TW200815422A - Heteroaryl derivatives as cytokine inhibitors - Google Patents

Heteroaryl derivatives as cytokine inhibitors Download PDF

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Publication number
TW200815422A
TW200815422A TW096130616A TW96130616A TW200815422A TW 200815422 A TW200815422 A TW 200815422A TW 096130616 A TW096130616 A TW 096130616A TW 96130616 A TW96130616 A TW 96130616A TW 200815422 A TW200815422 A TW 200815422A
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butyl
methyl
phenyl
alkyl
group
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TW096130616A
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Chinese (zh)
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Erik Boman
Justin Ernst
Antonio Garrido Montalban
Christopher J Larson
Christopher Lum
Yazhong Pei
Jan Urban
Zhijun Wang
Lubomir Sebo
Jay Zhu
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Kemia Inc
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Publication of TW200815422A publication Critical patent/TW200815422A/en

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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract

The present invention provides low molecular weight compounds useful as cytokine inhibitors, and compositions thereof. There are further provided methods for the preparation of such agents and their use in preventing or treating conditions mediated by cytokines. In particular, compounds of the invention are useful as anti-inflammatory, anti-pain or anti-cancer agents.

Description

200815422 九、發明說明： 相關申請案 本申請案係關於2006年8月17日提出申請之美國專利申 請案號6咖，795,錢題為"作為細料抑制狀雜芳基衍 生物2007年2月23日提出申請之美國專利申請案號廣·，·， 其標題為’’作為細胞素抑制劑之雜芳基衍生物"，2〇〇6年2 月23曰提出申請之國際申請案號pCT/US2〇〇6/〇〇6682，其標題 為π細胞素抑制劑及其在治療上之用途„，2〇〇6年丨丨月13曰 提出申請之國際申請案號PCT/US06/043896，其標題為”使用 細胞素抑制劑之療法”，及2007年6月8日提出申請之國際申 請案號PCT/US2007/070547，其標題為”使用細胞素抑制劑之 療法"，其每一案之全部内容均併於本文供參考。 【發明所屬之技術領域】 本發明係關於可作為例如細胞素抑制劑使用之低分子量 化合物及其組合物，以及其製備。本發明係關於治療、預 防、修正及處理多種症狀，包括細胞素所媒介病症或相關 病症之方法，其包括細胞素抑制劑之投藥，單獨或併用已 知治療劑。本發明亦關於使用所揭示化合物之醫藥組合物 及服藥使用法，視情況搭配其他療法，供治療多種症狀， 包括自身免疫疾病、炎性疾病、心血管疾病、癌症等。 【先前技術】 免疫系統之發揮功能係精密地藉由預發炎與消炎介體或 細胞素之活性達成平衡。一些細胞素會促進發炎，且係被 稱為預發炎細胞素，然而其他細胞素會壓抑預發炎細胞素 123505 200815422 之活〖生且係被稱為消炎細胞素。例如，n 及心I) 為B淋巴細胞之有效活化劑，但亦為有效消炎劑。由於豆 壓:關於預發炎細胞素譬如IL]、及化學細胞素之基因 之能力’故其係為消炎細胞素(C.A. Dirwell。，Chest. 2_，118 503)。 ， 此等介體之未經調節活性可導致嚴重炎性症狀之發展。 例如，當免疫系統細胞（淋巴細胞、巨噬細胞）針對”自體，， 變得敏化時，自身免疫疾病係發生。、淋巴細胞以及巨噬細 胞於此系統中通常係在控制之下。但是，㈣統針對身體 自有組織之方向錯誤可發生，以回應仍未經解釋之觸發。 一項假說是淋巴細胞會辨識模擬”自體”之抗原，且免疫系 統不同成份之活化作用之階式反應會發生，最後導致組織 破壞。遺傳傾向亦已被假設為負責自身免疫病症。 腫瘤壞死因子· α (TNF- α)與間白金球活素]瓜-丨）係為預 發炎細胞素，其會媒介與感染劑及其他細胞壓力有關聯之 炎性回應。咸認細胞素譬如Li與ΤΝΡπ之過度生產係成為 許多炎性疾病進展之基礎，其中特別是包括風濕性關節炎 (RA)、克隆氏病 '炎性腸疾病、多發性硬化、内毒素休克、 骨質疏鬆症、阿耳滋海默氏病、鬱血性心衰竭及牛皮癬 (Dinarello, C.A·等人，Rev· infect· Diseases 1984, 6, 51 ; Salituro 等人 Curr· Med. Chem· 1999，6，807 ; Henry 等人，Drugs Fut. 1999，24, 1345)。得自臨床試驗之最近數據係支持使用細胞素之蛋白 質拮抗劑，例如可溶性TNF- α受體融合蛋白質（恩塔臬西伯 (etanercept)) (Moreland 等人，Ann. Intern. Med· 1999, 130, 478)或單株 123505 200815422 TNFa抗體（因弗利西馬（infliximab))，以治療風濕性關節炎、 克隆氏病、幼年慢性關節炎及牛皮癬關節炎（Rankin等人，扮 J. Rhe_t〇1· 1995, 34, 334 ; GaIadari 等人，加 了 以麵⑹ 2〇〇3, 42 2W ’· Reimo丨d，Am j Med Sci· 2〇〇3,奶⑺，^。因此預發炎細 胞素譬如TNF- α (亦稱為TNFa)與間白金；求活素 j万（IL· i的之 降低，對於在此等症狀中之可能藥物介入，已變成一種所 接受之治療途徑。 【發明内容】 本發明係提供低分子量化合物及其醫藥組合物。特定言 之，本發明化合物可用於多種應用，包括例如作為細胞素 釋出抑制劑。其係進一步提供製備此種化合物，及使用單 獨之此等化合物、其混合物或與其他治療劑之混合物於製 «劑上之方法’該藥劑制於治療各種疾病狀態。例如， 提ί、利用本發明化合物以預防與治療藉由細胞素所媒介之 各種病症之方法，該病症譬如炎性、心血管與自身免疫病 症、癌症、疼痛及其他。 2此’根據本發明之—方面係提供—種化合物，其包含： 目田教部份基團’ ™，包含醯胺ΝΗ與幾基，此瞒乾部份 基團旎夠與一種標的蛋白質形成一或多個氫鍵； 袋形擴大部份基團，ΡΕΜ，直接連接至晦乾部份基團之 幾基或ΝΗ’此袋形擴大部份基團包含經連接至龐大非平面 ^疏水性部份基團之平面狀部份基團，其中非平面狀部份 基團係能約與一種標的蛋白質形成疏水性交互作用. 指向部份基團，0M，包含6_員雜芳基環，且連接至瞒乾 123505 200815422 伤基團之NH或魏基，其中指向部份基團係能夠與一種標 的蛋白質形成疏水性交互作用； 連結基部份基團，L，經連接至指向部份基團中與瞄靶 部份基團不同之原子，其中連結基部份基團係包含6_員芳 基或雜芳基部份基團；及 錨定部份基團，AM，藉由連結基部份基團L，連接至指 向部份基團，其中錨定部份基團係能夠與該標的蛋白質之 ATP-結合袋一起形成至少1個氫鐽交互作用； 其中該化合物為細胞素抑制劑。 於本發明之此方面，細胞素抑制劑係具有結構pem_tm_ OM-L-AM。在10/Μ之濃度下，此種化合物典型上係抑制自 細胞所引致之TOFa·釋出，達約5〇%或大於5〇%。 瞒乾部份基團可氫鍵結合至標的蛋白質之結合位置上之 殘基。典型上，瞄靶部份基團為醯胺基。 袋形擴大部份基團係具有足夠大小，以在標的蛋白質中 迫使構形改變，而於其中造成擴大結合袋。此種部份基團 包括6-員芳基與雜芳基，例 、上+ ]如本基、吡啶基或其類似基團， 被龐大部份基團取代。在血彳 ㈣亡# 一 u如甲基比較下，龐大部份基 團係充填大體積之空間，且一 ,^ ^ , 匕括些基團，譬如經取代或 未、、、坐取代之C2_4烷基，例如 一 楚一丁A 取代或未經取代之異丙基、 弟二-丁基、異丁基或第二· P、P其π 1 土，！取代或未經取代之c3_9 %烧基，例如、經取代或未經取代之斗 取代或未經取代之雜環其^ ' 土或正伯基；或經 u S’譬如經取代或未經取代之，福 啉基、四氫吡咯基、‘— 八< Θ子田 /、虱吡啶基或硫代嗎福啉基。 123505 200815422 指向部份基團，藉由結合至標的蛋白質上之疏水性袋， 係提供瞄靶部份基團與袋形擴大部份基團之適當取向，供 細胞素抑制劑結合至其標的蛋白質。此種部份基團包括例 如吡啶基、吡啶基-N-氧化物或嗒畊基，被小疏水性部份基 團取代，實例為鹵素、甲基、三氟甲基等。 典型上，連結基部份基團L包括苯基、吡啶基、嘧啶基 或嗒畊基，例如，L為苯基、2-吡啶基、3_吡啶基或4-吡啶 基。 在一些具體實施例中，錨定部份基團為氫鍵受體。在其 他具體實施例中，錨定鍵結部份基團包括氫鍵供體與受體 兩者。例如，錨定部份基團可包括醯胺、胺、羰基、烷氧 基、胺基甲酸酯、亞颯、磺醯胺或〇C(0)基團，且可進一步 包括經取代或未經取代之甲基、乙基、正-丙基、異丙基、 正-丁基、第三-丁基、第二-丁基、異丁基、新戊基、苯基、 芊基、苯乙基、2-吡啶基、（CH2)-24啶基、（CH2)2-2-吡啶基、 (CH2 )3 _2_吡啶基、3-吡啶基、（CH2 )-3·吡啶基、（CH2 )2 -3-吡啶基、 (CH2 )3-3-吡啶基、4-吡啶基、（CH2 )-4-吡啶基、（CH2 )2-4-吡啶基、 (CH2)3-4-卩比σ定基、四氫咬喃基、（CH2)-四氫P失喃基、（CH2)2· 四氫咬喃基、（CH2 )3 -四氫咬喃基、四氫喊喃基、（CH2 )-四氫 喊喃基、（CH2 )2 -四氫成喃基、（CH2 )3 -四氫♦喃基、四氫卩比咯 基、（CH2)-四氫峨嘻基、（CH2)2-四氫卩比洛基、（CH2)3-四氫外匕 咯基、六氫吡啶基、（ch2)-六氫吡啶基、（CH2)2-六氫吡啶基、 (CH2)3-六氫吡啶基、嗎福啉基、（CH2)-嗎福啉基、（CH2)2-嗎 福啉基或（ch2)3-嗎福啉基。 123505 -12- 200815422 於另一方面，本發明係提供式j化合物：200815422 IX. INSTRUCTIONS: RELATED APPLICATIONS This application is related to U.S. Patent Application Serial No. 6, 795, entitled, " as a fine-suppressed heteroaryl derivative, 2007, filed on August 17, 2006. The US patent application filed on February 23, pp., entitled "Hyperaryl Derivatives as Cytokine Inhibitors", International Application for Application, February 23, 2006 Case No. pCT/US2〇〇6/〇〇6682, entitled π-cytokine inhibitors and their use in therapy „, International Patent Application No. PCT/US06, filed on March 13, 2013 / 043,896, entitled "Therapeutic Use of Cytokine Inhibitors", and International Application No. PCT/US2007/070547, filed on June 8, 2007, entitled "Therapeutic Use of Cytokine Inhibitors", The entire contents of each case are hereby incorporated by reference. TECHNICAL FIELD OF THE INVENTION The present invention relates to low molecular weight compounds and compositions thereof that can be used, for example, as cytokine inhibitors, and to the preparation thereof. The present invention relates to methods of treating, preventing, modifying and treating a variety of conditions, including cytokine-mediated conditions or related conditions, including administration of a cytokine inhibitor, alone or in combination with a known therapeutic agent. The invention also relates to pharmaceutical compositions and methods of administration using the disclosed compounds, optionally in combination with other therapies, for the treatment of a variety of conditions, including autoimmune diseases, inflammatory diseases, cardiovascular diseases, cancer, and the like. [Prior Art] The function of the immune system is precisely balanced by the activity of pre-inflammatory and anti-inflammatory mediators or cytokines. Some cytokines promote inflammation and are known as pre-inflammatory cytokines, whereas other cytokines suppress the activity of pre-inflammatory cytokines 123505 200815422 and are known as anti-inflammatory cytokines. For example, n and heart I) are effective activators of B lymphocytes, but are also effective anti-inflammatory agents. Due to soy pressure: the ability to pre-inflammatory cytokines such as IL] and the genes of chemical cytokines, it is an anti-inflammatory cytokine (C.A. Dirwell., Chest. 2_, 118 503). The unregulated activity of these mediators can lead to the development of severe inflammatory symptoms. For example, when immune system cells (lymphocytes, macrophages) are "autologous," become autosensitized, autoimmune diseases occur. Lymphocytes and macrophages are usually under control in this system. However, (4) errors in the direction of the body's own organization can occur in response to the unexplained trigger. A hypothesis is that lymphocytes recognize the antigen of the simulated "self" and the activation of different components of the immune system. The reaction will occur and eventually lead to tissue destruction. The genetic predisposition has also been hypothesized to be responsible for autoimmune disorders. Tumor necrosis factor alpha (TNF-α) and interleukocytokinin] melon-丨 is a pre-inflammatory cytokine, It mediates the inflammatory response associated with infectious agents and other cellular stresses. The overproduction of cytokines such as Li and ΤΝΡπ is the basis for the progression of many inflammatory diseases, including rheumatoid arthritis (RA), Crohn's disease inflammatory bowel disease, multiple sclerosis, endotoxic shock, osteoporosis, Alzheimer's disease, septic heart failure and psoriasis (Dinarello, CA Et al., Rev·infect· Diseases 1984, 6, 51; Salituro et al. Curr· Med. Chem. 1999, 6, 807; Henry et al., Drugs Fut. 1999, 24, 1345). The data support protein antagonists using cytokines, such as soluble TNF-α receptor fusion proteins (etanercept) (Moreland et al., Ann. Intern. Med 1999, 130, 478) or 123505 200815422 TNFa antibody (infliximab) for the treatment of rheumatoid arthritis, Crohn's disease, juvenile chronic arthritis and psoriatic arthritis (Rankin et al., J. Rhe_t〇1·1995, 34, 334 GaIadari et al., added face (6) 2〇〇3, 42 2W '· Reimo丨d, Am j Med Sci· 2〇〇3, milk (7), ^. Therefore, pre-inflammatory cytokines such as TNF-α (also known as TNF-α) It is TNFa) and interleukin; the reduction of IL-1 (IL·i, which has become a accepted therapeutic route for possible drug intervention in these symptoms.) SUMMARY OF THE INVENTION The present invention provides low molecular weight. Compounds and pharmaceutical compositions thereof. In particular, the compounds of the invention are useful For a variety of applications including, for example, as a cytokine release inhibitor, which further provides for the preparation of such compounds, and the use of such compounds alone, mixtures thereof or mixtures with other therapeutic agents in the formulation of the agent For the treatment of various disease states, for example, methods of using the compounds of the invention to prevent and treat various conditions mediated by cytokines such as inflammatory, cardiovascular and autoimmune disorders, cancer, pain and others . 2 In the aspect of the invention, there is provided a compound comprising: a group of a group of 'Metida', comprising an amidoxime and a plurality of groups, the stem portion of which is formed with a target protein One or more hydrogen bonds; a pocket-shaped enlarged moiety, ΡΕΜ, directly attached to a few groups of the thiophore moiety or ΝΗ' This pocket-shaped enlarged moiety comprises a large non-planar ^ hydrophobicity a planar partial moiety of a moiety in which a non-planar moiety is capable of forming a hydrophobic interaction with a target protein. Pointing to a moiety, 0M, comprising a 6-membered heteroaryl ring, And is linked to the NH or Wei group of the sputum 123505 200815422, wherein the directed group is capable of forming a hydrophobic interaction with a target protein; the linking moiety, L, is linked to the pointing moiety An atom in a group different from a target group, wherein the linker moiety comprises a 6-membered aryl or heteroaryl moiety; and an anchor moiety, AM, via a linker a moiety L, attached to a moiety that anchors a moiety The system is capable of forming at least one hydroquinone interaction with the ATP-binding pocket of the target protein; wherein the compound is a cytokine inhibitor. In this aspect of the invention, the cytokine inhibitor has the structure pem_tm_OM-L-AM. At a concentration of 10/Torr, such compounds typically inhibit TOFa release from cells, up to about 5% or greater than 5%. The dry part of the group can be hydrogen bonded to the residue at the binding position of the target protein. Typically, the target moiety is an amidino group. The pocket-shaped enlarged portion of the group is of sufficient size to force a change in configuration in the target protein, thereby causing an enlarged binding pocket therein. Such a moiety includes a 6-membered aryl group and a heteroaryl group, and, for example, an upper +] group such as a benzyl group, a pyridyl group or the like, is substituted with a bulky moiety. In the bloody (four) death #一u, such as methyl comparison, a large part of the group is filled with a large volume of space, and one, ^ ^, including some groups, such as replaced or not,, sit and replace C2_4 Alkyl group, for example, a substituted or unsubstituted isopropyl group, di-butyl group, isobutyl group or second P, P π 1 soil,! a substituted or unsubstituted c3_9 % alkyl group, for example, a substituted or unsubstituted heterocyclic ring or a non-substituted heterocyclic ring; or a sub-substituent such as substituted or unsubstituted Of, a florinyl group, a tetrahydropyrrolyl group, an 'eight' scorpion field, an anthracene pyridyl group or a thiomorphine group. 123505 200815422 Pointing to a moiety, by binding to a hydrophobic pocket on the target protein, providing the proper orientation of the target moiety and the pocket-shaped enlarged moiety for binding of the cytokine inhibitor to its target protein . Such a moiety includes, for example, a pyridyl group, a pyridyl-N-oxide or a ruthenium group, and is substituted with a small hydrophobic moiety such as a halogen, a methyl group, a trifluoromethyl group or the like. Typically, the linking moiety L comprises a phenyl, pyridyl, pyrimidinyl or hydrazine group, for example, L is phenyl, 2-pyridyl, 3-pyridine or 4-pyridyl. In some embodiments, the anchoring moiety is a hydrogen bond acceptor. In other embodiments, the anchoring moiety moiety includes both a hydrogen bond donor and a acceptor. For example, the anchor moiety can include a guanamine, amine, carbonyl, alkoxy, urethane, sulfonium, sulfonamide or hydrazine C(0) group, and can further include substituted or unsubstituted Substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, di-butyl, isobutyl, neopentyl, phenyl, decyl, benzene Ethyl, 2-pyridyl, (CH2)-24 pyridine, (CH2)2-2-pyridyl, (CH2)3 _2-pyridyl, 3-pyridyl, (CH2)-3.pyridyl, CH2)2-3-pyridyl, (CH2)3-3-pyridyl, 4-pyridyl, (CH2)-4-pyridyl, (CH2)2-4-pyridyl, (CH2)3-4-卩 σ 定 、, tetrahydroanthracene, (CH 2 )-tetrahydro P, cyclyl, (CH 2 ) 2 · tetrahydrocarbyl, (CH 2 ) 3 -tetrahydroethylene, tetrahydropyranyl, (CH2)-tetrahydropyranyl, (CH2)2-tetrahydrofuranyl, (CH2)3-tetrahydrofuranyl, tetrahydroindoleyl, (CH2)-tetrahydroindenyl, CH2)2-tetrahydroindolebiloyl, (CH2)3-tetrahydroexopurinyl, hexahydropyridyl, (ch2)-hexahydropyridyl, (CH2)2-hexahydropyridyl, (CH2) 3-hexahydropyridyl, morpholinyl , (CH2)-morpholinyl, (CH2)2-morphine or (ch2)3-morpholine. 123505 -12- 200815422 In another aspect, the invention provides a compound of formula j:

式I 其立體異構物、其互變異構物、其溶劑合物、其前體藥 物及其藥學上可接受之鹽； 其中 f X 為 CH、N 或 NO ; Y為CH、N或NO，其條件是X與γ不皆為ch或NO ; A為F、Cl、Br、I、NR2或(^_3烷基或-CKCu烷基），其中 烧基係視情況經部份或完全_化； G為芳基或雜芳基，其中g係被一或多個Ri，R2或R3取代； Ar為6-員芳基或雜芳基； L1 為 _C(0)NH-; L2 為共價鍵、（CR，2)S、（CR，2)n〇(CR，2)t、（CR，2)nNR(CR，2)t、 , (CRf2 )n C(NOR) > (CRf2 )n S02 NR(CRf2 )t ^ (CRf2 )n C(0)(CRf2 )t > 0(CRf2)tC(0)(CRf2)n ^ 0(CRf2)sNR(CRf2)n ^ 0(CRf2 )n C(0)NR(CRf2 )t ^ 〇(CR，2)sNRC(0)(CR，2)n、（CR，2)nC(0)NR(CRf2)t、（CR，2)nC(0)NRNR-(CR’2 )t 或（CR’2 )n NRC(0)0(CR，2 )t 基團； Q為經取代或未經取代之烷基、環烷基、芳基、雜環基、 環烷基烷基、芳烷基或雜環基烷基； 各R1係獨立為F、Cl、Br、I、-NR2、-CN，或經取代或未 經取代之烷基、烯基、炔基、環烷基、環烯基、芳基、雜 123505 -13 - 200815422 環基或雜環基烷基； 各R2係獨立為F、Cl、Br、I、-CN、-NO〗、經取代或未經 取代之烷基或雜環基烷基、-〇R，…C(〇)R，…C(〇)〇R,、 C(0)NR’2、（(皿)皿2、-C(NR)NR〇R、、 （CR，2)tNRR，、 -NRC(0)R”、-NR’C(0)〇R”、-Nr，S〇2R"、视，。(〇)概，2、 -nr’c(s)nr’2、·δ(0)ηιΚ，，或 _s〇2NR，2 ; 各R3係獨立為經取代或未經取代之烷基、烯基或炔基， 或-ο%-4烷基），其中Ci j烷基係視情況經部份或完全鹵化； 各R係獨立為氫，或經取代或未經取代之Ci 6烷基； 各R係獨立為氫，或經取代或未經取代之烷基、環烷基、 ㈣基烧基、芳烧基、雜環基或雜環基烧基； 各R係獨立為經取代或未經取代之烷基、環烷基、芳基、 雜衣基、ί衣烷基烷基、芳烷基或雜環基烷基； 各m係獨立為〇, 1或2 ; η為〇，1或2 ;a stereoisomer thereof, a tautomer thereof, a solvate thereof, a prodrug thereof, and a pharmaceutically acceptable salt thereof; wherein f X is CH, N or NO; Y is CH, N or NO, The condition is that X and γ are not all ch or NO; A is F, Cl, Br, I, NR2 or (^_3 alkyl or -CKCu alkyl), wherein the alkyl group is partially or completely _ G is an aryl or heteroaryl group, wherein g is substituted by one or more Ri, R2 or R3; Ar is a 6-membered aryl or heteroaryl; L1 is _C(0)NH-; Valence bond, (CR, 2) S, (CR, 2) n 〇 (CR, 2) t, (CR, 2) nNR (CR, 2) t, , (CRf2 ) n C (NOR) > (CRf2 ) n S02 NR(CRf2 )t ^ (CRf2 )n C(0)(CRf2 )t > 0(CRf2)tC(0)(CRf2)n ^ 0(CRf2)sNR(CRf2)n ^ 0(CRf2 ) n C(0)NR(CRf2 )t ^ 〇(CR,2)sNRC(0)(CR,2)n, (CR,2)nC(0)NR(CRf2)t, (CR,2)nC( 0) NRNR-(CR'2)t or (CR'2)n NRC(0)0(CR,2)t group; Q is substituted or unsubstituted alkyl, cycloalkyl, aryl, Heterocyclyl, cycloalkylalkyl, aralkyl or heterocyclylalkyl; each R1 is independently F, Cl, Br, I, -NR2, -CN, or a substituted or unsubstituted alkyl , alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, hetero 123505 -13 - 200815422 cyclic or heterocyclylalkyl; each R2 is independently F, Cl, Br, I, -CN, - NO, substituted or unsubstituted alkyl or heterocyclylalkyl, -〇R,...C(〇)R,...C(〇)〇R,,C(0)NR'2, (( ) 2, -C(NR)NR〇R, (CR,2)tNRR, -NRC(0)R", -NR'C(0)〇R", -Nr,S〇2R", (〇), 2, -nr'c(s)nr'2, ·δ(0)ηιΚ, or _s〇2NR,2 ; each R3 is independently substituted or unsubstituted alkyl , alkenyl or alkynyl, or -ο%-4 alkyl), wherein the Ci j alkyl group is partially or completely halogenated as appropriate; each R is independently hydrogen or a substituted or unsubstituted Ci 6 alkane Each R is independently hydrogen, or substituted or unsubstituted alkyl, cycloalkyl, (tetra)alkyl, aryl, heterocyclyl or heterocyclyl; each R is independently substituted Or unsubstituted alkyl, cycloalkyl, aryl, decyl, decylalkyl, aralkyl or heterocyclylalkyl; each m is independently 〇, 1 or 2; η is 〇 , 1 or 2;

5两乜2或3 ;且 各t係獨立為〇, 1或2 ; 其條件是該化合物$ k π ^ 物不為如本斗基）·6-氯-N-(6-甲氧基吡 基）於鹼醯胺。 在式I化合物之一此且體每# ^丨山 破一盆 一，、體貝施例中，Ar為苯基、吡啶基、 山疋基或嗒畊基。在其他 一 I 、他具體只施例中，Ar為苯基、2-吡 疋土、比咬基或比咬基。 所有下列化合物係意欲被式π函蓋在内： 123505 -14- 2008154225 two 乜 2 or 3; and each t is independently 〇, 1 or 2; the condition is that the compound $ k π ^ is not as the base of the bucket) · 6-chloro-N-(6-methoxypyridyl Base) to a base amide. In one of the compounds of formula I, the body breaks one pot per #^丨山, and in the case of body shell, Ar is a phenyl group, a pyridyl group, a behenyl group or a ruthenium group. In the other one, in his specific example, Ar is a phenyl group, a 2-pyridinium, a bite base or a bite base. All of the following compounds are intended to be covered by the formula: 123505 -14- 200815422

Q 123505 -15- 200815422Q 123505 -15- 200815422

Ι-ΥΙ-Υ

GG

Rn L2 \ QRn L2 \ Q

l-AHl-AH

l-AKl-AK

〇- l-AL〇- l-AL

l-AMl-AM

〇· l-AN 123505 -16- 200815422〇· l-AN 123505 -16- 200815422

Rn L2Rn L2

RnRn

GT"Yyv ο 〇-〇，Ν 认A Q l-ASGT"Yyv ο 〇-〇,Ν A Q l-AS

L2 在一些具體實施例中，式I化合物為L2 In some embodiments, the compound of formula I is

於又再其他具體實施例中，化合物為 123505 17- 200815422In still other specific embodiments, the compound is 123505 17- 200815422

在式I化合物之一些具體實施例中，A為F、-CH3或-CF3。 在其他具體實施例中，G為苯基、嘧啶基、吡啶基、吟唑 基、異吟唾基、说唾基或吱喃基。例如，G為In some embodiments of the compound of Formula I, A is F, -CH3 or -CF3. In other specific embodiments, G is phenyl, pyrimidinyl, pyridyl, oxazolyl, isoindolyl, sinyl or decyl. For example, G is

在式I化合物之一些其他具體實施例中，L2為共價鍵、 Ο、NR、C(0)(CH2)n、C(NOR)、S02NR、0(CH2)tC(0)、C(0)NR、 C(0)NRNR或NRC(0)0基團。在其他具體實施例中，L2為共價 鍵、Ο、OC(O)、C(NOH)、S02NH、OCH2C(0)、C(O)、C(0)CH2、 C(0)CH2CH2、C(0)NHNH 或 C(0)NH。 在式I化合物之一些具體實施例中，Q為經取代或未經取 代之烷基、環烷基、（CG_4烷基）苯基、（〇)_4烷基>比啶基、（C〇_4 烷基）嘧啶基、（CG_4烷基）嗎福啉基、（CG_4烷基）硫代嗎福啉 基、（CG_4烷基）嗝啶基、（CG_4烷基）(10-氧斗氮·三環并[5.2.1.02,6] 癸基）、（C〇_4烷基）(8-氧-3-氮-雙環并[；3·2·1]辛烷基）、（CG-4烷基） 四氫咬喃基、（〇)_4烧基）四氫咬喃基、（C〇_4烧基）四氫吡咯基、 (C〇-4烷基）六氫吡啶基或（C〇_4烷基）六氫吡畊基。例如，Q為 經取代或未經取代之甲基、乙基、正-丙基、異丙基、正-丁基、第三-丁基、第二-丁基、異丁基、新戊基、環丙基、 (ch2)-環丙基、（ch2)2-環丙基、（ch2)3-環丙基、環丁基、（ch2)-環丁基、（ch2)2-環丁基、（ch2)3-環丁基、環戊基、（ch2)-環 123505 -18 - 200815422 戊基、（ch2)2-環戊基、（ch2)3-環戊基、環己基、（ch2)-環己 基、（CH2)2-環己基、（CH2)3-環己基、雙環并[2.2.1]庚烷基、（CH2)-雙環并P.2.1]庚烷基、（CH2)2-雙環并[2.2.1]庚烷基、（CH2)3-雙 環并[2.2.1]庚烷基、環庚基、苯基、苄基、苯乙基、2-吡啶 基、（CH2)-2-^ σ定基、（CH2)2-2-#b σ定基、（CH2)3-2-p比 σ定基、3-口比 σ定基、（CH2 )-3-^ σ定基、（CH2 )2_3-ρ比咬基、（CH2 )3-3-#b σ定基、 4-吡啶基、（CH2 )-4-吡啶基（CH2 )2 -4-吡啶基、（CH2 )3 -4-吡啶基、 四氫呋喃基、（CH2)-四氫呋喃基、（CH2)2-四氫呋喃基、（CH2)3-四氫呋喃基、四氫哌喃基、（CH2)-四氫哌喃基、（CH2)2-四氫 哌喃基、（CH2)3-四氫哌喃基、四氫吡咯基、（CH2)-四氫吡咯 基、（CH2)2-四氫吡咯基、（Ch2)3_四氫吡咯基、ίο·氧-4_氮-三 環并[5.2.1.02,6]癸基、8_氧净氮_雙環并[3.2]]辛烷基、六氫吡 咬基、（CH2)·六氫吡啶基、（CH2)2-六氫吡啶基、（CH2)3-六氫 峨咬基、六氫吡畊基、（Ch2卜六氫吡畊基、（Ch2)2-六氫吡畊 基、（CH2)3·六氫吡畊基、嗎福啉基、（CH2)_嗎福啉基、（CH2)2-嗎福琳基或（CH2 )3 -嗎福琳基。 在式I化合物之一些具體實施例中，Ri為F、-CN、-NR2， 或經取代或未經取代之Ci 4烷基、C3_9環烷基、雜環基或雜 環基烷基。例如，R1為F、_CN、_N(Ci 3烷基）2，其中各Ci _3 炫*基係獨立為經取代或未經取代；或R1為經取代或未經取 代之甲基、異丙基、第三_丁基、異丁基、第二-丁基、新戊 基、裱己基、四氫吡咯基、咪唑基、吡唑基、三唑基、酮 基一嗤基、異气唾基、2,3_二氫異噚唑基、六氫吡啶基、六 氫吡畊基、氧氮七圜基、嗎福啉基、硫代嗎福啉基（CH2)_ 123505 -19- 200815422 四氫吡咯基、（ch2)-六氫吡啶基、（ch2)_氧氮七圜基、（ch2)-嗎福啉基或（ch2)·六氫吡畊基。 在一些具體實施例中，R2為經取代或未經取代之（Cw烷 基）或雜環基烷基、F、Cl、-CN、-N02、-OR·、-C(0)0R’、 -C(0)NR，2、-(CH2)tNRR，，、-C(NR)NR2、-C(NR)NROR、-NRC(0)Rn、 -NRC(0)0Rn、-NR，S02R’，、-NR，C(0)NR，2 或-S02NR，2。例如，R2 為F、-CN、-CF3、-N02、烷基）、-(:(0)0((^-6烷基）、 -C(0)NH2、-CXCONI^Cii 烷基）、-C(0)NH(C3-6 環烷基）[0]、 -C(0)NH(環烷基烷基）[0]、-C(0)NH(芳烷基）、-(CH2ΜΗ% _6 烷 基）、-(CH2 )NH(芳烷基）、-(CH2 )NH(雜環基烷基）、-C(NH)NH2、 -(ΧΝΙ^ΝΗγυ烷基）、-C(NH)NHOH、-C(NH)NHO(CV6烷基）、 -NHCXOXC〗· 6 烷基）、-NHC(0)(C3 _ 6 環烷基）、-NHC(0)(環烷基烷 基）、-NHC(0)(芳基）、-NHC(0)(芳烷基）、-NHS02(Ch烷基）、 -NHS02(C3_6環烷基）、-NHS02(環烷基烷基）、-NHS02(芳基）、 -NHS02(芳烷基）、-SC^NH^Ch烷基）、_S02NH(C3-6環烷基）、 -S02NH(環烷基烷基）、-S02NH(芳基）或-S02NH(芳烷基），其 中各烷基、C3_6環烷基、環烷基烷基芳基及芳烷基係為 經取代或未經取代。 在一些具體實施例中，R3為經取代或未經取代之q _4烷 基或-OCCiM烷基），或為經部份或完全鹵化之-0((^-2烷基）。 在式I化合物之一些具體實施例中，G為苯基，且R1為F、 Cl、-CN、-N(C卜3烷基）2，其中各Ci -3烷基係獨立為經取代 或未經取代；或R1為經取代或未經取代之嗎福啉基、硫代 嗎福琳基、四氫p比洛基、哺唾基、p比唆基、三峻基、酮基 123505 -20 - 200815422 二唑基、異吟唑基、2,3-二氫異呤唑基、六氫吡啶基、六氫 吡畊基、氧氮七圜基、（CH2)-四氫吡咯基、（CH2)-六氫吡啶 基、（CH2)-氧氮七圜基、（CH2)-嗎福啉基、（CH2)-六氫吡畊基、 甲基、異丙基、第三-丁基、異丁基、第二-丁基、新戊基或 環己基。在一些此種具體實施例中，Ri為F、C1、經取代或 未經取代之嗎福p林基、四氮P比洛基、味U坐基、p比吐基、三 唑基、酮基二唑基、異呤唑基、2,3-二氫異嘮唑基、六氫吡 啶基、（CH2>四氫吡咯基、（CH2)-六氫吡啶基、（CH2)-嗎福啉 基、（CH2)-六氫吡畊基、甲基、第三_丁基或環己基。在其 他具體實施例中，R2為F、-CN、-CF3、-Ν02、-Ο% _6烷基）、 ((0)0((^ - 6 烷基）、-C(0)NH2、. 6 烷基）、-C(0)NH(C3 - 6 環烷基）[〇]、-C(0)NH(環烷基烷基）[〇]、-C(0)NH(芳烷基）、 -ΝΗΟΧΟ)% _ 6 烷基）、-NHC(0)(C3 _ 6 環烷基）、-NHC(0)(環烷基烷 基）、-NHC(O)(芳基）、-NHC(0)(芳烷基）、-(CH2 )ΝΗ((^ 6 烷基）、 -(CH2)NH(芳烷基）、-(CH2)NH(雜環基烷基）、-NHSOJCh 烷 基）、-NHS〇2(C3_6環烷基）、-NHS02(環烷基烷基）、-nhso2(芳 基）、-NHS02(芳烷基）、-SC^NI^Ch烷基）、-S02NH(C3_6環烷 基）、-S02NH(環烷基烷基）、-S02NH(芳基）或-S02NH(芳烷 基），其中各q—6烷基、C3_6環烷基、環烷基烷基芳基及芳 烷基係為經取代或未經取代。在又其他具體實施例中，F、 CN、-CF3、-C(0)NH2、-C(0)NH(CV6烷基）、-c(o)nh(c3_6環烷 基）[ο]、-C(0)NH(環烷基烷基）[〇]、-(CHONHCh 烷基）、 -(CH2)NH(雜環基烷基）_6 烷基）或-S02NH(Cb6 烷 基），其中各Cu烷基係為經取代或未經取代。於又再其他 123505 21 - 200815422 具體實施例中，R3為經取代或未經取代之q _4烷基或-Ο% -4 烧基）’或為經部份或完全鹵化之_〇(Ci ·2烷基）。 在式1化合物之一些具體實施例中，L2為〇、OC(O)、C(O)、 C(0)NH > C(〇)NHNH > C(0)NMe > 0CH2C(0) > S02NH > CH(OH) 或C(NOH)，且Q為In some other specific embodiments of the compound of Formula I, L2 is a covalent bond, Ο, NR, C(0)(CH2)n, C(NOR), S02NR, 0(CH2)tC(0), C(0 ) NR, C(0)NRNR or NRC(0)0 groups. In other specific embodiments, L2 is a covalent bond, Ο, OC(O), C(NOH), S02NH, OCH2C(0), C(O), C(0)CH2, C(0)CH2CH2, C (0) NHNH or C(0)NH. In some specific embodiments of the compound of Formula I, Q is substituted or unsubstituted alkyl, cycloalkyl, (CG-4 alkyl)phenyl, (〇)-4 alkyl> pyridine group, (C〇 _4 alkyl)pyrimidinyl, (CG_4 alkyl)morpholinyl, (CG_4 alkyl)thiomorpholinyl, (CG_4 alkyl) acridine, (CG_4 alkyl) (10-oxo nitrogen ·Tricyclic [5.2.1.02,6] mercapto), (C〇_4 alkyl) (8-oxo-3-nitro-bicyclo[;3·2·1]octyl), (CG- 4-alkyl) tetrahydrocarbamate, (〇)-4 alkyl) tetrahydrocarbyl, (C〇_4 alkyl)tetrahydropyrrolyl, (C〇-4 alkyl)hexahydropyridyl or C〇_4 alkyl) hexahydropyrrole. For example, Q is substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, second-butyl, isobutyl, neopentyl , cyclopropyl, (ch2)-cyclopropyl, (ch2)2-cyclopropyl, (ch2)3-cyclopropyl, cyclobutyl, (ch2)-cyclobutyl, (ch2)2-cyclobutyl , (ch2) 3-cyclobutyl, cyclopentyl, (ch2)-ring 123505 -18 - 200815422 pentyl, (ch2) 2-cyclopentyl, (ch2) 3-cyclopentyl, cyclohexyl, Ch2)-cyclohexyl, (CH2)2-cyclohexyl, (CH2)3-cyclohexyl, bicyclo[2.2.1]heptyl, (CH2)-bicyclo and P.2.1]heptyl, (CH2) 2-bicyclo[2.2.1]heptyl, (CH2)3-bicyclo[2.2.1]heptanyl, cycloheptyl, phenyl, benzyl, phenethyl, 2-pyridyl, (CH2 -2-^ σ定基, (CH2)2-2-#b σ定基, (CH2)3-2-p ratio σ定基, 3-port ratio σ定基, (CH2)-3-^ σ定基, ( CH2)2_3-ρ ratio bite group, (CH2)3-3-#b σ group, 4-pyridyl group, (CH2)-4-pyridyl (CH2)2-4-pyridyl group, (CH2)3 -4 -pyridyl, tetrahydrofuranyl, (CH2)-tetrahydrofuranyl, (CH2)2-tetrahydrofuranyl, (C H2) 3-tetrahydrofuranyl, tetrahydropyranyl, (CH2)-tetrahydropyranyl, (CH2)2-tetrahydropyranyl, (CH2)3-tetrahydropyranyl, tetrahydropyrrolyl, (CH2)-tetrahydropyrrolyl, (CH2)2-tetrahydropyrrolyl, (Ch2)3-tetrahydropyrrolyl, ίο.oxy-4-nitro-tricyclo[5.2.1.02,6] fluorenyl, 8_Oxygen nitrogen_bicyclo[3.2]]octyl, hexahydropyridyl, (CH2)·hexahydropyridyl, (CH2)2-hexahydropyridyl, (CH2)3-hexahydropurine Base, hexahydropyrrole, (Ch2 hexahydropyrazine, (Ch2) 2-hexahydropyrrole, (CH2)3. hexahydropyrrole, morpholinyl, (CH2)_? Orolinyl, (CH2)2-moffolinyl or (CH2)3-norfosine. In some embodiments of the compound of formula I, Ri is F, -CN, -NR2, or substituted or unsubstituted Substituted Ci 4 alkyl, C 3-9 cycloalkyl, heterocyclyl or heterocyclylalkyl. For example, R 1 is F, —CN, —N(Ci 3 alkyl) 2, wherein each Ci _3 炫* group is independently Substituted or unsubstituted; or R1 is substituted or unsubstituted methyl, isopropyl, tert-butyl, isobutyl, second-butyl, neopentyl, decyl, tetrahydropyrrole Base, imidazolyl, pyrazolyl, triazolyl, keto-indenyl, iso-saltyl, 2,3-dihydroisoxazolyl, hexahydropyridyl, hexahydropyrryl, oxynitride Base, morpholinyl, thiomorpholine (CH2) _ 123505 -19- 200815422 tetrahydropyrrolyl, (ch2)-hexahydropyridyl, (ch2) _ oxynitridinyl, (ch2)- Tropoline or (ch2)·hexahydropyrrole. In some embodiments, R2 is substituted or unsubstituted (Cw alkyl) or heterocyclylalkyl, F, Cl, -CN, -N02, -OR., -C(0)0R', -C(0)NR,2,-(CH2)tNRR,,, -C(NR)NR2, -C(NR)NROR, -NRC(0)Rn, -NRC(0)0Rn, -NR,S02R' ,, -NR, C(0)NR, 2 or -S02NR, 2. For example, R2 is F, -CN, -CF3, -N02, alkyl), -(:(0)0((^-6 alkyl), -C(0)NH2, -CXCONI^Cii alkyl), -C(0)NH(C3-6 cycloalkyl)[0], -C(0)NH(cycloalkylalkyl)[0], -C(0)NH(aralkyl), -(CH2ΜΗ % _6 alkyl), -(CH2)NH(aralkyl), -(CH2)NH(heterocyclylalkyl), -C(NH)NH2, -(ΧΝΙ^ΝΗγυalkyl), -C(NH NHOH, -C(NH)NHO(CV6 alkyl), -NHCXOXC〗 6 alkyl), -NHC(0)(C3 -6 cycloalkyl), -NHC(0)(cycloalkylalkyl) , -NHC(0)(aryl), -NHC(0)(aralkyl), -NHS02(Ch alkyl), -NHS02(C3_6cycloalkyl), -NHS02(cycloalkylalkyl), - NHS02 (aryl), -NHS02 (aralkyl), -SC^NH^Ch alkyl), _S02NH(C3-6 cycloalkyl), -S02NH(cycloalkylalkyl), -S02NH(aryl) Or -S02NH(aralkyl) wherein each alkyl group, C3_6 cycloalkyl group, cycloalkylalkylaryl group and aralkyl group is substituted or unsubstituted. In some embodiments, R3 is substituted or unsubstituted q_4 alkyl or -OCCiM alkyl), or is partially or fully halogenated-0 ((^-2 alkyl). In some specific embodiments of the compound, G is phenyl, and R1 is F, Cl, -CN, -N(Cb3 alkyl)2, wherein each Ci-3 alkyl group is independently substituted or unsubstituted Or R1 is substituted or unsubstituted oxabulinyl, thiofenoflavinyl, tetrahydrop-pyrrolyl, sulphate, p-indenyl, succinyl, keto 123505 -20 - 200815422 Diazolyl, isoxazolyl, 2,3-dihydroisoxazolyl, hexahydropyridyl, hexahydropyrrole, oxynitridinyl, (CH2)-tetrahydropyrrolyl, (CH2)- Hexahydropyridyl, (CH2)-oxoazinyl, (CH2)-morpholinyl, (CH2)-hexahydropyrrole, methyl, isopropyl, tert-butyl, isobutyl , a second-butyl group, a neopentyl group or a cyclohexyl group. In some such specific embodiments, Ri is F, C1, substituted or unsubstituted phoranyl-p-linyl, tetra-nitro-P-l- yl, taste U-based, p-pyrylene, triazolyl, ketodiazolyl, isoxazolyl, 2,3-dihydroisoxazole , hexahydropyridyl, (CH2>tetrahydropyrrolyl, (CH2)-hexahydropyridyl, (CH2)-morpholinyl, (CH2)-hexahydropyrrole, methyl, tert-butyl Or cyclohexyl. In other specific embodiments, R2 is F, -CN, -CF3, -Ν02, -Ο% _6 alkyl), ((0)0((^ - 6 alkyl), -C(0) NH2.6 alkyl), -C(0)NH(C3-6 cycloalkyl)[〇], -C(0)NH(cycloalkylalkyl)[〇], -C(0)NH (aralkyl), -ΝΗΟΧΟ)% _ 6 alkyl), -NHC(0)(C3 _ 6 cycloalkyl), -NHC(0)(cycloalkylalkyl), -NHC(O)(aryl) ,) -NHC(0)(aralkyl), -(CH2)ΝΗ((^6 alkyl), -(CH2)NH(aralkyl), -(CH2)NH(heterocyclylalkyl) , -NHSOJCh alkyl), -NHS〇2 (C3_6 cycloalkyl), -NHS02 (cycloalkylalkyl), -nhso2 (aryl), -NHS02 (aralkyl), -SC^NI^Chane a group, -S02NH(C3_6 cycloalkyl), -S02NH(cycloalkylalkyl), -S02NH(aryl) or -S02NH(aralkyl), wherein each q-6 alkyl group, C3_6 cycloalkyl group, The cycloalkylalkylaryl and aralkyl groups are substituted or unsubstituted. In still other embodiments, F, CN, -CF3, -C(0)NH2, -C(0)NH(CV6 alkyl), -c(o)nh(c3_6cycloalkyl)[ο], -C(0)NH(cycloalkylalkyl)[〇], -(CHONHCh alkyl), -(CH2)NH(heterocyclylalkyl)-6 alkyl) or -S02NH(Cb6 alkyl), wherein Each Cu alkyl group is substituted or unsubstituted. In still other examples, 123505 21 - 200815422, R3 is a substituted or unsubstituted q _4 alkyl group or -Ο% -4 alkyl group) or is a partially or fully halogenated _ 〇 (Ci · 2 alkyl). In some embodiments of the compound of Formula 1, L2 is 〇, OC(O), C(O), C(0)NH > C(〇)NHNH > C(0)NMe > 0CH2C(0) > S02NH > CH(OH) or C(NOH), and Q is

在一些具體實施例中，G為苯基。 在式I化合物之一些具體實施例中，於1〇 _濃度下之化 合物會抑制自細胞所引致之TNFa-釋出，達約50%或大於 50%。 、 在本發明之特徵或方面係以Markush基團或替代物之其他 基團群為觀點描述之情況下，熟諳此藝者將明瞭的是，本 發明於是亦以Markush基團或其他基團成員之任何個別成員 123505 -22- 200815422 或亞組為觀點作描述。以下述作為說明而非限制，表1係列 示如本文中所述式I取代基之各種組合。因此，例如組合 1025係描述其中Ar為2-吡啶基，且G為苯基之具體實施例。 表1 :關於式I之G與Ar之舉例組合In some embodiments, G is phenyl. In some embodiments of the compounds of formula I, the compound at a concentration of 1 〇 inhibits TNFa-release from cells, up to about 50% or greater than 50%. In the case where the features or aspects of the present invention are described in terms of a Markush group or other group of alternatives, it will be apparent to those skilled in the art that the present invention is also a Markush group or other group member. Any individual member 123505 -22- 200815422 or subgroup is described for the point of view. The following table is illustrative and not limiting, and Table 1 series shows various combinations of substituents of formula I as described herein. Thus, for example, combination 1025 describes a specific embodiment in which Ar is 2-pyridyl and G is phenyl. Table 1: Example combination of G and Ar for Formula I

Ar G \ α\ os 黎 4> to A U) 芳基 1001 1002 1003 1004 1005 1006 1007 1008 1009 雜芳基 1010 1011 1012 1013 1014 1015 1016 1017 1018 苯基 1019 1020 1021 1022 1023 1024 1025 1026 1027 嘧啶基 1028 1029 1030 1031 1032 1033 1034 1035 1036 外匕σ定基 1037 1038 1039 1040 1041 1042 1043 1044 1045 σ号σ坐基 1046 1047 1048 1049 1050 1051 1052 1053 1054 異噚唑基 1055 1056 1057 1058 1059 1060 1061 1062 1063 外t11坐基 1064 1065 1066 1067 1068 1069 1070 1071 1072 呋喃基 1073 1074 1075 1076 1077 1078 1079 1080 1081 A R3 1082 1083 1084 1085 1086 1087 1088 1089 1090 Λ R3 1091 1092 1093 1094 1095 1096 1097 1098 1099 Λ R3 1100 1101 1102 1103 1104 1105 1106 1107 1108Ar G \ α\ os 黎 4> to AU) aryl 1001 1002 1003 1004 1005 1006 1007 1008 1009 Heteroaryl 1010 1011 1012 1013 1014 1015 1016 1017 1018 Phenyl 1019 1020 1021 1022 1023 1024 1025 1026 1027 Pyrimidinyl 1028 1029 1030 1031 1032 1033 1034 1035 1036 External 匕σ定基 1037 1038 1039 1040 1041 1042 1043 1044 1045 σ号σ坐基1046 1047 1048 1049 1050 1051 1052 1053 1054 Isoxazolyl 1055 1056 1057 1058 1059 1060 1061 1062 1063 Outside t11 sit Base 1064 1065 1066 1067 1068 1069 1070 1071 1072 furanyl 1073 1074 1075 1076 1077 1078 1079 1080 1081 A R3 1082 1083 1084 1085 1086 1087 1088 1089 1090 Λ R3 1091 1092 1093 1094 1095 1096 1097 1098 1099 Λ R3 1100 1101 1102 1103 1104 1105 1106 1107 1108

表2係列示式I之取代基L2與Q之各種組合。因此，例如 組合4311係描述其中L2為C(O)，且Q為嗎福啉基之具體實施 例。再者，熟諳此藝者將明瞭取代基之組合，只有在此種 -23 - 123505 200815422 組合會造成化學上安定之化合物下才允許，且得自描述Ar 與G之表1之任何組合可與得自描述L2與Q之表2之任何組 合合併。例如，得自表1之組合1025與得自表2之組合4311 係描述其中Ar為2-吡啶基，G為苯基，L2為C(O)，且Q為嗎 福啉基之式I具體實施例。應明瞭表中之各G與Q係如本文 中所述視情況經取代。再者，A之各意義（-F、Cl、Br、I、 NR2或(：卜3烷基或-(XCu)烷基）可與得自表1或表2之任何組 合或得自該兩個表之任何組合對合併。因此，例如，應明 ( 瞭的是，組合4311係描述其中A為-F，L2為C(O)，且Q為嗎 福啉基之具體實施例，以及其中A為-CH3，L2為C(O)，且Q 為嗎福琳基者’專專。 表2·關於式I之L2與Q之舉例組合 \ 命 & πν Κ) S Κ) 〇 to S to 〇 ίο η 〇 5 S ro 00 η to s K) η Κ) Ο Ο "ο Κ)- Ο Π 芝 Ο Ο Ο 为 η I ο to Ο Ο to” 烷基 1500 1501 1502 1503 1504 1505 1506 1507 1508 1509 1510 環烷基 1532 1533 1534 1535 1536 1537 1538 1539 1540 1541 1542 芳基 1564 1565 1566 1567 1568 1569 1570 1571 1572 1573 1574 雜環基 1596 1597 1598 1599 1600 1601 1602 1603 1604 1605 1606 環烷基烷基 1628 1629 1630 1631 1632 1633 1634 1635 1636 1637 1638 芳烧基 1660 1661 1662 1663 1664 1665 1666 1667 1668 1669 1670 雜環基烧基 1692 1693 1694 1695 1696 1697 1698 1699 1700 1701 1702 (C〇.4烷基)苯基 1724 1725 1726 1727 1728 1729 1730 1731 1732 1733 1734 烷基)吡啶基 1756 1757 1758 1759 1760 1761 1762 1763 1764 1765 1766 (Co _4烷基)嘧啶基 1788 1789 1790 1791 1792 1793 1794 1795 1796 1797 1798 -24- 123505 200815422 \ πν 8 Κ) s Ο π Is) s K) 1 s μ Q ro o o 3 to' 00 I s K) 8 K) o K) 〇 〇 K) K) ^ 〇 o to 乂 η Κ) Ο Ο Ν) ο κΤ Ο Ο 方 方 ο ο Ν) (C0_4烷基） 嗎福琳基 1820 1821 1822 1823 1824 1825 1826 1827 1828 1829 1830 (ε〇·4烷基） 硫代嗎福啉基 1852 1853 1854 1855 1856 1857 1858 1859 1860 1861 1862 (c0_4烷基)嗫啶基 1884 1885 1886 1887 1888 1889 1890 1891 1892 1893 1894 (C〇 · 4烧基） (10-氧-4·氮-三環 二[5.2.1.02,6]癸基） 1916 1917 1918 1919 1920 1921 1922 1923 1924 1925 1926 (C〇 · 4烧基） (8-氧-3-氮-雙環 -[3.2.1]辛烷基） 1948 1949 1950 1951 1952 1953 1954 1955 1956 1957 1958 (C〇 _ 4烧基） 四氫哌喃基 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 (C〇 _ 4烧基） 四氫呋喃基 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 (C〇-4烷基） 四氫吡咯基 2044 2045 2046 2047 2048 2049 2050 2051 2052 2053 2054 (C〇_4烷基） 六氫吡啶基 2076 2077 2078 2079 2080 2081 2082 2083 2084 2085 2086 (C〇 _ 4烧基） 六氫吡畊基 2108 2109 2110 2111 2112 2113 2114 2115 2116 2117 2118 曱基 2140 2141 2142 2143 2144 2145 2146 2147 2148 2149 2150 乙基 2172 2173 2174 2175 2176 2177 2178 2179 2180 2181 2182 正-丙基 2204 2205 2206 2207 2208 2209 2210 2211 2212 2213 2214 異丙基 2236 2237 2238 2239 2240 2241 2242 2243 2244 2245 2246 正-丁基 2268 2269 2270 2271 2272 2273 2274 2275 2276 2277 2278 第三·丁基 2300 2301 2302 2303 2304 2305 2306 2307 2308 2309 2310 第二-丁基 2332 2333 2334 2335 2336 2337 2338 2339 2340 2341 2342 異丁基 2364 2365 2366 2367 2368 2369 2370 2371 2372 2373 2374 新戊基 2396 2397 2398 2399 2400 2401 2402 2403 2404 2405 2406 -25- 123505 200815422 \ ί ΠΨ Ν) Κ) 〇 〇 Κ) (CR，2)nNR(CR，2)t to" Ο ο 艺 ζ/) 〇 η Ν) to Ο Q to 〇 o K) g to 〇 n K) n K)· 〇 n to n I O n K) p o bO 穴 n to 環丙基 2428 2429 2430 2431 2432 2433 2434 2435 2436 2437 2438 (CH2)-環丙基 2460 2461 2462 2463 2464 2465 2466 2467 2468 2469 2470 (CH2)2環丙基 2492 2493 2494 2495 2496 2497 2498 2499 2500 2501 2502 (CH2)3-環丙基 2524 2525 2526 2527 2528 2529 2530 2531 2532 2533 2534 環丁基 2556 2557 2558 2559 2560 2561 2562 2563 2564 2565 2566 (CH2)-環丁基 2588 2589 2590 2591 2592 2593 2594 2595 2596 2597 2598 (CH2)2 環丁基 2620 2621 2622 2623 2624 2625 2626 2627 2628 2629 2630 (CH2)3-環丁基 2652 2653 2654 2655 2656 2657 2658 2659 2660 2661 2662 環戊基 2684 2685 2686 2687 2688 2689 2690 2691 2692 2693 2694 (CH2)-環戊基 2716 2717 2718 2719 2720 2721 2722 2723 2724 2725 2726 (CH2)2環戊基 2748 2749 2750 2751 2752 2753 2754 2755 2756 2757 2758 (CH2)3-環戊基 2780 2781 2782 2783 2784 2785 2786 2787 2788 2789 2790 環己基 2812 2813 2814 2815 2816 2817 2818 2819 2820 2821 2822 (ch2)-環己基 2844 2845 2846 2847 2848 2849 2850 2851 2852 2853 2854 (CH2)2環己基 2876 2877 2878 2879 2880 2881 2882 2883 2884 2885 2886 (CH2)3-環己基 2908 2909 2910 2911 2912 2913 2914 2915 2916 2917 2918 雙環并[2.2.1] 庚烷基 2940 2941 2942 2943 2944 2945 2946 2947 2948 2949 2950 (CH2)-雙環并 [2.2.1]庚烷基 2972 2973 29/4 2975 2976 2977 2978 2979 2980 2981 2982 (CH2)2-雙環并 [2.2.1]庚烷基 3004 3005 3006 3007 3008 3009 3010 3011 3012 3013 3014 (CH2)3-雙環并 [2.2.1]庚烷基 3036 3037 3038 3039 3040 3041 3042 3043 3044 3045 3046 環庚基 3068 3069 3070 3071 3072 3073 3074 3075 3076 3077 3078 苯基 3100 3101 3102 3103 3104 3105 3106 3107 3108 3109 3110 爷基 3132 3133 3134 3135 3136 3137 3138 3139 3140 3141 3142 苯乙基 3164 3165 3166 3167 3168 3169 3170 3171 3172 3173 3174 123505Table 2 provides a series of combinations of substituents L2 and Q of Formula I. Thus, for example, combination 4311 describes a specific embodiment in which L2 is C(O) and Q is a morpholinyl group. Furthermore, those skilled in the art will recognize that combinations of substituents are only permitted if such combinations of -23 - 123505 200815422 result in chemically stable compounds, and any combination of Table 1 describing Ar and G can be used with Merged from any combination of Table 2 describing L2 and Q. For example, the combination 1025 from Table 1 and the combination 4311 from Table 2 describe Formula I in which Ar is 2-pyridyl, G is phenyl, L2 is C(O), and Q is morpholinyl. Example. It should be understood that each of the G and Q lines in the table is replaced as described herein. Furthermore, the meaning of A (-F, Cl, Br, I, NR2 or (: 3 alkyl or - (XCu) alkyl) may be combined with or derived from any combination of Table 1 or Table 2 Any combination of pairs of tables is combined. Thus, for example, it should be understood that the combination 4311 describes a specific embodiment in which A is -F, L2 is C(O), and Q is a morpholinyl group, and A is -CH3, L2 is C(O), and Q is the hollyn's 'specialized. Table 2. · Example combination of L2 and Q of Formula I\Life & πν Κ) S Κ) 〇to S To 〇ίο η 〇5 S ro 00 η to s K) η Κ) Ο Ο "ο Κ)- Ο Ο Ο Ο Ο η η I ο to Ο Ο to” alkyl 1500 1501 1502 1503 1504 1505 1506 1507 1508 1509 1510 cycloalkyl 1532 1533 1534 1535 1536 1537 1538 1539 1540 1541 1542 aryl 1564 1565 1566 1567 1568 1569 1570 1571 1572 1573 1574 heterocyclic 1596 1597 1598 1599 1600 1601 1602 1603 1604 1605 1606 cycloalkylalkyl 1628 1629 1630 1631 1632 1633 1634 1635 1636 1637 1638 Aromatic base 1660 1661 1662 1663 1664 1665 1666 1667 1668 1669 1670 Heterocyclic alkyl 1692 1693 1694 1695 1696 1697 1698 1699 1700 1701 1702 (C〇.4 alkyl)phenyl 1724 1725 1726 1727 1728 1729 1730 1731 1732 1733 1734 alkyl)pyridyl 1756 1757 1758 1759 1760 1761 1762 1763 1764 1765 1766 (Co _4 alkyl)pyrimidinyl 1788 1789 1790 1791 1792 1793 1794 1795 1796 1797 1798 -24- 123505 200815422 \ πν 8 Κ) s Ο π Is) s K) 1 s μ Q ro oo 3 to' 00 I s K) 8 K) o K) 〇 〇K) K) ^ 〇o to 乂η Κ) Ο Ο Ν) ο κΤ Ο Ο square ο ο Ν) (C0_4 alkyl) 沃福琳基1820 1821 1822 1823 1824 1825 1826 1827 1828 1829 1830 (ε〇 · 4 alkyl) thiomorphine base 1852 1853 1854 1855 1856 1857 1858 1859 1860 1861 1862 (c0_4 alkyl) acridinyl 1884 1885 1886 1887 1888 1889 1890 1891 1892 1893 1894 (C〇·4 alkyl) 10-oxo-4·nitro-tricyclod[[5.2.1.02,6]fluorenyl) 1916 1917 1918 1919 1920 1921 1922 1923 1924 1925 1926 (C〇·4 alkyl) (8-oxo-3-nitrogen-bicyclic) -[3.2.1]octyl) 1948 1949 1950 1951 1952 1953 1954 1955 1956 1957 1958 (C〇_ 4 alkyl) Tetrahydropyranyl 1980 1981 1982 1983 1984 1985 1986 1987 19 88 1989 1990 (C〇_ 4 alkyl) Tetrahydrofuranyl 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 (C〇-4 alkyl) Tetrahydropyrrolyl 2044 2045 2046 2047 2048 2049 2050 2051 2052 2053 2054 (C〇 _4 alkyl) hexahydropyridyl 2076 2077 2078 2079 2080 2081 2082 2083 2084 2085 2086 (C〇_ 4 alkyl) Hexahydropyrryl 2108 2109 2110 2111 2112 2113 2114 2115 2116 2117 2118 曱 2140 2141 2142 2143 2144 2145 2146 2147 2148 2149 2150 Ethyl 2172 2173 2174 2175 2176 2177 2178 2179 2180 2181 2182 n-propyl 2204 2205 2206 2207 2208 2209 2210 2211 2212 2213 2214 isopropyl 2236 2237 2238 2239 2240 2241 2242 2243 2244 2245 2246 -butyl 2268 2269 2270 2271 2272 2273 2274 2275 2276 2277 2278 Third butyl 2300 2301 2302 2303 2304 2305 2306 2307 2308 2309 2310 Second-butyl 2332 2333 2334 2335 2336 2337 2338 2339 2340 2341 2342 Isobutyl 2364 2365 2366 2367 2368 2369 2370 2371 2372 2373 2374 Neopentyl 2396 2397 2398 2399 2400 2401 2402 2403 2404 2405 2406 -25- 123505 200815422 \ ί Ψ Ν) Κ) 〇〇Κ) (CR, 2) nNR(CR, 2)t to" Ο ο ζ ζ /) 〇η Ν) to Ο Q to 〇o K) g to 〇n K) n K) · 〇n to n IO n K) po bO acupoints n to cyclopropyl 2428 2429 2430 2431 2432 2433 2434 2435 2436 2437 2438 (CH2)-cyclopropyl 2460 2461 2462 2463 2464 2465 2466 2467 2468 2469 2470 (CH2)2 Cyclopropyl 2492 2493 2494 2495 2496 2497 2498 2499 2500 2501 2502 (CH2)3-cyclopropyl 2524 2525 2526 2527 2528 2529 2530 2531 2532 2533 2534 Cyclobutyl 2556 2557 2558 2559 2560 2561 2562 2563 2564 2565 2566 (CH2) -cyclobutyl 2588 2589 2590 2591 2592 2593 2594 2595 2596 2597 2598 (CH2) 2 cyclobutyl 2620 2621 2622 2623 2624 2625 2626 2627 2628 2629 2630 (CH2) 3-cyclobutyl 2652 2653 2654 2655 2656 2657 2658 2659 2660 2661 2662 cyclopentyl 2684 2685 2686 2687 2688 2689 2690 2691 2692 2693 2694 (CH2)-cyclopentyl 2716 2717 2718 2719 2720 2721 2722 2723 2724 2725 2726 (CH2) 2 cyclopentyl 2748 2749 2750 2751 2752 2753 2754 2755 2756 2757 2758 (CH2)3-cyclopentyl 2780 2781 2782 2783 2784 2785 2786 2787 2788 278 9 2790 Cyclohexyl 2812 2813 2814 2815 2816 2817 2818 2819 2820 2821 2822 (ch2)-cyclohexyl 2844 2845 2846 2847 2848 2849 2850 2851 2852 2853 2854 (CH2) 2 cyclohexyl 2876 2877 2878 2879 2880 2881 2882 2883 2884 2885 2886 ( CH2)3-cyclohexyl 2908 2909 2910 2911 2912 2913 2914 2915 2916 2917 2918 bicyclo[2.2.1] heptyl 2940 2941 2942 2943 2944 2945 2946 2947 2948 2949 2950 (CH2)-bicyclo[2.2.1]g Alkyl 2972 2973 29/4 2975 2976 2977 2978 2979 2980 2981 2982 (CH2) 2-bicyclo[2.2.1]heptyl 3004 3005 3006 3007 3008 3009 3010 3011 3012 3013 3014 (CH2)3-bicyclo[2.2 .1]heptyl 3036 3037 3038 3039 3040 3041 3042 3043 3044 3045 3046 Cycloheptyl 3068 3069 3070 3071 3072 3073 3074 3075 3076 3077 3078 Phenyl 3100 3101 3102 3103 3104 3105 3106 3107 3108 3109 3110 贵基3132 3133 3134 3135 3136 3137 3138 3139 3140 3141 3142 phenylethyl 3164 3165 3166 3167 3168 3169 3170 3171 3172 3173 3174 123505

-26- 200815422-26- 200815422

\ ί ΠΨ Κ) S> Ο ο Κ) (CR’2)nNR(CR，2)t 9 Κ) η ο κ>- 00 ζ η κΤ κΤ ο Κ)' Ο Ο to "ο κΤ Ο Ο 穴 to* Ο 穴 to· Ο Ο 方 κΤ η η to· Ο Ο Ν) η ο 2-吡啶基 3196 3197 3198 3199 3200 3201 3202 3203 3204 3205 3206 (CH2 )-2-吡啶基 3228 3229 3230 3231 3232 3233 3234 3235 3236 3237 3238 (CH2)2-2-吡啶基 3260 3261 3262 3263 3264 3265 3266 3267 3268 3269 3270 (CH2)3-2-吡啶基 3292 3293 3294 3295 3296 3297 3298 3299 3300 3301 3302 3-吡啶基 3324 3325 3326 3327 3328 3329 3330 3331 3332 3333 3334 (CH2 )_3_吡啶基 3356 3357 3358 3359 3360 3361 3362 3363 3364 3365 3366 (CH2 )2_3_吡啶基 3388 3389 3390 3391 3392 3393 3394 3395 3396 3397 3398 (CH2 )3 -3-吡啶基 3420 3421 3422 3423 3424 3425 3426 3427 3428 3429 3430 4-^σ定基 3452 3453 3454 3455 3456 3457 3458 3459 3460 3461 3462 (CH2 )-4-吡啶基 3484 3485 3486 3487 3488 3489 3490 3491 3492 3493 3494 (CH2 )2 -4-吡啶基 3516 3517 3518 3519 3520 3521 3522 3523 3524 3525 3526 (CH2)3-4-吡啶基 3548 3549 3550 3551 3552 3553 3554 3555 3556 3557 3558 四氫呋喃基 3580 3581 3582 3583 3584 3585 3586 3587 3588 3589 3590 (ch2)- 四氫呋喃基 3612 3613 3614 3615 3616 3617 3618 3619 3620 3621 3622 (ch2)2- 四氫呋喃基 3644 3645 3646 3647 3648 3649 3650 3651 3652 3653 3654 (ch2)3- 四氫呋喃基 3676 3677 3678 3679 3680 3681 3682 3683 3684 3685 3686 四氫咬喃基 3708 3709 3710 3711 3712 3713 3714 3715 3716 3717 3718 (ch2)- 四氫味喃基 3740 3741 3742 3743 3744 3745 3746 3747 3748 3749 3750 (ch2)2- 四氫喊喃基 3772 3773 3774 3775 3776 3777 3778 3779 3780 3781 3782 (ch2)3- 四氫哌喃基 3804 3805 3806 3807 3808 3809 3810 3811 3812 3813 3814 四氫咐略基 3836 3837 3838 3839 3840 3841 3842 3843 3844 3845 3846 (CH2> 四氫卩比σ各基 3868 3869 3870 3871 3872 3873 3874 3875 3876 3877 3878 123505 -27- 200815422 \ Ϊ & ΠΨ Μ Κ) 〇 K) δ Κ) 1 to to n % δ K) C/3 1 ts) s K) o Q K) 〇 〇 K) 一o O K) 〇 〇 to O K) Ο Ο Κ) Ρ I ο Κ) (W/ Ο Ο κ> 誇 ο 8 Κ) (CH2)2-四氫吡咯基 3900 3901 3902 3903 3904 3905 3906 3907 3908 3909 3910 (CH2)3-四氮p比嘻基 3932 3933 3934 3935 3936 3937 3938 3939 3940 3941 3942 (10-氧-4-氮-三環 -[5.2.1.02,6]-癸基） 3964 3965 3966 3967 3968 3969 3970 3971 3972 3973 3974 (8-氧-3-氮-雙環并 [3.2.1]辛烧基） 3996 3997 3998 3999 4000 4001 4002 4003 4004 4005 4006 六·®比σ定基 4028 4029 4030 4031 4032 4033 4034 4035 4036 4037 4038 (ch2)- 六氫定基 4060 4061 4062 4063 4064 4065 4066 4067 4068 4069 4070 (CH2)2-六氫吡啶基 4092 4093 4094 4095 4096 4097 4098 4099 4100 4101 4102 (ch2)3- 六氫峨σ定基 4124 4125 4126 4127 4128 4129 4130 4131 4132 4133 4134 六氫说17井基 4156 4157 4158 4159 4160 4161 4162 4163 4164 4165 4166 (ch2)-六氫吡畊基 4188 4189 4190 4191 4192 4193 4194 4195 4196 4197 4198 (ch2)2- 六氫说畊基 4220 4221 4222 4223 4224 4225 4226 4227 4228 4229 4230 (CH2)3· 六氫?比〃井基 4252 4253 4254 4255 4256 4257 4258 4259 4260 4261 4262 嗎福'^林基 4284 4285 4286 4287 4288 4289 4290 4291 4292 4293 4294 (CH2)-嗎福啉基 4316 4317 4318 4319 4320 4321 4322 4323 4324 4325 4326 (Cl·^ )2 -嗎福p林基 4348 4349 4350 4351 4352 4353 4354 4355 4356 4357 4358 (CH^ )3-嗎福p林基 4380 4381 4382 4383 4384 4385 4386 4387 4388 4389 4390 28- 123505 200815422 表2 (續） \ Q K) η η Ν) S to η 1 Κ) K) I /g s S) O 〇 〇 孕 o o 00 Ο "η Ο 1 Ο § 烧基 1511 1512 1513 1514 1515 1516 1517 1518 1519 1520 1521 壞烧基 1543 1544 1545 1546 1547 1548 1549 1550 1551 1552 1553 芳基 1575 1576 1577 1578 1579 1580 1581 1582 1583 1584 1585 雜環基 1607 1608 1609 1610 1611 1612 1613 1614 1615 1616 1617 環烷基烷基 1639 1640 1641 1642 1643 1644 1645 1646 1647 1648 1649 芳烷基 1671 1672 1673 1674 1675 1676 1677 1678 1679 1680 1681 雜環基烷基 1703 1704 1705 1706 1707 1708 1709 1710 1711 1712 1713 (C〇. 4烷基)苯基 1735 1736 1737 1738 1739 1740 1741 1742 1743 1744 1745 (C〇_4烷基） 峨11 定基 1767 1768 1769 1770 1771 1772 1773 1774 1775 1776 1777 (C〇 _ 4烧基） 哺σ定基 1799 1800 1801 1802 1803 1804 1805 1806 1807 1808 1809 (C〇 _ 4燒基） 嗎福琳基 1831 1832 1833 1834 1835 1836 1837 1838 1839 1840 1841 (C〇 · 4烧基） 硫代嗎福淋基 1863 1864 1865 1866 1867 1868 1869 1870 1871 1872 1873 (C〇 _ 4烧基） 嗝啶基 1895 1896 1897 1898 1899 1900 1901 1902 1903 1904 1905 (C〇 _ 4烧基） (10·氧斗氮-三 環-[5.2.1.02,6] 癸基） 1927 1928 1929 1930 1931 1932 1933 1934 1935 1936 1937 (C〇 · 4院基） (8-氧-3-氮-雙環 _[3·2·1]辛烷基） 1959 1960 1961 1962 1963 1964 1965 1966 1967 1968 1969 (C〇 · 4烧基） 四氫哌喃基 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 (C〇 · 4烧基） 四氫呋喃基 2023 2024 2025 2026 2027 2028 2029 2030 2031 2032 2033 123505 -29- 200815422\ ί ΠΨ Κ) S> Ο ο Κ) (CR'2)nNR(CR,2)t 9 Κ) η ο κ>- 00 ζ η κΤ κΤ ο Κ)' Ο Ο to "ο κΤ Ο Ο To* Ο to to Τ Τ Τ Τ Τ η · Τ Ν Ν η η 吡啶 吡啶 Ν η η ο 吡啶 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 3235 3236 3237 3238 (CH2)2-2-pyridyl 3260 3261 3262 3263 3264 3265 3266 3267 3268 3269 3270 (CH2)3-2-pyridyl 3292 3293 3294 3295 3296 3297 3298 3299 3300 3301 3302 3-pyridyl 3324 3325 3326 3327 3328 3329 3330 3331 3332 3333 3334 (CH2 )_3_pyridyl 3356 3357 3358 3359 3360 3361 3362 3363 3364 3365 3366 (CH2 ) 2_3_pyridyl 3388 3389 3390 3391 3392 3393 3394 3395 3396 3397 3398 (CH2 )3 - 3-pyridyl 3420 3421 3422 3423 3424 3425 3426 3427 3428 3429 3430 4-^σ定基3452 3453 3454 3455 3456 3457 3458 3459 3460 3461 3462 (CH2)-4-pyridyl 3484 3485 3486 3487 3488 3489 3490 3491 3492 3493 3494 (CH2)2 -4-pyridyl 3516 3517 3518 3519 3520 3521 3522 3523 3524 3525 3526 ( CH2)3-4-pyridyl 3548 3549 3550 3551 3552 3553 3554 3555 3556 3557 3558 Tetrahydrofuranyl 3580 3581 3582 3583 3584 3585 3586 3587 3588 3589 3590 (ch2)-tetrahydrofuranyl 3612 3613 3614 3615 3616 3617 3618 3619 3620 3621 3622 ( Ch2)2-tetrahydrofuranyl 3644 3645 3646 3647 3648 3649 3650 3651 3652 3653 3654 (ch2)3-tetrahydrofuranyl 3676 3677 3678 3679 3680 3681 3682 3683 3684 3685 3686 tetrahydroanthracene 3708 3709 3710 3711 3712 3713 3714 3715 3716 3717 3718 (ch2)- tetrahydrofuranyl 3740 3741 3742 3743 3744 3745 3746 3747 3748 3749 3750 (ch2)2-tetrahydropyranyl 3772 3773 3774 3775 3776 3777 3778 3779 3780 3781 3782 (ch2)3-tetrahydroperidine喃基3804 3805 3806 3807 3808 3809 3810 3811 3812 3813 3814 tetrahydroindole 3836 3837 3838 3839 3840 3841 3842 3843 3844 3845 3846 (CH2> Tetrahydropyrene ratio σ each 3868 3869 3870 3871 3872 3873 3874 3875 3876 3877 3878 123505 -27- 200815422 \ Ϊ & ΠΨ Κ Κ) 〇K) δ Κ) 1 to to n % δ K) C/3 1 ts) s K) o QK) 〇〇K) one o OK) 〇〇to OK) Ο Ο Κ) I ο Κ) (W/ Ο Ο κ> 夸ο 8 Κ) (CH2)2-tetrahydropyrrolyl 3900 3901 3902 3903 3904 3905 3906 3907 3908 3909 3910 (CH2)3-tetrazine p 嘻 393 3932 3933 3934 3935 3936 3937 3938 3939 3940 3941 3942 (10-oxo-4-nitro-tricyclo-[5.2.1.02,6]-fluorenyl) 3964 3965 3966 3967 3968 3969 3970 3971 3972 3973 3974 (8-oxo-3-nitrogen -bicyclo[3.2.1]octyl) 3996 3997 3998 3999 4000 4001 4002 4003 4004 4005 4006 hexa® ratio sigma 4028 4029 4030 4031 4032 4033 4034 4035 4036 4037 4038 (ch2)- hexahydro group 4060 4061 4062 4063 4064 4065 4066 4067 4068 4069 4070 (CH2)2-hexahydropyridyl 4092 4093 4094 4095 4096 4097 4098 4099 4100 4101 4102 (ch2)3-hexahydropurine sigma 4124 4125 4126 4127 4128 4129 4130 4131 4132 4133 4134 Hydrogen says 17 well base 4156 4157 4158 4159 4160 4161 4162 4163 4164 4165 4166 (ch2)-hexahydropyrrole 4188 4189 4190 4191 4192 4193 4194 4195 4196 4197 4198 (ch2)2- hexamethylene said cultivating base 4220 4221 4222 4223 4224 4225 4226 4227 4228 4229 4230 (CH2)3· hexahydro? 〃 well base 4252 4253 4254 4255 4256 4 257 4258 4259 4260 4261 4262 福福'^林基4284 4285 4286 4287 4288 4289 4290 4291 4292 4293 4294 (CH2)-morpholinyl 4316 4317 4318 4319 4320 4321 4322 4323 4324 4325 4326 (Cl·^ ) 2 -?福普林基4348 4349 4350 4351 4352 4353 4354 4355 4356 4357 4358 (CH^)3-Fufu p-Linji 4380 4381 4382 4383 4384 4385 4386 4387 4388 4389 4390 28- 123505 200815422 Table 2 (continued) \ QK) η η Ν) S to η 1 Κ) K) I /gs S) O 〇〇 oo 00 Ο "η Ο 1 Ο § Burning base 1511 1512 1513 1514 1515 1516 1517 1518 1519 1520 1521 Bad burning base 1543 1544 1545 1546 1547 1548 1549 1550 1551 1552 1553 aryl 1575 1576 1577 1578 1579 1580 1581 1582 1583 1584 1585 Heterocyclyl 1607 1608 1609 1610 1611 1612 1613 1614 1615 1616 1617 cycloalkylalkyl 1639 1640 1641 1642 1643 1644 1645 1646 1647 1648 1649 Aralkyl 1671 1672 1673 1674 1675 1676 1677 1678 1679 1680 1681 Heterocyclylalkyl 1703 1704 1705 1706 1707 1708 1709 1710 1711 1712 1713 (C〇. 4 alkyl)phenyl 1735 1736 1737 1738 1739 1740 1741 1742 1743 1744 17 45 (C〇_4 alkyl) 峨11 fixed base 1767 1768 1769 1770 1771 1772 1773 1774 1775 1776 1777 (C〇_ 4 burning base) feeding σ定基1799 1800 1801 1802 1803 1804 1805 1806 1807 1808 1809 (C〇_ 4 Burning base) 福福琳基1831 1832 1833 1834 1835 1836 1837 1838 1839 1840 1841 (C〇·4 burning base) thiomethalin base 1863 1864 1865 1866 1867 1868 1869 1870 1871 1872 1873 (C〇_ 4 burning base Acridine 1895 1896 1897 1898 1899 1900 1901 1902 1903 1904 1905 (C〇_ 4 alkyl) (10·Oxygen nitro-tricyclic-[5.2.1.02,6] sulfhydryl) 1927 1928 1929 1930 1931 1932 1933 1934 1935 1936 1937 (C〇·4) (8-oxo-3-nitro-bicyclo_[3·2·1]octyl) 1959 1960 1961 1962 1963 1964 1965 1966 1967 1968 1969 (C〇· 4 Pyridyl) tetrahydropyranyl 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 (C〇·4 alkyl) tetrahydrofuranyl 2023 2024 2025 2026 2027 2028 2029 2030 2031 2032 2033 123505 -29- 200815422

\ Q K) 〇 〇 to K) η % § 〇 K) s K) 秀 ο ο ο 内 Κ) Ο 2 § Ο Ο 00 to 2 Ο Ο κ Κ) "π ο Ο η § (C〇_4烷基） 四氫吡咯基 2055 2056 2057 2058 2059 2060 2061 2062 2063 2064 2065 (C0_4烷基） 六氫吡啶基 2087 2088 2089 2090 2091 2092 2093 2094 2095 2096 2097 (C〇_4烷基） 六氫井基 2119 2120 2121 2122 2123 2124 2125 2126 2127 2128 2129 曱基 2151 2152 2153 2154 2155 2156 2157 2158 2159 2160 2161 乙基 2183 2184 2185 2186 2187 2188 2189 2190 2191 2192 2193 正-丙基 2215 2216 2217 2218 2219 2220 2221 2222 2223 2224 2225 異丙基 2247 2248 2249 2250 2251 2252 2253 2254 2255 2256 2257 正-丁基 2279 2280 2281 2282 2283 2284 2285 2286 2287 2288 2289 第三-丁基 2311 2312 2313 2314 2315 2316 2317 2318 2319 2320 2321 第二-丁基 2343 2344 2345 2346 2347 2348 2349 2350 2351 2352 2353 異丁基 2375 2376 2377 2378 2379 2380 2381 2382 2383 2384 2385 新戊基 2407 2408 2409 2410 2411 2412 2413 2414 2415 2416 2417 環丙基 2439 2440 2441 2442 2443 2444 2445 2446 2447 2448 2449 (CH2)-環丙基 2471 2472 2473 2474 2475 2476 2477 2478 2479 2480 2481 (CH2)2環丙基 2503 2504 2505 2506 2507 2508 2509 2510 2511 2512 2513 (CH2)3-環丙基 2535 2536 2537 2538 2539 2540 2541 2542 2543 2544 2545 環丁基 2567 2568 2569 2570 2571 2572 2573 2574 2575 2576 2577 (CH2)-環丁基 2599 2600 2601 2602 2603 2604 2605 2606 2607 2608 2609 (CH2)2 環丁基 2631 2632 2633 2634 2635 2636 2637 2638 2639 2640 2641 (CH2)3-環丁基 2663 2664 2665 2666 2667 2668 2669 2670 2671 2672 2673 環戊基 2695 2696 2697 2698 2699 2700 2701 2702 2703 2704 2705 (CH2)-環戊基 2727 2728 2729 2730 2731 2732 2733 2734 2735 2736 2737 (CH2)2環戊基 2759 2760 2761 2762 2763 2764 2765 2766 2767 2768 2769 (CH2)3-環戊基 2791 2792 2793 2794 2795 2796 2797 2798 2799 2800 2801 環己基 2823 2824 2825 2826 2827 2828 2829 2830 2831 2832 2833 123505 -30- 200815422 \ 8 N) 〇 I η to 8 Κ) ο 1 § η Κ) Κ) S to Ο Ο κ> ο Ο 5 00 to Ο Ο "ο ο Ο η 1 (CH2)-環己基 2855 2856 2857 2858 2859 2860 2861 2862 2863 2864 2865 (CH2)2環己基 2887 2888 2889 2890 2891 2892 2893 2894 2895 2896 2897 (CH2)3_環己基 2919 2920 2921 2922 2923 2924 2925 2926 2927 2928 2929 雙環并[2.2.1] 庚烷基 2951 2952 2953 2954 2955 2956 2957 2958 2959 2960 2961 (CH2)-雙環并 [2.2.1]庚烷基 2983 2984 2985 2986 2987 2988 2989 2990 2991 2992 2993 (CH2)2-雙環并 [2.2.1]庚烷基 3015 3016 3017 3018 3019 3020 3021 3022 3023 3024 3025 (CH2)3-雙環并 [2.2.1]庚烷基 3047 3048 3049 3050 3051 3052 3053 3054 3055 3056 3057 環庚基 3079 3080 3081 3082 3083 3084 3085 3086 3087 3088 3089 苯基 3111 3112 3113 3114 3115 3116 3117 3118 3119 3120 3121 苄基 3143 3144 3145 3146 3147 3148 3149 3150 3151 3152 3153 苯乙基 3175 3176 3177 3178 3179 3180 3181 3182 3183 3184 3185 2-吡啶基 3207 3208 3209 3210 3211 3212 3213 3214 3215 3216 3217 (CH2 >2-吡啶基 3239 3240 3241 3242 3243 3244 3245 3246 3247 3248 3249 (CH2)2-2- 吡啶基 3271 3272 3273 3274 3275 3276 3277 3278 3279 3280 3281 (CH2 )3-2-p比咬基 3303 3304 3305 3306 3307 3308 3309 3310 3311 3312 3313 3-吡啶基 3335 3336 3337 3338 3339 3340 3341 3342 3343 3344 3345 (CH2 )-3-吡啶基 3367 3368 3369 3370 3371 3372 3373 3374 3375 3376 3377 (CH2)2-3- 叶匕咬基 3399 3400 3401 3402 3403 3404 3405 3406 3407 3408 3409 (CH2 )3-3-叶匕咬基 3431 3432 3433 3434 3435 3436 3437 3438 3439 3440 3441 4-ρ比咬基 3463 3464 3465 3466 3467 3468 3469 3470 3471 3472 3473 (CH2 )-4-吡啶基 3495 3496 3497 3498 3499 3500 3501 3502 3503 3504 3505 •31 - 123505 200815422 h 〇 % § 〇 K) 〇 K) 〇 η ο X to η ο 3 00 5 一Ο Ο % Ο 1 § 叶匕咬基 3527 3528 3529 3530 3531 3532 3533 3534 3535 3536 3537 (CH2 )3-4· p比咬基 3559 3560 3561 3562 3563 3564 3565 3566 3567 3568 3569 四氫呋喃基 3591 3592 3593 3594 3595 3596 3597 3598 3599 3600 3601 (CH2> 四氫吱喃基 3623 3624 3625 3626 3627 3628 3629 3630 3631 3632 3633 (ch2)2- 四氫呋喃基 3655 3656 3657 3658 3659 3660 3661 3662 3663 3664 3665 (CH2)3-四氩呋喃基 3687 3688 3689 3690 3691 3692 3693 3694 3695 3696 3697 四氫峰喃基 3719 3720 3721 3722 3723 3724 3725 3726 3727 3728 3729 (CH2). 四氫喊喃基 3751 3752 3753 3754 3755 3756 3757 3758 3759 3760 3761 (ch2)2- 四氫旅喃基 3783 3784 3785 3786 3787 3788 3789 3790 3791 3792 3793 (CH2)3-四氫旅喃基 3815 3816 3817 3818 3819 3820 3821 3822 3823 3824 3825 四氫吡洛基 3847 3848 3849 3850 3851 3852 3853 3854 3855 3856 3857 (CH2> 四氫吡洛基 3879 3880 3881 3882 3883 3884 3885 3886 3887 3888 3889 (ch2)2- 四氫吡咯基 3911 3912 3913 3914 3915 3916 3917 3918 3919 3920 3921 (CH2)3-四氫吡咯基 3943 3944 3945 3946 3947 3948 3949 3950 3951 3952 3953 (10-氧三 環-[5·2·1_02,6]-癸基） 3975 3976 3977 3978 3979 3980 3981 3982 3983 3984 3985 (8-氧-3-氮-雙環 并[3.2.1]辛烷基) 4007 4008 4009 4010 4011 4012 4013 4014 4015 4016 4017 六氫定基 4039 4040 4041 4042 4043 4044 4045 4046 4047 4048 4049 -32- 123505 200815422 \ 8 K) 〇 K) Κ) η § ο Κ) to /g p o K) 〇 § 〇 s to 〇 o 00 〇 〇 g 0 1 n § (ch2)- 六氫说咬基 4071 4072 4073 4074 4075 4076 4077 4078 4079 4080 4081 (ch2)2- 六氫P比唆基 4103 4104 4105 4106 4107 4108 4109 4110 4111 4112 4113 (CH2)3-六氫P比咬基 4135 4136 4137 4138 4139 4140 4141 4142 4143 4144 4145 六氫P比畊基 4167 4168 4169 4170 4171 4172 4173 4174 4175 4176 4177 (ch2)- 六氫井基 4199 4200 4201 4202 4203 4204 4205 4206 4207 4208 4209 (CH2)2. 六氫P比畊基 4231 4232 4233 4234 4235 4236 4237 4238 4239 4240 4241 (CH2)3-六氫井基 4263 4264 4265 4266 4267 4268 4269 4270 4271 4272 4273 嗎福啉基 4295 4296 4297 4298 4299 4300 4301 4302 4303 4304 4305 (CH2)-嗎福啉基 4327 4328 4329 4330 4331 4332 4333 4334 4335 4336 4337 (ch2)2- 嗎福淋基 4359 4360 4361 4362 4363 4364 4365 4366 4367 4368 4369 (CH2)3-嗎福啉基 4391 4392 4393 4394 4395 4396 4397 4398 4399 4400 4401 表2 (續） X 〇 〇 〇 η 1 in 〇 % X Ο Ο ο ο η η X Κ) Ο Ο η ο η 1 § ffi η I 烷基 1522 1523 1524 1525 1526 1527 1528 1529 1530 1531 環炫基 1554 1555 1556 1557 1558 1559 1560 1561 1562 1563 芳基 1586 1587 1588 1589 1590 1591 1592 1593 1594 1595 雜環基 1618 1619 1620 1621 1622 1623 1624 1625 1626 1627 -33- 123505 200815422\ QK) 〇〇to K) η % § 〇K) s K) 秀ο ο ο Κ Κ Ο 2 § Ο Ο 00 to 2 Ο κ κ Κ) "π ο Ο η § (C〇_4 Tetrahydropyryl 2055 2056 2057 2058 2059 2060 2061 2062 2063 2064 2065 (C0_4 alkyl) Hexahydropyridyl 2087 2088 2089 2090 2091 2092 2093 2094 2095 2096 2097 (C〇_4 alkyl) Hexahydrogen well 2119 2120 2121 2122 2123 2124 2125 2126 2127 2128 2129 曱 base 2151 2152 2153 2154 2155 2156 2157 2158 2159 2160 2161 Ethyl 2183 2184 2185 2186 2187 2188 2189 2190 2191 2192 2193 n-propyl 2215 2216 2217 2218 2219 2220 2221 2222 2223 2224 2225 Isopropyl 2247 2248 2249 2250 2251 2252 2253 2254 2255 2256 2257 n-Butyl 2279 2280 2281 2282 2283 2284 2285 2286 2287 2288 2289 Third-Butyl 2311 2312 2313 2314 2315 2316 2317 2318 2319 2320 2321 Second-Ding Base 2343 2344 2345 2346 2347 2348 2349 2350 2351 2352 2353 Isobutyl 2375 2376 2377 2378 2379 2380 2381 2382 2383 2384 2385 Neopentyl 2407 2408 2409 2410 2411 2412 2413 2414 2415 2416 2417 Cyclopropyl 2439 2440 2 441 2442 2443 2444 2445 2446 2447 2448 2449 (CH2)-cyclopropyl 2471 2472 2473 2474 2475 2476 2477 2478 2479 2480 2481 (CH2) 2 cyclopropyl 2503 2504 2505 2506 2507 2508 2509 2510 2511 2512 2513 (CH2)3- Cyclopropyl 2535 2536 2537 2538 2539 2540 2541 2542 2543 2544 2545 Cyclobutyl 2567 2568 2569 2570 2571 2572 2573 2574 2575 2576 2577 (CH2)-cyclobutyl 2599 2600 2601 2602 2603 2604 2605 2606 2607 2608 2609 (CH2)2 Cyclobutyl 2631 2632 2633 2634 2635 2636 2637 2638 2639 2640 2641 (CH2) 3-cyclobutyl 2663 2664 2665 2666 2667 2668 2669 2670 2671 2672 2673 Cyclopentyl 2695 2696 2697 2698 2699 2700 2701 2702 2703 2704 2705 (CH2) -cyclopentyl 2727 2728 2729 2730 2731 2732 2733 2734 2735 2736 2737 (CH2) 2 cyclopentyl 2759 2760 2761 2762 2763 2764 2765 2766 2767 2768 2769 (CH2) 3-cyclopentyl 2791 2792 2793 2794 2795 2796 2797 2798 2799 2800 2801 Cyclohexyl 2823 2824 2825 2826 2827 2828 2829 2830 2831 2832 2833 123505 -30- 200815422 \ 8 N) 〇I η to 8 Κ) ο 1 § η Κ) Κ) S to Ο Ο κ> ο Ο 5 00 to Ο Ο &Quo;ο ο Ο η 1 (CH2)-cyclohexyl 2855 2856 2857 2858 2859 2860 2861 2862 2863 2864 2865 (CH2) 2 cyclohexyl 2887 2888 2889 2890 2891 2892 2893 2894 2895 2896 2897 (CH2) 3_cyclohexyl 2919 2920 2921 2922 2923 2924 2925 2926 2927 2928 2929 bicyclic [2.2.1] heptyl 2951 2952 2953 2954 2955 2956 2957 2958 2959 2960 2961 (CH2)-bicyclo[2.2.1]heptanyl 2983 2984 2985 2986 2987 2988 2989 2990 2991 2992 2993 (CH2)2-bicyclo[2.2.1]heptyl 3015 3016 3017 3018 3019 3020 3021 3022 3023 3024 3025 (CH2)3-bicyclo[2.2.1]heptyl 3047 3048 3049 3050 51 30 30 30 30 30 30 3175 3176 3177 3178 3179 3180 3181 3182 3183 3184 3185 2-pyridyl 3207 3208 3209 3210 3211 3212 3213 3214 3215 3216 3217 (CH2 > 2-pyridyl 3239 3240 3241 3242 3243 3244 3245 3246 3247 3248 3249 (CH2)2- 2 - pyridyl 3271 3272 3273 3274 3275 3276 3277 3278 3279 3280 3281 (CH2 ) 3-2-p ratio bite 3303 3304 3305 3306 3307 3308 3309 3310 3311 3312 3313 3-pyridyl 3335 3336 3337 3338 3339 3340 3341 3342 3343 3344 3345 (CH2)-3-pyridyl 3367 3368 3369 3370 3371 3372 3373 3374 3375 3376 3377 (CH2)2-3- 匕 匕 3399 3400 3401 3402 3403 3404 3405 3406 3407 3408 3409 (CH2 ) 3-3-Leaf匕 基 343 343 343 343 343 343 343 343 343 343 •31 - 123505 200815422 h 〇% § 〇K) 〇K) 〇η ο X to η ο 3 00 5 一Ο Ο % Ο 1 § 匕 匕 35 3527 3528 3529 3530 3531 3532 3533 3534 3535 3536 3537 (CH2 ) 3-4· p ratio bite base 3559 3560 3561 3562 3563 3564 3565 3566 3567 3568 3569 tetrahydrofuranyl 3591 3592 3593 3594 3595 3596 3597 3598 3599 3600 3601 (CH2> tetrahydrofuranyl 3623 3624 3625 3626 3627 3628 3629 3630 3631 3632 3633 (ch2)2- Hydrofuranyl 3655 3656 3657 3658 3659 3660 3661 3662 3663 3664 3665 (CH2) 3-tetrahydrofuranyl 3687 3688 3689 3690 3691 3692 3693 3694 3695 3696 3697 Tetrahydropyranyl 3719 3720 3721 3722 3723 3724 3725 3726 3727 3728 3729 (CH2). Tetrahydropyranyl 3751 3752 3753 3754 3755 3756 3757 3758 3759 3760 3761 (ch2)2- Tetrahydronethane 3783 3784 3785 3786 3787 3788 3789 3790 3791 3792 3793 (CH2)3-Tetrahydrogen Base 3815 3816 3817 3818 3819 3820 3821 3822 3823 3824 3825 Tetrahydropyrrol 3847 3848 3849 3850 3851 3852 3853 3854 3855 3856 3857 (CH2> Tetrahydropyrrol 3879 3880 3881 3882 3883 3884 3885 3886 3887 3888 3889 (ch2) 2-tetrahydropyrrolyl 3911 3912 3913 3914 3915 3916 3917 3918 3919 3920 3921 (CH2)3-tetrahydropyrrolyl 3943 3944 3945 3946 3947 3948 3949 3950 3951 3952 3953 (10-oxytricyclo-[5·2·1_02 ,6]-癸基) 3975 3976 3977 3978 3979 3980 3981 3982 3983 3984 3985 (8-oxo-3-nitro-bicyclo[3.2.1]octyl) 4007 4008 4009 4010 4011 4012 4013 4014 4015 4016 4017 Hydrogen group 4039 4040 4041 4042 404 3 4044 4045 4046 4047 4048 4049 -32- 123505 200815422 \ 8 K) 〇K) Κ) η § ο Κ) to /gpo K) 〇§ 〇s to 〇o 00 〇〇g 0 1 n § (ch2)- Hexahydrogen bite base 4071 4072 4073 4074 4075 4076 4077 4078 4079 4080 4081 (ch2)2-hexahydro-P thiol group 4103 4104 4105 4106 4107 4108 4109 4110 4111 4112 4113 (CH2)3-hexahydro-P ratio bite base 4135 4136 4137 4138 4139 4140 4141 4142 4143 4144 4145 Hexahydrogen P ratio tillage 4167 4168 4169 4170 4171 4172 4173 4174 4175 4176 4177 (ch2)- Hexahydro well base 4199 4200 4201 4202 4203 4204 4205 4206 4207 4208 4209 (CH2)2 Hexahydrogen P ratio cultivating base 4231 4232 4233 4234 4235 4236 4237 4238 4239 4240 4241 (CH2)3-hexahydro well base 4263 4264 4265 4266 4267 4268 4269 4270 4271 4272 4273 Novoline 4295 4296 4297 4298 4299 4300 4301 4302 4303 4304 4305 (CH2)-morpholinyl 4327 4328 4329 4330 4331 4332 4333 4334 4335 4336 4337 (ch2)2- wholly-based 4359 4360 4361 4362 4363 4364 4365 4366 4367 4368 4369 (CH2)3-morpholine Base 4391 4392 4393 4394 4395 4396 4397 4398 4399 4400 4401 Table 2 (continued) X 〇〇〇η1 in 〇% X Ο Ο ο ο η η X Κ) Ο η η ο η 1 § ffi η I alkyl 1522 1523 1524 1525 1526 1527 1528 1529 1530 1531 环炫基 1554 1555 1556 1557 1558 1559 1560 1561 1562 1563 aryl 1586 1587 1588 1589 1590 1591 1592 1593 1594 1595 Heterocyclic group 1618 1619 1620 1621 1622 1623 1624 1625 1626 1627 -33- 123505 200815422

〇 〇 /^\ 〇 S GO X 〇 η § Ο Ο η = 3 ο Ο § X Ο 1 X 環烷基烷基 1650 1651 1652 1653 1654 1655 1656 1657 1658 1659 芳烧基 1682 1683 1684 1685 1686 1687 1688 1689 1690 1691 雜環基烷基 1714 1715 1716 1717 1718 1719 1720 1721 1722 1723 (C〇.4烷基)苯基 1746 1747 1748 1749 1750 1751 1752 1753 1754 1755 (C〇_4烷基)吡啶基 1778 1779 1780 1781 1782 1783 1784 1785 1786 1787 (C〇_4烷基)嘧啶基 1810 1811 1812 1813 1814 1815 1816 1817 1818 1819 (c0_4烷基） 嗎福琳基 1842 1843 1844 1845 1846 1847 1848 1849 1850 1851 烷基)硫代嗎 福琳基 1874 1875 1876 1877 1878 1879 1880 1881 1882 1883 (CQ _ 4炫基)卩昆σ定基 1906 1907 1908 1909 1910 1911 1912 1913 1914 1915 (C〇 · 4院基） (10-氧-4-氮-三環 -[5.2.1.02’6]癸基） 1938 1939 1940 1941 1942 1943 1944 1945 1946 1947 (C0 “烷基） (8-氧-3-氮-雙環 -[3.2.1]辛烷基） 1970 1971 1972 1973 1974 1975 1976 1977 1978 1979 (C0_4烷基） 四氫喊喃基 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 (C0_4烷基） 四氫吱喃基 2034 2035 2036 2037 2038 2039 2040 2041 2042 2043 (C〇_4烷基） 四氫吡咯基 2066 2067 2068 2069 2070 2071 2072 2073 2074 2075 (C〇_4烷基） 六氫吡啶基 2098 2099 2100 2101 2102 2103 2104 2105 2106 2107 (C〇_4烷基） 六氫吡畊基 2130 2131 2132 2133 2134 2135 2136 2137 2138 2139 甲基 2162 2163 2164 2165 2166 2167 2168 2169 2170 2171 乙基 2194 2195 2196 2197 2198 2199 2200 2201 2202 2203 正-丙基 2226 2227 2228 2229 2230 2231 2232 2233 2234 2235 異丙基 2258 2259 2260 2261 2262 2263 2264 2265 2266 2267 正-丁基 2290 2291 2292 2293 2294 2295 2296 2297 2298 2299 123505 •34- 200815422〇〇/^\ 〇S GO X 〇η § Ο Ο η = 3 ο Ο § X Ο 1 X cycloalkylalkyl 1650 1651 1652 1653 1654 1655 1656 1657 1658 1659 Aromatic base 1682 1683 1684 1685 1686 1687 1688 1689 1690 1691 Heterocyclylalkyl 1714 1715 1716 1717 1718 1719 1720 1721 1722 1723 (C〇.4 alkyl)phenyl 1746 1747 1748 1749 1750 1751 1752 1753 1754 1755 (C〇_4 alkyl)pyridyl 1778 1779 1780 1781 1782 1783 1784 1785 1786 1787 (C〇_4 alkyl)pyrimidinyl 1810 1811 1812 1813 1814 1815 1816 1817 1818 1819 (c0_4 alkyl) Koflinky 1842 1843 1844 1845 1846 1847 1848 1849 1850 1851 Alkyl) Sulfur代福福基 1874 1875 1876 1877 1878 1879 1880 1881 1882 1883 (CQ _ 4 炫基)卩昆σ定基1906 1907 1908 1909 1910 1911 1912 1913 1914 1915 (C〇·4 yard base) (10-oxy-4 -N-tricyclic-[5.2.1.02'6]fluorenyl) 1938 1939 1940 1941 1942 1943 1944 1945 1946 1947 (C0 "alkyl" (8-oxo-3-nitro-bicyclo-[3.2.1]octane Base) 1970 1971 1972 1973 1974 1975 1976 1977 1978 1979 (C0_4 alkyl) Tetrahydropyranyl 2002 2003 2004 2005 200 6 2007 2008 2009 2010 2011 (C0_4 alkyl) Tetrahydrofurfuryl 2034 2035 2036 2037 2038 2039 2040 2041 2042 2043 (C〇_4 alkyl) Tetrahydropyrrolyl 2066 2067 2068 2069 2070 2071 2072 2073 2074 2075 (C 〇_4 alkyl) hexahydropyridyl 2098 2099 2100 2101 2102 2103 2104 2105 2106 2107 (C〇_4 alkyl) hexahydropyrrole 2130 2131 2132 2133 2134 2135 2136 2137 2138 2139 methyl 2162 2163 2164 2165 2166 2167 2168 2169 2170 2171 Ethyl 2194 2195 2196 2197 2198 2199 2200 2201 2202 2203 n-propyl 2226 2227 2228 2229 2230 2231 2232 2233 2234 2235 isopropyl 2258 2259 2260 2261 2262 2263 2264 2265 2266 2267 n-butyl 2290 2291 2292 2293 2294 2295 2296 2297 2298 2299 123505 •34- 200815422

