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TW200812588A - CRF1 receptor ligands comprising heteroaryl fused bicycles - Google Patents

CRF1 receptor ligands comprising heteroaryl fused bicycles Download PDF

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Publication number
TW200812588A
TW200812588A TW96117169A TW96117169A TW200812588A TW 200812588 A TW200812588 A TW 200812588A TW 96117169 A TW96117169 A TW 96117169A TW 96117169 A TW96117169 A TW 96117169A TW 200812588 A TW200812588 A TW 200812588A
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ethyl
isopropyl
compound
salt
ratio
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TW96117169A
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Chinese (zh)
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Raymond F Horvath
Lu-Yan Zhang
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Neurogen Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Substituted heteroaryl fused pyridine and pyrazine compounds that act as selective modulators of CRF1 receptors are provided. These compounds are useful in the treatment of a number of CNS and periphereal disorders, particularly stress, anxiety, depression, cardiovascular disorders, gastrointestinal disorders, and eating disorders. Methods of treatment of such disorders as well as packaged pharmaceutical compositions are also provided. Compounds provided herein are also useful as probes for the localization of CRF receptors and as standards in assays for CRF receptor binding. Methods of using the compounds in receptor localization studies are given.

Description

200812588 九、發明說明： 相關申請案 本申請案主張2006年5月15曰所申請的美國第 60/747,241號臨時專利申請案的優先權。該前述臨時專利 申請案所揭露之内容係完全合併於本文中作參考。 【發明所屬之技術領域】 本發明係有關對於促腎上腺皮質釋放因子 (corticotropin-releasing factor 9 簡稱作 CRF)，尤其 釀 胃是CRF1，之受體的結合具高選擇性和/或高親和性的新穎 經取代之雜芳基稠合的吡啶、吡哄以及嘧啶化合物。本發 明亦有關包含上述該等化合物之醫藥組成物，並且有關該 等化合物及醫藥組成物用於治療下述各者之用途··精神疾 病和神經疾病（包括憂營症、焦慮相關之病症、創傷後壓力 心理障礙症（post-traumatic stress disorder，簡稱作 PTSD)、上核麻痺症（supranuclearpalsy)以及飲食障礙 (feeding disorders);以及用於治療下述各者之用途：免 疫、心血管或心臟相關疾病與消化道疾病（包括與精神失調 和壓力相關性之結腸過敏，包括激躁性結腸症（I rr i tab 1 e Bowel Syndrome，簡稱作IBS))。此外，本發明係關於使 用此等化合物作為探針以用於將細胞與組織中的CFR受體 定位。 【先前技術】 促腎上腺皮質釋放因子（CRF)為一種藉由結合和調節 特定的細胞表面受體（包括CRF1受體以及CRF2受體）的訊 5 93966 200812588 息傳導活性（signal transduct ion activity)而引起作用 的胜肽。咸相信該CFR受體在對壓力的整體反應中扮演重 要的角色。 CRF已被證實與精神疾病和神經疾病（包括憂鬱症、焦 慮相關之病症、消化道疾病以及飲食障礙）有關。 【發明内容】 本發明提供新穎之式I (下方）化合物，以及提供包含 此等化合物和醫藥上可接受之載劑或賦形劑之至少一者之 醫藥組成物。該等化合物與細胞表面之受體，尤其是G-耦 合蛋白質受體，特別是CRF受體（包括CRF1與CRF2受體）， 而最佳為CRF1受體，結合。較佳之該等化合物對CRF受體， 尤其是CRF1受體，具有高親和性。此外，較佳之該等化合 物亦對CRF受體展現高度專一性（亦即，相較於與非CRF 受體之結合，該等化合物展現高度選擇性）。較佳之該等化 合物對CRF1受體展現高度專一性。 因此，在某些態樣中，本發明提供下式I之化合物以 及其醫藥上可接受之鹽類。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 The disclosure of the aforementioned provisional patent application is hereby incorporated by reference in its entirety. TECHNICAL FIELD OF THE INVENTION The present invention relates to a high selectivity and/or high affinity for the binding of corticotropin-releasing factor 9 (CRF), especially to the receptor of CRF1. Novel substituted heteroaryl fused pyridine, pyridinium and pyrimidine compounds. The present invention also relates to pharmaceutical compositions comprising the above-mentioned compounds, and to the use of the compounds and pharmaceutical compositions for the treatment of mental and neurological diseases (including sorrow, anxiety-related disorders, Post-traumatic stress disorder (PTSD), supranuclearpalsy, and feeding disorders; and for the treatment of: immunization, cardiovascular or heart Related diseases and digestive tract diseases (including colon allergies related to mental disorders and stress, including Irr i tab 1 e Bowel Syndrome (abbreviated as IBS)). Furthermore, the present invention relates to the use of such Compounds are used as probes for localization of CFR receptors in cells and tissues. [Prior Art] Adrenal cortex releasing factor (CRF) is a receptor that binds and regulates specific cell surface receptors (including CRF1 receptor and CRF2). Receptor) 5 93966 200812588 The signal transductive activity caused by the peptide. Xian believes that C FR receptors play an important role in the overall response to stress. CRF has been shown to be associated with mental and neurological diseases including depression, anxiety-related disorders, digestive tract diseases, and eating disorders. Providing a novel compound of formula I (below), and a pharmaceutical composition comprising at least one of such compounds and a pharmaceutically acceptable carrier or excipient. These compounds are associated with receptors on the cell surface, especially G - coupling protein receptors, in particular CRF receptors (including CRF1 and CRF2 receptors), and preferably CRF1 receptors, preferably having high affinity for CRF receptors, especially CRF1 receptors. Furthermore, it is preferred that the compounds also exhibit a high degree of specificity for the CRF receptor (i.e., the compounds exhibit a high degree of selectivity compared to binding to a non-CRF receptor). Preferably, the compounds are CRF1 receptors. Showing a high degree of specificity. Thus, in certain aspects, the invention provides a compound of formula I below and a pharmaceutically acceptable salt thereof

其中： R為氫（H)、CrG烷基、鹵素、氰基、C1 -6環烷基或 S(0)nCl-C4 烧基；Wherein: R is hydrogen (H), CrG alkyl, halogen, cyano, C1 -6 cycloalkyl or S(0)nCl-C4 alkyl;

Ar為視需要經取代之芳基或雜芳基； 6 93966 200812588 Z3為視需要經取代之氮或碳； 下式基團：Ar is an optionally substituted aryl or heteroaryl; 6 93966 200812588 Z3 is optionally substituted nitrogen or carbon;

代表飽和的、未飽和的或芳香族5一員環系統，其中1和 Z2中的一者代表氮； 以及 η=0、1、或 2〇 本發明進一步提供使用治療有效量之本文中所提供之 至少一種化合物來治療患有某些病症之患者之方法。這些 病症包括CNS病症，尤其是情感性疾病（affective disorder)、焦慮症、壓力相關性疾病（stress_related disorders)、|人食失調症（eating disorders)以及藥物濫 用（substance abuse)。患有該等疾病之患者可為人類或其 馨他動物（較佳為哺乳類動物），例如被訓養的陪伴性動物 (domesticated companion animal)(寵物）或家畜 (^livestock animal)。用於此治療目的之較佳化合物為彼 等拮抗CRF結合至CRF受體（較佳為_，或次佳為㈣ 受體)之化合物。該等化合物作為拮抗劑用之能力可用以下 所述之I CsG值予以量測。 根據本發明之又-其他態樣，本發明提供包含式ι之 化合物或鹽之至少一者(較佳為表！之化合物或鹽之至少 -者）或其醫藥上可接受之鹽類（如下所界定者）的醫藥組 93966 7 200812588 成物等醫藥組成物係用於治療上述該等病症。本發明 提供使用治療有效量之本文中所提供之化合物或組 成物來治療患有任何上述該等病症之患者之方法。 除此之外，本發明亦關於所提供之該等化合物（尤苴是 經標記化合物）之用途，其係使用作為探針以用於在細胞和 組織中將受體定位以及使用作為用於測定測試化合物的受 體結合特性之標準品和試劑。 _ 於以下實施例7所提供之標準活體外CRF1受體結合試 驗中，較佳之化合物係展現小於5微莫耳 隶大半抑制濃度（hal f-maximal inhibitory concentration)(即IC5〇)。特別較佳之化合物係展現約工 微莫耳或小於1微莫耳之ICu值，更佳者其π”值為約1〇〇 奈莫耳（nanomolar)或小於1〇〇奈莫耳，或又更佳者其IC5 值為約10奈莫耳或小於1〇奈莫耳。在此等標準結合試驗 中，某些特別較佳之化合物係展現1奈莫耳或小於1奈莫 儀I耳之IC5G值。 【實施方式】 金1示性化会物 表I列出編號1至562之式I化合物，該等化合物中 有許多為預示性者。於本文中或於申請專利範圍令所提# 之「表I之化合物或鹽」包含任何該等編號之化合物和及 其醫藥上可接受之鹽類。“莫耳重量”為各個化合物所古十 鼻出之分子量。 8 93966 200812588 表 編號 結構 分子量 化學名稱 1 OH 394.56 (3S)-3-[3- 乙基-2-(2-乙基-6-異丙基〇比 啶-3-基）-7-甲基-5H - σ比洛并[2, 3-b]吼 啡-5-基]戊-1-醇 2 k 353.47 (2S)-2-[6-（6- 乙氧 基-2-乙基σ比咬-3-基)-1，5-二甲基-1Η-°比洛并[2, 3-b]吼咬 -3-基]丙-1-醇 3 OH 380. 54 (38)-3-[2-乙基-3- (2-乙基-6-異丙基叶匕 啶-3-基）-5-曱基-5H -11比嘻并[2, 3-b>比哄 -7-基]丁-1-醇 9 93966 200812588 4 OH 382·51 (3f〇-3-[2- 乙基-3-(6-異丙基-2-甲氧基 吼啶-3-基）-5-曱基 -5H-吼嘻并[2, 3-b] °比啡-7-基]丁-1-醇 5 OH ^5ι\ 366. 51 (3S)-3-[3-（2-乙基 -6-異丙基σ比咬-3-基）-2,5-二甲基-5Η -啦咯并[2, 3-b]吼畊 - 7-基]丁-1-醇 6 %V 365.52 5-（6-異丙基-2-甲氧 基σ比咬-3-基）-3, 6-二甲基-1-（1 -曱基丁 基）-1Η- °比嘻并[3、 2-b]11比咬Representative of a saturated, unsaturated or aromatic 5-membered ring system wherein one of 1 and Z2 represents nitrogen; and η = 0, 1, or 2 〇 further provides for the use of a therapeutically effective amount as provided herein At least one compound for treating a patient having certain conditions. These conditions include CNS disorders, particularly affective disorders, anxiety disorders, stress-related disorders, | eating disorders, and substance abuse. The patient suffering from such diseases may be a human or a succulent animal (preferably a mammal) such as a domesticated companion animal (pet) or a livestock (^livestock animal). Preferred compounds for such therapeutic purposes are those which antagonize the binding of CRF to a CRF receptor, preferably _, or less preferably a (four) receptor. The ability of such compounds to act as antagonists can be measured using the I CsG values described below. According to still another aspect of the present invention, the present invention provides at least one of a compound or a salt of the formula (preferably at least one of the compounds or salts of the formula) or a pharmaceutically acceptable salt thereof (hereinafter The medical group of the defined group) 93966 7 200812588 is used to treat the above-mentioned diseases. The present invention provides a method of treating a subject suffering from any of the above mentioned conditions using a therapeutically effective amount of a compound or composition provided herein. In addition, the invention also relates to the use of such compounds (especially labeled compounds), which are used as probes for the localization and use of receptors in cells and tissues for assays. Standards and reagents for testing the receptor binding properties of a compound. In the standard in vitro CRF1 receptor binding assay provided in Example 7 below, preferred compounds exhibit less than 5 micromolar concentration of half-maximal inhibitory (i.e., IC5). Particularly preferred compounds exhibit an ICu value of about micromoles or less than 1 micromolar, more preferably a π" value of about 1 nanomolar or less than 1 nanomolar, or More preferably, the IC5 value is about 10 nanomoles or less than 1 nanomolar. In these standard binding assays, some particularly preferred compounds exhibit 1 nanomolar or less than 1 nanometer IC5G. [Embodiment] Gold 1 shows that the compounds of the formula I are numbered 1 to 562, and many of the compounds are predictive, as described herein or in the scope of the patent application. "Compound or salt of Table I" includes any such numbered compound and its pharmaceutically acceptable salts. The "mole weight" is the molecular weight of each compound. 8 93966 200812588 Table number structure molecular weight chemical name 1 OH 394.56 (3S)-3-[3-ethyl-2-(2-ethyl-6-isopropylpyridin-3-yl)-7-methyl -5H - σ piroxi[2,3-b] morphine-5-yl]pentan-1-ol 2 k 353.47 (2S)-2-[6-(6-ethoxy-2-ethyl σ咬-3-yl)-1,5-dimethyl-1Η-°piro[2,3-b]bit-3-yl]propan-1-ol 3 OH 380. 54 (38)- 3-[2-ethyl-3-(2-ethyl-6-isopropylyliden-3-yl)-5-mercapto-5H-11 is more than [2, 3-b> 哄-7-yl]butan-1-ol 9 93966 200812588 4 OH 382·51 (3f〇-3-[2-ethyl-3-(6-isopropyl-2-methoxyacridin-3-yl) )-5-mercapto-5H-indolo[2,3-b] ° than phenyl-7-yl]butan-1-ol 5 OH ^5ι\ 366. 51 (3S)-3-[3-( 2-ethyl-6-isopropyl σ 咬 -3-yl)-2,5-dimethyl-5 Η-lado[2,3-b]吼耕-7-yl]but-1- Alcohol 6% V 365.52 5-(6-isopropyl-2-methoxy σ butyl-3-yl)-3,6-dimethyl-1-(1-indenylbutyl)-1 Η- ° Compared with [3, 2-b] 11 bite

10 93966 200812588 7 Ί 394. 56 (2R)-2-[3-乙基-2-(2-乙基-6-異丙基吡 啶-3-基）-7-甲基-5H -吼洛并[2, 3-b>比哄 -5-基]戊-1-醇 8 Q 掌性 HO : Ν / 417.52 (18,28)-2-{2-[2-甲 氧基-4-(1Η-吡唑-1-基）苯基]-3,7-二甲 基-5H- °比嘻并[2， 3-b]吡哄-5-基}環己 醇 9 OH 394.56 (3R)-3-[2- 乙基-3-(2-乙基-6-異丙基σ比 啶-3-基）-5-甲基-5Η - σ比嘻并[2，3-b] °比哄 - 7-基]戍-1-醇 11 93966 200812588 10 掌性 451.61 N- {2-[ (3-{6- 乙基-1 -[(1S)-2-曱氧基-1-曱基乙基]-3-甲基 -1H- σ比嘻并[3, 2-b] 吡啶-5-基}-6-異丙 基吼啶-2-基）胺基] 乙基}乙醯胺 11 h〇/^Cn_ 368.48 (2R)-2-[3-(6-異丙 基-2-曱氧基11比咬-3-基）-2,5-二甲基-511-°比咯并[2, 3-b] °比哄 - 7-基]丁-1-醇 12 掌性 366. 51 (2S)_2-[2-(2-乙基 -6-異丙基σ比咬-3-基）-3,7-二甲基-5Η -°比17各并[2, 3-b]吼哄 -5-基]丁-1-醇10 93966 200812588 7 394 394. 56 (2R)-2-[3-ethyl-2-(2-ethyl-6-isopropylpyridin-3-yl)-7-methyl-5H-indolo [2, 3-b> 哄-5-yl]pentan-1-ol 8 Q Palm HO: Ν / 417.52 (18,28)-2-{2-[2-methoxy-4-(1Η -pyrazol-1-yl)phenyl]-3,7-dimethyl-5H- ° than hydrazino[2,3-b]pyridin-5-yl}cyclohexanol 9 OH 394.56 (3R)- 3-[2-ethyl-3-(2-ethyl-6-isopropyl-7-pyridin-3-yl)-5-methyl-5Η-σ ratio 嘻[2,3-b] ° ratio哄-7-yl]nonanol 11 93966 200812588 10 palmity 451.61 N- {2-[ (3-{6-ethyl-1 -[(1S)-2-decyloxy-1-fluorenyl) Ethyl]-3-methyl-1H- σ is more than [3, 2-b]pyridin-5-yl}-6-isopropyl acridine-2-yl)amino]ethyl}acetamide 11 h〇/^Cn_ 368.48 (2R)-2-[3-(6-isopropyl-2-indolyl 11-buty-3-yl)-2,5-dimethyl-511-° ratio And [2, 3-b] ° than 哄-7-yl]butan-1-ol 12 palmity 366. 51 (2S)_2-[2-(2-ethyl-6-isopropyl σ than bite- 3-yl)-3,7-dimethyl-5Η-° ratio 17 and [2,3-b]indol-5-yl]butan-1-ol

12 93966 200812588 13 OH 366.51 (3R)-3-[3-(2-乙基 -6-異丙基吼σ定-3-基）-2, 5-二甲基-5H-σ比嘻并[2, 3-b] nb哄 - 7-基]丁-1-醇 14 OH ^a〇 k 381.52 (3S)-3-[6-（6-乙氧 基-2-乙基吼π定-3-基）-5-乙基-1_曱基 -1Η- 0比洛并[2, 3-b] ϋ比咬-3-基]丁-1-醇 15 366.51 (2R)-2-{6-乙基 -異 丙基- 2-（ 曱胺 基）吡啶-3-基]-3-甲 基-1Η- °比嘻并[3， 2-b]吡啶-1-基}丙 -1-醇12 93966 200812588 13 OH 366.51 (3R)-3-[3-(2-ethyl-6-isopropyloxazolidine-3-yl)-2, 5-dimethyl-5H-σ is 嘻[ 2, 3-b] nb哄-7-yl]butan-1-ol 14 OH ^a〇k 381.52 (3S)-3-[6-(6-ethoxy-2-ethylindole π--3 -yl)-5-ethyl-1_mercapto-1Η- 0 piroxi[2,3-b] guanidin-3-yl]butan-1-ol 15 366.51 (2R)-2-{6 -ethyl-isopropyl-2-(indolyl)pyridin-3-yl]-3-methyl-1Η- ° than hydrazino[3,2-b]pyridin-1-yl}propan-1- alcohol

13 93966 20081258813 93966 200812588

16 353. 47 (2R)-2-[6-(6-異丙 基-2-曱氧基吡啶-3-基）-1，5-二甲基-1H-吼嘻并[2, 3-b]吼啶 -3-基]丙-1-醇 17 OH / 366.51 (3S)-3-[2-（2-乙基 -6-異丙基11比°定-3-基）-3,7-二曱基-5H_ 吼咯并[2,3-b]吼畊 -5-基]丁-1-醇 18 、人 381.53 (2R)-2-{2*~ 乙基 _3-[6-異丙基-2-(曱胺 基）吡啶-3-基]-5-甲 基-5H-吼咯并[2, 3-b]吡哄-7-基} 丁 -1-醇16 353. 47 (2R)-2-[6-(6-Isopropyl-2-decyloxypyridin-3-yl)-1,5-dimethyl-1H-indole[2, 3- b] acridine-3-yl]propan-1-ol 17 OH / 366.51 (3S)-3-[2-(2-ethyl-6-isopropyl 11 decyl-3-yl)-3, 7-dimercapto-5H_ fluoren[2,3-b]indole-5-yl]butan-1-ol 18, human 381.53 (2R)-2-{2*~ ethyl_3-[6 -isopropyl-2-(decylamino)pyridin-3-yl]-5-methyl-5H-indolo[2,3-b]pyridin-7-yl}butan-1-ol

14 93966 200812588 19 tcc /1 N 、人 366.51 (2R)-2-{6-[6-異丙 基-2-(甲胺基）°比咬 -3-基]-1，5-二曱基 - 1H-吼嘻并[2, 3-b] °比咬-3-基} 丁-1-醇 20 J 、。人 Ni^Y^ 382.51 (2R)-2-[2-乙基-δα-異丙基-2-甲氧基 吼σ定-基）-5-曱基 -5Η-1比嘻并[2, 3-b] 吡哄-7-基]丁-1-醇 21 、c/^ l·0 ^CV 431.55 5-（6-異丙基-2-曱氧 基°比咬-3-基）-1-[as)-2-甲氧基-1-甲基乙基]-3-曱基 -6-(甲基磺醯基）- 1.H 比咯并[3, 2-b]°比咬14 93966 200812588 19 tcc /1 N , human 366.51 (2R)-2-{6-[6-isopropyl-2-(methylamino) ° ratio -3-yl]-1,5-didecyl - 1H-indole[2,3-b] ° is more than -3-yl}butan-1-ol 20 J. Human Ni^Y^ 382.51 (2R)-2-[2-ethyl-δα-isopropyl-2-methoxyindole sigma-yl)-5-mercapto-5Η-1 is 嘻[2, 3-b] pyridin-7-yl]butan-1-ol 21, c/^ l·0 ^CV 431.55 5-(6-isopropyl-2-indolyl ° ratio -3-yl)- 1-[as)-2-methoxy-1-methylethyl]-3-indolyl-6-(methylsulfonyl)- 1.H ratio of [3, 2-b]° bite

15 93966 200812588 22 fa η 365.52 (2R)-2-[5-乙基-6-(2-乙基-6_異丙基°比 啶-3-基）-1-甲基-1Η -吼嘻并[2, 3-1)]°比咬 -3-基]丙-1-醇 23 4 459. 61 5- [ 2-乙氧基-6-乙基 -5-（曱基磺醯基）吼 °定-3-基]-1-[(1R) -1-（甲氧基甲基）丙 基]-3,6-二曱基-1Η-°比略并[3, 2-b>比咬 24 V 掌性 ^Χα 391.48 (2R，3R)-3-{2 - [2-曱 氧基-4-(1H-吼嗤-1 -基）苯基]-3, 7-二曱 基-5H- 11比洛并[2， 3-b]吼畊-5-基} 丁 - 2-醇15 93966 200812588 22 fa η 365.52 (2R)-2-[5-ethyl-6-(2-ethyl-6-isopropyl-bipyridin-3-yl)-1-methyl-1Η-吼嘻And [2, 3-1)]° ratio -3-yl] propan-1-ol 23 4 459. 61 5- [2-ethoxy-6-ethyl-5-(nonylsulfonyl)吼°-3-yl]-1-[(1R)-1-(methoxymethyl)propyl]-3,6-diindolyl-1Η-° ratio [[3, 2-b> Specific bite 24 V palmity ^ Χ α 391.48 (2R, 3R) -3-{2 - [2-methoxy-4-(1H-indol-1-yl)phenyl]-3, 7-didecyl -5H- 11 piroxi[2, 3-b] 吼-5-yl} butyl-2-ol

16 93966 200812588 25 掌性 W γ 438. 61 3-{6-乙基-1-[(IS) -2 -曱氧基-1-曱基乙 基]-3-甲基-1H-吡咯 并[3, 2-b]吼咬-5-基}一6-異丙基-N-(3-曱氧基丙基）吡啶-2-胺 26 OH k 382.51 (31〇-3-[2-（6-乙氧 基-2-乙基ϋ比咬-3-基）-3, 7-二甲基-5Η -邱匕11各并[2, 3-b]比哄 - 5-基]戊-1-醇 27 ho^Q 掌性 417.52 (lS，3S)-3-{2-[2-曱 氧基-4-(1H-吼峻-1 -基）苯基]-3, 7-二甲 基-5H- °比σ各并[2， 3 - b]吡畊-5-基}環己 醇16 93966 200812588 25 Palmitic W γ 438. 61 3-{6-Ethyl-1-[(IS) -2 -nonyloxy-1-hydrazinoethyl]-3-methyl-1H-pyrrolo[ 3, 2-b]biting-5-yl}-6-isopropyl-N-(3-decyloxypropyl)pyridin-2-amine 26 OH k 382.51 (31〇-3-[2-( 6-ethoxy-2-ethylindole ratio -3-yl)-3,7-dimethyl-5Η-qiu匕11 each [2,3-b] than 哄-5-yl]penta- 1-alcohol 27 ho^Q palmity 417.52 (lS,3S)-3-{2-[2-oxime-4-(1H-indol-1-yl)phenyl]-3, 7-dimethyl Base-5H- ° ratio σ and [2, 3 - b] pyridin-5-yl} cyclohexanol

17 93966 20081258817 93966 200812588

28 ^ 掌性 、。吟 365.52 6-乙基-5-(6-異丙基 - 2-曱基吼σ定-3-基） -l-[(lS)-2-甲氧基 -1-甲基乙基]-3-甲 基-1H-吡咯并[3, 2-1)]°比咬 29 ^〇ν 421.49 1-(2,5-二氟苯曱基） -5-（6-異丙基-2-曱 氧基吼啶-3-基） -3, 6-二甲基-1H-吡 洛并[3, 2-1)>比咬 30 Η01ΐ：4 χηΑν Τ 367.50 (2S)-2-{2- 乙基-3~~ [6-異丙基-2-(曱胺 基）吡啶-3-基]-5-甲 基-5H-吼哈并[2， 3-b]吡畊-7-基}丙 -1-醇 18 93966 200812588 31 424· 54 2-[(6-乙基-5-{l- [as)-2-甲氧基-1-曱基乙基]-3,6_二甲 基-1H-吼嘻并[3， 2_b ]π比咬-5-基卜比咬 - 2-基）氧基]-Ν-甲基 丙醯胺 32 ^ 掌性 HO V Ν . 405.50 (2R，3R)-3-{2-[2-曱 氧基-4- (1 Η-σ比峻-1 -基）苯基]-3, 7-二曱 基-5Η- °比洛并[2， 3-b] σ比哄-5-基}戊 - 2-醇 OH (3R)-3-[5-(6-異丙 基-2-甲氧基吡啶-3- 33 νχχ^ 381.52 基）-3, 6-二甲基-1H- 广 ίΧΧζ °比咯并[3, 2-b] °比咬 、。八 -1-基]戊-1-醇28 ^ palmity,.吟365.52 6-Ethyl-5-(6-isopropyl-2-indolylindole-3-yl)-l-[(lS)-2-methoxy-1-methylethyl]- 3-methyl-1H-pyrrolo[3, 2-1)]° ratio bitter 29 ^〇ν 421.49 1-(2,5-difluorobenzoinyl)-5-(6-isopropyl-2-曱 吼 aridin-3-yl) -3, 6-dimethyl-1H-pyrrolo[3, 2-1)> than bite 30 Η01ΐ:4 χηΑν Τ 367.50 (2S)-2-{2 - Ethyl-3~~[6-isopropyl-2-(decylamino)pyridin-3-yl]-5-methyl-5H-haha[2,3-b]pyrazine-7- }-1-propanol 18 93966 200812588 31 424· 54 2-[(6-ethyl-5-{l- [as)-2-methoxy-1-indolylethyl]-3,6_ Dimethyl-1H-indole[3, 2_b]π ratio bite-5-kibbitbiti-2-yl)oxy]-indole-methylpropionamide 32 ^ palmity HO V Ν . 405.50 ( 2R,3R)-3-{2-[2-曱oxy-4-(1 Η-σ 峻 -1-1 -yl)phenyl]-3,7-diindolyl-5Η- °Biluo[ 2, 3-b] σ 哄-5-yl}pent-2-ol OH (3R)-3-[5-(6-isopropyl-2-methoxypyridine-3- 33 νχχ^ 381.52 )-3,6-Dimethyl-1H- 广ίΧΧζ ° ratio of [3, 2-b] ° than bite. Octa-1-ylpentan-1-ol

19 93966 20081258819 93966 200812588

34 OH 382.51 (31〇-3-[3-（6-乙氧 基-2-乙基ntb σ定-3-基）-2-乙基-5-曱基 -5Ή-吼嘻并[2, 3-b] 吡畊-7-基]丁-1-醇 35 掌性 仁V 391.48 (3R)-3-{2-[2- 甲氧 基-4_(1H- °比 口坐-1- 基）苯基]-3, 7-二曱 基-5H- ϋ比洛并[2， 3-b]吡畊-5-基} 丁 -1-醇 36 掌性 〜。 410.56 6-異丙基-N-(2-曱氧 基乙基）-3-{1- [(1R) -1 -（曱氧基曱基）丙 基]-3-甲基-1H-吡咯 并[3, 2-b]吼 σ定 -5-基}吡啶-2-胺34 OH 382.51 (31〇-3-[3-(6-ethoxy-2-ethylntb σ-3-yl)-2-ethyl-5-mercapto-5Ή-吼嘻[2, 3-b] pyridin-7-yl]butan-1-ol 35 palm kernel V 391.48 (3R)-3-{2-[2-methoxy-4_(1H- ° ratio -1- group Phenyl]-3,7-dimercapto-5H-indolobi[2,3-b]pyrrol-5-yl}butan-1-ol 36 palmity~. 410.56 6-isopropyl- N-(2-decyloxyethyl)-3-{1-[(1R) -1 -(decyloxyindolyl)propyl]-3-methyl-1H-pyrrolo[3, 2-b吼σ定-5-yl}pyridin-2-amine

20 93966 200812588 37 ^Or 383.49 5-（6-異丙基-2-甲氧 基吼啶-3-基）-1-[2-曱氧基-1_ (曱氧基曱 基）乙基]-3-曱基 -1H- w比嘻并[3, 2-b] 38 鬼。 k 395.55 (2S)-2-[5-(6-乙氧 基-2-乙基°比σ定-3-基）-6-乙基-3-曱基 -1Η- 11比嘻并[3, 2-b] σ比咬-1-基]戊-1-醇 39 H〇/^rV ^Ν〇α〇 k 354. 46 (2S)-2-[2-（6-乙氧 基-2-乙基吼°定-3-基）-3,7-二甲基-5Η-°比咯并[2, 3-b]吼哄 -5-基]丙-1-醇20 93966 200812588 37 ^Or 383.49 5-(6-Isopropyl-2-methoxyacridin-3-yl)-1-[2-decyloxy-1_(decyloxy)ethyl]- 3-mercapto-1H-w is more than [3, 2-b] 38 ghost. k 395.55 (2S)-2-[5-(6-ethoxy-2-ethyl ° σ -3-yl)-6-ethyl-3-indolyl-1 Η- 11 嘻 嘻 [3 , 2-b] σ 比 bit-1-yl]pentan-1-ol 39 H〇/^rV ^Ν〇α〇k 354. 46 (2S)-2-[2-(6-ethoxy-2 -ethyl hydrazin-3-yl)-3,7-dimethyl-5 oxime-pyrho[2,3-b]indole-5-yl]propan-1-ol

21 93966 200812588 40 \cr^ 掌性 408·59 3-{6-乙基-1-[(IS) -2-曱氧基-1-甲基乙 基]-3-曱基-1H-吡咯 并[3,2-1)]°比咬-5-基} -N，6-二異丙基0比 唆-2-胺 41 掌性 H—0 1 365· 52 (2S)-2-[5-(2-乙基 -6-異丙基°比σ定-3-基）-3,6-二曱基-1H-°比嘻并[3, 2-b]σ比咬 -1-基]丁-1-醇 42 掌性 337. 46 5-（6-異丙基0比。定-3-基）-1-[(1R)-1-（甲 氧基甲基）丙基]-3-甲基-1H-吡咯并[3, 2-b]吡啶21 93966 200812588 40 \cr^ Palm 408·59 3-{6-Ethyl-1-[(IS)-2-decyloxy-1-methylethyl]-3-indolyl-1H-pyrrole [3,2-1)]° than bite-5-yl} -N,6-diisopropyl 0 to indole-2-amine 41 Palm H-0 1 365· 52 (2S)-2-[5 -(2-ethyl-6-isopropyl ratio σ -3-yl)-3,6-dimercapto-1H-° than 嘻[3, 2-b]σ ratio bit -1- group ] Butan-1-ol 42 palmity 337. 46 5-(6-isopropyl 0 ratio. -3-yl)-1-[(1R)-1-(methoxymethyl)propyl]- 3-methyl-1H-pyrrolo[3,2-b]pyridine

22 93966 200812588 43 1 HO V a J 393· 58 (2R)-2-[6- 乙基-2- 乙基 - 6- 異丙基σ比 啶-3-基)-3-甲基-1Η -咐^各并[3, 2-1)>比唆 -1-基]戊-1-醇 44 掌性 380.53 6-異丙基-3-{1-[(lS)-l-(甲氧基甲 基）丙基]-3, 6-二曱 基-1H-吼咯并[3, 2-b] °比咬-5-基}-N-曱基吡啶-2-胺 45 / 掌性 366.51 2-(2-乙基-6-異丙基 口比σ定-3-基）-5-[ (1S) -2-甲氧基-1-甲基乙 基]-3，7-二甲基-5Ή- π比口各并[2, 3-1)]°比啡22 93966 200812588 43 1 HO V a J 393· 58 (2R)-2-[6-ethyl-2-ethyl-6-isopropyl σ-pyridin-3-yl)-3-methyl-1Η -咐^ Each [3, 2-1) > than 唆-1-yl] pent-1-ol 44 palmity 38.53 6-isopropyl-3-{1-[(lS)-l-(methoxy Methyl)propyl]-3,6-dimercapto-1H-indolo[3,2-b] ° than 5-amino-5-yl}-N-decylpyridin-2-amine 45 / palm 366.51 2-(2-Ethyl-6-isopropyl port ratio sigma-3-yl)-5-[ (1S)-2-methoxy-1-methylethyl]-3,7-di Methyl-5Ή-π is more than [2, 3-1)]° than brown

23 93966 20081258823 93966 200812588

46 OH %。 k 367· 50 (3R)-3-[5-(6-乙氧 基-2-乙基吼σ定-3-基）-3,6-二甲基-1Η-σ比嘻并[3, 2-b]σ比咬 -1-基]丁-1-醇 47 、〆 掌性 449. 64 6-乙基-5-[6-異丙基 -2-(4-甲基σ底哄-1 -基）吼啶-3-基]-1 -[(lS)-2 -甲氧基-1 -曱基乙基]-3-曱基 - 1H- σ比略并[3, 2-b] σ比咬 48 394· 56 (2R)-2-[2-乙基-3-(2-乙基-6-異丙基°比 啶-3-基）-5-甲基 -5Η- °比咯并[2, 3-b] 〇比哄-7-基]戊-1-醇46 OH %. k 367· 50 (3R)-3-[5-(6-ethoxy-2-ethyl吼σ-3-yl)-3,6-dimethyl-1Η-σ is 嘻[3, 2-b]σ 咬 -1--1-yl]butan-1-ol 47, 〆 palm 449. 64 6-ethyl-5-[6-isopropyl-2-(4-methyl sigma- 1-based) acridine-3-yl]-1 -[(lS)-2 -methoxy-1 -mercaptoethyl]-3-indolyl-1H- σ ratio slightly [3, 2-b ] σ than bite 48 394· 56 (2R)-2-[2-ethyl-3-(2-ethyl-6-isopropyl-pyridin-3-yl)-5-methyl-5Η- ° Bisolo[2,3-b]pyridinium-7-yl]pentan-1-ol

24 93966 200812588 49 351.50 (2S)-2-[6-（2-乙基 -6-異丙基吼咬-3-基）-1，5-二曱基-1H -吼嘻并[2, 3-b] °比咬 -3-基]丙-1-醇 50 ^ V, N J k 382.51 (2R)-2-[2-(6-乙氧 基-2-乙基吼咬-3-基）-3-乙基-7-曱基 -5Ή- π比嘻并[2, 3-b] 〇比哄-5-基]丁 -1-醇 51 OH 、口人 381.53 (3S)-3-{2-乙基-3-[6-異丙基-2-（甲胺 基）吡啶-3-基]-5-曱 基-5H-吼咯并[2, 3-b]吼畊-7-基} 丁 -1-醇 25 93966 200812588 52 支5〇v 366.51 (2S)-2-[3-(2-乙基 -6-異丙基吼咬-3-基）-2, 5-二甲基-5H -口比嘻并[2, 3-b]吼畊 -7*基]丁 -1-醇 53 / 〇 掌性 、。叹 396· 49 5-（6-異丙基-2-甲氧 基吼啶-3-基）-1-[US)-2-甲氧基-1 -曱基乙基]-3-曱基 -1H- 0比嘻并[3, 2-b] 吼咬-6-曱醯胺 54 OH 户丫 γ 380.54 (3R)-3-[2-(2-乙基 - 6-異丙基^比咬-3 -基）-3,7-二曱基-5H -σ比嘻并[2, 3-b]吼哄 -5-基]戊_1-醇24 93966 200812588 49 351.50 (2S)-2-[6-(2-ethyl-6-isopropylindole-3-yl)-1,5-dimercapto-1H-indole[2, 3 -b] ° than -3-yl] propan-1-ol 50 ^ V, NJ k 382.51 (2R)-2-[2-(6-ethoxy-2-ethylindole-3-yl) -3-ethyl-7-mercapto-5Ή-π is more than [2, 3-b] indole-5-yl]butan-1-ol 51 OH, mouth 381.53 (3S)-3-{ 2-ethyl-3-[6-isopropyl-2-(methylamino)pyridin-3-yl]-5-mercapto-5H-indolo[2,3-b]indole-7- Benzene-1-butanol 25 93966 200812588 52 branch 5〇v 366.51 (2S)-2-[3-(2-ethyl-6-isopropylindole-3-yl)-2, 5-dimethyl Base-5H-port is more than 嘻[2,3-b]吼耕-7*yl]butan-1-ol 53 / 〇 palmity. Sing 396· 49 5-(6-isopropyl-2-methoxyacridin-3-yl)-1-[US)-2-methoxy-1 -mercaptoethyl]-3-indenyl -1H- 0 is more than 嘻[3, 2-b] bite-6-nonylamine 54 OH 丫 γ 380.54 (3R)-3-[2-(2-ethyl- 6-isopropyl^ ratio Bit-3-yl)-3,7-dimercapto-5H-σ is more than [2,3-b]indol-5-yl]pentanol

26 93966 20081258826 93966 200812588

55 / 掌性 392. 54 3-{6-環丙基-1-[(IS)-2-甲氧基-1-曱基乙基]-3-甲基 - 1H-吡咯并[3,2-b] 0比σ定-5-基}_6-異丙 基-N-甲基吼11定-2-胺 56 479· 66 6-異丙基-3-{l-[(IR)-l-(甲氧基曱 基）丙基]-3, 6-二曱 基-1H-吼嘻并[3， 2_b] ^比咬-5-基卜N-(2-嗎琳-4-基乙基） 吼口定-2-胺 ,0Η 57 367.50 (3S)-3-[6-(6-異丙 基-2-甲氧基吡啶-3-基）-1，5-二甲基-1H-吼17各并[2, 3-b] °比咬 - 3-基]丁 -1 -醇 27 93966 200812588 58 OH %v 379.55 (3R)-3-[5-（2-乙基 -6-異丙基ϋ比咬-3-基）-3,6-二曱基-1Η -11比咯并[3, 2-b]吼咬 -1-基]戊-1-醇 59 ,0H k 368.48 (31〇-3-[3-(6-乙氧 基-2-乙基吼σ定-3-基）-2,5-二甲基-5Η -ϋ比嘻并[2, 3-b]吼哄 - 7-基]丁-1-醇 60 380.54 (28)-2-{5-乙基_6-[6-異丙基-2-(曱胺 基）吡啶-3-基]-1-甲 基-1H- ϋ比洛并[2， 3-b] °比咬-3 -基~} 丁 -卜醇55 / palmity 392. 54 3-{6-cyclopropyl-1-[(IS)-2-methoxy-1-indolylethyl]-3-methyl-1H-pyrrolo[3,2 -b] 0 is more than sigma-5-yl}_6-isopropyl-N-methylindole-11-diamine 56 479· 66 6-isopropyl-3-{l-[(IR)-l -(methoxyindolyl)propyl]-3,6-dimercapto-1H-indole[3, 2_b] ^ than bite-5-yl b N-(2-morphin-4-yl Base) 吼口定-2-amine, 0Η 57 367.50 (3S)-3-[6-(6-isopropyl-2-methoxypyridin-3-yl)-1,5-dimethyl-1H -吼17 each [2, 3-b] ° than bite - 3-yl] but-1-ol 27 93966 200812588 58 OH %v 379.55 (3R)-3-[5-(2-ethyl-6- Isopropyl hydrazine is more than -3-yl)-3,6-dimercapto-1 Η -11 is more than [3, 2-b] guanidin-1-yl] pent-1-ol 59 ,0H k 368.48 (31〇-3-[3-(6-ethoxy-2-ethyl吼σ-3-yl)-2,5-dimethyl-5Η-ϋ 嘻[[,3-b]吼哄-7-yl]butan-1-ol 60 380.54 (28)-2-{5-ethyl_6-[6-isopropyl-2-(decylamino)pyridin-3-yl]-1 -Methyl-1H-deutero[2,3-b] ° ratio biting -3 -yl~} butanol

28 93966 20081258828 93966 200812588

61 \ 掌性 、％v 386. 92 2-(2-氯-6-異丙基吡 啶-3-基）-5-[(1R) -1-（曱氧基甲基）丙 基]-3, 7-二甲基-5H-ϋ比略并[2, 3-1)]吼哄 62 、人 Ν’丫 352. 48 (2R)-2-{5-[6-異丙 基-2-（曱胺基）吡啶 -3-基]-3, 6-二曱基 - 1Η- 11比洛并[3, 2-b] 口比咬-1-基}丙-1-醇 63 352.48 (2R)-2-[3-（2-乙基 -6-異丙基11比咬-3-基）-2,5-二甲基-5H-吼洛并[2, 3-b] °比哄 -7-基]丙-1-醇61 \ palmity, %v 386. 92 2-(2-chloro-6-isopropylpyridin-3-yl)-5-[(1R) -1-(decyloxymethyl)propyl]-3 , 7-Dimethyl-5H-indolebi[2, 3-1)]吼哄62, human Ν'丫352. 48 (2R)-2-{5-[6-isopropyl-2- (曱Amino)pyridin-3-yl]-3,6-dimercapto- 1Η- 11 piroxi[3,2-b] 咬-1-yl}propan-1-ol 63 352.48 (2R -2-[3-(2-ethyl-6-isopropyl 11 butyl-3-yl)-2,5-dimethyl-5H-indolo[2,3-b] ° -7-yl]propan-1-ol

29 93966 200812588 64 OH 379. 55 (3S)-3-[6-（2-乙基 ~~6-異丙基吼σ定-3-基）-1，5-二曱基-1Η -ϋ比洛并[2, 3-b]11比咬 - 3-基]戊-1-醇 65 382.51 (3R)-3-[2-(6-異丙 基一2一曱氧基0比咬一3-基）-3, 7-二甲基-5H-吼咯并[2, 3-bh比畊 -5-基]戊-1-醇 66 380· 54 (3R)-3-[3-（2-乙基 -6-異丙基°比啶-3-基）-2,5-二甲基-511-σ比σ各并[2, 3-b] °比哄 - 7-基]戊-1-醇29 93966 200812588 64 OH 379. 55 (3S)-3-[6-(2-ethyl~~6-isopropyl吼σding-3-yl)-1,5-diindolyl-1Η-ϋ ratio洛和[2,3-b]11 than bite-3-yl]pentan-1-ol 65 382.51 (3R)-3-[2-(6-isopropyl- 2 methoxy 0-bite a 3 -yl)-3,7-dimethyl-5H-indolo[2,3-bh than phage-5-yl]pentan-1-ol 66 380· 54 (3R)-3-[3-(2 -ethyl-6-isopropyl-pyridin-3-yl)-2,5-dimethyl-511-σ ratio σ[2,3-b] ° 哄-7-yl]penta- 1-alcohol

30 93966 20081258830 93966 200812588

67 394.56 N-乙基-6-異丙基-3-{1 - [(lR)-l-(曱氧基 甲基）丙基]-3, 6-二 甲基-1H-吡咯并[3, 2-b]ϋ比咬-5-基}π比咬 - 2-胺 68 、0^V 378.47 [(6-乙基-5-{1-[(lS)-2-甲氧基-1 -甲基乙基]-3, 6-二甲 基-1H-吼嘻并[3， 2-b]吡啶-5-基}吡啶 -2-基）氧基]乙腈 69 381.52 (2R)-2-[6-（6-乙氧 基-2-乙基^比ϋ定-3-基）-5-乙基-1-曱基 -1Η- σ比洛并[2, 3-b] °比ϋ定-3-基]丁 _ 1 -脖67 394.56 N-Ethyl-6-isopropyl-3-{1 -[(lR)-l-(decyloxymethyl)propyl]-3,6-dimethyl-1H-pyrrolo[3 , 2-b]ϋ 咬-5-基}π than bite- 2-amine 68, 0^V 378.47 [(6-ethyl-5-{1-[(lS)-2-methoxy-1 -methylethyl]-3,6-dimethyl-1H-indolo[3,2-b]pyridin-5-yl}pyridin-2-yl)oxy]acetonitrile 69 381.52 (2R)-2 -[6-(6-ethoxy-2-ethyl^pyridin-3-yl)-5-ethyl-1-indenyl-1Η-σ pyrrolo[2,3-b] ° ratio ϋ定-3-基]丁_ 1 - neck

31 93966 20081258831 93966 200812588

70 OH 、人 366.51 (3R)-3-{5-[6-異丙 基-2-（曱胺基>比啶 -3-基]-3, 6-二曱基 - 1H-吼咯并[3,2-b] 吡啶-1-基}丁-1-醇 71 H0 k 人/ 、人A 381.53 (2R)-2-{3-[6-異丙 基-2-（甲胺基）吡啶 -3-基]-2, 5-二曱基 -5H-吼嘻并[2, 3-b] 〇比哄-7-基}戍-1-醇 72 OH 368.48 (3R)-3-[3-(6-異丙 基-2-曱氧基吡啶-3-基）-2, 5-二甲基-5H-°比嘻并[2, 3-b]吼.哄 -7-基]丁-1-醇70 OH, human 366.51 (3R)-3-{5-[6-isopropyl-2-(decylamino)-pyridin-3-yl]-3,6-dimercapto-1H-indole [3,2-b] pyridin-1-yl}butan-1-ol 71 H0 k human / , human A 381.53 (2R)-2-{3-[6-isopropyl-2-(methylamino) Pyridin-3-yl]-2,5-dimercapto-5H-indolo[2,3-b]indole 哄-7-yl}indol-1-ol 72 OH 368.48 (3R)-3-[ 3-(6-isopropyl-2-indolylpyridin-3-yl)-2, 5-dimethyl-5H-° is more than [2,3-b]吼.哄-7-yl] Butan-1-ol

32 93966 200812588 7332 93966 200812588 73

367· 50 (3R)-3-{2-[6-異丙 基-2-（甲胺基）吡啶 -3-基]-3, 7-二甲基 -5H- σ比 17各并[2, 3_b] σ比明二^-基} 丁 -1-醇 74367· 50 (3R)-3-{2-[6-isopropyl-2-(methylamino)pyridin-3-yl]-3, 7-dimethyl-5H- σ ratio 17 and [2 , 3_b] σ 比明二^-yl} Butan-1-ol 74

394· 56 (2S)-2-[2-乙基 -3-(2-乙基-6-異丙基°比 啶-3-基）-5-甲基-5Η -吼嘻并[2, 3-b>比哄 - 7-基]戊-1-醇 75394· 56 (2S)-2-[2-ethyl-3-(2-ethyl-6-isopropyl-pyridin-3-yl)-5-methyl-5Η-吼嘻[2, 3-b> 哄- 7-yl] pent-1-ol 75

367· 50 (3S)-3-[5-(6_ 乙氧 基-2-乙基°比咬-3-基）-3， 6-二 曱基-1H -0比咯并[3, 2-b] °比唆 -1- 基]丁 -1- 醇 33 93966 200812588 76 、人 381.53 (2S)-2-{2-乙基-3-[6-異丙基-2-（曱胺 基）吡啶-3-基]-5-曱 基-5H-吼洛并[2， 3-bp比畊-7-基} 丁 -卜醇 77 OH 、人 367.50 (3S)-3-{2-[6-異丙 基-2-(甲胺基）吡啶 -3-基]_3, 7-二曱基 -5H- ϋ比咯并[2, 3-b] 口比哄-5-基} 丁-1-醇 78 OH Ί^υ 、。人 382.51 (3R)-3-[3-乙基-2-(6-異丙基-2-曱氧基 °比σ定-3-基）-7-曱基 -511-11比洛并[2，3-b] 吡啡-5-基]丁-1_醇 34 93966 200812588 79 HO \· a fee Oy 380. 54 (2R)-2-{5-[6-異丙 基-2-（甲胺基）吡啶 -3-基]-3，6- 二曱基 - 1H- ϋ比嘻并[3, 2-b] 吡啶-1-基}戊-卜醇 80 HO 1 m / 掌性 乂 ύ 405· 50 (2S，3S)-3-{2-d 氧基-4- (1 Η- °比ϋ坐-1 -基）苯基]-3, 7-二曱 基-5Η-吡咯并[2, 3-b]吡啡-5-基}戊 - 2-醇 2-[3-乙基-2-(6-異 丙基-2-曱基-3-吡啶 81 γ^Λ Oy 366.51 基）-7-曱基-5H-吡咯 并[2,3_b]吼啡-5-基]-1-丁醇367· 50 (3S)-3-[5-(6-ethoxy-2-ethyl° ratio -3-yl)-3,6-dimercapto-1H-0 ratio 咯[3, 2- b] ° than 唆-1-yl]but-1-ol 33 93966 200812588 76, human 381.53 (2S)-2-{2-ethyl-3-[6-isopropyl-2-(decylamino) Pyridin-3-yl]-5-mercapto-5H-indolo[2,3-bp ratio till-7-yl}butanol 77 OH, human 367.50 (3S)-3-{2-[6 -isopropyl-2-(methylamino)pyridin-3-yl]_3,7-dimercapto-5H-indolepy[2,3-b] 哄-5-yl} - alcohol 78 OH Ί ^ υ , . 382.51 (3R)-3-[3-ethyl-2-(6-isopropyl-2-indolyl ° ratio σ -3--3-)-7-fluorenyl-511-11 piroxi[ 2,3-b] pyridin-5-yl]butan-1-ol 34 93966 200812588 79 HO \· a fee Oy 380. 54 (2R)-2-{5-[6-isopropyl-2-( Methylamino)pyridin-3-yl]-3,6-dimercapto-1H-indole-[3,2-b]pyridin-1-yl}pentanol 80 HO 1 m / palm 乂405 405· 50 (2S,3S)-3-{2-doxy-4-(1 Η- ° than ϋ-1 -yl)phenyl]-3,7-dimercapto-5Η-pyrrole [2,3-b]pyridin-5-yl}pent-2-ol 2-[3-ethyl-2-(6-isopropyl-2-indolyl-3-pyridine 81 γ^Λ Oy 366.51 -7-mercapto-5H-pyrrolo[2,3_b]indol-5-yl]-1-butanol

35 93966 200812588 82 P 掌性 HO V 403.49 (1R，2R)-2-{2-[2- 曱 氧基-4- (1 H_11比嗤-1 -基）苯基]-3, 7-二曱 基-5H-吨咯并[2, 3-bh比畊-5-基}環戊 醇 83 k 368. 48 (2S)-2-[2-(6-乙氧 基-2-乙基σ比咬-3-基）-3-乙基-7-曱基 -5Η- °比 17各并[2, 3-b] 吡哄-5-基]丙-1-醇 84 381.52 (2S)-2-[5-(6-乙氧 基-2-乙基。比σ定-3-基）-6-乙基-3-曱基 - 1Η- σ比 11各并[3, 2_b] °比°定-1-基]丁-1-醇35 93966 200812588 82 P Palm HO V 403.49 (1R,2R)-2-{2-[2- methoxy-4-(1 H_11 嗤-1 -yl)phenyl]-3, 7-dioxin -5H-tondro[2,3-bh than tillage-5-yl}cyclopentanol 83 k 368. 48 (2S)-2-[2-(6-ethoxy-2-ethyl σ ratio Benz-3-yl)-3-ethyl-7-indolyl-5Η-° ratio 17 and [2,3-b]pyridin-5-yl]propan-1-ol 84 381.52 (2S)-2 -[5-(6-ethoxy-2-ethyl. σσ-3-yl)-6-ethyl-3-fluorenyl-1 Η-σ ratio 11 and [3, 2_b] ° ratio ° Din-1-yl]butan-1-ol

36 93966 200812588 85 450. 58 6-乙基-5-{6-乙基 -1 -[2-甲氧基-1-(甲 氧基曱基）乙基]-3-曱基-1H-吡咯并[3, 2-b] 0比咬-5-基}-2-異丙氧基菸鹼甲腈 86 380· 54 (2R)-2-{6- 乙基-5-[6-異丙基-2-(曱胺 基）0比咬-3-基]-3-曱 基-1H-吡咯并[3, 2-b]吼咬-1-基} 丁 -1-醇 87 掌性 399.51 5-（2-乙基-6-異丙氧 基吡啶-3-基）-1-[(1S)-2-氟-1-（甲氧 基甲基）乙基]-3, 6-二甲基-1H- σ比嘻并 [3, 2-b；h比啶36 93966 200812588 85 450. 58 6-Ethyl-5-{6-ethyl-1 -[2-methoxy-1-(methoxyindolyl)ethyl]-3-indolyl-1H-pyrrole And [3, 2-b] 0 than bite-5-yl}-2-isopropoxy nicotine carbonitrile 86 380· 54 (2R)-2-{6-ethyl-5-[6-isopropyl Benzyl-2-(decylamino)0 is more than -3-yl]-3-mercapto-1H-pyrrolo[3,2-b]indole-1-yl}butan-1-ol 87 palm 399.51 5-(2-ethyl-6-isopropoxypyridin-3-yl)-1-[(1S)-2-fluoro-1-(methoxymethyl)ethyl]-3, 6-di Methyl-1H- σ is more than 嘻[3, 2-b; h is pyridine

37 93966 20081258837 93966 200812588

88 掌性 446·59 3-{6- 乙基-1-[(1S) - 2-甲氧基-1-甲基乙 基]-3-甲基-1H-吡咯 并[3, 2-b] 11比咬-5-*}-N-(2-呋喃基曱 基）-6-異丙基°比σ定 - 2-胺 89 \ 掌性 391.48 (2R)-卜{2-[2-甲氧 基-4-(1Η- σ比 0坐-1-基）苯基]-3, 7-二曱 基-5Η-吼咯并[2, 3-b]吼畊-5-基} 丁 - 2-醇 90 409.57 5-(2-異丙氧基-6-異 丙基吡啶-3-基）-1 -[(lR)-l-(曱氧基曱 基)丙基]-3，6-二曱 基-1H-吼咯并[3, 2-bp比咬88 palmity 446·59 3-{6-ethyl-1-[(1S)-2-methoxy-1-methylethyl]-3-methyl-1H-pyrrolo[3, 2-b ] 11 than bite -5-*}-N-(2-furylmercapto)-6-isopropyl ratio σ determinate - 2-amine 89 \ palmity 391.48 (2R)-b {2-[2- Methoxy-4-(1Η-σ ratio 0-n-l-yl)phenyl]-3,7-dimercapto-5Η-indolo[2,3-b]indole-5-yl} - 2-alcohol 90 409.57 5-(2-isopropoxy-6-isopropylpyridin-3-yl)-1 -[(lR)-l-(decyloxy)propyl]-3, 6-dimercapto-1H-indole [3, 2-bp ratio bite

