1-羧酸乙酯The title compound (73 mg) was obtained as the fumarate. Using the compound of Reference Example 32, in the same manner as in Example 1, 323406 131 201211028 !H-NMR (CDC13, 400 MHz) 5 1.22-1.29 (t, J = 7.1 Hz, 3H), 1.65-1.77 (m, 2H) ), 1.90-1.98 (d, J=12. 0Hz, 2H), 2.13-2.28 (br, 2H), 2.76-2.90 (br, 2H), 2.93-3.08 (br, 2H), 3.09-3.21 (m, 2H), 3.38-3.48 (m, 1H), 3.56 (s, 2H), 3.61-3.70 (d, J=10.5Hz, 2H), 4. 10-4. 18 (q, J=7.1Hz, 2H) , 4. 30-4.45 (br, 2H), 4. 69-4. 81 (m, 1H), 7. 20-7. 25 (m, 1H), 7.26-7.32 (d, J=8. 3Hz, 1H), 7. 54-7. 58 (d, J=8. 3Hz, 1H). LC-MS: RT 6. 6 min., m/z 406. 1 (M+1). Example 29 4- [4-(5-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl)piperidine-1-yl]piperidine-1-carboxylic acid ethyl ester

使用參考例34之化合物，依照與實施例1相同的方法 ^ 而得到標題化合物（12mg)。 'H-NMR (CDCh, 400MHz) 5 1.23-1.31 (t, J=7. 1Hz, 3H), 1.63-1.76 (in, 2H), 1.88-1.99 (d, J=12.2Hz, 2H), 2.15-2.31 (br, 2H), 2.75-2.91 (br, 2H), 2.91-3.09 (br, 2H), 3.11-3.28 (m, 2H), 3.31-3.43 (m, 1H), 3.56 (s, 2H), 3.60-3.69 (d, J=11.5Hz, 2H), 4.11-4.18 (q, J=7. 1Hz, 2H), 4.27-4.50 (br, 2H), 4.71-4.82 (br, 1H), 6.93-7.09 (m, 2H), 7.63-7.09 (m, 2H), 7.63-7.69 (m, 1H). LC-MS ：R.T. 5. 9 min., m/z 390. 1(M+1). 132 323406 201211028 實施例30 4-{4-[3, 3-雙（3-曱氧基丙基）-2-側氧基-2, 3-二氫引 嗓-1-基]娘唆-l-基}氮雜環庚烧-1-緩酸乙酯The title compound (12 mg) was obtained from m. 'H-NMR (CDCh, 400MHz) 5 1.23-1.31 (t, J=7. 1Hz, 3H), 1.63-1.76 (in, 2H), 1.88-1.99 (d, J=12.2Hz, 2H), 2.15- 2.31 (br, 2H), 2.75-2.91 (br, 2H), 2.91-3.09 (br, 2H), 3.11-3.28 (m, 2H), 3.31-3.43 (m, 1H), 3.56 (s, 2H), 3.60-3.69 (d, J=11.5Hz, 2H), 4.11-4.18 (q, J=7.11Hz, 2H), 4.27-4.50 (br, 2H), 4.71-4.82 (br, 1H), 6.93-7.09 (m, 2H), 7.63-7.09 (m, 2H), 7.63-7.69 (m, 1H). LC-MS: RT 5. 9 min., m/z 390. 1(M+1). 132 323406 201211028 Example 30 4-{4-[3,3-bis(3-decyloxypropyl)-2-yloxy-2,3-dihydroindol-1-yl]Nanthene-l-yl} Azacycloheptane-1-acid acid ethyl ester

使用實施例15之化合物，並使用1-峨-3-甲氧基丙产 以取代1，3-二溴丙烷，依照與實施例6步驟2相同的方法 而得到標題化合物。 LC-MS:R. T. 1.2min.，m/z 530.1(M+l).條件 c 實施例31 4-{4-[5-氟-3,3-雙（羥基曱基）-2-側氧基-2,3-二氫-111一 Π引哚-1-基]派α定-1—基丨痕嘴_1_叛酸乙酯Using the compound of Example 15 and substituting 1-indole-3-methoxypropane to give 1,3-dibromopropane, the title compound was obtained in the same manner as in Step 2 of Example 6. LC-MS: RT 1.2 min., m/z </RTI> </RTI> </RTI> <RTIgt; </RTI> <RTIgt; -2,3-dihydro-111-indole-1-yl]pyridine-1-based scar _1_oleic acid ethyl ester

使用實施例29之化合物，並使用聚曱醛 (Paraformaldehyde)以取代1，3-二溴丙烷，依照與實施例 6步驟2相同的方法而得到標題化合物。 'H-NMR (CDCh, 400MHz)5 7. 17 (m, 2H), 6.99 (m, 1H), 4· 16 (m, 2H), 3. 95 (m, 4H), 3. 10 (m, 3H), 2. 75 (m, 2H), 2-51-2.39 (m, 5H), 1.82 (m, 2H), 1.71 (m, 2H), 1.63 (m, 2H), 1.44 (m, 2H), 1.26 (t, 3H).The title compound was obtained in the same manner as in the step 2 of Example 6 using the compound of Example 29 and using </ RTI> </ RTI> 'H-NMR (CDCh, 400MHz) 5 7. 17 (m, 2H), 6.99 (m, 1H), 4· 16 (m, 2H), 3. 95 (m, 4H), 3. 10 (m, 3H), 2. 75 (m, 2H), 2-51-2.39 (m, 5H), 1.82 (m, 2H), 1.71 (m, 2H), 1.63 (m, 2H), 1.44 (m, 2H) , 1.26 (t, 3H).

LC-MS:R.T. 6. 2min.，m/z 450. 1 條件 A 133 323406 201211028 參考例39至45 使用對應之可取得的原料，依照與參考例28至31相 同的方法而得到下述化合物。 [表ljLC-MS: R.T. 6. 2 min., m/z 451. 1 </ RTI> A 133 323406 201211028 Reference Examples 39 to 45 The following compounds were obtained in the same manner as in Reference Examples 28 to 31 using the corresponding materials. [Table lj

134 323406 201211028 參考例46至51 使用參考例39至41、43至45之化合物，依照與參考 例4相同的方法而得到下述化合物。 [表2]134 323406 201211028 Reference Examples 46 to 51 Using the compounds of Reference Examples 39 to 41 and 43 to 45, the following compounds were obtained in the same manner as in Reference Example 4. [Table 2]

135 323406 201211028 參考例52至61 使用參考例31、33、37、39或40之化合物，依照與 參考例13、參考例20或參考例35相同的方法而得到下述 化合物。135 323406 201211028 Reference Examples 52 to 61 Using the compounds of Reference Example 31, 33, 37, 39 or 40, the following compounds were obtained in the same manner as in Reference Example 13, Reference Example 20 or Reference Example 35.

136 323406 201211028 [表3] 參考例 所使用之合成法 構造 52 參考例20 / 53 參考例13 F 54 參考例13 c\ 55 參考例20 P 56 參考例13 9 57 參考例20 C^^N'H Μθ 58 參考例13 Me 59 參考例35 Me 60 參考例20 C^&gt;H OMe 61 參考例35 ci^'f 137 323406 201211028 5-氟-3, 3-二甲基-1-(旅咬-4-基）1，3-二氫-211-吲°朵-2-硫 酮136 323406 201211028 [Table 3] Synthetic construction used in the reference example 52 Reference example 20 / 53 Reference example 13 F 54 Reference example 13 c\ 55 Reference example 20 P 56 Reference example 13 9 57 Reference example 20 C^^N' H Μ θ 58 Reference Example 13 Me 59 Reference Example 35 Me 60 Reference Example 20 C^&gt;H OMe 61 Reference Example 35 ci^'f 137 323406 201211028 5-Fluoro-3, 3-dimethyl-1-(Break bite -4-yl)1,3-dihydro-211-吲°-2-thione

毛〇H / 使用參考例35之化合物，依照與參考例36相同的方 法而得到標題化合物。 參考例62The title compound was obtained by the same method as the reference compound 36. Reference example 62

2-（2-胺基-4-曱氧基苯基）-1,3-丙二酸二第三丁酉旨2-(2-Amino-4-methoxyphenyl)-1,3-propanedioic acid

iBu 〇2汨U Λ： 使用2-氯-5-曱氧基硝苯以取代4-氣-2-氟硝苯，依照 與實參考例28及參考例29相同的方法而得到標題化合物。 參考例63 2_(2~{[1-(第三丁氧基幾基）π底咬_4-基]胺基卜4_曱氧基iBu 〇2汨U Λ: The title compound was obtained by the same method as the referenced Example 28 and Reference Example 29, using 2-chloro-5-decyloxybenzene. Reference Example 63 2_(2~{[1-(Tertidinoxy)) π bottom _4-yl]aminodi-4-yloxy

使用參考例62之化合物，依照與參考例3〇相同的方 法而得到標題化合物。 參考例64 2-(2-{ [ 1-(第三丁氧基叛基&gt;辰咬基_4_基]胺基卜曱氧 323406 138 201211028 基苯基）（甲基）_1，3-丙二酸二（第三丁酯）Using the compound of Reference Example 62, the title compound was obtained according Reference Example 64 2-(2-{ [1-(Terti-butoxy)-aminophenanthyl-4-yl]amino oxime 323406 138 201211028 phenyl) (methyl)-1,3- Malonate di(t-butyl ester)

Me^°2iBU |j^Y^C02iBu Me〇^s^^NHMe^°2iBU |j^Y^C02iBu Me〇^s^^NH

Boc 將參考例63的化合物（2. 〇g)溶解於DMF(20ml)後，於 冰浴下加入氫化鈉（185mg)。攪拌10分鐘後，於之加入甲 基蛾（60Gmg) ’於室溫攪拌5小時。於反應液加人水，以乙 進行萃取，以飽和食鹽切有機層洗淨。以硫 水各液進行乾燥後’以石夕藻土過據，將遽液 將所得到的殘潰以石夕膠管柱層析進行〜/塗濃縮。 合物（1為，63%)。 ㈣為標題化 參考例65 4一（6-甲氧基-3-曱基-2-侧氧-2, 3-咬-1-基-羧酸第三丁酯 虱~1H1哚基)哌Boc After dissolving the compound of Example 63 (2. g) in DMF (20 ml), sodium hydride (185 mg). After stirring for 10 minutes, the methyl moth (60 Gmg) was added thereto and stirred at room temperature for 5 hours. Add water to the reaction solution, extract with B, and wash the organic layer with saturated salt. After drying with each sulphur water solution, the sputum solution was subjected to chromatography on a Shixi rubber column to carry out ~/coating concentration. Compound (1 is 63%). (4) Titled Reference Example 65 4-(6-methoxy-3-indolyl-2-oxo-2,3-bit-1-yl-carboxylic acid tert-butyl ester 虱~1H1 fluorenyl) piperidine

〇Me 使用參考例64之化合物’依照與參考 媒5,丨4® 人仏„ W 1 31相同的方 法而得到標題化合物 參考例6 6 甲。氧基~3-甲基-1-(哌啶-1-基）~1，3_ ，〇Me The compound of Reference Example 64 was used in the same manner as the reference medium 5, 丨4® 仏 W W 1 31 to give the title compound. Reference Example 6 6 A. Oxyl~3-methyl-1-(piperidine) -1-base)~1,3_ ,

氫〜2H〜吲哚-2- 〇Me 323406 139 201211028 使用參考例65之化合物，依照與參考例4相同的方法 而得到標題化合物。 參考例67至69 使用對應之市售原料，依照與參考例62至66相同的 方法而得到下述化合物。 [表4]Hydrogen~2H~吲哚-2- 〇Me 323406 139 201211028 Using the compound of Reference Example 65, the title compound was obtained according Reference Examples 67 to 69 The following compounds were obtained in the same manner as in Reference Examples 62 to 66, using the corresponding commercially available materials. [Table 4]

參考例 構造 67 Q Me 68 9 F 69 x rVH Q F 參 實施例32至93 使用參考例 4、22、32、34、37、46 至 62、67 至 69 之化合物，依照與實施例1或實施例15相同的方法而得到 下述化合物。亦有使用1-曱氧基幾基旅唆_4-酮、3-側氧 降莨菪驗-8-叛酸乙酯（3-〇xonortropane-8-carboxylic acid ethyl)、或1-乙氧基幾基-4-曱醯基°底咬以取代1-乙氧羰基哌啶者。 140 323406 201211028[表5]Reference Example Configuration 67 Q Me 68 9 F 69 x rVH QF Reference Examples 32 to 93 The compounds of Reference Examples 4, 22, 32, 34, 37, 46 to 62, 67 to 69 were used in accordance with Example 1 or Example. The following compound was obtained in the same manner. Also used is 1-methoxyl-based 唆4-ketone, 3-oxonortropane-8-carboxylic acid ethyl, or 1-ethoxyl A few bases are substituted for 1-ethoxycarbonyl piperidine. 140 323406 201211028 [Table 5]

MS 實施例 構造 (鹽） (m/z) 分鐘 條件 NMR (MHz,溶劑） 32 33 34 35 36 37 38 39MS Example Structure (Salt) (m/z) Minute Condition NMR (MHz, solvent) 32 33 34 35 36 37 38 39

(延胡索酸鹽） 472. 1 (M+Na) 6.4 N.D. 486. 1 (M+Na) 6. 6 N. D. 442. 2 (M+Na)(fumarate) 472. 1 (M+Na) 6.4 N.D. 486. 1 (M+Na) 6. 6 N. D. 442. 2 (M+Na)

ciCi

(延胡索酸鹽）(fumarate)

414. 2 (M+Na)414. 2 (M+Na)

426. 3 (M+H) 6. 7 496. 2 (M+Na) 6. 3 454. 2 (M+Na) 6. 7 418. 2 (M+H) 6. 5 Ή-NMR (DHS0-d«, 400 MHz) 51.01-1.09 (□, 1H), 1.12-1.18 (td, J = 7.1，3.3 Hz), 1.38-1.40 (id 2H), 1.55-1.65 (m, 3H), 1.77-1.97 (m, 3H), 2.28-2.40 (m, 2H), 2. 50-2.58 (m, 1H), 2.63-2.70 (br, 1H), 2.91-2.99 (br, 1H), 3. 18-3. 27 (br, 2H), 3. 40-3. 50 (m, 2H), 3.55 (s, 2H), 3. 99-4. 07 (q, J = 7. 1 Hz, 2H), 4. 10-4. 20 (br, 1H), 6.58 (s, 2H, fumaric acid), 7.16-7.19 (dd, J = 8.4, 3.2 Hz, 1H), 7.25-7.30 (d, J = 8.4 Hz, 1H), 7. 31-7. 32 (d, J = 3. 2 Hz, 1H)._ Ή-NMR (DMSO-d·, 400 MHz) δ 1. 41-1. 52 (qd, J = 11.4, 4.5 Hz，2H), 1.66-1.73 (d, J = 11.7 Hz), 1-87-1.92 (d, J = 11.4 Hz), 2.38-2. 43 (m, 2H), 2.55-2.67 (m, 2H), 2.79-2.92 (br, 3H), 3.13-3.22 (d, J = 10.7 Hz), 3.63 (s，2H), 3.64 (s，3H), 4.03-4.15 (br，2H), 4.20-4.31 (br, 1H), 6.66 (s, 2H, fumaric acid), 7.24-7.27 (d, J = 8.5 Hz, 1H), 7.32-7.36 (d, J = 8.5 Hz, 1H), 7. 39 (s. 1H)._ Ή-NMR (DMSO-de, 400 MHz) δ 1. 12-1. 19 (t, J = 7. 2 Hz, 3H)，1.20-1.38 (m，2H), 1.53-1.80 (m, 6H)，2.20-2.30 (bt, 4H), 2. 68-2. 81 (br, 2H)t 2. 90-2. 97 (m, 2H), 3. 31 (s，3H), 3. 72-3.81 (η, 2H), 3. 93-4.09 (q, J = 7. 2 Hz, 7H), 7.01-7.17 (in, 2H), 7.43-7.49 (dd, J = 11.2, 3.4426. 3 (M+H) 6. 7 496. 2 (M+Na) 6. 3 454. 2 (M+Na) 6. 7 418. 2 (M+H) 6. 5 Ή-NMR (DHS0- d«, 400 MHz) 51.01-1.09 (□, 1H), 1.12-1.18 (td, J = 7.1, 3.3 Hz), 1.38-1.40 (id 2H), 1.55-1.65 (m, 3H), 1.77-1.97 ( m, 3H), 2.28-2.40 (m, 2H), 2. 50-2.58 (m, 1H), 2.63-2.70 (br, 1H), 2.91-2.99 (br, 1H), 3. 18-3. 27 (br, 2H), 3. 40-3. 50 (m, 2H), 3.55 (s, 2H), 3. 99-4. 07 (q, J = 7. 1 Hz, 2H), 4. 10- 4. 20 (br, 1H), 6.58 (s, 2H, fumaric acid), 7.16-7.19 (dd, J = 8.4, 3.2 Hz, 1H), 7.25-7.30 (d, J = 8.4 Hz, 1H), 7 31-7. 32 (d, J = 3. 2 Hz, 1H)._ Ή-NMR (DMSO-d·, 400 MHz) δ 1. 41-1. 52 (qd, J = 11.4, 4.5 Hz, 2H), 1.66-1.73 (d, J = 11.7 Hz), 1-87-1.92 (d, J = 11.4 Hz), 2.38-2. 43 (m, 2H), 2.55-2.67 (m, 2H), 2.79 -2.92 (br, 3H), 3.13-3.22 (d, J = 10.7 Hz), 3.63 (s, 2H), 3.64 (s, 3H), 4.03-4.15 (br, 2H), 4.20-4.31 (br, 1H) ), 6.66 (s, 2H, fumaric acid), 7.24-7.27 (d, J = 8.5 Hz, 1H), 7.32-7.36 (d, J = 8.5 Hz, 1H), 7. 39 (s. 1H)._ Ή-NMR (DMSO-de, 400 MHz) δ 1. 12-1. 19 (t, J = 7. 2 Hz, 3H), 1.20-1.3 8 (m, 2H), 1.53-1.80 (m, 6H), 2.20-2.30 (bt, 4H), 2. 68-2. 81 (br, 2H)t 2. 90-2. 97 (m, 2H) , 3. 31 (s, 3H), 3. 72-3.81 (η, 2H), 3. 93-4.09 (q, J = 7. 2 Hz, 7H), 7.01-7.17 (in, 2H), 7.43- 7.49 (dd, J = 11.2, 3.4

Hz, 1H)._ Ή-NMR (DMSO-di, 400 MHz) 5 1.13-1.19 (dt, J = 7.0, 3.4 Hz 3H), 1.32-1.49 (m, 2H)( 1.51-1.70 (m, 5H), 1.71-1.89 (m, 5H), 2.18-2.36 (m, 4H), 2.43-2.53 (m, 1H), 2.77-2.87 (m, 2H), 3.17-3.28 (m, 2H), 3.39-3.51 (m, 2H), 2. 72-2.8 0 (m, 2H), 3. 93-4. 10 (q, J = 7.0 Hz, 5H) 7.03-7.18 (m, 2H), 7.43-7.49 (dd, J = 8.5( 2.7Hz, 1H)._ Ή-NMR (DMSO-di, 400 MHz) 5 1.13-1.19 (dt, J = 7.0, 3.4 Hz 3H), 1.32-1.49 (m, 2H) ( 1.51-1.70 (m, 5H) , 1.71-1.89 (m, 5H), 2.18-2.36 (m, 4H), 2.43-2.53 (m, 1H), 2.77-2.87 (m, 2H), 3.17-3.28 (m, 2H), 3.39-3.51 ( m, 2H), 2. 72-2.8 0 (m, 2H), 3. 93-4. 10 (q, J = 7.0 Hz, 5H) 7.03-7.18 (m, 2H), 7.43-7.49 (dd, J = 8.5 ( 2.7

Hz, 1H),_ lH-NMR (DMSO-d., 400 MHz) δ 1.43-1. 79 (t, J = 7. 2 Hz, 3H), 1.23-1.48 (m, 2H), 1.49-1.53 (q, J = 3. 5 Hz, 2H), 1.54-1.62 (m, 2H), 1.62-1.69 (q, J - 3.5 Hz, 2H), 1. 71-1. 76 (m, 2H), 2. 19-2. 30 (m, 4H)( 2. 64-2. 81 (br, 2H), 2.88-2.94 (m( 2H), 3.22 (s, 1H), 3.90-4.02 (q, J = 7.2 Hz, 2H), 4.04-4.12 (br, 1H), 7.14-7.15 (d, J = 2.2 Hz( 1H), 7.18-7.21 (d, J = 8.4 Hz, 1H), 7.22-7.26 (dd, J = 8.4, 2.2 Hz, 1H)._ Ή-NMR (DMSO-d., 400 MHz) 5 1.23-1.37 (m, 2H), 1.48-1.53 (q, J = 4.2 Hz, 2H), 1.58-1.64 (br, 2H), K64-1.68 (q, J = 4.2 Hz, 2H), 1.69-1.73 (m 2H), 2.21-2.31 (m, 4H), 2.68-2.83 (br, 2H), 2.88-2.95 2H)，3. 35 (s, 1H), 3. 93-4. 02 (br, 2H), 4. 03-4. 14 (br, 1H), 7.14-7.15 (d, J = 2.2 Hz, 1H), 7.18-7.21 (d, J =8.4 Hz, 1H), 7.22-7.26 (dd, J = 8.4, 2.2 Hz, 1H). 141 323406 201211028Hz, 1H), _ lH-NMR (DMSO-d., 400 MHz) δ 1.43-1. 79 (t, J = 7. 2 Hz, 3H), 1.23-1.48 (m, 2H), 1.49-1.53 ( q, J = 3. 5 Hz, 2H), 1.54-1.62 (m, 2H), 1.62-1.69 (q, J - 3.5 Hz, 2H), 1. 71-1. 76 (m, 2H), 2. 19-2. 30 (m, 4H) ( 2. 64-2. 81 (br, 2H), 2.88-2.94 (m( 2H), 3.22 (s, 1H), 3.90-4.02 (q, J = 7.2 Hz , 2H), 4.04-4.12 (br, 1H), 7.14-7.15 (d, J = 2.2 Hz( 1H), 7.18-7.21 (d, J = 8.4 Hz, 1H), 7.22-7.26 (dd, J = 8.4 , 2.2 Hz, 1H)._ Ή-NMR (DMSO-d., 400 MHz) 5 1.23-1.37 (m, 2H), 1.48-1.53 (q, J = 4.2 Hz, 2H), 1.58-1.64 (br, 2H), K64-1.68 (q, J = 4.2 Hz, 2H), 1.69-1.73 (m 2H), 2.21-2.31 (m, 4H), 2.68-2.83 (br, 2H), 2.88-2.95 2H), 3 35 (s, 1H), 3. 93-4. 02 (br, 2H), 4. 03-4. 14 (br, 1H), 7.14-7.15 (d, J = 2.2 Hz, 1H), 7.18- 7.21 (d, J = 8.4 Hz, 1H), 7.22-7.26 (dd, J = 8.4, 2.2 Hz, 1H). 141 323406 201211028

40 CI 440.2 (M+Na) 6.5 lH-NMR CDMSO-dt( 400 MHz) δ 1.12-1.18 (t, J = 7.1 Hz, 3H), 1.33-1.48 (m, 2H), 1.49-1.51 (q, J = 4.2Hz, 2H), 1.53-1.61 (m, 2H), 1.61-1.67 (q, J-4.2HZ, 2H), 1.73-1. 90 (m, 3H), 2. 21-2. 34 (m, 4H), 2.74-2.86 (br, 2H), 3.13-3.27 (br, 2H), 3.32 (s, 1H), 3.39-3.50 (br 2H), 3.98-4.05 (q, J = 7.1 Hz, 2H), 4.01-4.12 (br, 2H), 7.14-7.15 (dt J = 2.2 Hz, 1H), 7.17-7.22 (d, J = 8.4 Hz, 1H), 7.23-7.26 (dd, J =8.4，2.2 Hz, 1H). 41 420.2 (M+Na) 6.2 A lH-NMR (DMSO-d., 400 MHz) &lt;51.14-1.80 (t, J = 7.1 Hz. 3H), 1.22-1.38 (m, 2H), 1.48-1.52 (q J = 4. 2 Hz, 2H), 1.53-1.62 (mf 4H) 1.68-1.74 (d, J = 11.5Hz, 2H)2.21-2.32(m, 4H), 2.66-2.82 (br, 2H), 2.89-2.97 (in, 2H), 3. 33 (s, 1H) 3. 93-4. 05 (q, J = 7.1 Hz, 4H)f 4.00-4.13 (br, 1H), 6.94-7.03 (mt 2H), 7.12-7.19 (dd, J = 8.8, 4.4 Hz, 1H). 42 / 402.2 (M+H) 6.1 A Ή-NMR (DMSO-ds, 400 MHz) 51.25-1.36 (dq, J = 12.2, 3.9 Hz, 2H), 1.47-1.52 (m, 2H), 1.53-1.64 (ra, 4H), 1·68-1.76 (d, J = U.O Hz, 2H), 2.10-2.31 On, 4H), 2. 90-2· 98 (d, J = 6.6 Hz, 2H), 3.32 (s, 3H), 3.56(s, 3H), 3.92-4.02 (br, 2H), 4.02-4.14 (br, 1H), 6. 92-7. 02 (m, 2H), 7.11-7.19 (dd, J = 8.8, 4.4 Hz, 1H). 43 4 452.2 (H+Na) 6.5 A *H-NMR (DMSO-d*, 400 MHz) &lt;51.12-1.19 (dt, J = 7.2, 2.4 Hz, 3H), 1.3-1.50 (m, 4H), 1.51-1.63 (m, 5H), 1. 73-1. 89 (m, 3H), 2.20-2.32 (m, 4H), 2.77-2.35 (br, 2H), 3.35-3.17 (br, 2H), 3.30 (s, 1H), 3.39-3.50 (br, 2H), 3.98-4.03 (q, J = 7. 2 Hz, 2H), 4.03-4. 12 (br, 1H), 6.94-7.04 (m, 2H), 7.13-7.19 (m, 1H). 44 Μ· 478.3 (M+Na) 6.5 Ή-NMR (DMSO-de, 400 MHz) 51.13-1.18 (t, J = 7. 2 Hz, 3H)t 2. 25-2.36 (m, 2H), 2.50-2.58 (br, 2H), 2. 61-2. 77 (m, 5H), 2.22-2.29 Cm, 7H), 2.65-2. 80 (br( 2H), 2. 89-2. 96 (br, 2H), 3. 32 (s, 2H), 2.73-2.81 (m, 2H), 3. 95-4.07 (qt J = 7.2Hz, 7H), 7.00-7. 07 (m, 2H)( 7. 33 Cs, 1H). 45 〇^y° (延胡索酸鹽） 494.3 (M+Na) 6.6 A Ή-MKR (DMSO-d., 400 MHz) dl. 12-1.19 (dt, J = 7.2, 3.2 Hz, 3H), 1.35-1.48 (br, 2H), 1.54-1.69 Cm, 7H), 1. 75-1. 96 (m, 3H), 2.27 (s, 3H), 2.28-2.37 (br, 1H), 2.60-2.68 (br, 1H), 2.90-2.98 (br, 2H), 3.17-3.51 (m, 7H), 3.76-3.81 (m, 2H), 3.97-4.07 (q, J = 7. 2 Hz, 4H), 4. 08-4.14 (br, 1H), 6.58 (s, 2Hf fumaric acid), 7.05 (s, 2H), 7.34 (s, 1H). 46 Hi/ 412.3 (M+H) 6.5 Ή-NMR (DMSO-d., 400 MHz) 51.13-1. 19 (t, J = 7. 2 Hz, 3H), 2.24-2.36 (m, 2H), 1.42-1.47 (m, 2HX 1.49-1.54 (m, 2H), 1.54-1.61 (m, 2H), 1.67-1.74 (m, 2H), 2.21-2.59 (m, 7H), 2.64-2.79 (br, 2H), 2.88-2.93 (d, J = 7.1 Hz, 2H), 3.32 (st 1H), 3.93-4.01 (q, J = 7.2 Hz, 4H),4.01-4.11 (br, 1H), 6.81 (s, 1H), 6. 99-7. 02 (d, J = 8. 0 Hz, 1H), 7.04-7.07 (d, J - 8.0 Hz, 1H). 47 hJ (延胡索酸鹽） 426.3 (M+H) 6.7 Ή-NMR (DMSO-d., 400 MHz) 51.11-1.11.19 (dt, J = 7. 2, 3.7 Hz, 3H), 1.41-1.47 (m, 3H), 1. 50-1. 54 (m, 3H), 1. 58-1. 65 (in, 3H), 1.77-1.82 Cm, 3H), 2.23 Cs, 3H), 2.31-2.39 Cbr, 2H)f 2.58-2.68 (br, IH), 2.88-2.94 (brt 2H), 3.20-3.50 (m, 5H), 3.99-4.06 (q( J = 7.2 Hz, 2H), 4.12-4.20 (br, 1H), 6. 58 (s, 2H, fumaric acid), 6. 82 (s, 1H), 6.98-7..02 (d, J = 7.8 Hz, 1H), 7.07-7.12 (m, 1H). 142 323406 20121102840 CI 440.2 (M+Na) 6.5 lH-NMR CDMSO-dt ( 400 MHz) δ 1.12-1.18 (t, J = 7.1 Hz, 3H), 1.33-1.48 (m, 2H), 1.49-1.51 (q, J = 4.2Hz, 2H), 1.53-1.61 (m, 2H), 1.61-1.67 (q, J-4.2HZ, 2H), 1.73-1. 90 (m, 3H), 2. 21-2. 34 (m , 4H), 2.74-2.86 (br, 2H), 3.13-3.27 (br, 2H), 3.32 (s, 1H), 3.39-3.50 (br 2H), 3.98-4.05 (q, J = 7.1 Hz, 2H) , 4.01-4.12 (br, 2H), 7.14-7.15 (dt J = 2.2 Hz, 1H), 7.17-7.22 (d, J = 8.4 Hz, 1H), 7.23-7.26 (dd, J = 8.4, 2.2 Hz, 1H). 41 420.2 (M+Na) 6.2 A lH-NMR (DMSO-d., 400 MHz) &lt;51.14-1.80 (t, J = 7.1 Hz. 3H), 1.22-1.38 (m, 2H), 1.48 -1.52 (q J = 4. 2 Hz, 2H), 1.53-1.62 (mf 4H) 1.68-1.74 (d, J = 11.5Hz, 2H) 2.21-2.32(m, 4H), 2.66-2.82 (br, 2H ), 2.89-2.97 (in, 2H), 3. 33 (s, 1H) 3. 93-4. 05 (q, J = 7.1 Hz, 4H)f 4.00-4.13 (br, 1H), 6.94-7.03 ( Mt 2H), 7.12-7.19 (dd, J = 8.8, 4.4 Hz, 1H). 42 / 402.2 (M+H) 6.1 A Ή-NMR (DMSO-ds, 400 MHz) 51.25-1.36 (dq, J = 12.2 , 3.9 Hz, 2H), 1.47-1.52 (m, 2H), 1.53-1.64 (ra, 4H), 1·68-1.76 (d, J = UO Hz, 2H), 2.10-2.31 On, 4H), 2 90-2· 98 ( d, J = 6.6 Hz, 2H), 3.32 (s, 3H), 3.56(s, 3H), 3.92-4.02 (br, 2H), 4.02-4.14 (br, 1H), 6. 92-7. 02 ( m, 2H), 7.11-7.19 (dd, J = 8.8, 4.4 Hz, 1H). 43 4 452.2 (H+Na) 6.5 A *H-NMR (DMSO-d*, 400 MHz) &lt;51.12-1.19 ( Dt, J = 7.2, 2.4 Hz, 3H), 1.3-1.50 (m, 4H), 1.51-1.63 (m, 5H), 1. 73-1. 89 (m, 3H), 2.20-2.32 (m, 4H ), 2.77-2.35 (br, 2H), 3.35-3.17 (br, 2H), 3.30 (s, 1H), 3.39-3.50 (br, 2H), 3.98-4.03 (q, J = 7. 2 Hz, 2H ), 4.03-4. 12 (br, 1H), 6.94-7.04 (m, 2H), 7.13-7.19 (m, 1H). 44 Μ· 478.3 (M+Na) 6.5 Ή-NMR (DMSO-de, 400 MHz) 51.13-1.18 (t, J = 7. 2 Hz, 3H)t 2. 25-2.36 (m, 2H), 2.50-2.58 (br, 2H), 2. 61-2. 77 (m, 5H) , 2.22-2.29 Cm, 7H), 2.65-2. 80 (br( 2H), 2. 89-2. 96 (br, 2H), 3. 32 (s, 2H), 2.73-2.81 (m, 2H) , 3. 95-4.07 (qt J = 7.2Hz, 7H), 7.00-7. 07 (m, 2H)( 7. 33 Cs, 1H). 45 〇^y° (fumarate) 494.3 (M+Na) 6.6 A Ή-MKR (DMSO-d., 400 MHz) dl. 12-1.19 (dt, J = 7.2, 3.2 Hz, 3H), 1.35-1.48 (br, 2H), 1.54-1.69 Cm, 7H), 1 75-1. 96 (m, 3H), 2.27 (s, 3H), 2.28-2.37 (br, 1H), 2. 60-2.68 (br, 1H), 2.90-2.98 (br, 2H), 3.17-3.51 (m, 7H), 3.76-3.81 (m, 2H), 3.97-4.07 (q, J = 7. 2 Hz, 4H ), 4. 08-4.14 (br, 1H), 6.58 (s, 2Hf fumaric acid), 7.05 (s, 2H), 7.34 (s, 1H). 46 Hi/ 412.3 (M+H) 6.5 Ή-NMR ( DMSO-d., 400 MHz) 51.13-1. 19 (t, J = 7. 2 Hz, 3H), 2.24-2.36 (m, 2H), 1.42-1.47 (m, 2HX 1.49-1.54 (m, 2H) , 1.54-1.61 (m, 2H), 1.67-1.74 (m, 2H), 2.21-2.59 (m, 7H), 2.64-2.79 (br, 2H), 2.88-2.93 (d, J = 7.1 Hz, 2H) , 3.32 (st 1H), 3.93-4.01 (q, J = 7.2 Hz, 4H), 4.01-4.11 (br, 1H), 6.81 (s, 1H), 6. 99-7. 02 (d, J = 8 . 0 Hz, 1H), 7.04-7.07 (d, J - 8.0 Hz, 1H). 47 hJ (fumarate) 426.3 (M+H) 6.7 Ή-NMR (DMSO-d., 400 MHz) 51.11-1.11. 19 (dt, J = 7. 2, 3.7 Hz, 3H), 1.41-1.47 (m, 3H), 1. 50-1. 54 (m, 3H), 1. 58-1. 65 (in, 3H) , 1.77-1.82 Cm, 3H), 2.23 Cs, 3H), 2.31-2.39 Cbr, 2H)f 2.58-2.68 (br, IH), 2.88-2.94 (brt 2H), 3.20-3.50 (m, 5H), 3.99 -4.06 (q( J = 7.2 Hz, 2H), 4.12-4.20 (br, 1H), 6. 58 (s, 2H, fumaric acid), 6. 82 (s, 1H), 6.98-7..02 ( d, J = 7.8 Hz, 1H), 7.07-7.12 (m , 1H). 142 323406 201211028

48 49 50 51 5348 49 50 51 53

Μ· (延胡索酸鹽）Μ· (fumarate)

(延胡索酸鹽） (延胡索酸鹽）(fumarate) (fumarate)

(延胡索酸鹽）(fumarate)

MeMe

COjMe (延胡索酸鹽） &quot;C02Et (延胡索酸鹽）COjMe (Fumarate) &quot;C02Et (Fumarate)

5555

(延胡索酸鹽） 414.3 (Η+Η) 6.7 400.2 (M+H)6.6 450.3 (M+Na)6.8 412.2 (M+H)6.6(fumarate) 414.3 (Η+Η) 6.7 400.2 (M+H)6.6 450.3 (M+Na)6.8 412.2 (M+H)6.6

398.2 (M+H) 6.7 A 426.2 (M+H) 6.7 478.3 (M+Na) 6.5 492.2 (M+Na)6.6 Ή-NMR (DMSO-ds, 400 MHz) δ 1.13-1.19 (t, J = 7. 0 Hz, 3H), 1.19 (s, 6H), 1.28-1.40 (m, 2H), 1.57-1.63 (d, J = 12.4 Hz, 2H), 1.75-1.81 (d J = 11.2 Hz, 2H)t 2.30 (s, 3H), 2.30-2.45 (m, 4H), 2.58-2.64 (m 1H), 2. 68-2.80 (br, 2H), 3. 00-3. 06 (d, J = 10. 0 Hz, 2H), 3.96-4.10 (q, J = 7.0 Hz, 5H), 6.59 (s, 2H, fumaric acid), 6.79-6.83 (d, J -7.3 Hz, 1H), 6.97 (s, 1H), 7.16-7.20 (d, J = 7.3 Hz, 1H). Ή-NMR (DMSO-d», 400 MHz) dl.20 (s, 6H), 1.28-1.40 (m, 2H), 1. 57-1. 63 (d, J = 12.4 Hz( 2H), 1.75-1.81 (d J = 11. 2 Hz, 2H)( 2. 30 (s, 3H), 2.30-2.45 (m, 4H), 2.58-2.64 (m 1H), 2.68-2.80 (br, 2H), 3. 00-3.06 (df J = 10.0 Hz, 2H), 3.57(sf 3H). 3. 95-4.10 (br, 3H), .59 (s, 2H, fumaric acid), 6.79-6.83 (d, J = 7. 3 Hz, 1H), 6.97(s, 1H), 7.16-7.20 (d, J = 7.3 Hz, 1H). lH-NMR (DMSO-ds, 400 MHz) 51.13-1.20 (¢, 9H), 1.38-1.47 (m, 2H), 1.53-1.65 (m, 3H), 1.75-1.99 (m, 3H), 2.30 (s, 3H), 2.31-2.60 (m, 4H), 2.62-2.72 (m, 1H), 2.91-3.00 (br, 2H), 3.17-3.28 (br, 2H), 3. 38-3.50 (m, 2H), 4. 00-4.06 (q, J = 7. 0 Hz, 2H), 4. 09-4.17 (m, 1H), 6.58 (s 2H, fumaric acid), 6.80-6.83 (dt J = 7. 6 Hz, 1H), 7.00 (s 1H)( 7.18-7.20 (d, J = 7.6 Hz, 1H). Ή-NMR (DMSO-d., 400 MHz) 51.14-1.19 (t, J = 7. 0 Hz, 3H), 1.30-1.42 (m2H), 1.42-1.46 (m, 2H), 1.47-1. 53 (m 2H), 1.59-1. 67 (d. J = 12.0 Hz, 2H), 1.76-1.83 (d J = 12.2 Hz, 2H), 2.32 (s 3H) 2.32-1.49 (m, 4H) 2.62-2.81 Cm, 3H), 3.02-3.06 (d, J = 9.5 Hz, 2H), 3.97-4.04 (q, J = 7.0 Hz, 4H), 4.13-4.21 (m, 1H)( 6.59 (s. 2H, fumaric acid), 6.75-6.79 (d( J = 7. 3 Hz, 1H), 6.84-6. 88 (d, J = 7. 3 Hz, 1H), 7.04398.2 (M+H) 6.7 A 426.2 (M+H) 6.7 478.3 (M+Na) 6.5 492.2 (M+Na) 6.6 Ή-NMR (DMSO-ds, 400 MHz) δ 1.13-1.19 (t, J = 7 . 0 Hz, 3H), 1.19 (s, 6H), 1.28-1.40 (m, 2H), 1.57-1.63 (d, J = 12.4 Hz, 2H), 1.75-1.81 (d J = 11.2 Hz, 2H)t 2.30 (s, 3H), 2.30-2.45 (m, 4H), 2.58-2.64 (m 1H), 2. 68-2.80 (br, 2H), 3. 00-3. 06 (d, J = 10. 0 Hz, 2H), 3.96-4.10 (q, J = 7.0 Hz, 5H), 6.59 (s, 2H, fumaric acid), 6.79-6.83 (d, J -7.3 Hz, 1H), 6.97 (s, 1H), 7.16-7.20 (d, J = 7.3 Hz, 1H). Ή-NMR (DMSO-d», 400 MHz) dl.20 (s, 6H), 1.28-1.40 (m, 2H), 1. 57-1. 63 (d, J = 12.4 Hz ( 2H), 1.75-1.81 (d J = 11. 2 Hz, 2H) ( 2. 30 (s, 3H), 2.30-2.45 (m, 4H), 2.58-2.64 (m 1H), 2.68-2.80 (br, 2H), 3. 00-3.06 (df J = 10.0 Hz, 2H), 3.57 (sf 3H). 3. 95-4.10 (br, 3H), .59 (s, 2H , fumaric acid), 6.79-6.83 (d, J = 7. 3 Hz, 1H), 6.97(s, 1H), 7.16-7.20 (d, J = 7.3 Hz, 1H). lH-NMR (DMSO-ds, 400 MHz) 51.13-1.20 (¢, 9H), 1.38-1.47 (m, 2H), 1.53-1.65 (m, 3H), 1.75-1.99 (m, 3H), 2.30 (s, 3H), 2.31-2.60 ( m, 4H), 2.62-2.72 (m, 1H), 2.91-3.00 (br, 2H), 3.17-3.28 (br, 2H), 3. 38-3.50 (m, 2H), 4. 00-4.06 (q, J = 7. 0 Hz, 2H), 4. 09-4.17 ( m, 1H), 6.58 (s 2H, fumaric acid), 6.80-6.83 (dt J = 7. 6 Hz, 1H), 7.00 (s 1H) ( 7.18-7.20 (d, J = 7.6 Hz, 1H). Ή -NMR (DMSO-d., 400 MHz) 51.14-1.19 (t, J = 7. 0 Hz, 3H), 1.30-1.42 (m2H), 1.42-1.46 (m, 2H), 1.47-1. 53 (m (2), 1.59-1. 3H), 3.02-3.06 (d, J = 9.5 Hz, 2H), 3.97-4.04 (q, J = 7.0 Hz, 4H), 4.13-4.21 (m, 1H) ( 6.59 (s. 2H, fumaric acid), 6.75-6.79 (d( J = 7. 3 Hz, 1H), 6.84-6. 88 (d, J = 7. 3 Hz, 1H), 7.04

