TW200412345A - Novel deazapurines and uses thereof - Google Patents

Novel deazapurines and uses thereof Download PDF

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Publication number
TW200412345A
TW200412345A TW092114905A TW92114905A TW200412345A TW 200412345 A TW200412345 A TW 200412345A TW 092114905 A TW092114905 A TW 092114905A TW 92114905 A TW92114905 A TW 92114905A TW 200412345 A TW200412345 A TW 200412345A
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Taiwan
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aryl
heteroaryl
aliphatic
substituted
group
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TW092114905A
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Chinese (zh)
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TWI322807B (en
Inventor
Jane Daun
Heather A Davis
Fabian Gusovsky
Ieharu Hishinuma
Yimin Jiang
Kaneko Toshihiko
Kikuchi Kouichi
Seiichi Kobayashi
Lescarbeau Andre
Li Xiang-Yi
Muramoto Kenzo
Ohi Norihito
Pesant Marc
Seletsky Boris
Soejima Motohiro
Tremblay Lynda
Yao Ye
Yokohama Hiromitsu
Janet Zhao Yan
Zheng Wanjun
De Costa Bruce
Spyvee Mark
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Eisai Co Ltd
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Priority claimed from PCT/US2003/000366 external-priority patent/WO2003057696A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Abstract

The present invention provides compounds having formula (I): wherein R1, R2, R3 and n are as described generally and in classes and subclasses herein, and additionally provides pharmaceutical compositions thereof, and methods for the use thereof in the treatment of inflammatory or autoimmune and proliferative disorders and as inhibitors of cell adhesion molecule expression and inflammatory cytokine signal transduction generally.

Description

200412345 玖、發明說明： 請求優先權200412345 发明 、 Explanation of invention: Claim priority

編 請 併於本文供參考。 【發明所屬之技術領域】 本發明係提供可用於治療炎性或自身免疫與增生病症之化 口物、％•樂組合物及其用途，以及一般性地作為細胞黏連 分子表現與炎性細胞活素訊息轉導之抑制劑。 【先前技術】 發炎為一種由於在損傷或感染位置處之血管擴大與增加滲 透性所造成之過程。在此位置釋出之化學細胞活素與細胞 活素’會增加細胞表面蛋白質在内皮細胞上之表現，允許 白血球循環以黏附至血管壁，並潛移至組織内之損傷/感染 位置。此等細胞表面蛋白質稱為，，細胞黏連分子”，允許白 血球與内皮細胞間之交互作用，並媒介白血球潛移至組織 中。此外，在炎性與免疫回應中，許多細胞對細胞交互作 用係需要細胞黏連分子。有三種黏連分子類型：選擇素、 整合素及免疫球蛋白相關之蛋白質，其可在白血球與内皮 細胞上表現。數種黏連分子，包括E-選擇素與ICAM，係被 細胞活素譬如IL-1與TNF所引致，而其表現係藉由轉錄因子 NF- /cB所媒介。 黏連分子之持續或不適當表現可導致炎性或自身免疫病症 85762 200412345 ι擇素及/或ICAM之過度增大表現可造成慢性發炎， 八係η數種炎.性或自身免疫病症有關聯。因此，細胞黏連 分子之抑制劑可用於治療此等疾病。 一 3人自身免疫疾病無法藉由現行療法良好地處理，故廣 l求更良好樂物之發展。例如，風濕性關節炎為一種 關^内之性發炎狀態，其特徵為軟骨與骨質破壞。對 炎性或自身免疫性疾病譬如風濕性關節炎之傳統治療劑， 包括非類固醇消炎藥物與柳酸鹽、金化合物、羥氣喹、硫 酸沙’If-azine) '皮質類固醇、口服青黴胺及細胞毒性或 免疫抑制藥物。但是年多此種治療劑不一定足夠有效， 且已造成嚴重之副作用。最近中和蛋白質之可注射 形式，已被成功地銷售，用於治療風濕性關節炎與克隆氏 但是，口服上有效之抑制劑尚未被發展出來，用於此 等炎性或自身免疫疾病。 顯然地，仍然需要確認新穎治療劑種類，以治療炎性或自 身免疫及增生疾病，該藥劑較佳為口服上有效，且無嚴重 副作用。亦期望界定新穎治療劑種類，以一般性地治療炎 性或自身免疫及增生病症。 【發明内容】 正如上文所討論者，仍然需要發展可用於治療炎性或自身 免疫及增生疾病之新穎治療劑。本發明係提供新穎通式① 化合物 85762 -10- 200412345Please refer to this article for reference. [Technical field to which the present invention belongs] The present invention provides a mouthwash, a composition for use in the treatment of inflammatory or autoimmune and proliferative disorders, and its use, as well as the expression of cell adhesion molecules and inflammatory cells in general Inhibitor of Voxel Message Transduction. [Prior art] Inflammation is a process caused by the enlargement of blood vessels and increased permeability at the site of injury or infection. Chemical cytokines and cytokines released at this location will increase the expression of cell surface proteins on endothelial cells, allow white blood cells to circulate to adhere to the vessel wall, and sneak to the site of injury / infection in the tissue. These cell surface proteins are called, "cell adhesion molecules," allowing white blood cells to interact with endothelial cells, and mediate white blood cells to sneak into tissues. In addition, many cells interact with cells in the inflammatory and immune response The system requires cell adhesion molecules. There are three types of adhesion molecules: selectin, integrin, and immunoglobulin-related proteins that can be expressed on white blood cells and endothelial cells. Several adhesion molecules, including E-selectin and ICAM It is caused by cytokines such as IL-1 and TNF, and its performance is mediated by the transcription factor NF- / cB. Continuous or inappropriate expression of adhesion molecules can lead to inflammatory or autoimmune disorders Excessive increase in selectin and / or ICAM can cause chronic inflammation, and there are several inflammatory or autoimmune disorders in the eight lines. Therefore, inhibitors of cell adhesion molecules can be used to treat these diseases. 3 people Autoimmune diseases cannot be well treated by current therapies, so the development of better fun is required. For example, rheumatoid arthritis is a state of sexual inflammation, which Characterized by cartilage and bone destruction. Traditional treatments for inflammatory or autoimmune diseases such as rheumatoid arthritis, including non-steroidal anti-inflammatory drugs and salicylate, gold compounds, oxyquine, sand sulfate 'If-azine)' Corticosteroids, oral penicillamine, and cytotoxic or immunosuppressive drugs. However, this treatment has not been effective enough for many years and has caused serious side effects. Recently, injectable forms of neutralizing proteins have been successfully sold for use in Treatment of rheumatoid arthritis and Crohn's disease However, orally effective inhibitors have not been developed for these inflammatory or autoimmune diseases. Obviously, there is still a need to identify new therapeutic agents to treat inflammatory or autoimmune diseases. And proliferative diseases, the agent is preferably orally effective without serious side effects. It is also desirable to define new types of therapeutic agents to generally treat inflammatory or autoimmune and proliferative disorders. [Summary of the Invention] As discussed above There is still a need to develop novel therapeutic agents that can be used to treat inflammatory or autoimmune and proliferative diseases. The present invention is to provide ① 85762 -10-200412345 novel compounds of formula

及其醫藥組合⑯’如—般性地且在本文之種類與亞組中所 描述者，以及製造與使用此種化合物之方法。 本發明某些較佳具體實施例之描述 、在〜知對於研咒與界定新穎治療劑種類以治療風濕性關節 人及其他病症（在某些具體實施例中，為炎性或自身免疫及 增生病症）之需求下，本發明係提供如在本文中更詳細地描 込之新頑脫氮嘌呤及其類似物，其可一般性地用於治療炎 I4生或自身免疫及增生病症。在某些具體實施例中，本發明 化口物可用於治療疾病與病症，包括但不限於風濕性關節 炎、潰瘍性結腸炎/克隆氏病、中樞神經系統疾病(CNS)， 譬如多發性硬化、全身性紅斑狼瘡、氣喘、同種移植排斥/ 移植物對宿主疾病(GVHD)、牛皮癖、異位性皮炎、濕疹、 尊麻殄、過敏性鼻炎、重症肌無力、:糖尿病、自發性血小 板減少性紫斑病、絲球體性腎炎、心與血管疾病及癌症。 本發明化合物亦發現可用於預防易豸受到譬如血管造形術 與支架置放術之損傷之血管再狹窄。 1)本發明化合物之一般描述 本發明化合物包括如進一步定義於下文之通式①化合物（ 及其互變異構物）： 85762 -11 - 200412345And their pharmaceutical combinations, as generally described in the species and subgroups herein, and methods of making and using such compounds. The description of certain preferred embodiments of the present invention, research and development, and the definition of novel therapeutic agents to treat rheumatic joints and other disorders (in certain embodiments, inflammatory or autoimmune and proliferative In accordance with the requirements of the present invention, the present invention provides a new recalcitrant deazapurine and its analogs as described in more detail herein, which can be generally used to treat inflammatory or autoimmune and proliferative disorders. In certain embodiments, the oral products of the present invention can be used to treat diseases and conditions, including but not limited to rheumatoid arthritis, ulcerative colitis / cloned's disease, central nervous system disease (CNS), such as multiple sclerosis , Systemic lupus erythematosus, asthma, allograft rejection / graft-versus-host disease (GVHD), psoriasis, atopic dermatitis, eczema, respectable anesthesia, allergic rhinitis, myasthenia gravis, diabetes, spontaneous platelets Reduced purple spot disease, filamentous nephritis, heart and vascular disease, and cancer. The compounds of the present invention have also been found to be useful in preventing restenosis of blood vessels that are susceptible to damage such as angioplasty and stent placement. 1) General description of the compounds of the present invention The compounds of the present invention include compounds of general formula ① (and tautomers thereof) as further defined below: 85762 -11-200412345

其中η為整數0-4 ; Ri 為氫…ΝΗ2、-NHMe、—NHAc、_〇Η、F、-OMe、_CN 或-NH(C=0)〇Et ; R2為氫、-nrarb、-0Ra、脂族、雜脂族、芳基或雜芳基部 伤基團其中ra與RB各獨立為氫或脂族、雜脂族、芳基或 雜芳基部份基團； 各存在處係獨立為氫、齒素、氰基，或脂族、雜脂族 、芳基或雜芳基部份基團，或基團-G-Rc，其中G係不存在 或為-CH2_、-NRd-、-0_或（c=〇)，且其中心為氫…NRfR^ 〇Rf、-SRf，或脂族、雜脂族、芳基或雜芳基部份基團， 其中RD、RF及心各獨立為氫、视為，脂族、環脂族、雜 月曰狹、％雜脂族、芳基或雜芳基部份基圈，被脂族、雜脂 版万基或雜方基部份基團取代之醯基部份基團，或其中rd 與Rc或Rf與R〇，一起採用為3_，4-，5_，6-，7_或8_員經取代或未 經取代（環脂族或環雜脂族部份基團；其中心與心之各存 在處係獨立為氫，脂族、環脂族、雜脂族、環雜脂族、芳 基或雜万基α卩份基團，被脂族、雜脂族、芳基或雜芳基部 份錢取代切基部份基團，或其中r^r广起採用為U 或6員、π取代或未經取代之飽和或不飽和環脂族或環雜脂族 85762 -12- 200412345 部份基團； 而其中各前述脂族或雜脂族部份基團可獨立為經取代或未 、’、二取代狀或非％狀、線性或分枝狀、飽和或不飽和， 且其中各前述芳基或雜芳基部份基團可獨立為經取代或未 經取代。 在某些具體實施例中，本發明係定義某些特別令人感興趣 〈化合物種類。例如，一種特別令人感興趣之化合物類別 包括被&之兩個存在處取代之化合物，其中化合物具有以 下結構：Where η is an integer 0-4; Ri is hydrogen ... N… 2, -NHMe, -NHAc, _〇Η, F, -OMe, _CN or -NH (C = 0) 〇Et; R2 is hydrogen, -nrarb, -0Ra , Aliphatic, heteroaliphatic, aryl or heteroaryl moieties wherein each of ra and RB is independently hydrogen or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety; each occurrence is independently Hydrogen, halogen, cyano, or aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or group -G-Rc, where G is absent or is -CH2_, -NRd-,- 0_ or (c = 〇), and its center is hydrogen ... NRfR ^ 〇Rf, -SRf, or aliphatic, heteroaliphatic, aryl, or heteroaryl partial groups, where RD, RF, and X are each independent For hydrogen, it is considered to be aliphatic, cycloaliphatic, heterocyclohexyl,% heteroaliphatic, aryl or heteroaryl moiety, and is substituted by aliphatic, heterolipidyl or heteroaryl moiety. A substituted fluorenyl moiety, or where rd and Rc or Rf and Ro are used together as 3_, 4-, 5_, 6-, 7_ or 8_ members substituted or unsubstituted (cycloaliphatic Or cycloheteroaliphatic part of the group; its center and heart where each exists is independently hydrogen, aliphatic, cycloaliphatic, heteroaliphatic, cycloheterocyclic Group, aryl group, or heteroaeroyl group, substituted with an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety, or a cleavage moiety, or where r ^ r is widely used as U or 6-membered, π-substituted or unsubstituted saturated or unsaturated cycloaliphatic or cycloheteroaliphatic 85762 -12- 200412345 partial groups; and each of the aforementioned aliphatic or heteroaliphatic partial groups may be independently Substituted or unsubstituted, ', disubstituted or non-%, linear or branched, saturated or unsaturated, and each of the aforementioned aryl or heteroaryl moiety groups may be independently substituted or unsubstituted. In certain embodiments, the present invention defines certain compounds of particular interest. For example, a class of compounds of particular interest includes compounds substituted by two occurrences of & structure:

其中R3 a與R·3 b各獨立為氫、自素、氰基，或脂族、雜脂族 、芳基或雜芳基部份基團，或基團_G-Rc，其中G為不存在 、-CH2-、-NRD-、_0-或（c=〇)，且其中心為氫、_NRfRq、_〇~ 、-srf，或脂族、雜脂族、芳基或雜芳基部份基團，其中知 、RF及Rq各獨JL為氫、-NRxRy，脂族、環脂族、雜脂族、環 4月曰放、芳基或雜芳基部份基團，被脂族、雜脂族、芳基 或雜芳基邵份基團取代之醯基部份基團，或其中RD與心或 與R〇，一起採用為3-，4-，5-，6-，7-或8-員經取代或未經取代之 環脂族或環雜脂族部份基團；其中&與心之各存在處係獨 正為氳，脂族、環脂族、雜脂族、環雜脂族、芳基或雜芳 基部份基團，被脂族、雜脂族、芳基或雜芳基部份基團取 85762 -13- 200412345 代之驢基部份基團’或其中RjRy_S採用為4_,5_或6_員經 取代或未經取代、飽和或不飽和之環脂族或環雜脂族部份 基團； 而其中各前述脂族或雜脂族部份基團可獨立為經取代或未 經取代、環狀或非¥狀、線性或分枝狀、飽和或不飽和； 且其中各前述芳基或雜芳基部份基團可獨立為經取代或未 經取代。 另一種特別令人感興趣化合物之類別，係包括具有以下結 構之化合物：Wherein R3 a and R · 3 b are each independently hydrogen, autogen, cyano, or aliphatic, heteroaliphatic, aryl, or heteroaryl moiety, or the group _G-Rc, where G is not Is present, -CH2-, -NRD-, _0- or (c = 〇) and its center is hydrogen, _NRfRq, _〇 ~, -srf, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety Groups, in which R, R, and Rq are each independently hydrogen, -NRxRy, aliphatic, cycloaliphatic, heteroaliphatic, cycloaliphatic, aryl, or heteroaryl moiety, and are aliphatic, A heteroaliphatic, aryl, or heteroaryl moiety substituted with a fluorenyl moiety, or where RD is taken together with the heart or with R0 as 3-, 4-, 5-, 6-, 7- Or 8-membered substituted or unsubstituted cycloaliphatic or cycloheteroaliphatic partial groups; where & and each place of the heart are uniquely 氲, aliphatic, cycloaliphatic, heteroaliphatic, Cycloheteroaliphatic, aryl or heteroaryl moieties are replaced by aliphatic, heteroaliphatic, aryl or heteroaryl moieties 85762 -13- 200412345 substituted donkey moieties' or Among them, RjRy_S is a cycloaliphatic or cycloheteroaliphatic moiety with 4_, 5_ or 6_ members substituted or unsubstituted, saturated or unsaturated And each of the aforementioned aliphatic or heteroaliphatic moiety may be independently substituted or unsubstituted, cyclic or non- ¥ -like, linear or branched, saturated or unsaturated; and each of the aforementioned aromatic The radical or heteroaryl moiety may be independently substituted or unsubstituted. Another class of compounds of particular interest includes compounds having the following structure:

其中^&與尺^各獨立為氫、_素、氰基，或脂族、雜脂族 、芳基或雜芳基部份基團，或基團—G^^，其中^為不存在 、-ch2-、-NRD-、-0-或（〇=〇)，且其中心為氫、_叫心、為 、-srf，或脂族、雜脂族、芳基或雜芳基部份基團，其中心 、Rf&Rg各獨立為氫、-NRxRy，脂族、環脂族、雜脂族、環 雜脂族、芳基或雜芳基部份基團，被脂族、雜脂族、芳基 或雜芳基部份基團取代之醯基部份基團，或其中知與心或心 與R〇，一起採用為3_，4-，5-，6-，7-或8-員經取代或未經取代之 環脂族或環雜脂族部份基團；其中心與心之各存在處係獨 亙為氫，脂族、環脂族、雜脂族、環雜脂族、芳基或雜芳 基部份基團，被脂族、雜脂族、芳基或雜芳基部份基團取 85762 -14- 200412345 代之醯基部份基團，或其中Rx與Ry—起採用為4-，5-或6-員經 取代或未經取代、飽和或不飽和、環脂族或環雜脂族部份 基團， 而其中各前述脂族或雜脂族部份基團可獨立為經取代或未 經取代、環狀或非環狀、線性或分枝狀、飽和或不飽和； 且其中各前述芳基或雜芳基部份基團可獨立為經取代或未 經取代。 另一種特別令人感興趣化合物之類別，係包括具有式①結 構之化合物，其中RSa為—CE^NRfRg，且R3b為氫，而該化合 物具有以下結構：Where ^ & and ^ are each independently hydrogen, hydrogen, cyano, or an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety, or the group -G ^^, where ^ is absent , -Ch2-, -NRD-, -0-, or (〇 = 〇), and its center is hydrogen, _Xinxin, Wei, -srf, or aliphatic, heteroaliphatic, aryl, or heteroaryl moiety Group, its center, Rf & Rg are each independently hydrogen, -NRxRy, aliphatic, cycloaliphatic, heteroaliphatic, cycloheteroaliphatic, aryl or heteroaryl moiety, aliphatic, heterolipid Group, aryl or heteroaryl partial group substituted fluorenyl partial group, or in which the consciousness or the heart and R0 are used together as 3_, 4-, 5-, 6-, 7- or 8 -A substituted or unsubstituted cycloaliphatic or cycloheteroaliphatic partial group; each center and heart where it exists is uniquely hydrogen, aliphatic, cycloaliphatic, heteroaliphatic, cycloheterolipid Group, aryl or heteroaryl part group, replaced by aliphatic, heteroaliphatic, aryl or heteroaryl part group 85762 -14- 200412345 fluorenyl part group, or Rx and Ry—from 4-, 5- or 6-membered substituted or unsubstituted, saturated or unsaturated, cycloaliphatic or cyclic Heteroaliphatic moieties, and each of the aforementioned aliphatic or heteroaliphatic moieties may be independently substituted or unsubstituted, cyclic or acyclic, linear or branched, saturated or unsaturated; And each of the aforementioned aryl or heteroaryl moiety may be independently substituted or unsubstituted. Another class of compounds of particular interest includes compounds having the structure of formula ①, where RSa is -CE ^ NRfRg, and R3b is hydrogen, and the compound has the following structure:

其中Ri、R2、rf及均如一般性地於上文及在本文之種類 與亞組中之定義。 另一種特別令人感興趣化合物之類別，係包括具有式①結 構之化合物，其中R3b*-CH2NRFRG，且Rsa為氫，而該化合 物具有以下結構：Where Ri, R2, rf, and R are as defined above and in the categories and subgroups herein. Another class of compounds of particular interest includes compounds having the structure of formula ①, where R3b * -CH2NRFRG, and Rsa is hydrogen, and the compound has the following structure:

其中Ri、&、rf及％均如一般性地於上文及在本文之種類 85762 -15- 200412345 與亞組中之定義。 另一種特別令人感興趣化合物之類別，係包括具有式①結 構之化合物’其中R3c^-CH2NRfRg，且R3d為氫，而該化合 物具有以下結構：Ri, &, rf, and% are as defined above and generally in the categories 85762-15-200412345 and subgroups of this document. Another class of compounds of particular interest includes compounds having the structure of formula ① where R3c ^ -CH2NRfRg and R3d are hydrogen, and the compound has the following structure:

其中Ri、&、RF及Rq均如一般性地於上文及在本文之種類 與亞組中之定義。 另一種特別令人感興趣化合物之類別，係包括具有式①結 構之化合物，其中R3a為，且R3b為 氫，而該化合物具有以下結構：Where Ri, &, RF and Rq are as defined above and in the categories and subgroups herein. Another class of compounds of particular interest includes compounds having the structure of formula ①, where R3a is and R3b is hydrogen, and the compound has the following structure:

其中q與r各獨立為〇或};且心、&、^及心均如一般性地 於上文及在本文之種類與亞組中之定義。 另一種特別令人感興趣化合物之類別，係包括具有式①結 構之化合物，其中R3a為氫，且R3b為_(CH<：H)qCH2(CH^NRFRG ，而該化合物具有以下結構·· 85762 -16- 200412345Where q and r are each independently 0 or}; and Xin, &, ^, and Xin are as defined above and generally in the categories and subgroups herein. Another class of compounds of particular interest includes compounds having the structure of formula ①, where R3a is hydrogen and R3b is _ (CH <: H) qCH2 (CH ^ NRFRG, and the compound has the following structure ... -16- 200412345

其中q與r各獨立為0或1 ;且心、r2、％及1^均如一般性地 於上文及在本文之種類與亞組中之定義。 另一種特別令人感興趣化合物之類別，係包括具有式①結 構之化合物，其中為_(C=〇)NRfR〇，且R3b為氫，而該化合 物具有以下結構：Where q and r are each independently 0 or 1; and Xin, r2,%, and 1 ^ are as defined above and generally in the categories and subgroups herein. Another class of compounds of particular interest includes compounds having the structure of formula ①, where _ (C = 〇) NRfR0 and R3b is hydrogen, and the compound has the following structure:

其中Rl、R2、RF及均如一般性地於上文及在本文之種類 與亞組中之定義。 另一種特別令人感興趣化合物之類別，係包括具有式（I)結 構（化合物，其中R3b為-(C=0)NRfRg，且R3a為氫，而該化合 物具有以下結構：Wherein R1, R2, RF and are generally defined above and in the categories and subgroups herein. Another class of compounds of particular interest includes compounds having the structure of formula (I) (wherein R3b is-(C = 0) NRfRg and R3a is hydrogen, and the compound has the following structure:

其中Rl、反2、Rf&Rg均如一般性地於上文及在本文之種類 與亞組中之定義。 85762 -17- 200412345 另一種特別令人感興趣化合物之類別，係包括具有式①結 構之化合物，其中，且R3b為氫，而該 化合物具有以下結構：Among them, R1, trans2, Rf & Rg are as defined above and in the categories and subgroups herein. 85762 -17- 200412345 Another class of compounds of particular interest includes compounds having the structure of formula ①, where R3b is hydrogen, and the compound has the following structure:

其中&與R2均如一般性地於上文及在本文之種類與亞組中 之定義； m為0、1或2 ;及 rf為脂族、環脂族、雜脂族、環雜脂族、芳基或雜芳基部 份基團； 而其中各珂述脂族或雜脂族部份基團可獨立為經取代或未 、、'二取代、％狀或非環狀、線性或分枝狀、飽和或不飽和·, 且其中各七述方基或雜芳基部份基團可獨立為經取代或未 經取代。 另種特别令人感興趣化合物之類別，係包括具有式①結 、5物其中R3 a為-CH2 ORF，且R3 b為氫，而該化合物 具有以下結構：Where & and R2 are as defined above and generally in the categories and subgroups herein; m is 0, 1 or 2; and rf is aliphatic, cycloaliphatic, heteroaliphatic, cycloheterolipid Group, aryl or heteroaryl moiety; and each of the aliphatic or heteroaliphatic moiety may be independently substituted or unsubstituted, 'disubstituted,% -shaped or acyclic, linear or Branched, saturated or unsaturated, and each of the seven-squared or heteroaryl groups may be independently substituted or unsubstituted. Another class of compounds of particular interest includes compounds having the formula ①, and R3 a is -CH2 ORF, and R3 b is hydrogen, and the compound has the following structure:

/、中Ri^R2均如一般性地於上文及在本文之種類與亞組中 85762 200412345 之定義；且 rf為氫、保護基，或脂族、環脂族、雜脂族、環雜脂族、 芳基或雜芳基部份基團；而其中各前述脂族或雜脂族部份 基團可獨立為經取代或未經取代、環狀或非環狀、線性或 分枝狀、飽和或不飽和；且其中各前述芳基或雜芳基部份 基團可獨立為經取代或未經取代。 各前述種類之許多重要亞組值得個別指出；此等亞組包括 前述種類之亞組，其中： i) R1^NH2 ； ii) &為氫； iii) 心為 NHMe ; iv) 為 NHAc ; ν)^為NH2、OH、烷基或CVC6烯基，該烷基與烯基 係視情況被自素或輕基取代； vi) R2 為 q -C2 烷基； vii) R2為甲基； viii) R2 為氫； ix) RF或R〇之一為氳或低碳烷基；而另一個為烷基、雜烷 基、芳基、雜芳基、烷基芳基或烷基雜芳基，對各存在處 ，視情況獨立被一或多個_素、烷氧基、硫基烷基或經取 代或未經取代之烷基、雜烷基、芳基或雜芳基取代，或其 中RF與h —起採用為6胃員經取代或未經取代之雜環族部份 基團； x) RF或R〇之一為氫或低碳烷基；而另一個為芳基、雜芳基 85762 -19- 200412345 、燒基芳基或燒基雜芳基部份基團，對各存在處，視情況 獨立被一或多侗自素、烷氧基、硫基烷基或經取代或未經 取代之fe基、雜基、芳基或雜芳基取代，或其中知與 一起採用為6-員經取代或未經取代之環狀或雜環族部份基團； xi) RF或R〇之一為氫或低碳烷基；而另一個為苯基、说淀 基、（烷基）苯基或（烷基）吡啶基，視情況取代被一或多個存 在處之1¾素、三氟甲氧基、甲氧基、三氟甲基、甲硫基或 經取代或未經取代之低碳烷基、低碳雜烷基、芳基或雜芳 基取代；及/, Ri ^ R2 are as defined above and generally in the categories and subgroups of this document 85762 200412345; and rf is hydrogen, protecting group, or aliphatic, cycloaliphatic, heteroaliphatic, cycloheterocyclic Aliphatic, aryl or heteroaryl moiety; each of the aforementioned aliphatic or heteroaliphatic moiety may be independently substituted or unsubstituted, cyclic or acyclic, linear or branched , Saturated or unsaturated; and wherein each of the aforementioned aryl or heteroaryl moiety groups may be independently substituted or unsubstituted. Many important subgroups of each of the aforementioned species deserve individual identification; these subgroups include subgroups of the aforementioned species, where: i) R1 ^ NH2; ii) & is hydrogen; iii) NHMe is the heart; iv) is NHAc; ν ) ^ Is NH2, OH, alkyl, or CVC6 alkenyl, and the alkyl and alkenyl are optionally substituted with autogen or light group; vi) R2 is q-C2 alkyl; vii) R2 is methyl; viii) R2 is hydrogen; ix) one of RF or R0 is fluorene or lower alkyl; and the other is alkyl, heteroalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl, for Where each exists, it is independently substituted by one or more 素 prime, alkoxy, thioalkyl or substituted or unsubstituted alkyl, heteroalkyl, aryl or heteroaryl, or where h—from 6 substituted or unsubstituted heterocyclic partial groups; x) one of RF or R0 is hydrogen or lower alkyl; and the other is aryl, heteroaryl 85762 -19- 200412345, partial aryl or aryl heteroaryl groups, for each place where they are independently replaced by one or more fluorene, alkoxy, thioalkyl, or substituted or unsubstituted Substituted fe group, hetero group Aryl or heteroaryl substitution, or a 6-membered substituted or unsubstituted cyclic or heterocyclic partial group which is known to be used together; xi) one of RF or R0 is hydrogen or lower alkyl And the other is phenyl, said phenyl, (alkyl) phenyl, or (alkyl) pyridyl, optionally substituted by 1¾, trifluoromethoxy, methoxy , Trifluoromethyl, methylthio, or substituted or unsubstituted lower alkyl, lower heteroalkyl, aryl, or heteroaryl; and

Xu) RF或Rq之一為氫或低碳烷基；而另一個為環狀或非環 狀、線性或分枝狀脂族部份基團，視情況被一或多個經取 代或未經取代之芳基、雜芳基、醯胺、烷氧基、羥基、硫 基fe基、硫醇、驢基或胺基取代； xiii) RF為烷基、環烷基、雜烷基、環雜烷基、芳基、雜芳 基、烷基方基或烷基雜芳基，對各存在處，視情況獨立被 一或多個S素、烷氧基、硫基烷基或經取代或未經取代之 烷基、雜烷基、芳基或雜芳基取代；及/或 xiv) rf為氫、保護基，或烷基、環烷基、雜烷基、環雜烷 基、芳基、雜芳基、燒基芳基或燒基雜芳基，對各存在處 ’視情況獨立被-或多個自t、燒氧基、硫基垸基或經取 代或未經取代之烷基、雜烷基'芳基或雜芳基取代。 正如讀者將明瞭的，特別令人感興趣之化合物包括，其中 特：是，共有—或多種前述亞組之特質者。-些此等亞組 係藉由下列化合物種類說明： 85762 >20- 200412345 i)下式化合物（及其藥學上可接受之衍生物）··Xu) One of RF or Rq is hydrogen or lower alkyl; while the other is cyclic or non-cyclic, linear or branched aliphatic moiety, optionally one or more substituted or unsubstituted Substituted aryl, heteroaryl, ammonium, alkoxy, hydroxy, thiofe, thiol, donkey or amine; xiii) RF is alkyl, cycloalkyl, heteroalkyl, cyclohetero Alkyl, aryl, heteroaryl, alkyl square, or alkylheteroaryl, where each is present, is independently substituted by one or more S-, alkoxy, thioalkyl, or unsubstituted or unsubstituted Substituted with a substituted alkyl, heteroalkyl, aryl, or heteroaryl; and / or xiv) rf is hydrogen, a protecting group, or an alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl, Heteroaryl, alkynyl, or alkheteroaryl, for each occurrence, are optionally independently-or more from t, alkoxy, thiofluorenyl, or substituted or unsubstituted alkyl, Heteroalkyl'aryl or heteroaryl substitution. As the reader will appreciate, particularly interesting compounds include, among others: those that share—or more than one of the aforementioned subgroup characteristics. -Some of these subgroups are illustrated by the following types of compounds: 85762 > 20- 200412345 i) compounds of the formula (and their pharmaceutically acceptable derivatives) ...

其中Rl與R2均如一般性地及在本文之種類與亞組中之定義 ;〇為〇^或-(〇〇)，且心或心之一為氫或低碳烷基；而另 一個為烷基、雜烷基、芳基、雜芳基、烷基芳基或烷基雜 籲 芳基邵伤基團’對各存在處，視情況獨立被一或多個齒素 、燒氧基、硫基烷基或經取代或未經取代之烷基、雜烷基 、万基或雜芳基取代，或其中心與、一起採用為3至8_員經 取代或未經取代之環狀或雜環族部份基團。 於某些具體貫施例中，rf或％之一為氫或低碳烷基；而另 一個為芳基、雜芳基、烷基芳基或烷基雜芳基部份基團， 對各存在處，視情況獨立被一或多個卣素、烷氧基、硫基 烷基或經取代或未經取代之烷基、雜烷基、芳基或雜芳基 _ 取代’或其中Rf與Rg 一起採用為3至8-員經取代或未經取代 之環狀或雜環族部份基團。 於某些其他具體實施例中，心或^之一為氫或低碳烷基； 而另一個為苯基、吡啶基、（烷基）苯基或（燒基 >比啶基，視 情況被一或多個存在處之_素、三氟甲氧基、甲氧基、三 氣甲基、甲硫基或經取代或未經取代之低碳烷基、低碳雜 燒基、芳基或雜芳基取代。 万；又其他具體實施例中，Rf或R〇之一為氫或低碳烷基；而 -85762 -21 - 200412345 另一個為環狀或非環狀、線性或分枝狀脂族部份基團，視 情況被一或多侗經取代或未經取代之芳基、雜芳基、醯胺 、烷氧基、羥基、硫基烷基、硫醇、醯基或胺基取代。 η)下式化合物（及其藥學上可接受之衍生物）··Where R1 and R2 are as defined generally and in the categories and subgroups herein; 〇 is 〇 ^ or-(〇〇), and one of the hearts or hearts is hydrogen or lower alkyl; and the other is Alkyl, heteroalkyl, aryl, heteroaryl, alkylaryl, or alkylheteroaryl groups are present at each place where they are independently identified by one or more halide, alkoxy, Thioalkyl or substituted or unsubstituted alkyl, heteroalkyl, wanyl, or heteroaryl substitution, or its center is taken with, together with 3 to 8-membered substituted or unsubstituted cyclic or Heterocyclic moiety. In certain embodiments, one of rf or% is hydrogen or lower alkyl; and the other is aryl, heteroaryl, alkylaryl, or alkylheteroaryl moiety. For each Where present, optionally substituted by one or more halogen, alkoxy, thioalkyl, or substituted or unsubstituted alkyl, heteroalkyl, aryl, or heteroaryl ', or where Rf and Rg is taken together as a 3 to 8-membered substituted or unsubstituted cyclic or heterocyclic moiety. In certain other specific embodiments, one of X or Y is hydrogen or lower alkyl; and the other is phenyl, pyridyl, (alkyl) phenyl, or (alkyl)> pyridyl, as appropriate Is substituted by one or more of the following elements, trifluoromethoxy, methoxy, trimethyl, methylthio, or substituted or unsubstituted lower alkyl, lower alkyl, aryl Or heteroaryl substitution. In other embodiments, one of Rf or R0 is hydrogen or lower alkyl; and -85762 -21-200412345 the other is cyclic or acyclic, linear or branched Aliphatic moiety, optionally with one or more substituted or unsubstituted aryl, heteroaryl, amido, alkoxy, hydroxy, thioalkyl, thiol, fluorenyl, or amine Group substitution. Η) Compounds of the formula (and their pharmaceutically acceptable derivatives) ...

其中Ri與&均如一般性地及在本文之種類與亞組中之定義 ’ G 為 CH2 或-(C=0) ’ 且 X 為 〇、s、c=0、S=0、C=CR4R5、NR4 或CR4R5 ;其中R4與Rs之各存在處係獨立為氫、羥基、鹵素 、氰基，脂族、雜脂族、芳基或雜芳基部份基團，或被脂 族、雜脂族、芳基或雜芳基部份基團取代之醯基部份基團； 而其中各前述脂族或雜脂族部份基團可獨立為經取代或未 經取代、環狀或非環狀、線性或分枝狀，且其中各前述芳 基或雜芳基部份基團可獨立為經取代或未經取代。· 下式化合物（及其藥學上可接受之衍生物）··Where Ri and & are as defined generally and in the categories and subgroups herein, 'G is CH2 or-(C = 0)' and X is 0, s, c = 0, S = 0, C = CR4R5, NR4, or CR4R5; where each of R4 and Rs is independently hydrogen, hydroxyl, halogen, cyano, aliphatic, heteroaliphatic, aryl, or heteroaryl moiety, A fluorenyl moiety substituted with an aliphatic, aryl or heteroaryl moiety; each of the aforementioned aliphatic or heteroaliphatic moiety may be independently substituted or unsubstituted, cyclic or Cyclic, linear or branched, and wherein each of the aforementioned aryl or heteroaryl moiety groups may be independently substituted or unsubstituted. · Compounds of the formula (and their pharmaceutically acceptable derivatives) ...

其中R!與R2均如一般性地及^ ;G為〇^2或-(〇0)，且心或民 一個為燒基、雜燒基、芳基、 般性地及在本文之種類與亞組中之定義 且或RF之一為氫或低碳烷基；而另 方基、雜芳基、烷基芳基或烷基雜 85762 -22- 200412345 芳基，對各存在處，視情況獨立被一或多個自素、烷氧基 、硫基燒基或經取代或未經取代之烷基、雜烷基、芳基或 雜芳基取代，或其中RF與Rg —起採用為3至8-員經取代或未 經取代之環狀或雜環族部份基團。 於某些具體實施例中，rf或％之一為氫或低碳燒基；而另 一個為芳基、雜芳基、烷基芳基或烷基雜芳基部份基團， 對各存在處，視情況獨立被一或多個函素、烷氧基、硫基 燒基或經取代或未經取代之烷基、雜烷基、芳基或雜芳基 取代’或其中巧與心一起採用為3至8_員經取代或未經取代 之環狀或雜環族部份基團。 於某些其他具體實施例中，rf或％之一為氫或低碳烷基； 而另一個為苯基、吡啶基、（烷基）苯基或（燒基）吡啶基，視 情況被一或多個存在處之_素、三氟甲氧基、甲氧基、三 敦甲基、甲硫基或經取代或未經取代之低碳燒基、低竣雜 烷基、芳基或雜芳基取代。 於又再其他具體實施例中，RF或心之一為氫或低碳烷基； 而另一個為環狀或非環狀、線性或分枝狀脂族部份基團， 視情況被一或多個經取代或未經取代之芳基、雜芳基、醯 胺、燒氧基、每基、硫基燒基、硫醇、醯基或胺基取代。 下式化合物（及其藥學上可接受之衍生物）··Among them, R! And R2 are as general and ^; G is 〇2 or-(〇0), and the heart or the group is an alkyl group, a heteroalkyl group, an aryl group, generally and the types and Subgroup definition and or one of RF is hydrogen or lower alkyl; while the other group, heteroaryl, alkylaryl or alkyl hetero85762 -22- 200412345 aryl, for each existence, as the case may be Independently substituted by one or more sulfonyl, alkoxy, thioalkyl, or substituted or unsubstituted alkyl, heteroalkyl, aryl, or heteroaryl groups, or where RF and Rg are used together as 3 To 8-membered substituted or unsubstituted cyclic or heterocyclic moiety. In certain embodiments, one of rf or% is hydrogen or a low-carbon alkyl group; and the other is an aryl, heteroaryl, alkylaryl, or alkylheteroaryl moiety. Where it is independently substituted with one or more functional elements, alkoxy, thioalkyl, or substituted or unsubstituted alkyl, heteroalkyl, aryl, or heteroaryl, as appropriate, or together with the heart A substituted or unsubstituted cyclic or heterocyclic partial group of 3 to 8 members is used. In certain other specific embodiments, one of rf or% is hydrogen or lower alkyl; and the other is phenyl, pyridyl, (alkyl) phenyl, or (carbyl) pyridyl, as appropriate Or more where it exists, trifluoromethoxy, methoxy, trimethyl, methylthio, or substituted or unsubstituted low carbon alkyl, low heteroalkyl, aryl or hetero Aryl substitution. In still other specific embodiments, one of the RF or the core is hydrogen or a lower alkyl group; and the other is a cyclic or acyclic, linear or branched aliphatic partial group, which is optionally Multiple substituted or unsubstituted aryl, heteroaryl, amidino, alkoxy, peryl, thioalkyl, thiol, fluorenyl, or amine groups. Compounds of the formula (and their pharmaceutically acceptable derivatives) ...

85762 -23- 200412345 其中RAR2均如-般性地及在本文之種類與亞組中之定義 ;G4CH2或-(〇〇)，且 X為 〇、s、CK)、s=c> 、_ 或CIUR5 ;其中&與Rs之各存在處係獨立為氫、羥基、鹵素 、氰基，脂族、雜脂族、芳基或雜芳基部份基團，或被脂 族、雜脂族、芳基或雜芳基部份基團取代之醯基部份基團； 而其中各前述脂族或雜脂族部份基團可獨立為經取代或未 經取代、環狀或非環狀、線性或分枝狀，且其中各前述芳 基或雜芳基部份基團可獨立為經取代或未經取代。 V)下式化合物（及其藥學上可接受之衍生物）··85762 -23- 200412345 where RAR2 is as general and as defined in the categories and subgroups herein; G4CH2 or-(〇〇), and X is 〇, s, CK), s = c >CIUR5; where each of & and Rs is independently hydrogen, hydroxyl, halogen, cyano, aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or is aliphatic, heteroaliphatic, An aryl or heteroaryl moiety substituted with a fluorenyl moiety; and each of the aforementioned aliphatic or heteroaliphatic moiety may be independently substituted or unsubstituted, cyclic or acyclic, Linear or branched, and wherein each of the aforementioned aryl or heteroaryl moiety groups may be independently substituted or unsubstituted. V) Compounds of the formula (and their pharmaceutically acceptable derivatives) ...

其中Ri與&均如一般性地及在本文之種類與亞組中之定義 ，G為CH2或-(〇〇)，且h或Rf之一為氫或低碳烷基；而另 一個為燒基、雜烷基、芳基、雜芳基、烷基芳基或烷基雜 芳基’對各存在處’視情況獨立被一或多個函素、虎氧基 、硫基垸基或經取代或未經取代之烷基、雜烷基、芳基或 雜芳基取代，或其中化與％一起採用為3至8_員經取代或未 經取代之環狀或雜環族部份基團。 於某些具體實施例中，％或R〇之一為氳或低碳烷基；而另 一個為芳基、雜芳基、烷基芳基或烷基雜芳基部份基團， 對各存在處，視情況獨立被一或多個函素、烷氧基、硫基 85762 200412345 烷基或經取代或未經取代之烷基、雜烷基、芳基或雜芳基 取代，或其中Ερ與R〇 —起採用為3至8-員經取代或未經取代 之環狀或雜環族部份基團。 於某些其他具體實施例中，rf或k之一為氫或低碳烷基； 而另一個為苯基、p比咬基、（燒基）苯基或（燒基比淀基，視 情沉被一或多個存在處之_素、三氟甲氧基、甲氧基、三 氟甲基、甲硫基或經取代或未經取代之低碳燒基、低碳雜 烷基、芳基或雜芳基取代。 於又再其他具體實施例中，心或心之一為氫或低碳烷基； 而另一個為環狀或非環狀、線性或分枝狀脂族部份基團， 視情況被一或多個經取代或未經取代之芳基、雜芳基、醯 胺、烷氧基、幾基、硫基烷基、硫醇、醯基或胺基取代。 yi)下式化合物（及其藥學上可接受之衍生物）··Where Ri and & are as defined generally and in the categories and subgroups herein, G is CH2 or-(〇〇), and one of h or Rf is hydrogen or lower alkyl; and the other is Alkyl, heteroalkyl, aryl, heteroaryl, alkylaryl, or alkylheteroaryl is 'for each occurrence' independently by one or more functional elements, oxo, thio, or Substituted or unsubstituted alkyl, heteroalkyl, aryl, or heteroaryl substitutions, or wherein the cyclic or heterocyclic moiety is substituted with 3 to 8 members Group. In certain embodiments, one of% or R0 is fluorene or lower alkyl; and the other is aryl, heteroaryl, alkylaryl, or alkylheteroaryl moiety. For each Where it exists, it is independently substituted with one or more functional elements, alkoxy groups, thio groups 85762 200412345 alkyl or substituted or unsubstituted alkyl, heteroalkyl, aryl, or heteroaryl, or Ερ With R0-, a 3 to 8-membered substituted or unsubstituted cyclic or heterocyclic moiety is used. In some other specific embodiments, one of rf or k is hydrogen or lower alkyl; and the other is phenyl, p-phenyl, (alkyl) phenyl, or (alkyl-based, as appropriate) Shen is present in one or more of the following places: trioxin, trifluoromethoxy, methoxy, trifluoromethyl, methylthio, or substituted or unsubstituted low-carbon alkyl, low-carbon heteroalkyl, aromatic Group or heteroaryl group. In yet other specific embodiments, one of the hearts or hearts is hydrogen or a lower alkyl group; and the other is a cyclic or acyclic, linear or branched aliphatic moiety. Group, optionally with one or more substituted or unsubstituted aryl, heteroaryl, fluorenylamine, alkoxy, aryl, thioalkyl, thiol, fluorenyl, or amine group. Compounds of the formula (and their pharmaceutically acceptable derivatives) ...

其中&與&均如一般性地及在本文之種類與亞組中之定義 G 為 CH2 或-(C-0)，且 X 為 〇、s、c=〇、s==〇、C=C〜R5、碼 或CR4R5 ;其中心與^之各存在處係獨立為氫、羥基、鹵素 :氰基，月旨族、雜脂族、芳基或雜芳基部份基團，或被脂 狹邊月日族、万基或雜芳基邵份基團取代之酸基部份基團； 而其中各前述脂族或雜脂族部份基團可獨立為經取代或未 85762 200412345 經取代、環狀或非環狀、線性或分枝狀，且其中各前述芳 基或雜芳基部份基團可獨立為經取代或未經取代。 VII)下式化合物（及其藥學上可接受之衍生物）：Where & and & are as defined generally and in the categories and subgroups herein. G is CH2 or-(C-0), and X is 0, s, c = 0, s = = 0, C = C ~ R5, code or CR4R5; its center and each place where ^ is present are independently hydrogen, hydroxyl, halogen: cyano, moon group, heteroaliphatic, aryl or heteroaryl moiety, or by An acidic partial group substituted with an aliphatic narrow moon group, a vanillyl group or a heteroaryl group; and each of the aforementioned aliphatic or heteroaliphatic group groups may be independently substituted or un85762 200412345 via Substituted, cyclic or acyclic, linear or branched, and each of the aforementioned aryl or heteroaryl moiety groups may be independently substituted or unsubstituted. VII) Compounds of the formula (and their pharmaceutically acceptable derivatives):

其中rf、R1與R2均如一般性地及在本文之種類與亞組中之 足義；P為整數0-3 ; S為整數〇_4 ; A、B、D、E及κ之各存 在處係獨立為不存在、〇、S、c=〇、s=〇、c=c㈣皿*或 CR4%，其中心與^之各存在處係獨立為氫、羥基、商素、 亂基、-〇Rx、-SRX、-NRxRy，脂族、雜脂族、芳基或雜芳基 部份基團，或被脂族、雜脂族、芳基或雜芳基部份基團取 代之醯基部份基團；且其中八與6,3與D，D與E，E與κ ，及任兩個相鄰K基團，當價鍵允許時，可藉由單或雙键連 接，其中1與Ry之各存在處係獨立為氫、保護基，.或脂族 雜如族、芳基、雜芳基、脂族芳基、雜脂族芳基、脂族 雜方基或雜脂族雜芳基部份基團，而其中各前述脂族或雜 脂族部份基團可獨立為經取代或未經取代、環狀或非環狀 、線性或分枝狀、飽和或不飽和，且其中各前述芳基、雜 方基脂族芳基、雜脂族芳基、脂族雜芳基或雜脂族雜芳基 部份基團可獨立為經取代或未經取代。 於某些列舉具體實施例中Among them, rf, R1 and R2 are as general as they are in this category and subgroup; P is an integer 0-3; S is an integer 0_4; each of A, B, D, E and κ Presence locations are independently absent, 〇, S, c = 0, s = 0, c = c㈣ ㈣ * or CR4%, and the respective locations of the center and ^ are independently hydrogen, hydroxyl, quotient, random group, -〇Rx, -SRX, -NRxRy, aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or substituted with aliphatic, heteroaliphatic, aryl or heteroaryl moiety Base groups; and eight and 6, 3 and D, D and E, E and κ, and any two adjacent K groups, when the valence bond allows, can be connected by single or double bonds, where Each occurrence of 1 and Ry is independently hydrogen, protecting group, or aliphatic hetero, such as family, aryl, heteroaryl, aliphatic aryl, heteroaliphatic aryl, aliphatic heterofang or heteroaliphatic Heteroaryl moiety groups, wherein each of the aforementioned aliphatic or heteroaliphatic moiety groups may be independently substituted or unsubstituted, cyclic or acyclic, linear or branched, saturated or unsaturated, And each of the aforementioned aryl, heterosaliphatic aliphatic aryl, heteroaliphatic aryl, aliphatic A heteroaryl or heteroaliphatic heteroaryl moiety may be independently substituted or unsubstituted. In some specific examples

表示經取代或未經取代 85762 -26 - 200412345 之苯基、吡啶基或呋喃基部份基團。於某些其他具體實施 例中Represents a substituted or unsubstituted phenyl, pyridyl, or furyl moiety of 85762 -26-200412345. In some other specific embodiments

表示經取代或未經取代、飽和或不飽和之3-，4-， 5-，6-，7-，或8-員環燒基或環雜燒基部份基團。 於某些列舉具體實施例中 表示經取代或未經取代之 環丙基、環丁基、環戊基、環己基、環庚基或環辛基。Represents a substituted, unsubstituted, saturated or unsaturated 3-, 4-, 5-, 6-, 7-, or 8-membered cycloalkyl group or cycloheteroalkyl group moiety. In certain listed specific examples, substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl are represented.

於某些列舉具體實施例中，E(Kf、/表示經取代或未經取代 之雙ί哀狀脂族邵份基團。 於某些列舉具體實施例中，rf為氫或低碳烷基。於某些具 體實施例中，rf為氫或甲基。 亦應明瞭的是，對上述各亞族群I-VII而言，多種其他亞組 疋特別令人感興趣的，包括但不限於上述i)_xiv)之種類，以 及上文及在本文貪例中所述之化合物種類、亞組及物種。 -些前述化合物可包含一或多個不對稱中心，因此可以各In certain listed embodiments, E (Kf, / represents a substituted or unsubstituted bis-alkyl aliphatic group. In some listed embodiments, rf is hydrogen or a lower alkyl group. In certain embodiments, rf is hydrogen or methyl. It should also be clear that for each of the above subgroups I-VII, a variety of other subgroups are particularly interesting, including but not limited to i) _xiv), and the types, subgroups, and species of compounds described above and in the examples herein. -Some of the foregoing compounds may contain one or more asymmetric centers, and

種異構形式存在，例如立體異構物及:·/或非對映異構物。 此本！又明化口 ％及其醫藥組合物可呈個別對掌異構物 非對映異構物或幾何異構物形式，或可呈立體異構物之 合物形式。在某政且轉奋社A丨士 , ^ 木一/、阮Λ她例中，本發明化合物係為對 、屯化口物纟木些其他具體實施例中，係提供立體異構 或非對映異構物之混合物。 、料，前述化合物之任何與所有互«構物係被本發明 涵盖。本發明並不限於本文中所騎之互變異構結構。 85762 -27- 200412345 為僅只是一項實例，一般性地被描述且描繪為以下之化合 物： —There are various isomeric forms, such as stereoisomers and / or diastereomers. This! And Minghuakou% and its pharmaceutical composition may be in the form of individual paraisomers, diastereomers or geometric isomers, or may be in the form of stereoisomers. In a certain example, Zhuanfenshe A, Shi Yi, and Mu Yi, the compounds of the present invention are para- and tun-huakou materials. In some other specific examples, they provide stereoisomers or non-pairs. A mixture of enantiomers. It is expected that any and all interfacial structures of the foregoing compounds are encompassed by the present invention. The invention is not limited to the tautomeric structures used herein. 85762 -27- 200412345 is just one example, generally described and depicted as a compound of the following: —

亦可被描述且描繪為：It can also be described and depicted as:

或多個雙 發Or multiple double

’其可以無論是異構物存在，除非夕固 另外涵蓋此等化合物，成為實質上不含其他二:本: 】構物’及：者，成為各種異構物之混合物，例如：體 物·^外消旋混合物。除了上文所提及之化t ，本發明亦涵蓋此等化合物之藥學上 β 身以 -或多種本發明化合物及一或多種藥學 蜊或添加劑之組合物。 又貝式 本發明化合物可藉由式⑴化合物於不同條件下之 用製成，且可以通式①化合物之多晶型物：下=化 ’其係構成本發明之一部份。例如，曰刑存 ，式確認及/或製備，使用不同溶劑或溶劑:；同I: 結晶作用；藉由在不同溫度下進行結晶化作;Γ 85762 -28- 200412345 利用各種冷卻模式，在結晶化作 _ 卜用期間涵盍之範圍從 速至極緩慢冷卻。多晶型物亦可細 一 J、、二由加熱或熔解化合物， 接著慢慢或快速冷卻而獲得。多曰'It can exist regardless of isomers, unless Xigu additionally covers these compounds and becomes substantially free of the other two: this:] structure' and: or, it becomes a mixture of various isomers, such as: ^ Racemic mixture. In addition to the chemical compounds mentioned above, the present invention also encompasses the pharmacological beta of these compounds as well as a combination of one or more compounds of the present invention and one or more pharmaceutical clams or additives. The compound of the present invention can be prepared by using the compound of the formula 于 under different conditions, and can be a polymorph of the compound of the general formula ①: down = chemical ', which constitutes a part of the present invention. For example, Xing Xun Cun, formula confirmation and / or preparation, using different solvents or solvents :; I: crystallization; by crystallization at different temperatures; Γ 85762 -28- 200412345 using various cooling modes in crystallization Transformation_ The range of the culvert during the use of the cool down from rapid to extremely slow. Polymorphs can also be obtained by heating or melting the compound, followed by slow or rapid cooling. More

曰曰土物之存在，可藉由固 體探測物NMR光譜學、IR井哉與 —、 M 九阳予、不至掃描卡計法、粉末X- 射線繞射圖及/或其他技術測定。 U此本發明係涵蓋本發 明化合物、其衍生物、其互變異構形式、其立體異構物： 其多晶型物、其藥學上可接受之鹽、其藥學上可接受之溶 劑合物及含有彼等之藥學上可接受之組合物。 2)化合物與定義 正如上文所討論者，本發明係提供具有一範圍生物學性質 之新穎化合物。本發明化合物具有與炎性或自身免疫病症 及/或增生病症之治療有關聯之生物學活性。在某些且髀每 結腸火/克隆氏病、中樞神經系統疾病㈣幻，譬如多發性 硬化、、全身性紅斑狼瘡、氣喘、同種移植排斥/移植㈣宿 王疾病（GVHD)、牛皮癖、異位性皮炎、濕疹、蓴麻疹、過 敏性鼻炎、重症肌無力、糖尿病、自發性血小板減少性紫 斑病、絲球體性腎炎、心與血管疾病及癌症。在某些其他 具fa貫她例中，本發明化合物亦發現可用於預防易遭受到 譬如血官造形術與支架置放術之損傷之血管再狹窄。 本發明化合物包括明確地於上文提出及於本文中描述者， 且係一邵份藉由本文別處揭示之不同種類、亞種屬及物種 說明。 此外’本發明係提供本發明化合物之藥學上可接受之衍生 85762 -29- 200412345 物，及使用此等化合物，甘殿— - 口物其亩樂組合物，或其中任一個且 併用-或多種其他治療劑1治療病患之方法。於本文中 :用之”藥學上可接受之衍生物"之措辭，係表示此種化合 物之任何藥學上可接受 ^ ^ f ^ 、 又乏|、酉日或此種酯之鹽，或任何其 他加成物或衍生物，並A 7 、 、 ，、在扠丁病患時，能夠提供（直接或間 其 /、他万面所逑 < 化合物，或其新陳代謝產物或殘 :二因：，藥學上可接受之衍生物係包括特別是前體藥物The existence of soil objects can be determined by NMR spectroscopy of solid probes, IR wells, —M Jiuyangyu, not scanning card method, powder X-ray diffraction patterns and / or other techniques. The invention encompasses the compounds of the invention, their derivatives, their tautomeric forms, their stereoisomers: their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, and Contains their pharmaceutically acceptable compositions. 2) Compounds and definitions As discussed above, the present invention provides novel compounds having a range of biological properties. The compounds of the invention have biological activities associated with the treatment of inflammatory or autoimmune disorders and / or proliferative disorders. In some cases, colonic fire / cloned's disease, central nervous system diseases, such as multiple sclerosis, systemic lupus erythematosus, asthma, allograft rejection / transplantation King's disease (GVHD), psoriasis, heterogeneity Atopic dermatitis, eczema, urticaria, allergic rhinitis, myasthenia gravis, diabetes, spontaneous thrombocytopenic purpura, filamentous nephritis, heart and vascular disease, and cancer. In certain other cases, the compounds of the present invention have also been found to be useful in the prevention of restenosis of blood vessels that are susceptible to damage such as haemoplasty and stent placement. The compounds of the invention include those explicitly set forth above and described herein, and are a description of the different species, subspecies, and species disclosed elsewhere herein. In addition, the present invention provides a pharmaceutically acceptable derivative of the compound of the present invention, 85762 -29- 200412345, and the use of these compounds, Gan Dian--Mouth composition, or any combination of them-or more Other Therapeutics 1 Methods for treating patients. In this text: The wording "pharmaceutically acceptable derivative" means any pharmaceutically acceptable ^ ^ f ^ of this compound, 乏 |, the following day or a salt of such an ester, or any Other adducts or derivatives, and A 7,,,, can provide (directly or indirectly /, other compounds, or their metabolites or residues) in fork disease: two reasons: Pharmaceutically acceptable derivatives include especially prodrugs

— ’生物’通^具有顯著地降低之 樂理學活性，並本古兄 ., ^ σ有另一個邵份基團，其容易在活體内移 除’產生作為藥理聲法祕从&、 _ 予活性物種乏母分子。前體藥物之一種 貫例為酿，其係在活體内***而產生吾人感興趣之化合物 。！種化合物之前體藥物，及將母體化合物衍化以產生前 體樂物之物質盘方丰你& 、”万法係為已知，且可適合本發明。某些舉 例之醫藥組合物及藥學上 、 木子上τ接文《何生物，將更詳細地討 論於下文。— 'Biological' Tong ^ has a significantly reduced pharmacological activity, and this ancient brother., ^ Σ has another Shao component group, which can be easily removed in vivo 'is generated as a pharmacological sound method from & The active species lacks the parent molecule. A common example of prodrugs is brewing, which is divided in vivo to produce compounds of interest to us. !! A compound precursor drug, and a substance derived from the parent compound to produce a precursor fungus, Pan & Fung, & " Wenfa system is known and can be suitable for the present invention. Certain exemplary pharmaceutical compositions and pharmacy , Muzi on τ followed by the text "He Biology, will be discussed in more detail below.

、本發明之某些化合物及特定官能基之定義，亦更詳細地描 八、下文對本發明《目的而言，化學元素係根據版之 疋素週期表’化學與物理手冊，第75版，封面内而確認，且特 α能基係如其切述作—般性地定義。此外，有機化學 、、"叙原理，以及特疋官能性部份基團與反應性，係描述 於”有機化學"，Th〇mas Sorrdl，大學科學圖書公司（s__ :丨999 中’其全部内容均併於本文供參考。，一般熟諸此藝 =應明瞭的是，如本文中所述之合成方法，係利用多種保 ^ 已糸本文中使用之所謂"保護基"一詞，係指特定官 85762 -30- 200412345 能性部份基團，例如ο、S4N，其係暫時被阻斷，以致反 應可選擇性地在多官能性化合物中之另—個反應性位置進 行。在較佳具體實施例中，保護基係選擇性地以良好產率 反應，以獲得經保護之受質，其對於所計劃之反應係為安 定的；保護基必須藉由易於取得，較佳為無毒性，而不會 攻擊其他官能基之試劑，以良好產率被選擇性地移除；保 護基係形成可容易地分離之衍生物（更佳為不會產生新立體 原中心），且保護基具有最少之額外官能基度，以避免其他 反應位置。如本文詳述，氧、硫、氮及碳保護基均可利用 。例如，在某些具體實施例中，如本文詳述，係利用某些 舉例之氧保護基。此等氧保護基包括但不限於甲基醚類、 經取代之甲基醚類（例如M0M (甲氧基甲基醚）、MTM (甲硫 基甲基醚）、BOM (苄氧基甲基酸）、pmbm或MPM (對·甲氧基 芊氧基甲基醚），僅指稱其中一小部份）、經取代之乙基醚 類、經取代之苄基醚類、矽烷基醚類（例如TMS (三甲基矽烷 基醚）、TES (三乙基矽烷基醚）、TIPS(三異丙基矽烷基醚）、 TBDMS (第三-丁基二甲基矽烷基醚）·、三苄基矽烷基醚、 TBDPS(第三-丁基二苯基矽烷基醚），僅指稱其中一小部份） 、酯類（例如甲酸酯、醋酸酯、苯甲酸酯（Bz)、三氟醋酸酯 、二氯醋酸酯，僅指稱其中一小部份）、碳酸酯類、環狀縮 酸類及縮酮類。在某些其他列舉之具體實施例中，係利用 氮保護基。此等氮保護基包括但不限於胺基甲酸酯類（包括 甲基、乙基及經取代之乙基胺基甲酸酯類（例如Tr〇c)，僅指 稱其中一小部份）、醯胺類、環狀亞胺衍生物、N-烷基與N_ 85762 -31 - 200412345 芳基胺類、亞胺衍生物及烯胺衍生物，僅指稱其中一小部 份。某些其他舉例之保護基係詳述於本文中，但是，應明 瞭的是，本發明並非意欲受限於此等保護基；而是，多種 其他等效保護基可容易地使用上述標準確認，且使用於本 發明中。此外，多種保護基係被描述於”有機合成之保護基，,， 第三版，Greene T·W·與 Wuts，RG·編著，john Wiley & s〇ns，⑽ γ〇Λ ·· 1999中，其全邵内容均據此併於本文供參考。 應明瞭的是，如本文中所述之化合物，可被任何數目之取 代基或官能性部份基團取代。一般而言，”經取代"一詞， 無論是否在其之前置放"視情況”一詞，且被包含在本發明 化學式中之取代基，係指在一特定結構中之氫基係被所指 定之取代基置換。當在任何特定結構中之一個以上位置， 可被一個以上之選自所指定基團之取代基取代時，該取代 基在每一位置處可無論是相同或不同。於本文中使用之，，經 取代"一詞，係意欲包括有機化合物之所有允許取代基。在 廣義方面，允許之取代基係包括有機化合物之非環狀與環 狀、分枝狀與未分枝、碳環族與雜環族、芳族與非芳族取 代基。對本發明之目的而言，雜原子，譬如氮，可具有氫 取代基及/或本文中所述有機化合物之任何可允許而滿足雜 原子價鍵之取代基。再者，本發明並不意欲以任何方式受 限於有機化合物之可允許取代基。藉由本發明所設想得= 之取代基與變數之組合，較佳係為會造成安定化合物形成 者，而可用於治療例如炎性與增生病症，包括但不限於風 濕性關節炎、牛皮癬、氣喘及癌症。於本文中使用之"安定 85762 • 32 - 200412345 一詞，較佳係指化合物具有足以允許製造之安定性，且其 係保持化合物-之完整性，歷經一段足夠時間以被檢出，且 較佳係歷經一段足夠時間以用於本文所詳述之目的。 万；本文中使用之”脂族”一詞，包括飽和與不飽和、直鏈（ 意即未分枝）、分枝狀、環狀或多環狀脂族烴類，其係視情 況被一或多個官能基取代。正如將被一般熟諳此藝者所明 瞭的，’’脂族’’於本文中係意欲包括但不限於烷基、烯其、 決基、環烷基、環錦Γ基及環炔基部份基團。因此，於本文 中使用之”烷基” 一詞包括直鏈、分枝狀及環狀烷基。'類似 慣用法係適用於其他總稱術語，譬如，，烯基”、，，块基，，等。 再者，於本文中使用之術語”烷基”、”缔基"、，，块基，，等， 係涵蓋經取代與未經取代之基團。在某些具體實施例中， 於本文中使用之，，低碳烷基”係用以表示具有丨_6個碳原子之 烷基（環狀、非環狀、經取代、未經取代、分枝或未分枝）。 在某些具體實施例中，於本發明中採用之烷基、埽基及炔 基，係含有1-20個脂族碳原子。在某些其他具體實施例中， 於本發明中採用之烷基、烯基及炔基：，係含有1-1〇個脂族碳 原子。在又其他具體實施例中，於本發明中採用之烷基、 少市基及決基，係含有1-8個脂族碳原子。於又再其他具體實 施例中，於本發明中採用之烷基、烯基及块基，係含有μ6 個月曰叙峡原子。在又其他具體實施例中，於本發明中採用 之烷基、烯基及块基，係含有Μ個碳原子。因此，說明性 脂族基團係包括但不限於例如甲基、乙基、正-丙基、異丙 基、烯丙基、正-丁基、第二-丁基、異丁基、第三_ 丁基、 85762 -33- 200412345 正-戊基、第二-戊基、異戊基、第三_戊基、正·己基、第二 -己基部份基團:等，其再-次可帶有一或多個取代基。烯基 包括但不限於例如乙埽基、丙烯基、丁 (-基等。代表性炔基包括但不限於乙块基、2__基（^ 基）、1-丙炔基等。 於本又中使用之"垸氧基"（或，，垸基氧基"）或"硫基燒基"術 語，係指如前文定義之燒基，經過氧原子或經過硫原子， 連接至母分子部份基團。在某些具體實施例中，燒基含有i· 2〇個脂族碳原子。在某些其他具體實施例中，烷基含有丨_1〇 個脂族碳原子。在又其他具體實施例中，於本發明中採用 <烷基、烯基及炔基含有丨_8個脂族碳原子。於又再其他具 體實施例中，燒基含有丨_6個脂族碳原子。在又其他具體實 她例中，烷基含有1-4個脂族碳原子。烷氧基之實例包括但 不限於曱氧基、乙氧基、丙氧基、異丙氧基、正·丁氧基、 第三-丁氧基、新戊氧基及正·己氧基。硫基烷基之實例包 括但不限於甲硫基、乙硫基、丙硫基、異丙硫基、正-丁硫 基等。 ”烷胺基”一詞係指具有結構-NHR，之基團，其中R，為如本 文中定義之烷基。”胺基烷基，，一詞係指具有結構顺〗^之基 團，其中Rf為如本文中定義之燒基。在某些具體實施例中， 烷基含有1-20個脂族碳原子。在某些其他具體實施例中，烷 基含有1-10個脂族碳原子。在又其他具體實施例中，於本發 明中採用之烷基、烯基及炔基含有1-8個脂族碳原子。於又 再其他具體實施例中，烷基含有丨_6個脂族碳原子。在又其 85762 -34- 200412345 他具體實施例中，烷基含有Μ個脂族碳原子。烷胺基之實 例包括但不限於甲胺基、乙胺基、異丙胺基等。 上述本發明化合物之脂族（及其他）部份基團之取代基之一 些實例’包括但不限於脂族；雜脂族；芳基；雜芳基；烷 基芳基；烷基雜芳基；燒氧基；芳氧基；雜燒氧基；雜芳 基氧基；烷硫基；芳基硫基；雜烷基硫基；雜芳基硫基；F ;Cl; Br; I; -OH; -N02 ; -CN; -CF3 ; _CH2CF3 ; -CHC12 ; -CH2OH ；-CH2CH2OH； -CH2NH2 ； -CH2S02CH3 ； -C(0)Rx ； -C02(Rx)； -CON(Rx)2 ; _0C(0)Rx ; -oco2rx ; _ocon(rx)2 ; -n(rx)2 ; -s(o)2rx ;-NRx(CO)Rx，其中Rx之每一存在處，係獨立包括但不限於 脂族、雜脂族、芳基、雜芳基、烷基芳基或烷基雜芳基， 其中上文及本文中所述之任何脂族、雜脂族、烷基芳基或 烷基雜芳基取代基，可為經取代或未經取代、分枝或未分 枝、環狀或非環狀，且其中上文及本文中所述之任何芳基 或雜芳基取代基，可為經取代或未經取代。一般性地可應 用取代基之其他實例，係藉由本文描述之實例中所示之特 殊具體實施例說明。 一般而言，於本文中使用之”芳基f’與’’雜芳基π術語，係 指安定早-或多橡族、雜$募族、多環族及多雜環族不飽和部 份基團’較佳係具有3-14個破原子，其每一個可為經取代或 未經取代。亦應明瞭的是，芳基與雜芳基部份基團，如本 文中定義，可經由脂族、脂環族、雜脂族、雜脂環族、烷 基或雜烷基部份基團連接，因此亦包括-(脂族）芳基、_(雜脂 族）芳基、-(脂族）雜芳基、-(雜脂族）雜芳基、-(烷基）芳基、·( 85762 -35- 200412345 祕：：基、伽完基)芳基及伽基)雜芳基部份基團。因 此，於本又中使用之措辭”芳基或雜芳基，，與,,芳基、雜芳基 、-(脂族）芳基、·(雜脂族）芳基、_( 土 v狹摊不基、-(雜脂族）雜 1 、懒㈣基、條紐基及伽 麟万基’’係可叉換。取代基包括但不限於任何切所提及 (取代基，意即關於脂族部份基團，4關於如本文中所揭 示之其他部份基圈所列舉，而會造成安定化合物形成之取The definitions of certain compounds and specific functional groups of the present invention are also described in more detail. 8. For the purpose of the present invention, “the chemical elements are based on the periodic table of halogens,” Handbook of Chemistry and Physics, 75th edition, cover. It is confirmed internally, and the special α-energy system is defined as it is. In addition, organic chemistry, "quotation principles, and functional groups and reactivity of specific functional groups are described in" Organic Chemistry ", Thomas Sorrdl, University Science Book Company (s__: 丨 999 in the The entire contents are incorporated herein by reference. Generally familiar with this art = It should be understood that the synthetic method as described in this article uses a variety of protections ^ The so-called " protecting group " used in this article has been used , Refers to a specific functional group of 85762 -30- 200412345, such as ο, S4N, which is temporarily blocked, so that the reaction can be selectively carried out at another reactive position in the polyfunctional compound. In a preferred embodiment, the protecting group is selectively reacted in good yield to obtain a protected substrate, which is stable to the planned reaction system; the protecting group must be easily accessible, preferably Non-toxic reagents that do not attack other functional groups are selectively removed in good yields; the protecting group forms derivatives that can be easily separated (more preferably, no new stereogenic centers are generated) and protects Base has the most Additional functionalities to avoid other reaction sites. As detailed herein, oxygen, sulfur, nitrogen and carbon protecting groups can be used. For example, in some specific embodiments, as detailed herein, certain examples are used Oxygen protecting groups. These oxygen protecting groups include, but are not limited to, methyl ethers, substituted methyl ethers (such as MOM (methoxymethyl ether), MTM (methylthiomethyl ether), BOM ( Benzyloxymethyl acid), pmbm or MPM (p-methoxymethyloxymethyl ether), which refers to only a small part), substituted ethyl ethers, substituted benzyl ethers, Silyl ethers (such as TMS (trimethylsilyl ether), TES (triethylsilyl ether), TIPS (triisopropylsilyl ether), TBDMS (third-butyldimethylsilyl ether) ) ·, Tribenzylsilyl ether, TBDPS (third-butyldiphenylsilyl ether), which refers only to a small part), esters (such as formate, acetate, benzoate ( Bz), trifluoroacetate, dichloroacetate, to name only a small part), carbonates, cyclic acetals and ketals. In some others In a specific embodiment, a nitrogen protecting group is used. Such nitrogen protecting groups include, but are not limited to, carbamates (including methyl, ethyl, and substituted ethyl carbamates (such as Troc ), Only a small part of which is referred to), amidines, cyclic imine derivatives, N-alkyl and N_85762 -31-200412345 arylamines, imine derivatives and enamine derivatives, only referred to A few of them. Some other examples of protecting groups are detailed herein, but it should be understood that the present invention is not intended to be limited to these protecting groups; rather, a variety of other equivalent protecting groups may be readily obtained. It is confirmed using the above standards and is used in the present invention. In addition, a variety of protecting groups are described in "Protective Groups for Organic Synthesis,", Third Edition, Greene T.W. and Wuts, RG. Ed., John Wiley & sons, ⑽γ〇Λ ·· 1999 Its entire contents are hereby incorporated herein by reference. It should be understood that compounds as described herein may be substituted with any number of substituents or functional partial groups. Generally speaking, "substituted The term " whether or not it is placed before " " as the case may be " and a substituent included in the chemical formula of the present invention refers to a hydrogen group in a specific structure as the designated substituent Substitution. When one or more positions in any particular structure can be substituted with more than one substituent selected from the specified groups, the substituents can be the same or different at each position. As used herein The term "substituted" is intended to include all permissible substituents of organic compounds. In a broad sense, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic organic compounds Family and heterocyclic, aromatic and non For the purposes of the present invention, heteroatoms, such as nitrogen, may have a hydrogen substituent and / or any permissible substituent of the organic compound described herein that satisfies the valence of the heteroatom. Furthermore, the present invention It is not intended to be limited in any way by the permissible substituents of organic compounds. By the combination of substituents and variables envisaged by the present invention, preferably those that will cause the formation of stable compounds can be used to treat, for example, inflammatory And proliferative disorders, including but not limited to rheumatoid arthritis, psoriasis, asthma and cancer. As used herein " stable 85762 • 32-200412345, preferably means that the compound has sufficient stability to allow manufacture, and Is to maintain the integrity of the compound- for a sufficient period of time to be detected, and preferably for a period of time sufficient for the purposes detailed herein. 10,000; the term "aliphatic" as used herein, including saturation And unsaturated, linear (meaning unbranched), branched, cyclic or polycyclic aliphatic hydrocarbons, which are optionally substituted with one or more functional groups. As will be As understood by those skilled in the art, `` aliphatic '' is intended herein to include, but is not limited to, alkyl, alkenyl, decyl, cycloalkyl, cycloalkyl, and cycloalkynyl groups. . Therefore, the term "alkyl" as used herein includes straight-chain, branched, and cyclic alkyl groups. 'Similar customary terms apply to other generic terms, such as, alkenyl,', and block groups, ,Wait. Furthermore, the terms "alkyl", "alkenyl", "block," and the like, as used herein, encompass both substituted and unsubstituted groups. In certain embodiments, as used herein As used herein, "lower alkyl" is used to indicate an alkyl group (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 6 carbon atoms. In certain embodiments, the alkyl, fluorenyl, and alkynyl groups used in the present invention contain 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl, alkenyl and alkynyl groups used in the present invention contain 1 to 10 aliphatic carbon atoms. In still other specific embodiments, the alkyl group, oligomeric group and decyl group used in the present invention contain 1-8 aliphatic carbon atoms. In still other specific embodiments, the alkyl group, alkenyl group, and block group used in the present invention contain 6 months of Syrian atoms. In still other embodiments, the alkyl, alkenyl and bulk groups used in the present invention contain M carbon atoms. Thus, illustrative aliphatic groups include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, allyl, n-butyl, second-butyl, isobutyl, third _ Butyl, 85762 -33- 200412345 n-pentyl, second-pentyl, isopentyl, third-pentyl, n-hexyl, second-hexyl partial groups: etc. With one or more substituents. Alkenyl includes, but is not limited to, for example, ethenyl, propenyl, butyl (-, etc.). Representative alkynyl groups include, but are not limited to, ethyl block, 2- (yl), 1-propynyl, etc. The term " fluorenyloxy " (or, fluorenyloxy ") or " thiocarbyl " used in the term refers to a carbamoyl group, as defined above, connected via an oxygen atom or via a sulfur atom. To the parent molecular moiety. In some specific embodiments, the alkyl group contains i · 20 aliphatic carbon atoms. In some other specific embodiments, the alkyl group contains 1-10 aliphatic carbon atoms In yet other specific embodiments, the present invention adopts < alkyl, alkenyl and alkynyl containing 8 aliphatic carbon atoms. In still other specific embodiments, the alkyl group contains 6 Aliphatic carbon atoms. In yet other specific examples, alkyl groups contain 1-4 aliphatic carbon atoms. Examples of alkoxy groups include, but are not limited to, fluorenyloxy, ethoxy, propoxy, isopropoxy , N-butoxy, tert-butoxy, neopentyloxy, and n-hexyloxy. Examples of thioalkyl include, but are not limited to, methylthio, ethylthio, Thio, isopropylthio, n-butylthio, etc. The term "alkylamino" refers to a group having the structure -NHR, where R is an alkyl group as defined herein. "Aminoalkyl , The term refers to a group having the structure cis ^^, where Rf is an alkyl group as defined herein. In certain embodiments, the alkyl group contains 1-20 aliphatic carbon atoms. In some other In specific embodiments, the alkyl group contains 1-10 aliphatic carbon atoms. In still other specific embodiments, the alkyl, alkenyl, and alkynyl groups used in the present invention contain 1-8 aliphatic carbon atoms. In still other specific embodiments, the alkyl group contains 6 aliphatic carbon atoms. In other specific embodiments thereof, the alkyl group contains M aliphatic carbon atoms. Examples of the alkylamine group include But not limited to methylamino, ethylamino, isopropylamino, etc. Some examples of the substituents of the aliphatic (and other) partial groups of the compounds of the present invention described above include, but are not limited to, aliphatic; heteroaliphatic; aromatic Heteroaryl; Alkylaryl; Alkylheteroaryl; Carbooxy; Aryloxy; Hetaoxy; Heteroaryloxy; Alkyl Group; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; -OH; -N02; -CN; -CF3; _CH2CF3; -CHC12; -CH2OH; -CH2CH2OH; -CH2NH2; -CH2S02CH3; -C (0) Rx; -C02 (Rx); -CON (Rx) 2; _0C (0) Rx; -oco2rx; _ocon (rx) 2; -n (rx) 2; -s (o) 2rx; -NRx (CO) Rx, where each occurrence of Rx independently includes but is not limited to aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl Wherein any of the aliphatic, heteroaliphatic, alkylaryl or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or Acyclic, and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted. Other examples of generally applicable substituents are illustrated by the specific embodiments shown in the examples described herein. In general, the terms "aryl f '" and "heteroaryl π" as used herein refer to the unsaturated moieties of the stable and early-or-more oak, hetero-, heterocyclic, and polycyclic heterocyclic groups. The group 'preferably has 3 to 14 broken atoms, each of which may be substituted or unsubstituted. It should also be understood that aryl and heteroaryl moiety groups, as defined herein, may be via Aliphatic, cycloaliphatic, heteroaliphatic, heteroalicyclic, alkyl or heteroalkyl moieties are attached and therefore also include-(aliphatic) aryl, _ (heteroaliphatic) aryl,-( Aliphatic) heteroaryl,-(heteroaliphatic) heteroaryl,-(alkyl) aryl, · (85762 -35- 200412345) Secret :: yl, galenyl) aryl and galanyl) heteroaryl Partial groups. Therefore, the wording "aryl or heteroaryl", and aryl, heteroaryl,-(aliphatic) aryl, · (heteroaliphatic) aryl, _ (Soil v narrow base,-(heteroaliphatic) hetero-1, lazy base, tertiary base, and galanthyl base are interchangeable. Substituents include, but are not limited to, all mentioned (substitute Radical, meaning with respect to the aliphatic moiety, 4 with respect to as disclosed herein Listed in other parts of the base circle, which will cause the formation of stable compounds