38 93966 200812588 91 452· 60 6-乙基-2-異丙氧基 -5 - U — [(1R)- 1一（甲 氧基甲基）丙基]-3,6 -二曱基-1H-吡咯并 [3,2-b]吼啶-5-基} - N-曱基菸鹼醯胺 92 掌性 % 367.49 6-乙基-5-(2-乙基 -甲氧基σ比咬-3-基）-l-[(lS)-2-甲氧 基-1-甲基乙基]-3-曱基-1H-吡咯并[3, 2-1)]°比咬 93 掌性 、。^八 ^Oy 379. 54 5-(6-異丙基-2-丙基 吼啶-3-基）-l- [(1R) -1 -(曱氧基甲基）丙 基]-3-甲基-1H-吡咯 并[3, 2-1)]σΗ：σ定38 93966 200812588 91 452· 60 6-Ethyl-2-isopropoxy-5 - U — [(1R)- 1 -(methoxymethyl)propyl]-3,6-dimercapto-1H -pyrrolo[3,2-b]acridin-5-yl}-N-mercapto nicotine decylamine 92 palmity % 367.49 6-ethyl-5-(2-ethyl-methoxy σ ratio bite -3-yl)-l-[(lS)-2-methoxy-1-methylethyl]-3-indolyl-1H-pyrrolo[3, 2-1)]° than bite 93 palm ,. ^八^Oy 379. 54 5-(6-Isopropyl-2-propylindole-3-yl)-l- [(1R) -1 -(decyloxymethyl)propyl]-3- Methyl-1H-pyrrolo[3, 2-1)]σΗ: σ定

39 93966 200812588 94 Γ ΗΝ入Μ入广 408· 59 Ν，6-二異丙基-3- {1 -[(110-1 -（甲氧基曱 基）丙基]-3, 6-二曱 基-1H-吼洛并[3， 2-b ] °比σ定-5-基} °比ϋ定 令胺 95 HO V Ν . 405.50 (2R，3R)-2-{2-[2-甲 氧基-4- (1 Η-ϋ比唆-1 -基）苯基]-3, 7-二曱 基-5Η-吼咯并[2， 3-b]吼啡-5-基}戊 -3-醇 5 - [2-乙基-6-異丙氧 、〇^γ^ν 掌性 基-5 -（1Η-四 口坐-5 - 基）0比ϋ定-3-基]-1- 96 463.58 [(1ί〇-1-(甲氧基曱 λΛ 基）丙基]-3, 6-二甲 广又 基-1H-吼咯并[3， 2-b]17比咬39 93966 200812588 94 Γ Intrusion into the 408· 59 Ν,6-diisopropyl-3-{1 -[(110-1 -(methoxycarbonyl)propyl]-3,6-dioxin -1-1H-吼洛和[3, 2-b ] ° ratio σ定-5-基} ° ratio 令定定amine 95 HO V Ν . 405.50 (2R,3R)-2-{2-[2- Oxy-4-(1 Η-ϋ 唆-1 -yl)phenyl]-3,7-dimercapto-5Η-indolo[2,3-b]indan-5-yl}penta- 3-alcohol 5-[2-ethyl-6-isopropoxy, 〇^γ^ν palmyl-5-(1Η-tetra-n-n-5-yl) 0-pyridin-3-yl]-1 - 96 463.58 [(1ί〇-1-(methoxy曱λΛyl)propyl]-3,6-dimethylglycolyl-1H-indolo[3,2-b]17 ratio bite

40 93966 200812588 掌性 5-(2_氯-6-異丙基吼 啶-3-基）-l-[(lS) 97 fix c〆 令N Oy 465·79 -2-甲氧基-1_曱基乙 基]-3-曱基-1H-吡咯 并[3,2-b]吡啶-6-甲 腈 掌性 (IS，3R)-3-{2-[2-曱 氧基-4-( 1H- °比吐-1 - 98 403· 49 基）苯基]-3, 7-二曱 基-5H-吡咯并[2, 1、。又 人ό 3-b]σ比卩井_5-基}環戊 醇 OH (3S)-3-[3- 乙基-2- (2-乙基-6-異丙基°比 99 hX 380· 54 啶-3-基）-7-甲基 -5Η- °比洛并[2, 3-b] 吡畊_5-基]丁-1-醇 41 93966 200812588 100 、。十 掌性 379.54 5-（6-異丙基-2-甲基 啦啶-3-基）-1- [(1R) -1-（曱氧基曱基）丁 基]-3, 6-二曱基-1H-啦17各并[3, 2-b]吼咬 101 ^ J k 396. 54 (2R)-2-[3-（6-乙氧 基-2-乙基°比咬-3-基）-2-乙基-5-曱基 -5H-吼咯并[2,3-b] 口比畊-7-基]戊-1-醇 102 掌性 406.53 2-乙氧基-6-乙基-5-{6-乙基-1-[(1S) -2-曱氧基-1-甲基乙基] -3-甲基-1H-吡咯并 [3,2-13]吼啶-5-基} 於驗曱猜40 93966 200812588 Palm 5-(2_chloro-6-isopropylacridin-3-yl)-l-[(lS) 97 fix c〆N Oy 465·79 -2-methoxy-1_ Mercaptoethyl]-3-mercapto-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile palmate (IS,3R)-3-{2-[2-decyloxy-4- (1H-° ratio 吐-1 - 98 403· 49 base) phenyl]-3,7-dimercapto-5H-pyrrolo[2, 1,. Ό3-b]σ 卩 __5-yl}cyclopentanol OH (3S)-3-[3-ethyl-2-(2-ethyl-6-isopropyl ° than 99 hX 380 · 54 pyridine-3-yl)-7-methyl-5 Η- ° piroxi[2,3-b] pyridin-5-yl]butan-1-ol 41 93966 200812588 100,. Ten palm 379.54 5-(6-isopropyl-2-methyl-piperidin-3-yl)-1-[(1R)-1-(indolyl)butyl]-3, 6-di曱基-1H-啦17 Each [3, 2-b] bite 101 ^ J k 396. 54 (2R)-2-[3-(6-ethoxy-2-ethyl ° ratio bite-3 -yl)-2-ethyl-5-mercapto-5H-indolo[2,3-b] hydroxy-7-yl]pentan-1-ol 102 palm 406.53 2-ethoxy-6 -ethyl-5-{6-ethyl-1-[(1S)-2-decyloxy-1-methylethyl]-3-methyl-1H-pyrrolo[3,2-13]fluorene Pyridin-5-yl}

42 93966 200812588 10342 93966 200812588 103

396. 54 (2S)-2-[2-（6-乙氧 基-2-乙基吡啶-3-基）-3-乙基-7-曱基 -5H-吼嘻并[2, 3-b] 吼畊-5-基]戊-1-醇396. 54 (2S)-2-[2-(6-Ethoxy-2-ethylpyridin-3-yl)-3-ethyl-7-indolyl-5H-indole[2, 3- b] 吼耕-5-yl]pentan-1-ol

OH 104OH 104

405. 50 4-{2-[2-曱氧基-4-(1H-吼唑-1-基）苯 基]-3,7-二曱基-511-口比洛并[2, 3-b]吼口井 -5-基}-2-甲基丁-2-醇 105405. 50 4-{2-[2-decyloxy-4-(1H-indazol-1-yl)phenyl]-3,7-diindenyl-511-portpirol [2, 3- b] Sakaguchi-5-yl}-2-methylbutan-2-ol 105

454.40 1 -（2, 6-二氯苯甲基） -5-（6-異丙基-2-曱 氧基吼啶-3-基）-3,6 -二曱基-10比咯弁 [3, 2-bp比咬 43 93966 200812588454.40 1 -(2,6-Dichlorobenzyl)-5-(6-isopropyl-2-decyloxyacridin-3-yl)-3,6-dimercapto-10-pyrrole[ 3, 2-bp than bite 43 93966 200812588

106 OH 人。 k 396. 54 (3R)-3-[3-(6-乙氧 基乙基吼咬-3-基）-2-乙基-5-甲基 - 5Η- °比。各并[2, 3-b] 吡畊-7-基]戊-1-醇 107 \〇八/ 掌牲 trr 392.50 8-{6-乙基-1-[(1S) - 2-甲氧基-1-曱基乙 基]-3-曱基-1H-吡咯 弁[3, 2-b] π比咬-5-基}-5-異丙基四唑并 [1，5-a]比咬 108 ^5〇ν 353.47 (2S)-2-[5-（6-異丙 基-2-甲氧基吼啶-3-基）-3,6-二甲基-1H-°比嘻并[3, 2-b]吼咬 -1-基]丙-醇106 OH people. k 396. 54 (3R)-3-[3-(6-Ethoxyethyl guan-3-yl)-2-ethyl-5-methyl-5 Η- ° ratio. Each [2, 3-b] pyridin-7-yl]pentan-1-ol 107 \〇八/ 掌生 trr 392.50 8-{6-ethyl-1-[(1S)-2- 2-methoxy -1-mercaptoethyl]-3-mercapto-1H-pyrrole[3,2-b] π ratio bit-5-yl}-5-isopropyltetrazolo[1,5-a] ratio Biting 108 ^5〇ν 353.47 (2S)-2-[5-(6-isopropyl-2-methoxyacridin-3-yl)-3,6-dimethyl-1H-° [3, 2-b]bite-1-yl]propanol

44 93966 200812588 109 OH 379.55 (3R)-3-[6-（2-乙基 -6-異丙基°比咬-3-基）-l，5-二甲基-lH-〇比洛并[2, 3-b]吡咬 -3-基]戊-1-醇 110 掌性 406. 53 2-乙氧基-6-乙基-5-{1 -[(1R)-1 -（甲氧基 曱基）丙基]-3, 6-二 曱基-1H-吡咯并[3， 於驗 曱腈 111 OH k 368.48 (3R)-3-[2-(6-乙氧 基-2-乙基σ比ϋ定-3-基）-3,7-二甲基-5Η-°比嘻并[2, 3-b]ϋ比哄 - 5-基]丁-1-醇44 93966 200812588 109 OH 379.55 (3R)-3-[6-(2-ethyl-6-isopropyl-pyranyl-3-yl)-l,5-dimethyl-lH-debbipro[ 2, 3-b]pyridin-3-yl]pentan-1-ol 110 palmity 406. 53 2-ethoxy-6-ethyl-5-{1 -[(1R)-1 -(methoxy Propyl]propyl]-3,6-dimercapto-1H-pyrrolo[3, in the presence of nitrile 111 OH k 368.48 (3R)-3-[2-(6-ethoxy-2-ethyl Base σ is ϋ-3-yl)-3,7-dimethyl-5Η-° than 嘻[2,3-b]ϋ 哄-5-yl]butan-1-ol

45 93966 200812588 112 OH 394. 56 (3R)-3-[2- 乙基-3-(2-乙基-β-異丙基0比 啶-3-基）-5-曱基-5Η 比洛并[2, 3-1)>比哄 - 7-基]戊-1-醇 113 421.49 1 -（3, 4-二氟苯曱基） -5-（6-異丙基-2-曱 氧基吼啶-3-基） -3, 6-二甲基-1Η-吡 洛并[3, 2-b]吡啶 114 351.50 (2R)-2-[6_(2_ 乙基 -6-異丙基σ比σ定-3-基）-1，5-二甲基-1Η-°比咯并[2, 3-b]吡咬 -3~~基]丙-1 -醇45 93966 200812588 112 OH 394. 56 (3R)-3-[2-ethyl-3-(2-ethyl-β-isopropyl 0-pyridin-3-yl)-5-mercapto-5Η Bilo And [2, 3-1) > 哄-7-yl]pentan-1-ol 113 421.49 1 -(3, 4-difluorophenylindenyl)-5-(6-isopropyl-2-indole Oxypyridin-3-yl)-3,6-dimethyl-1Η-pyrolo[3,2-b]pyridine 114 351.50 (2R)-2-[6_(2_ethyl-6-isopropyl Base σ ratio σ -3-yl)-1,5-dimethyl-1 Η-° ratio 咯[2,3-b]pyrodo-3~~yl]propan-1-ol

46 93966 200812588 115 广< 351.49 (2S)-2-[6- 乙基-5-(6-異丙基-2-曱基 - 3- °比σ定基）-3-曱基 - 1Η- ϋ比嘻并[3, 2~~b] 哒啶-1-基]-1-丙醇 116 掌性 381.52 (2R)-2-[5-乙基-6-(6-異丙基-2-曱氧基 η比唆-3-基）-1-曱基 -1Η- π比咯并[2, 3-b] 吡啶-3-基]丁-1-醇 117 掌性 366.50 5-（4-異丙基-2-曱氧 基苯基）-1-[(1R) -1-(曱氧基曱基）丙基] -3-曱基-1Η-σ比咯并 [3, 2-1>]啦啶46 93966 200812588 115 broad < 351.49 (2S)-2-[6-ethyl-5-(6-isopropyl-2-indenyl- 3- ° σ定基)-3-indolyl-1 Η- ϋ Comparative 嘻[3, 2~~b] acridin-1-yl]-1-propanol 116 palmity 381.52 (2R)-2-[5-ethyl-6-(6-isopropyl-2-曱oxy η is more than 唆-3-yl)-1-indolyl-1Η-π-pyrolo[2,3-b]pyridin-3-yl]butan-1-ol 117 palm 366.50 5-(4- Isopropyl-2-decyloxyphenyl)-1-[(1R)-1-(indolyl)propyl]-3-indolyl-1Η-σ ratio [3, 2-1>;]

47 93966 200812588 118 396· 54 (2R)-2-[3- 乙基-2-(6-異丙基-2-曱氧基 ϋ比咬-3-基）-7-曱基 -5Η- σ比嘻并[2, 3-b] 吡畊-5-基]戊-1-醇 119 380.54 (2S)-2-[3-乙基-2-(2-乙基-6-異丙基117比 啶-3-基）-7-曱基-5H 比嘻并[2, 3-1)>比哄 - 5-基]丁-1-醇 120 38L52 (3S)-3-[6-(6-異丙 基-2-曱氧基吡啶-3-基M，5-二甲基-1H-吼咯并[2, 3-b]吼咬 -3-基]戊-1-醇47 93966 200812588 118 396· 54 (2R)-2-[3-ethyl-2-(6-isopropyl-2-indolyl hydrazide) -7-mercapto-5Η- σ嘻[[,3-b] pyridin-5-yl]pentan-1-ol 119 380.54 (2S)-2-[3-ethyl-2-(2-ethyl-6-isopropyl 117 Bipyridin-3-yl)-7-mercapto-5H is more than [2, 3-1) > 哄-5-yl]butan-1-ol 120 38L52 (3S)-3-[6-( 6-isopropyl-2-indolylpyridin-3-yl M,5-dimethyl-1H-indolo[2,3-b]indole-3-yl]pentan-1-ol

48 93966 20081258848 93966 200812588

121 掌性 420.60 6-乙基-5-(6-異丙基 - 2-吼嘻烷-1-基吼咬 -3-基）-l-[(lS)-2-甲氧基-1-甲基乙基] -3-甲基-1H-吡咯并 [3, 2-b]0比咬 5-（6-乙氧基-2-甲基 旱性 kl ▲ ▲ 吡啶-3-基）-6-乙基 122 pocx 367. 49 -l-[(lS)-2-曱氧基 严N^n -1-甲基乙基]-3-曱 基-1H- ^比咯并[3， 2-bp比咬 5-(6-異丙基-2-曱氧 p 基。比咬-3-基）-3，6- 123 /W" 435.57 二曱基-1-(2-萘基曱 基）-1H- 11比17各并[3， 、。工 ϊΡγ" 2-b]吡啶121 palmity 420.60 6-ethyl-5-(6-isopropyl-2-oxan-1-ylindole-3-yl)-l-[(lS)-2-methoxy-1- Methylethyl]-3-methyl-1H-pyrrolo[3,2-b]0 is more than 5-(6-ethoxy-2-methylidid kl ▲ ▲ pyridin-3-yl)- 6-ethyl122 pocx 367. 49 -l-[(lS)-2-decyloxy N^n-1-methylethyl]-3-indolyl-1H-^pyrho[3, 2 -bp ratio bite 5-(6-isopropyl-2-oxooxyp-yl. than -3-yl)-3,6-123 /W" 435.57 dimercapto-1-(2-naphthylfluorenyl) )-1H- 11 to 17 each [3, ,. Work ϊΡγ" 2-b]pyridine

49 93966 200812588 124 OH 、{!{人 380.54 (3R)-3-{5-乙基-6-[6-異丙基-2-（甲胺 基）吡啶-3-基]-1-甲 基-1H-吼咯并[2， 3-b]吡啶-3-基} 丁 -1-醇 125 ^ 掌性 392.54 6-環丙基-5-(4-異丙 基-2-曱氧基苯基） -1-K1S)-2-曱氧基 -1-曱基乙基]-3-曱 基-1H- °比嘻并[3， 2-b]°tb^ 126 367.50 (2R)-2-[5- 乙基 -6-(6-異丙基-2-曱氧基 吡啶-3-基）-1-甲基 -1H-吼 17各并[2, 3-b] 吡啶-3-基]丙-1-醇49 93966 200812588 124 OH , {!{人380.54 (3R)-3-{5-ethyl-6-[6-isopropyl-2-(methylamino)pyridin-3-yl]-1-methyl -1H-indolo[2,3-b]pyridin-3-yl}butan-1-ol 125 ^ palm 392.54 6-cyclopropyl-5-(4-isopropyl-2-decyloxybenzene -1-K1S)-2-decyloxy-1-mercaptoethyl]-3-mercapto-1H- ° 嘻[3, 2-b]°tb^ 126 367.50 (2R)-2 -[5-ethyl-6-(6-isopropyl-2-indolylpyridin-3-yl)-1-methyl-1H-indole 17-[2,3-b]pyridine-3- Propan-1-ol

50 93966 200812588 127 掌性 365.52 5-（2-乙基-6-異丙基 吼啶-3-基）-l- [(1R) -1 -（甲氧基曱基）丙 基]-3-甲基-1H-吡咯 并[3, 2-b]吡啶 128 广%、 9¾. 381.51 (2S)-2-[5-（6-異丙 基一2一甲氧基一3-吼咬 基）-3, 6-二曱基-1H-σ比洛并[3, 2-b]吼咬 -1-基]-3-甲基-1-丁 醇 129 ^CV 414.55 5 -（6-異丙基-2-曱氧 基口比咬-3-基）-3，6-二曱基-1-(1-吡啶 - 2-基丙基）-1H-吡咯 并[3, 2-b]吡啶50 93966 200812588 127 Palm 365.52 5-(2-Ethyl-6-isopropylacridin-3-yl)-l- [(1R) -1 -(methoxyindolyl)propyl]-3- Methyl-1H-pyrrolo[3,2-b]pyridine 128%, 93⁄4. 381.51 (2S)-2-[5-(6-isopropyl- 2 -methoxy- 3-indanyl) -3,6-dimercapto-1H-σpiro[3,2-b]bite-1-yl]-3-methyl-1-butanol 129 ^CV 414.55 5 -(6-isopropyl Benzyl-2-oxoyloxyl-butyl-3-yl)-3,6-dimercapto-1-(1-pyridin-2-ylpropyl)-1H-pyrrolo[3,2-b]pyridine

51 93966 200812588 130 526.67 6-乙基-5-{6-乙基 -1 -[2-甲氧基-1-(曱 氧基曱基）乙基]-3-曱基-1H-吡咯并[3, 2-b]σ比咬-5-基}-2-異丙氧基-Ν-(2-曱氧 基乙基）菸鹼醯胺 131 k 381.52 (3S)-3-[5-(6-乙氧 基-2-乙基吡啶-3-基）-6-乙基-3-甲基 -1H- σ比洛并[3, 2-b] 0比〇定-1-基]丁-1-醇 132 掌性 424· 54 2-乙氧基-6-乙基-5-{6-乙基-1- [(lS)-2-甲氧基-1-曱基乙基] -3-曱基-111- °比u各并 [3,2-b；h比啶-5-基} 於驗醢胺51 93966 200812588 130 526.67 6-Ethyl-5-{6-ethyl-1 -[2-methoxy-1-(decyloxyindolyl)ethyl]-3-indolyl-1H-pyrrolo[ 3, 2-b] σ than biting -5-yl}-2-isopropoxy-indole-(2-decyloxyethyl)nicotinamide 131 k 381.52 (3S)-3-[5-( 6-ethoxy-2-ethylpyridin-3-yl)-6-ethyl-3-methyl-1H- σpyrolo[3,2-b] 0 is 〇-1-yl] -1-ol 132 palmity 424· 54 2-ethoxy-6-ethyl-5-{6-ethyl-1-[(lS)-2-methoxy-1-indolylethyl] - 3-mercapto-111- ° is more than u[3,2-b;h is pyridine-5-yl}

52 93966 20081258852 93966 200812588

133 ,〇 掌性 ΗΟ' Λ 403.49 (1R，2S)-2-{2-[2-曱 氧基-4- (1 Η-ϋ比嗤-1 -基）苯基]-3, 7-二曱 基-5Η-吼咯并[2, 3-b]吼畊-5-基}環戊 醇 134 366.51 (2R)-2-[3-（2-乙基 -異丙基σ比咬-3-基）-2,5-二 甲基-5H-邱匕略并[2,3-1)]吼哄 -7-基]丁-1-醇 135 354.46 (2S)~~2-[2-(6-異.丙 基-2-曱氧基吼啶-3-基）-3, 7-二甲基-5H-0比洛并[2, 3-b]吼畊 -5-基]丙-1-醇133, 〇手性ΗΟ' Λ 403.49 (1R,2S)-2-{2-[2-曱oxy-4-(1 Η-ϋ 嗤-1 -yl)phenyl]-3, 7-di曱基-5Η-吼 并[2,3-b]吼耕-5-yl}cyclopentanol 134 366.51 (2R)-2-[3-(2-ethyl-isopropyl σ ratio bite-3 -yl)-2,5-dimethyl-5H-qiu 匕 并[2,3-1)]吼哄-7-yl]butan-1-ol 135 354.46 (2S)~~2-[2- (6-Isopropyl-2-decyloxyacridin-3-yl)-3,7-dimethyl-5H-0piro[2,3-b]indole-5-yl]-propyl -1-ol

53 93966 200812588 136 OH 394. 56 (3R)-3-[3-乙基-2-(2-乙基-6-異丙基°比 啶-3-基）-7-甲基 -5H- σ比嘻并[2, 3-b] 吡畊-5-基]戊-1-醇 137 广f 掌性 H—0 V fvt / V^n5〇l 390.49 (2R)-2-{2-[2-乙基 -6-(1Η-吼 °坐-1_ 基） 吡啶-3-基]-3, 7-二 曱基-5H-吡咯并[2, 3-b] °比哄-5—基}丁 -1-醇 (2R)-2-[5-(6-乙氧 基-2-乙基°比u定-3- 138 ηππ 367· 50 基）-3, 6-二曱基-1H- I °比17各并[3, 2-b] ^比唆 k -1-基]丁-1-醇53 93966 200812588 136 OH 394. 56 (3R)-3-[3-ethyl-2-(2-ethyl-6-isopropyl-pyridin-3-yl)-7-methyl-5H- σ嘻和[2, 3-b] pyridin-5-yl]pentan-1-ol 137 broad f palmity H-0 V fvt / V^n5〇l 390.49 (2R)-2-{2-[2 -ethyl-6-(1Η-吼° sits -1_yl) pyridin-3-yl]-3,7-dimercapto-5H-pyrrolo[2,3-b] ° 哄-5-yl} Butan-1-ol (2R)-2-[5-(6-ethoxy-2-ethyl ° ratio -3- 138 ηππ 367· 50 base)-3, 6-dimercapto-1H- I ° ratio of 17 and [3, 2-b] ^ than 唆k -1-yl] butan-1-ol

54 93966 200812588 139 Η 掌性 F^〇v 353.48 6-乙基-l-[(lS)-2-氟-1-曱基乙基]-5-(6-異丙基-2-曱基°比 啶-3_基）-3-甲基-1H -吼嘻并[3，2-bh比咬 140 掌性 380.53 6-異丙基-3-{l-[(IRM-(甲氧基甲 基）丙基]- 3-甲基-1H -吼咯并[3, 2-1)]°比咬 -5-基}-N，N-二甲基 °比啶-2-胺 141 κ0Η 掌性 405.50 (3S)-3-{2-[2-曱氧 基-4-(1H-吼嗅-1 -基）苯基]-3, 7-二甲 基-5H- σ比嘻并[2， 3-b]吡哄-5-基}戊 -1-醇54 93966 200812588 139 掌 Palmity F^〇v 353.48 6-Ethyl-l-[(lS)-2-fluoro-1-indolylethyl]-5-(6-isopropyl-2-indenyl ° Bipyridin-3-yl)-3-methyl-1H-indole[3,2-bh is more than 140 bit palmity 380.53 6-isopropyl-3-{l-[(IRM-(methoxyl) Propyl]- 3-methyl-1H-indolo[3, 2-1)]° than bite-5-yl}-N,N-dimethyl-pyridin-2-amine 141 κ0Η 405.50 (3S)-3-{2-[2-decyloxy-4-(1H-indolyl-1 -yl)phenyl]-3,7-dimethyl-5H- σ is 嘻[2 , 3-b]pyridin-5-yl}pentan-1-ol

55 93966 200812588 142 HO飞 N 少 丫 Oy 353·47 (2R)-2-{2-[6_ 異丙 基-2-（甲胺基）吡啶 -3-基]-3, 7-二曱基 -5H-吼咯并[2, 3-b] 吡畊-5-基}丙-1-醇 143 掌性 405.50 (2S，3R)-2-{2-[2-甲 氧基_4- (1H- °比峻-1 -基）苯基]-3, 7-二甲 基-5H-吼洛并[2， 3-1>>比哄-5-基}戊-3 -醇 ^〇H /w j (3R)-3-[5-（6-乙氧 基-2"·乙基^比σ定-3- 144 a 、0 k 395.55 基）-6-乙基-3-甲基 - 1Η-吡咯并[3,2-b] °比σ定-1 -基]戊-1 -醇55 93966 200812588 142 HO fly N Lesser Oy 353·47 (2R)-2-{2-[6-Isopropyl-2-(methylamino)pyridin-3-yl]-3, 7-didecyl- 5H-indolo[2,3-b] pyridin-5-yl}propan-1-ol 143 palm 405.50 (2S,3R)-2-{2-[2-methoxy_4- (1H - ° ratio -1-1 -yl)phenyl]-3,7-dimethyl-5H-indolo[2, 3-1>> 哄-5-yl}pent-3-ol^〇H /wj (3R)-3-[5-(6-ethoxy-2"·ethyl^ ratio σ定-3- 144 a, 0 k 395.55 base)-6-ethyl-3-methyl- 1Η -pyrrolo[3,2-b] ° ratio sigma-1 -yl]pentan-1 -ol

56 93966 20081258856 93966 200812588

145 入。 k 368.48 (2R)-2-[3-(6-乙氧 基-2-乙基吡啶-3-基）-2-乙基-5-曱基 - 5H-吡咯并[2,3-b] 吡哄-7-基]丙-1-醇 146 OH 1ί4 、。入 isi^Y^ 396.54 (3R)-3-[3- 乙基-2-(6-異丙基-2-曱氧基 吡啶-3-基）-7-甲基 -5H- °比洛并[2, 3-b] 〇比口井-5-基]戍-1-醇 147 OH 、人 381.53 (3R)_3-{3-[6- 異丙 基-2-(曱胺基）吼啶 -3-基]-2, 5- 二甲基 "5H- σ比嘻弁[2，3_b] °比卩井-7-基}戊-1 -醇145 in. k 368.48 (2R)-2-[3-(6-Ethoxy-2-ethylpyridin-3-yl)-2-ethyl-5-mercapto-5H-pyrrolo[2,3-b] Pyridin-7-yl]propan-1-ol 146 OH 1ί4 ,. Iso^Y^ 396.54 (3R)-3-[3-ethyl-2-(6-isopropyl-2-indolylpyridin-3-yl)-7-methyl-5H- ° [2, 3-b] 〇比井-5-yl]戍-1-ol 147 OH, human 381.53 (3R)_3-{3-[6-isopropyl-2-(decylamino)acridine -3-yl]-2, 5-dimethyl "5H- σ ratio 嘻弁[2,3_b] ° ratio 卩-7-yl}pent-1-ol

57 93966 200812588 148 396. 54 (2R)_2-[2- 乙基-3_ (6-異丙基-2-甲氧基 吡啶-3-基）-5-曱基 -5H_ 吼嘻并[2, 3-b] °比哄-7-基]戍-1-醇 149 、人 395.55 (2S)-2-{3- 乙基-2-[6-異丙基-2-（甲胺 基）吡啶-3-基]- 7-曱 基-5H-吼洛并[2， 3-bp比畊-5-基}戊 -1-醇 150 OH 366.51 (3S)-3-{5-[6-異丙 基-2-(甲胺基）σ比咬 -3-基]-3, 6- 二甲基 - 1Η-吼咯并[3，2-b] 吡啶-1-基}丁-1-醇57 93966 200812588 148 396. 54 (2R)_2-[2-ethyl-3-(6-isopropyl-2-methoxypyridin-3-yl)-5-mercapto-5H_ 吼嘻[2, 3-b] ° than 哄-7-yl] 戍-1-alcohol 149, human 395.55 (2S)-2-{3-ethyl-2-[6-isopropyl-2-(methylamino)pyridine -3-yl]- 7-mercapto-5H-indolo[2,3-bp ratio till-5-yl}pentan-1-ol 150 OH 366.51 (3S)-3-{5-[6-iso Propyl-2-(methylamino)σ 咬-3-yl]-3,6-dimethyl- 1Η-indolo[3,2-b]pyridin-1-yl}butan-1-ol

58 93966 200812588 151 OH k 367. 50 (3S)-3-[6-(6-乙氧 基-2-乙基吡啶- -二 曱基-1H-11比嘻并[2, 3-b]σ比咬 - 3-基]丁-1-醇 6-乙基-5-(2-乙基 1 -6-甲氧基σ比咬-3- 152 prxx 397. 52 基）-1 -[2-甲氧基-1 - /^N iT^ (曱氧基甲基）乙基] rV -3-曱基-1Η- 0比嘻并 1 1 [3, 2-1)]吼°定 OH (3R)-3-[6-（6-異丙 r\ 基-2-曱氧基〇比。定-3- 153 OCC% 381.52 基）-1，5-二甲基-1H - 丨 COl. 口比洛并[2, 3-b] °比咬 -3-基]戊-1-醇58 93966 200812588 151 OH k 367. 50 (3S)-3-[6-(6-ethoxy-2-ethylpyridine-dioxal-1H-11 is 嘻[[,3-b]σ Specific bite 3-yl]butan-1-ol 6-ethyl-5-(2-ethyl 1 -6-methoxy σ ratio bite-3- 152 prxx 397. 52 base)-1 -[2- Methoxy-1 - /^N iT^ (decyloxymethyl)ethyl] rV -3-indolyl-1Η- 0 is more than 1 1 [3, 2-1)] 吼 ° OH (3R )-3-[6-(6-isopropylr\yl-2-oxooxyindole ratio. -3-3-5 OCC% 381.52 base)-1,5-dimethyl-1H-丨COl. Luohe [2, 3-b] ° than bit-3-yl] pent-1-ol

59 93966 200812588 154 OH 、人 367.50 (3S)-3-{3-[6_ 異丙 基-2-(曱胺基）吡啶 -3-基]-2，5- 二甲基 -5H-吡咯并[2,3-b] 吡哄-7-基}丁-1-醇 155 368.48 (2R)-2-[2-乙基-3-(6-異丙基-2-甲氧基 吡啶-3-基）-5-甲基 -5H-吼嘻并[2, 3-b] 吡哄-7-基]丙-1-醇 156 掌性 ^〇r 380· 53 N-乙基-6-異丙基-3-{1 -[(lR)-l-(曱氧基 曱基）丙基]-3-甲基 H σ比洛弁[3, 2-b] 〇比咬-5-基}吼咬-2-胺59 93966 200812588 154 OH, human 367.50 (3S)-3-{3-[6-isopropyl-2-(decylamino)pyridin-3-yl]-2,5-dimethyl-5H-pyrrolo[ 2,3-b] pyridin-7-yl}butan-1-ol 155 368.48 (2R)-2-[2-ethyl-3-(6-isopropyl-2-methoxypyridine-3- 5-)-5-methyl-5H-indolo[2,3-b]pyridin-7-yl]propan-1-ol 156 palmity^〇r 380· 53 N-ethyl-6-isopropyl Base-3-{1 -[(lR)-l-(decyloxyindolyl)propyl]-3-methylH σ is more than fluorene [3, 2-b] 〇 咬 -5 - base}吼Chito-2-amine

60 93966 200812588 157 OH 394. 56 (3R)-3-[3- 乙基-2-(2-乙基-6-異丙基11比 啶-3-基）-7-曱基-5H -口比洛并[2, 3-b]吼哄 - 5-基]戊-1-醇 158 r 394.56 6-異丙基-3-{1-[(lR)-l-(甲氧基甲 基）丙基]-3, 6-二曱 基-1H-吼咯并[3, 2-b]吡啶-5-基} -N，N-二曱基°比咬-2-胺 159 P 385.51 1-苯曱基-5-(6-異丙 基-2-甲氧基°比°定-3-基）-3,6-二甲基-1H-°比咯并[3, 2-b]°比唆60 93966 200812588 157 OH 394. 56 (3R)-3-[3-ethyl-2-(2-ethyl-6-isopropyl 11-pyridin-3-yl)-7-fluorenyl-5H-port Bilo[2,3-b]indole-5-yl]pentan-1-ol 158 r 394.56 6-isopropyl-3-{1-[(lR)-l-(methoxymethyl) Propyl]-3,6-dimercapto-1H-indolo[3,2-b]pyridin-5-yl}-N,N-didecyl ° butyl-2-amine 159 P 385.51 1- Phenylhydrazino-5-(6-isopropyl-2-methoxyl ratio -3-yl)-3,6-dimethyl-1H-° ratio 3[3, 2-b]° Comparison

61 93966 20081258861 93966 200812588

160 y 393.57 5 -（6-異丙基-2-丙基 吡啶-3-基）-1-[(1R) -1 -（曱氧基甲基）丙 基]-3，6-二曱基-1H-σ比咯并[3, 2-b]。比°定 161 HO7^^ 351.50 (2R)-2-[5-(2·乙基 -6-異丙基吡啶-3-基）-3，6-二甲基-1H-吼嘻并[3, 2-b]吼咬 -1-基]丙-1-醇 162 ΟΗ 、人 382.51 (3S)_3-[2-(6-異丙 基-2-曱氧基吡啶-3-基）-3,7-二甲基-5H -σ比咯并[2, 3-b] °比.哄 -5-基]戊-1-醇160 y 393.57 5-(6-isopropyl-2-propylpyridin-3-yl)-1-[(1R) -1 -(decyloxymethyl)propyl]-3,6-didecyl -1H-σ ratio is [3, 2-b].约°定161 HO7^^ 351.50 (2R)-2-[5-(2·ethyl-6-isopropylpyridin-3-yl)-3,6-dimethyl-1H-indole[3 , 2-b]bite-1-yl]propan-1-ol 162 人 , human 382.51 (3S)_3-[2-(6-isopropyl-2-indolylpyridin-3-yl)-3 ,7-Dimethyl-5H-σ-pyrolo[2,3-b] ° ratio.哄-5-yl]pentan-1-ol

62 93966 20081258862 93966 200812588

163 /^0 %, 370.46 (2S)-3-敗-2-{5- [6-異丙基-2-（曱胺基） -3-吼咬基]-3, 6 -二 曱基-1Η-吡咯并[3, 2-b]吡啶-1-基}-1-丙醇 164 493. 69 6-異丙基-3-{1-[UR)-l-(甲氧基甲 基）丙基]-3, 6-二曱 基-1H-吼咯并[3, 2-b]吼11 定-5-基} -N-(3·嗎琳-4-基丙基） 吡唆-2-胺 165 OH 381.52 (3R)-3-[6-（6-乙氧 基-2-乙基吡啶-3-基)-1，5-二曱基-1H -σ比洛并[2, 3-b] nb咬 -3-基]戊-1-醇163 /^0%, 370.46 (2S)-3-Oxo-2-{5-[6-Isopropyl-2-(decylamino)-3-indenyl]-3,6-didecyl- 1Η-pyrrolo[3,2-b]pyridin-1-yl}-1-propanol 164 493. 69 6-isopropyl-3-{1-[UR)-l-(methoxymethyl) Propyl]-3,6-dimercapto-1H-indolo[3,2-b]indole-11--5-yl}-N-(3·?-lin-4-ylpropyl)pyridinium- 2-amine 165 OH 381.52 (3R)-3-[6-(6-ethoxy-2-ethylpyridin-3-yl)-1,5-dimercapto-1H-σpyrho[2, 3-b] nb ate-3-yl]pentan-1-ol

63 93966 200812588 166 0 402. 54 5-（6-異丙基-2-曱氧 基吼啶_3-基）-3, 6-二甲基-1 -[3-(1H-吡 洛-1-基)丙基]-1H-σ比略并[3, 2-1)]吼唆 掌性 (2R)-2-[2-(2-乙基 "~° /vV - 6-異丙基吼σ定-3- 167 366.51 基）-3,7-二甲基-5Η - 厂CCv 吼咯并[2, 3-bp比畊 N 丫 - 5-基]丁-1-醇 5-(2-乙基-6-甲氧基 I 口比啶-3-基）-l- [(1S) 168 371.45 -2-氟-1-(甲氧基甲 基）乙基]-3, 6-二曱 人〆 基-1H- °比洛并[3， i 2-b]吡啶63 93966 200812588 166 0 402. 54 5-(6-Isopropyl-2-decyloxyacridin-3-yl)-3,6-dimethyl-1 -[3-(1H-pyrrole-1 -yl)propyl]-1H-σ ratio slightly [3, 2-1)] palmar (2R)-2-[2-(2-ethyl"~° /vV - 6-isopropyl吼 定 -3- -3- 167 366.51 ))-3,7-dimethyl-5Η - plant CCv 吼 并 [2, 3-bp than argon N 丫 5-yl] butan-1-ol 5- ( 2-ethyl-6-methoxyl-Isopyridin-3-yl)-l-[(1S) 168 371.45 -2-fluoro-1-(methoxymethyl)ethyl]-3, 6- Diterpenoid thiol-1H- °piro[3, i 2-b]pyridine

64 93966 200812588 169 OH 卞Ν5〇γ 382.51 (3S)-3-[3-(6-異丙 基-2-甲氧基吡啶-3-基）-2, 5-二甲基-5H-"比咯并[2, 3-b；h比哄 - 7-基]戊-1-醇 170 381.53 (2S)-2-{3-乙基 _2-[6-異丙基-2-（甲胺 基）σ比唆-3-基]-7-甲 基-5Η- σ比嘻并[2， 3-b；h比畊-5-基} 丁 -1-醇 171 OH 393. 58 (3R)-3-[6-乙基 -5-(2-乙基-6-異丙基°比 啶-3-基）-3-甲基 -1H- σ比洛并[3, 2-b] ϋ比咬-1-基]戊-1-醇 65 93966 200812588 172 395. 55 (3S)-3-[6-乙基-5-(6-異丙基-2 -甲氧基 吡啶-3-基）-3-曱基 - 1H-吼嘻并[3, 2-b] 吼咬-1-基]戊-1-醇 173 掌性 366.51 6-異丙基-3-{1-[(lR)-l-(曱氧基曱 基）丙基]-3-曱基-1H 比咯并[3, 2-b>比咬 -5-基}曱基ϋ比淀 - 2-胺 174 。广嘌八八 365. 51 (2R)-2-[6-乙基-5-(6-異丙基-2-曱基 -3-吡啶基）-3-甲基 - 1H- °比嘻并[3, 2-b] π比咬-1-基]-1-丁醇 66 93966 20081258864 93966 200812588 169 OH 卞Ν5〇γ 382.51 (3S)-3-[3-(6-isopropyl-2-methoxypyridin-3-yl)-2, 5-dimethyl-5H-"咯 并 [2, 3-b; h than 哄-7-yl] pent-1-ol 170 381.53 (2S)-2-{3-ethyl_2-[6-isopropyl-2-(A Amino) σ is more than 唆-3-yl]-7-methyl-5Η- σ is more than [2, 3-b; h is more than phage-5-yl} butan-1-ol 171 OH 393. 58 (3R )-3-[6-ethyl-5-(2-ethyl-6-isopropyl~pyridin-3-yl)-3-methyl-1H-σpyrolo[3,2-b] Deuterium-1-yl]pentan-1-ol 65 93966 200812588 172 395. 55 (3S)-3-[6-ethyl-5-(6-isopropyl-2-methoxypyridine-3- ))-3-mercapto- 1H-indolo[3,2-b] 吼-1-yl]pentan-1-ol 173 palm 366.51 6-isopropyl-3-{1-[(lR )-l-(indolyl)propyl]-3-mercapto-1H is more than [3, 2-b> than butyl-5-yl} fluorenylpyrimidin-2-amine 174.广嘌八八365. 51 (2R)-2-[6-ethyl-5-(6-isopropyl-2-indolyl-3-pyridyl)-3-methyl- 1H- ° [3, 2-b] π than bit-1-yl]-1-butanol 66 93966 200812588

175 381.52 (2R)-2-[6-(6-異丙 基-2-甲氧基0比咬-3-基）-1，5-二甲基-1H -°比洛并[2, 3-b]吡咬 - 3-基]戊-1-醇 176 319.45 5-（2-乙基-6-異丙基 吡啶-3-基）-3, 6-二 曱基-1-乙烯基-1H-吼嘻并[3, 2-b]吼咬 177 k 353· 47 (2R)-2-[6-（6-乙氧 基-2-乙基吡啶-3-基）-1，5-二曱基-1H-吼嘻并[2, 3-b] °比咬 - 3-基]丙-1-醇175 381.52 (2R)-2-[6-(6-isopropyl-2-methoxy 0-biti-3-yl)-1,5-dimethyl-1H-°Bilo[2, 3 -b]Pyridine-3-yl]pentan-1-ol 176 319.45 5-(2-Ethyl-6-isopropylpyridin-3-yl)-3,6-dimercapto-1-yl- 1H-indolo[3,2-b]bite 177 k 353· 47 (2R)-2-[6-(6-ethoxy-2-ethylpyridin-3-yl)-1,5- Dimercapto-1H-indolo[2,3-b] ° ratio biting 3-yl]propan-1-ol

67 93966 200812588 178 365· 52 (2S)-2-[6-乙基-5-(2-乙基-6-異丙基13比 啶-3-基）-3-甲基 - 1H- °比嘻并[3, 2-b] 咣啶-1-基]丙-1-醇 179 OH 380.54 (3S)-3-{5-[6-異丙 基-2-（甲胺基）吼啶 -3-基]-3, 6-二曱基 -1H- σ比 17各并[3, 2_b] °比咬-1-基}戊-1-醇 180 / 掌性 366. 51 3-乙基-2-(6 -異丙基 -2-曱基σ比咬-3-基） -5-[(lS)-2-甲氧基 -1-甲基乙基]-7-甲 基-5H-吼洛并[2， 3-b]nt_ 68 93966 20081258867 93966 200812588 178 365· 52 (2S)-2-[6-ethyl-5-(2-ethyl-6-isopropyl 13-pyridin-3-yl)-3-methyl- 1H- ° ratio嘻[[,2-b] acridine-1-yl]propan-1-ol 179 OH 380.54 (3S)-3-{5-[6-isopropyl-2-(methylamino) acridine- 3-yl]-3,6-dimercapto-1H- σ ratio 17 and [3, 2_b] ° ratio biting-1-yl}pentan-1-ol 180 / palmity 366. 51 3-ethyl- 2-(6-isopropyl-2-indenyl σ-Bitter-3-yl)-5-[(lS)-2-methoxy-1-methylethyl]-7-methyl-5H-吼洛和[2, 3-b]nt_ 68 93966 200812588

181 182 183181 182 183

/ 452.60 2-乙氧基-6-乙基-5-{1-[(1R)-1 -（曱氧基 曱基）丙基]-3, 6-二 甲基-1H-吡咯并[3, 2-b]吡啶-5-*}-N，N -二甲基於驗酸胺/ 452.60 2-Ethoxy-6-ethyl-5-{1-[(1R)-1 -(decyloxy)propyl]-3,6-dimethyl-1H-pyrrolo[3 , 2-b]pyridine-5-*}-N,N-dimethyl based acid test amine

OHOH

(3S)-3-[5-（2_ 乙基 —6-異丙基ϋ比咬-3- 379.55 基）-3,6-二甲基-1Η-〇比嘻并[3, 2-b] °比唆 -1-基]戊-1-醇(3S)-3-[5-(2_ethyl-6-isopropylpyridinyl nitrile-3-379.55 base)-3,6-dimethyl-1Η-〇比嘻[3, 2-b] ° 唆-1-yl]pentan-1-ol

(lS，2R)-2-{2-[2-甲 氧基-4- (1°比。坐-1 -基）笨基]-3, 7-二甲 基-5H- °比洛并[2, 3-b]吼畊-5-基}環戊 醇 69 93966 200812588 184 /~¥ 掌性 ^5〇v 384,50 2- （2-乙基-6-異丙基 吡啶-3-基）-5_[(1S) -2-氟-1-（甲氧基甲 基）乙基]-3, 7-二甲 基-5H-吼咯并[2, 3- b>比畊 185 、0 掌性 HO **·. n / 417.52 (lR，2S)-2-{2-[2-甲 氧基-4-(1Η-°比嗤-1 -基）苯基]-3, 7-二甲 基-5H- °比洛并[2， 3 -1)>比畊-5_基}環己 醇 186 z^(^F 掌性 385· 48 5-（6-乙氧基-2-乙基 吼啶-3-基）-1-[(1S) -2-氟-1-(曱氧基甲 基）乙基]-3, 6-二甲 基-1H-吼咯并[3, 2-1)]吼咬(lS, 2R)-2-{2-[2-methoxy-4-(1° ratio. sit-1 -yl) stupid]-3,7-dimethyl-5H- °bilu[ 2, 3-b]吼耕-5-yl}cyclopentanol 69 93966 200812588 184 /~¥ palmity^5〇v 384,50 2- (2-ethyl-6-isopropylpyridin-3-yl) )-5_[(1S)-2-fluoro-1-(methoxymethyl)ethyl]-3,7-dimethyl-5H-indolo[2,3-b> 耕185,0 Palmer HO **·. n / 417.52 (lR, 2S)-2-{2-[2-methoxy-4-(1Η-° than 嗤-1 -yl)phenyl]-3, 7-di Methyl-5H- °biluo[2,3 -1)> than tillage-5_yl}cyclohexanol 186 z^(^F palm 385·48 5-(6-ethoxy-2- Ethyl acridine-3-yl)-1-[(1S)-2-fluoro-1-(decyloxymethyl)ethyl]-3,6-dimethyl-1H-indole[3, 2-1)] bite

70 93966 200812588 187 391.56 1- (環己基甲基）-5-(6-異丙基-2-曱氧基 吡咬-3-基）-3, 6-二 甲基-1H-吼略并[3， 2- b]°比咬 188 ,0H 、0入 396.54 (3S)-3-[3-乙基-2-(6-異丙基-2-曱氧基 吡啶-3-基）-7-甲基 -5H-吡咯并[2,3-b] 吼哄-5-基]戊-1-醇 189 ¢6 〜。、 482. 62 2-乙氧基-6-乙基-Να-甲氧 基乙基 ）-5-{1 -[(1R)-1 -（甲氧基 曱基）丙基]-3, 6-二 甲基-1H-吼洛并[3， 2-b]吡啶-5-基}菸鹼 醯胺70 93966 200812588 187 391.56 1-(cyclohexylmethyl)-5-(6-isopropyl-2-oximeoxypyridin-3-yl)-3,6-dimethyl-1H-oxime and [ 3, 2- b]° than bite 188,0H, 0 into 396.54 (3S)-3-[3-ethyl-2-(6-isopropyl-2-indolylpyridin-3-yl)-7 -Methyl-5H-pyrrolo[2,3-b]indol-5-yl]pentan-1-ol 189 ¢6~. 482. 62 2-Ethoxy-6-ethyl-Να-methoxyethyl)-5-{1 -[(1R)-1 -(methoxyindolyl)propyl]-3, 6 -Dimethyl-1H-indolo[3,2-b]pyridin-5-yl}nicotinamide

71 93966 200812588 190 掌性 403.49 (lR，3S)-3-{2 - [2-甲 氧基-4-(1Η-吡唑-1 -基）苯基]-3, 7-二甲 基-5H-吡咯并[2, 3-b]11比哄-5-基}環戊 醇 191 鬼 k 395.55 (2S)_2-[6-（6-乙氧 基-2-乙基σ比咬-3-基）-5-乙基-1-甲基 - 1Η- 111 比洛并[2, 3~~b] 0比淀_3_基]戍-1-醇 192 Η0^\ Η / 380.54 (2R)-2-[2-（2-乙基 -6-異丙基-5 -甲基°比 啶-3-基）-3, 7-二甲 基-5H- °比嘻并[2， 3-b] 11 比哄-5-基]丁 -卜醇 72 93966 20081258871 93966 200812588 190 Palm 403.49 (lR,3S)-3-{2 - [2-Methoxy-4-(1Η-pyrazol-1-yl)phenyl]-3, 7-dimethyl-5H -pyrrolo[2,3-b]11 哄-5-yl}cyclopentanol 191 ghost k 395.55 (2S)_2-[6-(6-ethoxy-2-ethyl σ ratio bite -3- ))-5-ethyl-1-methyl- 1Η-111 piroxi[2, 3~~b] 0 than _3_yl] 戍-1-ol 192 Η0^\ Η / 380.54 (2R) -2-[2-(2-ethyl-6-isopropyl-5-methyl~pyridin-3-yl)-3,7-dimethyl-5H- ° 嘻[2, 3- b] 11 哄-5-yl]butanol 72 93966 200812588

193 366.50 (2S)-2-{6-乙基-5-[6-異丙基-2-（甲胺 基）吡啶-3-基]-3-甲 基-1H- 0比哈并[3， 2-b]吡啶-1-基}丙 -1-醇 194 OH 382.51 (3R)-3-[2_(6_ 乙氧 基-2-乙基0比咬-3-基）-3-乙基-7-曱基 -5H- σ比 11各并[2, 3-b] σ比哄-5-基]丁-1-醇 195 OH 掌性 ^Χα 391.48 (3S)-3-{2-[2-甲氧 基-4-(1Η- °比 °坐-1 -基）苯基]-3, 7-二甲 基-5Η_ σ比洛并[2， 3-b]吡畊-5-基} 丁 -1-醇193 366.50 (2S)-2-{6-ethyl-5-[6-isopropyl-2-(methylamino)pyridin-3-yl]-3-methyl-1H- 0 than haha[3 , 2-b]pyridin-1-yl}propan-1-ol 194 OH 382.51 (3R)-3-[2_(6-ethoxy-2-ethyl 0-bit-3-yl)-3-ethyl -7-mercapto-5H- σ ratio 11 and [2, 3-b] σ ratio 哄-5-yl] butan-1-ol 195 OH palmity ^ Χ α 391.48 (3S)-3-{2-[ 2-methoxy-4-(1Η-° ratio °-1 -yl)phenyl]-3,7-dimethyl-5Η_ σ pyloro[2,3-b]pyrazine-5-yl } Butan-1-ol

73 93966 200812588 196 掌性 F^〇v 375· 87 6-氣-1-[(1S)-2- It -1 -（甲氧基甲基）乙 基]-5-(6-異丙基吡 啶-3-基）-3-甲基 -1H- °比嘻并[3, 2-b] 11比咬 197 396.54 (2R)-2-[2-(6-乙氧 基-2-乙基吼ϋ定-3-基）-3-乙基-7-甲基 -5H-吼洛并[2, 3-b] 邱匕哄-5-基]戍-1 -醇 198 395.55 (2S)-2-[5- 乙基-6-(6-異丙基-2-曱氧基 吼σ定-3-基）-1-甲基 - 1Η- °比洛并[2, 3-b] 吡啶-3-基]戊-1-醇73 93966 200812588 196 Palm-like F^〇v 375· 87 6-Gas-1-[(1S)-2-It-1 -(methoxymethyl)ethyl]-5-(6-isopropylpyridine -3-yl)-3-methyl-1H- ° is more than 嘻[3,2-b] 11 than bite 197 396.54 (2R)-2-[2-(6-ethoxy-2-ethylindole ϋ -3- -3-yl)-3-ethyl-7-methyl-5H-indolo[2,3-b] 匕哄-5-yl] 戍-1 -ol 198 395.55 (2S)-2 -[5-ethyl-6-(6-isopropyl-2-oxooxyindolo-3-yl)-1-methyl- 1Η- °piro[2,3-b]pyridine- 3-yl]pentan-1-ol

74 93966 200812588 199 H〇^；_ 367.50 (2R)-2-{3-[6-異丙 基-2-(甲胺基）吼啶 -3-基]-2，5- 二曱基 -5H- °比嘻弁[2, 3-b] 吡畊-7-基}丁-1-醇 200 OH 、人 366.51 (3R)-3-{6-[6_ 異丙 基-2-(甲胺基）吡啶 - 3-基]-1，5- 二曱基 - 1H- 0比嘻并[2, 3-b] 口比唆-3-基}丁-1-醇 201 、。^r 掌性 ^XV 406.57 5-（6_異丙基-2-吡咯 烧-1-基吡啶-3-基） -l-[(lR)-l-(甲氧基 甲基）丙基]-3-甲基 - 1H-吡咯并[3,2-b] 口比咬74 93966 200812588 199 H〇^;_ 367.50 (2R)-2-{3-[6-Isopropyl-2-(methylamino)acridin-3-yl]-2,5-dimercapto-5H - ° 嘻弁[2, 3-b] pyridin-7-yl}butan-1-ol 200 OH, human 366.51 (3R)-3-{6-[6-isopropyl-2-(methylamino) Pyridine-3-yl]-1,5-dimercapto-1H- 0 is more than indeno[2,3-b] than indole-3-yl}butan-1-ol 201. ^r palmity ^XV 406.57 5-(6-isopropyl-2-pyrrole-1-ylpyridin-3-yl)-l-[(lR)-l-(methoxymethyl)propyl] -3-methyl-1H-pyrrolo[3,2-b] mouth bite

75 93966 200812588 202 、。^Γ 掌性 420. 60 5 -（6-異丙基-2-哌咬 -1-基吼α定-3 -基）-1-[(lR)-l-(甲氧基曱 基）丙基]_3-甲基 - 1H- ϋ比嘻并[3, 2-b] 203 Λ Ν ^ 403.49 (1S，2S>2 - {2-[2-甲 氧基-4- (1 Η-σ比嗤-1 -基）苯基]-3, 7-二曱 基-5Η-吼嘻并[2， 3-b] 0比哄-5-基}環戊 醇 204 掌性 HO N / 417.52 (1R，2S)-1- 環丙基 -1-{2-[2- 曱氧基-4-(1H- ^比ϋ坐-1-基）苯 基]-3,7-二甲基-5H-吼洛并[2, 3-b]σ比:哄 -5-基}異-2-醇 76 93966 200812588 205 、人 367. 50 (2R)-2-{2- 乙基-3-[6-異丙基-2-(甲胺 基）11比唆-3-基]-5-曱 基-5H-吼咯并[2, 3-b] 口比畊-7-基}丙 -1-醇 206 / 掌性 ΗΟ^^, Ν . 405.50 (2R，3S)-2-{2-[2-甲 氧基-4- (1 Η-ϋ比嗤-1 -基）苯基]-3, 7-二甲 基-5Η-吼嘻并[2， 3-b]吼畊-5-基}戊 -3-鮮 207 兮掌性 HO V H . 、cAA^ 405. 50 (2R)-2-{2-[2-甲氧 基-4*-(lH- 11 比 口坐-1- 基）苯基]-3, 7-二甲 基-5H- °比嘻并[2， 3-b] °比哄-5-基}-3-曱基丁-1-醇75 93966 200812588 202 ,. ^Γ Palm 420. 60 5 -(6-isopropyl-2-piperidin-1-ylindole-1,3-decyl)-1-[(lR)-l-(methoxyindolyl)propene ]]_3-methyl-1H- ϋ 嘻 [ [3, 2-b] 203 Λ Ν ^ 403.49 (1S,2S>2 - {2-[2-methoxy-4-(1 Η-σ ratio嗤-1 -yl)phenyl]-3,7-dimercapto-5Η-indolo[2,3-b] 0 哄-5-yl}cyclopentanol 204 palmity HO N / 417.52 (1R , 2S)-1-cyclopropyl-1-{2-[2-oxime-4-(1H-^ than ϋ-1-yl)phenyl]-3,7-dimethyl-5H-吼洛和[2,3-b]σ ratio: 哄-5-yl}iso-2-ol 76 93966 200812588 205, human 367. 50 (2R)-2-{2-ethyl-3-[6- Isopropyl-2-(methylamino)11 is more than indol-3-yl]-5-mercapto-5H-indolo[2,3-b] hydroxy-7-yl}propan-1-ol 206 / palm ΗΟ ^^, Ν . 405.50 (2R,3S)-2-{2-[2-methoxy-4-(1 Η-ϋ 嗤-1 -yl)phenyl]-3, 7 - dimethyl-5Η-indole[2,3-b]indole-5-yl}pent-3-sodium 207 兮 palm HO VH . , cAA^ 405. 50 (2R)-2-{2 -[2-methoxy-4*-(lH-11 than ketone-1-yl)phenyl]-3,7-dimethyl-5H- ° than 嘻[2, 3-b] ° ratio Indole-5-yl}-3-mercaptobutan-1-ol