Cs, 1H)._ Ή-NMR (DMSO-ds, 400 MHz) 51.30-1.42 (in 2H), 1.42-1.46 (m( 2H), 1.47-1.53 (m 2H), 1.59-1.67 (d, J = 12.0 ffz, 2H), 1.76-1.83 (d J =12.2 Hz, 2H), 2.32 (s 3H) 2.32-1.49 (ra, 4H)，2.58-2.70 (m· 1H)， 2.70-2.82 (br, 2H), 3.02-3.06 (d, J = 9.5 Hz, 2H), 3.57 (s, 3H), 3. 98-4.07 (br, 2H), 4.11-4.18 (br, 1H), 6. 59 Cs, 2H, fumaric acid), 6.75-6.79 (d, J = 7. 3 Hz, 1H), 6.84-6.88 (d, J = 7.3 Hz, 1H), 7.04 (s, 1H)._ Ή-NMR (DMSO-d., 400 MHz) 61.13-1.19 Cdt, J = 7.0, 3.4 Hz, 3H), 1.39-1.50 (m, 7H), 1.57-1.68 (m, 3H), 1.86-1.98 (m, 3H), 2.31 (s, 3H), 2.33-2.45 (m, 2H), 2.50-2.60 (m, 1H), 2.63-2.73 (m, 1H), 2.93-3.00 (m, 2H)t 3.18-3.26 (br, 2H), 3.40-3.51 (m, 2H), 3.99-4.06 (q( J = 7.0Hz( 2H), 4.17-4.26 (m, 1H), 6.59 (s, 2H, fumaric acid), 6.75-6.79 (d, J = 7. 6 Hz, 1H), 6.84-6.88 (d, J = 7. 6 Hz, 1H), 7.06 (s, 1H). lH-NMR (DMSO-d., 400 MHz) 61.13-1.19 (t, J = 7. 0 Hz 3H), 1. 29-1. 39 (mf 2H), 1.55-1.68 (m, 6H), 1.73-1.80 (m, 2H), 2.31 (s, 3H), 2.31-2.45 (m, 4H), 1.53-1. 63 (m, 1H), 1. 63-1.80 (br 2H), 2.99-3.03 (m, 2H)t 3.73-3.80 (m, 2H)( 3.97-4.08 (q, J = 7.0 Hz, 7H), 6.59 (s, 2H, fumaric acid), 6.81-6.84 (d, J = 7.6 Hz, 1H), 6.98 (st 1H), 7.36-7.40 (d, J = 7.6 Hz, 1H). lH-NMR (DMSO-de, 400 MHz) 51.13-1.19 (dt, J = 7.0, 3.4 Hz, 3H), 1.39-1.49 (m, 2H), 1.53-1.68 (m, 7H), 1.77-1.95 (m, 3H), 2.31 (s, 3H)( 2.31-2.50 (m, 5H), 2.60-2.68 (br, 1H), 2.90-2.97 (br, 2H), 3.18-3.26 (br( 2H), 3.38-50 (m, 2H), 3.73-3.81 (m, 2H), 4.00-4.06 (q, J = 7.0Hz, 3H), 4.06-4.14 (m, 1H), 6. 58 (s, 2H, fumaric acid), 6.80-6.84 (d, J = 7.8 Hz, 1H)( 7.00 (s, 1H), 736-7.40 (d, J = 7. 8Cs, 1H)._ Ή-NMR (DMSO-ds, 400 MHz) 51.30-1.42 (in 2H), 1.42-1.46 (m( 2H), 1.47-1.53 (m 2H), 1.59-1.67 (d, J = 12.0 ffz, 2H), 1.76-1.83 (d J = 12.2 Hz, 2H), 2.32 (s 3H) 2.32-1.49 (ra, 4H), 2.58-2.70 (m·1H), 2.70-2.82 (br, 2H) , 3.02-3.06 (d, J = 9.5 Hz, 2H), 3.57 (s, 3H), 3. 98-4.07 (br, 2H), 4.11-4.18 (br, 1H), 6. 59 Cs, 2H, fumaric Acid), 6.75-6.79 (d, J = 7. 3 Hz, 1H), 6.84-6.88 (d, J = 7.3 Hz, 1H), 7.04 (s, 1H)._ Ή-NMR (DMSO-d., 400 MHz) 61.13-1.19 Cdt, J = 7.0, 3.4 Hz, 3H), 1.39-1.50 (m, 7H), 1.57-1.68 (m, 3H), 1.86-1.98 (m, 3H), 2.31 (s, 3H ), 2.33-2.45 (m, 2H), 2.50-2.60 (m, 1H), 2.63-2.73 (m, 1H), 2.93-3.00 (m, 2H)t 3.18-3.26 (br, 2H), 3.40-3.51 (m, 2H), 3.99-4.06 (q( J = 7.0Hz( 2H), 4.17-4.26 (m, 1H), 6.59 (s, 2H, fumaric acid), 6.75-6.79 (d, J = 7. 6 Hz, 1H), 6.84-6.88 (d, J = 7. 6 Hz, 1H), 7.06 (s, 1H). lH-NMR (DMSO-d., 400 MHz) 61.13-1.19 (t, J = 7. 0 Hz 3H), 1. 29-1. 39 (mf 2H), 1.55-1.68 (m, 6H), 1.73-1.80 (m, 2H), 2.31 (s, 3H), 2.31-2.45 (m, 4H) , 1.53-1. 63 (m, 1H), 1 63-1.80 (br 2H), 2.99-3.03 (m, 2H)t 3.73-3.80 (m, 2H) ( 3.97-4.08 (q, J = 7.0 Hz, 7H), 6.59 (s, 2H, fumaric acid) , 6.81-6.84 (d, J = 7.6 Hz, 1H), 6.98 (st 1H), 7.36-7.40 (d, J = 7.6 Hz, 1H). lH-NMR (DMSO-de, 400 MHz) 51.13-1.19 ( Dt, J = 7.0, 3.4 Hz, 3H), 1.39-1.49 (m, 2H), 1.53-1.68 (m, 7H), 1.77-1.95 (m, 3H), 2.31 (s, 3H) (2.31-2.50 ( m, 5H), 2.60-2.68 (br, 1H), 2.90-2.97 (br, 2H), 3.18-3.26 (br ( 2H), 3.38-50 (m, 2H), 3.73-3.81 (m, 2H), 4.00-4.06 (q, J = 7.0Hz, 3H), 4.06-4.14 (m, 1H), 6. 58 (s, 2H, fumaric acid), 6.80-6.84 (d, J = 7.8 Hz, 1H) ( 7.00 (s, 1H), 736-7.40 (d, J = 7. 8

Hz, 1H). 143 323406 201211028Hz, 1H). 143 323406 201211028

56 5756 57

Me (延胡索酸鹽）Me (fumarate)

(延胡索酸鹽）(fumarate)

(延胡索酸鹽） 422.3 (M+Na) 6.3 Ή-NMR (DMSO-d., 400 MHz) d 1.13-1.19 (dt, J = 7. 2, 3.7 Hz, 3H), 1.40-1.49 (m, 2H)f 1. 57-1. 68 (m, 3H), 1.89-1. 99 (m, 3H), 2.29 (s, '3H), 2.34-2.50 (m, 2H), 2.53-2.68 (m. 2H), 2.70-2.78 (m, 1H), 2. 96-3.03 (br, 2H), 3.18-3. 27 (br, 2H), 2.40-2.49 (m, 4H), 3.99-4.06 (q, J = 7.2Hz, 2H), 4.11-4. 20 (br, 1H), 6. 58 (s, 2H, fumaric acid), 6.76-6.80 (d, J = 7.4 Hz, 1H), 6.99 (st 1H), 7.08-7.12 (d, J = 7. 4(fumarate) 422.3 (M+Na) 6.3 Ή-NMR (DMSO-d., 400 MHz) d 1.13-1.19 (dt, J = 7. 2, 3.7 Hz, 3H), 1.40-1.49 (m, 2H) f 1. 57-1. 68 (m, 3H), 1.89-1. 99 (m, 3H), 2.29 (s, '3H), 2.34-2.50 (m, 2H), 2.53-2.68 (m. 2H) , 2.70-2.78 (m, 1H), 2. 96-3.03 (br, 2H), 3.18-3. 27 (br, 2H), 2.40-2.49 (m, 4H), 3.99-4.06 (q, J = 7.2 Hz, 2H), 4.11-4. 20 (br, 1H), 6. 58 (s, 2H, fumaric acid), 6.76-6.80 (d, J = 7.4 Hz, 1H), 6.99 (st 1H), 7.08- 7.12 (d, J = 7. 4

Hz, 1H).Hz, 1H).

402.2 (M+H) 5.8 A 388.2 (M+H) 5.0 Ή-NMR (DMSO-d., 400 MHz) 51.13-1.19 (t, J = 7.2Hz, 3HX 1.30-1.41 (m, 2H), 1.56-1.63 (d, J = 11.1 Hz, 2H), 1.75-1.80 (d, J = 11.1 Hz, 2H), 2.30-2.50 (m, 4H), 2.61-2.80 (m, 3H), 2.99-3.05 (d, J = Π. 1 Hz, 2H), 3.42 (s, 2H), 3,74 (s, 3H), 3,94-4.10 (q，J = 7,2 Hz，5H), 6.51-6.55 (dd, J = 8.1, 2.2 Hz, 1H), 6.59 (s, 2H, fumaric acid), 6.69-6.71 (d, J = 2.2 Hz, 1H), 7.11-7.14 (d, J = 8.1 Hz, 1H). Ή-NMR (DMSO-di, 400 MHz) δ 1.30-1.41 (m, 2H), 1.56-1.63 (d, J = ll.l Hz, 2H), 1.74-1.80 (d, J = 11.1 Hz, 2H), 2.30-2. 52 (m, 4H), 2.60-2.81 (m, 3H), 2.99-3.05 (d, J = 11.1 Hz, 2H), 3.42 (st 2H), 3.57 (s, 3H), 3.74 (s, 3H), 3.94-4.10 (br, 3H), 6.52-6.55 (dd, J = 8.1, 2.2 Hz, 1H), 6.58 (s, 2H, fumaric acid), 6.69-6.71 (d, J = 2.2 Hz, 1H), 7.11-7.14 (d, J = 8.1 Hz, 1H). 59 61 62 63402.2 (M+H) 5.8 A 388.2 (M+H) 5.0 Ή-NMR (DMSO-d., 400 MHz) 51.13-1.19 (t, J = 7.2 Hz, 3HX 1.30-1.41 (m, 2H), 1.56- 1.63 (d, J = 11.1 Hz, 2H), 1.75-1.80 (d, J = 11.1 Hz, 2H), 2.30-2.50 (m, 4H), 2.61-2.80 (m, 3H), 2.99-3.05 (d, J = Π. 1 Hz, 2H), 3.42 (s, 2H), 3,74 (s, 3H), 3,94-4.10 (q, J = 7,2 Hz, 5H), 6.51-6.55 (dd, J = 8.1, 2.2 Hz, 1H), 6.59 (s, 2H, fumaric acid), 6.69-6.71 (d, J = 2.2 Hz, 1H), 7.11-7.14 (d, J = 8.1 Hz, 1H). NMR (DMSO-di, 400 MHz) δ 1.30-1.41 (m, 2H), 1.56-1.63 (d, J = ll.l Hz, 2H), 1.74-1.80 (d, J = 11.1 Hz, 2H), 2.30 -2. 52 (m, 4H), 2.60-2.81 (m, 3H), 2.99-3.05 (d, J = 11.1 Hz, 2H), 3.42 (st 2H), 3.57 (s, 3H), 3.74 (s, 3H), 3.94-4.10 (br, 3H), 6.52-6.55 (dd, J = 8.1, 2.2 Hz, 1H), 6.58 (s, 2H, fumaric acid), 6.69-6.71 (d, J = 2.2 Hz, 1H ), 7.11-7.14 (d, J = 8.1 Hz, 1H). 59 61 62 63

(延胡索酸鹽）(fumarate)

(延胡索酸鹽）(fumarate)

(延胡索酸鹽）(fumarate)

(延胡索酸鹽）(fumarate)

438.1 (M+Na) 6.0 A438.1 (M+Na) 6.0 A

450.1 (M+Na)6.2 A 438.1 (M+Na) 6.1 494.2 (M+Na)6.2450.1 (M+Na)6.2 A 438.1 (M+Na) 6.1 494.2 (M+Na)6.2

486.3_) 6.3 A Ή-NMR (DMS0-d«, 400 MHz) 51.143-1.120 (dt, J - 7. 2, 3.7 Hz, 3H), 1.36-1.49 (mt 2fi), 1.53-1. 66 (m, 3H), 1. 76-1. 92 (π, 3H), 2.30-2.41 (m, 2H), 2.40-2.67 (m, 2H), 2.88-2.91 (brt 2H), 3.18-3. 26 (br, 2H), 2.39-2.50 (br, 2H), 3.42 (s, 5H), 3.74 (s, 3H), 4.00-4.1 0 (q, J =7.2 Hz, 3H), 6.51-6.55 (dd, J = 8.3, 2.2 Hz, 1H), 6.56 (s, 2H, fumaric acid), 6.71 (br, 1H), 7.10-7.14 (d, J = 8.3 Hz, 1H). Ή-NMR (DMSO-di, 400 MHz) dO. 90-1. 02 (m, 2H)( 1.12-1.18 (t, J = 7.1 Hz, 3H), I. 54-1. 59 (d, J = 11.0 Hz, 2H), 1. 64-1. 76 (d, J = 9.3Hz, 3H), 2.07-2.17 (m, 2H), 2.22-2.37 (d, J = 6.6 Hz, 2H), 2.31-2.42 (m, 2H), 2.64-2.81 (br, 2H), 2.95-3.02 (d, J = 11.0 Hz( 2H), 3.42 (s, 2H), 3.75(s, 3H), 3. 92-4.08 (q, J - 7.1 Hz, 5H), 6.51-6. 57 (dd, J = 8. 3, 2.2 Hz, 1H), 6.59 (s, 2H, fumaric acid), 6.69-6.71 (d, J =2.2 Hz, 1H), 7.10-7.12 (d，J = 8.3 Hz, 1H). lH-NMR (CIWJD, 400 MHz) 51.23-1.29 (t, J = 7. 2 Hz, 3H)f 1.59-1.81 (in, 7H), 1.90-1.97 (m, 2H), 2.06-2.13 (m, 2H), 2.72-2.91 (br, 3H), 3.08-3.14 (m, 2H), 3.55-3.61 (m, 2H), 3.81 (s, 3H), 3.86-3.91 (br, 2H), 4.10-4.19 (q, J = 7.2 Hz, 5H), 4.27-4.40 (m, 3H), 6.61-6.67 (dd, J = 8.3, 2.2 Hz, 1H), 6.71 (s, 2H, fumaric acid), 6.81-6.82 (d, J = 2.2 Hz, 1H), 7.38-7.43 (d, J = 8.3 Hz, 1H). Ή-NMR (CDsOD, 400 MHz) 51.13-1.30 (mt 3H), 1.63-2.05 (m, 10H), 2.14-2.20 (br, 1H), 2.20-2. 29 (br, 1H), 2.72-2. 86 (m, 2H), 3.15-3.25 (m, 2H), 3.33-3.50 (m, 4H), 3.54-3.61 (m, 1H), 3.63-3.71(m, 1H)， 3.81 (s, 3H), 3.84-3.91 (m, 2H), 4.10-4.19 (m, 4H), 4.31-4.40 (mt 1H), 6.62-6. 66 (dd, J = 8.3, 2. 2 Hz, 1H), 6.71 (s, 2H, fumaric acid), 6.82-6.83 (br, 1H), 7.39-7.42 (d, J - 8.3 Hz, 1H). 144 323406 201211028486.3_) 6.3 A Ή-NMR (DMS0-d«, 400 MHz) 51.143-1.120 (dt, J - 7. 2, 3.7 Hz, 3H), 1.36-1.49 (mt 2fi), 1.53-1. 66 (m , 3H), 1. 76-1. 92 (π, 3H), 2.30-2.41 (m, 2H), 2.40-2.67 (m, 2H), 2.88-2.91 (brt 2H), 3.18-3. 26 (br , 2H), 2.39-2.50 (br, 2H), 3.42 (s, 5H), 3.74 (s, 3H), 4.00-4.1 0 (q, J = 7.2 Hz, 3H), 6.51-6.55 (dd, J = 8.3, 2.2 Hz, 1H), 6.56 (s, 2H, fumaric acid), 6.71 (br, 1H), 7.10-7.14 (d, J = 8.3 Hz, 1H). Ή-NMR (DMSO-di, 400 MHz) dO. 90-1. 02 (m, 2H)( 1.12-1.18 (t, J = 7.1 Hz, 3H), I. 54-1. 59 (d, J = 11.0 Hz, 2H), 1. 64-1 76 (d, J = 9.3Hz, 3H), 2.07-2.17 (m, 2H), 2.22-2.37 (d, J = 6.6 Hz, 2H), 2.31-2.42 (m, 2H), 2.64-2.81 (br , 2H), 2.95-3.02 (d, J = 11.0 Hz ( 2H), 3.42 (s, 2H), 3.75 (s, 3H), 3. 92-4.08 (q, J - 7.1 Hz, 5H), 6.51- 6. 57 (dd, J = 8. 3, 2.2 Hz, 1H), 6.59 (s, 2H, fumaric acid), 6.69-6.71 (d, J = 2.2 Hz, 1H), 7.10-7.12 (d, J = 8.3 Hz, 1H). lH-NMR (CIWJD, 400 MHz) 51.23-1.29 (t, J = 7. 2 Hz, 3H)f 1.59-1.81 (in, 7H), 1.90-1.97 (m, 2H), 2.06 -2.13 (m, 2H), 2.72-2.91 (br, 3H) , 3.08-3.14 (m, 2H), 3.55-3.61 (m, 2H), 3.81 (s, 3H), 3.86-3.91 (br, 2H), 4.10-4.19 (q, J = 7.2 Hz, 5H), 4.27 -4.40 (m, 3H), 6.61-6.67 (dd, J = 8.3, 2.2 Hz, 1H), 6.71 (s, 2H, fumaric acid), 6.81-6.82 (d, J = 2.2 Hz, 1H), 7.38- 7.43 (d, J = 8.3 Hz, 1H). Ή-NMR (CDsOD, 400 MHz) 51.13-1.30 (mt 3H), 1.63-2.05 (m, 10H), 2.14-2.20 (br, 1H), 2.20-2 . 29 (br, 1H), 2.72-2. 86 (m, 2H), 3.15-3.25 (m, 2H), 3.33-3.50 (m, 4H), 3.54-3.61 (m, 1H), 3.63-3.71 ( m, 1H), 3.81 (s, 3H), 3.84-3.91 (m, 2H), 4.10-4.19 (m, 4H), 4.31-4.40 (mt 1H), 6.62-6. 66 (dd, J = 8.3, 2. 2 Hz, 1H), 6.71 (s, 2H, fumaric acid), 6.82-6.83 (br, 1H), 7.39-7.42 (d, J - 8.3 Hz, 1H). 144 323406 201211028

64 OM· 520.2 (M+Na) 6.4 A N. D. 65 Cl F 466.1 _) 1.4 Ή-NMR (CDCls, 300 MHz) 5 1.23-1.28 (td, J = 71, 3. 2 Hz, 3H), 1.32 (s, 6H), 1.38-1.72 (m, 5H), 1.82-2.04 (π, 3H), 2.20-2.48 (m, 4H), 2.50-2.51 (br, 1H), 2.86-2.98 (brf 2H), 3.20-3.37 (br, 2H), 3.44-3.60 (m, 2H), 4.10-4.18 (q, J = 7.1 Hz, 3H), 4.18-4.30 (br, 1H), 6.99-7.08 (br, 1H), 7.14-7.17 (d, J=7.2 Hz). 66 ? rxy^ Q M· (延胡索酸鹽） 400.4 (M+H) 6.5 A Ή-NMR (DMSO-d., 400 MHz) 51.13-1.19 (t, J = 7.2Hz, 3HX 1.25-1.29 (d, J = 7.7Hz, 3H), 1.30-1.41 (m, 2H), 1.55-1.61 (br, 2H), 1.74-1.80 (d, J = 12.2 Hz, 2H), 2.30 (s, 3H), 2.30-2.46 (m, 4H), 2.59-2.69 (m, 1H), 2.70-2.81 (br, 2H), 2.99-3. 04 (d, J = 9.3Hzf 2H), 3.34-3.38 (q, J = 7.7 Hz, 1H), 3.96-4.10 (q, J = 7.2 Hz, 5H), 6.59 (s, 2H, fumaricacid), 6. 78-6. 82 (d, J = 7.4Hz, 1H), 6. 95 (s, 1H), 7.13-7.17 (d, J = 7.4 Hz). 67 Me (延胡索睃鹽） 386.3 (M+H) 6.2 Ή-NMR (DMSO-de, 400 MHz) δ\. 25-1. 29 (d, J = 7. 7 Hz, 3H), 1.30-1.41 (m, 2H), 1.55-1.61 (br, 2H), 1.74-1.80 (d, J = 12.2 Hz, 2H), 2.30 (s, 3H), 2. 30-2.46 (m, 4H), 2. 59-2. 69 (m, 1H), 2. 70-2. 82 (br, 2H), 2. 98-3.04 (d, J = 9.3Hz, 2H), 3.34-3.39 (q, J = 7. 7 Hz, 1H), 3.57 (s, 3H), 3.99-4.10 (br, 3H), 6.59(s, 2H, fumaric acid), 6.78-6.82 (d, J = 7.4 Hz, 1H), 6.95 (s, 1H), 7.13-7.17 (d, J = 7.4 Hz). 68 Μ* (延胡索酸鹽） 436.3 (M+Na) 6.6 A Ή-NMR (DMSO-de, 400 MHz) &lt;51.13-1.20 (dt, J = 7.2, 3.7 Hz, 3H), 1.21-1.23 (brt 1H), 1.26-1.29 (d, J = 7.7 Hz, 3H)t 1.38-1.49 (m, 2H), 1.54-.63 (ra, 3H), 1.77-1.98 (mf 3H)( 2.30 (s, 3H), 2.30-2.42 (m, 3H), 2. 62-2. 69 (m, lH)f 2. 91-2.98 (br, 2H), 3.19-3. 27 (br, 2H), 3.34-3.38 (q, J = 7.7 Hz, 1H), 3.39-49 (m, 2H), 3.99-4.06 (q, J = 7.2 Hz, 2H), 4.07-4.12 (m, 1H), 6.58(s, 2H, fumaric acid), 6.78-6.82 (dt J = 7.4 Hz, 1H), 6.97 (s, 1H), 7.13-7.17 (d, J = 7.4 Hz, 1H). 69 418 (M+H) 6.3 lH-NMR (CDCh, 300 MHz) &lt;51.27 (td, J = 7. 0, 2.2 Hz, 3H), 1.45 (d, J = 7.5 Hz, 3H), 1.61-1.83 (m, 5H), 1.84-2.03 (m, 3H), 2.24-2.50 (m, 4H), 2.56 (dd, J = 9.8, 9.8 Hz, 1H), 2.91 (br-sf 2H), 3.19-3.45 On, 2H), 3.38 (q, J = 7.5 Hz, 1H), 3_46-3.71 (m, 2H), 4.14 (q, J = 7.0 Hz, 2H), 4.21-4.36 (m, 1H), 6.86-7.01 (m, 2H), 7. 05-7.14 (m, 1H). 70 418.4 (M+H) 3.1 B Ή-NMR (CDCh, 300 MHz) 51.02-1.19 (m, 2H), 1.26 (t, J = 7.1 Hzf 3H), 1.46 (d, J = 7.5 Ηζ» 3H), 1.58-1.73 (m, 3H), 1.78 (br-d, J = 12.2 Hz, 2H), 2.08 (br-dd, J = 12.2, 12.2 Hz, 2H), 2.20 (d( J = 7.0 H2, 2H), 2.39 (br-ddd, J = 12.2, 12.2, 12.2 Hz, 2H), 2.75 (dd, J =12.2，12.2 Hz, 2H), 2.98 (br-d, J = 12.2 Hz, 2H)t 3.39 (q，J = 7. 5 Hz, 1H), 4. 07-4.35 (m, 3H), 4.13 (q, J = 7.1 Hz( 2H), 6.88-7.01 (m, 2H), 7.01-7.09 (m, 1H). 71 400.4 (M+H) 3.0 B H-NMR (CDCU 300 MHz) 51.02-1.21 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H), 1.47 (d, J = 7.5 Hz, 3H), 1.55-1.74 (m, 4H), 1.80 (br-d, J = 12.2 Hz, 2H), 2.00-2.16 (m, 1H), 2.21 (br-s, 2H)( 2.44 (br~s, 2H), 2.76 (ddt J = 12.2, 12.2 Hzt 2H)( 2.99 (br-s, 2H), 3.40 (qf J = 7.5 Hz，IH), 4. 07-4. 23 (m, 2H)t 4.13 (q, J = 7.1 Hz, 2H)，4. 23-4. 39 (id, 1H), 7.04 (dd( J = 7.9 Hz, 1H), 7.09-7.19 (m, 1H), 7.20-7.30 (in, 2H). 145 323406 20121102864 OM· 520.2 (M+Na) 6.4 A ND 65 Cl F 466.1 _) 1.4 Ή-NMR (CDCls, 300 MHz) 5 1.23-1.28 (td, J = 71, 3. 2 Hz, 3H), 1.32 (s , 6H), 1.38-1.72 (m, 5H), 1.82-2.04 (π, 3H), 2.20-2.48 (m, 4H), 2.50-2.51 (br, 1H), 2.86-2.98 (brf 2H), 3.20- 3.37 (br, 2H), 3.44-3.60 (m, 2H), 4.10-4.18 (q, J = 7.1 Hz, 3H), 4.18-4.30 (br, 1H), 6.99-7.08 (br, 1H), 7.14- 7.17 (d, J=7.2 Hz). 66 ? rxy^ QM· (fumarate) 400.4 (M+H) 6.5 A Ή-NMR (DMSO-d., 400 MHz) 51.13-1.19 (t, J = 7.2 Hz) , 3HX 1.25-1.29 (d, J = 7.7Hz, 3H), 1.30-1.41 (m, 2H), 1.55-1.61 (br, 2H), 1.74-1.80 (d, J = 12.2 Hz, 2H), 2.30 ( s, 3H), 2.30-2.46 (m, 4H), 2.59-2.69 (m, 1H), 2.70-2.81 (br, 2H), 2.99-3. 04 (d, J = 9.3Hzf 2H), 3.34-3.38 (q, J = 7.7 Hz, 1H), 3.96-4.10 (q, J = 7.2 Hz, 5H), 6.59 (s, 2H, fumaricacid), 6. 78-6. 82 (d, J = 7.4Hz, 1H ), 6. 95 (s, 1H), 7.13-7.17 (d, J = 7.4 Hz). 67 Me (corydial salt) 386.3 (M+H) 6.2 Ή-NMR (DMSO-de, 400 MHz) δ\ 25-1. 29 (d, J = 7. 7 Hz, 3H), 1.30-1.41 (m, 2H), 1.55-1.61 (br, 2H), 1.74-1.80 (d, J = 12.2 Hz, 2H), 2.30 (s, 3H), 2. 30-2.46 (m, 4H), 2. 59-2. 69 (m, 1H), 2. 70-2. 82 (br, 2H ), 2. 98-3.04 (d, J = 9.3Hz, 2H), 3.34-3.39 (q, J = 7. 7 Hz, 1H), 3.57 (s, 3H), 3.99-4.10 (br, 3H), 6.59(s, 2H, fumaric acid), 6.78-6.82 (d, J = 7.4 Hz, 1H), 6.95 (s, 1H), 7.13-7.17 (d, J = 7.4 Hz). 68 Μ* (fumarate) 436.3 (M+Na) 6.6 A Ή-NMR (DMSO-de, 400 MHz) &lt;51.13-1.20 (dt, J = 7.2, 3.7 Hz, 3H), 1.21-1.23 (brt 1H), 1.26-1.29 (d , J = 7.7 Hz, 3H)t 1.38-1.49 (m, 2H), 1.54-.63 (ra, 3H), 1.77-1.98 (mf 3H) ( 2.30 (s, 3H), 2.30-2.42 (m, 3H ), 2. 62-2. 69 (m, lH)f 2. 91-2.98 (br, 2H), 3.19-3. 27 (br, 2H), 3.34-3.38 (q, J = 7.7 Hz, 1H) , 3.39-49 (m, 2H), 3.99-4.06 (q, J = 7.2 Hz, 2H), 4.07-4.12 (m, 1H), 6.58(s, 2H, fumaric acid), 6.78-6.82 (dt J = 7.4 Hz, 1H), 6.97 (s, 1H), 7.13-7.17 (d, J = 7.4 Hz, 1H). 69 418 (M+H) 6.3 lH-NMR (CDCh, 300 MHz) &lt;51.27 (td, J = 7. 0, 2.2 Hz, 3H), 1.45 (d, J = 7.5 Hz, 3H), 1.61-1.83 (m, 5H), 1.84-2.03 (m, 3H), 2.24-2.50 (m, 4H) , 2.56 (dd, J = 9.8, 9.8 Hz , 1H), 2.91 (br-sf 2H), 3.19-3.45 On, 2H), 3.38 (q, J = 7.5 Hz, 1H), 3_46-3.71 (m, 2H), 4.14 (q, J = 7.0 Hz, 2H), 4.21-4.36 (m, 1H), 6.86-7.01 (m, 2H), 7. 05-7.14 (m, 1H). 70 418.4 (M+H) 3.1 B Ή-NMR (CDCh, 300 MHz) 51.02-1.19 (m, 2H), 1.26 (t, J = 7.1 Hzf 3H), 1.46 (d, J = 7.5 Ηζ» 3H), 1.58-1.73 (m, 3H), 1.78 (br-d, J = 12.2 Hz, 2H), 2.08 (br-dd, J = 12.2, 12.2 Hz, 2H), 2.20 (d( J = 7.0 H2, 2H), 2.39 (br-ddd, J = 12.2, 12.2, 12.2 Hz, 2H) , 2.75 (dd, J = 12.2, 12.2 Hz, 2H), 2.98 (br-d, J = 12.2 Hz, 2H)t 3.39 (q, J = 7. 5 Hz, 1H), 4. 07-4.35 (m , 3H), 4.13 (q, J = 7.1 Hz ( 2H), 6.88-7.01 (m, 2H), 7.01-7.09 (m, 1H). 71 400.4 (M+H) 3.0 B H-NMR (CDCU 300 MHz 51.02-1.21 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H), 1.47 (d, J = 7.5 Hz, 3H), 1.55-1.74 (m, 4H), 1.80 (br-d, J = 12.2 Hz, 2H), 2.00-2.16 (m, 1H), 2.21 (br-s, 2H) ( 2.44 (br~s, 2H), 2.76 (ddt J = 12.2, 12.2 Hzt 2H) ( 2.99 (br- s, 2H), 3.40 (qf J = 7.5 Hz, IH), 4. 07-4. 23 (m, 2H)t 4.13 (q, J = 7.1 Hz, 2H), 4. 23-4. 39 (id , 1H), 7.04 (dd( J = 7.9 Hz, 1H), 7.09-7.19 (m, 1H), 7.20-7.30 (in, 2H). 145 323406 201211028

72 P 400.4 (M+H) 3.0 B Ή-NMR (CDCh, 300 MHz) 51.27 (td, J = 7.1, 2.4 Hz, 3H), 1.36-1.77 (m, 5H), 1.81-2.07 (m, 3H), 2.32 (s, 3H), 2.25-2.49 (m, 4H), 2.55 (dd, J = 9.2, 9.2 Hz, 1H), 2. 90 (br-s, 2H), 3.19-3. 39 (m, 2H), 3.47 (s, 2H), 3.41-3.70 (m, 2H), 4.15 (q, J = 7.1 Hz, 2H), 4.21-4.40 (m, 1H), 6. 97-7.14 (m, 3H). 73 Μ· 400.5 (M+H) 3.1 Ή-NMR (CDCIj, 300 MHz) 51.11 (dddd, J = 12.2, 12.2, 12.2, 4.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H), 1.60-1.71 (m, 3H), 1.79 (br-d, J = 12.2 Hz, 2H), 2.07 (dd, J = 12.2, 12.2 Hz, 2H), 2.20 (d, J = 7.1 Hz, 2H), 2.32 (s, 3H), 2.41 (dddd, J - 12.2, 12.2, 12.2, 4.0 Hz, 2H), 2.76 (dd, J = 12.2, 12.2 Hz, 2H), 2.97 (br-d, J = 12.2 Hz, 2H), 3.48 (s( 2H), 4.07-4.22 (m, 2H), 4.13 (q, J = 7.1 Hz, 2H), 4.29 (dddd, J = 12.2, 12.2, 4.0, 4.0 Hz, 1H), 7.01-7.10 (m, 3H). 74 386.4 (M+H) 3.4 B *H-NMR (CDCU, 300 MHz) 51.10 (dddd, J = 12.2, 12.2, 12.2, 4.0 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H), 1.59-1.73 (m, 3H), 1.79 (br-d, J = 12.7 Hz, 2H), 2.08 (dd，J = 12.2，12.2 Hz, 2H), 2.20 (d, J = 7.1 Hz, 2H), 2.44 (dddd, J = 12.2, 12.2, 12.2, 4.0 Hz, 2H), 2.76 (dd, J = 12.2, 12.2 Hz, 2H), 2.98 (br-d, J = 12.2 Hz, 2H), 3.51 (s, 2H), 4.07-4.23 (m, 2H), 4.13 (q, J = 7.1 Hz, 2H), 4.31 (dddd, J = 12.2, 12.2, 4.0, 4.0 Hz, 1H), 7.02 (dd, J = 7.4, 7.4 Hz. 1H), 7.13 (d, J = 7.4 Hz, 1H), 7.20-7.30 (m, 2H). 75 Q F 404.1 (M+H) 4.7 Ή-NMR (CDCU 400 MHz) δ 1.20 (t, J = 7.1 Hz, 3H), 1.37, 1.39 (sf 3Hf ratio = 1 : 1),1.50-2.51 (m, 10H), 2.65-2.76 (m, 2H), 2.98-3.12 (m, 2H), 3. 27-3. 34 (m, 2H), 4. 07 (q, J = 7.1 Hz, 2H), 4.12-4.31 (m, 1H), 6.61-6.67 (m, 1H), 7.06-7.09 (m, 1H), 7.15-7.19 (m, 1H). 76 F 418.2 (M+H) 5.4 N.D. 77 F 376 (M+H) 6.2 lH-NMR (CDCU 400 MHz) &lt;51.47 (m 4H), 1.70 Cm 2H), 1.80 (m, 2H), 2.37 (m, 3H), 2.50 (m, 1H), 2.77 (m, 2H), 3.01 (m, 2H), 3.12 (m( 1H), 3.51 (s, 2H)，3.69 (s, 3H), 3.87 (in, 1H), 4.29 (m，2H), 6.91 (m, 1H), 6.98 (m, 1H)( 7.07 (m 1H). 78 Me 372 _) 5.7 lH-NMR (CDCls, 400 MHz) 51.49 (m 2H)( 1.73 (m 2H), 1.86 (m, 2H), 2.43-2.45 (mt 6H), 2.77 (t, 2H), 3.05 (m, 2H), 3.46 (s, 2H), 3.70 (s, 3H), 4.28 (m, 2H), 6.84 (d, 1H), 6.98 (s, 1H), 7.13 (d, 1H). 79 Br 450 (M+H) 6.2 Ή-NMR CCDCh, 400 MHz) 51.26 (t, 3H), 1.68 (m, 2H), 1.83 (m, 2H), 2.10 (m, 2H), 2.68 (m, 2H), 2.84 {m, 2H), 2.96 (m, 2H), 3.54 (m, 4H), 3.70 (m, 2H), 4.18 (m, 2H), 4.45 (m, 1H), 4.66 (m, 1H), 7.09 (m, 1H), 7.22 (m, 1H), 7.40 (m, 1H). 80 Br 465 (M+H) 6.4 A N.D. 146 323406 20121102872 P 400.4 (M+H) 3.0 B Ή-NMR (CDCh, 300 MHz) 51.27 (td, J = 7.1, 2.4 Hz, 3H), 1.36-1.77 (m, 5H), 1.81-2.07 (m, 3H) , 2.32 (s, 3H), 2.25-2.49 (m, 4H), 2.55 (dd, J = 9.2, 9.2 Hz, 1H), 2. 90 (br-s, 2H), 3.19-3. 39 (m, 2H), 3.47 (s, 2H), 3.41-3.70 (m, 2H), 4.15 (q, J = 7.1 Hz, 2H), 4.21-4.40 (m, 1H), 6. 97-7.14 (m, 3H) 73 Μ· 400.5 (M+H) 3.1 Ή-NMR (CDCIj, 300 MHz) 51.11 (dddd, J = 12.2, 12.2, 12.2, 4.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H), 1.60-1.71 (m, 3H), 1.79 (br-d, J = 12.2 Hz, 2H), 2.07 (dd, J = 12.2, 12.2 Hz, 2H), 2.20 (d, J = 7.1 Hz, 2H), 2.32 (s, 3H), 2.41 (dddd, J - 12.2, 12.2, 12.2, 4.0 Hz, 2H), 2.76 (dd, J = 12.2, 12.2 Hz, 2H), 2.97 (br-d, J = 12.2 Hz, 2H ), 3.48 (s( 2H), 4.07-4.22 (m, 2H), 4.13 (q, J = 7.1 Hz, 2H), 4.29 (dddd, J = 12.2, 12.2, 4.0, 4.0 Hz, 1H), 7.01- 7.10 (m, 3H). 74 386.4 (M+H) 3.4 B *H-NMR (CDCU, 300 MHz) 51.10 (dddd, J = 12.2, 12.2, 12.2, 4.0 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H), 1.59-1.73 (m, 3H), 1.79 (br-d, J = 12.7 Hz, 2H), 2.08 (dd, J = 12.2, 12.2 Hz, 2 H), 2.20 (d, J = 7.1 Hz, 2H), 2.44 (dddd, J = 12.2, 12.2, 12.2, 4.0 Hz, 2H), 2.76 (dd, J = 12.2, 12.2 Hz, 2H), 2.98 (br -d, J = 12.2 Hz, 2H), 3.51 (s, 2H), 4.07-4.23 (m, 2H), 4.13 (q, J = 7.1 Hz, 2H), 4.31 (dddd, J = 12.2, 12.2, 4.0 , 4.0 Hz, 1H), 7.02 (dd, J = 7.4, 7.4 Hz. 1H), 7.13 (d, J = 7.4 Hz, 1H), 7.20-7.30 (m, 2H). 75 QF 404.1 (M+H) 4.7 Ή-NMR (CDCU 400 MHz) δ 1.20 (t, J = 7.1 Hz, 3H), 1.37, 1.39 (sf 3Hf ratio = 1 : 1), 1.50-2.51 (m, 10H), 2.65-2.76 (m, 2H), 2.98-3.12 (m, 2H), 3. 27-3. 34 (m, 2H), 4. 07 (q, J = 7.1 Hz, 2H), 4.12-4.31 (m, 1H), 6.61- 6.67 (m, 1H), 7.06-7.09 (m, 1H), 7.15-7.19 (m, 1H). 76 F 418.2 (M+H) 5.4 ND 77 F 376 (M+H) 6.2 lH-NMR (CDCU 400 MHz) &lt;51.47 (m 4H), 1.70 Cm 2H), 1.80 (m, 2H), 2.37 (m, 3H), 2.50 (m, 1H), 2.77 (m, 2H), 3.01 (m, 2H), 3.12 (m( 1H), 3.51 (s, 2H), 3.69 (s, 3H), 3.87 (in, 1H), 4.29 (m, 2H), 6.91 (m, 1H), 6.98 (m, 1H) ( 7.07 (m 1H). 78 Me 372 _) 5.7 lH-NMR (CDCls, 400 MHz) 51.49 (m 2H) ( 1.73 (m 2H), 1.86 (m, 2H), 2.43-2.45 (mt 6H), 2.77 (t, 2H), 3.05 (m, 2H), 3.46 (s, 2H), 3.70 (s, 3H), 4.28 (m, 2H), 6.84 (d, 1H), 6.98 (s, 1H), 7.13 (d, 1H). 79 Br 450 (M+H) 6.2 Ή-NMR CCDCh, 400 MHz) 51.26 (t, 3H), 1.68 (m, 2H), 1.83 (m, 2H), 2.10 (m, 2H) , 2.68 (m, 2H), 2.84 {m, 2H), 2.96 (m, 2H), 3.54 (m, 4H), 3.70 (m, 2H), 4.18 (m, 2H), 4.45 (m, 1H), 4.66 (m, 1H), 7.09 (m, 1H), 7.22 (m, 1H), 7.40 (m, 1H). 80 Br 465 (M+H) 6.4 A ND 146 323406 201211028

81 82 83 84 85 86 87 88 89 go U&gt;° rC〇2Me81 82 83 84 85 86 87 88 89 go U&gt;° rC〇2Me

438 (M+H) 5.9 A 400 (M+H) 6.5 Ή-NMR (CDCh, 400 MHz) &lt;51.46 (m, 2H), 1.71 (m, 1H), 1.85 (m, 4H) 2.37 (m 3H), 2.53 (m, 1H), 2.77 (m, 2H) 3.03 (m, 2H), 3.45 (s, 2H), 3.70 (s, 3H), 4.24 (m, 2HX 7. 14 (m, 2H), 7.29 (m，1H). N. D. 广/〇2Et438 (M+H) 5.9 A 400 (M+H) 6.5 Ή-NMR (CDCh, 400 MHz) &lt;51.46 (m, 2H), 1.71 (m, 1H), 1.85 (m, 4H) 2.37 (m 3H ), 2.53 (m, 1H), 2.77 (m, 2H) 3.03 (m, 2H), 3.45 (s, 2H), 3.70 (s, 3H), 4.24 (m, 2HX 7. 14 (m, 2H), 7.29 (m,1H). ND 广/〇2Et

414 (M+H)6.6 A N.D. COzEt414 (M+H)6.6 A N.D. COzEt

414 (M+H)6.8 A 442.1 (M+Na) 6.5 432.2 (M+H) 6.5414 (M+H) 6.8 A 442.1 (M+Na) 6.5 432.2 (M+H) 6.5

404.2 (M+H)6.0 A N.D. N.D. N. D. N.D. 人404.2 (M+H)6.0 A N.D. N.D. N. D. N.D. People