代基。在本發明之某些具體實施例中，"芳基"係指單-或雔 環狀碳環族環系統，具有一或兩個芳族環，包括但不心 苯基、審基、四氫蕃基，基，等。在本發明之某 些具體貫施例中，於本文中使用之"雜芳基詞，係指具 有五至十個環原子之環狀芳族基團，其中一個環原子係選 自s、0及N;零、一或兩個環原子係為其他雜原子，獨立 選自S、G及N ’而其餘環原子係為後，此基團係經由任何 環原子接合至分子之其餘部份，例如吡啶基、吡p井基、嘧Daiki. In certain embodiments of the present invention, "aryl" refers to a mono- or fluorene cyclic carbocyclic ring system having one or two aromatic rings, including but not phenyl, triphenyl, Tetrahydrobenzyl, base, etc. In certain specific embodiments of the present invention, the "heteroaryl word" as used herein refers to a cyclic aromatic group having five to ten ring atoms, wherein one ring atom system is selected from the group consisting of s, 0 and N; zero, one or two ring atoms are other heteroatoms, independently selected from S, G, and N ', and after the remaining ring atoms are, this group is bonded to the rest of the molecule via any ring atom , Such as pyridyl, pyridyl, pyrimyl

啶基、吡咯基、吡唑基、咪唑基、喧唑基、噚唑基、異噚 唑基、嚷二唑基、噚二唑基、硫苯基、呋喃基、喹啉基、 異喳琳基等。Pyridyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, thiophenyl, furyl, quinolinyl, isoxazolyl Base etc.

應明瞭的是，芳基與雜芳基（包括雙環狀芳基）可為未經取 代或、纟二取代，其中取代包括獨立以任一個或多個下列部份 基團置換一、二或三個於其上之氫原子，該部份基團包括 但不限於：脂族；雜脂族；芳基；雜芳基；烷基芳基；烷 基雜芳基；烷氧基；芳氧基；雜烷氧基；雜芳基氧基；烷 硫基’方基硫基；雜烷基硫基；雜芳基硫基；F ; α ;玢；I 85762 -36- 200412345 ；-OH； -N〇2 ； -CN； -CF3 ； -CH2CF3 ； -CHC12 ； -CH2OH； -CH2CH2OH ；-CH2NH2 ； -CH2S02CH3 ； -C(0)Rx ； -C02(Rx)； -CON(Rx)2 ； -0C(0)Rx ;-0C02Rx ; -OCON(Rx)2 ; -N(RX)2 ; -S(0)2Rx ; -NRx(CO)Rx，其 中Rx之每一存在處，係獨立包括但不限於脂族、雜脂族、 芳基、雜芳基、烷基芳基或烷基雜芳基，其中上文及本文 中所述之任何脂族、雜脂族、烷基芳基或烷基雜芳基取代 基，可為經取代或未經取代、分枝或未分枝、環狀或非環 狀，且其中上文及本文中所述之任何芳基或雜芳基取代基 ，可為經取代或未經取代。一般性地可應用取代基之其他 實例，係藉由本文描述之實例中所示之特殊具體實施例說 明。 於本文中使用之’’環烷基π —詞，係特別指具有三至七個， 較佳為三至十個碳原子之基團。適當環烷基包括但不限於 環丙基、環丁基、環戊基、環己基、環庚基等，其當在脂 族、雜脂族或雜環族部份基團之情況中時，可視情況被取 代基取代，取代基包括但不限於脂族；雜脂族；芳基；雜 芳基；烷基芳基；烷基雜芳基；烷氧基；芳氧基；雜烷氧 基；雜芳基氧基；烷硫基；芳基硫基；雜烷基硫基；雜芳 基硫基；F; Cl; Br; I; -OH; -NO〗；-CN; -CF3 ; -CH2CF3 ; -CHC12 ；-CH2OH； -CH2CH2OH； -CH2NH2 ； -CH2S02CH3 ； -C(0)Rx ； -C02(Rx) ；-CON(Rx)2 ^ -〇C(〇)Rx ； -0C02Rx ； -OCON(Rx)2 ； -N(Rx)2 ； -S(0)2Rx ;-NRx(CO)Rx，其中Rx之每一存在處，係獨立包括但不限於 脂族、雜脂族、芳基、雜芳基、烷基芳基或烷基雜芳基， 其中上文及本文中所述之任何脂族、雜脂族、烷基芳基或 85762 -37- 200412345 烷基雜芳基取代基可為經取代或未經取代、分枝或未分枝 、環狀或非環且其中上文及本文中所述之任何芳基或 雜芳基取代基可為經取代或未經取代。一般性地可應$取 代基之其他實例，係藉由本文描述之實例中所示之特殊具 體實施例說明。 ^It should be understood that aryl and heteroaryl (including bicyclic aryl) may be unsubstituted or disubstituted, wherein substitution includes independently replacing one, two or Three hydrogen atoms above it, the partial groups include but are not limited to: aliphatic; heteroaliphatic; aryl; heteroaryl; alkylaryl; alkylheteroaryl; alkoxy; aryloxy Heteroalkoxy; Heteroaryloxy; Alkylthio 'Sulfurylthio; Heteroalkylthio; Heteroarylthio; F; α; Rhenium; I 85762 -36- 200412345; -OH; -NO2; -CN; -CF3; -CH2CF3; -CHC12; -CH2OH; -CH2CH2OH; -CH2NH2; -CH2S02CH3; -C (0) Rx; -C02 (Rx); -CON (Rx) 2;-- 0C (0) Rx; -0C02Rx; -OCON (Rx) 2; -N (RX) 2; -S (0) 2Rx; -NRx (CO) Rx, where each Rx exists independently including but not Limited to aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the aliphatic, heteroaliphatic, alkylaryl, or alkyl groups described above and herein Heteroaryl substituents may be substituted or unsubstituted, branched or unbranched, cyclic Non-cyclic, and wherein the above and herein any aryl or heteroaryl substituent group, may be substituted or unsubstituted. Other examples of generally applicable substituents are illustrated by the specific embodiments shown in the examples described herein. As used herein, the term '' cycloalkylπ 'refers specifically to a group having three to seven, preferably three to ten carbon atoms. Suitable cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, when in the case of an aliphatic, heteroaliphatic or heterocyclic moiety, Optionally substituted with substituents, including but not limited to aliphatic; heteroaliphatic; aryl; heteroaryl; alkylaryl; alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy ; Heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; -OH; -NO; -CN; -CF3;- CH2CF3; -CHC12; -CH2OH; -CH2CH2OH; -CH2NH2; -CH2S02CH3; -C (0) Rx; -C02 (Rx); -CON (Rx) 2 ^ -〇C (〇) Rx; -0C02Rx; -OCON (Rx) 2; -N (Rx) 2; -S (0) 2Rx; -NRx (CO) Rx, where each Rx exists independently includes but is not limited to aliphatic, heteroaliphatic, aryl, Heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the aliphatic, heteroaliphatic, alkylaryl, or 85762-37-200412345 alkylheteroaryl substituents described above and herein may be Is substituted or unsubstituted, branched or unbranched, cyclic or acyclic and wherein above and herein Any of the aryl or heteroaryl substituents may be substituted or unsubstituted. Other examples of generically replaceable bases are illustrated by the specific specific embodiments shown in the examples described herein. ^

於本文中使用之’’雜脂族”一詞，係指脂族部份基團，其含 有一或多個氧、硫、氮、磷或矽原子，例如替代碳原子。 雜脂族部份基團可為分枝狀、未分枝、環狀或非環，狀，且 包括飽和與不飽和雜環，譬如嗎福啉基、四氫吡咯基等。 在木些具體贪施例中，雜脂族部份基團係以一或多個部份 基團，獨立置換位於其上之一或多個氫原子而被取代，該 邵份基團包括但不限於脂族；雜脂族；芳基；雜芳基；烷 基芳基；烷基雜芳基；烷氧基；芳氧基；雜烷氧基；雜芳 基氧基，燒硫基；芳基硫基；雜烷基硫基；雜芳基硫基；F ;Cl ; Br ; I; ·〇Η ; -N02 ; -CN ; -CF3 ; -CH2CF3 ; -CHC12 ; -CH2OH ;-ch2ch2oh； -ch2nh2 ； -CH2S02CH3 ； -C(0)Rx ； -C02(Rx); -CON(Rx)2 ； -0C(0)Rx ； -0C02Rx ； -0C0N(Rx)2 ; -N(Rx)2 ； -S(0)2Rx ;-NRx(CO)Rx ’其中Rx之各存在處，係獨立包括但不限於脂 族、雜脂族、芳基、雜芳基、烷基芳基或烷基雜芳基，其 中上文及本文中所述之任何脂族、雜脂族、烷基芳基或烷 基雜芳基取代基，可為經取代或未經取代、分枝或未分枝 、環狀或非環狀，且其中上文及本文所述之任何芳基或雜 芳基取代基可經取代或未經取代。一般性地可應用取代基 之其他實例，係藉由本文描述之實例中所示之特殊具體實 85762 -38- 200412345 施例說明。 w浯’係指選自氟、氣 於本文中使用之’’卣基，’與”鹵素 、溴及硤之原子。 ”㈣”-詞係表示如上文定義之境基 三個卣原子連接至其上，且其 二、有―、二或 乙基、三氟甲基等基團。 土甲基、溴基 於本文中使用之”雜環烷基”或，，雜 、6弋7 。ί成斗、夕四社 叮货口 ’係指非芳放ς 6-或7-貝喊多環基團，包括但不限於 /万扶5、 括經稠合之六員環，且有一盥- ;又$ — J衣基圈，包 氧、硫及氮，其·員環具;原子， 具有0至2個雙鍵，⑼氮與硫雜原子可視情:鍵:而各6_員環 雜原子可視情況被四級化，及㈣ $ i化’（111)鼠 芳基或雜芳基環。代表性雜環包括合至 ^ 孩1一不限於四氫吡咯基、 km、四氫心基、二氫❹基、四氫咪峻基、二 虱吡哫基、六氫吡啡基、四氫嘮唑基、異四氫噚唑基、嗎 福琳基、㈣基、異，塞吱咬基及四氫吱喃基。在某地且 體實施例中，係使用"經取代之雜我基或雜環”，而當於 本文中使用時，係指如上文定義之雜環燒基或雜環基團， 藉由獨立置換-、二或三個於其上之氫原子而被取代，取 代基係為(但不限於)脂族；雜脂》；芳基；雜芳基；烷基 芳基；燒基雜芳基；燒氧基；芳氧基；雜垸氧基；雜芳基 氧基；烷硫基；芳基硫基；雜烷基硫基；雜芳基硫基；F; Cl ； Br ； I ; -OH ； -N02 ； -CN ； .CF3 ； -CH2CF3 ; .CHC12 ； -CH2OH ；-CH2CH2〇H； -CH2NH2 ； -CH2S02CH3 ； -C(〇)Rx ; -C〇2(Rx)；- 85762 -39- 200412345 CON(Rx)2 ; -0C(0)Rx ； -〇C02Rx ; -OCON(Rx)2 ； -N(Rx)2 ； >s(〇)2rx ，-NRX (CO)Rx ’其中Rx之母一存在處，係獨立包括但不限於 脂族、雜脂族、芳基、雜芳基、烷基芳基或烷基雜芳基， 其中上文及本文中所述之任何脂族、雜脂族、烷基芳基或 烷基雜芳基取代基，可為經取代或未經取代、分枝或未分 枝、環狀或非環狀，且其中上文及本文中所述之任何芳基 或雜芳基取代基可為經取代或未經取代。一般性地可應用 取代基之其他實例係藉由本文描述之實例中所示之特殊具 體實施例說明。 3)研究用途、配方及投藥 根據本發明，本發明化合物可以此項技藝中已知之任何可 採用之檢測法進行檢測，以確認具有預定生物學活性之化 a物例如，此檢測可為細胞或非細胞、活體内或活體外 、高-或低_通過量格式等。於某些列舉之具體實施例中， 本發明化合物係在檢測中測試，以確認此等化合物具有抗 增生/抗癌活性、炎性細胞活素發出訊息途徑抑制活性、黏 連分子表現抑制活性及/或消炎作用：。 因此’於一方面’特別令人感興趣之本發明化合物包括： …、示叙〖生地作為在以炎性細胞活素刺激時於内皮細胞 表面上 < 黏連分子表現之抑制劑之活性； 顯不作為炎性細胞活素發出訊息途徑之抑制劑之活性； •對於被保持在活體外之適當細胞系，或在使用科學上可 接受模式之動物研究中，顯示消炎作用； 對方、被保持在活體外之適當細胞系，或在使用科學上可 85762 200412345 接受模式之動物研究中，顯示抗增生及/或抗癌作用； 及 ： •顯不有利治療形態（例如安全性、功效及安定性）。 正如上又所討論者，如本文中所述之某些化合物顯示一般 性地作為内皮細胞上之細胞黏連分子（E_選擇素與icam)，及 精由炎性細胞活素發出訊息所引致之轉錄活化作用之抑制 训 < 活性。更明確言之，本發明化合物証實免疫調節活性 ’且因此本發明進-步提供—種治療炎性或自身免疫病症 或增生病症之方法。此方法係涉及對需要治療之病患(包括 但不限於人類4動物），#予治療上有效量之化合物或其藥 學上可接受之衍生物。於某些具體實施例中，本發明化合 物可用於治療風濕性關節炎、潰瘍性結腸炎/克隆氏病、中 樞神經系統疾病（CNS)，譬如多發性硬化、全身性紅斑狼瘡 氣％、同種移植排斥/移植物對宿主疾病（gvhd)、牛皮 癖、異位性皮炎、濕疹、蓴麻疹、過敏性鼻炎、重症肌無 力糖尿病、自發性血小板減少性紫斑病、絲球體性腎炎 、心與血管疾病及癌症。 於某些具體實施例中，此方法係涉及對需要治療之病患（ 包括但不限於人類或動物），投予治療上有效量之化合物或 其藥學上可接受之衍生物。於某些具體實施例中，係提供 一種醫樂組合物，其包含本發明化合物（或其藥學上可接受 之衍生物），錢或稀釋劑，及視情況包含另—種治療劑。 醫藥組合物 正如上又所討論者，本發明係提供具有可用於治療炎性與 85762 -41- 200412345The term "heteroaliphatic" as used herein refers to an aliphatic moiety group that contains one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms, for example, instead of a carbon atom. Heteroaliphatic moiety The group can be branched, unbranched, cyclic or acyclic, and includes saturated and unsaturated heterocycles, such as morpholinyl, tetrahydropyrrolyl, etc. In some specific embodiments, Heteroaliphatic partial groups are substituted with one or more partial groups, independently replacing one or more hydrogen atoms located thereon. The aliphatic groups include, but are not limited to, aliphatic; heteroaliphatic; Aryl; heteroaryl; alkylaryl; alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy, thiothio; arylthio; heteroalkylthio Group; heteroarylthio; F; Cl; Br; I; · 〇Η; -N02; -CN; -CF3; -CH2CF3; -CHC12; -CH2OH; -ch2ch2oh; -ch2nh2; -CH2S02CH3; -C ( 0) Rx; -C02 (Rx); -CON (Rx) 2; -0C (0) Rx; -0C02Rx; -0C0N (Rx) 2; -N (Rx) 2; -S (0) 2Rx; -NRx (CO) Rx 'where each occurrence of Rx independently includes, but is not limited to, aliphatic, heteroaliphatic, aryl, Aryl, alkylaryl or alkylheteroaryl, wherein any of the aliphatic, heteroaliphatic, alkylaryl or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted Substituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted. Substituents may generally be applied Other examples are illustrated by the specific specific examples shown in the examples described in this document 85762 -38- 200412345. w 浯 'means selected from the group "fluorenyl," and " Atoms of halogen, bromine and thorium. The “㈣” -word system means that as defined above, three rhenium atoms are attached to it, and the second one has —, di or ethyl, trifluoromethyl and other groups. Ethylmethyl, bromo is used herein as "heterocycloalkyl" or, hetero, 6-7. "Du Chengdou and Xisi Sheding Dingkou" refers to non-fragrant 6- or 7-belt polycyclic groups, including, but not limited to, Wanfu 5, including six-membered fused rings, and a bathroom -; And $ — J-kidney ring, containing oxygen, sulfur and nitrogen, its member ring; atom, with 0 to 2 double bonds, nitrogen and sulfur heteroatoms depending on the situation: bond: and each 6_member ring Heteroatoms can be quaternized as appropriate, and ㈣ $ i '(111) mouse aryl or heteroaryl ring. Representative heterocycles include hydrazine, but not limited to tetrahydropyrrolyl, km, tetrahydrocarbyl, dihydrofluorenyl, tetrahydroimidyl, dipyridyl, hexahydropyridyl, tetrahydro Oxazolyl, isotetrahydrooxazolyl, morpholinyl, fluorenyl, iso, stilbene and tetrahydrocranyl. In some embodiments, "substituted heterocyclyl or heterocyclic ring" is used, and when used herein, refers to a heterocyclic alkyl group or heterocyclic group as defined above, by Independently replaced by-, two or three hydrogen atoms on it, the substituents are (but not limited to) aliphatic; heterolipids; aryl; heteroaryl; alkylaryl; Radical; aryloxy; aryloxy; heterofluorenyloxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; -OH; -N02; -CN; .CF3; -CH2CF3; .CHC12; -CH2OH; -CH2CH2OH; -CH2NH2; -CH2S02CH3; -C (〇) Rx; -C〇2 (Rx);-85762- 39- 200412345 CON (Rx) 2; -0C (0) Rx; -〇C02Rx; -OCON (Rx) 2; -N (Rx) 2; > s (〇) 2rx, -NRX (CO) Rx 'where Where Rx exists, it independently includes, but is not limited to, aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, where any of the aliphatics described above and herein , Heteroaliphatic, alkylaryl or alkylheteroaryl substituents, which may be substituted or unselected , Branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted. Substituents may generally be applied Other examples are illustrated by specific specific examples shown in the examples described herein. 3) Research Uses, Formulations and Administration According to the present invention, the compounds of the present invention can be detected by any applicable detection method known in the art. In order to confirm that the substance has a predetermined biological activity, for example, the test may be cellular or non-cellular, in vivo or in vitro, high- or low-throughput format, etc. In certain listed embodiments, the present The compounds of the invention are tested in tests to confirm that these compounds have anti-proliferative / anti-cancer activity, inflammatory cytokine signaling pathway inhibitory activity, adhesion molecule expression inhibitory activity and / or anti-inflammatory effect: therefore 'on one hand 'Specially interesting compounds of the present invention include: ..., which are described as "inhibitory effects of adhesion molecules on the surface of endothelial cells when stimulated with inflammatory cytokines" Activity of the agent; Significantly no activity as an inhibitor of the inflammatory cytokine signaling pathway; • Display of anti-inflammatory effects on appropriate cell lines maintained in vitro or in animal studies using scientifically acceptable models; Appropriate cell lines maintained in vitro, or in animal studies using scientifically acceptable models of 85762 200412345, showing antiproliferative and / or anticancer effects; and: • showing no favourable therapeutic modality (eg safety, efficacy And stability). As discussed above, certain compounds as described herein have been shown to act generally as cell adhesion molecules (E_selectin and icam) on endothelial cells, and are caused by messages from inflammatory cytokines Inhibition of transcription activation < activity. More specifically, the compounds of the present invention demonstrate immunomodulatory activity 'and therefore the present invention further provides a method for treating inflammatory or autoimmune or proliferative disorders. This method involves treating a patient in need of treatment (including but not limited to human 4 animals) with a therapeutically effective amount of a compound or a pharmaceutically acceptable derivative thereof. In certain embodiments, the compounds of the present invention can be used for the treatment of rheumatoid arthritis, ulcerative colitis / Clond's disease, central nervous system disease (CNS), such as multiple sclerosis, systemic lupus erythematosus gas%, allograft Rejection / graft against host disease (gvhd), psoriasis, atopic dermatitis, eczema, urticaria, allergic rhinitis, myasthenia gravis, spontaneous thrombocytopenic purpura, filamentous nephritis, heart and blood vessels Illness and cancer. In certain embodiments, the method involves administering to a patient in need of treatment (including but not limited to a human or animal) a therapeutically effective amount of a compound or a pharmaceutically acceptable derivative thereof. In certain embodiments, a medical music composition is provided, which comprises a compound of the present invention (or a pharmaceutically acceptable derivative thereof), money or a diluent, and optionally another therapeutic agent. Pharmaceutical Compositions As discussed above, the present invention provides compounds having properties that can be used to treat inflammatory conditions and 85762 -41- 200412345.

增生病症 < 生―物學性質之新穎化合物，該病症包括但不限 於風濕性關節炎、潰瘍性結腸炎/克隆氏病、中樞神經系統 疾病(CNS)，譬如多發性硬化、全身性紅斑狼瘡、氣喘、同 種移植排斥/移植物對宿主疾病（GVHD)、牛皮癬、異位性 皮炎、濕疹、蓴麻疹、過敏性鼻《、重症肌無力、糖尿病 自發性血小板減少性紫斑病、絲球體性腎炎、心與血管 疾病及癌症。本發明化合物亦發現可用於預防易遭受到譬 如血管造形術與支架置放術之損傷之血管再狹窄。 Q此於本發明之另一方面，係提供醫藥組合物，其包$ 種本文中所述之化合物（或其前體藥物、藥學上可接受 〈鹽或其他藥學上可接受之衍生物），且視情況包含藥學』 口、、又之載封】在木些具體實施例中，此等組合物視情货 進-步包含-或多種其他治療劑。例如，與本發明化人礙 共同投藥或加入醫藥組合物中之其他治療劑，可為消炎劑: 例如—種料治療風濕性關節炎或牛皮癖之藥劑）或細胞毒Proliferative disorders < Bio-physical novel compounds, including but not limited to rheumatoid arthritis, ulcerative colitis / clone's disease, central nervous system diseases (CNS) such as multiple sclerosis, systemic lupus erythematosus , Asthma, allograft rejection / graft-versus-host disease (GVHD), psoriasis, atopic dermatitis, eczema, rash measles, allergic nose, myasthenia gravis, diabetic spontaneous thrombocytopenic purpura, silky sex Nephritis, heart and vascular disease, and cancer. The compounds of the present invention have also been found to be useful in preventing restenosis of blood vessels that are susceptible to damage such as angioplasty and stent placement. In another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound described herein (or a prodrug thereof, a pharmaceutically acceptable salt, or other pharmaceutically acceptable derivative), And optionally contain pharmacology. In some specific embodiments, these compositions may be further included, or may include other therapeutic agents, as appropriate. For example, the co-administration or other therapeutic agents added to the pharmaceutical composition of the present invention may be anti-inflammatory agents: for example, a drug for treating rheumatoid arthritis or psoriasis or cytotoxicity

劑：經許可用於治療癌症之抗癌劑，如更詳細地於本文中 冴-者’或其可為正在食品藥物管瑝局中接受認可，而丑 最終將獲得認可’以治療免疫病症或癌症之多種藥劑之^ :種。亦應明瞭的是，某些本發明化合物可以自由態形式 :在’以供治療，或在適當情況下，以其藥學上可接受之 竹生物。根據本發明雜與 ……… 木予上可接受〈衍生物包括但不限 ι木学上可接受之赜、而匕 .^ ^ 1 -曰、此種酉曰之鹽，或本發明化合物 物或其他加成物或衍生物，其在投予有需要之病 心時，能夠直接或間接提# 杈仏如本又其他万面所述之化合物 85762 -42- 200412345 ，或其新陳代謝產物或殘基。 於本文中使用之，，藥學上可接受之鹽 靠醫學判斷之範園Θ *，係指在安全可 阅鬥，通用於與人類及俏 觸，而無不當毒性、釗I ^ 低寺動物之組織接 母注刺激性、過敏性回馗竺 理利益/風險比之鹽。胺·〜 口應彳，且伴隨著合 月文木、、叙類及其他類刑 人、# 學上可接受之鹽，係A &瑁妯一 + 、，、土化5物《樂 糸為此員技蟄中所習知。 人係詳細地描述藥聲μ ^ v > 如S.M. Berge寺 ,、头予上可接受之鹽於聲藥矜學身糸仏：卜19 (1977)中，併於本文供參 ^ 此寺鹽可在本發明化合物之最 後早離與純化期間當埸劍成 白…… 成’或個別地經由使自由態驗或 基與適當試劑反應，如-般性地於下文描述 者。例如’自由態驗官能基可與適當酸反應。再者，於本 發明化合物帶有酸性部份其圚 、> 丨切基團心情況中，其適當藥學上可 接受之鹽可包括金屬鹽’譬如驗金屬冑’例如鋼或卸鹽； 及驗土金屬鹽，例如_或鎂鹽。藥學上可接受無毒酸加成 鹽之實例’係為胺基與無機酸形成之鹽，該無機酸譬如鹽 酸、氫溴酸、磷酸、硫酸及過氯酸，或與有機酸類譬如酷 酸草酸順丁埽—酸、酒石酸、棒樣酸、號轴酸或丙二 酸所形成之鹽，或利用此項技藝中使用之其他方法，譬如 離子父換。其他樂學上可接受之鹽，包括己二酸鹽、海藻 酸鹽、抗壞血酸鹽、天冬胺酸鹽、苯磺酸鹽、苯甲酸鹽、 酸性硯酸鹽、硼酸鹽、丁酸鹽、樟腦酸鹽、樟腦磺酸鹽、 檸檬酸鹽、稼戊fe丙酸鹽、二葡萄糖酸鹽、十二基硫酸鹽 、乙烷磺酸鹽、甲酸鹽、反丁烯二酸鹽、葡庚糖酸鹽、甘 油磷fel鹽、葡萄糖fel鹽、半硫酸鹽、庚酸鹽、己酸鹽、氫 85762 -43. 200412345 琪酸鹽、2-羥基-乙烷磺酸鹽、乳酸生物酸鹽、乳酸鹽、月 桂酸鹽、月桂:基硫酸鹽、蘋果酸鹽、順丁烯二酸鹽、丙二 酸鹽、甲燒績酸鹽、2_莕續酸鹽、於驗酸鹽、硝酸鹽、油酸 鹽、草酸鹽、棕櫚酸鹽、雙羥茶酸鹽、果膠酯酸鹽、過硫 酸鹽、3-苯基丙酸鹽、磷酸鹽、苦味酸鹽、三甲基醋酸鹽、 丙酸鹽、硬脂酸鹽、琥珀酸鹽、硫酸鹽、酒石酸鹽、硫氰 酸鹽、對-甲苯磺酸鹽、十一烷酸鹽、戊酸鹽等。代表性鹼 金屬或驗土金屬鹽包括鈉、鋰、鉀、鈣、鎂等。其他藥學 上可接受之鹽，包括在適當時，無毒性銨、四級銨及胺陽 離子，使用抗衡離子所形成者，譬如商化物、氫氧化物、 羧酸鹽、硫酸鹽、磷酸鹽、硝酸鹽、低碳烷基磺酸鹽及芳 基磺酸鹽。Agent: An anti-cancer agent licensed for the treatment of cancer, as described in more detail herein, or it may be accepted in the Food and Drug Administration, and Ugly will eventually be approved to treat immune disorders or Cancer's multiple agents ^: species. It should also be clear that certain compounds of the invention may be in free form: 'for treatment, or, where appropriate, with their pharmaceutically acceptable bamboo organisms. In accordance with the present invention, hybrids are acceptable on wood. Derivatives include, but are not limited to, wood-acceptable hydrazones and daggers. ^ ^ 1-such salts, or compounds of the present invention Or other adducts or derivatives, which can directly or indirectly improve the compound 85762 -42- 200412345 as described in this and other aspects, or its metabolites or residues, when administered to the sick heart in need. base. As used in this article, pharmaceutically acceptable salt depends on the medical judgment of Fanyuan Θ *, which means that it is safe and legible, and is commonly used with humans and humans without improper toxicity. Tissue recipients inject irritating, allergic bactericidal benefits / risk ratio salts. Amine · ~ Mouth should be 合, and accompanied by He Yue Wen Mu, 叙, and other types of prisoners, # academically acceptable salt, is A & 瑁 妯 一 + ,,, and earthen 5 things "乐 糸This is known to the staff. The human line describes the medicine sound μ ^ v > Such as SM Berge Temple, the acceptable salt on the head is in the sound medicine 矜 Xueshen 糸 仏: Bu 19 (1977), and is provided here for reference ^ This temple salt This can be achieved during the final early isolation and purification of the compounds of the present invention ... or by individually reacting a free-form assay or group with a suitable reagent, as described generally below. For example, the ' free-state functional group may be reacted with a suitable acid. Furthermore, in the case where the compound of the present invention has an acidic moiety, > a group, its suitable pharmaceutically acceptable salt may include a metal salt 'such as metal test' such as steel or desalting salt; and Test soil metal salts, such as _ or magnesium salts. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amine groups with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as cis-acid oxalic acid Butanidine—Salts formed by acids, tartaric acids, bacciform acids, horn acids, or malonic acids, or other methods used in this technique, such as ion exchange. Other musically acceptable salts include adipic acid, alginate, ascorbate, aspartate, besylate, benzoate, acid sulfonate, borate, butyrate, Camphor salt, camphor sulfonate, citrate, pentamylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptane Sugar salt, glycerophosphorus Fel salt, glucose Fel salt, hemisulfate, heptanoate, hexanoate, hydrogen 85762 -43. 200412345 Ketanoate, 2-Hydroxy-ethanesulfonate, Lactic acid bicarbonate, Lactate, laurate, laurate: sulphate, malate, maleate, malonate, mesalate, 2-ammonium salt, test salt, nitrate, Oleate, oxalate, palmitate, glycolate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, trimethylacetate, propionate Acid salts, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, and the like. Representative alkali metal or soil test metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts, including, where appropriate, non-toxic ammonium, quaternary ammonium and amine cations, formed using counter ions, such as commercial compounds, hydroxides, carboxylates, sulfates, phosphates, nitric acid Salts, lower alkyl sulfonates and aryl sulfonates.

、丙締酸酯及乙基琥珀酸酯。, Acrylic and ethyl succinate.

比，且對於其所意欲之用途有效， 且伴隨著合理利益/風險 ’以及在可能之情況下， 85762 -44- 200412345 為本發明化合物之兩性離子形式。”前體藥物”一詞係指會 在活體内迅速弛轉變，而產生上式母體化合物之化合物， 例如經由在血液中水解。充分討論係提供於T_ffiguchi與 V. Stella，前體藥物作為新穎傳輸系統，A C S•討論會系列之第 14A卷，及在EdwardB.Roche編著，於藥物設計上之生物可逆載 體，美國醫藥協會與Pergamon出版社，1987，此兩者均併於本 文供參考。 如上文所述，本發明之醫藥組合物另外包含藥學上可接受 之載劑，其在使用於本文中時，係包括任何及所有溶劑、 稀釋劑或其他液體媒劑、分散液或懸浮助劑、表面活性劑 二等滲劑、稠化或乳化劑、防腐劑、固體黏合劑、潤滑劑 等〃適σ所要之特定劑量形式。Remington氏醫藥科學，第 十六版，E. W. Martin (Mack出版公司（East〇n，pA)，_揭示用於, 配醫藥組合物之各種載劑，及其製備之已知技術。除非達 到任何習用載劑媒質與本發明化合物不相容之程度，嬖如 ^生任何不期望之生物學效應或者以有害方式與醫藥^ 2任何其他成份交互作用’否則其使用係意欲涵蓋在本 :=圍内。可充作藥學上可接受載劑之物質，其—： 二一不限於糖類，譬如乳糖、葡萄糖及藏糖；殿粉 二：：米殿粉與馬鈴薯澱粉；纖維素及其衍生物，譬如 :㈣缄：素鋼、乙基纖維素及醋酸纖維素；粉末狀西普 :树：：麥芽；白明膠；滑石；賦形劑，譬如可可豆月匕血 全劑％類；油類，譬如花生油 5 ’、 —玉米油與大豆油;二醇二Γ二之麻油 吁靖-如丙二酯類 85762 -45- 200412345 ’譬如油酸乙^旨與月桂酸乙酯；瓊脂；緩衝劑，譬如氫氧 化鎂與氫氧化藓；海藻酸；不含熱原水；等滲鹽水；林格 氏落液；乙醇與磷酸鹽緩衝劑溶液，以及其他無毒性可相 容潤α劑’譬如月桂基硫酸鈉與硬脂酸鎂，以及著色劑、 離型劑、塗覆劑，增甜、矯味及芳香劑，防腐劑與抗氧化 釗’亦可存在於組合物中，根據配方設計師之判斷。 本發明化合物之用途與配方 正如更詳細於本文中所述者，一般而言，本發明係提供可 用於治療炎性或自身免疫病症及治療增生病症之化合物。 不希望被任何特足理論所束縛，更一般性而言，本發明化 合物已被証實會抑制黏連分子，譬如£_選擇素與ΚΑΜ-丨，在 I由以炎性細胞活素刺激所引致之内皮細胞表面上表現。 此種細胞表面分子對於炎性細胞浸潤及炎性與免疫回應内 之、’、田肊細胞交互作用，係扮演一個關鍵角色。此等化合物 亦會降低轉錄因子抓⑼之活化作用，並抑制炎性細胞活素 發出訊息途徑中之轉錄活化作用，其係調節涉及數種炎性 疾病病理學之許多基因，譬如^❹與胃^。更一般性而言 ，NF-zcB在發炎之發病原理上作為關鍵角色之確認，係指出 以NF- /c B為標的之治療劑可對炎性與免疫病症有效（一般性 地參閱防禦與疾病中之NF_c/k /m卿电2〇〇1，川7，乃。 正如在本文之範例中所詳述者，在測定化合物抑制細胞活 素所引致之黏連分子藉由内皮細胞表現之能力纟檢測中， 某些本發明化合物（通常其中&之_個存在處為氫，而&之 另-個存在處為如一般性地於本文中描述之一種部份基團） 85762 -46- 200412345 、、>、示IC5 〇值（E-選擇素與ICAM-1)低於1 。在其他具體實施 例中，舉例之牝合物顯示IC5〇值低於1〇 。 正如上文所討論者’本發明化合物顯示免疫調節活性，並 員示對於腫瘤細胞生長抑制之活性。因此，本發明化合物 特别可用於治療疾病與病症，包括但不限於風濕性關節炎 /貝瘍性結腸炎/克隆氏病、中樞神經系統疾病（CNS)，譬 如夕發性硬化、全身性紅斑狼瘡、氣喘、同種移植排斥/移Ratio, and is effective for its intended use, with a reasonable benefit / risk ′ and, where possible, 85762 -44- 200412345 is the zwitterionic form of the compound of the invention. The term "prodrug" refers to a compound that rapidly relaxes in vivo and produces the parent compound of the above formula, for example, by hydrolysis in blood. Full discussion is provided by T_ffiguchi and V. Stella, Prodrugs as Novel Delivery Systems, Volume 14A of the ACS Seminar Series, and Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Medical Association and Pergamon Press, 1987, both of which are incorporated herein by reference. As mentioned above, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, which, as used herein, includes any and all solvents, diluents or other liquid vehicles, dispersions or suspension aids. , Surfactants isotonicity agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and other suitable dosage forms required by σ. Remington's Medical Sciences, Sixteenth Edition, EW Martin (Mack Publishing, Easton, pA), discloses various carriers used in formulating pharmaceutical compositions, and known techniques for their preparation. Unless any conventional use is achieved The degree of incompatibility between the carrier medium and the compound of the present invention, such as the development of any undesired biological effect or the harmful interaction with any other ingredients of the medicine ^ 2 otherwise its use is intended to be covered within this: . Substances that can be used as pharmaceutically acceptable carriers, which are:-21 is not limited to sugars, such as lactose, glucose, and Tibetan sugar; Dian Fen 2: rice flour and potato starch; cellulose and its derivatives, such as : ㈣ 缄: plain steel, ethyl cellulose, and cellulose acetate; powder Xip: tree :: malt; white gelatin; talc; excipients, such as cocoa beans and moon blood whole agent%; oils, For example, peanut oil 5 ', corn oil and soybean oil; diol di-two di sesame oil called Jing-like propylene glycols 85762 -45- 200412345' such as ethyl oleate and ethyl laurate; agar; buffers Such as magnesium hydroxide and moss hydroxide; sea Alginic acid; pyrogen-free water; isotonic saline; Ringer's drip; ethanol and phosphate buffer solutions, and other non-toxic compatible alpha wetting agents such as sodium lauryl sulfate and magnesium stearate, and coloring Agents, release agents, coating agents, sweeteners, flavors and fragrances, preservatives and antioxidants can also be present in the composition, at the discretion of the formulator. The use and formulation of the compounds of the present invention are as detailed in more detail As described herein, in general, the present invention provides compounds useful in the treatment of inflammatory or autoimmune disorders and in the treatment of proliferative disorders. Without wishing to be bound by any particular theory, more generally, the compounds of the present invention It has been shown to inhibit adhesion molecules, such as £ _selectin and KAM- 丨, on the surface of endothelial cells caused by stimulation with inflammatory cytokines. Such cell surface molecules are useful for inflammatory cell infiltration and inflammation. The interaction between sex and immune response plays a key role. These compounds also reduce the activation of transcription factor scratching and inhibit inflammatory cell activity. Transcriptional activation in the signaling pathway regulates many genes involved in the pathology of several inflammatory diseases, such as ^ ❹ and stomach ^. More generally, NF-zcB plays a key role in the pathogenesis of inflammation. It is confirmed that the therapeutic agent with NF- / c B as the target can be effective on inflammatory and immune disorders (see NF_c / k / m in General for Defense and Disease, 2001, Chuan 7, No. As detailed in the examples herein, in determining the ability of compounds to inhibit the expression of adhesion molecules caused by cytokines by endothelial cells, certain compounds of the invention (of which & Is hydrogen, and & another place is a partial group as generally described herein) 85762 -46- 200412345,, >, IC50 value (E-selectin and ICAM- 1) Below 1. In other embodiments, the exemplified compounds show IC50 values of less than 10. As discussed above, the compounds of the present invention exhibit immunomodulatory activity and exhibit activity against tumor cell growth inhibition. Therefore, the compounds of the present invention are particularly useful in the treatment of diseases and disorders, including, but not limited to, rheumatoid arthritis / shellfish colitis / Clondell's disease, central nervous system diseases (CNS), such as evening sclerosis, systemic lupus erythematosus , Asthma, allograft rejection / migration

植物對宿主疾病（GVHD)、牛皮癖、異位性皮炎、濕疹、荨 麻療、過敏性鼻炎、重症肌無力、糖尿病、自發性血小板 減少性紫斑病、絲球體性腎炎、心與血管疾病及癌症。 正如上又所討論者，本發明化合物亦發現可用於預防易遭 又到譬如血官造形術與支架置放術之損傷之血管再狹窄。 例如，思欲涵盍的是，本發明化合物將可作為塗層，用於 被植入之醫療裝置’譬如管件、旁路、導管、人工植入物 針銷，電植人物，譬如起搏器，及尤其是用於動脈或靜Plant to host disease (GVHD), psoriasis, atopic dermatitis, eczema, urticaria, allergic rhinitis, myasthenia gravis, diabetes, spontaneous thrombocytopenic purpura, filamentous nephritis, heart and vascular disease And cancer. As discussed above, the compounds of the present invention have also been found to be useful in preventing restenosis of blood vessels that are susceptible to damage, such as haemoplasty and stent placement. For example, it is implied that the compounds of the present invention will serve as coatings for medical devices to be implanted, such as tubing, bypasses, catheters, artificial implant pins, implanted characters, such as pacemakers. , And especially for arterial or static

血&支木，包括氣球可膨脹支架。在某些具體實施例中 本毛明化合物可結合至可植入醫療裝置，或者，可被動 地吸附土可植入裝置之表面。在某些其他具體實施例中， 本發明化合物可經調配，以被包含在手術或醫療裝置或植 入物内：4通合藉其釋出，例如血管支架、缝合線、留駐 在内之導管、彌補物等。 在某些列舉之具體實施例中，本發明化合物可作為血管支 架（塗層使用。血管支架典型上為一種開放管狀結構，具 有孔洞（一種圖樣（或多種圖樣），自支架之外部表面延伸 85762 -47- 200412345 至腔管。使用雷射機器，製造生物可相容金屬材料之血管 支架’在其表:面上具有經切割之圖樣，是很平常的事。血 管支架可經電拋光，以使表面不整齊性降至最低，因為此 等不整齊性可能會觸發不利生物回應。但是，血管支架仍 然可刺激外物反應，造成血栓形成或再狹窄。為避免此等 併發症，多種支架塗層與組合物已在先前技藝文獻中被提 出，以降低此等併發症或其他併發症之發生率，及獨自恢 復組織功能，或經由傳輸治療化合物至腔管。例如，具有 抗增生與消炎活性之藥物，已被評估作為支架塗層，且已 証實有希望預防再狹窄（參閱，例如Presbitero P.等人，’’藥物溶 離支架使其確實有差異？"，M/nemz ⑽gzW，2002, 50(5): 431-442 ;RuygrokP.N.等人，”於心與血管醫藥上之雷帕黴素”， /咐em· Μ以/· J·，2003, 33(3) : 103-109 ;及 Marx SO.等人，，，工作台至 臨床：雷帕黴素之發展及其應用至血管支架再狹窄”，C/roz/油·洲， 2001，104(8) : 852-855，各此等參考資料係以其全文併於本文 供參考。因此，在不希望被任何特定理論束缚下，申請人 提出具有消炎及/或抗增生作用之本發明化合物，可作為支 架塗層及/或在支架藥物傳輸裝置中使用，尤其是預防再狹 窄或降低再狹窄速率。與支架塗層及/或局部支架藥物傳輸 有關聯之預防再狹窄之多種組合物與方法，係為此項技藝 中已知（參閱，例如美國專利案號：6,517,889; 6,273,913 ; 6,258，121 ;6,251，136 ; 6,248，127 ; 6,231，600 ; 6,203,551 ; 6，153,252 ; 6,071，305 ;5,891，507 ; 5,837,313，及已公告之美國專利申請案： US2001/0027340，其每一件均以其全文併於本文供參考）。例 85762 -48- 200412345 如，可將支架塗覆聚合體-藥物共輛物，其方式是將支架浸 潰在聚合體·藥:物溶液中’或以此種溶液噴塗支架。在某些 具體實施例中’供可植入裝置用之適當材料，包括生物可 相容且無毒性材料，並可選自金屬，譬如鎳-鈦合金、鋼， 或生物可相容聚合體、水凝膠、聚胺基甲酸酯、聚乙烯、 乙缔酷酸乙婦酉旨共聚物等。在某些具體實施例巾，係將本 發月化口物塗覆於支架上’以在氣脹血管造形術之後，供 ***動脈或靜脈中。Blood & branches, including balloon inflatable stents. In certain embodiments, the humor compound can be incorporated into an implantable medical device, or it can passively adsorb the surface of an implantable device. In certain other specific embodiments, the compounds of the invention can be formulated for inclusion in a surgical or medical device or implant: 4 releases can be released therefrom, such as vascular stents, sutures, resident catheters , Make-up, etc. In certain listed embodiments, the compounds of the present invention can be used as a vascular stent (coating. A vascular stent is typically an open tubular structure with holes (a pattern (or multiple patterns) extending from the outer surface of the stent 85762 -47- 200412345 to the lumen. It is common to use laser machines to make a vascular stent with a biocompatible metal material with a cut pattern on its surface: the vascular stent can be electropolished to Minimize surface irregularities, as these irregularities may trigger adverse biological responses. However, vascular stents can still stimulate foreign body reactions, causing thrombosis or restenosis. To avoid these complications, various stents are coated Layers and compositions have been proposed in prior art literature to reduce the incidence of these or other complications, and to restore tissue function alone, or to deliver therapeutic compounds to the lumen. For example, have antiproliferative and anti-inflammatory activity The drug has been evaluated as a stent coating and has proven promising for preventing restenosis (see, for example, Presbitero P. People, "Drug dissolution makes it really different?", M / nemz ⑽gzW, 2002, 50 (5): 431-442; Ruygrok P.N. et al., "Rapain in Cardiac and Vascular Medicine素 ”， / em · M 以 / · J ·, 2003, 33 (3): 103-109; and Marx SO. Et al. ,, Workbench to Clinical: Development of rapamycin and its application to blood vessels Stent restenosis ", C / roz / Yau · Zhou, 2001, 104 (8): 852-855, each of which is hereby incorporated by reference in its entirety. Therefore, without wishing to be bound by any particular theory The applicant proposes that the compounds of the present invention with anti-inflammatory and / or anti-proliferative effects can be used as stent coatings and / or used in stent drug delivery devices, especially to prevent restenosis or reduce the rate of restenosis. With stent coatings and / Various compositions and methods for preventing restenosis associated with local or local stent drug delivery are known in the art (see, for example, U.S. Patent Nos .: 6,517,889; 6,273,913; 6,258,121; 6,251,136; 6,248,127 ; 6,231,600; 6,203,551; 6,153,252; 6,071,305; 5,891,507; 5,837,313, Published U.S. patent applications: US2001 / 0027340, each of which is incorporated by reference in its entirety). Example 85762 -48- 200412345 For example, a stent can be coated with a polymer-drug common vehicle. Is the stent immersed in a polymer drug solution or spray the stent with such a solution. In some embodiments, 'appropriate materials for implantable devices, including biocompatible and non-toxic materials And can be selected from metals, such as nickel-titanium alloys, steel, or biocompatible polymers, hydrogels, polyurethanes, polyethylene, ethylene vinyl acetate copolymers, and the like. In certain embodiments, the present invention is applied to a stent ' to be inserted into an artery or vein after angioplasty.

/因此，在某些廣義方面’可將本發明描述為抑制血管損」 後之動脈再狹t或動脈堵塞之方法，其包括對有需要之劣 患& 丁包含經共輛至適當聚合體或聚合材料之本發明化^ 物之組合物。在此方法之實施中，患者可為例如冠狀分: :血官手術、器官移植或冠狀或任何其他動脈血管造形抽 病患’且此組合物可以直接方式、以靜脈内方式投予，連 在人目擊二管損傷時，甚至是被塗❹欲被植人之支架上。/ Therefore, in some broad aspects 'the present invention can be described as a method of inhibiting arterial restenosis or arterial blockage after vascular damage', which includes the need to treat the disadvantages & Or a composition of a polymer material of the invention. In the practice of this method, the patient may be, for example, a coronary artery: a patient undergoing blood surgery, organ transplantation, or coronary or any other arteriovascular angioplasty, and the composition may be administered directly, intravenously, in conjunction with When people witnessed the injury of the second tube, they were even painted on the stent to be implanted.

面’本發明係涵蓋植人物與手術或醫療裝置，^ 括血管支架與移植物，並 t 本及/或經山士、 /、已盒覆或以其他方式建造，以包The present invention encompasses implants and surgical or medical devices, including vascular stents and grafts, and includes books and / or shanshi, /, boxed or otherwise constructed to

_、 S 又中所揭示之任何本發明化合物。在某此JL 體實施例中，此筈仆人k〇在木些具 此並他… 合物具有消炎及/或抗增生活性。在某 一 /、他，、月豆只施例中，仆 發明植入物盘手術… 抑制平滑肌細胞增生。本 ~ # 、 或w療裝置之代表性實例，包括心盥血 管裝置（例如可植入 匕揞血 ，慢性灌、、i M + a ’官、#脈4 n、隨道式靜脈導管 屬線，可植：:二氣門’包括肝動脈灌注導管，起搏器金 纖維頸動器）；神經病/神經外科裝置（例如 85762 -49- 200412345 心罜腹膜旁路、心室動脈旁路、神經刺激裝置、硬膜貼片 及植入物，以預防椎板切除術後之硬膜上纖維變性，用於 連續场蛛膜下灌注之裝置）；胃腸裝置（例如慢性留駐在内^ 導管、進食管、Η體靜脈旁路、水腹用之旁路、藥物傳輸 用之腹膜植入物、腹膜滲析導管、疝脫用之可植入網片7 懸净液或固體植入物以預防手術黏連，包括網片）；生殖哭 與泌尿器裝置（例如子宮植人物，包括子宮内裝置_，^ 為預防子宮内膜增生之裝置，輸_管植人物，包括可逆不 育裝置、輸#管支架、人造括約肌’及失禁用之尿道周圍 植入物’輸尿管支架、慢性留駐在内之導管、膀胱強化作 用物，或輸精管兩段造口吻合術用之包覆物或夾板）；眼科 學植入物（例如多植人物’及新血管青光眼用之其他植入物 ，翼狀贅肉用之藥物溶離隱形眼鏡，失敗之淚囊鼻腔造口 術用之夾板、角膜新血管狀態用之藥物溶離隱形眼鏡、糖 尿病患者之視網膜病用之植人物、高危險角膜移植物用之 藥物溶離隱形眼鏡）；耳鼻喉科裝置（例如小骨植入物，膠耳 或慢性耳炎用之歐斯泰交氏f夾板錢架，作為___ 排乾之—種替代方式）；塑膠製手術植人物（例如，預防纖維 狀攣縮”乂回應在胸肌下或腺下處理方式中或***切除術 後之含凝膠或鹽水用之***植人物，或_植人物），及整形 植入物（例如膠合之整形彌補物）。 植入物及其他手術或醫療裝置可以多種方式塗覆（或以其 他方式配合調整以釋出)本發明組合物，包括例如⑻藉由 接使本|明化口物或組合物固著至植入物或裝置(例如， 85762 -50- 200412345 藉由無論是於植入物或裝置上噴塗聚 由將植入物或装置浸潰於聚合體/藥物溶液;=由：藉 共價或非共價方式)·’⑼經由以譬如水凝膠之物心枯: 物或裝置，其將依次吸收本發明化合物或組合物:_, S and any of the compounds of the present invention disclosed herein. In a certain embodiment of the JL body, the servant K0 has some other properties, such as anti-inflammatory and / or anti-proliferative properties. In one of the examples, he, and moon beans, the servant invented implant disc surgery ... to inhibit smooth muscle cell proliferation. Representative examples of this ~ # or w therapy device include cardiac vascular devices (such as implantable dipper blood, chronic perfusion, i M + a '官, # 脉 4 n, follow-line venous catheter line Can be implanted :: Two valves' include hepatic artery perfusion catheter, pacemaker gold fiber neck actuator; neuropathy / neurosurgery device (eg 85762 -49- 200412345 palpitation peritoneal bypass, ventricular artery bypass, nerve stimulation device, Dural patches and implants to prevent epidural fibrosis after laminectomy, a device for continuous field subarachnoid perfusion); gastrointestinal devices (such as chronic residency in the ^ catheter, feeding tube, Η Body vein bypass, hydroperitoneal bypass, peritoneal implant for drug delivery, peritoneal dialysis catheter, implantable mesh for hernia prolapse 7 Suspension or solid implant to prevent surgical adhesions, including Mesh); reproductive crying and urinary devices (such as uterine implants, including intrauterine devices), ^ devices to prevent endometrial hyperplasia, intubation / transplantation characters, including reversible infertility devices, infusion stent, artificial sphincter 'And around the incontinence of the urethra Implants' ureteral stent, chronic resident catheter, bladder reinforcement, or wrap or splint for two-stage vasectomy]; ophthalmic implants (such as multiple implants) and new blood vessels Other implants for glaucoma, drug-dissolved contact lenses for pterygium, splints for failed dacryocystorhinostomy, drug-dissolved contact lenses for corneal neovascular status, and implants for retinopathy in diabetic patients 2. High-risk corneal graft medicine dissolves contact lenses); otolaryngology devices (such as small bone implants, gel ears or chronic ear infections, Ostelloy F splint money holders, as ___ drained— Alternatives); plastic surgical implants (for example, to prevent fibroid contractures) 乂 respond to breast implants containing gels or saline in the treatment of the pectoral muscle or subgland or after mastectomy, or ), And orthopedic implants (such as glued orthopedic prosthetics). Implants and other surgical or medical devices can be coated in a variety of ways (or otherwise adjusted to release) Inventive compositions, including, for example, by attaching the present mouthpiece or composition to an implant or device (e.g., 85762 -50- 200412345 by spraying polymer onto the implant or device) Immersion of an implant or device in a polymer / drug solution; = by: by covalent or non-covalent means) · '⑼ via a substance such as a hydrogel: the object or device will sequentially absorb the present invention Compound or composition:

將本發明化合物或組合物塗覆之絲線(或聚合體本身製：、 絲線）交織至植人物或裝置中；⑷經由將植人物或裝置插〈 包含或已塗覆本發明化合物或組合物之套筒或網片中；二 建構本身具有本發明化合物或組合物之植入物或裝置.二 經由以其他方式配合調整植人物或裝置，以釋出本發^化 合物。在某些具體實施例中，組合物在儲存期間及：*** 時，應牢固地黏著至植入物或裝置。本發明化合物或也人 物較佳亦應在儲存期間’在***之前或在***身體内部： 被溫熱至體溫時（若這是需要的）不會降解。此外，較佳應 平滑且均勾地塗覆植人物或裝置，具有均句分佈之本發： 化合物’ g時不會改變支架外形。在本發明之較佳具體實 施例中’本發明植入物或裝置’一旦其已被佈署時:、：： 供均勻、可預測、長期釋出本發明化合物或組合物至圍繞 該植入物或裝置之組織中。對血管支架而言1 了上述： 質以外’組合物不應使得支架具有凝血酶原性（會造成血凝 塊形成），或在血液流動上造成顯著擾流（超過支架本身若 未經塗覆時所預期會造成者）。 在支架之情況中，可發展極多種支架，以包含及/或釋出 本文中所提供之本發明化合物或組合物，纟包括食管支架 、胃腸支架、血管支架、膽管支架、結腸支架、胰支架木 85762 -51 - 0412345 輸尿管與尿道支架、淚管支架、歐斯泰交氏管支架、㈣ 管支架及氣管/枝氣管支架（參閱，例如美國專利：6,5i5,〇i6 ，其全部内容係併於本文供參考）。支架可容易地得自商業 來源，或根據習知技術建造。支架之代表性實例，包括在 以下專利中所述者，美國專利4,768,523，其標題為"水凝膠 黏著劑美國專利4,776,337，其標題為”可膨服管腔内移植 物，及植入可膨脹管腔内移植物之方法與裝置"；美國專利 5,041，126 ’其標題為”血管内支架與傳輸系統 '美國專利 5’052’998 ’其標題為"留駐在内之支架及使用方法”；美國專 利5,064,435其;^越為具有安定軸長度之自動膨服彌補物" ;美國專利5，_，606，其標題為"供醫學應用之水不溶性多 料凝膠發泡體"；美國專利讽37q，其標題為"中空本體 導管用之Nitind支架"；美國專利5，176,626，其標題為”留駐在 内之支架”；美國專利5,213,58〇，其標題為"生物可降解之聚 合體：腔内密封方法'•及美國專利與471，其標題為，，在 中芝官狀器言及其他組織腔管中治療病灶疾病之.法 置”。 / 文所讶^^者，已塗覆（或以其他方式配合調整以釋 出）本發明組合物之支架，可用以排除血管阻塞，及預防再 狹乍或降低再狹窄速率。在本發明之其他方面中，係提供 已塗覆（或以其他方式配合調整以釋出）本發明組合物之支 架:以使身體通道之腔管膨脹。明確言之，可將具有大致 上官狀結構，且表面已塗覆（或以其他方式配合調整以釋幻 本4明化合物或組合物之支架’***通道中，以致使通道 85762 -52- ^00412345 =脹。在某些具體實施例中，已塗覆（或以其他方式配合調 整以釋出）本發:明組合物之支架，可用以排除膽管、胃腸、 食管、氣管/枝氣管、尿道或血管阻塞。 因此，如前文所述，在本發明之另一方面，係提供用於治 療炎性或自身免疫及增生病症之方法，其包括對有需要之 病患投予如本文中所述之治療上有效量之式①化合物。在 某些具體實施例中，本發明化合物可用於治療風濕性關節 炎/男瘍性結細炎/克隆氏病、中樞神經系統疾病（CNS)， 譬如多發性硬化、全身性紅斑狼瘡、氣喘、同種移植排斥/ 移植物對宿主疾病（GVHD)、牛皮癖、異位性皮炎、濕疹、 蓴麻疹、過敏性鼻炎、重症肌無力、糖尿病、自發性血小 板減少性紫斑病、絲球體性腎炎、心與血管疾病及癌症。 應明瞭的是，根據本發明之方法，化合物與組合物可使用 有效治療炎性或自身免疫及增生病症之任何量及任何投藥 途徑投藥。因此，於本文中使用之”有效量，，措辭，係指殺 死或抑制腫瘤細胞生長之足量藥劑，或係指降低炎性或自 身免疫回應或病症作用之足夠量。所需要之確實量係隨著 病患而改變，依病患之物種、年齡及一般狀況，疾病之嚴 重性，特定抗癌劑，其投藥模式等而定。本發明化合物較 佳係被調配成劑量單位形式，以易於投藥與劑量之均勻性 。於本文中使用之”劑量單位形式，，之措辭，係指適於待治 療病患之治療劑之物理上不連續單位。但是，應明瞭的是 ，本發明化合物與組合物之總每日用量，係由負責醫師在 女全可靠醫學判斷之範圍内決定。對任何特定病患或生物 85762 -53- 200412345 體之特定治療上有效劍量程度，係依多種因素而定，包括 被治療之病症與病症之嚴重性；所採用特定化合物之活性 •’所採用之特定組合物；病患之年齡、體重、一般健康狀 態、性別及飲食；所採用特定化合物之投藥時間、投藥途 徑及***速率；治療之延續時間；與所採用之特定化合物 合併或同時使用之藥物；及醫學技藝上習知之類似因素（參 閱，例如Goodman與Gilman，’’治療學之藥理學基礎”，第十版，Interweaving a silk thread coated with a compound or composition of the present invention (or a thread made by the polymer itself, or silk thread) into a plant or device; ⑷ inserting the plant or device into or containing the compound or composition of the invention In a sleeve or mesh; secondly, construct an implant or device having the compound or composition of the present invention; secondly, adjust the planting character or device in other ways to release the compound of the present invention. In certain embodiments, the composition should be firmly adhered to the implant or device during storage and upon insertion. The compounds of this invention or also humans should preferably also be stored during storage ' before insertion or into the body: they will not degrade when warmed to body temperature, if this is desired. In addition, it is preferred that the planted person or device be coated smoothly and uniformly, and the hair with a uniform sentence distribution: Compound ′ g does not change the shape of the stent. In a preferred embodiment of the invention, the 'implant or device of the invention', once it has been deployed ::: provides a uniform, predictable, long-term release of a compound or composition of the invention to surround the implant In the organization of objects or devices. For vascular stents: 1 The above: The composition should not make the stent thrombinogenic (which can cause blood clot formation) or cause significant turbulence in the blood flow (beyond the stent itself if not coated) As expected. In the case of stents, a wide variety of stents can be developed to include and / or release the compounds or compositions of the invention provided herein, including esophageal stents, gastrointestinal stents, vascular stents, bile duct stents, colon stents, and pancreatic stents. Wood 85762 -51-0412345 ureter and urethral stent, lacrimal stent, osteoclast stent, sacral stent, and trachea / bronchial stent (see, for example, US patents: 6,5i5, 0i6, all of which are And for reference in this article). The scaffold can be easily obtained from commercial sources or constructed according to conventional techniques. Representative examples of stents include those described in the following patents, U.S. Patent 4,768,523, entitled " Hydrogel Adhesive, U.S. Patent 4,776,337, entitled " Inflatable Endovascular Graft, and Implantable Method and device for expanding an intraluminal graft " US patent 5,041,126 'titled "Intravascular Stent and Delivery System' US Patent 5'052'998 'titled " Retained Stent and Use Method "; U.S. Patent 5,064,435; ^ Yue is an automatic swelling supplement with a stable shaft length " U.S. Patent 5, 606, entitled " Water-insoluble multi-material gel foam for medical applications " U.S. Patent 37q, whose title is " Nitind Stent for Hollow Body Catheters "; U.S. Patent 5,176,626, which has the title "Stent Resident"; U.S. Patent 5,213,580, which has the title " Biodegradable polymer: Intracavity sealing method 'and U.S. Patent No. 471, which is entitled "Methods for the treatment of focal diseases in Zhongzhi's official device and other tissue lumen". / Astonished by the text, a stent that has been coated (or otherwise adjusted to release) the composition of the present invention can be used to exclude vascular obstruction and prevent restenosis or reduce the rate of restenosis. In other aspects of the invention, a stent is provided that has been coated (or otherwise coordinated to release) the composition of the invention: to expand the lumen of a body passage. Specifically, a stent having a substantially official structure with a surface that has been coated (or otherwise coordinated to adjust to explain the compound or composition of the invention) may be inserted into the channel, so that the channel 85762 -52- ^ 00412345 = Swelling. In certain embodiments, the stent of the present invention has been coated (or otherwise adjusted to release) the composition: it can be used to exclude bile ducts, gastrointestinal tract, esophagus, trachea / bronchotrachea, urethra or Vascular occlusion. Therefore, as described above, in another aspect of the present invention, there is provided a method for treating inflammatory or autoimmune and proliferative disorders, which comprises administering to a patient in need as described herein A therapeutically effective amount of a compound of formula (1). In certain embodiments, the compound of the present invention can be used to treat rheumatoid arthritis / male ulcerative sarcoiditis / Clond's disease, central nervous system disease (CNS), such as multiple Sclerosis, systemic lupus erythematosus, asthma, allograft rejection / graft-versus-host disease (GVHD), psoriasis, atopic dermatitis, eczema, urticaria, allergic rhinitis, myasthenia gravis, sugar Disease, spontaneous thrombocytopenic purpura, filamentous nephritis, heart and vascular disease, and cancer. It should be understood that according to the methods of the present invention, compounds and compositions can be used to effectively treat inflammatory or autoimmune and proliferative disorders. Administration in any amount and by any route of administration. Therefore, "effective amount," as used herein, refers to a sufficient amount of an agent that kills or inhibits the growth of tumor cells, or refers to reducing the inflammatory or autoimmune response or the effect of a disorder. Sufficient amount. The exact amount required varies with the patient, depending on the species, age, and general condition of the patient, the severity of the disease, the specific anticancer agent, its mode of administration, etc. The compound of the present invention is preferably Formulated into a dosage unit form for ease of administration and uniformity of dosage. As used herein, "dose unit form," as used herein, refers to physically discrete units of a therapeutic agent suitable for the patient to be treated. However, It should be understood that the total daily dosage of the compounds and compositions of the present invention is determined by the responsible physician within the scope of reliable medical judgment of women. The degree of effective treatment of a particular patient or organism in a particular treatment 85762 -53- 200412345 depends on a number of factors, including the severity of the condition being treated and the severity of the condition; the activity of the specific compound used Composition; patient's age, weight, general health status, gender and diet; time of administration, route of administration and excretion rate of specific compounds used; duration of treatment; drugs combined with or used with specific compounds used; And similar factors known in medical technology (see, for example, Goodman and Gilman, "The Pharmacological Basis of Therapeutics", Tenth Edition,

A· Gilman，J.Hardman 及 L. Limbird 編著，McGraw-Hill 出版社，155-173, 2001 ’其全文係併於本文供參考）。Edited by A. Gilman, J. Hardman, and L. Limbird, McGraw-Hill Press, 155-173, 2001 (the entire text is incorporated herein by reference).

