TW201245158A - New aryl-benzocycloalkyl amide derivatives - Google Patents

Abstract

The invention provides novel compounds having the general formula (I) wherein R1, R2, R3, R4 R5, R6, R7, R8, R9, R10, R11, R12, A1, A2 and n are as described herein, compositions including the compounds and methods of using the compounds.

Description

201245158 六、發明說明： 【發明所屬之技術領域】 本發明係關於適用於哺乳動物中之治療或預防之有機化 合物’且詳言之係關於治療或預防絲球體腎炎、亨偌_絲 奇恩賴紫癜性腎病變（Henoch-SchSnlein purpura nephro_ pathy，HSPN)、ANCA相關新月型絲球體腎炎、狼瘡性腎 炎及IgA腎炎之緩激肽B1受體（BDKRB1或B1R)拮抗劑或反 向促效劑。 本發明提供新穎式（I)化合物：201245158 VI. Description of the Invention: [Technical Field of the Invention] The present invention relates to an organic compound suitable for the treatment or prevention in a mammal' and in particular relates to the treatment or prevention of spheroid nephritis, Henry _Siqi Enlai Renoch-SchSnlein purpura nephro_ pathy (HSPN), ANCA-associated crescentic glomerulonephritis, lupus nephritis, and IgA nephritis bradykinin B1 receptor (BDKRB1 or B1R) antagonist or inverse agonist . The present invention provides novel compounds of formula (I):

2 1R \ly I fv 其中 R 為炫*基、〗衣烧基、環烧基烧基、烧氧基、烧氧基 烧基、私院乳基、環烧氧基炫基、齒院基、鹵烧 氧基、齒烷氧基烷基、ii環烷基、齒環烷基烷 基、鹵環烧氧基、齒環炫氧基烧基、烧氧基羰 基、環烷氧基羰基、齒烷氧基羰基、鹵環烷氧基 羰基、氰基、芳基、經取代之芳基、雜芳基或經 取代之雜^基’其中經取代之芳基及經取代之雜 芳基經一至三個獨立地選自以下之取代基取代： I60800.doc 201245158 烷基、環烷基、烷基環烷基、環烷基烷基、環烷 基烷氧基、環烷基烷氧基烷基、環烷氧基、環烷 氧基烧基、烧基環烧基烧基、函環烧基、ώ環烧 基烧基、鹵素、氰基、鹵烧基、烧氧基、烧氧基 烷基、鹵烷氧基、烷氧基烷氧基、烷氡基烷氧基 烷基、胺基及經取代之胺基，其中經取代之胺基 經一至兩個獨立地選自以下之取代基取代：烷 基、環烷基、烷基環烷基、環烷基烷基、烷基環 烧基炫•基、經基烧基及烧氧基烧基； R2 為氫、烷基、鹵烷基、烷氧基、環烷基、氰基或 鹵素， R3 為氫、烷基、鹵烷基、烷氧基、環烷基、氰基或 _素， R4 為氫、烷基、鹵烷基、烷氧基、環烷基、氰基或 鹵素； R5 為氫、烷基、鹵烷基、烷氧基、環烷基、氰基或 _素， R6 為氫、烷基、鹵烷基、烷氧基、環烷基、氰基或 鹵素； R7 為氫、烷基或環烷基； R8 為氫、烷基或環烷基； R9 為氫、烷基或環烷基； R10 為氫、烷基或環烷基； 或R9及R1()與其所連接之碳一起形成環烷基或雜環烷 160800.doc 201245158 基； R11 為氫、烷基或環烷基； R12 為氫、烷基、環烷基或-C(0)-R13 ; R13 為烷基、環烷基、環烷基烷基、烷氧基、烷氧基 烷氧基、環烷氧基、鹵環烷氧基、烷氧基院基、 環炫•氧基烧基、齒烧基、鹵烧氧基炫基、函環烧 基、齒環烧基烧基、函雄烧乳基烧基、芳基、經 取代之芳基、雜芳基或經取代之雜芳基，其中經 取代之芳基及經取代之雜芳基經一至三個獨立地 〇 選自以下之取代基取代：烷基、環烷基、烷基環 烷基、環烷基烷基、環烷基烷氧基、環烷基烧氧 基炫基、環烧氧基、環烧氧基烧基、烧基環烧基 烧基、ΐ環烧基、齒環烧基烧基、_素、氰基、 鹵烷基、羥基、羥基烷基、烷氧基、烷氧基烧 基、鹵烷氧基、羥基烷氧基、烷氧基烷氧基、烷 氧基烧氧基烧基、經基i烧基、胺基及經取代之 胺基’其中經取代之胺基經一至兩個獨立地選自 l 以下之取代基取代：烧基、環烧基、烧基環烧 基、環烷基烷基、烷基環烷基烷基、羥基烷基及 — 烷氧基烷基； - R14 為氫、烷基、烷氧基或環烷基； R15 為氫、烷基或環烷基； R16為氫、烷基、鹵烷基、烷氧基、環烷基、氰基或 鹵素； 160800.doc 201245158 A1 為 CR14、Ο、NR15 或 S ; A2 為 CR16或 N; n 為1、2或3 ; 或醫藥學上可接受之鹽。 【先前技術】 激肽屬於在體液及組織中自非活性前驅激肽原以逐步蛋 白水解過程產生之生物活性八肽至十肽家族。激肽為由一 組9-11胺基酸肽形成之激素，該等肽包括緩激肽（BK)、胰 激肽（KD/Lys-BK)及其活性代謝物（des-Arg9-BK及des-Arg1G-胰激肽/Lys-des-Arg9-BK)。激肽在發炎性及傷害感 受性過程中起重要生理作用。BK及其他激肽之生物作用 係由兩種生理學上不同之G蛋白偶合受體（GPCR)介導，稱 為BDKRBI(BIR)及BDKRB2(B2R)。咸信，在生理條件 下’組成性表現之B2R介導循環性或局部產生之激肽的作 用，此係由於B 1R不在正常組織中表現之故。B2R在中樞 神經系統及周邊神經系統之眾多細胞類型、血管内皮細胞 及發炎性細胞中組成性表現，且由短壽命之天然配體BK 及胰激肽（KD)活化。一旦合成，BK即致使血管舒張且藉 由與B2R相互作用而使血管滲透性增加。然而，B2R在由 内源性配體結合及活化之後快速脫敏及内化。激肽由包括 羧肽酶N及羧肽酶Μ之酶催化降解得到des-Arg9-BK(DABK) 及des-Arg1。-胰激肽/Lys-des-Arg9-BK，其優先活化B1R。 儘管不在正常組織中表現（或以極低程度表現），但B1R在 細菌感染、組織損傷及發炎性介體釋放之後快速誘導，且 160800.doc 201245158 已在交感神經元、巨噬細胞、纖維母細胞、平滑肌細胞及 血管内皮中觀測到。内源性B1R促效劑，包括des_Arg9_BK 及des-Arg1G-胰激肽/Lys-des-Arg9-BK，為相對長久之肽。 此外，B1R在刺激後不會經歷快速脫敏及内化。一旦上 調，B1R活性即在受損或發炎組織中持久存在且據信參與 延長對激肽之病理反應。因此，B1R已牵涉於維持慢性疼 痛、血管舒張、血漿外滲、嗜中性白血球募集及諸如化_ 1β、TNF-α及IL-6之發炎性介體的進一步釋放中，該等發 炎性介體在B1R表現與發炎之間維持正反饋迴路。B1R僅 在包括發炎、創傷、灼傷、休克及過敏之病理條件下之預 期上調’使得B1R成為尤其具吸引力之藥物標靶。 激肽在介導疼痛及發炎中之預期作用已推動了對發現有 效且具選擇性之BK拮抗劑的關注。新近證據表明緩激肽 又體亦可在許多病理過程或疾病中起重要作用包括缺 血-再灌注損傷、糖尿病性視網膜病變、動脈粥樣硬化、 腎病。因此，迫切需要在阻斷或逆轉緩激肽受體之活化方 、有效的新穎化合物。该等化合物將適用於處理疼痛及發 炎’以及治療或預防由緩激肽介導之疾病及病症；此外， 該等化合物亦適用作研究工具。 【發明内容】 =本文所述，式（I)化合物為緩激肽受體、尤其緩激肽 B1受體（B1R)之拮抗劑或反向促效劑，且因而適用於治療 及預防經由刺激緩激肽受體路㈣導之疾病及病狀（諸如 疼痛、發炎）、血管舒張、血後外滲、嗜中性白血球募 160800.doc 201245158 集、巨噬細胞浸潤及諸如IL-Ιβ及TNF-α之發炎性介體進一 步釋放。 本發明之目的為式（I)化合物及其前述鹽及酯及其作為治 療上之活性物質之用途；製造該等化合物、中間物、醫藥 組合物、含有該等化合物、其醫藥學上可接受之鹽或酯之 藥物的方法；該等化合物、鹽或酯用於治療或預防疾病， ' 尤其治療或預防絲球體腎炎、亨偌-絲奇恩賴紫癜性腎病 變（HSPN)、ANCA相關新月型絲球體腎炎、狼瘡性腎炎及 f)2 1R \ly I fv where R is a dazzle* group, a melamine group, a cycloalkyl group, an alkoxy group, an alkoxy group, a private dairy base, a cycloalkyloxy group, a dental base, Haloalkoxy, dentateoxyalkyl, ii cycloalkyl, cycline alkyl, halocycloalkyloxy, cyclyl oxyalkyl, alkoxycarbonyl, cycloalkoxycarbonyl, dentate Alkoxycarbonyl, halocycloalkoxycarbonyl, cyano, aryl, substituted aryl, heteroaryl or substituted heteroaryl wherein the substituted aryl and substituted heteroaryl are passed through Three substituents independently selected from the group consisting of: I60800.doc 201245158 alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl , cycloalkoxy, cycloalkoxyalkyl, arylcycloalkyl, rhenyl, anthracenyl, halogen, cyano, halogen, alkoxy, alkoxyalkyl a aryl group, a haloalkoxy group, an alkoxy alkoxy group, an alkylalkyl alkoxy group, an amine group, and a substituted amine group, wherein the substituted amino group is independently selected from one to two substituents selected from the group consisting of Substitution: alkyl a cycloalkyl group, an alkylcycloalkyl group, a cycloalkylalkyl group, an alkylcycloalkyl group, a carbyl group and an alkoxy group; R2 is hydrogen, an alkyl group, a haloalkyl group, an alkoxy group , cycloalkyl, cyano or halogen, R 3 is hydrogen, alkyl, haloalkyl, alkoxy, cycloalkyl, cyano or _, R 4 is hydrogen, alkyl, haloalkyl, alkoxy, Cycloalkyl, cyano or halogen; R5 is hydrogen, alkyl, haloalkyl, alkoxy, cycloalkyl, cyano or _, R6 is hydrogen, alkyl, haloalkyl, alkoxy, ring Alkyl, cyano or halogen; R7 is hydrogen, alkyl or cycloalkyl; R8 is hydrogen, alkyl or cycloalkyl; R9 is hydrogen, alkyl or cycloalkyl; R10 is hydrogen, alkyl or naphthenic Or R9 and R1() together with the carbon to which they are attached form a cycloalkyl or heterocycloalkane 160800.doc 201245158; R11 is hydrogen, alkyl or cycloalkyl; R12 is hydrogen, alkyl, cycloalkyl or -C(0)-R13; R13 is alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkoxy, cycloalkoxy, halocycloalkoxy, alkoxy环环•oxyalkyl, dentate, halogenated oxy, cyclist a aryl group, a cyclyl group, a aryl group, an aryl group, a substituted aryl group, a heteroaryl group or a substituted heteroaryl group, wherein the substituted aryl group and the substituted heteroaryl group Substituents substituted with one to three substituents independently selected from the group consisting of alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkyloxyalkyl , ring alkoxy, cycloalkyloxyalkyl, decyl carbyl, anthracenyl, cyclyl, cyano, cyano, haloalkyl, hydroxy, hydroxyalkyl, alkane Oxyl, alkoxyalkyl, haloalkoxy, hydroxyalkoxy, alkoxyalkoxy, alkoxyalkyloxyalkyl, thiol, amine and substituted amine Wherein the substituted amine group is substituted with one to two substituents independently selected from the group consisting of: an alkyl group, a cycloalkyl group, a alkyl group, a cycloalkyl group, an alkylcycloalkyl group, a hydroxy alkane. And alkoxyalkyl; - R14 is hydrogen, alkyl, alkoxy or cycloalkyl; R15 is hydrogen, alkyl or cycloalkyl; R16 is hydrogen, alkyl, haloalkyl, alkoxy Cycloalkyl, cyanide Or halogen; 160800.doc 201245158 A1 is CR14, Ο, NR15 or S; A2 is CR16 or N; n is 1, 2 or 3; or a pharmaceutically acceptable salt thereof. [Prior Art] Kinin is a biologically active octapeptide to decapeptide family produced by a stepwise protein hydrolysis process from an inactive pre-excited kininogen in body fluids and tissues. Kinin is a hormone formed by a group of 9-11 amino acid peptides including bradykinin (BK), kallikrein (KD/Lys-BK) and its active metabolite (des-Arg9-BK and des-Arg1G-tryipin/Lys-des-Arg9-BK). Kinin has an important physiological role in the process of inflammatory and nociceptive sexual activity. The biological effects of BK and other kinins are mediated by two physiologically distinct G-protein coupled receptors (GPCRs), designated BDKRBI (BIR) and BDKRB2 (B2R). It is believed that B2R constitutively circulates or locally produces kinins under physiological conditions, since B 1R is not expressed in normal tissues. B2R is constitutively expressed in numerous cell types of the central nervous system and peripheral nervous system, vascular endothelial cells, and inflammatory cells, and is activated by short-lived natural ligands BK and kallikrein (KD). Once synthesized, BK causes vasodilation and increases vascular permeability by interacting with B2R. However, B2R rapidly desensitizes and internalizes after binding and activation by endogenous ligands. The kinins are catalytically degraded by an enzyme including carboxypeptidase N and carboxypeptidase to obtain des-Arg9-BK (DABK) and des-Arg1. - Pancreatic kinin/Lys-des-Arg9-BK, which preferentially activates B1R. Although not expressed in normal tissues (or at a very low level), B1R is rapidly induced after bacterial infection, tissue damage, and inflammatory mediator release, and 160800.doc 201245158 has been in sympathetic neurons, macrophages, and fibroblasts. Observed in cells, smooth muscle cells, and vascular endothelium. Endogenous B1R agonists, including des_Arg9_BK and des-Arg1G-tryipin/Lys-des-Arg9-BK, are relatively long-lasting peptides. In addition, B1R does not experience rapid desensitization and internalization after stimulation. Once upregulated, B1R activity persists in damaged or inflamed tissues and is believed to be involved in prolonging the pathological response to kinins. Therefore, B1R has been implicated in the maintenance of chronic pain, vasodilation, plasma extravasation, neutrophil recruitment, and further release of inflammatory mediators such as _1β, TNF-α, and IL-6. The body maintains a positive feedback loop between B1R performance and inflammation. B1R is only expected to be up-regulated under pathological conditions including inflammation, trauma, burns, shock and allergies, making B1R a particularly attractive drug target. The expected role of kinins in mediating pain and inflammation has spurred attention to the discovery of effective and selective BK antagonists. Recent evidence suggests that bradykinin can also play an important role in many pathological processes or diseases including ischemia-reperfusion injury, diabetic retinopathy, atherosclerosis, and kidney disease. Therefore, there is an urgent need for effective novel compounds that block or reverse the activation of bradykinin receptors. Such compounds will be useful in the treatment of pain and inflammation' and in the treatment or prevention of diseases and conditions mediated by bradykinin; in addition, such compounds are also useful as research tools. SUMMARY OF THE INVENTION As described herein, the compound of formula (I) is an antagonist or inverse agonist of a bradykinin receptor, particularly a bradykinin B1 receptor (B1R), and is therefore suitable for use in therapy and prevention via stimulation. Bradykinin receptor pathway (4) diseases and conditions (such as pain, inflammation), vasodilation, post-traumatic extravasation, neutrophil recruitment 160800.doc 201245158 episodes, macrophage infiltration and such as IL-Ιβ and TNF - The inflammatory mediator of alpha is further released. The object of the present invention is a compound of the formula (I), and the aforementioned salts and esters thereof, and their use as therapeutically active substances; the manufacture of such compounds, intermediates, pharmaceutical compositions, the inclusion of such compounds, and their pharmaceutically acceptable a method of treating a salt or an ester; the compound, salt or ester is used for the treatment or prevention of a disease, 'in particular for treating or preventing spheroid nephritis, Henry-Syracuse, purulent nephropathy (HSPN), ANCA-related new Lunar glomerulonephritis, lupus nephritis and f)

IgA腎炎之用途；及該等化合物、鹽或酯用於產生用以治 療或預防絲球體腎炎、亨偌-絲奇恩賴紫癜性腎病變 (HSPN)、ANCA相關新月型絲球體腎炎、狼瘡性腎炎及 IgA腎炎之藥物的用途。 術語「促效劑」表示增強另一化合物或受體位點之活性 的化合物，如例如Goodman及Gilman, 「The Pharmacological Basis of Therapeutics,第 7版」第 35 頁， 0 Macmillan出版公司，Canada, 1985中所定義。「完全促效 劑」實現完全反應，而「部分促效劑」甚至當佔據全部受 體群體時仍不足以實現完全活化。「反向促效劑」產生與 促效劑相反之作用，仍結合於相同受體結合位點。 ' 術語「拮抗劑」表示減小或阻止另一化合物或受體位點 之作用的化合物，如例如Goodman及Gilman, 「The Pharmacological Basis of Therapeutics,第 7版」第 35 頁， Macmillan出版公司，Canada, 1985中所定義。詳言之，括 抗劑係指削弱促效劑作用之化合物。「競爭性括抗劑」與 160800.doc 201245158 促效劑結合於相同位點，但不會活化該位點，由此阻斷促 效劑之作用。「非競爭性拮抗劑」結合於受體上之別位（非 促效劑）位點以阻止該受體活化。「可逆拮抗劑」以非共價 方式結合於受體’因此可被「洗淨」。「不可逆拮抗劑」以 共價方式結合於受體且不可由競爭配體或洗滌而置換。 術語「烷氧基」表示式_〇_R，之基團，其中R，為烷基。烷 氧基之實例包括甲氧基、乙氧基、正丙氧基、異丙氧基、 正丁氧基、異丁氧基及第三丁氧基。特定烷氧基包括甲氧 基及乙氧基。更特定之烷氧基為甲氧基。 術5吾「烧氧基烧氧基」表示烧氧基之至少一個氳原子已 經另一烧氧基置換之烷氧基。烷氧基烷氧基之實例包括曱 氧基甲氧基、乙氧基甲氧基、甲氧基乙氧基、乙氧基乙氧 基、甲氧基丙氧基及乙氧基丙氧基。特定烷氧基烷氧基包 括曱氧基甲氧基及甲氧基乙氧基。 術邊「娱•氧基烧氧基烧基」表示烧基之至少一個氫原子 已經烷氧基烷氧基置換之烷基。烷氧基烷氧基烷基之實例 包括曱氧基曱氧基甲基、乙氧基甲氧基甲基、甲氧基乙氧 基甲基、乙氧基乙氧基曱基、甲氧基丙氧基甲基、乙氧基 丙氧基曱基、曱氧基甲氧基乙基、乙氧基甲氧基乙基、曱 氧基乙氧基乙基、乙氧基乙氧基乙基、子氧基丙氧基乙基 及乙氧基丙氧基乙基。 術語「烷氧基烷基」表示烷基之至少—個氫原子已經烷 氧基置換之烷基。例示性烷氧基烷基包括甲氧基甲基、乙 氧基曱基、甲氧基曱基、乙氧基乙基、曱氧基丙基及乙氧 160800.doc -10· 201245158 » 基丙基。特定烷氧基烷基包括曱氧基曱基及甲氧基乙基。 更特定之烷氧基烷基為甲氧基曱基。 術語「燒氧基羰基」表示式_C(0)_R，之基團其中&，為 烷氧基。烷氧基羰基之實例包括式-c(o)-R，之基團，其中 . R|為甲氧基或乙氧基。特定烷氧基羰基為式_C(0)_R，之基 團’其中R，為曱氧基。 術語「烷基」表示具有1至12個碳原子、尤其丨至7個碳 0 原子、更特定1至4個碳原子之單價直鏈或分支鏈飽和烴 基，例如甲基、乙基、丙基、異丙基、正丁基異丁基、 第二丁基及第三丁基。特定烷基包括甲基或乙基。更特定 烷基為甲基。 術語「烷基環烷基」表示環烷基之至少一個氫原子經烧 基置換之環烷基。烷基環烷基之實例包括甲基_環丙基、 二甲基-環丙基、甲基-環丁基、二甲基-環丁基、甲基_環 戊基、二曱基-環戊基、甲基_環己基及二甲基_環己基。特 Q 定烷基環烷基包括曱基-環丙基及二曱基-環丙基。 術§吾「烧基環院基烧基」表示烧基之至少一個氫原子經 烧基％炫基置換之烧基。院基環烧基炫<基之實例包括曱 基-環丙基甲基、二甲基-環丙基曱基、曱基_環丙基乙基、 一甲基-環丙基乙基、甲基-環丁基甲基、二甲基-環丁基甲 基、甲基-環丁基乙基、二甲基-環丁基乙基、曱基-環戊基 甲基、二甲基-環戊基甲基、甲基-環戊基乙基、二甲基_環 戊基乙基、甲基-環己基甲基、二甲基-環己基甲基、甲基_ 環己基乙基、二甲基-環己基乙基、甲基-環庚基甲基、二 160800.doc 201245158 甲基-環庚基甲基、f基-環庚基乙基、二甲基-環庚基乙 基、甲基-環辛基甲基、二甲基-環辛基甲基、甲基-環辛基 乙基及二甲基-環辛基乙基。 術語「胺基」表示-nh2基團。 術語「芳基」表示包含6至10個碳環原子之單價芳族碳 環單環或雙環系統。芳基之實例包括苯基及萘基。特定芳 基為苯基。 術語「羰基」表示-c(o)-基團。 術語「氰基」表示-C三N基團。 術語「環烷氧基」表示式-0-R’之基團，其中W為環烷 基。環烷氧基之實例包括環丙氧基、環丁氧基、環戊氧 基、環己氧基、環庚氧基及環辛氧基。特定環烷氧基為環 丙氧基。 術語「環烷氧基烷基」表示烷基之至少一個氫原子已經 環烷氧基置換之烷基。環烷氧基烷基之實例包括環丙氧基 甲基、環丙氧基乙基、環丁氧基甲基、環丁氧基乙基、環 戊氧基甲基、環戊氧基乙基、環己氧基甲基、環己氧基乙 基、環庚氧基甲基、環庚氧基乙基、環辛氧基甲基及環辛 氧基乙基。 術語「環烷氧基羰基」表示式-C(0)-R’之基團，其中R’ 為環烷氧基。環烷氧基羰基之實例包括式-C(0)-R'之基 團，其中R'為環丙氧基、環丁氧基、環戊氧基、環己氧 基、環庚氧基及環辛氧基。特定環烷氧基羰基為式-C(O)-R'之基團，其中R'為環丙氧基。 160800.doc -12- 201245158 、 術語「環烧基」表示具有3至1 〇個環碳原子之單價飽和 單環或雙環烴基’尤其具有3至8個環碳原子之單價飽和單 環烴基。雙環意謂由具有兩個共用碳原子之兩個飽和碳環 組成。特定環烷基為單環。單環環烷基之實例為環丙基、 , 環丁基、環戊基、環己基或環庚基。雙環環烷基之實例為 雙環[2_2.1]庚基或雙環[2.2.2]辛基。特定單環環烷基為環 丙基。 〇 術語「環烧基烧氧基」表示烷氧基之至少一個氫原子經 環烷基置換之烷氧基。環烷基烷氧基之實例包括環丙基曱 氧基、環丁基甲氧基、環戊基甲氧基、環己基甲氧基、環 庚基甲氧基及環辛基甲氧基。 術語「環烷基烷氧基烷基」表示烷基之至少一個氫原子 經環烷基烷氧基置換之烷基^環烷基烷氧基烷基之實例包 括環丙基曱氧基曱基、環丙基甲氧基乙基、環丁基甲氧基 甲基、環丁基Τ氧基乙基、環戊基甲氧基乙基、環戊基曱 〇 氧基乙基、環己基甲氧基甲基、環己基甲氧基乙基、環庚 基甲氧基甲基、環庚基甲氧基乙基、環辛基甲氧基甲基及 環辛基甲氧基乙基。 術語「環烷基烷基」表示烷基之至少一個氫原子經環烷 基置換之炫基。環烷基烷基之實例包括環丙基甲基、環丙 基乙基、環丁基丙基及環戊基丁基。 術語「鹵烷氧基」表示烷氧基之至少一個氫原子已經相 同或不同鹵素原子置換之烷氧基。術語「全豳烷氧基」表 示烷氧基之所有氫原子已經相同或不同鹵素原子置換之烷 160800.doc -13· 201245158 氧基。鹵烷氧基之實例包括氟甲氧基、二氟甲氧基、三氟 甲氧基、三氟乙氧基、三氟甲基乙氧基、三氟二甲基乙氧 基及五氟乙氧基。特定i烷氧基為三氟甲氧基及2,2-二氟 乙氧基。更特定之鹵烷氧基為2,2-二氟乙氧基。 術語「鹵烷氧基烷基」表示烷基之至少一個氫原子已經 鹵烷氧基置換之烷基。鹵烷氧基烷基之實例包括氟甲氧基 曱基、二氟甲氧基甲基、三氟甲氧基曱基、氟乙氧基曱 基、二氟乙氧基甲基、三氟乙氧基甲基、氟甲氧基乙基、 二氟曱氧基乙基、三氟甲氧基乙基、氟乙氧基乙基、二氟 乙氧基乙基、三氟乙氧基乙基、氟曱氧基丙基、二氟曱氧 基丙基、三氟曱氧基丙基、氣乙氧基丙基、二氣乙乳基丙 基及三氣乙氧基丙基。 術語「鹵烷氧基羰基」表示式-C(0)-R’之基團，其中R’ 為鹵烷氧基。鹵烷氧基羰基之實例包括式-C(0)-R|之基 團，其中R’為氟甲氧基、二氟曱氧基、三氟曱氧基、三氟 乙氧基、三氟甲基乙氧基、三氟二f基乙氧基或五氟乙氧 基。 術語「鹵烷基」表示烷基之至少一個氫原子已經相同或 不同鹵素原子置換之烷基。術語「全鹵烷基」表示烷基之 所有氫原子已經相同或不同鹵素原子置換之烷基。鹵烷基 之實例包括氟曱基、二氟曱基、三氟曱基、三氟乙基、三 氟甲基乙基及五氟乙基。特定鹵烷基為三氟曱基及三氟乙 基。 術語「ii環烷氧基」表示環烷氧基之至少一個氫原子已 160800.doc -14- 201245158 經相同或不同鹵素原子、尤其氟原子置換之環烧氧基。鹵 環烷氧基之實例包括氟環丙氧基、二氟環丙氧基、氟環丁 氧基及二氟環丁氧基。 Ο Ο 術語「i環烧氧基烧基」表示烧基之至少一個1原子已 經鹵環烷氧基置換之烷基。鹵環烷氧基烷基之實例包括氣 環丙氧基曱基、二氟環丙氧基甲基、氟環丙氧基乙基、二 氟環丙氧基乙基、氟環丁氧基甲基、二氟環丁氧基曱基、 氟環丁氧基乙基及二氟環丁氧基乙基。 術語「鹵環烷氧基羰基」表示式_C(0)_RI之基團，其中 R為鹵環烧氧基。鹵環烧氧基幾基之實例包括式_C(〇)_RI 之基團’其中R’為氟環丙氧基曱基、二氟環丙氧基曱基、 氟環丙氧基乙基、二氟環丙氧基乙基、氟環丁氧基曱基、 二敗環丁氧基甲基、氟環丁氧基乙基及二氟環丁氧基乙 基。. 術語「i環烧基」表示環烧基之至少—個氫原子已經相 同或不同_素原子、尤其氟原子置換之環燒基。_環烧基 之實例包括氟環丙基、二氣環丙美、翁s I艰丙基、軋％丁基及二氟環丁 基。 術語「齒環烷基烷基」表示烷基之至少—個氫原子已經 齒環烷巧換之烧基。齒環烷基烧基之實例包括氟環丙基 甲基、氣ί哀丙基乙基、-急搭石竟田甘 一氣％丙基甲基、二氟環丙基乙 基、氟環丁基曱基、氟環丁美7其 一 Ά 丁基乙基、—氟環丁基甲基及-氟環丁基乙基。 η及一 術語「i素」及「_基在本 又甲了互換使用且表示 160800.doc 201245158 氟、氯、溴或埃。特定鹵素為氯及氟。 術語「雜芳基」表示具有5至12個環原子之單價芳族雜 環單環或雙環系統，該等環原子包含1、2、3或4個選自 N、0及S之雜原子，其餘環原子為碳。雜芳基之實例包括 °比η各基、吱喃基、°塞吩基、味°坐基、°惡°坐基、°塞°坐基、三 °坐基、°惡二。坐基、°塞二°坐基、四β坐基、11比α定基、吼°秦基、 0比唾基、噠嗓基、嘴咬基、三嗓基、氮呼基、二氮呼基、 異噁唑基、苯并呋喃基、異噻唑基、苯并噻吩基、吲哚 基、異吲哚基、異苯并呋喃基、苯并咪唑基、苯并噁唑 基、苯并異噁唑基、苯并噻唑基、苯并異噻唑基、苯并噁 二吐基、苯并嗔二α坐基、苯并三。坐基、嘌呤基、喹琳基、 異喧琳基、喧。坐琳基及喧°若琳基。特定雜芳基包括α比略 基、。夫喃基、11塞吩基、味β坐基、°惡11坐基、°塞α坐基、三。坐 基、喔二峻基、嘆二唾基、四嗤基、〇比咬基、°比嗓基、。比 α坐基、噠嗪基、σ密咬基、異嚼。坐基及異°塞。坐基。更特定之 雜芳基包括咪唑基、噁唑基、噻唑基、噁二唑基、噻二唑 基、四β坐基、°比σ定基、°比°秦基、°比α坐基、違嗓基、α密咬 基、異噁唑基及異噻唑基。在R1取代基之定義中，雜芳基 之更特定實例包括噁二唑基及四唑基。在R13取代基之定 義中，雜芳基之更特定實例包括噁二唑基、四唑基、噠唤 基、哺咬基及異°惡α坐基。 術語「雜環烷基」表示具有4至9個環原子之單價飽和或 部分不飽和單環或雙環系統，該等環原子包含1、2或3個 選自Ν、0及S之環雜原子，其餘環原子為碳。雙環意謂由 160800.doc -16- 201245158 具有兩個共用環原子Use of IgA nephritis; and the use of such compounds, salts or esters for the treatment or prevention of spheroid nephritis, Hens-Syracuse purulent nephropathy (HSPN), ANCA-associated crescentic glomerulonephritis, lupus Use of drugs for nephritis and IgA nephritis. The term "agonist" means a compound that enhances the activity of another compound or receptor site, such as, for example, Goodman and Gilman, "The Pharmacological Basis of Therapeutics, 7th Edition", page 35, 0 Macmillan Publishing Company, Canada, 1985 Defined in . The “complete agonist” achieves complete response, while the “partial agonist” is not sufficient to achieve full activation even when it occupies the entire recipient population. The "reverse agonist" produces the opposite effect of the agonist and still binds to the same receptor binding site. The term "antagonist" refers to a compound that reduces or prevents the action of another compound or receptor site, such as, for example, Goodman and Gilman, "The Pharmacological Basis of Therapeutics, 7th Edition", page 35, Macmillan Publishing Company, Canada , as defined in 1985. In particular, an antagonist refers to a compound that impairs the action of an agonist. The "competitive antagonist" binds to the same site with the 160800.doc 201245158 agonist, but does not activate the site, thereby blocking the action of the agonist. A "non-competitive antagonist" binds to a different (non-agonist) site on the receptor to prevent activation of the receptor. "Reversible antagonists" bind to the receptor in a non-covalent manner and can therefore be "washed". An "irreversible antagonist" binds to a receptor in a covalent manner and cannot be replaced by a competing ligand or wash. The term "alkoxy" denotes a radical of the formula _〇_R, wherein R is alkyl. Examples of the alkoxy group include a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, and a third butoxy group. Specific alkoxy groups include methoxy and ethoxy groups. More specific alkoxy groups are methoxy groups. The "oxygen alkoxy group" means that at least one of the alkoxy groups having an alkoxy group has been replaced by another alkoxy group. Examples of the alkoxyalkoxy group include a decyloxymethoxy group, an ethoxymethoxy group, a methoxyethoxy group, an ethoxyethoxy group, a methoxypropoxy group, and an ethoxypropoxy group. . Specific alkoxy alkoxy groups include decyloxymethoxy and methoxyethoxy. The "enhanced oxygen oxyalkyl group" means an alkyl group in which at least one hydrogen atom of the alkyl group has been replaced by an alkoxyalkoxy group. Examples of alkoxyalkoxyalkyl groups include decyloxymethoxymethyl group, ethoxymethoxymethyl group, methoxyethoxymethyl group, ethoxyethoxy fluorenyl group, methoxy group. Propyloxymethyl, ethoxypropoxydecyl, decyloxymethoxyethyl, ethoxymethoxyethyl, decyloxyethoxyethyl, ethoxyethoxyethyl , oxypropoxyethyl and ethoxypropoxyethyl. The term "alkoxyalkyl" denotes an alkyl group wherein at least one hydrogen atom of the alkyl group has been replaced by an alkoxy group. Exemplary alkoxyalkyl groups include methoxymethyl, ethoxylated, methoxyindenyl, ethoxyethyl, methoxypropyl, and ethoxy 160800.doc -10· 201245158 » base. Particular alkoxyalkyl groups include decyloxy fluorenyl and methoxyethyl. More specific alkoxyalkyl groups are methoxyindenyl groups. The term "alkoxycarbonyl" means a group of the formula _C(0)-R, wherein & is an alkoxy group. Examples of the alkoxycarbonyl group include a group of the formula -c(o)-R, wherein . R| is a methoxy group or an ethoxy group. The specific alkoxycarbonyl group is a group of the formula _C(0)_R, wherein R is a decyloxy group. The term "alkyl" denotes a monovalent straight or branched chain saturated hydrocarbon group having from 1 to 12 carbon atoms, especially to 7 carbon atoms, more specifically from 1 to 4 carbon atoms, such as methyl, ethyl, propyl. , isopropyl, n-butyl isobutyl, second butyl and tert-butyl. Particular alkyl groups include methyl or ethyl. More specific alkyl is methyl. The term "alkylcycloalkyl" means a cycloalkyl group in which at least one hydrogen atom of a cycloalkyl group is substituted by a burnt group. Examples of the alkylcycloalkyl group include methyl-cyclopropyl, dimethyl-cyclopropyl, methyl-cyclobutyl, dimethyl-cyclobutyl, methyl-cyclopentyl, di-decyl-ring. Pentyl, methyl-cyclohexyl and dimethyl-cyclohexyl. The specific Q-alkylcycloalkyl group includes a fluorenyl-cyclopropyl group and a dimethyl-cyclopropyl group. The "burning base ring base" means that the at least one hydrogen atom of the burnt group is replaced by a burnt group. Examples of the base-based ring-based group include fluorenyl-cyclopropylmethyl, dimethyl-cyclopropylindenyl, fluorenyl-cyclopropylethyl, monomethyl-cyclopropylethyl, Methyl-cyclobutylmethyl, dimethyl-cyclobutylmethyl, methyl-cyclobutylethyl, dimethyl-cyclobutylethyl, decyl-cyclopentylmethyl, dimethyl-cyclopentyl Methyl, methyl-cyclopentylethyl, dimethyl-cyclopentylethyl, methyl-cyclohexylmethyl, dimethyl-cyclohexylmethyl, methyl-cyclohexylethyl, dimethyl -cyclohexylethyl, methyl-cycloheptylmethyl, di 160800.doc 201245158 methyl-cycloheptylmethyl, f-cycloheptylethyl, dimethyl-cycloheptylethyl, methyl - cyclooctylmethyl, dimethyl-cyclooctylmethyl, methyl-cyclooctylethyl and dimethyl-cyclooctylethyl. The term "amino" refers to a -nh2 group. The term "aryl" means a monovalent aromatic carbon ring monocyclic or bicyclic system containing from 6 to 10 carbon ring atoms. Examples of the aryl group include a phenyl group and a naphthyl group. The specific aryl group is a phenyl group. The term "carbonyl" means a -c(o)- group. The term "cyano" denotes a -C three N group. The term "cycloalkoxy" denotes a group of the formula -0-R' wherein W is a cycloalkyl group. Examples of the cycloalkoxy group include a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, a cyclohexyloxy group, a cycloheptyloxy group, and a cyclooctyloxy group. The specific cycloalkoxy group is a cyclopropoxy group. The term "cycloalkoxyalkyl" means an alkyl group wherein at least one hydrogen atom of the alkyl group has been replaced by a cycloalkoxy group. Examples of the cycloalkoxyalkyl group include a cyclopropoxymethyl group, a cyclopropoxyethyl group, a cyclobutoxymethyl group, a cyclobutoxyethyl group, a cyclopentyloxymethyl group, a cyclopentyloxyethyl group. , cyclohexyloxymethyl, cyclohexyloxyethyl, cycloheptyloxymethyl, cycloheptyloxyethyl, cyclooctyloxymethyl and cyclooctyloxyethyl. The term "cycloalkoxycarbonyl" means a group of the formula -C(0)-R' wherein R' is cycloalkyloxy. Examples of the cycloalkoxycarbonyl group include a group of the formula -C(0)-R' wherein R' is a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, a cyclohexyloxy group, a cycloheptyloxy group, and Cyclooctyloxy. A specific cycloalkoxycarbonyl group is a group of the formula -C(O)-R' wherein R' is cyclopropoxy. 160800.doc -12- 201245158, The term "cycloalkyl" means a monovalent saturated monocyclic or bicyclic hydrocarbon group having 3 to 1 ring carbon atoms, especially a monovalent saturated monocyclic hydrocarbon group having 3 to 8 ring carbon atoms. Bicyclic means consisting of two saturated carbon rings with two common carbon atoms. A particular cycloalkyl group is a single ring. Examples of monocyclic cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Examples of bicyclic cycloalkyl groups are bicyclo [2_2.1] heptyl or bicyclo [2.2.2] octyl. A specific monocyclic cycloalkyl group is a cyclopropyl group. 〇 The term "cycloalkyl alkoxy" means an alkoxy group in which at least one hydrogen atom of the alkoxy group is replaced by a cycloalkyl group. Examples of the cycloalkylalkoxy group include a cyclopropylmethoxy group, a cyclobutylmethoxy group, a cyclopentylmethoxy group, a cyclohexylmethoxy group, a cycloheptylmethoxy group, and a cyclooctylmethoxy group. The term "cycloalkylalkoxyalkyl" denotes an alkyl-cycloalkylalkoxyalkyl group in which at least one hydrogen atom of the alkyl group is replaced by a cycloalkylalkoxy group, and includes cyclopropylnonyloxyalkyl group. , cyclopropylmethoxyethyl, cyclobutylmethoxymethyl, cyclobutyloxyethyl, cyclopentylmethoxyethyl, cyclopentyloxyethyl, cyclohexylmethoxy Methyl, cyclohexylmethoxyethyl, cycloheptylmethoxymethyl, cycloheptylmethoxyethyl, cyclooctylmethoxymethyl and cyclooctylmethoxyethyl. The term "cycloalkylalkyl" denotes a sapon group in which at least one hydrogen atom of the alkyl group is replaced by a cycloalkyl group. Examples of the cycloalkylalkyl group include a cyclopropylmethyl group, a cyclopropylethyl group, a cyclobutylpropyl group, and a cyclopentylbutyl group. The term "haloalkoxy" means an alkoxy group in which at least one hydrogen atom of the alkoxy group has been replaced by the same or different halogen atoms. The term "perdecyloxy" means an alkane in which all of the hydrogen atoms of the alkoxy group have been replaced by the same or different halogen atoms. 160800.doc -13· 201245158 Oxyl. Examples of haloalkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoromethylethoxy, trifluorodimethylethoxy, and pentafluoroethane. Oxygen. The specific i alkoxy group is a trifluoromethoxy group and a 2,2-difluoroethoxy group. More specific haloalkoxy groups are 2,2-difluoroethoxy groups. The term "haloalkoxyalkyl" means an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a haloalkoxy group. Examples of haloalkoxyalkyl groups include fluoromethoxyindenyl, difluoromethoxymethyl, trifluoromethoxyindenyl, fluoroethoxyindenyl, difluoroethoxymethyl, trifluoroethyl Oxymethyl, fluoromethoxyethyl, difluoromethoxyethyl, trifluoromethoxyethyl, fluoroethoxyethyl, difluoroethoxyethyl, trifluoroethoxyethyl , fluoromethoxypropyl, difluoromethoxypropyl, trifluoromethoxypropyl, gas ethoxypropyl, diethylene glycol propyl and triethoxyethoxypropyl. The term "haloalkoxycarbonyl" means a group of the formula -C(0)-R' wherein R' is haloalkoxy. Examples of haloalkoxycarbonyl include a group of the formula -C(0)-R| wherein R' is fluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoro Methyl ethoxy, trifluorodifylethoxy or pentafluoroethoxy. The term "haloalkyl" denotes an alkyl group wherein at least one hydrogen atom of the alkyl group has been replaced by the same or different halogen atoms. The term "perhaloalkyl" means an alkyl group in which all of the hydrogen atoms of the alkyl group have been replaced by the same or different halogen atoms. Examples of the haloalkyl group include a fluoromethyl group, a difluorodecyl group, a trifluoromethyl group, a trifluoroethyl group, a trifluoromethylethyl group, and a pentafluoroethyl group. The specific haloalkyl group is a trifluoromethyl group and a trifluoroethyl group. The term "ii cycloalkoxy" denotes at least one hydrogen atom of a cycloalkoxy group. 160800.doc -14- 201245158 A cyclic alkoxy group substituted by the same or different halogen atom, especially a fluorine atom. Examples of the halocycloalkoxy group include a fluorocyclopropoxy group, a difluorocyclopropoxy group, a fluorocyclobutoxy group, and a difluorocyclobutoxy group. Ο Ο The term "i-ring alkoxyalkyl" means an alkyl group in which at least one atom of the alkyl group has been replaced by a halocycloalkoxy group. Examples of halocycloalkoxyalkyl groups include gas cyclopropoxymethyl, difluorocyclopropoxymethyl, fluorocyclopropoxyethyl, difluorocyclopropoxyethyl, fluorocyclobutoxy Base, difluorocyclobutoxycarbonyl, fluorocyclobutoxyethyl and difluorocyclobutoxyethyl. The term "halocycloalkoxycarbonyl" denotes a radical of the formula _C(0)-RI wherein R is halocycloalkyloxy. Examples of the halocyclic alkoxy group include a group of the formula -C(〇)_RI where R' is a fluorocyclopropoxyfluorenyl group, a difluorocyclopropoxyfluorenyl group, a fluorocyclopropoxyethyl group, Difluorocyclopropoxyethyl, fluorocyclobutoxycarbonyl, bis-cyclobutoxymethyl, fluorocyclobutoxyethyl and difluorocyclobutoxyethyl. The term "i-ring group" means that at least one of the hydrogen atoms of the cycloalkyl group has been the same or different, and the ring atom is replaced by a fluorine atom. Examples of the _cycloalkyl group include a fluorocyclopropyl group, a dicyclopropene, a propyl group, a butyl group, and a difluorocyclobutyl group. The term "dental alkylalkyl" means that at least one of the hydrogen atoms of the alkyl group has been replaced by a ring cycloalkane. Examples of the ring-shaped alkyl alkyl group include a fluorocyclopropylmethyl group, a gas propyl propyl ethyl group, an urgency stone, a turmeric gas, a propyl methyl group, a difluorocyclopropyl ethyl group, a fluorocyclobutyl group. Mercapto, fluorocyclobutene 7 其 butyl ethyl, fluorocyclobutyl methyl and fluorocyclobutyl ethyl. η and a term "i" and "_" are used interchangeably and mean 160800.doc 201245158 fluorine, chlorine, bromine or argon. The specific halogen is chlorine and fluorine. The term "heteroaryl" means having 5 to A monovalent aromatic heterocyclic monocyclic or bicyclic ring system of 12 ring atoms, the ring atoms comprising 1, 2, 3 or 4 heteroatoms selected from N, 0 and S, the remaining ring atoms being carbon. Examples of the heteroaryl group include a ratio of η to each group, a fluorenyl group, a thiophene group, a stagnation base group, a stagnation base group, a stagnation base group, a three-seat base group, and a stagnation base. Sitting base, ° plug 2 ° sitting base, 4 β sitting base, 11 ratio α base, 吼 ° Qin base, 0 than salivation, sulfhydryl, mouth bite, triterpene, aziridine, diazepeq , isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, fluorenyl, isodecyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzoisomeric Azolyl, benzothiazolyl, benzisothiazolyl, benzooxazepine, benzoindole, and benzotrien. Sit-base, sulfhydryl, quinoline, iso-linyl, 喧. Take the Linji and 喧°若琳基. Particular heteroaryl groups include alpha ratios. Furamyl, 11 thiophene, taste β sitting base, ° evil 11 sitting base, ° plug α sitting base, three. Sitting on the base, 喔 峻 基 、, 叹 唾 唾 、, 四 四 base, 〇 than bite base, ° than 嗓 base. More than α sitting base, pyridazinyl, σ dense bite base, chew. Sitting base and different ° plug. Sitting on the base. More specific heteroaryl groups include imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, tetrapyridyl, ° ratio σ base, ° ratio, base group, ° ratio α, base Sulfhydryl, alpha-tackyl, isoxazolyl and isothiazolyl. In the definition of the R1 substituent, more specific examples of the heteroaryl group include oxadiazolyl and tetrazolyl. In the definition of the R13 substituent, more specific examples of the heteroaryl group include an oxadiazolyl group, a tetrazolyl group, a carbaryl group, a guanidinyl group, and an iso-α group. The term "heterocycloalkyl" denotes a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system having from 4 to 9 ring atoms, which ring atoms contain 1, 2 or 3 ring heteroatoms selected from the group consisting of fluorene, 0 and S. The remaining ring atoms are carbon. Double ring means that there are two shared ring atoms by 160800.doc -16- 201245158