77 93966 200812588 208 OH k 382.51 (3S)-3-[3-(6-乙氧 基-2-乙基ϋ比咬-3-基）-2, 5-二甲基-5Η-吼咯并[2, 3-b]吼哄 - 7-基]戊-1-醇 209 365.52 (2S) - 2-[6 -（2*乙基 -6-異丙基吡啶-3-基）-l，5-二 甲基-1H-口比洛并[2, 3-b]吼啶 -3-基]丁-1-醇 210 、人 f/γ 366.51 (2S)-2-{5-乙基-6-[6-異丙基-2-（甲胺 基）°比^定-3-基]-1-甲 基-1H- ϋ比洛并[2， 3-b] σ比°定_3-基}丙 -1-醇77 93966 200812588 208 OH k 382.51 (3S)-3-[3-(6-Ethoxy-2-ethylindole-Butyl-3-yl)-2,5-dimethyl-5Η-吼-[ 2,3-b]吼哄-7-yl]pentan-1-ol 209 365.52 (2S) - 2-[6 -(2*ethyl-6-isopropylpyridin-3-yl)-l,5 - dimethyl-1H-port piroxi[2,3-b]acridin-3-yl]butan-1-ol 210, human f/γ 366.51 (2S)-2-{5-ethyl-6 -[6-isopropyl-2-(methylamino)° ratio 1,4--3-yl]-1-methyl-1H-deutero[2, 3-b] σ ratio _3- Propan-1-ol

78 93966 200812588 211 445. 58 5-[2-乙基-6-曱氧基 -5-（甲基石簧酿基）σ比 啶-3-基]-1-[(1卫） -1 -（曱氧基甲基）丙 基]-3,6-二曱基-1Η-σ比咯并[3, 2-b]吼咬 212 438.57 6-乙基-2-異丙氧基 -5 - U-[(lR)-l-(甲 氧基曱基）丙基]-3,6 -二曱基-1H-吼嘻并 [3,2-13]吼啶-5-基} 菸鹼醯胺 213 395.55 (2S)-2-[6- 乙基-5-(6-異丙基-2-甲氧基 吡啶-3-基）-3-曱基 - 1H-吼咯并[3, 2-b] σ比咬-1-基]戊-1-醇78 93966 200812588 211 445. 58 5-[2-Ethyl-6-decyloxy-5-(methyl stellite) σ pyridine-3-yl]-1-[(1 卫) -1 - (曱oxymethyl)propyl]-3,6-dimercapto-1Η-σ-pyrolo[3,2-b]bite 212 438.57 6-ethyl-2-isopropoxy-5 - U-[(lR)-l-(methoxyindolyl)propyl]-3,6-dimercapto-1H-indeno[3,2-13]acridin-5-yl} nicotine 醯Amine 213 395.55 (2S)-2-[6-ethyl-5-(6-isopropyl-2-methoxypyridin-3-yl)-3-indolyl-1H-indole[3, 2 -b] σ than bit-1-yl]pentan-1-ol

79 93966 200812588 214 393. 58 (28)-2-[6-乙基-5-(2-乙基-6-異丙基0比 啶-3-基）_3-曱基-1Η -0比嘻并[3,2-1>]吼咬 -1-基]戊-1-醇 215 395.55 (2R)-2-{3-乙基-2-[6-異丙基-2-(甲胺 基）吡啶-3-基]-7-曱 基-5H-吼洛并[2， 3-b] °比哄-5-基}戍 -1-醇 216 366·51 (2S)-2-{6-乙基-5-6-異丙基-2-（甲胺 基^比咬-^-基}-3-曱 基-1H-吼咯并[3， 2-b]吡啶-1-基}丙 -卜醇79 93966 200812588 214 393. 58 (28)-2-[6-Ethyl-5-(2-ethyl-6-isopropyl 0-pyridin-3-yl)_3-indolyl-1Η -0 嘻And [3, 2-1 >] bite-1-yl] pent-1-ol 215 395.55 (2R)-2-{3-ethyl-2-[6-isopropyl-2-(methylamino) Pyridin-3-yl]-7-mercapto-5H-indolo[2,3-b] ° than 哄-5-yl}indol-1-ol 216 366·51 (2S)-2-{6 -ethyl-5-6-isopropyl-2-(methylamino)-bito-^-yl}-3-mercapto-1H-indolo[3,2-b]pyridin-1-yl} Propanol

80 93966 200812588 217 、口人 353.47 (2R)-2-{3-[6-異丙 基-2-（甲胺基）吼啶 -3- 基]-2，5- 二曱基 -5H-吡咯并[2,3-b] 吡畊-7-基}丙-1-醇 218 323. 44 5-（6-異丙基吼σ定-3-基）-1 -（2-甲氧基乙 基）-3, 6-二曱基-1Η-σ比口各并[3, 2-b]°比咬 219 OH 人。 k 396.54 (3R)-3-[2-（6-乙氧 基-2-乙基π比σ定-3-基）-3-乙基-7_曱基 -5Ή- ϋ比洛并[2，. 3-b] 吼畊-5-基]戊-1-醇80 93966 200812588 217, 353.47 (2R)-2-{3-[6-isopropyl-2-(methylamino)acridin-3-yl]-2,5-dimercapto-5H-pyrrole And [2,3-b] pyridin-7-yl}propan-1-ol 218 323. 44 5-(6-isopropyloxazolidine-3-yl)-1 -(2-methoxy B The base-3,6-dimercapto-1Η-σ ratio is [3, 2-b]° than the bite 219 OH. k 396.54 (3R)-3-[2-(6-Ethoxy-2-ethylπ~σ-3-yl)-3-ethyl-7-mercapto-5Ή-debido[2 , 3-b] 吼耕-5-yl]pentan-1-ol

81 93966 200812588 220 ^J> 掌性 H0’ N 7 403. 49 (2S)-2-環丙基-2-{2-[2- 甲氧基-4-(1Η - Π比σ坐-1 -基）苯基] -3, 7- 二曱基-5Η- 吡 咯并[2,3-b]i比畊-5-基}乙醇 o 5-(6-異丙基-2-曱氧 基吼啶-3-基）-3,6- 221 il ΓΥ 399.53 二曱基-1-（1-苯基乙 r 、N"Vl 基）-1Η-吼咯并[3, 、。人 2~b]°tb^ /S 6-乙基-1-異丙基-5 - 999 o CXI qqc a n (6-異丙基-2-甲基呢 lLL r N^n OoD» ^±u 啶-3-基）-3-甲基-1H 比嘻并[3, 2-1)]°比°定81 93966 200812588 220 ^J> Palm H0' N 7 403. 49 (2S)-2-cyclopropyl-2-{2-[2-methoxy-4-(1Η - Π σ sit-1 - Phenyl]-3,7-dimercapto-5Η-pyrrolo[2,3-b]i than tillage-5-yl}ethanol o 5-(6-isopropyl-2-indolyl oxime Acridine-3-yl)-3,6-221 il ΓΥ 399.53 Dimercapto-1-(1-phenylethylr, N"Vl group)-1Η-吼 并[[,,. Human 2~b]°tb^ /S 6-ethyl-1-isopropyl-5 - 999 o CXI qqc an (6-isopropyl-2-methyl-lLL r N^n OoD» ^±u Pyridin-3-yl)-3-methyl-1H is more than [3, 2-1)] °

82 93966 200812588 223 OH 394.56 (3S)-3-[2- 乙基-3-(2-乙基-6-異丙基σ比 啶-3-基）-5-甲基-5Η -吼咯并[2, 3-1)>比哄 - 7-基]戊-1-醇 224 OH 、人N人^ 380.54 (3R)-3-{6_[6-異丙 基-2-(曱胺基）吼啶 -3-基]-1，5-二曱基 -1H-吡咯并[2,3-b] 吡啶-3-基}戊-1-醇 225 /0 425.57 5-[6-異丙基-2-(2-甲氧基乙氧基）吼啶 -3-基]-1-[(1R)-1-(曱氧基甲基）丙基] -3, 6-二甲基-1H-吡 洛并[3, 2-b>比咬82 93966 200812588 223 OH 394.56 (3S)-3-[2-ethyl-3-(2-ethyl-6-isopropyl σ-pyridin-3-yl)-5-methyl-5Η-吼 并[2, 3-1) > 哄-7-yl]pentan-1-ol 224 OH, human N ^ 380.54 (3R)-3-{6_[6-isopropyl-2-(decylamino) Acridine-3-yl]-1,5-dimercapto-1H-pyrrolo[2,3-b]pyridin-3-yl}pentan-1-ol 225 /0 425.57 5-[6-isopropyl 2-(2-methoxyethoxy) acridine-3-yl]-1-[(1R)-1-(decyloxymethyl)propyl]-3,6-dimethyl- 1H-pyrrole [3, 2-b> than bite

83 93966 200812588 226 ,0H 、人N人广 381.53 (3S)-3-{3-[6-異丙 基-2-（甲胺基）吡啶 -3-基]-2, 5- 二甲基 -5H- ϋ比嘻并[2, 3-b] 吼哄-7-基}戊-1-醇 227 OH 381.53 (3S)-3-{3-乙基 -2-[6-異丙基-2-（甲胺 基）吡啶-3-基]-7-甲 基-5H-吼嘻并[2， 3-b] °比哄-5_ 基} 丁 -1-醇 228 380.54 (2S)-2-[2-(2-乙基 -6_異丙基11比咬-3-基）-3,7-二甲基-5H- 口比咯并[2, 3-b]吼畊 - 5-基]戊-1-醇 84 93966 200812588 229 ' 掌性 、cAA^ 417.52 順-4-{2-[2_曱氧基 -4-（ 1 Η-σ比 σ坐-1 -基） 苯基]-3, 7-二甲基 -5Η-吼洛并[2, 3-b] 吼畊-5-基}環己醇 230 383.49 5 -（2-乙基-6-甲氧基 吡啶-3-基）-1-[2-甲 氧基-1-（甲氧基甲 基）乙基]-3, 6-二甲 基-1H-吡咯并[3, 2-b]0比咬 231 368.48 (2R)-2-[3-乙基-2-(6-異丙基-2 -甲氧基 吡啶-3-基）-7-甲基 -5Η~· °比洛并[2, 3-b] 吡畊-5-基]丙-1-醇83 93966 200812588 226 ,0H , 人N人广381.53 (3S)-3-{3-[6-isopropyl-2-(methylamino)pyridin-3-yl]-2, 5-dimethyl- 5H- ϋ 嘻 [ [2, 3-b] 吼哄-7-yl} pent-1-ol 227 OH 381.53 (3S)-3-{3-ethyl-2-[6-isopropyl-2 -(Methylamino)pyridin-3-yl]-7-methyl-5H-indolo[2,3-b] ° 哄-5_yl} Butan-1-ol 228 380.54 (2S)-2- [2-(2-ethyl-6-isopropyl 11-buty-3-yl)-3,7-dimethyl-5H-porto[2,3-b]indole-5-yl ]pentan-1-ol 84 93966 200812588 229 ' Palm, cAA^ 417.52 cis-4-{2-[2_曱oxy-4-( 1 Η-σ ratio σ sitting -1 -yl) phenyl]- 3,7-Dimethyl-5Η-吼洛和[2,3-b] 吼耕-5-yl}cyclohexanol 230 383.49 5 -(2-ethyl-6-methoxypyridin-3-yl )-1-[2-methoxy-1-(methoxymethyl)ethyl]-3,6-dimethyl-1H-pyrrolo[3,2-b]0 ratio bite 231 368.48 (2R )-2-[3-ethyl-2-(6-isopropyl-2-methoxypyridin-3-yl)-7-methyl-5Η~· °Biluo[2,3-b] Pyridin-5-yl]propan-1-ol

85 93966 200812588 232 OH 433. 59 4-(6-異丙基-3- {1 -[(1R)-1 -（甲氧基甲 基）丙基]-3, 6-二甲 基-1H- ϋ比嘻并[3， 2-b ] °比咬-5-基卜比咬 -2-基）-2-曱基丁 -3-快-2-醇 233 k 368· 48 (2R)-2-[2-（6-乙氧 基-2-乙基ϋ比咬-3-基）-3-乙基-7-甲基 - 5Η-吡咯并[2,3-b] ϋ比啡-5-基]丙-1 -醇 234 OH 、人 rA^ 380.54 (3S)-3-{5-乙基-6-[6-異丙基-2-（甲胺 基）吡啶-3-基]-1-甲 基-1Η- σ比洛并[2， 3-b]吡啶-3-基}丁 -1-醇85 93966 200812588 232 OH 433. 59 4-(6-Isopropyl-3-{1 -[(1R)-1 -(methoxymethyl)propyl]-3,6-dimethyl-1H- ϋ 嘻 [ [3, 2-b ] ° than bite -5 - kibbitin-2-yl)-2-mercapto-3- keto-2-ol 233 k 368 · 48 (2R)-2 -[2-(6-ethoxy-2-ethylindole-Butyl-3-yl)-3-ethyl-7-methyl-5Η-pyrrolo[2,3-b]indole-5 -yl]propan-1-ol 234 OH, human rA^ 380.54 (3S)-3-{5-ethyl-6-[6-isopropyl-2-(methylamino)pyridin-3-yl]- 1-methyl-1Η-σpyrolo[2,3-b]pyridin-3-yl}butan-1-ol

86 93966 200812588 235 379· 55 (2S)-2-[6-(2-乙基 -6-異丙基吡啶-3-基）-1，5-二曱基-1H-σ比嘻并[2, 3-b] °比σ定 - 3-基]戊-1-醇 236 /-F 掌性 356.44 5 - [(1R) - 2-氟-1-（曱 氧基曱基）乙基]-2-(6-異丙基σ比咬-3-基）-3,7-二曱基-5Η-吼咯并[2, 3-b>比畊 237 382.51 (2S)-2-[2-乙基-3-(6-異丙基-2-甲氧基 吼啶-3-基）-5-曱基 -5H- ϋ比 σ各并[2, 3-b] 吡畊-7-基]丁-1-醇86 93966 200812588 235 379· 55 (2S)-2-[6-(2-ethyl-6-isopropylpyridin-3-yl)-1,5-dimercapto-1H-σ ratio 嘻[2 , 3-b] ° ratio σ--3-yl]pentan-1-ol 236 /-F palm 356.44 5 - [(1R)-2-fluoro-1-(decyloxy)ethyl]- 2-(6-isopropyl σ 咬 -3-yl-3-)-3,7-dimercapto-5Η-吼 并[2, 3-b> 耕 237 382.51 (2S)-2-[2- Ethyl-3-(6-isopropyl-2-methoxyacridin-3-yl)-5-mercapto-5H- ϋ σ 并 [2, 3-b] pyridin-7-yl Butan-1-ol

87 93966 200812588 238 381.53 (2R)-2-{3- 乙基-2-[6-異丙基-2-(曱胺 基）〇比σ定-3-基]-7-甲 基-5Η-吼咯并[2, 3-b] °比啡_5-基} 丁 -1-醇 239 ηο,,ΧΛ 掌性 417.52 (lR，3R)-3 - {2 - [2-甲 氧基-4-(1H-吼唑-1 -基）苯基]-3, 7-二甲 基-5H- °比嘻并[2， 3-b]。比哄-5-基}環己 醇 240 OH Ιϊ^ν 、人 IsAj/ 395.55 (3S)-3-{3-乙基 -2-[6-異丙基-2-（甲胺 基）吡啶-3-基]-7-甲 基-5H- σ比略并[2， 3-b]吼畊-5-基}戊 -1-醇87 93966 200812588 238 381.53 (2R)-2-{3-ethyl-2-[6-isopropyl-2-(decylamino)pyrene than sigma-3-yl]-7-methyl-5Η-吼 并 [2, 3-b] ° than cyano-5-yl} butan-1-ol 239 ηο,, ΧΛ palmity 417.52 (lR, 3R)-3 - {2 - [2-methoxy-4 -(1H-carbazol-1 -yl)phenyl]-3,7-dimethyl-5H- ° is more than [2, 3-b].哄-5-yl}cyclohexanol 240 OH Ιϊ^ν, human IsAj/ 395.55 (3S)-3-{3-ethyl-2-[6-isopropyl-2-(methylamino)pyridine- 3-yl]-7-methyl-5H- σ ratio slightly [2, 3-b] indole-5-yl}pentan-1-ol

88 93966 200812588 241 380. 54 (2R)-2-{5-乙基-6-[6-異丙基-2-（曱胺 基）吡啶-3-基]-1-甲 基-1H- 11比嘻并[2， 3-b]吡啶-3-基} 丁 -1-醇 242 379.44 (2R) - 2-{3,7-二甲基 -2-[2-氟-4-(1Η- σ比 唑-1-基）苯基]-5Η-°比咯并[2, 3-b]0比哄 -5-基}丁-1-醇 243 366.51 (2S)-2-[3-乙基-2-(2-乙基-6-異丙基〇比 啶-3-基）-7-甲基 -5H- °比洛并[2, 3-b] 〇比啡-5-基]丙-1-醇88 93966 200812588 241 380. 54 (2R)-2-{5-Ethyl-6-[6-isopropyl-2-(decylamino)pyridin-3-yl]-1-methyl-1H- 11嘻[[,3-b]pyridin-3-yl}butan-1-ol 242 379.44 (2R) - 2-{3,7-dimethyl-2-[2-fluoro-4-(1Η- σBizozol-1-yl)phenyl]-5Η-°pyrho[2,3-b]0 哄-5-yl}butan-1-ol 243 366.51 (2S)-2-[3-B Benzyl-2-(2-ethyl-6-isopropylindolepyridin-3-yl)-7-methyl-5H- °piro[2,3-b]indole-5-yl] Propan-1-ol

89 93966 20081258889 93966 200812588

244 兄。 k 367· 50 (2S)-2-[5-(6-乙氧 基-2-乙基吡啶-3-基）-6-乙基-3-曱基 - 1H-吡咯并[3,2-b] 吡啶-1-基]丙-1-醇 OH y^f (3R)-3-[5-乙基-6- (2-乙基-6-異丙基σ比 245 PCC, 393.58 啶-3-基）-1-甲基-1Η ^ cxx -吼嘻并[2,3-1)>比咬 - 3-基]戊-1-醇 (2R)-2-[2- 乙基-3- H〇W (2-乙基-6-異丙基外匕 246 cow 380.54 啶-3-基）-5-甲基 '〇〇L. -5H- 11比嘻并[2, 3-b] 吡畊-7-基]丁-1-醇 90 93966 200812588 247 cu々 479.66 3-{6-乙基-1-[(1S) -2-甲氧基-1-甲基乙 基]-3-曱基-1H-吡咯 并[3, 2-b]吡啶-5-基}-6-異丙基邛-（2-嗎淋-4-基乙基）°比唆 - 2-胺 248 掌性 365.52 5 -（6-異丙基-2-曱基 °比咬-3-基）-1 - [ (1R) -1 -（甲氧基曱基）丙 基]-3,6-二甲基-1H-°比洛并[3, 2-1>>比咬 249 ^5α〇 k 367. 50 (3R)-3-[6-(6-乙氧 基-2-乙基°比σ定-3-基）-1，5-二曱基-1Η-°比咯并[2, 3-b] °比咬 -3-基]丁-1-醇244 brother. k 367· 50 (2S)-2-[5-(6-ethoxy-2-ethylpyridin-3-yl)-6-ethyl-3-indolyl-1H-pyrrolo[3,2- b] pyridin-1-yl]propan-1-ol OH y^f (3R)-3-[5-ethyl-6-(2-ethyl-6-isopropyl σ ratio 245 PCC, 393.58 pyridine- 3-yl)-1-methyl-1Η^ cxx -吼嘻[2,3-1)>Bite-3-yl]pentan-1-ol (2R)-2-[2-ethyl- 3-H〇W (2-ethyl-6-isopropyl oxime 246 cow 380.54 pyridine-3-yl)-5-methyl'〇〇L. -5H- 11 嘻[2, 3-b Pyridin-7-yl]butan-1-ol 90 93966 200812588 247 cu々479.66 3-{6-Ethyl-1-[(1S)-2-methoxy-1-methylethyl]-3 -mercapto-1H-pyrrolo[3,2-b]pyridin-5-yl}-6-isopropylindole-(2-oxalin-4-ylethyl) ° 唆 2-amine 248 palm 365.52 5-(6-isopropyl-2-indenyl) than 1--3-yl)-1 - [(1R) -1 -(methoxyindolyl)propyl]-3,6-dimethyl Base-1H-° piroxi[3, 2-1>> than bite 249^5α〇k 367. 50 (3R)-3-[6-(6-ethoxy-2-ethyl ° ratio σ D--3-yl)-1,5-dimercapto-1 Η-° ratio 咯[2, 3-b] ° ratio -3-yl]butan-1-ol

91 93966 200812588 250 OH 365.52 (3S)-3-[5-(2-乙基 -6-異丙基。比σ定-3-基）-3,6-二曱基-lH-吡咯并[3,2-b]吡啶 -1- 基]丁-1-醇 251 k 368.48 (2R)-2-[3-(6-乙氧 基-2_乙基吼σ定-3-基）-2，5-二甲基-5Η-σ比咯并[2,3-b；h比畊 - 7-基]丁-1-醇 252 W 掌性 HO N / 、cAA^ 391.48 (2R，3S)-3-{2-[2-甲 氧基-4- (1H-11比吐-1 -基）苯基]-3, 7-二甲 基-5H- σ比咯并[2， 3-b]吼畊-5-基} 丁 -2-醇91 93966 200812588 250 OH 365.52 (3S)-3-[5-(2-ethyl-6-isopropyl. than sigma-3-yl)-3,6-dimercapto-lH-pyrrolo[3 ,2-b]pyridin-1-yl]butan-1-ol 251 k 368.48 (2R)-2-[3-(6-ethoxy-2-ethylpyridin-3-yl)-2, 5-Dimethyl-5Η-σpyrolo[2,3-b;h-rough-7-yl]butan-1-ol 252 W Palmitic HO N / , cAA^ 391.48 (2R,3S)-3 -{2-[2-methoxy-4-(1H-11bi-l-yl)phenyl]-3,7-dimethyl-5H- σ-pyrolo[2,3-b]indole Plow-5-yl}butan-2-ol

92 93966 200812588 253 347· 50 5-（2-乙基-6-異丙基 吼啶-3-基）-3,6-二 曱基-i-α-亞曱基丙 基）-1Η-吼咯并[3, 2-1)]°比咬 ^0H, (3R)-3_[6-乙基-5- (6-異丙基-2-甲氧基 254 0(Χ^ 395.55 吡啶-3-基）-3-甲基 广 ίΧΧ/ - 1H- °比咯并[3, 2-b] 、。八 °比。定-1-基]戊_1-醇 (2R)-2-[5-乙基-6- 丨 H〇 (6-異丙基-2-甲氧基 255 οχ^ 395.55 °比σ定-3-基）-1-曱基 广OCX -1Η-吼嘻并[2, 3-b] '0 八 Νί^γ^ 吡啶-3-基]戊-1-醇92 93966 200812588 253 347· 50 5-(2-Ethyl-6-isopropylacridin-3-yl)-3,6-dimercapto-i-α-arylenepropyl)-1Η-吼咯[3, 2-1)]° ratio bite ^0H, (3R)-3_[6-ethyl-5-(6-isopropyl-2-methoxy 254 0(Χ^ 395.55 pyridine-3) -yl)-3-methylpolyίΧΧ/ - 1H- ° ratio 咯[3, 2-b], 八° ratio. -1- yl]pent-1-ol (2R)-2-[5 -ethyl-6- 丨H〇(6-isopropyl-2-methoxy 255 οχ^ 395.55 ° σ -3-yl)-1-fluorenyl OCX -1Η-吼嘻[2, 3-b] '0 八Νί^γ^ pyridin-3-yl]pentan-1-ol

93 93966 200812588 256 380. 54 (2S)-2-[3-（2-乙基 -6-異丙基σ比咬-3-基）-2, 5-二甲基-5Η-π比洛并[2, 3-b]吼哄 - 7-基]戊-1-醇 257 、人 38L53 (2S)-2-{3-[6-異丙 基-2-(甲胺基）吼°定 -3-基]-2, 5-二甲基 -5H-吼嘻并[2, 3-b] σ比哄_7-基}戊-1-醇 258 OH ^cv 380.54 (3S)-3-{6-乙基-5-[6-異丙基-2-(甲胺 基）吡啶-3-基]-3-甲 基-1Η- °比洛并[3， 2- b] 0比 σ定-1-基} 丁 -1-醇93 93966 200812588 256 380. 54 (2S)-2-[3-(2-ethyl-6-isopropyl σ 咬-3-yl)-2, 5-dimethyl-5Η-π piroxime [2,3-b]吼哄-7-yl]pentan-1-ol 257, human 38L53 (2S)-2-{3-[6-isopropyl-2-(methylamino) 吼 ° - 3-yl]-2,5-dimethyl-5H-indolo[2,3-b] σ ratio 哄7-yl}pentan-1-ol 258 OH ^cv 380.54 (3S)-3-{ 6-ethyl-5-[6-isopropyl-2-(methylamino)pyridin-3-yl]-3-methyl-1Η- °piro[3,2-b] 0 ratio σ -1-yl}butan-1-ol

94 93966 20081258894 93966 200812588

259 367.50 (2S)-2-{3_ 乙基-2-[6 -異丙基-2-（曱胺 基）吡啶-3-基]-7-甲 基-5H- °比洛并[2， 3~~b]吼哄-5-基}丙 -1-醇 OH (3R)-3-[2-乙基-3- 1 (6-異丙基-2-曱氧基 260 0( 396.54 吡啶-3-基）-5-甲基 -5H- σ比略并[2, 3-b] 、。八 吡哄-7-基]戊-1-醇 (2S)-2-{2-[6-異丙 H0 /VNv^ 基-2-（曱胺基V比啶 261 381.53 -3- 基]-3, 7- 二甲基 广 0(X/ -5H-吡咯并[2,3-b] 口比畊-5-基}戊-1-醇 95 93966 200812588 262 OH 382.51 (3R)-3-[3-(6-乙氧 基-2-乙基吼啶-3-基）-2, 5-二甲基-5H-°比洛并[2, 3-b]咕哄 -7-基]戊-1-醇 (3S)-3-{6- 乙基-5- [6-異丙基-2-（甲胺 263 394. 56 基）吡啶-3-基]-3-曱 / Ν^Ί 基-1H-吼咯并[3， 、N人 2-b] π比σ定-1-基}戍 Η 1 -1-醇 W 掌性 5-（2-乙基-6-甲氧基 吡啶-3-基）-1-[(1ί〇 264 353.46 -2-甲氧基-1-曱基乙 厂n 基]-3, 6-二甲基-1Η- f N 1 11比嘻并[3, 2-b>比咬259 367.50 (2S)-2-{3_ethyl-2-[6-isopropyl-2-(decylamino)pyridin-3-yl]-7-methyl-5H- ° piroxi[2, 3~~b]吼哄-5-yl}propan-1-ol OH (3R)-3-[2-ethyl-3- 1 (6-isopropyl-2-yloxy 260 0 ( 396.54 pyridine) -3-yl)-5-methyl-5H- σ ratio slightly [2, 3-b], octapyr-7-yl]pentan-1-ol (2S)-2-{2-[6 -isopropyl H0 /VNv^yl-2-(decylamine V-pyridine 261 381.53 -3-yl]-3, 7-dimethylpoly 0 (X/ -5H-pyrrolo[2,3-b] Mouth ratio tillage-5-yl}pentan-1-ol 95 93966 200812588 262 OH 382.51 (3R)-3-[3-(6-ethoxy-2-ethylacridin-3-yl)-2, 5 -Dimethyl-5H-°piro[2,3-b]indol-7-yl]pentan-1-ol (3S)-3-{6-ethyl-5-[6-isopropyl -2-(methylamine 263 394. 56 yl)pyridin-3-yl]-3-indole/ Ν^Ίyl-1H-indolo[3, N,2-b] π ratio sigma-1戍Η} -1- 1 alcohol W palm 5-(2-ethyl-6-methoxypyridin-3-yl)-1-[(1ί〇264 353.46 -2-methoxy-1-oxime Base B plant n base]-3,6-dimethyl-1Η-f N 1 11 than 嘻[3, 2-b> than bite

96 93966 200812588 265 掌性 HO V μ . 417.52 (112幻-2-{2-[2-曱 氧基-4-(ΙΗ-吼唑-1 -基）苯基]-3, 7-二曱 基-5H-吡咯并[2, 3 - b]吡哄-5-基}環己 醇 266 掌性 445· 58 6-乙基-5-[2-乙基 -6-甲氧基-5-（曱基 石黃隨基）°比咬_3*~基] -l-[(lS)-2-甲氧基 -1-甲基乙基]-3-甲 基-1H- σ比咯并[3， 2-b]11比咬 5-（6-乙氧基-2-乙基 吡啶-3-基）-1-[2-甲 267 397. 52 氧基-1 -（甲氧基曱 基）乙基]-3, 6-二甲 基-1H- ϋ比洛并[3， 1 2-b]吡啶96 93966 200812588 265 Palm HO V μ . 417.52 (112 Magic-2-{2-[2-Methoxy-4-(anthracene-oxazol-1-yl)phenyl]-3,7-didecyl -5H-pyrrolo[2,3-b]pyridin-5-yl}cyclohexanol 266 palm 445· 58 6-ethyl-5-[2-ethyl-6-methoxy-5-(曱基石黄随基)°Bite _3*~基] -l-[(lS)-2-methoxy-1-methylethyl]-3-methyl-1H- σ ratio [3, 2 -b]11 bite 5-(6-ethoxy-2-ethylpyridin-3-yl)-1-[2-methyl 267 397. 52 oxy-1 -(methoxyindolyl)ethyl ]-3,6-Dimethyl-1H-debido[3,1 2-b]pyridine

97 93966 200812588 268 351.49 (2S)-2-[5-(6-異丙 基-2-甲基-3-吡啶 基）-3,6-二甲基-1H-口比嘻并[3, 2-b] °比啶 -1-基]-1-丁醇 269 掌性 369.48 6-乙基-1-[(1S)-2-氟-1-甲基乙基]-δα-異丙基-2-曱氧基 °比咬-3-基）-3-曱基 - 1H-吼咯并[3,2-b] 吼咬 270 393. 58 (2R)_2-[5-乙基-δα-乙基-6- 異丙基π比 0定-3-基）-1-甲基 - 1Η- °比 ρ各并[2, 3-b] 0比〇定-3_基]戊-1-醇97 93966 200812588 268 351.49 (2S)-2-[5-(6-Isopropyl-2-methyl-3-pyridyl)-3,6-dimethyl-1H-port 嘻[3, 2 -b] °pyridin-1-yl]-1-butanol 269 palm 369.48 6-ethyl-1-[(1S)-2-fluoro-1-methylethyl]-δα-isopropyl- 2-曱oxyl ratio -3-yl)-3-mercapto-1H-indolo[3,2-b] bite 270 393. 58 (2R)_2-[5-ethyl-δα- Ethyl-6-isopropyl π is 0-but-3-yl)-1-methyl- 1Η-° ratio ρ and [2, 3-b] 0 is more than -3 -yl] pent-1- alcohol

98 93966 200812588 271 OH ^Ογ 393· 58 (3R)-3-[5-乙基-6-(2-乙基-6-異丙基0比 啶-3-基）-1-曱基 -1H-吡咯并[2,3-b] 吡啶-3-基]戊-1-醇 272 366.51 (2S)_2-{6-[6-異丙 基-2-（曱胺基）吡啶 -3-基]-1，5-二曱基 -1H- 11比洛并[2, 3-b] °比咬-3-基}丁-1-醇 273 、口人 366.51 (2R)-2-{5- 乙基-6-[6-異丙基-2-(甲胺 基）吡啶-3-基]-1-甲 基—1H- σ比洛并[2， 3-b] 11比咬-3-基}丙 -1-醇98 93966 200812588 271 OH ^Ογ 393· 58 (3R)-3-[5-ethyl-6-(2-ethyl-6-isopropyl 0-pyridin-3-yl)-1-indenyl-1H -pyrrolo[2,3-b]pyridin-3-yl]pentan-1-ol 272 366.51 (2S)_2-{6-[6-isopropyl-2-(decylamino)pyridin-3-yl ]-1,5-dimercapto-1H- 11 piroxi[2,3-b] ° ratio -3-yl}butan-1-ol 273, mouth 366.51 (2R)-2-{5- Ethyl-6-[6-isopropyl-2-(methylamino)pyridin-3-yl]-1-methyl-1H- σ pyrrolo[2,3-b] 11 ratio -3- Propan-1-ol

99 93966 20081258899 93966 200812588

274 HO^V, μ / k 354. 46 (2R)-2-[2-(6-乙氧 基-2-乙基吡啶-3-基）-3, 7-二甲基-5H-吼咯并[2,3-b；h比哄 - 5-基]丙-1-醇 275 私。 k 381.52 (2尺）-2-[5-（6-乙氧 基-2-乙基°比σ定-3-基）-6-乙基-3-甲基 -1Η-啦咯并[3,2-b] 〇比°定-1-基]丁-1-醇 276 354.46 (2R)-2-[3-(6-異丙 基-2-甲氧基吡啶-3-基）-2,5-二甲基-5H -°比嘻并[2, 3-b] °比哄 - 7-基]丙-卜醇 100 93966 200812588274 HO^V, μ / k 354. 46 (2R)-2-[2-(6-ethoxy-2-ethylpyridin-3-yl)-3,7-dimethyl-5H-indole And [2,3-b;h is 哄-5-yl]propan-1-ol 275 private. k 381.52 (2 ft) -2-[5-(6-ethoxy-2-ethyl ° σ -3-yl)-6-ethyl-3-methyl-1 Η-la-l-[3 ,2-b] 〇比°-1-yl]butan-1-ol 276 354.46 (2R)-2-[3-(6-isopropyl-2-methoxypyridin-3-yl)-2 ,5-dimethyl-5H-° than 嘻[2,3-b] ° 哄-7-yl]propanol 100 93966 200812588

277 掌性 370.47 3-氟-2-[5-(6-異丙 基-2-甲胺基-吡啶 -3-基）-3，6-二甲基-吼洛并[3, 2_b] °比σ定 -1-基]-丙-1-醇 278 掌性 394· 56 3-{6-乙基-1-[(1S) -2-曱氧基-1-曱基乙 基]-3-甲基-1Η-σ比咯 并[3, 2-b] π比咬-5-基}-6-異丙基-Ν，Ν-二甲基吡啶-2-胺 279 365.52 (2R)-2-[6-（2"~ 乙基 -6-異丙基吡啶-3-基）-l，5-二甲基-1Η-°比洛并[2, 3-b]吼啶 -3-基]丁-1-醇277 palm 370.47 3-fluoro-2-[5-(6-isopropyl-2-methylamino-pyridin-3-yl)-3,6-dimethyl-indolizine [3, 2_b] ° Ratio σ -1--1-yl]-propan-1-ol 278 palm 394· 56 3-{6-ethyl-1-[(1S) -2-decyloxy-1-mercaptoethyl]-3 -Methyl-1Η-σ ratio 3[3,2-b] π ratio biting-5-yl}-6-isopropyl-oxime, Ν-dimethylpyridin-2-amine 279 365.52 (2R)- 2-[6-(2"~ethyl-6-isopropylpyridin-3-yl)-l,5-dimethyl-1Η-°piro[2,3-b]acridin-3- Butyl-1-ol

101 93966 200812588 280 OH 368.48 (3R)-3-[2""(6-異丙 基-2-甲氧基吡啶-3-基）-3，7-二甲基-5H-σ比咯并[2, 3-b]ϋ比哄 -5-基]丁-1-醇 281 、广Γ 掌性 394. 56 16_二異丙基-3-{1-[(1RM-(曱氧基曱 基）丙基]- 3-甲基-1Η -口比洛并[3, 2-b>比咬 - 5-基卜比ϋ定-2-胺 282 掌性 444.41 1- [(lS)-l-(溴曱基） -2-甲基丙基]-5-(6-異丙基-2-甲氧基吼 啶-3-基）-3, 6_ 二甲 基—1H-。比洛并[3， 2- b]u比咬101 93966 200812588 280 OH 368.48 (3R)-3-[2""(6-isopropyl-2-methoxypyridin-3-yl)-3,7-dimethyl-5H-σ ratio [2, 3-b] indole-5-yl]butan-1-ol 281, Γ Γ palm 394. 56 16_diisopropyl-3-{1-[(1RM-(曱 曱 曱) Base) propyl]- 3-methyl-1 Η - 口比洛和[3, 2-b> than bite- 5-kibbibidine-2-amine 282 palm 444.41 1- [(lS)-l -(bromoindolyl)-2-methylpropyl]-5-(6-isopropyl-2-methoxyacridin-3-yl)-3,6-dimethyl-1H-. [3, 2- b]u than bite

102 93966 200812588 283 OH 380.54 (3R)-3-[3-乙基-2-(2-乙基-6-異丙基°比 啶-3-基)-7-甲基-5H -吼嘻并[2, 3-b]吼 畊-5-基]丁-1-醇 284 掌性 I 354·45 5_(2, 4-二甲氧基苯 基）-1-[(1R)-1-（甲 氧基甲基）丙基]-3-甲基-1H-吡咯并[3, 2-b]°比咬 285 掌性 385.48 3-{5-[ (1R)-2-氟-1-(曱氧基曱基）乙基] -3, 7-二曱基-5H-吡 咯并[2, 3-b]吡畊-2-基} -異丙基-N-曱 基吡啶-2-胺 103 93966 200812588102 93966 200812588 283 OH 380.54 (3R)-3-[3-ethyl-2-(2-ethyl-6-isopropyl-pyridin-3-yl)-7-methyl-5H-indole [2, 3-b]吼耕-5-yl]butan-1-ol 284 Palm I 354·45 5_(2,4-Dimethoxyphenyl)-1-[(1R)-1-( Methoxymethyl)propyl]-3-methyl-1H-pyrrolo[3,2-b]° ratio biting 285 palm 385.48 3-{5-[ (1R)-2-fluoro-1-(曱 曱 ))ethyl] -3,7-dimercapto-5H-pyrrolo[2,3-b]pyrylene-2-yl}-isopropyl-N-decylpyridin-2-amine 103 93966 200812588

286 HO^f N k 354. 46 (2R)-2-[3-(6-乙氧 基-2-乙基吡啶-3-基）-2, 5-二曱基-5H-叶匕咯并[2, 3-b；h比哄 - 7-基]丙-1-醇 OH (3R)-3-[3-(6-異丙 基-2-甲氧基吡啶-3- 287 382.51 基）-2,5-二曱基-5H - / CCu ϋ比嘻并[2, 3-b] °比哄 \〇 八 -7-基]戊-1-醇 / 6-乙基-5~*[2-乙基 w^° -6-甲氧基-5-（甲基 〇 /V"V^ 〇〇 石黃蕴基）0比唆-3~基] 288 475. 61 -1 -[2-曱氧基-1-(甲 广ODC 氧基甲基）乙基]-3- 卜？ 曱基-1Η-吡咯并[3, 2-b]°比唆286 HO^f N k 354. 46 (2R)-2-[3-(6-ethoxy-2-ethylpyridin-3-yl)-2, 5-dimercapto-5H-anthracene [2, 3-b; h is more than 7-yl] propan-1-ol OH (3R)-3-[3-(6-isopropyl-2-methoxypyridine-3- 287 382.51 base) -2,5-dimercapto-5H - / CCu ϋ 嘻 [ [2, 3-b] ° 哄 \〇8-7-yl]pent-1-ol / 6-ethyl-5~*[ 2-ethyl w^° -6-methoxy-5-(methyl 〇/V"V^ 〇〇石黄蕴基)0 唆-3~ base] 288 475. 61 -1 -[2-曱 oxygen Base-1-(methyl wide ODC oxymethyl)ethyl]-3- b? Mercapto-1Η-pyrrolo[3,2-b]° 唆

104 93966 200812588 289 OH 381.53 (3R)-3-{2-乙基-3-[6-異丙基-2-(甲胺 基）ϋ比唆-3-基]-5-甲 基-5Η-吡咯并[2, 3-b] nb 畊-7-基} 丁 -1-醇 290 掌性 367.49 5-（6-乙氧基-2-曱基 口比啶-3-基）-l-[(lR) -ι-(甲氧基甲基）丙 基]-3，6-二曱基-1H-ϋ比略并[3, 2-b>比唆 291 、〆 掌性 437.63 1^’-(3-{6-乙基-1-[(1S)-2- 甲氧基-1-曱基乙基]-3-甲基 -1H-吼 17各并[3, 2-b] 吡啶-5-基}-6-異丙 基吼啶-2-基）-N，N-二曱基乙烧-1，2-二 胺 105 93966 200812588 292 掌性 385. 94 5-(2-氯_6-異丙基吨匕 啶-3-基）-6-乙基-1 -[(1S)-2-曱氧基-1-甲基乙基]-3-曱基 -1Η- σ比洛弁[3, 2-b] 吼咬 293 353· 47 (2R)-2-[5-(6-乙氧 基-2-乙基吡啶-3-基）-3, 6-二甲基-1H-°比口各并[3, 2-b] °比咬 -卜基]丙-1-醇 294 ^〇ν 421.49 1-(3,5-二氟苯曱基） -5-(6-異丙基-2-曱 氧基0比σ定-3-基） -3，6-二甲基-ΙΗ—1^ 嘻并[3, 2-b>比啶 106 93966 200812588 295 /Ο 425. 57 6-乙基-5_[6-異丙基 -2-(2-甲氧基乙氧 基）吡啶-3-基]-1 -[(lS)-2-甲氧基-1 -甲基乙基]-3-甲基 - 1H- °比嘻并[3, 2_b] °比咬 296 381.52 (2S)-2-[6-（6-異丙 基-2-曱氧基17比咬-3-基）-l，5-二甲基-lH-吼略并[2, 3-b]吼唆 -3-基]戍_1-醇 297 k 367.50 (2S)-2-[6-（6-乙氧 基-2_乙基吼。定-3~~ 基）-5-乙基-1-甲基 - 1H- σ比咯并[2, 3-b] 11比咬-3-基]丙-1-醇104 93966 200812588 289 OH 381.53 (3R)-3-{2-ethyl-3-[6-isopropyl-2-(methylamino)pyridinium-3-yl]-5-methyl-5Η- Pyrrolo[2,3-b] nb cultivable-7-yl}butan-1-ol 290 palm 367.49 5-(6-ethoxy-2-indolylpyridin-3-yl)-l-[ (lR)-ι-(methoxymethyl)propyl]-3,6-dimercapto-1H-indole ratio [3, 2-b> 唆291, palm 437.63 1^'- (3-{6-Ethyl-1-[(1S)-2-methoxy-1-indolylethyl]-3-methyl-1H-indole 17-[3,2-b]pyridine- 5-yl}-6-isopropylacridin-2-yl)-N,N-didecyl-ethene-1,2-diamine 105 93966 200812588 292 Palm 385. 94 5-(2-Chloro_ 6-Isopropyl acridine-3-yl)-6-ethyl-1 -[(1S)-2-decyloxy-1-methylethyl]-3-indolyl-1Η- σ Bilo弁[3, 2-b] bite 293 353· 47 (2R)-2-[5-(6-ethoxy-2-ethylpyridin-3-yl)-3,6-dimethyl-1H -° ratio of each [3, 2-b] ° ratio bite-buki] propan-1-ol 294 ^〇ν 421.49 1-(3,5-difluorophenylindenyl)-5-(6-iso Propyl-2-decyloxy 0 to sigma-3-yl) -3,6-dimethyl-oxime-1^ 嘻[3, 2-b> pyridine 106 93966 200812588 295 /Ο 425. 57 6-ethyl-5_[6-isopropyl -2-(2-methoxyethoxy)pyridin-3-yl]-1 -[(lS)-2-methoxy-1 -methylethyl]-3-methyl- 1H- ° ratio嘻[3, 2_b] ° ratio biting 296 381.52 (2S)-2-[6-(6-isopropyl-2-yloxy 17-buty-3-yl)-l,5-dimethyl- lH-吼[[,3-b]吼唆-3-yl]戍_1-ol 297 k 367.50 (2S)-2-[6-(6-ethoxy-2-ethyl oxime. -3~~yl)-5-ethyl-1-methyl- 1H- σ-pyrolo[2,3-b] 11-but-3-yl]propan-1-ol

107 93966 200812588 298 409. 57 6-乙基-5-(2-異丙氧 基-6-異丙基吡啶-3-基）-1-[(18)-2-曱氧 基- I-甲基乙基]-3-甲基-1H-吡咯并[3, 2-1)]°比唆 299 379.55 (2S)-2-[6-乙基-5-(2-乙基-6-異丙基吡 啶-3-基）-3-曱基-1H 比嘻并[3, 2-b>比咬 -1-基]丁-1-醇 300 掌性 卞Vr 380.49 (2S)-2-[2-(2-乙基 - 6-異丙基ntb 12定-3-基）-3, 7-二曱基-5H-口比咯并[2, 3-b] °比,哄 - 5-基]丁酸107 93966 200812588 298 409. 57 6-Ethyl-5-(2-isopropoxy-6-isopropylpyridin-3-yl)-1-[(18)-2-decyloxy-I-A乙基ethyl]-3-methyl-1H-pyrrolo[3, 2-1)]° ratio 唆299 379.55 (2S)-2-[6-ethyl-5-(2-ethyl-6-iso Propylpyridin-3-yl)-3-indolyl-1H is more than [3, 2-b> butyl-1-yl]butan-1-ol 300 palm 卞Vr 380.49 (2S)-2-[ 2-(2-ethyl-6-isopropylntb 12-but-3-yl)-3,7-dimercapto-5H-portpyrho[2,3-b] ° ratio, 哄- 5- Butyric acid

108 93966 200812588 301 Xv 368.48 (2S)-2-[2- 乙基-3-(6-異丙基-2-甲氧基 吼σ定-3-基）-5-曱基 -5Η-吡咯并[2,3-b] π比哄-7-基]丙-1-鮮 302 ho^Q 掌性 417.52 (lS，3R)-3-{2-[2-甲 氧基-4- 〇 Η-σ比ϋ坐-1 -基）苯基]-3, 7-二曱 基-5Η-吼咯并[2, 3-b]吡哄-5-基}環己 醇 303 368.48 (2S)-2-[3-（6-乙氧 基-2-乙基σ比咬-3-基）-2-乙基-5-甲基 -5Η- ^比 17各并[2, 3-b] 吡畊-7-基]丙-1-醇108 93966 200812588 301 Xv 368.48 (2S)-2-[2-ethyl-3-(6-isopropyl-2-methoxyindole-3-yl)-5-mercapto-5Η-pyrrole [2,3-b] π is more than 哄-7-yl]prop-1-n 302 ho^Q palmity 417.52 (lS,3R)-3-{2-[2-methoxy-4- 〇Η- σ ϋ -1-1 -yl)phenyl]-3,7-dimercapto-5Η-fluoren[2,3-b]pyridin-5-yl}cyclohexanol 303 368.48 (2S)-2 -[3-(6-ethoxy-2-ethyl σ butyl-3-yl)-2-ethyl-5-methyl-5 Η- ^ ratio 17 and [2, 3-b] pyridin -7-yl]propan-1-ol

109 93966 200812588 304 Ή N<J 366. 51 (2R)-2-{5-[6-異丙 基-2-(甲胺基）吼啶 -3- 基]-3, 6- 二曱基 -1H- 0比嘻并[3, 2_b] 吡啶-1-基}丁-1-醇 305 380.54 (2S)-2-[2-乙基-3-(2-乙基-6-異丙基σ比 啶-3-基）-5-甲基 -5Ή-吼咯并[2,3-b] 吡畊-7-基]丁-1-醇 306 十 掌性 Ήν 368· 50 3-乙基 -5-[(11〇-1-(氟甲基）丙基]-2-(6-異丙基-2-甲基吼 啶-3-基）-7-曱基-5H -σ比洛并[2, 3-1)]°比哄109 93966 200812588 304 Ή N<J 366. 51 (2R)-2-{5-[6-isopropyl-2-(methylamino)acridin-3-yl]-3,6-didecyl- 1H- 0 is more than [3, 2_b] pyridin-1-yl}butan-1-ol 305 380.54 (2S)-2-[2-ethyl-3-(2-ethyl-6-isopropyl σ Bipyridin-3-yl)-5-methyl-5Ή-indolo[2,3-b]pyrrol-7-yl]butan-1-ol 306 Ten palm Ήν 368· 50 3-ethyl- 5-[(11〇-1-(fluoromethyl)propyl]-2-(6-isopropyl-2-methylacridin-3-yl)-7-indolyl-5H-σpiro [2, 3-1)]°°哄

130 93966 200812588 307 424. 54 2-乙氧基-6-乙基-5-{1 -[(1R)-1 -（甲氧基 甲基）丙基]-3, 6-二 曱基-1H-吡咯并[3, 2-b]°比唆-5-基}於驗 醯胺 308 ,0H ί(Υ Ά 368.48 (3S)-3-[3-(6-異丙 基-2-曱氧基σ比咬-3-基)-2, 5-二甲基-5Η-σ比嘻并[2, 3-b] °比口井 -7-基]丁-1-醇 309 OH 380. 54 (3R)-3-{6-乙基 異丙基-2-（曱胺 基）吡啶-3-基]-3-甲 基-1Η-吼咯并[3, 2-b] °比咬-1-基} 丁 -卜醇130 93966 200812588 307 424. 54 2-Ethoxy-6-ethyl-5-{1 -[(1R)-1 -(methoxymethyl)propyl]-3,6-dimercapto-1H -pyrrolo[3,2-b]° than 唆-5-yl} in the test guanamine 308,0H ί(Υ 368 368.48 (3S)-3-[3-(6-isopropyl-2-oxo The base σ is more than -3-yl)-2,5-dimethyl-5Η-σ is more than [2, 3-b] ° than well-7-yl]butan-1-ol 309 OH 380. 54 (3R)-3-{6-ethylisopropyl-2-(decylamino)pyridin-3-yl]-3-methyl-1Η-indolo[3,2-b] ° ratio bite- 1-yl}butanol

111 93966 200812588111 93966 200812588

310 Vr 掌性 HO *M N / 405. 50 (2R，3S)-3—{2-[2-曱 氧基-4-(1Η-°比嗤-1-基）苯基]-3,7-二甲 基-5H-吡咯并[2, 3-b；h比畊-5-基}戊 - 2-醇 311 掌性 379. 54 5-(2-乙基-6-異丙基 吡啶-3-基）-l-[(lS) -1 -（甲氧基甲基）丙 基]-3,6-二曱基-111-σ比嘻并[3, 2-1)]°比咬 312 353.47 (2S)-2-[6-(6-異丙 基-2-曱氧基吡啶-3-基）-1，5-二曱基-1Η -ϋ比洛并[2, 3-b]。比咬 -3-基]丙-1-醇310 Vr palmity HO *MN / 405. 50 (2R,3S)-3—{2-[2-oxime-4-(1Η-° than 嗤-1-yl)phenyl]-3,7- Dimethyl-5H-pyrrolo[2,3-b;h ratio tillin-5-yl}pentyl-2-ol 311 palm 379. 54 5-(2-ethyl-6-isopropylpyridine-3 -yl)-l-[(lS) -1 -(methoxymethyl)propyl]-3,6-dimercapto-111-σ than 嘻[3, 2-1)]° ratio bite 312 353.47 (2S)-2-[6-(6-Isopropyl-2-oxoxypyridin-3-yl)-1,5-diindolyl-1Η-debido[2,3-b] . Specific -3-yl]propan-1-ol

112 93966 200812588 313 OH ίϊο, 368· 48 (3S)-3-[2-（6-異丙 基-2-甲氧基吡啶-3-基）-3,7-二甲基-5H -吼咯并[2,3-b；h比哄 - 5-基]丁-1-醇 314 380· 54 (2R)-2-[3-乙基 -2-(2-乙基-6-異丙基吡 啶-3-基）- 7-曱基-5H - °比17各并[2，3-b]ϋ比哄 - 5-基]丁-1-醇 315 1¾ 381.52 (2S)-2-[6-乙基 -5-(6-異丙基-2-曱氧基 0比17定-3-基）-3-曱基 - 1H- °比咯并[3, 2-b] °比°定-1-基]丁-1-醇 113 93966 200812588 316 W 掌性 V, 367· 49 5-（6-乙氧基-2-乙基 吼啶-3-基）-1-[(1R) -2 -曱氧基-1-曱基乙 基]-3, 6-二曱基-1Η-咬洛并[3, 2-b>比咬 317 OH 380.54 (3R)-3-{5-[6-異丙 基-2-（甲胺基）吡啶 -3-基]-3,6-二曱基 - 1H-吼咯并[3, 2-b] 吡啶-1-基}戊-1-醇 318 、人 395.55 (2S)-2-{2-乙基-3-[6-異丙基-2-（甲胺 基）0比σ定-3-基]-5-曱 基-5Η- °比洛并[2， 3-b]吼畊-7-基}戊 -1-醇112 93966 200812588 313 OH ίϊο, 368· 48 (3S)-3-[2-(6-isopropyl-2-methoxypyridin-3-yl)-3,7-dimethyl-5H-indole And [2,3-b;h is 哄-5-yl]butan-1-ol 314 380· 54 (2R)-2-[3-ethyl-2-(2-ethyl-6-isopropyl) Pyridin-3-yl)-7-indenyl-5H-° ratio 17 and [2,3-b]pyridinium-5-yl]butan-1-ol 315 13⁄4 381.52 (2S)-2-[6 -ethyl-5-(6-isopropyl-2-indolyloxy 0 to 17-3-yl-3-yl)-3-indenyl-1H- ° ratio [3, 2-b] ° -1-yl]butan-1-ol 113 93966 200812588 316 W palmity V, 367· 49 5-(6-ethoxy-2-ethylacridin-3-yl)-1-[(1R)- 2-methoxy-1-indolylethyl]-3,6-dimercapto-1Η-bito[3,2-b> than bite 317 OH 380.54 (3R)-3-{5-[6 -isopropyl-2-(methylamino)pyridin-3-yl]-3,6-dimercapto-1H-indolo[3,2-b]pyridin-1-yl}pentan-1-ol 318, human 395.55 (2S)-2-{2-ethyl-3-[6-isopropyl-2-(methylamino)0 σσ-3-yl]-5-mercapto-5Η- ° Biluo[2,3-b]吼耕-7-yl}pentan-1-ol