在某些其他具體實施例中，係提供方法，以使用已塗覆（ 或以其他方式配合調整以釋出）本發明化合物與組合物之本 發明植入物及其他手術或醫療裝置。在某些具體實施例中 ，:提供方法，以預防再狹窄，包括將支架***經阻塞之 血官中，此支架具有大致上管狀結構，結構之表面已塗覆（ 或以其他万式配合調整以釋出）本發明化合物或組合物，以 致使阻塞被排除，且本發明化合物或組合㈣以有效量傳 輸，以預防再狹_。在其他具體實施例中，係提供方法， 以預防再狹有，包括將支架***經阻塞之血管巾，支架且 =致上管狀結構’結構之表面已塗覆(或以其他方式配： ::以釋出)本發明化合物或組合物，以致使阻塞被排除， 細胞增生。戈、、且.物係以有效量傳輸’以抑制平滑肌 在本發明之其他方面中 、 管膨脹，包括將支架***通道V万支二通道之腔 ^ τ 支木具有大致上管狀結 85762 -54- 200412345 構’結構之表面已塗覆（或以其他方式配合調整以釋出）本 發明化合物或;组合物，以致使通道膨脹。在某些具體實施 例中’身體通道之腔管係被膨脹，以排除膽管、胃腸、食 管、氣管/枝氣管、尿道及/或血管阻塞。 使用支架以排除膽管、胃腸、食管、氣管/枝氣管、尿道 及/或血管阻塞之方法，係為此項技藝中已知的。熟練執業 商師將知道如何配合調整此等方法以實施本發明。例如， 可參閱美國專利申請案編號：20030004209段落[0146]-[0155]中 <指引，該段落係據此併於本文供參考。 再者，在與適當藥學上可接受之載劑調配成所要之劑量後 ，本發明之醫藥組合物可以口服、直腸、非經腸、腦池内 、***内、腹膜腔内、局部（譬如藉由粉末、軟膏、乳膏或 滴硬）、面頰方式，以口腔或鼻喷霧劑或其類似物，投予人 類及其他動物，依被治療之感染之嚴重性而定。在某些具 仏只施例中，本發明化合物可在每天約〇 〇〇1毫克/公斤至約 %笔克/公斤，約0·01毫克/公斤至約25毫克/公斤，或約〇1 毛克/么斤至約10耄克/公斤病患體重之劑量程度下投藥， -天-或多次，以獲得所要之治療效果。亦應明瞭的是， 可對病患投予低於α〇〇1毫克/公斤或大於5〇毫克/公斤（例 如50·毫克/公斤）之劑量。在某些具體實施例中，化合物 係以口服或非經腸方式投予。 供口服投藥之液體劑量形式，包括但不限於藥學上可接受 之乳化液、微乳化液、溶液、懸浮液、糖漿及酏劑。除了 活〖生化合物以外，液體劑量形式可含有常用於此項技藝中 85762 -55- 200412345 <惰性稀釋劑，例如水或其他溶劑、促溶劑及乳化劑，譬 如乙醇、異丙:醇、碳酸乙酯、醋酸乙酯、苄醇、笨甲酸’ 酯、丙二醇、1，3_ 丁二醇、二甲基甲醯胺、油類（特別是棉 籽、落把生、玉米、胚芽、橄揽、蓖麻及芝麻油）、甘油 四氳呋喃甲醇、聚乙二醇及花楸聚糖之脂肪酸酯類，及其 混合物。除了惰性稀釋劑之外，口服組合物亦可包含佐劑 ，譬如潤濕劑、乳化與懸浮劑，增甜、矯味及芳香劑。， 可注射製劑，例如無菌可注射水性或油性懸浮液，可根據 已知技藝，使用適當分散或潤濕劑與懸浮劑調配。無菌可 注射製劑亦可為無菌可注射溶液、懸浮液或乳化液，在矣 毒性非經腸上可接受之稀釋劑或溶劑中，例如在丨，3_丁二= 中作成溶液。其中可採用之可接受媒劑與溶劑，係為水、 林格氏溶液、U.S.P.及等滲氯化鈉溶液。此外，習用上係採 用無菌不揮發油作為溶劑或懸浮媒質。對此項目的而言P 任何溫和之不揮發油均可採用，包括合成甘油單酯或二酉旨 。此外，脂肪酸類，譬如油酸，係使用於可注射劑之製備。 可汪射配万可被減菌，例如經過留住細菌之濾器過濾，或 藉由摻入滅菌劑，呈無菌固體組合物形式，其可在使用之 箾被/谷解或为散在無菌水或其他無菌可注射媒質中。 為延長藥物之作用，經常需要減緩來自皮下或肌内注射之 藥物吸收。這可利用液體懸浮液或具有不良水溶解度之結 晶性或非m質達％。於I’藥物之吸收速率係依其溶 解速率而定，其依次可依晶體大小與結晶形式而定。或者 ，以非經腸方式投予之藥物形式之延遲吸收，係經由使藥 85762 -56- 物溶解或懸浮於油媒劑中而達成〇 形成藥物在生物可降解乏取入。可注射積貯形式係藉由 之微膠囊基質而製成。依二:譬如聚内交酿-聚乙交醋中 之特定聚合體之性質而定，藥物;;=例，及所採用 其他生物可降解之聚合體之 ^率可加以控制。 纤類卜積貯可注射配方亦：由使藥^ 容之微脂粒或微乳化液中而製成。▲“人可與身體組織相 本:η!這投藥用之組合物，較佳為栓劑，其可經由將 本發明化合物與適當無刺激性賦形劑或載劑混合而製成， 該載劑譬如可可豆脂、卺r 灰恥 氷乙一每或栓劑蠟，其在環境溫度 為固虹仁在恤,皿下為液體，因此會溶解於直腸或*** 孔穴中，並釋出活性化合物。 供口服投藥之固體劑量形式，包括膠囊、片劑、丸劑、粉 末及顆粒。在此種固體劑量形式巾，活性化合物係與至少 -種惰性藥學上可接受之賦形劑或載劑混纟，譬如擰檬酸 納或鱗酸二_，及/或&)填料或增量劑，譬如殿粉、·乳糖、 蔗糖、葡萄糖、甘露醇及矽酸，b)黏合劑，例如羧甲基纖維 素/母藻酸鹽、明膠、聚乙晞基四氫p比哈酮、蔗糖及阿拉 伯膠’ c)保濕劑，譬如甘油，d)崩解劑，譬如瓊脂-瓊脂、 碳酸#5、馬鈴薯或木薯澱粉、海藻酸、某些矽酸鹽及碳酸 納’ e)么解阻滞劑，譬如石蠛，〇吸收加速劑，譬如四級铵 化合物’ g)潤濕劑，例如鯨蠟醇與單硬脂酸甘油酯，h)吸收 劑’譬如高嶺土與膨土，及〇潤滑劑，譬如滑石、硬脂酸鈣 、硬脂酸鎂、固體聚乙二醇、月桂基硫酸鈉，及其混合物 85762 -57- 200412345 。在膠囊、片劑及丸劑之情況中，劑量形式亦可包含緩衝 劑。In certain other specific embodiments, methods are provided for using the present implants and other surgical or medical devices that have been coated (or otherwise coordinated to release) the compounds and compositions of the present invention. In some embodiments, a method is provided to prevent restenosis, which includes inserting a stent into an obstructed hemorrhoid, the stent has a generally tubular structure, and the surface of the structure has been coated (or adjusted in other ways) To release) the compound or composition of the present invention such that obstruction is eliminated, and the compound or combination of the present invention is delivered in an effective amount to prevent restenosis. In other specific embodiments, a method is provided to prevent re-narrowing, including inserting a stent into an obstructed vascular towel, and the surface of the stent and the structure leading to the tubular structure has been coated (or otherwise equipped with: :: To release) the compound or composition of the present invention, so that the obstruction is eliminated and the cells proliferate. Ge, and, and the system is transmitted in an effective amount 'to inhibit smooth muscle in other aspects of the invention, tube expansion, including the insertion of a stent into the channel V million branch two channel cavity ^ τ branch wood has a generally tubular knot 85762 -54 -200412345 The surface of the structure has been coated (or otherwise adjusted to release) the compound or composition of the invention, so that the channel is expanded. In certain embodiments, the luminal system of the ' body channel is inflated to exclude obstruction of the bile ducts, gastrointestinal tract, esophagus, trachea / bronchus, urethra and / or blood vessels. Methods of using a stent to exclude bile ducts, gastrointestinal tracts, esophagus, trachea / bronchial tubes, urethra, and / or vascular obstructions are known in the art. Skilled practitioners will know how to coordinate these methods to implement the invention. For example, see U.S. Patent Application No. 20030004209 paragraphs [0146]-[0155] < Guidelines, which paragraph is hereby incorporated herein by reference. Furthermore, the pharmaceutical composition of the present invention can be formulated orally, rectally, parenterally, intracranially, intravaginally, intraperitoneally, locally (e.g., by Powder, ointment, cream or hard drops), cheeks, oral or nasal spray or the like, administered to humans and other animals, depending on the severity of the infection being treated. In certain specific embodiments, the compounds of the present invention may be present at about 0.001 mg / kg to about% peng / kg, about 0.01 mg / kg to about 25 mg / kg, or about 0.01 mg / kg per day. Dosing at a dose ranging from gross weight / mesh to about 10 g / kg of the patient's body weight,-days-or multiple times, to obtain the desired therapeutic effect. It should also be clear that patients may be administered doses below α 0.001 mg / kg or greater than 50 mg / kg (e.g., 50 mg / kg). In certain embodiments, the compound is administered orally or parenterally. Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to living compounds, liquid dosage forms may contain 85762 -55- 200412345 < inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropyl alcohol, carbonic acid Ethyl acetate, ethyl acetate, benzyl alcohol, stearic acid 'ester, propylene glycol, 1,3-butanediol, dimethylformamide, oils (especially cottonseed, barley, corn, germ, olive, castor Hemp and sesame oil), glycerol tetramethylfuran methanol, polyethylene glycol and fatty acid esters of anthocyanin, and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and flavoring agents. Injectable preparations, such as sterile injectable aqueous or oily suspensions, can be formulated according to known techniques using appropriate dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion, and the solution may be prepared in a toxic parenterally-acceptable diluent or solvent, for example, in 3, butadiene. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, conventional non-volatile oils are used as solvents or suspension media. For this project, any mild non-volatile oil can be used, including synthetic monoglycerides or dioxin. In addition, fatty acids, such as oleic acid, are used in the preparation of injectables. It can be sterilized, for example, by filtering through a bacteria-retaining filter, or by incorporating a sterilizing agent, in the form of a sterile solid composition, which can be lysed / decomposed or dispersed in sterile water or In other sterile injectable vehicles. To prolong the effect of a drug, it is often necessary to slow the absorption of the drug from subcutaneous or intramuscular injection. This can take advantage of liquid suspensions or crystalline or non-m% uptakes with poor water solubility. The absorption rate of I 'drug depends on its dissolution rate, which in turn can depend on the crystal size and crystal form. Or, the delayed absorption of the form of the drug administered parenterally is achieved by dissolving or suspending the drug 85762-56- in the oil vehicle. 0 The formation of the drug in the biodegradable lack of intake. The injectable storage form is made by a microcapsule matrix. Based on two: For example, the properties of specific polymers in polylactone-polyglycolide, drugs;; = examples, and the rate of other biodegradable polymers used can be controlled. The fibrous injectable formula is also made from micro-lipids or micro-emulsions. ▲ "People can relate to body tissue: η! This pharmaceutical composition, preferably a suppository, can be prepared by mixing the compound of the present invention with a suitable non-irritating excipient or carrier, such as Cocoa butter, 卺 r gray shaved ice Yiyi or suppository wax, which is liquid at the ambient temperature of solid Hongren shirt, dish, so it will dissolve in the rectum or vaginal cavity and release the active compound. For oral administration Solid dosage forms including capsules, tablets, pills, powders, and granules. In this solid dosage form, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as a lemon. Sodium or phosphonic acid, and / or &) fillers or extenders, such as powder, lactose, sucrose, glucose, mannitol and silicic acid, b) binders, such as carboxymethyl cellulose / parent Alginate, gelatin, polytetrahydrop-bihalone, sucrose, and gum arabic 'c) humectants, such as glycerol, d) disintegrants, such as agar-agar, carbonate # 5, potato or tapioca starch, Alginic acid, certain silicates and sodium carbonate 'e) solution Retarding agents, such as stone, 0 absorption accelerators, such as quaternary ammonium compounds' g) wetting agents, such as cetyl alcohol and glyceryl monostearate, h) absorbents, such as kaolin and bentonite, and 0 lubrication Agents, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof 85762 -57- 200412345. In the case of capsules, tablets and pills, dosage forms are also possible Contains buffering agents.

亦可採用類似型式之固體組合物，作為柔軟與堅硬充填明 膠膠囊中之填料，使用譬如乳糖或牛奶糖之賦形劑，以及 高分子量聚乙二醇等。片劑、糖衣錠、膠囊、丸劑及顆粒 之固體劑量形式’可被製成具有塗層與殼層’譬如腸溶性 塗層，及在醫藥調配技藝上習知之其他塗層。其可視情況 含有遮光劑，且亦可為一種只會在或優先地在某一部份腸 道中釋出活性成份之組合物’視情況以延遲方式。可使用 之包埋組合物之實例，包括聚合體物質與蠘類。亦可採用 同樣類型之固體組合物，作為柔軟與堅硬充填明膠膠囊中 之填料，使用譬如乳糖或牛奶糖之賦形劑，以及高分子量 聚乙二醇等。 活性化合物亦可呈微包覆形式，使用一或多種如上述之 形劑。片劑、糖衣錠、膠囊、 可被製成具有塗層與殼層，譬 層及在醫藥調配技藝上習知之 形式中’可將活性化合物與至 如蔑糖 '乳糖及澱粉。於正常 g έ 性稀釋劑以外之其他物 及其他製藥片用助劑，譬如硬 膠囊、片劑及丸劑之情況中， /、可視情況含有遮光劑，且亦 木一部份腸道中釋出活性成份 丸劑及顆粒之固體劑量形式 如％〉谷性塗層’釋出控制塗 其他塗層。在此種固體劑量 少一種惰性稀釋劑混合，譬 實施中，此種劑量形式亦可 質’例如製藥片用潤滑劑， 脂酸鎂與微晶性纖維素。在 劑量形式亦可包含緩衝劑。 可為一種只會在或優先地在 之組合物，視情況以延遲方Similar solid compositions can also be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols. The solid dosage forms of tablets, dragees, capsules, pills and granules can be made with coatings and shells such as enteric coatings, and other coatings known in the art of pharmaceutical formulation. It may optionally contain opacifying agents, and may also be a composition which releases the active ingredient only or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and amidines. Solid compositions of the same type can also be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols. The active compounds may also be in micro-encapsulated form using one or more of the above-mentioned excipients. Tablets, sugar-coated tablets, capsules, can be made with coatings and shells, such as layers and forms known in the art of pharmaceutical formulation ', which can incorporate active compounds such as lactose and starch. In the case of substances other than normal diluents and other pharmaceutical tablet auxiliaries, such as hard capsules, tablets, and pills, it may contain opacifiers, and may also release activity in part of the intestine The solid dosage form of the ingredients pills and granules, such as%> 'grain coating' release control other coatings. In such a solid dosage, one inert diluent is mixed, for example, in the practice, this dosage form can also be used as a lubricant for pharmaceutical tablets, magnesium stearate and microcrystalline cellulose. Buffers may also be included in the dosage form. Can be a composition that will only or preferentially be, delayed as appropriate

85762 -58 - 200412345 式。可使用之包埋組合物之實㈣’包括聚合體物質與。 供本發明化今物局部或經皮投藥之劑量形式，包括耖二 糊劑、乳膏、洗劑、凝膠、粉末、溶液、喷霧劑、二 貼樂。活性成份係於無菌條件下，與藥學上、3 妖又之載荆 ，及▲可能需要時之任何必須之防腐劑或緩衝劑混合。: 藥配方、滴耳液及眼藥水，亦意欲被涵蓋在本發明之^眼 内。此外，本發明意欲涵蓋使用經皮姑藥，其具有對身^85762 -58-200412345. Examples of the embedding composition that can be used include polymer materials and. Dosage forms for topical or transdermal administration of the present invention include tinctures, creams, lotions, gels, powders, solutions, sprays, and pastes. The active ingredients are mixed under sterile conditions with pharmacological agents, and any necessary preservatives or buffers that may be needed. : Medicinal formula, ear drops and eye drops are also intended to be included in the eyes of the present invention. In addition, the present invention is intended to cover the use of transdermal drugs, which have

提供化合物之經控制傳輸之附加利益。此種劑量形式係^ 由使化合物溶解或分配於適當媒質中而製成。吸收增強= 亦可使用以增加化合物越過皮膚之通量。速率可藉由a ^ 是提供速率控制薄膜或經由使化合物分散於聚合體基= 凝膠中而加以控制。 胃或Provides the added benefit of controlled transmission of compounds. Such dosage forms are made by dissolving or dispensing the compound in a suitable vehicle. Absorption Enhancement = Can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlling film or by dispersing the compound in a polymer-based = gel. Stomach or

、亦應明瞭的是，本發明之化合物與醫藥組合物可經調配， 並採用於組合療法中’冑即，可將此等化合物與醫藥紐合 物：和-或多種其他所要之治療劑或醫療程序，_起調： 、或Λ A同時、在其之前或在其之後投藥。採用於合併服 法中H组合療法（治療劑或程序），將考量所要治 及/或程序與欲被達成之所要治療效果之相容性。亦應明： 的是’所採用之療法係可對相同病症達成所要之作用（例如 、:本發明化合物可與另—種免疫調節劑、抗癌劑或可用於 治療牛皮癖之藥劑同時投藥）’或其可達成不同作用： 控制任何不利作用）。 例如，可與本發明化合物合併使用之其他療法或抗癌劑， 包括手術、射線治療（在僅有之少數實例中，厂放射、中子 85762 -59- 200412345 束射線療法、電子束射線療法、質子療法、近距療法及系 統放射性同位章，僅指稱其中一小部份）、内分泌療法、生 物學回應改變劑（干擾素、間白血球活素及腫瘤壞死因子（TNF) ，僅指稱其中一小邵份）、高熱與低溫療法、使任何不利作 用減弱之藥劑（例如止吐藥），及其他被認可之化學治療藥 物，包括但不限於娱:基化藥物（氮芬、苯丁酸氮芥（chlorambucil) 、環磷酿胺、***酸氮芥、依發斯it胺（ifosfamide))、抗代 謝物（胺甲喋呤）、嘌呤拮抗劑與嘧啶拮抗劑（6-黢基嘌呤、5-氟尿喊淀、西塔拉比（cytarabile)、真西塔賓（gemcitabine))、纺錘 體毒物（長春花驗、長春新驗、威諾賓（vinorelbine)、培克里他 索（paclitaxel))、鬼臼脂素（衣托糖甞（etoposide)、伊利諾提肯 (irinotecan)、拓波提肯（topotecan))、抗生素（多克索紅菌素、博 來霉素、絲裂霉素）、亞硝基脲類（亞硝基脲氮芥、環己亞 硝脲）、無機離子（順氯胺舶、碳氯胺始）、酵素（天冬醯胺酶） 及激素（他摩西吩（tamoxifen)、留普内酯（leuprolide)、弗如酸胺 (flutamide)及甲地孕酮），僅指稱其中一小部份。關於更新癌 症治療劑之更全面性討論，可參閱http : //www.nci.nih.gov/，FDA 許可腫瘤學藥物之清單在http : //www. fda.gov/cder/cancer/ dmglistframe.htm處，及Merck手冊，第十七版，1999，其全部内容 均據此併於本文供參考。 在某些具體實施例中，本發明之醫藥組合物進一步包含一 或多種其他具治療活性成份（例如化學治療及/或姑息藥）。 對本發明之目的而言，〃叙总桌"一詞，係指專注於疾病徵 候及/或治療服用法副作用之緩解之治療，而非治癒。例如 85762 -60- 200412345 、某口療，係/函盖除痛劑、去除惡心藥療法及抗疾病藥 物此外，化费療法、射線治療及手術，均可以姑息方式 使用（思即，減少病徵，而未進行治療；例如，縮小腫瘤， 及降低壓力、出血、疼痛及癌症之其他病徵）。 、在其他具體貫施例中，本發明係關於一種可合宜且有效扣 進行=據本發明方法之套件。—般而言，醫藥包裝或套令It should also be clear that the compounds and pharmaceutical compositions of the present invention can be formulated and used in combination therapies. That is, these compounds can be combined with pharmaceutical conjugates: and-or any other desired therapeutic agent or Medical procedures, _ upset:, or Λ A at the same time, before or after. The H combination therapy (therapeutic agent or procedure) used in the combined service will consider the compatibility of the treatment and / or procedure with the desired therapeutic effect to be achieved. It should also be noted that: 'The therapy used can achieve the desired effect on the same disease (for example, the compound of the present invention can be administered at the same time as another immune modulator, anticancer agent or agent that can be used to treat psoriasis) 'Or it can achieve a different effect: control any adverse effects). For example, other therapies or anticancer agents that can be used in combination with the compounds of the present invention include surgery, radiation therapy (in only a few examples, plant radiation, neutrons 85762 -59- 200412345 beam radiation therapy, electron beam radiation therapy, Proton therapy, brachytherapy, and systemic radioisotope chapters only refer to a small number of them), endocrine therapy, biological response modifiers (interferon, mesothelin, and tumor necrosis factor (TNF), only one of which is referred to Shao Fen), high fever and low temperature therapy, agents that reduce any adverse effects (such as antiemetics), and other approved chemotherapeutic drugs, including but not limited to recreational: basic drugs (nitrophen, phenylbutyrate nitrogen mustard) (Chlorambucil), cyclophosphamide, amphetamine mustard, ifosfamide), antimetabolites (aminopterin), purine antagonists and pyrimidine antagonists (6-amidopurine, 5- Fluorinated urine, cytarabile, gemcitabine), spindle poisons (Changchun test, Changchun test, vinorelbine, paclitaxel) Podophyllotoxin (etoposide, irinotecan, topotecan), antibiotics (doxoxanthin, bleomycin, mitomycin), Nitrosoureas (nitrosourea nitrogen mustard, cyclohexyl nitrosourea), inorganic ions (cischloramine, chlorochloramine starting), enzymes (asparaginase) and hormones (tamoxifen ), Leuprolide, flutamide, and megestrol), all but a small percentage. For a more comprehensive discussion of updating cancer treatments, see http://www.nci.nih.gov/. The list of FDA-approved oncology drugs is at http://www.fda.gov/cder/cancer/dmglistframe. At htm, and Merck Handbook, Seventeenth Edition, 1999, the entire contents of which are hereby incorporated by reference. In certain embodiments, the pharmaceutical composition of the present invention further comprises one or more other therapeutically active ingredients (such as chemotherapy and / or palliative drugs). For the purposes of the present invention, the term "general table" refers to a treatment that focuses on the relief of the symptoms and / or side effects of the treatment, rather than a cure. For example, 85762 -60- 200412345, a certain oral treatment, department / letter pain reliever, nausea removal therapy and anti-disease drugs. In addition, chemical therapy, radiation therapy and surgery can be used in a palliative manner (think to reduce symptoms Without treatment; for example, shrinking tumors and reducing stress, bleeding, pain, and other symptoms of cancer). In other specific embodiments, the present invention relates to a kit that can be conveniently and effectively deducted = according to the method of the present invention. —In general, pharmaceutical packaging or rituals

:: 或夕個充填一或多種本發明醫藥組合物成份之| 口口此種套件特別週合傳輸固體口服形g，譬如片劑或瑪 囊。此種套件較佳係包含多個單位劑量，且亦可包含一信 卡片具有才曰向其所意欲用途順序之服用量。若需要，可 提供記憶輔㈣’例如呈數字、字母或其他記號之形式， 或具有日曆***物，指 、 疋/、中可投予劑量之治療時間表之 天數。或者’可包含安慰劑之劑量或純食:: Or even filled with one or more ingredients of the pharmaceutical composition of the present invention | This mouthpiece kit is particularly suitable for delivering solid oral g, such as tablets or capsules. Such kits preferably contain multiple unit doses, and may also contain a letter card with dosages in the order in which they are intended. If necessary, a memory aid can be provided, for example, in the form of numbers, letters, or other marks, or with a calendar insert that refers to the number of days in the treatment schedule of the dose that can be administered. Or ’can include a placebo dose or pure food

㈣醫藥組合物之劑量類似或不同之形式，以提供= 母天^用劑量之套件。视情況伴隨著此種容.^ ::書…政f機構所開立管制醫藥產物之製造、使: 2《①式’ β通知書係反映㈣機構許可製造、使用 或销售’以供人類投藥。 下述代表性實例係意㈣ 應將其解釋輕制本發Hi 修正及其許多進一步且 、 S月惑各種 、姐爲她例，除了本文中所-者以外，對熟諳此藝者、 不人所述 者而言，將從此文件之全部内容而明 85762 -61- 200412345 瞭，包括下述實例及於本文中引用之科學與專利文獻之參 考資料。應進:一步明瞭的是，所引用參考資料之内容係併 於本文供參考，以幫助說明此項技藝之目前狀態。 下述實例含有重要之其他資訊、範例及指引，在其各種具 體實施例與其等效事物上，其可適合本發明之實施。 範例 本發明化合物及其製備可藉由實例而更為明瞭，其係說明 一些藉以製備或使用此等化合物之方法。但是，應明瞭的 是，此等實例並非限制本發明。目前已知或進一步發展之 本發明變型，咸認係落在如本文中所述及如後文所請求之 本發明範圍内。 根據本發明，可使用任何可採用之技術，以製造或製備本 發明化合物或包含彼等之組合物。例如，可使用多種溶液 相合成方法，譬如下文所詳細討論者。替代地或外加地， 本發明化合物可使用此項技藝中已知之多種結合技術、平 行合成及/或固相合成方法之任一種製成。 應明瞭的是，如下文所述，多種本發明化合物可根據本文 所述之方法合成。用於製備此等化合物之起始物質與試劑 ，係為無論是可得自市售供應商，譬如Aldrich化學公司 (Milwaukee，WI)、Bachem 公司（Torrance，CA)、Sigma 公司（St. Louis，Mo) ，或係藉由一般熟諳此藝者所習知之方法，按照參考資料 中所述之程序製成，譬如Fieser與Fieser 1991，”有機合成之試劑 ’，，第 1-17 卷，John Wiley & Sons，New York，NY，1991 ; Rodd 1989，’ 碳化 合物之化學"，第1-5卷及補充版，Elsevier科學出版社，1989 ;’f有 85762 -62- 200412345 機反應 f’，第 1-40 卷，John Wiley & Sons，New York，ΝΥ，1991 ; 2001 年 3 月，’’高等有機t 學”，第 5 版，JohnWiley&Sons，NewYork，NY ;及 Larock 1990, ’’综合有機轉變：官能基製備之指引”，第2版，VCH 出版社。此等合成體系僅只是可用以合成本發明化合物之 一些方法之說明例而已，並可對此等合成體系施行各種修 正，且將對關切本揭示内容之一般熟諳此藝者提供建議。 本發明之起始物質、中間物及化合物可使用習用技術單離 與純化，包括過濾、蒸餾、結晶化作用、層析等。其可使 用習用方法作特徵鑒定，包括物理常數與光譜數據。 【實施方式】 1)舉例之化合物 本發明之某些舉例化合物係列示於下文，且藉由如所指示 之化合物編號指稱。 85762 63- 200412345 85762㈣The dosage of the pharmaceutical composition is similar or different, so as to provide a kit for the mother's day dose. This situation is accompanied by this situation. ^ :: ... The manufacturing and control of pharmaceutical products issued by the government agency: 2 "①" 'β notification is a reflection of the agency's permission to manufacture, use or sell' for human administration . The following representative examples are intended to be interpreted. This amendment should be interpreted lightly. This amendment and its many further, S, and various examples, are her examples. In addition to those in this article, for those who are familiar with this artist, not others As far as they are concerned, 85762-61-200412345 will be made clear from the entire contents of this document, including the following examples and references to scientific and patent literature cited herein. What to do: One step is clear. The content of the reference materials is incorporated herein by reference to help explain the current state of the art. The following examples contain important other information, examples, and guidelines, which may be suitable for the implementation of the invention in its various specific embodiments and their equivalents. Exemplification The compounds of the present invention and their preparation can be made clearer by examples, which illustrate some methods by which these compounds can be prepared or used. However, it should be understood that these examples do not limit the invention. The presently known or further developed variants of the invention fall within the scope of the invention as described herein and as claimed later. According to the present invention, any available technique can be used to make or prepare the compounds of the present invention or compositions containing them. For example, a variety of solution phase synthesis methods can be used, such as those discussed in detail below. Alternatively or additionally, the compounds of the present invention can be made using any of a variety of binding techniques, parallel synthesis, and / or solid phase synthesis methods known in the art. It should be understood that, as described below, a variety of compounds of the invention can be synthesized according to the methods described herein. The starting materials and reagents used to prepare these compounds are available from commercial suppliers, such as Aldrich Chemical Company (Milwaukee, WI), Bachem Company (Torrance, CA), and Sigma Company (St. Louis, Mo), or is made by a method familiar to the artist and follows the procedures described in the reference materials, such as Fieser and Fieser 1991, "Reagents for Organic Synthesis", Volumes 1-17, John Wiley & Sons, New York, NY, 1991; Rodd 1989, 'Chemistry of Carbon Compounds', Volumes 1-5 and Supplementary Edition, Elsevier Science Press, 1989; 'f have 85762 -62- 200412345 organic reaction f' , Volumes 1-40, John Wiley & Sons, New York, ΝΥ, 1991; March 2001, "Advanced Organic Studies", 5th Edition, John Wiley & Sons, New York, NY; and Larock 1990, ' 'Integrated Organic Transformation: Guidelines for the Preparation of Functional Groups', 2nd Edition, VCH Press. These synthetic systems are merely illustrative examples of methods that can be used to synthesize the compounds of this invention, and various modifications can be made to these synthetic systems , And will be relevant Those of ordinary skill in the present disclosure provide suggestions. The starting materials, intermediates, and compounds of the present invention can be isolated and purified using conventional techniques, including filtration, distillation, crystallization, chromatography, etc., which can use conventional methods. Characteristic identification, including physical constants and spectral data. [Embodiments] 1) Exemplified compounds Certain exemplary compound series of the present invention are shown below, and are designated by the compound number as indicated. 85762 63- 200412345 85762

64-64-

200412345 85762200412345 85762

-65--65-

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-66- 200412345 85762-66- 200412345 85762

20 806010 nh2 Η HN 丫N Φ OMe 21 806014 νη2 ΝΌ^ Η ΗΝ〇Ν 22 806094 νη2 TBS0^O>^n Η ην^ 23 806095 ΝΗ2 ΗΟΧ〇^ Η ΗΝ^Ν 24 806097 Βο、 N-Boc TBS〇a^ Boc 一Boc 25 806107 Bo、 N-Boc Boc N<^N~Boc 26 806123 nh2 H f^NH -67- 200412345 85762 27 806136 nh2 28 806181 nh2 Cn〇>^N H 丫 H 29 806221 MeojX〇Dc^H2 H 丫 H 30 806220 nh2 0 N^NH 31 806224 J) H 丫H 32 806228 nh2 kJJ 丫 H 33 806276 NH2 . Me〇V VH Me〇 1 34 806275 Me〇 N^NH 35 806274 (X^O>^H2 H n^nh 68- 200412345 85762 36 806273 nh2 kji 丫 H 37 806286 1 _/NH2 38 806287 nh2 HN 丫 N cf3 I 39 806311 H N^NH 40 806317 nh2 丫 H 41 806320 nh2 X^O^H. 42 806329 9ONH2 nh2 Η ΝγΝΗ 43 806333 9〇2Me nh2 αν^^Η 69- 200412345 8576220 806010 nh2 Η HN λN Φ OMe 21 806014 νη2 ΝΌ ^ Η ΗΝΝΝ 22 22 806094 νη2 TBS0 ^ O > ^ n Η ην ^ 23 806095 ΝΗ2 Η〇Χ〇 ^ Η ΗΝ ^ Ν 24 806097 Βο, N-Boc TBS. ^ Boc-Boc 25 806107 Bo, N-Boc Boc N < ^ N ~ Boc 26 806123 nh2 H f ^ NH -67- 200412345 85762 27 806136 nh2 28 806181 nh2 Cn〇 > ^ NH YH 29 806221 MeojX〇Dc ^ H2 H Ya H 30 806220 nh2 0 N ^ NH 31 806224 J) H Ya H 32 806228 nh2 kJJ Ya H 33 806276 NH2. Me〇V VH Me〇1 34 806275 Me〇N ^ NH 35 806274 (X ^ O > ^ H2 H n ^ nh 68- 200412345 85762 36 806273 nh2 kji ah H 37 806286 1 _ / NH2 38 806287 nh2 HN ah N cf3 I 39 806311 HN ^ NH 40 806317 nh2 ah H 41 806320 nh2 X ^ O ^ H. 42 806329 9ONH2 nh2 Η ΝγΝΗ 43 806333 9〇2Me nh2 αν ^^ Η 69- 200412345 85762

70- 200412345 8576270- 200412345 85762

-71 - 200412345 85762 63 806419 64 806420 65 806421 66 806432 〇V〇>^H2 Η Ν 丫 ΝΗ 67 806435 1 νη2 〇ν〇>·^ Η n^Jnh 68 806437 = νη2 0^0)·^ Η Ν^ΝΗ 69 806569 U Η NyNH 70 806609 71 806610 νη2 〇Me Ν 丫 ΝΗ -72- 200412345 85762-71-200412345 85762 63 806419 64 806420 65 806421 66 806432 〇V〇 > ^ H2 Η Ν YaNΗ 67 806435 1 νη2 〇ν〇 > · ^ Η n ^ Jnh 68 806437 = νη2 0 ^ 0) · ^ Η Ν ^ ΝΗ 69 806569 U Η NyNH 70 806609 71 806610 νη2 〇Me Ν ΑΝΝΗ -72- 200412345 85762

72 806644 NH2 73 806645 nh2 74 806646 NH2 75 806647 〇?叫： 76 806653 77 806671 H N NH T 78 806781 MeO、 79 806790 nh2 々rC〇^N ό T -73 - 200412345 85762 80 806796 H N 丫 NH 81 806820 H H ΝγΝΗ 82 806839 Cl 〇 KJU H N 丫 NH 83 806840 9 nh2 H N 丫 NH 84 806841 ciixA^H2 H N 丫 NH 85 806842 nh2 OOJ〇Q^0n H N 丫 NH * 86 806843 fjC^OjCq~^n H N^NH 87 806844 nh2 〇nXcv^n H N 丫 NH 88 806860 H 〇 〇/、、 H ΝγΝΗ -74- 200412345 85762 89 806874 Η L〇J H 丫㈠ 90 806875 乂 1 1 Η Ν’丫'ΝΗ 91 806878 Η ΝγΝΗ 92 806899 ? νη2 0 Η Ν 丫 ΝΗ 93 806900 νη2 0 Η Ν 丫 ΝΗ 94 806901 0 Η Ν^ΝΗ 95 806902 νη2 ΌΝγΧΧ}-^Ν S Η 96 806903 Η Ν 丫 ΝΗ 97 806904 νη2 〇，ΧΤ'^〇ν^Ν Η Ν 丫 ΝΗ -75- 200412345 98 806905 nh2 Η Ν^ΝΗ 99 806987 Η Ν^ΝΗ 100 807014 Η Ν 丫 ΝΗ 101 807015 9 9 νη2 Ν Η νΓ；ΝΗ 102 807139 OMe Η Ν 丫 ΝΗ 103 807140 νη2 Η Ν^ΝΗ 104 807183 MeO 〇 Μμ Η Ν^ΝΗ ·· τ 105 807240 MeO Μμ Η Ν^ΝΗ 106 807313 Γ^ΪΙ 1 νη2 Η Ν 丫 ΝΗ72 806644 NH2 73 806645 nh2 74 806646 NH2 75 806647 〇? Name: 76 806653 77 806671 HN NH T 78 806781 MeO, 79 806790 nh2 々rC〇 ^ N T -73-200412345 85762 80 806796 HN ah NH 81 806820 HH ΝγΝΗ 82 806839 Cl 〇KJU HN AHNH 83 806840 9 nh2 HN AHNH 84 806841 ciixA ^ H2 HN AHNH 85 806842 nh2 OOJ〇Q ^ 0n HN AHNH * 86 806843 fjC ^ OjCq ~ ^ n HN ^ NH 87 806844 nh2 〇 nXcv ^ n HN YANH 88 806860 H 〇〇 /, H ΝγΝΗ -74- 200412345 85762 89 806874 Η L〇JH ㈠ 90 806875 乂 1 1 Η Ν '丫' ΝΗ 91 806878 Η ΝγΝΗ 92 806899? νη2 0 Η Ν ΝΝΝΗ 93 806900 νη2 0 Η Ν ΝΝΝΗ 94 806901 0 Η Ν ^ ΝΗ 95 806902 νη2 ΌΝγΧΧ}-^ Ν S Η 96 806903 Η Ν ΝΝΝΗ 97 806904 νη2 〇, χΤ '^ 〇ν ^ Ν Ν Ν ΝΝΝΗ -75- 200412345 98 806905 nh2 Η Ν ^ ΝΗ 99 806987 Η Ν ^ ΝΗ 100 807014 Η Ν ΑΝΝΗ 101 807015 9 9 νη2 Ν Η νΓ; ΝΗ 102 807139 OMe Η ΝΝΝΗ 103 807140 νη2 Η Ν ^ ΝΗ 104 807183 Me 〇Μμ Η Ν ^ ΝΗ ·· 105 807240 MeO Μμ Η Ν ^ ΝΗ 106 807313 Γ ^ ΪΙ 1 νη2 Η Ν Ah ΝΗ

85762 76- 200412345 85762 107 807377 nh2 F3CXT'Xcv^^ H N^NH 108 807392 nh2 H N^NH 109 807400 nh2 COX^ H N 丫 NH 110 807401 H NH2 H H N^NH 反式外消旋 T 111 807399 Η ΝΗ2 Η Η nQnh 順式外消旋 τ 112 807447 (fl 」ΝΗ2 Η Ν^ΝΗ 113 807448 νη2 :· Η 114 807449 νη2 115 807450 νη2 〇cf3 η ν 丫 νη -77- 200412345 8576285762 76- 200412345 85762 107 807377 nh2 F3CXT'Xcv ^^ HN ^ NH 108 807392 nh2 HN ^ NH 109 807400 nh2 COX ^ HN ^ NH 110 807401 H NH2 HHN ^ NH trans racemic T 111 807399 Η ΝΗ2 Η Η nQnh Cis racem τ 112 807447 (fl `` ΝΗ2 Η Ν ^ ΝΗ 113 807448 νη2: · Η 114 807449 νη2 115 807450 νη2 〇cf3 η ν γνη -77- 200412345 85762

116 807451 nh2 H N^NH 117 807452 nh2 Cl H N 丫 NH 118 807453 nh2 H ΝγΝΗ 119 807454 nh2 0^'Xcv^N F H N丫 NH 120 807457 H N^NH 121 807458 〒f3 NH2 H N 丫、NH 122 807459 nh2 CI1X'XCV^N Cl H n^nh - 了 123 807460 p3c〇 nh2 0^?XCV^， H N^NH 124 807462 nh2 Xrccy^ 1 H N丫 NH -78- 200412345 85762116 807451 nh2 HN ^ NH 117 807452 nh2 Cl HN ^ NH 118 807453 nh2 H ΝγΝΗ 119 807454 nh2 0 ^ 'Xcv ^ NFHN ^ NH 120 807457 HN ^ NH 121 807458 〒f3 NH2 HN ^, NH 122 807459 nh2 CI1X'XC ^ N Cl H n ^ nh-123 807460 p3c〇nh2 0 ^? XCV ^, HN ^ NH 124 807462 nh2 Xrccy ^ 1 HNγNH -78- 200412345 85762

125 807463 nh2 H n^nh 126 807464 nh2 d'^Xcv^^ H N 丫 NH 127 807465 Cl 」NH2 H N 丫 NH 128 807466 nh2 H n^nh 129 807467 nh2 Q^XC^ H N 丫 NH 130 807469 nh2 〇rr〇>^ H N^NH 131 807496 oxo·^ H N^NH 132 807497 nh2 (T'Xcv^^ T H HyHH 133 807498 nh2 XT'Xcv^N H N 丫、NH 79- 200412345 85762125 807463 nh2 H n ^ nh 126 807464 nh2 d '^ Xcv ^^ HN ah NH 127 807465 Cl `` NH2 HN ah NH 128 807466 nh2 H n ^ nh 129 807467 nh2 Q ^ XC ^ HN ah 130 130 807469 nh2 〇rr〇 > ^ HN ^ NH 131 807496 oxo · ^ HN ^ NH 132 807497 nh2 (T'Xcv ^^ TH HyHH 133 807498 nh2 XT'Xcv ^ NHN, NH 79- 200412345 85762

134 807505 nh2 135 807506 136 807528 137 807531 nh2 H N 丫'NH 138 807532 nh2 0^ H N^NH 139 807543 nh2 αχο>^ U H〒H 140 807544 nh2 - kj : ΝγΝΗ 141 807546 OH H、ΝΗ 142 807548 nh2 CN H N^NH -80- 200412345 85762134 807505 nh2 135 807506 136 807528 137 807531 nh2 HN y'NH 138 807532 nh2 0 ^ HN ^ NH 139 807543 nh2 αχο > ^ UH〒H 140 807544 nh2-kj: ΝγΝΗ 141 807546 OH H, ΝH2 142 CN 548 NH -80- 200412345 85762

143 807549 H n^nh 144 807550 H ΝγΝΗ 145 807562 nh2 0 NrNH 146 807571 nh2 ncIT'Xcv^n H N^NH 147 807573 nh2 H N^NH 148 807584 a>Xcv^N . H N 丫 NH 149 807585 H N 丫 NH 150 807586 °T^X ,nh^ ^rXcv^N H N^NH 151 807587 fjX?Xcv^n H N 丫、NH -81 - 200412345 85762143 807549 H n ^ nh 144 807550 H ΝγΝΗ 145 807562 nh2 0 NrNH 146 807571 nh2 ncIT'Xcv ^ n HN ^ NH 147 807573 nh2 HN ^ NH 148 807584 a > Xcv ^ N .HN ^ NH 149 807585 HN 586 NH 150 ° T ^ X, nh ^ ^ rXcv ^ NHN ^ NH 151 807587 fjX? Xcv ^ n HN ah, NH -81-200412345 85762

152 807636 nh2 H N 丫、NH 153 807649 」H2 H N 丫 NH 154 807660 I nh2 H n^/NH 155 807662 i _T2 H N 丫 NH 156 807663 丄 _Γ2 H N 丫、NH 157 807703 nh2 Cro^ . H N^NH 158 807704 nh2 H N^NH 159 807748 nh2 O^'Xcv^n H N^NH -82- 200412345 85762152 807636 nh2 HN Ya, NH 153 807649 `` H2 HN Ya NH 154 807660 I nh2 H n ^ / NH 155 807662 i _T2 HN Ya NH 156 807663 丄 _Γ2 HN Ya, NH 157 807703 nh2 Cro ^. HN ^ NH 158 807704 nh2 HN ^ NH 159 807748 nh2 O ^ 'Xcv ^ n HN ^ NH -82- 200412345 85762

160 807749 nh2 H N 丫 NH 161 807750 H N^NH 162 807751 H n^nh 163 807754 H N^NH 164 807758 H N^NH 165 807759 H N^NH 166 807762 ^ 叫. ·， H n^；nh 167 807779 ^xcv^lH2 H N^NH 168 807787 H N 丫VlH -83- 200412345 85762 169 807788 H N^NH 170 807789 Me〇’N^^ NH2 H N 丫'NH 171 807790 H〇Y^i nh2 H N^NH 172 807794 nh2 HO HCI H N’ 'Nhi 丁 173 807835 ^XCV^r H N 丫'NH 174 807836 5 」h2 H ν^,νη T · 175 807837 H〇〆 O nh2 H N^NH 176 807862 nh2 〇XtV^N H N^NH 177 807865 O^xc^ H Ν^,ΝΗ -84- 200412345 85762160 807749 nh2 HN ^ NH 161 807750 HN ^ NH 162 807751 H n ^ nh 163 807754 HN ^ NH 164 807758 HN ^ NH 165 807759 HN ^ NH 166 807762 ^ Call, ·, H n ^; nh 167 807779 ^ xcv ^ lH2 HN ^ NH 168 807787 HN Ya VlH -83- 200412345 85762 169 807788 HN ^ NH 170 807789 Me〇'N ^^ NH2 HN Ya'NH 171 807790 H〇Y ^ i nh2 HN ^ NH 172 807794 nh2 HO HCI H N ' 'Nhi Ding 173 807835 ^ XCV ^ r HN ^' NH 174 807836 5 `` h2 H ν ^, νη T · 175 807837 H〇〆O nh2 HN ^ NH 176 807862 nh2 〇XtV ^ NHN ^ NH 177 807865 O ^ xc ^ H Ν ^, ΝΗ -84- 200412345 85762

178 807876 nh2 HCI H N^NH 179 807892 nh2 二. H N^NH 180 807920 nh2 H N 丫 NH 181 807930 nh2 Ηχτα>^ H ΝγΝΗ 182 807931 nh2 Q^〇cv^n OH H N 丫 NH 183 807952 Cl _T2 H NyNH 184 807956 9Sx〇~^H2 H N^NH 185 807962 ΓΊ _/NH2 1 H N 丫、NH -85- 200412345 85762178 807876 nh2 HCI HN ^ NH 179 807892 nh2 II. HN ^ NH 180 807920 nh2 HN ^ NH 181 807930 nh2 Ηχτα > ^ H ΝγΝΗ 182 807931 nh2 Q ^ 〇cv ^ n OH HN ^ NH 183 807952 Cl _T2 HN 9Sx〇 ~ ^ H2 HN ^ NH 185 807962 ΓΊ _ / NH2 1 HN Ah, NH -85- 200412345 85762

186 807976 F F个'[ 严2 Η N^NH 187 807977 Γΐ _Γ2 Η Ν^ΝΗ 188 807978 Λ νη2 Η Ν^ΝΗ 189 807980 αΐΧ〇^Ν" Η Ν^ΝΗ 190 808009 ar〇>^ Η ^ΗΗ 191 808028 νη2 η η m ‘ Τ 192 808036 fl _yNH2 H N 丫 NH 193 808039 nh2 H N^NH -86- 200412345 85762 194 808040 Γ^Ι 、ΝΗ Η Ν 丫 ΝΗ 195 808041 ^iXcv^H2 HCI Η Ν^,ΝΗ 了 196 808069 Η Ν^ΝΗ 197 808078 νη2 FYcr〇h^ F Η Ν 丫 ΝΗ 198 808079 νη2 ^ν〇>-^Ν 1 Η Ν 丫 ΝΗ 199 808080 νη2 1 Η ν^νη 了 - 200 808081 1 Η Ν 丫 ΝΗ 201 808082 Γΐ 」ΝΗ2 以 r〇>^ Η Ν 丫、ΝΗ 202 808083 Η Ν 丫、ΝΗ -87- 200412345 85762186 807976 FF pieces' [YAN 2 Η N ^ NH 187 807977 Γΐ _Γ2 Η Ν ^ ΝΗ 188 807978 Λ νη2 Η Ν ^ ΝΗ 189 807980 αΐΧ〇 ^ Ν " Η Ν ^ ΝΗ 190 808009 ar〇 > ^ Η ^ ΗΗ 191 808028 νη2 η η m 'Τ 192 808036 fl _yNH2 HN ah NH 193 808039 nh2 HN ^ NH -86- 200412345 85762 194 808040 Γ ^ Ι, ΝΗ Η Ν ΝΝΝΗ 195 808041 ^ iXcv ^ H2 HCI Η Η Ν ^, ΝΗ 808069 Η Ν ^ ΝΗ 197 808078 νη2 FYcr〇h ^ F Η ΝΝΝΗ 198 808079 νη2 ^ ν〇 >-^ N 1 Η Ν ΝΝΝΗ 199 808080 νη2 1 Η ν ^ νη-200 808081 1 Η Ν ΝΑΝΗ 201 808082 Γΐ ″ ΝΗ2 to r〇 &^; ^ Ν Ya, ΝΗ 202 808083 Η Ν Ya, ΝΗ -87- 200412345 85762

203 808084 fl nh2 H N 丫 NH 204 808085 H N 丫、NH 205 808086 ρΛΓ1 /NH2 H N^NH 206 808101 nh2 〇cr?^〇v^N H N^/NH 207 808102 C/Ί ;NH2 H N^/NH 208 808103 iTl 」NH2 以。^a>·^ · H N 丫'NH 209 808107 nh2 H n^nh 210 808128 Cl 以n〇c>~^ H N 丫、NH -88 - 200412345 85762 211 808151 Λ _/ΝΗ2 Η Ν^ΝΗ 212 808152 ΡΥΊ ；ΝΗ^ Η Ν^ΝΗ 213 808153 νη2 Η Ν^ΝΗ 214 808160 αΓΊ〇^ Η Ν^,ΝΗ 215 808164 Η ΝγΝΗ 216 808247 Me0/7 L1 」νη2 Η Ν^,ΝΗ Τ - 217 808254 νη2 Η ΝγΝΗ 218 808255 ' νη2 kJ Η ΝγΝΗ -89- 200412345 85762 219 808256 Η ΝγΝΗ 220 808257 Η Ν 丫 ΝΗ 221 808259 Η Ν^ΝΗ 222 808260 Η Ν^ΝΗ 223 808261 OnJ〇C)-^n Η ν 丫 ΝΗ 224 808262 CfXOh^ Η Η Ν^ΝΗ 225 808266 CF3C〇2H Η ν 丫 ΝΗ 226 808268 Η 丫Η 227 808269 Η Ν^ΝΗ 228 808281 Η Ν 丫、ΝΗ -90-203 808084 fl nh2 HN Ah NH 204 808085 HN Ah, NH 205 808086 ρΛΓ1 / NH2 HN ^ NH 206 808101 nh2 〇cr? ^ 〇v ^ NHN ^ / NH 207 808102 C / Ί; NH2 HN ^ / NH 208 808103 iTl '' With NH2. ^ a > · ^ · HN ya'NH 209 808107 nh2 H n ^ nh 210 808128 Cl to n〇c > ~ ^ HN ya, NH -88-200412345 85762 211 808151 Λ _ / ΝΗ2 Η Ν ^ ΝΗ 212 808152 ΡΥΊ; ΝΗ ^ Η Ν ^ ΝΗ 213 808153 νη2 Η Ν ^ ΝΗ 214 808160 αΓΊ〇 ^ Η Ν ^, ΝΗ 215 808164 Η ΝγΝΗ 216 808247 Me0 / 7 L1 `` νη2 Η Ν ^, ΝΤ Τ-217 808254 255 22 Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν 2 νη2 kJ Η ΝγΝΗ -89- 200412345 85762 219 808256 Η ΝγΝΗ 220 808257 Η Ν ΑΝΝΗ 221 808259 Η Ν ^ ΝΗ 222 808260 Η Ν ^ ΝΗ 223 808261 OnJ〇C)-^ n Η ν ΝΝΗ 224 224 808O Cf Ν ^ ΝΗ 225 808266 CF3C〇2H Η ν ΗΝΝΗ 226 808268 Η Η Η 227 808269 Η Ν ^ ΝΗ 228 808281 Η Ν Ya, ΝΗ -90-

200412345 85762 229 808283 Η〇ΤΊ /ΝΗ^ CF3C02H Η ν 丫 νη 230 808284 Η Ν 丫、ΝΗ 231 808285 Η Ν^ΝΗ 232 808286 Η Ν^ΝΗ 233 808287 Η Ν^,ΝΗ 234 808288 Jo Η 丫 Η 235 808289 J〇 Η 丫Η 236 808290 ?'ΎΧν^1Η2 Η Ν 丫 ΝΗ 237 808291 Η 丫Η -91 -200412345 85762 229 808283 Η〇ΤΊ / ΝΗ ^ CF3C02H Η ν νν 230 230 808284 Η Ν Ya, ΝΗ 231 808285 Η Ν ^ ΝΗ 232 808286 Η Ν ^ ΝΗ 233 808287 Η Ν ^, ΝΗ 234 808288 Jo Η J J 235 808 〇Η 丫 Η 236 808290? 'ΎΧν ^ 1Η2 Η Ν ΑΝΝΗ 237 808291 Η 丫 Η -91-

200412345 85762 238 808310 α Η ΝγΝΗ 239 808311 Ο Η ΝγΝΗ 240 808312 Ο, Ν^ΝΗ 241 808313 θ' h Ν^ΝΗ 242 808319 Η Ν^ΝΗ : τ 243 808322 〇CTfXrv^N Η ν^νη 244 808346 νη2 〜ij〇cy^N Η Ν 丫 ΝΗ 245 808347 νη2 Η ΝγΝΗ -92- 200412345 85762 246 808355 nh2 ^nJ〇^v^n ij H 247 808356 nh2 u h〒h 248 808361 h〇^ H ΝγΝΗ 249 808362 Cu H N^NH 250 808363 H n^nh 251 808364 〇Λ H N^NH T * 252 808365 6c^H2 H ΝγΝΗ 253 808370 〇Χ〇-^Ν H N^NH 254 808371 nh2 H 问丫、， -93- 200412345 85762200412345 85762 238 808310 α Η ΝγΝΗ 239 808311 Ο Η ΝγΝΗ 240 808312 Ο, Ν ^ ΝΗ 241 808313 θ 'h Ν ^ ΝΗ 242 808319 Η Ν ^ ΝΗ: τ 243 808322 〇CTfXrv ^ N Η ν ^ νη 244 808 〇cy ^ N Η Ν ΝΝΗ 245 808347 νη2 Η ΝγΝΗ -92- 200412345 85762 246 808355 nh2 ^ nJ〇 ^ v ^ n ij H 247 808356 nh2 uh〒h 248 808361 h〇 ^ H ΝγΝΗ 249 808362 Cu HN ^ NH 250 808363 H n ^ nh 251 808364 〇Λ HN ^ NH T * 252 808365 6c ^ H2 H ΝγΝΗ 253 808370 〇〇〇- ^ Ν HN ^ NH 254 808371 nh2 H Question ,, -93- 200412345 85762

255 808372 Η N^NH 256 808385 Η N^/NH 257 808386 H H N^NH 258 808387 nh2 CF3CO2H 259 808388 H N^NH 260 808469 H N 丫'NH 261 808470 丫H . 262 808473 H N^NH 263 808496 〇XJ H γπ 264 808497 rijCQ>~^N LJ H N^NH 94- 200412345 85762255 808372 Η N ^ NH 256 808385 Η N ^ / NH 257 808386 HHN ^ NH 258 808387 nh2 CF3CO2H 259 808388 HN ^ NH 260 808469 HN ^ 'NH 261 808470 ^ H. 262 808473 HN ^ NH 263 808496 〇XJ H γ π 264 808497 rijCQ > ~ ^ N LJ HN ^ NH 94- 200412345 85762

265 808498 ^nJ〇Q-^n ◦rJ H n^nh 266 808499 V H N?N}H 267 808500 CF3C〇2H cf3c〇2h h n?nh 268 808501 0^1 CF^H nh2 cf3c〇2h h N/yNH 269 808513 cf3co2h 〇O^XXV^N CF3C〇2H η N’yNH 270 808514 CF3CO2H nh2 cf3co2h h NyNH 271 808541 H nvnh cf3co2h ' CF3C02H I 272 808542 nh2 H nvnh CF3C02H CF3CO2H 1 273 808543 O〇 H nC；nh cf3co2h cf3c〇2h I -95- 200412345 85762 274 808544 nh2 Ο Η ΝγΝΗ CF3CO2H cf3co2h 1 275 808548 νη2 fNjOC)-^N Η Ν^ΝΗ 276 808571 Η Ν^ΝΗ 277 808576 νη2 ο>-^ν iy Η ΝτΝΗ 278 808600 ^nJ〇c)-^n U Η ν^νη 278 808617 OXcv^N Η ν^νη 279 808620 \ Η Ν 丫 ΝΗ 280 808622 〇〇Γ&νςΝ Η Ν 丫 ΝΗ 281 808623 〇nXcv^n HCI Η Ν^ΝΗ -96-265 808498 ^ nJ〇Q- ^ n ◦rJ H n ^ nh 266 808499 VHN? N} H 267 808500 CF3C〇2H cf3c〇2h hn? Nh 268 808501 0 ^ 1 CF ^ H nh2 cf3c〇2h h N / yNH 269 808513 cf3co2h 〇O ^ XXV ^ N CF3C〇2H η N'yNH 270 808514 CF3CO2H nh2 cf3co2h h NyNH 271 808541 H nvnh cf3co2h 'CF3C02H I 272 808542 nh2 H nvnh CF3C02H CF3CO2 808 CF3CO2 I -95- 200412345 85762 274 808544 nh2 〇 Η ΝγΝΗ CF3CO2H cf3co2h 1 275 808548 νη2 fNjOC)-^ N Ν Ν ^ ΝΗ 276 808571 Ν ^^ NΗ 277 808576 νη2 ο >-^ ν iΗ 808 Ν 〇 )-^ n U Η ν ^ νη 278 808617 OXcv ^ N Η ν ^ νη 279 808620 \ Η Ν ΑΝΝΗ 280 808622 〇〇Γ & νςΝ Ν ΝΝΝΗ 281 808623 〇nXcv ^ n HCI Η Ν ^ ΝΗ -96-

200412345 85762 282 808624 Η Ν^ΝΗ 283 808627 νη2 ^ hci ΝγΝΗ 284 808628 iJ〇CV^N ^ hci ΝγΝΗ 285 808629 Η Ν^ΝΗ 286 808631 Η ΝγΝΗ 287 808635 Η Ν^ΝΗ 288 808636 Η N^NH 289 808637 〇nJlD〇~^n hci Η ΝγΝΗ 290 808658 I] NHAc 'Xcv^N Η Ν^ΝΗ 291 808660 Η ΝγΝΗ -97- 200412345 85762200412345 85762 282 808624 Η Ν ^ ΝΗ 283 808627 νη2 ^ hci ΝγΝΗ 284 808628 iJ〇CV ^ N ^ hci ΝγΝΗ 285 808629 Η Ν ^ ΝΗ 286 808631 Η ΝγΝΗ 287 808635 Η Ν ^ ΝΗ l 288 808 636 〇 ~ ^ n hci Η ΝγΝΗ 290 808658 I] NHAc 'Xcv ^ N Η Ν ^ ΝΗ 291 808660 Η ΝγΝΗ -97- 200412345 85762

292 808661 M N^NH 293 808663 H Ν^,ΝΗ 294 808665 o, H H N^NH 295 808672 o H ΝγΝΗ 296 808673 M N^NH 297 808675 /〇 1 /NH2 0CV^N Hr H N 丫 nh 298 808691 H n^nh 299 808692 ^nJ(Xv^n H N^NH -98- 200412345 85762 300 808702 〇Cr0cv^H2 Η N^NH 301 808703 H N^NH cf3c〇2h T 302 808704 H N^NH CF3C〇2H 丫 303 808705 H N^NH cf3co2h T 304 808711 H N 丫 NH 305 808712 "1 H N?NH 306 808713 H n^nh 307 808714 〇nJ〇^Pn H N^NH 308 808717 H n^nh 309 808719 餘 對掌性 H n^nh -99- 200412345 85762292 808661 MN ^ NH 293 808663 H Ν ^, ΝΗ 294 808665 o, HHN ^ NH 295 808672 o H ΝγΝΗ 296 808673 MN ^ NH 297 808675 / 〇1 / NH2 0CV ^ N Hr HN yann 298 808691 H n ^ nh 299 808692 ^ nJ (Xv ^ n HN ^ NH -98- 200412345 85762 300 808702 〇Cr0cv ^ H2 Η N ^ NH 301 808703 HN ^ NH cf3c〇2h T 302 808704 HN ^ NH CF3C〇2H ^ 303 808705 HN ^ NH cf3co2h T 304 808711 HN ah NH 305 808712 " 1 HN? NH 306 808713 H n ^ nh 307 808714 〇nJ〇 ^ Pn HN ^ NH 308 808717 H n ^ nh 309 808719 more palmarity H n ^ nh -99- 200412345 85762

310 808720 Ο Η ΝγΝΗ 311 808833 nh2 MeO^J H ΝγΝΗ 312 808834 MeO^J ΝγΝΗ 313 808835 H K^NH 314 808836 Me〇、^^ T 1 」NH2 'Xcv^N H N^NH 315 808849 H N^NH 316 808983 HO^ H n?nh 317 808984 nh2 H ΝγΝΗ 318 809047 H。㈣ HO 人 CF3 丫H 319 809187 HI H N^NH -100- 200412345 85762 320 809189 nh2 Η Ν 丫 ΝΗ 321 809190 νη2 Η nC；nh 322 809191 μη2 Η nC；NH 323 809192 νη2 Η Ν 'ΝΗ 324 809193 Νη2 Η ν^νη 325 809196 H〇^XcvqN 2 CF3CO2H NVNH 326 809197 2CF3C02H Η ΝγΝΗ - 327 809198 2 CF3C02H NVNH 328 809199 3 cf3co2h ΝγΝΗ 329 809200 ΗΟ. 2 CF3C02H ΝγΝΗ -101 -310 808720 〇 Ν ΝγΝΗ 311 808833 nh2 MeO ^ JH ΝγΝΗ 312 808834 MeO ^ J ΝγΝΗ 313 808835 HK ^ NH 314 808836 Me〇, ^^ T 1 `` NH2 'Xcv ^ NHN ^ NH 315 808849 HN ^ NH 316 808983 HO ^ H n? nh 317 808984 nh2 H ΝγΝΗ 318 809047 H. ㈣ HO human CF3 ah H 319 809187 HI HN ^ NH -100- 200412345 85762 320 809189 nh2 Η Ν ΝΝΗ 321 809190 νη2 Η nC; nh 322 809191 μη2 Η nC; NH 323 809192 νη2 Η Ν 'ΝΗ 324 809 NR2 ^ νη 325 809196 H〇 ^ XcvqN 2 CF3CO2H NVNH 326 809197 2CF3C02H Η ΝγΝΗ-327 809198 2 CF3C02H NVNH 328 809199 3 cf3co2h ΝγΝΗ 329 809200 Η〇. 2 CF3C02H ΝγΝΗ -101

200412345 85762 330 809201 2CF3c〇2h nVnh 331 809202 2 cf3co2h ΝγΝΗ 332 809203 〇Ν，ΝΧπ>^ 3 CF3C02H NVNH 333 809204 HO. 2 cf3co2h ΝγΝΗ 334 809205 2CF3C〇2H ΝγΝΗ 335 809206 人 2 CF3CO2H ΝγΝΗ 336 809207 3 CF3CO2H ΝγΝΗ 337 809208 3 CF3CO2H ΝγΝΗ 338 809209 2 CF3CO2H ΝγΝΗ -102- 200412345 85762 339 809210 2CF3C02H Η nVnh 340 809211 2 CF3C02H NVNH 341 809212 3 CF3C02H NVNH 342 809213 一 2 CF3C02H ΝγΝΗ 343 809214 2 CF3CO2H ΝγΝΗ 344 809215 2 CF3C02H ΝγΝΗ 345 809216 2 CF3CO2H 346 809217 α«Χ0^Ν ' 2 CF3CO2H ΝγΝΗ 347 809218 Η Ν κ ΝΗ 2 CF3C〇2H γ 348 809219 η Ν ν ΝΗ 2 CF3C02H γ -103- 200412345 85762 349 809220 一 2CF3C02H H ΝγΝΗ 350 809221 2 CF3C02H ΝγΝΗ 351 809222 3 CF3C02H ΝγΝΗ 352 809223 \ 2 CF3C02H NVNH 353 809224 〇 N^NH cf3c〇2h 1 354 809225 0 NyNH cf3c〇2h I 355 809226 J o N^NH 356 809227 〇 N^NH cf3c〇2h I 357 809228 〇 N^NH cf3co2h I 358 809229 2 CF3C〇2H 丁 104- 200412345 85762200412345 85762 330 809201 2CF3c〇2h nVnh 331 809202 2 cf3co2h ΝγΝΗ 332 809203 〇Ν, Νχπ > ^ 3 CF3C02H NVNH 333 809204 HO. 2 cf3co2h ΝγΝΗ 334 809205 2CF3C2 2 NH2N ΝγNΗNΗ 3 CF3CO2H ΝγΝΗ 338 809209 2 CF3CO2H ΝγΝΗ -102- 200412345 85762 339 809210 2CF3C02H Η nVnh 340 809211 2 CF3C02H NVNH 341 809212 3 CF3C02H NV2 2C3C02H 2N3 NH2 2152 α «× 0 ^ Ν '2 CF3CO2H ΝγΝΗ 347 809218 Η Ν κ ΝΗ 2 CF3C〇2H γ 348 809219 η Ν ν ΝΗ 2 CF3C02H γ -103- 200412345 85762 349 809220-2CF3C02H H ΝγΝΗ 350 809 2221 2CF3C02 352 809223 \ 2 CF3C02H NVNH 353 809224 〇N ^ NH cf3c〇2h 1 354 809225 0 NyNH cf3c〇2h I 355 809226 J o N ^ NH 356 809227 〇N ^ NH cf3c〇2h I 357 809228 〇N ^ NH cf3co2h I 358 809229 2 CF3C〇2H Ding 104- 2004123 45 85762

359 809230 〇 N>^/NH 1 CF3C〇2H I 360 809231 1 〇 N^NH cf3co2h I 361 809232 丨 〇 N^NH cf3co2h 丁 362 809233 o n.nh 2 CF3C〇2H I 363 809234 〇N^J!YJC5^pN 〇 N^NH 2 CF3C02H 1 364 809235 /) 〇 N<yNH CF3CO2H 丁 365 809236 ^ 0 N^NH cf3co2h 丁 366 809237 〇 _ n^nh CF3CO2H 1 367 809238 H。」0 rFrnw V CF3CO2H 1 368 809251 Qn^j5>-^n 1 N 丫 NH -105-359 809230 〇N> ^ / NH 1 CF3C〇2H I 360 809231 1 〇N ^ NH cf3co2h I 361 809232 丨 〇N ^ NH cf3co2h ding 362 809233 o n.nh 2 CF3C〇2H I 363 809234 〇N ^ J! YJC5 ^ pN 〇N ^ NH 2 CF3C02H 1 364 809235 /) 〇N < yNH CF3CO2H Ding 365 809236 ^ 0 N ^ NH cf3co2h Ding 366 809237 〇_ n ^ nh CF3CO2H 1 367 809238 H. `` 0 rFrnw V CF3CO2H 1 368 809251 Qn ^ j5 >-^ n 1 N ah NH -105-

200412345 85762200412345 85762

369 809252 H N 丫 NH 370 IC261 H N^NH 371 IC375 nh2 H N^NH 372 IC380 nh2 〇cv^n H HN NH Ϊ 373 IC395 HN、0 飞 邮。 M N^NH 374 IC396 NH2 M N^NH 375 IC400 nh2 H N 丫 NH 376 IC401 nh2 fO>^n hc, H N^NH -106-369 809252 H N ah NH 370 IC261 H N ^ NH 371 IC375 nh2 H N ^ NH 372 IC380 nh2 〇cv ^ n H HN NH Ϊ 373 IC395 HN, 0 Airmail. M N ^ NH 374 IC396 NH2 M N ^ NH 375 IC400 nh2 H N y NH 376 IC401 nh2 fO > ^ n hc, H N ^ NH -106-

2)2)

炙所述，本發明係提供新穎脫氮嘌呤，具有如上3As mentioned above, the present invention provides a novel deazapurine having the above-mentioned 3

夂夂策些種類與亞紕中所述之式（I)。數種舉例化^ 在条 二、， ，舍成，係詳細描述於下文中。應明瞭的是，如本文 ，舍成....... A Μ卜又千。應明瞟的是，如本文 述實例係产、十、甘A $ 农可π白 替代起始物皙之 仁應明瞭的 似物。 、生本發明所涵蓄 述之方法，可應用於如本文中所揭示之各化合物及其 :。此二f些試劑與起始物質係為熟諳此藝者所習 85762 -107- 200412345 :=A反應程序： 除非特別指出，否則反應混合物係使用磁驅動攪拌棒塊進 行攪拌。惰性大氣係指無論是乾燥氬或乾燥氮。反應係無 論是藉反應混合物之經適當處理試樣之薄層層析法或質^ 核磁共振監測。 ’ 二般處理程序： 除非特別指出，否則係使反應混合物冷卻至室溫或較低， 然後當必要時，以無論是水或氯化銨或碳酸氫鈉之飽和水 溶液使反應淬滅。所要之產物係藉由在水與適當水不可溶 混溶劑（例如醋酸乙酯、二氯甲烷、***）之間作分液處理 而進行萃取。含有所要產物之萃液係適當地以水，接著以 飽和鹽水洗滌。在含有產物之萃液被認為包含殘留氧化劑 之場合中，係在前文所提及之诜滌程序之前，將萃液以亞 硫酸鈉在碳酸氫納飽和水溶液中之10%溶液洗條。在各有產 物之萃液被認為包含殘留酸之場合中，係在前文所提及之 洗滌程序之前，將萃液以碳酸氫鈉飽和水溶液洗滌（惟在所 要之產物本身具有酸性特性之情況中除外）。在含有產物之 萃液被認為包含殘留鹼之場合中，係在前文所提及之洗條 程序之前，將萃液以10%擰檬酸水溶液洗滌（惟在所要之產 物本身具有鹼性特性之情況中除外）。於洗滌之後，使含有 所要產物之萃液，以無水硫酸鍰脫水乾燥，然後過滤。接 著’藉迴轉式蒸發’在減壓及適當溫度（通常低於45°C )下， 藉由移除溶劑，分離粗產物。 一般純化裎序： 85762 -108- 200412345 除非特別指出，否則層析純化係指於矽膠上之急驟式管柱 層析，使用單-一溶劑或混合溶劑作為溶離劑。將含有已適 當純化之所要產物之溶離物合併，並在減壓及適當溫度（通 常低於45°C )下濃縮至恒定質量。 關於某些舉例化合物之實驗：Advise these types and the formula (I) described in Arya. Several examples are given in the following sections. It should be clear that, as in this article, shecheng ... A MU Bu Qian. It should be noted that, as described in this article, the example is a similar product that Xing, Gan, A A, Nong Ke Pi Bai, the substitute of the starting material, should be clear. The method described in the present invention can be applied to each compound and its compounds as disclosed herein. These reagents and starting materials are familiar to those skilled in the art 85762 -107- 200412345: = A Reaction Procedure: Unless otherwise specified, the reaction mixture is stirred using a magnetically driven stir bar. Inert atmosphere refers to either dry argon or dry nitrogen. The reaction system can be monitored by thin-layer chromatography or mass spectrometry NMR of a properly processed sample of the reaction mixture. ′ Two general processing procedures: Unless otherwise specified, the reaction mixture is allowed to cool to room temperature or lower, and then when necessary, the reaction is quenched with either a water or a saturated aqueous solution of ammonium chloride or sodium bicarbonate. The desired product is extracted by liquid separation between water and a suitable water-immiscible solvent (e.g. ethyl acetate, dichloromethane, diethyl ether). The extract containing the desired product is suitably washed with water, followed by saturated brine. Where the product-containing extract is considered to contain residual oxidants, the extract is washed with a 10% solution of sodium sulfite in a saturated aqueous solution of sodium bicarbonate before the cleaning procedure mentioned above. Where the extracts of each product are considered to contain residual acid, the extracts are washed with a saturated aqueous solution of sodium bicarbonate before the washing procedure mentioned above (but in the case where the desired product itself has acidic properties except). Where the product-containing extract is considered to contain residual alkali, the extract should be washed with a 10% aqueous solution of citric acid before the strip washing procedure mentioned above (but only if the desired product itself has alkaline properties). Except in cases). After washing, the extract containing the desired product was dehydrated and dried over anhydrous sulphuric acid, and then filtered. The crude product is then separated by removing the solvent under reduced pressure and an appropriate temperature (usually below 45 ° C) by 'rotary evaporation'. General purification procedure: 85762 -108- 200412345 Unless otherwise specified, chromatographic purification refers to flash column chromatography on silica gel, using a mono- or mixed solvent as the eluent. Eluates containing the desired product that has been appropriately purified are combined and concentrated to a constant mass under reduced pressure and at an appropriate temperature (usually below 45 ° C). Experiments with certain example compounds:

NHC02Et NNHC02Et N

ClCl

N^NHN ^ NH

CICI

h2n NHC02Eth2n NHC02Et

:N NH2 1 在某些具體實施例中’化合物1與2係根據Temple，C.; Smithy， Β· Η· ; Montgomery, J.A. ; J Org 1973,从 613_5 之程序製成。: N NH2 1 In certain embodiments, 'Compounds 1 and 2 were prepared according to the procedures of Temple, C .; Smithy, B. ;; Montgomery, J.A .; J Org 1973, from 613_5.