X 〇 〇 〇 〇 η 〇 Ε Ο Ο ο ο Ο Ο η Ε Κ) X Ν) Ο Ο § X Ο i X 第三-丁基 2322 2323 2324 2325 2326 2327 2328 2329 2330 2331 第二-丁基 2354 2355 2356 2357 2358 2359 2360 2361 2362 2363 異丁基 2386 2387 2388 2389 2390 2391 2392 2393 2394 2395 新戊基 2418 2419 2420 2421 2422 2423 2424 2425 2426 2427 環丙基 2450 2451 2452 2453 2454 2455 2456 2457 2458 2459 (ch2)-環丙基 2482 2483 2484 2485 2486 2487 2488 2489 2490 2491 (ch2)2環丙基 2514 2515 2516 2517 2518 2519 2520 2521 2522 2523 (CH；2 )3 -環丙基 2546 2547 2548 2549 2550 2551 2552 2553 2554 2555 環丁基 2578 2579 2580 2581 2582 2583 2584 2585 2586 2587 (CH2)-環丁基 2610 2611 2612 2613 2614 2615 2616 2617 2618 2619 (CH2)2 環丁基 2642 2643 2644 2645 2646 2647 2648 2649 2650 2651 (CH2)3-環丁基 2674 2675 2676 2677 2678 2679 2680 2681 2682 2683 環戊基 2706 2707 2708 2709 2710 2711 2712 2713 2714 2715 (CH2)-環戊基 2738 2739 2740 2741 2742 2743 2744 2745 2746 2747 (CH2)2環戊基 2770 2771 2772 2773 2774 2775 2776 2777 2778 2779 (CH2)3-環戊基 2802 2803 2804 2805 2806 2807 2808 2809 2810 2811 環己基 2834 2835 2836 2837 2838 2839 2840 2841 2842 2843 (ch2)-環己基 2866 2867 2868 2869 2870 2871 2872 2873 2874 2875 (CH2)2環己基 2898 2899 2900 2901 2902 2903 2904 2905 2906 2907 (CH〗）3 -環己基 2930 2931 2932 2933 2934 2935 2936 2937 2938 2939 雙環并[2.2.1]庚烷基 2962 2963 2964 2965 2966 2967 2968 2969 2970 2971 (CH2)-雙環并 [2.2.1]庚烷基 2994 2995 2996 2997 2998 2999 3000 3001 3002 3003 (CH2)2-雙環并 [2.2.1]庚烷基 3026 3027 3028 3029 3030 3031 3032 3033 3034 3035 (CH2)3-雙環并 [2.2.1]庚烷基 3058 3059 3060 3061 3062 3063 3064 3065 3066 3067 環庚基 3090 3091 3092 3093 3094 3095 3096 3097 3098 3099 苯基 3122 3123 3124 3125 3126 3127 3128 3129 3130 3131 卞基 3154 3155 3156 3157 3158 3159 3160 3161 3162 3163 123505 -35- 200815422 \ 〇 〇 〇 〇 〇 00 Z E 〇 〇 η Ο Ο £ Κ) η ο ο ο 5 1 § Ο X 苯乙基 3186 3187 3188 3189 3190 3191 3192 3193 3194 3195 2-吡啶基 3218 3219 3220 3221 3222 3223 3224 3225 3226 3227 (CH2 )-2-叶匕ϋ定基 3250 3251 3252 3253 3254 3255 3256 3257 3258 3259 (CH2 )2 -2-吡啶基 3282 3283 3284 3285 3286 3287 3288 3289 3290 3291 (CH2 )3 -2-吡啶基 3314 3315 3316 3317 3318 3319 3320 3321 3322 3323 3-吡啶基 3346 3347 3348 3349 3350 3351 3352 3353 3354 3355 (CH2 )-3-吡啶基 3378 3379 3380 3381 3382 3383 3384 3385 3386 3387 (CH2 )2 -3-吡啶基 3410 3411 3412 3413 3414 3415 3416 3417 3418 3419 (CH2 )3 -3-吡啶基 3442 3443 3444 3445 3446 3447 3448 3449 3450 3451 4-ρ比咬基 3474 3475 3476 3477 3478 3479 3480 3481 3482 3483 (CH2 )-4·吡啶基 3506 3507 3508 3509 3510 3511 3512 3513 3514 3515 (CH2)2-4-吡啶基 3538 3539 3540 3541 3542 3543 3544 3545 3546 3547 (CH2 )3 -4-吡啶基 3570 3571 3572 3573 3574 3575 3576 3577 3578 3579 四氫呋喃基 3602 3603 3604 3605 3606 3607 3608 3609 3610 3611 (CH2)-四氫呋喃基 3634 3635 3636 3637 3638 3639 3640 3641 3642 3643 (CH2)2-四氫呋喃基 3666 3667 3668 3669 3670 3671 3672 3673 3674 3675 (CH2)3-四氫呋喃基 3698 3699 3700 3701 3702 3703 3704 3705 3706 3707 四氫喊喃基 3730 3731 3732 3733 3734 3735 3736 3737 3738 3739 (CH2)-四氫旅π南基 3762 3763 3764 3765 3766 3767 3768 3769 3770 3771 (CH2 )2 -四氫峰。南基 3794 3795 3796 3797 3798 3799 3800 3801 3802 3803 (CH2 -四氫泰0南基 3826 3827 3828 3829 3830 3831 3832 3833 3834 3835 四氫被洛基 3858 3859 3860 3861 3862 3863 3864 3865 3866 3867 (CH2 )-四氫吡咯基 3890 3891 3892 3893 3894 3895 3896 3897 3898 3899 (CH^ )2-四比洛基 3922 3923 3924 3925 3926 3927 3928 3929 3930 3931 (CH2 )3 -四氫吡咯基 3954 3955 3956 3957 3958 3959 3960 3961 3962 3963 (10-氧-4-氮-三環 -[5.2.1.02,6]-癸基） 3986 3987 3988 3989 3990 3991 3992 3993 3994 3995 -36- 123505 200815422 \ 1 〇 〇 〇 00 % Ο η ο ο η ο η Κ) η η X Κ) η § X Ο X (8-氧_3-氮-雙環并 [3.2.1]辛烷基） 4018 4019 4020 4021 4022 4023 4024 4025 4026 4027 六鼠1^比唆基 4050 4051 4052 4053 4054 4055 4056 4057 4058 4059 (CH2 )-六氫p比咬基 4082 4083 4084 4085 4086 4087 4088 4089 4090 4091 (CH2 )2 -六氣p比咬基 4114 4115 4116 4117 4118 4119 4120 4121 4122 4123 (CH2 )3 -六氫P比咬基 4146 4147 4148 4149 4150 4151 4152 4153 4154 4155 六氫吡p井基 4178 4179 4180 4181 4182 4183 4184 4185 4186 4187 (CH2)-六氫吡畊基 4210 4211 4212 4213 4214 4215 4216 4217 4218 4219 (CH2)2-六氫吡畊基 4242 4243 4244 4245 4246 4247 4248 4249 4250 4251 (CH2)3-六氫吡畊基 4274 4275 4276 4277 4278 4279 4280 4281 4282 4283 嗎福淋基 4306 4307 4308 4309 4310 4311 4312 4313 4314 4315 (CH2)-嗎福淋基 4338 4339 4340 4341 4342 4343 4344 4345 4346 4347 (CH2 )2 -嗎福啉基 4370 4371 4372 4373 4374 4375 4376 4377 4378 4379 (CH2)3-嗎福啉基 4402 4403 4404 4405 4406 4407 4408 4409 4410 4411 於本發明之另一方面，係提供式II化合物：X Ν Ο η η Κ X) Ο § § X Ο i X Third-butyl 2322 2323 2324 2325 2326 2327 2328 2329 2330 2331 Second-butyl 2354 2355 2356 2357 2358 2359 2360 2361 2362 2363 Isobutyl 2386 2387 2388 2389 2390 2391 2392 2393 2394 2395 Neopentyl 2418 2419 2420 2421 2422 2423 2424 2425 2426 2427 Cyclopropyl 2450 2451 2452 2453 2454 2455 2456 2457 2458 2459 (ch2) -cyclopropyl 2482 2483 2484 2485 2486 2487 2488 2489 2490 2491 (ch2) 2 cyclopropyl 2514 2515 2516 2517 2518 2519 2520 2521 2522 2523 (CH; 2 ) 3 - cyclopropyl 2546 2547 2548 2549 2550 2551 2552 2553 2554 2555 Cyclobutyl 2578 2579 2580 2581 2582 2583 2584 2585 2586 2587 (CH2)-cyclobutyl 2610 2611 2612 2613 2614 2615 2616 2617 2618 2619 (CH2)2 Cyclobutyl 2642 2643 2644 2645 2646 2647 2648 2649 2650 2651 (CH2 3-cyclobutyl 2674 2675 2676 2677 2678 2679 2680 2681 2682 2683 cyclopentyl 2706 2707 2708 2709 2710 2711 2712 2713 2714 2715 (CH2)-cyclopentyl 2738 2739 2740 2741 2742 2743 2744 2745 2746 2747 (CH2)2 Cyclopentyl 2770 2771 2772 2773 2774 2775 2776 2777 2778 2779 (CH2) 3-cyclopentyl 2802 2803 2804 2805 2806 2807 2808 2809 2810 2811 Cyclohexyl 2834 2835 2836 2837 2838 2839 2840 2841 2842 2843 (ch2)-cyclohexyl 2866 2867 2868 2869 2870 2871 2872 2873 2874 2875 (CH2)2 cyclohexyl 2898 2899 2900 2901 2902 2903 2904 2905 2906 2907 (CH)) 3 -cyclohexyl 2930 2931 2932 2933 2934 2935 2936 2937 2938 2939 Double ring [2.2.1] Heptyl 2962 2963 2964 2965 2966 2967 2968 2969 2970 2971 (CH2)-bicyclo[2.2.1]heptanyl 2994 2995 2996 2997 2998 2999 3000 3001 3002 3003 (CH2)2-bicyclo[2.2.1]g Alkyl 3026 3027 3028 3029 3030 3031 3032 3033 3034 3035 (CH2) 3-bicyclo[2.2.1]heptanyl 3058 3059 3060 3061 3062 3063 3064 3065 3066 3067 cycloheptyl 3090 3091 3092 3093 3094 3095 3096 3097 3098 3099 Phenyl 3122 3123 3124 3125 3126 3127 3128 3129 3130 3131 卞 3 3154 3155 3156 3157 3158 3159 3160 3161 3162 3163 123505 -35- 200815422 \ 〇〇〇〇〇00 ZE 〇〇 Ο Ο Κ £ Κ) η ο ο ο 5 1 § X phenethyl 3186 3187 3188 3189 3190 3191 3192 3193 3194 3195 2-pyridyl 3218 3219 3220 3221 3222 3223 3224 3225 3226 3227 (CH2 )-2-leafidine 3250 3251 3252 3253 3254 3255 3256 3257 3258 3259 (CH2 ) 2 -2-pyridyl 3282 3283 3284 3285 3286 3287 3288 3289 3290 3291 (CH2 ) 3 -2-pyridyl 3314 3315 3316 3317 3318 3319 3320 3321 3322 3323 3-pyridyl 3346 3347 3348 3349 3350 3351 3352 3353 3354 3355 (CH2)-3-pyridyl 3378 3379 3380 3381 3382 3383 3384 3385 3386 3387 (CH2)2 -3-pyridyl 3410 3411 3412 3413 3414 3415 3416 3417 3418 3419 (CH2 )3 -3-pyridyl 3442 3443 3444 3445 3446 3447 3448 3449 3450 3451 4-ρ ratio bite base 3474 3475 3476 3477 3478 3479 3480 3481 3482 3483 (CH2 )-4·pyridyl 3506 3507 3508 3509 3510 3511 3512 3513 3514 3515 (CH2)2-4-pyridyl 3538 3539 3540 3541 3542 3543 3544 3545 3546 3547 (CH2)3 -4-pyridyl 3570 3571 3572 3573 3574 3575 3576 3577 3578 3579 Tetrahydrofuranyl 3602 3603 3604 3605 3606 3607 3608 3609 3610 3611 (CH2)-tetrahydrofuranyl 3634 363 5 3636 3637 3638 3639 3640 3641 3642 3643 (CH2)2-tetrahydrofuranyl 3666 3667 3668 3669 3670 3671 3672 3673 3674 3675 (CH2)3-tetrahydrofuranyl 3698 3699 3700 3701 3702 3703 3704 3705 3706 3707 Tetrahydropyranyl 3730 3731 3732 3733 3734 3735 3736 3737 3738 3739 (CH2)-Tetrahydrogen brigade π Nanji 3762 3763 3764 3765 3766 3767 3768 3769 3770 3771 (CH2)2 - Tetrahydrogen peak. South Base 3794 3795 3796 3797 3798 3799 3800 3801 3802 3803 (CH2 - Tetrahydro 0 South Base 3826 3827 3828 3829 3830 3831 3832 3833 3834 3835 Tetrahydrogen Loki 3858 3859 3860 3861 3862 3863 3864 3865 3866 3867 (CH2 )- Tetrahydropyrrolyl 3890 3891 3892 3893 3894 3895 3896 3897 3898 3899 (CH^)2-tetrabylamine 3922 3923 3924 3925 3926 3927 3928 3929 3930 3931 (CH2)3 -tetrahydropyrrole 3954 3955 3956 3957 3958 3959 3960 3961 3962 3963 (10-oxo-4-nitro-tricyclo-[5.2.1.02,6]-fluorenyl) 3986 3987 3988 3989 3990 3991 3992 3993 3994 3995 -36- 123505 200815422 \ 1 〇〇〇00 % Ο η ο ο η ο η Κ) η η X Κ) η § X Ο X (8-oxo_3-nitro-bicyclo[3.2.1]octyl) 4018 4019 4020 4021 4022 4023 4024 4025 4026 4027 ^比唆基4050 4051 4052 4053 4054 4055 4056 4057 4058 4059 (CH2)-hexahydrop ratio bite base 4082 4083 4084 4085 4086 4087 4088 4089 4090 4091 (CH2)2 - six gas p ratio bite base 4114 4115 4116 4117 4118 4119 4120 4121 4122 4123 (CH2)3 - Hexahydrogen P to bite base 4146 4147 4148 4149 4150 4151 4152 4153 4154 4155 Hexahydropyridyl wells 4178 4179 4180 4181 4182 4183 4184 4185 4186 4187 (CH2)-hexahydropyrrole 4210 4211 4212 4213 4214 4215 4216 4217 4218 4219 (CH2)2-hexahydropyrrole 4242 4243 4244 4245 4246 4247 4248 4249 4250 4251 (CH2)3-hexahydropyrrole 4274 4275 4276 4277 4278 4279 4280 4281 4282 4283 福福基4306 4307 4308 4309 4310 4311 4312 4313 4314 4315 (CH2)- 福福基4338 4339 4340 4341 4342 4343 4344 4345 4346 4347 (CH2)2 - morpholinyl 4370 4371 4372 4373 4374 4375 4376 4377 4378 4379 (CH2) 3-morpholine 4402 4403 4404 4405 4406 4407 4408 4409 4410 4411 Another of the present invention In one aspect, a compound of formula II is provided:

_ l2，Q_ l2, Q

式II 其立體異構物、其互變異構物、其溶劑合物、其前體藥 物及其藥學上可接受之鹽； 其中 X 為 CH、N 或 NO ; Y為CH、N或NO，其條件是X與Y不皆為CH或NO ; A為F、Cl、Br、I、烧基或-(XCh烧基），其中 -37- 123505 200815422 烷基係視情況經部份或完全_化； B與D各獨立為CR或N; G為芳基或雜芳基，其中g係被一或多個R1，R2或R3取代； L1 為-C(0)NH-; L2 為共價鍵、CR，2 Ο、(CR，2 )m C(0)(CR，2 )t、(CR，2 )m C(0)NR(CR，2 )t、 (CRf2 )m C(0)NRNR(CRf2 )t > (CRf2 )m C(NOR)(CRf2 )t A (CR?2 )m NRC(0)0-(CI^2)t基團； Q為經取代或未經取代之烷基、環烷基、芳基、雜環基、 %烧基烧基、芳烧基或雜環基烧基； 各R1係獨立為F、Cl、Br、I、-NR2、_CN，或經取代或未 經取代之烷基、烯基、炔基、環烷基、環烯基、芳基、雜 環基或雜環基烷基； 各R2係獨立為F、Cl、Br、I、-CN、-N02、經取代或未經 取代之烷基或雜環基烷基、_〇R，、-c(〇)R，、_c(〇)〇R,、 -C(0)NR,2 . -NRf2 ^ -(CR^XNRR1 > -NRC(0)Rff > ^^(0)0^» ^ -NR^SO,^· . ^C(0)NR«2 > ^C(S)NR*2 > .S(0)mR^，1.S02NR^2 ； 各R3係獨立為經取代或未經取代之烷基、烯基或炔基， 或N 0((：! M燒基），其中c1M烧基係視情況經部份或完全鹵 化； 各R係獨立為氫，或經取代或未經取代之烷基； 各R係獨立為氫，或經取代或未經取代之烷基、環烷基、 %烷基烷基、芳烷基、雜環基或雜環基烷基； 各Rn係獨立為經取代或未經取代之烷基、環烷基、芳基、 雜環基、環㈣隸、㈣基或雜環基烧基； 123505 -38- 200815422 各m係獨立為0, 1或2 ;且 t為0, 1或2。 在式II化合物之一些具體實施例中，化合物為a stereoisomer thereof, a tautomer thereof, a solvate thereof, a prodrug thereof, and a pharmaceutically acceptable salt thereof; wherein X is CH, N or NO; Y is CH, N or NO, The condition is that X and Y are not both CH or NO; A is F, Cl, Br, I, alkyl or - (XCh alkyl), wherein -37- 123505 200815422 alkyl is partially or completely _ B and D are each independently CR or N; G is an aryl or heteroaryl group, wherein g is substituted by one or more R1, R2 or R3; L1 is -C(0)NH-; L2 is a covalent bond , CR, 2 Ο, (CR, 2 ) m C(0)(CR, 2 )t, (CR, 2 ) m C(0)NR(CR, 2 ) t, (CRf2 ) m C(0)NRNR (CRf2 )t > (CRf2 )m C(NOR)(CRf2 )t A (CR?2 )m NRC(0)0-(CI^2)t group; Q is substituted or unsubstituted alkane a group, a cycloalkyl group, an aryl group, a heterocyclic group, a decyl group, an aryl group or a heterocyclic group; each R1 is independently F, Cl, Br, I, -NR2, _CN, or substituted Or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heterocyclylalkyl; each R2 is independently F, Cl, Br, I, -CN , -N02, substituted or unsubstituted alkyl or heterocyclic group Base, _〇R,, -c(〇)R,, _c(〇)〇R,, -C(0)NR,2 . -NRf2 ^ -(CR^XNRR1 > -NRC(0)Rff > ^^(0)0^» ^ -NR^SO,^· . ^C(0)NR«2 > ^C(S)NR*2 > .S(0)mR^,1.S02NR^2 Each R3 is independently a substituted or unsubstituted alkyl, alkenyl or alkynyl group, or N 0 ((:! M alkyl), wherein the c1M alkyl group is partially or completely halogenated as appropriate; Is independently hydrogen, or substituted or unsubstituted alkyl; each R is independently hydrogen, or substituted or unsubstituted alkyl, cycloalkyl, % alkylalkyl, aralkyl, heterocycle Or a heterocyclic alkyl group; each Rn is independently substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocyclic, cyclo (tetra), (tetra) or heterocyclyl; 123505 -38 - 200815422 each m is independently 0, 1 or 2; and t is 0, 1 or 2. In some embodiments of the compound of formula II, the compound is

在其他具體實施例中，化合物為In other specific embodiments, the compound is

所有下列化合物係意欲被式II涵蓋在内：All of the following compounds are intended to be covered by Formula II:

ΙΙ-Ε II-F ll-G II-HΙΙ-Ε II-F ll-G II-H

123505 -39 200815422123505 -39 200815422

〆 % 在式II化合物之一些具體實施例中，B為N。在其他具體 實施例中，D為N。在又其他具體實施例中，A為F、-CH3 或-CF3 〇 在一些具體實施例中，G為苯基、嘧啶基或吡啶基。在 其他具體實施例中，G為〆 % In some embodiments of the compound of formula II, B is N. In other specific embodiments, D is N. In still other specific embodiments, A is F, -CH3 or -CF3". In some embodiments, G is phenyl, pyrimidinyl or pyridyl. In other embodiments, G is

在一些具體實施例中，L2為共價鍵、C(O)、CH20、 C(0)NHNH、C(NOH)或 C(0)NH 〇 在其他具體實施例中，Q為經取代或未經取代之烷基、 環烷基、10-氧-4-氮-三環并[5.2.1.02,6]癸基、8-氧-3-氮-雙環并 123505 -40- 200815422 [3·2·1]辛烷基、（CG_4烷基）環烷基、（C〇_4烷基）苯基、（CG_4烷 基Η啶基、（CG_4烷基）嘴啶基、（CG_4烷基）喂啶基、（CG_4烷 基）嗎福啉基、（C〇_4烷基）硫代嗎福啉基、（C〇_4烷基）四氫哌 喃基、（CQ_4烷基）四氫呋喃基、（C〇_4烷基）四氫吡咯基、（C〇_4 烷基）六氫吡啶基或（CG_4烷基）六氫吡畊基。例如，Q為經取 代或未經取代之甲基、乙基、正-丙基、異丙基、正-丁基、 第三-丁基、第二-丁基、異丁基、新戊基、環丙基、（CH2)-環丙基、（ch2)2-環丙基、（ch2)3-環丙基、環丁基、（ch2)-環 丁基、（CH2)2-環丁基、（CH2)3-環丁基、環戊基、（CH2)-環戊 基、（CH2)2-環戊基、（CH2)3-環戊基、環己基、（CH2)-環己基、 (CH2)2-環己基、（CH2)3-環己基、雙環并[2·2·1]庚烷基、（CH2) 雙環并[2.2.1]庚烷基、（CH2)2雙環并[2.2.1]庚烷基、（CH2)3雙環 并[2.2.1]庚烷基、環庚基、苯基、苄基、苯乙基、2-吡啶基、 (CH2 )-2-吡啶基、（CH2 )2 -2·吡啶基、（CH2 )3 -2-吡啶基、3-吡啶基、 (CH2)-3-吡啶基、（CH2)2-3-吡啶基、（CH2)3-3-吡啶基、4-吡啶基、 (CH2 )-4-吡啶基、（CH2 )2-4-吡啶基、（CH2 )3-4-吡啶基、嗝啶基、 (CH2)-嗝啶基、（CH2)2-喵啶基、（CH2)3-嗝啶基、10-氧-4-氮-三 環并[5.2.1.02,6]癸基、8-氧-3-氮·雙環并[3.2.1]辛烷基、四氫呋 喃基、（CH2)-四氫咬喃基、（CH2 )2 -四氫咬喃基、（CH〗)3 四氫 咬喃基、四氮味喃基、（CH2)-四氮岐ϋ南基、（CH〗)2 -四氮11瓜喃 基、（CH2 )3 -四氫旅喃基、四氫卩比洛基、（CH2)-四氫卩比洛基、 (CH2 )2 -四氫卩比洛基、（CH2 )3 -四氫卩比洛基、六氫卩比p井基、（CH2 )-六氫吡畊基、（CH2)2-六氫吡畊基、（CH2)3·六氫吡畊基、六氫 外匕咬基、（CH2)-六氫p比咬基、（CH2)2-六氫叶定基、（CH2)3-六 123505 -41 - 200815422 氫外1： σ定基、嗎福琳基、（CH2)-嗎福淋基、（CH2 )2 -嗎福p林基或 (CH2 )3 -嗎福琳基。 在式II化合物之一些具體實施例中，R1為F、_CN、-NR2， 或經取代或未經取代之(^_4烷基、C3-9環烷基、雜環基或雜 環基烷基。例如，R1為F、-CN、-N(Ci -3烷基)2，其中各q _3 烷基係獨立為經取代或未經取代；或R1為經取代或未經取 代之曱基、異丙基、第三-丁基、異丁基、第二-丁基、新戊 基、環己基、四氫p比洛基、味ϋ坐基、说ϋ坐基、三嗅基、酮 基二ϋ坐基、異0号峻基、2,3-二氫異$嗤基、六氫ρ比淀基、六 氫吡畊基、氧氮七圜基、嗎福啉基、硫代嗎福啉基、（CH2)-四氫吡咯基、（CH2)-六氫吡啶基、（CH2)-氧氮七圜基、（CH2)-嗎福啉基或（CH2)-六氫吡畊基。 在其他具體實施例中，R2為經取代或未經取代之（q _6烷 基）或雜環基烷基、F、Cl、-CN、-N02、-OR’、-C(0)0R’、 -C(0)NR，，2、_(CH2)tNRR’，、-NRC(0)R，、-NRC(0)0R，，、-NR，S02R"、 -NR，C(0)NR，2 或-S02NR’2。例如，R2為 F、-CN、-CF3、-N02、 -0(4-6烷基）、-C(0)0(Cp6烷基）、-C(0)NH2、-C(0)NH(C卜6 烷 基）、-C(0)NH(C3_6 環烷基）[〇]、-C(0)NH(環烷基烷基）[〇]、 -C(0)NH(芳烷基）、-(ch2)NH(Ch 烷基）、-(CH2)NH(芳烷基）、 -(CH2 )NH(雜環基烷基）…· 6 烷基）_ 6 環 烧基）、-NHC(〇)(環烷基烷基）、-NHC(0)(芳基）、-NHC⑼(芳烷 基）、-NHS〇2(Cl·6 烷基）、-NHSCMC：3·6 環烷基）、-nhso2(環烷 基烧基）、-丽8〇2(芳基）、-nhso2(芳烷基）、-S〇2nh(Ci_6烷 基）、-S〇2NH(C3·6環烷基）、-SC^NH(環烷基烷基）、_s〇2NH(芳 123505 -42- 200815422 基）4_s〇2NH(芳烷基），其中各c 烷美、 ^ T分^卜6况丞、C3·6環烷基、環烷 基烷基、芳基及芳烷基係為經取代或未經取代。 在又其他具體實施例中，R3為經取代或未經取代之Cl Μ 烷基或-Ο%—4烷基），或為經部份或完全鹵化之_〇(c^烷 基）。 在式II之一些具體貫施例中，G為苯基，且Rl為F、α、 -CN、-Nf^3烷基L，其中各Cl s烷基係獨立為經取代或未 經取代’或R為經取代或未經取代之嗎福淋基、硫代嗎福 啉基、四氫吡咯基、咪唑基、吡唑基、三唑基、酮基二唾 基、異吟唾基、2,3-二氫異号唑基、六氫峨σ定基、六氫吡畊 基、氧氮七圜基、（CH2)-四氫吡咯基、（ch2)-六氫吡啶基、（ch2> 氧氮七圜基、（CH2)-嗎福啉基、（ch2)-六氫吡呼基、甲基、 異丙基、苐二-丁基、異丁基、弟二-丁基或環己基。在'atb 此種具體實施例中，R1為F、Cl、經取代或未經取代之嗎福 淋基、四氫P比洛基、味tl坐基、u比唾基 '三σ坐基、酮基二嗤 基、異哼唑基、2,3-二氫異嘮唑基、六氫吡啶基、（ch2)-四 氫吡咯基、（CH2)-六氫吡啶基、（CH2)-嗎福啉基、（CH2)-六氫 竹匕p井基、甲基、第三-丁基或環己基。在其他具體實施例中， R2 為 F、-CN、-CF3、-N02、-CKCh烷基）、-C(0)0(CV6烷基）、 -C(0)NH2、-CCC^NHCCh 烷基）、-C(0)NH(C3-6 環烷基）、 -C(0)NH(環烷基烷基）、-C(0)NH(芳烷基）、-NHCXOXCi - 6 烷基）、 -NHC(0)(C3-6 環烷基）、-NHC(0)(環烷基烷基）、-NHC(0)(芳 基）、-NHC(0)(芳烷基）、-(CHJM^Ch 烷基）、-(CH2)NH(芳烷 基）、-(CH2)NH(雜環基烷基）、-NHSOJCu烷基）、-NHS02(C3-6 123505 -43- 200815422 環烷基）、-nhso2(環烷基烷基）、-nhso2(芳基）、-nhso2(芳 烷基）、-802ΝΗ((^-6烷基）、-S02NH(C3_6環烷基）、-S02NH(環 烷基烷基）、-S02NH(芳基）或-S02NH(芳烷基），其中各Ci_6 烷基、c3_6環烷基、環烷基烷基、芳基及芳烷基係為經取 代或未經取代。例如，R2為F、-CN、-CF3、-C(0)NH2、 -C(0)NH(C卜 6 烷基）、-C(0)NH(C3 - 6 環烷基）[0]、-C(0)NH(環烷基 烷基）[0]、-(CHJNI^Ch 烷基）、-(CH2)NH(雜環基烷基）、 -NHSOdCu烷基）或-SC^NI^Cu烷基），其中各CV6烷基係為 經取代或未經取代。在其他具體實施例中，R3為經取代或 未經取代之（^_4烷基或-0((^ _4烷基），或為經部份或完全鹵 化之-0((^-2烷基）。 在式II化合物之一些具體實施例中，L2為鍵結、CH20、 C(O)、C(0)0、C(0)NH、C(0)NHNH、C(NOR)或 C(CH3)2C(0)NH， 且Q為In some embodiments, L2 is a covalent bond, C(O), CH20, C(0)NHNH, C(NOH), or C(0)NH 〇 In other embodiments, Q is substituted or not Substituted alkyl, cycloalkyl, 10-oxo-4-nitro-tricyclo[5.2.1.02,6]decyl, 8-oxo-3-nitro-bicyclo and 123505-40- 200815422 [3·2 1] octyl, (CG 4 alkyl)cycloalkyl, (C〇_4 alkyl)phenyl, (CG 4 alkyl acridine, (CG 4 alkyl) sulfinyl, (CG 4 alkyl) Pyridyl, (CG 4 alkyl) oxabulin, (C 〇 4 alkyl) thiotropulin, (C 〇 4 alkyl) tetrahydropyranyl, (CQ 4 alkyl) tetrahydrofuranyl, (C〇_4 alkyl) tetrahydropyrrolyl, (C〇_4 alkyl)hexahydropyridyl or (CG-4 alkyl)hexahydropyrrole. For example, Q is a substituted or unsubstituted methyl group. , ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, second-butyl, isobutyl, neopentyl, cyclopropyl, (CH2)-cyclopropyl, (ch2) 2-cyclopropyl, (ch2)3-cyclopropyl, cyclobutyl, (ch2)-cyclobutyl, (CH2)2-cyclobutyl, (CH2)3-cyclobutyl, cyclopentyl Base, (CH2)-cyclopentyl , (CH2)2-cyclopentyl, (CH2)3-cyclopentyl, cyclohexyl, (CH2)-cyclohexyl, (CH2)2-cyclohexyl, (CH2)3-cyclohexyl, bicyclo[2] ·1·1]heptyl, (CH2)bicyclo[2.2.1]heptanyl, (CH2)2bicyclo[2.2.1]heptanyl, (CH2)3bicyclo[2.2.1]g Alkyl, cycloheptyl, phenyl, benzyl, phenethyl, 2-pyridyl, (CH2)-2-pyridyl, (CH2)2-2,pyridyl, (CH2)3-2-pyridyl , 3-pyridyl, (CH2)-3-pyridyl, (CH2)2-3-pyridyl, (CH2)3-3-pyridyl, 4-pyridyl, (CH2)-4-pyridyl, ( CH2)2-4-pyridyl, (CH2)3-4-pyridyl, acridinyl, (CH2)-acridinyl, (CH2)2-acridinyl, (CH2)3-acridinyl, 10 -oxy-4-nitro-tricyclo[5.2.1.02,6]decyl, 8-oxo-3-nitrobisbicyclo[3.2.1]octyl, tetrahydrofuranyl, (CH2)-tetrahydroethylene Base, (CH2)2-tetrahydrocarbamate, (CH)) 3 tetrahydrocarbyl, tetrazinyl, (CH2)-tetraziridine, (CH))2-tetrazine 11 Guamanyl, (CH2)3-tetrahydrobunyl, tetrahydroindole, carbazyl, (CH2)-tetrahydroindole, and (CH2)2-tetrahydropyridyl , (CH2)3-tetrahydroindolebiloyl, hexahydropyrene ratio p well base, (CH2)-hexahydropyrrole, (CH2)2-hexahydropyrrole, (CH2)3·hexahydropyridyl Plough base, hexahydro outer guanidine, (CH2)-hexahydrop ratio bite group, (CH2)2-hexahydrozetidine, (CH2)3-hexa 123505 -41 - 200815422 Hydrogen outside 1: σ-based, Fulin, (CH2)-moffipyl, (CH2)2-ifu p-linyl or (CH2)3-norfolkin. In some specific embodiments of the compound of Formula II, R1 is F, —CN, —NR 2 , or substituted or unsubstituted (^-4 alkyl, C3-9 cycloalkyl, heterocyclyl or heterocyclylalkyl) For example, R1 is F, -CN, -N(Ci -3 alkyl) 2, wherein each q _3 alkyl group is independently substituted or unsubstituted; or R 1 is a substituted or unsubstituted thiol group, Isopropyl, tert-butyl, isobutyl, second-butyl, neopentyl, cyclohexyl, tetrahydrop-pyrrolyl, miso-sodium, squat, tris-olyl, keto Diterpenoid, iso-N-thin, 2,3-dihydroiso-indenyl, hexahydro-p-aryl, hexahydropyrryl, oxynitridinyl, morpholinyl, thiofolf Polinyl, (CH2)-tetrahydropyrrolyl, (CH2)-hexahydropyridyl, (CH2)-oxoazinyl, (CH2)-morpholinyl or (CH2)-hexahydropyrrole. In other specific embodiments, R2 is substituted or unsubstituted (q-6 alkyl) or heterocyclylalkyl, F, Cl, -CN, -N02, -OR', -C(0)0R' -C(0)NR,,2,_(CH2)tNRR',, -NRC(0)R,, -NRC(0)0R,,,-NR,S02R", -NR,C(0)NR , 2 or -S02NR'2. For example , R2 is F, -CN, -CF3, -N02, -0(4-6 alkyl), -C(0)0(Cp6 alkyl), -C(0)NH2, -C(0)NH( C 6 alkyl), -C(0)NH(C3_6 cycloalkyl)[〇], -C(0)NH(cycloalkylalkyl)[〇], -C(0)NH(aralkyl ), -(ch2)NH(Ch alkyl), -(CH2)NH(aralkyl), -(CH2)NH(heterocyclylalkyl).... 6 alkyl)-6 (cycloalkyl), - NHC(〇)(cycloalkylalkyl), -NHC(0)(aryl), -NHC(9)(aralkyl), -NHS〇2(Cl·6 alkyl), -NHSCMC:3·6 naphthenic Base), -nhso2 (cycloalkylalkyl), -Li 8〇2 (aryl), -nhso2(aralkyl), -S〇2nh(Ci_6 alkyl), -S〇2NH (C3·6 ring) Alkyl), -SC^NH(cycloalkylalkyl), _s〇2NH (aryl 123505 -42- 200815422) 4_s〇2NH(aralkyl), wherein each c is alkane, ^T is divided into 6 The hydrazine, C3.6 cycloalkyl, cycloalkylalkyl, aryl and aralkyl groups are substituted or unsubstituted. In still other embodiments, R3 is substituted or unsubstituted Cl 烷基 alkyl or -Ο%-4 alkyl, or is partially or fully halogenated _ c (c alkyl). In some specific embodiments of Formula II, G is phenyl, and R1 is F, α, -CN, -Nf^3 alkyl L, wherein each Cl s alkyl group is independently substituted or unsubstituted' Or R is substituted or unsubstituted wholfolide, thiomorpholine, tetrahydropyrrolyl, imidazolyl, pyrazolyl, triazolyl, keto-di-salyl, iso-indolyl, 2 , 3-dihydroisoxazolyl, hexahydropyridinium, hexahydropyridinyl, oxynitridinyl, (CH2)-tetrahydropyrrolyl, (ch2)-hexahydropyridyl, (ch2> oxygen Aziridine, (CH2)-morpholinyl, (ch2)-hexahydropyrhyl, methyl, isopropyl, decyl-butyl, isobutyl, di-butyl or cyclohexyl. In a specific embodiment of 'atb, R1 is F, Cl, substituted or unsubstituted wholfolide, tetrahydro P-l-l base, taste tl-based, u-salt-tris-sine, Keto-dimercapto, isoxazolyl, 2,3-dihydroisoxazolyl, hexahydropyridyl, (ch2)-tetrahydropyrrolyl, (CH2)-hexahydropyridyl, (CH2)-? Florinyl, (CH2)-hexahydropyrene, well, methyl, tert-butyl or cyclohexyl. In other embodiments, R2 is F, -CN, -CF3, -N02, -CKCh alkyl), -C(0)0(CV6 alkyl), -C(0)NH2, -CCC^NHCCh alkyl), -C(0 NH(C3-6 cycloalkyl), -C(0)NH(cycloalkylalkyl), -C(0)NH(aralkyl), -NHCXOXCi-6 alkyl), -NHC(0) (C3-6 cycloalkyl), -NHC(0)(cycloalkylalkyl), -NHC(0)(aryl), -NHC(0)(aralkyl), -(CHJM^Ch alkyl ), -(CH2)NH(aralkyl), -(CH2)NH(heterocyclylalkyl), -NHSOJCualkyl), -NHS02 (C3-6 123505 -43-200815422 cycloalkyl), -nhso2 (cycloalkylalkyl), -nhso2(aryl), -nhso2(aralkyl), -802ΝΗ((^-6 alkyl), -S02NH(C3_6cycloalkyl), -S02NH(cycloalkylane a group, -S02NH(aryl) or -S02NH(aralkyl), wherein each Ci_6 alkyl, c3-6 cycloalkyl, cycloalkylalkyl, aryl and aralkyl is substituted or unsubstituted. For example, R2 is F, -CN, -CF3, -C(0)NH2, -C(0)NH(Cb6 alkyl), -C(0)NH(C3-6cycloalkyl)[0] , -C(0)NH(cycloalkylalkyl)[0], -(CHJNI^Ch alkyl), -(CH2)NH(heterocyclylalkyl), -NHSOdCualkyl) or -SC^NI ^Cu alkyl), where CV6 alkyl type substituted or unsubstituted. In other specific embodiments, R3 is substituted or unsubstituted (^-4 alkyl or -0((^_4 alkyl), or is partially or fully halogenated-0 ((^-2 alkyl) In some specific embodiments of the compound of Formula II, L2 is a bond, CH20, C(O), C(0)0, C(0)NH, C(0)NHNH, C(NOR), or C( CH3) 2C(0)NH, and Q is

123505 -44- 200815422123505 -44- 200815422

在一些此種具體實施例中，B血η去x /、D為Ν。在一些其他此種In some such embodiments, B blood η goes to x /, D is Ν. In some other such

具體實施例中，G為苯基。 在式II化合物之一些具體實施例中，於1〇 _濃度下之化 合物會抑制自細胞所引致之TNFi釋出，達約5〇%或大於 50〇/〇 〇 如前述’表3係列示如本文中所述式II之G與含B，D環之 各種組合，然而表4係描述L2與Q之各種組合。 123505 -45- 200815422 表3 ··關於式II之G與含B，D環之舉例組合 X 環\\ 芳 基 雜 芳 基 苯 基 口密 啶 基 口比 啶 基 Λ R3 Λ R3 Λ R3 Q 3000 3001 3002 3003 3004 3005 3006 3007 3008 3009 3010 3011 3012 3013 3014 3015 n^d R 3016 3017 3018 3019 3020 3021 3022 3023 3024 3025 3026 3027 3028 3029 3030 3031 3032 3033 3034 3035 3036 3037 3038 3039 3040 3041 3042 3043 3044 3045 3046 3047 Q 3048 3049 3050 3051 3052 3053 3054 3055 iQn R 3056 3057 3058 3059 3060 3061 3062 3063 R 3064 3065 3066 3067 3068 3069 3070 3071 表4.關於式II之L2與Q之舉例組合 [\ & 〇 〇 Q to 〇 Q K) Q o o K) to n § o K> s to n 〇 S Q to s K> z o 〇 N) o 〇 o 1 § n 〇 n 1 X 3500 3501 3502 3503 3504 3505 3506 3507 3508 3509 3510 3511 環烷基 3512 3513 3514 3515 3516 3517 3518 3519 3520 3521 3522 3523 芳基 3524 3525 3526 3527 3528 3529 3530 3531 3532 3533 3534 3535 雜環基 3536 3537 3538 3539 3540 3541 3542 3543 3544 3545 3546 3547 123505 -46- 200815422In a particular embodiment, G is phenyl. In some embodiments of the compound of formula II, the compound at a concentration of 1 〇 _ inhibits the release of TNFi from the cell, up to about 5 % or more than 50 〇 / 〇〇 as described in the above table 3 The G of Formula II described herein is in combination with various B and D containing rings, while Table 4 describes various combinations of L2 and Q. 123505 -45- 200815422 Table 3 ··················································· 3001 3002 3003 3004 3005 3006 3007 3008 3009 3010 3011 3012 3013 3014 3015 n^d R 3016 3017 3018 3019 3020 3021 3022 3023 3024 3025 3026 3027 3028 3029 3030 3031 3032 3033 3034 3035 3036 3037 3038 3039 3040 3041 3042 3043 3044 3045 3046 3047 Q 3048 3049 3050 3051 3052 3053 3054 3055 iQn R 3056 3057 3058 3059 3060 3061 3062 3063 R 3064 3065 3066 3067 3068 3069 3070 3071 Table 4. Example combination of L2 and Q for Equation II [\ & 〇〇Q to 〇QK) Q oo K) to n § o K> s to n 〇SQ to s K> zo 〇N) o 〇o 1 § n 〇n 1 X 3500 3501 3502 3503 3504 3505 3506 3507 3508 3509 3510 3511 Base 3512 3513 3514 3515 3516 3517 3518 3519 3520 3521 3522 3523 aryl 3524 3525 3526 3527 3528 3529 3530 3531 3532 3533 3534 3535 Heterocyclyl 3536 3537 3538 3539 3540 3541 3542 3543 3544 3545 3546 3547 123505 -46- 20 0815422

\ 〇 〇 to* p Ο to 0 1 K)^ Q K) n i n K) n K) n 〇 Q K) Q K) Z o p n to* o n o 〇 § n 〇 〇 I ffi 環烷基烷基 3548 3549 3550 3551 3552 3553 3554 3555 3556 3557 3558 3559 芳烷基 3560 3561 3562 3563 3564 3565 3566 3567 3568 3569 3570 3571 雜環基烷基 3572 3573 3574 3575 3576 3577 3578 3579 3580 3581 3582 3583 10-氧-4-氮-三環并 [5.2.1.02,6] 癸基 3584 3585 3586 3587 3588 3589 3590 3591 3592 3593 3594 3595 8-氧-3-氮-雙 環并[3.2.1] 辛烷基 3596 3597 3598 3599 3600 3601 3602 3603 3604 3605 3606 3607 (C0_4烷基） 環烷基 3608 3609 3610 3611 3612 3613 3614 3615 3616 3617 3618 3619 (C〇 _ 4烧基） 苯基 3620 3621 3622 3623 3624 3625 3626 3627 3628 3629 3630 3631 (C0 _ 4烧基） 外匕咬基 3632 3633 3634 3635 3636 3637 3638 3639 3640 3641 3642 3643 (C〇 _ 4烧基） 定基 3644 3645 3646 3647 3648 3649 3650 3651 3652 3653 3654 3655 (C〇 _ 4炫基） 嗝啶基 3656 3657 3658 3659 3660 3661 3662 3663 3664 3665 3666 3667 (c0-4烷基） 嗎福淋基 3668 3669 3670 3671 3672 3673. 3674 3675 3676 3677 3678 3679 (c0_4烷基） 硫代嗎福 淋基 3680 3681 3682 3683 3684 3685 3686 3687 3688 3689 3690 3691 (C〇_4烷基） 四氫喊喃基 3692 3693 3694 3695 3696 3697 3698 3699 3700 3701 3702 3703 (c0-4烷基） 四氫吱喃基 3704 3705 3706 3707 3708 3709 3710 3711 3712 3713 3714 3715 (c0.4烷基） 四氫卩比哈基 3716 3717 3718 3719 3720 3721 3722 3723 3724 3725 3726 3727 123505 -47- 200815422 \ & ΠΨ 〇 K) 〇 η Κ) η Κ) K) η 1 Κ) to η | 麵 〇 Κ) K) 〇 〇 R to 穴 η η Κ) 〇 〇 η X Κ) ο Ο § 53 Ο Ο S Ο X (c0_4烷基） 六氫P比唆基 3728 3729 3730 3731 3732 3733 3734 3735 3736 3737 3738 3739 (C〇_4烷基） 六氫吡畊基 3740 3741 3742 3743 3744 3745 3746 3747 3748 3749 3750 3751 甲基 3752 3753 3754 3755 3756 3757 3758 3759 3760 3761 3762 3763 乙基 3764 3765 3766 3767 3768 3769 3770 3771 3772 3773 3774 3775 正-丙基 3776 3777 3778 3779 3780 3781 3782 3783 3784 3785 3786 3787 異丙基 3788 3789 3790 3791 3792 3793 3794 3795 3796 3797 3798 3799 正-丁基 3800 3801 3802 3803 3804 3805 3806 3807 3808 3809 3810 3811 第三-丁基 3812 3813 3814 3815 3816 3817 3818 3819 3820 3821 3822 3823 第二-丁基 3824 3825 3826 3827 3828 3829 3830 3831 3832 3833 3834 3835 異丁基 3836 3837 3838 3839 3840 3841 3842 3843 3844 3845 3846 3847 新戊基 3848 3849 3850 3851 3852 3853 3854 3855 3856 3857 3858 3859 環丙基 3860 3861 3862 3863 3864 3865 3866 3867 3868 3869 3870 3871 (CH2)- 環丙基 3872 3873 3874 3875 3876 3877 3878 3879 3880 3881 3882 3883 (CH2)2- 環丙基 3884 3885 3886 3887 3888 3889 3890 3891 3892 3893 3894 3895 (CH2)3· 環丙基 3896 3897 3898 3899 3900 3901 3902 3903 3904 3905 3906 3907 環丁基 3908 3909 3910 3911 3912 3913 3914 3915 3916 3917 3918 3919 (ch2)- 環丁基 3920 3921 3922 3923 3924 3925 3926 3927 3928 3929 3930 3931 (CH2)2- 環丁基 3932 3933 3934 3935 3936 3937 3938 3939 3940 3941 3942 3943 (CH2)3- 環丁基 3944 3945 3946 3947 3948 3949 3950 3951 3952 3953 3954 3955 環戊基 3956 3957 3958 3959 3960 3961 3962 3963 3964 3965 3966 3967 (ch2)- 環戊基 3968 3969 3970 3971 3972 3973 3974 3975 3976 3977 3978 3979 123505 -48- 200815422 \ % 〇 〇 S K) η to" s to O K) § 〇 K)' 〇 〇 s K) kT S K) 〇 n o 〇 § n o a 〇 1 E (CH2)2- 環戊基 3980 3981 3982 3983 3984 3985 3986 3987 3988 3989 3990 3991 (ch2)3- 環戊基 3992 3993 3994 3995 3996 3997 3998 3999 4000 4001 4002 4003 環己基 4004 4005 4006 4007 4008 4009 4010 4011 4012 4013 4014 4015 (CH2)- 環己基 4016 4017 4018 4019 4020 4021 4022 4023 4024 4025 4026 4027 (ch2)2- 環己基 4028 4029 4030 4031 4032 4033 4034 4035 4036 4037 4038 4039 (CH2)3- 環己基 4040 4041 4042 4043 4044 4045 4046 4047 4048 4049 4050 4051 雙環并[2.2.1] 庚烧基 4052 4053 4054 4055 4056 4057 4058 4059 4060 4061 4062 4063 (ch2)- 雙環并[2.2.1] 庚烧基 4064 4065 4066 4067 4068 4069 4070 4071 4072 4073 4074 4075 (ch2)2- 雙環并[2.2.1] 庚烷基 4076 4077 4078 4079 4080 4081 4082 4083 4084 4085 4086 4087 (CH2)3-雙環并[2.2.1] 庚烷基 4088 4089 4090 4091 4092 4093 4094 4095 4096 4097 4098 4099 環庚基 4100 4101 4102 4103 4104 4105 4106 4107 4108 4109 4110 4111 苯基 4112 4113 4114 4115 4116 4117 4118 4119 4120 4121 4122 4123 卞基 4124 4125 4126 4127 4128 4129 4130 4131 4132 4133 4134 4135 苯乙基 4136 4137 4138 4139 4140 4141 4142 4143 4144 4145 4146 4147 2-吡啶基 4148 4149 4150 4151 4152 4153 4154 4155 4156 4157 4158 4159 (CH2)-2-叶匕咬基 4160 4161 4162 4163 4164 4165 4166 4167 4168 4169 4170 4171 (CH2)2-2- 吡啶基 4172 4173 4174 4175 4176 4177 4178 4179 4180 4181 4182 4183 -49- 123505 200815422 \ πτ η Κ) 〇 8 to Ο ο 3 Κ) Q Κ) η ο ο Κ) s K) o § o K> s K) o O s K) p O p o K) n 〇 〇 o 〇 § K 〇 〇 〇 1 (CH2 )3-2-外匕咬基 4184 4185 4186 4187 4188 4189 4190 4191 4192 4193 4194 4195 3-吡啶基 4196 4197 4198 4199 4200 4201 4202 4203 4204 4205 4206 4207 (CH2)-3-外匕。定基 4208 4209 4210 4211 4212 4213 4214 4215 4216 4217 4218 4219 (CH2)2-3- 叶匕σ定基 4220 4221 4222 4223 4224 4225 4226 4227 4228 4229 4230 4231 (CH2)3-3- 吡啶基 4232 4233 4234 4235 4236 4237 4238 4239 4240 4241 4242 4243 4-^σ定基 4244 4245 4246 4247 4248 4249 4250 4251 4252 4253 4254 4255 (CH2)-4-外匕唆基 4256 4257 4258 4259 4260 4261 4262 4263 4264 4265 4266 4267 (CH2 )2-4-叶匕咬基 4268 4269 4270 4271 4272 4273 4274 4275 4276 4277 4278 4279 (CH2 )3-4-叶匕。定基 4280 4281 4282 4283 4284 4285 4286 4287 4288 4289 4290 4291 嗝啶基 4292 4293 4294 4295 4296 4297 4298 4299 4300 4301 4302 4303 (CH2> 17昆唆基 4304 4305 4306 4307 4308 4309 4310 4311 4312 4313 4314 4315 (CH2)2. 琨啶基 4316 4317 4318 4319 4320 4321 4322 4323 4324 4325 4326 4327 (ch2)3- p昆咬基 4328 4329 4330 4331 4332 4333 4334 4335 4336 4337 4338 4339 10-氧-4-氮_ 三環并 [5.2.1.02,6] 癸基 4340 4341 4342 4343 4344 4345 4346 4347 4348 4349 4350 4351 8-氧-3-氮-雙環并[3.2.1] 辛烧基 4352 4353 4354 4355 4356 4357 4358 4359 4360 4361 4362 4363 四氫呋喃基 4364 4365 4366 4367 4368 4369 4370 4371 4372 4373 4374 4375 -50- 123505 200815422 \ tw 〇 K) 〇 Ο Ο Κ) Κ) η η to (W to' Ο § η κΤ 9 Κ) Ο 1 5 S κ> Q Ν) 1 ο η Ν) Ο Ο ο Ο η % § Ο Ο X % X (ch2)- 四氫呋喃基 4376 4377 4378 4379 4380 4381 4382 4383 4384 4385 4386 4387 (CH2)2-四氫呋喃基 4388 4389 4390 4391 4392 4393 4394 4395 4396 4397 4398 4399 (CH2)3-四氫呋喃基 4400 4401 4402 4403 4404 4405 4406 4407 4408 4409 4410 4411 四氫哌喃基 4412 4413 4414 4415 4416 4417 4418 4419 4420 4421 4422 4423 (CH2). 四氫哌喃基 4424 4425 4426 4427 4428 4429 4430 4431 4432 4433 4434 4435 (ch2)2_ 四氫哌喃基 4436 4437 4438 4439 4440 4441 4442 4443 4444 4445 4446 4447 (CH2)3-四氫哌喃基 4448 4449 4450 4451 4452 4453 4454 4455 4456 4457 4458 4459 四氫外1^各基 4460 4461 4462 4463 4464 4465 4466 4467 4468 4469 4470 4471 (ch2)- 四氫吡咯基 4472 4473 4474 4475 4476 4477 4478 4479 4480 4481 4482 4483 (CH2)2-四氫卩比洛基 4484 4485 4486 4487 4488 4489 4490 4491 4492 4493 4494 4495 (CH2)3-四氫吡咯基 4496 4497 4498 4499 4500 4501 4502 4503 4504 4505 4506 4507 六氫吡畊基 4508 4509 4510 4511 4512 4513 4514 4515 4516 4517 4518 4519 (CH2)-六氫井基 4520 4521 4522 4523 4524 4525 4526 4527 4528 4529 4530 4531 (CH2)2-六氫吡畊基 4532 4533 4534 4535 4536 4537 4538 4539 4540 4541 4542 4543 (CH2)3-六氫吡畊基 4544 4545 4546 4547 4548 4549 4550 4551 4552 4553 4554 4555 六氫定基 4556 4557 4558 4559 4560 4561 4562 4563 4564 4565 4566 4567 (CH2)-六氫P比咬基 4568 4569 4570 4571 4572 4573 4574 4575 4576 4577 4578 4579 123505 -51 - 200815422 \ 〇 K) 〇 S K) Ο /g 8 Κ) 3 Κ) Ο 1 μ， κΤ 麵 ο η Κ) S to η ο 3 νΤ κΤ § Ο /pN κΤ Ο Ο Ο 1 § ffi η ο κ Ο Ε (ch2)2- 六氫吡啶基 4580 4581 4582 4583 4584 4585 4586 4587 4588 4589 4590 4591 (ch2 )3 _ 六氫吡啶基 4592 4593 4594 4595 4596 4597 4598 4599 4600 4601 4602 4603 嗎福P林基 4604 4605 4606 4607 4608 4609 4610 4611 4612 4613 4614 4615 (CH2> 嗎福P林基 4616 4617 4618 4619 4620 4621 4622 4623 4624 4625 4626 4627 (CH2)2-嗎福w林基 4628 4629 4630 4631 4632 4633 4634 4635 4636 4637 4638 4639 (CH2 )3 -3啉基 4640 4641 4642 4643 4644 4645 4646 4647 4648 4649 4650 4651\ 〇〇to* p Ο to 0 1 K)^ QK) nin K) n K) n 〇QK) QK) Z opn to* ono 〇§ n 〇〇I ffi cycloalkylalkyl 3548 3549 3550 3551 3552 3553 3554 3555 3556 3557 3558 3559 Aralkyl 3560 3561 3562 3563 3564 3565 3566 3567 3568 3569 3570 3571 Heterocyclylalkyl 3572 3573 3574 3575 3576 3577 3578 3579 3580 3581 3582 3583 10-oxo-nitrogen-tricyclo[ 5.2.1.02,6] sulfhydryl 3584 3585 3586 3587 3588 3589 3590 3591 3592 3593 3594 3595 8-oxo-3-nitro-bicyclo[3.2.1] octyl 3596 3597 3598 3599 3600 3601 3602 3603 3604 3605 3606 3607 (C0_4 alkyl) cycloalkyl 3608 3609 3610 3611 3612 3613 3614 3615 3616 3617 3618 3619 (C〇_ 4 alkyl) phenyl 3620 3621 3622 3623 3624 3625 3626 3627 3628 3629 3630 3631 (C0 _ 4 alkyl) Bite base 3632 3633 3634 3635 3636 3637 3638 3639 3640 3641 3642 3643 (C〇_ 4 burning base) Dingli 3644 3645 3646 3647 3648 3649 3650 3651 3652 3653 3654 3655 (C〇_ 4 dyl) Acridine 3656 3657 3658 3659 3660 3661 3662 3663 3664 3665 3666 3667 (c0-4 alkyl)淋基3668 3669 3670 3671 3672 3673. 3674 3675 3676 3677 3678 3679 (c0_4 alkyl) thiotropinol 3680 3681 3682 3683 3684 3685 3686 3687 3688 3689 3690 3691 (C〇_4 alkyl) tetrahydron Base 3692 3693 3694 3695 3696 3697 3698 3699 3700 3701 3702 3703 (c0-4 alkyl) Tetrahydrofuranyl 3704 3705 3706 3707 3708 3709 3710 3711 3712 3713 3714 3715 (c0.4 alkyl) Tetrahydropyrene 3716 3717 3718 3719 3720 3721 3722 3723 3724 3725 3726 3727 123505 -47- 200815422 \ & ΠΨ )K) 〇η Κ) η Κ) K) η 1 Κ) to η | 〇Κ)) K) 〇〇R to Ηη η Κ) 〇〇η X Κ) ο Ο § 53 Ο Ο S Ο X (c0_4 alkyl) HexahydroP 唆 3 3728 3729 3730 3731 3732 3733 3734 3735 3736 3737 3738 3739 (C〇_4 alkyl Hexahydropyrazine 3740 3741 3742 3743 3744 3745 3746 3747 3748 3749 3750 3751 Methyl 3752 3753 3754 3755 3756 3757 3758 3759 3760 3761 3762 3763 Ethyl 3764 3765 3766 3767 3768 3769 3770 3771 3772 3773 3774 3775 n-propyl 3776 3777 3778 3779 3780 3781 3782 3783 3784 3785 3786 3 787 isopropyl 3788 3789 3790 3791 3792 3793 3794 3795 3796 3797 3798 3799 n-butyl 3800 3801 3802 3803 3804 3805 3806 3807 3808 3809 3810 3811 third-butyl 3812 3813 3814 3815 3816 3817 3818 3819 3820 3821 3822 3823 Di-butyl 3824 3825 3826 3827 3828 3829 3830 3831 3832 3833 3834 3835 Isobutyl 3836 3837 3838 3839 3840 3841 3842 3843 3844 3845 3846 3847 Neopentyl 3848 3849 3850 3851 3852 3853 3854 3855 3856 3857 3858 3859 Cyclopropyl 3860 3861 3862 3863 3864 3865 3866 3867 3868 3869 3870 3871 (CH2)-cyclopropyl 3872 3873 3874 3875 3876 3877 3878 3879 3880 3881 3882 3883 (CH2)2-cyclopropyl 3884 3885 3886 3887 3888 3889 3890 3891 3892 3893 3894 3895 (CH2)3·cyclopropyl 3896 3897 3898 3899 3900 3901 3902 3903 3904 3905 3906 3907 cyclobutyl 3908 3909 3910 3911 3912 3913 3914 3915 3916 3917 3918 3919 (ch2)-cyclobutyl 3920 3921 3922 3923 3924 3925 3926 3927 3928 3929 3930 3931 (CH2)2-cyclobutyl 3932 3933 3934 3935 3936 3937 3938 3939 3940 3941 3942 3943 (CH2)3-cyclobutyl 3944 3 945 3946 3947 3948 3949 3950 3951 3952 3953 3954 3955 Cyclopentyl 3956 3957 3958 3959 3960 3961 3962 3963 3964 3965 3966 3967 (ch2)- Cyclopentyl 3968 3969 3970 3971 3972 3973 3974 3975 3976 3977 3978 3979 123505 -48- 200815422 \ % 〇〇SK) η to" s to OK) § 〇K)' 〇〇s K) kT SK) 〇no 〇§ noa 〇1 E (CH2)2-cyclopentyl 3980 3981 3982 3983 3984 3985 3986 3987 3988 3989 3990 3991 (ch2)3-cyclopentyl 3992 3993 3994 3995 3996 3997 3998 3999 4000 4001 4002 4003 cyclohexyl 4004 4005 4006 4007 4008 4009 4010 4011 4012 4013 4014 4015 (CH2)- cyclohexyl 4016 4017 4018 4019 4020 4021 4022 4023 4024 4025 4026 4027 (ch2)2-cyclohexyl 4028 4029 4030 4031 4032 4033 4034 4035 4036 4037 4038 4039 (CH2)3-cyclohexyl 4040 4041 4042 4043 4044 4045 4046 4047 4048 4049 4050 4051 double ring and [2.2.1 ] heptyl 4052 4053 4054 4055 4056 4057 4058 4059 4060 4061 4062 4063 (ch2)-bicyclo[2.2.1] heptyl 4064 4065 4066 4067 4068 4069 4070 4071 4072 4073 4074 4075 (ch2)2-bicyclo[ 2.2.1] Alkyl 4076 4077 4078 4079 4080 4081 4082 4083 4084 4085 4086 4087 (CH2)3-bicyclo[2.2.1]heptyl 4088 4089 4090 4091 4092 4093 4094 4095 4096 4097 4098 4099 Cycloheptyl 4100 4101 4102 4103 4104 4105 4106 4107 4108 4109 4110 4111 phenyl 4112 4113 4114 4115 4116 4117 4118 4119 4120 4121 4122 4123 卞 4124 4125 4126 4127 4128 4129 4130 4131 4132 4133 4134 4135 phenylethyl 4136 4137 4138 4139 4140 4141 4142 4143 4144 4145 4146 4147 2 -pyridyl 4148 4149 4150 4151 4152 4153 4154 4155 4156 4157 4158 4159 (CH2)-2-leaf bite base 4160 4161 4162 4163 4164 4165 4166 4167 4168 4169 4170 4171 (CH2) 2-2- Pyridyl 4172 4173 4174 4175 4176 4177 4178 4179 4180 4181 4182 4183 -49- 123505 200815422 \ πτ η Κ) 〇8 to Ο ο 3 Κ) Q Κ) η ο ο Κ) s K) o § o K> s K) o O s K) p O po K) n 〇〇o 〇§ K 〇〇〇1 (CH2)3-2-external bite base 4184 4185 4186 4187 4188 4189 4190 4191 4192 4193 4194 4195 3-pyridyl 4196 4197 4198 4199 4200 4201 4202 4203 4204 4205 4206 4207 (CH2)-3- Dagger. Stationary 4208 4209 4210 4211 4212 4213 4214 4215 4216 4217 4218 4219 (CH2)2-3- Leaf 匕 定 42 4220 4221 4222 4223 4224 4225 4226 4227 4228 4229 4230 4231 (CH2) 3-3- Pyridyl 4232 4233 4234 4235 4236 4237 4238 4239 4240 4241 4242 4243 4-^σ定基4244 4245 4246 4247 4248 4249 4250 4251 4252 4253 4254 4255 (CH2)-4- outer base 4256 4257 4258 4259 4260 4261 4262 4263 4264 4265 4266 4267 (CH2 )2 -4-Yellow bite base 4268 4269 4270 4271 4272 4273 4274 4275 4276 4277 4278 4279 (CH2)3-4-leaf. Stationary 4280 4281 4282 4283 4284 4285 4286 4287 4288 4289 4290 4291 Acridine 4292 4293 4294 4295 4296 4297 4298 4299 4300 4301 4302 4303 (CH2> 17 Kunyu 4304 4305 4306 4307 4308 4309 4310 4311 4312 4313 4314 4315 (CH2) 2. acridinyl group 4316 4317 4318 4319 4320 4321 4322 4323 4324 4325 4326 4327 (ch2)3-p butyl base 4328 4329 4330 4331 4332 4333 4334 4335 4336 4337 4338 4339 10-oxo-4-nitrogen_tricyclo[ 5.2.1.02,6] sulfhydryl 4340 4341 4342 4343 4344 4345 4346 4347 4348 4349 4350 4351 8-oxo-3-nitro-bicyclo[3.2.1] octyl 4352 4353 4354 4355 4356 4357 4358 4359 4360 4361 4362 4363 Tetrahydrofuranyl 4364 4365 4366 4367 4368 4369 4370 4371 4372 4373 4374 4375 -50- 123505 200815422 \ tw 〇K) 〇Ο Κ Κ) Κ) η η to (W to' Ο § η κΤ 9 Κ) Ο 1 5 S κ&gt ; Q Ν) 1 ο η Ν) Ο Ο ο Ο η % § Ο Ο X % X (ch2)-tetrahydrofuranyl 4376 4377 4378 4379 4380 4381 4382 4383 4384 4385 4386 4387 (CH2) 2-tetrahydrofuranyl 4388 4389 4390 4391 4392 4393 4394 4395 4396 4397 4398 4399 (CH2)3-tetrahydrofuran喃基4400 4401 4402 4403 4404 4405 4406 4407 4408 4409 4410 4411 Tetrahydropyranyl 4412 4413 4414 4415 4416 4417 4418 4419 4420 4421 4422 4423 (CH2). Tetrahydropyranyl 4424 4425 4426 4427 4428 4429 4430 4431 4432 4433 4434 4435 (ch2)2_tetrahydropyranyl 4436 4437 4438 4439 4440 4441 4442 4443 4444 4445 4446 4447 (CH2)3-tetrahydropyranyl 4448 4449 4450 4451 4452 4453 4454 4455 4456 4457 4458 4459 Tetrahydrogen 1^ Each base 4460 4461 4462 4463 4464 4465 4466 4467 4468 4469 4470 4471 (ch2)-tetrahydropyrrolyl 4472 4473 4474 4475 4476 4477 4478 4479 4480 4481 4482 4483 (CH2) 2-tetrahydroindoleloyl 4484 4485 4486 4487 4488 4489 4490 4491 4492 4493 4494 4495 (CH2)3-tetrahydropyrrole 4496 4497 4498 4499 4500 4501 4502 4503 4504 4505 4506 4507 Hexahydropyrryl 4508 4509 4510 4511 4512 4513 4514 4515 4516 4517 4518 4519 (CH2)-six Hydrogen well base 4520 4521 4522 4523 4524 4525 4526 4527 4528 4529 4530 4531 (CH2) 2-hexahydropyrrole 4532 4533 4534 4535 4536 4537 4538 4539 4540 4541 4542 4543 (CH2) 3-hexahydropyrryl 4544 4545 4546 4547 4548 4549 4550 4551 4552 4553 4554 4555 hexahydro group 4556 4557 4558 4559 4560 4561 4562 4563 4564 4565 4566 4567 (CH2)-hexahydro-P ratio bite 4568 4569 4570 4571 4572 4573 4574 4575 4576 4577 4578 4579 123505 - 51 - 200815422 \ 〇K) 〇SK) Ο /g 8 Κ) 3 Κ) Ο 1 μ, κΤ face ο η Κ) S to η ο 3 νΤ κΤ § Ο /pN κΤ Ο Ο Ο 1 § ffi η ο κ Ο Ε (ch2) 2-hexahydropyridyl 4580 4581 4582 4583 4584 4585 4586 4587 4588 4589 4590 4591 (ch2 ) 3 _ hexahydropyridyl 4592 4593 4594 4595 4596 4597 4598 4599 4600 4601 4602 4603 Kfford P Linki 4604 4605 4606 4607 4608 4609 4610 4611 4612 4613 4614 4615 (CH2) 福福 P林基 4616 4617 4618 4619 4620 4621 4622 4623 4624 4625 4626 4627 (CH2) 2- 福福 w林基 4628 4629 4630 4631 4632 4633 4634 4635 4636 4637 4638 4639 (CH2)3 -3 morpholinyl 4640 4641 4642 4643 4644 4645 4646 4647 4648 4649 4650 4651

於本發明之另一方面，係提供製備式i化合物之方法，此 方法包括使式ΠΙΑ化合物In another aspect of the invention, there is provided a process for the preparation of a compound of formula i, which process comprises

式 ΙΙΙΑ R〇 x 與（i) G-COOH，於偶合劑與鹼存在下；或與（ii) G-CO-Z，於鹼 存在下接觸，其中該接觸係在適合提供式I化合物之條件下 發生，其中八、又、丫、11、[2、（^及0均如式1中之定義， 且Z為活化部份基團，其可例如被胺置換。 於本發明之另一方面，係提供製備式I化合物之方法，此 方法包括 -52- 123505 200815422 (i) 使式ΙΠΒ化合物 οRΙΙΙΑx and (i) G-COOH, in the presence of a coupling agent and a base; or (ii) G-CO-Z, in the presence of a base, wherein the contact is in a condition suitable for providing a compound of formula I Occurs, wherein VIII, 丫, 11, [2, (^ and 0 are all as defined in Formula 1, and Z is an activating moiety, which may be substituted, for example, by an amine. In another aspect of the invention Is a method of preparing a compound of formula I, which comprises -52- 123505 200815422 (i) a compound of formula ο

式 IIIB 與G-NH2,於偶合劑與鹼存在下接觸；或 (ii) 使式IIIC化合物 〇Formula IIIB and G-NH2, in contact with a coupling agent in the presence of a base; or (ii) a compound of formula IIIC

Γ Q χ\人Γ Q χ\人

式 IIIC 與G-NH2，於驗存在下接觸，其中該接觸係在適合提供式I 化合物之條件下發生，1 Φ A、Υ ν ^ τ9 、 丁 r知王具Τ Α、Χ、Υ ' R、L2、Q及G均如 式I中之疋義’且z為活化部份基團，其可例如被胺置換。 於本發明之另—方面，係提供製備式II化合物之方法， 此方法包括使式IVA化合物Formula IIIC is contacted with G-NH2 in the presence of a test, wherein the contact occurs under conditions suitable for providing a compound of formula I, 1 Φ A, Υ ν ^ τ9 , 丁尔知王 Τ Α, Χ, Υ 'R , L2, Q and G are all as defined in the formula I and z is an activating moiety which may, for example, be replaced by an amine. In a further aspect of the invention, there is provided a process for the preparation of a compound of formula II, which process comprises a compound of formula IVA

L2—QL2—Q

與（i)G-COOH，於偶合劑與驗存在下；或與⑼G_c〇_z，於鹼 存在下接觸’彡中該接觸係在適合提供式II化合物之條件 下發f ;其中A、B、D、X、Y、R、L2、QAG均如式π 中之定義’且Z為活化之部份基團，纟可例如被胺置換。 123505 -53 - 200815422 於本發明之另一方面，係提供製備式II化合物之方法， 此方法包括 ⑴使式IVB化合物And (i) G-COOH, in the presence of a coupling agent; or in contact with (9) G_c〇_z, in the presence of a base, wherein the contact is in a condition suitable for providing a compound of formula II; wherein A, B , D, X, Y, R, L2, QAG are all defined as in the formula π and Z is a part of the activated group, and hydrazine can be replaced, for example, by an amine. 123505 - 53 - 200815422 In another aspect of the invention, there is provided a process for the preparation of a compound of formula II, which process comprises (1) a compound of formula IVB

[2/Q[2/Q

與g-nh2，於偶合劑與鹼存在下接觸；或 (ii)使式IVC化合物 l2-^qContacting g-nh2 in the presence of a coupling agent with a base; or (ii) bringing a compound of formula IVC l2-^q

與G_NH2，於鹼存在下接觸，其中該接觸係在適合提供式II 化合物之條件下發生；其中A、B、D、X、Y、R、L2、Q 及G均如式II中之定義，且Z為活化部份基團，其可例如被 胺置換。 典型偶合劑包括 DCC、EDC、CDI、BOP、PyBOP、HATU、 HBTU、HCTU、TATU、TBTU、TDBTU、DEPBT、TSTU 等。 活化部份基團典型上為F、Cl、Br、I、N3、N-羥基琥珀醯 亞胺醯基、1-羥基苯并三唑、1-羥基-7-氮苯并三唑、五氟基 苯氧基、五氣苯氧基、對-琐基苯氧基或-〇C(0)-ORy，其中Ry 為經取代或未經取代之Ci-6烷基。適當鹼包括碳酸氫鈉， 123505 -54- 200815422 丙基乙胺 之方法 或適當有機胺，譬如吡啶、N-罗基嗎福啦、一 、田^^異 或三乙胺。 於本發明之另一方面提供製備式V化合物Contacting G_NH2 in the presence of a base, wherein the contacting occurs under conditions suitable for providing a compound of formula II; wherein A, B, D, X, Y, R, L2, Q and G are as defined in formula II, And Z is an activating moiety which can be replaced, for example, by an amine. Typical coupling agents include DCC, EDC, CDI, BOP, PyBOP, HATU, HBTU, HCTU, TATU, TBTU, TDBTU, DEPBT, TSTU, and the like. The active moiety is typically F, Cl, Br, I, N3, N-hydroxysuccinimide fluorenyl, 1-hydroxybenzotriazole, 1-hydroxy-7-nitrobenzotriazole, pentafluoro A phenoxy group, a penta phenoxy group, a p-dodecylphenoxy group or a hydrazine C(0)-ORy, wherein Ry is a substituted or unsubstituted Ci-6 alkyl group. Suitable bases include sodium bicarbonate, 123505-54-200815422 propylethylamine or a suitable organic amine such as pyridine, N-roylofaflu, mono-, di- or triethylamine. In a further aspect of the invention provides the preparation of a compound of formula V

N w 式V 此方法包括使式VI化合物 7 At1N w Formula V This method includes the compound of formula VI 7 At1

〇 W〇 W

式VI 與硝基丙二醛鈉鹽，在適合提供式V化合物之條件下接 觸，其中Ar’為5或6-員芳族或雜芳族基團，視情況被L3_Q取 代；W為（V6烷基或（：3_6環烷基；L3為共價鍵、CH2〇、c(〇)、 c(0)0、（CR2 )m C(0)NR、C(0)NRNR、C(NOR)或 NRC(0)0 基團； Q為氫、經取代或未經取代之烷基 '環烷基、芳基、雜環 基、芳烷基或雜環基烷基；且各R係獨立為氫或經取代或 未"二取代之Cl ·6烧基。例如·· Ar，為苯基、三唾基、峨略基 或米坐基。此反應典型上係於醋酸錄存在下，在例如EtOH/ %〇 /谷劑混合物中，及典型上於約5〇艽與約8〇。〇間之溫度下 進行。 於本發明之另一方面，係提供式VII化合物Formula VI with sodium nitromalonate in contact with a compound suitable for providing a compound of formula V wherein Ar' is a 5 or 6-membered aromatic or heteroaromatic group, optionally substituted by L3_Q; W is (V6 Alkyl or (:3_6 cycloalkyl; L3 is a covalent bond, CH2〇, c(〇), c(0)0, (CR2)m C(0)NR, C(0)NRNR, C(NOR) Or an NRC(0)0 group; Q is hydrogen, substituted or unsubstituted alkyl 'cycloalkyl, aryl, heterocyclic, aralkyl or heterocyclylalkyl; and each R is independently Hydrogen or a substituted or un-disubstituted C1-6 alkyl group. For example, Ar is a phenyl group, a trisalyl group, an anthranyl group or a milano group. This reaction is typically carried out in the presence of acetic acid. For example, in an EtOH/%〇/troreal mixture, and typically at a temperature of about 5 Torr and about 8 Torr. In another aspect of the invention, a compound of formula VII is provided

123505 -55- 200815422123505 -55- 200815422

式VII 其中Hal為Cl、Br或I; T為Ο或（CH2 )n ; Rm為η或經取代或 未經取代之烷基、芳烷基或雜環烷基；且η為〇，1或2。 於又另一方面，係提供式VIII化合物Wherein Hal is Cl, Br or I; T is deuterium or (CH2)n; Rm is η or substituted or unsubstituted alkyl, aralkyl or heterocycloalkyl; and η is deuterium, 1 or 2. On the other hand, a compound of formula VIII is provided

式 VIII 其中 Τ 為 〇 或（CH2)n ; U 為 F、α、Br、CN、-S02NR，2、-qc〇NR，2 或-NRS〇2Rn，v為-ΟΑ ·6燒基）；Rm為H或經取代或未經取 代之烷基、芳烷基或雜環烷基；各R，係獨立為氫，或經取 代或未經取代之烷基、芳烷基、雜環基或雜環基烷基；各 R”係獨立為經取代或未經取代之烷基、芳基、雜環基、芳 烷基或雜環基烷基；且η為〇，ι或2。 亦提供者為式IX化合物Wherein Τ is 〇 or (CH2)n; U is F, α, Br, CN, -S02NR, 2, -qc〇NR, 2 or -NRS〇2Rn, v is -ΟΑ ·6 alkyl); Rm Is H or substituted or unsubstituted alkyl, aralkyl or heterocycloalkyl; each R, independently hydrogen, or substituted or unsubstituted alkyl, aralkyl, heterocyclic or hetero a cycloalkyl group; each R" is independently substituted or unsubstituted alkyl, aryl, heterocyclic, aralkyl or heterocyclylalkyl; and η is 〇, ι or 2. Also provided Compound of formula IX

式IX 視情況經部份或完全鹵 ，各R’係獨立為氫，或經 雜環基或雜環基烷基； 其中Τ為（C2-6)烧基或環烧基，$ 化；U為-CN、402见1，2或_服，8〇211”； 取代或未經取代之烷基、芳烷基、 123505 -56 - 200815422 本發明進一步提供組合物，其包含如本文中所述之化合 物及藥學上可接受之載劑。 於又另一方面，本發明係提供治療藉由細胞素所媒介病 症之方法，該病症包括但不限於炎性病症、自身免疫病症、 心血管病症、癌症及疼痛。該方法包括對需要此種治療之 病患投予治療上有效量之如本文中所述之化合物。在一些 此種具體實施例中，細胞素所媒介之病症為ρ38ΜΑρκ所媒 介之病症。在其他具體實施例中，細胞素係選自、 IL-1、IL-6、IL-8、GM_CSF&IFN_r，或其任兩種或多種之組 合。在其他具體實施例中，細胞素為MFa或^。在一些 具體實施例中，此方法進一步包括投予如本文中所述之其 他治療成份（後文稱為成份A)。 細胞素所媒介之病症包括風濕性關節炎、骨關節炎、克 隆氏病、潰瘍性結腸炎、牛皮癖關節炎、外傷性關節炎、 風疹關節炎、炎性腸疾病、多發性硬化、移植物對宿主疾 病、系統性紅斑狼瘡、毒性休克徵候簇、刺激性腸徵候蔟、 肌肉退化、同種移植排斥、胰腺炎、胰島炎、絲球體性腎 炎、糖尿病患者之腎病、腎纖維變性、慢性腎衰竭、痛風、 麻風、急性滑膜炎、賴透氏徵候簇、痛風性關節炎、 氏疾病 '脊椎炎、子宮内膜組織異位形成，非關節炎性症 狀，譬如椎間盤徵候簇症狀、滑囊炎、腱炎、腱滑膜炎或 纖維肌痛徵候簇；〗急性或慢性疼痛，包括但不限於神經 病疼痛、神經病、多神經病、糖尿病相關之多神經病、創 ^偏頭痛、緊張與群集頭痛、Horton氏病、曲張潰瘍、神 123505 •57- 200815422 經痛、肌骨疼痛、料傷性疼痛、骨折、痛性營養不良、 椎關節炎、纖維肌痛、幻想肢疼痛、背痛、椎骨疼痛、手 :後疼痛、脫出椎間盤所引致之坐骨神經痛、癌症相關疼 痛、血管疼痛、内臟疼痛、生產相關之疼痛或勝相關之 疼痛。Formula IX is optionally partially or completely halogenated, each R' is independently hydrogen, or is heterocyclic or heterocyclylalkyl; wherein hydrazine is (C2-6)alkyl or cycloalkyl, $; U -CN, 402, 1, 2 or _, 8 〇 211"; substituted or unsubstituted alkyl, aralkyl, 123505 - 56 - 200815422 The present invention further provides a composition comprising as described herein And a pharmaceutically acceptable carrier. In yet another aspect, the invention provides a method of treating a condition mediated by a cytokine, the condition including, but not limited to, an inflammatory condition, an autoimmune condition, a cardiovascular condition, Cancer and pain. The method comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound as described herein. In some such embodiments, the cytokine-mediated condition is mediated by ρ38ΜΑρκ In other embodiments, the cytokine is selected from the group consisting of IL-1, IL-6, IL-8, GM_CSF & IFN_r, or a combination of any two or more thereof. In other embodiments, the cytokinin Is MFa or ^. In some embodiments, this method is further Including administration of other therapeutic ingredients as described herein (hereinafter referred to as ingredient A). Cytochrome-mediated conditions include rheumatoid arthritis, osteoarthritis, Crohn's disease, ulcerative colitis, psoriatic arthritis , traumatic arthritis, rubella arthritis, inflammatory bowel disease, multiple sclerosis, graft versus host disease, systemic lupus erythematosus, toxic shock syndrome, irritating intestinal syndrome, muscle degeneration, allograft rejection, pancreatitis , insulitis, spheroid nephritis, kidney disease in diabetic patients, renal fibrosis, chronic renal failure, gout, leprosy, acute synovitis, Lai's syndrome, gouty arthritis, 'spine disease', spondylitis Membrane tissue ectopic formation, non-arthritic symptoms, such as symptoms of intervertebral disc syndrome, bursitis, gingivitis, sputum synovitis or fibromyalgia syndrome; acute or chronic pain, including but not limited to neuropathic pain, neuropathy , polyneuropathy, diabetes-related polyneuropathy, traumatic migraine, tension and cluster headache, Horton's disease, varicose ulcer, God 123505 •57- 2008 15422 Menstrual pain, musculoskeletal pain, bruises, fractures, painful malnutrition, vertebral arthritis, fibromyalgia, imaginary limb pain, back pain, vertebral pain, hand: post-pain, sciatica caused by the removal of the intervertebral disc , cancer-related pain, vascular pain, visceral pain, production-related pain, or pain associated with victory.

其他細胞素所媒介之病症為 血症、再灌注損傷、絕血再灌 栓形成、血管生成、冠狀心臟 艰狀徵候蔟、Takayasu動脈炎， 中風、慢性心臟衰竭、内毒 注、心肌絕血、再狹窄、血 疾病、冠狀動脈疾病、急性 心力衰竭，譬如心臟衰竭、 i两、心肌炎、脈管炎、血管再狹窄'瓣膜疾病或冠狀 動脈分流；與血液凝g]或血纖維蛋白溶酶作用㈣聯之高 膽固醇血錢或餘，例如急性靜脈血栓形成、肺插塞、 姓娠期間之血栓形成、出血性皮膚壞死、急性或慢性散佈 性血管内凝聚(DIC)，來自手術、長久臥床休息或長期固定 之血塊形成，靜脈血栓形成、暴發腦膜炎球菌血症、急性 血栓形成中風、急性冠狀閉塞、急性末梢動脈閉塞、巨大 肺插塞、腋#脈血栓形《、巨A絡與股靜脈金栓形成、堵 塞動脈或靜脈套管、心肌病、肝臟之靜脈閉塞疾病、低血 壓、降低心臟輸出、降低血管抵抗性、肺高血壓、減少肺 臟順應性、白血球減少症或血小板減少症；或動脈粥瘤硬 化。又其他細胞素所媒介之病症為過敏性結合膜炎、葡萄 膜炎、青光眼、視神經炎、視網膜絕血、糖尿病患者之視 網膜病、雷射所引致之視覺傷害或手術或外傷所引致之增 生性玻璃體視網膜病。細胞素所媒介之病症進一步包括過 123505 -58 - 200815422 敏性鼻炎、氣喘、成人呼吸困難徵候簇、慢性肺發炎、慢 性阻塞肺病、閉塞性細枝氣管炎、氣腫、枝氣管炎、黏液 過度分泌、矽土沉著病、SARS感染及呼吸道發炎。亦被包 含者為牛皮癖、天癌瘡、濕療、異位性皮炎、接觸性皮膚 炎或痤瘡。又其他細胞素所媒介之病症為徵候 叙、巴金生氏病、亨丁頓氏病、阿耳滋海默氏病、肌萎縮 性侧索硬化、多發性硬化及其他髓勒脫失病、病毒與細菌 (、腦膜炎、CNS損傷、脊髓損傷、發作、摇揭、撤禮體橋腦 小腦萎縮、AIDS癡呆症複徵、MERRF與MELAS徵候簇、乙此沉 氏疾病、Wernicke氏腦病、Rett氏徵候簇、高半胱胺酸尿、 高脯胺酸血症、血高半胱胺酸過多、非酮病高甘胺酸血症、 經丁酸胺基酸尿、亞硫酸鹽氧化酶缺乏、合併之系統疾病、 鉛中毒性腦病、Tourett氏徵候簇、肝腦病、藥瘾、藥物耐藥 性、藥物依賴性、抑t、焦慮、精神分裂症、動脈瘤或癲 癇。於本發明之另一方面，細胞素所媒介之病症包括骨質 ί ,耗損疾病，譬如骨質石化病、骨質疏鬆症或骨關節炎。亦 被包含者為糖尿病、系統惡病質、感染或惡性病症之續發 性惡病質、後天免疫不全徵候簇（AIDS)i續發性惡病質、肥 胖、厭食或貪食神經質。此外，細胞素所媒介之疾病可為 敗血病、HIV感染、HCV感染、瘧疾、感染性關節炎、利什 曼病、Lyme疾病，癌症，包括但不限於乳癌、結腸癌、肺 癌、前列腺癌症、多發性骨髓瘤、急性骨髓性白血病、脊 髓發育不良徵候簇、非Hodgkins氏淋巴瘤、骨肉瘤或濾胞淋 巴瘤、Castleman氏疾病或抗藥性。在一些具體實施例中，細 123505 -59- 200815422 胞素所媒介之病症為風濕性關節炎、骨關節炎、克隆氏病、 /貝瘍^腸炎、炎性腸疾病、糖尿病、牛皮癖關節炎、牛 皮癣二天疱瘡、慢性阻塞肺病、疼痛、動脈粥瘤硬化、絕 血再灌/主'再狹窄、急性冠狀徵候簇、心臟衰竭、多發性 骨體瘤、濾胞淋巴瘤或骨肉瘤。 在本毛明之一些具體實施例中，細胞素所媒介之病症為 曰中性白血球所媒介之病症，例如枝氣管性氣喘、鼻炎、 流行性感胃 '中風、心肌梗塞、熱損傷、成人呼吸困難徵 ㈣_S)、創傷續發之多重器官傷害、急性絲球體性腎 人/、有w性火性成份之皮膚病、急性含膿腦膜炎、血液 透析白血球电,永、粒性血球輸血有關聯之徵候蔟或壞死 性小腸結腸炎。 在本發明之 -Η»Other cytokines are characterized by inflammation, reperfusion injury, reperfusion of resecting blood vessels, angiogenesis, coronary heart disease, Takayasu arteritis, stroke, chronic heart failure, endotoxic injection, myocardial ischemia, Restenosis, blood disease, coronary artery disease, acute heart failure, such as heart failure, i., myocarditis, vasculitis, vascular restenosis, valvular disease or coronary shunt; with blood coagulation or plasmin (d) high cholesterol blood or excess, such as acute venous thrombosis, pulmonary embolism, thrombosis during surname pregnancy, hemorrhagic skin necrosis, acute or chronic dispersive intravascular coagulation (DIC), from surgery, long bed rest Or long-term fixed clot formation, venous thrombosis, outbreak meningococcalemia, acute thrombotic stroke, acute coronary occlusion, acute peripheral arterial occlusion, giant pulmonary embolism, 腋#脉 thrombiform, giant A and femoral vein Gold plug formation, occlusion of arterial or venous cannula, cardiomyopathy, venous occlusion disease of the liver, hypotension, lowering of heart output, lowering Tube resistance, pulmonary hypertension, pulmonary dirty reducing compliance, leukopenia or thrombocytopenia; atheroma or hardened. Other cytokines are caused by allergic conjunctivitis, uveitis, glaucoma, optic neuritis, retinal blood vessels, retinopathy of diabetic patients, visual injuries caused by lasers, or hyperplasia caused by surgery or trauma. Vitreoretinopathy. The cytokine-mediated condition further includes 123505 -58 - 200815422 sensitive rhinitis, asthma, adult dyspnea syndrome, chronic lung inflammation, chronic obstructive pulmonary disease, occlusive trochanteric bronchitis, emphysema, bronchitis, mucus hyperactivity Secretion, stagnation, SARS infection and inflammation of the respiratory tract. Also included are psoriasis, ascites, moist therapy, atopic dermatitis, contact dermatitis or acne. Other cytokines are characterized by signs of syndrome, Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis and other myeloablative diseases, viruses And bacteria (, meningitis, CNS injury, spinal cord injury, seizures, shakes, withdrawals, pons cerebellar atrophy, AIDS dementia relapse, MERRF and MELAS syndrome, B. Shen's disease, Wernicke's encephalopathy, Rett's Symptoms, homocysteine, hyperglutaemia, hyperhomocysteinemia, non-ketotic hyperglycemia, butyric acid uric acid, sulfite oxidase deficiency, Combined systemic disease, lead toxic encephalopathy, Tourett's syndrome, hepatic encephalopathy, drug addiction, drug resistance, drug dependence, depression, anxiety, schizophrenia, aneurysm or epilepsy. Another aspect of the invention In contrast, cytokine-mediated conditions include bone mass, depletion of diseases, such as osteopetrosis, osteoporosis or osteoarthritis. Also included are diabetic, systemic cachexia, infectious or malignant pathological cachexia, acquired immunity Incomplete sign AIDS i is a persistent cachexia, obesity, anorexia or bulimia. In addition, cytokine-mediated diseases can be septicemia, HIV infection, HCV infection, malaria, infectious arthritis, leishmaniasis, Lyme. Disease, cancer, including but not limited to breast cancer, colon cancer, lung cancer, prostate cancer, multiple myeloma, acute myeloid leukemia, spinal dysplasia syndrome, non-Hodgkins' lymphoma, osteosarcoma or squamous lymphoma, Castleman's disease Or drug resistance. In some embodiments, the conditions mediated by cytosolic 123505 -59-200815422 are rheumatoid arthritis, osteoarthritis, Crohn's disease, /intestinal inflammation, inflammatory bowel disease, diabetes, Psoriatic arthritis, psoriasis, diphtheria, chronic obstructive pulmonary disease, pain, atherosclerosis, resecting of the blood vessels / main 'restenosis, acute coronary syndrome, heart failure, multiple bone tumors, lymphocytic lymphoma or osteosarcoma In some embodiments of the present invention, the cytokine-mediated condition is a condition mediated by sputum neutrophils, such as bronchial asthma and rhinitis. Popular sexy stomach 'stroke, myocardial infarction, thermal injury, adult dyspnea syndrome (4) _S), multiple organ injury with traumatic continuation, acute spheroid kidney disease, skin disease with w-flaming ingredients, acute purulent meningitis Hemodialysis white blood cell electricity, permanent, granulocyte blood transfusion associated with symptoms of sputum or necrotizing enterocolitis. In the present invention -Η»

體實施例中，病症係為以下或由於其 所造成，#常出血、膿腫、光化網狀徵候蔟、急性混亂偏 頭痛急性此亂老年癡呆症、急性肝細胞損傷、急性管狀 壞死垂體腺性部疾病、腺病毒感染、黏連物、黏連囊炎、 子宮附件炎求蛋白血症、過敏反應、充髮、纖維化 肺胞炎、澱粉樣變性病、血管造形術、狹心症、抗雄脂徵 候族、動脈硬化癡呆症、顳動脈炎、節肢動物先天性腦炎、 窒息、異位過敏性、心房纖維顫動、海狸熱、膽硬化、骨 質耗損、細枝氣管炎、内分泌腺癌、喉癌、念珠菌病、小 細胞肺癌、心臟肥大、心臟手術、心臟擴大、心臟炎、頸 動脈血管造形術、職脈„切除術、頸動脈支架、頸動 脈潰瘍、腹腔疾病、肝硬變、結腸炎、結腸炎肉芽腫、冠 123505 -60- 200815422 狀動脈分流移植、冠狀動脈 ,^ , 狐刀/瓜手術、皮質白内障、.質 類固醇抗藥性氣喘'變性 、 又隱關即疾病、皮膚炎、腹瀉、勃起 神經病、勃起脈管病（特 J疋搪尿病妫起神經病與脈管 病）、眼乾、脂血症障礙（台红 一 ^ 礙（匕括血脂肪過多（增加之脂質）、 尚膽固醇血症（增加之膽固 吁j间妝基乙酸血症（增加之甘 油酉旨）、、血三酸甘油醋過多（增加之三酸甘油酉旨）、血脂蛋白 r 過夕（〜加之脂蛋白）、血中乳糜微粒過多（增加之乳康微 粒)」合併之血脂肪過多（增加之LDL與三酸甘油醋）、家族 性局膽固醇血症（由於染色體19 (19pi3」_133)上之缺陷所致 之高膽固醇血症）、血脂蛋白過低（降低之脂蛋白）、低膽固 醇血（降低之膽固醇）、脂蛋白血缺乏症（降低之石脂蛋白） 及T:氏病(降低之高密度脂蛋白))、呼吸困難、水腫、 末期腎病、愛氏噸-巴爾（epstein_barr)病毒感染、發熱、遽胞 甲狀腺癌瘤、胃腸炎、心臟病發作、心臟分流手術、:臟 手術、心臟移植、A型肝炎、B型肝炎、c型肝炎、慢性肝 炎、胰島素抗藥性、腎力衰竭、腎臟移植、成人慢性白血 病、肝硬化、肝臟移植、腦膜炎、細菌腦膜炎、骨髓增生 病症、肌病、肌炎、新生兒展開之多系統炎性疾病、腎炎、 神經肌肉病症、神經病、閉塞性細枝氣管炎、口腔癌、經 皮冠狀介入、齒周膜骨質耗損、末梢神經病症、神經病' 腹膜滲析、胸膜疾病、肺炎、多肌炎、後囊混濁、搔癢病（包 括眼睛、皮膚及一般搔癢病）、肺纖維變性、腎癌、腎滲析、 硬皮病、敗血性關節炎、Sj〇gren氏徵候簇、關節黏連脊椎 k Still氏疾病、父感性眼炎、毒血症、結核病、蓴麻療、 123505 -61 - 200815422 病毒肝炎或Wegener氏肉芽腫病。 於本發明之另—方面’係提供在病患中降低細胞素含量 之方法：此等方法包括對病患譬如有需要之病患投予一數 量之化“勿，譬如細胞素抑制劑’相對於投予該化合物前 之含量，其係有效降低細胞素之含量，其中該化合物係如 ^文中所34，或其立體異構物、互變異構物、溶劑合物、 前體藥物或藥學上可接受之鹽。在-些具體實施例中，於 細胞素含量上之降低為至少1〇%，至少3〇%，至少5 ' 少70%，或至少90%。在一此且 —八體貝鈿例中，病患係患有或 處於如本文中所述之細胞素所媒介病症之危險下。在一些 具體實施例中，細胞素係選自H、辽^、辽^ — GM-CSF、勝，或其任兩種或多種之組合。在其他且體實 施例中’細胞素為職或以。在—些具體實施例中，〜 胞素含量係在病患或得自病患之試樣中度量，例如組織或 體液’譬如病患之血液。在其他具體實施例中，細胞素含 量係在病患之滑膜中度量。於又其他具體實施例中，細胞 素含量係在病患之皮膚中度量。在本發明之一些具體實施 例中，此方法係進-步包括投予如本文中所述之其他^療 成份（後文稱為成份A)。 於本發明之又另一方面’係提供降低細胞回應預發炎刺 激所釋出之細胞素含量之方法。此等方法包括使細胞曝露 至一數量之化合物，譬如細胞素抑制劑，相對於使細胞鱼 化合物接觸前所釋出細胞素之含量’其係有效降低細胞= 應預發炎刺激所釋出之細胞素含量，其中該化合物係如本 123505 -62- 200815422 文中所述，或其立體異構物、互變異構物、溶劑合物、前 體藥物或藥學上可接受之鹽。在一些具體實施例中，於細 胞素含里上之降低為至少10%，至少3〇%，至少5〇%，至少 70%或至J 90%。在一些具體實施例中，預發炎刺激係由 於脆、正-!、IL-6、IL_8、GM_CSF、聰个⑽或其任兩 種或多種之組合之存在所造成。在其他具體實施例中，細 胞素含量為 TNFa、IL]、IL_6、IL_8、GM csf、脈1 或其 任兩種或多種之組合之含量。在本發明之一些具體實施例 中，此方法係進一步包括使細胞曝露至如本文中所述之其 他治療成份（後文稱為成份A)。 々於本發明之又另-方面，係提供抑制p38活性之方法。此 等方法包括使P38與有效抑制p38活性、p38之磷醯化作用或 兩者之里之化合物接觸，譬如細胞素抑制劑，其中該化合 物係如本文中所述’或其立體異構物、互變異構物、溶； 合物、前體藥物或藥學上可接受之鹽。在一些具體實施例 中P38，舌性或P38之磷醯化作用之抑制為至少10%，至少 30/〇 ’至少5〇%，至少7〇%，或至少9〇%。p38可被單離嬖 如在不含細胞之活體外系統中，細胞製劑，或其可在細胞 中。在一些其他具體實施例中，p38係於病患中。在一些具 體實施例中’病患係患有或處於如本文中所述之細胞相 媒介病症之危險下。在本發明之一些具體實施例中，其中 P38係於病患、中，财法係進一纟包括對病患投予如本文中 所述之其他治療成份（後文稱為成份A)。 於本發明之另一方面，係提供降低預發炎介體活性之方 123505 -63- 200815422 法。此等方法包括對病患譬如有需要之病患投予一數量之 化合物，譬如細胞素抑制劑，相對於投予該化合物前之、、舌 性’其係有效降低預發炎介體之活性，其中該化合物係如 本文中所述，或其立體異構物、互變異構物、溶劑合物、 前體藥物或藥學上可接受之鹽。在一些具體實施例中，於 預發炎介體活性上之降低為至少10%，至少30%，至少5〇%'， 至少70%，或至少90%。在某些具體實施例中，病患係患有 或處於如本文中所述之細胞素所媒介病症之危險下。在一 些具體實施例中，於活性上之降低係由於相對於投予該化 合物前之循環含量，降低預發炎介體之循環含量所造成。 在一些此種具體實施例中，於循環預發炎介體含量上之降 低為至少10%，至少30%，至少50%，至少7〇%，或至少_。In the embodiment, the condition is as follows or due to it, #常出血, abscess, actinic reticular syndrome, acute confusion, migraine, acute Alzheimer's disease, acute hepatocyte injury, acute tubular necrosis pituitary gland Disease, adenovirus infection, adhesions, bursitis, uterine annexitis, proteinemia, allergic reaction, hyperemia, fibrotic cytotoxicity, amyloidosis, angioplasty, angina, anti-drug Male lipid syndrome, arteriosclerosis dementia, temporal arteritis, arthropod congenital encephalitis, asphyxia, ectopic hypersensitivity, atrial fibrillation, beaver fever, biliary sclerosis, bone loss, twig bronchitis, endocrine adenocarcinoma, Laryngeal cancer, candidiasis, small cell lung cancer, cardiac hypertrophy, cardiac surgery, cardiac enlargement, carditis, carotid angioplasty, vascular resection, carotid stent, carotid ulcer, celiac disease, cirrhosis, Colitis, colitis granuloma, crown 123505 -60- 200815422 arterial shunt transplantation, coronary artery, ^, fox knife/melon surgery, cortical cataract, steroid steroid resistant asthma Sexuality and concealment are diseases, dermatitis, diarrhea, erectile neuropathy, erectile vasculature (special J urinary neuropathy and vascular disease), dry eyes, and lipemia disorders (Taiwano Excessive blood fat (increased lipids), cholesterolemia (increased gallbladder, methicillin), and triglyceride (additional triglyceride) Purpose), blood lipoprotein r eve (~ plus lipoprotein), excessive chylomicrons in the blood (increased milk granules) combined with excessive blood fat (increased LDL and triglyceride), familial hypercholesterolemia (hypercholesterolemia due to defects on chromosome 19 (19pi3"_133)), hypolipoproteins (lowering lipoprotein), hypocholesterolemia (lowering cholesterol), lipoproteinemia (lowering stones) Lipoprotein) and T: disease (lowering high-density lipoprotein), dyspnea, edema, end stage renal disease, epstein-barr virus infection, fever, squamous cell thyroid carcinoma, gastroenteritis, heart disease Attack, heart Flow surgery: dirty surgery, heart transplantation, hepatitis A, hepatitis B, hepatitis C, chronic hepatitis, insulin resistance, kidney failure, kidney transplantation, adult chronic leukemia, liver cirrhosis, liver transplantation, meningitis, bacteria Meningitis, myeloproliferative disorders, myopathy, myositis, multiple systemic inflammatory diseases, nephritis, neuromuscular disorders, neuropathy, occlusive trochanteric bronchitis, oral cancer, percutaneous coronary intervention, periarticular bone Depletion, peripheral neuropathy, neuropathy 'peritoneal dialysis, pleural disease, pneumonia, polymyositis, posterior capsule opacification, scrapie (including eyes, skin and general scrapie), pulmonary fibrosis, kidney cancer, renal dialysis, scleroderma, Septic arthritis, Sj〇gren's syndrome, joint adhesion to the spine k Still's disease, paternal ocular inflammation, toxemia, tuberculosis, ramie therapy, 123505 -61 - 200815422 viral hepatitis or Wegener's granulomatosis. In another aspect of the invention, a method for reducing cytokine levels in a patient is provided: the method comprises administering to the patient, if necessary, a quantity of "Do not, such as a cytokine inhibitor" relative to The amount prior to administration of the compound is effective to reduce the content of cytokines, wherein the compound is as described in 34, or a stereoisomer, tautomer, solvate, prodrug or pharmaceutically thereof thereof. An acceptable salt. In some embodiments, the reduction in cytokine content is at least 1%, at least 3%, at least 5' less 70%, or at least 90%. In the case of Beller, the patient has or is at risk of a cytokine-mediated condition as described herein. In some embodiments, the cytokine is selected from the group consisting of H, Liao, Liao, GM-CSF , 胜, or a combination of two or more thereof. In other embodiments, 'cytokine is or is employed. In some embodiments, the cytokine content is in the patient or from the patient. Measure in the sample, such as tissue or body fluids, such as the blood of patients. In other specific In one embodiment, the cytokine content is measured in the synovium of the patient. In still other embodiments, the cytokine content is measured in the skin of the patient. In some embodiments of the invention, the method is - the step comprises administering to the other therapeutic ingredients as described herein (hereinafter referred to as ingredient A). In yet another aspect of the invention, the method of providing a method for reducing the cytokine content released by the cells in response to the pre-inflammatory stimuli These methods include exposing the cells to a quantity of a compound, such as a cytokine inhibitor, relative to the amount of cytokine released prior to contacting the cell fish compound, which is effective in reducing cells = release of pre-inflammatory stimuli Cytokine content, wherein the compound is as described herein, or a stereoisomer, tautomer, solvate, prodrug or pharmaceutically acceptable salt thereof. In one embodiment, the reduction in cytokine content is at least 10%, at least 3%, at least 5%, at least 70% or to J 90%. In some embodiments, the pre-inflammatory stimuli are fragile and positive. -!, IL-6, IL_8 , GM_CSF, Cong (10) or a combination of two or more thereof, in other specific embodiments, the cytokine content is TNFa, IL], IL_6, IL_8, GM csf, pulse 1 or any two Or a combination of ingredients. In some embodiments of the invention, the method further comprises exposing the cells to other therapeutic ingredients (hereinafter referred to as ingredient A) as described herein. In another aspect, a method of inhibiting p38 activity is provided. The methods comprise contacting P38 with a compound that effectively inhibits p38 activity, phosphorylation of p38, or both, such as a cytokine inhibitor, wherein the compound is As used herein, or a stereoisomer, tautomer, lysate, prodrug or pharmaceutically acceptable salt thereof. In some embodiments, the inhibition of phosphorylation of P38, tongue or P38 is at least 10%, at least 30/〇' at least 5%, at least 7%, or at least 9%. P38 can be isolated, such as in a cell-free in vitro system, a cellular preparation, or it can be in a cell. In some other specific embodiments, p38 is in a patient. In some embodiments, the patient has or is at risk of a cellular mediator disorder as described herein. In some embodiments of the invention, wherein P38 is in a patient, the financial system further comprises administering to the patient other therapeutic ingredients as described herein (hereinafter referred to as ingredient A). In another aspect of the invention, there is provided a method of reducing the activity of a pre-inflammatory mediator 123505-63-200815422. Such methods include administering to a patient, if desired, a quantity of a compound, such as a cytokine inhibitor, which is effective to reduce the activity of the pre-inflammatory mediator prior to administration of the compound. Wherein the compound is as described herein, or a stereoisomer, tautomer, solvate, prodrug or pharmaceutically acceptable salt thereof. In some embodiments, the reduction in pre-inflammatory mediator activity is at least 10%, at least 30%, at least 5% by weight, at least 70%, or at least 90%. In certain embodiments, the patient has or is at risk of a cytokine-mediated condition as described herein. In some embodiments, the decrease in activity is due to a decrease in the circulating content of the pre-inflammatory mediator relative to the circulating amount prior to administration of the compound. In some such embodiments, the reduction in circulating pre-inflammatory mediator content is at least 10%, at least 30%, at least 50%, at least 7%, or at least _.