114 93966 200812588 319 379.55 (2R)-2-[6-（2-乙基 -6-異丙基吼咬-3-基）-1,5-二曱基-1H-°比洛并[2, 3-b]ϋ比咬 - 3-基]戊-1-醇 320 r^T 367.50 (2R)-2-[6-(6-異丙 基-2-曱氧基吡啶-3-基）-1，5-二曱基-1H-吼洛并[2, 3-b]0比啶 -3-基]丁 -1 -醇 321 379.55 (2R)-2-[5- 乙基-6-(2-乙基-6-異丙基σ比 啶-3-基）-1-甲基 - 1Η- π比略并[2, 3-b] 吼°定-3-基]丁-1 -醇114 93966 200812588 319 379.55 (2R)-2-[6-(2-ethyl-6-isopropylindole-3-yl)-1,5-dimercapto-1H-°Bilo[2, 3-b]ϋ 咬 -3-yl]pentan-1-ol 320 r^T 367.50 (2R)-2-[6-(6-isopropyl-2-indolylpyridin-3-yl)- 1,5-dimercapto-1H-indolo[2,3-b]0-pyridin-3-yl]butan-1-ol 321 379.55 (2R)-2-[5-ethyl-6-( 2-ethyl-6-isopropyl σ-pyridin-3-yl)-1-methyl- 1Η- π ratio succinyl [2, 3-b] 吼 定 -3-yl] butyl-1-ol

115 93966 200812588 322 私。 k 381.52 (2S)-2-[6-(6-乙氧 基-2-乙基吡啶-3-基）-5-乙基-1-曱基 -1H-吼 p各弁[2, 3-b] 吼唆-3-基]丁-1-醇 323 OH 381.53 (3R)-3-{3-乙基-2-[6-異丙基-2-(曱胺 基）吡啶-3-基]-7-甲 基-5H- °比17各并[2， 3-b]吼畊-5-基}丁 -1-醇 324 OH 381.52 (3S)-3-[6-（6-乙氧 基-2-乙基°比σ定-3-基）-1，5-二甲基-1Η-吼嘻并[2,3-1)]°比咬 - 3-基]戊-1-醇115 93966 200812588 322 Private. k 381.52 (2S)-2-[6-(6-ethoxy-2-ethylpyridin-3-yl)-5-ethyl-1-indolyl-1H-indole p [2, 3- b] Ind-3-yl]butan-1-ol 323 OH 381.53 (3R)-3-{3-ethyl-2-[6-isopropyl-2-(decylamino)pyridin-3-yl ]-7-Methyl-5H-° ratio 17 and [2, 3-b] 吼-5-yl}butan-1-ol 324 OH 381.52 (3S)-3-[6-(6-ethoxy Benzyl-2-ethyl ratio σ -3--3-)-1,5-dimethyl-1 Η-吼嘻[2,3-1)]° ratio biting 3-yl]pentan-1-ol

116 93966 200812588 325 391.56 5-（2-環丙基-6-異丙 基啦啶-3-基）-1-[(1R)-1 -（甲氧基甲 基）丙基]-3, 6-二甲 基-1H- 11比咯并[3， 2-b]11比咬 326 掌性 390· 49 (2S)-2-{2-[2-乙基 -6-（1H-σ比嗤-1-基） 吼咬-3-基]-3, 7-二 曱基-5Ή- °比嘻并[2， 3-b]吼 D井-5-基} 丁 -1-醇 327 /—f 掌性 一0 N^Nv^ 384. 50 2- （2-乙基-6-異丙基 吡啶-3-基）-5-K1R) -2-氟-1 -（甲氧基曱 基）乙基]-3, 7-二曱 基-5H- σ比洛并[2， 3- b]吼畊 117 93966 200812588 328 353. 47 (2S)-2-{3-[6-異丙 基-2-(甲胺基）吼啶 -3-基]-2, 5- 二曱基 -5H-吼嘻并[2, 3-b] 吼哄-7-基}丙-1-解 329 434. 62 5-（6-異丙基-2-旅咬 -1 -基σ比σ定-3-基）-1 -[(1R)-1 -（甲氧基甲 基）丙基]-3, 6-二甲 基-1H-吡咯并[3, 2-1)]ϋ比口定 330 掌性 ό.' 450. 62 3-{6-乙基-1-[(1S) -2-曱氧基-1-甲基乙 基]-3-甲基-1H-吡咯 并[3, 2-b]吼咬-5-基}_6_異丙基-N-[(2S)-四氫呋喃-2:-基曱基>比咬-2-胺116 93966 200812588 325 391.56 5-(2-Cyclopropyl-6-isopropyl-hlopenidin-3-yl)-1-[(1R)-1 -(methoxymethyl)propyl]-3, 6 -Dimethyl-1H-11 is more than [3, 2-b]11 than bite 326 palm 390. 49 (2S)-2-{2-[2-ethyl-6-(1H-σ 嗤-1-yl) 吼-3-yl]-3,7-dimercapto-5Ή- ° is more than [2, 3-b]吼D well-5-yl} butan-1-ol 327 / f palmity - 0 N^Nv^ 384. 50 2-(2-ethyl-6-isopropylpyridin-3-yl)-5-K1R)-2-fluoro-1 -(methoxyindolyl) Ethyl]-3,7-dimercapto-5H- σ pyrrolo[2,3-b] 吼耕117 93966 200812588 328 353. 47 (2S)-2-{3-[6-isopropyl- 2-(Methylamino)acridin-3-yl]-2, 5-dimercapto-5H-indeno[2,3-b]indol-7-yl}propan-1-solution 329 434. 62 5-(6-isopropyl-2-branched-1 -yl σ ratio σ-3-yl)-1 -[(1R)-1 -(methoxymethyl)propyl]-3, 6-Dimethyl-1H-pyrrolo[3, 2-1)] ϋ 口 330 330 330 330 330 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 450 -1-methylethyl]-3-methyl-1H-pyrrolo[3,2-b]indole-5-yl}_6-isopropyl-N-[(2S)-tetrahydrofuran-2: -基基基> than bite-2-amine

118 93966 200812588 331 OH 395.55 (3S)-3-[5-乙基-δα-異 丙基-2-曱氧基 吡啶-3-基）-1-曱基 - 1Η-吼洛弁[2, 3-b] 吡啶-3-基]戊-1-醇 332 436.60 6-乙基-5-(6_異丙基 -2-嗎琳-4-基吡啶 -3-基）-l-[〇S)-2-甲氧基-1-甲基乙 基]-3-曱基-1H-吡咯 并[3, 2_b]吼啶 333 、。"祝 391.56 5-（2-環丙基-6-異丙 基吼啶-3-基）-6-乙 基-1-[(1S)-2-甲氧 基-1-曱基乙基]- 3-甲基-1Η-σ比咯并[3:， 2-bp比咬118 93966 200812588 331 OH 395.55 (3S)-3-[5-ethyl-δα-isopropyl-2-indolylpyridin-3-yl)-1-indenyl- 1Η-吼洛弁[2, 3 -b] pyridin-3-yl]pentan-1-ol 332 436.60 6-ethyl-5-(6-isopropyl-2-morphin-4-ylpyridin-3-yl)-l-[〇S )-2-methoxy-1-methylethyl]-3-indolyl-1H-pyrrolo[3, 2_b]acridine 333. " Wish 391.56 5-(2-cyclopropyl-6-isopropylacridin-3-yl)-6-ethyl-1-[(1S)-2-methoxy-1-indenylethyl ]- 3-methyl-1Η-σ ratio [3:, 2-bp ratio bite

119 93966 200812588 334 卞fey 352. 48 (2S)-2-[3-（2-乙基 -6-異丙基σ比咬-3-基）-2,5-二曱基-5Η-°比咯并[2, 3-b] °比畊 - 7-基]丙-1-醇 335 394. 56 (2S)-2-{6-乙基-5-[6-異丙基-2-（曱胺 基）吡啶-3-基]-3-曱 基-1H-吡咯并[3, 2-b]吼σ定-1-基}戍 -1-醇 336 ρα 339.43 2-[5-（2- 乙基-6-甲 氧基-3-吼啶基）-3,6 -二甲基-1Η- ^比嘻并 [3,2-1〇]吼啶-1-基] -1-丙醇119 93966 200812588 334 卞fey 352. 48 (2S)-2-[3-(2-ethyl-6-isopropyl σ 咬-3-yl)-2,5-dimercapto-5Η-° ratio咯[2,3-b] ° ratio tillage-7-yl]propan-1-ol 335 394. 56 (2S)-2-{6-ethyl-5-[6-isopropyl-2-(曱Amino)pyridin-3-yl]-3-indolyl-1H-pyrrolo[3,2-b]吼σ定-1-yl}戍-1-ol 336 ρα 339.43 2-[5-(2 - Ethyl-6-methoxy-3-acridinyl)-3,6-dimethyl-1Η-^ is more than [3,2-1〇]acridin-1-yl]-1-propane alcohol

120 93966 200812588120 93966 200812588

337 OH k 382.51 (3S)-3-[3-（6-乙氧 基-2-乙基吡啶-3-基）-2-乙基-5-曱基 -5H一比洛并[2, 3-b] °比口井-7-基]丁-醇 338 掌性 422; 57 5- (6~~異丙基-2·嗎淋 -4-基吼咬-3-基）-1-[(1R)-1-(甲氧基甲 基）丙基]-3-甲基 -1H- σ比嘻并[3, 2-b] °比咬 〜,0H (38)-3-[3-（6-乙氧 基-2-乙基°比咬-3- 339 368. 48 基）-2,5-二曱基-5H- 丄。 吼u各并[2, 3-b] °比哄 k -7-基]丁-1-醇337 OH k 382.51 (3S)-3-[3-(6-ethoxy-2-ethylpyridin-3-yl)-2-ethyl-5-mercapto-5H-bipiro[2, 3 -b] ° than well 7-based] butanol 338 palmity 422; 57 5- (6~~isopropyl-2·oxalin-4-yl-bito-3-yl)-1-[ (1R)-1-(methoxymethyl)propyl]-3-methyl-1H- σ is more than [3, 2-b] ° bite ~,0H (38)-3-[3- (6-Ethoxy-2-ethyl ° bit -3- 339 368. 48 base)-2,5-dimercapto-5H- oxime.吼u each [2, 3-b] ° than 哄 k -7-yl] butan-1-ol

121 93966 200812588121 93966 200812588

340 453. 58 6-乙基-2-異丙氧基 -5-{1一[(1R)—1-（甲 氧基甲基）丙基] -3, 6-二甲基-1H-吡 洛并[3, 2-b>比咬-5-基}菸鹼酸甲酯 341 、人 354. 46 (2S)-2-[3-(6-異丙 基-2-曱氧基11比咬-3-基）-2,5-二甲基-5H-σ比17各并[2, 3-b]吼哄 -7-基]丙-1-醇 342 HO V N . 380.54 (2R)-2-[2-(2-乙基 -6-異丙基σ比咬-3-基）-3,7-二甲基-5H-吼洛并[2, 3-b] η比哄 -5-基]戊-1-醇340 453. 58 6-Ethyl-2-isopropoxy-5-{1-[(1R)-1-(methoxymethyl)propyl]-3,6-dimethyl-1H-pyridyl Luohe [3, 2-b> than biting-5-yl} nicotinic acid methyl ester 341, human 354. 46 (2S)-2-[3-(6-isopropyl-2-yloxy 11 ratio Bite-3-yl)-2,5-dimethyl-5H-σ ratio 17 and [2,3-b]indol-7-yl]propan-1-ol 342 HO VN . 380.54 (2R)- 2-[2-(2-ethyl-6-isopropyl σ butyl-3-yl)-3,7-dimethyl-5H-indolo[2,3-b] η than 哄-5 -yl]pentan-1-ol

122 93966 200812588 343 H0 k 人/ k 382.51 (2R)-2-[3-(6-乙氧 基-2-乙基ϋ比σ定~3-基)-2,5-二甲基-5H_ 口比咯并[2, 3-b；h比哄 - 7-基]戊-1-醇 344 438. 57 2-乙氧基-6-乙基-5_ {1-[(1R)-1-(甲氧基 甲基）丙基]-3, 6-二 甲基-1H-吡咯并 [3,2-bh比啶-5-基} - N-曱基菸鹼醯胺 OH (3S)-3-[5-乙基-6- 1 (2-乙基-6-異丙基°比 345 ccc. 379. 55 啶-3-基）-1-甲基-1H / OCX/ -吼洛并[2，3-b]0比咬 - 3-基]丁-1-醇122 93966 200812588 343 H0 k human / k 382.51 (2R)-2-[3-(6-ethoxy-2-ethylindole σ ~~3-yl)-2,5-dimethyl-5H_咯 并 [2, 3-b; h than 哄-7-yl] pent-1-ol 344 438. 57 2-ethoxy-6-ethyl-5_ {1-[(1R)-1-( Methoxymethyl)propyl]-3,6-dimethyl-1H-pyrrolo[3,2-bh-pyridin-5-yl}-N-fluorenylnicotinium OH (3S)-3 -[5-ethyl-6- 1 (2-ethyl-6-isopropyl ratio 345 ccc. 379. 55 pyridine-3-yl)-1-methyl-1H / OCX/ - 吼洛和[ 2,3-b]0 than bite-3-yl]butan-1-ol

123 93966 200812588 346 H-0^\, N . 417.52 1 -（{2-[2_ 曱氧基-4-(1Η-吼唑-1-基）苯 基]-3,7_ 二甲基-5Η -吼咯并[2, 3-bp比哄 -5-基}甲基）環戊醇 347 γ 掌性 HO V N . 405. 50 (2S，3R) - 3-{2-[2-曱 氧基-4-( 1H- °比σ坐-1 -基）苯基]-3, 7-二甲 基-5Η- °比嘻并[2， 3-b] °比哄-5-基}戍 - 2-醇 348 H0Vq^ 掌性 403.49 (lS，3S)-3-{2-|>1 氧基-4- (1 Η-吼ϋ坐-1 -基）苯基]-3,7-二曱 基-5Η- °比略并[2， 3-b>比畊-5-基}環戊 醇123 93966 200812588 346 H-0^\, N . 417.52 1 -({2-[2_ 曱oxy-4-(1Η-indazol-1-yl)phenyl]-3,7_dimethyl-5Η -吼 并 [2, 3-bp 哄-5-yl}methyl)cyclopentanol 347 γ palmity HO VN . 405. 50 (2S,3R) - 3-{2-[2-oxime- 4-( 1H- ° ratio σ sitting -1 -yl)phenyl]-3,7-dimethyl-5Η- ° is more than [2, 3-b] ° 哄-5-yl}戍-2 - alcohol 348 H0Vq^ palmity 403.49 (lS,3S)-3-{2-|>1 oxy-4-(1 Η-吼ϋ-1-1-yl)phenyl]-3,7-dioxin Base-5Η- ° ratio slightly [2, 3-b> than tillage-5-yl} cyclopentanol

124 93966 200812588124 93966 200812588

349 OH 379. 55 (3R)-3-[5-乙基 -6-(2-乙基-6-異丙基°比 啶-3-基）-1-甲基-1H -吼洛并[2, 3-b]吼咬 - 3-基]丁 _1-醇 350 395.54 5-(6-異丙基-2-甲氧 基吡啶-3-基）-1-[(1S)-1 -（甲氧基曱 基）-2-甲基丙基] -3, 6-二甲基-1H-吡 洛并[3, 2_b>比啶 351 353.46 (2R)-2-[5-(6-乙氧 基-2-甲基-3- σ比咬 基）-3，6-二甲基-1Η-17比嘻并[3, 2-b] °比咬 -1-基]-1-丁醇349 OH 379. 55 (3R)-3-[5-ethyl-6-(2-ethyl-6-isopropyl-pyridin-3-yl)-1-methyl-1H-indolo[ 2, 3-b] bite - 3-yl]but-1-ol 350 395.54 5-(6-isopropyl-2-methoxypyridin-3-yl)-1-[(1S)-1 - (methoxy methoxy)-2-methylpropyl] -3,6-dimethyl-1H-pyrolo[3, 2_b> than pyridine 351 353.46 (2R)-2-[5-(6- Ethoxy-2-methyl-3- σ than dimethyl)-3,6-dimethyl-1Η-17 is more than [3, 2-b] ° than -1-yl]-1-butyl alcohol

125 93966 200812588 352 掌性 /0 424. 59 6-異丙基-N -（2-曱氧 基乙基）-3-{l-[(lR) -1 -(甲氧基甲基）丙 基]-3 -甲基-1H-吡咯 并[3, 2-b]吼咬-5-基}-N-甲基吡啶-2-胺 353 ^ 掌性 381.52 5 -（6-異丙基-2-曱氧 基吼啶-3-基）-1 -[(lS)-l-(甲氧基甲 基）丙基]-3, 6-二甲 基-1H- °比洛并[3， 2-1)]吼°定 354 OH 367· 50 (3S)-3-[5-(6-異丙 基-2-甲氧基。比11定-3-基）-3,6-二甲基-1H-°比口各并[3, 2-1)]，比咬 -1-基]丁-1-醇125 93966 200812588 352 palmity / 0 424. 59 6-isopropyl-N-(2-decyloxyethyl)-3-{l-[(lR) -1 -(methoxymethyl)propyl ]-3 -Methyl-1H-pyrrolo[3,2-b] 吼-5-yl}-N-methylpyridin-2-amine 353 ^ palmity 381.52 5 -(6-isopropyl-2 -曱oxyacridin-3-yl)-1 -[(lS)-l-(methoxymethyl)propyl]-3,6-dimethyl-1H- °bilo[3, 2 -1)] 吼 ° 354 OH 367· 50 (3S)-3-[5-(6-isopropyl-2-methoxy. than 11--3-yl)-3,6-dimethyl -1H-° ratios each [3, 2-1)], bite-1-yl]butan-1-ol

126 93966 200812588 355 掌性 424. 59 3-{6-乙基-1_[(1S) -2-曱氧基-1-曱基乙 基]-3-曱基-1H-吡咯 并[3, 2-b]吼咬-5-基}-6-異丙基-N-(2 -甲氧基乙基）吡啶-2-胺 356 OH 、人 t/y 396. 54 (3S)-3-[2-乙基-3-(6-異丙基-2-甲氧基 0比σ定-3-基）-5-甲基 -5Η- °比咯并[2, 3-b] 吼哄-7-基]戊-1-醇 357 、人 367. 50 (2S)-2-{3-[6-異丙 基-2-(甲胺基）吼啶 -3-基]-2，5- 二甲基 -5H- °比咯并[2, 3-b] 吡啡-7-基}丁-1-醇126 93966 200812588 355 Palm 424. 59 3-{6-Ethyl-1_[(1S)-2-yloxy-1-indolylethyl]-3-indolyl-1H-pyrrolo[3, 2 -b] bite-5-yl}-6-isopropyl-N-(2-methoxyethyl)pyridin-2-amine 356 OH, human t/y 396. 54 (3S)-3-[ 2-ethyl-3-(6-isopropyl-2-methoxy 0-s-ziridine-3-yl)-5-methyl-5Η-° ratio 咯[2,3-b] 吼哄- 7-yl]pentan-1-ol 357, human 367. 50 (2S)-2-{3-[6-isopropyl-2-(methylamino)acridin-3-yl]-2,5- Dimethyl-5H-° ratio of p-[2,3-b]pyridin-7-yl}butan-1-ol

127 93966 200812588 358 HO V a / k 381.52 (2f〇-2-[5-(6-乙氧 基-2-乙基吡啶-3-基）-3, 6-二曱基-1H-°比17各并[3, 2-b]σ比咬 -1-基]戊-1-醇 359 掌性 PC% wN 376.50 5-(7-乙基味嗤并[1， 2-a] ^比 ΰ定 _6-基）-1-[(lR)-l-(甲氧基甲 基）丙基]-3, 6-二甲 基-1H- °比洛并[3， 2-1)]0比〇定 360 /\ 掌性 "%V 380. 53 3-乙基-2-(6 -異丙基 - 2-甲基〇比咬-3-基） -5-[(lR)-1-(甲氧基 曱基）丙基]-7-甲基 -5H-吼嘻并[2, 3-b] 口比畊127 93966 200812588 358 HO V a / k 381.52 (2f〇-2-[5-(6-ethoxy-2-ethylpyridin-3-yl)-3,6-dimercapto-1H-° ratio 17 Each [3, 2-b] σ ratio ni-1-yl] pent-1-ol 359 palm PC% wN 376.50 5-(7-ethyl miso[1, 2-a] ^ ratio _6-yl)-1-[(lR)-l-(methoxymethyl)propyl]-3,6-dimethyl-1H- ° piroxi[3, 2-1)]0 ratio 360定360 /\ palmity"%V 380. 53 3-ethyl-2-(6-isopropyl-2-methylindole than -3-yl) -5-[(lR)-1- (methoxy methoxy) propyl]-7-methyl-5H-indole[2, 3-b]

128 93966 200812588 361 OH 382.51 (3S)-3-[2-(6-乙氧 基-2-乙基°比定-3-基）-3-乙基-7-甲基 -5Η- ϋ比嘻并[2, 3-b] 吡哄-5-基]丁-1-醇 362 Λ^~ 掌性 ^5cv 394. 56 5-[(lR)-l-(乙氧基 甲基）丙基]-2-（2-乙 基-6-異丙基°比咬-3-基）-3,7-二甲基-5H-0比洛并[2,3-13]°比啡 363 367.50 (2S)-2-{2-[6-異丙 基-2-(甲胺基）吡啶 -3-基]-3, 7-二曱基 -5H- ϋ比 ρ各并[2, 3-b] 吡畊-5-基}丁-1-醇 129 93966 200812588 364 ^OH 掌性 、cAA^ 391.48 (2R)-4-{2-[2-曱氧 基-4-( 1H- 11 比峻-1 -基）苯基]-3,7-二曱 基-5H-吼咯并[2, 3-b]吼畊-5-基}丁 - 2-醇 365 «-，Γν 掌性 391.48 (2S)-2-{2-[2-甲氧 基-4-(1H- 口比峻-1- 基）苯基]-3, 7-二甲 基-5H- 0比嘻并[2， 3-b] σ比哄-5-基} 丁 -1-醇 J (2ί〇-2-[5-(6-乙氧 ίϊχ 基-2-乙基°比咬-3- 366 V^Tl 367. 50 基）-6-乙基-3-甲基 人 1 - 1Η-吼洛并[3, 2-b] k 吡啶-1-基]丙-Γ-醇 130 93966 200812588 367 HO V N γ 、人 381.53 (2R)-2-{2-[6-異丙 基-2-（曱胺基）吡啶 -3-基]-3, 7-二曱基 -5H-吡咯并[2,3-b] °比哄-5-基}戍-1-醇 368 J> 掌性 ^ V, M . 1¾ 、cAA^ 403· 49 (2R)-2-環丙基-2-{2-[2-甲氧基-4-(1Η 一 σ比tj坐-1 -基）苯基] -3,7-二曱基-5!1-吡 洛弁[2，3-b]σ比哄-5-基}乙醇 369 ^ 掌性 HO N γ 417. 52 (1S，2R)-1-環丙基 -1-{2 - [2 -甲氧基-4 -(1H-吼唑-1-基）苯 基]-3, 7-二甲基-5H-ϋ比嘻并[2,3_b] D比 畊-5-基}丙-2-醇128 93966 200812588 361 OH 382.51 (3S)-3-[2-(6-Ethoxy-2-ethyl-pyridin-3-yl)-3-ethyl-7-methyl-5Η-ϋ比嘻And [2, 3-b] pyridin-5-yl]butan-1-ol 362 Λ^~ palmity^5cv 394. 56 5-[(lR)-l-(ethoxymethyl)propyl] -2-(2-ethyl-6-isopropyl) butyl-3-yl)-3,7-dimethyl-5H-0 piroxime [2,3-13]° than 363 367.50 ( 2S)-2-{2-[6-isopropyl-2-(methylamino)pyridin-3-yl]-3,7-dimercapto-5H- ϋ ρ 并 [2, 3-b Pyridin-5-yl}butan-1-ol 129 93966 200812588 364 ^OH Palm, cAA^ 391.48 (2R)-4-{2-[2-曱oxy-4-( 1H- 11 is more than - 1-phenyl)phenyl]-3,7-dimercapto-5H-indolo[2,3-b]indole-5-yl}but-2-ol 365 «-,Γν palmity 391.48 (2S -2-{2-[2-methoxy-4-(1H-portage-1 -yl)phenyl]-3,7-dimethyl-5H- 0 is more than [2, 3- b] σ is more than --5-yl} butan-1-ol J (2ί〇-2-[5-(6-ethoxyoxinyl-2-ethyl ° bite-3-366 V^Tl 367. 50 -6-ethyl-3-methyl-human 1 - 1 fluorene-[3,2-b] k pyridin-1-yl]propan-ol-ol 130 93966 200812588 367 HO VN γ, human 381.53 ( 2R)-2-{2-[6-isopropyl Benzyl-2-(decylamino)pyridin-3-yl]-3,7-dimercapto-5H-pyrrolo[2,3-b] ° 哄-5-yl}戍-1-ol 368 J&gt Palmity ^ V, M . 13⁄4 , cAA^ 403· 49 (2R)-2-cyclopropyl-2-{2-[2-methoxy-4-(1Η-σ ratio tj sit-1 -yl )phenyl] -3,7-dimercapto-5!1-pyrrole[2,3-b]σ 哄-5-yl}ethanol 369 ^ palm HO γ 417. 52 (1S, 2R )-1-cyclopropyl-1-{2-[2-methoxy-4-(1H-indazol-1-yl)phenyl]-3,7-dimethyl-5H-indole [2,3_b] D than tillage-5-yl}propan-2-ol

131 93966 200812588131 93966 200812588

370 ^OH 掌性 391.48 (2S)-4-{2-[2-甲氧 基-4-(1 Η- 11 比 ϋ坐-1-基）苯基]-3, 7-二甲 基-5Η- σ比嘻并[2， 3-b] σ比畊-5-基} 丁 - 2-醇 371 rP 413.56 5 -（6-異丙基-2-甲氧 基 nb 啶-3-基）-3,6-二甲基-1-（1-苯基丙 基）-1Η-吼咯并[3, 2-b]utb^ 372 \0产、^ 掌性 395. 54 5-（2_乙氧基_6-異丙 基σ比咬-3-基）-6-乙 基-1-[(lS)-2-甲氧 基-1-甲基乙基]-3-甲基-1H-吡咯并[3, 2-b]吼咬370 ^OH palm 391.48 (2S)-4-{2-[2-methoxy-4-(1 Η- 11 ϋ -1--1-yl)phenyl]-3, 7-dimethyl-5Η - σ 嘻 嘻 [2, 3-b] σ ratio tillr-5-yl} butyl-2-alcohol 371 rP 413.56 5 -(6-isopropyl-2-methoxynb pyridine-3-yl)- 3,6-Dimethyl-1-(1-phenylpropyl)-1Η-吼 并[3, 2-b]utb^ 372 \0Production, ^ Palm 395. 54 5-(2_B Oxy-6-isopropyl σ 咬-3-yl)-6-ethyl-1-[(lS)-2-methoxy-1-methylethyl]-3-methyl-1H- Pyrrole [3, 2-b] bite

132 93966 200812588 參 373 掌性 HO -- a / 367.49 (2S)-2-[5-(6-異丙 基-2-甲氧基吡啶-3-基）-3, 6-二甲基-1H-σ比嘻并[3, 2-b]ib咬 -1- 基]丁-醇 374 f&V 382.51 (2R)-2-[3-(6-異丙 基-2-甲氧基吡啶-3-基）-2,5-二甲基-5H-σ比嘻并[2, 3-b] °比畊 - 7-基]戊-1-醇 375 ,0H 365.52 (3S)-3-[6-（2-乙基 -6-異丙基11比ϋ定-3-基）-1，5-二甲基-1Η-σ比17各并[2, 3-b] σ比咬 - 3-基]丁-1-醇 133 93966 200812588 376 掌性 HO N . 417.52 (IS,2S)-1-環丙基 -1 -{2-[2-曱氧基-4-(1H-吼唑-卜基）苯 基]-3，7-二甲基-5H-ϋ比洛并[2, 3-b]吼哄 - 5-基}丙-2-醇 377 379.55 (2S)-2-[5-(2-乙基 -6-異丙基σ比咬-3-基）-3,6-二曱基-1H-〇比洛并[3, 2-b]吼咬 -1-基]戍-1-醇 378 、人 Νί^γ^ 367.50 (2R)-2_{3- 乙基-2-[6-異丙基-2-（甲胺 基）吡啶-3-基]-7-甲 基-5H- °比洛并[2， 3-b] σ比哄-5-基}丙 - ；1-醇132 93966 200812588 Reference 373 palmity HO -- a / 367.49 (2S)-2-[5-(6-isopropyl-2-methoxypyridin-3-yl)-3,6-dimethyl-1H -σ is more than [3, 2-b]ib bit-1-yl]butanol 374 f&V 382.51 (2R)-2-[3-(6-isopropyl-2-methoxypyridine- 3-yl)-2,5-dimethyl-5H-σ is more than [2, 3-b] ° than argon-7-yl]pentan-1-ol 375 ,0H 365.52 (3S)-3-[ 6-(2-ethyl-6-isopropyl 11-pyridin-3-yl)-1,5-dimethyl-1Η-σ ratio 17 and [2, 3-b] σ ratio bite-3 -yl]butan-1-ol 133 93966 200812588 376 Palmitic HO N . 417.52 (IS, 2S)-1-cyclopropyl-1 -{2-[2-decyloxy-4-(1H-carbazole- Phenyl)phenyl]-3,7-dimethyl-5H-indolobi[2,3-b]indole-5-yl}propan-2-ol 377 379.55 (2S)-2-[5 -(2-ethyl-6-isopropyl σ 咬 -3-yl)-3,6-dimercapto-1H-deutero[3,2-b] guanidin-1-yl]戍-1-ol 378, human Νί^γ^ 367.50 (2R)-2_{3-ethyl-2-[6-isopropyl-2-(methylamino)pyridin-3-yl]-7-methyl -5H- ° piroxime [2, 3-b] σ 哄-5-yl} propyl-; 1-alcohol

134 93966 200812588 379 /° 419.57 5-[6-異丙基-2-(3-甲氧基丙-1-炔-1-基）σ比咬-3-基]-1-[(1R)-1 -（曱氧基甲 基）丙基]-3, 6-二甲 基-1H-吼咯并[3, 2-b]吡咬 ^〇H (3S)-3-[5-（6_ 乙氧 基-2-乙基σ比咬-3- 380 381·52 基）-3,6-二甲基-111- ϋ比洛并[3, 2-b]σ比咬 k -1-基]戊-1-醇 掌性 5-(6-異丙基吡啶-3- 基）-1-[(1S)-1-（甲 381 351.49 氧基曱基）丙基]-3, 6 / iX -二曱基-1 Η- σ比洛弁 N 丫 [3, 2-b]°比咬134 93966 200812588 379 /° 419.57 5-[6-Isopropyl-2-(3-methoxyprop-1-yn-1-yl)σ ratio -3-yl]-1-[(1R)- 1-(decyloxymethyl)propyl]-3,6-dimethyl-1H-indolo[3,2-b]pyridine^(H)(3S)-3-[5-(6_ B Oxy-2-ethyl σ ratio biting -3- 380 381·52 yl)-3,6-dimethyl-111- ϋbilo[3, 2-b] σ ratio k -1- group] Pentan-1-ol palmity 5-(6-isopropylpyridin-3-yl)-1-[(1S)-1-(methyl 381 351.49 oxomethoxy)propyl]-3, 6 / iX - Dimercapto-1 Η-σ 弁洛弁N 丫[3, 2-b]° bite

135 93966 200812588135 93966 200812588

382 366.51 (2R)-2-[2-乙基 -3-(2-乙基-6-異丙基吼 咬-3-基）-5-甲基 -5Η-吡咯并[2,3-b] 吡畊-7-基]丙-1-醇 383 、入 Μ^Υ 352.48 (2S)-2-{6-[6-異丙 基-2-(甲胺基）吼啶 -3-基]-1，5-二甲基 -1H-吼咯并[2, 3-b] °比咬-3-基}丙-1-醇 384 -〇 掌性 417.52 (1R，3S)-3-{2-[2-甲 氧基-4-(1Η-σΛ^-1-基）苯基]-3, 7-二曱 基-5Η- σ比洛并[2， 3 - b]吡畊-5-基}環己 醇 136 93966 200812588 385 掌性 396. 53 5-（4_異丙基-2，6-二 曱氧基苯基）-1 -[(lR)-l-(甲氧基甲 基）丙基]-3-甲基 -1H- °比洛并[3, 2-b] 吼咬 386 \ 掌性 \ Η-Ο \ μ 少 391.48 (2S)-1-{2-[2- 甲氧 基-4-(1Η- σ比峻-1-基）苯基]-3,7-二甲 基-5Η- °比嘻并[2， 3-b]吼哄-5-基} 丁 - 2-醇 387 OH 、人N入f 394. 56 (3S)-3-{5- 乙基-6-[6-異丙基-2-(甲胺 基）吡啶-3-基]-1-甲 基-1H-吼咯并[2, 3 - b]吡啶-3-基}戊 -1-醇382 366.51 (2R)-2-[2-ethyl-3-(2-ethyl-6-isopropylindole-3-yl)-5-methyl-5Η-pyrrolo[2,3-b Pyridin-7-yl]propan-1-ol 383, Μ^Υ 352.48 (2S)-2-{6-[6-isopropyl-2-(methylamino)acridin-3-yl] -1,5-dimethyl-1H-indolo[2,3-b] ° ratio -3-yl} propan-1-ol 384 - palmarity 417.52 (1R,3S)-3-{2 -[2-methoxy-4-(1Η-σΛ^-1-yl)phenyl]-3,7-diindolyl-5Η-σpyrho[2,3-b]pyrazine-5- Cyclohexanol 136 93966 200812588 385 Palm 396. 53 5-(4_Isopropyl-2,6-dimethoxyphenyl)-1 -[(lR)-l-(methoxymethyl) )propyl]-3-methyl-1H- °biluo[3,2-b] bite 386 \ palmity \ Η-Ο \ μ less 391.48 (2S)-1-{2-[2- A Oxy-4-(1Η-σ ratio -1--1-yl)phenyl]-3,7-dimethyl-5Η-° is more than 嘻[2,3-b]吼哄-5-yl} butyl- 2-alcohol 387 OH, human N into f 394. 56 (3S)-3-{5-ethyl-6-[6-isopropyl-2-(methylamino)pyridin-3-yl]-1- Methyl-1H-indolo[2,3-b]pyridin-3-yl}pentan-1-ol

137 93966 200812588 388 HO V. N . 382.51 (2R)_2-[2-(6-乙氧 基-2-乙基吡啶-3-基）-3，7-二曱基-511-11比嘻并[2, 3-b]p比畊 -5-基]戍-1-醇 389 -/ 掌性 /O 1 438.61 3-{6-乙基-1-[(1S) -2-甲氧基-1-曱基乙 基]-3-曱基-1H-吡咯 并[3，2-b]吼 σ定-5-基}-6-異丙基-Ν-(2-甲氧基乙基）-Ν-甲基 吼啶-2-胺 390 / 掌性 393.53 6-環丙基-5-(6-乙氧 基-2_乙基σ比σ定-3-基）-1 - [(1S) - 2-甲氧 基-1-甲基乙基]-3-甲基-1Η-°比洛并[3， 2-1>>比咬 138 93966 200812588 391 OH 395· 55 (3R)-3-[5-乙基-6-(6-異丙基-2 -曱氧基 0比ϋ定-3-基）-1-甲基 - 1Η-ι比洛并[2, 3-b] 吡啶-3-基]戊-1-醇 392 掌性 339. 45 6- 乙基-1-[(1S)-2-氟-1-曱基乙基]-5-(6-異丙基0比咬-3-基）-3-甲基-1H-吡咯 并[3,2-b；h比啶 393 382.51 (2S)-2-[3-(6-異丙 基-2-甲氧基吡啶-3 -基）-2，5-二曱基-5H-σ比嘻并[2, 3-b] °比哄 - 7-基]戊-1-醇137 93966 200812588 388 HO V. N . 382.51 (2R)_2-[2-(6-ethoxy-2-ethylpyridin-3-yl)-3,7-dimercapto-511-11 [2, 3-b]p than cultivable-5-yl]nonanol 389 -/ palmity / O 1 438.61 3-{6-ethyl-1-[(1S)-2-methoxy- 1-mercaptoethyl]-3-mercapto-1H-pyrrolo[3,2-b]indolozide-5-yl}-6-isopropyl-indole-(2-methoxyethyl) -Ν-methyl acridine-2-amine 390 / palm 393.53 6-cyclopropyl-5-(6-ethoxy-2_ethyl σ σ -3--3-)-1 - [(1S ) - 2-methoxy-1-methylethyl]-3-methyl-1Η-°Biluo[3, 2-1>> than bite 138 93966 200812588 391 OH 395. 55 (3R)- 3-[5-ethyl-6-(6-isopropyl-2-oxooxy 0-pyridin-3-yl)-1-methyl- 1Η-ι比洛和[2, 3-b] Pyridin-3-yl]pentan-1-ol 392 palm 339. 45 6-ethyl-1-[(1S)-2-fluoro-1-indolylethyl]-5-(6-isopropyl 0咬-3-yl)-3-methyl-1H-pyrrolo[3,2-b;h than pyridine 393 382.51 (2S)-2-[3-(6-isopropyl-2-methoxy Pyridin-3-yl)-2,5-dimercapto-5H-σ is more than [2, 3-b] ° 哄-7-yl]pentan-1-ol

139 93966 200812588 394 掌性 393.57 6-乙基-5-(6-異丙基 -2-丙基°比17定-3-基） -l-[(lS)-2-甲氧基 -1-曱基乙基]-3-曱 基-1H-批咯并[3, 2-b]0比咬 395 OH 381.52 (3R)-3-[6-乙基-5-(6-異丙基-2 -曱氧基 〇比σ定-3-基）-3-甲基 - 1Η- σ比洛并[3, 2-b] 。比〇定-1-基]丁-1-醇 396 OH 知。 k 382.51 (3S)_3-[2-(6-乙氧 基-2-乙基°比σ定-3-基）-3,7-二曱基-5H-°比17各并[2, 3-b]吼哄 - 5-基]戊-1-醇139 93966 200812588 394 Palm 393.57 6-ethyl-5-(6-isopropyl-2-propyl ° ratio 17--3-yl) -l-[(lS)-2-methoxy-1- Mercaptoethyl]-3-mercapto-1H-bendo[3,2-b]0 is more than 395 OH 381.52 (3R)-3-[6-ethyl-5-(6-isopropyl- 2 - oxime oxime is more specific than sigma-3-yl)-3-methyl- 1 Η- σ piroxi[3, 2-b].比〇定-1-基]丁-1-ol 396 OH Know. k 382.51 (3S)_3-[2-(6-ethoxy-2-ethyl ° σ -3-yl)-3,7-dimercapto-5H-° ratio 17 and [2, 3 -b]吼哄- 5-yl]pentan-1-ol

140 93966 200812588 397 OH 367. 50 (3R)-3-[6-(6-異丙 基-2-曱氧基0比咬-3 -基）-1，5-二甲基-1H-吼嘻并[2, 3-b] °比咬 -3-基]丁 _1-醇 398 H-o-r 掌性 365. 52 (2R)-2-[5-（2-乙基 -6-異丙基ϋ比咬-3-基）-3, 6-二甲基-1Η-°比洛并[3, 2-b]ϋ比咬 -1- 基]丁-1- 醇 399 掌性 378. 47 5-(6-異丙基-2-曱氧 基吼啶-3-基）-1-[(1S)-2-曱氧基-1-甲基乙基]-3-甲基 - 1Η-吼洛并[3, 2-b] 吡啶-6-曱腈 141 93966 200812588 400 掌性 404:91 3-{6-氯-l-[(lS)-2-氟-1-(甲氧基甲基） 乙基]-3-甲基-1H-吡 咯并[3,2-b>比啶-5-基}-6-異丙基-N-甲 基吡啶-2-胺 401 OH 380.54 (3S)-3-{6-[6-異丙 基-2-(甲胺基）吡啶 - 3-基]-1,5-二甲基 - 1H- °比嘻并[2, 3~~b] ϋ比咬-3-基}戊-1-醇 402 ^〇v 335.49 1-異丁基-5-(6-異丙 基-2-甲基°比σ定-3-基）-3,6-二曱基-1Η-0比洛并[3, 2-1)]吼咬 142 93966 200812588 403 掌性 403.49 (1R，3R)-3-{2-[2-甲 氧基-4-(1H- nb 嗤-1 -基）苯基]-3, 7-二曱 基-5H-吼咯并[2, 3-b] °比啡-5-基}環戊 醇 404 / 掌性 397.95 5-(2-氯-6-異丙基°比 ϋ定-3-基）-6-環丙基 -l-[(lS)-2-曱氧基 -1-曱基乙基]-3-甲 基-1H-吼嘻并[3， 2-b]°fcb^ 405 379.55 (2S)-2-[5-乙基-6-(2-乙基-6-異丙基〇比 啶-3-基）-1-甲基 - 1H- °比咯并[2, 3-b] 吡啶-3-基]丁-1-醇140 93966 200812588 397 OH 367. 50 (3R)-3-[6-(6-isopropyl-2-indolyloxy 0-bito-3-yl)-1,5-dimethyl-1H-indole And [2, 3-b] ° than biting-3-yl]but-1-ol 398 Hor palm 365. 52 (2R)-2-[5-(2-ethyl-6-isopropylpyrenepyrene Bite-3-yl)-3,6-dimethyl-1Η-°piro[3,2-b]indole-1-one]but-1-ol 399 palm 378. 47 5-( 6-isopropyl-2-decyloxyacridin-3-yl)-1-[(1S)-2-decyloxy-1-methylethyl]-3-methyl- 1Η-吼洛和[3, 2-b] Pyridine-6-indoleonitrile 141 93966 200812588 400 Palm 404:91 3-{6-Chloro-l-[(lS)-2-fluoro-1-(methoxymethyl) B 3-methyl-1H-pyrrolo[3,2-b>pyridin-5-yl}-6-isopropyl-N-methylpyridin-2-amine 401 OH 380.54 (3S)-3 -{6-[6-isopropyl-2-(methylamino)pyridine-3-yl]-1,5-dimethyl- 1H- ° than hydrazine [2, 3~~b] -3-yl}pentan-1-ol 402 ^〇v 335.49 1-Isobutyl-5-(6-isopropyl-2-methyl ° σ -3--3-)-3,6-di Base-1Η-0 比洛和[3, 2-1)] bite 142 93966 200812588 403 Palm 403.49 (1R,3R)-3-{2-[2-methoxy-4-(1H- nb 嗤-1 -yl)phenyl]-3,7-dimercapto-5H-indole[2, 3 -b] °pyr-5-yl}cyclopentanol 404 / palmity 397.95 5-(2-chloro-6-isopropylpyridine-3-yl)-6-cyclopropyl-l-[ (lS)-2-decyloxy-1-mercaptoethyl]-3-methyl-1H-indole[3, 2-b]°fcb^ 405 379.55 (2S)-2-[5-B -6-(2-ethyl-6-isopropylindolepyridin-3-yl)-1-methyl-1H- °pyrho[2,3-b]pyridin-3-yl]- 1-alcohol

143 93966 200812588 406 H0 f&v 380. 54 (2R)-2-[3-（2-乙基 -6-異丙基吡啶-3-基）-2,5-二甲基-5H-°比洛并[2, 3-b] °比哄 -7-基]戊-1-醇 OH (3S)-3-[6-乙基-5- (2-乙基·~6-異丙基0比 407 393. 58 啶-3-基）-3-甲基-1Η -〇比洛并[3, 2-b>比咬 -1-基]戊-1-醇 OH ^ | (3R)-3-[5-(6-乙氧 /VV 基-2-乙基吡啶-3- 408 381.52 基）-6-乙基-3-甲基 厂〇d - 1H-吼 p各并[3, 2-b] 1 吡啶-1-基]丁-1-醇143 93966 200812588 406 H0 f&v 380. 54 (2R)-2-[3-(2-ethyl-6-isopropylpyridin-3-yl)-2,5-dimethyl-5H-° ratio洛和[2, 3-b] ° than 哄-7-yl] pent-1-ol OH (3S)-3-[6-ethyl-5- (2-ethyl·~6-isopropyl 0 Ratio 407 393. 58 pyridin-3-yl)-3-methyl-1Η-dehydrazo[3, 2-b> butyl-1-yl]pentan-1-ol OH ^ | (3R)-3 -[5-(6-ethoxy/VV-yl-2-ethylpyridine-3- 408 381.52 yl)-6-ethyl-3-methyl 〇d - 1H-吼p each [3, 2- b] 1 pyridin-1-yl]butan-1-ol

144 93966 200812588144 93966 200812588

409 、㈡入 352.48 (2ί〇-2-{6-[6-異丙 基-2-(曱胺基）吡啶 -3-基]-1，5-二曱基 - 1Η-吼洛并[2, 3-b] 吡啶-3-基}丙-1-醇 410 ^5α〇 k 368.48 (2S)-2-[3-（6-乙氧 基-2-乙基°比σ定-3-基）-2,5-二甲基-5Η -吼咯并[2, 3-b；h比畊 - 7-基]丁-1-醇 411 382.51 (2R)-2-[3-(6-乙氧 基-2_乙基°比°定-3-基）-2-乙基-5-甲基 -5H-吼嘻并[2, 3-b] °比啡-7-基]丁-1-醇409, (b) into 352.48 (2ί〇-2-{6-[6-isopropyl-2-(decylamino)pyridin-3-yl]-1,5-dimercapto- 1Η-吼洛和[2 , 3-b] pyridin-3-yl}propan-1-ol 410^5α〇k 368.48 (2S)-2-[3-(6-ethoxy-2-ethyl° ratio σ--3-yl -2,5-Dimethyl-5Η-吼 并[2, 3-b; h than tillage-7-yl]butan-1-ol 411 382.51 (2R)-2-[3-(6-B Oxy-2-phenyl-ethyl-pyrene-3-yl)-2-ethyl-5-methyl-5H-indole[2,3-b] ° than phenyl-7-yl] butyl-1 -alcohol

145 93966 200812588145 93966 200812588

412 掌性 395.54 5-（2-異丙氧基_6-異 丙基吼咬-3-基）-1-[(1R)-1-(甲氧基甲 基）丙基]-3-甲基-1H -σ比嘻并[3, 2-^^比咬 413 351.49 5-（2-乙基-6-異丙基 吡啶-3-基）-1 -（2-甲 氧基乙基)-3，6-二曱 基-1Η- °比洛并[3， 2-b]T,tbt^ 414 掌性 445. 58 5-[2_乙氧基-6-乙基 - 5-（曱基石黃酿基）口比 啶-3-基]-1-[(1R) -1 -（甲氧基甲基）丙 基]-3-甲基-1H-吡咯 并[3, 2-b]吡啶412 palm 395.54 5-(2-isopropoxy-6-isopropylindole-3-yl)-1-[(1R)-1-(methoxymethyl)propyl]-3-methyl Base-1H -σ is more than 嘻[3, 2-^^ than bite 413 351.49 5-(2-ethyl-6-isopropylpyridin-3-yl)-1 -(2-methoxyethyl) -3,6-dimercapto-1Η- °Bilo[3,2-b]T, tbt^ 414 palmity 445. 58 5-[2_ethoxy-6-ethyl-5-(曱Cornerstone yellow base) 比pyridin-3-yl]-1-[(1R) -1 -(methoxymethyl)propyl]-3-methyl-1H-pyrrolo[3, 2-b] Pyridine

146 93966 200812588 415 Η—0 \ N / 391.48 1 -{2-[2- 甲氧基-4-(1Η-吼唑-1_基）苯 基]-3, 7-二曱基-5H-ϋ比洛并[2, 3-b] °比哄 -5-基}-2-甲基丙-2-醇 416 366.51 (2R)-2-[3-乙基-2-(2-乙基-6-異丙基σ比 啶-3-基）-7-甲基 -5H- ϋ比嘻并[2, 3-b] 吡畊-5-基]丙-1-醇 417 394.56 (2ΪΟ-2-{6-乙基-5-[6-異丙基-2-(甲胺 基）吡啶-3-基]-3-甲 基-1H-吼嘻并[3， 2-b]吼σ定-1-基}戊 -1-醇146 93966 200812588 415 Η—0 \ N / 391.48 1 -{2-[2-methoxy-4-(1Η-indazol-1_yl)phenyl]-3,7-diindolyl-5H-indole Biluo[2,3-b] ° 哄-5-yl}-2-methylpropan-2-ol 416 366.51 (2R)-2-[3-ethyl-2-(2-ethyl- 6-Isopropyl σ-pyridin-3-yl)-7-methyl-5H-indole 嘻[2,3-b] pyridin-5-yl]propan-1-ol 417 394.56 (2ΪΟ-2 -{6-ethyl-5-[6-isopropyl-2-(methylamino)pyridin-3-yl]-3-methyl-1H-indolo[3,2-b]吼σ -1-yl}pentan-1-ol

147 93966 200812588 418 包。 k 395. 55 (2R)-2-[5-(6-乙氧 基-2-乙基σ比咬-3-基）-6-乙基甲基 - 1Η- ϋ比嘻并[3, 2-b] 11比咬-1-基]戊-1-醇 OH (3S)-3-[2-乙基-3- (6-異丙基-2 -曱氧基 419 382.51 〇比σ定-3-基）-5-甲基 / ό〇υ -5Η- 0比咯并[2, 3-b] 、。人 〇比哄-7-基]丁-1-醇 (2R)-2-{6-[6-異丙 Η0 >rv 基-2-（甲胺基）吼啶 420 380. 54 -3-基]-1，5-二曱基 r OCX/ - 1H-吼嘻弁[2, 3-b] 、八 吼°定-3_基}戊-1-醇147 93966 200812588 418 package. k 395. 55 (2R)-2-[5-(6-ethoxy-2-ethyl σ 咬-3-yl)-6-ethylmethyl- 1 Η-ϋ 嘻 嘻 [3, 2 -b] 11 butyl-1-yl]pentan-1-ol OH (3S)-3-[2-ethyl-3-(6-isopropyl-2-yloxy 4 918 382.51 〇 σ 定 - 3-yl)-5-methyl/ ό〇υ -5Η- 0 is more than [2, 3-b]. Human 〇-7-yl]butan-1-ol (2R)-2-{6-[6-isopropyl oxime 0 > rv-yl-2-(methylamino) acridine 420 380. 54 -3- 1,1,5-dimercapto-r-OCX/ - 1H-吼嘻弁[2, 3-b], octadecyl-3-yl}pent-1-ol

148 93966 200812588 421 ^r’ fOC, 363. 50 5 -（2-乙基-6-異丙基 0比咬-3-基）-1-[1 -(曱氧基甲基）乙烯 基]-3，6-二甲基-1H-11比洛并[3, 2-b>比〇定 422 掌性 465.64 6-異丙基-3-{1-[〇R)-l-(曱氧基曱 基）丙基]-3-甲基 - 1H-吡咯并[3,2-b] °比咬-5-基}-N-(2-嗎 琳-4-基乙基）°比σ定 -2-胺 423 OH %v 367. 50 (3R)-3-[5-(6-異丙 基-2-曱氧基吡啶-3 -基）-3, 6-二甲基-1Η-°比洛并[3, 2-b] °比咬 -1-基]丁-1-醇148 93966 200812588 421 ^r' fOC, 363. 50 5 -(2-Ethyl-6-isopropyl 0 to -3-yl)-1-[1 -(decyloxymethyl)vinyl]- 3,6-Dimethyl-1H-11 piroxi[3, 2-b> 〇定定422 palm 465.64 6-isopropyl-3-{1-[〇R)-l-(曱oxy Mercapto)propyl]-3-methyl- 1H-pyrrolo[3,2-b] ° than bite-5-yl}-N-(2-morphin-4-ylethyl) ° ratio -2-amine 423 OH %v 367. 50 (3R)-3-[5-(6-isopropyl-2-indolylpyridin-3-yl)-3,6-dimethyl-1Η-° Bilo and [3, 2-b] ° than bit-1-yl] butan-1-ol

149 93966 200812588 424 420.60 5-(6-異丙基-2-吡咯 烷-1-基吡啶-3-基） -1-[(1R)-1 -（甲氧基 曱基）丙基]-3, 6-二 甲基-1H-吡咯并[3, 2-b]吡啶 OH /-/ I (38)-3-[6-乙基-5- (2-乙基-6-異丙基σ比 425 ocx^ 379.55 啶-3-基）-3-曱基 广 cxx^ - 1Η- °比洛并[3, 2-b] 吡啶-1-基]丁-1-醇 o \ 2-[5-(2-乙基-6-異 丙基-3-吼啶基） 426 coc^ 337· 46 -3, 6-二甲基-1H-吡 ^icX/ 洛弁[3，2-b] utbϋ定-1- 基]乙醇149 93966 200812588 424 420.60 5-(6-Isopropyl-2-pyrrolidin-1-ylpyridin-3-yl)-1-[(1R)-1 -(methoxyindolyl)propyl]-3 , 6-Dimethyl-1H-pyrrolo[3,2-b]pyridine OH /-/ I (38)-3-[6-ethyl-5- (2-ethyl-6-isopropyl σ Ratio 425 ocx^ 379.55 pyridine-3-yl)-3-indolyl wide cxx^ - 1Η- °piro[3,2-b]pyridin-1-yl]butan-1-ol o \ 2-[5 -(2-ethyl-6-isopropyl-3-azulidine) 426 coc^ 337· 46 -3, 6-dimethyl-1H-pyridyl^icX/ 弁[3,2-b] utbϋ Ding-1-yl]ethanol