兩個環、‘且成，亦即，隔開兩個環之 :=具有—或兩個環原子之鏈。單環飽和雜二 之實例為氧雜環丁燒基、氮雜環丁烧基、料唆基、四氫 夫南基、四虱-噻吩基、吡唑啶基、咪唑啶基、噁唑啶 基、異°惡嗤°定基、D塞哇π定基、派淀基、四氫旅喃基、四氫 硫代娘喃基、料基、嗎錢、硫代料基、u•二側氧 基-硫代嗎琳-4-基、氮雜環庚烧基、二氮雜環庚燒基、高 娘嗪基或氧氮雜環聽基。雙㈣和雜魏基之實例為 氮雜-雙環[3.2.1]辛基、定基、8_氧雜-3-氮雜-雙環 = .2.1]辛基、9·氮雜_雙環[331]壬基、3_氧雜冬氮雜雙 環[3.3.1]壬基或3_硫雜_9_氮雜_雙環[3.31]壬基。部分不飽 和雜環烧基之實例為二氫吱嗔基，啉基、二氫_喔唾 基、四氫J比唆基H辰_基。雜環烧基之更特定實例 為氧雜環丁烷基。 術語「經基」表示基團。 術語「經隸氧基」表示垸氧基之至少—個氫原子已經 羥基置換之烷氧基。羥基烷氧基之實例包括羥基乙氧基、 羥基丙氧基、羥基甲基丙氧基及二羥基丙氧基。 術語「羥基幽烷基」表示烷基之至少一個氫原子已經羥 基置換且烷基之至少一個氫原子已經鹵素置換之烷基。羥 基i烷基之實例包括羥基三氟乙基、羥基三氟丙基及羥基 六氟丙基。 術語「羥基烷基」表示烷基之至少一個氫原子已經羥基 置換之烷基。羥基烷基之實例包括羥基甲基、羥基乙基、 160800.doc •17· 201245158 經基丙基、羥基甲基丙基及二羥基丙基。 術語「醫藥學上可接受之鹽」係指保留游離鹼或游離酸 之生物有效性及特性之鹽，其在生物學上或其他方面不會 不合需要。該等鹽係由以下酸形成：無機酸，諸如鹽酸、 氫溴酸、硫酸、硝酸、磷酸及其類似酸，尤其鹽酸；及有 機酸，諸如乙酸、丙酸、乙醇酸、丙酮酸、草酸、順丁烯 二酸、丙二酸、丁二酸、反丁烯二酸、酒石酸、檸檬酸、 苯曱酸、肉桂酸、杏仁酸、甲烷磺酸、乙烷磺酸、對甲笨 石黃酸、水楊酸、N-乙醯基半胱胺酸及其類似酸。另外，此 等鹽可由無機鹼或有機鹼與游離酸加成而製備。衍生自無 機驗之鹽包括（但不限於）納鹽、鉀鹽、鋰鹽、録鹽、舞 鹽、鎂鹽及其類似鹽。衍生自有機鹼之鹽包括（但不限於） 以下之鹽：一級胺、二級胺及三級胺；經取代之胺，包括 天然產生之經取代之胺；環胺及驗性離子交換樹脂，諸如 異丙胺、三甲胺、二乙胺、三乙胺、三丙胺'乙醇胺、離 胺酸、精胺酸、N-乙基哌啶、哌啶、聚亞胺樹脂及其類似 物。式（I)化合物之特定醫藥學上可接受之鹽為鹽酸鹽、甲 烷磺酸鹽及檸檬酸鹽。 「醫藥學上可接受之酯」意謂通式⑴化合物可在官能基 衍化以提供能在活體内轉化回母體化合物之衍生物。該等 化合物之實例包括生理學上可接受且代謝上不穩定之酯衍 生物，諸如甲氧基甲酯、甲基硫甲酯及特戊醯氧基甲酯。 另外，類似於代謝上不穩定之酯且能在活體内產生通式⑴ 之母體化合物的通式（I)化合物之任何生理學上可接受之相 160800.doc 18· 201245158 等物皆於本發明之範嘴内。 術語「保護基」（PG)表示選擇性地阻斷多官能基化合物 中之反應性位點以使化學反應可選擇性地在另—未經保護 之反應性位點進行的基團，其含義通常與合成化學中之含 義相關。保護基可在適當點移除。例示性保護基為胺基保 護基、《㈣基或㈣㈣基。特U護基為第三丁氧 基幾基（B。。）、¥氧錢基（Cbz)、第基甲氧 及节基㈣。更特定之保護基為第三丁氧基艘基（b〇c)及第 基甲氧基幾基（F·)。更特定之保護基為第三丁氧基幾基 (Boc)。 式⑴化合物可含有數個不對稱中心，且可以光學純對映 異構體、對映異構體之混合物（諸如外消旋體）、光學純非 對映異構體、非對映異構體之混合物、非對映異構外消旋 體或非對映異構外消旋體之混合物形式存在。 根據Cahn-Ingold-Prelog慣例，不對稱碳原子可具有 「R」或「S」組態。 又，本發明之一實施例為如本文所述之式（I)化合物及其 醫藥學上可接受之鹽或酯，尤其如本文所述之式⑴化合物 及其醫藥學上可接受之鹽，更特定為如本文所述之式⑴化 合物。 本發明之另一實施例為如本文所述之式⑴化合物，其中 R1為i烷氧基、烷氧基羰基、環烷氧基羰基、齒烷氧基羰 基、雜芳基或經取代之雜芳基，其中經取代之雜芳基經一 至三個燒基取代。 160800.doc -19- 201245158 本發明之一特定實施例為如本文所述之式⑴化合物，其 中R1為齒炫氧基、烷氧基羰基或經取代之雜芳基，其中經 取代之雜芳基經一至三個烷基取代。 本發明之另一實施例為如本文所述之式⑴化合物，其中 R為鹵烧氧基、烷氧基羰基、烷基噁二唑基或烷基四唑 基。 本發明之另一其他實施例為如本文所述之式（1)化合物， 其中R1為烧基。惡二α坐基。 本發明之另一實施例為如本文所述之式⑴化合物，其中 R1為甲基°惡二σ坐基。 本發明之另一其他實施例為如本文所述之式⑴化合物， 其中R1為烧基四。坐基。 本發明之另一實施例為如本文所述之式⑴化合物，其中 R1為甲基四。坐基。 本發明亦關於如本文所述之式⑴化合物，其中R2為氫或 鹵素。 本發明之另一特定實施例為如本文所述之式⑴化合物， 其中R2為鹵素。 本發明之一更特定實施例為如本文所述之式（I)化合物， 其中R為氣或氣。 又本發明之一貫施例為如本文所述之式（I)化合物，其 中R3為氫。 、 本發明亦關於如本文所述之式⑴化合物，其中R4為氣 鹵素。 160800.doc 20- 201245158 本發明之另一實施例為如本文所述之式（i)化合物，其中 R4為鹵素。 本發明之另一特定實施例為如本文所述之式（I)化合物， 其中R4為氯。 本發明之一特定實施例為如本文所述之式（I)化合物，其 中R5為氫。 又，本發明之一實施例為如本文所述之式⑴化合物，其 中R6為氫。 〇 本發明亦關於如本文所述之式⑴化合物，其中R7為氣咬 烷基。 本發明之另一實施例為如本文所述之式⑴化合物，其中 R7為氣。 本發明亦關於如本文所述之式⑴化合物，其中R8為氫。 又，本發明之一實施例為如本文所述之式⑴化合物，其 中R9為氫、烷基或環烷基。 〇 又，本發明之一實施例為如本文所述之式（I)化合物，其 中R10為氫、烷基或環烷基。 本發明之另一實施例為如本文所述之式（I)化合物，其中 R及R與其所連接之碳一起形成環烷基或雜環烷基。 本發明之一特定實施例為如本文所述之式（I)化合物，其 中R及R肖其所連接之碳一起形成環烧基。 本發明之另一特定實施例為如本文所述之式（I)化合物， 其中R及R與其所連接之碳一起形成雜環烧基。 本發明之一更特定實施例為如本文所述之式（I)化合物， 160800.doc -21 - 201245158 其中R9及R1G與其所連接之碳一起形成環烷基或氧雜環丁 烷基。 又’本發明之一特定實施例為如本文所述之式（I)化合 物’其中R及R與其所連接之碳一起形成環丙基。 又’本發明之一特定實施例為如本文所述之式（I)化合 物’其中R9及R1Q與其所連接之碳一起形成氧雜環丁烷 基。 本發明之另一實施例為如本文所述之式化合物，其中 R11為氫。 本發明之另一實施例為如本文所述之式（j)化合物，其中 R12為氫、烷基或環烷基。 又’本發明之一實施例為如本文所述之式⑴化合物，其 中R12為氫。 又，本發明之一實施例為如本文所述之式⑴化合物，其 中 R12為氫或-C(0)-r13。 本發明之另一實施例為如本文所述之式（1)化合物，其中 R12為-C(0)-R13。 本發明之另一實施例為如本文所述之式⑴化合物， R為烧氧基、烧氡基烧基、 烧氧基烧基、_環烧基、鹵 、環烧氧基烧基、_烧基、鹵 鹵環烷基烷基、鹵環烷氧基烷 基、芳基、經取代之芳基、雜芳基或經取代之雜芳基其The two rings, ‘and, that is, the two rings are separated by:= having or – a chain of two ring atoms. Examples of monocyclic saturated heterodimers are oxetanyl, azetidinyl, fluorenyl, tetrahydrofuranyl, tetradecyl-thienyl, pyrazolyl, imidazolidinyl, oxazolidine Base, iso- 嗤 定 定 、, D 塞 π 定 、 派 派 派 派 派 派 派 派 派 派 派 派 派 派 派 派 派 派 派 派 派 派 派 派 派 派 派 派 派 派 派 派 派 派 派 派 派 派- thiomorphin-4-yl, azepanyl, diazepine, oxazinyl or oxazepine. Examples of bis(tetra) and heterowei groups are aza-bicyclo[3.2.1]octyl, decyl, 8-oxa-3-aza-bicyclic= .2.1]octyl, 9·aza-bicyclo[331] Sulfhydryl, 3_oxahydroazabicyclo[3.3.1]fluorenyl or 3-sulfo-9-aza-bicyclo[3.31]fluorenyl. Examples of partially unsaturated heterocyclic alkyl groups are dihydroindenyl, phenyl, dihydro-indenyl, tetrahydro-J-indenyl-H-yl. A more specific example of a heterocyclic alkyl group is an oxetane group. The term "base group" means a group. The term "peroxy" denotes an alkoxy group wherein at least one hydrogen atom of the oxime has been replaced by a hydroxy group. Examples of the hydroxyalkoxy group include a hydroxyethoxy group, a hydroxypropoxy group, a hydroxymethylpropoxy group, and a dihydroxypropyloxy group. The term "hydroxy ceyl group" means an alkyl group wherein at least one hydrogen atom of the alkyl group has been replaced by a hydroxy group and at least one hydrogen atom of the alkyl group has been replaced by a halogen. Examples of the hydroxy ialkyl group include a hydroxytrifluoroethyl group, a hydroxytrifluoropropyl group, and a hydroxyhexafluoropropyl group. The term "hydroxyalkyl" means an alkyl group wherein at least one hydrogen atom of the alkyl group has been replaced by a hydroxyl group. Examples of the hydroxyalkyl group include a hydroxymethyl group, a hydroxyethyl group, 160800.doc • 17· 201245158 a propyl group, a hydroxymethyl group, and a dihydroxypropyl group. The term "pharmaceutically acceptable salts" refers to salts which retain the biological effectiveness and properties of the free base or free acid, which are not biologically or otherwise undesirable. The salts are formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, especially hydrochloric acid; and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, Maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-methyl tartaric acid , salicylic acid, N-ethinyl cysteine and its analogs. Alternatively, such salts can be prepared by addition of an inorganic or organic base to the free acid. Salts derived from computer tests include, but are not limited to, sodium salts, potassium salts, lithium salts, salt, salt, magnesium salts and the like. Salts derived from organic bases include, but are not limited to, the following salts: primary amines, secondary amines, and tertiary amines; substituted amines, including naturally occurring substituted amines; cyclic amines and organic ion exchange resins, Such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine 'ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resin and the like. Particular pharmaceutically acceptable salts of the compounds of formula (I) are the hydrochloride, methanesulfonate and citrate salts. "Pharmaceutically acceptable ester" means that the compound of formula (1) can be derivatized at a functional group to provide a derivative which can be converted back to the parent compound in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives such as methoxymethyl ester, methylthiomethyl ester and pivalate methyl ester. Further, any physiologically acceptable phase of a compound of the formula (I) which is similar to a metabolically labile ester and which is capable of producing the parent compound of the formula (1) in vivo, is in the form of the invention 160800.doc 18 201245158 In the mouth of the van. The term "protecting group" (PG) denotes a group which selectively blocks a reactive site in a polyfunctional compound such that the chemical reaction can be selectively carried out at another unprotected reactive site, the meaning of which Usually related to the meaning in synthetic chemistry. The protecting group can be removed at the appropriate point. Exemplary protecting groups are amine protecting groups, "(tetra)yl or (tetra)(tetra)yl. The special U protecting group is a third butoxy group (B.), an oxycarbonyl group (Cbz), a methoxy group and a benzyl group (4). More specific protecting groups are the third butoxy group (b〇c) and the methoxy group (F·). A more specific protecting group is a third butoxy group (Boc). The compound of formula (1) may contain several asymmetric centers and may be optically pure enantiomers, mixtures of enantiomers (such as racemates), optically pure diastereomers, diastereomers A mixture of the bodies, a diastereomeric racemate or a mixture of diastereomeric racemates is present. According to the Cahn-Ingold-Prelog convention, asymmetric carbon atoms can have an "R" or "S" configuration. Further, an embodiment of the invention is a compound of formula (I) as described herein, and a pharmaceutically acceptable salt or ester thereof, especially a compound of formula (1) as described herein, and a pharmaceutically acceptable salt thereof, More specifically, it is a compound of formula (1) as described herein. Another embodiment of the invention is a compound of formula (1) as described herein, wherein R1 is i alkoxy, alkoxycarbonyl, cycloalkoxycarbonyl, orthooxycarbonyl, heteroaryl or substituted An aryl group wherein the substituted heteroaryl group is substituted with one to three alkyl groups. 160800.doc -19- 201245158 A specific embodiment of the invention is a compound of formula (1) as described herein, wherein R1 is dentyloxy, alkoxycarbonyl or substituted heteroaryl, wherein substituted heteroaryl The base is substituted with one to three alkyl groups. Another embodiment of the invention is a compound of formula (1) as described herein, wherein R is halooxy, alkoxycarbonyl, alkyloxadiazolyl or alkyltetrazolyl. Another additional embodiment of the invention is a compound of formula (1), wherein R1 is alkyl, as described herein. Evil two alpha sitting base. Another embodiment of the invention is a compound of formula (1) as described herein, wherein R1 is methyl oxazolidine. Another additional embodiment of the invention is a compound of formula (1) as described herein, wherein R1 is alkyl. Sitting on the base. Another embodiment of the invention is a compound of formula (1) as described herein, wherein R1 is methyltetra. Sitting on the base. The invention also relates to compounds of formula (1) as described herein, wherein R2 is hydrogen or halogen. Another particular embodiment of the invention is a compound of formula (1) as described herein, wherein R2 is halogen. A more specific embodiment of the invention is a compound of formula (I) as described herein, wherein R is gas or gas. Still a consistent embodiment of the invention is a compound of formula (I) as described herein wherein R3 is hydrogen. The invention also relates to compounds of formula (1) as described herein, wherein R4 is a halogen. 160800.doc 20-201245158 Another embodiment of the invention is a compound of formula (i) as described herein, wherein R4 is halogen. Another particular embodiment of the invention is a compound of formula (I) as described herein, wherein R4 is chloro. A particular embodiment of the invention is a compound of formula (I) as described herein, wherein R5 is hydrogen. Further, an embodiment of the invention is a compound of formula (1) as described herein, wherein R6 is hydrogen. The invention also relates to compounds of formula (1) as described herein, wherein R7 is a gas acene alkyl group. Another embodiment of the invention is a compound of formula (1) as described herein, wherein R7 is a gas. The invention also relates to compounds of formula (1) as described herein, wherein R8 is hydrogen. Further, an embodiment of the invention is a compound of formula (1) as described herein, wherein R9 is hydrogen, alkyl or cycloalkyl. Further, an embodiment of the invention is a compound of formula (I) as described herein, wherein R10 is hydrogen, alkyl or cycloalkyl. Another embodiment of the invention is a compound of formula (I), as described herein, wherein R and R, together with the carbon to which they are attached, form a cycloalkyl or heterocycloalkyl group. A particular embodiment of the invention is a compound of formula (I) as described herein, wherein R and R together with the carbon to which they are attached form a cycloalkyl group. Another particular embodiment of the invention is a compound of formula (I) as described herein, wherein R and R, together with the carbon to which they are attached, form a heterocyclic alkyl group. A more specific embodiment of the invention is a compound of formula (I) as described herein, 160800.doc -21 - 201245158 wherein R9 and R1G together with the carbon to which they are attached form a cycloalkyl or oxetanyl group. A further embodiment of the invention is a compound of formula (I) as described herein wherein R and R together with the carbon to which they are attached form a cyclopropyl group. A further embodiment of the invention is a compound of formula (I) as described herein wherein R9 and R1Q together with the carbon to which they are attached form an oxetane group. Another embodiment of the invention is a compound of the formula: wherein R11 is hydrogen. Another embodiment of the invention is a compound of formula (j), as described herein, wherein R12 is hydrogen, alkyl or cycloalkyl. A further embodiment of the invention is a compound of formula (1) as described herein, wherein R12 is hydrogen. Further, an embodiment of the invention is a compound of formula (1) as described herein, wherein R12 is hydrogen or -C(0)-r13. Another embodiment of the invention is a compound of formula (1) as described herein, wherein R12 is -C(0)-R13. Another embodiment of the invention is a compound of formula (1) as described herein, R is alkoxy, decylalkyl, alkoxyalkyl, _cycloalkyl, halo, cycloalkyloxyalkyl, _ An alkyl, halohalocycloalkyl, halocycloalkoxyalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl

160800.doc •22- 201245158 取代之胺基經-至兩個冑立地選自㈣及帛烷基之取代基 取代。 本發明之另一實施例為如本文所述之式（1)化合物，其中 R13為烷氧基、烷氧基烷基、_烷基、經取代之苯基、雜 芳基或經取代之雜芳基，其中經取代之苯基及經取代之雜 芳基經一至三個獨立地選自烷基、齒素、齒烷基' 烷氧基 及胺基之取代基取代。 本發明之一特定實施例為如本文所述之式⑴化合物，其 中R為烧氧基、鹵烧基、雜芳基或經取代之雜芳基，其 中經取代之雜芳基經一至三個烷氧基取代基取代。 本發明之一更特定實施例為如本文所述之式⑴化合物， 其中R13為烷氧基、烷氧基烷基、齒烷基、咪唑基、異噁 °坐基、11 惡· — 11坐基、11 塞二β坐基、比咬基、建11秦基、痛咬基， 或選自經一至三個獨立地選自烷基、函素、鹵烷基、烷氧 基及胺基之取代基取代之苯基、咪唑基、異噁唑基、噁二 唑基、噻二唑基、吡啶基、噠嗪基及嘧啶基。 本發明之一更特定實施例為如本文所述之式（I)化合物， 其中R13為烷氡基、i烷基、異噁唑基、噁二唑基、噠°秦 基、嘧啶基，或選自經一至三個烷氧基取代基取代之異噁 唑基或噁二唑基。 本發明之另一實施例為如本文所述之式（I)化合物’其中 R13為鹵烷基、烷氧基異噁唑基、噠嗪基或烷氧基嘧咬 基。 本發明之另一特定實施例為如本文所述之式（1)化合物’ 160800.doc -23· 201245158 其中R 4三氟甲基、甲氧基異噁唑基、噠嗪基或甲氧基 ^密咬基。 本發3明之另-特定實施例為如本文所述之式⑴化合物， 其中R A三氟曱基、甲氧基異噁唑基、噠嗪基、嘧啶基 或曱氧基喷唆基。 本發明之—特定實施例為如本文所述之式（I)化合物，其 中 A1 為 CR14、〇 或 S。 又，本發明之一實施例為如本文所述之式（I)化合物，其 中 A1 為 CR14。 本發明之另一實施例為如本文所述之式（I)化合物，其中 A1為 0。 本發明亦關於如本文所述之式⑴化合物，其中Αι為S。 本發明之另一實施例為如本文所述之式（I)化合物，其中 A1 為 NR15。 本發明之—實施例為如本文所述之式⑴化合物，其中A2 為 CR16 〇 又，本發明之一實施例為如本文所述之式（I)化合物’其 中A2為N。 本發明亦關於如本文所述之式（I)化合物’其中R14為 氫。 本發明亦關於如本文所述之式（I)化合物’其中Rl5為 氫。 本發明之另一實施例為如本文所述之式（Ϊ)化合物’其中 R為氧或鹵素。 160800.doc -24 ‘ 201245158 本發明之另一實施例為如本文所述之式⑴化合物，其 R16為氫。 ’、 又，本發明之另一實施例為如本文所述之式⑴化合物， 其中R 6為卣素。 本發明之一特定實施例為如本文所述之式⑴化合物， 中R16為氟。 、 本發明之另一實施例為如本文所述之式（I)化合物，其中 π*為1或2。 Ο 本發明之另一實施例為如本文所述之式（I)化合物，其中 η為1。 本發明之另一實施例為具有式（la)之如本文所述之式（1) 化合物：160800.doc •22- 201245158 Substituted amine groups are substituted with two substituents which are erected from (iv) and a decyl group. Another embodiment of the invention is a compound of formula (1) as described herein, wherein R13 is alkoxy, alkoxyalkyl, _alkyl, substituted phenyl, heteroaryl or substituted An aryl group wherein the substituted phenyl group and the substituted heteroaryl group are substituted with one to three substituents independently selected from the group consisting of an alkyl group, a dentate, a dentate alkyl group, and an amine group. A particular embodiment of the invention is a compound of formula (1), wherein R is an alkoxy group, a haloalkyl group, a heteroaryl group or a substituted heteroaryl group, wherein the substituted heteroaryl group is one to three Alkoxy substituents are substituted. A more specific embodiment of the invention is a compound of formula (1) as described herein, wherein R13 is alkoxy, alkoxyalkyl, dentyl, imidazolyl, isopropanyl, and 11 oxi. a base, an 11-spin beta-seat group, a bite base, a 11-methyl group, a bitter base, or selected from one to three independently selected from the group consisting of an alkyl group, a functional group, a haloalkyl group, an alkoxy group, and an amine group. Substituents substituted phenyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl and pyrimidinyl. A more specific embodiment of the invention is a compound of formula (I) as described herein, wherein R13 is alkylindolyl, ialkyl, isoxazolyl, oxadiazolyl, indolyl, pyrimidinyl, or It is selected from the group consisting of isoxazolyl or oxadiazolyl substituted with one to three alkoxy substituents. Another embodiment of the invention is a compound of formula (I) as described herein wherein R13 is haloalkyl, alkoxyisoxazolyl, pyridazinyl or alkoxypyrimidine. Another particular embodiment of the invention is a compound of formula (1) as described herein - 160800.doc-23.201245158 wherein R 4 trifluoromethyl, methoxyisoxazolyl, pyridazinyl or methoxy ^Secret bite. Another specific embodiment of the invention is a compound of formula (1) as described herein, wherein R A trifluoromethyl, methoxyisoxazolyl, pyridazinyl, pyrimidinyl or decyloxy oxime. A particular embodiment of the invention is a compound of formula (I) as described herein, wherein A1 is CR14, 〇 or S. Further, an embodiment of the invention is a compound of formula (I) as described herein, wherein A1 is CR14. Another embodiment of the invention is a compound of formula (I) as described herein, wherein A1 is 0. The invention also relates to compounds of formula (1) as described herein, wherein Αι is S. Another embodiment of the invention is a compound of formula (I) as described herein, wherein A1 is NR15. An embodiment of the invention is a compound of formula (1) as described herein, wherein A2 is CR16 〇. Further, an embodiment of the invention is a compound of formula (I) as described herein wherein A2 is N. The invention also relates to compounds of formula (I) as described herein wherein R14 is hydrogen. The invention also relates to compounds of formula (I) as described herein wherein R15 is hydrogen. Another embodiment of the invention is a compound of the formula (Ϊ) as described herein wherein R is oxygen or halogen. 160800.doc -24 '201245158 Another embodiment of the invention is a compound of formula (1) as described herein, wherein R16 is hydrogen. Further, another embodiment of the invention is a compound of formula (1) as described herein, wherein R6 is halogen. A particular embodiment of the invention is a compound of formula (1) as described herein, wherein R16 is fluoro. Another embodiment of the invention is a compound of formula (I) as described herein, wherein π* is 1 or 2. Another embodiment of the invention is a compound of formula (I) as described herein, wherein η is 1. Another embodiment of the invention is a compound of formula (1) as described herein having formula (la):

又’本發明之另一實施例為具有式（lb)之如本文所述之 式（I)化合物：Yet another embodiment of the invention is a compound of formula (I) having formula (lb) as described herein:

160800.doc -25- 201245158 如本文所述之式（i)化合物之特定實例係選自： (外消旋）-2-(1-{[1-(2,2,2-三氟-乙醯胺基）_環丙烷羰基]_ 胺基卜茚滿-5-基）-苯甲酸曱酯； 1(12,2-三氟-乙醯胺基）-環丙烷甲酸{(外消旋）_5_[3,5_ 二氯-2-(2,2-二氟-乙氧基）-苯基]-茚滿-丨_基卜醯胺； (外消旋）-2-氯-6-(1-{[1-(2,2,2-三氟-乙醯胺基）-環丙烷羰 基]-胺基}-茚滿-5-基）-苯甲酸甲酯； 1-(2,2,2-三I -乙酸胺基）-環丙烧曱酸{(外消旋）_5·[5-氯 -3-氟-2-(5-甲基-[1，2,4]噁二唑-3-基）-苯基]-茚滿- l-基}-醯 胺； 1- (2,2,2-三氟-乙醯胺基）-環丙烷甲酸{(s)-5-[5-氯-3-氟 -2-(5-甲基-[1，2,4]噁二唑-3-基）-笨基]-茚滿-i-基}-醯胺； 2- 氯-6-((8)-1-{[3-(2,2,2-三氟-乙醯胺基）_氧雜環丁烷-3-幾基]-胺基}_茚滿_5 -基）_苯甲酸甲酷； 3- (2,2,2-三氟-乙醯胺基）-氧雜環丁烷-3-甲酸{(S)-5-[5-氯-3-氣-2-(5 -甲基-[1，2,4]σ惡—。坐-3 -基）-苯基]-茚滿-1-基}_ 醯胺； 3-(2,2,2-三氟-乙醯胺基）-氧雜環丁烷_3-曱酸{(3)-5-[5-氯-3-氟-2-(2-甲基-2Η-四唑-5、基）_苯基]-茚滿-1-基卜醯 胺； 1-(2,2,2 -二氣-乙醢胺基）-環丙燒甲酸{(外消旋）-6-[3,5-二氯-2-(2,2-二氟-乙氧基）-苯基]四氫-萘-丨_基卜醯 胺； (外消旋）-2_氯- Π _(2,2,2-三氟_乙醢胺基）-環丙烧羰 160800.doc -26- 201245158 基]_胺基}-5,6,7,8-四氫-萘-2-基）-苯甲酸甲酯； 1-(2,2,2-三氟-乙醯胺基）_環丙烷甲酸{(外消旋）-6-[5-氯 -3-氟-2-(5-甲基-[1，2,4]噁二唑-3-基）-苯基]-1，2,3,4-四氫-蔡- l-基}-酿胺； 1-(2,2,2-三氟-乙醯胺基）·環丙烷甲酸{(外消旋）-3_[5_氣 -3-氟-2-(5-曱基-[1，2,4]噁二唑-3-基）-苯基]-6,7_ 二氫 _5H_ [1]吡啶-7-基}•醯胺； 1-(2,2,2-三氟-乙醯胺基）-環丙烷甲酸{(外消旋）-3_[5_氣 -3·氟-2-(2-曱基-2H-四唑-5-基）-苯基]-6,7-二氫-阳-⑴0比 啶-7-基}-醯胺； 1-(2,2,2-三氟-乙醯胺基）-環丙烷甲酸{(外消旋）_7_[5_氣 -3-氟-2-(5-曱基-[1，2,4]噁二唑-3-基）-苯基]-咣烷_4_基}_醯 胺； 1-(2,2,2-三氟-乙醯胺基）-環丙烷甲酸{(外消旋）_7_[5_氣 -3-氟-2-(2-曱基-2H-四唑-5-基）-苯基]-咣烷_4-基}_酿胺； 1-(2,2,2-三氟-乙醯胺基）-環丙烷甲酸{(外消旋氣 -3-氟-2-(5-曱基-[1，2,4]噁二唑-3-基）-苯基]-7-氟_茚滿_1_ 基醯胺； 1-(2,2,2-三氟-乙醯胺基）-環丙烷甲酸{(外消旋）_5_[5-氣 -3-氟-2-(5-曱基-[1，2,4]噁二唑-3-基）-苯基]-卜甲基滿-1 基}-醯胺； 1-(2,2,2-三氟-乙醯胺基）-環丙烷甲酸{5-[5_氯氣_2 (2 曱基-2H-四唑-5-基）-苯基]-1-甲基-茚滿-卜基卜酿胺’ 1-(2,2,2-三氟-乙醯胺基）-環丙烷曱酸{(外消旋）_6-[5氣 160800.doc -27- 201245158 -3-氟-2-(5-曱基-[1，2,4]噁二唑-3- 基)_苯基]_2,3-二氪-本并 咬喃-3 -基}-酿胺； 衫 1-(2,2,2-三氟-乙醯胺基）-環丙烷甲酸{(外》肖旋）6[5'氣 。<5二_氫-苯并呋喃 -3-氟-2-(2-曱基-211-四唑-5-基）-苯基]-2,3·· -3-基}-醯胺； 1-(2,2,2-三氟-乙醯胺基）-環丙烷甲酸{(外〉肖旋）-6_[5氣 + 一基一贫林 -3 -氟-2-(5 -曱基- Π，2,41β惡二 1 [b]噻吩-3-基卜醯胺； 1-(2,2,2-三氟-乙醯胺基）-環丙烷甲酸{(外消旋）_6-[5_氣 -3-氟-2-(2-甲基-2H-四唑-5-基）-苯基]-2,3-二氫-苯并[b]〇塞 吩-3 -基}-酿胺， (l-{(S)-5-[5-氯-3-氟-2-(5-甲基-[1，2,4]噁二。坐 _3_基）_ 苯 基]-茚滿-1-基胺甲醯基卜環丙基）-胺基甲酸第三丁醋； 1- 胺基-環丙烷曱酸{(S)-5-[5-氣-3-氟-2-(5-甲基-Π，2,4] 噁二唑-3-基）-苯基]-節滿-l-基}•醯胺； 嘧啶 _5_ 曱酸（l-{(S)-5-[5-氣-3-氟-2-(5-甲基-Π，2,4]。惡二 唑-3-基）-苯基]•茚滿-1-基胺曱醯基卜環丙基）-醯胺； 2- 曱氧基-嘧啶-5-甲酸（l-{(S)-5-[5-氯-3-氟-2-(5-甲基 -[1，2,4]β惡一 °坐-3-基）-苯基]-節滿-ΐ_基胺甲酿基}-環丙基） 醢胺； 噠嗪-4-曱酸（l-{(s)-5_[5-氯 _3_ 氟-2-(5-曱基-[1，2,4]噁二 唑-3-基）-苯基]-節滿-1-基胺甲醯基卜環丙基）_醯胺； 異噁唑-5-曱酸（i_{(S)-5-[5-氣-3-氟-2-(5-曱基-[1，2,4]噁 二唑-3-基）-苯基]-茚滿-1-基胺曱醯基環丙基 >醯胺； 160800.doc •28· 201245158 5-曱基 _Π，3,4]噁二唑-2-曱酸（hRS)-5·^5·氣-3-氟 _2_(5_ 甲基-[1’2,4]噁二唑-3-基）-苯基]-茚滿_1_基胺甲醯基卜環丙 基）-醯胺； 3-甲氧基-異噁唑_5_甲酸（1_{(S)_5_[5_氣-3'氟-2-(5-甲基 -[1，2,4]噁二唑-3-基）_苯基]茚滿_1_基胺甲醯基}-環丙基广 醯胺； ' 及其醫藥學上可接受之鹽。 如本文所述之式⑴化合物之特定實例亦選自： 〇 (1_{(外消旋）-5-[5 -氯-3 -氟-2-(5 -甲基-[I，2,4]。惡二唾 _3_ 基）-苯基]-7-氟·茚滿-1-基胺甲醯基卜環丙基）-胺基甲酸第 三丁酯； 1- 胺基-環丙烷曱酸{(外消旋）_5-[5_氣_3'氟-2-(5 -甲基 -(1,2,4]17惡二。坐-3-基）-苯基]-7-氟-茚滿_1_基卜醯胺， 2- 曱氧基-嘧咬甲酸（1_{(外消旋）-5·[5-氯-3-氟-2-(5-甲 基-[1，2,4]噁二唑-3-基）-苯基]-7-氟-茚滿-1-基胺曱醯基}-環 丙基）-醢胺； 達嗪_4_甲酸（卜{(外消旋）-5-[5-氯-3-氟-2-(5 -甲基-[1，2,4] 噁二唑-3-基）-苯基]-7·氟-茚滿-1-基胺曱醯基卜環丙基）·酿 胺； ' 3-曱氧基-異噁唑-5-甲酸（1-{(外消旋）-5·[5-氯_3-氟-2-(5- 曱基-[1，2,4]噁二唑-3-基）-苯基]-7-氟··節滿_1_基胺曱醯基卜 環丙基）-醯胺； (1-{(外消旋）-3-[5-氣-3_氟-2-(5-甲基_[1，2,4]噁二唑-3-基）-苯基]-6,7-二氫-5H-[1]'•比啶-7-基胺甲醯基}·環丙基）_胺 160800.doc -29- 201245158 基甲酸第三丁酯； -氯-3-氟-2-(5-曱 5Η-Π]吡啶-7-基}- 1-胺基-環丙烷甲酸{(外消旋）-3-[5 基-[1，2,4]噁二唑-3-基）-苯基]-6,7-> 氬- 醯胺； 3-甲氧基-異嗯唾-5-甲酸（1_{(外消計3_[5_lL_3_H(5 氫-5Η-Π]吡啶-7-基 曱基-[1，2,4]噁二唑-3-基）-苯基]-6,7-二· 胺曱醯基}-環丙基）-醯胺； 1 r 1 氣-2 - ( 5 -曱基 * [ 1，2，4 ] 噠嗪-4-甲酸（1-{(外消旋）-3-[5-氯-3-取 嗯二嗤-3-基）-苯基]-6,7-二氫-沾-⑴1^11定_7基胺甲醯基） 環丙基）-醯胺； 噠嗪-4-曱酸（1-{(R或 S)-3-[5-氯-3-氟 _2_(5-甲基 _[1’2’4]°惡 二吐-3-基）-苯基]-6,7-二氫-5H-[l]d7-基月安甲醯基}_環 丙基）-醯胺； β Γ 5 -甲基-[1，2，4 ] °惡 噠嗪-4-甲酸（1-{(S或R)-3-[5-氯-3-氟々Η ^ —7其胺甲酿基卜環· 二唑-3-基）-苯基]-6,7-二氫-5H-[1]吡0疋-7-备 丙基）_醯胺； r《翁-3-氣-2-(5-甲 2-甲氧基-嘧啶-5-甲酸（1-{(外消旋热^ >= Γ110 比0定 -基胺 基-[1，2,4]噁二唑-3-基）-苯基]-6,7-二乱-5H-L J 甲醯基}-環丙基）-醯胺； r c # ]-氣 _ 2 - ( 5 _ 甲 異噁唑-5 -曱酸（1 - {(外消旋）-3 - [5 -乳- ^ 基-[1，2,4]嚼二吐-3-基）-苯基]-6,7-二氫·5Η·[1]°比"疋7基胺 甲醯基}-環丙基）-醯胺； (卜{(外消旋）-6-[5-氯-3-氟-2-(5-甲基^1，2,4]心一坐— 基）-苯基]-2,3-二氫-苯并咬口南-3-基胺甲醞基卜環丙基）女 160800.doc • 30- 201245158 基曱酸第三丁酯； 1_胺基-環丙烷甲酸{(外消旋）-6-[5-氣-3-氟-2-(5-甲基 -[1，2,4]噁二唑-3-基）_笨基]_2,3_二氫-笨并呋喃_3_基卜醯 胺； 噠嗪-4-甲酸（1-{(外消旋）_6_[5_氯_3_氟_2_(5_曱基- 噁二唑-3-基）-苯基]_2,3_二氫-苯并呋喃-3-基胺甲醯基卜環 丙基）-醯胺； 2- 甲氧基-嘧啶-5-曱酸（1_{(外消旋）-6-[5-氯_3_氟_2_(5_曱 基-[1,2,4]11 惡—°坐-3-基）-苯基]-2,3-二敷_笨并吱喃-3-基胺甲 醯基}-環丙基）-醯胺； 3- 曱氧基-異噁唑·5-甲酸（1·{(外消旋）_6-[5-氯-3-氟-2-(5-曱基-[1，2,4]噁二唑-3-基）-苯基]-2,3-二氫-笨并呋喃-3-基胺 甲醯基環丙基）-醯胺； 3-胺基-氧雜環丁烷-3-曱酸{(S)-5-[5-氣-3-氟-2-(5-甲基 -[1,2,4]噁二唑-3-基）-苯基]-茚滿-1-基}-醯胺； 嘧0定-5-曱酸（3-{(S)-5-[5 -氯-3-氟-2-(5 -甲基噁二 β坐-3-基）-苯基]-茚滿-卜基胺曱醯基}_氧雜環丁烧_3_基）-酿 胺； 異噁唑-5-曱酸（3-{(S)-5-[5-氯-3 -氟-2-(5-曱基- pj〆]噁 二嗤-3 -基）-苯基]-節滿基胺甲醢基氧雜環丁烧-3 -基）-醯胺； 3-甲基-異噁唑_5_甲酸（3-{(S)-5-[5-氣-3-氟_2-(5-甲基 -[1，2,4]噁二唑-3-基）-苯基]-茚滿-卜基胺甲醯基}_氧雜環丁 烧-3-基）-酿胺， 160800.doc •31- 201245158 3-甲氧基-異噁唑-5-甲酸（3-{(S)-5-[5-氯-3-氟-2-(5-甲基 -Π，2,4]噁二唑-3-基）-苯基]-茚滿-1-基胺甲醯基}-氧雜環丁 烧-3-基）-酿胺， (1-{(外消旋）-3-[5 -氣-3-氟-2-(2-曱基-2H-四唾-5 -基）-苯 基]-6,7-二氫-5H-[1]°比啶-7-基胺甲醯基卜環丙基）-胺基甲 酸第三丁酯； 1- 胺基-環丙烷甲酸{(外消旋）-3-[5-氯-3-氟-2-(2-甲基 -211-四 °坐-5-基）_ 苯基]-6,7-—虱- 5Η-[1]ηϋ°^-7-基}"-S蓝胺； 2- 甲氧基-嘧啶-5-甲酸（1-{(外消旋）-3-[5-氣-3-氟-2-(2-曱 基-2H -四0坐-5-基）-苯基]_6,7 -二氫- 5Η-[1]Π比咬-7-基胺甲酿 基}-環丙基）-醯胺； 異°惡0坐-5-甲酸（1-{(外消旋氣-3 -風<-2-(2 -甲基- 2Η-四唑-5-基）-苯基]-6,7-二氫-5Η-[1]吡啶-7-基胺曱醯基卜環 丙基）-酿胺， 3_曱基-異°惡0生-5-甲酸（1-{(外消旋）_3_[5 -氧-3-氟-2-(2-甲 基- 2H-四0坐-5-基）-苯基]_6,7 -二氫- 5Η-[1]πΛσ疋-7-基胺甲醯 基}-環丙基）-醯胺； 3- 曱氧基-異噁唑_5-甲酸（1气（外消旋氯_3_氟_2_(2_ 曱基-2Η_四唑-5-基）-苯基]-6,7-二氫-5Η-[1]。比啶-7-基胺曱 酿基}-環丙基）_醯胺； (1_{(外消旋）-6-[5-氯-3-氟-2-(2-甲基-2Η-四唑-5-基）_苯 基]_2,3_二氫·苯并[b]噻吩-3-基胺甲醯基}_環丙基）_胺基甲 酸第三丁醋’ 1-胺基-環丙烷甲酸{(外消旋）_6-[5_氯_3-氟_2_(2-曱基 • 32· 160800.doc 201245158 -2H-四嗤-5-基）_苯基]_2,3_二氫'笨并[b]噻吩-3-基}-醯胺； 5-曱基-[1，3,4]°惡二唾I曱酸（K{(外消旋）_M5_氣冬氟 -2-(2-曱基-2H-四唑-5-基）-苯基]-2,3_二氫-苯并[b]噻吩·3_ 基胺曱醯基}-環丙基醯胺； 嘧啶-5-甲酸（1_((外消旋）-6_[5·氣-3-氟-2-(2-甲基_2Η-四 唑-5-基）-苯基]_2,3-二氫·苯并[bl·塞吩-3-基胺甲醯基卜環丙 基）-醯胺； 異噁唑-5-甲酸（1_{(外消旋）-6-[5-氯-3-氟-2-(2-甲基-2H-四唑-5-基）-苯基l·2,3*·二氫-苯并[b]噻吩-3-基胺甲醯基}-環 丙基）-醯胺； 3-曱氧基-異噁唑-5-甲酸G-U外消旋）-6-[5-氣-3-氟-2-(2-甲基-2H-四唑-5-基）-苯基]-2,3-二氫·苯并[b；]噻吩_3-基胺甲 醯基卜環丙基）-醯胺； 及其醫藥學上可接受之鹽。 如本文所述之式（I)化合物之更特定實例係選自： 1-(2,2,2-三氟-乙醯胺基）-環丙烷甲酸{(s)-5-[5-氣-3-氣 -2-(5_曱基-[1，2,4]噁二唑-3-基）-苯基]-茚滿-1-基}_酿胺； 1-(2,2,2-三氟-乙醯胺基）-環丙烷甲酸{(外消旋）_3-[5-氯 -3-氟-2-(5-甲基噁二唑-3-基）-苯基 l·6,7-二氫 [1]°比啶-7·基卜醯胺； 1-(2,2,2-三氟-乙醯胺基）-環丙烷甲酸{(外消旋）_5-[5-氣 -3-氟-2-(5-甲基-[1，2,4]噁二唑_3_基）_苯基]_7_氟節 基}-醯胺； 曱氧基-嘧啶·5_曱酸（l_{(S)-5-[5-氣-3-氟-2-(5_甲土 160800.doc • 33· 201245158 -[1，2,4]噁二唑-3-基）_苯基]-茚滿-1-基胺甲醯基}_環丙基）-醯胺； 噠嗪-4-甲酸（卜{(S)-5-[5-氣-3-氟-2-(5-甲基-[1，2,4]°惡二 唑-3-基）-苯基]-茚滿-卜基胺曱醯基}-環丙基）-醯胺； 3-甲氧基_異噁唑-5_曱酸（l-{(S)-5_[5-氣-3-氟-2-(5-曱基 -Π，2,4]α惡二β坐-3 -基）-苯基]-茚滿-i_基胺甲醯基卜ί哀丙基）_ 醢胺； 及其醫藥學上可接受之鹽。 如本文所述之式（I)化合物之更特定實施例亦選自： 2- 甲氧基-嘧啶-5-甲酸（1-{(外消旋）-5_[5-氯-3-氟-2-(5-甲 基-[1,2,4]噁二唑-3-基）-苯基]-7-氟_節滿_1-基胺甲醯基}_私 丙基）-醯胺； 3_甲氧基_異噁唑-5-甲酸〇-{(外消旋）-3-[5_氯_3氟（ 甲基-[1，2,4]噁二唑-3-基）-苯基]-6,7-二氫-5H-[1]0比定 土 胺甲醯基卜環丙基）·醯胺； $甲 2_甲氧基-嘧啶-5-曱酸（1-{(外消旋）-3-[5_氯_3_氟 > 基-[i,2,4]噁二唑-3-基）_ 苯基]-6,7-二氫比定 甲醢基卜環丙基）-醯胺； 2 (5-甲 2_甲氧基-峨啶-5-甲酸（1-{(外消旋）_6-[5-氣小氟 甲 基-Π，2,4]噪二吐_3_基）_苯基]-2,3-二氫-苯并咬喃3 土 醯基}-環丙基）_醯胺； #2(5甲基160800.doc -25- 201245158 A specific example of a compound of formula (i) as described herein is selected from the group consisting of: (racemic)-2-(1-{[1-(2,2,2-trifluoro-B)醯 ) ) _ 环 羰 羰 羰 羰 -5 -5 -5 ; ; ; ; ; ; ; ; ; ; 1 1 1 1 1 1 1 1 ( ( ( ( ( ( ( ( ( _5_[3,5-Dichloro-2-(2,2-difluoro-ethoxy)-phenyl]-indan-indole_bromide; (racemic)-2-chloro-6-( 1-{[1-(2,2,2-trifluoro-acetamido)-cyclopropanecarbonyl]-amino}-indan-5-yl)-benzoic acid methyl ester; 1-(2,2 ,2-tri-I-acetic acid amino)-cyclopropanone decanoic acid {(racemic) _5·[5-chloro-3-fluoro-2-(5-methyl-[1,2,4] oxadi Zin-3-yl)-phenyl]-indan-l-yl}-decylamine; 1-(2,2,2-trifluoro-acetamido)-cyclopropanecarboxylic acid {(s)-5- [5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-indan-i-yl}-nonylamine; 2- Chloro-6-((8)-1-{[3-(2,2,2-trifluoro-acetamido)-oxetan-3-yl]-amino}_茚满_ 5-(yl)-benzoic acid methyl; 3-(2,2,2-trifluoro-acetamido)-oxetane-3-carboxylic acid {(S)-5-[5-chloro-3 -Gas-2-(5-methyl-[1,2,4]σ--. Sitting -3 -yl)- ]]-indan-1-yl}_ guanamine; 3-(2,2,2-trifluoro-acetamido)-oxetane _3-decanoic acid {(3)-5-[ 5-chloro-3-fluoro-2-(2-methyl-2-indole-tetrazol-5,yl)-phenyl]-indan-1-ylbuminamide; 1-(2,2,2-di Gas-acetamido)-cyclopropanecarboxylic acid {(racemic)-6-[3,5-dichloro-2-(2,2-difluoro-ethoxy)-phenyl]tetrahydro- Naphthoquinone-indole hydrazide; (racemic)-2_chloro- Π _(2,2,2-trifluoro-acetamido)-cyclopropane carbonyl 160800.doc -26- 201245158 base] _Amino}-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzoic acid methyl ester; 1-(2,2,2-trifluoro-acetamido)-cyclopropanecarboxylic acid { (racemic)-6-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-1,2,3 , 4-tetrahydro-cai-l-yl}-bristamine; 1-(2,2,2-trifluoro-acetamido)·cyclopropanecarboxylic acid {(racemic)-3_[5_gas- 3-fluoro-2-(5-fluorenyl-[1,2,4]oxadiazol-3-yl)-phenyl]-6,7-dihydro-5H_[1]pyridin-7-yl}•醯Amine; 1-(2,2,2-trifluoro-acetamido)-cyclopropanecarboxylic acid {(racemic)-3_[5_gas-3·fluoro-2-(2-mercapto-2H-) Tetrazolium-5-yl)-phenyl]-6,7-dihydro-cation-(1)0-pyridin-7-yl}-decylamine; 1-(2,2,2-trifluoro-acetamidamine )-cyclopropanecarboxylic acid {(racemic)_7_[5_gas-3-fluoro-2-(5-fluorenyl-[1,2,4]oxadiazol-3-yl)-phenyl]-indole Alkyl-4_yl}-decylamine; 1-(2,2,2-trifluoro-acetamido)-cyclopropanecarboxylic acid {(racemic)_7_[5_gas-3-fluoro-2-( 2-mercapto-2H-tetrazol-5-yl)-phenyl]-nonane-4-yl}-bristamine; 1-(2,2,2-trifluoro-acetamido)-cyclopropane Formic acid {(racemic -3-fluoro-2-(5-fluorenyl-[1,2,4]oxadiazol-3-yl)-phenyl]-7-fluoro_indan_1_ 醯Amine; 1-(2,2,2-trifluoro-acetamido)-cyclopropanecarboxylic acid {(racemic)_5_[5-gas-3-fluoro-2-(5-fluorenyl-[1, 2,4]oxadiazol-3-yl)-phenyl]-p-methyl-full-1 yl}-decylamine; 1-(2,2,2-trifluoro-acetamido)-cyclopropanecarboxylic acid {5 -[5_Chlorine_2 (2 fluorenyl-2H-tetrazol-5-yl)-phenyl]-1-methyl-indan-bukibamine' 1-(2,2,2-three Fluoro-acetamido)-cyclopropane decanoic acid {(racemic) _6-[5 gas 160800.doc -27- 201245158 -3-fluoro-2-(5-mercapto-[1,2,4] Oxadiazol-3-yl)-phenyl]_2,3-dioxime-benzate-3-yl}-bristamine; lacquer 1-(2,2,2-trifluoro-ethylamino) -cyclopropanecarboxylic acid {(external) spirulina) 6 [5' gas. <5 di-hydrogen-benzofuran-3-fluoro-2-(2-indolyl-211-tetrazol-5-yl)-phenyl]-2,3··-3-yl}-decylamine ; 1-(2,2,2-trifluoro-acetamido)-cyclopropanecarboxylic acid {(external > spirulina)-6_[5 gas + one base one lean forest-3 - fluoro-2-(5 - Mercapto-purine, 2,41β-oxadi- 1 [b]thiophen-3-yl-beptinamine; 1-(2,2,2-trifluoro-acetamido)-cyclopropanecarboxylic acid {(racemic) _6-[5_gas-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)-phenyl]-2,3-dihydro-benzo[b]decanophene-3 -yl}-bristamine, (l-{(S)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4] oxazide. sitting _3_yl) _ phenyl]-indan-1-ylamine-mercaptopropylcyclopropyl)-aminocarboxylic acid tert-butyl vinegar; 1-amino-cyclopropane decanoic acid {(S)-5-[5-gas- 3-fluoro-2-(5-methyl-indole, 2,4)oxadiazol-3-yl)-phenyl]-indo-l-yl}•decalamine; pyrimidine _5_ decanoic acid (l- {(S)-5-[5-Gas-3-fluoro-2-(5-methyl-oxime, 2,4). Oxadiazol-3-yl)-phenyl]•Indan-1-yl Amidoxime cyclopropyl)-guanamine; 2-decyloxy-pyrimidine-5-carboxylic acid (l-{(S)-5-[5-chloro-3-fluoro-2-(5-methyl) -[1,2,4]β恶一° sit-3-yl)-phenyl]-frozen-ΐ_ylamine-branthyl}-cyclopropyl) decylamine; pyridazine -4-decanoic acid (l-{(s)-5_[5-chloro-3_fluoro-2-(5-fluorenyl-[1,2,4]oxadiazol-3-yl)-phenyl]- -1--l-aminoamine-mercaptopropylcyclopropyl)-decylamine; isoxazole-5-decanoic acid (i_{(S)-5-[5-gas-3-fluoro-2-(5- Mercapto-[1,2,4]oxadiazol-3-yl)-phenyl]-indan-1-ylamine decylcyclopropyl>decylamine; 160800.doc •28· 201245158 5-曱基_Π,3,4]oxadiazol-2-furic acid (hRS)-5·^5·gas-3-fluoro_2_(5-methyl-[1'2,4]oxadiazole-3 -yl)-phenyl]-indan_1_ylamine-mercaptopuridyl)-decylamine; 3-methoxy-isoxazole_5_carboxylic acid (1_{(S)_5_[5_ Gas-3'fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]indano-1_ylamine-methylhydrazino}-cyclopropyl broad Amine; and its pharmaceutically acceptable salts. Specific examples of compounds of formula (1) as described herein are also selected from the group consisting of: 〇(1_{(racemic)-5-[5-chloro-3-fluoro] -(5-Methyl-[I,2,4]. Ethylene-salt-3-yl)-phenyl]-7-fluoroindan-1-ylamine-methylpyridylcyclopropyl)-carbamic acid Third butyl ester; 1-amino-cyclopropane decanoic acid {(racemic) _5-[5_gas_3' fluoro-2-(5-methyl-(1,2,4)17 oxazet. Sodium-3-yl)-phenyl]-7-fluoro-indan_1_carbetamine, 2-methoxy-pyrimidinecarboxylic acid (1_{(racemic)-5·[5-chloro- 3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-7-fluoro-indan-1-ylamine fluorenyl}-cyclopropane ))-decalamine; darazine _4_carboxylic acid (Bu {(racemic)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4] oxadiazole) -3-yl)-phenyl]-7-fluoro-indan-1-ylamine decylcyclopropyl)-bristamine; '3-decyloxy-isoxazole-5-carboxylic acid (1- {(racemic)-5·[5-chloro-3-fluoro-2-(5-fluorenyl-[1,2,4]oxadiazol-3-yl)-phenyl]-7-fluoro· ·Expansion _1_ 曱醯 曱醯 曱醯 卜 ) ) ) ) ) ; ( ( ( ( 1-{(racemic)-3-[5-gas-3_fluoro-2-(5-methyl-[ 1,2,4]oxadiazol-3-yl)-phenyl]-6,7-dihydro-5H-[1]'•pyridin-7-ylaminocarbamoyl}·cyclopropyl)_ Amine 160800.doc -29- 201245158 tert-butyl carboxylic acid; -chloro-3-fluoro-2-(5-曱5Η-Π]pyridin-7-yl}- 1-amino-cyclopropanecarboxylic acid {(outside Cyclo)-3-[5-yl-[1,2,4]oxadiazol-3-yl)-phenyl]-6,7->argon-decylamine; 3-methoxy-iso-salt -5-formic acid (1_{(external 3_[5_lL_3_H(5-hydro-5Η-Π]pyridin-7-ylindolyl-[1,2, 4]oxazol-3-yl)-phenyl]-6,7-diaminoamine}-cyclopropyl)-guanamine; 1 r 1 gas-2 - ( 5 -mercapto** 1 , 2,4 ] pyridazine-4-carboxylic acid (1-{(racemic)-3-[5-chloro-3-dean-2-indole-3-yl)-phenyl]-6,7-dihydrol - dip-(1)1^11定_7-aminoamine-mercapto)cyclopropyl)-decylamine; pyridazine-4-decanoic acid (1-{(R or S)-3-[5-chloro-3-fluoro _2_(5-Methyl_[1'2'4]°Ethion-3-yl)-phenyl]-6,7-dihydro-5H-[l]d7-ylureanylmethyl} _cyclopropyl)-guanamine; β Γ 5 -methyl-[1,2,4 ] ° oxazine-4-carboxylic acid (1-{(S or R)-3-[5-chloro-3- Fluoroquinone^-7, its amine, alkylcyclohexane, oxazol-3-yl)-phenyl]-6,7-dihydro-5H-[1]pyridinium-oxime-7-propyl) Amine; r "Ong-3-gas-2-(5-methyl 2-methoxy-pyrimidine-5-carboxylic acid (1-{(racemic heat ^ >= Γ110 is more than 0-amino-[ 1,2,4]oxadiazol-3-yl)-phenyl]-6,7-disorder-5H-LJ formazan}-cyclopropyl)-guanamine; rc #]-qi_ 2 - (5 _methylisoxazole-5-decanoic acid (1 - {(racemic)-3 - [5 -lacto-^-yl-[1,2,4] chelate di--3-yl)-phenyl) ]-6,7-dihydro·5Η·[1]° ratio "疋7-aminoamine-mercapto}-cyclopropyl)- Amine; (b{(racemic)-6-[5-chloro-3-fluoro-2-(5-methyl^1,2,4)-spin-yl)-phenyl]-2,3 -Dihydro-benzo-Binding-N--3-ylamine-methyl sulfonylcyclopropyl) Female 160800.doc • 30- 201245158 Tert-butyl phthalate; 1_Amino-cyclopropanecarboxylic acid {(external Cyclo)-6-[5-gas-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-styl]_2,3-dihydro-stupid Furan_3_carbetamine; pyridazine-4-carboxylic acid (1-{(racemic)_6_[5_chloro_3_fluoro_2_(5-mercapto-oxadiazol-3-yl)- Phenyl]_2,3-dihydro-benzofuran-3-ylaminemethantipylidene propyl)-decylamine; 2-methoxy-pyrimidine-5-decanoic acid (1_{(racemic)) -6-[5-chloro_3_fluoro_2_(5_mercapto-[1,2,4]11 oxa-°--3-yl)-phenyl]-2,3-di- _ stupid Indole-3-ylaminocarbamoyl}-cyclopropyl)-guanamine; 3-decyloxy-isoxazole·5-carboxylic acid (1·{(racemic)_6-[5-chloro-3 -Fluoro-2-(5-fluorenyl-[1,2,4]oxadiazol-3-yl)-phenyl]-2,3-dihydro-benzofuran-3-ylaminecarbinyl ring Propyl)-guanamine; 3-amino-oxetan-3-indole {(S)-5-[5-gas-3-fluoro-2-(5-methyl-[1,2 , 4]oxazol-3-yl)-phenyl]-indan-1-yl}-guanamine;定-5-decanoic acid (3-{(S)-5-[5-chloro-3-fluoro-2-(5-methyloxadi-β-yl-3-yl)-phenyl]-indole-基 曱醯 } } _ _ oxetane _3_ yl)-nitramine; isoxazole-5-decanoic acid (3-{(S)-5-[5-chloro-3-fluoro-2 -(5-fluorenyl-pj〆)oxadiazin-3-yl)-phenyl]-indoylamine-methyl oxirane oxetane-3-yl)-decylamine; 3-methyl-iso Oxazole _5_carboxylic acid (3-{(S)-5-[5-gas-3-fluoro_2-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzene ]]-茚满-卜基胺甲醯基}_oxebutan-3-yl)-nitramine, 160800.doc •31- 201245158 3-methoxy-isoxazole-5-carboxylic acid (3 -{(S)-5-[5-chloro-3-fluoro-2-(5-methyl-indole, 2,4)oxadiazol-3-yl)-phenyl]-indan-1-yl Aminomethyl}-oxetan-3-yl)-bristamine, (1-{(racemic)-3-[5-gas-3-fluoro-2-(2-mercapto-2H) - tetras--5-yl)-phenyl]-6,7-dihydro-5H-[1]° pyridine-7-ylaminemethionylcyclopropyl)-carbamic acid tert-butyl ester; 1-Amino-cyclopropanecarboxylic acid {(racemic)-3-[5-chloro-3-fluoro-2-(2-methyl-211-tetrasyl-5-yl)-phenyl]-6 ,7--虱- 5Η-[1]ηϋ°^-7-yl}"-S leucine; 2-methoxy-pyrimidine-5-carboxylic acid (1-{ (racemic)-3-[5-gas-3-fluoro-2-(2-indolyl-2H-tetrasyl-5-yl)-phenyl]_6,7-dihydro-5Η-[1 ] Π 咬 -7-7-ylamine aryl}-cyclopropyl)-decylamine; iso- ox 0 sitting -5-carboxylic acid (1-{(racemic gas-3 - wind <-2-( 2-Methyl- 2Η-tetrazol-5-yl)-phenyl]-6,7-dihydro-5Η-[1]pyridin-7-ylamineindolylcyclopropyl)-bristamine, 3 _曱基-异°0生-5-carboxylic acid (1-{(racemic)_3_[5-oxo-3-fluoro-2-(2-methyl- 2H-tetra- 0-spin-5-yl)) -phenyl]_6,7-dihydro-5Η-[1]πΛσ疋-7-ylaminemethanyl}-cyclopropyl)-guanamine; 3-decyloxy-isoxazole-5-carboxylic acid ( 1 gas (racemic chlorine_3_fluoro_2_(2_indolyl-2Η_tetrazol-5-yl)-phenyl]-6,7-dihydro-5Η-[1]. (1_{(racemic)-6-[5-chloro-3-fluoro-2-(2-methyl-2-indole-)-pyridyl-7-ylamine hydrazinyl}-cyclopropyl)-decylamine Tetrazolium-5-yl)-phenyl]_2,3-dihydrobenzo[b]thiophen-3-ylaminecarbazide}-cyclopropyl)-aminocarboxylic acid tert-butyl vinegar '1-amine Base-cyclopropanecarboxylic acid {(racemic)_6-[5_chloro-3-trifluoro_2_(2-mercapto•32.160800.doc 201245158-2H-tetraindole-5-yl)-phenyl]_2 , 3_dihydro'-p-[b]thiophen-3-yl}-decylamine; 5-indolyl-[1,3,4]° dihydropyroxylinic acid (K{(racemic)_M5_ Gasoline Fluor-2-(2-indolyl-2H-tetrazol-5-yl)-phenyl]-2,3-dihydro-benzo[b]thiophene-3-aminoamine}-cyclopropane Amidoxime; pyrimidine-5-carboxylic acid (1_((racemic)-6_[5·gas-3-fluoro-2-(2-methyl-2-indole-tetrazol-5-yl)-phenyl]_2 , 3-dihydro-benzo[bl.sup.3-ylaminocarbamylcyclopropyl)-decylamine; isoxazole-5-carboxylic acid (1_{(racemic)-6-[5 -Chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)-phenyl l·2,3*·dihydro-benzo[b]thiophen-3-ylaminecarboxamidine }-cyclopropyl)-guanamine; 3-methoxy-isoxazole-5-carboxylic acid GU racemic)-6-[5-gas-3-fluoro-2-(2-methyl-2H -tetrazol-5-yl)-phenyl]-2,3-dihydro· And [B;] thiophen-ylamine A _3- Jibu acyl cyclopropyl) - Amides; and the pharmaceutically acceptable salts thereof. More specific examples of compounds of formula (I) as described herein are selected from the group consisting of: 1-(2,2,2-trifluoro-acetamido)-cyclopropanecarboxylic acid {(s)-5-[5-gas 3- gas-2-(5-fluorenyl-[1,2,4]oxadiazol-3-yl)-phenyl]-indan-1-yl}-bristamine; 1-(2,2 ,2-trifluoro-acetamido)-cyclopropanecarboxylic acid {(racemic)_3-[5-chloro-3-fluoro-2-(5-methyloxadiazol-3-yl)-phenyl l·6,7-Dihydro[1]° pyridine-7· cisplatin; 1-(2,2,2-trifluoro-acetamido)-cyclopropanecarboxylic acid {(racemic) _5 -[5-gas-3-fluoro-2-(5-methyl-[1,2,4]oxadiazole_3_yl)-phenyl]_7_fluoro]}-decylamine; -pyrimidine·5_decanoic acid (l_{(S)-5-[5-gas-3-fluoro-2-(5_甲土160800.doc • 33· 201245158 -[1,2,4]oxadiazole -3-yl)-phenyl]-indan-1-ylaminocarbamoyl}_cyclopropyl)-guanamine; pyridazine-4-carboxylic acid (Bu {(S)-5-[5-gas- 3-fluoro-2-(5-methyl-[1,2,4]°oxadiazol-3-yl)-phenyl]-indan-butylaminyl}-cyclopropyl)-oxime Amine; 3-methoxy-isoxazole-5-decanoic acid (l-{(S)-5_[5-gas-3-fluoro-2-(5-fluorenyl-hydrazine, 2,4] alpha Ββ sit-3-yl)-phenyl]-indan-i_ylamine-methyl hydrazinyl ί ) ))) guanamine; Acceptable salts thereof pharmaceutically. A more specific embodiment of a compound of formula (I) as described herein is also selected from the group consisting of: 2-methoxy-pyrimidine-5-carboxylic acid (1-{(racemic)-5-[5-chloro-3-fluoro- 2-(5-Methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-7-fluoro-pumpy-1-ylamine-methylhydrazino}_ propyl)-醯Amine; 3-methoxy-isoxazole-5-carboxylic acid oxime-{(racemic)-3-[5-chloro-3-fluoro(methyl-[1,2,4]oxadiazole-3- ))-phenyl]-6,7-dihydro-5H-[1]0 is more than azepine methionylcyclopropyl) decylamine; $2_methoxy-pyrimidine-5-decanoic acid (1-{(racemic)-3-[5_chloro_3_fluoro] ki-[i,2,4]oxadiazol-3-yl)-phenyl]-6,7-dihydro比 定 醢 卜 ) ) ) ) ) ; 2; 2 (5-methyl 2-methoxy-acridin-5-carboxylic acid (1-{(racemic) _6-[5-gas small fluoromethyl -Π,2,4]Noise 吐_3_基)_Phenyl]-2,3-dihydro-benzo-doping 3 fluorenyl}-cyclopropyl)-decylamine; #2(5甲base