在一些此種具體實施例中，預發炎介體為前列腺素或白三 烯素’或其兩種或多種之組合。在—些其他具體實施例中， 於活性上之降低係由於抑制預發炎介體之生產所造成。在 一些此種具體實施例中，㈣發炎介體生產上之抑制為至 少10%，至少30%，至少5〇%，至少70%，或至少·。在一 些此種具體實施例中，預發炎介體為前列腺素、白三烯素、 cox 2 NO-合成酶或其任兩種或多種之組合。在本發明之 -些具體實施例中，該方法係進一步包括投予如本文中所 述之其他治療成份（後文稱為成份A)。 於本發明之另-方面，係提供降低c_反應性蛋白質或類 風濕因子或兩者之循環含 ,^ ^ 、 辟 俯衣3里之方法。此荨方法包括對病患 " 有需要之病患投予一數詈务入必 数里之化5物，誊如細胞素抑制 123505 -64- 200815422 劑，相對於投予該化合物前 液中之cm生蛋s 〃係有效降低病患血 其中該化合物係、如本文^ 子或兩者之循環含量， 禮物、、v^, 文中所述’或其立體異構物、互變異 “口物、厨體藥物或藥學上可接受之鹽。在一些 =實施例中，於投藥前之循環C·反應性蛋 於約2·87毫克/升。在-些具體實施例中，於循環含量上之 降低為至少1〇〇/0，5小1Λ〇/ γ , 至夕30/。，至少5〇%，至少7〇%，或至少In some such embodiments, the pre-inflammatory mediator is prostaglandin or leukotriene' or a combination of two or more thereof. In some other specific embodiments, the decrease in activity is due to inhibition of the production of the pre-inflammatory mediator. In some such embodiments, (iv) the inhibition of inflammatory mediator production is at least 10%, at least 30%, at least 5%, at least 70%, or at least. In some such embodiments, the pre-inflammatory mediator is prostaglandin, leukotriene, cox 2 NO-synthetase, or a combination of any two or more thereof. In some embodiments of the invention, the method further comprises administering to the other therapeutic ingredients (hereinafter referred to as ingredient A) as described herein. In another aspect of the invention, there is provided a method of reducing the cyclic content of a c-reactive protein or a rheumatoid factor or both, and a method of reducing the appearance of the coating. This method includes administering to the patient a patient in need of a number of substances, such as cytokine inhibition 123505-64-200815422, relative to the pre-solution of the compound. The cm raw egg s 〃 is effective in reducing the blood of the patient, the circulating content of the compound, such as this or both, gifts, v^, as described herein, or its stereoisomers, mutual mutations a medicinal or pharmaceutically acceptable salt. In some = embodiments, the circulating C·reactive egg prior to administration is about 2.87 mg/L. In some embodiments, in the circulating amount The decrease is at least 1 〇〇 / 0, 5 small 1 Λ〇 / γ, 30 。, at least 5%, at least 7%, or at least

/. i. 9CU。在-些具體實施例中，病患係患有或處於如本文中 所述之細胞素所媒介病症之危險下。在本發明之某些具體 實施例中’該方法係進一步包括投予如本文中所述之其他 /口療成伤（後文稱為成份Α)，例如該方法進一步包括胺甲喋 呤之投藥。 μ 於本發明之又另-方面，係提供降低風濕性關節炎之至 少-種標記之方法。此等方法包括對顯示風濕性關節炎之 -或多種標記之H投予有效降低至少—種標記至低於 投予該化合物前所存在含量之量之化合物，譬如細胞素抑 制劑，且其中該化合物係如本文中所述，或其立體異構物、 互變異構物、溶劑合物、前體藥物或藥學上可接受之鹽， 其中該標記係選自紅血球沉降速率（ESR)、疼痛與觸痛關節 之數目、關節疼痛之程度、Ritchie關節指數、早晨僵硬之延 續時間、關節不動性、關節腫脹及/或循環c_反應性蛋白質 含量。在本發明之一些具體實施例中，該方法係進一步包 括投予如本文中所述之其他治療成份（後文稱為成份A)。 亦提供降低牛皮癖臨床跡象之數目或嚴重性之方法。此 123505 -65 - 200815422 等方法包括對顯示牛皮癣之一或多種臨床跡象之病串，投 予一數量之化合物，譬如細胞素抑制劑，相對於投予該化 合物前存在於病患中者，其係有效降低牛皮癬臨床跡象之 數目或嚴重性，其中牛皮癬之臨床跡象為受牛皮癬所影響 之全身表面積（BSA)之百分比、牛皮癖斑點厚度、在牛皮癖 損害内之淋巴細胞之含量、表皮厚度、丁_細胞浸潤、病理 學表皮增生、細胞所媒介之免疫反應、破傷風抗體回應、 淋巴細胞亞個體群或其任兩種或多種，且其中該細胞素抑 制劑係如本文中所述，或其立體異構物、互變異構物、溶 劑合物、前體藥物或藥學上可接受之鹽。在一些具體實施 例中’牛皮癣之-或多種臨床跡象，尤其是職，係被降/. i. 9CU. In some embodiments, the patient has or is at risk of a cytokine-mediated condition as described herein. In certain embodiments of the invention 'the method further comprises administering an additional/oral treatment injury as described herein (hereinafter referred to as ingredient Α), for example, the method further comprises administering an amine formazan . In yet another aspect of the invention, there is provided a method of reducing at least a marker of rheumatoid arthritis. Such methods comprise administering to the H-showing rheumatoid arthritis- or a plurality of labeled H-effective compounds at least in an amount less than the amount present prior to administration of the compound, such as a cytokine inhibitor, and wherein The compound is as described herein, or a stereoisomer, tautomer, solvate, prodrug or pharmaceutically acceptable salt thereof, wherein the label is selected from the group consisting of red blood cell sedimentation rate (ESR), pain and The number of tender joints, the degree of joint pain, the Ritchie joint index, the duration of morning stiffness, joint immobility, joint swelling, and/or circulating c_reactive protein content. In some embodiments of the invention, the method further comprises administering to the other therapeutic ingredients (hereinafter referred to as ingredient A) as described herein. Methods of reducing the number or severity of clinical signs of psoriasis are also provided. The methods of 123505-65 - 200815422 include administering a quantity of a compound, such as a cytokine inhibitor, to a patient string showing one or more clinical signs of psoriasis, relative to the patient present in the patient prior to administration of the compound. Effectively reduce the number or severity of clinical signs of psoriasis, where the clinical signs of psoriasis are the percentage of total body surface area (BSA) affected by psoriasis, the thickness of psoriasis spots, the amount of lymphocytes in psoriasis lesions, the thickness of the epidermis, Ding_cell infiltration, pathological epidermal hyperplasia, cell-mediated immune response, tetanus antibody response, lymphocyte subpopulation or any two or more thereof, and wherein the cytokine inhibitor is as described herein, or Stereoisomers, tautomers, solvates, prodrugs or pharmaceutically acceptable salts. In some specific embodiments, 'psoriasis' or a variety of clinical signs, especially in the occupation, are dropped

供有利之治療作用， 與其他治療成份A之組合療法， ’特別是相加成拍t 1 1For the beneficial therapeutic effect, combined with other therapeutic ingredients A, 'especially add to t 1 1

細胞素所媒介之病症或症狀。 ’係提 多種，典型上為一種本文中 施例中，該方法係用於治療 在一些具體實施例中， 123505 -66 - 200815422 種或多種成份A之組合係與如本文中所述之化合物一起投 予。當與單獨本發明個別化合物或單獨成份A比較時，根 I月之w樂組合之相加或超過相加（例如增效）作用， 係提供劑量降低、副作用降低及/或間隔延長。上文所提及 之作用係當兩種物質於單一配方中同時投予時，及當其在 個別配方中連續投予時被發現。在成份A為可注射尤其是 生物劑之情況中，可發現添加如本文中所述化合物例如細 胞素抑制劑之其他利益，例如藉由間隔及/或劑量降低之成 本降低。在一些具體實施例中，如本文中所述之化合物與 成份A兩者係以口服方式投藥。在其他具體實施例中，化 合物與成份A兩者係以靜脈内方式、皮下方式或藉吸入投 藥。於又其他具體實施例中，化合物係以經口方式投藥， 而成份A係以靜脈内方式、皮下方式或藉吸入投藥。或者， 化合物可以靜脈内方式、皮下方式或藉吸入投藥，而成份 A可以口服方式投藥。鐾於本發明揭示内容，決定關於本 發明化合物與成份A之組合供特定應用之適當劑量、配方 及投藥方法，係在此項技藝之技術範圍内。 應明瞭生物劑係意謂如此項技藝中已知之任何天然或人 工/合成生物分子或其片段，譬如抗體、蛋白質、融合蛋白 質、文體、核酸、脂質、碳水化合物等。因此，成份A包 括生物劑’譬如恩i合臬西伯（etanercept)、因弗利西馬 (infliximab)、阿列發謝特（alefacept)、阿達利母馬（adalimumab)、 也發利祖馬（efalizumab)、安那金拉（anakinra) ' IL_1RA、仏干擾 素、干擾素/51-B、CTLA-4，及針對、汇-丨與IL6、LFA1 123505 -67 - 200815422 或C5之其他抗體或受體構造物。 多種成份A係意欲供使用於本發明之組合中。例如，可 使用非類固醇消炎藥物（NSAID)，其係被廣泛地使用於治療 發炎、疼痛及發熱。此種NSAID包括乙醯胺吩（acetaminophen)、 阿斯匹靈、異丁苯丙酸（ibuprofen)、膽驗柳酸饈、柳酸膽驗、 二可吩拿克（diclofenac)、二氟苯柳酸、依托多拉克（etodolac)、 菲諾丙吩(fenoprofen)舞、氟雙丙吩、啕嗓美薩辛（indomethacin)、 酮基丙吩（ketoprofen)、卡丙吩、Θ卜朵丙吩（indoprofen)、酮洛拉 克（ketorolac) 丁三醇胺、柳酸鎭、甲氯滅酸鈉、甲滅酸、5 普羅辛（oxaprozin)、峨氧胺（piroxicam)、柳酸納、沙林達克 (sulindac)、四苯醯 ρ比洛乙酸（tolmetin)、美氧胺（meloxicam)、羅 費庫西比（rofecoxib)、塞拉庫西比（celecoxib)、依托庫西比 (etoricoxib)、維德庫西比（valdecoxib)、那布美東（nabumetone)、 那丙新（naproxen)、羅莫氧胺（lomoxicam)、尼美沙利得 (nimesulide)、β丨嗓丙吩（indoprofen)、瑞米吩宗（remifenzone)、沙 沙雷特（salsalate)、提普若吩克酸（tiaprofenic acid)、弗蘇利得 (flosulide)等，或其兩種或多種之組合。 血管生成抑制劑可充作成份A，譬如VEGF抑制劑、紅豆 杉醇、己酮可可豆鹼及/或酞胺哌啶酮。 亦在關於成份A之本發明範圍内者為類固醇，譬如類皮 質糖，與維生素D3及其類似物（膽骨化醇），單獨（後者大部 份係用於牛皮癬）或併用。類固醇包括布蝶松化物、地塞米 松、氟西諾奈得、氫基可體松、占-美塞松、鹵貝他索（halobetasol) (優洛貝塔松（ulobetasol))、曱基氫化潑尼松、氫化潑尼松、 123505 -68 - 200815422 潑尼松、氯氟美松_、地弗雜可（deflazacort)、二氟經去二氫 可體i同丙驢、福路替卡松（fluticasone)、丙g同化氟經脫氫皮留 醇、莫美塔松（mometasone)及二氟皮酮四醇。在維生素D3衍 生物中者為:ί弓波三醇（calcipotriol)、塔可洛西妥（tacalcitol)、美 沙妈醇（maxacalcitol)與塔可利妥（tacalitol)、向飼性激素、1 (2,2,5-二羥維生素D3及甲狀旁腺激素相關之肽。 許多類型之免疫調制、免疫壓抑或細胞抑制藥物可與如 本文中所述之細胞素抑制劑合併使用。舉例之藥劑包括經 氯口奎、D-青黴胺、硫酸沙啡（sulfasalazine)、歐蘭諾吩（auranofin)、 硫基蘋果酸金鈉、二曱胺四環素、達普松（dapsone)、苯丁酸 氮芥（chlorambucil)、魏基嘌呤、塔可利馬斯（tacrolimus)、喜洛 利莫斯（sirolimus)、皮美洛利馬（pimecrolimus)、分枝紛酸莫非 替（mycophenolate mofetil)、環孢素、列弗諾醯胺（leflunomide)、 胺甲ϋ票呤、硝基脒峻硫嘌呤、環鱗酿胺、大環内酯類、阿 斯可黴素（ascomycin)、羥基脲、6-硫基鳥嘌呤（Orfanos C Ε.，1999, Cutis 64(5)，347);阿列發謝特（alefacept)、列弗諾醯胺 (leflunomide)、因弗利西馬（infliximab)、恩塔臬西伯（etanercept)、 也發利祖馬（efalizumab)、抗-CD4、抗-CD25、肽 T、LFA3TIP、 阿利卡弗先（alicaforsen)、DAB3 8 9、CTLA-4Ig，抗-CD80，例如 IDEC-114 或 ABX-IL8，DAB-IL-2、IL-10、抗-TAC、巴西利馬伯 (basiliximab)及達可利諸伯（daclizumab)。此外，作用於其他標 的或免疫所媒介產物之藥劑或療法，係適合作為成份A。 其包括例如蛋白質酪胺酸激酶（PTK)譬如表皮生長因子受 體（EGFR)之抑制劑，E-選擇素抑制劑，及廣泛地使用於牛皮 123505 -69- 200815422 癣之療法，譬如蒽林、煤焦油，光療法，包括紫外光B (UVB) 或補骨脂内脂紫外光A (PUVA)、光動態療法及雷射療法。 類視色素療法亦可作為成份A使用。因此，例如貝克沙 羅汀（bexarotene)、亞西催丁（acitretin)、也催亭那特（etretinate)、 塔雜若汀（tazarotene)、經基脲、6-硫基鳥嘌呤及光療法均為 適當之其他成份（Orfanos C E·，1999, Cutis 64(5)，347;亦參閱 Saumt J H·，1999, J. Am. Acad. Derm. 41(3 Pt 2)，S2)。 可使用於本發明之成份A係進一步包括針對涉及訊息轉 導途徑之酵素或細胞黏連分子例如LFA-1或ICAM-1之小分 子抑制劑。 制菌素與HMG-CoA還原酶抑制劑亦可被採用作為成份 A，包括例如阿托瓦制菌素（atorvastatin) (LIPITOR，TORVAST)、 弗伐制菌素（fluvastatin) (LESCOL)、洛伐制菌素（lovastatin) (MEVACOR，ALTOCOR)、美伐制菌素（mevastatin)、皮塔伐制菌 素（pitavastatin) (LIVALO，PITAVA)、普拉伐制菌素（pravastatin) (PRAVACHOL，SELEKTINE, LIPOSTAT)、洛蘇伐制菌素 (rosuvastatin) (CRESTOR)或辛伐制菌素（simvastatin) (ZOCOR， LIPEX)。意欲使用於本發明方法中之其他成份A包括纖維酸 酯，譬如苯雜纖酸酯（bezafibrate)(例如BEZALIP)、西普纖酸 酯（ciprofibrate)(例如 MODALIM)、氣苯丁酯（clofibrate)、可利諾 纖酸酯（clinofibrate)、傑非布洛吉（gemfibrozil)(例如LOPID)或非 諾纖酸酯（fenofibrate);膽固醇吸收抑制劑，譬如也吉提麥伯 (ezetimibe)(例如ZETIA);於驗酸；膽汁酸多價螯合劑，譬如 消膽胺（cholestyramine) (QUESTRAN)與可歹斯替保（colestipol) 123505 -70- 200815422A condition or symptom that is mediated by cytokines. 'A variety of lines, typically one of the examples herein, is used in the treatment. In some embodiments, a combination of 123505 - 66 - 200815422 or a plurality of ingredients A is combined with a compound as described herein. Cast. When compared to the individual compounds of the invention alone or to component A alone, the addition or over-addition (e.g., synergistic) effect of the root-month combination provides a reduction in dosage, a reduction in side effects, and/or an increase in interval. The above mentioned effects are found when the two substances are administered simultaneously in a single formulation and when they are administered continuously in individual formulations. In the case where component A is injectable, especially a biological agent, other benefits of adding a compound such as a cytokine inhibitor as described herein, such as a decrease in cost by interval and/or dose reduction, may be found. In some embodiments, both the compound as described herein and ingredient A are administered orally. In other embodiments, both the Compound and Component A are administered intravenously, subcutaneously or by inhalation. In still other embodiments, the compound is administered orally, and component A is administered intravenously, subcutaneously, or by inhalation. Alternatively, the compound can be administered intravenously, subcutaneously or by inhalation, while ingredient A can be administered orally. It is within the skill of the art to determine appropriate dosages, formulations, and methods of administration for the particular application of the combination of a compound of the invention and ingredient A in the present disclosure. It is to be understood that the biological agent means any natural or artificial/synthetic biomolecule or fragment thereof known in the art, such as antibodies, proteins, fusion proteins, stylistics, nucleic acids, lipids, carbohydrates and the like. Therefore, ingredient A includes biological agents such as etanercept, infliximab, alefacept, adalimumab, and alizuma ( Efalizumab), anakinra 'IL_1RA, 仏 interferon, interferon/51-B, CTLA-4, and other antibodies or antibodies against, 丨-丨 and IL6, LFA1 123505 -67 - 200815422 or C5 Body structure. A variety of ingredients A are intended for use in the combinations of the present invention. For example, non-steroidal anti-inflammatory drugs (NSAIDs) can be used, which are widely used to treat inflammation, pain, and fever. Such NSAIDs include acetaminophen, aspirin, ibuprofen, bismuth citrate, bismuth citrate, diclofenac, diflubene Acid, etodolac, fenoprofen dance, fluorodipropion, indomethacin, ketoprofen, carprofen, indoprofen ( Indoprofen), ketorolac tromethamine, bismuth citrate, sodium chlorfenate, mefenamic acid, 5 oxaprozin, piroxicam, lysinate, sarindak (sulindac), tolmetin, meloxicam, rofecoxib, celecoxib, etoricoxib, weide Valdecoxib, nabumetone, naproxen, lomoxicam, nimesulide, indoprofen, remistatin Remifenzone), salsalate, tiaprofenic acid, flosulide, etc. A combination of two or more thereof. An angiogenesis inhibitor can be used as component A, such as a VEGF inhibitor, taxol, pentoxone, and/or sulphonic acid. Also within the scope of the invention relating to ingredient A are steroids, such as dermal sugars, and vitamin D3 and its analogs (cholecalciferol), alone (most of which are used in psoriasis) or in combination. Steroids include pterosax, dexamethasone, flunixide, hydrocortisone, cum-meserone, halobetasol (ulobetasol), thiol hydrogenation Nisson, prednisolone, 123505 -68 - 200815422 Prednisone, clofibrate _, deflazacort, difluoro-dehydrogenate i with acetamidine, fluticasone ( Fluticasone), propyl g assimilation of fluorine via dehydroglucopicol, mometasone and diflupirone. Among the vitamin D3 derivatives are: calcipotriol, tacalcitol, maxacalcitol and tacitol, orthotropin, 1 (2, 2,5-Dihydroxyvitamin D3 and parathyroid hormone-related peptides.Many types of immunomodulatory, immunosuppressive or cytostatic drugs can be used in combination with cytokine inhibitors as described herein. Chlorhexidine, D-penicillamine, sulfasalazine, auranofin, sodium thiomalate, diammonium tetracycline, dapsone, chlorambucil ), Wei Kezhen, tacrolimus, sirolimus, pimecrolimus, mycophenolate mofetil, cyclosporine, lev Leflunomide, amide, nitroguanidine, cyclic amine, macrolide, ascomycin, hydroxyurea, 6-thioguanine Orfanos C Ε., 1999, Cutis 64(5), 347); alefacept, Leflunomide, infliximab, etanercept, efalizumab, anti-CD4, anti-CD25, peptide T, LFA3TIP, Alikaf First (alicaforsen), DAB3 89, CTLA-4Ig, anti-CD80, such as IDEC-114 or ABX-IL8, DAB-IL-2, IL-10, anti-TAC, basilicimab and dako In addition, agents or therapies that act on other target or immunologically mediated products are suitable as component A. These include, for example, protein tyrosine kinase (PTK) such as epidermal growth factor receptor (EGFR). Inhibitors, E-selectin inhibitors, and are widely used in the treatment of cowhide 123505-69-200815422 譬, such as 蒽林, coal tar, light therapy, including ultraviolet B (UVB) or psoralen A (PUVA), photodynamic therapy, and laser therapy. Retinoid therapy can also be used as ingredient A. Therefore, for example, bexarotene, acitretin, and etretinate , tazarotene, transurea, 6-thioguanine and light Other components of the method are suitable (Orfanos C E ·, 1999, Cutis 64 (5), 347; see also Saumt J H ·, 1999, J. Am Acad Derm 41 (3 Pt 2), S2...). The component A which can be used in the present invention further includes a small molecule inhibitor against an enzyme or cell adhesion molecule involved in a signal transduction pathway such as LFA-1 or ICAM-1. The bacteriocin and HMG-CoA reductase inhibitors can also be used as ingredient A, including, for example, atorvastatin (LIPITOR, TORVAST), fluvastatin (LESCOL), and lovage Lovastatin (MEVACOR, ALTOCOR), mevastatin, pitavastatin (LIVALO, PITAVA), pravastatin (PRAVACHOL, SELEKTINE, LIPOSTAT), rosuvastatin (CRESTOR) or simvastatin (ZOCOR, LIPEX). Other ingredients A intended for use in the process of the invention include fibrous acid esters such as bezafibrate (e.g., BEZALIP), ciprofibrate (e.g., MODILIC), clofibrate. , clinofibrate, gemfibrozil (eg LOPID) or fenofibrate; cholesterol absorption inhibitors, such as ezetimibe (eg ZETIA) Acid test; bile acid sequestrants, such as cholestyramine (QUESTRAN) and colestipol (colostipol) 123505 -70- 200815422

亦意欲涵蓋在内者為上述兩種或多種之組合，例如也吉提 麥伯（ezetimibe)/ 辛伐制菌素（simvastatin) (vyt〇rin 或施价）之 組合。具有上述成份A之組合療法係意欲使用於本發明之 任何方法中，包括細胞素所媒介病症與症狀之治療。 於另方面，係提供上文所提及之組合，其包含如本文 中所述之成h A與-或多種化合物，例如細胞素抑制劑， 典31上以/口療上有效量’供作為具有抗細胞素活性之醫藥 組合物使用。再者，包含成份A與如本文中所述化合物之 組合可用於製備醫藥組合物’供治療及/或預防細胞素所媒 介之病症或症狀。&醫藥製劑，其含有包含如本文中所述 /成伤/、化口物之一或多種化合物組合作為活性物質， 系進v G括其藥學上可接受之衍生物，且可視情況與習 用賦形劑、載劑或其組合合併。 在牛皮癖中， 為旋轉療法，供 掏時。大部份細 已知之組合治療已為有效Also intended to be included is a combination of two or more of the above, such as a combination of ezetimibe/simvastatin (vyt〇rin or price). Combination therapies having the above ingredient A are intended to be used in any of the methods of the invention, including the treatment of conditions and symptoms mediated by cytokines. In another aspect, the combination of the above is provided, comprising as described herein, h A and/or a plurality of compounds, such as a cytokine inhibitor, on the 31st / orally effective amount 'serving as A pharmaceutical composition having anti-cytokine activity is used. Further, a combination comprising ingredient A and a compound as described herein can be used in the preparation of a pharmaceutical composition for treating and/or preventing a condition or symptom mediated by a cytokine. & medicinal preparation containing a combination of one or more compounds as described herein/injury/promoting substance as an active substance, pharmaceutically acceptable derivative thereof, and optionally and conventionally used The excipient, carrier or combination thereof is combined. In psoriasis, for spin therapy, when it is supplied. Most of the known combinations of treatments have been effective

匕組合，係包括本文中所述之化合 物，其包括環孢素、皮美洛利馬 123505 -71 - 200815422 (pimecrolimus)、塔可利馬斯（tacrolimus)、阿斯可黴素（ascomycin)、 抗-CD4、抗-CD25、肽 T、LFA3TIP、DAB3 8 9、CTLA_4Ig、E-選擇素抑制劑、阿列發謝特（alefacept)、因弗利西馬 (infliximab)、恩塔臬西伯（etanercept)、也發利祖馬（efalizumab)， 及在 Griffiths，Christopher Ε· M·，1998 醫院醫藥，59 第 7 期中所揭 示者，以及其變型。用於治療牛皮癖之另一種典型組合， 係為如本文中所述之化合物與胺甲喋呤（ΜΤΧ)。預期若緩解 之維持係伴隨著良好生命品質而獲得，則由於ΜΤΧ在短期 内之良好耐藥性，及由於可接受性，故此組合係為有效。 用於治療牛皮癣之另一種典型組合，係為如本文中所述之 化合物與環孢素，尤其是由於環孢素對於引致缓解之效 率。本發明之另一項具體實施例係包括以下列順序之投 藥：以本文中所述之化合物與環孢素誘發，接著於減少服 藥及停止環孢素後，持續使用該化合物。用於治療牛皮癖 之另一種典型組合，係為本文中所述之化合物，且併用類 視色素。類視色素係提供最低功效，伴隨著潛在之Cyt Ρ450 交互作用與畸形發生性之危險，而其將經由以該化合物之 連續治療而被減輕。用於治療牛皮癖之又另一種典型組 合，係為本文中所述之化合物，且併用成份A，選自類固 醇，譬如皮質糖類固醇、維生素D類似物、類視色素及二 史蘭醇（dithranol)。在一些此種組合治療中，類固醇與類視 色素可以局部方式投藥。用於治療牛皮癣之一種較典型組 合，係為如本文中所述之化合物與維生素D衍生物，最典 型上為鈣波三醇（calcipotriol)或塔可洛西妥（tacalcitol)。用於治 123505 -72- 200815422 療牛皮癣之另一種典型組合，係為本文中所述之化合物， 且併用大壞内S旨類’敢典型上為阿斯可徽素（asc〇myCin)類似 物，以局部方式投藥，而又更典型上為可以經口方式取用 者，譬如皮美洛利馬（pimecrolimus)。用於治療牛皮癖之另一 種典型組合，係為本文中所述之化合物，且併用細胞黏連 分子抑制劑，譬如抗LFA3及/或抗LFA1。這包括黏連分子阻 斷’耩由重組融合蛋白質，例如阿列發謝特（alefacept)、抗 LFA3-IgCl，或精由抗-CD11早株抗體、也發利祖馬加匕） 及其顯著變型。細胞黏連分子抑制劑顯示會提供可接受之 回應率，具有有限之而寸藥性問題。與本文中所述化合物之 組合應避免其可注射形式之缺點，其中CAM抑制劑係被間 歇性地使用。本發明之另一項具體實施例係包括以下列川貝 序之投藥··以如本文中所述之化合物與CAM抑制劑誘發， 接著單獨以該化合物維持治療，而若顯著復發則以CAM抑 制劑再治療。 用於治療牛皮癬之另一種典型組合，係為如本文中所述 之化合物與另一種抗-TNFa成份。典型具體實施例為其中另 一種抗-TNFa成份係選自因弗利西馬（infliximab)或恩塔臬西 伯（etanercept)，典型上為因弗利西馬（infliximab)者。在本發明 之範圍内者為TNFa之局部或一般反有意義抑制劑之使用， 譬如阿利卡弗先（alicaforsen)與細胞素抑制劑化合物合併。用 於治療牛皮癬之另一種典型組合，係為本文中所述之化合 物與抗-CD4、抗-CD80 (IDEC-114 或 ABX-IL8)、DAB-IL_2、 DAB3 8 9 -IL-2、CTLA4-Ig、IL10，IL-2 受體抑制劑，譬如達可 123505 -73 - 200815422 利諸伯（daclizmnab)(抗-TAC)或巴西利馬伯（basiliximab)(參閱A combination of hydrazines, including the compounds described herein, including cyclosporine, pimelolima 123505-71 - 200815422 (pimecrolimus), tacrolimus, ascomycin, anti-CD4, anti-CD25, peptide T, LFA3TIP, DAB3 8 9, CTLA_4Ig, E-selectin inhibitor, alefacept, infliximab, entnercept ), also known as efalizumab, and in Griffiths, Christopher Ε·M·, 1998 Hospital Medicine, 59, Issue 7, and its variants. Another typical combination for the treatment of psoriasis is a compound as described herein and an amine formazan. It is expected that if the maintenance of the relief is obtained with good quality of life, the combination is effective due to the good resistance in the short term and the acceptability. Another typical combination for the treatment of psoriasis is a compound as described herein and cyclosporin, especially due to the effect of cyclosporine on the remission. Another embodiment of the invention comprises administering the compound in the following order: with the compound described herein and cyclosporine, followed by continued use of the compound after reducing the administration and stopping cyclosporine. Another typical combination for the treatment of psoriasis is the compound described herein, and a retinoid is used in combination. Retinoids provide minimal efficacy, with the potential for Cyt(R) 450 interaction and malformation, which will be alleviated by continuous treatment with the compound. Yet another typical combination for the treatment of psoriasis is the compound described herein, in combination with ingredient A, selected from the group consisting of steroids, such as corticosteroids, vitamin D analogs, retinoids, and dithranol. ). In some such combination therapies, steroids and retinoids can be administered in a localized manner. A more typical combination for the treatment of psoriasis is a compound and a vitamin D derivative as described herein, most typically calcipotriol or tacalcitol. Another typical combination for the treatment of psoriasis 123505 -72- 200815422 is the compound described in this article, and the combination of the big bad inside S is a typical example of asc〇 myCin analogue. It is administered in a local manner, and more typically it can be taken by oral means, such as pimecrolimus. Another typical combination for the treatment of psoriasis is the compound described herein, and a cell adhesion molecule inhibitor such as anti-LFA3 and/or anti-LFA1 is used in combination. This includes blocking molecules that block the 'recombinant fusion protein, such as alefacept, anti-LFA3-IgCl, or anti-CD11 early-type antibody, also rifampin plus sputum and its significant transform. Cell adhesion inhibitors have been shown to provide an acceptable response rate with limited and susceptibility problems. Combinations with the compounds described herein should avoid the disadvantages of injectable forms thereof, wherein the CAM inhibitors are used intermittently. Another embodiment of the present invention comprises administration of the following Chuanbei sequence with a compound as described herein and a CAM inhibitor, followed by maintenance of the compound alone, and CAM inhibition if significant recurrence Re-treatment. Another typical combination for the treatment of psoriasis is a compound as described herein and another anti-TNFa component. A typical embodiment is one in which the anti-TNFa component is selected from the group consisting of infliximab or etanercept, typically infliximab. Within the scope of the present invention is the use of a topical or general anti-significant inhibitor of TNFa, such as alicaforsen combined with a cytokine inhibitor compound. Another typical combination for the treatment of psoriasis is the compound described herein with anti-CD4, anti-CD80 (IDEC-114 or ABX-IL8), DAB-IL_2, DAB3 8 9 -IL-2, CTLA4- Ig, IL10, IL-2 receptor inhibitors, such as dako 123505-73 - 200815422 daclizmnab (anti-TAC) or brazilian lima (basiliximab) (see

Tutrone，”關於牛皮癣之生物學療法，簡略歷史，〗，，，關於牛皮 癬之生物學療法，2001，68, 331 ; Ben-Bassat，，，酪胺酸激酶抑制 劑之生物學活性··關於牛皮癖療法之新穎藥劑，，，在研究藥 物上之現行見解，2001，2(11)，1539 ; Salim等人，”以間白血球活 素-2作為治療牛皮癖之標的”，在研究藥物上之現 2001，2(11)，1546)。 ’ 亦可使用本文中所述之組合，以降低牛皮癖臨床跡象之 數目或嚴重性。 在本赉明範圍内之任何上文所提及之組合，可藉由此項 技藝中已知之動物模式測試。關於此點可參考：Schon，Michael R 1999牛皮癬之動物模式—吾人可從彼等學習到什麼，研 究皮膚病學學會—回顧，112.第4期，4〇5。 在風濕十生㈣1中，（疫壓抑或免疫調制劑之組合係為 長』且良好建立之治療範例。組合配對物可選自各種治療 坏叉符之、、驗資料為基礎 礎。此等藥劑係一般 或以明確定義之作用模式為基Tutrone, "Biological Therapy for Psoriasis, A Brief History,",, Biotherapeutics for Psoriasis, 2001, 68, 331; Ben-Bassat,,, Biological Activity of Tyrosine Kinase Inhibitors Novel remedies for sputum therapy, current observations on research drugs, 2001, 2(11), 1539; Salim et al., "The use of interleukocytokinin-2 as a marker for the treatment of psoriasis", on research drugs Now 2001, 2(11), 1546). 'The combination described herein can also be used to reduce the number or severity of clinical signs of psoriasis. Any combination of the above mentioned within the scope of the present invention, It can be tested by animal model known in the art. For this, please refer to: Schon, Michael R 1999 Animal Model of Psoriasis - What Can We Learn From They, Research Society of Dermatology - Review, 112. 4 Period, 4〇5. In rheumatism (4)1, (the combination of epidemic depression or immunomodulator is long) and a well-established treatment paradigm. The combination partner can be selected from various treatments for bad forks, and the test data is Foundation basis Or to act agent system is generally defined as a group of patterns

只體其確涊係無論是以藉由展開關於其從屬機制之知識 所支持之經驗杳刹^ ^ 用於治療風濕性關節炎之 性關節炎之典型組合，係為如本文中所述 或多種下列免疫壓抑、免疫調制或細胞抑 123505 -74- 200815422 制藥物合併’例如每氣4、D-青徽胺、硫酸沙_ (sulfasalazine)、 歐蘭諾吩（auranofm)、硫基蘋果酸金鈉、二甲胺四環素、達 普松（dapsone)、苯丁酸氮界（chlorambucil)、魏基η票呤、塔可利 馬斯（tacrolimus)、喜洛利莫斯（sirolimus)、分枝酚酸莫非替 (mycophenolate mofetil)、環孢素、列弗諾醯胺（leflunomide)、胺 甲喋呤、硝基脒唑硫嘌呤或環磷醯胺。用於治療風濕性關 節炎之另一種典型組合，係為如本文中所述之化合物，與 血管生成抑制劑合併，譬如針對VEGF之化合物、紅豆杉 醇、己酮可可豆驗、g太胺喊唆酮、干擾素分1B及α-干擾素。 用於治療風濕性關節炎之又另一種典型組合，係為如本文 中所述之化合物，且併用細胞黏連之抑制劑，譬如LFA-1抑 制劑或ICAM-1抑制劑。 用於治療風濕性關節炎之另一種典型組合，係為如本文 中所述之化合物，且併用抗-TNFa抗體或TNFa-受體拮抗劑， 譬如恩塔臬西伯（etanercept)、因弗利西馬（infliximab)、阿達利 母馬（adalimumab) (D2E7)，或生物劑，譬如CTLA-4，或針對標 的譬如 CD-4、LFA-1、IL-6、ICAM-1、C5 或 IL-1 受體之生物 劑。在另一項具體實施例中，如本文中所述之化合物係與 單獨因之弗利西馬（infliximab)或因弗利西馬與胺甲喋呤合 併。用於治療風濕性關節炎之另一種典型組合，係為如本 文中所述之化合物，且併用IL-1受體拮抗劑，譬如安那金 拉（anakinra) (KINERET)。用於治療風濕性關節炎之又另一種 典型組合，係為如本文中所述之化合物，與NSAID合併’ 包括乙醯胺吩（acetaminophen) '阿斯匹靈、異丁苯丙酸 123505 -75 - 200815422 (ibuprofen)、膽驗柳酸鎮、柳酸膽驗、二可吩拿克（diclofenac)、 二氟苯柳酸、依托多拉克（etodolac)、菲諾丙吩（fenoprofen)妈、 氟雙丙吩、Η丨嗓美薩辛（indomethacin)、酮基丙吩（ketoprofen)、 卡丙吩、4丨嗓丙吩（indoprofen)、酮洛拉克（ketorolac) 丁三醇胺、 柳酸鎮、甲氯滅酸納、甲滅酸、崎普羅辛（oxaprozin)、p比氧 胺（piroxicam)、柳酸鈉、沙林達克（sulindac)、四苯醯p比洛乙酸 (tolmetin)、美氧胺（meloxicam)、羅費庫西比（rofecoxib)、塞拉庫 西比（celecoxib)、依托庫西比（etoricoxib)、維德庫西比 (valdecoxib)、那布美東（nabumetone)、丙新（naproxen)、羅莫氧 胺（lomoxicam)、尼美沙利得（nimesulide)、Θ 卜朵丙吩（indoprofen)、 瑞米吩宗（remifenzone)、沙沙雷特（salsalate)、提普若吩克酸 (tiaprofenic acid)、弗蘇利得（flosulide)等。用於治療風濕性關節 炎之另一種典型組合，係為如本文中所述之化合物，與類 固醇合併，譬如皮質糖類固醇，例如分美塞松、地塞米松、 甲基氫化潑尼松、氫化潑尼松及地弗雜可（deflazacort)。 亦可使用本文中所述之組合，以降低風濕性關節炎之至 少一種標記。 在本發明範圍内之任何本文所提及之組合，可藉由此項 技藝中已知之動物模式測試（參閱Wooley，P· H· 1998，關節炎 之動物模式，Klippel J· H·，Dieppe，P. A·(編著）Rheumatology，第 二版，5.8.1，Mosby，London，Philadelphia，St. Louis，Sydney，Tokio)。 在克隆氏病中，下列藥物組群可與如本文中所述之化合 物合併：類固醇，譬如布蝶松化物，5-ASA藥物，例如美沙 胺（mesalamine)、免疫壓抑劑、生物劑及黏連分子抑制劑。用 123505 -76- 200815422 於治療克隆氏病之典型組合，係為如本文中所述之化合物 與下列之一或多種：類固醇，包括所有此處所列示者， 5-ASA，胺甲喋呤及瑣基脒唑硫嘌呤。用於治療克隆氏病之 另一種典型組合，係為本文中所述之化合物，與IL-1受體 拮抗劑合併，譬如安那金拉（anakinra) (KINERET)。用於治療 克隆氏病之又另一種典型組合，係為本文中所述之化合物 與抗-TNFa抗體或TNFa-受體拮抗劑，譬如恩塔臬西伯 (etanercept)、因弗利西馬（infliximab)、阿達利母馬（adalimumab) (D2E7)，或生物劑，譬如CTLA-4，或針對標的譬如CD-4、 LFA-1、IL-6、ICAM-1或C5之生物劑。在另一項具體實施例 中，本文中所述之化合物係與因弗利西馬（infliximab)與胺甲 喋呤合併。該化合物更典型上為細胞素抑制劑，且與因弗 利西馬（infliximab)合併。用於治療克隆氏病之另一種典型組 合，係為本文中所述之化合物，與IL-10、阿利卡弗先（alicaforsen) (抗ICAM 1)或安替葛連（antegren)(VCAM受體拮抗劑）合併。 於本發明之另一方面，係提供增加病患之HDL-含量之方 法。此等方法包括對病患，譬如有需要之病患，投予一數 量之化合物，譬如細胞素抑制劑，相對於投予該化合物前 之含量，其係有效增加該病患之HDL-含量，其中該化合物 係如本文中所述，或其立體異構物、互變異構物、溶劑合 物、前體藥物或藥學上可接受之鹽。在一些具體實施例中， 化合物為p38抑制劑。在某些具體實施例中，病患係患有或 處於如本文中所述之細胞素所媒介病症之危險下。在一些 具體實施例中，於投藥前之HDL含量係低於約70毫克/公 123505 -77- 200815422 合，低於約65毫克/毫升，低於約60毫克/公合，低於約55 毫克/公合，低於約50毫克/公合，低於約45毫克/公合，或 低於約40毫克/公合。例如，於投藥前之HDL含量係低於約 55毫克/公合。在一些具體實施例中，HDL為HDL2，然而在 其他具體實施例中，其為HDL3。在其他具體實施例中，病 患具有LDL含量低於約150毫克/毫升。 在病患中增加HDL-含量之方法之一些具體實施例中，病 患係處於血管事件之危險下，例如血栓形成病症、心肌梗 塞、絞痛、中風、短暫絕血性發作、於冠狀介入程序後之 血栓形成再閉塞及/或其中至少一個主冠狀動脈顯示大於 50%狹窄之病症之一或多種。在一些此種具體實施例中， 血管事件為心血管事件或腦血管事件。在一些具體實施例 中，相對於處於血管事件之危險下，尚未被投予該化合物 之病患，血管事件之發生或嚴重性之降低係存在。於又其 他具體實施例中，病患正患有或處於患有糖尿病、胰島素 抗藥性或代謝徵候簇之危險下。 在一些具體實施例中，於病患中增加HDL-含量之方法係 另外包括投予制菌素或HMG-CoA還原酶抑制劑，譬如阿托 瓦制菌素（atorvastatin) (LIPITOR，TORVAST)、弗伐制菌素 (fluvastatin) (LESCOL)、洛伐制菌素（lovastatin) (MEVACOR， ALTOCOR)、美伐制菌素（mevastatin)、皮塔伐制菌素（pitavastatin) (LIVALO，PITAVA)、普拉伐制菌素（pravastatin) (PRAVACHOL， SELEKTINE，LIPOSTAT)、洛蘇伐制菌素（rosuvastatin) (CRESTOR) 或辛伐制菌素（simvastatin) (ZOCOR, LIPEX);纖維酸酯，譬如傑 123505 -78 - 200815422 非布洛吉（gemfibrozil)、非諾纖酸酯（fenofibrate)、苯雜纖酸酯 (bezafibrate)、西普纖酸酯（ciprofibrate)、氯苯丁酯（clofibrate)或可 利諾纖酸酯（clinofibrate);膽汁酸多價螯合劑，譬如消膽胺 (cholestyramine) (QUESTRAN);膽固醇吸收抑制劑，譬如可列斯 替保（colestipol) (COLESTID)或也吉提麥伯（ezetimibe) (ZETIA);菸 鹼酸；含植物固醇之產物；ω3-脂肪酸類；或其兩種或多種 之組合，例如也吉提麥伯（ezetimibe)/辛伐制菌素（simvastatin) (VYTORIN或INEGY)。在一些具體實施例中，病患之HDL含 量係被增加達至少約5%，達至少約7%，達至少約10%，或 達至少約15%。例如，病患之HDL含量係被增加達至少約 12%。在其他具體實施例中，病患之HDL含量可被增加達約 5%至約20%。 於另一方面，係提供增加病患之Αρο-Α1·含量之方法。此 等方法包括對病患投予一數量之化合物，譬如細胞素抑制 劑，相對於投予該化合物前之含量，其係有效增加該病患 之Αρο-Al-含量，其中該化合物係如本文中所述，或其立體 異構物、互變異構物、溶劑合物、前體藥物或藥學上可接 受之鹽。在一些具體實施例中，AP〇-A1_含量係被增加達至 少約5%，或達至少約10%。在其中Apo-Al含量係被增加之 某些病患中，於投藥前之病患HDL含篁係低於約70宅克/么 合，低於約65毫克/公合，低於約60毫克/公合，低於約55 毫克/公合，低於約50毫克/公合，低於約45毫克/公合’或 低於約40毫克/公合。在其他具體實施例中’於投藥别之 HDL含量係低於約55毫克/公合；或於投藥前之病患LDL含 123505 -79- 200815422 ί =係低於約15〇毫克/毫升。在—些具體實施例中，病患係 t於血管事件之危險下’例如血栓形成病症、心肌梗塞、 紋痛、中風、短暫絕血性發作、於冠狀介入程序後之血检 形成再閉塞及其中至少一個主冠狀動脈顯示大於鄕狹窄 之=症之-或多種。例如，血管事件可為心血管事件或腦 血官事件。在_些具體實施例中’相對於處於血管事件之 、下尚未被投予細胞素抑制劑之病患，血管事件之發 生或嚴重性之降低係存在。在其他具體實施例中，病患正 '。有或處於患有糖尿病、胰島素抗藥性或代謝徵候襄之危 險下°在—些具體實施例中，病患之HDL含量係被增加達 至少約5%，達至少約7%，達至少約1 〇%，或達至少約i 5 %。 :如’病患之HDL含量係被增加達至少約12%。在其他具體 只施例中’病患之HDL含量可被增加達約5%至約2〇%。 ;另方面’係提供降低或防止增加有需要病患之收縮 或舒張血麼之方法。此等方法包括對病患投予一數量之化 合物’相對於投予該化合物前之’其係有效降低或防 止增加該病患之收縮或舒張血麼，其中該化合物係如本文 中所述，或其立體異構物、互變異構物、溶劑合物、前體 藥物或藥學上可接受之鹽。在一些具體實施例中，血慶為 縮壓在其他具體實施例中，血壓為舒張血壓。在一 些具體實施例中’於投藥前之病患收縮血麼係高於140毫米 Hg ’而於投予化合物前之舒張血壓係高於卯毫米％。在其 他具體實施例中’於投予化合物前之舒張血塵係高於以毫 米Hg。在-些具體實施例中，收縮或舒張血屬或兩者之降 123505 200815422 =係為至少約5毫米Hg，至少約3毫米Hg，或至少約2毫米 H§在其中收縮或舒張血壓係被降低或被防止增加之某些 ;匕中於技藥鈾之病患HDL含量係低於約7〇毫克/公合， 低於約65毫克/公合，低於約60毫克/公合，低於約55毫克/ 公^，低於約50毫克/公合，低於約45毫克/公合或低於約 /毫克/ a a。在其他具體實施例中，於投藥前之含量 係低於約55毫克/公合；或於投藥前之病患LDL含量係低於 Γ約⑼毫克/毫升。在—些具體實施例中，病患係、處於血管 事件之危險下，例如血栓形成病症、心肌梗塞、絞痛、中 風、短暫絕血性發作、於冠狀介入程序後之血栓形成再閉 塞及其中至少一個主冠狀動脈顯示大於狹窄之病症之 一或多種。例如，血管事件可為心血管事件或腦血管事件。 在一些具體實施例中，相對於處於血管事件之危險下，尚 未被投予本文中所述化合物之病患，本發明方法係在病患 中產生血管事件之發生或嚴重性之降低。在其他具體實施 、例中，病患正患有或處於患有糖尿病、胰島素抗藥性或代 謝徵候簇之危險下。在一些具體實施例中，病患之1^1含 量可被增加達至少約5%，達至少約7%，達至少約1〇%，或 達至少約15%。例如，病患之hdL含量係被增加達至少約 12%。在其他具體實施例中，病患之hdl含量可被增加達約 5%至約20%。 於本文中所揭示之化合物，譬如細胞素抑制劑，可於組 合療法中併用一或多種抗高血壓劑，例如ACE抑制劑、約 通道阻斷劑、酸固酮拮抗劑、血管收縮素π拮抗劑、利尿 123505 200815422 劑、苯并硫氮七圜烯衍生物、/3阻斷劑、二氫吡啶衍生物、 鉀節制劑、泌尿科學劑、績醯胺類或p塞唾化物。實例包括 貝那皆普利（benazepril)、安那拉普利（enalapril)、利辛諾普利 (lisinopril)、奎那普利（quinapril)、卡普脫普利（captopril)、瑞米 普利（ramipril)、螺甾内醋、臥美沙坦（olmesartan)、法沙坦 (valsartan)、貼米沙坦（telmisartan)、法沙坦（valsartan)、若沙坦 (losartan)、愛貝沙坦（irbesartan)、迪耳替阿簡（diltiazem)、異博 停（verapamil)、特蘭多普利（trandolapril)、胺 St 心安（atenolol)、 必梭普羅（bisoprolol)、美多心安（metoprolol)、托普洛（toprol)、 填諾瑞提（tenoretic)、胺若地平（amlodipine)、硝苯吡啶 (nifedipine)、非若地平（felodipine)、尼索地平（nisoldipine)、胺苯 喋唆、利尿磺胺、速尿劑（lasix)、旅嗤畊（prazosin)、丙喏羅 (propanolol)、氫氯p塞p井或其兩種或多種之組合。 於另一方面，係提供降低PAI-1含量或防止其升高之方法。 此等方法包括對處於增加PAM含量危險下之病患（例如在 患有或處於肥胖、代謝徵候簇或炎性症狀危險下之病患中） 投予一數量之化合物’相對於未經治療病患中之含量，其 係有效降低該病患之pAI_l_含量或防止其升高，其中化合物 係如本文中所述，或其立體異構物、互變異構物、溶劑合 物、前體藥物或藥學上可接受之鹽。 於本發明之又另一方面’係提供降低病患之三酸甘油酯 含量之方法。此等方法包括對病患譬如有需要之病患投予 一數量之化合物，譬如細胞素抑制劑，相對於投予該化合 物前之含量，其係有效降低該病患之三酸甘油酯含量，其 123505 -82· 200815422 中該化合物係如本文中所述，或其立體異構物、互變異構 物、溶劑合物、前體藥物或藥學上可接受之鹽。在一些具 體實施例中，於投藥前之三酸甘油酯含量係高於500毫克/ 公合，高於200毫克/公合，或高於150毫克/公合。例如， 於投藥前之三酸甘油酯含量係高於200毫克/公合。在某些 具體實施例中，病患係患有或處於如本文中所述之細胞素 所媒介病症之危險下。在其他具體實施例中，病患係處於 血管事件之危險下，例如血栓形成病症、心肌梗塞、絞痛、 中風、短暫絕血性發作、於冠狀介入程序後之血栓形成再 閉塞及其中至少一個主冠狀動脈顯示大於50%狹窄之病症 之一或多種。在一些此種具體實施例中，血管事件為心血 管事件或腦血管事件。在一些具體實施例中，相對於處於 血管事件之危險下，尚未被投予化合物之病患，血管事件 之發生或嚴重性之降低係存在。在本發明之一些具體實施 例中，該方法另外包括投予制菌素或HMG-CoA還原酶抑制 劑，譬如阿托瓦制菌素（atorvastatin) (LIPITOR，TORVAST)、弗伐 制菌素（fluvastatin) (LESCOL)、洛伐制菌素（lovastatin) (MEVACOR， ALTOCOR)、美伐制菌素(mevastatin)、皮塔伐制菌素(pitavastatin) (LIVALO，PITAVA)、普拉伐制菌素（pravastatin) (PRAVACHOL， SELEKTINE，LIPOSTAT)、洛蘇伐制菌素（rosuvastatin) (CRESTOR) 或辛伐制菌素（simvastatin) (ZOCOR，LIPEX);纖維酸酯，譬如傑 非布洛吉（gemfibrozil)、非諾纖酸酯（fenofibrate)、苯雜纖酸酯 (bezafibrate)、西普纖酸酯（ciprofibrate)、氯苯丁酯（clofibrate)或可 利諾纖酸酯（clinofibrate);膽汁酸多價螯合劑，譬如消膽胺 123505 -83 - 200815422 (cholestyramine) (QUESTRAN);膽固醇吸收抑制劑，譬如可列斯 替保（colestipol) (COLESTID)或也吉提麥伯（ezetimibe) (ZETIA);於 鹼酸；含植物固醇之產物；ω3_脂肪酸類；或其兩種或多 種之組合，例如也吉提麥伯（ezetimibe)/辛伐制菌素（simvastatin) (VYTORIN或INEGY)。在其他具时施財，病患正患有或 處於患有糖尿病、胰島素抗藥性或代謝徵候簇之危險下。 在一些具體實施例中，病患為靈長類動物，特別是人類。 在本發明之-些具體實施射，病患之三酸甘油§旨含量係 被降低達至少約10%。在其他具體實施例中，病患之三酸 甘油酯含量係被降低達至少約20%。 於本發明之又另-方面，係提供在病患中降低斷食葡萄 糖含量之方法。此等方法包括對病患譬如有需要之病患投 予一數量之化合物，譬如細胞素抑制劑，相對於投予該化 合物前之含量’其係有效降低病患中之斷食葡萄糖含量， 其中該化合物係如本文中所述，或其立體異構物、互變異 構物、溶劑合物、前體藥物或藥學上可接受之鹽。在一些 具體實施例中’於投藥前之葡萄糖含量係高於：13。毫克二/ 公合。在其他具體實施财，葡萄糖含量係被降低達約 5%，約·，約20%或約3〇%。在某些具體實施例中，病患 係患有或處於如本文中所述之細胞素所媒介病症之危險 下。在其他具體實施例中，病患係患有或處於患有糖尿病、 騰島素抗藥性或代謝徵候簇之危險下。在一些具體實施例 中’該方法係進-步包括投Η料丁脉、醋績環己腺、 甲石黃氮革脲、氯續丙脉、葛利皮再得(gUpizide)、葛來布賴得 123505 • 84 - 200815422It is a typical combination of arthritis for the treatment of rheumatoid arthritis, whether it is based on the knowledge supported by its knowledge of its subordinate mechanisms, as described herein or in various The following immunosuppressive, immunomodulatory or cytostatic drugs are combined with drugs such as glycerol, sulfasalazine, auranof, and sodium thiomalate. , minocycline, dapsone, chlorambucil, weiki η, tacrolimus, sirolimus, branched phenolic acid Mycophenolate mofetil, cyclosporine, leflunomide, amidoxime, nitrooxazolium or cyclophosphamide. Another typical combination for the treatment of rheumatoid arthritis is a compound as described herein, in combination with an angiogenesis inhibitor, such as a compound against VEGF, taxol, ketone cocoa, and g-amine Anthrone, interferon 1B and alpha-interferon. Yet another typical combination for the treatment of rheumatoid arthritis is a compound as described herein, in combination with an inhibitor of cell adhesion, such as an LFA-1 inhibitor or an ICAM-1 inhibitor. Another typical combination for the treatment of rheumatoid arthritis is a compound as described herein, in combination with an anti-TNFa antibody or a TNFa-receptor antagonist, such as etanercept, Inverness Horse (infliximab), adalimumab (D2E7), or biological agent, such as CTLA-4, or against target such as CD-4, LFA-1, IL-6, ICAM-1, C5 or IL-1 Receptor biological agent. In another specific embodiment, the compound as described herein is combined with infliximab or inflixima and amidoxime alone. Another typical combination for the treatment of rheumatoid arthritis is a compound as described herein, and in combination with an IL-1 receptor antagonist, such as anakinra (KINERET). Yet another typical combination for the treatment of rheumatoid arthritis is a compound as described herein, combined with an NSAID 'including acetaminophen 'aspirin, ibuprofen 123505-75 - 200815422 (ibuprofen), biliary acid, sulphuric acid, diclofenac, diflufenic acid, etodolac, fenoprofen, fluorocarbon Propione, indomethacin, ketoprofen, cefprophene, indoprofen, ketorolac, succinylamine, salicylic acid, A Sodium chlorate, mefenamic acid, oxaprozin, p piroxicam, sodium citrate, sulindac, tetraphenyl hydrazine, tolmetin, methoxyamine (meloxicam), rofecoxib, celecoxib, etoricoxib, valdecoxib, nabumetone, naproxen ), lomoxicam, nimesulide, indoprofen Remy thiophene cases (remifenzone), Rett rustle (salsalate), if Kip thiophene grams acid (tiaprofenic acid), to give Fu Suli (flosulide) and the like. Another typical combination for the treatment of rheumatoid arthritis is a compound as described herein, in combination with a steroid, such as a corticosteroid, such as mesacon, dexamethasone, methylprednisolone, hydrogenated Prednisone and deflazacort. Combinations described herein can also be used to reduce at least one marker of rheumatoid arthritis. Any of the combinations mentioned herein within the scope of the present invention can be tested by animal models known in the art (see Wooley, P. H. 1998, Animal Model of Arthritis, Klippel J. H., Dieppe, P. A. (ed.) Rheumatology, Second Edition, 5.8.1, Mosby, London, Philadelphia, St. Louis, Sydney, Tokio). In Crohn's disease, the following drug groups can be combined with a compound as described herein: a steroid, such as a cedar, a 5-ASA drug, such as mesalamine, an immunosuppressive agent, a biological agent, and a adhesion agent. Molecular inhibitors. A typical combination of 123505-76-200815422 for the treatment of Crohn's disease is a compound as described herein with one or more of the following: steroids, including all those listed herein, 5-ASA, Aminoguanidine and Zilgicarbazole thiopurine. Another typical combination for the treatment of Crohn's disease is the compound described herein, in combination with an IL-1 receptor antagonist, such as anakinra (KINERET). Yet another typical combination for the treatment of Crohn's disease is a compound described herein with an anti-TNFa antibody or a TNFa-receptor antagonist, such as etanercept, infliximab (infliximab) ), adalimumab (D2E7), or a biological agent, such as CTLA-4, or a biological agent against a target such as CD-4, LFA-1, IL-6, ICAM-1 or C5. In another specific embodiment, the compounds described herein are combined with infliximab and amidoxime. This compound is more typically a cytokine inhibitor and is combined with infliximab. Another typical combination for the treatment of Crohn's disease is the compound described herein, with IL-10, alicaforsen (anti-ICAM 1) or antigren (VCAM receptor). Antagonists) combined. In another aspect of the invention, a method of increasing the HDL-content of a patient is provided. Such methods include administering to a patient, such as a patient in need, a quantity of a compound, such as a cytokine inhibitor, effective to increase the HDL-content of the patient relative to the amount prior to administration of the compound, Wherein the compound is as described herein, or a stereoisomer, tautomer, solvate, prodrug or pharmaceutically acceptable salt thereof. In some embodiments, the compound is a p38 inhibitor. In certain embodiments, the patient has or is at risk of a cytokine-mediated condition as described herein. In some embodiments, the HDL content prior to administration is less than about 70 mg/cm 123505-77-200815422, less than about 65 mg/ml, less than about 60 mg/cm, less than about 55 mg. /Male, less than about 50 mg / metric, less than about 45 mg / metric, or less than about 40 mg / metric. For example, the HDL content prior to administration is less than about 55 mg/m. In some embodiments, the HDL is HDL2, while in other embodiments it is HDL3. In other embodiments, the patient has an LDL content of less than about 150 mg/ml. In some embodiments of the method of increasing HDL-content in a patient, the patient is at risk of a vascular event, such as a thrombotic disorder, myocardial infarction, colic, stroke, transient episodes of episodes, after a coronary intervention procedure Thrombosis reocclusion and/or one or more of the conditions in which at least one primary coronary artery exhibits greater than 50% stenosis. In some such embodiments, the vascular event is a cardiovascular event or a cerebrovascular event. In some embodiments, a decrease in the occurrence or severity of a vascular event is present in a patient who has not been administered the compound at risk of a vascular event. In still other embodiments, the patient is suffering from or at risk of having diabetes, insulin resistance, or metabolic syndrome. In some embodiments, the method of increasing HDL-content in a patient additionally comprises administering a bacteriocin or an HMG-CoA reductase inhibitor, such as atorvastatin (LIPITOR, TORVAST), Fluvastatin (LESCOL), lovastatin (MEVACOR, ALTOCOR), mevastatin, pitavastatin (LIVALO, PITAVA), Pravastatin (PRAVACHOL, SELEKTINE, LIPOSTAT), rosuvastatin (CRESTOR) or simvastatin (ZOCOR, LIPEX); fiber ester, 譬如杰123505 -78 - 200815422 non-brofibrozil, fenofibrate, bezafibrate, ciprofibrate, clofibrate or cola A clinofibrate; a bile acid sequestrant, such as cholestyramine (QUESTRAN); a cholesterol absorption inhibitor such as colestipol (COLESTID) or also Jetiger (a) Ezetimibe) (ZETIA); nicotinic acid; containing phytosterols Thereof; omega] 3-fatty acids; or a combination of two or more of, for example, as Seen Maibo (ezetimibe) / simvastatin prepared streptozotocin (simvastatin) (VYTORIN or INEGY). In some embodiments, the patient's HDL content is increased by at least about 5%, by at least about 7%, by at least about 10%, or by at least about 15%. For example, the patient's HDL content is increased by at least about 12%. In other embodiments, the patient's HDL content can be increased by from about 5% to about 20%. On the other hand, there is a method of increasing the Αρο-Α1· content of a patient. Such methods comprise administering to the patient a quantity of a compound, such as a cytokine inhibitor, effective to increase the Αρο-Al- content of the patient relative to the amount prior to administration of the compound, wherein the compound is as herein Said herein, or a stereoisomer, tautomer, solvate, prodrug or pharmaceutically acceptable salt thereof. In some embodiments, the AP〇-A1_ content is increased by up to about 5%, or by at least about 10%. In some patients in which the Apo-Al content is increased, the HDL containing lanthanide is less than about 70 ng/m, less than about 65 mg/cm, less than about 60 mg. /combined, less than about 55 mg / metric, less than about 50 mg / metric, less than about 45 mg / metric ' or less than about 40 mg / metric. In other embodiments, the HDL content of the drug is less than about 55 mg/cm; or the patient's LDL before administration is 123505-79-200815422 ί = less than about 15 mg/ml. In some embodiments, the patient t is at risk of a vascular event such as a thrombotic disorder, myocardial infarction, striated pain, stroke, transient episodes of episodes, re-occlusion of the blood after coronary intervention, and At least one of the main coronary arteries shows more than - or more than the stenosis. For example, a vascular event can be a cardiovascular event or a cerebral blood event. In some embodiments, a decrease in the occurrence or severity of a vascular event is present relative to a patient who has not been administered a cytokine inhibitor under a vascular event. In other embodiments, the patient is '. Having or at risk of having diabetes, insulin resistance, or metabolic syndrome ° In some embodiments, the patient's HDL content is increased by at least about 5% to at least about 7% to at least about 1 〇%, or at least about i 5%. : The HDL content of the patient is increased by at least about 12%. In other specific examples, the patient's HDL content can be increased by from about 5% to about 2%. Another aspect is to provide a means of reducing or preventing the contraction or diastolic blood of a patient in need. Such methods comprise administering to the patient a quantity of a compound which is effective to reduce or prevent an increase in contraction or diastolic blood of the patient prior to administration of the compound, wherein the compound is as described herein, Or a stereoisomer, tautomer, solvate, prodrug or pharmaceutically acceptable salt thereof. In some embodiments, blood is reduced. In other embodiments, the blood pressure is diastolic blood pressure. In some embodiments, the patient's contractile blood is higher than 140 mm Hg' prior to administration and the diastolic blood pressure before administration of the compound is greater than 卯 mm%. In other embodiments, the diastolic blood dust system prior to administration of the compound is higher than the Hg in millimeters. In some embodiments, the systolic or diastolic genus or both fall 123505 200815422 = is at least about 5 mm Hg, at least about 3 mm Hg, or at least about 2 mm H § where the systolic or diastolic blood pressure is Some of which reduce or are prevented from increasing; the HDL content of the uranium in the uranium is less than about 7 mg/cm, less than about 65 mg/cm, less than about 60 mg/cm, low. At about 55 mg/m^, less than about 50 mg/cm, less than about 45 mg/cm or less/about/mg/aa. In other embodiments, the amount prior to administration is less than about 55 mg/cm; or the LDL content of the patient prior to administration is less than about (9) mg/ml. In some embodiments, the patient is at risk of a vascular event, such as a thrombotic disorder, myocardial infarction, colic, stroke, transient episodes of episodes, thrombosis reocclusion after a coronary intervention procedure, and at least One primary coronary artery shows one or more of the conditions greater than stenosis. For example, a vascular event can be a cardiovascular event or a cerebrovascular event. In some embodiments, the method of the invention produces a reduction in the occurrence or severity of a vascular event in a patient relative to a patient who has not been administered a compound described herein at risk of a vascular event. In other embodiments, the patient is suffering from or at risk of having diabetes, insulin resistance, or metabolic syndrome. In some embodiments, the patient's 1 can be increased by at least about 5%, by at least about 7%, by at least about 1%, or by at least about 15%. For example, the patient's hdL content is increased by at least about 12%. In other embodiments, the hdl content of the patient can be increased by from about 5% to about 20%. The compounds disclosed herein, such as cytokine inhibitors, can be used in combination therapy with one or more antihypertensive agents, such as ACE inhibitors, about channel blockers, acid ketone antagonists, angiotensin π antagonism Agent, diuretic 123505 200815422 agent, benzothiazepine heptaene derivative, /3 blocker, dihydropyridine derivative, potassium preparation, urological agent, sulphate or p-salt. Examples include benazepril, enalapril, lisinopril, quinapril, captopril, rimipril (ramipril), snail vinegar, olmesartan, valsartan, telmisartan, valsartan, losartan, abesartan ( Irbesartan), diltiazem, verapamil, trandolapril, amine St atenolol, bisoprolol, metoprolol, care Toprol, tenoretic, amlodipine, nifedipine, felodipine, nisoldipine, amidoxime, diuretic sulfonamide, A urinary tract (lasix), prazosin, propanolol, hydrochloro p-plug, or a combination of two or more thereof. In another aspect, a method of reducing the PAI-1 content or preventing it from rising is provided. Such methods include administering a quantity of a compound to a patient at risk of increasing the level of PAM (eg, in a patient suffering from or at risk of obesity, metabolic syndrome, or inflammatory symptoms) versus untreated disease The content of the disease, which is effective to reduce or prevent the increase of the pAI_l_ content of the patient, wherein the compound is as described herein, or a stereoisomer, tautomer, solvate or prodrug thereof Or a pharmaceutically acceptable salt. In yet another aspect of the invention, a method of reducing the triglyceride content of a patient is provided. Such methods include administering to a patient, if desired, a quantity of a compound, such as a cytokine inhibitor, effective to reduce the triglyceride content of the patient relative to the amount prior to administration of the compound. The compound is as described herein, or a stereoisomer, tautomer, solvate, prodrug or pharmaceutically acceptable salt thereof, in 123505-82.200815422. In some embodiments, the triglyceride content prior to administration is greater than 500 mg/m, greater than 200 mg/m, or greater than 150 mg/m. For example, the triglyceride content prior to administration is greater than 200 mg/m. In certain embodiments, the patient has or is at risk of a cytokine-mediated condition as described herein. In other embodiments, the patient is at risk of a vascular event, such as a thrombotic disorder, myocardial infarction, colic, stroke, transient episodes of episodes, thrombosis reocclusion after coronary intervention, and at least one of the subjects The coronary artery shows one or more of the conditions of greater than 50% stenosis. In some such embodiments, the vascular event is a cardiovascular event or a cerebrovascular event. In some embodiments, the occurrence or severity of a vascular event is present relative to a patient who has not been administered a compound at risk of a vascular event. In some embodiments of the invention, the method additionally comprises administering a bacteriocin or an HMG-CoA reductase inhibitor, such as atorvastatin (LIPITOR, TORVAST), avermectin ( Fluvastatin) (LESCOL), lovastatin (MEVACOR, ALTOCOR), mevastatin, pitavastatin (LIVALO, PITAVA), prasin (pravastatin) (PRAVACHOL, SELEKTINE, LIPOSTAT), rosuvastatin (CRESTOR) or simvastatin (ZOCOR, LIPEX); fibrous acid esters, such as gemfibrozil ), fenofibrate, bezafibrate, ciprofibrate, clofibrate or clinofibrate; bile acid A chelating agent, such as cholestyramine 123505-83 - 200815422 (cholestyramine) (QUESTRAN); a cholesterol absorption inhibitor such as colestipol (COLESTID) or ezetimibe (ZETIA); Acidic acid; product containing phytosterols; omega-3 fatty acid a class; or a combination of two or more thereof, such as ezetimibe/simvastatin (VYTORIN or INEGY). At other time, the patient is suffering from or at risk of developing diabetes, insulin resistance or metabolic syndrome. In some embodiments, the patient is a primate, particularly a human. In some embodiments of the invention, the triglyceride content of the patient is reduced by at least about 10%. In other embodiments, the triglyceride content of the patient is reduced by at least about 20%. In still another aspect of the invention, there is provided a method of reducing the fasting glucose content in a patient. Such methods include administering to a patient, if necessary, a quantity of a compound, such as a cytokine inhibitor, relative to the amount prior to administration of the compound, which is effective to reduce the level of fasting glucose in the patient, wherein The compound is as described herein, or a stereoisomer, tautomer, solvate, prodrug or pharmaceutically acceptable salt thereof. In some embodiments, the glucose content prior to administration is higher than: 13. Mg 2 / metric. In other embodiments, the glucose content is reduced by about 5%, about 20% or about 3%. In certain embodiments, the patient has or is at risk of a cytokine-mediated condition as described herein. In other embodiments, the patient has or is at risk of having diabetes, tamper resistance or metabolic syndrome. In some embodiments, the method comprises the steps of: feeding the sputum, the vinegar, the sulphate, the sulphate, the chlorinated granule, the gupizide, the grebe. Laid 123505 • 84 - 200815422

/ k (glyburide)、葛利美皮利得（glimepiride)、葛利可拉再（glidazide)、 知？巴葛奈（repaglinide)、拿貼葛奈（nateglinide)、二曱雙脈 (metformin)、米葛利妥（miglitol)、阿卡糖（acarb〇se)、乙先素 (exendin)、普拉林太（p]:amlintide)、胰島素或其兩種或多種之 組合。在本發明之一些具體實施例中，病患係處於血管事 件之危險下’例如血栓形成病症、心肌梗塞、絞痛、中風、 短暫絕血性發作、於冠狀介入程序後之血栓形成再閉塞及/ 或其中至少一個主冠狀動脈顯示大於5〇%狹窄之病症之一 或多種。在一些此種具體實施例中，血管事件為心血管事 件或腦血管事件。在一些具體實施例中，相對於處於血管 事件之危險下，尚未被投予化合物之病患，血管事件之發 生或嚴重性之降低係存在。 於本發明之另一方面，係提供在病患中降低扭^ &值之方 法。此等方法包括對病患譬如有需要之病患投予一數量之 ^合物’譬如細胞素抑制劑，相對於投予該化合物前之含 量’其係有效降低病患中之Η^值，其中該細胞素抑制劑 係如本文中所述，或其立體異構物、互變異構物、溶劑合 物、剷體藥物或攀學/ k (glyburide), glimepiride, glidazide, know? Repaglinide, nateglinide, metformin, miglitol, acarbium, adenin, pralin Too (p): amlintide), insulin or a combination of two or more thereof. In some embodiments of the invention, the patient is at risk of a vascular event such as a thrombotic disorder, myocardial infarction, colic, stroke, transient episodes of episodes, thrombosis re-occlusion after a coronary interventional procedure, and/or Or one or more of the conditions in which at least one primary coronary artery exhibits greater than 5% stenosis. In some such embodiments, the vascular event is a cardiovascular event or a cerebrovascular event. In some embodiments, a decrease in the occurrence or severity of a vascular event is associated with a patient who has not been administered a compound at risk of a vascular event. In another aspect of the invention, a method of reducing the torque & value is provided in a patient. Such methods include administering to a patient, if necessary, a quantity of a compound such as a cytokine inhibitor, relative to the amount prior to administration of the compound, which is effective in reducing the value of the patient. Wherein the cytokine inhibitor is as described herein, or a stereoisomer, tautomer, solvate, shovel drug or climbing

飞梁子上了接文之鹽。在-些此種具體實施 Β ’病患係具有麗於約8%，高於約75%，U 於約7%。在复#且骑每 ^ ，、他-體貝細例中’ HbAlc含量係被降至約4% 間/在某些具體實施例中，病患係患有或處於 &述之細胞素所媒介病症之危險下。在其他1體 實施例中，痣*尨*七々各 你，、他具體 或代魅# 患有糖尿病、胰島素抗藥性 戈代錢候簇之危險下。在—些具體實施財，該方法係 123505 •85- 200815422 進一步包括投予甲苯石黃丁月尿、醋磺環己脲、甲磺氮革躲、 a ^ ^ ^ # (glipizide) ^ ^ ^ # (glyburide) ^ ^ 利美皮利得（glimepiride)、葛利可拉再（glidazide)、瑞巴葛夺 (repaglinide)、拿貼葛奈（nateglinide)、二甲雙胍（metf〇rmin)= 葛利妥（migl_、阿卡糖（acarbose)、乙先素（exendin)、普拉林 太（pramlintide)、胰島素或其兩種或多種之組合。在本發明之 -些具體實施例中，病患係處於血管事件之危險下，例如The flying beam was covered with salt. In some of these specific implementations, the patient has a level of about 8%, more than about 75%, and a U of about 7%. 'HbAlc content is reduced to about 4% in the complex # and riding every ^, and his body-shell example / in some embodiments, the patient has or is in the <> The danger of the vector illness. In the other 1 embodiment, 痣*尨*七々 each, you, or 代魅# have the risk of diabetes, insulin resistance, and God's money. In some specific implementations, the method is 123505 • 85- 200815422. Further includes administration of toluene yellow dimethyl urine, acesulfame, sulfonamide, a ^ ^ ^ # (glipizide) ^ ^ ^ # (glyburide ) ^ ^ glimepiride, glidazide, repaglinide, nateglinide, metf〇rmin = glitto (migl_, ar Acarbose, exendin, pramlintide, insulin, or a combination of two or more thereof. In some embodiments of the invention, the patient is at risk of a vascular event Next, for example

血栓形成病症、心肌梗塞、絞痛、中風、短暫絕血性發作、 於冠狀介入程序後之血栓形成再閉塞及/或其中至少一個 主冠狀動脈顯示大於50%狹窄之病症之一或多種。在一必 此種具體實施例中，血管事件為心、血管事件或腦血管事 件。在一些具體實施例中，相對於處於血管事件之危險下， 尚未被投予化合物之病患，血管事件之發生或嚴重性之降 低係存在。 於本發明之又另-方面，係提供在病患中降低胰島素含 Ϊ之方法。此等方法包括對病患譬如有需要之病患投予一 數量之化合物，譬如細胞素抑制劑，相對於投予該化合物 前之含量，其係有效降低病患中之胰島素含量，其中該化 合物係如本文中所述，或其立體異構物 '互變異構物、溶 劑合物、前體藥物或藥學上可接受之鹽。在一些此種具體 K施例中，病患係具有在投藥前之斷食胰島素含量高於約 Η)〇微微莫耳/升，高於約150微微莫耳/升，高於約2〇〇微微 莫耳/升，高於約250微微莫耳/升，高於約3〇〇微微莫耳/升， 而於約350微微莫耳/升，焉於約4〇〇微微莫耳/升，成高於 123505 -86 - 200815422A thrombotic disorder, myocardial infarction, colic, stroke, transient episodes of seizures, thrombosis reocclusion after a coronary interventional procedure, and/or one or more of the conditions in which at least one primary coronary artery exhibits greater than 50% stenosis. In a particular embodiment, the vascular event is a cardiac, vascular event or cerebrovascular event. In some embodiments, the occurrence or severity of a vascular event is present relative to a patient who has not been administered a compound at risk of a vascular event. In still another aspect of the invention, there is provided a method of reducing insulin sputum in a patient. Such methods include administering to a patient, if desired, a quantity of a compound, such as a cytokine inhibitor, effective to reduce insulin levels in the patient relative to the amount prior to administration of the compound, wherein the compound As described herein, or a stereoisomer 'tautomer, solvate, prodrug or pharmaceutically acceptable salt thereof. In some such specific K embodiments, the patient has a fasting insulin level above about Η) 〇 picomol/L, above about 150 picomoles per liter, above about 2 〇〇. Pico Moules / liters, above about 250 picomoles per liter, above about 3 〇〇 micromole / liter, and at about 350 picomol / liter, 焉 about 4 〇〇 pico liters / liter, Into higher than 123505 -86 - 200815422

約500微微莫耳/升。在其他具體實施例中，病患係具有餐 後胰島素纟量高於約400微微莫耳/升，高於約微微莫耳 /升，高於約600微微莫耳/升’高於約7〇〇微微莫耳/升，或 高於約_微微莫耳/升。在-些具體實施例中，騰島素含 量係被降低達約，約20% ’約3〇%，或約4〇%。在某些 具體實施例中，病患係患有或處於如本文中所述之細胞; 所媒介病症之危險下。在又其他具體實施例中，病患係患 有或處於患有糖尿病、冑島素抗藥性或代謝徵候蔟之危險 下。在本發明之-些具體實施例中，該方法係進—步包括 投予甲苯磺丁脲、醋磺環己脲、甲磺氮萆脲、氯磺丙脲、 葛利皮再得（glipizide)、葛來布賴得（glyburide)、葛利美皮利得 (glimepiride)、葛利可拉再（gliclazide)、瑞巴葛奈（哪峡刪、拿 貼葛奈（nateglinide)、二甲雙胍(metf〇nnin)、米葛利妥（migUt〇i)、 阿卡糖（acarbose)、乙先素（exendin)、普拉林太（pramiintide)、胰 島素或其兩#或多#之組合。“發明之一些具體實施例 中’病患係處於血管事件之危險下，例如血栓形成病症、 心肌梗塞、絞痛、中風、短暫絕血性發作、於冠狀介入程 序後之血栓形成再閉塞及/或其中至少—個主冠狀動脈顯 示大於50%狹窄之病症之一或多種。在一些此種具體實施 例中，血管事件為心血管事件或腦血管事件。在一些具體 實施例中，相對於處於血管事件之危險下，尚未被投予化 合物之病患，血管事件之發生或嚴重性之降低係存在。 於本發明之另一方面，係提供在病患中降mH〇MA胰島 素抗藥性指數之方法。此等方法包括對病患譬如有需要之 123505 -87- 200815422About 500 picomoles per liter. In other embodiments, the patient has a postprandial insulin dose greater than about 400 picomoles per liter, above about pico-mole/liter, above about 600 picomoles per liter' above about 7 inches. 〇 slightly moir / liter, or higher than about _ pico m / liter. In some embodiments, the content of temsin is reduced by up to about 20% by about 3%, or about 4%. In certain embodiments, the patient has or is at a risk of a disease as described herein; In still other embodiments, the patient is at or at risk of having diabetes, sputum resistance, or metabolic syndrome. In some embodiments of the invention, the method further comprises administering tolbutamide, acesulfame hexaurea, methotrexate, chlorpropamide, glilipide (glipizide) , glyburide, glimepiride, gliclazide, ribagana (which is removed from the gorge, nateglinide, metformin (metf〇nnin) ), migUlt〇i, acarbose, exendin, pramiintide, insulin or a combination of two or more #. In the examples, the patient is at risk of a vascular event, such as a thrombotic disorder, myocardial infarction, colic, stroke, transient episodes of episodes, thrombosis reocclusion after coronary intervention, and/or at least one of them The coronary artery exhibits one or more of the conditions of greater than 50% stenosis. In some such embodiments, the vascular event is a cardiovascular event or a cerebrovascular event. In some embodiments, relative to the risk of a vascular event, Not yet administered to a compound In the other aspect of the invention, there is provided a method for reducing the insulin resistance index of mH〇MA in a patient. Such methods include, if necessary, for a patient. 123505 -87- 200815422

病」又予-數量之化合物’譬如細胞素抑制劑，相對於投 予該，合物前之指數，其係有效降低病患中之hqma姨島 素抗樂性指數’其中該化合物係如本文中所述，或其立體 異構物、互變異構物、溶劑合物、前體藥物或藥學上可接 受之鹽。在-些此種具體實施例中，冑島素抗藥性指數係 被降至低於約2.5，低於約2.0，或低於約u。在一些具體實 施例中，騰島素抗藥性指數係被降低達約1()%，約观，或 約30。？^些具體實施例中，病患係需要降低之醜a胰 島素抗藥性指數，因為例如病患係患有或處於如本文中所 述細胞素所媒介病症之危險下。在其他具體實施例中，病 患係患有或處於患有糖尿病、胰島素抗藥性或代謝徵候義 之危險下。在本發明之一些具體實施例中，該方法係進一 步包括投予甲苯績T脲、醋確環己脲、甲魏萆脲、氯續 丙脲、葛利皮再得（glipizide)、葛來布賴得（glyburide)、葛利美 皮利得（glimepiride)、葛利可拉再（gliclazide)、瑞巴葛奈 (repagUnide)、拿貼葛奈（她glinide)、二甲雙胍（metf〇nnin)、= 葛利妥（miglitol)、阿卡糖（acarb〇se)、乙先素㈣邱伽）、普拉林 太（pmmlintide)、胰島素或其兩種或多種之組合。在本發明之 一些具體實施例中，病患係處於血管事件之危險下，例如 血栓形成病症、心肌梗塞、絞痛、中風、短暫絕血性發作、 於成狀介入程序後之血栓形成再閉塞及/或其中至少一個 主冠狀動脈顯示大於50%狹窄之病症之一或多種。在一些 此種具體實施例中，血管事件為心血管事件或腦血管事 件。在一些具體實施例中，相對於處於血管事件之危險下， 123505 -88- 200815422 尚未被投予化合物之症* 低係存在。 μ ’㈣件之發生或嚴重性之降 於本發明之又γ 人旦 、 ’係提供在病患中增加間接膽紅 素含S之方法0此耸古、、土 4 Λ 、/匕括對病患譬如有需要之病患投 合物，譬如細胞素抑制劑，相對於投予該化 J 3里其係有效增加病患中之間接膽紅素含量， 其中该=合物係如本文中所述，或其立體異構物、互變異 構物、溶劑合物、前㈣雜从 刖體樂物或藥學上可接受之鹽。在一些 具體貫施例中，間接瞒4春人 Π接膽紅素含量係被增加至約0.4毫克/公 l. 合，至約0.5耄克/公合，至約〇6毫克/公合，或至約毫克 /公合。在其他具體實施例中，間接膽紅素含量係被增加達 約祕’約·，或約3〇%。在其他具體實施例中，膽紅素 含量係被增加，而不會造成黃殖。在某些具體實施例中， 病患係需要增加之間接膽紅素含量，因為例如病患係患有 或處於如本文中所述細胞素所媒介病症之危險下。在本發 明此方面之-些具體實施例中，病患係處於血管事件之^ 險下’例如血管事件為血栓形成病症、心肌梗塞、绞痛^ 中風、短暫絕血性發作、於冠狀介人程序後之血栓形成再 閉塞及其中至少一個主冠狀動脈顯示大於鄕狹窄之病症 之-或多#。在其他具體實施例中，血管事件為心血管； 件或腦血管事件。在—些具體實施例中，相對於處於血管"Disease" - a quantity of a compound such as a cytokine inhibitor, relative to the index before administration, which is effective in reducing the hqma 姨 抗 抗 抗 ' ' ' 其中 其中 其中 其中Said herein, or a stereoisomer, tautomer, solvate, prodrug or pharmaceutically acceptable salt thereof. In some such embodiments, the insulin resistance index is reduced to less than about 2.5, less than about 2.0, or less than about u. In some embodiments, the Tengdamycin resistance index is reduced by about 1 (%), about spectroscopy, or about 30. ? In some embodiments, the patient requires a reduced ugly a insulin resistance index because, for example, the patient has or is at risk of a cytokine-mediated condition as described herein. In other embodiments, the patient has or is at risk of having diabetes, insulin resistance or metabolic signs. In some embodiments of the invention, the method further comprises administering toluene, T-urea, acesulfame, carbendazim, chloral propylurea, glipizide, grebe ray (glyburide), glimepiride, gliclazide, repagUnide, glinide, metf〇nnin, = glito (miglitol), acarbose (acarb〇se), beta (4) qi ga), plmlintide, insulin or a combination of two or more thereof. In some embodiments of the invention, the patient is at risk of a vascular event, such as a thrombotic disorder, myocardial infarction, colic, stroke, transient episodes of episodes, thrombosis re-occlusion after the interventional procedure, and / or one or more of the conditions in which at least one primary coronary artery exhibits greater than 50% stenosis. In some such embodiments, the vascular event is a cardiovascular event or a cerebrovascular event. In some embodiments, the 123505-88-200815422 has not been administered a compound* low profile relative to the risk of a vascular event. The occurrence or severity of the μ '(4) piece falls below the γ-man, the 'system provides a method for increasing the indirect bilirubin-containing S in the patient. 0 This is a sacred, earthy 4 Λ, / 匕A patient, such as a cytokine inhibitor, is effective in increasing the amount of bilirubin in the patient relative to the administration of the cytokine inhibitor, wherein the compound is as described herein. Or a stereoisomer, tautomer, solvate, pre-(4) hetero-organism or pharmaceutically acceptable salt. In some specific embodiments, the bilirubin content of the indirect 瞒4 spring is increased to about 0.4 mg / ng, to about 0.5 gram / metric, to about 毫克 6 mg / metric, Or to about mg / metric. In other embodiments, the indirect bilirubin content is increased to about 约, or about 3%. In other embodiments, the bilirubin content is increased without causing yellow colonization. In certain embodiments, the patient line needs to increase the intermolecular bilirubin content because, for example, the patient has or is at risk of a cytokine-mediated condition as described herein. In some embodiments of this aspect of the invention, the patient is at risk of a vascular event, such as a vascular event, a thrombotic disorder, myocardial infarction, colic, stroke, transient episodes of episodes, and a coronary intervention procedure. The posterior thrombosis reocclusion and at least one of the main coronary arteries shows a greater than stenosis - or more #. In other embodiments, the vascular event is a cardiovascular; a component or a cerebrovascular event. In some embodiments, relative to being in a blood vessel

事件之危險下’尚未被投予化合物之病患，血管事件之發 生或嚴重性之降低係存在。 X 在一些具體實施例中，本文中所述之化合物對於人類毒 123505 -89- 200815422 血症期間之促凝與原分解纖維蛋白回應具有抑制作用 因 此，於另一方面，本發明亦提供抗凝血劑與分解纖維蛋白 治療之方法’用於有關血液凝固或血纖維蛋白溶酶作用之 疾病或症狀，此方法包括對有需要之病患投予藥學上有岐 量之如本文中所述之化合物，例如細胞素抑制劑。此投藥 可有利地無論是以預防方式給予處於危險下之病患，或以 治療方式給予已發展出有關此等途徑之併發症之病串。At the risk of an event, a patient who has not been administered a compound has a reduction in the occurrence or severity of a vascular event. X In some embodiments, the compounds described herein have an inhibitory effect on procoagulant and profibrillar fibrin responses during human toxicity 123505-89-200815422. Thus, in another aspect, the invention also provides anticoagulation Blood and deficient fibrin treatment methods for 'diseases or symptoms associated with blood coagulation or plasmin action, the method comprising administering to a patient in need thereof a pharmaceutically acceptable amount as described herein A compound, such as a cytokine inhibitor. This administration may advantageously be administered to a patient at risk, either in a prophylactic manner, or in a therapeutic manner to a diseased string that has developed complications associated with such routes.

於本文中所揭示‘之化合物，譬如細胞素抑制劑，可與一 或多種其他抗凝血劑或纖維蛋白溶解劑一起使用於組^療 法中。其包括重組組織血纖維蛋白溶酶原活化劑（rtpA)、鏈 激酶(SK)、尿激酶(UK)、proUK、肝素、内 _ 肝素(en〇x〇parin)、 達喋肝素（dalteparin)、香豆素抗凝血劑、阿斯匹靈、二嘧達 莫（dipyrimidamole)、阿葛瑞諾斯（aggrem〇x)、替克羅匹定 (ticlopidme)、克羅匹多葛瑞（cl〇pid〇grd) (piavix)、亞伯西瑪伯 (abdximab)、、因替葛利林（integriiin)、阿葛瑞斯特 teestad抗凝血劑與纖維蛋白溶解劑之特定劑量、配 方及投藥方法係為此項技藝中已知。 本U之另-方面，係、提供_種方法，其包括對病患 :予如本文中所述之化合物，例如細胞素抑制冑，及一或 多種成份A之組合，其量可在有需要之病患中，有效控制、 治療或預防肥胖或肥胖相關症狀或病症1中成份A係選 自可用於治療肥胖或肥胖相關症狀或病症之藥劑。在_些 =種具體實施财，肥胖相_症係選自過食、狂吃1 欠病II冋之血漿胰島素濃度、胰島素抗藥性、代 123505 -90- 200815422 谢徵候簇、脂血症障礙、血脂肪過多、脂肪代謝障礙、骨 關郎乂受形性關郎炎、腰痛、月經病、阻塞性睡眠窒息、 膽石病、膽結石、非酒精性皮脂腺肝炎、心臟疾病、異常 心動節律與異常心臟節律不齊、心肌梗塞、鬱血性心衰竭、 虺狀〜臟疾病、冠狀動脈疾病、心狡痛、高血壓、猝死、 中風、大腦梗塞、大腦血栓形成、短暫絕血性發作、多囊 卵巢疾病、顱咽管瘤、Pickwickian徵候簇、脂肪肝、prader-Wim 徵候簇、弗留立什氏徵候簇、GH•不足、正常變型短身高、 Turner氏徵候簇、兒科急性淋巴胚細胞白血病、不孕症、男 性中之性腺機能減退、女性中之婦女多毛症、胃腸能動性 病症、呼吸病症、心血管病症、發炎、動脈硬化、高膽固 醇血症、高尿酸血症、下背痛、膽囊疾病、痛風、子宮内 膜癌、乳癌、前列腺癌、結腸癌或腎臟癌。在本發明之其 他體貫％例+，相對於投予該組合前之病患體重，病患 μ要減輕體重。在一些具體實施例中，該方法係另外包括 以月曰造形、胃分流、腹腔鏡可調整胃結合、膽胰轉換或垂 直帶狀胃造形術治療病患。 可用於治療肥胖或肥胖相關症狀或病症之成份Α之實 例，係包括胰島素敏化劑、胰島素或騰島素擬似价、績酿 脲、α-葡萄糖嘗酶抑制劑、膽固醇降低劑、ppARM動劑、 CB叉體配位體、5邊色胺能劑、腎上腺素受體催動劑、膜 月曰肪酶抑制劑、ApoB/MTp抑制劑、mch受體拮抗劑、糊精 及/或降A鈣素受體催動劑、_拮抗劑、奥瑞辛（_的拮 H GUM催動劑、MC催動劑、葛瑞林（ghrelin)拮抗劑、 123505 200815422 勒帕茄鹼催動劑、CCK催動劑、PYY催動劑、CNTF、GH促 分泌素、GH促分泌素受體調制劑、DP-IV抑制劑、H3拮抗 劑或逆催動劑、5HT催動劑、血清素輸送或再攝取抑制劑、 多巴胺催動劑、NE輸送抑制劑、DAG抑制劑、葡萄糖輸送 子抑制劑、/S-HSD-1抑制劑、CETP抑制劑、角鯊烯合成酶抑 制劑、類皮質糖拮抗劑、PDE抑制劑、破壞血小板劑、ACE 抑制劑、All受體拮抗劑、UCP-1，-2或-3活化劑、曱狀腺激 素召催動劑、COX-2抑制劑、單胺再攝取抑制劑、mGlu5受 體拮抗劑、醯基-雌激素、FAS抑制劑、ACC2抑制劑、促腎 上腺皮質激素_釋放激素催動劑、高良薑黃素拮抗劑、BRS3 催動劑、PTP-1B抑制劑、脂肪酸輸送子抑制劑、二羧酸鹽 輸送子抑制劑、磷酸鹽輸送子抑制劑、尿可體素結合蛋白 質拮抗劑、尿可體素配位體、人類刺鼠相關蛋白質、神經 激素U受體催動劑、托皮拉美（topiramat)、催產調制素、褡格 糖、CP741952、坐尼斯醯胺（zonisamide)、ID1KU、BDC03、S2367、 AOD9604、弗史特隆（fluasterone)、GT389255、QCBT16、MK0916、 MK〇493、MK0364、PD6735、c2735、脂結合素或其兩種或多 種之組合。在一些此種具體實施例中，成份A為胰島素敏 化劑、胰島素或胰島素擬似物、磺醯脲、α-葡萄糖苷酶抑 制劑或葡萄糠輸送子抑制劑。在其他具體實施例中，成份 Α為膽固醇降低劑或PPAR5催動劑。於又其他具體實施例 中，成份A為CB受體配位體、5-羥色胺能劑、腎上腺素受 體催動劑、胰脂肪酶抑制劑、ApoB/MTP抑制劑、DP-IV抑制 劑、H3拮抗劑或逆催動劑、5HT催動劑、血清素輸送或再 123505 -92- 200815422 攝取抑制劑、多巴胺催動劑、NE輸送抑制劑、CETP抑制劑、 角鯊烯合成酶抑制劑、PDE抑制劑或醯基-雌激素。在其他 具體實施例中，成份A為MCH受體拮抗劑、NPY拮抗劑、奥 瑞辛（orexin)拮抗劑、GLP-1催動劑、MC催動劑、葛瑞林(ghrelin) 拮抗劑、勒帕茄鹼催動劑、CCK催動劑、PYY催動劑、CNTF、 GH促分泌素或GH促分泌素受體調制劑。在一些具體實施 例中，成份A為利夢那班（rimonabant)、希布拉胺（sibutramine)、 氣西汀（fluoxetine)、吩特明（phentermine)、丁胺苯丙酮、拉達 發辛（radafaxine)、奥麗斯特（orlistat)、些替麗斯特（cetilistat)、催 產調制素或油醜基-雌酮。 可與本文中所述之化合物合併以治療或預防肥胖及/或 肥胖相關病症，無論是個別地或在相同醫藥組合物中投藥 之成份A及其任兩種或多種之組合，其典型實例包括但不 限於： (a) 胰島素敏化劑，包括（i)過氧化物酶體增生物活化受體 (PPAR) 7催動劑，譬如葛塔宗類（glitazones)(例如愛沙葛塔宗 (isaglitazone);皮歐葛塔宗（pioglitazone);若西葛塔宗（rosiglitazone); 利弗葛塔宗（rivoglitazone)、臬托葛塔宗（netoglitazone))、那維葛 塔札（naveglitazar)、發葛利塔札（farglitazar)、間葛達山 (metaglidasen)、GW6779542、CS038、MBX2044、AZD6610、 PLX204、LBM642、AMG131、AVE0847、AVE5376、0N05129、 TAK654、CLX0921 等）；（ii)雙縮胍類，譬如二甲雙胍（metformin) 與苯乙雙胍(phenformin); (b) 胰島素或胰島素擬似物，譬如胰島素阿斯帕特 123505 -93 - 200815422 (aspart)、胰島素葡利新（glulisine)、胰島素葛拉金(glargine)、胰 島素利思普羅（lispro)、胰島素迪特摩（detemir)、NN5401、 NN9101、NN344、AT1391、DTY001、/2Rx、胰島素鋅懸浮液（連 提（lente)與超連提（ultralente));親胰島素（所謂”胰島素”係意 指可用於調節血糖含量之多肽或其相當物。此種胰島素之 一般描述係提供於Goodman與Gilman氏治療學之藥理學基 礎，第8版，Pergamon出版社（1990)中。此種騰島素可為快速 作用、中間期作用或長期作用。胰島素之不同衍生物係存 在，且可使用於本發明中。此種組合物可藉任何標準途徑 投藥，包括口服、鼻、肺或經皮投藥）； (c) 磺醯基脲類，譬如醋磺環己脲；氯磺丙脲；優降糖 (glibenclamide);葛利皮再得（glipizide);葛來布賴得（glyburide); 葛利美皮利得（glimepiride);葛利可拉再（gliclazide);葛來片太 得（glipentide);葛利奎東（gliquidone);葛來索醯胺（glisolamide); 曱磺氮革脲；及曱苯磺丁脲； (d) α-葡萄糖嘗酶抑制劑，譬如阿葡萄糖：y：酶(alglucosidase) α、 沃葛利糖（voglibose)、謝果西維（celgosivir)、米葛利妥（miglitol)、 阿卡糖（acarbose)等； (e) 膽固醇降低劑，譬如（i) 3-羥基-3-甲基戊二醯基-輔酶A (HMG-CoA)還原酶抑制劑（阿托瓦制菌素（at〇rvastatin)、皮塔伐 制菌素（pitavastatin)、弗伐制菌素（fluvastatin)、洛蘇伐制菌素 (rosuvastatin)、普拉伐制菌素（pravastatin)、辛伐制菌素 (simvastatin)、洛伐制菌素（l〇vastatin)及其他制菌素）；（ii)膽汁 酸吸收劑/多價螯合劑，譬如可列西威蘭（colesevelam)、可列 123505 -94- 200815422 斯替保（colestipol)、消膽胺（cholestyramine)、交聯葡聚·之二烧 胺基脂環基衍生物等；⑼菸鹼基醇、菸鹼酸或其鹽；（iii) PPAR α催動劑，譬如非諾纖酸衍生物（西普纖酸醋（ciprofibrate)、 傑非布洛吉（gemfibrozil)、氯苯丁酯（clofibrate)、非諾纖酸酉旨 (fenofibrate)及苯雜纖酸酯（benzafibrate))、GW677954、CS038、 ABT335、LY674、GFT14、PLX204、Kill、那維葛塔札 (naveglitazar)、LBM642、GW590735、NS220、AVE5376、AVE8134、 DRF10945、ON05129、KRP101、GW641597 及 DRF4832; (iv)膽 固醇吸收之抑制劑，譬如史坦醇（stanol)酯類，/5-谷留醇，固 醇糖替，譬如提奎糖嘗（tiqueside);與一氮四圜酮，譬如也吉 提麥伯（ezetimibe)等，及醯基CoA膽固醇醯基轉移酶（ACAT) 抑制劑，譬如SMP797、K604及SR-45023A，（v)抗氧化劑，譬 如普洛布可（probucol)，（vi)維生素E，及（vii)甲狀腺擬似物； (f) PPAR 6 催動劑，譬如 GW677954、CS068、RWJ800025、 GW501516 及 CKD501 ;及 (g) 其他治療劑，包括抗肥胖與抗糖尿病劑，譬如 (1)類大蔴苷（CB)受體配位體，譬如CB-1受體拮抗劑或逆 催動劑，例如利夢那班（rimonabant)、速利那班（surinabant)、 AVE1625、CP945598 及 SLV-319，以及在美國專利 6,344,474, 6,028,084， 5,747,524， 5,596，106， 5,532,237， 4,973,587， 5,013,837, 5,081，122, 5，112,820, 5,292/736, 5,624,941，PCT 申請案號 WO 96/33159, WO 98/33765, WO 98/43636, WO 98/43635, WO 01/09120, WO 98/31227, WO 98/41519, WO 98/37061，WO 00/10967, WO 00/10968, WO 97/29079, WO 99/02499, WO 01/58869, WO 01/64632, WO 01/64633, WO 01/64634, 123505 -95- 200815422 WO 02/076949 及 WO 03/007887, WO 02/076949;以及 EPO 申請案號 EP-658546, EP-656354, EP-576357 中所揭示者； (2) 抗肥胖5-經色胺能劑，譬如芬弗拉胺（fenfluramine)、迪 芬弗拉胺（dexfenfluramine)、吩特明（phentermine)、DOV102677、 吉美定（zimeldine)及希布拉胺（sibutramine); (3) 腎上腺素受體催動劑，包括/33-腎上腺素受體催動劑， 譬如索拉卜瑞剛（solabregon)、YM178、安米卜瑞岡彳（amibregon)、 提索吩辛（tesofensince)、芬弗拉胺（fenfluramine)、安非他命、菲 曼 _ (phenmetrazine)、吩特明（phentermine)及 N5984 ; ⑷胰脂肪酶抑制劑，譬如奥麗斯特（orlistat)、些替麗斯特 (cetilistat)及 GT389255 ; (5) 載脂蛋白-B分泌/微粒體三酸甘油酯轉移蛋白質 (Apo-B/MTP)抑制劑，譬如ISIS301012、ISIS301012、JTT130 及 SLx4090 ； (6) 黑色素聚集激素（MCH)受體拮抗劑，包括MCH1R與 MCH2R拮抗劑，例如856464與AMG076，及在美國專利申請 案公報 2005/0009815, 2005/0026915, 2004/0152742, 2004/0209865; PCT 專利申請案公報 WO 01/82925，WO 01/87834，WO 02/06245, WO 02/04433及WO 02/51809 ;以及日本專利申請案號JP 13226269中 所述者； · (7) 神經肽Y (NPY)拮抗劑，譬如NPY1拮抗劑，例如 BIBP3226、Π15814、BEBO3304、LY357897、CP671906、GI264879A， 及在美國專利6,001，836與PCT申請案號WO 96/14307，WO 01/23387, WO 99/51600, WO 01/85690, WO 01/85098, WO 01/85173 及 123505 -96- 200815422 WO01/89528中所揭示者；NPY5拮抗劑，例如S2367、FMS586、 GW569180A、GW594884A、GW587081、GW548118、FR226928、 FR240662、FR252384、1229U91、GI264879A、CGP71683A、 LY377897、PD160170、SR120562A、SR120819A 及 JCF104，以及 在美國專利 6，124,331，6，140,354，6，191，160，6,214,853，6,258,837, 6,313,298, 6,337,332, 6,329,395, 6,326,375, 6,335,345 及 6,340,683，歐洲 專利 EP-01010691 與 EP-01044970，及 PCT 申請案號 WO 97/19682, WO 97/20820, WO 97/20821，WO 97/20822, WO 97/20823, WO 98/27063, WO 00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO 01/14376, WO 01/85714, WO 01/85730, WO 01/07409, WO 01/02379, WO 01/23388, WO 01/23389, WO 01/44201，WO 01/62737, WO 01/62738, WO 01/09120, WO 02/22592, WO 0248152 以及 WO 02/49648 中所揭示者； (8)肽YY (PYY)催動劑，譬如PYY、PYY 3-36、肽YY類似 物及 PYY 催動劑，例如 AC162352、N-乙醯基[Leu(28,31)]NPY24-36 與 ΡΥΥ(3·36)ΝΗ2、環-(28/32)-Ac_[Lys28_Glu32]_(25-36)-pNPY 、 TASP-V、胰肽（PP)、122U91，及在美國專利公報2002/0141985 與 PCT 申請案公報 WO 2005/077094, WO 03/026591，WO 03/057235 及WO 03/027637中所揭示者； ⑼奥瑞辛（orexin)拮抗劑，譬如奥瑞辛（orexin)-l受體拮抗 劑，例如 SB334867-A，及在 PCT 申請案號 WO 01/96302，WO 01/68609, WO 02/51232 以及 WO 02/51838 中所揭示者； (10)似胰高血糖素肽（GLP)-l催動劑，包括GLP-1、GUM類 似物及衍生物，譬如約辛那太得（exenatide)、約辛那太得 (exenatide)-LAR、利拉葡肽（liraglutide)、CJC1134PC、LY548806、 123505 -97- 200815422 716155 及 AVE0010 ; (11) 褪黑激素（MC)催動劑，包括MC4催動劑與MC4R催動 劑，譬如曬黑素π、PT15、BL3020、AP1030，或在PCT申請 案號 WO 99/64002, WO 00/74679, WO 01/991752, WO 01/74844, WO 02/12166, WO 02/11715, WO 02/12178, WO 03/007949, WO 02/068388, WO 02/068387，WO 02/067869，WO 03/040117，WO 03/066587, WO 03/068738, WO 03/094918 及 WO 03/031410 中所述者； (12) 葛瑞林（ghrelin)受體拮抗劑，譬如 NOXB11、CYT009GhrQb、 TZP300、EP01492，及在 PCT 申請案號 WO 01/87335 與 WO 02/08250中所揭示者；The compounds disclosed herein, such as cytokine inhibitors, can be used in combination therapy with one or more other anticoagulants or fibrinolytic agents. It includes recombinant tissue plasminogen activator (rtpA), streptokinase (SK), urokinase (UK), proUK, heparin, endogenous heparin (en〇x〇parin), dalteparin, Coumarin anticoagulant, aspirin, dipyrimidamole, aggrem〇x, ticlopidme, clopidovir (cl〇 Pid〇grd) (piavix), abdximab, integriiin, agristene teestad anticoagulant and fibrinolytic agent specific dosage, formulation and administration method This skill is known. Another aspect of the present invention is to provide a method comprising: a compound as described herein, such as a cytokine inhibitor, and a combination of one or more components A, the amount of which may be needed In a patient, effective control, treatment or prevention of obesity or obesity-related symptoms or conditions 1 ingredient A is selected from agents useful for treating obesity or obesity-related symptoms or conditions. In the case of _ some = specific implementation of the financial, obesity phase _ disease is selected from overeating, mad eating 1 ill disease II 冋 plasma insulin concentration, insulin resistance, generation 123505 -90- 200815422 Xie Zheng waiting cluster, lipemia disorder, blood Excessive fat, lipodystrophy, bone stagnation, stagnation, low back pain, menstrual disease, obstructive sleep apnoea, cholelithiasis, gallstones, nonalcoholic sebaceous hepatitis, heart disease, abnormal cardiac rhythm and abnormal heart Rhythm, myocardial infarction, septic heart failure, sickle-dirty disease, coronary artery disease, palpitations, hypertension, sudden death, stroke, cerebral infarction, cerebral thrombosis, transient episodes of episodes, polycystic ovarian disease, Craniopharyngioma, Pickwickian syndrome, fatty liver, prader-Wim syndrome, Freurish syndrome, GH deficiency, normal variant short height, Turner's syndrome, pediatric acute lymphoblastic leukemia, infertility , hypogonadism in men, hirsutism in women, gastrointestinal motility, respiratory, cardiovascular, inflammation, arteriosclerosis, high cholesterol Disease, hyperuricaemia, lower back pain, gallbladder disease, gout, endometrial cancer, breast cancer, prostate cancer, colon cancer or renal cancer. In the other cases of the present invention, the patient μ has to lose weight relative to the patient's body weight before administration of the combination. In some embodiments, the method further comprises treating the patient with a crescent, a gastric shunt, a laparoscopic adjustable gastric union, a biliary-pancreatic transition, or a vertical banded gastroplasty. Examples of ingredients that can be used to treat obesity or obesity-related symptoms or conditions include insulin sensitizers, insulin or tamsine pseudo-valency, urea, alpha-glucose inhibitors, cholesterol lowering agents, ppARM agonists , CB fork ligand, 5-sided tryptophan, adrenergic receptor stimulant, membrane sputum enzyme inhibitor, ApoB/MTp inhibitor, mch receptor antagonist, dextrin and/or A Calcium receptor agonist, _ antagonist, Orexin ( _ H HUM mobilizer, MC motility agent, grelinin antagonist, 123505 200815422 Leptin base mobilizer, CCK catalyzed Agent, PYY motility agent, CNTF, GH secretagogue, GH secretagogue receptor modulator, DP-IV inhibitor, H3 antagonist or reverse agonist, 5HT mobilizer, serotonin delivery or reuptake inhibition Agent, dopamine agonist, NE delivery inhibitor, DAG inhibitor, glucose transporter inhibitor, /S-HSD-1 inhibitor, CETP inhibitor, squalene synthetase inhibitor, corticosteroid antagonist, PDE Inhibitors, platelet disrupting agents, ACE inhibitors, All receptor antagonists, UCP-1, -2 or -3 activators Gonadotropin stimulant, COX-2 inhibitor, monoamine reuptake inhibitor, mGlu5 receptor antagonist, thiol-estrogen, FAS inhibitor, ACC2 inhibitor, adrenocorticotropic hormone Agent, galangin antagonist, BRS3 agonist, PTP-1B inhibitor, fatty acid transporter inhibitor, dicarboxylate transporter inhibitor, phosphate transporter inhibitor, urinary voxel binding protein antagonist , urinary voxel ligand, human squirrel-associated protein, neurohormone U receptor priming agent, topiramat, oxytocin, sputum, CP741952, zonisamide, ID1KU , BDC03, S2367, AOD9604, fluasterone, GT389255, QCBT16, MK0916, MK〇493, MK0364, PD6735, c2735, lipoconjugate or a combination of two or more thereof. In some such embodiments Ingredients A are insulin sensitizers, insulin or insulin mimics, sulfonamides, alpha-glucosidase inhibitors or grapevine transporter inhibitors. In other embodiments, the component is a cholesterol lowering agent or PPAR5 agonist. In still other embodiments, component A is a CB receptor ligand, a serotoninergic agent, an adrenergic receptor agonist, a pancreatic lipase inhibitor, an ApoB/MTP inhibitor, DP -IV inhibitor, H3 antagonist or inverse agonist, 5HT motility agent, serotonin delivery or re-123505 -92- 200815422 uptake inhibitor, dopamine mobilizer, NE delivery inhibitor, CETP inhibitor, squalene Synthase inhibitor, PDE inhibitor or thiol-estrogen. In other specific embodiments, component A is a MCH receptor antagonist, an NPY antagonist, an orexin antagonist, a GLP-1 agonist, an MC agonist, a ghrelin antagonist, a Lepa Solanine stimulating agent, CCK motivator, PYY motivator, CNTF, GH secretagogue or GH secretagogue receptor modulator. In some embodiments, component A is rimonabant, sibutramine, fluoxetine, phentermine, acetophenone, radafine ( Radafaxine), orlistat, some cetistat, oxytocin or oleic-estrone. A typical example of a compound A, which may be combined with a compound described herein, for treating or preventing obesity and/or obesity-related disorders, whether administered individually or in the same pharmaceutical composition, and a combination of two or more thereof, includes However, it is not limited to: (a) Insulin sensitizers, including (i) peroxisome proliferator-activated receptor (PPAR) 7 agonists, such as glitazones (eg Aisha Ta Tazon ( Isaglitazone); pioglitazone; rosiglitazone; rivoglitazone, netoglitazone, naveglitazar, hair (farglitazar, metaglidasen, GW677954, CS038, MBX2044, AZD6610, PLX204, LBM642, AMG131, AVE0847, AVE5376, 0N05129, TAK654, CLX0921, etc.); (ii) bismuth, such as metformin (metformin) with phenformin; (b) insulin or insulin mimics, such as insulin asparta 123505-93 - 200815422 (aspart), insulin glulisine, insulin glargine , insulin lispro, insulin detemir, NN5401, NN9101, NN344, AT1391, DTY001, /2Rx, zinc suspension of insulin (lente and ultralate); pro Insulin (so-called "insulin" means a polypeptide or equivalent thereof that can be used to modulate blood glucose levels. A general description of such insulin is provided in the pharmacological basis of Goodman and Gilman's Therapeutics, 8th Edition, Pergamon Press (1990) Such a tamponin may be a rapid action, an intermediate phase action or a long-term effect. Different derivatives of insulin are present and can be used in the present invention. Such a composition can be administered by any standard route, including oral administration. Nasal, pulmonary or transdermal administration); (c) sulfonyl ureas, such as acesulfame hexacarbazide; chlorpropamide; glibenclamide; glipizide; Glyburide; glimepiride; gliclazide; glipentide; gliquidone; glisolamide; sulfonamide Leather urea; and chlorfenapyr; d) α-glucosidase inhibitors, such as glucosamine: y: alglucosidase α, voglibose, celgosivir, miglitol, acarbose Acarbose); (e) cholesterol lowering agents such as (i) 3-hydroxy-3-methylpentadienyl-coenzyme A (HMG-CoA) reductase inhibitor (atova vinostatin) ), pitavastatin, fluvastatin, rosuvastatin, pravastatin, simvastatin, Lovastatin and other bacteriocins; (ii) bile acid absorbers/sequestrants, such as colesevelam, can be listed as 123505-94-200815422 (colestipol), cholestyramine, cross-linked oligosaccharide, adiamine alicyclic derivative, etc.; (9) nicotinic alcohol, nicotinic acid or a salt thereof; (iii) PPAR α priming agent, Such as non-noic acid derivatives (ciprofibrate, gemfibrozil, clofibrate, fentanyl lanthanum) (fenofibrate) and benzoic acid ester (benzafibrate), GW677954, CS038, ABT335, LY674, GFT14, PLX204, Kill, Naviglitazar, LBM642, GW590735, NS220, AVE5376, AVE8134, DRF10945, ON05129, KRP101, GW641597 and DRF4832; (iv) inhibitors of cholesterol absorption, such as stanol esters,/5-valerol, sterol sugar substitutes, such as tiqueside; Azathione, such as ezetimibe, and thiol-based CoA cholesterol thiol transferase (ACAT) inhibitors, such as SMP797, K604 and SR-45023A, (v) antioxidants such as probu Probucol, (vi) vitamin E, and (vii) thyroid mimics; (f) PPAR 6 agonists, such as GW677954, CS068, RWJ800025, GW501516, and CKD501; and (g) other therapeutic agents, including anti-obesity And anti-diabetic agents, such as (1) cannabinoid (CB) receptor ligands, such as CB-1 receptor antagonists or counteractivators, such as rimonabant, surinabant ), AVE1625, CP945598 and SLV-319, as well as in US patent 6,344 , 474, 6,028,084, 5,747,524, 5,596,106, 5,532,237, 4,973,587, 5,013,837, 5,081,122, 5,112,820, 5,292/736, 5,624,941, PCT Application No. WO 96/33159, WO 98/33765, WO 98/43636, WO 98/43635, WO 01/09120, WO 98/31227, WO 98/41519, WO 98/37061, WO 00/10967, WO 00/10968, WO 97/29079, WO 99/02499, WO 01/58869, WO 01/64632, WO 01/64633, WO 01/64634, 123505-95-200815422 WO 02/076949 and WO 03/007887, WO 02/076949; and EPO Application No. EP-658546, EP-656354, EP- (576) Anti-obesity 5-tryiamine, such as fenfluramine, dexfenfluramine, phentermine, DOV102677, zimeldine And sibutramine; (3) adrenergic receptor motivators, including /33-adrenergic receptor priming agents, such as sorabregon, YM178, amibregon , tesofensince, fenfluramine, amphetamine, phenmetrazine, phentermine, and N5984; Pancreatic lipase inhibitors, such as orlistat, cetistat, and GT389255; (5) apolipoprotein-B secreting/microsomal triglyceride transfer protein (Apo-B/MTP) Inhibitors, such as ISIS301012, ISIS301012, JTT130, and SLx4090; (6) melanin-concentrating hormone (MCH) receptor antagonists, including MCH1R and MCH2R antagonists, such as 856464 and AMG076, and in U.S. Patent Application Publication No. 2005/0009815, 2005/0026915, 2004/0152742, 2004/0209865; PCT Patent Application Publication No. WO 01/82925, WO 01/87834, WO 02/06245, WO 02/04433, and WO 02/51809; and Japanese Patent Application No. JP 13226269 (7) Neuropeptide Y (NPY) antagonists, such as NPY1 antagonists, such as BIBP3226, Π15814, BEBO3304, LY357897, CP671906, GI264879A, and U.S. Patent No. 6,001,836 and PCT Application No. WO 96 /14307, WO 01/23387, WO 99/51600, WO 01/85690, WO 01/85098, WO 01/85173 and 123505-96-200815422 WO01/89528; NPY5 antagonists, such as S2367, FMS586, GW569180A, GW594884A, GW587081, GW548118, FR226928 FR240662, FR252384, 1229U91, GI264879A, CGP71683A, LY377897, PD160170, SR120562A, SR120819A, and JCF104, and in U.S. Patents 6,124,331, 6,140,354, 6,191,160, 6,214,853, 6,258,837, 6,313,298, 6,337,332, 6,329,395, 6,326,375, 6, 335, 345 and 6, 340, 683, European Patent No. EP-01010691 and EP-01044970, and PCT Application No. WO 97/19682, WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO 98/27063, WO 00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO 01/14376, WO 01/85714, WO 01/85730, WO 01/07409, WO 01/02379, WO 01/23388, WO 01/23389, WO 01/44201, WO 01/62737, WO 01/62738, WO 01/09120, WO 02/22592, WO 0248152, and WO 02/49648; (8) Peptide YY (PYY) reminder Moostering agents, such as PYY, PYY 3-36, peptide YY analogs and PYY catalyzing agents, such as AC162352, N-ethyl fluorenyl [Leu (28, 31)] NPY24-36 and hydrazine (3 · 36) ΝΗ 2, ring -(28/32)-Ac_[Lys28_Glu32]_(25-36)-pNPY, TASP-V, pancreatic peptide (PP), 122U91, and in US Patent Publication No. 2002/0141985 and PCT Application Publication No. WO 2005/077094, WO 03/0 26591, WO 03/057235 and WO 03/027637; (9) Orexin antagonists, such as orexin-l receptor antagonists, such as SB334867-A, and in PCT applications No. WO 01/96302, WO 01/68609, WO 02/51232 and WO 02/51838; (10) glucagon-like peptide (GLP)-l agonist, including GLP-1, GUM And derivatives, such as exenatide, exenatide-LAR, liraglutide, CJC1134PC, LY548806, 123505-97-200815422 716155 and AVE0010; (11) Melatonin (MC) motivator, including MC4 agonist and MC4R agonist, such as tanning π, PT15, BL3020, AP1030, or in PCT Application No. WO 99/64002, WO 00/74679, WO 01/991752, WO 01/74844, WO 02/12166, WO 02/11715, WO 02/12178, WO 03/007949, WO 02/068388, WO 02/068387, WO 02/067869, WO 03/040117, WO 03/066587, WO 03/068738, WO 03/094918 and WO 03/031410; (12) ghrelin receptor antagonists such as NOXB11, CYT009GhrQb, TZP300, EP01492, and in PCT Docket No. WO 01/87335 and in WO 02/08250 are disclosed;