150 93966 200812588 參 427 k 367. 50 (2S)-2_[6-(6-乙氧 基-2-乙基σ比咬-3-基）-1，5-二甲基-1Η-ϋ比洛并[2, 3-b] °比咬 - 3-基]丁-1-醇 428 381.52 (2S)-2-[5-乙基 -6-(6-異丙基-2-甲氧基 吡啶-3-基）-1-甲基 -IHh 吼 17各并[2, 3_b] °比。定-3-基]丁-1-醇 429 、〇^v^ 掌性 493.69 3-{6-乙基-1-[(1S) -2-曱氧基-1-甲基乙 基]-3-甲基-1Η-σ比洛 并[3, 2-b]吡啶-5-基}-6-異丙基-N-(3-嗎琳-4-基丙基）H比ϋ定 - 2-胺 151 93966 200812588 430 393.58 (2S)-2-[5-乙基--乙基- 6- 異丙 基 °比 啶-3-基）-1-甲基-1H -吼嘻并[2, 3-b]吼啶 - 3-基]戊-1-醇 431 352.48 (2S)-2-[2-(2-乙基 -6-異丙基σ比咬-3-基）-3,7-二曱基-5Η-11比嘻并[2, 3-b] °比哄 - 5-基]丙-1-醇 432 ji—f 掌性 —〇 386.47 5-K1R)-2-氟-1-（甲 氧基甲基）乙基]-2-(6-異丙基-2 -甲氧基 °比 σ定-3-基）-3, 7-二 曱基-5Η-吡咯并[2, 3-b>比哄 152 93966 200812588 433 \〇 人 396. 54 (2S)-2-[2-乙基-3-(6-異丙基-2-曱氧基 吼咬-3-基）-5-曱基 -5H-吼咯并[2,3-b] 吼畊-7-基]戊-1-醇 434 〆 掌性 394.56 N-乙基-3-{6-乙基 -1 -[(lS)-2_ 曱氧基 -1-甲基乙基]-3-曱 基-1H-咐咯并[3, 2-b] ϋ比咬-5-基}-6-異丙基σ比σ定_2-胺 435 366.51 (2S)_2-[2-乙基 -3-(2-乙基-6-異丙基°比 啶-3-基）-5-甲基 -5H- °比洛并[2, 3-b] 吡畊-7-基]丙-1-醇 153 93966 200812588 436 掌性 377.53 5 -（2-環丙基-6-異丙 基吼啶-3_基）-1-[(lR)-l-(甲氧基甲 基）丙基]-3-曱基 -1H-吼咯并[3,2-b] 437 掌性 391.48 (2幻-2-{2-[2-甲氧 基-4-(1Η- π比 °坐-1 -基）苯基]-3, 7-二曱 基-5Η-吼咯并[2, 3-b]吡畊-5-基丨丁 -1-醇 438 、。^v /0 424.59 6-異丙基-N-(2-曱氧 基乙基）-3-{ 1-[ (1R) -1-（甲氧基曱基）丙 基]-3，6~~ 二甲基-1H-吼洛并[3, 2-b]咐咬 -5-基}π比唆-2-胺150 93966 200812588 Ref. 427 k 367. 50 (2S)-2_[6-(6-Ethoxy-2-ethyl σ 咬-3-yl)-1,5-dimethyl-1 Η-ϋbilo And [2, 3-b] ° ratio biting - 3-yl] butan-1-ol 428 381.52 (2S)-2-[5-ethyl-6-(6-isopropyl-2-methoxypyridine -3-yl)-1-methyl-IHh 吼17 each [2, 3_b] ° ratio. Ding-3-yl]butan-1-ol 429, 〇^v^ palm 493.69 3-{6-ethyl-1-[(1S)-2-decyloxy-1-methylethyl]-3 -Methyl-1Η-σpyrolo[3,2-b]pyridin-5-yl}-6-isopropyl-N-(3-morphin-4-ylpropyl)H than ϋ- 2 -amine 151 93966 200812588 430 393.58 (2S)-2-[5-ethyl--ethyl-6-isopropylpyranidin-3-yl)-1-methyl-1H-indole[2, 3-b] acridine-3-yl]pentan-1-ol 431 352.48 (2S)-2-[2-(2-ethyl-6-isopropyl σ 咬-3-yl)-3,7 -Dimercapto-5Η-11 is more than [2, 3-b] ° 哄- 5-yl] propan-1-ol 432 ji-f palm- 〇 386.47 5-K1R)-2-fluoro-1 -(methoxymethyl)ethyl]-2-(6-isopropyl-2-methoxyl ratio σ-3-yl)-3,7-dimercapto-5Η-pyrrolo[2 , 3-b> 哄152 93966 200812588 433 \〇人396. 54 (2S)-2-[2-ethyl-3-(6-isopropyl-2-oxime oxime-3-yl) -5-mercapto-5H-indolo[2,3-b] indole-7-yl]pentan-1-ol 434 palmar 394.56 N-ethyl-3-{6-ethyl-1 - [(lS)-2_ 曱oxy-1-methylethyl]-3-indolyl-1H-indolo[3,2-b] ϋ 咬-5-yl}-6-isopropyl σ Σσ定_2-amine 435 366.51 (2S)_2-[2-ethyl-3-(2- -6-isopropyl-pyridin-3-yl)-5-methyl-5H- °piro[2,3-b]pyrrol-7-yl]propan-1-ol 153 93966 200812588 436 Palm 377.53 5-(2-cyclopropyl-6-isopropylacridin-3-yl)-1-[(lR)-l-(methoxymethyl)propyl]-3-indolyl- 1H-吼 并[3,2-b] 437 palm 391.48 (2 magic-2-{2-[2-methoxy-4-(1Η-ππ°°-1 -yl)phenyl]- 3,7-dimercapto-5-indole[2,3-b]pyrrol-5-ylindole-1-ol 438, .^v /0 424.59 6-isopropyl-N-(2 -methoxyethyl)-3-{ 1-[ (1R) -1-(methoxyindolyl)propyl]-3,6~~ dimethyl-1H-indolo[3, 2- b] bite-5-based}π than indole-2-amine

154 93966 200812588 439 OH 381.52 (3S)-3-[6-乙基-5-(6-異丙基-2-曱氧基 吡啶-3-基）-3-曱基 - 1H-吼咯并[3,2-b] 吡啶-1-基]丁-1-醇 440 396.54 (2S)-2-[3-（6-乙氧 基-2-乙基11比σ定-3-基）-2-乙基-5-曱基 -5Η- °比洛并[2, 3-b] 吼畊-7-基]戊-1-醇 441 OH 、人 381.53 (3S)-3-{2-[6-異丙 基-2-（甲胺基）吡啶 -3-基]-3, 7- 二曱基 -5H- 11 比 口各并[2, 3-b] 吡畊-5-基}戊-1-醇154 93966 200812588 439 OH 381.52 (3S)-3-[6-ethyl-5-(6-isopropyl-2-indolylpyridin-3-yl)-3-indolyl-1H-indole[ 3,2-b] pyridin-1-yl]butan-1-ol 440 396.54 (2S)-2-[3-(6-ethoxy-2-ethyl 11 σσ-3-yl)-2 -ethyl-5-mercapto-5Η- °piro[2,3-b] 吼-7-yl]pentan-1-ol 441 OH, human 381.53 (3S)-3-{2-[6 -Isopropyl-2-(methylamino)pyridin-3-yl]-3,7-dimercapto-5H- 11 比[2,3-b] pyridin-5-yl}penta- 1-alcohol

155 93966 200812588 442 /^0 。广1 乂 381.51 (2^)-2-[5-（2- 乙基 -6-異丙基-3- °比咬 基）-3,6-二甲基-1H-π比洛并[3, 2-b]u比咬 -1-基]-3-曱氧基-1 -丙醇 443 k 367· 50 (2S)-2-[5-(6-乙氧 基-2-乙基σ比咬-3-基）-3, 6-二甲基-1Η-σ比咯并[3, 2-b] °比σ定 -1-基]丁-1-醇 444 、人々 394.56 (2S)-2-{5- 乙基-6-[6-異丙基-2-（曱胺 基）吡啶-3-基]-1-甲 基-1Η-啦咯并[2, 3-b]吡啶-3-基Γ戊 -1-醇155 93966 200812588 442 /^0 .广1 乂381.51 (2^)-2-[5-(2-ethyl-6-isopropyl-3-° ratio dimethyl)-3,6-dimethyl-1H-π piroxi[3 , 2-b]u than bit-1-yl]-3-decyloxy-1-propanol 443 k 367· 50 (2S)-2-[5-(6-ethoxy-2-ethyl σ Than -3-yl)-3,6-dimethyl-1Η-σ ratio [3, 2-b] ° ratio σ -1--1-butan-1-ol 444, human 々 394.56 (2S) -2-{5-Ethyl-6-[6-isopropyl-2-(decylamino)pyridin-3-yl]-1-methyl-1Η-lahydro[2,3-b]pyridine -3-ylindole-1-ol

156 93966 200812588 445 382.51 (2R)-2-[3-乙基-2-(6-異丙基-2 -甲氧基 吼啶-3-基）-7-曱基 -5H- u比洛弁[2, 3-b] 吡哄-5-基]丁-1-醇 446 r^T HO 二 366.51 (2S)-2-{5-[6-異丙 基-2-（甲胺基）σ比咬 -3-基]-3, 6-二甲基 - 1Η- ^比洛并[3, 2-b] 吼咬-1 -基} 丁 -1 -醇 447 OH 393.58 (3R)-3-[6-乙基 -5-(2-乙基-6 -異丙基ϋ比 啶-3-基）-3-曱基 - 1Η- 11比咯并[3, 2-b] 吡啶-1-基]戊-1-醇156 93966 200812588 445 382.51 (2R)-2-[3-ethyl-2-(6-isopropyl-2-methoxyoxaridin-3-yl)-7-indenyl-5H-u [2, 3-b] pyridin-5-yl]butan-1-ol 446 r^T HO II 366.51 (2S)-2-{5-[6-isopropyl-2-(methylamino) σ咬-3-yl]-3,6-dimethyl- 1Η- ^Biloze[3,2-b] bite-1 -yl}but-1-ol 447 OH 393.58 (3R)-3- [6-ethyl-5-(2-ethyl-6-isopropylindole-3-yl)-3-indolyl-1 Η- 11-pyrolo[3,2-b]pyridine-1- Pent-1-ol

157 93966 200812588 448 \ /掌性 380.49 (21〇-2-[2-（2_乙基 - 6-異丙基吡啶-3-基）-3,7-二曱基-5H-11比11各并[2, 3-b]σ比哄 - 5-基]丁酸 449 OH 393.58 (3S)-3-[5-乙基-δα- 乙基-6- 異 丙基吡 啶-3-基）-1-甲基-1Η -吼洛并[2, 3-b>比咬 - 3-基]戍-1-醇 450 H0^\_ N / 368.48 (2R)-2_[2-(6-異丙 基-2-甲氧基吡啶-3-基）-3,7_二曱基-5H-口比π各并[2, 3-b] t哄 -5-基]丁-1-醇157 93966 200812588 448 \ / palm 380.49 (21〇-2-[2-(2_ethyl-6-isopropylpyridin-3-yl)-3,7-dimercapto-5H-11 ratio 11 And [2, 3-b]σ 哄-5-yl]butyric acid 449 OH 393.58 (3S)-3-[5-ethyl-δα-ethyl-6-isopropylpyridin-3-yl)- 1-Methyl-1Η-吼洛和[2, 3-b>Bite-3-Base]戍-1-ol 450 H0^\_ N / 368.48 (2R)-2_[2-(6-isopropyl 2-yloxypyridin-3-yl)-3,7-diindenyl-5H-port ratio π[2,3-b]t哄-5-yl]butan-1-ol

158 93966 200812588158 93966 200812588

OH (3R)-3-[5-(2-乙基 -6-異丙基吼σ定-3- 451 365· 52 基）-3,6-二甲基-1Η- σ比17各并[3, 2-b]吼咬 -1-基]丁-1-醇 堂恍 6-環丙基-5-(2-乙基 -6-甲氧基〇比σ定-3- 452 〇C(^ 379· 50 基）-1 - [(lS)-2-曱氧 基-1-曱基乙基]-3- 八6〆 甲基-1H-吡咯并[3, 2-b]°比咬 OH j (3R)-3-{3-[6-異丙 基-2-（甲胺基）吼啶 453 《』」 367.50 -3-基]-2,5-二曱基 /N N 丫、 -5H- σ比哈并[2, 3-b] 、丨 σ比哄-7-基} 丁-1-醇OH (3R)-3-[5-(2-ethyl-6-isopropyl吼σding-3- 451 365· 52 base)-3,6-dimethyl-1Η-σ ratio 17 and [ 3, 2-b]bite-1-yl]butan-1-ol, 6-cyclopropyl-5-(2-ethyl-6-methoxyindole, sigma-3-452 〇C ( ^ 379· 50 base)-1 -[(lS)-2-decyloxy-1-mercaptoethyl]-3- octa-6〆methyl-1H-pyrrolo[3,2-b]° bite OH j (3R)-3-{3-[6-isopropyl-2-(methylamino)acridine 453 "』" 367.50 -3-yl]-2,5-diindenyl/NN 丫, - 5H- σ Biha and [2, 3-b], 丨σ 哄-7-yl} Butan-1-ol

159 93966 200812588159 93966 200812588

454 372. 44 (2R)-2-[3-氣-2-(6-異丙基-2-曱氧基-3-σ比ϋ定基）-7-甲基-5H-σ比嘻并[2,3-b] °比 畊-5-基]-1-丁醇 455 Ο 、㈡人[ΝΓ^γ^ 395.55 (2R)-2-{2-乙基-3-[6-異丙基-2_(曱胺 基）吡啶-3-基]- 5-甲 基-5H-吡咯并[2, 3-b] °比哄-7-基}戊 -1-醇 456 ^/^〇Η I ^(χ k 381.52 (3R)-3-[6-（6-乙氧 基-2-乙基吡啶-3-基）-5-乙基-1-甲基 - 1H- ϋ比洛并[2, 3-b] 吼〇定-3-基]丁 -1 -醉454 372. 44 (2R)-2-[3-Gas-2-(6-isopropyl-2-indolyl-3-σ ϋ ϋ ))-7-methyl-5H-σ 嘻 嘻 [ 2,3-b] ° than cultivative-5-yl]-1-butanol 455 Ο, (b) human [ΝΓ^γ^ 395.55 (2R)-2-{2-ethyl-3-[6-isopropyl -2_(decylamino)pyridin-3-yl]- 5-methyl-5H-pyrrolo[2,3-b] ° than 哄-7-yl}pent-1-ol 456 ^/^〇Η I ^(χ k 381.52 (3R)-3-[6-(6-Ethoxy-2-ethylpyridin-3-yl)-5-ethyl-1-methyl- 1H- ϋ比洛和[2 , 3-b] 吼〇定-3-基]丁-1 - drunk

160 93966 200812588 457 367.50 (2S)-2-[5- 乙基-6-(6-異丙基-2-曱氧基 吡啶-3-基）-1-曱基 -1H-吡咯并[2,3-b] 吡啶-3-基]丙-1-醇 458 411.54 5-[6-異丙基-2-(2-曱氧基乙氧基）ϋ比啶 -3-基]-1-[(1R)-1-(曱氧基曱基）丙基] -3-甲基-1H- 口比口各并 [3,2-b> 比啶 459 \ 掌性 ΗΟ^<； Ν . 405.50 (2S)-2-{2-[2-甲氧 基—吼 0坐-基）苯基]-3, 7-二曱 基-5H- σ比洛并[2， 3-b；h比畊-5-基}-3-曱基丁-1-醇160 93966 200812588 457 367.50 (2S)-2-[5-Ethyl-6-(6-isopropyl-2-indolylpyridin-3-yl)-1-indenyl-1H-pyrrolo[2, 3-b] pyridin-3-yl]propan-1-ol 458 411.54 5-[6-isopropyl-2-(2-decyloxyethoxy)indolepyridin-3-yl]-1-[ (1R)-1-(indolyl hydrazino)propyl]-3-methyl-1H- is more than the mouth [3,2-b> pyridine 459 \ palmity ΗΟ^<; Ν . 405.50 (2S)-2-{2-[2-methoxy-oxime-iso-yl)phenyl]-3,7-dimercapto-5H- σ piroxi[2, 3-b; -5-yl}-3-mercaptobutan-1-ol

161 93966 200812588161 93966 200812588

460 X— 掌性 353. 48 1-[(IS)-1-（ H 甲基） 丙基]-5-(6_異丙基 - 2-甲基吡啶-3-基） -3，6- 二甲基-1H- π比 嘻并[3, 2-b]吡啶 461 OH 368.48 (3S)-3-[2-（6- 乙氧 基-2-乙基0比咬-3-基）-3, 7-二曱基-5H-0比σ各并[2, 3-b] °比啡 - 5-基]丁-1-醇 462 482· 62 6-乙基-5-{6-乙基 -1 -[2-曱氧基-1-(甲 氧基曱基）乙基]-3-甲基-1H- °比σ各并 [3,2-b]吼啶-5-基} -2-異丙氧基-N-曱基 於驗醯胺460 X—palmability 353. 48 1-[(IS)-1-(H-methyl)propyl]-5-(6-isopropyl-2-methylpyridin-3-yl)-3,6- Dimethyl-1H- π is more than [3, 2-b]pyridine 461 OH 368.48 (3S)-3-[2-(6-ethoxy-2-ethyl 0 to -3-yl)- 3, 7-dimercapto-5H-0 ratio σ each [2, 3-b] ° than morphine 5-yl]butan-1-ol 462 482· 62 6-ethyl-5-{6-B -1-[2-decyloxy-1-(methoxyindolyl)ethyl]-3-methyl-1H- ° ratio σ[3,2-b]acridin-5-yl} -2-isopropoxy-N-indole based on guanamine

162 93966 200812588 463 365. 52 5-(6-異丙基-2-甲氧 基吼啶-3-基）_3,6-二甲基-1 -（3-曱基丁 基）·~1Η- ϋ比洛并[3， 2-bp比咬 464 掌性 Ν"Τ 385.48 3-{5—[ (1S)-2-氟-1-(曱氧基曱基）乙基] -3,7-二甲基-511-吡 咯并[2,3-b>比畊-2-基}-6-異丙基-N-甲 基吡啶-2-胺 465 Η-〇-Γ_ _ 、。人 392. 46 (2R)-2-{2-[2-甲氧 基-6-(1H- ϋ比峻-1 -基）吼啶-3-基]-3, 7-二曱基-5Η- σ比嘻并 [2,3-b]吼畊-5-基} 丁-1-醇162 93966 200812588 463 365. 52 5-(6-Isopropyl-2-methoxyacridin-3-yl)_3,6-dimethyl-1 -(3-indolylbutyl)·~1Η- ϋ比洛和[3,2-bp ratio bite 464 palm Ν"Τ 385.48 3-{5-[ (1S)-2-fluoro-1-(decyloxydecyl)ethyl] -3,7- Dimethyl-511-pyrrolo[2,3-b>pyrylene-2-yl}-6-isopropyl-N-methylpyridin-2-amine 465 Η-〇-Γ_ _. 392. 46 (2R)-2-{2-[2-Methoxy-6-(1H-indenyl-1 -yl)acridin-3-yl]-3,7-didecyl-5Η - σ is more than [2,3-b] 吼-5-yl} butan-1-ol

163 93966 200812588 466 、人 380.54 (2S)-2-{6-乙基-5-[6-異丙基-2-(曱胺 基）吡啶-3-基]-3-甲 基-1H-吼咯并[3, 2-b] 11 比咬-1-基} 丁 -1-醇 467 HO \· a / 379· 55 (2R)-2-[5-（2~乙基 -6-異丙基ϋ比咬-3-基）-3，6-二甲基-1Η-11比洛并[3, 2-b] °比咬 -1-基]戊-1-醇 468 掌性 —，ϊ〇ν 386.92 3-氯-2-(2-乙基-6-異丙基σ比唆_3_基） -5-[(1S)-2-甲氧基 -1-甲基乙基]-7-曱 基-5Η-吼σ各并[2.，. 3-b]吼畊163 93966 200812588 466, human 380.54 (2S)-2-{6-ethyl-5-[6-isopropyl-2-(decylamino)pyridin-3-yl]-3-methyl-1H-indole咯[3,2-b] 11 than bit-1-yl}butan-1-ol 467 HO \· a / 379· 55 (2R)-2-[5-(2~ethyl-6-isopropyl Base ϋ-3-yl)-3,6-dimethyl-1Η-11 piroxi[3,2-b] ° than bit-1-yl]pentan-1-ol 468 palm-, ϊ 〇ν 386.92 3-Chloro-2-(2-ethyl-6-isopropylσ唆唆_3_yl)-5-[(1S)-2-methoxy-1-methylethyl]- 7-曱基-5Η-吼σ each [2.,. 3-b] tillage

164 93966 200812588 469 395.55 (2R)-2-[6- 乙基-5-(6-異丙基-2-曱氧基 吡啶-3-基）-3-甲基 - 1H- °比洛并[3, 2-b] 吡啶-1-基]戊-1-醇 470 ^&L0 k 367.50 (2R)-2-[6-（6_ 乙氧 基-乙基σ比咬-3-基）-1，5-二甲基-1Η-口比嘻并[2, 3-b] °比咬 -3-基]丁-1-醇 471 k 367. 50 (2R)-2-[6-(6-乙氧 基-2-乙基ϋ比咬-3-基）-5-乙基-1-甲基 -1H- 0比洛并[2, 3-b] 定-3-基]丙-1-醇164 93966 200812588 469 395.55 (2R)-2-[6-ethyl-5-(6-isopropyl-2-indolylpyridin-3-yl)-3-methyl- 1H- °bilo[ 3, 2-b] pyridin-1-yl]pentan-1-ol 470 ^&L0 k 367.50 (2R)-2-[6-(6-ethoxy-ethyl σ 咬-3-yl)- 1,5-Dimethyl-1Η-port ratio 嘻[2,3-b] ° ratio -3-yl]butan-1-ol 471 k 367. 50 (2R)-2-[6-(6 -ethoxy-2-ethylindole butyl-3-yl)-5-ethyl-1-methyl-1H- 0 piroxi[2,3-b]din-3-yl]propan-1 -alcohol

165 93966 200812588 472 掌性 394. 56 N-乙基-6-異丙基-3-{1 -[(lR)-l-(甲氧基 曱基）丙基]-3-甲基 - 1H- °比嘻弁[3, 2-b] 吡啶-5-基}-N-曱基 11比咬-2-胺 5-(6-異丙基-2-甲氧 基吼°定-3-基）-3, 6- 473 393. 57 二曱基-（1-丙基丁 广 OOl^ 基MH-吼咯并[3, 2-b]n比咬 (2S)-2-[2-(6-異丙 H0 > w 基-2-甲氧基啦啶-3- 474 382.51 基）-3,7-二曱基-5H- 广OCu °比洛并[2, 3-b]吼哄 \〇八 - 5-基]戍-1-醇165 93966 200812588 472 Palm 394. 56 N-Ethyl-6-isopropyl-3-{1 -[(lR)-l-(methoxyindolyl)propyl]-3-methyl- 1H-嘻弁[3,2-b]pyridin-5-yl}-N-fluorenyl 11-biti-2-amine 5-(6-isopropyl-2-methoxyindole-3-yl )-3, 6- 473 393. 57 Dimercapto-(1-propylbutyro OOl^ MH-吼-[3,2-b]n ratio bite (2S)-2-[2-(6 -isopropyl H0 > w-yl-2-methoxyl-pyridin-3- 474 382.51 yl)-3,7-dimercapto-5H- wide OCu ° piroxi[2, 3-b]吼哄\ 〇8- 5-yl]nonanol

166 93966 200812588 475 396· 54 (2S)-2-[3-乙基-2-(6-異丙基-2 -曱氧基 吡啶-3-基）-7-曱基 -5H- °比咯并[2, 3-b] 吼畊-5-基]戊-1-醇 476 363. 50 1 -環戍基-5-(6-異丙 基-2-曱氧基σ比咬-3-基）-3, 6-二曱基-1Η-°比口各并[3,2-1)]°比咬 477 ^5α〇 k 354. 46 (2S)-2-[3-(6-乙氧 基-2_乙基σ比咬-3-基）-2,5-二甲基-5Η -吼洛并[2, 3-b]ϋ比哄 -7-基]丙-1-醇166 93966 200812588 475 396· 54 (2S)-2-[3-ethyl-2-(6-isopropyl-2-oxoxypyridin-3-yl)-7-fluorenyl-5H- ° ratio And [2, 3-b] 吼耕-5-yl]pentan-1-ol 476 363. 50 1 -cyclodecyl-5-(6-isopropyl-2-oximeoxy σ ratio -3- Base)-3,6-dimercapto-1Η-° ratios each [3,2-1)]° than bite 477 ^5α〇k 354. 46 (2S)-2-[3-(6-B Oxy-2-ethyl σ is more than -3-yl)-2,5-dimethyl-5Η-吼洛和[2,3-b]ϋ 哄-7-yl]propan-1-ol

167 93966 200812588 478 k 381.52 (2S)-2-[6-(6-乙氧 基-2-乙基吡啶-3-基M，5-二甲基-1H -°比咯并[2, 3-b]吡咬 -基]戊-1-醇 479 W 掌性 1¾ 381.52 5-（2-乙基-6-異丙氧 基吡啶-3-基）-1-[(lR)-2-甲氧基-1-甲基乙基]-3, 6-二甲 基-1H-吼咯并[3, 2-b]吼咬 480 HO^( N 、入 353.47 (2S)-2-{2-[6-異丙 基-2-(甲胺基）吼啶 -3-基]-3, 7-二甲基 -5H-1比洛并[2, 3-b] 吡畊-5-基}丙-1-醇167 93966 200812588 478 k 381.52 (2S)-2-[6-(6-Ethoxy-2-ethylpyridin-3-yl M,5-dimethyl-1H-° ratio [[2, 3- b]Pyridine-yl]pentan-1-ol 479 W palmity 13⁄4 381.52 5-(2-ethyl-6-isopropoxypyridin-3-yl)-1-[(lR)-2-methoxy -1-methylethyl]-3,6-dimethyl-1H-indolo[3,2-b] bite 480 HO^(N, into 353.47 (2S)-2-{2-[ 6-isopropyl-2-(methylamino)acridin-3-yl]-3,7-dimethyl-5H-1piro[2,3-b]pyrrol-5-yl}-propyl -1-ol

168 93966 200812588 481 掌性 367.51 6-乙基-5-(2-乙基 -6-異丙基吡啶-3-基）-卜[(1S)-2-貌 -1-曱基乙基]-3-曱 基-1H-吼咯并[3, 2-b]吡啶 OH (3S)-3-{6-[6-異丙 基-2-（曱胺基）吼啶 482 cXX^ 366.51 - 3-基]-1，5-二甲基 ^ uX - 1H-吡咯并[2,3-b] 吡啶-3-基}丁-1-醇 OH (3S)~~3-[3-乙基-2- (6-異丙基-2 -甲氧基 483 382.51 口比啶-3-基）-7-甲基 -5H-吼洛并[2, 3-b] 、。人 吡畊-5-基]丁-1-醇168 93966 200812588 481 Palm 367.51 6-Ethyl-5-(2-ethyl-6-isopropylpyridin-3-yl)-b[(1S)-2-phenanthyl-1-ylethyl]- 3-mercapto-1H-indolo[3,2-b]pyridine OH (3S)-3-{6-[6-isopropyl-2-(decylamino)acridine 482 cXX^ 366.51 - 3 -yl]-1,5-dimethyl^uX-1H-pyrrolo[2,3-b]pyridin-3-yl}butan-1-ol OH (3S)~~3-[3-ethyl- 2-(6-Isopropyl-2-methoxy-483 382.51:pyridin-3-yl)-7-methyl-5H-indolo[2,3-b]. Human pyridin-5-yl]butan-1-ol

169 93966 200812588 484 Xv 371.90 (2S)-2-[5-(2-氯-6-異丙基啦啶-3-基） -6-乙基-3_甲基-1H-吼哈并[3, 2-b]比咬 -1-基]丙-1-醇 485 365.52 (2R)-2_[6- 乙基-5-(2-乙基-6-異丙基°比 啶-3-基）-3-甲基-1H 4比嘻并[3, 2-b>比咬 -1 -基]丙-醇 486 广 掌性 八 ^XV 367.49 5-(6-異丙基-2-甲氧 基吡啶-3-基）-1-[(1R)-1-（甲氧基甲 基)丙基]- 3-甲基-1H -吼嘻并[3, 2-b]°比唆 170 93966 200812588 487 /_/夂- 掌性 479· 66 6-異丙基-3-{1-[(1R)-1 -（甲氧基甲 基）丙基]-3-甲基-1H -〇比嘻并[3,2-1)>比咬 - 5-基}-N-(3-嗎琳-4 -基丙基定-2-胺 488 369.46 2 - [5 -（2-乙基-6-曱 氧基-3-吼啶基）-3, 6 -二曱基-IH-0比洛弁 [3,2-b]吡啶-1-基] -3-甲氧基-1-丙醇 489 人。 k 382.51 (2S)-2-[2-（6-乙氧 基-2-乙基σ比咬-3-基）-3-乙基-7-曱基 -5Η-吼嘻并[2, 3-b] 〇比哄-5-基]丁-1-醇169 93966 200812588 484 Xv 371.90 (2S)-2-[5-(2-Chloro-6-isopropyl-hlopenidin-3-yl)-6-ethyl-3_methyl-1H-吼哈和[3 , 2-b]biti-1-yl]propan-1-ol 485 365.52 (2R)-2_[6-ethyl-5-(2-ethyl-6-isopropyl-pyridin-3-yl )-3-methyl-1H 4 is more than 嘻[3, 2-b> than bite-1 -yl]propanol 486 broad palmity eight^XV 367.49 5-(6-isopropyl-2-methoxy Pyridin-3-yl)-1-[(1R)-1-(methoxymethyl)propyl]-3-methyl-1H-indeno[3,2-b]° 唆170 93966 200812588 487 /_/夂- palm 479· 66 6-isopropyl-3-{1-[(1R)-1 -(methoxymethyl)propyl]-3-methyl-1H-indole ratio嘻[3,2-1)> than bite- 5-yl}-N-(3-morphin-4-ylpropylidene-2-amine 488 369.46 2 - [5 -(2-ethyl- 6-decyloxy-3-acridinyl)-3,6-dimercapto-IH-0 piroxi[3,2-b]pyridin-1-yl]-3-methoxy-1-propanyl Alcohol 489. k 382.51 (2S)-2-[2-(6-ethoxy-2-ethyl σ butyl-3-yl)-3-ethyl-7-fluorenyl-5Η-吼嘻[2, 3-b] indole-5-yl]butan-1-ol

171 93966 200812588 490 OH 381.52 (3S)-3-[5-乙基-6-(6-異丙基-2-曱氧基 吡啶-3-基）-1-曱基 -1H-啦 口各并[2, 3-b] °比唆-3-基]丁-1-醇 OH (3S)-3-[5-(6_ 異丙 基-2-曱氧基吡啶-3- 491 381.52 基）-3,6-二甲基-1H- ϋ比嘻并[3, 2-b]°比唆 -1-基]戊-1-醇 / 掌性 6-氯-5-(2-乙基-6- F - η 異丙基°比咬-3-基） 492 CCC^ 403. 93 -1-[(lS)-2-氟-1 - (曱氧基甲基）乙基] -3-甲基-1H-σ比洛并 1 [3, 2-1)]>比啶171 93966 200812588 490 OH 381.52 (3S)-3-[5-ethyl-6-(6-isopropyl-2-indolylpyridin-3-yl)-1-indenyl-1H- [2, 3-b] ° than 唆-3-yl]butan-1-ol OH (3S)-3-[5-(6-isopropyl-2-oxoxypyridine-3- 491 381.52 base)- 3,6-Dimethyl-1H-indole is more than [3, 2-b] ° 唆-1-yl] pent-1-ol / palm 6-chloro-5-(2-ethyl-6 - F - η isopropyl ° ratio -3- C) 492 CCC^ 403. 93 -1-[(lS)-2-fluoro-1 -(decyloxymethyl)ethyl]-3-methyl -1H-σBiluo 1 [3, 2-1)]>

172 93966 200812588172 93966 200812588

493 391.48 (2S，3S)-3-{2 - [2-曱 氧基_4-( 1H-吼嗤-1 -基)苯基]-3, 7-二曱 基-5Η_ σ比洛并[2， 3-b]吼畊-5-基} 丁 - 2-醇 494 / 掌性 352· 48 2-（6-異丙基-2-甲基 吡啶-3-基）-5-[(lS) - 2 -甲氧基-1-曱基乙 基]-3, 7-二曱基-5H-σ比洛并[2, 3-1)]°比哄 495 436· 60 5 - (6-異丙基-2 -嗎淋 -基吼唆-3-基1 -[(1R)-1-(甲氧基甲 基）丙基]-3, 6-二甲 基-1Η- °比洛并[3， 2-bp比咬493 391.48 (2S,3S)-3-{2 - [2-decyloxy_4-(1H-indol-1-yl)phenyl]-3,7-diindolyl-5Η_ σ pylorin[ 2, 3-b]吼耕-5-yl} Butyl-2-ol 494 / palm 352· 48 2-(6-isopropyl-2-methylpyridin-3-yl)-5-[(lS ) - 2 -Methoxy-1-mercaptoethyl]-3, 7-dimercapto-5H-σpyrolo[2, 3-1)]° 哄495 436· 60 5 - (6- Isopropyl-2-oxalin-ylindole-3-yl-1-[(1R)-1-(methoxymethyl)propyl]-3,6-dimethyl-1Η-°Bilo [3, 2-bp than bite

173 93966 200812588 496 掌性 0 Ρχν 424. 59 6-異丙基_3-{1 -[(1R)-1-(曱氧基甲 基）丙基]-3-曱基-1Η -°比嘻并[3, 2-b>比咬 -5-基}_N-（3-甲氧基 丙基）吡啶-2-胺 497 fi ^〇ν 421.49 1-(2, 4-二就苯曱基） -5-（6-異丙基-2-曱 氧基σ比咬-3-基） -3, 6-二甲基-1Η-吡 咯并[3, 2-b]/比啶 498 ^Oy 362.47 4-[5-(6-異丙基-2-甲氧基吼啶-3-基） -3,6-二甲基-1H-吡 口各并[3, 2-13>比啶-1 -基]丁腈 174 93966 200812588173 93966 200812588 496 Palmity 0 Ρχν 424. 59 6-Isopropyl_3-{1 -[(1R)-1-(indolylmethyl)propyl]-3-indolyl-1Η -° 嘻And [3, 2-b> than biting -5-yl}_N-(3-methoxypropyl)pyridin-2-amine 497 fi ^〇ν 421.49 1-(2,4-dibenzoyl) -5-(6-isopropyl-2-oximeoxy σ-But-3-yl)-3,6-dimethyl-1Η-pyrrolo[3,2-b]/pyridyl 498 ^Oy 362.47 4-[5-(6-isopropyl-2-methoxyacridin-3-yl)-3,6-dimethyl-1H-pyrryl-[3, 2-13> -yl]butyronitrile 174 93966 200812588

499 500 501499 500 501

399· 53 395. 55 397.52 5-(6-異丙基-2-甲氧 基吼啶-3-基）-3, 6-二甲基-1 - (2-甲基苯 甲基）-1Η-吼咯并[3, 2-1>]°比咬 (3S)_3-{2- 乙基-3-[6-異丙基-2-（甲胺 基）吡啶-3-基]-5-甲 基-5H- °比洛并[2, 3-b]吼畊-7-基}戊 -1 一醇 1-[(lS)-2_ 乙氧基 -1-（甲氧基甲基）乙 基]-5-(2-乙基-6-甲 氧基σ比咬-3-基）-3, 6 -二甲基-1Η-σ比咯并 [3, 2-b]吡啶 175 93966 200812588 502 405. 54 3-（6-異丙基-3-{l-[(1R)_1-(甲氧基曱 基）丙基]-3, 6-二甲 基-1H- ϋ比洛并[3， 2-b ]ϋ比咬_5-基}π比咬 - 2-基）丙-2-快-1-醇 503 365.52 6-乙基-5_(6-異丙基 外匕 口定-3-基）-l-[(1R) -1 -（曱氧基曱基）丙 基]-3-曱基-1Η-吡咯 并[3, 2-b]11比咬 504 1¾ 391·48 (2S，3R)-3 - {2 - [2-甲 氧基-4-(1 Η_ϋ比峻-1-基）苯基]-3, 7-二甲 基-5Η- °比洛并[2， 3-b]吼啡-5-基} 丁 -2-醇 176 93966 200812588 505 fO 468. 59 6-乙基_5-{6-乙基 -1 - [2 -甲氧基-1 -（曱 氧基甲基）乙基]-3-甲基-1 Η-ϋ比咯弁[3， 2-b]吡啶-5-基}-2-異丙氧基終驗酸胺 506 、〆 fa 掌性 令N x\ 377.49 5-(4-異丙基-2-曱氧 基苯基）-1-[ (lS)-2-曱氧基-1-曱基乙基] - 3-甲基-1H-ϋ比嘻并 [3, 2-b]吡啶-6-甲腈 507 367. 50 (2S)-2-[6-(6-異丙 基-2 -甲氧基吡啶-3-基)-1，5-二曱基-1H-邱匕洛并[2, 3-b] °比咬 - 3-基]丁-1-醇 177 93966 200812588 OH (38)-3-[3-（2-乙基 -6-異丙基ϋ比咬-3- 508 / 380.54 基）-2,5-二曱基-5Η-°比17各并[2, 3-b]吼哄 - 7-基]戍-1-醇 OH (3R)-3-[2-(2-乙基 - 6 -異丙基0比σ定-3 - 509 366.51 基）-3,7-二甲基-511-ϋ比洛并[2, 3-b]吼哄 - 5-基]丁-1-醇 HO^( N J /Ύτ (2S)-2-[3-乙基 Ια-異 丙基-2-曱氧基 510 368.48 吡啶-3-基）-7-甲基 -5Η- °比洛并[2, 3-b] ~0’、’ r σ比哄-5-基]丙-1 -醇 178 93966 200812588 511 掌性 434. 62 6-乙基-5-(6_異丙基 -2-旅咬-1-基吡咬 -3-基）-l-[(lS)-2-甲氧基-1-甲基乙基] -3-甲基-1H-吡咯并 [3, 2-b]吼咬 512 ΗΟ^Γ_ ^5α 人。 k 368. 48 (2S)-2-[2-(6-乙氧 基-2-乙基°比σ定-3-基）-3, 7-二曱基-5Η-11比洛并[2, 3-b]ϋ比哄 -5-基]丁-1-醇 513 F 掌性 356· 44 5-[(lS)-2-氟-1-（甲 氧基甲基）乙基]-2-(6 -異丙基°比σ定-3 -基）-3,7-二甲基-5Η-0比口各并[2, 3-b]吼哄399· 53 395. 55 397.52 5-(6-Isopropyl-2-methoxyacridin-3-yl)-3,6-dimethyl-1 -(2-methylbenzyl)-1Η - 吼 并 [3, 2-1 >] ° than bite (3S) _3-{2-ethyl-3-[6-isopropyl-2-(methylamino)pyridin-3-yl]-5 -Methyl-5H- °piro[2,3-b]indole-7-yl}pentan-1-ol 1-[(lS)-2_ethoxy-1-(methoxymethyl) Ethyl]-5-(2-ethyl-6-methoxy σ than -3-yl)-3,6-dimethyl-1Η-σ-pyrolo[3,2-b]pyridine 175 93966 200812588 502 405. 54 3-(6-Isopropyl-3-{l-[(1R)_1-(methoxyindolyl)propyl]-3,6-dimethyl-1H- indolobi [3, 2-b] ϋ _ _ _ _ _ _ _ _ _ _ _ _ _ -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -3-yl)-l-[(1R) -1 -(decyloxyindolyl)propyl]-3-indolyl-1Η-pyrrolo[3,2-b]11 ratio bite 504 13⁄4 391·48 (2S,3R)-3 - {2 - [2-methoxy-4-(1 Η_ϋ比峻-1-yl)phenyl]-3,7-dimethyl-5Η- °Biluo[2 , 3-b] morphine-5-yl}butan-2-ol 176 93966 200812588 505 fO 468. 59 6-ethyl_5-{6-ethyl-1 - [2-methoxy-1 - (曱oxymethyl)ethyl]-3-methyl Base-1 Η-ϋ比弁弁[3,2-b]pyridine-5-yl}-2-isopropoxy group acetazide 506, 〆fa palmity order N x\ 377.49 5-(4-iso Propyl-2-decyloxyphenyl)-1-[(lS)-2-decyloxy-1-hydrazinoethyl]-3-methyl-1H-indole-pyrene[3,2-b Pyridine-6-carbonitrile 507 367. 50 (2S)-2-[6-(6-isopropyl-2-methoxypyridin-3-yl)-1,5-diindenyl-1H-qiu匕洛和[2, 3-b] ° ratio biting - 3-yl] butan-1-ol 177 93966 200812588 OH (38)-3-[3-(2-ethyl-6-isopropyl hydrazine bite -3- 508 / 380.54 base)-2,5-dimercapto-5Η-° ratio 17 and [2,3-b]吼哄-7-yl]nonan-1-ol OH (3R)-3- [2-(2-ethyl-6-isopropyl-0) sigma-3 - 509 366.51 yl)-3,7-dimethyl-511-indolobi[2,3-b]吼哄- 5-yl]butan-1-ol HO^(NJ /Ύτ(2S)-2-[3-ethylΙα-isopropyl-2-indolyl 510 368.48 pyridin-3-yl)-7-methyl -5Η- °Biluo[2,3-b] ~0', 'r σ 哄-5-yl]propan-1-ol 178 93966 200812588 511 Palm 434. 62 6-ethyl-5-( 6_isopropyl-2-branches-1-ylpyridin-3-yl)-l-[(lS)-2-methoxy-1-methylethyl]-3-methyl-1H- Pyrrole [3, 2-b] bite 512 ΗΟ^Γ_ ^5α person. k 368. 48 (2S)-2-[2-(6-ethoxy-2-ethyl ° σ -3--3-)-3, 7-dimercapto-5Η-11 piroxi[2 , 3-b] indole-5-yl]butan-1-ol 513 F palmity 356· 44 5-[(lS)-2-fluoro-1-(methoxymethyl)ethyl]-2 -(6-isopropyl ratio σ定-3 -yl)-3,7-dimethyl-5Η-0 than each of the groups [2, 3-b]吼哄

179 93966 200812588179 93966 200812588

514 掌性 381.52 5 -（2-乙氧基-6-異丙 基吡啶-3-基）-1-[(1R)-1 -（甲氧基甲 基）丙基]-3-甲基-1H 比嘻并[3, 2-b>比咬 515 OH k 381.52 (3R)-3-[5-(6-乙氧 基-2-乙基1^比σ定-3-基）-3, 6- 二曱基-1Η-°比17各并[3, 2-b]吼唆 -1-基]戊-1-醇 516 HO - px. 351.50 (2S)-2_[5-(2-乙基 -6-異丙基ϋ比咬-3-基）-3, 6-二曱基-1Η-口比咯并[3, 2-b]吼咬 -1-基]丙-1-醇514 palmity 381.52 5-(2-ethoxy-6-isopropylpyridin-3-yl)-1-[(1R)-1 -(methoxymethyl)propyl]-3-methyl- 1H is more than [3, 2-b> than biting 515 OH k 381.52 (3R)-3-[5-(6-ethoxy-2-ethyl 1^ than σ-3-yl)-3, 6- Dimercapto-1Η-° ratio 17 and [3, 2-b]吼唆-1-yl]pentan-1-ol 516 HO - px. 351.50 (2S)-2_[5-(2-B -6-isopropyl hydrazide is more than -3-yl)-3,6-dimercapto-1 oxime-to-mouth conjugated [3, 2-b] guanidin-1-yl] propan-1-ol

180 93966 200812588180 93966 200812588

反式-4-{2-[2-曱氧 基-4-(1Η- ϋ比峻-1 -基）苯基]-3, 7-二曱 基-5Η-吼咯并[2, 3-1)]°比〇井-5-基}環己 醇 518 519Trans-4-{2-[2-曱oxy-4-(1Η-ϋ比峻-1 -yl)phenyl]-3,7-dimercapto-5Η-吼 并[2, 3- 1)]°°〇井-5-yl}cyclohexanol 518 519

掌性 ύ 438· 61 6-異丙基-3-{1-[(lR)-l-(甲氧基甲 基）丙基]-3,6-二甲 基—1H- a比σ各并[3， 2-b] °比唆-5-基}-Ν-(3-甲氧基丙基）ϋ比咬 -2-胺 (1R，2R)-1-環丙基 -1 -{2-[2-甲氧基-4-(1H- ntb 坐-1-基）笨 基]-3,7-二甲基-5H-°比洛并[2, 3-b]吼哄 -5-基}異丙醇 181 93966 200812588Palmitic ύ 438· 61 6-isopropyl-3-{1-[(lR)-l-(methoxymethyl)propyl]-3,6-dimethyl-1H-a ratio σ [3, 2-b] ° 唆-5-yl}-Ν-(3-methoxypropyl)pyrene-bite-2-amine (1R,2R)-1-cyclopropyl-1 -{2 -[2-methoxy-4-(1H- ntb-s-yl)phenyl]-3,7-dimethyl-5H-°piro[2,3-b]吼哄-5- Isopropanol 181 93966 200812588

520 、。^Γ 395.54 5 -（2-乙氧基-6-異丙 基吼咬-3-基）-1-[(lR)-l-(曱氧基曱 基）丙基]-3, 6-二曱 基-1H-吼咯并[3, 2-b]吡啶 521 HO V N . 382.51 (2R)-2-[2-(6-異丙 基-2-曱氧基吡啶-3 -基)-3,7- 二甲基-5H-σ比咯并[2, 3-b]吼哄 - 5-基]戊-1-醇 522 掌性 405. 50 (3R)-3-{2-[2-甲氧 基-4- (1 Η- σ比峻-1 -基）苯基]-3, 7-二甲 基-5Η-吼咯并[2， 3-b] °比哄-5-基}戍 -1-醇520. ^Γ 395.54 5 -(2-Ethoxy-6-isopropylindole-3-yl)-1-[(lR)-l-(decyloxy)propyl]-3, 6-di Mercapto-1H-indolo[3,2-b]pyridine 521 HO VN . 382.51 (2R)-2-[2-(6-isopropyl-2-indolylpyridin-3-yl)-3 ,7-Dimethyl-5H-σ-pyrolo[2,3-b]indole-5-yl]pentan-1-ol 522 Palm 405. 50 (3R)-3-{2-[2- Methoxy-4-(1 Η-σ ratio -1-1 -yl)phenyl]-3,7-dimethyl-5Η-fluorenyl[2,3-b] ° 哄-5-yl}戍-1-ol

182 93966 200812588 523 掌性 367.51 6-乙基-卜[(1R)-1-(氟曱基）丙基]-5-(6-異丙基-2-甲基σ比 啶-3-基）-3-甲基-1Η -吼口各并[3, 2-1>]°比咬 524 k 382.51 (2S)-2-[3-(6-乙氧 基-2-乙基吡啶-3-基）-2-乙基-5-曱基 -5Η-吼咯并[2, 3-b] 吡畊-7-基]丁-1-醇 525 OH 381.52 (3R)-3-[5- 乙基-θα-異丙基-2 -曱氧基 口比σ定-3-基）-1 -甲基 - 1Η- nfcb 洛并[2, 3-b] 吼咬-3-基]丁-1-醇182 93966 200812588 523 Palm 367.51 6-Ethyl-Bu[(1R)-1-(fluoroindolyl)propyl]-5-(6-isopropyl-2-methylσ-pyridin-3-yl) -3-methyl-1Η -吼口[3, 2-1>]° ratio bite 524 k 382.51 (2S)-2-[3-(6-ethoxy-2-ethylpyridine-3- 2-ethyl-5-mercapto-5Η-indolo[2,3-b]pyrrol-7-yl]butan-1-ol 525 381.52 (3R)-3-[5- B Base-θα-isopropyl-2-oxooxyl group σ -3-yl)-1 -methyl- 1 Η- nfcb oxo[2,3-b] 吼-3-yl] butyl-1 -alcohol

183 93966 200812588 526 HO N / 1¾ 368.48 (2R)-2-[2-(6-乙氧 基-2-乙基吡啶-3-基）-3,7-二甲基-5H-口比洛并[2, 3-b]吼哄 - 5-基]丁-1-醇 527 、0/^ 掌性 % * N=N 364.45 5-乙基-6-{1-[as) - 2-甲氧基-1-甲基乙 基]卜3，6-二曱基-111-°比嘻并[3, 2-b]吡唆 -5-基}四嗤并[1， 5-a]11比咬 528 382.51 (2S)-2-[3-乙基 -2-(6-異丙基-2-曱氧基 吼啶-3-基）-7-曱基 -5H- 11比咯并[2, 3-b] °比哄-5-基]丁-1-醇 184 93966 200812588 529 θ&ν 380· 54 (3S)-3-[2-（2-乙基 -6-異丙基σ比咬-3-基）-3, 7-二甲基-5Η-0比咯并[2, 3-b]比哄 -5-基]戊-1-醇 530 鬼。 k 382· 51 (2S)-2-[3-（6-乙氧 基-2-乙基^比σ定-3-基）-2,5-二曱基-511-σ比洛并[2, 3_b] °比哄 -7-基]戊-1-醇 531 、广Γ 掌性 379. 54 6-乙基-5-(6-異丙基 -2-曱基吡啶-3-基） -l-[(lR)-l-(甲氧基 曱基）丙基]-3-甲基 - 1H- ^比洛并[3, 2-b] η匕咬183 93966 200812588 526 HO N / 13⁄4 368.48 (2R)-2-[2-(6-Ethoxy-2-ethylpyridin-3-yl)-3,7-dimethyl-5H-portpirol [2, 3-b]吼哄- 5-yl]butan-1-ol 527,0/^ palmity % * N=N 364.45 5-ethyl-6-{1-[as) - 2-methoxy -1--1-methylethyl]bu 3,6-dimercapto-111-° than 嘻[3,2-b]pyridin-5-yl}tetraindolo[1, 5-a]11 ratio Bite 528 382.51 (2S)-2-[3-ethyl-2-(6-isopropyl-2-decyloxyacridin-3-yl)-7-indolyl-5H- 11 ratio [2] , 3-b] ° 哄-5-yl]butan-1-ol 184 93966 200812588 529 θ&ν 380· 54 (3S)-3-[2-(2-ethyl-6-isopropyl σ ratio Bite-3-yl)-3,7-dimethyl-5Η-0 is more than [2,3-b] than 哄-5-yl]pentan-1-ol. k 382· 51 (2S)-2-[3-(6-ethoxy-2-ethyl^by sigma-3-yl)-2,5-dimercapto-511-σpyrolo[2 , 3_b] ° than 哄-7-yl] pent-1-ol 531, Γ Γ palm 379. 54 6-ethyl-5-(6-isopropyl-2-mercaptopyridine-3-yl) - L-[(lR)-l-(methoxyindolyl)propyl]-3-methyl- 1H-^Biluo[3,2-b] η匕 bite

185 93966 200812588 532 OH k 395.55 (3R)-3-[6-(6-乙氧 基-2-乙基吡啶-3-基）-5-乙基-曱基 - 1H-吡咯并[2,3-b] 吡啶-3-基]戊-1-醇 533 ^α〇 k 395. 55 (2R)-2-[6-（6-乙氧 基-2-乙基11比咬-3-基）-5-乙基-1-曱基 - 1H- °比 17各并[2, 3-b] °比咬-3-基]戊-1-醇 534 421.49 1-(2, 3-二氟苯甲 基）-5-(6-異丙基-2 -甲氧基吼啶-3-基） -3,6-二甲基-1H-吡 口各并[3, 2-b>比咬 186 93966 200812588185 93966 200812588 532 OH k 395.55 (3R)-3-[6-(6-Ethoxy-2-ethylpyridin-3-yl)-5-ethyl-indenyl-1H-pyrrolo[2,3 -b] pyridin-3-yl]pentan-1-ol 533 ^α〇k 395. 55 (2R)-2-[6-(6-ethoxy-2-ethyl 11-biti-3-yl) -5-ethyl-1-indenyl-1H- ° ratio 17 and [2, 3-b] ° ratio -3-yl] pent-1-ol 534 421.49 1-(2, 3-difluorobenzene Methyl)-5-(6-isopropyl-2-methoxyacridin-3-yl)-3,6-dimethyl-1H-pyrrole each [3, 2-b> than bite 186 93966 200812588

535 536 537535 536 537

OHOH

393· 58 380·54 394.56 (2S)-2-[5-乙基-6-(2-乙基-6-異丙基吼 啶-3-基）-1-甲基-1H -口比嘻并[2, 3-b>比咬 - 3-基]戊-1-醇 (3R)-3-[2-乙基-3-(2-乙基-6-異丙基°比 啶-3-基）-5-甲基-5H 比咯并[2, 3-b>比明1 - 7-基]丁 -1 -醇 (2R)-2-{5-乙基 -6-[6-異丙基-2-（甲胺 基）°比°定-3-基]-1-甲 基-1H-吼嘻并[2, 3 - b]吡啶-3-基}戊-1 一醇 187 93966 200812588 538 HO7V.N . 352.48 (2R)-2-[2-（2-乙基 -6-異丙基吡啶-3 -基）-3，7-二甲基-5H-口比咯并[2, 3-b]ϋ比哄 -5-基]丙-1-醇 539 、人 367.50 (2R)-2-[5-(6-異丙 基-2-曱氧基°比唆-3-基）-3，6-二曱基-1H-ϋ比略并[3, 2-b]吡咬 -1-基]丁-1-醇 540 u 掌性 HO N . 405.50 (2S，3S)-2-{2令甲 氧基-4- (1H- °比σ坐-1 -基）苯基]-3, 7-二甲 基-5Η-吼洛并[2， 3-b]吼畊-5-基}戊 - 3-醇393· 58 380·54 394.56 (2S)-2-[5-ethyl-6-(2-ethyl-6-isopropylacridin-3-yl)-1-methyl-1H-port 嘻And [2, 3-b> butyl-3-yl]pentan-1-ol (3R)-3-[2-ethyl-3-(2-ethyl-6-isopropylpyridinium-3 -yl)-5-methyl-5H pyrrolo[2,3-b> than 1,4- 1-7-yl]butan-1-ol (2R)-2-{5-ethyl-6-[6- Isopropyl-2-(methylamino)° ratio 定-3-yl]-1-methyl-1H-indolo[2,3-b]pyridin-3-yl}pentan-1-ol 187 93966 200812588 538 HO7V.N . 352.48 (2R)-2-[2-(2-Ethyl-6-isopropylpyridin-3-yl)-3,7-dimethyl-5H-oral ratio 2, 3-b] indole-5-yl] propan-1-ol 539, human 367.50 (2R)-2-[5-(6-isopropyl-2-yloxyl ratio 唆-3- ,3,6-dimercapto-1H-indole, and [3,2-b]pyridin-1-yl]butan-1-ol 540 u palmity HO N . 405.50 (2S,3S)- 2-{2 methoxy-4-(1H-° ratio σ sitting-1 -yl)phenyl]-3,7-dimethyl-5Η-吼洛和[2, 3-b]吼耕- 5-based}pent-3-ol

188 93966 200812588 541 人 392. 50 2-[(6- 乙基-5_{1-[(1S)-2- 曱氧基-1-甲基乙基]-3, 6-二甲 基-1Η- ϋ比洛并[3， 2-b ]吼咬-5-基} 0比咬 - 2-基）氧基]丙腈 542 HO : 381.52 (2S)-2-[5-(6-異丙 基-2-曱氧基吡啶-3-基）-3,6-二甲基-1H -0比洛并[3, 2-b]吼唆 -1-基]戊-1-醇 543 、人 380. 54 (2S)-2-{6-[6-異丙 基-2-(甲胺基）吼啶 -3-基]-1，5-二甲基 - 1H- °比洛并[2, 3-b] 吡啶-3-基}戊-1-醇188 93966 200812588 541 person 392. 50 2-[(6-ethyl-5_{1-[(1S)-2- methoxy-1-methylethyl]-3, 6-dimethyl-1Η- Debilozepine [3, 2-b] bite-5-yl} 0-bite-2-yl)oxy]propanenitrile 542 HO : 381.52 (2S)-2-[5-(6-isopropyl -2-decyloxypyridin-3-yl)-3,6-dimethyl-1H-0piro[3,2-b]indol-1-yl]pentan-1-ol 543, human 380 . 54 (2S)-2-{6-[6-Isopropyl-2-(methylamino)acridin-3-yl]-1,5-dimethyl- 1H- °Biluo[2, 3-b] pyridin-3-yl}pentan-1-ol

189 93966 200812588 544 \〇 人 368.48 (2S)-2_[3-(6-異丙 基-2-曱氧基吡啶-3-基）-2,5-二 甲基-5Η-口比嘻并[2, 3-b]11比哄 -7-基]丁_1-醇 掌性 (2R)-2-[2-（2-乙基 -6-異丙基吡啶-3- 545 364· 49 基）-3,7-二甲基-5H- 广〇ίν 11比咯并[2, 3-b]σ比哄 ΓΝ τ -5-基]丁醛 ΟΗ (3R)-3-{2-[6-異丙 基-2-（甲胺基）ϋ比咬 546 〇Χ^ 381·53 -3-基]-3, 7-二曱基 /ΝΓ1 -5Η- 0比 ρ各并[2, 3-b] 、人 吡畊-5-基}戊_1-醇189 93966 200812588 544 \〇人368.48 (2S)-2_[3-(6-isopropyl-2-indolylpyridin-3-yl)-2,5-dimethyl-5Η-mouth 嘻[ 2, 3-b]11 than 哄-7-yl]but-1-ol palmate (2R)-2-[2-(2-ethyl-6-isopropylpyridine-3- 545 364. 49 base -3,7-Dimethyl-5H- 广〇ίν 11 ratio 咯[2,3-b]σ ratio 哄ΓΝ τ -5-yl]butyraldehyde oxime (3R)-3-{2-[6 -Isopropyl-2-(methylamino)pyrene than 546 〇Χ^ 381·53 -3-yl]-3, 7-diindenyl/ΝΓ1 -5Η- 0 ratio ρ各[2, 3- b], human pyridin-5-yl}penta-1-ol