416.2 (M+H) 6.1 A N.D. .,COjEt416.2 (M+H) 6.1 A N.D. .,COjEt

Me (延胡索酸鹽） C〇2Et 422.3 (M+Na) 6.3 Ή-NMR (DMSO-de, 400 MHz) δ 1.13-1.19 (dtt J = 7.2, 3.7 Hz, 3HX 1.40-1.49 (m, 2H), 1.57-1.68 (m, 3H), 1.89-1.99 (m, 3H), 2.29 (s, 3H), 2.34-2.50 (m, 2H), 2.53-2.68 (m, 2H), 2. 70-2.78 (m, 1H), 2.96-3. 03 (br, 2H), 3.18-3.27 (br, 2H), 2.40-2.49 (m, 4H), 3.99-4.06 (q, J = 7.2Hz, 2H), 4.11-4.20 (br, 1H), 6.58(s, 2H, fumaric acid), 6.76-6.80 (d, J = 7.4 Hz, 1H), 6.99 (s, 1H), 7.08-7.12 (d, J = 7.4 Hz, 1H). 400 (M+H) 6.3 lH-NMR (CDCh, 400 MHz) δ 1.06-1.18 (m, 2H), 1.26 (t, J = 7.1Hz, 3H), 1.63-1.71 (in, 3H), 1.73-1.86 (m, 2H), 2.06-2.13 On, 2H)，2.21 (d，J = 7.1 Hz, 2H)，2.33-2.49 (m，2H), 2.39 (s, 3H), 2.69-2.82 (m, 2H), 3.00(d, J = 11.5Hz, 2H), 3.46 (s, 2H), 4.13 (q, J = 7.1 Hz, 2H), 4.11-4.31 (m, 3H), 6.83 (d, J = 7. 6 Hz, 1H), 6. 94 (s, 1H), 7.11 (d( J = 7.6 Hz, 1H). 147 323406 201211028 0 ^-- 91 η 404 (Μ+Η) 6.0 A Ή-NMR (CDCht 400 MHz) δ 1.05-1.16 (m, 2Η), 1.26 (t, J = 7.1 Hz. 3H), 1.64-1.70 (m, 3H), 1.79(d, J = 13.4 Hz, 2H), 2.07(t, J = ll.7 Hz, 2H), 2.20 (d, J = 7.1 Hz, 2H), 2.38 (dt, J = 12.4t 3.7 Hz, 2H), 2.62-2.79 (m, 2H), 2.97-3.01 (m, 2H), 3.47 (s, 2H), 4.13 (q, J = 7.1 Hz( 2H), 4.11-4.29 (m, 3H)t 6.68-6.73 (m, 1HX 6.78 (dd, J = 9.8, 2.4 Hz, 1H), 7.14-7.18 (m, 1H). ' 92 F 404.7 (M+H) 2.9 (CDCK 400 MHz) δ 1.21-1.71 (η，8H), 2.02-2.81 (n，2H), 2.28-2.47 (m, 4H), 2.51-2.58 (m, 2H), 2.87-2.99 (η, 2H), 3.23-3.36 (m, 2H). 3.46-3.68 (m, 4H), 4.07-4.31 (m, 5H), 7.68-7.73 (m, 1H), 6.89-6.97 Cm, 1H), 7.13-7.18 (m, IH). ' * 93 433.9 (M+H) 1.1 N.D.Me (fumarate) C〇2Et 422.3 (M+Na) 6.3 Ή-NMR (DMSO-de, 400 MHz) δ 1.13-1.19 (dtt J = 7.2, 3.7 Hz, 3HX 1.40-1.49 (m, 2H), 1.57 -1.68 (m, 3H), 1.89-1.99 (m, 3H), 2.29 (s, 3H), 2.34-2.50 (m, 2H), 2.53-2.68 (m, 2H), 2. 70-2.78 (m, 1H), 2.96-3. 03 (br, 2H), 3.18-3.27 (br, 2H), 2.40-2.49 (m, 4H), 3.99-4.06 (q, J = 7.2Hz, 2H), 4.11-4.20 ( Br, 1H), 6.58(s, 2H, fumaric acid), 6.76-6.80 (d, J = 7.4 Hz, 1H), 6.99 (s, 1H), 7.08-7.12 (d, J = 7.4 Hz, 1H). 400 (M+H) 6.3 lH-NMR (CDCh, 400 MHz) δ 1.06-1.18 (m, 2H), 1.26 (t, J = 7.1Hz, 3H), 1.63-1.71 (in, 3H), 1.73-1.86 (m, 2H), 2.06-2.13 On, 2H), 2.21 (d, J = 7.1 Hz, 2H), 2.33-2.49 (m, 2H), 2.39 (s, 3H), 2.69-2.82 (m, 2H) , 3.00 (d, J = 11.5 Hz, 2H), 3.46 (s, 2H), 4.13 (q, J = 7.1 Hz, 2H), 4.11-4.31 (m, 3H), 6.83 (d, J = 7. 6 Hz, 1H), 6. 94 (s, 1H), 7.11 (d( J = 7.6 Hz, 1H). 147 323406 201211028 0 ^-- 91 η 404 (Μ+Η) 6.0 A Ή-NMR (CDCht 400 MHz ) δ 1.05-1.16 (m, 2Η), 1.26 (t, J = 7.1 Hz. 3H), 1.64-1.70 (m, 3H), 1.79 (d, J = 13.4 Hz, 2H), 2.07(t, J = ll.7 Hz, 2H), 2.20 (d, J = 7.1 Hz, 2H), 2.38 (dt, J = 12.4t 3.7 Hz, 2H), 2.62-2.79 (m, 2H), 2.97 -3.01 (m, 2H), 3.47 (s, 2H), 4.13 (q, J = 7.1 Hz( 2H), 4.11-4.29 (m, 3H)t 6.68-6.73 (m, 1HX 6.78 (dd, J = 9.8 , 2.4 Hz, 1H), 7.14-7.18 (m, 1H). ' 92 F 404.7 (M+H) 2.9 (CDCK 400 MHz) δ 1.21-1.71 (η,8H), 2.02-2.81 (n,2H), 2.28-2.47 (m, 4H), 2.51-2.58 (m, 2H), 2.87-2.99 (η, 2H), 3.23-3.36 (m, 2H). 3.46-3.68 (m, 4H), 4.07-4.31 (m , 5H), 7.68-7.73 (m, 1H), 6.89-6.97 Cm, 1H), 7.13-7.18 (m, IH). ' * 93 433.9 (M+H) 1.1 ND

C N. D.:無數據（No Data)C N. D.: No data (No Data)

參考例70 4一0’4_二氧雜〜8-吖螺[4.5]癸烷-8_基）-4-甲基哌啶一卜 羧酸第三丁酯Reference Example 70 4 -0'4-dioxa-8-indole [4.5]decane-8-yl)-4-methylpiperidine-dicarboxylic acid tert-butyl ester

將 4 底咬_ 乙稀縮搭（4-piperid〇ne Ethylene Acetal) (32g)、N-Boc-4-哌啶酮（40g)、1，2, 3-***（17g)溶解於曱 ®苯（200ml)後，經由迪安—斯塔克装置（Dean-Stark trap) 一面脫水一面加熱回流8小時。將反應液冷卻至室溫，使 反應液成為24°C以下加入溴化甲基鎂（2〇〇mm〇13M in ether)之THF(200ml)溶液’於室溫攪拌1小時。使反應液 溫度成為30°C以下’於反應液加入2〇%氯化銨水溶液。以 乙酸乙酯進行萃取，以2mol/L氫氧化鈉及水洗淨，將有機 層進行減壓濃縮。將所得之殘渣以矽膠管柱層析精製，得. 到標題化合物（2〇g，29«。 參考例71 323406 148 201211028 4-(1，4-二氧雜-8-吖螺[4· 5]癸烷-8-基）-4-曱基派咬鹽酸Dissolve 4-piperid〇ne Ethylene Acetal (32g), N-Boc-4-piperidone (40g), 1,2,3-triazole (17g) in 曱® After benzene (200 ml), it was heated to reflux for 8 hours while dehydrating via a Dean-Stark trap. The reaction solution was cooled to room temperature, and the reaction solution was added to a solution of methylmagnesium bromide (2 〇〇mm 〇 13M in ether) in THF (200 ml). The temperature of the reaction mixture was changed to 30 ° C or lower. A 2% aqueous ammonium chloride solution was added to the reaction liquid. The extract was extracted with ethyl acetate, washed with 2 mol/L sodium hydroxide and water, and the organic layer was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give the title compound (2 〇g, 29 «. Reference Example 71 323406 148 201211028 4-(1,4-dioxa-8- snail [4·5 ] decane-8-yl)-4-hydrazino

將參考例70之化合物（14g)溶解於1，二曙烧（i〇〇mi)， 加入6mol/L鹽酸（100ml) ’於室溫攪拌1〇小時。將反應液 進行減壓濃縮，得到標題化合物（l〇g)。 參考例72The compound of Reference Example 70 (14 g) was dissolved in 1, dioxime (i〇〇mi), and 6 mol/L hydrochloric acid (100 ml) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure toiel Reference example 72

4-(1,4 -一氧雜_8_σ丫螺[4. 5]癸院-g-基）—4一曱基派咬_ι_ 羧酸乙酯4-(1,4-oxo-oxa_8_σ丫 snail [4. 5] brothel-g-base)—4 曱 派 派 _ _ _ _ ethyl carboxylate

將參考例71之化合物（5g)溶解於水（5〇mi)、thf (50ml)，加入碳酸鈉（llg)。將反應液於室溫攪拌3〇分鐘 後，加入氯曱酸乙酯（2. 9g)，於室溫攪拌1〇小時。以二氯 甲烧萃取反應液，以硫酸納進行乾燥後，藉由減壓濃縮而 得到標題化合物（6g)。The compound of Reference Example 71 (5 g) was dissolved in water (5 〇mi), thf (50 ml), and sodium carbonate (llg) was added. After the reaction mixture was stirred at room temperature for 3 minutes, ethyl chloroacetate (2.9 g) was added and stirred at room temperature for 1 hr. The reaction mixture was extracted with methylene chloride (MgSO4).

參考例73 4-(4-侧氧基哌啶-1-基）-4-曱基哌啶-1-竣酸乙醋 曰 將參考例72之化合物（6.〇g)溶解於丨，4_二噚烷 (240ml)，加入6mol/L鹽酸（24〇ml)後，加熱回流15小時。 將反應液冷卻至室溫，加入10%氫氧化鈉水溶液。以二氣 甲烷進行萃取後，以硫酸鈉進行乾燥，並藉由減壓濃縮而 得到標題化合物（5. lg)。 323406 149 201211028 參考例74 4-(4-側氧基哌啶-1-基）-4-曱基哌啶-1-羧酸甲酯 Q=^ ^N-CQ2Me 使用參考例71之化合物，並使用氯甲酸曱酯以取代氣 曱酸乙酯，依照與參考例72至73相同的方法而得到標題 化合物。 參考例75Reference Example 73 4-(4-Sideoxypiperidin-1-yl)-4-mercaptopiperidine-1-decanoic acid ethyl acetate The compound of Reference Example 72 (6. g) was dissolved in hydrazine, 4 Dioxane (240 ml) was added to 6 mol/L hydrochloric acid (24 mL) and heated to reflux for 15 hours. The reaction solution was cooled to room temperature, and a 10% aqueous sodium hydroxide solution was added. After extraction with methylene chloride, the title compound (5. lg) was obtained. 323406 149 201211028 Reference Example 74 4-(4-Axylpiperidin-1-yl)-4-mercaptopiperidine-1-carboxylic acid methyl ester Q=^ ^N-CQ2Me The compound of Reference Example 71 was used, and The title compound was obtained by the same procedure as the referenced. Reference example 75

2(2-{1-[(1-乙氧基羰基）-4-曱基哌啶-4-基]哌啶-4-基} 胺基-4-曱氧基苯基）-1，3-丙二酸二第三丁酯 C〇2^Bu C02Et 齡 ΗΝΌι〇 使用參考例62之化合物與參考例73之化合物，並依 照與參考例30相同的方法而得到標題化合物。 實施例94 4-[4-(6-曱氧基-2-侧氧基-2, 3-二氫-1H-吲哚-卜基）-哌 啶-1-基]-4-曱基哌啶-1-羧酸乙酯2(2-{1-[(1-ethoxycarbonyl)-4-mercaptopiperidin-4-yl]piperidin-4-yl}amino-4-methoxyphenyl)-1,3 -D-butyl succinate C 〇 2 ^Bu C02Et ΗΝΌ 〇 〇 〇 〇 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Example 94 4-[4-(6-Methoxy-2-oxo-2,3-dihydro-1H-indole-buyl)-piperidin-1-yl]-4-indolyl Ethyl pyridine-1-carboxylate

OMe 將參考例75之化合物（115mg)、4-乙基苯橫酸（145mg) 溶解於曱烷（2ml)，於125°C攪拌3小時。將4mol/L氫氧 化鈉加入至反應液後，以氯仿進行萃取。以飽和食鹽水洗 淨有機層後，以硫酸鈉進行乾燥，以矽藻土過濾。將濾液 進行減壓濃縮後，藉由將所得之殘渣以矽膠管柱層析精製OMe The compound of Reference Example 75 (115 mg) and 4-ethylbenzene-yield (145 mg) were dissolved in decane (2 ml) and stirred at 125 ° C for 3 hours. After 4 mol/L of sodium hydroxide was added to the reaction liquid, extraction was carried out with chloroform. The organic layer was washed with brine, dried over sodium sulfate and filtered over Celite. After the filtrate was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography.

150 323406 S 201211028 而得到標題化合物之延胡索酸鹽（40mg)。 LC-MS:R.T. 5. 5min·，m/z 430. 2(M+H).條件 A。 'H-NMR (CDsOD, 400MHz) ά 1. 25-1. 30 (t, J=7. 0Hz, 3H), 1.45 (s, 3H), 1.79-1.86 (m, 2H). 1.94-2.06 (m, 4H), 2.74-2.85 (m, 2H), 3.05-3.15 (m, 4H), 3.48 (s, 2H), 2.68-2. 74 (m, 2H), 3.81 (s, 3H), 4. 11-4. 19 (q, J=7. 0Hz, 4H), 4.34-4.47 (br, 1H), 6.60-6.64 (d, J=8. 0Hz, 1H), 鲁 6·71 (s2H, furaaric acid), 6.80 (s, 1H), 7.16-7.20 (d, J=8. 〇Hz, 1H). 實施例95至96 使用對應之中間物，依照與實施例94相同的方法而得 到下述化合物。[4 6] 實施例 ------- 構造 (鹽） MS (m/z) 分餚 條件 _ ----- NMR (MHz,溶劑） 95 ------ 404,1 _) 3.5 A lH-NMR (CDC13，400 MHz) δ 0.95 (s，3H)，1.28 (t, j = 7 3 Hz, 3H)，1.37-1.46 (m* 2H)，1.69-1.76 (m, 2H), 2·2卜2 34 (m, 4H)( 3.04-3.10 (m( 2H), 3.39-3.49 (m, 4H)( 3.52-3. 63 (ra，2H)，4.15 (q，J = 7.3 Hz，2H〉，4.18-4.18 (m, ih) 6.68-6. 73 (m，1H)，6.84 (dd，J = 9.5, 2.2 Hz，1H)，7.14_7 ^ (m, 1H). 96 Me 400.2 (_ 5.2 A ----------一一 1H-NMR (CDC13，400 MHz) δ 0.96 (s，3H)，1.28 (t, j = 7 1 Hz, 3H)，1.38-1.46 (m，2H&gt;, 1.69-1.76 (m，2H), 2.24-2.40 (m，4H&gt;，2.40 (s, 3H), 3.06 (d, J= 1〇 5 Hz, 2H) 3. 51—3.44 (m, 4H), 3.52—3.61 (m, 2H), 4.13 (q&gt; J = 7 j 2H), 4.19-4.27 (ra, 1H)，6_ 83 (d，J = 7.3 Hz，1H), 6.91 (s’ 1H)，7.12 (d，J = 7.3 Hz, 1H). ’ 參考例76 2(2〜{1-[(1-乙氧基羰基）_4—甲基哌啶_4_基]哌啶_4_基} 151 323406 201211028 胺基-4-甲氧基笨基）（曱基）-1，3-丙二酸二第三丁醋150 323406 S 201211028 The title compound of fumarate (40 mg) was obtained. LC-MS: R.T. 5. 5 min·, m/z 430. 2 (M+H). 'H-NMR (CDsOD, 400MHz) ά 1. 25-1. 30 (t, J=7. 0Hz, 3H), 1.45 (s, 3H), 1.79-1.86 (m, 2H). 1.94-2.06 (m , 4,,,,, -4. 19 (q, J=7. 0Hz, 4H), 4.34-4.47 (br, 1H), 6.60-6.64 (d, J=8. 0Hz, 1H), Lu 6·71 (s2H, furaaric acid) 6.80 (s, 1H), 7.16-7.20 (d, J = 8. 〇 Hz, 1H). Examples 95 to 96 The following compounds were obtained in the same manner as in Example 94 using the corresponding intermediate. [4 6] Example ------- Construction (salt) MS (m/z) Subdivision conditions _ ----- NMR (MHz, solvent) 95 ------ 404,1 _) 3.5 A lH-NMR (CDC13, 400 MHz) δ 0.95 (s, 3H), 1.28 (t, j = 7 3 Hz, 3H), 1.37-1.46 (m* 2H), 1.69-1.76 (m, 2H), 2·2卜 2 34 (m, 4H)( 3.04-3.10 (m( 2H), 3.39-3.49 (m, 4H)( 3.52-3. 63 (ra, 2H), 4.15 (q, J = 7.3 Hz, 2H>, 4.18-4.18 (m, ih) 6.68-6. 73 (m,1H), 6.84 (dd, J = 9.5, 2.2 Hz, 1H), 7.14_7 ^ (m, 1H). 96 Me 400.2 (_ 5.2 A ----------1H-NMR (CDC13,400 MHz) δ 0.96 (s,3H), 1.28 (t, j = 7 1 Hz, 3H), 1.38-1.46 (m, 2H&gt;, 1.69-1.76 (m, 2H), 2.24-2.40 (m, 4H&gt;, 2.40 (s, 3H), 3.06 (d, J = 1〇5 Hz, 2H) 3. 51-3.44 (m, 4H ), 3.52—3.61 (m, 2H), 4.13 (q&gt; J = 7 j 2H), 4.19-4.27 (ra, 1H), 6_ 83 (d, J = 7.3 Hz, 1H), 6.91 (s' 1H) , 7.12 (d, J = 7.3 Hz, 1H). 'Reference Example 76 2(2~{1-[(1-ethoxycarbonyl)_4-methylpiperidine-4-yl]piperidine _4_yl } 151 323406 201211028 Amino-4-methoxyphenyl)(indenyl)-1,3-propanedioic acid

COafBUCOafBU

使用參考例75之化合物，依照與參考例64相同的方 法而得到標題化合物。 實施例97 4-[4-(6_曱氧基-3-曱基_2_側氧基_2, 3_二氣Using the compound of Reference Example 75, the title compound was obtained according Example 97 4-[4-(6-曱oxy-3-indolyl-2-sideoxy-2, 3_digas

基）-派咬-1-基]-4-曱基哌啶一卜羰酸乙酯 L r-NH〇*c〇iEt 94相同的 使用參考例76之化合物，並依照與實施例 方法而得到標題化合物。 條件A。 LC-MS.R.T. 5.5 min., m/z 430.2(M+1). 參考例77The compound of the reference example 76 was used in the same manner as in the method of the example, and the compound of the formula 76 was obtained by the same method as the method of the example. Title compound. Condition A. LC-MS.R.T. 5.5 min., m/z 430.2 (M+1).

(3-^-3-胺基如丫雙環[3. 2· u辛烧_8_幾酸 H2N-^N_C〇2Et 乙酯 側氧降k ^'驗-8-叛酸（3. 3g)溶解於甲醇（5〇ml) t(5mn ’加入曱酸銨（9.5g)與 10% Pd/C(3.0g)後，於 至溫攪拌24小時。藉由過滤反應液且進行減壓濃縮而得到 標題化合物（3. 9g，74%)。 參考例78 1-乙基甲基-4，氧基麵填化物 ㊀ &quot;Me 152 323406 201211028 將卜乙基-4-哌啶酮溶解於丙酮（8〇ml)，加入碳酸鈉 (llg)。室溫下加入甲基填（3. 18ml)，授拌2. 5小時。滤取 所析出的固體’於減壓下進行乾燥後，得到標題化合物 (9. llg，860/〇)。 參考例79 (3-内）-3-(4-侧氧基娘°定-1-基）-8-σ丫雙環[3. 2. 1]辛炫1 -8-羧酸乙酯(3-^-3-Amino group such as fluorene double ring [3. 2· u 辛烧_8_ 酸酸H2N-^N_C〇2Et ethyl ester side oxygen drop k ^ ' test -8- tas acid (3. 3g) After dissolving in methanol (5 〇ml) t (5 mn', ammonium citrate (9.5 g) and 10% Pd/C (3.0 g) were added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered and concentrated under reduced pressure. The title compound (3.9 g, 74%) was obtained.. Reference Example 78 1-ethylmethyl-4, oxy surface-filling &lt;Me 152 323406 201211028 Dissolve the ethyl 4-piperidone in acetone (8 〇) Ml), sodium carbonate (llg) was added. The methyl ester (3. 18 ml) was added at room temperature, and the mixture was stirred for 2.5 hours. The precipitated solid was filtered and dried under reduced pressure to give the title compound. Lgg,860/〇). Reference Example 79 (3-inner)-3-(4-Sideoxynidyl-1-yl)-8-σ丫bicyclo[3. 2. 1] Xin Xuan 1 - 8-carboxylic acid ethyl ester

將參考例77之化合物（2· Og)溶解於乙醇（6〇ml)與水 (30ml) ’加入參考例78之化合物（2. 7g)與碳酸鉀（2. 8g) 後，加熱回流24小時。將反應液冷卻至室溫後，將溶媒減 壓濃縮。以乙酸乙酯萃取所得之殘渣並以水洗淨後，以硫 酸鈉將有機層進行乾燥。以矽藻土過濾後，將濾液減壓濃 縮，並將所得之殘渣以矽膠管柱層析精製，得到標題化合 物（1.9g，67°/〇。 • 參考例80 2-[(3-外）-8-曱基-8-吖雙環[3. 2. 1]辛烷-3-基]-1H-吲哚 -1，3(2H)-二酮The compound of Reference Example 77 (2·Og) was dissolved in ethanol (6 ml) and water (30 ml). The compound of Reference Example 78 (2.7 g) and potassium carbonate (2.8 g) were added, and the mixture was heated under reflux for 24 hours. . After cooling the reaction mixture to room temperature, the solvent was concentrated under reduced pressure. The obtained residue was extracted with ethyl acetate and washed with water, and then organic layer was dried over sodium sulfate. After filtration through celite, the filtrate was concentrated under reduced pressure, and the obtained residue was purified to silica gel column chromatography to afford the title compound (1.9 g, 67° / 〇). Reference Example 80 2-[(3-) -8-mercapto-8-indole bicyclo[3.2.1]octane-3-yl]-1H-indole-1,3(2H)-dione

將莨菪鹼（tropine)(15· Og)、鄰苯二甲醯亞胺（18. 8g) 及三苯基膦（42. Og)溶解於四氫呋喃，冷卻至〇°c後，加入 6mol/L鹽酸（240ml)後，加熱回流15小時。將反應液冷卻 至室溫，加入偶氮二甲酸二異丙酯（31.3ml)，升溫至室溫 153 323406 201211028 後攪拌20小時。以lmol/L之鹽酸水溶液萃取反應液，以 乙酸乙酯進行洗淨。在水槽中加入碳酸鈉，使溶液成為鹼 性後，以乙酸乙酯進行萃取。以硫酸鈉將有機層進行乾燥， 並以矽藻土過濾後，將濾液進行減壓濃縮。將所得之殘渣 以矽膠管柱層析進行精製，得到標題化合物（8. Og，28%)。 參考例81Dissolve tropine (15·Og), phthalimide (18.8 g) and triphenylphosphine (4. Og) in tetrahydrofuran, cool to 〇°c, and add 6 mol/L hydrochloric acid. After (240 ml), it was heated to reflux for 15 hours. The reaction solution was cooled to room temperature, diisopropyl azodicarboxylate (31.3 ml) was added, and the mixture was warmed to room temperature 153 323406 201211028 and stirred for 20 hours. The reaction solution was extracted with a 1 mol/L aqueous hydrochloric acid solution and washed with ethyl acetate. Sodium carbonate was added to the water bath to make the solution alkaline, and then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and filtered over Celite. The residue was purified by silica gel column chromatography toield Reference example 81

(3-外）-3(1，3-二側氧基-1，3-二氫-2H-異吲哚-2-基）-8-吖雙環[3. 2. 1]辛烷-羧酸乙酯 〇L^N-〇N_c〇2Et 將參考例80之化合物（8. Og)溶解於曱苯，於室溫滴下 氯曱酸乙酯（4. 3ml)後，於10分鐘後進行升溫，加熱回流 24小時。冷卻至室溫後，加入水，以乙酸乙酯進行萃取。 以飽和食鹽水洗淨有機層，並以硫酸鈉進行乾燥後，以矽 藻土過濾，並將濾液進行減壓濃縮。將所得之殘渣以矽膠 管柱層析進行精製，得到標題化合物（4. 9g，50%)。 參考例82 (3-外）-3-胺基-8-°丫雙環[3. 2. 1]辛烧-8-缓酸乙酉旨 C02Et Η2Ν&quot;_· Ον&quot; 將參考例81之化合物（4. 9g)溶解於乙醇（50ml)，加入 肼一水合物後，進行升溫，加熱回流24小時。將反應液冷 卻至室溫後，進行減壓濃縮。將所得之固體以乙醇洗淨3 次後，將濾液減壓濃縮而得到白色固體。將所得之固體溶 解於乙酸乙酯後進行過濾，藉由將濾液進行減壓濃縮而得 154 323406 201211028 到標題化合物（2· 9g，定量）。 參考例83 (3-外）-3-(4-侧氧基哌啶-1 —基）_8_吖雙環[3. 2. 1]辛烷 -8-羧酸乙酯 〇=Gn，-On&quot; C02Et 使用參考例82之化合物，並依照與參考例79相同的 方法而得到標題化合物。 參考例84 2(2-{1-[(3_内）-8-(乙氧基羰基）_8_吖雙環[3.2. 1]辛烷 -3-基]哌啶_4-基}胺基-4-甲基苯基）-1, 3-丙二酸二第三 丁酯(3-exo)-3(1,3-di-oxy-1,3-dihydro-2H-isoindol-2-yl)-8-indole bicyclo[3.2.1]octane-carboxylate Acid ethyl ester 〇L^N-〇N_c〇2Et The compound of Reference Example 80 (8.0 g) was dissolved in toluene, and ethyl chlorodecanoate (4.3 ml) was added dropwise at room temperature, and then the temperature was raised after 10 minutes. Heated to reflux for 24 hours. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The residue was purified by EtOAc EtOAc (EtOAc) Reference Example 82 (3-Exo)-3-amino-8-°丫bicyclo[3. 2. 1]octyl-8-hypoacid oxime C02Et Η2Ν&quot;_· Ον&quot; The compound of Reference Example 81 (4) 9 g) was dissolved in ethanol (50 ml), and after adding hydrazine monohydrate, the temperature was raised, and the mixture was heated under reflux for 24 hours. After cooling the reaction mixture to room temperature, it was concentrated under reduced pressure. After the obtained solid was washed three times with ethanol, the filtrate was concentrated under reduced pressure to give a white solid. The obtained solid was dissolved in ethyl acetate and filtered, and the filtrate was concentrated under reduced pressure to give 154 323406 201211028 to the title compound (2·9 g, quantitative). Reference Example 83 (3-Exo)-3-(4-Sideoxypiperidine-1-yl)_8-indolebicyclo[3.2.1]octane-8-carboxylic acid ethyl ester 〇=Gn,-On&quot C02Et The title compound was obtained by the same procedure as the the the the Reference Example 84 2(2-{1-[(3_内)-8-(ethoxycarbonyl)_8_吖bicyclo[3.2.1]octane-3-yl]piperidine-4-yl}amino group -4-methylphenyl)-1,3-propionic acid di-t-butyl ester

使用參考例47之合成中間物與參考例79 ’並依照與 參考例30相同的方法而得到標題化合物。 # 實施例98 (3-内）-3-[4-(6-曱基-2-側氧基-2, 3-二氫-1H-吲哚-卜基） -哌啶-1-基]-8-吖雙環[3. 2· 1]辛烷-8-羧酸乙酯The title compound was obtained by the same procedure as that of Reference Example 30. #例例98 (3-Inter)-3-[4-(6-Mercapto-2-yloxy-2,3-dihydro-1H-indole-buyl)-piperidin-1-yl] -8-indole bicyclo[3. 2·1]octane-8-carboxylic acid ethyl ester

使用參考例84之化合物，並依照與實施例94相同的 方法而得到標題化合物。 ^-NMRCCDCh，400MHz) (51.27 (t，J=7.1Hz, 3H)，1.50一 323406 155 201211028 1.76 (m, 4H), 1.85-2.09 (m, 6H), 2.10-2.30 (m, 2H), 2.37 (s, 3H), 2.33-2.49 (m, 2H), 3.22 (d, J=11.2Hz, 2H) 4. 09-4. 42 (m, 5H), 6. 83 (d, J=7. 3Hz, 1H), 6. 91 (s, 1H), 7. 11 (d，J=7.3Hz，1H)· LC-MS : R. T. 3. 3 min., m/z 412. 3(M+1).條件 B。 實施例99至103 使用對應之中間物與參考例79或參考例83之化合 物，並依照與實施例98相同的方法而得到下述化合物。 •[表 7] 實施例 構造 (鹽） MS (m/z) 分鐘 條件 NMR (MHz,溶劑） 99 1 〇XN'c〇2Et Me 412 (M+H) 6.4 A 'H-NMR(CDCU 400 MHz) δ 1.27(t, J = 7.3Hz, 3H), 1.63-1.80 (m, 6H), 1.96-2. 00 (m，2H), 2.24-2.31 (ra, 2H), 2.37 (s，3H), 2.34-2.45 (m，2H)，2.81-2.90(m，1H), 3.05(d，J=11.5Hz, 2H), 3.48 (q, J = 7.3 Hz, 2H), 4. 24-4.42 (m, 3H), 6.82 (d, J = 7.3 Hz, 1H), 6.99 (s, 1H), 7.11 (d, J = 7.3 Hz, 1H). 100 F 416.5 (M+H) 3.0 B Ή-NMR (CDCla, 400 MHz) δ 1.27(t, J = 7.1 Hz, 3H), 1.62-1.76 (m, 4H), 1.87-2.07 (m, 6H), 2.19-2.24 (m, 2H), 2.29-2.41 (m, 3H), 3.23 (d, J = 11.0 Hz, 2H)f 3.47 (s, 3H), 4.11-4.31 (mr 5H), 7. 68-7. 73 (ra, 1H), 6. 83 (dd, J = 9. 5, 2. 2 Hz, 1H), 7.15-7.18 (m, 1H). 101 416.2 (M+H) 5.9 A Ή-NMR (CDCh, 400 MHz) 5 1.27 (t, J = 7.1 Hz, 3H), 2. 58-2.78 Cm, 6H), 1.95-2.00 (m, 2H), 2.25-2.39 (m, 4H), 2.81-2.89 (m, 1H), 3.03 (dt J = 9.5 Hz, 2H), 3.47 (s, 2H), 4.15 (q, J = 7.1 Hz, 2H), 4.20-4.41 (m, 3H), 6.68-6.73 (m, 1H), 6.89-6.94 (m, 1H), 7.13-7.16 (m, 1H). 102 398.0 (M+H) 1.1 C 〇· 103 398.1 (M+H) 0.9 C Ή-NMR (CDCh, 300 MHz) 51.24-1.29 (t, J = 7.1 Hz, 3H), 1.65-1.76 (br, 2HX 1.83-2.10 (m, 8HX 2.29-2.49 (br, 1H), 2.82-3.03 (m, 4H), 3.50-3.63 (m, 4H), 3.83 (s, 1H), 4.10-4.19 (q, J = 7.1 Hz, 2H), 4.47 (s, 2H), 4.63-4.78 (m 1H), 7.00-7.07 (m, 1H), 7.20-7.30 (m, 2H), 7.41-7.44 (m, 1H). N.D.:無數據（No Data) 參考例85 156 323406 201211028 2(2-{1-[(3-内）-8-(乙氧基羰基）-8-吖雙環[3. 2. 1]辛烷 -3-基]哌啶一4-基}胺基-4-曱基苯基）（甲基）-1，3-丙二酸 二第三丁酯The title compound was obtained in the same manner as in Example 94. ^-NMRCCDCh, 400MHz) (51.27 (t, J=7.1Hz, 3H), 1.50-323406 155 201211028 1.76 (m, 4H), 1.85-2.09 (m, 6H), 2.10-2.30 (m, 2H), 2.37 (s, 3H), 2.33-2.49 (m, 2H), 3.22 (d, J=11.2Hz, 2H) 4. 09-4. 42 (m, 5H), 6. 83 (d, J=7. 3Hz , 1H), 6. 91 (s, 1H), 7. 11 (d, J=7.3Hz, 1H)· LC-MS : RT 3. 3 min., m/z 412. 3(M+1). Condition B. Examples 99 to 103 Using the corresponding intermediates and the compounds of Reference Example 79 or Reference Example 83, the following compounds were obtained in the same manner as in Example 98. [Table 7] Example Structure (salt) MS (m/z) min conditions NMR (MHz, solvent): EtOAc (MH): </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 3H), 1.63-1.80 (m, 6H), 1.96-2. 00 (m, 2H), 2.24-2.31 (ra, 2H), 2.37 (s, 3H), 2.34-2.45 (m, 2H), 2.81 2.90(m,1H), 3.05(d,J=11.5Hz, 2H), 3.48 (q, J = 7.3 Hz, 2H), 4. 24-4.42 (m, 3H), 6.82 (d, J = 7.3 Hz , 1H), 6.99 (s, 1H), 7.11 (d, J = 7.3 Hz, 1H). 100 F 416.5 (M+H) 3.0 B Ή-NMR (CDCla, 400 MHz) δ 1.27 (t, J = 7.1 Hz, 3H), 1.62-1.76 (m, 4H), 1.87-2.07 (m, 6H), 2.19-2.24 (m, 2H), 2.29-2.41 (m, 3H), 3.23 (d, J = 11.0 Hz, 2H)f 3.47 (s, 3H), 4.11-4.31 (mr 5H) , 7. 68-7. 73 (ra, 1H), 6. 83 (dd, J = 9. 5, 2. 2 Hz, 1H), 7.15-7.18 (m, 1H). 101 416.2 (M+H) 5.9 A Ή-NMR (CDCh, 400 MHz) 5 1.27 (t, J = 7.1 Hz, 3H), 2. 58-2.78 Cm, 6H), 1.95-2.00 (m, 2H), 2.25-2.39 (m, 4H ), 2.81-2.89 (m, 1H), 3.03 (dt J = 9.5 Hz, 2H), 3.47 (s, 2H), 4.15 (q, J = 7.1 Hz, 2H), 4.20-4.41 (m, 3H), 6.68-6.73 (m, 1H), 6.89-6.94 (m, 1H), 7.13-7.16 (m, 1H). 102 398.0 (M+H) 1.1 C 〇· 103 398.1 (M+H) 0.9 C Ή-NMR (CDCh, 300 MHz) 51.24-1.29 (t, J = 7.1 Hz, 3H), 1.65-1.76 (br, 2HX 1.83-2.10 (m, 8HX 2.29-2.49 (br, 1H), 2.82-3.03 (m, 4H ), 3.50-3.63 (m, 4H), 3.83 (s, 1H), 4.10-4.19 (q, J = 7.1 Hz, 2H), 4.47 (s, 2H), 4.63-4.78 (m 1H), 7.00-7.07 (m, 1H), 7.20-7.30 (m, 2H), 7.41-7.44 (m, 1H). ND: no data (No Data) Reference Example 85 156 323406 201211028 2(2-{1-[(3- 8-(Ethoxycarbonyl)-8-indole bicyclo[3.2.1]octane-3-yl]piperidine-4-yl}amino-4-mercaptophenyl)(methyl) - 1,3-malonic acid di-t-butyl ester

使用參考例84之化合物，並依照與參考例64相同的 方法而得到標題化合物。 實施例104 (3-内）-3-[4-(3, 6)-二曱基-2-側氧基-2, 3-二氫-1H-吲哚 -1-基]哌啶-1-基]-8-吖雙環[3. 2. 1]辛烷-8-羧酸乙酯The title compound was obtained in the same manner as in the title compound 64. Example 104 (3-Inter)-3-[4-(3,6)-Dimercapto-2-yloxy-2,3-dihydro-1H-indol-1-yl]piperidine-1 -yl]-8-indole bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester

使用參考例85之化合物，並依照與實施例94相同的 方法而得到標題化合物。 ^-NMR (CDCh, 400MHz)5 1.20 (t, J=7. 1Hz, 3H), 1.36, φ 1.38 (s, 3H ratio=l : 1)，2.55-2.68 (m, 4H)，2.02-2. 76 (m, 6H), 2.21-2.04 (m, 2H), 2.31 (s, 3H), 2.41-2.31 (m, 2H), 3.12-3.32 (m, 4H), 4.07 (q, J=7. 1Hz, 2H), 4. 13-4. 28 (m, 1H), 6. 78 (d, J=7. 4Hz, 1H), 6.84(s, 1H), 7.04 (d, J=7.4Hz, 1H). LC-MS:R.T. 6. lmin.，m/z 426_2(M+l).條件 實施例105至106 使用對應之中間物，並依照與實施例l〇4相同的方法 323406 157 201211028 而得到下述化合物。 [表8 ]The title compound was obtained in the same manner as in Example 94. ^-NMR (CDCh, 400MHz) 5 1.20 (t, J = 7. 1Hz, 3H), 1.36, φ 1.38 (s, 3H ratio=l: 1), 2.55-2.68 (m, 4H), 2.02-2. 76 (m, 6H), 2.21-2.04 (m, 2H), 2.31 (s, 3H), 2.41-2.31 (m, 2H), 3.12-3.32 (m, 4H), 4.07 (q, J=7. 1Hz 2, 2, 4, 4. LC-MS: RT 6. lmin., m/z 426 s (M+l). </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Said compound. [Table 8]

實施例 構造 (鹽） MS (m/z) 分鐘 條件 tiMR (MHz,溶劑） 105 〇 Q F 430.2 (M+H) 5.6 A N_D. 430.6 (M+H) 3.1 B Ή-NMR (CDCh, 300 MHz) 51. 27 (t, J = 7.1 Hz, 3H), 1.46 (d, J = 7.7 Hz, 3H), 1.60-1.78 (m, 4H), 1.81-2.27 (m, 8H), 106 Β F 2.27-2.47 (m, 3H), 3.22 (br-d, J = 10.6 Hz, 2H), 3.39 (q, J = 7.7 Hz, 1H), 4.08-4.38 (m, 3H), 4.14 (q, J = 7.1 Hz, 2H), 6.87-7.06 (m, 3H). N. D.:無數據（No Data) 參考例86 4-[5-氟-2-側氧基-3-(丙燒-2 -亞基）-2，3_二氫_1Η-πβ|π朵 -1-基]哌啶-1-羧酸第三丁酯EXAMPLES Construction (salt) MS (m/z) min condition tiMR (MHz, solvent) 105 〇QF 430.2 (M+H) 5.6 A N_D. 430.6 (M+H) 3.1 B Ή-NMR (CDCh, 300 MHz) 51. 27 (t, J = 7.1 Hz, 3H), 1.46 (d, J = 7.7 Hz, 3H), 1.60-1.78 (m, 4H), 1.81-2.27 (m, 8H), 106 Β F 2.27-2.47 (m, 3H), 3.22 (br-d, J = 10.6 Hz, 2H), 3.39 (q, J = 7.7 Hz, 1H), 4.08-4.38 (m, 3H), 4.14 (q, J = 7.1 Hz, 2H), 6.87-7.06 (m, 3H). ND: No data (No Data) Reference Example 86 4-[5-Fluoro-2-oxo-3-(propan-2-ylidene-2)-2, 3_Dihydro_1Η-πβ|π朵-1-yl] piperidine-1-carboxylic acid tert-butyl ester

F 在參考例33之化合物（lOOmg)的二氣曱烷（2ml)溶液 中，加入四異丙氧化鈦（425mg)、丙酮（87mg)，於50°C徹 夜擾拌。於反應液加入飽和碳酸氫鈉水溶液，以石夕藻土過 濾，並以氯仿洗淨後進行萃取。將所得之有機層以硫酸鈉 進行乾燥，並減壓濃縮。將所得之殘渣以矽膠管柱層析精 製而得到標題化合物（122mg，定量）。 參考例87 4-[5-氟-2-侧氧基-3-(丙烷-2-亞基）-2, 3-二氫-1H-吲哚 -1-基]-α辰啶 158 323406 201211028F To a solution of the compound of Example 33 (100 mg) in dioxane (2 ml), tetraisopropyltitanium oxide (425 mg) and acetone (87 mg) were added and the mixture was stirred overnight at 50 °C. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and the mixture was filtered over Celite, washed with chloroform and then extracted. The resulting organic layer was dried over sodium sulfate and evaporated. The residue was purified by silica gel column chromatography toield Reference Example 87 4-[5-Fluoro-2-oxooxy-3-(propane-2-ylidene)-2,3-dihydro-1H-indol-1-yl]-α-cindine 158 323406 201211028

法而得到標題化合物。 實施例107 4-{4-[5-氟-2-側氧基-3-(丙烷-2-亞基）-2, 3-二氣〜11} 〇引 °朵_1_基]°底°定-1-基}派°定-丨-緩酸乙@旨The title compound was obtained by the method. Example 107 4-{4-[5-Fluoro-2-oxooxy-3-(propane-2-ylidene)-2,3-dioxane~11} 〇引°朵_1_基]°底°定-1-基}派定定-丨-缓酸乙@旨

使用參考例87之化合物，並依照與實施例1相同的方 法而得到標題化合物。 !H-NMR (CDCla, 400MHz)5 1.26 (m, 3H), 1.44-1.84 (m 14H), 2.48-2.36 (m, 5H), 2.76 (t, 2H), 3.02-3.15 (m, 4H), 3.77-3.87 (m, 5H), 4.18 (m, 4H), 6.90 (m, 1H), 7.06 (m, 1H), 7.29 (in, 1H). 參 LC-MS : R. T_ 6. 8 min.，m/z 430(M+H).條件 A。 實施例108 4-{4-[5-氟，2-側氧基-3-(丙烧-2-基）-2, 3-二氫-1H-d弓卜朵 _1-基]旅咬_1_基}·旅咬-1-叛酸乙醋The title compound was obtained in the same manner as in Example 1 using the compound of the title compound. !H-NMR (CDCla, 400MHz) 5 1.26 (m, 3H), 1.44-1.84 (m 14H), 2.48-2.36 (m, 5H), 2.76 (t, 2H), 3.02-3.15 (m, 4H), 3.77-3.87 (m, 5H), 4.18 (m, 4H), 6.90 (m, 1H), 7.06 (m, 1H), 7.29 (in, 1H). Reference LC-MS: R. T_ 6. 8 min. , m/z 430 (M+H). Condition A. Example 108 4-{4-[5-Fluoro, 2-o-oxo-3-(propan-2-yl)-2,3-dihydro-1H-d-bundo-1-yl] _1_基}·Travel bite-1-rebel vinegar

將實施例107之化合物（20mg)溶解於甲醇（lml)，加入 10%鈀/碳（10mg)後，於氫環境下徹夜攪拌》將反應液以矽 159 323406 201211028 藻土過濾，藉由進行減壓濃縮而得到標題化合物（13mg， 65%)。 'H-NMR (CDCh, 400MHz)5 0.83 (d, 3H), 1.06 (d, 3H), 1.26 (t, 3H), 1.42 (in, 2H), 1.67-1.83 (m, 6H), 2.36-2.48 (m, 5H), 2.85 (t, 2H), 3.02 (in, 2H), 3.32 (m, 1H), 4. 10-4. 27 (m, 5H), 6.90 (m, 1H), 6. 95 (m, 1H), 7.05 (in, 1H). LC-MS:R.T. 7. Omin.，m/z 432(M+H).條件 A。 ®實施例109至147 使用參考例3、31、33或40之化合物與對應之試劑， 並依照與實施例107或108相同的方法而合成下述化合物。The compound of Example 107 (20 mg) was dissolved in methanol (1 ml), 10% palladium/carbon (10 mg) was added, and stirred overnight under a hydrogen atmosphere. The reaction solution was filtered with 矽159 323406 201211028 algae, by subtraction The title compound (13 mg, 65%) was obtained. 'H-NMR (CDCh, 400MHz) 5 0.83 (d, 3H), 1.06 (d, 3H), 1.26 (t, 3H), 1.42 (in, 2H), 1.67-1.83 (m, 6H), 2.36-2.48 (m, 5H), 2.85 (t, 2H), 3.02 (in, 2H), 3.32 (m, 1H), 4. 10-4. 27 (m, 5H), 6.90 (m, 1H), 6. 95 (m, 1H), 7.05 (in, 1H). LC-MS: RT 7. Omin., m/z 432 (M+H). ® Examples 109 to 147 The following compounds were synthesized in the same manner as in Example 107 or 108, using the compound of Reference Example 3, 31, 33 or 40 and the corresponding reagent.