(13) 勒帕茄鹼催動劑，包括重組人類勒帕茄鹼與重組甲硫 丁胺醯基人類勒帕茄鹼，及勒帕茄鹼衍生物，譬如OB3， 及在美國專利 5,552,524, 5,552,523, 5,552,522, 5,521，283, 6,777,388 及 6,936,439，與 PCT 申請案號 WO 96/23513，WO 96/23514，WO 96/23515, WO 96/23516, WO 96/23517, WO 96/23518, WO 96/23519, WO 96/23520, WO 96/05309, WO 96/40912; WO 97/06816, WO 00/20872, WO 97/18833, WO 97/38014, WO 98/08512, WO 98/284427，美國專利公 報 2004/0072219，2003/049693，2003/0166847 及 2003/0092126 中所揭 不者， (14) 縮膽囊肽（CCK)催動劑，譬如 ARR15849、GI181771、 JMV180、A71378、A71623、SR146131、UCL2000 及 A71378，以 及在美國專利5,739，106中所述者； (15) 睫狀神經營養因子（CNTF)，包括CNTF、CNTF調制劑 及CNTF衍生物，譬如約克索活素（Axokine)與NT501，及在美 123505 -98 - 200815422 國專利6,680,291與6,767,894，以及在PCT申請案號WO 94/09134, WO 98/22128 及 WO 99/43813 中所揭示者； (16) 生長激素（GH)促分泌素、生長激素促分泌素受體調制 劑，譬如SUN11031、RCH91、提沙莫瑞林(tesamorelin)、色莫 瑞林（sermorelin)、約沙莫瑞林（examorelin)、NN703、六釋放素、 MK677、SM-130686、CP-424,391、L-692,429 及 L-163,255; (17) 二肽基肽酶IV (DP-IV或DPP-IV)抑制劑，譬如登那葛菌 素（denagliptin)、西塔葛菌素（sitagliptin)、SYR322、R00730699、 TS021、ALS20426、維達葛利亭（vidagliptin)、GRC8200、MP513、 PHX1149、PSN9301、TA6666、沙克沙葛菌素（saxagliptin)、 SSR162369、R1438、KRP104、825964，及在 PCT 申請案號 WO 03/004498 ； WO 03/004496 ； EP 1 258 476 ； WO 02/083128 ； WO 02/062764 ； WO 03/000250 ； WO 03/002530 ； WO 03/002531 ； WO 03/002553 ; WO 03/002593 ; WO 03/000180 ;以及 WO 03/000181 中 所揭示之化合物； (18) 組織胺受體-3 (H3)拮抗劑/逆催動劑，譬如GSK189254A、 A331440、ABT239、ABT834、BP294、硫伯醯胺（thioperamide)、 3-(1Η-咪唑-4-基）丙基N-(4-戊烯基）胺基甲酸酯、氣苯丙比特 (clobenpropit)、峨苯丙比特（iodophenpropit)、愛莫丙氧凡 (imoproxifan)、GT2394，及在 PCT 申請案號 WO 02/15905 中所述 與所揭示者； (19) 5-羥色胺（5HT)催動劑，例如5HT2C (血清素受體2C)催 動劑，譬如洛卡色林（lorcaserin)、威比卡色林（vabicaserin)、 APD356，及在美國專利3,914,250與PCT申請案號WO 02/36596, 123505 -99- 200815422 WO 02/48124, WO 02/10169, WO 01/66548, WO 02/44152, WO 02/51844, WO 02/40456及WO 02/40457中所揭示者；與5HT6催動劑，譬 如 PRX07034 ; (20) 血清素輸送或血清素再攝取抑制劑，譬如那發坐酮 (nefazodone)、西塔洛蘭（citalopram)、達波西汀（dapoxetine)、杜 奥西汀（duloxetine)、脫文拉發辛（desvenlafaxine)、氟伯斯胺 (fluvoxamine)、約西塔洛蘭（escitalopram)、希布拉胺（sibutramine)、 溫拉發辛（venlafaxine)、維拉左酮（vilazodone)、DOV21947、 LUAA21004、BGC201259、NS2359、UK416244、DOV102677、 SEP225289、OPC14523、SLV314、WL1011、WL1017、吉美定 (zimeldine)、氟西、;丁（fluoxetine)、帕西汀（paroxetine)、芬弗拉胺 (fenfluramine)、丙_ p井及色他林（sertraline)，以及在美國專利 6,365,633 與 PCT 申請案號 WO 01/27060 及 WO 01/162341 中所揭示 者； (21) 多巴胺催動劑，例如多巴胺D2催動劑，譬如羅賓尼 羅（ropinirole)、雙非普蘭（bifeprunox)、阿利叶b 拉唾（aripiprazole)、 伯郭内酯（pergolide)、塔利佩唆（talipexole)、ACP104、奎那葛來 (quinagolide)、諾羅米洛（nolomirole)、NH001、SLV308、皮利貝 迪（piribedil)、利蘇來得（lisuride)、溴麥角環肽、阿普林多 (aplindore)、提索吩辛（tesofensine)及普瑞可拉莫（preclamol); (22) 正腎上腺素（NE)輸送抑制劑，譬如利迭非塔胺 (lisdexamfetamine)、阿托莫西汀（atomoxetine)、杜奥西 ί丁 (duloxetine)、SLE381、脫文拉發辛（desvenlafaxine)、安非布塔蒙 (amfebutamone)、希布拉胺（sibutramine)、溫拉發辛（venlafaxine)、 123505 -100- 200815422 DOC21947、拉達發辛（radafaxine)、丁胺苯丙酮、DOV216303、 瑞玻西汀（reboxetine)、AD337、NS2359、DOV102677、SEP225289、 Xen2174、因達崎 _ (indeloxazine)、丙替林(protriptyline)及 S33005 ; (23) 二醯基甘油醯基轉移酶（DAG)抑制劑，譬如BAY744113; (24) 葡萄糖輸送子抑制劑，例如鈉葡萄糖共輸送子（SGLT) 抑制劑，譬如 KGT1251、189075、AVE2268 及 SGL0010; (25) 11 /3-羥基類固醇脫氫酶-1 (/9-HSD-1)抑制劑，譬如 INCB13739 與 AMG221 ; (26) 膽固醇酯轉移蛋白質（CETP)抑制劑，譬如妥西卓比 (torcetrapib)、CETil、JTT705、BAY605521 及 JTT302; (27) 角鯊烯合成酶抑制劑，例如拉巴奎斯特（lapaquistat); (28) 類皮質糖拮抗劑，例如米非普利史東（mifepristone)、 Org34517 及 Org34850 ; (29) 磷酸二酯酶(PDE)抑制劑，包括磷酸二酯酶-3B (PDE3B) 抑制劑，例如帖妥米拉特（tetomilast)、塔達拉費（tadalafil)、阿 托皮克（atopik)、閥塾那費（vardenafil)、提佩利卡特（tipelikast)、 HT0712、QAD171A、SK3530、歐列米拉特（oglemilast)、阿肯那 非（acanafil)、西洛史塔唾（cilostazol)、洛弗拉斯特（roflumilast)、 巴洛葛瑞利（parogrelil)、烏墊那費（udenafil)、EHT0202、達山塔 非（dasantafil)、MEM1414、SLx2101、CC10004、256066、西若米 拉斯特（cilomilast)、長春波西亭（vinpocetine)、艾布迪拉特 (ibudilast)、皮莫苯丹（pimobendan)、ND7001、LAS37779、K123、 UK357903、ND1251、托非米拉斯特（tofimilast)、UK169003、山 那左單（senazodan)、卓匹迪（trapidil)、阿洛非林（arofylline)、茶 123505 -101 - 200815422 鹼、多索非林（doxofylline)、歐普林酮（olprinone)、己酮可可豆 鹼、札普那斯特（zaprinast)、席墊那費（sildenafil)、安利農 (amrinone)、米爾利農（milrinone)、席若塔醯胺（cilostamide)、羅 利普蘭（rolipram)及西若米拉斯特（cilomilast); (30) 破壞血小板劑，譬如林馬普斯特（limaprost)、克羅匹多 葛瑞（clopidogrel)、非賓拿克（felbinac)、約伯提菲巴太 (eptifibatide)、NCX4016、提卡瑞洛（ticagrelor)、提洛飛邦 (tirofiban)、阿西馬伯（abcixmab)、沙普瑞拉迪（sarpogrelade)、 DA697B、阿革搓汴（argatroban)、SCH530348、西洛史塔唑 (cilostazol)、YSPSL、巴洛葛瑞利（parogrelil)、阿沙山亭 (asasantin)、DG041 、普拉蘇葛瑞（prasugrel)、雷馬脫爲 (ramatroban)、肯葛瑞樂（cangrelor)、衣波普提誤（epoprostenol)、 貝拉洛斯特（beraprost) '阿斯匹靈、K134、三弗沙（triflusal)、 YY280、克些米洛飛邦（xemilofiban)、歐札葛瑞爾（ozagrel)、阿 普史達阿發迪（alprostadil alfadex)、TP9201、普魯卡因醯胺、 AT1015、Z335、BGC728、葛來洛芳（glyrofam)、EF5077、SH529 及 ME3229 ; (31) 血管收縮素轉化酶（ACE)抑制劑，譬如培利多利 (peridopril)、安那拉普利（enalapril)、瑞米普利（ramipril)、弗新 諾普利（fosinopril)、奎那普利（quinapril)、利辛諾普利（lisinopril)、 衣米達普利（imidapril)、貝那皆普利（benazepril)、愛列巴利 (ilepatril)、卡普脫普利（captopril)、特蘭多普利（trandolapril)、天 卡普利（temcapil)、席拉札普利（cilazapril)、MC4232、CHF1521、 歐馬巴列特（omapatrilat)、史p比拉普利（spirapril)、莫約克西普 -102- 123505 200815422 利（moexipril)、坐非諾普利（zofenopril)、迪拉普利（delapril)、阿 拉謝普利（alacepril)、S5590 及法多三爾（fasidotril); (32) 血管收縮素II (All)受體拮抗劑，例如若沙坦（losartan)、 坎地沙坦（candesartan)、天米沙坦（temisartan)、可阿普洛維 (coaprovel)、衣米達普利（imidapril)、阿吉沙坦（azilsartan)、法沙 坦（valsartan)、愛貝沙坦（irbesartan)、队美沙坦（olmesartan)、 CYT006AngQb、TAK491、伊普洛沙坦（eprosartan)、VNP489、 CGP63170、非美沙坦（fimesartan)、普拉托沙坦（pratosartan)及沙 拉拉辛（saralasin); (33) 解偶聯蛋白質（UCP)-l，2或3活化劑，譬如植烷酸、 4-[(E)-2-(5,6,7,8-四氫·5,5,8,8_四甲基-2-莕）小丙烯基]苯甲酸 (ΤΤΝΡΒ)、視黃酸，及在PCT專利申請案號WO 99/00123中所 揭示者； (34) 曱狀腺激素/3催動劑，譬如曱狀腺激素、左旋甲狀腺 素、ΚΒ2115、3,5-二碘基甲狀腺丙酸、親油甲腺原胺酸、曱 硫咪唑，及在PCT專利申請案號WO 02/15845與日本專利申請 案號JP 2000256190中所揭示者； (35) 環氧化酶（COX)-2抑制劑，譬如依托庫西比（etoricoxib)、 GW406381、美氧胺（meloxicam)、魯米庫西比（lumiracoxib)、二 可吩拿克（diclofenac)、維德庫西比（valdecoxib)、培瑞庫西比 (parecoxib)、PMI001、6444784、SVT2016、尼美沙發（nimesulfide)、 CS706、西米庫西比（cimicoxib)、LR3001、LAS34475、P54、羅 費庫西比（rofecoxib)、塞拉庫西比（celecoxib)及阿可西亞（arcoxia); (36) 單胺再吸收抑制劑，譬如在PCT申請案號WO 01/27068 123505 -103 - 200815422 與WO 01/62341中所揭示者； (37) 代謝移變麩胺酸酯5 (mGlu5)受體拮抗劑，譬如 ADX10059、AFQ-056、2-甲基-6-(苯基乙炔基）-吡啶（MPEP)、（3-[(2-甲基-l，3-p塞唆-4-基）乙炔基]外b °定）（MTEP)，及在Anderson等人 (2003) J_ Eur. J. Pharmacol· 473: 35-40; Cosford 等人（2003) Bioorg· Med· Chem· Lett· 13(3) ·· 351_4 ;以及 Anderson 等人（2002) J. Pharmacol. Exp. Ther. 303 : 1044-1051中所述之化合物； (38) 酸基-雌激素，譬如油醯基-雌酮，於del Mar-Grasa，Μ·等 人，肥胖研究，9 : 202-9 (2001)中所揭示； (39) 脂肪酸合成酶（FAS)抑制劑，譬如淺藍菌素與C75 ; (40) 乙醯基-CoA羧化酶-2 (ACC2)抑制劑； (41) 促腎上腺皮質激素-釋放激素催動劑； (42) 高良薑黃素拮抗劑； (43) 朋貝辛（bombesin)受體亞型3 (BRS3)催動劑； (44) 蛋白質酪胺酸磷酸酶-IB (PTP-1B)抑制劑； (45) 脂肪酸輸送子抑制劑； (46) 二羧酸鹽輸送子抑制劑； (47) 鱗酸鹽輸送子抑制劑； (48) 尿可體素結合蛋白質拮抗劑與尿可體素配位體，譬如 尿可體素II ; (49) 人類刺鼠相關蛋白質（AGRP); (50) 神經激素U受體催動劑； (51) 托皮拉美（topiramat)、催產調制素、褡格糖、CP741952、 坐尼斯醯胺（zonisamide)、ID1101、BDC03、S2367、AOD9604、 123505 -104- 200815422 弗史特隆（fluasterone)、GT389255、QCBT16、MK0916、MK0493、 MK0364、PD6735、C2735 及脂結合素。 可與本文中所述之化合物合併採用之其他抗肥胖劑之實 例，係揭示於M對於新穎抗肥胖劑之專利聚焦"5 Exp. Opin. Ther. Patents，10 : 819-831 (2000) ; f’ 新穎抗肥胖藥物 ’’，Exp. Opin. Invest. Drugs，9 : 1317-1326 (2000);及"進食壓抑劑之最近進展： 關於治療肥胖之可能治療策略，Exp· Opin· Ther. Patents，11 : 1677-1692 (2001)中。神經肤Y在肥胖中之角色係討論於Exp. I Opin· Invest. Drugs，9 : 1327-1346 (2000)中。類大蔴甞受體配位體 係討論於 Exp· Opin· Invest· Drugs，9 ·· 1553-1571 (2000)中。 可搭配本文中所述化合物使用之肥胖與體重減輕治療， 亦包括手術。典型上，體重減輕手術程序為抽脂或脂造形。 手術肥胖治療係包括胃分流、腹腔鏡可調整胃結合、膽胰 轉換或垂直帶狀胃造形術。 於另一方面，係提供一種方法，其包括對有需要之病患 投予化合物，譬如細胞素抑制劑，及一或多種成份A，以 V 有效增加或增強成份A單獨使用時之有效性之量，其中成 份A係選自可用於治療肥胖或肥胖相關症狀或病症之藥 劑，且其中化合物係如本文中所述，或為其任兩種或多種 之混合物及/或其立體異構物、互變異構物、溶劑合物、前 體藥物或藥學上可接受之鹽。在一些具體實施例中，相對 於單獨使用任一種藥劑，有效性增強係藉由允許投予組合 中所使用之一或多種成份A之較低劑量獲得。 於本發明之另一方面，係提供一種方法，其包括對病患 123505 •105- 200815422 又予如本文中所述之化合物，例如細胞素抑制劑，與成份 A ’相對於投予該化合物與成份a前之病患危險，其量可在 有需要之病患中有效降低代謝病症之危險，其申成份八係 選自可用於治療肥胖或肥胖相關症狀或病症之藥劑。在一 些具體實施例中，相對於投予細胞素抑制劑與成份A之組 合珂之病患體重，代謝病症危險之降低係藉由減少病患之 體重而獲得。 於本發明之又另一方面，係提供治療癌症之方法。此等 方法包括對需要此種治療之病患投予一種組合物，其包含 治療上有效量之化合物，譬如，如本文中所述之細胞素抑 制劑’或其藥學上可接受之鹽、溶劑合物或立體異構物。 在本發明之一些具體實施例中，治療癌症之方法進一步 包括以手術、放射、低溫療法或一或多種抗增生劑或其組 合治療病患。在一些此種具體實施例中，抗增生劑為烧基 化劑、鉑藥劑、抗代謝物、拓樸異構酶抑制劑、抗腫瘤抗 生素、抗有絲分裂劑、芳香酶抑制劑、胸甞化物合成酶抑 制劑、DNA拮抗劑、法呢基轉移酶抑制劑、泵送抑制劑' 組織蛋白乙醯轉移酶抑制劑、金屬蛋白酶抑制劑、核糖核 苷還原酶抑制劑、内皮肽受體拮抗劑、視黃酸受體催動劑、 免疫調制劑、激素或抗激素劑、光動態劑、血管生成抑制 劑或酪胺酸激酶抑制劑。在一些此等具體實施例中，烧基 化劑為白血福恩（busulfan)、甲基苄肼、依發斯醯胺 (ifosfamide)、阿催塔胺（altretamine)、六甲三聚氰胺、雌气芥 (estramustine)填酸鹽、嘧替喊(thiotepa)、氮芬、氮烯咪胺、鏈 123505 -106- 200815422 黴亞琐基素、環己亞硕躁、天莫洛醯胺（temozolomide)、環石粦 醯胺、賽氮芥（semustine)或苯丁酸氮芥（chlorambucil)。翻藥劑 之實例包括螺胺翻（spiroplatin)、羅巴翻胺（lobaplatin)(Aetema)、 四氯胺舶（tetraplatin)、沙催麵胺（satraplatin)(Johnson Matthey)、歐 馬胺始（ormaplatin)、衣普氣胺鉑（iproplatin)、米利胺鉑 (miriplatin)(Sumitomo)、内克斯胺鉑（nexplatin)(AnorMED)、聚合體 鉑酸鹽（Access)、草酸鉑或碳氣胺鉑。在一些具體實施例中， 抗代謝物為氮胞答、胺三甲嗓吟（trimetrexate)、5-氟脫氧尿 苷、脫氧共間型黴素、2-氯基脫氧腺苷、戊托制菌素 (pentostatin)、6-巯基嘌呤、羥基脲、6-硫基鳥嘌呤、得西塔賓 (decitabine)(SuperGen)、阿糖胞菩、可洛法拉賓（clofarabine) (Bioenvision)、2-氟基脫氧胞嘗、衣洛弗凡（irofUlven)(MGI Pharma)、胺甲嗓呤、托目地斯（tomudex)、乙炔基胞嘴咬核芬 (Taiho)、弗達拉賓（fludarabine)、真西塔賓（gemcitabine)、瑞提崔 斯得（raltitrexed)或卡配西塔賓（capecitabine)。在其他具體實施 例中，拓樸異構酶抑制劑為阿姆薩素（amsacrine)、也沙提肯 (exatecan)甲烧磺酸鹽（Daiichi)、表紅菌素、奎阿美得(quinamed) (ChemGenex)、衣托糖替（etoposide)、吉馬提肯（gimatecan) (Sigma-Tau)、天尼嘗（teniposide)、絲裂黃酮（mitoxantrone)、二氟 莫提肯（diflomotecan)(Beaufour-Ipsen)、7-乙基-10·經基·喜樹驗、 得拉。坐山特（dexrazoxanet)(TopoTarget)、約薩米如辛（elsamitrucin) (Spectrum)、皮克山從（Pixantrone)(Novuspharma)、約多提卡林 (edotecarin)(Merck 公司）、貝卡提卡林(becatecarin)(Exelixis)、卡瑞 尼特辛（karenitecin)(BioNumerik)、BBR-3576 (Novuspharma)、貝洛 123505 -107- 200815422 提肯（belotecan)(Chong Kun Dang)、魯比提肯（rubitecan)(SuperGen)、 伊利諾提肯（irinotecan)(CPT-ll)或拓波提肯（topotecan)。於又其 他具體實施例中，抗腫瘤抗生素為達克汀黴素（放線菌素 D)、阿左那懷（azonafide)、瓦爾紅菌素、蒽外坐、道諸紅菌 素（道諾黴素）、歐山垂°坐(oxantrazole)、色拉紅菌素（therarubicin)、 洛索山酮（losoxantrone)、依達紅菌素、博來黴素酸、如比達 宗（rubidazon)、沙巴紅菌素（sabarubicin)(Menarini)、普利卡黴素、 13-去氧多克索紅菌素鹽酸鹽（Gem醫藥）、甲基絲裂黴素、表 紅菌素、絲裂黃酮（mitoxantrone)(諾凡從（novantrone))或阿蒙那 懷（amonafide)。抗有絲分裂劑之實例為秋水仙素、ABT-751 (Abbott)、長春花驗、西歐塔斯（xyotax)(Cell治療劑）、長春花 素、IDN 5109 (Bayer)、多拉制菌素 10 (NCI)、A 105972 (Abbott)、 利坐素（rhizoxin)(Fujisawa)、A 204197 (Abbott)、米沃蛋白 (mivobulin)(Wamer-Lambert)、新沙多亭（synthadotin)(BASF)、西馬 多、;丁（cemadotin)(BASF)、因地布林（indibulin)(ASTAMedica)、RPR 109881A(Aventis)、TXD 258 (Aventis)、風車子制菌素 A4 (BMS)、 艾波希酮B (Novartis) '異高哈利軟骨素-B (PharmaMar)、T 900607 (圖拉利克（Tularik)) ' ZD 6126 (AstraZeneca)、巴塔布林 (batabulin)(Tularik))、隱藻素 52 (Eli Lilly)、溫弗路寧（vinflimine) (Fabre)、海拉文（hydravin)(Prescient NeuroPharma)、歐利制菌素 (auristatin) PE (Teikoku 激素）、氮約波席隆（azaepothilon) B (BMS)、 衣沙貝比隆（ixabepilone)(BMS)、塔渴謝特（tavocept)(BioNumerik)、 BMS 184476 (BMS)、肯瑞制菌素（combrestatin) A4 磷酸氫二鈉 (OXiGENE)、BMS 188797 (BMS)、多拉制菌素-10 (NIH)、紅豆 123505 -108- 200815422 杉普辛（taxoprexin)(Protarga)、肯圖馬伯莫天辛（cantuzumab mertansine)(GlaxoSmithKline)、多謝他索（docetaxel)、威諾賓 (vinorelbine)或長春新驗。在一些具體實施例中，芳香酶抑制 劑為胺基導眠能（aminoglutethimide)、阿塔美斯坦（atamestane)(生 物醫學）、弗美斯烧（formestane)、發德羅4 (fadrozole)、列特羅 峻（letrozole)、約克美斯烧（exemestane)或安那史峻（Anastrazole)。 在其他具體實施例中，胸苷化物合成酶抑制劑為佩美催西 得（pemetrexed)(Eli Lilly)、諾拉催西得（nolatrexed)(Eximias)、ZD-9331 (BTG)、多西弗利叮（doxifluridine)(NipponRoche)或5，10-亞甲基四 氫葉酸鹽（BioKeys)。在又其他具體實施例中，DNA拮抗劑為 左貝克提定（trabectedin)(PharmaMar)、約祿催提（edotreotid) (Novartis)、葡填醢胺（glufosfamide)(Baxter International)、馬弗斯醯 胺（mafosfamide)(Baxter International)、阿帕吉昆（apaziquone) (Spectrum 醫藥）或席美克塔辛（thymectacin)(NewBiotics)。於又再 其他具體實施例中，法呢基轉移酶抑制劑為阿葛拉賓 (arglabin)(NuOncology Labs)、替皮法尼伯（tipifamib)(Johnson & Johnson)、洛那法尼伯（lonafamib)(Schering_Plough)、紫蘇醇（DOR BioPharma)或索拉非尼伯（sorafenib)(Bayer)。泵送抑制劑之實例 為左蘇奎達（zosuquidar)三鹽酸鹽（Eli Lilly)、塔利奎達 (tariquidar)(Xenova)、必利可達（biricodar)二檸檬酸鹽（Vertex)或 MS-209 (Schering AG)。組織蛋白乙醯轉移酶抑制劑之實例包 括塔西地那林（tacedinaline)(Pfizer)、丁酸三甲基乙酿基氧基甲 酯（Titan)、AP-CANC-03 與 AP-CANC-04 (Aton Pharma)、縮肽 (Fujisawa)或MSJ75 (Schering AG)。在一些具體實施例中，金屬 123505 -109- 200815422 蛋白酶抑制劑為新維制菌素（neovastat)(Aetema Laboratories)、美 塔制菌素（metastat)(CollaGenex)或馬利制菌素（marimastat)(British Biotech)。在其他具體實施例中，核糖核甞還原酶抑制劑為 麥芽酸鎵（Titan)、帖札西塔賓（tezacitabine)(Aventis)、三阿平 (triapine)(Vion)或迪多克斯（didox)(保健分子）。在又其他具體實 施例中，内皮肽受體拮抗劑為阿卓仙坦（atrasentan)(Abbott)、 伯仙坦（bosentan)(Roche)、安伯利仙坦（ambrisentan)(BASF)、西塔 仙坦（sitaxsentan)(Encysive)、可拉坐仙坦（clazosentan)(Roche)、達 魯仙坦（darusentan)(Knoll)及 ZD-4054 (AstraZeneca)。於又再其他具 體實施例中，視黃酸受體催動劑為吩瑞亭奈德（fenretinide) (Johnson & Johnson)、阿利崔替諾因（alitretinoin)(Ligand)、塔雜若 汀（tazarotene)(Allergan)、提利諾因（tetrinoin)(Roche)、異崔替諾因 (isotretinoin)(Roche)、13-順式·視黃酸（UCSD)或 LGD-1550 (Ligand) 〇 在一些具體實施例中，免疫調制劑為干擾素、Roferon-A (Roche)、得克索山（dexosome)療法（Anosys)、腫瘤嗟菌體 (oncophage)(Antigenics)、片催克斯（pentrix)(澳洲癌症技術）、GMK 疫苗（Progenies)、CD154 細胞療法（Tragen)、腺癌疫苗（Biomira) ' 傳維克斯（transvax)(Intercell)、勒槽驗（AVI BioPharma)、諾瑞林 (norelin)(Biostar)、IRX-2 (Immuno Rx)、BLP-25 微脂粒疫苗 (Biomira)、PEP-005 (Peplin Biotech)、多神經節嘗脂疫苗 (Progenies)、同步維克（synchrovax)疫苗（CTL Immnuo)、b_阿列辛 (alethine) (Dovetail)、黑色素瘤疫苗（CTL Immnuo)、護血管劑 (Vasogen)、利圖西馬伯（rituximab)(Genentech/Biogen Idee)或 p21 RAS疫苗（Gem Vax)。在其他具體實施例中，激素劑為雌激 123505 •110- 200815422 素、地塞米松、共軛雌激素、潑尼松、炔雌二醇、甲基氫 化潑尼松、氣三安生（chlortrianisen)、氫化潑尼松、埃定睪酮 (idenestrol)、胺基導眠能（aminoglutethimide)、己酸經孕酮、留 普内酯（leuprolide)、甲孕酮、八瑞歐肽（octreotide)、睪酮、米 托坦（mitotane)、睪酮丙酸鹽、氟羥甲睪酮、甲基睪酮、2-甲 氧雌二醇（EntreMed)、二乙基己烯雌紛、阿左西吩（arzoxifen)(Eli Lilly)、甲地孕酮、他摩西吩(tamoxifen)、二卡如酸胺(bicalutamide)、 妥瑞莫吩（toremofin)、弗如酸胺（flutamide)、郭捨瑞林 (goserelin)、尼如醯胺（nilutamide)或留普瑞林（leuporelin)。在又 其他具體實施例中，光動態劑為塔拉波吩（talaporfin)(Light Science)、Pd-細菌脫鎂葉綠二酸化物（Yeda)、捨拉路克斯 (theralux)(Theratechnologies)、銷提沙啡琳(texaphyrin)(Pharmacyclics)、 莫提沙吩（motexafin)、乳（Pharmacyclics)或金絲桃慈酮。於又再 其他具體實施例中，血管生成抑制劑為新維制菌素 (neovastat)(AEtema Zentaris)、ATN-224 (Attenuon)、索拉非尼伯 (sorafenib)(Bayer)、酉太胺口瓜咬酮、貝發西馬伯（bevacizumab) (Genentech)、瑞尼必祖馬（ranibizumab)(Genentech)、貝尼吩 (benefm)(Lane Labs)、L-651582 (Merck & Co)、維塔拉尼伯 (vatalanib)(Novartis)或蘇坦特（sutent)(Sugen)。酿胺酸激酶抑制劑 之實例包括愛馬>'丁尼伯（imatinib)(Novartis)、列弗諾酿胺 (leflunomide)(Sugen/Pharmacia)、卡鹵化物（kahalide) F (PharmaMar)、 愛瑞沙（iressa)(AstraZeneca)、列托提尼伯（lestaurtinib)(Cephalon)、 啊羅提尼伯（erlotinib)(Oncogene Science)、肯内提尼伯（canertinib) (Pfizer)、坦杜提尼伯（tandutinib)(Millenium)、角鯊胺（Genaera)、 123505 -Ill - 200815422 米多星孢素（Novartis)、吩諾二醇（phenoxodiol)、SU6668 (Pharmacia)、些圖西馬伯（cetuximab)(Imclone)、rhu-Mab (Genentech)、 ZD6474 (AstraZeneca)、MDX-H210 (Medarex)、維塔拉尼伯 (vatalanib)(Novartis)、歐尼塔革（omnitarg)(Genentech)、拉巴提尼伯 (lapatinib)(GlaxoSmithKline)、片尼圖努馬伯（panitumumab)(Abgenix)、 IMC-1C11 (Imclone)、索拉非尼伯（sorafenib)(Bayer)或搓史圖諸馬 伯（trastuzumab)(Genentech)。在一些具體實施例中，抗增生劑為 苯丙胺酸氮芥、亞硝基脲氮芥、順氯胺鉑、5-氟尿嘧啶、 絲裂黴素C、亞德里亞黴素（多克索紅菌素）、博來黴素或 培克里他索（paclitaxel)(Taxol®)。 在本發明之一些具體實施例中，癌症為骨肉瘤、卡波西 氏肉瘤、結腸直腸癌、腦癌、上皮細胞衍生之細胞增生（上 皮癌）、基底細胞癌、腺癌、胃腸癌、唇癌、口癌、食管癌、 小腸癌、胃癌、胃癌、結腸癌、肝癌、膀胱癌、胰臟癌、 卵巢癌、子宮頸癌、肺癌、乳癌、皮膚癌、鱗狀細胞癌症、 基底細胞癌症、前列腺癌、腎細胞癌；白血病、淋巴瘤、 母紅血球瘤、神經膠質母細胞瘤、神經膠質瘤、腦膜瘤、 星細胞瘤、肌胚細胞瘤、多發性骨髓瘤、急性骨髓性白血 病、脊髓發育不良徵候簇、非Hodgkins淋巴瘤或濾胞淋巴 瘤。在一些此種具體實施例中，癌症為肢端雀斑黑色素瘤、 光化角化病、腺癌、腺樣膽囊癌、腺瘤、腺肉瘤、腺鱗狀 癌瘤、星形細胞腫瘤、巴多林氏腺癌、基底細胞癌、枝氣 管腺癌瘤、微企管輕癌、癌瘤、癌肉瘤、海綿狀膽管癌、 軟骨肉瘤、脈絡叢乳頭狀瘤/癌瘤、透明細胞癌、囊腺瘤、 123505 -112- 200815422 、子宮内膜增生、子宮内膜基質肉瘤、(13) Lepazone catalyzing agents, including recombinant human leptin and recombinant methotrexate sulfhydryl human leptin, and leptin derivatives, such as OB3, and U.S. Patent 5,552,524, 5,552,523 , 5, 552, 522, 5, 521, 283, 6, 777, 388 and 6, 936, 439, and PCT Application No. WO 96/23513, WO 96/23514, WO 96/23515, WO 96/23516, WO 96/23517, WO 96/23518, WO 96/23519 , WO 96/23520, WO 96/05309, WO 96/40912, WO 97/06816, WO 00/20872, WO 97/18833, WO 97/38014, WO 98/08512, WO 98/284427, US Patent Publication 2004 (007) Cholecystokinin (CCK) agonists, such as ARR15849, GI181771, JMV180, A71378, A71623, SR146131, UCL2000, and A71378, as disclosed in /0072219, 2003/049693, 2003/0166847, and 2003/0092126, And as described in U.S. Patent 5,739,106; (15) Ciliary Neurotrophic Factor (CNTF), including CNTF, CNTF modulators, and CNTF derivatives, such as Yorkoxin (Axokine) and NT501, and in the United States 123505 -98 - 200815422, US Patent No. 6,680,291 and 6,767,894, and in PCT Application No. WO 94/09134, WO 98/22128 and WO 99/4 (13) Growth hormone (GH) secretagogue, growth hormone secretagogue receptor modulator, such as SUN11031, RCH91, tesamorelin, sermorelin, Examorelin, NN703, hexacycline, MK677, SM-130686, CP-424, 391, L-692, 429 and L-163, 255; (17) Dipeptidyl peptidase IV (DP-IV or DPP-IV) Inhibitors such as denagliptin, sitagliptin, SYR322, R00730699, TS021, ALS20426, vidagliptin, GRC8200, MP513, PHX1149, PSN9301, TA6666, Shaksha Staxagliptin, SSR162369, R1438, KRP104, 825964, and in PCT Application No. WO 03/004498; WO 03/004496; EP 1 258 476; WO 02/083128; WO 02/062764; WO 03/000250 WO 03/002530; WO 03/002531; WO 03/002553; WO 03/002593; WO 03/000180; and the compounds disclosed in WO 03/000181; (18) histamine receptor-3 (H3) antagonism Agent/reverse catalyzer, such as GSK189254A, A331440, ABT239, ABT834, BP294, thiocarbamide Thioperamide), 3-(1Η-imidazol-4-yl)propyl N-(4-pentenyl)carbamate, clobenpropit, iodophenpropit, amopro Oxyproxifan, GT2394, and as disclosed in PCT Application No. WO 02/15905; (19) serotonin (5HT) agonist, such as 5HT2C (serotonin receptor 2C) Agents, such as lorcaserin, vabicaserin, APD 356, and U.S. Patent 3,914,250 and PCT Application No. WO 02/36596, 123505-99-200815422 WO 02/48124, WO 02/ 10169, WO 01/66548, WO 02/44152, WO 02/51844, WO 02/40456 and WO 02/40457; with 5HT6 agonist, such as PRX07034; (20) serotonin delivery or serotonin re Intake inhibitors such as nefazodone, citalopram, dapoxetine, duloxetine, desvenlafaxine, fluvoxamine ), escitalopram, sibutramine, venlafaxine, vilazodone ), DOV21947, LUAA21004, BGC201259, NS2359, UK416244, DOV102677, SEP225289, OPC14523, SLV314, WL1011, WL1017, zimeldine, fluoxetine, fluoxetine, paroxetine, fenfluramine (fenfluramine), propylene-p well and sertraline, and those disclosed in U.S. Patent No. 6,365,633, issued to PCT Application No. WO 01/27060, and WO 01/162341; (21) Dopamine activators, such as dopamine D2 agonists, such as ropinirole, bifeprunox, aripiprazole, pergolide, talipexole, ACP104, quina Quinagolide, nolomirole, NH001, SLV308, piribedil, lisuride, bromocriptine, aplindore, sorrel Tesofensine and preclamol; (22) Adrenergic (NE) delivery inhibitors, such as lisdexamfetamine, atomoxetine, and duocitin (duloxetine), SLE381, off text Desvenlafaxine, amfebutamone, sibutramine, venlafaxine, 123505 -100- 200815422 DOC21947, radafaxine, acetophenone , DOV216303, reboxetine, AD337, NS2359, DOV102677, SEP225289, Xen2174, indeloxazine, protriptyline, and S33005; (23) dimercaptoglycerol thiol transferase ( DAG) inhibitors, such as BAY744113; (24) glucose transporter inhibitors, such as sodium glucose co-transporter (SGLT) inhibitors, such as KGT1251, 189075, AVE2268, and SGL0010; (25) 11 /3-hydroxysteroid dehydrogenase -1 (/9-HSD-1) inhibitors, such as INCB13739 and AMG221; (26) cholesterol ester transfer protein (CETP) inhibitors such as torcetrapib, CETil, JTT705, BAY605521 and JTT302; a squalene synthetase inhibitor, such as lapaquistat; (28) a corticosteroid antagonist, such as mifepristone, Org34517, and Org34850; (29) phosphodiesterase ( PDE) inhibitors, including phosphorus Diesterase-3B (PDE3B) inhibitors, such as tetomilast, tadalafil, atopik, vardenafil, tipelikat ( Tipelikast), HT0712, QAD171A, SK3530, oglemilast, acanafil, cilostazol, roflumilast, parogrelil , udenafil, EHT0202, dasantafil, MEM1414, SLx2101, CC10004, 256066, cilomilast, vinpocetine, Abu Dharat (ibudilast), pimobendan, ND7001, LAS37779, K123, UK357903, ND1251, tofimilast, UK169003, senazodan, trapidil, ar Arfylline, tea 123505 -101 - 200815422 Alkali, doxofylline, olprinone, pentoxifylline, zaprinast, matnafe Sildenafil), amrinone, millinon (mil Rinone), cilostamide, rolipram, and cilomilast; (30) destruction of platelet agents, such as limaprost, cropido Clopidogrel, felbinac, eptifibatide, NCX4016, ticagrelor, tirofiban, abcixmab, Sarpogrelade, DA697B, argatroban, SCH530348, cilostazol, YSPSL, parogrelil, asasantin, DG041, Pula Prasugrel, ramatroban, cangrelor, epoprostenol, beraprost 'aspirin, K134, triflusal ), YY280, xemilofiban, ozagrel, aprostadil alfadex, TP9201, procainamide, AT1015, Z335, BGC728, Glyrofam, EF5077, SH529 and ME3229; (31) Vascular collection Inhibitors (ACE) inhibitors, such as peridopril, enalapril, ramipril, fosinopril, quinapril , lisinopril, imidapril, benazepril, ilepatril, captopril, randopril (trandolapril), temcapil, cilazapril, MC4232, CHF1521., omapatrilat, spirapril, moy sip-102 - 123505 200815422 moexipril, zofenopril, deLapril, aracepril, S5590 and fasidotril; (32) angiotensin II (All) Receptor antagonists, such as losartan, candesartan, temisartan, coaprovel, imidapril, aji Azilsartan, valsartan, irbesartan, team methadone Olmesartan), CYT006AngQb, TAK491, eprosartan, VNP489, CGP63170, fimesartan, pratosartan and saralasin; (33) uncoupling protein (UCP)-l, 2 or 3 activator, such as phytanic acid, 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 2-荇) small propenyl]benzoic acid (oxime), retinoic acid, and as disclosed in PCT Patent Application No. WO 99/00123; (34) scorpion hormone/3 agonist, such as scorpion Glandular hormone, levothyroxine, guanidine 2115, 3,5-diiodothyronine, oleophilic thymidine, guanidinium, and PCT Patent Application No. WO 02/15845 and Japanese Patent Application No. JP (25) Cyclooxygenase (COX)-2 inhibitors, such as etoricoxib, GW406381, meloxicam, lumiracoxib, bis-phenophene Dicofenac, valdecoxib, parecoxib, PMI001,6444784, SVT2016, nimesulfide, CS706, simi kusi ( Cimicoxib), LR3001, LAS34475, P54, rofecoxib, celecoxib, and arcoxia; (36) monoamine reuptake inhibitors, such as in the PCT application number WO 01/27068 123505 -103 - 200815422 and WO 01/62341; (37) Metabolically shifted glutamate 5 (mGlu5) receptor antagonists, such as ADX10059, AFQ-056, 2-methyl- 6-(phenylethynyl)-pyridine (MPEP), (3-[(2-methyl-l,3-p-sei-4-yl)ethynyl)] (b), (MTEP), and Anderson et al. (2003) J_Eur. J. Pharmacol· 473: 35-40; Cosford et al. (2003) Bioorg· Med·Chem· Lett· 13(3) ·· 351_4 ; and Anderson et al. (2002) J. Pharmacol. Exp. Ther. 303: Compounds as described in 1044-1051; (38) Acid-estrogens, such as oleoreyl-estrone, in del Mar-Grasa, Μ· et al, Obesity Studies, 9: (39) Fatty acid synthase (FAS) inhibitors, such as cerulenin and C75; (40) acetyl-CoA carboxylase-2 (ACC2) inhibitor; 41) adrenocorticotropic hormone-releasing hormone priming agent; (42) Gao Liang Flavin antagonist; (43) Bombesin receptor subtype 3 (BRS3) catalyzer; (44) Protein tyrosine phosphatase-IB (PTP-1B) inhibitor; (45) Fatty acid delivery Sub-inhibitor; (46) dicarboxylate transporter inhibitor; (47) sulphate transporter inhibitor; (48) urinary voxel-binding protein antagonist and urinary voxel ligand, such as urine Voxel II; (49) Human squirrel-associated protein (AGRP); (50) Neurohormone U receptor agonist; (51) Topiramat, oxytocin, 褡格糖, CP741952, sitting in Nice Zonisamide, ID1101, BDC03, S2367, AOD9604, 123505-104-200815422 fluasterone, GT389255, QCBT16, MK0916, MK0493, MK0364, PD6735, C2735 and lipoconjugate. Examples of other anti-obesity agents that can be used in combination with the compounds described herein are disclosed in M. Patent Focus on Novel Anti-obesity Agents "5 Exp. Opin. Ther. Patents, 10: 819-831 (2000); f' Novel anti-obesity drugs'', Exp. Opin. Invest. Drugs, 9: 1317-1326 (2000); and " Recent advances in eating suppressors: Exp. Opin· Ther. Patents, 11: 1677-1692 (2001). The role of neuropeptide Y in obesity is discussed in Exp. I Opin· Invest. Drugs, 9: 1327-1346 (2000). The class of cannabinoid receptor ligands is discussed in Exp. Opin·Invest· Drugs, 9 · 1553-1571 (2000). Obesity and weight loss treatments that can be used in conjunction with the compounds described herein, including surgery. Typically, the weight loss surgical procedure is liposuction or liposuction. Surgical obesity treatment includes gastric shunt, laparoscopic adjustable gastric union, biliary-pancreatic transition, or vertical banded gastroplasty. In another aspect, there is provided a method comprising administering to a patient in need thereof a compound, such as a cytokine inhibitor, and one or more ingredients A, effective to increase or enhance the effectiveness of ingredient A when used alone. And wherein the ingredient A is selected from the group consisting of agents useful for treating obesity or obesity-related symptoms or conditions, and wherein the compound is as described herein, or a mixture of two or more thereof and/or a stereoisomer thereof, A tautomer, solvate, prodrug or pharmaceutically acceptable salt. In some embodiments, the effectiveness enhancement is achieved by allowing a lower dose of one or more of the ingredients A used in the combination to be administered, relative to the use of either agent alone. In another aspect of the invention, there is provided a method comprising administering to a patient 123505 • 105-200815422 a compound as described herein, such as a cytokine inhibitor, and component A' relative to administration of the compound The risk of the disease before the component a is effective in reducing the risk of a metabolic disorder in a patient in need thereof, and the ingredients are selected from the agents which can be used for the treatment of symptoms or disorders related to obesity or obesity. In some embodiments, the reduction in the risk of a metabolic disorder relative to the weight of a patient who is administered a combination of a cytokine inhibitor and a component A is obtained by reducing the body weight of the patient. In yet another aspect of the invention, a method of treating cancer is provided. Such methods comprise administering to a patient in need of such treatment a composition comprising a therapeutically effective amount of a compound, such as a cytokine inhibitor as described herein or a pharmaceutically acceptable salt thereof, a solvent Compound or stereoisomer. In some embodiments of the invention, the method of treating cancer further comprises treating the patient with surgery, radiation, cryotherapy or one or more anti-proliferative agents or a combination thereof. In some such embodiments, the anti-proliferative agent is an alkylating agent, a platinum agent, an antimetabolite, a topoisomerase inhibitor, an anti-tumor antibiotic, an anti-mitotic agent, an aromatase inhibitor, and a chest chelate synthesis. Enzyme inhibitors, DNA antagonists, farnesyl transferase inhibitors, pumping inhibitors, tissue protein acetyltransferase inhibitors, metalloproteinase inhibitors, ribonucleoside reductase inhibitors, endothelin receptor antagonists, Retinoic acid receptor agonists, immunomodulators, hormone or antihormonal agents, photodynamic agents, angiogenesis inhibitors or tyrosine kinase inhibitors. In some such embodiments, the alkylating agent is busulfan, procarbazine, ifosfamide, altretamine, hexamethylene melamine, and female mustard ( Estramustine) sulphate, thiotepa, nitrofen, azomethamine, chain 123505 -106- 200815422 Moldy succinyl, cycloheximide, temozolomide, ring stone Indoleamine, semustine or chlorambucil. Examples of doubling agents include spiroplatin, lobaplatin (Aetema), tetraplatin, satraplatin (Johnson Matthey), ormaplatin , iproplatin, miriplatin (Sumitomo), nexplatin (AnorMED), polymer platinum (Access), oxalic acid platinum or carbon gas amine platinum. In some embodiments, the antimetabolite is azide, trimetrexate, 5-fluorodeoxyuridine, deoxy-intermycin, 2-chlorodeoxyadenosine, pentomycin (pentostatin), 6-mercaptopurine, hydroxyurea, 6-thioguanine, decitabine (SuperGen), arabinose, clofarabine (Bioenvision), 2-fluorodeoxygenation Cell taste, irofUlven (MGI Pharma), amide hyperthyroidism, tomudex, acetylene cytosine (Taiho), fludarabine (fludarabine), true sitabin ( Gemcitabine), raltitrexed or capecitabine. In other specific embodiments, the topoisomerase inhibitor is amsacrine, butatecan, acetophenone, acenabin, quinamed (ChemGenex), etoposide, gimatecan (Sigma-Tau), teniposide, mitoxantrone, diflomotecan (Beaufour-Ipsen) ), 7-ethyl-10· Jingji·Xishu, pull. Dexrazoxanet (TopoTarget), elsamitrucin (Spectrum), Pixantrone (Novuspharma), edotecarin (Merck), Bekatikarin (becatecarin) (Exelixis), Karenitecin (BioNumerik), BBR-3576 (Novuspharma), Belo 123505 -107- 200815422 Belocan (Chong Kun Dang), Rubiconcan (rubitecan) ) (SuperGen), irinotecan (CPT-ll) or topotecan. In still other embodiments, the anti-tumor antibiotic is dydtinmycin (actinomycin D), azonafide, valvidin, sputum, and erythromycin (Danomycin)素), Oxantrazole, therbicubicin, losoxantrone, idadamycin, bleomycin, such as rubidazon, Sabah red Sabarubicin (Menarini), pricarmycin, 13-deoxy-drosoerythrulin hydrochloride (Gem medicine), methyl mitomycin, epirubicin, mitoxantrone ) (novantrone) or amonafide. Examples of anti-mitotic agents are colchicine, ABT-751 (Abbott), periwinkle test, xyotax (Cell therapeutic), vinca, IDN 5109 (Bayer), and doxorubicin 10 ( NCI), A 105972 (Abbott), rhizoxin (Fujisawa), A 204197 (Abbott), mivobulin (Wamer-Lambert), synthadotin (BASF), West Malaysia More, cemadotin (BASF), indibulin (ASTAMedica), RPR 109881A (Aventis), TXD 258 (Aventis), windmill bacteriocin A4 (BMS), epoch ketone B ( Novartis) 'Horg Chondroitin-B (PharmaMar), T 900607 (Tularik) 'ZD 6126 (AstraZeneca), batabulin (Tularik), cryptophyll 52 (Eli Lilly), vinflimine (Fabre), hydravin (Prescient NeuroPharma), auristatin PE (Teikoku hormone), nitrogen azeepothilon B (BMS) ), ixabepilone (BMS), tavocept (BioNumerik), BMS 184476 (BMS), cobristatin A4 hydrogen phosphate Sodium (OXiGENE), BMS 188797 (BMS), Doxorubicin-10 (NIH), Red Bean 123505 -108- 200815422 Taxoprexin (Protarga), Cantuuzumab mertansine (cantuzumab mertansine) GlaxoSmithKline), thank you (docetaxel), vinorelbine (vinorelbine) or Changchun new test. In some embodiments, the aromatase inhibitor is aminoglutethimide, atamestane (biomedicine), formestane, fadrozole, column Letrozole, exemestane or Anastrazole. In other specific embodiments, the thymidine synthase inhibitor is pemetrexed (Eli Lilly), nolatrexed (Eximias), ZD-9331 (BTG), Dorset Doxifluridine (Nippon Roche) or 5,10-methylenetetrahydrofolate (BioKeys). In still other embodiments, the DNA antagonist is trabectedin (PharmaMar), edotreotid (Novartis), glufosfamide (Baxter International), Maphus 醯Mafosfamide (Baxter International), apaziquone (Spectrum Medicine) or thymectacin (NewBiotics). In still other embodiments, the farnesyl transferase inhibitors are arglabin (NuOncology Labs), tipifamib (Johnson & Johnson), and Lonofanib ( Lonafamib) (Schering_Plough), perillyl alcohol (DOR BioPharma) or sorafenib (Bayer). Examples of pumping inhibitors are zosuquidar trihydrochloride (Eli Lilly), tariquidar (Xenova), biricodar dicitrate (Vertex) or MS. -209 (Schering AG). Examples of tissue protein acetyltransferase inhibitors include tacedinaline (Pfizer), trimethyl ethanomethyl butyrate (Titan), AP-CANC-03 and AP-CANC-04 (Aton Pharma), Reduced Peptide (Fujisawa) or MSJ75 (Schering AG). In some embodiments, the metal 123505-109-200815422 protease inhibitor is neovastat (Aetema Laboratories), metastat (CollaGenex), or marimastat (marimastat) (British Biotech). In other specific embodiments, the ribonucleoside reductase inhibitor is gallium maltate (Titan), tezacitabine (Aventis), triapine (Vion) or didox (didox) ) (health molecule). In still other embodiments, the endothelin receptor antagonists are atrasentan (Abbott), bosentan (Roche), ambrisentan (BASF), and xitar Sitaxsentan (Encysive), clazosentan (Roche), darusentan (Knoll) and ZD-4054 (AstraZeneca). In still other embodiments, the retinoic acid receptor agonist is fenretinide (Johnson & Johnson), alitretinoin (Ligand), and tacroster ( Tazarotene) (Allergan), tetrinoin (Roche), isotretinoin (Roche), 13-cis retinoic acid (UCSD) or LGD-1550 (Ligand) In a specific embodiment, the immunomodulatory agent is interferon, Roferon-A (Roche), dexosome therapy (Anosys), oncophage (Antigenics), pentrix ( Australian cancer technology), GMK vaccine (Progenies), CD154 cell therapy (Tragen), adenocarcinoma vaccine (Biomira) 'transvax (intercell), levator test (AVI BioPharma), norelin (norelin) (Biostar), IRX-2 (Immuno Rx), BLP-25 liposome vaccine (Biomira), PEP-005 (Peplin Biotech), multi-ganglion lipoprotein vaccine (Progenies), synchronous synchovax vaccine (CTL) Immnuo), b_alethine (Dovetail), melanoma vaccine (CTL Immnuo), vascular care agent (Vasogen), benefit Xi Mabo (rituximab) (Genentech / Biogen Idee) or p21 RAS vaccine (Gem Vax). In other embodiments, the hormonal agent is estrogen 123505 •110-200815422, dexamethasone, conjugated estrogen, prednisone, ethinyl estradiol, methylprednisolone, chlortrianisen , prednisolone, idenestrol, aminoglutethimide, progesterone hexanoate, leuprolide, medroxyprogesterone, octreotide, anthrone, Mitotane, anthrone propionate, hydroxymethyl ketone, methyl ketone, 2-methoxyestradiol (EntreMed), diethyl hexene, arzoxifen (Eli Lilly) ), megestrol, tamoxifen, bicalutamide, toremofin, flutamide, goserelin, nitra Nilutamide or leuporelin. In still other embodiments, the photodynamic agent is talapor (Light Science), Pd-bacteria leucophora (Yeda), theralux (Theratechnologies), pin Texaphyrin (Pharmacyclics), Motexafin, Pharmacyclics or Hypericin. In yet other specific embodiments, the angiogenesis inhibitors are neovastat (AEtema Zentaris), ATN-224 (Attenuon), sorafenib (Bayer), and sputum melon. Ketone, bevacizumab (Genentech), ranibizumab (Genentech), benefm (Lane Labs), L-651582 (Merck & Co), Vita VARalanib (Novartis) or Sutent (Sugen). Examples of the tyrosine kinase inhibitors include Emma > 'imatinib (Novartis), leflunomide (Sugen/Pharmacia), kahalide F (PharmaMar), Ari Iressa (AstraZeneca), lestaurtinib (Cephalon), erlotinib (Oncogene Science), canertinib (Pfizer), tandutinib (tandutinib) (Millenium), squalamine (Genaera), 123505 -Ill - 200815422 Novartis, phenoxodiol, SU6668 (Pharmacia), some cetuximab (cetuximab) Imclone), rhu-Mab (Genentech), ZD6474 (AstraZeneca), MDX-H210 (Medarex), vatalanib (Novartis), omnitarg (Genentech), Labatinibo ( Lapadinib) (GlaxoSmithKline), panitumumab (Abgenix), IMC-1C11 (Imclone), sorafenib (Bayer) or trastuzumab (Genentech) . In some embodiments, the anti-proliferative agent is amphetamine, nitrosourea, cisplatin, 5-fluorouracil, mitomycin C, and doxorubicin (doxorubicin) ), bleomycin or paclitaxel (Taxol®). In some embodiments of the invention, the cancer is osteosarcoma, Kaposi's sarcoma, colorectal cancer, brain cancer, epithelial cell-derived cell hyperplasia (epithelial cancer), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip Cancer, oral cancer, esophageal cancer, small intestine cancer, stomach cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, squamous cell cancer, basal cell cancer, Prostate cancer, renal cell carcinoma; leukemia, lymphoma, erythroblastoma, glioblastoma, glioma, meningioma, astrocytoma, myoblastoma, multiple myeloma, acute myeloid leukemia, spinal cord development Bad syndrome, non-Hodgkins lymphoma or squamous lymphoma. In some such embodiments, the cancer is acral freckle melanoma, actinic keratosis, adenocarcinoma, adenoid gallbladder carcinoma, adenoma, adenosarcoma, adenosquamous carcinoma, astrocytic tumor, and bardot. Lin's adenocarcinoma, basal cell carcinoma, bronchial adenocarcinoma, microvascular cancer, carcinoma, carcinosarcoma, cavernous cholangiocarcinoma, chondrosarcoma, choroid plexus papilloma/cancer, clear cell carcinoma, cystadenoma , 123505 -112- 200815422 , endometrial hyperplasia, endometrial stromal sarcoma,

内胚葉竇腫瘤、 内膜樣腺癌，室 瘤、肝腺瘤病、肝細胞癌、胰島腺瘤、上皮内腫瘤形成、 上皮間鱗狀細胞腫瘤形成、侵入性鱗狀細胞癌、大細胞癌、 平滑肌肉瘤、雀斑惡性黑色素瘤、惡性黑色素瘤、惡性間 皮腫瘤、神經管胚細胞瘤、神經上皮瘤、黑色素瘤，腦膜、 間皮、轉移性癌瘤，黏膜表皮樣癌瘤、神經胚細胞瘤、神 經上皮腺癌結狀黑色素瘤、燕麥細胞癌，募樹突膠質、骨 肉瘤，胰多肽、乳頭狀漿液性腺癌，松果腺細胞、垂體腫 瘤，漿細胞腫瘤、假肉瘤、肺胚細胞瘤、腎細胞癌、視網 膜胚細胞瘤、橫紋肌肉瘤、肉瘤、漿液性癌瘤、小細胞癌 瘤、柔軟組織癌瘤、生長激素釋放抑制因子分泌腫瘤、鱗 狀癌瘤、鱗狀細胞癌，間皮下、表面擴展黑色素瘤，未鑒 別癌瘤、葡萄膜黑色素瘤、疣癌瘤、蛇狀瘤、經良好地鑒 別之癌瘤或Wilm氏腫瘤。 在一些具體實施例中，癌症為白血病、母紅血球瘤、多 發性骨髓瘤、急性骨髓性白血病、脊髓發育不良徵候簇、 非霍奇金（Hodgkin)氏淋巴瘤或濾胞淋巴瘤。在一些具體實施 例中’癌症為濾胞淋巴瘤、急性骨髓性白血病、多重骨髓 細胞瘤或非霍奇金（Hodgkin)氏淋巴瘤。 在其他具體實施例中，癌症為腦癌、神經膠質母細胞瘤、 腦膜瘤、星細胞瘤、神經管胚細胞瘤、神經胚細胞瘤或視 123505 -113- 200815422 網膜胚細胞瘤。在一些此種具體實施例中，癌症為神經膠 質瘤或神經膠質母細胞瘤。 在又其他具體實施例中，癌症為骨肉瘤、卡波西氏肉瘤、 軟骨肉瘤、Ewing氏肉瘤或肌胚細胞瘤。在一些此種具體實 施例中，癌症為骨肉瘤骨癌。 在一些具體實施例中，癌症為乳房、肺臟、腎臟或前列 腺癌轉移。在一些此種具體實施例中，贅瘤為骨質轉移。 於本發明之又另一方面，係提供治療、修正或處理疼痛 之方法。此等方法包括對需要此種治療、修正或處理之病 患投予一種組合物，其包含治療上有效量之化合物，譬如， 如本文中所述之細胞素抑制劑，或其藥學上可接受之鹽、 溶劑合物或立體異構物。在一些具體實施例中，此組合物 進一步包含抗抑鬱劑、抗高血壓藥、解焦慮劑、鈣通道阻 斷劑、a-腎上腺素能受體催動劑、a-腎上腺素能受體拮抗 劑、氣胺酮、麻醉劑、肌肉鬆弛劑、非麻醉性止痛劑、類 阿片止痛劑、NSAID、免疫調制劑、免疫壓抑劑、皮質類 固醇、抗搐搦藥、高比重氧、a2d配位體、NMDA受體拮抗 劑或其任兩種或多種之組合。在一些此種具體實施例中， 抗抑鬱劑為諾三替林(nortriptyline)、阿米替林（amitriptyline)、丙 味_、多慮平（doxepin)、可洛米胺（clomipramine)、氟西汀 (fluoxetine)、色他林（sertraline)、那發坐酮（nefazodone)、溫拉發 辛（venlafaxine)、搓嗤_ (trazodone)或丁胺苯丙酮。在其他具體 實施例中，抗高血壓藥為硝苯p比咬（nifedipine)、特拉嗤辛 (terazosin)、喊峻呼（prazosin)、若沙坦（losartan)、異博停 123505 -114- 200815422 (verapamil)、貼米沙坦（telmisartan)、弗新諸普利（fosinopril)、伯 仙坦（bosentan)或队美沙坦（olmesartan)。在又其他具體實施例 中，解焦慮劑為氟西丁（fluoxetine)、帕西〉'丁（paroxetine)、色他 林（sertraline)或溫拉發辛（venlafaxine)。药通道阻斷劑之實例包 括石肖苯ρ比唆（nifedipine)、異博停（verapamil)及可樂寧（clonidine)。 在其他具體實施例中，a-腎上腺素能受體催動劑為可樂寧 (clonidine)或曱氧胺福林（midodrine) 〇在又其他具體實施例 中，a-腎上腺素能受體拮抗劑為特拉。坐辛（terazosin)、|唾_ (prazosin)或多沙索金（doxasozin)。在一些具體實施例中，麻醉 劑為普魯卡因、利多卡因、甲哌卡因、阿提卡因（articaine)、 丙胺卡因、也提卡因（etidocaine)、丁旅卡因(bupivacaine)或洛 皮發卡因（ropivacaine)。類阿片止痛劑之實例包括氫莫風 (hydromorphone)、經基二氫待因酮（oxycodone)、嗎啡硫酸鹽、 唪啶及芬太尼（fentanyl)經皮貼藥。在一些具體實施例中， NSAID為COX-2抑制劑、柳酸醋酸鹽、異丁苯丙酸⑼upr〇fen)、 酮基丙吩（ketoprofen)、那丙新（naproxen)納、g同洛拉克 (ketorolac)、二可吩拿克（diclofenac)、啕哚美塔辛（ind〇metacin) 或乙醢胺吩（acetaminophen)。在一些此種具體實施例中， COX-2抑制劑為羅費庫西比（rofecoxib)、塞拉庫西比（cdec〇xib) 或維德庫西比（valdecoxib)。在又其他具體實施例中，皮質類 固醇為潑尼松、地塞米松或氫基可體松。在其他且體實施 例中，抗搐搦藥為胺甲醯氮萆、鲮咪哨：、加巴潘亭 (gabapentin)、普瑞加巴林(pregabalin)、笨妥英、法普酸納、克 羅那吉片（clonazepam)、托皮拉美（topiramat)、拉莫三金桌 123505 -115- 200815422 (lamotrigine)、坐尼斯醯胺（z〇nisamide)、提耳加賓（tiagabine)、發 莫托定（famotodine)、苯巴比妥、二苯基乙内醯脲、曱苯妥英 (mephenytoin)、乙基苯妥英、美發巴比妥（meph〇barbital)、去氧 苯比妥（primidone)、乙琥胺、甲琥胺、苯琥胺、三甲雙酮、 苯并二氮七圜、苯乙醯脲、乙醯唑磺胺、丙加拜得 (progabide)、二維丙若斯（divalproex)納、硫酸鎮注射液、美沙 必妥（metharbital)、甲乙雙酮、克羅巴尖（clobazam)、硫嘧美 (sulthiame)、代蘭汀（dilantin)、二苯蘭（diphenylan)或 L-5·羥色胺 酸。在一些具體實施例中，NMDA受體拮抗劑為右美沙芬 (dextromethorphan)、右羥嗎喃（dextr〇rphan)、氯胺酮、美漫汀 (memantine)、金剛胺、精胺、阿提加尼爾（aptiganei)、加維提 尼爾（gavestinel)、席發提爾（seifotei)、7-氯基犬尿酸鹽、瑞馬 西醯胺（remacemide)、利魯唑（riluz〇le)、外匕咯并喳啉醌或順式 -4-(膦酸基甲基）-2-六氫吡啶羧酸。在其他具體實施例中，a2d 配位體為加巴潘亭（gabapentin)、普瑞加巴林（pregabalin)、 [(lR，5R，6S)-6-(胺基甲基）雙環并[3.2.0]庚-6-基]醋酸、3-(1-胺基甲 基-環己基甲基）-4H-[l，2,4]-崎二唾-5-酮與C-[1-(1H-四唆-5-基甲 基)-¾庚基]-甲胺、（3S，4S)-(1-胺基曱基-3,4-二甲基-環戊基）-酉皆 酸、（la，3a，5a)(3-胺基·甲基-雙環并[3.2.0]庚-3-基）-醋酸、（3S，5R>3-胺基甲基·5·甲基-辛酸、（3S，5R)-3-胺基-5-曱基-庚酸、（3S，5R)-3-胺基-5-甲基-壬酸及（3S,5R)-3-胺基_5-甲基-辛酸。在又其他具 體實施例中，此組合物進一步包含乙醯柳酸 '二可吩拿克 (diclofenac)、異丁 苯丙酸（ibuprofen)、4 卜朵美塔辛（indometacin)、 氟滅酸、甲滅酸、嗎啡、喊替定、美沙giq (methadone)、芬太 123505 -116- 200815422 尼（fentanyl)、丁潑 t若吩（buprenorphine)、搓馬噪（tramadol)、加巴 潘亭（gabapentin)、普瑞加巴林(pregabalin)、胺甲醯氮萆、拉莫 三金（lamotrigin)、托皮拉美（topiramat)、苯偶因（phenyloin)、列 維提拉坦（levitiracetam)、普魯卡因、利多卡因、甲旅卡因、 阿提卡因（articaine)、丙胺卡因、也提卡因（etidocaine)、丁喊卡 因（bupivacaine)、洛皮發卡因（ropivacaine)、阿米催替林 (amitryptiline)、帕西汀（paroxetine)、西塔洛蘭（dtalopram)、丁胺 苯丙S同、都索列、;丁（duxoletine)、氯胺ί同、美漫汀（memantine)、 2,3-苯弁二氮七圜類或其任兩種或多種之組合。 在本發明之一些具體實施例中，疼痛為急性疼痛、慢性 疼痛、由於來自急性創傷之柔軟組織與周圍傷害所造成之 疼痛；神經病原性疼痛；中風後疼痛；癌疹後神經痛、枕 骨神經痛、三叉神經痛、節段或肋間神經痛及其他神經痛； 與骨關節炎及風濕性關節炎有關聯之疼痛；肌骨疼痛；椎 骨疼痛、中樞神經系統疼痛；下背痛、坐骨神經痛、牙痛、 肌筋膜疼痛徵候簇、女陰切開術疼痛、痛風疼痛及由於灼 傷所造成之疼痛；深層與内臟疼痛；肌肉疼痛、眼睛疼痛、 炎性疼痛、口面疼痛；腹痛、婦科疼痛；軀體原疼痛；與 神經及根部傷害有關聯之疼痛；與截肢有關聯之疼痛、抽 搐疼痛、神故瘤或脈管炎；糖尿病患者之神經病、化學療 法所引致之神經病、急性疱疹及疱疹後神經痛；非常型面 部疼痛、神經病原性下背痛與蜘蛛膜炎、三叉神經痛、節 段或肋間神經痛、Ηΐν有關聯之神經痛、AIDS相關之神經 痛及其他神經痛；感覺異常、痛覺過敏、灼傷疼痛、自發 123505 -117- 200815422 性疼痛、因化學療法所造成之疼痛 雨桄月神經痛、精神性 疼痛、臂神經叢撕除、與不安寧腳部 I 1吸恢族有關聯之疼痛； 與膽結石有關聯之疼痛；因慢性 ^ ^ ^ ^ ^ ^ ^ 7月T t或甲狀腺機能減 退症或尿毋症或維生素缺乏所造成之疼痛；與癌 之神經病原性與非神經病原性疼 伸届症疼痛、幻想肢疼 痛、功能性腹痛；頭痛；顯骨與下領疼痛及上領寶疼痛；、 由於關節黏連脊椎炎所造成之疼 、、雨 、屌，因增加膀胱收縮作用 之疼心複合區域性疼痛徵候蔟、交感性維持疼痛 被候族、反射父感性失春痄 只鱼 失養症、反射神經血管營養障礙 射營養障礙、骨頭之Sudeck蓋娘 Λ -Endodermal sinus tumor, endometrial adenocarcinoma, ventricular tumor, hepatic adenoma, hepatocellular carcinoma, islet adenoma, intraepithelial neoplasia, epithelial squamous cell tumor formation, invasive squamous cell carcinoma, large cell carcinoma , leiomyosarcoma, freckle malignant melanoma, malignant melanoma, malignant mesothelioma, neural tube blastoma, neuroepithelial neoplasia, melanoma, meninges, mesothelioma, metastatic carcinoma, mucosal epidermoid carcinoma, neuroblast Tumor, neuroepithelial adenocarcinoma, nodular melanoma, oat cell carcinoma, dendritic glia, osteosarcoma, pancreatic polypeptide, papillary serous adenocarcinoma, pineal gland cells, pituitary tumor, plasma cell tumor, pseudosarcoma, lung blastoma , renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma, small cell carcinoma, soft tissue carcinoma, growth hormone release inhibitor secretory tumor, squamous carcinoma, squamous cell carcinoma, subcutaneous Surface extension of melanoma, no identification of cancer, uveal melanoma, squamous cell carcinoma, serpentoma, well-identified cancer or Wilm's tumor. In some embodiments, the cancer is leukemia, maternal erythrocytoma, multiple myeloma, acute myeloid leukemia, spinal dysplasia syndrome, non-Hodgkin's lymphoma or squamous lymphoma. In some embodiments, the cancer is a lymphocytic lymphoma, an acute myeloid leukemia, a multiple myeloid cell tumor, or a non-Hodgkin's lymphoma. In other specific embodiments, the cancer is brain cancer, glioblastoma, meningioma, astrocytoma, cerebroblastoma, neuroblastoma or retinal blastoma. In some such embodiments, the cancer is a glioma or a glioblastoma. In still other embodiments, the cancer is osteosarcoma, Kaposi's sarcoma, chondrosarcoma, Ewing's sarcoma, or myocyte blastoma. In some such specific embodiments, the cancer is osteosarcoma bone cancer. In some embodiments, the cancer is metastasis to the breast, lung, kidney or prostate cancer. In some such embodiments, the tumor is bone metastasis. In yet another aspect of the invention, a method of treating, modifying or treating pain is provided. Such methods comprise administering to a patient in need of such treatment, modification or treatment a composition comprising a therapeutically effective amount of a compound, such as a cytokine inhibitor as described herein, or a pharmaceutically acceptable thereof a salt, solvate or stereoisomer. In some embodiments, the composition further comprises an antidepressant, an antihypertensive, an anxiolytic, a calcium channel blocker, an adrenergic receptor agonist, a-adrenergic receptor antagonism Agent, amiodarone, anesthetic, muscle relaxant, non-narcotic analgesic, opioid analgesic, NSAID, immunomodulator, immunosuppressant, corticosteroid, anticonvulsant, high specific gravity oxygen, a2d ligand, NMDA A receptor antagonist or a combination of two or more thereof. In some such specific embodiments, the antidepressant is nortriptyline, amitriptyline, propanol, doxepin, clomipramine, flurazepam Fluoxetine, sertraline, nefazodone, venlafaxine, trazodone or acetophenone. In other specific embodiments, the antihypertensive drug is nifedipine, terazosin, prazosin, losartan, and iso-stop 123505-114- 200815422 (verapamil), telmisartan, fosinopril, bosentan or olmesartan. In still other embodiments, the anxiolytic agent is fluoxetine, paroxetine, sertraline, or venlafaxine. Examples of drug channel blockers include nifedipine, verapamil, and clonidine. In other embodiments, the a-adrenergic receptor agonist is clonidine or midodrine. In still other embodiments, the a-adrenergic receptor antagonist For Trat. Sitting on terazosin, prazosin or doxasozin. In some embodiments, the anesthetic is procaine, lidocaine, mepivacaine, articaine, prilocaine, etidocaine, bupivacaine Or ropivacaine. Examples of opioid analgesics include hydromorphone, oxycodone, morphine sulfate, acridine, and fentanyl. In some embodiments, the NSAID is a COX-2 inhibitor, an acid acetate, an ibuprofen (9) upr〇fen), a ketoprofen, a naproxen sodium, a g-Lorak (ketorolac), diclofenac, indmetacincin or acetaminophen. In some such embodiments, the COX-2 inhibitor is rofecoxib, cdec〇xib, or valdecoxib. In still other embodiments, the corticosteroid is prednisone, dexamethasone or hydrocortisone. In other embodiments, the anticonvulsant is a methotrexate, a scorpion whistle: gabapentin, pregabalin, stupidin, caprolactone, and cros Clonazepam, topiramat, Lamo three gold table 123505 -115- 200815422 (lamotrigine), sit 醯nisamide (z〇nisamide), tiagabine, famotidine (famotodine), phenobarbital, diphenylacetamidine, mephenytoin, ethylphenytoin, meph〇barbital, primidone, ethosuxamine, Methyl sulphate, phenyl sulphonate, trimethyl ketone, benzodiazepine, phenethyl carbamide, acetoxime sulfonamide, progabide, two-dimensional divalproex sodium, sulphuric acid injection Liquid, metharbital, methyl ethanedione, clobazam, sulthiame, dilantin, diphenylan or L-5 serotonin. In some embodiments, the NMDA receptor antagonist is dextromethorphan, dextr〇rphan, ketamine, memantine, amantadine, spermine, Attani (aptiganei), gavestinel, seifotei, 7-chloroguanine, remacemide, riluz〇le, outer sputum And porphyrin oxime or cis-4-(phosphonomethyl)-2-hexahydropyridinecarboxylic acid. In other specific embodiments, the a2d ligand is gabapentin, pregabalin, [(lR,5R,6S)-6-(aminomethyl)bicyclo[3.2. 0]hept-6-yl]acetic acid, 3-(1-aminomethyl-cyclohexylmethyl)-4H-[l,2,4]-succinyl-5-one and C-[1-( 1H-tetrakis-5-ylmethyl)-3⁄4heptyl]-methylamine, (3S,4S)-(1-aminomercapto-3,4-dimethyl-cyclopentyl)-guanidine , (la, 3a, 5a) (3-amino-methyl-bicyclo[3.2.0]heptan-3-yl)-acetic acid, (3S,5R>3-aminomethyl·5·methyl- Octanoic acid, (3S,5R)-3-amino-5-mercapto-heptanoic acid, (3S,5R)-3-amino-5-methyl-decanoic acid and (3S,5R)-3-amino group _5-Methyl-octanoic acid. In still other embodiments, the composition further comprises dicofolic acid, dibufenac, ibuprofen, 4 budomemine (indometacin), flufenamic acid, mefenamic acid, morphine, sedative, methadone, fentai 123505 -116- 200815422 fentanyl, buprenorphine, tramagno ), gabapentin, pregablin (pregab) Alin), amidoxime, lamotrigin, topiramat, phenyloin, levitiracetam, procaine, lidocaine, Travelin, articaine, prilocaine, etidocaine, bupivacaine, ropivacaine, amitryptiline, pa Paroxetine, dtalopram, butylamine phenylpropanoid S, doxorubicin, dicene (duxoletine), chloramine oxime, memantine, 2,3-benzoquinone A scorpion or a combination of two or more thereof. In some embodiments of the invention, the pain is acute pain, chronic pain, pain due to soft tissue from acute trauma and peripheral injuries; neuropathic pain Post-stroke pain; post-cancer neuralgia, occipital neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia and other neuralgia; pain associated with osteoarthritis and rheumatoid arthritis; musculoskeletal pain; vertebral pain Central nervous system pain; lower back pain Sciatica, toothache, myofascial pain syndrome, vaginal incision pain, gout pain and pain caused by burns; deep and visceral pain; muscle pain, eye pain, inflammatory pain, oropharyngeal pain; abdominal pain, Gynecological pain; somatic pain; pain associated with nerve and root injury; pain associated with amputation, convulsion pain, sputum or vasculitis; neuropathy in diabetic patients, neuropathy caused by chemotherapy, acute herpes and Postherpetic neuralgia; very facial pain, neuropathogenic lower back pain and arachnoiditis, trigeminal neuralgia, segmental or intercostal neuralgia, neuralgia associated with Ηΐν, AIDS-related neuralgia and other neuralgia; Abnormal, hyperalgesia, burn pain, spontaneous 123505 -117- 200815422 Sexual pain, pain caused by chemotherapy, rain pain, monthly neuralgia, mental pain, arm nerve plexus tear, and restless feet I 1 Associated pain; pain associated with gallstones; due to chronic ^ ^ ^ ^ ^ ^ ^ July T t or hypothyroidism or urinary fistula Or pain caused by vitamin deficiency; neuropathogenic and non-neurogenic pain of cancer, pain in the limbs, functional abdominal pain; headache; pain in the bones and lower collar and pain in the upper collar; Adhesive spondylitis caused by pain, rain, phlegm, painful heart area due to increased bladder contraction, regional pain syndrome, sympathetic maintenance of pain by the family, reflection of the father's sensational loss of spring frog dystrophy, reflection Neurovascular dystrophy, dystrophic, bones, Sudeck, mother-in-law

Sudeck錢、痛神經營養障礙、肩手徵 ，霧、外傷後營養障礙、慢性疲勞徵候蔟、神經根病、梅 毋神經病；或自藥物所引致之痛苦神經病原性症狀、手衔 後疼痛、傷症疼痛或慢性非神經病原性疼痛 在-些此種具體實施例中，肌骨疼痛為 破碎骨頭有關聯之疼痛。在其他具體實施例中’中枢神ΐ 糸統疼痛為由於脊髓或腦幹傷害所致之疼痛二 體實施射，深層與㈣疼痛為, 施例中，口面疼痛A I隹 如 他/、他，、體只 届為回痛。在一些具體實施例中，婦科疚 痛為痛經、分娩疼敍與子μ额 ^ 疼痛。在其他具體實施例中，與神經及根部傷=:之 疼痛為與末梢神經病症有關聯之疼痛。在此^ "Ρ之 施例中，末梢神經病症為神經捕““種具體實 些其他具體實施例中神經叢撕除。在— 碩痛為有先兆之偏頭痛、益 偏頭痛、血管頭痛急性、 … 之 一m緊張碩痛、竇房結頭痛或 123505 200815422 群集頭痛。在又其他具體實施例中，慢性非神經病原性疼 痛為與mv有關聯之疼痛、關節痛、脈管炎或纖維肌痛。 在一些具體實施财，複合區域性㈣徵候簇為類型！或類 型 II。 、 、在一些其他具體實施例中，相為感受傷害疼痛或神經 病原性疼痛。在一歧此種且I#宭始士 一裡/、體貫鉍例中，感受傷害疼痛係 與化學或熱灼傷、皮膚之割傷、皮膚之挫傷1關節炎、 風濕性關節炎、系統性狼瘡紅斑(SLE)、腱炎或肌筋膜疼痛 有關聯。在其他具體實施例中，神經病原性疼痛為糖尿病 患者之神經病、癌療後神經痛、三又神經痛、中風後疼痛、 複合區域性疼痛徵候蔟、交感性維持疼痛徵候蔟、反射交 1性失養症、反射神經也管營養障礙、反射營養障礙、脊 髓損傷疼痛、骨頭之Sudeek萎縮、痛神經營養障礙、肩手徵 候簇、外傷後營養障礙、與癌症或轉移有關聯之疼痛、幻 想肢疼痛、纖維肌痛、慢性疲勞徵候蔟、神經根病、梅毒 神經病或因藥物所引致之痛苦神經病原性症狀。於其中疼 削系關於癌症或轉移之具體實施例中，癌症為骨肉瘤、結 腸直腸癌、腦癌、上皮細胞衍生之腫瘤形成(上皮癌卜基 :細胞癌、腺癌、胃腸癌、唇癌、口癌、食管癌、小腸癌、 胃癌、結腸癌、肝癌、膀胱癌、胰臟癌、卵巢癌、子宮頸 癌、肺癌 '乳癌、皮膚癌、鱗狀細胞及/或基底細胞癌、前 列腺癌、腎細胞癌及其他會影響全身上皮細胞之已知癌 Ί白;淋巴瘤；或血管生成’包括腫瘤形成。在其 他具體實施例中，轉移為乳房、肺臟、腎臟或前列腺癌轉 123505 -119- 200815422 移。 々於本發明之又另一方面，係提供治療天疱瘡之方法。此 : 套匕括對需要此種治療之病患投予一種組合物，其包 各冶療上有效量之化合物，譬如，如本文中所述之細胞素 抑制劑，或其立體異構物、互變異構物、溶劑合物、前體 某物或某车上可接受之鹽。在治療天癌瘡方法之一些具體 貫施例中，天疱瘡為尋常天疱瘡、增生性天疱瘡、葉狀天 疱瘡、紅斑性天疱瘡、大泡型類天疱瘡、副贅瘤天疱瘡、 瘢痕類天疱瘡、大水疱膿皰病或葡萄球菌頭鱗癖皮膚徵候 簇。 （ 、 於另方面，係提供一些方法，其包括對有需要之病患 扠予可用於治療如本文中所述天疱瘡之⑴有效量之本發明 化合物，與（ii)有效量之一或多種治療成份A之組合，其中 成份A之有效量係低於成份a當單獨使用時之有效量。 亦k供者為降低天癌瘡臨床標記之數目及/或嚴重性之 方法。此等方法包括對顯示天疱瘡之一或多種臨床標記之 病患投予一數量之本發明化合物，譬如細胞素抑制劑，有 效降低天疱瘡臨床標記之數目及/或嚴重性，相對於投予細 胞素抑制劑前存在於病患中者，其中天疱瘡之臨床標記包 括受天疱瘡所影響之全身表面積（BSA)之百分比、天疱瘡損 傷厚度、新天疱瘡損傷之數目、活性天疱瘡損傷之數目（包 括水疱與糜爛）、活性損傷之痊癒時間（例如至80%痊癒之時 間）、血清抗-維管束原-1 (〇8(}1)抗體含量、血清抗七犯3抗 體含量、血清TNFa-含量、血清IL_6含量、皮膚含 123505 -120- 200815422 里、皮膚IL-6 mRNA含量或其任兩種或多種。在本發明之一 些具體實施例中，此方法另外包括對該病患投予有效量之 一或多種可用於治療如本文中所述天疱瘡之成份A。在一 些此種具體實施例中，成份A之有效量係低於成份A當單獨 使用時之有效量。 在本鲞明方法之一些具體實施例中，此等方法進一步包 括對病患投予成份A，其中成份a為消炎劑、免疫壓抑劑、 抗感染劑、抗生素、金鹽、烷基化劑、免疫球蛋白或其兩 種或多種之組合。 在其中成份A為消炎劑之一些具體實施例中，消炎可為 皮質類固醇、COX-2抑制劑、非類固醇消炎藥物（NSAID)、 TNFa拮抗劑或IL-1拮抗劑。例如，皮質類固醇可為潑尼松、 氫化潑尼松或甲基氫化潑尼松。譬如此等之皮質類固醇， 亦可與無論是苯丁酸氮芥（chl〇rambusil)或分枝紛酸莫非替 (mycophenylate mofetil) —起投藥。在一些具體實施例中， 拮抗劑為因弗利西馬（infliximab)、恩塔臬西伯（etanercept)或阿 達利母馬（adalimumab)。在其他具體實施例中，IL]拮抗劑為 安那金拉（anakinra)。 在其他具體實施例中，免疫壓抑劑為分枝酚酸莫非替 (mycophenylate mofetil)、環孢素、硝基脒唑硫嘌呤、胺甲喋呤、 阿列發謝特（alefacept)、利圖西馬伯（rituximab)、抗_干择素^ 或環磷酿胺。在一些其他具體實施例中，抗感染劑為達普 松（dapsone)或羥氯喳。在一些具體實施例中，金鹽為硫代蘋 果酸金鈉或金硫葡萄糖。在一些具體實施例中，燒其化叫 123505 -121 - 200815422 為留可蘭（lukemn)。在一些具體實施例中，抗生素為四環 素、二曱胺四環素或強力黴素。在一些此種具體實施例中， 此方法進一步包括投予菸鹼醯胺或尼克醯胺。在本發明方 法之其他具體實施例中，本發明之方法進一步包括對病患 投予血漿除去療法或光泳療法。Sudeck money, painful neurotrophic disorders, shoulder and hand signs, fog, post-traumatic dystrophy, chronic fatigue syndrome, radiculopathy, mei 毋 neuropathy; or painful neuropathogenic symptoms caused by drugs, post-hand pain, injury Pain or chronic non-neurogenic pain In some such embodiments, musculoskeletal pain is associated with broken bone. In other specific embodiments, the central nervous system pain is caused by pain caused by spinal cord or brain stem injury, and the deep and (four) pain is, in the example, the oral pain AI is like him/he, The body is only painful. In some embodiments, gynecological analgesia is dysmenorrhea, labor pain, and sub-M pain. In other embodiments, the pain associated with nerve and root injury = is pain associated with a peripheral nerve disorder. In this example, the peripheral neuropathy is a neurological "removal" of the plexus in other specific embodiments. In — Shuo pain is a migraine with aura, a migraine headache, an acute vascular headache, ... a nervous tension, sinus node headache or 123505 200815422 cluster headache. In still other embodiments, the chronic non-neurogenic pain is pain, joint pain, vasculitis or fibromyalgia associated with mv. In some specific implementations, the composite regional (four) syndrome cluster is of the type! Or type II. In some other specific embodiments, the phase is a nociceptive pain or a neuropathic pain. In the case of Yiqi and I#宭始士一里/, 体贯铋, the painful pain system is combined with chemical or thermal burns, skin cuts, skin contusions, arthritis, rheumatoid arthritis, systemic Lupus erythema (SLE), tendonitis, or myofascial pain are associated. In other specific embodiments, the neuropathic pain is a neuropathy of a diabetic patient, a neuropathic pain after cancer, a tri-analgia, a post-stroke pain, a compound regional pain syndrome, a sympathetic maintenance pain symptom, and a reflex. Atrophy, reflex nerves also prevent dystrophies, reflex dystrophies, spinal cord pain, Sudeek atrophy of bones, painful neurotrophic disorders, shoulder-hand syndrome, post-traumatic dystrophies, pain associated with cancer or metastasis, fantasy limbs Pain, fibromyalgia, chronic fatigue syndrome, radiculopathy, syphilitic neuropathy or painful neuropathic symptoms caused by drugs. In a specific embodiment in which the pain is about cancer or metastasis, the cancer is osteosarcoma, colorectal cancer, brain cancer, epithelial cell-derived tumor formation (epithelial cancer: cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer) , oral cancer, esophageal cancer, small intestine cancer, gastric cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, squamous cell and/or basal cell carcinoma, prostate cancer , renal cell carcinoma and other known cancer whites that affect systemic epithelial cells; lymphoma; or angiogenesis 'including tumor formation. In other embodiments, metastasis to breast, lung, kidney or prostate cancer turns 123505-119 - 200815422. In another aspect of the invention, there is provided a method of treating pemphigus. The kit comprises administering to a patient in need of such treatment a composition comprising an effective amount of each of the treatments. A compound, such as a cytokine inhibitor as described herein, or a stereoisomer, tautomer, solvate, precursor thereof or an acceptable salt thereof. It In some specific examples, pemphigus is pemphigus vulgaris, proliferative pemphigus, phyllodes pemphigus, erythematous pemphigus, vesicular pemphigus, parapnomitis pemphigus, scar pemphigus, large blisters pus A blister or staphylococcal scaly skin syndrome. (In another aspect, the method is provided, comprising administering to a patient in need thereof an effective amount of (1) effective for treating pemphigus as described herein. a compound, in combination with (ii) an effective amount of one or more therapeutic ingredients A, wherein the effective amount of ingredient A is less than the effective amount of ingredient a when used alone. Also the donor is the number of clinical markers for reducing the cancer And/or method of severity. The methods comprise administering to a patient exhibiting one or more clinical markers of pemphigus a quantity of a compound of the invention, such as a cytokine inhibitor, effective to reduce the number of pemphigus clinical markers and/or Or severity, relative to the patient present in the patient prior to administration of the cytokine inhibitor, wherein the clinical markers of pemphigus include the percentage of systemic surface area (BSA) affected by pemphigus, pemphigus injury Thickness, number of new pemphigus lesions, number of active pemphigus lesions (including blisters and erosions), healing time of active damage (eg up to 80% recovery time), serum anti-vascular bundle proto-1 (〇8(} 1) Antibody content, serum anti-seven antibody content, serum TNFa-content, serum IL_6 content, skin containing 123505-120-200815422, skin IL-6 mRNA content or any two or more thereof. In a particular embodiment, the method additionally comprises administering to the patient an effective amount of one or more of ingredients A useful for treating pemphigus as described herein. In some such embodiments, the effective amount of ingredient A is It is lower than the effective amount of ingredient A when used alone. In some embodiments of the method of the present invention, the method further comprises administering to the patient ingredient A, wherein component a is an anti-inflammatory agent, an immunosuppressive agent, or an anti-infective agent. Agent, antibiotic, gold salt, alkylating agent, immunoglobulin or a combination of two or more thereof. In some embodiments in which component A is an anti-inflammatory agent, the anti-inflammatory may be a corticosteroid, a COX-2 inhibitor, a non-steroidal anti-inflammatory drug (NSAID), a TNFa antagonist or an IL-1 antagonist. For example, the corticosteroid can be prednisone, prednisolone or methylprednisolone. Such corticosteroids can also be administered in combination with either chl〇rambusil or mycophenylate mofetil. In some embodiments, the antagonist is infliximab, etanercept, or adalimumab. In other specific embodiments, the IL] antagonist is anakinra. In other specific embodiments, the immunosuppressive agent is mycophenylate mofetil, cyclosporine, nitrocarbazole thiopurine, amine formazan, alefacept, and rituxi. Rituximab, anti-dry auxin ^ or cyclophosphamide. In some other specific embodiments, the anti-infective agent is dapsone or hydroxychloropurine. In some embodiments, the gold salt is sodium gold thiopalate or gold thioglucose. In some embodiments, the burn is called 123505 - 121 - 200815422 is lukemn. In some embodiments, the antibiotic is tetracycline, diamine tetracycline or doxycycline. In some such embodiments, the method further comprises administering nicotinamide or nicotinic amine. In other specific embodiments of the methods of the invention, the method of the invention further comprises administering to the patient a plasmapheresis or photopheresis.