190 93966 200812588 547 HO l 八 ft? XX k 381.52 (2R)-2-[6-(6-乙氧 基-2-乙基σ比咬-3-基）-l， 5- 二曱基-1H-°比17各并[2, 3-b] °比σ定 - 3-基]戊-1-醇 548 f〇5 掌性 Γχ 392.46 (2S)-2-{2-[2-曱氧 基-6-(1Η-吼 w坐-l-基） 吡啶-3-基]-3,7-二甲基-5Η- ϋ比嘻并 [2,3-1>]吼啡-5-基} 丁-1-醇 549 365.52 (2S)-2-[5_ 乙基-6-(2-乙基-6-異丙基σ比 啶-3-基）-1-曱基-1Η -口比洛并[2, 3-b]吼咬 -3-基]丙-1-醇 191 93966 200812588 550 HO N . 05 382.51 (2S)-2-[2-（6-乙氧 基-2-乙基11比咬-3-基）-3, 7-二甲基-5H-吼咯并[2, 3-b]吼哄 - 5-基]戊-1-醇 551 HO : 352.48 (2S)-2-{5-[6-異丙 基-2-（曱胺基）σ比咬 -3-基]-3, 6- 二曱基 - 1Η-吼嘻并[3, 2-b] 吡啶-1_基}丙-1-醇 .0H 552 〇v 379· 55 (3R)-3-[6- 乙基-δα-乙基-6- 異丙 基 〇比 啶-3-基）-3-甲基-1Η -〇比洛并[3, 2-1)]吼咬 -1-基]丁-1-醇 192 93966 200812588190 93966 200812588 547 HO l 八 ft? XX k 381.52 (2R)-2-[6-(6-ethoxy-2-ethyl σ butyl-3-yl)-l, 5-dimercapto-1H -° ratio 17 and [2, 3-b] ° ratio σ 3-amino] pent-1-ol 548 f〇5 palm Γχ 392.46 (2S)-2-{2-[2-曱oxy -6-(1Η-吼w-l-yl)pyridin-3-yl]-3,7-dimethyl-5Η-ϋ比嘻[2,3-1>] morphine-5-yl} Butan-1-ol 549 365.52 (2S)-2-[5_ethyl-6-(2-ethyl-6-isopropyl σ-pyridin-3-yl)-1-indenyl-1Η - Orallo And [2, 3-b] 吼-3-yl] propan-1-ol 191 93966 200812588 550 HO N . 05 382.51 (2S)-2-[2-(6-ethoxy-2-ethyl 11 Specific -3-yl)-3,7-dimethyl-5H-indolo[2,3-b]indole-5-yl]pentan-1-ol 551 HO : 352.48 (2S)-2- {5-[6-Isopropyl-2-(decylamino) σ-Bis-3-yl]-3,6-dimercapto- 1Η-indolo[3,2-b]pyridine-1_ }-1-propanol. 0H 552 〇v 379· 55 (3R)-3-[6-ethyl-δα-ethyl-6-isopropylpyridin-3-yl)-3-methyl -1Η -〇比洛和[3, 2-1)]吼 bit-1-yl]butan-1-ol 192 93966 200812588

553 / 掌性 393.53 6-環丙基-5-(6-異丙 基-2-甲氧基吡啶-3-基）-1 -[US)-2-曱氧 基曱基乙基]-3-甲基-1H-吡咯并[3, 2-b]nl^ 554 、入 n V" 367· 50 (2R)-2-{2-[6-異丙 基-2-（甲胺基）吼咬 -3-基]-3, 7-二甲基 -5H-吼 π各并[2, 3-b] 吼哄-5-基} 丁-1-醇 555 HO \· 八少 k 381.52 (2S)-2-[5-（6-乙氧 基-2-乙基σ比咬-3-基）-3，6-二曱基-1Η-σ比嘻并[3, 2-b]11比°定 -1-基]戊-1-醇553 / palm 393.53 6-cyclopropyl-5-(6-isopropyl-2-methoxypyridin-3-yl)-1 -[US)-2-decyloxydecylethyl]-3 -Methyl-1H-pyrrolo[3,2-b]nl^ 554, into n V" 367· 50 (2R)-2-{2-[6-isopropyl-2-(methylamino) fluorene Bite-3-yl]-3,7-dimethyl-5H-吼π each [2, 3-b] 吼哄-5-yl} butan-1-ol 555 HO \· eight less k 381.52 (2S -2-[5-(6-ethoxy-2-ethyl σ butyl-3-yl)-3,6-dimercapto-1 Η-σ ratio 嘻[3,2-b]11 ratio定-1-yl]pentan-1-ol

193 93966 200812588 556 掌性 417.52 (1S，2R)-2-{2-[> 曱 氧基-4- (1 Η_σ比嗤-1 -基）苯基]-3, 7-二甲 基-5Η_吼略并[2, 3-b]吡畊-5-基}環己 醇 557 ΗΟ : 380.54 (2S)-2-{5_[6-異丙 基-2-（曱胺基）吡啶 -3- 基]-3, 6- 二甲基 - 1H- σ比洛并[3, 2-b] 吡啶-1-基}戊-1-醇 558 379.55 (2ΪΟ-2-[6-乙基 -5-(2-乙基-6-異丙基吡 啶-3-基）-3-甲基-1H 比洛并[3, 2-b]σ比唆 -1-基]丁-1-醇193 93966 200812588 556 Palm 417.52 (1S,2R)-2-{2-[> 曱oxy-4-(1 Η_σ 嗤-1 -yl)phenyl]-3, 7-dimethyl-5Η _ 吼 并 [2, 3-b] pyridin-5-yl} cyclohexanol 557 ΗΟ : 380.54 (2S) -2-{5_[6-isopropyl-2-(decylamino)pyridine-3 -yl]-3,6-dimethyl- 1H-σpyrolo[3,2-b]pyridin-1-yl}pentan-1-ol 558 379.55 (2ΪΟ-2-[6-ethyl-5 -(2-ethyl-6-isopropylpyridin-3-yl)-3-methyl-1H piroxi[3,2-b]σ 唆-1-yl]butan-1-ol

194 93966 200812588 559 ^/掌性 368.50 3-{6-乙基-1-[(1S) -2-氟-1-甲基乙基] -3-甲基-1Η-σ比咯并 [3,2-b]吼啶 _5-基} -6-異丙基-N-曱基〇比 啶-2-胺 560 OH 365· 52 (3R)-3-[6-(2-乙基 -6-異丙基吡啶-3-基）-l，5-二甲基-1H-ϋ比洛并[2, 3-b] 0比咬 -3-基]丁-1-醇 561 、。人 354· 46 (2R)-2-[2-(6-異丙 基-2-甲氧基吡啶-3-基）-3, 7-二甲基-5H-"比咯并[2, 3_b]U井 -5-基]丙-1-醇 562 rO \〇an^Y" 399.53 5-（6-異丙基-2-曱氧 基吼啶-3-基）-3, 6-二曱基-1 -（2-苯基乙 基）-1H-吼咯并[3, 2-b]a比咬 195 93966 200812588 上述所列舉之所有化合物可至少以NMR以及下列 LCMS方法之一者描述其性質： 方法1. HPLC設備：該等試驗係使用Waters 600系列型泵（Waters 公司出品）、Waters 996型陣列二極體偵測器（Diode Array Detector :簡稱作DAD)以及Gi Ison 215型自動取樣器 (Auto Sampler)(Gilson公司出品）予以進行。數據係使用 OpenLynx程序處理之MassLynx 4· 0軟體獲得之。 HPLC的條件：4· 6X50毫米、XTerra MS C18、5毫米的管 柱（Waters公司出品）；肝1〇光譜/秒，使用220、254奈 米之波長；流逮為4·0毫升/分鐘；注入體積為1至1(F微 升1);梯度條件-移動相A為含有〇· 05%蟻酸之95%水與 5%甲醇之溶液；移動相B為含有0· 025%蟻酸之95%甲醇與 5%水之溶液； 梯度：194 93966 200812588 559 ^/ Palm 368.50 3-{6-Ethyl-1-[(1S)-2-fluoro-1-methylethyl]-3-methyl-1Η-σ ratio [3, 2-b]Acridine-5-yl}-6-isopropyl-N-indolylpyridin-2-amine 560 OH 365· 52 (3R)-3-[6-(2-ethyl-6 -Isopropylpyridin-3-yl)-l,5-dimethyl-1H-indolobi[2,3-b] 0 is more than benzyl-3-butan-1-ol 561. 354. 46 (2R)-2-[2-(6-isopropyl-2-methoxypyridin-3-yl)-3,7-dimethyl-5H-" 3_b]U Well-5-yl]propan-1-ol 562 rO \〇an^Y" 399.53 5-(6-isopropyl-2-decyloxyacridin-3-yl)-3, 6-di Mercapto-1 -(2-phenylethyl)-1H-indolo[3,2-b]a ratio bite 195 93966 200812588 All of the compounds listed above can be described at least by NMR and one of the following LCMS methods Its properties: Method 1. HPLC equipment: These tests use Waters 600 series pump (Waters company), Waters 996 array diode detector (Diode Array Detector: DAD for short) and Gi Ison 215 type automatic The sampler (Auto Sampler) (produced by Gilson) was carried out. The data was obtained using the MassLynx 4.0 software handled by the OpenLynx program. HPLC conditions: 4·6×50 mm, XTerra MS C18, 5 mm column (produced by Waters); liver 1 〇 spectrum/second, using a wavelength of 220, 254 nm; flow capture of 4·0 ml/min; The injection volume is 1 to 1 (F microliter 1); the gradient condition - mobile phase A is a solution containing 95% water and 5% methanol of 〇·05% formic acid; mobile phase B is 95% containing 0. 025% formic acid. a solution of methanol and 5% water; gradient:

時間（分鐘） 0/〇B 0 5 01 5 1·0 100 Μ) 100 2· 1 5 MS設備··該等LC-MS實驗係使用Waters ZMD II質譜儀予 以進行。 MS 條件· ％ 嘴灑正離子化（eiectr〇Spray ionization) ’ 毛細管電壓（capi 1 iary v〇Hage)為 3· 5 千 196 93966 200812588 伏（kV);進樣錐電塵（cone voltage)為30伏特（V);溶媒 揮散溫度（desolvation temperature)以及離子源溫度 (source temperature)分別為 250°C 與 10CTC ;使用掃瞄時 間0· 5秒以及内掃猫延遲（inter scan del ay) 0· 1分鐘之 質量範圍120至800。 方法2. 流體注入條件： 使用Perkin Elmer HPLC系統（拖曳式系列200型之微 m 量LC泵（micro LC pumps):泵A以及泵B，具有系列200 型自動取樣器）進行流動注入。該移動相為85%甲醇（泵B) 與15%水（泵A)之組合。該流速為1. 〇毫升/分鐘；而該注 入體積為3微升。 MS設備：該等LC-MS實驗係使用Sciex 150MA質譜儀予以 進行。 MS條件：離子源為加熱式霧化器（Heated Nebul izer)(大 _ 氣壓力化學游離（atmosphere pressure chemical ionization :簡稱作APCI))。該質量範圍為100至looo 原子質量單位（atomic mass unit :簡稱a· m· u·)。正離子 模式和負離子模式兩者皆為適用者。就正離子模式而言， 該霧化器電流為2· 0毫安培（mA)且該溫度為3501。該霧 化氣體為10而且該氣簾氣體（Curtain gas)為12。該去叢 集電位（declustering potential)為 30 伏特（V)。該聚焦 電位（Focusing potential)為200伏特（V)，而該入射電位 (entrance potential)為-10伏特（V)。就負離子模式而 93966 197 200812588 言’該霧化器電流為-2· 0毫安培（mA)且該溫度為35(TC。 該霧化氣體為10而且該氣簾氣體為12。該去叢集電位為 -30伏特（V)。聚焦電位為—200伏特（V)，而該入射電位為 10伏特（V)。 方法3. HPLC設備：HP1100型泵、具有220奈米波長之HP1100 UV 4貞測器、躍進技術（Leap Techno logy)之HTS/PAL自動取樣 擊器，由Micromass Ma獲得數據。 HPLC 的條件：Synergi 2U HYDR0-RP 20x4· 0 毫米的管柱， 流速為1· 0毫升/分鐘，注入體積為5微升。 梯度條件：先以含〇· 1%蟻酸之1〇至90%乙腈水溶液進行 3分鐘’之後再用1〇0%乙腈進行，終止於5分鐘。Time (minutes) 0/〇B 0 5 01 5 1·0 100 Μ) 100 2· 1 5 MS equipment · These LC-MS experiments were carried out using a Waters ZMD II mass spectrometer. MS condition · % eiectr〇Spray ionization ' Capillary voltage (capi 1 iary v〇Hage) is 3 · 5 thousand 196 93966 200812588 volts (kV); injection cone dust (cone voltage) is 30 Volt (V); solvent desolvation temperature and source temperature are 250 ° C and 10 CTC respectively; use scan time 0.5 seconds and inter scan del ay 0 · 1 The mass range of minutes is 120 to 800. Method 2. Fluid Injection Conditions: Flow injection was performed using a Perkin Elmer HPLC system (drag-type Series 200 micro LC pumps: Pump A and Pump B with a Series 200 autosampler). The mobile phase is a combination of 85% methanol (pump B) and 15% water (pump A). The flow rate was 1. 〇 ml/min; and the injection volume was 3 μl. MS equipment: These LC-MS experiments were performed using a Sciex 150MA mass spectrometer. MS conditions: The ion source is a Heated Nebulizer (atmosphere pressure chemical ionization (abbreviated as APCI)). The mass range is from 100 to looo atomic mass unit (abbreviated as a·m·u·). Both positive ion mode and negative ion mode are suitable. In terms of positive ion mode, the nebulizer current is 2.0 milliamperes (mA) and the temperature is 3501. The atomizing gas was 10 and the curtain gas was 12. The declining potential is 30 volts (V). The Fosing potential is 200 volts (V) and the entrance potential is -10 volts (V). In the negative ion mode, 93966 197 200812588 says that the atomizer current is -2.0 milliamperes (mA) and the temperature is 35 (TC. The atomizing gas is 10 and the curtain gas is 12. The de-cluster potential is -30 volts (V). The focus potential is -200 volts (V), and the incident potential is 10 volts (V). Method 3. HPLC equipment: HP1100 pump, HP1100 UV 4 detector with 220 nm wavelength , Leap Technology's HTS/PAL automatic sampler, obtained from Micromass Ma. HPLC conditions: Synergi 2U HYDR0-RP 20x4 · 0 mm column, flow rate of 1.0 mL / min, injection The volume was 5 microliters. Gradient conditions: firstly carried out with 1% to 1% of formic acid in 1% to 90% aqueous acetonitrile for 3 minutes' followed by 1% 0% acetonitrile and terminated for 5 minutes.

MS 設備：Micromass LCT-TOF MS MS條件：掃瞄m/z為100至1200、毛細管電壓為3000r伏 特（V);進樣錐電壓（c〇ne v〇itage)為25伏特〇〇 ;溶媒揮 _散溫度為200°C而離子源溫度為100°C。 沒療方 該等式I之化合物及鹽類（較佳為表I)係有用於治療 各種包括情感性疾病、焦慮症、壓力相關性疾病、飲食失 調症以及藥物成瘾（drug addiction)之病症。因此該等式 ί之化合物及鹽之各者皆可用於製造治療上述此等病症用 之藥劑。 情感性疾病包括所有型態之憂#症（depression)、雙 極性情感疾病（bipolar disorder)、循環精神病 198 93966 200812588 (〇7(：1〇让7111丨&)以及輕鬱症（(1乂3让7111丨3)。焦慮症包括廣泛 性焦慮症（general ized anxiety disorder)、恐慌症（panic disorder)、恐懼症（Phobias)以及強迫症（OBSESSIVE COMPULSIVE DISORDER :簡稱OCD)。該等式I之化合物及 鹽類（較佳為表I)係有用於治療情感性疾病以及焦慮症之 症狀。該等症狀包括增強的覺醒、增強的快速動眼期（Rapid Eye Movement :簡增作REM)密度以及相關的睡眠方面的疾 病（例如，失眠症）和皮膚性病症（dermatologic m conditions)包括異位性皮炎（atopic dermatitis)、蓴麻 療（urticaria)以及牛皮癖（psoriasis)。 壓力相關性疾病包括創傷後壓力心理障礙症（Post-traumatic stress disorder :簡稱作 PTSD)、出血性壓力 病症（hemorrhagic stress)、壓力所引發之精神病發作 (stress-induced psychotic episodes)、心理社會侏儒症 (psychosocial dwarfism)、壓力性頭痛（stress _ headaches)、壓力所引發之免疫系統之疾病（stress- induced immune systems disorders)(例如，壓力性發熱 以及與壓力有關之睡眠疾病）。 飲食失調症包括神經性厭食症（anorexia nervosa)、 神經性暴食症（bulimia nervosa)以及肥胖症（obesity)。 本文中所提供之該等化合物亦有用於治療（例如，對症 治療法（symptomatic treatment))各種神經性疾病，其包 括上核麻痒症（supranuclear palsy)、AIDS相關之癡呆症 (dementias)、多發梗塞性老年癡呆症（multiinfarct 199 93966 200812588 dementia)、神經退化性病變（neurodegenerative disorders)例如阿滋海默症（Alzheimer’s disease)、帕 金森症（Parkinson’s disease)以及亨丁頓舞蹈症 (Huntington’s disease)、頭部外傷、脊髓外傷、局部缺 血性神經元損傷（ischemic neuronal damage)、肌萎縮性 脊聽侧索硬化症（amyotrophic lateral sclerosis)、疼痛 方面的疾病諸如纖維肌痛症（fibromyalgia)以及癲癇 (epilepsy) ° ® 此外該等式I之化合物及鹽類（較佳為表I)還用於治 療（例如，對症治療法）數種消化道疾病、心血管疾病、荷 爾蒙性、自體免疫性以及發炎性病症。此等病症包括激躁 性結腸症（irritable bowel syndrome (IBS))、潰瘍、克 隆氏症（Crohn’s disease)、結腸過敏（spastic colon)、 腹丨寫、手術後腸閉塞（post operative ilius)以及與精神 病理失調或壓力有關之結腸性過敏（co 1 on i c _ hypersensitivity);高血壓、心跳過速、心臟衰竭 (congestive heart failure)、不孕症以及假性低曱狀腺 功能症（euthyroid sick syndrome);以及與類風濕性關節 炎（rheumatoid arthritis)、骨性關節炎 (osteoarthritis)、疼痛、氣喘、牛皮癖以及過敏症有關 或由上述該等症狀所引起的發炎性病症。 在與異常的CRF濃度有關之動物疾病的治療中，該等 式I之化合物及鹽類（較佳為表I)亦用作CRF1受體的調節 劑。此等病症包括豬的緊迫敏感綜合症候群（Pore i ne 200 93966 200812588 stress syndrome:簡稱作 PSS)、牛隻運輸熱（b〇vine shipping fever)、馬的陣發性心房顫動（equine paroxysmal fibrillation)以及由雞分娩、綿羊偏向壓力 (sheering stress in sheep)或與人和動物（狗）互動有關 的壓力、心理社會侏儒症以及血糖過低（hyp〇glycemia)所 引發之官能障礙。 可投予該等式I之化合物（較佳為表I)的典型受試者 擊包括哺乳類動物，較佳為靈長類動物，更佳者為人類。就 獸醫方面施用而言，寬廣地各種受試者皆適合使用，例如 家畜如牛、綿羊、山羊、乳牛、豬等；家禽如雞、鴨、鵝、 火雞等；以及其他被馴養的動物，尤其是寵物如狗和貓。 就診斷或研究方面施用而言，寬廣地各種哺乳類動物為皆 為適用之受試者，其包括齧齒目動物（例如小鼠、大鼠、倉 鼠）、兔子、靈長類動物以及豬，例如經同系繁殖之豬等。 除此之外，就活體外試驗wtro)的應用而言，例如活 _體外的診斷和研究施用而言，體液（例如血液、血漿、血清、 透明的腦脊騎液（(：61^]：)]：〇叩11^1『111;[(1:簡稱作08卩）、淋 巴’夜、細胞間質液（cellular interstitial fluid)、水樣 液（aqueous humor)、唾液、滑液（synovial fluid)、排泄 物或尿液））以及上述受試者的細胞與組織樣本皆適合使 用。 本文中所提供之該等化合物亦用作測定該等測試化合 物（例如’具潛力之醫藥）與CRF受體結合之能力之標準品 和試劑。 201 93966 200812588 本文中所提供之該等標記化合物亦用作正子放射型電 月包辦層攝影（Positron Emission Tomography:簡稱作 PET ) 成像用或單光子放射斷層掃瞄（Single Photon EmissionMS equipment: Micromass LCT-TOF MS MS conditions: scan m/z is 100 to 1200, capillary voltage is 3000 rV (V); injection cone voltage (c〇ne v〇itage) is 25 volts 溶; solvent The _ dispersion temperature was 200 ° C and the ion source temperature was 100 ° C. Compounds of the formula I and salts (preferably Table I) are useful in the treatment of a variety of conditions including affective disorders, anxiety disorders, stress related disorders, eating disorders, and drug addiction. . Thus, each of the compounds and salts of the formula can be used in the manufacture of a medicament for the treatment of such conditions. Affective diseases include all types of depression, depression, bipolar disorder, circulatory psychosis 198 93966 200812588 (〇7(:1〇让7111丨&) and mild depression ((1乂3) Let 7111丨3). Anxiety disorders include generalized anxiety disorder, panic disorder, phobias, and obsessive-compulsive disorder (OBSESSIVE COMPULSIVE DISORDER: OCD for short). And salts (preferably Table I) are used to treat symptoms of affective disorders and anxiety disorders, including enhanced arousal, enhanced rapid eye movement (Rapid Eye Movement: REM) density, and related Sleep-related diseases (eg, insomnia) and dermatologic m conditions include atopic dermatitis, urticaria, and psoriasis. Stress-related diseases include post-traumatic stress. Post-traumatic stress disorder (PTSD), hemorrhagic stress, stress-induced psychosis Stress-induced psychotic episodes, psychosocial dwarfism, stress _ headaches, stress-induced immune systems disorders (eg, stress-induced fever and Stress-related sleep disorders. Eating disorders include anorexia nervosa, bulimia nervosa, and obesity. The compounds provided herein are also useful in therapy (eg, Symptomatic treatment of various neurological diseases, including supranuclear palsy, AIDS-related dementias, multiple infarct dementia (multiinfarct 199 93966 200812588 dementia), neurodegeneration Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, head trauma, spinal cord trauma, ischemic neuronal damage ( Ischemic neuronal damage) Amyotrophic lateral sclerosis, pain-related diseases such as fibromyalgia and epilepsy ° ® In addition, the compounds and salts of the formula I (preferably Table I) are also used For treatment (eg, symptomatic treatment) several digestive tract diseases, cardiovascular diseases, hormonal, autoimmune and inflammatory conditions. These conditions include irritable bowel syndrome (IBS), ulcers, Crohn's disease, spastic colon, abdominal hernia, post operative ilius, and mental Pathological disorder or stress-related colonic hypersensitivity (co 1 on ic _ hypersensitivity); hypertension, tachycardia, congestive heart failure, infertility, and euthyroid sick syndrome And inflammatory conditions associated with or caused by rheumatoid arthritis, osteoarthritis, pain, asthma, psoriasis and allergies. In the treatment of animal diseases associated with abnormal CRF concentrations, the compounds of the formula I and salts (preferably Table I) are also useful as modulators of the CRF1 receptor. These include the pig's urgent sensitive syndrome (Pore i ne 200 93966 200812588 stress syndrome: PSS for short), bovine transport fever, equine paroxysmal fibrillation of the horse, and A dysfunction caused by chicken labor, sheering stress in sheep, or interactions with humans and animals (dogs), psychosocial dwarfism, and hypoglycemia. A typical subject to which a compound of the formula I, preferably Table I, can be administered includes mammals, preferably primates, and more preferably humans. For veterinary applications, a wide variety of subjects are suitable for use, such as livestock such as cattle, sheep, goats, cows, pigs, etc.; poultry such as chickens, ducks, geese, turkeys, etc.; and other domesticated animals, Especially pets such as dogs and cats. For diagnostic or research application, a wide variety of mammals are suitable subjects, including rodents (eg, mice, rats, hamsters), rabbits, primates, and pigs, such as Pigs of the same breed. In addition to this, in the case of the application of the in vitro test (wtro), for example, in vitro and in vitro administration, body fluids (for example, blood, plasma, serum, transparent cerebrospinal fluid ((:61^):) ]:〇叩11^1『111;[(1: referred to as 08卩), lymphatic night, cellular interstitial fluid, aqueous humor, saliva, synovial fluid , excreta or urine)) and the cell and tissue samples of the above subjects are suitable for use. The compounds provided herein are also useful as standards and reagents for determining the ability of such test compounds (e.g., 'potential drugs) to bind to CRF receptors. 201 93966 200812588 The labeled compounds provided herein are also used as Positron Emission Tomography (PET) imaging or single photon emission tomography (Single Photon Emission).

Computerized Tomography :簡稱作 SPECT)用之追蹤劑。 尤有甚者，本文中所提供之該等化合物係有用於驗證 在細胞或組織樣本中有CRF受體存在。此驗證係藉由製備 複數個相配的（matched)細胞或组織樣本而予以進行，其中 修至少一個相配的細胞或組織樣本係製備成實驗樣本而其中 至少一個相配的細胞或組織樣本係製備成對照組樣本。該 實驗樣本係藉由下述方式製備：使至少一個先前未與任何 本文中所提供之化合物或鹽接觸之相配的細胞或組織樣本 與貫驗溶液接觸（於允許細胞或組織樣本中的CRF結合至 CRF受體之條件下）該實驗溶液包含具有第一量測莫耳濃 度之選定化合物或鹽的可偵測標記製劑（detectaM” labeled preparation)之。該對照組樣本係以相似於該實 _驗樣本之方法予以製備並將該對照組樣本培育於含有相^ 成分但復含有比第一量測莫耳濃度更大莫耳濃度之本文中 所提供之相同的化合物或鹽之未標定製劑的實驗溶液中。 之後將該等實驗樣本與對照組樣本予以清洗以移除未 結合之可偵測標記化合物。然後量測結合至各樣本中之可 偵測標記化合物殘留量並比較該等實驗樣本盥對昭组 中可偵測標記化合物之量。從比較中顯示，在清洗過S杏 驗樣本之至少-者中所制到的可制標記量係大於任^ 清洗過的對照組樣本之至少一者中所偵測到之量，這證實 93966 202 200812588 在該實驗樣本中有CRF受體存在。 用於此私序中之可债測標記化合物可使用任何可偵測 到的標記（例如，輻射性標記、生物性標靶（例如生物素（其 可藉由與可偵测標記之抗生物素蛋白之結合而予以偵 測））、酵素（例如，鹼性磷酸酵素（alkaline 汕0SphataSe)、半乳糖甘酵素（beta galactosidase)或該 等可在比色試驗法（col〇rimetric assay)中偵測到活性之 之酵素）或直接或非直接螢光性之標記）予以標記之。當組 織切片係用於此程序中並且該可侧標記化合物為輕射性 標記者’則該經鍵結、標記之化合物可以放射線自動顯影 债，以產生放射線自動顯影像。使用放射線自動顯影時， 該實驗樣本與對照組樣本中的可㈣標記之量可由觀察該 放射線自動顯影像以及比較該等放射線自動顯影的曝:密 度予以量測。 本發明亦關於抑制CRF與CRF受體（尤其*CRF1受體） 結合之方法’該方法涉及使含有本文中所提供之化合物之 溶液與表現CRF受體之細胞接觸，其中存在溶液中之化合 物的濃度需足以於活體外抑制CRF結合至CRF受體。此^ 法包括於活體内（h 抑制CRF結合至crf受體，例 如，於患者中給予足以於活體内抑制CRF結合至crf受體 的量的，等式I之化合物或鹽（較佳為表υ。在一具體例 中，該等方法係有用於治療與過高的CRF濃度有關之生理 障礙（Physi0l0gical disorders)。於活體外足以抑制⑽ 結合至CRF受體之化合物含量可輕易地由⑽受體結合試 93966 203 200812588 驗（見於，例如，實施例7)予以決定或由使用CRF受體的 功能性試驗（functional assay)(例如，實施例6的CRF 受體活性的標準試驗）所測定之IC5〇而決定。用於測定活體 外結合之該等CRF受體可由各種來源而獲得，例如由能自 然表現CRF受體之細胞（例如IMR32細胞）或由表現選殖之 人體CRF受體之細胞而獲得。 本發明亦有關改變CRF受體活性之方法，該方法包括 使表現該等受體之細胞暴露於有效量之本文所提供之化合 胃物中，其中存在溶液中之化合物的濃度需足以於活體外具 體改變該表現CRF受體的細胞對應於CRF的訊息傳導活 性。用於此目的之較佳細胞為那些能表現高濃度CRF受體 之細胞（即，等於或大於在分化之IMR-32人類神經胚細胞 瘤細胞（IMR-32 human neuroblastoma cel 1)中所發現的每 細胞的CRF1受體之數量），對於測試改變CRF1受體活性所 需之化合物濃度而言，較佳者為使用IMR-32細胞。此方法 ❿包括改變活體内CRF受體的訊息傳導活性，例如，於患者 中給予一定量之該等式I之化合物及鹽（較佳為表I)，該 量係足以於活體外改變該表現CRF受體的細胞對應於CRF 的訊息傳導活性。足以於活體外改變CRF受體對應於CRF 的訊息傳導活性之化合物含量亦可經由CRF受體媒介的訊 息傳導（CRF receptor mediated signal transduction) 之試驗而決定，例如，於試驗中，CRF結合至細胞表面的 CRF受體會致使報導基因表現（reporter gene expression) 產生變化。 204 93966 200812588 本發=有_於治療對CRF受體調節有反應之疾病 "έ 失5周症、焦慮症、壓力相關性疾病）的經包f 7:組成物。該經包裳之醫藥組成物包括容納有劑量單= (含有治療有效量之至少—種式！化合物或鹽（較^立 之谷器m療患者巾對贈受_節有反應之疾病^ 使用說明書。 、届之 ifcA敘述以及化Computerized Tomography: referred to as SPECT). In particular, the compounds provided herein are useful for verifying the presence of CRF receptors in cell or tissue samples. The verification is carried out by preparing a plurality of matched cells or tissue samples, wherein at least one matched cell or tissue sample is prepared as an experimental sample and at least one of the matched cells or tissue samples is prepared. Control sample. The experimental sample is prepared by contacting at least one cell or tissue sample that has not previously been contacted with any of the compounds or salts provided herein with a test solution (allowing CRF binding in a cell or tissue sample) The test solution comprises a detectaM labeled preparation having a first measured molar concentration of the selected compound or salt to the CRF receptor. The control sample is similar to the actual _ The method of preparing a sample is prepared and the control sample is incubated with an unlabeled custom compound containing the same compound or salt as provided herein, which contains a phase component but a molar concentration greater than the first molar concentration. In the test solution, the test sample and the control sample are then washed to remove the unbound detectable labeled compound, and then the detectable labeled compound residue bound to each sample is measured and compared.量 量 昭 昭 昭 昭 昭 昭 昭 昭 昭 昭 昭 昭 昭 昭 昭 昭 昭 昭 昭 昭 昭 昭 昭 昭 昭 昭 昭 昭 昭 昭 昭 昭 昭 昭 昭The amount is greater than the amount detected in at least one of the cleaned control samples, which confirms the presence of CRF receptors in the experimental sample 93966 202 200812588. The bond detectable marker used in this private sequence The compound can use any detectable label (eg, a radioactive label, a biological target (eg, biotin (which can be detected by binding to a detectably labeled avidin)), an enzyme (eg, alkaline phosphatase (alkaline 汕0SphataSe), beta galactosidase or such enzymes that detect activity in a col〇rimetric assay) either directly or indirectly The fluorescent label is marked. When the tissue section is used in this procedure and the labelable compound is a light-labeling marker', the bonded, labeled compound can be automatically developed by radiation to generate radiation. Automatic image display. When using automatic radiation development, the amount of the (4) mark in the sample of the experimental sample and the control group can be automatically observed by the observation of the radiation and the radiation is compared. Exposure to Dynamic Development: Density is measured. The present invention also relates to a method of inhibiting the binding of CRF to a CRF receptor (especially *CRF1 receptor). The method involves reacting a solution containing a compound provided herein with a CRF receptor. Cell contact, wherein the concentration of the compound present in the solution is sufficient to inhibit CRF binding to the CRF receptor in vitro. This method is included in vivo (h inhibits CRF binding to the crf receptor, for example, in a patient, sufficient for living A compound or salt of the formula I, preferably in the form of an internal inhibition of the binding of CRF to the crf receptor. In a specific example, the methods are useful for treating physiological disorders associated with excessive CRF concentrations ( Physi0l0gical disorders). The amount of the compound sufficient to inhibit (10) binding to the CRF receptor in vitro can be easily determined by (10) receptor binding test 93966 203 200812588 (see, for example, Example 7) or by functional test using a CRF receptor (functional The assay (for example, the standard test for CRF receptor activity of Example 6) is determined by IC5. The CRF receptors for determining the in vitro binding can be obtained from a variety of sources, for example, from cells which naturally express the CRF receptor (e.g., IMR32 cells) or from cells which express the human CRF receptor. The invention also relates to a method of altering the activity of a CRF receptor, the method comprising exposing cells exhibiting said receptor to an effective amount of a compounded stomach provided herein, wherein the concentration of the compound in the solution is sufficient to be in vitro Specifically, the cells expressing the CRF receptor correspond to the signaling activity of CRF. Preferred cells for this purpose are those which exhibit high concentrations of CRF receptors (i.e., equal to or greater than those found in differentiated IMR-32 human neuroblastoma cel 1). The number of CRF1 receptors per cell) is preferably IMR-32 cells for testing the concentration of the compound required to alter the activity of the CRF1 receptor. The method comprises the step of altering the signaling activity of a CRF receptor in vivo, for example, administering to a patient an amount of a compound of the formula I and a salt (preferably Table I) sufficient to alter the expression in vitro. The cells of the CRF receptor correspond to the signaling activity of CRF. The amount of the compound sufficient to in vitro to alter the CRF receptor signaling activity corresponding to CRF can also be determined by a CRF receptor mediated signal transduction assay, for example, in the assay, CRF binds to the cell. Surface CRF receptors cause changes in the reporter gene expression. 204 93966 200812588 The present invention is a composition of a disease that is responsive to the treatment of CRF receptor modulation "έ5 weeks of illness, anxiety, stress-related disease. The pharmaceutical composition of the package includes the dosage form = (containing at least a therapeutically effective amount of the formula! Compound or salt (compared to the disease of the patient) Manual, the ifcA narrative and

•…本文中之該等化合物—般係使用標準命名法描述。片 浯視需要經取代”意指一基團可未經取代或在任何可行的 7個或多個位置上，典型地在卜2、3、4或5個位置上， 以一個或多個適合之如下文中所揭露之該等取代基予以取 代。適合的取代基包括，例如，鹵素、氰基、胺基、經基、 硝基、疊氮基、曱醯胺基、—c〇〇H、SO?·2、烷基（例如， 匕-(：8烷基）、烯基（例如，C2—Cs烯基）、炔基（例如，匕一^ 炔基）、烷氧基（例如，Cl—Cs烷氧基）、烷基醚（例如，&一G _烷基醚）、烷基硫基（例如，Cl—G烷基硫基）、鹵烷基（例如， Ci-C8鹵烷基）、羥烷基（例如，Ci-C8羥烷基）、胺烷基（例如， Ci-G胺烷基）、鹵烷氧基（例如，Ci-C8鹵烷氧基）、烷醯基 (例如，C!-C8烧醯基）、烧酮（例如，Cl—C8^_)、烷醯氧基 (例如，C!-C8烧酿氧基）、院氧基幾基（例如，Cl—C8烷氧基 羰基）、單-和二-（G-c8烧基）胺基、單-和二-(Cl—C8烷基） 胺基C!-C8烷基、單-和二-（C!_C8烷基）曱醯胺基、單—和二 -（Ci-Cs烧基）％隨胺基、燒基亞續醯基（例如，Ci-Cs烧基亞 磺醯基）、烷基磺醯基（例如，C!-C8烷基磺醯基）、芳基（例 205 93966 200812588 如，苯基）、芳烷基（例如，（a—Cu芳基）Ci_C8烷基，如苯 甲基以及苯乙基）、芳氧基（例如，Ce-Ci8芳氧基如苯氧基）、 方烷氧基（例如，（C^Cu芳基）c〗-C8烷氧基）及/或3-至8-員的滩環基例如，香豆素基、喹嚇基、。比σ定基、吼哄基、 山疋基、呋喃基、吡咯基、噻吩基、嗟唑基、噚唑基、咪 生基弓丨木基、本并σ夫喃基、苯并嗔峻基、四氫n夫π南基、 四氫吡喃基、哌啶基、N-嗎啉基或吡咯啶基。於本文中所 鲁提供之該等式之某些基團係視需要使用1至3個、1至4 個或1至5個各自獨立選定之取代基予以取代。 、不位於兩字母或符號之間的破折號（"-，，）係用於指出 取代基之附接點。例如，-c〇NH2係透過碳原子附接。 本文中所使用者，烧基"意指包括分支鏈與直鏈兩 =之飽和脂肪族烴基，並且該等基團中具體指明，其具有 石反原子的明確數目。因此，如本文中所用到的術語，，Ci—G 烷基’’意指具有1至6個碳原子之烷基。該等烷基包括具有 _ 1至8個碳原子（Cl —C8烧基）、具有1至6個碳原子（Ci—Ce 烷基）以及具有i至4個碳原子（Ci-C4烷基）之基團，例如 甲基乙基、正丙基、異丙基、正丁基、第二丁基、第二 丁基、戊基、2-戊基、異戊基、新戊基、己基、2—己基、 3己基以及3-甲基戊基。在某些實施例中，較佳烷基為 曱基、乙基、丙基、丁基以及3一戊基。 … 術居i素”意指氟、氣、溴以及蛾。 ”雜原子”為除了碳以外之原子，例如氧、硫或氮。 術語“芳基，，意指含有至少一個芳香環之基團。該等 93966 206 200812588 方基之例子包括苯基以及萘基。 術語”雜芳基"意指含有至少一個且 之芳香環。若雜芳基中的 = 4個雜原子 該等雜原子不會彼此相鄰;較= = ,1時，則 子的總數係不超過卜2或心方‘ ：s:〇原 ，基、㈣、嫩It:基之例子包括心定基、咬 基、嗟吩基、嗟、三:基:fi:井基、味哇基、-哇 竭以及5,6,7,8—四氫異噎琳。 比各基、 對具有不對稱中心的# f ^ Α , 有其他特別的說明之外應瞭解到（除非 物及其混合物。該等含有^對口 Α盖所有的光學異構 活性报W . 不對稱取代基之化合物可呈光學 "optically actlve f〇rms)或外消旋形式 ?:所周知者，例如藉由外消旋形式(外消旋物心:項 =對稱合成或藉由光學活性起始物質合成等。::旋 物㈣析可藉由，例如，習知方法如藉由在拆分劑 #r=rn^agent)存在下形成結日日日或藉由層析法（例如， 能液相層析管柱（㈤ral_HPLC，而 形式α二此之Γ、’該等具有碳—碳雙鍵之化合物可出現2 :工orms形式（E_f_s)，若無其他 明，則其所具有之化合物的異構物皆包含於本發明中該 处之化口物可月匕存在各式各樣的互變異構體(細士〇阶二 orms)戶斤列舉出的化合物並沒有限制於任何一種特定的 93966 207 200812588 互變體，但並沒有要涵蓋所有 ^^ ^ ^^ 吓’幻互、交異構體。烯烴的許多 丈= 雙料，亦可存在於本文中所描述之化 :物二二斤有此等適合的異構物係皆為本發明所預期 t專本㈣之順式和反式幾何⑽物化合物係被描述 、'且可由该專異構物的混合物或分離的異構體單離出來。 :列舉之該等化合物係預計進—步涵蓋—個或多個以同位 '、曰代之原子（即，具有相同原子數但不同質量數之原 子)。作為，等同位素的例子並沒有特別的限制，如氫的同 位素包括氘和氣以及碳的同位素包括llc、13。以及"c。 如本文中所使用者，“醫藥上可接受之鹽類”意指在 所揭露的料化合物的衍生物巾，該母化合物係藉由製成 無毒性的酸鹽或驗鹽而改質者，且進—步意指該等化合物 以及該等鹽類之醫藥上可接受之溶劑化物。該等醫藥上可 接受之鹽類之例子包括，但不限於，含⑽性殘基（如胺） 之無機或有機酸鹽；含有酸性殘基（如羧酸）之鹼金屬或有 機鹽類，等。該等醫藥上可接受之鹽類包括本發明化合物 所形成（例如以無毒性之無機或有機酸）之習知無毒性之鹽 類以及四級銨鹽。例如，該等習知無毒性之酸鹽包括衍生 自無機酸’例如氫氣酸、氫溴酸、硫酸、續胺酸、鱗酸、 硝酸等之該等無毒性之酸鹽；以及由有機酸製備的鹽類， 例如乙酸、丙酸、琥珀酸、甘醇酸、硬脂酸、乳酸、蘋果 酸、酒石酸、檸檬酸、抗壞血酸、雙羥萘酸、馬來酸、羥 馬來酸、苯乙酸、麩胺酸、苯甲酸、水揚酸、曱磺酸、胺 基苯磺酸、2-乙醯氧基苯曱酸、富馬酸、曱苯磺酸、曱烷 208 93966 200812588 磺酸、乙烷二磺酸、草酸、羥乙基磺酸、H00C-(CH2)n-C00H 其中η為0至4,等。該等本發明之醫藥上可接受之鹽類 可由含有酸或鹼部分體之母化合物以習知化學方法合成。 一般來說，此等鹽類可由此等化合物的游離酸形式與等當 量比（stoichiometric amount)的適當之驗類（例如，納、 鈣、鎂或鉀的氫氧化物、碳酸鹽、碳酸氫鹽等）反應，或 可由此等化合物的游離鹼形式與等當量比的適當之酸類反 應，予以製備。此等反應係典型在水或有機溶劑，或其兩 @者的混合物中進行。通常，非水性的介質例如醚、乙酸乙 酯、乙醇、異丙醇或乙腈為較佳者，該等在此處為較適合 者。其他適合的鹽類之列表可於，例如，Remington’s Pharmaceutical Sciences, 17th ed.，Mack Publishing Company, Easton，PA，p· 1418 (1985)中可找到。 明顯地本文中所提供之各個化合物可，但非必須，配 製成溶劑化物（例如，水合物）、醚或非共價之錯合物。此 鲁外，各者的各種結晶形與多晶形皆屬本發明的範圍内。同 樣地，本文亦提供所述化學式之化合物之前藥。π前藥" 為一種可能還不完全符合本文中所提供之該等化合物之結 構需求之化合物，但在投與患者後，該前藥於體内改質， 以產生本文中所提供之化學式之化合物。例如，該前藥可 為如本發明所提供之化合物之經醯化之衍生物。前藥包括 其中的羥基、胺基或硫氫基與任何基團鍵結之化合物，當 投予至哺乳類動物的受試者時，將各自分解成游離的經 基、胺基或硫氫基。該等前樂的例子包括’但不限於，本 209 93966 200812588 文中所提供之該等化合物之酯類，例如醇與胺官能基的乙 酉文酉曰、甲酸醋以及本甲酸_，之衍生物。本文中所提供之 該等化合物之前藥可藉由修飾存在於化合物中之官能基而 製備，經此方式，該等修飾係於活體内分解以產生母化合 物。 術語“治療有效量”意指表丨的化合物或鹽，在投予 至人類或非人類之患者時，含量為有效者以提供治療效益 鲁例如症狀之改善，例如，有效拮抗達致病濃度的CRF所引 起的影響的量或有效治療列於上述小標題“治療方法，，下 之任何疾病之症狀的量。顯然地，當按照症狀根據預期攝 取里技予所用之化合物時，以單一劑量投藥之後將明顯可 見該治療效益，或在重複投予治療有效劑量之後，該治療 效益將變得明顯。 醫藥製劑 式I (較佳為表I)之該等化合物可經口服、局部、經皮 ♦吸收、非經口、藉由吸入或喷霧或直腸或陰道塞入含有習 =無毒性之醫藥上可接受之載劑、佐劑以及賦形劑之劑量 單位之調劑予以投入。如本文中所使用之術語“非經口” 其包括^下、靜脈、肌肉、囊内等種類之注射或灌輸技術。 此外:還提供-種含有本文中所提供之化合物以及醫藥上 可接文之載劑之醫藥製劑。式丨（較佳為表丨）之一種或多種 化合物可與-種或多種無毒性之醫藥上可接受之載劑和/ 或稀釋劑和/或佐劑以及所欲之其他活性成分結合。含該等 式1(較佳為表I)之化合物之醫藥組成物可為適合口服使 93966 210 200812588 :二二，做成錠劑、片劑、口含錠、水性或油性 触”二放之粉劑或粒劑、乳劑、硬質或軟質膠囊或 糖漿或酏劑（elixirs)。 物rt口服使用之該等化合物可依照任何習知醫藥組成 链之技藝方法予以製傷並且該等組成物可含有- 丄 J捫禾y、者色劑以及保藏劑所組成 =且：！Γ提供醫藥上美觀且美味之製劑。該較劑 ====，之適合用於製造_之賦形 刀此等賦形劑可為例如，惰性 =劑例如碳_、碳_、乳糖、碟_或魏納；造 明=及崩解劑例如玉米殿粉或藻酸；黏結劑例如殿粉、 月：或阿拉伯膠，以及潤滑劑例如硬脂酸鎂、硬脂酸或滑 該等錠劑可未經塗覆者或經由習知技料以塗覆以 解並於消化道中吸收，藉此在較長的週期下提供持 ^仙。例如，時間延遲物質例如單硬脂酸甘油醋或甘 ✓由一硬脂酸醋皆可使用者。 該等口服用之調劑亦可製成硬質明膠膠囊，盆中該活 ^成分係與惰性U體稀義（例如，碳_、磷軸或高屬 =合’或製成軟質明轉囊，其中該活性成分係與水或 ，媒介（例如，花生油、液體石蠟或撤視油）混人。 I等水性懸浮液於具有適合用於製造水性_劑的混 I 含有活性物質。此等賦形劑為懸浮劑，例如，缓f f纖維錢、甲基麟素、“基甲基纖維素、藻酸鈉、 來乙料略烧酮、黃書膠以及阿拉伯膠；分散劑或濕潤劑 93966 211 200812588 產::碟腊’例如，㈣脂，或環氧燒與脂游酸 *、’、口 ’列如’硬脂酸聚氧乙烯酯，或環氧乙燒盥 ，肪醇的縮合產物，例如，十七碳乙烤氧基錄醇 ==thy 1咖吻咐勘1) ’或環氧乙燒與自脂肪酸 -何生之不完全酯（partial ester)的縮合產 物，例如’聚氧乙烯山梨醇單油酸酯，環 酸和已糖醇軒所衍生之不完全醋的縮合產物，例 稀山梨醇早油酸酯。該等水性懸浮液亦可含有-種或多種 防腐劑（例如，對經基苯甲酸乙醋或對經基苯甲酸正丙 酯一種或多種著色劑，—種或多種調味劑以及—種 種甜味劑（例如，蔗糖或糖精）。 油性懸浮液可藉由將活性&分懸浮於幸直物油中（例 如’“花生油、撖欖油、芝麻油、椰子油或礦物油例如液態 石蠟）予以配製。該油性懸浮液可含有增稠劑，例如，密蠟、 硬石蝶或錄蟻醇。如先前所述之該等甜味劑以及調味劑亦 擧可加入於其中以獲得美味的口服製劑。該等組成物可藉由 添加抗氧化劑（例如抗壞血酸）予以保存。 曰 適合藉由加入水製備成水性懸浮液之可分散之粉劑或 粒劑係提供活性成分於具有分散劑或濕潤劑、懸浮劑以及 一種或多種防腐劑的混合物之中。適合的該等分散劑或濕 潤劑以及懸浮劑係以如上述所列舉者。纟他的賦形劑，例 如甜味劑、調味劑以及著色劑亦可用於本發明中。 本文中所提供之醫藥組成物亦可為水中油滴型乳化液 (oil-in-water emulsions)之形式。該油相可為植物油（例 93966 212 200812588• The compounds in this article are generally described using standard nomenclature. "Substituting for contempt" means that a group may be unsubstituted or at any feasible 7 or more positions, typically at positions 2, 3, 4 or 5, in one or more suitable Substituting such substituents as disclosed below. Suitable substituents include, for example, halogen, cyano, amine, thio, nitro, azide, decyl, -c〇〇H, SO?, 2, alkyl (for example, 匕-(:8 alkyl), alkenyl (for example, C2-Cs alkenyl), alkynyl (for example, alkynyl), alkoxy (for example, Cl) -Cs alkoxy), alkyl ether (for example, & mono G-alkyl ether), alkylthio (for example, Cl-G alkylthio), haloalkyl (for example, Ci-C8 halogen) A hydroxyalkyl group (for example, a Ci-C8 hydroxyalkyl group), an amine alkyl group (for example, a Ci-G amine alkyl group), a haloalkoxy group (for example, a Ci-C8 haloalkoxy group), an alkyl fluorenyl group. (for example, C!-C8), ketone (for example, Cl-C8^_), alkoxy group (for example, C!-C8), and alkoxy groups (for example, Cl) —C8 alkoxycarbonyl), mono- and di-(G-c8 alkyl)amine, mono- And di-(Cl-C8 alkyl)amino C!-C8 alkyl, mono- and di-(C!-C8 alkyl) decylamino, mono- and di-(Ci-Cs alkyl)% Amino, anthracenyl (for example, Ci-Cs alkylsulfinyl), alkylsulfonyl (for example, C!-C8 alkylsulfonyl), aryl (Example 205 93966 200812588 , phenyl), aralkyl (for example, (a-Cu aryl) Ci_C8 alkyl, such as benzyl and phenethyl), aryloxy (for example, Ce-Ci8 aryloxy such as phenoxy), a s-alkoxy group (for example, (C^Cu aryl)c--C8 alkoxy group) and/or a 3- to 8-membered beach ring group, for example, a coumarin group, a quinone group, a sigma group , fluorenyl, fluorenyl, furyl, pyrrolyl, thienyl, oxazolyl, oxazolyl, imidazolyl, oxazepine, benzoxanthyl, tetrahydron π南南, tetrahydropyranyl, piperidinyl, N-morpholinyl or pyrrolidinyl. Certain groups of the equations provided herein are 1 to 3, 1 as needed. Replace to 4 or 1 to 5 independently selected substituents. Not between two letters or symbols The number ("-,,) is used to indicate the attachment point of the substituent. For example, -c〇NH2 is attached through a carbon atom. As used herein, the term "burning base" means both branched and straight chain. a saturated aliphatic hydrocarbon group of two = and specifically indicated in the groups, which has a definite number of stone antiatoms. Thus, as the term is used herein, Ci-G alkyl '' means having 1 to 6 An alkyl group having from 1 to 8 carbon atoms (Cl - C8 alkyl group) having from 1 to 6 carbon atoms (Ci-Ce alkyl group) and having from 1 to 4 carbon atoms a group of (Ci-C4 alkyl) such as methylethyl, n-propyl, isopropyl, n-butyl, t-butyl, t-butyl, pentyl, 2-pentyl, isopentyl , neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl. In certain embodiments, preferred alkyl groups are decyl, ethyl, propyl, butyl, and 3-pentyl. "Processing" means fluorine, gas, bromine and moth. "Hetero atom" is an atom other than carbon, such as oxygen, sulfur or nitrogen. The term "aryl" means a group containing at least one aromatic ring. . Examples of such 93966 206 200812588 square groups include phenyl and naphthyl. The term "heteroaryl" means at least one aromatic ring. If the heteroatoms in the heteroaryl are = 4 heteroatoms, the heteroatoms will not be adjacent to each other; if ==, 1, the total number of sub-states is not More than Bu 2 or heart ' : s: 〇原, 基, (四), 嫩 It: Examples of base include heart base, bite base, 嗟 基 嗟, 嗟, three: base: fi: well base, taste base, - Wow and 5,6,7,8-tetrahydroisoindole. For each base, for #f ^ 具有 with asymmetric center, there should be other special explanations (unless the substance and its mixture. All optical isomerization activities containing a pair of oxime caps W. Compounds of asymmetric substituents may be optically "optically actlve f〇rms) or racemic forms?: well known, for example by racemic form (Racemic core: term = symmetric synthesis or synthesis by optically active starting materials, etc.:: Spinel (iv) can be resolved by, for example, conventional methods such as by resolving agent #r=rn^agent) In the presence of the formation of the day of the day or by chromatography (for example, a liquid chromatography column ((5) ral_HPLC, and the form α is the same, 'these have carbon-carbon double bonds The compound may be in the form of 2: working orms form (E_f_s). If there is no other explicit, the isomers of the compound which it has are included in the present invention, and there are various kinds of mutual compounds in the present. The compounds listed in the isomers are not limited to any particular 93966 207 200812588 tautomer, but do not cover all ^^ ^ ^^ scare Structures. Many of the olefins are also present in the materials described herein: the two or two kilograms of the suitable isomers are the cis and trans of the expected t (4) of the present invention. The geometric (10) compound is described, 'and can be isolated from the mixture of the specific isomers or the isolated isomers. : The compounds listed are expected to cover one or more of the same position', 曰The atom (i.e., an atom having the same atomic number but different mass numbers). As an example of the isotopic isotope, there are no particular limitations, such as isotopes of hydrogen including helium and gas, and isotopes of carbon including llc, 13. and "c As the user of this article, "medical "Substituted salt" means a derivative of the disclosed compound which is modified by making a non-toxic acid salt or salt, and further means the compound and Pharmaceutically acceptable solvates of such salts. Examples of such pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts containing (10) residues (such as amines); An alkali metal or an organic salt such as a carboxylic acid, etc. such pharmaceutically acceptable salts include the conventional non-toxic salts formed by the compounds of the present invention (for example, in the form of non-toxic inorganic or organic acids) and Grade ammonium salt. For example, such conventional non-toxic acid salts include such non-toxic acid salts derived from inorganic acids such as hydrogen acid, hydrobromic acid, sulfuric acid, dextroamine, citric acid, nitric acid, and the like; and prepared from organic acids. Salts such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, Gluten, benzoic acid, salicylic acid, hydrazine sulfonic acid, amino benzene sulfonic acid, 2- ethoxy benzoic acid, fumaric acid, terephthalic acid, decane 208 93966 200812588 Sulfonic acid, ethane Disulfonic acid, oxalic acid, isethionic acid, H00C-(CH2)n-C00H wherein η is 0 to 4, and the like. The pharmaceutically acceptable salts of the present invention can be synthesized by a conventional chemical method from a parent compound containing an acid or a base moiety. In general, such salts may be suitably tested for the free acid form and the stoichiometric amount of such compounds (eg, sodium, calcium, magnesium or potassium hydroxides, carbonates, bicarbonates) Alternatively, the reaction may be prepared by reacting the free base form of the compound with an equivalent equivalent of an appropriate acid. These reactions are typically carried out in water or an organic solvent, or a mixture of two of them. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred, and are preferred herein. A list of other suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, p. 1418 (1985). It will be apparent that the individual compounds provided herein may, but need not, be formulated as solvates (e.g., hydrates), ethers or non-covalent complexes. In addition to this, various crystal forms and polymorphs of each are within the scope of the present invention. Similarly, prodrugs of the compounds of the formula are also provided herein. π prodrugs are compounds that may not fully comply with the structural requirements of the compounds provided herein, but after administration to a patient, the prodrug is modified in vivo to produce the chemical formula provided herein. Compound. For example, the prodrug can be a deuterated derivative of a compound as provided herein. Prodrugs include compounds in which a hydroxy, amine or sulfhydryl group is bonded to any group, and when administered to a mammalian subject, each decomposes into a free radical, amine or sulfhydryl group. Examples of such pre-existing includes, but are not limited to, the esters of such compounds as provided herein, such as the ethyl esters of the alcohol and amine functional groups, the formic acid vinegar, and the derivatives of the present formic acid. The prodrugs of the compounds provided herein can be prepared by modifying the functional groups present in the compounds, in such a manner that the modifications are decomposed in vivo to produce the parent compound. The term "therapeutically effective amount" means a compound or salt of the form that, when administered to a human or non-human patient, is effective in providing a therapeutic benefit, such as an improvement in symptoms, for example, effective antagonism to a disease-causing concentration. The amount of effect caused by CRF or the effective treatment is listed in the sub-heading "Therapeutic methods, the amount of symptoms of any disease. Obviously, when the compound is administered according to the symptoms according to the expected intake, the drug is administered in a single dose. The therapeutic benefit will be apparent afterwards, or the therapeutic benefit will become apparent after repeated administration of a therapeutically effective dose. Pharmaceutical Formulations I (preferably Table I) may be administered orally, topically, or transdermally. Ingestion, parenteral, administration by inhalation or inhalation or rectal or vaginal infusion of a dosage unit containing a pharmaceutically acceptable carrier, adjuvant, and excipient that is non-toxic, as described herein. The term "non-oral" is used to include injection or infusion techniques of the lower, intravenous, intramuscular, intracapsular, etc. In addition: a compound containing the compounds provided herein is also provided. And pharmaceutical preparations which are pharmaceutically acceptable carriers. One or more compounds of the formula (preferably the surface) may be combined with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or Or an adjuvant and other active ingredients to be combined. The pharmaceutical composition containing the compound of the formula 1 (preferably Table I) may be suitable for oral administration of 93966 210 200812588: 22, into tablets, tablets, Oral, aqueous or oily touches of powder or granules, emulsions, hard or soft capsules or syrups or elixirs. The compounds for oral administration of the rt can be injurious according to any of the techniques of the conventional pharmaceutical composition chain and the compositions may contain - 丄 J扪禾, a coloring agent and a preservative composition = and:! ΓProvides a medicinal aesthetic and delicious preparation. The agent ====, which is suitable for use in the manufacture of knives, such excipients may be, for example, inert = agents such as carbon _, carbon _, lactose, dish _ or Weiner; Decomposing agents such as corn powder or alginic acid; binders such as temple powder, moon: or gum arabic, and lubricants such as magnesium stearate, stearic acid or slipper may be uncoated or conventionally known The technique is applied to dissolve and absorb in the digestive tract, thereby providing retention over a longer period of time. For example, a time delay material such as glycerol monostearate or glycerin is available from a stearic acid vinegar. The oral preparations can also be made into hard gelatin capsules in which the active ingredients are inferior to the inert U body (for example, carbon_, phosphorus axis or high genus = combined) or made into a soft gelatin capsule. The active ingredient is admixed with water or a medium (for example, peanut oil, liquid paraffin or withdrawal oil). The aqueous suspension of I, etc., contains the active substance which is suitable for the preparation of the aqueous preparation. Suspending agent, for example, ff fiber, methyl lin, "methyl cellulose, sodium alginate, ketone ketone, lycopene and gum arabic; dispersant or wetting agent 93966 211 200812588 :: dish wax 'for example, (iv) fat, or epoxy burning with a fatty acid *, ', mouth' column such as 'stearic acid polyoxyethylene ester, or epoxy sulphur, a condensation product of fatty alcohol, for example, Hexadecane bakeoxy alcohol ==thy 1 咐 咐 1) 'or condensation products of epoxy bake and partial esters from fatty acids - such as 'polyoxyethylene sorbitol a condensation product of incomplete vinegar derived from monooleate, cyclic acid and hexitol, such as dilute sorbitol oil The aqueous suspension may also contain one or more preservatives (for example, one or more coloring agents for ethyl benzoate or n-propyl benzobenzoate, one or more flavoring agents, and various Sweeteners (eg, sucrose or saccharin). Oily suspensions can be prepared by suspending the active & amps in a straight oil (eg, 'peanut oil, eucalyptus oil, sesame oil, coconut oil or mineral oil such as liquid paraffin) The oily suspension may contain a thickening agent, for example, a dense wax, a hard stone butterfly or a phytol alcohol. The sweeteners and flavoring agents as described above may also be added thereto to obtain a delicious oral preparation. The compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. A dispersible powder or granule suitable for preparation into an aqueous suspension by the addition of water provides the active ingredient in a dispersion or wetting agent, suspension. And a mixture of one or more preservatives. Suitable such dispersing or wetting agents and suspending agents are as listed above. Other excipients such as sweeteners Flavoring agents and coloring agents can also be used in the present invention. The pharmaceutical compositions provided herein can also be in the form of oil-in-water emulsions. The oil phase can be a vegetable oil (example 93966). 212 200812588