160 323406 201211028 [表9] 實施例 構造 (鹽） MS (m/z) 分鍺 條件 NMR (MHz,溶剞） 109 416 (M+H) 6.4 Ή-NMR (CDCh, 400 MHz) 51.26 (t, 3H), 1.44-1.60 (m, 11H), 1.89 (in, 2H), 2.48-2.37 (ra, 5H), 2.76 (t, 2H), 3.09-3.15 (m, 4H), 3.78 (m, 4H), 4.18 (m, 4H), 6.93 (m, 1H)( 7.07 (m, 1H), 7.18 (m, 1H). 110 418 (M+H) 6.3 Ή-NMR (CDCh, 400 MHz) 50.80 (t, 3H), 1.25 (t, 3H), 1.44-1.64 (m, 8H), 1.80 (ra, 2H), 2.00 (m, 2H), 2.35-2.50 (m, 3H), 3.02 (m, 2H), 3.40 (m, 1H), 4.10-4.24 (m, 4H), 6.92-7.10 (m，3H). 111 / 444 (M+H) 7.0 Ή-NMR (CDCK 400 MHz) dl. 13-1.25 (m, 9HX 1.45 (m, 2H), 1.64(m, 2H), 1.83(m, 2H), 2.35-2.48 (in, 5H), 2.76(t, 2H), 3.15 (m, 2H), 4.10-4.31 (m, 5H), 6.90 (m, 2H), 7.03 (m, 1H), 7.29 (m, 1H). 112 F 446 (M+H) 7.5 Ή-NMR (CDCls, 400 MHz) 5 0.90 (m, 6H), 1.24 (t, 3H), 1.43-1.85 (m, 8H), 2.36(m, 4H), 2.49(m, 1H), 2.75(m, 2H), 3.40(t, 1H), 4. 09-4. 25 (m, 5H), 6.91 (m, 2H), 7. 06 (m, 1H). 113 ¥ 458 (M+H) 7.0 A Ή-NMR (CDCh, 400 MHz) 51.25 (t, 3H), 1.47-1.67 (m, 14H), 1.83 (m, 2H), 2.40-3.53 (m, 5HX 2.75 (m, 2H), 3.01 (m, 2H), 3.45 (m, 1H), 4.11-4.27 (m, 4H), 6.89 (m, 1H), 7.01-7.06 (m, 2H). 114 430 (M+H) 6.8 A Ή-NMR (CDCh, 400 MHz) &lt;51.20-1.45 (m, 6H), 1.48-1.51 (m, 4H), 1.71 (m, 2H), 1.83(m, 2H), 2.38(m, 4H), 2. 50 (m, 1H), 2.68 (m, 2H), 3.02 (m, 2H), 4.10-4.16 (m, 5H), 7.00-7.25 (瓜，3H)_ 115 F 432 (M+H) 6.7 Ή-NMR (CDCh, 400 MHz) &lt;5 0.88 (t, 3H), 1.25 (t, 3H), 1.32-1.59 (m, 6Η),1.79(ι, 2H), 1.90 (m, 2H), 2.38(d), 4H), 2.50(m, 1H), 2.75(m, 2H), 3.02(m, 2H), 4.10-4.16 (m, 5H), 6.91-7.09 (m, 3H). 116 0^0, 474 (M+H) 6.2 A N. D. 117 Cl· 432.3 (M+H) 7.0 A N.D. 118 446 (M+H) 6.2 A Ή-NMR (CDCla, 400 MHz) 51.24-1.79 (m, 7H), 2.35 (ra, 2H), 2.77(m, 2H), 3. 08-3.14 (m, 3H), 3.38(m, 1H), 3.75 (in, 2H), 3.87(m, 1H), 4. 24 (m, 4H), 4.83-4. 97 (in 4HX 6. 91-6. 96 (m, 2H)f 7.10 (m, 1H). 161 323406 201211028160 323406 201211028 [Table 9] Example Construction (salt) MS (m/z) Bifurcation conditions NMR (MHz, solvent) 109 416 (M+H) 6.4 Ή-NMR (CDCh, 400 MHz) 51.26 (t, 3H), 1.44-1.60 (m, 11H), 1.89 (in, 2H), 2.48-2.37 (ra, 5H), 2.76 (t, 2H), 3.09-3.15 (m, 4H), 3.78 (m, 4H) , 4.18 (m, 4H), 6.93 (m, 1H) (7.07 (m, 1H), 7.18 (m, 1H). 110 418 (M+H) 6.3 Ή-NMR (CDCh, 400 MHz) 50.80 (t, 3H), 1.25 (t, 3H), 1.44-1.64 (m, 8H), 1.80 (ra, 2H), 2.00 (m, 2H), 2.35-2.50 (m, 3H), 3.02 (m, 2H), 3.40 (m, 1H), 4.10-4.24 (m, 4H), 6.92-7.10 (m, 3H). 111 / 444 (M+H) 7.0 Ή-NMR (CDCK 400 MHz) dl. 13-1.25 (m, 9HX 1.45 (m, 2H), 1.64(m, 2H), 1.83(m, 2H), 2.35-2.48 (in, 5H), 2.76(t, 2H), 3.15 (m, 2H), 4.10-4.31 (m, 5H), 6.90 (m, 2H), 7.03 (m, 1H), 7.29 (m, 1H). 112 F 446 (M+H) 7.5 Ή-NMR (CDCls, 400 MHz) 5 0.90 (m, 6H), 1.24 (t, 3H), 1.43-1.85 (m, 8H), 2.36 (m, 4H), 2.49 (m, 1H), 2.75 (m, 2H), 3.40 (t, 1H), 4. 09-4. 25 (m, 5H), 6.91 (m, 2H), 7. 06 (m, 1H). 113 ¥ 458 (M+H) 7.0 A Ή-NMR (CDCh, 400 MHz) 51.25 (t, 3H), 1.47 -1.67 (m, 14H), 1.83 (m, 2H), 2.40-3.53 (m, 5HX 2.75 (m, 2H), 3.01 (m, 2H), 3.45 (m, 1H), 4.11-4.27 (m, 4H), 6.89 (m , 1H), 7.01-7.06 (m, 2H). 114 430 (M+H) 6.8 A Ή-NMR (CDCh, 400 MHz) &lt;51.20-1.45 (m, 6H), 1.48-1.51 (m, 4H) , 1.71 (m, 2H), 1.83 (m, 2H), 2.38 (m, 4H), 2. 50 (m, 1H), 2.68 (m, 2H), 3.02 (m, 2H), 4.10-4.16 (m , 5H), 7.00-7.25 (melon, 3H)_ 115 F 432 (M+H) 6.7 Ή-NMR (CDCh, 400 MHz) &lt;5 0.88 (t, 3H), 1.25 (t, 3H), 1.32- 1.59 (m, 6Η), 1.79 (ι, 2H), 1.90 (m, 2H), 2.38(d), 4H), 2.50(m, 1H), 2.75(m, 2H), 3.02(m, 2H), 4.10-4.16 (m, 5H), 6.91-7.09 (m, 3H). 116 0^0, 474 (M+H) 6.2 A ND 117 Cl· 432.3 (M+H) 7.0 A ND 118 446 (M+H 6.2 A Ή-NMR (CDCla, 400 MHz) 51.24-1.79 (m, 7H), 2.35 (ra, 2H), 2.77 (m, 2H), 3. 08-3.14 (m, 3H), 3.38 (m, (H, 1H) , 1H). 161 323406 201211028

119 0^0, / 460 (Μ+Η) 6.0 A Ή-NMR (CDCh, 400 MHz) &lt;51.23 (t, 3H), 1.46 (m, 3H), 1.60 (m, 3H), 1.81 (m, 4H), 2.48(m, 1H), 2.77 (m 4H), 3.00-3.18 (m, 2H), 3.35 (m, 4H), 3. 68-3. 96 (m, 3H), 4. 09-4. 25 (m, 4H), 6.94 (m 1H), 7.05 (m, 1H), 7.24 (s, 1H). 120 450.2 (M+Na) 5.4 A N.D. 121 445 (Μ+Η) 3.9 A N. D. 122 454.2 (M+Na) 4.9 A N.D. 123 444 (M+H) 6.1 A N.D. 124 Μ· 400 (M+H) 6.6 N.D· 125 、Μ· 400 (M+H) 6.9 A N.D. 126 432 (M+H) 7.0 A Ή-NMR (CDCh, 400 MHz) &lt;5 0.83 (d, 3H), 1.06 (d, 3H), 1.26 (t, 3H), 1.42 (m, 2H), 1.67-1.83 (m, 6H), 2. 36-2.48 (m, 5H), 2.75(t, 2H), 3.02(m, 2H), 3.32(m, 1H), 4.10-4.27 (m, 5H), 6.90 (m, 1H), 6.95 (m, 1H), 7.05 (m, 1H). 127 432 (M+H) 6.5 A Ή-NMR (CDCh, 400 MHz) 50.81 (t, 3H), 1.26 (m, 4H), 1.45-1.62 (m, 4H), 1. 91-2. 03 (m, 5H), 2.40 (m 4H), 2. 54 (m, 1H), 2.90 (m, 2H), 3.30-3.39 (m, 3H), 3.61-3.69 (ηι, 2H), 4.14 (m, 2H), 4.27 (m, 1H), 6.96 (m, 2H), 7.07 (m, 1H). 128 414 (M+H) 1.3 C Ή-NMR (CDCU 400 MHz) &lt;50.82 (d, J = 5.4Hz, 3H), 1.04(d, J = 5.4 Hz, 3fl), 1.26 (t, J = 5.4 Hz, 3H), 1.52-1.78 (m, 2H)t 1.87 (d, J = 9.6 Hz, 1H), 1.94 (d, J = 9. 6 Hz, 1HX 2.10 (d, J = 8.1 Hz, 2H), 2.40-2.52 (m, 1H), 2.75-3.11 (m, 6H), 3.37 (d, J = 2.4 Hz, 1H), 3.51 (dd, J = 9. 0, 9.0 Hz, 1H), 3.68 (d, J = 7.2 Hz, 2H), 4.13 (q, J = 5.4 Hz, 2H), 4.37 (br-s, 2HX 4.67-4.79 (m, 1H), 7.01-7.10 (m, 1H), 7.15-7.40 (m, 3H). 162 323406 201211028119 0^0, / 460 (Μ+Η) 6.0 A Ή-NMR (CDCh, 400 MHz) &lt;51.23 (t, 3H), 1.46 (m, 3H), 1.60 (m, 3H), 1.81 (m, 4H), 2.48(m, 1H), 2.77 (m 4H), 3.00-3.18 (m, 2H), 3.35 (m, 4H), 3. 68-3. 96 (m, 3H), 4. 09-4 . 25 (m, 4H), 6.94 (m 1H), 7.05 (m, 1H), 7.24 (s, 1H). 120 450.2 (M+Na) 5.4 A ND 121 445 (Μ+Η) 3.9 A ND 122 454.2 (M+Na) 4.9 A ND 123 444 (M+H) 6.1 A ND 124 Μ· 400 (M+H) 6.6 ND· 125 Μ· 400 (M+H) 6.9 A ND 126 432 (M+H) 7.0 A Ή-NMR (CDCh, 400 MHz) &lt;5 0.83 (d, 3H), 1.06 (d, 3H), 1.26 (t, 3H), 1.42 (m, 2H), 1.67-1.83 (m, 6H) , 2. 36-2.48 (m, 5H), 2.75(t, 2H), 3.02(m, 2H), 3.32(m, 1H), 4.10-4.27 (m, 5H), 6.90 (m, 1H), 6.95 (m, 1H), 7.05 (m, 1H). 127 432 (M+H) 6.5 A Ή-NMR (CDCh, 400 MHz) 50.81 (t, 3H), 1.26 (m, 4H), 1.45-1.62 (m , 4H), 1. 91-2. 03 (m, 5H), 2.40 (m 4H), 2. 54 (m, 1H), 2.90 (m, 2H), 3.30-3.39 (m, 3H), 3.61- 3.69 (ηι, 2H), 4.14 (m, 2H), 4.27 (m, 1H), 6.96 (m, 2H), 7.07 (m, 1H). 128 414 (M+H) 1.3 C Ή-NMR (CDCU 400 MHz) &lt;50.82 (d, J = 5.4 Hz, 3H), 1.04(d, J = 5.4 Hz, 3fl), 1.26 (t, J = 5.4 Hz, 3H), 1.52-1.78 (m, 2H)t 1.87 (d, J = 9.6 Hz, 1H), 1.94 (d, J = 9. 6 Hz, 1HX 2.10 (d, J = 8.1 Hz, 2H), 2.40-2.52 (m, 1H), 2.75-3.11 (m, 6H), 3.37 (d, J = 2.4 Hz , 1H), 3.51 (dd, J = 9. 0, 9.0 Hz, 1H), 3.68 (d, J = 7.2 Hz, 2H), 4.13 (q, J = 5.4 Hz, 2H), 4.37 (br-s, 2HX 4.67-4.79 (m, 1H), 7.01-7.10 (m, 1H), 7.15-7.40 (m, 3H). 162 323406 201211028

COsEt (三氟乙酸鹽） 426 (M+H) 130 131 132 133COsEt (trifluoroacetate) 426 (M+H) 130 131 132 133

xy C〇2Et 440 (M+H) 1.4 lH-NMR (CDCb, 400 MHz) 51.28 (t, J = 5.4Hz, 3H), 1.60-1.75 (ra( 2H), 1.75-2.17 (m, 10H), 2.71 (ddd, J = 6. 0, 6.0, 6.0 Hz, 1H), 2.73-3.05 (mt 6H), 3.37 (d, J = 6.0Hz, 1H), 3.49 (dd, J = 8.7, 8.7 H2, 1H), 3.67 (br-s, 2H), 4.14 (q, J = 5.4 Hz, 2H), 4.38 (br-s, 2H), 4.69 (br-s, 1H), 7.04 (dd, J = 5.1, 5.1 Hz, 1HX 7.22-7.32 (m, 3H)._ ]H-NMR (CDCU 400 MHz) 51.19-1.30 (m, IH), 1.25 (t, J = 5.4 Hz, 3H), 1.40-1.70 (m, 8H), 1.74-1.80 (m, 3H), 2.03 (br-d, J = 7.2Hz, 2H), 2.37-2.49 (m, 1H), 2.79(br-s, 6H)f 3.12 (br-s, 1H), 3.43 (br-s, 2H), 3.46 (d, J = 3. 9 Hz, 1H), 4.12 (q, J = 5.4 Hz, 2H), 4.31 (br-s, 2HX 4.55 (br-s, 1H), 7.00 (dd, J = 5.7, 5.7 Hz, 1H), 7.20-7.34 (m, 3H).Xy C〇2Et 440 (M+H) 1.4 lH-NMR (CDCb, 400 MHz) 51.28 (t, J = 5.4 Hz, 3H), 1.60-1.75 (ra( 2H), 1.75-2.17 (m, 10H), 2.71 (ddd, J = 6. 0, 6.0, 6.0 Hz, 1H), 2.73-3.05 (mt 6H), 3.37 (d, J = 6.0Hz, 1H), 3.49 (dd, J = 8.7, 8.7 H2, 1H ), 3.67 (br-s, 2H), 4.14 (q, J = 5.4 Hz, 2H), 4.38 (br-s, 2H), 4.69 (br-s, 1H), 7.04 (dd, J = 5.1, 5.1 Hz, 1HX 7.22-7.32 (m, 3H)._ ]H-NMR (CDCU 400 MHz) 51.19-1.30 (m, IH), 1.25 (t, J = 5.4 Hz, 3H), 1.40-1.70 (m, 8H ), 1.74-1.80 (m, 3H), 2.03 (br-d, J = 7.2Hz, 2H), 2.37-2.49 (m, 1H), 2.79(br-s, 6H)f 3.12 (br-s, 1H ), 3.43 (br-s, 2H), 3.46 (d, J = 3. 9 Hz, 1H), 4.12 (q, J = 5.4 Hz, 2H), 4.31 (br-s, 2HX 4.55 (br-s, 1H), 7.00 (dd, J = 5.7, 5.7 Hz, 1H), 7.20-7.34 (m, 3H).

co^tCo^t

co2eCo2e

414 (M+H) 1.1 c 456 (M+H) 1.0 442 (M+H) 456 (M+H) 1.2 Ή-NMR (CDCU 400 MHz) 50.87 (t, 3H), 1.31 (t, 3H), 1.71 (m, 2H), 1.91 (m, 3H), 2.12 (m, 2H), 2. 85-2. 99 (m, 5H), 3.51 (m, 2H), 3.69 (m, 2H), 4.12 (m, 2H), 4.40 (m, 5H), 4.72 (m, 1H), 7.05 (m, 1H), 7.26 (m, 3H). lH-NMR (CDCU 400 MHz) &lt;51.25 (t, 3HX 1.33 (m, 1HX 1.55 (ni( 1H), 1.71 (m, 3HX 1.89-1. 96 (m, 2H), 2.12 (m, 2H), 2.34 (m，1H), 2.84-3· 00 (m, 5H), 3.38 (m, 2H), 3.52 (m，1H)，3.70 (m，2H)，3.98(ra，2H)，4.14 (m，2H)，4.39 (m，2H)，4.74 (m， 1H)，7_05 (m，1H)，7.27 (m，3H)._ Ή-NMR (CDCh, 400 MHz) 50.80 (t, 3H), 0.99 (t, 3H), 1.19 (m, 1H), 1.23 (t, 3H), 1.40 (m, 1H), 1.53 (m, 1H), 1.67(m( 2H), 1.84-1.98 (m, 2H), 2.01 (m, 1H), 2.14 (m, 2H), 2.83 (m, 2H)f 2.98 (m, 4H), 3.47 (m, 1H), 3.56 (ra, 1H), 3.65 (m, 2H), 4.16 (m, 2H), 4.38(m, 2H), 4.74(m, 1H), 7. 03 (m, 1H), 7.21-7.35 (m, 3H). Ή-NMR (CDCh, 400 MHz) 51.25 (t, 3H), 1.54-1.71 (m, 3H), 1.67-2.13 (m, 7H), 2.37 (in, IB), 2.83-3.01 (m, 5H)f 3.26-3.48 (m, 3H), 3.67 (m, 3H), 3.83 (m, 1HX 4.12-4.38 (m, 6H), 4.71 (m, 1H), 7.05 (in, 1H), 7.30 (m, 3H). Ή-NMR (CDCh, 400 MHz) 5 0.03-0.14 (m, 2H), 0.34 (m, 2H), 0.64(m, 1H), 1.25 (t, 3H), 1.68(m, 3H), 1. 87-1.95 (m, 2HX 2.12(01, 2H), 2.83-3.00 (m, 6H), 3.45 (m, 2H), 3.71 (m, 2H), 4.12(m, 2H), 4.38(m, 2H), 4.73(m, 1H), 7.10 (m, 1H), 7.31 (m, 3H). 400 Ή-NMR (CDCh, 400 MHz) 50.82 (t, 3H), 2.17 (t, 3H), 1.73 (M+H) (m, 2H), 1.85-2.11 (m, 6H), 2.83-3.04 (m, 6H), 3. 50 (m, 2H), 1.0 3.66 (m, 2H), 4.14 (m, 2H), 4.39 (m, 2H), 4.73 (in, 1H), 7.05 C (mt 1H), 7.24-7.35 (m, 3H). 414 Ή-NMR (MeOD 400 MHz) 50.76(t, 3H), 1.27(m, 3H), (M+H) 1.67-2.10(ra, 8H), 2.17(m, 1H), 2.28(m, 1HX 2.87(m, 1H), 1.3 3.37-3.58(m( 9H), 3.73(m, 1H), 4.13(m, 1H), 4.40(m, 1H), C 7.15(ffl, 2H)，7.32(m，2H). Ή-NMR (MeOD 400 MHz) 51.25 (t, 3H), 1.71 (m, 2fl), 2.13 (m, 4fl), 2. 92 (mf 4H), 3. 30 (id, 2H), 3. 50 (id, 2H), 3. 72 (m, 2H), 3.94(m, 1H), 4.16^ 2H), 4.35(m, 2H), 4.43(m, 1H), 4.94 (ra，1H), 6.99(m, 1H), 7.10(m, 2H), 7.24(m，1H), 7.73〇n, 1H). 163 323406 201211028 139 428 (Μ+Η) 1.1 C Ή-NMR (CDC1&gt; 400 MHz) 50.81 (t, 3H), 1.11 (ΐ, 3Η), 1.24 (m, 3Η), 1.62(m, 2H), 1.80-1. 94 (m, 3H), 2.06-2. 30 (m, 3H), 2.45 (m, 1H), 2.94-3.71 (m, 11H), 3.82 (m, 1H), 4.13 (m, 2H), 4.70 (m, 1H), 7.01 (m, 1H), 7.28 (m, 3H). 140 428 (Μ+Η) 1.1 C Ή-NMR (CDCh 400 MHz) 50.82-0.98 (m, 8H), 1.12-1.28 (m, 7H), 1.49-1.94 (m, 10H), 2.01-2.32 (m, 4H), 2.95-3. 26 (m, 5H), 3.45-3. 60 (m, 7H), 3.80 (m, 1H), 4.15 (in, 2H), 4. 71 (m, 1H), 7.04 (m, 1H), 7.27 (m, 3H). 141 0^0心 456 (Μ+Η) 1.0 Ή-NMR (CDCh 400 MHz) 51.25 (m, 3H), 1.62 (m, 2H), 1.83-2.31 (m, 8H), 2.75(m, 1H), 3.06(m, 4H), 3.27(m, 1H), 3.48-3.61 (m, 6H), 3.83-3.90 (m, 4H). 4.02 (id, 1H), 4.16 (m, 2H), 4.70 (m, 1H), 4.98 (m, 4H), 7.05 (m, 1H), 7.31 (m, 3H). 142 484 (Μ+Η) 1.3 Ή-NMR (CDCh 400 MHz) 50.80 (t, 3H), 0.89 (t, 3H), 1.08-1.44 (m, 11H), 1.66 (m, 2H), 1.82-1.94 (m, 3H), 2.01-2.30 (m, 4H), 2.99(01, 4H), 3.26(m, 1H), 3.46(m, 4H), 3.60(m, 2H), 3.83(m, 1H), 4.14 (m, 2H), 4.75(m, 1H), 7.05 (m, 1H), 7.28 (m, 3H). 143 广严* 0^0心 470 (Μ+Η) 1.0 Ή-NMR (CDCh 400 MHz) 51.24 (m, 4H), 1.43-1.67 (m, 7H), 1.74 (m, 1H), 2.40 (m, 5H), 2.54 (m, 1H), 2.89 (m, 2H), 3.28-3.41 (m, 5H), 3.42-3.60 (m, 2H), 3.86 (m, 1H), 3.96 (m, 2H), 4.12 (d, 2H), 4. 20 (m 1H), 6. 99 (m, 1H), 7.15-7. 27 (m, 3H). 144 456 (Μ+Η) 1.2 Ή-NMR (CDCh 400 MHz) 50.80 (t, 3H), 0.99 (t, 3H), 1.24 (m, 5H), 1.37(m, 1H), 1.65(m, 3H), 1. 79-2.28 (m, 7H), 2.98 (m, 4H), 3.25 (m, 1H), 3.46 (m, 3H), 3.57 (m, 3H), 3.83 (m, 1H), 4.15(111, 2H), 4. 74 (m, 1H), 6.19 (m, 2H), 7.03(m, 1H), 7.26 (m, 3H). 145 442 (Μ+Η) 0.9 C Ή-NMR (CDCh, 400 MHz) &lt;51.26 (t, 3H), 1.68 (m, 2H), 1.88 (m, 2H), 2.11 (m, 2H), 2.85-3.01 (m, 6H), 3.51 (m, 2H), 3.71-3. 93 (m, 4H), 4. 02 (m, 1H), 4.15 (m, 2H), 4.49(m, 2H), 4.73 (m, 3H), 7.07 (m, 1H), 7.29 (in, 3H), 12.1 (s, 1H). 146 (三氟乙酸鹽） 428 (Μ+Η) 1.1 C Ή-NMR (HeOD 400 MHz) 50.85(t, 3H), 1.17-1.32 (m, 7H), 1.74 (m, 2H), 1. 98-2.18 (m, 6H), 2.93(m, 4H), 3.30(m, 2H), 3.52 (m, 2H), 3.73 (m, 2H), 4.14 (m, 2H), 4.33-4.43 (m, 3H), 7.10-7.18 (m, 2H), 7.34 (m, 2H). 147 W (三氟乙酸鹽） 466 (Μ+Η) 1.1 C Ή-NMR (MeOD 400 MHz) 51.27(m, 3H), 1. 72-1.93 (m, 5H), 2.06 (m, 1H), 2.18(m, 1H), 2.27(m, 1H), 2.69-2.81 (m, 2H), 3.15 (in，2H), 3.30-3.63 (m，8H)，4_14(m，2H), 4.32(瓜，1H), 5.88 (s，1H)，7.02 (s，1H)，7.09 (m，2H)，7.22 (s，1H)，7.34 〇n， 2H). N.D·:無數據（No Data) 參考例88 4-{4-[6-甲氧基-3-曱基_2-側氧基-2, 3-二氫-1H-吲哚-1-基]哌啶-l-基}哌啶-1-羧酸乙酯 164 323406 201211028414 (M+H) 1.1 c 456 (M+H) 1.0 442 (M+H) 456 (M+H) 1.2 Ή-NMR (CDCU 400 MHz) 50.87 (t, 3H), 1.31 (t, 3H), 1.71 (m, 2H), 1.91 (m, 3H), 2.12 (m, 2H), 2. 85-2. 99 (m, 5H), 3.51 (m, 2H), 3.69 (m, 2H), 4.12 ( m, 2H), 4.40 (m, 5H), 4.72 (m, 1H), 7.05 (m, 1H), 7.26 (m, 3H). lH-NMR (CDCU 400 MHz) &lt;51.25 (t, 3HX 1.33 ( m, 1HX 1.55 (ni( 1H), 1.71 (m, 3HX 1.89-1. 96 (m, 2H), 2.12 (m, 2H), 2.34 (m, 1H), 2.84-3· 00 (m, 5H) , 3.38 (m, 2H), 3.52 (m, 1H), 3.70 (m, 2H), 3.98 (ra, 2H), 4.14 (m, 2H), 4.39 (m, 2H), 4.74 (m, 1H), 7_05 (m,1H), 7.27 (m,3H)._ Ή-NMR (CDCh, 400 MHz) 50.80 (t, 3H), 0.99 (t, 3H), 1.19 (m, 1H), 1.23 (t, 3H) ), 1.40 (m, 1H), 1.53 (m, 1H), 1.67 (m ( 2H), 1.84-1.98 (m, 2H), 2.01 (m, 1H), 2.14 (m, 2H), 2.83 (m, 2H)f 2.98 (m, 4H), 3.47 (m, 1H), 3.56 (ra, 1H), 3.65 (m, 2H), 4.16 (m, 2H), 4.38 (m, 2H), 4.74 (m, 1H) ), 7. 03 (m, 1H), 7.21-7.35 (m, 3H). Ή-NMR (CDCh, 400 MHz) 51.25 (t, 3H), 1.54-1.71 (m, 3H), 1.67-2.13 (m , 7H), 2.37 (in, IB), 2.83-3.01 (m, 5H)f 3.26-3.48 (m, 3H) , 3.67 (m, 3H), 3.83 (m, 1HX 4.12-4.38 (m, 6H), 4.71 (m, 1H), 7.05 (in, 1H), 7.30 (m, 3H). Ή-NMR (CDCh, 400 MHz) 5 0.03-0.14 (m, 2H), 0.34 (m, 2H), 0.64 (m, 1H), 1.25 (t, 3H), 1.68 (m, 3H), 1. 87-1.95 (m, 2HX 2.12 (01, 2H), 2.83-3.00 (m, 6H), 3.45 (m, 2H), 3.71 (m, 2H), 4.12 (m, 2H), 4.38 (m, 2H), 4.73 (m, 1H), 7.10 (m, 1H), 7.31 (m, 3H). 400 Ή-NMR (CDCh, 400 MHz) 50.82 (t, 3H), 2.17 (t, 3H), 1.73 (M+H) (m, 2H), 1.85-2.11 (m, 6H), 2.83-3.04 (m, 6H), 3. 50 (m, 2H), 1.0 3.66 (m, 2H), 4.14 (m, 2H), 4.39 (m, 2H), 4.73 (in, 1H), 7.05 C (mt 1H), 7.24-7.35 (m, 3H). 414 Ή-NMR (MeOD 400 MHz) 50.76(t, 3H), 1.27(m, 3H), (M+H) 1.67-2.10(ra, 8H), 2.17(m, 1H), 2.28(m, 1HX 2.87(m, 1H), 1.3 3.37-3.58(m( 9H), 3.73(m, 1H), 4.13(m, 1H ), 4.40 (m, 1H), C 7.15 (ffl, 2H), 7.32 (m, 2H). Ή-NMR (MeOD 400 MHz) 51.25 (t, 3H), 1.71 (m, 2fl), 2.13 (m, 4fl), 2. 92 (mf 4H), 3. 30 (id, 2H), 3. 50 (id, 2H), 3. 72 (m, 2H), 3.94(m, 1H), 4.16^ 2H), 4.35(m, 2H), 4.43(m, 1H), 4.94 (ra,1H), 6.99(m, 1H), 7.10(m, 2H), 7.24(m, 1H), 7.73〇n, 1H). 163 323406 201211028 139 428 (Μ+Η) 1.1 C Ή-NMR (CDC1> 400 MHz) 50.81 (t, 3H), 1.11 (ΐ, 3Η), 1.24 (m, 3Η) ), 1.62(m, 2H), 1.80-1. 94 (m, 3H), 2.06-2. 30 (m, 3H), 2.45 (m, 1H), 2.94-3.71 (m, 11H), 3.82 (m , 1H), 4.13 (m, 2H), 4.70 (m, 1H), 7.01 (m, 1H), 7.28 (m, 3H). 140 428 (Μ+Η) 1.1 C Ή-NMR (CDCh 400 MHz) 50.82 -0.98 (m, 8H), 1.12-1.28 (m, 7H), 1.49-1.94 (m, 10H), 2.01-2.32 (m, 4H), 2.95-3. 26 (m, 5H), 3.45-3. 60 (m, 7H), 3.80 (m, 1H), 4.15 (in, 2H), 4. 71 (m, 1H), 7.04 (m, 1H), 7.27 (m, 3H). 141 0^0 heart 456 (Μ+Η) 1.0 Ή-NMR (CDCh 400 MHz) 51.25 (m, 3H), 1.62 (m, 2H), 1.83-2.31 (m, 8H), 2.75 (m, 1H), 3.06 (m, 4H) , 3.27(m, 1H), 3.48-3.61 (m, 6H), 3.83-3.90 (m, 4H). 4.02 (id, 1H), 4.16 (m, 2H), 4.70 (m, 1H), 4.98 (m , 4H), 7.05 (m, 1H), 7.31 (m, 3H). 142 484 (Μ+Η) 1.3 Ή-NMR (CDCh 400 MHz) 50.80 (t, 3H), 0.89 (t, 3H), 1.08- 1.44 (m, 11H), 1.66 (m, 2H), 1.82-1.94 (m, 3H), 2.01-2.30 (m, 4H), 2.99 (01, 4H), 3.26 (m, 1H), 3.46 (m, 4H), 3.60(m, 2H), 3.83(m, 1H), 4.14 (m, 2H), 4.75 (m, 1H), 7.05 (m, 1H), 7.28 (m, 3H). 143 Guang Yan* 0^0 heart 470 (Μ+Η) 1.0 Ή-NMR (CDCh 400 MHz 51.24 (m, 4H), 1.43-1.67 (m, 7H), 1.74 (m, 1H), 2.40 (m, 5H), 2.54 (m, 1H), 2.89 (m, 2H), 3.28-3.41 (m , 5H), 3.42-3.60 (m, 2H), 3.86 (m, 1H), 3.96 (m, 2H), 4.12 (d, 2H), 4. 20 (m 1H), 6. 99 (m, 1H) , 7.15-7. 27 (m, 3H). 144 456 (Μ+Η) 1.2 Ή-NMR (CDCh 400 MHz) 50.80 (t, 3H), 0.99 (t, 3H), 1.24 (m, 5H), 1.37 (m, 1H), 1.65(m, 3H), 1. 79-2.28 (m, 7H), 2.98 (m, 4H), 3.25 (m, 1H), 3.46 (m, 3H), 3.57 (m, 3H) ), 3.83 (m, 1H), 4.15 (111, 2H), 4. 74 (m, 1H), 6.19 (m, 2H), 7.03 (m, 1H), 7.26 (m, 3H). 145 442 (Μ +Η) 0.9 C Ή-NMR (CDCh, 400 MHz) &lt;51.26 (t, 3H), 1.68 (m, 2H), 1.88 (m, 2H), 2.11 (m, 2H), 2.85-3.01 (m, 6H), 3.51 (m, 2H), 3.71-3. 93 (m, 4H), 4. 02 (m, 1H), 4.15 (m, 2H), 4.49 (m, 2H), 4.73 (m, 3H) , 7.07 (m, 1H), 7.29 (in, 3H), 12.1 (s, 1H). 146 (trifluoroacetate) 428 (Μ+Η) 1.1 C Ή-NMR (HeOD 400 MHz) 50.85(t, 3H ), 1.17-1.32 (m, 7H), 1.74 (m, 2H), 1. 98-2.18 (m, 6H), 2. 93(m, 4H), 3.30(m, 2H), 3.52 (m, 2H), 3.73 (m, 2H), 4.14 (m, 2H), 4.33-4.43 (m, 3H), 7.10-7.18 (m, 2H), 7.34 (m, 2H). 147 W (trifluoroacetate) 466 (Μ+Η) 1.1 C Ή-NMR (MeOD 400 MHz) 51.27 (m, 3H), 1. 72-1.93 (m, 5H ), 2.06 (m, 1H), 2.18 (m, 1H), 2.27 (m, 1H), 2.69-2.81 (m, 2H), 3.15 (in, 2H), 3.30-3.63 (m, 8H), 4_14 ( m, 2H), 4.32 (melon, 1H), 5.88 (s, 1H), 7.02 (s, 1H), 7.09 (m, 2H), 7.22 (s, 1H), 7.34 〇n, 2H). ND·: No Data Reference Example 88 4-{4-[6-Methoxy-3-indolyl-2-sideoxy-2,3-dihydro-1H-indol-1-yl]piperidine -l-yl}piperidine-1-carboxylic acid ethyl ester 164 323406 201211028

COjEt 使用參考例66之化合物，並依照與實施例1相同的方 法而得到標題化合物。 實施例148 4-{4-[3-羥基曱基-6-甲氧基-3-甲基-2-侧氧基-2, 3-二氫 -11]-11弓丨11朵-1-基]〇辰咬-1-基}51底'1定-1-缓酸乙酉旨COjEt The title compound was obtained according to the same procedure as in Example 1 using the compound of the title compound. Example 148 4-{4-[3-Hydroxyindolyl-6-methoxy-3-methyl-2-oxo-2,3-dihydro-11]-11 丨 11-11基]〇辰 bit-1-base}51 bottom '1 fixed-1-acidic acid

ΟΜθ 將參考例88之化合物（33mg)、碳酸鉀（33mg)、聚曱醛 (paraformaldehyde)(2lmg)溶解於 THF(2ml)’ 於 60°C 擾拌 2小時。過濾反應液後，將濾液進行減壓濃縮。將所得之 殘渣以矽膠管柱層析精製，得到為延胡索酸鹽之標題化合 物（19mg，43%)。 ^-NMR (CD3〇D, 400MHz) (5 1.41-1.21 (t, J=7. 1Hz, 3H), • 1.23-1.27 (t, J=7.2Hz, 3H), 1.58-1.66 (m, 2H), 1.91- 1.98 (m, 2H), 2.04-2.11 (ra, 2H), 2.70-2.92 (br4H), 3.00-3.09 (m， 2H), 3.44-3.51 (q, J=7.2Hz, 1H), 3.51-3.58 (m, 2H), 3.73 (s, 2H), 3.81 (s, 3H), 4.08-4.15 (q, J=7. 1Hz, 2H), 4.23-4.36 (m, 3H), 6.62-6.65 (ddJ=8. 1Hz, 2.2Hz, 1H), 6.79-6.81 (d, J=2.2Hz, 1H), 7.18-7.22 (d, J=7. 1Hz, 3H), 6.79-6.81 (d, J=2.2Hz, 1H), 7. 18-7. 22 (d, J=8. 1Hz, 1H). 165 323406 201211028 LC-MS:R. T. 5.7min.，m/z 446.2(M+H).條件 A。 實施例149至160 使用實施例1、66至71、75、76、104、105或136之 化合物，並依照與實施例148相同的方法而得到下述化合 物。ΟΜ θ The compound of Reference Example 88 (33 mg), potassium carbonate (33 mg), and paraformaldehyde (2lmg) were dissolved in THF (2ml) to be stirred at 60 ° C for 2 hours. After filtering the reaction mixture, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (19 mg, 43%). ^-NMR (CD3〇D, 400MHz) (5 1.41-1.21 (t, J=7. 1Hz, 3H), • 1.23-1.27 (t, J=7.2Hz, 3H), 1.58-1.66 (m, 2H) , 1.91- 1.98 (m, 2H), 2.04-2.11 (ra, 2H), 2.70-2.92 (br4H), 3.00-3.09 (m, 2H), 3.44-3.51 (q, J=7.2Hz, 1H), 3.51 -3.58 (m, 2H), 3.73 (s, 2H), 3.81 (s, 3H), 4.08-4.15 (q, J=7. 1Hz, 2H), 4.23-4.36 (m, 3H), 6.62-6.65 ( ddJ=8. 1Hz, 2.2Hz, 1H), 6.79-6.81 (d, J=2.2Hz, 1H), 7.18-7.22 (d, J=7.11Hz, 3H), 6.79-6.81 (d, J=2.2 Hz, 1H), 7. 18-7. 22 (d, J=8. 1Hz, 1H). 165 323406 201211028 LC-MS: RT 5.7min., m/z 446.2(M+H). Condition A. Examples 149 to 160 Using the compounds of Example 1, 66 to 71, 75, 76, 104, 105 or 136, the following compounds were obtained in the same manner as in Example 148.

