TW200846342A - Bicyclic aryl derivative - Google Patents

Abstract

The invention provides a novel compound, which exhibits S1P receptor agonist activity and is excellent as an immunosuppressive agent. In addition, the compound of this invention has few side effects and may be orally administrated. The S1P receptor agonist of the invention includes the compound set forth in the general formula (I), salts thereof, and solvates thereof as active ingredients. In the formula (I), n represents 1, 2, 3, or 4; R.sup.1 represents a hydrogen or C1-C6 alkyl group. R.sup.2 and R.sup.2a each independently represents a hydrogen atom or C1-C6 alkyl group, or R.sup.2 and R.sup.2a may combine together to form a methylene or ethylene group; Ar1 represents a bivalent group derived from naphthalene, 1H-indole, 1H-pyrrolopyridine or benzofuran. Ar.sup.2 represents a phenyl group that can be substituted, a thiophenyl group that can be substituted, or a 1H-pyrazolyl group that can be substituted.

Description

200846342 九、發明說明： 【發明所屬之技術領域】 本發明係關於一種具有神經胺醇-丨_磷酸受體激動劑活 性，可用作免疫抑制劑之二環性芳基衍生物化合物及含有 該專之醫樂。 【先前技術】 .神經胺醇-1-磷酸（以下，簡稱為811>)之受體，屬於作為 G 蛋白偶聯型受體之 Endothelial Differentiation Gene (EDG，内皮細胞分化基因）族，包括sipl、S1p2、S1P3、 S1P4及S1P5之5種亞型，分別稱為edG-1、EDG_5、EDG-3、EDG-6及EDG-8 〇 已知具有神經胺醇類似結構之FTY72〇[2-胺基-2-[2-(4-辛基苯基）乙基]-1，3-丙二醇鹽酸鹽]具有免疫抑制作用（專 利文獻1)。業者認為FTY720係在in vitro(體外）並不顯示抑 制IL-2等細胞激素產生之作用，而藉由不同於既存免疫抑 _ 制劑FK506或環孢黴素之作用機制而顯示免疫抑制作用。 最近’業者瞭解到FTY720係藉由在生物體内磷酸化而作 為S1P受體激動劑發揮作用，誘導血中之淋巴球減少作 用’從而顯不免疫抑制作用（非專利文獻丨）。fTY72〇係以 内臟器官移植之排斥反應及多發性硬化症作為對象而進行 - 臨床試驗，但有報告指出會引起心搏徐緩之副作用（非專 利文獻2)。因此，業者期望開發一種克服該問題點，且顯 示較南效果之新型免疫抑制劑。 又，揭示有具有S1P1 (EDG-1)受體激動劑作用之(苄 121200.doc 200846342 基甲基）吖丁啶-3-羧酸衍生物、N-(苯幷呋喃基甲基）胺基 丙酸衍生物’及具有SlP4(EDG-6)受體結合能之喷嗓基 甲基）胺基丙酸衍生物可表現免疫抑制作用（專利文獻 2〜4) ’但業者期望一種發揮優異之效果，副作用較少，可 進行經口投與，且作用之持續性優異之新穎低分子slp受 體激動劑化合物。 [專利文獻1]國際公開第94/008943號手冊 • [專利文獻2]國際公開第2003/062252號手冊 [專利文獻3]國際公開第20〇5/00〇833號手冊 [專利文獻4]國際公開第2005/020882號手冊 [非專利文獻 1] Science, 296，346-349 (2002) [非專利文獻 2] Journal of the American Society of Nephrology，13(4)，1073-1083 (2002) 【發明内容】 [發明所欲解決之問題] _ 本發明之目的在於提供一種具有Sip受體激動劑活性， 作為免疫抑制劑而發揮優異之效果，且副作用較少，可進 行經口投與之新穎化合物。 [解決問題之技術手段] 本案餐明者專人為解決上述課題進行積極研究之結果發 現，具有不同於先前化合物之二環性芳基結構的新穎化合 物’具有S1P受體激動劑活性，且於小鼠in viv〇(體内）模 型中，藉由經口投與而使小鼠末梢血中之淋巴球數持續減 > ’可用作心搏徐緩等副作用較少之免疫抑制劑，從而完 121200.doc 200846342 成本發明。200846342 IX. Description of the Invention: [Technical Field] The present invention relates to a bicyclic aryl derivative compound having a neuroamine-quinone-phosphate receptor agonist activity and useful as an immunosuppressive agent and containing the same Special medical music. [Prior Art] Receptors of ceramide-1-phosphate (hereinafter abbreviated as 811) belong to the Endothelial Differentiation Gene (EDG) family of G protein-coupled receptors, including sipl, Five subtypes of S1p2, S1P3, S1P4, and S1P5, respectively, are called edG-1, EDG_5, EDG-3, EDG-6, and EDG-8. FTY72〇[2-amino group, which is known to have a neuroamine-like structure. -2-[2-(4-octylphenyl)ethyl]-1,3-propanediol hydrochloride] has an immunosuppressive action (Patent Document 1). The FANT720 system is not considered to inhibit the production of cytokines such as IL-2 in vitro (in vitro), but exhibits immunosuppressive action by a mechanism different from that of the existing immunosuppressive agent FK506 or cyclosporine. Recently, the industry has learned that FTY720 functions as an S1P receptor agonist by phosphorylation in vivo, and induces lymphopenia in blood, thereby showing no immunosuppressive action (Non-patent document). The fTY72 tether is used for the rejection of multiple organ transplantation and multiple sclerosis - clinical trials, but there are reports of side effects that cause bradycardia (Non-patent literature 2). Therefore, the industry is looking to develop a novel immunosuppressant that overcomes this problem and shows a more souther effect. Further, it is disclosed that a benzylidene 121200.doc 200846342-based methyl azetidin-3-carboxylic acid derivative having an S1P1 (EDG-1) receptor agonist function, N-(benzofuranylmethyl)amino group The propionic acid derivative 'and the succinylmethyl) aminopropionic acid derivative having the S1P4 (EDG-6) receptor binding energy can exhibit an immunosuppressive action (Patent Documents 2 to 4) 'But the manufacturer expects an excellent one. The effect is that the novel low-molecular slp receptor agonist compound which is administered orally and has excellent persistence is possible. [Patent Document 1] International Publication No. 94/008943 Handbook • [Patent Document 2] International Publication No. 2003/062252 Handbook [Patent Document 3] International Publication No. 20/5/833, 833 [Patent Document 4] International Publication No. 2005/020882 [Non-Patent Document 1] Science, 296, 346-349 (2002) [Non-Patent Document 2] Journal of the American Society of Nephrology, 13(4), 1073-1083 (2002) [Invention [Problem to be Solved by the Invention] _ The object of the present invention is to provide a novel compound which has an Sip receptor agonist activity and which is excellent as an immunosuppressive agent and has few side effects and can be orally administered. . [Technical means for solving the problem] The results of the active research conducted by the person in charge of the case to solve the above problems revealed that the novel compound having a bicyclic aryl structure different from the previous compound has S1P receptor agonist activity and is small. In the mouse in viv〇 (in vivo) model, the number of lymphocytes in the peripheral blood of mice is continuously reduced by oral administration. 'It can be used as an immunosuppressant with less side effects such as bradycardia. 121200.doc 200846342 Cost invention.

示之化合物 即，本發明係提供一種以下述通式（1)所表 其鹽或彼等之溶劑合物， [化1]The present invention provides a salt of the following formula (1) or a solvate thereof, [Chemical Formula 1]

[式中，[in the formula,

η表示1、2、3或4， R表不氫原子或C1〜C6烷基； 及Ra表示分別獨立為氫原子或（:丨〜以烷基，或者反2與 R亦可一體化而形成亞甲基或伸乙基；η represents 1, 2, 3 or 4, R represents no hydrogen atom or C1 to C6 alkyl group; and Ra represents independently hydrogen atom or (: 丨~ to alkyl group, or inverse 2 and R may be integrated to form Methylene or ethyl;

Ar1表示由萘、瓜吲哚、m_吡咯幷[2,3，吡啶、见吡咯 幷[3,2-b]吡啶、1H_吡咯幷[2,3_c]吼啶或苯幷呋喃衍生之2 知基（该等基團亦可分別獨立含有自i原子、羥基、氰 基、硝基、C1〜C6烷基、鹵代C1〜C6烷基、C3〜C6環烷 基、卣代C3〜C6環烷基、C1〜C6烷氧基及鹵代C1〜C6烷氧 基所組成族群中選擇之1〜3個基團作為取代基）；Ar1 represents 2 derived from naphthalene, melon, m_pyrrole [2,3, pyridine, pyrrolidinium [3,2-b]pyridine, 1H-pyrrole [2,3_c] acridine or benzofuran Known groups (these groups may also independently contain from i atom, hydroxyl group, cyano group, nitro group, C1~C6 alkyl group, halogenated C1~C6 alkyl group, C3~C6 cycloalkyl group, deuterated C3~C6 1 to 3 groups selected from the group consisting of a cycloalkyl group, a C1 to C6 alkoxy group and a halogenated C1 to C6 alkoxy group as a substituent);

Ar表示苯基、.吡啶基、呋喃基、噻吩基、吡咯基、噁唑 基、售嗅基、1H-吼唑基或1H-[1，2,4]***基[該等基團表 不亦可分別獨立含有自鹵原子、硝基、氰基、C1〜C6烷 基、鹵代C1〜C6烷基、C1〜C6烷氧基C1〜C6烷基、C3〜C6環 烧基、鹵代C3〜C6環烷基、（C3〜C6環烷基）甲基、C1〜C6烷 121200.doc 200846342 氧基、_代（：1〜C6烷氧基、C3〜C6環烷氧基、（C3〜C6環烷 基）甲氧基及苯基[該苯基亦可含有自鹵原子、氰基、碗 基、C1〜C6烷基、C3〜C6環烷基、i代C3〜C6環烷基、 (C3〜C6環烷基）甲基、（:卜以烷氧基、C3〜C6環烷氧基及 (C3〜C6環烷基）甲氧基所組成族群中選擇之1或2個基團作 為取代基]所組成族群中選擇之i〜3個基團作為取代基]]。 又，本發明係提供一種含有上述化合物、其鹽或彼等之 溶劑合物作為有效成分之醫藥；S1P受體激動劑；免疫抑 制劑；對於移植之排斥反應、自體免疫性疾病、及/或過 敏性疾病之治療劑及/或預防劑。 進而本舍明係*^供一種將上述化合物、其鹽或彼等之 心劑合物’與自免疫抑制劑、免疫抑制中所使用之抗體、 排斥反應治療藥、抗生素及類固醇藥中所選擇之丨種或2種 以上加以組合而成之醫藥。 又，本發明係提供一種上述化合物、其鹽或彼等之溶劑 合物用在醫藥製造之用途。 、進而，本發明係提供一種Slp受體參與之疾病之預防及/ 或治療方法，其特徵在於：投與上述化合物、其鹽或彼等 之溶劑合物之有效量。 [發明之功效] 本發明中所提供之二環性芳基衍生物、其鹽及彼等之溶 1 °物’具有S1M體激動劑活性，又，於小鼠in vivo模 :中，藉由經口投與而使小鼠末梢血中之淋巴球數持續減 乂因此可用作為免疫抑制劑等醫藥之有效成分，例如可 121200.doc 200846342 ^ _哺㈣物’尤其是人體移植之排斥 免疫性疾症、、風& & ^ ^ 八 义 疾病之治療劑及/或預防劑之有效成 Λ 藉由、、二口投與而使小鼠末梢血中之淋巴球數 減少，故切盔-4 一 心為可經口投與該等醫藥。進而，該等醫藥係直 激_中所見之心搏徐緩等副作用較少者。 【實施方式】 以下’就本說明書中之取代基加以說明。 作為「齒原子」，可列舉氟原子、氣原子、漠 原子。 二 C6燒基」，表示碳數為卜6之直鏈狀或支鏈狀 飽和烴基，例如可列舉甲基、乙基、正丙基、異丙基、卜 乙基丙基、2,2-二甲基丙基、正丁基、異丁基、第三丁 基、正戊基及正己基等。 乍為鹵代C1〜C6烷基」，表示含有鹵原子作為取代基 之上述C1〜C6烷基，鹵原子之數既可為丨個亦可為]個以 上，2個以上之情形之各齒原子之種類既可相同，亦可不 同。例如’可列舉氯甲基、氣甲基、三氣甲基、三氣甲 基、2·氯乙基、2,2,2-三氟乙基、u，2，四氟乙基及五氟 乙基等。 作為「C1〜C6烧氧基」，表示碳數為卜6之直鍵狀或支鏈 狀烷氧基，例如可列舉曱氧基、乙氧基、正丙氧基、異丙 氧基、卜乙基丙氧基、2,2_二甲基丙氧基、正丁氧基、異 丁氧基、第三丁氧基、正戊氧基及正己氧基等。 作為「C1〜C6烷氧基C1〜C6烷基」，表示含有C1〜C6烷氧 I21200.doc -10 - 200846342 基作為取代基之上述C1〜C6烧基。例如，可列舉甲氧基甲 基、乙氧基甲基、2-甲氧基乙基、2_乙氧基乙基等。 作為「鹵代C1〜C6烧氧基」，表示含有南原子作為取代 基之上述。〜以烧氧基’商原子之數既可為⑽亦可為2個 以上’ 2個以上之情形之各鹵原子之種類既可相同，亦可 例如，可列舉氟甲氧基、氯甲氧基、二氣甲氧基、 二氟甲氧基、三氯甲氧基、五氟乙氧基等。 作為「C3〜C6環烧基」，表示包含3〜6員之飽和煙環之基 團’例如可列舉環丙基、環丁基、環戊基及環己基。 作為「（C3〜C6環烧基）甲基」，表示含有上述c3〜c6環烧 基作為取代基之甲基，可列舉（環丙基）甲基、（環丁基）甲 基、（環戊基）甲基及（環己基）甲基。 作為「i代C3〜C6環烧基」，表示含有齒原子作為取代 基之上述C3〜C6環烷基，可列舉2_氟環丙基、2,2_二氟環 丙基、3-氟ί衣丁基、3,3-二氟環丁基、4_氟環己基及七‘二 II環己基。 作為「C3〜C6環烷氧基」，表示3〜6員之環烧氧基，例如 可列舉環丙氧基、環丁氧基、環戊氧基及環己氧基。 作為「（C3〜C6環烷基）甲氧基」，表示含有上述^以環 烷基作為取代基之曱氧基，可列舉（環丙基）甲氧基、（環丁 基）甲氧基、（環戊基）甲氧基及（環己基）曱氧基。 通式（I)中之η表示1、2、3或4，較好的。 通式⑴中之R1表示氫原子或C1〜C6烷基，較好的是氫原 子、甲基、乙基及第三丁基。 121200.doc -11- 200846342 二及R、示分別獨立為氫原子或。〜以烧基，或者作 亦可一體化而形成亞曱基或伸乙基。 較：的是、別獨立為氫原子、甲基或乙基，或 ^體化而形成亞甲基或伸乙基，更好的是R2及 句為，原子’或者進行一體化而形成亞甲基。 口 Μ表示由萘、1朵、各幷[2,3_bp比咬、1H4 u手[3’2 b]比啶、1H_吡咯幷[2,3_c]吡啶或苯幷呋喃衍生 • 之2價基(該等基團亦可分別獨立含有自齒原子、羥基、氰 基、硝基、C1〜C6烷基、®代〇1〜C6烷基、C3〜C6環烷 基、幽代C3〜C6環烷基、C1〜C6烷氧基及幽代C1〜C6烷氧 土所、、且成叔群中選擇之丨〜3個基團作為取代基）。Ar represents phenyl, pyridyl, furyl, thienyl, pyrrolyl, oxazolyl, succinyl, 1H-carbazolyl or 1H-[1,2,4]triazolyl [such groups] It may not be independently contained from a halogen atom, a nitro group, a cyano group, a C1 to C6 alkyl group, a halogenated C1 to C6 alkyl group, a C1 to C6 alkoxy group C1 to C6 alkyl group, a C3 to C6 cycloalkyl group, or a halogen. Generation C3~C6 cycloalkyl, (C3~C6 cycloalkyl)methyl, C1~C6 alkane 121200.doc 200846342 oxy, _ ((1~C6 alkoxy, C3~C6 cycloalkoxy, ( C3~C6 cycloalkyl)methoxy and phenyl [The phenyl group may also contain a halogen atom, a cyano group, a bowl base, a C1 to C6 alkyl group, a C3 to C6 cycloalkyl group, an i generation C3 to C6 cycloalkane. 1 or 2 of the group consisting of (C3~C6 cycloalkyl)methyl, (: alkoxy, C3~C6 cycloalkoxy and (C3~C6 cycloalkyl)methoxy) a group of i~3 groups selected as a substituent group as a substituent]]. The present invention provides a medicine containing the above compound, a salt thereof or a solvate thereof as an active ingredient; S1P receptor agonist; immunosuppressant; A therapeutic agent and/or a prophylactic agent for an autoimmune disease, and/or an allergic disease. Further, the present invention provides a compound or a salt thereof or a self-immunized compound. An inhibitor, an antibody used in immunosuppression, a therapeutic drug for rejection, a drug selected from an antibiotic or a steroid drug, or a combination of two or more thereof. Further, the present invention provides a compound, a salt thereof or The solvates thereof are used for the manufacture of medicines. Further, the present invention provides a method for preventing and/or treating a disease in which a SLP receptor is involved, which comprises administering the above compounds, salts thereof or the like. An effective amount of the solvate. [Effect of the invention] The bicyclic aryl derivative, the salt thereof and the same 1° of the present invention have S1M agonist activity, and, in mouse, Vivo model: In the middle, the number of lymphocytes in the peripheral blood of mice is continuously reduced by oral administration, so it can be used as an effective component of medicines such as immunosuppressive agents, for example, 121200.doc 200846342 ^ _ feeding (four) things especially Human transplantation The effective sputum of the therapeutic agent and/or prophylactic agent for immune disease, wind && ^ ^ VIII disease reduces the number of lymphocytes in the peripheral blood of mice by two-way administration. Therefore, the helmets are used for the purpose of administering such medicines. In addition, these medicines are less likely to have fewer side effects such as slow heartbeats. [Embodiment] The following are the substituents in this specification. The "atom atom" includes a fluorine atom, a gas atom, and a desert atom. The di-C6 alkyl group represents a linear or branched saturated hydrocarbon group having a carbon number of 6, and examples thereof include a methyl group and a Base, n-propyl, isopropyl, ethylidenepropyl, 2,2-dimethylpropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl.乍 is a halogenated C1 to C6 alkyl group, and the above-mentioned C1 to C6 alkyl group having a halogen atom as a substituent, and the number of halogen atoms may be one or more, and two or more teeth may be used. The types of atoms can be the same or different. For example, 'chlorinated methyl group, gas methyl group, tri-gas methyl group, tri-gas methyl group, 2·chloroethyl group, 2,2,2-trifluoroethyl group, u, 2, tetrafluoroethyl group and pentafluorocarbon Ethyl and the like. Examples of the "C1 to C6 alkoxy group" include a straight-chain or branched alkoxy group having a carbon number of 6, and examples thereof include a decyloxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, and a ethyl group. Propyloxy, 2,2-dimethylpropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentyloxy and n-hexyloxy. The "C1 to C6 alkoxy group C1 to C6 alkyl group" means the above C1 to C6 alkyl group having a C1 to C6 alkoxy group I21200.doc -10 - 200846342 as a substituent. For example, a methoxymethyl group, an ethoxymethyl group, a 2-methoxyethyl group, a 2-ethoxyethyl group, etc. may be mentioned. The "halogenated C1 to C6 alkoxy group" means that the above contains a south atom as a substituent. The number of the oxy-activator atoms may be (10) or two or more. In the case of two or more, the types of the halogen atoms may be the same, and examples thereof include a fluoromethoxy group and a chloromethoxy group. Base, dimethoxy methoxy, difluoromethoxy, trichloromethoxy, pentafluoroethoxy, and the like. The "C3 to C6 cycloalkyl group" means a group containing a saturated tobacco ring of 3 to 6 members, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group. The "(C3~C6 cycloalkyl)methyl group") means a methyl group containing the above c3 to c6 cycloalkyl group as a substituent, and examples thereof include (cyclopropyl)methyl group and (cyclobutyl)methyl group. Amyl)methyl and (cyclohexyl)methyl. The "i-C3 to C6 cycloalkyl group" means the above-mentioned C3 to C6 cycloalkyl group having a tooth atom as a substituent, and examples thereof include a 2-fluorocyclopropyl group, a 2,2-difluorocyclopropyl group, and a 3-fluoro group.衣 butyl, 3,3-difluorocyclobutyl, 4-fluorocyclohexyl and hepta-di-IIcyclohexyl. The "C3 to C6 cycloalkoxy group" represents a cycloalkyloxy group of 3 to 6 members, and examples thereof include a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, and a cyclohexyloxy group. The "(C3~C6 cycloalkyl)methoxy group" means an oxiranyl group containing the above cycloalkyl group as a substituent, and examples thereof include (cyclopropyl)methoxy group and (cyclobutyl)methoxy group. (cyclopentyl)methoxy and (cyclohexyl)decyloxy. η in the formula (I) represents 1, 2, 3 or 4, preferably. R1 in the formula (1) represents a hydrogen atom or a C1 to C6 alkyl group, preferably a hydrogen atom, a methyl group, an ethyl group and a tert-butyl group. 121200.doc -11- 200846342 Two and R, respectively, are independently hydrogen atoms or. ~ It can be formed into a mercapto group or an ethyl group by an alkyl group. Compared with: it is not a hydrogen atom, a methyl group or an ethyl group, or a methylene group or an ethyl group, and it is better that R2 and the sentence are, or the atom is 'integrated to form a sub. base. Oral Μ represents a divalent group derived from naphthalene, 1 , each 幷 [2, 3 bp ratio bite, 1H4 u hand [3'2 b] pyridine, 1H_pyrrole [2,3_c] pyridine or benzofuran (These groups may also independently contain a self-dentate atom, a hydroxyl group, a cyano group, a nitro group, a C1 to C6 alkyl group, a carboxylic acid 1 to C6 alkyl group, a C3 to C6 cycloalkyl group, a crypto C3 to C6 ring. The alkyl group, the C1 to C6 alkoxy group, and the oxime C1 to C6 alkoxylate are selected as the substituents selected from the group consisting of 丨~3 groups.

Ar2表示苯基、吡啶基、呋喃基、噻吩基、吡咯基、噁 土坐基1Η_σ比唑基或1H-[1，2,4]***基[該等基團 表不亦可分別獨立含有自鹵原子、硝基、氰基、。〜C6烷 基、鹵代C1〜C6烧基、C1〜C6烧氧基C1〜C6燒基、以〜㈤裒 肇 烷基、鹵代C3〜C6環烷基、（C3〜C6環烷基）甲基、以〜以烷 乳基、鹵代C1〜C6烷氧基、C3〜C6環烷氧基、（C3〜C6環烷 基）甲氧基及苯基[該苯基亦可含有自鹵原子、氰基、硝 基C1〜C6烷基、C3〜C6環烷基、自代C3〜(^環烷基、 (C3〜C6環烷基）f基、C1〜C6烷氧基、以〜以環烷氧基及 (C3〜C6環烷基）f氧基所組成族群中選擇之〗或2個基團作 為取代基]所組成族群中選擇之^3個基團作為取代基]。 作為Ar1之較好具體例，可列舉以下述式（n_a)〜⑴…所 表示之基團， 121200.doc -12- 200846342 [化2]Ar2 represents a phenyl group, a pyridyl group, a furyl group, a thienyl group, a pyrrolyl group, a sulphide group, or a 1H-[1,2,4]triazolyl group. From halogen atoms, nitro groups, cyano groups. ~C6 alkyl, halogenated C1~C6 alkyl, C1~C6 alkoxy C1~C6 alkyl, 〜(五) decyl, halogenated C3~C6 cycloalkyl, (C3~C6 cycloalkyl) a methyl group, an alkane group, a halogenated C1 to C6 alkoxy group, a C3 to C6 cycloalkoxy group, a (C3 to C6 cycloalkyl)methoxy group, and a phenyl group [the phenyl group may also contain a self-halogen Atom, cyano group, nitro C1~C6 alkyl group, C3~C6 cycloalkyl group, self-generation C3~(^cycloalkyl group, (C3~C6 cycloalkyl)f group, C1~C6 alkoxy group, with ~ a group selected from the group consisting of a cycloalkoxy group and a (C3~C6 cycloalkyl)foxy group or two groups as a substituent] is used as a substituent]. Preferable examples of Ar1 include a group represented by the following formula (n_a) to (1), and 121200.doc -12-200846342 [Chemical 2]

R3a、R3、、R3d R 、R、R3g、R3h、R3i、R3j、R3k 及R分別獨立表示氫肩4 占 虱原子、i原子、羥基、氰基、硝基、R3a, R3, R3d R , R, R3g, R3h, R3i, R3j, R3k and R each independently represent a hydrogen shoulder 4 occupies a ruthenium atom, an i atom, a hydroxyl group, a cyano group, a nitro group,

Cl C6烧基、齒代C1〜C6燒基、C3〜c6環烧基、函代 壞烧基、C1〜C6烧氧基或鹵代ci〜C6燒氧基； R a、H4b、及R4d分別獨立表示氫原子或(^〜以烷基]。Cl C6 alkyl, dentate C1~C6 alkyl, C3~c6 cycloalkyl, functional bad alkyl, C1~C6 alkoxy or halogenated ci~C6 alkoxy; R a, H4b, and R4d respectively Independently represents a hydrogen atom or (^~ to an alkyl group).

Arl更好的是該等之中以式（Π-a)、（Il-b)、（II-c)及（Il-f) 所表示之基團。Arl is more preferably a group represented by the formulae (Π-a), (Il-b), (II-c) and (Il-f).

Ar1 更好的是以下述式（n-a-l)、（II-b-1)、（11_〇1)及（n-f· 1)所表示之基團， [化3]Ar1 is more preferably a group represented by the following formulas (n-a-1), (II-b-1), (11_〇1), and (n-f·1), [Chemical 3]

121200.doc -13- 200846342121200.doc -13- 200846342

[式中，*表示與通式⑴中之氧原子之鍵結位置，*氺 表示與通式（I)中之亞甲基之鍵結位置；Wherein * represents a bonding position with an oxygen atom in the formula (1), and * 氺 represents a bonding position with a methylene group in the formula (I);

R3、0、W、^、妙、r3i分別獨立表示氫 原子、鹵原子、羥基、氰基、硝基、C1〜C6烷基、函代 C1〜C6烷基、C3〜C6環烷基、鹵代C3〜(^環烷基、以〜以烷 氧基或鹵代C1〜C6烷氧基； R a及化❹分別獨立表示氫原子或(：1〜(：6烷基]。Arl尤其好的 是以式（IIU)、（n-b-l)、（II-c-1)或（Π-f-l)所表示之基 團，R3a、R3、Rk、R3d、R3e、R3f、R3k及 r31 為氫原子， R及尺化分別獨立為氫原子或甲基者。 作為Ar之較好具體例，可列舉以下述式（IH-a)〜(Ill-i)所表 不之基團， [化4]R3, 0, W, ^, m, and r3i each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group, a C1 to C6 alkyl group, a C1 to C6 alkyl group, a C3 to C6 cycloalkyl group, and a halogen. Generation C3~(^cycloalkyl, ～~alkoxy or halogenated C1~C6 alkoxy; R a and hydrazine respectively represent a hydrogen atom or (:1~(:6 alkyl). Arl is particularly good. Is a group represented by the formula (IIU), (nbl), (II-c-1) or (Π-fl), and R3a, R3, Rk, R3d, R3e, R3f, R3k and r31 are a hydrogen atom. R and the sizing are each independently a hydrogen atom or a methyl group. Preferred examples of Ar include a group represented by the following formulas (IH-a) to (Ill-i), and [Chem. 4]

200846342 ,7b200846342, 7b

R5a、R5b、R5c、RW、R5e、R5f、R5g、R5h、R5i、R5j、 R5k、R51、R5m、R5n、r5o、R5p R5q、R5r、r5s R5t、r5u [式中， 及r5v分別獨立表示氫原子、鹵原子、硝基、氰基、C1〜C6R5a, R5b, R5c, RW, R5e, R5f, R5g, R5h, R5i, R5j, R5k, R51, R5m, R5n, r5o, R5p R5q, R5r, r5s R5t, r5u [wherein, and r5v each independently represent a hydrogen atom , halogen atom, nitro, cyano group, C1~C6

烧基、鹵代Cl〜C6烷基、ci〜C6烷氧基Cl〜C6烷基、C3〜C6 環烧基、鹵代C3〜C6環烷基、（C3〜C6環烷基）甲基、C1〜C6 燒氧基、#代(：1〜C6烷氧基、C3〜C6環烷氧基、（C3〜C6環 烧基）曱氧基或苯基[該苯基亦可含有自鹵原子、氰基、硝 基 C1〜C6烧基、C3〜C6i^烧基、_代〇3〜C6環烧基、 (C3〜C6環统基）甲基、C1〜C6烧氧基、C3〜C6環烧氧基及 (C3〜C6環烷基）曱氧基所組成族群中選擇之1或2個基團作 為取代基]; R6表示氫原子或C1〜C6烷基； R7a& R7b分別獨立表示C1〜C6烷基、鹵代C1〜C6烷基、 C1〜C6烷氧基C1〜C6烷基、C3〜C6環烷基、鹵代C3〜C6環燒 基、（C3〜C6環烷基）曱基或苯基[該苯基亦可含有自鹵原 子、氰基、硝基、C1〜C6烷基、C3〜C6環烷基、鹵代 C3〜C6環烷基、（C3〜C6環烷基）甲基、（：1〜€6烷氧基、 C3〜C6環烷氧基及（C3〜C6環烷基）甲氧基所組成族群中選 擇之1或2個基團作為取代基]]。 121200.doc -15- 200846342 :二好的是以下述式叫(IV_d)所表示之基團An alkyl group, a halogenated Cl~C6 alkyl group, a ci~C6 alkoxy group C~C6 alkyl group, a C3~C6 cycloalkyl group, a halogenated C3~C6 cycloalkyl group, a (C3~C6 cycloalkyl)methyl group, C1-C6 alkoxy, #代(:1~C6 alkoxy, C3~C6 cycloalkoxy, (C3~C6 cycloalkyl) alkoxy or phenyl [The phenyl group may also contain a halogen atom , cyano group, nitro C1~C6 alkyl group, C3~C6i^alkyl group, _ 〇3~C6 cycloalkyl group, (C3~C6 cycloalkyl) methyl group, C1~C6 alkoxy group, C3~C6 1 or 2 groups selected from the group consisting of a cyclic alkoxy group and a (C3~C6 cycloalkyl)methoxy group as a substituent]; R6 represents a hydrogen atom or a C1 to C6 alkyl group; and R7a& R7b are independently represented C1 to C6 alkyl, halogenated C1 to C6 alkyl, C1 to C6 alkoxy C1 to C6 alkyl, C3 to C6 cycloalkyl, halogenated C3 to C6 cycloalkyl, (C3 to C6 cycloalkyl) Mercapto or phenyl [The phenyl group may also contain a halogen atom, a cyano group, a nitro group, a C1 to C6 alkyl group, a C3 to C6 cycloalkyl group, a halogenated C3 to C6 cycloalkyl group, (C3 to C6 cycloalkane) a group selected from the group consisting of methyl, (1: to 6 alkoxy, C3 to C6 cycloalkoxy, and (C3 to C6 cycloalkyl) methoxy) 2 group as a substituent]] 121200.doc -15- 200846342:. Two based on the following formula called good (IV_d) a group represented by the

(IV—d) 8 2l、"R 8 d 8 e 、R及R8f分別獨立表示氫原子、鹵原子、硝基、 亂基、C1〜C6燒基、鹵代C1〜C6烧基、C1〜C6院氧基C1〜C6(IV-d) 8 2l, "R 8 d 8 e , R and R8f independently represent a hydrogen atom, a halogen atom, a nitro group, a chaotic group, a C1 to C6 alkyl group, a halogenated C1 to C6 alkyl group, C1~ C6 hospital oxygen C1~C6

烷基、C3〜C6環烷基、_代〇3〜C6環烷基、（C3〜C6環烷基） 甲基、C1〜C6烷氧基、鹵代ci〜C6烷氧基、C3〜C6環烷氧 基或（C3〜C6環烷基）甲氧基； R9a、R9b、R9。、R9d、R9e、R9f、R9g 及 R9h 分別獨立表示氫 原子、鹵原子、氰基、硝基、Cl〜C6烷基、C3〜C6環燒 基、鹵代C3〜C6環烷基、（C3〜C6環烷基）甲基、C1〜C6烷氧 基、C3〜C6環烷氧基或（C3〜C6環烷基）曱氧基]。Alkyl, C3~C6 cycloalkyl, _ 〇3~C6 cycloalkyl, (C3~C6 cycloalkyl) methyl, C1~C6 alkoxy, halogenated ci~C6 alkoxy, C3~C6 Cycloalkoxy or (C3~C6 cycloalkyl)methoxy; R9a, R9b, R9. And R9d, R9e, R9f, R9g and R9h each independently represent a hydrogen atom, a halogen atom, a cyano group, a nitro group, a Cl~C6 alkyl group, a C3~C6 cycloalkyl group, a halogenated C3~C6 cycloalkyl group, (C3~). C6 cycloalkyl)methyl, C1 to C6 alkoxy, C3 to C6 cycloalkoxy or (C3 to C6 cycloalkyl)decyloxy].

Ar2較好的是以式（IV_a)、（IV-b)、（IV_C)4 (IV_d)所表示 基團，且式（IV-a)、（IV-b)、（IV-c)及（IV-d)中之 R8a、Rw、 R及R分別獨立為自硝基、氰基、C1〜C6烧基、鹵代 Cl〜C6烧基及Cl〜C6烧氧基Cl〜C6烧基所組成族群中選擇 121200.doc -16- 200846342 之任一基團者。 及RH’更好的是分別獨立為自氰基、商 代C1〜C6烧基及CK6烧氧基ci〜c6烷基所組成族群中選 擇之任一基團，更好的是鹵代Cl〜C6烷基。 鹵代C1〜C6烷基之情形之鹵原子較好的是氟原子，尤其 好的是鹵代C1〜C6烷基為三氟甲基者。Ar2 is preferably a group represented by the formulae (IV_a), (IV-b), (IV_C)4 (IV_d), and the formulae (IV-a), (IV-b), (IV-c) and R8a, Rw, R and R in IV-d) are respectively composed of nitro, cyano, C1~C6 alkyl, halogenated Cl~C6 alkyl and Cl~C6 alkoxyCl~C6 alkyl. Select one of the groups 121200.doc -16- 200846342 in the group. And RH' is preferably any one selected from the group consisting of a cyano group, a quotient C1 to C6 alkyl group, and a CK6 alkoxy ci~c6 alkyl group, and more preferably a halogenated Cl~ C6 alkyl. The halogen atom in the case of a halogenated C1 to C6 alkyl group is preferably a fluorine atom, and particularly preferably a halogenated C1 to C6 alkyl group is a trifluoromethyl group.