於-10°c下，使無水HC1(氣體）起泡經過腈（R2_CN)在乙酸中 ’含有1莫耳當量乙醇之2 Μ溶液，歷經1-2小時。於室溫下 攪拌另一小時至過夜後，使氮起泡經過，以滌除過量11〇1氣 體與_。將殘留漿液或懸浮液過濾，以醚洗務三次，然後 在真空下乾燥，獲得其相應之醯亞胺酸乙酯氯化氯。將i (1 毫莫耳）與醯亞胺酸乙酯氯化氫（1.1毫莫耳）在5毫升乙醇中 之混合物，於65_7(TC下加熱，直到反應完成為止（15小時至 過夜）。使混合物冷卻至室溫，以20毫升水稀釋，授掉％八 85762 -109- 200412345 4里，過濾，及以水洗滌。收集濾餅，並在真空下乾燥，而 得所要之產物3。Anhydrous HC1 (gas) was bubbled through a 2M solution of nitrile (R2_CN) in acetic acid at -10 ° C in acetic acid for 1-2 hours. After stirring at room temperature for another hour to overnight, nitrogen was bubbled through to remove excess 1101 gas and oxygen. The residual slurry or suspension was filtered, washed three times with ether, and then dried under vacuum to obtain its corresponding ethyl imidate chloride. A mixture of i (1 mmol) and ethyl imidate hydrogen chloride (1.1 mmol) in 5 ml of ethanol was heated at 65_7 (TC until the reaction was complete (15 hours to overnight). The mixture was allowed to Cool to room temperature, dilute with 20 ml of water, and give 5% 85762 -109- 200412345 4 miles, filter, and wash with water. Collect the filter cake and dry under vacuum to get the desired product 3.

將3(1毫莫耳）在2.8毫升57%111(水溶液，2〇毫莫耳）中之溶 液，於回流下加熱，直到反應完成為止（12-20小時）。使混合 物冷卻至0°C，慢慢地以5NNa0H溶液（19毫莫耳），然後以i 耄升飽和NaHC〇3稀釋至pH〜9。將所形成之混合物以無論是 醋酸乙酯或醋酸乙酯/ THF混合物萃取，直到萃取完成為止 。使合併义萃液以Na2S〇4脫水乾燥，過濾，及濃縮，而得所 要之產物4，為自由態形式。在某些情況中，若必要，將產 物以醋酸乙酯洗滌，造成更良好純度。於反應混合物冷卻 土至溫，過濾，以水洗滌，並使已收集之黃色固體在高真 空中乾燥後，獲得4之HI單鹽形式。 nh2A solution of 3 (1 mmol) in 2.8 ml of 57% 111 (aqueous solution, 20 mmol) was heated under reflux until the reaction was complete (12-20 hours). The mixture was allowed to cool to 0 ° C, and was slowly diluted with 5N NaOH solution (19 mmol), and then diluted to pH ~ 9 with 1 mL saturated NaHC0. The resulting mixture is extracted with either ethyl acetate or an ethyl acetate / THF mixture until the extraction is complete. The combined sense extracts were dried over Na2SO4, filtered, and concentrated to give the desired product 4 in free form. In some cases, if necessary, the product is washed with ethyl acetate, resulting in a better purity. The reaction mixture was cooled to a warm temperature, filtered, washed with water, and the collected yellow solid was dried in a high-frequency air to obtain the HI mono-salt form. nh2

Cl—<^N N 丫 NH 〇Et 5 於室溫下，將1 (300毫克，1.3毫莫耳）與原碳酸四乙酯（2·6 毫莫耳）在10毫升醋酸中之混合物，攪拌過夜，並完成反應 。使反應混合物在減壓真空下濃縮，並將殘留物以飽和 NaHC〇3稀釋，以EtOAc萃取，以Na2S04脫水乾燥，過濾，濃 85762 -110- 200412345 縮，而得褐色固體。使此固體溶於24毫升含有1.2克KOH之 H20-MeOH (1 : ί)溶液中，並在回流下加熱2.5小時。於冷卻 至室溫後，將混合物以EtOAc萃取。將萃液以水洗滌，以Na2S04 脫水乾燥，過濾，濃縮，並使產物藉層析純化（10% MeOH-EtOAc) ，獲得5 (45毫克，16%)。Cl— < ^ NN Ya NH 〇 Et 5 A mixture of 1 (300 mg, 1.3 mmol) and tetraethyl orthocarbonate (2.6 mmol) in 10 ml of acetic acid was stirred at room temperature and stirred Overnight and complete the reaction. The reaction mixture was concentrated under reduced pressure in vacuo, and the residue was diluted with saturated NaHC03, extracted with EtOAc, dried over Na2S04, filtered, and concentrated 85762-110-200412345 to give a brown solid. This solid was dissolved in 24 ml of a H20-MeOH (1: 1) solution containing 1.2 g of KOH and heated under reflux for 2.5 hours. After cooling to room temperature, the mixture was extracted with EtOAc. The extract was washed with water, dried over Na 2 SO 4, filtered, concentrated, and the product was purified by chromatography (10% MeOH-EtOAc) to obtain 5 (45 mg, 16%).

將1 (203毫克，0.88毫莫耳）在三氟醋酸（2毫升）中之溶液， 於70°C下，加熱12小時，冷卻至室溫，濃縮，並將殘留物以 飽和NaHCO3(10毫升）與EtOAc (10毫升）稀釋。將已分離之水 相以4x10毫升EtOAc萃取，並使合併之有機層以Na2 S04脫水 乾燥，過濾，及濃縮，而得黃色固體。將此黃色固體與3毫 升多磷酸混合，於200°C下加熱3小時，並冷卻至室溫。以飽 和NaHC03 (80毫升）小心地使反應混合物淬滅，並以4x20毫升 EtOAc萃取。使合併之有機層以Na2 S〇4脫水乾燥，過滤，及 濃縮，而得褐色黃色固體。使此固體溶於5毫升57% HI溶液 中，並在110°C下加熱12小時。於冷卻至室溫後，將反應混 合物小心地倒入含有3毫升INNaOH之飽和NaHC03 (60毫升）中 ，並以4x20毫升EtOAc萃取。使合併之有機層以Na2 S04脫水 乾燥，過濾，並濃縮，且使產物藉層析純化（50至100% EtOAc-己烷），而得所要之產物6 (132毫克，46%，歷經3個步驟）。 85762 -111- 200412345A solution of 1 (203 mg, 0.88 mmol) in trifluoroacetic acid (2 ml) was heated at 70 ° C for 12 hours, cooled to room temperature, concentrated, and the residue was saturated with NaHCO3 (10 ml ) And diluted with EtOAc (10 mL). The separated aqueous phase was extracted with 4x10 ml of EtOAc, and the combined organic layers were dried over Na2SO4, filtered, and concentrated to give a yellow solid. This yellow solid was mixed with 3 ml of polyphosphoric acid, heated at 200 ° C for 3 hours, and cooled to room temperature. The reaction mixture was carefully quenched with saturated NaHC03 (80 mL) and extracted with 4 x 20 mL of EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated to give a brown-yellow solid. This solid was dissolved in 5 ml of 57% HI solution and heated at 110 ° C for 12 hours. After cooling to room temperature, the reaction mixture was carefully poured into saturated NaHC03 (60 ml) containing 3 ml of INNaOH and extracted with 4 x 20 ml of EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated, and the product was purified by chromatography (50 to 100% EtOAc-hexane) to give the desired product 6 (132 mg, 46% over 3 steps). step). 85762 -111- 200412345

將吲哚-5-羧酸甲酯（27克，155毫莫耳）（或其相應之4-，6-及7-羧酸酯）、二碳酸二-第三-丁酯（40克，1.2當量）、Et3N(26毫 升，1.2當量）及DMAP (0.1克，0.005當量）在THF (165毫升）中 之混合物，於室溫下，攪拌過夜。藉由添加飽和NaHC03 (350 毫升）使反應混合物淬滅。將已分離之水層以EtOAc萃取一次 。使合併之有機相濃縮，並使產物藉層析純化（5%與10% EtOAc-己烷），提供 7(42 克，100%)。Indole-5-carboxylic acid methyl ester (27 g, 155 mmol) (or its corresponding 4-, 6- and 7-carboxylic acid esters), di-tertiary-butyl dicarbonate (40 g, A mixture of 1.2 equivalents), Et3N (26 ml, 1.2 equivalents) and DMAP (0.1 g, 0.005 equivalents) in THF (165 ml) was stirred overnight at room temperature. The reaction mixture was quenched by the addition of saturated NaHC03 (350 mL). The separated aqueous layer was extracted once with EtOAc. The combined organic phases were concentrated and the product was purified by chromatography (5% and 10% EtOAc-hexanes) to provide 7 (42 g, 100%).

在30分鐘期間，於7 (42克，152毫莫耳）在二氯甲烷（400毫 升）中之溶液内，在-78°C下，添加DIBAL-H在甲苯中之1 Μ溶 液（460毫升，3.0當量）。將冷卻浴以-40°C替代，將反應混合 物攪拌，並溫熱至-30°C，且TLC顯示反應完成。小心添加MeOH (57毫升，9.0當量）與水（19毫升，9.0當量）使反應淬滅，以EtOAc (150毫升）稀釋，然後溫熱至室溫。使所形成之懸浮混合物 經過矽藻土過濾，以EtOAc洗滌，直到不再偵測出產物為止 。使濾液濃縮，並使產物藉層析純化（15%與30% EtOAc-己烷） ，提供 8 (29 克，75% )。Over a period of 30 minutes, in a solution of 7 (42 g, 152 mmol) in dichloromethane (400 ml) at -78 ° C was added a 1 M solution of DIBAL-H in toluene (460 ml) , 3.0 equivalents). The cooling bath was replaced with -40 ° C, the reaction mixture was stirred and warmed to -30 ° C, and TLC showed that the reaction was complete. The reaction was quenched by careful addition of MeOH (57 mL, 9.0 equivalents) and water (19 mL, 9.0 equivalents), diluted with EtOAc (150 mL), and allowed to warm to room temperature. The resulting suspended mixture was filtered through diatomaceous earth and washed with EtOAc until the product was no longer detected. The filtrate was concentrated and the product was purified by chromatography (15% and 30% EtOAc-hexanes) to provide 8 (29 g, 75%).

85762 -112- 200412345 於0°C下，將氯化甲烷磺醯（1(λ1毫升，1.2當量），在5分鐘 期間，添加至8(27·0克，109毫莫耳，1.0當量）與二異丙基乙 胺（57毫升，3.0當量）在二氯甲烷（250毫升）中之溶液内。在 攪拌另外15分鐘後，將嗎福啉（14.3毫升，1.5當量，或環狀 或非環狀R’R’’NH)添加至反應混合物中，並於室溫下攪掉過 夜。將混合物倒入飽和NaHC03 (100毫升）與水（20毫升）中，以 4x50毫升EtOAc萃取已分離之水相。使合併之有機相以Na2S04 脫水乾燥，過濾，濃縮，並使產物藉層析純化（15%至40% EtOAc-己烷），提供 9 (34_0 克，99% )。85762 -112- 200412345 At 0 ° C, add methanesulfonium chloride (1 (λ1 ml, 1.2 equivalents)) over a period of 5 minutes to 8 (27.0 g, 109 millimoles, 1.0 equivalent) and A solution of diisopropylethylamine (57 ml, 3.0 eq) in dichloromethane (250 ml). After stirring for another 15 minutes, morpholine (14.3 ml, 1.5 eq, or cyclic or acyclic) R'R''NH) was added to the reaction mixture and stirred overnight at room temperature. The mixture was poured into saturated NaHC03 (100 ml) and water (20 ml), and the separated water was extracted with 4 x 50 ml of EtOAc. The combined organic phases were dried over Na 2 SO 4, filtered, concentrated, and the product was purified by chromatography (15% to 40% EtOAc-hexanes) to provide 9 (34_0 g, 99%).

方法A :於二異丙基胺（17.0毫升，1.2當量）在THF (350毫升） 中之溶液内，於-78°C下，在15分鐘期間内，添加n-BuLi (2.5 Μ ，在己烷中，48.6毫升，1.2當量），並攪拌反應混合物，及 在移除冷卻浴後，溫熱至室溫。使反應混合物冷卻回復至-78 °C，並將9 (32克，101毫莫耳）在THF (120毫升）中之溶液，藉 由套管***法，在15分鐘期間内引進。攪拌所形成之混合 物，並在15分鐘期間溫熱至-20t，然後引進Bu3SnCl(31.5毫 升，1.15當量）。將混合物攪拌，並溫熱至室溫，及倒入飽 和NH4C1 (300毫升）中。將已分離之水相以3x100毫升EtOAc萃 取。使合併之有機相以Na2 S〇4脫水乾燥，過滤，濃縮，並使 產物藉真空層析純化（5%至50% EtOAc-己烷），提供10 (55克， 89%)。 85762 -113 - 200412345 支逢卫：此反應亦按照如用以從14製備15之相同擬案進行。Method A: In a solution of diisopropylamine (17.0 ml, 1.2 equivalents) in THF (350 ml), at -78 ° C, add n-BuLi (2.5 Μ, Hexane, 48.6 ml, 1.2 equivalents), and the reaction mixture was stirred, and after removing the cooling bath, allowed to warm to room temperature. The reaction mixture was cooled back to -78 ° C, and a solution of 9 (32 g, 101 mmol) in THF (120 ml) was introduced by cannula insertion over a period of 15 minutes. The resulting mixture was stirred and warmed to -20 t over a period of 15 minutes, and then Bu3SnCl (31.5 ml, 1.15 equivalents) was introduced. The mixture was stirred and warmed to room temperature and poured into saturated NH4C1 (300 mL). The separated aqueous phase was extracted with 3 x 100 ml of EtOAc. The combined organic phases were dried over Na2SO4, filtered, concentrated, and the product was purified by vacuum chromatography (5% to 50% EtOAc-hexane) to provide 10 (55 g, 89%). 85762 -113-200412345 Zhi Fengwei: This reaction is also carried out according to the same proposal as used to prepare 15 from 14.

化合物11係按照關於從9製備10之相同程序，製自吲嗓4 羧酸第三-丁酯，86%。Compound 11 was prepared according to the same procedure as for preparation of 10 from 9, third-butyl ester of indole 4 carboxylic acid, 86%.

化合物12係按照關於製備7與10之類似程序，製自單-或二 取代之4丨嗓。Compound 12 was prepared from a mono- or di-substituted 4a according to a similar procedure as for preparations 7 and 10.

將4 (0.4毫莫耳，ι·〇當量，或2或5或、1〇 (1·6當量，或u 或12)及[(QHAPLPd (0.1當量）在已脫氣之DMF (丨毫升）中之混 合物，於氮氣下，使用或未使用k：2C〇3(i.o當量），在11(Γ(：τ 加熱18-28小時，冷卻至室溫，及在高真空下濃縮。將殘留 物以飽和NaHC〇3(l〇毫升）與Et0Ac稀釋。將已分離之水相以 EtOAc萃取多次，直到沒有產物被檢出為止。使合併之有機 相以Na] SO4脫水乾燥，過濾，及濃縮。使產物藉層析純化（5 %或10% MeOH-EtOAc)，而得所要之產物13。 85762 -114- 200412345 化合物# -(ER# 或 IC#) 結構13 MS (ES) 或/及 NMR IC 400 nh2 H N^/NH 'HNMR 806014 H N 丫 NH 287.3 (M-H)' 806006 nh2 H HN? cf3 316.3 (M-H)· 805985 nh2 HN^N 278.3 (M+H)+ 85762 -115- 200412345Mix 4 (0.4 millimolar, ι · 〇 equivalent, or 2 or 5 or, 10 (1.6 equivalent, or u or 12) and [(QHAPLPd (0.1 equivalent)) in degassed DMF (丨 ml) The mixture was heated under nitrogen with or without k: 2C03 (io equivalent), heated at 11 (Γ (: τ for 18-28 hours, cooled to room temperature, and concentrated under high vacuum. The residue was concentrated. Diluted with saturated NaHC03 (10 mL) and Et0Ac. The separated aqueous phase was extracted multiple times with EtOAc until no product was detected. The combined organic phases were dried over Na] SO4, filtered, and concentrated The product was purified by chromatography (5% or 10% MeOH-EtOAc) to give the desired product 13. 85762 -114- 200412345 Compound #-(ER # or IC #) Structure 13 MS (ES) or / and NMR IC 400 nh2 HN ^ / NH 'HNMR 806014 HN Ah NH 287.3 (MH)' 806006 nh2 H HN? Cf3 316.3 (MH) 805805 nh2 HN ^ N 278.3 (M + H) + 85762 -115- 200412345

805984 r^H2 OhR HN^N 292.3 (M+H)+ 806002 nh2 H rn? 306.3 (M+H)+ 805969 nh2 326.3 (M+H)+ 805971 nh2 H hnO. 354.3 (M+H)+ 805996 nh2 a>^ : H HnQ SMe 'H NMR 805639 nh2 丄 HNMR (IC 379) H / ' HN^N805984 r ^ H2 OhR HN ^ N 292.3 (M + H) + 806002 nh2 H rn? 306.3 (M + H) + 805969 nh2 326.3 (M + H) + 805971 nh2 H hnO. 354.3 (M + H) + 805996 nh2 a > ^: H HnQ SMe 'H NMR 805639 nh2 丄 HNMR (IC 379) H /' HN ^ N

85762 -116 200412345 805895 (IC 405) mi H HN^ 'H NMR 806007 nh2 H HN^N cf3 425.2 (M-H)' 805976 nh2 CT〇^N H hn^n 'HNMR 805975 nh2 H [H NMR 805999 nh2 〇o^o>-^n {R NMR 806011 NH2 Cna>^N Η HN 丫 N 393.3 (M+H)+ 85762 -117- 20041234585762 -116 200412345 805895 (IC 405) mi H HN ^ 'H NMR 806007 nh2 H HN ^ N cf3 425.2 (MH)' 805976 nh2 CT〇 ^ NH hn ^ n 'HNMR 805975 nh2 H [H NMR 805999 nh2 〇o ^ o >-^ n {R NMR 806011 NH2 Cna > ^ N Η HN λN 393.3 (M + H) + 85762 -117- 200412345

85762 118- 20041234585762 118- 200412345

於8 (以5-經甲基-啕嗓-1-獲酸第三·丁酯作為實例，24.4克， 98.8毫莫耳）、Et3N (41毫升，3當量）及DMAP (1.2克，0.1當量） 在二氯甲烷（185毫升）中之混合物内，於室溫下，添加TBSC1 (23.1克，1·5當量），並將所形成之混合物攪拌過夜。藉由添 加飽和NaHC03 (200毫升）使反應淬滅，並將已分離之水層以 3x50毫升二氯甲烷萃取。使合併之有機相以Na2S04脫水乾燥 ，過濾，濃縮，並使產物藉真空層析純化（3% EtOAc-己烷）， 提供14 (5-第三-丁基-二甲基-石夕烷基氧基甲基）_吲哚小羧酸第 三-丁酯），為無色油（33.9克，95% )。In 8 (Third-Butyl 5-Methyl Acetate-1-Acid as an example, 24.4 g, 98.8 mmol), Et3N (41 ml, 3 eq) and DMAP (1.2 g, 0.1 eq ) In a mixture in dichloromethane (185 ml), TBSC1 (23.1 g, 1.5 equivalents) was added at room temperature, and the resulting mixture was stirred overnight. The reaction was quenched by the addition of saturated NaHC03 (200 mL), and the separated aqueous layer was extracted with 3 x 50 mL of dichloromethane. The combined organic phases were dried over Na2S04, filtered, concentrated, and the product was purified by vacuum chromatography (3% EtOAc-hexane) to provide 14 (5-tert-butyl-dimethyl-lithium (Oxymethyl) -indole small carboxylic acid tert-butyl ester) as a colorless oil (33.9 g, 95%).

於14 (以5-第三-丁基-二甲基-石夕烷基氧基甲基哚小羧酸 85762 -119- 200412345 第二-丁酯作為貫例，33.5克，92.7毫莫耳）在(65〇毫升）中 炙溶液内，低於-72。(：下，在45分鐘期間内，逐滴添加tBuLi⑹ 笔升，1.7M，在戊燒中，1.2當量），並再持續擾拌4〇分鐘。 使所形成之褐色溶液短暫地溫熱至_60°c，然後冷卻回復至 低於-72C。接著將Bu3SnCl(31.6毫升，U當量）引進反應混合 物中’並於-40 C下揽拌15分鐘。在-35°C下，以飽和NaHC03 (250 毫升）使反應泮滅’並將已分離之水層以毫升Et〇Ac萃 取。使合併之有機相以NazSO4脫水乾燥，過濾，濃縮，並使 產物藉真空層析純化（己烷），提供15 (5_(第三—丁基_二甲基矽 烷基氧基甲基）-2-三丁基錫烷基蚓哚小羧酸第三-丁醋），為 無色油（60·6克，1〇〇% )。Yu 14 (using 5-third-butyl-dimethyl-lithium alkyloxymethyl indole small carboxylic acid 85762 -119- 200412345 as second example, 33.5 g, 92.7 mmol) The solution was lowered to -72 in (650 ml). (: Next, tBuLi⑹ pen liters, 1.7M, in pentamole, 1.2 equivalents were added dropwise over a period of 45 minutes, and stirring was continued for another 40 minutes. The resulting brown solution was briefly warmed to -60 ° C and then cooled back to below -72C. Bu3SnCl (31.6 ml, U equivalent) was then introduced into the reaction mixture 'and stirred at -40 C for 15 minutes. The reaction was quenched 'with saturated NaHC03 (250 ml) at -35 ° C and the separated aqueous layer was extracted with ml of EtoAc. The combined organic phases were dried over NazSO4, filtered, concentrated, and the product was purified by vacuum chromatography (hexane) to provide 15 (5- (third-butyl-dimethylsilyloxymethyl) -2 -Tributyltin alkyl worm indole small carboxylic acid tert-butyl vinegar) as a colorless oil (60. 6 g, 100%).

於110°c及氮大氣下，將15(以5_(第三·丁基_二甲基，烷基 氧基甲基）-2-三丁基錫燒基，嗓+羧酸第三叮酯作為實例， 60.6克，3.0當量）在DMF(100毫升）中之溶液，於料小時期間 ，以四份添加至 4 (R2=Me，8,51 克，31·〇 毫莫耳）、pd(ph3p)4(3 2 克，0.09當τ )及EtsN (26耄升，3.0當量）在DMF (1〇〇毫升）中 而使用或未使用K：2 C〇3 (1.0當量）之溶液内。將所形成之混合 物攪拌20小時，冷卻至室溫，及濃縮。將殘留物以飽和NaHC〇3 (300笔升）與EtOAc (300毫升）稀釋，過濾，並以Et〇Ac洗滌， 以除去暗灰色淤泥。以6x200 *升Et〇Ac萃取已從濾液分離之 85762 -120- 200412345 水相，直到沒有所要之產物藉丁!^檢測出為止。使合併之有 機相以Na〗S〇4胞水乾爍，過濾，及濃縮。以Et〇Ac稀釋殘留 物’並將所形成之懸浮液過濾、，以EtOAc與2xMeOH洗條，獲 传16 (4.27克）。使;慮液濃縮，並使殘留產物藉層析純化（〇至5 % MeOH-EtOAc) ’而得另外之16 (2.59克）。將產物合併，而得16 (7_[5-(第三-丁基-二甲基-矽烷基氧基甲基）-1Η-吲哚-2-基]-2-甲基 -3H_咪唑并[4,5婦比啶-5_基胺），為綠灰色固體（6 86克，54% )。At 110 ° C and nitrogen atmosphere, 15 (using 5_ (third · butyl_dimethyl, alkyloxymethyl) -2-tributyltin, methylbenzene and carboxylic acid third butyl ester as examples , 60.6 g, 3.0 eq) in DMF (100 ml), added to 4 (R2 = Me, 8,51 g, 31.0 mmol), pd (ph3p) in four portions during the material hour. 4 (3 2 g, 0.09 equivalents τ) and EtsN (26 liters, 3.0 equivalents) in DMF (100 mL) with or without K: 2 CO3 (1.0 equivalent) solution. The resulting mixture was stirred for 20 hours, cooled to room temperature, and concentrated. The residue was diluted with saturated NaHC03 (300 strokes) and EtOAc (300 mL), filtered, and washed with EtoAc to remove dark gray sludge. The 85762-120-200412345 aqueous phase that has been separated from the filtrate was extracted with 6x200 * liters of EtOAc until no desired product was detected by Ding! ^. The combined organic phases were dried over NaSO4, filtered, and concentrated. The residue 'was diluted with EtoAc and the resulting suspension was filtered and the strip was washed with EtOAc and 2xMeOH to give 16 (4.27 g). The solution was concentrated and the residual product was purified by chromatography (0 to 5% MeOH-EtOAc) 'to give an additional 16 (2.59 g). The products were combined to give 16 (7_ [5- (third-butyl-dimethyl-silyloxymethyl) -1'-indol-2-yl] -2-methyl-3H_imidazo [4,5 Bipyridin-5-ylamine) as a green-gray solid (6 86 g, 54%).

將tBuOK在THF中之溶液（1.66M，96.3毫升，9.5當量），於40 分鐘期間，在低於-28。(：下，添加至16 (以7-[5-(第三-丁基-二甲 基-石夕烷基氧基甲基）_1H-吲哚-2-基]-2-甲基-3H-咪唑并[4,5七]吡啶 基胺作為實例，6_86克，16·8毫莫耳）與二碳酸二-第三-丁 醋（39毫升，1〇當量）在THF (U升）中之混合物内。攪拌1〇分 鐘後，藉由添加飽和NaHC03 (300毫升）使反應淬滅，並溫熱 至室溫。將已分離之水層藉由3x150毫升EtOAc萃取。使合併 之有機相以Na2 S04脫水乾燥，過濾，濃縮，並使產物藉真空 層析純化（10至20% EtOAc /己烷），提供經二-Boc-保護之中間 物。 然後使經二-Boc-保護之中間物溶於含有Et3N(55毫升）、 DIBOC (22·5 克，6·0 當量）及 DMAP (0.21 克，0·1 當量）之 55 毫升 THF中，並在65 °C下加熱5小時。於冷卻至室溫後’使混合 85762 -121 - 200412345 物濃縮，並使產物藉真空層析純化（10% EtOAc-己烷），提供 經四-Boc-保護乏中間物。 接著使經四-Boc-保護之中間物溶於HF /外1：淀在THF中之溶 液（0·89 Μ ’ 5.3當量，HF / p比淀溶液係經由將10克70% HF /外匕 啶、52·5毫升吡啶及330毫升THF混合而製成）内，並於室溫 下攪拌40小時。然後以飽和NaHC〇3 (25〇毫升）小心地使反應 混合物淬滅，並將已分離之水層藉由3x5〇毫升EtOAc萃取。 將合併之有機相以鹽水（5〇毫升）洗滌，以Na2S04脫水乾燥， 過濾，濃縮，並使產物藉真空層析純化（10至50% EtOAc-己烷） ’提供17 (5-二-(第三-丁氧羰基）胺基_7_(1-第三-丁氧羰基净羥 基甲基_1Η·吲哚-2-基）_2_甲基·咪唑并[4,5_b]吡啶-3-羧酸第三_丁 酯’ 5.64克’ 48%，歷經三個步騾），為淡黃色固體。A solution of tBuOK in THF (1.66M, 96.3 ml, 9.5 eq) was below -28 over a period of 40 minutes. (: Next, add to 16 (as 7- [5- (third-butyl-dimethyl-lithium alkyloxymethyl) _1H-indole-2-yl] -2-methyl-3H -Imidazo [4,5 hepta] pyridylamine as an example, 6-86 g, 16.8 mmol) and di-tertiary-butyric acid dicarbonate (39 ml, 10 equivalents) in THF (U liter) The mixture was stirred. After stirring for 10 minutes, the reaction was quenched by the addition of saturated NaHC03 (300 mL) and allowed to warm to room temperature. The separated aqueous layer was extracted with 3 x 150 mL of EtOAc. The combined organic phases were separated by Na2S04 was dried, filtered, concentrated, and the product was purified by vacuum chromatography (10 to 20% EtOAc / hexanes) to provide a di-Boc-protected intermediate. The di-Boc-protected intermediate was then Dissolved in 55 ml of THF containing Et3N (55 ml), DIBOC (22.5 g, 6.0 equivalents), and DMAP (0.21 g, 0.1 equivalent), and heated at 65 ° C for 5 hours. Cooling After reaching room temperature, the mixed 85762-121-200412345 was concentrated and the product was purified by vacuum chromatography (10% EtOAc-hexanes) to provide the tetra-Boc-protected intermediate. The tetra-Boc- Protective intermediate At HF / outside 1: a solution deposited in THF (0.89 M '5.3 equivalent, the HF / p ratio is at about 10 g of 70% HF / outer dipper, 52.5 ml of pyridine and 330 ml of THF And prepared), and stirred at room temperature for 40 hours. Then the reaction mixture was carefully quenched with saturated NaHC03 (250 ml), and the separated aqueous layer was extracted with 3 x 50 ml of EtOAc. The combined organic phases were washed with brine (50 mL), dried over Na2S04, filtered, concentrated, and the product was purified by vacuum chromatography (10 to 50% EtOAc-hexane). Tri-butoxycarbonyl) amino group_7_ (1-third-butoxycarbonyl net hydroxymethyl_1Η · indol-2-yl) _2_methyl · imidazo [4,5_b] pyridine-3-carboxyl Acid tertiary-butyl ester '5.64 g' 48% over three steps), as a pale yellow solid.

於〇°c下，將氯化甲基磺醯（0·14毫升，h5當量）添加至17( 以5 一（第一*丁氧氣基）胺基-7-(1-第三-丁氧羰基_5-邊基甲基_ 1EM丨哚-2-基）-2_甲基-咪唑并[4,5七]吡啶各羧酸第三叮酯作為 實例，830耄克，12毫莫耳）與二異丙基乙胺（2 〇8毫升，川 當里）在一氯甲烷（10毫升）中之混合物内，並攪拌所形成之 混合物，及溫熱至室溫。在室溫下攪拌7小時後，將混合物 於0°C下保持兩天，溫熱至室溫，並濃縮至其體積之一半。 然後使產物藉層析純化（20%至30% EtOAc /己烷），而得18 (5_ 85762 -122- 200412345 一-(第二-丁氧羰基）胺基-7_(1_第三_丁氧羰基_5_氯基甲基-吲 果2基）_2_甲基：咪唑并[4,5_b>比啶_3·羧酸第三-丁酯，770毫克 ，90%) 〇At 0 ° C, methylsulfonium chloride (0.14 ml, h5 eq) was added to 17 (with 5 mono (first * butoxy) amino-7- (1-third-butoxy Carbonyl_5-side group methyl_1EM 丨 indol-2-yl) -2_methyl-imidazo [4,5hepta] pyridine carboxylic acid third butyl ester as an example, 830 g, 12 mmol ) And diisopropylethylamine (208 ml, Chuandangli) in a mixture of monochloromethane (10 ml), and the resulting mixture was stirred and warmed to room temperature. After stirring at room temperature for 7 hours, the mixture was held at 0 ° C for two days, warmed to room temperature, and concentrated to half its volume. The product was then purified by chromatography (20% to 30% EtOAc / hexane) to give 18 (5-85762 -122- 200412345 mono- (second-butoxycarbonyl) amino-7_ (1_third_butan Oxycarbonyl_5-chloromethyl-indigo-2)) 2-methyl: imidazo [4,5_b > pyridin-3-carboxylic acid tert-butyl ester, 770 mg, 90%).

將17 (以5-二(第三-丁氧羰基）胺基冬…第三-丁氧羰基净羥 基甲基-1H-吲哚-2-基）_2_甲基-咪唑并[4,5七]吡啶各羧酸第三_丁 酉曰作為只例，122耄克，毫莫耳）與Dess Martin過硤燒（223 *克，3.0當量）在二氯甲烷（4毫升）中之混合物，於室溫下 ，攪拌1小時。將所形成之混合物以***（6〇毫升）稀釋，攪 拌20分叙，並經過矽藻土過濾，以***洗滌。將濾液以含 有Na2S2〇3(500毫克）之飽和NaHC〇3(2〇毫升）洗滌，並將水相 以2x25笔升***逆萃取。使合併之有機層以s〇4脫水乾燥 ，過濾，濃縮，並使產物藉層析純化（1〇至3〇% Et〇Ac_己烷） ，提供19 (5_二-(第三-丁氧羰基）胺基-7-(1-第三-丁氧羰基彳甲 醯基-1H-啕哚-2-基）-2-甲基-咪唑并[4,5七]吡啶各羧酸第三·丁酯 ，117 毫克，96%)。Add 17 (as 5-bis (tertiary-butoxycarbonyl) amino ... Tertiary-butoxycarbonyl net hydroxymethyl-1H-indole-2-yl) _2_methyl-imidazo [4,5 7) Pyridyl carboxylic acid, tertiary butadiene, as an example, a mixture of 122 耄 g, millimoles) and Dess Martin over sintered (223 * g, 3.0 equivalents) in dichloromethane (4ml) Stir for 1 hour at room temperature. The resulting mixture was diluted with ether (60 ml), stirred for 20 minutes, filtered through celite, and washed with ether. The filtrate was washed with saturated NaHC03 (20 ml) containing Na2S203 (500 mg), and the aqueous phase was back-extracted with 2 x 25 liters of ether. The combined organic layers were dried over sodium sulfate, filtered, concentrated, and the product was purified by chromatography (10 to 30% EtoAc_hexane) to provide 19 (5-di- (third-butane) Oxycarbonyl) amino-7- (1-tert-butoxycarbonylmethylmethylfluorenyl-1H-pyridin-2-yl) -2-methyl-imidazo [4,5hepta] pyridine Tributyl ester, 117 mg, 96%).

將KMn〇4(436毫克，2當量）與ΚΗ2Ρ04(563毫克，3當量）在 85762 -123- 200412345 水（15毫升）中之溶液，於室溫下，在3分鐘期間，添加至19( 以5-二-(第三-ΐ氧羰基）胺基-7-(1_第三_丁氧羰基_5_甲醯基_既 ⑼嗓-2-基）-2_甲基-咪唑并[4,5-b]吡啶_3邊酸第三_丁酯為實例， 958毫克，L38毫莫耳）在tBuOH(10毫升）中之溶液内，並將所 形成之混合物攪拌30分鐘。然後，將混合物以Et〇Ac (2〇毫升） 稀釋，經過矽藻土過濾，以EtOAc洗滌。以鹽水（6〇毫升）、 水（40毫升）及EtOAc (200毫升）稀釋濾液。將已分離之水相以 3x30毫升EtOAc萃取。使合併之有機層以Na2 S04脫水乾燥， 過濾，濃縮，並使產物藉層析純化（30至1〇〇% EtOAc /己燒） ，提供20(2-(3-第三-丁基羰基-5-二-(第三-丁基羰基）胺基冬甲 基-3H-味峻并[4,5-b]p比淀-7-基卜朵-1，5-叛酸1_第三-丁酉旨，678 毫克，69% )。A solution of KMnO4 (436 mg, 2 eq.) And KZ2P04 (563 mg, 3 eq.) In 85762-123- 200412345 water (15 ml) was added to 19 (to 5-di- (tertiary-fluorenyloxycarbonyl) amino-7- (1-tertiary_butoxycarbonyl_5_methylfluorenyl_bothyl-2-yl) -2_methyl-imidazo [ An example of 4,5-b] pyridine 3-acid tert-butyl ester, 958 mg, L38 mmol) in a solution of tBuOH (10 ml), and the resulting mixture was stirred for 30 minutes. The mixture was then diluted with EtoAc (20 mL), filtered through celite, and washed with EtOAc. The filtrate was diluted with brine (60 ml), water (40 ml) and EtOAc (200 ml). The separated aqueous phase was extracted with 3x30 ml of EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated, and the product was purified by chromatography (30 to 100% EtOAc / hexane) to provide 20 (2- (3-tert-butylcarbonyl- 5-bis- (tertiary-butylcarbonyl) amino acetomethyl-3H-weijun and [4,5-b] p biyodo-7-kibodol-1,5-metanoic acid 1_third -Ding Yizhi, 678 mg, 69%).

於室溫下，將（單-或二-)取代之苄氯化物（或溴化物）或溴 基甲基蓁或氯基甲基吡啶鹽酸鹽（20毫莫耳）與甲胺（22毫升 ，在水中之40%，10當量）在MeOH (18毫升）中之混合物，攪 拌1-5天，直到反應完成為止。於濃縮後，將反應混合物以 飽和NaHCO3(50毫升）稀釋，以EtOAc萃取，直到沒有產物被 檢出為止。使合併之萃液以Na2S04脫水乾燥，過濾濃縮，而 传產物21。 85762 -124- 200412345Combine (mono- or di-) benzyl chloride (or bromide) or bromomethylphosphonium or chloromethylpyridine hydrochloride (20 mmol) with methylamine (22 ml) at room temperature (40% in water, 10 equivalents) in MeOH (18 mL), and stirred for 1-5 days until the reaction is complete. After concentration, the reaction mixture was diluted with saturated NaHCO3 (50 mL) and extracted with EtOAc until no product was detected. The combined extracts were dried over Na2S04, filtered and concentrated to give product 21. 85762 -124- 200412345

胺類22-26係按照揭示於已公告之PCT申請案WO 01/00610 A1 中之修正程序製成。Amines 22-26 are made in accordance with the amendment procedure disclosed in published PCT application WO 01/00610 A1.

將氯化甲烷磺醯（0.80毫升，1.2當量），於0°C下，添加至2-( 乙基-苯基-胺基）-乙醇（1.43克，8.65毫莫耳）與二異丙基乙胺 (3.0毫升，2.0當量）在二氯甲烷（10毫升）中之溶液内，並將所 形成之混合物攪拌15分鐘。然後，引進氨溶液（20毫升，2 Μ ，在MeOH中），並將所形成之混合物於室溫下攪拌五天，及 濃縮。將殘留物以HC1溶液（7毫升，1 N)稀釋，並以3xEtOAc 洗滌。將水相以NaOH溶液（15毫升，1 N)處理，並以EtOAc萃 取一次。使萃液以Na2S04脫水乾燥，過濾，濃縮，而得產物 27 〇Methanesulfonium chloride (0.80 ml, 1.2 equivalents) was added to 2- (ethyl-phenyl-amino) -ethanol (1.43 g, 8.65 mmol) and diisopropyl at 0 ° C. Ethylamine (3.0 ml, 2.0 equivalents) in a solution of dichloromethane (10 ml), and the resulting mixture was stirred for 15 minutes. Then, an ammonia solution (20 ml, 2 M in MeOH) was introduced, and the resulting mixture was stirred at room temperature for five days, and concentrated. The residue was diluted with HC1 solution (7 mL, 1 N) and washed with 3xEtOAc. The aqueous phase was treated with NaOH solution (15 mL, 1 N) and extracted once with EtOAc. The extract was dried over Na2S04, filtered, and concentrated to give product 27.

於2-芊氧基-丙烷-1，3-二醇（5.0克，27.4毫莫耳）在5: 1 THF-DMF (200毫升）中之溶液内，在Ot：下，添加NaH (1.5克，2.3當量） ，接著是碘化甲烷（5.1毫升，3.0當量）。將所形成之白色漿 85762 -125- 200412345 液混合物，於室溫下攪拌度過週末。以飽和NH4 Cl使反應混 合物淬滅，以BtOAc萃取，以Na2S04脫水乾燥，過濾，濃縮 ，並使產物藉層析純化（50% EtOAc /己烷），獲得（2-甲氧基小 甲氧基甲基_2_乙氧基甲基）-苯（5.6克，97% )。 將（2-甲氧基-1-甲氧基甲基-2-乙氧基甲基）-苯（5.5克）與Pd(0H)2 (0.4克）在MeOH (150毫升）中之混合物，於室溫及氫氣下攪拌 ，直到反應完成為止。過滤反應混合物，及濃縮，而得1，3-二甲氧基-丙-2-醇（3.0克，96% )。 於〇°C下，將氯化甲烷磺醯（0.61毫升，2.0當量）添加至1，3-二 甲氧基-丙-2-醇（0.50克，4.14毫莫耳）與三乙胺（2.3毫升，4.0當 量）在二氯甲烷（2毫升）中之溶液内，並將所形成之混合物攪 拌15分鐘。藉由飽和NaHC03使反應淬滅，並以EtOAc萃取混 合物。使合併之萃液以Na2 S〇4脫水乾燥，過滤，及濃縮。使 殘留物與NaN3(0.80克，3.0當量）溶於DMSO(10毫升）中，並在 90°C下加熱度過週末。於冷卻至室溫後，將混合物以飽和 NaHC03稀釋，並以***萃取。使合併之萃液以Na2S04脫水乾 燥，過濾，及濃縮，而得疊氮化物中間物（320毫克，48% )。 將疊氮化物中間物（320毫克）與Pd(OH)2在MeOH (15毫升）中 之混合物，於室溫及氫氣下，攪拌1小時。過滤反應混合物 ，及濃縮，而得28 (150毫克，63%)。 85762In a solution of 2-methoxy-propane-1,3-diol (5.0 g, 27.4 mmol) in 5: 1 THF-DMF (200 ml), under Ot :, NaH (1.5 g , 2.3 equivalents), followed by methane iodide (5.1 ml, 3.0 equivalents). The resulting white slurry 85762 -125- 200412345 was stirred at room temperature over the weekend. The reaction mixture was quenched with saturated NH4Cl, extracted with BtOAc, dried over Na2S04, filtered, concentrated, and the product was purified by chromatography (50% EtOAc / hexane) to obtain (2-methoxysmallmethoxy) Methyl-2-ethoxymethyl) -benzene (5.6 g, 97%). A mixture of (2-methoxy-1-methoxymethyl-2-ethoxymethyl) -benzene (5.5 g) and Pd (0H) 2 (0.4 g) in MeOH (150 ml), Stir at room temperature under hydrogen until the reaction is complete. The reaction mixture was filtered and concentrated to give 1,3-dimethoxy-propan-2-ol (3.0 g, 96%). Methanesulfonium chloride (0.61 ml, 2.0 equivalents) was added to 0,3-dimethoxy-prop-2-ol (0.50 g, 4.14 mmol) and triethylamine (2.3 Ml, 4.0 equivalents) in a solution of dichloromethane (2 ml), and the resulting mixture was stirred for 15 minutes. The reaction was quenched by saturated NaHC03, and the mixture was extracted with EtOAc. The combined extracts were dried over Na2SO4, filtered, and concentrated. The residue was dissolved in DMSO (10 ml) with NaN3 (0.80 g, 3.0 eq.) And heated at 90 ° C over the weekend. After cooling to room temperature, the mixture was diluted with saturated NaHC03 and extracted with ether. The combined extracts were dried over Na2S04, filtered, and concentrated to give the azide intermediate (320 mg, 48%). A mixture of the azide intermediate (320 mg) and Pd (OH) 2 in MeOH (15 ml) was stirred at room temperature under hydrogen for 1 hour. The reaction mixture was filtered and concentrated to give 28 (150 mg, 63%). 85762

-126- 200412345 將乙基-苯基-胺（4.15毫升，33毫莫耳）、3-溴丙烯（4.3毫升 ，1.5當量）及$2C03(9.1克，2.0當量）在丙酮（50毫升）中之混 合物，於回流下加熱過夜。於冷卻至室溫後，將反應混合 物以水（50毫升）與EtOAc (100毫升）稀釋。使已分離之有機相 以NazSO4脫水乾燥，過濾，並濃縮，且使產物藉層析純化（1〇 % EtOAc /己烷），獲得晞丙基-乙基-苯基-胺（5.32克，1〇〇% )。 於室溫下，將0s04溶液（7.8毫升，0·1 Μ，在水中，〇·〇3當量） 添加至晞丙基-乙基-苯基-胺（4.10克，25.3毫莫耳）與ΝΜΟ (5.92 克，2.0當量）在9 : 1丙酮-水（40毫升）中之混合物内，並將所 形成之混合物攪拌過夜。將混合物以飽和NaHC03 (80毫升）、 飽和Na2S2〇3(20毫升）及1 : 1 Et20-己烷（100毫升）稀釋。以2〇〇 毫升EtOAc萃取已分離之水相，並使合併之有機相以Na2 s〇4 脫水乾燥’過濾，並濃縮，且使產物藉層析純化（3〇% Et〇Ac-己：fe) ’而得3-(乙基-苯基胺基）-丙燒-i，2_二醇（4.25克，86%)。 於JO至-35 C下’將氣化甲續驢（2.5毫升，1.5當量）添加 至3-(乙基-麥基-胺基）_丙虎-i，2-二醇（4.22克，21.6毫莫耳）與三 乙胺（9.03毫升，3.0當量）在二氯甲烷（20毫升）中之溶液内， 並攪拌所形成之混合物，及溫熱至〇。<：。藉由飽和NaHC〇3(3〇 毫升）使反應淬滅’並將已分離之水相以2x20毫升ch2 CI2與20 毫升EtOAc萃取。使合併之萃液以Na2s〇4脫水乾燥，過滤， 及丨辰知§。使殘留物落於MeOH (30晕升）中，並在65-70°C下， 以NaOMe(2.3克，2.0當量）處理3小時。於冷卻至室溫後，將 混合物以飽和NaHCCMSO毫升）稀釋，並以3x3〇毫升Et〇Ac萃 取。使合併之萃液以N^SO4脫水乾燥，過滤，並濃縮，且使 85762 -127- 200412345 產物藉層析純化（10% EtOAc /己烷），獲得乙基_環氧乙燒基 甲基·苯基_胺（1:72克，45%)。 於回流下’將乙基-環氧乙fe基甲基-苯基-胺（1.72克，9 65 毫莫耳）與NaOMe (1.04克，2.0當量）在MeOH (8毫升）中之溶液 ’加熱度過週末。於冷卻至室溫後，將混合物以飽和NaHC〇3 (20毫升）稀釋，並以3x20毫升EtOAc萃取。使合併之萃液以 NazSO4脫水乾燥，過濾，並濃縮，且使產物藉層析純化（3〇%-126- 200412345 Put ethyl-phenyl-amine (4.15 ml, 33 mmol), 3-bromopropene (4.3 ml, 1.5 eq) and $ 2C03 (9.1 g, 2.0 eq) in acetone (50 ml) The mixture was heated at reflux overnight. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and EtOAc (100 mL). The separated organic phase was dried over NazSO4, filtered, and concentrated, and the product was purified by chromatography (10% EtOAc / hexane) to give propyl-ethyl-phenyl-amine (5.32 g, 1 〇〇%). At room temperature, a solution of 0S04 (7.8 ml, 0.1 M in water, 0.03 equivalent) was added to propyl-ethyl-phenyl-amine (4.10 g, 25.3 mmol) and NMΟ (5.92 g, 2.0 equivalents) in a 9: 1 acetone-water (40 ml) mixture, and the resulting mixture was stirred overnight. The mixture was diluted with saturated NaHC03 (80 ml), saturated Na2S203 (20 ml) and 1: 1 Et20-hexane (100 ml). The separated aqueous phase was extracted with 200 mL of EtOAc, and the combined organic phases were dried over Na2s04, filtered, and concentrated, and the product was purified by chromatography (30% EtoAc-Hex: fe ) 'To give 3- (ethyl-phenylamino) -propane-i, 2-diol (4.25 g, 86%). Add gasified formazan (2.5 ml, 1.5 eq.) To 3- (ethyl-mycyl-amino) _propyl tiger-i, 2-diol (4.22 g, 21.6) at JO to -35 C MM) and triethylamine (9.03 ml, 3.0 eq.) In dichloromethane (20 ml), and the resulting mixture was stirred and warmed to zero. <:. The reaction was quenched 'by saturated NaHC03 (30 mL) and the separated aqueous phase was extracted with 2 x 20 mL of ch2 CI2 and 20 mL of EtOAc. The combined extracts were dried over Na 2 SO 4, filtered, and known. The residue was dropped in MeOH (30 liters) and treated with NaOMe (2.3 g, 2.0 equivalents) at 65-70 ° C for 3 hours. After cooling to room temperature, the mixture was diluted with saturated NaHCCMS (mL) and extracted with 3x30 mL of EtoAc. The combined extracts were dried over N ^ SO4, filtered, and concentrated, and the 85762 -127- 200412345 product was purified by chromatography (10% EtOAc / hexane) to obtain ethyl-ethylene oxide ethyl methyl. Phenylamine (1:72 g, 45%). 'Heat a solution of ethyl-ethylene glycol-methyl-phenyl-amine (1.72 g, 9 65 mmol) and NaOMe (1.04 g, 2.0 eq.) In MeOH (8 mL) under reflux. Spend the weekend. After cooling to room temperature, the mixture was diluted with saturated NaHC03 (20 mL) and extracted with 3 x 20 mL of EtOAc. The combined extracts were dried over NazSO4, filtered, and concentrated, and the product was purified by chromatography (30%

EtOAc-己烷），而得1-(乙基-苯基-胺基）_3_甲氧基_丙_2_醇（195克 ，97%) 〇 將K乙基-苯基-胺基）-3·甲氧基-丙_2_醇（1.95克，9·32毫莫耳） 與ΝΜΟ (2.18克，2.0當量）在二氯甲烷（15毫升）中之溶液，於 室溫下，以ΤΡΑΡ(150毫克，0.05當量）處理，直到反應完成為 止。將反應混合物以飽和NaHC〇3 (50毫升）稀釋，並以3χ3〇毫 升EtOAc萃取。使合併之萃液以Na2S〇4脫水乾燥，過滤，並 濃縮，且使產物藉層析純化（1〇至15% Et0Ac_己烷），獲得 乙基-苯基-胺基）-3-甲氧基-丙·2-酮（0.98毫克，51% )。 於室溫下，將1-(乙基-苯基-胺基）_3-:甲氧基-丙1酮（17毫克 ，0.08毫莫耳）、羥胺鹽酸鹽（30毫克）與吡啶（〇·3毫升）在撕册 (0.4毫升）中之混合物，攪拌ι·5小時。將反應混合物以飽和 NaHC〇3稀釋，並以3xEtOAc萃取。使合併之萃液以Na2S〇4脫 水乾燥，過濾，及濃縮。使殘留物溶於THF (〇·8毫升）中，並 在室溫下，以氫化鋰鋁（〇·3毫升，1 μ，在THF中）處理過夜 。處理並藉層析純化（5 : 95比例之MeOH中之2 MNH3 : CH2C12) ，獲得29，為淡黃色油。 85762 -128- 200412345EtOAc-hexane) to give 1- (ethyl-phenyl-amino) _3-methoxy_propan-2-ol (195 g, 97%) (K ethyl-phenyl-amino) -3 · methoxy-propan-2-ol (1.95 g, 9.32 mmol) and NMIO (2.18 g, 2.0 equivalents) in dichloromethane (15 ml) at room temperature to TAPAP (150 mg, 0.05 equivalent) was processed until the reaction was complete. The reaction mixture was diluted with saturated NaHC03 (50 mL) and extracted with 3 x 30 mL of EtOAc. The combined extracts were dried over Na2SO4, filtered, and concentrated, and the product was purified by chromatography (10 to 15% EtAc_hexane) to give ethyl-phenyl-amino) -3-form Oxy-propan-2-one (0.98 mg, 51%). At room temperature, 1- (ethyl-phenyl-amino) _3-: methoxy-propanone (17 mg, 0.08 mmol), hydroxylamine hydrochloride (30 mg), and pyridine ( 3 ml) of the mixture in a torn book (0.4 ml) and stirred for 5 hours. The reaction mixture was diluted with saturated NaHC03 and extracted with 3xEtOAc. The combined extracts were dried over Na2SO4, filtered, and concentrated. The residue was dissolved in THF (0.8 ml) and treated with lithium aluminum hydride (0.3 ml, 1 µ in THF) at room temperature overnight. Work up and purify by chromatography (5:95 ratio of 2 MNH3: CH2C12 in MeOH) to obtain 29 as a pale yellow oil. 85762 -128- 200412345

30 化合物30係按照關於從3-(乙基苯基-胺基）_丙烷q，2_二醇製 備29之相同程序，製自3-苯氧基-丙燒-i，2-二醇，21%總產率。30 Compound 30 is prepared from 3-phenoxy-propane-i, 2-diol according to the same procedure as for the preparation of 29 from 3- (ethylphenyl-amino) -propane q, 2-diol. 21% overall yield.

31 32 將MeOH中之3-(溴-丙基）-苯或溴基甲基·環己燒（丨μ，1.0當 量）與40% MeNH2(60當量）在水中之混合物，於室溫或45°c下 攪拌’直到反應完成為止。於冷卻至室溫後，使混合物濃 縮，並將殘留物以飽和NaHC03稀釋，並以3xCh2C12(及/或3x EtOAc)萃取。使合併之萃液以Na2 s〇4脫水乾燥，過滤，及濃 縮，而得31或32。 CTr : · 33 於〇°C下，將氣化甲烷磺醯（〇·8毫升，1.0當量）添加至環戊 基-甲醇（U毫升，1.0當量）與乙基二異丙胺（3.9毫升，10當 量）在CI^Cl2 (5毫升）中之混合物内，並攪拌所形成之混合物 ’及溫熱至室溫。於添加飽和NaHC03後，將已分離之水相 以CI^Cl2萃取，並使合併之有機層濃縮，而得粗製甲烷磺酸 酿中間物。然後將此甲烷磺酸酯按照關於製備31/32之相同 程序，以MeNH2處理，獲得33。 85762 -129- 20041234531 32 A mixture of 3- (bromo-propyl) -benzene or bromomethylcyclohexane (丨 μ, 1.0 equivalent) and 40% MeNH2 (60 equivalent) in water in MeOH at room temperature or 45 Stir at ° c until the reaction is complete. After cooling to room temperature, the mixture was concentrated and the residue was diluted with saturated NaHC03 and extracted with 3xCh2C12 (and / or 3x EtOAc). The combined extracts were dried over Na2s04, filtered, and concentrated to give 31 or 32. CTr: · 33 At 0 ° C, gasified methanesulfonium (0.8 mL, 1.0 equivalent) was added to cyclopentyl-methanol (U mL, 1.0 equivalent) and ethyldiisopropylamine (3.9 mL, 10 (Equivalent) in a mixture of CI ^ Cl2 (5 ml), and the resulting mixture was stirred and warmed to room temperature. After the addition of saturated NaHC03, the separated aqueous phase was extracted with CI ^ Cl2, and the combined organic layers were concentrated to obtain a crude methanesulfonic acid intermediate. This methanesulfonate was then treated with MeNH2 following the same procedure as for 31/32 to obtain 33. 85762 -129- 200412345

於〇°C下，將TiCl4在(¾%中之溶液（1 μ，1.56毫莫耳）添加 至1，2-二苯基-乙酮（307毫克，1.56毫莫耳）、Et3N (655微升）及 甲胺（1·02毫升）在THF (5毫升）中之混合物内。攪拌15小時後 ’添加NaBH4 (280毫克’ 37.8毫莫耳）在MeOH (8毫升）中之溶 液，並將所形成之混合物攪拌2小時。然後，添加飽和Na2C03 ，並將反應混合物儲存於冷凍庫中過夜。於解凍後，移除 有機層，並將水相以3xCH2C12萃取。使合併之有機相以Na2S〇4 脫水乾燥，過濾，及濃縮。藉預備之薄層層析法純化（8〇% Et〇Ac /己烷），提供34 (195毫克，59% )。 化合物35與36係以類似方式，個別製自2-甲氧基小苯基-乙 酮與環庚酮。At 0 ° C, a solution of TiCl4 in (¾% (1 μ, 1.56 mmol)) was added to 1,2-diphenyl-ethanone (307 mg, 1.56 mmol), Et3N (655 μm L) and methylamine (1.02 ml) in a mixture of THF (5 ml). After stirring for 15 hours, a solution of 'NaBH4 (280 mg' 37.8 mmol) in MeOH (8 ml) was added and The resulting mixture was stirred for 2 hours. Then, saturated Na2C03 was added and the reaction mixture was stored in a freezer overnight. After thawing, the organic layer was removed and the aqueous phase was extracted with 3xCH2C12. The combined organic phases were treated with Na2S04. Dehydrate, dry, filter, and concentrate. Purified by preparative thin-layer chromatography (80% EtoAc / hexane) to provide 34 (195 mg, 59%). Compounds 35 and 36 were prepared in a similar manner, individually. From 2-methoxy-small phenyl-ethanone and cycloheptanone.

39 於Boo去甲顛茄酮（0·5克，2·2毫莫耳，L0當量）在cH2Cl2(1〇 毫升）中之溶液内，添加TFA (10毫升）。將反應混合物揽拌2 小時’然後濃縮。於添加EtOAc與飽和NaHC03後，以3xEt〇Ac 年取反應混合物。使合併之有機層以SO4脫水乾燥，過滤 ，及濃縮，而得37 (0_25克）。 HOv ΥΛη 85762 -130- 38 200412345 於❻二氫-㈣]遗酸苯酿（2克，ι〇毫莫耳，ι〇當量）在丙 酉同/水（9: H·毫升）中之溶液内，添加〇S〇4(在水中之4%， 1¾升）與ΝΜΟ(2·3克，20毫莫耳，2當量）。將混合物於室溫 下k拌過夜，；辰縮，以移除大部份丙酮，倒入飽和NaHcc^ 中’並以3xEtOAc萃取。使合併之有機層以脫水乾燥 ’過滤’ 1濃縮。使粗製混合物藉碎膠層析純化（7()%至9〇% EtOAc-己烷）’而彳于3,4-二羥基_四氫吡咯小羧酸苯酯（2 〇4克，88 %)。 於3,4-二羥基-四氫吡咯小羧酸笨酯（1·93克，81毫莫耳，1〇 當量）在Me〇H(2〇毫升）中之溶液内，添加氫氧化免，並在Η2 下放置4小時。經過矽藻土濾出觸媒，並以Me〇H沖洗。使 濾液濃縮（25 C )，獲得38，為帶紅色油（84〇毫克，1〇〇% )。 39 於NaH(8.99克，0.225莫耳，4.6當量）在DME(70毫升）中之懸 浮液内，在0°C下，忮忮添加1，4-二氧-螺[4·5]癸冬酮（7·56克，〇 〇48 莫耳，1·0當量）在DME (24毫升）中之溶液。攪拌3〇分鐘後， 於7小時内，慢慢引進Mel (14毫升，〇·225莫耳，4·6當量）在dme (70耄升）中之么液，並使所开> 成之混合物慢慢溫熱至室溫， 及攪拌過夜。藉由緩慢添加水使反應淬滅，直到不再發現 起泡為止。將反應混合物傾倒於冰水上，並以3χ己燒萃取 。將有機層合併，以Mgs〇4脫水乾燥，過濾，及濃縮。使粗 製混合物藉層析純化（1⑻％己燒，以移除油，然後是5 : 1己 85762 - 131 - 200412345 烷-EtOAc)，而得 7,7,9,9_四甲基-1，4-二氧-螺[4·5]癸-8-酮（4·16 克， 40%)。 —· 於 7,7,9,9-四甲基 _1，4_二氧螺[4.5]癸-8-酮（4.15 克，0.019 莫耳，1.〇 當量）在THF (60毫升）中之溶液内，添加1NHQ (3〇毫升），並 將所形成之混合物於室溫下攪拌過夜，濃縮，以移除大部 份THF，以3xEtOAc萃取。將有機層合併，以MgS〇4脫水乾燥， 過濾，及濃縮，而得2,2,6,6-四甲基-環己烷-i，4-dione，為白色 固體（3.43 克，>100% )。 於2,2,6,6-四甲基-環己燒-i，4-二嗣（〇·4〇克，2.4毫莫耳，ι·〇當 量）在THF (8毫升）中之溶液内，添加分子篩（4Α，8〇毫克）、 MeNH2在THF中之2 Μ溶液（1.3毫升，2.6毫莫耳，1.1當量）及 AcOH(0.17毫升，3.0毫莫耳，1.2當量）。攪拌5分鐘後，添加 NaBH(OAc)3(0_71克，3.33毫莫耳，L4當量），並將所形成之混 合物於▲溫下攪拌過夜。藉由添加飽和NaHC03使反應淬滅 。然後使混合物濃縮，並以3xEtOAc萃取水層。將合併之有 機層以飽和NaHC〇3洗滌一次，以MgS04脫水乾燥，過濾，及 濃縮’獲得粗製淡黃色油，使其結晶，而·得39，為白色結晶（〇 4〇 克，>100%)。39 To a solution of Boo norbone solone (0.5 g, 2.2 mmol, L0 equivalent) in cH2Cl2 (10 ml), add TFA (10 ml). The reaction mixture was stirred for 2 hours' and then concentrated. After the addition of EtOAc and saturated NaHC03, the reaction mixture was taken at 3xEtoAc. The combined organic layers were dried over SO4, filtered, and concentrated to give 37 (0-25 g). HOv ΥΛη 85762 -130- 38 200412345 Yudidihydro-Hydroxy] benzoic acid benzene (2 g, ιοmmol, ιο equivalent) in a solution of acetone / water (9: H · ml) Add 0SO4 (4% in water, 1¾ liters) and NM0 (2.3 grams, 20 millimoles, 2 equivalents). The mixture was stirred overnight at room temperature; it was condensed to remove most of the acetone, poured into saturated NaHcc ^ 'and extracted with 3xEtOAc. The combined organic layers were dehydrated and dried 'filtered' 1 and concentrated. The crude mixture was purified by crushing gel chromatography (7 ()% to 90% EtOAc-hexanes) and purified by 3,4-dihydroxy-tetrahydropyrrole small carboxylic acid phenyl ester (204 g, 88%). ). To a solution of 3,4-dihydroxy-tetrahydropyrrole carboxylic acid benzyl ester (1.93 g, 81 mmol, 10 eq.) In MeOH (20 ml), add hydrogen peroxide, And let stand for 4 hours under Η2. The catalyst was filtered through diatomaceous earth and washed with MeOH. The filtrate was concentrated (25 C) to give 38 as a reddish oil (84 mg, 100%). 39 In a suspension of NaH (8.99 g, 0.225 moles, 4.6 equivalents) in DME (70 ml), add 1,4-dioxo-spiro [4 · 5] decidone at 0 ° C. A solution of ketone (7.56 g, 0.0048 mol, 1.0 equivalent) in DME (24 ml). After stirring for 30 minutes, slowly introduce Mel (14 ml, 0.225 mol, 4.6 eq.) In dme (70 liters) over 7 hours, and let it open > The mixture was slowly warmed to room temperature and stirred overnight. The reaction was quenched by slowly adding water until no more foaming was found. The reaction mixture was poured onto ice water and extracted with 3xhexane. The organic layers were combined, dried over MgS04, filtered, and concentrated. The crude mixture was purified by chromatography (1% hexanes to remove oil, then 5: 1 hexanes 85762-131-200412345 alkane-EtOAc) to give 7,7,9,9_tetramethyl-1, 4-Dioxo-spiro [4 · 5] dec-8-one (4.16 g, 40%). — · In 7,7,9,9-tetramethyl_1,4-dioxospiro [4.5] dec-8-one (4.15 g, 0.019 mol, 1.0 equivalent) in THF (60 ml) To the solution, 1NHQ (30 ml) was added, and the resulting mixture was stirred at room temperature overnight, concentrated to remove most of the THF, and extracted with 3xEtOAc. The organic layers were combined, dried over MgS04, filtered, and concentrated to give 2,2,6,6-tetramethyl-cyclohexane-i, 4-dione as a white solid (3.43 g, > 100%). In a solution of 2,2,6,6-tetramethyl-cyclohexane-i, 4-difluorene (0.40 g, 2.4 mmol, ι.e equivalent) in THF (8 mL) Add molecular sieves (4A, 80 mg), a 2 M solution of MeNH2 in THF (1.3 ml, 2.6 mmol, 1.1 eq) and AcOH (0.17 ml, 3.0 mmol, 1.2 eq). After stirring for 5 minutes, NaBH (OAc) 3 (0-71 g, 3.33 mmol, L4 equivalent) was added, and the resulting mixture was stirred at ▲ overnight. The reaction was quenched by the addition of saturated NaHC03. The mixture was then concentrated and the aqueous layer was extracted with 3xEtOAc. The combined organic layers were washed once with saturated NaHC0, dried over MgS04, filtered, and concentrated to obtain a crude pale yellow oil, which crystallized to give 39 as white crystals (0.40 g,> 100 %).