\ 在本發明方法之一些具體實施例中，成份A之劑量係被 降低達約10%至約90% ’在與單獨使用成份a以達成相同治 療作用之劑量比較下。在一些具體實施例中，劑量係被降 低達至少約10%，約20%，約30%，約40%，約50%，或約6〇%。 在一些具體實施例中，成份A為皮質類固醇，例如潑尼松 或氫化潑尼松。在一些其他具體實施例中，成份A包括皮 λ類固醇與無論是苯丁酸氮芥（chl〇rambusil)或分枝酚酸莫非 替（mycophenylate mofetil)。在一些具體實施例中，潑尼松之叫 量係被降至低於約70毫克/天，低於約5〇毫克/天，低於: 毫克/天，低於約20毫克/天，低於約15毫克/天或低於約 10毫克/天。 隹又其他具體實施例中，細胞素抑制劑係以經口方式或 以局部方式投藥。在一些具體實施例中，成份A為皮；類 固醇或抗生素，且係以經口方式、局部方式，在漱口水中，、 ^在口部喷霧劑中投藥。對治療用途而言，成份A與本文 所述化合物之醫藥組合可以任何習用劑型，以任何習用 ，包括本文中所述之任何途徑投予。因此，投藥：徑 :不限於靜脈内、肌内、皮下、滑膜内、藉由灌注、 下、經皮、口腔、局部及藉吸入。典型投藥模式為口腔、 123505 -122- 200815422 局部或靜脈内。 成份A與如本文中所述化合物 在與其他成份或佐劑之组合配方中投=二，可個別地或 制劑之安定性，有助於投予含有彼係提高抑 增加之溶解或分散，增加抑制活性，提:附^物，提供 供類似利益。此種組合療法典型上传=、：加療法’或提 治療劑，且避免當此等藥劑作為單1用/父低劑量之習用 _ Λ.. 為早療法使用時所押致之 可一與不利副作用。成份Α與該 : 因此以物理方式與習用治療劑 西糸、，且5可 兹，人 J ^其他佐劑合併成為單一醫 条、、且a物。成份A及/或該化合物 ^ s ^ ^ J以鹽、溶劑合物、互變 構物及/或前體藥物，及以單一 體異構物或立體異構物 之此合物，包括外消旋物，使用於組合中。 其中兩種成份，成份A與如本文中所述之化合物，可根 據本發明使用於組合中之比例，係為可改變。成份A盘該 =合物係視情況以其溶劑合物或水合物之形式存在。依成 份A與如本文中所述化合物之選擇而定’可在本發明範圍 内使用之重置比，係以各種化合物之不同分子量及其不同 功效為基準而改變。重量比之決定係依特定成份A與該化 合物而定，且係在此項技藝之技術範圍内。 根據本發明之又另一方面，係提供下列清單ς之化合物， 包括式I與π化合物之代表性實例：In some embodiments of the methods of the invention, the dosage of ingredient A is reduced by from about 10% to about 90%' in comparison to the dosage of ingredient a alone to achieve the same therapeutic effect. In some embodiments, the dosage system is reduced by at least about 10%, about 20%, about 30%, about 40%, about 50%, or about 6%. In some embodiments, component A is a corticosteroid, such as prednisone or prednisolone. In some other specific embodiments, ingredient A comprises a pico- λ steroid with either lycium bromate or mycophenylate mofetil. In some embodiments, the prednisone amount is reduced to less than about 70 mg/day, less than about 5 mg/day, less than: mg/day, less than about 20 mg/day, low At about 15 mg/day or less than about 10 mg/day. In still other embodiments, the cytokine inhibitor is administered orally or in a topical manner. In some embodiments, ingredient A is a skin; a steroid or an antibiotic, and is administered orally, in a topical manner, in mouthwash, in a mouth spray. For therapeutic use, the pharmaceutical combination of ingredient A with a compound described herein can be administered in any conventional form, including any of the routes described herein. Therefore, administration: diameter: not limited to intravenous, intramuscular, subcutaneous, intrasynovial, by perfusion, under, percutaneous, oral, topical and inhalation. The typical mode of administration is oral, 123505 -122- 200815422 local or intravenous. Ingredient A and the compound as described herein are administered in combination with other ingredients or adjuvants, and may be administered individually or in a formulation to aid in the dissolution or dispersion of the compound containing the increase or increase. Inhibition of activity, mention: attachment, provide for similar benefits. This combination therapy typically uploads =,: plus therapy' or provides a therapeutic agent, and avoids the use of these agents as a single 1 parent/parent low dose _ Λ.. side effect. Ingredients Α and this: Therefore, it is physically combined with the conventional therapeutic agent, Xiqiao, and 5, and other human adjuvants are combined into a single medical article, and a substance. Ingredient A and/or the compound ^ s ^ ^ J are salts, solvates, tautomers and/or prodrugs, and such compounds as monomeric or stereoisomers, including exogenous Spins, used in combination. Two of the ingredients, component A, and the compounds as described herein, which can be used in the combination according to the present invention, are changeable. Ingredient A disk This compound is present in the form of its solvate or hydrate. The reset ratio, which may be used within the scope of the invention, depending on the choice of component A and the compound as described herein, varies based on the different molecular weights of the various compounds and their different potencies. The weight ratio is determined by the particular ingredient A and the compound and is within the skill of the art. According to still another aspect of the present invention, there is provided a compound of the following list, including representative examples of the compounds of Formula I and π:

清單I L第二-丁基氰基_Ν-(6-甲基Κ3侦戊基胺曱醯基）苯基> 峨啶I基）苯曱醯胺； 123505 -123 - 200815422 N (5 〇4-(爷氧基）苯基）各甲基卩比咬各基）各第三_丁基氰基 苯甲醯胺； 3—第三-丁基咎氰基1(5-(4-(3,3-二甲基_2_酮基丁氧基）苯 基）-6-甲基吡啶；基）苯甲醯胺； 醋酸4-(5-(5-第三-丁基冬甲氧基苯甲醯胺基）_2_甲基吡啶_3· 基）苯i旨； 3-第三丁基_5_氰基_Ν·(5_(4_甲氧基冬甲基苯基）各甲基吡啶 -3-基）苯甲酸胺； 3-第二-丁基_5_氰基_Ν-(卜甲基_5_(4_(新戊基胺甲醯基偉基）_ 吡啶-3_基）苯甲醯胺； 3-氟-Ν_(6-甲基-5-(4-(新戊基胺曱醯基）苯基）_吡啶各基）_5•嗎 福啉基苯甲醯胺； 3-第二-丁基·5_氰基_N_(6_甲基_5_(4_(四氫_2H-哌喃_4_基胺甲 醯基）苯基）吡啶_3_基）苯甲醯胺； 3-氟-N-(5-(4-甲氧苯基）_6_甲基吡啶-3_基）嗎福啉基苯甲醯 胺； N_(5-(4-乙醯基苯基）各甲基吡啶各基）_5_第三_丁基各氰基 -2-甲氧基苯甲酿胺； 3-(胺基甲基）-5-第三-丁基_Ν_(5·(4·(1_羥乙基）苯基）各甲基吡 啶-3-基）-2-甲氧基苯曱醯胺； 5-第三-丁基-3-(N-羥基碳胺基亞胺基）_N分…(1_(經亞胺基） 乙基）笨基）-6-曱基吡啶_3_基>2-甲氧基苯甲醯胺； 5L(3·第三-丁基氰基苯甲醯胺基）-2，-甲基-N-((四氫呋喃-2-基）甲基）-2,3’-聯峨唆-5-緩醯胺； 123505 -124- 200815422 5H3-第三-丁基-5-氰基苯甲醯胺基）-2’-曱基((四氫呋喃-2_ 基）甲基）-3,3，-聯吡啶-6-羧醯胺； 3-弟二-丁基-5-氰基-N-(6-曱基-5-(4-(六氫外b唆-1-基胺曱醯 基）苯基 >比啶-3-基）苯甲醯胺； 3-第三-丁基-5-氰基-N-(6-甲基-5-(4-(N-新戊基胺磺醯基）苯 基）吡啶_3_基）苯曱醯胺； 1-(5-(3-氟基-5-嗎福淋基苯甲酿胺基）-2-甲基比唆各 基）_N-((四氫呋喃-2-基）甲基）-1Η-1，2,3-三唑冰羧醯胺； N-(5-(4-第三-丁基-1H_1，2,3_三唑小基）各甲基吡啶斗基）-3-敦 基-5-嗎福啉基苯甲醯胺； 3-氟_N-(6_甲基-5-(4-(外匕唆-2-基）_1Η·1，2,3-三嗤小基）π比σ定一3_ 基）-5-嗎福淋基苯甲醯胺； 3-氟-N-(5-(4-(甲氧基甲基）-1Η-1，2,3-三嗤-1-基）-6-甲基p比。定·3_ 基）-5-嗎福啉基苯甲醯胺； 1-(5-(3-第三-丁基-5-氰基苯甲酿胺基）-2-曱基峨σ定-3-基）-N·* 新戊基-1Η-1，2,3-三唑-4-羧醯胺； 3-第三-丁基-5-氰基 _Ν-(6-甲基-5-(4-(3-甲基 丁醯基）_1Η-1，2,3_ 三唑-1-基）吡啶-3-基）苯曱醯胺； (Ζ)-3-第三-丁基氰基-N-(5-(4_(l-(經亞胺基）-3-甲基丁 基）_1H-1，2,3-三吐·1-基）-6-曱基p比咬-3-基）苯曱醢胺； 3-第三-丁基-5-氰基-N-(6-甲基-5-(4-(2-甲基-1-(新戊基胺 基）小酮基丙烧-2-基）-1Η-1，2,3-三嗤-1-基）外b °定-3-基）苯曱醯胺； N-(3-第三-丁基-5-氰基笨基）-6-甲基-5-(4-(新戊基胺甲酸 基）_1Η-1，2,3·三唑小基）菸鹼醯胺； 123505 •125· 200815422 心(6•甲基-5-(4-(新戊基胺甲醯基）-m-l，2,3-三唑-1-基风咬！ 基）_2_嗎福琳基異於驗酸胺； 队(6-甲基-5-(4-(新戊基胺甲醯基）-111-1，2,3-三唑小基>比咬_3-基）-2-(六氫吡啶小基）異菸鹼醯胺； 3_氟-N-(6-甲基-5-(3-(新戊基胺甲醯基）苯基）,比啶各基>5-嗎 福琳基苯曱醯胺； 3-第三_丁基-5-氰基-N-(5-(3-(二甲基胺甲醯基）苯基）-6-曱基 吡啶-3-基）苯甲醯胺； 1-(5-(5-第三-丁基-2-甲氧基苯甲醯胺基）冬曱基吡啶_3_ 基）·Ν·新戊基·1Η_1，2,3-三唑冬羧醯胺； 1-(5-(3-氣基-5-嗎福淋基本甲3&胺基）-2-甲基咏°定-3-基）·»Ν·新 戊基-1Η-1，2,3-三唑-4-羧醯胺； 5-第三-丁基-2-甲氧基-Ν-(5-(6-甲氧基莕-2-基）各甲基吡啶-3-基）苯甲醯胺； 3-第三-丁基氰基-Ν-(5-(3_(3,3-二曱基丁醯胺基）苯基）各曱 基吡啶-3-基）苯甲醯胺； Ν-(2,6’_二曱基-3,4’-聯被唆-5-基）各氟基-5-嗎福淋基苯甲醯 胺； 3-第三-丁基-5-氰基-Ν-(2,6’-二甲基_3,4’_聯ρ比ϋ定_5_基）苯甲醯 胺； 3-氟·Ν-(5-(4-曱氧基-3-甲基苯基）-6-曱基吡啶各基）-5-嗎福琳 基笨曱醯胺； N-(5-(4-乙酿基苯基）-6·甲基批σ定-3-基）-5-第三-丁基-2-甲氧 基苯甲醯胺； 123505 -126- 200815422 Ν·(5-(4-乙醯基苯基）各甲基吡啶_3_基）_5_第三_ 丁基_2_甲氧 基-3-(甲基磺醯胺基）苯甲醯胺； Ν-(5·(4-乙醯基苯基）_6_甲基吡啶_3_基>3_氟基_5_嗎福啉基苯 曱醯胺； 仏(5-(4〇基胺甲醯基）苯基）-6-甲基ρ比咬_3-基）-5-第三》丁基 _2_甲氧基苯甲醯胺； 5-第三-丁基4(5-(4_(3,4-二甲氧基芊基胺曱醯基）苯基)-6一甲 基吡啶-3-基>2-甲氧基苯曱醯胺； 5-弟二-丁基_2_甲氧基-N-(5-(4-(3-甲氧基苄基胺甲醯基）苯 基）-6-甲基吡啶_3_基）苯甲醯胺； N-(5-(4-(苄基胺甲醯基）苯基）-6-甲基吡啶_3-基）-3-氟基-5-嗎 福啉基苯甲醯胺； N-(5-(4-(3,5-二甲氧基苄基胺甲醯基）苯基>6_甲基吡咬_3· 基）-3-氟基-5-嗎福琳基苯甲醯胺； 3-氟-N-(5-(4-(3-甲氧基苄基胺甲醯基）苯基）各甲基峨咬·3一 基）-5-嗎福淋基苯甲醯胺； 3·氟-N-(5-(4-(4-甲氧基苄基胺甲醯基）苯基>6_甲基峨咬各 基）-5-嗎福p林基苯甲酿胺； N-(5-(4-(苯并[d][l，3]二氧伍圜烯-5-基甲基胺甲醯基）苯基）各 甲基吡啶-3-基）-3_氟基-5-嗎福琳基苯甲醯胺； 1-(5-(3-氟基_5_嗎福啉基苯甲醯胺基甲基峨咬-> 基）_N七比啶_3_基甲基）-1Η·1，2,3-三唑斗羧醯胺； 1-(5-(3-亂基-5-嗎福琳基本甲胺基）_2·甲基V?比σ定基）·ν g 丁基-111-1，2,3-二 °坐-4-魏酿胺， 123505 -127- 200815422 丙基甲基）-1-(5-(3-氣基-5-嗎福淋基苯甲酿胺基）-2-甲 基吡啶-3·基>1H-1，2,3-三唑-4-羧醯胺； 1-(5-(3-氟基-5-嗎福啉基苯甲醯胺基）-2-甲基吡啶各 基）-N-(3,3,3-三氟丙基）-1Η-1，2,3-三唑冬羧醯胺； 3-氟-Ν-(6-甲基-5-(4-((四氫-2Η-哌喃-4-基）甲基胺甲醯基）苯 基）吡啶-3·基）_5_嗎福啉基苯曱醯胺； 3-氟-N-(6-甲基-5-(4-((四氫呋喃-2-基）甲基胺甲醯基）苯基）吡 啶_3_基）-5-嗎福啉基苯甲醯胺； 5-第三-丁基-N-(5-(4-(3,5-二曱氧基芊基胺甲醯基）苯基）-6-甲 基吡啶-3-基）-2-甲氧基苯甲醯胺； N-(5-(4-(苯并[d][l，3]二氧伍圜烯-5_基甲基胺甲醯基）苯基）_6_ 甲基吡啶-3-基）-5-第三-丁基_2_甲氧基苯甲醯胺； 5-第三-丁基-2-甲氧基-N-(6-曱基-5-(4-(吡啶-3-基甲基胺甲醯 基）苯基）吡啶-3-基）苯甲醯胺； 5-第三-丁基-2-甲氧基_N-(6-甲基-5-(4-(四氫-2沁哌喃-4-基胺 甲醯基）苯基）吡啶-3-基）苯甲醯胺； 5_第三-丁基-2-甲氧基-N-(6-甲基-5-(4-((四氫-2H-哌喃斗基）甲 基胺甲醯基）苯基）p比σ定-3-基）苯甲醯胺； 5-第三-丁基_2_曱氧基-Ν_(6-曱基-5-(4-((四氫呋喃-2-基）曱基 胺甲醯基）苯基）吡啶-3-基）苯甲醯胺； N-(5-(4-(3,4-二甲氧基芊基胺甲醯基）苯基）-6-甲基吡啶-3-基）-3-氣基-5-嗎福琳基本甲酿胺， 3-氟·Ν-(6-甲基-5-(4-(吡啶-3-基甲基胺甲醯基）苯基）吡啶各 基）-5-嗎福啉基苯甲醯胺； 123505 -128- 200815422 4-((4-(5-(5-第三-丁基·2_甲氧基苯甲醯胺基>2_甲基吡啶各 基）苯甲醯胺基）甲基）苯甲酸甲酯； 3ϋ(6-甲基-5-(4-(四氫-2Η-哌喃斗基胺甲醯基）苯基风啶 -3-基）-5-嗎福淋基苯甲酿胺； 4-((4-(5-(3-氟基-5-嗎福啉基苯甲醯胺基）-2-甲基吡啶-3-基）苯 甲醯胺基）甲基）苯甲酸甲酯； 3_第二-丁基·5_氰基-N-(6-甲基_5_(4-((四氫呋喃-2-基）甲基胺 甲醯基）苯基）吡啶-3·基）苯甲醯胺； 3-弟二-丁基_5_氰基_N-(6_甲基-5-(4-((四氫-2H-喊喃冰基）曱基 胺甲醯基）苯基）p比啶_3_基）苯甲醯胺； Ν·(5-(4·(芊基胺甲醯基）苯基）_6_甲基吡啶·3_基）-3-第三_丁基 -5-氰基苯曱醯胺； 1 (5·(3-氣基-5-嗎福ρ林基苯甲酿胺基）-2-甲基ρ比σ定_3_基）-Ν，Ν_ 二甲基-1Η-1，2,3-三。坐-4-魏醯胺； Η2-甲基-5-(3-嗎福啉基-5-(三氟甲基）苯甲醯胺基）ρ比啶_3_ 基）_N-新戊基_ih-1，2,3-三唑-4-羧醯胺； H2-甲基-5-(3-(四氫吡咯小基）-5-(三氟甲基）_苯曱醯胺基风 啶-3·基）-N-新戊基-1H-1，2,3-三唑-4-羧醯胺； ^(5-(3-氟基-5-(六氫吡。定-1-基）苯甲醯胺基）-2-曱基吡咬-3-基）_Ν·新戊基-1H-1，2,3-三唑-4_羧醯胺； K5-(3-氟基-5-(四氳吡咯-1·基）苯甲醯胺基）-2-甲基吡啶各 基）新戊基-1H-1，2,3-三唑-4-羧醯胺； 1-(5-(3-氣基-5-嗎福琳基苯甲酿胺基）-2-甲基p比唆-3-基）-N-(2_ 甲基丁基）_1H-1，2,3-三唑-4-羧醯胺； 123505 •129- 200815422 N-(環己基甲基）-1-(5-(3-敦基-5-嗎福琳基苯甲醯胺基）_2-甲 基外b 17定-3-基）-1Η-1，2,3-三嗤-4-魏醯胺； 1-(5-(3-氟基-5-嗎福啉基苯甲醯胺基）-2_甲基吡啶_3_ 基）_N-((izg氫々Η-哌喃_4·基）甲基）-iH]，2,3s。坐_4邊醯胺； 1-0(3·氟基-5-嗎福啉基苯甲醯胺基）-2-甲基吡啶各基）养(2_ 經基-2-苯基乙基）-1Η-1，2,3-三β坐·4_叛醯胺； 1-(5-(3-氟基-5-嗎福啉基苯甲醯胺基）_2·甲基吡啶_3·基）-Ν-(1-經基-3-甲基丁 -2-基）-1Η-1，2,3-三吐冰魏酷胺； Ν-(〇乙基四氫被略-2_基）甲基）-1-(5-(3-氟基-5-嗎福啉基苯 曱醯胺基）_2_甲基外b σ定-3-基）-lH-l，2,3-三唾-4-魏Si胺； 5-第三-丁基-3-氰基-N-(5-(4-((l-乙基四氫吡咯-2-基）甲基胺 甲醯基）苯基）-6_甲基吡啶斗基）·2·甲氧基苯甲醯胺； 5-第三-丁基-3-氰基-2-甲氧基-Ν-(6-甲基-5-(4-(1-甲基六氫吡 啶-4-基胺甲醯基）苯基）吡啶基）苯曱醯胺； 5-第三-丁基-3-氰基-2-甲氧基-N-(6-甲基-5-(4-((1-甲基六氫吡 唆冰基）甲基胺甲醯基苯基）吡啶_3_基）苯甲醯胺； 3_氟-N-(6-甲基-5-(4-(1-甲基六氫吡啶斗基胺甲醯基）苯基）口比 啶-3-基）_5_嗎福琳基苯甲醯胺； 3-說-N-(6-甲基-5-(4-((1-甲基六氫吡啶-4-基）曱基胺甲醯基） 苯基 >比啶-3-基）-5-嗎福啉基苯甲醯胺； 5-第三-丁基-3-氰基_2_甲氧基-N-(6-甲基-5-(4-(吡啶各基甲基 胺曱醯基）苯基）吡啶_3_基）苯甲醯胺； ^(5-(3-氣基-5-嗎福啉基苯甲醯胺基）-2-甲基吡啶各 基）_队(四氫-2H-哌喃-4-基）-lH_l，2,3-三唑-4-羧醯胺； 123505 -130- 200815422 N-環己基小(5-(3-氟基·5·嗎福啉基苯曱醯胺基）_2·甲基吡啶 -3-基）-111-1，2,3-三唾_4_魏目|胺； Ν-環戊基-1-(5-(3-氟基-5-嗎福啉基苯曱醯胺基）-2-甲基吡啶 -3-基）-1Η_1，2,3-三唾-4-魏醯胺； H5-(3-氟基-5-嗎福啉基苯甲醯胺基）_2•甲基吡啶-3-基）·Ν-(3-經基一甲基丙基）-11^-1，2,3-三嗤-4-緩酸胺； 1-(5-(3-第三-丁基-5-氰基苯甲醯胺基）-2-曱基吡啶-3-基）-N-((四氫呋喃-2-基）曱基）-iH-l，2,3-三唑-4-羧醯胺； 1-(5-(5-第三-丁基；氰基-2-甲氧基苯甲醯胺基）-2-甲基吡啶 _3·基）·1Η·1，2,3-三唾-4-魏酸第三-丁酯； 1-(5_(3-氰基-5-嗎福啉基苯甲醯胺基）-2-甲基吡啶-3-基）((四鼠咬喃-2-基）甲基）-1Η-1，2,3-三峻_4_魏酿胺； H5-(3•氰基_5-(六氫吡啶小基）苯甲醯胺基）-2-甲基吡啶-3-基）_N-((四氫呋喃_2_基）甲基）-lH-l，2,3-三唑-4-羧醯胺； 1-(5-(3-氰基-5-(四氫吡咯-1-基）苯甲醯胺基）-2-曱基吡啶-3-基）·Ν-((四氫呋喃-2-基）甲基）-1Η-1，2,3-三唑-4-羧醯胺； N-(5-(4-((l-乙基四氫吡咯-2-基）甲基胺甲醯基）苯基）冬甲基 吡啶-3-基）_3_氟基-5-嗎福啉基苯甲醯胺； 1-(5-(5_第三-丁基-3-氰基-2-曱氧基苯曱醯胺基）-2-曱基吡啶 -3-基）_N-新戊基-1Η-1，2,3·三唑-4-羧醯胺； 1-(5-(5-第三-丁基-3-氰基-2-甲氧基苯甲醯胺基）-2-甲基吡啶 -3_基）-N-(吡啶-3-基甲基）-1Η-1，2,3-三唑-4-羧醯胺； 1-(5-(3-第三-丁基-5·氰基苯曱醯胺基）-2-甲基吡啶-3-基）-N-(〇乙基四氫p比洛-2-基）曱基）-1Η·1，2,3-三。坐-4_羧醯胺； 123505 • 131 - 200815422 3-第三-丁基-5-氰基-N-(6-甲基-5-(4-(4-甲基六氫吡畊-1-羰 基）-1Η-1，2,3-三唑小基）吡啶-3-基）苯甲醯胺； 1-(5-(5-第三-丁基-3-氰基-2_甲氧基苯曱醯胺基）-2-甲基吡啶 -3-基）-N-((四氫呋喃-2-基）甲基）-iH-l，2,3-三唑冬羧醯胺； .3-第三-丁基-5-氰基_N-(6-甲基-5-(4_(嗎福淋冬幾基）-1Η-1，2,3_ 三唑_1·基）吡啶-3-基）苯甲醯胺； 1-(5-(3-第三-丁基-5-氰基苯甲醯胺基）-2·甲基吡啶-3-基）-N-(l-甲基六氫吡啶冰基>1H-1，2,3-三唑冰羧醯胺； 1-(5-(3-第三-丁基-5-氰基苯甲醯胺基）-2-甲基吡啶各 基）_N-(2-(四氫吡咯小基）乙基）-1Η-1，2,3_三唑-4-羧醯胺； 1-(5-(3-第三-丁基-5-氰基苯曱醯胺基）-2•甲基吡啶各 基:)-Ν·(2-(二甲胺基）乙基）-1Η-1，2,3-三唑-4-羧醯胺； 1-(5-(3-第三-丁基-5-氰基苯甲醯胺基）-2-曱基吡啶-3-基）-N-(2-甲氧基乙基）-1Η-1，2,3-三唑-4-羧醯胺； 1-(5-(3-第三-丁基-5-氰基苯曱醯胺基）-2-甲基吡啶-3-基）-N-0昆啶_3_基）·1Η-1，2,3_三唑-4_羧醯胺； 1-(5-(3-第三-丁基-5-氰基苯甲酿胺基）-2-甲基外1： σ定_3_ 基）-队(六氫吡啶-4-基）-1沁1，2,3-三唑-4-羧醯胺； 1-(5-(3-第三·丁基-5-氰基苯曱醯胺基）-2-甲基吡啶各 基）-N-(六氫吡啶_3_基）-1H-1，2,3-三唑-4-羧醯胺； 1-(5-(3-第三-丁基-5-氰基苯甲醯胺基）-2-甲基吡啶_3_ 基）-N-(2-羥丙基）_ih_1，2,3-三唑-4-羧醯胺； K5-(3-氟基-5-(l，4-氧氮七圜斗基）苯曱醯胺基）-2-甲基吡咬 -3-基）-N-((四氫呋喃_2·基）甲基）-1Η_1，2,3-三唑-4-羧醯胺； 123505 -132- 200815422 l-(5_(3-氟基_5-(四氫外ti洛-1-基）苯甲酿胺基）甲基ρ比唆-3-基）-Ν-((四氫咬喃-2-基）甲基）-1Η_1，2,3-三σ坐斗致醯胺； 1-(5-(3-鼠基-5-(四氫叶I：洛-1-基）苯甲酿胺基）_2•甲基ρ比咬-3-基）-N-新戊基-1H-1，2,3-三唑-4-羧醯胺； 1-(5-(3-氰基-5-(六氫ρ比咬-1-基）苯甲酿胺基）·2·甲基说唆-3-基）_Ν-新戊基-1Η-1，2,3_三唑冬羧醯胺； 1-(5-(3-氰基-5-嗎福啉基苯甲醯胺基）_2_曱基吨。定-3-基）-Ν-新 戊基-1H-1，2,3-三°坐-4-緩酿胺； 1-(5-(3-敗基-5-硫代嗎福淋基苯甲酿胺基）_2_甲基外匕咬-3-基）~N-新戍基-1H-1，2,3-二11 坐-4-魏酿胺； 1-{5-[3-氟基-5-(1-酮基-1 λ 4-石荒代嗎福p林-4-基）-苯曱醢胺 基>2-甲基^比啶-3-基}-1Η_[1，2,3]三唑-4_羧酸（2,2-二甲基-丙基）-醯胺； 1-(5·(3·第三-丁基-5-氰基苯甲醯胺基）-2-曱基吡啶-3-基）-N-((l-甲基六氫吡啶_4_基）甲基）-1Η-1，2,3-三唑-4-羧醯胺； 3_弟二-丁基-5-氣基-N-(5-(4-(4_(2-經乙基）六氫p比”井-1•罗炭 基HH-1，2,3-三唑小基）-6-甲基吡啶-3-基）苯甲醯胺； 1-(5-(3-第三-丁基-5-氰基苯甲醯胺基>2-曱基吡啶-3-基）-N-(2,2,6,6-四曱基六氫吡啶冰基）-1Η-1，2,3-三唑-4-羧醯胺； 1-(2_甲基-5-(3-(四氫吡咯小基）_5-(三氟曱基）笨甲醯胺基）-吡 啶-3-基）-N-(吡啶-2-基甲基）·1Η-1，2,3-三唑-4-羧醯胺； 1-{5_[3-(1，1_二酮基-1久6·硫代嗎福淋-4-基）-5-氟-苯甲醯胺 基]_2-甲基-吡啶各基}·1Η_[1，2,3]三唑-4-羧酸（2,2-二甲基-丙基）-醯胺； 123505 -133- 200815422 1-(5-(3-第三-丁基-5-氰基苯曱醯胺基）-2-甲基吡啶_3· 基）-N十比啶-2-基甲基）·ιη_1，2,3-三唑斗羧醯胺； 5-第三-丁基-3-氰基-2-甲氧基-Ν-(6-曱基-5-(4-(新戊基胺甲醯 基）苯基）17比唆-3-基）苯甲酷胺； 3-漠基-5-第三-丁基-2-甲氧基_N-(6-甲基-5-(4-(新戊基胺甲醯 基）苯基）p比咬-3-基）苯甲酿胺； (R)-5-弟二-丁基-3-氰基-N_(5-(4_((l-乙基四氫p比υ各_2·基）甲基 胺曱醯基）苯基）-6-曱基吡啶各基）-2-甲氧基苯甲醯胺； 1-(5-(3-氰基-5-(六氫p比α定-1-基）苯甲醯胺基甲基p比咬各 基）-Ν十比啶-2-基甲基）-lH_l，2,3-三唑斗羧醯胺； 3-第三-丁基-5-氰基-Ν·(6-甲基_5-(4-(吡啶-2-基甲基胺甲醯 基）苯基 >比啶-3-基）苯甲醯胺； Ν-(6-曱基-5-(4-(吡啶-2-基甲基胺甲醯基）苯基）吡啶各 基）-3•(四氫吡咯-1-基）_5·(三氟甲基）苯甲醯胺； 3·第三-丁基-5-氰基·Ν-(6_甲基-5-(4-((1-曱基六氫吡啶-2-基） 甲基月女甲酿基）本基）p比淀基）苯甲酿胺； N-(6-甲基-5-(4-((1-甲基六氫吡啶基）甲基胺甲醯基）苯基） 峨σ疋-3_基）-3-(四氫u比洛_1-基）-5-(三氟甲基）苯甲醯胺； 5-第三·丁基-3-氰基-2-甲氧基·Ν-(6-甲基-5-(4-((1-甲基六氫吡 啶-2-基）甲基胺甲醯基）·苯基）峨咬各基）苯甲醯胺； (R)-3_第三-丁基-5-氰基-Ν-(5-(4·((1-乙基四氫吡咯-2-基）曱基 I*甲醯基）苯基）-6-甲基ρ比咬-3-基）苯甲酿胺； (R)-N-(5-(4-((l-乙基四氫吡咯-2·基）甲基胺甲醯基）苯基）各甲 基吡啶-3-基）-3-嗎福啉基-5-(三氟甲基）苯甲醯胺； 123505 -134- 200815422 (R)-N-(5-(4-((l-乙基四氫ϊτ比u各-2-基）甲基胺甲酸基）苯基）-6·甲 基吡啶-3-基）各(四氫吡咯-1-基）-5-(三氟甲基）苯甲醯胺； (R)-N-(5-(4-((l-乙基四氫吡咯-2-基）甲基胺甲醯基）苯基）-6·甲 基吡啶-3-基）-3-(六氫吡啶-1-基）-5-(三氟甲基）苯甲醯胺； 1-(5-(3-第三-丁基-5-氰基苯甲醯胺基）-2-甲基吡啶-3-基）-Ν·((1-甲基六氫吡啶-2-基）甲基）·1Η-1，2,3-三唑-4·羧醯胺； 1-(5-(5-第三-丁基各氰基-2-甲氧基苯曱醯胺基）-2-甲基吡啶 -3-基）-N-((l-甲基六氫吡啶-2-基）甲基）-1Η-1，2,3-三唑-4-羧醯胺； 1-(5-(3-第三-丁基-5-氰基苯甲醯胺基）-2-甲基吡啶-3-基）-N-環己基-1H-1，2,3-三。坐-4-叛S篮胺； 1-(5-(3-第三-丁基-5-氰基苯甲醯胺基）-2-甲基吡啶-3-基）-N-(六氫吨咬_1_基）·1Η·1，2,3·三。坐-4-魏SS胺； 3-第三丁基-5-氰基-Ν-(6_甲基·5-(4-((6-曱基吡啶-2-基）甲基 胺曱醯基）苯基）吡啶-3-基）苯甲醯胺； 5-第三-丁基-3-氰基-2·甲氧基善(6-甲基_5-(4-((6-曱基吡啶-2-基）甲基胺甲醯基）苯基）吡啶-3-基）苯甲醯胺； N-(6-甲基-5-(4-((6_甲基吡啶-2-基）甲基胺甲醯基）苯基风啶 -3-基）-3-(四氫吡咯-1-基）-5-(三氟曱基）苯甲醯胺； 3-第二-丁基-5-(6-甲基-5-(4-(新戊基胺甲醯基）_苯基）峨啶各 基胺甲醯基）苯甲酸甲酯； 3-第二-丁基-5-(6-曱基-5-(4-(新戊基胺曱醯基）_苯基）p比啶各 基胺甲醯基）苯曱酸； N-(6-曱基-5-(4-(新戊基胺甲醯基）苯基）吡啶_3_基）_2<六氫吡 咬小基）異終驗醯胺； 123505 -135- 200815422 5-第三-丁基-N1 -(2-(二甲胺基）乙基）_N31甲基-5作(新戊基 胺甲醯基）苯基）-吡啶-3_基）間苯二甲醯胺； 3·氟·Ν-(5-(4·(1-(羥亞胺基）乙基）苯基）-6_甲基吡啶基）_5_嗎 福啉基苯甲醯胺； 4-(5-(3-第三-丁基-5-氰基苯甲醯胺基）_2_甲基吡啶！基）苯 甲酸甲酯； 1-(5-(3-第三-丁基-5-氰基苯甲醯胺基）-2-甲基吡啶_3_ 基）-1Η-1，2,3-三唑-4-羧酸乙酯； 1-(5-(3-第三-丁基-5-氰基苯甲醯胺基）-2-甲基吡啶 基）-队(2-(二乙胺基）乙基）-出-1，2,3-三唑-4-羧醯胺； 1-(5-(3-第三-丁基-5-氰基苯甲醯胺基）-2-甲基吡啶_3_ 基）-N_(2-(二異丙基胺基）乙基wh-W}三唑-4-羧醯胺； 1-(5-(3-第三-丁基-5·氰基苯甲醯胺基）-2-甲基吡啶； 基）-N-(2-甲基-2-(六氫吡啶-1-基）丙基）_ih-1,2,3-三唑-4·羧醯胺； 1-(5-(3-第三·丁基_5_氰基苯甲醯胺基）_2_甲基吡啶各基）_N_ ((1-(六氫吡啶-1-基）環己基）甲基）_1H-1，2,3-三唑-4-羧醯胺； N-(6-甲基-5-(4-(新戊基胺甲醯基）苯基）-吡啶_3_基）-2-嗎福琳 基異於驗醯胺； 3-氰基-N-(6-曱基-5-(4-((6-甲基吡啶-2-基）甲基胺曱醯基）笨 基 >比啶_3_基）_5·嗎福啉基苯甲醯胺； 3-氰基-N-(6-甲基-5-(4-((6-甲基吡啶-2-基）甲基胺甲醯基）笨 基风啶-3-基）-5-(四氫吡咯小基）苯甲醯胺； 3-氰基-N-(6_甲基-5-(4-((6-甲基吡啶-2-基）甲基胺甲醯基）苯 基Η啶-3-基）-5-(六氫吡啶小基）苯甲醯胺； 123505 -136- 200815422 4-(5-(5-第三-丁基-3-氰基-2-曱氧基苯曱醯胺基）-2-甲基p比π定 •3-基）苯甲酸甲酯； 3-第三-丁基-5-氰基-Ν-(5-(4-(環己基胺曱醯基）苯基）-6-曱基 吡啶-3-基）苯甲醯胺； 3-第三-丁基-5-氰基·Ν-(5-(4-(2·(二乙胺基）乙基胺曱醯基）·苯 基）-6-甲基吡啶-3-基）苯甲醯胺； 3-第三-丁基-5-氰基-N-(5-(4-(2-(二異丙基胺基）乙基胺曱醯 基）苯基）-6-甲基说咬-3-基）苯甲酿胺； 3-第三-丁基-5-氰基-N-(6-曱基-5-(4-(2-曱基-2-(六氫吡啶-1-基）丙基胺甲醯基）苯基 >比啶-3-基）苯甲醯胺； 3-第三-丁基-5-氰基-N-(6-甲基_5-(4-((1-(六氫峨咬-1·基）環己 基）甲基胺甲醯基）苯基风ϋ定-3_基）苯甲醯胺； 3-第三-丁基-5-(((2-曱氧基乙基）(甲基）胺基）曱基曱基 -5-(4-(新戊基胺甲醯基）苯基）-ϊτ比u定—3-基）苯甲醯胺； 3-第三-丁基善(6-甲基-5-(4-(新戊基胺曱醯基）苯基㈣啶·3_ 基）·5_(四氫吡咯-1-基甲基）苯甲醯胺； 3-第三-丁基-Ν-(6-甲基-5-(4-(新戊基胺甲醯基）苯基）,比啶_3_ 基）-5_(六氫吡啶-1·基甲基）苯曱醯胺； 3-氟-N-(5-(4-(l_羥乙基）苯基）各甲基吡啶-3-基）-5-嗎福啉基 苯甲醯胺； 1-(5-(3-第三-丁基-5-氰基苯曱醯胺基）_2_甲基吡啶各基）_N_ 嗎福淋基-111-1，2,3-三唾-4-魏酿胺； 1-(5-(3-弟二-丁基-5-氰基苯甲醯胺基>2-甲基u比咬各 基）氫-2H-味喃-4-基）_ih-1，2,3-三唑-4-羧醯胺； 123505 •137- 200815422 5-第三-丁基-3-氰基-Ν·(5-(4-(環己基胺曱醯基）苯基）_6_曱基 吡啶-3-基）-2-甲氧基苯甲醯胺； 5-弟二-丁基-3-氰基-2-甲氧基·Ν-(6-甲基-5-(4-(六氫p比咬-1-基 胺甲酿基）苯基）p比唆-3-基）苯甲醯胺； 5-第三-丁基_3_氰基-2-甲氧基-Ν-(6·曱基-5-(4-(四氫_2Η-哌喃 -4-基月女甲&&基）本基）ρ比°定_3_基）苯甲酿胺； 5-弟二_丁基-3-氰基-2·甲氧基-Ν-(6-甲基-5-(4-(嗎福琳基胺甲 酸基）苯基）〜比τι定-3·基）苯甲酿胺； 3-苐三丁基-N-(6-甲基-5-(4-(新戊基胺甲醢基）苯基）喻唆_3_ 基）-5·((4-甲基六氫p比口井-1-基）甲基）苯甲醯胺； 3-第三-丁基-Ν-(6-甲基-5-(4-(新戊基胺曱醯基）苯基比咬 基）-5-(((四氫呋喃-2-基）甲胺基）甲基）苯甲醯胺； 3-第三-丁基-N-(6-甲基-5-(4-(新戊基胺曱醯基）苯基）_吡啶-3_ 基）_5-((丙-2_炔基胺基）甲基）苯甲醯胺； 3-第三-丁基-N-(6-甲基-5-(4-(新戊基胺曱醯基）苯基 >吡啶-3_ 基）-5-(嗎福啉基甲基）苯甲醯胺； 3-第三·丁基-N-(6-甲基-5-(4-(新戊基胺甲醯基）苯基）巧比咬各 基）-5-((3-酮基六氫吡畊-1-基）甲基）苯甲醯胺； 3-第三-丁基-N-(5-(4-(2-第三-丁基耕幾基）三嗤小 基）冬甲基吡啶-3-基）-5·氰基苯甲醯胺； 3-第三-丁基-5-氰基-N-(5_(4-(2-環己基肼幾基）_ih_1，2,3-三哇 -1-基>6-曱基吡啶-3-基）苯甲醯胺； 1·(5-(3-第三-丁基-5-氰基苯甲醯胺基>2-曱基p比。定各 基）-Ν-(2,6-二甲基六氫峨σ定-1-基）-1Η-1，2,3_三吐-4-魏醯胺； 123505 -138- 200815422 N-(6-甲基_5普(新戊基胺甲醯基）苯基）_吡啶士基片(四氫 口比σ各小基）異於驗醢胺； 3-第三-丁基-Ν-(6-甲基-5-(4-(新戊基胺甲醯基）苯基）_吡啶各 基）-5-((2-(曱硫基）乙胺基）甲基）_苯甲醯胺； 3-第三-丁基-5-(((L(二甲胺基）乙基）(甲基）胺基）曱基）_N-(6-甲基_5-(4-(新戍基胺曱醯基）苯基）_吡啶各基）苯曱醯胺； 弟二-丁基-5-氰基-N-(6-甲基-5-(4-(嗎福琳基胺甲醯基）苯 基）·吡啶-3_基）苯甲醯胺； 3-第三-丁基善(5-(4-(2_第三-丁基肼羰基）苯基）_6_甲基吡啶 -3-基）-5-氰基苯甲酸胺； 3-第三-丁基·5_氰基-N-(5-(4-(2_環己基肼羰基）_苯基）冬甲基 吡啶-3-基）苯甲醯胺； 5_第三-丁基-Ν·(5·(4-(2-第三-丁基肼羰基）苯基）-6-甲基吡啶 -3-基）-3-氰基-2-甲氧基苯甲醯胺； ^(5-(3-氟基-2-甲氧基-5-嗎福啉基苯甲醯胺基）-2-甲基吡。定 -3-基>N-新戊基-1H-1，2,3-三唑-4-羧醯胺； ^(5-(3-氟基-2-甲氧基-5-嗎福啉基苯甲醯胺基）-2-甲基吡啶 -3-基）((四氫呋喃-2-基）甲基）-1Η-1，2,3·三唑-4_羧醯胺； Κ5-(3-氟基-2-甲氧基-5-嗎福啉基苯甲醯胺基）-2-甲基吡啶 _3_基）-N七比啶各基甲基）-lH-l，2,3-三唑-4_羧醯胺； 3-1基-2-甲氧基-N-(6-甲基-5-(4-(吡啶-3-基甲基胺甲醯基）苯 基 >比咬-3-基）-5-嗎福琳基苯甲醯胺； 3-氟基-2-甲氧基-N-(6-甲基-5-(4-((四氫呋喃-2-基）甲基胺甲 酿基）苯基）吡啶-3-基）-5-嗎福啉基苯甲醯胺； 123505 -139- 200815422 3遠基1甲氧基-N-(6-甲基-5-(4-(新戊基胺甲醯基）苯基）-吡 咬各基）_5_嗎福啉基苯甲醯胺； 3弟一 -丁基4·氰基-N-(5-(4-(2,6-二甲基六氫外1：唆-1-基胺甲 酸基）苯基）-6-甲基吡啶_3_基）苯甲醯胺； 5-第二-丁基-3-氰基-N-(5-(4-(2,6-二甲基六氫吡啶小基胺甲 酷基）苯基）_6_甲基吡啶各基）_2_甲氧基苯甲醯胺； 1-(5-(5-第三-丁基_3_氰基甲氧基苯甲醯胺基）-2_甲基吡啶 士基沖-^二甲基六氫吡啶+基”叫幻-三唑冰羧醯胺； 1-(5-(5-第三-丁基_3_氰基-2-甲氧基苯甲醯胺基）-2-甲基吡啶 -3-基）-N_(六氫吡啶-μ基卜丨沁丨又^三唑冬羧醯胺； 5_第三-丁基-N-(5-(4-(2-第三-丁基肼羰基）-iH-l，2,3-三唑-1-基）-6-甲基吡啶-3-基>3-氰基-2-甲氧基苯曱醯胺； 1-(5-(3-第三-丁基_5-(嗎福啉基甲基）苯甲醯胺基）_2_曱基吡 咬-3-基）-N-新戊基-1H-1，2,3-三唾-4-魏酿胺； 5-第三-丁基-3-氰基_N-(5-(4-(2-環己基肼羰基）_1H-1，2,3-三唑 小基）-6-甲基吡啶_3_基）_2·甲氧基苯甲醯胺； 1-(5-(3-第三-丁基-5-((4-甲基六氫吡p井小基）甲基）苯甲醯胺 基）_2_甲基吨淀-3-基>N-新戊基_1114,2,3_三。坐-4·魏醯胺； 3-氰基-N-(6-曱基-5-(4-(新戊基胺甲醯基）苯基）_吡啶各基)-5-嗎福啉基苯甲醯胺； N-(5-第三-丁基_3_氰基-2-甲氧苯基）-6-甲基-5-(4-(新戊基胺 曱醯基）-1Η-1，2,3-三唾-1-基）於驗醯胺； N-(3-氰基-5-嗎福淋基苯基）_6_甲基_5-(4-(新戊基胺甲醯 基）-1Η-1，2,3-三唑-1-基）菸鹼醯胺； 123505 -140· 200815422 N-(3-氟基-5-嗎福琳基苯基）各甲基-5-(4-(新戊基胺甲醯 基）-1凡1，2,3-三嗤-1-基）於驗酸胺； N-(3-第三-丁基-1-甲基-lH-p比唾-5-基）-6-甲基-5-(4·(新戊基胺 甲醯基）_1Η-1，2,3_三唾-1-基）於驗酿胺； 1- (5-(3-((lS，5R)_8·氧-3-氮·雙環并[3.2.1]辛-3-基）-5-氟基苯曱醯 胺基）-2-甲基吡啶-3-基）-N-新戊基·1Η-1，2,3-三唑冰羧醯胺； 3-氰基-Ν-(6-甲基-5-(4-((四氫呋喃-2-基）甲基胺甲醯基）苯基） 外匕咬-3-基）-5-嗎福琳基苯甲酿胺； 3-氰基-N-(6-甲基-5-(4-〇比啶各基甲基胺甲醯基）苯基）_吡啶 -3-基）-5_嗎福4木基苯甲醯胺； N-(3-第三-丁基苯基）-6-甲基-5-(4-(新戊基胺曱醯基）-1Η-1，2,3-三唾-1-基）於驗酿胺； N-(5-第三-丁基-2-甲氧苯基）_6_甲基-孓(4气新戊基胺甲醯 基）-1Η_1，2,3·三唑-1_基）於鹼醯胺； 2_(3_第三·丁基-5-(6-甲基-5-(4-(新戊基胺甲醯基）-ΐΗ-1，2,3-三 嗤-1-基）ρ比啶-3-基胺甲醯基）爷胺基）醋酸第三_丁酯； 2- (3-第三-丁基-5-(6-甲基-5-(4-(新戊基胺甲醯基）苯基y吡啶 -3-基胺甲醯基）爷胺基）醋酸第三_丁酯； 2-(3-第三-丁基_5-(6-甲基-5-(4-(新戊基胺甲醯基）苯基 >吡啶 士基胺甲醯基）爷胺基）醋酸； Ν·(5-(4-(8-氧-3-氮-雙環并[m]辛烷羰基）苯基）各甲基吡 咬-3-基）·3-第三·丁基_5_氰基苯甲醯胺； Ν-(5-(4-(8_氧-3-氮-雙環并[3·2·1]辛烷-3-羰基）-1Η-1，2,3-三唑-1- 基>6_甲基吡啶_3_基）_5_第三_丁基_3_氰基冬甲氧基苯曱醯胺； 123505 -141 - 200815422 3_第三-丁基-5-氰基-Ν·(6-甲基-5-(4-(2,2,6,6-四甲基嗎福啉-4-羰基）苯基）峨咬-3-基）苯曱醯胺； 5-第三-丁基-3-氰基-2-甲氧基-N-(6-甲基-5-(4-(2,2,6,6-四甲基 嗎福琳-4-羰基）-1Η-1，2,3-三唑-l-基 >比唆-3-基）苯甲醯胺； N-(5-(4-(8-氧-3-氮-雙環并[3.2_1]辛烷各羰基）-iH-l，2,3-三唑-1-基）-6-曱基吡啶-3-基）各第三-丁基-5-氰基苯甲醯胺； 3-弟二-丁基氣基_N_(6-甲基-5-(4-(2,2,6,6-四曱基嗎福琳-4· 羰基）-1Η_1，2,3-三唑-l-基 >比啶-3·基）苯甲醯胺； N-(5-第三-丁基-3-胺甲醯基-2-甲氧苯基）-6-甲基-5-(4-(新戊 基胺曱醯基）-1Η-1，2,3-三唾-1-基）於驗醯胺； N-(5-第三-丁基-3-(環丙基胺曱醯基）-2_甲氧苯基）·6•甲基 -5-(4-(新戊基胺甲醯基）-11^1，2,3-三唾小基）於驗醯胺； Ν-(5-第三·丁基-2-甲氧基-3-(甲基磺醯胺基）苯基）_6_曱基 -5-(4-(新戊基胺甲醢基）-1Η-1，2,3-三嗤-1-基）於驗醯胺； N-(5-(4-(8-氧-3-氮-雙環并[3·2·1]辛烧-3-叛基）苯基）-6_曱基p比 啶-3-基）-5-第三-丁基-3-氰基-2-甲氧基苯甲醯胺； 5-第三-丁基-3-氰基-2-曱氧基·Ν-(6-曱基-5-(4-(2,2,6,6-四甲基 嗎福啉·4_羰基）苯基）吡啶-3-基）苯甲醯胺； 5-第三-丁基-3-氰基-2-甲氧基-Ν-{6-甲基-5-[4-(1〇-氧-4-氮-三 環并[5_2丄02,6]癸烷-4-羰基）-苯基]•吡啶净基}-苯甲醯胺； 5_第三-丁基-3-氰基-2-甲氧基_Ν-{6-曱基-5-[4-(1〇-氧斗氮·三 環并[5·2·1.02,6]癸烷_4_羰基）_[1，2,3]三唑-1-基]-吡啶-3-基卜笨甲 醯胺； 3-第二-丁基-5-鼠基-Ν-{6-曱基-5-[4-(10-氧-4-氮-三環并 123505 -142- 200815422 [5·2·1·〇2,6]癸燒_4_羰基叩二习王唑_卜基]_峨啶I基卜苯甲醯胺； 3一第二-丁基-5-氰基|{6-曱基-5-[4_(l〇-氧斗氮_三環并 [5·2·1·02,6]癸燒冰幾基）_苯基p比唆各基丨_苯甲醯胺； 3-第二·丁基_Ν_(6_甲基_5_(4·(新戊基胺曱醯基）苯基比啶各 基）-5-((2-(甲基亞磺醯基）乙胺基）甲基）苯甲醯胺； 第二-丁基·Ν-(6-曱基-5_(4_(新戊基胺甲醯基）苯基）_吡啶各 基）-5-((2-(甲磺醯基）乙胺基）甲基）苯曱醯胺； N-(3-第三·丁基_5_氰基苯基）各甲基⑷(六氫吡啶小基胺 甲醯基）-1Η-1，2,3-三唑-1-基）终鹼醯胺； N-(5-第三-丁基-2-甲氧基-3-(甲基磺醯胺基）苯基）-6-甲基 -5-(4·(六氫吡啶小基胺曱醯基）-1Η-1，2,3-三唑小基）菸鹼醯胺； N-(5-第三-丁基各氰基-2-甲氧苯基>6-甲基-5-(4-(六氫吡啶 基胺甲基）·1Η-1，2,3-三唾-1-基）於驗酿胺； 1-(5-(5-第三-丁基-3-氰基-2-(2-(4·甲基六氫吡畊-1-基）乙氧基） 本甲醯月女基）-2-甲基峨σ定各基）-N-新戊基三唾-4-緩醯 胺； 5-第三-丁基-3-氰基-N-(6-甲基-5_(4-(新戊基胺甲醯基）苯基）_ 吡啶各基）-2-(2-(4_甲基六氫吡啡-μ基）乙氧基）苯甲醯胺； 3-氰基善(6-甲基-5-(4_(N_新戊基胺磺醯基）苯基风啶各 基）-5-嗎福淋基苯甲酿胺； 3·氰基-N-(6-甲基-5-(4-(N-新戊基胺磺醯基）苯基风咬_3_ 基）-5-(四氫毗咯-1-基）苯甲醯胺； 5-第三-丁基-3-氰基-2-甲氧基-Ν-(6-甲基-5-(4_(N-新戊基胺石黃 醯基）苯基）毗啶1基）苯甲醯胺； 123505 -143- 200815422 N-(6-甲基_5_(4-(新戊基胺甲醯基）苯基）4比咬各基）異τι号峻-3-羧醯胺； 3_第三-丁基-1-曱基-Ν-(6-甲基-5-(4-(新戊基胺甲醯基）苯基）· 吡啶-3-基）-1Η-吡唑-5-羧醯胺； 5-第三-丁基_2_甲基-Ν·(6-甲基-5-(4-(新戊基胺甲醯基）_苯基） 吡啶-3-基）呋喃-3-羧醯胺； 3-第三_丁基-N-(6-甲基-5-(4-(新戊基胺曱醯基）苯基）咐σ定-3_ 基）-1Η-吡唑-5-羧醯胺； 5_第三_丁基-Ν-(6-甲基-5_(4·(新戊基胺曱隨基）苯基）_ρ比咬各 基）異噚唑-3-羧醯胺； 1-(5-(3-第三-丁基-5-氰基苯甲醯胺基）-2-乙基吡啶_3-基）_Ν_ 新戊基-1Η-1，2,3-三唑-4-羧醯胺； 5-第三_丁基-Ν1 -甲基-Ν3 -(6-甲基_5-(4-(新戊基胺甲醯基）苯 基）吡啶-3-基）間苯二甲醯胺； 5-第三-丁基-Ν1 -環丙基-Ν3 -(6-甲基-5-(4-(新戊基胺甲醯基） 苯基）吡啶-3-基）間苯二甲醯胺； 5-第三-丁基-N1 -(環丙基甲基）-N3 -(6-甲基-5-(4-(新戊基胺曱 酉&基）本基比咬-3-基）間苯二甲酸胺； 5-第三_丁基-N1 -(6-甲基-5-(4-(新戊基胺甲醯基）苯基风啶_3-基）間苯二甲醯胺； H5-(3-氟基-5-嗎福啉基苯甲醯胺基）_2_甲基吡啶各 基）-1Η-1，2,3-三唑-4-羧酸乙酯； 3-第三-丁基-5-(6-甲基-5-(4-(新戊基胺甲醯基）_ih4,2,3-三唑 -1-基）p比咬-3-基胺甲醯基）苯甲酸甲g旨； 123505 -144- 200815422 H5-(3-氟基-5-(三氟甲基）苯甲醯胺基甲基吡啶各基）具 新戊基-1H-1，2,3-三唑-4-羧醯胺； 3_第三-丁基_5_(6_甲基新戊基胺甲醯基）_1H_1，2,3-三唑 小基风啶各基胺甲醯基）苯甲酸； 5-(3-第三-丁基_5_氰基苯甲醯胺基）_2_甲基各(4-(新戊基胺 甲醯基）苯基）吡啶1-氧化物； 5-(3-第三-丁基氰基苯甲醯胺基）_2_甲基各…(新戊基胺 甲醯基）_1H-1，2,3-三唑小基）吡啶丨_氧化物； 第二-丁基-Nl <環丙基甲基）-N3 -(6-甲基-5-(4-(新戊基胺甲 醯基）-1Η-1，2,3_三唑-1-基）p比啶各基）間苯二甲醯胺； 1-(5-(2,5_二甲氧基笨甲醯胺基甲基吡啶基新戊基 -1H-1，2,3-三口坐-4·幾醢胺； 5-第三-丁基-Νι_甲基-N3_(6•曱基_5_(4_(新戊基胺甲醯 基）-1Η_1，2,3-二唑+基 >比啶基）間苯二甲醯胺； 3-氰基-5-(4-甲基-1H-咪唑+基甲基_5普(新戊基胺甲 醯基）苯基）ϊι比嚏_3·基）苯曱醯胺； H2-曱基-5-(3-(4-甲基-1H-咪唑-1-基）_5·(三氟甲基）苯甲醯胺 基 >比唆各基）-N_新戊基_1凡1，2,3-三唑_4_魏醯胺； H5-(3-氰基甲基-1Η-咪唑+基）苯甲醯胺基）_2_甲基吡 咬士基）_Ν_新戊基-1Η-1，2,3-三唑_4·羧醯胺； 1-(5-(3-第二_丁基_5_氰基苯甲醯胺基）_2_甲基吡啶-> 基）4(3令基_2,2-二甲基丙基）_讯1，2,3-三嗤冰叛醯胺； (RH-(5-(3-第三_ 丁基_5_氰基苯甲醯胺基）_2_甲基吡啶·3_ 基»^((四氫呋喃_2•基）甲基>1H_U，3_三唑冰羧醯胺； 123505 -145- 200815422 (S)-l-(5-(3-第三-丁基-5-氰基苯甲醯胺基）_2_甲基吡啶_3· 基）-1^-((四氫吱喃-2-基）甲基）-11^_1，2,3-三嗤-4-叛醯胺； 1-(5-(5-第三-丁基-3-氰基-2-甲氧基苯甲醯胺基）_2—甲基吡啶 -3-基）-N-((l_經基環丙基）甲基）-iH-l，2,3-三唆冰羧醯胺； 1-(5-(3,5-雙三甲基乙醯胺基苯甲醯胺基）_2_甲基吡啶-3-基）-N-新戊基-1H-1，2,3-三嗤-4-魏醯胺； N-(3-第三-丁基-5-氰基苯基）-6-甲基-5-(4-(新戊基胺甲醯基） 苯基）菸鹼醯胺； N-(5-第三-丁基-3-氰基-2-甲氧苯基）各甲基-5-(4-(新戊基胺 甲醯基）苯基）於驗醯胺； 5-第三-丁基-3-氰基-Ν-(5-(4-(3·羥基-2,2-二曱基丙基胺甲醯 基）苯基）-6-曱基吡唆-3-基）-2-甲氧基苯甲醯胺； 5·第三-丁基-3-氰基_Ν-(5-(4-((1-經基環丙基）甲基胺曱醯基） 本基）-6-甲基P比σ定-3-基）-2-甲氧基苯甲酿胺； 1-(5-(5-第三-丁基-3-氰基-2-曱氧基苯曱醯胺基）-2-甲基吡啶 -3-基）-N-(3-羥基-2,2-二甲基丙基）·1Η-1，2,3-三唑-4-羧醯胺； 1-(5-(3-第三-丁基-5-(正-丙基胺磺醯基）苯曱醯胺基）-2-曱基 吡啶-3_基）-N-新戊基-1H-1，2,3-三唑_4_羧醯胺； 1-(5-(3,5-雙（新戊氧基）苯曱醯胺基）_2_甲基吡啶各基）-N-新 戊基_1Η·1，2,3-三嗤-4-叛酸胺； 3-弟二-丁基氣基-Ν·(5·(4_(3-經基-2,2-二甲基丙基胺曱酿 基）苯基）_6·甲基吡啶-3-基）苯甲醯胺； 3-第三-丁基-5-氰基-N-(5-(4-((l-經基環丙基）曱基胺曱醯基） 苯基）-6-曱基吡啶-3-基）苯甲醯胺； 123505 -146- 200815422 5-第三-丁基_Νι，Νι _二甲基_n3 _(6_曱基净(4_(新戊基胺曱醯 基）苯基Η啶-3-基）間苯二甲醯胺； Ν-(5-(4-(2-胺基-2-甲基丙基胺甲醯基）苯基）各甲基吡咬 基>3-第三-丁基-5-氰基苯甲醯胺； ^(2-甲基-5-(3_三曱基乙醯胺基苯甲醯胺基）吡啶_3_基）新 戊基_1Η_1，2,3-三唑-4-羧醯胺； 5-第三·丁基-Ν1 -(6-甲基-5-(4-((四氫呋喃-2-基）曱基胺曱醯 〆 基）本基）p比咬-3·基）-N3七比咬-3-基甲基）間苯二甲醯胺； 1-(5-(5-第三·丁基-2-甲氧基斗硝基苯曱醯胺基）-2-甲基吡咬 -3-基）-N-新戊基-1H-1，2,3-三唑-4-羧醯胺； 5-第三-丁基-2-曱氧基-N-(6_曱基-5-(4-(新戊基胺甲醯基）笨 基）外b °定-3-基）-3-石肖基苯曱醯胺； (R)-l-(5-(5-第三-丁基-2·甲氧基·3·(四氫吡咯-2·羧醯胺基）笨 甲醯胺基）-2-甲基吡啶-3-基）-Ν-新戊基-1Η-1，2,3-三唑-4遗酿 胺； ( (R)-N-(5-第三-丁基-2-甲氧基-3-(6-甲基-5-(4-(新戊基胺甲醯 基）苯基Η啶·3_基胺甲醯基）苯基）四氫吡咯胃2_羧醯胺； 5-第三-丁基-Ν1 -(6-甲基-5-(4-(新戊基胺甲醯基）苯基风啶1 基）-N3 -(吡啶各基甲基）間苯二甲醯胺； N-(5-第三-丁基-2-甲氧基-3-(6-甲基-5-(4-(新戊基胺甲醯基） 苯基）峨受-3·基胺甲酸基）苯基）-5-酮基四氫被π各-2·叛醯胺； 5-第三-丁基各(1H-咪唑-1_基）-2-甲氧基-N-(6-甲基-5-(4-(新戊 基胺甲醯基）苯基）吡啶-3_基）苯甲醯胺； 1-(5-(5-第三-丁基-3-(1Η-咪唑-μ基）-2-甲氧基苯甲醯胺基）-2- 123505 -147- 200815422 甲基吡啶-3-基>N-新戊基-1H-1，2,3-三唑-4-羧醯胺； 3-弟二-丁基-5-(6-甲基-5-(4-((四鼠咬喃-2-基）甲基胺甲酿基） 苯基）吡啶-3-基胺甲醯基）苯甲酸甲酯； 3-第三-丁基-5·氰基-N-(6-甲基-5-(4-(2-(六氫吡啶小基）乙醯 基）苯基）吡啶-3-基）苯甲醯胺； 3-(5-(3-第三-丁基-5-甲氧基苯甲醯胺基）-2-曱基吡啶-3-基）-N-新戊基-1H-1，2,3-三唑-4-羧醯胺； 3-第三-丁基-5-曱氧基-N-(6-甲基-5-(4-(新戊基胺甲醯基）苯 基）吡啶-3-基）苯甲醯胺； 3_第三丁基-5-(6-曱基-5-(4-((四氫呋喃-2-基）甲基胺甲醯基） 苯基）吡啶-3-基胺甲醯基）苯甲酸； 5_第三-丁基-N1 ,Ν1 -二甲基-N3 -(6-甲基-5-(4-((四氫呋喃-2-基） 甲基胺甲醯基）苯基 >比啶-3-基）間苯二甲醯胺； 5-第三-丁基-N1-甲氧基-N1-甲基-N3-(6-甲基-5-(4-((四氫呋喃 -2-基）曱基胺甲醯基）苯基）吡啶-3-基）間苯二甲醯胺； 3-第三-丁基-N-(6-甲基-5-(4-(新戊基胺曱醯基）苯基）戒啶-3-基）-5-(2-嗎福啉基乙氧基）苯甲醯胺； 5-第三-丁基-2-甲氧基-3-(4-甲基-1H-咪唑-1-基）·Ν·(6·甲基 -5-(4-(新戊基胺甲醯基）苯基）吡啶-3-基）苯甲醯胺； 1-(5-(5-第三-丁基-2-甲氧基-3·(4-甲基-1H_咪唑小基）苯甲醯 胺基）-2-甲基说唆-3-基）-N-新戊基-1H-1，2,3-三ϋ坐-4-魏酿胺； 5-第三-丁基羥基環丙基）甲基）-N3-(6-甲基-5-(4-((四氫 呋喃-2-基）甲基胺甲醯基）苯基风啶-3-基）間苯二甲醯胺； 5_第三-丁基-3-氰基-N-(5_(4-(環戊基胺甲醯基）苯基）-6-甲基 123505 -148- 200815422 吡啶-3_基）-2-甲氧基苯甲醯胺； 5-第二-丁基-3-氰基-Ν·(5-(4-(4,4-二氟環己基胺甲醯基）苯 基）-6-甲基吡啶_3_基）-2-甲氧基苯甲醯胺； 5-弟二-丁基-3-氰基-N-(5-(4-(異丙基胺甲醯基）苯基）各甲基 吡啶-3-基）-2-甲氧基苯曱醯胺； 5_第二-丁基-3-氰基-Ν-(5·(4·(異丁基胺甲醯基）苯基）-6_甲基 吡啶-3-基）-2-甲氧基苯甲醯胺； 弟二丁基-3-氰基-Ν-(5-(4·(環丙基胺甲醯基）苯基）-曱基 吡啶_3-基）-2-曱氧基苯曱醯胺； 5-第三-丁基各氰基-2-甲氧基-N-(6-甲基-5-(4-(2-(六氫吡啶-μ 基）乙醯基）苯基）吡啶-3-基）苯甲醯胺； 5-弟二·丁基甲基-5-(4-(新戊基胺甲醯基）-ΐΗ-1，2,3-三 峻-1-基风啶-3-基）_N3 -(2-(四氫吡咯-1-基）乙基）間苯二甲醯胺； 5-弟二·丁基-N1%-甲基-5-(4-(新戊基胺甲酿基）·ιη-1，2,3-三 唑·1_基 >比啶各基）-Ν3-((1-甲基六氫吡啶-2-基）甲基）間苯二甲 醯胺； 5-第三-丁基-3·氰基_N-(5-(4-((lr，4r)-4-羥基環己基胺甲醯基） 苯基）-6-甲基p比。定-3-基）-2-甲氧基苯甲醯胺； N-(5-(4-((lR，2R，4S)·雙環并[2.2.1]庚-2-基胺甲醯基）苯基）冬甲 基叶1：唆-3-基）·5-第三-丁基-3-氰基-2-甲氧基苯甲醯胺； 5-弟二-丁基-3-氣基-Ν-(5-(4-(3-經丙基胺甲驢基）苯基）冬甲 基吡啶-3-基）-2-甲氧基苯甲醯胺； 5-第三-丁基-3-氰基-N-(5-(4-(2-羥乙基胺甲醯基）苯基）冬甲 基吡啶-3-基）-2-甲氧基苯甲醯胺； 123505 -149- 200815422 5_第二-丁基-N1 -(6-甲基-5-(4-(新戊基胺曱醯基）苯基风啶-3_ 基）_N3 -(2-(四氫吡咯-1·基）乙基）間苯二甲醯胺； 5_第二-丁基-N1 -(6-曱基-5-(4-(新戊基胺甲醯基）苯基风啶_3_ 基）_N3-((1-甲基六氫吡啶_2_基）甲基）間苯二甲醯胺； 1-(5-(3-第三-丁基-5-(N，N_二甲基胺磺醯基）苯甲醯胺基）_2_ 甲基外1： °疋-3-基）新戊基-1H-1，2,3-三嗤-4-羧醯胺； 3_第二·丁基-5-氰基-N-(5-(4-(2-(二甲胺基）·2_甲基丙基胺甲 醯基）苯基）-6_甲基吡啶-3-基）苯甲醯胺； 5-第三-丁基-Ν1 -(3_經基-2,2-二甲基丙基）_Ν3 ·(6_甲基净(4侦 戊基胺甲醯基）苯基）吡啶各基）間苯二甲醯胺； 5-第三-丁基各氰基_队(5_(4_(2,2_二甲基環己基胺甲醯基）苯 基）-6-甲基吡啶_3_基）-2-甲氧基苯甲醯胺； N-(5-(4-((lR，2S，4R)-雙環并[2·2·· _2_基胺甲醯基）苯基）_6•甲 基吡啶各基）-5-第三-丁基各氰基冬甲氧基苯甲醯胺； 1-(5-(3-第二-丁基-5-(N-甲基胺磺醯基）苯甲醯胺基）_2_甲基 峨咬_3_基）-N-新戊基_1凡1，2,3-三唑斗羧醯胺； 3·第三-丁基-N_(6_甲基·5_(4_(新戊基胺甲醯基）苯基风啶_3_ 基）-5-(N-甲基胺磺醯基;)苯甲醯胺； 5-第三-丁基·3_(異噚唑冬基>2_甲氧基_N_(6_甲基_5_⑷衝戊 基胺甲醯基）笨基）吡啶基）苯甲醯胺； 5-第三-丁基_3_(2,3_二氫異呤唑斗基）_2_甲氧基_N_(卜甲基 -5-(4-(新戊基胺甲醯基）苯基）,比啶_3_基）苯甲醯胺，· 土 3_第二-丁基-5-(5-環丙基-1，2,4-嘮二唑各基）甲基 -5-(4_(新戊基胺甲醯基）苯基风啶各基）苯甲醯胺； 土 123505 -150- 200815422 3_第三_丁基-5-(5_(甲氧基甲基）4,2,4^号二唑各基>N-(卜甲基 -5-(4-(新戊基胺甲醯基）苯基）吡啶斗基）苯甲醯胺； 3-第三-丁基-N-(5-(4-(3-羥基-2,2-二甲基丙基胺甲醯基）苯 基）-6-甲基吡啶-3-基）-5-(N-甲基胺磺醯基）苯甲醯胺； 3-第三-丁基-；NH>(4-(4,4-二氟環己基胺甲醯基）苯基）各甲基 吡啶各基）_5-(N-甲基胺磺醯基）苯甲醯胺； 3-第二-丁基-5-(5-第三—丁基]，2,4』号二唑_3_基）-N-(6-甲基 -5-(4-(新戊基胺甲醯基）苯基）吡啶各基）苯甲醯胺； 5-第三-丁基-2-甲氧基-N-(6-甲基-5-(4-(新戊基胺甲醯基）苯 基）峨淀_3_基）-3-(1H-p比嗤-1-基）苯甲醯胺； 5-第三-丁基各氰基善(5-(4-(2,2-二甲基-3-(四氫吡咯小基）丙 基胺甲醯基）苯基）-6-甲基吡啶-3-基）-2-甲氧基苯甲醯胺； 5_第三-丁基-3-氰基4(5-(4-(2,2-二甲基各(4-甲基六氫吡啡 -1-基）丙基胺甲醯基）苯基）-6-曱基吡啶；基）-2-甲氧基苯甲醯 胺； 5-第三-丁基-3-氰基-N-(5-(4-(2,2-二甲基-3-嗎福淋基丙基胺 曱醯基）苯基）-6-甲基外1：咬-3-基）-2-甲氧基苯甲醯胺； N-(5-(4-(3-胺基-2,2·二甲基丙基胺甲醯基）苯基）各甲基响σ定 -3-基）·5_第三-丁基-3-氰基-2-甲氧基苯甲醯胺； 5-第三-丁基-3-氰基-Ν-(5-(4-(3-(二曱胺基）_2,2_二甲基丙基胺 甲醯基）苯基）-6-曱基外1：唆-3-基）-2-甲氧基苯甲醯胺； 5-第三-丁基-3-(4-(經甲基）-1Η-1，2,3-三唑-1-基）-2-甲氧基_ν·(6- 甲基-5-(4-(新戊基胺曱醯基）苯基）响啶_3_基）苯甲醯胺； 5-第三-丁基-2-甲氧基-N-(6-甲基-5-(4-(新戊基胺曱醯基）笨 123505 -151 - 200815422 基Η啶-3-基）-3-(4-(四氫吡咯小基甲基）_1Η-1，2,3-三唑小基）苯 甲醯胺； 5-第三-丁基_2_甲氧基-Ν-(6-甲基-5-(4-(新戊基胺甲醯基）苯 基风啶-3-基）-3-(4-(六氫吡啶-1-基甲基三唑小基）苯 甲醯胺； 5-第三-丁基-2-甲氧基_N-(6-甲基-5·(4·(新戊基胺曱醯基）苯 基）外1:咬-3-基）-3-(4-((4-甲基六氫π比畊小基）甲基）_ιη_1，2,3-三。坐 -1·基）苯甲醯胺； 5-弟二-丁基-2-曱氧基-Ν-(6-甲基-5-(4-(新戊基胺甲酸基）苯 基 >比咬·3-基）-3-(4-(嗎福p林基甲基）-iH-l，2,3-三唑-1-基）苯甲酿 胺； 5-第三-丁基-3-(4-((二乙胺基）曱基唑小基）-2•甲 氧基-N-(6-甲基-5-(4-(新戊基胺甲醯基）苯基）,比啶_3-基）苯甲醯 胺； 5_第三-丁基各(4-((二曱胺基）甲基）-见以义三唑小基）_2•甲 氧基-N-(6-甲基-5-(4_(新戊基胺甲醯基）苯基）峨啶_3_基）苯甲醯 胺； 5-第三-丁基-3-(4-((異丙基胺基）甲基）巧沁以^三唑+基）_2_ 曱氧基善(6-甲基-5_(4-(新戊基胺甲醯基）苯基㈣啶_3_基）苯甲 醯胺； 5-第三-丁基-3_(4-((環丙胺基）甲基wh-U}三唑小基峰甲 氧基甲基-5-(4-(新戊基胺甲醯基）苯基风啶_3·基）苯曱酿 胺；及 5-第三_ 丁基-3·氰基-N-(5-(4-(2-(二甲胺基）_2·甲基丙基胺甲 123505 -152- 200815422 酿基）本基）-6-甲基说°定-3-基）-2-甲氧基笨甲酿胺。 發明詳述 下列術語係按下文定義，使用於全文中。 一般而言，對某一元素譬如氫或Η之指稱，係意謂包括 該元素之所有同位素。例如，若R基團係經定義以包含氫 或Η，則其亦包括氘與氣。因此，以同位素方式標識之化 合物係在本發明之範圍内。 f' 一般而言經取代"係指如下文定義之有機基團（例如烷 ^基），其中被包含於其中之一或多_氫原子之鍵結係被對 非氫或非碳原子之鍵結所置換。經取代之基團亦包括其中 對碳或氫原子之一或多個鍵結係被對雜原子之一或多個鍵 結（包括雙或參鍵）所置換之基團。因此，經取代之基團將 被一或多個取代基取代，除非另有指明。在一些具 例中’經取代之基團係被U，3, 4,5或6個取代基取代。取 代基之實例包括鹵素（意即卜€1、&及1);經基；烧氧基、 …職基、炔氧基、芳氧基、芳貌氧基、雜環基氧基及雜環 基院氧基；幾基類㈤基）；緩基類；酯類；聚胺基甲酸醋 類；肪類；羥基胺類；燒氧基胺類；芳院氧基胺類；硫醇 颂’石m化物，亞规類，鐵類；續醯基類；績醯胺類；胺類； Ν·氧化物；月井類；醯肼類；腺類；疊氮化物；醯胺類；腺 類；脒類；胍類，·稀胺類；醯亞胺類；異氛酸醋類；異硫 鼠酸西旨類；氰酸鹽，·硫氰酸鹽；亞胺類；腊類（意即CN)等。 絲代之環基團，譬如絲代之我基、芳基、雜環基 及雜方基，亦包括環與祠合環系統，其中對氯原子之鍵結 123505 • 153 - 200815422 係被對％原子之鍵結置換。因此，經取代之環燒基、芳基、 雜環基及雜芳基亦可被如下文定義之經取代或未經取代之 烷基、烯基及炔基取代。 烷基包括直鏈與分枝狀烷基，具有丨至約2〇個碳原子， 且典型上為1至12個碳，或在一些具體實施例中，為丨至8 個，1至6個，或1至4個碳原子。烷基進一步包括如下文定 義之環烷基。直鏈烷基之實例包括具有丨至8個碳原子者， Γ 譬如甲基、乙基、正-丙基、正-丁基、正-戊基、正-己基、 正·庚基及正-辛基。分枝狀烷基之實例包括但不限於異丙 基、異丁基、第二-丁基、第三_ 丁基、新戊基、異戊基及2,2_ 一甲基丙基。代表性經取代之烧基可被譬如上文列示之取 代基取代一或多次。 環烷基為環狀烷基，譬如但不限於環丙基、環丁基、環 戊基、壤己基、環庚基及環辛基。在一些具體實施例中， 環烷基具有3至10個，或3至8個環員，然而在其他具體實 ι 施例中，環碳原子數目之範圍為3至5個，3至6個，或3至7 個。環烷基進一步包括單…雙環狀及多環狀環系統，例如 下文所述之橋接環烷基，與稠合環，譬如但不限於十氫萘 基等。在一些具體實施例中，多環狀環烷基具有三個環。 經取代之環烷基可被如上文定義之非氫與非碳基團取代一 或多次。但是，經取代之環烷基亦包括被如上文定義之直 鏈或分枝鏈烷基取代之環。代表性經取代之環烷基可被單 取代或取代超過一次，譬如但不限於2,2_，2,3_，2,4_，2,5_或2，孓 二取代之環己基’其可被譬如上文列示之取代基取代。 123505 -154- 200815422 橋接我基為環絲’其巾兩個或多個氫料係被次烧 基橋基置換，其中若兩個氫原子係位在相同碳原子上，則 橋基可含有2至6個碳原子，或若兩個氫原子係位在相鄰碳 原子上，則可含有i至5個碳原子，或若兩個氫原子係位在 被1或2個碳原子分隔之碳原子上，則可含有2至4個碳原 子。橋接環烧基可為雙環狀，例如雙環并[211]己烧，或三 環狀，例如金剛烧基。代表性橋接環燒基包括雙環并[2ιι] 〔己基、雙i哀并[2.2.1]庚基、雙環并[3 21]辛基、雙環并[2·2 2] 辛基、雙環并[3.2.2]壬基、雙環并[3 31]壬基、雙環并[3 3习 夭基孟剛院基、去甲金剛烧基、莅基或正萡基。經取代 之橋接環烧基可被如上文定義之非氫與非碳基團取代-或 多次。代表性經取代之橋接環烷基可被單取代或取代超過 一次，譬如但不限於單_、二_或三_取代之金剛烷基，其可 被譬如上文列示之取代基取代。 環烷基烷基為如上文定義之烷基，其中烷基之氫或碳鍵 ( 係被對如上文定義之環烷基之鍵結置換。在一些具體實施 例中，環烷基烷基具有4至2〇個碳原子，4至16個碳原子， 且典型上為4至1〇個碳原子。經取代之環烷基烷基可在該基 團之烷基、環烷基或烷基與環烷基兩部份上經取代。代表 性經取代之環烷基烷基可被單取代或取代超過一次，譬如 但不限於被譬如上文列示之取代基單_、二_或三_取代。 烯基包括如上文定義之直鏈與分枝鏈及環烷基，惟至少 一個雙鍵存在於兩個碳原子之間。因此，烯基具有2至約2〇 個碳原子，且典型上為2至12個碳，或在一些具體實施例 123505 -155- 200815422 中，為2至8個，2至6個，或2至4個碳原子。在一些具體實 施例中，烯基包括環烯基，具有4至2〇個碳原子，5至2〇個 碳原子，5至1〇個碳原子，或甚至5, 6, 7或8個碳原子。實例 包括但不限於其中特別是乙烯基、烯丙基、)、 -CH=C(CH3 )2 > ^C(CH3 hCH2 ^ -C(CH3 )=CH(CH3) ^ -C(CH2 ch3 )=CH2 ^ 環己烯基、環戊烯基、環己二烯基、丁二烯基、戊二烯基 及己二烯基。代表性經取代之烯基可被單取代或取代超過List IL II-butylcyano-indole-(6-methylindole 3 pentylamine fluorenyl)phenyl> acridine Iyl)benzamide; 123505 -123 - 200815422 N (5 〇4 -(yloxy)phenyl)methyl oxime ratio bit each base) each third-butylcyanobenzamide; 3 -tri-butylcyanocyano 1 (5-(4-(3) ,3-dimethyl-2-oxobutoxy)phenyl)-6-methylpyridine; benzyl)benzamide; 4-(5-(5-tri-butyl-butoxy)acetate Benzylamino)_2-methylpyridine _3. phenyl) Benzene; 3-tert-butyl _5-cyano- Ν·(5_(4-methoxy-4-methylphenyl) Aminopyridin-3-yl)benzoic acid amine; 3-second-butyl_5-cyano-indole-(p-methyl_5_(4_(neopentylmethylmercapto)-pyridin-3-yl) Benzalamine; 3-fluoro-indole-(6-methyl-5-(4-(neopentylamino)phenyl)-pyridyl)-5•morpholinobenzamide; 3 -Second-butyl·5-cyano_N_(6-methyl_5_(4_(tetrahydro-2H-piperidin-4-yl)methyl)pyridinyl-3-yl)benzamide Indoleamine; 3-fluoro-N-(5-(4-methoxyphenyl)-6-methylpyridin-3-yl)norfosfylbenzamide; N_(5-(4-ethenylbenzene) Methyl Acridine each)_5_third-butyl cyano-2-methoxybenzoic acid; 3-(aminomethyl)-5-third-butyl Ν Ν (5·(4·( 1-hydroxyethyl)phenyl)methylpyridin-3-yl)-2-methoxybenzamide; 5-tris-butyl-3-(N-hydroxycarbamidoimido) _N minutes...(1_(imido)ethyl)phenyl)-6-mercaptopyridine_3_yl>2-methoxybenzamide; 5L (3·th-butylcyano) Benzylguanidino)-2,-methyl-N-((tetrahydrofuran-2-yl)methyl)-2,3'-biindole-5-carbamide; 123505 -124- 200815422 5H3- Tri-butyl-5-cyanobenzoguanamine)-2'-mercapto ((tetrahydrofuran-2-yl)methyl)-3,3,-bipyridyl-6-carboxamide; 3-different -butyl-5-cyano-N-(6-fluorenyl-5-(4-(hexahydroexo b唆-1-ylamino)phenyl]>pyridin-3-yl)benzene Guanidine; 3-tert-butyl-5-cyano-N-(6-methyl-5-(4-(N-neopentylamine sulfonyl)phenyl)pyridine-3-yl)benzene Indoleamine; 1-(5-(3-fluoro-5-m-fosyl phenylamino)-2-methyl-pyridyl)-N-((tetrahydrofuran-2-yl)methyl) -1Η-1,2,3-triazole ice carboguanamine; N-(5-(4-tri-butyl-1) H_1,2,3_triazole small group) each methylpyridyl)-3-dunk-5-morpholinebenzamide; 3-fluoro_N-(6-methyl-5-(4) -(Exopurin-2-yl)_1Η·1,2,3-triterpenoid) π ratio σ1 - yl)-5-morphine-based benzamide; 3-fluoro-N-( 5-(4-(Methoxymethyl)-1Η-1,2,3-trian-1-yl)-6-methyl p ratio. ·3_yl)-5-morpholinebenzamide; 1-(5-(3-tri-butyl-5-cyanobenzoyl)-2-mercaptopurine- 3-yl)-N·* neopentyl-1Η-1,2,3-triazole-4-carboxyguanamine; 3-tert-butyl-5-cyano-indole-(6-methyl- 5-(4-(3-methylbutyryl)_1Η-1,2,3_triazol-1-yl)pyridin-3-yl)phenylhydrazine; (Ζ)-3-tris-butylcyano -N-(5-(4-(l-(imido)-3-methylbutyl)_1H-1,2,3-tris-l-l-yl)-6-mercapto-p-bit-3 -yl)benzamine; 3-tris-butyl-5-cyano-N-(6-methyl-5-(4-(2-methyl-1-(neopentylamino)) small Ketopropylpropan-2-yl)-1Η-1,2,3-triazin-1-yl)-external b °-3-yl)benzamine; N-(3-tri-butyl- 5-cyanophenyl)-6-methyl-5-(4-(neopentylcarbamate)-1Η2,2,3·triazole small) nicotine amide; 123505 •125· 200815422 heart (6•Methyl-5-(4-(neopentylcarbinyl)-ml, 2,3-triazol-1-yl wind bite! Base)_2_isofenyl is different from acid test amine; Team (6-methyl-5-(4-(neopentylcarbamyl)-111-1,2,3-triazole small group> than bit _3-yl)-2-(hexahydropyridine Small base) isonicotinic acid amide; 3_fluorine -N-(6-methyl-5-(3-(neopentylcarbinyl)phenyl), pyridyl group >5-fyfrylinylbenzamide; 3-third 5--5-cyano-N-(5-(3-(dimethylaminocarbamido)phenyl)-6-mercaptopyridin-3-yl)benzamide; 1-(5-(5) -Third-butyl-2-methoxybenzimidamide)-mercaptopyridine _3_yl)·Ν·neopentyl·1Η_1,2,3-triazole winter carboxamide; 1-(5 -(3-carbyl-5-moffine basic methyl 3&amino)-2-methylindole-3-yl)·»Ν·neopentyl-1Η-1,2,3-triazole -4-carboxyguanamine; 5-tert-butyl-2-methoxy-oxime-(5-(6-methoxyindol-2-yl)methylpyridin-3-yl)benzamide Amine; 3-t-butylcyano-indenyl-(5-(3-(3,3-dimercaptobutylamino)phenyl)pyridinylpyridin-3-yl)benzamide; -(2,6'-dimercapto-3,4'-linked to-5-yl) each fluoro-5-moffylbenzamide; 3-tert-butyl-5-cyanide Ν-Ν-(2,6'-dimethyl-3,4'-linked ρ ϋ _ _5_yl)benzamide; 3-fluoro-indole-(5-(4-decyloxy)- 3-methylphenyl)-6-mercaptopyridine each)-5-moffinyl azelaamine; N-(5-(4-ethylphenylphenyl)-6·methyl batch sigma -3-yl -5-Terti-butyl-2-methoxybenzamide; 123505 -126- 200815422 Ν·(5-(4-Ethylphenyl)methylpyridine _3_yl)_5_ Third _ butyl-2-methoxy-3-(methylsulfonylamino)benzamide; Ν-(5·(4-ethylmercaptophenyl)_6-methylpyridine _3_yl >3_Fluoro-5-homofolinyl benzoguanamine; 仏(5-(4-mercaptoaminocarbamoyl)phenyl)-6-methyl ρ than _3-yl)-5- Third" Butyl-2-methoxybenzylamine; 5-Terti-butyl 4(5-(4-(3,4-dimethoxydecylamino)phenyl)-6 Monomethylpyridin-3-yl>2-methoxybenzamide; 5-di-dibutyl-2-methoxy-N-(5-(4-(3-methoxybenzyl) Aminomethyl)phenyl)-6-methylpyridine-3-yl)benzamide; N-(5-(4-(benzylaminecarbamimidyl)phenyl)-6-methylpyridine 3-yl)-3-fluoro-5-morpholinebenzimidamide; N-(5-(4-(3,5-dimethoxybenzylaminecarbamyl)phenyl>6 _Methyl-pyridyl _3·yl)-3-fluoro-5-moffinylbenzamide; 3-fluoro-N-(5-(4-(3-methoxybenzylamine) Phenyl) phenyl) each methyl octopus · 3 - yl) - 5 - morphine benzoguanamine; 3 · fluoro-N- (5-(4-(4-) Oxybenzylaminocarbamyl)phenyl>6-methyl thiol base)-5-fosfo p-linylbenzamide; N-(5-(4-(benzo[d][ l,3]dioxosulphone-5-ylmethylaminemethane)phenyl)methylpyridin-3-yl)-3-fluoro-5-moffinylbenzamide; 1 -(5-(3-Fluoro-5-norfosfylbenzimidylmethyl oxime-> base)_N-7-pyridyl_3_ylmethyl)-1Η·1,2,3- Triazole carboxy guanamine; 1-(5-(3-ranyl-5-norfosine basic methylamino)_2·methyl V? ratio σ base)·ν g butyl-111-1,2, 3-two-seat-4-Wei-enamine, 123505-127- 200815422 propylmethyl)-1-(5-(3-carbyl-5-morphine-based benzoylamino)-2-methyl Pyridin-3-yl>1H-1,2,3-triazole-4-carboxamide; 1-(5-(3-fluoro-5-morpholinobenzoguanamine)-2 -methylpyridyl)-N-(3,3,3-trifluoropropyl)-1Η-1,2,3-triazole winter carboxamide; 3-fluoro-indole-(6-methyl- 5-(4-((tetrahydro-2Η-piperidin-4-yl)methylaminemethanyl)phenyl)pyridin-3yl)-5-morpholinylbenzamide; 3-fluoro- N-(6-methyl-5-(4-((tetrahydrofuran-2-yl)methylaminemethane)phenyl)pyridine-3-yl)-5-morpholinyl Benzalamine; 5-tris-butyl-N-(5-(4-(3,5-didecyloxydecylaminomethyl)phenyl)-6-methylpyridin-3-yl -2-methoxybenzamide; N-(5-(4-(benzo[d][l,3]dioxosyl-5-ylmethylaminemethanyl)phenyl) _6_methylpyridin-3-yl)-5-tri-butyl-2-methoxybenzamide; 5-tris-butyl-2-methoxy-N-(6-fluorenyl- 5-(4-(pyridin-3-ylmethylaminemethane)phenyl)pyridin-3-yl)benzamide; 5-tris-butyl-2-methoxy_N-(6 -methyl-5-(4-(tetrahydro-2沁piperazin-4-ylaminecarbamimidyl)phenyl)pyridin-3-yl)benzamide; 5_T-butyl-2- methoxy-N-(6-methyl-5-(4-((tetrahydro-2H-piperidinyl)methylaminemethanyl)phenyl)p than sigma-3-yl)benzene Indoleamine; 5-tert-butyl-2-oxooxy-indole-(6-fluorenyl-5-(4-((tetrahydrofuran-2-yl)decylamine)-yl)phenyl)pyridine-3 -yl)benzamide; N-(5-(4-(3,4-dimethoxydecylaminomethyl)phenyl)-6-methylpyridin-3-yl)-3- gas 5--5-Walfine basic ketoamine, 3-fluoro-indole-(6-methyl-5-(4-(pyridin-3-ylmethylamine)methyl)phenyl)pyridine -5-morpholinylbenzamide; 123505 -128- 200815422 4-((4-(5-(5-Tern-butyl-2-methoxybenzoguanamine)> Methylpyridinyl)benzamide amino)methyl)benzoic acid methyl ester; 3ϋ(6-methyl-5-(4-(tetrahydro-2-indole-piperidinylmethylguanidino)phenyl) 3-yl)-5-morphine-based benzoic acid; 4-((4-(5-(3-fluoro)-5-morphobolinylbenzamide)-2-methylpyridine 3-yl)benzamide amino)methyl)benzoic acid methyl ester; 3_second-butyl·5-cyano-N-(6-methyl-5-(4-((tetrahydrofuran-2-) Methylaminomethylmercapto)phenyl)pyridin-3-yl)benzamide; 3-di-butyl-5-cyano-N-(6-methyl-5-(4-( (tetrahydro-2H-fluorenyl) decylamine-methyl hydrazino)phenyl)p-pyridyl-3-yl)benzamide; Ν·(5-(4·(mercaptoamine) Phenyl)_6-methylpyridine·3_yl)-3-tris-butyl-5-cyanobenzoquinone; 1 (5·(3-carbyl-5-rhofosin) Amine amino)-2-methyl ρ ratio σ _3 _)) Ν, Ν _ dimethyl-1 Η-1, 2, 3-three. -4--4-Weiamine; Η2-methyl-5-(3-morpholino-5-(trifluoromethyl)benzylideneamino)pyridine_3_yl)_N-neopentyl _ Ih-1,2,3-triazole-4-carboxyguanamine; H2-methyl-5-(3-(tetrahydropyrrole small)-5-(trifluoromethyl)-benzoguanamine Pyridin-3-yl)-N-neopentyl-1H-1,2,3-triazole-4-carboxyguanamine; ^(5-(3-fluoro-5-(hexahydropyridinium-1) -yl)benzhydrylamino)-2-mercaptopyridin-3-yl)-indole neopentyl-1H-1,2,3-triazole-4-carboxyguanamine; K5-(3-fluoro 5--5-(tetrapyrrole-1·yl)benzimidamide)-2-methylpyridinyl) neopentyl-1H-1,2,3-triazole-4-carboxamide; 1 -(5-(3-carbyl-5-moffinylbenzoylamino)-2-methylp is indol-3-yl)-N-(2-methylbutyl)_1H-1,2 , 3-triazole-4-carboxyguanamine; 123505 • 129-200815422 N-(cyclohexylmethyl)-1-(5-(3-dunyl-5-moffinylbenzamide)_2- Methyl-external b 17-but-3-yl)-1Η-1,2,3-trimethyl-4-propanol; 1-(5-(3-fluoro-5-morpholinebenzamide) Base)-2-methylpyridine_3_yl)_N-((izghydroquinone-pyran-4-yl)methyl)-iH], 2,3s. _4 醯 醯 ;; 1-0 (3 · fluoro-5-homofolinylbenzimidino)-2-methylpyridine each) (2_yl-2-phenylethyl) -1Η-1,2,3-Tris(β)·4_Rebelamine; 1-(5-(3-Fluoro-5-morphobolinylbenzimidamide)_2·methylpyridine_3· Base)-Ν-(1-carbyl-3-methylbutan-2-yl)-1Η-1,2,3-three-pour-wet-weenamine; Ν-(〇ethyltetrahydro is slightly -2_ Methyl)-1-(5-(3-fluoro)-5-morpholinebenzoinyl)_2_methylexyl b σ-3-yl)-lH-l,2,3 - tris-s--4-di-Si amine; 5-tris-butyl-3-cyano-N-(5-(4-((l-ethyltetrahydropyrrol-2-yl)methylamine) Phenyl)-6-methylpyridinyl)·2·methoxybenzamide; 5-tris-butyl-3-cyano-2-methoxy-oxime-(6-A) 5-(4-(1-methylhexahydropyridin-4-ylaminocarbamoyl)phenyl)pyridyl)phenylamine; 5-tris-butyl-3-cyano-2- methoxy-N-(6-methyl-5-(4-((1-methylhexahydropyridinyl)methylamine-methylphenyl)pyridinyl-3-yl)benzamide; 3-_Fluoro-N-(6-methyl-5-(4-(1-methylhexahydropyridyl)carbinyl)phenyl)-p-pyridin-3-yl)_5_moffene-based benzene Hyperthyroidism 3-say-N-(6-methyl-5-(4-((1-methylhexahydropyridin-4-yl)decylaminecarbinyl)phenyl)>pyridin-3-yl) -5-morpholinylbenzamide; 5-tris-butyl-3-cyano-2-methoxy-N-(6-methyl-5-(4-(pyridylmethyl)methyl) Amidino)phenyl)pyridine-3-yl)benzamide; ^(5-(3-carbyl-5-morphobolinylbenzimidyl)-2-methylpyridine) _ team (tetrahydro-2H-pyran-4-yl)-lH-1,2,3-triazole-4-carboxamide; 123505-130- 200815422 N-cyclohexyl small (5-(3-fluoro) ·-cyclopentyl-1-(2) 5-(3-Fluoro-5-morpholinebenzoinyl)-2-methylpyridin-3-yl)-1Η_1,2,3-tris-s--4-propanamide; H5-( 3-fluoro-5-morpholinebenzimidino)_2•methylpyridin-3-yl)·Ν-(3-carbyl-methylpropyl)-11^-1,2,3 - triterpenoid-4-oxoamine; 1-(5-(3-tris-butyl-5-cyanobenzamide)-2-mercaptopyridin-3-yl)-N-(( Tetrahydrofuran-2-yl)indolyl)-iH-l,2,3-triazole-4-carboxamide; 1-(5-(3-tri-butyl; cyano-2-methoxybenzene) Hyperthyroidism ))-2-methylpyridine _3·yl)·1Η·1,2,3-tris-s--4-weilic acid tert-butyl ester; 1-(5-(3-cyano-5-morpholine) Benzobenzamide)-2-methylpyridin-3-yl)((tetrapoxan-2-yl)methyl)-1Η-1,2,3-trisyl-4-propanol; H5-(3.Cyano-5-(hexahydropyridyl)benzimidyl)-2-methylpyridin-3-yl)-N-((tetrahydrofuran-2-yl)methyl)-lH- l,2,3-triazole-4-carboxyguanamine; 1-(5-(3-cyano-5-(tetrahydropyrrol-1-yl)benzamide)-2-mercaptopyridine- 3-yl)·Ν-((tetrahydrofuran-2-yl)methyl)-1Η-1,2,3-triazole-4-carboxamide; N-(5-(4-((l-ethyl) Tetrahydropyrrol-2-yl)methylamine-mercapto)phenyl)methylenepyridin-3-yl)_3_fluoro-5-morpholinebenzamide; 1-(5-(5) _T-butyl-3-cyano-2-indolyl benzoguanidino)-2-mercaptopyridin-3-yl)-N-neopentyl-1Η-1,2,3·triazole -4-carboxyguanamine; 1-(5-(5-tris-butyl-3-cyano-2-methoxybenzamide)-2-methylpyridin-3-yl)-N -(pyridin-3-ylmethyl)-1Η-1,2,3-triazole-4-carboxamide; 1-(5-(3-t-butyl-5-cyanobenzoguanamine) 2-methylpyridine-3- Base) -N-(indolyltetrahydrop-bi-2-yl)indenyl)-1Η·1,2,3-tri. Sit-4-carboxyguanamine; 123505 • 131 - 200815422 3-T-butyl-5-cyano-N-(6-methyl-5-(4-(4-methylhexahydropyrazine-1) -carbonyl)-1Η-1,2,3-triazole small group)pyridin-3-yl)benzamide; 1-(5-(5-tri-butyl-3-cyano-2) Oxyphenylamino)-2-methylpyridin-3-yl)-N-((tetrahydrofuran-2-yl)methyl)-iH-l,2,3-triazole winter carboxamide; 3-Terti-butyl-5-cyano-N-(6-methyl-5-(4-(norfosine)-1Η-1,2,3-3-triazol-1-yl)pyridine- 3-yl)benzamide; 1-(5-(3-tris-butyl-5-cyanobenzamide)-2·methylpyridin-3-yl)-N-(l- Methyl hexahydropyridine ice base > 1H-1,2,3-triazole glacial guanamine; 1-(5-(3-tert-butyl-5-cyanobenzamide)-2 -methylpyridyl)_N-(2-(tetrahydropyrrole small)ethyl)-1Η-1,2,3-triazole-4-carboxyguanamine; 1-(5-(3-third -butyl-5-cyanobenzoguanamine)-2•methylpyridine each::-Ν·(2-(dimethylamino)ethyl)-1Η-1,2,3-triazole -4-carboxyguanamine; 1-(5-(3-tris-butyl-5-cyanobenzoguanidino)-2-mercaptopyridin-3-yl)-N-(2-methoxy Base ethyl)-1Η-1,2,3-three Oxazole-4-carboxyguanamine; 1-(5-(3-tris-butyl-5-cyanobenzoguanamine)-2-methylpyridin-3-yl)-N-0 quinidine 3_yl)·1Η-1,2,3_triazole-4_carboxyguanamine; 1-(5-(3-tert-butyl-5-cyanobenzoyl)-2-methyl Outside the base 1: σ定_3_ base)-team (hexahydropyridin-4-yl)-1沁1,2,3-triazole-4-carboxyguanamine; 1-(5-(3-third· Butyl-5-cyanobenzoguanamine)-2-methylpyridinyl)-N-(hexahydropyridine-3-yl)-1H-1,2,3-triazole-4-carboxyindole Amine; 1-(5-(3-tert-butyl-5-cyanobenzoguanamine)-2-methylpyridine-3-yl)-N-(2-hydroxypropyl)_ih_1,2, 3-triazole-4-carboxyguanamine; K5-(3-fluoro-5-(1,4-oxo-7-phenylindoleyl)phenylamino)-2-methylpyridin-3-yl )-N-((tetrahydrofuran-2-yl)methyl)-1Η_1,2,3-triazole-4-carboxyguanamine; 123505-132- 200815422 l-(5_(3-fluoroyl_5-(four) Hydrogen ti-l-yl-1-phenyl)benzamide)methyl ρ than 唆-3-yl)-indole-((tetrahydromethane-2-yl)methyl)-1Η_1,2,3-three σ 坐 醯 醯 ;; 1-(5-(3-murine-5-(tetrahydroleaf I: oxa-1-yl)benzamide)_2•methyl ρ than -3-yl) -N-neopentyl-1H-1,2,3-triazole- 4-carboxyguanamine; 1-(5-(3-cyano-5-(hexahydro-p-but-1-yl)benzamide)·2·methyl-唆-3-yl)-Ν- Neopentyl-1Η-1,2,3_triazole winter carboxamide; 1-(5-(3-cyano-5-morphobolinylbenzimidyl)_2-mercapto ton. Ding-3-yl)-indole-neopentyl-1H-1,2,3-tris-sodium-4-storied amine; 1-(5-(3-f-yl-5-thio-norfosine) Benzoylamino)_2_methylisoindole-3-yl)~N-xindecyl-1H-1,2,3-di 11 -4-weilan; 1-{5-[3 -Fluoro-5-(1-keto-1 λ 4-stone, ruthenium, phenyl-4-yl)-benzoguanamine group > 2-methyl^pyridin-3-yl}-1Η_ [1,2,3]triazole-4_carboxylic acid (2,2-dimethyl-propyl)-decylamine; 1-(5·(3·th-butyl-5-cyanobenzoic acid) Amidino)-2-mercaptopyridin-3-yl)-N-((l-methylhexahydropyridin-4-yl)methyl)-1Η-1,2,3-triazole-4-carboxylate Indoleamine; 3_di-butyl-5-carbyl-N-(5-(4-(4-(2-ethyl))hexahydro-p ratio" well-1•罗炭基HH-1,2 , 3-triazole small group)-6-methylpyridin-3-yl)benzamide; 1-(5-(3-tri-butyl-5-cyanobenzoguanamine)>2 -pyridylpyridin-3-yl)-N-(2,2,6,6-tetradecylhexahydropyridyl)-1Η-1,2,3-triazole-4-carboxamide; 1- (2-methyl-5-(3-(tetrahydropyrrole small))-5-(trifluoromethyl)phenylaminoamino)-pyridin-3-yl)-N-(pyridin-2-ylmethyl) ··1Η-1,2,3-triazole-4-carboxyguanamine; 1-{5_[3-(1,1_dione--1 long 6·sulfur代福福-4-yl)-5-fluoro-benzylaminoamido]_2-methyl-pyridine each}}1Η_[1,2,3]triazole-4-carboxylic acid (2,2- Dimethyl-propyl)-guanamine; 123505-133- 200815422 1-(5-(3-Terti-butyl-5-cyanobenzoguanamine)-2-methylpyridine_3·yl )-N-depyridin-2-ylmethyl)·ιη_1,2,3-triazole carboxy guanamine; 5-tris-butyl-3-cyano-2-methoxy-oxime-(6 - mercapto-5-(4-(neopentylcarbinyl)phenyl)17-indol-3-yl)benzamide; 3-Momot-5-T-butyl-2-methyl oxy_N-(6-methyl-5-(4-(neopentylcarbinyl)phenyl)p than -3-yl)benzamide; (R)-5-di- Butyl-3-cyano-N_(5-(4-((1-ethyltetrahydrop) υ(2)-yl)methylamine fluorenyl)phenyl)-6-fluorenylpyridine) -2-methoxybenzamide; 1-(5-(3-cyano-5-(hexahydrop to α-1,3-yl)benzimidamide methyl p to bite each base)- Ν10-pyridin-2-ylmethyl)-lH_l,2,3-triazole carboxy guanamine; 3-tert-butyl-5-cyano-oxime (6-methyl_5-(4) -(pyridin-2-ylmethylaminemethanyl)phenyl>pyridin-3-yl)benzamide; Ν-(6-mercapto-5-(4-(pyridin-2-yl) Aminoamine (phenyl)pyridinyl)-3•(tetrahydropyrrol-1-yl)_5·(trifluoromethyl)benzamide; 3·t-butyl-5-cyano·Ν-( 6-Methyl-5-(4-((1-indolylhexahydropyridin-2-yl)methyl-methyl ketone) base group) p-precipitate) benzoic acid; N-(6- Methyl-5-(4-((1-methylhexahydropyridinyl)methylaminemethanyl)phenyl) 峨σ疋-3_yl)-3-(tetrahydrou-bi-l-l-yl) -5-(trifluoromethyl)benzamide; 5-t-butyl-3-cyano-2-methoxyindole-(6-methyl-5-(4-((1) -methylhexahydropyridin-2-yl)methylamine-methyl fluorenyl)-phenyl) acenaphthyl)benzamide; (R)-3_tri-butyl-5-cyano-oxime -(5-(4-((1-ethyltetrahydropyrrol-2-yl)indolyl) 1*methylindolyl)phenyl)-6-methyl-p-but-3-yl)benzamide; (R)-N-(5-(4-((l-ethyltetrahydropyrrole-2yl)methylaminemethanyl)phenyl)methylpyridin-3-yl)-3-ifu Lolinyl-5-(trifluoromethyl)benzamide; 123505-134- 200815422 (R)-N-(5-(4-((l-ethyltetrahydroindole) than u-2-yl) Methylcarbamic acid)phenyl)-6-methylpyridin-3-yl) each (tetrahydropyrrol-1-yl)-5-(trifluoromethyl Benzoguanamine; (R)-N-(5-(4-((l-ethyltetrahydropyrrol-2-yl)methylaminemethanyl)phenyl)-6-methylpyridine-3 -yl)-3-(hexahydropyridin-1-yl)-5-(trifluoromethyl)benzamide; 1-(5-(3-tri-butyl-5-cyanobenzoquinone) Amino)-2-methylpyridin-3-yl)-indole ((1-methylhexahydropyridin-2-yl)methyl)·1Η-1,2,3-triazole-4·carboxyindole Amine; 1-(5-(5-tri-butyl-cyano-2-methoxybenzoguanamine)-2-methylpyridin-3-yl)-N-((l-methyl) Hexahydropyridin-2-yl)methyl)-1Η-1,2,3-triazole-4-carboxamide; 1-(5-(3-tri-butyl-5-cyanobenzoquinone) Amino)-2-methylpyridin-3-yl)-N-cyclohexyl-1H-1,2,3-tri. Sodium-4-destroyed S-amine; 1-(5-(3-t-butyl-5-cyanobenzamide)-2-methylpyridin-3-yl)-N-(hexahydro) Tons bite_1_base)·1Η·1,2,3·three. Sodium-4-Weisamine; 3-tert-butyl-5-cyano-indole-(6-methyl·5-(4-((6-decylpyridin-2-yl)methylamine) Phenyl)pyridin-3-yl)benzamide; 5-tris-butyl-3-cyano-2.methoxyl (6-methyl-5-(4-((6-) Mercaptopyridin-2-yl)methylamine-carboxamidine)phenyl)pyridin-3-yl)benzamide; N-(6-methyl-5-(4-((6-methylpyridine)- 2-yl)methylamine-mercapto)phenyl oxaridin-3-yl)-3-(tetrahydropyrrol-1-yl)-5-(trifluoromethyl)benzamide; 3-second -butyl-5-(6-methyl-5-(4-(neopentylcarbamoyl)-phenyl)acridinemethylamine carbazyl)benzoic acid methyl ester; 3-second-butyl 5-(6-fluorenyl-5-(4-(neopentyl)indolyl)-phenyl)p-pyridylamine-carbamoyl-benzoic acid; N-(6-fluorenyl- 5-(4-(neopentylcarbinyl)phenyl)pyridine-3-yl)_2 <Hexahydropyrazole small base) Isoprostamine; 123505 -135- 200815422 5-Terve-butyl-N1 -(2-(dimethylamino)ethyl)_N31 methyl-5 (New Amylaminocarbazyl)phenyl)-pyridin-3-yl)m-xylyleneamine; 3·fluoro·Ν-(5-(4·(1-(hydroxyimino)ethyl)phenyl) -6-methylpyridyl)_5_morpholinobenzamide; 4-(5-(3-tris-butyl-5-cyanobenzamide)-2-methylpyridine! Methyl benzoate; 1-(5-(3-tri-butyl-5-cyanobenzylidinium)-2-methylpyridine-3-yl)-1Η-1,2,3- Ethyl triazole-4-carboxylate; 1-(5-(3-tris-butyl-5-cyanobenzoguanidino)-2-methylpyridyl)-team (2-(2-B) Amino)ethyl)-exo-1,2,3-triazole-4-carboxamide; 1-(5-(3-tris-butyl-5-cyanobenzamide)-2 -methylpyridine-3-yl)-N-(2-(diisopropylamino)ethyl wh-W}triazole-4-carboxyguanamine; 1-(5-(3-tri-butyl-) 5-cyanobenzylamino)-2-methylpyridine; yl)-N-(2-methyl-2-(hexahydropyridin-1-yl)propyl)_ih-1,2,3- Triazole-4·carboxycarboxamide; 1-(5-(3-t-butyl-5-cyanobenzamide)_2-methylpyridinium Alkyl)_N_((1-(hexahydropyridin-1-yl)cyclohexyl)methyl)_1H-1,2,3-triazole-4-carboxamide; N-(6-methyl-5 -(4-(neopentylaminomethyl)phenyl)-pyridyl-3-yl)-2-ifolinyl is different from decylamine; 3-cyano-N-(6-mercapto-5 -(4-((6-methylpyridin-2-yl)methylamine fluorenyl) phenyl)>pyridyl_3_yl)-5 oxalinylbenzamide; 3-cyano- N-(6-Methyl-5-(4-((6-methylpyridin-2-yl)methylaminemethanyl)pyridinyl-3-yl)-5-(tetrahydropyrrole small group Benzoguanamine; 3-cyano-N-(6-methyl-5-(4-((6-methylpyridin-2-yl)methylaminemethanyl)phenyl acridine-3- 5-(5-(5-tris-butyl-3-cyano-2-nonyloxybenzoguanamine) 4-(5-(5-tris-butyl-3-cyano-2-nonyloxybenzoguanamine) Methyl)-2-methyl p-pyridyl-3-yl)methyl benzoate; 3-tert-butyl-5-cyano-indole-(5-(4-(cyclohexylamine fluorenyl)) Phenyl)-6-fluorenylpyridin-3-yl)benzamide; 3-tris-butyl-5-cyano-indole-(5-(4-(2)(diethylamino)) Amino) phenyl)-6-methylpyridin-3-yl)benzamide; 3-tert-butyl-5-cyano-N-(5-(4) -(2-(diisopropylamino)ethylamine fluorenyl)phenyl)-6-methyl-n--3-yl)benzamide; 3-tert-butyl-5-cyanide --N-(6-fluorenyl-5-(4-(2-mercapto-2-(hexahydropyridin-1-yl)propylaminemethanyl)phenyl>pyridin-3-yl) Benzylamine; 3-tert-butyl-5-cyano-N-(6-methyl-5-(4-((1-(hexahydropurine-1)ylcyclohexyl)methyl) Aminomethyl hydrazino) phenyl hydrazin-3-yl) benzamide; 3-tert-butyl-5-(((2-methoxyethyl)(methyl)amino) fluorenyl Mercapto-5-(4-(neopentylcarbinyl)phenyl)-indole[rho]-but-3-yl)benzamide; 3-tri-butyl-(6-methyl-5-( 4-(neopentylamine decyl)phenyl(tetra)pyridinyl-3-yl)·5_(tetrahydropyrrole-1-ylmethyl)benzamide; 3-tris-butyl-indole-(6- Methyl-5-(4-(neopentylcarbinyl)phenyl), pyridinyl-3-yl)-5-(hexahydropyridin-1ylmethyl)phenylhydrazine; 3-fluoro-N -(5-(4-(l-hydroxyethyl)phenyl)methylpyridin-3-yl)-5-morpholinebenzamide; 1-(5-(3-third-butyl) 5--5-cyanobenzoylamino)_2-methylpyridyl)_N_morphine--111-1,2,3-tris--4-wei Amine; 1-(5-(3-di-di-butyl-5-cyanobenzoguanamine)> 2-methylu-specific base hydrogen)-2H-misan-4-yl)_ih- 1,2,3-triazole-4-carboxyguanamine; 123505 •137- 200815422 5-tris-butyl-3-cyano-indole·(5-(4-(cyclohexylamine fluorenyl)benzene )6_曱pyridin-3-yl)-2-methoxybenzamide; 5-di-dibutyl-3-cyano-2-methoxy oxime-(6-methyl- 5-(4-(hexahydrop-Bit-1-ylamine)-phenyl)p-p--3-yl)benzamide; 5-tris-butyl-3-ylcyano-2 -Methoxy-indole-(6. fluorenyl-5-(4-(tetrahydro-2-indole-pyran-4-yl-moon-female &&>) base) ρ ratio _3_ base Benzoylamine; 5-di-di-butyl-3-cyano-2.methoxy-indole-(6-methyl-5-(4-(moffinyl)-phenyl)phenyl) ~~τι定-3·yl)benzamide; 3-tert-tributyl-N-(6-methyl-5-(4-(neopentylcarbinyl)phenyl) 唆_3_ Base)-5-((4-methylhexahydro-p-butan-1-yl)methyl)benzamide; 3-tris-butyl-indole-(6-methyl-5-(4) -(neopentylamine fluorenyl)phenyl butyl)-5-(((tetrahydrofuran-2-yl)methylamino)methyl)benzamide; 3-third- -N-(6-methyl-5-(4-(neopentylamino)phenyl)-pyridin-3-yl)-5-((propan-2-ynylamino)methyl)benzene Methionine; 3-tert-butyl-N-(6-methyl-5-(4-(neopentylamino)phenyl]pyridin-3-yl)-5-(morphine Methyl)benzamide; 3-t-butyl-N-(6-methyl-5-(4-(neopentylcarbinyl)phenyl) -((3-ketohexahydropyrrol-1-yl)methyl)benzamide; 3-tris-butyl-N-(5-(4-(2-T-butyl) Base) triterpenoid) winter methylpyridin-3-yl)-5-cyanobenzamide; 3-tert-butyl-5-cyano-N-(5_(4-(2-ring) Hexyl quinone) _ih_1,2,3-triwax-yl>6-decylpyridin-3-yl)benzamide; 1·(5-(3-tri-butyl-5-) Cyanobenzylamino group > 2-mercapto p ratio. Each base)-Ν-(2,6-dimethylhexahydroindole σ-decyl-1-yl)-1Η-1,2,3_three-prop-4-amine; 123505-138- 200815422 N- (6-Methyl-5-Pentyl (neopentylaminomethane)phenyl)-pyridyl substrate (tetrahydro port ratio σ each small group) is different from the test amine; 3-tert-butyl-hydrazine -(6-methyl-5-(4-(neopentylcarbinyl)phenyl)-pyridyl)-5-((2-(indolyl)ethylamino)methyl)-benzene Methionine; 3-tert-butyl-5-(((L(dimethylamino)ethyl)(methyl)amino)indolyl)-N-(6-methyl-5-(4- (nethiononyl) phenyl)-pyridyl) benzoguanamine; di-butyl-5-cyano-N-(6-methyl-5-(4-() Hydrazinyl)phenyl)pyridin-3-ylbenzamide; 3-tert-butyl-(5-(4-(2-tri-butyl-carbonyl)phenyl) Aminopyridin-3-yl)-5-cyanobenzoic acid amine; 3-tert-butyl·5-cyano-N-(5-(4-(2-cyclohexylhydrazinocarbonyl)-phenyl) winter Methylpyridin-3-yl)benzamide; 5_T-butyl-indole·5·(4-(2-Tertiary-butylindolecarbonyl)phenyl)-6-methylpyridine- 3-yl)-3-cyano-2-methoxybenzamide; ^(5-(3-fluoro-2-) Methoxy-5-morpholinylbenzimidino)-2-methylpyrrolidine-3-yl>N-neopentyl-1H-1,2,3-triazole-4-carboxylate Indoleamine; ^(5-(3-fluoro-2-methoxy-5-morphobolinylbenzimidyl)-2-methylpyridin-3-yl)((tetrahydrofuran-2-yl) Methyl)-1Η-1,2,3·triazole-4_carboxamide; Κ5-(3-fluoro-2-methoxy-5-morpholinebenzimidyl)-2- Methylpyridine-3-yl)-N heptadineylmethyl)-lH-l,2,3-triazole-4-carboxamide; 3-1-yl-2-methoxy-N-( 6-methyl-5-(4-(pyridin-3-ylmethylaminemethanyl)phenyl>butyl-3-yl)-5-norfosylbenzamide; 3-fluoro 2-methoxy-N-(6-methyl-5-(4-((tetrahydrofuran-2-yl)methylamine)-phenyl)pyridin-3-yl)-5-morpholine Benzobenzamide; 123505 -139- 200815422 3 far-base 1 methoxy-N-(6-methyl-5-(4-(neopentylcarbinyl)phenyl)-pyridyl) _5_morpholinobenzamide; 3 di-butyl-4·cyano-N-(5-(4-(2,6-dimethylhexahydroexo 1: indole-1-ylamine) Phenyl)-6-methylpyridine-3-yl)benzamide; 5-second-butyl-3-cyano-N-(5-(4-(2,6-dimethyl) six Hydropyridine small amine amine methyl ketone) phenyl) _6-methyl pyridine each) _2 methoxy benzyl carbamide; 1- (5-(5-tri-butyl _3 cyanomethoxy) Benzobenzamide)-2-methylpyridyl-chromium-^ dimethylhexahydropyridine+yl"-phantom-triazole ice-carboxamide; 1-(5-(5-tri-butyl) _3_Cyano-2-methoxybenzimidino)-2-methylpyridin-3-yl)-N-(hexahydropyridine-μ-dipyridinium-triazole-carboxamide; 5_T-butyl-N-(5-(4-(2-tris-butylfluorenylcarbonyl)-iH-l,2,3-triazol-1-yl)-6-methylpyridine- 3-yl>3-cyano-2-methoxybenzamide; 1-(5-(3-tri-butyl-5-(hhofolinylmethyl)benzamide) _2_曱-ylpyridin-3-yl)-N-neopentyl-1H-1,2,3-tris-s--4-carbylamine; 5-tris-butyl-3-cyano-N- (5-(4-(2-cyclohexylindolecarbonyl)_1H-1,2,3-triazole small)-6-methylpyridine-3-yl)_2-methoxybenzamide; (5-(3-Terve-butyl-5-((4-methylhexahydropyridinyl))methyl)benzhydryl)_2_methylton-3-yl>N - Neopentyl_1114, 2, 3_three. -4 -Wylanamine; 3-cyano-N-(6-fluorenyl-5-(4-(neopentylcarbinyl)phenyl)-pyridyl)-5-morpholinyl Benzoamide; N-(5-tert-butyl-3-ylcyano-2-methoxyphenyl)-6-methyl-5-(4-(neopentylamine)-hydrazine -1,2,3-tris-s-l-yl) for the determination of decylamine; N-(3-cyano-5-morphofylphenyl)_6-methyl_5-(4-(neopentyl) Aminomethylmercapto)-1Η-1,2,3-triazol-1-yl)nicotinium amide; 123505-140· 200815422 N-(3-fluoro-5-moffolinylphenyl) 5-(4-(neopentylcarbamoyl)-1 - 1,2,3-trian-1-yl) in acid-amine; N-(3-tri-butyl-1- Methyl-lH-p is more than sal-5-yl)-6-methyl-5-(4·(neopentylcarbamyl)_1Η-1,2,3_tris-s--1-yl) Amine; 1-(5-(3-((lS,5R)_8.Oxy-3-nitrobisbicyclo[3.2.1]oct-3-yl)-5-fluorophenylhydrazinyl)- 2-methylpyridin-3-yl)-N-neopentyl-1Η-1,2,3-triazole glacial guanamine; 3-cyano-indole-(6-methyl-5-(4- ((tetrahydrofuran-2-yl)methylamine-methyl hydrazino)phenyl), anthracenyl-3-yl)-5-moffinylbenzamide; 3-cyano-N-(6-methyl -5-(4-indolepyridylmethylaminemethine Phenyl)-pyridin-3-yl)-5-morphine 4-phenylbenzamide; N-(3-tert-butylphenyl)-6-methyl-5-(4-( Neopentylamine thiol)-1Η-1,2,3-tris-s--1-yl) in the amine; N-(5-tris-butyl-2-methoxyphenyl)_6_A Base-oxime (4 gas neopentylamine methyl hydrazino)-1Η_1,2,3·triazole-1_yl) in the base amide; 2_(3_Third-butyl-5-(6-methyl) -5-(4-(neopentylaminomethane)-oxime-1,2,3-triazin-1-yl)p-pyridin-3-ylaminemethanyl)-amino-amino)acetic acid _ butyl ester; 2-(3-tert-butyl-5-(6-methyl-5-(4-(neopentylcarbenyl)phenyl ypyridin-3-ylaminecarbamyl) Tert-butyl ester; 2-(3-tert-butyl-5-(6-methyl-5-(4-(neopentylaminomethyl)phenyl)>胺·(5-(4-(8-oxo-3-nitro-bicyclo[m]octanecarbonyl)phenyl)methylmethylpyridin-3-yl 3-tert-butyl-5-cyanobenzamide; Ν-(5-(4-(8-oxo-3-nitro-bicyclo[3·2·1]octane-3- Carbonyl)-1Η-1,2,3-triazol-1-yl group>6-methylpyridine_3_yl)_5_third-butyl_3_cyano-m-methoxybenzamide;123505 -141 - 200815422 3_T-Butyl-5-cyano-indole·(6-methyl-5-(4-(2,2,6,6-tetramethylmorpholine-4-carbonyl) Phenyl) indole-3-yl)phenylhydrazine; 5-tris-butyl-3-cyano-2-methoxy-N-(6-methyl-5-(4-(2) , 2,6,6-tetramethylfosfosin-4-carbonyl)-1Η-1,2,3-triazole-l-yl>pyr-3-yl)benzamide; N-( 5-(4-(8-oxo-3-nitro-bicyclo[3.2_1]octane carbonyl)-iH-l,2,3-triazol-1-yl)-6-mercaptopyridine-3- Each of the third-butyl-5-cyanobenzamide; 3-di-dibutyl group _N_(6-methyl-5-(4-(2,2,6,6-four)曱基福福琳-4·carbonyl)-1Η_1,2,3-triazole-l-yl>pyridin-3-yl)benzamide; N-(5-tri-butyl-3- Aminomethylmercapto-2-methoxyphenyl)-6-methyl-5-(4-(neopentylamino)-1Η-1,2,3-tris-s--1-yl) Indoleamine; N-(5-tert-butyl-3-(cyclopropylaminoindenyl)-2-methoxyphenyl)·6•methyl-5-(4-(neopentylamine)醯-)-(1,2,3-tris-small group) in the test of decylamine; Ν-(5-tris-butyl-2-methoxy-3-(methylsulfonylamino)benzene Base)_6_mercapto-5-(4-(neopentylaminomethane)-1Η-1,2,3-嗤-1-yl) in the test of decylamine; N-(5-(4-(8-oxo-3-nitro-bicyclo[3·2·1] octyl-3-phenyl)phenyl)-6 _mercapto p-pyridin-3-yl)-5-tris-butyl-3-cyano-2-methoxybenzamide; 5-tris-butyl-3-cyano-2-曱oxy·Ν-(6-fluorenyl-5-(4-(2,2,6,6-tetramethylmorpholine·4-carbonyl)phenyl)pyridin-3-yl)benzamide ; 5-Terti-butyl-3-cyano-2-methoxy-oxime-{6-methyl-5-[4-(1〇-oxo-4-nitro-tricyclo[5_2丄02 , 6]decane-4-carbonyl)-phenyl]•pyridyl}}-benzamide; 5_t-butyl-3-cyano-2-methoxy_Ν-{6-曱-5-[4-(1〇-Oxygen, nitrogen, tricyclo[5·2·1.02,6]decane_4_carbonyl)-[1,2,3]triazol-1-yl]- Pyridin-3-yl bromide; 3-second-butyl-5-muro-indole-{6-mercapto-5-[4-(10-oxo-4-nitro-tricyclo-123505) -142- 200815422 [5·2·1·〇2,6]癸烧_4_carbonyl 叩二习王唑_卜基]_峨pyridine I benzylbenzamide; 3 a second-butyl- 5-cyano group|{6-mercapto-5-[4_(l〇-oxygen oxime_tricyclo[5·2·1·02,6] 癸 冰 几 )) _ phenyl p than each丨 苯 苯 醯 醯 ;; 3- · 丁基 Ν Ν ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( Benzyl)phenylpyridinyl)-5-((2-(methylsulfinyl)ethylamino)methyl)benzamide; second-butyl·Ν-(6-fluorenyl) -5_(4_(neopentylcarbinyl)phenyl)-pyridyl)-5-((2-(methylsulfonyl)ethylamino)methyl)phenylamine; N-(3 - a third butyl 5-5 cyanophenyl) methyl (4) (hexahydropyridine small carbyl carbhydryl)-1 Η-1,2,3-triazol-1-yl) decyl decylamine; N-(5-Terve-butyl-2-methoxy-3-(methylsulfonylamino)phenyl)-6-methyl-5-(4.(hexahydropyridine small amide) Base)-1Η-1,2,3-triazole small group) nicotine decylamine; N-(5-tert-butylcyanocyano-2-methoxyphenyl>6-methyl-5- (4-(hexahydropyridylaminemethyl)·1Η-1,2,3-tris-s-l-yl) in the amine; 1-(5-(5-tri-butyl-3-cyanide) Benzyl-2-(2-(4.methylhexahydropyroxy-1-yl)ethoxy), methionyl)-2-methylindole sigma)-N-neopentyl Salivation 4-carboamine; 5-tris-butyl-3-cyano-N-(6-methyl-5-(4-(neopentylcarbinyl)phenyl)-pyridine) -2-(2-(4-methylhexahydropyridin-μ)ethoxy)benzamide; 3-cyano-good (6-A) -5-(4_(N_neopentylamine sulfonyl)phenyl oxaridinyl)-5-morphine-based benzoylamine; 3·cyano-N-(6-methyl-5- (4-(N-Pentylamine sulfonyl) phenyl wind bite _3_yl)-5-(tetrahydropyrrol-1-yl)benzamide; 5-tris-butyl-3- Cyano-2-methoxy-indole-(6-methyl-5-(4-(N-neopentylamine sulphate)phenyl)pyridinyl 1 benzyl)benzamide; 123505 -143- 200815422 N -(6-methyl_5_(4-(neopentylcarbinyl)phenyl)4 is a bit of each base) iso- τι: tern-3-carboxyguanamine; 3_third-butyl-1- Mercapto-indole-(6-methyl-5-(4-(neopentylcarbinyl)phenyl)pyridin-3-yl)-1Η-pyrazole-5-carboxamide; 5- Tri-butyl-2-methyl-oxime (6-methyl-5-(4-(neopentylcarbamoyl)-phenyl)pyridin-3-yl)furan-3-carboxamide; 3-tert-butyl-N-(6-methyl-5-(4-(neopentyl)indolyl)phenyl)indole-3-yl)-1Η-pyrazole-5-carboxyindole Amine; 5_Third-butyl-hydrazine-(6-methyl-5-(4·(neopentylamine oxime)phenyl)_ρ ratio base) isoxazole-3-carboxyguanamine; 1-(5-(3-Terve-butyl-5-cyanobenzamide)-2-ethylpyridine-3-yl)-indole_neopentyl-1 Η-1,2,3-triazole-4-carboxamide; 5-tris-butyl-Ν1-methyl-Ν3 -(6-methyl-5-(4-(neopentylamine) Phenyl)pyridin-3-yl)m-xylylenediamine; 5-tris-butyl-indole-1 -cyclopropyl-indole-3-(6-methyl-5-(4-(neopentylamine) Mercapto) phenyl)pyridin-3-yl)m-xylyleneamine; 5-tris-butyl-N1-(cyclopropylmethyl)-N3-(6-methyl-5-(4) -(neopentylamine oxime & base) kebido-3-yl)isophthalic acid amine; 5-tris-butyl-N1 -(6-methyl-5-(4-(new Amylaminomethyl phenyl) phenyl azide -3-yl) m-xylylenediamine; H5-(3-fluoro-5-homofolinylbenzimidyl)_2-methylpyridine )-1Η-1,2,3-triazole-4-carboxylic acid ethyl ester; 3-tert-butyl-5-(6-methyl-5-(4-(neopentylcarbamyl)) _ih4,2,3-triazol-1-yl)p than -3--3-aminocarbamoyl)benzoic acid methyl; 123505 -144- 200815422 H5-(3-fluoro-5-(trifluoromethyl) Benzo) benzylaminomethylpyridinyl) with neopentyl-1H-1,2,3-triazole-4-carboxamide; 3_tri-butyl-5_(6-methylxin Amylamine methyl hydrazino)_1H_1,2,3-triazole small oxazolidine carbaryl benzoic acid 5-(3-Terve-butyl-5-cyanobenzamide)-2-methyl each (4-(neopentylaminomethyl)phenyl)pyridine 1-oxide; 5- (3-Tertiary-butylcyanobenzimidino)_2-methyl each (p-amylamine-methylhydrazino)-1H-1,2,3-triazole small) pyridinium-oxide; Second-butyl-Nl <Cyclopropylmethyl)-N3 -(6-methyl-5-(4-(neopentylcarbamoyl)-1Η-1,2,3-triazol-1-yl)p-pyridinium Each base) m-xylyleneamine; 1-(5-(2,5-dimethoxycarbamylaminomethylpyridyl neopentyl-1H-1,2,3-three-seat-4· a few amines; 5-tris-butyl-indenyl-methyl-N3_(6•indolyl_5_(4_(neopentylcarbamyl)-1Η_1,2,3-diazole+yl] ratio Iridinyl) m-xylyleneamine; 3-cyano-5-(4-methyl-1H-imidazole+ylmethyl-5 pentyl (neopentylaminomethyl)phenyl)pyrene 嚏3 Benzylamine; H2-mercapto-5-(3-(4-methyl-1H-imidazol-1-yl)-5(trifluoromethyl)benzylideneamine> ))-N_neopentyl_1, 1,2,3-triazole _4_weisamine; H5-(3-cyanomethyl-1 Η-imidazole+yl)benzamide)_2_ Methylpyridinyl)_Ν_neopentyl-1Η-1,2,3-triazole-4,carboxamide; 1-(5-(3-second-butyl-5-cyanobenzoate) Amidino)_2-methylpyridine-> yl) 4 (3,2,2,2-dimethylpropyl)-, 1,2,3-tri-ammonium tremamine; (RH-(5) -(3-Tertiary-butyl-5-cyanobenzamide)_2-methylpyridine·3_yl»^((tetrahydrofuran_2•yl) )methyl>1H_U,3_triazole ice carboguanamine; 123505-145- 200815422 (S)-l-(5-(3-tert-butyl-5-cyanobenzamide)_2 _Methylpyridine_3·yl)-1^-((tetrahydrofuran-2-yl)methyl)-11^_1,2,3-trimethyl-4-dexamine; 1-(5- (5-Third-butyl-3-cyano-2-methoxybenzimidyl)_2-methylpyridin-3-yl)-N-((l-ylcyclopropyl)methyl -iH-l,2,3-triterpene carbarylamine; 1-(5-(3,5-bistrimethylethylammonium benzhydryl)-2-methylpyridin-3-yl -N-neopentyl-1H-1,2,3-trimethyl-4-propanol; N-(3-t-butyl-5-cyanophenyl)-6-methyl-5 -(4-(neopentylaminomethane)phenyl)nicotinium amide; N-(5-tris-butyl-3-cyano-2-methoxyphenyl)methyl-5- (4-(neopentylcarbamoyl)phenyl) in proline; 5-tris-butyl-3-cyano-indole-(5-(4-(3.hydroxy-2,2-) Dimercaptopropylamine-mercapto)phenyl)-6-fluorenylpyridin-3-yl)-2-methoxybenzamide; 5·T-butyl-3-cyano-Ν -(5-(4-((1-)-cyclopropyl)methylamino) benzyl)-6-methyl-P-pyridin-3-yl)-2-methoxybenzyl Amine; 1-(5-(5- Tri-butyl-3-cyano-2-indolyl phenylamino)-2-methylpyridin-3-yl)-N-(3-hydroxy-2,2-dimethylpropyl) ·1Η-1,2,3-triazole-4-carboxyguanamine; 1-(5-(3-tri-butyl-5-(n-propylaminesulfonyl)phenylhydrazinyl) -2-mercaptopyridine-3-yl)-N-neopentyl-1H-1,2,3-triazole-4-carboxyguanamine; 1-(5-(3,5-bis(neopentyloxy) Phenylamino)_2-methylpyridinyl)-N-neopentyl-1Η·1,2,3-tris--4-indolylamine; 3-di-tert-butyl group- Ν·(5·(4_(3-carbyl-2,2-dimethylpropylamine oxime)phenyl)-6(methylpyridin-3-yl)benzamide; 3-third- Butyl-5-cyano-N-(5-(4-((l-propylcyclopropyl)decylamine decyl)phenyl)-6-mercaptopyridin-3-yl)benzimidazole Amine; 123505 -146- 200815422 5-Terti-butyl_Νι,Νι _Dimethyl_n3 _(6_曱基净(4_(neopentylamino)phenyl acridine-3-yl M-xylguanamine; Ν-(5-(4-(2-amino-2-methylpropylaminecarbamimidyl)phenyl)methylpyrazine>3-third-butyl 5-(cyanobenzamide); ^(2-methyl-5-(3-trimethylsulfonylaminobenzamide)pyridine-3-yl) Neopentyl_1Η_1,2,3-triazole-4-carboxamide; 5-t-butyl-anthracene 1-(6-methyl-5-(4-((tetrahydrofuran-2-yl)) fluorenyl) Amidino)amino)p)-3-yl)-N3-7-methyl-3-m-xylylenediamine; 1-(5-(5-tributyl)- 2-methoxyxynitrophenylamino)-2-methylpyridin-3-yl)-N-neopentyl-1H-1,2,3-triazole-4-carboxamide; 5-tert-Butyl-2-oxooxy-N-(6-mercapto-5-(4-(neopentylcarbenyl)phenyl)- external b °--3-yl)-3 - schiffyl benzoguanamine; (R)-l-(5-(5-tris-butyl-2.methoxy.3.(tetrahydropyrrole-2.carboguanamine)) -2-methylpyridin-3-yl)-indole-neopentyl-1Η-1,2,3-triazole-4-retaining amine; ((R)-N-(5-tert-butyl -2-methoxy-3-(6-methyl-5-(4-(neopentylcarbinyl)phenyl acridine·3_ylaminecarbinyl)phenyl)tetrahydropyrrole stomach 2 _ Carboxylamidine; 5-Terti-butyl-indole-1 -(6-methyl-5-(4-(neopentylcarbamoyl)phenyl azide 1 base)-N3 -(pyridine each Benzyl decylamine; N-(5-tert-butyl-2-methoxy-3-(6-methyl-5-(4-(neopentylaminomethyl) phenyl) )峨-3·ylaminocarboxylic acid)phenyl)-5-ketotetrahydro π each-2·rebel amine; 5-tri-butyl each (1H-imidazole-1-yl)-2-methoxy -N-(6-methyl-5-(4-(neopentylcarbinyl)phenyl)pyridin-3-yl)benzamide; 1-(5-(5-third-butyl) 3-(1Η-imidazole-μ-yl)-2-methoxybenzimidyl)-2- 123505 -147- 200815422 Methylpyridin-3-yl >N-neopentyl-1H-1 , 2,3-triazole-4-carboxyguanamine; 3-di-dibutyl-5-(6-methyl-5-(4-((tetramethylpyran-2-yl)methylamine) Styrene) phenyl)pyridin-3-ylaminocarbamoyl)benzoic acid methyl ester; 3-tert-butyl-5-cyano-N-(6-methyl-5-(4-(2-) (hexahydropyridine small) etidinyl)phenyl)pyridin-3-yl)benzamide; 3-(5-(3-tert-butyl-5-methoxybenzamide) -2-decylpyridin-3-yl)-N-neopentyl-1H-1,2,3-triazole-4-carboxamide; 3-tert-butyl-5-decyloxy-N -(6-methyl-5-(4-(neopentylcarbinyl)phenyl)pyridin-3-yl)benzamide; 3_t-butyl-5-(6-fluorenyl- 5-(4-((tetrahydrofuran-2-yl)methylaminemethanyl)phenyl)pyridin-3-ylaminecarbazyl)benzoic acid; 5_Third-butyl -N1 , Ν 1 -dimethyl-N3 -(6-methyl-5-(4-((tetrahydrofuran-2-yl)methylaminemethanyl)phenyl)pyridin-3-yl)-phenylene Dimethylamine; 5-tert-butyl-N1-methoxy-N1-methyl-N3-(6-methyl-5-(4-((tetrahydrofuran-2-yl)decylamine) Phenyl)pyridin-3-yl)m-xylylenediamine; 3-tert-butyl-N-(6-methyl-5-(4-(neopentylamino)phenyl)戒 啶 -3-yl)-5-(2-morpholinoethoxy)benzamide; 5-tris-butyl-2-methoxy-3-(4-methyl-1H -imidazol-1-yl)·Ν·(6·methyl-5-(4-(neopentylcarbenyl)phenyl)pyridin-3-yl)benzamide; 1-(5-( 5-tri-butyl-2-methoxy-3·(4-methyl-1H-imidazolyl) benzylideneamino)-2-methyl 唆-3-yl)-N-new pentyl-1H-1,2,3-triterpenoid-4-propanol; 5-tris-butylhydroxycyclopropyl)methyl)-N3-(6-methyl-5-(4- ((tetrahydrofuran-2-yl)methylamine-methyl hydrazino)phenyl oxaridin-3-yl)m-xylylenediamine; 5_T-butyl-3-cyano-N-(5_(4) -(cyclopentylaminecarbamimidyl)phenyl)-6-methyl 123505 -148- 200815422 pyridin-3-yl)-2-methoxybenzamide 5-second-butyl-3-cyano-indole·(5-(4-(4,4-difluorocyclohexylamine)methyl)phenyl)-6-methylpyridine-3-yl)- 2-methoxybenzamide; 5-dibutyl-butyl-3-cyano-N-(5-(4-(isopropylaminecarbamido)phenyl)methylpyridine-3- 2-methoxy-2-phenylbenzamine; 5_second-butyl-3-cyano-indole-(5·(4·(isobutylamine)methyl)phenyl)-6-A Pyridin-3-yl)-2-methoxybenzimidamide; dibutyl-3-cyano-indole-(5-(4.(cyclopropylaminomethyl)phenyl)-anthracene Pyridyl-3-yl)-2-nonyloxybenzamine; 5-tris-butylcyano-2-methoxy-N-(6-methyl-5-(4-(2) -(hexahydropyridine-μ-yl)ethenyl)phenyl)pyridin-3-yl)benzamide; 5-dibutyl-butyl-5-(4-(neopentylcarbamyl)- ΐΗ-1,2,3-trisino-1-ylidazin-3-yl)_N3-(2-(tetrahydropyrrol-1-yl)ethyl)m-xylyleneamine; 5-different Butyl-N1%-methyl-5-(4-(neopentylamine)-yota-1,2,3-triazole·1_yl>pyridinyl)-Ν3-(( 1-methylhexahydropyridin-2-yl)methyl)m-xylyleneamine; 5-tris-butyl-3.cyano_N-(5-(4-((lr,4) r) -4-hydroxycyclohexylamine carbhydryl) phenyl)-6-methyl p ratio. Benz-3-yl)-2-methoxybenzamide; N-(5-(4-((lR,2R,4S)·bicyclo[2.2.1]heptan-2-ylaminocarbamoyl) Phenyl) winter methyl leaf 1: indole-3-yl)·5-tris-butyl-3-cyano-2-methoxybenzamide; 5-di-dibutyl-3- Gas-indole-(5-(4-(3-propylaminomethylmercapto)phenyl)methylenepyridin-3-yl)-2-methoxybenzamide; 5-third- Butyl-3-cyano-N-(5-(4-(2-hydroxyethylamine)methyl)phenyl)methylenepyridin-3-yl)-2-methoxybenzimidamide; 123505 -149- 200815422 5_Second-butyl-N1 -(6-methyl-5-(4-(neopentylamino)phenylidene-3_yl)_N3 -(2-(four Hydropyrrole-1·yl)ethyl)m-xylyleneamine; 5_second-butyl-N1 -(6-fluorenyl-5-(4-(neopentylaminomethyl)phenyl) Acridine_3_yl)_N3-((1-methylhexahydropyridine-2-yl)methyl)m-xylyleneamine; 1-(5-(3-tri-butyl-5-(N, N-dimethylamine sulfonyl) benzhydryl) 2_methyl 1 : °疋-3-yl) neopentyl-1H-1,2,3-trimethyl-4-carboxamide; 3_Secondylbutyl-5-cyano-N-(5-(4-(2-(dimethylamino))-2-methylpropylamine-methyl)phenyl)- 6-methylpyridin-3-yl)benzamide; 5-tris-butyl-indole-1 -(3_transyl-2,2-dimethylpropyl)_Ν3 ·(6-methyl net ( 4 Detecting amylamine methyl hydrazino) phenyl) pyridine each) m-xylyleneamine; 5-tri-butyl cyano _ team (5_(4_(2,2-dimethylcyclohexylamine) Mercapto)phenyl)-6-methylpyridine-3-yl)-2-methoxybenzamide; N-(5-(4-((lR,2S,4R)-bicyclo[2] ·2················································ -Second-butyl-5-(N-methylamine sulfonyl)benzamide)_2_methyl 峨3_yl)-N-neopentyl-1, 1, 2, 3 - triazole carboxy guanamine; 3 · tert-butyl-N_(6-methyl·5_(4_(neopentylaminomethyl) phenyl azide _3_yl)-5-(N-A胺 醯 醯 ; ; ) ) ) ) ) ) ) ) ) 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- 5- ) styryl)pyridyl)benzamide; 5-tris-butyl_3_(2,3-dihydroisoxazole) 2-methoxy-N_(bu methyl-5-(4-( Neopentylamine-methylphenyl)phenyl),pyridyl-3-yl)benzamide Amine, · soil 3_second-butyl-5-(5-cyclopropyl-1,2,4-oxadiazoleyl)methyl-5-(4_(neopentylcarbamyl)benzene Benzymidin) Benzoylamine; Soil 123505 -150- 200815422 3_Third-Butyl-5-(5-(methoxymethyl)4,2,4^diazole each > N -(imethyl-5-(4-(neopentylcarbinyl)phenyl)pyridinyl)benzamide; 3-tris-butyl-N-(5-(4-(3-hydroxy) -2,2-dimethylpropylamine-mercapto)phenyl)-6-methylpyridin-3-yl)-5-(N-methylaminesulfonyl)benzamide; 3- Tri-butyl-;NH>(4-(4,4-difluorocyclohexylaminecarboxylidene)phenyl)methylpyridinyl)-5-(N-methylaminesulfonyl)benzamide Amine; 3-t-butyl-5-(5-tri-butyl), 2,4-diazole-oxazol-3-yl)-N-(6-methyl-5-(4-(new Amylamine, phenyl)pyridinyl)benzamide; 5-tris-butyl-2-methoxy-N-(6-methyl-5-(4-(neopentyl) Aminomethyl phenyl) phenyl) hydrazine _3_ yl)-3-(1H-p than 嗤-1-yl) benzamide; 5-tri-butyl cyano acyl (5-(4) -(2,2-dimethyl-3-(tetrahydropyrroleyl)propylaminemethanyl)phenyl)-6-A Pyridin-3-yl)-2-methoxybenzamide; 5_T-butyl-3-cyano-4(5-(4-(2,2-dimethyl)(4-methyl Hexahydropyridin-1-yl)propylaminecarbazyl)phenyl)-6-mercaptopyridine; yl)-2-methoxybenzamide; 5-tris-butyl-3-cyanide --N-(5-(4-(2,2-dimethyl-3-)-formylpropylamino)phenyl)-6-methyl 1 : -3-yl)- 2-methoxybenzamide; N-(5-(4-(3-amino-2,2-dimethylpropylaminemethyl)phenyl)methylmethyl sigma-3- 5-)-t-butyl-3-cyano-2-methoxybenzamide; 5-tris-butyl-3-cyano-oxime-(5-(4-(3- (diammonium) 2,2-dimethylpropylamine-methylhydrazino)phenyl)-6-fluorenyl 1 :indol-3-yl)-2-methoxybenzamide; 5- Third-butyl-3-(4-(methyl)-1Η-1,2,3-triazol-1-yl)-2-methoxy_ν·(6-methyl-5-( 4-(neopentylamine decyl)phenyl)cycline-3-yl)benzamide; 5-tris-butyl-2-methoxy-N-(6-methyl-5- (4-(neopentylamine sulfhydryl) stupid 123505 -151 - 200815422 pyridin-3-yl)-3-(4-(tetrahydropyrrolidinylmethyl)_1Η-1,2,3-three Azole 5-tert-Butyl-2-yl-2-methoxy-indole-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)-3-yl)-3-() 4-(hexahydropyridin-1-ylmethyltriazole small)benzamide; 5-tris-butyl-2-methoxy_N-(6-methyl-5·(4·( Neopentylamine fluorenyl)phenyl)exyl 1:di--3-yl)-3-(4-((4-methylhexahydropyrene)-methyl)_ιη_1,2,3-three . -1-1·yl)benzamide; 5-dibutyl-2-oxooxy-oxime-(6-methyl-5-(4-(neopentylcarbamate)phenyl)> Specific bite 3-yl)-3-(4-(i-fu-p-linylmethyl)-iH-l,2,3-triazol-1-yl)benzamide; 5-tri-butyl -3-(4-((diethylamino)carbazoleazole)-2•methoxy-N-(6-methyl-5-(4-(neopentylcarbinyl)phenyl) ), pyridin-3-yl)benzamide; 5_t-butyl each (4-((diguanyl)methyl)--------triazole) _2-methoxy- N-(6-methyl-5-(4-(p-pentylaminomethyl)phenyl)acridin-3-yl)benzamide; 5-tris-butyl-3-(4-( (isopropylamino)methyl) 沁 沁 tri triazole + yl) _2 曱 曱 善 (6-methyl-5_(4-(neopentylaminomethyl) phenyl (tetra) pyridine _3_ Benzomethane; 5-tert-butyl-3_(4-((cyclopropylamino)methyl wh-U} triazole small base methoxymethyl-5-(4-(new Amidoxime)phenyl benzoazinyl-3-ylphenylamine; and 5-tris-butyl-3-cyano-N-(5-(4-(2-(dimethylamino)) )_2·Methylpropylamine A 123505 -152- 200815422 Stuffed base) Benyl)-6-Methyl group 定-3-yl)-2-A The following terms are used throughout the text and are used throughout the text. In general, an indication of an element, such as hydrogen or helium, is meant to include all isotopes of that element. For example, if R A group is defined to include hydrogen or helium, and it also includes helium and gas. Therefore, an isotope-labeled compound is within the scope of the invention. f' is generally substituted " An organic group (for example, an alkyl group) in which a bond contained in one or more hydrogen atoms is replaced by a bond to a non-hydrogen or non-carbon atom. The substituted group also includes a carbon to be bonded thereto. Or one or more of the hydrogen atoms are replaced by one or more bonds (including double or ginseng) of the hetero atom. Thus, the substituted group will be replaced by one or more substituents. Substituted, unless otherwise indicated. In some instances, the 'substituted group is substituted with U, 3, 4, 5 or 6 substituents. Examples of substituents include halogen (ie, €1, &1);mercapto; alkoxy, ..., alkynyl, aryloxy, aryloxy Heterocyclyloxy and heterocyclyloxy; several bases (five); slow bases; esters; polyamino carboxylic acid vinegars; fatty acids; hydroxylamines; alkoxyamines; Amines; thiol 颂 'stone m compounds, sub-species, irons; continued sulfhydryl groups; oxime amines; amines; antimony oxides; moon wells; terpenoids; glandular; azide Compounds; guanamines; glands; steroids; guanidines, dilute amines; quinone imines; isophthalic acid vinegars; isothioxanthine; cyanate, thiocyanate; Amines; waxes (meaning CN), etc. The ring group of the silk, such as the silk, the aryl, heterocyclic and heterocyclic groups, also includes the ring and the ring system, in which the bond to the chlorine atom 123505 • 153 - 200815422 is % Atomic bond substitution. Thus, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups may also be substituted by substituted or unsubstituted alkyl, alkenyl and alkynyl groups as defined below. Alkyl groups include straight-chain and branched alkyl groups having from about 2 to about carbon atoms, and typically from 1 to 12 carbons, or in some embodiments, from 丨 to 8, from 1 to 6 , or 1 to 4 carbon atoms. The alkyl group further includes a cycloalkyl group as defined below. Examples of the linear alkyl group include those having from 丨 to 8 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl and n- Xinji. Examples of the branched alkyl group include, but are not limited to, isopropyl, isobutyl, second-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-monopropyl. Representative substituted alkyl groups can be substituted one or more times by substituents such as those listed above. The cycloalkyl group is a cyclic alkyl group such as, but not limited to, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a hexyl group, a cycloheptyl group, and a cyclooctyl group. In some embodiments, the cycloalkyl group has from 3 to 10, or from 3 to 8 ring members, whereas in other specific embodiments, the number of ring carbon atoms ranges from 3 to 5, from 3 to 6 , or 3 to 7. The cycloalkyl group further includes a mono...bicyclic and polycyclic ring system such as a bridged cycloalkyl group as described below, and a fused ring such as, but not limited to, decahydronaphthyl group and the like. In some embodiments, the polycyclic cycloalkyl has three rings. The substituted cycloalkyl group may be substituted one or more times with non-hydrogen and non-carbon groups as defined above. However, substituted cycloalkyl groups also include rings substituted with a straight or branched chain alkyl group as defined above. A representative substituted cycloalkyl group may be monosubstituted or substituted more than once, such as but not limited to 2,2_, 2,3_, 2,4_, 2,5_ or 2, a disubstituted cyclohexyl group which may be Substituted for the substituents listed above. 123505 -154- 200815422 Bridging my base is a loop wire. The two or more hydrogen systems of the towel are replaced by a secondary alkyl group. If two hydrogen atoms are on the same carbon atom, the bridging group can contain 2 Up to 6 carbon atoms, or if two hydrogen atoms are on adjacent carbon atoms, may contain i to 5 carbon atoms, or if two hydrogen atoms are in a carbon separated by 1 or 2 carbon atoms On the atom, it can contain 2 to 4 carbon atoms. The bridged cyclic alkyl group may be bicyclic, such as bicyclic and [211] calcined, or tricyclic, such as an albino group. Representative bridged cycloalkyl groups include bicyclic and [2ιι] [hexyl, bis-[2.2.1] heptyl, bicyclo[3 21]octyl, bicyclo[2·2 2]octyl, bicyclo[ 3.2.2] fluorenyl, bicyclic and [3 31] fluorenyl, bicyclic and [3 3 夭 孟 孟 孟 孟 院 、 去 去 去 去 去 去 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 The substituted bridged cycloalkyl group can be substituted - or multiple times by non-hydrogen and non-carbon groups as defined above. Representative substituted bridged cycloalkyl groups can be monosubstituted or substituted more than once, such as, but not limited to, mono-, di- or tri-substituted adamantyl groups, which can be substituted with, for example, the substituents listed above. A cycloalkylalkyl group is an alkyl group as defined above wherein the hydrogen or carbon bond of the alkyl group is replaced by a bond to a cycloalkyl group as defined above. In some embodiments, the cycloalkylalkyl group has 4 to 2 carbon atoms, 4 to 16 carbon atoms, and typically 4 to 1 carbon atoms. The substituted cycloalkylalkyl group may be an alkyl group, a cycloalkyl group or an alkyl group of the group. Substituted with a cycloalkyl moiety. A representative substituted cycloalkylalkyl group may be monosubstituted or substituted more than once, such as, but not limited to, a substituent such as those listed above, _, _ or _ Alkenyl includes straight-chain and branched chains and cycloalkyl as defined above, except that at least one double bond is present between two carbon atoms. Thus, alkenyl groups have from 2 to about 2 carbon atoms, and are typically 2 to 12 carbons, or in some embodiments 123505-155-200815422, 2 to 8, 2 to 6, or 2 to 4 carbon atoms. In some embodiments, alkenyl includes a cycloalkenyl group having 4 to 2 carbon atoms, 5 to 2 carbon atoms, 5 to 1 carbon atoms, or even 5, 6, 7 or 8 carbon atoms. Including but not limited to, especially vinyl, allyl, ), -CH=C(CH3)2 > ^C(CH3 hCH2 ^ -C(CH3 )=CH(CH3) ^ -C(CH2 ch3 )= CH 2 ^ cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl and hexadienyl. Representative substituted alkenyl groups may be monosubstituted or substituted