式（IV-a)〜(IV-d)中之 R9a、R9b、r9c、R9d、R9e m 及R9h較好的是氫原子。 通式⑴中之Ri尤其好的是氫原子。 具體而言可列舉以 、其C1〜C6烷基酯、 下述式 彼等之 作為本發明之較好化合物， (V ^ (V·73)所表示之化合物 鹽或彼等之溶劑合物。 [化6]R9a, R9b, r9c, R9d, R9e m and R9h in the formulae (IV-a) to (IV-d) are preferably a hydrogen atom. Particularly preferred in the formula (1) is a hydrogen atom. Specific examples thereof include the C1 to C6 alkyl esters and the following formulas, which are preferred compounds of the present invention, and the compound salts represented by (V^(V.73)) or the solvates thereof. [Chemical 6]

(V — 2)(V — 2)

121200.doc -17 · 200846342121200.doc -17 · 200846342

co2hCo2h

[化7][Chemistry 7]

C02HC02H

)X5X^C¥)X5X^C¥

(V — 1 5)(V — 1 5)

121200.doc -18 - 200846342121200.doc -18 - 200846342

[化8][化8]

(V—2 7)(V—2 7)

121200.doc -19- 200S46342121200.doc -19- 200S46342

(V-4〇) [/lb l〇](V-4〇) [/lb l〇]

1212〇〇.d〇c -20 2008463421212〇〇.d〇c -20 200846342

[化 11][化11]

co2h 121200.doc -21 200846342Co2h 121200.doc -21 200846342

C02H (V — 5 5) (V— 5 6)C02H (V — 5 5) (V— 5 6)

ir' co2hIr' co2h

(V — 5 8) (V—5 7)(V — 5 8) (V—5 7)

(V— 6 1)(V-6 1)

)聲)sound

Nv^ co2h (V — 6 0 )Nv^ co2h (V — 6 0 )

[化 12] 馨[化12] 馨

〜^cd2h (V- 6 3)~^cd2h (V- 6 3)

Ns^ C02HNs^ C02H

(V — 6 5) co2h(V — 6 5) co2h

121200.doc -22- 200846342121200.doc -22- 200846342

(V— 6 7 ) (ν - 6 9) (V— 7 1〉(V— 6 7 ) (ν - 6 9) (V—7 1>

(V — 6 δ)(V — 6 δ)

(V—7 2)(V-7 2)

(V 一 7 3)(V-7 3 3)

該等之中，尤其好的是式（V-1)〜（V-10)及（ν-73)之化合 物、C1〜C6烷基酯、彼等之鹽或彼等之溶劑合物。 本發明之以通式⑴所表示之化合物含有胺基等鹼性基團 之情形時，根據期望，可使用鹽酸、硫酸、燐酸等無機酸 或甲酸、醋酸、曱磺酸等有機酸，製成生理學上許可之 里。又，以通式（I)所表示之本發明化合物含有羧基等酸性 基=之情形時’通常可形成驗加成鹽。作為生理學上許可 之鹽，可為有機鹽類或無機鹽類之任一種，作為其較佳 例，例如可^ 與 土 2 牛、’氣、鈉鹽或者鉀鹽等鹼金屬鹽，鎂鹽瘙 者鈣鹽等綠+描人P ^ 類至屬鹽，銨鹽、三乙胺鹽、環己基胺蹿、 121200.doc -23 - 200846342 派嗪鹽、錢鹽、㈣鹽、N，N，·二f基乙 基葡糖胺鹽或三(經甲基)胺基甲燒鹽等。 N-甲 本發明之以通式⑴所表示之化合物、或其鹽，亦可作 游離體或者溶劑合物而存在。作為溶劑合物，若丄 可許可者’則無特別限定，具體而言可列舉水合物：：醇 以通式⑴所表示之本發明化合物中存在氮原^ h I日守’亦可成為N-氧化I#。兮望w 屬於本發明之範圍内 …谷劑合物及N•氧化體亦 又，以通式⑴所表示之本發明化合&、或其鹽中， 取代基之種類或組合，可存在順式體、反式體等幾❹構 體或d體、1體等光學異構體等各種異構體，但本發明之化 合物^特別限定之情形時，亦包含彼等所有立體異構體 及任思比率之該等立體異構體混合物。 本發明之化合物、其鹽或彼等之溶劑合物，亦可作為前 驅藥物存在。作為前驅藥物，例如可列舉以通式⑴所表示 之化合物之羧基被酯化或醯胺化之化合物等。 '以下’就以通式⑴所表示之化合物之製造方法加以敍 过其中製造方法並未限定於下述方法。 以通式（I)所表*之化合物及其製造中間體，可利用以下 所述之各種眾所周知之反應而製造。此時，有時於原料或 中間體之階段，藉由適當保護基而保護官，能基。作為上述 官能基，例如可列舉羥基、羧基、胺基、羰基等，保護基 之種類、暨彼等保護基之導入與去除之條件，例如可參考 揭示於protective Groups in 〇rganie Symhesis (T w Green 121200.doc -24- 200846342 and RG.Wuts，John Wiley & s〇ns，Inc，New Y〇rk，1991) 者。 本發明之化合物（I)，係例如可藉由下述[製造法1]或[製 造法2」而製造。 [化 13] [製造法1]Among these, particularly preferred are the compounds of the formulae (V-1) to (V-10) and (ν-73), the C1 to C6 alkyl esters, the salts thereof or the solvates thereof. In the case where the compound represented by the formula (1) contains a basic group such as an amine group, an inorganic acid such as hydrochloric acid, sulfuric acid or citric acid or an organic acid such as formic acid, acetic acid or hydrazine sulfonic acid can be used as desired. Physiologically licensed. Further, when the compound of the present invention represented by the formula (I) contains an acidic group such as a carboxyl group =, the addition salt can be usually formed. The physiologically acceptable salt may be any of an organic salt or an inorganic salt, and as a preferred example thereof, for example, an alkali metal salt such as a ox, a gas, a sodium salt or a potassium salt, or a magnesium salt may be used.瘙 钙 钙 钙 钙 钙 钙 钙 钙 钙 钙 钙 钙 钙 钙 钙 钙 钙 钙 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , a bis-f-ethylethyl glucosamine salt or a tris(methyl)aminomethyl carbamide salt or the like. N-A The compound represented by the formula (1) or a salt thereof of the present invention may be present as a free form or a solvate. The solvate is not particularly limited, and specific examples thereof include a hydrate: an alcohol is present in the compound of the present invention represented by the formula (1), and a nitrogen atom is present in the compound of the present invention. - Oxidation I#. The present invention is in the range of the present invention. The solvate and the N• oxidant may be present in the compound of the present invention represented by the formula (1), or a salt thereof, and the type or combination of the substituent may exist. a plurality of isomers such as a steroid or a trans-form, or an optical isomer such as a d-body or a mono-, etc., but in the case where the compound of the present invention is particularly limited, all stereoisomers thereof are also included. A mixture of such stereoisomers of the ratio. The compounds of the present invention, salts thereof or solvates thereof may also be present as prodrugs. The prodrug may, for example, be a compound obtained by esterifying or decylating a carboxyl group of a compound represented by the formula (1). The following description of the method for producing a compound represented by the formula (1) is not limited to the following method. The compound represented by the formula (I) and the intermediate thereof can be produced by various well-known reactions described below. At this time, at the stage of the raw material or the intermediate, the officer and the energy group are protected by an appropriate protecting group. Examples of the functional group include a hydroxyl group, a carboxyl group, an amine group, a carbonyl group, and the like. The types of the protecting group and the conditions for introduction and removal of the protecting groups can be found, for example, in Protective Groups in 〇rganie Symhesis (Tw Green). 121200.doc -24- 200846342 and RG.Wuts, John Wiley & s〇ns, Inc, New Y〇rk, 1991). The compound (I) of the present invention can be produced, for example, by the following [Production Method 1] or [Production Method 2". [Production 13] [Manufacturing Method 1]

⑴(1)

H0 — Ar1 - C02R1a (2)H0 — Ar1 - C02R1a (2)

⑸ [還原性 胺基化反應](5) [Reductive amination reaction]

C02R 1a ，(CHQ/Ar^0H (4)C02R 1a , (CHQ/Ar^0H (4)

(la)(la)

[式中’ R1 a表示低級烧基，W1表示經基或脫離基，η、 Ar1、Ar2、R2及1^表示與通式⑴相同者] 本發明之化合物（I)中之8旨衍生物（la)，可藉由如下方式 製造：於化合物（1)與苯酚衍生物（2)之醚化反應中製成化 合物（3)，繼而使化合物（3)還原而製成醇衍生物（4)後，藉 由氧化反應導入酸衍生物（5)，繼而進行與胺體（6)或其鹽 之還原性胺基化反應。又，羧酸衍生物（lb)可藉由將_衍 生物（la)進行驗或酸水解而製造。 上述酯衍生物（la)亦可藉由下述[製造法2]而製造。 121200.doc -25- 200846342 [化 14] [製造法2] A 2/ (CH2)[wherein R1 a represents a lower alkyl group, W1 represents a trans group or a leaving group, and η, Ar1, Ar2, R2 and 1^ represent the same as in the formula (1)] The derivative of the compound (I) of the present invention (la), which can be produced by subjecting the compound (3) to an etherification reaction of the compound (1) and the phenol derivative (2), followed by reduction of the compound (3) to produce an alcohol derivative (4). After that, the acid derivative (5) is introduced by an oxidation reaction, followed by a reductive amination reaction with the amine (6) or a salt thereof. Further, the carboxylic acid derivative (lb) can be produced by subjecting the derivative (la) to acid hydrolysis. The above ester derivative (la) can also be produced by the following [Production Method 2]. 121200.doc -25- 200846342 [Chemical Method 2] A 2/ (CH2)

Ar /OHAr / OH

Ar-(CH^-〇- ,ArL /W2 ⑷ ⑺ R2a R2 hn^^co2ru ⑹ 、2aAr-(CH^-〇- , ArL /W2 (4) (7) R2a R2 hn^^co2ru (6) , 2a

Ar (CH9)Ar (CH9)

ArAr

II

X09R (la) (式中’ W2表示脫離基，n、Ar1、Ar2、Rla、R2及R2a表示 與上述相同者） 酯衍生物（la)，可將上述醇衍生物（4)之羥基轉換為脫離 基W2而製成化合物（7)後，藉由與胺體（6)之求核取代反應 而製造。 其次，詳細說明[製造法1]及「製造法2」之各步驟。 [製造法1-1]中，說明利用[製造法丨]中所示之化合物（1) 與苯盼衍生物（2)之醚化反應製造化合物（3)的方法。 [化 15] [製造法1·1]X09R (la) (wherein W2 represents a leaving group, n, Ar1, Ar2, Rla, R2 and R2a represent the same as above) an ester derivative (la), which can convert the hydroxyl group of the above alcohol derivative (4) into After the compound (7) is produced by leaving the group W2, it is produced by a nuclear substitution reaction with the amine (6). Next, each step of [Manufacturing Method 1] and "Manufacturing Method 2" will be described in detail. In the [Production Method 1-1], a method of producing the compound (3) by the etherification reaction of the compound (1) and the phenanthrene derivative (2) shown in [Production Process] will be described. [Chem. 15] [Manufacturing Law 1·1]

Ar2〆(CH入I1 + HO*ArT -C02Ru-⑴ ⑵Ar2〆(CH into I1 + HO*ArT -C02Ru-(1) (2)

Ar 2/ (CH2),Ar 2/ (CH2),

V (3) co2r la 示與上 (式中，W1表示羥基或脫離基，n、Ar1、Ar2及RU表 述相同者） 121200.doc -26- 200846342 上述[製造法Ul]大致可分為下述兩種情況。 (1) w1為羥基之情形 产口物（3)，可藉由將醇衍生物（1)與苯酚衍生物（2)利用 =氮式^及膦化物進行處理（光延反應）之醚化反應而製 作為偶氮試劑，可列舉偶氮二羧酸二乙酯、偶氮二羧 '、丙8曰I，1’-(偶氮二羰基）二哌啶及1，1，·偶氮雙（Ν，Ν_ —甲^甲Sm胺）等。偶氮試劑之使用量，較好的是相對於 苯齡订生物（2)為等莫耳〜12倍莫耳之範圍。作為膦化物， 可列舉三苯基膦、二& 曰 一正丁基膦及三甲基膦等。膦化物之使 曰較子的疋相對於苯紛衍生物（2)為等莫耳〜1 ·3倍莫耳 之靶圍。作為溶劑，較好的是四氫呋喃、^***等醚系溶 乙腈等非質子性極性溶劑，甲苯、苯等煙系溶劑及二 氣甲燒*、1 2 -—备 7 Μ I» 一虱乙烷專函化烴系溶劑。作為反應溫度， 為η：〜溶料點之範圍’較好的是G〜啊之範圍。反應時 間通常為1〜24小時左右。 (2) W1為脫離基之情形 化合物（3)，亦可藉由於驗之存在下’將苯紛衍生物⑺ ==_料@基化而製造。作為化合物⑴之脫離 二原子、甲磺醯氧基、對甲苯磺醯氧基及 广等。作為鹼，可列舉氫氧化鈉、氫氧化鉀、氫 :化：專鹼金屬之氫氧化物’氫化鈉、氫化鉀等鹼金屬之 風b 2碳酸納、碳酸鉀、碳酸絶等驗金屬之碳酸鹽。鹼 之 $，較好的是相對於化合物⑴為等莫耳 之範圍。作為溶劑，可列舉N，N•二甲基曱醯胺、二= 121200.doc -27- 200846342 砜、N甲基吡咯烷酮、乙腈等非質子性極性溶劑，四氫呋 南:乙趟等喊系溶劑。作為反應溫度，為_2代〜溶劑彿 點之範圍’較好的是〇〜15〇。。之範圍。反應時間通常為 1〜48小時左右。 ' 化合物（1)為市售或者可藉由以下所示之方法而製造。 [化 16] [製造法1-1A]V (3) co2r la is shown above (wherein W1 represents a hydroxyl group or a leaving group, and n, Ar1, Ar2 and RU are the same) 121200.doc -26- 200846342 The above [manufacturing method Ul] can be roughly classified into the following Two situations. (1) When the w1 is a hydroxyl group, the product (3) can be treated by etherification of the alcohol derivative (1) with the phenol derivative (2) by using a nitrogen compound and a phosphonide (gloss reaction). The azo reagent can be exemplified by diethyl azodicarboxylate, azodicarboxylate, propylene-8,1'-(azodicarbonyl)dipiperidine, and 1,1, azobis. (Ν, Ν _ — A ^ A Sm amine) and so on. The amount of the azo reagent to be used is preferably in the range of from 0 to 12 moles relative to the benzene-based organism (2). Examples of the phosphonide include triphenylphosphine, di & 曰-n-butylphosphine, and trimethylphosphine. The phosphine of the hydrazine is compared to the benzoic acid derivative (2) which is a target range of equal molars ~1 · 3 times mole. The solvent is preferably an aprotic polar solvent such as tetrahydrofuran or ethyl ether such as acetonitrile, a flue-based solvent such as toluene or benzene, and a gas-fired product of a gas, a gas, and a gas. Specialized hydrocarbon solvents. As the reaction temperature, the range of η:~solute point is preferably a range of G~. The reaction time is usually about 1 to 24 hours. (2) When W1 is a leaving group Compound (3) can also be produced by the fact that the benzene derivative (7) ==_material is formed in the presence of the test. As the compound (1), it is detached from diatomic, methanesulfonyloxy, p-toluenesulfonyloxy and the like. Examples of the base include sodium hydroxide, potassium hydroxide, and hydrogen: a hydroxide of an alkali metal, an alkali metal such as sodium hydride or potassium hydride, b 2 sodium carbonate, potassium carbonate, and carbonic acid. salt. The base of the base is preferably in the range of equimolar relative to the compound (1). Examples of the solvent include N,N•dimethylamine, two=121200.doc -27-200846342 sulfone, N-methylpyrrolidone, acetonitrile and other aprotic polar solvents, and tetrahydrofuran: acetamidine Solvent. As the reaction temperature, the range of the _2 generation to the solvent point is preferably 〇 15 15 。. . The scope. The reaction time is usually about 1 to 48 hours. 'Compound (1) is commercially available or can be produced by the method shown below. [Chem. 16] [Manufacturing Law 1-1A]

Ar - (CH2)n —0H-^ Ar2一 (CHz)n —Wla (1 -1) (1-2) wla表示脫離基，η及Ar2表示Ar - (CH2)n -0H-^ Ar2 - (CHz)n - Wla (1 -1) (1-2) wla represents the leaving group, η and Ar2 represent

Ar2-(CH2)n^C〇2R3〇〇一_ (8) (式中，R3GG表示低級烷基 與上述相同者） 化口物（1)中，W1為經基之化合物（1·。可藉由使醋體⑻ 還原而製造。作為還原反應之參考文獻，可列舉實驗化學 講座（第四版，vg1.26.日本化學會編，丸4股份有限公司） 「有機合成週：+對稱合成·還原、.糖.標記化合物， P185〜P248」。 化合物⑴中，wl為脫離基之化合物（1_2)可藉由自醇體 (1-1) ’根據常法將羥基轉換為烷基磺醯氧基、芳基磺醯氧 基或函原子等脫離基W1、製造。作為轉換為脫離基之反 應之參考文獻，可列舉實驗化學講座（第四版，vol l9.曰 本化學會編，丸善股份有限公司）「有機合成1:烴齒化 物，P438〜P446及P465〜470」。 上述化合物（8)為市售或者可根據下述（a)〜⑴中列舉之方 121200.doc -28- 200846342 法而製造。 (a) Pierre，Μ·等人之方法（Tetrahedron Letters，1985, 26(33)，3947-3950·); (b) Illig，C.R·等人之方法（WO 99/40088號公報）； (c) Gattuso.M.等人之方法（Atti della Societa Peloritana di Science Fische，Matematiche Naturali，1968，14(4)，371-- 380.)； • (d) Matsuo, M·等人之方法（WO 91/19708號公報）； (e) Vicentini，C_B·等人之方法（Heterocycles，2000, 53(6)，1285-1292·); (f) Tensmeyer，L.G·等人之方法（j.〇rg.Chem，1966，31， 1878-1883·); (g) Padwa，Α·等人之方法（J.Org.chem·，1982，47，786-791.)； (h) Capuano，L·等人之方法（Liebigs Annalen der Chemie， φ 1985, 12, 2305-2312·); (1) Rafferty, M.F.等人之方法（j.Med.Chem.1982，25, 1204-1208.);及 (j) Wright，S_W·等人之方法（j.Org.Chem，1994, 59, 6095-6097.) 化合物（1)中之W1為氯原子、溴原子或碘原子之化合物 (1-3)亦可藉由下述方法製造。 [化 17] [製造法1-1B] 121200.doc -29- 200846342Ar2-(CH2)n^C〇2R3〇〇一_(8) (wherein R3GG represents the same as the lower alkyl group). In the hydration material (1), W1 is a trans group compound (1. It is produced by reducing the vinegar (8). As a reference for the reduction reaction, a lecture on experimental chemistry (fourth edition, vg1.26. edited by the Chemical Society of Japan, Maru 4 Co., Ltd.) "Organic Synthesis Week: + Symmetrical Synthesis" ·Reduction, saccharide. Labeling compound, P185~P248". In compound (1), the compound (1_2) whose wl is a leaving group can be converted into an alkyl sulfonate by a conventional method from the alcohol (1-1) ' The oxy group, the arylsulfonyloxy group or the functional atom can be produced by the cleavage group W1. As a reference for the reaction to be converted into a cleavage group, a lecture on experimental chemistry (fourth edition, vol l9. 曰本化学会编,丸善Co., Ltd.) "Organic Synthesis 1: Hydrocarbon Teeth, P438~P446 and P465~470". The above compound (8) is commercially available or can be listed according to the following (a) to (1). 121200.doc -28- 200846342 Manufactured by law. (a) Method by Pierre, Μ· et al. (Tetrahedron Letters, 1985, 26(33), 3947-395 0·); (b) Method of Illig, CR et al. (WO 99/40088); (c) Method of Gattuso.M. et al. (Atti della Societa Peloritana di Science Fische, Matematiche Naturali, 1968, 14 (4), 371-- 380.); • (d) Method of Matsuo, M. et al. (WO 91/19708); (e) Vicentini, C_B· et al. (Heterocycles, 2000, 53 ( 6), 1285-1292·); (f) Tensmeyer, LG et al. (j. 〇rg. Chem, 1966, 31, 1878-1883·); (g) Padwa, Α· et al. J. Org. Chem., 1982, 47, 786-791.); (h) Capuano, L. et al. (Liebigs Annalen der Chemie, φ 1985, 12, 2305-2312·); (1) Rafferty, MF et al. (j. Med. Chem. 1982, 25, 1204-1208.); and (j) Wright, S_W et al. (j. Org. Chem, 1994, 59, 6095-6097.) The compound (1-3) in which the W1 in the compound (1) is a chlorine atom, a bromine atom or an iodine atom can also be produced by the following method. [Chem. 17] [Manufacturing Law 1-1B] 121200.doc -29- 200846342

Ar2 — CH3--- Ar2 ——CH2-W3 (9) (1-3) (式中，w3表示氯原子、溴原子或碘原子，Ar2表示與上述 相同者） 化合物（1-3)，可進行於化合物（9)中使用氯、溴、硫醯 氣、N-溴代丁二醯亞胺、N_氯代丁二醯亞胺、冰碘代丁二 醯亞胺或次氣酸第三丁酯等i化試劑之鹵化反應而製造。 本i化反應亦可於光照射下或過苯甲酸等觸媒之存在下實 %。作馬鹵化反應之參考文獻，可列舉實驗化學講座（第 四版，ν〇1· 19.日本化學會編，丸善股份有限公司）「有機 合成I :烴· i化合物，Ρ427〜Ρ429」。 上述化合物（9)為市售或者可參考下述（k)〜(p)t文獻而 製造。 (k) Gupta，Α·Κ·專人之方法（Synlett·，2004，12， 2229·); (l) Casalnuovo，A.L·等人之方法aAm Chem S〇c l99〇, 112, 4324-4330.); (m) Schlosser，Μ·等人之方法（Eur j 〇rg cheni 2〇〇2, 2913-2920·); (n) Kotone，Α·等人之方法（日本專利特開昭51_〇93999號 公報）； (〇) Lyga，J.W·等人之方法（jounai 〇f heterocyclic Chemistry 1990，27(4)，9191-921.);及 121200.doc -30- 200846342 (p) Shridhar，D.R·等人之方法（Indian Journal of che mistry, Section B: Organic Chemistry Including Medicinal Chemistry 1983, 22B(12)，1187-1190,) [製造法1 -1 ]中所使用之化合物（2)為市售或者可藉由以 下所不之方法而製造。 (1) Ar1為萘環之化合物（2·ι) [化 18]Ar2 — CH3--- Ar2 —CH2-W3 (9) (1-3) (wherein w3 represents a chlorine atom, a bromine atom or an iodine atom, and Ar2 represents the same as above) Compound (1-3), For the compound (9), chlorine, bromine, sulfonium, N-bromosuccinimide, N-chlorobutanediimide, ice iodide butyric acid or third gas It is produced by halogenation reaction of a butyl ester or the like. The present reaction can also be carried out under light irradiation or in the presence of a catalyst such as perbenzoic acid. For reference to the halogenation reaction of horses, a lecture on experimental chemistry (fourth edition, ν〇1·19, edited by the Chemical Society of Japan, Maruzen Co., Ltd.) "Organic Synthesis I: Hydrocarbon·i Compound, Ρ427~Ρ429". The above compound (9) is commercially available or can be produced by referring to the following documents (k) to (p). (k) Gupta, Α·Κ·personal methods (Synlett·, 2004, 12, 2229·); (l) Casalnuovo, AL et al. method aAm Chem S〇c l99〇, 112, 4324-4330.) (m) Schlosser, Μ· et al. (Eur j 〇rg cheni 2〇〇2, 2913-2920·); (n) Kotone, Α· et al. (Japanese Patent Laid-Open No. 51_〇93999) No.); (〇) Lyga, JW et al. (jounai 〇f heterocyclic Chemistry 1990, 27(4), 9191-921.); and 121200.doc -30- 200846342 (p) Shridhar, DR·etc. The method (2) used in [Indian Journal of che mistry, Section B: Organic Chemistry Including Medicinal Chemistry 1983, 22B (12), 1187-1190,) [Production Method 1-1] is commercially available or can be used. It is manufactured by the following methods. (1) Ar1 is a naphthalene ring compound (2·ι) [Chem. 18]

(2-1} [式中’ R、R3b表示與通式⑴相同者，Rla表示盘上述相 同者] 化合物（2-1)為市售或者例如可藉由以〇, γ等人之方法(2-1) [wherein R and R3b represent the same as in the formula (1), and Rla represents the same as the above-mentioned disk] The compound (2-1) is commercially available or can be, for example, by the method of hydrazine, γ or the like.

aMed.Chem•顧，44, 2869 2878)或 _麵 t 等人之方 法（J.Med.Chem.2〇〇4,47 3518 3536)而製造。 (2) Afl為1H-吲哚環之化合物（2_2) [化 19]Manufactured by a method of AMed. Chem., 44, 2869 2878) or _face t et al. (J. Med. Chem. 2, 4, 3, 3,518,536). (2) Afl is a compound of 1H-anthracene ring (2_2) [Chem. 19]

(2-2) [式中，R3c、反3 d芬主一 示與上 述相同者] 、不與通式⑴相同者，表 之方 物（2 2)為市售或者例如可藉由—丽，d.等人 121200.doc -31 - 200846342 法（J. Med. Chem.2004, 47, 6270-6282·)、Bashford，K.E.等 人之方法（1.(31^111.8〇〇.，？61^111^&113.1.2002，1672-1687·)、Hiroya，Κ·等人之方法（J. Org. Chem.，2004，69, 1 126-113 6.)或 Ezuquerra, J.等人之方法（J. Org. Chem. 1996, 61，5804-5812·)而製造。 (3) Ar1為1H-吡咯幷[2,3-b]吡啶環之化合物（2-3) [化 20](2-2) [In the formula, R3c, anti-3f is the same as the above], and is not the same as the general formula (1), and the square (2 2) is commercially available or can be, for example, , d. et al. 121200.doc -31 - 200846342 Method (J. Med. Chem. 2004, 47, 6270-6282·), Bashford, KE et al. (1. (31^111.8〇〇.,?61 ^111^&113.1.2002,1672-1687·), Hiroya, Κ· et al. (J. Org. Chem., 2004, 69, 1 126-113 6.) or Ezuquerra, J. et al. Process (J. Org. Chem. 1996, 61, 5804-5812·). (3) Ar1 is a compound of 1H-pyrrole [2,3-b]pyridine ring (2-3) [Chem. 20]

[式中，R3e、R3f&R4b表示與通式（I)相同者，1^表示與上 述相同者] 化合物（2-3)’例如可藉由Molina，P.等人之方法（J. Org· Chem· 2003，68，489-499)或 Blench，Τ·等人之方法（WO 05/000849號公報）而製造。Wherein R3e, R3f&R4b represents the same as in the formula (I), and 1^ represents the same as above] The compound (2-3)' can be, for example, by the method of Molina, P. et al. (J. Org) • Chem. 2003, 68, 489-499) or Blench, Τ et al. (WO 05/000849).

(4) Ar1為1H-吼洛幷[3,2-b]吡唆環之化合物（2-4) [化 21](4) Ar1 is a compound of 1H-吼洛幷[3,2-b]pyridinium ring (2-4) [Chem. 21]

述相同者] [式中，R3g、R及R表示與通式（I)相同者，Rla表示與上 121200.doc -32- 200846342 化合物（2-4)例如可藉由適用Frydman，B.等人之方法（J. Org· Chem· 1968. 33(10)，3762-3766)而製造。 (5) Ar1為1H-吡咯幷[2,3-c]吡啶環之化合物（2-5) [化 22]In the formula, R3g, R and R represent the same as in the formula (I), and Rla is represented by the above 121200.doc-32-200846342 compound (2-4), for example, by applying Frydman, B., etc. Manufactured by the method of humans (J. Org Chem. 1968. 33(10), 3762-3766). (5) Ar1 is a compound of 1H-pyrrole [2,3-c]pyridine ring (2-5) [Chem. 22]

[式中，R3i、R3j&R4e表示與通式（I)相同者，1^表示與上 述相同者] 化合物（2-5)例如可藉由Frydman，B.等人之方法（J. Org. Chem. 1968· 33(10)，3762-3766)或 Jochen，G·等人之方法 (WO 04/075 891公報）而製造。 (6) Ar1為苯幷呋喃環之化合物（2-6) [化 23]Wherein R3i, R3j&R4e represents the same as in the formula (I), and 1^ represents the same as the above]. The compound (2-5) can be, for example, by the method of Frydman, B. et al. (J. Org. Manufactured by Chem. 1968, 33(10), 3762-3766) or by Jochen, G. et al. (WO 04/075 891). (6) Ar1 is a compound of benzofuran ring (2-6) [Chem. 23]

(2 - 6) 3k co2ru [式中，R3k&R31表示與通式（I)相同者，Rla表示與上述相 同者] 化合物（2-6)為市售或者例如可藉由Kolasa，T.等人之方 法（J. Med. Chem. 2000, 43, 690-705)、Lanitte，G·等人之方 &(Eur.J.Med.Chem.-Chem.Ther” 1986，21(5)，379-3 83.)、Ple，Ρ·Α·等人之方法（J. Med. Chem· 2004, 47，871- 121200.doc -33- 200846342 1986， 9， 749-751) 887)或 Arcadi，Α·等人之方法（Synthesis 而製造。 [製造法1]中所示之醇衍生物（4)可藉由下述方 [化 24] [製造法1-2](2 - 6) 3k co2ru [wherein R3k & R31 represents the same as in the formula (I), and Rla represents the same as above] The compound (2-6) is commercially available or may be, for example, by Kolasa, T., etc. Human Method (J. Med. Chem. 2000, 43, 690-705), Lanitte, G. et al. (Eur. J. Med. Chem.-Chem. Ther" 1986, 21(5), 379-3 83.), Ple, Ρ·Α· et al. (J. Med. Chem. 2004, 47, 871-121200.doc -33-200846342 1986, 9, 749-751) 887) or Arcadi, The method of Α· et al. (manufactured by Synthesis. The alcohol derivative (4) shown in [Production Method 1] can be obtained by the following method [Chemical Method 1-2]

Ar C0〆Ar C0〆

Ar (CH2) nD*Ar (CH2) nD*

Ar1Ar1

OH ⑶ ⑷OH (3) (4)

(式中，η、Ar1、Ar2及Rla表示與上述相 醇衍生物（4)可根據眾所周知之方法 合物（3)而製造。 同者） ’藉由還原上述化 作為參考文獻，可列舉實驗化學講座（第四版，v〇i26 曰本化學會編’丸善股份有限公司）「有機合成观：不對 稱合成·還原·糠·標記化合物，P185〜P248」。(In the formula, η, Ar1, Ar2 and Rla represent the same as the above-mentioned phase alcohol derivative (4), which can be produced according to the well-known method compound (3). The same) 'Reduced by the above-mentioned reduction as a reference, an experiment can be cited Chemical Lecture (Fourth Edition, v〇i26, Sakamoto Chemical Society, 'Maruzen Co., Ltd.) "Organic Synthesis: Asymmetric Synthesis, Reduction, 糠·Labeling Compound, P185~P248".