3- 曱氧基_異嗔。坐_5_甲酸（3-{(S)-5-[5氯择λ. # T π 9 A1 甲醯基卜軋雜 -Π，2,4]噁二唑_3_基）_苯基]-卽滿_卜基妝 烧-3-基）_醯胺； 160800.doc -34- 201245158 2 -曱氧基-响咬-5-甲酸（1-{(外消旋）-3-[5 -氣_3_氟_2_(2_甲 基-2H-四唑_5_基）·苯基]·6,7·二氫-5H-[1]%啶基胺甲醯 基}-環丙基）-醯胺； 3_甲氧基-異噁唑_5-甲酸（1-{(外消旋）-3-[5_氣_3_敦_2_(2_ 曱基-2H-四唑-5-基）-苯基]-6,7_二氫-5Η-[η吡啶_7_基胺曱 醯基}-環丙基）-醯胺； 嘧啶-5-甲酸（1-{(外消旋）-6_[5-氯-3-氟，2-(2·甲基_211_四 嗤-5-基）-苯基]_2,3_二氫-苯并[b]°塞吩-3-基胺甲酿美卜環丙 基）-醯胺； 及其醫藥學上可接受之鹽。 製造如本文所述之式（I)化合物之方法為本發明之—目 的。 本發明之式（I)化合物之製備可以連續或彙集合成途徑進 行。本發明之合成展示於以下一般流程中。進行反應及純 化所得產物所需之技術為熟習此項技術者已知。在反應期 間產生對映異構體或非對映異構體之混合物的狀況下，此 等對映異構體或非對映異構體可由本文所述或熟習此項技 術者已知之方法分離，諸如對掌性層析或結晶。以下方法 描述中所用之取代基及指數具有本文所給出之意義。 本文中使用以下縮寫：3-decyloxy-isoindole. _5_carboxylic acid (3-{(S)-5-[5 chloroselect λ. # T π 9 A1 甲 醯 轧 轧 Π 2 2, 2,4] oxadiazole _3 _) phenyl ]-卽满_卜基妆烧-3-基)_醯amine; 160800.doc -34- 201245158 2 -曱-oxygen-snack-5-carboxylic acid (1-{(racemic)-3-[ 5-gas _3_fluoro_2_(2_methyl-2H-tetrazole_5_yl)·phenyl]·6,7·dihydro-5H-[1]% pyridineaminecarbamyl}- Cyclopropyl)-guanamine; 3_methoxy-isoxazole_5-carboxylic acid (1-{(racemic)-3-[5_gas_3_敦_2_(2_ fluorenyl-2H-) Tetrazol-5-yl)-phenyl]-6,7-dihydro-5Η-[ηpyridine-7-ylaminoindenyl}-cyclopropyl)-decylamine; pyrimidine-5-carboxylic acid (1- {(racemic)-6_[5-chloro-3-fluoro,2-(2.methyl_211_tetradec-5-yl)-phenyl]_2,3-dihydro-benzo[b] °Septaphen-3-ylamine-methylbuticyclopropyl)-guanamine; and pharmaceutically acceptable salts thereof. The method of making a compound of formula (I) as described herein is the object of the present invention. The preparation of the compounds of formula (I) of the present invention can be carried out in a continuous or pooled synthetic route. The synthesis of the present invention is shown in the following general scheme. The techniques required to carry out the reaction and to purify the resulting product are known to those skilled in the art. In the case where a mixture of enantiomers or diastereomers is produced during the reaction, such enantiomers or diastereomers may be separated by methods known to those skilled in the art or as known to those skilled in the art. , such as for palm chromatography or crystallization. The substituents and indices used in the description of the following methods have the meanings given herein. The following abbrils are used in this article:

AcOH=乙酸，BOC=第三丁氧基幾基，BuLi=丁基鐘， CDI = 1，1-羰基二咪唑，Ch2Ci2=二氣曱烷， DBU=2,3,4,6,7,8,9，10_ 八氫-嘧咬并[i，2-a]氮呼，DCE=1，2. 二氣乙烧，DIBALH=氫化二異丁基銘，dCC=N,N'-二環已 160800.doc -35- 201245158 基碳化二亞胺，DMA=iV,iV-二甲基乙醯胺，〇ΜΑΡ=4-二甲 基胺基吡啶，DMF=W-二甲基甲醯胺，EDCI=；V-(3-二甲 基胺基丙基）-N'-乙基碳化二亞胺鹽酸鹽，gt〇Ac=乙酸乙 酯，EtOH=乙醇’ Et20=***，Et3N=三乙胺，eq=當量， HATU=六氟碟酸0-(7 -氮雜苯并三〇坐-1-基）_ι，ι，3,3-四甲基 錁，HPLO高效液相層析’ ΗΟΒΤ=1-羥基苯并三嗤，許尼 希氏鹼（Huenig’s base)=iPr2NEt=iV-乙基二異丙胺，IPC =過 程控制，LAH=氳化裡I呂’ LDA=二異丙基胺基鐘，LiBH4= 硼氫化鋰’ MeOH=甲醇，NaBH3CN=氰基硼氫化鈉， NaBH4=棚氫化納’ Nal=破化納，Red-Al=氫化雙（2-甲氧基 乙氧基）鋁鈉，RT=室溫，TBDMSC1=氣化第三丁基二曱基 石夕烧’ TFA=二氟乙酸’ THF =四氮0夫。南，quant=定量。 可藉由使用熟知偶合方法使胺1(流程la)與酸2偶合，得 到醢胺3 ’如例如’視情況在h〇BT(1-羥基苯并***）及如 §午尼希氏驗（iV-乙基二異丙胺）之驗存在下，在如兄二曱 基甲醯胺之溶劑中，較佳在〇°c與室溫之間，與edci(tv_ (3-二甲基胺基丙基乙基碳化二亞胺鹽酸鹽）偶合；或 在W-二曱基甲酸胺中’較佳在〇與室溫之間，使用 HATU (六氟填酸〇-(7 -氮雜苯并三嗤_1_基）_1，1，3,3_四甲基 錄）、三乙胺（步驟a)。在如二甲亞砜或二噁烷之溶劑中， 在乙酸鉀及如二氣化（1，1，_雙（二苯基膦基）_二茂鐵）鈀 (11)(與一氣曱院之1:1複合物）之催化劑存在下，在至多約 1 0 0 C之溫度下，醯胺3與例如4，4,4', 4，，5，5，5'，5'-八甲基 -2,2’-聯（1，3,2-二氧硼咮）反應，得到芳基_酬酸酯化合物 160800.doc * 36 - 201245158 4(步驟b)。芳基鹵化物3與適人 ， D之方基蝴酸或芳基蝴酸略衍 生物縮合或蝴酸醋衍生物4愈、*人 4與適合之芳基鹵化物縮合，得 到加合物5或得到通式7化人舳 _ . Λ ^ 匕。物，可在鈴木條件（Suzuki ⑽仙㈣下進L ,在諸如三鄰甲苯基膦/乙酸把 (11)、肆(三苯基膦)·纪或視情況呈二氯甲炫複合物㈣形 式之二氯[1，1·-雙（二苯基膦基） 土一戊鐵]把（II)之催化劑存在 下，及在諸如鱗酸鉀水溶液赤 仗或非水溶液、碳酸鈉或碳酸鉀 Ο 之驗存在下’在諸如二甲亞 + 兑碼甲本、二噁烷、四氫呋喃 或TVj-二甲基甲醯胺之溶劑中 mΎ及在诸如虱氣或氮氣之惰 性祝圍中’在較佳介於宏、、w 。Λ。 、至/皿與約130 C之間的溫度範圍内AcOH = acetic acid, BOC = third butoxy group, BuLi = butyl group, CDI = 1, 1-carbonyldiimidazole, Ch2Ci2 = dioxane, DBU = 2,3,4,6,7,8 , 9,10_ octahydro-pyrimidine and [i,2-a] nitrogen, DCE=1, 2. Diethylene b, DIBALH = hydrogen diisobutyl, dCC=N, N'-bicyclic has 160800. Doc -35- 201245158 carbodiimide, DMA=iV, iV-dimethylacetamide, 〇ΜΑΡ=4-dimethylaminopyridine, DMF=W-dimethylformamide, EDCI=; V-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, gt〇Ac=ethyl acetate, EtOH=ethanol ' Et20=ether, Et3N=triethylamine, eq = equivalent, HATU = hexafluorodisc 0-(7-azabenzotriazin-1-yl)_ι,ι,3,3-tetramethylguanidine, HPLO high performance liquid chromatography' ΗΟΒΤ=1- Hydroxybenzotriazine, Huenig's base = iPr2NEt = iV-ethyl diisopropylamine, IPC = process control, LAH = 氲化里 I Lu' LDA = diisopropylamino clock, LiBH4 = lithium borohydride ' MeOH = methanol, NaBH 3CN = sodium cyanoborohydride, NaBH 4 = shed hydrogenated sodium ' Nal = broken sodium, Red-Al = hydrogenated bis(2-methoxyethoxy) aluminum sodium, RT = Room temperature, TBDM SC1 = gasified tert-butyl bis-indenyl sulphate ' TFA = difluoroacetic acid' THF = tetra-nitrogen. South, quant=quantitative. Coupling of amine 1 (Scheme la) with acid 2 can be accomplished by using well-known coupling methods to give the indoleamine 3' as for example, as appropriate, in h〇BT (1-hydroxybenzotriazole) and as § 尼西氏In the presence of (iV-ethyldiisopropylamine), in a solvent such as diterpene carbamide, preferably between 〇°c and room temperature, and edci(tv_(3-dimethylamino) Propylethylcarbodiimide hydrochloride) coupling; or in W-dicarbazylamine, preferably between 〇 and room temperature, using HATU (hexafluoroantimonate-(7-azabenzene) And three 嗤_1_ base)_1,1,3,3_tetramethyl group), triethylamine (step a). In a solvent such as dimethyl sulfoxide or dioxane, in potassium acetate and as two Gasification (1,1,_bis(diphenylphosphino)-ferrocene) palladium (11) (with a 1:1 complex of a gas enthalpy) catalyst in the presence of up to about 1000 C At a temperature, indoleamine 3 and, for example, 4,4,4',4,5,5,5',5'-octamethyl-2,2'-(1,3,2-dioxaboron) The reaction is carried out to obtain an aryl-based acid ester compound 160800.doc * 36 - 201245158 4 (step b). The aryl halide 3 and the aptamer, the D-group of the acid or aryl butterfly Slightly derivative condensation or oleic acid vinegar derivative 4, * human 4 and a suitable aryl halide condensation, to obtain adduct 5 or to obtain a formula 7 of human 舳 _ Λ ^ 匕., can be in Suzuki conditions (Suzuki (10) cents (4) is introduced into L, in the form of di-chlorophosphonium complex (4), such as tri-o-tolylphosphine/acetic acid, (11), hydrazine (triphenylphosphine) or, as the case may be, dichloromethane complex (4). 1·-bis(diphenylphosphino)-p-ferro-iron] in the presence of a catalyst of (II), and in the presence of a solution such as cerium potassium citrate or non-aqueous solution, sodium carbonate or potassium carbonate ' In a solvent such as dimethyl hydrazine + methacrylate, dioxane, tetrahydrofuran or TVj-dimethylformamide, m Ύ and in an inert atmosphere such as helium or nitrogen are preferably in macro, w. Λ., to / within the temperature range between about 130 C

(步驟c、d)。移除化合物5中在A 观T存在之保護基可在關於各別保 羞吕月b所无、知之;^準條件下進行，由此釋放游離胺化合物 (步驟。胺化合物6與適合衍生物在如例如步驟钟所述或 熟習此項技術者已知之條件下偶合，得到通式⑴化合物 (步驟f)。 Ο 流程la(Steps c, d). Removal of the protecting group present in the compound A in the presence of A. T can be carried out under conditions which are not known to each of the shy, and thereby release the free amine compound (step. amine compound 6 and suitable derivatives) Coupling is carried out as described, for example, in the step clock or under conditions known to those skilled in the art to give a compound of the formula (1) (step f).

3或43 or 4

X為鹵素或oso2cf5 Y為PG或R12，其中P 為-C(0>R13 PG為保護基 Ή R101及^102例如與其所連接之硼原子一起形2 160800.doc -37- 201245158 或者（流程lb) ’保護基可連接於 之胺8(步驟g)。進行如上文所述之“到經保護 化，得到經胺基保護之聯若美彳卜人 轉 土化0物10。移除保護基，釋 放游離胺η(步驟h)，在如上文所述（步驟之條件下偶 合’得到再次帶有保護基之醮胺12。移除化合物η中之保 護基’繼而得到化合物6(步驟k)。 ’' 流程lb «7X is halogen or oso2cf5 Y is PG or R12, wherein P is -C (0> R13 PG is a protecting group Ή R101 and ^102, for example, together with the boron atom to which it is attached 2 160800.doc -37- 201245158 or (flow lb The 'protecting group can be attached to the amine 8 (step g). Performing as described above "to the protected, the amine-protected hydrazine is removed. The protecting group is removed. , releasing the free amine η (step h), coupling as described above (step to give a further protecting group of indoleamine 12. removing the protecting group in compound η) and then obtaining compound 6 (step k) '' Flow lb «7

、PG R，' I™, PG R, ' ITM

8或98 or 9

10 1010 10

1111

12 ?溫或基叫F: R101及'R102例如與其所連接之硼原子一起形成 胺衍生物1、102、1〇7、1〇8、115及121(流程以及叫為 已知的或可由此項技術中已知之程序製備。酮衍生物101 之還原胺化，例如藉由在如異丙醇之溶劑中、較佳在回流 下用氰基硼氳化鈉、乙酸銨處理，得到外消旋胺基衍生物 102(步驟a)。光學純或光學增濃之胺化合物1〇7及ι〇8可由 160800.doc -38- 201245158 不同方法製備，諸如： 1)由此項技術中已知之方法使外消旋胺基化合物1〇2分離 成其對映體，諸如經由非對映異構性鹽藉由用光學純之酸 結晶而分離對映體或藉由特定層析法使用對掌性吸附劑或 對掌性溶離劑分離對映體；或 ii)以例如酮衍生物101為起始物進行對映選擇性合成： 酮衍生物101之對映選擇性還原可例如以曱硼烧-二甲基硫 醚複合物及（S或R) 1-甲基_3,3_二苯基_四氫」比咯并π，2_ c] [ 1,3,2] °惡氮翊雜環戊稀作為催化劑，在如曱苯、二氣甲 烧或四氫°夫喃之溶劑中，在_78至室溫之溫度下進行， 知到光學純或光學增濃之二級醇衍生物j或j〇4(步驟b)。 二級醇衍生物103或104接著可轉化成具有反轉絕對組態之 相應疊氮基衍生物’例如藉由在如曱苯之溶劑中，在較佳 〇C至室溫之溫度下與二苯基磷醯基疊氮化物（DppA)及 1，8-二氮雜雙環[5_4.0]十一碳烯_7(DBU)反應（步驟c)。疊 氮基衍生物105或106接著可還原成相應胺基衍生物1〇7或 108 ’例如藉由在甲醇中在約室溫下用二氣化錫處理或在 如四氫呋喃/水之溶劑混合物中在約室溫下用三苯基膦， 視情況用如氫氧化鉀之鹼處理’得到光學純或光學增濃之 胺基化合物107或108(步驟d)。 在如四氫呋喃之溶劑中’在-30°C至室溫之溫度下，1，3_ 二噻烷鋰（在約-30°C之溫度下自1，3-二噻烷及正丁基鋰製 備）與酮101加成，得到羥基化合物1 〇9(步驟e)。水消除， 例如使用含對甲苯磺酸之苯或甲苯，由迪恩-斯達克戴留 160800.doc -39- 201245158 器（Dean-Stark trap)移除水，得到烯烴n〇(步驟f)。烯烴 110可轉化成酸1Π，例如藉由在乙酸與鹽酸之混合物中， 較佳在回流下加熱（步驟g)。藉由標準酯化（步驟h)獲得之 酉曰112可在如四氫呋喃之溶劑中在_78它下用雙（三甲基矽烷 基）乙醯胺鋰在α位置處鋰化，繼而在_78〇c與室溫之間與 烷基鹵化物反應，得到經取代之酯化合物113(步驟〇。酯 水解，例如藉由在四氫呋喃中於回流下使用三甲基矽烷酸 鈉，得到酸114(步驟k)。在甲苯、三乙胺中於回流下例如 用二苯基磷醯基疊氮化物（DPPA)處理酸114，且在四氫呋 喃中在約室溫下用三甲基矽烷酸鈉淬滅異氰酸酯，得到具 有烷基取代基R7之胺11S(步驟1)。經由形成非對映異構性 鹽或藉由特定層析法使用對掌性吸附劑或對掌性溶離劑分 離對映體而使胺115可視情況分離成其對映體。胺115可視 情況在胺氮原子處經烷基化，例如藉由引入B〇c基團在 添加如烷基_化物或環烷基^化物、甲苯磺酸烷基_或曱 苯磺酸ί哀烷基酯或甲磺酸烷基酯或甲磺酸環烷基酯之烷基 化劑之後與如氫化鈉之鹼反應而進行烷基化，繼而移除12 或温基基 F: R101 and 'R102 together with the boron atom to which they are attached, for example, form amine derivatives 1, 102, 1〇7, 1〇8, 115 and 121 (the process is also known or can be known Preparation by a procedure known in the art. Reductive amination of ketone derivative 101, for example by treatment with sodium cyanoborohydride or ammonium acetate in a solvent such as isopropanol, preferably under reflux, to give racemic Amino derivative 102 (step a). Optically pure or optically enriched amine compounds 1〇7 and ι 8 can be prepared by various methods from 160800.doc -38 to 201245158, such as: 1) Methods known in the art Isomerization of the racemic amine compound 1〇2 to its enantiomer, such as separation of the enantiomer by crystallization from an optically pure acid via a diastereomeric salt or by the use of specific chromatography The adsorbent or the enantiomer is separated by a palm eliminator; or ii) the enantioselective synthesis is carried out, for example, starting from the ketone derivative 101: The enantioselective reduction of the ketone derivative 101 can be, for example, borax-boron- Dimethyl sulfide complex and (S or R) 1-methyl_3,3_diphenyl-tetrahydro"pyrylene π,2_ c] [ 1,3,2] ° The nitrogen sulfonium heterocyclic pentene is used as a catalyst in a solvent such as toluene, dioxin or tetrahydrofuran, at a temperature of from -78 to room temperature, and is known to be optically pure or optically enriched. Alcohol derivative j or j〇4 (step b). The secondary alcohol derivative 103 or 104 can then be converted to the corresponding azide derivative having an inverted absolute configuration, for example by using a solvent such as toluene, preferably at a temperature of from 〇C to room temperature and two Phenylphosphonium azide (DppA) and 1,8-diazabicyclo[5_4.0]undecene-7 (DBU) reaction (step c). The azido derivative 105 or 106 can then be reduced to the corresponding amine derivative 1〇7 or 108', for example by treatment with tin di-sulphide in methanol at about room temperature or in a solvent mixture such as tetrahydrofuran/water. The optically pure or optically enriched amine based compound 107 or 108 is obtained with triphenylphosphine, optionally treated with a base such as potassium hydroxide at about room temperature (step d). In the solvent such as tetrahydrofuran, at a temperature of -30 ° C to room temperature, lithium 1,3-dithialate (prepared from 1,3-dithiane and n-butyllithium at a temperature of about -30 ° C) Addition to ketone 101 gives hydroxy compound 1 〇9 (step e). Water removal, for example using benzene or toluene containing p-toluenesulfonic acid, water is removed by Dean-Stark 16800.doc -39-201245158 (Dean-Stark trap) to obtain olefins n〇 (step f) . The olefin 110 can be converted to an acid, for example, by heating in a mixture of acetic acid and hydrochloric acid, preferably under reflux (step g). The oxime 112 obtained by standard esterification (step h) can be lithiated at the alpha position with bis(trimethyldecyl)acetamide lithium in a solvent such as tetrahydrofuran under _78, followed by _78. The reaction between 〇c and room temperature with an alkyl halide gives a substituted ester compound 113 (step 〇. ester hydrolysis, for example by using sodium trimethylsulfonate in refluxing in tetrahydrofuran to give acid 114 (step k) treating the acid 114 with toluene, triethylamine under reflux, for example with diphenylphosphonium azide (DPPA), and quenching the isocyanate with sodium trimethylsulfonate in tetrahydrofuran at about room temperature An amine 11S having an alkyl substituent R7 is obtained (step 1). The enantiomer is separated by formation of a diastereomeric salt or by a specific chromatography using a palmitic adsorbent or a palmitic eluent. The amine 115 can optionally be separated into its enantiomer. The amine 115 can optionally be alkylated at the amine nitrogen atom, for example by introducing a B〇c group such as an alkyl group or a cycloalkyl compound, toluene. Acid alkyl or sulfonate alkyl or methanesulfonate or cycloalkyl methanesulfonate After the alkylating agent of sodium hydride as a base and alkylation with, and then removed

Boc基團，得到帶有烷基或環烷基取代基RS之胺丨（步驟 m)。 160800.doc •40- 201245158The Boc group gives an amine oxime with an alkyl or cycloalkyl substituent RS (step m). 160800.doc •40- 201245158

在如甲醇之溶劑中用4-甲氧基·苯胺處理i/f-吲哚-2,3-二 _ n6(流程’得到希夫鹼（Sehiff-base)U7(步驟幻，其 可在如甲醇之溶劑中在其巾 氧基-苯胺基取代之2,3:Τ例如_氫化納還原成經甲 乙腈與水之溶劑屁合物氣〃 5丨朵118(步驟。）。例如在 用硝酸鈽銨移除甲氧基_苯基部 I60800.doc -41. 201245158 分，得到經胺基取代之以-二氯^引嗓^步驟^帶 有兩個正交保護基之經胺基取代之2,3_二氫魯十朵121可 自經胺基取代之2,3·二氫m#119，藉由首先在―級胺 部分引人醜醯基保護基’繼而引人保護基阶，移除狀酿 基4刀且引人保4基pGb來製備（步驟^。使用類似於針 對化cr物8進一步轉化所述之方法及程序（流程ib)的方法及 程序，化合物121可用於進—步轉化成式（1)化合物。Treatment of i/f-吲哚-2,3-di-n6 with 4-methoxy-aniline in a solvent such as methanol (flow 'sehiff-base U7 (step illusion, which can be as In the solvent of methanol, the 2,3: hydrazine substituted by the oxime-anilinyl group, for example, is reduced to a solvent of methyl acetonitrile and water, which is a gas 〃 5 丨 118 (step.), for example, with nitric acid. Ammonium removal of methoxy-phenyl moiety I60800.doc -41. 201245158 points, obtained by the amine group substituted by -dichloro group 嗓 ^ step ^ with two orthogonal protecting groups substituted by an amine group 2 , 3_ Dihydroluth eleven 121 can be replaced by an amine group 2,3 · dihydro m#119, by first introducing an ugly base protecting group in the -amine moiety, and then introducing a protective basis, In addition to the 4 knives and the introduction of 4 base pGb to prepare (step ^. Using a method and procedure similar to the method and procedure (flow ib) for further conversion of the chemical substance 8, the compound 121 can be used for further steps Conversion to a compound of formula (1).

XX

116116

流程2bProcess 2b

P(?及PG%保護基 X為鹵素或OSO,CF， 酮衍生物204、207、209、212、216及22〇為已知的或可 由此項技術中已知之程序製備。因此，酸衍生物2〇1(流程 3)可轉化成相應酸氣化物衍生物2〇2，例如藉由在如苯或 二氣甲烷之溶劑中在較佳介於〇t：與各別溶劑之回流溫度 之間的溫度下與亞硫醯氯反應（步驟a)。在如三氣化鋁之路 易斯酸（Lewis acid)催化劑存在下，在如二氯乙烷之溶劑 中’較佳在約室溫下’用乙烯處理酸氯化物衍生物2〇2， I60800.doc -42- 201245158 得到氯乙基酮203，其可在氣化鋁及視情況在如氯化鈉之 添加劑存在下在高溫（至多約200。(：）下進一步反應，得到環 酮204(步驟b、c)。在氯化鋁及三氯化硼存在下，在如二氣 甲烷之溶劑申，較佳在約室溫下，苯酚衍生物2〇5例如與 氯乙腈反應’得到氯曱基酮衍生物2〇6，其可在如三乙胺 之驗存在下在例如乙腈之溶劑中環化成環酮2〇7(步驟d、 ' e)。在如氫氧化鈉之鹼存在下’例如在水中，苯酚衍生物 205例如與3-溴丙酸反應，得到3_羥基丙酸衍生物2〇8，且 〇 3-經基丙酸衍生物208可在五氯化磷及三氯化鋁存在下在 尚溫下環化成環酮209(步驟f、g)。在如水之溶劑中及在如 氫氧化納之驗存在下，在達到回流之溫度下’硫紛衍生物 210例如與2-氯-乙酸反應，得到硫乙酸衍生物211(步驟 h) °硫乙酸衍生物211接著可轉化成相應酸氯化物，例如 藉由在回流下與亞硫醯氯反應，且隨後在如i，2_二氣-苯之 溶劑中在至多約1〇〇。〇之溫度下藉助於三氣化鋁而環化（步 驟1)。在如1，1’-雙（二苯基膦基）_二茂鐵與參（二亞苄基丙 〇 酮）_二鈀之催化劑混合物存在下，在如况#-二甲基甲醯胺 之溶劑中及在如三乙胺之鹼存在下，在至多約100»c之溫 度下，碘酚衍生物213與3-巯基丙酸烷基酯反應，得到醋 化合物214(步驟k)。游離酸215(藉由在酸性或鹼性條件下 醋水解而獲得）可例如在濃硫酸中在約室溫之溫度下環化 成酮216(步驟卜m)。增環吡啶衍生物217可氧化成相應N_ 氧化物衍生物218，例如藉由在如二氣甲烷之溶劑中、較 佳在約室溫下使用間氯過苯曱酸，或在乙酸中在達到回流 溫度之溫度下使用過氧化氫水溶液（步驟n);隨後例如在二 160800.doc -43- 201245158 氯甲烧中在約室溫之溫度下用三氟乙酸酐進行重排繼而 進行’皿和息化’得到增環羥基化合物219(步驟〇)。增環羥 基化合物219可直接用於如流程2所述合成胺基化合物1， 或者’例如藉由在如二氣曱烷之溶劑中、較佳在室溫下使 用二氧化猛氧化增環羥基化合物219，得到增環酮衍生物 220(步驟p)。 流程3P (? and PG% protecting group X are halogen or OSO, CF, ketone derivatives 204, 207, 209, 212, 216 and 22 are known or can be prepared by procedures known in the art. Thus, acid derivatization Substance 2〇1 (Scheme 3) can be converted to the corresponding acid gasification derivative 2〇2, for example by being in a solvent such as benzene or dihalomethane, preferably between 〇t: and the reflux temperature of the respective solvent Reacts with sulfinium chloride at a temperature (step a). In the presence of a Lewis acid catalyst such as tri-aluminum hydride, in a solvent such as dichloroethane, preferably at about room temperature Ethylene Treatment Acid Chloride Derivative 2〇2, I60800.doc -42- 201245158 gives chloroethyl ketone 203 which can be at elevated temperatures (up to about 200 in the presence of vaporized aluminum and optionally in the presence of additives such as sodium chloride. Further reaction (:) to obtain cyclic ketone 204 (steps b, c). In the presence of aluminum chloride and boron trichloride, in a solvent such as di-methane, preferably at about room temperature, the phenol derivative 2〇5, for example, reacting with chloroacetonitrile to give the chlorodecyl ketone derivative 2〇6, which can be, for example, in the presence of triethylamine in, for example, acetonitrile Cyclization to cycloketone 2〇7 (step d, 'e). In the presence of a base such as sodium hydroxide, for example, in water, phenol derivative 205 is reacted, for example, with 3-bromopropionic acid to give 3-hydroxypropionic acid. 2〇8, and the 〇3-transpropionic acid derivative 208 can be cyclized to a cyclic ketone 209 at a temperature in the presence of phosphorus pentachloride and aluminum trichloride (steps f, g). And in the presence of, for example, sodium hydroxide, at a temperature at which reflux is reached, the sulfur derivative 210 is reacted, for example, with 2-chloro-acetic acid to obtain a sulfuric acid derivative 211 (step h). The sulfuric acid derivative 211 can then be Conversion to the corresponding acid chloride, for example by reaction with sulfinium chloride under reflux, and then in a solvent such as i,2-dialdehyde-benzene at a temperature of up to about 1 Torr. Aluminizing and cyclizing (step 1). In the presence of a catalyst mixture such as 1,1'-bis(diphenylphosphino)-ferrocene and bis(dibenzylidenepropanone)-di-palladium, In the solvent of #-dimethylformamide and in the presence of a base such as triethylamine, the iodophenol derivative 213 and 3-mercaptopropane are present at a temperature of up to about 100»c. The ester is reacted to give vinegar compound 214 (step k). Free acid 215 (obtained by hydrolysis of vinegar under acidic or basic conditions) can be cyclized to ketone 216, for example, in concentrated sulfuric acid at a temperature of about room temperature (step 卜) m). The cyclopyridine derivative 217 can be oxidized to the corresponding N-oxide derivative 218, for example by using m-chloroperbenzoic acid in a solvent such as di-methane, preferably at about room temperature, or in acetic acid. Using an aqueous hydrogen peroxide solution at a temperature at which the reflux temperature is reached (step n); followed by rearrangement with trifluoroacetic anhydride at a temperature of about room temperature, for example, in two 160,800.doc -43 - 201245158 'Dish and interest' gave an increase in the hydroxy compound 219 (step 〇). The cycloaddition hydroxy compound 219 can be used directly for the synthesis of the amine compound 1 as described in Scheme 2, or 'for example, by oxidizing the hydroxy compound by oxidative oxidation in a solvent such as dioxane, preferably at room temperature. 219, a cyclodextrin derivative 220 is obtained (step p). Process 3

X為鹵素或oso2cf3 160800.doc -44 201245158 又’本發明之—實施例為一種製備如上文所定義之式（ι) 化合物之方法，其包含以下反應： a)式（II)化合物在式（m)化合物存在下反應；X is halogen or oso2cf3 160800.doc -44 201245158 Further 'Inventive' - an embodiment is a process for the preparation of a compound of formula (I) as defined above, which comprises the following reaction: a) a compound of formula (II) in formula ( m) reacting in the presence of a compound;

R5R5

詳言之，在纪催化劑 '尤其二氣化（1，Γ_雙（二苯基膦 基）-二茂鐵）le (π)存在下，在存在或不存在國酸衍生物、 尤其 4,4,4'，4'，5,5,5'，5，-八甲基 _2,2'_聯（1，3,2 -二氧硼咮）之情 Ο 況下’在存在或不存在鹼之情況下，尤其在反0心及〖2(：〇3 存在下’在溶劑、尤其DMF及DMSO中，在室温與回流之 間所含之溫度下進行，其中A1、A2、R1、R2、R3、R4、 R5、R6、R7、R8、R9、Rig、Rn、Ri2及 n如本文所定義且 其中X1及X2為鹵素、尤其氣或溴，蝴酸或晒酸酯，尤其 4,4,5,5-四曱基-[1，3,2]二氧硼崠基，其中若χΐ或X2之一為 函朋酸或S明酸酯，則另一者為鹵素；或 b)式（IV)化合物在式（V)化合物存在下反應；In particular, in the presence of the catalyst 'especially two gasification (1, Γ_bis(diphenylphosphino)-ferrocene)le (π), in the presence or absence of an acid derivative, especially 4, 4,4',4',5,5,5',5,-octamethyl-2,2'-linked (1,3,2-dioxaboron) in the presence or absence of 'in the presence or absence In the presence of a base, especially in the anti-zero and 2 (in the presence of 〇3) in a solvent, especially DMF and DMSO, at a temperature comprised between room temperature and reflux, where A1, A2, R1 R2, R3, R4, R5, R6, R7, R8, R9, Rig, Rn, Ri2 and n are as defined herein and wherein X1 and X2 are halogen, especially gas or bromine, ceradic acid or sun acid ester, especially 4, a 4,5,5-tetradecyl-[1,3,2]dioxaboronyl group, wherein if one of hydrazine or X2 is a haonic acid or a S-acid ester, the other is a halogen; or b) a compound of formula (IV) is reacted in the presence of a compound of formula (V);

R11 10 ：R12 160800.doc 45- 201245158 詳σ之在偶合齊I、尤其EDCI、Η〇Βτ或HATU存在 下.，在存在或不存在驗之情況下，纟其在尼希氏驗 (unigs base)及二乙胺存在下’在溶劑、尤其圓戸中在 〇t：與回流之間所含之溫度下進行，其中v、a2、r1、 一 Ί — ·3 4 . R、R、R/、r8、R9、R1G、R11、n如本文所 定義且其中rU為·⑽·r13 ’其中如本文所定義。 又本發明之一目#為一種如本文所述之式⑴化合物， 其係用作治療上之活性物質。 本發月之目的為一種包含如本文所述之式（I)化合 物及治療上之惰性載劑之醫藥組合物。 又，本發明之一目的為如本文所述之式⑴化合物之用 途，其係用於治療或預防由經由刺激緩激肽受體路徑而介 導之病症所引起的疾病。 本發明亦關於如本文所述之式⑴化合物之用途，其係用 於治療或預防絲球體腎炎、亨偌絲奇恩賴紫癜性腎病 變、ANCA相關新月型絲球體腎炎、狼瘡性腎炎及IgA腎 炎0 又’本發明之一實施例為如本文所述之式（I)化合物之用 途，其係用於治療或預防絲球體腎炎。 本發明之一特定實施例為一種如本文所述之式⑴化合 物’其係用於治療或預防絲球體腎炎、亨偌-絲奇恩賴紫 瘋性腎病變、ANCA相關新月型絲球體腎炎、狼瘡性腎炎 及IgA腎炎。 又’本發明之一特定實施例為—種如本文所述之式⑴化 160800.doc -46- 201245158 合物，其係用於治療或預防絲球體腎炎。 又，本發明之一目的為一種治療或預防絲球體腎炎、亨 偌··絲奇恩賴紫癜性腎病變、ANCA相關新月型絲球體腎 炎、狼瘡性腎炎及IgA腎炎之方法，該方法包含投與有效 量之如本文所述之式（I)化合物。 又，本發明之一實施例為一種治療或預防絲球體腎炎之 方法，該方法包含投與有效量之如本文所述之式（I)化合 物。 本發明亦關於如本文所述之式（I)化合物之用途，其係用 於製備用以治療或預防絲球體腎炎、亨偌-絲奇恩賴紫癜 性腎病變、ANCA相關斩月型絲球體腎炎、狼瘡性腎炎及 IgA腎炎之藥物。 又，本發明之一實施例為如本文所述之式（I)化合物之用 途，其係用於製備用以治療或預防絲球體腎炎之藥物。 本發明之另一目的包含根據任一所述方法製造之如本文 所述之式（I)化合物。 分析程序 受體結合分析 結合分析係以來自過度表現緩激肽-1受體之CHO-K1細 胞之膜進行。 對於結合，將含多種濃度之緩激肽-1受體拮抗劑化合物 之 50 mM Tris(pH 7.4)、5 mM MgCl2 以及 6 nM 胰激肽（Des Arg10，Leu9)[3,4-Prolyl-3,4-3H(N)](PerkinElmer，1.85-4.44 TBq/mmol)添加至含有約1 fmol缓激肽-1受體之40 pg膜蛋 •47- 160800.doc 201245158 白中，且在27°C下培育1 5分鐘。為測定非特異性結合’添 加 10 pMLys-(Des-Arg9)-缓激肽（Bachem)。經 GF/B(玻璃纖 維過濾器；PerkinElmer)板收集膜’用0.5%聚伸乙基亞胺 平衡，在50。(：下經空氣乾燥2小時。藉由在頂式計數器 (topcounter，NXT Packard)中計數來測定放射能。特異性 結合定義為總結合減去非特異性結合且通常代表總結合之 約90-95%。拮抗劑活性以Ki表示：針對放射性配體之濃度 校正之抑制50%特異性結合所需的抑制劑濃度。 鈣移動分析 在補充有10%經透析FBS、1% NEAA(非必需胺基酸）、 1%青黴素/鏈黴素、1% G418及0.1 mg/ml勻黴素（zeocin)之 DMEM(高葡萄糖）中培養穩定地過度表現人類緩激肽1受體 之 GeneBLAzer®缓激肽（Bl)-NFAT-bla CHO-K1 細胞（來自 Invitrogen) ° 對於分析，使細胞在37°C、5% C02下，於384孔黑色透 明平底聚苯乙烯盤（Costar)中生長隔夜。用DMEM、20 mM Hepes、2.5 mM 丙石黃舒（probenecid)、0.1% BSA(DMEM分 析緩衝液）洗滌後，在30°C下用含4 μΜ Fluo_4之相同 DMEM分析缓衝液負載細胞，持續2小時。移除過量染 料，且用DMEM分析緩衝液洗滌細胞。以具有或不具有多 種濃度之測試化合物之DMEM分析緩衝液/0.5% DMSO製 備3 84孔化合物盤。通常測試化合物之促效劑及拮抗劑活 性。 將測試化合物添加至分析盤中，且利用FLIPR(488 nm激 160800.doc -48· 201245158 發；510-570 nm發射；Molecular Devices)以營光形式監測 促效劑活性，持續80秒。在30°C下培育20-30分鐘後，添 加20 nM MCP-1(R&D ; Roche)，且再次監測螢光，持續80 秒。將胞内約之增加報導為促效劑暴露後之最大螢光減去 暴露前之基礎螢光。將拮抗劑活性表示為抑制50%特異性 鈣增加所需之抑制劑濃度。R11 10 :R12 160800.doc 45- 201245158 Detailed σ is in the presence of coupling I, especially EDCI, Η〇Βτ or HATU. In the presence or absence of the test, it is in the Niigs test (unigs base) And in the presence of diethylamine in a solvent, especially in a crucible, at a temperature comprised between 〇t: and reflux, wherein v, a2, r1, Ί - 3 4 . R, R, R/ , r8, R9, R1G, R11, n are as defined herein and wherein rU is (10)·r13 ' as defined herein. Still another aspect of the invention is a compound of formula (1) as described herein for use as a therapeutically active substance. The purpose of this month is a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier. Further, one of the objects of the present invention is the use of a compound of the formula (1) as described herein for the treatment or prevention of a disease caused by a condition mediated by stimulating a bradykinin receptor pathway. The invention also relates to the use of a compound of formula (1) as described herein for the treatment or prevention of spheroid nephritis, Henschel sinensis purpura nephropathy, ANCA-associated crescentic glomerulonephritis, lupus nephritis and IgA Nephritis 0 Further, an embodiment of the invention is the use of a compound of formula (I) as described herein for the treatment or prevention of spheroid nephritis. A particular embodiment of the invention is a compound of formula (1) as described herein for use in the treatment or prevention of spheroid nephritis, Henry-Sisien-Zi-Irish nephropathy, ANCA-associated crescentic glomerulonephritis , lupus nephritis and IgA nephritis. Further, a specific embodiment of the invention is a compound of formula (1) 160800.doc-46-201245158 as described herein for use in the treatment or prevention of spheroid nephritis. Moreover, one of the objects of the present invention is a method for treating or preventing spheroid nephritis, Henry·Sickey's purpura nephropathy, ANCA-associated crescentic glomerulonephritis, lupus nephritis, and IgA nephritis, the method comprising An effective amount of a compound of formula (I) as described herein is administered. Further, an embodiment of the invention is a method of treating or preventing spheroid nephritis comprising administering an effective amount of a compound of formula (I) as described herein. The invention also relates to the use of a compound of formula (I) as described herein for the preparation or treatment of spheroid nephritis, Henzen-Sirin Lai purulent nephropathy, ANCA-associated spheroidal spheroid Nephritis, lupus nephritis and IgA nephritis drugs. Further, an embodiment of the invention is the use of a compound of formula (I) as described herein for the manufacture of a medicament for the treatment or prevention of spheroid nephritis. Another object of the invention comprises a compound of formula (I) as described herein, produced according to any of the methods described. Analytical Procedures Receptor Binding Assay The Binding Assay was performed on a membrane derived from CHO-K1 cells overexpressing the bradykinin-1 receptor. For binding, 50 mM Tris (pH 7.4), 5 mM MgCl2, and 6 nM chymokinin (Des Arg10, Leu9) [3,4-Prolyl-3] containing various concentrations of the bradykinin-1 receptor antagonist compound , 4-3H(N)] (PerkinElmer, 1.85-4.44 TBq/mmol) was added to 40 pg of membrane egg•47-160800.doc 201245158 white containing about 1 fmol of bradykinin-1 receptor, at 27° C5 for 15 minutes. To the determination of non-specific binding '10 pMLys-(Des-Arg9)-bradykinin (Bachem) was added. The film collected by GF/B (glass fiber filter; PerkinElmer) plate was equilibrated with 0.5% polyethylenimine at 50. (: air dried for 2 hours. Radioactivity was determined by counting in a top counter (NXT Packard). Specific binding was defined as total binding minus non-specific binding and usually representing about 90- of total binding. 95%. Antagonist activity is expressed as Ki: concentration of inhibitor required to inhibit 50% specific binding against concentration of radioligand. Calcium shift assay supplemented with 10% dialyzed FBS, 1% NEAA (non-essential amine) GeneBLAzer® slow stimulation of human bradykinin 1 receptor stably cultured in DMEM (high glucose) in 1% penicillin/streptomycin, 1% G418 and 0.1 mg/ml zeocin Peptide (Bl)-NFAT-bla CHO-K1 cells (from Invitrogen) ° For analysis, cells were grown overnight in a 384-well black clear flat-bottom polystyrene dish (Costar) at 37 ° C, 5% CO 2 . After washing with DMEM, 20 mM Hepes, 2.5 mM probenecid, 0.1% BSA (DMEM assay buffer), the cells were loaded with the same DMEM assay buffer containing 4 μΜ Fluo_4 at 30 ° C for 2 hours. Remove excess dye and wash cells with DMEM assay buffer Prepare a 3 84-well compound dish in DMEM assay buffer / 0.5% DMSO with or without various concentrations of test compound. Test the agonist and antagonist activity of the compound. Add the test compound to the assay plate and utilize FLIPR (488 nm. 160800.doc -48·201245158; 510-570 nm emission; Molecular Devices) monitors agonist activity in camp light for 80 seconds. After incubation at 30 ° C for 20-30 minutes, add 20 nM MCP-1 (R&D; Roche), and the fluorescence was monitored again for 80 seconds. The intracellular increase was reported as the maximum fluorescence after the agonist exposure minus the baseline fluorescence before exposure. Antagonist activity is expressed as the concentration of inhibitor required to inhibit 50% specific calcium increase.

實例 B1R結合 分析 Κί『μΜ1 Ca移動分析 IC50 [μΜ] 1 2.17 2.25 2 0.146 0.0768 3 0.123 0.0474 4 0.0202 0.002 5 0.0062 0.0006 6 0.381 0.455 7 0.0374 0.0286 8 0.0303 0.0244 9 0.236 0.0826 10 0.522 0.118 11 0.0416 0.004 12 0.0044 0.0005 13 0.0095 0.0005 14 0.212 0.0248 15 0.170 0.0246 16 0.0110 0.0005 17 0.0059 0.0006 18 0.0067 0.0005 19 0.0333 0.0045 20 0.0240 0.0036 21 0.0095 0.0023 22 0.0066 0.0008 23 0.669 0.332 24 0.0364 0.005 25 0.0031 0.0001 26 0.0026 0.0002 27 0.0036 0.0004 28 0.0041 0.0003 29 0.0095 0.0034 30 0.0039 0.0001 31 0.4754 0.1353 32 0.4580 0.0956 實例 B1R結合 分析 Ki [μΜΙ Ca移動分析 IC50 [μΜ] 33 0.0189 0.0005 34 0.0151 0.0006 35 0.0171 0.0005 36 0.3606 0.0036 37 0.5908 0.3006 38 0.0030 0.0002 39 0.0075 0.0006 40 0.1298 0.0352 41 0.0040 0.0002 42 0.0040 0.0002 43 0.0063 0.0003 45 1.5296 0.7006 46 0.0191 0.0047 47 0.0054 0.0002 48 0.0238 0.0040 50 0.0048 0.0004 51 0.0118 0.0027 52 0.0257 0.0043 53 0.0036 0.0004 54 0.0632 0.0058 55 0.2108 0.0611 56 0.0045 0.0002 57 0.0058 0.0004 58 0.0063 0.0004 59 0.0035 0.0003 61 0.2644 0.0174 62 0.0122 0.0048 63 0.0048 0.0002 64 0.0071 0.0005 65 0.0044 0.0002 160800.doc -49- 201245158 如本文所述之式（i)化合物及其醫藥學上可接受之鹽或酯 的IC5〇值介於0.000001 μΜ與1000 μΜ之間，特定化合物之 IC50值介於0.000005 μΜ與500 μΜ之間，更特定化合物之 ICso值介於0.00005 μΜ與5 μΜ之間。如本文所述之式⑴化 合物及其醫藥學上可接受之鹽或酯的Ki值介於〇.〇〇〇〇〇〇 i μΜ與1000 μΜ之間，特定化合物之Ki值介於〇.〇〇〇〇〇〇5 μΜ 與500 μΜ之間’更特定化合物之Ki值介於〇 〇〇〇〇〇5 μΜ與 50 μΜ之間。此等結果已藉由使用前述結合分析及/或妈移 動分析而獲得。 式（I)化合物及其醫藥學上可接受之鹽可用作藥物（例如 以醫藥製劑之形式）。醫藥製劑可内部投與，諸如經口（例 如以錠劑、包衣錠劑、糖衣錠、硬明膠膠囊及軟明膠膠 囊、溶液、乳液或懸浮液之形式）、經鼻（例如以鼻用噴霧 之形式）或經直腸（例如以栓劑之形式）。然而，投藥亦可以 非經腸方式進行，諸如肌肉内或靜脈内（例如以注射溶液 之形式）。 ' 式（I)化合物及其醫藥學上可接受之鹽可用醫藥學上惰性 之無機或有機佐劑加工以製備錠劑、包衣錠劑、糖衣錠及 硬明膠膠囊。可使用例如乳糖、玉米 木叔粉或其衍生物、滑 石、硬脂酸或其鹽等作為用於鍵劑、 之佐劑 用糖衣叙及硬明膠膠囊 脂肪、半固 適於軟明膠膠囊之佐劑為例如植物油、 體物質及液體多元醇等。 庶糖、 適於製備溶液及糖漿之佐劑為例如水、多元醇 160800.doc -50- 201245158 轉化糖、葡萄糖等。 多元醇、甘油、植 適於注射溶液之佐劑為例如水、醇 物油等。 適於栓劑之㈣為例如m切化油 固體多元醇或液體多元醇等。 曰、半 此::，醫藥製劑可含有防腐劑、增溶劑、黏度增加物 質、敎劑、濕潤劑、乳化劑、甜味劑、著色劑、Example B1R Binding Analysis Κί『μΜ1 Ca Mobility Analysis IC50 [μΜ] 1 2.17 2.25 2 0.146 0.0768 3 0.123 0.0474 4 0.0202 0.002 5 0.0062 0.0006 6 0.381 0.455 7 0.0374 0.0286 8 0.0303 0.0244 9 0.236 0.0826 10 0.522 0.118 11 0.0416 0.004 12 0.0044 0.0005 13 0.0095 0.0005 14 0.212 0.0248 15 0.170 0.0246 16 0.0110 0.0005 17 0.0059 0.0006 18 0.0067 0.0005 19 0.0333 0.0045 20 0.0240 0.0036 21 0.0095 0.0023 22 0.0066 0.0008 23 0.669 0.332 24 0.0364 0.005 25 0.0031 0.0001 26 0.0026 0.0002 27 0.0036 0.0004 28 0.0041 0.0003 29 0.0095 0.0034 30 0.0039 0.0001 31 0.4754 0.1353 32 0.4580 0.0956 Example B1R Binding Analysis Ki [μΜΙ Ca Mobility Analysis IC50 [μΜ] 33 0.0189 0.0005 34 0.0151 0.0006 35 0.0171 0.0005 36 0.3606 0.0036 37 0.5908 0.3006 38 0.0030 0.0002 39 0.0075 0.0006 40 0.1298 0.0352 41 0.0040 0.0002 42 0.0040 0.0002 43 0.0063 0.0003 45 1.5296 0.7006 46 0.0191 0.0047 47 0.0054 0.0002 48 0.0238 0.0040 50 0.0048 0.0004 51 0.0118 0.0027 52 0.0257 0.0043 53 0.0036 0.0004 54 0.0632 0.0058 55 0.2108 0.0611 56 0.0045 0.0002 57 0.0058 0.0004 58 0.0063 0.0004 59 0.0035 0.0003 61 0.2644 0.0174 62 0.0122 0.0048 63 0.0048 0.0002 64 0.0071 0.0005 65 0.0044 0.0002 160800.doc -49- 201245158 As described herein ( i) The IC5 value of the compound and its pharmaceutically acceptable salt or ester is between 0.000001 μΜ and 1000 μΜ, and the IC50 value of the specific compound is between 0.000005 μΜ and 500 μΜ, and the ICso value of the specific compound is Between 0.00005 μΜ and 5 μΜ. The Ki value of the compound of the formula (1) and a pharmaceutically acceptable salt or ester thereof as described herein is between 〇.〇〇〇〇〇〇i μΜ and 1000 μΜ, and the Ki value of the specific compound is between 〇.〇. K5 μΜ and 500 μΜ 'The specific compound Ki value is between 〇〇〇〇〇〇5 μΜ and 50 μΜ. These results have been obtained by using the aforementioned combination analysis and/or mother movement analysis. The compound of the formula (I) and a pharmaceutically acceptable salt thereof can be used as a medicament (e.g., in the form of a pharmaceutical preparation). The pharmaceutical preparations can be administered internally, such as orally (for example in the form of lozenges, coated lozenges, dragees, hard gelatin capsules and soft gelatin capsules, solutions, emulsions or suspensions), nasally (for example with nasal sprays) Form) or transrectal (eg in the form of a suppository). However, administration can also be carried out parenterally, such as intramuscularly or intravenously (e.g., in the form of an injectable solution). The compound of the formula (I) and its pharmaceutically acceptable salt can be processed with a pharmaceutically inert inorganic or organic adjuvant to prepare a tablet, a coated tablet, a sugar-coated tablet and a hard gelatin capsule. For example, lactose, corn gluten or a derivative thereof, talc, stearic acid or a salt thereof can be used as a binder, an adjuvant for sugar coating, and a hard gelatin capsule fat, and a semi-solid suitable for soft gelatin capsules. The agents are, for example, vegetable oils, body materials, liquid polyols, and the like. The sugar, an adjuvant suitable for preparing a solution and a syrup is, for example, water, polyol 160800.doc -50-201245158 invert sugar, glucose, and the like. The polyol, glycerin, and an adjuvant suitable for injectable solutions are, for example, water, alcohol oil, and the like. The (4) suitable for the suppository is, for example, an m-cut oil, a solid polyol or a liquid polyol.曰, 半::, pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, tinctures, wetting agents, emulsifiers, sweeteners, colorants,