〇 40 於甲基三苯基溴化鱗（17克，h5當量）在THF (100毫升）中之 溶液内，在0°c下，逐滴添加正-丁基鋰（2.5 Μ，在己烷中，18 毫升’ 1.4當量），並將所形成之混合物攪拌1小時。然後， 85762 -132- 200412345 逐滴引進1，4-二氧_螺[4.5]癸_8_酮（5.0克，32毫莫耳，1.0當量） 在THF (10毫升):中之溶液，並使所形成之混合物溫熱至室溫 ，及攪拌過夜。藉由添加飽和NaHC〇3使反應淬滅，並將已 分離之水層以4xEtOAc萃取。使合併之有機相以Na2S〇4脫水 乾燥，過濾’及濃縮。使殘留物藉層析純化（5%至1〇% Et〇Ac /己烷）’獲得8-亞甲基4,4_二氧-螺[屯5]癸烷（3.92克，79% )。 於8-亞甲基-1，4-二氧-螺[45]癸烷（2〇克，13毫莫耳，ι·〇當量） 在THF (10毫升）中之溶液内，在下，逐滴添加9_ββν (〇 5 μ ，在THF中，104毫升，4.〇當量），並將所形成之混合物攪拌 15分鐘，然後溫熱至室溫，及攪拌過夜。接著，於下， 分次引進NaBCU ·4Η2〇(32克，16當量），並使所形成之混合 物溫熱至室溫，及攪拌過夜，以己烷（3〇毫升）稀釋，並以Et〇Ac 萃取已分離之水相。使合併之有機相以Na2S〇4脫水乾燥，過 遽，及濃縮。使殘留物藉矽膠層析純化（5〇%至1〇〇% Et〇Ac_ 己烷），而得（1，4-二氧螺[4.5]癸_8_基）-甲醇（1·5克，67%)。 於（1，4-二氧-螺[4·5]癸-8-基）-甲醇（10克，58毫莫耳，1〇當量） 與乙基二異丙基胺（17毫升，3·〇當量）:在二氯甲烷（4毫升）中 之溶液内，於0°C下，逐滴添加MsC1(0.46毫升，1〇當量），並 使所形成之混合物溫熱至室溫，及攪拌2小時。藉由添加飽 和NaHC〇3使反應淬滅，並將已分離之水相以叔二氯甲烷與 4xEt〇Ac萃取。使合併之有機相以Ν々3〇4脫水乾燥，過濾， 及濃縮，獲得粗製甲烷磺酸丨，4_二氧_螺[4 5]癸各基甲酯。 一於回流下，將粗製甲烷磺酸Μ_二氧噶[4·5]癸冬基甲酉旨（4〇〇 毫克）在MeOH(2毫升）與MeNH2水溶液(4〇%w/w，5毫升）中之 85762 -133- 200412345 混合物，加熱（60°C油）過夜。藉由添加飽和NaHC〇3使反應淬 滅，並將已分離之水相以4x二氯甲烷與4xEtOAc萃取。使合 併之有機相以NazSO4脫水乾燥，過濾，及濃縮，而得粗製4〇 ’為褐色油。 ·〇40 In a solution of methyltriphenyl bromide scale (17 g, h5 equivalents) in THF (100 ml), n-butyllithium (2.5 M in hexane was added dropwise at 0 ° C. Medium, 18 ml '1.4 equivalent), and the resulting mixture was stirred for 1 hour. Then, 85762 -132- 200412345 dropwise introduced a solution of 1,4-dioxospiro [4.5] dec_8_one (5.0 g, 32 mmol, 1.0 equivalent) in THF (10 ml): and The resulting mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched by the addition of saturated NaHC03, and the separated aqueous layer was extracted with 4xEtOAc. The combined organic phases were dried over Na2SO4, filtered 'and concentrated. The residue was purified by chromatography (5% to 10% EtoAc / hexane) 'to obtain 8-methylene 4,4-dioxo-spiro [tun5] decane (3.92 g, 79%). In a solution of 8-methylene-1,4-dioxo-spiro [45] decane (20 g, 13 mmol, ι · e equivalent) in THF (10 mL), dropwise, dropwise 9_ββν (05 μ in THF, 104 mL, 4.0 equivalents) was added, and the resulting mixture was stirred for 15 minutes, then allowed to warm to room temperature, and stirred overnight. Next, NaBCU · 4.20 (32 g, 16 eq) was introduced in portions, and the resulting mixture was allowed to warm to room temperature and stirred overnight, diluted with hexane (30 ml), and Et. Ac extracts the separated aqueous phase. The combined organic phases were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (50% to 100% EtOAc_hexane) to obtain (1,4-dioxo [4.5] dec_8_yl) -methanol (1.5 g , 67%). In (1,4-dioxo-spiro [4 · 5] dec-8-yl) -methanol (10 g, 58 mmol, 10 equivalents) and ethyldiisopropylamine (17 ml, 3 · (Equivalent): In a solution in dichloromethane (4 ml), MsC1 (0.46 ml, 10 equivalents) was added dropwise at 0 ° C, and the resulting mixture was allowed to warm to room temperature, and stirred. 2 hours. The reaction was quenched by the addition of saturated NaHC03, and the separated aqueous phase was extracted with tert-dichloromethane and 4xEtoAc. The combined organic phases were dried over NH 3 04, filtered, and concentrated to give the crude methanesulfonic acid, 4-dioxo-spiro [4 5] decyl methyl ester. Once at reflux, the crude methanesulfonic acid M_dioxa [4.5] decylmethylformamidine (400 mg) in MeOH (2 ml) and MeNH2 aqueous solution (40% w / w, 5 Ml) of 85762-133-200412345 mixture, heated (60 ° C oil) overnight. The reaction was quenched by the addition of saturated NaHC03, and the separated aqueous phase was extracted with 4x dichloromethane and 4x EtOAc. The combined organic phases were dried over NazSO4, filtered, and concentrated to give crude 40 'as a brown oil. ·

於4-酮基-六氫吡啶小羧酸苄酯（〇·5〇克，214毫莫耳，1〇當 量）在THF (20毫升）中之溶液内，在_3〇°c下，添加二溴基二敦 甲烷（0·90毫升，4.5當量），接著是HMPA (1.75毫升，4.5當量） 。和除冷卻浴，並使反應混合物週期性地旋滿打轉。3〇分 鐘後，添加鋅粉（0.63克，4.5當量）與ΗΜΡΑ (80微升，〇·4當量） ’並將混合物於回流下加熱18小時。於冷卻至室溫後，將 殘留物以***洗滌數次。將合併之醚洗液連續以硫酸銅（π) 飽和水溶液、鹽水洗滌，以Na2 S04脫水乾燥，及濃縮。使殘 留物藉層析純化（20% EtOAc-己烷），而得4-二氟亞甲基-六氫 吡啶-1-羧酸芊酯（0.32克，56% )，為無·色油。 和4- 一氟亞甲基-六氮外b咬-1-叛酸爷醋（269毫克）與Pearlman 氏觸媒在甲醇（2.5毫升）中之混合物，於氫大氣（使用以氫充 填之氣瓶）及室溫下，攪拌4小時。將反應混合物經過矽藻 土過遽’並使漉液濃縮，獲得41 (138毫克），為淡黃色油。To a solution of 4-keto-hexahydropyridine benzyl small carboxylate (0.50 g, 214 mmol, 10 equivalents) in THF (20 ml) was added at -30 ° C. Dibromoditown methane (0.90 ml, 4.5 equivalents), followed by HMPA (1.75 ml, 4.5 equivalents). The cooling bath was removed and the reaction mixture was spun periodically. After 30 minutes, zinc powder (0.63 g, 4.5 equivalents) and UMPA (80 microliters, 0.4 equivalents) were added and the mixture was heated under reflux for 18 hours. After cooling to room temperature, the residue was washed several times with ether. The combined ether washings were washed successively with a saturated aqueous solution of copper sulfate (π), brine, dried over Na2S04, and concentrated. The residue was purified by chromatography (20% EtOAc-hexane) to give 4-difluoromethylene-hexahydropyridine-1-carboxylic acid ethyl ester (0.32 g, 56%) as a colorless oil. And 4-monofluoromethylene-hexaaza-b-bite-1-acetic acid vinegar (269 mg) and Pearlman's catalyst in methanol (2.5 ml) in a hydrogen atmosphere (using hydrogen-filled gas Bottle) and stirred at room temperature for 4 hours. The reaction mixture was passed through diatomaceous earth and the mash was concentrated to obtain 41 (138 mg) as a pale yellow oil.

85762 -134- 200412345 按照製備41之相同程序，4-二氟亞甲基_六氫吡啶小羧酸2,2-二甲基-丙酯（36_8毫克）係使用4-酮基-六氫吡啶小羧酸2,2-二甲 基-丙醋（500毫克）製成。將4_二氟亞甲基_六氫吡啶小羧酸2,2-二甲基-丙酯（368毫克）在二氣甲烷（1.〇毫升）中，於室溫下， 以三氟酷酸（TFA，0_5毫升）處理1.5小時。於濃縮反應混合物 後，直接使用粗製42，無需進一步純化。85762 -134- 200412345 According to the same procedure as in Preparation 41, 4-difluoromethylene-hexahydropyridine small carboxylic acid 2,2-dimethyl-propyl ester (36-8 mg) was used 4-keto-hexahydropyridine Made from 2,2-dimethyl-propionic vinegar (500 mg). 4-Difluoromethylene_hexahydropyridine small carboxylic acid 2,2-dimethyl-propyl ester (368 mg) was dissolved in methane (1.0 ml) at room temperature, and trifluoromethane was used. Treatment with acid (TFA, 0-5 ml) for 1.5 hours. After concentrating the reaction mixture, crude 42 was used directly without further purification.

43 於2-胺基-環己醇（3·5〇克，23·0毫莫耳，L0當量）在CH2Cl2(l〇〇 毫升）中之溶液内，添加氯甲酸乙酯（2.65毫升，1·2當量）， 接著是K：2CO3(16.0克，在200毫升Η20中）水溶液。將混合物 激烈攪拌1小時。將已分離之水層以CH2C12萃取兩次。使合 併之有機層以MgS04脫水乾燥，過濾，及濃縮，而得（2-羥基-環己基）-胺甲基酸乙酯（4.36克，>100% )。 於（2-輕基-環己基）_胺甲基酸乙酯（2·〇6克，11.0毫莫耳，1·〇 當量）在THF(80毫升）中之溶液内，添加LiAlH4(1.09克，28.7毫 莫耳，2.6當量），並將所形成之混合物於65°C下加熱2小時 。使反應混合物冷卻至，以水使反應淬滅，並將已分離 之水相以3xEtOAc萃取。使合併之有機相以MgS〇4脫水乾燥， 過濾，及濃縮，而得2-甲胺基-環己醇（U9克，84% )。 於2-甲胺基-環己醇（0,204克，1.58毫莫耳，1·〇當量）與二碳 酸二-第三-丁酯（0.422克，1.2當量）在CH2C12(7.0毫升）中之溶 液内，添加K2C03在水中之溶液（1.09克，在14.0毫升AO中） 85762 -135- 200412345 ’並將所形成之混合物激烈揽拌1小時。將已分離之水層以 0¾¾萃取兩蟓。使合併之有機相以MgS〇4脫水乾燥，過濾 ’及濃縮，而得（2-羥基-環己基）_甲基-胺甲基酸第三-丁酯 (0.332 克，92%)。 於（2-羥基·環己基）-甲基·胺甲基酸第三丁酯（0.237克，1.03 毫莫耳’ 1.0當1)在CH2 (¾ (7.0毫升）中之溶液内，於〇。〇下， 添加分子篩（4人，3毫升）。將反應物攪拌5分鐘，然後引進NMO (0.422克，3.5當量）與TPAP (0.025克，〇.〇7當量）。將反應混合 物於0°C下攪拌5分鐘，接著在室溫下40分鐘。以己烷稀釋後 ’使反應混合物通過矽膠墊，一開始使用己烷，以移除Ch2 cl2 ’然後使用己 元-EtOAc之1 · 1混合物，獲得所要之產物。使 己烷-EtOAc濾液濃縮後，獲得甲基_(2_酮基-環己基）_胺甲基酸 第三-丁酯，為白色固體（〇_235克，1〇〇% )。 於甲基-(2·酮基·環己基）_胺甲基酸第三-丁酯（〇 2〇2克，〇 89 耄莫耳’ 1.0當I)在CH2 Cl2 (3.0耄升）中之溶液内，添加TFA (1.0 毫升），並將反應混合物在室溫下攪拌3小時。然後，使反 應混合物濃縮，而得43 (0.285克，>1〇〇% )。 44 於環戊胺（5·8毫升，59毫莫耳，ι·〇當量）在ch2C12(250毫升） 中之溶液内，於室溫下，添加氯甲酸乙酯（7·3毫升，ι·3當量） ，接著是ACC)3水溶液（37克，在500毫升Η20中）。將混合物 激烈攪拌1小時。將已分離之水層以CI^Cl2萃取兩次。使合 併之有機層以MgS〇4脫水乾燥，過濾，及濃縮，而得環戊基· 85762 -136- 200412345 胺甲基酸乙酯（9·6克，88% )。 於環戊基胺甲基酸乙酯（6.00克，32.4毫莫耳，L0當量）在THF (250毫升）中之溶液内，添加LiAlH4 (3.08克，2.5當量），並將 所形成之混合物，於65°C下加熱2小時。然後，使反應物冷 卻至〇°C，並藉由添加水使反應淬滅。以3xEtOAc萃取已分離 之水層。使合併之有機相以MgS04脫水乾燥，過濾，及濃縮 ，而得 44 (2.01 克，62%)。43 To a solution of 2-amino-cyclohexanol (3.50 g, 23.0 mmol, L0 equivalent) in CH2Cl2 (100 ml) was added ethyl chloroformate (2.65 ml, 1 • 2 equivalents), followed by K: 2CO3 (16.0 g in 200 ml of Η20) in water. The mixture was stirred vigorously for 1 hour. The separated aqueous layer was extracted twice with CH2C12. The combined organic layer was dried over MgS04, filtered, and concentrated to give (2-hydroxy-cyclohexyl) -aminomethyl ethyl acetate (4.36 g, > 100%). To a solution of (2-light-cyclohexyl) -aminomethyl ethyl acetate (2.06 g, 11.0 mmol, 1.0 equivalent) in THF (80 mL) was added LiAlH4 (1.09 g , 28.7 millimoles, 2.6 equivalents), and the resulting mixture was heated at 65 ° C for 2 hours. The reaction mixture was cooled to, the reaction was quenched with water, and the separated aqueous phase was extracted with 3xEtOAc. The combined organic phases were dried over MgS04, filtered, and concentrated to give 2-methylamino-cyclohexanol (U9 g, 84%). In 2-methylamino-cyclohexanol (0,204 g, 1.58 mmol, 1.0 equivalent) and di-tertiary-butyl dicarbonate (0.422 g, 1.2 equivalent) in CH2C12 (7.0 ml) Inside, a solution of K2C03 in water (1.09 g, in 14.0 ml AO) 85762 -135- 200412345 was added and the resulting mixture was stirred vigorously for 1 hour. The separated aqueous layer was extracted two times with 0¾¾. The combined organic phases were dried over MgS04, filtered and concentrated to give (2-hydroxy-cyclohexyl) -methyl-aminomethyl acid tertiary-butyl ester (0.332 g, 92%). In a solution of (2-hydroxy · cyclohexyl) -methyl · aminomethyl acid tert-butyl ester (0.237 g, 1.03 mmoles' 1.0 when 1) in CH 2 (¾ (7.0 ml)), at 0 ° C. 〇, molecular sieves (4 persons, 3 ml) were added. The reaction was stirred for 5 minutes, then NMO (0.422 g, 3.5 eq) and TPAP (0.025 g, 0.07 eq) were introduced. The reaction mixture was at 0 ° C Stir for 5 minutes and then at room temperature for 40 minutes. After diluting with hexane, 'pass the reaction mixture through a silicone pad, initially using hexane to remove Ch2 cl2' and then use the hexane-EtOAc 1.1 mixture, The desired product was obtained. After concentrating the hexane-EtOAc filtrate, methyl- (2-keto-cyclohexyl) -aminomethyl acid tert-butyl ester was obtained as a white solid (0-235 g, 100%). %). Methyl- (2 · keto · cyclohexyl) -aminomethyl acid tertiary-butyl ester (0.202 g, 0.089 mol '1.0 when I) in CH2Cl2 (3.0 liters) To the solution in), TFA (1.0 ml) was added, and the reaction mixture was stirred at room temperature for 3 hours. Then, the reaction mixture was concentrated to obtain 43 (0.285 g, > 100%). 44 In a solution of cyclopentylamine (5.8 ml, 59 mmol, ι · 〇 equivalent) in ch2C12 (250 ml), ethyl chloroformate (7.3 ml, ι · 3) was added at room temperature. Eq), followed by ACC) 3 aqueous solution (37 g, in 500 ml Η20). The mixture was stirred vigorously for 1 hour. The separated aqueous layer was extracted twice with CI ^ Cl2. The combined organic layer was dried over MgS04, filtered, and concentrated to give cyclopentyl 85762-136-200412345 ethyl amine methylate (9.6 g, 88%). To a solution of cyclopentylamine ethyl methylate (6.00 g, 32.4 mmol, L0 equivalent) in THF (250 ml) was added LiAlH4 (3.08 g, 2.5 equivalent), and the resulting mixture was Heat at 65 ° C for 2 hours. The reaction was then cooled to 0 ° C and the reaction was quenched by the addition of water. The separated aqueous layer was extracted with 3xEtOAc. The combined organic phases were dried over MgS04, filtered, and concentrated to give 44 (2.01 g, 62%).

化合物45-58係按照關於從其相應之一級胺類製備44之相同 程序製成。Compounds 45-58 were prepared according to the same procedure as for the preparation of 44 from their corresponding primary amines.

於環戊酮（25·0毫升，〇·28莫耳，1.0當量）在甲苯（100毫升） 中之溶液内，添加四氫吡咯（27·5毫升:，1.2當量）。此反應係 裝有Dean-Stark，並於回流下加熱過夜。使反應混合物冷卻至 室溫，及濃縮，而得粗製1-環戊-1-烯基-四氫吡咯(45.8克，>1〇〇 %)。 於 Pd(OAc)2 (0·06 克，〇.〇6 當量）、PPh3 (0.32 克，0.24 當量）及碳 酸2-乙氧羰基氧基甲基-烯丙酯乙酯（1.23克，5.30毫莫耳，1·〇 當量，按照 1998, 54 (49)，14885-14904 製成）在 CH3 CN (30 毫升）中之溶液内，添加1-環戊小烯基·四氫吡咯（1·〇1克，1.4 85762 -137- 200412345 當量）’並將所形成之混合物，於45°C下加熱35分鐘。然後 ’引進水（15毫:升），並將反應混合物於5〇°C下加熱1小時， 冷卻至室溫，並以Et0Ac (3〇毫升）稀釋。將已分離之水相以 EtOAc萃取兩次。使合併之有機相以MgS〇4脫水乾燥，過遽 ’及濃縮。使殘留物藉矽膠層析純化（10%至15% EtOAc-己烷） ’獲得3_亞甲基·雙環并[3,2，1]辛各酮（al4克，70% )，為淡黃 色液體。 於3-亞甲基雙環并[w]辛各酮（〇14克，1〇4毫莫耳，1 〇當 量）在苯（丨〇毫升）中之溶液内，添加乙二醇（0.65克，16當量） 與PTSA (0.01克，〇·〇6當量）。此反應係裝有Dean-Stark，並於 回流下加熱過夜。於冷卻至室溫後，引進Et3N (0.15毫升）， 並使所形成之混合物通過Si02與MgS04濾餅。以CH2C12洗滌 漉餅’並使合併之濾液濃縮，而得3-亞甲基雙環并卩又丨]辛各 酮乙烯縮酮（0·21克，〉100% )。 於3-亞甲基雙環并卩又:^辛各酮乙烯縮酮（〇·21克，115毫莫 耳’ 1.0當量）在CH2C12(2毫升）中之溶液内，在-78°C下，使03 起泡’直到反應保持在藍色為止（約3 ·分鐘）。停止〇3起泡， 並將反應混合物，於-78°C下攪拌5分鐘。藉由添加三苯膦（0.43 克’ 1·4當量）使反應淬滅，並在_78°C下攪拌10分鐘。使反應 混合物於室溫下溫熱，攪拌40分鐘，及濃縮。使殘留物藉 石夕膠層析純化（10%至15% EtOAc-己烷），獲得雙環并[3,2，1]辛 乾-3,8-二酮8-乙錦r縮酮，為無色油（〇.〇8克，40% )。To a solution of cyclopentanone (25.0 ml, 0.28 mol, 1.0 equivalent) in toluene (100 ml), tetrahydropyrrole (27.5 ml :, 1.2 equivalent) was added. The reaction was loaded with Dean-Stark and heated under reflux overnight. The reaction mixture was cooled to room temperature and concentrated to obtain crude 1-cyclopent-1-enyl-tetrahydropyrrole (45.8 g, > 100%). In Pd (OAc) 2 (0.06 g, 0.06 equivalent), PPh3 (0.32 g, 0.24 equivalent) and 2-ethoxycarbonyloxymethyl-allyl ethyl carbonate (1.23 g, 5.30 mmol) Moore, 1.0 equivalent, made according to 1998, 54 (49), 14885-14904) in a solution of CH3 CN (30 ml), 1-cyclopentylalkenyl · tetrahydropyrrole (1 · 〇 1 g, 1.4 85762 -137- 200412345 equivalent) 'and the resulting mixture was heated at 45 ° C for 35 minutes. Water was then introduced (15 milliliters: liters), and the reaction mixture was heated at 50 ° C for 1 hour, cooled to room temperature, and diluted with Et0Ac (30 mL). The separated aqueous phase was extracted twice with EtOAc. The combined organic phases were dehydrated and dried over MgS04, filtered and concentrated. The residue was purified by silica gel chromatography (10% to 15% EtOAc-hexane) to obtain 3-methylene bicyclo [3,2,1] octanone (4 g, 70%) as a pale yellow color. liquid. To a solution of 3-methylenebicyclo [w] octanone (0.14 g, 104 mmol, 10 equivalents) in benzene (10 mL) was added ethylene glycol (0.65 g, 16 equivalents) and PTSA (0.01 g, 0.06 equivalents). The reaction was loaded with Dean-Stark and heated under reflux overnight. After cooling to room temperature, Et3N (0.15 ml) was introduced and the resulting mixture was passed through a Si02 and MgS04 filter cake. The cake was washed with CH2C12 and the combined filtrates were concentrated to obtain 3-methylenebicyclopyridine and acetophenone ethylene ketal (0.21 g,> 100%). In a solution of 3-methylenebicyclopyridine: octyl ketoethylene ketal (0.21 g, 115 mM '1.0 equivalent) in a solution of CH2C12 (2 ml) at -78 ° C, Bubble 03 'until the reaction remains blue (approximately 3 minutes). The 03 foaming was stopped, and the reaction mixture was stirred at -78 ° C for 5 minutes. The reaction was quenched by adding triphenylphosphine (0.43 g'1.4 equivalent) and stirred at -78 ° C for 10 minutes. The reaction mixture was allowed to warm at room temperature, stirred for 40 minutes, and concentrated. The residue was purified by silica gel chromatography (10% to 15% EtOAc-hexane) to obtain the bicyclo [3,2,1] octane-3,8-dione 8-ethylammonium ketal as Colorless oil (0.08 g, 40%).

於雙環并[3,2，1]辛烷-3,8-二酮乙烯縮酮（53.1毫克，0.27毫莫 耳’ 1·〇當量）在THF(1.0毫升）中之溶液内，在(TC下，添加Et3N 85762 -138- 200412345 (0.11毫升，2.9當量），接著是MeNH2(2〇M，在THF中，0.21毫 升’ 1·5當量）。·於室溫下攪拌5分鐘後，逐滴引進Ticl4(〇.3〇 毫升’ 10.0當量）’並將所形成之混合物，在下攪拌45分 鐘。然後’引進NaBH4(53.1毫克，5.1當量）在MeOH(2.0毫升） 中之落液，並將所形成之混合物，於〇°c下攪拌1小時。以飽 和NaHC〇3使反應淬滅，並以3xEt〇Ac萃取已分離之水層。使 合併之有機相以MgS〇4脫水乾燥，過濾，及濃縮，而得粗產 物’ 3-甲胺基-雙環并[3,2，1]辛各酮乙烯縮酮（241毫克）。 於3-甲胺基-雙環并[3,2，1]辛各酮乙烯縮酮（94·5，〇·48毫莫耳 ’ ΐ·〇當量）在丙酮（2·ο毫升）中之溶液内，添加1ΝΗα(1·5毫升） ’並將反應物於室溫下攪拌過夜。以飽和NaHC〇3使反應混 泛物中和’直到pH而於7為止，以3xEtOAc萃取。使合併之 有機相以MgS〇4脫水乾燥，過濾，及濃縮，而得49 (4〇 〇毫克 ，54% ) 〇In a solution of bicyclo [3,2,1] octane-3,8-dione ethylene ketal (53.1 mg, 0.27 mmoles' 1.0 equivalent) in THF (1.0 ml), in (TC Next, add Et3N 85762 -138- 200412345 (0.11 ml, 2.9 equivalents), followed by MeNH2 (20 M in THF, 0.21 ml '1.5 equivalent). After stirring at room temperature for 5 minutes, dropwise Introduce Ticl4 (0.30 ml '10 .0 equivalents ') and stir the resulting mixture for 45 minutes. Then' introduce NaBH4 (53.1 mg, 5.1 equivalents) in MeOH (2.0 ml) and drop The resulting mixture was stirred at 0 ° C. for 1 hour. The reaction was quenched with saturated NaHC0 3 and the separated aqueous layer was extracted with 3 × EtoAc. The combined organic phases were dried over MgS04, filtered, and Concentration to give the crude product '3-methylamino-bicyclo [3,2,1] octanone vinyl ketal (241 mg). In 3-methylamino-bicyclo [3,2,1] octyl In a solution of each ketene ketal (94,5,48.48 millimoles' ΐ · 0 equivalents) in acetone (2.ml), 1NΗα (1.5ml) was added and the reaction was placed in a chamber Stir under temperature Overnight. The reaction mixture was neutralized with saturated NaHC03 until pH reached 7 and extracted with 3xEtOAc. The combined organic phases were dried over MgS04, filtered, and concentrated to give 49 (4.0). Mg, 54%)

於（3,3-二甲基-i，5-二氧_螺[5,习十一冬基 >甲基-胺鹽酸鹽G.〇克 ’ 4毫莫耳’ L0當量）在THF(12毫升）中之溶液内，添加二碳 酸二-第三-丁酯（1.1毫升，1.2當量）、三乙胺（2毫升）及DMAP ( 催化量）°將所形成之混合物，於90°C下加熱6小時，冷卻至 室溫’傾倒在飽和NaHC〇3中，並將已分離之水層以3xEt〇Ac 萃取。使合併之有機層以Na2S04脫水乾燥，過濾，及濃縮。 使殘留物藉矽膠層析純化（1〇% Et〇Ac /己烷），獲得（3,3-二甲 基―1，5-二氧·螺[5,5]十一 _9_基）-甲基-胺甲基酸第三-丁酯（1.4克， 85762 -139- 200412345 91% )，為白色固體。 於（3,3-二甲基:_1，5_二氧螺[5,5]十一 -9-基）-甲基-胺甲基酸第三 丁酯（1.27克，3·63毫莫耳，1.0當量）在丙酮（40毫升）與水（20 毫升）中之溶液内，添加PPTS (228毫克，0.25當量），並將所 形成之反應物加熱至回流過夜，冷卻至室溫，濃縮至20毫 升，傾倒在飽和NaHC03中，並以3xEtOAc萃取。使合併之有 機層以Na2S04脫水乾燥，過濾，及濃縮。使殘留物藉矽膠層 析純化（己烷至20% EtOAc /己烷），而得甲基-(4-酮基-環己基）-胺甲基酸第三-丁酯（735毫克，88% )，為白色固體。 於甲基-(4-酮基-環己基）-胺甲基酸第三-丁酯（〇·69克，3.04毫 莫耳，1.0當量）在THF (25毫升）中之溶液内，在-30°C下，添 加CBr2F2(1.25毫升，4.5當量），接著緩慢添加P(N(CH3)2)3。使 所形成之混合物溫熱至室溫，歷經0.5小時，並引進Zn。將 所形成之混合物於回流下攪拌16小時，冷卻至室溫，並以 Et2 0稀釋。傾析有機相，並以2xEt2 Ο萃取水相。將合併之有 機相以飽和CuS04溶液洗滌，直到保持在藍色為止，以Na2 S04 脫水乾燥，過濾，及濃縮。使殘留物藉層析純化（20% EtOAc-己烷），獲得（4-二氟亞甲基-環己基）甲基_胺甲基酸第三-丁酯 (475毫克，60% )，為白色固體。 於(4-二氟亞甲基-環己基）-甲基-胺甲基酸第三-丁酯（150毫克 ，0·57毫莫耳，1.〇當量）在CH2C12(1.5毫升）中之溶液内，添 加TFA (1.5毫升）。將反應混合物攪拌4小時，然後濃縮，而 得50 (85毫克）。將粗製化合物取用至下一步·驟，無需進一步 純化。 85762 -140- 200412345 ΗIn (3,3-Dimethyl-i, 5-dioxo-spiro [5, Xiundecyl > methyl-amine hydrochloride G. 0 g '4 mmoles' L0 equivalent) in THF (12 ml), add di-tertiary-butyl dicarbonate (1.1 ml, 1.2 equivalents), triethylamine (2 ml), and DMAP (catalytic amount). Add the resulting mixture at 90 ° It was heated at C for 6 hours, cooled to room temperature and poured into saturated NaHC0, and the separated aqueous layer was extracted with 3xEtoAc. The combined organic layers were dried over Na 2 SO 4, filtered, and concentrated. The residue was purified by silica gel chromatography (10% EtoAc / hexane) to obtain (3,3-dimethyl-1,5-dioxospiro [5,5] undec-9-yl) -Methyl-aminomethyl acid tert-butyl ester (1.4 g, 85762 -139- 200412345 91%) as a white solid. In (3,3-dimethyl: _1,5_dioxo [5,5] undec-9-yl) -methyl-aminomethyl acid tert-butyl ester (1.27 g, 3.63 mmol Ear, 1.0 eq.) In a solution of acetone (40 ml) and water (20 ml), PPTS (228 mg, 0.25 eq.) Was added, and the resulting reaction was heated to reflux overnight, cooled to room temperature, and concentrated To 20 ml, poured into saturated NaHC03 and extracted with 3xEtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated. The residue was purified by silica gel chromatography (hexane to 20% EtOAc / hexane) to give methyl- (4-keto-cyclohexyl) -aminomethyl acid tert-butyl ester (735 mg, 88% ) As a white solid. In a solution of methyl- (4-keto-cyclohexyl) -aminomethyl acid tert-butyl ester (0.69 g, 3.04 mmol, 1.0 eq.) In THF (25 ml), in- At 30 ° C, CBr2F2 (1.25 ml, 4.5 equivalents) was added, followed by the slow addition of P (N (CH3) 2) 3. The resulting mixture was allowed to warm to room temperature over 0.5 hours and Zn was introduced. The resulting mixture was stirred at reflux for 16 hours, cooled to room temperature, and diluted with Et20. The organic phase was decanted and the aqueous phase was extracted with 2xEt2O. The combined organic phases were washed with a saturated CuS04 solution until it remained blue, dried over Na2S04, filtered, and concentrated. The residue was purified by chromatography (20% EtOAc-hexane) to obtain (4-difluoromethylene-cyclohexyl) methyl-aminomethyl acid tert-butyl ester (475 mg, 60%) as White solid. In (4-difluoromethylene-cyclohexyl) -methyl-aminomethyl acid tert-butyl ester (150 mg, 0.57 mmol, 1.0 equivalent) in CH2C12 (1.5 ml) To the solution, TFA (1.5 ml) was added. The reaction mixture was stirred for 4 hours and then concentrated to give 50 (85 mg). The crude compound was taken to the next step without further purification. 85762 -140- 200412345 Η

~ HCI ’· 51 於環丙基胺（5.0克，87·5毫莫耳）與三乙胺（30毫升）在二氯 甲烷（100毫升）中之溶液内，在下，逐滴添加氯甲酸苄酯 (15.0毫升，10.5毫莫耳），並將所形成之混合物攪拌2小時。 添加另外之氯甲酸苄酯（1毫升），並將所形成之反應混合物 攪拌過夜。然後，藉由添加飽和NaHC03使反應淬滅，並將 已分離之水相以二氯甲烷萃取數次。使合併之二氯甲烷萃 液以Na2 S04脫水乾燥，過滤，及濃縮。使殘留物藉層析純化 (15% EtOAc至5% MeOH/EtOAc)，獲得環丙基-胺甲基酸苄酯（11.8 克，71%)。 於環丙基-胺甲基酸苄酯（11.8克）與碘化甲烷（過量）在THF (80毫升）與DMF (20毫升）中之溶液内，在0°C下，添加NaH (2.20 克，91.6毫莫耳），並使所形成之混合物溫熱至室溫，及攪 拌過夜。然後，在〇°C下，藉由飽和NaHC03使反應淬滅。將 已分離之水相以EtOAc萃取數次。使合併之萃液以Na2 S04脫 水乾燥，過滤，及濃縮。使殘留物藉層:析純化（5%至20% EtOAc /己烷），而得環丙基-甲基-胺甲基酸芊酯（11.32克，91% )。 將環丙基·甲基-胺甲基酸苄酯（10.7克）與Pd(OH)2在MeOH (100 毫升）中之混合物，於室溫及H2氣瓶下，攪拌17小時，以濃 HC1 (4.8毫升）稀釋，經過矽藻土過濾，及濃縮。使殘留物與 甲苯共沸數次，獲得環丙基-甲基-胺鹽酸鹽（51，5.75克）。使 用此粗製物質，無需進一步純化。 85762 -141- 200412345~ HCI '· 51 In a solution of cyclopropylamine (5.0 g, 87.5 mmol) and triethylamine (30 ml) in dichloromethane (100 ml), add benzyl chloroformate dropwise below Ester (15.0 ml, 10.5 mmol), and the resulting mixture was stirred for 2 hours. Additional benzyl chloroformate (1 ml) was added and the resulting reaction mixture was stirred overnight. The reaction was then quenched by the addition of saturated NaHC03, and the separated aqueous phase was extracted several times with dichloromethane. The combined dichloromethane extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (15% EtOAc to 5% MeOH / EtOAc) to obtain benzyl cyclopropyl-aminomethylate (11.8 g, 71%). To a solution of cyclopropyl-aminomethyl benzyl ester (11.8 g) and methyl iodide (excess) in THF (80 mL) and DMF (20 mL) was added NaH (2.20 g) at 0 ° C. , 91.6 mmol), and the resulting mixture was allowed to warm to room temperature and stirred overnight. The reaction was then quenched by saturated NaHC03 at 0 ° C. The separated aqueous phase was extracted several times with EtOAc. The combined extracts were dried over Na2S04, filtered, and concentrated. The residue was borrowed: purification (5% to 20% EtOAc / hexanes) to give cyclopropyl-methyl-aminomethyl phosphonate (11.32 g, 91%). A mixture of cyclopropyl · methyl-aminomethyl benzyl ester (10.7 g) and Pd (OH) 2 in MeOH (100 ml) was stirred at room temperature under a H2 gas cylinder for 17 hours to obtain HC1. (4.8 ml) diluted, filtered through celite, and concentrated. The residue was azeotroped several times with toluene to obtain cyclopropyl-methyl-amine hydrochloride (51, 5.75 g). This crude material was used without further purification. 85762 -141- 200412345

52 於（四氫-呋喃-3-基）-甲醇（1·00克，9·79毫莫耳，1.0當量）、pph3 (3.85克，1.5當量）及咪唑（1.33克，2.0當量）在CH2C12(15毫升） 中之溶液内，在0°C下，添加12(3.73克，1.5當量），並將所形 成之混合物在0°C下攪拌30分鐘，然後於室溫下30分鐘。將 反應混合物以飽和Na2S2〇3溶液稀釋，並將已分離之水層藉 由3xEtOAc與4xCH2C12萃取。使合併之萃液以Na2S04脫水乾燥 ，過濾，及濃縮。使殘留物藉層析純化（15% EtOAc /己烷）， 而得3-碘基甲基-四氫-咬喃，為黃色油（ι·59克，76% )。 將3-碘基甲基-四氫-吱喃（5〇〇毫克，2.36毫莫耳，1.0當量） 與MeNH2(在氏0中之40%，1.62毫升，8·0當量）在MeOH (1毫 升）中之混合物，於60°C下，加熱3小時。於冷卻至室溫後， 將反應混合物以過量EtsN稀釋，及濃縮。重複此方法，直 到無法藉1HNMR偵測出MeNH2為止。直接使用此殘留黃色油 (52)，無需進一步純化。 ^nh hci 53 於1-甲氧基甲基-丙胺(2.50克，24.3亳莫耳，U)當量）在二氧 陸圜(15毫升)中之溶液内’添加崎水溶液⑴克，在”毫 升％〇中），並使混合物冷卻至〇〇c。然後，引進 毛升1.2當里）’並使所形成之混合物溫熱至室$显，及授摔 3小時’以Et0Ac萃取。使合併之有機相以¥〇4脫水乾燥， 85762 -142- 200412345 過濾’及濃縮。使殘留物藉層析純化（己烷至4〇% Et0Ac /己 悦）’獲得（1-甲-氧基甲基-丙基）_胺甲基酸芊酯（4.4克，76% ) ’為白色固體。 於（1-甲氧基甲基-丙基）-胺甲基酸芊酯（4.4克，18.5毫莫耳， 1.0當量）與Mel (6.9毫升，111毫莫耳，6當量）在THF/DMF (4 : 1 ’ 50毫升）中之溶液内，在下，慢慢添加NaH(U5克，555 毫莫耳’ 3當量）。使所形成之混合物溫熱至室溫，並攪拌 過夜。藉由緩慢添加水小心地使反應淬滅，直到沒有發現 起泡（H2)為止。將反應混合物傾倒於冰水上，並以3xEtQAc 萃取。使合併之有機相以Na2S04脫水乾燥，過濾，及濃縮。 使殘留物藉矽膠層析純化（30%至5〇% Et〇Ac_己烷），而得（μ 甲氧基甲基-丙基）-甲基-胺甲基酸苄酯（4.4克，94% )。52 (tetrahydro-furan-3-yl) -methanol (1.00 g, 9.79 mmol, 1.0 equivalent), pph3 (3.85 g, 1.5 equivalent), and imidazole (1.33 g, 2.0 equivalent) in CH2C12 In a solution (15 ml), 12 (3.73 g, 1.5 equivalents) was added at 0 ° C, and the resulting mixture was stirred at 0 ° C for 30 minutes, and then at room temperature for 30 minutes. The reaction mixture was diluted with saturated Na2S203 solution, and the separated aqueous layer was extracted with 3xEtOAc and 4xCH2C12. The combined extracts were dried over Na2S04, filtered, and concentrated. The residue was purified by chromatography (15% EtOAc / hexanes) to give 3-iodomethyl-tetrahydro-tetrapyran as a yellow oil (ι 59 g, 76%). Combine 3-iodomethyl-tetrahydro-squean (500 mg, 2.36 mmol, 1.0 equivalent) with MeNH2 (40% in 0 ° C, 1.62 ml, 80.0 equivalents) in MeOH (1 Ml) and the mixture was heated at 60 ° C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with excess EtsN and concentrated. Repeat this method until MeNH2 cannot be detected by 1HNMR. This residual yellow oil (52) was used directly without further purification. ^ nh hci 53 In a solution of 1-methoxymethyl-propylamine (2.50 g, 24.3 mol, U) equivalent) in dioxolane (15 ml), add 崎 solution of hydrazine, in "ml %%), and the mixture was allowed to cool to 0 ° C. Then, 1.2 liters of gross liters were introduced) and the resulting mixture was allowed to warm to room temperature, and allowed to stand for 3 hours, and extracted with EtoAc. The organic phase was dried over ¥ 04, filtered and concentrated at 85762-142-200412345. The residue was purified by chromatography (hexane to 40% EtAc / Hexyl) to obtain (1-methoxy-oxymethyl- (Propyl) -aminomethyl methyl ester (4.4 g, 76%) 'is a white solid. (1-methoxymethyl-propyl) -aminomethyl methyl ester (4.4 g, 18.5 mmol) , 1.0 eq.) And Mel (6.9 ml, 111 mM, 6 eq.) In a solution of THF / DMF (4: 1 '50 ml), and then slowly add NaH (U5 g, 555 mM ') 3 equivalents). The resulting mixture was allowed to warm to room temperature and stirred overnight. The reaction was carefully quenched by slowly adding water until no foaming (H2) was found. The reaction mixture Pour on ice water and extract with 3xEtQAc. The combined organic phases are dried over Na2S04, filtered, and concentrated. The residue is purified by silica gel chromatography (30% to 50% EtoAc_hexane) to obtain (Μmethoxymethyl-propyl) -methyl-aminomethyl benzate (4.4 g, 94%).

於（1-甲氧基甲基-丙基）-甲基-胺甲基酸苄酯（4·4克，17·5毫莫 耳’ 1.0當量）在MeOH (30毫升）中之溶液内，添加氫氧化鈀， 並將所形成之混合物，於室溫及h2下攪拌15小時。然後， 經過兮藻土過濾混合物，並以Me0H洗滌。將濾液以濃HC1 (16 *升，1當量）處理，及濃縮，而得53 (2.67克，100% )。iHNMR 確認此化合物。將粗製化合物用於下一步·驟，無需進一步 純化。In a solution of (1-methoxymethyl-propyl) -methyl-aminomethyl benzyl ester (4.4 g, 17.5 millimoles' 1.0 equivalent) in MeOH (30 ml), Palladium hydroxide was added, and the resulting mixture was stirred at room temperature under h2 for 15 hours. The mixture was then filtered through celite and washed with Me0H. The filtrate was treated with concentrated HC1 (16 * L, 1 equivalent) and concentrated to give 53 (2.67 g, 100%). iHNMR confirmed this compound. The crude compound was used in the next step without further purification.

54 化合物54係按照關於製備53之步驟2與3之相同程序，製 自（1-节基-2-經基-乙基）-胺甲基酸苄酯。 85762 -143- 20041234554 Compound 54 was prepared from (1-benzyl-2-meryl-ethyl) -aminomethyl acid benzyl ester according to the same procedure as for steps 2 and 3 of Preparation 53. 85762 -143- 200412345

55 (1-環己基甲基-2-幾其,其、甲茸… 工基-乙基）-甲基-胺甲基酸芊酯係按照關於 製備53之步騾2之相目# |自f 、 u狂斤 I目…5衣己基甲基-2-羥基_乙基 )-胺甲基酸宇醋。然德 力當、、w 了 、 …、傻，在至μ下，將（1_環己基甲基丨羥基_ 乙基）-甲基-胺甲基酸羊酿以TFA-ΓΗ ΓΊ /1 故下酉日以itA LH2Cl2(l ·· G處理4小時。接 著使混合物濃縮，獲得55。55 (1-cyclohexylmethyl-2-guichi, its, citronella ... eryl-ethyl) -methyl-amine methyl acetic acid esters are in accordance with the steps of Preparation 53 532 的 相 目 # | From f, u, I, ... 5 hexylmethyl-2-hydroxy_ethyl) -aminomethyl acid vinegar. However, Delida ,, w ,, ..., silly, at 1 μ, (1_cyclohexylmethyl 丨 hydroxy_ethyl) -methyl-aminomethyl acid sheep was brewed with TFA-ΓΗ ΓΊ / 1 The next day was treated with itA LH2Cl2 (l · · G for 4 hours. The mixture was then concentrated to obtain 55.

U > 丨.TFA 56 於⑻分白胺醇（2·0克，17毫莫耳，1_〇當量）、Et3N(3.6毫升 ，1·5當量）及DMAP(l〇毫克）在THF(2毫升）中之溶液内，在 至溫下，添加BoqO (4.5克，L2當量）。在攪拌5小時後，藉 水使反應泮滅’並將已分離之水相以4X醚萃取。使合併之 有機相以Na2S〇4脫水乾燥，過濾，及濃縮。使殘留物藉層析 純化(20%至30% EtOAc /己烷），而得（1-羥甲基_3_甲基_丁基）_ 胺甲基酸第三·丁酯（1.9克，53%)。hNMR確認此化合物。 化合物56係按照關於製備55之相同程序，製自（丨_護甲基_3_ 甲基·•丁基）-胺甲基酸第三-丁酯。 Η 57 85762 • 144 - 200412345 於-78°C下，將甲基鋰（1M，在THF中）(120毫升，3·5當量）添 加至4-經基-環己叛fei (順/反混合物）(5.00克’ 1當量）在thf (350毫升）中之溶液内。在-78°C下攪拌45分鐘後，移除冷卻 浴，並使所形成之混合物溫熱至室溫，及攪拌過夜。在總 計24小時後，將所形成之反應混合物倒入冰/水（8〇〇毫升） 中。將此混合物激烈搅拌。將已分離之水相以MeOH/EtOAc (〜1/20)萃取。使合併之有機層以Na2S〇4脫水乾燥，過濾，及 濃縮。使粗產物藉層析純化（50%至100% EtOAc /己燒），獲得 1-(4-羥基-環己基）-乙酮（2.08克，42% )。 將1-(4-#垔基-環己基）-乙酮（2.24克，1當量）、甲苯（16〇毫升） 、新戊二醇（1.96克，1.2當量）及pTsOH (150毫克，0·05當量）之 混合物’在裝有Dean-Stark裝置之燒瓶中，加熱至回流過夜。 使混合物冷卻至室溫，並濃縮。使粗產物藉矽膠管柱層析 純化（25%至50% EtOAc /己烷），而得4-(2,5,5-三甲基_[1，3]二氧 陸圜-2-基）-環己醇（2.23克，62% )。 將TPAP (161晕克，〇·〇5當量）添加至4-(2,5,5-三甲基_[1，3]二氧 陸圜-2-基環己醇（2.22克，1當量）與NMO (2.28克，2當量）在U >. TFA 56 was divided into leukosamine (2.0 g, 17 mmol, 1.0 equivalent), Et3N (3.6 mL, 1.5 equivalent), and DMAP (10 mg) in THF ( 2 ml) of the solution was added BoqO (4.5 g, L2 equivalent) at room temperature. After stirring for 5 hours, the reaction was quenched with water 'and the separated aqueous phase was extracted with 4X ether. The combined organic phases were dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (20% to 30% EtOAc / hexane) to give (1-hydroxymethyl_3_methyl_butyl) _aminomethyl acid tert-butyl ester (1.9 g, 53%). hNMR confirmed this compound. Compound 56 was prepared from (丨 _protecting methyl_3_methyl · • butyl) -aminomethyl acid tert-butyl ester according to the same procedure as for preparation 55. Η 57 85762 • 144-200412345 At -78 ° C, methyl lithium (1M in THF) (120 ml, 3.5 equivalents) was added to 4-Cycyl-Cyclohexanone fei (cis / trans mixture) ) (5.00 g '1 eq) in a solution in thf (350 ml). After stirring at -78 ° C for 45 minutes, the cooling bath was removed and the resulting mixture was allowed to warm to room temperature and stirred overnight. After a total of 24 hours, the reaction mixture formed was poured into ice / water (800 ml). This mixture was stirred vigorously. The separated aqueous phase was extracted with MeOH / EtOAc (~ 1/20). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by chromatography (50% to 100% EtOAc / hexane) to give 1- (4-hydroxy-cyclohexyl) -ethanone (2.08 g, 42%). Add 1- (4- # fluorenyl-cyclohexyl) -ethanone (2.24 g, 1 equivalent), toluene (160 mL), neopentyl glycol (1.96 g, 1.2 equivalent), and pTsOH (150 mg, 0 · 05 equiv) in a flask equipped with a Dean-Stark device and heated to reflux overnight. The mixture was cooled to room temperature and concentrated. The crude product was purified by silica gel column chromatography (25% to 50% EtOAc / hexane) to give 4- (2,5,5-trimethyl_ [1,3] dioxolane-2-yl ) -Cyclohexanol (2.23 g, 62%). TPAP (161 g, 0.05 equivalent) was added to 4- (2,5,5-trimethyl_ [1,3] dioxolidine-2-ylcyclohexanol (2.22 g, 1 equivalent) ) With NMO (2.28 g, 2 eq) in

MeCN (65毫升）中之溶液内。將反應混合物於室溫下擾拌過 夜。將Na2S2〇3飽和水溶液添加至混合物中，並將所形成之 混合物激烈攪拌15分鐘。以（:1¾¾萃取已分離之水相。使合 併之有機層以Naz SO4脫水乾燥，經過碎藻土過漉，及濃縮。 使粗產物藉矽膠管柱層析純化（25%至50% Et〇Ac /己烷），獲 得4-(2,5,5-二甲基_[1，3]二氧陸圜基）_環己酮（1.87克，85% )。 化合物57係按照從ι，2-二苯基_乙酮製備34之程序，製自‘ 85762 -145- 200412345 (2,5,5-三甲基-[1，3]二氧陸圜_2-基 >環己酮。MeCN (65 mL). The reaction mixture was stirred at room temperature overnight. A saturated aqueous Na2S203 solution was added to the mixture, and the resulting mixture was stirred vigorously for 15 minutes. The separated aqueous phase was extracted with (: 1¾¾). The combined organic layers were dried over Naz SO4, dried over celite, and concentrated. The crude product was purified by silica gel column chromatography (25% to 50% Et. Ac / hexane) to obtain 4- (2,5,5-dimethyl_ [1,3] dioxalyl) _cyclohexanone (1.87 g, 85%). Compound 57 was obtained from Procedure for the preparation of 2-diphenyl_ethyl ketone 34 from '85762 -145- 200412345 (2,5,5-trimethyl- [1,3] dioxolane_2-yl> cyclohexanone .

CF3C〇2H cf3co2h 58 59 於（3,3-一甲基-1，5-一氧-螺[5,5]十一 -9_基）-甲基-胺鹽酸鹽（6.9克 ，27.6毫莫耳，1.0當量）、Et3N(i5毫升，4.0當量）及DMAP( 催化量）在THF-MDF (1 : 1，1〇〇毫升）中之懸浮液内，添加二 竣酸二-第三-丁酯（7.6毫升，1·2當量），並將所形成之混合物 ，於90°C下加熱6小時。於冷卻至室溫後，將反應混合物以 飽和NaHC〇3稀釋，並以2xEtOAc萃取已分離之水層。使合併 之有機層以Na〗SO4脫水乾燥，過濾，及濃縮。使粗產物藉層 析純化（10%至20% EtOAc /己烷），而得（3,3_二甲基{5•二氧螺 [5,5]十一 -9-基）-甲基-胺甲基酸第三-丁酯，為白色固體（9 53克 ，99% ) 〇 於80 C下，將（3,3_二甲基-1，5-二氧_螺[5,5]·:|---9_基）-甲基胺甲 基酸第三-丁酯（9.53克，27.2毫莫耳，lo當量）與卯^卩丨克， 〇_3當量）在丙酮-水（2 ·· 1，500毫升）中之溶液，加熱18小時 ’冷卻至室溫’及濃縮’以移除丙嗣。將殘留水溶液以NaHC〇3 稀釋，並以2xEt〇Ac萃取。使合併之有機層以Na2S〇4脫水乾 Ί，過濾，及濃縮。使粗產物藉層析純化（2〇%至5〇% Et〇Ac /己燒）’獲得甲基-(4_酮基-環己基）胺甲基酸第三_ 丁酯，為 白色固體（5.38克，87% )。 於甲基-(4-酮基-環己基）-胺甲基酸第三-丁酯（134毫克，〇·59 耄莫耳，1_〇當量）在CH2C12(0.5毫升）中之溶液内，於室溫下 85762 -146- 200412345 ，添加（MeOCH^CHANSFWn微升，2.0當量），接著是乙醇（1〇 微升，〇·3當夏〕。在攪拌1小時後，藉由添加飽和NaHcc^小 心地使反應淬滅，並攪拌，直到停止氣體釋出為止。以CH2Cl2 萃取已分離之水相。使合併之有機萃液以Na〗s〇4脫水乾燥， 過漉，及濃縮。使粗製混合物藉層析純化（5%至1〇% Et〇Ac / 己fe ) ’而知（4,4-二氟-環己基）_甲基_胺甲基酸第三-丁酯與（4_ 二氟-環己-3-烯基）-甲基-胺甲基酸第三_丁酯之混合物。於此 混合產物在CH2 CL (1.5毫升）中之溶液内，在室溫下，添加三 氟醋酸（1.5毫升），並將所形成之混合物攪拌2·5小時，及濃 縮，而得58與59之混合物（2 : 1比例，藉Hi -NMR)。CF3C〇2H cf3co2h 58 59 (3,3-monomethyl-1,5-monooxo-spiro [5,5] undec-9-yl) -methyl-amine hydrochloride (6.9 g, 27.6 mmol) In a suspension of Mohr, 1.0 eq., Et3N (i5 ml, 4.0 eq.) And DMAP (catalytic amount) in THF-MDF (1: 1, 100 ml), di-dicarboxylic acid di-third- Butyl ester (7.6 ml, 1.2 equivalents), and the resulting mixture was heated at 90 ° C for 6 hours. After cooling to room temperature, the reaction mixture was diluted with saturated NaHC03 and the separated aqueous layer was extracted with 2xEtOAc. The combined organic layers were dried over NaSO4, filtered, and concentrated. The crude product was purified by chromatography (10% to 20% EtOAc / hexane) to give (3,3-dimethyl {5 • dioxo [5,5] undec-9-yl) -methyl -Aminomethyl acid third-butyl ester as a white solid (9 53 g, 99%). At 80 C, (3,3-dimethyl-1,5-dioxo-spiro [5,5 ] ·: || -9-yl) -methylaminomethyl acid tert-butyl ester (9.53 g, 27.2 mmol, lo equivalent) and 卯 ^ 卩 丨 g, 〇3 equivalent) in acetone- The solution in water (2, 1,500 ml) was heated 'cooled to room temperature' and concentrated 'for 18 hours to remove propane. The residual aqueous solution was diluted with NaHC0 3 and extracted with 2 × EtoAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by chromatography (20% to 50% EtoAc / hexane) to give methyl- (4-keto-cyclohexyl) amine methyl acid tert-butyl ester as a white solid ( 5.38 grams, 87%). In a solution of methyl- (4-keto-cyclohexyl) -aminomethyl acid tert-butyl ester (134 mg, 0.59 mol, 1.0 equivalent) in CH2C12 (0.5 ml), At room temperature 85762-146-200412345, add (MeOCH ^ CHANSFWn microliters, 2.0 equivalents), followed by ethanol (10 microliters, 0.33 summers). After stirring for 1 hour, add saturated NaHcc ^ The reaction was carefully quenched and stirred until gas evolution ceased. The separated aqueous phase was extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, dried, and concentrated. The crude mixture was made Purification by chromatography (5% to 10% Eto-Ac / Hexyl) '(4,4-difluoro-cyclohexyl) _methyl_aminomethyl acid third-butyl ester and (4_difluoro -Cyclohex-3-enyl) -methyl-aminomethyl acid tertiary-butyl ester mixture. Here, a solution of the mixed product in CH2CL (1.5 ml) was added with trifluoroacetic acid at room temperature. (1.5 ml), and the resulting mixture was stirred for 2.5 hours and concentrated to give a mixture of 58 and 59 (2: 1 ratio, by Hi-NMR).

於3-氯基-2-氯基甲基-1-丙烯（2〇·〇克，；16〇毫莫耳，ι·〇當量） 在THF (40毫升）中之溶液内，在〇°c下，添加Na〇Me (在甲醇 中之100毫升25%溶液，2.8當量）。在移除冷卻浴後，·將反應 混合物於室溫下攪拌20小時，並在35°C下20小時。以飽和 NH^Cl (10毫升）使反應淬滅，並以醚（2〇〇毫升）稀釋混合物， 及以醚過濾洗滌。在大氣壓力下，藉由蒸餾醚、THF及EtOH ’使濾液濃縮，而得淡黃色液體殘留物，分餾殘留物，獲 得3-甲氧基-2-甲氧基甲基-1-丙烯（8.9克，43% )。沸點=：12(M3〇 t。 於3-甲氧基-2-甲氧基甲基-1-丙烯（3·5克，30毫莫耳，ι·〇當 量）在THF (10毫升）中之溶液内，在〇°c下，添加βη3 · THF (1Μ 85762 -147- 200412345 ’在THF中’ 18毫升，〇·6當量），並將所形成之混合物攪拌4〇 分鐘。以水’条著以過硼酸鈉（1〇·6克，2·3當量）使反應淬滅 ，溫熱至室溫，攪拌過夜，以CH2C12稀釋，並經過矽藻土過 濾。以鹽水稀釋濾液，並將已分離之水層以CH2 Cl2萃取。使 合併之萃液以Na2S〇4脫水乾燥，及過濾。使濾液在大氣壓力 下蒸餾’獲得淡黃色液體殘留物。於4〇毫托下，分餾殘留 物，獲得3-甲氧基-2-甲氧基甲基丙小醇（1·93克，48% )。沸點 = 90-110〇C 〇 於醇3-甲氧基-2-甲氧基甲基丙小醇（0·90克，6.7毫莫耳，1 : 〇當量）在CH2Ci2(i〇毫升）中之溶液内，在0°c下，添加Ε^Ν(19 毫升，2·0當量），接著是MsC1 (〇·63毫升，12當量）。在攪拌4〇 分鐘後，以甲胺（在水中之4〇% )使反應淬滅。使反應混合物 在室溫下濃縮後，將殘留物以甲醇（2毫升）與甲胺（3毫升， 在水中之40% )稀釋，於5〇它下加熱18小時，冷卻至室溫， 以Na〗CO3飽和’並以_萃取。使合併之萃液以恤〗go#脫水乾 燥’及過遽。使濾液在大氣壓力下蒸餾，而得粗產物6〇 (〇·78 克’ 80% )’為淡黃色液體。In a solution of 3-chloro-2-chloromethyl-1-propene (20.0 g ,; 160 mmol, 1 · eq) in THF (40 ml) at 0 ° C Next, NaOM (100 ml of a 25% solution in methanol, 2.8 equivalents) was added. After the cooling bath was removed, the reaction mixture was stirred at room temperature for 20 hours and at 35 ° C for 20 hours. The reaction was quenched with saturated NHCl (10 mL), and the mixture was diluted with ether (200 mL) and washed with ether and filtered. At atmospheric pressure, the filtrate was concentrated by distillation of ether, THF, and EtOH ′ to obtain a pale yellow liquid residue, and the residue was fractionated to obtain 3-methoxy-2-methoxymethyl-1-propene (8.9 G, 43%). Boiling point =: 12 (M3Ot. In 3-methoxy-2-methoxymethyl-1-propene (3.5 g, 30 mmol, ι.e equivalent) in THF (10 mL) In the solution, βη3 · THF (1M 85762 -147- 200412345 'in THF' 18 ml, 0.6 equivalent) was added at 0 ° C, and the resulting mixture was stirred for 40 minutes. The reaction was quenched with sodium perborate (10.6 g, 2.3 equivalents), warmed to room temperature, stirred overnight, diluted with CH2C12, and filtered through celite. The filtrate was diluted with brine, and the The separated aqueous layer was extracted with CH2Cl2. The combined extracts were dehydrated and dried over Na2SO4, and filtered. The filtrate was distilled under atmospheric pressure to obtain a light yellow liquid residue. The residue was fractionated at 40 mTorr, Obtained 3-methoxy-2-methoxymethylpropanol (1.93 g, 48%). Boiling point = 90-110 ° C. Alcohol 3-methoxy-2-methoxymethyl In a solution of propanol (0.90 g, 6.7 mmol, 1: 0 equiv.) In CH2Ci2 (10 ml), E ^ N (19 ml, 2.0 equiv.) Was added at 0 ° C. , Followed by MsC1 (0.63 ml, 12 equivalents ). After stirring for 40 minutes, the reaction was quenched with methylamine (40% in water). After the reaction mixture was concentrated at room temperature, the residue was methanol (2 ml) and methylamine (3 ml (40%) diluted in water, heated at 50 ° C for 18 hours, cooled to room temperature, saturated with Na [CO3] and extracted with _. The combined extracts were dehydrated and dried over Go # The filtrate was distilled at atmospheric pressure to obtain the crude product 60 (0.88 g '80%) 'as a pale yellow liquid.

Me〇&quot;&quot;〈 ^-*NH . CF3〇〇2H 61 於反式-4-胺基-環己醇鹽酸鹽（5·〇克，32·9毫莫耳，L〇當量） 在水（80笔升）與THF (60毫升）中之溶液内，在室溫下，添加 NaHC〇3(6.4 克，2.3 當量）與(Boc)2〇 (14·8 毫升，2 〇 當量）。攪拌 48小時後，藉濃縮使大部份THF自反應混合物移除，並以 85762 -148- 200412345Me〇 &quot; &quot; <^-* NH. CF3〇〇2H 61 in trans-4-amino-cyclohexanol hydrochloride (5.0 g, 32.9 millimoles, L0 equivalent) at In a solution of water (80 liters) and THF (60 ml), NaHC03 (6.4 g, 2.3 equivalents) and (Boc) 2 0 (14.8 ml, 20 equivalents) were added at room temperature. After stirring for 48 hours, most of the THF was removed from the reaction mixture by concentration, and was 85762 -148- 200412345

EtOAc萃取含水殘留物。使合併之有機萃液以Na2S04脫水乾 燥，過濾，及滚縮。使粗產物自EtOAc-己烷（9 : 1)結晶，獲 得（4-反式-羥基-環己基）-胺甲基酸第三-丁酯（5.2克，75% )。 於（4-反式-羥基-環己基）-胺甲基酸第三·丁酯（3.0克，13.9毫 莫耳，1.0當量）與碘化甲烷（4.3毫升，5.0當量）在N-甲基_2_四 氫外I：洛酮（NMP)(50毫升）中之溶液内，在0°C下，以經控制之 分次方式，添加礦油中之60% NaH (1.67克，3.0當量），並將 所形成之混合物，在室溫下攪拌3小時。以甲醇（3.0毫升）使 反應混合物淬滅，攪拌30分鐘，以飽和NH4C1稀釋，並將混 合物以EtOAc萃取三次。使合併之有機萃液以Na2S04脫水乾 燥，過濾，及濃縮。使粗製混合物藉矽膠層析純化（20% EtOAc /己烷），而得（4-反式·甲氧基-環己基）-甲基，胺甲基酸第三_丁 酯（3.25 克，96% )。 於反式-(4-甲氧基·壤己基）-甲基-胺甲基酸第三-丁 g旨（445毫 克，1.83毫莫耳，1.0當量）在CH2C12(2毫升）中之溶液内，在 室溫下，添加三氟醋酸（2毫升）。在攪拌2小時後，使反應 混合物濃縮，獲得61 (685毫克，145%，含有殘留TFA)。iHNMR 確認此結構，並使用此產物，無需進一步純化。 或者，化合物61可根據下列圖式製成：The aqueous residue was extracted with EtOAc. The combined organic extracts were dried over Na2S04, filtered, and rolled. The crude product was crystallized from EtOAc-hexane (9: 1) to obtain (4-trans-hydroxy-cyclohexyl) -aminomethyl acid tert-butyl ester (5.2 g, 75%). In (4-trans-hydroxy-cyclohexyl) -aminomethyl acid tert-butyl ester (3.0 g, 13.9 mmol, 1.0 eq.) And methane iodide (4.3 mL, 5.0 eq.) In N-methyl _2_Extra-hydrogen I: In a solution in NMP (50ml), at 60 ° C, add 60% NaH (1.67 g, 3.0 equivalents) in mineral oil in a controlled and divided manner. ), And the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with methanol (3.0 ml), stirred for 30 minutes, diluted with saturated NH4C1, and the mixture was extracted three times with EtOAc. The combined organic extracts were dried over Na2S04, filtered, and concentrated. The crude mixture was purified by silica gel chromatography (20% EtOAc / hexanes) to give (4-trans-methoxy-cyclohexyl) -methyl, amine methyl acid tert-butyl ester (3.25 g, 96 %). In a solution of trans- (4-methoxy · lohexyl) -methyl-aminomethyl acid tertiary-butyl g (445 mg, 1.83 mmol, 1.0 equivalent) in CH2C12 (2 ml) At room temperature, add trifluoroacetic acid (2 ml). After stirring for 2 hours, the reaction mixture was concentrated to obtain 61 (685 mg, 145%, containing residual TFA). iHNMR confirmed this structure and used this product without further purification. Alternatively, compound 61 can be made according to the following scheme:

因此，在適當條件（例如TPAP、NM0)下，4-甲氧基環己醇 在適當溶劑（例如二氯甲烷）中之氧化作用，係獲得其相應 85762 -149- 200412345 之嗣。4-甲氧基環己酮在適當條件（例如二甲胺、ΝαΒΗ(〇Α(^ 、AcOH ’在THF中）下之還原胺化作用，係獲致具有良好立 體選擇性（意即反式）之相應胺61。 ^&gt;—NH · CF3C02H 62 於甲基-(4-酮基-環己基）-胺甲基酸第三叮酯（關於製備58與 59之中間物，580毫克，2.56毫莫耳，1〇當量）在THF (8毫升） 中之懸浮液内，在_78°C下，添加LS-選擇劑（在THF中之1 Μ 溶液，5.7毫升，2·2當量）。於攪拌2·5小時後，使反應混合 物溫熱至0 C，並擾拌30分鐘。以飽和C1使反應淬滅，並 將已分離之水層以EtOAc-己(1 : 1)萃取。使合併之有機萃 液以Na2S〇4脫水乾燥，過漉，及濃縮。使粗製混合物藉矽膠 層析純化（33%至50% EtOAc-己燒），而得⑷順式_羥基-環己基） 甲基-胺甲基酸第三-丁酯（391毫克，67% )。 化合物62係按照從（4-反式-經基-環己基）_胺甲基酸第三_丁 酯製備61之相同程序，製自（4-順式-羥基_環己基）_甲基胺甲 基酸第三-丁酯。Therefore, under appropriate conditions (such as TPAP, NMO), the oxidation of 4-methoxycyclohexanol in a suitable solvent (such as dichloromethane) is to obtain its corresponding 85762 -149- 200412345. The reductive amination of 4-methoxycyclohexanone under appropriate conditions (such as dimethylamine, NαΒΗ (〇Α (^, AcOH 'in THF)), resulting in good stereoselectivity (meaning trans) Corresponding amine 61. ^ &gt; —NH · CF3C02H 62 in methyl- (4-keto-cyclohexyl) -aminomethyl acid tert-butyl ester (for the preparation of intermediates 58 and 59, 580 mg, 2.56 mmol In a suspension of Moore, 10 equivalents) in THF (8 mL), LS-selective agent (1 M solution in THF, 5.7 mL, 2.2 equivalents) was added at -78 ° C. After stirring for 2.5 hours, the reaction mixture was warmed to 0 C and stirred for 30 minutes. The reaction was quenched with saturated C1, and the separated aqueous layer was extracted with EtOAc-hexane (1: 1). The combined The organic extract was dried over Na2S04, dried, and concentrated. The crude mixture was purified by silica gel chromatography (33% to 50% EtOAc-hexane) to give cis-hydroxy-cyclohexyl) methyl -Aminomethyl acid tert-butyl ester (391 mg, 67%). Compound 62 was prepared according to the same procedure as (61) from (4-trans-Aryl-cyclohexyl) -aminomethyl acid tert-butyl ester. , Made from (4 -Cis-hydroxy-cyclohexyl) -methylaminomethyl tertiary-butyl ester.