[製造法1]中所示之經衍生物（5)可藉由下述方法製造[化 25] [製造法1-3]The derivative (5) shown in [Production Method 1] can be produced by the following method [Chemical Formula 25] [Production Method 1-3]

Ar2/ (CH2)n^〇/Ar^〇H-^ Ar2〆(⑶人、〆々 0 CH0(4) (5) (式中，η、Ar1及Ar2表示與上述相同者） 醛衍生物（5)例如可藉由使用氧化錳使上述醇衍生物 氧化而製造。氧化錳之使用量，可列舉相對於醇衍生物（4) 為等莫耳〜20倍莫耳之範圍，較好的是等莫耳〜15倍莫耳 121200.doc -34- 200846342 之範圍。作為反應溶劑，較好的是甲苯、苯、己烷等烴系 溶劑，二***等醚系溶劑，氯仿、四氯化碳等鹵化烴系溶 劑。反應溫度，可於ot:〜溶劑沸點之範圍内實施，較好的 是室溫〜溶劑沸點之範圍。反應時間通常為4小時至48小時 左右。 又，醛衍生物（5)亦可藉由下述⑴〜(u)中所示之氧化方法 而製造。 (r) Swern氧化Ar2/(CH2)n^〇/Ar^〇H-^ Ar2〆((3)人,〆々0 CH0(4) (5) (wherein, η, Ar1 and Ar2 represent the same as above) aldehyde derivative ( 5) It can be produced, for example, by oxidizing the above alcohol derivative using manganese oxide. The amount of manganese oxide used is, for example, a range of from 20 to 20 moles per mole of the alcohol derivative (4). The range of the molars is less than 15 times the temperature of 121200.doc -34-200846342. As the reaction solvent, a hydrocarbon solvent such as toluene, benzene or hexane, an ether solvent such as diethyl ether, chloroform or carbon tetrachloride is preferred. The halogenated hydrocarbon solvent may be carried out at a temperature ranging from ot: to the boiling point of the solvent, preferably from room temperature to the boiling point of the solvent. The reaction time is usually from about 4 hours to about 48 hours. 5) It can also be produced by the oxidation method shown in the following (1) to (u). (r) Swern oxidation

Giordano，C·等人之方法，J. Org. Chem.1991，56(21)， 6114-6118 ; Konradi，A.W·等人之方法，J. Org. Chem， 1992, 57(1)，28-32 ; (s) 使用次氯酸-tempo(2,2,6,6-四甲基-1-派咬氧基，自由基） 之氧化Giordano, C. et al., J. Org. Chem. 1991, 56(21), 6114-6118; Konradi, AW et al., J. Org. Chem, 1992, 57(1), 28- 32 ; (s) Oxidation using hypochlorous acid-tempo (2,2,6,6-tetramethyl-1-pyraloxy, free radical)

Jurczak，J·等人之方法，Tetrahedron Letters，1993, 34(44)，7107-7110 ; ⑴使用DMSO-三聚氯化氰之氧化Jurczak, J. et al., Tetrahedron Letters, 1993, 34(44), 7107-7110; (1) Oxidation using DMSO-cyanuric chloride

De Luca，L·等人之方法，J· Org. Chem.2001，66(23)， 7907-7909 ; De Luca，L·等人之方法，Org. Letters，2001， 3(19)，3041-3043 ;及 (u)使用三氧化硫吡啶絡合物之氧化De Luca, L. et al., J. Org. Chem. 2001, 66(23), 7907-7909; De Luca, L. et al., Org. Letters, 2001, 3(19), 3041- 3043; and (u) oxidation of sulfur trioxide pyridine complex

Konradi，A.W·等人之方法，LOrg.Chem.1990，55(15)， 4506-4508 ; Takemoto，Y.等人之**;Chem.Pharm.Bull· 1991，39(9)，2425-2428 ° [製造法1]中所示之酯衍生物（la)可藉由下述方法製造。 121200.doc -35- 200846342 [化 26] [製造法1-4]Konradi, AW et al., LOrg. Chem. 1990, 55(15), 4506-4508; Takemoto, Y. et al.; Chem. Pharm. Bull. 1991, 39(9), 2425-2428 The ester derivative (la) shown in [Production Method 1] can be produced by the following method. 121200.doc -35- 200846342 [Manufacturing Law 1-4]

[還原性 胺基化反應] (la} (式中’ Wl表示羥基或脫離基，η、Ar1、Ar2及Rla、R2及 R2a表示與上述相同者）[Reductive amination reaction] (wherein ' Wl represents a hydroxyl group or a leaving group, and η, Ar1, Ar2 and Rla, R2 and R2a represent the same as above)

酉旨街生物（la)可藉由進行於還原劑之存在下處埋醛衍生 物（5)與市售或可藉由眾所周知之方法製造之胺體（6)或其 鹽類（例如’鹽酸鹽）的還原性胺基化反應而製造。作為本 反應中所使用之還原劑，較好的是三乙醯氧基氫化硼鈉、 或者氛基氯化爛鈉，作為參考文獻，可列舉Gordon，D.等 人之方去 ’（Bi〇〇rg· Med. Chem· Letters，1995，5(1)，47-50) 或 Kelley，J.L·等人之方法（J Med Chem 199〇, 33 ⑺，i9i〇_ 1914·)。 [製造法2]中所使用之化合物⑺可藉由下述方法製造。 [化 27] [製造法2-1]The 酉 街 street organism (la) can be immersed in the presence of a reducing agent to bury the aldehyde derivative (5) with an amine (6) or a salt thereof (for example, 'salt) which is commercially available or can be produced by a well-known method. Manufactured by a reductive amination reaction of an acid salt). As the reducing agent used in the reaction, sodium triethoxy hydride hydride or sodium chlorinated sodium chloride is preferred, and as a reference, Gordon, D. et al. 〇rg· Med. Chem. Letters, 1995, 5(1), 47-50) or Kelley, JL et al. (J Med Chem 199〇, 33 (7), i9i〇 _ 1914·). The compound (7) used in [Production Method 2] can be produced by the following method. [Chem. 27] [Manufacturing Law 2-1]

Ar 2〆 ,ArAr 2〆 , Ar

Ar 2/ (CH2) .Ar1 ⑺ ⑷ (式中n Ar、Ar2及W2表示與上述相同者） 化合物（7)可藉由將醇衍生物（4)之經基轉換為院基綠酿 氧基、♦基伽氧基或自素等麟基而製造。作為轉換為 121200.doc -36- 200846342 脫離基之反應之參考文獻，可列舉實驗化學講座（第四 版，ν〇1· 19·日本化學會編，丸善股份有限公司）「有機合 成I ·煙·齒化合物’ Ρ43 8〜Ρ446及Ρ465〜470」。 [製造法2]中所示之化合物（Ia)可藉由下述方法製造。 [化 28]Ar 2 / (CH 2 ) . Ar 1 (7) (4) (wherein n Ar, Ar 2 and W 2 represent the same as above) Compound (7) can be converted to a hospital-based green oxy group by converting the base of the alcohol derivative (4) ♦ 基 伽 氧基 或 or self-prime and other linings. As a reference for the conversion to 121200.doc -36- 200846342, the lecture on experimental chemistry can be cited as a lecture on experimental chemistry (fourth edition, ν〇1·19·Edited by the Chemical Society of Japan, Maruzen Co., Ltd.) "Organic Synthesis I·Smoke · Teeth compounds 'Ρ43 8~Ρ446 and Ρ465~470". The compound (Ia) shown in [Production Method 2] can be produced by the following method. [化 28]

[製造法2-2J[Manufacturing Method 2-2J

Ar^(CH2)_rAr^W2 (7) HNvn^C02r13 —_叫)Ar^(CH2)_rAr^W2 (7) HNvn^C02r13 —_called)

(la) (式中 ’ n、Ar1、Ar2、Rla、R2、w2 主一 Λ ，丄， 八 κ κ及臀表不與上述相同 者）(la) (wherein 'n, Ar1, Ar2, Rla, R2, w2 main one, 丄, eight κ κ and hip table are not the same as above)

化合物（la)可藉由於鹼之存在下，化合物（7)與市售或可 藉由水所周知之方法製造之胺體（6)或其鹽類（例如，鹽酸 鹽）之求核取代反應而製造。作為所使用之鹼，可列舉三 乙胺、二異丙基乙胺、N-甲基嗎啉、吡啶、4-(N，N-二甲 基胺基）吡啶等有機胺系鹼或碳酸鉀、碳酸铯等無機鹼。 2為鹼之使用量，可列舉相對於化合物（la)為1〜30當量之 乾=，較好的是1〜10當量之範圍。使用胺體（6)之鹽之情 形％，為中和其鹽，必須使用化學最論上等量以上之上述 鹼」乍為反應溶劑，較好的是二氯甲烷等鹵化烴系溶劑， 曱苯等烴系溶劑，四氫呋喃等醚系溶劑以及乙腈、N，N-二 I基甲ϋ胺等非質子性極性溶劑。作為反應溫度，HC〜 命J沸點之範圍，較好的是室溫〜8〇。〇之範圍。反應時間 121200.doc -37- 200846342 通常為1〜4 8小時左右。作為本反應之參考文獻，例如可列 舉 Zhao，H·等人之方法（Bioorg. Med· Chem· Lett. 2002, 12，3105-3109·)，Jiang，Χ· -H.等人之方法（Tetrahedr〇n， 2005，61，1281-1288·)，Nam，J·等人之方法（Tetrahedr〇n Lett· 2003，44，7727-7730)或 Hayashi，K.等人之方法（j.The compound (la) can be substituted by the nucleus of the amine (6) or its salt (for example, hydrochloride) which is commercially available or can be produced by a method known by water in the presence of a base. Manufactured by reaction. The base to be used may, for example, be an organic amine base such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine or 4-(N,N-dimethylamino)pyridine or potassium carbonate. An inorganic base such as cesium carbonate. The amount of use of the base is preferably from 1 to 30 equivalents based on the compound (la), and preferably from 1 to 10 equivalents. When the salt of the amine (6) is used, the salt is neutralized, and it is necessary to use the above-mentioned base, which is the most basic chemical amount, as the reaction solvent, preferably a halogenated hydrocarbon solvent such as dichloromethane. A hydrocarbon solvent such as benzene, an ether solvent such as tetrahydrofuran, or an aprotic polar solvent such as acetonitrile or N,N-dimethionamide. As the reaction temperature, the range of the boiling point of HC to J is preferably from room temperature to 8 Torr. The scope of 〇. The reaction time is 121200.doc -37- 200846342 usually about 1~4 8 hours. As a reference for the reaction, for example, the method of Zhao, H. et al. (Bioorg. Med. Chem. Lett. 2002, 12, 3105-3109·), Jiang, Χ·-H. et al. (Tetrahedr) 〇n, 2005, 61, 1281-1288·), Nam, J. et al. (Tetrahedr〇n Lett. 2003, 44, 7727-7730) or Hayashi, K. et al. (j.

Med. Chem.1989, 32, 289-297) 〇Med. Chem. 1989, 32, 289-297) 〇

以上，如[製造法1]〜[製造法2-2]所示而製造之本發明化 合物，可藉由眾所周知之方法，例如萃取、沈澱、分餾、 色層分析、分步結晶、再結晶等，進行離析、純化。 又，本發明化合物具有不對稱碳之情形時，存在光學異 構體。該等光學異構體，可藉由與適當之鹽進行再結晶之 分步結晶（鹽分離）或管柱色層分析等常法，而離析、純化 分別之異構體。 、如上所述，S1P受體激動劑可用作為免疫抑制劑。以通 式（I)所表示之本發明之化合物、其鹽及彼等之溶劑合物， 對於S1P受體（尤其是811>1受體）具有較強之激動劑作用， 因此可作為免疫抑制劑之有效成分，可作為對於哺乳動 物’尤其是人體移植之排斥反應，自體免疫性疾病，過敏 性疾病等之治療劑及/或預防劑之有效成分…本發明 之化：物、其鹽及彼等之溶劑合物係於小鼠in ν—模型 ::精由經口投與而使小鼠末梢血中之淋巴球數持續減 =口此可用作可經口投與之免疫抑制劑等醫藥之有效成 該等醫藥係其他Slp受體激動劑中所見之徐 緩4副作用較少者。 121200.doc -38- 200846342 此處，所謂對於移植之排斥反應，係表示移植肝臟、腎 臟、心臟、肺、小腸、皮膚、角膜、骨、胎兒組織、骨纖 細胞、造血幹細胞'末梢血幹細胞、濟帶血幹細胞、胰島 細胞、肝細胞、神經細胞、腸管上皮細胞等移植物後，3 個月以内引發之急性排斥反應及隨後引發之慢性排斥反 應，暨移植物抗宿主病。As described above, the compound of the present invention produced as shown in [Production Method 1] to [Production Method 2-2] can be subjected to a well-known method such as extraction, precipitation, fractionation, chromatography, fractional crystallization, recrystallization, and the like. , isolated and purified. Further, in the case where the compound of the present invention has an asymmetric carbon, an optical isomer exists. The optical isomers can be isolated and purified by a conventional method such as fractional crystallization (salt separation) or column chromatography using recrystallization from a suitable salt. As described above, S1P receptor agonists can be used as immunosuppressive agents. The compound of the present invention represented by the formula (I), a salt thereof and the solvates thereof have a strong agonist action on the S1P receptor (especially 811 > 1 receptor), and thus can be used as immunosuppressive The active ingredient of the agent can be used as an active ingredient for a therapeutic agent and/or a prophylactic agent for rejection of a mammal, particularly a human transplant, an autoimmune disease, an allergic disease, etc. And their solvates are in mice in ν-model:: The spermatozoon in the peripheral blood of mice is continuously reduced by oral administration. This can be used as an immunosuppression for oral administration. The effective effect of a drug or the like is that the side effects of the other Slp receptor agonists of the medical system are less. 121200.doc -38- 200846342 Here, the rejection reaction for transplantation refers to transplantation of liver, kidney, heart, lung, small intestine, skin, cornea, bone, fetal tissue, bone fibrocytes, hematopoietic stem cells, peripheral blood stem cells, After acute grafting, such as blood stem cells, islet cells, hepatocytes, nerve cells, and intestinal epithelial cells, acute rejection and subsequent chronic rejection, and graft-versus-host disease, are triggered within 3 months.

又，作為自體免疫性疾病，例如可列舉膠原病、全身性 紅斑狼瘡、關節風濕病、多發性硬化症、腎病綜合症、狼 瘡性腎炎、乾燥綜合征、硬皮病、多發性肌炎、牛皮癖、 炎症性腸病、節段性回腸炎、混合性膠原病、原發性黏液 水腫、艾迪森氏病、再生不良性貧血、自體免疫溶血性貧 血、自體免疫性血小板減少症、自體免疫性糖尿病、葡萄 膜炎、抗文體病、重症肌無力症、曱狀腺中毒症、甲狀 腺炎、慢性甲狀腺炎等。 人’㈣過敏性疾病’例如可列舉異位性皮膚炎、哮 喘、鼻炎、結膜炎、花粉病等。 將以通式⑴所表示之本發明之化合物、其鹽、或彼等之 溶劑合物投與哺乳動物（尤其是人）之情形時，可對全身或 局部經口或非經口投與。 本發明之醫藥，可柄擔 常使用方法選擇適當形態，藉由通 各種製劑之製備法而製備。 作為經口用醫藥 粒劑、«#卜_二：；列舉片劑、丸劑、散劑、顆 該形態之醫藥之製備，；=乳劑、糖装劑、_等。 了使用根據需要自通常用作添加劑 121200.doc -39- 200846342 之賦形』、黏合劑、崩解劑、潤滑劑、膨潤劑、增潤劑、 複皿』可塑劑、穩定劑、防腐劑、抗氧化劑、著色劑、 增溶劑、料劑、乳化劑、甜味劑、保存劑、緩衝劑、稀 釋劑u劑等適當選擇者，根據常法而進行。 作為非經π用醫藥之形態，可列舉注射劑、軟膏劑、凝 膠劑、礼貧劑、濕布劑、黏附劑、喷霧劑、吸入劑、噴霧 劑（spray agent)、滴眼劑、滴鼻劑、栓劑、吸入劑等。該Further, examples of the autoimmune diseases include collagen disease, systemic lupus erythematosus, articular rheumatism, multiple sclerosis, nephrotic syndrome, lupus nephritis, Sjogren's syndrome, scleroderma, polymyositis, Psoriasis, inflammatory bowel disease, Crohn's disease, mixed collagen disease, primary mucinous edema, Addison's disease, aplastic anemia, autoimmune hemolytic anemia, autoimmune thrombocytopenia Autoimmune diabetes, uveitis, anti-sports disease, myasthenia gravis, sputum gland poisoning, thyroiditis, chronic thyroiditis, etc. The human '(four) allergic disease' may, for example, be atopic dermatitis, asthma, rhinitis, conjunctivitis, pollinosis or the like. When a compound of the present invention represented by the formula (1), a salt thereof, or a solvate thereof is administered to a mammal (especially a human), it can be administered systemically or locally, orally or parenterally. The medicine of the present invention can be prepared by a method of preparing various preparations by selecting a suitable form by a method of usual use. As a medicinal granule for oral use, «#卜_二:; a tablet, a pill, a powder, a preparation of a medicine in this form; = an emulsion, a sugar preparation, _, and the like. The use of the additives as commonly used as additives 121200.doc -39- 200846342, binders, disintegrants, lubricants, swelling agents, humectants, compounding agents, stabilizers, preservatives, An appropriate choice of an antioxidant, a colorant, a solubilizer, a material, an emulsifier, a sweetener, a preservative, a buffer, a diluent, and the like is carried out according to a conventional method. Examples of the form of the non-π-medicine include an injection, an ointment, a gel, a remedy agent, a wet cloth, an adhesive, a spray, an inhalant, a spray agent, an eye drop, and a drop. Nasal, suppository, inhalant, etc. The

形態之醫藥之製備，可使用根據需要自通常用作添加劑之 穩定劑、防腐齊卜增溶劑、保濕劑、保存劑、抗氧化劑、 賦香劑、凝膠化劑、中和劑、增溶劑、緩衝劑、等張劑、 界面活性劑、著色劑、緩衝劑、增黏劑、濕潤劑、填充 劑、吸收促進劑、懸浮劑、黏合劑等適當選擇者，根據常 法而進行。 本發明之醫藥，亦可製成將以通式（I)所表示之化合物、 其鹽、或彼等之溶劑合物，肖自免疫抑制劑、免疫抑制中 所使用之抗體、排斥反應治療藥、抗生素及類固醇藥中所 選擇之1種或2種以上加以組合而成之醫藥。該醫藥，係將 以通式⑴所表示之本發明之化合物、其鹽、或彼等之溶劑 合物與其他藥劑之i種或2種以上加以組合而作為併用劑投 與者，以通式⑴所表示之本發明之化合物、其鹽、或彼等 之溶劑合物與其他藥劑之併用劑，既可製成一種製劑中調 配有兩種成分之合劑，亦可為作為單獨製劑投與者。分別 投與之情形時’各種製劑既可同時投與，亦可間隔時間差 投與。又，各種製劑之投與方法既可相同，亦可不同。該 121200.doc -40- 200846342 等醫藥’亦可製成將以通式（1)所表示之化合物、其鹽、或 彼等之溶劑合物，與自免疫抑制劑、免疫抑制中所使用之 抗體、排斥反應治療藥、抗生素及類固醇藥中所選擇之1 種或2種以上等其他藥劑加以組合而成之套組。 更具體而言，作為免疫抑制劑、免疫抑制中所使用之抗 體、排斥反應治療藥，例如可列舉環孢黴素A、他克莫司 (FK506)、硫唑嘌呤、咪唑立賓、甲胺蝶呤、麥考酚酸For the preparation of the form of medicine, a stabilizer, an antiseptic solvent, a moisturizer, a preservative, an antioxidant, a scenting agent, a gelling agent, a neutralizing agent, a solubilizing agent, and the like, which are usually used as an additive, may be used. Suitable buffers, isotonic agents, surfactants, colorants, buffers, tackifiers, wetting agents, fillers, absorption enhancers, suspending agents, and binders are suitably selected according to conventional methods. The pharmaceutical of the present invention may also be a compound represented by the formula (I), a salt thereof, or a solvate thereof, an autoimmune inhibitor, an antibody used in immunosuppression, or a therapeutic agent for rejection reaction. One or a combination of two or more selected from the group consisting of antibiotics and steroids. This medicine is a combination of a compound of the present invention represented by the formula (1), a salt thereof, or a solvate thereof, and two or more of the other agents, and is used as a concomitant agent. (1) The compound of the present invention, a salt thereof, or a solvate thereof and other agents may be formulated as a mixture of two components in one preparation, or as a separate preparation. . In the case of separate administration, the various preparations may be administered at the same time or may be administered at intervals. Further, the methods of administration of the various preparations may be the same or different. The pharmaceuticals such as 121200.doc -40-200846342 can also be used as a compound represented by the formula (1), a salt thereof, or a solvate thereof, and a self-immunosuppressive agent and immunosuppressive agent. A kit in which one or two or more selected from the group consisting of an antibody, a rejection therapeutic drug, an antibiotic, and a steroid drug are combined. More specifically, as an immunosuppressive agent, an antibody used in immunosuppression, and a therapeutic agent for rejection, for example, cyclosporine A, tacrolimus (FK506), azathioprine, imidazophan, methylamine can be cited. Chrysalis, mycophenolic acid

酉旨、環填醯胺、西羅莫司、依維莫司、潑尼松龍、甲基潑 尼松龍、奥素健體〇KT3、抗人淋巴球球蛋白、去氧精脈 啉等。 作為抗生素，例如可列舉頭孢呋辛鈉、美羅培南三水合 物、硫酸奈替米星、硫酸西索米星、頭抱布缔、Μ· 脳、m-367、妥布黴素、ρα·142〇、多柔比星、硫酸阿 司米星、鹽酸頭孢他美酯等。 作為類固醇藥，例如可列舉丙酸氯倍他索、醋酸雙氟拉 松、酷酸氟輕鬆、糠酸莖丰^ 稼杈異水松、二丙酸倍他米松、倍他米 松丁酸丙酸醋、戊酸倍他米松、地敦孕留丁輯、布地夺 德、雙氟可龍戊酸酉旨、安西奈德、哈西奈德、***、 丙酸地基未松、戊酸地宾丰4 地塞水松、醋酸***、醋酸氫化 可的松、丁酸氫化可的松、 斤 丁酉文丙酸氣化可的松、丙酸地 潑羅酮、潑尼松龍醋酸戊萨 ^ _ 戍馱|曰、亂輕鬆、丙酸倍氯米 松、曲安奈德、特戊酴虫h ^双以鼠水松、二丙酸阿氯米松、丁酸 氯倍他松、潑尼松龍、丙酴隹 枝卜 文倍氣未松、鼠氫縮松、醋酸可的 松、氮化可的松、氮化可从上止^ 了的权磷酸鈉 '氫化可的松琥珀酸 121200.doc 200846342 鈉、醋酸氟氫可的松、醋酸潑尼松龍、潑尼松龍琥珀酸 鈉、丁基醋酸潑尼松龍、潑尼松龍磷酸鈉、醋酸鹵潑尼 松、曱基潑尼松龍、醋酸曱基潑尼松龍、甲基潑尼松龍琥 珀酸鈉、去炎松、醋酸去炎松、***磷酸鈉、地塞米 松棕櫚酸s旨、醋酸帕拉米松、倍他米松、丙酸氟替卡松、 氟尼縮松 、ST-126P、環索奈德、dexamethasone palomithionate、糠酸莫米松、續酸普拉睾酮、地夫可特、 石黃庚甲基潑尼松龍（methylprednisolone suleptanate)、曱基 潑尼松龍琥珀酸鈉等。 以通式（I)所表示之本發明之化合物、其鹽或彼等之溶劑 合物之投與量，根據症狀、年齡、體重、組合投與之藥劑 種類或投與量等而有所不同，但通常，較好的是按化合物 (I)之換算量，成人每人每次於0.001 mg至1000 mg之範圍 内，對於全身或局部，每日一次至數次經口或非經口投 與，或者每曰於1小時至24小時之範圍内持續投與至靜脈 内。 [實施例] 以下，列舉實施例詳細說明本發明，但本發明並非限定 於此。酉 、, 醯 醯 、, sirolimus, everolimus, prednisolone, methylprednisolone, octopus 〇 KT3, anti-human lymphoglobulin, deoxygenated porphyrin, etc. . Examples of the antibiotic include cefuroxime sodium, meropenem trihydrate, netilmicin sulfate, sisomicin sulfate, cephalopod, Μ·脳, m-367, tobramycin, and ρα·142. 〇, doxorubicin, astem sulfate sulfate, cefetamet pivoxil hydrochloride, etc. Examples of the steroid drug include clobetasol propionate, diflunisone acetate, fluocinolone acetonide, citric acid stem stalks, bismuth sulphate, betamethasone dipropionate, and betamethasone butyrate propionate. Vinegar, betamethasone valerate, diarrhea, dexamethasone, budesonide, dicetaxel, acesulfide, dexamethasone, propionate, valproate丰4 塞塞松松, dexamethasone acetate, hydrocortisone acetate, hydrocortisone butyrate, chlorinated cortisone, cortisone propionate, propidone propionate, prednisolone acetate penta ^ _ 戍驮 曰 曰 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱 乱, 酴隹 酴隹 卜 倍 倍 倍 、 、 、 、 、 、 、 鼠 鼠 鼠 、 、 、 、 、 、 、 、 、 、 、 、 、 、 1200 1200 1200 1200 1200 1200 1200 1200 1200 1200 1200 1200 1200 1200 1200 1200 1200 1200 200846342 Sodium, hydrocortisone acetate, prednisolone acetate, prednisolone sodium succinate, prednisolone butyl acetate, prednisolone sodium phosphate, acetic acid Pine, guanidinoprednisolone, decyl prednisolone acetate, methylprednisolone sodium succinate, triamcinolone, triamcinolone acetonide, dexamethasone sodium phosphate, dexamethasone palmitic acid Paramisone acetate, betamethasone, fluticasone propionate, flunisolide, ST-126P, ciclesonide, dexamethasone palomithionate, mometasone furoate, prasone testosterone, difluxate, scutellaria methyl Methylprednisolone suleptanate, decyl prednisolone sodium succinate and the like. The amount of the compound of the present invention represented by the formula (I), a salt thereof or a solvate thereof may vary depending on the symptoms, age, body weight, the type of the drug to be administered, or the amount administered. , but usually, it is preferably in the range of 0.001 mg to 1000 mg per adult per adult, in the range of 0.001 mg to 1000 mg per person, once or several times a day, orally or several times. And, or every sputum, continue to be administered to the vein within the range of 1 hour to 24 hours. [Examples] Hereinafter, the present invention will be described in detail by way of examples, but the invention is not limited thereto.

紅外光譜（IR)，係使用 Hitachi 270-30 spectrometer 或 Horiba FT-720 (S.T.Japan Durascope (Diamond/KRS-5) j # 由 KBr壓片法或 ATR (Attenuation Total Reflection，衰減全 反射）法測定。元素分析係以Perkin-Elmer CHNS/O 2400II 進行測定。至於質量分析器，使用JEOL JMS-AX505W 121200.doc -42- 200846342Infrared spectroscopy (IR) was measured by a KBH tablet method or an ATR (Attenuation Total Reflection) method using a Hitachi 270-30 spectrometer or a Horiba FT-720 (STJapan Durascope (Diamond/KRS-5) j #. Elemental analysis was performed using a Perkin-Elmer CHNS/O 2400II. As for the mass analyzer, JEOL JMS-AX505W 121200.doc -42- 200846342 was used.

(EI、CI)、JEOL JMS_HX110(FD、FAB) spectrometer、 Thermoquest Finning AQA (ESI)、Agilent Thechnologies AgilentllOO series LC/MSD及PE SCIEX API150EX (ESI)、 或 JMS-T100LP AccuTOF LC_plus。核磁共振光譜（NMR)係 使用JEOL JNM-EX400測定，未加以特別表示之情形時， 意指質子Oi^-NNIR，使用四甲基矽烷作為内部標準。 NMR 中之多重度表示 s=singlet、d=doublet、t=triplet、 q=quintet及m=multiplet。管柱色層分析中所使用之石夕膠係 使用 E-Merck公司之 Kiesel-gel 60 (particle size(粒度）： 0.060〜0.200 mm或0.040〜0.063 mm)。又，薄層色層分析 (TLC)之培養皿係使用E-Merck公司製造之Kieselgel 60 F251。 又，於說明書中使用以下縮寫。(EI, CI), JEOL JMS_HX110 (FD, FAB) spectrometer, Thermoquest Finning AQA (ESI), Agilent Thechnologies AgilentllOO series LC/MSD and PE SCIEX API150EX (ESI), or JMS-T100LP AccuTOF LC_plus. Nuclear magnetic resonance spectroscopy (NMR) was measured using JEOL JNM-EX400. When not specifically indicated, it means proton Oi^-NNIR, using tetramethyl decane as an internal standard. The multiplicity in NMR means s=singlet, d=doublet, t=triplet, q=quintet, and m=multiplet. The Shiyue gum used in the column chromatography analysis used Kiesel-gel 60 (particle size: 0.060 to 0.200 mm or 0.040 to 0.063 mm) of E-Merck Co., Ltd. Further, as a thin layer chromatography (TLC) culture dish, Kieselgel 60 F251 manufactured by E-Merck Co., Ltd. was used. Also, the following abbreviations are used in the specification.

Boc :第三丁氧基羰基Boc: third butoxycarbonyl

Bn :苄基Bn: benzyl

Cbz :苄氧基羰基 Z :苄氧基羰基 CDC13 :氘氣仿 DEAD ··偶氮二曱酸二乙酯 DIAD :偶氮二甲酸二異丙酯 DIEA :二異丙基乙胺 DMAP : 4-(N，N-二甲基胺基)吡啶 DMF : N，N-二甲基甲醯胺 DMSO :二曱基亞颯 121200.doc -43- 200846342 EDC: 1-乙基_3-(3-二曱基胺基丙基）碳二醯亞胺鹽酸鹽 HOBt: 1-羥基苯幷*** Ms :曱磺醯基 tBu :第三丁基 TEA :三乙胺 THF :四氫咬喃 e TLC :薄層色層分析 ⑩ [實施例苯基·5·三氟甲基-2-噻吩基）甲氧基]萘_ 2-基]甲基]σ丫丁咬_3_叛酸 (1)4-苯基-5-三氟甲基嗟吩·2_曱醇 [化 29]Cbz : benzyloxycarbonyl Z : benzyloxycarbonyl CDC 13 : helium-like DEAD · diethyl azodicarboxylate DIAD : diisopropyl azodicarboxylate DIEA : diisopropylethylamine DMAP : 4- (N,N-Dimethylamino)pyridine DMF : N,N-dimethylformamide DMSO : Dimercaptopurine 121200.doc -43- 200846342 EDC: 1-ethyl_3-(3- Dimercaptopropyl propyl) carbodiimide hydrochloride HOBt: 1-hydroxybenzotriazole Ms: sulfonyl sulfonyl tBu: tert-butyl TEA: triethylamine THF: tetrahydroanion e TLC :Thin color layer analysis 10 [Example phenyl·5·trifluoromethyl-2-thienyl)methoxy]naphthalene-2-yl]methyl]σ丫丁 bite_3_Resin (1) 4-phenyl-5-trifluoromethyl porphin·2_nonanol [Chemical 29]

將4-本基-5-二氟曱基嗟吩_2_叛酸（3.52 g)溶解於THF(60 ml)中，於室溫下滴加BHrTHF錯合物（1m_THF溶液）（26 ml)。使反應混合液加熱回流3小時後，冷卻至，滴加 水而結束反應。將反應混合液以醋酸乙酯進行萃取。將萃 取液利用飽和食鹽水進行清洗，藉由無水硫酸鈉乾燥後， 進行減壓濃縮’獲得標記化合物（3 42 g)。 NMR (CDC13) δ: 1.99 (iH> t5 J=6.0 Hz)5 4.87 (2H, d5 J-5.6 Hz)，6.98-7.00 (1H，m)，7 37-742 (5H，m)。 (2) 5-氯甲基-3-苯基三氟甲基噻吩 [化 3 0] 121200.doc •44- 2008463424-Benzyl-5-difluorodecyl porphin-2_reaction acid (3.52 g) was dissolved in THF (60 ml), and BHrTHF complex (1m_THF solution) (26 ml) was added dropwise at room temperature. . After the reaction mixture was heated to reflux for 3 hours, it was cooled, and water was added dropwise to terminate the reaction. The reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. NMR (CDC13) δ: 1.99 (iH> t5 J=6.0 Hz) 5 4.87 (2H, d5 J-5.6 Hz), 6.98-7.00 (1H, m), 7 37-742 (5H, m). (2) 5-Chloromethyl-3-phenyltrifluoromethylthiophene [Chem. 3 0] 121200.doc •44- 200846342

於4_苯基三氟甲基噻吩-2-甲醇（482 mg)之二氯甲烷 (7·0 ml)溶液中，於室溫下添加亞硫醯氯（708 μΐ)。將反應 混合液於5(TC下攪拌16小時後，進行減壓濃縮，將所獲得 之殘 >查使用石夕膠快速管柱色層分析（Bi〇tage 4〇M)進行純 化’獲得標記化合物（434 mg)。 NMR (CDC13) δ: 4.77 (2H5 d, J=0.7 Hz)? 7.07 (1H5 br s)? 7.35-7.44 (5H5 m) 〇 (3) 6-[(4-苯基-5-三氟曱基_2-噻吩基）甲氧基]萘_2_羧酸 曱酯 [化 31]To a solution of 4_phenyltrifluoromethylthiophene-2-methanol (482 mg) in dichloromethane (7·0 ml), sulphur chloride (708 μM) was added at room temperature. After the reaction mixture was stirred at 5 (TC for 16 hours, concentrated under reduced pressure, and the residue obtained was purified by using Shiqi gum rapid tube chromatography (Bi〇tage 4〇M) to obtain a mark. Compound (434 mg) NMR (CDC13) δ: 4.77 (2H5 d, J=0.7 Hz)? 7.07 (1H5 br s)? 7.35-7.44 (5H5 m) 〇(3) 6-[(4-phenyl- 5-trifluoroindolyl-2-thienyl)methoxy]naphthalene-2-carboxylic acid oxime ester [Chem. 31]

於5_氯甲基-3-苯基-2-三氟曱基噻吩（615 mg)之DMF(4.0 ml)溶液中，於室溫下添加6_羥基萘羧酸甲酯（45〇 mg) 及碳酸鉀（615 mg)。將反應混合液於7(rc下攪拌18小時 後，進行冷卻，冷卻至室溫為止。將反應混合液藉由過濾 去除不溶物。於濾液中添加醋酸乙酯（1〇〇 ml)、飽和氯化 銨水溶液（20 ml)及水（200 ml)，將有機層分液後，進而藉 由醋酸乙酯（30 ml)萃取水層。將合併之萃取液利用飽和氣 化銨水溶液（1〇〇 ml)進行清洗，利用無水硫酸鈉乾燥後， 121200.doc -45· 200846342 進行減壓濃縮。將所獲得之殘渣，使用矽膠快速管柱色層 分析（Biotage 40M)進行純化，獲得標記化合物（98〇 mg)。 MS (ESI) m/z: 443 (M+H)、 NMR (CDC13) δ: 3.97 (3H5 s)? 5.37 (2H, s)3 7.16 (1H5 d? >1·5 Hz)，7.25-7.31 (2H，m)，7.37-7.46 (5H，m)，7·78 (1H， d，J=8.5 Hz)，7·90 (1H，d，J=8.3 Hz)，8·05 (1H，dd，J=8 5 1.7 Hz)，8·55 (1H，d，J=1.5 Hz)。 (4) 6-[(4·苯基-5-三氟甲基-2-噻吩基）曱氧基]萘_2_甲醇 [化 32]Add methyl 6-hydroxynaphthalenecarboxylate (45 〇 mg) at room temperature to a solution of 5-chloromethyl-3-phenyl-2-trifluorodecylthiophene (615 mg) in DMF (4.0 ml) And potassium carbonate (615 mg). The reaction mixture was stirred at 7 (rc) for 18 hours, then cooled and cooled to room temperature. The reaction mixture was filtered to remove insolubles. ethyl acetate (1 ml) and saturated chlorine were added to the filtrate. The aqueous solution of ammonium chloride (20 ml) and water (200 ml) were separated, and then the organic layer was separated, and then the aqueous layer was extracted with ethyl acetate (30 ml). (ml) was washed, dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 121200.doc -45·200846342. The obtained residue was purified by silica gel chromatography (Biotage 40M) to obtain the labeled compound (98). 〇mg) MS (ESI) m/z: 443 (M+H), NMR (CDC13) δ: 3.97 (3H5 s)? 5.37 (2H, s)3 7.16 (1H5 d? >1·5 Hz) , 7.25-7.31 (2H, m), 7.37-7.46 (5H, m), 7·78 (1H, d, J=8.5 Hz), 7·90 (1H, d, J=8.3 Hz), 8.05 (1H, dd, J = 8 5 1.7 Hz), 8·55 (1H, d, J = 1.5 Hz) (4) 6-[(4·Phenyl-5-trifluoromethyl-2-thienyl)曱oxy]naphthalene_2_methanol [32]

於6-[(4-苯基-5-三氟甲.基）-2-噻吩基]甲氧基]萘·2_羧酸 甲酯（840 mg)之THF(15 ml)溶液中，於室溫下添加氫化硼 經（124 mg)。將反應混合液加熱回流丨$小時後，使反廡液 冷卻至室溫為止，添加水（30 1111)及1 N鹽酸水溶液（3〇 ml)，藉由醋酸乙酯（2x30 ml)進行萃取。合併萃取液利用 飽和食鹽水（30 ml)清洗後，利用無水硫酸鈉乾燥，進行減 壓濃縮。將所獲得之殘渣，使用矽膠快速管柱色層分析 (Biotage 40M)進行純化，獲得標記化合物（761 mg)。 MS (El) m/z: 414 (M)+。 ISiMR (CDC13) δ: 1·71 (1H，t，J=6.0 Ηζ)，4·84 (2H，d，J=6 〇In a solution of 6-[(4-phenyl-5-trifluoromethyl)-2-thienyl]methoxy]naphthalene-2-carboxylic acid methyl ester (840 mg) in THF (15 ml) Boron hydride (124 mg) was added at room temperature. The reaction mixture was heated to reflux for hr. hr., and then, the mixture was cooled to room temperature, and water (301111) and 1 N aqueous hydrochloric acid (3 ml) were added and extracted with ethyl acetate (2×30 ml). The combined extracts were washed with saturated brine (30 ml), dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by silica gel flash chromatography (Biotage 40M) to give the title compound (761 mg). MS (El) m/z: 414 (M)+. ISiMR (CDC13) δ: 1·71 (1H, t, J=6.0 Ηζ), 4.84 (2H, d, J=6 〇

Hz)，5.35 (2H, s)，7.14 (1H，dd，J=1.2 Hz)，Du·”（2H 121200.doc -46- 200846342 m)，7·36-7·46 (5H，m)，7·48 (1H，dd5 J=8.3, u Hz) 7 74 7.80 (3H，m) 〇 ’ (5)6_[(4 -苯基 三 i 甲 [化 33] •2-噻吩基）曱氧基；I萘_2_甲 醛Hz), 5.35 (2H, s), 7.14 (1H, dd, J = 1.2 Hz), Du·” (2H 121200.doc -46- 200846342 m), 7·36-7·46 (5H, m), 7·48 (1H, dd5 J=8.3, u Hz) 7 74 7.80 (3H,m) 〇' (5)6_[(4-Phenyltrimethyl)[2-33]-2-thienyloxyloxy ;I naphthalene_2_formaldehyde

mg)，攪拌24小時。將反應混合物使用矽藻土過濾後，將 濾液減壓濃縮，獲得標記化合物（569 mg)。 MS (ESI) m/z: 413 (M+H). 〇 NMR (CDC13) δ: 5·39 (2H，s)，7·19-7·14 (1H，m)，7·34_7 28 (2H，m)，7.49-7.36(5H，m)，7.83(lH，d，JUHz)，7.97-7·93 (2H，m)，8·28 (1H，s)，10.10 (1H，d，J=12.2 Hz)。 (6)l-[[6-[(4-苯基三氟甲基-2-噻吩基）曱氧基]萘_2-基]f 基]吖丁啶_3-羧酸 [化 34]Mg), stir for 24 hours. After the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound ( 569 mg). MS (ESI) m/z: 413 (M+H). NMR (CDC13) δ: 5·39 (2H, s), 7·19-7·14 (1H, m), 7·34_7 28 (2H , m), 7.49-7.36 (5H, m), 7.83 (lH, d, JUHz), 7.97-7·93 (2H, m), 8·28 (1H, s), 10.10 (1H, d, J= 12.2 Hz). (6) l-[[6-[(4-Phenyltrifluoromethyl-2-thienyl) decyloxy]naphthalene-2-yl]fyl]azetidine-3-carboxylic acid [Chem. 34]

混合6-[(4-苯基-5·三氟甲基-2-噻吩基）甲氧基]萘_2_曱醛 121200.doc -47- 200846342 (569 mg)、吖丁咬缓酸（427 mg)、甲醇（10 ml)及酷酸（i ml)，於攪拌下添加氰基硼氫化鈉（183 mg)，攪拌24小時。 於反應混合液中添加飽和碳酸氫鈉水溶液加以中和，利用 2 0 /〇甲醇/氣仿進行萃取。將举取液利用無水硫酸納乾燥 後，進行減壓濃縮，將所獲得之殘渣使用矽膠快速管柱色 層分析（山善高速管柱2 L)進行純化，獲得標記化合物（1〇8 mg)。 MS (ESI)m/z: 498 (M++l)+ 〇Mixing 6-[(4-phenyl-5·trifluoromethyl-2-thienyl)methoxy]naphthalene-2-furfural 121200.doc -47- 200846342 (569 mg), butyl butyl acid ( 427 mg), methanol (10 ml) and citric acid (1 ml) were added sodium cyanoborohydride (183 mg) with stirring and stirred for 24 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture for neutralization, and extraction was carried out using 20 / methanol/methanol. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using a silica gel column chromatography (2L), to obtain a labeled compound (1 〇 8 mg). MS (ESI) m/z: 498 (M++l)+ 〇

NMR (CDC13) δ: 3·32-3·42 (1H，m)，3.91-4.02 (2H，m)， 4.05-4.13 (2H，m)，4·19 (2H，s)，5.27 (2H，s)，7·07_7·12 (1H，m)，7.16-7.21 (2H，m)，7.35-7.50 (6H，m)，7 75_7·67 (2H，m)，7.78 (1H，s)。NMR (CDC13) δ: 3·32-3·42 (1H, m), 3.91-4.02 (2H, m), 4.05-4.13 (2H, m), 4·19 (2H, s), 5.27 (2H, s), 7·07_7·12 (1H, m), 7.16-7.21 (2H, m), 7.35-7.50 (6H, m), 7 75_7·67 (2H, m), 7.78 (1H, s).