166 323406 201211028166 323406 201211028

[表 10 — 貧施例 構造 (鹽） MS (m/z) 分鉉 條件 NMR (MHz,溶劑） 149 I rJ〇^ :令心 M· 430.3 (M+H) 4.7 N. D. 150 448 (M+H) 6.7 'H-NMRCCDCla, 300 MHz) &lt;51.28 (t, J = 7. 0 Hz, 3H), 1.37 (s, 3H), 1.51-1.96 (m, 6H), 1. 99-2. 20 (m, 2H), 2.44(br-s, 1H), 2.68(br-s, 1H), 2.89-3.14 (m, 2H), 3.18-3.61 (m, 7H), 3.74 (d, J = 10.8Hz, 1H), 3.85(d, J = 10.8 Hz, 1H), 4.08-4.23 (m, 2H), 4.70(br-s, 1H), 6. 92-7. 00 (m, 1H), 7. 05-7.17 (m, 1H), 7.85-7.95 (m, 1H), 12.64 (br-s, 1H). 151 430.6 (M+H) 2.7 Ή-NMR (CDCk 300 MHz) &lt;51.10 (dddd, J = 12.2, 12.2, 12.2, 4.0 Hz, 2H), 1.27 (t, J = 7.0 Hz, 3H), 1.40 (s, 3H), 1.57-1.73 (m, 3H), 1.79(br-d, J = 12.2Hz, 2H), 2.08(br-dd, J = 12.2, 12.2 Hz, 2H), 2.21 (d, J = 7.2 Kz, 2H), 2.44 (ddd, J = 12.2, 12.2, 12.2 Hz, 2H)f 2.75(dd, J = 12.2, 12.2 Hz, 2H), 2.98 (br-d, J = 12.2 Hz, 2H), 3.71 (d, J = 10.8 Hz, 1H), 3.83 (d, J = 10.8 Hz, 1H), 4.06-4.35 (m, 3H), 4.13 (q, J = 7.0 Hz, 2H), 7.07 (dd, J = 7.4, 7.4 Hz, 1H), 7.17 (d, J = 7.4 Hz, 1H), 7.22 (d, J = 7.4 Hz, 1H), 7.28 (dd, J = 7.4, 7.4 Hz, 1H). 152 F 448.5 (M+H) 2.8 B Ή-NMR (CDCh, 300 MHz) 51.10 (dddd, J = 12.2, 12.2, 12.2, 4.1Hz, 2H), 1.26(t, J = 7.IHz, 3H), 1.39(s, 3H), 1.56-1.73 (m, 3H), 1.78(br-d, J=12.2Hz, 2H), 2. 08 (br-dd, J = 12.2, 12.2 Hz, 2H), 2. 20 (d, J = 7.0 Hz, 2H), 2.39 (ddd, J = 12. 2, 12.2，12.2 Hz, 2H)，2.75 (dd, J = 12.2，12.2 Hz, 2H)，2.98 (br-d, J = 12.2 Hz, 2H), 3.71 (d, J = 10.6 Hz, 1H), 3.82 (d，J = 10.6 Hz，1H)，4.07-4.33 (m，3H)，4.13 (q, J = 7.1 Hz, 2H), 6.91-7.01 (m, 2H), 7.05-7.12 (m, 1H). 153 〇 、F 434.2 (M+H) 2.9 A N.D. 154 、F 448.2 (M+H) 3.8 A N. D. 155 Ma 430.3 (M+H) 4.7 A N.D. 156 ：P^° M· 444.2 (M+H) 5.3 N.D. 167 323406 201211028[Table 10 - Structure of the poor example (salt) MS (m/z) Bifurcation conditions NMR (MHz, solvent) 149 I rJ〇^ : Order M· 430.3 (M+H) 4.7 ND 150 448 (M+H 6.7 'H-NMRCCDCla, 300 MHz) &lt;51.28 (t, J = 7. 0 Hz, 3H), 1.37 (s, 3H), 1.51-1.96 (m, 6H), 1. 99-2. 20 ( m, 2H), 2.44 (br-s, 1H), 2.68 (br-s, 1H), 2.89-3.14 (m, 2H), 3.18-3.61 (m, 7H), 3.74 (d, J = 10.8Hz, 1H), 3.85 (d, J = 10.8 Hz, 1H), 4.08-4.23 (m, 2H), 4.70 (br-s, 1H), 6. 92-7. 00 (m, 1H), 7. 05- 7.17 (m, 1H), 7.85-7.95 (m, 1H), 12.64 (br-s, 1H). 151 430.6 (M+H) 2.7 Ή-NMR (CDCk 300 MHz) &lt;51.10 (dddd, J = 12.2 , 12.2, 12.2, 4.0 Hz, 2H), 1.27 (t, J = 7.0 Hz, 3H), 1.40 (s, 3H), 1.57-1.73 (m, 3H), 1.79 (br-d, J = 12.2Hz, 2H), 2.08 (br-dd, J = 12.2, 12.2 Hz, 2H), 2.21 (d, J = 7.2 Kz, 2H), 2.44 (ddd, J = 12.2, 12.2, 12.2 Hz, 2H)f 2.75 (dd , J = 12.2, 12.2 Hz, 2H), 2.98 (br-d, J = 12.2 Hz, 2H), 3.71 (d, J = 10.8 Hz, 1H), 3.83 (d, J = 10.8 Hz, 1H), 4.06 -4.35 (m, 3H), 4.13 (q, J = 7.0 Hz, 2H), 7.07 (dd, J = 7.4, 7.4 Hz, 1H), 7.17 (d, J = 7.4 Hz, 1H), 7 .22 (d, J = 7.4 Hz, 1H), 7.28 (dd, J = 7.4, 7.4 Hz, 1H). 152 F 448.5 (M+H) 2.8 B Ή-NMR (CDCh, 300 MHz) 51.10 (dddd, J = 12.2, 12.2, 12.2, 4.1Hz, 2H), 1.26(t, J = 7.IHz, 3H), 1.39(s, 3H), 1.56-1.73 (m, 3H), 1.78(br-d, J =12.2Hz, 2H), 2. 08 (br-dd, J = 12.2, 12.2 Hz, 2H), 2. 20 (d, J = 7.0 Hz, 2H), 2.39 (ddd, J = 12. 2, 12.2 , 12.2 Hz, 2H), 2.75 (dd, J = 12.2, 12.2 Hz, 2H), 2.98 (br-d, J = 12.2 Hz, 2H), 3.71 (d, J = 10.6 Hz, 1H), 3.82 (d , J = 10.6 Hz, 1H), 4.07-4.33 (m, 3H), 4.13 (q, J = 7.1 Hz, 2H), 6.91-7.01 (m, 2H), 7.05-7.12 (m, 1H). 153 〇 , F 434.2 (M+H) 2.9 A ND 154 , F 448.2 (M+H) 3.8 A ND 155 Ma 430.3 (M+H) 4.7 A ND 156 :P^° M· 444.2 (M+H) 5.3 ND 167 323406 201211028

N. D.:無數據（No Data) 實施例161 4-{4-[3-乙基-3, 6-二甲基-2-側氧基-2, 3-二氫-1H-吲哚 -1-基]哌啶-l-基}哌啶-1-羧酸乙酯ND: No data. Example 161 4-{4-[3-ethyl-3,6-dimethyl-2-oxo-2,3-dihydro-1H-indole-1- Ethyl piperidine-l-yl}piperidine-1-carboxylate

-COzEt Me-COzEt Me

使用實施例1之化合物，並使用乙基碘以取代聚甲 醛，依照與實施例148相同的方法而得到為延胡索酸鹽之 標題化合物。 實施例162 4-{4-[6-氟-2-側氧基-2’，3’，5’，6’ -四氫螺（吲哚-3, 4’ -哌喃）-1(2Η)-基]哌啶-1-基}-4-甲基哌啶-1-羧酸乙酯Using the compound of Example 1 and using ethyl iodide in place of polyformaldehyde, the title compound as the fumarate was obtained in the same manner as in Example 148. Example 162 4-{4-[6-Fluoro-2-oxo-2',3',5',6'-tetrahydrospiro(吲哚-3,4'-pyran)-1 (2Η Ethyl)piperidin-1-yl}-4-methylpiperidine-1-carboxylate

F 使用實施例95之化合物，並使用雙（2-溴乙基）醚以取 168 323406 201211028 代1，3-二溴丙烷，依照與實施例6步驟2相同的方法而得 到標題化合物。 實施例163至165 使用實施例96、98或101之化合物，並依照與實施例 162相同的方法而得到下述化合物。 [表 11_ 實施例 構造 (鹽） MS (m/z) 分鐘 條件 NMR (MHz,溶剤） 163 Me 470.2 (M+H) 5.9 A N.D. 164 Me 482.2 (M+H) 6.1 N. D. 165 F 486.2 (M+H) 5.8 A N.D. N. D.:無數據（No Data) φ 參考例89 4-(4-側氧基哌啶-1-基）哌啶-1-羧酸乙酯 〇=CHCn C02Et 使用可取得之1-乙氧基羰基-4-哌啶酮與參考例78之 化合物，並依照與參考例79相同的方法而得到標題化合 物。 參考例90 4-[4-(4-氯苯基）胺基旅咬-1-基]'1底°定-1-幾_酸乙酉旨 169 323406 201211028 HN-^~^N—^~V C02Et 將對-氣苯胺（752mg)、參考例89之化合物（1. 5g)溶解 於二氯曱烷（10ml)，加入三乙醯氧基硼氫化鈉（1.6g)、乙 酸（500mg)，於室溫授拌6小時。於反應液中加入飽和碳酸 氫鈉水溶液，以氣仿進行萃取。將所得之有機層以硫酸氫 鈉進行乾燥，並進行減壓濃縮。將所得之殘渣以矽膠管柱 層析精製，得到標題化合物（1.6g，74%)。 # 參考例91 4-{4-[5-氯-2, 3-二侧氧基-2, 3-二氫-1H-吲哚-1-基]哌啶 -l-基}哌啶-1-羧酸乙酯The title compound was obtained in the same manner as in the step 2 of Example 6 using the compound of Example 95 and using bis(2-bromoethyl)ether to afford 168 323406 201211028 1,3-dibromopropane. Examples 163 to 165 Using the compound of Example 96, 98 or 101, the following compound was obtained in the same manner as in Example 162. [Table 11_ Example construction (salt) MS (m/z) minute condition NMR (MHz, solvent) 163 Me 470.2 (M+H) 5.9 A ND 164 Me 482.2 (M+H) 6.1 ND 165 F 486.2 (M+ H) 5.8 A NDND: no data (No Data) φ Reference Example 89 4-(4-Sideoxypiperidin-1-yl)piperidine-1-carboxylic acid ethyl ester 〇=CHCn C02Et Use 1- Ethoxycarbonyl-4-piperidone and the compound of Reference Example 78 were obtained to give the title compound in the same procedure as Reference Example 90 4-[4-(4-Chlorophenyl)amine-based brigade-l-yl]'1 bottom -1- _ _ acid 酉 169 323406 201211028 HN-^~^N—^~V C02Et was dissolved in chloroaniline (752 mg), the compound of Reference Example 89 (1. 5 g) in dichloromethane (10 ml), and sodium triethyloxyborohydride (1.6 g) and acetic acid (500 mg) were added. Mix at room temperature for 6 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and the mixture was evaporated. The obtained organic layer was dried over sodium hydrogen sulfate and concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj #参考例91 4-{4-[5-Chloro-2,3-di-oxy-2,3-dihydro-1H-indol-1-yl]piperidine-1-yl}piperidine-1 -carboxylic acid ethyl ester

將參考例90之化合物（1. 6g)溶解於二乙基醚（50ml)， 加入二氯化草醯（1. 1 m 1 )，加熱回流2小時。將反應液回至 室溫，進行減壓濃縮後，使溶解於二氯曱烷，並於冰冷下 加入三氯化鋁（3. 48g)。之後，於室溫攪拌2小時後，加入 飽和碳酸氫鈉。將反應液以矽藻土過濾、且將濾液進行減 壓濃縮後，以矽膠管柱層析精製，得到標題化合物。 參考例92 4-{4-[5-氯-3-羥基-2-側氧基-2, 3-二氫-1H-吲哚-1-基] 0底咬-l-基}π底咬-1-叛酸乙酯The compound of Reference Example 90 (1.6 g) was dissolved in diethyl ether (50 ml), and dichloromethane (1. The reaction mixture was returned to room temperature, concentrated under reduced pressure, and then dissolved in dichloromethane, and then evaporated. Thereafter, after stirring at room temperature for 2 hours, saturated sodium hydrogencarbonate was added. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. Reference Example 92 4-{4-[5-Chloro-3-hydroxy-2-oxo-2,3-dihydro-1H-inden-1-yl] 0 bottom bite-l-yl} -1- oleic acid ethyl ester

CI 170 323406 201211028 將參考例91之化合物（150mg)溶解於甲醇（3ml)，於冰 冷下加入硼氫化鈉（67mg)後，攪拌丨小時。於反應液加入 飽和碳酸氫鈉水溶液，以氣仿進行萃取。藉由將有機層以 硫酸鈉進行乾燥並進行減壓濃縮而得到標題化合物（8^ 56%)。 ’ 實施例166 4-{4-[3-羥基-2-側氧基-2, 3-二氫-in-吲哚-1-基μ哌啶CI 170 323406 201211028 The compound of Reference Example 91 (150 mg) was dissolved in methanol (3 ml), and sodium borohydride (67 mg) was added under ice cooling, and stirred for hr. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and the mixture was evaporated. The title compound (8^56%) was obtained. Example 166 4-{4-[3-Hydroxy-2-oxo-2,3-dihydro-in-indol-1-yl-piperidine

-l-基}哌啶-i-羧酸乙酯 广 N-cOja Ο 使用苯胺以取代對'氯苯胺，並依照與參考例90至92 相同的方法而知到標題化合物。 實施例167炱hi 依照與實施例16之步驟3相同的方法，使用可取得之 氯曱酸酯以取代乙基硫羰氯，合成下述化合物。-l-yl}ethyl piperidine-i-carboxylate N-cOja Ο The title compound was obtained by substituting aniline for p-chloroaniline in the same manner as in Reference Examples 90 to 92. Example 167 炱hi The following compound was synthesized in the same manner as in the step 3 of Example 16 by using the obtained chloro phthalic acid ester instead of ethyl thiocarbonyl chloride.

171 3234〇6 201211028 [表 12] 實施例 _____ (¾) MS (m/z) 分鐘 條件 NHR (HHz，溶劑） 167 395.2 (M+H) 0.9 C N.D. 168 452 (M+H) 1.2 Ή-NMR (CDCli, 300 MHz) &lt;51.50-1.71 (m, 2H), 1.82 (br-d, J =10.8 Hz, 2H), 2.07 (br-s, 2H). 2.52-3.03 (m, 7H), 3.29 (br-s, 2H), 3.50 (s, 2H), 3.43-3.49 (m, 1H), 3.68 (dd, J =5.7, 5.7 Hz, 1H), 4.20-4.60 (m, 5H), 7.00 (dd, J = 7.5, 7.5 Hz, 1H), 7.32-7.18 (m, 2H), 7.42 (br-s, 1H). 169 ---— 406 (M+H) 3.0 A Ή-NMR (CDCh, 400 MHz) 51.47-1.51 (m 2H), 1.72-1.86 (〇, 4H), 2.38-2.54 (m, 5H), 2. 80 (m, 2H), 3.04 (d, J = 7.2 Hz, 2H), 3.51 (s, 2H), 3.69 (t, J = 5.6 Hz, 2H), 4.15-4.43 (m, 3H), 4.33 (t, J = 5.6 Hz, 2H), 7.01 (t, J = 8.0 Hz, 1H), 7.19-7.26 (in, 3H). 170 ^-〇-ΟλΛ. 386 (M+H) 3.8 A 'H-NMR(CDCK 400 MHz) &lt;51.23(d, J = 6.4Hz, 6H), 1.39-1.55 (m, 2H), 1.70-1.84 (m, 4H), 2.35-2.52 (m, 5H), 2.73 (t, J =12 Hz, 2H), 3.05 (d, J = 8.8 Hz, 2H), 3.50 (s, 2H), 4.13-4.46 (m, 3H), 4.85-4. 95 (m, 1H), 7.00 (t, J = 7.6 Hz, lfl), 7.21-7.26 (m, 3H). 171 ----〜 ^0-0^- 358 (M+H) 2.0 A Ή-NMR (CDCh, 400 MHz) 51.45-1.55 (m, 2H), 1.69-1.83 (m 4H), 2.37-2.51 (m, 5H), 2. 75 (t, J = 11.2 Hz, 2H), 3.03(d, J = 7.6 Hz, 2H), 3.49 (s, 2H), 3.68 (s, 3H) 4.12-4.37 (m, 3H), 6.99 (t, J = 7.6 Hz, 1H), 7.18-7.26 (η, 3H). N_ D.:無數據（No Data) 實施例172至175 Φ 依照與實施例16之步驟1至3相同的方法，使用1 一 第三丁氧基羰基-4-氮雜環庚酮以取代卜 -4-哌啶酮，且使用可取得 矛一』乳丞叛丞 合成下述化合物。 氣’酸醋以取代乙基硫羰氯， 323406 172 201211028[表 13· 參171 3234〇6 201211028 [Table 12] Example _____ (3⁄4) MS (m/z) Minute condition NHR (HHz, solvent) 167 395.2 (M+H) 0.9 C ND 168 452 (M+H) 1.2 Ή- NMR (CDCli, 300 MHz) &lt;51.50-1.71 (m, 2H), 1.82 (br-d, J = 10.8 Hz, 2H), 2.07 (br-s, 2H). 2.52-3.03 (m, 7H), 3.29 (br-s, 2H), 3.50 (s, 2H), 3.43-3.49 (m, 1H), 3.68 (dd, J = 5.7, 5.7 Hz, 1H), 4.20-4.60 (m, 5H), 7.00 ( Dd, J = 7.5, 7.5 Hz, 1H), 7.32-7.18 (m, 2H), 7.42 (br-s, 1H). 169 ---— 406 (M+H) 3.0 A Ή-NMR (CDCh, 400 MHz) 51.47-1.51 (m 2H), 1.72-1.86 (〇, 4H), 2.38-2.54 (m, 5H), 2. 80 (m, 2H), 3.04 (d, J = 7.2 Hz, 2H), 3.51 (s, 2H), 3.69 (t, J = 5.6 Hz, 2H), 4.15-4.43 (m, 3H), 4.33 (t, J = 5.6 Hz, 2H), 7.01 (t, J = 8.0 Hz, 1H) , 176 (M+H) 3.8 A 'H-NMR (CDCK 400 MHz) &lt;51.23 (d, J = 6.4 Hz, 6H), 1.39- 1.55 (m, 2H), 1.70-1.84 (m, 4H), 2.35-2.52 (m, 5H), 2.73 (t, J =12 Hz, 2H), 3.05 (d, J = 8.8 Hz, 2H), 3.50 (s, 2H), 4.13-4.46 (m, 3H), 4.85-4. 95 (m, 1H), 7.00 (t, J = 7.6 Hz, lfl), 7.21- 7.26 (m, 3H). 171 ----~ ^0-0^- 358 (M+H) 2.0 A Ή-NMR (CDCh, 400 MHz) 51.45-1.55 (m, 2H), 1.69-1.83 (m 4H), 2.37-2.51 (m, 5H), 2. 75 (t, J = 11.2 Hz, 2H), 3.03 (d, J = 7.6 Hz, 2H), 3.49 (s, 2H), 3.68 (s, 3H) ) 4.12-4.37 (m, 3H), 6.99 (t, J = 7.6 Hz, 1H), 7.18-7.26 (η, 3H). N_ D.: No Data (Examples 172 to 175) Φ Compliance and implementation In the same manner as in Steps 1 to 3 of Example 16, 1-tert-butoxycarbonyl-4-azepanone was used in place of Bu-4-piperidone, and the spear-yellow sputum rebellion synthesis was used. The following compounds. Gas 'sour vinegar to replace ethyl thiocarbonyl chloride, 323406 172 201211028 [Table 13·

MS (m/z) 分鐘 條件 414 (M+H) 1.1 372 (M+H) 396 (M+H) 1.1 c 410 (M+H) 1.2 N. D.:無數據（No Data) NMR (MHz,溶剞） N.D. 'H-NMKMeODWOMHz) δ1·77〇η，2H), l_93(m· 5H), 3H), 2.21 On, 1H), 2.31 (m, 1H), 3.93 (m, 2H),九4 ’ 7 18 3.56 (m, 5H), 3.70 (m, 4H), 4.43 (m, 1H), 7. 〇4 tt’ ’ (m, 1H), 7.28 (m, 2H). Ή-NMR (CDCh, 400 MHz) 51.72 (m, 2H), &gt;96_.2· 〇2,l' 3 55 2.21-2.33 (m, 2H), 2.85-2.96 (m, 3H), 3.32 (®. (m, 5H), 3.71 (m, 1H), 4.50 (□, 1H), 4.72 (m, 2H), &lt; ’ 1H), 7.20-7.29 Cm, 3H). ___一- ' 1~ 1 , 〇1|\ I 92 'H-NMR (CDCk 40。MHz) 51.75 On, 2H), 1·82 (ΊΛ86·(|η (m, 1H), 2.05 (m, 3H), 2.21 (m, 1H), 2.31 (m. lH)· ^ 4g 2H), 3.30-3.44 (m, 5H), 3.56 (m, 5H), 3.71 (m, 1, ,〇 (m, 1H), 4.67(m, 2H), 7.05(m, 1H), 7. 20 (m. lH)&gt; L0 ’ 2H). _ 實施例176至182 使用參考例32或47之化合物，並依照與實施例16記 載之步驟1至3相同的方法’使用可取得之氯甲酸酯以取 • 代乙基硫羰氯，合成下述化合物。 323406 173 201211028MS (m/z) min condition 414 (M+H) 1.1 372 (M+H) 396 (M+H) 1.1 c 410 (M+H) 1.2 ND: no data (No Data) NMR (MHz, solvent ND 'H-NMKMeODWOMHz) δ1·77〇η, 2H), l_93(m· 5H), 3H), 2.21 On, 1H), 2.31 (m, 1H), 3.93 (m, 2H), nine 4' 7 18 3.56 (m, 5H), 3.70 (m, 4H), 4.43 (m, 1H), 7. 〇4 tt' ' (m, 1H), 7.28 (m, 2H). Ή-NMR (CDCh, 400 MHz 5,72 (m, 2H) (m, 1H), 4.50 (□, 1H), 4.72 (m, 2H), &lt; '1H), 7.20-7.29 Cm, 3H). ___一- ' 1~ 1 , 〇1|\ I 92 ' H-NMR (CDCk 40.MHz) 51.75 On, 2H), 1·82 (ΊΛ86·(|η (m, 1H), 2.05 (m, 3H), 2.21 (m, 1H), 2.31 (m. lH) · ^ 4g 2H), 3.30-3.44 (m, 5H), 3.56 (m, 5H), 3.71 (m, 1, , 〇(m, 1H), 4.67(m, 2H), 7.05(m, 1H), 7. 20 (m. lH) &gt; L0 ' 2H). _ Examples 176 to 182 The compounds of Reference Example 32 or 47 were used, and the same method as in the steps 1 to 3 described in Example 16 was used. The following compounds were synthesized from chloroformate using ethylthiocarbonyl chloride. 323406 17 3 201211028

[表 14] 實施例 構造 (鹽） MS (m/z) 分鐘 條件 NMR (MHz,溶劑） 176 424 _) 6.0 A N.D. 177 420 (M+H) 6.4 A 'H-NMR(CDCh, 400 MHz) 51.24(d, J = 4.0Hz, 6H), 1.35-1.42 Cm, 2H), 1.55-1.85 (m, 4H), 2.26-2.55 (m, 5H), 2.66-2.78 (m, 2H), 2. 99-3. 05 (m, 2H), 3.50(s, 2H), 4.13-4.35 (m, 3H), 4.88-4.94 (m, 1H), 7.02-7.24 (m, 3H). 178 又广N-O^0〜叫 420 (M+H) 6.5 A Ή-NMR (CDCh, 400 MHz) 5 0.95(t, J = 8. 0 Hz, 3H), 1.40-1.82 (m, 8H), 2.30-2.39 (m, 4H), 2,47-2.53 (m, 1H), 2.71-2.84 (m, 2H), 2. 99-3.08 (m, 2H), 3.50 (s, 2H), 4.03 (t, J = 8.0 Hz, 2H), 4.15-4.38 (m, 3H), 7.08 (d, J = 8.0 Hz, 1H), 7.19-7.24 (m, 2H). 179 436 (M+H) 6.0 A Ή-NMR (CDCK 400 MHz) 51.41-1.55 (m, 2H), 1.70-1.81 (mt 5H)，2.31-2.55 (m, 4H), 270-2.85 (m，2H), 2.96-3.05 (m, 2H), 3.40 (s, 3H), 3.50 (s, 2H), 3.61 (t, J = 8.0 Hz, 2H), 4.16-4.32 (ra, 5H), 7.10-7.25 (m, 3H). 180 0 Μ· N.D. Ή-NMR (CDCls, 300 MHz) δ 1.42-1.60 (m, 2H), 1.70-1.73 (m, 2H), 1.82-1.86 (m, 2H), 2.30-2.59 (m, 4H), 2.38 (s, 3H), 2.70-2.86 (m, 2H), 3.03-3.05 (m, 2H), 3.71 (s, 2H), 3.65-3.78 (m, 1H), 4.19-4.34 (m, 3H), 4.58-4.60 (m, 2H), 5.20-5.34 (m, 1H), 5.88-6.00 (m, 1H), 6.81-6.84 (m, 1H), 6.98 (s, 1H), 7.09-7.12 (m, 1H). 181 pxy°x^ Μ* 404.3 (M+H) 5.9 A Ή-NMR (CDCh, 300 MHz) 51.42-1.59 (m 2H), 1.64 (s, 4H), 1.70-1. 78 (m, 2H), 1.82-1.91 (m, 2H), 2.41 (s, 3H) 1.48-1.59 (m, 1H), 1.74-1.90 (br, 2H), 3.03-3. 09 (m, 2H), 3.46(s2H), 4.20-4.34 (m, 4H), 3.38-4.41 (m 1H), 4.52-4.5 7(m, 1H), 4.69-4.72 Cm, 1H), 6.82-6.88 (m 1H), 6.98 (s, 1H), 7.10-7.167(m, 1H). 182 420 (M+H) 4.9 A Ή-NMR (CDCh, 400 MHz) 51.26 (m, 2H), 1.66 (m, 3H), 1.70 (ra, 2H), 1.80 (m, 2H), 2.36 (m, 4H), 2.50 (m, 1H), 2.77 (m, 2H), 3.03 (m 2H) 3.40 (s, 3H), 3.51 (s, 2H), 3.61 (t, 2H), 4.23 (m, 4H), 6.91 (ni, 1H), 7.00 (m, 1H), 7.08 (m, 1H). N_ D.:無數據（No Data) 實施例183 4-{4-[5-氯-2-側氧基-2，3_二氮-1Η_Π3基]_σ辰咬-1-基}氮雜環庚烷-1-羧酸甲酯 174 323406 201211028[Table 14] Example configuration (salt) MS (m/z) minute condition NMR (MHz, solvent) 176 424 _) 6.0 A ND 177 420 (M+H) 6.4 A 'H-NMR (CDCh, 400 MHz) 51.24(d, J = 4.0Hz, 6H), 1.35-1.42 Cm, 2H), 1.55-1.85 (m, 4H), 2.26-2.55 (m, 5H), 2.66-2.78 (m, 2H), 2. 99 -3. 05 (m, 2H), 3.50(s, 2H), 4.13-4.35 (m, 3H), 4.88-4.94 (m, 1H), 7.02-7.24 (m, 3H). 178 广广NO^0 ~ 420 (M+H) 6.5 A Ή-NMR (CDCh, 400 MHz) 5 0.95(t, J = 8. 0 Hz, 3H), 1.40-1.82 (m, 8H), 2.30-2.39 (m, 4H ), 2,47-2.53 (m, 1H), 2.71-2.84 (m, 2H), 2. 99-3.08 (m, 2H), 3.50 (s, 2H), 4.03 (t, J = 8.0 Hz, 2H ), 4.15-4.38 (m, 3H), 7.08 (d, J = 8.0 Hz, 1H), 7.19-7.24 (m, 2H). 179 436 (M+H) 6.0 A Ή-NMR (CDCK 400 MHz) 51.41 -1.55 (m, 2H), 1.70-1.81 (mt 5H), 2.31-2.55 (m, 4H), 270-2.85 (m, 2H), 2.96-3.05 (m, 2H), 3.40 (s, 3H), 3.50 (s, 2H), 3.61 (t, J = 8.0 Hz, 2H), 4.16-4.32 (ra, 5H), 7.10-7.25 (m, 3H). 180 0 Μ· ND Ή-NMR (CDCls, 300 MHz ) δ 1.42-1.60 (m, 2H), 1.70-1.73 (m, 2H), 1.82-1.86 (m, 2H), 2.30-2.59 (m, 4H), 2.38 (s, 3H), 2.70 -2.86 (m, 2H), 3.03-3.05 (m, 2H), 3.71 (s, 2H), 3.65-3.78 (m, 1H), 4.19-4.34 (m, 3H), 4.58-4.60 (m, 2H) , 5.20-5.34 (m, 1H), 5.88-6.00 (m, 1H), 6.81-6.84 (m, 1H), 6.98 (s, 1H), 7.09-7.12 (m, 1H). 181 pxy°x^ Μ * 404.3 (M+H) 5.9 A Ή-NMR (CDCh, 300 MHz) 51.42-1.59 (m 2H), 1.64 (s, 4H), 1.70-1. 78 (m, 2H), 1.82-1.91 (m, 2H), 2.41 (s, 3H) 1.48-1.59 (m, 1H), 1.74-1.90 (br, 2H), 3.03-3. 09 (m, 2H), 3.46(s2H), 4.20-4.34 (m, 4H ), 3.38-4.41 (m 1H), 4.52-4.5 7(m, 1H), 4.69-4.72 Cm, 1H), 6.82-6.88 (m 1H), 6.98 (s, 1H), 7.10-7.167 (m, 1H) ) 182 420 (M+H) 4.9 A Ή-NMR (CDCh, 400 MHz) 51.26 (m, 2H), 1.66 (m, 3H), 1.70 (ra, 2H), 1.80 (m, 2H), 2.36 ( m, 4H), 2.50 (m, 1H), 2.77 (m, 2H), 3.03 (m 2H) 3.40 (s, 3H), 3.51 (s, 2H), 3.61 (t, 2H), 4.23 (m, 4H) ), 6.91 (ni, 1H), 7.00 (m, 1H), 7.08 (m, 1H). N_ D.: no data (No Data) Example 183 4-{4-[5-Chloro-2-side oxygen Methyl-2,3_diaza-1Η_Π3yl]_σ辰分-1-yl}azepane-1-carboxylic acid methyl ester 174 323406 201211028

使用參考例32之化合物，並依照與實施例16記載之 步驟1至3相同的方法，使用1-第三丁氧基羰基-4-氮雜 環庚酮以取代1_第三丁氧基羰基-4-派咬酮，且使用可取 得之氯甲酸甲酯以取代乙基硫羰氣’得到標題化合物之延 胡索酸鹽。 φ ^-NMR (DMSO-de, 400ΜΗζ) δ 1.01-1.09 (m, ιη), 1.12-1.18 (td, J=7. 1, 3.3Hz), 1.38-1.40 (m, 2H), 1.55-1.65 (m, 3H), 1.77-1.97 (m, 3H), 2.28-2.40 (m, 2H), 2.50-2.58 (in, 1H), 2.63-2.70 (br, 1H), 2.91-2.99 (br, 1H), 3.18-3.27 (br, 2H), 3.40-3.50 (m, 2H), 3.55 (s, 2H), 3.99-4.07 (q, J=7. 1Hz, 2H), 4.10-4.20 (br, 1H), 6.58 (s2H, fumaric acid)，7.16-7. 19 (dd, J=8. 4, 3. 2Hz, 1H) 7.25-7.30 (d, J=8.4Hz, 1H), 7.31-7.32 (d, • J=3.2Hz, 1H) LC-MS : R. T. 6. 3 min.，m/z 422. 2(M+Na)·條件 a。 參考例93 4-(3, 3-二氟-2-侧氧基-2, 3-二氫吲D朵-1-基）辰咬_i_叛 酸第三丁醋The compound of Reference Example 32 was used, and 1-tert-butoxycarbonyl-4-azepanone was used in the same manner as in Steps 1 to 3 described in Example 16 to substitute 1 -3 -butoxycarbonyl group. -4- ketone, and the available methyl chloroformate is used in place of ethyl thiocarbonyl to give the title compound of fumarate. φ ^-NMR (DMSO-de, 400ΜΗζ) δ 1.01-1.09 (m, ηη), 1.12-1.18 (td, J=7. 1, 3.3Hz), 1.38-1.40 (m, 2H), 1.55-1.65 ( m, 3H), 1.77-1.97 (m, 3H), 2.28-2.40 (m, 2H), 2.50-2.58 (in, 1H), 2.63-2.70 (br, 1H), 2.91-2.99 (br, 1H), 3.18-3.27 (br, 2H), 3.40-3.50 (m, 2H), 3.55 (s, 2H), 3.99-4.07 (q, J=7. 1Hz, 2H), 4.10-4.20 (br, 1H), 6.58 (s2H, fumaric acid), 7.16-7. 19 (dd, J=8. 4, 3. 2Hz, 1H) 7.25-7.30 (d, J=8.4Hz, 1H), 7.31-7.32 (d, • J= 3.2 Hz, 1H) LC-MS: RT 6. 3 min., m/z 422. 2 (M+Na). Reference Example 93 4-(3,3-Difluoro-2-indolyl-2,3-dihydroindole D-l-yl) Chen _i_Resin third vinegar

將參考例3之化合物（340mg)溶解於二曱基曱醯胺 323406 175 201211028 (5ml)，於冰浴下加入氫化納（i4lmg)後，授拌1分鐘。之 後加入Ν-氟苯磺醯亞胺（1· 〇2g) ’升溫至室溫後，攪拌2. 5 小時。於反應液加入水，並以氯仿進行萃取後，以水、飽 和食鹽水洗淨有機層。以硫酸鈉進行乾燥後，以矽藻土過 濾，將濾液減壓濃縮。將所得之殘渣以矽膠管柱層析精製 而得到標題化合物（338mg，89%)。 實施例184至186The compound of Reference Example 3 (340 mg) was dissolved in dimercaptoamine 323406 175 201211028 (5 ml), and sodium hydride (i4lmg) was added to the ice bath, and the mixture was stirred for 1 minute. 5小时。 After adding Ν-fluorobenzenesulfonimide (1· 〇 2g) ‘after heating to room temperature, stirring for 2.5 hours. After adding water to the reaction mixture and extracting with chloroform, the organic layer was washed with water and saturated brine. After drying over sodium sulfate, it was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography toiel Examples 184 to 186

使用參考例93之化合物，並依照與參考例4、實施例 30至93相同的方法而合成下述化合物。 [表 15: 實施例 構造 (鹽） MS (m/z) 分餚 條件 NMR (MHz，溶劑） 184 408.1 (M+H) 4.8 A Ή-NMR (CDCh, 300 MHz) 51.22-1.29 (t, J = 7.1 H「3H) ~ 1.38-1.49 (m 2H)，1.68-1.83 (m，4H)，2.30-2.40 (in, 4H)’ 2.41-2.52 (m, 1H), 2.68-2.81 (m, 2H), 2.98-3.10 (br, 2H)' 4.07-4. 30 (q, J = 7.1 Hz, 3H), 7.11-7.19 (m, 2H), 7.42-7 49 (t, J = 7.8 Hz, 1H), 7.53-7.58 (d, J = 6.1 Hz, 1H). 185 434.2 (M+H) 5.6 A N. D. 186 422.2 (M+H) 5.2 A ^-NMR (CDCK 300 MHz) &lt;5 1.22-1.29 (dt, J = 7.1, 3.9 Hz, 3HX L 38-1.78 (m, 5HX 1.83-1.99 (m, 3H). 2.28-2.40 (m! 4H), 2.49-2.57 (m, 1HX 2.87-2.96 (m, 2H). 3.11-3.32 (mi 2H), 3.46-3.68 (m, 2H), 4.10-4.19 (dq, J = 7.1, 2.9 Hz, 3H), 7.11-7.19 (m, 2H), 7.42-7.49 (t, J = 7.8Hz, 1H), 7.53-7.58 (d, J = 6.1 Hz, 1H). N. D.:無數據（No Data) 實施例187至189 依照與實施例149至160相同的方法而得到下述化合 物。 176 323406 201211028 [表 16: 實施例 構造 (鹽） MS (m/z) 分鐘 條件 NMR (MHz,溶劑） 187 OM· 472.2 (M+H) 6.0 N. D. 188 OMo 460.3 (M+H) 5.7 N.D. 189 434.0 (M+H) 1.2 C lH-NMR (CDCb, 400 MHz) 51.23-1.28 (t, J = 7.0 Hz, 3HX 1.43 (s, 3H), 1.48-1.60 (m, 2H), 1.61-1.69 (in, 2H), 1.89-2.00 (brf 2HX 2.50-2.81 (m, 7H), 3.12-3.24 (br 2H), 3.70-3.83 (m, 2H), 4.09-4.18 (q, J = 7. 0 Hz, 2H), 4.19-4.43 (m, 3H), 6.92-7.01 (m, 2H), 7.27-7.41 (br, 1H). N.D.:無數據（No Data)The following compound was synthesized in the same manner as in Reference Example 4 and Examples 30 to 93 using the compound of Reference Example 93. [Table 15: Example Construction (Salt) MS (m/z) Dividing Condition NMR (MHz, solvent) 184 408.1 (M+H) 4.8 A Ή-NMR (CDCh, 300 MHz) 51.22-1.29 (t, J = 7.1 H "3H) ~ 1.38-1.49 (m 2H), 1.68-1.83 (m, 4H), 2.30-2.40 (in, 4H)' 2.41-2.52 (m, 1H), 2.68-2.81 (m, 2H) , 2.98-3.10 (br, 2H)' 4.07-4. 30 (q, J = 7.1 Hz, 3H), 7.11-7.19 (m, 2H), 7.42-7 49 (t, J = 7.8 Hz, 1H), 7.53-7.58 (d, J = 6.1 Hz, 1H). 185 434.2 (M+H) 5.6 A ND 186 422.2 (M+H) 5.2 A ^-NMR (CDCK 300 MHz) &lt;5 1.22-1.29 (dt, J = 7.1, 3.9 Hz, 3HX L 38-1.78 (m, 5HX 1.83-1.99 (m, 3H). 2.28-2.40 (m! 4H), 2.49-2.57 (m, 1HX 2.87-2.96 (m, 2H). 3.11-3.32 (mi 2H), 3.46-3.68 (m, 2H), 4.10-4.19 (dq, J = 7.1, 2.9 Hz, 3H), 7.11-7.19 (m, 2H), 7.42-7.49 (t, J = 7.8 Hz, 1H), 7.53-7.58 (d, J = 6.1 Hz, 1H). ND: No data. Examples 187 to 189 The following compounds were obtained in the same manner as in Examples 149 to 160. 323406 201211028 [Table 16: Example construction (salt) MS (m/z) minute condition NMR (MHz, solvent) 187 OM· 472.2 (M+H) 6.0 ND 188 OMo 460.3 (M+H) 5.7 ND 189 434.0 (M+H) 1.2 C lH-NMR (CDCb, 400 MHz) 51.23-1.28 (t, J = 7.0 Hz, 3HX 1.43 (s, 3H), 1.48- 1.60 (m, 2H), 1.61-1.69 (in, 2H), 1.89-2.00 (brf 2HX 2.50-2.81 (m, 7H), 3.12-3.24 (br 2H), 3.70-3.83 (m, 2H), 4.09- 4.18 (q, J = 7. 0 Hz, 2H), 4.19-4.43 (m, 3H), 6.92-7.01 (m, 2H), 7.27-7.41 (br, 1H). ND: No Data

實施例190至191 依照與實施例163至165相同的方法而得到下述化合 物。 [表 17_ 實施例 構造 (鹽） MS (m/z) 分鐘 條件 NMR (MHz,溶劑） 190 〆明 474.2 (M+H) 5.7 N.D. 191 F 460.3 (M+H) 5.4 A N.D. N.D·:無數據（No Data) 177 323406 201211028 實施例192至194 使用參考例67或69之化合物，依照與實施例1相同 的方法而得到下述化合物。 [表 18: 實施例 構造 (鹽） MS (m/z) 分鐘 條件 NMR (MHz,溶劑） 192 广π Me 414.1 (M+H) 5.9 N.D. 193 1 Q F 404.1 (M+H) 4.7 A N.D. 194 F 456.2 (M+H) 5.4 A N.D. N· D.:無數據（No Data) 參考例94Examples 190 to 191 The following compounds were obtained in the same manner as in Examples 163 to 165. [Table 17_ Example Construction (Salt) MS (m/z) Minute Condition NMR (MHz, Solvent) 190 47 474.2 (M+H) 5.7 ND 191 F 460.3 (M+H) 5.4 A NDND·: No data ( No Data) 177 323406 201211028 Examples 192 to 194 Using the compound of Reference Example 67 or 69, the following compound was obtained in the same manner as in Example 1. [Table 18: Example construction (salt) MS (m/z) minute condition NMR (MHz, solvent) 192 π Me 414.1 (M+H) 5.9 ND 193 1 QF 404.1 (M+H) 4.7 A ND 194 F 456.2 (M+H) 5.4 A ND N· D.: No Data Reference Example 94

4-(4-侧氧基哌啶-1-基）-4-曱基氮雜環庚烷-1-羧酸乙酯 使用N-Boc-氮雜環庚酮以取代N-Boc-派咬S同，依照與 參考例70至73相同的方法，合成標題化合物。 實施例195至199 使用參考例73之化合物或參考例94之化合物，依照 與實施例94相同的方法而得到下述化合物。 178 323406 201211028 [表 19_ 實施例 構造 (鹽） MS (m/z) 分鐘 條件 NMR (MHz,溶劑） 195 广严Et 400.2 (M+H) 3.7 A N. D. 196 χ Γ,Ό^1 386,2 (M+H) 3.0 A N.D. 197 F 404.2 (M+H) 3.0 N. D. 198 400.2 (M+H) 5.2 A N.D. 199 χόΡ^ P 416.2 (M+H) 3.2 A N.D_ N.D·:無數據（No Data) # 實施例200至202 使用參考例37之化合物或參考例38之化合物，依照 與實施例1相同的方法而得到下述化合物。 179 323406 201211028 [表 20: 實施例 構造 (鹽） MS (m/z) 分鐘 條件 NMR (MHz,溶劑） 200 Me厂 400.2 (M+H) 5.2 N.D. 201 MeO 428.2 (M+H) 4.4 A N.D. 202 416.2 (M+H) 4.9 A N.D. N.D.:無數據（No Data)Ethyl 4-(4-oxopiperidin-1-yl)-4-mercaptoazepane-1-carboxylate using N-Boc-azepanone to replace N-Boc-bite The title compound was synthesized in the same manner as in Reference Examples 70 to 73. Examples 195 to 199 Using the compound of Reference Example 73 or the compound of Reference Example 94, the following compound was obtained in the same manner as in Example 94. 178 323406 201211028 [Table 19_ Example Construction (Salt) MS (m/z) Minute Condition NMR (MHz, Solvent) 195 Guang Yan Et 400.2 (M+H) 3.7 A ND 196 χ Γ, Ό^1 386,2 ( M+H) 3.0 A ND 197 F 404.2 (M+H) 3.0 ND 198 400.2 (M+H) 5.2 A ND 199 χόΡ^ P 416.2 (M+H) 3.2 A N.D_ ND·: No data (No Data #Examples 200 to 202 Using the compound of Reference Example 37 or the compound of Reference Example 38, the following compound was obtained in the same manner as in Example 1. 179 323406 201211028 [Table 20: Example construction (salt) MS (m/z) minute condition NMR (MHz, solvent) 200 Me plant 400.2 (M+H) 5.2 ND 201 MeO 428.2 (M+H) 4.4 A ND 202 416.2 (M+H) 4.9 A NDND: No Data (No Data)

實施例203至204 依照製法6、方案12記載之一般方法，合成下述化合 物。 [表21 實施例 構造 (鹽） MS (m/z) 分鐘 條件 NMR (MHz,溶劑） 〇 ζ rvc〇毋 420.2 (M+H) 1.2 'H-NMR(MeOD, 400 MHz) 51.22-1.29 (t J = 7.1 Hz, 3H), 1.49 (s，3H), 1.63-1.74 (m，2H)，2.03-2.17 (m，4H)，2_7卜2.94 203 F (m, 4H), 3.20-3.31 (m, 2H)( 3.41-3.50 (m, 1H), 3.64-3.72 (ra, 2H), 4.11-4.27 (q，J = 7.1 Hz, 2H)，4.25-4.37 (瓜，2H), 7.02-7.20 (m, 3H). F 406.2 Ή-NMR (MeOD, 400 MHz) 51.51 (s, 3H), 1.65-1.76 (m, 2H), 204 (M+H) 1.4 2.05-2.19 (m, 4H), 2.74-2.97 (m, 4H), 3.24-3.35 (m, 2H), 3.43-3.52 (m, 1H), 3.64-3.72 (m, 2H), 3.72 (s, 3H), 4. 28-4.40 (m, 2H), 7. 05-7.23 (m, 3H). 實施例205至206 依照製法7、方案13記載之一般方法，合成下述化合 物。 180 323406 201211028 [表 22]Examples 203 to 204 The following compounds were synthesized in accordance with the general methods described in Process 6 and Scheme 12. [Table 21 Example Construction (salt) MS (m/z) min. condition NMR (MHz, solvent) 〇ζ rvc 〇毋 420.2 (M+H) 1.2 'H-NMR (MeOD, 400 MHz) 51.22-1.29 (t J = 7.1 Hz, 3H), 1.49 (s, 3H), 1.63-1.74 (m, 2H), 2.03-2.17 (m, 4H), 2_7, 2.94 203 F (m, 4H), 3.20-3.31 (m, 2H) (3.41-3.50 (m, 1H), 3.64-3.72 (ra, 2H), 4.11-4.27 (q, J = 7.1 Hz, 2H), 4.25-4.37 (melon, 2H), 7.02-7.20 (m, 3H). F 406.2 Ή-NMR (MeOD, 400 MHz) 51.51 (s, 3H), 1.65-1.76 (m, 2H), 204 (M+H) 1.4 2.05-2.19 (m, 4H), 2.74-2.97 ( m, 4H), 3.24-3.35 (m, 2H), 3.43-3.52 (m, 1H), 3.64-3.72 (m, 2H), 3.72 (s, 3H), 4. 28-4.40 (m, 2H), 7. 05-7.23 (m, 3H). Examples 205 to 206 The following compounds were synthesized according to the general methods described in Process 7 and Scheme 13. 180 323406 201211028 [Table 22]