Me〇 63 於（4·順式-罗呈基-環己基）-甲基-胺甲基酸第三丁酯（I·%克， 8.52毫莫耳，1.0當量）在DMF (20毫升）中之溶液内，在〇它下 ，添加NaH (559毫克，2.5當量）。在攪拌1〇分鐘後，引進琪 化甲烷（3.9毫升，7.6當量），且移除冰浴。於室溫下攪掉$小 時後，以甲醇（1.5毫升）使反應淬滅，攪拌15分鐘，並以飽 85762 -150- 200412345 和NH4C1稀釋。以Et0Ac_己烷（1 : υ萃取混合物。使合併之有 機萃液以Na2SO·4脫水乾燥，過濾，及濃縮。使粗製混合物藉 矽膠層析純化（10%至25% EtOAc /己烷），獲得（4-順式-甲氧基 -環己基）-甲基_胺甲基酸第三丁酯（L73克，84% )。 於（4-順式-甲氧基-環己基 &gt; 甲基_胺甲基酸第三_丁酯（1·73克 ，7_12毫莫耳，ΐ·〇當f )在CH2 C12 (4毫升）中之溶液内，在室 溫下，添加三氟醋酸（4毫升）。在攪拌3·5小時後，使反應混 合物濃縮，獲得粗產物。使此產物溶於CH2 cl2 (5〇毫升）中， 並以飽和Naz CO3 (40毫升）洗滌。以5XCH2 Cl2逆萃取水層。使 合併之有機萃液以Na〗SO#脫水乾燥，過濾，及濃縮，而得自 由態胺63(1.12克，1〇9%，含有殘留。112(：12)。Me〇63 in (4 · cis-Rosyl-cyclohexyl) -methyl-aminomethyl acid third butyl ester (I ·% g, 8.52 mmol, 1.0 equivalent) in DMF (20 ml) Then, below it, NaH (559 mg, 2.5 equivalents) was added. After stirring for 10 minutes, chimerized methane (3.9 mL, 7.6 equivalents) was introduced and the ice bath was removed. After stirring at room temperature for $ hours, the reaction was quenched with methanol (1.5 mL), stirred for 15 minutes, and diluted with 85762-150-200412345 and NH4C1. The mixture was extracted with Et0Ac_hexane (1: υ. The combined organic extracts were dried over Na2SO · 4, filtered, and concentrated. The crude mixture was purified by silica gel chromatography (10% to 25% EtOAc / hexane), (4-cis-methoxy-cyclohexyl) -methyl-aminomethyl acid tert-butyl ester (L73 g, 84%) was obtained. (4-cis-methoxy-cyclohexyl) &gt; A Tris-butyl methylamine (1.73 g, 7-12 mol, ΐ · 〇 当 f) in a solution of CH2 C12 (4 ml) at room temperature, add trifluoroacetic acid ( 4 ml). After stirring for 3.5 hours, the reaction mixture was concentrated to obtain a crude product. This product was dissolved in CH2cl2 (50 ml) and washed with saturated Naz CO3 (40 ml). Reverse with 5XCH2 Cl2 The aqueous layer was extracted. The combined organic extracts were dried over Na SO 2, filtered, and concentrated to give the free amine 63 (1.12 g, 10%, containing residues. 112 (: 12).

將18 (0.01-0.1 Μ ’ 1.0當量）、二異丙基乙胺（5 〇當量）及得自 21-63之任一種胺或其他市購可得之一級或二級烷基胺（34〇 當量）在二氯甲烷中之混合物，於室溫或4〇 °c下，攪拌數小 時至五天，直到反應完成為止。使反應混合物濃縮，並使 中間產物，無論是藉由或未藉由層析純化（Et0Ac /己烷），溶 於二氯甲烷與三氟酷酸之1 : 1混合物（0·05 M)中，並在室溫 下使用或未使用甲苯醚（5-10當量）攪拌3_4小時，直到反應完 成為止。然後，以飽和NaHC〇3小心地使反應淬滅，以Et〇Ac 萃取，直到沒有產物被檢出為止。使合併之萃液以Na2 S04脫 85762 -151- 200412345 水乾燥，過濾，濃縮，並使產物64藉逆相HPLC純化（MeOH-水）。 ： 下述程序已被使用於芳族胺類（心及/或Rg=Ai〇。於N-乙胺 基苯（47微升，6當量）在THF (1毫升）中之溶液内，在-78t下 ，添加n-BuLi (148微升，2.5 Μ，在己燒中，6當量），接著是 ΗΜΡΑ (200微升），並攪拌10分鐘。經由以THF (0.3毫升）沖洗 ，引進18 (44毫克，0.062毫莫耳）在THF (0.7毫升）中之溶液。 攪拌10分鐘後，以飽和NaHC03 (15毫升）使反應混合物淬滅， 以3xEtOAc萃取。使合併之萃液以Na2 S04脫水乾燥，過渡， 濃縮，並使產物藉層析純化（EtOAc)，獲得中間物。使此中 間物與甲苯醚（100微升）溶於二氯甲烷與三氟醋酸之1 ·· 1混 合物（2毫升）中，並在室溫下攪拌3小時。然後，以飽和NaHC03 小心地使反應淬滅，以4xEtOAc萃取。將合併之萃液以Na2 SO4 脫水乾燥，過濾，濃縮，並使產物64藉逆相HPLC純化（MeOH-水）。18 (0.01-0.1 M '1.0 equivalent), diisopropylethylamine (50 equivalent), and any of the amines 21-63 or other commercially available primary or secondary alkylamines (34. Equivalent) A mixture in dichloromethane is stirred at room temperature or 40 ° C. for several hours to five days until the reaction is complete. The reaction mixture was concentrated and the intermediate product, whether with or without purification by chromatography (Et0Ac / hexane), was dissolved in a 1: 1 mixture of dichloromethane and trifluoroacid (0.05 M). And stirred at room temperature with or without toluene ether (5-10 equivalents) for 3-4 hours until the reaction is complete. The reaction was then carefully quenched with saturated NaHC03 and extracted with EtoAc until no product was detected. The combined extracts were dehydrated with Na 2 SO 4 85762 -151- 200412345, dried over water, filtered, concentrated, and the product 64 was purified by reverse-phase HPLC (MeOH-water). : The following procedure has been used for aromatic amines (heart and / or Rg = Ai.) In a solution of N-ethylaminobenzene (47 μl, 6 eq.) In THF (1 ml), in- At 78t, n-BuLi (148 μl, 2.5 M, in hexane, 6 equivalents) was added, followed by UMPA (200 μl), and stirred for 10 minutes. Rinse with THF (0.3 mL) and introduce 18 ( 44 mg, 0.062 mmol) in THF (0.7 ml). After stirring for 10 minutes, the reaction mixture was quenched with saturated NaHC03 (15 ml) and extracted with 3xEtOAc. The combined extracts were dried over Na2S04 and dried. , Transition, concentrated, and the product was purified by chromatography (EtOAc) to obtain the intermediate. This intermediate and toluene ether (100 μl) were dissolved in a 1 ·· 1 mixture of dichloromethane and trifluoroacetic acid (2 ml ) And stirred at room temperature for 3 hours. Then, the reaction was carefully quenched with saturated NaHC03 and extracted with 4xEtOAc. The combined extracts were dried over Na2SO4, filtered, concentrated, and the product 64 was reversed-phased. Purified by HPLC (MeOH-water).

將二異丙基乙胺（1.6當量），於室溫下，添加至20 (0.03-0.05 Μ ，1·〇當量）與TOTU(1.5當量）在DMF中之溶液内，並攪拌15分 鐘。在所形成之混合物中，添加得自21-63之任一種胺或其 他市購可得之一級或二級胺（1.5當量）。將反應混合物攪拌 數小時至過夜，直到反應完成為止。使反應混合物濃縮， 85762 -152- 200412345 並使中間產物，無論是藉由或未藉由層析純化（EtOAc /己烷） ，溶於二氯甲烷與三氟醋酸之1 ·· 1混合物（0.01-0Ό5Μ)中，並 在室溫下，使用或未使用甲苯醚（5-10當量）攪拌3-4小時，直 到反應完成為止。然後，以飽和NaHC03小心地使反應淬滅 ，以EtOAc萃取，直到沒有產物被檢出為止。使合併之萃液 以Na2 S04脫水乾燥，過濾，濃縮，並使產物65藉逆相HPLC 純化（MeOH-水）。 於下表中之化合物，係無論是按照13或64或65之製備製成。 153- 85762 200412345 化合物# ~ (ER# 或 IC#) 結構64或65 MS (ES) 或/及 ^NMR 806094 nh2 TBs°^〇y0 H HN? 'HNMR 806095 nh2 Η HN 丫 N 'H NMR 806123 nh2 H N^NH 361.4 (M+H)+ 806136 〇 N 丫 NH 404.3 (M+H)+ 806181 nh2 H、nh !hnmr 806221 _xr^o^H2 H 丫 H 413,3 (M+H)+Diisopropylethylamine (1.6 eq.) Was added to a solution of 20 (0.03-0.05 M, 1.0 eq.) And TOTU (1.5 eq.) In DMF at room temperature, and stirred for 15 minutes. To the resulting mixture, any of the amines 21-63 or other commercially available primary or secondary amines (1.5 equivalents) were added. The reaction mixture was stirred for several hours to overnight until the reaction was complete. The reaction mixture was concentrated, 85762 -152- 200412345 and the intermediate product, whether with or without purification by chromatography (EtOAc / hexane), was dissolved in a 1 ·· 1 mixture of dichloromethane and trifluoroacetic acid (0.01 -0.5 μM), and stirred at room temperature with or without toluene ether (5-10 equivalents) for 3-4 hours until the reaction is complete. The reaction was then carefully quenched with saturated NaHC03 and extracted with EtOAc until no product was detected. The combined extracts were dried over Na 2 SO 4, filtered, concentrated, and the product 65 was purified by reverse-phase HPLC (MeOH-water). The compounds in the table below are prepared in accordance with 13 or 64 or 65. 153- 85762 200412345 Compound # ~ (ER # or IC #) Structure 64 or 65 MS (ES) or / and NMR 806094 nh2 TBs ° ^ 〇y0 H HN? 'HNMR 806095 nh2 Η HN γN' H NMR 806123 nh2 HN ^ NH 361.4 (M + H) + 806136 〇N Yah NH 404.3 (M + H) + 806181 nh2 H, nh! Hnmr 806221 _xr ^ o ^ H2 H Yah H 413,3 (M + H) +

85762 -154- 200412345 806220 NH2 465.3 (M+H)+ 806224 Jo H 丫H 409.3 (M+H)+ 806228 nh2 kJJ 丫 H 412.3 (M+H)+ 806276 nh2 Me〇V ΎΝΗ Me〇 1 471.3 (M+H)+ 806275 Me〇 N^yNH 487.3 (M+H)+ 806274 nh2 (χη〇&gt;·0 H n^nh 397.3 (M+H)+ 806273 NH_2 kjj 丫H 411.3 (M+H)+ 806317 NH2 kJJ 丫H 398.2 (M+H)+ 85762 -155- 200412345 8576285762 -154- 200412345 806220 NH2 465.3 (M + H) + 806224 Jo H ah H 409.3 (M + H) + 806228 nh2 kJJ ah H 412.3 (M + H) + 806276 nh2 Me〇V ΎΝΗ Me〇1 471.3 (M + H) + 806275 Me〇N ^ yNH 487.3 (M + H) + 806274 nh2 (χη〇 &gt; · 0 H n ^ nh 397.3 (M + H) + 806273 NH_2 kjj yah 411.3 (M + H) + 806317 NH2 kJJ Ah 398.2 (M + H) + 85762 -155- 200412345 85762

-156--156-

200412345 85762200412345 85762

157- 200412345 806402 α^α&gt;^Η2 Η ΝγΝΗ 411.2 (Μ+Η)+ 433.2 (M+Na)+ 806417 Η ΝγΝΗ 397.1 (Μ+Η)+ 806419 9 νη2 469·2 (Μ+Η)+ 806421 511.2 (Μ+Η)+ 806435 1 νη2 〇ν〇&gt;^ Η ΝγΝΗ 411.3 (Μ+Η)+ 806437 = νη2 Η Ν^ΝΗ 411.3 (Μ+Η)+ 806569 9 νη2 11^1 丫 Η 452.3 (Μ+Η)+ 806609 σ:^α^: 495.3 (Μ-Η)' 85762 -158- 200412345157- 200412345 806402 α ^ α &gt; ^ Η2 Η ΝγΝΗ 411.2 (Μ + Η) + 433.2 (M + Na) + 806417 Η ΝγΝΗ 397.1 (Μ + Η) + 806419 9 νη2 469 · 2 (Μ + Η) + 806421 511.2 (Μ + Η) + 806435 1 νη2 〇ν〇 &^; ^ Η ΝγΝΗ 411.3 (Μ + Η) + 806437 = νη2 Η Ν ^ ΝΗ 411.3 (Μ ++) + 806569 9 νη2 11 ^ 1 452.3 (Μ + Η) + 806609 σ: ^ α ^: 495.3 (Μ-Η) '85762 -158- 200412345

806610 nh2 OMe H N^/NH 425.4 (M-H)' 806647 〇?叫: 496.3 (M+H)+ 806653 ? /NH2 454.3 (M+H)+ 806671 bxO^2 H N^NH 409.3 (M+H)+ 806781 MeO. ^ Ί 9 NH 丄 HNMR 806790 nh2 〇Vv〇^: J 〗H N NH 6 509.3 (M-H)&quot; 806796 H H N 丫 NH 'HNMR806610 nh2 OMe HN ^ / NH 425.4 (MH) '806647 〇? Name: 496.3 (M + H) + 806653? / NH2 454.3 (M + H) + 806671 bxO ^ 2 HN ^ NH 409.3 (M + H) + 806781 MeO. ^ Ί 9 NH 丄 HNMR 806790 nh2 〇Vv〇 ^: J 〖HN NH 6 509.3 (MH) &quot; 806796 HHN ^ NH 'HNMR

85762 -159- 200412345 806820 H ΝγΝΗ 496.3 (M+H)+ 806839 Cl 0 MU H N 丫 NH 467.2 (M+Na)+ 806840 J nh2 Η Ν^,ΝΗ 467.2 (M+Na)+ 806841 H N^NH 445.3 (M+H)+ 806842 nh2 H N^NH 397.3 (M+H)+ 806843 Fjy〇J〇&gt;^：H2 H N^NH 483.3 (M+H)+ 505.3 (M+Na)+ 806844 nh2 H N 丫 NH 363.3 (M+H)+ 3853 (M+Na)+ 806860 H T 1 _/NH2 H n^nh 496.3 (M+H)+ 85762 -160- 200412345 85762 806874 Η H νη L〇J Η ν^νη 'HNMR 806875 Η ^Υ〇〇 ΝΗ: 1 1 Μ Ν^ΝΗ 'HNMR 806878 〇νΧο&gt;^ Η Ν 丫 ΝΗ 'HNMR 806899 ? ·νη2 0 Η Ν丫 ΝΗ 丄HNMR 806900 νη2 0 Η Ν丫ΝΗ [H NMR 806901 FjD^OyCcy·^ 0 Η Ν丫ΝΗ 497.1 (M+H)+ 806902 νη2 0 Η Ν 丫 ΝΗ 377.3 (M+H)+ 161 -85762 -159- 200412345 806820 H ΝγΝΗ 496.3 (M + H) + 806839 Cl 0 MU HN AH NH 467.2 (M + Na) + 806840 J nh2 Η Ν ^, ΝΗ 467.2 (M + Na) + 806841 HN ^ NH 445.3 ( M + H) + 806842 nh2 HN ^ NH 397.3 (M + H) + 806843 Fjy〇J〇 &^; ^: H2 HN ^ NH 483.3 (M + H) + 505.3 (M + Na) + 806844 nh2 HN λNH 363.3 (M + H) + 3853 (M + Na) + 806860 HT 1 _ / NH2 H n ^ nh 496.3 (M + H) + 85762 -160- 200412345 85762 806874 Η H νη L〇J Η ν ^ νη 'HNMR 806875 Η ^ Υ〇〇ΝΗ: 1 1 Μ Ν ^ ΝΗ 'HNMR 806878 〇ν × ο &gt; ^ Ν Ν ΝΝΝΗ' HNMR 806899? · Νη2 0 Η ΝΑΝΗ 丄 HNMR 806900 νη2 0 Η ΝΑΝΗ [H NMR 806901 FjD ^ OyCcy · ^ 0 Η Ν 丫 ΝΗ 497.1 (M + H) + 806902 νη2 0 Η Ν ΑΝΝΗ 377.3 (M + H) + 161-

200412345 806903 Cl fUU Η Ν^ΝΗ 431.1 (Μ+Η)+ 806904 νη2 c，1X'Xcv^n Η Ν^ΝΗ 431.2 (Μ+Η)+ 806905 νη2 c1JX'O&gt;^n Η Ν^ΝΗ 431.2 (Μ+Η)+ 806987 Η ΝγΝΗ 441.3 (Μ+Η)+ 463.2 (M+Na)+ 807014 Η ΝγΝΗ 343.3 (M+Na)+ 807139 (^α^Η2 OMe Η Ν 丫 ΝΗ 丄 HNMR 807140 ΝΗ2 Η Ν^ΝΗ 427.3 (M+H)+ 807183 Μθ〇 〇 MU Η Ν^ΝΗ 463.3 (M+Na)+ 441.3 (M+H)+ 85762 162- 200412345200412345 806903 Cl fUU Η Ν ^ ΝΗ 431.1 (Μ + Η) + 806904 νη2 c, 1X'Xcv ^ n Η Ν ^ ΝΗ 431.2 (Μ + Η) + 806905 νη2 c1JX'O &gt; ^ n Η Ν ^ ΝΗ 431.2 (ΜΜ + Η) + 806987 Η ΝγΝΗ 441.3 (Μ + Η) + 463.2 (M + Na) + 807014 Η ΝγΝΗ 343.3 (M + Na) + 807139 (^ α ^ Η2 OMe Η Ν ΝΝΝΗ 丄 HNMR 807140 ΝΗ2 Η Ν ^ ΝΗ 427.3 (M + H) + 807183 Μθ〇〇MU Η Ν ^ ΝΗ 463.3 (M + Na) + 441.3 (M + H) + 85762 162- 200412345

807377 nh2 F3Cxt^o^ H N 丫 NH [Η NMR 807392 nh2 H N 丫、NH !hnmr 807400 nh2 H N 丫 NH !hnmr 807401 H NH2 OXO)^ Η H N^NH 反式外消旋 T 'Η NMR 807399 Η ΝΗ2 CDXcv^， Η Η Ν^ΝΗ 順式外消旋 Τ 'Η NMR 807447 Η Ν 丫 ΝΗ 'HNMR 807448 νη2 Π Η Ν?Η 'Η NMR 807449 νη2 ^NMR807377 nh2 F3Cxt ^ o ^ HN ^ NH [Η NMR 807392 nh2 HN ^, NH! Hnmr 807400 nh2 HN ^ NH! Hnmr 807401 H NH2 OXO) ^ Η HN ^ NH trans racemic T 'Η NMR 807399 Η ΝΗ2 CDXcv ^, Η Ν Ν ^ ΝΗ cis-racemic T 'Η NMR 807447 Η Ν ΑΝΗ' HNMR 807448 νη2 Π Η Ν? Η 'Η NMR 807449 νη2 ^ NMR

85762 -163- 200412345 807450 nh2 ocf3 h n 丫、nh 481.1 (M+H)+ 807451 nh2 H N^NH 481.1 (M+H)+ 807452 nh2 cl H N 丫， 465.1 (M+H)+ 807453 nh2 Fxr H N 丫 NH lR NMR 807454 nh2 (T'XCV^N F H N 丫 NH !h nmr 807457 0^Xc^: H N^NH [HNMR 807458 〒F3 NH2 H n^nh [HNMR 807459 nh2 0ΙΤΤ'Ί〇ν^Ν Cl H N 丫'NH 丄 HNMR 807460 ρ3^〇 nh2 H N^NH t 481.1 (M+H)+85762 -163- 200412345 807450 nh2 ocf3 hn, nh 481.1 (M + H) + 807451 nh2 HN ^ NH 481.1 (M + H) + 807452 nh2 cl HN, 465.1 (M + H) + 807453 nh2 Fxr HN AH lR NMR 807454 nh2 (T'XCV ^ NFHN ah NH! h nmr 807457 0 ^ Xc ^: HN ^ NH [HNMR 807458 〒F3 NH2 H n ^ nh [HNMR 807459 nh2 0ΙΤΤ'Ί〇ν ^ Ν Cl HN aya'NH丄 HNMR 807460 ρ3 ^ 〇nh2 HN ^ NH t 481.1 (M + H) +

85762 -164- 20041234585762 -164- 200412345

807460 nh2 1 H N^NH [H NMR 807463 nh2 cTkXcv^， H N 丫 NH 'HNMR 807464 nh2 H N^NH 'H NMR 807465 Cl /NH2 H N 丫 NH 'HNMR 807466 nh2 H n^nh 'HNMR 807467 nh2 H n^nh 'HNMR 807469 nh2 H n^nh !H NMR 807497 nh2 1 H N^/NH 'HNMR 807498 nh2 H N 丫 NH 'HNMR 85762 -165- 200412345807460 nh2 1 HN ^ NH [H NMR 807463 nh2 cTkXcv ^, HN ^ NH'HNMR 807464 nh2 HN ^ NH 'H NMR 807465 Cl / NH2 HN ^ NH' HNMR 807466 nh2 H n ^ nh 'HNMR 807467 nh2 H n ^ nh 'HNMR 807469 nh2 H n ^ nh! H NMR 807497 nh2 1 HN ^ / NH' HNMR 807498 nh2 HN ^ NH 'HNMR 85762 -165- 200412345

807505 nh2 H 丫&quot; !hnmr 807506 n~λ NH2 H n^nh 'hnmr 807528 nh2 Kj h n^；nh }HNMR 807531 nh2 H N 丫、NH !hnmr 807532 nh2 (X^Xc^ H N^NH 'HNMR 807543 nh2 (rr〇v^N kj h 丫H 'HNMR 807544 nh2 丫 Θ 'HNMR 807548 nh2 CN H N^NH 'HNMR 807549 丄 HNMR807505 nh2 H ah &quot;! Hnmr 807506 n ~ λ NH2 H n ^ nh 'hnmr 807528 nh2 Kj hn ^; nh} HNMR 807531 nh2 HN ah, NH! Hnmr 807532 nh2 (X ^ Xc ^ HN ^ NH' HNMR 807543 nh2 (rr〇v ^ N kj h ^ H 'HNMR 807544 nh2 ^ Θ' HNMR 807548 nh2 CN HN ^ NH 'HNMR 807549 丄 HNMR

85762 -166- 20041234585762 -166- 200412345

807550 Η N^NH [HNMR 807562 nh2 〇 H NrNH 'HNMR 807571 nh2 H n^nh 'HNMR 807573 nh2 cr?^〇cv^N H ΝγΝΗ 387.3 (M+H)+ 807586 Cl /nh2 H n^/NH 'H NMR 807636 nh2 CT'Xcv^N H N 丫 NH ^NMR 807649 °ro&gt;·^: H N 丫 NH 'HNMR 807660 'X0-^N H N 丫 NH 'HNMR 807662 nh2 H N 丫 NH 'HNMR807550 Η N ^ NH [HNMR 807562 nh2 〇H NrNH 'HNMR 807571 nh2 H n ^ nh' HNMR 807573 nh2 cr? ^ 〇cv ^ NH ΝγΝΗ 387.3 (M + H) + 807586 Cl / nh2 H n ^ / NH 'H NMR 807636 nh2 CT'Xcv ^ NHN ^ NH ^ NMR 807649 ° ro &gt; ... ^: HN ^ NH NMR 807660 'X0- ^ NHN ^ NH' HNMR 807662 nh2 HN ^ NH 'HNMR

85762 -167- 200412345 807663 丄 」H2 H N^NH XHNMR 807703 nh2 H N 丫 NH 'HNMR 807704 nh2 H N 丫 NH !h nmr 807748 nh2 crrxo-^N H ΝγΝΗ 'HNMR 807749 nh2 今 H nvnh T 'H NMR 807751 H N^NH !h NMR 807754 ar〇&gt;^2 H N^NH lH NMR 807758 a'Xcv^N&quot; H n^nh !hnmr 807762 十Ία NH2 H 丫Η 'hnmr85762 -167- 200412345 807663 丄 `` H2 HN ^ NH XHNMR 807703 nh2 HN ^ NH 'HNMR 807704 nh2 HN ^ NH! H nmr 807748 nh2 crrxo- ^ NH ΝγΝΗ' HNMR 807749 nh2 Today H nvnh T 'H NMR 807751 HN ^ ! h NMR 807754 ar〇 &gt; ^ 2 HN ^ NH lH NMR 807758 a'Xcv ^ N &quot; H n ^ nh! hnmr 807762 Ίαα NH2 H 丫 Η 'hnmr

85762 -168- 200412345 8576285762 -168- 200412345 85762

807779 ^X^H2 H N 丫 NH lU NMR 807794 nh2 HO HCI H NyNH 'HNMR 807836 nh2 H N^NH 'H NMR 807862 nh2 〇n^^n H N 丫 NH [HNMR 807876 nh2 HCI H N^NH 了 丄 HNMR 807892 nh2 F2HCXTO&gt;^n H N^NH !hnmr 807920 〇人广1 nh2 H N^NH !hnmr 807930 nh2 χτ〇&gt;^ H n^nh 'hnmr 807931 nh2 OH H ΝγΝΗ 'HNMR -169- 200412345807779 ^ X ^ H2 HN ^ NH lU NMR 807794 nh2 HO HCI H NyNH 'HNMR 807836 nh2 HN ^ NH' H NMR 807862 nh2 〇n ^^ n HN ^ NH [HNMR 807876 nh2 HCI HN ^ NH is 丄 HNMR 807892 nh2 F2HCXTO &; ^ n HN ^ NH! hnmr 807920 〇renguang1 nh2 HN ^ NH! hnmr 807930 nh2 χτ〇 &gt; ^ H n ^ nh 'hnmr 807931 nh2 OH H ΝγΝΗ' HNMR -169- 200412345

807952 Γΐ 」_ Η Ν 丫 ΝΗ 'Η NMR 807956 Η Ν 丫 ΝΗ 'HNMR 807962 °τα&gt;^Η2 Η Ν^ΝΗ 'Η NMR 807977 Γΐ 」νη2 Η Ν 丫 ΝΗ 丄 HNMR 807978 °^Xcv^H2 Η Ν 丫 ΝΗ 'Η NMR 807980 Η Νν,ΝΗ 'Η NMR 808028 Η Ν^ΝΗ [Η NMR 808039 νη2 cto^n Η Ν^ΝΗ 'HNMR 85762 -170- 200412345807952 Γΐ '' _ Η Ν ΑΝΝΗ 'Η NMR 807956 Η Ν ΝΝΗ' HNMR 807962 ° τα &gt; ^ Η2 Η Ν ^ ΝΗ 'Η NMR 807977 Γΐ `` νη2 Η Ν ΝΝΗ 丄 HNMR 807978 ° ^ Xcv ^ H2 Η Ν Ν ΝΗ 'Η NMR 807980 Η Νν, ΝΗ' Η NMR 808028 Η Ν ^ ΝΗ [Η NMR 808039 νη2 cto ^ n Η Ν ^ ΝΗ 'HNMR 85762 -170- 200412345

808069 η /ΝΗ2 Η Ν^ΝΗ 'HNMR 808078 νη2 F Η Ν 丫 ΝΗ 'Η NMR 808079 νη2 1 Η Ν^ΝΗ Τ jHNMR 808084 Η Ν 丫 ΝΗ !Η NMR 808086 F ρΛΓχ ；ΝΗ^ Η Ν^ΝΗ !Η NMR 808101 νη2 0ΠΧι&gt;^ Η Ν^,ΝΗ 'HNMR 808102 Η Η^ΗΗ 丄 HNMR 808107 νη2 ίΧ^α&gt;^ Η ΝγΝΗ [HNMR808069 η / ΝΗ2 Η Ν ^ ΝΗ 'HNMR 808078 νη2 F Η ΝΝΝΗ' Η NMR 808079 νη2 1 Η Ν ^ ΝΗ Τ jHNMR 808084 Η Ν ΝΝΗ! Η NMR 808086 F ρΛΓχ; ΝΗ ^ Η Ν ^ ΝΗ! 808101 νη2 0Πχι &gt; ^ Η Ν ^, ΝΗ 'HNMR 808102 Η Η ^ ΗΗ 丄 HNMR 808107 νη2 ίΧ ^ α &gt; ^ Η ΝγΝΗ [HNMR

85762 171 - 20041234585762 171-200412345

808151 Λ Η Ν 丫 ΝΗ 'HNMR 808153 νη2 Η Ν^ΝΗ 'HNMR 808164 Π /ΝΗ2 Η Ν 丫 ΝΗ jHNMR 808247 MeO/, Q I2 Η ΝγΝΗ 'hnmr 808254 Jxc^2 kj '丫Η 'hnmr 808255 ’〇、Ξ νη2 H N^/NH 'HNMR 808283 cf3co2h h 丫h 'HNMR 808290 H N 丫 NH 'HNMR 85762 -172- 200412345808151 Λ Η Ν ΝΝΝΗ 'HNMR 808153 νη2 Η Ν ^ ΝΗ' HNMR 808164 Π / ΝΗ2 Η ΝγΝΗ jHNMR 808247 MeO /, Q I2 Η ΝγΝΗ 'hnmr 808254 Jxc ^ 2 kj' 丫 Η 'hnmr 808255'〇, νη2 HN ^ / NH 'HNMR 808283 cf3co2h h ah h' HNMR 808290 HN ah NH 'HNMR 85762 -172- 200412345

85762 -173- 20041234585762 -173- 200412345

808371 nh2 Η N^NH !hnmr 808387 νη2 cf3co2h H ΝγΝΗ [HNMR 808548 nh2 H ΝγΝΗ 丄 HNMR 808661 &quot;W H N 丫 NH 丄 HNMR 808663 σ6^Η2 H N^NH 'HNMR 808665 〇s M N^NH 'HNMR 808675 /〇/ΎνΊ /nh^ ^〇v^N HI H N^iH 'HNMR 808702 〇Cr0cv^H2 H ΝγΝΗ 'HNMR 85762 -174- 200412345808371 nh2 Η N ^ NH! Hnmr 808387 νη2 cf3co2h H ΝγΝΗ [HNMR 808548 nh2 H ΝγΝΗ 丄 HNMR 808661 &quot; WHN ^ NH 丄 HNMR 808663 σ6 ^ Η2 HN ^ NH 'HNMR 808665 〇s MN ^ NH' ΎνΊ / nh ^ ^ 〇v ^ N HI HN ^ iH 'HNMR 808702 〇Cr0cv ^ H2 H ΝγΝΗ' HNMR 85762 -174- 200412345

將偶氮二羧酸二乙酯（9.1微升，2·0當量），於室溫下，添 加至17 (20 φ克’ 0.03毫莫耳，ι·〇當量）、三苯膦（15毫克，2·〇 當量）及鄰苯二甲醯亞胺（8.5毫克，2.0當量）在甲苯(2毫升） 中之溶液内，並將所形成之混合物攪拌19小時。使反應混 合物濃縮，並使中間物藉層析純化（30% EtOAc-己烷），而得19.3 毫克（81% )。使此中間物溶於二氯甲烷與三氟醋酸之1 : 1混 合物（2毫升）中，並在室溫下攪拌2小時，直到反應完成為 止。然後，以飽和NaHC03 (15毫升）小心地使反應淬滅，以7x10 毫升EtOAc萃取。使合併之萃液以Na2 S〇4脫水乾燥，過濾， 濃縮，並使產物藉逆相HPLC純化（MeOH-水），獲得ER-806286 (2.4 毫克，24%)。MS(ES)423.2 (M+H)+· -175 - 85762 200412345Diethyl azodicarboxylate (9.1 μl, 2.0 equivalents) was added at room temperature to 17 (20 φ g '0.03 mmol, ι · 〇 equivalent), triphenylphosphine (15 mg , 2.0 equivalents) and phthalimide (8.5 mg, 2.0 equivalents) in a solution of toluene (2 ml), and the resulting mixture was stirred for 19 hours. The reaction mixture was concentrated and the intermediate was purified by chromatography (30% EtOAc-hexane) to give 19.3 mg (81%). This intermediate was dissolved in a 1: 1 mixture of dichloromethane and trifluoroacetic acid (2 ml) and stirred at room temperature for 2 hours until the reaction was completed. The reaction was then carefully quenched with saturated NaHC03 (15 mL) and extracted with 7x10 mL of EtOAc. The combined extracts were dried over Na2S04, filtered, concentrated, and the product was purified by reverse-phase HPLC (MeOH-water) to obtain ER-806286 (2.4 mg, 24%). MS (ES) 423.2 (M + H) + · -175-85762 200412345

τ ER-806287 化合物ER-806287係按照關於製備ER-806286之相同程序，製 自 4-三氟甲基酚。MS (ES) 438·2 (M+H)+ ·τ ER-806287 Compound ER-806287 was prepared from 4-trifluoromethylphenol according to the same procedure as for the preparation of ER-806286. MS (ES) 438 · 2 (M + H) + ·

T ER-806311 將18 (12.5毫克，0.018毫莫耳）、二異丙基乙胺（0·2毫升，65 當量）及硫酚（10微升，5.5當量）在DMF (0.5毫升）中之混合物 ，於室溫下攪拌兩天。使反應混合物濃縮，並藉層析純化（30 % EtOAc-己烷），而得中間物12.7毫克（92% )。使此中間物與 甲苯醚（100微升）溶於二氯甲烷與三氟醋酸之1 : 1混合物（2 毫升）中，並在室溫下攪拌40分鐘。然後，以飽和NaHC03 (15 毫升）小心地使反應淬滅，以7xEtOAc萃取。使合併之萃液以 Na2S04脫水乾燥，過濾，濃縮，並使產物藉層析純化（5% MeOH-EtOAc)，獲得 ER-806311 (4.5 毫克，65%)。MS(ES) 386.2 (M+H)'T ER-806311 mixes 18 (12.5 mg, 0.018 mmol), diisopropylethylamine (0.2 ml, 65 eq) and thiophenol (10 µl, 5.5 eq) in DMF (0.5 ml) The mixture was stirred at room temperature for two days. The reaction mixture was concentrated and purified by chromatography (30% EtOAc-hexanes) to give 12.7 mg (92%) of the intermediate. This intermediate and toluene ether (100 µl) were dissolved in a 1: 1 mixture (2 ml) of dichloromethane and trifluoroacetic acid and stirred at room temperature for 40 minutes. The reaction was then carefully quenched with saturated NaHC03 (15 mL) and extracted with 7xEtOAc. The combined extracts were dried over Na2S04, filtered, concentrated, and the product was purified by chromatography (5% MeOH-EtOAc) to obtain ER-806311 (4.5 mg, 65%). MS (ES) 386.2 (M + H) '

T ER-806355 85762 -176- 200412345 將氯化甲基磺醯（9微升，2當量），於〇°C下，添加至17 (40.5 毫克’ 0.058毫莫耳）與二異丙基乙胺（1〇〇微升，1〇當量）在二 氣甲燒（1毫升）至中之溶液内，並攪拌30分鐘。引進本羥基 六氫说淀（30毫克，5.0當量）與DMF (0.5毫升），並使反應混合 物溫熱至室溫，及攪拌2·5天。以飽和NaHC03 (10毫升）使反 應淬滅，並將已分離之水相以4xEtOAc萃取。使合併之有機 萃液以Na〗SO*脫水乾燥，過濾，及濃縮，且使產物藉逆HpLC 純化（MeOH-水）’而得中間物（25毫克，65% )。使此中間物 溶於二氯甲烷（〇·5毫升）中，並在室溫下，以TPAP(5毫克）與!^4〇 (20毫克）處理1〇分鐘。藉由添加水與Na2S2〇3使反應淬滅， 以4xEtOAc萃取。使合併之有機萃液以Na2s〇4脫水乾燥，過 濾，並濃縮，且使產物藉層析純化（15% EtOAc-己烷），獲得 中間物（13.7毫克）。使此中間物與甲苯醚（10〇微升）溶於二氯 甲烷（1毫升）中，並在室溫下，以三氟醋酸（1毫升）處理4小 時。然後，以飽和NaHC03 (15毫升）小心地使反應淬滅，以 4xEtOAc萃取。使合併之萃液以Na2s〇4脫水乾燥，過濾，濃 縮，並使產物藉逆相HPLC純化（MeOH-:水），而得ER-806355 (3.4 毫克，16%，歷經三個步驟）。iHNMR(DMSO-d6) (52.35(t，J = 6Hz， 4H)，2·49 (s，3H)，2.70 (t，J = 6 Hz，4H)，3.67 (s，2H)，5.74 (s，2H)，6.73 (s，1H)， 7.16 (dd，J = 8.2 與 1_2 Hz，1H)，7.28 (d，J = 1.2 Hz，1H)，7.53 (d，J = 8·2,1H)， 7.55 (s? 1H). 85762T ER-806355 85762 -176- 200412345 Add methylsulfonium chloride (9 μl, 2 eq.) At 0 ° C to 17 (40.5 mg '0.058 mmol) with diisopropylethylamine (100 microliters, 10 equivalents) in a solution of dichloromethane (1 ml) to the solution and stirred for 30 minutes. Introduce hexahydroxanthine (30 mg, 5.0 equivalents) and DMF (0.5 ml), and allow the reaction mixture to warm to room temperature and stir for 2.5 days. The reaction was quenched with saturated NaHC03 (10 mL), and the separated aqueous phase was extracted with 4xEtOAc. The combined organic extracts were dried over NaSO *, filtered, and concentrated, and the product was purified by reverse HpLC (MeOH-water) 'to give the intermediate (25 mg, 65%). This intermediate was dissolved in dichloromethane (0.5 ml) and treated with TPAP (5 mg) and! 40 (20 mg) at room temperature for 10 minutes. The reaction was quenched by adding water and Na2S203, and extracted with 4xEtOAc. The combined organic extracts were dried over Na 2 SO 4, filtered, and concentrated, and the product was purified by chromatography (15% EtOAc-hexanes) to give the intermediate (13.7 mg). This intermediate and toluene ether (100 µl) were dissolved in dichloromethane (1 ml) and treated with trifluoroacetic acid (1 ml) at room temperature for 4 hours. The reaction was then carefully quenched with saturated NaHC03 (15 mL) and extracted with 4xEtOAc. The combined extracts were dried over Na 2 SO 4, filtered, concentrated, and the product was purified by reverse-phase HPLC (MeOH-: water) to give ER-806355 (3.4 mg, 16% over three steps). iHNMR (DMSO-d6) (52.35 (t, J = 6Hz, 4H), 2.49 (s, 3H), 2.70 (t, J = 6 Hz, 4H), 3.67 (s, 2H), 5.74 (s, 2H), 6.73 (s, 1H), 7.16 (dd, J = 8.2 and 1_2 Hz, 1H), 7.28 (d, J = 1.2 Hz, 1H), 7.53 (d, J = 8.2, 1H), 7.55 (s? 1H). 85762

-177- 200412345 於室溫下，將過氧化氫（4毫升，在水中之30%，3.6當量） 添加至硫代嗎福啉（1.0克，9.7毫莫耳）在醋酸（12毫升）中之溶 液内。將所形成之混合物於100°C下攪拌過夜，冷卻至室溫 ，及濃縮。使得自殘留物之硫代嗎福琳亞颯自乙醇結晶， 為深色固體。按照關於製備64之一般程序，化合物ER-806401 係製自18與硫代嗎福啉亞颯。MS (ES) 417·2 (M+Na)+ ·-177- 200412345 Add hydrogen peroxide (4 ml, 30% in water, 3.6 equivalents) to thiomorpholine (1.0 g, 9.7 mmol) in acetic acid (12 ml) at room temperature. Inside the solution. The resulting mixture was stirred at 100 ° C overnight, cooled to room temperature, and concentrated. The thiomorphine from the residue was crystallized from ethanol as a dark solid. Following general procedures for preparation of 64, compound ER-806401 was prepared from 18 and thiomorpholine sulfonium. MS (ES) 417 · 2 (M + Na) + ·

r ER-806404 於室溫下，將18 (5毫克）與苄醇（100微升）之混合物以tBuOK (1毫升，1.66 Μ，在THF中）處理過夜。以飽和NaHC03使反應 混合物淬滅，並以3xEtOAc萃取。使合併之萃液以Na2 S〇4脫 水乾燥，過濾，濃縮，並使粗製中間物與甲苯醚（50微升）溶 於二氯甲烷（〇_5毫升）中，及在室溫下，以三氟醋酸（0.5毫升） 處理3小時。然後，以飽和NaHC03小心地使反應淬滅，以 4xEtOAc萃取。使合併之萃液以Na2S04脫水乾燥，過濾，濃 縮，並使產物藉薄層層析儀純化（10% MeOH/EtOAc)，獲得ER-806404 (1.0 毫克，37%)。MS (ES)384.2(M+H)+.r ER-806404 A mixture of 18 (5 mg) and benzyl alcohol (100 μl) was treated with tBuOK (1 mL, 1.66 M in THF) at room temperature overnight. The reaction mixture was quenched with saturated NaHC03 and extracted with 3xEtOAc. The combined extracts were dried over Na2S04, filtered, concentrated, and the crude intermediate and toluene ether (50 μl) were dissolved in dichloromethane (0-5 mL), and at room temperature, Trifluoroacetic acid (0.5 ml) was treated for 3 hours. The reaction was then carefully quenched with saturated NaHC03 and extracted with 4xEtOAc. The combined extracts were dried over Na2S04, filtered, concentrated, and the product was purified by thin layer chromatography (10% MeOH / EtOAc) to obtain ER-806404 (1.0 mg, 37%). MS (ES) 384.2 (M + H) +.

ER-806644 85762 -178- 200412345 於5-碘基啕哚（5·0克，20·6毫莫耳）、笨乙炔（3·4毫升，15當 量）及二乙胺（10毫升）在DMF(2毫升）中之溶液内，在氮大氣 及冷卻水溫度下’添加Pd(Ph3 P)4 (120毫克，〇 〇〇5當量）與CuI (39 毫克’ 〇·〇1當f ) ’並將所形成之混合物，在室溫下授摔3小 時。將反應物以飽和NaHC〇3 (50毫升）稀釋，以4χ3〇毫升Et〇Ac 萃取。使合併之萃液以Na〗SO4脫水乾燥，過滤，濃縮，並使 產物藉層析儀純化（15至20% EtOAc /己烷），而得苯基乙決 基 _1H-啕哚（4.41 克，98% )。 化合物5_本基乙決基丨嗓-1-叛酸第三-丁酿係按照關於從 吲哚-5-羧酸甲酯製備7(以啕哚-1，5-二羧酸μ第三_丁醋5_甲酉旨 作為貫例）之程序’製自5-苯基乙決基-ΙΗ-^丨嗓。 化合物5-苯基乙決基-2-三丁基锡燒基丨嗓小幾酸第丁酉旨 係按照關於從9製備10之程序，製自5-苯基乙決基4丨嗓小叛 酸第三-丁酯。 化合物ER-806644係按照製備13之程序，製自5_苯基乙決基_ 2-三丁基錫烷基丨哚小羧酸第三-丁酯與4 (R1==Me：)。‘MS 〇EQ 364.2 (M+H)+.ER-806644 85762 -178- 200412345 in 5-iodopyridine (5.0 g, 20.6 mmol), benzyne (3.4 ml, 15 eq) and diethylamine (10 ml) in DMF In a solution in (2 ml), Pd (Ph3 P) 4 (120 mg, 0.005 equivalent) and CuI (39 mg '0.001 equivalent f)' were added at the nitrogen atmosphere and the temperature of the cooling water. The resulting mixture was allowed to fall for 3 hours at room temperature. The reaction was diluted with saturated NaHC03 (50 mL) and extracted with 4 x 30 mL of EtoAc. The combined extracts were dried over NaSO4, filtered, concentrated, and the product was purified by chromatography (15 to 20% EtOAc / hexane) to give phenylethyl_1H-pyridol (4.41 g , 98%). Compound 5_benzylidene 丨 Hydroxy-1-butyric acid tertiary-butyrate is prepared in accordance with the preparation of 7 from methyl indole-5-carboxylic acid _Butyl vinegar 5_ formamidine is intended as an example) The procedure is made from 5-phenylethoxyl-lΗ- ^ 丨. The compound 5-phenylethoxy-2-tributyltin is a compound of diphenylsulfinic acid, which is prepared from 5-phenylethoxyl-4 in accordance with the procedure for preparing 10 from 9. -Butyl ester. Compound ER-806644 was prepared according to the procedure of Preparation 13 from 5-phenylethlyl-2-tributylstannyl indole small carboxylic acid third-butyl ester and 4 (R1 == Me :). ‘MS 〇EQ 364.2 (M + H) +.

將ER-806644 (6.5毫克）與Lindlar觸媒（50晕克）在thf (2毫升） 中之溶液，於室溫及氫氣下，攪拌1小時。將所形成之混合 物經過矽藻土過濾，並使濾液濃縮。將殘留固體以Et〇Ac洗 85762 -179- 200412345 滌數次，獲得ER-806645，為淡黃色固體（2.0毫克，31% )。MS (ES) 366.3 (M+H)+.；A solution of ER-806644 (6.5 mg) and Lindlar catalyst (50 g) in thf (2 ml) was stirred at room temperature under hydrogen for 1 hour. The resulting mixture was filtered through celite and the filtrate was concentrated. The residual solid was washed with EtOAc 85762-179-200412345 several times to obtain ER-806645 as a pale yellow solid (2.0 mg, 31%). MS (ES) 366.3 (M + H) + .;

ER-806646 將ER-806644 (5毫克）與Pd(OH)2(10毫克）在THF (2毫升）中之溶 液，於室溫及氫氣下，攪拌過夜。將所形成之混合物經過 矽藻土過濾，並使濾液濃縮，且使產物藉逆相HPLC純化 (MeOH-水），而得 ER-806646 (1.3 毫克，26% )。MS (ES) 368.3 (M+H)+ ·ER-806646 A solution of ER-806644 (5 mg) and Pd (OH) 2 (10 mg) in THF (2 ml) was stirred overnight at room temperature under hydrogen. The resulting mixture was filtered through celite, and the filtrate was concentrated, and the product was purified by reverse-phase HPLC (MeOH-water) to give ER-806646 (1.3 mg, 26%). MS (ES) 368.3 (M + H) +

T ER-806095 於室溫下，將16 (20毫克）在1 : 1 THF-MeOH (3毫升）中之溶 液，以1NHC1溶液（0.5毫升）處理30分鐘。將反應混合物以飽 和NaHC03稀釋，並以EtOAc萃取。使合併之萃液以Na2S04脫 水乾燥，過滤’濃縮’並使產物藉逆相HPLC純化（MeOH-水） ，獲得ER-806095(2.6 毫克，18%)。iHNMR·T ER-806095 treated a solution of 16 (20 mg) in 1: 1 THF-MeOH (3 ml) with 1NHC1 solution (0.5 ml) at room temperature for 30 minutes. The reaction mixture was diluted with saturated NaHC03 and extracted with EtOAc. The combined extracts were dried over Na2S04, filtered, 'concentrated' and the product was purified by reverse phase HPLC (MeOH-water) to obtain ER-806095 (2.6 mg, 18%). iHNMR ·

T ER-806420 85762 -180- 200412345 將ER-806393 (1.3毫克）在MeOH (0.5毫升）中之溶液，於室溫 下，以1 NLiOH溶液（0.1毫升）處理過夜。然後，以1NHC1溶 液（0.1毫升）使反應混合物中和至pH=5，及濃縮。使殘留物 溶於1: 1 MeOH-EtOAc中，及過滤。使滤液濃縮，並藉逆相HPLC 純化（MeOH-水），獲得 ER-806420 (0.5 毫克，40% )。MS (ES) 496.3 (M-H)·.T ER-806420 85762 -180- 200412345 A solution of ER-806393 (1.3 mg) in MeOH (0.5 ml) was treated with a 1 N LiOH solution (0.1 ml) at room temperature overnight. Then, the reaction mixture was neutralized with 1NHC1 solution (0.1 ml) to pH = 5, and concentrated. The residue was dissolved in 1: 1 MeOH-EtOAc and filtered. The filtrate was concentrated and purified by reverse-phase HPLC (MeOH-water) to obtain ER-806420 (0.5 mg, 40%). MS (ES) 496.3 (M-H) ..

將18 (15.5毫克，0.02毫莫耳）與甲胺（0.11毫升，2·0 Μ，在THF 中，1.0當量）在二氯甲烷（0.5毫升）中之混合物，於室溫下攪 拌過夜，以飽和NaHC03稀釋，並以3xEtOAc萃取。使合併之 萃液以Na2S04脫水乾燥，過濾，及濃縮。使殘留物溶於DMF(0.5 毫升）中，為溶液A。 將二異丙基乙胺（5.3微升，1.4當量），於室溫下，添加至 苯甲酸（3.4毫克，1.3當量）與TOTU (10毫克，1.4當量）在DMF (0·3 毫升）中之溶液内，並攪拌15分鐘。然後，經由以3x0.5毫升 DMF沖洗而引進溶液，並將所形成之混合物攪拌過夜，濃 縮，以飽和NaHC03稀釋，並以3xEtOAc萃取。使合併之萃液 以Na2 S〇4脫水乾燥，過遽，及濃縮。使殘留物與甲苯醚（50 微升）溶於二氯甲烷（0.5毫升）中，並在室溫下，以三氟醋酸（0.5 毫升）處理3小時。以飽和NaHC03與EtOAc小心地使反應混合 物淬滅，並將已分離之水相以3xEtAOc萃取。使合併之萃液 85762 -181 - 200412345 以Na〗S〇4脫水乾燥，過滤，濃縮，並使產物藉逆相hplc純 化（MeOH-水），：而得ER-806432 (1.4毫克，16%，歷經三個步驟） 。MS (ES) 411.2 (Μ+Η)+·A mixture of 18 (15.5 mg, 0.02 mmol) and methylamine (0.11 ml, 2.0 M in THF, 1.0 equivalent) in dichloromethane (0.5 ml) was stirred at room temperature overnight to Saturated NaHC03 was diluted and extracted with 3xEtOAc. The combined extracts were dried over Na2S04, filtered, and concentrated. The residue was dissolved in DMF (0.5 ml) as solution A. Diisopropylethylamine (5.3 μl, 1.4 eq) was added to benzoic acid (3.4 mg, 1.3 eq) and TOTU (10 mg, 1.4 eq) in DMF (0.3 ml) at room temperature. The solution was stirred for 15 minutes. Then, the solution was introduced by rinsing with 3x0.5 ml of DMF, and the resulting mixture was stirred overnight, concentrated, diluted with saturated NaHC03, and extracted with 3xEtOAc. The combined extracts were dried over Na2SO4, filtered, and concentrated. The residue was dissolved in toluene ether (50 µl) in dichloromethane (0.5 ml) and treated with trifluoroacetic acid (0.5 ml) at room temperature for 3 hours. The reaction mixture was carefully quenched with saturated NaHC03 and EtOAc, and the separated aqueous phase was extracted with 3xEtAOc. The combined extracts 85762 -181-200412345 were dried over Na 2 SO 4, filtered, concentrated, and the product was purified by reverse phase hplc (MeOH-water) to obtain ER-806432 (1.4 mg, 16%, Go through three steps). MS (ES) 411.2 (Μ + Η) + ·

5-硝基蚓哚-1-叛酸第三汀酯係按照關於從吲哚净羧酸甲醋 籲 製備7之相同程序，製自5-硝基吲嗓。 將5-硝基·^丨哚-1_羧酸第三-丁酿（〇·5〇克）與催化量之pd(〇H)2 在MeOH-EtOAc混合物中之溶液，於室溫及氫下，攪拌1小時 。將反應混合物經過矽藻土過濾，並使濾液濃縮，提供5_胺 基-2,3-二氫^引哚-丨_羧酸第三-丁酯（〇·44克，98% )。 將氯化苯甲醯（305微升，ι·5當量），於〇它下添加至5-胺基_2,3_ 二氫’噪小羧酸第三叮酯（4〇7毫克，1J4毫莫耳）與三乙胺 (1·2毫升，5.0當量）在二氯甲烷（5毫升）中之溶液内，·並將所 _ 形成之混合物攪拌15分鐘。然後，藉由添加飽*NaHC〇3使 反應淬滅，並將混合物以3xEt〇Ac萃取。使合併之萃液以 NazSO4脫水乾燥’過濾，濃縮，並使產物藉層析純化（2〇至 % EtOAc-己燒）’獲得5_苯甲醯胺基_2,3•二氫—丨哚羧酸第三-丁酯（588 毫克，100% )。 將氫化鈉（60毫克，1·5當量）於〇°C下添加至5-苯甲醯胺基-2,3-二氮’嗓-ι_羧酸第三_丁酯（57〇毫克，168毫莫耳）與碘化甲 烷（0.42毫升，4.0當量）在DMF (1〇毫升）中之混合物内，並將 85762 -182- 200412345 所形成之混合物攪拌20分鐘。於濃縮後，將得自反應混合 物之殘留物以靼和NaHC03稀釋，並以3xEtOAc萃取。使合併 之萃液以Na〗S〇4脫水乾燥，過濾，濃縮，並使產物藉層析純 化（30% EtOAc-己烷），而得5-(苯甲醯基甲基-胺基）_2,3_二氫』?丨 嗓-1-叛酸第三-丁醋（547毫克，93% )。 將5-(苯甲醯基-甲基-胺基）-2,3-二氫丨嗓-1-叛酸第三-丁酯 (500毫克）與Mn〇2 (5克）在甲苯（2〇毫升）中之混合物，於8〇°c 下加熱1小時。引進另外之Mn02(5克），並將所形成之混合 物於80°C下揽拌1小時。於冷卻至室溫後，將混合物經過矽 藻土過濾’並使濾液濃縮。使產物藉層析純化（3〇% EtOAc-己 烷），獲得5-(苯甲醯基-甲基-胺基 &gt;吲哚羧酸_丨_第三_丁醋（372 毫克，75% )。 5-(苯甲醯基-甲基-胺基）-2-三丁基錫烷基，哚小羧酸第三_ 丁酯係按照關於從9製備1〇之程序，製自5_(苯甲酸基_甲基_ 胺基）-#卜朵-1-叛酸第三-丁酯。 化合物ER-807313係按照關於製備13之程序，製自5-(苯甲驢 基甲基-胺基）-2-三丁基錫垸基丨嗓·小羧酸第三—丁酯與4 (Ri =Me)。MS (ES) 397.2 (M+H)+ 與 419.1 (M+Na)+ ·5-Nitroearmidine-1-teric acid tertene ester was prepared from 5-nitroindole according to the same procedure as for the preparation of 7 from indole carboxylic acid methyl acetate. A solution of 5-nitro-dodo-1-carboxylic acid tert-butane (0.50 g) and a catalytic amount of pd (〇H) 2 in a MeOH-EtOAc mixture, at room temperature and hydrogen Then, stir for 1 hour. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated to provide 5-amino-2,3-dihydroindoline-carboxylic acid tertiary-butyl ester (0.44 g, 98%). Add benzamidine chloride (305 microliters, 1 · 5 equivalents) to 5-amino-2,3_dihydro'no small carboxylic acid tert-butyl ester (407 mg, 1J4 mmol) Mol) and triethylamine (1.2 ml, 5.0 eq.) In dichloromethane (5 ml), and the resulting mixture was stirred for 15 minutes. The reaction was then quenched by the addition of saturated NaHC0 3 and the mixture was extracted with 3 × EtoAc. The combined extracts were dehydrated and dried over NazSO4, 'filtered, concentrated, and the product was purified by chromatography (20 to% EtOAc-hexane)' to obtain 5-benzylamino-2,3 • dihydro-indole Tertiary-butyl carboxylic acid (588 mg, 100%). Sodium hydride (60 mg, 1.5 equivalents) was added to 5-benzylamino-2,3-diazepine-carboxylic acid tertiary-butyl ester (57 mg, 168 millimolar) and methane iodide (0.42 ml, 4.0 eq) in DMF (10 ml), and the mixture formed by 85762-182-200412345 was stirred for 20 minutes. After concentration, the residue from the reaction mixture was diluted with osmium and NaHC03 and extracted with 3xEtOAc. The combined extracts were dried over Na2SO4, filtered, concentrated, and the product was purified by chromatography (30% EtOAc-hexane) to give 5- (benzylidenemethyl-amine) _2 , 3_dihydro ”? 丨 Homo-1-acid tertiary-butyric acid (547 mg, 93%). Combine 5- (benzylidene-methyl-amino) -2,3-dihydro 丨 3-butanoic acid tertiary-butyl ester (500 mg) with MnO2 (5 g) in toluene (2 (0 ml) and heated at 80 ° C for 1 hour. Another Mn02 (5 g) was introduced, and the resulting mixture was stirred at 80 ° C for 1 hour. After cooling to room temperature, the mixture was filtered through Celite 'and the filtrate was concentrated. The product was purified by chromatography (30% EtOAc-hexane) to give 5- (benzylidene-methyl-amino) &gt; indolecarboxylic acid tertiary-butyric acid (372 mg, 75% ). 5- (benzylidene-methyl-amino) -2-tributyltin alkyl, indole small carboxylic acid tert-butyl ester is prepared from 5- (benzoic acid) according to the procedure for preparing 10 from 9 -Methyl_amino group)-# Budor-1-tert-acid tert-butyl ester. Compound ER-807313 was prepared from 5- (benzylidenemethyl-amino group) according to the procedure for Preparation 13. -2-Tributyltin amidino 丨 Hydroxycarboxylic acid third-butyl ester with 4 (Ri = Me). MS (ES) 397.2 (M + H) + and 419.1 (M + Na) + ·

化合物ER-807015係在從立體位阻之胺類製備65之期間，以 副產物製成，並產生令人滿意之iHNMR光譜。 -183- 85762 200412345Compound ER-807015 was produced as a by-product during the preparation of sterically hindered amines 65 and produced a satisfactory iHNMR spectrum. -183- 85762 200412345

ER-807586 r 將 18 (51 毫克，1.0 當量）、（3,3-二甲基-1，5_二氧-螺[5,5]十一 -9-基）-甲基-胺鹽酸鹽（71毫克，4.0當量）、乙基二異丙基胺（0.25 毫升，20當量）及DMF (0.3毫升）在CH2C12(2.5毫升）中之混合 物，於室溫下攪拌23小時。於濃縮後，使殘留物溶於1NHC1 (0.6 毫升）與丙酮（0.6毫升）中，並在回流下加熱16小時。於冷卻 至室溫後，然後，以飽和NaHC03小心地使反應淬滅，以EtOAc 萃取，直到沒有產物被檢出為止。使合併之萃液以Na2S04脫 水乾燥，過濾，濃縮，並使產物藉逆相HPLC純化（MeOH-水） ，獲得 ER-807586 (6.4 毫克，22% )。1H NMR 與 MS (ES) 403.5 (M+H)+ ·ER-807586 r will be 18 (51 mg, 1.0 equivalent), (3,3-dimethyl-1,5-dioxo-spiro [5,5] undec-9-yl) -methyl-amine hydrochloride A mixture of salt (71 mg, 4.0 eq), ethyldiisopropylamine (0.25 ml, 20 eq) and DMF (0.3 ml) in CH2C12 (2.5 ml) was stirred at room temperature for 23 hours. After concentration, the residue was dissolved in 1NHC1 (0.6 ml) and acetone (0.6 ml) and heated under reflux for 16 hours. After cooling to room temperature, the reaction was then carefully quenched with saturated NaHC03 and extracted with EtOAc until no product was detected. The combined extracts were dried over Na2S04, filtered, concentrated, and the product was purified by reverse-phase HPLC (MeOH-water) to obtain ER-807586 (6.4 mg, 22%). 1H NMR and MS (ES) 403.5 (M + H) +

π Ν^ΝΗ ER-807759 ER-807759係按照關於13 (以ER-805639作為實例）在Stille偶合 反應中，及關於ER-807586，在縮酮水解反應中之相同程序 製成。iHNMR 與 MS(ES) 389 (M+H)+. 85762π Ν ^ ΝΗ ER-807759 ER-807759 was prepared according to the same procedure for 13 (taking ER-805639 as an example) in the Stille coupling reaction and for ER-807586 in the ketal hydrolysis reaction. iHNMR and MS (ES) 389 (M + H) +. 85762

ER-807789 -184- 200412345 於ER_807586 (5毫克，0.0124毫莫耳，1.0當量）在水（0.5毫升） 中之懸浮液内：，添加NH2OMe · HC1 (5.2毫克，0.623毫莫耳，50 當量）。此固體變成可溶性，且慢慢添加飽和NaHC03 (0.3毫 升），並將所形成之混合物攪拌過夜。以EtOAc與飽和NaHC03 稀釋反應混合物，並以4xEtOAc萃取。將有機層合併，以MgS04 脫水乾燥，過濾，及濃縮。使粗製混合物藉矽膠層析純化（10 % MeOH-EtOAc)，而得 ER-807789，為白色固體（5.3 毫克，100% ) 。1H NMR 與 MS (ES) 432 (M+H)+ ·ER-807789 -184- 200412345 in a suspension of ER_807586 (5 mg, 0.0124 mmol, 1.0 eq) in water (0.5 ml): with the addition of NH2OMe · HC1 (5.2 mg, 0.623 mmol, 50 eq) . This solid became soluble, and saturated NaHC03 (0.3 mL) was slowly added, and the resulting mixture was stirred overnight. The reaction mixture was diluted with EtOAc and saturated NaHC03 and extracted with 4xEtOAc. The organic layers were combined, dried over MgS04, filtered, and concentrated. The crude mixture was purified by silica gel chromatography (10% MeOH-EtOAc) to give ER-807789 as a white solid (5.3 mg, 100%). 1H NMR and MS (ES) 432 (M + H) +

ER-807790 於ER-807586 (15毫克）在MeOH-THF (1 : 1，1毫升）中之溶液 内，添加NaBH4(20毫克），並將混合物攪拌30分鐘，以飽和 NaHC03稀釋，及以4xEtOAc萃取。將有機層合併，以MgS04脫 水乾燥，過濾，及濃縮。使粗製混合物藉逆HPLC純化（MeOH-H20)，獲得 ER-807790。iHNMR 與 MS(ES)405.5 (M+H)+·ER-807790 in a solution of ER-807586 (15 mg) in MeOH-THF (1: 1, 1 ml), NaBH4 (20 mg) was added, and the mixture was stirred for 30 minutes, diluted with saturated NaHC03, and 4xEtOAc extraction. The organic layers were combined, dried over MgS04, filtered, and concentrated. The crude mixture was purified by reverse HPLC (MeOH-H20) to obtain ER-807790. iHNMR and MS (ES) 405.5 (M + H) + ·

ER-807835 於n-BuLi(1.6M，在己烷中，0.35毫升，0.56毫莫耳，31.3當 量）在THF (2.0毫升）中之溶液内，於〇°C下，添加甲基三苯基 溴化鱗（0.20克，0.56毫莫耳，31當量）。使反應物溫熱至室 85762 -185- 200412345 溫，並攪拌40分鐘。將一部份溶液(0.6毫升）轉移至另一個 燒瓶中，並添和ER-807586 (7.2毫克，0.0179毫莫耳，1.0當量） 。將所形成之混合物於室溫下攪拌18小時，並添加水，及 以3xEtOAc萃取混合物。將有機層合併，以MgS04脫水乾燥， 過濾，及濃縮。使粗製混合物藉逆HPLC純化（Me0H-H20)， 而得 ER-807835 (0.8 毫克，12% )。1H NMR 與 MS (ES) 401.5 (M+1 Η)·ER-807835 in a solution of n-BuLi (1.6M in hexane, 0.35 ml, 0.56 mmol, 31.3 eq) in THF (2.0 ml), at 0 ° C, methyl triphenyl was added Brominated scales (0.20 g, 0.56 mmol, 31 eq). The reaction was warmed to room temperature 85762 -185- 200412345 and stirred for 40 minutes. A portion of the solution (0.6 ml) was transferred to another flask and ER-807586 (7.2 mg, 0.0179 mmol, 1.0 equivalent) was added. The resulting mixture was stirred at room temperature for 18 hours, water was added, and the mixture was extracted with 3xEtOAc. The organic layers were combined, dried over MgS04, filtered, and concentrated. The crude mixture was purified by reverse HPLC (Me0H-H20) to give ER-807835 (0.8 mg, 12%). 1H NMR and MS (ES) 401.5 (M + 1 Η)

ER-807837 於 ER-807586(11.5 毫克，0.0286 毫莫耳，1·0 當量）在 THF(2.0 毫 升）中之溶液内，在0°C下，添加MeMgCl (3.0 Μ，在THF中，0.25 毫升，0.75毫莫耳，26.3當量）。使反應物溫熱，並於室溫下 攪拌18小時。以飽和NaHC03使反應淬滅，然後以3xEtOAc萃 取。將有機層合併，以MgS04脫水乾燥，過濾，及濃縮。使 所形成之混合物藉矽膠層析純化（100% EtOAc，然後10%至30 %MeOH-EtOAc)，獲得ER-807837(0.8 毫克，7%)。iHNMR 與 MS (ES) 419.4 (M+1H).ER-807837 was added to a solution of ER-807586 (11.5 mg, 0.0286 mmol, 1.0 equivalent) in THF (2.0 mL) at 0 ° C, and MeMgCl (3.0 M in THF, 0.25 mL) was added. , 0.75 millimoles, 26.3 equivalents). The reaction was warmed and stirred at room temperature for 18 hours. The reaction was quenched with saturated NaHC03 and extracted with 3xEtOAc. The organic layers were combined, dried over MgS04, filtered, and concentrated. The resulting mixture was purified by silica gel chromatography (100% EtOAc, then 10% to 30% MeOH-EtOAc) to obtain ER-807837 (0.8 mg, 7%). iHNMR and MS (ES) 419.4 (M + 1H).