劑、改變滲透壓之鹽、緩衝劑、掩蔽劑或抗氧化劑。其亦 可含有其他治療上有價值之物質。 劑量可在廣泛限度内變化，且當然將適於各特定狀況下 之個體需求。-般而言，在經口投藥之狀況下，每日劑量 以每公斤體重約(M毫克至20毫克、較佳每公斤體重約〇·5 毫克至4毫克(例如每人約3〇〇毫克)，較佳分成Μ個可由例 如相同量組成之個別劑量應為適當的。然而，顯然當顯示 需要時’可超過本文所給之上限。 根據本發明，式⑴化合物或其醫藥學上可接受之鹽及酯 可用於治療或預防疼痛，包括例如内臟痛（諸如胰臟炎、 間質性膀胱炎、腎絞痛、***炎、慢性骨盆痛）、神經 痛（諸如疱疹後神經痛、急性帶狀疱疹痛、神經損傷、「疼 痛（dynia)」（例如外陰疼痛）、幻肢痛、根部撕脫、神經根 病變、疼痛創傷性單神經病變、疼痛壓迫性神經病變、腕 随道症候群、尺骨神經病變、踩管症候群、疼痛糖尿病性 神經病變、疼痛多發性神經病變、三叉神經痛）、中樞性 疼痛症候群（潛在地由實質上在神經系統之任何層面上之 160800.doc •51 - 201245158 任何病灶引起，包括（但m於）巾風 髓損傷>，Α 夕發性硬化症、含 群痛症候群（例如***切除術後症候 群、胸廓切開術後症候群 關節炎）、脊梏、虐〜丨月絡及關卽疼痛（骨 )編(例如急性及慢性下背痛、頸部痛、脊椎 反覆性運動疼痛、牙痛、喉嚨痛、癌痛、 =祕痛（肌肉損傷、肌肉纖維疼痛）、術後疼痛、圍術 2痛及超前鎮痛（包括（㈣限於）㈣外科、矯形外科及 )¾性疼痛、痛經（原發性及繼發性），以及與絞痛相 之疼痛’及不同起源之發炎性疼痛(例如骨關節炎、類 風濕性關節炎、風濕病、腱稍炎及錢、僵直性脊椎炎、 滑囊炎）。 此外，如本文所述之式⑴化合物或其醫藥學上可接受之 鹽及醋亦可用㈣療氣管過度反應及治療與氣管疾病相關 之i火事件（例如哮$，包括過敏性哮喘（異位性或非異位 ί·生）以及運動誘發之支氣管收縮、職業性哮喘、哮喘之病 毒性或細g性加重、其他非過敏性哮喘及「喘鳴嬰兒症候 如本文所述之式⑴化合物或其醫藥學上可接受之鹽及酯 亦可用於治療慢性阻塞性肺病（包括肺氣腫）、成人呼吸窘 迫症候群、支氣管炎、肺炎、過敏性鼻炎（季節性及常年 性）及血管舒縮性鼻炎。其亦可有效對抗塵肺病，包括鋁 塵肺、戾塵肺、石棉肺、石末肺、駝鳥毛塵肺、鐵塵肺、 石夕肺病、煙塵肺及棉塵肺。 在另一實施例中，如本文所述之式⑴化合物或其醫藥學 16〇80〇.d〇c 52· 201245158 上可接受之鹽及酯亦可用於治療發炎性腸病，包括克羅恩 氏病（Crohn’s disease)及潰瘍性結腸炎、大腸急躁症候群； 胰臟炎；腎炎；膀胱炎（間質性膀胱炎）；葡萄膜炎；發炎 性皮膚病’諸如牛皮癖及濕疹；類風濕性關節炎；及由與 灼傷、扭傷或骨折相關之創傷所引起之水腫；腦水腫；腦 炎；中風及血管性水腫。 如本文所述之式（I)化合物或其醫藥學上可接受之鹽及酯 ◎ 亦可用於治療絲球體腎炎及其他發炎性腎病，包括亨偌_ 絲奇恩賴紫癜性腎病變（HSPN)及ANCA相關新月型絲球體 腎炎。其可用於治療肥胖、糖尿病、糖尿病性血管病變、 糖尿病性神經病變、糖尿病性視網膜病變、毛細管後阻力 或與胰島炎相關之糖尿病症狀（例如高血糖症、多尿症、 蛋白尿及亞硝酸鹽增多及血管舒緩素尿***）。其可用作 平滑肌鬆弛劑以治療胃腸道或子宮之痙攣。另外，其可有 效對抗肝病；多發性硬化症；心血管疾病，例如動脈粥樣 〇 硬化、充血性心臟衰竭、心肌梗塞；神經退化性疾病，例 如帕金森氏病（Parkinson’s disease)及阿兹海默氏病 (Alzheimers disease);癲癇症；敗血性休克，例如作為抗 低J&L谷劑及/或抗低血_麼劑；頭痛， 頭痛（包括預防性及急性用途）；中月 雨’包括叢集性頭痛、偏 中風；閉合性頭部損傷； 癌症；敗血症；齒齦炎；骨質疏鬆症；良性***增生； 及膀胱過動症。此等疾病及病狀之動物模型—般在此項技 術中為熟知的，且可適於評估本發明化合物之潛在效用。a salt, a salt that changes the osmotic pressure, a buffer, a masking agent, or an antioxidant. It may also contain other therapeutically valuable substances. The dosage can vary within wide limits and will of course be adapted to the individual needs in each particular condition. In general, in the case of oral administration, the daily dose is about (M mg to 20 mg, preferably about 5 mg to 4 mg per kg of body weight per kg body weight (for example, about 3 mg per person). It is preferred that the individual doses, which may be, for example, the same amount, be appropriate. However, it will be apparent that the upper limit given herein may be exceeded when deemed necessary. According to the invention, the compound of formula (1) or its pharmaceutically acceptable Salts and esters can be used to treat or prevent pain, including, for example, visceral pain (such as pancreatitis, interstitial cystitis, renal colic, prostatitis, chronic pelvic pain), neuralgia (such as post-herpetic neuralgia, acute Herpes zoster pain, nerve damage, "dynia" (eg vulvar pain), phantom limb pain, root avulsion, radiculopathy, painful traumatic mononeuropathy, painful neuropathy, carpal syndrome, Ulnar neuropathy, embolization syndrome, painful diabetic neuropathy, painful polyneuropathy, trigeminal neuralgia, central pain syndrome (potentially by the nervous system) Level 160800.doc •51 - 201245158 Any lesion caused, including (but m) towel tortillasis>, cerebral sclerosis, group pain syndrome (eg postoperative mastectomy syndrome, thoracotomy) Syndrome arthritis), ridge spasm, sputum ~ 丨 络 及 及 及 及 及 及 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( Pain (muscle damage, muscle fiber pain), postoperative pain, perioperative pain, and preemptive analgesia (including (4) limited) (4) surgery, orthopedic surgery and 3⁄4 sexual pain, dysmenorrhea (primary and secondary), and Pain associated with colic 'and inflammatory pain of different origins (eg osteoarthritis, rheumatoid arthritis, rheumatism, sputum inflammation and money, ankylosing spondylitis, bursitis). Also, as this article The compound of formula (1) or a pharmaceutically acceptable salt thereof and vinegar may also be used to (4) treat the tracheal overreaction and treat i fire events associated with tracheal diseases (eg, roaring $, including allergic asthma (atopic or non-ectopic) ί·生) and Exercise-induced bronchoconstriction, occupational asthma, viral or fine aggravation of asthma, other non-allergic asthma, and "wheeze infant syndrome, such as the compound of formula (1) or its pharmaceutically acceptable salts and esters as described herein. It can be used to treat chronic obstructive pulmonary disease (including emphysema), adult respiratory distress syndrome, bronchitis, pneumonia, allergic rhinitis (seasonal and perennial) and vasomotor rhinitis. It can also effectively combat pneumoconiosis, including Aluminum pneumoconiosis, pneumoconiosis, asbestosis lung, stone end lung, ostrich hair pneumoconiosis, iron pneumoconiosis, Shixia lung disease, soot lung and cotton pneumoconiosis. In another embodiment, a compound of formula (1) or a pharmaceutical thereof as described herein 80〇.d〇c 52· 201245158 Acceptable salts and esters can also be used to treat inflammatory bowel disease, including Crohn's disease and ulcerative colitis, large intestine irritability syndrome; pancreatitis; nephritis Cystitis (interstitial cystitis); uveitis; inflammatory skin diseases such as psoriasis and eczema; rheumatoid arthritis; and related to burns, sprains or fractures Edema caused by trauma; cerebral edema; encephalitis; stroke and angioedema. A compound of formula (I), or a pharmaceutically acceptable salt and ester thereof, as described herein, may also be used in the treatment of spheroid nephritis and other inflammatory nephropathy, including Henry _ Sichen Lai purpura nephropathy (HSPN) And ANCA-related crescentic spheroid nephritis. It can be used to treat obesity, diabetes, diabetic angiopathy, diabetic neuropathy, diabetic retinopathy, post-capillary resistance or diabetes symptoms associated with isletitis (eg hyperglycemia, polyuria, proteinuria and nitrite) Increased and vasopressin urinary excretion). It can be used as a smooth muscle relaxant to treat the gastrointestinal tract or the uterus. In addition, it is effective against liver disease; multiple sclerosis; cardiovascular diseases such as atherosclerosis, congestive heart failure, myocardial infarction; neurodegenerative diseases such as Parkinson's disease and Azhai Alzheimers disease; epilepsy; septic shock, for example, as an anti-low J&L granule and/or anti-hypoxic agent; headache, headache (including prophylactic and acute use); Including cluster headache, partial stroke; closed head injury; cancer; sepsis; gingivitis; osteoporosis; benign prostatic hyperplasia; and overactive bladder. Animal models of such diseases and conditions are generally well known in the art and may be suitable for assessing the potential utility of the compounds of the invention.

160800.doc 工具（活體内及活體 -53- 201245158 外）。 【實施方式】 本發明在下文中由不具有限制性特徵之實例來說明。 在以對映異構體之混合物形式獲得製備實例之狀況下， 純對映異構體可由本文所述之方法或由熟習此項技術者已 知之方法分離，諸如對掌性層析或結晶。 實例 所有實例皆在氬氣氛圍下製備。 中間物A-1 1-(2,2,2-三氟-乙醯胺基）_環丙烷甲酸【（外消旋）5(4,4,5,5_ 四甲基-[1，3,2]二氧硼咮_2·基）_茚滿·1基卜醯胺160800.doc Tools (in vivo and in vivo -53- 201245158). [Embodiment] The present invention is hereinafter explained by an example having no restrictive features. In the case where a preparation example is obtained as a mixture of enantiomers, the pure enantiomer may be isolated by the methods described herein or by methods known to those skilled in the art, such as palm chromatography or crystallization. EXAMPLES All examples were prepared under an argon atmosphere. Intermediate A-1 1-(2,2,2-trifluoro-acetamido)-cyclopropanecarboxylic acid [(racemic) 5 (4,4,5,5-tetramethyl-[1,3, 2]diboron 咮_2·yl)_茚满·1 kibamine

[A】 1-(2,2,2-三氟-乙醢胺基）_環丙烷甲酸 Ο[A] 1-(2,2,2-Trifluoro-acetamido)-cyclopropanecarboxylic acid Ο

將1-月女基-環丙烧曱酸（2.483 g，23.8 mmol)添加至MeOH (60 ml)中’得到白色懸浮液。添加Et3N(2 65 g，3 65 ml， 26.2 mmol)及三氟-乙酸乙酯（3 72 g，3 12 ml，26.2 160800.doc -54- 201245158 職〇 )’且在室溫下授拌混合物。24小時後，將其傾倒至 冰上’们n Ηα酸化，且㈣心萃取四次。用水洗蘇有 機層-次且用1 N HC1H次，經MgS〇4乾燥，過滤且 蒸發；在真空中乾燥所形成之殘餘物，得到呈無色固體狀 之標題化合物（4.07 g，87%)。MS: 196_0 (M-Η·)。 [BJ 1-(2,2,2-三氟-乙醢胺基）_環丙烷甲酸（（外消旋卜$溴茚 滿-1-基）-酸胺 ο1-Monthyl-cyclopropanedecanoic acid (2.483 g, 23.8 mmol) was added to MeOH (60 mL) to afford a white suspension. Add Et3N (2 65 g, 3 65 ml, 26.2 mmol) and trifluoro-ethyl acetate (3 72 g, 3 12 ml, 26.2 160800.doc -54 - 201245158) and mix the mixture at room temperature . After 24 hours, it was poured onto ice and they were acidified and (iv) extracted four times. The title compound (4.07 g, 87%) was obtained eluted eluted eluted eluted eluted eluted MS: 196_0 (M-Η·). [BJ 1-(2,2,2-Trifluoro-acetamido)-cyclopropanecarboxylic acid ((racemic b bromoindole-1-yl)-acid amine ο

BrBr

HN οHN ο

FF

FF

F 將1-(2,2,2·二I乙醯胺基）環丙烧曱酸（390 mg，^ 98 mmol)及 HATU(753 mg，1.98 mmol)溶解於 DMF(12 ml) 中’接著添加 Et3N(601 mg，828 μΐ，5.94 mmol)，且擾拌 反應混合物30分鐘。隨後，添加溶解於DMF(3 ml)中之（外 〇 消旋）_5_溴-茚滿-1-基胺（0.42 g ’ 1.98 mmol)，且在室溫下 授拌混合物15小時。接著將其傾倒至h2〇(5〇 mi)中，且用 CH2C12(2x25 ml)萃取。經MgS〇4乾燥有機層，過渡且在真 空中濃縮’得到粗產物（0.876 g)，藉由急驟層析（梦膠，20 g，含0%至5°/。MeOH之C^Ch)純化該粗產物，得到呈淡 棕色油狀之標題化合物（0.64 g，83%)。MS: 389.0 (M-H·， IBr)。 [C】1-(2,2,2-三氟-乙酿胺基）_環丙燒甲酸丨（外消旋）_5_ (4,4,5,5-四甲基-【1，3,2]二氧硼崠-2-基）-茚滿_1_基】-醯胺 160800.doc •55- 201245158F Dissolve 1-(2,2,2·diIethylamino)cyclopropanoic acid (390 mg, ^ 98 mmol) and HATU (753 mg, 1.98 mmol) in DMF (12 ml). Et3N (601 mg, 828 μΐ, 5.94 mmol) was added and the reaction mixture was stirred for 30 min. Subsequently, (exo-racemic) _5-bromo-indan-1-ylamine (0.42 g ' 1.98 mmol) dissolved in DMF (3 ml) was added, and the mixture was stirred at room temperature for 15 hours. It was then poured into h2 (5 〇 mi) and extracted with CH2C12 (2 x 25 ml). The organic layer was dried <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0> The title compound (0.64 g, m. MS: 389.0 (M-H·, IBr). [C] 1-(2,2,2-trifluoro-ethinyl)-cyclopropanecarboxylate (racemic) _5_ (4,4,5,5-tetramethyl-[1,3, 2]Bornomyl-2-yl)-indan_1_yl]-nonylamine 160800.doc •55- 201245158

將l-(2,2,2-三氟-乙醯胺基）-環丙烷甲酸（（外消旋）-5-溴-茚滿-1-基）-醯胺（1.32 g，3_37 mmol)、4,4,4’，4'，5,5,5',5’-八 甲基-2,2'-聯（1，3,2-二氧硼嗱）（1.71 g，6.75 mmol)、乙酸鉀 (994 mg，10.1 mmol)及二氣化（1,1'_ 雙-二苯基膦基）_ 二茂 鐵）把（11)(與 CH2CI2 之 1:1 複合物）（123 mg，169 μπιοί，〇.〇5 當量）溶解於二噁烷（33.7 ml)中，且在90°C下攪拌反應混合 物3小時。接著將其傾倒至H2〇(50 ml)中，且用 EtOAc(2&gt;&lt;25 ml)萃取。經MgSCU乾燥有機層，過濾且在真 空中濃縮’得到粗產物（2.370 g)，藉由急驟層析（石夕膠，2〇 g’含10%至50% EtOAc之庚烷）純化該粗產物，得到呈淡 黃色非晶形固體狀之標題化合物（1.06 g，72%)。MS: 439.2 (MH+)。 中間物A-2 1-(2,2,2-三氟-乙醯胺基）_環丙烷甲酸[(s)_5 (4,4，s，5-四甲 基-【1,3,2】一氧邵p東-2-基）-節滿-1-基]-酸胺1-(2,2,2-Trifluoro-acetamido)-cyclopropanecarboxylic acid ((rac)-5-bromo-indan-1-yl)-decylamine (1.32 g, 3-37 mmol) , 4,4,4',4',5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxaboron) (1.71 g, 6.75 mmol) , potassium acetate (994 mg, 10.1 mmol) and di-vaporized (1,1'-bis-diphenylphosphino)-ferrocene) (11) (1:1 complex with CH2CI2) (123 mg) , 169 μπιοί, 〇.〇5 eq.) was dissolved in dioxane (33.7 ml), and the reaction mixture was stirred at 90 ° C for 3 hours. It was then poured into H2 (50 ml) and extracted with EtOAc (2 &lt; The organic layer was dried <RTI ID=0.0>(M </RTI> EtOAc, EtOAc (EtOAc) The title compound (1.06 g, 72%) MS: 439.2 (MH+). Intermediate A-2 1-(2,2,2-trifluoro-acetamido)-cyclopropanecarboxylic acid [(s)_5 (4,4,s,5-tetramethyl-[1,3,2 Oxyxopyridin-2-yl)-indol-1-yl]-acid amine

160800.doc -56- 201245158160800.doc -56- 201245158

將[S]-l-甲基-3,3-二苯基六氫吡咯并[^^^^，”噁氮硼 雜環戊烯（7.11 ml ’ 7·11 mnrl〇l，0.15當量）溶解於 CHzChGOO ml)中，在劇烈攪拌下添加甲硼烷_甲硫醚複合 0 物（3.96 g，4.95 ml，52.1 mmol)，且冷卻溶液至 _7〇〇c。隨 後，在低於-75°C下逐滴（0.5 ml/min)添加5-溴-茚滿-1-酮 (10.0 g ’ 47.4 mmol)於 CH2C12(50.0 ml)中之溶液。接著使 反應混合物在C〇2/丙酮浴中極緩慢地升溫至室溫隔夜。此 時，緩慢添加冷水（50 ml)(起泡），且用CH2C12萃取反應混 合物兩次。經MgS〇4乾燥有機層，過滤且在真空中濃縮， 得到粗產物（10.786 g) ’藉由急驟層析（矽膠，1〇〇 g，含 0%至5 0% EtO Ac之庚烷）純化該粗產物，得到增濃之標題 〇 化合物（9.716 g ’ R:S=88:12)。隨後藉由HPLC層析 (Chiralpak AD HPLC管柱，含5% EtOH之庚烧）分離此混合 - 物，得到（R)-5-溴-茚滿-1-醇，[a]D (2〇-c)=-4.288 » (c=1.259，於 MeOH 中）（7.83 g，78%)及（S)-5-溴-茚滿-1-醇，[a]D (2(rC)=+4.294，（c=1.025，於 MeOH 中）（1.16 g， 12°/。），均呈淡黃色固體。 [B】（S)-l-疊氮基 _5_演-2,3-二氫-1J7-茚 160800.doc •57· 201245158 +Dissolve [S]-l-methyl-3,3-diphenylhexahydropyrrolo[^^^^," oxazoborole (7.11 ml '7.11 mnrl〇l, 0.15 equivalent) In CHzChGOO ml), borane-methyl sulfide complex 0 (3.96 g, 4.95 ml, 52.1 mmol) was added with vigorous stirring, and the solution was cooled to _7 〇〇c. Subsequently, below -75 ° A solution of 5-bromo-indan-1-one (10.0 g '47.4 mmol) in CH2C12 (50.0 ml) was added dropwise dropwise (0.5 ml/min) C. The reaction mixture was then taken in a C 2 / acetone bath The temperature was raised very slowly to room temperature overnight. At this time, cold water (50 ml) was added slowly (foaming), and the reaction mixture was extracted twice with CH2C12. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. Product (10.786 g) 'The crude product was purified by flash chromatography (jjjjjjjjjjjjjjjjjjjjjjjjjjjjjj S = 88: 12). This mixture was then separated by HPLC chromatography (Chiralpak AD HPLC column, 5% EtOH in hexane) to give (R)-5-bromo-indan-1-ol. [a]D (2〇-c)=-4.288 » (c=1.259, in MeOH (7.83 g, 78%) and (S)-5-bromo-indan-1-ol, [a]D (2(rC)=+4.294, (c=1.025 in MeOH) (1.16 g, 12 °/.), all are pale yellow solids. [B](S)-l-azido group_5_演-2,3-dihydro-1J7-茚160800.doc •57· 201245158 +

將（R)-5-漠-茚滿-1-醇α47 g，35a mm〇i)溶解於甲苯 (175 ml)中，且冷卻混合物至，接著用三苯基鱗酿基疊 氮化物（12.5 g ’ 10.2 nU’ 45.6 mmol)、ι，8-二氮雜雙環 [5.4.0]·十一碳-7·烯（7.47 g，7.4 如，49」mm〇1)於曱苯 (3 ·0 ml)中之溶液依序處理。隨後，在2_51下攪拌反應混 合物2小時，接著緩慢升溫至室溫。接著將其傾倒至 H20(200 ml)1!7，且用 EtOAc(2&gt;&lt;150 ml)萃取。經MgS〇4乾 燥有機層’過濾且在真空中濃縮，得到粗產物（1〇.731 g) ’藉由急驟層析（矽膠’ 70 g，含5°/。至10% EtOAc之庚 烧）純化該粗產物’得到呈淡黃色油狀之標題化合物（8 J 〇 g，97%)。MS: 236.9 (M + , IBr)。 [C] (S)-5-溴-茚滿-1-基胺(R)-5-indo-indan-1-ol α47 g, 35a mm〇i) was dissolved in toluene (175 ml), and the mixture was cooled to, followed by triphenylscale azide (12.5) g ' 10.2 nU' 45.6 mmol), ι,8-diazabicyclo[5.4.0]·undec-7-ene (7.47 g, 7.4, 49"mm〇1) in benzene (3 ·0) The solution in ml) is processed sequentially. Subsequently, the reaction mixture was stirred at 2 to 51 for 2 hours, and then slowly warmed to room temperature. It was then poured into H20 (200 ml) 1! 7 and extracted with EtOAc (2 &gt;&lt; The organic layer was filtered <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; The title compound (8 J 〇g, 97%) was obtained as a pale yellow oil. MS: 236.9 (M + , IBr). [C] (S)-5-bromo-indan-1-ylamine

將（S)-l-疊氮基-5_ 溴 _2,3_ 二氫-1//-節（8.09 g，34.0 mmol)溶解於thF(155 ml)中，接著依序添加水（17·2 ml)' 三苯基膦（9.8 g，37.4 mmol)。在低於25°C下向此混合物中 逐滴添加氫氧化鉀（1·〇 N，34.0 ml，34.0 mmol)，且在室 160800.doc •58- 201245158 溫下持續攪拌隔夜。接著將反應混合物傾倒至H20(1 50 ml)中’且用Et〇Ac(2xl00 ml)萃取。經MgS04乾燥有機 層’過渡且在真空中濃縮，得到粗產物（17.34 g)，藉由急 驟層析（矽膠’ 100 g,含〇%至4〇% MeOH之CH2C12)純化該 粗產物’得到呈淡黃色油狀之標題化合物（5.81 g，81%)。 MS: 211 (M+，lBr)。 [D] l-(2,2,2-三氟-乙醯胺基環丙烷甲酸[(s)-5-(4,4,5,5_ra 甲基-[1，3,2】二氧硼崠_2·基）-茚滿_ι_基】-醯胺(S)-l-azido-5-bromo-2,3-dihydro-1//- segment (8.09 g, 34.0 mmol) was dissolved in thF (155 ml), followed by water (17·2) M)) Triphenylphosphine (9.8 g, 37.4 mmol). Potassium hydroxide (1·〇 N, 34.0 ml, 34.0 mmol) was added dropwise to this mixture below 25 ° C, and stirring was continued overnight at room temperature 160800.doc • 58-201245158. The reaction mixture was then poured into H20 (1 50 ml) and extracted with EtOAc (2×100 mL). The organic layer was dried over <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI></RTI></RTI> <RTI ID=0.0> The title compound (5.81 g, 81%). MS: 211 (M+, lBr). [D] l-(2,2,2-Trifluoro-acetamidocyclopropanecarboxylic acid [(s)-5-(4,4,5,5_ra methyl-[1,3,2]diboron崠_2·基)-茚满_ι_基】-醯amine

類似於針對製備中間物A_i [Β]及A_1 [C]所述之程序， (S)-5-溴-茚滿-1-基胺已與i-(2,2,2-三氟乙醯胺基）環丙烷甲 酸（中間物人-1[八])偶合，得到1-(2,2,2-三氟-乙醯胺基）_環 丙烷曱酸（（S)-5-溴-茚滿-1-基）-醯胺，其隨後與 4,4,4|，4'，5,5,5’，5'-八曱基-2,2，-聯（1，3,2-二氧硼(1東）反應’得 到呈淡棕色固體狀之標題化合物。MS: 439.3 (MH+)。 中間物A-3 3-(2,2,2-三氟-乙醯胺基）_氧雜環丁烷-3-甲酸[(S)-5-(4,4,5,5-四甲基-[1，3,2]二氧硼崠-2-基）-茚滿-1-基]-醯胺 160800*&lt;J〇c -59· 201245158Similar to the procedure described for the preparation of intermediates A_i [Β] and A_1 [C], (S)-5-bromo-indan-1-ylamine has been associated with i-(2,2,2-trifluoroacetamidine) Amino)cyclopropanecarboxylic acid (intermediate human-1[oc]) coupled to give 1-(2,2,2-trifluoro-acetamido)-cyclopropanoic acid ((S)-5-bromo- Indole-1-yl)-guanamine, which is subsequently associated with 4,4,4|,4',5,5,5',5'-octadecyl-2,2,- (1,3,2 - </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; Oxetane-3-carboxylic acid [(S)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaboroin-2-yl)-indan-1 -基]-decylamine 160800*&lt;J〇c -59· 201245158

、：針對製備中間物A-1 [B]及A-1 [c]所述之程序， ()_臭茚滿基胺已與3_(2,2,2_三氟-乙醯胺基）-氧雜環 丁烷-3-甲酸（類似於針對製備中間物A」[A]所述之程序， 自3-胺基-氧雜環丁烷_3_甲酸及三氟-乙酸乙酯製備）偶合， 得到3-(2,2,2-三氟-乙醢胺基氧雜環丁烷—3_甲酸（（s)_5_ 溴·茚滿-1-基）-醯胺，其隨後與4,4,4i,4，，5,5,5I，5I_八曱基_ 2，2'-聯（1，3，2 -二氧棚p柬）反應，得到呈暗標色黏性油狀之標 題化合物。MS: 453_3 (M-Η-)。 中間物A-4 1-(2,2,2-三氟-乙醯胺基）-環丙烷甲酸[(外消旋）-6-(4,4,5,5-四甲基-[1，3,2】二氧硼崃基）-1，2,3,4-四氫-萘基】-酿胺, for the preparation of the intermediates A-1 [B] and A-1 [c], () skunkinylamine has been combined with 3_(2,2,2-trifluoro-acetamido) -oxetane-3-carboxylic acid (similar to the procedure described for the preparation of intermediate A" [A], prepared from 3-amino-oxetane-3-carboxylic acid and trifluoro-ethyl acetate Coupling to give 3-(2,2,2-trifluoro-acetamidooxybutane-3-carboxylic acid ((s)_5_bromoindan-1-yl)-decylamine, which is subsequently 4,4,4i,4,,5,5,5I,5I_octadecyl _ 2,2'-linked (1,3,2-dioxy shed), which gives a dark-colored viscous oil Title compound: MS: 453_3 (M-Η-). Intermediate A-4 1-(2,2,2-trifluoro-acetamido)-cyclopropanecarboxylic acid [(racemic)-6- (4,4,5,5-tetramethyl-[1,3,2]dioxaboronyl)-1,2,3,4-tetrahydro-naphthyl]-bristamine

[A](外消旋）-6-溴-1，2,3,4-四氫萘-1-胺 160800.doc •60- 201245158 nh2[A] (racemic)-6-bromo-1,2,3,4-tetrahydronaphthalen-1-amine 160800.doc •60- 201245158 nh2

使 6-漠-3,4-二氫-2//·萘-1-酮（9.5 g，42.2 mmol)懸浮於 2-丙醇（250 ml)中；接著依序添加NaBH3CN(13.3 g，211 mmol)、乙酸銨（65.1 g，844 mmol)。接著在室溫下擾拌反 應混合物4小時。隨後將其加熱至回流且繼續攪拌22小 時。接著冷卻反應混合物至室溫且傾倒至冷H20(500 ml) 中；用氫氧化鈉溶液將pH值調整至&gt;10，且用CH2C12(2x25 ml)萃取混合物。經MgS04乾燥有機層，過渡且在真空中 濃縮，得到粗產物（9.842 g)，藉由急驟層析（矽膠，100 g，含2%至10% MeOH之CH2C12)純化該粗產物，得到呈淡 紅色油狀之標題化合物（8.08 g，85%)。MS: 226.0 (MH+， IBr)。 [B] l-(2,2,2-三氟-乙醯胺基）-環丙烷甲酸[(外消旋）-6-(4,4,5,5-四甲基-[1，3,2]二氧棚》»東-2-基）-1，2,3,4-四氮-蔡_1-基]-醯胺6-Di-3,4-dihydro-2//naphthalen-1-one (9.5 g, 42.2 mmol) was suspended in 2-propanol (250 ml); then NaBH3CN (13.3 g, 211) was added sequentially. Methyl), ammonium acetate (65.1 g, 844 mmol). The reaction mixture was then spoiled at room temperature for 4 hours. It was then heated to reflux and stirring was continued for 22 hours. The reaction mixture was then cooled to room temperature and poured into cold H20 (500 ml); pH was adjusted to &gt;10 with sodium hydroxide solution and mixture was extracted with CH2C12 (2x25 ml). The organic layer was dried <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> The title compound (8.08 g, 85%). MS: 226.0 (MH+, IBr). [B] l-(2,2,2-Trifluoro-acetamido)-cyclopropanecarboxylic acid [(racemic)-6-(4,4,5,5-tetramethyl-[1,3 , 2] Dioxane»East-2-yl)-1,2,3,4-tetrazine-cai-1-yl]-guanamine

類似於針對製備中間物A-1 [B]及A-1 [C]所述之程序， 160800.doc -61 - 201245158 (外消旋）-6-溴_1，2,3,4-四氫萘-1-胺已與1_(2,2,2_三氟乙醯 胺基）環丙烷甲酸（中間物A] [A])偶合，得到1_(2,2,2-三 氟-乙醢胺基）-環丙燒甲酸（（外消旋）-6务U，3,4·四氫-萘' 1-基）-醯胺，其隨後與4,4,4’，4’，5,5,5’，5'-八甲基-2,2'-聯 (1，3，2 -二氧棚峰）反應，得到呈淡標色/由狀之彳示通化合物。 MS: 453.2 (MH+)。 中間物A-5 1-(2,2,2-三氟-乙醢胺基）-環丙烷甲酸（（外消旋）-3_溴-6,7-二 氫-5好-【1】吡啶-7-基）-醢胺Similar to the procedure described for the preparation of intermediates A-1 [B] and A-1 [C], 160800.doc -61 - 201245158 (racemic)-6-bromo_1,2,3,4-four Hydronaphthalen-1-amine has been coupled with 1_(2,2,2-trifluoroacetamido)cyclopropanecarboxylic acid (Intermediate A] [A]) to give 1-(2,2,2-trifluoro-B Amidino)-cyclopropanecarboxylic acid ((racemic)-6 U,3,4·tetrahydro-naphthalene' 1-yl)-decylamine, which is followed by 4,4,4',4', The reaction of 5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxy shed peak) gives a light-colored/formed compound. MS: 453.2 (MH+). Intermediate A-5 1-(2,2,2-trifluoro-acetamido)-cyclopropanecarboxylic acid ((racemic)-3_bromo-6,7-dihydro-5--[1] Pyridyl-7-yl)-guanamine

0 Br [A】（外消旋）-3-演-6,7-二氫-5丑-[1】吡啶-7-醇0 Br [A] (racemic)-3-act-6,7-dihydro-5 ugly-[1]pyridine-7-ol

BrBr

OH 將 3-溴-6,7-二氫-5/7-[l]吡啶 1-氧化物（6 97 g，32 6 mm〇1)溶解於CH2Cl2(150 ml)中；接著，在低於25t下於劇 烈攪拌下逐滴添加三氟乙酸酐（2〇 5 〗 &amp; Aj.o ml » 97.1 mmol)，且在室溫下繼續挽摔6小時。 ^ m l ivi iNaUH7j 溶液淬滅混合物。攪拌水性混合物兩小時且用cH2ci2/2_ 醇（4:1)萃取三次。經MgS〇4乾燥有機層過濾且在真空 160800.doc -62· 201245158 濃縮’得到粗產物（6.279 g)，藉由急驟層析（矽膠，50 g， 含20%至100% EtOAc之庚烷）純化該粗產物，得到呈淡棕 色固體狀之標題化合物（5.38 g，77%)。MS: 214.0 (MH+， IBr)。 【B](外消旋）-3-溴-6,7-二氩-5丑-[1]&quot;比啶-7·基胺OH 3-bromo-6,7-dihydro-5/7-[l]pyridine 1-oxide (6 97 g, 32 6 mm 〇1) was dissolved in CH 2 Cl 2 (150 ml); Trifluoroacetic anhydride (2〇5 〗 &amp; Aj.o ml » 97.1 mmol) was added dropwise with vigorous stirring at 25t, and continued to fall for 6 hours at room temperature. ^ m l ivi iNaUH7j solution quench the mixture. The aqueous mixture was stirred for two hours and extracted three times with cH2ci2/2-ol (4:1). Filtration of the dried organic layer over EtOAc EtOAc EtOAc (EtOAc:EtOAc: The title compound (5.38 g, 77%). MS: 214.0 (MH+, IBr). [B] (racemic)-3-bromo-6,7-di-argon-5 ugly-[1]&quot;bipyridin-7-amine

NH2 〇 將（外消旋）-3-溴-6,7-二氫-5/ί-[ 1]°比咬-7-醇（4.84 g，22.6 mmol)及異吲哚啉-1，3-二酮（3.66 g，24.9 mmol)溶解於 丁1^(13〇1111)中；接著在低於5°(：下依序添加三苯基膦（7.41 g，28·3 mmol)、偶氮二甲酸二第三丁酯（6.25 g，27.1 mmol)於THF(3.0 ml)中之溶液；接著在室溫下持續攪拌2〇 小時。在真空中濃縮反應混合物，得到粗產物（23.507 g)，藉由急驟層析（矽膠，100 g，含10%至50〇/〇 EtOAc之庚 〇 炫* )純化該粗產物’得到2-((外消旋）-3-演-6,7-二氫-5//-環 戊二烯并[b]吼啶-7-基）異吲哚琳-l，3-二酮（11.114 g，不 • 純）。將此中間物溶解於乙醇（140 ml)中，接著在授拌下添 加水合肼（3.01 g，2.95 ml ’ 75.1 mmol)，且加熱反應混合 物至回流。2小時後’將其傾倒至1 n NaOH(150 ml)中且 用CHsCIWxlOO ml)萃取。經MgSCU乾燥有機層，過濾且 在真空中濃縮’得到粗產物（8.845 g)，藉由急驟層析（矽 膠，100 g，含0%至20% MeOH之CH2C12)純化該粗產物， 160800.doc -63- 201245158 得到呈紫色油狀之標題化合物（丨· 8〇 g，3 7%)。MS: 2 1 3 .0 (MH+，IBr)。 [Cl 1-(2,2,2-三氟-乙醢胺基）_環丙烷甲酸（（外消旋）_3•溴_ 6,7-二氫-5/ί-【1]吡啶-7-基）-醢胺NH2 oxime (racemic)-3-bromo-6,7-dihydro-5/ί-[1]° ratio bit-7-alcohol (4.84 g, 22.6 mmol) and isoindoline-1,3 -dione (3.66 g, 24.9 mmol) was dissolved in butyl 1^(13〇1111); then triphenylphosphine (7.41 g, 28.3 mmol), azo was added sequentially below 5° (: A solution of di-tert-butyl dicarboxylate (6.25 g, 27.1 mmol) in THF (3.sub.3 mL). The crude product was purified by flash chromatography (100 g, 10% to 50 〇 / EtOAc EtOAc) to afford 2-((racemic)-3- -6,7- Hydrogen-5//-cyclopenta[b]acridin-7-yl)isoindolin-l,3-dione (11.114 g, not pure). This intermediate was dissolved in ethanol (140). In ml), hydrazine hydrate (3.01 g, 2.95 ml '75.1 mmol) was then added with stirring, and the reaction mixture was heated to reflux. After 2 hours, it was poured into 1 n NaOH (150 ml) with CHsCIWxlOO ml )extraction. The organic layer was dried <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; -63- 201245158 The title compound (丨·8〇g, 3 7%) was obtained as a purple oil. MS: 2 1 3 .0 (MH+, IBr). [Cl 1-(2,2,2-Trifluoro-acetamido)-cyclopropanecarboxylic acid ((racemic)_3•bromo-6,7-dihydro-5/ί-[1]pyridine-7 -yl)-guanamine

類似於針對製備中間物Α-1 [Β]所述之程序，（外消旋）-3_ 漠-6,7-二氫孖·以]吡啶_7_基胺已與1_(2,2,2_三氟乙醯胺 基）環丙烷*曱酸（中間物A-1 [A])偶合，得到呈灰色固體狀 之標題化合物。MS: 392.0 (MH+, IBr)。 中間物A-6 1-(2,2,2-三氟·乙醢胺基）環丙烷甲酸[(外消旋）_7_(4,4,5,5_ 四甲基-[1，3,2]二氧硼崠_2_基）_咣烷_4_基】-醢胺Similar to the procedure described for the preparation of the intermediate Α-1 [Β], (racemic)-3_ -6,7-dihydroanthracene]pyridyl-7-ylamine has been associated with 1_(2,2, Coupling of 2-trifluoroacetamido)cyclopropane* decanoic acid (Intermediate A-1 [A]) gave the title compound as a white solid. MS: 392.0 (MH+, IBr). Intermediate A-6 1-(2,2,2-trifluoroethylamino)cyclopropanecarboxylic acid [(racemic)_7_(4,4,5,5-tetramethyl-[1,3,2 Dioxaboron-2-yl)-decane_4_yl]-guanamine

[A](外消旋）-7-溴-咣烷_4-基胺 160800.doc -64 - 201245158[A] (racemic)-7-bromo-decane_4-ylamine 160800.doc -64 - 201245158

類似於針對製備中間物A-2 [B]及A-2 [C]所述之程序， 用二苯基磷醯基疊氮化物、含DBU之甲苯處理在60-70°C 下自7-漠-吱烷_4_酮與含硼氫化鈉之乙醇製備之（外消旋） -7-演-咬烧-4-醇，得到（外消旋）-4-疊氮基-7-溴-咬烷，其 隨後用含三苯基膦之THF/水還原，得到呈淡黃色油狀之標 題化合物。MS: 227 (M+，IBr)。 [B] l-(2,2,2-三氟-乙醢胺基）-環丙烷甲酸丨（外消旋）_7_ (4,4,5,5-四甲基二氧硼唓_2_基）_咣烷_4_基卜醯胺Similar to the procedure described for the preparation of intermediates A-2 [B] and A-2 [C], treatment with diphenylphosphonium azide, DBU-containing toluene at 60-70 ° C from 7- Preparation of (racemic)-4-azido-7-bromo by cyclohexane--4-one and sodium borohydride-containing ethanol (racemic) -7-de-battery-4-ol - The title compound is obtained as a light yellow oil. MS: 227 (M+, IBr). [B] l-(2,2,2-Trifluoro-acetamido)-cyclopropanecarboxylic acid hydrazine (racemic) _7_ (4,4,5,5-tetramethyldioxaboron_2_ Base) _ decane _4_ kibamine

類似於針對製備中間物A-1 [B]及A-1 [C]所述之程序， (外消旋）-7-溴-咣烷-4-基胺已與1-(2,2,2-三氟乙醯胺基）環 丙燒甲酸（中間物A-1 [A])偶合，得到1-(2,2,2-三氟-乙醯胺 基）_環丙烷甲酸（（外消旋）-7-溴-咣烷-4-基）-醯胺，其隨後 與 4,4,4，，4，，5,5,5’，5，-八甲基-2,2_-聯（1，3,2-二氧硼崠）反應， 得到呈淡黃色固體狀之標題化合物。MS: 453.2 (M-Η—；)。 中間物A-7 160800.doc -65- 201245158 l-(2,2,2-三氟-乙醯胺基）-環丙烷甲酸[(外消旋）-7-氟-5-(4,4,5,5-四曱基-[1,3,2]二氧硼冰-2-基）-茚滿-1-基]-醢胺Similar to the procedure described for the preparation of intermediates A-1 [B] and A-1 [C], (racemic)-7-bromo-decane-4-ylamine has been associated with 1-(2,2, 2-Trifluoroacetamido)cyclopropanecarboxylic acid (intermediate A-1 [A]) coupled to give 1-(2,2,2-trifluoro-acetamido)-cyclopropanecarboxylic acid (external Racemic)-7-bromo-nonan-4-yl)-guanamine, which is followed by 4,4,4,,4,,5,5,5',5,-octamethyl-2,2_- The reaction was carried out in the title compound (1,3,2-dioxaboron) to give the title compound as a pale yellow solid. MS: 453.2 (M-Η-;). Intermediate A-7 160800.doc -65- 201245158 l-(2,2,2-Trifluoro-acetamido)-cyclopropanecarboxylic acid [(racemic)-7-fluoro-5-(4,4) ,5,5-tetradecyl-[1,3,2]diboronium-2-yl)-indan-1-yl]-guanamine

[A】 1-(4-溴-2-氟-苯基）-3-氣-丙-1-酮[A] 1-(4-Bromo-2-fluoro-phenyl)-3- gas-propan-1-one

向4-溴-2-歡-苯曱酸（10 g，45.65 mmol)於苯（50 ml)中之 懸浮液中添加亞硫醯氯（7.8 m卜12.79 g’ 91.32 mmol)， 且加熱所得混合物至回流，維持12小時。蒸發亞硫醯氯， 用1,2-二氯乙烷（50 ml)稀釋反應混合物且在室溫下添加至 氣化鋁（5.7 g，42.53 mmol)於1,2-二氯乙烷（50 ml)中之漿 液中。使乙稀鼓泡通過反應混合物，持續5小時，且在室 溫下再攪拌反應混合物2小時。接著用2 N HC1(5 0 ml)淬滅 *亥反應混合物。分離各層。用1〇〇 ml二氣甲烷萃取水相兩 次。用飽和碳酸氫鈉溶液（50ml)、水（5〇ml)依序洗滌經合 併之有機相。接肩 發’得到粗產物， 接著經NaJO4乾燥該有機相且在減壓下蒸 物’隨後藉由管柱層析(矽膠，〇_5〇/。乙酸乙 ，0-5%乙酸乙 160800.doc • 66 - 201245158To a suspension of 4-bromo-2-indolyl benzoic acid (10 g, 45.65 mmol) in benzene (50 ml) was added sulphur chloride (7.8 m, 12.79 g, 91.32 mmol) and the mixture was heated. Until reflux, maintain for 12 hours. Ethyl sulfite chloride was evaporated, and the reaction mixture was diluted with 1,2-dichloroethane (50 ml) and added to a gasified aluminum (5.7 g, 42.53 mmol) at 1,2-dichloroethane (50) at room temperature. In the slurry in ml). Ethyl blister was bubbled through the reaction mixture for 5 hours and the reaction mixture was stirred at room temperature for additional 2 hours. The mixture was then quenched with 2 N HCl (50 mL). Separate the layers. The aqueous phase was extracted twice with 1 ml of methane. The combined organic phases were washed sequentially with saturated sodium bicarbonate solution (50 ml) and water (5 mL). The shoulder was sent 'to obtain the crude product, then the organic phase was dried over NaJO4 and the product was evaporated under reduced pressure' followed by column chromatography (gelatin, 〇5〇/. acetic acid, 0-5% acetic acid, 160,800.doc) • 66 - 201245158

之標題化合物。 [B】5-溴-7-1-茚滿-1-嗣The title compound. [B]5-Bromo-7-1-茚满-1-嗣

在 130C 下，向A1C13(37.5 g，282.48 mmol)與 NaCl(ll 〇 g，l88.32 mmol)之混合物中添加苯基）_3_氣_ 丙-1-酮（5 g，18.83 mmol)。使反應溫度緩慢增至18(rc且 保持1小時。將其冷卻’將混合物傾倒至冰中且用乙酸乙 醋（2x100 ml)萃取兩次。經]^&amp;28〇4乾燥經合併之乙酸乙酯 相且蒸發’得到粗產物’藉由管柱層析（矽膠，5-1 〇%乙酸 乙酯/己烷）純化該粗產物，得到2.4 g(55%)呈棕色固體狀 之標題化合物。MS: 229.2 (MH+，IBr)。 [C】（外消旋）-5-溴-7-氟-茚滿-1-基胺To a mixture of A1C13 (37.5 g, 282.48 mmol) and NaCl (ll 〇 g, l88.32 mmol) was added phenyl)_3_ gas-propan-1-one (5 g, 18.83 mmol) at 130C. The reaction temperature was slowly increased to 18 (rc and kept for 1 hour. Cooling it). The mixture was poured into ice and extracted twice with ethyl acetate (2 x 100 ml). The combined acetic acid was dried with &lt;2&gt; The title compound was obtained as a brown solid. MS: 229.2 (MH+, IBr) [C] (racemic)-5-bromo-7-fluoro-indan-1-ylamine

類似於針對製備中間物A-4 [A]所述之程序，在回流下 使5-溴-7-氟-茚滿-1-酮與氰基硼氫化鈉及乙酸銨在2-丙醇 中反應，得到呈淡黃色油狀之標題化合物。MS: 228 (ΜΗ·， IBr) 。 [D] 1-(2,2,2-三氟-乙醯胺基）-環丙烷甲酸[(外消旋）-7-氟-5- 160800.doc -67- 201245158 (4,4,5,5-四甲基-[ny二氧硼崠_2_基）·茚滿^-基卜醢胺Similar to the procedure described for the preparation of intermediate A-4 [A], 5-bromo-7-fluoro-indan-1-one was reacted with sodium cyanoborohydride and ammonium acetate in 2-propanol under reflux. Reaction gave the title compound as a pale yellow oil. MS: 228 (ΜΗ·, IBr). [D] 1-(2,2,2-Trifluoro-acetamido)-cyclopropanecarboxylic acid [(racemic)-7-fluoro-5-160800.doc -67- 201245158 (4,4,5 ,5-tetramethyl-[ny-dioxaboron-2-yl)·茚满^-gibamine

類似於針對製備中間物A-1 [B]及A-1 [C]所述之程序， (外消旋）-5-溴-7-氟-茚滿-1-基胺已與1-(2,2,2-三氟乙醯胺 基）環丙烷甲酸（中間物A-1 [A])偶合，得到i-UJ，2-三氟-乙醯胺基）-環丙烷甲酸（（外消旋）-5-溴_7_氟_茚滿_1_基醯 胺，其隨後與4,4,4，，4,，5,5,5’，5’-八甲基-2,2_聯（1，3,2_二氧 硼崠）反應，得到呈淡黃色非晶形固體狀之標題化合物。 MS: 455.2 (M-Η·)。 中間物A-8 1-(2,2,2-三氟-乙醯胺基）_環丙烷甲酸【（外消旋）_M4,4,5,5-四甲基-【1，3,2】二氧硼崠-2-基）-2,3-二氫-苯并呋喃_3_基]-醯胺Similar to the procedure described for the preparation of intermediates A-1 [B] and A-1 [C], (racemic)-5-bromo-7-fluoro-indan-1-ylamine has been associated with 1-( Coupling of 2,2,2-trifluoroacetamido)cyclopropanecarboxylic acid (intermediate A-1 [A]) gives i-UJ, 2-trifluoro-acetamido)-cyclopropanecarboxylic acid (outer Racemic)-5-bromo-7-fluoro_indan_1_ylamine, which is followed by 4,4,4,,4,5,5,5',5'-octamethyl-2, Reaction with 2-(1,3,2-dioxaboron) gave the title compound as a pale-yellow solid. MS: 455.2 (M- Η·). Intermediate A-8 1-(2,2 ,2-trifluoro-acetamido)-cyclopropanecarboxylic acid [(racemic)_M4,4,5,5-tetramethyl-[1,3,2]dioxaboroin-2-yl)- 2,3-dihydro-benzofuran_3_yl]-guanamine

F FF F

[A】（外消旋）-6-演-2,3-二氫-苯并呋喃-3-醇 160800.doc -68- 201245158[A](racemic)-6-actino-2,3-dihydro-benzofuran-3-ol 160800.doc -68- 201245158

在0°c下，向6_溴-苯并呋喃-3-酮（10.5g’ 49 28 mm〇1)於 曱醇（100 ml)中之溶液中添加g，6107 mmol)。接著在室溫下攪拌反應混合物2小時。隨後用飽和 氣化銨溶液（50 mi)淬滅該反應混合物且用乙酸乙酯（2χ5〇 ml)萃取兩次。經NhSCU乾燥經合併之有機相且在減壓下 蒸發，得到9_75 g(92%)呈無色液體狀之標題化合物。 [B】（外消旋）-6-溴-2,3-二氫-苯并呋喃-3-基胺To a solution of 6-bromo-benzofuran-3-one (10.5 g' 49 28 mm 〇1) in decyl alcohol (100 ml) was added g, 6107 mmol). The reaction mixture was then stirred at room temperature for 2 hours. The reaction mixture was then quenched with a saturated aqueous solution of EtOAc (EtOAc) (EtOAc) The combined organic phase was dried with EtOAc (EtOAc m. [B](racemic)-6-bromo-2,3-dihydro-benzofuran-3-ylamine

NH2 類似於針對製備中間物A_2 [B]及A-2 [C]所述之程序， 用二苯基碟醯基疊氮化物、含DBU之曱苯處理（外消旋）-6-O 漠-2，3 - 一風-苯并咬01¾ - 3 -醇，得到（外消旋）-3 -疊氮基-6 - 溴-2,3-二氫-苯并呋喃，其隨後用含三苯基膦之THF/水還 - 原’得到呈淡黃色油狀之標題化合物。MS: 213 (M+， IBr)。 【C] 1-(2,2,2-三氟-乙酿胺基）環丙炫甲酸[(外消旋）-6-(4,4,5,5-四甲基-[H2】二氧硼崠_2_基）-2,3-二氫_苯并呋 味-3_基卜酿胺 160800.doc -69- 201245158NH2 is similar to the procedure described for the preparation of intermediates A_2 [B] and A-2 [C], treated with diphenyl sulfonium azide, DBU-containing fluorene (racemic)-6-O -2,3 - a wind-benzophenone 013⁄4 - 3 -alcohol, giving (racemic)-3 -azido-6 -bromo-2,3-dihydro-benzofuran, which is subsequently used in three The THF/water of phenylphosphine was also obtained as the title compound as a pale yellow oil. MS: 213 (M+, IBr). [C] 1-(2,2,2-Trifluoro-ethinyl)cyclopropanic acid [(racemic)-6-(4,4,5,5-tetramethyl-[H2] II Boron bromide_2_yl)-2,3-dihydro-benzofuran-3-yl bromide 160800.doc -69- 201245158

FF

F 類似於針對製備中間物A-l [B]及A-l [C]所述之程序， (外消旋）-6-溴_2,3-二氫-苯并呋喃-3-基胺已與l-(2,2,2-三 氟乙醯胺基）環丙燒曱酸（中間物A-1 [A])偶合，得到1 _ (2,2,2-三氟-乙醯胺基）_環丙烷甲酸（（外消旋）-6-溴-2,3-二 氫-苯并呋喃-3-基）-醯胺，其隨後與4,4,4'，4’，5,5,5|，5’-八曱 基-2,2，-聯（1，3,2-二氧硼崠）反應，得到呈淡棕色固體狀之 標題化合物。MS: 439.2 (M-H_)。 中間物A-9F is similar to the procedure described for the preparation of the intermediates Al [B] and Al [C], (racemic)-6-bromo-2,3-dihydro-benzofuran-3-ylamine has been combined with l- Coupling of (2,2,2-trifluoroacetamido)cyclopropanoic acid (intermediate A-1 [A]) to give 1 _ (2,2,2-trifluoro-acetamido) Cyclopropanecarboxylic acid ((racemic)-6-bromo-2,3-dihydro-benzofuran-3-yl)-decylamine, which is subsequently followed by 4,4,4',4',5,5, Reaction with 5|,5'-octadecyl-2,2,-(1,3,2-dioxaboron) gave the title compound as a pale brown solid. MS: 439.2 (M-H_). Intermediate A-9

1-(2,2,2-三氟-乙醢胺基）-環丙烷甲酸[(外消旋）-6-(4,4,5,5-四甲基_[1，3,2]二氧硼咮-2-基）-2,3_二氫-苯并【办】嘍吩 基】-醯胺 [A】（外消旋）-6-溴-2,3-二氫-苯并[A]嘍吩基胺1-(2,2,2-trifluoro-acetamido)-cyclopropanecarboxylic acid [(racemic)-6-(4,4,5,5-tetramethyl-[1,3,2] Dioxaboron-2-yl)-2,3-dihydro-benzo[indenyl]-p-amine [A] (racemic)-6-bromo-2,3-dihydro-benzene And [A] porphinylamine

160800.doc -70- 201245158 類似於針對製備中間物A-8 [A]、中間物a-2 [B]及A-2 [C]所述之程序’使6_溪_苯并[6]α塞吩_3-酮與含棚氫化納之 乙醇反應，得到（外消旋）-6-溴-2,3-二氫-苯并[6]噻吩_3-醇，其隨後與二苯基磷醯基疊氮化物、含DBU之曱苯反 應’得到（外消旋）-3-疊氮基-6-溴-2,3-二氫-苯并μ]噻吩， 其接著用含三苯基膦之THF/水還原，得到呈淡黃色油狀之 標題化合物。MS: 229 (M+，IBr)。 [B] 1-(2,2,2-三氟-乙醢胺基）-環丙烷甲酸[(外消旋）_6_ (4,4，S，S-四甲基-[^，之】二氧硼崠_2_基）_2,3_二氫苯并【6】嘆 吩-3·基卜醢胺160800.doc -70- 201245158 Similar to the procedure described for the preparation of intermediates A-8 [A], intermediates a-2 [B] and A-2 [C] '6_溪_Benz[6] Reaction of α-cetin-3-ketone with ethanol containing sodium hydride to obtain (racemic)-6-bromo-2,3-dihydro-benzo[6]thiophene-3-ol, which is followed by diphenyl Reaction of phosphinyl azide and benzene with DBU to give (racemic)-3-azido-6-bromo-2,3-dihydro-benzo[mu]thiophene, which is followed by three Reduction of the phenylphosphine in THF/water afforded the title compound. MS: 229 (M+, IBr). [B] 1-(2,2,2-Trifluoro-acetamido)-cyclopropanecarboxylic acid [(racemic)_6_ (4,4,S,S-tetramethyl-[^,] 2 Oxyborium 崠_2_yl)_2,3_dihydrobenzo[6] sinter-3-3 carbamide