AnaLCalcd for C27H22F3NO3S O.25H2O: C, 60.22; H 4 40* N，2·60AnaLCalcd for C27H22F3NO3S O.25H2O: C, 60.22; H 4 40* N,2·60

Found: C，60.11; H，4·26; N，2.69。 [實施例2]1-[[6-[(1-本基-5_二鼠甲基_^〇比嗤_3_基）甲氧 基]萘-2-基]甲基]ϋ丫丁咬―3-魏酸鹽酸鹽 (1) 3-溴甲基-1-苯基三氟曱基_1Η-η比唾 [化 35]Found: C, 60.11; H, 4·26; N, 2.69. [Example 2] 1-[[6-[(1-Benzyl-5-di-methyl-methyl)-methoxy-naphthalen-2-yl]methyl] Bite 3-Ze hydrochloride (1) 3-bromomethyl-1-phenyltrifluoromethyl-1-pyrene-n ratio saliva [Chem. 35]

口比唑（Eur· J, 〇rg· 121200.doc -48- 200846342Oral azole (Eur·J, 〇rg· 121200.doc -48- 200846342

Chem· 2002, 2913_292〇.)(679 mg)之四氯化碳（25 响溶液 中添加Nw臭代丁二醯亞胺（641 mg)及過氧化苯甲醯（19 mg)，於攪拌下加熱回流21小時。使反應混合液冷卻至室 溫為止後，濾去不溶物，將濾液減壓濃縮。將所獲得之殘 渣藉由矽膠管柱色層分析進行純化，獲得標記化合物（315 mg)。 MS (ESI) m/z: 305 (M+H)+。 NMR (CDC13) δ: 4·52 (2H, s)，6.88 (1H，s)，7.47-7.50 (5H， m) 〇 (2) 6-[(l-苯基三氟甲基·比嗤-3_基）甲氧基]萘_2_ 曱醛 [化 36]Chem· 2002, 2913_292〇.) (679 mg) of carbon tetrachloride (25% solution is added with Nw odorant dimethyleneimine (641 mg) and benzamidine peroxide (19 mg), heated with stirring The reaction mixture was refluxed for 21 hours. After the reaction mixture was cooled to room temperature, the insoluble material was filtered out, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel column chromatography to give the title compound (315 mg). MS (ESI) m/z: 305 (M+H) + NMR (CDC13) δ: 4·52 (2H, s), 6.88 (1H, s), 7.47-7.50 (5H, m) 〇(2) 6-[(l-phenyltrifluoromethyl)pyrim-3-yl)methoxy]naphthalene_2_furfural [Chem. 36]

於3-溴曱基-1-苯基-5-三氟甲基·1Η·吡唑（305 mg)及6-經 基萘-2-曱醛（和光純藥）（172 mg)之DMF(2 ml)溶液中，添 加碳酸鉀（415 mg)，於6(TC下攪拌22小時。使反應混合液 恢復至室溫後，濾去不溶物，減壓濃縮濾液。將所獲得之 殘渣使用矽膠快速管柱色層分析（Biotage 25S)進行純化， 獲得標記化合物（3 00 mg)。 MS (ESI) m/z: 397 (M+H)+。 NMR (CDC13) δ: 5·31 (2H，s)，6·98 (1H，s)，7·30-7·38 (2H， 121200.doc -49- 200846342 m)’ 7·51 (5H，s)，7·83 (1H，d，J=8、6 Hz)，7.94 (2H，dd， J=8.5, 1·6 Hz)，8·28 (1H，s)，lo.n (1H，s)。DMF of 3-bromodecyl-1-phenyl-5-trifluoromethyl·1Η·pyrazole (305 mg) and 6-naphthyl-2-furaldehyde (Wako Pure Chemical Industries) (172 mg) 2 ml) of the solution, potassium carbonate (415 mg) was added, and the mixture was stirred at 6 (TC for 22 hours). After the reaction mixture was returned to room temperature, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Purification by flash column chromatography (Biotage 25S) gave the title compound (3 00 mg) MS (ESI) m/z: 397 (M+H) + NMR (CDC13) δ: 5·31 (2H, s),6·98 (1H,s),7·30-7·38 (2H, 121200.doc -49- 200846342 m)' 7·51 (5H,s),7·83 (1H,d,J =8,6 Hz), 7.94 (2H, dd, J=8.5, 1·6 Hz), 8·28 (1H, s), lo.n (1H, s).

(3) 1_[[6-[(1·苯基·5_三氟甲比唑_3_基）甲氧基]萘_2_ 基]甲基]吖丁咬-3-羧酸甲醋 [化 37](3) 1_[[6-[(1·Phenyl·5_trifluoromethylpyrazole-3-yl)methoxy]naphthalene-2-yl]methyl]pyrene-3-carboxylic acid methyl vinegar [ 37]

醛（200 mg)及吖丁啶_3一羧酸甲酯鹽酸鹽（91·2 mg)之二氯乙 烷（5 ml)>谷液中，添加三乙醯氧基氫化硼鈉（32〇 ，於 比唑-3-基）甲氧基]萘-2-甲 室溫下攪拌14小時。於反應混合液中添加飽和碳酸氫鈉水 >谷液後，以二氯甲烷進行萃取。將萃取液利用飽和食鹽水 進行清洗，藉由無水硫酸鈉乾燥後，進行減壓濃縮，將所Aldehyde (200 mg) and azetidine-3-carboxylate methyl ester hydrochloride (91·2 mg) in dichloroethane (5 ml)> 32 Torr, bisazol-3-yl)methoxy]naphthalene-2-methyl was stirred at room temperature for 14 hours. After adding saturated sodium hydrogencarbonate water > gluten solution to the reaction mixture, extraction was carried out with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.

獲得之殘渣使用矽膠快速管柱色層分析（Bi〇tage 25S)進行 純化，獲得標記化合物（81 mg)。 MS (ESI) m/z: 496 (M+H). 〇 NMR (CDC13) δ: 3.31-3.40 (3H，m)，3·51-3·59 (2H，m)，3·71 (3H，s)，3.74 (2H，s)，5·35 (2H，t，J=35.9 Hz)，6.96 (1H，s)5 7.22 (1H? dd, J=9.1, 2.5 Hz), 7.27 (1H, d? J=3.2 Hz), 7.38 (1H，dd，J=8.3，1.7 Hz)，7.45-7.53 (5H，m)，7·65 (1H，s)， 7·70 (1H，d，J=8.6 Hz)，7·73 (1H，d，J=8.3 Hz)。 (4) l-[[6-[(l-苯基-5-三氟曱基-iH-nb唑基）曱氧基]萘-1- 121200.doc -50- 200846342 基]曱基]吖丁啶-3-羧酸鹽酸鹽 [化 38]The residue obtained was purified by silica gel flash chromatography (Bi〇tage 25S) to give the title compound (81 mg). MS (ESI) m/z: 495 (M+H). NMR (CDC13) δ: 3.31-3.40 (3H,m),3·51-3·59 (2H,m),3·71 (3H, s), 3.74 (2H, s), 5·35 (2H, t, J = 35.9 Hz), 6.96 (1H, s) 5 7.22 (1H? dd, J=9.1, 2.5 Hz), 7.27 (1H, d ? J=3.2 Hz), 7.38 (1H, dd, J=8.3, 1.7 Hz), 7.45-7.53 (5H, m), 7·65 (1H, s), 7·70 (1H, d, J=8.6 Hz), 7.73 (1H, d, J = 8.3 Hz). (4) l-[[6-[(l-Phenyl-5-trifluoromethyl-iH-nbzolyl) decyloxy]naphthalene-1- 121200.doc -50- 200846342 曱]曱]]吖Butyridine-3-carboxylic acid hydrochloride [Chem. 38]

於1-[[6-[(1-苯基-5-三氟曱基-1H-吡唑-3-基）甲氧基]萘_ 卜基]甲基；K 丁啶-3-羧酸甲酯（81 mg)之曱醇/丁肝混合溶液 (1 : 2，3 ml)中，於室溫下添加i n氫氧化鈉水溶液（1 ml)，攪拌3天。將反應混合液於減壓下進行濃縮，於所獲 得之殘渣中添加1 N鹽酸水溶液。濾取所析出之固體，於 減壓下進行乾燥，獲得標記化合物（89 mg)。 MS (ESI) m/z: 482 (M+H)、 HRMS (FAB) Calcd for C26H23F3N303 (M+H)-·· 482.1692·1-[[6-[(1-Phenyl-5-trifluoromethyl-1H-pyrazol-3-yl)methoxy]naphthalenyl)-methyl; K-butidine-3-carboxylic acid To a solution of methyl ester (81 mg) in decyl alcohol/butyric liver (1:2,3 ml), an aqueous solution of sodium hydroxide (1 ml) was added at room temperature, and the mixture was stirred for 3 days. The reaction mixture was concentrated under reduced pressure and a 1N aqueous solution of hydrochloric acid was added to the obtained residue. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (89 mg). MS (ESI) m/z: 482 (M+H), HRMS (FAB) Calcd for C26H23F3N303 (M+H)-·· 482.1692·

Found: 482.1680 ° NMR (DMSO-d6) δ: 3.56-3.66 (1H，m)，4.08-4.23 (3H，m)， 4.45 (2H，s)，5.30 (2H，s)，7.30 (1H，d5 J=2.2 Hz)，7·33 (2H， s)，7·52-7·63 (7H，m)，7.86-7.93 (2H，m)，8.07 (1H，s)。 IR (ATR)cm·1: 2796, 2765, 2617, 2563, 2521，1709, 1635。 Anal.Calcd for C26H22F3N303.HC1: C，60·29; H，4·48; Cl， 6.85; F，11.00; N，8.11 〇Found: 482.1680 ° NMR (DMSO-d6) δ: 3.56-3.66 (1H, m), 4.08-4.23 (3H, m), 4.45 (2H, s), 5.30 (2H, s), 7.30 (1H, d5 J = 2.2 Hz), 7·33 (2H, s), 7·52-7·63 (7H, m), 7.86-7.93 (2H, m), 8.07 (1H, s). IR (ATR) cm·1: 2796, 2765, 2617, 2563, 2521, 1709, 1635. Anal.Calcd for C26H22F3N303.HC1: C,60·29; H,4·48; Cl, 6.85; F,11.00; N,8.11 〇

Found: C，60·08; H，4.39; Cl, 6.67; F，11.10; N，7.85 〇 [實施例3]l-[[5-[(4·苯基-5-三氟甲基-2-噻吩基）曱氧基]-1H-吲哚-2-基]甲基]吖丁啶-3-羧酸 121200.doc •51 - 200846342 ⑴1_甲基-5-[(4-苯基-5-三氟甲基_2-噻吩基）甲氧基]_1Η-吲哚-2-羧酸乙酯 [化 39]Found: C, 60·08; H, 4.39; Cl, 6.67; F, 11.10; N, 7.85 〇 [Example 3] l-[[5-[(4·phenyl-5-trifluoromethyl-2) -thienyl)nonyloxy]-1H-indol-2-yl]methyl]azetidine-3-carboxylic acid 121200.doc •51 - 200846342 (1)1_methyl-5-[(4-phenyl- Ethyl 5-trifluoromethyl_2-thienyl)methoxy]_1Η-indole-2-carboxylate [Chem. 39]

於5-氯甲基-3·苯基-2-三氟甲基噻吩(568 mg)之DMF(4.〇 ml)溶液中，於室溫下添加5_羥基甲基]H-吲哚_2_羧酸 乙酉旨（450 mg)及碳酸鉀（567 mg)。將反應混合液於70°C下 擾拌18小時後，進行過濾，去除不溶物。於濾液中添加醋 酸乙酯（100 ml)、飽和氣化銨水溶液（2〇 ml)及水（200 ml)， 將有機層分液。進而，將水層利用醋酸乙酯（5〇 ml)進行萃 取。將合併之萃取液利用飽和氯化銨水溶液G 〇〇 ml)加以 清洗’利用無水硫酸鈉乾燥後，進行減壓濃縮。將所獲得 之殘渣使用矽膠快涟管柱色層分析（Bi〇tage 4〇M)進行純 化，獲得標記化合物（673 mg)。 MS (ESI) m/z: 460 (M+H) +。 NMR (CDC13) δ: 1.41 (3H，t，J=7.1 Ηζ)，4·06 (3H，s)，4·37 (2H, q5 J=7.1 Hz)，5.27 (2H，s)，7·〇9 (1H, br s)，7·11 (1H， dd，J=9.0，2.4 Hz)，7·17 (1H，d，J=2.4 Hz)，7·22 (1H，d， J=0.7 Hz)，7·32 (1H，d，J=9.0 Hz)，7.37-7.45 (5H，m)。 (2) 1-曱基-5-[(4-苯基-5-三氟甲基_2_噻吩基）甲氧基]_1H一 吲哚-2-甲醇 121200.doc -52- 200846342 [化 40]Add 5-hydroxymethyl]H-吲哚_ at room temperature to a solution of 5-chloromethyl-3·phenyl-2-trifluoromethylthiophene (568 mg) in DMF (4. 〇ml) 2_Carboxylic acid (450 mg) and potassium carbonate (567 mg). The reaction mixture was stirred at 70 ° C for 18 hours, and then filtered to remove insolubles. Ethyl acetate (100 ml), a saturated aqueous solution of ammonium chloride (2 ml) and water (200 ml) were added to the filtrate, and the organic layer was separated. Further, the aqueous layer was extracted with ethyl acetate (5 〇 ml). The combined extracts were washed with a saturated aqueous solution of ammonium chloride (G?) and dried over anhydrous sodium sulfate. The residue obtained was purified using a silica gel column chromatography (Bi〇tage 4〇M) to obtain a labeled compound (673 mg). MS (ESI) m/z: 460 (M+H)+. NMR (CDC13) δ: 1.41 (3H, t, J=7.1 Ηζ), 4·06 (3H, s), 4·37 (2H, q5 J=7.1 Hz), 5.27 (2H, s), 7·〇 9 (1H, br s), 7·11 (1H, dd, J=9.0, 2.4 Hz), 7·17 (1H, d, J=2.4 Hz), 7·22 (1H, d, J=0.7 Hz) ), 7·32 (1H, d, J = 9.0 Hz), 7.37-7.45 (5H, m). (2) 1-Mercapto-5-[(4-phenyl-5-trifluoromethyl_2-thienyl)methoxy]_1H-indole-2-methanol 121200.doc -52- 200846342 40]

於1-甲基-5·[(4-苯基-5-三氟曱基-2-噻吩基）曱氧基]·1Η_ 吲哚羧酸乙酯（670 mg)之THF(15 ml)溶液中，於室溫下 添加鼠化硼鐘（100 mg)。將反應混合液加熱回流16小時 後’冷卻至室溫為止，添加水（30 ml)及1 N鹽酸水溶液（30 ml)，利用醋酸乙酯（4〇 ml)進行萃取。將萃取液利用飽和 碳酸氫鈉水溶液（40 ml)清洗後，利用無水硫酸鈉乾燥，進 行減壓濃縮。將所獲得之殘渣使用矽膠快速管柱色層分析 (Bi〇tage25M)進行純化，獲得標記化合物（59〇mg)。 NMR (CDCi3) δ: 1.54 (1H5 t5 J=6.l Hz)5 3.80 (3H5 s)5 4.79 (2H, d5 1=6.1 Hz)5 5.26 (2H? s), 6.40 (1H5 s), 6.98 (1H) dd J=8.8, 2.4 Hz), 7.08 (1H5 d5 J=1.2 Hz)5 7.15 (1H5 d5 J=2.4 Hz)，7·24 (1H，d，J=8.8 Hz)，7·35_7·45 (5H，m)。 MS (ESI) m/z: 418 (M+H) + 〇 (3)卜甲基-5_[(4-苯基-5_三i甲基〜塞吩基）甲氧基]·1H_ 吲哚-2-曱醛 [化 41]a solution of ethyl 1-methyl-5.[(4-phenyl-5-trifluoromethyl-2-thienyl) decyloxy]·1Η_ hydrazinecarboxylate (670 mg) in THF (15 ml) A ratified boron clock (100 mg) was added at room temperature. The reaction mixture was heated under reflux for 16 hrs and then cooled to room temperature. Water (30 ml) and 1 N aqueous hydrochloric acid (30 ml) were added and extracted with ethyl acetate (4 ml). The extract was washed with a saturated aqueous solution of sodium bicarbonate (40 ml), dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by silica gel flash chromatography (Bi〇tage 25M) to give the title compound (59 〇mg). NMR (CDCi3) δ: 1.54 (1H5 t5 J=6.l Hz)5 3.80 (3H5 s)5 4.79 (2H, d5 1=6.1 Hz)5 5.26 (2H? s), 6.40 (1H5 s), 6.98 ( 1H) dd J=8.8, 2.4 Hz), 7.08 (1H5 d5 J=1.2 Hz) 5 7.15 (1H5 d5 J=2.4 Hz), 7·24 (1H, d, J=8.8 Hz), 7·35_7·45 (5H, m). MS (ESI) m/z: 418 (M+H) + 〇(3) </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> -furfural [Chem. 41]

121200.doc •53· 200846342 於1-甲基-5-[(4-苯基-5-三氟甲基-2-噻吩基）曱氧基]-1Η_ °引ϋ朵-2-甲醇（500 mg)之二氯曱烧（10 ml)溶液中，於室溫下 添加二氧化猛（3 12 mg)。將反應混合液於室溫下授摔1 5小 時。過濾反應混合液，減壓濃縮濾液。將所獲得之殘清使 用矽膠快速管柱色層分析（Biotage 25M)進行純化，獲得標 記化合物。 MS (ESI) m/z: 414 (M-H)+。 NMR (CDC13) δ·· 4.07 (3H，s)，5.26 (2H，s)，7·09 (1H，d J=1.22 Hz)，7.15-7.21 (3H，m)，7·32-7·45 (6H，m)5 9.86 (1H，s)。 ’ (4) l-[5-[(4-苯基-5-三氟甲基-2-噻吩基）甲氧基哚_ 9-基]甲基]吖丁啶-3-羧酸甲酯 [化 42]121200.doc •53· 200846342 in 1-methyl-5-[(4-phenyl-5-trifluoromethyl-2-thienyl) decyloxy]-1Η_ ° ϋ ϋ-2-methanol (500 In a solution of mg) in dichlorohydrazine (10 ml), oxidized sulphur (3 12 mg) was added at room temperature. The reaction mixture was allowed to stand at room temperature for 15 hours. The reaction mixture was filtered, and the filtrate was evaporated. The obtained residue was purified by silica gel flash chromatography (Biotage 25M) to obtain a labeled compound. MS (ESI) m/z: 414 (MW). NMR (CDC13) δ·· 4.07 (3H, s), 5.26 (2H, s), 7.09 (1H, d J=1.22 Hz), 7.15-7.21 (3H, m), 7·32-7·45 (6H,m)5 9.86 (1H, s). '(4) l-[5-[(4-Phenyl-5-trifluoromethyl-2-thienyl)methoxyindole-9-yl]methyl]azetidine-3-carboxylic acid methyl ester [化42]

混合5-[(4-苯基_5-三氟甲基_2·噻吩基）甲氧基]·1Η“弓丨哚-2-甲醛_ mg)、π丫丁啶_3·羧酸甲醋鹽酸鹽⑽珍 仏二氯乙燒⑽ml)及醋酸（22〇 μ1)，於檀掉下添加三乙酿 氧基氫化硼鈉(1.29 g)’攪拌15小時。於反應混合液中添 加飽和碳酸氫納水溶液⑼ml)後1用二氯甲烧進行萃 取。將萃取液利用無水硫酸納乾燥後，進行㈣濃縮，將 所獲得之殘錢时膠快速管柱色層分析（山善高速管柱： 121200.doc •54- 200846342 L)進行純化，獲得標記化合物（991 mg)。 MS (ESI) m/z: 515 (M+H)+。 NMR (CDC13) δ: 3.28-3.37 (3H，m)，3·48-3·58 (2H，m)， 3.70-3.73 (8H，m)，5.25 (2H，s)，6.31 (1H，s)5 6.93 (1H，dd， J=8.9, 2·6 Hz)，7·09-7·06 (1H，m)，7·12 (1H，d，J=2.2 Hz)， 7·20 (1H，d，J=8.8 Hz)，7·44-7·35 (5H，m)。 (5) l-[[5-[(4-苯基-5·三氟甲基-2-嘆吩基）甲氧基]-1Η-ϋ弓卜朵-2-基]甲基]吖丁啶-3-羧酸 [化 43]Mixing 5-[(4-phenyl-5-trifluoromethyl_2.thienyl)methoxy]·1Η“bend-2-formaldehyde_mg”, π-butidine _3·carboxylic acid Vinegar hydrochloride (10) 仏 仏 dichloroethene (10) ml) and acetic acid (22 〇 μ1), add triethyl borohydride sodium hydride (1.29 g) under a falling sand drop and stir for 15 hours. Add saturation to the reaction mixture. After the aqueous sodium hydrogencarbonate solution (9) ml) is extracted with methylene chloride, the extract is dried with anhydrous sulfuric acid, and then concentrated (4), and the obtained color residue is analyzed by the color column chromatography (Shanshan high-speed pipe column: 121200.doc •54- 200846342 L) Purification to obtain the labeled compound (991 mg) MS (ESI) m/z: 515 (M+H)+ NMR (CDC13) δ: 3.28-3.37 (3H,m) ,3·48-3·58 (2H,m), 3.70-3.73 (8H,m),5.25 (2H,s),6.31 (1H,s)5 6.93 (1H,dd, J=8.9, 2·6 Hz),7·09-7·06 (1H,m),7·12 (1H,d,J=2.2 Hz), 7·20 (1H,d,J=8.8 Hz),7·44-7· 35 (5H,m). (5) l-[[5-[(4-Phenyl-5·trifluoromethyl-2-indolyl)methoxy]-1Η-ϋ弓卜朵-2- Methyl]azetidine-3-carboxylic acid [Chemical 43]

混合1-[|&gt;[(4-苯基-5-三氟甲基·2-噻吩基）曱氧基]-1Η-吲 。朵-2-基-]甲基]吖丁啶_3_羧酸甲酯（991 mg)、THF(15 ml)及 0.25 N氫氧化鈉水溶液（154 ^1)，攪拌24小時。將反應混 合液使用1 N鹽酸水溶液加以中和後，利用2〇%曱醇/氯仿 混合液進行萃取。將萃取液利用無水硫酸鈉乾燥後，進行 減壓》辰縮’獲得標記化合物（894 mg)。 MS (ESI) m/z: 501 (M+H)+ 〇 NMR (CDC13) δ·、3·17-3·27 (3H，m)，3·38-3·45 (2H，m)，3 66 (3H，s)，3.69 (2H，s)，5.37 (2H，s)，6·28 (1H，s)5 6.87 (lH dd，J = 8.8, 2·4 Hz)，7·15 (1H，d，J=2.2 Hz)，7.36-7.30 (2h m)，7.52-7.41 (5H，m)。 ’ 121200.doc •55- 2008463421-[|&gt;[(4-Phenyl-5-trifluoromethyl.2-thienyl)decyloxy]-1Η-吲 was mixed. Methyl-2-methyl-]methyl]azetidine_3_carboxylate (991 mg), THF (15 ml) and 0.25 N aqueous sodium hydroxide (154^1) were stirred for 24 hours. The reaction mixture was neutralized with a 1 N aqueous solution of hydrochloric acid, and then extracted with a mixture of 2% methanol/chloroform. After the extract was dried over anhydrous sodium sulfate, the mixture was subjected to reduced pressure to give the title compound (894 mg). MS (ESI) m/z: 501 (M+H) + NMR (CDC13) δ·, 3·17-3·27 (3H, m), 3·38-3·45 (2H, m), 3 66 (3H, s), 3.69 (2H, s), 5.37 (2H, s), 6·28 (1H, s) 5 6.87 (lH dd, J = 8.8, 2·4 Hz), 7·15 (1H , d, J = 2.2 Hz), 7.36-7.30 (2h m), 7.52-7.41 (5H, m). ’ 121200.doc •55- 200846342

Anal.Calcd for C26H23F3N203S.H20: C，60·22; H，4.86; F， 10.99; N，5.40; S，6.18。Anal.Calcd for C26H23F3N203S.H20: C, 60·22; H, 4.86; F, 10.99; N, 5.40; S, 6.18.

Found: C，60.09; H，4.82; F，11·23; N，5.33; S，6.30 〇 [實施例4]l-[[5-[3,5-雙-(三氟甲基）苄氧基甲基吲 哚-2-基]甲基]吖丁啶_3_羧酸 (1) 1-[[5-苄氧基甲基_1H-吲哚_2_基·]甲基]吖丁啶_3_羧 酸甲酉旨 [化 44]Found: C, 60.09; H, 4.82; F, 11·23; N, 5.33; S, 6.30 〇 [Example 4] l-[[5-[3,5-bis-(trifluoromethyl)benzyloxy) Methyl fluoren-2-yl]methyl]azetidine _3_carboxylic acid (1) 1-[[5-benzyloxymethyl_1H-吲哚_2_yl]methyl] hydrazine Butyridine_3_carboxylic acid formazan [化44]

混合5-苄氧基-1-曱基-1H-吲哚-2_曱醛（12i g)、吖丁唆_ 3-叛酸曱酯鹽酸鹽〇 〇4 g)、氯仿（1〇 mi)及醋酸（ο.]? ml)， 於擾拌下’於0°C添加三乙醯氧基氫化硼鈉（2.03 g)，同溫 下授拌2小時。於反應混合液中添加飽和碳酸氫鈉水溶液 加以中和，利用二氯甲垸進行萃取。將萃取液利用無水硫 酸納乾燥，進行減壓濃縮，將所獲得之殘渣藉由矽膠快速 管柱色層分析（山善高速管柱2 L)進行純化，獲得標記化合 物（1.62 g) 〇 MS (ESI) m/z: 365 (M+H)+。 NMR (CDC13) δ: 3·25-3·36 (3H，m)，3.46-3.55 (2H，m)， 3.68-3.72 (8H，m)，5.09 (2H，s)，6.27 (1H，s)，6·9〇_6 95 (1H，m)，7_l〇 (1H，d，J=2.2 Hz)，7·17 (1H，d，Ju Hz)， 7·28-7·33 (1H，m)，7·35-7·40 (2H，m)，7·48-7·44 (2H，m)。 121200.doc -56- 200846342 (2) 1-[[5-經基-1-曱基-1H-吲哚-2-基]-甲基]吖丁唆-3-羧酸 甲酯 [化 45]Mix 5-benzyloxy-1-indenyl-1H-indole-2_furfural (12i g), 吖丁唆_ 3-treazone 盐 ester 〇〇 4 g), chloroform (1〇mi And acetic acid (ο.]? ml), adding sodium triethoxy borohydride (2.03 g) at 0 ° C under stirring, and mixing at the same temperature for 2 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture for neutralization, and extraction was carried out using dichloromethane. The extract was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (2L of Shanshan high-speed column) to obtain the labeled compound (1.62 g) 〇MS (ESI) m/z: 365 (M+H)+. NMR (CDC13) δ: 3·25-3·36 (3H, m), 3.46-3.55 (2H, m), 3.68-3.72 (8H, m), 5.09 (2H, s), 6.27 (1H, s) ,6·9〇_6 95 (1H,m),7_l〇(1H,d,J=2.2 Hz),7·17 (1H,d,Ju Hz), 7·28-7·33 (1H,m ), 7·35-7·40 (2H, m), 7·48-7·44 (2H, m). 121200.doc -56- 200846342 (2) 1-[[5-Pyridyl-1-indolyl-1H-indol-2-yl]-methyl]azinium-3-carboxylic acid methyl ester ]

於甲醇（30 ml)中溶解l-[5-苄氧基-1-甲基吲哚基]吖丁 啶-3-羧酸甲酯（623 mg)，添加4 N鹽酸/ι，4-二氧雜環己烷 /谷液（855 μΐ)及 10%Pd(〇H)2/C(600 mg)，於檀拌下進行 18 小時接觸氫化。將觸媒過濾分離，減壓濃縮濾液。將所獲 得之殘渣藉由飽和碳酸氫鈉水溶液進行中和，添加水後， 利用醋酸乙酯進行萃取。將萃取液利用無水硫酸鈉乾燥， 進行減壓濃縮。將所獲得之殘液藉由矽膠快速管柱色層分 析（山善Ultra Pack U40)進行純化，獲得標記化合物ο% mg) 〇 MS (ESI) m/z: 275 (M+H)+。 NMR(CDC13) 5: 3.30-3.38 3.48-356 (2H,m) 3 72 3.68 (8H，m)，6.21 (1H，s)，6.74 〇H，机卜8% 2 — 6.92 (1H, d，J=2.4 Hz)，7.11 (1H，d，J=8.5 Hz)。 ， (3)h[5-[3,5-雙-(三氟甲基）节氧基]小甲基基] 甲基]吖丁啶-3-羧酸甲酯 i [化 46] 121200.doc -57- 200846342Dissolve methyl l-[5-benzyloxy-1-methylindolyl]azetidine-3-carboxylate (623 mg) in methanol (30 ml), add 4 N hydrochloric acid / ι, 4- Oxane/valley (855 μΐ) and 10% Pd(〇H) 2/C (600 mg) were subjected to contact hydrogenation under sandalwood for 18 hours. The catalyst was separated by filtration and the filtrate was concentrated under reduced pressure. The obtained residue was neutralized with a saturated aqueous sodium hydrogencarbonate solution, and water was added, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel flash chromatography (manufactured by Shanshan Ultra Pack U40) to obtain the labeled compound ο% mg) 〇 MS (ESI) m/z: 275 (M+H)+. NMR (CDC13) 5: 3.30-3.38 3.48-356 (2H,m) 3 72 3.68 (8H,m), 6.21 (1H,s), 6.74 〇H, machine 8% 2 — 6.92 (1H, d, J =2.4 Hz), 7.11 (1H, d, J = 8.5 Hz). , (3) h[5-[3,5-bis-(trifluoromethyl)oxy]methoxymethyl]methyl]azetidine-3-carboxylic acid methyl ester i [Chem. 46] 121200. Doc -57- 200846342

於3,5-雙-(三氟甲基）苯甲氯（341叫）及1β[[5_羥基-曱 基-111-’哚_2-基]甲基]。丫丁啶_3•羧酸曱酯（169叫）之DMF (2 ml)溶液中，添加碳酸鉀（128 mg)，於70°C下攪拌16小 日守。使反應混合液恢復至室溫後，過濾分離不溶物，於減 壓下濃縮濾液。將所獲得之殘渣藉由矽膠薄層色層分析進 _ 行純化，獲得標記化合物（91 mg)。 MS (ESI) m/z: 501 (M+H)+。 NMR (CDC13) δ: 3.28-3.38 (3H，m)，3·48-3·57 (2H，m)， 3.66-3.78 (8H，m)，5.19 (2H，s)，6.30 (1H，s)，6·94 (1H，dd， J=9.0, 3.4 Hz)，7.10 (1H，d，J=2.4 Hz)，7·21 (1H，d，J=8.8It is 3,5-bis-(trifluoromethyl)benzyl chloride (341) and 1β[[5-hydroxy-indenyl-111-'哚_2-yl]methyl]. To a solution of azetone -3-carboxylate (169) in DMF (2 ml), potassium carbonate (128 mg) was added and stirred at 70 ° C for 16 hours. After returning the reaction mixture to room temperature, the insoluble material was separated by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give the title compound (91 mg). MS (ESI) m/z: 501 (M+H)+. NMR (CDC13) δ: 3.28-3.38 (3H, m), 3·48-3·57 (2H, m), 3.66-3.78 (8H, m), 5.19 (2H, s), 6.30 (1H, s) ,6·94 (1H, dd, J=9.0, 3.4 Hz), 7.10 (1H, d, J=2.4 Hz), 7·21 (1H, d, J=8.8

Hz)，7·83 (1H，s)，7.94 (2H，s)。 (4) l-[[5-[3,5-雙-(三氟甲基）苄氧基]曱基_1Η_σ引哚_2_基] 甲基]吖丁啶-3-羧酸 • [化 47]Hz), 7·83 (1H, s), 7.94 (2H, s). (4) l-[[5-[3,5-Bis-(Trifluoromethyl)benzyloxy]indolyl_1Η_σ哚哚_2_yl]methyl]azetidine-3-carboxylic acid• 47]

於1_[[5-[3,5-雙-(三氟曱基;)苄氧基]·i甲基」弓丨哚_2_ 基]甲基]吖丁啶-3-羧酸甲酯（9ΐ·〇 mg)及甲醇: 2,3 ml)溶液中，於室溫下添加丨^氫氧化鈉水溶液Q ml)，攪 拌23小時。將反應混合液減壓濃縮，於所獲得之殘渣中添 121200.doc • 58 · 200846342 加1 N鹽酸，將PH值設為7，藉由10%曱醇/氯仿混人液進 行萃取。將萃取液利用飽和食鹽水加以清洗，藉由無水石责 酸鈉乾燥後，進行減壓濃縮。將所獲得之殘渣藉由薄層色 層分析進行純化，獲得標記化合物（56 mg)。 MS (ESI) m/z: 487 (M+H)+ 〇 NMR (DMSO-d6) δ·· 3.16-3.24 (2H，m)，3.33-3.46 (5H m) 3·66 (4H，s)，5.30 (2H，s)，6·24 (1H，s)，6·88 (1H，dd，J=8.8 2·2 Hz)，7.U (m，d，卜2.2 Hz)，7·31 (1H，d，j=8’8 HZ): 8·〇7 (1H，s)，8.16 (2H，s)。 ’ HRMS (FAB) Calcd for C23H2〇F6N203M·: 486.1378。To 1_[[5-[3,5-bis-(trifluoromethyl)-benzyloxy]·imethyl"丨哚丨哚_2_yl]methyl]azetidine-3-carboxylic acid methyl ester ( 9 ΐ·〇mg) and methanol: 2,3 ml), a solution of hydrazine sodium hydroxide aqueous solution (Q ml) was added at room temperature, and stirred for 23 hours. The reaction mixture was concentrated under reduced pressure, and then, to the residue obtained, 12 1200.doc • 58 · 200846342 was added with 1 N hydrochloric acid, and the pH was set to 7, and extracted by a 10% methanol/chloroform mixed solution. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified by thin layer chromatography to give the title compound (56 mg). MS (ESI) m/z: 487 (M+H) + NMR (DMSO-d6) δ·· 3.16-3.24 (2H,m),3.33-3.46 (5H m) 3·66 (4H, s), 5.30 (2H, s), 6·24 (1H, s), 6.88 (1H, dd, J = 8.8 2·2 Hz), 7.U (m, d, 卜 2.2 Hz), 7·31 ( 1H,d,j=8'8 HZ): 8·〇7 (1H, s), 8.16 (2H, s). ' HRMS (FAB) Calcd for C23H2〇F6N203M·: 486.1378.