本發明的化。物作為醫藥之有用性係透過可確認藥 理作用之藥理試驗、可確認體内代謝之藥物代謝動力試 驗、可確認安全性之安全性試驗所證明。此等試驗係可綠 認簟毒驗MJM4受體作用性之生理活性以及隨葦毒驗受體 亞型之選擇性提升而安全性提升者即無特別限定，例如可 以以下之試驗證明。以藥理試驗而言，可舉體外打幻 之蕈毒鹼受體作用性測定試驗、確認抗精神病作用或認知 # 障礙改善作用之體外試驗，具體之體外試驗可舉如：變嗎 啡驗誘發攀爬（apomorphine induced climbing)試驗、甲 基***（me thamphetam ine)誘發運動量亢進試驗、前顫 抑制（prepulse inhibition)試驗、微透析（micr〇dialysis) 試驗、被動性迴避反應（passive avoidance response)試 驗、Y型迷津（Y-maze)試驗等。以藥物代謝動力試驗而言， 可舉例如：血中濃度評估試驗、腦内遷移性（bl*ain transfer)、P-醣蛋白基質辨識（P-glycoproteinsubstrate recognition)試驗、藥物交互作用試驗、藥物代謝途捏鑑 323406 181 201211028 別試驗、丹續酿（Dansyl)加成麩胱甘肽（glutathi〇ne)試驗 等。以安全性試驗而言，除了诎抓抑制試驗（hERG inhibition assay)、細胞毒性試驗、Ames試驗等體外試 驗以外，可舉如血壓或心搏數之測定試驗、心電圖測定試 驗、大鼠制約味覺厭惡（c〇nd i t i oned taste aversion)試 驗、唾液分泌量測定試驗、體溫測定試驗、消化器官症狀 §平估试驗、共價結合試驗、錐體外徑路（extrapyramidal ^ tract)症狀評估試驗、一般症狀觀察、一般毒性試驗等。 此等試驗一般係可以小鼠、大鼠、犬或猴子進行。此外， 可因應所需而於清醒或麻醉狀態下實施。下述係以試驗例 對本發明的化合物作為醫藥之有用性進行說明。 試驗例1人類型蕈毒鹼沁至M5受體之體外作用性試驗 對於各受體之作用性，各受體的穩定表現細胞之胞内 鈣濃度變化係以螢光強度作為指標而進行評估。將人類ml 受體表現質體（pcDNA3. l_hMl)或者人類m3受體表現質體 • (pcDNA3. l_hM3)導入至CH0-K1細胞，以極限稀釋法 (limited dilution method)取得耐建那黴素（geneticin) 性之穩定細胞株。將人類m2受體表現質體（pcDNA3. l_hM2)、 人類m4受體表現質體（pcDNA3. l_hM4)及人類m5受體表現 質體（pcDNA3· l_hM5)分別與編碼有Ga 16基因之cDNA—同 導入CH0-K1細胞，取得耐選用藥劑博萊霉素（ZE0CIN)及 HygroGold性之細胞穩定株。人類ml及人類m3受體穩定 表現細胞係以4xl04cells/100//L/well之比例，人類m2、 人類m4及人類m5受體穩定表現細胞係以2xl04cells/100 182 323406 201211028 &quot;L/well之比例種入96孔板（96-well plate)，於C〇2培 養器培養一晚。各受體穩定表現細胞若達100%融合 (confluent)則使用 FLIPR Calcium 4 assay kit (MolecularThe invention is abbreviated. The usefulness of the drug as a medicine is demonstrated by a pharmacological test capable of confirming pharmacological action, a pharmacokinetic test for confirming metabolism in the body, and a safety test for confirming safety. These tests are not particularly limited as long as the safety of the MJM4 receptor is physiologically active and the safety of the receptor subtype is increased, for example, the following test can be proved. In the pharmacological test, it can be used in vitro to test the muscarinic receptor action test in vitro, to confirm the antipsychotic effect or the improvement effect of cognitive # dysfunction, and the specific in vitro test can be as follows: morphine test induced climbing (apomorphine induced climbing) test, methamphetamine inductive hyperactivity test, prepulse inhibition test, micr〇dialysis test, passive avoidance response test, Y Type maze (Y-maze) test, etc. In the case of the drug metabolism kinetic test, for example, a blood concentration evaluation test, a bl*ain transfer, a P-glycoprotein substrate recognition test, a drug interaction test, and a drug metabolism may be mentioned. Tujiajian 323406 181 201211028 Do not test, Dansyl addition glutathione (glutathi〇ne) test. In terms of safety tests, in addition to in vitro tests such as hERG inhibition assay, cytotoxicity test, and Ames test, blood pressure or heart rate measurement test, electrocardiogram test, and rat restriction taste aversion are mentioned. (c〇nd iti oned taste aversion) test, saliva secretion test, body temperature test, digestive organ symptoms § flattening test, covalent binding test, extrapyralidal tract symptom evaluation test, general symptoms Observation, general toxicity test, etc. Such tests are generally performed in mice, rats, dogs or monkeys. In addition, it can be implemented in a state of waking or anesthesia as needed. The usefulness of the compound of the present invention as a medicine will be described below by way of a test example. Test Example 1 In vitro test for human type muscarinic mash to M5 receptor For the action of each receptor, the stable expression of each receptor The intracellular calcium concentration change of the cells was evaluated by using the fluorescence intensity as an index. The human ml receptor expression plastid (pcDNA3.1 l_hMl) or the human m3 receptor expression plastid (pcDNA3.1 l_hM3) was introduced into CH0-K1 cells, and resistant to Jiannamycin was obtained by the limited dilution method. Geneticin) A stable cell strain of sex. The human m2 receptor plastid (pcDNA3.1 l_hM2), the human m4 receptor plastid (pcDNA3.1 l_hM4) and the human m5 receptor plastid (pcDNA3·l_hM5) were respectively encoded with the cDNA encoding the Ga 16 gene. CH0-K1 cells were introduced, and a cell stable strain resistant to the selected drugs bleomycin (ZE0CIN) and HygroGold was obtained. Human ml and human m3 receptors stably expressed cell lines at a ratio of 4xl04cells/100//L/well, human m2, human m4 and human m5 receptors stably expressed cell lines at 2xl04cells/100 182 323406 201211028 &quot;L/well The ratio was implanted into a 96-well plate and cultured overnight in a C 2 incubator. The FLIPR Calcium 4 assay kit (Molecular) is used for stable expression of each receptor in cells that are 100% confluent.

Devices 公司）’以 FLIPRtetra(註冊商標）（M〇lecular Devices 公司）測疋因添加受檢化合物而暫時性上升之榮光強度 (RFU(max-min))。由對照藥劑乙醯膽鹼（3//M)之螢光強度 作為100%時，求出各受檢化合物之螢光強度之相對值，以 此作為致效劑活性（幻。 使用實施例化合物，依照試驗例【進行之人類型孽毒 驗受體之料藥理触的結果料Μ解。Devices Inc.'s FLIPRtetra (registered trademark) (M〇lecular Devices) measures the glory intensity (RFU (max-min)) that is temporarily increased by the addition of the test compound. When the fluorescence intensity of the control agent acetylcholine (3//M) was taken as 100%, the relative value of the fluorescence intensity of each test compound was determined as the synergist activity (illusion. Using the example compound) According to the test case [the type of human steroid test]

183 323406 201211028 [表 23] 受驗物質 (實施例編號） Μι致效劑活性 (l^M) M2致效劑活性 (l^M) M3致效劑活性 (1//M) M4致效劑活性 (1/iM) M5致效劑活性 (10/zM) 1 87 66 14 93 16 2 70 49 27 94 20 3 95 59 3 60 N.T. 4 45 40 9 40 N.T. 5 62 50 1 63 2 6 50 52 7 92 8 C1//M) 7 80 59 8 97 3 8 68 42 3 93 5 9 68 29 4 97 1 10 58 46 1 63 7 11 40 18 3 94 19 12 49 29 4 64 13 13 62 34 3 111 5 14 58 27 3 102 14 N. T.=未驗(No Tested)183 323406 201211028 [Table 23] Test substance (example number) Μι agonist activity (l^M) M2 agonist activity (l^M) M3 agonist activity (1//M) M4 agonist Activity (1/iM) M5 agonist activity (10/zM) 1 87 66 14 93 16 2 70 49 27 94 20 3 95 59 3 60 NT 4 45 40 9 40 NT 5 62 50 1 63 2 6 50 52 7 92 8 C1//M) 7 80 59 8 97 3 8 68 42 3 93 5 9 68 29 4 97 1 10 58 46 1 63 7 11 40 18 3 94 19 12 49 29 4 64 13 13 62 34 3 111 5 14 58 27 3 102 14 NT=No Tested

184 323406 201211028 [表 24] 受驗物質 (實施例編號） Μι致效劑活性 (0· 3M) M2致效劑活性 (0· 3M) M3致效劑活性 (0·3M) M4致效劑活性 (0. 3M) Ms致效劑活性 (IOjuM) 15 100 31 20 86 12 16 81 19 5 94 7 17 69 22 9 79 25 18 86 44 7 71 10 19 79 14 4 55 14 20 106 42 5 77 22 21 72 9 5 37 9 22 92 53 17 82 24 23 66 34 4 88 13 24 33 26 4 67 13 25 98 69 19 98 28 26 102 27 7 96 N.T. 27 126 21 8 90 Ν·Τ· N. T.=未驗184 323406 201211028 [Table 24] Test substance (Example No.) Μι agonist activity (0·3M) M2 agonist activity (0·3M) M3 agonist activity (0·3M) M4 agonist activity (0. 3M) Ms synergist activity (IOjuM) 15 100 31 20 86 12 16 81 19 5 94 7 17 69 22 9 79 25 18 86 44 7 71 10 19 79 14 4 55 14 20 106 42 5 77 22 21 72 9 5 37 9 22 92 53 17 82 24 23 66 34 4 88 13 24 33 26 4 67 13 25 98 69 19 98 28 26 102 27 7 96 NT 27 126 21 8 90 Ν·Τ· NT=Untested

[表 25] 受驗物質 Μι致效劑活性 M2致效劑活性 M3致效劑活性 M&lt;致效劑活性 Ms致效劑活性 (實施例编號） (0· 1M) (0.1M) (0· 1M) (0.1M) C1//M) 28 92 40 2 59 17 29 88 47 8 123 10 (0.1 μΜ) 185 323406 201211028 [表 26][Table 25] Test substance Μι agonist activity M2 agonist activity M3 agonist activity M&lt;activator activity Ms agonist activity (Example No.) (0·1M) (0.1M) (0 · 1M) (0.1M) C1//M) 28 92 40 2 59 17 29 88 47 8 123 10 (0.1 μΜ) 185 323406 201211028 [Table 26]

受驗物質 (實施例編號） Μι致效劑活性 (3juU) Jfe致效劑性 (3βΜ) M3致效劑活性 (3uM) M4致效劑活性 (3β1ί) m5致效劑活性 (l〇uM) 30 37 5 6 33 N.T. 37 81 2 5 97 Ν·Τ· 52 65 3 8 54 Ν.Τ. 53 65 18 4 70 Ν. Τ. 54 48 10 14 72 Ν.Τ. 55 51 9 10 69 Ν.Τ· 62 89 24 21 60 Ν.Τ. 63 76 6 16 41 Ν. Τ. 65 62 4 2 91 Ν. Τ. 70 80 17 7 40 Ν. Τ. 71 77 10 7 41 Ν. Τ. 73 73 6 10 34 Ν.Τ. 75 61 25 59 99 Ν.Τ. 76 78 19 64 85 Ν.Τ· 85 45 9 12 62 Ν. Τ. 86 83 10 4 68 Ν.Τ. 87 73 1 7 60 Ν. Τ. 90 74 2 5 29 Ν. Τ. 91 76 3 7 30 Ν.Τ. 93 69 21 3 90 Ν. Τ. 94 69 21 54 73 Ν.Τ. 95 69 23 63 86 Ν.Τ. 96 61 23 59 76 Ν. Τ. 97 50 14 31 53 Ν. Τ. 112 69 28 7 92 Ν. Τ. 113 75 35 8 100 Ν. Τ. 121 49 41 5 71 Ν. Τ. 122 40 27 10 82 Ν.Τ. 124 69 14 3 44 Ν.Τ. 133 71 29 7 88 23 134 31 10 10 49 Ν. Τ. 136 77 51 10 102 Ν. Τ. 140 39 4 4 64 Ν. Τ. 141 65 5 4 66 Ν. Τ. 142 56 3 4 49 Ν.Τ. 143 45 3 7 67 Ν. Τ. 144 61 10 9 78 Ν.Τ. 148 57 5 14 64 Ν. Τ. 186 323406 201211028Test substance (Example No.) Μι agonist activity (3juU) Jfe agonist (3βΜ) M3 agonist activity (3uM) M4 agonist activity (3β1ί) m5 agonist activity (l〇uM) 30 37 5 6 33 NT 37 81 2 5 97 Ν·Τ· 52 65 3 8 54 Ν.Τ. 53 65 18 4 70 Ν. Τ. 54 48 10 14 72 Ν.Τ. 55 51 9 10 69 Ν.Τ · 62 89 24 21 60 Ν.Τ. 63 76 6 16 41 Ν. Τ. 65 62 4 2 91 Ν. Τ. 70 80 17 7 40 Ν. Τ. 71 77 10 7 41 Ν. Τ. 73 73 6 10 34 25.Τ. 75 61 25 59 99 Ν.Τ. 76 78 19 64 85 Ν.Τ· 85 45 9 12 62 Ν. Τ. 86 83 10 4 68 Ν.Τ. 87 73 1 7 60 Ν. Τ. 90 74 2 5 29 Ν. Τ. 91 76 3 7 30 Ν.Τ. 93 69 21 3 90 Ν. Τ. 94 69 21 54 73 Ν.Τ. 95 69 23 63 86 Ν.Τ. 96 61 23 59 76 50. 50. 97 50 14 31 53 Ν. Τ. 112 69 28 7 92 Ν. Τ. 113 75 35 8 100 Ν. Τ. 121 49 41 5 71 Ν. Τ. 122 40 27 10 82 Ν.Τ. 124 69 14 3 44 Ν.Τ. 133 71 29 7 88 23 134 31 10 10 49 Ν. Τ. 136 77 51 10 102 Ν. Τ. 140 39 4 4 64 Ν. Τ. 141 65 5 4 66 Ν. Τ. 142 56 3 4 49 Ν.Τ. 143 45 3 7 67 Ν. Τ. 144 61 10 9 78 Ν.Τ. 148 57 5 14 64 Ν. Τ. 186 323406 201211028

149 54 15 31 77 Ν. Τ. 150 80 18 10 93 Ν.Τ. 153 48 18 9 83 Ν.Τ. 154 57 8 11 87 Ν. Τ. 155 54 15 31 77 Ν.Τ. 156 45 10 15 75 Ν·Τ· 157 51 8 5 91 Ν. Τ. 159 56 9 31 31 Ν. Τ. 162 52 21 33 65 Ν. Τ. 163 64 16 47 73 Ν. Τ. 165 51 14 42 31 Ν. Τ. 177 65 5 7 44 Ν. Τ. 187 59 17 35 48 Ν. Τ. 188 57 6 18 50 Ν. Τ. 189 57 14 24 81 Ν. Τ. 190 67 1 5 79 Ν. Τ. 191 66 3 2 87 Ν. Τ. 204 38 7 22 50 Ν. Τ. N. T.:未驗 187 323406 201211028 表 27].149 54 15 31 77 Ν. Τ. 150 80 18 10 93 Ν.Τ. 153 48 18 9 83 Ν.Τ. 154 57 8 11 87 Ν. Τ. 155 54 15 31 77 Ν.Τ. 156 45 10 15 75 157·Τ· 157 51 8 5 91 Ν. Τ. 159 56 9 31 31 Ν. Τ. 162 52 21 33 65 Ν. Τ. 163 64 16 47 73 Ν. Τ. 165 51 14 42 31 Ν. Τ. 177 65 5 7 44 Ν. Τ. 187 59 17 35 48 Ν. Τ. 188 57 6 18 50 Ν. Τ. 189 57 14 24 81 Ν. Τ. 190 67 1 5 79 Ν. Τ. 191 66 3 2 87 Ν 204. 204 38 7 22 50 Ν. Τ. NT: not verified 187 323406 201211028 Table 27].

受驗物質 Μι致效劑活性 M2致效劑活性 M3致效劑活性 m4致效劑活性 M5致效劑活性 (實施例編號） (0.3//M) (0.3/zM) (0.3/zM) (0.3juM) (ΙΟ^Μ) 31 91 13 5 95 N.T. 33 115 15 12 97 N.T. 34 ' 92 45 15 52 41 35 85 42 5 67 N. T. 36 115 15 12 97 36 (3#M) 38 52 22 1 65 N.T. 40 47 6 14 69 Ν·Τ_ 41 70 17 19 82 Ν. Τ. 42 46 35 7 70 Ν·Τ_ 43 76 4 12 83 Ν. Τ. 46 67 31 7 79 Ν. Τ. 47 42 12 1 77 Ν. Τ. 48 58 3 2 72 43 50 68 11 7 78 19 51 57 4 2 69 72 56 91 14 61 63 16 57 98 16 50 61 13 (30^Μ) 58 101 25 25 68 15 (30^Μ) 59 104 40 58 64 Ν. Τ. 60 79 15 64 64 Ν. Τ. 66 73 15 38 53 Ν. Τ. 67 70 37 15 62 Ν. Τ. 68 79 19 48 58 Ν. Τ. 69 77 31 20 75 Ν. Τ. 72 92 44 10 84 Ν. Τ. 74 61 6 2 30 Ν. Τ. 77 101 51 4 91 Ν. Τ. 79 97 27 70 69 10 80 106 23 79 60 12 81 87 33 38 55 Ν. Τ. 82 80 25 34 53 Ν. Τ. 83 86 16 60 69 Ν. Τ. 84 83 20 51 59 Ν. Τ. 88 83 23 18 59 Ν. Τ. 89 91 14 61 63 16 188 323406 201211028Test substance Μι agonist activity M2 agonist activity M3 agonist activity m4 agonist activity M5 agonist activity (example number) (0.3//M) (0.3/zM) (0.3/zM) ( 0.3juM) (ΙΟ^Μ) 31 91 13 5 95 NT 33 115 15 12 97 NT 34 ' 92 45 15 52 41 35 85 42 5 67 NT 36 115 15 12 97 36 (3#M) 38 52 22 1 65 NT 40 47 6 14 69 Ν·Τ_ 41 70 17 19 82 Ν. Τ. 42 46 35 7 70 Ν·Τ_ 43 76 4 12 83 Ν. Τ. 46 67 31 7 79 Ν. Τ. 47 42 12 1 77 Ν. 58. 48 58 3 2 72 43 50 68 11 7 78 19 51 57 4 2 69 72 56 91 14 61 63 16 57 98 16 50 61 13 (30^Μ) 58 101 25 25 68 15 (30^Μ) 59 104 40 58 64 Ν. Τ. 60 79 15 64 64 Ν. Τ. 66 73 15 38 53 Ν. Τ. 67 70 37 15 62 Ν. Τ. 68 79 19 48 58 Ν. Τ. 69 77 31 20 75 Ν. 92. 72 92 44 10 84 Ν. Τ. 74 61 6 2 30 Ν. Τ. 77 101 51 4 91 Ν. Τ. 79 97 27 70 69 10 80 106 23 79 60 12 81 87 33 38 55 Ν. Τ. 82 80 25 34 53 Ν. Τ. 83 86 16 60 69 Ν. 83. 84 83 20 51 59 Ν. Τ. 88 83 23 18 59 Ν. Τ. 89 91 14 61 63 16 188 323406 201211028

101 87 12 32 48 Ν·Τ_ 102 103 9 11 50 Ν·Τ· 103 109 9 10 46 Ν·Τ_ 104 85 26 74 57 Ν. Τ. 106 85 19 37 57 Ν.Τ. 107 55 16 12 73 Ν. Τ. 108 43 51 7 81 Ν. Τ. 109 49 16 12 75 Ν.Τ· 110 76 68 7 109 Ν.Τ. 111 53 5 3 58 Ν.Τ· 114 56 57 13 85 Ν. Τ. 115 60 30 1 85 Ν.Τ. 116 35 4 1 71 Ν.Τ. 117 89 71 10 76 Ν. Τ. 118 83 45 5 106 Ν.Τ. 119 74 30 4 76 Ν.Τ. 120 92 53 6 109 Ν. Τ. 123 109 49 2 88 Ν. Τ. 125 85 23 6 54 Ν.Τ. 126 43 51 7 81 Ν.Τ. 127 98 17 4 79 13 128 81 35 2 82 12 129 60 13 2 78 7 130 88 9 2 78 3 131 63 17 8 73 30 132 64 10 1 74 3 135 43 15 4 79 39 137 63 10 5 86 10 138 69 23 2 77 Ν.Τ. 139 79 8 2 86 Ν. Τ. 160 28 4 8 82 Ν.Τ. 161 49 4 2 64 18 166 91 26 1 73 4 167 83 73 15 82 Ν. Τ. 168 80 2 1 38 3 169 98 4 2 39 7 170 59 4 8 40 Ν.Τ. 171 87 58 2 81 9 173 75 20 8 79 Ν. Τ. 176 77 28 1 73 7 178 78 15 3 52 Ν. Τ. 179 62 4 8 46 Ν.Τ. 189 323406 201211028 182 80 22 4 48 N.T. 183 102 45 15 84 41 184 58 22 7 97 Ν. T. 185 59 2 4 34 N.T. 186 61 1 3 84 Ν. T. Ν· Τ·:未驗 表28] 受驗物質 (實施例編號） Μι致效劑活性 (0. 03^M) M2致效劑活性 (0.03//M) M3致效劑活性 (0.03/zM) M4致效劑活性 (0.03//M) Ms致效劑活性 (10/ζΜ) 32 74 36 8 69 Ν_Τ· 78 85 19 6 52 11 92 80 11 5 67 Ν·Τ· 98 100 5 36 32 Ν.Τ. 99 76 2 13 22 Ν. Τ. 100 93 5 9 52 Ν.Τ. 174 82 37 17 79 19 175 65 21 8 51 10 Ν. Τ.:未驗101 87 12 32 48 Ν·Τ_ 102 103 9 11 50 Ν·Τ· 103 109 9 10 46 Ν·Τ_ 104 85 26 74 57 Ν. Τ. 106 85 19 37 57 Ν.Τ. 107 55 16 12 73 Ν. 43. 108 43 51 7 81 Ν. Τ. 109 49 16 12 75 Ν.Τ· 110 76 68 7 109 Ν.Τ. 111 53 5 3 58 Ν.Τ· 114 56 57 13 85 Ν. Τ. 115 60 30 1 85 Ν.Τ. 116 35 4 1 71 Ν.Τ. 117 89 71 10 76 Ν. Τ. 118 83 45 5 106 Ν.Τ. 119 74 30 4 76 Ν.Τ. 120 92 53 6 109 Ν. Τ 123 109 49 2 88 Ν. Τ. 125 85 23 6 54 Ν.Τ. 126 43 51 7 81 Ν.Τ. 127 98 17 4 79 13 128 81 35 2 82 12 129 60 13 2 78 7 130 88 9 2 78 3 131 63 17 8 73 30 132 64 10 1 74 3 135 43 15 4 79 39 137 63 10 5 86 10 138 69 23 2 77 Ν.Τ. 139 79 8 2 86 Ν. Τ. 160 28 4 8 82 Ν . 161 49 4 2 64 18 166 91 26 1 73 4 167 83 73 15 82 Ν. Τ. 168 80 2 1 38 3 169 98 4 2 39 7 170 59 4 8 40 Ν.Τ. 171 87 58 2 81 9 173 75 20 8 79 Ν. Τ. 176 77 28 1 73 7 178 78 15 3 52 Ν. Τ. 179 62 4 8 46 Ν.Τ. 189 323406 201211028 182 80 22 4 48 NT 183 102 45 15 84 41 184 58 22 7 9 7 Ν. T. 185 59 2 4 34 NT 186 61 1 3 84 Ν. T. Ν· Τ·: Untested Table 28] Test substance (example number) Μι agonist activity (0. 03^M) M2 agonist activity (0.03//M) M3 agonist activity (0.03/zM) M4 agonist activity (0.03//M) Ms agonist activity (10/ζΜ) 32 74 36 8 69 Ν_Τ· 78 85 19 6 52 11 92 80 11 5 67 Ν·Τ· 98 100 5 36 32 Ν.Τ. 99 76 2 13 22 Ν. Τ. 100 93 5 9 52 Ν.Τ. 174 82 37 17 79 19 175 65 21 8 51 10 Ν. Τ.: not tested

φ 試驗例2 小鼠之抗變嗎啡鹼誘發攀爬作用評估 將小鼠放入攀爬籠（Climbing Cdge)(不鎮鋼製，直徑 11. 8cmx高度13. 5cm之圓柱形），將變嗎啡驗（lmg/kg)經由 皮下投予，則有攀爬（Climbing)行動之表現，故可想作本 行動係反映出精神***症之陽性症狀的一部分病狀。對於 本模式，係可藉由投予本發明化合物時對於變嗎啡鹼作用 的拮抗程度而評價抗精神病作用。將5週齡大的雄性ddY 小鼠於攀爬籠内馴化30分鐘後，將本發明化合物經由皮 下、腹腔内或經口進行投予，在20分鐘後（經口投予時為 190 323406 201211028 ㈣錢1G分鐘後至 估。將僅投讀她並進行評 之數值表示抑制率平刀作為基準藉由以0至100 羊（）可進行統計學上的處理。 結果係如以下^合物，依照試驗例2進行之體外試驗的φ Test Example 2 Evaluation of anti-mutation morphine-induced climbing in mice. The mice were placed in a climbing cage (Climbing Cdge) (a cylinder of 11.8 cm x 13.5 cm in diameter), which will become morphine. The test (lmg/kg) is administered subcutaneously, and there is a performance of Climbing action. Therefore, this action system may reflect a part of the symptoms of schizophrenia. For this mode, the antipsychotic effect can be evaluated by the degree of antagonism of the action of the compound of the present invention on the action of the morphine base. After 5 weeks old male ddY mice were acclimated in a climbing cage for 30 minutes, the compound of the present invention was administered subcutaneously, intraperitoneally or orally, after 20 minutes (orally administered 190 323406 201211028) (4) After 1 minute of money, the estimate will be taken only by her and the value of the evaluation will be expressed as the inhibition rate of the flat knife as a reference by statistical processing with 0 to 100 sheep (). The result is as follows. In vitro test according to test example 2

因將甲基***（lmg/kg)經由腹腔内投予至 隨後1小時左右運動量將為宄進，故如此之行動可= 反映出精神***症之陽性症狀的—部分病狀。對於本模 式’係可藉自投予本發明化合物㈣以基料他命作用 的拮抗程度而評價抗精神病作用。將本發明化合物經由皮 下、腹腔内或經口進行投予至7週齡大的雄性大白鼠 (SpragUe-DawleyRat)，在30分鐘後（經口投予時為⑼二 鐘後）投予甲基***。將大鼠同時移至實驗蘢（無色^ 明塑料製），測定其10分鐘後至80分鐘後之運動量二測定 323406 191 201211028 係使用Super Mex(室町機械股份公司）。以僅投予曱美— 非他命之群的運動量作為8〇分鐘之間的總二量= 準，藉由以G至100之數值表示抑制率（％)而可進行統計$ 上的處理。 干 使用實施例化合物，依照試驗例3進行體外試驗的結 果係如以下所示。 [表 30] 受驗物質 抑制率00 ---^ (實施例編號） (3 mg/kg) 投予方法 1 53 ___經口 15 37 ----— ________ 經口 28 91 經口 試驗例4大鼠制約味覺厭惡試驗 若於給予具有未曾嘗試之味道的溶液（制約刺激， conditioned stimulus ; CS)後，注射誘發胃腸障礙/嘔吐 專之藥物（非制約刺激，unconditioned stimulus ; US)， 則動物會將CS與US作聯結學習，下次再給予CS則會以該 味道為線索而拒絕攝取。可藉由使用如此之制約條件的實 驗組’對本發明化合物之作嘔感誘發作用進行評估。 實驗係使用9週齡大的雄性prague_Dawley大鼠。 i)訓練（Training) 訓練係藉由於斷水15小時後，以裝有水之供水瓶對大 鼠提示1小時並確實供水而進行。使之後8小時為自由供 水’至翌日再斷水15小時。 192 323406 201211028 ii)制約 於與前一天相同時間時，以裝有〇. 5%糖精（saccharin) 水（CS)之給水瓶對斷水條件下的大鼠提示丨小時。 以制約時之糖精攝取量算出各個體於實驗時之糖精攝取 量’以投予溶媒之群與該者比較的減少比例作為厭惡反應 形成率而進行評估。 使用實施例化合物’依照試驗例4進行之體外試驗的 結果係如以下所示。 [表 31 ] 受驗物質 (實施例編號） 厭惡反應形成率(%) 投予方法 28 35 經口 試驗例5 hERG抑制試驗 使用自動膜片箝制（Automatic patch clamp)裝置 Qpatch HT(Sophion Bioscience A/S)，藉由全細胞膜片箝 制（Whole cel 1 patch c.larop)法’紀錄 hERG(hunian ether_ a-go-go)基因為穩定表現之CHO細胞的hERG卸電流。hERG 電流於電壓箝制（Vol tage clamp)模式之膜電位保持為 _80mV，20毫秒之間為-5〇mV後的5秒之間為+20mV使去極 化（depolarization) ’對接下來5秒之間以-5〇mV使再極 化時的尾電流（tail current)之振幅進行評估。刺激係以 15秒間隔重複進行，實驗係於室溫（22±2°C)進行。以每一 細胞的化合物為4濃度進行5分鐘之間各濃度的累積投 予’比較各濃度之化合物於適應前的電流大小以算出被抑 193 323406 201211028Because methylphenidate (1 mg/kg) is administered intraperitoneally until the next hour or so, the amount of exercise will be hyperactive, so this action can be - part of the condition reflecting the positive symptoms of schizophrenia. For the present mode, the antipsychotic effect can be evaluated by the degree of antagonism of the compound (4) administered to the present invention as a basal feed. The compound of the present invention is administered subcutaneously, intraperitoneally or orally to 7-week-old male rats (SpragUe-Dawley Rat), and after 30 minutes (after (9) two hours after oral administration), methyl is administered. Amphetamine. The rat was simultaneously transferred to an experimental 茏 (manufactured by a colorless plastic), and the amount of exercise was measured after 10 minutes to 80 minutes. 323406 191 201211028 Super Mex (Muromachi Machinery Co., Ltd.) was used. The amount of exercise that is only administered to the beauty-non-life group is taken as the total amount between 8 minutes and minutes, and the processing on the statistical $ can be performed by expressing the inhibition rate (%) from the value of G to 100. The results of the in vitro tests according to Test Example 3 using the Example compounds are shown below. [Table 30] Test substance inhibition rate 00 ---^ (Example number) (3 mg / kg) Administration method 1 53 ___ Oral 15 37 ----- ________ Oral 28 91 Oral test case 4 Rats restricting taste aversion test If a drug that induces gastrointestinal disorders/vomiting (unconditioned stimulus; US) is injected after administration of a solution with unseen taste (conditioned stimulus; CS), then the animal CS and US will be linked to learn, and the next time you give CS, you will refuse to take it with the taste as a clue. The nausea-evoked effect of the compounds of the present invention can be evaluated by using the experimental group of such constraints. The experimental system used 9-week-old male prague_Dawley rats. i) Training The training was carried out by reminding the rats for one hour and supplying water with a water supply bottle after 15 hours of water cut. Allow 8 hours for free water supply to the next day for another 15 hours. 192 323406 201211028 ii) Restrictions At the same time as the previous day, rats in water-discharging conditions were prompted for sputum hours with a water bottle containing 5% saccharin water (CS). The saccharin intake amount of each body at the time of the experiment was calculated by taking the amount of saccharin intake at the time of the restriction, and the reduction ratio of the group to which the solvent was administered was compared with the rate of the aversion reaction as the abjection reaction formation rate. The results of the in vitro test using the Example Compound' in accordance with Test Example 4 are shown below. [Table 31] Test substance (Example No.) Aversion reaction formation rate (%) Administration method 28 35 Oral test Example 5 hERG inhibition test using an automatic patch clamp device Qpatch HT (Sophion Bioscience A/ S), the hERG unloading current of the CHO cells stably recorded by the hERG (hunian ether_a-go-go) gene was recorded by the Whole cel 1 patch c. larop method. The membrane potential of the hERG current in the voltage clamp mode is maintained at _80mV, +20mV between 5ms after -5〇mV between 20ms, depolarization' for the next 5 seconds The amplitude of the tail current at the time of repolarization was evaluated by -5 〇 mV. Stimulation was repeated at 15 second intervals and the experiment was performed at room temperature (22 ± 2 °C). Cumulative administration of each concentration for 5 minutes at a concentration of 4 cells per cell was compared to compare the currents of the compounds at each concentration before the adaptation to calculate the inhibition. 193 323406 201211028

制的電流抑制率，藉由Hill式計算50%抑制濃度（IC50[&quot; Μ])。試驗溶液係使用以下者：細胞外溶液（mM) : 2CaClz、 lMgCU、10HEPES、4KC1、145NaCl、10 葡萄糖；細胞内溶 液（mM) : 5· 4CaCh、1. 8MgCh、10 HEPES、31 Κ0Η、10 EGTA、 120 KC1 &gt; 4 ATP 使用實施例化合物，依照試驗例5進行之hERG抑制試 驗的結果係如以下所示。 [表 32] 受驗物質 (實施例編號） ICs。（10&quot;M) 9 &gt;10 試驗例6 大鼠PK試驗 對於7週齡大的大鼠，以本發明化合物之生理食鹽水 溶液進行靜脈投予或是以曱基纖維素水溶液進行經口投 予，分別於以下時間採集血液。 φ 靜脈投予：投予後5分、15分、30分、1小時、2小時、4 小時、6小時及24小時。 經口投予：15分、30分、1小時、2小時、4小時、6小時 及24小時。 使用設定為4°C的冷卻離心機以300rpmxl0分鐘將所 採集的血液進行離心，以HLPC對所得之血漿進行測定，依 據所得之時間曲線（time curve)算出藥物代謝動力參數。 藉由此試驗，係可證明本發明化合物之藥物代謝動力 優異，例如：實施例28之於生物學上的利用率為79%。 194 323406 201211028 此外，使用上述試驗例1之方法，以構造上與本發明 近似之公知的化合物作為比較例，測定對於簟毒驗受體之 作用性，進行與本案之實施例化合物的比較。 專利文獻1所揭示的化合物群中，構造上與本發明近 似之化合物，例如為下述比較例1及比較例2所表示。 比較例1 0The current suppression rate was calculated by Hill's formula to determine the 50% inhibitory concentration (IC50 [&quot; Μ]). The test solution used the following: extracellular solution (mM): 2CaClz, lMgCU, 10HEPES, 4KC1, 145NaCl, 10 glucose; intracellular solution (mM): 5·4CaCh, 1.8MgCh, 10 HEPES, 31 Κ0Η, 10 EGTA 120 KC1 &gt; 4 ATP The results of the hERG inhibition test according to Test Example 5 using the Example compounds are shown below. [Table 32] Test substance (Example No.) ICs. (10&quot;M) 9 &gt; 10 Test Example 6 Rat PK test For 7-week-old rats, intravenous administration of a physiological saline solution of the compound of the present invention or oral administration with a thioglycolic acid aqueous solution , blood was collected at the following times. φ intravenous administration: 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours and 24 hours after administration. Oral administration: 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours and 24 hours. The collected blood was centrifuged at 300 rpm x 10 minutes using a cooling centrifuge set at 4 ° C, and the obtained plasma was measured by HLPC, and the drug metabolism dynamic parameters were calculated based on the obtained time curve. By this test, it was confirmed that the compound of the present invention is excellent in drug metabolism kinetics, for example, the biological utilization rate of Example 28 was 79%. 194 323406 201211028 Further, using the method of the above Test Example 1, a compound which is structurally similar to the present invention was used as a comparative example, and the reactivity to the scorpion venom receptor was measured, and comparison with the compound of the example of the present invention was carried out. Among the compound groups disclosed in Patent Document 1, a compound similar in structure to the present invention is shown, for example, in Comparative Example 1 and Comparative Example 2 below. Comparative Example 1 0

Λ OEt 比較例2 0 •人 0Λ. OEtΛ OEt Comparative Example 2 0 • Person 0Λ. OEt

[表 33] 受驗物質 (實施例編號） Μι致效劑活性 (1//M) M2致效劑活性 (ΙμΜ) M3致效劑活性 (1//Μ) Μ4致效劑活性 (ΙμΜ) Ms致效劑活性 (i&quot;m) 28 113 53 9 103 17 (比較例編號） 1 96 105 73 115 Ν.Τ. 2 105 90 53 98 Ν.Τ_ N. T.=未驗 由表33可明瞭，比較例1及2之化合物完全無簟毒驗 受體選擇性，1位氮原子係與哌啶結合、且3位為碳原子 之本發明化合物於簟毒鹼受體選擇性方面為優異。 專利文獻2所揭示之化合物群中，構造上與本發明近 195 323406 201211028 似之化合物，例如為比較例3所表示。 比較例3[Table 33] Test substance (Example No.) Μι agonist activity (1//M) M2 agonist activity (ΙμΜ) M3 agonist activity (1//Μ) Μ4 agonist activity (ΙμΜ) Ms agonist activity (i&quot;m) 28 113 53 9 103 17 (Comparative example number) 1 96 105 73 115 Ν.Τ. 2 105 90 53 98 Ν.Τ_ NT=Untested by Table 33, the comparative example The compounds of 1 and 2 are completely devoid of steroid selectivity, and the compound of the present invention in which the nitrogen atom of the 1-position is bonded to piperidine and the carbon atom at the 3-position is excellent in the selectivity of the muscarinic receptor. Among the compound groups disclosed in Patent Document 2, a compound similar in structure to the present invention, which is similar to that of the present invention, is shown in Comparative Example 3. Comparative example 3

[表 34] 受驗物質 Μι致效劑活性 M2致效劑活性 M3致效劑活性 致效劑活性 Ms致效劑活性 (實施例編號） (0.1/zM) (0.1//M) (0.1/zM) (0.1/zM) (0.1/zM) 28 92 40 2 59 17 (比較例編號） 3 21 3 3 18 N.T· N.T.=未驗[Table 34] Test substance Μι agonist activity M2 agonist activity M3 agonist activity agonist activity Ms agonist activity (Example No.) (0.1/zM) (0.1//M) (0.1/ zM) (0.1/zM) (0.1/zM) 28 92 40 2 59 17 (Comparative example number) 3 21 3 3 18 NT· NT=Untested

由表34可明暸，比較例3之化合物的Μι受體作用性非 常弱，1位氮原子係與哌啶結合、且3位為碳原子之本發 明化合物於沁受體作用性方面為優異。 專利文獻3所揭示之化合物群中，構造上與本發明近 ^ 似之化合物，例如為比較例4所表示。 比較例4As is clear from Table 34, the compound of Comparative Example 3 has a very weak 作用1 receptor action, and the compound of the present invention in which the nitrogen atom at the 1-position is bonded to piperidine and the carbon atom at the 3-position is excellent in the action of the oxime receptor. Among the compound groups disclosed in Patent Document 3, a compound similar in structure to the present invention is represented, for example, by Comparative Example 4. Comparative example 4

196 323406 201211028 [表 35] 受驗物質 Μι致效劑活性 Sfc致效劑活性 M3致效劑活性 M4致效劑活性 Μ5致效劑活性 (實施例編號） (1&quot;M) (l^M) (1//M) (1“Μ) (1//Μ) 28 113 53 9 103 17 (比較例編號） 4 76 3 3 9 Ν. Τ. N. T.=未驗196 323406 201211028 [Table 35] Test substance Μι agonist activity Sfc agonist activity M3 agonist activity M4 agonist activity Μ5 agonist activity (example number) (1&quot;M) (l^M) (1//M) (1"Μ) (1//Μ) 28 113 53 9 103 17 (Comparative Example No.) 4 76 3 3 9 Ν. Τ. NT=Untested

由表35可明暸，比較例4之化合物的Μ4受體作用性非 常弱，而本發明化合物於Μ4受體作用性方面為優異。 專利文獻4所揭示之化合物群中，構造上與本發明近 似之化合物，例如為比較例5及比較例6所表示。 比較例5As is clear from Table 35, the Μ4 receptor of the compound of Comparative Example 4 was very weak, and the compound of the present invention was excellent in the action of the Μ4 receptor. Among the compound groups disclosed in Patent Document 4, a compound similar in structure to the present invention is represented, for example, by Comparative Example 5 and Comparative Example 6. Comparative Example 5

比較例6Comparative Example 6

F 比較例5及比較例6係揭示了於專利文獻4之Μ4受體 作用性非常弱，而可明瞭本發明化合物於Μ4受體作用性方 面為優異。 (產業上之可利用性） 197 323406 201211028 本發明之化合物係選擇性地作用於簟毒鹼沁及m4受 體，故具有包含抗精神病作用、認知障礙改善作用等優異 的中樞改善效果，同時可減低透過其他的蕈毒鹼受體或其 他受體的副作用。因此，本發明之化合物係可作為非常有 用的醫藥。 【圖式簡單說明】 無。 【主要元件符號說明】F Comparative Example 5 and Comparative Example 6 disclose that the receptor activity of Patent Document 4 is extremely weak, and it is understood that the compound of the present invention is excellent in the action of the Μ4 receptor. (Industrial Applicability) 197 323406 201211028 The compound of the present invention selectively acts on muscarinic mash and m4 receptor, and thus has an excellent central improvement effect including an antipsychotic effect and a cognitive impairment improving effect. Reduce side effects through other muscarinic receptors or other receptors. Therefore, the compound of the present invention can be used as a very useful medicine. [Simple description of the diagram] None. [Main component symbol description]

Claims (1)