Ο FΟ F

〇 類似於針對製備中間物A_1 [B]及[c]所述之程序 (外消旋）-6-溴-2,3-二氫-苯并[6]噻吩-3-基胺已與u(2 2 2 三敗乙醯胺基）環丙烷甲酸（中間物A_1 [A])偶合，〜 1于到1 _ (2,2,2-三氟-乙醯胺基）_環丙烷曱酸（（外消旋）_6•壤々3 一 氣-笨并[6]噻吩-3-基）-醯胺，其隨後與4,4,4，，4，,5 5 9 c, ，5 -八 甲基-2,2’-聯（1，3,2-二氧硼崠）反應，得到呈黃色油狀之俨 題化合物。MS: 455.4 (M-Η-)。 160800.doc •71· 201245158 中間物A-10 1-(2,2,2-三氟-乙醢胺基）_環丙烷甲酸（（外消旋）-5_溴-1甲 基-茚滿-1 -基）-酿胺〇 is similar to the procedure described for the preparation of intermediates A_1 [B] and [c] (racemic)-6-bromo-2,3-dihydro-benzo[6]thiophen-3-ylamine (2 2 2 tri-acetamido) cyclopropanecarboxylic acid (intermediate A_1 [A]) coupled, ~1 to 1 _ (2,2,2-trifluoro-acetamido)-cyclopropanoic acid ((racemic) _6 • 々 3 3 gas-stupid [6] thiophen-3-yl)-guanamine, which is followed by 4, 4, 4, 4, 5 5 9 c, , 5 - 8 Reaction with methyl-2,2'-linked (1,3,2-dioxaboron) gives the title compound as a yellow oil. MS: 455.4 (M-Η-). 160800.doc •71· 201245158 Intermediate A-10 1-(2,2,2-Trifluoro-acetamido)-cyclopropanecarboxylic acid ((racemic)-5_bromo-1methyl-indane) -1 -yl)-bristamine

[A】（外消旋）-5-演小[1，3】二噻烷_2_基_節滿小醇[A] (racemic)-5-small [1,3]dithiane_2_yl_small alcohol

在-30°C 下，向 1，3-二噻烷（1.82 g，14.7 mm〇i)於無水 THF(20 ml)中之溶液中逐滴添加正丁基鋰（8 62 m卜13 8 mmol，1.6 Μ，於己烷中）。在—^乞下攪拌所得混合物2小 時。接著，逐滴添加5-溴_2S3-二氫-1//-茚-1-酮（2 g，9 19 mmol)於無水THF(24 ml)中之溶液，同時維持溫度介於 1 5 C與-6 C之間。添加完成後，使棕色溶液升溫至〇它， 接著儲存於冰箱中隔夜。接著，添加丨N HC1且用***萃 取棕色混合物兩次。用鹽水洗滌經合併之有機層，經 NajCU乾燥且蒸發。藉由層析（矽膠；庚烷/Et〇Ac %: 75:25)純化剩餘殘餘物，獲得呈淡黃色膠狀之標題化合物 (2.167 g ’ 71%)。MS·· 330.1 [M+H]+。 160800.doc •72· 201245158 [BJ 2-(5-溴·茚滿亞基）_[]t，3】二噻烷To a solution of 1,3-dithiane (1.82 g, 14.7 mm 〇i) in anhydrous THF (20 ml) was added n-butyllithium (8 62 m b 13 8 mmol) at -30 °C , 1.6 Μ, in hexane). The resulting mixture was stirred under a period of 2 hours. Next, a solution of 5-bromo-2S3-dihydro-1//-indol-1-one (2 g, 9 19 mmol) in dry THF (24 ml) was added dropwise while maintaining a temperature between 1 and 5 C. Between -6 C. After the addition was complete, the brown solution was allowed to warm to sputum and then stored in the freezer overnight. Next, 丨N HCl was added and the brown mixture was extracted twice with diethyl ether. The combined organic layers were washed with brine, dried over Na EtOAc and evaporated. The residue was purified by chromatography (jjjjjjjjjjj MS·· 330.1 [M+H]+. 160800.doc •72· 201245158 [BJ 2-(5-bromoindanyl)_[]t,3]dithiane

將（外消旋）-5-溴-1-[ι,3]二噻烷_2_基_茚滿_丨_酵（215 g， 6.49 mmol)及單水合對甲苯磺酸（3〇9 mg，162 mm〇1)於苯 〇 (3〇 ml)中之混合物加熱至回流，維持2小時，使用迪恩-斯 達克戴留器移除水。使棕色溶液冷卻至室溫且用飽和 NaHC〇3溶液稀釋。分離各層，且用鹽水洗滌有機層，經 NhSO4乾燥且蒸發。獲得呈棕色膠狀之標題化合物（2〇24 g，99%)且其未經純化即用於下一反應步驟。 [C](外消旋）_5_溴-茚滿甲睃(racemic)-5-bromo-1-[ι,3]dithiane_2_yl_茚满_丨_ leaven (215 g, 6.49 mmol) and p-toluenesulfonic acid monohydrate (3〇9 A mixture of mg, 162 mm 〇 1) in phenylhydrazine (3 〇 ml) was heated to reflux for 2 hours and water was removed using a Dean-Stark holder. The brown solution was allowed to cool to room temperature and diluted with a saturated NaHC solution. The layers were separated and the organic layer was washed with brine, dried over NaH. The title compound (2 〇 24 g, 99%) was obtained as a brown gum. [C](racemic)_5_bromo-茚满甲睃

〇 向2-(5-演-節滿小亞基）_[13]二噻烷（2 〇2 g6牦mm〇i) 於乙酸（34 ml)中之混合物中添加37%腿⑴叫。添加 後’加熱棕色混合物至回流’維持3小時；接著，使反應 混合物冷卻以溫且濃縮至乾燥，使料苯作 容 劑以移除乙酸及水。重複此過 ， 人猎由層析（矽膠； 160800.doc -73- 201245158 CHaCh/EtOAc 100:0-0:1 〇〇)純化剩餘棕色油狀物，獲得呈 淡棕色固體狀之標題化合物（1.335 g，86%)。MS: 238.6 [D](外消旋）-5-溴-茚滿-i_甲酸甲酯37 Add 37% leg (1) to a mixture of 2-(5-actual-small-small subunit)_[13]dithiane (2 〇2 g6牦mm〇i) in acetic acid (34 ml). After the addition, the mixture was heated to reflux for 3 hours; then, the reaction mixture was cooled to warmness and concentrated to dryness, and benzene was used as a solvent to remove acetic acid and water. The title compound (1.335) was obtained as a pale brown solid (yield: EtOAc, EtOAc: EtOAc: g, 86%). MS: 238.6 [D] (racemic)-5-bromo-indan-i-formic acid methyl ester

用含4 N HC1之二噁烷（15 ml)處理（外消旋）_5_溴-茚滿-l 甲酸（1.326 g，5_5 mmol)於MeOH(55 ml)中之溶液，且在 回流下搜拌混合物7小時。使黃色溶液冷卻至室溫且移除 所有揮發物。藉由層析（矽膠；庚烷/Et〇Ac 95:5)純化剩餘 掠色油狀物’獲得呈淡黃色油狀之標題化合物（1.31 g， 93%) 〇 【E】（外消旋）-5-溴-1-甲基-茚滿-1-甲酸甲酯A solution of (racemic) _5_bromo-indan-l-formic acid (1.326 g, 5_5 mmol) in MeOH (55 ml) eluted with EtOAc (EtOAc) Mix the mixture for 7 hours. The yellow solution was allowed to cool to room temperature and all volatiles were removed. The title compound (1.31 g, 93%) was obtained as a pale yellow oil (yield: EtOAc) -5-bromo-1-methyl-indan-1-carboxylic acid methyl ester

在-78°C下，將雙（三曱基矽烷基）胺基鋰（6,16 ml，6 16 mmol，1 M溶液，於THF中）逐滴添加至（外消旋）_5溴一茚 滿，1-甲酸曱酯31 g，5.14 mmol)於無水THF(25 ml)中之 溶液中。添加完成後，在-78°C下攪拌溶液45分鐘。接 160800.doc 74· 201245158 著’添加蛾甲烧（2.19 g ’ 959 μΐ，15.4 mmol)，使溶液升 溫至室溫且攪拌48小時。藉由添加飽和NH4C1溶液淬滅反 應物且用EtOAc萃取兩次。用鹽水洗滌經合併之有機層， 經NajCU乾燥且蒸發。藉由層析（矽膠；庚烷/EtOAc 95:5) 純化剩餘黃色油狀物，獲得呈黃色油狀之標題化合物 (1.319 g，95%)。MS: 269.2 [M+H]+。Lithium bis(tridecyldecylalkyl)amine (6,16 ml, 6 16 mmol, 1 M solution in THF) was added dropwise to (racemic) _5 bromide at -78 °C. </ RTI> </ RTI> </ RTI> <RTIgt; </RTI> <RTIgt; After the addition was completed, the solution was stirred at -78 ° C for 45 minutes. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The reaction was quenched by the addition of saturated aq. The combined organic layers were washed with brine, dried over Naj EtOAc and evaporated. The title compound (1.319 g, EtOAc) MS: 269.2 [M+H]+.

[F】（外消旋）-5-溴-1-甲基-茚滿-1-甲酸 HO[F](racemic)-5-bromo-1-methyl-indan-1-carboxylic acid HO

〇〇

Br 將（外消旋）-5-溴-1-甲基-茚滿-i_甲酸甲酯（1.3 18 g，4.9 mmol)及三甲基矽醇化鉀（3 _14 g，24 5 mmol)於無水 THF(25 ml)中之溶液在回流下攪拌1小時。使反應混合物 冷卻至室溫，添加水，且用第三丁基甲基醚萃取混合物兩 次。藉由添加1 N HC1將水層之pH值小心調整至3，且用 EtOAc萃取水層兩次。用鹽水洗滌經合併之Et〇Ac層，經 NaaSCU乾燥且蒸發。將甲苯添加至剩餘殘餘物中且蒸發其 以移除水。獲得呈淡黃色固體狀之標題化合物（1 2〇4 g， 96%)。MS: 252.7 [M-H]、 [G](外消旋）-5-溴-1-甲基_茚滿小基胺Br (racemic)-5-bromo-1-methyl-indan-i-formic acid methyl ester (1.3 18 g, 4.9 mmol) and potassium trimethylnononate (3 _14 g, 24 5 mmol) The solution in anhydrous THF (25 ml) was stirred at reflux for 1 hour. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted twice with tri-butyl methyl ether. The pH of the aqueous layer was carefully adjusted to 3 by addition of 1 N EtOAc and aqueous layer was extracted twice with EtOAc. The combined Et 〇 Ac layer was washed with brine, dried over Naa SCU and evaporated. Toluene was added to the remaining residue and evaporated to remove water. The title compound (1 2 〇 4 g, 96%) was obtained as a pale yellow solid. MS: 252.7 [M-H], [G] (racemic)-5-bromo-1-methyl-indanylamine

160800.doc •75· 201245158 向（外消旋）-5-溴-1-甲基-茚滿-1-曱酸（1.197 g，4.69 mmol)於無水甲苯（65 ml)中之溶液中添力口三乙胺（570 mg， 475 μΐ，5.63 mmol)及二苯基填酿基疊氮化物（1.33 g，1.04 ml，4.69 mmol)，且加熱無色溶液至回流，維持3小時。 冷卻至〇°C後，添加三曱基矽醇化鈉（9.38 ml，9.38 mmol ’ 1 Μ溶液，於THF中），且在室溫下攪拌混合物3〇分 鐘。用5°/。檸檬酸（1 〇〇 ml)淬滅反應物之後，藉由添加3 Ν NaOH將pH值調整至12-13，且用CH2C12萃取混合物三次。 用鹽水洗蘇經合併之有機層，經Na2S04乾燥且蒸發。將剩 餘粗物質分配於0.1 N HC1與***之間，且用乙鍵萃取水 層。藉由添加0.1 N NaOH將水層之pH值調整至12，且用 ci^ci2萃取水層三次。用鹽水洗務經合併之層，經 NhSCU乾燥且蒸發，獲得呈淡黃色油狀之標題化合物（963 mg，910/〇)。MS: 209.1 [M+H-NH3]+ 〇 [H] 1-(2,2,2-三氟·乙醢胺基）_環丙烷甲酸（（外消旋溴^ 甲基-茚滿-1-基）-酿胺160800.doc •75· 201245158 Adding to a solution of (racemic)-5-bromo-1-methyl-indan-1-decanoic acid (1.197 g, 4.69 mmol) in anhydrous toluene (65 ml) Triethylamine (570 mg, 475 μΐ, 5.63 mmol) and diphenyl-filled azide (1.33 g, 1.04 ml, 4.69 mmol), and the colorless solution was heated to reflux for 3 h. After cooling to 〇 ° C, sodium tridecyl sulfonate (9.38 ml, 9.38 mmol y 1 Μ solution in THF) was added, and the mixture was stirred at room temperature for 3 Torr. Use 5°/. After quenching the reaction with citric acid (1 〇〇 ml), the pH was adjusted to 12-13 by adding 3 NaOH, and the mixture was extracted three times with CH2C12. The combined organic layers were washed with brine, dried over Na 2 EtOAc and evaporated. The remaining crude material was partitioned between 0.1 N HCl and diethyl ether and the aqueous layer was extracted with ethyl ether. The pH of the aqueous layer was adjusted to 12 by the addition of 0.1 N NaOH and the aqueous layer was extracted three times with ci. The combined layers were washed with EtOAc EtOAc EtOAc m. MS: 209.1 [M+H-NH3]+ 〇[H] 1-(2,2,2-trifluoroethylamino)-cyclopropanecarboxylic acid ((racemic bromo-methyl-indane-1) -base)-bristamine

類似於針對製備中間物^ [B]所述之程序，（外消旋）_5 溪-1-曱基-節滿+基胺已〜(2,2,2_三氟乙醯胺基）環丙劳 甲酸(中間物Μ [A])偶合，得到呈淡標色固體狀之標題… 160800.doc -76- 201245158 合物。MS: 402.9 (M-H·，IBr)。 中間物A-ll ⑻-5_【5_m2_(5_甲基七，24]嗓二〇基卜苯基]節 滿-1 -基胺Similar to the procedure described for the preparation of intermediates [B], (racemic) _5 xi-1-indenyl-------amine-~(2,2,2-trifluoroacetamido) ring Propionate (intermediate Μ [A]) is coupled to give the title of a pale solid (160800.doc -76- 201245158). MS: 402.9 (M-H·, IBr). Intermediate A-ll (8)-5_[5_m2_(5_methyl-7,24]嗓dimethylphenyl)]-1-1-amine

〇 [Α】(⑻-5-溴-節滿小基卜胺基甲酸第三丁酯〇 [Α]((8)-5-bromo-supplemented tributyl butyl amide

ηνΆ 政:） 〇 將二碳酸二第三了酿（4.7 §，2ll6 mmol)及⑻_5冬節 滿-1-基胺（中間物A_2 [c])a8l g，18〇 mm〇l)溶解於二嚼 烷（4〇_〇 ml)中；接著，在攪拌下添加碳酸氫鈉（3 32 g， 39.5 mmol)於水（1〇 mi)中之溶液，且在室溫下繼續攪拌 小犄。接著用NaOH(5 N，20 ml)處理反應混合物，且繼續 劇烈授拌90分鐘（BOGO分解p接著將反應混合物傾倒至 H20(1〇〇 ml)中且用 EtOAc(2x50 ml)萃取。經 MgS〇4 乾燥有 機層，過濾且在真空中濃縮，得到粗產物（5.690 g)，藉由 急驟層析（矽膠，20 g，含0%至20% EtOAc之庚烷）純化該 160800.doc -77- 201245158 粗產物，得到呈無色固體狀之標題化合物（5.31 g，95%)。ηνΆ 政:) 〇 Dicarbonate second brewing (4.7 §, 2ll6 mmol) and (8) _5 winter festival full-1-amine (intermediate A_2 [c]) a8l g, 18〇mm〇l) dissolved in two Cetane (4 〇 〇 ml); then, a solution of sodium bicarbonate (3 32 g, 39.5 mmol) in water (1 〇mi) was added with stirring, and stirring was continued at room temperature. The reaction mixture was then treated with NaOH (5 N, 20 mL) and EtOAc (EtOAc) (EtOAc (EtOAc) (EtOAc) The organic layer was dried <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> The title compound (5.31 g, 95%).

[】{( ) 5 [5-氣_3_象-2-(5-甲基-[1，2,4】嚼二咬_3-基）-苯 基l·節滿-1-基卜胺基甲睃第三丁酯[]{( ) 5 [5-gas_3_icon-2-(5-methyl-[1,2,4] chew two bites_3-yl)-phenyl l·feet-1-base Aminoguanidine tert-butyl ester

類似於針對製備中間物A-1 [C]及實例5所述之程序， ((S)-5-漠-節滿-^基）_胺基曱酸第三丁酯已與 4,4,4’，4’，5,5,5’，5’-八曱基 _2,2，_聯（1，3,2_二氧硼崠）反應，得 到[(S)-5-(4,4,5,5-四曱基 _[1,3,2]二氧硼嗱-2-基）-茚滿-1-基]-胺基曱酸第三丁酯’其與3_(2_溴_4_氣_6_氟_苯基）_5_ 甲基-[1，2,4]»惡二唾（中間物Β·2)進一步反應，得到呈黃色 非晶形固體狀之標題化合物。MS: 444 2 (MH+，1C1)。 [C] (S)-5-[5-氣-3-氟·2·(5_ 甲基·嚼二唑 _3_基）_ 苯基】_ 茚滿-1-基胺Similar to the procedure described for the preparation of intermediates A-1 [C] and Example 5, ((S)-5-in----------------- 4',4',5,5,5',5'-octadecyl_2,2,_(1,3,2-dioxaboron) reaction gives [(S)-5-(4 ,4,5,5-tetradecyl_[1,3,2]dioxaboron-2-yl)-indan-1-yl]-aminodecanoic acid tert-butyl ester' with 3_(2 Further, the title compound is obtained as a yellow amorphous solid. mp. MS: 444 2 (MH+, 1C1). [C] (S)-5-[5-Gas-3-fluoro.2·(5-methyl·choxadiazole _3_yl)_phenyl]_indan-1-ylamine

160800.doc -78- 201245158 將{(S)-5-[5-氯-3-氟-2_(5_ 曱基 _π，2,4]噁二唑 _3_ 基）_ 苯 基]-茚滿-ι-基}-胺基曱酸第三丁酯（0 22 g，496 μιη〇1)溶解 於CH2Cl2(l〇.〇 ml)中；接著，在攪拌下添加9〇0/〇 2,2,2-三 Ο 氟乙酸（628 μΐ ’ 1〇〇。/〇三氟乙酸/水=9:1(¥~))，且在室溫下 繼續攪拌25小時。接著將反應混合物傾倒至飽和k2c〇3水 溶液中且用CH2C12萃取兩次。經MgS04乾燥有機層，過濾 且在真空中濃縮，得到粗產物（0.1 73 g)，藉由急驟層析（矽 膠，CH2Cl2/MeOH)純化該粗產物，得到呈淡黃色油狀之 標題化合物（〇·129 g ’ 76%)。MS: 344·1 (MH+，1C1) ° 中間物A-12 (3-US)-5-【5-氣-3-氟-2-(5-甲基-[1，2,4]噁二唑-3-基）-苯基]-茚滿基胺甲酿基}-氧雜環丁烧-3-秦）-胺基甲酸9好-苐-9- 基甲酯160800.doc -78- 201245158 will {(S)-5-[5-chloro-3-fluoro-2_(5_ fluorenyl-π,2,4]oxadiazole_3_yl)-phenyl]-indole -ι-yl}-aminobutyl citrate (0 22 g, 496 μηη〇1) was dissolved in CH 2 Cl 2 (l〇.〇ml); then, 9 〇 0 / 〇 2, 2 was added with stirring. 2-trifluoroacetic acid (628 μΐ '1〇〇./〇 trifluoroacetic acid/water = 9:1 (¥~)), and stirring was continued for 25 hours at room temperature. The reaction mixture was then poured into a saturated aqueous solution of k2c3 and extracted twice with CH2C12. The organic layer was dried <RTI ID=0.0></RTI>jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj · 129 g '76%). MS: 344·1 (MH+, 1C1) ° Intermediate A-12 (3-US)-5-[5-gas-3-fluoro-2-(5-methyl-[1,2,4] Zyridin-3-yl)-phenyl]-indanylamine-yl}}-oxetan-3-yl)-aminocarboxylic acid 9-purine-9-ylmethyl ester

[A] 3-(9丑-苐-9-基甲氧基幾胺基）-氧雜環丁烧_3_甲後[A] 3-(9 ugly-fluoren-9-ylmethoxyamino)-oxeane _3_A

160800.doc -79- 201245158 將2,5-二側氧基吡咯啶基碳酸（9孖_苐_9_基）甲酯（3·2 g，9.5 mmol)於二噁烷（30 m〇中之溶液添加至3胺基-氧雜 環丁烷-3-甲酸（1.17 g，1〇 mm〇i)及碳酸鉀（2 76 g，2〇 〇 mmol)於水（30 ml)中之溶液中。在室溫下攪拌淡黃色不透 明溶液75分鐘。在該段時間内，沈澱出白色固體。用水稀 釋混合物且用***萃取兩次。白色固體不溶解且因此保持 處於水層中，藉由添加1 N HC1將該水層酸化至pH 2且用 EtOAc萃取三次。用鹽水洗滌經合併之Et〇Ac層，經160800.doc -79- 201245158 2,5-di-side oxypyrrolidinyl carbonate (9孖_苐_9_yl)methyl ester (3·2 g, 9.5 mmol) in dioxane (30 m〇) The solution was added to a solution of 3 amino-oxetane-3-carboxylic acid (1.17 g, 1 〇mm〇i) and potassium carbonate (2 76 g, 2 〇〇mmol) in water (30 ml). The pale yellow opaque solution was stirred for 75 minutes at room temperature. During this time a white solid precipitated. The mixture was diluted with water and extracted twice with diethyl ether. White solids did not dissolve and thus remained in the aqueous layer by adding 1 The aqueous layer was acidified to pH 2 and extracted three times with EtOAc. The combined Et.

NhSO4乾燥且蒸發。獲得呈白色固體狀之粗標題化合物且 其未經進一步純化即使用。 [B] (3-{(S)-5-[5-氣-3-氟-2_(5-曱基-[^，訇噁二唑 _3_ 基）苯 基】-茚滿-1-基胺甲醯基}-氧雜環丁烷基）胺基甲酸9孖_ 苐-9-基甲醋NhSO4 was dried and evaporated. The crude title compound was obtained as a white solid and was used without further purification. [B] (3-{(S)-5-[5-Gas-3-fluoro-2_(5-fluorenyl-[^,oxadiazole-3-yl)phenyl]-indan-1-yl Aminomethyl}-oxetanyl)urethane 9孖_苐-9-yl acetate

CICI

在室溫下’向3-(9//-苐-9-基甲氧基羰胺基）_氧雜環丁 院-3-甲酸（u g，5.01 mm〇i)於無水dmf(5〇 〇 ml)中之溶 液中添加#-(3-二甲基胺基丙基）乙基碳化二亞胺鹽酸鹽 (l6〇 g’ 8.35 mmol)及水合 1-羥基苯并***（0.95 g，62() 160800.doc -80- 201245158 mmol)。攪拌所得無色溶液ι〇分鐘，隨後添加（s)-5-[5-氣 -3-氟-2-(5-甲基-[1，2,4]噁二唑-3-基）-苯基]-茚滿-1-基胺 (1.64 g ’ 4.77 mmol ’ 中間物 A-11)於無水 DMF(2.0 ml)中之 Ο 溶液。在室溫下挽拌此混合物20小時。接著添加水，用飽 和KaCO3溶液將pH值調整至9，且用MeCl2萃取混合物兩 次。用水及鹽水洗滌經合併之有機層，經MgS04乾燥且蒸 發。藉由層析（石夕膠；MeCl2/MeOH 100:0至98:2%)純化剩 餘淡棕色泡沫狀物’且獲得呈灰白色泡沫狀之標題化合物 (3.17 g，100%)。MS: 665.2 (MH+，1C1)。 中間物B-1 1-漠-3,5-二氣-2-(2,2-二氟-乙氧基）_苯'To 3-(9//-苐-9-ylmethoxycarbonylamino)-oxetan-3-carboxylic acid (ug, 5.01 mm〇i) in anhydrous dmf (5 室温 at room temperature) #-(3-Dimethylaminopropyl)ethylcarbodiimide hydrochloride (16 g g' 8.35 mmol) and hydrated 1-hydroxybenzotriazole (0.95 g, 62 () 160800.doc -80- 201245158 mmol). The resulting colorless solution was stirred for 1 min, followed by the addition of (s)-5-[5-gas-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzene A solution of hydrazin-1-ylamine (1.64 g ' 4.77 mmol ' intermediate A-11) in anhydrous DMF (2.0 ml). The mixture was stirred at room temperature for 20 hours. Water was then added, the pH was adjusted to 9 with a saturated KaCO3 solution, and the mixture was extracted twice with MeCl2. The combined organic layers were washed with water and brine, dried over MgSO 4 and evaporated. The title compound (3.17 g, 100%) was obtained. MS: 665.2 (MH+, 1C1). Intermediate B-1 1-Di-3,5-di-gas-2-(2,2-difluoro-ethoxy)-benzene

ο [A】2-溴-4,6-二氣-苯酚ο [A] 2-Bromo-4,6-di-gas-phenol

在-50°C下，向2,4-二氯-笨酚（15 g，19〇2 mm〇1)於甲苯 (200 ml)中之溶液中逐滴添加溴（5」ml，184 〇4 mm〇1)。 160800.doc •81· 201245158 接著，逐滴添加第三丁胺（19.4 ml，99.02 mmol)且在-5(TC 下攪拌反應混合物30分鐘。藉由添加3 8% NaHS03水溶液 序滅反應物’分離有機層且用EtOAc萃取水層兩次。經 NadO4乾燥經合併之有機萃取物，過濾且蒸發，獲得呈白 色固體狀之標題化合物（21.5 g，96%)。 [B】甲烧確酸2,2-二氟-乙酯Add bromine (5" ml, 184 〇4 to a solution of 2,4-dichloro- phenol (15 g, 19 〇 2 mm 〇1) in toluene (200 ml) at -50 °C. Mm〇1). 160800.doc •81· 201245158 Next, third butylamine (19.4 ml, 99.02 mmol) was added dropwise and the reaction mixture was stirred at -5 (TC for 30 minutes. The reaction was separated by adding 3 8% NaHS03 aqueous solution). The organic layer was extracted with EtOAc EtOAc (EtOAc m. 2-difluoro-ethyl ester

Μ 在〇〇C下，向2,2-二氟-乙醇（6 g，73.12 mmol)及曱磺醯 氣（6.26 1111’80,43 111111〇1)於(：112(：12(4〇1111)中之溶液中逐滴 添加三乙胺（12.66 m卜87.74 mmol)。添加完成後，使混合 物升溫至室溫且攪拌1小時。接著用水及鹽水洗滌反應混 合物兩次且經NajCU乾燥。蒸發溶劑，得到呈黃色液體狀 之標題化合物（10.7 g，92%)。 [C】1-溴-3,5-二氣-2-(2,2-二氟-乙氧基）_苯Μ Under 〇〇C, to 2,2-difluoro-ethanol (6 g, 73.12 mmol) and sulfonium sulfonate (6.26 1111'80, 43 111111〇1) at (:112 (:12 (4〇1111) Triethylamine (12.66 m, 87.74 mmol) was added dropwise to the solution. After the addition was completed, the mixture was warmed to room temperature and stirred for 1 hour, then the mixture was washed twice with water and brine and dried over NajCU. The title compound (10.7 g, 92%) was obtained as a yellow liquid. [C] 1-bromo-3,5-di-s- 2- (2,2-difluoro-ethoxy)-benzene

向 2-漠-4,6-二氣-苯盼（14.6 g，60.3 mmol)(中間物 B-1 [A])於 DMF(10 ml)中之溶液中添加 k2c〇3(16.53 g，120.6 160800.doc • 82 201245158 mmol)及甲烷磺酸2,2-二氟-乙酯（10.7 g，66_4 mmol)(中間 物B-1 [B])，且加熱混合物至回流，維持i6小時。接著在 真空中蒸發DMF，且將所得殘餘物溶解於EtOAc(30〇 中。用水、鹽水洗滌此溶液兩次，經NasSO4乾燥且蒸發β 藉由層析（矽膠；己烷）純化剩餘粗產物，且獲得呈白色固 體狀之標題化合物（14.5 g，79。/。）。MS: 304 (M+，IBr)。 中間物B-2 3-(2-溴-4-氣-6-氟-苯基）-5-甲基-[1，2,4]噁二唑 〇Add k2c〇3 (16.53 g, 120.6) to a solution of 2-di-4,6-diox-benzophenone (14.6 g, 60.3 mmol) (intermediate B-1 [A]) in DMF (10 ml) 160800.doc • 82 201245158 mmol) and 2,2-difluoro-ethyl methanesulfonate (10.7 g, 66_4 mmol) (intermediate B-1 [B]), and the mixture was heated to reflux for i6 h. DMF was then evaporated in vacuo and the residue was crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The title compound (14.5 g, 79%) was obtained as a white solid. MS: 304 (M+, IBr) Intermediate B-2 3-(2-bromo-4- -6-fluoro-phenyl )-5-methyl-[1,2,4]oxadiazolidine

[A] 2-溴-4-氣-6-氟-苯甲醛[A] 2-Bromo-4-gas-6-fluoro-benzaldehyde

向 —漠-5-亂-3-乳-本（10 g ’ 34.68 mmol)於庚烧（27 ml)中之溶液中添加THF(44 ml)，且冷卻混合物至-45=。 接著’將iPrMgCl(38.14 ml，38.14 mmo卜 1 M溶液，於 THF中）逐滴添加至反應混合物中，同時維持溫度介於 -40°C至-45°C之間。在-40 C下攪拌混合物3 〇分鐘，隨後將 160800.doc -83- 201245158 DMP(13_4 rrd’ 173·4 mm〇i)逐滴添加至反應混合物中，同 時維持溫度介於_45°C至-2(TC之間。在-2(TC下再攪拌15分 鐘後，在(TC下將其傾倒至2 N HC1(20 ml)與***（5〇 之 混合物中。分離有機層，且用***萃取水層兩次。經THF (44 ml) was added to a solution of &lt;RTI ID=0.0&gt;&gt;&gt;&gt; Next, iPrMgCl (38.14 ml, 38.14 mmo 1 M solution in THF) was added dropwise to the reaction mixture while maintaining the temperature between -40 ° C and -45 ° C. The mixture was stirred at -40 C for 3 , minutes, then 160800.doc -83-201245158 DMP (13_4 rrd' 173·4 mm〇i) was added dropwise to the reaction mixture while maintaining the temperature at _45 ° C to -2 (between TC. After stirring for another 15 minutes at -2 (TC), pour it to a mixture of 2 N HCl (20 ml) and diethyl ether (5 。. Extract the aqueous layer twice.

NajCU乾燥經合併之有機層且在真空中蒸發，獲得呈黃色 固體狀之標題化合物（7 8 g，95%)。 【B] 2-溴-4-氣-6_氟-笨甲搭肟The combined organic layers were dried with EtOAc EtOAcjjjjjjj [B] 2-bromo-4-gas-6-fluoro-stupid

BrBr

在25t下向2-溴-4-氯-6-氟-苯甲醛（15 g，63·16 mm〇1)於 2-丙醇（130 ml)中之溶液中添加羥胺（5〇〇/〇溶液，於水中， 4.55 g，68.90 mmol)，且使混合物升溫至4〇°c，維持2小 時。接著將水（55 ml)緩慢添加至此混合物中，且使聚液在 2 0 C下老化1小時。過滤反應混合物，且用2 _丙醇與水 (1.5:1)之混合物洗滌剩餘固體且在真空下乾燥，得到呈白 色固體狀之標題化合物（12.5 g，77%)。 [C】2_演-4·氣_6-氣-N-窥基-节脖Add hydroxylamine (5〇〇/〇) to a solution of 2-bromo-4-chloro-6-fluoro-benzaldehyde (15 g, 63·16 mm〇1) in 2-propanol (130 ml) at 25t The solution, in water, 4.55 g, 68.90 mmol), and the mixture was warmed to 4 <RTIgt; Water (55 ml) was then slowly added to the mixture, and the polymerization was aged at 20 C for 1 hour. The reaction mixture was filtered, EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj [C] 2_演-4·气_6-气-N- 窥基-section neck

在5(TC下，將N-氯代丁二醯亞胺（S.34 g, 62 49 160800.doc -84- 201245158At 5 (TC, N-chlorobutanediimide (S.34 g, 62 49 160800.doc -84- 201245158

於DMF(25 ml)中之溶液緩慢添加至2-溴-4-氯-6-氟-苯甲醛 肟（15 g，59.52 mmol)於DMF(50 ml)中之溶液中。添加完 成後，在50°C下攪拌反應混合物30分鐘。接著冷卻該反應 混合物至3-5°C ’且逐滴添加NH4OH(4.6 m卜119 mmol)。 在添加期間，維持溫度介於0_10°c之間，且在相同溫度下 再授拌反應混合物15分鐘。接著添加EtOAc及鹽水，且劇 烈擾動混合物1 〇分鐘’隨後使各相沈降。分離水層且用 EtOAc萃取兩次。經NazSO4乾燥經合併之有機層且蒸發， 獲得呈灰白色固體狀之標題化合物（13g, 82%)。 [D] 3-(2-溪-4-氣-6-氟苯基）-5-甲基-[1,2,4】噁二唑The solution in DMF (25 ml) was slowly added to a solution of 2-bromo-4-chloro-6-fluoro-benzaldehyde oxime (15 g, 59.52 mmol) in DMF (50 ml). After the addition was completed, the reaction mixture was stirred at 50 ° C for 30 minutes. The reaction mixture was then cooled to 3-5 ° C ' and NH 4 OH (4.6 m 119 mmol) was added dropwise. During the addition, the temperature was maintained between 0 and 10 ° C and the reaction mixture was stirred for another 15 minutes at the same temperature. Then EtOAc and brine were added and the mixture was shaken vigorously for 1 min. then the phases were allowed to settle. The aqueous layer was separated and extracted twice with EtOAc. The combined organic layer was dried with EtOAc EtOAcjjjjjj [D] 3-(2-溪-4-气-6-fluorophenyl)-5-methyl-[1,2,4]oxadiazole

Br N 一0、Br N a 0,

在25 C下向2-溴-4-氣-6-氟-N-羥基·苄脒（26.5 g，99.25 mmol)於2-丙醇（200 ml)中之溶液中緩慢添加队小二甲基乙 醯胺一甲縮醛（35_2 m卜23 8.20 mmol)，且攪拌反應混合物 3〇分鐘。反應完成後，蒸發所有揮發物，且藉由層析（矽 膠；己烷/EtOAc 97:3)純化所得粗產物，獲得呈白色固體 狀之標題化合物（27.5 g，58%)。MS: 290 (M+, IBr)。 中間物B-3 5-(2-溴-4-氣-6-氟-苯基）-2-甲基-2丑-四唑 160800.doc -85 - 201245158Slowly add a small dimethyl group to a solution of 2-bromo-4-gas-6-fluoro-N-hydroxy-benzyl hydrazine (26.5 g, 99.25 mmol) in 2-propanol (200 ml) at 25 ° C. Acetamide-methylacetal (35_2 m b 23 8.20 mmol) and the reaction mixture was stirred for 3 min. After the reaction was completed, the title compound (27.5 g, 58%). MS: 290 (M+, IBr). Intermediate B-3 5-(2-Bromo-4-gas-6-fluoro-phenyl)-2-methyl-2 ugly-tetrazole 160800.doc -85 - 201245158

[A] 2-漠-4-氣-6-氟-苯甲赌[A] 2-Moine-4-gas-6-fluoro-benzoic bet

CI 向2-溴-4-氣-6-氟-苯基胺（1〇 g，44.5 mmol)於無水 CHzCl^lOO ml)中之溶液中添加四氟硼酸亞硝鑌（5.72 g， 49.01 mm〇l) ’且在25°C下攪拌混合物丨小時。接著冷卻反 應混合物至0。(： ’隨後添加KCN(5.8 g，89.1 mmol)，繼而 逐滴添加六水合硫酸銅（22.24 g，89.1 mmol)之水溶液（50 ml)°在〇°c下攪拌40分鐘後，使反應混合物升溫至25。(：， 且繼續攪拌1小時。用CH2Cl2(l〇〇 ml)稀釋反應混合物，且 藉由添加NaHCCb飽和水溶液緩慢淬滅，直至不再觀測到 氣體逸出。接著經由矽藻土墊過濾所得異質混合物，且分 離有機層，用鹽水洗滌兩次，經NajO4乾燥且蒸發。藉由 層析（石夕膠；己烷/EtOAc 90:10)純化由此獲得之粗殘餘 物’獲得呈微紅色固體狀之標題化合物（4 g，38%)。 [B】5-(2-演_4-氣_6_氣-苯基）_2好四唑 160800.doc -86· 201245158CI To a solution of 2-bromo-4-gas-6-fluoro-phenylamine (1 〇g, 44.5 mmol) in anhydrous CHzCl^100 ml), nitroxonium tetrafluoroborate (5.72 g, 49.01 mm 〇) l) 'And stir the mixture at 25 ° C for an hour. The reaction mixture was then cooled to zero. (: 'Subsequent addition of KCN (5.8 g, 89.1 mmol), followed by dropwise addition of an aqueous solution of copper sulfate hexahydrate (22.24 g, 89.1 mmol) (50 ml). After stirring at 〇 °c for 40 minutes, the reaction mixture was allowed to warm. To 25. (:, and continue to stir for 1 hour. The reaction mixture was diluted with CH.sub.2Cl.sub.2 (l.sub.ml) and slowly quenched by the addition of a saturated aqueous solution of NaHCCb until gas evolution was no longer observed. The resulting heterogeneous mixture was filtered, and the organic layer was separated, washed twice with brine, dried over Naj.sub. The title compound (4 g, 38%) as a reddish solid. [B]5-(2- _ _ _ _ _ _ _ _ _ phenyl) _2 good tetrazol 160800.doc -86 · 201245158

BrBr

Η Ν-Ν // \ NyNΗ Ν-Ν // \ NyN

F 將2-溴-4-氯-6-氟-苯甲腈（4 g，17.06 mmol)及疊氣基三 甲基錫（3.86 g，18.77 mmol)於甲苯（100 ml)中之混合物加 熱至120°C，維持72小時。反應完成後，將混合物分配於 EtOAc(50 ml)與0.5 N HC1水溶液（40 ml)之間。分離有機 層，用水及鹽水洗滌，經Na2S04乾燥且在減壓下濃縮，得 到呈紅色固體狀之標題化合物（4.2 g，87%)。 [C] 5-(2-溴-4-氣-6-氟-苯基）-2-甲基-2丑-四唑a mixture of 2-bromo-4-chloro-6-fluoro-benzonitrile (4 g, 17.06 mmol) and a mixture of trimethyltin (3.86 g, 18.77 mmol) in toluene (100 ml) 120 ° C, maintained for 72 hours. After the reaction was completed, the mixture was partitioned between EtOAc (50 ml) The organic layer was separated, washed with w~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ [C] 5-(2-Bromo-4-gas-6-fluoro-phenyl)-2-methyl-2 ugly-tetrazole

N-N // \ Nx^NN-N // \ Nx^N

F 將 5-(2-溴-4-氯-6-氟苯基）-2丑-四唑（4.15 g，14.95 mmol)、K2C03(3.1 g，22.43 mmol)及埃甲院（1.3 ml， 20.94 mmol)於DMF(30 ml)中之混合物在25°C下攪拌3小 時。將混合物分配於EtOAc(80 ml)與水（60 ml)之間，分離 有機層，用水及鹽水洗滌，經Na2S04乾燥且濃縮。藉由層 析（矽膠；己烷/EtOAc 100:0-90:10)純化剩餘殘餘物，獲得 160800.doc -87- 201245158 呈淺黃色固體狀之5-(2-漠-4-氯-6-乳-苯基）-1_甲基_ 四 唑（1.5 g，35°/。）及呈微紅色液體狀之標題化合物（1.7 g， 39%)。MS: 291.0 (MH+，IBr)。 實例1 (外消旋）-2-(1-{[1-(2,2,2-三氟-乙醢胺基）-環丙烷幾基】_胺 基}-茚滿-5-基）-苯甲酸甲酯F 5-(2-Bromo-4-chloro-6-fluorophenyl)-2 ugly-tetrazole (4.15 g, 14.95 mmol), K2C03 (3.1 g, 22.43 mmol) and A. (1.3 ml, 20.94 The mixture of mmol) in DMF (30 ml) was stirred at 25 ° C for 3 h. The mixture was partitioned between EtOAc (EtOAc m. The residue was purified by chromatography (EtOAc: EtOAc/EtOAc:EtOAc:EtOAc:EtOAc - Milk-phenyl)-1 -methyl-tetrazole (1.5 g, 35 °/.) and the title compound (1.7 g, 39%). MS: 291.0 (MH+, IBr). Example 1 (racemic)-2-(1-{[1-(2,2,2-trifluoro-acetamido)-cyclopropanyl]-amino}-indan-5-yl) -methyl benzoate

將1-(2,2,2-三氟-乙醯胺基）-環丙烷甲酸（（外消旋）_5_溴_ 茚滿-1-基）-醯胺（中間物 A-1 [B])(0.20 g，511 μηιοί)及2-(曱氧基幾基）苯基蝴酸（184 mg，1.02 mmol)溶解於二°惡烧 (9.0 ml)中；接著，在攪拌下添加溶解於水中之碳酸鈉（163 mg ’ 1_53 mmol)。隨後，添加二氣化（ι,ι'_雙（二苯基膦 基）-二茂鐵）鈀（11)(與 CH2C12 之 1:1 複合物）（18.7 mg，25.6 μπιοί ’ 〇·〇5當量），且加熱反應混合物至50°C，維持5小 時。接著將其傾倒至H2〇(50 ml)中且用EtOAc(2&gt;&lt;25 mL)萃 取。經MgSCU乾燥有機層，過濾且在真空申濃縮，得到粗 產物（0.296 g)，藉由急驟層析（矽膠，2〇 g，含〇%至2% MeOH之CHsCl2)純化該粗產物，得到呈淡棕色油狀之標題 化合物（0.21 g，91%)。MS: 445.1 (M-Η.)。 160800.doc •88· 201245158 實例2 1-(2,2,2-三氟-乙醢胺基）-環丙烷甲酸（外消旋）-{5-[3’5 氣-2-(2,2-二氟-乙氧基）-苯基】-茚滿-l-基}-醯胺1-(2,2,2-Trifluoro-acetamido)-cyclopropanecarboxylic acid ((racemic)_5_bromo-indan-1-yl)-decylamine (Intermediate A-1 [B ]) (0.20 g, 511 μηιοί) and 2-(decyloxy)phenyl-fatanoic acid (184 mg, 1.02 mmol) were dissolved in dioxane (9.0 ml); then, dissolved under stirring Sodium carbonate in water (163 mg '1_53 mmol). Subsequently, add two gasified (ι, ι'_bis(diphenylphosphino)-ferrocene) palladium (11) (1:1 complex with CH2C12) (18.7 mg, 25.6 μπιοί ' 〇·〇5 Equivalent), and the reaction mixture was heated to 50 ° C for 5 hours. It was then poured into H.sub.2 (50 mL) and extracted with EtOAc (2 &lt;&gt;&lt; The organic layer was dried <RTI ID=0.0>(M </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> The title compound (0.21 g, 91%). MS: 445.1 (M-Η.). 160800.doc •88· 201245158 Example 2 1-(2,2,2-Trifluoro-acetamido)-cyclopropanecarboxylic acid (racemic)-{5-[3'5 gas-2-(2, 2-difluoro-ethoxy)-phenyl]-indan-l-yl}-guanamine

將1-(2,2,2-三氟-乙醯胺基）-環丙烷甲酸[(外消旋）-5_ (4,4,5,5-四甲基-[1,3,2]二氧硼崠-2-基）-茚滿-卜基]-酿胺（中 間物 A-l)(0.22 g，502 μιηοΐ)、1-溴-3,5-二氯-2-(2,2-二氟-1-(2,2,2-Trifluoro-acetamido)-cyclopropanecarboxylic acid [(racemic)-5_ (4,4,5,5-tetramethyl-[1,3,2] Diboron-2-yl)-indan-buki]-bristamine (intermediate Al) (0.22 g, 502 μιηοΐ), 1-bromo-3,5-dichloro-2-(2,2- Difluoro-

乙氧基）-苯（中間物B-l)(169 mg，552 μιηοΐ)及三鄰甲苯基 膦（30.6 mg，100 μηι〇1，〇.2 當量）溶解於 THF(l〇.〇 ml)中； 接著依序添加乙酸把（11)(5.64 mg，25.1 μιηοΐ，〇·〇5當 量）、溶解於水（1.0 ml)中之碳酸鉀（173 mg，1·25 mmol)。 在室溫下攪拌反應混合物隔夜，接著傾倒至H2O(50 ml)中 且用EtOAc(2x25 mL)萃取。經MgS04乾燥有機層，過濾且 在真空中濃縮’得到粗產物（0.377 g)，藉由急驟層析（矽 膠’ 20 g，含1〇%至50% EtOAc之庚烷）純化該粗產物，得 到呈淡頁色非晶形固體狀之標題化合物（0.15 g， MS: 535.1 2CM)。 160800.doc -89- 201245158 實例3 (外消旋^氣^例㈣从三氟-乙酿胺基卜環丙燒幾 基卜胺基卜茚滿-5-基）-苯甲酸甲酯Ethoxy)-benzene (intermediate Bl) (169 mg, 552 μιηοΐ) and tri-o-tolylphosphine (30.6 mg, 100 μηι〇1, 〇.2 eq.) are dissolved in THF (l〇.〇ml); Next, acetic acid (173) (5.64 mg, 25.1 μm ηοΐ, 〇·〇 5 equivalent) and potassium carbonate (173 mg, 1.25 mmol) dissolved in water (1.0 ml) were added in that order. The reaction mixture was stirred with EtOAc EtOAc (EtOAc) The organic layer was dried <RTI ID=0.0></RTI> to EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The title compound (0.15 g, MS: 535.1. 160800.doc -89- 201245158 Example 3 (racemic ^ gas ^ (4) from trifluoro-ethyl amido propyl acetoin, benzylamino-5-yl)-benzoic acid methyl ester

類似於針對製備實例2所述之程序，使1-(2,2,2_三氟_乙 醯胺基）_環丙烷甲酸[(外消旋）_5_(4,4,5,5_四曱基-Π，3,2]二 氧t束-2-基）-節滿小基]-醯胺（中間物Μ與2~演-6-氯-苯 曱酸曱S旨反應，得到$淡黃色固體狀之標題化合物。MS: 479.1 (M-H·，1C1)。 實例4 心Λ )-環丙烷甲酸（外消旋）-{5-[5-氣_3_ 1-(2,2,2-三氟-乙醯胺疹/ id &gt;唑-3-基）-苯基]-茚滿-l-基}-酿胺 氟-2-(5-甲基-[1,2,4]魂Similar to the procedure described for Preparation Example 2, 1-(2,2,2-trifluoro-acetamido)-cyclopropanecarboxylic acid [(racemic)_5_(4,4,5,5_4曱-Π,3,2]dioxyt-2-yl)-frozen small group]-decylamine (intermediate Μ and 2~ -6-chloro-benzoic acid 曱S are reacted to obtain $ The title compound is obtained as a pale yellow solid. MS: 479.1 (MH·, 1C1). Example 4 Λ Λ)-cyclopropanecarboxylic acid (racemic)-{5-[5-gas_3_ 1-(2,2,2 -Trifluoro-acetamide rash / id &gt; oxazol-3-yl)-phenyl]-indan-l-yl}-bristamine fluoride-2-(5-methyl-[1,2,4] soul

-90- 160800.doc 201245158 類似於針對製備實例2所述之程序，使l-(2,2,2-三氟-乙 醯胺基）-環丙炫甲酸[(外消旋）-5-(4,4,5,5-四曱基-[1，3,2]二 氧棚咮-2-基）-茚滿-1-基]-醯胺（中間物A-1)與3-(2-溴-4-氣_ 6-氟-苯基）-5-曱基-[1，2,4]噁二唑（中間物心2)反應，得到 呈淡黃色非晶形固體狀之標題化合物。MS: 521.1 (M-H·， 1C1)。 實例5-90-160800.doc 201245158 Similar to the procedure described for Preparation Example 2, l-(2,2,2-trifluoro-acetamido)-cyclopropanoic acid [(racemic)-5- (4,4,5,5-tetradecyl-[1,3,2]dioxoin-2-yl)-indan-1-yl]-nonylamine (intermediate A-1) and 3- (2-Bromo-4-gas-6-fluoro-phenyl)-5-fluorenyl-[1,2,4]oxadiazole (intermediate core 2) was reacted to give the title compound as a pale yellow amorphous solid. . MS: 521.1 (M-H·, 1C1). Example 5

1-(2,2,2_三氟-乙醯胺基）_環丙烷甲酸{(s)_5_[5_氣_3_氟_2 (5-甲基-[1，2,4]噁二唑-3-基）-苯基]-茚滿_1_基卜醢胺1-(2,2,2-trifluoro-acetamido)-cyclopropanecarboxylic acid {(s)_5_[5_gas_3_fluoro-2 (5-methyl-[1,2,4] evil Diazol-3-yl)-phenyl]-indan_1_carbetamine

將1-(2,2,2-三氟-乙醯胺基環丙烷曱酸[(s)_5_(4,4,5,5_ 四曱基-[1，3,2]二氧蝴p東-2-基）-茚滿_ι_基]_醯胺（中間物八_ 2)(0.145 g，331 μηιοί)及 3-(2-溴-4-氯-6-氟_苯基）_5_ 甲基 -[1，2,4]嗔二嗤（十間物B_2)(1〇6 mg，364叫〇1)溶解於 DMSO(5.00 ml)中，接著依序添加溶解於水（〇63以）中之 碳酸鈉（87.7 mg，827 μιηοΐ)、二氣化（U1，-雙（二笨基膦 基）-二茂鐵）鈀（ιι)(與 ch2ci2 之 i:i 複合物）（121 mg，165 μιηοΐ，0.05當量）。加熱此混合物至8〇〇c，維持2小時，接 160800.doc -91 - 201245158 著傾倒至H2O(50 ml)中且用CH2C12(2x25 mL)萃取。經 MgS〇4乾燥有機層，過濾且在真空中濃縮，得到粗產物 (0·213 g)，藉由急驟層析（石夕膠，2〇 g，含ι〇〇/〇至5〇〇/0 EtOAc之庚烷）純化該粗產物，得到呈淡黃色固體狀之標題 化合物（0.094 g，54%)。MS: 523.1 (MH+, 1CI)。 實例6 2-氣-6-((S)-l-{【3-(2,2,2-三氟-乙醢胺基）_氧雜環丁烷_3·羰 基]-胺基}_茚滿-5-基）-苯甲酸甲酯1-(2,2,2-trifluoro-acetamidocyclopropanedecanoic acid [(s)_5_(4,4,5,5-tetradecyl-[1,3,2]dioxanthene -2-yl)-茚满_ι_基]_decylamine (intermediate eight _ 2) (0.145 g, 331 μηιοί) and 3-(2-bromo-4-chloro-6-fluoro-phenyl)_5_ Methyl-[1,2,4]嗔二嗤 (10 substances B_2) (1〇6 mg, 364 is called 〇1) was dissolved in DMSO (5.00 ml), followed by sequential addition to water (〇63 Sodium carbonate (87.7 mg, 827 μιηοΐ), two gasification (U1,-bis(diphenylphosphino)-ferrocene) palladium (i1i complex with ch2ci2 i:i) (121 mg , 165 μιηοΐ, 0.05 eq.) Heat the mixture to 8 ° C for 2 hours, pour to 160800.doc -91 - 201245158 and pour into H2O (50 ml) and extract with CH2C12 (2x25 mL). 4 The organic layer was dried, filtered and evaporated in vacuo tolujjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The title compound (0.094 g, 54%) was obtained as a pale yellow solid. MS: 523.1 (MH+, 1CI). Example 6 2- gas-6-((S)-l-{ [3-(2,2,2-trifluoro) -acetamido)-oxetane_3.carbonyl]-amino}_indan-5-yl)-benzoic acid methyl ester

類似於實例5中所述之程序’使3-(2,2,2-三氟-乙醯胺 基）-氧雜環丁烷_3_甲酸[(S)-5-(4,4,5,5-四曱基-[1，3,2]二氧 蝴棟-2 -基）_茚滿_1_基]-酿胺（中間物a_3)與2 -溴-6-氯-苯甲 酸甲酯在二氣化雙（二笨基膦基二茂鐵）鈀與 CH2Cl2之1:1複合物）存在下反應，得到呈淡黃色固體狀之 標題化合物。MS: 514.1 (Μ+ΝΗΛ 1C1)。 實例7 3·(2,2,2-三氟-乙醯胺基）-氧雜環丁烷_3_甲酸丨（8)_5_[5_氣_ 3氟-2-(5、甲基_[1，2,4】嗔二峻-3-基）-苯基]-茚滿-1-基卜酿胺 160800.doc -92· 201245158Similar to the procedure described in Example 5, '3-(2,2,2-trifluoro-acetamido)-oxetane_3_carboxylic acid [(S)-5-(4,4, 5,5-tetradecyl-[1,3,2]dioxoline-2-yl)_indan_1_yl]-bristamine (intermediate a_3) and 2-bromo-6-chloro-benzene Methyl formate is reacted in the presence of a 1:1 complex of bis(diphenylphosphinoferrocene) palladium and CH 2 Cl 2 to give the title compound as a pale yellow solid. MS: 514.1 (Μ+ΝΗΛ 1C1). Example 7 3·(2,2,2-trifluoro-acetamido)-oxetane_3_carboxylic acid hydrazine (8)_5_[5_gas_3fluoro-2-(5, methyl_ [1,2,4]嗔二峻-3-yl)-phenyl]-indan-1-yl-bristamine 160800.doc -92· 201245158