Found: 486.1382 〇 [實施例5]l-[[5-[(2-氰基_4_聯苯基）甲氧基]_丨·甲基-吲 哚-2-基]甲基]吖丁啶羧酸 (1) 4-氯甲基聯苯基_2_甲腈 [化 48]Found: 486.1382 〇 [Example 5] l-[[5-[(2-Cyano-4-phenylbiphenyl)methoxy]- oxime methyl-indol-2-yl]methyl] Pyridinecarboxylic acid (1) 4-chloromethylbiphenyl-2-carbonitrile [48]

C1 於4 |工甲基聯苯基甲腈（12〇 mg)之二氯乙烧溶液（1〇 ml)中’以巴斯德吸管添加1滴亞硫醯氣（2〇8 及dMF， 於50 C下授拌一晚。使反應混合液冷卻至室溫為止後，進 订減壓濃縮。將所獲得之殘渣藉由矽膠快速管柱色層分析 (山善高速管柱L)進行純化，獲得標記化合物（136mg)。 121200.doc -59- 200846342 MS (ESI) m/z: 228 (M+H)+。 NMR (CDC13) δ: 4.63 (2H? s)y 7.46-7.57 (6H5 m)5 7.67 (1H, dd3 J=8.13 2.0 Hz)? 7.79 (lH3 d? J=2.〇 Hz) 〇 (2) 5-[(2-氰基-4-聯苯基）甲氧基]小甲基_m弓丨哚_2羧酸 乙酯 [化 49]Add 1 drop of sulfoxide (2〇8 and dMF) to a Pasteur pipette in a solution of 4% methyl 2-benzonitrile (12〇mg) in dichloroethane (1〇ml). After mixing at 50 C for one night, the reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (Shanshan high-speed column L). Labeled Compound (136 mg) 121200.doc -59-200846342 MS (ESI) m/z: 228 (M+H)+ NMR (CDC13) δ: 4.63 (2H?s)y 7.46-7.57 (6H5 m)5 7.67 (1H, dd3 J=8.13 2.0 Hz)? 7.79 (lH3 d? J=2.〇Hz) 〇(2) 5-[(2-Cyano-4-biphenyl)methoxy]methylene _m bow 丨哚 2 carboxylate ethyl ester [49]

於5-羥基-1-甲基-1H-吲哚_2_羧酸乙酯（219 mg)2DMF溶 液（5 mi)中，添加4_氯甲基聯苯基甲腈（273瓜幻及碳酸 卸（2〇7 mg) ’於贼下攪拌3天。使反應混合液冷卻至室溫 為止後，添加飽和碳酸氫鈉水溶液，利用醋酸乙醋萃取3 次。將萃取液利用飽和食鹽水加以清洗，制無水硫酸納Add 4-chloromethylbiphenylcarbonitrile (273 phantom and carbonic acid) to a solution of 5-hydroxy-1-methyl-1H-indole-2-carboxylic acid ethyl ester (219 mg) in 2DMF (5 mi) Discharge (2〇7 mg) 'with stirring for 3 days under thief. After cooling the reaction mixture to room temperature, add saturated aqueous sodium hydrogencarbonate solution and extract three times with ethyl acetate. Wash the extract with saturated brine. , anhydrous sodium sulfate

乾燥後，進行減壓濃縮。將所獲得之殘㈣由快速管枉色 層分析（山善高速管柱L)進行純化，獲得標記化合物（Μ mg)。 MS (ESI) m/z: 411 (M+H).。 (3H，s)，4.37 (2H，m)，7.22 m)5 7.72-7.74 麵R (CDC13) δ: L41 (3H，t.jy.i Hz)，4 〇7 (2H，q，Jd Ηζ)，5·16 (2H，s)，7 π·7 η (1H5 s)5 7.32-7.34 (1H5 m)? 7.45-7.58 (6H, (1H，m)，7·88 (1H，m) 〇 (3) 5-(2-氰基_4_聯苯基甲氧基）]_甲基仙令朵冬缓酸 121200.doc -60- 200846342 [化 50]After drying, it was concentrated under reduced pressure. The obtained residue (IV) was purified by rapid tube chromatography (Shanshan Express column L) to obtain a labeled compound (Μ mg). MS (ESI) m/z: 411 (M+H). (3H, s), 4.37 (2H, m), 7.22 m) 5 7.72-7.74 Surface R (CDC13) δ: L41 (3H, t.jy.i Hz), 4 〇7 (2H, q, Jd Ηζ) ,5·16 (2H,s),7 π·7 η (1H5 s)5 7.32-7.34 (1H5 m)? 7.45-7.58 (6H, (1H,m),7·88 (1H,m) 〇( 3) 5-(2-Cyano-4-phenylbimethoxy)]-methyl sulphate winter acid 121200.doc -60- 200846342 [化50]

於5-[(2·氰基-4-聯苯基）甲氧基 乙酿（335 mg)之 THF 溶液（1G ml)中 土·111·^2'緩酸 簡氧化納水溶液（2.45ml)，於室、、：；加甲醇（2.45叫及】 、 )於至溫下攪拌一晚。於反應 混a液中添加1 Ν鹽酸水溶液，進行 w 仃减壓滚細。於所獲得 之殘渣中添加水，遽取所析出之固體，並進行乾燥，獲得 標記化合物（3 18 mg)。 MS (ESI) m/z: 383 (M+H)+。 丽 R(DMS〇-d6)S:4.00(3H，s)，5 24 (2H s)，7ii7i3 (2H, m), 7.27 (1H, d, J=2.5 Hz), 7.48.7&gt;67 (?H&gt; ? g? (1H，dd，J=1.5, 8.1 Hz)，8.04 (1H，d，J=i 5 Hz)。 (4) 5-[(2-氰基-4-聯笨基）甲氧基甲基_1H_吲哚_2_甲醇 [化 51]In a solution of 5-[(2·Cyano-4-biphenyl)methoxyethyl (335 mg) in THF (1G ml), a solution of a solution of a solution of sodium sulphate (2.45ml) , in the room,,:; add methanol (2.45 called and), and stir for one night at the temperature. To the reaction mixture, a 1 Torr hydrochloric acid aqueous solution was added, and the mixture was depressurized and rolled. Water was added to the obtained residue, and the precipitated solid was taken and dried to obtain a labeled compound (3 18 mg). MS (ESI) m/z: 381 (M+H)+.丽R(DMS〇-d6)S: 4.00(3H, s), 5 24 (2H s), 7ii7i3 (2H, m), 7.27 (1H, d, J=2.5 Hz), 7.48.7&gt;67 (? H&gt; ? g? (1H, dd, J=1.5, 8.1 Hz), 8.04 (1H, d, J=i 5 Hz). (4) 5-[(2-Cyano-4-linked) oxymethyl_1H_吲哚_2_methanol [化51]

於5-[(2-氰基-4-聯苯基）甲氧基]-1-甲基緩酸 (310 mg)之THF溶液（10 ml)中，添加三乙胺（17〇 μ1)，於冰 121200.doc 61 - 200846342 浴冷卻攪拌下添加氯碳酸乙酯(93 μ1)，於室溫下攪拌η、 時。於氫化硼鈉（184 mg)之乙醇懸浮液（3 ml)中，冰浴冷 部下添加上述反應混合液，於室溫下攪拌丨小時。於反應 混合液中添加1 N鹽酸水溶液，利用醋酸乙酯萃取2次。將 萃取液利用1 N氫氧化鈉水溶液及飽和食鹽水加以清洗， 利用無水硫酸鈉乾燥後，進行減壓濃縮。將所獲得之殘渣 藉由矽膠快速管柱色層分析（山善高速管柱乙）進行純化， 獲得標記化合物（247 mg)。 MS (ESI) m/z: 369 (M+H) +。 NMR (CDC13) δ: 1.52 (1Η5 t, J=6.1 Hz), 3.79 (3H, s)5 4.79 (2H，d，J=6.1 Hz)，5·16 (2H，s)5 6.39 (1H，s)，6·99 (1H，dd， J=2.5, 8·8 Hz)，7·12 (1H，d，J=2.5 Hz)，7,24-7.26 (1H，m)， 7·43-7·57 (6H，m)，7·73 (1H，dd，J=l.l，8.0 Hz)，7·87 (1H， s) 0 (5) 5-[(2-氰基-4·聯苯基）甲氧基]小曱基-吲哚_2-甲駿 [化 52]Add 3-ethylamine (17〇μ1) to a solution of 5-[(2-cyano-4-biphenyl)methoxy]-1-methyl-acid (310 mg) in THF (10 ml).于冰121200.doc 61 - 200846342 Add ethyl chlorocarbonate (93 μl) under cooling with stirring, and stir at room temperature for η. The above reaction mixture was added to an ethanol suspension of sodium borohydride (184 mg) (3 ml), and the mixture was stirred at room temperature for an hour. A 1 N aqueous hydrochloric acid solution was added to the reaction mixture, and extracted twice with ethyl acetate. The extract was washed with a 1 N aqueous sodium hydroxide solution and brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by silica gel chromatography (Shanshan High Speed Column B) to obtain a labeled compound (247 mg). MS (ESI) m/z: 369 (M+H)+. NMR (CDC13) δ: 1.52 (1Η5 t, J=6.1 Hz), 3.79 (3H, s)5 4.79 (2H,d,J=6.1 Hz),5·16 (2H,s)5 6.39 (1H,s ),6·99 (1H,dd, J=2.5, 8·8 Hz), 7·12 (1H,d,J=2.5 Hz), 7,24-7.26 (1H,m), 7·43-7 ·57 (6H,m),7·73 (1H,dd,J=ll,8.0 Hz),7·87 (1H, s) 0 (5) 5-[(2-cyano-4·biphenyl) )methoxy]small fluorenyl-吲哚_2-甲骏 [化52]

於5-[(2-氰基·4-聯苯基）甲氧基]-1-曱基弓卜朵-2 -甲醇 (349 mg)之THF(10 ml)溶液中，添加氯化鈉（12〇 mg)及二 氧化錳（3 72 mg)，於室溫下攪拌一晚。將反應混合液進行 石夕藻土過濾，減壓濃縮濾液。將所獲得之殘渣藉由;s夕膠快 121200.doc -62- 200846342 速管柱色層分析(山善高速管柱Lm行純化，獲得標記化 合物（225 mg)。 NMR (DMSO-d6) δ: 4.02 (3H5 s)5 5.26 (2H5 s)5 7.22 (1H5 dd5 J=2.5? 9.1 Hz), 7.36 (2H? s)5 7.50-7.68 (7H, m)j 7.88 (1H’ 机 J 8·1’ 15 Hz)，8·05 (1H，d，J=1.5 Hz)，9·88 (1H， s) 〇 (6) 1 [[5 [(2-氰基_4_聯苯基）甲氧基卜丨―甲基^仏叫I哚·2_ 基]曱基]σ丫丁啶-3-羧酸甲酯 [化 53]Add sodium chloride to a solution of 5-[(2-cyano-4-phenyl)methoxy]-1-indolyl-2 -methanol (349 mg) in THF (10 ml) 12 〇 mg) and manganese dioxide (3 72 mg) were stirred at room temperature for one night. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue obtained was obtained by sigmatism 121200.doc -62-200846342 speed column chromatography (Lanshan high-speed column Lm purification to obtain the labeled compound (225 mg). NMR (DMSO-d6) δ: 4.02 (3H5 s)5 5.26 (2H5 s)5 7.22 (1H5 dd5 J=2.5? 9.1 Hz), 7.36 (2H? s)5 7.50-7.68 (7H, m)j 7.88 (1H' machine J 8·1' 15 Hz),8·05 (1H,d,J=1.5 Hz),9·88 (1H, s) 〇(6) 1 [[5 [(2-cyano-4_biphenyl)methoxy]丨 丨 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基

Ό^χ&gt;γ、 於5-[(2-氰基_4_聯苯基）曱氧基曱基_1Η_吲哚_2_曱醛 (214 mg)之氯仿（1〇 ml)溶液中，添加吖丁啶_3•羧酸甲酯鹽 酸鹽（133 mg)及醋酸（33 μ1)，於室溫下攪拌3〇分鐘。將反 應此a液進行冰浴冷卻，添加三乙酸氧基氫化硼鈉（26工 mg)，於室溫下攪拌4小時。於反應混合液中添加飽和碳酸 氫鈉水溶液，利用氯仿萃取3次。將萃取液利用飽和食鹽 水進行清洗’利用無水硫酸鈉乾燥後，進行減壓濃縮。將 所獲付之殘〉查藉由快速管柱色層分析（山善高速管柱L)進 行純化’獲得標記化合物（245 mg)。 NMR (CDC13) δ: 3.29-3.36 (3H，m)，3.47-3.53 (2H，m)， 3·71-3·73 (8H，m)，5·16 (2H，s)，6·30 (1H，s)，6·94 (1H，dd， 121200.doc -63- 200846342 J=2.5, 8·8 Ηζ)，7·09 (1H，d，&gt;2·5 Hz)，7.21 (1H，d，J=8.8Ό^χ&gt;γ, in a solution of 5-[(2-cyano-4-(biphenyl) decyloxy fluorenyl-1Η_吲哚_2_furfural (214 mg) in chloroform (1 〇 ml) Add azetidine _3•carboxylic acid methyl ester hydrochloride (133 mg) and acetic acid (33 μl), and stir at room temperature for 3 minutes. This solution was cooled in an ice bath, and sodium triacetoxyborohydride (26 mg) was added thereto, and the mixture was stirred at room temperature for 4 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and the mixture was extracted three times with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by rapid column chromatography (Shanshan Express column L) to obtain a labeled compound (245 mg). NMR (CDC13) δ: 3.29-3.36 (3H,m), 3.47-3.53 (2H,m), 3·71-3·73 (8H,m),5·16 (2H,s),6·30 ( 1H, s), 6·94 (1H, dd, 121200.doc -63- 200846342 J=2.5, 8·8 Ηζ), 7·09 (1H, d, &gt; 2·5 Hz), 7.21 (1H, d, J=8.8

Hz)，7·43-7·55 (6H，m)，7.73 (1H，dd，J=2.0, 8.1 Hz)，7.88 (1H, d? J=1.2 Hz) 〇 (7) M[5-[(2-氰基-4·聯苯基）甲氧基^^甲基-丨仏吲哚^-基l·甲基]吖丁啶-3-羧酸 、 [化 54]Hz), 7·43-7·55 (6H, m), 7.73 (1H, dd, J=2.0, 8.1 Hz), 7.88 (1H, d? J=1.2 Hz) 〇(7) M[5-[ (2-cyano-4·biphenyl)methoxy^^methyl-丨仏吲哚^-yl l·methyl]azetidine-3-carboxylic acid, [Chem. 54]

°ΧΧ^-Ν〇γΗ 於^[5-(2-氰基聯苯基-4-基曱氧基）曱基-丨仏吲垛-2_ 基曱基]吖丁啶-3-羧酸甲酯（240 mg)之THF(5 ml)溶液中， 添加甲醇（1·55 ml)及1 N氫氧化鈉水溶液（1·55 ml)，於室溫 下攪拌2小時。於反應混合液中添加i N鹽酸水溶液加以中 和後，進行減壓濃縮。於所獲得之殘渣中添加水，濾取所 析出之固體，於減壓下進行乾燥，獲得標記化合物（226 mg) 〇 MS (ESI) m/z: 452 (M+H)+ 〇 NMR (DMSO-d6) δ: 3.20-3.24 (3H，m)，3.37-3.41 (2H，m)， 3.66 (5H，s)，5·21 (2H，s)，6·25 (1H, s)，6·88 (1H，dd，J=2.5, 8·8 Hz)，7·11 (1H，d，J=2.5 Hz)，7.31 (1H，d，J=8.8 Hz)， 7.49-7.66 (6H，m)，7.86 (1H，dd，J=2.7，8.1)，8.01 (1H，d， J=1.7 Hz) 〇 IR (ATR)cm·1: 2981，2231， 1592， 1481， 1353， 1191. 121200.doc _ 200846342°ΧΧ^-Ν〇γΗ ^^[5-(2-Cyanobiphenyl-4-ylindenyloxy)indolyl-indole-2_ylindolyl]azetidine-3-carboxylic acid To a solution of the ester (240 mg) in THF (5 ml), methanol (1·55 ml) and 1 N aqueous sodium hydroxide (1·55 ml) were added and stirred at room temperature for 2 hours. After neutralizing the aqueous solution of i N hydrochloric acid to the reaction mixture, the mixture was concentrated under reduced pressure. Water was added to the obtained residue, and the precipitated solid was filtered, and dried under reduced pressure to give the title compound (226 mg) 〇MS (ESI) m/z: 452 (M+H) + NMR (DMSO) -d6) δ: 3.20-3.24 (3H,m), 3.37-3.41 (2H,m), 3.66 (5H,s),5·21 (2H,s),6·25 (1H, s),6· 88 (1H, dd, J=2.5, 8·8 Hz), 7·11 (1H, d, J=2.5 Hz), 7.31 (1H, d, J=8.8 Hz), 7.49-7.66 (6H, m) , 7.86 (1H, dd, J = 2.7, 8.1), 8.01 (1H, d, J = 1.7 Hz) 〇IR (ATR) cm·1: 2981, 2231, 1592, 1481, 1353, 1191. 121200.doc _ 200846342

AnaLCalcd for C28HmN，Pi 〇 ^ TT 25γμ3〇3: c，74·48; H，5 58; N，9 31。AnaLCalcd for C28HmN, Pi 〇 ^ TT 25γμ3〇3: c, 74·48; H, 5 58; N, 9 31.

Found: C，74·10; H，5.57; N，9 〇6。 ' [貝施例6]1-[[5-[(2-二氣甲基_4_聯苯基）甲氧基]m 2-基]曱基]σ丫丁咬-3-羧酸^ (1) 2-二敗甲基聯苯基_4、羧酸甲酷 [化 55]Found: C, 74·10; H, 5.57; N, 9 〇 6. ' [Best example 6] 1-[[5-[(2-dimethylmethyl_4_biphenyl)methoxy]m 2-yl] fluorenyl] σ丫丁丁-3-carboxylic acid^ (1) 2- sec-methylphenyl _4, carboxylic acid 甲 [[55]

於3-三氟甲基-4-(三氟甲石黃醯氧基）苯甲酸甲醋（361叫) 之甲苯（10 ml)’合液中’於室溫下添加苯基爛酸（，叫）、 碳酸铯（1.00g)及水aGml)。於混合溶液中通入3分鐘氮氣 後外、加四一苯基科！巴（236 。將反應混合液於9代下 攪:拌9 0分鐘後’冷卻至家炎 土至/皿為止，添加醋酸乙酯（20 ml)及 飽和食鹽水（2G ml)，並進行分液。收集有機層，將其利用 無水硫酸鈉乾燥後，進行減壓濃縮。將所獲得之殘渣藉由 矽膠快速管柱色層分析（Biotage MM)進行純化，獲得標記 化合物（278 mg)。 雇R (CDC13) δ: 3·98 (3H，s)，7.29-7.45 (6H，m)，8·21 (1H， dd，J—8.0，1.4 Ηζ)，8·43 (1H，d，J=1.4 Hz) (2) 2·三氟甲基聯苯基_4-甲醇 [化 56] •65- 121200.doc 200846342Adding phenyl rotten acid at room temperature in toluene (10 ml) in a mixture of 3-trifluoromethyl-4-(trifluoromethylxanthoxy)benzoic acid methyl vinegar (361) Call), cesium carbonate (1.00g) and water aGml). After passing nitrogen gas for 3 minutes in the mixed solution, add tetraphenylbenzene! Bar (236. Mix the reaction mixture in the 9th generation: after mixing for 90 minutes, 'cool down to the home soil to / dish, add ethyl acetate (20 ml) and saturated brine (2G ml), and divide The organic layer was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (Biotage MM) to obtain the labeled compound (278 mg). R (CDC13) δ: 3·98 (3H, s), 7.29-7.45 (6H, m), 8·21 (1H, dd, J-8.0, 1.4 Ηζ), 8.43 (1H, d, J= 1.4 Hz) (2) 2·trifluoromethylbiphenyl_4-methanol [56] •65- 121200.doc 200846342

於2·三氟甲基聯苯基-4-羧酸甲酯（215 mg)之THF(10 ml) 溶液中，於室溫下添加氫化硼鋰（5〇·〇 mg)。將反應混合液 於攪拌下加熱回流15小時後，冷卻至室溫為止，添加水 (30 ml)及1 n鹽酸水溶液（30 ml)，利用醋酸乙酯（2x30 ml) 進行萃取。將萃取液利用飽和碳酸氫鈉水溶液（3〇 ml)加以 清洗’利用無水硫酸鈉乾燥後，進行減壓濃縮。將所獲得 之殘 &gt;查使用石夕膠快速管柱色層分析（Biotage 25M)進行純 化’獲得標記化合物（1 82 mg)。 NMR (CDC13) δ: 1.85 (1Η, t? J=5.9 Hz)? 4.81 (2H? d? J=5.9To a solution of methyl 2,trifluoromethylbiphenyl-4-carboxylate (215 mg) in THF (10 ml), lithium borohydride (5 〇·〇 mg) was added at room temperature. The reaction mixture was heated to reflux with stirring for 15 hr. and then cooled to room temperature. Water (30 ml) and 1 n aqueous hydrochloric acid (30 ml) were added, and ethyl acetate (2×30 ml) was used for extraction. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate (3 mL) and dried over anhydrous sodium sulfate. The obtained residue &gt; was purified by using Shishi gum rapid tube chromatography (Biotage 25M) to obtain a labeled compound (1 82 mg). NMR (CDC13) δ: 1.85 (1Η, t? J=5.9 Hz)? 4.81 (2H? d? J=5.9

Hz)，7.27-7.48 (6H，m)，7·56 (1H，br d，J=8.3 Hz)，7.76 (1H，br s) 〇 (3) 5-[(2-三氟曱基聯苯基）曱氧基；j_1H-吲哚-2-羧酸乙酯 [化 57]Hz), 7.27-7.48 (6H, m), 7.56 (1H, br d, J = 8.3 Hz), 7.76 (1H, br s) 〇(3) 5-[(2-Trifluorodecylbiphenyl) Ethyloxyl;j_1H-indole-2-carboxylic acid ethyl ester [57]

於2-三氟甲基聯苯基-4-甲醇（2〇〇 mg)之THF(2.0 ml)溶液 中’於至溫下添加5·經基· 1 Η-°引ϋ朵-2 -緩酸乙醋（209 mg)、 二笨基膦（265 mg)及DEAD(0.160 ml)。將反應混合液於室 溫下攪拌12小時後，進行減壓濃縮。將所獲得之殘渣使用 121200.doc •66· 200846342 矽膠管柱快速色層分析（Biotage 25M)進行純化，獲得標記 化合物（215 mg)。 MS (ESI) m/z: 440 (M+H).。 NMR (CDC13) δ: 1.41 (3H，t，J=7.1 Ηζ)，4·40 (2H，q，J==7el Hz)，5.18 (2H，s)，7·11 (1H，dd，J=9.0, 2.2 Hz)，7.13-7.20 • (2H，m)，7,20-7.43 (7H，m)，7·66 (1H，d，J=7.2 Hz)、7.85 β (1H，s)，8·77 (1H，br s)。 (4) 5-[(2-三氟甲基-4-聯苯基）甲氧基]-1H-吲哚-2-甲醇 ^ [化 58]In a solution of 2-trifluoromethylbiphenyl-4-methanol (2〇〇mg) in THF (2.0 ml), add 5················ Ethyl acetate (209 mg), diphenylphosphine (265 mg) and DEAD (0.160 ml). The reaction mixture was stirred at room temperature for 12 hours and then concentrated under reduced pressure. The residue obtained was purified using a 121200.doc •66·200846342 gel column chromatography (Biotage 25M) to give the labeled compound (215 mg). MS (ESI) m/z: 440 (M+H). NMR (CDC13) δ: 1.41 (3H, t, J = 7.1 Ηζ), 4·40 (2H, q, J==7el Hz), 5.18 (2H, s), 7·11 (1H, dd, J= 9.0, 2.2 Hz), 7.13-7.20 • (2H,m), 7,20-7.43 (7H,m),7·66 (1H,d,J=7.2 Hz), 7.85 β (1H,s),8 · 77 (1H, br s). (4) 5-[(2-Trifluoromethyl-4-biphenyl)methoxy]-1H-indole-2-methanol ^ [Chem. 58]

於氫化铭鋰（60·0 mg)之THF(2.0 ml)懸浮液中，於〇。〇下 滴加5-[(2-三氟曱基-4-聯苯基）甲氧基]-1H-吲哚_2-羧酸乙 酯（210 mg)之THF(2.0 ml)溶液。將反應混合液加熱回流4 小時後，冷卻至〇°C，小心添加水（0· 1 50 ml)。藉由過據去 除所生成之沈澱物，減壓下濃縮濾液，將所獲得之殘渣使 用石夕膠快速管柱色層分析（Biotage 25M)進行純化，獲得標 記化合物（15 1 mg)。 MS (ESI) m/z: 398 (M+H).。 NMR (CDC13) δ: 1·71 (1H，t，J=5.9 Hz)，4.82 (2H，d，J=5.9 Hz)，5.17 (2H，s)，6·35 (1H，d，J=1.2 Hz)，6.95 (1H，dd J=8.8, 2·4 Hz)，7.14 (1H，d，J=2.4 Hz)，7·27 (1H，d，J=8.8 121200.doc -67- 200846342In a suspension of Hydrazine (60. 0 mg) in THF (2.0 ml). A solution of 5-[(2-trifluorodecyl-4-biphenylyl)methoxy]-1H-indole-2-carboxylic acid ethyl ester (210 mg) in THF (2.0 ml) was dropwise. The reaction mixture was heated to reflux for 4 h then cooled to EtOAc and water (0·1 50 ml). The precipitate formed was removed by evaporation, and the filtrate was concentrated under reduced pressure. The obtained residue was purified using EtOAc EtOAc (EtOAc) MS (ESI) m/z: 398 (M+H). NMR (CDC13) δ: 1·71 (1H, t, J = 5.9 Hz), 4.82 (2H, d, J = 5.9 Hz), 5.17 (2H, s), 6.35 (1H, d, J = 1.2) Hz), 6.95 (1H, dd J=8.8, 2·4 Hz), 7.14 (1H, d, J=2.4 Hz), 7·27 (1H, d, J=8.8 121200.doc -67- 200846342

Hz)，7·84 (1H，Hz), 7.84 (1H,

Hz)，7.29-7.43 (6H，m)，7.65 (1H，d s)，8·24 (1H，br s) 〇 (5) 5-[(2-三l甲基-4-聯苯基）甲氧基]_ih令朵_2_甲搭 [化 59]Hz), 7.29-7.43 (6H, m), 7.65 (1H, ds), 8·24 (1H, br s) 〇(5) 5-[(2-Tri-l-methyl-4-biphenyl) A Oxy]_ih makes a flower_2_甲搭[化59]

於5-[(2-三氟曱基-4-聯苯基）甲氧基_111_吲哚_2_甲醇（15〇 mg)之THF(50 ml)溶液中，於室溫下添加食鹽（2〇〇 mg)及二 氧化猛（200 mg)。將反應混合液於室溫攪拌下3天後，藉 由過濾去除不溶物，減壓濃縮濾液。將所獲得之殘潰使用 矽膠快速管柱色層分析（Biotage 25M)進行純化，獲得標記 化合物（93.8 mg)。 MS (ESI) m/z: 396 (M+H)十。 NMR (CDC13) δ: 5.19 (2H? s), 7.18-7.25 (3Η5 m)? 7.30^7.45 (7Η，m)，7.67 (1Η，d，J=7.8 Hz), 7.86 (1Η，s)5 8·9〇 (1Η，br s)，9·82 (1H，s) 〇 (6) l-[[5-[(2-三氟甲基-4-聯苯基）甲氧基]-1H_，《朵_2_基]甲 基]吖丁啶-3-羧酸 ‘ [化 60] 121200.doc -68- 200846342Add salt to room temperature at room temperature in a solution of 5-[(2-trifluoromethyl-4-biphenyl)methoxy_111_吲哚_2-methanol (15 mg) in THF (50 ml) (2 〇〇 mg) and oxidized violent (200 mg). After the reaction mixture was stirred at room temperature for 3 days, the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel flash chromatography (Biotage 25M) to give the title compound (93.8 mg). MS (ESI) m/z: 396 (M+H). NMR (CDC13) δ: 5.19 (2H? s), 7.18-7.25 (3Η5 m)? 7.30^7.45 (7Η,m), 7.67 (1Η,d,J=7.8 Hz), 7.86 (1Η,s)5 8 ·9〇(1Η,br s),9·82 (1H,s) 〇(6) l-[[5-[(2-Trifluoromethyl-4-biphenyl)methoxy]-1H_, "Duo_2_yl]methyl]azetidine-3-carboxylic acid '[60] 121200.doc -68- 200846342

於5-[(2-二氟甲基-4 -聯苯基）甲氧基]-1H· 弓I鳴_2_甲酸 (930 mg)及吖丁啶_3·羧酸（lls mg)之甲醇（1〇以）懸浮液 中，添加醋酸（1·〇 ml)，於室溫下攪拌3〇分鐘。於混合液 中添加氰基硼氫化鈉（50.0 mg)，於室溫下攪拌15小時。於 反應混合液中添加飽和碳酸氫鈉水溶液，將PH值調整為約 8後’添加氯仿（50 ml)，藉由過濾去除不溶物。將濾液分 液後’利用氣仿（50 ml)萃取水層。將萃取液減壓濃縮後， 合併不溶物溶解於DMSO(3.0 ml)中。藉由矽藻土過濾去除 不溶物後，減壓濃縮濾液，將所獲得之殘渣使用逆相高速 液體色層分析（野村化學Develosil Combi-RP-5)進行純化， 獲得標記化合物（5 6.5 mg)。 MS (FAB) m/z: 481 (M+H)+ 〇 NMR (DMSO-d6) δ: 3·10·3·42 (5H，m)，3.61 (2H，s)，5·21 (2H，s)，6.16 (1H，s)，6.78 (1H，dd，J=8.6, 2·3 Hz)，7·〇7 (1H，d，J=2.3 Hz)，7.19 (1H5 d，J=8.6 Hz)，7·26-7·34 (2H， m)，7.38-7.47 (4H，m)，7·77 (1H，d，J=7.6 Hz)，7·89 (1H，s)， 10·83 (1H，br s)。未觀到測緩酸之質子。 IR (ATR)cm-1: 3170，1572，1389，1317，1184，1126，1070, 845, 700 〇5-[(2-Difluoromethyl-4-(biphenylyl)methoxy]-1H· I I _2 carboxylic acid (930 mg) and azetidine _3·carboxylic acid (lls mg) To the suspension of methanol (1 Torr), acetic acid (1·〇ml) was added, and the mixture was stirred at room temperature for 3 minutes. Sodium cyanoborohydride (50.0 mg) was added to the mixture, and stirred at room temperature for 15 hr. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, and the pH was adjusted to about 8, then chloroform (50 ml) was added, and insolubles were removed by filtration. After the filtrate was separated, the aqueous layer was extracted with a gas mixture (50 ml). After the extract was concentrated under reduced pressure, the combined insoluble material was dissolved in DMSO (3.0 ml). After the insoluble matter was removed by filtration through celite, the filtrate was concentrated under reduced pressure, and the obtained residue was purified using reverse phase high-speed liquid chromatography (Nevec Chemical Devalosil Combi-RP-5) to obtain a labeled compound (5 6.5 mg). . MS (FAB) m/z: 481 (M+H) + NMR (DMSO-d6) δ: 3·10·3·42 (5H, m), 3.61 (2H, s), 5·21 (2H, s), 6.16 (1H, s), 6.78 (1H, dd, J=8.6, 2·3 Hz), 7·〇7 (1H, d, J=2.3 Hz), 7.19 (1H5 d, J=8.6 Hz) ),7·26-7·34 (2H, m), 7.38-7.47 (4H,m),7·77 (1H,d,J=7.6 Hz),7·89 (1H,s), 10·83 (1H, br s). No protons were detected. IR (ATR) cm-1: 3170, 1572, 1389, 1317, 1184, 1126, 1070, 845, 700 〇