l 一次，譬如但不限於被譬如上文列示之取代基單_、二-或 三-取代。 環稀基烧基為如上文定義之減，其中録之氫或碳鍵 係被對如上文定義之環烯基之鍵結置換。經取代之環稀基 烧基可在該基團之燒基、環烯基或烧基與環烯基兩部份上 經取代。代表性Μ取代之環烯基烧基可被譬如上文列示之 取代基取代一或多次。l Once, for example, but not limited to, the substituents listed above are listed as _, di- or tri-substituted. The cycloalkyl group is a subtraction as defined above wherein the hydrogen or carbon bond is replaced by a bond to a cycloalkenyl group as defined above. The substituted cycloalkyl group may be substituted on the alkyl, cycloalkenyl or alkyl and cycloalkenyl groups of the group. A representative anthracene substituted cycloalkenyl group can be substituted one or more times by the substituents as listed above.

炔基包括直鏈與分枝鏈燒基，惟至少-個參鍵存在於兩 個石反原子之間。因此’块基具有2至約2G個碳原子，且典型 上為2至12個碳’或在—些具體實施例中，為2至8個，2至 6個，或2至4個碳原子。實例包括但不限於其中特別是 -C^CH ^ -C^C(CH3) . -€Ξ〇(〇Η2€Η3) ^ -CH2C^CH > -CH2CS C(CH3)及-CH2 C Ξ C(CH2 CH3)。代表性經取代之炔基可被單取 代或取代超過一次，链 言如但不限於被譬如上文列示之取代 基单-、二-或三-取代。 芳基為未含有雜；^ u ’、子之核狀方族烴類。芳基包括單環 狀、雙ί哀狀及多環狀淨备 衣糸、、先。因此，芳基包括但不限於苯 123505 -156- 200815422Alkynyl groups include straight chain and branched chain alkyl groups, but at least one of the reference bonds exists between the two stone counter atoms. Thus the 'block group has from 2 to about 2G carbon atoms, and typically from 2 to 12 carbons' or, in some embodiments, from 2 to 8, from 2 to 6, or from 2 to 4 carbon atoms. . Examples include, but are not limited to, specifically -C^CH^-C^C(CH3). -€Ξ〇(〇Η2€Η3) ^ -CH2C^CH > -CH2CS C(CH3) and -CH2 C Ξ C (CH2 CH3). Representative substituted alkynyl groups can be substituted or substituted more than once, and the chain name is, for example, but not limited to, mono-, di- or tri-substituted by the substituents listed above. The aryl group is a nucleus-like hydrocarbon having no impurity; ^ u '. The aryl group includes a single ring shape, a double mourning shape, and a multi-ring net preparation 糸, first. Therefore, aryl groups include, but are not limited to, benzene 123505 -156- 200815422

基、奠基、蔑苊基、次聯苯基、茚莘基、苐基、菲美、一 苯基烯基、菠基、茶革基、鑽基、聯苯基、愚基非二基了 氫雖基、雙伍圜基及蕃基。在一些具體實施例中，芳^含 有6-M個碳，而在其他具體實施例中為，或甚土至: 至H)個碳原子，在該基團之環部份中。雖然，，芳基”措辭包 ^含有稠合環之基團，譬如稠合芳族姻環系統（例如氯 茚基、四氫萘基等）’但其不包括具有經結合至環員之一之 其他基團(譬如烷基或齒基)之芳基。而是，—些基團，孽 如甲苯基’係被稱為經取代之芳基。代表性經取代之芳基 可被單取代或取代超過一次。例如，經單取代之芳基包括 但不限於2-，3-，4-，5-或6·取代之苯基或蓁基，其可被譬如上 文列示之取代基取代。 芳烧基為如上文^義之院基’其中烧基之氫或碳鍵係被 對如上文定義之芳基之鍵結置換。在—些具體實施例中， 芳烷基含有7至20個碳原子，7至14個碳原子’或7至1〇個 碳原子。經取代之芳烧基可在該基團之燒基、芳基或烧基 與芳基兩部份上經取代。代表性芳烧基包括但不限於爷基 與苯乙基及稠合(環烷基芳基)烷基，譬如‘乙基_氫茚基。代 表性經取A之芳院基可被譬如上文列示之取代基取代-或 多次。 雜環基包括芳族（亦被稱為雜芳基）與非芳族環化合物， 含有3或多個環員，其中一或多個為雜原子，譬如但不限於 Ν、Ο及S。在一些具體實施例中，雜環基包含3至2〇個環 員，然而其他此種基團具有3至6個，3至1〇個，3至12個， 123505 •157- 200815422 5 個％員。雜環基係涵蓋不飽和、部份飽和及飽和環 系先例如咪唑基、二氫咪唑基及四氫咪唑基。"雜環基，， 措辭包括稠合環物種，包括含有稠合芳族與非芳族基團 者例如苯并三唾基、2,3_二氫笨并[1，4]二氧陸圜烯基及苯 并2二氧A圜稀基。該措辭亦包括含有雜原子之橋接多環 狀衣系、、先，譬如但不限於嗝啶基。但是，該措辭不包括具 有、、、二…合至裱員之一之其他基團（譬如烷基、酮基或鹵基） 〔 之雜％基。而是，此等係被稱為，，經取代之雜環基，，。雜環 基包括但不限於氮丙啶基、一氮四圜基、四氫吡咯基、四 氯味嗤基、四氫，比峻基”塞㈣基、四氮硫苯基、四Μ 南基、一氧伍圜烯基、呋喃基、硫苯基、吡咯基、二氩吡 各基咪唑基、二氫咪唑基、吡唑基、二氫吡唑基、三唑 基、四唑基、唠唑基、異呤唑基、嘧唑基、嘧唑啉基、異 嘧唑基、嘍二唑基、呤二唑基、六氫吡啶基、六氫吡畊基、 馬福ρ林基、硫代嗎福琳基、四氫喊喃基、四氫硫代喊喃基、 ν 氧瓜陸圜、一氧基、二硫陸圜基、喊喃基、峨σ定基、。密咬 基、。合畊基、吡畊基、三畊基、二氫吡啶基、二氫二硫陸 圜烯基、二氫二硫酮基、高六氫吡畊基、嗝啶基、吲哚基、 二氫峭哚基、異啕哚基、氮峋哚基（吡咯并吡啶基）、啕唑 基、啕π井基、苯并三唑基、苯并咪唑基、苯并呋喃基、苯 并硫苯基、苯并嘧唑基、苯并噚二唑、苯并呤喑基、苯并 二硫陸圜烯基、苯并氧硫陸圜烯基、苯并嘍畊基、苯并噚 唑基、苯并噻唑基、苯并嘍二唑基、苯并[^3]二氧伍圜烯基、 峨嗤并吡啶基、咪唑并吡啶基（氮苯并咪唑基）、三 123505 -158- 200815422Base, foundation, sulfhydryl, phenylene, fluorenyl, fluorenyl, phenanthrene, monophenylenyl, porphyrin, tea-based, drill-based, biphenyl, oligo-dihydrogen Although the base, the double Wuji and the base. In some embodiments, the aryl contains 6-M carbons, and in other embodiments, or from 1: to H) carbon atoms, in the ring portion of the group. Although, the "aryl" phrase contains a group containing a fused ring, such as a fused aromatic ring system (eg, chloroindenyl, tetrahydronaphthyl, etc.) but does not include one having a bond to the ring member An aryl group of another group (such as an alkyl group or a dentate group). Instead, a group such as a tolyl group is referred to as a substituted aryl group. A representative substituted aryl group may be monosubstituted or Substituted more than once. For example, a monosubstituted aryl group includes, but is not limited to, a 2-, 3-, 4-, 5- or 6-substituted phenyl or fluorenyl group which may be substituted with a substituent such as those listed above. The aryl group is a group wherein the hydrogen or carbon bond of the alkyl group is replaced by a bond to an aryl group as defined above. In some embodiments, the aralkyl group contains 7 to 20 a carbon atom, 7 to 14 carbon atoms' or 7 to 1 carbon atoms. The substituted aryl group may be substituted on the alkyl group, the aryl group or the alkyl group and the aryl group of the group. The aryl group includes, but is not limited to, aryl and phenethyl and fused (cycloalkylaryl)alkyl, such as 'ethyl-hydroquinone. Substituted as substituents listed above - or multiple times. Heterocyclyl groups include aromatic (also known as heteroaryl) and non-aromatic ring compounds containing 3 or more ring members, one or more of which are Heteroatoms such as, but not limited to, ruthenium, osmium, and S. In some embodiments, the heterocyclic group contains 3 to 2 ring members, while other such groups have 3 to 6, 3 to 1 ring, 3 to 12, 123505 • 157 - 200815422 5 %. The heterocyclic group covers unsaturated, partially saturated and saturated ring systems such as imidazolyl, dihydroimidazolyl and tetrahydroimidazolyl. "Heterocyclyl , the wording includes fused ring species, including those containing fused aromatic and non-aromatic groups such as benzotrisyl, 2,3-dihydroindol [1,4]dioxanthene and benzene And 2 dioxin A. The phrase also includes a bridged polycyclic coat containing a hetero atom, such as, but not limited to, an acridinyl group. However, the phrase does not include a bond with a compound, a Any other group (such as an alkyl group, a keto group or a halogen group) [is a hetero-based group. Instead, these are referred to as, substituted heterocyclic groups, Heterocyclyl groups include, but are not limited to, aziridine, nitrotetradecyl, tetrahydropyrrolyl, tetrachloromethane, tetrahydro, tetrasyl (tetra), tetrazinc thio, tetradecyl , monooxyl alkenyl, furyl, thiophenyl, pyrrolyl, diarsenopylimidazolyl, dihydroimidazolyl, pyrazolyl, dihydropyrazolyl, triazolyl, tetrazolyl, anthracene Azyl, isoxazolyl, pyrazolyl, pyrazolinyl, isoxazolyl, oxadiazolyl, oxadiazolyl, hexahydropyridyl, hexahydropyrryl, sulfanyl, sulphur代福福基基, tetrahydro sulfanyl, tetrahydrothio sulfanyl, ν oxime, oxime, dithiolanyl, sulfonyl, 峨σ. Close bite base. Ploughing base, pyridinyl, tri-cultivation, dihydropyridyl, dihydrodithioglutenyl, dihydrodithione, high hexahydropyrrole, acridinyl, fluorenyl, dihydrogen Chalcedyl, isodecyl, aziridine (pyrrolopyridyl), oxazolyl, 啕π well, benzotriazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl , benzopyrazolyl, benzoxadiazole, benzindenyl, benzodithioglutenyl, benzoxylthiodecenyl, benzofluorene, benzoxazolyl, benzene And thiazolyl, benzoxadiazolyl, benzo[^3]dioxolanyl, indenylpyridyl, imidazopyridyl (nitrobenzimidazolyl), three 123505-158- 200815422

啶基、異噚唑并吡啶基、嘌呤基、黃嘌呤基、腺嘌呤、鳥 嘌呤、喳啉基、異喳啉基、喹畊基、喳喏啉基、喹唑啉基、 4琳基、吹定基m、硫茶基、二氫苯并嚷 喷基、二氫苯并吱喃基、二氫巧哚基、二氫苯并二氧陸園 烯基、四氫㈣基、四氫^基、四氫苯并㈣基、四氯 苯并三唑基、四氫吡咯并吡啶基、四氫吡唑并吡啶基、四 氫味嗤并峨咬基、四氫三唾并❹基及四氫如林基。代表 性經取代之雜環基可被單取代或取代超過—次譬如但不 限於峨咬基或嗎福,林基，其係被譬如上文列示之各種取代 基2-，3-，4-，5-或6-取代或二取代。 芳基為含有5或更多個環員之芳族環化合物，其中一 或多個為雜原子，譬如但不限於N、〇及8。雜芳基包括但 不限於—些基團，譬如吡咯基、吡唑基、咪唑基、三唑基、 :唑基”号唑基、異噚唑基”塞唑基、吡啶基、嗒畊基、 哺咬基m、硫苯基、苯并硫苯基、呋d南基、苯并呋 =基、啊基、氮十朵基（峨略并㈣基）κ基、苯并 f圭基、味嗤并吨咬基（氮苯并咪唑基）、吡唑并吡啶基、 —坐并吡啶基、苯并三唑基、苯并呤唑基、苯并嘧唑基、 2嗔二唾基、咪峻#—基、異^并❹基、硫茶基、 四2基Θ嘌呤基、腺嘌呤、鳥嘌呤、喹啉基、異喳啉基、 ί奎林基、喳喏啉基及喹唑啉基。雖然&quot;雜芳基&quot;措辭包 7 口王长化合物，譬如4噪基與2,3_二氮十朵基，但該措辭 芳=括具有經結合至環員之一之其他基團（譬如烷基）之雜 方土而疋，具有此種取代之雜芳基係被稱為&quot;經取代之雜 123505 -159- 200815422 芳基&quot;。代表性之經取代雜芳基可被譬如上文列示之各種取 代基取代一或多次。 雜環基烷基為如上文定義之烷基，其中烷基之氫或碳鍵 係被對如上文定義之雜環基之鍵結置換。經取代之雜環基 烷基可在該基團之烷基、雜環基或烷基與雜環基兩部份上 經取代。代表性雜環基烷基包括但不限於冬乙基_嗎福啉 基、4-丙基嗎福啉基、呋喃么基甲基、呋喃氺基甲基、吡啶 -3-基甲基、四氫呋喃_2_基乙基及峭哚么基丙基。代表性經 取代之雜環基烷基可被譬如上文列示之取代基取代一或多 次。 雜芳烷基為如上文定義之烷基’其中烷基之氫或碳鍵係 被對如上文定義之雜芳基之鍵結置換。經取代之雜芳烷基 可在該基團之録、雜芳基或烧基與雜芳基兩部份上經取 代。代表性經取代之㈣院基可被譬如上文麻之取代基 取代一或多次。 —燒氧基驗基（_〇H)，其巾對氫原子之鍵結係被對如上文 定義之經取代或未經取代烷基之碳原子之鍵結置換。線性 烷氧基之實例包括但不限於甲氧基、乙氧基、丙氧基、丁 乳基、戊氧基、己氧基等。分枝狀烧氧基之實例包括但不 限：異丙氧基、第二丁氧基、第三叮氧基、異戊氧基、異 基等。環烷氧基之實例包括但不限於環丙氧基、環丁 氧基、環戊氧基、環己氧基等。代表性經取代之院氧基可 被譬如上文列示之取代基取代一或多次。 ’’芳氧基”與&quot;芳基烷氧基&quot;術語制固別指經結合至氧原 123505 200815422 子之經取代或未經取代之芳基，與在烧基上經結合至氧原 子之經取代或未經取代之芳烧基。實例包括但不限於苯氧 基、莕氧基及爷氧基。代表性經取代之芳氧基與芳基烧氧 基可被譬如上文列示之取代基取代一或多次。 烧基、«及炔基可為二價以及單價。烧基、烯基或块 基之價鍵將為熟諳此藝者容易地自内文而明瞭。例如，在 芳烷基中之烷基為二價。在一些具體實施例中，二價鍵係 (曰月確地藉由附加字尾，，ene”或” ylene&quot;至本文中所定義之術語 而顯示。因此，例如”次烷基，，係指二價烷基，而次烯基係 指二價烯烴基團。 於本文中使用之’’羧酸基&quot;一詞係指_c〇〇H基團。 於本文中使用之”羧酸酯，，一詞係指_C〇〇R3〇基團。RS〇為 如本文定義之經取代或未經取代之烷基、環烷基、烯基、 炔基、芳基、芳烷基、雜環基烷基或雜環基。 ’’醯胺（或’’醯胺基”）一詞包括c-與N_醯胺基團，意即個 、 別為&lt;(0)观31尺32與-NR31C(〇)R32基團。R31與r32係獨立為 氫，或如本文定義之經取代或未經取代之烷基、烯基、炔 基、裱烷基、芳基、芳烷基、雜環基烷基或雜環基。因此， 醯胺基包括但不限於胺甲醯基K(〇)NH2)與甲醯胺基圏 (_NHC(0)H) 〇 胺基甲酸酯基包括N-與α胺基甲酸酯基，意即個別為 撕33c(o)or“與-ocxcon^rw基團。r33與r34係獨立為氫： 或如本文定義之經取代或未經取代之烷基、烯基、炔基、 環燒基、芳基、芳烷基、雜環基烷基或雜環基。 123505 -161- 200815422 於本文中使用之”胺·，（或”胺基&quot;）一詞，係指_nhr35盘 -NR叫7基團，其中r35，r36及R37係獨立為氫，或如本μ 義之經取代或未經取代之烧基、烯基、炔基、環烧基、芳 基、芳烷基、雜環基烷基或雜環基。在一些具體實施例中方 胺為ΝΗ2、甲胺基、二甲胺基、乙胺基、二乙胺基、丙胺基、 異丙基胺基、苯基胺基或苄胺基。Pyridyl, isoxazolopyridinyl, fluorenyl, xanthine, adenine, guanine, porphyrin, isoindolyl, quinacyl, porphyrin, quinazolinyl, 4 linyl, Blowing base m, sulfur tea base, dihydrobenzoindole, dihydrobenzopyranyl, dihydro fluorenyl, dihydrobenzodioxanyl, tetrahydro (tetra), tetrahydro , tetrahydrobenzo(tetra)yl, tetrachlorobenzotriazolyl, tetrahydropyrrolopyridinyl, tetrahydropyrazolopyridyl, tetrahydromyristin and acenaphthyl, tetrahydrotrisalinyl and tetrahydrogen Such as Lin Ji. A representative substituted heterocyclic group may be monosubstituted or substituted more than - for example, but not limited to, a bite group or a ruthenium, which is a base such as the various substituents 2-, 3-, 4- listed above. , 5- or 6-substituted or disubstituted. The aryl group is an aromatic ring compound containing 5 or more ring members, one or more of which are heteroatoms such as, but not limited to, N, fluorene and 8. Heteroaryl groups include, but are not limited to, those groups such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolylzolyl, isoxazolyl, oxazolyl, pyridyl, hydrazine , biting base m, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, yl, nitrogen, ten, benzyl, benzof, Miso with a bite (nitrobenzimidazolyl), pyrazolopyridyl, —pyridylpyridyl, benzotriazolyl, benzoxazolyl, benzopyrazolyl, 2嗔disal,咪峻#—yl, iso-indenyl, thiochalyl, tetramethylenethiol, adenine, guanine, quinolinyl, isoindolyl, ί奎林, porphyrin and quinazoline Alkyl group. Although the &quot;heteroaryl&quot; wording consists of seven king compounds, such as 4 noise bases and 2,3_diaza ten bases, the wording includes all other groups that have been bonded to one of the ring members ( For example, an alkyl group is a heterocyclic ring, and a heteroaryl group having such a substitution is called &quot;substituted pyridine 123505-159-200815422 aryl&quot;. Representative substituted heteroaryl groups can be substituted one or more times by various substituents such as those listed above. Heterocyclylalkyl is an alkyl group as defined above wherein the hydrogen or carbon bond of the alkyl group is replaced by a bond to a heterocyclic group as defined above. The substituted heterocyclic alkyl group may be substituted on the alkyl group, the heterocyclic group or the alkyl group and the heterocyclic group of the group. Representative heterocyclylalkyl groups include, but are not limited to, winter ethyl-morpholinyl, 4-propylmorpholine, furanylmethyl, furanylmethyl, pyridin-3-ylmethyl, tetrahydrofuran _2_ylethyl and cholesterylpropyl. Representative substituted heterocyclylalkyl groups can be substituted one or more times with substituents such as those listed above. A heteroaralkyl group is an alkyl group as defined above wherein the hydrogen or carbon bond of the alkyl group is replaced by a bond to a heteroaryl group as defined above. The substituted heteroarylalkyl group can be substituted on the group, heteroaryl or the alkyl and heteroaryl groups of the group. A representative substituted (iv) institution may be replaced by one or more substituents such as the above. An alkyl group (_〇H) whose bond to a hydrogen atom is replaced by a bond to a carbon atom of a substituted or unsubstituted alkyl group as defined above. Examples of linear alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butyl, pentyloxy, hexyloxy and the like. Examples of the branched alkoxy group include, but are not limited to, isopropoxy group, second butoxy group, third decyloxy group, isopentyloxy group, hetero group, and the like. Examples of cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like. Representative substituted oxy groups may be substituted one or more times with substituents as listed above. ''Aroyloxy" and "arylalkoxy" are defined as substituted or unsubstituted aryl groups bonded to oxygen 123505 200815422 and bonded to an oxygen atom on a burnt group. Substituted or unsubstituted aryl groups. Examples include, but are not limited to, phenoxy, decyloxy and aryloxy. Representative substituted aryloxy and aryl alkoxy groups can be as listed above The substituent is substituted one or more times. The alkyl group, «and alkynyl group may be divalent and monovalent. The valence bond of the alkyl group, the alkenyl group or the block group will be readily known from the art. For example, The alkyl group in the aralkyl group is divalent. In some embodiments, the divalent bond system (shown by adding a suffix, ene" or "ylene" to the terms defined herein Thus, for example, "alkylene," refers to divalent alkyl, and subalkenyl refers to divalent olefin groups. The term 'carboxylic acid group' as used herein refers to _c〇〇H. The term "carboxylate" as used herein refers to a _C〇〇R3 fluorene group. RS〇 is substituted or not as defined herein. Substituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl. The term ''nonylamine (or ''amine)) includes c- And the N_protonide group, that is, one, and the other are <31) 32 and -NR31C(〇)R32 groups. R31 and r32 are independently hydrogen, or substituted or not as defined herein. Substituted alkyl, alkenyl, alkynyl, decyl, aryl, aralkyl, heterocyclylalkyl or heterocyclic group. Thus, sulfhydryl groups include, but are not limited to, amine carbaryl K (〇) NH2) with carbenamide oxime (_NHC(0)H) phthalic acid ester group includes N- and alpha urethane groups, meaning that individually tearing 33c(o)or "with -ocxcon^rw The group r33 and r34 are independently hydrogen: or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heteroalm as defined herein. 123505 -161- 200815422 As used herein, the term "amine," or "amine" refers to the radical _nhr35-NR is a 7-group wherein r35, r36 and R37 are independently hydrogen. Or a substituted or unsubstituted alkyl, alkenyl or alkynyl group as defined herein Cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclic. In some embodiments the arylamine is oxime 2, methylamino, dimethylamino, ethylamino, diethylamine, propylamine Base, isopropylamino, phenylamino or benzylamino.

&quot;磺醯胺基，，一詞包括S_與Ν_磺醯胺基團，意即個別為 -S〇2NI^R39與视38s〇2R39基團。R38與R39係獨立為氫，或 如本文定義之經取代或未經取代之烷基、烯基、炔基、環 烷基、芳基、芳烷基、雜環基烷基或雜環基。因此，磺醯 胺基包括但不限於胺磺醯基（_S〇2NH2)。 石鼠醇一 5司係指-SH基團，然而硫化物包括_队4 〇基團， 亞砜類包括-S(0)R41基團，砜類包括名〇2^2基團，及磺醯基 類包括-S〇2〇R43。化4〇，1141，1142及1143各獨立為如本文定義之 經取代或未經取代之烷基、環烷基、烯基、炔基、芳基芳 燒基、雜環基或雜環基烷基。 ”脲’’ 一詞係指-NR44-C(0)-NR45R46基團。R44，R45 及 R46 基團 二獨立為風’或如本文定義之經取代或未經取代之燒基、 烯基、炔基、環烷基、芳基、芳烷基、雜環基或雜環基烷 基。 脒’’ 一詞係指-C(NR47)NR48R49 與-nr47c(nr48)r49，其中 ’ R及R4 9各獨立為氫，或如本文定義之經取代或未經 取代之烷基、環烷基、烯基、炔基、芳基芳烷基、雜環基 或雜環基烷基。 123505 200815422 ”胍’’ 一詞係指-NR50C(NR51)NR52R53，其中 R50, R51，R52及 各獨立為氫’或如本文定義之經取代或未經取代之烧 基％烷基、烯基、炔基、芳基芳烷基、雜環基或雜環基 烷基。 烯胺” 一詞係指 _c(r54)=C(r55)nr56r57 與 NR54C(R55hc(R56)R57，其中r54，r55，r56 及 R57 各獨立為氮， 如本文疋義之經取代或未經取代之烷基、環烷基、烯基、 炔基、芳基芳烷基、雜環基或雜環基烷基。 ’’醯亞胺’’ 一詞係指-c(0)nr58c(0)r59，其中r58與r59各獨 立為氫，或如本文定義之經取代或未經取代之烷基、環烷 基烯基、炔基、芳基芳烷基、雜環基或雜環基烷基。 ”亞胺’’一詞係指_cr60(nr61:^-n(cr60r61)基團，其中r60 與R各獨立為氫，或如本文定義之經取代或未經取代之烷 基、環烧基、烯基、炔基、芳基芳烧基、雜環基或雜環基 烷基，其附帶條件是]^()與R01兩者不同時為氫。 關於搜基、胺基、羧基及氫硫基之，，經保護”一詞，係指 此等官能基之藉由保護基保護而免於不想要反應之形式。 保護基係A熟諳&amp;藝者所已#，且可使用f知程序添加或 移除，譬如在有機合成之保護基，Greene，T.W.; Wuts，P.G.M，John Wiley &amp; Sons，New Y〇rk，Νγ (第3版，1999)中所提出者。經保護 羥基之實例包括但不限於矽烷基醚類，譬如藉由羥基與試 劑之反應所獲得者，該試劑譬如但不限於第三-丁基二甲基 -氯基矽烷、三甲基氯基矽烷、三異丙基氯基矽烷 '三乙基 氯基矽烷；經取代之曱基與乙基醚類，譬如但不限於甲氧 123505 -163- 200815422 基甲基醚、甲硫基甲基醚、苄氧基甲基醚、第三-丁氧基甲 基_、2·甲氧基乙氧基甲基醚、四氫|喃基_類、卜乙氧基 乙基醚、#丙基醚、苄基醚；s旨類，譬如但不限於苯甲醯 基甲酸酯、甲酸酯、醋酸酯、三氯醋酸酯及三氟醋酸酯。 N-保遵基包括醯基，譬如甲醯基、乙醯基、丙醯基、三 甲基乙酿基、第二-丁基乙醯基、2_氯基乙酿基、2·漠基乙醯 基、二氟乙醯基、三氣乙醯基、鄰苯二甲醯基、鄰-琐基苯 氧基乙醯基、a-氯基丁醯基、苯甲醯基、4_氯基苯甲醯基、 4-溴基苯甲醯基、4_硝基苯甲醯基等；磺醯基，譬如苯磺醯 基、對-甲苯磺醯基等；可形成胺基甲酸酯之基團，譬如芊 氧羰基、對-氣苄基氧基羰基、對呷氧基苄氧羰基、對_頌 基+氧纟厌基、2-琐基爷基氧基隸基、對_演基爷氧幾基、3,4_ 二曱氧基苄氧羰基、3,5_二甲氧基芊氧羰基、2,4_二甲氧基芊 氧羰基、4-甲氧基苄氧羰基、2_硝基_4,5_二甲氧基苄氧羰基、 3,4,5-三甲氧基芊氧羰基、μ(對-聯苯基）小甲基乙氧羰基、 α，α-二甲基-3,5-二甲氧基芊氧羰基、二苯甲基氧基羰基、第 二-丁氧幾基、二異丙基甲氧幾基、異丙氧幾基、乙氧羰基、 甲氧羰基、烯丙氧基羰基、2,2,2-三氯乙氧基羰基、苯氧基 羰基、4-硝基苯氧基羰基、苇基-9-甲氧羰基、環戊氧基羰基、 金剛烷基氧基羰基、環己基氧基羰基、苯基硫代羰基等； 烷基，譬如苄基、三苯甲基、苄氧基甲基等；及矽烷基， 譬如三甲基矽烷基等。典型Ν-保護基為甲醯基、乙醯基、 苯曱醯基、三甲基乙醯基、第三·丁基乙醯基、苯磺醯基、 芊基、9-苐基甲基氧基羰基(Fmoc)、第三-丁氧羰基(Boc)及苄 123505 •164- 200815422 氧羰基（Cbz)。 經保護氫硫基之實例包括但不限於硫醚類，譬如S-苄基 硫醚、S-第三-丁基硫醚及S-4-甲基吡啶硫醚；經取代之S-甲 基衍生物，譬如半硫基、二硫基及胺基硫基縮醛；及其他。 代表性羧基保護基為&lt;^至(：8烷基（例如甲基、乙基或第三 丁基等）；鹵烷基；烯基；環烷基及其經取代之衍生物，譬 如環己基、環戊基等；環烧基烧基及其經取代之衍生物， 譬如環己基甲基、環戊基曱基等；芳烷基，例如苯乙基或 爷基及其經取代之衍生物’譬如烧氧基爷基或琐基爷基 等；芳烯基，例如苯基乙烯基等；芳基及其經取代之衍生 物，例如5-氫茚基等；二烷胺基烷基（例如二甲胺基乙基 等）；烷醯氧基烷基，.譬如乙醯氧基甲基、丁醯基氧基甲基、 戊醯氧基甲基、異丁醯基氧基甲基、異戊醯基氧基甲基、 1-(丙酿氧基）-1-乙基、1-(二甲基乙酸基氧基）-1-乙基、1-甲基 -1-(丙醯氧基）-1-乙基、三曱基乙醯基氧基甲基、丙醯氧基曱 基等；環烷醯基氧基烷基，譬如環丙基羰基氧基甲基、環 丁基羰基氧基甲基、環戊基羰基氧基甲基、環己羰基氧基 甲基等；芳醯基氧基烷基，譬如苯甲醯氧基甲基、苯甲醯 氧基乙基等；芳烷基羰基氧基烷基，譬如苄基羰基氧基甲 基、2-苄基羰基氧基乙基等；烷氧羰基烷基，譬如甲氧羰 基曱基、環己基氧基羰基甲基、1-曱氧羰基-1-乙基等；烷氧 羰基氧基烷基，譬如甲氧羰基氧基曱基、第三-丁氧羰基氧 基甲基、1-乙氧羰基氧基-1-乙基、1·環己基氧基羰基氧基小 乙基等；烷氧羰基胺基烷基，譬如第三-丁氧羰基胺基甲基 123505 -165- 200815422 等；烧胺基魏基胺基烧基，譬如甲胺基幾基胺基甲基等； 烧酸胺基烷基，譬如乙醯胺基甲基等；雜環族羰基氧基烷 基，譬如4-甲基六氫吡畊基羰基氧基甲基等；二烷胺基羰 基烧基’譬如二甲胺基羰基甲基、二乙胺基羰基甲基等； (5-(烧基）-2-酮基-1，3-二氧伍圜烯_4_基）烧基，譬如（5-第三·丁基 -2·酉同基-1，3-二氧伍圜烯基）甲基等；及（孓苯基_2•酮基二 氧伍圜烯_4_基）烷基，譬如（5-苯基_2_酮基-；1，3_二氧伍圜烯冰 基）甲基等。&quot;sulfonamide, the term includes the S_ and Ν_sulfonamide groups, meaning that the individual is -S〇2NI^R39 and the 38s〇2R39 group. R38 and R39 are independently hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl as defined herein. Thus, sulfonamide groups include, but are not limited to, amidoxime (_S〇2NH2). The squirrel- 5 division refers to the -SH group, whereas the sulphide includes the _ team 4 oxime group, the sulfoxide group includes the -S(0)R41 group, the sulfone group includes the 〇2^2 group, and the sulfonate. The thiol group includes -S〇2〇R43. 4,1141,1142 and 1143 are each independently substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylalkyl, heterocyclyl or heterocycloalkane as defined herein. base. The term "urea" refers to the group -NR44-C(0)-NR45R46. The R44, R45 and R46 groups are independently windy or substituted or unsubstituted alkyl, alkenyl, as defined herein. Alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl. The term 脒'' refers to -C(NR47)NR48R49 and -nr47c(nr48)r49, where 'R and R4 9 each independently hydrogen, or substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylalkyl, heterocyclyl or heterocyclylalkyl as defined herein. 123505 200815422 ” The term 胍'' means -NR50C(NR51)NR52R53, wherein R50, R51, R52 and each independently hydrogen or a substituted or unsubstituted alkyl, alkenyl, alkynyl group, as defined herein, Arylarylalkyl, heterocyclyl or heterocyclylalkyl. The term "enamine" means _c(r54)=C(r55)nr56r57 and NR54C(R55hc(R56)R57, wherein r54, r55, r56 and R57 are each independently nitrogen, as substituted or unsubstituted as defined herein. Alkyl, cycloalkyl, alkenyl, alkynyl, arylalkyl, heterocyclyl or heterocyclylalkyl. The term ''imine'' refers to -c(0)nr58c(0) R59, wherein r58 and r59 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkylalkenyl, alkynyl, arylarylalkyl, heterocyclyl or heterocyclylalkyl group, as defined herein The term "imine" refers to the _cr60 (nr61:^-n(cr60r61) group, wherein each of r60 and R is independently hydrogen, or a substituted or unsubstituted alkyl group, as defined herein, or a ring-burning a base, an alkenyl group, an alkynyl group, an arylalkylalkyl group, a heterocyclic group or a heterocyclic alkyl group, with the proviso that hydrogen is not the same as R01. The term "hydrogenthio-, protected" refers to a form in which such functional groups are protected from unwanted reactions by protecting groups. The protecting group A is familiar with &amp; the artist has used #, and can use f Know the program to add or remove, such as Protected groups for organic synthesis, Greene, TW; Wuts, PGM, John Wiley &amp; Sons, New Y〇rk, Νγ (3rd edition, 1999). Examples of protected hydroxyl groups include, but are not limited to, decyl ethers And, for example, by a reaction of a hydroxyl group with a reagent such as, but not limited to, tert-butyldimethyl-chlorodecane, trimethylchlorodecane, triisopropylchlorodecane, triethyl Alkyl chlorodecane; substituted thiol and ethyl ether such as, but not limited to, methoxy 123505-163-200815422 methyl ether, methylthiomethyl ether, benzyloxymethyl ether, third-butyl Oxymethyl-, 2, methoxyethoxymethyl ether, tetrahydro-methane-based, ethoxylated ethyl ether, #propyl ether, benzyl ether; s intended, such as but not Restricted to benzamidine phthalate, formate, acetate, trichloroacetate and trifluoroacetate. N-protection includes sulfhydryl groups, such as formazan, ethyl acetyl, propyl ketone, trimethyl Ethyl bromide, second-butylethyl hydrazino, 2-chloroethyl ketone, 2·glycidyl, difluoroacetinyl, triethylene acetyl, phthalic acid, ortho - Zoji benzene Oxidyl, a-chlorobutyryl, benzhydryl, 4-bromobenzylidene, 4-bromobenzylidene, 4-nitrobenzhydryl, etc.; a phenylsulfonyl group, a p-toluenesulfonyl group, or the like; a group capable of forming a carbamate such as a fluorenyloxycarbonyl group, a p-oxybenzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, a p-fluorenyl group + oxo anthraquinone, 2-trisyl yloxy aryl group, p-radical oxyl group, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxyfluorenylcarbonyl, 2 , 4-dimethoxycarbonylcarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxyfluorenyloxycarbonyl, μ(p-biphenyl) small methyl ethoxycarbonyl, α,α-dimethyl-3,5-dimethoxyfluorenyloxycarbonyl, diphenylmethyloxycarbonyl, second-butoxy , diisopropylmethoxymethyl, isopropoxy, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4- Nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthio Group and the like; alkyl groups, such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and alkyl silicon, such as trimethyl silicon group. Typical anthracene-protecting group is a methyl group, an ethyl fluorenyl group, a phenyl fluorenyl group, a trimethyl ethane group, a third butyl ethoxy group, a benzene sulfonyl group, a fluorenyl group, a 9-fluorenyl methyl group. Alkylcarbonyl (Fmoc), tert-butoxycarbonyl (Boc) and benzyl 123505 • 164-200815422 Oxycarbonyl (Cbz). Examples of protected thiol groups include, but are not limited to, thioethers such as S-benzyl sulfide, S-tert-butyl sulfide, and S-4-methylpyridine sulfide; substituted S-methyl Derivatives such as hemithio, disulfide and aminothio acetals; and others. Representative carboxy protecting groups are &lt;^ to (8 alkyl (e.g., methyl, ethyl or t-butyl, etc.); haloalkyl; alkenyl; cycloalkyl and substituted derivatives thereof, such as a ring a hexyl group, a cyclopentyl group or the like; a cycloalkyl group and a substituted derivative thereof, such as a cyclohexylmethyl group, a cyclopentyl fluorenyl group or the like; an aralkyl group such as a phenethyl group or a aryl group and a substituted derivative thereof a substance such as an alkoxy group or a triaryl group; an aralkenyl group such as a phenylvinyl group; an aryl group and a substituted derivative thereof such as a 5-hydroindenyl group; a dialkylaminoalkyl group; (e.g. dimethylaminoethyl, etc.); alkyl alkoxyalkyl, such as ethoxymethyl, butyl methoxymethyl, pentyloxymethyl, isobutyl methoxymethyl, isovaleryl Hydroxymethyl, 1-(propenyloxy)-1-ethyl, 1-(dimethylacetoxy)-1-ethyl, 1-methyl-1-(propenoxy) 1-ethyl, tridecylethenyloxymethyl, propyloxycarbonyl, etc.; cycloalkylhydrazineoxyalkyl, such as cyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxy Methyl, cyclopentylcarbonyloxymethyl, cyclohexylcarbonyl An oxymethyl group or the like; an arylalkyloxyalkyl group such as a benzylideneoxymethyl group, a benzamidineoxyethyl group or the like; an aralkylcarbonyloxyalkyl group such as a benzylcarbonyloxymethyl group; 2-benzylcarbonyloxyethyl, etc.; alkoxycarbonylalkyl, such as methoxycarbonylhydrazino, cyclohexyloxycarbonylmethyl, 1-decyloxycarbonyl-1-ethyl, etc.; alkoxycarbonyloxyalkane a group such as a methoxycarbonyloxycarbonyl group, a third-butoxycarbonyloxymethyl group, a 1-ethoxycarbonyloxy-1-ethyl group, a cyclohexyloxycarbonyloxyethyl group, or the like; An oxycarbonylaminoalkyl group, such as a tris-butoxycarbonylaminomethyl group 123505-165-200815422; an amine-based carbylamino group, such as a methylaminomethylamino group; An alkyl group, such as an acetaminomethyl group; a heterocyclic carbonyloxyalkyl group, such as a 4-methylhexahydropyridylcarbonyloxymethyl group; a dialkylaminocarbonyl group; Aminocarbonylmethyl, diethylaminocarbonylmethyl, etc.; (5-(alkyl)-2-keto-1,3-dioxolan-4-yl)alkyl, such as (5- Tris-butyl-2·indenyl-1,3-dioxolanyl) And (p-phenyl-2- ketodioxanthene-4-yl)alkyl group, such as (5-phenyl-2-keto--; 1,3-dioxy-cetene-based ice-based ) methyl etc.

V 热和此藝者將明瞭，本發明化合物可顯示互變異構現 象、構形異構現象、幾何異構現象及/或旋光異構現象等現 象。因在本專利說明書與請求項内之化學式附圖僅可表示 可能互變異構、構形異構、光學異構或幾何異構形式之一， 故應明瞭的是，本發明係涵蓋具有本文中所述之一或多種 利用性之化合物之任何互變異構、構形異構、光學異構及/ 或幾何異構形式，以及此等各種不同形式之混合物。 卜互變異構物”係指化合物之異構形式，其係彼此呈平 衡:異構形式之濃度係依其中發現該化合物之環境而定， 可為不同，依例如化合物是否為固體或係在有機或水溶 疋例如，在水溶液中，三唑類可顯示下列異構形 式，其係被稱為彼此之互變異構物：V heat and the art will recognize that the compounds of the invention may exhibit tautomeric phenomena, conformational isomerism, geometric isomerism, and/or optical isomerism. Since the chemical formulae in this patent specification and the claims can only represent one of the possible tautomeric, conformational, optical, or geometric isomeric forms, it should be understood that the present invention is encompassed by the present disclosure. Any tautomeric, conformational, optical, and/or geometric isomeric form of the one or more of the compounds of the use, and mixtures of such various forms. Isomorphism means an isomeric form of a compound which is in equilibrium with each other: the concentration of the isomeric form depends on the environment in which the compound is found, and may vary, depending on, for example, whether the compound is solid or organic Or water-soluble oxime, for example, in aqueous solution, triazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:

壯：如立即為熟諳此藝者所明瞭者，才亟多種官能基及其他 可顯不互變異構現象，且如本文中所述化合物之所有 123505 -166 - 200815422 互變異構物係在本發明之範圍内。 化合物之立體異構物（亦稱為光學異構物）包括-種結構 之所有對掌性、非對映異構及外消旋形式，除非明確地指 2特定立體化學。因此，本發明中所使用之化合物係包括 虽含或經解析之任何或所有不對稱原子處之光學異構物， 其可自描繪而明瞭。外消旋與非對映異構混合物兩者，以 及個別光學異構物可經單離或合成，以致能夠實質上不含 Γ其對掌異構或非對映異構配對物，且此等均在本發明之範 ^於本文中使用時，溶劑合物為分子與一或多個溶劑分 人聚集體些化合物具有與固定莫耳比之溶劑分子締 合於固態中之傾向。溶劑分子可藉由偶極_偶極交互作用、 離子-偶極交互作用、配位鍵等，與非溶劑分子交互作用。 ^劑為水時，溶劑合物係被稱為水合物。許多有機溶劑 '、了形成溶劑合物，包括例如醚類，譬如乙醚與四氫呋喃， :類，譬如甲醇與乙醇，酮類，譬如丙_，膽、咖〇及 溶劑合物可藉由此項技藝中已知之各種方法確認。 突，其中溶劑分子含有氯之溶劑合物可藉由1H NMR觀 =可用於確認溶劑合物之其他方法係包括熱重分析、示 地僅\^言十法、Χ_射線分析及元素分析。溶劑合物係容易 例經由使化合物溶解於溶劑中，並藉由適當技術’ ^ )東乾或結晶化作用技術移除未締合之溶劑而形 内產生此種溶劑合物係良好地在此項技藝之技術 事只上，經常情況是，化合物之小心乾燥係為移除作 123505 -167- 200815422 為溶劑合物—部份之殘留溶劑所必須。本文中所述之化合 物可形成溶劑合物，且所有此種溶劑合物係在本發明之範 圍内。 /在本么日月|&amp;圍内之某些化合物係為被稱為”前體藥物，，之 订生物别體藥物&quot;措辭表示已知直接作用藥物之衍生 物例如s曰類與醯胺類，當與藥物比較時，該衍生物具有 曰強之傳輸特徵與治療價值，且藉由酵素或化學方法轉變 成=性藥物’·參閱Notari，R.E.，”前體藥物動力學之理論與實 乃，錄予才以仏3〇9-323⑽5)，· Bodor，N·，’，前體藥物設計 之新賴途控”，未來襄# 6 : 16M82 (1981);及此响喊h， ’’前體藥物之設計··關於各種官能基與化學實體之生物可逆 何生物，，，在#邀#勿之設妒(Η· Bundgaard編著），段⑽㈣NewZhuang: As immediately apparent to those skilled in the art, a variety of functional groups and other tautomerisms can be exhibited, and all 123505-166 - 200815422 tautomers of the compounds as described herein are in the present invention. Within the scope. Stereoisomers (also known as optical isomers) of a compound include all pairs of palmitic, diastereomeric, and racemic forms of the structure unless specifically referenced to a particular stereochemistry. Thus, the compounds used in the present invention include optical isomers of any or all of the asymmetric atoms, whether contained or resolved, which are self-explanatory. Both racemic and diastereomeric mixtures, as well as individual optical isomers, may be isolated or synthesized such that they are substantially free of ruthenium or diastereomeric counterparts, and such As used herein, when used in the context of the present invention, a solvate is a molecule which is associated with one or more solvents. Some of the compounds have a tendency to associate with a solvent molecule having a fixed molar ratio in a solid state. Solvent molecules can interact with non-solvent molecules by dipole-dipole interaction, ion-dipole interaction, coordination bonds, and the like. When the agent is water, the solvate is called a hydrate. Many organic solvents have formed solvates, including, for example, ethers such as diethyl ether and tetrahydrofuran, such as methanol and ethanol, ketones, such as propyl, gall, curry and solvates. Various methods known in the art are confirmed. The process in which the solvent molecule contains a solvate of chlorine can be determined by 1H NMR = other methods which can be used to confirm the solvate include thermogravimetric analysis, display only, Χ-ray analysis and elemental analysis. The solvate is readily exemplified by the dissolution of the compound in a solvent and the removal of the unassociated solvent by a suitable technique of ' ^ ) totem or crystallization techniques. The technical work of the art is only on the occasion that the careful drying of the compound is necessary to remove the residual solvent as a solvate from 123505 to 167-200815422. The compounds described herein can form solvates, and all such solvates are within the scope of the invention. / Some of the compounds in the Japanese and Japanese |&amp;&quot; are known as "prodrugs," which are known to be direct bioactive derivatives such as scorpoids and quinones. Amines, when compared with drugs, have a reluctant transmission characteristic and therapeutic value, and are converted into a sex drug by enzyme or chemical method. See also Notari, RE," Theory of Prodrug Kinetics and Shi Nai, the record is only 仏3〇9-323(10)5),· Bodor,N·,', the new drug control of the prodrug design", the future 襄# 6 : 16M82 (1981); and this shout h, ''Precursor Design····························································································

York (1985)中，Goodman與Gilmans，治療學之痹理學差遽，第8 版，McGraw_Hill，Int Ed· 1992。前述參考資料及此處所列示之 所有參考資料，均據此以其全文併於本文供參考。 本發明化合物之藥學上可接受鹽係被認為是在本發明之 範圍内。當本發明化合物具有鹼性基團例如胺基時，藥學 上可接文之鹽可以無機酸類（譬如鹽酸、氫硼酸、硝酸、硫 西文及磷酸）、有機酸類（例如甲酸、醋酸、三氟醋酸、反丁 烯二酸、草酸、酒石酸、乳酸、順丁烯二酸、檸檬酸、琥 珀酸、蘋果酸、甲烷磺酸、苯磺酸及對_甲苯磺酸）或酸性 胺基酸（譬如天門冬胺酸與麩胺酸）形成。當本發明化合物 具有酸性基團例如羧酸基時，其可以金屬，譬如鹼金屬與 土 鹼金屬（例如 Na+、Li+、K+、Ca2+、Mg2+、Zn2 + )、氨、有 123505 -168- 200815422 基吡啶、乙醇胺、 如精胺酸、離胺酸 機胺類（例如三甲胺、三乙胺、峨σ定、甲 二乙醇胺、三乙醇胺）或鹼性胺基酸（例 及鳥胺酸）形成鹽。 本發明化合物可容易地藉由熟諳此藝者所f知之技術合 成。例如，式I化合物，其中L，為對L2之先質（參閱下文），York (1985), Goodman and Gilmans, Therapeutic Differences in Therapeutics, 8th ed., McGraw_Hill, Int Ed. 1992. The above references and all references cited herein are hereby incorporated by reference in their entirety. The pharmaceutically acceptable salts of the compounds of the invention are considered to be within the scope of the invention. When the compound of the present invention has a basic group such as an amine group, the pharmaceutically acceptable salt may be a mineral acid (such as hydrochloric acid, borohydride, nitric acid, thiazol and phosphoric acid), an organic acid (for example, formic acid, acetic acid, trifluoromethane). Acetic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid) or acidic amino acids (such as Aspartic acid is formed with glutamic acid. When the compound of the present invention has an acidic group such as a carboxylic acid group, it may be a metal such as an alkali metal and a soil alkali metal (for example, Na+, Li+, K+, Ca2+, Mg2+, Zn2+), ammonia, and has a 123505-168-200815422 basis. Pyridine, ethanolamine, such as arginine, amide amine amines (such as trimethylamine, triethylamine, hydrazinodine, methyldiethanolamine, triethanolamine) or basic amino acids (for example and ornithine) form salts . The compounds of the present invention can be readily synthesized by techniques known to those skilled in the art. For example, a compound of formula I, wherein L, is a precursor to L2 (see below),

Hal為鹵素，譬如Br、C1或I，且g、l1、y v Α 9 η a、γ、a、、R、 n及Q均如本文定義，可按圖式1中所 〇2N^^/Hal +表凤Hal is halogen, such as Br, C1 or I, and g, l1, yv Α 9 η a, γ, a, R, n and Q are as defined herein, and can be 2N^^/Hal as shown in Figure 1. +表凤

HpN A Hal AHpN A Hal A

圖式1 經適當衍化之鹵化吡啶（χ=Ν，Y=CH，或X==CH，γ=Ν)或 σ答呼（X、γ=Ν)係經由把所媒介之交又偶合，與適當芳基或 雜芳基二羥基硼烷，於鹼譬如AGO3、&amp;2〇〇3或Na2C〇3存在 下偶合’而產生中間物c，其中L，為對L2-Q之先質，或其中 L’為L、Q (中間物e)。例如，當L，含有羰基部份基團或氧鏈 123505 -169· 200815422 結時，L’可為L2-Q，其中L2係個別為-C(O)-或0(CH2)nC(0)， 且Q係如本文定義。或者，當L’含有經保護之羧酸根基團（例 如g旨）時，此基團係在驗性或酸性條件（例如個別為NaOH或 TFA)下去除保護，接著與HNR_Q偶合，以形成化合物e，其 中L2為C(0)NR。同樣地，當L’含有經保護之胺時，其可藉 由本文中所述之方法去除保護，並與Q-COOH偶合，導致化 合物e，其中L2為C(0)NR。 在胺與含羧酸酯部份基團間之偶合，可例如利用典型可 形成醯胺鍵結之試劑，譬如DCC、EDC、CDI、BOP、PyBOP、 HATU、HBTU、HCTU、TATU、TBTU、TDBTU、DEPBT、TSTU 等，或藉由引進活化部份基團於羧酸酯上而達成。活化部 份基團為充分反應性之脫離基，以允許在溫和條件下之醯 胺鍵結形成。典型活化部份基團包括F、Cl、Br、I、N3、 Ν·羥基琥珀醯亞胺、1-羥基苯并三唑、1-羥基-7-氮苯并三 唑、五氟基酚、五氯酚、對·硝基酚或oc(o)-〇Ry，其中Ry為 C^6烷基。適當鹼包括碳酸氫鈉，或適當有機胺，譬如吡 啶、N-甲基嗎福啉、二異丙基乙胺或三乙胺。因此，可使 用任何適當可形成醯胺鍵結之程序，譬如在Bodanszky，M.與 Bodanszky，A.，双合 A 紫務，Springer-Verlag (1984);或 Jones，J·展 基艘與双合政 Steven G· Davies 編著，Oxford Science (1992)中所 述者。 合成可經由使化合物e之硝基還原成如在化合物f中之胺 而被持續。任何適當方法可用於還原作用，包括例如氫化 作用，在溶劑中，譬如MeOH、EtOH或其類似物，使用阮尼 123505 -170- 200815422 f 錄或Pd/C作為㈣，或與Snci2反應，在溶劑中，譬如DMF， 於至溫下。標的式1化合物可藉由本文中所述偶合方法之 吏θ物f與G-COOH部份基團偶合而獲得。或者，使 用本文中所述之方法，首先使化合物e中之硝基還原，接著 與(ΚΧ)〇Η偶合’及最後為[’之轉化成l2_q。在又另一途捏 中，再一次使用本文中所述之方法，使化合物a中之硝基還 原，接著為月安基與G-CO〇H之偶合，與適當芳基二經基侧烷 之交又偶合’以獲得化合物h ’及最後為L’之轉化成Μ。 、、員似方去’含有L1之替代取向之化合物亦可經由從含 ^、、工保| g旨替代硝’基部份基團之經衍化❸定開始而獲 、匕口物’其中B與D為Ν’可按圖式2中所示製成Figure 1 The appropriately derivatized halogenated pyridine (χ=Ν, Y=CH, or X==CH, γ=Ν) or σ-answer (X, γ=Ν) is coupled by the intersection of the medium, and Suitably aryl or heteroaryl dihydroxyborane, coupled in the presence of a base such as AGO3, &amp; 2〇〇3 or Na2C〇3 to produce intermediate c, wherein L is a precursor to L2-Q, or Where L' is L, Q (intermediate e). For example, when L, containing a carbonyl moiety or an oxygen chain 123505 -169· 200815422, L' can be L2-Q, where L2 is individually -C(O)- or 0(CH2)nC(0) And Q is as defined herein. Alternatively, when L' contains a protected carboxylate group (eg, g), the group is deprotected under test or acidic conditions (eg, NaOH or TFA, respectively), followed by coupling with HNR_Q to form a compound. e, where L2 is C(0)NR. Similarly, when L' contains a protected amine, it can be removed by the methods described herein and coupled with Q-COOH, resulting in compound e, where L2 is C(0)NR. Coupling between the amine and the carboxylate-containing moiety can, for example, utilize reagents that typically form a guanamine linkage, such as DCC, EDC, CDI, BOP, PyBOP, HATU, HBTU, HCTU, TATU, TBTU, TDBTU , DEPBT, TSTU, etc., or by introducing an activating moiety to the carboxylic acid ester. The activating moiety is a fully reactive debonding group to allow for the formation of guanamine linkages under mild conditions. Typical activating moiety includes F, Cl, Br, I, N3, hydroxy hydroxy succinimide, 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, pentafluorophenol, Pentachlorophenol, p-nitrophenol or oc(o)-〇Ry, wherein Ry is C^6 alkyl. Suitable bases include sodium hydrogencarbonate or a suitable organic amine such as pyridine, N-methylmorpholine, diisopropylethylamine or triethylamine. Therefore, any suitable procedure for forming a guanamine bond can be used, such as in Bodanszky, M. and Bodanszky, A., Double A, Purpleer-Verlag (1984); or Jones, J. Edited by Steven G. Davies, ed., as described in Oxford Science (1992). The synthesis can be continued by reducing the nitro group of compound e to the amine as in compound f. Any suitable method can be used for the reduction, including, for example, hydrogenation, in a solvent such as MeOH, EtOH or the like, using Muni 123505-170-200815422 f or Pd/C as (d), or reacting with Snci2 in a solvent In the middle, such as DMF, to the temperature. The compound of the formula 1 can be obtained by coupling the 吏θ element f of the coupling method described herein with a G-COOH moiety. Alternatively, the nitro group in compound e is first reduced using the method described herein, followed by coupling with (ΚΧ) ’ and finally [' to l2_q. In yet another pass, the nitro group in compound a is reduced again using the method described herein, followed by coupling of the acetamino group to G-CO〇H, and the appropriate aryl di-based side alkane Crossing and coupling 'to obtain compound h' and finally L' is converted into hydrazine. , and the member may go to the 'alternate-containing compound containing L1, which can also be obtained from the derivatization of the nitric acid group containing the group, and the mouthpiece 'B And D is Ν' can be made as shown in Figure 2

圖式2 ’或 X=CH，Y=N)或 酉文性條件下（例如於 接著以疊氮化鈉處 ^適當衍化之胺基^比。定（χ=Ν， 胺基-嗒啡（X、Y=N)係例如經由在含水 HC1、H2S〇4存在下）以亞硝酸鈉處理， 123505 -171 - 200815422 理，而被轉化成其疊氮化物衍生物i。或者，錢化物部份 基團係經由使經適當衍化之溴比啶或溴_嗒畊與有機鋰= 劑，接著與甲苯磺醯基疊氮化物反應而被引進。將疊氮化 物與經衍化之炔烴（R_c三c_L〇在質子性溶劑中，例如水、乙 腈或其混合物，視情況於銅（Q/W金屬、或CuOU鷗）存 在下加熱（40-10(TC )，會導致含三唑中間物〗之形成，其中l 為對P-Q之先質，或其中L，g2。例如，红，為燒基:環燒 (、基、芳*、雜環基、芳烧基或雜環基烧基時，L，可為l2/ 其中L2為共價鍵，且q係如本文定義。或者，當[含有經保 護之羧酸根基團（例如酯）時，此基團係在鹼性或酸性條件 (例如個別為NaOH或TFA)下去除保護，接著與__卩偶合， 以形成化合物m，其中。為c(〇)NR。在下一步驟中化人 物m之石肖基係藉由本文中所述之方法還原成如在化合物: 中之胺。標的式II化合物，其中MMN，係藉由本文中 所述偶合方法之一，使化合物11與G_C00H部份基團偶合而 [獲得。或者’使用本文中所述之方法，首先可使化合物j 中之確基還原’接著與（KXX3H偶合，及最後為L•之轉化成 L2-Q。 結構q之中間物可充作對式Π化合物之先質，其中B為 Ν’且D為CR。結構q之中間物可按圖式3中所*製成（亦參 閱美國專利公報US2005/0256113)。 123505 -172- 200815422 02Ν&gt;^^ΝΗ2Figure 2 'or X = CH, Y = N) or under the conditions of the ( (for example, the amine group which is appropriately derivatized with sodium azide) (定=Ν, amino- morphine ( X, Y=N) is converted to its azide derivative i by treatment with sodium nitrite, for example, in the presence of aqueous HCl, H2S〇4, 123505 -171 - 200815422. The group is introduced by reacting a suitably derivatized bromopyridinium or bromine with an organolithium reagent followed by a toluenesulfonyl azide. The azide and the derivatized alkyne (R_c III) c_L〇 in a protic solvent such as water, acetonitrile or a mixture thereof, optionally in the presence of copper (Q/W metal, or Cuou gull) (40-10(TC), resulting in a triazole intermediate) Formed, wherein l is a precursor to PQ, or wherein L, g2. For example, red, is a burnt group: a ring-burning (, aryl, aryl*, heterocyclic, aryl or heterocyclic group, L And may be l2/ wherein L2 is a covalent bond, and q is as defined herein. Alternatively, when [containing a protected carboxylate group (eg, an ester), the group is in a basic or acidic condition The protection is removed (for example, NaOH or TFA, respectively), followed by coupling with __卩 to form compound m, where c(〇)NR. In the next step, the stone matrix of the character m is as described herein. The method is reduced to an amine as in the compound: the compound of formula II, wherein MMN is coupled to the G_C00H moiety by one of the coupling methods described herein [obtained. Or used herein In the method described above, the exact group in the compound j can be first reduced 'subsequently coupled with (KXX3H, and finally L• is converted to L2-Q. The intermediate of the structure q can be used as a precursor to the compound of the formula, wherein B is Ν' and D is CR. The intermediate of structure q can be made as shown in Figure 3 (see also US Patent Publication US 2005/0256113). 123505 -172- 200815422 02Ν&gt;^^ΝΗ2

圖式3 經適當衍化之胺基-吡啶（X=N，Y=CH，或x=CH，γ=Ν)或 胺基-塔畊（X、Υ=Ν)係例如經由重氮鹽以之還原作 用，而被轉化成肼P。與（Z)-2-甲醯基-3-羥基丙烯酸乙§旨（L 〇rg. Chem·，1982, 47, 2216)之反應，會導致吡唑中間物^之形成， 其中R為Η，且Γ為C(0)0Et。或者，p係與例如2_乙醯基_3_ 酮基丁酸曱酯反應，以形成中間物q，其中r為甲基。如前 述，I；可藉由去除保護及與HNR-Q偶合，而被轉化成L2-Q， 其中L2為C(0)NR。最後，式Π化合物，其中b為N，且D為 CR，係使用本文中所述之方法，經由使硝基還原，及所形 成胺與g-c(o)oh之偶合而獲得。 圖式3亦顯示結構r中間物之合成，其係為對式π化合物 之先質’其中Β為CR，且D為Ν。於原甲酸四甲酯存在下， 經適當衍化之胺基·吡啶（X=N，Y=CH，或x=CH，γ=Ν)或胺 基-塔呼（X、Υ=Ν)以2_硝基醋酸乙酯（US2005/0256113)，及在後 續步驟中以Fe之處理，係提供中間物r，如前述，其可使用 本文中所述之方法被轉化成標的式II化合物。衍化作用之 順序亦可被逆轉，以致首先使G-L2連接至核心環，接著為 圖式3中所示之合成步驟。 123505 -173 - 200815422 圖式4顯示針對關 °2Nv ^ ^ 於式II化合物中間物之其他合成途徑Figure 3 is a suitably derivatized amino-pyridine (X=N, Y=CH, or x=CH, γ=Ν) or an amine-tower (X, Υ=Ν), for example via a diazonium salt The reduction is converted to 肼P. The reaction with (Z)-2-methylindolyl-3-hydroxyacrylic acid (L 〇rg. Chem., 1982, 47, 2216) results in the formation of a pyrazole intermediate, where R is Η, And Γ is C(0)0Et. Alternatively, the p-series is reacted with, for example, 2-ethylidene-3-ylketobutanoate to form an intermediate q wherein r is a methyl group. As described above, I; can be converted to L2-Q by removing the protection and coupling with HNR-Q, where L2 is C(0)NR. Finally, a hydrazine compound of the formula wherein b is N and D is CR is obtained by reduction of the nitro group and coupling of the formed amine with g-c(o)oh using the methods described herein. Scheme 3 also shows the synthesis of the structure r intermediate, which is the precursor of the compound of formula π where Β is CR and D is Ν. In the presence of tetramethyl orthoformate, the appropriately derivatized amine-pyridine (X=N, Y=CH, or x=CH, γ=Ν) or amine-tower (X, Υ=Ν) to 2 Ethyl nitroacetate (US 2005/0256113), and treatment with Fe in a subsequent step, provides an intermediate r, as described above, which can be converted to the standard compound of formula II using the methods described herein. The order of the derivatization can also be reversed so that G-L2 is first linked to the core loop, followed by the synthetic steps shown in Scheme 3. 123505 -173 - 200815422 Scheme 4 shows other synthetic pathways for the intermediate of the formula II2vv ^ ^

圖式4 ( 化合物V可藉由經氟化吡啶或嗒畊衍生物s被經適當衍化 5-員雜％之親核性芳香族取代而獲得。或者，可使結構t (其 tHal為Br、C1或I)或u(其中W為二羥基硼烷或二羥基硼烷 酉旨衍生物）之化合物接受與經適當衍化雜環之鈀或銅所媒 介父叉偶合反應，以獲得中間物v，其可如前述進一步精巧 地製成。結構u之化合物可得自結構t之化合物，其中Hal 為Br。如前述，合成步驟之順序可改變，以致使G-L2之偶 合係在5-員雜環基部份基團之連接前進行。 ί 於上文圖式中所使用之經適當衍化吡啶與嗒畊起始物質 可按此項技藝中所已知者獲得。例如，對L1之替代取向之 吡啶先質，可藉由已報告之方法（參閱，例如國際申請案 PCT/US06/042679, J· Med. Chem·，1974, 17, 172; J· Org. Chem·，1984, 49, 193 ; J· Am. Chem. Soc·，1953, 75，737 ; J· Med_ Chem·，1977, 20, 129 ; J. Am. Chem· Soc·，1961，26, 3420 ; J. Am. Chem· Soc·，1947, 69, 2574 ; J· Med. Chem.，1978, 21，194 ; J. Med. Chem·，1993, 36, 2676 ; J. Med· Chem.，1990, 33, 1859 ;合成，1986, 400)，或藉由此等方法之例 123505 -174- 200815422 行修正或延伸而製成。Scheme 4 (Compound V can be obtained by substituting a fluorinated pyridine or a ruthenium derivative s with a suitably derivatized 5-membered nucleophilic aromatic. Alternatively, the structure t can be obtained (its tHal is Br, a compound of C1 or I) or u (wherein W is a dihydroxyborane or a dihydroxyborane derivative) is subjected to a coupling reaction with a palladium or copper-mediated parent fork of a suitably derivatized heterocyclic ring to obtain an intermediate v, It can be further elaborated as described above. The compound of structure u can be obtained from a compound of structure t, wherein Hal is Br. As described above, the order of the synthesis steps can be changed so that the coupling of G-L2 is in the 5-member The ring-forming moiety is attached prior to the linkage. The appropriately derivatized pyridine and hydrazine starting materials used in the above scheme can be obtained as known in the art. For example, an alternative orientation to L1. The pyridine precursor can be used by the reported method (see, for example, International Application No. PCT/US06/042679, J. Med. Chem., 1974, 17, 172; J. Org. Chem., 1984, 49, 193 J. Am. Chem. Soc., 1953, 75, 737; J. Med_Chem., 1977, 20, 129; J. Am. Chem. Soc·, 1961, 2 6, 3420; J. Am. Chem. Soc., 1947, 69, 2574; J. Med. Chem., 1978, 21, 194; J. Med. Chem., 1993, 36, 2676; J. Med·Chem , 1990, 33, 1859; Synthesis, 1986, 400), or by the method of the method 123505 - 174 - 200815422 modified or extended.