類似於實例5中所述之程序，使3-(2,2,2-三氟-乙醯胺 基）-氧雜環丁烷-3-甲酸[(s)_5-(4,4,5,5-四曱基-[1，3,2]二氧 硼崠-2-基）-茚滿-1-基]-醯胺（中間物A-3)與3-(2-溴-4-氣-6-氟-苯基）-5_甲基-[1,2,4]噁二唑（中間物B_2)在二氣化（11，_ 雙（二苯基膦基）-二茂鐵）鈀（Π)(與CH2C12之1:1複合物）存在 下反應，得到呈淡黃色固體狀之標題化合物。MS: 537.1 (M-H , 1C1)。 實例8Similar to the procedure described in Example 5, 3-(2,2,2-trifluoro-acetamido)-oxetane-3-carboxylic acid [(s)_5-(4,4,5 ,5-tetradecyl-[1,3,2]dioxaboroin-2-yl)-indan-1-yl]-nonylamine (intermediate A-3) and 3-(2-bromo-4) - gas-6-fluoro-phenyl)-5-methyl-[1,2,4]oxadiazole (intermediate B_2) in di-gasification (11,_bis(diphenylphosphino)-dioxin The title compound is obtained as a pale yellow solid in the presence of EtOAc (m.). MS: 537.1 (M-H, 1C1). Example 8

3_(2,2,2-三氟-乙醯胺基）-氧雜環丁烷_3甲酸{(s)_5_丨5氣_ 3_氟-2-(2-甲基_2好_四唑-5-基）-苯基卜茚滿j基卜醢胺3_(2,2,2-trifluoro-acetamido)-oxetane_3carboxylic acid {(s)_5_丨5 gas_3_fluoro-2-(2-methyl_2 good_ Tetrazolium-5-yl)-phenyl bromide

類似於實例5中所述之程序，使3_(2,2,2_三氟-乙醯胺 基）-氧雜環m甲酸[⑻·5_(4,4,5,5_四甲基_π，3,2]二氧 160800.doc -93- 201245158 棚崠-2-基）-茚滿-i_基]_醯胺（中間物八_3)與5-(2-溴-4-氣-6-氟-苯基）-2-曱基-2//-四唑（中間物B_3)在二氣化（1，1'_雙（二 苯基膦基）-二茂鐵）鈀（11)(與CH2C12之1:1複合物）存在下反 應’得到呈淡棕色固體狀之標題化合物。MS: 539·1 (MH+, 1C1)。 實例9 1-(2,2,2-三氟-乙醯胺基）_環丙烷甲酸{(外消旋）_6_[3,5-二 氣-2-(2,2-二氟-乙氧基）-苯基]_ι，2,3,4-四氫-萘-l-基}-酿胺Similar to the procedure described in Example 5, 3_(2,2,2-trifluoro-acetamido)-oxocycle m-carboxylic acid [(8)·5_(4,4,5,5-tetramethyl) π,3,2]dioxy 160800.doc -93- 201245158 shed 崠-2-yl)-indan-i_yl]-decylamine (intermediate eight_3) and 5-(2-bromo-4- Gas-6-fluoro-phenyl)-2-mercapto-2//-tetrazole (intermediate B_3) in di-gasification (1,1'-bis(diphenylphosphino)-ferrocene) palladium (11) (Reaction in the presence of a 1:1 complex with CH2C12) to give the title compound as a pale brown solid. MS: 539·1 (MH+, 1C1). Example 9 1-(2,2,2-Trifluoro-acetamido)-cyclopropanecarboxylic acid {(racemic)_6_[3,5-di-gas-2-(2,2-difluoro-ethoxy) Base)-phenyl]_ι,2,3,4-tetrahydro-naphthalene-l-yl}-bristamine

類似於實例5中所述之程序，使^(2,2,2—三氟-乙醯胺 基）-環丙烷甲酸[(外消旋）-6-(4,4,5,5-四甲基-[1，3,2]二氧硼 嗱-2-基）-1，2,3,4_四氫-萘-1-基]-醯胺（中間物a-4)與1-演 -3,5_二氯-2-(2,2 - —氟-乙氧基）-苯（中間物B-1)及二氯化 (1，1，-雙（二苯基膦基二茂鐵）!巴（II)(與CHAh之1:1複合物） 反應，得到呈淡棕色非晶形固體狀之標題化合物。Ms: 549.1 (M-Η' 2C1) 〇 160800.doc -94- 201245158 實例ίο (外消旋）-2-氣-6-(5-{[l-(2,2,2-三氟-乙醯胺基）-環丙烷羰 基】-胺基}·_5,6,7,8-四氮-蔡-2-基）-苯甲酸甲醋Similar to the procedure described in Example 5, ^(2,2,2-trifluoro-acetamido)-cyclopropanecarboxylic acid [(racemic)-6-(4,4,5,5-four Methyl-[1,3,2]dioxaboroin-2-yl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-decylamine (intermediate a-4) and 1- -3,5-Dichloro-2-(2,2-fluoro-ethoxy)-benzene (intermediate B-1) and dichloride (1,1,-bis(diphenylphosphino) Reaction of the ferrocene (B) (II) (1:1 complex with CHAh) gave the title compound as a light brown amorphous solid. Ms: 549.1 (M-Η' 2C1) 〇160800.doc -94- 201245158 Example ίο (racemic)-2-gas-6-(5-{[l-(2,2,2-trifluoro-acetamido)-cyclopropanecarbonyl]-amino}·_5,6, 7,8-tetrazine-cai-2-yl)-benzoic acid methyl vinegar

CI Ο \ 類似於實例5中所述之程序，使1-(2,2,2-三氟-乙醯胺 基）-環丙烷甲酸[(外消旋）-6-(4,4,5,5-四曱基-[1,3,2]二氧硼 東-2 -基）-1，2,3,4 -四鼠-秦-1-基]-酿胺（中間物A - 4 )與2 - &gt;臭-6 -氯-苯甲酸曱酯反應，得到呈灰白色固體狀之標題化合 物。MS: 512.2 (M+NH4+，1C1)。 實例11CI Ο \ Similar to the procedure described in Example 5, 1-(2,2,2-trifluoro-acetamido)-cyclopropanecarboxylic acid [(racemic)-6-(4,4,5) ,5-tetradecyl-[1,3,2]dioxaboron-2-yl)-1,2,3,4-tetra-zhen-1-yl]-nitramine (intermediate A-4 Reaction with 2 - &gt; ox-6-chloro-benzoic acid decyl ester gave the title compound as a white solid. MS: 512.2 (M+NH4+, 1C1). Example 11

1-(2,2,2-三氟-乙酿胺基）-環丙烷甲酸{(外消旋）-6-[5-氣-3-氟-2-(5-甲基-[1，2,4】噁二唑-3-基）-苯基】-1，2,3,4-四氫-萘-1-基}-醯胺1-(2,2,2-trifluoro-ethinyl)-cyclopropanecarboxylic acid {(racemic)-6-[5-gas-3-fluoro-2-(5-methyl-[1, 2,4]oxazol-3-yl)-phenyl]-1,2,3,4-tetrahydro-naphthalen-1-yl}-decylamine

160800.doc -95- 201245158160800.doc -95- 201245158

應，得到呈淡黃色固體狀之標題化合物。Ms: 537.i(MH， 1C1)。 實例12 1-(2,2,2-三氟乙醢胺基）_環丙烷甲酸{(外消旋）_3_[5-氣_3-氟-2-(5_甲基-[U，4】噁二唑-3-基）-苯基l·6,7-二氫吡 咬-7-基}-酸胺The title compound is obtained as a pale yellow solid. Ms: 537.i (MH, 1C1). Example 12 1-(2,2,2-Trifluoroacetamido)-cyclopropanecarboxylic acid {(racemic)_3_[5-gas_3-fluoro-2-(5-methyl-[U,4 Oxadiazol-3-yl)-phenyl l·6,7-dihydropyridin-7-yl}-acid amine

將1-(2,2,2-三氟-乙醯胺基）-環丙烷曱酸（（外消旋）-3-溴 -6,7-二氫-5//-Π]吡啶-7-基）-醯胺（中間物 Α-5)(0·2 g，510 μπαοί)、乙酸鉀（150 mg，1.53 mmol)及 4,4,4，，4，，5,5,5'，5'-八 曱基-2,2’-聯（1,3,2 -二氧爛 p東）（155 mg，612 μιηοΐ)溶解於 DMSO(8.0 ml)中。密閉反應容器且抽真空，接著饋入氬 氣；重複此程序五次。1〇分鐘後，添加二氯化。，丨匕雙（二 苯基膦基）-二茂鐵）鈀（11)(與CH2C12之1:1複合物）（18.7 160800.doc -96· 201245158 mg，25·5 μηιοί，0.05當量）， 且在9〇°C下攪拌反應混合物1-(2,2,2-Trifluoro-acetamido)-cyclopropanoic acid ((racemic)-3-bromo-6,7-dihydro-5//-anthracene]pyridine-7 -yl)-guanamine (intermediate Α-5) (0·2 g, 510 μπαοί), potassium acetate (150 mg, 1.53 mmol) and 4,4,4,4,5,5,5', 5'-Octadecyl-2,2'-linked (1,3,2-dioxagen p-east) (155 mg, 612 μιηοΐ) was dissolved in DMSO (8.0 ml). The reaction vessel was sealed and evacuated, followed by argon; this procedure was repeated five times. After 1 minute, dichlorination was added. , bis(diphenylphosphino)-ferrocene)palladium (11) (1:1 complex with CH2C12) (18.7 160800.doc -96·201245158 mg, 25·5 μηιοί, 0.05 equivalent), And stirring the reaction mixture at 9 ° C

基-[1，2,4]噁二唑（中間 *b_2)(164 mg ’ 561 μιη〇ι)，繼而添 加一氣化（1，1 _雙（一苯基膦基）_二茂鐵）纪（Η)(與之 1:1複合物）（18.7 mg，25·5 μηιοί，0.05 當量）。在 80°c 下攪 拌此反應混合物3小時，接著傾倒至h2〇(5〇 ml)中且用 CH2C12(3x25 ml)萃取。經MgS04乾燥有機層，過濾且在真 空中濃縮，得到粗產物（0.364 g)，藉由急驟層析（矽膠，20 g ’含0%至2% MeOH之CH2C12)純化該粗產物，得到呈淡 灰色固體狀之標題化合物（0.134 g，50%)。MS: 524.1 (MH+, 1C1)。 實例13 1-(2,2,2-三氟-乙醯胺基）-環丙烷甲酸{(外消旋）-3-[5-氣-3-氟-2-(2-曱基-2好-四唑-5-基）-苯基]-6,7-二氫-5好-[1】咕啶_7_ 基}-醢胺Base-[1,2,4]oxadiazole (intermediate *b_2) (164 mg ' 561 μιη〇ι) followed by a gasification (1,1 bis(monophenylphosphino)-ferrocene) (Η) (with a 1:1 complex) (18.7 mg, 25·5 μηιοί, 0.05 equivalent). The reaction mixture was stirred at 80 &lt;0&gt;C for 3 h then poured into H.sub.2 (5 mL) and extracted with CH.sub.2 C.sub.2 (3.times.25 ml). The organic layer was dried <RTI ID=0.0></RTI> tojjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The title compound (0.134 g, 50%) MS: 524.1 (MH+, 1C1). Example 13 1-(2,2,2-Trifluoro-acetamido)-cyclopropanecarboxylic acid {(racemic)-3-[5-gas-3-fluoro-2-(2-indolyl-2) Good-tetrazol-5-yl)-phenyl]-6,7-dihydro-5-[1] acridine_7_yl}-decylamine

類似於實例12中所述之程序，使1-(2,2,2-三氟-乙醢胺 基）-環丙烷甲酸（（外消旋）-3-溴-6,7-二氫-5/f-[l]°比咬-7-基）_ 160800.doc •97· 201245158 醯胺（中間物八-5)與4,4,4’，4，,5,5,5，，5，-八曱基-2,2，-聯（1,3,2_ 二氧硼崠）、二氯化（1，1，_雙（二苯基膦基）_二茂鐵）鈀（π)(與 CH/l2之1··1複合物）反應且隨後與5-(2-溴-4-氣-6-氟-笨 基）-2-曱基-2/ί-四唑（中間物B-3)反應，得到呈灰白色固體 狀之標題化合物。MS: 524.2 (ΜΗ+，1C1)。 實例14 1-(2,2,2-三氟-乙醯胺基）-環丙烷f酸{(外消旋）-7-[5-氣-3-氟-2-(5-甲基-【1，2,4】噁二唑-3-基）-苯基】-咣烷-4-基卜酿胺Analogously to the procedure described in Example 12, 1-(2,2,2-trifluoro-acetamido)-cyclopropanecarboxylic acid ((racemic)-3-bromo-6,7-dihydro-) 5/f-[l]° than bite-7-base)_160800.doc •97· 201245158 Indoleamine (intermediate eight-5) and 4,4,4',4,,5,5,5,, 5,-octadecyl-2,2,-linked (1,3,2-dioxaboron), dichloro(1,1,_bis(diphenylphosphino)-ferrocene)palladium (π (reacted with CH/l2 1·1 complex) and subsequently with 5-(2-bromo-4-gas-6-fluoro-phenyl)-2-mercapto-2/ί-tetrazole (middle) The title compound was obtained as a white solid. MS: 524.2 (ΜΗ+, 1C1). Example 14 1-(2,2,2-Trifluoro-acetamido)-cyclopropane f acid {(rac)-7-[5-gas-3-fluoro-2-(5-methyl- [1,2,4]oxadiazol-3-yl)-phenyl]-nonane-4-ylbumin

F F 類似於實例5中所述之程序，使二氟-乙酿胺 基）-環丙烧甲酸[(外消旋）_7_(4,4,5,5-四甲基-丨1，3,2]二氧棚 唓-2-基）-咣烷-4-基]-醯胺（中間物A_6)與3_(2_溴氯-6-氟-苯基）-5-曱基-[1 2,4]π惡二。坐（中間物B-2)反應’仔到呈淡黃 色固體狀之標題化合物。MS:兄9·1 (MH+，1C1) ° 實例15 l-(2,2,2-三氟-乙醯胺基）_環丙烷甲睃{(外消旋氣_3_ 氟-2-(2-甲基-2孖-四唑基）_苯基】-咣烷_4_基卜醢胺 -98- 160800.doc 201245158FF is similar to the procedure described in Example 5, such that difluoro-ethionyl)-cyclopropanecarboxylic acid [(racemic)_7_(4,4,5,5-tetramethyl-indole 1,3, 2] Dioxazol-2-yl)-nonan-4-yl]-nonylamine (intermediate A_6) and 3-(2-bromochloro-6-fluoro-phenyl)-5-fluorenyl-[1 2,4] π evil two. Sit (Intermediate B-2) to react to the title compound as a pale yellow solid. MS: Brother 9·1 (MH+, 1C1) ° Example 15 l-(2,2,2-Trifluoro-acetamido)-cyclopropanecarboxamide {(racemic gas_3_fluoro-2-(2) -Methyl-2-indole-tetrazolyl)-phenyl]-decane_4_carbetamine-98-160800.doc 201245158

F 類似於實例5中所述之程序，使^2,2,2·三氟_乙醯胺 基）-環丙烷甲酸[(外消旋）-7-(4,4,5,5-四甲基-[1，3,2]二氧棚 Ο 味-2-基）-咬炫&gt;-4-基]-醯胺（中間物A-6)與5-(2-溪-4-氯-6-氟- 苯基）-2-曱基-2丑-四唑（中間物B-3)反應，得到呈淡黃色固 體狀之標題化合物。MS: 539.1 (MH+, 1C1)。 實例16 1-(2,2,2-三氟·乙醯胺基）_環丙烷甲酸{(外消旋）-5-[5-氣-3-氟-2-(5-甲基-丨1，2,4】噁二唑-3-基）-苯基】-7-氟-茚滿-1-基}_ 醯胺F is similar to the procedure described in Example 5, such that ^2,2,2·trifluoro-acetamido)-cyclopropanecarboxylic acid [(racemic)-7-(4,4,5,5-four Methyl-[1,3,2]dioxoxanthene-2-yl)-bistile&gt;-4-yl]-nonylamine (intermediate A-6) with 5-(2-xi-4- Reaction of chloro-6-fluoro-phenyl)-2-mercapto-2 ugly-tetrazole (Intermediate B-3) gave the title compound as a pale yellow solid. MS: 539.1 (MH+, 1C1). Example 16 1-(2,2,2-Trifluoroethylamino)-cyclopropanecarboxylic acid {(racemic)-5-[5-vapor-3-fluoro-2-(5-methyl-oxime) 1,2,4]oxadiazol-3-yl)-phenyl]-7-fluoro-indan-1-yl}-decylamine

類似於實例5中所述之程序，使1-(2,2,2-三氟-乙醯胺 基兴環丙烷甲酸“外消旋卜了-氟乃气七斗一”-四曱基^^^二 氧硼崠-2-基）-茚滿-卜基]-醯胺（中間物A-7)與3-(2-漠_4-氯 160800.doc -99- 201245158 -6-氟-苯基）-5-甲基-[1,2,4]噁二唑（中間物8-2)反應，得到 呈淡黃色非晶形固體狀之標題化合物。MS·· 541.1 (MH+， 1C1)。 實例17 1-(2,2,2-三氟-乙醯胺基）-環丙烷甲酸{(外消旋）-5-丨5-氣-3-氟-2-(5-甲基-[1，2,4]噁二唑-3-基）-苯基]-1-甲基-茚滿-1 基}-醯胺Similar to the procedure described in Example 5, 1-(2,2,2-trifluoro-acetamidylcyclopropanecarboxylic acid was "exocyclic-fluorine-gas-seven"-tetradecyl^ ^^Bismomium-2-yl)-indan-buki]-guanamine (intermediate A-7) and 3-(2- desert_4-chloro 160800.doc -99- 201245158 -6-fluoro -Phenyl)-5-methyl-[1,2,4]oxadiazole (Intermediate 8-2) gave the title compound as a pale yellow solid. MS·· 541.1 (MH+, 1C1). Example 17 1-(2,2,2-Trifluoro-acetamido)-cyclopropanecarboxylic acid {(rac)-5-丨5-gas-3-fluoro-2-(5-methyl-[ 1,2,4]oxadiazol-3-yl)-phenyl]-1-methyl-indan-1 base}-nonylamine

類似於實例12中所述之程序，使1-(2,2,2-三氟-乙醯胺 基）-環丙烷曱酸（（外消旋）-5-溴-1-甲基-茚滿-1-基）-醯胺（中 間物 A-10)與 4,4,4，，4，，5,5,5，，5，-八曱基-2,2，-聯（1，3,2-二氧蝴 崠）、二氣化（1，1，-雙（二苯基膦基）-二茂鐵）鈀（II)(與CH2Cl2 之1:1複合物）反應且隨後與3-(2-溴-4-氣-6-氟-苯基卜5_曱 基-[1，2,4]噁二唑（中間物B_2)反應，得到呈無色非晶形固 體狀之標題化合物。MS: 535.1 (M-H·，1C1)。 實例18 1-(2,2,2-三敗-乙醯胺基）-環丙烷甲酸{(外消旋）-5-【5-氣_3 氟-2-(2-甲基-2丑-四唑_5_基）_苯基】甲基-茚滿基卜醢胺 160800.doc -100· 201245158Similar to the procedure described in Example 12, 1-(2,2,2-trifluoro-acetamido)-cyclopropanoic acid ((racemic)-5-bromo-1-methyl-oxime) Full-1-yl)-guanamine (intermediate A-10) and 4,4,4,,4,5,5,5,5,-octadecyl-2,2,-linked (1, 3,2-dioxolan), di-vaporized (1,1,-bis(diphenylphosphino)-ferrocene)palladium(II) (1:1 complex with CH2Cl2) and subsequently Reaction of 3-(2-bromo-4-gas-6-fluoro-phenyl)5-fluorenyl-[1,2,4]oxadiazole (intermediate B 2 ) to give the title compound as a colorless amorphous solid MS: 535.1 (MH·, 1C1). Example 18 1-(2,2,2-Tris-ethylamino)-cyclopropanecarboxylic acid {(racemic)-5-[5-gas_3 Fluorine -2-(2-methyl-2 ugly-tetrazol-5-yl)-phenyl]methyl-indanyl guanidinamine 160800.doc -100· 201245158

類似於實例12中所述之程序 基）-環丙烷曱酸（（外消旋）-5-溴- 使1-(2,2,2-三氟-乙醯胺 甲基-茚滿_1_基）_醯胺（中 間物 A-10)與 4,4,4'，4’,5,5,5’,5'-八 甲基-2,2’-聯（ι，3,2-二氧硼 棟）、一氣化（ι，ι _雙（一苯基膦基）·二茂鐵）把（π)(與CH2Cl2 之1·1複合物）反應且隨後與5-(2-溪_4_氣-6-說-苯基）_2-甲 基-2/ί-四唑（中間物B-3)反應，得到呈無色非晶形固體狀之 標題化合物。MS: 534.8 (M-Η·, 1C1)。 實例19Similar to the procedure described in Example 12)-cyclopropanedecanoic acid ((racemic)-5-bromo-) 1-(2,2,2-trifluoro-acetamidomethyl-indan-1 _ base) _ decylamine (intermediate A-10) with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-linked (ι,3,2 - Dioxonium), a gasified (ι,ι _ bis(monophenylphosphino)·ferrocene) reacts (π) (with a complex of CH2Cl2) and subsequently with 5-(2- The reaction of the title compound was obtained as a colorless amorphous solid. MS: 534.8 (M- Η·, 1C1). Example 19

1-(2,2,2-三氟-乙醯胺基）-環丙烷甲酸K外消旋）_6-[5_氯_3_ 氟-2-(5-曱基-[1，2,4]噁二唑_3_基）_苯基】-2,3-二氫-苯并呋 味-3-基}_酸胺1-(2,2,2-trifluoro-acetamido)-cyclopropanecarboxylic acid K racemic)_6-[5_chloro_3_fluoro-2-(5-fluorenyl-[1,2,4 Oxadiazole _3_yl)-phenyl]-2,3-dihydro-benzofuran-3-yl}-acid amine

-(2,2,2 -二氟乙酿胺 類似於實例5中所述之程序，使 -101- 160800.doc 201245158 基）-環丙烷曱酸[(外消旋）-6-(4,4,5,5·四曱基气1，3,2]二氧硼 ρ東-2 -基）-2,3-二氫苯并咬喃-3_基]-酿胺（中間物A-8)與3-(2-溴-4-氣-6-氟-苯基）_5_甲基-[1,2,4]鳴二唾（中間物丑-2)反 應，得到呈淡黃色固體狀之標題化合物。MS: 525.1 (MH+， 1C1)。 實例20 1-(2,2,2-三氟-乙醯胺基）-環丙烷甲酸{(外消旋）-6-【5-氣-3-氟-2-(2-甲基-2孖-四唑-5-基）-苯基]-2,3_二氫·苯并呋喃_3_ 基}-醢胺-(2,2,2-difluoroethylamine is similar to the procedure described in Example 5, making -101-160800.doc 201245158 base)-cyclopropanoic acid [(racemic)-6-(4, 4,5,5·tetrakilyl gas 1,3,2]dioxaboron-6-yl)-2,3-dihydrobenzopyran-3-yl]-bristamine (intermediate A- 8) reacting with 3-(2-bromo-4-gas-6-fluoro-phenyl)_5-methyl-[1,2,4] dioxin (intermediate ugly-2) to give a pale yellow solid The title compound. MS: 525.1 (MH+, 1C1). Example 20 1-(2,2,2-Trifluoro-acetamido)-cyclopropanecarboxylic acid {(racemic)-6-[5-vapor-3-fluoro-2-(2-methyl-2)孖-tetrazol-5-yl)-phenyl]-2,3-dihydrobenzofuran_3_yl}-decylamine

類似於實例5中所述之程序，使1-(2,2,2_三氟-乙醯胺 基）-環丙烷甲酸[(外消旋）-6-(4,4,5,5-四曱基-[1，3,2]二氧硼 ρ東-2-基）-2,3-二氫-苯并吱喃-3-基]-醯胺（中間物A-8)與5-(2-溪-4-氯-6-戴-苯基）-2-甲基-2//-四唾（中間物B-3)反應， 得到呈淡黃色固體狀之標題化合物。MS: 525.1 (MH+， 1C1)。 實例21 1-(2,2,2-三氟-乙酸胺基）-環丙烧甲酸{(外消旋）_6_[5_氣_3_ 160800.doc -102^ 201245158Similar to the procedure described in Example 5, 1-(2,2,2-trifluoro-acetamido)-cyclopropanecarboxylic acid [(racemic)-6-(4,4,5,5- Tetrakilyl-[1,3,2]dioxabordol-6-yl)-2,3-dihydro-benzofuran-3-yl]-decylamine (Intermediate A-8) and 5 -(2-Xi-4-chloro-6-D-phenyl)-2-methyl-2//-tetras-s------- MS: 525.1 (MH+, 1C1). Example 21 1-(2,2,2-Trifluoro-acetic acid amino)-cyclopropanecarboxylic acid {(racemic)_6_[5_气_3_160800.doc -102^ 201245158

類似於實…中所述之程序，使1_(2,2,2·三氟-乙酿胺 基)-環丙⑥甲酸[(外消旋)冬(4,4,5,5-四甲基·[1，3,2]二氧硼Similar to the procedure described in the real..., 1_(2,2,2·trifluoro-ethinyl)-cyclopropane 6-formic acid [(racemic) winter (4,4,5,5-tetra Base·[1,3,2]diboron

G 嗱-2-基）-2,3-二氫-苯并噻吩_3_基]-醯胺（中間物Α-9)與 3-(2-溴-4-氣-6-氟-苯基）-5_甲基-Π，2,4]噁二唑（中間物Β_2) 反應，得到呈淡黃色固體狀之標題化合物。MS: 541.1 (MH+，1C1)。 實例22 1-(2,2,2-三氟·乙醯胺基）_環丙烷甲酸{(外消旋）_6_[5-氣_3_ 氟_2_(2_甲基-2丑-四嗤-5-基）_苯基卜2,3·二氫-苯并【办]嗟吩-G 嗱-2-yl)-2,3-dihydro-benzothiophene-3-yl]-decylamine (intermediate Α-9) and 3-(2-bromo-4- gas-6-fluoro-benzene Reaction of the oxazolidine (intermediate Β_2) gave the title compound as a pale yellow solid. MS: 541.1 (MH+, 1C1). Example 22 1-(2,2,2-trifluoroethylamino)-cyclopropanecarboxylic acid {(racemic)_6_[5-gas_3_ fluoro_2_(2_methyl-2 ugly-four 嗤-5-yl) phenylphenyl 2,3·dihydro-benzo[[]] 嗟-

F 3-基}-酸胺 160800.doc • 103 - 201245158 類似於實例5中所述之程序’使三氟-乙醯胺 基）-環丙烷甲酸[(外消旋）-6-(4,4,5,5-四甲基-[1，3,2]二氧硼 崠-2-基）-2,3-二氫-苯并[办]噻吩_3_基]-醯胺（中間物A-9)與 5-(2-溴-4-氯-6-氟-苯基）_2-曱基-2开-四唑（中間物13)反 應，得到呈淡黃色固體狀之標題化合物。MS: 541.1 (MH+， 1C1)。 實例23 (1-{(8)-5-[5-氣-3-氟-2-(5-甲基-[1，2,4】嗔二唾_3-基）-笨基】_ 茚滿-1-基胺甲醯基}-環丙基胺基甲酸第三丁酯F 3-yl}-acid amine 160800.doc • 103 - 201245158 similar to the procedure described in Example 5 ''Trifluoro-acetamido)-cyclopropanecarboxylic acid [(racemic)-6-(4, 4,5,5-tetramethyl-[1,3,2]dioxaboroin-2-yl)-2,3-dihydro-benzo[thiophene-3-yl]-decylamine Reaction of 5-(2-bromo-4-chloro-6-fluoro-phenyl)_2-indenyl-2-openo-tetrazole (Intermediate 13) to give the title compound as a pale yellow solid . MS: 541.1 (MH+, 1C1). Example 23 (1-{(8)-5-[5-Gas-3-fluoro-2-(5-methyl-[1,2,4]indole dis-3-yl)-styl]_ 茚Tert-butyl-1-ylcarbamoyl}-cyclopropylaminocarbamate

類似於針對製備中間物A-1 [B]所述之程序，使（S)-5-[5- 氯-3-氟-2-(5-曱基-[1，2,4]噁二唑-3-基）-苯基]-茚滿-l_基胺 (中間物A-11)與1_第三丁氧基羰胺基_環丙烷曱酸偶合，得 到呈淡黃色非晶形固體狀之標題化合物。MS: 527.2 (MH+, 1C1) 〇 實例24 1-胺基-環丙烷甲酸{(s)_5_[5_氣_3_氟_2_(s_甲基_[12 4】噁 二唑-3_基）_苯基]-茚滿-l-基}-醯胺 16080〇.d〇c 201245158Similar to the procedure described for the preparation of intermediate A-1 [B], (S)-5-[5-chloro-3-fluoro-2-(5-fluorenyl-[1,2,4] Coupling of oxazol-3-yl)-phenyl]-indan-l-ylamine (intermediate A-11) with 1 -t-butoxycarbonylamino-cyclopropane decanoic acid to give a pale yellow amorphous solid The title compound. MS: 527.2 (MH+, 1C1) 〇 Example 24 1-amino-cyclopropanecarboxylic acid {(s)_5_[5_gas_3_fluoro_2_(s_methyl_[12 4]oxadiazole-3_ Base)_phenyl]-indole-l-yl}-nonylamine 16080〇.d〇c 201245158

nh2 類似於針對製備中間物A-ll [C]所述之程序，用含三氟_Nh2 is similar to the procedure described for the preparation of intermediates A-ll [C], with trifluoro-containing

乙酸（90%)之 CH2C12處理（l-{(S)-5-[5-氣-3-氟-2-(5 -甲基 -[1，2,4]噁二唑-3-基）-苯基]-茚滿-1-基胺甲醯基卜環丙基）_ 胺基甲酸第三丁酯（實例23)，得到呈淡黃色非晶形固體狀 之標題化合物。MS: 427.1 (MH+，1C1)。 實例25 嘧啶-5-甲酸（1_{(S)_5_[5-氣-3-氟-2-(5-甲基-U，2,4】噁二唑_ 3-基）-苯基卜節滿基胺甲醯基卜環丙基）酿胺Treatment of acetic acid (90%) with CH2C12 (1-{(S)-5-[5-gas-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl) -Phenyl]-indan-1-ylaminocarbazinylcyclopropyl)-tert-butylcarbamate (Example 23) gave the title compound as a pale yellow solid. MS: 427.1 (MH+, 1C1). Example 25 Pyrimidine-5-carboxylic acid (1_{(S)_5_[5-gas-3-fluoro-2-(5-methyl-U,2,4)oxadiazole-3-yl)-phenyl) Manganylmethionylcyclopropyl)

G :員似於針對製備中間物A-1 [B]所述之程序，使1 _胺基_ 衣丙，甲酸I⑻_5_[5m_2 (5_曱基-[H4]嗔二唑_3_ 苯基]-節滿_卜基卜醯胺（實例24)與嘧啶_5_甲酸偶合， 汽色固體狀之標題化合物。]V4S: 533 2 (MH+ 1C1)。 160800.doc 201245158 實例26 2-甲氧基-嘧啶-5-甲酸（l-{(S)-5-[5-氣-3-氟-2-(5-甲基-[1,2,4】噁二唑-3-基）-苯基卜茚滿-1-基胺甲醯基卜環丙基）-醢胺G: a member of the procedure described for the preparation of intermediate A-1 [B], 1 _ amino group _ propyl, formic acid I (8) _5_[5m 2 (5_ fluorenyl-[H4] oxadiazole _3 phenyl] - abbreviated - bromodiamine (Example 24) coupled with pyrimidine _5-carboxylic acid, the title compound as a viscous solid.] V4S: 533 2 (MH+ 1C1). 160800.doc 201245158 Example 26 2-methoxy -pyrimidine-5-carboxylic acid (l-{(S)-5-[5-gas-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzene) Kebumin-1-ylaminemethantipylidene propyl)-decylamine

類似於針對製備中間物A-1 [B]所述之程序，使卜胺基-環丙烷曱酸{(S)-5-[5-氯-3-氟-2-(5-甲基-[1，2,4]噁二唑-3-基）-苯基]-節滿- l-基}-醯胺（實例24)與2-甲氧基-嘧啶-5-甲 酸偶合，得到呈淡黃色固體狀之標題化合物。MS: 563.2 (MH+，1C1)。 實例27 噠嗪-4-甲酸（l-{(S)-5-[5-氣-3-氟-2-(5-甲基-[1，2,4]噁二唑-3 -基）-苯基]節滿-1 -基胺曱酿基}-環丙基）-酿胺Similar to the procedure described for the preparation of intermediate A-1 [B], the amino-cyclopropane decanoic acid {(S)-5-[5-chloro-3-fluoro-2-(5-methyl-) [1,2,4]oxadiazol-3-yl)-phenyl]-p-full-l-yl}-decylamine (Example 24) coupled with 2-methoxy-pyrimidine-5-carboxylic acid to give The title compound is obtained as a pale yellow solid. MS: 563.2 (MH+, 1C1). Example 27 Pyridazine-4-carboxylic acid (1-{(S)-5-[5-gas-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)) -phenyl]pump-1 -ylamine aryl]}-cyclopropyl)-bristamine

160800.doc -106 201245158 m類似於針對製備中間物A-l [B]所述之程序，使1-胺基-衣丙燒甲酸{(S)-5-[5-氣-3-氟-2-(5-甲基-[1，2,4]噁二唑-3-基）苯基]、節滿-丨-基}-醯胺（實例24)與噠嗪-4-曱酸偶合， 付到呈S爷龙a 之汽色固體狀之標題化合物。MS: 533.2 (MH+， 1C1)。 實例28160800.doc -106 201245158 m Similar to the procedure described for the preparation of the intermediate Al [B], 1-amino-propionaldehyde formic acid {(S)-5-[5-gas-3-fluoro-2- (5-Methyl-[1,2,4]oxadiazol-3-yl)phenyl], anthracene-fluorenyl-mercaptoamine (Example 24) coupled with pyridazine-4-decanoic acid, The title compound which is in the form of a solid of a solid color of S. MS: 533.2 (MH+, 1C1). Example 28

異喔唾-5- W Xk ΐ t r 酸（l-{(S)-5-[5 -氣- 3-1-2-(5-甲基-【1，2,4]鳴 唑3基苯基]-茚滿-1-基胺甲醯基卜環丙基卜醯胺Iso-salt-5- W Xk ΐ tr acid (l-{(S)-5-[5-gas-3-1-2-(5-methyl-[1,2,4]- oxazole 3-ylbenzene)茚]-indan-1-ylaminemethionylcyclopropyl decylamine

s員乜於針對製備中間物A-1 [B]所述之程序，使卜胺基_ :丙，甲酸{(S)_5-[5-氣-3-H-2-(5-曱基-[1，2,4]嗔二唑_3· 八+基]茚滿_1_基}_酿胺（實例24)與異鳴嗤_5甲酸偶 ' j呈&amp;汽色固體狀之標題化合物。MS: 522.1 (MH+, 1C1) 〇 實例29 _[1，3,4】噁二唑-2-甲酸（l-{(S)-5-[5-氣-3-氟-2_(5_ 甲 】嗔一唾_3-基）_笨基】_節滿_ι_基胺甲酿基 丙 基）-敢胺 160800.doc -107- 201245158s 乜 针对 针对 针对 针对 针对 针对 针对 针对 针对 针对 针对 针对 针对 针对 针对 针对 针对 针对 针对 针对 针对 针对 针对 针对 针对 针对 针对 针对 针对 针对 针对 针对 针对 针对 针对 针对 针对 针对 针对 针对 针对 针对 针对 针对-[1,2,4]oxadiazole_3· octa-yl]indan_1_yl}_bristamine (example 24) and oxime 嗤5 carboxylic acid couple 'j is &amp; vapor color solid Title compound: MS: 522.1 (MH+, 1C1) 〇 Example 29 _[1,3,4]oxadiazole-2-carboxylic acid (l-{(S)-5-[5-gas-3-fluoro-2_( 5_ A] 嗔一唾_3-基)_笨基】_节满_ι_基胺甲基基)- 敢amine160800.doc -107- 201245158

類似於針對製備中間物A-l [B]所述之程序，使1-胺基-% 丙烷曱酸{(S)-5_[5-氣-3-氟-2-(5-甲基-[1，2,4]噁二唑-3-基）_苯基]-茚滿-1-基卜醯胺（實例24)與5-甲基-[1，3,4]噁二 唾-2-甲酸偶合’得到呈淡黃色固體狀之標題化合物。MS: 534.2 (MH+，1C1)。 實例30 甲氧基-異噁唑_5_曱酸（1_{(s)_5_[5_氣_3氟_2(5甲基_ [1,2,4】噁二唑_3_基广苯基】茚滿j基胺甲醯基卜環丙基卜 酿胺Similar to the procedure described for the preparation of the intermediate Al [B], 1-amino-% propane decanoic acid {(S)-5_[5-gas-3-fluoro-2-(5-methyl-[1] , 2,4]oxadiazol-3-yl)-phenyl]-indan-1-yl decylamine (Example 24) and 5-methyl-[1,3,4]oxadipine-2- The title compound was obtained as a pale yellow solid. MS: 534.2 (MH+, 1C1). Example 30 methoxy-isoxazole _5_ decanoic acid (1_{(s)_5_[5_gas_3 fluoro-2(5methyl_[1,2,4]oxadiazole_3_base wide Phenyl] indane-j-amine

類似於針對製備中間物A-l [B]所述之程序，使^胺基 環丙烷甲酸《（S)~5-[5-氯-3-氟_2-(5·甲基-[1，2,4]噁二唑_3 基）_苯基茚滿-丨-基}-醯胺（實例24)與3-甲氧基_異噁唑_5 160800.doc -108· 201245158 甲酸偶合’得到呈淡黃色固體狀之標題化合物。Ms 552.2 (MH+，1C1)。 實例31 (1_{(外消旋）_5-[5 -氣-3-氣-2-(5-甲基-[1，2,4】福二唾-3-基） 苯基卜7-襄-茚滿-1-基胺甲醯基}-環丙基）_胺基甲酸第三丁輯Similar to the procedure described for the preparation of the intermediate Al [B], the amine cyclic cyclopropanecarboxylic acid "(S)~5-[5-chloro-3-fluoro_2-(5.methyl-[1,2] , 4] oxadiazole _3 yl) phenyl phenyl fluorenyl-fluorenyl- decylamine (Example 24) and 3-methoxy-isoxazole _5 160800.doc -108· 201245158 Formic acid coupling 'obtained The title compound is obtained as a pale yellow solid. Ms 552.2 (MH+, 1C1). Example 31 (1_{(racemic)_5-[5-gas-3-gas-2-(5-methyl-[1,2,4]fusin-3-yl)phenyl) 7-oxime -Indane-1-ylaminocarbamoyl}-cyclopropyl)-aminocarboxylic acid third

類似於針對製備中間物A-1 [B]及製備實例I2所述之程 序，（外消旋）-5-&gt;臭-7-氣-節滿-1-基胺（中間物A-7 [C])已也 1-第三丁氧基羰胺基-環丙烷甲酸偶合，得到[1-((外消旋） -5-溴-7-氟-茚滿-1-基胺曱醯基）-環丙基]-胺基曱酸第三丁 酯，其接著與 4,4,4|,4、5,5,5|，5’-八甲基-2,2'-聯（1,3,2-二氧 硼嗱）及二氯化（1，Γ-雙（二苯基膦基）-二茂鐵）鈀（11)(與 CH2C12之1:1複合物）反應且隨後與3-(2-溴-4-氣-6-氟-苯 基）-5-甲基-[1，2,4]噁二唑（中間物B-2)反應’得到呈淡棕色 固體狀之標題化合物。MS: 545.2 (MH+，1C1)。 實例32 1-胺基-環丙烷甲酸{(外消旋）-5-[5-氣-3-氟-2-(5-甲基-[1，2,4】噁二唑-3-基）-苯基】-7-氟-茚滿-l-基}-醯胺 160800.doc •109- 201245158 οSimilar to the procedure described for the preparation of Intermediate A-1 [B] and Preparation Example I2, (racemic)-5-&gt;Smell-7-gas-supplemental-1-amine (Intermediate A-7) [C]) has also been coupled with 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid to give [1-((racemic)-5-bromo-7-fluoro-indan-1-ylamine oxime] Tert-butyl]-cyclopropyl]-aminodecanoic acid tert-butyl ester, which is then bonded to 4,4,4|,4,5,5,5|,5'-octamethyl-2,2'- 1,3,2-dioxaboron) and di(1,p-bis(diphenylphosphino)-ferrocene)palladium (11) (1:1 complex with CH2C12) and subsequently Reaction with 3-(2-bromo-4-gas-6-fluoro-phenyl)-5-methyl-[1,2,4]oxadiazole (intermediate B-2) gave a pale brown solid The title compound. MS: 545.2 (MH+, 1C1). Example 32 1-Amino-cyclopropanecarboxylic acid {(rac)-5-[5-gas-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl )-phenyl]-7-fluoro-indan-l-yl}-decylamine 160800.doc •109- 201245158 ο

νη2 類似於針對製備中間物Α-11 [C]所述之程序，已用三氟 乙酸（90%)處理（1-{(外消旋）-5-[5-氣-3-氟-2-(5-甲基-Π，2,4]嚼二唑_3_基）_苯基卜7_氟-茚滿-^基胺甲醯基卜環丙 基）-胺基甲酸第三丁酯（實例3丨），得到呈淡棕色油狀之標 題化合物。MS: 445.1 (MH+，1C1)。 實例33 甲氧基·嘴酸（1_{(外消旋）-5-[5-氯-3·氟-2-(5-甲 j ’2’4以_嗤_3_基）苯基】、7氟節滿小基胺甲醯基卜環 丙基）-醜胺 ΟΝη2 is similar to the procedure described for the preparation of the intermediate Α-11 [C], which has been treated with trifluoroacetic acid (90%) (1-{(racemic)-5-[5-gas-3-fluoro-2) -(5-methyl-indole, 2,4) chemodiazole _3_yl)-phenyl phenyl 7-fluoro-indan-[ylamine-methyl hydrazinylcyclopropyl)-carbamic acid tert-butyl The title compound was obtained as a pale brown oil. MS: 445.1 (MH+, 1C1). Example 33 Methoxy·Butonic Acid (1_{(racemic)-5-[5-chloro-3·fluoro-2-(5-methylj '2'4 with _嗤_3_yl)phenyl) , 7-fluorine-small-small-small-amine-methyl sulfonyl-cyclopropyl)- ugly amine

類似於牡# 丙炫田 寸製備中間物A-1 [B]所述之程序，1-胺基-環 卜消旋）-5-[5-氣-3-氟-2-(5-曱基-[1，2,4]噁二 160800.doc 201245158 唑-3-基）-苯基]-7-氟-茚滿-l-基}-醯胺（實例32)已與2-甲氧 基-嘧啶-5-甲酸偶合，得到呈淡黃色固體狀之標題化合 物。MS: 581.2 (MH+，1C1)。 實例34 噠嗪-4-甲酸（1-{(外消旋）-5-[5-氣-3-氟-2-(5-甲基-丨1，2,4】噁 二唑-3-基）-苯基1-7-氟-茚滿-1-基胺甲醢基卜環丙基）-醯胺Similar to the procedure described in the preparation of the intermediate A-1 [B], 1-amino-cyclopyridyl)-5-[5-gas-3-fluoro-2-(5-曱) Base-[1,2,4] oxa 2160800.doc 201245158 oxazol-3-yl)-phenyl]-7-fluoro-indan-l-yl}-decylamine (Example 32) has been combined with 2-methoxy Co-pyrimidine-5-carboxylic acid coupling afforded the title compound as a pale yellow solid. MS: 581.2 (MH+, 1C1). Example 34 Pyridazine-4-carboxylic acid (1-{(racemic)-5-[5-gas-3-fluoro-2-(5-methyl-indole-1,2,4)oxadiazole-3- Benzyl)-phenyl 1-7-fluoro-indan-1-ylamine-mercaptopropylcyclopropyl)-guanamine

類似於針對製備中間物A-1 [B]所述之程序，1-胺基-環 丙烷曱酸{(外消旋）-5-[5-氣-3-氟-2-(5-甲基-[1，2,4]噁二唑 -3-基）-苯基]-7-氟-茚滿-1-基}-醯胺（實例32)已與噠嗪-4-曱 酸偶合’得到呈淡黃色固體狀之標題化合物。MS: 5 5 1.1 (MH+，1C1)。 實例35 3-甲氧基-異噁唑-5_甲酸（1_{(外消旋）_5_[5_氣_3_氟_2_(5_甲 基-[1，2,4]噁二唑-3-基）-苯基]-7-氟-節滿_ι_基胺甲醯基卜環 丙基）-醯胺 160800.doc -111 · 201245158Similar to the procedure described for the preparation of intermediate A-1 [B], 1-amino-cyclopropane decanoic acid {(racemic)-5-[5-gas-3-fluoro-2-(5-A) Base-[1,2,4]oxadiazol-3-yl)-phenyl]-7-fluoro-indan-1-yl}-decylamine (Example 32) has been coupled with pyridazine-4-decanoic acid 'The title compound was obtained as a pale yellow solid. MS: 5 5 1.1 (MH+, 1C1). Example 35 3-methoxy-isoxazole-5-carboxylic acid (1_{(racemic)_5_[5_gas_3_fluoro_2_(5-methyl-[1,2,4]oxadiazole -3-yl)-phenyl]-7-fluoro-segmentation_ι_ylaminemethionylcyclopropyl)-decylamine 160800.doc -111 · 201245158

F N 類似於針對製備中間物A-l [B]所述之程序，1-胺基-環 丙烷甲酸{(外消旋）-5-[5-氣-3-氟-2-(5-甲基-[1，2,4]噁二 唑-3-基）-苯基]-7-氟-茚滿- l-基}-醯胺（實例32)已與3-曱氧 基-異噁唑-5-甲酸偶合，得到呈淡紅色油狀之標題化合 物。MS: 570.1 (MH+，1C1)。 實例36 (1-{(外消旋）-3-丨5-氣-3-氟-2-(5-甲基-【1，2,4]噁二唑-3-基）- 苯基卜6,7-二氫_5H-[1]«比啶_7_基胺甲醢基卜環丙基卜胺基 甲酸第三丁酯FN is similar to the procedure described for the preparation of the intermediate Al [B], 1-amino-cyclopropanecarboxylic acid {(racemic)-5-[5-gas-3-fluoro-2-(5-methyl-) [1,2,4]oxadiazol-3-yl)-phenyl]-7-fluoro-indan-l-yl}-decylamine (Example 32) has been combined with 3-decyloxy-isoxazole- 5-carboxylic acid coupling gave the title compound as a pale red oil. MS: 570.1 (MH+, 1C1). Example 36 (1-{(rac)-3-丨5-gas-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl) 6,7-dihydro-5H-[1]«pyridyl-7-ylamine-methylglycolylcyclopropylaminocarbamic acid tert-butyl ester

類似於針對製備中間物A_u [。]及製備中間物A-1『 U [A]、實例12、中間物A-11 [B]所述之裎序，已由以下反應次序 160800.doc •112. 201245158 製備標題化合物：i)使（外消旋）-3-溴-6,7-二氫-5好-[1]°比咬 -7-基胺（中間物a-5 [B])轉化成（（外消旋）-3-溴_6,7_二氫 咣啶_7_基）_胺基甲酸第三丁酯；ϋ)使（（外消旋）-3_ 溴-6,7-二氫_5//-[1]吡啶-7-基）-胺基甲酸第三丁酯與 ^^^^，。。。，。'-八甲基-之^^聯^苫一-二氧硼一^及二氯化 (U，-雙（二苯基膦基）-二茂鐵）把（11)(與CHiCh之1:1複合物） 反應且隨後與3-(2-溴-4-氣-6-氟-苯基）-5-曱基-[1，2,4]噁二 唑（中間物B-2)反應，得到{(外消旋）-3-[5-氯-3-氟-2-(5-甲 基-[1,2,4]噁二唑-3-基）-苯基]-6,7-二氫-5//-[1]°比啶-7-基}-胺基甲酸第三丁酯；iii)移除BOC保護基，得到（外消旋）-3-[5 -亂-3 -氣- 2- (5 -甲基-[1，2,4]°惡二0坐-3-基）-苯基]-6,7-· — 鼠-5丑-[1]吡啶_7_基胺；iv)與1-第三丁氧基羰胺基-環丙烷曱 酸偶合，得到呈淡紅色油狀之標題化合物。MS: 528.2 (MH+，1C1)。 實例37 1-胺基-環丙烷甲酸{(外消旋）-3-[5-氣-3-氟-2-(5-甲基-[1，2，4]嚼二峻_3-基）_苯基】- 6,7-二氮-5丑-[1】π比咬-7-基} 酿胺Similar to the preparation of the intermediate A_u [. And the preparation of the intermediate A-1 "U [A], Example 12, intermediate A-11 [B], the title compound has been prepared by the following reaction sequence 160800.doc • 112. 201245158: i) (racemic)-3-bromo-6,7-dihydro-5--[1]° is converted to ((racemic)- than the bit-7-ylamine (intermediate a-5 [B]) 3-bromo-6,7-dihydroacridine-7-yl)-tert-butyl methacrylate; hydrazine) ((racemic)-3_bromo-6,7-dihydro-5//- [1] Pyridyl-7-yl)-carbamic acid tert-butyl ester and ^^^^. . . ,. '- octamethyl-^^^^^-dioxabor- and di-chlorinated (U,-bis(diphenylphosphino)-ferrocene) (11) (with CHiCh 1: 1 complex) reaction and subsequent reaction with 3-(2-bromo-4-gas-6-fluoro-phenyl)-5-mercapto-[1,2,4]oxadiazole (intermediate B-2) , {(racemic)-3-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-6, 7-Dihydro-5//-[1]° pyridine-7-yl}-aminocarboxylic acid tert-butyl ester; iii) removal of the BOC protecting group to give (racemic) -3-[5-disorder -3 - gas - 2-(5-methyl-[1,2,4]°dioxin-3-yl-3-yl)-phenyl]-6,7-·-rat-5 ugly-[1]pyridine Coupling of _7-ylamine; iv) with 1-t-butoxycarbonylamino-cyclopropanoic acid afforded the title compound as a pale red oil. MS: 528.2 (MH+, 1C1). Example 37 1-Amino-cyclopropanecarboxylic acid {(racemic)-3-[5-gas-3-fluoro-2-(5-methyl-[1,2,4] chewed dijun-3-yl )_phenyl]- 6,7-diaza-5 ugly-[1]π ratio bit-7-yl}

160800.doc -113· 201245158 類似於針對製備中間物A-ll [C】所述之程序，已用三氟 乙酸（90%)處理（1_{(外消旋）_3_[5_氯_3_氟_2_(5_甲基 -[1，2,4]噁二唑-3-基）_苯基]_6,7_二氫 啶 _7_基胺甲 醯基}-環丙基）-胺基甲酸第三丁酯（實例36)，得到呈淡黃 色油狀之標題化合物。MS: 428.1 (MH+，1C1)。 實例38 3-曱氧基-異噁唑-5_甲酸（1_κ外消旋）_3_〖s氯_3氟_2(5_甲 基-[1，2,4]噁二唑-3-基）-苯基】_6,7-二氫_5丑-丨1]吡啶-7-基胺 甲斑基}-環丙基）-酿胺160800.doc -113· 201245158 Similar to the procedure described for the preparation of intermediates A-ll [C], has been treated with trifluoroacetic acid (90%) (1_{(racemic)_3_[5_chlorine_3_ Fluorine 2_(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]_6,7-dihydropyridine-7-ylaminecarbamyl}-cyclopropyl)- The title compound was obtained as a pale yellow oil. MS: 428.1 (MH+, 1C1). Example 38 3-decyloxy-isoxazole-5-carboxylic acid (1_κ racemic)_3_[schloro-3-3fluoro-2(5-methyl-[1,2,4]oxadiazol-3-yl )-phenyl]_6,7-dihydro_5 ugly-丨1]pyridin-7-ylaminemethyl plaque}-cyclopropyl)-nitramine

類似於針對製備中間物A-1 [B]所述之程序，1-胺基-環Similar to the procedure described for the preparation of intermediate A-1 [B], 1-amino-ring

實例39Example 39

丙基）-酸胺 160800.doc -114. 201245158 οPropyl)-acid amine 160800.doc -114. 201245158 ο

類似於針對製備中間物Α-1 [Β]所述之程序，1-胺基-環 丙燒甲酸{(外消旋）-3-[5-氯-3-氟-2-(5-甲基-[1，2,4]噁二 11 坐_3-基）-苯基]-6,7-二氫-5丑-[1]»比啶-7-基}-醯胺（實例37) 已與噠嗪-4-曱酸偶合，得到呈淡棕色非晶形固體狀之標題 化合物。MS: 534.1 (MH+, 1C1)。 實例40 噠嗪-4-曱酸（1_{(R或S) 3·[5-氣-3-氟-2-(5-甲基-[1，2,4】噁二 唑-3-基）-苯基】-6,7-二氫-5丑-[1]吼啶-7-基胺甲醯基卜環丙 基）-醢胺Similar to the procedure described for the preparation of the intermediate Α-1 [Β], 1-amino-cyclopropanecarboxylic acid {(racemic)-3-[5-chloro-3-fluoro-2-(5-A) -[1,2,4]Ethyl 2 -sodium-3-yl)-phenyl]-6,7-dihydro-5 ugly-[1]»pyridin-7-yl}-decylamine (Example 37 Coupling with pyridazine-4-furic acid gave the title compound as a light brown amorphous solid. MS: 534.1 (MH+, 1C1). Example 40 Pyridazine-4-furoic acid (1_{(R or S) 3·[5-gas-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl) )-phenyl]-6,7-dihydro-5 ugly-[1] acridine-7-ylaminecarboxamidocyclopropyl)-guanamine