Anal.Calcd for C27H23F3〇3N2-H2〇: C，65.05; Η, 5·05; F， 11.43; N，5.62 〇 121200.doc -69- 200846342Anal.Calcd for C27H23F3〇3N2-H2〇: C,65.05; Η, 5·05; F, 11.43; N,5.62 〇 121200.doc -69- 200846342

Found: C，64.81; H，4.97; F，11.09; Ν，5·65 〇 [實施例7]3·[Ν-[1-甲基-5-[(4-苯基-5-三氟甲基-2-噻吩基） 甲氧基]-1Η-吲哚-2-基]曱基胺基]丙酸 (1) 3 - [Ν- [1-甲基-5-[(4 -苯基-5-二氟甲基-2-嘆吩基）甲氧 基]-1Η-吲哚-2-基]曱基胺基]丙酸乙酯 * [化 61]Found: C, 64.81; H, 4.97; F, 11.09; Ν, 5·65 〇 [Example 7] 3·[Ν-[1-methyl-5-[(4-phenyl-5-trifluoromethyl) Methyl-2-thienyl) methoxy]-1Η-indol-2-yl]nonylamino]propionic acid (1) 3 - [Ν-[1-methyl-5-[(4-phenyl) -5-Difluoromethyl-2-indolyl)methoxy]-1Η-indol-2-yl]nonylamino]propionic acid ethyl ester* [Chem. 61]

於1·甲基-5-[(4-苯基-5-三氟甲基-2-噻吩基）甲氧基]· 1Η_ 吲哚-2-甲醛（1.13 g)、3-胺基丙酸乙酯鹽酸鹽（46· 1 mg)及 ΤΕΑ(92·0 μΐ)之二氣曱烧（5.0 ml)溶液中，於室溫下添加硫 酸鎂（40 mg)。將反應混合液擾拌15小時後，於室溫下添 加氣基侧氮化納（31.8 mg)，進而擾摔14小時。於反應液中 添加氯仿（10 ml)及飽和碳酸氫鈉水溶液（1〇 mi)，進行分 液’利用氣仿（5 mix2)萃取水層。將萃取液利用無水硫酸 鈉乾燥後，進行減壓濃縮。將所獲得之殘渣藉由矽膠快速 管柱色層分析（Biotage 25M)進行純化，獲得標記化合物 (91.4 mg) 〇 MS (ESI) m/z: 517 (M+H)+。 NMR (CDC13) δ: 1·24 (3H，t，J=7.2 Hz)，2·50 (2H，t，J=6.3 Hz)，2·94 (2H，t，J=6.3 Hz)，3.72 (3H，s)5 3.91 (2H，s)，4.13 (2H，q5 J=7.1 Hz)，5.23 (2H，s)，6.32 (1H，s)，6.92 (1H，dd， J=8.8, 2.4 Hz)，7.06 (1H，br s)，7·12 (1H，d，J=2.4 Hz)，7.19 121200.doc -70- 200846342 (1H，d，J=8.8 Ηζ)，7·44-7·36 (5H，m)。 (2) 3-[Ν-Π-甲基-5-[(4-苯基-5_三氟甲基_2_噻吩基）甲氡 基]-1Η-σ弓卜朵-2-基]曱基胺基]丙酸 [化 62]1·Methyl-5-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]· 1Η_吲哚-2-carbaldehyde (1.13 g), 3-aminopropionic acid To a solution of ethyl ester hydrochloride (46·1 mg) and hydrazine (92·0 μΐ) in dioxane (5.0 ml), magnesium sulfate (40 mg) was added at room temperature. After the reaction mixture was stirred for 15 hours, a gas-based side sodium nitride (31.8 mg) was added at room temperature, and the mixture was disturbed for 14 hours. Chloroform (10 ml) and a saturated aqueous solution of sodium hydrogencarbonate (1 〇mi) were added to the reaction mixture, and the aqueous layer was extracted by gas mixture (5 mix 2). The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel flash chromatography (Biotage 25M) to give the title compound (91.4 mg) 〇 MS (ESI) m/z: 517 (M+H)+. NMR (CDC13) δ: 1·24 (3H, t, J = 7.2 Hz), 2·50 (2H, t, J = 6.3 Hz), 2·94 (2H, t, J = 6.3 Hz), 3.72 ( 3H, s) 5 3.91 (2H, s), 4.13 (2H, q5 J = 7.1 Hz), 5.23 (2H, s), 6.32 (1H, s), 6.92 (1H, dd, J = 8.8, 2.4 Hz) ,7.06 (1H,br s),7·12 (1H,d,J=2.4 Hz),7.19 121200.doc -70- 200846342 (1H,d,J=8.8 Ηζ),7·44-7·36 ( 5H, m). (2) 3-[Ν-Π-Methyl-5-[(4-phenyl-5-trifluoromethyl_2_thienyl)methylindenyl]-1Η-σ-bend-2-yl] Mercaptoamine]propionic acid

於3-[Ν·[1_甲基·5-[(4_苯基三氟甲基-2·噻吩基）甲氧 基]-1Η-吲哚-2-基]甲基胺基]丙酸乙酯（914 mg)之33%甲醇/ THF(3 ml)混合溶液中，添加丨^^氫氧化鈉水溶液（1加）， 於室溫下攪拌14小時。於反應混合液中添加水（5 ml)後， 添加1 N鹽酸水溶液直至成為弱酸性（ph值4)為止。將該混 合液利用10%甲醇/氯仿混合液進行萃取，將萃取液利用無 水硫酸鈉乾燥後，進行減壓濃縮。於所獲得之殘渣中添加 氯仿（2 ml)，濾取所析出之固體，利用少量氣仿加以清洗 後，於減壓下乾燥，獲得標記化合物（39.3 mg)。 NMR (DMSO-d6) δ: 2.50-2.42 (2H，brm)，2.93-2.87 (2H， brm)，3.71 (3H，s)，4·〇3 (2H，s)，5.37 (2H，s)，6·39 (1H，s)， 6.88 (1H，d，J=8.3 Hz)，7·18(1Η，s)，7.37-7.33 (2H，m)， 7·50·7·40 (5H，m) 〇 [實施例8] 1-[[1-甲基-5-[(4-苯基-5-三氟甲基-2-噻吩基）甲 氧基]-1H-吡咯幷[2,3-b]吡啶-2-基]甲基-吖丁啶-3-羧酸 甲酯 (1) 1-(第三丁氧基羰基）苯基-5-三氟曱基-2-噻吩基） 121200.doc -71 - 200846342 甲氧基]-1Η-吡咯幷[2,3-b]吡啶-2-羧酸乙酯 [化 63]3-[Ν·[1_Methyl·5-[(4_phenyltrifluoromethyl-2·thienyl)methoxy]-1Η-indol-2-yl]methylamino]propyl To a mixed solution of ethyl acetate (914 mg) in 33% methanol / THF (3 ml), EtOAc (EtOAc) After adding water (5 ml) to the reaction mixture, a 1 N aqueous hydrochloric acid solution was added until it became weakly acidic (pH 4). The mixture was extracted with a 10% methanol/chloroform mixture, and the extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Chloroform (2 ml) was added to the obtained residue, and the precipitated solid was filtered, washed with a small amount of air, and dried under reduced pressure to give the title compound (39.3 mg). NMR (DMSO-d6) δ: 2.50-2.42 (2H, brm), 2.93-2.87 (2H, brm), 3.71 (3H, s), 4·〇3 (2H, s), 5.37 (2H, s), 6.39 (1H, s), 6.88 (1H, d, J = 8.3 Hz), 7.18 (1Η, s), 7.37-7.33 (2H, m), 7·50·7·40 (5H, m 〇 [Example 8] 1-[[1-Methyl-5-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]-1H-pyrrole[2,3 -b]pyridin-2-yl]methyl-azetidine-3-carboxylic acid methyl ester (1) 1-(t-butoxycarbonyl)phenyl-5-trifluoromethyl-2-thienyl) 121200.doc -71 - 200846342 Ethyl methoxy]-1 Η-pyrrole [2,3-b]pyridine-2-carboxylic acid ethyl ester [Chem. 63]

於5-經基-1H_吼咯幷[2,3-b]咕咬-2-缓酸乙酯（w〇 05/000849 號公報）（500 mg)之 DMF(10 ml)溶液中，添加 5一 氯甲基-3-苯基_2_三氟甲基嗟吩（678 mg)及碳酸鉀（271 mg)，於70°C下攪拌一晚。使反應混合液冷卻至室溫為止 後，添加飽和碳酸氫鈉水溶液，利用醋酸乙酯萃取3次。 將萃取液利用飽和食鹽水清洗，利用無水硫酸鈉乾燥後， 進行減壓濃縮。將所獲得之殘渣藉由矽膠快速管柱色層分 析（山善高速管柱L)進行純化，獲得標記化合物（677 mg)。 MS (ESI) m/z: 547 (M+H)+。 NMR (CDC13) δ: 1.40 (3H，t，J=7.1 Hz)，1·63 (9H，s)，4.40 (2H，q，J=7.1 Hz)，5·30 (2H，s)，7.01 (1H，s)，710 (1H，d5 J=0.7 Hz)，7.40-7.42 (5H，m)，7·49 (1H，d，J=2.9 Hz)，8.40 (1H，d，J=2.9 Hz)。 (2) 5-[(4-苯基-5-三氟甲基-2-噻吩基）曱氧基；|·1Η_。比咯幷 [2,3-b]吡啶-2-羧酸乙酯 [化 64] 121200.doc -72- 200846342Addition to a solution of 5-amino-1H-pyrrole [2,3-b] octazone-2-hypoacid ethyl ester (w〇05/000849) (500 mg) in DMF (10 ml) 5-Chloromethyl-3-phenyl-2-trifluoromethyl porphin (678 mg) and potassium carbonate (271 mg) were stirred at 70 ° C overnight. After the reaction mixture was cooled to room temperature, a saturated aqueous solution of sodium hydrogencarbonate was added and the mixture was extracted three times with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (Shanshan high-speed column L) to obtain a labeled compound (677 mg). MS (ESI) m/z: 547 (M+H)+. NMR (CDC13) δ: 1.40 (3H, t, J = 7.1 Hz), 1.63 (9H, s), 4.40 (2H, q, J = 7.1 Hz), 5·30 (2H, s), 7.01 ( 1H, s), 710 (1H, d5 J = 0.7 Hz), 7.40-7.42 (5H, m), 7·49 (1H, d, J = 2.9 Hz), 8.40 (1H, d, J = 2.9 Hz) . (2) 5-[(4-Phenyl-5-trifluoromethyl-2-thienyl)decyloxy; |·1Η_. Ethyl [2,3-b]pyridine-2-carboxylic acid ethyl ester [Chem. 64] 121200.doc -72- 200846342

於(第三丁氧基羧基[5鲁苯基·5 J氟m㈣ 基）甲氧基]-1Η-吡咯幷[2,3-b]吡啶-2-羧酸匕§曰（677 mg)之 二氯甲烷（10 ml)溶液中，冰浴冷卻下添加二敗醋酸（5 ml)，於室溫下攪拌45分鐘。減壓濃縮反應混合液後’於 殘渣中添加飽和碳酸鈉水溶液使之成為弱鹼性後，利用醋 酸乙S曰卒取3次。將卒取液利用飽和食鹽水加以清洗，利 用無水硫酸鈉乾燥後，進行濃縮，獲得標記化合物（521 mg，94%) 〇 MS (ESI) m/z: 447 (M+H)+。 NMR (CDC13) δ: 1·43 (3H，t，J = 7.1 Hz)，4 44 (2H q j=7 丄To (t-butoxycarboxy[5-luphenyl-5J-fluorom(tetra)yl)methoxy]-1Η-pyrrole[2,3-b]pyridine-2-carboxylic acid 匕§曰 (677 mg) Dichloroacetic acid (5 ml) was added to a solution of dichloromethane (10 ml), and the mixture was stirred at room temperature for 45 min. After concentrating the reaction mixture under reduced pressure, a saturated aqueous sodium carbonate solution was added to the residue to make it weakly alkaline, and then it was taken three times with acetic acid. The mixture was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate and concentrated to give the title compound (521 mg, 94%) 〇 MS (ESI) m/z: 447 (M+H)+. NMR (CDC13) δ: 1·43 (3H, t, J = 7.1 Hz), 4 44 (2H q j=7 丄

Hz)，5.31 (2H，s)，7.11-7.13 (2H，m)，7·38_7 44 (5H，m)， 7.59 (1H，d，J=2.7 Hz)，8·45 (1H，d，J-2.7 Hz)，10.97 (1H， s) o (3)卜甲基-5-[(4-笨基-5-二氟甲基·2-嗟吩基）甲氧基]· 口比嘻幷[2,3-1)]σ比咬-2-竣酸乙醋 [化 65]Hz), 5.31 (2H, s), 7.11 - 7.13 (2H, m), 7·38_7 44 (5H, m), 7.59 (1H, d, J = 2.7 Hz), 8·45 (1H, d, J -2.7 Hz), 10.97 (1H, s) o (3) 甲基methyl-5-[(4-phenyl-5-difluoromethyl·2-indolyl)methoxy]· 口比嘻幷[2 , 3-1)] σ than bite-2-acetic acid ethyl vinegar [Chemistry 65]

121200.doc -73 * 200846342 於5-[(4-笨基-5-三氟甲基-2-噻吩基）甲氧基]_1H_吡咯幷 [2,3-b]吡啶-2_羧酸乙酯（521 mg)之DMF(1〇⑷）溶液中，冰 浴冷部下添加55%氫化鈉（56 mg)，於室溫下攪拌3〇分鐘 後，添加碘甲烷（145 μΐ)，於室溫下攪拌！小時。於反應混 ν液中添加飽和碳酸氫鈉水溶液，利用醋酸乙_萃取2 •次。將萃取液利用飽和食鹽水加以清洗，利用無水硫酸鈉 ‘乾燥後，進行減壓濃縮。於所獲得之殘渣中添加二異丙醚 及正己烷，濾取所析出之固體，進行乾燥，獲得標記化合 物（405 mg) 〇 MS (ESI) m/z: 461 (M+H)+ 〇 NMR (CDC13) δ: 1.42 (3H，t，J=7.2 Hz)，4·15 (3H，s)，4·4〇 (2H，q，J=7.2 Hz)，5·29 (2H，s)，7·ι〇 (1Ή，d，J==1〇 Hz)， 7.17 (1H，s)，7.38-7.43 (5H，m)，7.52 (1H，d，J=：2.7 Hz)， 8·34 (1H，d，J=2_7 Hz)。 (4) 1-甲基- 5-[(4-苯基-5-三氟甲基_2-噻吩基）甲氧基]-1H_ φ 吡咯幷[2,3-b]吡啶-2-曱醇 [化 66]121200.doc -73 * 200846342 on 5-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]_1H_pyrrole[2,3-b]pyridine-2-carboxylic acid Ethyl ester (521 mg) in DMF (1 〇 (4)) solution, 55% sodium hydride (56 mg) was added to the cold portion of the ice bath, stirred at room temperature for 3 hrs, then iodomethane (145 μM) was added to the chamber. Stir under temperature! hour. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. Diisopropyl ether and n-hexane were added to the obtained residue, and the precipitated solid was collected by filtration and dried to give the title compound (405 mg) 〇MS (ESI) m/z: 461 (M+H)+ 〇NMR (CDC13) δ: 1.42 (3H, t, J = 7.2 Hz), 4·15 (3H, s), 4·4〇 (2H, q, J = 7.2 Hz), 5·29 (2H, s), 7·ι〇(1Ή,d,J==1〇Hz), 7.17 (1H,s), 7.38-7.43 (5H,m),7.52 (1H,d,J=:2.7 Hz), 8·34 ( 1H, d, J = 2_7 Hz). (4) 1-Methyl-5-[(4-phenyl-5-trifluoromethyl_2-thienyl)methoxy]-1H_ φpyrrole[2,3-b]pyridin-2-indole Alcohol [66]

於1-甲基- 5-[(4-苯基-5-三氟曱基嘆吩基）甲氧基]-1H-吡咯幷[2,3-b]吡啶-2-羧酸乙酯（4〇〇 mg)之THF(20 ml)溶液 中，添加氫化鋁鋰（38 mg)，於加熱回流下攪拌3〇分鐘。 121200.doc -74- 200846342 將反應混合液進行冰浴冷卻，於反應混合液中添加飽和碳 酸氫納水溶液’利用醋酸乙酯萃取2次。將萃取液利用飽 和食鹽水加以清洗，利用無水硫酸鈉乾燥後，進行減壓濃 縮。將所獲得之殘渣藉由矽膠快速管柱色層分析（山善高 速管柱2 L)進行純化’獲得標記化合物（349 nig)。 MS (ESI) m/z: 419 (M+H)+。 NMR (CDC13) δ·· 3.89 (3H，s)，4.82 (2H，d，卜4.9 Hz)，5·27 (2H，s)，6·35 (1H，s)，7.08 (1H，s)，7.37-7.48 (7H，m)，8 16 (1H，d，J=2.7 Hz)。 (5) 1_甲基-5-[(4-苯基-5-三氟甲基-2·噻吩基）甲氧基]·1H_ 吡咯幷[2,3-b]吡啶-2-甲醛 [化 67]Ethyl 1-methyl-5-[(4-phenyl-5-trifluoroindolyl)methoxy]-1H-pyrrole[2,3-b]pyridine-2-carboxylate ( To a solution of 4 mg of THF (20 ml), lithium aluminum hydride (38 mg) was added, and the mixture was stirred under reflux for 3 hr. 121200.doc -74- 200846342 The reaction mixture was cooled in an ice bath, and a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and extracted twice with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (2 L of Shanshan high speed column) to obtain a labeled compound (349 nig). MS (ESI) m/z: 419 (M+H)+. NMR (CDC13) δ·· 3.89 (3H, s), 4.82 (2H, d, 4.9 Hz), 5·27 (2H, s), 6.35 (1H, s), 7.08 (1H, s), 7.37-7.48 (7H,m), 8 16 (1H,d,J=2.7 Hz). (5) 1-Methyl-5-[(4-phenyl-5-trifluoromethyl-2.thienyl)methoxy]·1H_pyrrole[2,3-b]pyridine-2-carbaldehyde [ 67]

於1-甲基-5-[(4-苯基-5-三氟甲基-2_噻吩基）甲氧基]_111_ 吡咯幷[2,3-b]吡啶-2-甲醇（349 mg)之THF(15 ml)溶液中， 添加氯化鈉（125 mg)及二氧化錳（412 mg)，於室溫下檀掉 一晚。將反應混合液進行矽藻土過濾，減壓濃縮濾液。將 所獲得之殘渣藉由矽膠快速管柱色層分析（山善高速管枝 L)進行純化，獲得標記化合物（291 mg)。 MS (ESI) m/z: 417 (M+H)+ 〇 121200.doc -75- 200846342 NMR (CDC13) δ: 4.17 (3H，s)，5.30 (2H，s)，7.11-7.14 (2H, m), 7.38-7.43 (5H, m)? 7.57 (1H5 d5 J=2.7 Hz), S.41 (1H, d? J=2.7 Hz)，9·92 (1H，s)。 (6) 1 -[[ 1 -曱基-5-[(4-苯基-5-三氟甲基-2-嘆吩基）甲氧基]-1H-吡咯幷[2,3-b]吡啶·2-基]曱基]吖丁啶-3-羧酸甲酯 [化 68]1-Methyl-5-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]-111-pyrrole[2,3-b]pyridine-2-methanol (349 mg) In a solution of THF (15 ml), sodium chloride (125 mg) and manganese dioxide (412 mg) were added and the mixture was allowed to stand overnight at room temperature. The reaction mixture was filtered through Celite, and the filtrate was evaporated. The obtained residue was purified by silica gel rapid column chromatography (Shanshan high-speed tube L) to obtain a labeled compound (291 mg). MS (ESI) m/z: 417 (M+H) + 〇121200.doc -75 - 200846342 NMR (CDC13) δ: 4.17 (3H, s), 5.30 (2H, s), 7.11-7.14 (2H, m ), 7.38-7.43 (5H, m)? 7.57 (1H5 d5 J=2.7 Hz), S.41 (1H, d? J=2.7 Hz), 9.92 (1H, s). (6) 1 -[[ 1 -Mercapto-5-[(4-phenyl-5-trifluoromethyl-2-indolyl)methoxy]-1H-pyrrole[2,3-b] Pyridine-2-yl]fluorenyl]azetidine-3-carboxylic acid methyl ester [Chem. 68]

於1-曱基-5-[(4-苯基-5-三氟甲基-2-噻吩基）甲氧基]_1H- σ比咯幷[2,3-b]吼唆-2-甲醛（185 mg)之氯仿（1〇 mi)溶液中， 添加吖丁啶-3-羧酸甲酯鹽酸鹽（101 mg)、醋酸（25 μΐ)，於 室溫下攪拌30分鐘。將反應混合液進行冰浴冷卻，添加三 乙醯氧基氫化硼鈉（198 mg)，於室溫下攪拌1小時。於反 應混合液中添加飽和碳酸氫納水溶液，利用氯仿萃取3 次。將萃取液利用飽和食鹽水加以清洗，利用無水硫酸鈉 乾燥後，進行減壓濃縮。將所獲得之殘渣藉由矽膠快速管 柱色層分析（山善高速管柱L)進行純化，獲得標記化合物 (；211 mg)。 MS (ESI) m/z: 516 (M+H).。 NMR (CDC13) δ： 3.32-3.38 (3H, m), 3.53-3.56 (2H, m), 3.71 (3H, s), 3.74 (2H, s), 3.S3 (3H, s), 5.27 (2H, s), 6.26 (1H, s), 7.08 (1H, d, J=1.5 Hz), 7.38-7.45 (6H, m)} 8.12 〇H&gt; d? 121200.doc -76- 200846342 J=2.7 Hz)。 (7) 1-[[1-甲基·5-[(4_苯基三氟甲基-2_噻吩基)甲氧基]_ 1H-吼洛幷[2,3-b]吡啶^-基]甲基]吖丁啶_3-羧酸 [化 69]1-mercapto-5-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]_1H- σ pyrrole [2,3-b]indole-2-carbaldehyde (185 mg) of a solution of chloroform (1 〇mi) was added with azetidine-3-carboxylic acid methyl ester hydrochloride (101 mg) and acetic acid (25 μM), and stirred at room temperature for 30 minutes. The reaction mixture was cooled in an ice-bath, and sodium triacetoxyborohydride (198 mg) was added and stirred at room temperature for one hour. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, and extracted with chloroform three times. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Shanshan high-speed column L) to obtain a labeled compound (; 211 mg). MS (ESI) m/z: 516 (M+H). NMR (CDC13) δ: 3.32-3.38 (3H, m), 3.53-3.56 (2H, m), 3.71 (3H, s), 3.74 (2H, s), 3.S3 (3H, s), 5.27 (2H , s), 6.26 (1H, s), 7.08 (1H, d, J=1.5 Hz), 7.38-7.45 (6H, m)} 8.12 〇H&gt; d? 121200.doc -76- 200846342 J=2.7 Hz) . (7) 1-[[1-Methyl·5-[(4-phenyltrifluoromethyl-2-thienyl)methoxy]- 1H-indolyl[2,3-b]pyridine^- Methyl]azetidine-3-carboxylic acid [Chem. 69]

• 於1-[[1_甲基_5-[(4_苯基-5-三氟甲基-2-噻吩基）甲氧基]· 1H-吡咯幷[2,3-b]吡啶-2-基]甲基]吖丁啶-3_羧酸曱酯（2〇5 mg)之THF(5 ml)溶液中，添加甲醇（1 2以）及1 ^^氫氧化鈉 水浴液（1 · 1 8 ml)，於室溫下攪拌一晚。於反應混合液中添 加1 N鹽酸水溶液，加以中和後，進行減壓濃縮。於殘逢 中添加水，利用氯仿萃取3次。將萃取液利用飽和食鹽水 加以清洗，利用無水硫酸鈉乾燥後，進行減壓濃縮。於所 獲得之殘潰中添加二乙鱗及己烷，濾取所析出之固形物， # 獲得粗生成物_叫）。將所獲得之粗生成物（71 mg)藉由 石夕膠快速管柱色層分析（山善高速管柱L)進行純化，獲得 標記化合物（52 mg)。 MS (ESI) m/z: 502 (M+H)+。 HRMS (FAB) Calcd for C25H23F3N3〇3S (m+h)+: 5〇2 i4i2; Found: 502.1440 o NMR (DMSO-d6) 6: 2.95 (1H, s), 3.17_3.36 (4H, m), 3.66-3.71 (5H, m), 5.40 (2H, s), 6.25 (1H, s)5 7.36-7.62 (7H, m), 121200.doc -77- 200846342 8.03 (1H，d，J=2.7 Hz)。 [貝施例9] 1_[[5-[(4-苯基-5-三氟甲基噻吩基）甲氧基]苯 幷呋喃-2-基]甲基]吖丁啶羧酸 (1) 5-[(4-苯基-5-三氟曱基-2-噻吩基）曱氧基]苯幷呋喃_2- 羧酸甲酯.• on 1-[[1_methyl_5-[(4_phenyl-5-trifluoromethyl-2-thienyl)methoxy]·1H-pyrrole[2,3-b]pyridine- To a solution of 2-yl]methyl]azetidine-3-carboxylic acid decyl ester (2〇5 mg) in THF (5 ml), add methanol (1 2) and 1 ^ sodium hydroxide water (1) · 1 8 ml), stir at room temperature for one night. After adding 1 N aqueous hydrochloric acid solution to the reaction mixture, the mixture was neutralized and concentrated under reduced pressure. Water was added to the residue and extracted three times with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Diethyl scale and hexane were added to the obtained residue, and the precipitated solid matter was collected by filtration, and the crude product was obtained. The obtained crude product (71 mg) was purified by a flash chromatography (yield of Shanshan high-speed column L) to obtain a labeled compound (52 mg). MS (ESI) m/z: 552 (M+H)+. HRMS (FAB) Calcd for C25H23F3N3〇3S (m+h)+: 5〇2 i4i2; Found: 502.1440 o NMR (DMSO-d6) 6: 2.95 (1H, s), 3.17_3.36 (4H, m), 3.66-3.71 (5H, m), 5.40 (2H, s), 6.25 (1H, s)5 7.36-7.62 (7H, m), 121200.doc -77- 200846342 8.03 (1H,d,J=2.7 Hz) . [Bei Shi Example 9] 1_[[5-[(4-phenyl-5-trifluoromethylthienyl)methoxy]benzofuran-2-yl]methyl]azetidinecarboxylic acid (1) 5-[(4-Phenyl-5-trifluoromethyl-2-thienyl) decyloxy]benzoquinone-2-carboxylate.

[化 70][化70]

將5_羥基苯幷呋喃-2-羧酸甲酯（550 mg)之DMF(30 ml)溶 液進行冰浴冷卻，於攪拌下添加55%氫化鈉（14〇 mg)。將 反應混合液攪拌30分鐘後，添加氯甲基苯基_2_三氟 曱基噻吩（950 mg)，於60。(：下攪拌一晚。使反應混合液冷 卻至室溫為止後，添加飽和食鹽水，利用醋酸乙酯萃取3 次。將萃取液利用飽和食鹽水加以清洗，利用無水硫酸鈉 乾燥後，進行減壓濃縮。將所獲得之殘渣藉由快速管柱色 層分析（山善高速管柱2L)進行純化，獲得標記化合物（126 g)。 MS (ESI) m/z: 433 (M+H)+ 〇 NMR (CDC13) δ: 3.98 (3H，s)，5·27 (2H，s)，7·10-7·26 (3H， m)，7·39_7·53 (7H，m) 〇 (2) 5-[(4-苯基-5-三氟甲基_2_噻吩基）甲氧基]苯幷呋喃-2_ 甲醇 121200.doc -78- 200846342 [化 71]A solution of methyl 5-hydroxybenzofuran-2-carboxylate (550 mg) in DMF (30 ml) was cooled in ice-cooling, and 55% sodium hydride (14 mg) was added with stirring. After the reaction mixture was stirred for 30 minutes, chloromethylphenyl-2-trifluorodecylthiophene (950 mg) was added at 60. (The mixture was stirred overnight. After the reaction mixture was cooled to room temperature, saturated brine was added and extracted with ethyl acetate three times. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by flash column chromatography (2 mL of Shanshan high-speed column) to give the title compound (126 g) MS (ESI) m/z: 433 (M+H)+ 〇 NMR (CDC13) δ: 3.98 (3H, s), 5·27 (2H, s), 7·10-7·26 (3H, m), 7·39_7·53 (7H, m) 〇(2) 5 -[(4-phenyl-5-trifluoromethyl_2-thienyl)methoxy]benzofuran-2_ methanol 121200.doc -78- 200846342 [Chem. 71]

於％[(‘笨基_5_三氟曱基-2-噻吩基）甲氧基]苯幷呋喃 羧酸甲酯（775 mg)之THF(35 ml)溶液中，添加氫化硼鋰 (17 mg)，於加熱回流下授拌2小時。使反應混合液冷卻至 室溫為止後，添加丨N鹽酸水溶液，利用醋酸乙酯萃取2 次。將萃取液利用飽和食鹽水加以清洗，利用無水硫酸鈉 乾燥後，進行減壓濃縮。將所獲得之殘渣藉由快速管柱色 層分析（山善高速管柱2 L)進行純化，獲得標記化合物（693 mg) 〇 MS (ESI) m/z: 405 (M+H)+。 NMR (CDC13) δ: 1.9H.96 (IH，m)，4.76 (2H，d，J=6.1 Hz)， 5.25 (2H，s)，6·62 (1H，s)，6.97 (1H，dd，J=2·?，8·8 Hz)， 7·〇8-7·11 (2H，m)，7.43-7.37 (6H，m)。 (3) 5-[(4-苯基-5-三氟曱基_2_噻吩基）甲氧基]苯幷呋喃_2_ 甲醛 [化 72]Add lithium borohydride (17 mg) in a solution of methyl [35 mg) of methyl [(')-(5-trifluoromethyl-2-thienyl)methoxy]benzofurancarboxylate (775 mg) (mg), stir-mixed under heating for 2 hours. After the reaction mixture was cooled to room temperature, a hydrazine N aqueous solution was added and extracted twice with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (2 mL of Shanshan high-speed column) to give the title compound (693 mg) 〇 MS (ESI) m/z: 405 (M+H)+. NMR (CDC13) δ: 1.9H.96 (IH, m), 4.76 (2H, d, J = 6.1 Hz), 5.25 (2H, s), 6.62 (1H, s), 6.97 (1H, dd, J=2·?,8·8 Hz), 7·〇8-7·11 (2H,m), 7.43-7.37 (6H,m). (3) 5-[(4-Phenyl-5-trifluoroindolyl-2-thiophenyl)methoxy]benzofuran-2-formaldehyde [Chem. 72]

於5-[(4-苯基-5-三氟甲基-2·噻吩基）甲氧基]苯幷呋喃_2_ 曱醇（680 mg)之二氣曱烷（20 ml)溶液中，添加二氧化猛 121200.doc -79- 200846342 (932 mg)，於室溫下攪拌一晚。將反應混合液進行矽藻土 過濾、，濃縮渡液。將所獲得之殘渣藉由快速管柱色層分析 (山善高速管柱2L)進行純化，獲得標記化合物（6Umg)。 MS (ESI) m/z: 403 (M+H)+ 〇 NMR (CDC13) δ·· 5·28 (2H，S)5 7·η (1H，d，J=1 〇 Hz)，7 22· 7.25 (2H5 m)5 7.39-7.44 (5H5 m)3 7.56-7.52 (2H5 m) 9 85 ‘ （1H，s) 〇 ， ⑷Κθ’4-苯基-5-三氟甲基，2“塞吩基）甲氧基]苯幷呋喃-_ 2-基]曱基]。丫丁啶-3-羧酸 [化 73]Add to a solution of 5-[(4-phenyl-5-trifluoromethyl-2·thienyl)methoxy]benzoquinone furan-2-yl sterol (680 mg) in dioxane (20 ml) Dioxide 121200.doc -79- 200846342 (932 mg), stirred at room temperature for one night. The reaction mixture was filtered through celite, and the mixture was concentrated. The obtained residue was purified by flash column chromatography (2L of Shanshan high-speed column) to obtain a labeled compound (6 Umg). MS (ESI) m/z: 403 (M+H) + NMR (CDC13) δ·· 5·28 (2H,S)5 7·η (1H,d,J=1 〇Hz), 7 22· 7.25 (2H5 m)5 7.39-7.44 (5H5 m)3 7.56-7.52 (2H5 m) 9 85 ' (1H,s) 〇, (4) Κθ'4-phenyl-5-trifluoromethyl, 2"secenyl ) methoxy]benzoquinone furan-_ 2-yl] fluorenyl]. azetidin-3-carboxylic acid [73]