二撖=花生油)或確物油(例如，液態石壤)或上述該 5物。適合的乳化劑可為天然生產之膠類（例如 阿拉t膠或續著膠）、天然生產之碟睦（例如，大Γ碟!V 人/ 和己醣醇、酸酐所衍生之酯類 完全醋之縮合產物心:以及該等具有環氧乙炫之不 …該等乳化二有=稀山梨糖醇軒單油酸 J 3有甜味劑以及調味劑。 糖滎或酿劑可俊用视^土 ▲剞」使用甜味劑（例如）予以調配。例如，甘 …丙-％、山梨醇或蔗糖 防腐劑以及調味劑和荽名卞， 刀有綾和劑、 4、i 、 背。該等醫藥組成物可為盔菌水 陸或或油性注射懸浮液之形式。該懸浮液可使用已;：= 所述之該等適合之分+ “十欣』便用已於先前 政劑或濕潤劑以及懸浮劑依昭習4妯 蟄調配成。該盔菌注斛制〜汙Μ依：恥I知技 南丨4、—卞丨士 ”、、 衣劑亦可為在無毒性的可接受稀釋 =洛劑中之無菌注射溶液或懸浮液（例如:稀釋 私中之溶液）。該等可使用 ，3 丁一 林格氏独及等張氯化㈣i 丨為水 油類（fixed 、 卜，該等無菌固定 的，任何溫和的固定油，^ =戍懸子媒介。為達此目 油醋，皆可使用、、主射用Γ 的單酸甘油醋或雙酸甘 用於製備注射劑。 再者，脂肪酸如油酸可 該等式I (較佳為表I) 如，以直腸給藥之方式）投入之化該=；7以检劑方式（例 其在常溫下為固體但在體^且成物可猎由混合具有 物之適合的非刺激性賊形料以製成。此等物質包 93966 213 200812588 括可可豆油以及聚乙二醇。 忒等式K較佳為表丨）之化合物可以用無菌介質經注 射方式予以投入。該藥物，依據賦形劑以及所使用之濃声， 其能懸浮或溶解於賦形劑中。更有利者，一種或多種佐又’ 例如防腐劑、缓衝劑或局部麻醉劑）亦可存在於賦形劑中。 —每曰每公斤體重用0·05毫克至1〇〇毫克，較佳為每曰 母一叉體每公斤用0·1至30毫克，而更佳為0.5至5亳克， ^級數劑量濃度係有詩上述該等症狀之治療 用：;產生[劑型之活性成分之含量將視被= 、伤”特疋的投藥模式而改變。該等劑量單位劑型一 ^ 將含有0.1毫克至750毫克之活性成分。 又 劑量的頻率亦可依照所使用之化合物以及所治療之特 ^疾病而改變1而，對大多數的⑽以及腸胃疾病之治 ^言’給藥的w (dQsage regimen)預計為每日四次， 較佳為每日三次，更祛兔戽 #, ^ ^α 更仫為母日兩次，而最佳為每日一次。 方2输疾病以及焦慮症之治療而言，較佳之給藥的 方式為母曰1至2次為特別較佳者。 按π 瞭解到’任何特定患者用之有效劑量濃度將 ^各種因數’包括所使用蚊化合物之活性、年齡、體 狀態、性別、飲食、服藥時間、用藥方式以及排 至2 5併用藥（即’其他用來治療該患者之藥物）以及受 到b療之特定疾病之嚴重濃度，而決定。 等二=3^為表υ之化合物將有某些藥理性質。此 于求现注貝包括，但不限於 ,Γ万、口服生物可利用率（oral 93966 214 200812588 b i oava i 1 ab i 1 i ty )，以致使上述較佳之口服劑型可於活體 内提供化合物之治療有效濃度。血腦障壁（Blood-Brain-Barr ier ··簡稱作BBB)之滲透力為大多數用於治療該等CNS 疾病之化合物所必須者，而一般用來治療末梢疾病 (periphereal disorders)之化合物以低腦濃度為較佳。 可用試驗來預測該等所欲之藥理特性。用於預測生物 可利用率之該等試驗包括運輸通過人類的腸細胞單層（包 括Caco-2細胞單層）。可使用對人工培養的肝細胞之毒性 來預測化合物的毒性，而以無毒性之化合物較佳。化合物 於人類的血腦障壁滲透性可從給予該化合物（例如從靜脈 給予）之實驗動物的化合物腦中濃度而預測。 血清蛋白結合之百分比可由白蛋白的結合試驗予以預 測。此等試驗之實施例係揭露於OravcovS等人（Journal of Chromatography B (1996) volume 677，pages 1-27)的評 述中。該等較佳之化合物顯示出可逆的血清蛋白結合。此 _結合百分比較佳為小於99%，更佳為小於95%，又佳為小於 90%，而最佳為小於80%。 投藥頻率一般與化合物的體内半衰期（in half - 1 ife)成反比。該等化合物之體内半衰期可由Kuhnz and Gieschen(Drug Metabolism and Disposition, (1998) volume 26，pages 1 120-1 127)所述之微粒體半衰期之體外 (in vi tro assays of microsomal hal f-1 i f e)試驗而預 測。該等較佳之半衰期者係提供較佳之投藥頻率。 如先前所述者，該等式I (較佳為表I)之較佳化合物於 215 93966 200812588 _ 下列實施例7所具體說明之標準活體外CRF受體結合試驗 中展現出活性。於本文中所指之“標準體外CRF受體結合 試驗”係意指此標準試驗協定。該等式K較佳為表I)之二 佳田化合物於標準活體外CRF受體結合試驗中具有之IC5。值 (取大半抑制濃度）為约1微莫耳或小於1微莫耳，更佳 其IC5°值為約100奈莫耳（nanomolar)或小於！ 00奈莫耳， =又更L者其I值為約1()奈莫耳或小於 甚至於為1奈莫耳或小⑹奈莫耳。 、耳成 化合物之 之方2 (_!又佺為表υ之該等化合物及其鹽類可使用下述 ί:二；習知合成有機化學技藝中之合成方法、❹“ 該項技蟄者所能體會到種 飞“、、心 該等方法包括，彳曰尤禋又"之方法予以合成。較佳之 熟悉該項技蓺麵流程圖1巾所狀該等方法。 ”之該等化：：：:：要得到特定之式1(較佳為表 驟。 類可改變起始物質並使用額外之步 93966 216 200812588Diterpene = peanut oil) or indeed oil (for example, liquid stone) or the above. Suitable emulsifiers can be naturally produced gums (such as ara gel or continuation gum), naturally produced mashes (for example, scorpion scorpion! V human / and hexitol, anhydride derived esters complete vinegar) Condensation product heart: and these have the epoxy Ethylene... The emulsified two have = Sorbitan Xuan monooleic acid J 3 has a sweetener and a flavoring agent. The sugar lozenge or the brewing agent can be used ▲ 剞 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 The composition may be in the form of a Helicobacter terrarium or an oily injection suspension. The suspension may be used;: = the appropriate fraction of the said + "10 Xin" used in the prior agent or humectant and suspension The agent is formulated according to the 昭 习 妯蛰 。 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 盔 盔 盔 盔 盔 盔 盔 盔Sterile injection solution or suspension (for example: dilute the solution in private). These can be used, 3 Ding Yi Ling Ge alone Isotonic chlorination (4) i 丨 is a water-oil type (fixed, Bu, such as sterile fixed, any mild fixed oil, ^ = 戍 子 媒介 。 。 。 。 。 。 。 。 。 。 。 。 。 达 达 达 达 达 达 达 达 达 达 达 达 达 达 达 达 达 达 达 达 达 达Monoglyceride or bis-glycolate is used for the preparation of an injection. Further, a fatty acid such as oleic acid can be used in the formula I (preferably in Table I), for example, in the form of rectal administration. The agent method (for example, it is solid at normal temperature but in the body and the product can be hunted by mixing the suitable non-irritating thief-shaped material. The material package 93966 213 200812588 includes cocoa butter and polyethylene. The compound of the formula K, preferably in the form of a compound, can be administered by injection in a sterile medium, which can be suspended or dissolved in the vehicle depending on the excipient and the loud sound used. Advantageously, one or more adjuvants such as preservatives, buffers or local anesthetics may also be present in the vehicle. - 0. 05 mg to 1 mg per kg body weight, preferably 0. 1 to 30 mg per kg of the parent body, and more preferably 0.5 to 5 g, ^ series dose The concentration is in the treatment of the above-mentioned symptoms of the poem:; the [the content of the active ingredient of the dosage form will vary depending on the mode of administration of the drug, the injury.] The dosage unit dosage form will contain 0.1 mg to 750 mg. The active ingredient. The frequency of the dose may also vary according to the compound used and the particular disease being treated. For most (10) and gastrointestinal diseases, the administration of w (dQsage regimen) is expected to be Four times a day, preferably three times a day, more 祛 rabbit 戽 #, ^ ^α is more than twice the mother's day, and the best is once a day. For the treatment of disease and anxiety, Preferably, the method of administration is 1 to 2 times for the female baboon. It is particularly preferred to press π to know that 'the effective dose concentration for any particular patient will be ^ various factors' including the activity, age, body state, sex of the mosquito compound used. , diet, time of medication, mode of administration, and medication to the 5 (ie, 'Other drugs used to treat this patient' and the serious concentration of the specific disease that is treated with b. It is decided that the compound of the two = 3^ will have certain pharmacological properties. This is included in the request, but Not limited to, 10,000, oral bioavailability (oral 93966 214 200812588 bi oava i 1 ab i 1 ty ), such that the preferred oral dosage form described above provides a therapeutically effective concentration of the compound in vivo. Blood brain barrier (Blood) -Brain-Barr ier · BBB for short) is essential for most compounds used to treat these CNS diseases, and compounds commonly used to treat peripheral disorders are preferably low brain concentrations. Experiments can be used to predict such desirable pharmacological properties. These assays for predicting bioavailability include transport through human intestinal cell monolayers (including Caco-2 cell monolayers). The toxicity of the cells is predictive of the toxicity of the compound, and the non-toxic compound is preferred. The permeability of the compound to the blood-brain barrier of humans can be from the administration of the compound (for example, from intravenous administration). Animal compounds are predicted in brain concentrations. The percentage of serum protein binding can be predicted by albumin binding assays. Examples of such assays are disclosed in OravcovS et al. (Journal of Chromatography B (1996) volume 677, pages 1-27 In the review, the preferred compounds exhibit reversible serum protein binding. The % binding ratio is preferably less than 99%, more preferably less than 95%, still preferably less than 90%, and most preferably less than 80%. The frequency of administration is generally inversely proportional to the in vivo half-life of the compound (in half - 1 ife). The in vivo half-life of such compounds can be in vitro by the microhavel half life of Kuhnz and Gieschen (Drug Metabolism and Disposition, (1998) volume 26, pages 1 120-1 127) (in vi tro assays of microsomal hal f-1 ife ) Experiment and predict. These preferred half-lives provide a preferred frequency of administration. As described previously, the preferred compound of Formula I (preferably Table I) exhibits activity in the standard in vitro CRF receptor binding assay as detailed in 215 93966 200812588 _ in the following Example 7. "Standard in vitro CRF receptor binding assay" as used herein means the standard protocol protocol. Preferably, the equation K is Table I) bis. The IC5 compound of the Jiatian compound has a standard in vitro CRF receptor binding assay. The value (takes a majority of the inhibitory concentration) is about 1 micromolar or less than 1 micromole, more preferably the IC5° value is about 100 nanomolar or less! 00 Nemo, = more L, its I value is about 1 () Nylon or less than even 1 Nemo or small (6) Nemo. The ear of the compound 2 (_! 佺 佺 υ 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 ; It can be realized that the methods of planting ", and the heart, including the method of 彳曰 禋 禋 & & & & & 。 。 。 。 。 。 。 。 较佳 较佳 较佳 较佳 较佳 较佳 较佳 较佳 较佳 较佳 较佳 较佳 较佳 较佳 较佳 较佳 较佳 较佳 较佳 较佳 较佳 较佳 较佳 较佳:::::To get the specific formula 1 (preferably the table. The class can change the starting material and use the extra step 93966 216 200812588

流程圖IIFlowchart II

ClCl

Cl 14 r2nh2Cl 14 r2nh2

RjfMl催化劑RjfMl catalyst

NBS ΙΝΎΝ丫 Ri ArB(QH)g (2) 人 Br 17NBS ΙΝΎΝ丫 Ri ArB(QH)g (2) People Br 17

流程圖111Flow chart 111

[實施例] 217 93966 200812588 a ^以下諸實施例係用來進一步說明式Γ(較佳為表^之 4等化合物及其鹽類之製備方法。其他相關之合成式i(較 為表I)之該等化合物及其鹽類之合成方法係以揭露於 明中的美國專利申請公開案第2嶋川撕9號、申請於 2004年9月3日申請’發明幺 、 考χ月名％為“作為CRF1受體之配 =減)之經雜芳基稍合的㈣、傘及射,，的美 國弟10/933, 834號的申請案中命 、 苐0284-0863段的該等實施例中 、 曙上―μ Τ〔正個貫施例4 9中），ρ、+、 该荨之内容係合併於本文中作 甲）上4 考。 教示料合成方法之參 實施例1: 2-（2-乙基-6〜里呙萁 之 氧基-1-甲基乙基齡二=定I基)-5-[〇W 合成 土〜5H〜吡咯并[2,3-b]^_ _ 93966 218 200812588 ci[Examples] 217 93966 200812588 a The following examples are used to further illustrate the preparation of the formula 较佳 (preferably the compound of Table 4 and the salts thereof). Other related synthetic formulas i (Comparative Table I) The method for synthesizing these compounds and their salts is disclosed in U.S. Patent Application Publication No. 2, No. 9 of the U.S. Patent Application Publication No. 9 filed on Sep. 3, 2004. In the examples of the CRF1 receptors, the subtraction of the heteroaryl groups (4), Umbrella and the shots, in the examples of the application of the American Brothers 10/933, 834, 苐0284-0863,曙上―μμ [正正例Example 4 9), ρ, +, the contents of the 荨 are combined in this article for a)) 4 test. Teaching materials synthesis method reference Example 1: 2- (2 -ethyl-6~ 呙萁 呙萁 oxy-1-methylethyl y ===1 base)-5-[〇W Synthetic soil ~5H~pyrrolo[2,3-b]^_ _ 93966 218 200812588 ci

步驟a rnh2Step a rnh2

NBSNBS

步驟BStep B

Pd(OAc)2 步驟FPd(OAc)2 Step F

ArB(OH)2 Pd(PPh3>4 步驟cArB(OH)2 Pd(PPh3>4 step c

步驟A:將2, 6-二氯啦畊（11. 7克）、（S)-( + )-l -甲氧基-2 -_丙基胺（7克）以及Et3N(15毫升）置於乙醇（EtOH)(100毫 升）中於105°C加熱持續2天。將該混合物蒸發並將其溶於 乙酸乙酯（EtOAc)中並之後用飽和碳酸氫鈉水溶液清洗並 乾燥之。蒸發後得到2 -氯-6 - [(S) -1 -甲氧基-2 -丙基]胺基 吡畊。LCMS : m/z 202· 3 以及 204· 3 (M+H) + 步驟B :將2-氯-6-[(S)-l-甲氧基-2-丙基]胺基吼畊（8. 3 克）溶於氯仿（CHC13)(250毫升）中。在NBS(7. 33克）加入 之後，隨即將反應混合物在25°C下攪拌30分鐘。之後， 將粗產物混合物蒸發並溶於乙酸乙酯/己烷（1 : 4，500毫 219 93966 200812588 升）中，之後以水清洗並以硫酸鈉乾燥之。將該混合物以石夕 膠純化獲得3-溴-2-氯-6-[(S)-l-曱氧基-2-丙基]胺基吼 畊。LCMS : m/z 280· 2，282· 2 以及 284. 2 (M+H) + 步驟C:將3-漠-2 -氣-6 - [ (S)-1 -甲氧基-2 -丙基]胺基吼0并 (10· 7克）與2-曱氧基-6-異丙基-3-吡啶硼酸（9· 7克）溶於 DME(250毫升）中。除氣10分鐘之後，加入四（三苯基膦） 鈀（0) (2· 2克），接著再除氣1分鐘。在加入in的碳酸納 0水溶液（76毫升）後，隨即將該反應混合物於9(rc加熱 小時。之後，將該粗產物混合物置於水（8〇〇毫升）中，用 乙酸乙酯/己烷（1 ·· 1，3次而每次250毫升）萃取並以硫酸 鈉乾燥之。將該混合物以矽膠純化獲得3-{2-氯-6-[(S) -1-甲氧基-2-丙基]胺基吡畊一3-基}-2-曱氧基-6-異丙基 口比啶。LCMS : m/z 351· 3 以及 353. 3 (M+H) + 步驟D :將3-{2-氯-6-[(S)-卜曱氧基-2-丙基]胺基吡畊 -3-基}-2-甲氧基-6-異丙基吡啶（4· 85克）溶於氯仿（60毫 #升）中。在NBS(2· 46克）加入之後，隨即將反應混合物在 25 C攪拌30分鐘。之後，將該粗產物混合物蒸發並溶於乙 酉欠乙S旨/己烷（1 ·· 4，250毫升）中之後以水清洗並以硫酸鈉 乾燥之。將該混合物以矽膠純化獲得3_{5_溴氣一6一 [(S)-1-曱氧基—2-丙基]胺基π比哄—3一基}一2-曱氧基一6-異 丙基0比唆。LCMS : m/z 429· 2，431· 2 以及 433· 2 (M+H) + 步驟E :將3-{5-溴-2-氯-6-[(S)-1-曱氧基-2-丙基]胺基 井〜3一基卜2一曱氧基一6-異丙基吡啶（4. 3g)溶於DMSO(50 笔升）中。在氫化鈉（60%，〇· 8克）加入之後，隨即將反應 220 93966 200812588 混合物在25°C攪拌30分鐘，之後將3-溴丙烯（1· 7毫升）加 入。將該反應混合物在25°C攪拌2小時。之後，將粗產物 混合物置於水（250毫升）中，用乙酸乙酯/己烷（1: 4，2 次而每次250毫升）萃取，並以硫酸鈉乾燥之。將該混合物 以矽膠純化獲得3-{5-溴-2-氯-6-[(S)-N-烯丙基-1-甲氧 基-2-丙基]胺基吡哄-3-基}-2-甲氧基-6-異丙基吡啶。 LCMS : m/z 469· 3，471· 3 以及 473· 3 (M+H) + ⑩步驟F :將3-{5-溴-2-氯-6-[(S)-N-烯丙基-1-甲氧基-2-丙基]胺基吼畊-3-基卜2-曱氧基-6-異丙基吼啶（4. 6g)溶 於DMF(80毫升）中。除氣1〇分鐘之後，加入？(1(〇^)2(225 毫克），接著再除氣1分鐘。在碳酸鉀（4. 1克）與BmNBr (4· 0克）加入之後，隨即將反應混合物在9〇^c加熱1小時。 之後，將該粗產物混合物置於水（5〇〇毫升）中，用乙酸乙 酯/己烷（1 : 2，3次而每次150毫升）萃取，並以硫酸鈉乾 燥之。將該混合物以矽膠純化獲得（S)-3-氯-2-(6-異丙基 _ -2-甲氧基-吡啶-3-基）-5-（2-曱氧基-1-甲基-乙基）-7-甲 基-5H-吼咯并[2, 3-b]吡畊。LCMS : m/z 389· 4 and 391. 4 (M+H)+ 步驟G :將（S)-3-氯-2-（6-異丙基-2-甲氧基-吼啶-3-基） -5-（2-甲氧基-1-甲基—乙基）一7-曱基-5H-吡咯并[2, 3-b] °比畊（2· 1克）與肆（三苯基膦）鈀（〇)(6〇毫克）溶於無水的 THF( 10毫升）中。在三甲基化鋁（2M溶於曱苯中，5. 3毫升） 加入之後’隨即將該反應混合物在65°C加熱8小時。之後， 將該粗產物混合物冷卻至室溫並將該粗產物混合物倒入至 221 93966 200812588 具有飽和的酒石酸鉀鈉的冰水中。將該混合物攪拌4小時 之後分離出該有機層並用乙酸乙酯萃取剩餘的水溶液。將 該合併之有機萃取物用水以及接著用飽和鹽水清洗並以硫 酸鈉乾燥之。以矽膠層析法獲得經純化之產物。 步驟Η ··將步驟G(4· 6克）的產物置於4N的鹽酸（40毫升） 中在75°C加熱18小時。將該反應混合物冷卻至〇。〇，用 50%的氫氧化納水溶液中和並用二氯曱烷次而每次丨5毫 _升）萃取。將合併之萃取物用水（35毫升）和用飽和鹽水（35 宅升）清洗以硫酸鈉乾燥之。以矽膠層析法獲得經純化之產 物。 步驟I ·將步驟H(4· 4g)的產物溶於二氯甲燒（4〇毫升）中。 於-5。(：下逐漸加入三氟甲磺酸酐（2· 6毫升），之後加入三 乙基胺（3· 4毫升）。將該反應混合物回溫至環境溫度並且 攪拌1小時。用飽和碳酸氫鈉溶液（2次而每次3〇毫升）、 水（2x30毫升）以及飽和鹽水（2〇毫升）清洗該混合物，之後 _以硫酸納乾燥之。以矽膠層析法獲得經純化之產物。 步驟J :將步驟1(40〇亳克）的產物溶於甲苯（5毫升）中。 除氣10分鐘之後，加入肆（三苯基膦）鈀&lt;;0)(35毫克），接 者再除氣1分鐘。在二乙基蝴烧（1N於己烧中，3毫升）盘 1N的碳酸鈉水溶液（2毫升）加入之後，隨即將該反應混人 物在110°C加熱36小時。之後，將該粗產物混合物置於水 (10毫升）中，用乙酸乙酯/己烷（1:3, 3次而每次25毫升） 萃取，並以硫酸鈉乾燥之。將該混合物以矽膠純化獲得 2-（2-乙基-6-異丙基吡啶一3-基）-5-[(lS)-2-曱氧基—〜甲 93966 222 200812588 基乙基]-3, 7-二甲基咯并[2, 3一b]吡哄。LCMS: m/z 367.4 (M+H) + 貫施例2 : 5-（2-乙基〜甲氧基吡啶一3一基）q一（（]们一2一甲 氧基-1_甲基乙基）-3, 二甲基—1H-吡咯并[3, 2_b]吡啶之 合成Step A: 2,6-dichloroline plowing (11.7 g), (S)-(+)-l-methoxy-2-propanamine (7 g) and Et3N (15 ml) It was heated at 105 ° C for 2 days in ethanol (EtOH) (100 ml). The mixture was evaporated and taken up in ethyl acetate (EtOAc) and then washed and evaporated. After evaporation, 2-chloro-6-[(S)-1 -methoxy-2-propyl]aminopyrazine was obtained. LCMS: m/z 202·3 and 204·3 (M+H) + Step B: 2-chloro-6-[(S)-l-methoxy-2-propyl]amine . 3 g) dissolved in chloroform (CHC13) (250 ml). After the addition of NBS (7.33 g), the reaction mixture was stirred at 25 ° C for 30 minutes. After this time, the crude product mixture was evaporated and dissolved in ethyl acetate / hexane (1: 4, 500 s 219 s s The mixture was purified by Shiqi gum to obtain 3-bromo-2-chloro-6-[(S)-l-methoxy-2-propyl]amine. LCMS: m/z 280· 2,282· 2 and 284. 2 (M+H) + Step C: 3-Hydran-2 - gas-6 - [(S)-1 -methoxy-2-propane The amino group 吼0 and (10·7 g) and 2-decyloxy-6-isopropyl-3-pyridineboronic acid (7.9 g) were dissolved in DME (250 ml). After degassing for 10 minutes, tetrakis(triphenylphosphine)palladium(0) (2.2 g) was added, followed by degassing for 1 minute. After the addition of the in aqueous sodium carbonate solution (76 ml), the reaction mixture was then heated at 9 (rc). After that, the crude product mixture was placed in water (8 mL) with ethyl acetate. The alkane (1 ··1,3 times each time 250 ml) was extracted and dried over sodium sulfate. The mixture was purified by silica gel to give 3-{2-chloro-6-[(S)-1-methoxy- 2-propyl]aminopyrazine-3-yl}-2-decyloxy-6-isopropylpyridinium. LCMS: m/z 351·3 and 353.3 (M+H) + Step D : 3-{2-Chloro-6-[(S)-dioxaoxy-2-propyl]aminopyramino-3-yl}-2-methoxy-6-isopropylpyridine (4 85 g) was dissolved in chloroform (60 mil # liter). After the addition of NBS (2.66 g), the reaction mixture was stirred at 25 C for 30 minutes. Thereafter, the crude product mixture was evaporated and dissolved in acetonitrile. After washing with water and drying with sodium sulfate, the mixture was purified by silica gel to obtain 3_{5_bromo gas-6-[[S)-1-曱oxy-2-propyl]amino π 哄 哄 一 一 3 一 一 曱 曱 曱 唆 LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC 433· 2 (M+H) + Step E: 3-{5-bromo-2-chloro-6-[(S)-1-decyloxy-2-propyl]amine-based well~3-based 2-methoxy-6-isopropylpyridine (4.3 g) was dissolved in DMSO (50 liters). After sodium hydride (60%, 〇·8 g) was added, the reaction was immediately followed by the reaction of 220 93966 200812588 After stirring for 30 minutes at 25 ° C, 3-bromopropene (1.7 ml) was added. The reaction mixture was stirred at 25 ° C for 2 hours. After that, the crude mixture was placed in water (250 ml) with acetic acid. Ethyl acetate/hexane (1:4, 2 times each time 250 ml) was extracted and dried over sodium sulfate. The mixture was purified by silica gel to give 3-{5-bromo-2-chloro-6-[(s) -N-allyl-1-methoxy-2-propyl]aminopyridin-3-yl}-2-methoxy-6-isopropylpyridine. LCMS: m/z 469·3 , 471· 3 and 473· 3 (M+H) + 10 Step F: 3-{5-bromo-2-chloro-6-[(S)-N-allyl-1-methoxy-2 -propyl]amino-indole-3-yl-2-methoxy-6-isopropyl acridine (4.6 g) was dissolved in DMF (80 ml). After degassing for 1 min, add ? 1 (〇^) 2 (225 mg), followed by degassing for 1 minute. In potassium carbonate (4.1 g) After BmNBr (4 · 0 g) was added, then the reaction mixture was heated for 1 hour 9〇 ^ c. After this time, the crude product mixture was taken in water (5 mL), and ethyl acetate/hexane (1: 2, 3 times, 150 ml each time), and dried over sodium sulfate. The mixture was purified by silica gel to obtain (S)-3-chloro-2-(6-isopropyl-2-methyl-pyridin-3-yl)-5-(2-decyloxy-1-methyl Base-ethyl)-7-methyl-5H-indolo[2,3-b]pyrazine. LCMS: m/z 389·4 and 391. 4 (M+H) + Step G: (S)-3-chloro-2-(6-isopropyl-2-methoxy-acridin-3- -5-(2-methoxy-1-methyl-ethyl)-7-fluorenyl-5H-pyrrolo[2,3-b] ° than tillage (2.11 g) and bismuth (three Phenylphosphine)palladium (〇) (6 mg) was dissolved in anhydrous THF (10 mL). After the addition of aluminum trimethylate (2M in benzene, 5.3 ml) was added, the reaction mixture was heated at 65 ° C for 8 hours. Thereafter, the crude product mixture was cooled to room temperature and the crude product mixture was poured into ice water having saturated sodium potassium tartrate in 221 93966 200812588. After the mixture was stirred for 4 hours, the organic layer was separated and ethyl acetate was evaporated. The combined organic extracts were washed with water and then with saturated brine and dried over sodium sulfate. The purified product was obtained by gelatin chromatography. Step Η · The product of Step G (4.6 g) was placed in 4N hydrochloric acid (40 mL The reaction mixture was cooled to hydrazine. For example, it was neutralized with a 50% aqueous solution of sodium hydroxide and extracted with dichloromethane (5 liters each time). The combined extracts were washed with water (35 ml) and brine (35 liters) and dried over sodium sulfate. The purified product was obtained by gelatin chromatography. Step I. The product of step H (4·4 g) was dissolved in dichloromethane (4 mL). At -5. (: Gradually add trifluoromethanesulfonic anhydride (2.6 ml), then add triethylamine (3.4 ml). The reaction mixture was warmed to ambient temperature and stirred for 1 hour. The mixture was washed (2 times each time 3 ml), water (2 x 30 ml) and saturated brine (2 ml), and then dried over sodium sulfate. The purified product was obtained by silica gel chromatography. The product of step 1 (40 g) was dissolved in toluene (5 ml). After degassing for 10 minutes, hydrazine (triphenylphosphine) palladium &lt;; 0) (35 mg) was added, followed by degassing 1 minute. After a diethyl bromide (1 N in hexanes, 3 mL) of 1N aqueous sodium carbonate (2 mL) was added, the reaction mixture was heated at 110 ° C for 36 hours. After this time, the crude product mixture was taken in water (10 ml), ethyl acetate/hexane (1:3, 3 times, 25 ml each time) and dried over sodium sulfate. The mixture was purified by silica gel to give 2-(2-ethyl-6-isopropylpyridin-3-yl)-5-[(lS)-2-nonyloxy-~methyl 93966 222 200812588 ylethyl]- 3,7-Dimethylhexa[2,3-b]pyridinium. LCMS: m/z 367.4 (M+H) + </RTI> Example 2: 5-(2-ethyl~methoxypyridin-3-yl)q-(() Synthesis of ethethyl)-3, dimethyl-1H-pyrrolo[3, 2_b]pyridine

步驟Α·將2, 5一二溴〜3〜甲基吼唆（18· 90克）以及先前所述 =2-乙基-6—甲氧基’3ι唆硼酸(13· 7()克）溶於臓（2〇〇 也!^中。除氣之後，加入肆（三苯基膦）飽⑻（3· 60克）。 進行第一除氣後隨即加入5N的碳酸鈉水溶液（3〇毫升）， 於是加熱該反應至8(TC維持16小時。之後，將淡黃色的 $合物置於水（500毫升）中，用DCM(2次而每次3〇〇毫升） 萃取並以4酸鈉乾燥之。以石夕膠純化獲得經偶合之產物。 LCMS ： m/z 306.94 (M+H)1 步驟B:將步驟a的經純化化合物（6. 40克）以及（及）-：[一甲 93966 223 200812588 氧基-2-胺基丙烷（2· 04克）溶於甲苯（8〇毫升）中並作短暫 除氣。之後，加入Pd2(dba)3(l· 〇3克）、對稱軸的2, 2, 一 雙（二苯基膦）-1，Γ -聯萘（ΒΙΝΑΡ)(0· 76克）以及第三丁氧 基鈉（2· 81克），隨後將該混合物加熱至7(rc維持16小聘。 之後將該黑色的混合物置於水（4 〇 〇毫升）和餘和的碳酸氫 鈉水溶液（100毫升）中，用二氯甲烷（3次而每次3〇〇毫升） 萃取，並以硫酸鈉乾燥之。將該粗產物質透過填充矽膠之 管柱沖提獲得5-胺基吼啶作為用於步驟0中的半粗產Step Α·2,5-dibromo~3~methyl hydrazine (18·90 g) and previously described 2-2-ethyl-6-methoxy '3 oxime boric acid (13·7() g) Soluble in 臓 (2〇〇 also! ^. After degassing, add 肆 (triphenylphosphine) to saturate (8) (3 · 60 g). After the first degassing, add 5N aqueous sodium carbonate solution (3 〇 ml) Then, the reaction was heated to 8 (TC was maintained for 16 hours. After that, the pale yellow compound was placed in water (500 ml), and extracted with DCM (2 times each time 3 liters) and sodium sulphate The product was obtained by the purification of the product. LCMS: m/z 306.94 (M+H)1 Step B: purified compound (6.40 g) and (and)-:[ A 93966 223 200812588 Oxy-2-aminopropane (2.42 g) is dissolved in toluene (8 ml) and briefly degassed. After that, Pd2(dba)3 (l·〇3 g) is added, symmetrical 2, 2, a pair of (diphenylphosphino)-1, fluorene-binaphthyl (fluorene) (0·76 g) and a third sodium butoxide (2·81 g), then the mixture is heated to 7 (rc maintains 16 small hires. Then the black mixture is placed Water (4 ml) and the aqueous sodium hydrogencarbonate solution (100 ml) were extracted with dichloromethane (3 times each time 3 mL) and dried over sodium sulfate. 5-Acryl acridine is obtained by pipe column filling with silica gel as semi-crude used in step 0

物。LCMS : m/z 316· 35 (M+HV 步驟C:將步驟B的胺基化合物溶於氯仿（200毫升）中並以 分成數份的方式加入NBS(0· 9至1· 〇當量）直到TCL控制驗 證出该起始物質完全轉化為止。之後將淡黃色的混合物置 於水（200毫升）中，用DCM(3次而每次1〇〇毫升）萃取，並 以石;IL目欠鈉乾燥之。將該混合物以秒膠純化獲得漠化物。 LCMS ： m/z 394.21 (M+H)+ φ步驟D:將步驟c之經純化的溴化物（7· 59克）以及3_溴丙 烯（2.04亳升）溶於DMF(1〇〇毫升）中。將氫化鈉（116g) 分成3等分加入並使該反應於室溫下攪拌9〇分鐘。在以 TLC控制確認仍留有一些起始物質之後，加入〇· 25等當量 的兩試劑以使該反應完成。之後將該混合物置於水（500毫 升）中’並用乙醚（2次而每次3〇〇毫升）萃取。將合併之有 機層用水（100毫升）清洗，用硫酸鎂乾燥之，並將該混合Things. LCMS: m/z 316·35 (M+HV) Step C: The amine compound of step B was dissolved in chloroform (200 ml) and NBS (0.99 to 1 〇 equivalent) was added in portions. The TCL control verified that the starting material was completely converted. The pale yellow mixture was then placed in water (200 mL) and extracted with DCM (3 times each time 1 mL) and stoned; The mixture was dried in celite to give a residue. LCMS: m/z 394.21. (M+H) + φ Step D: Purified bromide (7·59 g) and 3-bromopropene in step c (2.04 liters) was dissolved in DMF (1 mL). Sodium hydride (116 g) was added in 3 portions and the reaction was stirred at room temperature for 9 min. After the start of the reaction, two equivalents of 〇·25 equivalents were added to complete the reaction. The mixture was then taken up in water (500 ml) and extracted with diethyl ether (2 times each time 3 mL). The organic layer was washed with water (100 ml), dried over magnesium sulfate and

物以砍膠純化獲得烯丙基化之胺。LCMS: m/z 434. 23 (M+HV 步驟E :將步驟d之烯丙基化合物（7·89克）、溴化四丁基 224 93966 200812588 銨（5· 85克）、乙酸鈀（0· 41克）以及碳酸鉀（7· 53克）溶於 DMFC150毫升）中。將該混合物加熱至80°C維持30分鐘之 後，按照步驟D的方式處理該混合物。最後將該混合物以 矽膠純化獲得標題化合物。LCMS : m/z 354. 39 (M+H)+ 實施例3 : 5-(2-乙基-6-曱氧基地啶-3-基）-l-[US)-2-氟 -1-（甲氧基曱基）-乙基]-3, 6-二曱基-1H-吡咯并[3, 2-b] 吡啶之合成The material was purified by chopping to obtain an allylated amine. LCMS: m/z 434. 23 (M+HV Step E: </RTI> </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> · 41 g) and potassium carbonate (7.53 g) dissolved in DMFC 150 ml). After the mixture was heated to 80 ° C for 30 minutes, the mixture was treated in the same manner as in the step D. Finally, the mixture was purified by silica gel to give the title compound. LCMS: m/z 354. 39 (M+H) + </RTI> Example 3: 5-(2-ethyl-6-decoxy- dindin-3-yl)-l-[ Synthesis of (methoxymethoxy)-ethyl]-3,6-dimercapto-1H-pyrrolo[3,2-b]pyridine

步驟A :將胺基-3-曱氧基-丙-卜醇鹽酸鹽（CAS# : 148278-96-0)( 6· 74克）和咪唑（13· 7克）置入於無水的二 氯曱烷（300毫升）中。加入一份的TBDMSCK22· 7克）。使 該反應進行隔夜。以水（3次而每次200毫升）清洗該反應 混合物並用硫酸鈉乾燥之。移除所有的揮發物並濃縮之。 所得之粗產物無須進一步純化係直接用於下一個步驟的反 應中。 步驟B :將曱苯（80毫升）中的已知溴化物（6. 4克，0· 02 225 93966 200812588 莫耳）、胺（1·5 當量）、ΒΙΜΡ(1·0 克）、Pd2(dba)3(0.6 克）、 第三丁氧基鈉（4· 0克）混合物於氮氣氛下以85°C加熱並隔 夜。將該反應混合物冷卻至室溫並加入水終止其反應。分 層後所得到之混合物並用乙酸乙酯萃取。將合併之有機層 用水清洗並用硫酸鈉乾燥之。用己烧/乙酸乙酯進行石夕膠快 速層析法（Silica gel flash chromatography)獲得經純化 之產物。 _步驟C :將該起始物質（7· 3克）置於無水的氯仿（1〇〇毫升） 中。於0°C加入一份1·〇當量的NBS。該反應於〇·5小時内 完成。用飽和鹽水清洗該反應混合物並用硫酸鈉乾燥之。 用己烧/乙酸乙酯進行石夕膠快速層析法獲得經純化之產物。 步驟D :將起始物質（5· 9克）置入於無水的THF( 1〇〇毫升） 中。加入破丙烯（3· 6毫升）後，隨即在室溫下加入第三丁 氧基卸/TFH:谷液（1 · 〇M，44毫升）。該反應於室溫下攪拌3 小衅。用水終止該反應混合物。分層後所得到之混合物並 參用乙酸乙酯萃取。將該合併之有機層用飽和鹽水清洗並用 硫酸鈉乾燥之。用己烷/乙酸乙酯進行矽膠快速層析法獲得 經純化之產物。 ^ 步驟E :將先前反應之該粗產物（6· 4克）置入於磨⑽毫 升）中’隨後將漠·化四丁基錄（4.4克）、K2C〇3(4 6克）、 Pd〇(0Ac)2(130亳克）加人。將所得之混合物於氮氣氛下以 85 C加熱1小時。將該反應混合物冷卻至室溫並加水稀釋 之。所得之混合物用乙酸乙醋萃取。將該合併之有機層用 飽和鹽水清洗並用硫酸納乾燥之。用己燒/乙酸乙醋進二矽 93966 226 200812588 勝快速層析法獲得經純化之產物。 ㈣F:將起始物質（5.4克）置入於挪（㈣升）中，隨後 f至溫下將氣化四丁基銨（2當量）加入。於2小時後完成 =反應用水、飽和鹽水清洗該反應混合物並用硫酸鈉乾 、卞之用己烧/乙酸乙醋進行石夕膠快速層析法獲得經純化之 產物。 步驟G:將起始物質（11克）置入於無水的二氯甲烧⑽毫 • 1)中，後於室溫下加入三氟化[雙（2_甲氧*乙基）胺基] 硫（2當量）。該反應於室溫下攪拌隔夜。用冰水小心地將 f反應混合物終止。分層後所得到之混合物並用二氯甲烧 萃取，之後用硫酸鈉乾燥之。用己烷/乙酸乙酯進行矽膠快 速層析法獲得該標題化合物。Lcms : m/z 372. 4 (Μ+Ι〇 + 實施例4 : 2-[2-乙基一3-(6_異丙基_2_曱氧基吡啶_3一基） -5-甲基-5H-吡咯并[2,3-b]吡哄-7一基]丙—卜醇之合成Step A: Amino-3-methoxy-propanol hydrochloride (CAS#: 148278-96-0) (6.67 g) and imidazole (13·7 g) were placed in anhydrous In chlorodecane (300 ml). Add a portion of TBDMSCK22·7g). The reaction was allowed to proceed overnight. The reaction mixture was washed with water (3 times each time 200 ml) and dried over sodium sulfate. Remove all volatiles and concentrate. The crude product obtained was used in the next step without further purification. Step B: Known bromide (6.4 g, 0. 02 225 93966 200812588 Moule), amine (1.5 eq.), hydrazine (1.0 g), Pd2 in terpene (80 ml) A mixture of dba)3 (0.6 g) and sodium tributoxide (4.0 g) was heated at 85 ° C under a nitrogen atmosphere overnight. The reaction mixture was cooled to room temperature and water was added to terminate the reaction. The resulting mixture was separated and extracted with ethyl acetate. The combined organic layers were washed with water and dried over sodium sulfate. The purified product was obtained by silica gel flash chromatography using hexane/ethyl acetate. <Step C: The starting material (7.3 g) was placed in anhydrous chloroform (1 mL). A 1 〇 equivalent of NBS was added at 0 °C. The reaction was completed in 5 hours. The reaction mixture was washed with saturated brine and dried over sodium sulfate. The purified product was obtained by flash chromatography using hexane/ethyl acetate. Step D: The starting material (5.9 g) was taken in anhydrous THF (1 mL). After the addition of propylene (3.6 ml), a third butoxy-depleted/TFH: gluten solution (1 · 〇M, 44 ml) was added at room temperature. The reaction was stirred at room temperature for 3 hours. The reaction mixture was quenched with water. The resulting mixture was separated and extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over sodium sulfate. The purified product was obtained by flash chromatography using hexane/ethyl acetate. ^ Step E: The crude product (6.4 g) previously reacted was placed in a mill (10 ml). Then the tetrabutylate (4.4 g), K2C〇3 (46 g), Pd were prepared. 〇 (0Ac) 2 (130 gram) plus people. The resulting mixture was heated at 85 C for 1 hour under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and diluted with water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over sodium sulfate. The product was purified by flash chromatography/acetic acid acetonitrile. 96966 226 200812588 by flash chromatography. (4) F: The starting material (5.4 g) was placed in the (four) liter, and then vaporized tetrabutylammonium (2 equivalents) was added at a temperature of f to the temperature. After 2 hours, the reaction mixture was washed with water and saturated brine and dried over sodium sulfate. Step G: The starting material (11 g) was placed in anhydrous dichloromethane (10) mM 1), then added at room temperature [bis(2-methoxy]ethyl)amino] Sulfur (2 equivalents). The reaction was stirred overnight at room temperature. The f reaction mixture was carefully terminated with ice water. The resulting mixture was separated and extracted with methylene chloride, then dried over sodium sulfate. The title compound was obtained by flash chromatography on hexane/ethyl acetate. Lcms : m/z 372. 4 (Μ+Ι〇+ Example 4: 2-[2-ethyl-3-(6-isopropyl-2-oxoximepyridine-3-yl)-5-A Synthesis of 5-H-pyrrolo[2,3-b]pyridin-7-yl]propanol

步驟A:將已知的2, 6-二溴—3-氯—5-曱胺基吡哄（550毫克） 93966 227 200812588 與所顯示之烯丙基溴化物（560毫克，以Enders等人於 Synlett 2002，2280中所述之曱基-位向異構物（如-regioisomer)之相同方法合成）溶於DMF(10毫升）中。加入 氫化鈉（91毫克）之後，將暗紅色的反應混合物攪拌15分 鐘。之後，將該混合物置入於水（2〇〇毫升）和飽和的碳酸 氫鈉（100毫升）中，用乙醚（2次而每次1〇〇毫升）萃取，並 用硫酸鎂乾燥之。將該混合物以矽膠純化獲得烯丙基化之 化合物。TLC : Rf = 〇. 69(EE/hex=l/6) ®步驟B :將步驟A的烯丙基化之化合物（892毫克）、溴化四 丁基銨（57 5宅克）、乙酸把（40毫克）以及碳酸钾（737毫克） 洛於DMF(10耄升）中。將該混合物加熱至維持3〇分 鐘之後，該混合物按照步驟A的方式進行處理。將該混合 物以矽膠純化獲得Heck-產物。LCMS : m/z 417. 93 (Μ+ί〇 + 步驟C ·將步驟B的Heck產物（356毫克）溶於THF(2· 5毫 升）中並在- 78C下的THF(8· 5毫升）中加入卜BuLi (1. 05 _毫升，1·7Ν於戊烷中）溶液。將該混合物攪拌1〇分鐘之後， 加入乙基碘（0· 2毫升）並使該反應混合物在—78〇c下再攪 拌1小時。之後，將該混合物置入於水（1〇〇毫升）和飽和 的碳酸氫納（100毫升）中，用DCM(3次而每次1〇〇毫升）萃 取，並用硫酸鎂乾燥之。將該混合物以矽膠純化獲得其乙 基衍生物。 步驟D:將步驟C的乙基產物（238毫克）和已知的2 —異丙 基-6-甲氧基-5-吡啶硼酸（158毫克）溶於DME(5· 〇毫升） 中。除氣後，加入肆（三苯基膦）1巴（〇)(77毫克）。第二次 93966 228 200812588 除氣後隨即將IN的碳酸鈉溶液（1. 35毫升）加入並使該反 應加熱至80°C維持3小時。之後將淡黃色的混合物置入於 水（100毫升）中，用DCM(3次而每次100毫升）萃取，並用 硫酸鎂乾燥之。將該混合物以矽膠純化獲得經偶合之產物。 步驟E :將步驟D的鈴木反應產物（Suzuki product)溶於 THF( 5. 0毫升）中。加入一水氟化四丁銨（TBAF monohydrate) (650毫克）之後，將該反應混合物攪拌30分鐘。之後，將 黃色溶液置入於水（100毫升）中，用DCM(3次而每次100 ▼毫升）萃取，並用硫酸鎂乾燥之。該混合物以矽膠純化獲得 標題化合物。 實施例5 : 2 - [ 5 -乙基- 6 -（ 6 -異丙基-2 -曱氧基°比咬-3 -基） -：1-甲基-1H-吡咯并[2, 3-b]吡啶-3-基]丁-1-醇之合成Step A: The known 2,6-dibromo-3-chloro-5-amidopyrazine (550 mg) 93966 227 200812588 is shown with allyl bromide (560 mg, as Enders et al. Synthet 2002, 2280 is synthesized in the same manner as the thiol-position isomer (e.g., -regioisomer) dissolved in DMF (10 mL). After the addition of sodium hydride (91 mg), the dark red reaction mixture was stirred for 15 min. After that, the mixture was poured into water (2 mL) and EtOAc (EtOAc) The mixture was purified by silica gel to obtain an allylated compound. TLC : Rf = 〇. 69(EE/hex=l/6) ® Step B: The allylated compound of step A (892 mg), tetrabutylammonium bromide (57 5 house gram), acetic acid (40 mg) and potassium carbonate (737 mg) in DMF (10 liters). After the mixture was heated to maintain for 3 Torr, the mixture was treated as in the step A. The mixture was purified by silica gel to give the Heck-product. <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; Add a solution of BuLi (1. 05 _ml, 1.7 Torr in pentane). After stirring the mixture for 1 hr, add ethyl iodine (0.2 mL) and make the reaction mixture at -78 〇c After stirring for another hour, the mixture was placed in water (1 mL) and saturated sodium bicarbonate (100 mL) and extracted with DCM (3 times each time 1 mL) The magnesium is dried. The mixture is purified by hydrazine to give the ethyl derivative. Step D: The ethyl ester from step C (238 mg) and known 2-isopropyl-6-methoxy-5-pyridine Boric acid (158 mg) was dissolved in DME (5·ml). After degassing, hydrazine (triphenylphosphine) 1 bar (〇) (77 mg) was added. The second time 93966 228 200812588 was degassed and then IN The sodium carbonate solution (1. 35 ml) was added and the reaction was heated to 80 ° C for 3 hours. The pale yellow mixture was then placed in water (100 mL) with DCM (3 times) It was extracted with 100 ml each time and dried over magnesium sulfate. The mixture was purified by silica gel to give the coupled product. Step E: The Suzuki product of Step D was dissolved in THF (0.5 mL). After adding TBAF monohydrate (650 mg), the reaction mixture was stirred for 30 minutes. After that, the yellow solution was placed in water (100 ml) using DCM (3 times each time 100) The mixture was extracted with MgSO.sub.4. Synthesis of 3-methyl)-:1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]butan-1-ol

步驟A:將TBDMSC 1(20克）加入至溶有4^經基-2-丁嗣（17. 6 229 93966 200812588 克）、DMAP(200毫克）、咪唑（ι〇· 8克）的冷（〇艺）DMF 〇6〇 耄升）溶液中。使該反應混合物自然回溫至室溫並攪拌24 小日令。將水加入至反應混合物中並用乙酸乙酯萃取，之後 用硫酸鈉乾燥之。藉由用己烷/乙酸乙酯之管柱法純化獲得 產物。Rf : 〇· 4(己烧/乙酸乙酯：8 : 1) 步驟B ·將三乙基構酸乙酸酯（17· 3毫升）與thf (3 〇毫升） 开&gt; 成之溶液加入至含有氫化納（〇 · 131莫耳）的無水thf ( 8 〇 _毫升）的冷（〇°C )懸浮液中。所得到的混合物在〇。〇下攪拌1 小牯，之後將酮（17· 67g)與THF (10毫升）形成之溶液加入 於其中。該反應在室溫下持續再進行2小時。小心地加入 飽和的氯化銨水溶液並使之分層。用乙驗萃取該水層。將 該合併之有機層用水、飽和鹽水清洗。藉由用己烷/乙酸乙 酉曰之管柱法純化獲得產物。Rf : 〇· 4(己烧/乙酸乙酯：1 5 : 1) 步驟C:將起始物質（21· 3克）於（TC下用DIBAL-HU· 0M於 _甲本中，19 6耄升）處理β小時。將水小心地加入以淬息過 多的DIBAL。過濾該反應混合物並用乙酸乙酯清洗。濃縮 該滤液而獲得粗產物。Rf : 〇· 4(己烧/乙酸乙醋：3 : 1) 步驟D:將起始物質（8· 75克）置入於無水的二氯甲烷（11〇 毫升）中，並加入三乙胺。將所得到的混合物冷卻至一 4〇。〇。 逐滴加入MsCl並使該反應持續在下1小時，之後將 溴化鋰（13· 2克）與THF(120毫升）形成之溶液加入。將所 付到的反應混合物自然回溫至室溫並持續再進行1小時。 用水終止該反應並使之分層。用乙醚萃取該水層。將合併 230 93966 200812588 之有機層用飽和鹽水清洗並用硫酸鈉乾燥之。所得之粗產 物無須進一步純化而能直接用於下一個步驟的反應中。Step A: Add TBDMSC 1 (20 g) to cold (4. 6 229 93966 200812588 g), DMAP (200 mg), imidazole (ι 〇 8 g). 〇艺) DMF 〇 6 〇耄) in solution. The reaction mixture was allowed to naturally warm to room temperature and stirred for 24 hours. Water was added to the reaction mixture and extracted with ethyl acetate, followed by drying over sodium sulfate. The product was obtained by column chromatography using hexane/ethyl acetate. Rf : 〇· 4 (hexane/ethyl acetate: 8 : 1) Step B · Add triethyl oxy-acid acetate (17.3 ml) and thf (3 〇 ml) to the solution A cold (〇 ° C ) suspension containing sodium hydride (〇 · 131 mol) in anhydrous thf ( 8 〇 _ ml). The resulting mixture was in hydrazine. After stirring for 1 hour, the solution of the ketone (17.67 g) and THF (10 ml) was added thereto. The reaction was continued for an additional 2 hours at room temperature. A saturated aqueous solution of ammonium chloride was carefully added and allowed to separate. The aqueous layer was extracted by an assay. The combined organic layers were washed with water and saturated brine. The product was obtained by column chromatography using hexane / ethyl acetate. Rf : 〇· 4 (hexane/ethyl acetate: 1 5 : 1) Step C: The starting material (21.3 g) was used under (TC) with DIBAL-HU·0M in _book, 19 6 耄l) treated for β hours. Water was carefully added to quench the excess DIBAL. The reaction mixture was filtered and washed with ethyl acetate. The filtrate was concentrated to give a crude product. Rf: 〇·4 (hexane/acetic acid ethyl acetate: 3:1) Step D: The starting material (8.55 g) was placed in anhydrous dichloromethane (11 mL) and triethylamine was added. . The resulting mixture was cooled to a temperature of 4 Torr. Hey. MsCl was added dropwise and the reaction was continued for the next hour, after which a solution of lithium bromide (13.2 g) and THF (120 ml) was added. The reaction mixture was naturally warmed to room temperature and continued for an additional hour. The reaction was quenched with water and allowed to separate. The aqueous layer was extracted with diethyl ether. The organic layer of 230 93966 200812588 was washed with saturated brine and dried over sodium sulfate. The crude product obtained was used in the next step without further purification.