噠嗪-4-甲酸（1-{(外消旋）3-[5-氣-3-氟-2-(5-甲基-[1,2,4] 噁二唑-3-基）-苯基]-6,7-二氫-5//-Π]吡啶_7-基胺曱醯基}-環丙基）-醯胺（實例39)(200 mg)已藉由HPLC層析（Chiralpak 160800.doc -115- 201245158 AD HPLC管柱’含4〇% 2_丙醇之庚烷）分離成其對映體， 得到呈無色固體狀之標題化合物，[a]D (2(rc)=+7.52， (c=1.〇 ’ 於 CHCl3中）（81 mg);且參見實例41。 實例41 噠嗪_4_甲睃（1_{(S或R) 3-[5-氣-3-氟-2-(5-甲基-[1，2,4】噁二 唑-3-基）-苯基】-6,7-二氫_5好-丨q吼啶_7_基胺甲醢基卜環丙 基）-酿胺Pyridazine-4-carboxylic acid (1-{(racemic) 3-[5-gas-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)- Phenyl]-6,7-dihydro-5//-indole]pyridine-7-ylaminoindenyl}-cyclopropyl)-guanamine (Example 39) (200 mg) was chromatographed by HPLC ( Chiralpak 160800.doc -115- 201245158 AD HPLC column 'Heptane containing 4% by weight of 2-propanol) is isolated as the title compound to give the title compound as a colorless solid, [a]D (2(rc) = +7.52, (c=1.〇' in CHCl3) (81 mg); and see Example 41. Example 41 Pyridazine_4_ formazan (1_{(S or R) 3-[5-gas-3 -fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-6,7-dihydro-5-good-丨q吼idine_7-ylamine Mercaptocyclopropyl)-nitramine

噠嗪-4-甲酸（1-{(外消旋）3-[5-氯-3-氟-2-(5-甲基-[1，2,4] a惡一嗤-3-基）-苯基]-6,7-二氫-5//~[1]°比〇定_7-基胺曱釀基}-環丙基）-醯胺（實例39)(200 mg)已藉由HPLC層析（Chiralpak AD HPLC管柱，含40% 2-丙醇之庚烷）分離成其對映體， 得到呈灰白色固體狀之標題化合物，[a]D (2()ΐ广-7.50， (c=l.〇，於 CHC13中）（85 mg);且參見實例40。 實例42 2-甲氧基-嘧啶-5-甲酸（1-{(外消旋）-3-[5-氣-3-氟-2-(5-甲 基-[1，2,4】噪二唾-3-基）-苯基卜6,7-二氮-5丑-【1】&quot;Λ咬-7 -基胺 甲醢基}-環丙基）-醢胺 160800.doc -116. 201245158Pyridazine-4-carboxylic acid (1-{(racemic) 3-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4] a oxa-3-yl) -Phenyl]-6,7-dihydro-5//~[1]° ratio 〇7-ylamine aryl}}-cyclopropyl)-guanamine (Example 39) (200 mg) Separation to the enantiomers by HPLC chromatography (Chiralpak <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; (c=l.〇, in CHC13) (85 mg); and see Example 40. Example 42 2-Methoxy-pyrimidine-5-carboxylic acid (1-{(racemic)-3-[5- Gas-3-fluoro-2-(5-methyl-[1,2,4]noisem-3-yl)-phenyl b 6,7-diaza-5 ugly-[1]&quot;bite -7-ylaminocarbamyl}-cyclopropyl)-guanamine 160800.doc -116. 201245158

類似於針對製備中間物A-l [B]所述之Λ 私序，1Similar to the preparation of the intermediate A-l [B], the private order, 1

丙烷甲酸{(外消旋）-3-[5_氣-3-氟-2-(夂审w '按基-¾ 基[1 2 d 0圭-3-基）-苯基]-6,7-二氯-5//~[1]°比咬-7-其、 ’ ]°惡二 還·卜醯胺 已與2-甲氧基-嘧啶-5-曱酸偶合，得到呈 ^例37) 犬白色固體扯 標題化合物。MS: 564.2 (MH+，1C1)。 扯狀之 實例43 -(s-甲基 7-基胺甲釀基卜 異噁唑-5-甲酸（1-{(外消旋）-3-[5-氯_3-氟-2 噁二嗤-3-基）-苯基]-6,7-二氫-5好-[1】吨唆_ 環丙基）-醯胺Propanecarboxylic acid {(racemic)-3-[5_gas-3-fluoro-2-(夂审w 'by base-3⁄4 base [1 2 d 0--3-yl)-phenyl]-6, 7-Dichloro-5//~[1]° is better than bite-7-, ' ] ° dioxin also · oxime amine has been coupled with 2-methoxy-pyrimidine-5-decanoic acid 37) Canine white solid pull the title compound. MS: 564.2 (MH+, 1C1). Example 43-(s-methyl 7-ylamine-alkyl-isoxazole-5-carboxylic acid (1-{(racemic)-3-[5-chloro-3-trifluoro-2) Indole-3-yl)-phenyl]-6,7-dihydro-5--[1] ton 唆_cyclopropyl)-guanamine

G 類似於針對製備中間物A-1 [B]所述之程序’ 1-胺基-環 丙烧曱酸{(外消旋）-3-[5 -氣-3-氟- 2-(5 -甲基-[1，2,4]°惡二吐 160800.doc -117- 201245158 -3·基）_苯基]-6,7-二氫-5//-[l]n比唆_7_基}驢胺（實例37)已 與異噁唑-5-曱酸偶合，得到呈灰白色固體狀之標題化合 物。MS: 523.1 (MH+，1C1)。 實例44 (W(外消旋氣冬氟-2_(5_甲基·[124]嗔二唑_3_基）_ 苯基]-2,3-二氣-苯并呋喃_3_基胺甲釀基}環丙基）胺基甲 酸第三丁酯G is similar to the procedure described for the preparation of intermediate A-1 [B] '1-Amino-cyclopropanone {{racemic)-3-[5-gas-3-fluoro-2-(5) -Methyl-[1,2,4]°Essence vomit 160800.doc -117- 201245158 -3·yl)_phenyl]-6,7-dihydro-5//-[l]n 唆The title compound was obtained as an off-white succinic acid. MS: 523.1 (MH+, 1C1). Example 44 (W (racemic nitrofurazone-2_(5-methyl·[124] oxadiazole_3_yl)-phenyl]-2,3-diode-benzofuran_3_ylamine Tert-butyl}cyclopropyl)carbamic acid tert-butyl ester

類似於針對製備中間物A_i [B]及製備實例12所述之程 序，（外消旋）-6-溴_2,3_二氫-苯并呋喃_3_基胺（中間物a_8 [B])已與i -第二丁氧基羰胺基-環丙烷甲酸偶合，得到[1 _ ((外消旋）-6-溴_2,3-二氫-苯并呋喃_3_基胺甲醯基）環丙 基]胺基曱酸第三丁酯，其接著與4,4,4,，4,，5,5,5,，5,_八甲 基-2,2’-聯（1，3,2-二氧硼崠）及二氣化（丨’丨^雙（二苯基膦基）_ 二茂鐵）鈀（11)(與CHaCb之1:1複合物）反應且隨後與3_(2_ 溴-4-氯-6-氟-苯基）_5_甲基412,4]噁二唑（中間物I〕）反 應’得到呈淡黃色固體狀之標題化合物。Ms: 1C1)。 160800.doc .118- 201245158 實例45 1-胺基-環丙烷甲酸{(外消旋）-6-[5-氣-3-氟-2-(5-曱基-[1,2,4】噁二唑-3-基）-苯基】-2,3-二氫-苯并呋喃-3-基}-醯胺 ΟSimilar to the procedure described for the preparation of intermediate A_i [B] and Preparation Example 12, (racemic)-6-bromo-2,3-dihydro-benzofuran-3-ylamine (intermediate a_8 [B ]) has been coupled with i - 2 -butoxycarbonylamino-cyclopropanecarboxylic acid to give [1 _ ((racemic)-6-bromo-2,3-dihydro-benzofuran-3-ylamine) Tert-butyl)cyclopropyl]aminobutyric acid tert-butyl ester, which is then attached to 4,4,4,4,5,5,5,5,8-octamethyl-2,2'- (1,3,2-dioxaboron) and two gasified (丨'丨^ bis(diphenylphosphino)-ferrocene)palladium (11) (1:1 complex with CHaCb) and Subsequent reaction with 3_(2-bromo-4-chloro-6-fluoro-phenyl)-5-methyl 412,4]oxadiazole (Intermediate I) gave the title compound as a pale yellow solid. Ms: 1C1). 160800.doc .118- 201245158 Example 45 1-Amino-cyclopropanecarboxylic acid {(racemic)-6-[5-gas-3-fluoro-2-(5-fluorenyl-[1,2,4] Oxadiazol-3-yl)-phenyl]-2,3-dihydro-benzofuran-3-yl}-amidoxime

類似於針對製備中間物A-11 [C]所述之程序，已用三氟 乙酸（90%)處理（1-{(外消旋）-6-[5-氯-3-氟-2-(5-甲基-[1,2,4] °惡二。坐-3-基）-苯基]-2,3-二氮-苯并咬11 南-3-基胺甲酿基}-環 丙基）-胺基甲酸第三丁酯（實例44)，得到呈淡黃色油狀之 標題化合物。MS: 429.1 (MH+，1C1)。 實例46 〇 噠嗪-4-甲酸（1-{(外消旋）-6·[5-氣-3-氟-2-(5-甲基-[1，2,4】噁 二嗤-3-基）-苯基】-2,3-二氫·苯并夫味-3-基胺甲酿基}-環丙 基）-醯胺 ΟSimilar to the procedure described for the preparation of intermediate A-11 [C], has been treated with trifluoroacetic acid (90%) (1-{(racemic)-6-[5-chloro-3-fluoro-2- (5-Methyl-[1,2,4] °Ethylene. Sodium-3-yl)-phenyl]-2,3-diaza-benzo-bito 11-N--3-ylamine-branthyl}- The title compound was obtained as a pale yellow oil. MS: 429.1 (MH+, 1C1). Example 46 Pyridazine-4-carboxylic acid (1-{(racemic)-6·[5-gas-3-fluoro-2-(5-methyl-[1,2,4]oxadiazole-3) -yl)-phenyl]-2,3-dihydro-benzoffin-3-ylamineyl}}-cyclopropyl)-guanamine

160800.doc -119- 201245158 類似於針對製備中間物A-l [B]所述之程序，1 -胺基-環 丙烷甲酸{(外消旋）-6-[5-氯-3-氟-2-(5-曱基-[1，2,4]噁二 唑-3-基）-苯基]-2,3-二氳-苯并呋喃-3-基}-醯胺（實例45)已 與噠嗪-4-甲酸偶合，得到呈黃色固體狀之標題化合物。 MS: 535.1 (MH+, 1C1)。 實例47 2-甲氧基-嘧啶-5-甲酸（1-{(外消旋）-6-【5-氣-3-氟-2-(5-甲 基~丨1，2,4】噁二唑-3-基）-苯基】_2,3_二氫-苯并呋喃-3-基胺曱 醯基卜環丙基）-醯胺160800.doc -119- 201245158 Similar to the procedure described for the preparation of the intermediate Al [B], 1-amino-cyclopropanecarboxylic acid {(racemic)-6-[5-chloro-3-fluoro-2- (5-Mercapto-[1,2,4]oxadiazol-3-yl)-phenyl]-2,3-diindole-benzofuran-3-yl}-decylamine (Example 45) has been Couphazine-4-carboxylic acid coupling afforded the title compound as a yellow solid. MS: 535.1 (MH+, 1C1). Example 47 2-Methoxy-pyrimidine-5-carboxylic acid (1-{(racemic)-6-[5-gas-3-fluoro-2-(5-methyl~丨1,2,4) evil Diazol-3-yl)-phenyl]_2,3-dihydro-benzofuran-3-ylamine decylcyclopropyl)-decylamine

類似於針對製備中間物A-1 [B]所述之程序，丨_胺基_環 丙烷曱酸{(外消旋）-6-[5-氯-3-氟-2-(5-甲基-tl，2,4]嗔二 °坐-3-基）_苯基]-2,3-二氫-苯并呋喃-3-基卜酿胺（實例45)已 與2-甲氧基-嘧啶-5-甲酸偶合，得到呈淡黃色固體狀之標 題化合物。MS: 565.1 (MH+，1C1)。 實例48 3_甲氧基-異噁唑-5-曱酸（1-{(外消旋）-6-[5-氣·3_氟·2_(5_甲 基-[1，2,4]噁二唑_3-基）-苯基卜2,3-二氫·苯并呋喃_3_基胺甲 160800.doc -120· 201245158 醯基}-環丙基）-醯胺Similar to the procedure described for the preparation of intermediate A-1 [B], 丨-amino-cyclopropane decanoic acid {(racemic)-6-[5-chloro-3-fluoro-2-(5-A) Base-tl,2,4]嗔2°--3-yl)-phenyl]-2,3-dihydro-benzofuran-3-yl-bromoamine (Example 45) has been combined with 2-methoxy Co-pyrimidine-5-carboxylic acid coupling gave the title compound as a pale yellow solid. MS: 565.1 (MH+, 1C1). Example 48 3_Methoxy-isoxazole-5-decanoic acid (1-{(racemic)-6-[5-gas·3_fluoro·2_(5-methyl-[1,2,4) Oxadiazole-3-yl)-phenyl b 2,3-dihydrobenzofuran_3_ylamine A 160800.doc -120· 201245158 fluorenyl}-cyclopropyl)-guanamine

0 類似於針對製備中間物A-1 [B]所述之程 X --月 丙烷甲酸{(外消旋）_6_[5_氯_3_氟_2'(5-甲美r '壤 1 τ 丞-L 1，2,4]。惡二 0坐-3-基）-苯基]-2,3-二虱_本并°夫°南-3-基}_醢胺（實例45)已 與3-曱氧基-異噁唑-5-曱酸偶合’得到呈淡黃色油狀之標 題化合物。]VLS: 554.1 (MH+，1C1) 〇 實例49 3-胺基-氧雜環丁烷-3·甲酸{(S)-5-[S_氣-3_氟-2-(5-甲 基-[1，2,4】嗔二咬-3-基苯基]-茚滿-1-基卜酿胺0 is similar to the process described for the preparation of intermediate A-1 [B] X-month propanecarboxylic acid {(racemic)_6_[5_chloro_3_fluoro-2' (5-methyl-r-r'1) τ 丞-L 1,2,4]. Oxan-2-oxo-3-yl)-phenyl]-2,3-dioxime_benzol--------------- The title compound has been obtained as a pale yellow oil. ] VLS: 554.1 (MH+, 1C1) 〇 Example 49 3-Amino-oxetane-3·carboxylic acid {(S)-5-[S_gas-3_fluoro-2-(5-methyl- [1,2,4]嗔二咬-3-ylphenyl]-indan-1-yl-bristamine

向（3-{(S)-5-[5-氣_3_氟-2-(5-甲基噁二唑-3-基）_ 苯基]-茚滿-1-基胺甲醢基卜氧雜環丁烧-3 -基）-胺基甲酸 160800.doc -121- 201245158 ⑽基甲醋（中間物A_12)(2 94 g，4 42 _〇1)於 MeCl2(50.〇 ml)中之溶液中添加哌啶（4 38爪丨），且在室溫 下授摔混合物15小時。在室溫下於高真空下濃縮無色溶液 至乾燥。藉由層析（矽膠；MeCh/MeOH 100:0-95..5)純化剩 餘殘餘物，且獲得呈淡棕色油狀之標題化合物（1 〇9 g， 560/〇)。MS: 443.1 (MH+，1C1)。 實例50 嘧啶-5-甲酸（M(S)_5_[5_氣_3_氟_2_(5_甲基_【124丨噁二唑_ 3-基）-苯基卜節滿基胺甲醢基卜氧雜環丁烷_3基）醢胺To (3-{(S)-5-[5-Gas_3_fluoro-2-(5-methyloxadiazol-3-yl)-phenyl]-indan-1-ylaminocarbazide Oxetane-3-yl)-carbamic acid 160800.doc -121- 201245158 (10) methyl vinegar (intermediate A_12) (2 94 g, 4 42 _〇1) in MeCl2 (50. 〇ml) Piperidine (4 38 Xenopus) was added to the solution, and the mixture was dropped for 15 hours at room temperature. The colorless solution was concentrated to dryness under high vacuum at room temperature. The residue was purified by chromatography (jjjjjjjjjjjj MS: 443.1 (MH+, 1C1). Example 50 Pyrimidine-5-carboxylic acid (M(S)_5_[5_gas_3_fluoro_2_(5-methyl_[124oxaoxadiazole-3-yl)-phenyl-p-branched-amine Keb oxetane _3 yl) decylamine

類似於針對製備中間物A-1 [B]所述之程序，使3_胺基_ 氧雜環丁烷-3 -甲酸{(S)-5-[5-氯-3 -氟_2-(5 -曱基-[i,2 4]噁 二唑-3-基）-苯基]-茚滿-l-基}-醯胺（實例49)與嘧啶_5_甲酸 偶合，得到呈淡黃色固體狀之標題化合物。Ms: 549 i (MH+，1C1)。 實例51 異噁唑-5-甲酸（3-{(8)-5-[5-氣-3-氟_2_(5_甲基·口，2 4】噁二 唑-3-基）-苯基】-節滿-1-基胺甲醢基卜氧雜環丁烷_3_基）醯胺 160800.doc -122· 201245158Similar to the procedure described for the preparation of intermediate A-1 [B], 3-amino-oxetane-3-carboxylic acid {(S)-5-[5-chloro-3-fluoro-2- (5-Mercapto-[i,2 4]oxadiazol-3-yl)-phenyl]-indan-l-yl}-decylamine (Example 49) coupled with pyrimidine _5-carboxylic acid to give a light The title compound is a yellow solid. Ms: 549 i (MH+, 1C1). Example 51 Isoxazol-5-carboxylic acid (3-{(8)-5-[5-gas-3-fluoro-2-((5-methyl), 2 4]oxadiazol-3-yl)-benzene Base]--negative-1-ylamine-methyl hydrazinyl oxetane _3_yl) decylamine 160800.doc -122· 201245158

類似於針對製備中間物A-l [B]所述之程序，使3_胺基_Similar to the procedure described for the preparation of intermediate A-1 [B], 3_amino group _

氧雜環丁烷-3_甲酸{(S)-5-[5-氣-3·氟_2·(5_曱基·[H4]噁 一唑-3-基）-苯基]-茚滿_1_基卜醯胺（實例49)與異噁唑-甲 酸偶合，得到呈黃色油狀之標題化合物。MS: 538 1 (μη+， 1C1)。 ， 實例52 3_甲基-異噁唑_s_甲酸（3_{(s)_5_[5m 2…甲基_ [1’2,4]惡一唑_3_基）苯基】茚滿4基胺甲醢基卜氧雜環丁 烧基）-酿胺Oxetane-3_carboxylic acid {(S)-5-[5-gas-3·fluoro-2·(5_mercapto·[H4]oxazol-3-yl)-phenyl]-oxime Coupling of <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; MS: 538 1 (μη+, 1C1). , Example 52 3_Methyl-isoxazole_s_carboxylic acid (3_{(s)_5_[5m 2...methyl_[1'2,4]oxazol-3-yl)phenyl] indole 4 Amine oxime oxime oxirane)

ΟΟ

氧雜環丁 製備中間物A_1 [B]所述之程序，使3_胺基-、 甲酸{(S)-5-[5·氯-3 -氟-2-(5 -曱基- [ι，2,4]α惡 160800.doc -123· 201245158 一唑基）-苯基]•茚滿_1-基}-醯胺（實例49)與3-曱基-異噁 唑-5-曱酸偶合’得到呈淡黃色油狀之標題化合物。mS: 552.1 (MH+, ici)= 實例53 3-甲氧基-異喔唾甲酸（3 {(§) 5 [5_氣_3氣_2 (s甲基_ [1，2,4]噁二唑·3_基）-苯基1-茚滿-1-基胺甲醯基卜氧雜環丁 烧-3-基）·酿胺 ΟOxetane preparation of the intermediate A_1 [B], such as 3-amino-, formic acid {(S)-5-[5·chloro-3-fluoro-2-(5-fluorenyl-[ι] , 2,4]α恶160800.doc -123· 201245158 Iazozolyl)-phenyl]•indan_1-yl}-decylamine (Example 49) and 3-mercapto-isoxazole-5-oxime The acid is coupled to give the title compound as a pale yellow oil. mS: 552.1 (MH+, ici)= Example 53 3-methoxy-isoindolecarboxylic acid (3 {(§) 5 [5_气_3气_2 (smethyl_[1,2,4] evil) Diazole·3_yl)-phenyl-1-indan-1-ylaminemethanyl oxacyclobutane-3-yl)

類似於針對製備中間物A」所述之程序，使3_胺基_ 氧雜環丁烧^-甲酸以…^^-氣-^氟^-^曱基^^糾噁 一唑-3-基）-苯基]-茚滿_κ*}_醯胺（實例49)與3_曱氧基-異 嚼。坐-5-甲酸偶合’得到呈淡黃色黏性油狀之標題化合物。 MS: 568.1 (ΜΗ+，1C1)。 實例54 (1-{(外消旋）-3_[5-氣-3-氟_2_(2_甲基_2丑_四唑_5_基）_苯基卜 6,7-二氫-5孖-[1】吡啶-7-基胺甲醢基丨環丙基胺基甲酸第 三丁酯 160800.doc •124· 201245158Similar to the procedure described for the preparation of intermediate A", 3-amino-oxo-butane---carboxylic acid was used to modulate monozole-3- Base)-Phenyl]-indan_κ*}-decylamine (Example 49) and 3-methoxyl-isoche. The title compound is obtained as a pale yellow viscous oil. MS: 568.1 (ΜΗ+, 1C1). Example 54 (1-{(racemic)-3_[5-gas-3-fluoro_2_(2_methyl-2 ugly-tetrazol-5-yl)-phenyl) 6,7-dihydro- 5孖-[1]pyridin-7-ylaminecarboxylidene Cyclopropylaminocarbamic acid tert-butyl ester 160800.doc •124· 201245158

類似於針對製備實例12、中間物A-l 1 [c]及製備中間物 A-1 [B]所述之程序，已由以下反應次序製備標題化合物： 1)使（(外/肖旋）-3-&gt;臭-6,7-二氫_5好-[1]»比唆_7_基）_胺基曱酸第 二丁醋（實例 36)與 4,4,4,,4^5,5,5^-八甲基 _2,2'_ 聯（1,3,2-一氧硼棟）及一氣化（1，1'_雙（二苯基膦基）_二茂鐵）把（1；[)(與 CH2C12之1:1複合物）反應且隨後與5_(2_溴_4_氯_6_氟-苯 基）-2-曱基-2//-四唑（中間物B-3)反應，得到{(外消旋）-3-[5 -氣-3 -氟-2-(2-曱基-2//~ 四》坐-5_ 基）-苯基]_6,7_ 二氫-5//-[1]吡啶-7-基}-胺基甲酸第三丁酯；ii)移除BOC保護基， 得到（外消旋）-3-[5 -氣-3 -氟-2-(2-曱基-2/7-四吐-5 -基）-苯 基]-6,7-二氫-57/-ΠΡ比啶-7-基胺；出）與1-第三丁氧基羰胺 基-環丙烷曱酸偶合’得到呈紫色非晶形固體狀之標題化 合物。MS: 528·2 (MH+，1C1)。 實例55 1-胺基-環丙烷甲酸{(外消旋）-3-[5-氣·3·敗_2-(2-甲基 四唑-5-基）-笨基卜6,7-二氫-5孖-[1]吼啶_7_基}_醯胺 -125- 160800.doc 201245158Similar to the procedure described for Preparation Example 12, Intermediate Al 1 [c] and Preparation Intermediate A-1 [B], the title compound was prepared from the following reaction sequence: 1) ((External/Spin)-3 -&gt;Smell-6,7-dihydro- 5 good-[1]»比唆_7_yl)-amino phthalic acid second butyl vinegar (Example 36) and 4,4,4,,4^5 , 5,5^-octamethyl-2,2'-linked (1,3,2-oxoborom) and a gasified (1,1'-bis(diphenylphosphino)-ferrocene) Reacting (1;[) (with a 1:1 complex of CH2C12) and subsequently with 5_(2_bromo-4-iso-6-fluoro-phenyl)-2-indolyl-2//-tetrazole ( Intermediate B-3) is reacted to give {(racemic)-3-[5-gas-3-fluoro-2-(2-mercapto-2//~4)--5-yl)-phenyl] _6,7_Dihydro-5//-[1]pyridin-7-yl}-carbamic acid tert-butyl ester; ii) removal of the BOC protecting group to give (racemic)-3-[5-gas- 3-fluoro-2-(2-indolyl-2/7-tetraoxa-5-yl)-phenyl]-6,7-dihydro-57/-indolepyridin-7-ylamine; 1-Tertoxycarbonylamino-cyclopropane decanoic acid coupled to give the title compound as a purple amorphous solid. MS: 528·2 (MH+, 1C1). Example 55 1-Amino-cyclopropanecarboxylic acid {(racemic)-3-[5-gas·3·?2-(2-methyltetrazol-5-yl)-stupyl, 6,7- Dihydro-5孖-[1]acridine_7_yl}-decylamine-125-160800.doc 201245158

類似於針對製備中間物A-ll [c]所述之程序，已用三氟 乙酸（90%)處理（1_{(外消旋）_3-[5_氯_3_氟-2-(2-甲基-2β-四 唾-5-基）-苯基]_6,7_二氫比啶-7-基胺甲醯基卜環丙 基）-胺基曱酸第三丁酯（實例54)，得到呈淡棕色非晶形固 體狀之標題化合物。MS: 428.1 (ΜΗ+，1C1)。 實例56 2-甲氧基-嘧啶-5-曱酸（1-{(外消旋）-3-[5-氣-3-氟-2-(2-甲 基丑-四唑_5_基）-苯基】-6,7-二氫-5开-【1】吡啶-7-基胺甲醯 基卜環丙基）-醯胺 ΟSimilar to the procedure described for the preparation of intermediates A-ll [c], has been treated with trifluoroacetic acid (90%) (1_{(racemic)_3-[5_chloro_3_fluoro-2-(2) -Methyl-2β-tetras-5-yl)-phenyl]_6,7-dihydropyridin-7-ylamine-mercaptopropylcyclopropyl)-aminobutyric acid tert-butyl ester (Example 54 The title compound was obtained as a light brown amorphous solid. MS: 428.1 (ΜΗ+, 1C1). Example 56 2-Methoxy-pyrimidine-5-decanoic acid (1-{(racemic)-3-[5-gas-3-fluoro-2-(2-methyl ugly-tetrazole-5-yl) )-Phenyl]-6,7-dihydro-5-[1]pyridin-7-ylaminecarboxamidocyclopropyl)-guanamine

犬員似於針對製備中間物A-1 [B]所述之程序，使1-胺基- 環丙、# m 疋节酸{(外消旋）-3-[5-氯-3-氟-2-(2-甲基-2//-四唑-5- 160800.doc -126- 201245158 基）-本基]-6,7 -二虱-5 //- [1]°比°定-7-基}-酿胺（實例55)與2-曱 氧基-嘧咬-5-曱酸偶合，得到呈淡黃色固體狀之標題化合 物。MS: 562.2 (M-H.，1C1)。 實例57 異噁唑-5-甲酸（1-{(外消旋）-3-[5-氣-3-氟-2-(2-甲基-2丑-四 唾-5-基）-苯基]-6,7-二氫-5丑-[1]吨啶-7-基胺甲醢基卜環丙 基）-酿胺The canine is similar to the procedure described for the preparation of intermediate A-1 [B] to give 1-amino-cyclopropane, #m 疋 酸 { {racemic)-3-[5-chloro-3-fluoro -2-(2-methyl-2//-tetrazole-5-160800.doc -126- 201245158 base)-bens]-6,7-dioxi-5 //- [1]° ratio Coupling of -7-yl}-bristamine (Example 55) with 2-methoxy-pyrimidine-5-decanoic acid afforded the title compound as a pale yellow solid. MS: 562.2 (M-H., 1C1). Example 57 Isoxazole-5-carboxylic acid (1-{(racemic)-3-[5-gas-3-fluoro-2-(2-methyl-2 ugly-tetras-5-yl)-benzene) ]]-6,7-dihydro-5 ugly-[1] ton pyridine-7-ylamine carbazylcyclopropyl)-nitramine

F 類似於針對製備中間物A-1 [B]所述之程序，使卜胺基_ 環丙烷甲酸{(外消旋）-3-[5-氯-3-氟-2-(2-甲基_2丑-四嗤_5_ 基）-苯基]-6,7 -二氫- 5//-[ 1 ] °比咬_7-基}-酿胺（實例55)與異0惡 唑-5-甲酸偶合，得到呈淡黃色固體狀之標題化合物。MS: 523.1 (MH+，1C1)。 實例58 3-甲基-異噁唑-5-甲酸（1-{(外消旋）-3-[S_氣_3_敗_2_(2甲 基-2/Γ-四峻-5-基）-苯基]-6,7-二氫-5丑-[1】吨咬_7基胺甲敏 基卜環丙基）-醢胺 160800.doc • 127- 201245158F is similar to the procedure described for the preparation of intermediate A-1 [B] to give amino-cyclopropanecarboxylic acid {(racemic)-3-[5-chloro-3-fluoro-2-(2-methyl) Base_2 ugly-tetrakis_5_yl)-phenyl]-6,7-dihydro-5//-[1] ° than bit _7-yl}-bristamine (example 55) and isooxazolyl Coupling of -5-carboxylic acid gave the title compound as a pale yellow solid. MS: 523.1 (MH+, 1C1). Example 58 3-Methyl-isoxazole-5-carboxylic acid (1-{(racemic)-3-[S_qi_3_@2_(2methyl-2/Γ-四峻-5-) Base)-phenyl]-6,7-dihydro-5 ugly-[1] ton _7 amide amine methionylcyclopropyl)-guanamine 160800.doc • 127- 201245158

類似於針對製備中間物A-l [B]所述之程序，使1-胺基-環丙烷曱酸{(外消旋）-3-[5-氣-3-氟-2-(2-甲基-2丑-四唑-5-基）-苯基]-6,7-二氫-5//-Π]&quot;比啶-7-基}-醯胺（實例55)與3-甲 基-異噁唑-5-甲酸偶合，得到呈淡黃色固體狀之標題化合 物。MS: 537.2 (MH+, 1C1)。 實例59 3-甲氧基-異噪嗤-5-甲酸（1-{(外消旋）-3-[5-氣-3-氟-2-(2-甲 基-2丑-四唑_5_基）_苯基】_6,7_二氫-5及-丨1】吡啶_7_基胺甲醯 基}-環丙基）-酿胺 ΟSimilar to the procedure described for the preparation of the intermediate Al [B], 1-amino-cyclopropanodecanoic acid {(racemic)-3-[5-gas-3-fluoro-2-(2-methyl) -2 ugly-tetrazol-5-yl)-phenyl]-6,7-dihydro-5//-Π]&quot;bipyridin-7-yl}-decylamine (Example 55) with 3-methyl - Isooxazol-5-carboxylic acid coupling gave the title compound as a pale yellow solid. MS: 537.2 (MH+, 1C1). Example 59 3-Methoxy-isohaloindole-5-carboxylic acid (1-{(racemic)-3-[5-gas-3-fluoro-2-(2-methyl-2 ugly-tetrazole_) 5_yl)_phenyl]_6,7-dihydro-5 and -丨1]pyridine_7_ylaminemethanyl}-cyclopropyl)-bristamine

H JJH JJ

ΟΟ

ci\ a x 〇 \ 類似於針對製備中間物A-l [B]所述之程序，使胺基_ 環丙烧曱酸{(外消旋）_3-[5-氯-3-氟-2-(2-曱基-2仏四唆_5_ 基）-苯基]-6,7-二氫-5孖-[1]吡啶-7-基}-醯胺（實例55)與3_甲 160800.doc -128- 201245158 氧基-異噁唑-5-曱酸偶合，得到呈淡黃色固體狀之標題化 合物。MS: 553.2 (MH+, 1C1)。 實例60 (1-{(外消旋）-6-[5-氣-3-氟-2-(2-甲基-2丑-四唑-5-基）-苯基】-2,3-二氫-苯并μ]噻吩-3-基胺甲醢基卜環丙基）_胺基甲酸第 三丁酯Ci\ ax 〇\ is similar to the procedure described for the preparation of the intermediate Al [B] to give the amine _ cyproterone decanoic acid {(racemic) _3-[5-chloro-3-fluoro-2-(2) -mercapto-2仏tetrakis_5_yl)-phenyl]-6,7-dihydro-5孖-[1]pyridin-7-yl}-decylamine (Example 55) and 3_A 160800.doc -128- 201245158 oxy-isoxazole-5-nonanoic acid coupling afforded the title compound as a pale yellow solid. MS: 553.2 (MH+, 1C1). Example 60 (1-{(racemic)-6-[5-gas-3-fluoro-2-(2-methyl-2 ugly-tetrazol-5-yl)-phenyl]-2,3- Dihydro-benzo[mu]thiophen-3-ylaminemethantylcyclopropyl)-tert-butyl methacrylate

類似於針對製備中間物Α-1 [Β]及A-1 [C]及製備實例5所 述之程序’（外消旋）-6-溴-2,3-二氫-苯并[6]噻吩-3-基胺（中 間物Α-9 [Α])已與1-第三丁氧基羰胺基-環丙烷甲酸偶合， 得到[1-((外消旋）-6·溴-2,3-二氫-苯并[6]噻吩-3-基胺曱醯 Ο 基）_環丙基]-胺基甲酸第三丁酯，其接著與 4,4,4'，4'，5,5,5·，5’-八甲基-2,2·-聯（1，3,2-二氧硼崠）及二氣化 - G，1'-雙（二苯基膦基）-二茂鐵）鈀（Π)(與CH2C12之1:1複合物） , 反應’得到{1-[(外消旋）-6-(4,4,5,5-四甲基二氧硼 棟-2-基）-2,3-二氫-苯并|&gt;]噻吩-3-基胺甲醯基]•環丙基卜胺 基甲酸第三丁酯，其接著再次用二氯化（1，1，_雙（二苯基膦 基）-二茂鐵）鈀（11)(與CH2C12之1:1複合物）及5-(2-溴-4-氯-6-氟-苯基）-2-甲基-2好-四峻（中間物B -3)處理，得到呈淡黃色 160800.doc •129· 201245158 非晶形固體狀之標題化合物。MS: 545.2 (MH+，1C1)。 實例61 1-胺基-環丙烷甲酸{(外消旋兴^丨^氣-夂氟^^甲基^丑· 四唾_5_基）-苯基]-2,3-二氫-苯并[6]嗟吩_3_基卜酿胺Similar to the procedure described for the preparation of intermediates Α-1 [Β] and A-1 [C] and Preparation Example 5 '(racemic)-6-bromo-2,3-dihydro-benzo[6] Thiophen-3-ylamine (intermediate Α-9 [Α]) has been coupled with 1-t-butoxycarbonylamino-cyclopropanecarboxylic acid to give [1-((racemic)-6·bromo-2) , 3-dihydro-benzo[6]thiophen-3-ylamine fluorenyl)-cyclopropyl]-carbamic acid tert-butyl ester, which is followed by 4,4,4',4',5 ,5,5·,5'-octamethyl-2,2·-linked (1,3,2-dioxaboron) and di-gasified-G,1'-bis(diphenylphosphino)- Ferrocene) palladium (Π) (1:1 complex with CH2C12), reaction 'obtained {1-[(racemic)-6-(4,4,5,5-tetramethyldioxaboron) -2-yl)-2,3-dihydro-benzo-&gt;]thiophen-3-ylaminocarbamimidyl]-tert-butylcyclopropylcarbamate, which is followed by dichlorination again ( 1,1,_bis(diphenylphosphino)-ferrocene)palladium (11) (1:1 complex with CH2C12) and 5-(2-bromo-4-chloro-6-fluoro-phenyl </RTI> </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; MS: 545.2 (MH+, 1C1). Example 61 1-Amino-cyclopropanecarboxylic acid {(racemic 丨^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ And [6] porphin _3_ kibamine

F N 〜 類似於針對製備中間物A-ll [C]所述之程序，已用三說 乙酸（9〇%)處理（1_{(外消旋）-6_[5·氯_3_氟_2_(2_甲基_2丑四 唑-5-基）-苯基]_2,3_二氫-苯并[6]噻吩_3_基胺甲醯基卜環丙 基）-胺基曱酸第三丁酯（實例60)，得到呈淡黃色非晶形固 體狀之標題化合物。MS: 445.1 (MH+, icl)。 實例62 5-甲基-【I，3,4]噁二唑_2-甲酸（1-{(外消旋）_6_[5_氣、3氟 (2-甲基-2孖-四唑_5_基）-苯基】_2,3-二氫_苯并【杓噻吩基 胺甲醯基卜環丙基）_醢胺FN ~ similar to the procedure described for the preparation of intermediates A-ll [C], has been treated with three said acetic acid (9 〇%) (1_{(racemic)-6_[5·chloro_3_fluoro_2_ (2_Methyl-2 ugly tetrazol-5-yl)-phenyl]_2,3-dihydro-benzo[6]thiophene-3-ylamine-methylphenylidene propyl)-amino decanoic acid The title compound was obtained as a pale yellow amorphous solid. MS: 445.1 (MH+, icl). Example 62 5-Methyl-[I,3,4]oxadiazole_2-carboxylic acid (1-{(racemic)_6_[5-gas, 3-fluoro(2-methyl-2indole-tetrazole) 5_yl)-phenyl]_2,3-dihydro-benzo[inthylthiophenylaminomethylpyridylpropyl)-decylamine

F N—N 160800.doc • 130- 201245158 類似於針對製備中間物“ [B]所述之程序，ιF N—N 160800.doc • 130- 201245158 Similar to the procedure described for the preparation of the intermediate “[B], ι

:烧甲酸K外消旋)修氯_3_氣烟基_2細唾J 本基卜2’3-二氫-苯并㈧噻吩_3-基}-醯胺(實例61)已與：: 基似4]嚼…-甲酸偶合’得到呈淡黃色非晶形、固 狀之標題化合物。MS: 555 1 (MH+，lc〇。 實例63 嘧咬_5_甲酸（1_{(外消旋）_6_[5_氣_3_氣_2(2甲基_2丑四唉·: Burning formic acid K racem) Repairing chlorine_3_smoke base_2 fine saliva J Benib 2'3-dihydro-benzo(octa)thiophene-3-yl}-decylamine (Example 61) has been combined with: : Base 4] Chew...-formic acid coupling' gives the title compound as a pale yellow amorphous, solid. MS: 555 1 (MH+, lc〇. Example 63 Pyridine _5_carboxylic acid (1_{(racemic)_6_[5_气_3_气_2(2 methyl_2 ugly four 唉··

5-基）-苯基卜2,3-二氫-苯并μ】噻吩_3_基胺甲醯基卜環丙 基）-酿胺5-yl)-phenyl phenyl 2,3-dihydro-benzo[p] thiophene-3-ylamine carbazylcyclopropyl)-bristamine

類似於針對製備中間物Α-1 [Β]所述之程序，丨_胺基-環 丙烷曱酸{(外消旋）-6-[5-氯-3-氟-2-(2-甲基_27/·四唑巧_基）_ 苯基]-2,3_二氫-苯并[纟]嘆吩_3_基}-隨胺（實例61)已與喷 啶-5-曱酸偶合，得到呈淡黃色非晶形固體狀之標題化合 物。MS: 551.1 (MH+，1C1)。 實例64 異噁唑-5-甲酸（1-{(外消旋）-6-【5·氣-3-氟-2-(2-甲基-2丑-四 唑-5-基）-苯基〗-2,3_二氫-苯并[6】噻吩-3-基胺甲醯基卜環丙 基醯胺 160800.doc -131- 201245158Similar to the procedure described for the preparation of the intermediate Α-1 [Β], 丨-amino-cyclopropanoic acid {(racemic)-6-[5-chloro-3-fluoro-2-(2-) Base _27/·tetrazolidine _ yl) phenyl]-2,3-dihydro-benzo[纟] spur _3_yl}- with amine (Example 61) has been combined with pyridine-5-曱The title compound was obtained as a pale yellow amorphous solid. MS: 551.1 (MH+, 1C1). Example 64 Isoxazol-5-carboxylic acid (1-{(racemic)-6-[5·gas-3-fluoro-2-(2-methyl-2 ugly-tetrazol-5-yl)-benzene) Base -2,3_dihydro-benzo[6]thiophen-3-ylaminecarboxamidocyclopropyl decylamine 160800.doc -131- 201245158

胺基4 基)- 口惡 MS： 類似於針對製備中間物A-1 [B]所述之程序，] 丙烷曱酸{(外消旋氯-3-氟-2-(2-甲基-2β-四咬 笨基]-2,3-二氫-苯并[6]噻吩-3-基}-醯胺（實例61)已與異 唑-5-甲酸偶合，得到呈淡黃色油狀之標題化合物 540.1 (MH+, 1C1)。 實例65 3-甲氧基-異噁唑-5-甲酸（1-{(外消旋）-6-[5·氣-3-氣_2-(2-甲 基_2丑-四唑-5-基广苯基]-2,3-二氫-苯并[6】噻吩-3-基胺乎酿 基}-環丙基）-醯胺Amino 4-yl)- aceton MS: similar to the procedure described for the preparation of intermediate A-1 [B],] propane decanoic acid {(racemic chloro-3-fluoro-2-(2-methyl-) 2β-tetradentate]-2,3-dihydro-benzo[6]thiophen-3-yl}-decylamine (Example 61) has been coupled with isoxazol-5-carboxylic acid to give a pale yellow oil. Title Compound 540.1 (MH+, 1C1). Example 65 3-Methoxy-isoxazole-5-carboxylic acid (1-{(racemic)-6-[5·gas-3-gas_2-(2- Methyl-2 ugly-tetrazol-5-ylpolyphenyl]-2,3-dihydro-benzo[6]thiophen-3-ylamine}}-cyclopropyl)-guanamine

類似於針對製備中間物A-1 [B]所述之程序’ 1_胺基-環 丙烷曱酸{(外消旋）_6_[5-氯_3-氟_2_(2_曱基_2孖-四唑-5_基）_ 160800.doc * 132- 201245158 氧基-異噁峻-5-曱酸偶合，得到呈淡黃 物。MS: 570.1 (ΜΗ+，.1C1)。 實例A 式⑴化合物可依本身 已知之方式作為 具有以下組成之錠劑： 每錠劑 活性成分 200 mg 微晶纖維素 155 mg 玉米澱粉 25 mg 滑石 25 mg 羥丙基曱基纖維素 20 me 425 mg 油狀之標題化合Similar to the procedure described for the preparation of intermediate A-1 [B] '1_Amino-cyclopropane decanoic acid {(racemic)_6_[5-chloro-3-trifluoro_2_(2_mercapto-2-)孖-tetrazole-5-yl)_160800.doc * 132- 201245158 Oxy-isoxan-5-decanoic acid coupling gives a pale yellow color. MS: 570.1 (ΜΗ+,.1C1). Example A The compound of the formula (1) can be used as a tablet having the following composition in a manner known per se: 200 mg of microcrystalline cellulose 155 mg of corn starch 25 mg talc 25 mg hydroxypropyl decyl cellulose 20 me 425 mg per tablet active ingredient Oily title combination

Ο 實例Β 式⑴化合物可依本身已知之方式作 、作為活性成分用於劁 具有以下組成之膠囊： &amp;備 活性成分 每膠囊 100.0 mg 玉米澱粉 20.0 mg 乳糖 95.0 mg 滑石 4.5 mg 硬脂酸鎂 0.5 ms 220.0 mg 160800.doc • 133 -Β Example 化合物 The compound of the formula (1) can be used as an active ingredient in a capsule known per se for the following composition: &amp; Active ingredient 100.0 mg per capsule Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 Ms 220.0 mg 160800.doc • 133 -

Claims (1)