ER-808036 5-氯基甲基-蚓哚小羧酸第三-丁酯係按照關於製備9之程序 85762 -186 - 200412345 ’但未添加嗎福啉，製自8。 將5-氯基甲基:，哚-1-羧酸第三·丁酯（〇·82克，3.10毫莫耳，ι·〇 當量）、環己硫醇(0.53毫升，1·4當量）及K2C03 (0.90克，2·〇當 量）在DMF (6毫升）中之混合物，於40 °C下加熱，直到反應完 成為止。使反應混合物冷卻至室溫，以飽和NH4 C1稀釋，並 以***萃取。使有機萃液以MgS04脫水乾燥，過漉，及濃縮 。藉層析使所形成之混合物純化（5% EtOAc /己烷），而得5_ 環己基硫基甲基，哚小羧酸第三丁酯（0.79克，74% )。 ER_808036係按照從14製備16之程序，製自5-環己基硫基甲 基4哚-1-羧酸第三-丁酯。ER-808036 Tertiary-butyl 5-chloromethyl-eardodol small carboxylic acid was prepared according to the procedure for preparation 9 85762 -186-200412345 ′ without adding morpholine. 5-Chloromethyl: tert-butyl ester of indole-1-carboxylic acid (0.82 g, 3.10 mmol, 1.00 equivalent), cyclohexanethiol (0.53 mL, 1.4 equivalent) And K2C03 (0.90 g, 2.0 equivalents) in DMF (6 ml), heated at 40 ° C until the reaction is complete. The reaction mixture was allowed to cool to room temperature, diluted with saturated NH4C1, and extracted with ether. The organic extract was dried over MgS04, dried, and concentrated. The resulting mixture was purified by chromatography (5% EtOAc / hexane) to give 5-cyclohexylthiomethyl, tert-butyl tricarboxylic acid (0.79 g, 74%). ER_808036 was prepared from 5-cyclohexylthiomethyl 4 indole-1-carboxylic acid tertiary-butyl ester according to the procedure of Preparation 16 from 14.

於ER-808036 (60毫克，0·15毫莫耳，1·〇當量）在THF (2.5毫升） 與MeOH (1.5毫升）中之溶液内，在_78°C下，添加mCPBA (60毫 克，〜70%，1·6當量）在THF中之溶液。在攪拌2小時後，藉 由添加飽和Na2 S2 〇3與飽和NaHC〇3使反應淬滅。將已分離之 水層以5xEtOAc萃取，並使合併之有機相以脫水乾燥 ，過濾，及k縮。使粗製混合物藉層析純化（5%至1〇% Me〇H/ EtOAc)，獲得半純產物（各18毫克與32毫克）。藉逆相進 一步純化（MeOH-水）後，獲得 ER-808082 (3.2 毫克）與 ER_808083 (3·2毫克）。1H NMR確認此兩種產物。 85762 -187- 200412345To a solution of ER-808036 (60 mg, 0.15 mmol, 1.0 equivalent) in THF (2.5 ml) and MeOH (1.5 ml), mCPBA (60 mg, ~ 70%, 1.6 equivalents) in THF. After stirring for 2 hours, the reaction was quenched by adding saturated Na2S2O3 and saturated NaHC03. The separated aqueous layer was extracted with 5xEtOAc, and the combined organic phases were dried over anhydrous, filtered, and concentrated. The crude mixture was purified by chromatography (5% to 10% MeOH / EtOAc) to give semi-pure products (18 mg and 32 mg each). After further purification by reverse phase (MeOH-water), ER-808082 (3.2 mg) and ER_808083 (3.2 mg) were obtained. 1H NMR confirmed these two products. 85762 -187- 200412345

α〇 將5-氯基甲基，哚小叛酸第三·丁酯（〇·41克，1.55毫莫耳，1·〇 當量）、環己醇（0.82毫升，5.0當量）及Ag20 (1.80克，5.0當量） 在***（5毫升）中之混合物，於35°C下，攪拌度過週末。於 冷卻至室溫後’將反應混合物經過碎藻土過滤，以酸洗務 。使濾液濃縮，並使殘留物藉層析純化（3% EtOAc /己烷）， 而得N-Boc-5-環己基氧基甲基吲嗓（160毫克，28% )，為無色 油。1HNMR確認此化合物。 ER-808103係按照關於從14製備16之程序，製自5-環己基氧 基甲基4哚-1-羧酸第三-丁酯。MS (ES)與1 H NMR兩者均確認 此化合物。α〇 5-chloromethyl, indole tertiary acid tert-butyl ester (0.41 g, 1.55 mmol, 1.0 equivalent), cyclohexanol (0.82 ml, 5.0 equivalent) and Ag20 (1.80 G, 5.0 eq.) In ether (5 ml) and stirred at 35 ° C over the weekend. After cooling to room temperature, the reaction mixture was filtered through celite and washed with acid. The filtrate was concentrated, and the residue was purified by chromatography (3% EtOAc / hexane) to give N-Boc-5-cyclohexyloxymethylindole (160 mg, 28%) as a colorless oil. 1HNMR confirmed the compound. ER-808103 was prepared from 5-cyclohexyloxymethyl 4 indole-1-carboxylic acid tertiary-butyl ester according to the procedure for preparing 16 from 14. Both MS (ES) and 1 H NMR confirmed this compound.

於化合物3(R=Me，300毫克，ι·〇3微莫耳，ι·〇當量）在THF(5 毫升）中之懸浮液内’在室溫下，逐滴添加LiAH4(1.0 Μ，在THF 中，2.56毫升，2.5當量），然後將所形成之混合物，於65它 下加熱30分鐘。冷卻至0°C後，藉由添加MeOH (L2毫升，30 當量）與水（30當量）使反應淬滅，攪拌，並溫熱至室溫，及 經過&gt;5夕藻土過濾’以EtOAc洗滌。使濾液濃縮，並使殘留物 85762 -188- 200412345 藉矽膠層析純化（EtOAc，然後i〇% MeOH-EtOAc)，獲得7-氯基· 2-甲基-5-甲胺墓-3H-咪唑并[4,5-b&gt;比啶，為白色固體（19〇毫克 ，94% ) 〇 ER_808040係按照關於製備13之程序，製自7-氯基-2-甲基-5. 甲胺基-3H-咪唑并[4,5七]峨啶與5-[(環己基-甲基-胺基）_甲基]_2_ 三丁基錫烷基4丨哚小羧酸第三-丁酿（按照關於製備1〇之程 序，製自8與環己基-甲基·胺）。iH NMR確認此化合物。In a suspension of compound 3 (R = Me, 300 mg, ι · 03 micromolar, ι · 〇 equivalent) in THF (5 ml) 'was added dropwise LiAH4 (1.0 M, at THF, 2.56 ml, 2.5 equivalents), and the resulting mixture was heated at 65 for 30 minutes. After cooling to 0 ° C, the reaction was quenched by the addition of MeOH (L2 mL, 30 eq) and water (30 eq), stirred, and warmed to room temperature, and filtered through &gt; Celite filter 'with EtOAc washing. The filtrate was concentrated and the residue 85762 -188- 200412345 was purified by silica gel chromatography (EtOAc, then 10% MeOH-EtOAc) to obtain 7-chloro. 2-methyl-5-methylamine tomb-3H-imidazole And [4,5-b &gt; pyridine, as a white solid (190 mg, 94%). ER_808040 was prepared from 7-chloro-2-methyl-5. Methylamino- according to the procedure for Preparation 13. 3H-imidazo [4,5 hepta] eridine and 5-[(cyclohexyl-methyl-amino) _methyl] _2_ tributyltinalkyl 4 丨 indole small carboxylic acid The procedure of 10 was made from 8 and cyclohexyl-methyl · amine). iH NMR confirmed this compound.

ER-808128ER-808128

於 ER-807790 (17 毫克，0.042 毫莫耳，1.0 當量）在 CH2C12(1 毫 升）中之溶液内，在〇°C下，添加（MeOCH2CH2)2NSF3(14微升， 1.8當量），並在〇°c下，將所形成之混合物攪拌i小時，及在 室溫下1小時。以飽和NaHC03使反應淬滅，並將已分離之水 層以，接著以EtOAc-THF (1 ·· 1)萃取。使合併之有機萃 液以Naz SO4脫水乾燥，過滤，及濃縮。使殘留物藉逆HpLC(MeOCH2CH2) 2NSF3 (14 microliters, 1.8 equivalents) was added to a solution of ER-807790 (17 mg, 0.042 millimoles, 1.0 equivalent) in CH2C12 (1 mL) at 0 ° C, and The resulting mixture was stirred for 1 hour at ° C and 1 hour at room temperature. The reaction was quenched with saturated NaHC03, and the separated aqueous layer was extracted with EtOAc-THF (1 ·· 1). The combined organic extracts were dried over Naz SO4, filtered, and concentrated. Reverse the residue by HpLC

純化（MeOHoJc)，而得 ER_808128(2 毫克，13%)。iHNMR 與 MS 確認此結構。Purified (MeOHoJc) to give ER_808128 (2 mg, 13%). iHNMR and MS confirmed this structure.

Boc 5_甲醯基吲哚小羧酸第三-丁酯或6_甲醯基吲哚- 1-叛酸第三-丁酯 於8 (8·0克，32.4毫莫耳，1當量）在CH2C12(24毫升）中之溶 85762 -189- 200412345 液内，在〇°C下，分次添加Dess-Martin試劑（17.9克，1.3當量） ，並使所形成泛混合物慢慢溫熱至室溫，且攪拌30分鐘。 將反應混合物以Ε^Ο (100毫升）稀釋，經過矽藻土過滤，以 EbO (50毫升）沖洗。將濾液以飽和NaHC〇3洗滌，以施2804脫 水乾燥，過濾，及濃縮。使粗產物與甲苯共沸，獲得甲酉f 基吲哚小羧酸第三-丁酯（7.3克，95% )，或以類似方式獲得6_ 甲醯基蚓哚小羧酸第三-丁酯。Boc tert-butyl 5-carboxymethylindole small carboxylic acid or tert-butyl 6-methylformylindole-1-metacarboxylic acid at 8 (8.0 g, 32.4 mmol, 1 equivalent) Dissolved in CH2C12 (24 ml) 85762 -189- 200412345, at 0 ° C, add Dess-Martin reagent (17.9 g, 1.3 equivalents) in portions, and slowly warm the resulting pan-mixture to room temperature. Warm and stir for 30 minutes. The reaction mixture was diluted with E ^ 0 (100 ml), filtered through celite, and washed with EbO (50 ml). The filtrate was washed with saturated NaHC03, dried over 2804, filtered, and concentrated. The crude product was azeotroped with toluene to obtain formamidine f-based indole small carboxylic acid third-butyl ester (7.3 g, 95%), or in a similar manner, 6-formamyl vermidoline small carboxylic acid third-butyl ester .

使Mg (鐵屑）經由以in HC1與Et；2 Ο洗;條而被活化，並於高直 空下乾燥過夜。將％ Ο (4毫升）中之溴基甲基環己垸（〇·8毫升 ’ 1當量），慢慢添加至Ε^Ο (10毫升）中之經活化Mg (418毫克 ’ 3當量）内，以保持内部溫度在3〇_33它下。將所形成之反應 混合物於34°C下加熱1小時，並冷卻至〇。〇。然後，引進5_甲 醯基吲哚-1_羧酸第三丁酯（900毫克）在恥〇 (15毫升）中之溶液 ’並使所形成之混合物溫熱至室溫，於30_32°c下加熱4小時 ，冷卻至室溫，接著，添加飽和使反應淬滅。將已分 離之水相以EtOAc萃取，使合併之有機層以MgS〇4脫水乾燥 ’過濾，及濃縮。使粗產物藉層析純化（10%至25% Et〇Ac / 己燒）’獲得其相應之醇（949毫克，85% )。 於醇（513毫克，1當量）與恥&gt;1(625微升，3當量）在CH2C12(15 毛升）中之混合物内，在〇°C下，添加甲烷磺酸酐（39〇毫克，15 85762 •190- 200412345 當量）。移除冷卻浴，並將所形成之混合物攪拌25小時，及 以飽和NaHC〇3稀釋。以α^α2萃取已分離之水層。使合併之 有機層以NazSO4脫水乾燥，過濾，及濃縮。使粗產物藉層析 純化（己烷至10% EtOAc /己烷），獲得環己基-乙烯基）-啕 哚小羧酸第三_丁酯（380毫克，78% )。 ER-808281係按照關於從14製備16之程序，製自5_(2_環己基_ 乙烯基）-啕哚-1-羧酸第三-丁酯。MS(ES)與iHNMR確認此化 合物。Mg (iron shavings) was activated by washing the strips in HC1 and Et; 20, and dried under high vacuum overnight. Bromomethylcyclohexane (0.8 mL '1 equivalent) in% Ο (4 mL) was slowly added to activated Mg (418 mg' 3 equivalent) in E ^ 0 (10 mL) To keep the internal temperature below 30_33. The resulting reaction mixture was heated at 34 ° C for 1 hour and cooled to zero. 〇. Then, a solution of tert-butyl 5-methylindole-l-carboxylic acid (900 mg) in O (15 ml) was introduced and the resulting mixture was warmed to room temperature at 30-32 ° C. After heating for 4 hours and cooling to room temperature, the reaction was quenched by adding saturation. The separated aqueous phase was extracted with EtOAc, and the combined organic layers were dried over MgS04, filtered, and concentrated. The crude product was purified by chromatography (10% to 25% EtoAc / hexane) to obtain its corresponding alcohol (949 mg, 85%). To a mixture of alcohol (513 mg, 1 eq) and shame &gt; 1 (625 μl, 3 eq) in CH2C12 (15 gross liters), add methanesulfonic anhydride (39 mg, 15 85762 • 190- 200412345 equivalent). The cooling bath was removed, and the resulting mixture was stirred for 25 hours and diluted with saturated NaHC03. The separated aqueous layer was extracted with α ^ α2. The combined organic layers were dried over NazSO4, filtered, and concentrated. The crude product was purified by chromatography (hexane to 10% EtOAc / hexane) to give cyclohexyl-vinyl) -oxindole small carboxylic acid tert-butyl ester (380 mg, 78%). ER-808281 was prepared from 5- (2-cyclohexyl_vinyl) -oxindole-1-carboxylic acid tertiary-butyl ester according to the procedure for preparing 16 from 14. MS (ES) and iHNMR confirmed the compound.

使ER-808281 (〜10毫克，1當量）在MeOH (5毫升）中，並具有1〇 % Pd/C (觸媒）之溶液，於正Η?大氣及室溫下，保持過夜。然 後，將混合物裝填於矽膠上，以EtOAc至20% MeOH/EtOAc溶 離’而得ER-808469 (7_5毫克）。MS (ES)與1 H NMR確認此化合 物0A solution of ER-808281 (~ 10 mg, 1 eq.) In MeOH (5 ml) and 10% Pd / C (catalyst) was kept in the atmosphere at room temperature overnight. Then, the mixture was packed on silica gel and dissolved with EtOAc to 20% MeOH / EtOAc to obtain ER-808469 (7-5 mg). MS (ES) and 1 H NMR confirmed this compound.

5_乙烯基4丨哚-1·羧酸第三-丁酯或6-乙晞基4嗓_ 1-羧酸第三_丁酯 於甲基三苯基溴化鱗（8.1克，22.7毫莫耳）在THF (140毫升） 中之懸浮液内，在0°C下，於1〇分鐘内，逐滴添加n-BuLi (1.6 Μ ，在己烷中，14.2毫升，22.7毫莫耳）。擾拌20分鐘後，於20 85762 -191 - 200412345 分鐘内，慢慢引進5_甲醯基吲哚小叛酸第三-丁酯（463克，148 S莫耳）在THF (20毫升）中之洛液。使反應物慢慢溫熱至室溫 ，攪拌30分鐘。將反應混合物倒入飽和氯化銨中，並以醋 酸乙酯（3x100毫升）萃取已分離之水相。使合併之有機相以 硫酸鈉脫水乾燥，過濾，及濃縮。使殘留物藉層析純化（二 氯甲烷至1%丙酮-二氯甲烷），而得5-乙烯基4哚小叛酸第 三-丁酯（4.7克，100% )，或以類似方式獲得卜乙晞基一哚小 羧酸第三-丁酯。5_vinyl-4-indole-1 · carboxylic acid tert-butyl ester or 6-ethylfluorenyl 4-hexyl-1-carboxylic acid tert-butyl ester in methyltriphenyl bromide scale (8.1 g, 22.7 mmol) Mol) in suspension in THF (140 ml), n-BuLi (1.6 M in hexane, 14.2 ml, 22.7 mmol) was added dropwise over 10 minutes at 0 ° C. . After 20 minutes of stirring, slowly introduce 5-methylformylindole tertiary butyl tertiary-butyl ester (463 g, 148 S mole) in THF (20 ml) within 20 85762 -191-200412345 minutes. Zhiluo. The reaction was slowly warmed to room temperature and stirred for 30 minutes. The reaction mixture was poured into saturated ammonium chloride and the separated aqueous phase was extracted with ethyl acetate (3 x 100 ml). The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (dichloromethane to 1% acetone-dichloromethane) to give 5-vinyl 4-indole tertiary acid tert-butyl ester (4.7 g, 100%), or similarly Triethyl butyl triisobutyl carboxylic acid.

Boc 5_(2_禮基乙基）_啕嗓_1_羧酸第三-丁醋或6_(2_幾乙基X嗓_ 1-羧酸第三_丁酯 於5-乙缔基丨哚小羧酸第三·丁酯（4.5克，18·5毫莫耳，L〇 當量）在THF (46毫升）中之溶液内，在〇°c下，於10分鐘内， 添加9-BBN (0.5 Μ ’在THF中’ 87毫升，2.4當量）。將所形成 之反應混合物攪拌2.5小時，並以THF (150毫升）與水（15〇毫升） 稀釋，同時保持溫度在0°C下。然後引進NaB03 · 4Η2 Ο (44克） ’並授掉所形成之反應混合物，及溫熱至室溫，且攪掉。 將反應混合物以《 —鼠甲fe (100愛升）稀釋，並將已分離之水 層以3x100毫升二氯甲烷萃取。使合併之有機層以硫酸鈉脫 水乾燥’過滤’及▲纟倚。使殘留物精層析純化（二氯甲燒至5 %丙酮/二氯甲烷），獲得5-(2-羥基-乙基）_吲哚小羧酸第三_ 丁酯（3.82克，76% )，或以類似方式獲得卜(2-羥基·乙基）_,噪一 1-羧酸第三-丁酯。 85762 -192- 200412345Boc 5_ (2_ Lithylethyl) _ 啕 Hang_1_carboxylic acid tert-butyl vinegar or 6_ (2_Hexylxanthol 1-carboxylic acid tert-butyl ester at 5-ethenyl 丨Indole small carboxylic acid tert-butyl ester (4.5 g, 18.5 mmol, L0 equivalent) in a solution of THF (46 ml) at 0 ° C, within 10 minutes, 9-BBN was added (0.5 M 'in THF' 87 mL, 2.4 equivalents). The resulting reaction mixture was stirred for 2.5 hours and diluted with THF (150 mL) and water (150 mL) while maintaining the temperature at 0 ° C. Then introduce NaB03 · 4Η2 〇 (44g) 'and teach the reaction mixture formed, and warm to room temperature, and stir away. The reaction mixture was diluted with "-mouse fe (100 liters), and The separated aqueous layer was extracted with 3x100 ml of dichloromethane. The combined organic layers were dried over sodium sulfate, 'filtered', and dried. The residue was purified by chromatography (dichloromethane to 5% acetone / dichloromethane). ), To obtain 5- (2-hydroxy-ethyl) _indole small carboxylic acid tertiary butyl ester (3.82 g, 76%), or to obtain (2-hydroxy · ethyl) _ in a similar manner, Tert-butyl 1-carboxylic acid 85762 -19 2- 200412345

5-(2-嗎福啉_4_基-乙基）-〃?丨哚小羧酸第三-丁酯或5_[2_(環己基-甲基·胺基）_乙基卜啕哚_1_羧酸第三-丁酯或6-(2-嗎福啉-4-基-乙基)_吲哚-1_羧酸第三-丁酯或6-[2-(環己基-甲基-胺基）-乙基l· 峭哚-1-叛酸第三-丁酯 於5&lt;2·羥基-乙基）-啕哚小羧酸第三-丁酯（260毫克，1毫莫耳 ’ 1，〇當量）、三苯膦（391毫克，1.5當量）及咪唑（136毫克，2 當量）在二氯甲烷（5毫升）中之溶液内，在20分鐘内，於室溫 下’以小量分次添加碘（328毫克，1.3當量）。將反應混合物 倒入水中，並以4x100毫升二氯甲烷萃取。使合併之有機相 以硫酸鈉脫水乾燥，過濾，及濃縮。使殘留物藉矽膠層析 純化（20% EtOAc /己烷），而得半純琪化物（6〇〇毫克）。然後， 使此碘化物溶於MeOH (10毫升）中，並在6〇°C下，以嗎福啉（1.73 毫升，20當量）處理過夜。使反應混合物冷卻至室溫，倒入 水中’並以二氯甲烷萃取。使合併乏有機層以硫酸鈉脫水 乾燥，過濾，及濃縮。使殘留物藉矽膠管柱層析純化（二氯 甲’元至15%丙酬/ 一氣甲、^元）’獲得5-(2-嗎福淋_4_基-乙基丨 哚-1-羧酸第三-丁酯（290毫克’ 88% )，或以類似方式獲得孓[2_ (環己基-甲基-胺基）-乙基]-W嗓-1-羧酸第三-丁酯，或6_(2_嗎福 啉-4-基-乙基）嗓-1-羧酸第三-丁酯，或6-[2_(環己基甲基_胺 基）-乙基]-啕哚小羧酸第三-丁酯。 85762 -193- 2004123455- (2-morpholine_4_yl-ethyl) -〃? 丨 Indole small carboxylic acid tertiary-butyl ester or 5_ [2_ (cyclohexyl-methyl · amino) _ethylpyridine_ 1-carboxylic acid tertiary-butyl ester or 6- (2-morpholine-4-yl-ethyl) _indole-1-carboxylic acid tertiary-butyl ester or 6- [2- (cyclohexyl-formyl) -Amino group) -ethyl l-adol- 1-acid tertiary-butyl ester at 5 &lt; 2 · hydroxy-ethyl) -pyridine small carboxylic acid tert-butyl ester (260 mg, 1 mmol Ear '1.0 equivalent), triphenylphosphine (391 mg, 1.5 equivalents) and imidazole (136 mg, 2 equivalents) in dichloromethane (5 mL) in 20 minutes at room temperature' Iodine (328 mg, 1.3 equivalents) was added in small portions. The reaction mixture was poured into water and extracted with 4 x 100 ml of dichloromethane. The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (20% EtOAc / hexane) to give a semi-pure Qi compound (600 mg). This iodide was then dissolved in MeOH (10 mL) and treated with morpholine (1.73 mL, 20 eq.) At 60 ° C overnight. The reaction mixture was cooled to room temperature, poured into water 'and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. Purification of the residue by silica gel column chromatography (dichloromethane to 15% propane / one gas methyl chloride) to obtain 5- (2-morpholin_4_yl-ethyl 丨 indole-1- Tertiary-butyl carboxylic acid (290 mg '88%), or phosphonium [2- (cyclohexyl-methyl-amino) -ethyl] -W--1-carboxylic acid tertiary-butyl ester in a similar manner , Or 6- (2_morpholin-4-yl-ethyl) tert-butyl 1-carboxylic acid, or 6- [2_ (cyclohexylmethyl_amino) -ethyl] -indole Tertiary-butyl small carboxylic acid 85762 -193- 200412345

N B〇c 5-(2-甲氧羰基-乙烯基)_吲哚小叛酸第三·丁酯或6_(2呷氧羰基_ 乙烯基)-啕哚·1_羧酸第三丁酿 於5-甲醯基4哚小羧酸第三-丁酯（3.4克，13.8毫莫耳，1.0 當量）在甲苯（35 *升）中之落液内，於室溫下，添加ph3 ρ== CHC〇2Me(5.5克，1·2當量），並將所形成之混合物攪拌過夜 。於濃縮後，使粗產物藉矽膠管柱層析純化（二氯甲燒至 丙酮-二氯甲燒），而得5-(2-甲氧羰基-乙烯基）—吲哚_丨_羧酸第 三-丁酯（5.03克，90% )，或以類似方式獲得6-(2-甲氧羰基-乙 晞基）-啕哚-1-羧酸第三·丁酯。NB〇c 5- (2-methoxycarbonyl-vinyl) -indole tert-butyl tertiary acid or 6- (2-oxocarbonyl-vinyl) -oxo-1.carboxylic acid tert-butyl Tertiary-butyl 5-methylfluorenyl 4-indole small carboxylic acid (3.4 g, 13.8 mmol, 1.0 eq.) In toluene (35 * liters), at room temperature, add ph3 ρ == CHCO2Me (5.5 g, 1.2 equivalents) and the resulting mixture was stirred overnight. After concentration, the crude product was purified by silica gel column chromatography (dichloromethane to acetone-dichloromethane) to obtain 5- (2-methoxycarbonyl-vinyl) -indole_ 丨 _carboxylic acid. Tertiary-butyl ester (5.03 g, 90%), or tert-butyl 6- (2-methoxycarbonyl-ethenyl) -oxindole-1-carboxylic acid was obtained in a similar manner.

5-(3-#至基-丙烯基）_吲哚_1_羧酸第三-丁酯或6-(3·經基丙烯基&gt; 吲哚小叛酸第三-丁酯 於甲基5_(2_甲氧羰基-乙烯基）-吲嗓小羧酸第三_丁酯（4 64克 ，15.3毫莫耳，ΐ·〇當量）在THF(87毫升）中之溶液内，在，它 下，於20分鐘内，藉注射器泵添加LiA1H4(1 n，在THF中，ι8·6 毫升’ 1.2當量），並擾拌所形成之混合物，及溫熱至_5。〇。 於冷卻回復至-30°C後，接著藉由緩慢添加丙酮（1〇毫升）使反 應淬滅’保持溫度低於-15°C，在〇°C下倒入洛瑟爾鹽中，攪 拌1小時’並將已分離之水廣以EtOAc萃取。使合併之有機 相以硫酸鈉脫水乾燥，過濾，及濃縮。使殘留物藉管柱層 析純化（二氯甲烷至2%丙酮/二氯甲烷），而得5-(3-羥基-丙 85762 200412345 晞基）-啕嗓-1-叛酸第三-丁酯（2.89克，70% )，或以類似方式獲 得6_(3·羥基-丙烯基）_吲哚小羧酸第三-丁酯。5- (3- # to propyl-propenyl) _indole_1-carboxylic acid tert-butyl ester or 6- (3. In a solution of 5_ (2-methoxycarbonyl-vinyl) -indole small carboxylic acid tert-butyl ester (4 64 g, 15.3 mmol, ΐ · eq.) In THF (87 ml), Under it, LiA1H4 (1 n in THF, 8.6 ml '1.2 equivalent) was added by a syringe pump within 20 minutes, and the resulting mixture was stirred and warmed to _5.0. After cooling back After reaching -30 ° C, the reaction was then quenched by slowly adding acetone (10 ml) 'holding temperature below -15 ° C, pouring into Loser salt at 0 ° C, stirring for 1 hour' and The separated water was extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (dichloromethane to 2% acetone / dichloromethane), and 5- (3-Hydroxy-propyl-85762 200412345 fluorenyl)-sulfo-1-propanoic acid tert-butyl ester (2.89 g, 70%), or 6_ (3-hydroxy-propenyl) _ in a similar manner Third-butyl indole small carboxylic acid.

5-(3·嗎福啉-4-基-丙烯基)-巧丨哚-1-羧酸第三-丁酯或6-(3_嗎福琳_ 4_基_丙缔基)-&lt; 哚-1-叛酸第三-丁酯 於5-(3-經基-丙晞基）-4卜朵-1-叛酸第三-丁酯（〇·95毫克，3.48亳 莫耳，1.0當量）與Et3N(1.8毫升，3_0當量）在二氯甲烷（IQ毫 升）中之溶液内，在0°C下，添加MsCl (0.40毫升，1.5當量）。 將所形成之混合物揽拌30分鐘，並溫熱至室溫，且再攪拌1 小時。然後引進環己基-甲基-胺（8.3毫升，18當量），並將所 形成之混合物概掉度過週末，以飽和NaHC〇3稀釋，並將已 分離之水相以3xEtOAc萃取。使合併之有機相以Na2S〇4脫水 乾燥，過濾，及濃縮。使殘留物藉矽膠層析純化（50% Et0Ac /己燒），獲得5-(3-嗎福琳《4-基-丙烯基)_吲嗓-1_羧酸第三-丁酯 ，或以類似方式獲得6-(3-嗎福琳-4-基-丙烯基)_H卜朵·1_羧酸第 三-丁酯。5- (3 · morpholin-4-yl-propenyl) -quinone-indole-1-carboxylic acid tert-butyl ester or 6- (3_morpholin_4_yl_propenyl)-& lt Tert-butyl indole-1-metanoate at 5- (3-mercapto-propionyl) -4 tert-butyrate-1-butanoate (0.95 mg, 3.48 mol, 1.0 eq.) And Et3N (1.8 ml, 3_0 eq.) In a solution of dichloromethane (IQ ml) at 0 ° C, MsCl (0.40 ml, 1.5 eq.) Was added. The resulting mixture was stirred for 30 minutes, warmed to room temperature, and stirred for an additional hour. Cyclohexyl-methyl-amine (8.3 mL, 18 eq.) Was then introduced and the resulting mixture was spent over the weekend, diluted with saturated NaHC03, and the separated aqueous phase was extracted with 3xEtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (50% Et0Ac / hexane) to obtain 5- (3-morpholin "4-yl-propenyl) -indone-1_carboxylic acid tert-butyl ester, or In a similar manner, 6- (3-morpholin-4-yl-propenyl) -Hbudol.1-carboxylic acid tert-butyl ester was obtained.

ER-808501 ER-808514 -195- 85762 200412345ER-808501 ER-808514 -195- 85762 200412345

ER-8085042ER-8085042

ER-808544 類似物 ER-808501、ER-808514、ER-8085042 及 ER-808544，係 按照相同關於從14製備16之程序，製自5-(2-嗎福啉-4-基-乙基 )-口?1嗓-1-竣酸第二-丁酉旨、5-(3-嗎福淋-4-基-丙婦基）-口弓1 口朵-1-竣 酸第二-丁 @旨、6-(3-嗎福淋-4_基-丙締基）-4丨嗓-1_叛酸第三·丁酉旨 及6-(2-嗎福淋-4-基-乙基）-4丨嗓-1-竣酸第二-丁 @旨。ER-808544 Analogues ER-808501, ER-808514, ER-8085042 and ER-808544 were prepared from 5- (2-morpholine-4-yl-ethyl) following the same procedure for preparing 16 from 14. -Mouth? 1-three-acid acid second-butyrin purpose, 5- (3-Morphine-4-yl-propionyl) , 6- (3-Morpholin-4_yl-propenyl) -4 丨 Horse-1_metacarboxylic acid tertiary butan and 6- (2-Morpholin-4-yl-ethyl)- 4 丨 Hang-1-Jun acid second-Ding @ Purpose.

將20 (51毫克）在二氯甲烷（1毫升）中之溶液，於室溫下，以 三氟醋酸（1毫升）處理3小時，及濃縮。以Et20與MeOH洗滌 固體殘留物，而得粗產物（18.2毫克）。然後，使粗產物藉逆 相 HPLC 純化（MeOH-水），獲得 ER-809047 (9.6 毫克，44% )。MS (ES) 、19F及1HNMR確認此結構。A solution of 20 (51 mg) in dichloromethane (1 ml) was treated with trifluoroacetic acid (1 ml) at room temperature for 3 hours, and concentrated. The solid residue was washed with Et20 and MeOH to give the crude product (18.2 mg). The crude product was then purified by reverse-phase HPLC (MeOH-water) to obtain ER-809047 (9.6 mg, 44%). MS (ES), 19F and 1HNMR confirmed this structure.

於120°C下，將7-氯基·3Η_咪吐并[4,5-b]外1:淀(J·C/^m. 1982, 513)(250毫克，含有25% 5-氯基-3H-咪唑并[4,5-b]吡啶） 85762 -196- 200412345 、2-三丁基錫烷基1哚小羧酸第三-丁醋（11，822毫克）及肆（ 三苯膦）鈀（〇)(1盌毫克）毫升）中之混合物，加熱6小 時。將反應混合物以AcOEt萃取，並以水及鹽水洗滌。使有 機層以MgSCU脫水乾燥，並蒸發。使殘留物藉層析純化(Ac〇Et /己燒），而得7_(1H-吲哚-2-基）-3H-咪唑并[4,5_b]峨啶IC_261 (28 毫克），為淡褐色固體。1HNMR確認此結構。7-Chloro · 3Η_midol [4,5-b] outer 1: Yodo (J · C / ^ m. 1982, 513) (250 mg, containing 25% 5-chloride at 120 ° C -3H-imidazo [4,5-b] pyridine) 85762 -196- 200412345, 2-tributyltin alkyl 1 indole small carboxylic acid tert-butyl vinegar (11,822 mg) and triphenylphosphine The mixture in palladium (0) (1 bowl mg) ml) was heated for 6 hours. The reaction mixture was extracted with AcOEt and washed with water and brine. The organic layer was dried over MgSCU and evaporated. The residue was purified by chromatography (Ac0Et / hexane) to give 7_ (1H-indol-2-yl) -3H-imidazo [4,5_b] eridine IC_261 (28 mg) as a light brown solid. 1HNMR confirmed this structure.

將2 (1.66克，6毫莫耳）、2_三丁基錫烷基，哚小羧酸第三_ 丁酯（11，3.6克，7毫莫耳）、三乙胺（〇·83毫升，6毫莫耳）及 肆（三苯膦）鈀（0)(600毫克，1〇莫耳％ )在DMF (1〇毫升）中之混 合物，於130°C下，加熱6小時。於反應期間，以兩份添加η (i.oi 克X 2)。將反應混合物以醋酸乙酯萃取，並以水洗滌，及以 無水硫酸鎂脫水乾燥。在過濾後，將矽膠（4〇〇網目）添加至 殘留物中’並濃縮。使殘留物藉層析純化（Ac〇Et/MeOH)，獲 得IC-395(240毫克）與IC_375(80毫克）。iHNMR確認此結構。Add 2 (1.66 g, 6 mmol), 2-tributylstannyl, tert-butyl indole small carboxylic acid (11, 3.6 g, 7 mmol), triethylamine (0.83 ml, 6 A mixture of millimolar) and (triphenylphosphine) palladium (0) (600 mg, 10 mole%) in DMF (10 ml) was heated at 130 ° C. for 6 hours. During the reaction, η (i.oi g X 2) was added in two portions. The reaction mixture was extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. After filtration, silica gel (400 mesh) was added to the residue 'and concentrated. The residue was purified by chromatography (Ac0Et / MeOH) to obtain IC-395 (240 mg) and IC-375 (80 mg). iHNMR confirmed this structure.

(7_氣基-2_酮基_2,3_二氫-1H-咪唑并[4,5-b]吡啶_5_基)_胺甲基酸乙酯 於4-氯基-5-硝基-2,6-吡啶二胺基甲酸二乙酯（關於製備1之 85762 -197- 200412345 中間物）(500毫克）在EtOH(50毫升）中之溶液内，添加阮尼Ni(1 克）’並於氫大;氣及室溫下’揽拌12小時。將反應混合物於 矽藻土上過濾’並使濾液在減壓下濃縮。使殘留物溶於1丙 醇（10毫升）中’並在回流下擅拌60小時。使反應混合物冷卻 至室溫，並過滤沉澱物。使濾液濃縮，而得250毫克（7-氯基_ 2-酮基-2,3-一氫_1H-咪峻并[4,5-b&gt;比途j基）·胺甲基酸乙酯，為 灰色固體。1HNMR確認此結構。(7-Alkyl-2_keto_2,3_dihydro-1H-imidazo [4,5-b] pyridin_5_yl) _aminomethyl ethyl ester in 4-chloro-5- To a solution of nitro-2,6-pyridinediaminodiethyl ester (85762 -197- 200412345 intermediate of Preparation 1) (500 mg) in EtOH (50 ml) was added Raney Ni (1 g ) 'And stir at room temperature for 12 hours. The reaction mixture was filtered over celite and the filtrate was concentrated under reduced pressure. The residue was dissolved in 1 propanol (10 ml) and stirred well under reflux for 60 hours. The reaction mixture was allowed to cool to room temperature and the precipitate was filtered. The filtrate was concentrated to obtain 250 mg of (7-chloro-2-keto-2,3-monohydro_1H-imidazo [4,5-b &gt; bituryl) · ethylaminomethyl , As a gray solid. 1HNMR confirmed this structure.

於120°C下，將（7-氯基-2-酮基-2,3_二氫·1Η_咪唑并[4,5七]吡啶·5-基）-胺甲基酸乙酯（240耄克）、2-三丁基錫烷基一哚小羧酸第 二-丁酯（11，472毫克）及肆（三苯膦）鉋⑼(54毫克）在DMF (1〇毫 升）中之混合物，加熱4小時。引進另外之1三丁基錫烷基_ ⑹哚-1-羧酸第二-丁酿(11，472毫克）與肆（三苯膦）飽⑼(54毫 克），並將所形成之混合物於12〇它下，再加熱12小時。使反 應混合物在減壓下濃縮，並藉層析純化（Ac〇Et/Me〇H)，獲得 IC-380 (20耄克），為淡白灰色固體。iHNmr確認此結構。At 120 ° C, (7-chloro-2-keto-2,3_dihydro · 1Η_imidazo [4,5hepta] pyridine · 5-yl) -aminomethyl acid ethyl ester (240 G), a mixture of 2-tributyltinalkylindole small carboxylic acid second-butyl ester (11,472 mg), and triphenylphosphine (54 mg) in DMF (10 ml), Heat for 4 hours. Introduce additional 1-tributyltinalkyl-oxindole-1-carboxylic acid second-butanol (11,472 mg) and tris (triphenylphosphine) saturated (54 mg), and form the resulting mixture at Under it, heat for another 12 hours. The reaction mixture was concentrated under reduced pressure and purified by chromatography (Ac0Et / Me0H) to obtain IC-380 (20 g) as a pale white gray solid. iHNmr confirms this structure.

12 85762 -198- 200412345 (2-胺基_7_氣基_3H_咪唑并[4,5-b】吡啶_5_基)_胺甲基酸乙酯 於室溫下，蔣溴化氰（〇·55克，5.2毫莫耳）添加至5,6-二胺基-4-氯基-2-吡啶胺基甲酸乙酯（關於製備1之中間物，！.〇〇克，4.3 毫莫耳）在20毫升乙醇中之經攪拌溶液内。將溶液攪摔3小 時，然後在6(TC下3小時。過濾沉澱物，並以***洗滌，而 得（2-胺基_7_氯基-3H-咪峻并[4,5-b]峨淀-5-基）-胺甲基酸乙酯（0.55 克，38% )’為黃色粉末。1 η NMR確認此結構。12 85762 -198- 200412345 (2-Amino_7_amino_3H_imidazo [4,5-b] pyridine_5_yl) _aminomethyl ethyl acetate at room temperature, cyanogen bromide (0.55 g, 5.2 mmol) was added to ethyl 5,6-diamino-4-chloro-2-pyridinaminoformate (for the intermediate of Preparation 1,! .00 g, 4.3 mmol) Mol) in a stirred solution in 20 ml of ethanol. The solution was stirred for 3 hours, and then at 6 ° C for 3 hours. The precipitate was filtered and washed with ether to give (2-amino_7_chloro-3H-amido [4,5-b] Edo-5-yl) -aminomethanoic acid ethyl ester (0.55 g, 38%) 'was a yellow powder. 1 n NMR confirmed this structure.

IC-416 IC-416係利用關於κ&gt;380所述之典型程序，得自（2-胺基-7-氯 基-3Η-咪唑并[4,5七]吡啶-5-基）-胺甲基酸乙酯與11。1HNMR確 認此結構。IC-416 IC-416 is obtained from (2-amino-7-chloro-3Η-imidazo [4,5hepta] pyridin-5-yl) -carbamoyl using the typical procedure described for κ &gt; 380 This structure was confirmed by ethyl 1HNMR and 11.1HNMR.

7-破基-2_烷基-3H-咪唑并[4,5-b]吡啶 化合物7-碘基_2·烷基—3Η-咪唑并[4,5七]吡啶（7-碘基-3Η-咪唑并 [4,5-b]吡啶、7-碘基-2-甲基-3Η-咪唑并[4,5-b]吡啶、7-碘基_2-乙 基3H-咪峻并[4,5七]吡啶）及/或其HI鹽，係按照關於從1製備 2與4之相同程序，製自‘氯_峨啶2,3_二胺（Recueil，1969,抑，1263_ 1274)。 85762 -199- 2004123457-Bradyl-2_alkyl-3H-imidazo [4,5-b] pyridine compound7-iodo_2 · alkyl-3Η-imidazo [4,5hepta] pyridine (7-iodo- 3Η-imidazo [4,5-b] pyridine, 7-iodo-2-methyl-3Η-imidazo [4,5-b] pyridine, 7-iodo_2-ethyl 3H-imidazine [4,5,7] pyridine) and / or its HI salt were prepared from 'chloro_eridine 2,3_diamine (Recueil, 1969, 1263_ 1274) according to the same procedure as for preparing 2 and 4 from ). 85762 -199- 200412345

5_氟基-7_蛾基-2-甲基-3H-咪唑并[4,5_b】吡啶 於4 (R2=Me，HI單鹽，300毫克，〇·75毫莫耳，1.0當量）在HBF4( 在水中之48-51%，3毫升）中之溶液内，在〇°C下，於1小時期 間内，分次添加NaN02 (1.0克，19當量），將反應溫度保持在4 艺下。將所形成之混合物於(TC下攪拌40分鐘，並在室溫下3〇 分鐘。以飽和NaHC03使反應淬滅，並將所形成之混合物以 5xEt2〇萃取。使合併之有機相以Na2S〇4脫水乾燥，過滤，及 濃縮，而得5-說基-7-蛾基-2-甲基-3H-咪唆并[4,5七]峨淀，為淡 褐色固體（170毫克，86%)。19FNMR、iHNmr&amp;ms確認此 結構。5-fluoro-7-mothyl-2-methyl-3H-imidazo [4,5_b] pyridine at 4 (R2 = Me, HI monosalt, 300 mg, 0.75 mmol, 1.0 equivalent) at In a solution of HBF4 (48-51% in water, 3 ml) at 0 ° C, NaN02 (1.0 g, 19 equivalents) was added in portions over a period of 1 hour, and the reaction temperature was maintained at 4 ° C. . The resulting mixture was stirred at 40 ° C for 40 minutes and at room temperature for 30 minutes. The reaction was quenched with saturated NaHC03, and the resulting mixture was extracted with 5xEt20. The combined organic phases were Na2S04 Dehydrated, dried, filtered, and concentrated to give 5-syl-7-mothyl-2-methyl-3H-imidazo [4,5-7] Edian, a light brown solid (170 mg, 86%) 19FNMR, iHNmr &amp; ms confirmed this structure.

6666

= F R2 Me, Et 化合物66係按照關於製備13或64之相同.. , _ . 1J %序，製自7-碘基_ 2-烷基-3H-咪唑并[4,5-b]吡啶（或其HI單鹽）痞 7 一乂 ^鼠基-7-蛾基 基-3H-咪唑并[4,5b]吡啶及15。 85762 -200- 200412345 η= F R2 Me, Et Compound 66 is prepared according to the same order as for the preparation of 13 or 64., _. 1J%, prepared from 7-iodo-2-alkyl-3H-imidazo [4,5-b] pyridine (Or its HI mono-salt) 痞 7 鼠 muryl-7- mothyl-3H-imidazo [4,5b] pyridine and 15. 85762 -200- 200412345 η

化合物67係按照關於製備65之相同程序，製自7-碘基-2-甲 基-3Η-咪唑并[4,5-b]吡啶與15。Compound 67 was prepared from 7-iodo-2-methyl-3fluorene-imidazo [4,5-b] pyridine and 15 according to the same procedure as for Preparation 65.

ER-# 1. 結構66或67 'HNMR 及/或MS 807496 〇OXcv^N Η Ν^,ΝΗ 'HNMR 201 - 85762 200412345ER- # 1. Structure 66 or 67 'HNMR and / or MS 807496 〇OXcv ^ N Η Ν ^, ΝΗ' HNMR 201-85762 200412345

807584 Η Ν 丫 ΝΗ [HNMR 807585 Η Ν 丫 ΝΗ 'HNMR 807587 Fxrr〇&gt;^ Η Ν^,ΝΗ 'HNMR 807750 Η Ν^ΝΗ. 丄 HNMR 807787 〇CliXcv^N Η Ν 丫'ΝΗ 丄 HNMR 807788 °ΤΊ Η Ν^ΝΗ 丄 H NMR 807865 Η Ν^ΝΗ ^NMR 808009 Η ν^νη 'HNMR 808081 1 Η ν^νη 'HNMR 85762 -202- 200412345 85762807584 Η Ν ΝΝΗ [HNMR 807585 Η Ν ΝΝΝ '' HNMR 807587 Fxrr〇 &gt; ^ Η Ν ^, ΝΗ 'HNMR 807750 Η Ν ^ ΝΗ. 丄 HNMR 807787 〇CliXcv ^ N Η Ν Α'ΝΗ 丄 HNMR 807788 ° TΊ Η Ν ^ ΝΗ 丄 H NMR 807865 Η Ν ^ ΝΗ ^ NMR 808009 Η ν ^ νη 'HNMR 808081 1 Η ν ^ νη' HNMR 85762 -202- 200412345 85762

808085 H N 丫 NH !hnmr 808160 H N^NH 'HNMR 808256 H N 丫 NH 'HNMR 808257 H N 丫、NH 'HNMR 808259 H N&gt;_NH 丫 'H NMR 808260 H N 丫 NH ^HNMR 808261 〇J〇Q~^n H NVNH : T !hnmr 808262 H H N 丫、NH !H NMR 808266 CF3C〇2H H N 丫 NH 'H NMR -203 - 200412345 85762808085 HN ^ NH! Hnmr 808160 HN ^ NH 'HNMR 808256 HN ^ NH' HNMR 808257 HN ^, NH 'HNMR 808259 H N &gt; _NH ^' NMR 808260 HN ^ NH ^ HNMR 808261 〇J〇Q ~ ^ n H NVNH : T! Hnmr 808262 HHN Ah, NH! H NMR 808266 CF3C〇2H HN Ah NH 'H NMR -203-200412345 85762

808268 !hnmr 808269 H N 丫 NH 'HNMR 808284 〇^ij〇C)-^N H N 丫 NH 'HNMR 808285 ^nJ〇〇-^n H N NH 丁 'HNMR 808286 OjCQ~^n H N 丫 NH 丄 HNMR 808287 H -N^nh iHNMR 808288 /0 H 丫㈠ 'HNMR 808289 'HNMR 808291 kj H n^nh ^HNMR 808310 a H n7；NH [H NMR -204- 200412345 85762808268! Hnmr 808269 HN ^ NH'HNMR 808284 〇 ^ ij〇C)-^ NHN ^ NH'HNMR 808285 ^ nJ〇〇- ^ n HN NH D'HNMR 808286 OjCQ ~ ^ n HN ^ NH 丄 HNMR 808287 H -N ^ nh iHNMR 808288/0 H ^ 'HNMR 808289' HNMR 808291 kj H n ^ nh ^ HNMR 808310 a H n7; NH [H NMR -204- 200412345 85762

808311 -Ο Η Νν,ΝΗ 'HNMR 808319 Η Ν^ΝΗ 々NMR 808322 〇CT'Xcv^N Η ν^νη 丄 HNMR 808361 ΗΟ丁 Η 丫Η 'Η NMR 808362 Ou Ccvq^ Η ΝγΝΗ 丄 HNMR 808363 'HNMR 808370 Η Ν^ΝΗ Wnmr 808372 Η Ν^ΝΗ 丄 HNMR 808385 Η Ν^ΝΗ 'HNMR -205 - 200412345 85762808311 -Ο Η Νν, ΝΗ 'HNMR 808319 Η Ν ^ ΝΗ 々NMR 808322 〇CT'Xcv ^ N Η ν ^ νη 丄 HNMR 808361 Η〇 丁 Η Η Η Η NMR 808362 Ou Ccvq ^ Η ΝγΝΗ 丄 HNMR 808363' HNMR 808370 Η Ν ^ ΝΗ Wnmr 808372 Η Ν ^ ΝΗ 丄 HNMR 808385 Η Ν ^ ΝΗ 'HNMR -205-200412345 85762

808386 H H N^NH !hnmr 808388 H N 丫 NH !hnmr 808469 H n^nh !hnmr 808470 H NrNH 'HNMR 808473 H N^NH 丄HNMR 808496 H ΝγΝΗ !hnmr 808497 H N^NH 'H NMR 808498 〇U H n^nh 'HNMR 808499 V h NyNH 'HNMR 808500 cf3co2h ^n^〇&gt;-Cn cf3c〇2h h n?nh [H NMR -206- 200412345 85762808386 HHN ^ NH! Hnmr 808388 HN ^ NH! Hnmr 808469 H n ^ nh! Hnmr 808470 H NrNH 'HNMR 808473 HN ^ NH 丄 HNMR 808496 H ΝγΝΗ! Hnmr 808497 HN ^ NH' H NMR 808498 〇UH n ^ nh 'HNMR 808499 V h NyNH 'HNMR 808500 cf3co2h ^ n ^ 〇 &gt; -Cn cf3c〇2h hn? Nh [H NMR -206- 200412345 85762

808513 cf3c〇2h cf3co2h h n 丫 nh 'HNMR 808541 H n^nh cf3c〇2h CF3C〇2H I 'HNMR 808543 O〇 H nC；nh cf3c〇2h cf3co2h 1 !hnmr 808571 rA 'H NMR H N 丫、NH 808600 U H 'HNMR 808617 〇nJ〇^)~^n H N 丫 NH lHNMR 808620 H N^NH T ： iHNMR 808622 〇Cr0cv^N H N^NH 'HNMR 808623 HCI H 丫 H 'HNMR 808624 H N^NH 'HNMR -207 - 200412345 85762808513 cf3c〇2h cf3co2h hn ah nh 'HNMR 808541 H n ^ nh cf3c〇2h CF3C〇2H I' HNMR 808543 O〇H nC; nh cf3c〇2h cf3co2h 1! Hnmr 808571 rA 'H NMR HN UH, NH 808 600 HNMR 808617 〇nJ〇 ^) ~ ^ n HN AH NH lHNMR 808620 HN ^ NH T: iHNMR 808622 〇Cr0cv ^ NHN ^ NH 'HNMR 808623 HCI H AH H' HNMR 808624 HN ^ NH 'HNMR -207-200412345 85762

-208 - 200412345 85762-208-200412345 85762

808692 - H n^/NH !hnmr 808703 H N^NH cf3co2h T 'HNMR 808704 H N^NH cf3c〇2h i 'HNMR 808705 H N^NH cf3co2h T !hnmr 808711 H ΝγΝΗ [HNMR 808712 yjCOO1 &quot;1 H N?NH 'HNMR 808713 OnXcv^n H N^NH iHNMR 808714 〇njCQ~^n H N 丫 NH iHNMR 808717 ^kXcv^n H N^NH 'HNMR 808719 對掌性 H N^NH iHNMR -209- 200412345808692-H n ^ / NH! Hnmr 808703 HN ^ NH cf3co2h T 'HNMR 808704 HN ^ NH cf3c〇2h i' HNMR 808705 HN ^ NH cf3co2h T! Hnmr 808711 H ΝγΝΗ [HNMR 808712 yjCOO1 &quot; 1 HN? NH 'H 808713 OnXcv ^ n HN ^ NH iHNMR 808714 〇njCQ ~ ^ n HN AHNH iHNMR 808717 ^ kXcv ^ n HN ^ NH 'HNMR 808719 Palmar HN ^ NH iHNMR -209- 200412345

808720 -\J Η Ν?Η 'HNMR 808834 MeO^^ ΝγΝΗ 'HNMR 808835 MeOx^\ H N 丫'NH [H NMR 808849 V〇c&gt;^ H N^NH !H NMR 809187 • HI H N^^NH 'HNMR 809196 2CF3C02H H nVnh MS 809197 「CTXXhQ 2 cf3co2h nVnh MS 809198 2CF3co2h H nVnh MS 809199 3 CF3C02H N丫NH MS808720-\ J Η Ν? Η 'HNMR 808834 MeO ^^ ΝγΝΗ' HNMR 808835 MeOx ^ \ HN 丫 'NH [H NMR 808849 V〇c &gt; ^ HN ^ NH! H NMR 809187 • HI HN ^^ NH' HNMR 809196 2CF3C02H H nVnh MS 809197 「CTXXhQ 2 cf3co2h nVnh MS 809198 2CF3co2h H nVnh MS 809199 3 CF3C02H NammaNH MS

85762 -210- 200412345 8576285762 -210- 200412345 85762

809200 HO. 2CF3C02h H nVnh MS 809201 2CF3C02H H nvnh MS 809202 2 CF3C02H N丫NH MS 809203 3CF3C02H H nVnh MS 809204 HO. 2CF3C02h H nVnh MS 809205 乂 2CF3C02H H nVnh MS 809206 2CF3C02H H ΝγΝΗ MS 809207 3 CF3C02H ΝγΝΗ MS -211809200 HO. 2CF3C02h H nVnh MS 809201 2CF3C02H H nvnh MS 809202 2 CF3C02H Namma NH MS 809203 3CF3C02H H nVnh MS 809204 HO. 2CF3C02h H nVnh MS 809205 乂 2CF3C02H H nVnH MS2 809 206

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809208 3CF3C02H Η NVNH MS 809209 2CF3C02H η ΝγΝΗ MS 809210 2CF3C02H Η NVNH MS 809211 2 cf3co2h NVNH MS 809212 3CF3C02H Η NVNH MS 809213 2CF3C02H Η NVNH MS 809214 2CF3C02H Η ΝγΝΗ MS 809215 一 2 cf3co2h NVNH MS 809216 2cf3c〇2h η ΝγΝΗ MS 809217 2 CF3C02H ν丫νη MS 85762 -212- 200412345 85762809208 3CF3C02H Η NVNH MS 809209 2CF3C02H η ΝγΝΗ MS 809210 2CF3C02H Η NVNH MS 809211 2 cf3co2h NVNH MS 809212 3CF3C02H Η NVNH MS 809213 2CF3NH2 MS2H2 Η 2N CF3C02H ν 丫 νη MS 85762 -212- 200412345 85762

809218 2 cf3c〇2h NVNH MS 809219 2 cf3co2h NVNH MS 809220 2CF3co2H H nVnh MS 809221 2 cf3c〇2h nVnh MS 809222 O 3CF3C02H 丫H MS 809223 0cv^N 2CF3C02H H nVnh MS 809224 〇 N^NH cf3c〇2h T MS 809225 〇 Ν-,ΝΗ cf3c〇2h T MS 809226 0 N. NH 2 CF3C〇2H I MS -213 -809218 2 cf3c〇2h NVNH MS 809219 2 cf3co2h NVNH MS 809220 2CF3co2H H nVnh MS 809221 2 cf3c〇2h nVnh MS 809222 O 3CF3C02H ^ H MS 809223 0cv ^ N 2CF3C02H H nVnh MS 809 224 224. Ν-, ΝΗ cf3c〇2h T MS 809226 0 N. NH 2 CF3C〇2H I MS -213-

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809227 1 ΰ Ν. ΝΗ cf3c〇2h Τ MS 809228 0 NyNH cf3c〇2h I MS 809229 〇〜νΧ^Η 0 N&gt;yNH 2 cf3c〇2h I MS 809230 /k 〇 NvNH 1 CF3CO2H I MS 809231 1 〇 N^yNH CF3C〇2H I MS 809232 Y—Κ^^；Η 1 〇 N^NH cf3c〇2h I MS 809233 n.nh 2 CF3C〇2H I MS 809234 〇 n^nh 2 CF3C02H I MS 809235 〇 N&lt;yNH cf3co2h 丁 MS 809236 /J 〇 N&lt;yNH ,cf3co2h 丁 MS -214·809227 1 ΰ Ν. ΝΗ cf3c〇2h Τ MS 809228 0 NyNH cf3c〇2h I MS 809229 〇 ～ νχ ^ Η 0 N &gt; yNH 2 cf3c〇2h I MS 809230 / k 〇NvNH 1 CF3CO2H I MS 809231 1 〇N ^ yNH CF3C〇2H I MS 809232 Y-K ^^; Η 1 〇N ^ NH cf3c〇2h I MS 809233 n.nh 2 CF3C〇2H I MS 809234 〇n ^ nh 2 CF3C02H I MS 809235 〇N &lt; yNH cf3co2h but MS 809236 / J 〇N &lt; yNH, cf3co2h Ding MS-214 ·

200412345200412345

7-填基_2_甲基·1，4_二氫-咪嗤并丨4,5_b]p比淀酮 於化合物4 (R=Me，160毫克，〇·59毫莫耳）在10毫升2〇% H2s〇4 水/谷液中之落液内，在〇°C下，以小量分次添加亞硝酸鈉（154 *莫耳），並將所形成之混合物在室溫下攪拌過夜。以飽和 NH3水溶液使反應混合物中和至pH 7_8，並收集所形成之沉 澱物，獲得黃色固體。然後，使此固體在水中結晶，而得14〇 笔克產物7-硪基-2-甲基_1，4_二氫-咪唑并[4,5#比啶·5_嗣（87% ) ，具有令人滿意之MS與1 H NMR. 〇7-filler_2_methyl · 1,4_dihydro-imidopyrene 4,5_b] p than ketone ketone in compound 4 (R = Me, 160 mg, 0.59 mmol) in 10 ml In 20% H2s04 water / valley solution, sodium nitrite (154 * mol) was added in small portions at 0 ° C, and the resulting mixture was stirred at room temperature overnight . The reaction mixture was neutralized to pH 7-8 with a saturated aqueous NH3 solution, and the formed precipitate was collected to obtain a yellow solid. Then, the solid was crystallized in water to obtain 14 g of the product 7-fluorenyl-2-methyl_1,4-dihydro-imidazo [4,5 # 比比 ·· 5_fluorene (87%) With satisfactory MS and 1 H NMR. 〇

ER-807546係按照關於製備13之相同程序，製自7_碘基_2_甲 基]，4_ 一氬-咪峻并[4,5«b]p比淀-5_ 酮與 1〇 (RyphCH^’R^Me)。獲 得關於ER-807546之令人滿意ms與1 H NMR。 85762 -215- 200412345ER-807546 was prepared from 7_iodo_2_methyl], 4_argon-midazo and [4,5 «b] p thanyodo-5_one and 1〇 (RyphCH ^ 'R ^ Me). Satisfactory ms and 1 H NMR were obtained for ER-807546. 85762 -215- 200412345

ER-809251 ER-809252 類似物ER-809251與ER-809252係按照關於從14製備16之相同 程序，個別製自7-碘基-2-甲基-3H-咪唑并[4,5-b]吡啶，及6-[2-( ί哀己基-甲基-胺基）-乙基]丨11 朵-1-棱酸第二-丁酉旨與5-[2-(環己基 -甲基胺基）_乙基；Η丨哚小羧酸第三-丁酯。 3)生物學檢測 HUVEC檢測擬案： 將所匯集之人類臍靜脈内皮細胞（HLTVEC，Clonetics公司）在 5 X 104個細胞/毫升下，接種於96井板上，並在37°C下培養 。隔天，將20微升各化合物稀釋液添加至細胞中，並培養30 分鐘，接著於37°C下，以TNFa (1毫微克/毫升）刺激四小時 。在TNF刺激後，將板以含有0.5%BSA之PBS洗滌，以0.025% 戊二醛固定，並以一級與二級抗體染色，以偵測E-選擇素 與ICAM表現。將板使用已在含有0.5% BSA與5% FBS之PBS中 以1 : 500稀釋之100微升一級老鼠抗人類E-選擇素與抗人類 ICAM抗體（R&amp;D系統，Minneapolis，MN)，培養一小時，然後將 板洗滌，並使用已在PBS/0.5% BSA/5% FBS中以1 : 10,000稀釋 之100微升二級過氧化酶共輛山羊抗老鼠IgG抗體（Pierce， Rockford，IL)，培養30分鐘。然後將板洗滌，並添加100微升TMB 受質，且使顏色反應發展15-20分鐘。藉由添加50微升1 NH2S04 85762 -216- 200412345 使反應停止，並於微板分光光度計上，在450毫微米下，讀 取光密度（〇D) ; IC5〇值係以藉由下式計算之抑制百分比為基 準而測得： r %抑制=: V. 丨J(平均化合物OD-平均空白試驗OD) ]〕*1〇〇 、 J (平均TNF OD -平均空白試驗OD) ^ 85762 -217-ER-809251 ER-809252 Analogues ER-809251 and ER-809252 are individually prepared from 7-iodo-2-methyl-3H-imidazo [4,5-b] following the same procedure as for preparing 16 from 14 Pyridine, and 6- [2- (L-hexyl-methyl-amino) -ethyl] 11-dodecyl-1-peptidic acid second-butanthine and 5- [2- (cyclohexyl-methylamino) ) Ethyl; tert-butyl small carboxylic acid tert-butyl ester. 3) Biological test HUVEC test proposal: The collected human umbilical vein endothelial cells (HLTVEC, Clonetics) were seeded on a 96-well plate at 5 X 104 cells / ml, and cultured at 37 ° C. The next day, 20 microliters of each compound dilution was added to the cells and incubated for 30 minutes, followed by stimulation with TNFa (1 ng / ml) for four hours at 37 ° C. After TNF stimulation, the plates were washed with 0.5% BSA in PBS, fixed with 0.025% glutaraldehyde, and stained with primary and secondary antibodies to detect E-selectin and ICAM performance. Plates were cultured using 100 microliters of primary mouse anti-human E-selectin and anti-human ICAM antibodies (R &amp; D system, Minneapolis, MN) diluted 1: 500 in PBS containing 0.5% BSA and 5% FBS. The plate was washed for one hour, and then goat anti-mouse IgG antibody (Pierce, Rockford, IL) was used in 100 μl of secondary peroxidase diluted 1: 10,000 in PBS / 0.5% BSA / 5% FBS. Incubate for 30 minutes. The plate was then washed and 100 microliters of TMB substrate was added and the color reaction was allowed to develop for 15-20 minutes. The reaction was stopped by adding 50 μl of 1 NH2S04 85762 -216- 200412345, and the optical density (OD) was read on a microplate spectrophotometer at 450 nm; the IC50 value was calculated by the following formula The percentage of inhibition is measured as a reference: r% inhibition =: V. 丨 J (average compound OD-average blank test OD)]] * 100, J (average TNF OD-average blank test OD) ^ 85762 -217 -

Claims (1)