或者’式I與II化合物係個別按圖式5與6中所示，經由中 央核心部份基團之形成而獲得。Alternatively, the compounds of the formulae I and II are obtained individually as shown in Schemes 5 and 6, via the formation of a central core moiety.

肖基丙—經（按〇rg· Synth. c〇u，4, 觸中製成）與適當 酮’於醋酸銨存在下，在醇水混合物中，於高溫下之反應， 係獲得峨，其係、如前I㈣化，而產生式！化合物。基基丙--(According to 〇rg· Synth. c〇u, 4, made in the touch) and the appropriate ketone in the presence of ammonium acetate in an alcohol-water mixture at a high temperature to obtain hydrazine, Department, as before I (four), and production! Compound.

圖式6 弋化δ物之中間物y係以類似方式，經由2-硝基丙 與經適當衍化之（1H]，Hl·基）丙·2, X反應而獲得 述中間物X係自其相應之環氧化物衍生物開始，經由以 化納之開環作用製成，以產生疊氮基乙醇衍生物。後 間物係經由與適當炔煙反應，於銅線存在下，環. 123505 -175- 200815422 (1H-1，2,3-三吐-1-基）丙-2-醇中間物。最後，中間物x係藉習知 方法（例如Dess-Martin氧化作用），經由（1H-1，2,3-三吐-1-基）丙 -2-醇中間物之氧化作用而獲得。或者，中間物X係自無論是 其相應之氯基乙酮或甲苯磺醯基乙酮衍生物（製自羥基乙 酮衍生物）開始，經由與疊氮化納反應而製成，以產生疊氮 基乙酮中間物，其係以適當炔烴，於銅線存在下被環化。 在本發明内文中之”細胞素抑制劑π為一種化合物，其在 10 //Μ之濃度下會抑制所引致之細胞素自細胞釋出，達約 50%或大於50%。例如，TNFa釋出之引致可藉由但不限於細 胞或細胞系以脂多糖（LPS)或IL-lb之處理而達成，且係被本 文中所述之化合物抑制。 病症與特定細胞素含量上平衡缺失之結合係為此項技藝 中所習知，如藉由清單II中之參考資料所記載者。 清單II·描述細胞素所媒介之過程與病症之參考資料 病症 參考資料 異常出血 K Fassbender 等人，J Neurol Neurosurg Psychiatry 2001 70(4) : 534-7 ; JW Semple 等 人，TransfUs Apher Sci. 2003 28(3) : 237-342 膿腫 CE Lloyd 等人，Metabolism 2003 52(9): 1218-25 光化網狀徵候簇 J Hildesheim 等人，J Invest Dermatol. 2004 122(2) ： 497-502 急性混亂偏頭痛 F Perini 等人，Headache，2005 45(7) : 926-31 急性混亂老年癡呆症 I Ferrer 等人，Curr Alzheimer Res 2005 2(1): 3-18 急性肝細胞損傷 L Nagy 等人，Exp Biol Med 2003 228 ·· 882-890 123505 -176- 200815422 病症 參考資料 急性管狀壞死 K Fumichi 等人，Nephrol Dial Transplant 2002 17(3) ： 399-407 垂體腺性部疾病 H Kanasaki 等人，Biol Reprod 200 62(6): 1486-94 腺病毒感染 Q Liu 等人，Gene Ther· 2003 10(11) : 935_40 黏連物 J Yu 等人，J Biol Chem. 2004 279(48): 50446-54 黏連囊炎 I Voloshin 等人，Arthroscopy 2005 21(9): 1076 子宮附件炎 T Guvenal 等人，Eur Soc Hum Rep Emb 2001 16(8) ： 1732-1735 無γ球蛋白血症 C Ibanez 等人，BioDrugs 2005 19(1) : 59-65 原因不明髓樣化生 RA Mesa，Int J Hematol 2002 76 補充 2 : 296-304 過敏反應 KJ Escott 等人，Br J Pharmacol 2000 131 173-176 禿髮 MP Philpott 等人，Br J Dermatol 1996 135(6) ： 942-8 肺胞炎纖維化 H Matsuoka 等人，Am J physiol Lung Cell Mol Physiol 2002 283(1) ： L103-L112 殿粉樣變性病 K Migita 等人，Rheumatology (Oxford) 2005 44(4) ： 443.8 血管造形術 N Ohashi 等人，Arterioscler Thromb Base Biol 2000 20(12) ： 2521-6 狹心症 AS Gabriel 等人，J Intern Med 2000 248(1): 61-6 抗磷脂徵候簇 T. Koike 等人，Lupus 2005 14 : 799-801 動脈硬化癡呆症 A De Luigi 等人，Neurobiol Dis 2002 11(2): 208-14 顳動脈炎 AP Andonopoulos 等人，Ann Rheum Dis 2003 62 ： 1116 節肢動物先天性腦炎 SL Raung 等人，Biochem Biophys Res Commun 200511(327) · 399-406 123505 -177- 200815422 病症 參考資料 窒息 K Okazaki 等人，Biol Neonate 2006 89(3): 183-9 異位過敏性 WS Wong, Curr Opin Pharmacol 2005 5(3) · 264-71 心房纖維顫動 S Sanada 等人，Circulation 2001 104(6) ·· 705-10 ; J· Olgin 等人，WO 2007/053685 海狸熱 E Maciorkowska 等人，Med Wieku Rozwoj 2005 IX(4) ： 665-673 膽硬化 E Femandez-Martinez 等人，Exp Toxicol Pathol 2006 [在印刷前];TK Mao 等人， Hepatology 2005 42(4) : 802-8 骨質耗損 MA Karsdal 等人，J Biol Chem 2003 278(45) ·· 44975-87 ; M Matsumoto 等人，J Biol Chem 2000 275(40): 31155-61 ; M Matsumoto 等人， J Biol Chem 2004 279(44) ： 45969-79 細枝氣管炎 AS Farivar 等人，J Heart Lung Transplant 2004 23(8) ： 985-92 内分泌腺癌 M Moscova 等人，Cancer Res 2006 66(3): 1376-83 喉癌 J Westermarck 等人，Cancer Res 2000 60(24): 7156-62 念珠菌病 S NagafUchi 等人，Immunol Lett 2005 99(1): 130-5 ; R Deva 等人，J Immunol 2003 171(6) ： 3047-55 小細胞肺癌 AK Greenberg 等人，Am J Respir Cell Mol Biol 2002 26(5) ： 558-64 心臟肥大 L Xu 等人，J Mol Cell，Cardiol 2005 38(5) ·· 735-43 心臟手術 TA Khan 等人，J Thorac Cardiovasc Surg 2004 127(3) ·· 806-11 心臟擴大 S Wenzel 等人，Eur J Heart Fail 2005 7(4) ·· 453-60 123505 -178- 200815422 病症 參考資料 心臟炎 DA Neumann 等人，Clin Immunol Immunopathol 1993 68(2) ^ 181-90 頸動脈血管造形術 N Ohashi 等人，Arterioscler Thromb Base Biol 2000 20(12) ： 2521-6 頸動脈動脈内膜切除 術 E Profbmo 等人，J Cardiovasc Surg (Torino) 2003 44(2) ： 237-42 頸動脈支架 M Kotani 等人，Cardiovasc Res 2003 57(1): 265-76 頸動脈潰瘍 K Yoshida 等人，Circulation 2003 108(14): 1746-52 腹腔疾病 L Palova-Jelinkova 等人，J Immunol 2005 175(10) ： 7038-45 肝硬化 YP Zhang 等人，World J Gastroenterol 2006 12(9) ： 1392-6 結腸炎 E Hollenbach 等人，FASEB J 2004 18(13) ·· 1550-2 結腸炎肉芽腫的 D Hommes 等人，胃腸病學，2003 122(1) ·· 7-14 冠狀動脈分流移植 D Talmor 等人，Circ Res 2000 86(9) : 1004-7 冠狀動脈分流手術 D Talmor 等人，Circ Res 2000 86(9) : 1004-7 皮質白内障 J Zhou 等人，Invest Opthalmol Vis Sci 2004 45(7) ： 2314-23 皮質類固醇抗藥性氣喘 HT Holgate 等人，Lancet 2006 368 : 780-93 變性關節疾病 PH Marks 等人，Arthroscopy 2005 21(11): 1342-7 皮膚炎 J Hildesheim 等人，J Invest Dermatol· 2004 122(2): 497-502 ; Y Takanami-Ohnishi 等人，J Biol Chem 2002 277(40) ： 37896-903 糖尿病患者之 勃起神經病 MR Nangle 等人，Int J Impotence Res. 2006 18 ： 258-263 糖尿病患者之 勃起脈管病 MR Nangle 等人，Int J Impotence Res. 2006 18 ： 258-263 123505 -179- 200815422 病症 參考資料 腹瀉 MA Khan等人，免疫學2004 112⑷： 651-60 眼乾 SC Pflugfelder 等人，Curr Eye Res 1999 19(3) : 201-11 呼吸困難 H Lou 等人，Am J Physiol Heart Circ Physiol 2005 288(4) ： H1925-30 水腫 K Issbmcker 等人，FASEB J 2003 17(2): 262-4 末期腎病 SR Khan5 Clin Exp Nephrol 2004 8(2) ： 75-88 愛氏噸-巴爾 (Epstein_Barr)病毒感染 U Dirmeier 等人，Cancer Res 2003 63(11): 2982-9 發熱 BL Fiebich 等人，J Neurochem 2000 75(5): 2020-8 濾胞甲狀腺癌瘤 M Pomerance 等人，J Pathol 2006 209 : 298-306 胃腸炎 JM Kim等人，Eur J Immunol 2005 35(9): 2648-57 心臟病發作 YH Liu 等人，J Card Fail 2005 11(1) : 74-81 心臟分流手術 TA Khan 等人，J Thorac Cardiovasc Surg 2004 127(3) : 806-11 ; N Koike 等人，移植，2004 77(2) ： 286-92 心臟手術 TA Khan 等人，J Thorac Cardiovasc Surg 2004 127(3): 806-11 ; N Koike 等人，移植 2004 77(2) ： 286-92 心臟移植 TA Khan 等人，J Thorac Cardiovasc Surg 2004 127(3): 806-11 ; N Koike 等人，移植 2004 77(2) ： 286-92 肝炎 JP Moorman 等人，Respir Res 2005 6 : 105 ; C Tam 等人，J Virol 2002 76(19) : 9763-72 ; A Dolganiuc等人，胃腸病學2004 127(5) ： 1513-24 123505 -180- 200815422 病症 參考資料 A型肝炎 JP Moorman 等人，Respir Res 2005 6 ·· 105 ; C Tam 等人，J Virol 2002 76(19) : 9763-72 ; A Dolganiuc等人，胃腸病學2004 127(5) ： 1513-24 B型肝炎 JP Moorman 等人，Respir Res 2005 6 : 105 ; C Tam 等人，J Virol 2002 76(19) ·· 9763-72 ; A Dolganiuc等人，胃腸病學2004 127(5) ： 1513-24 C型肝炎 JP Moorman 等人，Respir Res 2005 6 : 105 ; C Tam 等人，J Virol 2002 76(19) : 9763-72 ; A Dolganiuc等人，胃腸病學2004 127(5) ： 1513-24 慢性肝炎 C Bureau 等人，J Biol Chem 2001 276(25): 23077-83 胰島素抗藥性 YH Shen 等人，J Biol Chem 2006 281(12): 7727-36; A Bloch_Damti 等人，Antioxid Redox Signal 2005 7(1M2)： 1553-67； AKushiyama 等人，J Biol Chem 2005 280(51) : 42016-25 腎力衰竭 T Kita 等人，Shock 2004 21(6) : 532-42 腎臟移植 K Fumichi 等人，Nephrol Dial Transplant 2002 17(3): 399-407; A Djamali 等人，移植 2005 79(12) ： 1645-57 成人慢性白血病 A Sainz-Perez 等人，白血病 2006 20(3): 498-504 肝硬化 HS Lee 等人，J Biomed Sci 2003 10(6 Pt 2) ·· 757-65 肝臟移植 T Liang 等人，Liver Transpl 2005 11(12): 1527-32 腦膜炎 D Constantin 等人，J Neurochem 2004 89(5)： 1166-74 腦膜炎細菌 D Constantin 等人，J Neurochem 200489(5): 1166-74 骨魏增生病症 E Katsoulidis 等人，Cancer Res 2〇〇5 65(19): 9029-37 123505 -181 - 200815422 病症 參考資料 肌病 A Migliore 等人，Eur Rev Med Pharmacol Sci 2005 9(6) : 373-8 ; DL Lefkowitz 等人，Med Hypotheses 2005 65(4) : 716-21 ; Le Gosselin 等人，Med Sci Sprots Exerc 2004 36(1): 44-51 ; IE Lundberg 等人，Rheum Dis Clin North Am 2002 28(4) ： 799-822 肌炎 GJ Hengstman 等人，Eur Neurol 2003 50(1): 10-5，H Sprott 等人，Rheumatology (Oxford) 2004 43(4) ： 524-6 新生兒展開之 多系統炎性疾病 R Goldbach-Mansky 等人，New Eng J Med 355(6) ： 581 腎炎 JR Timoshanko 等人，Curr Drug Targets Inflamm Allergy 2005 4(3) ： 353-62 神經肌肉病症 K Kaneyama 等人，Oral Surg Oral Med Pathol Oral Radiol Endod 2005 99(3) ： 276-84 ； N Ogura 等人，J Oral Pathol Med 2005 34(6): 657-63 ; DL Lefkowitz 等人，Med Hypotheses 2005 65(4) : 716-21 神經病 JM Gonzalez-Clemente 等人，Clin Endocrinol (Oxf) 2005 63(5) ： 525-9 閉塞性細枝氣管炎 AS Farivar 等人，J. Heart Lung Transplant， 2004 23(8) ： 985-92 口腔癌 NL Rhodus 等人，Mol Carcinog 2005 44(2): 77-82 經皮冠狀介入 N Ohashi 等人，Arterioscler Thromb Base Biol 2000 20(12) ： 2521-6 齒周膜骨質耗損 KL Kirkwood 等人，J Pharmacol Exp Ther 2007 320 ： 56-63 末梢神經病症 JM Gonzalez-Clemente 等人，Clin Endocrinol (Oxf) 2005 63(5) ： 525-9 神經病 JM Gonzalez-Clemente 等人，Clin Endocrinol (Oxf) 2005 63(5) ： 525-9 123505 -182- 200815422 病症 參考資料 腹膜滲析 I Daniels 等人，Clin Diagn Lab Immunol 1999 6(6) ： 878-84 胸膜疾病 CL Chung 等人，Chest 2005 128(2) : 690-7 肺炎 RT Sadikot J Immunol 2006 176(8) ： 4923-30 多肌炎 P Efthimiou 等人，Ann Rheum Dis 2006 65(9) ： 1233-6 後囊不透明化 S. Mendo, WO 2006/128152 播疼病 M Kato 等人，WO 2006/062069 肺纖維變性 LK Lundblad 等人，Am J Respir Crit Care Med 2005 171(12) : 1605-6 ; L Wang 等人， J Cell Physiol 2003 194(2) ： 215-24 ； R Vassall 等人，Chest 2002 124(1) : 413-414 ; P Pantelidis 等人，Respir Res 2001 2(6): 365-72 ; M Kolb 等人，J Clin Invest 2001 107(12) ： 1529-36 腎癌 S Ikemoto 等人，Oncol Rep 2003 10(6): 1947-55 腎滲析 G Tripepi 等人，J Am Soc Nephrol 2005 補充 1 ： S83-8 硬皮病 H Ihn 等人，J Invest Dermatol 2005 125(2): 247-55 ; Z Tutuncu 等人，Clin Exp Rheumatol 2002 20 (6 補充 28) : S146-51 ; AF Alexis 等 人，J Cutan Med Surg 2006 25 [在印刷之 前] 敗血性關節炎 J Anguita 等人，J Immunol 2002 168(12): 6352-7 Sjogren氏徵候蔟 Atzeni F 等人，Autoimmun Rev 2005 4(3): 144-52 脊椎炎關節黏連 J Braun 等人，Rheumatology (Oxford) 2004 43(9) ： 1072-84 Still氏疾病 Z Tutuncu 等人，Clin Exp Rheumatol 2002 20 (6 補充 28) : S146-51 ; J Cutan Med Surg 200625 [在印刷之前] 123505 -183 - 200815422 病症 ί性眼炎The intermediate y of the deuterated δ species is obtained in a similar manner by 2-nitropropane and the appropriately derivatized (1H), Hl. yl) propyl 2, X to obtain the intermediate X system from The corresponding epoxide derivative begins by ring opening with a naphthalene to produce an azidoethanol derivative. The latter system is reacted with an appropriate acetylene fumes in the presence of a copper wire, ring. 123505 - 175 - 200815422 (1H-1, 2, 3-trit-1-yl) propan-2-ol intermediate. Finally, the intermediate x is obtained by conventional methods (e.g., Dess-Martin oxidation) via oxidation of the (1H-1,2,3-trivo-1-yl)propan-2-ol intermediate. Alternatively, the intermediate X is prepared by reacting with sodium azide, whether it is its corresponding chloroethyl ketone or tolsulfonyl ketone derivative (produced from a hydroxyethyl ketone derivative), to produce a stack A nitrogen ketone intermediate, which is cyclized in the presence of a copper wire with a suitable alkyne. In the context of the present invention, the cytokine inhibitor π is a compound which inhibits the release of the induced cytokine from the cell at a concentration of 10 // ,, up to about 50% or more than 50%. For example, TNFa release This can be achieved by, but not limited to, the treatment of lipopolysaccharide (LPS) or IL-lb by cells or cell lines, and is inhibited by the compounds described herein. Combination of disorders with loss of balance in specific cytokine levels It is well known in the art, as described by the references in Listing II. List II. References describing the processes and conditions of cytokine mediators. References Abnormal bleeding K Fassbender et al., J Neurol Neurosurg Psychiatry 2001 70(4): 534-7; JW Semple et al., TransfUs Apher Sci. 2003 28(3) : 237-342 Abscess CE Lloyd et al., Metabolism 2003 52(9): 1218-25 Photochemical reticulate Syndrome J Hildesheim et al., J Invest Dermatol. 2004 122(2) : 497-502 Acute chaotic migraine F Perini et al., Headache, 2005 45(7): 926-31 Acute disorder Alzheimer's disease I Ferrer et al. 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Y Takanami-Ohnishi et al. , J Biol Chem 2002 277(40) : 37896-903 erectile neuropathy in diabetic patients MR Nangle et al., Int J Impotence Res. 2006 18 : 258-263 erectile vasculature in diabetic MR Nangle et al., Int J Impotence Res 2006 18 : 258-263 123505 -179- 200815422 Illness reference diarrhea MA Khan et al., Immunology 2004 112(4): 651-60 Eye dry SC Pflugfelder et al., Curr Eye Res 1999 19(3) : 201-11 Difficulty breathing H Lou et al, Am J Physiol Heart Circ Physiol 2005 288(4) : H1925-30 Edema K Issbmcker et al, FASEB J 2003 17(2): 262-4 End stage renal disease SR Khan5 Clin Exp Nephrol 2004 8(2) : 75-88 Epstein_Barr virus infection U Dirmeier et al, Cancer Res 2003 63(11): 2982-9 fever BL Fiebich et al, J Neurochem 2000 75(5): 2020-8 cytosolic thyroid carcinoma M Pomerance et al, J Pathol 2006 209: 298-306 Gastroenteritis JM Kim et al, Eur J Immunol 2005 35(9): 2648-57 Heart attack YH Liu et al, J Card Fail 2005 11(1) : 74 -81 Cardiac Shunt Surgery TA Khan et al., J Thorac Cardi Ovasc Surg 2004 127(3): 806-11; N Koike et al., Transplantation, 2004 77(2): 286-92 Cardiac Surgery TA Khan et al, J Thorac Cardiovasc Surg 2004 127(3): 806-11; N Koike et al., Transplantation 2004 77(2): 286-92 Heart Transplantation TA Khan et al, J Thorac Cardiovasc Surg 2004 127(3): 806-11; N Koike et al., Transplantation 2004 77(2): 286-92 Hepatitis JP Moorman et al, Respir Res 2005 6 : 105 ; C Tam et al, J Virol 2002 76(19) : 9763-72 ; A Dolganiuc et al, Gastroenterology 2004 127(5) : 1513-24 123505 -180 - 200815422 Disease Reference Hepatitis A JP Moorman et al, Respir Res 2005 6 ·· 105 ; C Tam et al, J Virol 2002 76(19) : 9763-72 ; A Dolganiuc et al, Gastroenterology 2004 127 (5 ) : 1513-24 Hepatitis B JP Moorman et al., Respir Res 2005 6 : 105 ; C Tam et al, J Virol 2002 76(19) · 9763-72 ; A Dolganiuc et al., Gastroenterology 2004 127 (5) ) : 1513-24 Hepatitis C JP Moorman et al, Respir Res 2005 6 : 105 ; C Tam et al, J Virol 2002 76(19) : 9763-72 ; A Dolganiuc et al., Gastroenterology 2004 127(5): 1513-24 Chronic hepatitis C Bureau et al, J Biol Chem 2001 276(25): 23077-83 Insulin resistance YH Shen et al, J Biol Chem 2006 281(12): 7727-36; A Bloch_Damti Etcin, Antioxid Redox Signal 2005 7(1M2): 1553-67; AKushiyama et al, J Biol Chem 2005 280(51) : 42016-25 Renal failure T Kita et al., Shock 2004 21(6): 532-42 Kidney Transplantation K Fumichi et al., Nephrol Dial Transplant 2002 17(3): 399-407; A Djamali et al., Transplantation 2005 79(12): 1645-57 Adult Chronic Leukemia A Sainz-Perez et al., Leukemia 2006 20 (3 ): 498-504 Liver Cirrhosis HS Lee et al, J Biomed Sci 2003 10(6 Pt 2) ·· 757-65 Liver Transplantation T Liang et al, Liver Transpl 2005 11(12): 1527-32 Meningitis D Constantin et al Human, J Neurochem 2004 89(5): 1166-74 Meningitis bacteria D Constantin et al, J Neurochem 200489(5): 1166-74 Osteoproliferative disorders E Katsoulidis et al., Cancer Res 2〇〇5 65(19) : 9029-37 123505 -181 - 200815422 Illness reference myopathy A Migliore et al., Eur Rev Med Pharmacol Sci 2005 9 ( 6): 373-8; DL Lefkowitz et al, Med Hypotheses 2005 65(4): 716-21; Le Gosselin et al, Med Sci Sprots Exerc 2004 36(1): 44-51; IE Lundberg et al., Rheum Dis Clin North Am 2002 28(4) : 799-822 Myositis GJ Hengstman et al., Eur Neurol 2003 50(1): 10-5, H Sprott et al., Rheumatology (Oxford) 2004 43(4): 524-6 A number of systemic inflammatory diseases R Goldbach-Mansky et al, New Eng J Med 355(6): 581 Nephritis JR Timoshanko et al, Curr Drug Targets Inflamm Allergy 2005 4(3) : 353-62 Neuromuscular disorders K Kaneyama Et al., Oral Surg Oral Med Pathol Oral Radiol Endod 2005 99(3): 276-84; N Ogura et al, J Oral Pathol Med 2005 34(6): 657-63; DL Lefkowitz et al, Med Hypotheses 2005 65 ( 4): 716-21 Neuropathy JM Gonzalez-Clemente et al., Clin Endocrinol (Oxf) 2005 63(5): 525-9 Occlusive tibial bronchitis AS Farivar et al., J. Heart Lung Transplant, 2004 23(8) : 985-92 Oral Cancer NL Rhodus et al, Mol Carcinog 2005 44(2): 77-82 Percutaneous Coronary Intervention N Ohashi Et al, Arterioscler Thromb Base Biol 2000 20(12) : 2521-6 Periorbital bone loss KL Kirkwood et al, J Pharmacol Exp Ther 2007 320 : 56-63 Peripheral neurological disorders JM Gonzalez-Clemente et al, Clin Endocrinol (Oxf) 2005 63(5) : 525-9 Neuropathy JM Gonzalez-Clemente et al., Clin Endocrinol (Oxf) 2005 63(5): 525-9 123505 -182- 200815422 Illness reference peritoneal dialysis I Daniels et al., Clin Diagn Lab Immunol 1999 6(6) : 878-84 Pleural disease CL Chung et al, Chest 2005 128(2) : 690-7 pneumonia RT Sadikot J Immunol 2006 176(8) : 4923-30 polymyositis P Efthimiou et al, Ann Rheum Dis 2006 65(9) : 1233-6 Posterior capsule opacity S. Mendo, WO 2006/128152 Pain in the disease M Kato et al, WO 2006/062069 Lung fibrosis LK Lundblad et al, Am J Respir Crit Care Med 2005 171 (12): 1605-6; L Wang et al, J Cell Physiol 2003 194(2): 215-24; R Vassall et al, Chest 2002 124(1): 413-414; P Pantelidis et al., Respir Res 2001 2(6): 365-72; M Kolb et al., J Clin Invest 2001 107(12) : 1529-36 Kidney Cancer S Ikemoto et al, Oncol Rep 2003 10(6): 1947-55 Renal Dialysis G Tripepi et al, J Am Soc Nephrol 2005 Supplement 1: S83-8 Scleroderma H Ihn et al, J Invest Dermatol 2005 125(2): 247-55; Z Tutuncu et al., Clin Exp Rheumatol 2002 20 (6 Supplement 28): S146-51; AF Alexis et al., J Cutan Med Surg 2006 25 [Before printing] Septic joints Yan J Anguita et al, J Immunol 2002 168(12): 6352-7 Sjogren's syndrome tzAtzeni F et al, Autoimmun Rev 2005 4(3): 144-52 spondylitis joint adhesion J Braun et al, Rheumatology (Oxford 2004 43(9) : 1072-84 Still's disease Z Tutuncu et al., Clin Exp Rheumatol 2002 20 (6 Supplement 28) : S146-51 ; J Cutan Med Surg 200625 [Before printing] 123505 -183 - 200815422 Illness ί Ophthalmitis

Weg^ner 氏肉穿腫病 參考資料 GN Palexas 等人 Scand J Immunol 1992 11 補充，173_5 D Klintman 等人，Ann Surg 2005 242(6) 830-8 S Haraguchi 等人，AIDS Res Ther 2006 3(1) : 8 [在印刷之前] G Chodorowska 等人，Ann Univ Mariae Curie Sklodowska [Med] 2003 58(2): 50-6 ; S Piconi 等人，Int Arch Allergy Immunol 2002 128(1): 59-66 ; B Hermes 等人，J Allergy Clin Immunol 1999 103(2 Pt 1) ： 307-14 JP Moorman 等人，Respir Res 2005 6 : 105 ; C Tam 等人，J Virol 2002 76(19) : 9763-72 ; A Dolganiuc等人，胃腸病學 2004 127(5): 1513-24 ; C Burea 等人，J Biol Chem 2001 276(25) ： 23077-83 D Huugen 等人，Am J Pathol 2005 167(1): 47-58 在 本發 整 明内文中之’’治療”，係意謂與病症或疾病有關聯 成部份減輕，或此等徵候之進一步進展或惡化 1 i彳爲止，或在處於發展疾病或病症危險下之病患 孃或1τ 之滅 中， 發明 牝合物之 成病症之防止或預防。當於本文中使用時，本 治療上有效量’’係指整體或一部份減輕與病 i關聯之徵候，或減緩或停止此等徵候之進一步 彳&amp;，或在處於發展疾病或病症危險下之病患中， 提供預防該疾病或病症之化合物量。正如熟諳此藝 ，預期本文中所揭示化合物之治療上有效量可依 症或 防止 威 Μ明綠 # · 於治療患有細胞素所媒介之病症或處於其危險 適^應徵而改變，例如本文中所述化合物之治療上 被治瘃之i〜 有蛛 -184- 123505 200815422 下之病患可能不同，相對於治療患有不同病症例如血管事 件、糖尿病、胰島素抗藥性或代謝徵候簇或處於其危險下 之病患之化合物治療上有效量》同樣地，亦預期例如在病 患中降低CRP-含量之化合物之治療上有效量，係可能與在 病患中提升HDL-含量之治療上有效量不同。 病患係為可得利於如本文中所述化合物之投藥之任何動 物。在一些具體實施例中，病患為哺乳動物，例如人類、 靈長類動物、#、貓、馬、乳牛、豬，齧齒動物，例如大 白鼠或老鼠。典型上，病患為人類。 C-反應性蛋白質(CRP)為血漿蛋白質，及藉由肝臟所產生 之急性期蛋白質。CRp為急性期反應物種類之一員，因其 含里會在發生於身體中之炎性過程期間急驟地上升。 係主要作為發炎之標記物使用。度量c_反應性蛋白質值並 將其記入表内，可証實可用於測定疾病進展或治療之有效 性。、經4被收集在血清分離管中之血液，係於醫學實驗室 中或在測喊點上分析。各種分析方法可用於CRi&gt;測定，鐾 如ELISA、免疫比濁法、快速免疫擴散及目視凝集作用。研 =才曰出具有CRP之高基底含量之病患係處於糖尿病、高血 壓及〜血官疾病之增加危險下。一般認為cRp含量毫克/ 升係表不低心血管危險，而含量&gt;3毫克/升係表示高危險。 ^蛋白為含有脂質與蛋白質兩者之複合物。在血漿中之 大。卩伤月曰質係以脂蛋白存在，並以本身被輸送。脂蛋白之 特被為其漂洋常數（例如密度）。不同種類之脂蛋白係存 在且包括高密度脂蛋白（HDL)與低密度脂蛋白（LDL)。hdl 123505 -185- 200815422Weg^ner's dental perforation reference GN Palexas et al. Scand J Immunol 1992 11 Supplement, 173_5 D Klintman et al, Ann Surg 2005 242(6) 830-8 S Haraguchi et al, AIDS Res Ther 2006 3(1) : 8 [Before printing] G Chodorowska et al., Ann Univ Mariae Curie Sklodowska [Med] 2003 58(2): 50-6 ; S Piconi et al., Int Arch Allergy Immunol 2002 128(1): 59-66 ; B Hermes et al, J Allergy Clin Immunol 1999 103 (2 Pt 1): 307-14 JP Moorman et al, Respir Res 2005 6 : 105 ; C Tam et al, J Virol 2002 76(19): 9763-72 ; A Dolganiuc Et al, Gastroenterology 2004 127(5): 1513-24; C Burea et al, J Biol Chem 2001 276(25): 23077-83 D Huugen et al, Am J Pathol 2005 167(1): 47-58 ''Treatment'' in the context of this disclosure means that it is associated with a condition or disease that is partially alleviated, or that further progression or deterioration of such signs is 1 i彳, or at risk of developing a disease or condition. In the prevention or prevention of the disease caused by the diseased mother or the 1τ, the treatment is used when used herein. An effective amount '' refers to a total or part that mitigates the signs associated with disease i, or slows or stops further progression of such symptoms, or provides prevention of the disease in a patient at risk of developing a disease or condition. Or the amount of the compound of the condition. As is well known in the art, it is expected that the therapeutically effective amount of the compound disclosed herein may be conditioned or prevented from deteriorating or treating the disease mediated by the cytokine or at risk. However, changes such as the therapeutic treatment of the compounds described herein may be different in patients with spiders 184-123505 200815422, with different conditions such as vascular events, diabetes, insulin resistance or metabolism relative to treatment. A therapeutically effective amount of a compound of a syndrome or a patient at risk thereof. Similarly, it is also expected that, for example, a therapeutically effective amount of a compound that lowers the CRP-content in a patient may increase HDL-content in the patient. The therapeutically effective amount is different. A patient is any animal that can be administered to a compound as described herein. In some embodiments, the patient is a mammal, such as a human, a primate, #, a cat, a horse, a cow, a pig, a rodent, such as a rat or a mouse. Typically, the patient is a human. C-reactive protein (CRP) is a plasma protein and an acute phase protein produced by the liver. CRp is a member of the acute phase of the reactants, as it contains a sharp rise during the inflammatory process that occurs in the body. It is mainly used as a marker of inflammation. The c_reactive protein value is measured and credited to the table to confirm the usefulness of the disease progression or treatment. The blood collected in the serum separation tube is analyzed in a medical laboratory or at a test point. Various assays are available for CRi&gt; assays such as ELISA, immunoturbidimetry, rapid immunodiffusion, and visual agglutination. Research = Only patients with a high substrate content of CRP are at increased risk of diabetes, high blood pressure and ~ blood disease. It is generally believed that the cRp content of mg/L is not a low cardiovascular risk, while the content of &gt; 3 mg/L represents a high risk. The protein is a complex containing both lipids and proteins. Large in plasma. The sputum sputum system is present as lipoprotein and is delivered as itself. Lipoproteins are characterized by their oceanic constants (such as density). Different types of lipoproteins exist and include high density lipoprotein (HDL) and low density lipoprotein (LDL). Hdl 123505 -185- 200815422

離份包含兩種主要離份，意即狐2(大的，漂浮職，密度 ㈣福克/毫升）與狐3(小的，稠密咖，密以脱21 克/宅升）。LDL係特別富含膽固醇g旨類。傳統上，高含量 LDL及/或低含量hdl係與冠狀動脈疾病有關聯。流行病學 研究已註實高漠度HDL (超過6G毫克/公合）具有抵抗心血 管疾病之保護價值。低濃度之胤（對於男性低於4〇毫克/ 公合’對於女性低於50毫克/公合）係為動脈粥瘤硬化性疾 病之正危險因子。LDL之接近最適宜含量係被認為在励至 129毫克/公合之間’其中低於i⑽毫克/公合之含量被認為 是最適宜’而極高LDL》量（高於19〇毫克/公合）係相應於心 臟疾病之最高增加危險。 此等含置之評估係與評估心血管及/或腦血管疾病之危 險有關聯。脂蛋白含量與三酸甘油_含量係使用此項技藝 中已知之例行方法度量與評估。市購可得之套件與檢測可 用以評估病患中之HDLHC之含量，及三酸甘油酯之 含ΐ。典型上，膽固醇分析係藉由兩種方法進行，意即nmr 為基礎之方法與超離心分離方法。第―種方法係以脂質環 ，之麵分析為基礎，以測定大小種類，且利用去旋以測 定各種類中之粒子數。第二種方法，以密度梯度超離心分 離為基礎，係度量跨越一範圍密度之膽固醇量。且利用去 旋以測定各離份中之膽固醇量（HDL，包括肋一與HDL3， LDL、IDL、VLDL) 〇 載脂蛋白A-I (ApoA-I)為血漿中HDL之主要蛋白質成份。此 蛋白質會促進從組織至肝臟之膽固醇流出以供排泄，且幫 123505 200815422 助從動脈清除膽固醇。 葡萄糖或’’血糖”通常係於約80-120毫克/公合之濃度下存 :於人類中’且為人類及許多其他生物體之碳水化：物能 量之主要來源。過量葡萄糖係被儲存於身體中（尤其是在肝 臟與肌肉中)作為糖原’一種似澱粉物質，其基本上為經聚 合之葡萄糖。糖原係按需要被生物代謝成為葡萄糖，以滿 足身體需要。 3葡萄糖通常會刺激胰島素之分泌與生物合成兩者。但 是’除了此葡萄糖刺激之胰島素分泌以外，係存在基底肤 島素分泌，意即生物學過程’胰島素係在藉由葡萄糖含量 或會促進胰島素分泌之其他藥劑之刺激不存在下，藉此過 程被釋入循環中，其係被提高，高於其&quot;斷食&quot;或未進食含 量。關於斷食與正餐後（用餐後）胰島素之數值，在健康人 們中，係個別為約14至145微微莫耳/升與1〇〇至3〇〇微微莫 耳/升，在胰島素抗藥性人們中具有可能3_至4_倍較高含量。 經糖基化（或經糖原化）之血紅素（血紅素Alc、hMc、 HbAlc或HgAlc)為一種主要用以確認隨著時間之血漿葡萄 糖濃度之血紅素形式。正常範圍（其已被發現於健康被實驗 者中）為4%至5_9%。患有糖尿病之人們經常具有較高含量之 HbAlc。雖然糖尿病患者治療目標會改變，但許多目標係包 括HbAlc值之標的範圍。具有良好葡萄糖控制之糖尿病患 者，係具有接近或在參考範圍内之HbAlc含量。國際糖尿病 聯盟與美國内分泌學學院建議册八。值低於6·5%，然而美國 糖尿病協會所建議之範圍係擴大至7%。極高表示不 123505 •187- 200815422 良葡萄糖控制。 胰島素抗藥性係為其中正常 肌肉；5 φ里之胰島素不足以從脂肪、 中之M H 1 素回應之症狀。在脂肪細胞 r之胰島素抗藥性會造成儲左 1合提-血將士 名存之三酸甘油酯之水解作用， 二“自由態脂肪酸。在肌肉中之胰島素抗藥 性自降低葡萄糖吸收，铁而為 ” y' 柄…、而在肝贓中之胰島素抗藥性會降 低葡萄糖儲存，1&gt; ，、中兩種作用均用以提高血糖。歸因於胰 、素机樂性之胰島素與葡萄糖之高血漿含量，、經常會導致 、Mi:候族與第2型糖尿病。代謝徵候蔟，亦稱為徵候襄 人代謝徵候簇X、胰島素抗藥性徵候族，係為醫學病症之 、、且，口/具有至少三種下列徵候與特徵：斷食高血糖（包括第 2型糖尿病或減弱之斷食葡萄糖、減弱之葡萄糖容許度或胰 島素抗藥性）、高血壓、中樞肥胖（亦稱為内臟肥胖病卜降 低之HDL膽固醇及提高之三酸甘油酯。 胰島素抗藥性可藉由下列適應徵偵測：以血液胰島素之 ^加g里’葡萄糖之增加血液含量，以回應口服葡萄糖容 許度試驗（OGTT)，經磷醯基化蛋白質激_B(AKT)之降低含 里’以回應胰島素投藥等。胰島素抗藥性可因細胞中胰島 素受體相關發出訊息系統之降低敏感性，及/或因胰臟中召 、、、田胞經過細胞凋零之損失而造成。亦有註據指出，胰島素 抗藥性可被特徵鑑定為具有從屬之炎性成份。 當紅血球死亡及其血紅素在巨噬細胞内破碎成血基質與 灰球蛋白時，膽紅素係被形成。血基質係經由中間化合物 膽綠素，進一步降解成Fe2+、一氧化碳及膽紅素。因為膽 123505 200815422The detachment consists of two main aliquots, namely fox 2 (large, floating, density (four) foke/ml) and fox 3 (small, dense coffee, dense to take off 21 g / house liter). The LDL system is particularly rich in cholesterol g. Traditionally, high levels of LDL and/or low levels of hdl have been associated with coronary artery disease. Epidemiological studies have documented that high-intensity HDL (over 6 Gmg/cm) is protective against cardiovascular disease. Low concentrations of bismuth (less than 4 mg/m for men) and 50 mg/m for women are positive risk factors for atherosclerotic disease. The approximate optimum content of LDL is considered to be between 129 mg/m2, where the content below i(10) mg/cm is considered to be the most suitable and extremely high LDL (more than 19 mg/m). ()) corresponds to the highest increased risk of heart disease. These assessments are associated with assessing the risk of cardiovascular and/or cerebrovascular disease. Lipoprotein content and triglyceride content are measured and evaluated using routine methods known in the art. Commercially available kits and tests can be used to assess the level of HDLHC in patients and the sputum of triglycerides. Typically, cholesterol analysis is performed by two methods, namely an nmr-based method and an ultracentrifugation method. The first method is based on the analysis of the lipid ring and the surface, to determine the size and type, and to use derotation to determine the number of particles in various classes. The second method, based on density gradient ultracentrifugation separation, measures the amount of cholesterol across a range of densities. Derotation was used to determine the amount of cholesterol in each fraction (HDL, including rib-and HDL3, LDL, IDL, VLDL). Apolipoprotein A-I (ApoA-I) is the major protein component of HDL in plasma. This protein promotes cholesterol efflux from the tissue to the liver for excretion and helps clear cholesterol from the arteries at 123505 200815422. Glucose or 'blood sugar' is usually stored at a concentration of about 80-120 mg/cm: in humans and carbon sequestration for humans and many other organisms: the main source of energy. Excess glucose is stored in In the body (especially in the liver and muscle) as a glycogen, a starch-like substance, which is basically a polymerized glucose. The glycogen is biometabolized into glucose as needed to meet the body's needs. 3 Glucose usually stimulates Both insulin secretion and biosynthesis. But 'in addition to this glucose-stimulated insulin secretion, there is basal peptide secretion, which means biological processes. 'Insulin is in other agents that use glucose or promote insulin secretion. The stimulus does not exist, and the process is released into the circulation, which is raised above its &quot;fasting&quot; or uneaten content. About the value of insulin after fasting and after dinner (after meal), in healthy people Medium, the individual is about 14 to 145 picomol / liter and 1 〇〇 to 3 〇〇 pico liter / liter, in the insulin resistance people have the possibility of 3 _ 4_ times higher content. The glycosylated (or glycogenylated) heme (heme Alc, hMc, HbAlc or HgAlc) is a heme form mainly used to confirm plasma glucose concentration over time. The normal range (which has been found in healthy subjects) is 4% to 5_9%. People with diabetes often have higher levels of HbAlc. Although the treatment goals of diabetic patients will change, many targets include HbAlc values. The scope of the target. Diabetes patients with good glucose control have HbAlc content close to or within the reference range. The International Diabetes Federation and the American College of Endocrinology recommend Book 8. The value is less than 6.5%, but the American Diabetes Association recommends The range is expanded to 7%. Extremely high means no 123505 • 187- 200815422 Good glucose control. Insulin resistance is the normal muscle; 5 φ of insulin is not enough to respond to symptoms from fat, MH 1 in the fat. Insulin resistance of the cell r will result in the hydrolysis of the left-handed-supplemented blood-triglyceride in the name of the blood, and the two "free-state fatty acids. Insulin resistance in muscle reduces glucose absorption, iron is "y' handle..., and insulin resistance in liver sputum reduces glucose storage, 1&gt;, both of which are used to increase blood sugar. Due to the high plasma content of insulin and glucose in pancreas and melanogenesis, it often leads to Mi: Houzu and Type 2 diabetes. Metabolic symptoms, also known as the sign of human metabolic syndrome X, insulin resistance The symptomatic family is a medical condition, and has at least three of the following symptoms and characteristics: fasting hyperglycemia (including type 2 diabetes or weakened fasting glucose, impaired glucose tolerance or insulin resistance), Hypertension, central obesity (also known as visceral obesity reduced HDL cholesterol and increased triglyceride. Insulin resistance can be detected by the following indications: the increase in glucose in the blood insulin Blood content in response to the oral glucose tolerance test (OGTT), which is reduced by the phosphorylation of protein _B (AKT) in response to insulin administration, etc. Insulin resistance Due to the reduced sensitivity of the insulin receptor-associated signaling system in the cell, and/or due to the loss of cell death in the pancreas, and the cell, there are also indications that insulin resistance can be characterized as It has a subordinate inflammatory component. When red blood cell death and its heme break down into a blood matrix and ash globulin in macrophages, bilirubin is formed. The blood matrix is further degraded into Fe2+ via the intermediate compound biliverdin. , carbon monoxide and bilirubin. Because of the gallbladder 123505 200815422

容於水中，故其係被運送至肝臟，且結合至白蛋白。 肝臟中經由與搭糖酸之共㈣用，而成為水溶 ,、、十I J之膽紅素或膽紅素葡萄糖荅酸係移動至肝臟之 ::二、官中’然後至膽囊中。膽紅素係被發現於血液中， 确疋呈經共_式（亦稱為直接膽紅素）或呈未經共輕形 /^稱為間接膽紅素）°總膽紅素之參考範圍為0.3-U)毫克 :接V對於直接膽紅素，其係為。丄0·3毫克/公合，然而對 間接膽紅素，其料克/公合。在其中過多血紅素 被破碎，或膽紅素之移除未能適#地發揮功能之疾病中， 在身體中之累積膽紅素會造成黃疫。血液中之總膽紅素之 -度’通常必須超過2_3毫克/公合，以提供容易 色。 處於心血管及/或腦血管事件危險下之病患，亦為以顯示 血官病症/事件之至少—種徵候作為表象之病患。顯示冠狀 相關血管事件之徵候，例如包括胸痛、異常心動電流波、 提高含量之絕血性標記物、壞死標記物或凝血酶/纖維蛋白 產生標記物。此種標記物包括但不限於具有肌肉及/或腦部 亞單位之肌酸激酶(，、0_二聚冑、札2、凝血酶抗凝血 酶(TAT)、可溶性纖維蛋白單體(SFM)、纖維蛋白肽入_、 肌血紅素、凝血酶先質蛋白質（TPP)、血小板單細胞聚集體 (PMA)及丘寧蛋白㈣。處於危險下之病患亦包括具有血检 形成事件（例如病症）病歷之病患，包括冠狀心臟疾病 (CHD)、中風或短暫絕血性發作（TIA)。CH〇之病歷可包括例 如MI、冠狀血管再形成程序、具有絕血性改變之絞痛之病 123505 -189- 200815422 歷，或正冠狀血管照片（例如顯示至少一個主冠狀動脈之大 於約50%狹窄）。 ’’癌症”一詞係指任何各種惡性贅瘤，其特徵為可侵入周 圍組織且轉移至新的身體位置之細胞增生。良性與惡性腫 瘤兩者係根據其中其被發現之組織類型作分類。例如，纖 維瘤係為纖維狀結締組織之贅瘤，而黑色素瘤為色素（黑色 素）細胞之異常生長。源自上皮組織，例如在皮膚、枝氣管Contained in water, it is transported to the liver and bound to albumin. The liver is used in combination with the tartrate (4) to become water-soluble, and the bilirubin or bilirubin glucose citrate is moved to the liver ::2, the middle of the body and then into the gallbladder. The bilirubin system is found in the blood, and is indeed a reference range of total bilirubin by total _ (also known as direct bilirubin) or unco-light/^ called indirect bilirubin. 0.3-U) mg: Connected to V for direct bilirubin.丄 0·3 mg / metric, whereas for indirect bilirubin, its gram / gram. In diseases where excessive hemoglobin is broken, or bilirubin is not removed, the accumulation of bilirubin in the body causes yellow plague. The total bilirubin in the blood - usually ' must must exceed 2 - 3 mg / metric to provide easy color. A patient at risk of cardiovascular and/or cerebrovascular events is also a patient with at least a manifestation of a blood disorder/event. Signs showing coronary-related vascular events include, for example, chest pain, abnormal cardiac current waves, increased levels of attenuating markers, necrotic markers, or thrombin/fibrin production markers. Such markers include, but are not limited to, creatine kinases with muscle and/or brain subunits (, 0-dimerization, Zha 2, thrombin antithrombin (TAT), soluble fibrin monomer (SFM) ), fibrin peptide into _, myoglobin, thrombin precursor protein (TPP), platelet unicellular aggregate (PMA) and quinine protein (4). Patients at risk also include blood test events (eg Illness) A patient with a medical record, including coronary heart disease (CHD), stroke, or transient episodes of exacerbation (TIA). The medical history of CH〇 may include, for example, MI, coronary revascularization procedures, and colic disease with a hemorrhagic change 123505 -189- 200815422 calendar, or a photograph of a positive coronary vessel (eg, showing at least about 50% of the stenosis of at least one primary coronary artery). The term ''cancer') refers to any of a variety of malignant neoplasms characterized by invasive surrounding tissue and metastasis Cell proliferation to new body locations. Both benign and malignant tumors are classified according to the type of tissue in which they are found. For example, fibroids are tumors of fibrous connective tissue, while melanoma is a pigment ( Abnormal color pigment) of cell growth. Derived from epithelial tissues, such as skin, trachea branches

及月中之惡性腫瘤，係被稱為癌瘤。上皮腺組織之惡性病 症，譬如已被發現於乳房、前列腺及結腸中者，係被稱為 腺癌。結締組織例如肌肉、軟骨、淋巴組織及骨頭之惡性 生長，係被稱為肉瘤。淋巴瘤與白血病係為發生在白血球 中之惡性病症。 就腫瘤形成、癌症、腫瘤生長或腫瘤細胞生長而論，可 #估抑制作用’其巾特別是藉由原發性或續發性腫瘤之延 遲出現，原發性或續發性腫瘤之減緩發展，原發性或續發 性腫瘤之降低發生，疾病續發作用之減緩或降低嚴重性， 遏制腫瘤生長與腫瘤之退化。於極端情況下，完全抑制係 於本文中稱為預防或化學預防。關於此點，”預防&quot;一詞係 包括無論是完全預防臨床上顯著腫瘤形成之展帛，或預防 在處於危險下之個體中腫瘤形成之臨床前顯著階段之展 開。亦意欲被此定義所涵蓋的是，預防轉變成為惡性細胞， 或遏制或逆轉惡性前細胞之進展成惡性細胞。這包括預防 治療處於發展腫瘤形成之危險下者。 、 ’感受傷害疼痛”一詞包括但不限於與化學或熱灼傷、皮 123505 -190- 200815422 膚之割傷、皮膚之挫傷、骨關節炎、風濕性關節炎、腱炎 及肌助膜疼痛有關聯之疼痛。 神經病原性疼痛，，一詞包括但不限於CRPS (複合區域性 疼痛徵候蔟）類型卜CRPS類型Π、反射交感性失養症 (RSD)、反射神經血管營養障礙、反射交感性失養症、反射 神、、二血g營養障礙、反射營養障礙、交感神經上保持之疼 痛徵候簇、灼狀神經痛、骨頭之Sudeck萎縮、痛神經營養障 (礙、肩手徵候蔟、外傷後營養障礙、三又神經痛、癌療後 神經痛、癌症及轉移相關之疼痛、幻想肢疼痛、纖維肌痛、 慢性疲勞徵候簇、脊髓損傷疼痛、中枢中風後疼痛、神經 根病、糖尿病患者之神經病、中風後疼痛、梅毒神經病， 及其他痛苦神經病原性症狀，譬如藉由藥物所引致者’壁 如長春新驗、㈣卡得（veleade)^时㈣。神經病原性 由於單神經病、多神經病、複合區域性疼痛徵候 族或去傳入神經所造成。 、、”神經病”-詞包括但不㈣神經系統上，尤 統上之功能性失調或病理學變化，且其臨床上之特 二神經病-詞表…神經 經表示來自身體一部份之感官輸入量 =神 是夹白由里心領失，且可因無論 成、由 糸統之末梢感官纖維或神經之中斷所迕 二神經病之病因學可為已知或未知。已括 : 之併發症或毒性狀態，譬如糖尿病，其係為最;見: 病症，會造成神經病’或照射、絕▲或脈管炎。應明 123505 -191 - 200815422 或未知病因學之此 瞭的是，本發明之方法可用以治療已知 等或其他慢性神經病之慢性疼痛。 於本發明中所使用之如本文所述化合物 v&gt;口療上有效 量，可依投藥途徑與劑型而改變。本發明化合物之有效θ 典型上係落在約0·001至高達100毫克/公斤/ 里 人之靶圍内，而And the malignant tumor in the middle of the month is called cancer. A malignant disease of the epithelial gland tissue, such as those found in the breast, prostate, and colon, is called adenocarcinoma. The malignant growth of connective tissue such as muscle, cartilage, lymphoid tissue and bone is called sarcoma. Lymphoma and leukemia are malignant conditions that occur in white blood cells. In terms of tumor formation, cancer, tumor growth, or tumor cell growth, it is possible to estimate the inhibition of the disease, especially by the delay of primary or secondary tumors, the slow development of primary or secondary tumors. The reduction of primary or secondary tumors occurs, and the continuation of the disease slows or reduces the severity, inhibiting tumor growth and tumor regression. In extreme cases, complete inhibition is referred to herein as prevention or chemoprevention. In this regard, the term "prevention" includes both the prevention of clinically significant tumor formation, or the prevention of pre-clinical significant stages of tumor formation in individuals at risk. It is also intended to be defined by this definition. Covering the prevention of transformation into malignant cells, or suppressing or reversing the progression of malignant cells into malignant cells. This includes prevention and treatment at risk of developing tumor formation. The term 'feeling pain' includes but is not limited to chemistry Or thermal burns, skin 123505 -190- 200815422 skin cuts, skin contusions, osteoarthritis, rheumatoid arthritis, tendonitis and muscle-assisted pain associated with pain. Neuropathogenic pain, including but not limited to CRPS (complex regional pain syndrome) type CRPS type Π, reflex sympathetic dystrophy (RSD), reflex neurovascular dystrophy, reflex sympathetic dystrophy, Reflex God, two blood g dystrophies, reflex dystrophies, pain syndromes maintained on sympathetic nerves, burning neuralgia, Sudeck atrophy of bones, painful neurotrophic disorders (obstruction, shoulder-hand syndrome, post-traumatic nutrition disorders, Third, neuralgia, post-therapy neuralgia, cancer and metastasis related pain, fantasy limb pain, fibromyalgia, chronic fatigue syndrome, spinal cord injury pain, central post-stroke pain, radiculopathy, diabetic neuropathy, stroke Post-pain, syphilitic neuropathy, and other painful neuropathic symptoms, such as those caused by drugs, such as the new wall of Changchun, (4) veleade (4). Neuropathogenicity due to mononeuropathy, polyneuropathy, complex area Sexual pain syndrome or afferent nerves., "Nervous disease" - words include but not (four) on the nervous system, the functional loss of the general system Tune or pathological changes, and its clinical special secondary neuropathy - vocabulary ... nerves indicate that the sensory input from a part of the body = God is the white is lost by the heart, and can be due to The etiology of peripheral sensory fibers or nerves may be known or unknown. The complication or toxic state, such as diabetes, is the most common; see: illness, can cause neuropathy' or irradiation, ▲ or vasculitis. It should be noted that 123505 -191 - 200815422 or unknown etiology, the method of the present invention can be used to treat chronic pain known or other chronic neuropathy. As used in the present invention The therapeutically effective amount of the compound v&gt; described herein may vary depending on the route of administration and the dosage form. The effective θ of the compound of the present invention typically falls within the target range of from about 0.001 to up to 100 mg/kg/min. and

更典型上係在約0.05至高達10毫克/公斤/天之範圍内。典型 上，於本發明中所使用之一或多種化合物係經選擇，2提 供顯示高治療指數之配方。治療指數為在毒性與治療作用 間之劑量比’其可以LDw與EDm間之比例表 LU5 Q為達 50%個體群致死之劑量，而ED”為在5〇%個體群中於治療上 有效之劑;f。LD5Q與ED5G係在動物細胞培養物或實驗動物 中’藉由標準醫藥程序測定。 治療亦可包括投予本發明之化合物或醫藥配方，且併用 其他療法。本發明之組合可同時、個別或相繼地投予。例 如’本發明之化合物與醫藥配方可在手術程序及/或放射療 法之前、期間或之後投予。或者’本發明化合物亦可搭配 本文中所述之其他消炎劑'抗癌劑及其他藥劑—起投予。 就發炎而論’如本文中所述許多類型之免疫_、免疫壓 抑或細胞抑制藥物可與細胞素抑制劑合併使用。 产=性劑之特定量係依所使用之特定藥劑、。被治療或 处^之矢頁型、症狀 之化合物與任何選用其他活性劑之量而定。 及^本=明之—些具體實施例中，-或多種本發明化合物 種活性劑係以一種順序且在時間間隔内投予病患， 123505 •192- 200815422 更典型上為人類，以致化合物可與其他藥劑一起發生作用， 相對於若其係以其他方式投予所獲得之利益’以提供增強 之利盈。例如，其他活性劑可藉由共同配方而共同投予， ’投藥’或以任何順序，在不同時點下相繼投藥；但是， 右非同時技藥，則其應在時間上足夠接近時投藥，以提供 所要之治療或預防作用。在—些具體實施例中，化合物與 -他活性劑係在重疊之時間下施加其作用。每—種其他活 f'性劑可以任何適當形 &lt;，且藉任何適當途徑，個別地投予。 在其他具體貫施例中，化合物係在其他活性劑投藥之前、 同時或之後投予。 在各種實例中，化合物與其他活性劑係在小於約1小時 間隔，在約1小時間隔，在約i小時至約2小時間隔，在約2 小時至約3小時間隔，在約3小時至約4小時間隔，在約4小 時至約M、時間隔，在約5小時至約6小時間隔，在約6小時 至約7小時間隔，在約7小時至約8小時間隔，在約8小時至 I約9小時間隔’在約9小時至約1〇小時間隔，在約ι〇小時至 約η小時間1%，在約u小時至約12小時間隔，不超過24小 時間隔，或不超過48小時間隔下投予。在其他實例中，化 合物與其他活性劑係同時地投予。在又其他實例中，化合 物與其他活性劑係藉由共同配方同時地投予。 在其他實例中，化合物與其他活性劑係在約2至4天間 隔，在約4至6天間隔，在約1週間隔，在約J至2週間隔， 或超過2週間隔下投予。 在某些實例中，本發明化合物與視情況選用之其他活性 123505 -193- 200815422 刮係循環地投m循環療法係涉及投予第—種藥劑， 歷經-段時間，接著投予第二種藥劑及/或第三種藥劑，歷 :奴日守間’並重複此相繼投藥。循環療法可提供多種利 盈’例如降低對-或多種療法之抗藥性之發展，避免或降 低-或多種療法之副作用，及/或改善治療之功效。 八他只例中，本發明化合物與視情況選用之其他活性 ，係以小於約3週之循環投予，每兩週約一次，每ι〇天約一More typically, it is in the range of from about 0.05 up to 10 mg/kg/day. Typically, one or more of the compounds used in the present invention are selected, and 2 provides a formulation that exhibits a high therapeutic index. The therapeutic index is the dose ratio between toxic and therapeutic effects. 'The ratio between LDw and EDm is LU5 Q is the dose of 50% of the individual group, and ED" is therapeutically effective in 5% of the individual population. The LD5Q and ED5G lines are determined in animal cell cultures or experimental animals by standard medical procedures. Treatment may also include administration of a compound or pharmaceutical formulation of the invention, in combination with other therapies. Administered individually or sequentially. For example, 'the compounds and pharmaceutical formulations of the invention may be administered before, during or after surgery procedures and/or radiation therapy. Or 'the compounds of the invention may also be combined with other anti-inflammatory agents described herein 'Anticancer agents and other agents are administered. As far as inflammation is concerned, as described herein, many types of immuno-, immunosuppressive or cytostatic drugs can be combined with cytokine inhibitors. Depending on the particular agent used, the type of the treatment, or the type of the symptom, the compound of the symptom, and the amount of any other active agent selected, and the specific embodiment, - or A plurality of active agents of the present invention are administered to a patient in a sequence and at intervals, 123505 • 192-200815422, more typically human, such that the compound can interact with other agents, as opposed to if it is otherwise Investing in the benefits obtained' to provide enhanced benefits. For example, other active agents can be co-administered by co-formulation, 'administering' or in any order, at different times, at the same time; however, right non-simultaneous technology The drug, which should be administered in close enough proximity to provide the desired therapeutic or prophylactic effect. In some embodiments, the compound and the other active agent exert their effects at overlapping times. The active agent can be administered in any suitable form &lt;RTIgt;&lt;&gt;&gt;&lt;&gt;&gt;&lt;&gt;&gt;&apos;&apos;&apos;&apos;&apos;&apos;&apos;&apos;&apos;&apos; The compound and the other active agent are at intervals of less than about 1 hour, at intervals of about 1 hour, at intervals of from about 1 hour to about 2 hours, and from about 2 hours to about 3 hours. Separation, at intervals of from about 3 hours to about 4 hours, at about 4 hours to about M, hourly intervals, at intervals of from about 5 hours to about 6 hours, at intervals of from about 6 hours to about 7 hours, from about 7 hours to about 8 The hour interval, at intervals of about 8 hours to about 9 hours, is between about 9 hours and about 1 hour interval, about 1% from about ι hr to about η small time, at intervals of about u hours to about 12 hours, no more than The administration is administered at intervals of 24 hours, or no more than 48 hours. In other examples, the compound is administered concurrently with other active agents. In still other examples, the compound and the other active agents are administered simultaneously by a co-formulation. In other examples, the compound is administered with other active agents at intervals of about 2 to 4 days, at intervals of about 4 to 6 days, at intervals of about 1 week, at intervals of about J to 2 weeks, or at intervals of more than 2 weeks. . In certain instances, the compounds of the invention and optionally other active agents 123505-193-200815422 are administered cyclically to the m-cycle therapy for administration of the first agent over a period of time followed by administration of the second agent. And / or a third agent, calendar: slaves to the day and repeat this drug. Circulatory therapy can provide a variety of benefits, such as reducing the development of resistance to - or multiple therapies, avoiding or reducing - or side effects of multiple therapies, and / or improving the efficacy of the treatment. In his only case, the compound of the present invention and other activities selected as appropriate are administered in a cycle of less than about 3 weeks, about once every two weeks, about one per 〇 day.

次’或每週約一次。一個循環可包括藉由灌注投予本發明 化合物與視情況選用之第二種活性劑，每循環歷經㈣分 鐘，每循環約i小時，每循環約45分鐘，每循環約3〇分鐘， 或每循環約15分鐘。各循環可包括至少i週休息，至少㉔ ^息’至少3週休息。投予之循環數目為^至約12個循 %，更典型上為約2至約1〇個循冑，而更典型上為約2至約 8個循環。 /口療之過私可以共同方式投予病患意即其他活性劑之 個別劑量係個別地投予，而係在—段時間間隔内，以致本 發明化合物可與其他活性劑—起發生作用。例如，一種成 料每週投予-次，且併用其他成份，其可每兩週一次或 每三週-次投予。換言之，服藥使用法係共同地進行，即 使治療劑並未同時或在同一天期間投予。 其他活性劑可與本發明化合物相加地， 效地發生作用。在一項實例中，本發明化合爾二 種第二種活性劑在相同醫藥組合物中同時投予。在另一項 實例中，本發明化合物係與—或多種第二種活性劑在個別 123505 -194- 200815422 醫藥組合物中同時投予。 物係在投予第項貫例中，本發明化合 涵蓋本發明化人私“卜戈之後杈予。本發明係意欲 俨之措蘂,r f J猎由相同或不同投藥途 k之投桌，例如口 太恭日日几人1 、非、、二知。在某些具體實施例中，當 &quot; ό物與可能產生不利 个W田Η乍用（包括但不限於毒性） 種活性劑同時投科，第二種活性射有利地在降 -、不利剎作用被誘出之閥值之劑量下投予。 本發明亦提供醫藥組合物與藥劑’其可藉由混合一或多 種本發明化合物、其前體藥物、其藥學上可接受之鹽、其 -八構物丨互麦異構物或其溶劑合物，伴隨著藥學上 可接受之載劑、賦形劑、黏合劑、稀釋劑或其類似物而製 成’以預防和治療與過量細胞素生產有關聯之病症。本發 明之化合物與組合物可用以製備配方與藥劑，其係預防或 治療如本文中所揭示與過量細胞素生產有關聯之多種病 症，例如涉及發炎之疾病與病理學症狀，疼痛，癌症等。 此種組合物可呈例如顆粒、粉末、片劑、膠囊、糖漿、栓 劑、注射液、乳化液、酏劑、懸浮液或溶液之形式。本發 明組合物可經調配，供各種投藥途徑用，例如藉由口腔、 非經腸、局部、直腸、鼻、陰道投藥，或經由植入儲器。 非經腸或系統投藥包括但不限於皮下、靜脈内、腹膜腔内、 肌内、關節内、滑膜内、胸骨内、鞘内、病灶内及顱内注 射。下述劑型係以實例方式給予，而不應被解釋為限制本 發明。 對於口腔、面頰及舌下投藥，粉末、懸浮液、顆粒、片 123505 •195- 200815422 劑'丸劑、膠囊、料的¥此&amp;„ 劑型。此^ 物及小藥囊係可接受作為固體 上了技/例如經由將-或多種本發明化合物或其藥學 =Γ鹽或互變異構物，與至少一種添加劑譬如澱粉 或其他添加劑混人&amp;制Λ、 . 口而製成。適*添加劑為蔗糖'乳糖、纖 龄越“、/露醇、麥芽糖醇、葡聚醣、殿粉、填脂、海藻 夂二幾丁貝、脫乙醯殼多糖、果膠、西黃蓍樹膠、阿拉Second or about once a week. One cycle can include administering a compound of the invention and optionally a second active agent by infusion, each cycle of (four) minutes, about one hour per cycle, about 45 minutes per cycle, about 3 minutes per cycle, or per cycle. Cycle for about 15 minutes. Each cycle may include at least i weeks of rest and at least 24 months of rest for at least 3 weeks. The number of cycles administered is from about 2 to about 12 cycles, more typically from about 2 to about 1 cycle, and more typically from about 2 to about 8 cycles. The oral administration of the oral administration can be administered to the patient in a common manner, i.e., the individual doses of the other active agents are administered separately, and within a time interval, such that the compounds of the invention can interact with other active agents. For example, one ingredient is administered once a week, and other ingredients are used in combination, which can be administered once every two weeks or every three weeks. In other words, the dosing regimen is performed collectively, even if the therapeutic agents are not administered simultaneously or during the same day. Other active agents may act additively in combination with the compounds of the invention. In one embodiment, the two second active agents of the present invention are administered simultaneously in the same pharmaceutical composition. In another example, the compounds of the invention are administered simultaneously with - or a plurality of second active agents in separate pharmaceutical compositions of 123505 - 194 - 200815422. In the case of the administration of the first embodiment, the present invention encompasses the invention of the invention. The invention is intended to be a singularity, and the invention is intended to be used for the same or different administration methods. For example, a few people on a daily basis, a non-, and a second. In some embodiments, when &quot; The second active shot is advantageously administered at a dose that lowers the threshold at which the adverse brake action is induced. The invention also provides pharmaceutical compositions and medicaments which are capable of mixing one or more compounds of the invention a prodrug thereof, a pharmaceutically acceptable salt thereof, an octa-artactant, or a pharmaceutically acceptable salt thereof, accompanied by a pharmaceutically acceptable carrier, excipient, binder, diluent Or an analogue thereof to form a 'prevention and treatment of a condition associated with excess cytokine production. The compounds and compositions of the invention may be used to prepare a formulation and an agent which is prophylactic or therapeutic as disclosed herein with excess cytokines Produce a variety of related conditions, such as Inflammatory diseases and pathological symptoms, pain, cancer, etc. Such compositions may be in the form of, for example, granules, powders, tablets, capsules, syrups, suppositories, injections, emulsions, elixirs, suspensions or solutions. The compositions of the invention may be formulated for various routes of administration, for example, by buccal, parenteral, topical, rectal, nasal, vaginal administration, or via an implanted reservoir. Parenteral or systemic administration includes, but is not limited to, subcutaneous, Intravenous, intraperitoneal, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injections. The following dosage forms are given by way of example and are not to be construed as limiting the invention. Oral, cheek and sublingual administration, powder, suspension, granules, tablets 123505 • 195- 200815422 Agents 'Pills, capsules, materials ¥ this &amp; „ dosage form. The drug and vesicles are acceptable as solids/for example by mixing - or a plurality of compounds of the invention or their pharmaceutically acceptable hydrazine salts or tautomers with at least one additive such as starch or other additives. Made of Λ, . Suitable additives are sucrose 'lactose, fiber age", / melitol, maltitol, dextran, temple powder, fat filling, seaweed diced diced bismuth, acetaminophen, pectin, scutellaria ,Allah

:膠、明膠、膠原、赂蛋白、白蛋白、合成或半合成聚合 :或：油醋。口服劑型可視情況含有其他成份以幫助投 樂’譬如不活性稀釋劑，或潤滑劑，譬如硬脂酸鎂，或防 腐劑’譬如對經基苯甲酸醋或花楸酸，或抗氧化劑，譬如 抗壞血酸、母育粉或半胱胺酸，崩解劑、黏合劑、增稠劑、 緩衝劑、增甜劑、橋味劑或芳香劑。片劑與丸劑可以此項 技藝中已知之適當塗覆物質進一步處理。 供口服投藥之液體劑型可呈藥學上可接受之乳化液、糖 漿、酏劑、懸浮液及溶液之形式，其可含有不活性稀釋劑， 譬如水。醫藥配方與藥劑可使用無菌液體，譬如但不限於 油、水、醇及此等之組合，製成液體懸浮液或溶液。可添 加某予上適當之界面活性劑、懸浮劑、乳化劑，供口服或 非經腸投藥。 如上述，懸浮液可包括油類。此種油類包括但不限於花 生油、芝麻油、棉籽油、玉米油及橄欖油。懸浮液製劑亦 了含有月曰肪酸之自旨類’譬如油酸乙醋、肉豆逢酸異丙醋、 月曰肪Sic甘油_及乙酿化脂肪酸甘油g旨。懸浮液配方可包括 醇類，譬如但不限於乙醇、異丙醇、十六醇、甘油及丙二 123505 -196- 200815422 醇。醚類，譬如但不限於聚( 油與石壤油；及水，亦 ：、石油烴類’譬如礙 J J便用於懸洋液配方中。 可注射劑型—般包括含水 適者公搿為丨々 又A，由懸汙液，其可使用 田Μ或潤關與_㈣成。可 相或呈懸浮液形式，以、了化式了呈令液 溶劑…，丨，二劑或稀釋劑製成。可接受之 ^戈^ 菌之水、林格氏溶液或等渗鹽水溶 二或者，可採用無菌油類作為溶劑或懸浮劑 :或脂肪酸為非揮發性’包括天然或合成油類，脂肪酸類， 早-、二-或三-甘油酯。 =注射，醫藥配方及/或藥劑可為適合以 對於、’、之叙纟#曰曰貝粉末，顆粒，沉澱物或微粒子。 ::主射’配方可視情況含有安定劑、PH改變劑、界面活 d、生物利用率改變劑及此等之組合。 關於直腸投藥，醫藥配方與藥劑可呈栓劑、軟膏 =片劑或乳膏之形式，供化合物在腸、S形彎曲及/或直 釋出。直腸栓劑，係經由將—或多種本發明化合物， 〆該化合物之藥學上可接受鹽或互變異構物，與可接受之 =例如可可豆脂或聚乙二醇混合而製成，其係在正常儲 子：度下以固相存在’而於適合身體内部譬如在直腸中釋 3藥物之/嚴度下以液相存在。油類亦可被採用於製備軟明 =員型與栓劑之配方。水、鹽水、右旋糖水溶液及相關糖 洛液’以及甘油’可被採用於製備懸浮液配方，其亦可含 ^ 言如果膠、碳聚體（carbomer)、甲基纖維素、_ 123505 197- 200815422 丙基識維素或幾甲基纖維素，以及緩衝劑與防腐劑。 X月之化合物可經過鼻子或口藉吸入投予肺臟。供吸 t適當醫藥配方包括溶液、喷霧劑、乾粉或含有任何適 田d k用之其他化合物之氣溶膠，該其他化合物譬如 於女疋剤、抗微生物劑、抗氧化劑、改變劑、界 面活性劑、生物利用率改質劑及此等之組合。供吸入投藥 之配方係含有賦形劑，例如乳糖、聚氧化乙烯-9-月桂基醚、: gelatin, gelatin, collagen, albumin, albumin, synthetic or semi-synthetic polymerization: or: oil vinegar. Oral dosage forms may optionally contain other ingredients to aid in the incorporation of, for example, inactive diluents, or lubricants, such as magnesium stearate, or preservatives such as p-benzoic acid vinegar or citric acid, or antioxidants such as ascorbic acid. , parenteral powder or cysteine, disintegrant, binder, thickener, buffer, sweetener, bridge or fragrance. Tablets and pills may be further processed by suitable coating materials known in the art. The liquid dosage form for oral administration can be in the form of a pharmaceutically acceptable emulsion, syrup, elixir, suspension, and solution, which may contain an inert diluent such as water. The pharmaceutical formulation and medicament can be formulated as a liquid suspension or solution using a sterile liquid such as, but not limited to, oil, water, alcohol, and combinations thereof. A suitable surfactant, suspending agent or emulsifier may be added for oral or parenteral administration. As mentioned above, the suspension may comprise oils. Such oils include, but are not limited to, flower oil, sesame oil, cottonseed oil, corn oil and olive oil. The suspension preparation also contains a self-cultivation class of ruthenium-fat acid, such as oleic acid vinegar, peas vinegar, vinegar, sucrose, and glycerin. Suspension formulations may include alcohols such as, but not limited to, ethanol, isopropanol, cetyl alcohol, glycerol, and propylene 123505-196-200815422 alcohol. Ethers, such as but not limited to poly (oil and rocky oil; and water, also: petroleum hydrocarbons), such as JJ, are used in suspension formulations. Injectable formulations generally include water-containing Also, A, from the suspended liquid, which can be used in the field of glutinous rice or Run and _ (four). Can be phase or in the form of a suspension, in the form of a liquid solvent, bismuth, two doses or thinner 2. Acceptable water, Ringer's solution or isotonic saline solution 2, or use sterile oils as solvent or suspension: or fatty acids are non-volatile' including natural or synthetic oils, fatty acids , early-, di- or tri-glycerides. = injection, pharmaceutical formulas and / or pharmaceutical agents may be suitable for, ',,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, The formulation may optionally contain a stabilizer, a pH-altering agent, an interface activity d, a bioavailability modifier, and a combination thereof. For rectal administration, the pharmaceutical formulation and the agent may be in the form of a suppository, ointment=tablet or cream for the compound. In the intestine, S-shaped bending and / or direct release. Rectal suppositories, through the - or a plurality of compounds of the invention, pharmaceutically acceptable salts or tautomers of the compound, prepared by mixing with acceptable = for example cocoa butter or polyethylene glycol, under normal storage: It exists in the solid phase, and is present in the liquid phase, such as in the rectum, in the form of a drug. The oil can also be used in the preparation of softness = type and suppository. Water, saline, right Aqueous solution of sugar and related sugar solution 'and glycerol' can be used in the preparation of suspension formulations, which can also be included in the case of gums, carbomers, methylcellulose, _ 123505 197- 200815422 Vitamin or methine cellulose, as well as buffers and preservatives. Compounds of X month can be administered to the lungs by inhalation through the nose or mouth. Suitable pharmaceutical formulations include solutions, sprays, dry powders or any suitable field. An aerosol of other compounds used in dk, such as virgin, antimicrobials, antioxidants, modifiers, surfactants, bioavailability modifiers, and combinations thereof. Formulations for inhalation administration contain Shape agents, such as lactose, polyoxyethylene-9-lauryl ether,

甘月女膽^鹽及去氧膽酸鹽。含水與未含水氣溶膠係典型上 用於藉吸入傳輸本發明化合物。 、、系3水氣〉谷膠係經由將化合物之水溶液或懸浮液， 與習用藥學上可接受之載劑與安錢_起調配而製成。載 劑與安定劑係隨著特定化合物之要求條件而改變，但典型 上包括非離子性界面活性劑（Wn、Pluronics或聚乙二醇）， 無=蛋白f，例如血清白蛋白，花楸聚㈣類、油酸、印 磷脂’胺錢，譬如甘胺酸，缓衝劑、冑、糖類或糖醇類。 般而a，氣溶膠係製自等滲溶液。非水性懸浮液（例如在 氟碳推進劑中）亦可用以傳輸本發明化合物。 含有供使用之根據本發明化合物之氣溶膠，係合宜地使 用吸入裔、霧化器、加壓包裝或霧化器及適當推進劑傳輪， 例：但不限於經加壓之二氯二氟甲烷、三氯氟甲烷、：氯 四氟乙烷t、空氣或二氧化碳。在加壓氣溶膠之情況中、， 其劑里單位可藉由提供閥加以控制，以傳輸經計量之量 供使用於吸入器或吹入器中之膠囊與藥筒，例如明膠，可 經調配而含有化合物與適當粉末基料譬如乳糖或澱粉之: 123505 -198- 200815422 =合物。本發明之氣溶膠使用音波霧化罐之傳輸係為有 的i因為霧化罐會使藥劑對剪切之曝露降至最低’該剪 切可此會造成化合物之降解。 關於鼻投藥’醫藥配方與藥劑可為噴霧劑、鼻滴劑或含Ganyue female bile salt and deoxycholate. Aqueous and non-aqueous aerosol systems are typically used to deliver the compounds of the invention by inhalation. , 3 water gas > gluten is prepared by blending an aqueous solution or suspension of the compound with a conventional pharmaceutically acceptable carrier and hydrazine. Carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Wn, Pluronics or polyethylene glycol), no = protein f, such as serum albumin, (d) class, oleic acid, printed phospholipids, amines, such as glycine, buffers, guanidines, sugars or sugar alcohols. As usual, the aerosol is made from an isotonic solution. Non-aqueous suspensions (e.g., in fluorocarbon propellants) can also be used to deliver the compounds of the invention. An aerosol containing a compound according to the invention for use, conveniently using an inhalation, nebulizer, pressurized pack or nebulizer and a suitable propellant transfer, such as, but not limited to, pressurized dichlorodifluorocarbon Methane, trichlorofluoromethane, chlorotetrafluoroethane t, air or carbon dioxide. In the case of a pressurized aerosol, the unit of the agent can be controlled by providing a valve for delivering a metered amount of capsules and cartridges for use in an inhaler or insufflator, such as gelatin, which can be dispensed. And containing the compound and a suitable powder base such as lactose or starch: 123505 -198- 200815422 = compound. The aerosol of the present invention uses a sonic atomization tank for transmission i because the atomization tank minimizes the exposure of the medicament to shearing. This shearing can cause degradation of the compound. About nasal administration 'medical formulas and pharmaceuticals can be sprays, nasal drops or