201245158 七、申請專利範圍： 1. 一種式（I)化合物，201245158 VII. Patent application scope: 1. A compound of formula (I), (I) 其中 r1為烷基、環烷基、環烷基烷基、烷氧基、烷氧基 烧基、環烷氧基、環烷氧基烷基、齒烷基、蟲烧 氧基、函烷氧基烷基、齒環烷基、函環烷基烷 基、i環烷氧基、_環烷氧基烷基、烷氧基羰 基、環烧氧基幾基、鹵烧氧基幾基、函環烧氧基 羰基、氰基、芳基、經取代之芳基、雜芳基或經 取代之雜芳基，其中經取代之芳基及經取代之雜 芳基經一至三個獨立地選自以下之取代基取代： 烷基、環烷基、烷基環烷基、環烷基烷基、環烷 基烧氧基、環院基燒氧基烧基、環烧氧基、環統 氧基烷基、烷基環烷基烷基、i環烷基、齒環烷 基烧基、ώ素、氰基、齒烧基、烧氧基、院氧基 烷基、鹵烷氧基、烷氧基烷氧基、烷氧基烷氧基 烷基、胺基及經取代之胺基，其中經取代之胺基 經一至兩個獨立地選自以下之取代基取代：烷 基、環烷基、烷基環烷基、環烷基烷基、烷基環 160800.doc -1 201245158 烷基烷基、羥基烷基及烷氧基烷基； R2 為氫、烷基、鹵烷基、烷氧基、環烷基、氰基或 鹵素； R3 為氫、烧基、鹵烧基、烧氧基、環烧基、氰基或 鹵素； R4 為氫、烷基、鹵烷基、烷氧基、環烷基、氰基或 鹵素； R5 為氫、烷基、鹵烷基、烷氧基、環烷基、氰基或 鹵素； R6 為氫、烷基、鹵烷基、烷氧基、環烷基、氰基或 鹵素； R7 為氫、烷基或環烷基； R8 為氫、烷基或環烷基； R9 為氮、烧基或環烧基； R10 為氫、烷基或環烷基； 或R及R與其所連接之碳一起形成環烧基或雜環院基； R11 為氫、烷基或環烷基； R12 為氫、烷基、環烷基或-C(0)-R13 ; R13為烷基、環烷基、環烷基烷基、烷氧基、燒氧基 烷氧基、環烷氧基、齒環烷氧基、烷氧基烧基、 環烷氧基烷基、函烷基、_烷氧基烷基、齒環烷 基、齒環烷基烷基、鹵環烷氧基烷基、芳臭、η ** '''jt-, 取代之芳基、雜芳基或經取代之雜芳基，其中妙 取代之芳基及經取代之雜芳基經一至三個獨立地 160800.doc 201245158 選自以下之取代基取代：烷基、環烷基、烷基環 烷基、環烷基烷基、環烷基烷氧基、環烷基烷氧 基烷基、環烷氧基、環烷氧基烷基、烷基環烷基 烧基、鹵環院基、_環院基院基、鹵素、氣基、 鹵烷基、羥基、羥基烷基、烷氧基、烷氧基烷 基、函烷氧基、羥基烷氧基、烷氧基烷氧基、烷 氧基烷氧基烷基、羥基_烷基、胺基及經取代之 胺基，其中經取代之胺基經一至兩個獨立地選自 以下之取代基取代：烷基、環烷基、烷基環烷 基、環烷基烷基、烷基環烷基烷基、羥基烷基及 烷氧基烷基； Rl4 為氫、烷基、烷氧基或環烷基； Rl5 為氫、烷基或環烷基； Rl6 為氫、烷基、鹵烷基、烷氧基、環烷基、氰基或 鹵素； A1 為 CR14、〇、NR15 或 S ; A2 為 CR16 或 N; n 為1、2或3 ; 或醫藥學上可接受之鹽。 2·如請求項1之化合物，其中Ri為鹵烷氧基、烷氧基羰 基·'環烷氧基羰基、鹵烷氧基羰基、雜芳基或經取代之 雜芳基’其中經取代之雜芳基經一至三個烷基取代。 3.如請求項1或2之化合物，其中R1為鹵烷氧基、烷氧基羰 基或經取代之雜芳基，其中經取代之雜芳基經一至三個 160800.doc 201245158 烧基取代。 4. 如請求項1或2之化合物，其中Ri為鹵烷氧基、烷氧基羰 基、燒基°惡二。坐基或烧基四°坐基。 5. 如請求項1或2之化合物，其中R1為烷基噁二唑基。 6·如請求項1或2之化合物，其中R1為甲基噁二唑基。 7.如請求項1或2之化合物，其中Ri為烷基四唑基。 8·如請求項1或2之化合物，其中R1為甲基四唑基。 9.如請求項1或2之化合物，其中R2為氫或鹵素。 10·如請求項1或2之化合物，其中R2為鹵素。 11，如請求項1或2之化合物，其中R2為氣或氟。 12. 如請求項1或2之化合物，其中R3為氫。 13. 如請求項1或2之化合物，其中R4為氫或鹵素。 14. 如請求項1或2之化合物，其中R4為鹵素。 15·如請求項1或2之化合物，其中R4為氯。 16·如請求項1或2之化合物，其中R5為氫。 17·如請求項1或2之化合物，其中R6為氫。 18·如請求項1或2之化合物，其中R7為氫或烷基。 19.如請求項1或2之化合物，其中R7為氫。 20·如請求項1或2之化合物，其中R8為氫。 21.如請求項1或2之化合物，其中R9為氫、烷基或環烷基。 22·如請求項丨或2之化合物，其中RlG為氫、烷基或環烷基。 23. 如請求項1或2之化合物，其中R9及rIG與其所連接之碳一 起形成環烷基或雜環烷基。 24. 如請求項丨或2之化合物，其中r9&amp;r1Q與其所連接之碳一 160800.doc 201245158 起形成環烷基。 25.如請求項1或2之化合物，其中R9及R1Q與其所連接之碳一 起形成雜環烷基。 26·如請求項1或2之化合物，其中R9及R1G與其所連接之碳一 起形成環烷基或氧雜環丁烷基。 27.如請求項1或2之化合物，其中R9及R1Q與其所連接之碳一 起形成環丙基。 ◎ 28·如請求項1或2之化合物，其中R9及R1G與其所連接之碳一 起形成氧雜環丁烷基。 29, 如請求項1或2之化合物，其中pu為氫。 30. 如請求項丨或2之化合物，其中R!2為氫、烷基或環烷基。 3 L如請求項1或2之化合物，其中R12為氫。 32.如请求項1或2之化合物，其中R12為氫或_c(0)-R13。 33，如请求項1或2之化合物，其中r12為_c(〇)_r13。 34. 如請求項1或2之化合物，其中為烷氧基、烷氧基烷 ◎ 基、環烷氧基烷基、鹵烷基、鹵烷氧基烷基、鹵環烷 基、i環烷基烷基、i環烷氧基烷基、芳基、經取代之 ^基、雜芳基或經取代之雜芳基，其中經取代之芳基及 經取代之雜芳基經一至三個獨立地選自以下之取代基取 代：烷基、環烷基、函素、氰基、_烷基、烷氧基、烷 氧基烧基、胺基及經取代之胺基，其中經取代之胺基經 一至兩個獨立地選自烷基及環烷基之取代基取代。 35. 如請求項1或2之化合物，其中Rn為烷氧基、烷氧基烷 基、鹵烧基、經取代之苯基、雜芳基或經取代之雜芳 160800.doc 201245158 基，其中經取代之苯基及經取代之雜芳基經一至三個獨 立地選自炫基、鹵素、鹵烧基、烧氧基及胺基之取代基 取代。 36.如請求項1或2之化合物，其中R13為烷氧基' 鹵烷基、雜 芳基或經取代之雜芳基，其中經取代之雜芳基經一至三 個烷氧基取代基取代。 3 7.如請求項1或2之化合物，其中R13為烷氧基、烷氧基烷 基、鹵貌基、咪嗤基、異噁唑基、噁二唑基、嗟二唆 基、°比啶基、噠嗪基、嘧啶基，或選自經一至三個獨立 地選***基、_素、_烧基、烧氧基及胺基之取代基取 代之苯基、V»米哇基、異。惡β坐基、噪二唾基、嘆二。坐基、 °比σ定基、健嗓基及嘯咬基。 3 8.如請求項！或2之化合物，其中R13為烷氧基、鹵烷基、異 噁唾基、噁二唑基、噠嗪基、嘧啶基，或選自經一至三 個烷氧基取代基取代之異噁唑基及噁二唑基。 39. 如請求項】或2之化合物，其中r】3為三氟甲基、甲氧基異 °惡α坐基、建°秦基、°密°定基或甲氧基0^ β定基。 40. 如請求項丨或2之化合物，其中R〗3為鹵烷基、烷氧基異噁 °坐基'噠嗪基或烷氧基嘧啶基。 41. 如請求項1或2之化合物，其中R!3為三氟曱基、曱氧基異 °惡σ坐基、噠嗪基或甲氧基嘧啶基。 42·如請求項1或2之化合物，其中Α1為CR丨4、Ο或S。 43. 如請求項1或2之化合物，其中Αι為CR&quot;。 44. 如請求項1或2之化合物，其中Αι為〇。 160800.doc 201245158 45.如請求項1或2之化合物 ，其中A1為S。 46·如請求項1或2之化合物 ，其中A1為NR15。 47.如請求項1或2之化合物 ，其中A2為CR16。 4 8·如請求項1或2之化合物 ，其中A2為N。 49.如請求項1或2之化合物 ，其中R14為氫。 5 0.如請求項1或2之化合物 ，其中R15為氫。 5 1 ·如請求項1或2之化合物 ，其中R16為氫戒鹵素。 52.如請求項1或2之化合物 ，其中R16為氫。 53·如請求項1或2之化合物 ，其中R16為鹵素。 54.如請求項1或2之化合物 ，其中R16為氟。 55·如請求項1或2之化合物 ，其中η為1或2。 56.如請求項1或2之化合物 ，其中η為1。 57·如請求項1或2之化合物 ，其係選自： (外消旋）-2-(l-{[ 1-(2,2,2-三氟-乙醯胺基）_環丙院艘 基]胺基}-茚滿（indan)-5-基）-苯甲酸甲酿， Q 1-(2,2,2-三氟_乙醯胺基）-環丙烷甲酸{(外消旋）_5_[3,5- 二氯_2-(2,2-二氟-乙氧基）-苯基]-茚滿-1-基h醯胺； . (外消旋）-2-氣-6-(1-{[1-(2,2,2-三氟-乙醯胺基）_環丙烷 幾基]-胺基}_茚滿-5·基）-苯甲酸曱酯； 1-(2,2,2-三氟-乙醯胺基）_環丙烷甲酸{(外消旋）-5_[5_ 氯氟-2-(5-甲基-[1，2,4]噁二唑-3-基）-苯基]茚滿_1_ 基}-醯胺； 1-(2,2,2-三氟-乙醯胺基）_環丙烷甲酸{(S)-5-[5-氣-3-氟 -2-(5-甲基-H4]噁二唑_3_基）-苯基卜茚滿-l-基 }-醯胺； 160800.doc 201245158 2- 氣-6-((8)-1-{[3-(2,2,2-三氟_乙醯胺基）_氧雜環丁烷 -3-幾基]-胺基}-茚滿-5-基）-苯甲酸甲醋； 3- (2,2,2-二氟-乙醯胺基）_氧雜環丁烷_3_甲酸《（s)_5_[5_ 氣-3-氟-2-(5-曱基-[1，2,4]噁二唑_3_基苯基]_茚滿_卜 基}-醯胺； 3-(2,2,2-三氟-乙醯胺基）-氧雜環丁烷_3_曱酸{(s)_5_[5_ 氣- 3-11-2-(2-曱基-2H-四嗤-5-基）_苯基]-茚滿- i-基}-醯 胺； 1-(2,2,2-三氟-乙酿胺基）-環丙烧甲酸{(外消旋）-6-[3,5-二氯-2-(2,2-二氟-乙氧基）-苯基]-1,2,3,4-四氫-萘-1-基}_ 醯胺； (外消旋）-2-氣-6-(5-{[l-(2,2,2-三氟-乙醯胺基）-環丙烧 羰基]-胺基}-5,6,7,8-四氫-萘-2-基）-苯甲酸曱醋； 1-(2,2,2-三氟-乙醯胺基）-環丙烷甲酸{(外消旋）_6_[5_ 氯-3-氟-2-(5-曱基-[1，2,4]噁二唑-3-基）-苯基]-1，2,3,4-四 虱-秦-l-基}-酿胺； 1-(2,2,2-三氟-乙醢胺基）-環丙烷甲酸（（外消旋）_3_[5_ 氯-3-氟-2-(5-曱基-[1,2,4]噁二唑-3-基）_苯基]-6,7一氫 -5H-[1]吡啶-7-基}-醯胺； 1-(2,2,2-三氟-乙醯胺基）-環丙烷甲酸{(外/肖旋）[ Ί 厶 二氫-5Η-Π] 氣-3-氟-2-(2-曱基-2Η-四唑-5-基）-苯基J-0，_ 一 吡啶-7-基醯胺； μ β祕Η外消旋）_7_ 1-(2,2,2-三氟-乙醯胺基）_環丙烷甲酸. a、策基]-&quot;克嫁 氯-3-氟-2-(5-甲基-[1，2,4]噁二唑-3-基）-冬 160800.doc -8 - 201245158 基}-醯胺； l-(2,2,2-三氟-乙醯胺基）-環丙烷甲酸{(外消旋）-7_[5 氣-3-氤-2-(2-曱基-2H-四唑-5-基）-苯基]-咣烷基卜酿 胺； 1-(2,2,2-三氟-乙醯胺基）-環丙烷甲酸{(外消旋）-5-[5 氯-3-氟-2-(5-曱基-[1,2,4]噁二唑-3-基）-苯基]_7-氣-節滿 -l-基} -醢胺； 1-(2,2,2-三氟-乙醯胺基）-環丙烷甲酸{(外消旋）_5-[5-氣-3-氟-2-(5-甲基-[1，2,4]噁二唑-3-基）-苯基]-1-甲基-節 滿-1 -基}-酿胺； 1-(2,2,2-三氟-乙醯胺基）-環丙烷甲酸{5-[5-氯-3-氟-2_ (2-甲基-2H-四唑-5-基）-苯基]-1·曱基-茚滿-卜基}_醯胺； 1-(2,2,2-三氟·乙醯胺基）_環丙烷甲酸{(外消旋）_6-[5· 氣-3-氟-2-(5-曱基-[1,2,4]噁二唑 _3_基）-苯基]-2,3-二氫_ 苯并呋喃-3-基}-醯胺； 1-(2,2,2-三氟-乙醯胺基）_環丙烷甲酸{(外消旋）-6-[5-氯-3-氟-2-(2-曱基-2H-四唑-5-基）-苯基]-2,3-二氫-苯并呋 喃-3-基}-醯胺； 1-(2,2,2-三氟-乙醯胺基）-環丙烧甲酸{(外消旋）-6-[5-氯-3-H-2-(5-甲基-[1，2,4]噁二唑 _3_ 基）_ 苯基]-2,3-二氫_ 苯并[b]噻吩_3_基}_醯胺； 。（。，之’：-三氟-乙醯胺基卜環丙烧曱酸^外消旋兴石-!^-氯-3-氟-2-(2-曱基-2H-四唑-5-基）-苯基]-2,3-二氫-苯并 [b]喧吩基卜醯胺； 160800.doc 201245158 (l-{(S)-5-[5-氯-3-氟-2-(5-甲基-[1,2,4]噁二唑-3-基）-苯 基]-茚滿-卜基胺曱醯基}-環丙基）-胺基甲酸第三丁酯； 1- 胺基-環丙烷甲酸{(S)-5-[5-氯-3-氟-2-(5-甲基-[1，2,4] 噁二唑-3-基）-苯基]-茚滿-l-基}-醯胺； 嘧啶-5-甲酸（l-{(S)-5-[5-氯-3-氟-2-(5-甲基-[1,2,4]噁 二唑-3-基）-苯基]-節滿-1-基胺甲醯基}-環丙基）-醯胺； 2- 曱氧基-嘧啶-5-曱酸（卜{(S)-5-[5-氯-3-氟-2-(5-曱 基-[1，2,4]噁二唑-3-基）-苯基]-茚滿-1-基胺曱醯基}-環丙 基）-醯胺； 噠嗪-4-甲酸（l-{(S)-5-[5-氯-3-氟-2-(5-甲基-[1，2,4]噁 二唑-3-基）-苯基]-茚滿-1-基胺甲醯基}-環丙基）-醯胺； 異噁唑-5-曱酸（l-{(S)-5-[5-氣-3-氟-2-(5-甲基-[1,2,4] 噁二唑-3-基）-苯基]-茚滿-1-基胺甲醯基卜環丙基）-醯 胺； 5-曱基-[1,3,4]噁二唑-2-甲酸（1-{(8)-5-[5-氯-3-氟-2-(5-甲基-[1，2,4]噁二唑-3-基）-苯基]-茚滿-1-基胺曱醯基}-環丙基）-醯胺； 3- 甲氧基-異噁唑-5-甲酸（l-{(S)-5-[5-氯-3-氟-2-(5-甲 基-[1,2,4]噁二唑-3-基）-苯基]-茚滿-1-基胺曱醯基}-環丙 基）-酿胺； 及其醫藥學上可接受之鹽。 58.如請求項1或2之化合物，其係選自： (1-{(外消旋）-5-[5-氯-3-氟-2-(5-甲基-[1，2,4]噁二唑-3-基）-苯基]-7-氟-茚滿-1-基胺甲醯基}-環丙基）-胺基曱酸 160800.doc -10- 201245158 第三丁酯 -胺基-環丙烷甲酸{(外消旋）-5-[5_氯 -氟 2 胺(I) wherein r1 is alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkoxyalkyl, alkenyl, oxalyloxy, Alkoxyalkyl, cycline, cycloalkylalkyl, i cycloalkoxy, _cycloalkoxyalkyl, alkoxycarbonyl, cycloalkoxy, alkoxy a cyclized oxycarbonyl group, a cyano group, an aryl group, a substituted aryl group, a heteroaryl group or a substituted heteroaryl group, wherein the substituted aryl group and the substituted heteroaryl group are independently one to three Substituted for substituents selected from the group consisting of alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, ring-based alkoxyalkyl, cycloalkoxy, ring Alkoxyalkyl, alkylcycloalkylalkyl, i cycloalkyl, cyclyl alkyl, halogen, cyano, dentate, alkoxy, alkoxyalkyl, haloalkoxy An alkoxyalkoxy group, an alkoxyalkoxyalkyl group, an amine group, and a substituted amine group, wherein the substituted amine group is substituted with one to two substituents independently selected from the group consisting of an alkyl group and a ring. Alkyl, alkylcycloalkyl, ring Alkyl, alkyl ring 160800.doc -1 201245158 alkylalkyl, hydroxyalkyl and alkoxyalkyl; R2 is hydrogen, alkyl, haloalkyl, alkoxy, cycloalkyl, cyano or Halogen; R3 is hydrogen, alkyl, haloalkyl, alkoxy, cycloalkyl, cyano or halogen; R4 is hydrogen, alkyl, haloalkyl, alkoxy, cycloalkyl, cyano or halogen; R5 is hydrogen, alkyl, haloalkyl, alkoxy, cycloalkyl, cyano or halogen; R6 is hydrogen, alkyl, haloalkyl, alkoxy, cycloalkyl, cyano or halogen; R7 is Hydrogen, alkyl or cycloalkyl; R8 is hydrogen, alkyl or cycloalkyl; R9 is nitrogen, alkyl or cycloalkyl; R10 is hydrogen, alkyl or cycloalkyl; or R and R are attached thereto The carbon together form a cycloalkyl or heterocyclic compound; R11 is hydrogen, alkyl or cycloalkyl; R12 is hydrogen, alkyl, cycloalkyl or -C(0)-R13; R13 is alkyl, cycloalkyl , cycloalkylalkyl, alkoxy, alkoxyalkoxy, cycloalkoxy, cyclidine, alkoxyalkyl, cycloalkoxyalkyl, alkoxy, _alkoxy Alkyl, cyclinyl, cyclylalkyl , halocycloalkoxyalkyl, aroma, η ** '''jt-, substituted aryl, heteroaryl or substituted heteroaryl, wherein the substituted aryl and substituted heteroaryl Substituted by one to three independently 160800.doc 201245158 substituents selected from the group consisting of alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxy Alkyl, cycloalkoxy, cycloalkoxyalkyl, alkylcycloalkylalkyl, halo ring, cycline, halogen, gas, haloalkyl, hydroxy, hydroxyalkyl, Alkoxy, alkoxyalkyl, alkoxy, hydroxyalkoxy, alkoxyalkoxy, alkoxyalkoxyalkyl, hydroxy-alkyl, amine and substituted amine, Wherein the substituted amine group is substituted with one to two substituents independently selected from the group consisting of alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, hydroxyalkyl And alkoxyalkyl; R14 is hydrogen, alkyl, alkoxy or cycloalkyl; Rl5 is hydrogen, alkyl or cycloalkyl; R16 is hydrogen, alkyl, haloalkyl, alkoxy, cycloalkane Base Or halogen; A1 is CR14, square, NR15 or S; A2 is CR16 or N; n is 1, 2 or 3; or a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein Ri is a haloalkoxy group, an alkoxycarbonyl group, a 'cycloalkoxycarbonyl group, a haloalkoxycarbonyl group, a heteroaryl group or a substituted heteroaryl group, which is substituted The heteroaryl group is substituted with one to three alkyl groups. 3. A compound according to claim 1 or 2, wherein R1 is haloalkoxy, alkoxycarbonyl or substituted heteroaryl, wherein the substituted heteroaryl is substituted with one to three 160800.doc 201245158 alkyl. 4. A compound according to claim 1 or 2, wherein Ri is haloalkoxy, alkoxycarbonyl, decyl. Sitting base or burning base four ° sitting base. 5. The compound of claim 1 or 2, wherein R1 is alkyloxadiazolyl. 6. The compound of claim 1 or 2, wherein R1 is methyloxadiazolyl. 7. The compound of claim 1 or 2 wherein Ri is an alkyltetrazolyl group. 8. The compound of claim 1 or 2 wherein R1 is methyltetrazolyl. 9. The compound of claim 1 or 2 wherein R2 is hydrogen or halogen. 10. The compound of claim 1 or 2 wherein R2 is halogen. 11. The compound of claim 1 or 2, wherein R2 is gas or fluorine. 12. The compound of claim 1 or 2, wherein R3 is hydrogen. 13. The compound of claim 1 or 2, wherein R4 is hydrogen or halogen. 14. The compound of claim 1 or 2, wherein R4 is halogen. 15. The compound of claim 1 or 2 wherein R4 is chloro. 16. The compound of claim 1 or 2 wherein R5 is hydrogen. 17. The compound of claim 1 or 2 wherein R6 is hydrogen. 18. The compound of claim 1 or 2 wherein R7 is hydrogen or alkyl. 19. The compound of claim 1 or 2, wherein R7 is hydrogen. 20. The compound of claim 1 or 2, wherein R8 is hydrogen. 21. The compound of claim 1 or 2 wherein R9 is hydrogen, alkyl or cycloalkyl. 22. The compound of claim 2 or 2, wherein R1G is hydrogen, alkyl or cycloalkyl. 23. The compound of claim 1 or 2, wherein R9 and rIG together with the carbon to which they are attached form a cycloalkyl or heterocycloalkyl group. 24. The compound of claim 2 or 2, wherein r9&amp;r1Q forms a cycloalkyl group with the carbon to which it is attached, 160800.doc 201245158. 25. The compound of claim 1 or 2, wherein R9 and R1Q together with the carbon to which they are attached form a heterocycloalkyl group. The compound of claim 1 or 2, wherein R9 and R1G together with the carbon to which they are attached form a cycloalkyl or oxetane group. 27. The compound of claim 1 or 2, wherein R9 and R1Q together with the carbon to which they are attached form a cyclopropyl group. The compound of claim 1 or 2, wherein R9 and R1G together with the carbon to which they are attached form an oxetane group. 29. The compound of claim 1 or 2, wherein pu is hydrogen. 30. The compound of claim 2 or 2, wherein R!2 is hydrogen, alkyl or cycloalkyl. 3 L. The compound of claim 1 or 2, wherein R12 is hydrogen. 32. The compound of claim 1 or 2, wherein R12 is hydrogen or _c(0)-R13. 33. The compound of claim 1 or 2, wherein r12 is _c(〇)_r13. 34. The compound of claim 1 or 2 which is alkoxy, alkoxyalkyl, cycloalkoxyalkyl, haloalkyl, haloalkoxyalkyl, halocycloalkyl, i cycloalkane An alkyl group, an i cycloalkoxyalkyl group, an aryl group, a substituted group, a heteroaryl group or a substituted heteroaryl group, wherein the substituted aryl group and the substituted heteroaryl group are independently one to three Substituted with a substituent selected from the group consisting of an alkyl group, a cycloalkyl group, a hydroxyl group, a cyano group, an alkyl group, an alkoxy group, an alkoxyalkyl group, an amine group, and a substituted amine group, wherein the substituted amine The group is substituted with one to two substituents independently selected from the group consisting of alkyl and cycloalkyl. 35. The compound of claim 1 or 2, wherein Rn is alkoxy, alkoxyalkyl, haloalkyl, substituted phenyl, heteroaryl or substituted heteroaryl 160800.doc 201245158, wherein The substituted phenyl and substituted heteroaryl are substituted with one to three substituents independently selected from the group consisting of leucine, halogen, haloalkyl, alkoxy and amine groups. 36. The compound of claim 1 or 2, wherein R13 is alkoxy 'haloalkyl, heteroaryl or substituted heteroaryl, wherein substituted heteroaryl is substituted with one to three alkoxy substituents . 3. The compound of claim 1 or 2, wherein R13 is alkoxy, alkoxyalkyl, halomorphyl, imidazyl, isoxazolyl, oxadiazolyl, indane, decyl a pyridyl group, a pyridazinyl group, a pyrimidinyl group, or a phenyl group selected from one to three substituents independently selected from the group consisting of an alkyl group, a sulfonyl group, a decyl group, an alkoxy group, and an amine group, and a V»miwa group ,different. The evil β is sitting on the base, the noise is two, and the second is sigh. Sitting base, ° ratio σ base, health base and squeak base. 3 8. As requested! Or a compound of 2, wherein R13 is alkoxy, haloalkyl, isopropyryl, oxadiazolyl, pyridazinyl, pyrimidinyl, or isoxazole selected from one to three alkoxy substituents And oxadiazolyl. 39. The compound of claim 2 or 2, wherein r 3 is trifluoromethyl, methoxyiso-α, or thiol-based or methoxy 0-β. 40. The compound of claim 2 or 2, wherein R is 3 haloalkyl, alkoxyisoxanylpyrazine or alkoxypyrimidinyl. 41. The compound of claim 1 or 2, wherein R!3 is trifluoromethyl, decyloxy, oxazino, pyridazinyl or methoxypyrimidinyl. 42. The compound of claim 1 or 2, wherein Α1 is CR丨4, Ο or S. 43. The compound of claim 1 or 2, wherein Αι is CR&quot;. 44. The compound of claim 1 or 2, wherein Αι is 〇. 160800.doc 201245158 45. The compound of claim 1 or 2 wherein A1 is S. 46. The compound of claim 1 or 2, wherein A1 is NR15. 47. The compound of claim 1 or 2, wherein A2 is CR16. 4 8. The compound of claim 1 or 2, wherein A2 is N. 49. The compound of claim 1 or 2, wherein R14 is hydrogen. The compound of claim 1 or 2, wherein R15 is hydrogen. 5. A compound according to claim 1 or 2 wherein R16 is hydrogen or halogen. 52. The compound of claim 1 or 2, wherein R16 is hydrogen. 53. The compound of claim 1 or 2, wherein R16 is halogen. 54. The compound of claim 1 or 2, wherein R16 is fluoro. 55. The compound of claim 1 or 2, wherein n is 1 or 2. 56. The compound of claim 1 or 2, wherein n is 1. 57. The compound of claim 1 or 2, which is selected from the group consisting of: (racemic)-2-(l-{[1-(2,2,2-trifluoro-acetamido)-cyclopropene Alkyl}-amino}-indan-5-yl)-benzoic acid, Q 1-(2,2,2-trifluoro-acetamido)-cyclopropanecarboxylic acid {(racemic) _5_[3,5-Dichloro-2-(2,2-difluoro-ethoxy)-phenyl]-indan-1-ylh-amine; (racemic)-2-gas- 6-(1-{[1-(2,2,2-trifluoro-acetamido)-cyclopropanyl]-amino}-indan-5-yl)-benzoic acid oxime ester; (2,2,2-trifluoro-acetamido)-cyclopropanecarboxylic acid {(racemic)-5_[5-chlorofluoro-2-(5-methyl-[1,2,4]oxadiazole -3-yl)-phenyl]indano_1_yl}-decylamine; 1-(2,2,2-trifluoro-acetamido)-cyclopropanecarboxylic acid {(S)-5-[5- Gas-3-fluoro-2-(5-methyl-H4)oxadiazole_3_yl)-phenylindole-l-yl}-decylamine; 160800.doc 201245158 2-gas-6-( (8)-1-{[3-(2,2,2-trifluoro-ethylamino)-oxetan-3-yl]-amino}-indan-5-yl)- Methyl benzoate; 3-(2,2,2-difluoro-acetamido)-oxetane_3_carboxylic acid "(s)_5_[5_ gas-3-fluoro-2-(5- Mercapto-[1,2,4]oxadiazole_3_ylphenyl]_茚__基基}-decylamine; 3-(2,2,2-trifluoro-acetamido)-oxetane_3_decanoic acid {(s)_5_[5_ gas - 3-11- 2-(2-indolyl-2H-tetraindole-5-yl)-phenyl]-indan-i-yl}-decylamine; 1-(2,2,2-trifluoro-ethinyl) - Cyclopropanecarboxylic acid {(racemic)-6-[3,5-dichloro-2-(2,2-difluoro-ethoxy)-phenyl]-1,2,3,4-tetra Hydrogen-naphthalen-1-yl}-decylamine; (racemic)-2-gas-6-(5-{[l-(2,2,2-trifluoro-acetamido)-cyclopropanone Carbonyl]-amino}-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzoic acid vinegar; 1-(2,2,2-trifluoro-acetamido)-cyclopropane Formic acid {(racemic)_6_[5-chloro-3-fluoro-2-(5-fluorenyl-[1,2,4]oxadiazol-3-yl)-phenyl]-1,2,3, 4-tetrahydro-Qin-l-yl}-bristamine; 1-(2,2,2-trifluoro-acetamido)-cyclopropanecarboxylic acid ((racemic)_3_[5_ chloro-3-fluoro -2-(5-fluorenyl-[1,2,4]oxadiazol-3-yl)-phenyl]-6,7-hydro-5H-[1]pyridin-7-yl}-decylamine; 1-(2,2,2-trifluoro-acetamido)-cyclopropanecarboxylic acid {(external/xisic) [ Ί 厶 dihydro-5 Η-Π] gas-3-fluoro-2-(2-曱Η-2Η-tetrazol-5-yl)-phenyl J-0,_-pyridin-7-yl decylamine; μ β secret Η racemic _7_ 1-(2,2,2-trifluoro- Acetylamino)-cyclopropanecarboxylic acid. a, ceramide]-&quot; gram graft chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)- Winter 160800.doc -8 - 201245158 base}-guanamine; l-(2,2,2-trifluoro-acetamido)-cyclopropanecarboxylic acid {(racemic)-7_[5 gas-3-氤2-(2-mercapto-2H-tetrazol-5-yl)-phenyl]-indenylalkylamine; 1-(2,2,2-trifluoro-acetamido)-cyclopropane Formic acid {(racemic)-5-[5 chloro-3-fluoro-2-(5-fluorenyl-[1,2,4]oxadiazol-3-yl)-phenyl]-7-gas-section --l-yl}-decylamine; 1-(2,2,2-trifluoro-acetamido)-cyclopropanecarboxylic acid {(racemic)_5-[5-gas-3-fluoro-2- (5-Methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-1-methyl-pump-1-yl}-bristamine; 1-(2,2,2 -trifluoro-acetamido)-cyclopropanecarboxylic acid {5-[5-chloro-3-fluoro-2_(2-methyl-2H-tetrazol-5-yl)-phenyl]-1 fluorenyl -茚满-卜基}_醯amine; 1-(2,2,2-trifluoroethylamino)-cyclopropanecarboxylic acid {(racemic)_6-[5·gas-3-fluoro-2 -(5-fluorenyl-[1,2,4]oxadiazole-3-yl)-phenyl]-2,3-dihydro-benzofuran-3-yl}-decylamine; 1-(2 , 2,2-trifluoro-acetamido)-cyclopropanecarboxylic acid {(racemic)-6-[5-chloro-3- -2-(2-amily-2H-tetrazol-5-yl)-phenyl]-2,3-dihydro-benzofuran-3-yl}-decylamine; 1-(2,2,2 -trifluoro-acetamido)-cyclopropanecarboxylic acid {(racemic)-6-[5-chloro-3-H-2-(5-methyl-[1,2,4]oxadiazole _3_基)_phenyl]-2,3-dihydro-benzo[b]thiophene-3-yl}-decylamine; (., ''-Trifluoro-acetamidopyridinium acetoacetate ^ racemic Xingshi-!^-chloro-3-fluoro-2-(2-mercapto-2H-tetrazole-5 -yl)-phenyl]-2,3-dihydro-benzo[b]nonyl phenyl hydrazide; 160800.doc 201245158 (l-{(S)-5-[5-chloro-3-fluoro- 2-(5-Methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-indan-b-ylaminomethyl}-cyclopropyl)-carbamic acid tert-butyl Ester; 1-amino-cyclopropanecarboxylic acid {(S)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)- Phenyl]-indan-l-yl}-decylamine; pyrimidine-5-carboxylic acid (l-{(S)-5-[5-chloro-3-fluoro-2-(5-methyl-[1, 2,4]oxadiazol-3-yl)-phenyl]-indol-1-ylaminemethanyl}-cyclopropyl)-guanamine; 2-decyloxy-pyrimidine-5-decanoic acid ( {{S)-5-[5-chloro-3-fluoro-2-(5-fluorenyl-[1,2,4]oxadiazol-3-yl)-phenyl]-indan-1- Amidoxime}-cyclopropyl)-guanamine; pyridazine-4-carboxylic acid (l-{(S)-5-[5-chloro-3-fluoro-2-(5-methyl-[1 , 2,4]oxadiazol-3-yl)-phenyl]-indan-1-ylaminemethanyl}-cyclopropyl)-guanamine; isoxazole-5-decanoic acid (l-{ (S)-5-[5-Gas-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-indan-1-ylamine Hyperthyroidism Propyl)-guanamine; 5-mercapto-[1,3,4]oxadiazol-2-carboxylic acid (1-{(8)-5-[5-chloro-3-fluoro-2-(5- Methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-indan-1-ylaminoindenyl}-cyclopropyl)-guanamine; 3-methoxy-iso Oxazole-5-carboxylic acid (l-{(S)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzene And the pharmaceutically acceptable salt thereof. The compound of claim 1 or 2, which is selected from the group consisting of: 1-{(racemic)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-7- Fluorine-indan-1-ylaminocarbamoyl}-cyclopropyl)-amino decanoic acid 160800.doc -10- 201245158 tert-butyl ester-amino-cyclopropanecarboxylic acid {(racemic)-5- [5_Chloro-fluoro 2 amine G n衣η * 基}… 基-[1，2,4]。惡二唑冬基）·苯基]·7_氣-知/ 氣拿2彳5 — 2- 甲氧基-嘧啶-5-甲酸外消旋乃5 [卜基脓^醯 甲基-[1，2,4]噁二唑-3_基苯基]氟-茚/ 基}-環丙基）-醢胺； λ 氣 噠嗪_仁甲酸（1-{(外消旋）-5-[5_氯胺子醯基卜環 •[1，2,4]β惡二咬-3-基）-苯基]·7·敦_茚滿基 丙基）-釀胺； 5氣—3—氣2 3- 曱氧基-異噁唑-5_甲酸（1气（外消鉍）$ β彳纂胺肀 洛-茆滿-^ (5-甲基-[1,2,4]噁二吐-3_基）_苯基]-7-氟 醯基}-環丙基）-醯胺’ * - ¢^. -3&quot; Μ 2 4 ] (1-{(外消旋）_3_[5-氯-3_氟_2_(5-甲基-[，，瓖丙基）一 基）-苯基]-6,7-二氫-5Η·[1]。比咬-7-基胺甲醢基卜衣 胺基甲酸第三丁酯； 〆2 (5-甲基 1-胺基-環丙烷甲酸忾外消旋）_3-[5_氯-3_氣 7八}_ -『1 2 41唤二唑-3-基）·苯基]_6,7-二氫-5H-[1]吡啶_ f基 醯胺； 3-甲氧基_異噁唑_5_甲酸（1_{(外消旋）_3-[5-氯-^氟&quot;&quot; (5 -甲基-[1，2,4]噁二唑-3-基）-苯基]-6,7-二氮-5H (1] °定-7-基胺甲醢基}-環丙基）_酿胺； 嗔唤_4_甲酸（1-{(外消旋）-3-[5 -氯_3_敢*_2 ( 基-[1，2,4]°惡二唑-3-基）-苯基]-6,7-二氫-51^-[1]°比啶-7基 胺曱醯基卜環丙基）-醯胺； 160800.doc •11 - 201245158 噠嗪-4-曱酸氟-2-(5-甲基-[1’2’ ] α |胳：甲酿 噁二唑-3-基）-苯基;|_6,7_二氫_511-[1]吡啶-7-綦 基}-環丙基）-醯胺； 噠嗪-‘曱酸^气”或…一吋^氯一-氟-玄彳^甲基」1’2’] ，1 gg：甲酿 噁二唑-3-基）-苯基]_6,7_二氫_5H-[1] °比。定_7_泰 基}-壞丙基）-¾胺； ^ 逾-2— (5 ** 2-甲氧基-嘧啶，5-甲酸（1-{(外消旋）-3-[5-氣--甲基-[1，2,4]噁二唑-3-基）-苯基]-6,7-二氫JH-l1]吡0疋7 基胺甲醯基}•環丙基）_醯胺； 異噁唑-5-曱酸（1_{(外消旋）_3-[5-氯-3-氟-2-(5甲 基-[1，2,4]噁二唑-3_基）_ 苯基]_6,7_二氫-5H-[1]°比啶 _7-基 胺曱醯基}-環丙基）-醯胺； (1-{(外消旋）-6-[5-氣-3-氟-2-(5-甲基_[1，2,4]噁二唑_3-基）-苯基]·2,3-二氫-苯并呋喃-3-基胺甲醯基卜環丙基）_胺 基曱酸第三丁酯； 1- 胺基-環丙烧曱酸{(外消旋）-6-[5-氣-3-氟-2-(5-甲 基-[1，2,4]噁二唑-3-基）-苯基]-2,3-二氫-苯并呋喃-3-基}_ 醯胺； 嗔°秦-4-甲酸（1-{(外消旋）-6-[5 -氣-3 -氣-2-(5 -曱 基-[1,2,4]噁二唑-3-基）-苯基]-2,3-二氫-苯并呋喃-3-基胺 曱酿基}-環丙基）-酿胺； 2- 甲氧基-嘧啶·5-甲酸（1-{(外消旋）-6-[5-氣-3-氟-2-(5-甲基-[1，2,4]。惡二嗤-3-基）-苯基]_2,3-二氣-苯并&lt;»夫喃-3-基 胺甲酿基}_環丙基）-酿胺； 160800.doc -12- 201245158 3-曱氧基-異噁唑-5-甲酸（1_{(外消旋氣_3_氟-2_ (5_甲基-[I，2,4]噁二唑_3-基）_苯基]_2,3_二氫”笨并呋喃_3_ 基胺曱酿基}-環丙基）_酿胺； 3-胺基-氧雜環丁烧-3-甲酸{(s)-5-[5-氣-3-氟_2_(5_甲 基-[1,2,4]°惡一嗤基）-苯基]_節滿-1 _基} _酿胺； 嘧啶-5-甲酸（3-{(S)-5-[5-氯-3-氟-2-(5-甲基 二唑-3-基）-苯基]-茚滿-1-基胺曱醯基}-氧雜環丁烧_3_ 基）-醯胺； ΟG n clothing η * base}... base - [1, 2, 4]. Oxadiazole winter base · phenyl]·7_gas-know/gas take 2彳5 — 2-methoxy-pyrimidine-5-carboxylic acid racemic is 5 [Buji pus ^醯methyl-[1 , 2,4]oxadiazole-3-ylphenyl]fluoro-indole/yl}-cyclopropyl)-guanamine; λ gas oxazine_renic acid (1-{(racemic)-5-[ 5_Chloramine 醯 醯 卜 • • [ [ • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • 5 5 Gas 2 3-decyloxy-isoxazole-5-carboxylic acid (1 gas (external consumption) $β amidoxime-茆满-^ (5-methyl-[1,2,4] evil two吐-3_基)_Phenyl]-7-fluoroindolyl}-cyclopropyl)-decylamine ' * - ¢^. -3&quot; Μ 2 4 ] (1-{(racemic)_3_[5 -Chloro-3_fluoro_2_(5-methyl-[,, fluorenyl)-yl)-phenyl]-6,7-dihydro-5Η·[1]. Tetrate -7-ylamine-methionyl-mercaptocarboxylic acid tert-butyl ester; 〆2 (5-methyl-1-amino-cyclopropanecarboxylic acid hydrazine racem)_3-[5_chloro-3_gas 7 八}_ - "1 2 41 oxadiazol-3-yl) phenyl]_6,7-dihydro-5H-[1]pyridine _f decylamine; 3-methoxy oxaisoxazole _ 5_carboxylic acid (1_{(racemic)_3-[5-chloro-^fluoro&quot;&quot; (5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]- 6,7-diaza-5H (1) ° -7-ylaminocarbamoyl}-cyclopropyl)-bristamine; 嗔4_carboxylic acid (1-{(racemic)-3-[ 5-Chloro_3_敢*_2 (yl-[1,2,4]°oxadiazol-3-yl)-phenyl]-6,7-dihydro-51^-[1]° pyridine- 7-amino hydrazinium cyclopropyl)-decylamine; 160800.doc •11 - 201245158 oxazine-4-furic acid fluoro-2-(5-methyl-[1'2' ] α | Brewed oxadiazol-3-yl)-phenyl;|_6,7-dihydro-511-[1]pyridine-7-fluorenyl}-cyclopropyl)-decylamine; pyridazine-'citric acid "or... one 吋 ^ chloro-fluoro-Xuan 彳 ^ methyl" 1 '2'], 1 gg: oxadiazol-3-yl)-phenyl]_6,7-dihydro _5H-[ 1] ° ratio. _7_泰基}--- propyl)-3⁄4 amine; ^ over-2—(5 ** 2-methoxy-pyrimidine, 5-carboxylic acid (1-{(racemic)-3-[5- Gas--methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-6,7-dihydro JH-l1]pyridinium oxime group; ) 醯 醯 amine; isoxazole-5-decanoic acid (1_{(racemic) _3-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4] oxadiazole- 3_yl)_phenyl]_6,7-dihydro-5H-[1]° pyridine-7-aminoamine]-cyclopropyl)-guanamine; (1-{(racemic)) -6-[5-Gas-3-fluoro-2-(5-methyl-[1,2,4]oxadiazole-3-yl)-phenyl]·2,3-dihydro-benzofuran -3-ylaminomethionylcyclopropyl)-aminobutyric acid tert-butyl ester; 1-amino-cyclopropanone decanoic acid {(racemic)-6-[5-gas-3-fluoro -2-(5-Methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-2,3-dihydro-benzofuran-3-yl}-decylamine; 嗔° Qin-4-carboxylic acid (1-{(racemic)-6-[5-gas-3-gas-2-(5-fluorenyl-[1,2,4]oxadiazol-3-yl)- Phenyl]-2,3-dihydro-benzofuran-3-ylamine oxime}-cyclopropyl)-bristamine; 2-methoxy-pyrimidine·5-carboxylic acid (1-{(external elimination) Cyclo)-6-[5-gas-3-fluoro-2-(5-methyl-[1,2,4].oxazol-3-yl)-phenyl] _2,3-dioxo-benzo&lt;»f-amyl-3-ylamine-aryl}}-cyclopropyl)-bristamine; 160800.doc -12- 201245158 3-decyloxy-isoxazole-5 -formic acid (1_{(racemic gas_3_fluoro-2_(5-methyl-[I,2,4]oxadiazole-3-yl)-phenyl]_2,3_dihydro" stupid Furan_3_ylamine aryl}}-cyclopropyl)-stoke; 3-amino-oxetan-3-carboxylic acid {(s)-5-[5-gas-3-fluoro_2_( 5_Methyl-[1,2,4]° Esteryl)-Phenyl]_Frozen-1 _Base} _ Brewing amine; Pyrimidine-5-carboxylic acid (3-{(S)-5-[ 5-chloro-3-fluoro-2-(5-methyldiazol-3-yl)-phenyl]-indan-1-ylamine fluorenyl}-oxequid _3_yl)-醯Amine 異噁唑-5-甲酸（3-{(S)-5-[5-氯-3-氟-2-(5-甲基 _[12 4] 噁二唑-3-基）-苯基]-茚滿-1-基胺甲醯基}-氧雜環丁烧_3_ 基）-醯胺； 3-曱基··異 °惡0全 _5-甲酸（3-{(S)-5-[5-氣-3_氟_2_(5-曱 基-[1，2,4]噁二唑基）·苯基]-茚滿-1·基胺甲醯基}-氧雜 環丁烷-3-基）-醯胺； 3-甲氧基-異噁唑_5-甲酸（3_{(S)_5_[5_氯氟-2_(5_甲 基-[1，2,4]。惡二唑_3_基）_苯基]-茚滿—基胺曱醯基丨·氧雜 環丁烷-3-基）-酿胺； (1_U外消旋）-3_[5-氯-3-氟-2-(2-曱基-2Η-四唑-5-基）-苯其]_6 7-二氫吡啶_7_基胺甲醯基卜環丙基胺基 酸第三丁酯； 卜胺其_環丙烷甲酸{(外消旋）-3-[5_氣_3_氟-2_(2_曱 _21^心5-基）-苯基]-6,7-二氮-511-[1]〇比咬-7-基}-酿 胺； 2-曱氧基-痛咬一 5_ 曱酸（1-{(外消旋）-3-[5-氯-3-氟-2-(2- • 13- 160800.doc 201245158 甲基-2H-四唑-5-基）-苯基]-6,7-二氫-5士[1]吼啶-7-基胺 曱醯基}-環丙基）-醯胺； 異噁唑-5 -甲酸（1-{(外消旋）-3-[5 -氣-3 -氟-2-(2-甲 基-2H-四峻-5-基）-苯基]-6,7 -二氣- 5H-[ 1 ]0比咬_7 -基胺甲 醯基}-環丙基）-醯胺； 3_曱基-異噁唑-5·甲酸G-U外消旋）_3-[5-氯氟-2-(2-曱基-2H-四唑-5-基）-苯基]-6,7-二氫-5Η-Π]吡啶-7-基胺 甲醯基}-環丙基）-醯胺； 3·曱氧基-異噁唑-5-曱酸（1-{(外消旋）-3-[5_氯-3-氟 (2_曱基-2H-四唑-5-基）-苯基]-6,7-二氫-5H-[1]吡啶-7-基 胺甲醯基}_環丙基）-醯胺； 〇-{(外消旋）-6-[5-氯-3-氟-2-(2_甲基-2H-四唑_5-基）_ 苯基]-2,3-二氫-苯并[b]嗟吩-3-基胺曱酿基}-環丙基）-胺 基曱酸第三丁酯； 1_胺基-環丙烷曱酸{(外消旋）-6-[5 -氣-3 -氟-2-(2-甲 基-2H-四唑_5_基）_苯基]_2,3_二氫-苯并[b]噻吩-3-基}_醯 胺； 5-甲基-[1,3,4]噁二唑-2-曱酸（卜{(外消旋）_6-[5-氣-3-氟-2-(2-甲基_2H-四唑-5-基）-苯基]-2,3_二氫-苯并[b]噻 吩-3-基胺甲醯基卜環丙基醯胺； °密D定-5-曱酸（1-{(外消旋）_6-[5-氯-3-氟-2-(2-曱基-2H-四唑-5-基）_苯基]_2,3_二氫-苯并[b]噻吩-3-基胺曱醯基}-環丙基）-酿胺； 異噁唑-5-甲酸（1-{(外消旋）-6-[5-氣-3-氟-2-(2-甲基 160800.doc -14- 201245158 -2H-四唑-5_基）·苯基]_2,3_二氫—苯并[b]噻吩_3_基胺甲醯 基卜環丙基）-醯胺； 3_甲氧基-異噁唑-5-甲酸（1_{(外消旋）_6_[5_氯_3_氟 (2-甲基-2H-四唑-5-基）-苯基]_2,3_二氫_苯并[b]噻吩_3_基 胺曱醯基}-環丙基）_醯胺； 及其醫藥學上可接受之鹽。 59·如請求項1或2之化合物，其係選自： ^(2,2,2-三氟-乙醯胺基）-環丙烷曱酸{(8)_5_[5_氣_3_ 1-2-(5-甲基-[1,2,4]噁二唑-3-基）-苯基]-茚滿-1-基}，醯 胺； ^(2,2,2-三氟·乙醯胺基）-環丙烷曱酸{(外消旋 氯-3-氟-2-(5-曱基-[1，2,4]噁二唑-3-基）-苯基]-6,7-二 氫-5H-[1]吡啶_7·基卜醯胺； ^(2,2,2-三氟-乙醯胺基）-環丙烷甲酸{(外消旋）_5-[5-氯-3-氟-2-(5-甲基-[1，2,4]噁二唑-3-基）_苯基]-7-氟-茚滿 -1-基卜醯胺； 2-甲氧基-嘧啶-5-曱酸（l-{(S)-5-[5-氣-3-氟-2-(5-甲 基-[1，2,4]噁二唑-3-基）-苯基]-茚滿-卜基胺甲醯基卜環丙 基）-醯胺； 噠嗪-4-甲酸（1-{(s)-5-[5-氣-3-氟-2-(5-甲基-Π，2,4]噁 二唑-3-基）-苯基]-茚滿-丨_基胺甲醯基}-環丙基）-驢胺； 3_甲氧基_異噁唑-5-甲酸（l-{(S)-5-[5-氯-3-氟_2_(5-甲 基-以，2,4]噁二唑-3-基）-苯基]-茚滿-1-基胺甲醯基卜環丙 基）-醯胺； 160800.doc -15- 201245158 及其醫藥學上可接受之鹽。 6 0.如請求項1或2之化合物，其係選自： 2 -曱氧基-哺咬-5 -曱酸（1_《（外消旋乳氣2 ( 曱基-[1，2,4]鳴二唑-3-基）_笨基]_7_氟-節滿小基胺甲酿 基}-環丙基）-醯胺； 3-甲氧基-異°惡0坐_5_曱酸（ι_{(外消旋）-3-[5-氣-3氟 (5-甲基-[1，2,4]噁二唑-3-基）_苯基]-6,7-二氫-5H-[1]〇比啶 -7-基胺甲酿基}-環丙基）-醯胺； 2-曱氧基-嘧啶-5-曱酸（1-{(外消旋）-3-[5-氣氟 曱基-[1,2,4]噁二唑-3-基）-苯基]_6,7-二氫-51_1_[1]吡啶 基胺曱醯基}-環丙基）-酿胺； 2- 甲氧基D定-5-曱酸（1-{(外消旋）-6-[5 -氣氟2 ( 甲基-[1,2,4]噁二唾-3-基）-苯基]_2,3-二氫_苯并呋喃3 土 胺曱醯基}-環丙基）-醢胺； 3- 曱氧基_異噁唑-5_甲酸（3-{(8)-5-[5-氯-3-氟-2(5甲 基-[1，2,4]噁二唑-3-基）-苯基]-節滿-1-基胺甲醯基丨氧雜 環丁烷-3-基）-醯胺； ^ / r\ 2- 甲氧基-嘧啶-5-甲酸（1-{(外消旋）-3-[5-氯_3_氣-甲基-2H-四唑-5-基）-苯基]-6,7-二氫-5Η-Π]吡啶-7-基胺 曱醯基}-環丙基）_醯胺； 3- 甲氧基-異噁唑-5-甲酸（1-{(外消旋）-3-[5-乳_ _ (2-甲基-2H-四唑-5-基）-苯基]-6,7-二氫-5Η-Π]0比啶_7'基 胺曱醯基}-環丙基）-醯胺； 田 A - 2 Η - 嘧啶-5_甲酸（1-{(外消旋）-6-[5-氯-3-氟-2-(2-甲土 160800.doc -16 - 201245158 四唑-5-基）-苯基]-2,3-二氫-苯并[b]噻吩-3-基胺甲酿基厂 環丙基）-醯胺； 及其醫藥學上可接受之鹽。 61. 一種製備如請求項1至60中任一項之化合物之方法’其 包含以下反應： a)式（II)化合物在式（III)化合物存在下反應； R5Isoxazole-5-carboxylic acid (3-{(S)-5-[5-chloro-3-fluoro-2-(5-methyl-[12 4]oxadiazol-3-yl)-phenyl] -Indole-1-ylaminocarbazinyl}-oxequid _3_yl)-decylamine; 3-indenyl-iso-oxo-all-_5-carboxylic acid (3-{(S)-5 -[5-Gas-3_fluoro_2_(5-fluorenyl-[1,2,4]oxadiazolyl)·phenyl]-indan-1·ylamine-methylhydrazine}-oxeidine Alk-3-yl)-decylamine; 3-methoxy-isoxazole-5-carboxylic acid (3_{(S)_5_[5-chlorofluoro-2_(5-methyl-[1,2,4] Oxadiazole _3_yl)-phenyl]-indan-ylamine hydrazino oxetane-3-yl)-bristamine; (1_U racemic)-3_[5-chlorine 3-fluoro-2-(2-indolyl-2-indole-tetrazol-5-yl)-benzoic acid-_6 7-dihydropyridine _7-ylamine-methyl sulfonyl propyl propyl amide Ester; oxime-cyclopropanecarboxylic acid {(racemic)-3-[5_gas_3_fluoro-2_(2_曱_21^心五-yl)-phenyl]-6,7-di Nitrogen-511-[1]〇 咬-7-yl}-bristamine; 2-methoxy-pain-5_ decanoic acid (1-{(racemic)-3-[5-chloro-3- Fluorine-2-(2- • 13-160800.doc 201245158 methyl-2H-tetrazol-5-yl)-phenyl]-6,7-dihydro-5士[1]acridin-7-ylamine Mercapto}-cyclopropyl)-guanamine; isoxazole-5 - Acid (1-{(racemic)-3-[5-gas-3-fluoro-2-(2-methyl-2H-tetras--5-yl)-phenyl]-6,7-diox - 5H-[ 1 ]0 than bit _7-ylaminocarbamoyl}-cyclopropyl)-guanamine; 3_mercapto-isoxazole-5·carboxylic acid GU racemic)_3-[5-chlorine Fluor-2-(2-indolyl-2H-tetrazol-5-yl)-phenyl]-6,7-dihydro-5Η-indole]pyridin-7-ylaminecarbamyl}-cyclopropyl) - guanamine; 3 · decyloxy-isoxazole-5-decanoic acid (1-{(racemic)-3-[5-chloro-3-fluoro(2_mercapto-2H-tetrazole-5) -yl)-phenyl]-6,7-dihydro-5H-[1]pyridin-7-ylaminocarbamoyl}-cyclopropyl)-decylamine; 〇-{(racemic)-6- [5-Chloro-3-fluoro-2-(2-methyl-2H-tetrazole-5-yl)-phenyl]-2,3-dihydro-benzo[b]porphin-3-ylamine Brewing base}-cyclopropyl)-amino phthalic acid tert-butyl ester; 1-amino-cyclopropane decanoic acid {(racemic)-6-[5-gas-3-fluoro-2-(2) -methyl-2H-tetrazole-5-yl)-phenyl]_2,3-dihydro-benzo[b]thiophen-3-yl}-decylamine; 5-methyl-[1,3,4 Oxadiazole-2-decanoic acid (Bu {(racemic)_6-[5-gas-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)-phenyl]- 2,3_Dihydro-benzo[b]thiophen-3-ylaminemethanylcyclopropyl decylamine; °D D--5-decanoic acid (1-{(outside Racemic) _6-[5-chloro-3-fluoro-2-(2-indolyl-2H-tetrazol-5-yl)-phenyl]_2,3-dihydro-benzo[b]thiophene-3 -Aminoguanidino}-cyclopropyl)-bristamine; Isoxazole-5-carboxylic acid (1-{(racemic)-6-[5-gas-3-fluoro-2-(2-) Base 160800.doc -14- 201245158 -2H-tetrazol-5-yl)-phenyl]_2,3-dihydro-benzo[b]thiophene-3-ylamine-methylidene-bupropyl)-oxime Amine; 3_methoxy-isoxazole-5-carboxylic acid (1_{(racemic)_6_[5_chloro-3-hydroxy-(2-methyl-2H-tetrazol-5-yl)-phenyl) ]_2,3_Dihydro-benzo[b]thiophene-3-ylamine}-cyclopropyl)-guanamine; and a pharmaceutically acceptable salt thereof. 59. The compound of claim 1 or 2, which is selected from the group consisting of: ^(2,2,2-trifluoro-acetamido)-cyclopropanoic acid {(8)_5_[5_气_3_ 1- 2-(5-Methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-indan-1-yl}, decylamine; ^(2,2,2-trifluoro· Acetylamino)-cyclopropane decanoic acid {(racemic chloro-3-fluoro-2-(5-fluorenyl-[1,2,4]oxadiazol-3-yl)-phenyl]-6 ,7-dihydro-5H-[1]pyridine-7-glycidylamine; ^(2,2,2-trifluoro-acetamido)-cyclopropanecarboxylic acid {(racemic)_5-[5 -Chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-7-fluoro-indan-1-ylbudecamide; 2 -Methoxy-pyrimidine-5-decanoic acid (1-{(S)-5-[5-gas-3-fluoro-2-(5-methyl-[1,2,4]oxadiazole-3 -yl)-phenyl]-indan-p-ylamine-mercaptopuridyl)-decylamine; pyridazine-4-carboxylic acid (1-{(s)-5-[5-gas-3-fluoro -2-(5-methyl-indole, 2,4)oxadiazol-3-yl)-phenyl]-indan-indole-ylamine-methylamino}-cyclopropyl)-guanamine; Methoxy-isoxazole-5-carboxylic acid (1-{(S)-5-[5-chloro-3-fluoro-2-(5-methyl-, 2,4)oxadiazol-3-yl) )-phenyl]-indan-1-ylamine-mercaptopropylcyclopropyl)-decylamine; 160800.doc -15- 201245158 and A pharmaceutically acceptable salt. 60. A compound according to claim 1 or 2 which is selected from the group consisting of: 2 - decyloxy-negative-5-decanoic acid (1_" (racemic lactose 2 ( 曱-[1,2,4]Nadiazol-3-yl)-styl]_7_Fluoro-supplemented small base amine}}-cyclopropyl)-guanamine; 3-methoxy-iso °恶零坐_5_曱酸(ι_{(racemic)-3-[5-gas-3fluoro(5-methyl-[1,2,4]oxadiazol-3-yl)-benzene ]]-6,7-dihydro-5H-[1]indolepyridin-7-ylamine-aryl}-cyclopropyl)-guanamine; 2-methoxy-pyrimidine-5-decanoic acid (1 -{(racemic)-3-[5-fluorofluoroindolyl-[1,2,4]oxadiazol-3-yl)-phenyl]_6,7-dihydro-51_1_[1]pyridinyl Aminoguanidino}-cyclopropyl)-bristamine; 2-methoxy D-but-5-decanoic acid (1-{(racemic)-6-[5-fluorofluoro 2 (methyl-[1 , 2,4] dioxazol-3-yl)-phenyl]_2,3-dihydro-benzofuran 3, aminyl fluorenyl}-cyclopropyl)-guanamine; 3-decyloxy- Oxazole-5-carboxylic acid (3-{(8)-5-[5-chloro-3-fluoro-2(5methyl-[1,2,4]oxadiazol-3-yl)-phenyl] -Fluky-1-ylamine-carbamoyloxybutan-3-yl)-nonylamine; ^ / r\ 2-methoxy-pyrimidine-5-carboxylic acid (1-{(racemic)) -3-[5-chlorine_3_ -methyl-2H-tetrazol-5-yl)-phenyl]-6,7-dihydro-5Η-Π]pyridin-7-ylaminoindenyl}-cyclopropyl)-decylamine; 3- Methoxy-isoxazole-5-carboxylic acid (1-{(racemic)-3-[5-milk__(2-methyl-2H-tetrazol-5-yl)-phenyl]-6 ,7-dihydro-5Η-Π]0-pyridyl-7'-aminoamine-yl}-cyclopropyl)-guanamine; A- 2 Η-pyrimidine-5-carboxylic acid (1-{(racemic) )-6-[5-chloro-3-fluoro-2-(2-carbamate 160800.doc -16 - 201245158 tetrazol-5-yl)-phenyl]-2,3-dihydro-benzo[b] a thiophen-3-ylamine-based sulfonyl plant, cyclopropyl)-guanamine; and a pharmaceutically acceptable salt thereof. 61. A process for the preparation of a compound according to any one of claims 1 to 60 which comprises the following reaction: a) a compound of formula (II) is reacted in the presence of a compound of formula (III); 或 b)式（IV)化合物在式（v)化合物存在下反應； Ο ϋOr b) a compound of formula (IV) is reacted in the presence of a compound of formula (v); Ο ϋ 其中在步驟b)中R12為_C(0)_Ri3，且其中A丨、a2、r1、 R2、R3、R4、R5、R6、r7、R8、r9、Rl。、Rll、r12、Ri3 及n係如請求項丨所定義，且其中义及⑴為函素、蝴酸或 晒酸酯，其中若χ1或X2之一為w酸或蝴酸酯，則另一者 為鹵素。 62. 如請求項丨或2之化合物，其係用作治療上之活性物質。 160800.doc •17· 201245158 63. -種醫藥’:組合物，其包含如請求 合物及治療上之惰性載劑。〇中任-項之化 64·Γ=項1或2之化合物，其係用於治療或預防絲球體腎 、了偌-絲奇恩賴紫癜性腎病變（Hen〇ch_Sch0niein Purpura nephropathy)、ANCA相關新月型絲球體腎炎' 狼瘡性腎炎及IgA腎炎。 65.如请求項}至60中任一項之化合物之用途，其係用於製 備用以治療或預防絲球體腎東、亨偌、絲奇恩賴紫癜性腎 病變' ANCA相關新月型絲球體腎炎、狼瘡性腎炎及IgA 腎炎之藥物。 66.如請求項.1或2之化合物，其係如讀求導卩丨爷方法製造。 160800.doc -18- 201245158 四、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： 0 五、本案若有化學式時，請揭示最能顯示發明特徵的化學式：Wherein in step b), R12 is _C(0)_Ri3, and wherein A丨, a2, r1, R2, R3, R4, R5, R6, r7, R8, r9, R1. , Rll, r12, Ri3 and n are as defined in the claim ,, and wherein (1) is a element, a ceradic acid or a tanning acid ester, wherein if one of χ1 or X2 is a w acid or a folic acid ester, the other It is halogen. 62. The compound of claim 2 or 2 is used as a therapeutically active substance. 160800.doc • 17· 201245158 63. - A pharmaceutical composition comprising a composition as claimed and a therapeutically inert carrier. 〇中任-Chemical 64·Γ= Item 1 or 2, which is used to treat or prevent spheroid kidney, 〇-丝 奇 奇 癜 ( ( (Hen〇ch_Sch0niein Purpura nephropathy), ANCA related Crescent spheroid nephritis ' lupus nephritis and IgA nephritis. The use of a compound according to any one of claims 1 to 60 for the treatment or prevention of spheroidal kidney, Henry, and sinensis purpura nephropathy 'ANCA related crescent silk A drug for glomerulonephritis, lupus nephritis, and IgA nephritis. 66. The compound of claim 1 or 2, which is produced by a method of reading a guide. 160800.doc -18- 201245158 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 0. If there is a chemical formula in this case, please reveal the best Chemical formula showing the characteristics of the invention: 160800.doc160800.doc