F 〇 於5-[(4-苯基-5-二氟曱基-2-噻吩基）曱氧基]苯幷呋喃-2_ 曱醛（201 mg)之甲醇（10 ml)溶液中，添加吖丁啶_3_羧酸 φ (152 mg)、醋酸〇 ml)及氰基硼氫化鈉（66 mg)，於室溫下 攪拌一晚。於反應混合液中添加飽和碳酸氫鈉水溶液加以 中和後，利用20%甲醇/氯仿混合液萃取3次。將萃取液利 用無水硫酸鈉進行乾燥並減壓濃縮。將所獲得之殘渣藉由 . 矽膠薄層色層分析進行純化，於所獲得之油狀物中添加二 ***及正己烷，濾取所析出之固體，獲得標記化合物（65 mg)。 MS (ESI) m/z: 488 (M+H)+ 〇 HRMS (FAB) Calcd for C25H21F3N04S (M+H)-: 488.1143· 121200.doc -80- 200846342 found 488.1108 ° NMR (DMSO-d6) δ: 3·15-3·47 (5H，m)，3.65 (2H，s)，5·40 (2H，s)，6.66 (1H，s)，6·96 (1H，dd，J=2.5，9.1 Hz)，7·25 (1H，d，J=2.5 Hz)，7·38 (m，s)，7.43-7.50 (6H，m)。 IR (ATROcnT1: 3031，1623, 1473, 1384, 1284, 1199, 1120。 Anal.Calcd for C25H20F3NO4S.0.5H2O: C，60.48; H，4·26; F， 11·48; N，2.82; S，6.46 〇Add hydrazine to a solution of 5-[(4-phenyl-5-difluoroindolyl-2-thienyl) decyloxy]benzofuran-2-yl furfural (201 mg) in methanol (10 ml) Butyridine _3_carboxylic acid φ (152 mg), hydrazine acetate (ml) and sodium cyanoborohydride (66 mg) were stirred at room temperature overnight. After adding a saturated aqueous solution of sodium hydrogencarbonate to the reaction mixture, the mixture was neutralized, and then extracted three times with a 20% methanol/chloroform mixture. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography, and diethyl ether and n-hexane were added to the obtained oil, and the precipitated solid was collected by filtration to obtain a labeled compound (65 mg). MS (ESI) m/z: 488 (M+H)+ 〇HRMS (FAB) Calcd for C25H21F3N04S (M+H)-: 488.1143· 121200.doc -80-200846342 found 488.1108 ° NMR (DMSO-d6) δ: 3·15-3·47 (5H,m), 3.65 (2H,s),5·40 (2H,s),6.66 (1H,s),6·96 (1H,dd,J=2.5,9.1 Hz ), 7·25 (1H, d, J = 2.5 Hz), 7·38 (m, s), 7.43-7.50 (6H, m). IR (ATROcnT1: 3031,1623, 1473, 1384, 1284, 1199, 1120. Anal.Calcd for C25H20F3NO4S.0.5H2O: C,60.48; H,4·26; F, 11·48; N,2.82; S,6.46 〇

Found: C，60.43; H，4·07; F，11.44; N，2·71; S，6·51。 [實施例10] l-[[6-[(4-苯基-5-三氟甲基-2-噻吩基）曱氧基] 苯幷呋喃-2-基]曱基]吖丁啶-3-羧酸 (1) 6-[(4-苯基-5-三氟甲基-2-噻吩基）甲氧基]苯幷呋喃-2-羧酸曱酯 [化 74]Found: C, 60.43; H, 4·07; F, 11.44; N, 2·71; S, 6. 51. [Example 10] l-[[6-[(4-Phenyl-5-trifluoromethyl-2-thienyl) decyloxy] benzofuran-2-yl]indenyl]azetidine-3 -carboxylic acid (1) 6-[(4-phenyl-5-trifluoromethyl-2-thienyl)methoxy]benzofuran-2-carboxylic acid oxime ester [Chem. 74]

於6-¾基苯幷吱喃-2-魏酸甲酯（5〇〇 mg)之DMF (3G ml) 溶液中，添加5-氯甲基-3-苯基_2_三氟甲基噻吩（86〇 mg)及 碳酸鉀（400 mg)，於5(TC下攪拌3小時。使反應混合液冷卻 至室溫為止後，添加飽和食鹽水，利用醋酸乙酯萃取3 次。將萃取液利用飽和食鹽水加以清洗，利用無水硫酸納 乾燥後，進行減壓濃縮。於所獲得之殘渣中添加二異丙 醚，濾取析出物，獲得標記化合物（98〇 mg)。 MS (ESI) m/z: 433 (M+H)+。 121200.doc -81 - 200846342 NMR (DMSO-d6) δ: 3·86 (3H，s)，5.48 (2H，s)，7.10 (1H， dd，J=2.2, 8.8 Hz)，7.43-7.50 (7H，m)5 7.70-7.72 (2H，m)。 (2) 6-[(4-苯基-5-三氟甲基-2-噻吩基）甲氧基]苯幷呋喃-2-甲醇 [化 75]Add 5-chloromethyl-3-phenyl-2-trifluoromethylthiophene to DMF (3G ml) solution of 6-3⁄4 benzofuran-2-carboxylate methyl ester (5 〇〇mg) (86 〇mg) and potassium carbonate (400 mg) were stirred at 5 (TC for 3 hours). After cooling the reaction mixture to room temperature, saturated brine was added and extracted with ethyl acetate three times. The mixture was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and diisopropyl ether was added to the obtained residue, and the precipitate was collected by filtration to obtain a labeled compound (98 〇mg). MS (ESI) m/ z: 433 (M+H)+. 121200.doc -81 - 200846342 NMR (DMSO-d6) δ: 3·86 (3H, s), 5.48 (2H, s), 7.10 (1H, dd, J=2.2 , 8.8 Hz), 7.43-7.50 (7H, m)5 7.70-7.72 (2H, m) (2) 6-[(4-Phenyl-5-trifluoromethyl-2-thienyl)methoxy Benzofuran-2-methanol [化75]

於6-[(4-苯基-5-三氟甲基-2-噻吩基）曱氧基]苯幷呋喃-2-羧酸甲酯（216 mg)之THF (10 ml)溶液中，添加氫化硼鋰 (3 3 mg)，加熱回流下攪拌2小時半。使反應混合液冷卻至 室溫為止後，添加1 N鹽酸，利用醋酸乙酯萃取3次。將萃 取液利用飽和食鹽水加以清洗，利用無水硫酸納乾燥後， 進行減壓濃縮。將所獲得之殘渣藉由矽膠快速管柱色層分 析（山善高速L)進行純化，獲得標記化合物（200 mg)。 NMR (CDC13) δ: 1·89 (1H，t，J=6.1 Hz)，4.74 (2H，d，J=6.1 Hz)，5·26 (2H，d，J=0.5 Hz)，6.61 (1H，s)，6.93-6.96 (1H， m)，7.09-7.10 (2H，m)，7.38-7.46 (6H，m)。 (3) 6-[(4-苯基-5-三氟甲基-2-噻吩基）甲氧基]苯幷呋喃-2-曱醛 [化 76] 121200.doc -82 - 200846342Add to a solution of methyl 6-[(4-phenyl-5-trifluoromethyl-2-thienyl) decyloxy]benzofuran-2-carboxylate (216 mg) in THF (10 ml) Lithium borohydride (33 mg) was stirred under reflux for 2 and a half hours. After the reaction mixture was cooled to room temperature, 1N hydrochloric acid was added and extracted with ethyl acetate three times. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (Shanshan High-speed L) to obtain a labeled compound (200 mg). NMR (CDC13) δ: 1·89 (1H, t, J = 6.1 Hz), 4.74 (2H, d, J = 6.1 Hz), 5·26 (2H, d, J = 0.5 Hz), 6.61 (1H, s), 6.93-6.96 (1H, m), 7.09-7.10 (2H, m), 7.38-7.46 (6H, m). (3) 6-[(4-Phenyl-5-trifluoromethyl-2-thienyl)methoxy]benzofuran-2-furaldehyde [Chem. 76] 121200.doc -82 - 200846342

甲醇（707 mg)之二氯甲燒⑽叫溶液中，添加二氧化猛 ⑽mg)’於室溫下授拌—晚。於反應混合液中進而添加 二氧㈣_ mg) ’於室溫下㈣—晚。將反應混合液進 打石夕澡土過濾、’減壓濃縮濾液。將所獲得之殘㈣由快速 管柱色層分析（山善高速L)進行純化，獲得標記化合物（612 mg)。 MS (ESI) m/z: 403 (M+H)+。 NMR (CDCI3) δ: 5.31 (2H, s), 7.07 (1H, dd, J=2.2, 8.8 Hz), 7.13-7.16 (2H, m), 7.40-7.44 (5H, m), ?&gt;52 (1Hj d? J=1 〇Methanol (707 mg) of methylene chloride (10) is called a solution, and dimethyl oxide (10) mg) is added to allow mixing at room temperature. Further, in the reaction mixture, dioxin (tetra)_mg) was added at room temperature (four) to night. The reaction mixture was filtered through a rock bath, and the filtrate was concentrated under reduced pressure. The obtained residue (IV) was purified by flash column chromatography (Shanshan Expressway L) to obtain a labeled compound (612 mg). MS (ESI) m/z: 403 (M+H)+. NMR (CDCI3) δ: 5.31 (2H, s), 7.07 (1H, dd, J=2.2, 8.8 Hz), 7.13-7.16 (2H, m), 7.40-7.44 (5H, m), ?&gt;52 ( 1Hj d? J=1 〇

Hz)，7·66 (1H，d，J=8.8 Hz)，9·78 (1H，s)。 (4) l-[6-(4-苯基-5-二氟甲基嗟吩I基甲氧基）苯幷咬嗔_2_ 基甲基]-吖丁啶-3-羧酸 [化 77]Hz), 7.66 (1H, d, J = 8.8 Hz), 9·78 (1H, s). (4) l-[6-(4-Phenyl-5-difluoromethyl porphin I methoxy) benzoquinone 幷_2_ ylmethyl]-azetidine-3-carboxylic acid [Chemical 77 ]

於M4-苯基·5_三氟甲基嗟吩丄基？氧基）苯并咬喃冬甲 酸（155 mg)之甲醇（10 ml)溶液中，添加竹唆小叛酸⑴7 121200.doc -83 · 200846342 mg)、醋酸（1 ml)及氰基硼氫化鈉（51 mg)，於室溫下擾摔 一晚。於反應混合液中添加飽和碳酸氫納水溶液加以中和 後，利用氯仿/甲醇（4 : 1)混合液萃取3次。將萃取液利用 無水硫酸鈉乾燥後，進行濃縮。將所獲得之殘渣藉由矽膠 薄層色層分析進行純化。於所獲得之油狀物中添加二乙_ 及己烧，濾取所析出之固形物，獲得標記化合物（41 mg)。 MS (ESI) m/z: 488 (M+H)+ 〇 HRMS (FAB) Calcd for C25H21F3N04S (M+H)+: 488.1143; found 488.1124 ° NMR (DMSO-d6) δ: 3.16-3.28 (3H5 m)? 3.44 (2H, t, J=7.6 Hz)，3.63 (2H，s)，5·43 (2H，s)，6·64 (1H，s)，6·95 (1H，dd， J=2.2, 8·6 Hz)，7.31 (1H，d，J=2.0 Hz)，7.40-7.51 (7H，m)。 IR (ATR)cm·1·· 3060，1619，1589，1369，1288，11559, 1108。On M4-phenyl·5-trifluoromethylindenyl thiol? A solution of oxyphenylene benzoic acid (155 mg) in methanol (10 ml) with the addition of P. sinensis (1) 7 121200.doc -83 · 200846342 mg), acetic acid (1 ml) and sodium cyanoborohydride (51 mg), disturbed for one night at room temperature. After neutralizing the reaction mixture with a saturated aqueous solution of sodium hydrogencarbonate, the mixture was extracted three times with a mixture of chloroform/methanol (4:1). The extract was dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel thin layer chromatography. Diethyl _ and hexane were added to the obtained oil, and the precipitated solid was collected by filtration to obtain a labeled compound (41 mg). MS (ESI) m/z: 488 (M+H) + 〇HRMS (FAB) Calcd for C25H21F3N04S (M+H)+: 488.1143; found 488.1124 ° NMR (DMSO-d6) δ: 3.16-3.28 (3H5 m) 3.44 (2H, t, J=7.6 Hz), 3.63 (2H, s), 5·43 (2H, s), 6·64 (1H, s), 6.95 (1H, dd, J=2.2, 8·6 Hz), 7.31 (1H, d, J=2.0 Hz), 7.40-7.51 (7H, m). IR (ATR) cm·1·· 3060, 1619, 1589, 1369, 1288, 11559, 1108.

Anal.Calcd for C25H2〇F3N04S.0.75H20: C, 59·93; H，4·33; F，11·38; N，2.80; S，6·40 〇Anal.Calcd for C25H2〇F3N04S.0.75H20: C, 59·93; H,4·33; F,11·38; N,2.80; S,6·40 〇

Found·· C，59.67; H，4.16; F，11.34; N，2.92; S，6·46 0 [實施例11] l-[6-(3_氰基-4-環己基苄氧基）萘_2-基甲基]吖 丁啶-3-羧酸 (1) 3-氰基-4-三氟甲磺醯氧基苯曱酸甲酯 [化 78] 121200.doc -84- 200846342Found·· C, 59.67; H, 4.16; F, 11.34; N, 2.92; S, 6·46 0 [Example 11] l-[6-(3-Cyano-4-cyclohexylbenzyloxy)naphthalene _2-ylmethyl]azetidine-3-carboxylic acid (1) methyl 3-cyano-4-trifluoromethanesulfonyloxybenzoate [Chem. 78] 121200.doc -84- 200846342

於3-氰基.4-¾基笨甲酸甲g|(87Q叫)之二氯甲即〇如) /合液中’於〇 C下緩慢添加°比唆（860 μΐ)及三氟甲磺酸酐 (in ml)。室溫下攪拌16小時後，藉由過滤去除所析出之 固體’減壓下濃縮濾液。於所獲得之殘渣中添加水（15叫 及醋酸乙酯（20 ml)並加以分液。將水層利用醋酸乙酯 (3 10 ml)萃取後，將合併之萃取液利用❹硫酸銅水溶液 及飽和&amp; I水加以π洗，利用無水硫酸鈉乾燥，減麼下濃 細 &gt;谷劑，獲得標記化合物（1.3 4 g)。 ^-NMR (CDC13) δ: 3.99 (3Η, s), 7.59 (1H, d, J=8.8 Hz), 8·37 (1H，dd，J=8.8, 2·2 Hz)，8.44 (1H，d，J=2.2 Hz)。 MS (ESI) m/z: 310 (M+H)+ 〇 (2) 3-氣基-4-環己基苯甲酸甲酉旨 [化 79]In the case of 3-cyano.4-3⁄4-based benzoic acid methyl g| (87Q), it is slowly added at 〇C to 860(860 μΐ) and trifluoromethane. Anhydride (in ml). After stirring at room temperature for 16 hours, the precipitated solid was removed by filtration. The filtrate was concentrated under reduced pressure. To the obtained residue, water (15 ml and ethyl acetate (20 ml) was added and liquid-separated. The aqueous layer was extracted with ethyl acetate (3 10 ml), and the combined extracts were treated with a copper sulphate aqueous solution and Saturated &amp; I water was washed with π, dried over anhydrous sodium sulfate, and reduced by weight &lt;&lt;&gt; (1H, d, J = 8.8 Hz), 8·37 (1H, dd, J = 8.8, 2·2 Hz), 8.44 (1H, d, J = 2.2 Hz) MS (ESI) m/z: 310 (M+H)+ 〇(2) 3-Alkyl-4-cyclohexylbenzoic acid formazan [Chem. 79]

於氮氣環境下，於3 -氰基-4-三敗甲石黃醯氧基苯甲酸甲酯 (928 mg)之THF(5.0 ml)溶液中，於室溫下添加雙（三第二 丁基膦）鈀（153 mg)及0·5 Μ環己基甲基溴化鋅/THF溶液 (6.60 ml)。加熱回2小時流後，放置冷卻至室溫為止，、 於 反應液中添加飽和碳酸氫鈉水溶液（10 ml)。室溫下_摔3〇 121200.doc -85- 200846342 分鐘後，藉由過濾去除所析出之固體。利用氯仿（3xl() ml) 對濾、液進行萃取’利用飽和食鹽水加以清洗後，藉由無水 硫酸鈉乾燥，於減壓下濃縮濾液。將所獲得之殘渣使用矽 膠管柱色層分析（Biotage 40S)進行純化，獲得標記化合物 (5 66 mg) ° H-NMR (CDC13) δ: 1.22-1.34 (1H，m)，1·40-1·55 (4H，m)， 1.58 (1Η, d? J=8.8 Hz)? 1.81 (1H5 d? J=12.9 Hz), 1.90 (3H, t，J=9.8 Hz)，3·00-3·06 (1H，m)，3·93 (3H，s)，7·46 (1H，d， J=8.3 Hz)，8.17 (1H，dd，J=8.3, 1.5 Hz)，8·27 (1H，d，J=1.5Add a double (three second butyl group) at room temperature in a solution of methyl 3-cyano-4-trimethylmethionine (928 mg) in THF (5.0 ml) under nitrogen. Palladium (153 mg) and 0.55 cyclohexylmethylzinc bromide/THF solution (6.60 ml). After heating to reflux for 2 hours, it was left to cool to room temperature, and a saturated aqueous solution of sodium hydrogencarbonate (10 ml) was added to the mixture. After room temperature _ falls 3 〇 121200.doc -85- 200846342 minutes, the precipitated solids were removed by filtration. The filtrate and the solution were extracted with chloroform (3×l () ml). After washing with saturated brine, the mixture was dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified using a chrome column chromatography (Biotage 40S) to give the title compound (5 66 mg) ° H-NMR (CDC13) δ: 1.22-1.34 (1H, m), 1·40-1 ·55 (4H,m), 1.58 (1Η, d? J=8.8 Hz)? 1.81 (1H5 d? J=12.9 Hz), 1.90 (3H, t, J=9.8 Hz), 3·00-3·06 (1H,m),3·93 (3H,s),7·46 (1H,d, J=8.3 Hz), 8.17 (1H,dd,J=8.3, 1.5 Hz),8·27 (1H,d , J=1.5

Hz) 〇 MS (ESI) m/z: 244 (M+H)+。 (3) 3-氰基-4-環己基苯曱酸、 [化 80]Hz) 〇 MS (ESI) m/z: 244 (M+H)+. (3) 3-cyano-4-cyclohexylbenzoic acid, [80]

於3-氰基-4-環己基苯曱酸甲酯（566 mg)之THF(6〇 ml)溶 液中，於室溫下添加甲醇（3.0 ml)及i ^^氫氧化鈉水溶液 (300 ml)。於室溫下攪拌3天後，於反應液中添加水（5〇 ml)，藉由1 N鹽酸使PH值達到3，添加氯仿（1〇 ml)加以分 液。將水層利用氯仿（3x7.5 ml)萃取後，合併萃取液，利 用無水硫酸納乾燥後，減壓下濃縮溶劑，獲得標記化合物 (483 mg) 〇 ]Η-ΝΜΚ (DMSO-d6) δ: 1.23-1.31 (1Η? m)5 1.33-1.56 (4Η, 121200.doc •86- 200846342 m)，1.73(lH，d，J=12.5HZ)，1.82(4H，t，J=lL7Hz)，2.86-2.94 (1H，m)，7·65 (1H，d，J=8.3 Hz)，8·15 (1H，dd，J=8.3, 1.7 Hz)，8.20 (1H，d，J=1.7 Hz)，13.36 (1H，s)。 MS (ESI) m/z: 459 (2M+ H)、 (4) 3-氰基-4-環己基苄基醇 [化 81]To a solution of methyl 3-cyano-4-cyclohexyl benzoate (566 mg) in THF (6 mL), MeOH (3.0 mL) ). After stirring at room temperature for 3 days, water (5 〇 ml) was added to the reaction mixture, and the pH was brought to 3 with 1 N hydrochloric acid, and then chloroform (1 〇 ml) was added thereto to carry out liquid separation. The aqueous layer was extracted with chloroform (3×7.5 ml), and the mixture was combined, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to give the title compound (483 mg) 〇]Η-ΝΜΚ (DMSO-d6) δ: 1.23-1.31 (1Η? m)5 1.33-1.56 (4Η, 121200.doc •86- 200846342 m), 1.73 (lH,d,J=12.5HZ),1.82(4H,t,J=lL7Hz),2.86- 2.94 (1H,m),7·65 (1H,d,J=8.3 Hz),8·15 (1H,dd,J=8.3, 1.7 Hz), 8.20 (1H,d,J=1.7 Hz), 13.36 (1H, s). MS (ESI) m/z: 459 (2M+H), (4) 3-cyano-4-cyclohexylbenzyl alcohol

於3-氰基-4-環己基苯甲酸（483 mg)之THF(5.0 ml)溶液 中，於0°C緩慢添加ΤΕΑ(440 μΐ)及氯醋酸乙酯（242 μΐ)。於 至溫下授拌1小時後，藉由過濾去除所析出之沈澱物。 於另外之長頸瓶中，於氫化硼鈉（520 mg)之乙醇（5.0 ml) 懸浮液中，於0°C緩慢添加苯甲酸衍生物之濾液。於〇°C攪 拌1小時後，緩慢添加1 N鹽酸，使ph值達到4。於反應液 中添加醋酸乙酯（1 〇 ml)進行分液，將水層利用醋酸乙酯 (3x5.0 ml)加以萃取。將合併之萃取液藉由無水硫酸鈉乾 燥，過濾不溶物後，減壓下濃縮濾液。將所獲得之殘渣使 用矽膠管柱色層分析（Biotage 40S)進行純化，獲得標記化 合物（249 mg)。To a solution of 3-cyano-4-cyclohexylbenzoic acid (483 mg) in THF (5.0 ml), EtOAc (EtOAc) After the mixture was stirred for 1 hour at the temperature, the precipitate precipitated was removed by filtration. In a separate flask, the filtrate of the benzoic acid derivative was slowly added at 0 ° C in a suspension of sodium borohydride (520 mg) in ethanol (5.0 ml). After stirring at 〇 ° C for 1 hour, 1 N hydrochloric acid was slowly added to bring the pH to 4. Ethyl acetate (1 〇 ml) was added to the reaction mixture for liquid separation, and the aqueous layer was extracted with ethyl acetate (3×5.0 ml). The combined extracts were dried over anhydrous sodium sulfate and filtered and evaporated. The residue obtained was purified by silica gel column chromatography (Biotage 40S) to give a labeled compound (249 mg).

7·61 (1H，d，J=1.5 Hz) 〇 121200.doc -87- 200846342 (5)2-環己基-5-(6-甲醯萘-2-基氧基甲基）苯基腈 [化 82]7·61 (1H, d, J=1.5 Hz) 〇121200.doc -87- 200846342 (5) 2-cyclohexyl-5-(6-carboxamonaphthalen-2-yloxymethyl)phenyl nitrile [ 82]

於3-氰基-4-環己基苄基醇（〇·8〇 g)中，於室溫下添加亞 硫醯氣（10 ml)，加溫至70t：，攪拌4小時。使反應液恢復 至至μ後，進行濃縮，獲得5-氯甲基-2-環己基苯基腈之組 合物（0.8 8 g)，繼而未進行純化直接供至隨後反應中。 於6-羥基-2-萘甲醛（和光純藥）(〇·16幻及5•氯甲基環 己基笨基腈（0·22 g)之DMF溶液（5 ml)中，於室溫下添加碳 酸鉀（0.39 g)，加溫至70°C，攪拌14小時。使反應液恢復至 室溫後，過濾分離不溶物，於減壓下濃縮所獲得之濾液。 將所獲得之殘渣使用矽膠快速管柱色層分析（Bi〇tage 4〇m) 進行純化，獲得標記化合物. 16 g)。To the 3-cyano-4-cyclohexylbenzyl alcohol (〇·8〇 g), sulfite gas (10 ml) was added at room temperature, and the mixture was warmed to 70 t: and stirred for 4 hours. After the reaction solution was returned to μ, concentration was carried out to obtain a mixture of 5-chloromethyl-2-cyclohexylbenzonitrile (0.88 g), which was then directly applied to the subsequent reaction without purification. Add 6-hydroxy-2-naphthaldehyde (Wako Pure Chemical) (〇·16 phantom and 5 • chloromethylcyclohexyl phenyl nitrile (0·22 g) in DMF (5 ml) at room temperature Potassium carbonate (0.39 g), warmed to 70 ° C, and stirred for 14 hours. After the reaction solution was returned to room temperature, the insoluble material was separated by filtration, and the obtained filtrate was concentrated under reduced pressure. Column chromatography (Bi〇tage 4〇m) was carried out to obtain the labeled compound. 16 g).

H-NMR (CDC13) δ: 1·23-1·58 (6H，m)，1.78-2.04 (4H，m)， 2·92-3·08 (1H，m)，5·17 (2H，s)，7.24 (1H，d，J=2.5 Hz)， 7.31 (1H，dd，J=8.8, 2.9 Hz)，7·43 (1H，d，J=7.6 Hz)，7.64 (1H，dd，J=8.3，2·0 Hz)，7.74 (1H，d，J=2.0 Hz)，7.81 (1H， d，J=8.6 Hz)，7.94 (2H，d，J=8.6 Hz)，8·20 (1H，s)，1〇·ΐ〇 (1H，s) 〇 MS (ESI) m/z··未觀測到 (6) 1-[6-(3-氰基-4-環己基苄氧基）萘_2_基甲基]吖丁啶_3 羧酸甲酯 121200.doc -88 - 200846342 [化 83]H-NMR (CDC13) δ: 1·23-1·58 (6H, m), 1.78-2.04 (4H, m), 2·92-3·08 (1H, m), 5·17 (2H, s ), 7.24 (1H, d, J = 2.5 Hz), 7.31 (1H, dd, J = 8.8, 2.9 Hz), 7.43 (1H, d, J = 7.6 Hz), 7.64 (1H, dd, J = 8.3,2·0 Hz), 7.74 (1H, d, J=2.0 Hz), 7.81 (1H, d, J=8.6 Hz), 7.94 (2H, d, J=8.6 Hz), 8·20 (1H, s),1〇·ΐ〇(1H,s) 〇MS (ESI) m/z··(6) 1-[6-(3-Cyano-4-cyclohexylbenzyloxy)naphthalene_ 2_ylmethyl]azetidine_3 methyl carboxylate 121200.doc -88 - 200846342 [Chem. 83]

於2-環己基-5-(6-甲醯萘-2-基氧基甲基）苯基腈（156 mg)、3-口丫 丁啶羧酸甲酯鹽酸鹽〇 92 mg)及醋酸（〇·5 ml)之 二氣乙烧溶液（5 ml)中，於室溫下添加乙醯氧基硼酸鈉 (268 mg) ’授拌4天。於該反應液中添加飽和破酸氫鈉溶 液，攪拌一會兒後，藉由二氯甲烷進行萃取。將合併之萃 取液利用飽和食鹽水加以清洗後，藉由無水硫酸鈉乾燥。 將餾去溶劑所獲得之殘渣使用矽膠快速管柱色層分析 (Biotage25S)進行純化，獲得標記化合物（g^mg)。 iH-NMR (CDC13) δ: 1.15-1.57 (5H，m)，1·67-1·96 (6H，m)， 2·91-3·07 (1Η，m)，3·26-3.43 (3Η，m)，3·52-3·59 (2Η，m)， 3.64-3.91(5H，m)，5.13(2H，s)，7.05-7.22 (2H，m)，7.33-7.44 (2H，m)，7.79-7.53 (4H，m)。 MS (ESI) m/z: 469 o (7) 1_[6-(3 -氰基-4-環己基苄氧基）萘基曱基]吖丁咬-3- 羧酸 [化 84]2-cyclohexyl-5-(6-methylindole-2-yloxymethyl)phenyl nitrile (156 mg), 3-methylazetidinecarboxylic acid methyl ester hydrochloride (92 mg) and acetic acid (〇·5 ml) in a solution of dioxin (5 ml), sodium acetoxyborate (268 mg) was added at room temperature for 4 days. A saturated sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was stirred for a while and then extracted with dichloromethane. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified using silica gel chromatography (Biotage 25S) to give the title compound (g^mg). iH-NMR (CDC13) δ: 1.15-1.57 (5H, m), 1.67-1·96 (6H, m), 2·91-3·07 (1Η, m), 3·26-3.43 (3Η ,m),3·52-3·59 (2Η,m), 3.64-3.91(5H,m),5.13(2H,s),7.05-7.22 (2H,m),7.33-7.44 (2H,m) , 7.79-7.53 (4H, m). MS (ESI) m/z: 469 o (7) 1_[6-(3 - cyano-4-cyclohexylbenzyloxy)naphthyl fluorenyl] butyl butyl-3-carboxylic acid [Chem. 84]

於1-[6_(3-氰基-4-環己基苄氧基）萘基甲基]吖丁啶-3- 121200.doc -89 - 200846342 羧酸甲酯（87 mg)之甲醇/四氫呋喃混合溶液（l/o.5 ml)中， 於室溫下添加1 N氫氧化鈉水溶液（0.36 ml)，攪拌3小時。 於減壓下濃縮反應液，於所獲得之殘渣中添加1 N鹽酸 (0.36 ml)，藉由甲醇/氯仿混合（10%)溶液進行萃取。將合 併之萃取液利用飽和食鹽水加以清洗，藉由無水硫酸鈉進 行乾燥。過濾分離不溶物後，於減壓下濃縮。將所獲得之 殘潰藉由石夕膠管柱色層分析進行純化。藉由醚/正己烧使 所獲得之殘渣固化而加以分樣並乾燥，獲得標記化合物 (45 mg)。 !H-NMR (DMSO-d6) δ: 0.79-0.90 (2H? m)5 1.16-1.57 (4Η5 m)，1_63·1·89 (4Η，m)，2·74-2·92 (1Η，m)。3·14_3.26 (3Η， m)，3.38 (2H，s)，3.64 (2H，s)，5.22 (2H，s)，7·21 (1H，dd， J=8.8，2. Hz)，7·29·7·43 (2H，m)，7.55 (1H，d，J=8.0 Hz)， 7.62-7.83 (5H，m)，7.89 (1H，s)。 IR (ATR)cm·1: 2956，2911，2873, 2767, 2671，2598，2457, 1732, 1670, 1603 ° MS (ESI) m/z: 455 (M+H)。 [評估例1]被驗物質之in vitro評估 (1) HA-Gqi5 DNA之選殖 使用 DNeasy Tissue Kit (QIAGEN)，自 HA-Gqi5 表現 CHO 細胞（自 Molecular Devices公司購入）萃取 genomic DNA。 將萃取液作為模板，使用KOD plus DNA polymerase (ΤΟΎΟΒΟ)進行PCR (polymerase chain reaction，聚合酶鏈 反應）。將目的之PCR產物進行純化及blunting kination(末 121200.doc -90- 200846342 端平滑與5’端磷酸化）處理（BKL Kit : TAKARA-BIO)，與 pUC118/HineII-BAP (TAKARA-BIO)進行 ligation(連接）。 將Ligation mix導入大腸桿菌DH5a (TOYOBO)，藉由PCR 法選擇陽性克隆後，獲得***有HA-Gqi5 DNA之質粒。 (2) HA-Gqi5表現質粒之構築 將***pUC118之HA-Gqi5基因以限制酶進行酶切並純化 後，與表現質粒 pcDNA3.1Hygro(+)(Invitrogen)進行 ligation。其次，導入大腸桿菌DH5a並選擇陽性克隆後， 獲得HA-Gqi5表現質粒。 (3) HA-Gqi5表現CHO細胞之製作 使用Fugene6 (Roehe Diagnostics股份有限公司）試劑，於 CHO-K1細胞中導入（2)中所獲得之HA-Gqi5表現質粒，使 用hygromycin(潮黴素）進行細胞篩選。細胞進行2次選殖， 藉由使用抗HA抗體之西方墨點法而選擇HA-Gqi5表現CHO 細胞。 (4) 人 SlPl(EDG-l)之選殖 將人 SlPl(EDG-l)之 cDNA克隆（open biosystems，cDNA collection #4071217)作為模板，藉由PCR而獲得人S1P1 (EDG-1) DNA。將該PCR產物***pUC118後，藉由site-directed mutagenesis kit (STRATAGENE)， ***獲 得*** 有目的序列（The Journal of Biological Chemistry Vol. 265. No· 16, 9308-9313, 1990)之DNA的質粒。 (5) 人S1P1 (EDG-1)表現質粒之構築 將*** PUC118 之人 S1P1 (EDG-1)基因（The Journal of 121200.doc -91 - 200846342Methyl carboxylic acid (87 mg) in methanol/tetrahydrofuran mixed with 1-[6-(3-cyano-4-cyclohexylbenzyloxy)naphthylmethyl]azetidin-3- 121200.doc -89 - 200846342 A 1 N aqueous sodium hydroxide solution (0.36 ml) was added to the solution (l/o. 5 ml) and stirred for 3 hr. The reaction mixture was concentrated under reduced pressure. &lt;RTI ID=0.0&gt;&gt;&gt; The combined extract was washed with saturated brine and dried over anhydrous sodium sulfate. After insoluble matter was separated by filtration, it was concentrated under reduced pressure. The obtained residue was purified by chromatography on a Shixia hose column. The residue obtained was solidified by ether/n-hexane to give a sample and dried to give a labeled compound (45 mg). !H-NMR (DMSO-d6) δ: 0.79-0.90 (2H? m)5 1.16-1.57 (4Η5 m),1_63·1·89 (4Η,m),2·74-2·92 (1Η,m ). 3·14_3.26 (3Η, m), 3.38 (2H, s), 3.64 (2H, s), 5.22 (2H, s), 7·21 (1H, dd, J=8.8, 2. Hz), 7 ·29·7·43 (2H, m), 7.55 (1H, d, J = 8.0 Hz), 7.62-7.83 (5H, m), 7.89 (1H, s). IR (ATR) cm·1: 2956, 2911, 2873, 2767, 2671, 2598, 2457, 1732, 1670, 1603 ° MS (ESI) m/z: 455 (M+H). [Evaluation Example 1] In vitro evaluation of the test substance (1) Selection of HA-Gqi5 DNA The genomic DNA was extracted from HA-Gqi5-expressing CHO cells (purchased from Molecular Devices) using the DNeasy Tissue Kit (QIAGEN). The extract was used as a template, and PCR (polymerase chain reaction) was carried out using KOD plus DNA polymerase (ΤΟΎΟΒΟ). Purification of the desired PCR product and blunting kination (end 121200.doc -90-200846342 end smoothing and 5' phosphorylation) treatment (BKL Kit: TAKARA-BIO), and pUC118/HineII-BAP (TAKARA-BIO) Ligation (connection). The Ligation mix was introduced into Escherichia coli DH5a (TOYOBO), and a positive clone was selected by PCR to obtain a plasmid into which HA-Gqi5 DNA was inserted. (2) Construction of HA-Gqi5 expression plasmid The HA-Gqi5 gene inserted into pUC118 was digested with restriction enzymes and purified, and then subjected to ligation with the expression plasmid pcDNA3.1Hygro(+) (Invitrogen). Next, after introducing Escherichia coli DH5a and selecting a positive clone, a HA-Gqi5 expression plasmid was obtained. (3) Preparation of HA-Gqi5-expressing CHO cells The HA-Gqi5 expression plasmid obtained in (2) was introduced into CHO-K1 cells using Fugene 6 (Roehe Diagnostics Co., Ltd.) reagent, and hygromycin (hygromycin) was used. Cell screening. The cells were subjected to 2 colonizations, and HA-Gqi5 was selected to express CHO cells by Western blotting using an anti-HA antibody. (4) Selection of human SlPl (EDG-1) Human S1P1 (EDG-1) DNA was obtained by PCR using cDNA clone (open biosystems, cDNA collection #4071217) of human SlPl (EDG-1) as a template. After the PCR product was inserted into pUC118, a plasmid into which a DNA having a desired sequence (The Journal of Biological Chemistry Vol. 265. No. 16, 9308-9313, 1990) was inserted was inserted by a site-directed mutagenesis kit (STRATAGENE). (5) Construction of human S1P1 (EDG-1) expression plasmid The human S1P1 (EDG-1) gene inserted into PUC118 (The Journal of 121200.doc -91 - 200846342

Biological Chemistry VoL265.No.16，9308-9313，1990)以限 制酶進行酶切並純化後，與表現質粒pcDNA3.1/mycHisA (Invitrogen)進行ligation。其次，選擇導入大腸桿菌DH5a 之陽性克隆後，獲得人S1P1(EDG-1)表現質粒。 (6) 人S1P1 (EDG-1)表現CHO細胞之製作 使用Fugene6 (Roche Diagnostics股份有限公司）試劑，於 (3)中獲得之HA-Gqi5表現CHO細胞中導入S1P1 (EDG-1)表 現質粒，使用G418進行細胞篩選。細胞進行2次選殖，藉 由S1P刺激而選擇細胞内鈣上升之細胞。 (7) 細胞内鈣流分析 將上述（6)中獲得之導入有人S1P1 (EDG-1)之Gqi5蛋白表 現CHO細胞，於黑色底面透明96孔板中以2.5xl04 cell/well 進行播種，培養一晚，利用不含血清之培養基清洗1次 後，添加100 pL含有2·5 mM probenicid(緩苯石黃胺）、0.25% 不含脂肪酸之BSA (bovine serum albumin，牛血清白蛋白） 之分析用緩衝液（Calcium Assay Kit，Molecular Devices)， 使之於37°C及5%C02下反應1小時。 以產生最終試驗濃度之5倍濃度之方式，添加25 pL將試 驗化合物加以稀釋之液體，藉由FLEXstation II (Molecular Devices)測定細胞内鈣濃度變化，作為細胞内鈣濃度之最 小值與最大峰值之差而求得。根據由測定值製作之S型曲 線，算出EC50值作為針對SlPl(EDG-l)受體之激動劑活 性。 [評估例2]被驗物質之in vivo評估（被驗化合物投與4小時後 121200.doc -92- 200846342 小鼠末梢血中淋巴球數減少試驗） 報告有於S1P受體激動劑投與後之小鼠中，末梢血中之 淋巴球減少之情況[SCIENCE，296，346-349(2002)]。使用 本#估法’實施被檢化合物之評估。被驗物質係使用 MC(甲基纖維素）溶液製備懸浮液或溶液之投與液（小鼠體 重每20 g，經口投與〇.2 ml之濃度）。Biological Chemistry VoL265. No. 16, 9308-9313, 1990) was digested with a restriction enzyme and purified, and subjected to ligation with the expression plasmid pcDNA3.1/mycHisA (Invitrogen). Next, after introducing a positive clone into Escherichia coli DH5a, a human S1P1 (EDG-1) expression plasmid was obtained. (6) Production of CHO cells by human S1P1 (EDG-1) The S1P1 (EDG-1) expression plasmid was introduced into CHO cells using HA-Gqi5 reagent obtained in (3) using Fugene6 (Roche Diagnostics Co., Ltd.) reagent. Cell screening was performed using G418. The cells were cultured twice, and cells with intracellular calcium elevation were selected by stimulation with S1P. (7) Analysis of intracellular calcium flux The Gqi5 protein obtained in the above (6) and introduced into human S1P1 (EDG-1) was expressed as CHO cells, and seeded in a black bottom transparent 96-well plate at 2.5×10 4 cells/well. In the evening, after washing once with serum-free medium, 100 pL of analysis containing 2·5 mM probenicid (buxoflavin) and 0.25% BSA (bovine serum albumin) without fatty acid was added. The buffer (Calcium Assay Kit, Molecular Devices) was allowed to react at 37 ° C and 5% CO 2 for 1 hour. 25 pL of the test compound was diluted to a concentration of 5 times the final test concentration, and the intracellular calcium concentration was measured by FLEXstation II (Molecular Devices) as the minimum and maximum peak of intracellular calcium concentration. Worse. Based on the S-shaped curve prepared from the measured values, the EC50 value was calculated as the agonist activity against the SlPl (EDG-1) receptor. [Evaluation Example 2] In vivo evaluation of the test substance (after the test compound was administered for 4 hours, 121200.doc -92-200846342 The lymphocyte count reduction test in the peripheral blood of the mouse) was reported after administration of the S1P receptor agonist. The decrease in lymphocytes in peripheral blood in mice [SCIENCE, 296, 346-349 (2002)]. The evaluation of the test compound was carried out using this #evaluation method. The test substance was prepared by using a MC (methylcellulose) solution to prepare a suspension or a solution of the solution (the body weight of the mouse was 20 g per day, and the concentration of 〇. 2 ml was orally administered).