200412345 拾、申請專利範園： 1· 一種具有結褚①之化合物：200412345 Patent and application for patent garden: 1. A compound with a compound: ⑴ 及其藥學上可接受之衍生物； 其中η為整數04 ; Ri 為氫、-NH2、-NHMe、-NHAc、-OH、F、-OMe、-CN 或·ΝΗ(〇0)0Εί ; R2為氫、-NRARB、_〇ra，脂族、雜脂族、芳基或雜芳 基邵份基團，其中心與^各獨立為氫，或脂族、雜脂族 、芳基或雜芳基部份基團； 心之各存在處係獨立為氫、自素、氰基，或脂族、雜 脂族、芳基或雜芳基部份基團，或基團，其中G為 不存在，或為_CH2_、-nrd_、·α或（c=o)，且其中心為氫 、-MUfRg、·〇%、_SRf，或脂族、雜脂族、芳基或雜芳基 刀基團，其中Rd、RF及R〇各獨立為氫、-NRxRy，脂族 、環脂族、雜脂族、環雜脂族、芳基或雜芳基部份基團 ，被脂族、雜脂族、芳基或雜芳基部份基團取代之^基 部份基團，或其中知與〜仏與〜…起採用為^^, Μ-或8·貝經取代或未經取代之環脂族或環雜脂族部份 基團；其中RjR〆各存在處係獨立為氫，脂族、環脂 族、雜脂族、環雜脂族、芳基或雜芳基部份基團，被脂 85762 200412345 族、雜脂族、芳基或雜芳基部份基團取代之醯基部份基 團’或其中:RX與Ry—起採，為4-，5_或6_員經取代或未 經取代之飽和或不飽和環脂族或環雜脂族部份基團； 而其中各前述脂族或雜脂族部份基團可獨立為經取代 或未經取代、環狀或非環狀、線性或分枝狀、飽和或不 飽和，且其中各前述芳基或雜芳基部份基團可獨立為經 取代或未經取代。 2·根據申請專利範圍第1項之化合物，其中化合物具有以下 結構：⑴ and pharmaceutically acceptable derivatives thereof; wherein η is an integer of 04; Ri is hydrogen, -NH2, -NHMe, -NHAc, -OH, F, -OMe, -CN, or · ΝΗ (〇0) 0Εί; R2 Is hydrogen, -NRARB, _〇ra, aliphatic, heteroaliphatic, aryl, or heteroaryl radicals, the center of which is independently hydrogen, or aliphatic, heteroaliphatic, aryl, or heteroaryl Radical groups; each place of the heart is independently hydrogen, autogen, cyano, or aliphatic, heteroaliphatic, aryl, or heteroaryl moiety, or group, where G is absent , Or _CH2_, -nrd_, · α or (c = o), and its center is hydrogen, -MUfRg, · 0%, _SRf, or aliphatic, heteroaliphatic, aryl, or heteroaryl knife group Where Rd, RF and R0 are each independently hydrogen, -NRxRy, aliphatic, cycloaliphatic, heteroaliphatic, cycloheteroaliphatic, aryl or heteroaryl partial groups, and are aliphatic, heteroaliphatic ^, Aryl or heteroaryl moieties substituted with ^ moieties, or ^ ^, Μ- or 8 · 贝 substituted or unsubstituted cyclic lipids which are known from ~ 仏 and ~ Or cycloheteroaliphatic partial groups; where RjR〆 exists independently as hydrogen, aliphatic Cycloaliphatic, heteroaliphatic, cycloheteroaliphatic, aryl or heteroaryl moieties, fluorenyl moieties substituted with aliphatic 85762 200412345 family, heteroaliphatic, aryl or heteroaryl moieties Groups' or among them: RX and Ry—starting, are 4-, 5- or 6-membered substituted or unsubstituted saturated or unsaturated cycloaliphatic or cycloheteroaliphatic partial groups; and each of them The aforementioned aliphatic or heteroaliphatic moiety may be independently substituted or unsubstituted, cyclic or acyclic, linear or branched, saturated or unsaturated, and each of the aforementioned aryl or heteroaryl moieties The moiety may be independently substituted or unsubstituted. 2. The compound according to item 1 of the scope of patent application, wherein the compound has the following structure: 其中各獨立為氫、_素、氰基，或脂族、 脂族、芳基或雜芳基部份基團，或基團，其中〇 不存在，或為-CH2-、-NRD-、-〇_或（〇〇)，且其中心為 、ARfRg、-〇Rf、_SRf，或脂族、雜脂族、芳基或雜芳 邛伤基團，其中RD、rf及h各獨立為氫、_NRxRy，脂 、環脂族、雜脂族、環雜脂族、芳基或雜芳基部份基 ，被脂族、雜脂族、芳基或雜芳基部份基團取代之醯基 部份基團，或其中心與心或^與％，一起採用為1»， 6-，7-或8-員經取代或未經取代之環脂族或環雜脂族部份 基團；其中Rx與心之各存在處係獨立為氫，脂族、環脂 族、雜脂族、環雜脂族、芳基或雜芳基部份基團，被脂 85762 200412345 族、雜脂族、芳基或雜芳基部份基團取代之醯基部份基 團，或其中:Rx與Ry —起採用為4-，5-或6-員經取代或未經 取代之飽和或不飽和環脂族或環雜脂族部份基團； 而其中各前述脂族或雜脂族部份基團可獨立為經取代 或未經取代、環狀或非環狀、線性或分枝狀、飽和或不 飽和；且其中各前述芳基或雜芳基部份基團可獨立為經 取代或未經取代。 3·根據申請專利範圍第1項之化合物，其中化合物具有以下 結構：Each of which is independently hydrogen, hydrogen, cyano, or an aliphatic, aliphatic, aryl, or heteroaryl moiety, or a group in which 0 is absent, or -CH2-, -NRD-,- 〇_ or (〇〇), and its center is, ARfRg, -〇Rf, _SRf, or an aliphatic, heteroaliphatic, aryl or heteroaryl group, wherein RD, rf and h are each independently _NRxRy, aliphatic, cycloaliphatic, heteroaliphatic, cycloheteroaliphatic, aryl or heteroaryl moieties, hydrazone bases substituted with aliphatic, heteroaliphatic, aryl or heteroaryl moieties Moieties, or their centers and hearts or ^ and%, are used together as 1 », 6-, 7- or 8-membered substituted or unsubstituted cycloaliphatic or cycloheteroaliphatic moieties; where Rx and the heart are independent of each other in hydrogen, aliphatic, cycloaliphatic, heteroaliphatic, cycloheteroaliphatic, aryl or heteroaryl moiety groups, and are 85857 200412345 family, heteroaliphatic, aromatic A fluorenyl moiety group substituted with a radical or heteroaryl moiety, or in which: Rx and Ry are taken together as a 4-, 5- or 6-membered substituted or unsubstituted saturated or unsaturated cycloaliphatic Group or cycloheteroaliphatic moiety; and each of the foregoing A family or heteroaliphatic moiety may be independently substituted or unsubstituted, cyclic or acyclic, linear or branched, saturated or unsaturated; and each of the foregoing aryl or heteroaryl moiety A group can be independently substituted or unsubstituted. 3. The compound according to item 1 of the scope of patent application, wherein the compound has the following structure: 其中15^與各獨立為氫、南素、氰基，或脂族、雜 脂族、芳基或雜芳基部份基團，或基團，其中g為 不存在，或為_CH2_、-NRD_、_〇_或（c=〇)，且其中心為氫 、-NRfRq、㈣、爲’或脂族、雜脂族、芳基或雜芳基 部份基團，其中RD、〜及〜各獨立為氫、视為，脂族 、環脂族、雜脂族、環雜脂族、芳基或雜芳基部份基團 '，被脂族、雜脂族、芳基或雜芳基部份基團取代之酿基 1M刀基團，或其中心與^或心與％，一起採用為I», 6、7-或8_員經取代或未經取代之環脂族或環雜脂族部产 基團；其中&amp;與&amp;之各存在處係獨立為氫，脂族、替 族、雜脂族、環雜脂族、芳基或雜芳基部份基團，被： 85762 200412345 味^族、方基或雜芳基部份基®取代之基部份λ 圈，或龙中跑ρ 土 、、/、L x」、Ry—起採用為4-，5_或6_員經取代或未經 取代：飽和或不飽和環脂族或環雜脂族部份基團； 、&quot;中各$述知族或雜脂族部份基團可獨立為經取代 或未取代、環狀或非環狀、線性或分枝狀、飽和或不 飽和；且其中各前述芳基或雜芳基部份基圏可獨立為經 取代或未經取代。 4·根據中請專利範圍第1項之化合物，其中化合物具有以下 結構： 義Where 15 ^ and each independently are a hydrogen, a nanin, a cyano, or an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety, or a group, wherein g is absent, or is _CH2_,- NRD_, _〇_ or (c = 〇), and its center is hydrogen, -NRfRq, ㈣, is' or aliphatic, heteroaliphatic, aryl or heteroaryl moiety, where RD, ~ and ~ Each is independently hydrogen and is considered to be an aliphatic, cycloaliphatic, heteroaliphatic, cycloheteroaliphatic, aryl or heteroaryl moiety group, being aliphatic, heteroaliphatic, aryl or heteroaryl Partially substituted 1M knife group, or its center and ^ or heart and%, are used together as I », 6, 7- or 8-membered substituted or unsubstituted cycloaliphatic or cycloheterocyclic Aliphatic moieties; where &amp; and &amp; are each independently hydrogen, aliphatic, substituted, heteroaliphatic, cycloheteroaliphatic, aryl or heteroaryl moiety groups, are: 85762 200412345 ^ group, square or heteroaryl moiety ® substituted base moiety λ circle, or Longzhong run ρ soil ,, /, L x ″, Ry—from 4-, 5_ or 6 _Member substituted or unsubstituted: saturated or unsaturated cycloaliphatic or cycloheteroaliphatic Each group may be independently substituted or unsubstituted, cyclic or acyclic, linear or branched, saturated or unsaturated; and Each of the aforementioned aryl or heteroaryl moieties may be independently substituted or unsubstituted. 4. The compound according to item 1 of the patent application, wherein the compound has the following structure: 其中h、R2、：^及、均如申請專 利範圍第1項中之定 5.=申請專利範圍第丨項之化合物:’其中化合物具有以下Among them, h, R2, ^, and ^ are the same as those in the first patent application scope. 5. = Compounds in the patent application scope item 丨: where the compounds have the following /、中Ri、&amp;、rf及％均如申請專利範圍第^項中之定 羲。 ’、 根據申請專利範圍第i項之化合物，其中化合物具有以下 85762 200412345 結構：/, Ri, &amp;, rf, and% are as defined in item ^ of the scope of patent application. ′, The compound according to item i of the scope of patent application, wherein the compound has the following structure: 85762 200412345: 義 ::申請專利範圍fi項之化合物，其中化合物具有以下Meaning :: A compound in the scope of application for patent fi, wherein the compound has the following r2 . 其中q與r各獨立為〇或1;且、、 查 》 1 2 Rp及R〇均如申士杳 專利乾圍第1項中之定義。 其中化合物具有以 8·根據申請專利範圍第1項之化合物， 結構：r2, where q and r are each independently 0 or 1; and, check "1 2 Rp and R0" are as defined in the first paragraph of the patent patent of Shen Shiyi. Among them, the compound has a compound whose structure is according to item 1 of the scope of patent application: 專利範園第1项中之定義。 9.根據申請專利範園第1項之化合物，其中化合物具有以下 85762 200412345 結構：The definition in the first paragraph of the patent park. 9. The compound according to item 1 of the patent application park, wherein the compound has the following structure: 85762 200412345: rgrfn r2 · 其中&amp;、R2、RF及R〇均如申請專利範圍第1項中之定 義。 10·根據申請專利範圍第1項之化合物，其中化合物具有以下 結構：rgrfn r2 · Wherein &amp;, R2, RF and R0 are as defined in the first patent application. 10. The compound according to item 1 of the scope of patent application, wherein the compound has the following structure: rgrfn 其中&amp;、R2、Rf及R〇均如申請專利範圍第1項中之定 義。 11.根據申請專利範圍第1項之化合物，其中化合物具有以下 結構·rgrfn where &amp;, R2, Rf, and R0 are as defined in item 1 of the scope of patent application. 11. The compound according to item 1 of the scope of patent application, wherein the compound has the following structure · 其中心與R2均如申請專利範圍第1項中之定義； m為0、1或2 ;且 RF為脂族、環脂族、雜脂族、環雜脂族、芳基或雜芳 85762 200412345 基部份基團； 而其中各·七述脂族或雜脂族部份基團可獨立為經取代 或未經取代、環狀或非環狀、線性或分枝狀、飽和或不 飽和，且其中各前述芳基或雜芳基部份基團可獨立為經 取代或未經取代。 12·根據申請專利範圍第！項之化合物，其中化合物具有以下 結構：Its center and R2 are as defined in the first patent application scope; m is 0, 1 or 2; and RF is aliphatic, cycloaliphatic, heteroaliphatic, cycloheteroaliphatic, aryl or heteroaryl 85762 200412345 Radicals; and each of the seven aliphatic or heteroaliphatic radicals may be independently substituted or unsubstituted, cyclic or acyclic, linear or branched, saturated or unsaturated, And each of the aforementioned aryl or heteroaryl moiety may be independently substituted or unsubstituted. 12 · According to the scope of patent application! The compound of item, wherein the compound has the following structure: 其中R1與R2均如申請專利範圍第1項中之定義；且 Rf為氫，保護基，或脂族、環脂族、雜脂族、環雜脂 族、方基或雜芳基部份基團； 而其中各前述脂族或雜脂族部份基團可獨立為經取代 或未經取代、環狀或非環狀、線性或分枝狀、飽和或不 飽和；且其中各前述芳基或雜芳基部份基團可獨立為經 取代或未經取代。 13.根據申請專利範圍第i項之化合物，其中化合物具有以下 結構：Wherein R1 and R2 are as defined in item 1 of the scope of the patent application; and Rf is hydrogen, a protecting group, or an aliphatic, cycloaliphatic, heteroaliphatic, cycloheteroaliphatic, square or heteroaryl moiety. And each of the aforementioned aliphatic or heteroaliphatic moiety may be independently substituted or unsubstituted, cyclic or acyclic, linear or branched, saturated or unsaturated; and each of the aforementioned aryl Or the heteroaryl moiety may be independently substituted or unsubstituted. 13. A compound according to item i of the application, wherein the compound has the following structure: 85762 2UU412345 -中K與112均如巾請專利範圍第1項中之定義； G 為 CH2 或-(〇〇);及 X 為 〇 S、C—0、S==0、CCR4R5、NR4 或 CR4R5 ;其中 、广r5《各存在處係獨立為氫、經基、自素、氰基，脂 :、/像月曰狹、方基或雜芳基部份基團，或為被脂族、雜 基或雜芳基部份基圏取代之酿基部份基團； 、而其中各則述脂族或雜脂族部份基團可獨立為經取代 2未經取代、％狀或非環狀、線性或分枝狀，且其中各 前述芳基或雜芳基部份基團可獨立為經取代或未經取代。 14·根據申_,J範圍第1項之化合物，*中化合物具有以下 結構：85762 2UU412345-Both K and 112 are as defined in item 1 of the patent scope; G is CH2 or-(〇〇); and X is 〇S, C-0, S == 0, CCR4R5, NR4 or CR4R5 Among them, Guang r5 "Each presence is independently hydrogen, meridian, self-prime, cyano, aliphatic :, / like Yueyue narrow, square or heteroaryl partial group, or is aliphatic, hetero Radicals or heteroaryl moieties, which are substituted by alkynyl moieties; and each of which is an aliphatic or heteroaliphatic moieties may be independently substituted 2 unsubstituted,% or acyclic , Linear or branched, and wherein each of the aforementioned aryl or heteroaryl moiety groups may be independently substituted or unsubstituted. 14. According to the compound in the first item of the scope of Shen J, J, the compound in * has the following structure: 其中R1與R2均如申請專利範圍第1項中之定義；· G 為 CH2 或 _(c=0);及 X 為 〇、s、〇=〇、s=o、c=cr4r5、NR4 或 cr4r5 ;其中 I與R5之各存在處係獨立為氫、羥基、鹵素、氰基，脂 族、雜脂族、芳基或雜芳基部份基團，或為被脂族、雜 脂族、芳基或雜芳基部份基團取代之醯基部份基團； 而其中各前述脂族或雜脂族部份基團可獨立為經取代 或未經取代、環狀或非環狀、線性或分枝狀，且其中各 利述芳基或雜芳基邵份基團可獨立為經取代或未經取代。 85762 200412345 項之化合物，其中化合物具有以下 15·根據申請專利範圍第 結構： -Where R1 and R2 are as defined in item 1 of the scope of patent application; G is CH2 or _ (c = 0); and X is 〇, s, 〇 = 〇, s = o, c = cr4r5, NR4 or cr4r5 ; Where each of I and R5 are independently hydrogen, hydroxyl, halogen, cyano, aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or are aliphatic, heteroaliphatic, aromatic A fluorenyl moiety group substituted with a radical or heteroaryl moiety; and each of the aforementioned aliphatic or heteroaliphatic moiety may be independently substituted or unsubstituted, cyclic or non-cyclic, linear Or branched, and wherein each of the aryl or heteroaryl groups may be independently substituted or unsubstituted. 85762 200412345 compounds, wherein the compounds have the following structure according to the scope of the patent application:- 專利項中之定義 入為〇 υ、、NR4 或 CR4R5 ;其中 心與R5之各存在處係獨立為氫1基1素、氰基，脂 ^雜f族1基或雜芳基部份基團，或為被脂族、雜 狹万基或旅万基邵份基團取代之醯基部份基團； 而其中各前述脂族或雜脂族部份基團可獨立為經取代 :未經取代、環狀或非環狀、線性或分枝狀，且其中各 則述芳基或雜芳基部份基團可獨立為經取代或㈣取代。 ·::申請專利範園第1項之化合物;其中化合物具有以下 85762The definition in the patent item is 0, NR4, or CR4R5; its center and each place of R5 are independently hydrogen 1 group 1 element, cyano group, aliphatic ^ f group 1 group or heteroaryl partial group Or is a fluorenyl moiety that is substituted with an aliphatic, heterozygous or bridging moiety; and each of the aforementioned aliphatic or heteroaliphatic moiety may be independently substituted: without Substituted, cyclic or acyclic, linear or branched, and each of the aryl or heteroaryl moieties may be independently substituted or substituted with fluorene. :: The compound applied for the first item in the patent application park; the compound has the following 85762 其中RAR2均如申請專利範圍第1項中之定義 P為整數0-3 ; 200412345 s為整數(Μ ; A、Β、ρ、Ε&amp;κ之各存在處係獨立為不存在、〇、s 〇 s 〇、_c—cr4 r5、-nr4 或-CR4 r5，其中 r4 與 之 各存在處係獨立為氫、羥基、鹵素、氰基…ORx、_SRx、 -NRxRy，脂族、雜脂族、芳基或雜芳基部份基團，或為 被知秩、雜脂族、芳基或雜芳基部份基團取代之醯基部 份基團 B與D，D與E，E與K，及任兩 且其中A與B 個相鄰K基團，當價鍵允許時，可藉由單或雙鍵連接； 其中1與Ry之各存在處係獨立為氫，保護基，或脂族、 雜脂族、芳基、雜芳基、脂族芳基、雜脂族芳基、脂族 雜芳基或雜脂族雜芳基部份基團； 而其中各前述脂族或雜脂族部份基團可獨立為經取代 或未經取代、環狀或非環狀、線性或分枝狀、飽和或不 飽和，且其中各前述芳基、雜芳基脂族芳基、雜脂族芳 基、脂族雜芳基或雜脂族雜芳基部份基團可獨立為經取 代或未經取代。 Π.根據申請專利範圍第M6項中任一項之化合物，其中&amp;為 nh2 〇 18.根據申請專利範圍第i_16項中任一項之化合物，其中Rl為 氫。 、、 19·根據申請專利範圍第1-16項中任一項之化合物，其中R2為 NH2、〇H、q-C6烷基或q-C6烯基，該烷基與烯基係視情 況被_素或幾基取代。 2〇.根據申請專利範圍第1-16項中任一項之化合物，其中&amp;為 85762 -10- 200412345 C1_C2烷基。 其中R2為 21. 根據申請專-利範圍第g項中任一項之化合物 甲基。 其中R2為 22. 根據申請專利範圍第項中任一項之化合物 氯。 其中R；f或 23. 根據申請專利範圍第4_1〇項中任—項之化合物一 TM %之—為氫或低碳燒基；而另—個為燒基、雜燒基、芳 基、雜芳基、燒基芳基或燒基雜芳基，斟各存在處，係 視情況獨立被一或多個齒素、燒氧基、硫基燒基或經取 代或未經取代之燒基、雜燒基、芳基或雜芳基取代，或 其中％與R〇-起採用為3_，4_,5、6_，7_或8_員經取代或未經 取代、飽和或不飽和環狀或雜環族部份基團。 24·根據申請專利範園第4_1〇項中任—項 W —為氫或低纽基；而另—個為芳基、雜 基方基或燒基雜芳基部份基團，對各存在處，係視情況 獨立被-或多個自素、燒氧基、硫基燒基或經取代或未 經取代找基、耗基m雜芳基取代，或其中rf 與R〇—起採用為3-，4-，5-，6-，7-或8-員經取代或未經取代、 飽和或不飽和環狀或雜環族部份基團。 25.根據中請專利範圍第24項之化合物，其中之一為 氫或低碳燒基；而另—個為苯基、❹基、（燒基）苯基或 悚基Η淀基，視情況被一或多個存在處之函t、三氣甲 氧基T氧基、二氟曱基、甲硫基或經取代或未經取代 之低碳烷基、低碳雜烷基、芳基或雜芳基取代。 85762 -11- 200412345 26·根據申請專利範圍第4-1〇項中任一項之化合物，其中心或 R〇之一為氫·或低碳烷基；而另一個為環狀或非環狀、線 性或分枝狀、飽和或不飽和脂族部份基團，視情況被一 或多個經取代或未經取代之芳基、雜芳基、醯胺、烷氧 基、羥基、硫基烷基、硫醇、醯基或胺基取代。 27·根據申請專利範圍第u項之化合物，其中Rf為烷基、環 燒基、雜燒基、環雜烷基、芳基、雜芳基、烷基芳基或 燒基雜芳基’對各存在處，係視情況獨立被一或多個鹵 素、燒氧基、硫基烷基或經取代或未經取代之烷基、雜 燒基、芳基或雜芳基取代。 28.根據申請專利範園第12項之化合物，其中Rf為氫，保護 基’或烷基、環烷基、雜烷基、環雜烷基、芳基、雜芳 基、烷基芳基或烷基雜芳基，對各存在處，係視情況獨 立被一或多個_素、烷氧基、硫基烷基或經取代或未經 取代之烷基、雜烷基、芳基或雜芳基取代。 29· —種醫藥組合物，其包含具有結構①之化合物：Among them, RAR2 is as defined in item 1 of the scope of patent application. P is an integer 0-3; 200412345 s is an integer (M; each existence of A, B, ρ, E &amp; κ is independently non-existent, 0, s 〇 s 〇, _c—cr4 r5, -nr4 or -CR4 r5, where each of r4 exists independently is hydrogen, hydroxyl, halogen, cyano ... ORx, _SRx, -NRxRy, aliphatic, heteroaliphatic, aryl Or a heteroaryl moiety, or a fluorenyl moiety groups B and D, D and E, E and K, and substituted by a known rank, heteroaliphatic, aryl or heteroaryl moiety. Any two and A and B adjacent K groups can be connected by single or double bonds when valence bonds are allowed; where each of 1 and Ry are independently hydrogen, protecting group, or aliphatic, hetero Aliphatic, aryl, heteroaryl, aliphatic aryl, heteroaliphatic aryl, aliphatic heteroaryl, or heteroaliphatic heteroaryl moiety; and each of the foregoing aliphatic or heteroaliphatic moiety The group may be independently substituted or unsubstituted, cyclic or acyclic, linear or branched, saturated or unsaturated, and each of the foregoing aryl, heteroaryl aliphatic aryl, and heteroaliphatic aryl groups ,fat The heteroaryl or heteroaliphatic heteroaryl moiety may be independently substituted or unsubstituted. Π. A compound according to any one of item M6 of the patent application scope, wherein &amp; is nh2 〇18. According to the application The compound of any one of the scope of patents i_16, wherein R1 is hydrogen. 19, The compound of any one of the scope of patents 1-16 of the application, wherein R2 is NH2, OH, q-C6 alkyl Or q-C6 alkenyl, the alkyl and alkenyl are optionally substituted by _ prime or several groups. 20. The compound according to any one of the claims 1-16 of the scope of the patent application, wherein &amp; is 85762 -10 -200412345 C1_C2 alkyl group, wherein R2 is 21. The methyl group according to any one of item g in the patent scope. Where R2 is 22. The chlorine compound according to any one of the scope of patent application. Where R ; F or 23. According to any one of the items in the scope of the application for patents-4%-1% of TM-is hydrogen or low-carbon alkyl; and the other is alkyl, heteroalkyl, aryl, heteroaryl , Alkynylaryl or alkynylheteroaryl, depending on where they exist, are independently Oxygen, thioalkyl, or substituted or unsubstituted alkyl, heteroalkyl, aryl, or heteroaryl, or 3%, 4_, 5, 6_, 7_ Or 8-membered substituted or unsubstituted, saturated or unsaturated cyclic or heterocyclic part of the group. 24. According to any of the items in the application patent park No. 4-10—item W—is hydrogen or low-newyl; The other one is an aryl group, a heteroaryl group, or a heteroalkyl group. For each place where it exists, it is independently-or more than one by itself, an alkoxy group, a sulfanyl group, or an alkyl group. Substituted or unsubstituted scavenging group, m-heteroaryl substitution, or wherein rf and Ro are taken as 3-, 4-, 5-, 6-, 7- or 8-membered substituted or unsubstituted , Saturated or unsaturated cyclic or heterocyclic moiety. 25. According to the 24th compound of the patent, one of them is hydrogen or low-carbon alkyl; and the other is phenyl, fluorenyl, (alkyl) phenyl, or alkynyl, as the case may be. Is represented by one or more occurrences of t, trisoxymethoxy Toxy, difluorofluorenyl, methylthio, or substituted or unsubstituted lower alkyl, lower heteroalkyl, aryl, or Heteroaryl substitution. 85762 -11- 200412345 26. The compound according to any one of claims 4-10 in the scope of patent application, one of which is hydrogen or lower alkyl at the center or R0; and the other is cyclic or acyclic , Linear or branched, saturated or unsaturated aliphatic moiety, optionally with one or more substituted or unsubstituted aryl, heteroaryl, ammonium, alkoxy, hydroxyl, thio Alkyl, thiol, fluorenyl or amine substituted. 27. The compound according to item u of the scope of patent application, wherein Rf is alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl, heteroaryl, alkylaryl, or alkylheteroaryl ' Where each exists, it is independently substituted with one or more halogen, alkoxy, thioalkyl, or substituted or unsubstituted alkyl, heteroalkyl, aryl, or heteroaryl, as appropriate. 28. The compound according to item 12 of the patent application garden, wherein Rf is hydrogen, protecting group 'or alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl, heteroaryl, alkylaryl, or Alkylheteroaryl, where it is present, is independently independent of one or more elements, alkoxy, thioalkyl or substituted or unsubstituted alkyl, heteroalkyl, aryl or hetero Aryl substitution. 29 · —A pharmaceutical composition comprising a compound having the structure ①: 及其藥學上可接受之衍生物； 其中η為整數0-4 ; Ri 為氫、-NH2、-NHMe、_NHAc、-OH、F、-OMe、-CN 或·ΝΗ(Ο0)0Εΐ ; 85762 -12- 200412345 &amp;為氫、-nrarb、_0Ra，脂族、雜脂族、芳基或雜芳 基部份基團:，其中r』Rb各獨立為氫或脂族 芳基或雜芳基部份基團； 曰抶、 各存在處係獨立為氫 '國常、氰基，或脂族、雜 脂族、芳基或雜芳基部份基團，或基團_〇_^，其中 不存在，或為-ch2_、-nrd_、-α或（c=0)，且其中々為氫 部份基團 、環脂族 ，被脂族 部份基團And pharmaceutically acceptable derivatives thereof; wherein η is an integer of 0-4; Ri is hydrogen, -NH2, -NHMe, _NHAc, -OH, F, -OMe, -CN, or · ΝΗ (Ο0) 0Εΐ; 85762- 12- 200412345 &amp; is hydrogen, -nrarb, _0Ra, aliphatic, heteroaliphatic, aryl or heteroaryl moiety: wherein each of R ′ and Rb are independently hydrogen or aliphatic aryl or heteroaryl moiety Part of the group; that is, each occurrence is independently hydrogen's group, cyano, or aliphatic, heteroaliphatic, aryl or heteroaryl partial group, or the group _〇_ ^, where Exists, or is -ch2_, -nrd_, -α, or (c = 0), and 々 is a hydrogen moiety group, a cycloaliphatic group, and an aliphatic moiety group 、-皿fR〇、_0Rf、為，或脂族、雜脂族、芳基或雜芳^ 其中Rd、RF&amp;R〇各獨立為氫、_NRxRy，脂族 雜脂族、環雜脂族、芳基或雜芳基部份2團 雜脂族、芳基或雜芳基部份基團取代之醯基 、 或其中知與心或心與心’一起採用為孓七^ y或8_員經取代或未經取代之環脂族或環雜脂族部份 土團，其中RjRy之各存在處係獨立為氫，脂族、較, -RfR0, _0Rf, is, or aliphatic, heteroaliphatic, aryl, or heteroaryl ^ where Rd, RF &R; are each independently hydrogen, _NRxRy, aliphatic heteroaliphatic, cycloheteroaliphatic, aromatic Base or heteroaryl moiety 2-group heteroaliphatic, aryl or heteroaryl moiety substituted with a fluorenyl group, or in which the consciousness and the heart or the heart and the heart are used together 孓 ^ y or 8_ 员 经Substituted or unsubstituted cycloaliphatic or cycloheteroaliphatic part of the soil group, where each of RjRy exists independently as hydrogen. ，、雜脂族、環㈣族、芳基或雜芳基料基團，被^ 族、雜脂族、芳基或雜芳基部份基團取代之醯基部心 團：或其中Wy 一起採用為4_，5_或6_員經取代或未二 取代、飽和或不飽和環脂族或環雜廇族部份基團； =其中各前述脂族或雜脂族部份基團可獨立為經取代 或未經取代、環狀或非環狀、線性或分枝狀、 飽和，且其中各前述芳基或 取代或未經取代；肖〆 n 土 ϋ可獨立為經 及視情況進一步包含 樂學上可接受之載劑或稀釋劑 另一種治療劑。 其中化合物係 30·根據申請專利範圍第29項之醫藥組合物 85762 -13- 200412345 以有致抑制炎性細胞活素途徑之量存在。 31 ·根據由上 、象申睛專:利範圍第29項之醫藥組合物，其中化合物係 以有致抑制細胞增生之量存在。 32·根據申請專利範圍第29項之醫藥組合物，其中化合物係 以有政顯示消炎作用之量存在。 33.根據申請專利範圍第29項之醫藥組合物，其中化合物具 有以下結構： 口 /、, Heteroaliphatic, cycloaliphatic, aryl, or heteroaryl radicals, amidine radicals substituted with ^, heteroaliphatic, aryl, or heteroaryl moieties: or where Wy is used together Is a 4_, 5_ or 6_ member substituted or unsubstituted, saturated or unsaturated cycloaliphatic or cycloheterocyclic moiety; = wherein each of the aforementioned aliphatic or heteroaliphatic moiety may be independently Substituted or unsubstituted, cyclic or acyclic, linear or branched, saturated, and each of the aforementioned aryl groups is substituted or unsubstituted; Xiao〆n 土 ϋ may be independently selected and further include Le A therapeutically acceptable carrier or diluent is another therapeutic agent. The compound is 30. The pharmaceutical composition according to item 29 of the application scope 85762 -13- 200412345 is present in an amount that inhibits the inflammatory cytokine pathway. 31. According to the above, Xiangshen Jingzhuan: The pharmaceutical composition of item 29, wherein the compound is present in an amount that inhibits cell proliferation. 32. The pharmaceutical composition according to item 29 of the scope of application, wherein the compound is present in an amount that has an anti-inflammatory effect. 33. The pharmaceutical composition according to item 29 of the scope of application for a patent, wherein the compound has the following structure: 匕其中RSa與各獨立為氫、鹵素、氰基，或脂族、雜 脂族、芳基或雜芳基部份基團，或基團，其中G為 不存在、偶…啊…仏或（〇=〇)，且其中r^為氯、视^ rf SRf，或脂叙、雜脂族、芳基或雜芳基部份基團 其中Rd、RF&amp;R〇各獨立為氫、_NRxRy，脂族、.環脂族 、雜脂族、環雜脂族、芳基或雜芳基部份基團，被脂族 、雜脂族、芳基或雜芳基部份基團取代之酿基部份基圈 或其中Rd與R〇或RF與％，一起採用為3_，4_，5_，6_，7_或8_ 員經取代或未經取代之環脂族或環雜脂族部份基團；其 中Rx與Ry〈各存在處係獨立為氫，脂族、環脂族、雜脂 族、環雜脂族、芳基或雜芳基部份基團，被脂族、雜脂 族、芳基或雜芳基部份基團取代之醢基部份基團，或其 中Rx與Ry -起採用為4_，5•或6_員經取代或未經取代之飽 85762 -14- 200412345 和或不飽和環脂族或環雜脂族部份基團； 而其中各:前述脂族或雜脂族部份基團可獨立為經取代 或未經取代、環狀或非環狀、線性或分枝狀、飽和或不 飽和；且其中各前述芳基或雜芳基部份基團可獨立為經 取代或未經取代。 34·根據申請專利範圍第29項之醫藥組合物，其中化合物具 有以下結構：Wherein RSa and each independently are a hydrogen, halogen, cyano, or aliphatic, heteroaliphatic, aryl, or heteroaryl moiety, or a group, wherein G is absent, even ... ah ... 仏 or ( 〇 = 〇), and where r ^ is chlorine, ^ rf SRf, or aliphatic, heteroaliphatic, aryl, or heteroaryl moiety, where Rd, RF &R; each independently is hydrogen, _NRxRy, lipid Family, .cycloaliphatic, heteroaliphatic, cycloheteroaliphatic, aryl or heteroaryl moiety groups, substituted with aliphatic, heteroaliphatic, aryl or heteroaryl moiety groups The base ring or Rd and Ro or RF and% are used together as 3_, 4_, 5_, 6_, 7_ or 8_ member substituted or unsubstituted cycloaliphatic or cycloheteroaliphatic moiety; Where Rx and Ry are independent of each other, hydrogen, aliphatic, cycloaliphatic, heteroaliphatic, cycloheteroaliphatic, aryl or heteroaryl partial groups are aliphatic, heteroaliphatic, aryl Or heteroaryl partial group substituted fluorenyl partial group, or Rx and Ry-from 4_, 5 • or 6_ members substituted or unsubstituted saturated 85762 -14- 200412345 and or not Saturated cycloaliphatic or cycloheteroaliphatic moiety; Each of the foregoing: the aforementioned aliphatic or heteroaliphatic moiety may be independently substituted or unsubstituted, cyclic or acyclic, linear or branched, saturated or unsaturated; and each of the aforementioned aryl or hetero The aryl moiety may be independently substituted or unsubstituted. 34. The pharmaceutical composition according to item 29 of the application, wherein the compound has the following structure: R2 ； 其中R3a與R3b各獨立為氫、鹵素、氰基，或脂族、雜 月曰族、万基或雜芳基部份基團，或基團-，其中G為 不存在或為-CH2-、|_、_α或（〇=〇)，且其中心為氫、·R2; wherein R3a and R3b are each independently hydrogen, halogen, cyano, or an aliphatic, heterocycle, wanyl, or heteroaryl moiety, or a group-wherein G is absent or -CH2 -, | _, _Α, or (〇 = 〇), and its center is hydrogen, · NRFR〇、·〇&amp;、為，或脂族、雜脂族、芳基或雜芳基部 f刀基團，其中Rd、Rf及各獨立為氫、-NRxRy，.脂族、 裒曰叙為月曰权、環雜脂族、芳基或雜芳基部份基團， 被脂族、雜脂族、芳基或雜芳基部份基團取代之酸基部 伤基團或其中心與心或心與^一起採用為^»» 或^貝經取代或未經取代之環脂族或環雜脂族部份基團 :、：：RX與Ry之各存在處係獨立為氫，脂族、環脂族、 :％雜脂族、芳基或雜芳基部份基團，被脂族、 2狹、万基或雖芳基部份基團取代之酸基部份基團， &quot; X人Ry起採用為5·或6-員經取代或未經取代 85762 -15- 200412345 之飽和或不飽和環脂族或環雜脂族部份基團； 而其中各述脂族或雜脂族部份基團可獨立為經取代 或未經取代、環狀或非環狀、線性或分枝狀、飽和或不 飽和·，且其中各前述芳基或雜芳基部份基團可獨立為經 取代或未經取代。 35.根據申請專利範圍第29項之醫藥組合物，其中化合物具 有以下結構： 義NRFR〇, · 〇 &amp;, is, or aliphatic, heteroaliphatic, aryl or heteroaryl moieties f knife group, wherein Rd, Rf and each independently are hydrogen, -NRxRy, aliphatic, 裒Yue Yue, cycloheteroaliphatic, aryl or heteroaryl moiety, acid radical damage group or its center and heart substituted with aliphatic, heteroaliphatic, aryl or heteroaryl moiety Or heart and ^ are used together as ^ »» or ^ shell substituted or unsubstituted cycloaliphatic or cycloheteroaliphatic partial groups:, :: where RX and Ry are independently hydrogen, aliphatic , Cycloaliphatic,:% heteroaliphatic, aryl or heteroaryl moieties, acid moieties substituted by aliphatic, 2-alkanoyl, or aryl moieties, &quot; X-Ry starts with 5 · or 6-membered substituted or unsubstituted 85762 -15- 200412345 saturated or unsaturated cycloaliphatic or cycloheteroaliphatic moiety; and each of them is aliphatic or heterolipid The partial groups of the group may be independently substituted or unsubstituted, cyclic or acyclic, linear or branched, saturated or unsaturated, and each of the aforementioned aryl or heteroaryl partial groups may be independent Is substituted or not Replaced. 35. The pharmaceutical composition according to item 29 of the application, wherein the compound has the following structure: 其中心、R2、知及&amp;均如中請專利範圍第四項中之定Its center, R2, knowledge and &amp; are as specified in the fourth item of the patent scope 36·根據申請專利範圍第29項 有以下結構： 之醫藥組合物，其中化合物具 RqRf^36. According to item 29 of the scope of patent application, the pharmaceutical composition has the following structure: wherein the compound has RqRf ^ 義其中Rl、R2、知及心均如申請專利範圍第29项中之定 =據中請專利範圍第29項之醫藥組 有以下結構： T化合物具 85762 -16 - 200412345The meaning is that R1, R2, knowledge and heart are as determined in the scope of application of the patent No. 29 = According to the request, the medicine group of the scope of patent No. 29 has the following structure: T compound has 85762 -16-200412345 ，其中Ri、R2、RF及R〇均如申請專利範圍第29項中之定 義。 38.根據申請專利範圍第29項之醫藥組合物，其中化合物且 有以下結構： “Among them, Ri, R2, RF and R0 are as defined in the 29th scope of the patent application. 38. The pharmaceutical composition according to item 29 of the application, wherein the compound has the following structure: " rgrfn r2 ； 其中q與r各獨立為0或1 ;且&amp;、ι、Rf及心均如申請 專利範圍第29項中之定義。 月 9·根據申请專利範圍第29項之醫藥組合物，其中化合物且 有以下結構： .rgrfn r2; wherein q and r are each independently 0 or 1; and &amp;, ι, Rf and Xin are as defined in the 29th scope of the patent application. Month 9. The pharmaceutical composition according to item 29 of the scope of patent application, wherein the compound has the following structure: rgrfn R2 . 其中q與r各獨立為〇或1;且Rl、化、^及心均如申請 專利範圍第29項中之定義。 丹 4〇·根據申請專利範圍第29項之醫藥組合物，其中化合物且 有以下結構： 〇 具 85762 -17- 200412345 其中K、R2 義0rgrfn R2. wherein q and r are each independently 0 or 1; and R1, H2, H2 and H2 are as defined in the 29th scope of the patent application. Dan 40. The pharmaceutical composition according to item 29 of the scope of patent application, wherein the compound has the following structure: 〇 85762 -17- 200412345 where K and R2 mean 0 RF及R〇均如申請專利範圍第29項中之定 41·根據申請專利範園第 有以下結構： 29項之醫藥組合物 其中化合物具Both RF and R0 are as specified in item 29 of the scope of the patent application. 41. According to the patent application, it has the following structure: The pharmaceutical composition of item 29, in which the compound has 其中&amp;、心、〜及〜均如申請專利範圍第29項中 義 之定 42.根據申請專利範圍第μ項 有以下結構： 之醫藥組合物，其中化合物 具Among them, &amp;, Xin, ~, and ~ are as defined in the 29th scope of the patent application. 42. According to the μ scope of the patent application, it has the following structure: A pharmaceutical composition, in which the compound has 其中〜與〜均如申請專利範圍第29項中之 m為0、1或2;及 我 芳基或雜芳 RF為脂族、環脂族、雜脂族、環雜脂族 基部份基團； 85762 -18- 200412345 而其中各前述脂族或雜脂族部份基團可獨立為經取代 或未經取代：、環狀或非環狀、線性或分枝狀、飽和或不 飽和，且其中各前述芳基或雜芳基部份基團可獨立為經 取代或未經取代。 43.根據申請專利範圍第29項之醫藥組合物，其中化合物具 有以下結構：Among them, ~ and ~ are as m in the scope of application for patent No. 29, m is 0, 1 or 2; and aryl or heteroaryl RF is an aliphatic, cycloaliphatic, heteroaliphatic, cycloheteroaliphatic radical moiety. 85762 -18- 200412345 and each of the aforementioned aliphatic or heteroaliphatic moiety may be independently substituted or unsubstituted: cyclic or acyclic, linear or branched, saturated or unsaturated, And each of the aforementioned aryl or heteroaryl moiety may be independently substituted or unsubstituted. 43. The pharmaceutical composition according to the scope of application for item 29, wherein the compound has the following structure: R2 . N N Η HN γΝ 其中h與&amp;均如申請專利範圍第29項中之定義；且 Rf為氫’保護基’或脂族、環脂族、雜脂族、環^ 族、芳基或雜芳基部份基團； ’ 而其中各前述脂族或雜脂族部份基團 或未經取代、環狀或非環狀、線性 、線性或分枝狀、 飽和；且其中各前述芳基或雜芳基部份基團 飽和； 可獨立為經取代 枝狀、飽和或不 取代或未經取代。 團可獨立為經 其中化合物具 44·根據申請專利範圍第29項之醫藥組合物 有以下結構：R2. NN Η HN γΝ where h and &amp; are as defined in the scope of application for patent No. 29; and Rf is hydrogen 'protecting group' or aliphatic, cycloaliphatic, heteroaliphatic, cyclo ^, aryl or Heteroaryl moiety; and wherein each of the aforementioned aliphatic or heteroaliphatic moiety is unsubstituted, cyclic or acyclic, linear, linear or branched, saturated; and wherein each of the aforementioned aromatic Or heteroaryl moiety is saturated; may be independently substituted dendritic, saturated or unsubstituted or unsubstituted. The group can be independently a compound in which the pharmaceutical composition according to item 29 of the scope of patent application has the following structure: 其中w2均如申請專利範圍第29項中之定義 85762 -19- 200412345 G 為 CH2 或-(c=〇);且 R ^ 為 0、？、c=0、S=0、C=CR4R5、NR4或 cr4r5 ;直中 广5之各存在處係獨立為氫、經基、函素、氰基，脂 :乂脂族：芳基或雜芳基部份基團，或為被脂族、雜 曰秩、芳基或雜芳基部份基團取代之醯基部份基團； 、而其中各前述脂族或雜脂族部份基團可獨立為經取代 2未、.工取代、ί哀狀或非環狀、線性或分枝狀’且其中各 月迷芳基或雜芳基部份基團可獨立為經取代或未經取代。 45·根據中請專利範圍第29項之醫藥組合物，其中化合物具 有以下結構：Where w2 is the same as defined in item 29 of the scope of patent application 85762 -19- 200412345 G is CH2 or-(c = 〇); and R ^ is 0,? , C = 0, S = 0, C = CR4R5, NR4, or cr4r5; each existence of Zhizhongguang 5 is independently hydrogen, meridian, gluten, cyano, lipid: 乂 aliphatic: aryl or heteroaryl A radical group, or a fluorenyl moiety group substituted with an aliphatic, hetero-rank, aryl, or heteroaryl moiety; and each of the aforementioned aliphatic or heteroaliphatic groups May be independently substituted, unsubstituted, substituted, cyclic or acyclic, linear or branched, and each of the aryl or heteroaryl groups may be independently substituted or unsubstituted . 45. The pharmaceutical composition according to item 29 of the patent application, wherein the compound has the following structure: G 為 CH2 或 _(C=〇);且 X為 0、S、C=〇、S=0、C=CR4R5、戰或 CR4Rs ;其中 〜與心之各存在處係獨立為氫、羥基、_素、氰基，脂 族、雜脂族、芳基或雜芳基部份基團，或為被脂族、雜 脂族、芳基或雜芳基部份基團取代之酿基部份基團； 而其中各前述脂族或雜脂族部❾基團立為經取代 或未經取代、環狀或非環狀、線性或分枝狀，且其中各 前述芳基或雜芳基部份基團可獨立為經取代或未經取代。 46.根據申請專利範圍第29項之醫藥組合物，其中化合物具 85762 -20- 200412345 有以下結構：G is CH2 or _ (C = 〇); and X is 0, S, C = 0, S = 0, C = CR4R5, Zhan, or CR4Rs; where ~ and the place where the heart exists are independently hydrogen, hydroxyl, _ Element, cyano, aliphatic, heteroaliphatic, aryl, or heteroaryl moiety, or an amino moiety substituted by an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety And each of the aforementioned aliphatic or heteroaliphatic fluorene groups is substituted or unsubstituted, cyclic or acyclic, linear or branched, and each of the aforementioned aryl or heteroaryl moieties Groups can be independently substituted or unsubstituted. 46. The pharmaceutical composition according to the scope of application for item 29, wherein the compound has the following structure: 85762-20-20200412345: 其中R#R2均如申請專利範：第 G 為 CH2 或-(〇〇);且 29項中之定義Among them, R # R2 is the same as the patent application: G is CH2 or-(〇〇); and the definition in item 29 X 為 0、S、c=〇、 bO、C=CR4R5、Nr4 或 Cr4r5 ;其中 w之=存在處係獨立為氫、經基、画素、氰基，脂 ^旅月“夭万基或雜芳基部份基團，或為被脂族、雜 脂族、芳基或雜芳基部份基團取代之醯基部份基團； 而其中各前述脂族或雜脂族部份基團可獨立為經取代 :未經取代、環狀或非環狀、線性或分枝狀，且其中各 則述芳基或雜芳基部份基團可獨立為經取代或未經取代。X is 0, S, c = 0, bO, C = CR4R5, Nr4 or Cr4r5; where w = where it is present is independently hydrogen, meridian, pixel, cyano, lipid Radical group, or a fluorenyl moiety group substituted with an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety; and each of the foregoing aliphatic or heteroaliphatic groups may be Independently substituted: unsubstituted, cyclic or acyclic, linear or branched, and each of these aryl or heteroaryl groups may be independently substituted or unsubstituted. 47.根據中請專利範園第四項之醫藥組合物，其中化合物具 有以下結構：47. The pharmaceutical composition according to item 4 of the Chinese Patent Application Park, wherein the compound has the following structure: 其中Rl與R2均如申請專利範圍第29項中之定義； P為整數0-3 ; s為整數0-4 ; 85762 -21 - 200412345 A B D、E，及K之各存在處係獨立為不存在、〇 、S、-〇0 、d4R5、风或（从，其中心與&amp; 之各存在處係獨立為氫、羥基、函素、氰基、七Rx、_SRX NRXRy知族、雜脂族、芳基或雜芳基部份基團，或 為被脂族、雜脂族、芳基或雜芳基部份基團取代之醯基 邵份基團；且其中A與B，B與D，〇與£，£與尺，及任 兩個相鄰K基團，當價鍵允許時，可藉由單或雙鍵連接 ，其中Rx與Ry之各存在處係獨立為氫，保護基，或脂族 、雜脂族、芳基、雜芳基、脂族芳基、雜脂族芳基、脂 族雜芳基或雜脂族雜芳基部份基團； 而其中各前述脂族或雜脂族部份基團可獨立為經取代 或未經取代、環狀或非環狀、線性或分枝狀、飽和或不 免和，且其中各前述芳基、雜芳基脂族芳基、雜脂族芳 基、脂族雜芳基或雜脂族雜芳基部份基團可獨立為經取 代或未經取代。 48·根據申請專利範圍第29_47項中任一項之醫藥組合物，其 中Ri為nh2。 49·根據申請專利範圍第29-47項中任一項之醫藥組合物，其 中Ri為氫。 5〇·根據申請專利範圍第29-47項中任一項之醫藥組合物，其 中&amp;為NH2、OH、（VQ烷基或晞基，該烷基與稀基 係視情況被卣素或羥基取代。 51·根據申請專利範圍第29-47項中任一項之醫藥組合物，其 中汉2為CVC2烷基。 ^5762 -22- 200412345 其 Μ.根據申請專利聋爸圍第29_47項中任一項之醫藥組合物 中r2為甲基：。 其 53. 根據申請專利範圍第29_47項中任一項之醫藥組合物 中r2為氫。 54. 根據中請專利範圍第35_41項中任一項之醫藥組合物，其 中〜或11〇之一為氫或低碳烷基；而另—個為烷基、雜烷 基、芳基、雜芳基、燒基芳基或燒基雜芳基，對各存在 處’係視情況獨立被一或多個齒素、燒氧基、硫基燒基 或經取代或未經取代之燒基、雜垸基、芳基或雜芳絲 代’或其中心與^一起採用為从从乂或^員經取代 或未經取代之飽和或不飽和環狀或雜環族部份基團。 55. 根據申請專利範圍第35_41項中任一項之醫藥^合物，其 中I^Re之-為氫或低碳燒基；而另—個為芳基、雜芳 基、燒基芳基或燒基雜芳基部份基團，料存在處，係 視情況獨立被-或多個自素、燒氧基、硫基燒基或經取 代或未經取代之烷基、雜烷基、芳基或雜芳基取代，或 其中〜與％-起採用為3.»，6_，7:或8_員經取代或未經 取代之飽和或不飽和環狀或雜環族部份基團。 56. 根據申請專利範圍第55項之醫藥組合物，其中Rp或％之 一為氫或低碳烷基；而另一個為苯基、吡啶基、（垸基）苯 基或（fe基）吡哫基，視情況被—或多個存在處之函素、三 氟甲氧基、甲氧基 '三氟甲基、甲硫基或經取代或未經 取代之低碳烷基、低碳雜烷基芳基或雜芳基取代。 57. 根據申請專利範圍第35-41項中任一項之醫藥組合物，其 85762 -23- 200412345 中心或Rg之一為氫或低碳烷基；而另—個為環狀或非環 狀、線性或:分枝狀、飽和或不飽和脂族部份基團，視情 況被一或多個經取代或未經取代之芳基、雜芳基、酸胺 ^元氧基、每基、硫基燒基、硫醇驢基或胺基取代。 58·根據申請專利範圍第42項之醫藥組合物，其中&amp;為燒基 、環烷基、雜烷基、環雜烷基、芳基、雜芳基、烷基芳 基或烷基雜芳基，對各存在處，係視情況獨立被一或多 個鹵素、烷氧基、硫基烷基或經取代或未經取代之烷基 、雜烷基、芳基或雜芳基取代。 59·根據申請專利範圍第43項之醫藥組合物，其中％為氯， 保護基，或烷基、環烷基、雜烷基、環雜烷基、芳基、 雜芳基、烷基芳基或烷基雜芳基，對各存在處，係視情 況獨立被一或多個i素、烷氧基、硫基烷基或經取代或 未經取代之烷基雜烷基芳基或雜芳基取代。 60· —種用於治療炎性或自身免疫病症或增生病症之醫藥組 合物，其包含： 治療上有效量之根據申請專利範圍第項中任一項 之化合物；及藥學上可接受之載劑或稀釋劑；且視情況 進一步包含另一種治療劑。 61·根據申請專利範圍第60項之醫藥組合物，其中醫藥組合 物係用以治療風濕性關節炎、潰瘍性結腸炎/克隆氏病 中樞神經系統疾病（CNS)，譬如多發性硬化、全身性紅 斑狼瘡、氣喘、同種移植排斥/移植物對宿主疾病（gvhd) 、牛皮癖、異位性皮炎、濕疹、荨麻疹、過敏性鼻炎、 85762 200412345 重症肌無力、糖尿病、自發性血小板減少性紫斑病、絲 球體性腎炎-、心與血管疾病或癌症。 62. 根據申請專利範圍第60項之醫藥組合物，其中該醫藥組 合物係用以治療風濕性關節炎。 63. 根據申請專利範圍第60項之醫藥組合物，其中該醫藥組 合物係用以治療潰瘍性結腸炎/克隆氏病。 64. 根據申請專利範圍第60項之醫藥組合物，其中該醫藥組 合物係用以治療多發性硬化。 _ 65·根據申請專利範圍第60項之醫藥組合物，其中該醫藥組 合物係用以治療氣喘。 66. 根據申請專利範圍第60項之醫藥組合物，其中該醫藥組 合物係用以治療牛皮癖。 67. 根據申請專利範圍第60項之醫藥組合物，其中該醫藥組 合物係用以治療同種移植排斥/ GVHD。 68. 根據申請專利範圍第60項之醫藥組合物，其中該醫藥組 合物係用以治療自發性血小板減少性紫斑病。 _ 69. 根據申請專利範圍第60項之醫藥組合物，其中該醫藥組 合物係用以治療過敏性鼻炎。 70. 根據申請專利範圍第60項之醫藥組合物，其中該醫藥組 合物係用以治療異位性皮炎。 71. 根據申請專利範圍第60項之醫藥組合物，其中該醫藥組 合物係用以治療全身性紅斑狼瘡。 72. 根據申請專利範圍第60項之醫藥組合物，其中該醫藥組 合物係用以治療絲球體性腎炎。 85762 -25- 200412345 73.根據申請專利範園第6〇 合物係用❹療糖尿病W樂組合物’其中該醫藥組 種血管中用於預防或降低再 ::支架具有大致上管狀結構，此結構之表面係塗覆( 或以其他方式配合調整以釋出）—種組合物m( 以下結構之化合物： 八匕》/、百Among them, R1 and R2 are as defined in the 29th scope of the patent application; P is an integer 0-3; s is an integer 0-4; 85762 -21-200412345 where each of ABD, E, and K exists independently is non-existent , 〇, S, -〇0, d4R5, wind or (from, its center and each existence of &amp; are independently hydrogen, hydroxy, functional element, cyano, seven Rx, _SRX NRXRy family, heteroaliphatic, An aryl or heteroaryl moiety, or a fluorenyl moiety substituted by an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety; and wherein A and B, B and D, 〇 and £, £ and ruler, and any two adjacent K groups, when the valence bond allows, can be connected by single or double bonds, where each occurrence of Rx and Ry is independently hydrogen, protecting group, or Aliphatic, heteroaliphatic, aryl, heteroaryl, aliphatic aryl, heteroaliphatic aryl, aliphatic heteroaryl, or heteroaliphatic heteroaryl moiety; and each of the foregoing aliphatic or heteroaliphatic The aliphatic moiety may be independently substituted or unsubstituted, cyclic or acyclic, linear or branched, saturated or inevitably, and each of the foregoing aryl, heteroaryl aliphatic aryl, hetero Aliphatic Group, aliphatic heteroaryl group or heteroaliphatic heteroaryl moiety may be independently substituted or unsubstituted. 48. The pharmaceutical composition according to any one of claims 29_47 in the scope of patent application, wherein Ri is nh2 49. The pharmaceutical composition according to any one of the claims 29-47, wherein Ri is hydrogen. 50. The pharmaceutical composition according to any one of the claims 29-47, wherein &amp; NH2, OH, (VQ alkyl or fluorenyl, the alkyl and dilute groups are optionally substituted by halogen or hydroxy. 51. The pharmaceutical composition according to any one of claims 29-47 in the scope of patent application, wherein Han 2 is a CVC2 alkyl group. ^ 5762 -22- 200412345 Its M. According to the patent application of any of the deaf parents in the pharmaceutical composition of any one of items 29_47 r2 is methyl: its 53. According to the scope of application for patents 29_47 In the pharmaceutical composition of any one of R 2 is hydrogen. 54. According to the pharmaceutical composition of any one of claims 35 to 41 of the patent scope, one of ~ or 110 is hydrogen or a lower alkyl group; and the other- An alkyl group, a heteroalkyl group, an aryl group, a heteroaryl group, a alkynyl aryl group, or a alkynyl heteroaryl group. Where 'is independently independent of one or more halide, alkoxy, thioalkyl or substituted or unsubstituted alkynyl, heterofluorenyl, aryl or heteroaryl' or its center and ^ Used together as a substituted or unsubstituted saturated or unsaturated cyclic or heterocyclic partial group from 乂 or 员 member. 55. A pharmaceutical compound according to any one of claims 35_41 Where I ^ Re- is hydrogen or a low-carbon alkyl group; and the other is an aryl, heteroaryl, alkylaryl or alkyl heteroaryl group. Where it exists, it is independent depending on the situation. Is substituted by-or more from voxel, alkoxy, thioalkyl or substituted or unsubstituted alkyl, heteroalkyl, aryl or heteroaryl, or where ~ and%-are used as 3. », 6_, 7: or 8_ member substituted or unsubstituted saturated or unsaturated cyclic or heterocyclic moiety. 56. The pharmaceutical composition according to item 55 of the application, wherein one of Rp or% is hydrogen or lower alkyl; and the other is phenyl, pyridyl, (fluorenyl) phenyl, or (feyl) pyridine Fluorenyl, optionally by—or more than one functional element, trifluoromethoxy, methoxy'trifluoromethyl, methylthio, or substituted or unsubstituted lower alkyl, Alkylaryl or heteroaryl substitution. 57. The pharmaceutical composition according to any one of claims 35-41 of the scope of application for patent, one of 85762 -23- 200412345 center or Rg is hydrogen or lower alkyl; and the other is cyclic or non-cyclic , Linear or: branched, saturated or unsaturated aliphatic partial group, optionally with one or more substituted or unsubstituted aryl, heteroaryl, acid amine ^ -oxyl group, per group, Substituted by thioalkyl, thiol or amine. 58. The pharmaceutical composition according to item 42 of the scope of patent application, wherein &amp; is alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl, heteroaryl, alkylaryl, or alkylheteroaryl Group, where it exists, is independently substituted with one or more halogen, alkoxy, thioalkyl, or substituted or unsubstituted alkyl, heteroalkyl, aryl, or heteroaryl, as appropriate. 59. The pharmaceutical composition according to item 43 of the scope of patent application, wherein% is chlorine, a protecting group, or an alkyl group, a cycloalkyl group, a heteroalkyl group, a cycloheteroalkyl group, an aryl group, a heteroaryl group, and an alkylaryl group Or alkylheteroaryl, for each occurrence, is independently independent of one or more i-prime, alkoxy, thioalkyl, or substituted or unsubstituted alkylheteroalkylaryl or heteroaryl Radical substitution. 60 · —A pharmaceutical composition for treating an inflammatory or autoimmune disorder or a proliferative disorder, comprising: a therapeutically effective amount of a compound according to any one of the items in the scope of patent application; and a pharmaceutically acceptable carrier Or a diluent; and optionally further comprising another therapeutic agent. 61. The pharmaceutical composition according to item 60 of the scope of the patent application, wherein the pharmaceutical composition is used to treat rheumatoid arthritis, ulcerative colitis / cloni disease central nervous system disease (CNS), such as multiple sclerosis, systemic Lupus erythematosus, asthma, allograft rejection / graft-versus-host disease (gvhd), psoriasis, atopic dermatitis, eczema, urticaria, allergic rhinitis, 85762 200412345 myasthenia gravis, diabetes, spontaneous thrombocytopenic purpura Disease, filamentous nephritis-heart and vascular disease or cancer. 62. The pharmaceutical composition of claim 60, wherein the pharmaceutical composition is used to treat rheumatoid arthritis. 63. The pharmaceutical composition according to item 60 of the application, wherein the pharmaceutical composition is used to treat ulcerative colitis / cloned's disease. 64. The pharmaceutical composition according to item 60 of the application, wherein the pharmaceutical composition is used to treat multiple sclerosis. 65. The pharmaceutical composition according to item 60 of the scope of patent application, wherein the pharmaceutical composition is used to treat asthma. 66. The pharmaceutical composition according to item 60 of the application, wherein the pharmaceutical composition is used to treat psoriasis. 67. The pharmaceutical composition of claim 60, wherein the pharmaceutical composition is used to treat allograft rejection / GVHD. 68. The pharmaceutical composition of claim 60, wherein the pharmaceutical composition is used to treat spontaneous thrombocytopenic purpura. _ 69. The pharmaceutical composition according to item 60 of the scope of patent application, wherein the pharmaceutical composition is used to treat allergic rhinitis. 70. The pharmaceutical composition according to item 60 of the application, wherein the pharmaceutical composition is used to treat atopic dermatitis. 71. The pharmaceutical composition of claim 60, wherein the pharmaceutical composition is used to treat systemic lupus erythematosus. 72. The pharmaceutical composition according to item 60 of the patent application, wherein the pharmaceutical composition is used for treating filamentous nephritis. 85762 -25- 200412345 73. According to the patent application Fanyuan No. 60 composition is used to treat diabetes W music composition 'wherein the medical group of blood vessels is used to prevent or reduce the re :: stent has a substantially tubular structure, this The surface of the structure is coated (or coordinated to release in other ways) —a composition m (compounds of the following structure: eight daggers), one hundred r2 (I) 及其藥學上可接受之衍生物； 其中η為整數0-4 ; -OMe、-CN Ri 為氫、-NH2、-NHMe、-NHAc、.OH、F 或 _NH(C=0)〇Et ; I為氫、-nrarb、_〇ra，脂族、雜脂族、芳基或雜芳 基部份基團，其中ra與rb各獨立為氳，或脂族、.雜脂族 、方基或雜芳基邵份基團； R3之各存在處係獨立為氫、函素、氰基，或脂族、雜 月曰权、务基或雜芳基邵份基團，或基團，其中g為 不存在，或為-αν、-nrd_、〇·或（〇〇)，且其中心為氫 、-NRfRq、-0RF、-SRF，或脂族、雜脂族' 芳基或雜芳基 邵份基團，其中RD、RF及Rq各獨立為氫、，脂族 、環脂族、雜脂族、環雜脂族、芳基或雜芳基部份基團 ’被脂族、雜脂族、芳基或雜芳基部份基團取代之酿基 85762 -26- 200412345 部份基團，或其，—起採用為3“ 5 6-，7_或8·^取代或未經取代之環脂族或環雜脂族部份 基團；其中Rx與R〆各存在處係獨立為氫，脂族、環听 族、雜脂族、環雜脂族、芳基或雜芳基部份基團，被^ 族、雜脂族、芳基或雜芳基部份基團取代之醯基部份^ 團，或其中心與心一起採用為4_，5_或6_員經取代或未經 取代之飽和或不飽和環脂族或環雜脂族部份基團； 而其中各前述脂族或雜脂族部份基團可獨立為經取代 或未、、二取代、環狀或非環狀、線性或分枝狀、飽和或不 飽和，且其中各前述芳基或雜芳基部份基團可獨立為經 取代或未經取代；及選用之 i學上可接受之載劑或稀釋劑； 以致使孩阻塞被排除，且該組合物係以有效預防或降 低再狹有速率之量傳輸。 75. 一種使身體通道之腔管膨脹之支架，該支架具有大致上 言狀結構’此結構之表面係塗覆（或以其他方式配合調整 以釋出）一種組合物，其包含具有以下結構之化合物：r2 (I) and pharmaceutically acceptable derivatives thereof; wherein η is an integer of 0-4; -OMe, -CN Ri is hydrogen, -NH2, -NHMe, -NHAc, .OH, F or _NH (C = 0) 〇Et; I is hydrogen, -nrarb, _〇ra, aliphatic, heteroaliphatic, aryl or heteroaryl moiety, wherein each of ra and rb is independently fluorene, or aliphatic, .heterolipid Groups, square or heteroaryl groups; each occurrence of R3 is independently hydrogen, halo, cyano, or aliphatic, heterocyclic, sulfo or heteroaryl groups, or Group, where g is absent, or is -αν, -nrd_, 〇, or (〇〇) and its center is hydrogen, -NRfRq, -0RF, -SRF, or aliphatic, heteroaliphatic 'aryl Or heteroaryl radicals, where RD, RF and Rq are each independently hydrogen, aliphatic, cycloaliphatic, heteroaliphatic, cycloheteroaliphatic, aryl or heteroaryl moiety radicals Group, heteroaliphatic, aryl or heteroaryl partial group substituted group 85762 -26- 200412345 partial group, or-from 3 to 5 6-, 7_ or 8 · ^ substitution Or unsubstituted cycloaliphatic or cycloheteroaliphatic partial groups; where Rx and R〆 exist independently , Aliphatic, cycloaliphatic, heteroaliphatic, cycloheteroaliphatic, aryl or heteroaryl moiety groups, fluorenyl groups substituted with ^, heteroaliphatic, aryl or heteroaryl moiety A partial ^ group, or its center and heart, together with a 4_, 5_ or 6_ member substituted or unsubstituted saturated or unsaturated cycloaliphatic or cycloheteroaliphatic partial group; and each of the aforementioned lipids The family or heteroaliphatic moiety may be independently substituted or unsubstituted, disubstituted, cyclic or acyclic, linear or branched, saturated or unsaturated, and each of the foregoing aryl or heteroaryl moieties The moieties can be independently substituted or unsubstituted; and a scientifically acceptable carrier or diluent is selected; so that child obstruction is eliminated, and the composition is effective to prevent or reduce the rate of restenosis 75. A stent for inflating a lumen of a body passage, the stent has a generally-shaped structure 'the surface of this structure is coated (or otherwise adjusted in coordination to release) a composition comprising: Structural compounds: (I) 及其藥學上可接受之衍生物； 其中η為整數0-4 ; Ri 為氫、-NH2、-NHMe、-NHAc、-OH、F、_〇Me、-CN 85762 -27- 200412345 或 NH(C=〇)〇Et ; R2為氫、：-nrarb、—0Ra，脂族、雜脂族、芳基或雜芳 基部份基團，其中、與知各獨立為氫，或脂族、雜脂族 、芳基或雜芳基部份基團； &amp;之各存在處係獨立為氫、卣素、氰基，或脂族、雜 脂族、芳基或雜芳基部份基團，或基團_G-Rc，其中G為 不存在，或為-CH2 _、_nrd -、或（c=〇)，且其中心為氣 、-NRfRq、-〇rf、_srf，或脂族、雜脂族、芳基或雜芳基 部份基團，其中rd、心及％各獨立為氫、_NRx&amp;，脂族 、環脂族、雜脂族、環雜脂族、芳基或雜芳基部份基團 ’被脂族、雜脂族、芳基或雜芳基部份基團取代之醯基 邯份基團，或其中RD與心或rf與心，一起採用為3_，4_，5_， 6-，7-或8-員經取代或未經取代之環脂族或環雜脂族部份 基團；其中Rx與~之各存在處係獨立為氫，脂族、環脂 族、雜脂族、環雜脂族、芳基或雜芳基部份基團，被脂 族、雜脂族、芳基或雜芳基部份基團取代之醯基部份基 團，或其中心與&amp;一起採用為4-，f或6_員經取代或未經 取代之飽和或不飽和環脂族或環雜脂族部份基團； 而其中各前述脂族或雜脂族部份基團可獨立為經取代 或未經取代、環狀或非環狀、線性或分枝狀、飽和或不 飽和，且其中各的述芳基或雜芳基部份基團可獨立為經 取代或未經取代；及選用之 藥學上可接受之載劑或稀釋劑； 以致使該通道膨脹。 85762 -28 - 200412345 76. 根據申請專利範圍第75項之支架，其中該支架係用以使 身體通道之:腔管膨脹，以排除膽管、胃腸、食管、氣管 /枝氣管、尿道及/或血管阻塞。 77. 根據申請專利範圍第75項之支架，其中該支架係用以使 身體通道之腔管膨脹，以排除血管阻塞。(I) and pharmaceutically acceptable derivatives thereof; wherein η is an integer of 0-4; Ri is hydrogen, -NH2, -NHMe, -NHAc, -OH, F, _〇Me, -CN 85762 -27- 200412345 Or NH (C = 〇) 〇Et; R2 is hydrogen,: -nrarb, -0Ra, aliphatic, heteroaliphatic, aryl or heteroaryl partial group, wherein, and each independently are hydrogen, or lipid Groups, heteroaliphatic, aryl or heteroaryl moieties; &amp; each occurrence is independently hydrogen, halogen, cyano, or aliphatic, heteroaliphatic, aryl or heteroaryl moieties Group, or group _G-Rc, where G is absent, or -CH2 _, _nrd-, or (c = 0), and its center is gas, -NRfRq, -〇rf, _srf, or lipid Group, heteroaliphatic, aryl or heteroaryl partial group, wherein rd, heart and% are each independently hydrogen, _NRx &amp;, aliphatic, cycloaliphatic, heteroaliphatic, cycloheteroaliphatic, aryl or Heteroaryl moiety groups are substituted by aliphatic, heteroaliphatic, aryl, or heteroaryl moiety groups, or wherein RD and xin or rf and xin are taken together as 3_, 4_, 5_, 6-, 7- or 8-membered substituted or unsubstituted cycloaliphatic or cycloheteroaliphatic The groups where Rx and ~ exist independently are hydrogen, aliphatic, cycloaliphatic, heteroaliphatic, cycloheteroaliphatic, aryl or heteroaryl partial groups, and are aliphatic, heterolipid Group, aryl or heteroaryl partial group substituted fluorenyl partial group, or its center is used together with &amp; 4-, f or 6-membered substituted or unsubstituted saturated or unsaturated ring Aliphatic or cycloheteroaliphatic moiety; each of the aforementioned aliphatic or heteroaliphatic moiety may be independently substituted or unsubstituted, cyclic or noncyclic, linear or branched, saturated Or unsaturated, and each of the aryl or heteroaryl moieties may be independently substituted or unsubstituted; and a pharmaceutically acceptable carrier or diluent selected; so that the channel swells. 85762 -28-200412345 76. The stent according to item 75 of the scope of patent application, wherein the stent is used to expand the passage of the body: lumen, to exclude the bile duct, gastrointestinal tract, trachea / bronchiobronchi, urethra and / or blood vessels Blocked. 77. The stent according to item 75 of the patent application scope, wherein the stent is used to expand the lumen of the body passage to exclude vascular obstruction. 85762 29- 200412345 柒、指定代表圖： (一) 本案指定代表圖為··第（ ）圖。 (二) 本代表圖之元件代表符號簡單說明： 捌、本案若有化學式時，請揭示最能顯示發明特徵的化學式：85762 29- 200412345 柒. Designated Representative Map: (1) The designated representative map in this case is the () chart. (2) A brief description of the component symbols in this representative map: 捌 If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention: 85762 200412345 ”” 發明專利說明書 中文說明書替換頁(92年1〇月) (本說明書格式、順岸及粗體字，請勿任意更動，※記號部分請勿填寫） ※申請案號·· 092114905 ※申請日期： 糸1卩〇:分類： 壹、 發明名稱：（中文/英文） 新穎脫氮嘌呤及其用途 NOVEL DEAZAPURINES AND USES THEREOF 貳、 申請人：（共1人） 姓名或名稱：（中文/英文） 〜 日商衛材股份有限公司 EISAI CO·，LTD. 代表人：（中文/英文） 吉野博史 fflROSHI YOSHINO 住居所或營業所地址··（中文/英文） 曰本國東京都文京區小石川四丁目6番10號 6-10 KOISHIKAWA 4-CHOME, BUNKYO-KU, TOKYO, JAPAN 112-8088 國籍：（中文/英文） 日本 JAPAN 200412345 第092114905號專利申請案 中文說明書替換頁(92年9月） 參、發明人··（共2〇人） 姓名：（中文/英文） 1. 珍唐恩 JANE DAUN 2. 海瑟A.大維絲 HEATHER A. DAVIS 3. 法比安古梭斯基 FABIAN GUSOVSKY ’ 4·菱沼家春 IEHARUfflSHINUMA 5. 宜民江 YIMIN JIANG 6. 金子俊彦 TOSHIHIKO KANEKO 7. 菊池廣一 KOUICHIKIKUCHI 8. 小林誠一 SEIICHIKOBAYASHI 9. 安德烈雷卡波 ANDRE LESCARBEAU 10. 山易李 XIANG-YI LI 11. 村本謙三 KENZO MURAMOTO ' 12.大井法人 | NORIHITO OHI / 13.馬可佩桑 MARC PESANT 14. 波力斯赛樂斯基 BORIS SELETSKY 15. 副島本弘 MOTOfflRO SOEJIMA 16. 琳達楚布蕾 LYNDA TREMBLAY -2- 85762.doc85762 200412345 "" Replacement page of the Chinese manual of the invention patent specification (October 1992) (This manual is in the format, along the shore, and bold type, please do not change it arbitrarily. ※ Please do not fill in the marked part.) ※ Application number ·· 092114905 ※ Application date: 糸 1 卩 〇: Classification: I. Name of invention: (Chinese / English) NOVEL DEAZAPURINES AND USES THEREOF, Applicant: (1 person in total) Name or name: (Chinese / English) ） ~ Nissho Eisai Co., Ltd. Representative: (Chinese / English) Yoshino Hiroshi fflROSHI YOSHINO Address of residence or business office ... (Chinese / English) 6-Ishikawa-cho, Bunkyo-ku, Tokyo, Japan Fan 10 No. 6-10 KOISHIKAWA 4-CHOME, BUNKYO-KU, TOKYO, JAPAN 112-8088 Nationality: (Chinese / English) Japanese JAPAN 200412345 No. 092114905 Patent Application Chinese Specification Replacement Page (September 1992) People ... (20 people in total) Name: (Chinese / English) 1. JANE DAUN 2. Heather A. Davis HEATHER A. DAVIS 3. Fabian Gousso FAFABIAN GUSOVSKY '4 · Ionuma Kaharu IEHARUfflSHINUMA 5. YIMIN JIANG 6. Yoshihiko Toshihiko Kaneko 7. Kikuchi Hiroichi KOUICHIKIKUCHI 8. Kobayashi Seiichi SEIICHIKOBAYASHI 9. Andre Lekabo ANDRE LESCARBEAU 10. Shan Yi Li Xiang -YI LI 11. Kenzo MuramOTO '12. Oi Corporation | NORIHITO OHI / 13. MARC PESANT 14. PORIS Selesky BORIS SELETSKY 15. Moto Offlro SOEJIMA 16. Bray Lynda TREMBLAY -2- 85762.doc
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