Rf : 0· 4(己娱：/乙酸乙酯：2〇 : 1)。 步驟E:將2,6-二氯料（17克）與甲胺（(：副2)的水溶液 (40%，26. 8克）置入於密封於試管中的THF(1〇〇毫升）中並 於80°C加熱24 λ}、時。將該反應冷卻至室溫並用水稀釋之。 使該反應混合物分層並用乙酸乙醋萃取。將合併之有機層 •用飽和鹽水清洗並用硫酸納乾燥之。所得之粗產物無須^ -步純化而能直接用於下—個步驟的反應中。聰：143 3 (M+H)+ 步驟F :將2-氯-6-甲胺基♦定（3. % 〇. 〇25莫耳）、2_ 甲氧基-6-異丙基-3-吼唆基删酸（6 33g)、pd(pph3)4抓 毫克）、碳酸鈉水溶液（1.〇M，5〇毫升）與甲苯（5〇毫升）於 10(TC的氮氣氛下加熱隔夜。將該反應冷卻至室溫並使之分 層。用乙酸乙醋萃取該水層。將該合併之有機層用飽和鹽 鲁水清洗並用硫酸鈉乾燥之。所得之粗產物無須進一步純化 而能直接用於下—個步驟的反應中。乙酸乙 酯：4 ·· 1) 〇 步驟G:將該粗起始物質置入於無水的氯仿（100毫升）中。 於（TC加入一份4.0當量的NBS。該反應於〇5小時内完 成。將該反應混合物用水清洗並用硫酸納乾燥之。用己燒/ 乙酉夂乙H了快速f柱層析法純化獲得呈清澈油狀之產 物。LCMS : m/z 496. 1 (M+IO + 步驟Η:將氫化納（795毫克，議於礦物油中）加入至溶有 93966 231 200812588 起始物質（6. 34克）的無水_ (刚毫升）中並於室溫下授 拌ίο分鐘。逐滴加入步冑D所製備漠化4勿（4.93§)並將所 得之混合物授拌3小時。用水小心地終止該反應混合物。 將所得之混合物用乙酸乙醋萃取。將合併之有機層用餘和 鹽水清洗並用硫酸鈉乾燥之。用己烷/乙酸乙酯進行快速管 柱層析法純化獲得呈清澈油狀之產物。Rf: 〇·4(己烷/乙酸 乙酯：12 : 1)。 _步驟I :將溶於DMF(80毫升）中的溴化物（9 26克）、溴化 四丁基銨（5. 95克）、碳酸鉀（6· 12克）、pMOAchd· 〇克） 混合物於80 C的氮氣氛下加熱20分鐘。將該反應混合物 /令部至至溫並用水稀釋之。所得之混合物用乙酸乙醋萃 取。將該合併之有機層用飽和鹽水清洗並用硫酸鈉乾燥 之。用己烧/乙酸乙酯進行快速管柱層析法純化獲得呈清澈 油狀之產物。LCMS : m/z 548. 4 (Μ+ί〇 + 步驟J :在-78°C下將溶有溴化物（3. 〇7克）的THF(5毫升） 春溶液加入至溶有BuLi(l· 7M/戊烷，7毫升）的THF(30毫升） /谷液中。在-7 8 C下授摔所得之混合物1 〇分鐘，之後將蛾 乙烷（1· 4毫升）加入。該反應持續進行3〇分鐘。用乙醇小 心地終止該反應混合物。所得之混合物用水和飽和鹽水清 洗，之後用硫酸鈉乾燥之。以使用己烷/乙酸乙酯之矽膠層 析法獲得經純化之產物。 步驟K :將起始物質（1· 26克）置入於THF (50毫升）中，接 著在室溫下加入氟化四丁基胺（1.5當量）。於4小時後完 成該反應。將反應混合物用水和飽和鹽水清洗，之後用硫 232 93966 200812588 酸鈉乾燥之。以使用己烷/乙酸乙酯之矽膠層析法獲得標題 化合物。 實施例6 : CRF受體的機能性活性（functional activity) 試驗 如上所述者，以下之試驗為本文以及申請專利範圍中 所稱之標準的活體外CRF受體的機能性活性試驗。使用化 學螢光之酵素連結免疫試驗系統（chemiluminescent ELISA system)(cAMP-Screen®, Applied Biosystems, ® Bedford, MA)並根據其製造手冊定量由人類神經胚細胞瘤 細胞株MR-32所萃取出而製備成之3’，5’-環單磷酸腺甘 (Cyclic AMP :簡稱作cAMP)之濃度，該人類神經胚細胞瘤 細胞株MR-32會内生性地表現人類的CRF1受體。該等 IMR32細胞（ATCC CCL 127)係成長並匯集成在一個或多個 T-175型的燒瓶中，在進行測試處理以及連結免疫試驗系 統之前，將每個T-175型燒瓶均勻切割成兩個預塗有96 -_孔的cAMP- Screen®試驗盤之孔，隨後將每個試驗盤培育 16小時並試驗之。培養物係在I MR-32培養基中：EMEM w/Earle’s BSS (JRH Biosciences，Cat# 51411)再加上， 例如補給品2mM的左旋麩醯胺酸、10%的胎牛血清（Fetal Bovine Serum :簡稱作FBS)、25mM的N-2_經乙基°比哄 -Ν’ -2-乙石黃酸（N-2-hydroxyethyl piperazine-N’ -2-ethanesul fonic acid : HEPES)(pH 7· 2)、ImM 的丙嗣酸鈉 以及非必須胺基酸（JRH Biosciences，Cat# 58572)，維持 16至20小時。就拮抗劑模式之特性而言，該等化合物給 233 93966 200812588 予的劑量係取決於拮抗CRF反應的cAMP產生量。CRF的EC6〇 反應係用於刺激該等IMR32細胞產生cAMP。用共培育的策 略（co-incubation strategy)決定出該等化合物的效力以 倒推刺激過的CRF之cAMP反應。使用非線性回歸試驗 (non-1 inear regression analysis)計算該等 ICso 以及 Ki 值。就對促進式之特性而言，該等化合物係單獨使用以處 理該等細胞。 實施例7 : CRF受體結合活性之試驗 — 如上所述者，以下之試驗為本文以及申請專利範圍中 所稱之標準的活體外CRF受體結合試驗。該CRF受體結合 試驗係使用描述於 Grigoriadis 和 De Souza (i/ei/jods /3 yVeuroscie/Jces，Vol. 5，1991)中的試驗之改良版予以進 行。IMR-32人類神經胚細胞瘤細胞（能自然地表現CRF1受 體的細胞株)係在IMR-32培養基中生長（參考先前的實施 例）。將成長的該等細胞匯集並分割成三份（所有的分割和 份量係使用 NO-ZYME-JRH Biosciences，Cat# 59226 進 行）。該等細胞分割成1 : 2連續培育3天，之後分割成1 : 3，而最培育4天並分割成1 : 5。之後將該等細胞額外多 培育4天，之後藉由用5-溴-2-脫氧尿苷（5 - bromo-2 -deoxyuridine:簡稱作 BrdU)(BrdU，Sigma，Cat# B9285) 之處理分化該等細胞。每3至4日該培養基係用IMR-32 培養基w/2. 5uM BrdU予以置換BrdU處理的第10天後收取 該等細胞並用不含鈣與鎂的PBS清洗。 為了製備含細胞膜之受體，將該等細胞均質化於洗液 234 93966 200812588 (wash buffer)(50 mM Tris HCl、10 mM 氯化鎂、2 mM EGTA、 ?117.4)中並在4°(：以48,00(^§離心1〇分鐘。將該離心 沉澱物（pel let)再懸浮於洗液中且該均質化與離心步驟係 額外多進行兩次。Rf: 0·4 (Entertainment: /ethyl acetate: 2〇: 1). Step E: 2,6-dichlorobenzene (17 g) and methylamine ((: 2) aqueous solution (40%, 26.8 g) were placed in THF (1 ml) sealed in a test tube. The mixture was heated to room temperature at 80 ° C. The reaction was cooled to room temperature and diluted with water. The reaction mixture was separated and extracted with ethyl acetate. The combined organic layers were washed with saturated brine and sodium sulfate. Drying. The obtained crude product can be directly used in the next step without purification. Cong: 143 3 (M+H)+ Step F: 2-chloro-6-methylamine (3. % 〇. 〇25 mol), 2_methoxy-6-isopropyl-3-indolyl acid (6 33g), pd(pph3)4 g), sodium carbonate aqueous solution (1. 〇M, 5 〇 ml) and toluene (5 〇 ml) were heated overnight at 10 (TC under nitrogen atmosphere. The reaction was cooled to room temperature and layered. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The obtained crude product was used in the next step without further purification. ethyl acetate: 4 ·· 1) 〇 Step G: Rough start Mass placed in dry chloroform (100 ml). Add a 4.0 equivalent of NBS to the TC. The reaction is completed in 5 hours. The reaction mixture is washed with water and dried over sodium sulfate. Purified by flash-purchase / acetonitrile-H. The product was obtained as a clear oil. LCMS: m/z 496. 1 (M+IO + Step Η: sodium hydride (795 mg, in mineral oil) was added to dissolve in 93966 231 200812588 starting material (6. 34 g In anhydrous _ (just ML) and mixed at room temperature for ί. minutes, add Desertification 4 (4.93 §) prepared by step D and mix the resulting mixture for 3 hours. Carefully terminate the water with water. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. Product: Rf: 〇·4 (hexane/ethyl acetate: 12:1) _ Step I: bromide (9 26 g) dissolved in DMF (80 ml), tetrabutylammonium bromide (5) 95 g), potassium carbonate (6·12 g), pMOAchd· gram) The mixture was heated under a nitrogen atmosphere of 80 C for 20 minutes. The reaction mixture was tempered with water and diluted with water. The mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over sodium sulfate. Purification by column chromatography gave the product as a crude oil. LCMS: m/z 548. 4 (Μ+ί〇+ Step J: bromide (3. 7 g) at -78 ° C THF (5 ml) was added to a solution of BuLi (1.7 M / pentane, 7 ml) in THF (30 ml) / broth, and the mixture was dropped at -7 8 C for 1 , min. The moth ethane (1.4 ml) was added. The reaction was continued for 3 minutes. The reaction mixture was carefully quenched with ethanol. The mixture was washed with water and saturated brine and then dried over sodium sulfate. The purified product was obtained by chromatography on ethyl acetate. Step K: The starting material (1·26 g) was placed in THF (50 ml), then tetrabutylamine fluoride was added at room temperature ( 1.5 equivalents. The reaction was completed after 4 hours. The reaction mixture was washed with water and saturated brine. The title compound was obtained by silica gel chromatography using hexane/ethyl acetate. Example 6: Functional activity of CRF receptors As described above, the following The test is a functional activity test of the in vitro CRF receptor as referred to herein and in the scope of the patent application. The chemical chemiluminescent ELISA system (cAMP-Screen®, Applied Biosystems, ®) is used. Bedford, MA) and according to its manufacturing manual, quantify the concentration of 3',5'-cyclic adenosine monophosphate (Cyclic AMP: cAMP) prepared by human neuroblastoma cell line MR-32. The human neuroblastoma cell line MR-32 endogenously expresses the human CRF1 receptor. The IMR32 cells (ATCC CCL 127) were grown and pooled into one or more T-175 flasks, and each T-175 flask was evenly cut into two before being tested and attached to the immunoassay system. The wells of the cAMP-Screen® test disc pre-coated with 96-_ holes were then incubated for 16 hours and tested. The culture is in I MR-32 medium: EMEM w/Earle's BSS (JRH Biosciences, Cat # 51411) plus, for example, 2 mM L-glutamic acid, 10% fetal bovine serum (Fetal Bovine Serum: Abbreviated as FBS), 25 mM N-2_ethyl-ethyl 2-hydroxyethyl piperazine-N' -2-ethanesul fonic acid (HEPES) (pH 7· 2) ImM sodium propionate and non-essential amino acids (JRH Biosciences, Cat# 58572) were maintained for 16 to 20 hours. The dosage of such compounds to 233 93966 200812588 is dependent on the amount of cAMP production that antagonizes the CRF response in terms of the nature of the antagonist pattern. The EC6(R) response of CRF is used to stimulate the production of cAMP by these IMR32 cells. The co-incubation strategy was used to determine the potency of these compounds to reverse the cAMP response of the stimulated CRF. These ICso and Ki values were calculated using a non-1 inear regression analysis. For the properties of the promoting formula, the compounds are used alone to treat the cells. Example 7: Test for CRF Receptor Binding Activity - As described above, the following assays are standard in vitro CRF receptor binding assays referred to herein and in the scope of the patent application. The CRF receptor binding assay was performed using a modified version of the assay described in Grigoriadis and De Souza (i/ei/jods / 3 yVeuroscie/Jces, Vol. 5, 1991). IMR-32 human neuroblastoma cells (cell lines capable of naturally expressing CRF1 receptors) were grown in IMR-32 medium (refer to the previous examples). The growing cells were pooled and divided into three portions (all fractions and fractions were performed using NO-ZYME-JRH Biosciences, Cat# 59226). The cells were divided into 1:2 for 3 consecutive days, then divided into 1:3, and most incubated for 4 days and divided into 1:5. The cells were then incubated for an additional 4 days, after which the cells were differentiated by treatment with 5-bromo-2-deoxyuridine (BrdU, Sigma, Cat# B9285). Wait for cells. The medium was harvested every 3 to 4 days after the 10th day of the BrdU treatment with IMR-32 medium w/2. 5uM BrdU and washed with PBS containing no calcium and magnesium. To prepare a cell membrane-containing receptor, the cells were homogenized in a wash solution 234 93966 200812588 (wash buffer) (50 mM Tris HCl, 10 mM magnesium chloride, 2 mM EGTA, ?117.4) at 4° (: 48 , 00 centrifugation for 1 minute. The pel let was resuspended in the wash and the homogenization and centrifugation steps were performed twice more.

該等細胞膜離心沉澱物（含CRF受體）係再懸浮於pH 7· 7含有1〇 mM氯化鎂與2 mM EDTA的50 mM Tris緩衝液 中並在4 C以48, 00Og離心1〇分鐘。再次清洗該等細胞膜 _並將其帶至最終濃度為1500 ug/毫升的結合緩衝液（該 Tris緩衝液具有超過^ % BSA、15 rnM的1.4枯草菌素 (bacitracin)以及〇·〇ΐ毫克/毫升的抗纖維溶解劑 (aprotinin))中。就結合試驗而言，將1〇〇#L的細胞膜製 劑加至含有IOOaL的125卜蛇皮降壓素（sauvagine)(SA 2200 Ci/毫莫耳，最終濃度為1〇〇pM)以及5〇//L的測試化 合物的96井的微量離心管的裝載板上。在室溫下進行結合 2小％。之後用BRANDEL 96孔的細胞收取器收取該等裝載 _板並用Wal lac 1205 BETAPLATE型的液態閃爍計數器 (liquid scintillation counter)的 r 射線計數該等過濾 物。非專一性結合（]1〇11-31^(：^1(：： binding)係被界定成1 mM的冷CRF。該等ICso值係用分線性曲線擬合軟體rs/1 (BBN Software Products Corp·，Cambridge，MA)予以計 #經測试’該專表I之化合物及鹽類之結合親和力（表示 成IC5〇值）一般在0.5奈莫耳至10微莫耳的範圍。該等 式I之較佳化合物及鹽類顯示出該等的IC5。值小於或等於 1 · 5微莫耳，該等式I之更佳化合物及鹽類顯示出該等的 93966 235 200812588 1C5。值小於或等於500奈莫耳，該等式I之更較佳化合物 及鹽類顯示出該等的IC5〇值小於或等於100奈莫耳，而該 等式I之最佳化合物及鹽類顯示出該等的ic5Q值小於或等 於10奈莫耳。該等較佳之化合物及其鹽類為該等表I中所 示者。 實施例8 :人類肝臟微粒體（human liver microsomes)中 的細胞色素 P450(CYP)1A2、2C8、2C9、2C19、2D6 與 3A4 的機理性抑制作用（mechanism-based inhibit ion)之評估 _ 化合物及鹽在1、2· 5、5、10、25以及次佳為5〇 # μ 下與混合人類肝臟微粒體在1)存在以及2)不存在NADPH (最終濃度為1 mM)之狀況下於37°C的震盪水槽中預培育 30分鐘。1 〇倍稀釋含有〇· 1M填酸鹽緩衝液（pH 7· 4)、選 擇性CYP探針受質（probe substrate)與NADPH(最終濃度 為1 mM)之預培育混合物之後，量測殘餘酵素活性 (residual enzyme activity)並評估兩處理間之抑制偏移 _的程度。於存在和不存在有NADPH中，每個與濃度有關並 統計上顯著減小之特定CYP活性意指該CYP異構酵素 (isozyme)之機理性抑制作用。每一 CYP異構酵素的賦形劑 和習知選擇性之機理性抑制劑亦會與該化合物或鹽平行分 開培育以作為陰性對照組與陽性對照組。正控制包括呋拉 茶鹼（{1^!7111116)(0丫？1人2)、吉非貝齊葡苷酸 (gemfibrozil glucuronide)或次佳為苯乙肼（phenelzine) (CYP2C8)、替尼酸（tienilic acid)(CYP2C9)、噻氯匹啶 (ticlopidine) (CYP2C19)、帕羅西、;丁（paroxetine) 236 93966 200812588 (CYP2D6)以及里貝拉地爾（ribefradil)(CYP3A4)。為了評 估所有的CYPs，該活性試驗係依下列線性條件進行： 酵素 預培育時 德ί粒體的濃度 (毫克/亳升） 活性試驗時 微粒體的濃度 (亳克/毫升） 探針受質 探針受質 濃度（以M) 預培育 時間 (分鐘） CYP1A2 1 0.1 非那西汀 (Phenacetin) 35 30 CYP2C8 0.1 0.01 氨齡奎 (Amodiaquine) 2.5 10 CYP2C9 5 0.5 甲苯磺丁脲 (Tolbutamide) 400 10 CYP2C19 2 0.2 S-美芬妥英 (S-Mephenytoin) 120 40 CYP2D6 1 0. 1 右美沙芬 (Dextromethorphan) 15 5 CYP3A4 2 0.2 睪丸酮 (Testosterone) 250 10 就每一個試驗，監控CYP個別代謝物的生成並用LC-MS (去曱右美沙芬（(!6又士1'0^11&amp;11))、丄〇118/118(4’-經基甲苯石黃 丁脲、去乙基氨酚奎、4-乙醯胺基苯酚（4- acetamidophenol)、4-羥基-S-美芬妥英）或 HPLC(6/3-羥 基 testosterone)定量之。 就每一個受測的異構酵素而言，相較於無NADPH下經 30分鐘預培育後，有NADPH預培養後異構酵素的機理性抑 制劑將顯示濃度相關性以及統計上活性顯著之減少（t-檢 定（student’s t-test) ·· ρ&lt;0· 05)。人類肝臟微粒體在有以 及沒有NADPH下與係與式I較佳之化合物及其鹽類在1、 2· 5、5、10、25以及50 // Μ的濃度下予以預培育時，若觀 察到在 CYP1A2、CYP2C8、CYP2C9、CYP2C19、CYP2D6 以及 237 93966 200812588 CYP3A4的該等活性之一個或多個（較佳為全部）中無統計 上顯著改變時’則證明其對每一異構酵素皆無機理性抑制。 實施例9 ··狗的噁心嘔吐試驗 該等式1(較佳為表I)之較佳化合物或及其鹽類若以 其治療有效里技予患者日守’則並不會惡心或σ區吐。此性質 的合適量測為，6隻狗當中若超過1隻狗以上在一小時内、 較佳3小時内或次佳為6小時内投予選自每公斤的體重佔 1、30、100、300以及1000毫克之劑量時無嘔吐。此無嘔 吐係由下列所測定··使用合於注射器之彈性管並沖入大約 10毫升的蒸餾水藉由經口插管之方式（oral intubati〇n) 將化合物或鹽之該等劑量予以投入。以認證過的狗食，第 5007 號（PMI Nutrition International，St· Louis，MO)， 以任意400克之量每日傻狗4小時。每日幾乎在相同的時 間提供食物。進食的i至2小時之前先服藥。水係經由自 動供水系統任意地提供。觀察化合物或鹽投入3〇分鐘之後 與投藥後之1小時、3小時和6小時等四次。於觀察期間 記錄觀察到的唱吐事件。 貝％例10 ·放射性標記化合物 compounds)之製備 一該等式丨（較佳為表I)之化合物及鹽係使用含有至少 、原r為放射’[生同位素之先驅物藉由進行該等之合成製備 成〜等的放射性標記探針（1^丨。1*16^^。|^)。放射性 同素較佳係選自下列中之至少一者K較佳為&quot;〇、氫 乂佺為H)、硫（較佳為35s)或碘（較佳為1251)。此等放射 93966 238 200812588 性標記探針係適合用放射性同位素供應商專門為客戶合成 之該等放射性標記探針化合物予以合成。此等供應商包括 安發瑪西亞生物技術公司（Amersham Corporation, Arlington Heights, IL);康橋同位素實驗室公司 (Cambridge Isotope Laboratories, Inc. Andover， MA)； 思研科技研發有限公司（SRI International，Menlo Park， CA);偉迪實驗室公司（Wizard Laboratories, West Sacramento, CA) ; ChemSyn 實驗室公司（ChemSyn 讎Laboratories，Lexena，KS);美國放射性標記化學公司 (American Radiolabeled Chemicals, Inc., St. Louis, MO ;以及 Moravek ±t&amp;3(MoravekBiochemicalsInc·， Brea, CA) o 用氣標記過的探針化合物亦適合在;気化的乙酸中經由 鉑催化交換、在氣化的三氟乙酸中經由酸催化交換或經由 具有氚氣之非均相的催化交換催化製備。當客戶經由前一 響段所列之任何供應商放射性標記所使用之未標記之化合物 當作受質，此等製劑亦適合進行。此外，某些先驅物還可 適合用氚氣、不飽和鍵的氣氣還原或使用硼氚化钠之還原 進行氣-鹵素的交換。 實施例11 :受體的自動放射攝影術（autoradiography) 使用如先前所述之流程圖與先前實施例所製備成之本 文所提供之該等放射性標記化合物，並藉由如Kuhar於 Current Protocols in Pharmacology (1998) John Wiley &amp; Sons，New York之第8· 1· 1至8· 1. 9節中所述之方法， 239 93966 200812588 於體外進行受體的自動放射攝影術（受體造影（receptor mapping)) 〇 實施例12 :微粒體的活體外半衰期 化合物的半衰期值（t!/2值）可經由下列標準肝臟微粒 體半衰期試驗予以量測。混合的人類肝臟微粒體係從 XenoTech LLC, 3800 Cambridge St. Kansas's City, Kansas，66103 (catalog # H0610)獲得。該等肝臟微粒體 亦可由 In Vitro Technologies, 1450 South Rol 1 ing Road， Baltamore, MD 21227 或 Tissue Transformation Technologies, Edison Corporate Center, 175 May Street, Suite 600，Edison, NJ 08837獲得。以下係進行該等反 應： 試劑： 鱗酸鹽的缓衝液:19毫升0· 1 M NaH2P〇4、81毫升0· 1 Na2HP〇4、用 H3P〇4 調整成 pH 7. 4。 • CoFactor混合物：4毫升100 mM氯化鎂中含16. 2毫克 NADP、45. 4毫克的葡萄糖六填酸鹽。 葡萄糖六磷酸鹽去氫酵音：將214. 3// L的葡萄糖六磷酸鹽 去氫酵素懸浮液（Boehringer-Manheim catalog no. 0737224, distributed by Roche Molecular Biochemicals, 9115 Hague Road， Ρ·0· Box 50414， Indianapolis, IN 46250)稀釋於1285.7//L的蒸餾水中。 起始反應混合物·· 3毫升的CoFactor混合物、1. 2毫升的 葡萄糖六碟酸鹽去氫酵素。 240 93966 200812588 反應： 準備6個試驗反應’其中每個皆含25〆L的微粒體、5 100//M的試驗化合物溶液以及399 #L 〇1 M磷酸鹽 的緩衝液。準備第七個作為陽性對照組其含有25以L的微 粒體、399 #L 0.1 Μ的磷酸鹽的緩衝液以及1〇〇//Μ 的具有已知代謝性質之化合物（例如，地西泮（diazepam) 或氯氮平（ci〇zepine))的溶液。該等反應係在39t：下預培 _育10分鐘。將71#L的起始反應混合物加入至6個試驗反 應的其中5個中並且也加入至陽性對照組中，將71#L 1〇〇 mM的氯化鎂加入至第六個試驗反應中，其用來當作陰性對 照組。於每個時間點（0、1、3、5以及1〇分鐘）從每個反 應混合物用移液管吸出75“加至含有75 “的冰冷乙腈 之96-孔的深孔平板的孔中。旋轉該等樣本並在35〇〇轉下 離心 10 分鐘（S〇RVAL T 6000D centrifuge，Η1〇〇〇β rotor)。從每個反應中將75#l的上層液輸送至每一孔中 響含有150//L 0. 5# Μ具有已知LCMS曲線（内標準）化合物 的溶液之96-孔平板的孔中。對每個樣本進行試驗並 用，驗級超高速離心機（AUC)量測未代謝掉的試驗化合物 之里之後將化合物的漢度對時間作圖並推斷該試驗化合 物之11/2值。 該等較佳化合物具有大於1〇分鐘而小於4小時之體外 —值。該等最佳化合物於人類肝臟微粒體中具有3〇分鐘 至1小時間的體外tl/2值。 較佳化合物之其他熊&amp; 93966 241 200812588 該等式ι(較佳為表i)之最佳化合物及鹽係適合醫藥 用於治療人類患者。因此，該等較佳化合物為無毒性者。 該專化合物不具有單劑量急毒性（single dose acute toxicity)或多劑量急毒性（multiple dose acute toxicity)或長期毒性（long-term toxicity)、誘突變性 (例如，determined in a以細菌回復突變試驗（bacterial reverse mutation assay)例如安姆氏試驗（Ames test)所 測定者）、致畸性、致癌性等以及當投予醫藥上有效之劑量 時很少有引發有害效應（副作用）。 較佳者，以某些劑量（即，在活體内產生治療有效作用 之該等劑量或較佳劑量為每公斤用卜3〇、1〇〇、3〇〇或1〇〇〇 毫克，其中每公斤用3〇〇毫克為最佳者，非經口服方式投 予而較佳者為口服）投予此等較佳化合物時並不會造成心 臟的QT間隔之延長（即，由心電圖所量測者，例如，用天 竺鼠、迷你豬或狗）。若以實驗室的齧齒動物(例如，小鼠 ，老鼠）作對照組’持續每天投藥5天或較佳ig天時，該 物之料㈣亦^會造成輯擴大而導致肝臟 ^體重之比增加至大於刪，較佳為不大於75%，而更佳 他實施態樣中’若以狗或其他非餐齒 勿治療之對照組時’該等較佳化合物 成肝臟擴大而導致肝臟對體重之比增加 不大於25%，而更佳為不大於⑽。 較佳亦不會促進hAA 么化S物之該專劑量The cell membrane pellets (containing CRF receptors) were resuspended in 50 mM Tris buffer containing 1 mM mM magnesium chloride and 2 mM EDTA at pH 7.7 and centrifuged at 4, 000 00 g for 1 minute at 4 C. The cell membranes were washed again and brought to a final concentration of 1500 ug/ml of binding buffer (the Tris buffer had more than 5% BSA, 15 rnM of 1.4 bacitracin and 〇·〇ΐ mg/ ML of anti-fibrinolytic agent (aprotinin). For the binding assay, a 1 〇〇 #L cell membrane preparation was added to a sauvagine (SA 2200 Ci/mole, final concentration of 1 〇〇pM) containing 100 μL and 5 〇 //L of the test compound on the loading plate of the 96-well microcentrifuge tube. The binding was carried out at room temperature by 2% by mole. These loading plates were then harvested using a BRANDEL 96-well cell harvester and counted using r-rays of a liquid scintillation counter of the Wal lac 1205 BETAPLATE type. Non-specific binding (]1〇11-31^(:^1(:: binding) is defined as 1 mM cold CRF. These ICso values are fitted with a linear curve fitting software rs/1 (BBN Software Products) Corp., Cambridge, MA) The measured binding affinities (expressed as IC5 enthalpy) of the compounds and salts of the Table I are generally in the range of 0.5 nm to 10 micromoles. Preferred compounds and salts of I exhibit such IC5 values of less than or equal to 1.5 micromoles, and preferred compounds and salts of the formula I exhibit such 93966 235 200812588 1C5. Equal to 500 nanomolar, the more preferred compounds and salts of the formula I exhibit an IC5 enthalpy of less than or equal to 100 nanomolar, and the preferred compounds and salts of the formula I exhibit such The ic5Q value is less than or equal to 10 nanomolar. The preferred compounds and their salts are those shown in Table 1. Example 8: Cytochrome P450 (CYP) in human liver microsomes Evaluation of mechanism-based inhibition of 1A2, 2C8, 2C9, 2C19, 2D6 and 3A4 And the salt is present at 1, 2, 5, 5, 10, 25 and suboptimal 5〇# μ with mixed human liver microsomes in 1) and 2) in the absence of NADPH (final concentration 1 mM) Pre-incubate for 30 minutes in a shaking trough at 37 °C. 1 Residual enzymes were measured after diluting a pre-incubation mixture containing 〇·1M sulphate buffer (pH 7.4), selective CYP probe substrate and NADPH (final concentration 1 mM) The residual enzyme activity was evaluated and the degree of inhibition offset _ between the two treatments was evaluated. In the presence and absence of NADPH, each concentration-dependent and statistically significant decrease in specific CYP activity means the mechanistic inhibition of the CYP isozyme. Excipients and known selective mechanism inhibitors of each CYP isomerase were also cultured in parallel with the compound or salt as a negative control group and a positive control group. Positive control includes furaphylline ({1^!7111116) (0丫?1 person 2), gemfibrozil glucuronide or sub-pene phenelzine (CYP2C8), fentanyl Tienilic acid (CYP2C9), ticlopidine (CYP2C19), paroxetine, paroxetine 236 93966 200812588 (CYP2D6) and ribefradil (CYP3A4). In order to evaluate all CYPs, the activity test was carried out according to the following linear conditions: concentration of granules in the pre-incubation of the enzyme (mg/μl) concentration of microsomes in the activity test (kg/ml) probe was probed Needle concentration (in M) Pre-incubation time (minutes) CYP1A2 1 0.1 Phenacetin 35 30 CYP2C8 0.1 0.01 Amodiaquine 2.5 10 CYP2C9 5 0.5 Tolbutamide 400 10 CYP2C19 2 0.2 S-Mephenytoin 120 40 CYP2D6 1 0. 1 Dextromethorphan 15 5 CYP3A4 2 0.2 Testosterone 250 10 For each test, monitor the production of individual CYP metabolites And use LC-MS (to 曱 dextromethorphan ((! 6 士士 1'0^11 &amp; 11)), 丄〇118/118 (4'-methionine toluene yellow butyrate, desethyl acetaminophen, 4- Quantitatively determined by 4-acetamidophenol, 4-hydroxy-S-mefenexin or HPLC (6/3-hydroxytestosterone). For each tested isomerase, compared to Mechanism inhibitor of isomerase after pre-incubation with NADPH after 30 minutes of pre-incubation without NADPH Shows concentration-related and statistically significant reductions in activity (t-check (student's t-test) ··ρ&lt;0.05). Human liver microsomes with and without NADPH and compounds of formula I and When the salts are pre-incubated at concentrations of 1, 2, 5, 5, 10, 25, and 50 // ,, such activities as CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and 237 93966 200812588 CYP3A4 are observed. When there is no statistically significant change in one or more (preferably all), it is proved to be inorganically inhibited for each isomerase. Example 9 · Dog nausea and vomiting test This equation 1 (preferably The preferred compounds of Table I) or their salts are not nausea or sputum sputum if they are treated with a therapeutically effective technique. The appropriate measure for this property is that more than 1 out of 6 dogs No vomiting is given to a dog at a dose selected from 1, 30, 100, 300 and 1000 mg per kilogram of body weight within one hour, preferably within 3 hours or less preferably within 6 hours. Measured··Use the elastic tube of the syringe and punch in about 10 The milliliters of distilled water are dosed by the oral intubatiation of the compound or salt. Certified dog food, No. 5007 (PMI Nutrition International, St. Louis, MO), stupid dog for 4 hours in any 400 grams. Food is served almost at the same time every day. Take the medicine 1 to 2 hours before eating. The water system is arbitrarily supplied via an automatic water supply system. The compound or salt was observed to stand for 3 minutes and then 4 times, 1 hour, 3 hours, and 6 hours after administration. The observed vocal events were recorded during the observation period. The preparation of a compound of the formula 丨 (preferably Table I) and the salt system use at least the original r is a radiation '[the precursor of the bioisotope by performing such a The radioactively labeled probe (1^丨.1*16^^.|^) was prepared by synthesis. Preferably, the radioactive element is at least one selected from the group consisting of &quot;〇, hydroquinone is H), sulfur (preferably 35s) or iodine (preferably 1251). Such radiation 93966 238 200812588 Sexually labeled probes are suitable for synthesis with such radiolabeled probe compounds synthesized by the radioisotope supplier specifically for the customer. These suppliers include Amersham Corporation, Arlington Heights, IL; Cambridge Isotope Laboratories, Inc. Andover, MA; SRI International, Menlo Park, CA); Wizard Laboratories, West Sacramento, CA; ChemSyn 雠 Laboratories, Lexena, KS; American Radiolabeled Chemicals, Inc., St. Louis , MO; and Moravek ±t&amp;3 (Moravek Biochemicals Inc, Brea, CA) o Gas-labeled probe compounds are also suitable for catalysis in platinum-catalyzed exchange via platinum-catalyzed exchange in gasified trifluoroacetic acid Exchange or catalyzed by heterogeneous catalytic exchange with helium. These formulations are also suitable when the customer uses the unlabeled compound used by any of the suppliers listed in the previous paragraph as an acceptor. In addition, some precursors may also be suitable for gas reduction with helium or unsaturated bonds or for the use of sodium borohydride. Gas-halogen exchange was carried out. Example 11: Autoradiography of the receptors The radiolabeled compounds provided herein were prepared using the flow diagrams as previously described and the previous examples, and by Autoradiation of recipients in vitro, as described by Kuhar in Current Protocols in Pharmacology (1998) John Wiley &amp; Sons, New York, Section 8.1.1 to 8.9.1, 239 93966 200812588 Procedure (receptor mapping) Example 12: In vitro half-life of microsomes The half-life value of the compound (t!/2 value) can be measured by the following standard liver microsomal half-life test. Mixed human liver microparticles The system is available from XenoTech LLC, 3800 Cambridge St. Kansas's City, Kansas, 66103 (catalog # H0610). These liver microsomes can also be obtained from In Vitro Technologies, 1450 South Rol 1 ing Road, Baltamore, MD 21227 or Tissue Transformation Technologies, Edison Corporate Center, 175 May Street, Suite 600, Edison, NJ 08837. The following reactions were carried out: Reagents: Buffer buffer: 19 ml of 0·1 M NaH2P〇4, 81 ml of 0·1 Na2HP〇4, adjusted to pH 7.4 with H3P〇4. • CoFactor mixture: 4 ml of 100 mM magnesium chloride containing 16.2 mg of NADP, 45.4 mg of glucose hexahydrate. Glucose hexaphosphate dehydrogenation: 214.3/3 L of glucose hexaphosphate dehydrogenase suspension (Boehringer-Manheim catalog no. 0737224, distributed by Roche Molecular Biochemicals, 9115 Hague Road, Ρ·0· Box 50414, Indianapolis, IN 46250) diluted in 1285.7 / / L of distilled water. Starting reaction mixture · 3 ml of CoFactor mixture, 1.2 ml of glucose six-dissolvate dehydrogenase. 240 93966 200812588 Reaction: Prepare 6 test reactions' each of which contains 25 μL of microsomes, 5 100//M of test compound solution and 399 #L 〇1 M phosphate buffer. Prepare a seventh positive control group containing 25 L microsomes, 399 #L 0.1 Μ phosphate buffer, and 1 〇〇//Μ of compounds with known metabolic properties (eg, diazepam ( A solution of diazepam) or clozapine (ci〇zepine). The reactions were pre-cultured at 39 t: for 10 minutes. 71#L of the initial reaction mixture was added to 5 of the 6 test reactions and was also added to the positive control group, and 71#L of 1 mM magnesium chloride was added to the sixth test reaction, which was used. Take it as a negative control group. At each time point (0, 1, 3, 5, and 1 minute), 75" was pipetted from each reaction mixture into a well of a 96-well deep well plate containing 75" ice-cold acetonitrile. Rotate the samples and centrifuge at 35 rpm for 10 minutes (S〇RVAL T 6000D centrifuge, Η1〇〇〇β rotor). From each reaction, 75#1 of the supernatant was transferred to a well of a 96-well plate containing 150//L 0. 5# 溶液 solution having a known LCMS curve (internal standard) compound. Each sample was tested and the test compound ultracentrifuge (AUC) was used to measure the unmetabolized test compound and the compound was plotted against time and the 11/2 value of the test compound was inferred. The preferred compounds have an in vitro value of greater than 1 minute and less than 4 hours. These optimal compounds have an in vitro tl/2 value of 3 to 1 minute in human liver microsomes. Other Bears of Preferred Compounds &amp; 93966 241 200812588 The best compounds and salts of the formula ι (preferably Table i) are suitable for use in the treatment of human patients. Therefore, the preferred compounds are non-toxic. The specific compound does not have single dose acute toxicity or multiple dose acute toxicity or long-term toxicity (long-term toxicity), mutagenicity (for example, determined in a bacterial back mutation test) (bacterial reverse mutation assay), for example, as measured by the Ames test, teratogenicity, carcinogenicity, and the like, and when a pharmaceutically effective dose is administered, rarely causes a harmful effect (side effect). Preferably, at a certain dose (i.e., the dose or preferred dose that produces a therapeutically effective effect in vivo is 3 〇, 1 〇〇, 3 〇〇 or 1 〇〇〇 mg per kg, each of which The best use of 3 mg in kilograms, preferably administered orally and preferably orally) does not cause an increase in the QT interval of the heart (ie, measured by an electrocardiogram) when administered with such preferred compounds. For example, use guinea pigs, mini pigs or dogs). If the laboratory rodent (for example, mouse, mouse) is used as a control group for 5 days or better ig days per day, the material (4) will also increase the ratio and increase the ratio of liver to body weight. It is greater than the deletion, preferably not more than 75%, and more preferably, in the embodiment of the invention, if the dog or other non-meal treatment is not treated, the preferred compounds become enlarged in the liver and cause the liver to be weight-bearing. The specific increase is not more than 25%, and more preferably not more than (10). Preferably, it does not promote the specific dose of hAA

θ促進脰内肝細胞的肝臟酵素（例如，ALT、LDH 93966 242 200812588 或AST)釋出。若以齧齒動物作為對照未 鮮劑量較佳不會㈣料酵素的血清濃度上升超過 100%、較佳不會趙過7π； / 更佳不會超過50%。同樣地， :!:=培養基中或在其他用於細胞活體外接觸或 ° 液中）等於兩倍、較佳為五倍、而最佳為十倍之最 小活體m農度時，其^會造纽何的料 自θ promotes the release of liver enzymes (eg, ALT, LDH 93966 242 200812588 or AST) from intrahepatic hepatocytes. If the rodent is used as a control, the fresh dose is not preferred. (4) The serum concentration of the enzyme is increased by more than 100%, preferably not more than 7π; / better than 50%. Similarly, when :!: = in the medium or in other cells for in vitro contact or in the case of liquid, equal to twice, preferably five times, and optimally ten times the minimum living m-degree of agriculture, What is the origin of the new

==外的培養基中而超過未治療細胞培養基 由於田J 4乍用it常係由不期望之受體活化作用 (receptor activati〇n)或受體拮抗作用（rece^〇r a^ntag〇nism)所致’因此該等較佳化合物將發揮其所具有之 高選擇性之受體-調節效應。此意味著該等化合物不會鱼某 些具有高親和力之其他受體(除了 CRF，尤其是CRF1::;卜 之受體）結合，而僅結合至下述受體、或活化或抑制下述受 體之活性：其他具有親和力常數（註：親和力常數越大則意 指結合越弱）大於100奈莫耳，較佳為大於丨微莫耳，更佳 為大於10微莫耳而最佳為大於1〇〇微莫耳之受體。該等受 體車又it係選自下列所組成之群組：a)離子通道受體（較佳為 鈉離子通道冗體）、b)神經傳遞質受體（較佳係選自^ _與卢 -腎上腺素受體、毒簟素性受體（muscarinic recept〇rs)_ 其中最佳為m卜m2或m3型的受體、多巴胺受體、GABM受 體以及代謝型麵胺酸鹽受體）、c)組織胺受體、们細胞介素 叉體（較佳係選自白細胞介素受體，最佳為IL_8受體）、㊀） 生物活性肽受體（較佳係選自Νργ以及νιρ受體）、f)神經 93966 243 200812588 激肽受體、g)緩激肽受體（較佳係選自611受體以及612 受體）以及h)激素受體（較佳係選自甲狀腺促素釋素受體 以及濃縮之黑色素細胞激素受體）。== outside the medium and exceed the untreated cell culture medium. Because it is used in the field, it is often caused by undesired receptor activation (receptor activati〇n) or receptor antagonism (rece^〇ra^ntag〇nism) As a result, these preferred compounds will exert the receptor-regulating effect of their high selectivity. This means that the compounds do not bind to certain other receptors with high affinity (except for CRF, especially CRF1:: receptors), but only bind to the following receptors, or activate or inhibit the following Reactivity of the receptor: other having an affinity constant (note: the greater the affinity constant means the weaker the binding) is greater than 100 nanomolar, preferably greater than 丨 micromolar, more preferably greater than 10 micromolar and most preferably More than 1 〇〇 micromolar receptor. The receptor vehicles are further selected from the group consisting of: a) ion channel receptors (preferably sodium ion channel complexes), b) neurotransmitter receptors (preferably selected from ^ _ and Lu-adrenergic receptor, muscarinic recept rs _ which is the best m, m2 or m3 receptor, dopamine receptor, GABM receptor and metabotropic face amine receptor , c) a histamine receptor, an interleukin (preferably selected from an interleukin receptor, preferably an IL-8 receptor), a) a biologically active peptide receptor (preferably selected from the group consisting of Νργ and νιρ) Receptor), f) nerve 93966 243 200812588 kinin receptor, g) bradykinin receptor (preferably selected from 611 receptor and 612 receptor) and h) hormone receptor (preferably selected from thyroid stimulating) Releasing receptors and concentrated melanocyte cytokines receptors).

244 93966244 93966

Claims (1)

200812588 十、申請專利範園： 1. 一種式I之化合物或鹽，其為表I之化合物或鹽，其為 (1R，2S)-2-{2-[2-甲氧基-4-(1H-吼tr坐-1-基）苯基] -3, 7-二曱基一5H-吡咯并[2, 3-b]吡畊-5_基}環己醇或 其醫藥上可接受之鹽類。 2· —種表I之化合物或鹽，其中，於標準活體外CRF受體 結合試驗中，該化合物展現小於或等於丨微莫耳的！。 值。 3· —種表I之化合物或鹽，其中，於標準活體外CRF受體 結合試驗中，該化合物展現小於或等於1〇〇奈莫耳的 I C50 值。 4· 一種表I之化合物或鹽，其中，於標準活體外CRF受體 結合式驗中’該化合物展現小於或等於1 〇奈莫耳的I C50 值。 5 · —種治療焦慮症、壓力相關性疾病或飲食失調症之至少 一種症狀之方法，包括對需要此治療之患者投予治療有 效量之表I之化合物或鹽。 6. —種治療憂鬱症或雙極性情感疾病之至少一種症狀之 方法，包括對需要此治療之患者投予治療有效量之表I 之化合物或鹽。 7· —種治療神經性厭食症、神經性暴食症或肥胖症之方 法’包括對需要此治療之患者投予治療有效量之表j 之化合物或鹽。 一種治療激躁性結腸症或克隆氏症之方法，包括對需要 93966 245 8· 200812588 此治療之患者投予治療有效量之表丨之化合物或鹽。 9. 種在細胞或組織樣本中驗證crf受體存在之方法，該 方法包括： 製備複數個相配之（matched)細胞或組織樣本； ‘備至少一個對照組樣本，其係藉由下述方式製 備：使至少一個相配之細胞或組織樣本（其先前並沒有 與申請專利範圍第1至4項中任一項之任何化合物或鹽 接觸）與對照組溶液接觸（在容許細胞或組織樣本中的 CRF結合至CRF受體之條件下），該對照組溶液包括具 有第一量測莫耳濃度之所選定的表丨化合物或鹽之可 偵測標記製劑，該對照組溶液進一步包括具有第二量測 莫耳/辰度之所選定的化合物或鹽之未標記製劑，其中該 第二量測莫耳濃度係大於該第一量測莫耳濃度； ‘備至少一個實驗樣本，其係藉由下述方式製備： 使至少一個相配之細胞或組織樣本（其先前並沒有與表 I的任何化合物或鹽接觸）與實驗溶液接觸（在容許細 胞與組織樣本中的CRF結合至CRF受體之條件下），該 實驗溶液包括具有第一量測莫耳濃度之所選定的化合 物或鹽之可偵測標記製劑，該實驗溶液並未進一步包括 具有/辰度大於或等於該第一量測濃度之任何表I化合 物或鹽的未標記製劑； 清洗該至少一個對照組樣本以移除未結合之所選 定的化合物或鹽，以產生至少一個經清洗之對照組樣 本； 93966 246 200812588 清洗該至少一個實驗樣本以移除未結合之所選定 的化合物或鹽，以產生至少一個經清洗之實驗樣本； 量測在該至少一個經清洗之對照組樣本中之任何 剩餘的經結合之可偵測標記所選定化合物或鹽的可偵 測標記量； 量測在該至少一個經清洗之實驗樣本中之任何剩 餘的經結合之可偵測標記所選定化合物或鹽的可偵測 標記量；以及 比較在各個該至少一個經清洗的實驗樣本中與在 各個該至少一個經清洗的對照組樣本中所量測到的可 偵測標記之量； 其中，比較指出在該至少一個經清洗的實驗樣本中 所偵測到的可偵測標記量大於在任何該至少一個經清 洗的對知、組樣本中所偵測到的可偵測標記量，其驗證 CRF受體存在於實驗樣本中。 10· —種抑制CRF結合至CRF1受體之方法，該方法包括： 使包含CRF以及表I之化合物或鹽的溶液與表現 叉體之細胞接觸，其中，該化合物或鹽係以足以抑制活 脰外CRF結合至IMR32細胞的濃度存在於該溶液中。 lh如申請專利範圍第10項之方法，其中，該表現CRF受 體之細胞為於動物中經活體内接觸之神經元細胞，且其 中該溶液為該動物的體液。 12·如申请專利範圍第11項之方法，其中，該動物為人類 患者。 、 247 93966 200812588 13· —種醫藥組成物，係包括醫藥上可接受之载劑與表j 之化合物或鹽。 14· 一種包裝，係包括含於容器中之申請專利範圍第以項 之醫藥組成物，且復包括含下列至少一者之扑示· 使用該組成物來治療患有焦慮症之患者之說明，或 使用該組成物來治療患有壓力相關性疾病之患者 之說明，或 u 使用該組成物來治療患有飲食失調症之患者之說 明。 15· —種包裝，係包括含於容器中之申請專利範圍第13項 之醫藥組成物，且復包括含下列至少一者之指示：使用 該組成物來治療患有憂鬱症之患者之說明，或使用該組 成物來治療患有雙極性情感疾病之患者之說明。 16· —種表I之化合物或鹽，當其以選自每公斤體重用工、 3 0、10 〇、3 0 0以及10 0 0毫克之劑量經口服投予狗時， 在投藥的3小時内，六隻狗中不會有超過1隻狗產生嘔 吐噁心現象。 17· 一種表I之化合物或鹽，其以選自5、1〇、15、2〇以及 25微莫耳的濃度使用於活體外細胞色素P450試驗中， 不會顯現任何 CYP1A2、CYP2C8、CYP2C9、CYP2C19、 CYP2D6 以及 CYP3A4 活性之機理性（mechanism-based) 抑制作用。 18·如申請專利範圍第17項之化合物或鹽，其中，該濃度 為2 5微莫耳。 248 93966 200812588 19. 一種表I之化合物或鹽，其以選自5、10、15、20以及 25微莫耳的濃度使用於活體外CYP2C8試驗中，不產生 CYP2C8的不可逆抑制作用。 20. 如申請專利範圍第5項之方法，其中，壓力疾病之該症 狀為睡眠病症或皮膚性病症。 249 93966 / 200812588 七、指定代表圖··無 (一） 本案指定代表圖為：第（）圖。 (二) 本代表圖之元件符號簡單說明： 參 八、本案若有化學式時，請揭示最能顯示發明特徵的化學式：200812588 X. Patent Application: 1. A compound or salt of formula I which is a compound or salt of Table I which is (1R, 2S)-2-{2-[2-methoxy-4-( 1H-吼tr-l-yl)phenyl]-3,7-dimercapto-5H-pyrrolo[2,3-b]pyrazine-5-yl}cyclohexanol or its pharmaceutically acceptable Salt. 2. A compound or salt of the formula I, wherein the compound exhibits less than or equal to 丨 micromole in a standard in vitro CRF receptor binding assay! . value. 3. A compound or salt of the formula I, wherein the compound exhibits an I C50 value of less than or equal to 1 〇〇Nemo in a standard in vitro CRF receptor binding assay. 4. A compound or salt of Table I, wherein the compound exhibits an I C50 value of less than or equal to 1 〇Nemo in a standard in vitro CRF receptor binding assay. 5. A method of treating at least one symptom of an anxiety disorder, a stress-related disorder, or an eating disorder, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or salt of Table I. 6. A method of treating at least one symptom of depression or a bipolar affective disorder comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or salt of Table I. 7. A method of treating anorexia nervosa, bulimia nervosa or obesity&apos; comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or salt of Table j. A method of treating irritable colon or Crohn's disease comprising administering a therapeutically effective amount of a compound or salt to a patient in need of such treatment as 93966 245 8 2008 12588. 9. A method of verifying the presence of a crf receptor in a cell or tissue sample, the method comprising: preparing a plurality of matched cells or tissue samples; 'preparing at least one control sample prepared by the following method : contacting at least one matched cell or tissue sample (which has not previously been contacted with any of the compounds or salts of any of claims 1 to 4) with a control solution (CRF in a permissive cell or tissue sample) The control solution comprises a detectable label preparation having a selected molar concentration of the selected surface compound or salt, the control solution further comprising a second measurement An unlabeled formulation of a selected compound or salt of Mohr/Chen, wherein the second measured molar concentration is greater than the first measured molar concentration; 'Prepared at least one experimental sample by the following Method of preparation: contacting at least one matched cell or tissue sample (which has not previously been contacted with any of the compounds or salts of Table I) with the test solution (allowing cells and tissues) The CRF of the present invention is conjugated to a CRF receptor, the test solution comprising a detectable labeling agent having a selected compound or salt of a first molar concentration, the experimental solution not further comprising An unlabeled formulation of any of the compounds or salts of Table I having a degree greater than or equal to the first measured concentration; washing the at least one control sample to remove unbound selected compound or salt to produce at least one washed control Group sample; 93966 246 200812588 cleaning the at least one experimental sample to remove unbound selected compound or salt to produce at least one washed experimental sample; measuring any of the at least one washed control sample Remaining detectably labeled detectable labeling amount of the selected compound or salt; measuring any remaining selected detectable label selected compound or salt in the at least one washed experimental sample Detecting the amount of the label; and comparing the cleaning in each of the at least one of the washed experimental samples and at each of the at least one The amount of detectable label measured in the control sample; wherein the comparison indicates that the detectable label amount detected in the at least one washed sample is greater than in any of the at least one washed pair The amount of detectable label detected in the known and group samples verified that the CRF receptor was present in the experimental sample. 10. A method of inhibiting binding of CRF to a CRF1 receptor, the method comprising: contacting a solution comprising a CRF and a compound or salt of Table I with a cell expressing a fork, wherein the compound or salt is sufficient to inhibit live sputum The concentration of exo CRF bound to IMR32 cells is present in the solution. Lh. The method of claim 10, wherein the cell representing the CRF receptor is a neuronal cell that is contacted in vivo in an animal, and wherein the solution is a body fluid of the animal. 12. The method of claim 11, wherein the animal is a human patient. 247 93966 200812588 13 - A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound or salt of Table j. A package comprising a pharmaceutical composition according to the scope of the patent application of the container, and including a description of at least one of the following: a description of the use of the composition for treating a patient suffering from anxiety. Or use the composition to treat a patient with a stress-related disease, or use the composition to treat a patient with an eating disorder. 15. A package comprising a pharmaceutical composition of claim 13 in a container, and comprising an indication comprising at least one of the following: instructions for using the composition to treat a patient suffering from depression, Or use the composition to treat a patient with a bipolar affective disorder. 16·—The compound or salt of Table I, when administered orally to a dog at a dose selected from the group consisting of 3, 10, 10, 300, and 100 mg per kilogram of body weight, within 3 hours of administration No more than one of the six dogs will have vomiting and nausea. 17. A compound or salt of Table I for use in a cytochrome P450 assay in vitro at concentrations selected from the group consisting of 5, 1 〇, 15, 2 〇, and 25 micromolar, without showing any CYP1A2, CYP2C8, CYP2C9, Mechanism-based inhibition of CYP2C19, CYP2D6, and CYP3A4 activity. 18. A compound or salt according to claim 17 wherein the concentration is 25 micromoles. 248 93966 200812588 19. A compound or salt of Table I for use in an in vitro CYP2C8 assay at a concentration selected from the group consisting of 5, 10, 15, 20 and 25 micromolar, without irreversible inhibition of CYP2C8. 20. The method of claim 5, wherein the symptom of the stress disorder is a sleep disorder or a skin disorder. 249 93966 / 200812588 VII. Designated representative map·· None (1) The representative representative of the case is: (). (2) A brief description of the symbol of the representative figure: VIII. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 4 939664 93966
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