級口投與被驗物質4小時後，於醚麻醉下使用EDTA4 hours after the target was administered to the test substance, EDTA was used under ether anesthesia.

(ethylene diamine tetraacetic acid，乙二胺四乙酸）作為抗 凝固劑，自後大靜脈採血（〇·5 ml)。末梢血中之淋巴球數 藉由綜合血液學檢査裝置ADVIA120 (Bayermedical)確 疋。被檢藥之藥理作用係以對照組（溶劑投與）群作為標準 值，根據被檢藥投與群之平均末梢血淋巴球數相對於標準 值之比T/C(%)而判定效果。 T/C(%)之計算式： T/c(%)=(被檢藥投與群之平均末梢血淋巴球數麟劑投與 群之平均末梢血淋巴球數）x丨 卜平估例3]被驗物質之in viv。持續性評估（被驗化合物投與 24小&amp;後小鼠末梢血中淋巴球數減少試驗） 上述[w平估例2]同樣，經口投與被驗物質後，同樣測 疋24小時後末梢血中之淋巴球數。 、 [試驗結果] 就實施例化合物進行試驗之結果 將根據上述試驗方法 示於下述表1〜表3。 121200.doc -93- 200846342 [表l] 表1 :被驗物質之in vitro評估結果 S1P1 EC50 (nM) 化合物1* 2.0 實施例1 1.8 實施例3 5.7 實施例5 2.1 實施例6 4.3(ethylene diamine tetraacetic acid, ethylenediaminetetraacetic acid) was used as an anticoagulant to collect blood from the posterior great vein (〇·5 ml). The number of lymphocytes in the peripheral blood was confirmed by the comprehensive hematology device ADVIA120 (Bayermedical). The pharmacological action of the test drug is based on the control group (solvent administration) group as a standard value, and the effect is determined based on the ratio T/C (%) of the average peripheral hemolymph sphere number of the test drug administration group to the standard value. The calculation formula of T/C (%): T/c (%) = (the average peripheral hemolymph sphere of the drug-administered group, the average number of peripheral hemolymphs in the group) x丨卜平3] In viv of the substance being tested. Persistence evaluation (the test compound was administered to 24 small &amp; mice after the lymphocyte count reduction test in the peripheral blood) The above [w flat estimate 2] Similarly, after oral administration of the test substance, the same test 24 hours later The number of lymphocytes in the peripheral blood. [Test Results] The results of tests on the compounds of the examples are shown in Tables 1 to 3 below in accordance with the above test methods. 121200.doc -93- 200846342 [Table 1] Table 1: In vitro evaluation results of the test substance S1P1 EC50 (nM) Compound 1* 2.0 Example 1 1.8 Example 3 5.7 Example 5 2.1 Example 6 4.3

*化合物1(國際公開第2003/062252號手冊中揭示之化合 物）· 1-{4-{(4 -苯基-5-二敦曱基塞吩基）曱基}节基}-3_ σ丫丁 σ定叛酸（l-{4-{(4-Phenyl-5-trifluoromethyl-2-thienyl) methyl} benzyl} - 3-azeti dine carboxylic acid) 本發明化合物具有針對S1P1受體之激動劑活性，其強度 與化合物1(國際公開第2003/062202號手冊中揭示之化合 物）同等。*Compound 1 (compound disclosed in the handbook of International Publication No. 2003/062252) · 1-{4-{(4-Phenyl-5-distanylthiophene) fluorenyl}-}}}} (1-Phenyl-5-trifluoromethyl-2-thienyl) methyl} benzyl} - 3-azeti dine carboxylic acid) The compound of the present invention has agonist activity against the S1P1 receptor, Its strength is equivalent to that of Compound 1 (a compound disclosed in International Publication No. 2003/062202).

121200.doc -94· 200846342 [表2] 表2 :被驗物質之in vivo評估結果(經口投與4天後） T/C(°/〇) (0.3 mg/kg) T/C(%) (1 mg/kg) T/C(%) (3 mg/kg) 化合物1* 52.0 23.2 13.2 實施例1 21.2 13.3 12.2 實施例3 23.1 10.9 9.0 實施例5 12.6 7.2 8.2 實施例6 20.2 21.5 14.9 *化合物1(國際公開第2003/062252號手冊中揭示之化合 物）：1-{4-{(4 -苯基-5-二氟甲基-2-σ塞吩基）甲基}节基}·3· σ丫 丁 σ定魏酸（l-{4-{(4-Plienyl-5-trifluoromet]iyl-2-thienyl) methyl} benzyl} - 3 - azeti dine car boxy lie acid) 本發明化合物於經口投與中顯示末梢血中之淋巴球數減 少效果。 化合物1(國際公開第2003/062252號手冊中揭示之化合 物）於0.3 mg/hg之經口投與中，末梢血中淋巴球數減少效 果顯示為標準值（溶劑投與群之平均末梢血淋巴球數）之 52.0%。另一方面，本發明化合物於0.3 mg/kg之經口投與 中顯示為標準值之12.6〜23.1%之低值，末梢血中淋巴球數 減少效果好於化合物1。 121200.doc -95- 200846342 [表3] 表3 :被驗物質之in vivo持續性評估結果(經口投與24小時後） T/C(%) T/C(%) 化合物 (1 mg/kg) (3 mg/kg) 化合物1* 105.0 115.0 實施例1 27.3 17.5 實施例3 10.1 〜25·1 實施例6 24.2 16.6 *化合物1(國際公開第2003/062252號手冊中揭示之化合 物）：1-{4-{(4-苯基-5-三氟甲基-2-噻吩基）甲基}苄基}-3-口丫丁唆魏酸（l-{4-{(4-Phenyl-5-trifluoromethyl-2-thienyl) methyl}benzyl}- 3-azetidinecarboxylie acid) 本發明化合物藉由經口投與而使末梢血中淋巴球數減 少，其有效性持續至24小時後。 化合物1(國際公開第2003/062252號手冊中揭示之化合 物）如表2所示，藉由1 mg/kg及3 mg/kg之經口投與，則4小 時後顯示有效性，但24小時後末梢血中淋巴球數減少效果 消失，恢復至標準值（溶劑投與群之平均末梢血淋巴球 數）。另一方面，本發明化合物藉由1 mg/kg及/或3 mg/kg 之經口投與，於24小時後仍顯示標準值之10.1〜27.3%之低 值，維持有效性。 [產業上之可利用性] 本發明之二環性芳基衍生物具有優異之S1P受體激動劑 活性、口服吸收性及持續性，因此提供一種可用作對於移 植之排斥反應、自體免疫性疾病、過敏性疾病之治療劑及/ 或預防劑且可經口投與之藥劑，臨床上之有用性極高。 121200.doc -96-121200.doc -94· 200846342 [Table 2] Table 2: In vivo evaluation results of the test substance (after 4 days of oral administration) T/C (°/〇) (0.3 mg/kg) T/C (% (1 mg/kg) T/C (%) (3 mg/kg) Compound 1* 52.0 23.2 13.2 Example 1 21.2 13.3 12.2 Example 3 23.1 10.9 9.0 Example 5 12.6 7.2 8.2 Example 6 20.2 21.5 14.9 * Compound 1 (compound disclosed in the handbook of International Publication No. 2003/062252): 1-{4-{(4-phenyl-5-difluoromethyl-2-σsecenyl)methyl}]} 3· σ 丫 σ 定 魏 魏 魏 魏 魏 魏 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( Oral administration shows the effect of reducing the number of lymphocytes in the peripheral blood. Compound 1 (a compound disclosed in the manual of International Publication No. 2003/062252) was administered orally at a dose of 0.3 mg/hg, and the effect of reducing the number of lymphocytes in the peripheral blood was shown as a standard value (average peripheral hemolymph of the solvent-administered group) 52.0% of the number of balls). On the other hand, the compound of the present invention showed a low value of 12.6 to 23.1% of the standard value in the oral administration of 0.3 mg/kg, and the effect of reducing the number of lymphocytes in the peripheral blood was better than that of the compound 1. 121200.doc -95- 200846342 [Table 3] Table 3: In vivo persistence evaluation results of the test substance (after oral administration for 24 hours) T/C (%) T/C (%) Compound (1 mg/ Kg) (3 mg/kg) Compound 1* 105.0 115.0 Example 1 27.3 17.5 Example 3 10.1 ～25·1 Example 6 24.2 16.6 *Compound 1 (compound disclosed in the International Publication No. 2003/062252): 1 -{4-{(4-Phenyl-5-trifluoromethyl-2-thienyl)methyl}benzyl}-3-hydroxyindolizine (l-{4-{(4-Phenyl-) 5-trifluoromethyl-2-thienyl)methyl}benzyl}- 3-azetidinecarboxylie acid) The compound of the present invention reduces the number of lymphocytes in peripheral blood by oral administration, and its effectiveness lasts for 24 hours. Compound 1 (the compound disclosed in the manual of International Publication No. 2003/062252), as shown in Table 2, was orally administered at 1 mg/kg and 3 mg/kg, and showed efficacy after 4 hours, but 24 hours. The effect of reducing the number of lymphocytes in the posterior peripheral blood disappeared and returned to the standard value (the average number of peripheral hemolymphocytes in the solvent-administered group). On the other hand, the compound of the present invention is orally administered at 1 mg/kg and/or 3 mg/kg, and after 24 hours, it still shows a low value of the standard value of 10.1 to 27.3%, maintaining the effectiveness. [Industrial Applicability] The bicyclic aryl derivative of the present invention has excellent S1P receptor agonist activity, oral absorption and persistence, and thus provides a kind of rejection and autoimmunity for transplantation. A therapeutic agent for a sexually transmitted disease, an allergic disease, and/or a prophylactic agent, which can be administered orally, is clinically highly useful. 121200.doc -96-

Claims (1)

200846342 十、申請專利範圍： 1 · 一種以下述、甬彳 人u i式（1)所表示之化合物、其鹽或彼等之溶劑 合物， 4 [化1]200846342 X. Patent application scope: 1 · A compound represented by the following formula (1), a salt thereof or a solvate thereof, 4 [Chemical Formula 1] A〆％) [式中A〆%) [in the formula n表示1、2、3或4， 表示氫原子或C1〜C6烷基 \及反表示分別獨立為氫原子或C1〜C6烷基，或者…與 R亦可一體化而形成亞甲基或伸乙基；n represents 1, 2, 3 or 4, and represents a hydrogen atom or a C1 to C6 alkyl group, and an inverted representation is independently a hydrogen atom or a C1 to C6 alkyl group, or ... and R may be integrated to form a methylene group or a stretching group. Ethyl; ΑΓ表不由萘、1H-吲哚、1H-吡咯幷[2,3-b]吡啶、1H-吡 咯幷[3,2_b]吡啶、1H_吡咯幷[2,3-c]吡啶或苯幷呋喃衍生 之2價基（該等基團亦可分別獨立含有自_原子、羥基、 氮基、石肖基、C1〜C6烷基、鹵代C1〜C6烷基、C3〜C6環烷 基、自代C3〜C6環烧基、Ci〜C6烧氧基及鹵代C1〜C6烧氧 基所組成族群中選擇之〗〜3個基團作為取代基）； Ar表示苯基、吡啶基、呋喃基、噻吩基、吡咯基、噁唑 基、噻唑基、1H-吼唑基或1H-[1，2,4]***基[該等基團表 不亦可分別獨立含有自鹵原子、硝基、氰基、C1〜C6烷 基、鹵代C1〜C6烷基、C1〜C6烷氧基C1〜C6烷基、C3〜C6 環烷基、鹵代C3〜C6環烷基、（C3〜C6環烷基）甲基、 121200.doc 200846342 Cl〜C6烷氧基、鹵代Cl〜C6烷氧基、C3〜C6環烷氧基、 (C3〜C6環烷基）甲氧基及苯基[該苯基亦可含有自鹵原 子、氰基、硝基、C1〜C6烷基、C3〜C6環烷基、鹵代 C3〜C6環烷基、（C3〜C6環烷基）甲基、ci〜C6烷氧基、 C3〜C6環烷氧基及（C3〜C6環烷基）甲氧基所組成族群中遂 擇之1或2個基團作為取代基]所組成族群中選擇之1〜3個 基團作為取代基];|。 2 ·如請求項1之化合物、其鹽或彼等之溶劑合物，其中通 式⑴中之Ar1為以下述式（ii-a)〜(II_f)所表示之任一基 團， [化2]The formula is not derived from naphthalene, 1H-indole, 1H-pyrrole [2,3-b]pyridine, 1H-pyrrole[3,2_b]pyridine, 1H-pyrrole[2,3-c]pyridine or benzofuran. Derivatized divalent groups (these groups may also independently contain from a _ atom, a hydroxyl group, a nitrogen group, a schlossyl group, a C1 to C6 alkyl group, a halogenated C1 to C6 alkyl group, a C3 to C6 cycloalkyl group, a self-generation C3 ～~3 groups selected as a substituent in the group consisting of C6 cycloalkyl, Ci~C6 alkoxy and halogenated C1~C6 alkoxy groups; Ar represents phenyl, pyridyl, furyl, thiophene , pyrrolyl, oxazolyl, thiazolyl, 1H-carbazolyl or 1H-[1,2,4]triazolyl [These groups may also independently contain self-halogen atoms, nitro groups, cyanogens a group, a C1 to C6 alkyl group, a halogenated C1 to C6 alkyl group, a C1 to C6 alkoxy group C1 to C6 alkyl group, a C3 to C6 cycloalkyl group, a halogenated C3 to C6 cycloalkyl group, (C3 to C6 cycloalkane) Methyl, 121200.doc 200846342 Cl~C6 alkoxy, halogenated Cl~C6 alkoxy, C3~C6 cycloalkoxy, (C3~C6 cycloalkyl)methoxy and phenyl [the benzene The group may also contain a halogen atom, a cyano group, a nitro group, a C1 to C6 alkyl group, a C3 to C6 cycloalkyl group, a halogenated C3 group. Among the groups consisting of C6 cycloalkyl, (C3~C6 cycloalkyl)methyl, ci~C6 alkoxy, C3~C6 cycloalkoxy and (C3~C6 cycloalkyl)methoxy groups Or 2 groups selected as a substituent] 1 to 3 groups selected as a substituent]; 2. The compound of claim 1, a salt thereof or a solvate thereof, wherein Ar1 in the formula (1) is any one represented by the following formula (ii-a) to (II-f), ] R a、R3b、R3c、R3d、R3e、、R3g、R3h、R3i、、r31c 及R为別獨立表示氫原子、齒原子、經基、氰基、硝 基、C1〜C6烷基、鹵代C1〜C6烷基、C3〜C6環烷基、鹵代 C3〜C6環烷基、C1〜C6烷氧基或鹵代C1〜C6烷氧基； 121200.doc 200846342 R4a、R4b 基]〇 尺4°及R4d1別獨立表示氫原子或〇1〜以烷 3·如請求項1或2之化合物、其鹽或彼等之溶劑合物，其中 通式⑴中之Ar1為以式（II_a)、（„_b)、（II e)或（ii f)所表 示之基團。 ^ 4·如請求項⑴中任一項之化合物、其鹽或彼等之溶劑人 物，其中通式⑴中之Ari為以下述式⑴+”、（nj/ (II-C-1)及（πυ)所表示之任一基團， [化3]R a , R 3b , R 3 c , R 3 d , R 3 e , R 3 g , R 3 h , R 3 i , r 31 c and R independently represent a hydrogen atom, a tooth atom, a trans group, a cyano group, a nitro group, a C 1 C C 6 alkyl group, a halogenated C 1 group. ~C6 alkyl, C3~C6 cycloalkyl, halogenated C3~C6 cycloalkyl, C1~C6 alkoxy or halogenated C1~C6 alkoxy; 121200.doc 200846342 R4a, R4b base] 4° And R4d1 independently represents a hydrogen atom or a hydrazine 1 to alkane. 3. The compound of claim 1 or 2, a salt thereof or a solvate thereof, wherein Ar1 in the formula (1) is represented by the formula (II-a), („ The group represented by the formula (1), the salt thereof or the solvent of the same, wherein the Ari in the formula (1) is the following Any of the groups represented by the formula (1)+", (nj/(II-C-1), and (πυ), [Chemical 3] 121200.doc 1 表示與通式⑴中之亞甲基之鍵結位置； 以、R3b、R3C、R3d、d3f、R&quot;分別獨立表示 氫原子、鹵原子、羥基、氰基、硝基、Cl〜C6烷基、鹵 代C1〜C6烷基、C3〜C6環烷基、鹵代c3〜以環烷基、 C1〜C6烷氧基或鹵代C1〜C6烷氧基； R4^R4b分別獨立表示氫原子或以〜以烷基]。 200846342 5·如請求項4之化合物、其鹽或彼等之溶劑合物，其中通 式（Ϊ)中之 Αι:1為以式（n_a_i)、（II-b-1)、（II-c·；^或 所表示之基團，式（n+i)、（ιι-b-i)、（ii-cq)及（nn) 中之 R3a、R3b、R3c、R3d、、R3f、R3k 及 r31為氫原 子’ R4a&amp;R4b分別獨立為氫原子或曱基。 6·如請求項1至5中任一項之化合物、其鹽或彼等之溶劑合 物’通式（I)中之Ar2為以下述式（πΐ-a)〜(Ill-i)所表示之任 一基團， [化4]121200.doc 1 represents a bonding position with a methylene group in the general formula (1); and R3b, R3C, R3d, d3f, and R&quot; respectively represent a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group, and a Cl~ group. C6 alkyl, halogenated C1 to C6 alkyl, C3 to C6 cycloalkyl, halogenated c3 to cycloalkyl, C1 to C6 alkoxy or halogenated C1 to C6 alkoxy; R4^R4b are independently represented Hydrogen atom or with ~ to alkyl]. 200846342 5. The compound of claim 4, a salt thereof or a solvate thereof, wherein Αι:1 in the formula (Ϊ) is of the formula (n_a_i), (II-b-1), (II-c) ·^ or the represented group, R3a, R3b, R3c, R3d, R3f, R3k and r31 in the formula (n+i), (ιι-bi), (ii-cq) and (nn) are hydrogen The atom 'R4a&amp; R4b is independently a hydrogen atom or a fluorenyl group. 6. The compound of any one of claims 1 to 5, a salt thereof or a solvate thereof, wherein Ar2 in the formula (I) is as follows Any group represented by the formula (πΐ-a)~(Ill-i), [Chemical 4] [式中， R5a、R5b、R5C、R5d、R5e、R5f、R5g、R5h、R5i、R5j R5k、R51、R5m、R5n、r5。、r5P、R5q、R5r、r5s、以 R及R5v分別獨立表示氫原子、齒原子、硝基、氰基 121200.doc -4- 200846342 Cl〜C6烷基、鹵代Cl〜C6烷基、Cl〜C6烷氧基Cl〜C6烷 基、C3〜C6環烷基、鹵代C3〜C6環烷基、（C3〜C6環烷基） 甲基、C1〜C6烷氧基、鹵代C1〜C6烷氧基、C3〜C6環烷氧 基、（C3〜C6環烷基）甲氧基或苯基[該苯基亦可含有自鹵 原子、氰基、硝基、C1〜C6烷基、C3〜C6環烷基、鹵代 C3〜C6環烷基、（C3〜C6環烷基）甲基、C1〜C6烷氧基、 C3〜C6環烷氧基及（C3〜C6環烷基）甲氧基所組成族群中選 擇之1或2個基團作為取代基]; R6表示氫原子或C1〜C6烷基； R7a及R7b分別獨立表示C1〜c6烷基、鹵代C1〜C6烷基、 C1〜C6烷氧基C1〜C6烷基、C3〜C6環烷基、鹵代C3〜06環 烷基、（C3〜C6環烷基）曱基或苯基[該苯基亦可含有自鹵 原子、氰基、硝基、C1〜C6烷基、C3〜C6環烷基、鹵代 C3〜C6環烷基、（C3〜C6環烷基）甲基、C1〜C6烷氧基、 C3〜C6環烷氧基及（C3〜C6環烷基）甲氧基所組成族群中選 擇之1或2個基團作為取代基]]。 7.如請求項1至6中任一項之化合物、其鹽或彼等之溶劑合 '物，其中通式（I)中之Ar2為以下述式（IV-a)〜(IV-d)所表示 之任一基團， [化5] 121200.doc 200846342[wherein R5a, R5b, R5C, R5d, R5e, R5f, R5g, R5h, R5i, R5j R5k, R51, R5m, R5n, r5. , r5P, R5q, R5r, r5s, R and R5v independently represent a hydrogen atom, a tooth atom, a nitro group, a cyano group 121200.doc -4- 200846342 Cl~C6 alkyl group, a halogenated Cl~C6 alkyl group, Cl~ C6 alkoxy Cl~C6 alkyl, C3~C6 cycloalkyl, halogenated C3~C6 cycloalkyl, (C3~C6 cycloalkyl)methyl, C1~C6 alkoxy, halogenated C1~C6 alkane Oxy group, C3~C6 cycloalkoxy group, (C3~C6 cycloalkyl)methoxy group or phenyl group [The phenyl group may also contain a halogen atom, a cyano group, a nitro group, a C1 to C6 alkyl group, a C3~ C6 cycloalkyl, halogenated C3~C6 cycloalkyl, (C3~C6 cycloalkyl)methyl, C1~C6 alkoxy, C3~C6 cycloalkoxy and (C3~C6 cycloalkyl)methoxy One or two groups selected from the group consisting of a substituent; R6 represents a hydrogen atom or a C1 to C6 alkyl group; and R7a and R7b each independently represent a C1 to C6 alkyl group, a halogenated C1 to C6 alkyl group, and C1; ~C6 alkoxy C1~C6 alkyl, C3~C6 cycloalkyl, halogenated C3~06 cycloalkyl, (C3~C6 cycloalkyl)fluorenyl or phenyl [the phenyl group may also contain a halogen atom , cyano, nitro, C1 to C6 alkyl, C3 to C6 cycloalkyl, halogenated C3 to C6 cycloalkyl, (C 1 or 2 groups selected from the group consisting of 3~C6 cycloalkyl)methyl, C1~C6 alkoxy, C3~C6 cycloalkoxy and (C3~C6 cycloalkyl)methoxy base]]. 7. The compound of any one of claims 1 to 6, a salt thereof or a solvent thereof, wherein Ar2 in the formula (I) is represented by the following formula (IV-a) to (IV-d) Any of the groups indicated, [Chem. 5] 121200.doc 200846342 (IV—d)(IV-d) [式中， R8a、n8d、1^及R8f分別獨立表示氫原子、鹵原子、硝 基、氰基、C1〜C6烷基、鹵代C1〜C6烷基、C1〜C6烷氧基 C1〜C6烧基、C3〜C6環烷基、鹵代C3〜C6環烷基、 (C3〜C6環烷基）曱基、C1〜C6烷氧基、鹵代C1〜C6烷氧 基、C3〜C6環烷氧基或（C3〜C6環烷基）甲氧基； R9a、R9b、R9、R9d、R9e、Rm、及 分別獨立表示 氫原子、鹵原子、氰基、硝基、Cl〜C6烧基、C3〜C6環 烷基、鹵代C3〜C6環烷基、（C3〜C6環烷基）甲基、C1〜C6 烷氧基、C3〜C6環烷氧基或（C3〜C6環烷基）曱氧基]。 8 ·如請求項7之化合物、其鹽或彼等之溶劑合物，其中式 (IV-a)、（IV_b)、（IV_c)&amp;(IV_d)中之 、R8d、^^及^^分 別獨立為自硝基、氰基、C1〜C 6烧基、鹵代c 1〜c 6烧基 及01〜C6烷氧基C1〜C6烷基所組成族群中選擇之任一基 團0 9·如請求項8之化合物、其鹽或彼等之溶劑合物，其中 121200.doc 200846342 氰基、鹵代C1〜C6烷基 成族群中選擇之任一基 R、…、…及〜別獨立為, 及C1〜C6烷氧基Cl〜C6烷基所組 團。 10·如μ求項9之化合物、纟鹽或彼等之溶劑合物，其中 R8a、H8d、R8e及R8f為豳代C1〜C6烷基。 ιι·如請求項ίο之化合物、其鹽或彼等之溶劑合物，其中函 代C1〜C 6烧基之鹵原子為氣原子。 12·如請求項10之化合物、其鹽或彼等之溶劑合物，其中鹵 代C1〜C6烷基為三氟甲基。 13.如請求項7之化合物、其鹽或彼等之溶劑合物，其中式 (IV-a)〜(iv-d)中之 R9a、R9b、R9e、R9d、R9e、R9f、R9g及 R9h為氫原子。 14·如請求項i至13中任一項之化合物、其鹽或彼等之溶劑 合物，其中通式（I)中之R1為氫原子。 15 ·如請求項1至14中任一項之化合物、其鹽或彼等之溶劑 合物，其中通式（I)中之η為1。 16· —種化合物、其C1〜C6烷基酯、彼等之鹽或彼等之溶劑 合物，該化合物以下述式（V-1)〜（V-10)及（V·73)表示。 [化6][wherein, R8a, n8d, 1^ and R8f each independently represent a hydrogen atom, a halogen atom, a nitro group, a cyano group, a C1 to C6 alkyl group, a halogenated C1 to C6 alkyl group, a C1 to C6 alkoxy group C1 to C6. Alkyl, C3~C6 cycloalkyl, halogenated C3~C6 cycloalkyl, (C3~C6 cycloalkyl)decyl, C1~C6 alkoxy, halogenated C1~C6 alkoxy, C3~C6 ring Alkoxy or (C3~C6 cycloalkyl)methoxy; R9a, R9b, R9, R9d, R9e, Rm, and independently represent a hydrogen atom, a halogen atom, a cyano group, a nitro group, a Cl~C6 alkyl group, C3~C6 cycloalkyl, halogenated C3~C6 cycloalkyl, (C3~C6 cycloalkyl)methyl, C1~C6 alkoxy, C3~C6 cycloalkoxy or (C3~C6 cycloalkyl)曱oxy]. 8. The compound of claim 7, a salt thereof or a solvate thereof, wherein R8d, ^^ and ^^ in the formulae (IV-a), (IV_b), (IV_c) &amp; (IV_d) respectively Any one selected from the group consisting of nitro, cyano, C1~C 6 alkyl, halogenated c 1~c 6 alkyl and 01~C6 alkoxy C1~C6 alkyl. The compound of claim 8, a salt thereof or a solvate thereof, wherein 121200.doc 200846342 any one selected from the group consisting of a cyano group, a halogenated C1 to C6 alkyl group, R, ..., and And a group of C1 to C6 alkoxy Cl~C6 alkyl groups. 10. A compound of the formula 9, a phosphonium salt or a solvate thereof, wherein R8a, H8d, R8e and R8f are deuterated C1 to C6 alkyl groups. The compound of claim ίο, a salt thereof or a solvate thereof, wherein the halogen atom of the C1 to C 6 alkyl group is a gas atom. 12. A compound according to claim 10, a salt thereof or a solvate thereof, wherein the halogenated C1 to C6 alkyl group is a trifluoromethyl group. 13. The compound of claim 7, a salt thereof or a solvate thereof, wherein R9a, R9b, R9e, R9d, R9e, R9f, R9g and R9h in the formulae (IV-a) to (iv-d) are A hydrogen atom. The compound of any one of claims 1 to 13, a salt thereof or a solvate thereof, wherein R1 in the formula (I) is a hydrogen atom. The compound of any one of claims 1 to 14, a salt thereof or a solvate thereof, wherein n in the formula (I) is 1. A compound, a C1 to C6 alkyl ester thereof, a salt thereof or a solvate thereof, which is represented by the following formulas (V-1) to (V-10) and (V.73). [Chemical 6] (V—1) (V—2) 121200.doc 200846342(V-1) (V-2) 121200.doc 200846342 (V — 3)(V — 3) (V — 4)(V — 4) (V — 5) ，C0ZH(V — 5) , C0ZH (V — 6&gt;(V — 6&gt; 1卿s〜C¥ (V-7)1卿s~C¥ (V-7) (V — 8)(V — 8) Xf^^N^C02H (V— 9〉Xf^^N^C02H (V-9) (V—l 〇)(V-l 〇) (V-7 3) U 1 7· 一種醫藥’其含有如請求項1至16中任-項之化人 其鹽或彼等之溶劑合物作為有效成分。 口 ^ 之 項 18· 一種S1P受體激動劑，其含有如請求項1至16中任1 化合物、其鹽或彼：夕 J 寻之 &gt;谷劑合物作為有效成分。 19· 一種S1P1受體激動劑， 八3有如睛求項1至16中任&lt; 之化合物、其鹽或尬楚&gt; a 專之〉谷劑合物作為有效成分。 121200.doc 200846342 2〇· —種免疫抑制劑，其含有如請求項〗至16中任一項之化 合物、其鹽或彼等之溶劑合物作為有效成分。 21 ·種對移植之排斥反應、自體免疫丨生疾病、及/或過敏性 .疾病之治療劑及/或預防劑，其含有如請求項i至丨6中任 一項之化合物、其鹽或彼等之溶劑合物作為有效成分。 22· —種醫藥，其將如請求項1至16中任一項之化合物、其 鹽或彼等之溶劑合物，與自免疫抑制劑、免疫抑制中所 使用之抗體、排斥反應治療藥、抗生素及類固醇藥中所 選擇之1種或2種以上加以組合而成。 121200.doc 200846342 七、 指定代表圖： (一) 本案指定代表圖為：（無） (二) 本代表圖之元件符號簡單說明： 八、 本案若有化學式時，請揭示最能顯示發明特徵的化學式：(V-7 3) U 1 7· A medicine which contains the salt of the human or the solvate of any of the above items 1 to 16 as an active ingredient. Item 18. An S1P receptor agonist comprising the compound of any one of claims 1 to 16, a salt thereof, or a compound of the formula &gt; An S1P1 receptor agonist, which is the compound of any of the above items 1 to 16, a salt thereof, or a pharmaceutically acceptable salt. 121200.doc 200846342 An immunosuppressant comprising the compound of any one of claims 1-6 to a salt thereof or a solvate thereof as an active ingredient. A therapeutic agent and/or a prophylactic agent for a rejection reaction, an autoimmune disease, and/or an allergic disease, which comprises a compound according to any one of claims 1 to 6, a salt thereof Or their solvates as active ingredients. A pharmaceutical composition according to any one of claims 1 to 16, a salt thereof or a solvate thereof, an autoimmunity inhibitor, an antibody used in immunosuppression, a therapeutic drug for rejection, One or two or more selected from the group consisting of antibiotics and steroids. 121200.doc 200846342 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please reveal the best indication of the characteristics of the invention. Chemical formula: 121200.doc121200.doc