201211028 七、申請專利範圍201211028 VII. Application for patent scope 5 、二？同或相異，分別為CH或CR5 ;5, two? Same or different, respectively CH or CR5; 二= 6，、雜芳基、^芳炫 c土以方^ 烯基、C2-6块基、^燒氧基、氰基、 ^其f基、_、胺姐基、雜、絲、硝基、Cl—6 烷基嶒醯基，或可經取代的Ci 6烷基； T為相同或相異，分別為氫原子、可經取代的心 原子、·、(:”環院基或3至7員的雜環基； \及R互相鍵結，R，及R2與相鄰的碳原子一同 P7 L衣烷或3至7員的雜環’或一起形成為=CR6R7; 為相同或相異，分別為氫原子或可經取代的Ch =基:或者是R6及R7互相鍵結，以R7與相_碳原 同形成C3—7環烷或3至7員的雜環； R3及R4為一起形成=〇或4 ; X為早鍵或亞甲基； γ及z為㈣或相異’分別為氧原子或硫原子； R為可經取代的c㈠烷基、G β炔基或C2 6烯基； % A為可經選自羥基、鹵原子、〇6烷基及Cl-6烷氧基 所構成群組中的i至2個取代基取代的6至7員之含氮 323406 1 201211028 雜環]。 2·如申請專利範圍第1項所述之化合物，其中，R5為鹵原 子、Ch烷氧基、氰基、烷基硫基、羥基、胺基、硝基、 或可經取代的Cl-6燒基。 3.如申請專利範圍第丨項所述之化合物，其中，RS為氟原 子、氯原子、溴原子、甲基、乙基、丙基、甲氧基或三 氟甲基。 馨4.如申請專利範圍第i項至第3項中任一項所述之化合 物，其中，環A為下述式（2)所示者： [_式中’ R8為氫原子、經基、齒原子、Ci 6院基或Ci 6烷 氧基]。 如申明專利範圍第1項至第4項中任一項所述之化合 _ 物’其中’ R8為氫原子、G 6烧基或6烧氧基。 ♦申=專利範圍第1項至第5項巾任—項所述之化合 物其中，c及b為相同或相異之CH或CR5。 申明專利||g第1項至第5項中任—項所述之化合 物其中，c及b其中一者為CH，另一者為cr5。 .如申請專利範圍第1項至第7項中任-項所述之化合 物，其令，Y及Z皆為氧原子。 9.![申請專利範圍第1項至第8項中任一項所述之化合 物，其中’RL起形成=〇。 •如申請專利範圍第i項至第9項中任—項所述之化合 323406 2 201211028 物，其中，…為相同_，分別為氫原子、氟原 子、經基、或可經取代的Cl_e燒基，或者反,及r2為互相 鍵結，R1及R2與相鄰的碳原子一同形成四氣娘喃環。 1’如申叫專利範圍第1項至第1〇項中任一項所述之化合 物，其中，R為可經取代的直鏈之Ch烷基。 12.如申請專利範圍第1項所述之化合物或其藥學上容許 的鹽，其係選自下述所構成群組者： 4~[4-(2-側氧基-2, 3-二氫-in-吲哚-1-基）哌啶-1-基] °辰啶-1-羧酸乙酯； 4-[4-(3-曱基-2-側氧基-2, 3-二氫-1H-吲哚-卜基）哌 咬~1-基]派咬_ι_緩酸乙酯； 4~~[4-(3, 3-二甲基-2-側氧基一2, 3-二氳-1H-吲哚-1-基） °底°定-丨-基]哌啶-1-羧酸乙酯； 4~[4-(3,3-二乙基-2-側氧基—2, 3-二氫-1H-吲哚-1-基） °辰咬-1_基]哌啶-1-羧酸乙酯； 4〜[4-(3-乙基-3-甲基-2-側氧基-2, 3-二氫-1H-吲哚 基）°辰咬-1-基]派咬_1_魏酸乙酯； 4-[4-(3, 3-二丙基-2-側氡基-2, 3-二氫-1H-吲哚-1-基） 定―丨-基]哌啶-1-羧酸乙酯； 4M4-[2’ -側氧螺（環丙烷_丨，3’ -吲哚）-Γ (2, H)-基]哌 °^-1-基}哌啶-1-羧酸乙酯； {4- [ 2’ -側氧螺（環丁烷_丨，3’ -吲哚）-Γ (2’ H)-基]哌 交~1-基}哌啶-1-羧酸乙酯； 4〜U-[2’ -側氧螺（環戊烷-丨，3’ -吲哚）-Γ (2, H)-基]哌 3 323406 201211028 啶-l-基}哌啶-1-羧酸乙酯； 4-{4-[2’ -侧氧螺（環己烷-1，3’ -吲哚）-1’（2’ H)-基]哌 啶-l-基}哌啶-1-羧酸乙酯； 4-{4-[2’_侧氧螺（四氮0辰喃-4，3’-11弓卜朵）_1(2 1〇-基] 哌啶-l-基}哌啶-1-羧酸乙酯； 4-[4-(3, 3-二曱基-2-側氧基-2, 3-二氫-1H-吲哚-1-基） 哌啶-1-基]甲基哌啶-1-羧酸乙酯； 4-{4-[2’ -侧氧螺（環丙烷-1，3’ -吲哚）-1’（2’ H)-基]哌 啶_1_基}甲基哌啶-1-羧酸乙酯； 3- [4-(3, 3-二乙基-2-側氧基-2, 3-二氫-1H-吲哚-1-基） 哌啶-1-基]-8-吖雙環[3. 2. 1]辛烷-8-羧酸乙酯； 4- [4-(3, 3-二曱基-2-側氧基-2, 3-二氬-1H-吲哚-1-基） 痕°定-1-基]π底咬-1-叛酸甲酉旨； 4-[4-(3, 3-二曱基-2-側氧基-2, 3-二氫-1Η-吲哚-1-基） 哌啶-1-基]哌啶-1-羧酸異丙酯； 4-[4-(2-側氧基-2, 3-二氫-1Η-吲哚-1-基）哌啶-1-基] 氮雜環庚烷-1-羧酸乙酯； 4-[4-(6-氟-2-側氧基-2, 3-二氫-1Η-吲哚-1-基）哌啶 -1-基]哌啶-1-羧酸乙酯； 4-[4-(6-氟-3, 3-二甲基-2-侧氧基-2, 3-二氫-1Η-吲哚 -1-基）哌啶-1-基]哌啶-1-羧酸乙酯； 4-[4-(5-氣-2-侧氧基-2, 3-二氫-1Η-吲哚-1-基）哌啶 -1-基]哌啶-1-羧酸乙酯； 4-[4-(5-氟-3, 3-二曱基-2-側氧基-2, 3-二氫-1Η-吲哚 4 323406 201211028 -1-基）哌啶-1-基]哌啶-1-羧酸乙酯； 4-[4-(5-象-2-側氧基-2，3_二氮_ 1 Η-α引π朵_1 -基）σ底咬 -1-基]哌啶基-羧酸乙酯； 4_({3-[1-(乙氧基幾基）〇辰σ定基-4-亞基]-6-氟-側氧 基-2，3 -二氮-1Η-α引°朵-1-基}σ底β定-丨-基）11辰咬_1_魏酸 乙酯； 4-({3-[1-(乙氧基羰基）哌啶基-4-基]-6-氟-2-側氧基 -2, 3-二氳-1Η-吲哚-l-基}哌啶-1-基）哌啶-1-羧酸乙 酯； 1-乙基硫幾_基-4-[4-(2-側氧基-2,3-二氫-111-°引°朵-1-基）哌啶-1-基]哌啶； 4-[4-(2-側氧基-2,3-二氩-lH-i11 朵底咬 _1-基] 哌啶-1-羧酸2-氟乙酯； 4-[4-(2-側氧基-2, 3-二氬-1H-吲哚-1-基）哌啶-1-基] 哌啶-1-羧酸2-丙烯酯； 4-[4-(2-側氧基-2，3-二氫-1Η-,π呆-1-基）°底咬_1_基] 哌啶-1-羧酸2-曱氧乙酯； 4-[4-(2-侧氧基-2, 3-二氩-1Η-吲哚-1-基)哌啶-1-基] 哌啶-1-羧酸丁酯； 1-曱基硫羰基-4-[4-(2-侧氧基-2, 3-二氫-1Η-吲哚-1-基）哌啶-1-基]哌啶； 4-[4-(2-側氧基-2, 3-二氫-1Η-吲哚-1-基）哌啶-1-基] 哌啶-1-羧酸丙酯； 4-[4-(5-氟-2-側氧基-2, 3-二氫-1Η-吲哚-1-基）哌啶 5 323406 201211028 -1-基]氮雜環庚烷-1-羧酸乙酯； 4-[4-(3, 3-二曱基-2-側氧基-2, 3-二氫-5-氟-1H-吲哚 -1-基）哌啶-1-基]氮雜環庚烷-1-羧酸乙酯； 4-[4-(3, 3-二曱基-2-硫_基-2, 3-二氫°朵-1-基） 哌啶-1-基]哌啶-1-羧酸乙酯； 4-[4-(5-曱基-2-側氧基-2, 3-二氫-1Η-吲哚-1-基）哌 咬-1-基]派咬-1—竣酸乙酯；2 = 6, heteroaryl, ^ Fangxuan c soil to square ^ alkenyl, C2-6 block, ^ alkoxy, cyano, ^ its f base, _, amine sister base, miscellaneous, silk, nitrate a group, a C 6 alkyl fluorenyl group, or a substituted Ci 6 alkyl group; T is the same or different, respectively a hydrogen atom, a replaceable cardinal atom, a (:" ring-based base or 3 To a heterocyclic group of 7 members; \ and R are bonded to each other, and R, and R2 together with an adjacent carbon atom are P7 L-cane or a heterocyclic ring of 3 to 7 members or together form =CR6R7; Different, respectively, a hydrogen atom or a substituted Ch = group: or R6 and R7 are bonded to each other, and R7 and phase_carbon are the same to form a C3-7 cycloalkane or a 3 to 7 membered heterocyclic ring; R3 and R4 Forming =〇 or 4 together; X is an early bond or a methylene group; γ and z are (four) or different from each other as an oxygen atom or a sulfur atom; R is a substituted c(mono)alkyl group, Gβ alkynyl group or C2 6 alkenyl; % A is a 6 to 7 member nitrogen-containing 323406 1 which may be substituted with i to 2 substituents selected from the group consisting of a hydroxyl group, a halogen atom, a fluorenyl 6 alkyl group and a Cl 6 alkoxy group. 201211028 Heterocycle]. 2. A compound according to claim 1, wherein R5 a halogen atom, a Ch alkoxy group, a cyano group, an alkylthio group, a hydroxyl group, an amine group, a nitro group, or a substituted C6 alkyl group. 3. The compound according to the above formula, wherein And RS is a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, a propyl group, a methoxy group or a trifluoromethyl group. The fragrance is as described in any one of the claims i to 3 a compound wherein ring A is represented by the following formula (2): [wherein R 8 is a hydrogen atom, a transatom, a tooth atom, a Ci 6 or a Ci 6 alkoxy group]. The compound of any one of items 1 to 4 wherein 'R8 is a hydrogen atom, a G 6 alkyl group or a 6 alkoxy group. ♦Application = Patent No. 1 to Item 5 - The compound described in the above, wherein c and b are the same or different CH or CR5. The patent is a compound of any one of items 1 to 5 wherein one of c and b is CH. The other one is the compound described in any one of the items 1 to 7 of the patent application, wherein Y and Z are both oxygen atoms. 9.! [Application No. 1 to Any of the 8th a compound of the formula wherein 'RL is formed = 〇. 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Atom, a meridine, or a substitutable Cl_e alkyl group, or a reverse, and r2 are bonded to each other, and R1 and R2 together with an adjacent carbon atom form a four gas ring. 1' The compound according to any one of the preceding claims, wherein R is a linear C chain which may be substituted. 12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of: 4~[4-(2- oxalyl-2, 3-di Hydrogen-in-indol-1-ylpiperidin-1-yl]-ethyl cyano-1-carboxylate; 4-[4-(3-indolyl-2-oxo-2, 3- Dihydro-1H-indole-byl) piperidine ~1-yl] piet bite_ι_ ̄ ̄ acid ethyl ester; 4~~[4-(3, 3-dimethyl-2-oxooxy-2 , 3-diindole-1H-indol-1-yl) ° bottom 定-丨-yl] piperidine-1-carboxylic acid ethyl ester; 4~[4-(3,3-diethyl-2- Side oxy-2, 3-dihydro-1H-indol-1-yl) ° chen-1-yl] piperidine-1-carboxylic acid ethyl ester; 4~[4-(3-ethyl-3 -Methyl-2-oxo-oxy-2,3-dihydro-1H-indenyl) ° chen-1-yl]-biting _1_ethyl formic acid; 4-[4-(3, 3 -dipropyl-2-indolyl-2,3-dihydro-1H-indol-1-yl) ethyl hydrazide-yl]piperidine-1-carboxylate; 4M4-[2'-side Oxyspiro(cyclopropane_丨,3'-吲哚)-Γ(2,H)-yl]piperazin-1-yl}piperidine-1-carboxylic acid ethyl ester; {4-[ 2'-side Oxyspiro(cyclobutane_丨, 3'-吲哚)-Γ(2' H)-yl]ethylidene~1-yl}piperidine-1-carboxylic acid ethyl ester; 4~U-[2' - Side oxo (cyclopentane - ,3'-吲哚)-Γ(2,H)-yl]piperidin 3 323406 201211028 pyridine-l-yl}piperidin-1-carboxylic acid ethyl ester; 4-{4-[2'-side oxane ( Ethyl cyclohexane-1,3'-indole-1'(2'H)-yl]piperidine-1-yl}piperidine-1-carboxylate; 4-{4-[2'-side Oxytropy (tetrazoxanthene-4,3'-11 xylindole)_1(2 1〇-yl) piperidine-1-yl}piperidine-1-carboxylic acid ethyl ester; 4-[4-( Ethyl 3, 3-dimercapto-2-oxo-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]methylpiperidine-1-carboxylate; 4 -{4-[2'-S. oxyspiro(cyclopropane-1,3'-indole)-1'(2'H)-yl]piperidine-1-yl}methylpiperidine-1-carboxylic acid Ethyl ester; 3-[4-(3,3-diethyl-2-oxo-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]-8-anthracene Bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester; 4-[4-(3,3-dimercapto-2-yloxy-2,3-diar-argon-1H-indole- 1-based) °-1-yl] π bottom bite-1-reo-acidic guanidine; 4-[4-(3, 3-dimercapto-2-yloxy-2,3-dihydro -1Η-吲哚-1-yl) piperidin-1-yl]piperidine-1-carboxylic acid isopropyl ester; 4-[4-(2-o-oxy-2,3-dihydro-1Η-吲哚-1-yl)piperidin-1-yl]azepane-1-carboxylic acid ethyl ester; 4-[4-(6 -fluoro-2-oxo-2,3-dihydro-1Η-indol-1-yl)piperidin-1-yl]piperidine-1-carboxylic acid ethyl ester; 4-[4-(6- Ethyl fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1Η-indol-1-ylpiperidin-1-yl]piperidine-1-carboxylate; 4 -[4-(5-Gas-2-oxo-2,3-dihydro-1Η-indol-1-yl)piperidin-1-yl]piperidine-1-carboxylic acid ethyl ester; 4- [4-(5-Fluoro-3, 3-dimercapto-2-oxo-2,3-dihydro-1Η-吲哚4 323406 201211028 -1-yl)piperidin-1-yl]piperidine 1-carboxylic acid ethyl ester; 4-[4-(5-icon-2-oxo-2,3_diaza-1 Η-α 引π朵_1-yl) σ bottom bit-1-yl ] piperidinyl-carboxylic acid ethyl ester; 4_({3-[1-(ethoxy)yl) succinyl-4-yl]-6-fluoro- oxo-2,3-dinitro -1Η-α引度-1-yl}σ bottom β定-丨-yl) 11 Chen bite_1_wei acid ethyl ester; 4-({3-[1-(ethoxycarbonyl)piperidinyl) Ethyl 4-[4-]fluoro-2-oxo-2,3-diindole-1Η-吲哚-l-yl}piperidin-1-yl)piperidine-1-carboxylate; -ethylthio-yl-4-[4-(2-oxo-2,3-dihydro-111-°-1-yl)piperidin-1-yl]piperidine; 4- [4-(2-Sideoxy-2,3-di-argon-lH-i11, bottom bite-1-yl] piperidine-1-carboxylic acid 2-fluoroethyl ester; 4-[4-(2-Sideoxy-2,3-diar argon-1H-indol-1-yl)piperidin-1-yl]piperidine-1-carboxylic acid 2-propenyl ester; 4-[ 4-(2-Sideoxy-2,3-dihydro-1Η-, π-d-l-yl) ° bottom bite_1_yl] piperidine-1-carboxylic acid 2-oxime ethyl ester; 4- [4-(2-Sideoxy-2,3-diar-ars-indol-1-yl)piperidin-1-yl] piperidine-1-carboxylic acid butyl ester; 1-mercaptothiocarbonyl- 4-[4-(2-Sideoxy-2,3-dihydro-1Η-indol-1-yl)piperidin-1-yl]piperidine; 4-[4-(2-Sideoxy- 2,3-Dihydro-1Η-indol-1-yl)piperidin-1-yl]piperidine-1-carboxylic acid propyl ester; 4-[4-(5-fluoro-2- oxo-2 , 3-dihydro-1Η-indol-1-yl)piperidine 5 323406 201211028 -1-yl]azetidene-1-carboxylic acid ethyl ester; 4-[4-(3, 3-dioxin) Ethyl-2-oxo-2,3-dihydro-5-fluoro-1H-indol-1-ylpiperidin-1-yl]azepane-1-carboxylic acid ethyl ester; 4- [4-(3,3-Dimercapto-2-thio-yl-2,3-dihydro-l-yl)piperidin-1-yl]piperidine-1-carboxylic acid ethyl ester; 4- [4-(5-Mercapto-2-yloxy-2,3-dihydro-1Η-indol-1-yl)piperidin-1-yl]pyridine-1-ethyl decanoate; 4-[4-(6-曱基-2-側氧基-2, 3-二氫-1Η-吲哚-1-基）π辰 啶-1-基]派啶-1-羧酸乙酯； 4-[4-(5-曱氧基-2-侧氧基-2, 3-二氫-ΐΗ-π引α朵_ι_基） 0底°定-1-基]派咬-1-致酸乙酯； 4-[4-(5-甲氧基一2-侧氧基—2,3—二氫_1Η_吲哚_卜基） 派咬-1-基]氮雜環庚烷_丨_羧酸乙酯； 4-{4-[3, 3-雙（3—曱氧基丙基）_2_侧氧基一2, 3一二氫 -1Η-吲哚-1-基]哌啶―丨—基丨氮雜環庚烷_丨_羧酸乙酯； 4-{4-[5-氟~3,3-雙（羥基甲基）-2一側氧基_2,3_二氫 -1Η-吲哚-1-基]哌啶―丨一基}哌啶_丨_羧酸乙酯； 4 [4 (5溴-2-側氧基—2, 3-二氫-1H-吲哚基）哌啶 -1-基]哌啶-1-羧酸乙酯； 4-[4-(5-漠-2-側氧基_2,3—二氫_1Η_+朵+基）派咬 -1-基]氮雜環庚烷―丨―羧酸乙酯； 4-[4-(5-氣—2-側氧基_2,3一二氫，一吲哚+基)哌啶 一卜基]氮雜環庚烷-1-羧酸乙酯； 4-[4-(5_氣-2,氧基_2,3_二氫冬吲哚+基)哌啶 323406 6 201211028 一1~基]哌啶-1-羧酸甲酯； 昝[昝（5-氟-2-侧氧基_2，，3’，5，，6，_四氫螺[，哚 ’4辰南]1(2H)-基）派咬-i—基]α辰咬一卜敌酸乙醋； [4 (5氟-2-侧氧基_2’，3’，5’，6’ _四氫螺[吲嗓 3,4 ~哌喃]_1(2Η)_基）哌啶_丨_基]氮雜環庚烷_ι一羧 酸乙酯； 4~[4-(5’ -氣-2’ -側氧螺_[環丙烷_丨，3, _吲哚] 1 (2 Η)-基）哌啶-1-基]派啶_ι_羧酸乙酯； 4~[4~(5’ -氯-2’ -側氧螺_[環丙烷_丨，3, _吲哚] 1 (2 Η)-基）娘啶-1-基]派啶一卜羧酸曱酯； 4~[4-(5’ -氣-2’ -側氧螺_[環丙烷_丨，3’ _吲哚] -Γ (2’H)-基）哌啶-1-基]氮雜環庚烷_丨_羧酸乙酯； 4~[4-(5’ -氟-2’ -側氧螺-[環丙烷_丨，3’ _吲哚] -Γ (2’ H)-基）哌啶-1-基]哌啶_丨_羧酸乙酯； 4-[4-(5’ -氟-2’ -侧氧螺-[環丙烷-1，3,-吲哚] -1’（2’H)-基）哌啶-1-基]派啶-1-羧酸曱酯； 4-[4-(5’ -氟-2’ -側氧螺-[環丙烷-1，3,-吲哚] -Γ (2’ H)-基）哌啶-1-基]氮雜環庚烷-1 —羧酸乙酯； 4-[4-(5-甲基-2-侧氧基-2’，3’，5’，6’ -四氫螺[吲哚 -3, 4’ -〇辰喃]-1(2H)-基）旅咬-1-基]派咬-1-缓酸乙酯； 4-[4-(5-曱基-2-侧氧基-2’，3’，5’，6’ -四氫螺[吲哚 -3, 4’ -哌喃]-1(2H)-基）哌啶-1-基]氮雜環庚烷-1-羧. 酸乙酯； 4-[4-(5 -甲基-2’ -侧氧螺-[環丙烧-1，3’ - σ引°朵] 7 323406 201211028 -1’（2,1〇-基）°底唆-1-基]。底。定-1-緩酸乙酉旨； 4-[4-(5’ -甲基-2’ -側氧螺-[環丙烷-!，3, _吲哚] -1’（2, H)-基）哌啶-1-基]氮雜環庚烷―丨―羧酸乙酯； 4-[4-(3, 3, 6-三曱基-2-側氧基-2, 3-二氫-1Η-, η朵-1 — 基）派咬-1-基]°底咬-1-緩酸乙酯； 4-[4-(3, 3, 6-三甲基-2-側氧基-2, 3-二氫-lH-°弓丨〇朵-1- 基底咬-1-基]11 辰咬-1-緩酸甲酯； 4-[4-(3, 3, 6-三甲基-2-侧氧基-2, 3-二氫-1Η-吲哚-1- 基）派咬-1-基]氮雜環庚烧-1-叛酸乙酯； 4-[4-(6’_甲基-2’-侧氧螺-[環丙烷_13’_吲哚] -Γ (2, Η)_基）派°定-1-基]派咬-1—叛酸乙酯； 4-[4-(6’ -甲基-2’-側氧螺-[環丙烷-13:吲哚] -1’（2’1〇-基）11底咬-1-基]派唆-1_缓酸曱酯； 4_[4-(6’-甲基-2’-側氧螺-[環丙烷一匕^一吲哚] -1’（2’ Η)_基）哌啶-1-基]氮雜環庚烷_丨_羧酸乙酯； 4-[4-(6-甲基-2-侧氧基-2’，3’，5’，6,-四氫螺[吲哚 -3,4 -痕畴]-1(21〇-基）旅。定_1_基]0底咬_ι_叛酸乙酯； 4-[4-(6-甲基-2-侧氧基-2’，3’，5,，6,-四氫螺[吲哚 -3, 4’ -哌喃]-1(2Η)-基）哌啶-1-基]氮雜環庚烷―丨一羧 酸乙酯； 4-[4-(6-甲基-2-侧氧基-2,3-二氫-1Η-吲哚-1-基）哌 啶-1-基]氮雜環庚烷-1_羧酸乙酯； 4-[4-(6-甲基-2-侧氧基一2, 3-二氫-1Η-吲哚-1-基）哌 唆-1-基]哌啶-1-羧酸乙酯； 323406 8 201211028 4-[4-(6-甲基-2-側氧基-2, 3-二氫-1Η-°弓卜朵-1-基）α辰 啶-1-基&gt;底啶-1-羧酸甲酯； 4-[4-(6-甲氧基-2-側氧基-2, 3-二氫-1Η-吲哚-1-基） 派咬-1-基]氮雜環庚烧-1-緩酸乙酯； (1R，5S)-3-[4-(6-甲氧基-2-側氧基-2, 3-二氫-1Η-吲 哚-1-基）哌啶-1-基]-8-吖雙環[3. 2. 1]辛烷-8-羧酸乙4-[4-(6-Mercapto-2-oxo-2,3-dihydro-1Η-indol-1-yl)π succin-1-yl]pyridin-1-carboxylic acid ethyl ester ; 4-[4-(5-decyloxy-2-yloxy-2,3-dihydro-indole-π引α朵_ι_基) 0 bottom-deciding-1-yl] pie bite-1 - acid-producing ethyl ester; 4-[4-(5-methoxy-2-o-oxy-2,3-dihydro-1-indole-indole) Alkyl-indole-carboxylate; 4-{4-[3,3-bis(3-methoxypropyl)_2_sideoxy-2,3-dihydro-1Η-indol-1-yl Piperidine-oxime-azinium azepane-oxime-carboxylate; 4-{4-[5-fluoro~3,3-bis(hydroxymethyl)-2-sideoxy-2, 3_Dihydro-1Η-indol-1-yl]piperidine-indenyl}piperidinyl-indole-carboxylate; 4 [4 (5-bromo-2-yloxy-2, 3-dihydro) -1H-indenyl)piperidin-1-yl]piperidine-1-carboxylic acid ethyl ester; 4-[4-(5-moly-2-oxo-2,3-dihydro-1Η_+ + base) ketone-1-yl]azepane-oxime-carboxylic acid ethyl ester; 4-[4-(5-aero-2-etheroxy-2,3-dihydrogen, one 吲哚+ Ethyl piperidine-diyl]azetidene-1-carboxylate; 4-[4-(5-gas-2,oxy-2,3-dihydroindole+yl)piperidine 323406 6 201211028 a 1~yl] piperidine Methyl-1-carboxylate; 昝[昝(5-fluoro-2-oxo-2,3',5,6,_tetrahydrospiro[,哚'4辰南]1(2H)- Base) bite-i-base] α辰 bite a diacetate vinegar; [4 (5 fluoro-2- oxo 2', 3', 5', 6' _ tetrahydro snail [吲嗓3 , 4 ~ Piper]_1(2Η)-yl) piperidine_丨_yl]azetidene-I monocarboxylate; 4~[4-(5'-gas-2'-side oxose _[cyclopropane_丨,3, _吲哚] 1 (2 Η)-yl)piperidin-1-yl]pyridinium_ι_carboxylate; 4~[4~(5'-chloro-2 '-Side oxo _ [cyclopropane _ 丨, 3, _ 吲哚] 1 (2 Η)-yl) dinyl-1-yl]pyridinyl carboxylic acid oxime ester; 4~[4-(5' - gas-2'-side oxo-[cyclopropane_丨,3' _吲哚] -Γ(2'H)-yl)piperidin-1-yl]azepane_丨_carboxylic acid B Ester; 4~[4-(5'-fluoro-2'-side oxo-[cyclopropane_丨,3' 吲哚]-Γ(2' H)-yl)piperidin-1-yl]peri啶_丨_carboxylate; 4-[4-(5'-fluoro-2'-side oxo-[cyclopropane-1,3,-吲哚]-1'(2'H)-yl) Piperidin-1-yl]pyridin-1-carboxylic acid oxime ester; 4-[4-(5'-fluoro-2'-side oxo-[cyclopropane-1,3,-吲哚]-Γ ( 2' H)-yl) piperidine-1- Aziridine-1 -carboxylic acid ethyl ester; 4-[4-(5-methyl-2-oxo-2',3',5',6'-tetrahydrospiro[吲哚- 3, 4'-〇辰喃]-1(2H)-yl) Bite-1-yl] sent bite-1-acidic ethyl ester; 4-[4-(5-mercapto-2-yloxy -2',3',5',6'-tetrahydrospiro[吲哚-3,4'-pyrano]-1(2H)-yl)piperidin-1-yl]azepane-1 -carboxyl. acid ethyl ester; 4-[4-(5-methyl-2'-side oxo-[cyclopropanone-1,3'- σ 引度] 7 323406 201211028 -1'(2,1 〇-base) ° bottom 唆-1-yl]. bottom. 4-[4-(5'-methyl-2'-side oxo-[cyclopropane-!,3, _吲哚]-1'(2,H)-yl Piperidin-1-yl]azepan-indole-carboxylate; 4-[4-(3,3,6-tridecyl-2-oxo-2,3-dihydro- 1Η-, η朵-1 — base) 派-1-基]° bottom bite-1-acid ethyl ester; 4-[4-(3, 3, 6-trimethyl-2-oxo- 2, 3-Dihydro-lH-° 丨〇 丨〇 -1- -1- basement bite-1-yl]11 chen -1--1-acid methyl ester; 4-[4-(3, 3, 6-trimethyl -2-Sideoxy-2,3-dihydro-1Η-indol-1-yl) ketone-1-yl]azetidin-1-ethylate; 4-[4-(6 '_Methyl-2'- side oxo-[cyclopropane_13'_吲哚] -Γ (2, Η)_yl) 派定-1--1-] 咬-1 - oleic acid ethyl ester; 4-[4-(6'-methyl-2'-side oxyspiro-[cyclopropane-13: fluorene] -1'(2'1〇-yl)11 bottom bit-1-yl]派唆- 1_sodium sulphate; 4_[4-(6'-methyl-2'-side oxyspiro-[cyclopropane- oxime]-1'(2' Η)-yl)piperidine-1 -yl]azetidinyl-indole-carboxylate; 4-[4-(6-methyl-2-oxo-2',3',5',6,-tetrahydrospiro[吲哚-3,4 - zonal domain]-1 (21〇-base) brigade. _1_1 base]0 bottom _ι_oleic acid ethyl ester; 4-[4-(6-methyl-2-oxo-2',3',5,6,-tetrahydrospiro[吲哚-3,4'-pyran -1(2Η)-yl)piperidin-1-yl]azepan-indolecarboxylic acid ethyl ester; 4-[4-(6-methyl-2- oxo-2,3- Ethyl dihydro-1Η-indol-1-ylpiperidin-1-yl]azepane-1_carboxylate; 4-[4-(6-methyl-2-yloxy- 2 , 3-dihydro-1Η-indol-1-yl)piperazin-1-yl]piperidine-1-carboxylic acid ethyl ester; 323406 8 201211028 4-[4-(6-methyl-2-side oxygen 2-[4-(6-methoxy) -2-Sideoxy-2,3-dihydro-1Η-indol-1-yl) ketone-1-yl]azepane-1-one acid ethyl ester; (1R,5S)-3 -[4-(6-Methoxy-2-oxo-2,3-dihydro-1Η-indol-1-yl)piperidin-1-yl]-8-indole bicyclo[3. 1] Octane-8-carboxylic acid B 4_{[4-(6-曱氧基-2-侧氧基-2, 3-二氫-1H-吲哚-1-基） 旅唆-1-基]甲基}0辰。定-1-叛酸乙酯； 4-{[4-(6-甲氧基-2-侧氧基-2’，3’，5’，6’ -四氫螺[〇引 〇朵-3, 4 _旅嚼]-1(2Η)-基）α底咬-1-基]n辰缓酸乙 酯； 4-{[4_(6-甲氧基-2-側氧基-2’，3,，5,，6,-四氫螺[口引 哚-3,4’-旅喃]-1(21〇-基）派咬-1-基]氮雜環庚烷_1_ 缓酸乙自旨； (1R, 5S)-3_[4-(6-甲氧基-2-侧氧基 ~2,，3,，5，6,-四 氫螺[吲哚_3,4’-哌喃]-1-(21〇-基）~哌唆_1_基]_8_〇丫 雙環[3. 2.1]辛烷-8-羧酸乙酯； 4-[ 4-(5_ 氣-6- I -3, 3-二曱基-2-側氧基一2, 3-二氫 _111-111弓丨1*朵_1_基）派咬_1_基]旅淀-1-幾酸乙酉旨· 4-[4-(3, 6-二曱基-2-側氧基-2, 3-二氫〜jH-t»弓丨嗓-1-基） 痕σ定-1_基]旅咬_ 1_叛酸乙.醋； 4-[4-(3, 6-二甲基-2-側氧基-2, 3-二氫-.叫卜朵+基） 派唆基]11 辰咬_1-幾酸甲酉旨； 323406 9 201211028 4-[4-(3, 6-二曱基-2-側氧基-2, 3-二氫-1H-吲哚-1_基） 派咬-1-基]氮雜環庚烧-1—竣酸乙g旨； 4-[4-(5-氟-3-曱基-2-側氧基-2, 3-二氫-1H-吲哚-1- 基）哌啶-1-基]氮雜環庚烷-1-羧酸乙酯； 4-{[4-(5-氟-3-曱基-2-側氧基-2, 3-二氫-1Η-°引哚-1- 基）0辰唆-1-基]曱基}派咬-1-叛酸乙酉旨； 4-{[4-(3-曱基-2-侧氧基-2,3-二氫-111-吲哚-1-基）哌 啶-1-基]甲基}哌啶-1-羧酸乙酯； 4-[4-(5-甲基-2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌 变基]氮雜環庚烧-1-緩酸乙酯； 4-{[4-(5-曱基-2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌 咬-1-基]甲基卜底咬-1-緩酸乙酯； 4~{[4-(2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌啶-1-基] 曱基}哌啶-1-羧酸乙酯； 4~[4-(6-氟-3-曱基-2-側氧基-2, 3-二氫-1H-吲哚-1- 基）0底咬-1-基]旅咬-1-叛酸乙酯； 4一[4-(6-氟-3-曱基-2-側氧基-2, 3-二氫-1H-吲哚-1- 基）哌啶-1-基]氮雜環庚烷羧酸乙酯； 4-[4-(5-氟-2-侧氧基-2, 3-二氫-1H-吲哚-1-基）哌啶 -1-基]哌啶-1-羧酸曱酯； 4-[4-(6-曱基-2-侧氧基-2, 3-二氫-1H-吲哚-1-基）哌 啶-1-基]哌啶-1-羧酸甲酯； 4~[4-(6-溴-2-侧氧基-2, 3-二氫-1H-吲哚-1-基）哌啶 -1-基]哌啶-1-羧酸乙酯； 323406 10 201211028 4-[4-(6-溴-2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌啶 -1-基]氮雜環庚烷-1-羧酸乙酯； 4-[4-(6-溴-2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌啶 -1-基]哌啶-1-羧酸曱酯； 4-[4-(6-乙基-2-側氧基-2,3-二氫-1H-吲哚-1-基）哌 啶-1-基]哌啶-1-羧酸乙酯； 4-[4-(6-乙基-2-側氧基-2, 3-二氩-1H-吲哚-1-基）哌 咬-1-基]氮雜環庚烷-1-羧酸乙酯； 4-[4-(2-側氧基-6-丙基-2, 3-二氫-1H-吲哚-1-基）哌 啶-1-基]哌啶-1-羧酸乙酯； 4-{[4-(5-氯-2-侧氧基-2,3-二氫-111-°弓丨'1朵_1-基）派唆 -1-基）甲基}哌啶-1-羧酸乙酯； (1R，5S)-3-[4-(5-氯-2-侧氧基-2, 3-二氫-1H-吲哚-1-基）-哌啶-1-基]-8-吖雙環[3. 2. 1]辛烷-8-羧酸乙酯； 4 {[4-(5 -就-2-側氧基-2, 3-二氫_1Η-σ3Ιπ朵-1-基）旅咬 ~1-基]甲基}哌啶-1-羧酸乙酯； (1R，5S)-3-[4-(5-氟-2-側氧基-2, 3-二氫-1Η-吲嗓 -1-基）-派咬-1-基]-8-吖雙環[3. 2. 1]辛烧-8-緩酸乙 酯； 4—[4-(6-甲基-2-側氧基-2,3-二氫-1H-吲哚-1-基）旅 咬~1~基]哌啶-1-羧酸乙酯； 4_{[4-(6-曱基-2-侧氧基-2,3-二氫-1H-吲哚-1一基）0辰 $—1-基]甲基}哌啶-1-羧酸乙酯； 4~U4-(6-氟-2-侧氧基-2,3-二氳-ΙΗ-弓卜朵-卜基&gt;辰咬 323406 11 201211028 -1-基]甲基}氮雜環庚烷一丨一羧酸乙酯； 4-[4-(6-氟-2-侧氧基__2,3_二氫_1H_吲哚基）哌啶 -1-基]氮雜環庚烷-丨_羧酸乙酯； 4-[4-(5-氟-3, 3-二甲基-2-硫酮基-2, 3-二氫-1H-吲哚 -1-基）哌啶-1-基]哌啶羧酸乙酯； 4-[4-(6-曱氧基-2-侧氧基一2, 3一二氫一 1H_吲哚_卜基） 哌啶-1-基]-4-甲基哌啶―卜羧酸乙酯； 4-[4-(6-氟-2-侧氧基_2,3_二氫_1H-吲哚_丨_基）哌啶 -1-基]-4-甲基哌啶-1—羧酸乙酯； 4-[4-(6-甲基-2-侧氧基-2, 3-二氫-1H-吲哚-1-基）哌 °定-1-基]-4-甲基哌啶-1-羧酸乙酯； 4-[4-(6-甲氧基-3-甲基-2-侧氧基-2, 3-二氫-1Η-°弓卜朵 -1-基）娘啶-1-基]-4-甲基哌啶-1-羧酸乙酯； (3-内）-3-[4-(6-曱基-2-側氧基-2, 3-二氫-1H-吲哚 -卜基）哌啶-1-基]-8-吖雙環[3.2. 1]辛烷-8-羧酸乙 酉旨； (3-外）-3-[4-(6-曱基-2-侧氧基-2, 3-二氫-1H-吲哚 -1-基）哌啶-1-基]-8-吖雙環[3.2. 1]辛烷-8-羧酸乙 酯； (3-内）-3-[4-(6 -氟-2-側氧基-2, 3-二氫-1Η-σ弓丨n朵-1-基）哌啶-1-基]-8-吖雙環[3. 2. 1]辛烷-8-羧酸乙酯； (3-外）-3-[4-(6-氟-2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌啶-1-基]-8-吖雙環[3. 2. 1]辛烷-8-羧酸乙酯； (3-内）-3-[4-(2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌 12 323406 201211028 啶-1-基]-8-吖雙環[3. 2. 1]辛烷-8-羧酸乙酯； (3-外）-3-[4-(2-側氧基-2, 3-二复-lH-i D朵-1-基）派 啶-1-基]-8-吖雙環[3. 2. 1]辛烷-8-羧酸乙酯； (3-内）-3-[4-(3, 6_二甲基_2-侧氧基-2, 3-二氩-1Η-°引 D朵-1-基）α底咬-1-基]-8-α丫雙環[3. 2. 1]辛烧-8-叛酸乙 酯； (3-内）-3-[4-(6-氟-3-甲基-2-侧氧基-2, 3-二氫-1Η-吲哚-1-基）哌啶-1-基]-8-吖雙環[3. 2. 1]辛烷-8-羧酸 ® 乙酯； (3-内）-3-[4-(5-氟-3-甲基-2-侧氧基-2, 3-二氫-1Η-吲哚-1-基）哌啶-1-基]-8-吖雙環[3. 2. 1]辛烷-8-羧酸 乙酯； 4-{4-[5-氟-2-側氧基-3-(丙烷-2-亞基）-2, 3-二氫 -1-11-吲哚-1-基]11辰。定-1-基}派11定_1_叛酸乙酯； 4-{4-[5-氟-2-侧氧基-3-(丙烷-2-基）-2,3-二氫-1-Η- • °引°朵一1-基]哌啶-l-基}氮雜環庚烷-1-羧酸乙酯； 4-{4-[(3Ζ)-3-亞乙基-5-氟-2-侧氧基-2, 3-二氫-1Η- ’ °朵-1-基]哌啶-l-基}氮雜環庚烷_丨_羧酸乙酯； 4-[4-(3-乙基-5-氟-2-側氧基-2, 3-二氫-1Η-吲哚-1- 基）派咬-1-基]β辰唆-1-緩酸乙醋； 4-{4-[ (3Ζ)-5-氟-3-(2-甲基亞丙基）-2-側氧基 ~2, 3~ 二氫-1Η-吲哚-1-基]哌啶―丨—基}哌啶_丨_羧酸乙醋； 4~{4-[5-氟-3-(2-甲基丙基）一 2_侧氧基_23一二氫_1Η_ 吲哚-1-基]哌啶-1-基丨哌啶_丨—羧酸乙酯； 323406 13 201211028 4-[4-(3-環戊基-5-氟-2-側氧基-2, 3-二氫-1H-吲哚 -1-基）娘啶-1-基]哌啶羧酸乙酯； 4-{4-[(32)-5-氟-2-側氧基-3-亞丙基-2,3-二氫-111- °引°朵-1-基]娘啶-1_基丨氮雜環庚烷_丨_羧酸乙酯； 4-[4-(5-氟-2-側氧基—3-丙基-2, 3-二氫-1H-吲哚-1 - 基）旅咬-1-基]哌啶羧酸乙酯； 4-{4-[5-氟-2-侧氧基-3_(四氫-2H_哌喃_4_基）2, 3_二 氫-1H-吲哚-1-基]哌啶_丨_基丨哌啶_ι_羧酸乙酯； 4-{4-[(32)-5-氣-3-亞乙基-2-侧氧基-2,3-二氫-111- 吲哚-1-基]哌啶-丨-基丨哌啶―卜羧酸乙酯； 4-{4-[5-氟-3-(氧雜環丁烷_3_基）_2_側氧基_2,3_二 氫-1H-吲哚—卜基]哌啶+基}哌啶-卜羧酸乙酯； 4_{4-[5-氟-2-側氧基_3_(四氫呋喃_3_基）_2 3_二氫 -1H-吲哚-1-基]哌啶_丨一基丨哌啶_丨_羧酸乙酯； 4-{4普（氧雜環了燒—3-基）-2,氧基-2,3-二氫-1H-㈣-1-基]_+基卜紋小⑽乙醋； 4-{4-[3-(四氫。丫唉+基）+氟_2_侧氧基_2,3_二氮 基^定基卜底咬-1-叛酸乙酯； 雜環丁烧—3-基）-2-侧氧基-2, 3-二 風_1Hm-基]哌啶-ι-基}哌啶-1-羧酸曱酯； 4_[4_(3~ 乙基'5~U-側氧基-2,3-二氫-IH-t朵 + 基）哌啶-1-基]哌啶_丨_羧酸乙酯； 4-[4-(3-環丁基|曱基_2_側氧基—23一二氫普巧哚 -1-基）哌啶-1-基]哌啶_丨_羧酸曱酯； 323406 14 201211028 4-{4-[6-(甲基-2-側氧基-3-(丙烷-2-基）-2, 3-二氫 -1H-吲哚-1-基]哌啶-l-基}哌啶-1-羧酸甲酯； 4-{4-[5-氟-2-側氧基-3-(丙烷-2-基）-2, 3-二氳-1H-吲哚-1-基]哌啶-l-基}哌啶-1-羧酸甲酯； 4_[4_(3_ 乙基-5-•氣_2_侧氧基_2，3_二氮-1H-0引 π朵 _1 -基）哌啶-1-基]哌啶-1-羧酸乙酯； 4-{4-[2 -側氧基-3-(丙烧-2-基）-2，3 -二氮-1Η-0引 D朵 -1-基]哌啶-l-基}哌啶-1-羧酸乙酯； 4-[4-(3-環丁基-2-側氧基-2，3 -二氮-1Η-α引 D朵-1-基） 哌啶-1-基]哌啶-1-羧酸乙酯； 4-[4-(3-環戊基-2-侧氧基-2, 3-二氫-1H-吲哚-1-基） 哌啶-1-基]哌啶-1-羧酸乙酯； 4-[4-(2-側氧基-3-丙基-2, 3-二氫-1H-吲哚-1-基）哌 啶-1-基]哌啶-1-羧酸乙酯； 4-{4-[2 -側氧基-3_(四氮- 2H-°辰喃基）_2，3_二氮 -1 Η-π引π朵-1 -基]π辰咬-1 -基}0底唆-1 -叛酸乙酉旨； 4-{4-[2-側氧基-3-(戊烷-3-基）-2, 3-二氩-1Η-吲哚 _1-基]α辰咬-1-基}娘咬-1-竣酸乙酉旨； 4-{4-[2-側氧基-3-(四氩11夫11南-3_基曱基）-2,3-二氫 -111-吲哚-1-基]哌啶-1-基}哌啶-1-羧酸乙酯； 4-{4-[3-(環丙基曱基）-2-侧氧基-2, 3-二氫-1Η-吲哚 _1_基]旅咬_1_基}旅咬-1-幾_酸乙酉旨； 4-[4-(3-乙基-2-側氧基-2，3-二氮-1Η-σ弓丨0朵-1 -基）σ辰 啶-1-基]哌啶-1-羧酸乙酯； 15 323406 201211028 4-[4-(3-乙基-2-侧氧基-2, 3-二氫-1H-吲哚-1-基）哌 咬-1~基]氮雜環庚烷-1-羧酸乙酯； 4_{4-[3-(1，3_曙β坐-2-基甲基）-2-侧氧基-2, 3-二氫 _1Η~吲哚-1-基]哌啶-l-基}哌啶-1-羧酸乙酯； 4_{4-[2-侧氧基-3-(丙烧-2-基）-2,3-二氫-111-°弓丨嗓 一1 一基]氮雜環庚烷-l-基}哌啶-1-羧酸乙酯； 4-[4-(2-側氧基-3-丙基-2, 3-二氫-1Η-吲哚-1-基）哌 啶-1-基]氮雜環庚烷-1-羧酸乙酯； 4-{4-[2-側氧基-3-(四氫呋喃-3-基）-2, 3-二氫-1Η-吲 °朵-1-基]哌啶-l-基}氮雜環庚烷_i_羧酸乙酯； 4-{4-[3-(庚烷-4-基）-2-侧氧基-2,3-二氫-111-吲哚 -卜基]哌啶-l-基}氮雜環庚烷-1-羧酸乙酯； 4-{4-[2-側氧基-3-(四氫-2H-哌喃-4-基）-2, 3-二氫 -1H-,哚-1-基]哌啶-i-基}氮雜環庚烷_丨_羧酸乙酯； 4-{4-[2-側氧基-3-(戊烷-3-基）-2, 3-二氫-1H-吲哚 -1-基]哌啶-l-基}氮雜環庚烷-1_羧酸乙酯； 4-{4-[2-側氧基-3-(四氫呋喃-3-基）-2, 3-二氫-1H-吲 哚-1-基]哌啶-l-基}哌啶-1-羧酸乙酯； 4-[4-(3-丁基-2-侧氧基-2, 3-二氫-1H-吲哚-1-基）哌 咬-1-基]旅咬-1-竣酸乙酯； 4-{4-[3-(呋喃-3-基甲基）-2-側氧基-2,3-二氫-111-吲 哚-1-基]哌啶-l-基}哌啶-1-羧酸乙酯； 4-{4-[3-(羥基甲基）-6-甲氧基_3_甲基_2_侧氧基 -2, 3-二氫-1H-吲哚-1-基]哌啶―卜基丨哌啶_丨_羧酸乙 323406 16 201211028 酯； [3-(羥基甲基）一3, 6一二甲基_2一側氧基一2, 3—二氫 _1H_吲哚—卜基]哌啶-ι-基}哌啶-1-羧酸乙酯； 4:{4-[5-氟-3-(羥基甲基）一3一甲基_2一側氧基—2, 3_二 氫一1H-吲哚_1—基]哌啶-ι-基}氮雜環庚烷-1-羧酸乙 酯； 羥基曱基）-3 一甲基_2_側氧基一23_二氫一⑺一 °弓卜朵-1-基]派咬-1-基丨甲基哌啶羧酸乙酯； 4-{4-[5-氟-3-(羥基甲基）一3_甲基一2_側氧基_2, 3一二 氯-1H-叫丨嗓-1 一基]哌啶_丨_基}甲基哌啶羧酸乙酯； 4-{4一[6-氟-3-(羥基曱基）一3_甲基_2_側氧基_2, 3_二 氣-1H-。引嗓-1-基]哌啶_丨_基}哌啶_丨_羧酸乙酯； 4-{4-[6-氟-3-(羥基甲基）—3一甲基_2一侧氧基一2, 3-二 氮-1H-叫丨嗓-卜基]哌啶_丨—基丨氮雜環庚烷_丨_羧酸乙 酯； 4_{4-[3-(羥基甲基）一3, 6-二曱基-2-側氧基-2, 3-二氫 -1H-吲哚-1-基]哌啶_ι_基}哌啶_丨_羧酸乙酯； 4-{4-[3-(羥基曱基）-3, 6-二曱基-2-側氧基-2, 3-二氫 -1H-吲哚-1-基]哌啶-丨—基丨氮雜環庚烷-丨-羧酸乙酯； 4-{4-[3-(羥基曱基）-3-曱基-2-側氧基-2,3-二氫-1H-吲哚-1-基]哌啶-l-基}哌啶_丨_羧酸乙酯； (3-内）-3-{4-[6-氟-3(羥基.甲基）-3-曱基-2-側氧基 -2, 3-二氫-1H-吲哚-卜基]哌啶-1-基}-8-吖雙環 [3. 2.1]辛烷-8-羧酸乙酯； 17 323406 201211028 (3-内W4-[3(經基陽3, 6_二f基*侧氧基 ，3-二氫-1H—吲哚-1-基]哌啶-1-基}-8-吖雙環 [3.2. 1]辛燒-8-幾酸乙酯； 4 {4 [3-乙基-3-(經基甲基）_2_側氧基_2 3_二氯一ih_ °引°朵+基]娘咬-1-基丨哌啶-1-羧酸乙酯； 4-[4-(3-乙基-3,6-二 τ 基_2_側氧基_2 3_二氫—1H_吲 哚-1-基）哌啶-1-基]哌啶―丨―羧酸乙酯； 4-[4「(6-氟-2-側氧基_2,，3,，5’，6, _四氫螺[十朵 一3, 4 -哌喃]-i-(2H)-基）哌啶-基]甲基哌啶―卜羧酸 乙醋； 4-(4-(6-甲基-2-側氧基-2,，3,，5,，6,—四氫螺[巧哚 -3’ 4’ -哌喃]-1-(2H)-基）哌啶-丨—基]f基哌啶_丨_羧酸 乙酯； (3-内）-3-[4-(6- 曱基-2-侧氧基-2,，3,，5,，6,-四氫螺 [吲哚-3,4’-哌喃]-1-(21〇-基）哌啶-1_基]_8_吖雙環 [3.2.1] 辛烧-8-叛酸乙g旨； (3_ 外）-3-[4-(6-氟-2-側氧基-2,，3,，5,，6,-四氫螺 [吲哚-3, 4 -哌喃]-1-(2H)-基）旅咬_1_基]吖雙環 [3.2.1] 辛烧-8-叛酸乙醋； 4-[4-(3-經基-2-侧氧基-2, 3-二氫-in-吲哚_丨_基）0底 啶-1-基]哌啶-1-羧酸乙酯； 4-[4-(2-側氧基-2,3-二氫-111-吲哚-1-基）哌咬_1_基] 哌啶-1-羧酸丁酯-2-炔； 4-[4-(2-側氧基-2’3-二氫-111-吲哚-1-基）哌咬_1_基] 323406 18 201211028 哌啶-1-羧酸2-溴乙酯； 4-[4-(2-側氧基-2, 3-二氫-1H-吲哚-1-基）派咬-1-基] 哌啶-1-叛酸2-氣乙酯； 4-[4-(2-側氧基-2, 3-二氫基）旅咬-1-基] 哌啶-1-羧酸2-丙酯； 4-[4-(2-侧氧基-2, 3-二氫-1H-吲哚-1-基）哌啶-1-基] 派β定一1一致酸甲g旨；4_{[4-(6-oxime-2-yloxy-2,3-dihydro-1H-indol-1-yl) 唆-1-yl]methyl}0 辰. 4--1-reoxamate ethyl ester; 4-{[4-(6-methoxy-2-oxo-2',3',5',6'-tetrahydrospiro[〇引〇朵-3 , 4 _Brigade]-1(2Η)-yl)α-biting-1-yl]n-cyanate ethyl ester; 4-{[4_(6-methoxy-2-sideoxy-2', 3,,5,,6,-tetrahydrospiro[口引哚-3,4'-旅喃]-1(21〇-yl)-biti-1-yl]azepane_1_ 慢酸乙(1R, 5S)-3_[4-(6-methoxy-2-indolyl~2,3,5,6,-tetrahydrospiro[吲哚_3,4'-per ]]-1-(21〇-yl)~piperidin-1_yl]_8_〇丫bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester; 4-[ 4-(5_ gas-6- I -3, 3-dimercapto-2-yloxy- 2,3-dihydro-111-111 丨 1* _1 _ _ _ _ _ _ _ _ _ _ _ _ _乙酉的4- 4-[4-(3, 6-Dimercapto-2-yloxy-2,3-dihydro~jH-t»丨嗓丨嗓-1-yl) σσ定-1_基] Travel bite _ 1_ taco-B. vinegar; 4-[4-(3, 6-dimethyl-2-oxo-2,3-dihydro-. called 卜多+基) 派唆基]11辰 _1 _1 _1 323 323 323 323 323 323 323 323 323 323 323 323 323 323 323 323 323 323 323 323 323 323 323 323 323 323 323 323 323 323 323 323 323 323 323 323 323 323 323 323 323咬--1-yl]azepane-1 - decanoic acid; 4-[4-(5-fluoro-3-曱-2-Sideoxy-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]azepane-1-carboxylic acid ethyl ester; 4-{[4-( 5-fluoro-3-indolyl-2-yloxy-2,3-dihydro-1Η-°哚哚-1-yl)0 唆唆-1-yl] fluorenyl}乙酉; 4-{[4-(3-Mercapto-2-yloxy-2,3-dihydro-111-indol-1-yl)piperidin-1-yl]methyl}piperidine- 1-carboxylic acid ethyl ester; 4-[4-(5-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl)piperidinyl]azepane- 1-o-acid ethyl ester; 4-{[4-(5-mercapto-2-oxo-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]methyl Bottom bite-1-acidic ethyl ester; 4~{[4-(2-o-oxy-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl] fluorenyl} Ethyl piperidine-1-carboxylate; 4~[4-(6-fluoro-3-indolyl-2-oxo-2,3-dihydro-1H-indol-1-yl)0 bottom bite -1-yl] brigade-1-resin ethyl ester; 4-[4-(6-fluoro-3-indolyl-2-oxo-2,3-dihydro-1H-indole-1- Ethyl)piperidin-1-yl]azepanecarboxylate; 4-[4-(5-fluoro-2-oxo-2,3-dihydro-1H-inden-1-yl) Ethyl piperidin-1-yl]piperidine-1-carboxylate; 4-[4-(6-fluorenyl-2-oxo-2,3-dihydro-1H-inden-1-yl) Piper Methyl pyridine-1-yl]piperidine-1-carboxylate; 4~[4-(6-bromo-2-yloxy-2,3-dihydro-1H-indol-1-yl)piperidine Ethyl-1-yl]piperidine-1-carboxylate; 323406 10 201211028 4-[4-(6-bromo-2-yloxy-2,3-dihydro-1H-indol-1-yl) Ethyl piperidin-1-yl]azetidin-1-carboxylate; 4-[4-(6-bromo-2-yloxy-2,3-dihydro-1H-indole-1- Ethyl piperidin-1-yl]piperidine-1-carboxylate; 4-[4-(6-ethyl-2-yloxy-2,3-dihydro-1H-indole-1- Ethyl piperidin-1-yl]piperidine-1-carboxylate; 4-[4-(6-ethyl-2-yloxy-2,3-diar-argon-1H-indole-1- Ethyl)-[4-(2-oxo-6-propyl-2,3-dihydro-1H-indole) Ethyl-1-yl)piperidin-1-yl]piperidine-1-carboxylate; 4-{[4-(5-chloro-2-oxo-2,3-dihydro-111-° bow)丨'1 _1-yl) 唆-1-yl)methyl}piperidine-1-carboxylic acid ethyl ester; (1R,5S)-3-[4-(5-chloro-2- oxooxy -2,3-Dihydro-1H-indol-1-yl)-piperidin-1-yl]-8-indole bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester; 4 {[ 4-(5-Iso-2-oxo-2,3-dihydro_1Η-σ3Ιπ-l-yl) brittle ~1-yl]methyl}piperidine-1-carboxylic acid ethyl ester; 1R , 5S)-3-[4-(5-fluoro-2-indolyl-2,3-dihydro-1Η-indol-1-yl)-pyran-1-yl]-8-indole bicyclo[ 3. 2. 1]octyl-8-acid ethyl ester; 4-[4-(6-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) brigade Bite ~1~yl]piperidin-1-carboxylic acid ethyl ester; 4_{[4-(6-fluorenyl-2-yloxy-2,3-dihydro-1H-indole-1-yl)0 Ethyl ester of ethyl-1-methyl]methyl}piperidine-1-carboxylate; 4~U4-(6-fluoro-2-oxo-2,3-diindole-indole-bamboo-buki &gt;Chen bite 323406 11 201211028 -1-yl]methyl}azepane-monocarboxylic acid ethyl ester; 4-[4-(6-fluoro-2-sidedoxy__2,3_dihydrogen 1-1H_mercapto)piperidin-1-yl]azetidin-indole-carboxylate; 4-[4-(5-fluoro-3,3-dimethyl-2-thiol) Ethyl 2-(3-dihydro-1H-indol-1-yl)piperidin-1-yl]piperidinecarboxylate; 4-[4-(6-decyloxy-2-yloxy- 2 , 3-dihydro-1H_吲哚_bu) piperidin-1-yl]-4-methylpiperidine-carboxylate; 4-[4-(6-fluoro-2-oxooxy Ethyl _2,3-dihydro-1H-indole-yl)piperidin-1-yl]-4-methylpiperidine-1 -carboxylate; 4-[4-(6-methyl- 2-sided oxy-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]-4-methylper Ethyl-1-carboxylate; 4-[4-(6-methoxy-3-methyl-2-oxo-2,3-dihydro-1Η-°bend-1-yl) Ethyl pyridine-1-yl]-4-methylpiperidine-1-carboxylate; (3-inter)-3-[4-(6-fluorenyl-2-oxo-2,3-dihydrol -1H-吲哚-buyl)piperidin-1-yl]-8-indole bicyclo[3.2. 1]octane-8-carboxylic acid acetamidine; (3-exo)-3-[4-(6- Mercapto-2-yloxy-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]-8-indole bicyclo[3.2. 1]octane-8-carboxylic acid B Ester; (3-in)-3-[4-(6-fluoro-2-indolyl-2,3-dihydro-1Η-σ丨丨n-1-yl)piperidin-1-yl] -8-indole bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester; (3-exo)-3-[4-(6-fluoro-2-oxo-2,3-dihydrol -1H-indol-1-yl)piperidin-1-yl]-8-indole bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester; (3-in)-3-[4- (2-Sideoxy-2,3-dihydro-1H-indol-1-yl)piper 12 323406 201211028 pyridine-1-yl]-8-indole bicyclo[3. 2. 1]octane-8- Ethyl carboxylate; (3-exo)-3-[4-(2-o-oxy-2, 3-di-l-i-D-D-l-yl)-pyridin-1-yl]-8-吖Bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester; (3-inter)-3-[4-(3,6-dimethyl-2-sideoxy-2, 3-di Argon-1Η-° cited D-l-based ) α 咬 -1-yl]-8-α 丫 bicyclo [3. 2. 1] octyl-8-tetrate ethyl ester; (3-in) -3-[4-(6-fluoro-3- Methyl-2-oxo-2,3-dihydro-1Η-indol-1-ylpiperidin-1-yl]-8-indole bicyclo[3.2.1]octane-8-carboxylate Acid® ethyl ester; (3-inter)-3-[4-(5-fluoro-3-methyl-2-oxo-2,3-dihydro-1Η-indol-1-yl)piperidine -1-yl]-8-indole bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester; 4-{4-[5-fluoro-2-o-oxo-3-(propane-2- Subunit)-2,3-dihydro-1-11-inden-1-yl]11 chen.定-1-基}派11定_1_Toxaic acid ethyl ester; 4-{4-[5-fluoro-2-oxo-oxy-3-(propan-2-yl)-2,3-dihydro- 1-Η- • °引一一1-基]piperidine-1-yl}azepane-1-carboxylic acid ethyl ester; 4-{4-[(3Ζ)-3-ethylene- 5-fluoro-2-oxo-2,3-dihydro-1 fluorene- ' °-1-yl]piperidine-1-yl}azepane-indole-carboxylate; 4-[ 4-(3-ethyl-5-fluoro-2-indolyl-2,3-dihydro-1Η-indol-1-yl) ketone-1-yl]β 唆-1-low acid B Vinegar; 4-{4-[(3Ζ)-5-fluoro-3-(2-methylpropylidene)-2-yloxy~2,3~dihydro-1Η-indol-1-yl] Piperidine-丨-yl} piperidine_丨_carboxylic acid ethyl acetate; 4~{4-[5-fluoro-3-(2-methylpropyl)- 2_sideoxy_23-dihydro-1Η_吲哚-1-yl]piperidin-1-ylpiperidinyl-indole-carboxylic acid ethyl ester; 323406 13 201211028 4-[4-(3-cyclopentyl-5-fluoro-2-sidedoxy-2 , 3-dihydro-1H-indol-1-yl)anthran-1-yl]piperidinecarboxylic acid ethyl ester; 4-{4-[(32)-5-fluoro-2-oxooxy-3 - propylene-2,3-dihydro-111- ° 引-1-yl] 娘 -1 _ _ 丨 丨 丨 丨 丨 丨 4- 4- 4- 4- 4- 4- 4- -fluoro-2-oxo-3-propyl-2,3-dihydro-1H-indol-1-yl) brigade-1-yl]piper Ethyl carboxylate; 4-{4-[5-fluoro-2-oxooxy-3_(tetrahydro-2H-pyran-4-yl)2,3-dihydro-1H-indol-1-yl Piperidine _ 丨 丨 丨 丨 啶 啶 _ ι ι 羧酸 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- -111- 吲哚-1-yl] piperidine-hydrazinyl-piperidine-ethyl carboxylate; 4-{4-[5-fluoro-3-(oxetan-3-yl)_2 _Sideoxy 2,3_dihydro-1H-indole-buyl] piperidine + yl} piperidine- carboxylic acid ethyl ester; 4_{4-[5-fluoro-2-sidedoxy_3_ (tetrahydrofuran_3_yl)_2 3_dihydro-1H-indol-1-yl] piperidine _ 丨 丨 丨 丨 啶 啶 羧酸 羧酸 羧酸 羧酸 羧酸 羧酸 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- —3-yl)-2,oxy-2,3-dihydro-1H-(tetra)-1-yl]-+ kebs small (10) vinegar; 4-{4-[3-(tetrahydro hydrazine) +yl)+fluoro-2-oxo-oxy-2,3-diaza-based succinyl-dibenzopyrene ethyl ester; heterocyclic butyl-(3-yl)-2-yloxy-2, 3-Diphos-1Hm-yl]piperidine-ι-yl}piperidine-1-carboxylic acid oxime ester; 4_[4_(3~ethyl'5~U-sideoxy-2,3-dihydro- IH-tdol + yl)piperidin-1-yl]piperidine oxime carboxylic acid ethyl ester; 4-[4-(3-cyclobutyl|fluorenyl-2-yloxy-23-dihydropropionate哚-1-yl)piperidin-1-yl]piperidine 丨 丨 carboxylate 323406 14 201211028 4-{4-[6-(methyl-2-Sideoxy-3-(propan-2-yl)-2,3-dihydro-1H-indol-1-yl]piperidine- Methyl l-piperidine-1-carboxylate; 4-{4-[5-fluoro-2-oxo-3-(propan-2-yl)-2,3-dioxan-1H-indole Methyl 哚-1-yl] piperidine-l-yl}piperidine-1-carboxylate; 4_[4_(3_ethyl-5-•gas_2_sideoxy-2,3_diaza-1H) -0 π π _1 -yl)piperidin-1-yl]piperidine-1-carboxylic acid ethyl ester; 4-{4-[2-o-oxy-3-(propan-2-yl)- 2,3-dinitro-1Η-0-d-d-l-yl]piperidine-1-yl}piperidine-1-carboxylic acid ethyl ester; 4-[4-(3-cyclobutyl-2- side Ethoxy-2,3-diaza-1Η-α-derived D-l-yl)piperidin-1-yl]piperidine-1-carboxylic acid ethyl ester; 4-[4-(3-cyclopentyl- Ethyl 2-oxo-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]piperidine-1-carboxylate; 4-[4-(2-trioxy) Ethyl 3-propyl-2,3-dihydro-1H-indol-1-ylpiperidin-1-yl]piperidine-1-carboxylate; 4-{4-[2-o-oxyl -3_(tetrazine-2H-°Chenyl)_2,3_diaza-1 Η-π引π朵-1 -yl]π辰咬-1 -基}0底唆-1 - 叛酸乙酉; 4-{4-[2-Sideoxy-3-(pentan-3-yl)-2,3-di-argon-1Η-吲哚_1-yl]α辰 bit-1-yl}Niss - 1-{4-[2-Sideoxy-3-(tetra-argon-11-11-N--3-ylindenyl)-2,3-dihydro-111-吲哚-1- Ethyl]piperidin-1-yl}piperidine-1-carboxylate; 4-{4-[3-(cyclopropylindolyl)-2-yloxy-2,3-dihydro-1Η-吲哚_1_基]Bed bite_1_基}Brigade bite-1-some_acid B; 4-[4-(3-ethyl-2-yloxy-2,3-diaza-1Η - σ 丨 0 0 -1 -yl) σ 啶 -1- -1-yl] piperidine-1-carboxylic acid ethyl ester; 15 323406 201211028 4-[4-(3-ethyl-2- oxo-2 , 3-dihydro-1H-indol-1-yl)piperidin-1~yl]azetidene-1-carboxylic acid ethyl ester; 4_{4-[3-(1,3_曙β sits Ethyl-2-ylmethyl)-2-oxo-2,3-dihydro_1Η~吲哚-1-yl]piperidine-1-yl}piperidine-1-carboxylate; 4_{4 -[2-Sideoxy-3-(propan-2-yl)-2,3-dihydro-111-° 丨嗓1-1-yl]azepane-l-yl}piperidine- 1-carboxylic acid ethyl ester; 4-[4-(2-o-oxy-3-propyl-2,3-dihydro-1Η-indol-1-yl)piperidin-1-yl]azacyclocycle Ethyl heptane-1-carboxylate; 4-{4-[2-oxo-3-(tetrahydrofuran-3-yl)-2,3-dihydro-1Η-吲°-1-yl]piperidin Acryl-l-yl}azepane-i-carboxylic acid ethyl ester; 4-{4-[3-(heptan-4-yl)-2-sideoxy -2,3-dihydro-111-indole-buyl] piperidine-1-yl}azepane-1-carboxylic acid ethyl ester; 4-{4-[2- oxo-3- (tetrahydro-2H-piperazin-4-yl)-2,3-dihydro-1H-,indol-1-yl]piperidine-i-yl}azepane-indole-carboxylate; 4-{4-[2-Sideoxy-3-(pentan-3-yl)-2,3-dihydro-1H-indol-1-yl]piperidine-1-yl}azepine Ethyl-1-carboxylic acid ethyl ester; 4-{4-[2-o-oxy-3-(tetrahydrofuran-3-yl)-2,3-dihydro-1H-indol-1-yl]piperidine- L-yl}piperidin-1-carboxylic acid ethyl ester; 4-[4-(3-butyl-2-oxooxy-2,3-dihydro-1H-indol-1-yl) piperidine- 1-yl] travel bite-1-ethyl decanoate; 4-{4-[3-(furan-3-ylmethyl)-2-yloxy-2,3-dihydro-111-吲哚- Ethyl 1-piperidine-l-yl}piperidine-1-carboxylate; 4-{4-[3-(hydroxymethyl)-6-methoxy-3-methyl-2-oxide Benzyl-2,3-dihydro-1H-indol-1-yl]piperidine-bupyridinylpiperidine oxime carboxylic acid 323406 16 201211028 ester; [3-(hydroxymethyl)-3, 6 Dimethyl-2-one-oxy-2,3-dihydro-1H-indole-pyl]piperidine-ι-yl}piperidine-1-carboxylic acid ethyl ester; 4:{4-[5- Fluor-3-(hydroxymethyl)-3-methyl-2-one-oxy-2, 3_ Hydrogen-1H-吲哚_1-yl]piperidine-ι-yl}azepane-1-carboxylic acid ethyl ester; hydroxyindenyl)-3 monomethyl_2_sideoxy-23_2 Hydrogen-(7)-°-bend-1-yl]-epi-1-yl-methylpiperidinylcarboxylate; 4-{4-[5-fluoro-3-(hydroxymethyl)-3- Base- 2_sideoxy-2,3-dichloro-1H-called 丨嗓-1-yl] piperidine_丨_yl}methylpiperidinecarboxylate; 4-{4-[6-fluoro -3-(hydroxyindenyl)-3-methyl_2_sideoxy-2, 3_diox-1H-. 4-(4-[6-fluoro-3-(hydroxymethyl)-3-methyl-2-one Oxyl-2,3-diaza-1H-called oxime-buki]piperidine oxime-azetidine azepane-oxime-carboxylate; 4_{4-[3-(hydroxymethyl) a 3,6-dimercapto-2-yloxy-2,3-dihydro-1H-indol-1-yl]piperidine-yl-yl}piperidinyl-indole-carboxylate; 4 -{4-[3-(Hydroxyfluorenyl)-3,6-dimercapto-2-yloxy-2,3-dihydro-1H-indol-1-yl]piperidine-indole-ylhydrazone Azacycloheptane-indole-carboxylate; 4-{4-[3-(hydroxyindenyl)-3-indolyl-2-yloxy-2,3-dihydro-1H-indole- 1-yl]piperidine-1-yl}piperidine-oxime-carboxylic acid ethyl ester; (3-inter)-3-{4-[6-fluoro-3(hydroxy.methyl)-3-indolyl- 2-sided oxy-2,3-dihydro-1H-indole-buyl]piperidin-1-yl}-8-indole bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester; 17 323406 201211028 (3-Inner W4-[3 (3,6-di-f-yl)-oxyl, 3-dihydro-1H-indol-1-yl]piperidin-1-yl}-8-indole bicyclic [3.2. 1] Xin-8-acid acid ethyl ester; 4 {4 [3-ethyl-3-(transmethyl)_2_sideoxy-2 3_dichloro-ih_ ° Nicotinus nitrile-1-ylpiperidine-1-carboxylic acid Ethyl ester; 4-[4-(3-ethyl-3,6-diτyl_2_sideoxy-2 3-dihydro-1H-indol-1-yl)piperidin-1-yl] Piperidine-indole-carboxylate; 4-[4"(6-fluoro-2-indolyl-2,3,5',6,_tetrahydrospiro[10-to-3,4-pipeper ]]-i-(2H)-yl) piperidinyl-methyl]methylpiperidine- carboxylic acid ethyl acetate; 4-(4-(6-methyl-2- oxo-2,,3,, 5,6,-tetrahydrospiro[巧哚-3' 4'-pyrano]-1-(2H)-yl)piperidine-indolyl]f-piperidinyl-indole-carboxylate; 3-)3-[4-(6-decyl-2-oxo-2,3,5,6,-tetrahydrospiro[吲哚-3,4'-pyran]- 1-(21〇-yl)piperidin-1_yl]_8_吖bicyclo[3.2.1] octyl-8-rebel acid g; (3_external)-3-[4-(6-fluoro- 2-sided oxy-2,,3,,5,,6,-tetrahydrospiro[吲哚-3,4-piperan]-1-(2H)-yl) brigade bite __yl] 吖 double ring [3.2.1] Xin Shao-8-Resorcinating Ethyl Acetate; 4-[4-(3-Cyano-2-epoxy-2,3-dihydro-in-吲哚_丨_yl)0 bottom Ethyl-1-yl]piperidine-1-carboxylate; 4-[4-(2-trioxy-2,3-dihydro-111-indol-1-yl)piperidinyl-1 Piperidine-1-carboxylic acid butyl ester-2-yne; 4-[4-(2-o-oxy-2'3-dihydro-111-fluoren-1-yl) piperidine_1_ Base] 323406 18 201211028 2-bromoethyl ester of piperidine-1-carboxylic acid; 4-[4-(2-trioxy-2,3-dihydro-1H-indol-1-yl) -yl]piperidin-1-resistole 2-oxoethyl ester; 4-[4-(2-o-oxy-2,3-dihydro) brigade-1-yl] piperidine-1-carboxylic acid 2-propyl ester; 4-[4-(2-o-oxy-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl] ; 4-[4-(2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌啶-1-基] 氮雜環庚烷-1-羧酸乙酯； 4-[4-(2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌啶-1-基] 鼠雜環庚烧-1-叛酸曱醋； 4-[4-(2-侧氧基-2, 3-二氫-1H-吲哚-1-基）哌啶-1-基] 氮雜環庚烷-1-羧酸丙酯-2-炔； 4-[4-(2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌啶-1-基] 氣雜環庚院-1-叛酸丁醋-2-基； 4-[4-(6 -氯-2-側氧基-2, 3-二氳π朵-1-基）派咬 一 1-基]哌啶-1-羧酸-2氟乙酯； 4~[4-(5-氣-2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌啶 —1-基]哌啶-1-羧酸2-丙酯； 4-[4-(5-氣-2-侧氧基-2, 3-二氫-1H-吲哚-1-基）旅咬 一 1-基]哌啶-1-羧酸丙-2烯酯； 4-[4-(5-氯-2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌啶 -1-基J哌啶-1-羧酸2-甲氧乙酯； 4~[4-(6-甲基-2-側氧基^-二氫-:^-吲哚一卜基^底 323406 19 201211028 咬-1-基]哌啶-1-羧酸丙_2_烯酯； 4_[4-(6-甲基—2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌 咬-1-基]哌啶-1 —羧酸2-氟乙酯； 4-[4-(5-氟-2-側氧基-2, 3-二氫-1H-吲哚-1-基）哌啶 一1 一基]哌啶-1-羧酸2-曱氧基乙酯； 4 [4-(5&quot;·氯-2-侧氧基-2, 3-二氫π朵-1-基）旅咬 -1-基]氮雜環庚院-1_缓酸曱酯； 4 [4 (3,3-二氟-2-侧氧基—2,3_二氩_111-°引'〇朵-1-基） °辰°定-1-基]哌啶_丨_羧酸乙酯； C1K’ 5S)~3-[4-(3, 3-二氟-2-側氧基-2, 3-二氫-1Η-吲 °朵~1-基）派啶-1-基]_8_吖雙環[3. 2. 1]辛烷-8-羧酸乙 醋； 4-[4-(3’3-二氟-2-侧氧基_2,3-二氫-111-吲哚-1-基） 〔定1基]氮雜j展庚燒一1一魏酸曱醋； UR，5S)-3-{4-[3-(羥基曱基）-6-曱氧基-3-甲基-2-側 氧基—2, 3-二氫-1H-吲哚-1-基]-哌啶-1-基}-8-吖雙環 [3.2. 1]辛烷-8_羧酸乙酯； 4 {4-[3-(羥基甲基）_6_曱氧基_3_甲基2_側氧基 2’ 3 一氫-if吲哚_丨_基]哌啶_丨_基丨氮雜環庚烷一卜 羧酸乙酯； ^ {4-[5-氟-3-(羥基曱基）一3_甲基_2_側氧基_2, 3_二 氫1Η弓卜木一基]旅咬-1-基卜辰咬_ι_叛酸乙酯； 4~[4&lt;6ϋ 側氧基-2’，3,，5,，6,-四氫螺[，哚 3’ 4哌喃μ卜（2Η)_基）哌啶_ι_基]氮雜環庚烷一羧 323406 20 201211028 酸乙酯， 4-[4-(6-氟-2-侧氧基-2’，3’，5’，6’ -四氫螺[吲哚 -3, 4’ 底喃]-1-(21〇-基）°辰淀-1-基]旅咬綾酸乙 酯； 4-[4-(3, 6-二曱基-2-侧氧基-2, 3-二氫-1H-吲哚-1-基） 旅咬_1_基]氮雜環庚烧_1_致酸乙醋； 4-[4-(6-氣-3-甲基_2-側氧基-2, 3-二氫-1Η-σ引 &lt;=&gt;朵-1- 基）哌啶-1-基]哌啶-1-羧酸乙酯； 4-[4-(6-氣-3-甲基-2-侧氧基-2, 3-二氫-1Η-°弓卜朵-1- 基）派咬-1-基]氮.雜壤庚烧—1—缓酸乙醋； 4-[4-(2-侧氧基-2, 3-二氫-1H-吲哚-1-基）哌啶一1_ 基]4-甲基氣雜環庚烧-丨-幾酸乙酯； 4-[4-(2-側氧基-2,3-二氫-1H-吲哚-1-基）哌啶-卜 基]-4-甲基哌啶-1-羧酸乙酯； 4-[4-(5-氟-2-侧氧基_2,3_二氫_1H-吲哚_卜基）哌啶 -1-基]-4-曱基哌啶-1一羧酸乙酯； 4 [4 (5甲基2-側氧基-2,3-二氫-lH-β引π朵一基）派 啶-1-基]-4-甲基哌啶—1一羧酸乙酯； 4一[4一（5一甲氧基'2一侧氧基-2,3-二氫-1ΗΚ卜基） 哌啶-1-基]-4-甲基哌啶_丨一羧酸乙酯； (lR，5S)-3-{4-[5-甲基_2_侧氧基_2,3_二氫_1Η_〇引哚 -卜基]-哌啶-1-基卜8—α丫雙環[3 2.丨]辛烷_8_羧酸乙 酯； (1R’5S)-3-{4-[5~ 曱氧基_2_側氧基一2,3一二氮_1H一吲 323406 21 201211028 1]辛烷-8-羧酸 °木 1_基]底咬丫雙環[3 2 乙酯； 4-[4-(3-羥基-3-甲基-2-側氧基一2, 3-二氫· -1-基）哌啶-1-基]-4-曱基哌啶一丨一羧酸乙酯； 4-[4-(3-羥基-3-甲基-2-侧氧基_2, 3_二氫._吲哚 1基）D辰咬-1-基]-4-甲基派咬一1 一叛酸曱酯；4-[4-(2-Sideoxy-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]azepane-1-carboxylic acid ethyl ester; 4- [4-(2-Sideoxy-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl] rat heterocyclic heptane-1-resine vinegar; 4-[4 -(2-o-oxy-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]azepane-1-carboxylic acid propyl-2-ene; 4- [4-(2-Sideoxy-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]cyclohexane Gengyuan-1-Resin Butyl-2-yl; 4-[4-(6-chloro-2-oxo-2,3-dioxazol-1-yl)-derived 1-yl]piperidine-1-carboxylic acid-2-fluoroethyl ester; 4 ~[4-(5-Gaxo-2-oxo-2,3-dihydro-1H-indol-1-yl)piperidine-1-yl]piperidine-1-carboxylic acid 2-propyl ester; 4-[4-(5-Gas-2-oxo-2,3-dihydro-1H-indol-1-yl) brigade 1-yl]piperidine-1-carboxylic acid prop-2-ene Ester; 4-[4-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl J piperidine-1-carboxylic acid 2- Methoxyethyl ester; 4~[4-(6-methyl-2-oxooxy^-dihydro-:^-吲哚一卜基^ bottom 323406 19 201211028 biting-1-yl] piperidine-1- Propyl-2-enyl carboxylate; 4_[4-(6-methyl-2-o-oxy-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl] Pyridin-1 - 2-fluoroethyl carboxylate; 4-[4-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl)piperidine-1-yl Piperidine-1-carboxylic acid 2-methoxyethyl ester; 4 [4-(5&quot;·Chloro-2-oxo-2,3-dihydroπ-l-yl) brigade bite-1- Aziridine-1 - oxalate; 4 [4 (3,3-difluoro-2-oxo- 2,3_di-argon_111-° 引'〇朵-1-yl ° ° ° de-1-yl] piperidine _ 丨 carboxylic acid ethyl ester; C1K ' 5S) ~ 3- [4- (3, 3-difluoro-2- oxo-2, 3-dihydro -1Η-吲°朵~1-yl)pyridin-1-yl]_8_吖bicyclo[3.2.1]octane-8-carboxylic acid ethyl acetate; 4-[4-(3'3-two Fluor-2-oxo-oxy-2,3-dihydro-111-indol-1-yl) [1] aza j-g-g-g- 1-W-wine vinegar; UR, 5S)-3- {4-[3-(Hydroxyindolyl)-6-methoxy-3-methyl-2-oxo- 2,3-dihydro-1H-indol-1-yl]-piperidine-1 -yl}-8-fluorene bicyclo [3.2. 1] octane-8-carboxylic acid ethyl ester; 4 {4-[3-(hydroxymethyl)_6_decyloxy_3_methyl 2_sideoxy 2' 3 -hydrogen-if吲哚_丨_yl] piperidine_丨_ylindole azepane-carboxylate; ^ {4-[5-fluoro-3-(hydroxyindenyl)- 3_methyl_2_sideoxy-2, 3_dihydrogen 1Η bow ]Brigade bite-1-kibchen bite_ι_oleic acid ethyl ester; 4~[4&lt;6ϋ side oxy-2',3,,5,6,-tetrahydrospiro[,哚3' 4 piperazine Μμ卜(2Η)_yl) piperidine_ι_yl]azepane-carboxyl 323406 20 201211028 ethyl acrylate, 4-[4-(6-fluoro-2- oxo-2',3 ',5',6'-tetrahydrospiro[吲哚-3, 4' base]-1-(21〇-yl) ° Chendian-1-yl] travel bite ethyl citrate; 4-[4 -(3,6-dimercapto-2-yloxy-2,3-dihydro-1H-indol-1-yl) brigade _1_yl]azepane _1_acid B Vinegar; 4-[4-(6-gas-3-methyl_2-sideoxy-2,3-dihydro-1Η-σ) &lt;=&gt;tooth-1-yl)piperidin-1- Ethyl piperidine-1-carboxylate; 4-[4-(6-gas-3-methyl-2-oxo-2,3-dihydro-1Η-°bend-1-yl ))-------------------------------------------------------------------------------- 4-[4-(2-Sideoxy-2, 3-dihydro-1H-inden-1-yl) Piperidine-1-1-yl]4-methylcycloheptane-indole-acid acid ethyl ester; 4-[4-(2-o-oxy-2,3-dihydro-1H-inden-1-yl) Ethyl piperidine-buki]-4-methylpiperidine-1-carboxylate; 4-[4-(5-fluoro-2-sided oxy-2,3-dihydro-1H-indole _ Piperidin-1-yl]-4-mercaptopiperidine-1 monocarboxylic acid Ethyl ester; 4 [4 (5-methyl 2- oxo-2,3-dihydro-lH-β π π-)-pyridin-1-yl]-4-methylpiperidine-1carboxylate Ethyl acetate; 4-[4-(5-methoxy '2 side oxy-2,3-dihydro-1 oxime) piperidin-1-yl]-4-methylpiperidine 丨Ethyl carboxylate; (lR,5S)-3-{4-[5-methyl_2_sideoxy-2,3_dihydro_1Η_〇引哚-卜基]-piperidin-1- Keb 8-α丫bicyclo[3 2.丨]octane_8_carboxylic acid ethyl ester; (1R'5S)-3-{4-[5~ 曱oxy_2_sideoxy-2,3 Mononitro-1H-indole 323406 21 201211028 1]octane-8-carboxylic acid °1 1 base] bottom bite bicyclo[3 2 ethyl ester; 4-[4-(3-hydroxy-3-methyl- Ethyl 2-oxo- 2,3-dihydro-1-yl)piperidin-1-yl]-4-mercaptopiperidine monocarboxylate; 4-[4-(3-hydroxy- 3-methyl-2-oxooxy-2,3-dihydro._吲哚1yl)D-chen-1-yl]-4-methyl-derived 1- 1 retinoic acid ester; 4-[4-(3-氟-3-羥基甲基-2_侧氧基_2,3_二氫_1{1_吲哚 -1-基）派唆-1-基]-4-甲基娘咬+賴乙醋；及 4-[4-(3-氟-3-羥基甲基|側氧基_2, 3_二氫_ih-吲哚 -1-基）哌啶-1-基]-4-甲基哌啶一卜羧酸甲酯。 H -種中樞疾病預防及/或治療劑’其係含有申請專利範 圍第1項至第12項中任一項所述之化合物。 K如申請專利範圍帛12項所述之預防及/或治療劑，其 中，中樞疾病係阿茲海默症及/或精神***症。 -種醫藥組絲，其係含有㈣專·㈣丨項至第 2項令任項所述之化合物或其藥學上容許的鹽及藥 學上容許的载體。 μ 323406 22 201211028 四、指定代表圖： (一) 本案指定代表圖為：本案無圖式。 (二) 本代表圖之元件符號簡單說明：無。4-[4-(3-Fluoro-3-hydroxymethyl-2_sideoxy-2,3_dihydro_1{1_吲哚-1-yl)pyr-1-yl]-4- Methyl Ninjabita + Lai vinegar; and 4-[4-(3-fluoro-3-hydroxymethyl)-oxy 2,3-dihydro-ih-indol-1-ylpiperidine-1 Methyl 4-methylpiperidine monocarboxylate. The H-type central disease prevention and/or treatment agent is a compound according to any one of the items 1 to 12 of the patent application. K is the prophylactic and/or therapeutic agent described in claim 12, wherein the central disease is Alzheimer's disease and/or schizophrenia. A pharmaceutical composition comprising (4) a compound according to any one of the items (4) to (2), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. μ 323406 22 201211028 IV. Designated representative map: (1) The representative representative of the case is: There is no schema in this case. (2) A brief description of the symbol of the representative figure: None. 五、本案若有化學式時，請揭示最能顯示發明特徵的化學式：5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 3 3234063 323406
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