有適當溶劑鱼選用夕甘A …〃他化5物之氣溶膠，該其他化合物 言如但不限於安定劑、抗微生物劑、抗氧化劑、PH改變劑、 界面活性劑、生物利用率改質劑及此等之組合。對於呈富 r =劑形式之投藥’化合物可在油性溶液中或以凝膠調配: 二對=鼻氣溶勝之投藥’可使用任何適當推進劑，包括 壓縮空氣、氮、二氧化碳或烴為基料之低彿點溶劑。 仏本發明化合物之局部（包括面頻與舌下）或經皮投藥之 劑型’係包括粉末、噴霧劑、軟膏、糊劑、乳膏、洗劑、 凝膠、溶液及貼藥。活性成份可於無菌條件下與藥學上可 接受之載劑或賦形劑，且與可能需要之任何防腐劑或緩衝 劑混合。粉末與噴霧劑可以賦形劑製成，譬如乳糖、滑石、 〔石夕酸、氫氧化鋁、矽酸鈣及聚醯胺粉末或此等物質之混人 物。軟膏、糊劑、乳膏及凝膠亦可含有賦形劑，譬如動： 與植物脂肪類、油類、蠛類、石蠛、搬粉、西黃箸樹膠、 纖維素衍生物、聚乙二醇、聚石夕氧、膨土、石夕酸、滑石及 氧化鋅或其混合物。 經皮貼藥具有提供本發明化合物之受控傳輸至身體之附 加利益。此種劑型可藉由溶解或分散藥劑於適當媒質中而 製成。吸收增強劑亦可用以增加本發明化合物越過皮膚之 通量。此種通量之速率可藉由無論是提供速率控制^或 123505 -199· 200815422 使化合物7刀散於聚合體基質或凝膠中而加以控制。 眼用配方、眼用軟膏、粉末、溶液等亦意欲被涵蓋在本 發明之範圍内。本發明化合物可被摻入各種類型之眼用配 方L 4輸至眼目月（例如以局部方式、眼房内或經由植 入）化口物典型上係被摻入局部眼用配方中，供傳輸至眼 睛。化合物可與—或多種眼科學上可接受之防腐劑、黏度 支曰強d /又透增強劑、緩衝劑、氯化鈉及水合併，以形成 含水、無菌眼用懸浮液或溶液。眼用溶液配方可經由使化 合物溶解於生理學上可接受之等滲緩衝水溶液中而製成。 再者’眼用溶液可包含眼科學上可接受之界面活性劑，以 幫助命解化合物。又再者，眼用溶液可含有一種藥劑以增 加黏度，譬如羥甲基纖維素、羥乙基纖維素、羥丙甲基纖 維素、甲基纖維素、聚乙烯基四氫吡咯酮或其類似物，以 改善配方在結合膜袋中之留存。亦可使用膠凝劑，包括但 不限膠侖（gellan)與三仙膠（xanthan gum)。為製備無菌眼用軟 f配方，係將本發明化合物與防腐劑在適當媒劑中合併， 言如礦油、液體羊毛脂或白蝶油。無菌眼用凝膠配方可根 據關於類似眼用製劑之已發表配方，經由使本發明化合物 懸浮於製自例如carb〇p〇l_974或其類似物之組合之親水性驗 中而製成。可視情況摻入防腐劑與滲透劑。 鞘内投藥，經由大丸劑之劑量或恒定灌注，係允許化合 物之局部投予脊髓之區域，譬如背側角區域，直接傳輸化 合物至含有CSF (腦脊髓液）之蜘蛛膜下間隙。 中樞傳輸至脊髓區域，亦可藉由硬膜外注射至蜘蛛膜外 123505 -200- 200815422 邛之脊髓區域進行。活性化合物經過腦膜之增強滲透，可 利用會增加腦膜滲透性之高滲性服用溶液，或藉由添加渗 透增強劑譬如衫限於微脂粒包覆、界面活_或離子配 對劑而達成。 :了上錢表性劑型之外，藥學上可接受之賦形劑與載 刮係-般性地為熟諳此藝者所已知，且因此被包含在本發 明，中。此種賦形劑與载劑係被描述於例如” Remingt⑽醫㈣ 學” Mack出版公司，New知卿⑽叫中，其係併於本文供參 本發明之配方可經設計為短期作用、快速❹、長期作 用及持續釋出，如下文所述。因此，醫藥时亦可經調配， 供受控釋出或供緩慢釋出。 本發明組合物亦可包括例如微胞或微脂粒或—些其他瘦 包覆形式，或可以長期釋出形式投予，以提供延長之儲： 及/或傳輸作用。因此’醫藥配方與藥劑可被壓縮成丸粒或 0柱體’及作為積貯注射劑或作為植入物譬如血管支年， 以：内方式或皮下方式植入。此種植入物可採用已知惰性 物質，譬如聚矽氧與生物可降解之聚合體。 本發明揭㈣容亦提供併人如本文中所述細胞素抑 =療裝置。-種代表„置包括以如本文中所述之 =_塗覆或浸潰之血管支架。該裝置可經設計 二血管中’其可於此處釋出如本文中所述之細 劑，以幫助降低或防止血管發炎，例如灰管發炎。 其他具體實施例係揭示醫療裝置，其包含如本文中所述 123505 •201 · 200815422 之細胞素抑制劑，或細胞素抑制劑與其他成份八之組合， 如本文中所述。如本文中所述之細胞素抑制劑可被塗覆於 醫療裝置之表面上，或該裝置可以細胞素抑制劑飽和，以 致使細胞素抑制劑自裝置釋出，例如歷經一段時間。包含 如本文中所揭示細胞素抑制劑之舉例醫療裝置，包括但不 限於血管醫療裝置，譬如血管支架。 血管支架及製造與使用以治療劑塗覆或浸潰之血管支架 之方法，係為此項技藝中所習知：參閱，例如美國專利申 請案號US2〇〇5_977與美國專利申請案號US2_129729。 特疋劑畺可依疾病之症狀，病患之年齡、體重、一般健 康狀態、性別及飲食，劑量間隔，投藥途徑，排泄速率及 藥物之、、且口而凋整。含有有效量之任何上述劑型係良好地 在例行實驗術之範圍内，因此良好地在本發明範圍内。 本發明化合物之治療上有效量，可依投藥途徑與劑型而 改變。本發明化合物之有效量典型上係落在約〇•⑽1至高達 100笔克/公斤/天之範圍内，而更典型上係在約〇 〇5至高達 10毫克/公斤/天之範圍内。典型上，一或多種本發明化合 物，經選擇’以提供顯示高治療指數之配方。治療指數為 在毒性與治療作„之劑量比，其可以LI^與取。間之比 例表不。LDw為達50%個體群致死之劑量，而EDw為在5〇% 個體群t於治療±有效之劑量。LD5q#ED5g係在動物細胞 培養物或實驗動物_，藉由標準醫藥程序測定。 就癌症而論，細胞素抑制劑可被使用於本發明之方法與 、、且口物中’無論是單獨或伴隨著其他治療法或活性成份或 123505 -202· 200815422 其組合。其他治療法包括藉由手術、放射或低溫療法之治 療」而以其他活性成份之治療係包括使用抗增生劑。藥 ^之組合係被投？ ’以嘗試在大部份癌症上獲得增效細胞 毒性作用，例如癌瘤、黑色素瘤、淋巴瘤及肉冑，且降低 或消除抗藥性細胞之出現，及減少對各藥物之副作用。其 他活性劑之特定量係依所㈣之特定_、被治療或處理 之癌症類型、癌症之嚴重性與階段，Α同時投予病患之細 胞素抑制劑與任何選用其他活性劑之量而定。典型上，可 與本發明細胞素抑㈣合併使用之其他活性成份係在此 項技藝中所習知之劑量下使用。 一般而言，對於具有臨床上局部疾病存在，且預期 活至少Η)年之7〇歲以下人類而言，手術與放射療法係被採 用作為潛在治病療法。 /抗增生劑&quot;措辭包括會預防細胞之發展、成熟或擴散之 藥』其方式是直接作用在細胞上，例如藉由細胞抑制或 傷害細胞_，而不間接地經過機制，譬如生物回應修正。 有讀目之抗增生劑可用於商業用途上、臨床評估上及於 上，其可被包括在本發明中，以藉由組合藥物化 子療法治療癌症。 典型k增生劑可被分類為烷基化劑、鉑藥劑、抗代謝物、 拓樸異構酶抑制劑、抗腫瘤抗生素、抗有絲分裂劑、芳夭 酶抑制劑、料化物合成酶抑制劑、職拮抗劑、法呢二 轉移酶抑制劑、系送抑制劑、組織蛋白乙醯轉移酶抑制劑土、 金屬蛋白酶抑制劑、核糖核替還原酶抑制劑、内皮肽 123505 -203 - 200815422 體拮抗劑、視黃酸受體催動劑、免疫調制劑、激素或抗激 素劑、光動態劑、血管生成抑制劑、酪胺酸激酶抑制劑等。 一些抗增生劑係經過多重或未知機制操作，且因此可被分 類至超過一個種類中。 可與本發明合併使用之抗增生劑之一種族群包括烷基化 型藥劑。咸認烧基化劑係經由使DNA中之鳥嘌呤及可能之 其他驗烧基化與交聯而發生作用，以遏制細胞分裂。典型 烷基化劑包括氮芥類、次乙亞胺化合物、烷基硫酸鹽、順 氯胺鉑及各種亞瑣基脲類。關於此等化合物之缺點，係為 其不僅攻擊惡性細胞，而且是其他自然地分裂之細胞，譬 如骨髓、皮膚、胃腸黏膜及胎兒組織之細胞。可使用於本 發明中之適當烷基化型藥劑包括但不限於白血福恩 (busulfan)、甲基爷肼、依發斯醯胺（ifosfamide)、阿催塔胺 (altretamine)、六甲三聚氰胺、雌氮界（estramustine)峨酸鹽、口塞 替哌(thiotepa)、氮芥、氮烯咪胺、鏈黴亞硝基素、環己亞硝 脲、天莫洛醯胺（temozolomide)、環磷酸胺、賽氮芬（semustine) 及苯丁 酸氮芥（chlorambucil)。 可與本發明合併使用之抗增生劑之一種族群係包括鉑藥 劑。可使用於本發明中之適當鉑藥劑包括但不限於螺胺鉑 (spiroplatin)、羅巴翻胺(lobaplatin) (Aetema)、四氯胺翻（tetraplatin)、 沙催鈾胺（satraplatin) (Johnson Matthey)、歐馬胺 Ιό (ormaplatin)、 衣普氣胺錄（iproplatin)、米利胺始（miriplatin)(Sumitomo)、内克斯 胺始（nexplatin)(AnorMED)、聚合體始酸鹽（Access)、草酸4自或 碳氯胺始。 123505 -204- 200815422 可與本發明合併使用之抗增生劑之另一族群包括抗代謝 物型藥劑。抗代謝物典型上為可逆或不可逆酵素抑制劑， 或以其他方式干擾核酸之複製、轉譯或轉錄之化合物。可 使用於本發明中之適當抗代謝劑包括但不限於氮胞苷、胺 三甲喋呤（trimetrexate)、5-氟脫氧尿苷、脫氧共間型黴素、2-氯基脫氧腺答、戊托制菌素（pentostatin)、6-魏基嗓吟、羥基 月尿、6-硫基鳥σ票呤、得西塔賓（decitabine) (SuperGen)、阿糖胞 楚、可洛法拉賓（clofarabine) (Bioenvision)、2-氟基脫氧胞嘗、 衣洛弗凡（irofulven) (MGI Pharma)、胺甲嗓吟、托目地斯 (tomudex)、乙炔基胞嘴唆核菩（Taiho)、弗達拉賓（fludarabine)、 真西塔賓（gemcitabine)、瑞提崔斯得（raltitrexed)或卡配西塔賓 (capecitabine) ° 可與本發明合併使用之抗增生劑之另一族群包括拓樸異 構酶抑制劑。可使用於本發明中之適當拓樸異構酶劑包括 但不限於阿姆薩素（amsacrine)、也沙提肯（exatecan)甲烧績酸鹽 (Daiichi)、表紅菌素、奎阿美得（quinamed) (ChemGenex)、衣托 糖嘗（etoposide)、吉馬提肯（gimatecan) (Sigma-Tau)、天尼嘗 (teniposide)、絲裂黃嗣（mitoxantrone)、二氟莫提肯（diflomotecan) (Beaufour-Ipsen)、7-乙基-10-經基-喜樹驗、得拉吐山（dexrazoxanet) (TopoTarget)、約薩米如辛（elsamitrucin) (Spectrum)、皮克山從 (pixantrone) (Novuspharma)、約多提卡林（edotecarin)(Merck 公司）、 貝卡提卡林（becatecarin)(Exelixis)、卡瑞尼特辛（karenitecin) (BioNumerik)、BBR-3576 (Novuspharma)、貝洛提肯（belotecan)(Chong Kun Dang)、魯比提肯（rubitecan) (SuperGen)、伊利諾提肯 123505 -205 - 200815422 (irinotecan) (CPT-11)或拓波提肯（topotecan)。 可與本發明合併使用之抗增生劑之另一族群包括抗生素 型抗增生劑。可使用於本發明中之適當抗生素型抗增生劑 包括但不限於達克汀黴素（放線菌素D)、阿左那懷 (azonafide)、瓦爾紅菌素、蒽吡唑、道諾紅菌素（道諾黴素）、 歐山垂a坐（oxantrazole)、色拉紅菌素（therambicin)、洛索山酮 (losoxantrone)、依達紅菌素、博來黴素酸、如比達宗 (rubidazon)、沙巴紅菌素（sabarubicin)(Menarini)、普利卡黴素、 13-去氧多克索紅菌素鹽酸鹽（Gem醫藥）、甲基絲裂黴素、表 紅菌素、絲裂黃酮（mitoxantrone)(諾凡從（novantrone))或阿蒙那 懷（amonafide) 〇 可與本發明合併使用之抗增生劑之另一族群包括抗有絲 分裂劑。可使用於本發明中之適當抗有絲分裂抗增生劑包 括但不限於秋水仙素、ABT-751 (Abbott)、長春花鹼、西歐塔 斯（xyotax)(Cein台療劑）、長春花素、IDN 5109 (Bayer)、多拉制 菌素 10 (NCI)、A 105972 (Abbott)、利坐素(rhizoxin) (Fujisawa)、A 204197 (Abbott)、米沃蛋白（mivobulin) (Warner-Lambert)、新沙多 亭（synthadotin)(BASF)、西馬多汀（cemadotin) (BASF)、因地布林 (indibulin)(ASTAMedica) 、RPR 109881A (Aventis)、TXD 258 (Aventis)、風車子制菌素A4 (BMS)、艾波希酮B (Novartis)、異 高哈利軟骨素-B (PharmaMar)、T 900607 (Tularik)、ZD 6126 (AstraZeneca)、巴塔布林(batabulin)(Tularik)、隱藻素 52 (Eli Lilly)、 溫弗路寧（vinflunine) (Fabre)、海拉文（hydravin)(Prescient NeuroPharma)、歐利制菌素（auristatin) PE (Teikoku Hormone)、氮 123505 -206- 200815422 約波席隆（azaepothilon) B (BMS)、衣沙貝比隆（ixabepilone)(BMS)、 塔渦謝特（tavocept)(BioNumerik)、BMS 184476 (BMS)、肯瑞制菌 素（combrestatin) A4 磷:酸氫二納（OXiGene)、BMS 188797 (BMS)、 多拉制菌素-10 (NIH)、紅豆杉普辛（taxoprexin) (Protarga)、肯圖 馬伯莫天辛（cantuzumab mertansine) (GlaxoSmithKline)、多謝他索 (docetaxel)、威諾賓（vinorelbine)或長春新驗。 可與本發明合併使用之抗增生劑之另一族群包括芳香酶 抑制劑。可使用於本發明中之適當芳香酶抑制劑包括但不 限於胺基導眠能（aminoglutethimide)、阿塔美斯坦（atamestane) (BioMedicines)、弗美斯烧（formestane)、發德羅嗤（fadrozole)、歹丨J 特羅唾（letrozole)、約克美斯烧（exemestane)或安那史嗤 (anastrazole)。 可與本發明合併使用之抗增生劑之另一族群包括胸苷化 物合成酶抑制劑。可使用於本發明中之適當胸苷化物合成 酶抑制劑包括但不限於佩美催西得（pemetrexed) (Eli Lilly)、諾 拉催西得（nolatrexed) (Eximias)、ZD_9331 (BTG)、多西弗利叮 @(^£11111(111^)(&gt;^0〇11以〇〇1^)或5，1〇-亞甲基四氫葉酸鹽出丨〇1^}^)。 可與本發明合併使用之抗增生劑之又另一族群包括DNA 拮抗劑。可使用於本發明中之適當DNA拮抗劑包括但不限 於左貝克提定（trabectedin) (PharmaMar)、約 i朵催提（edotreotid) (Novartis)、葡碟 g篮胺（glufosfamide) (Baxter 國際）、馬弗斯醯胺 (mafosfamide) (Baxter 國際）、阿帕吉昆（apaziquone) (Spectrum 醫藥） 或席美克塔辛（thymectacin) (NewBiotics)。 可與本發明合併使用之抗增生劑之另一族群包括法呢基 123505 •207 - 200815422 轉移酶抑制劑。可使用於本發明中之適當法呢基轉移酶抑 制劑包括但不限於阿葛拉賓（arglabin) (NuOncology Labs)、替皮 法尼伯（tipifamib) (Johnson &amp; Johnson)、洛那法尼伯（lonafamib) (Schering-Plough)、紫蘇醇（DOR BioPharma)或索拉非尼伯 (sorafenib) (Bayer) o 可與本發明合併使用之抗增生劑之另一族群包括泵送抑 制劑。可使用於本發明中之適當泵送抑制劑包括但不限於 左蘇奎達（zosuquidar)三鹽酸鹽（Eli Lilly)、塔利奎達（tariquidar) (Xenova)、必利可達（biricodar)二檸檬酸鹽（Vertex)或 MS-209 (Schering AG) 〇 可與本發明合併使用之抗增生劑之替代族群包括組織蛋 白乙醯轉移酶抑制劑。可使用於本發明中之適當組織蛋白 乙醯轉移酶抑制劑包括但不限於塔西地那林（tacedinaline) (Pfizer)、丁酸三甲基乙醯基氧基曱酯（Titan)、AP-CANC-03及 AP-CANC-04 (Aton Pharma)、縮肽（Fujisawa)或 MS-275 (Schering AG)。 可與本發明合併使用之抗增生劑之另一族群包括金屬蛋 白酶抑制劑。可使用於本發明中之適當金屬蛋白酶抑制劑 包括但不限於新維制菌素（neovastat) (Aetema Laboratories)、美塔 制菌素（metastat) (CollaGenex)或馬利制菌素（marimastat) (British Biotech) ° 亦可與本發明合併使用之抗增生劑之族群包括核糖核甞 還原酶抑制劑。可使用於本發明中之適當DNA拮抗劑包括 但不限於麥芽酸鎵（Titan)、帖札西塔賓（tezacitabine) (Aventis)、 123505 -208- 200815422 三阿平（triapine) (Vion)或迪多克斯（didox)(健康用分子）。 可與本發明合併使用之抗增生劑之另一族群包括内皮肽 A受體拮抗劑。可使用於本發明中之適當内皮肽A受體拮抗 劑包括但不限於阿卓仙坦（atrasentan) (Abbott)、伯仙坦（bosentan) (Roche)、安伯利仙坦（ambrisentan) (BASF)、西塔仙坦（sitaxsentan) (Encysive)、可拉坐仙坦（clazosentan) (Roche)、達魯仙坦（darusentan) (Knoll)及 ZD-4054 (AstraZeneca)。 可與本發明合併使用之抗增生劑之又另，一族群包括視黃 酸受體催動劑。視黃酸受體催動劑之族群包括視黃醇（維生 素A)之天然與合成類似物之化合物。類視色素係結合至一 或多種視黃酸受體，以引發各種不同過程，譬如生殖、發 育、骨質形成、細胞增生與分化、細胞凋零、造血、免疫 功能及視覺。類視色素係為保持幾乎所有細胞之正常分化 與增生所需要，且已被証實會在癌症之多種活體外與活體 内實驗模式中逆轉/壓抑致癌作用，參閱（Moon等人，第14 章類視色素與癌症·在類視色素，第2卷·大學出版公司 1984中）。可使用於本發明中之適當視黃酸受體催動劑包括 但不限於吩瑞亭奈德（fenretinide) (Johnson &amp; Johnson)、阿利崔替 諾因（alitretinoin) (Ligand)、塔雜若汀（tazarotene) (Allergan)、提利 諾因（tetrinoin)(Roche)、異崔替諾因（isotretinoin) (Roche)、13-順式 -視黃酸(UCSD)或 LGD-1550 (Ligand)。 可與本發明合併使用之抗增生劑之另一族群包括免疫調 制劑。可使用於本發明中之適當免疫調制劑包括但不限於 干擾素、R〇feron-A (Roche)、得克索山（dexosome)療法（Anosys)、 123505 -209- 200815422 腫瘤嗟菌體（oncophage) (Antigenics)、片催克斯（pentrix)(澳洲癌 症技術）、GMK 疫苗（Progenies)、CD154 細胞療法（Tragen)、腺 癌疫苗（Biomira)、傳維克斯（transvax)(Intercell)、勒檐驗（AVI BioPharma) ' 謹瑞林（norelin) (Biostar)、IRX-2 (Immuno，Rx)、BLP-25 微脂粒疫苗（Biomira)、PEP-005 (Peplin Biotech)、多神經節苷脂 疫苗（Progenies)、同步維克（synchrovax)疫苗（CTL Immuno)、/5· 阿列辛（alethine) (Dovetail)、黑色素瘤疫苗（CTL Immuno)、護血 管劑（Vasogen)、利圖西馬伯（rituximab) (Genentech/Biogen Idee)或 p21 RAS 疫苗（GemVax)。 可與本發明合併使用之抗增生劑之另一族群包括激素 劑。可使用於本發明中之適當激素劑包括但不限於雌激 素、地塞米松、共軛雌激素、潑尼松、炔雌二醇、甲基氫 化潑尼松、氯三安生（chlortrianisen)、氫化潑尼松、埃定睪酮 (idenestrol)、胺基導眠能（aminoglutethimide)、己酸經孕酮、留 普内S旨（leuprolide)、甲孕酮、八瑞歐肽（octreotide)、睪酮、米 托坦（mitotane)、睪酮丙酸鹽、氟羥甲睪酮、甲基睪酮、2-甲 氧雌二醇（EntreMed)、二乙基己稀雌盼、阿左西吩（arzoxifen) (Eli Lilly)、曱地孕酮、他摩西吩（tamoxifen)、二卡如醮胺 (bicalutamide)、妥瑞莫吩(toremofin)、弗如醯胺（flutamide)、郭捨 瑞林（goserelin)、尼如醯胺（nilutamide)或留普瑞林(Leuporelin)。 可與本發明合併使用之抗增生劑之又另一族群包括光動 態劑。可使用於本發明中之適當光動態劑包括但不限於塔 拉波吩（talaporfin) (Light Science)、Pd-細菌脫鎮葉綠二酸化物 (Yeda)、捨拉路克斯（theralux) (Theratechnologies)、錦提沙啡。林 123505 -210- 200815422 (texaphyrin) (Pharmacyclics)、莫提沙吩（motexafin)、IL (Pharmacyclics) 或金絲桃蒽酮。 可與本發明合併使用之抗增生劑之又另一族群包括血管 生成抑制劑。可使用於本發明中之適當血管生成抑制劑包 括但不限於新維制菌素（neovastat) (AEtema Zentaris)、ATN-224 (Attenuon)、索拉非尼伯（sorafenib) (Bayer)、酉太胺味淀酮、貝發 西馬伯（bevacizumab) (Genentech)、瑞尼必祖馬（ranibizumab) (Genentech)、貝尼吩（benefin)(Lane Labs)、L-651582 (Merck 公司）、 維塔拉尼伯（vatalanib) (Novartis)或蘇坦特（sutent) (Sugen)。 可與本發明合併使用之抗增生劑之另一族群包括酪胺酸 激酶抑制劑。可使用於本發明中之適當酪胺酸激酶抑制劑 包括但不限於愛馬丁尼伯（imatinib) (Novartis)、列弗諾醯胺 (leflunomide) (Sugen/Pharmacia)、卡鹵化物（kahalide) F (PharmaMar)、 愛瑞沙（iressa) (AstraZeneca)、列托提尼伯（lestaurtinib)(Cephalon)、 啊羅提尼伯（erlotinib) (Oncogene Science)、肯内提尼伯（canertinib) (Pfizer)、坦杜提尼伯（tandutinib)(Millenium)、角鯊胺（Genaera)、 米多星孢素（Novartis)、吩諾二醇（Phenoxodiol)、SU6668 (Pharmacia)、些圖西馬伯（cetuximab)(ImClone) 、 rhu-Mab (Genentech)、ZD6474 (AstraZeneca)、MDX-H210 (Medarex)、維塔 拉尼伯（vatalanib) (Novartis)、歐尼塔革（omnitarg) (Genentech)、拉 巴提尼伯（lapatinib) (GlaxoSmithKline)、片尼圖努馬伯 (panitumumab) (Abgenix)、IMC-1C11 (ImClone)、索拉非尼伯 (sorafenib) (Bayer)或搓史圖諸馬伯（trastuzumab) (Genentech)。 可與本發明合併使用之其他抗增生劑包括苯丙胺酸氮 123505 -211- 200815422 ‘絲裂黴素C、 、培克里他索 芥、亞硝基脲氮芥、順氯胺翻、5_氟尿嘧啶 亞德里亞黴素（多克索紅菌素）、博來黴素 (Paclitaxel) (Tax〇i®)等。 就疼痛治療而論，本發明之細胞素抑制劑可與其他活性 成份或藥劑一起使用於方法與組合物中。典型上，盆他活 性劑係能夠減輕疼痛，抑制炎性反應，提供鎮靜作用或止 神經痛作用，或確保病患舒適性。其他活性劑之實例包括 f、但不限於類阿片止痛齊卜非麻醉性止痛劑、消炎劑、cox_2 抑制劑、α-腎上腺素能受體催動劑或结抗劑、氯胺晒、麻 醉劑、NMDA拮抗劑、邮配位體、免疫調制劑、免錢 I1 d抗抑#劑、抗搐搦藥、抗高血壓劑、解焦慮劑、詞 通道阻斷劑、肌肉鬆他劑、皮質類固醇、高比重氧、已知 會減輕疼痛之其他治療劑’及其藥學上可接受之鹽、溶劑 口物、水合物、立體異構物、前體藥物及具藥理學活性之 新陳代謝產物。 i 類阿片可用以、冶療嚴重疼痛。類阿片止痛劑之實例包括 但不限於羥基二氫待因g同（〇xyc〇dxyC_inTM)、嗎啡硫 酸鹽（MS C〇ntinTM、Duram〇卬hTM、Astr__TM)、參啶(Dem^ 及芬太尼（fentanyl)經皮貼藥（DwagesicTM)及其他已知習用藥 物[參閱，例如醫師之桌上參考資料（physidans，Desk Ref_ce)， 594-595，2851 及 2991 (第 57 版，2003)]。羥基二氫待因酮 (oxycodone) (〇xyContmTM)為類阿片之長期作用形式，且可經 常被使用於CRPS之開始與後期階段中。嗎啡硫酸鹽可被使 用於止痛法中，此係由於可靠與可預測作用、安全作用形 123505 -212- 200815422 態及容易以那諾松（naloxone)之可逆性所致。嗎啡硫酸鹽係 以商標名 MS ContinT M、DuramorphT M 或 AstramorphT M 在美國銷售 [參閱，例如醫師之桌上參考資料，594_595 (第57版，2003)]。 芬太尼（fentanyl)經皮貼藥（DuragesicTM)為有效麻醉止痛劑，具 有比嗎啡硫酸鹽遠為較短之半生期。參咬（DemerolT M)與氫 莫風（hydromorphone) (DilaudidTM)亦可使用於疼痛處理[參閱， 例如醫師之桌上參考資料，2991 (第57版，2003)]。 非麻醉性止痛劑與消炎劑較佳係用於治療懷孕與餵奶期 間之疼痛。消炎劑，譬如非類固醇消炎藥物（NSAID)與cox-2 抑制劑，典型上係藉由降低負責前列腺素合成之環氧化酶 之活性而抑制炎性反應與疼痛。NSAID可在疼痛徵候簇之 早期階段中提供疼痛減輕。消炎劑之實例包括但不限於柳 酸醋酸鹽（AspirinTM)、異丁 苯丙酸（ibuprofen) (MotrinTM、 AdvilTM)、酮基丙吩（ketoprofen) (OmvailTM)、羅費庫西比 (rofecoxib) (VioxxT M )、那丙新（naproxen)鈉（AnaproxT M、NaprelanT M、 Naprosyn7 M)、酮洛拉克（ketorolac) (AcularT M)及其他已知習用藥 物。特定cox_2抑制劑為塞拉庫西比（celecoxib) (CELEBREXtm) [參閱，例如醫師之桌上參考資料，1990, 1910-1914及2891 (第 57版，2003);關於非處方藥物與飲食補充物之醫師桌上之參 考資料，511，667 及 773 (第 23 版，2002)]。 抗抑鬱劑會增加CNS中之血清素及/或正腎上腺素之胞 突接合濃度，其方式是抑制其被突觸前神經元細胞膜之再 吸收。一些抗抑營劑亦具有納通道阻斷能力，以降低受傷 害末梢傳入纖維之觸發速率。抗抑鬱劑之實例包括但不限 123505 -213- 200815422 於諾三替林（nortriptyline) (PamelorTM)、阿米替林（amitriptyline) (ElavilT M )、丙啤 口井（Tofranill)、多慮平（doxepin) (SinequanT M)、可 洛米胺（clomipramine) (AnafranilT M)、氟西 丁（fluoxetine) (ProzacT M)、色他林（sertraline) (ZoloflT M)、那發坐酮（nefazodone) (SerzoneT M)、溫拉發辛（venlafaxine) (EffexorT M)、搓 °坐酮（trazodone) (DesyrelTM)、丁胺苯丙酮（WellbutrinTM)及其他已知習用藥物 [參閱，例如醫師之桌上參考資料，329, 1417, 1831及3270 (第 57 版，2003)]。 抗搐搦藥物亦可使用於本發明之具體實施例中。抗搐搦 藥之實例包括但不限於胺甲醯氮蕈、羧咪畊、加巴潘亭 (gabapentin) (NeurontinTM)、苯妥英、法普酸鈉、克羅那吉片 (clonazepam)、托皮拉美（topiramat)、拉莫三金臬（lamotrigine)、 坐尼斯醯胺（zonisamide)及提耳加賓（tiagabine)[參閱，例如醫 師之桌上參考資料，2563 (第57版，2003)]。 皮質類固醇（例如潑尼松、地塞米松或氩基可體松）、口 服活性種類lb抗節律不齊劑（例如慢心利（mexiletine))、約通 道阻斷劑（例如硝苯吡啶（nifedipine))、分阻斷劑（例如丙喏羅 (propranolol))、α-阻斷劑（例如苯氧苄胺）及必腎上腺素能催 動劑（例如可樂寧（clonidine))亦可與細胞素抑制劑合併使用 [參閱，例如醫師之桌上參考資料，1979, 2006及2190 (第57版， 2003)]。 其他活性劑之特定量係依所使用之特定藥劑、被治療或 處理之疼痛類型、疼痛之嚴重性與階段，及同時投予病患 之細胞素抑制劑與任何選用其他活性劑之量而定。 123505 -214- 200815422 氫莫風（hydromorphone) (DilaudidTM)典型上係以首次劑量為 約2笔克，以經口方式，或約工毫克，以靜脈内方式投予， 以處理中等至嚴重疼痛[參閱，例如醫師之桌上參考資料 2991 (第 57 版，2003)]。硫酸嗎啡（DuramorphTM、Astram(&gt;rphTM、 MS ContinTM)典型上係以首次劑量為約2毫克iv/sc/im投予， 依病患是否已經服用麻醉止痛劑而定[參閱，例如醫師之桌 上苓考貧料，594-595 (第57版，2003)]。對可給予之量沒有本 ( 性限制存在，只要觀察病患關於不利作用之跡象即可，尤 其是呼吸抑鬱。可使用不同IV劑量，通常經調整，直到獲 得所要之作用為止。對於未使用長期藥劑之病患，低達2 毫克IV/SC可足夠。對於服用長期麻醉止痛劑之病患，典型 上需要較大劑量。硫酸嗎啡亦可以口服形式用於立即釋出 與按時釋出之製劑中。長期作用口服形式可每天投予兩 次。立即釋出形式可為疼痛突破期間所必須，其中劑量係 依先w使用而定。羥基二氫待因酮（oxycodone) (〇xyC〇ntinTM) I 為類阿片之長期作用形式，且可被使用於疼痛徵候簇之開 始與後期階段中。羥基二氫待因酮（〇xyc〇d〇ne) (〇xyC〇ntinTM) 通常係以約10-160毫克之量一天投予兩次[參閱，例如醫師 之桌上參考資料，2851 (第57版，2003)]。唪啶（DemerolTM)典型 上係以約50-15〇毫克PO/IV/IM/SC之量每3·4小時投予。嗪啶 (DemerolTM)之典型兒科劑量為每3-4小時1-1.8毫克/公斤 (〇·5-0·8毫克/碎）P0/IV/IM/SC [參閱，例如醫師之桌上參考資 料，2991 (弟 57 版，2003)]。分太尼（fentanyl)經皮貼藥（DuragesicT μ ) 可以經皮劑型取得。大部份病患係在72小時服用間隔中被 123505 -215- 200815422 投予藥物；但是，一些病患可能需要約48小時之服用間隔。 典型成人劑量為約25微克/小時（10平方公分），50微克/小時 (20平方公分），75微克/小時（75平方公分），或100微克/小 時（100平方公分）[參閱，例如醫師之桌上參考資料，1775 (第 57 版，2003)]。 非麻醉性止痛劑與消炎劑，譬如NSAID與cox-2抑制劑， 可用以治療患有溫和至中等疼痛之病患。異丁苯丙酸 (ibuprofen) (MotrinTM、AdvilTM)係以 400-800 毫克之量經 口投予 一天三次[參閱，例如醫師之桌上參考資料，1900-1904 (第57 版，2003);關於非處方藥物與飲食補充物之醫師桌上之參考 資料，511，667 及 773 (第 23 版，2002)]。那丙新（naproxen)鈉 (AnaproxT M、NaprelanT M、Naprosyn1 M)亦可用於減輕溫和至中 等疼痛，其量為約275毫克一天三次，或約550毫克一天兩 次[參閱，例如醫師之桌上參考資料，1417, 2193及2891 (第57 版，2003)]。 抗抑#劑，例如諾三替林（nortriptyline) (PamelorT M)亦可用於 本發明中，以治療患有慢性及/或神經病原性疼痛之病患。 口服成人劑量典型上為約25-100毫克之量，且通常不超過 200毫克/天。典型兒科劑量為約0.1毫克/公斤口服，作為首 次劑量，當容許時，增加至高達約0.5-2毫克/天。阿米替林 (amitriptyline) (EtrafonT M)典型上係用於神經病原性疼痛，其成 人劑量為約25-100毫克口服[參閱，例如醫師之桌上參考資 料，1417 與 2193 (第 57 版，2003)]。 抗搐搦藥，譬如加巴潘亭（gabapentin)(NeurontinTM)，亦可用 123505 -216- 200815422 以治療患有慢性與神經病原性疼痛之病患。典型上，加巴 潘亭（gabapentin)係以約100-1，200毫克之量經口投予一天三次 [參閱，例如醫師之桌上參考資料，2563 (第57版，2003)]。胺 甲醯氮萆（TegretoFM)係用以治療與真實三叉神經痛有關聯 之疼痛。口服成人劑量典型上為約100毫克之量一天兩次作 為首次劑量，當容許時，增加至高達約2,400毫克/天[參閱， 例如醫師之桌上參考資料，2323_25 (第57版，2003)]。 對於天癌瘡之治療，可與新穎本發明化合物合併使用之 其他藥劑包括但不限於消炎劑、免疫壓抑劑、抗感染劑、 抗生素、金鹽、烧基化劑、免疫球蛋白或其兩種或多種之 組合。消炎劑之實例包括皮質類固醇、C0X-2抑制劑、非類 固醇消炎藥物（NSAID)、TNFa拮抗劑及IL-1拮抗劑。例如， 皮質類固醇可為潑尼松、氫化潑尼松或甲基氫化潑尼松。 譬如此等之皮質類固醇，亦可與無論是苯丁酸氮芥 (chlorambusil)或分枝紛酸莫非替（mycophenylate mofetil) — 起投 予。TNFa拮抗劑之實例為因弗利西馬（infliximab)、恩塔臬西 伯（etanercept)及阿達利母馬（adalimumab)。IL-1拮抗劑之實例為 安那金拉（Anakinra)。免疫壓抑劑之實例為分枝紛酸莫非替 (mycophenylate mofetil)、環孢素、頌基脒嗤硫17票呤、胺甲嗓呤、 阿列發謝特（alefacept)、利圖西馬伯（rituximab)、抗-干擾素τ 及環磷醯胺，而抗感染劑包括達普松（dapsone)與羥氯喳。於 一些情況中，金鹽可為硫代蘋果酸金鈉或金硫葡萄糖（抗關 節炎藥）。烷基化劑之實例為留可蘭（lukeran)。可使用於組合 中之抗生素為四環素、二甲胺四環素及強力黴素，有時與 123505 -217- 200815422 终驗酸胺或尼克酸胺合併。 天疱瘡之治療亦可包括對病患之血漿除去療法或光泳療 法。 經如此一般性地描述之本發明，將參考下述實例而更容 易地明暸，其係以說明方式提供，並非意欲成為本發明之 限制。 【實施方式】 實例 下列縮寫係關於術語，使用於整個本申請案中：An appropriate solvent fish is used to select an aerosol of 5 substances, such as but not limited to stabilizers, antimicrobial agents, antioxidants, pH change agents, surfactants, bioavailability modifiers. And the combination of these. For administration in the form of a r-rich agent, the compound may be formulated in an oily solution or in a gel: two pairs of drugs that are used in a nasal spray may use any suitable propellant, including compressed air, nitrogen, carbon dioxide or hydrocarbons. The low point solvent. The topical (including facial frequency and sublingual) or transdermal administration of the compound of the present invention includes powders, sprays, ointments, pastes, creams, lotions, gels, solutions and patches. The active ingredient may be mixed under sterile conditions with apharmaceutically acceptable carrier or excipient, and any preservative or buffer may be required. Powders and sprays can be prepared from excipients such as lactose, talc, [linic acid, aluminum hydroxide, calcium citrate and polyamide powders or mixtures of such materials. Ointments, pastes, creams and gels may also contain excipients, such as: vegetable fats, oils, alfalfa, sarcophagus, powder, scutellaria, cellulose derivatives, polyethylene Alcohol, polyox, oxygen, bentonite, oxalate, talc and zinc oxide or mixtures thereof. Transdermal patches have the added benefit of providing controlled delivery of the compounds of the invention to the body. Such dosage forms can be made by dissolving or dispersing the agent in a suitable medium. Absorption enhancers can also be used to increase the flux of the compounds of the invention across the skin. The rate of such flux can be controlled by either providing rate control or 123505-199.200815422 to disperse the compound 7 in the polymer matrix or gel. Ophthalmic formulations, ophthalmic ointments, powders, solutions and the like are also intended to be encompassed within the scope of the invention. The compounds of the present invention can be incorporated into various types of ophthalmic formulations L4 to the eye of the eye (e.g., in a localized manner, in the eye, or via implantation). The vat is typically incorporated into a topical ophthalmic formulation for delivery. To the eyes. The compound may be combined with - or a variety of ophthalmically acceptable preservatives, viscous d / re-enhancement agents, buffers, sodium chloride and water to form aqueous, sterile ophthalmic suspensions or solutions. Ophthalmic solution formulations can be made by dissolving the compound in a physiologically acceptable isotonic buffered aqueous solution. Further, the ophthalmic solution may comprise an ophthalmically acceptable surfactant to aid in the resolution of the compound. Still further, the ophthalmic solution may contain a medicament to increase viscosity, such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinyltetrahydropyrrolidone or the like. To improve the retention of the formulation in the bonded film bag. Gelling agents can also be used, including but not limited to gellan and xanthan gum. For the preparation of a sterile ophthalmic soft f formulation, the compound of the invention is combined with a preservative in a suitable vehicle such as mineral oil, liquid lanolin or white butterfly oil. Sterile ophthalmic gel formulations can be prepared by suspending the compound of the invention in a hydrophilicity test from a combination such as carb〇p〇l_974 or an analog thereof, according to published formulations for ophthalmic formulations. Preservatives and penetrants may be incorporated as appropriate. Intrathecal administration, via dose or constant perfusion of the bolus, allows the local administration of the compound to the spinal cord region, such as the dorsal horn region, to directly transfer the compound to the subarachnoid space containing CSF (cerebrospinal fluid). The central transmission to the spinal cord region can also be performed by epidural injection into the spinal cord region of the arachnoid 123505 -200- 200815422 sputum. The enhanced penetration of the active compound through the meninges can be achieved by the use of a hypertonic administration solution which increases the permeability of the meninges, or by the addition of a permeation enhancer such as a microlipid coating, interfacial activity or ionomer. In addition to the above exemplary dosage forms, pharmaceutically acceptable excipients and carrier systems are known to those skilled in the art and are therefore included in the present invention. Such excipients and carriers are described, for example, in "Remingt (10) Medical (4)" Mack Publishing Company, New Zhiqing (10), which is incorporated herein by reference to the present invention, which is designed to be short-term, rapid. Long-term effects and sustained release, as described below. Therefore, the medicine can also be formulated for controlled release or for slow release. The compositions of the present invention may also include, for example, microvesicles or vesicles or some other thin coated form, or may be administered in a long-term release form to provide extended storage and/or delivery. Thus, the 'pharmaceutical formula and medicament can be compressed into pellets or cylinders' and implanted as a stock injection or as an implant, such as a vascular branch, in an internal or subcutaneous manner. Such implants may employ known inert materials such as polyoxynium and biodegradable polymers. The present invention also provides a cytokine therapy device as described herein. - a representative of a blood vessel stent comprising a coating or impregnation as described herein. The device may be designed in a blood vessel where it may release a fine agent as described herein to Helps reduce or prevent inflammation of blood vessels, such as ash tube inflammation. Other embodiments disclose a medical device comprising a cytokine inhibitor as described herein, 123505 • 201 · 200815422, or a combination of a cytokine inhibitor and other components As described herein, a cytokine inhibitor as described herein can be applied to the surface of a medical device, or the device can be saturated with a cytokine inhibitor such that the cytokine inhibitor is released from the device, for example An exemplary medical device comprising a cytokine inhibitor as disclosed herein, including but not limited to a vascular medical device, such as a vascular stent. A vascular stent and method of making and using a vascular stent coated or impregnated with a therapeutic agent It is known in the art: see, for example, U.S. Patent Application No. US 2 〇〇 5 _ 977 and U.S. Patent Application No. US 2 129 729. Symptoms, age, weight, general health status, gender and diet, dose interval, route of administration, rate of excretion, and drug, and dying. Any of the above dosage forms containing an effective amount is well-suited for routine experimentation. Within the scope of the invention, it is well within the scope of the invention. The therapeutically effective amount of the compound of the invention may vary depending on the route of administration and the dosage form. The effective amount of the compound of the invention typically falls from about 〇•(10)1 up to 100 In the range of grams per kilogram per day, and more typically in the range of from about 5 to as high as 10 milligrams per kilogram per day. Typically, one or more compounds of the invention are selected to provide a high therapeutic display. The formula of the index. The therapeutic index is the dose ratio between the toxicity and the treatment, which can be taken by LI^. The ratio between the examples is not. LDw is the dose that is lethal to 50% of the individual population, and EDw is the dose that is effective at 5% of the individual population. LD5q#ED5g is determined in animal cell cultures or experimental animals, by standard pharmaceutical procedures. In the case of cancer, cytokine inhibitors can be used in the methods of the invention and in the oral cavity, either alone or in combination with other therapies or active ingredients or 123505-202.200815422. Other treatments include treatment with surgery, radiation or cryotherapy, while treatment with other active ingredients includes the use of anti-proliferative agents. The combination of medicine ^ is cast? ' Attempts to obtain synergistic cytotoxic effects on most cancers, such as cancer, melanoma, lymphoma and meat mites, and to reduce or eliminate the emergence of drug-resistant cells and to reduce side effects on various drugs. The specific amount of other active agents depends on the specific type of (4), the type of cancer being treated or treated, the severity and stage of the cancer, and the amount of cytokine inhibitor administered to the patient at the same time as the amount of any other active agent selected. . Typically, other active ingredients which may be combined with the cytochrome of the present invention (4) are used at dosages conventionally known in the art. In general, surgery and radiation therapy are used as potential therapeutic therapies for humans under 7 years of age who have clinically localized disease and are expected to live for at least Η years. /anti-proliferative agents&quot;words include drugs that prevent the development, maturation, or spread of cells by directly acting on cells, such as by cells inhibiting or damaging cells, without indirectly passing through mechanisms, such as biological response corrections. . The anti-proliferative agents of the present invention are useful for commercial use, clinical evaluation, and the like, and can be included in the present invention to treat cancer by a combination of pharmacological agents. Typical k-proliferation agents can be classified as alkylating agents, platinum agents, antimetabolites, topoisomerase inhibitors, antitumor antibiotics, anti-mitotic agents, arylase inhibitors, compound synthase inhibitors, Antagonists, bismuth transferase inhibitors, sieving inhibitors, tissue protein acetyltransferase inhibitors, metalloproteinase inhibitors, ribonucleotide reductase inhibitors, endothelin 123505-203 - 200815422 antagonists, Retinoic acid receptor agonists, immunomodulators, hormone or antihormonal agents, photodynamic agents, angiogenesis inhibitors, tyrosine kinase inhibitors, and the like. Some anti-proliferative agents operate through multiple or unknown mechanisms and can therefore be classified into more than one species. One of the ethnic groups of anti-proliferative agents that can be used in conjunction with the present invention includes alkylating agents. Salty alkylating agents act by blocking and cross-linking guanine and possibly other calcination in DNA to suppress cell division. Typical alkylating agents include nitrogen mustards, ethyleneimine compounds, alkyl sulfates, cisplatin platinum, and various sulphonylureas. The disadvantages of these compounds are that they not only attack malignant cells, but also other naturally dividing cells, such as cells of the bone marrow, skin, gastrointestinal mucosa, and fetal tissues. Suitable alkylating agents which may be used in the present invention include, but are not limited to, busulfan, methyl sulfonium, ifosfamide, altretamine, hexamethylene melamine, and estradiol. Nitrogen (estramustine) citrate, thiotepa, nitrogen mustard, nitromethamine, streptavidin, cyclohexyl nitrosourea, temozolomide, cyclophosphamide , semustine and chlorambucil. One of the anti-proliferative agents that can be used in conjunction with the present invention is a race group comprising a platinum drug. Suitable platinum agents that can be used in the present invention include, but are not limited to, spiroplatin, lobaplatin (Aetema), tetraplatin, satraplatin (Johnson Matthey) ), ormaplatin, iproplatin, miriplatin (Sumitomo), nexplatin (AnorMED), polymer start acid (Access), Oxalic acid 4 starts with or with chloramine. 123505 - 204- 200815422 Another group of anti-proliferative agents that can be used in conjunction with the present invention include antimetabolite-type agents. Antimetabolites are typically reversible or irreversible enzyme inhibitors, or otherwise interfere with the replication, translation or transcription of a nucleic acid. Suitable antimetabolites that can be used in the present invention include, but are not limited to, azacytidine, trimetrexate, 5-fluorodeoxyuridine, deoxy-inter-mycin, 2-chlorodeoxyglycan, pentane Pentostatin, 6-weig oxime, hydroxy urethra, 6-thiol σ 呤, decitabine (SuperGen), arabinose, clofarabine (Bioenvision), 2-fluorodeoxybenzoic acid taste, irofulven (MGI Pharma), amine hyperthyroidism, tomudex, acetylene cytoplasmic cytoplasm (Taiho), Fudala Fludarabine, gemcitabine, raltitrexed or capecitabine ° Another group of anti-proliferative agents that can be used in combination with the present invention includes topoisomerase inhibition Agent. Suitable topoisomerase agents which may be used in the present invention include, but are not limited to, amsacrine, exatecan, Daiichi, erythromycin, and kumay. (quinamed) (ChemGenex), etoposide, gimatecan (Sigma-Tau), teniposide, mitoxantrone, diflomotecan (Beaufour-Ipsen), 7-ethyl-10-radio-Xishu, dexrazoxanet (TopoTarget), 约samimitrucin (Spectrum), pixantrone (pixantrone) Novuspharma), edotecarin (Merck), becatecarin (Exelixis), karenitecin (BioNumerik), BBR-3576 (Novuspharma), belotti Belocan (Chong Kun Dang), Rubiconcan (SuperGen), Illinois Tiken 123505 -205 - 200815422 (irinotecan) (CPT-11) or Topotecan (topotecan). Another group of anti-proliferative agents that can be used in conjunction with the present invention include antibiotic-type anti-proliferative agents. Suitable antibiotic-type anti-proliferative agents that can be used in the present invention include, but are not limited to, dydoxin (actinomycin D), azonafide, valvidin, pyridoxazole, and daunrobacter (danomycin), oxantrazole, thermambicin, losoxantrone, idadamycin, bleomycin, such as bismuzon ( Rubidazon), sabarubicin (Menarini), pricarmycin, 13-deoxy-drosoerythrulin hydrochloride (Gem medicine), methyl mitomycin, epirubicin, Another group of anti-proliferative agents that can be used in conjunction with the present invention include mitoxantrone (novantrone) or amonafide, including anti-mitotic agents. Suitable anti-mitotic anti-proliferative agents that can be used in the present invention include, but are not limited to, colchicine, ABT-751 (Abbott), vinblastine, xyotax (Cein station therapy), vinca, IDN 5109 (Bayer), doxorubicin 10 (NCI), A 105972 (Abbott), rhizoxin (Fujisawa), A 204197 (Abbott), miwobulin (Warner-Lambert), new Synthadotin (BASF), cemaadotin (BASF), indibulin (ASTAMedica), RPR 109881A (Aventis), TXD 258 (Aventis), windmill bacteriocin A4 (BMS), Novartis B, PharmaMar, T 900607 (Tularik), ZD 6126 (AstraZeneca), Batabulin (Tularik), Cryptophyta 52 (Eli Lilly), vinflunine (Fabre), hydravin (Prescient NeuroPharma), auristatin PE (Teikoku Hormone), nitrogen 123505 -206- 200815422 Azaepothilon B (BMS), ixabepilone (BMS), tavocept (BioNumerik), BMS 18447 6 (BMS), comprestatin A4 Phosphorus: OXiGene, BMS 188797 (BMS), Doramycin-10 (NIH), Taxoprexin (Protarga) ), cantuuzumab mertansine (GlaxoSmithKline), docetaxel (docetaxel), vinorelbine (vinorelbine) or Changchun new test. Another group of anti-proliferative agents that can be used in conjunction with the present invention include aromatase inhibitors. Suitable aromatase inhibitors that can be used in the present invention include, but are not limited to, aminoglutethimide, atamestane (BioMedicines), formestane, fadrozole ), 歹丨J letrozole, exemestane or anastrazole. Another group of anti-proliferative agents that can be used in conjunction with the present invention include thymidine synthase inhibitors. Suitable thymidine synthase inhibitors that can be used in the present invention include, but are not limited to, pemetrexed (Eli Lilly), nolatrexed (Eximias), ZD_9331 (BTG), Sifli 叮@(^£11111(111^)(&gt;^0〇11以〇〇1^) or 5,1〇-methylenetetrahydrofolate is produced 1^}^). Yet another group of anti-proliferative agents that can be used in conjunction with the present invention include DNA antagonists. Suitable DNA antagonists that can be used in the present invention include, but are not limited to, trabectedin (PharmaMar), about edotreotid (Novartis), and glufosfamide (Baxter International). , mafosfamide (Baxter International), apaziquone (Spectrum Medicine) or thymectacin (NewBiotics). Another group of anti-proliferative agents that can be used in conjunction with the present invention include farnesyl 123505 • 207 - 200815422 transferase inhibitors. Suitable farnesyltransferase inhibitors that can be used in the present invention include, but are not limited to, arglabin (NuOncology Labs), tipifamib (Johnson &amp; Johnson), Lonofani Lonafamib (Schering-Plough), DOR BioPharma, or sorafenib (Bayer) o Another group of anti-proliferative agents that can be used in conjunction with the present invention include pumping inhibitors. Suitable pumping inhibitors that can be used in the present invention include, but are not limited to, zosuquidar trihydrochloride (Eli Lilly), tariquidar (Xenova), biricodar (biricodar) The alternative group of anti-proliferative agents that can be used in conjunction with the present invention include Vertex or MS-209 (Schering AG). The tissue protein acetyltransferase inhibitor. Suitable tissue protein acetyltransferase inhibitors that can be used in the present invention include, but are not limited to, tacedinaline (Pfizer), trimethylethyl decyloxydecyl butyrate (Titan), AP- CANC-03 and AP-CANC-04 (Aton Pharma), Polypeptide (Fujisawa) or MS-275 (Schering AG). Another group of anti-proliferative agents that can be used in conjunction with the present invention include metalloproteinase inhibitors. Suitable metalloproteinase inhibitors that can be used in the present invention include, but are not limited to, neovastat (Aetema Laboratories), metastat (CollaGenex) or marimastat (marimastat) ( British Biotech) ° The population of anti-proliferative agents that may also be used in conjunction with the present invention include ribonucleoside reductase inhibitors. Suitable DNA antagonists that can be used in the present invention include, but are not limited to, gallium titanate (Titan), tezacitabine (Aventis), 123505-208-200815422 triapine (Vion) or di Didox (healthy molecule). Another group of anti-proliferative agents that can be used in conjunction with the present invention include endothelin A receptor antagonists. Suitable endothelin A receptor antagonists that can be used in the present invention include, but are not limited to, atrasentan (Abbott), bosentan (Roche), ambrisentan (BASF). ), Sitaxsentan (Encysive), Clazosentan (Roche), Darusentan (Knoll) and ZD-4054 (AstraZeneca). Still another group of anti-proliferative agents that can be used in conjunction with the present invention include retinoic acid receptor agonists. The population of retinoic acid receptor agonists includes compounds of natural and synthetic analogs of retinol (vitamin A). The retinoid binds to one or more retinoic acid receptors to elicit various processes such as reproduction, development, bone formation, cell proliferation and differentiation, cell dying, hematopoiesis, immune function, and vision. Retinoids are required to maintain normal differentiation and proliferation of almost all cells and have been shown to reverse/repress carcinogenesis in a variety of in vitro and in vivo experimental modes of cancer, see (Moon et al., Chapter 14 Visual pigments and cancers in retinoids, Volume 2, University Publishing Company, 1984). Suitable retinoic acid receptor agonists that can be used in the present invention include, but are not limited to, fenretinide (Johnson &amp; Johnson), alitretinoin (Ligand), and Tazaruo. Tazarotene (Allergan), tetrinoin (Roche), isotretinoin (Roche), 13-cis-retinoic acid (UCSD) or LGD-1550 (Ligand). Another group of anti-proliferative agents that can be used in conjunction with the present invention include immunomodulators. Suitable immunomodulatory agents that can be used in the present invention include, but are not limited to, interferon, R〇feron-A (Roche), dexosome therapy (Anosys), 123505-209-200815422 oncophage (oncophage) (Antigenics), pentrix (Australian cancer technology), GMK vaccine (Progenies), CD154 cell therapy (Tragen), adenocarcinoma vaccine (Biomira), transvax (Intercell), Le AVI BioPharma's norelin (Biostar), IRX-2 (Immuno, Rx), BLP-25 liposome vaccine (Biomira), PEP-005 (Peplin Biotech), polyganglioside Progenies, synchrovax vaccine (CTL Immuno), /5· alexine (Dovetail), melanoma vaccine (CTL Immuno), vascular care agent (Vasogen), Litosisma (rituximab) (Genentech/Biogen Idee) or p21 RAS vaccine (GemVax). Another group of anti-proliferative agents that can be used in conjunction with the present invention include hormonal agents. Suitable hormonal agents which may be used in the present invention include, but are not limited to, estrogen, dexamethasone, conjugated estrogen, prednisone, ethinyl estradiol, methylprednisolone, chlortrianisen, hydrogenation Prednisone, idenestrol, aminoglutethimide, progesterone hexanoate, leuprolide, medroxyprogesterone, octreotide, fluorenone, rice Mittane, anthrone propionate, hydroxymethyl ketone, methyl ketone, 2-methoxyestradiol (EntreMed), diethylhexidine, arzoxifen (Eli Lilly) , gesticoprogesterone, tamoxifen, bicalutamide, toremofin, flutamide, goserelin, ruthenium (nilutamide) or Leuporelin. Yet another group of anti-proliferative agents that can be used in conjunction with the present invention include photodynamic agents. Suitable photodynamic agents that can be used in the present invention include, but are not limited to, talaporfin (Light Science), Pd-bacteria defoliation (Yeda), and theralux (Theratechnologies) ), Jintiansha. Lin 123505 -210- 200815422 (texaphyrin) (Pharmacyclics), motexafin, IL (Pharmacyclics) or hypericin. Yet another group of anti-proliferative agents that can be used in conjunction with the present invention include angiogenesis inhibitors. Suitable angiogenesis inhibitors for use in the present invention include, but are not limited to, neovastat (AEtema Zentaris), ATN-224 (Attenuon), sorafenib (Bayer), amide Misodone, bevacizumab (Genentech), ranibizumab (Genentech), benefin (Lane Labs), L-651582 (Merck), Vitala Navalanib (Novartis) or Sutent (Sugen). Another group of anti-proliferative agents that can be used in conjunction with the present invention include tyrosine kinase inhibitors. Suitable tyrosine kinase inhibitors that can be used in the present invention include, but are not limited to, imatinib (Novartis), leflunomide (Sugen/Pharmacia), and kahalide F. (PharmaMar), iressa (AstraZeneca), lestaurtinib (Cephalon), erlotinib (Oncogene Science), and canertinib (Pfizer) , Tandutinib (Millenium), squalamine (Genaera), Novostis, Novenobis, SU6668 (Pharmacia), and some cetuximab (ImClone), rhu-Mab (Genentech), ZD6474 (AstraZeneca), MDX-H210 (Medarex), vatalanib (Novartis), omnitarg (Genentech), Labatinib (lapatinib) (GlaxoSmithKline), panitumumab (Abgenix), IMC-1C11 (ImClone), sorafenib (Bayer) or 图traduzumab (Genentech) ). Other anti-proliferative agents that may be used in conjunction with the present invention include phenylalanine nitrogen 123505-211-200815422 'Mitomycin C, Peclitaxel, nitrosourea, cis-chloramine, 5-fluorouracil Adriamycin (Doxorubicin), Paclitaxel (Tax〇i®), and the like. As far as pain treatment is concerned, the cytokine inhibitors of the invention can be used in methods and compositions with other active ingredients or agents. Typically, the Potassium Active Agent reduces pain, inhibits inflammatory reactions, provides sedative or analgesic effects, or ensures patient comfort. Examples of other active agents include, but are not limited to, opioid analgesics, non-narcotic analgesics, anti-inflammatory agents, cox_2 inhibitors, alpha-adrenergic receptor agonists or antagonists, chloramines, anesthetics, NMDA antagonists, postal ligands, immunomodulators, immune-free I1 d anti-repressive agents, anti-spasmodics, antihypertensives, anti-anxiety agents, word channel blockers, muscle relaxants, corticosteroids, high Specific gravity oxygen, other therapeutic agents known to reduce pain', and pharmaceutically acceptable salts, solvent salts, hydrates, stereoisomers, prodrugs, and pharmacologically active metabolites. Class I opioids can be used to treat severe pain. Examples of opioid analgesics include, but are not limited to, hydroxydihydrogenine g ((xyc〇dxyC_inTM), morphine sulfate (MS C〇ntinTM, Duram〇卬hTM, Astr__TM), pyridine (Dem^ and fentanyl) (fentanyl) transdermal patch (DwagesicTM) and other known conventional drugs [see, for example, physician's table reference (physidans, Desk Ref_ce), 594-595, 2851 and 2991 (57th ed., 2003)]. Oxycodone (〇xyContmTM) is a long-term form of opioid-like and can often be used in the early and late stages of CRPS. Morphine sulfate can be used in analgesia because of its reliability. The predictable action, safe action shape 123505 -212- 200815422 state and easy to be caused by the reversibility of naloxone. The morphine sulfate is sold in the United States under the trade name MS ContinT M, DuramorphT M or AstramorphT M [see, For example, the physician's table reference, 594_595 (57th edition, 2003)]. Fentanyl transdermal patch (DuragesicTM) is an effective narcotic analgesic with a shorter half-life than morphine sulfate. Biting (De MerolT M) and hydromorphone (DilaudidTM) can also be used for pain management [see, for example, the physician's table reference, 2991 (57th ed., 2003)]. Non-narcotic analgesics and anti-inflammatory agents are preferred. It is used to treat pain during pregnancy and breastfeeding. Anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs (NSAIDs) and cox-2 inhibitors, typically inhibit inflammatory responses by reducing the activity of the cyclooxygenase responsible for prostaglandin synthesis. With pain, NSAIDs can provide pain relief in the early stages of pain syndromes. Examples of anti-inflammatory agents include, but are not limited to, AspirinTM, ibuprofen (MotrinTM, AdvilTM), ketopropyl Ketoprofen (OmvailTM), rofecoxib (VioxxT M ), naproxen sodium (AnaproxT M, NaprelanT M, Naprosyn7 M), ketorolac (AcularT M) and Other known conventional drugs. The specific cox_2 inhibitor is celecoxib (CELEBREXtm) [See, for example, the physician's table reference, 1990, 1910-1914 and 2891 (57th ed., 2003); Physician's Desk Reference Materials and of the dietary supplement, 511,667 and 773 (23rd ed., 2002)]. Antidepressants increase the concentration of serotonin and/or norepinephrine in the CNS by inhibiting their resorption by the presynaptic neuronal cell membrane. Some anti-suppressants also have a nanochannel blocking capability to reduce the trigger rate of injured afferent fibers. Examples of antidepressants include, but are not limited to, 123505 - 213 - 200815422, nortriptyline (PamelorTM), amitriptyline (ElavilT M ), Tofranill, Doxepin ( Doxepin) (SinequanT M), clomipramine (AnafranilTM), fluoxetine (ProzacT M), sertraline (ZoloflT M), nefazodone (SerzoneT) M), venlafaxine (EffexorT M), trazodone (DesyrelTM), butanbupropone (WellbutrinTM) and other known conventional drugs [see, for example, physician's desk reference materials, 329, 1417, 1831 and 3270 (57th ed., 2003)]. Anti-caries drugs can also be used in the specific embodiments of the invention. Examples of anticonvulsants include, but are not limited to, methotrexate, carbohydrate, gabapentin (NeurontinTM), phenytoin, sodium decanoate, clonazepam, topiramide ( Topiramat), lamotrigine, zonisamide and tiagabine [see, for example, the physician's table reference, 2563 (57th ed., 2003)]. Corticosteroids (eg, prednisone, dexamethasone or argonyl cortisone), oral active lb anti-arrhythmic agents (eg mexiletine), about channel blockers (eg nifedipine) ), sub-blockers (such as propranolol), alpha-blockers (such as phenoxybenzamine) and adrenergic activators (such as clonidine) can also inhibit cytokine The agents are used in combination [see, for example, the physician's table reference, 1979, 2006 and 2190 (57th edition, 2003)]. The specific amount of other active agents will depend on the particular agent being used, the type of pain being treated or treated, the severity and stage of the pain, and the amount of cytokine inhibitor administered to the patient at the same time as the amount of any other active agent selected. . 123505 -214- 200815422 Hydromorphone (DilaudidTM) is typically administered intravenously at an initial dose of about 2 grams in an oral manner, or in milligrams, to treat moderate to severe pain. See, for example, the physician's desk reference 2991 (57th ed., 2003). Morphine sulfate (DuramorphTM, Astram (&gt;rphTM, MS ContinTM) is typically administered at a dose of about 2 mg iv/sc/im for the first dose, depending on whether the patient has taken an anesthetic analgesic [see, for example, a physician's table).苓 苓 贫, 594-595 (57th ed., 2003)]. There is no such thing as the amount that can be given (sexual limitation exists, as long as the patient is observed signs of adverse effects, especially respiratory depression. Different The IV dose is usually adjusted until the desired effect is achieved. For patients who do not use long-term medications, as low as 2 mg IV/SC is sufficient. For patients taking long-term narcotic analgesics, larger doses are typically required. Morphine sulfate can also be used in oral form for immediate release and timely release. The long-acting oral form can be administered twice daily. The immediate release form may be necessary during the pain breakout period, where the dose is used first. Oxycodone (〇xyC〇ntinTM) I is a long-term form of opioid and can be used in the early and late stages of pain syndromes. Hydroxydihydrobutanone ( Xyc〇d〇ne) (〇xyC〇ntinTM) is usually administered twice a day in an amount of about 10-160 mg [see, for example, the physician's table reference, 2851 (57th ed., 2003)]. (DemerolTM) is typically administered in an amount of about 50-15 mg of PO/IV/IM/SC every 3.4 hours. The typical pediatric dose of DemerolTM is 1-4 hours per 3-4 hours. 8 mg/kg (〇·5-0·8 mg/shred) P0/IV/IM/SC [See, for example, the physician's table reference material, 2991 (di version 57, 2003)]. The fentanyl transdermal patch (DuragesicT μ) can be obtained in a transdermal dosage form. Most patients were dosed with 123505 -215-200815422 during the 72-hour interval; however, some patients may require a dose interval of approximately 48 hours. A typical adult dose is about 25 micrograms per hour (10 square centimeters), 50 micrograms per hour (20 square centimeters), 75 micrograms per hour (75 square centimeters), or 100 micrograms per hour (100 square centimeters) [see, for example, a physician References on the table, 1775 (57th edition, 2003)]. Non-narcotic analgesics and anti-inflammatory agents, such as NSAIDs and cox-2 inhibitors, can be used to treat patients with mild to moderate pain. Ibuprofen (MotrinTM, AdvilTM) is administered orally three times a day in an amount of 400-800 mg [see, for example, the physician's table reference, 1900-1904 (57th edition, 2003); Reference materials on the physician's desk for over-the-counter medications and dietary supplements, 511, 667 and 773 (23rd ed., 2002). Naproxen sodium (AnaproxT M, NaprelanTM, Naprosyn1 M) can also be used to relieve mild to moderate pain in an amount of about 275 mg three times a day, or about 550 mg twice a day [see, for example, a physician's table. References, 1417, 2193 and 2891 (57th ed., 2003)]. Anti-rejection agents, such as nortriptyline (PamelorT M), can also be used in the present invention to treat patients suffering from chronic and/or neuropathic pain. The oral adult dose is typically from about 25 to 100 mg, and usually does not exceed 200 mg/day. A typical pediatric dose is about 0. 1 mg/kg orally, as the first dose, when allowed, increases up to about 0. 5-2 mg / day. Amitriptyline (EtrafonT M) is typically used for neuropathic pain and is administered orally in an adult dose of about 25-100 mg orally [see, for example, the physician's desk reference, 1417 and 2193 (57th edition, 2003)]. Anticonvulsants, such as gabapentin (NeurontinTM), can also be used to treat patients with chronic and neuropathic pain using 123505-216-200815422. Typically, gabapentin is administered orally three times a day in an amount of about 100-1,200 mg [see, for example, the physician's table reference, 2563 (57th ed., 2003)]. Aminoguanidine (TegretoFM) is used to treat pain associated with true trigeminal neuralgia. Oral adult doses are typically about 100 mg twice daily as the first dose, and when allowed, up to about 2,400 mg/day [see, for example, the physician's table reference, 2323_25 (57th ed., 2003)] . For the treatment of squamous cellulitis, other agents which may be combined with the novel compounds of the invention include, but are not limited to, anti-inflammatory agents, immunosuppressive agents, anti-infective agents, antibiotics, gold salts, alkylating agents, immunoglobulins or both thereof. Or a combination of multiple. Examples of anti-inflammatory agents include corticosteroids, COX-2 inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), TNFa antagonists, and IL-1 antagonists. For example, the corticosteroid can be prednisone, prednisolone or methylprednisolone. Corticosteroids of this type may also be administered in conjunction with either chlorambusil or mycophenylate mofetil. Examples of TNFa antagonists are infliximab, etanercept, and adalimumab. An example of an IL-1 antagonist is Anakinra. Examples of immunosuppressive agents are mycophenylate mofetil, cyclosporine, sulfonium sulfonate, 17 valence, amidoxime, alefacept, and rituximab ( Rituximab), anti-interferon tau and cyclophosphamide, and anti-infective agents include dapsone and hydroxychloropurine. In some cases, the gold salt can be sodium thiomalate or gold thioglucose (anti-inflammatory drug). An example of an alkylating agent is lukeran. The antibiotics that can be used in the combination are tetracycline, minocycline and doxycycline, sometimes combined with 123505-217-200815422 final acid amine or nicotinamide. The treatment of pemphigus may also include plasmapheresis or photophoresis for the patient. The invention, as generally described, is to be understood by reference to the appended claims [Embodiment] Examples The following abbreviations are related to the terminology and are used throughout this application:

AcN ： 乙腈 AcOH 或 HOAc : 醋酸 aq·: 水溶液 BOP ： 六氟磷酸苯并三唑-1-基氧基-參-(二甲 胺基）鱗 Bu : 丁基 CDI ： N，N’-羰基二咪唑 DCC ： 二環己基碳化二亞胺 DCM ： 二氯曱烷 DEPBT ： (3-(二乙氧基磷醯基氧基）-1，2,3-苯并三 畊-4(3H)·酮） DIEA ： N，N-二異丙基乙胺 DMF ： N，N-二甲基甲醯胺 DPPA ： 疊氮化二苯基磷醯 dppb : 1，4-二苯基膦基丁烷 123505 -218- 200815422 dppf ： U’-雙（二苯基膦基）二環戊二烯鐵 EDC ： 1-乙基-3-(3-二甲基胺基丙基）碳化二亞 胺鹽酸鹽 eq·: 當量AcN : Acetonitrile AcOH or HOAc : Acetic acid aq ·: aqueous solution BOP : benzotriazol hexafluorophosphate - cis - (dimethylamino) scale Bu : butyl CDI : N, N'-carbonyl Imidazole DCC : Dicyclohexylcarbodiimide DCM : Dichlorodecane DEPBT : (3-(diethoxyphosphonyloxy)-1,2,3-benzotrim-4(3H)·one DIEA : N,N-diisopropylethylamine DMF : N,N-dimethylformamide DPPA : Diphenylphosphonium azide dppb : 1,4-diphenylphosphinobutane 123505 - 218- 200815422 dppf : U'-bis(diphenylphosphino)dicyclopentadienyl iron EDC : 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride eq ·: equivalent

EtOAc : 醋酸乙酯EtOAc : ethyl acetate

EtOH ： 乙醇 HATU ： 六氟磷酸2-(7-氮-1H-苯并三唑-1- 基）-1，1，3,3-四甲基錁 HBTU ： 六氟磷酸2-(1Η·苯并三唑-1-基）-1，1，3,3-四 甲基錁 HCTU ： 六氟磷酸2-(6-氯基-1Η-苯并三唑-1- 基）-1，1，3,3-四甲基銨 Hex : 己烧 HOBt ： 羥基苯并三唑 HPLC · 南壓液相層析法 hr ： 小時 HV ： 高真空 IC5〇值： 會在經度量活性上造成50%降低之抑 制劑濃度 LC-MS ： 液相層析法-質譜EtOH : Ethanol HATU : 2-(7-nitro-1H-benzotriazol-1-yl)-hexafluorophosphate-1,1,3,3-tetramethylguanidine HBTU: 2-(1Η·benzene) hexafluorophosphate And triazol-1-yl)-1,1,3,3-tetramethylguanidine HCTU: 2-(6-chloro-1 - benzotriazol-1-yl)-1,1 hexafluorophosphate 3,3-Tetramethylammonium Hex : Hobbed HOBt : Hydroxybenzotriazole HPLC · Southern Pressure Liquid Chromatography hr : Hour HV : High Vacuum IC5 Depreciation: Will cause a 50% reduction in measured activity Inhibitor Concentration LC-MS : Liquid Chromatography-Mass Spectrometry

MeOH ： 甲醇 min : 分鐘MeOH : methanol min : minute

MTBE 甲基·第三-丁基醚 N-甲基嗎福啉 123505 -219- 200815422 NMR ： 核磁共振 PE ： 石油醚 PyBOP ： 六氣填酸笨并二0坐-1-基-氧基-參-四氮 吡咯并-鱗 PyBrOP ： 六氣填酸〉臭-蒼-四氮卩比嘻基鱗 RP-HPLC ： 逆相HPLC r.t.： 室溫 sat. * 飽和 TATU ： 四氟硼酸0(7-氮苯并三唑-1-基）以凡：^，]^-四甲基錁 TBTU ： 四氟硼酸2-(1Η-苯并三唑-1-基）-1，1，3,3-四 甲基鋸 TDBTU ： 四氟硼酸N，N，N’，N’-四甲基-0-(3,4-二氫-4-酮基-1，2,3-苯并三畊·3·基）鈾 TFA ： 三氟醋酸 THF ： 四氫吱喃 TSTU ： 四氟硼酸0-(Ν-琥珀醯亞胺醯基）-1，1，3,3-四甲基鈾 化合物係使用Chemdraw Ultra所提供之自動名稱產生工具 (CambridgeSoft)命名，其會產生關於化學結構之系統名稱， 具有Cahn-Ingold-Prelog規則關於立體化學之支援。 123505 -220- 200815422 中間物之合成MTBE methyl·tert-butyl ether N-methylmorpholine 123505-219- 200815422 NMR: NMR PE: petroleum ether PyBOP: six gas filled acid stupid and two zero sitting-1-yl-oxy-para - tetraazapyrrolo-square PyBrOP: hexa-gas-filled acid > odor-cyan-tetrazine quinone-based squama RP-HPLC: reverse phase HPLC rt: room temperature sat. * saturated TATU: tetrafluoroboric acid 0 (7-nitrogen Benzotriazol-1-yl) is: ^,]^-tetramethylguanidine TBTU: 2-(1Η-benzotriazol-1-yl)-tetrafluoroborate-1,1,3,3-tetra Methyl saw TDBTU: tetrafluoroboric acid N,N,N',N'-tetramethyl- 0-(3,4-dihydro-4-keto-1,2,3-benzotrim3·3· Uranium TFA: Trifluoroacetic acid THF: Tetrahydrofuran TSTU: Tetrafluoroborate 0-(Ν-ammonium iminoindenyl)-1,1,3,3-tetramethyluranium compound using Chemdraw Ultra Named after the automatic name generation tool (CambridgeSoft), which produces a system name for the chemical structure, with Cahn-Ingold-Prelog rules for support for stereochemistry. 123505 -220- 200815422 Synthesis of intermediates

5-嗎福淋基間苯二腈·將氟基間苯二腈（1·〇〇克，6.84毫 莫耳，1.0當量）、嗎福淋（1192微升，13.69毫莫耳，2.0當量）5-folfipyl phthalonitrile, fluoroisophthalonitrile (1·〇〇g, 6.84 mmol, 1.0 eq.), whollen (1192 μl, 13.69 mmol, 2.0 eq)

及DMSO (2·0毫升）之混合物於50°C下攪拌過夜。以2% Ηα水 溶液（30宅升）稀釋混合物’藉過渡分離固體，以2% HC1水 溶液、水洗滌，並在HV中乾燥，獲得純標的產物（白色固 體，1_35克，92%產率，99%純，藉LCMS_未發現物質）。 (DMSO-d6) 5 (ppm) 7.69 (s，3H)，3.71 (m，4H)，3.28 (m，4H). 3_胺甲醯基-5-嗎福啉基苯曱酸曱酯（A)在5〇毫升圓底 燒瓶中，放置5-嗎福啉基間苯二腈（336毫克，127毫莫耳） 與DCM(3毫升）。於此溶液中，添加製自觀（26毫升广他册 (6宅升)及氣化乙醯(2毫升)之溶液。將溶液緊密地加蓋， 並使其在室溫下靜置1M、時。移除溶劑，並使殘留物在 Me〇H(8°毫升)中回流1小時45分鐘。移除溶劑，並將殘留 物以謎研製。使殘留物乾燥，獲得⑸毫克3胺甲酿基·Η 福p林基苯甲酸甲g旨A (古+曾+併θ °才之質ΐ ·· 264，發現之質量：265)。 3-氰基_5_嗎福琳基笨甲酴 冬f酸甲酯.在100毫升圓底燒瓶中， 使3_胺甲酿基-5-嗎福琳其絮 暴本甲酸甲酯A (257毫克，0.97毫莫 耳）溶於DCM (15毫升）中〇、；丄 、 r 添加吡啶（851微升，9.7毫莫耳） 與氯化磷醯（445微升，49古 •宅莫耳），並使溶液於室溫下靜置 123505 •221- 200815422 1小時。移除溶劑，並使殘留物於矽膠上純化，以0-50% EtOAc/己烧溶離，而得197毫克3-氰基-5-嗎福琳基苯甲酸甲 酯（82%產率）（計算之質量：246，發現之質量：247)。 3-氰基-5-嗎福啉基苯甲酸(B). 使3-氰基-5-嗎福啉基苯甲 酸甲酯（197毫克，0.8毫莫耳）溶於MeOH (7毫升）與THF (7毫 升）中。添加NaOH溶液（2M，0_60毫升），並將溶液加熱至50 °C，歷經75分鐘。移除溶劑，並使殘留物懸浮於THF中。A mixture of DMSO (2.0 mL) was stirred at 50 °C overnight. The mixture was diluted with a 2% aqueous solution of Ηα (30 liters of water). The solid was isolated by transfer, washed with 2% aqueous HCl solution, water, and dried in HV to give the pure title product (white solid, 1-3 g, 92% yield, 99 % pure, by LCMS_ no substance found). (DMSO-d6) 5 (ppm) 7.69 (s, 3H), 3.71 (m, 4H), 3.28 (m, 4H). 3-aminomethylmercapto-5-morpholinol benzoate (A) In a 5 mL round bottom flask, 5-morpholine-isophthalonitrile (336 mg, 127 mmol) and DCM (3 mL) were placed. In this solution, a solution of self-contained (26 ml of Guangxu (6 house liter) and gasified acetonitrile (2 ml) was added. The solution was tightly capped and allowed to stand at room temperature for 1 M, The solvent was removed and the residue was refluxed in Me 〇H (8 mL) for 1 hour and 45 min. The solvent was removed and the residue was triturated. The residue was dried to give (5)基·Η 福 p 林基苯苯甲甲g A (古+曾+ and θ°才质ΐ·· 264, found quality: 265). 3-cyano _5_ 福福琳基笨甲酴Winter f-acid methyl ester. In a 100 ml round bottom flask, 3-aminoglycol-5-fofin was pulverized with methyl formate A (257 mg, 0.97 mmol) dissolved in DCM (15 ml) ) 〇, 丄, r Add pyridine (851 μl, 9.7 mmol) with phosphine chloride (445 μl, 49 Gu·House Mo) and allow the solution to stand at room temperature 123505 •221 - 200815422 1 hr. The solvent was removed and the residue was purified eluted eluted elut elut elut elut elut elut elut elut % yield) (calculated quality: 246, quality found : 247) 3-cyano-5-morpholinylbenzoic acid (B). Methyl 3-cyano-5-morpholinylbenzoate (197 mg, 0.8 mmol) was dissolved in MeOH ( 7 ml) and THF (7 ml), NaOH solution (2M, 0-60 ml) was added, and the solution was heated to 50 ° C for 75 minutes. The solvent was removed and the residue was suspended in THF.

添加2M HC1 (0.60毫升），及移除溶劑。使殘留物懸浮於THF 中，過濾溶液，並於真空中移除溶劑，而得281毫克標的化 合物，其含有一些氯化鈉（計算之質量：232，發現之質量： 233)。將其使用於後續反應中，無需進一步純化。 ( κAdd 2M HCl (0.60 mL) and remove the solvent. The residue was suspended in THF, the solution was filtered, and solvent was evaporated in vacuo to give 281 mg of the title compound, which contains some sodium chloride (calculated mass: 232, mass found: 233). It was used in the subsequent reaction without further purification. ( κ

5-第三-丁基-間苯二甲酸單甲酯（C). 於5-第三-丁基間苯 二甲酸（50克，0.225莫耳）在MeOH (700毫升）中之溶液内，添 加2毫升濃H2 S04。將反應物加熱，並攪拌過夜。在冷卻至 室溫後，添加固體NaHC03，以中和反應混合物。藉過濾移 除過量NaHC03。蒸發濾液，並將殘留物藉管柱層析純化（使 用DCM與MeOH作為溶離劑），獲得所要之單酯C (32克， 60%)。iH-NMR (DMSO-d6) 5 (ppm) 13.3 (s，1H)，8.35 (s，1H)，8.20 (s， 123505 -222- 200815422 1H)，8.24 (s，1H)，3.90 〇, 3H)，1.38 (s, 9H). 3-第三-丁基各胺曱醢基苯甲酸曱酯·於C(19克，8〇 42毫 莫耳）在DCM (600毫升）中之懸浮液内，添加氯化草酿⑼毫 升莫耳）與〇·8宅升DMF。將混合物於室溫下授拌2小 時。在真空下移除溶劑至乾涸。使殘留物在室溫下與氨⑺ 毫升，1·3Μ，在二氧陸圜中），於〇1从(46毫升）存在下，在 DCM (150晕升）中反應。將混合物於室溫下攪拌過夜。蒸發 溶液，並將殘留物藉管柱層析純化，使用己烷/Et〇Ac，獲 得標的化合物（15克，79%)，為白色固體。（計算之質量： 235.2，發現之質量：276·6 (M+AcN)+)。 3-第三-丁基-5·氰基苯甲酸甲醋(〇)·於上文獲得之化合 物（6克，25.5毫莫耳）在氯仿（13〇毫升）中之懸浮液内，添加 POCls (3.03 ^:升’ 33.15宅莫耳）在氣仿（2〇毫升）中之溶液。將 混合物於室溫下攪拌3小時。在〇t：下添加TEA。將混合物 於室溫下攪拌過夜。在真空下蒸發反應混合物，並使殘留 ，物藉管柱層析純化（己烷/EtOAc)，獲得標的化合物（4.12克， ^ 75%)，為白色固體。1h-NMR(CDC13) 3 8.31 (m，1Η)，8.17 (m，1Η)， 7.86 (m，1H)，3_98 (s，3H)，1.39 (s，9H)_ 3-第二-丁基-5-氰苯甲酸（E).使按上述獲得之3-第三-丁 基-5-氰基苯甲酸甲酯（4.35克，20毫莫耳）溶於THF (150毫 升）、MeOH (100毫升）中，並添加2N NaOH (15毫升）。將溶液 於室溫下攪拌130分鐘，然後濃縮混合物，及以MTBE (5〇毫 升）萃取，以移除未反應之起始物質。以12m HC1水溶液（3 毫升）中和水層，且白色固體沉澱。將固體過濾，以水洗滌， 123505 -223 - 200815422 風乾，並在HV中，於8(rc下乾燥2小時，而產生3 88克標的 物質。W-NMR (DMSO-d6) (5 (ppm) 13.50 (bs，1H)，8.20 (m，1H), 8.13 (m，1H)，8.11 (m，1H), 1.32 (s，9H)· 氣化3_第二-丁基-5-氰基苯甲醯(f)·於酸E (3·88克，19毫 莫耳）在DCM (10毫升）中之懸浮液内，添加氣化草醯（14.55 克’ 115耄莫耳）與催化量之5% DMF/DCM溶液（〇·5毫升）。將 反應物於室溫下擾拌80分鐘，並蒸發溶劑。使殘留物藉石夕 藻土蒸餾純化（HV，140-160°C )，而得純產物，為黃色油， 其係慢慢形成結晶性固體。1H-NMR (CDC13) 5 (；ppm) (m， 1H)，8.18 (m，1H)，7·89 (m，1H)，1.32 (s，9H).5-tert-butyl-isophthalic acid monomethyl ester (C). In a solution of 5-tris-butyl isophthalic acid (50 g, 0.225 mol) in MeOH (700 mL) Add 2 ml of concentrated H2 S04. The reaction was heated and stirred overnight. After cooling to room temperature, solid NaHC03 was added to neutralize the reaction mixture. Excess NaHC03 was removed by filtration. The filtrate was evaporated, and the residue was purified mjjjjjjjjjjj iH-NMR (DMSO-d6) 5 (ppm) 13.3 (s, 1H), 8.35 (s, 1H), 8.20 (s, 123505 -222 - 200815422 1H), 8.24 (s, 1H), 3.90 〇, 3H) , 1.38 (s, 9H). 3-tert-butyl-amino-amine-mercaptobenzoic acid ester in a suspension of C (19 g, 8 〇 42 mmol) in DCM (600 mL) Add chlorinated grass to brew (9 ml ml) with 〇·8 house liter DMF. The mixture was stirred at room temperature for 2 hours. The solvent was removed under vacuum to dryness. The residue was reacted in a DCM (150 halo) at room temperature with ammonia (7 mL mL, 1·3 Torr in dioxane) in the presence of 〇1 from (46 mL). The mixture was stirred at room temperature overnight. The solution was evaporated, and the~~~~~~~~~~~~~~~~~~~ (Calculated mass: 235.2, quality found: 276·6 (M+AcN)+). 3-T-butyl-5-cyanobenzoic acid methyl vinegar (〇)········································· (3.03 ^: liter '33.15 house Moer) in a solution of gas (2 〇 ml). The mixture was stirred at room temperature for 3 hours. Add TEA under 〇t:. The mixture was stirred at room temperature overnight. The reaction mixture was evaporated EtOAcjjjjjjjjjjj 1h-NMR(CDC13) 3 8.31 (m,1Η), 8.17 (m,1Η), 7.86 (m,1H),3_98 (s,3H), 1.39 (s,9H)_ 3-t-butyl- 5-Cyanobenzoic acid (E). Methyl 3-tert-butyl-5-cyanobenzoate (4.35 g, 20 mmol) obtained as above was dissolved in THF (150 mL), MeOH (100) In ml), add 2N NaOH (15 ml). The solution was stirred at room temperature for 130 minutes, then the mixture was concentrated and extracted with MTBE (5 mL) to remove unreacted starting material. The aqueous layer was neutralized with a 12 m aqueous HCl solution (3 mL) and a white solid precipitated. The solid was filtered, washed with water, 123505 - 223 - 200815422, air dried, and dried in HV at 8 (rc) for 2 hours to yield 3 88 g of the title material. W-NMR (DMSO-d6) (5 (ppm) 13.50 (bs,1H), 8.20 (m,1H), 8.13 (m,1H),8.11 (m,1H), 1.32 (s,9H)· gasification 3_second-butyl-5-cyanobenzene Methotrexate (f)·In a suspension of acid E (3·88 g, 19 mmol) in DCM (10 ml), add gasified grasshopper (14.55 g '115 耄mol) and catalytic amount 5% DMF/DCM solution (〇·5 ml). The reaction was stirred at room temperature for 80 minutes, and the solvent was evaporated. The residue was purified by distillation (HV, 140-160 ° C). The pure product is obtained as a yellow oil, which is formed as a crystalline solid. 1H-NMR (CDC13) 5 (ppm) (m, 1H), 8.18 (m, 1H), 7·89 (m, 1H), 1.32 (s, 9H).

3-(溪基甲基)_5_第二-丁基苯曱酸·於中間物C (0.5克，2·1 毫莫耳）與ΝΜΜ (0.64克，6.4毫莫耳）在THF (50毫升）中之溶 液内，在-78°C下，添加氣曱酸異丁酯（0·35克，2·5毫莫耳）。 將混合物於-78 C下擾拌15分鐘。使過量删氫化納（〇·4克）溶 於水（30宅升）中’然後’將溶液添加至混合酐之τηρ溶液 中。使混合物溫熱至室溫，接著添加至2〇〇毫升水中。以dcm 萃取混合物。使有機離份以MgS〇4脫水乾燥。藉過濾移除乾 燥劑，並使濾液在真空下濃縮，獲得苄醇中間物。使中間 物溶於THF/DCM混合物（50毫升3 : 1混合物）中，且冷卻至〇 °C。於此溶液中，添加三溴化磷（2.12毫升，在DCM中之1.0M 溶液），並將反應物在0°C下攪拌1小時，然後於室溫下4小 123505 -224- 200815422 時。將混合物添加至200毫升水中，並以DCM萃取。使有機 離份以MgS〇4脫水乾燥。藉過濾移除乾燥劑，及在真空下濃 縮濾液。使殘留物經由管柱層析純化（4:丨己烷Z^OAc)，而 得標的化合物，為透明油（〇·3克）。1hnmr(5〇〇MHz，cdc13) (5 (ppm) 8.02 (s，1H)，7.90 (s，1H)，7.60 (s，1H)，4.53 (s，2H)，3·93 (s，3H)， 1-36 (s，9Η).3-(xiylmethyl)_5_second-butylphthalic acid·in intermediate C (0.5 g, 2.1 μm) with hydrazine (0.64 g, 6.4 mmol) in THF (50 ml In the solution in the solution, isobutyl phthalate (0. 35 g, 2.5 mM) was added at -78 °C. The mixture was spoiled at -78 C for 15 minutes. An excess of sodium hydride (〇·4 g) was dissolved in water (30 liters) and then the solution was added to the τηρ solution of the mixed anhydride. The mixture was allowed to warm to room temperature and then added to 2 mL of water. The mixture was extracted in dcm. The organic fraction was dehydrated and dried with MgS〇4. The desiccant was removed by filtration and the filtrate was concentrated under vacuum to give a benzyl alcohol intermediate. The intermediate was dissolved in a THF/DCM mixture (50 mL 3:1 mixture) and cooled to EtOAc. To this solution, phosphorus tribromide (2.12 ml, 1.0 M solution in DCM) was added, and the reaction was stirred at 0 ° C for 1 hour and then at room temperature for 4 hours 123505 -224 - 200815422. The mixture was added to 200 ml of water and extracted with DCM. The organic fraction was dehydrated and dried with MgS 4 . The desiccant was removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (4: hexanes: EtOAc) to give the title compound as a transparent oil (3 g). 1hnmr(5〇〇MHz, cdc13) (5 (ppm) 8.02 (s, 1H), 7.90 (s, 1H), 7.60 (s, 1H), 4.53 (s, 2H), 3.93 (s, 3H) , 1-36 (s, 9Η).

3-G臭基甲基）-5_第三-丁基苯甲酸①)於上文獲得之化合 物（0.1克，0·35毫莫耳）在DCM(3毫升）中之溶液内，在〇χ：下， 添加三溴化硼（0.5毫升，在DCM中之溶液），並將反應 物於0 C下攪拌1小時，然後在室溫下2小時。接著，將混合 物添加至20毫升水中。以DCM萃取混合物。使有機離份以 MgS〇1 2脫水乾無。藉過濾移除乾燥劑，及在真空下濃縮滅 液，而得標題化合物D，為透明油（0.088克）。1 H NMR (5〇〇 MHz， CDC13) 5 (ppm) 8·01 (s，1Η)，7·93 (s，1Η)，7·74 (s，1H)，4·54 (s，2H)，1.38 (s，9H)·3-G odorylmethyl)-5-tri-butylbenzoic acid 1) In a solution of the compound obtained above (0.1 g, 0. 35 mmol) in DCM (3 mL) χ: Next, boron tribromide (0.5 ml, a solution in DCM) was added, and the mixture was stirred at 0 C for 1 hour and then at room temperature for 2 hours. Next, the mixture was added to 20 ml of water. The mixture was extracted with DCM. The organic fraction was dehydrated to dryness without MgS〇1 2 . The desiccant was removed by filtration and the residue was evaporated to dryness crystall 1 H NMR (5〇〇MHz, CDC13) 5 (ppm) 8·01 (s, 1Η), 7·93 (s, 1Η), 7·74 (s, 1H), 4·54 (s, 2H) , 1.38 (s, 9H)·

E X = Br，R = H F X = Br，R = Me G X = CN, R = Μθ H X = CN, R = H -225 - 1 一第三·丁基_2_甲氧基各溴苯甲酸(E).將NBS (1.31克，9 6 毫莫耳）添加至5-第三-丁基-2-甲氧基苯甲酸（1·0克，4.8毫莫 耳）在冰醋酸（15毫升）中之溶液内，並將混合物加熱至1〇〇 2 C ’歷經16小時。使反應物冷卻，並以1〇毫升水稀釋，然 後以DCM萃取。將合併之有機層以水洗滌，以MgS〇4脫水乾 燥’及濃縮，而得中間物Ε (1·2克，87%)，為淡黃色固體， 3 123505 200815422 &gt;90% 純度。1H-NMR (500 MHz，CDC13) 5 (ppm)⑽（s，1H)，7.78 (s， 1H)，4.00 (s，3H)，1.33 (s，9H)· 3-溴基-5-第三-丁基_2-甲氧基苯曱酸甲酯⑻於5_第三_ 丁基-2-甲氧基-3-溴苯甲酸E (0.63克，2,2毫莫耳）在DCM (18 宅升）中之〉谷液内，添加氯化草酸（10毫升，毫莫耳）與 六滴DMF。將混合物於室溫下攪拌丨小時，濃縮，使殘留物 溶於MeOH (10毫升）中，並進一步在室溫下攪拌15分鐘。蒸 發/谷劑’而传黏稠黃色油（定量），&gt;9〇%純度。1 h_nmR (500 MHz, CDC13) 5 (ppm) 7.75 (s5 1H)5 7.73 (s5 1H)5 3.95 (s5 3H)? 3.92 (s3 3H)，1.33 (s，9H). 5_第二丁基_3_氰基_2_甲氧基苯甲酸甲酯（G)於5-第三· 丁基-2-甲氧基-3-溴苯曱酸甲酯（015克，〇·5毫莫耳）在1 : 1 DMF/ 一氧陸圜（5毫升）混合物中之溶液内，添加KCN⑻毫 克 ’ 1 毫莫耳）、Pd(OAc)2(12 毫克，1〇 莫耳 ％)、csC〇3 (〇·49 克， 1.5毫莫耳）及ΒΙΝΑΡ (62毫克，20莫耳％)。將混合物於150°c 下，在微波中攪拌40分鐘，於矽藻土上過濾，及以DCM洗 滌固體。濃縮濾液，並使殘留物於逆相上純化，使用水中 之50-99% ACN，而得中間物氰基酯（49毫克，4〇%)，為淡黃 色固體。1H-NMR (500 MHz，CDC13) 5 (ppm) 8.00 (s，1H)，7.72 (s， 1H)，4.04 (s，3H)，3.94 (s，3H)，1·32 (s，9H)· 5·第三-丁基-3-氰基-2-甲氧基苯甲酸（h)於孓第三丁基 -2-甲氧基-3-氰苯甲酸甲酯（4〇毫克，〇16毫莫耳）在1 : 1 THF/MeOH (1毫升）混合物中之溶液内，添加2N Na〇H (〇·35毫 升）。將混合物於室溫下攪拌1小時，以1N HC1中和，及以 123505 -226- 200815422 、、’勺20笔升EtOAc萃取。將有機層以MgS〇4脫水乾燥，並濃縮， 而付中間物Η (定量），為白色固體，將其使用於下一步驟， 無需進一步純化。EX = Br, R = HFX = Br, R = Me GX = CN, R = Μθ HX = CN, R = H -225 - 1 a third · butyl 2 - methoxy bromobenzoic acid (E) Add NBS (1.31 g, 9 6 mmol) to 5-t-butyl-2-methoxybenzoic acid (1.0 g, 4.8 mmol) in glacial acetic acid (15 mL) Within the solution, the mixture was heated to 1 〇〇 2 C ' for 16 hours. The reaction was cooled and diluted with 1 mL water then extracted with DCM. The combined organic layers were washed with water, dried and dried with &lt;RTI ID=0.0&gt;&gt;&gt;&&&&&&&&&&&&&&& 1H-NMR (500 MHz, CDC13) 5 (ppm) (10) (s, 1H), 7.78 (s, 1H), 4.00 (s, 3H), 1.33 (s, 9H) · 3-bromo-5- Methyl butyl 2-methoxybenzoate (8) in 5_T-butyl-2-methoxy-3-bromobenzoic acid E (0.63 g, 2,2 mmol) in DCM ( In the house solution of 18 liters, add oxalic acid (10 ml, millimolar) and six drops of DMF. The mixture was stirred at room temperature for EtOAc (3 mL). Evaporation/troreal&apos; and viscous thick yellow oil (quantitative), &gt; 9% purity. 1 h_nmR (500 MHz, CDC13) 5 (ppm) 7.75 (s5 1H)5 7.73 (s5 1H)5 3.95 (s5 3H)? 3.92 (s3 3H), 1.33 (s, 9H). 5_Secondyl _ Methyl 3-cyano-2-methoxybenzoate (G) in methyl 5-tributyl-2-methoxy-3-bromobenzoate (015 g, 〇·5 mmol) Add KCN (8) mg '1 mmol', Pd(OAc) 2 (12 mg, 1 mol%), csC〇3 to a solution of 1:1 DMF/monooxin (5 ml) mixture. (〇·49 g, 1.5 mmol) and ΒΙΝΑΡ (62 mg, 20 mol%). The mixture was stirred at 150 ° C for 40 minutes in the microwave, filtered over celite, and washed with DCM. The filtrate was concentrated, and the residue was purified EtOAcjjjjjjj 1H-NMR (500 MHz, CDC13) 5 (ppm) 8.00 (s, 1H), 7.72 (s, 1H), 4.04 (s, 3H), 3.94 (s, 3H), 1·32 (s, 9H)· 5. Tri-tert-butyl-3-cyano-2-methoxybenzoic acid (h) methyl tributyl butyl-2-methoxy-3-cyanobenzoate (4 〇 mg, 〇 16 To a solution of a mixture of 1:1 THF / MeOH (1 mL), 2N Na? The mixture was stirred at room temperature for 1 hour, neutralized with 1N HCl, and extracted with &lt;RTI ID=0.0&gt;&gt; The organic layer was dried with EtOAc (EtOAc m.).

I 〇 雜環基苯甲酸衍生物①方法Α·(按WOOO/55153中所述 之方法）且為關於嗎福啉基衍生物之舉例步驟L &gt;氟基各 嗎福琳基苯甲腈(X：=F)·將3,5-二氟苯甲腈（5.00克，35.95毫莫 耳’ 1·〇當量）、嗎福啉（22·〇毫升，7 〇當量）及無水DMS〇 (7·5 毫升）之混合物加熱至6〇_65°C，歷經24小時。於冷卻後，將 混合物以氯仿（1〇〇毫升）稀釋，並以水（5〇〇毫升）洗滌。使有 機層脫水乾燥（Na2S04)，濃縮，及在hv中乾燥，而得3_氟基 -5-嗎福啉基苯甲腈，為白色固體（7 〇2克，94%產率，99%純， 藉LC-MS)(計算之質量：2〇7，發現之質量：2补（M+AcN)+)。 步驟2· 3-氟基-5-嗎福啉基苯曱酸(x=F) (I-a)·將上文獲得 之化合物（4·93克，23.92毫莫耳）與6M HC1水溶液（1〇0毫升） 之混合物加熱至100°C過夜。於冷卻至0°C後，使混合物以5〇% NaOH水溶液小心地中和，直到固體沉澱物形成（ρΗ〜1-2)為 止。藉過濾分離固體，以水洗滌，風乾，並在Η V中乾燥， 而得3-氟基-5-嗎福啉基苯曱酸i_a，為白色固體（4.79克，88% 產率，97%純，藉LC-MS)(計算之質量：225，發現之質量： 267 (M+AcN)+) 〇 123505 -227- 200815422I 〇 Heterocyclic benzoic acid derivative 1 method Α · (as described in WOOO/55153) and is an exemplary step L &gt; fluoro-based carbaryl-benzonitrile X:=F)·3,5-difluorobenzonitrile (5.00 g, 35.95 mmoles 1 〇 equivalent), morphine (22·ml, 7 〇 equivalent) and anhydrous DMS 〇 (7) • A mixture of 5 ml) was heated to 6 〇 _65 ° C for 24 hours. After cooling, the mixture was diluted with chloroform (1 mL) and washed with water (5 mL). The organic layer was dried (Na2SO4), concentrated, and dried in <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Pure, by LC-MS) (calculated quality: 2〇7, quality found: 2 (M+AcN)+). Step 2· 3-Fluoro-5-morpholinobenzoic acid (x=F) (Ia)· The compound obtained above (4.93 g, 23.92 mmol) and 6 M aqueous HCl solution (1 〇) The mixture of 0 ml) was heated to 100 ° C overnight. After cooling to 0 ° C, the mixture was carefully neutralized with a 5 % aqueous NaOH solution until a solid precipitate formed (ρ Η 1-2). The solid was isolated by filtration, washed with water, dried with EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Pure, by LC-MS) (Calculation quality: 225, quality found: 267 (M+AcN)+) 〇123505 -227- 200815422

〇 I Ο 方法Β· (3-氟基-5-嗎福啉基苯基）(嗎福啉基）甲酮（X=F). 將嗎福琳（4毫升，46毫莫耳）添加至3,5-二氟苯甲酸甲酯（2.53 克’ 15毫莫耳）中，並將混合物加熱至i6(rc，歷經5天，提 供標的化合物（計算之質量：225，發現之質量：266·9)與雙 f -嗎福啉基衍生物（計算之質量：295 〇，發現之質量：294 〇) 之混合物。使反應混合物冷卻至室溫，添加6N HC1水溶液（15 宅升）’並將混合物在125。〇下加熱3小時。於冷卻至室溫 後’以水（50毫升）稀釋反應混合物，並使用NaHC〇3水溶液 調整pH值至2。過濾已沉澱之產物，以水洗滌，及乾燥。 於減少體積後，自合併之洗液回收第二份收取產物之3_氟 基_5_嗎福I基苯甲酸fa (計算之質量：225，發現之質量： 267)。W-NMR (500 MHz，DMSO-d6) 5 (ppm) 13.15 (bs，1H)，7.285 (t， 1 1H)，7.05 (d，1H)，7.03 (s，1H)，3.73 (t，4H)，3_18 (t，4H)· 上述方法係用於合成下列經取代之苯甲酸·· 3-氟基-5_(六氫吡啶小基）苯甲酸（I_b)·(步驟1反應溫 度：40°C )·計算之質量：224，發現之質量：224. 3-氟基-5-(四氫吡咯小基）苯甲酸(I-c)·(步驟1反應溫度： 室溫）·計算之質量：210，發現之質量：251· 3-(2,6-二曱基嗎福啉基）-5_氟苯甲酸(i-d)·(步驟1反應溫 度·· 70°C )·計算之質量：254，發現之質量·· 254. 123505 -228- 200815422 3-氟基-5-(l，4-氧氣七圜-4·基）苯甲酸（I_e)·(步驟1反應溫 度：100°C )·計算之質量：240，發現之質量：240. 3-氟基-5-硫代嗎福啉基苯甲酸(I-f)·(步驟1反應溫度：70 t： )·計算之質量：242，發現之質量：283. 3-嗎福淋基_5-(三氟甲基）苯曱酸（I-g).(步驟1反應溫 度：60°C )·計算之質量：276，發現之質量：317. 3-(六氮外b咬-1-基）-5-(三氟甲基）苯甲酸（I-h)·(步驟1反應 溫度：40°C )·計算之質量：274，發現之質量：315.〇I Ο Method Β·(3-Fluoro-5-morpholinophenyl)(morpholinyl)methanone (X=F). Add whallin (4 ml, 46 mmol) to Methyl 3,5-difluorobenzoate (2.53 g '15 mmol), and the mixture was heated to i6 (rc, for 5 days to provide the title compound (calculated mass: 225, found quality: 266. 9) a mixture with a bis-f-fosfolinyl derivative (calculated mass: 295 〇, mass found: 294 〇). The reaction mixture was cooled to room temperature and a 6 N aqueous HCl solution (15 liters) was added. The mixture was heated at 125 ° C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and the pH was adjusted to 2 using a NaH.sub.3 aqueous solution. The precipitated product was filtered and washed with water. Drying. After reducing the volume, the second fraction of the product was recovered from the combined washing solution of 3_fluoroyl-5-ifu-Ibenzoic acid fa (calculated mass: 225, mass found: 267). W-NMR (500 MHz, DMSO-d6) 5 (ppm) 13.15 (bs, 1H), 7.285 (t, 1 1H), 7.05 (d, 1H), 7.03 (s, 1H), 3.73 (t, 4H), 3_18 ( t,4H)· on The method was applied to the synthesis of the following substituted benzoic acid·· 3-fluoro-5-(hexahydropyridine small) benzoic acid (I_b)·(Step 1 reaction temperature: 40 ° C) · Calculated mass: 224, found Mass: 224. 3-Fluoro-5-(tetrahydropyrrole small) benzoic acid (Ic) · (Step 1 Reaction temperature: room temperature) · Calculated mass: 210, found mass: 251 · 3-( 2,6-diamidinofosyl)-5-fluorobenzoic acid (id)·(Step 1 reaction temperature··70°C)·Calculated mass: 254, found quality·· 254. 123505 -228 - 200815422 3-Fluoro-5-(l,4-oxygen-7-yl)ylbenzoic acid (I_e)·(Step 1 Reaction temperature: 100 ° C)·Calculated mass: 240, found quality: 240 3-Fluoro-5-thiomorpholinylbenzoic acid (If)·(Step 1 Reaction temperature: 70 t: )·Calculated mass: 242, found quality: 283. 3-? 5-(Trifluoromethyl)benzoic acid (Ig). (Step 1 Reaction temperature: 60 ° C) · Calculated mass: 276, found mass: 317. 3-(hexanitrox b-butyl-1) )-5-(trifluoromethyl)benzoic acid (Ih)·(Step 1 reaction temperature: 40 ° C)·Calculated mass: 274, found Quality: 315.

3_(四氫叶1：哈-1-基）-5-(三氟甲基）苯甲酸（I-i)·(步驟1反應3_(tetrahydrogen leaf 1: ha-1-yl)-5-(trifluoromethyl)benzoic acid (I-i)·(Step 1 reaction

溫度：室溫）·計算之質量：260，發現之質量：301.Temperature: room temperature) · Calculated quality: 260, found quality: 301.

3,5-二氟-2_甲氧基苯甲酸乙酯·在冰浴中，於3,5_二氟_2-甲氧基苯甲酸（18.8克，100毫莫耳）在Et0H(2⑻毫升）中之混 合物内，逐滴添加SOCl2(35.7克，300毫莫耳）。在添加完成 後，將反應混合物加熱至回流過夜。使用几匚，以偵測反 應之完成。蒸發混合物，獲得3,5-二氟_2_甲氧基苯曱酸乙 酯，為白色固體（21.5克，99.5%)，將其以本身使用在下一步 123505 -229- 200815422 驟中。 3-氟基-2-甲氧基-5-嗎福啉-4-基苯甲酸乙酯· 將上文獲得 之化合物（10·5克，48.6毫莫耳）與嗎福啉（42.3克，486毫莫耳） 添加至DMSO (50毫升）中。將所形成之混合物加熱至i〇〇°C， 歷經24小時。使反應混合物冷卻後，添加水（15〇毫升）。以 DCM萃取所形成之混合物，並使有機相以無水MgS〇4脫水乾 燥，及蒸發。將殘留物藉管柱層析純化（EtOAc/PE = 1 : 9 (v : v))，提供未反應之3,5-二氟-2·甲氧基苯甲酸乙酯（8.0克）、5-氟基-2-甲氧基-3-嗎福啉-4·基苯甲酸乙酯（535毫克，3.89%)及 3-氟基-2-甲氧基-5-嗎福啉-4-基苯甲酸乙酯（187毫克，1.36%)。 ^-NMR (300 MHz5 CDC13) ： δ (ppm) 7.02-7.04 (q? 1H)5 6.76-6.82 (dd? 1H)，4.34-4.41 (q，2H)，3.82-3.89 (m，7H)，3.09-3.13 (m，4H)，1.37-1.42 (t5 3H). 3-氟基-2-曱氧基-5_嗎福啉·4_基苯甲酸⑺·於3-氟基-2-甲Ethyl 3,5-difluoro-2-methoxybenzoate in an ice bath at 3,5-difluoro-2-methoxybenzoic acid (18.8 g, 100 mmol) at Et0H (2 (8) In a mixture of ML), SOCl2 (35.7 g, 300 mmol) was added dropwise. After the addition was completed, the reaction mixture was heated to reflux overnight. Use a few turns to detect the completion of the response. Evaporation of the mixture gave ethyl 3,5-difluoro-2-methoxybenzoate as a white solid (21.5 g, 99.5%) which was used in the next step in the next step 123505-229-200815422. Ethyl 3-fluoro-2-methoxy-5-morpholine-4-ylbenzoate· The compound obtained above (10·5 g, 48.6 mmol) and morpholine (42.3 g, 486 mmol) was added to DMSO (50 mL). The resulting mixture was heated to i ° ° C for 24 hours. After allowing the reaction mixture to cool, water (15 mL) was added. The resulting mixture was extracted with DCM, and the organic phase was dried over anhydrous MgSO 4 and evaporated. The residue was purified by column chromatography (EtOAc /EtOAc = 1 : 9 (v: v)) to afford ethyl 3,5-difluoro-2- methoxybenzoate (8.0 g), 5 -Ethylfluoro-2-methoxy-3-morpholine-4-ylbenzoate (535 mg, 3.89%) and 3-fluoro-2-methoxy-5-morpholin-4- Ethyl benzoate (187 mg, 1.36%). ^-NMR (300 MHz5 CDC13): δ (ppm) 7.02-7.04 (q? 1H)5 6.76-6.82 (dd? 1H), 4.34-4.41 (q, 2H), 3.82-3.89 (m, 7H), 3.09 -3.13 (m,4H),1.37-1.42 (t5 3H). 3-fluoro-2-indolyl-5-morpholine-4-ylbenzoic acid (7)·3-fluoro-2-yl

氧基-5-嗎福啉-4-基苯甲酸乙酯（1·31克，4·63毫莫耳）在4〇毫 升MeOH/THF(v: ν=1: 1)中之混合物内，添加6毫升2NNa〇H 溶液。將所形成之混合物加熱至5(rc，歷經2小時。使用 TLC，以偵測反應之完成。蒸發溶劑，並以Et〇Ac (2〇毫升） 萃取水相。使水相酸化至pH = 5，並經由Et0Ac萃取。將有 機相以無水MgS〇4，脫水乾燥，及蒸發，提供3_氟基丨甲氧 基_5·嗎福淋冰基苯曱酸_毫克，67.8%)。1 H-NMR (300 MHz， 麵0-d0)㈣pm) D.〇5 (s，1Η)，π3·㈣，m)，616 % ㈨邱 3.68-3.73 (m，7H)，3.05-3.28 (t，4H).(計算之質量·· 255 ;發現之質 量：254.0). 123505 -230· 200815422Ethyl 5-oxoline-4-ylbenzoate (1·31 g, 4.63 mmol) in a mixture of 4 mL of MeOH / THF (v: ν = 1 : 1) Add 6 ml of 2NNa〇H solution. The resulting mixture was heated to 5 (rc for 2 hours. TLC was used to detect the completion of the reaction. The solvent was evaporated and the aqueous phase was extracted with Et.sub.2 (2 mL). The aqueous phase was acidified to pH = 5 And extracted with Et0Ac. The organic phase was dried over anhydrous MgSO.sub.4, dried and evaporated to afford 3- <RTIgt; 1 H-NMR (300 MHz, face 0-d0) (d) pm) D. 〇 5 (s, 1 Η), π 3 · (4), m), 616 % (9) Qiu 3.68-3.73 (m, 7H), 3.05-3.28 (t , 4H). (Quality of calculation · 255; quality found: 254.0). 123505 -230· 200815422

3-胺基-5-第三-丁基劣曱氧基苯甲酸甲酯·於孓第三·丁 基-2-甲氧基-3-硝基·苯甲酸（18克，71毫莫耳）（按 US2005/0107399中所述獲得）與DMF (〇 5毫升）在dcm (5〇毫升） r \ 中之溶液内’逐滴添加氯化草醯（31毫升，35 5毫莫耳），並 將混合物於20°C下攪拌16小時。蒸發溶劑，並使殘留物溶 於MeOH (50毫升）中。於此溶液中，添加一刮勺之pd/c (1〇 重量°/〇)，且將此懸浮液於2〇1及H2大氣下攪拌6〇小時。將 混合物過濾（矽藻土），以MeOH洗滌固體，及蒸發濾液，而 得標的化合物（L5克，90%)，為褐色油，將其使用於下一步 驟，無需進一步純化（計算之質量·· 237.3 ;發現之質量： 237.5)。 5-第三-丁基-2-甲氧基-3-甲基確醯胺基）-苯甲酸甲酯·於 上文獲得之化合物（1.5克，6.3毫莫耳）與TEA (1.3毫升，9.5 毫莫耳）在DCM(10毫升）中之溶液内，逐滴添加氯化甲烷磺 醯（0.74毫升，9.5毫莫耳），並將混合物於2〇°c下攪拌16小 時。將混合物以吒0洗滌，脫水乾燥（MgS〇4)，蒸發，且使 褐色殘留物於矽膠上層析（在己烷中之0-50% EtOAc)，而得標 的化合物（U克，55%)，為白色固體。 5-第三·丁基-2-甲氧基-3-(甲基續醯胺基）苯甲酸取)·將步 驟3中所獲得之化合物（U克，3.5毫莫耳）在6NHC1(5〇毫升） 123505 -231 - 200815422 中之懸浮液在80 C下加熱72小時。使混合物冷卻，於抽氣 下收集沉版物’以％ Ο洗務’並乾燥，而得中間物κ (〇 83 克，79%)，為白色固體。Methyl 3-amino-5-tert-butyl-indoleoxybenzoate·T-butyl-2-methoxy-3-nitrobenzoic acid (18 g, 71 mmol) (according to US2005/0107399) and DMF (〇 5 ml) in dcm (5 〇 ml) r \ in solution 'Dilution of chlorinated grasshopper (31 ml, 35 5 mmol), The mixture was stirred at 20 ° C for 16 hours. The solvent was evaporated and the residue was crystalljjjjjjjj To this solution, a spatula of pd/c (1 重量 weight / 〇) was added, and the suspension was stirred for 6 hrs under a temperature of 2 ° 1 and H 2 . The mixture was filtered (EtOAc), EtOAc (EtOAc) (EtOAc) · 237.3 ; Quality found: 237.5). 5-Tris-butyl-2-methoxy-3-methyl-decylamino)-benzoic acid methyl ester. Compound obtained above (1.5 g, 6.3 mmol) and TEA (1.3 mL, Methyl chloride sulfonium chloride (0.74 mL, 9.5 mmol) was added dropwise to a solution of EtOAc (EtOAc). The mixture was washed with EtOAc, dried (MgSO4), evaporated, mjjjjjjjjjjjjjj ), as a white solid. 5-Ter-butyl-2-methoxy-3-(methyl-hydroxylamino)benzoic acid)) The compound obtained in Step 3 (U g, 3.5 mmol) at 6 NHC1 (5) 〇ml) The suspension in 123505 -231 - 200815422 was heated at 80 C for 72 hours. The mixture was allowed to cool, and the precipitate was collected &lt;RTI ID=0.0&gt;&gt;

(E)-3-第二-丁基-5-(Nf •經基碳胺基亞胺基）苯甲酸甲醋· 使中間物D (1.5克，6.90耄莫耳）、氫氧化銨鹽酸鹽（1 gw克， 24.16 毫莫耳）及 NaHC〇3 (2·059 克，24.51 毫莫耳）溶於 Me〇H (2〇 毫升）中，並添加2滴水。將混合物在室溫下攪拌過夜，並 添加40毫升EtOAc。以NaHC〇3與水洗滌有機層，及蒸發。使 殘留物於HV中乾燥過夜，而產生u〇32克標的化合物（計算 之質量·· 250.3，發現之質量·· 251)。 (E)-3-(N’_乙醯氧基碳胺基亞胺基)第三-丁基苯甲酸甲酯 使上文獲得之化合物（116毫克，〇·464毫莫耳）溶於(Μ 笔升）中，並添加氯化乙醯（39.5微升，0.556毫莫耳）與DIEA (16L6微升，0.928耄莫耳）。將溶液於室溫下攪拌3天，然後(E)-3-Second-butyl-5-(Nf • transcarbamoyl imido) benzoic acid methyl vinegar · Intermediate D (1.5 g, 6.90 Torr), ammonium hydroxide hydrochloride Salt (1 gw g, 24.16 mmol) and NaHC〇3 (2·059 g, 24.51 mmol) were dissolved in Me〇H (2 mL) and 2 drops of water were added. The mixture was stirred at room temperature overnight and 40 mL EtOAc was added. The organic layer was washed with NaHC 3 and water, and evaporated. The residue was dried overnight in HV to give a compound of &lt;RTI ID=0.0&gt;&gt; (E)-3-(N'-Ethyloxycarbamicimido)methyl-tert-butylbenzoate The compound obtained above (116 mg, 〇·464 mmol) was dissolved ( Μ Pen liter), and add acetyl chloride (39.5 μl, 0.556 mmol) with DIEA (16 L 6 μl, 0.928 耄 Mo). Stir the solution at room temperature for 3 days, then

3-第三-丁基-5-(5-甲基_1，2,4-噚二唑各基）苯甲酸甲酯·使 :233)。 123505 -232- 200815422 上文獲得之化合物（115.3毫克）溶於二氧陸圜（2毫升）中，並 添加醋酸（3滴）。將反應混合物在i〇〇°c下攪拌24小時，然後 於室溫下過夜。藉由蒸發移除二氧陸圜，並使殘留物藉預 備之HPLC純化，而得67.5毫克標的化合物（計算之質量： 274.3，發現之質量：233)。 3_第三丁基_5_(5·甲基-I，2,4·崎二唑_3_基）苯曱酸·使前一 步驟中所獲得之化合物（67.5毫克，0.246毫莫耳）溶於thf (1 毫升）、MeOH(l毫升）及^0(0.2毫升）之混合物中，並添加 2Ν NaOH (246微升，0.492毫莫耳）。將反應物於室溫下攪拌 過夜，以1M HC1 (pH〜7)中和，及蒸發溶劑。於Ηγ中乾燥後， 獲得83.9毫克標的物質（含有NaCl)。 氣化第二丁基_5·(5_甲基-I，2,4』号二嗤各基）苯甲醯（L). 使前一步驟中所獲得之化合物（83.9毫克，0.246毫莫耳）溶於 DCM (3毫升）中，並添加氣化草醯(2〇8微升，2.46毫莫耳）， 接著為催化量之DMF。將反應物於室溫下攪拌2小時，然後 蒸發。使殘留物在HV中乾燥，並以本身使用在下一步驟中。3-Terti-butyl-5-(5-methyl-1,2,4-oxadiazoleyl)methyl benzoate · ???: 233). 123505 -232- 200815422 The compound obtained above (115.3 mg) was dissolved in dioxane (2 ml) and acetic acid (3 drops) was added. The reaction mixture was stirred at i ° ° C for 24 hours and then at room temperature overnight. The dioxane was removed by evaporation, and the residue was purified by preparative HPLC to give 67.5 mg of the title compound (mass: 274.3, mass found: 233). 3_Ternyl _5_(5·methyl-I, 2,4·soxadiazole _3_yl)benzoic acid · The compound obtained in the previous step (67.5 mg, 0.246 mmol) Dissolved in a mixture of thf (1 mL), MeOH (1 mL) and EtOAc (EtOAc) The reaction was stirred at room temperature overnight, neutralized with 1M EtOAc (pH ~ 7) and evaporated. After drying in Ηγ, 83.9 mg of the target substance (containing NaCl) was obtained. Gasification of the second butyl _5·(5-methyl-I, 2, 4 y) diazepam) benzamidine (L). The compound obtained in the previous step (83.9 mg, 0.246 mmol) The ear was dissolved in DCM (3 mL) and gasified grasshopper (2 〇 8 μl, 2.46 mmol) was added followed by a catalytic amount of DMF. The reaction was stirred at room temperature for 2 hours and then evaporated. The residue is dried in HV and used as itself in the next step.

孓第三-丁基·3_(1Η_咪嗤-1_基）_2_甲氧基苯曱酸讲=11) (M_a). 將中間物F (120.5毫克，0.4毫莫耳）、咪唑（68毫克，ΐ·〇毫莫 耳）、N，N-二甲基甘胺酸（8.2毫克，〇·〇8毫莫耳）、Cul (7.6毫克， 0.04毫莫耳）及k2C03(165.6毫克，1.2毫莫耳）在DMSO (2毫升） 中之混合物於120°C下加熱64小時。過濾反應物，並經由 123505 -233 - 200815422 LC-MS純化，而產生4〇 9赛古&amp; Λ 生笔克所要之產物（計算之質量 274.3，發現之質量：275.1)。 5-第三-丁基-2_甲氧基-3-Υ4 w I 1 ττ ， (4-甲基-iH-咪唑小基）-苯甲酸 (R=Me) (M-b)係以類似方式製成 、衣风（叶异之質量：288.3，發現孓T-Butyl·3_(1Η_米嗤-1_yl)_2_methoxybenzoic acid =11) (M_a). Intermediate F (120.5 mg, 0.4 mmol), imidazole ( 68 mg, ΐ·〇 mmol, N,N-dimethylglycine (8.2 mg, 〇·〇 8 mmol), Cul (7.6 mg, 0.04 mmol) and k2C03 (165.6 mg, A mixture of 1.2 mmoles in DMSO (2 mL) was heated at 120 °C for 64 hours. The reaction was filtered and purified via EtOAc (EtOAc): EtOAc: EtOAc (EtOAc) 5-Terti-butyl-2-methoxy-3-indole 4 w I 1 ττ , (4-methyl-iH-imidazolyl)-benzoic acid (R=Me) (Mb) is prepared in a similar manner Cheng, Yifeng (Ye Yizhi quality: 288.3, found

之質量：289.1)。Quality: 289.1).

3-第三-丁基各(烷氧羰基胺基）苯甲酸·於3_第三叮基 甲氧羰基）苯甲酸Β(0·465克，2〇毫莫耳）在dcm(i〇毫升） 中之溶液内，添加氯化草酸〇毫升，6當量）與2滴卿。將 混合物加熱至贼，直到均勻為止，然後在室溫下2小時。 蒸發溶劑，使殘留物溶於甲苯中，並再_次蒸發，而得粗 製氣化醯衍生物a。使化合物溶於甲苯（12毫升）中，並添加 過量疊氮化鈉（600毫克，9.2毫莫耳）、催化用四丁基氯 (20¾克，〇.〇9毫莫耳）及水（3毫升），且將混合物激烈攪拌。 反應之進展係藉IR追蹤，其方式是追蹤在1752公分下之 coci羰基伸縮之消失。典型上，反應係花費低於6〇分鐘完 成。移除水層，將甲苯層以水洗滌，並以MgS〇4脫水乾燥。 將此中間物疊氮化物b之甲苯溶液加熱至1〇yc，直到氣體 之釋出停止。反應之進展再一次藉由IR監測，其方式是於 測1688公分-1下之CO-N3羰基伸縮，與2137公分-1下之％之消 失。於所獲得異氰酸酯之甲苯溶液中，接著添加吾人感興 123505 -234 - 200815422 趣之醇（例如MeOH或t-BuOH)，並將反應物加熱，直到完成 (對MeOH至8(TC，對t-BuOH至110t)為止，如藉由瓜光譜中 2253公分1下之NCO羰基伸縮之消失所顯示者。蒸發溶液， 使殘留物溶於MeOH中，並添加1M NaOH水溶液毫升）。將 混合物在60°C下加熱2小時。蒸發MeOH，且以iM HC1 (4毫 升）使溶液酸化。在DCM-EtOAc混合物中萃取產物，將有機 層以MgS〇4脫水乾燥，及蒸發，而得標的產物，使用之而無 需進一步純化。3-tert-Butyl each (alkoxycarbonylamino)benzoic acid · 3,3 -Mercaptomethoxycarbonyl)benzoate (0.465 g, 2 〇 mmol) in dcm (i 〇 ml) In the solution, add chlorinated oxalate hydrate, 6 equivalents) and 2 drops of Qing. The mixture was heated to the thief until it was homogeneous and then at room temperature for 2 hours. The solvent was evaporated, the residue was dissolved in toluene, and evaporated again to give a crude gasified hydrazine derivative a. The compound was dissolved in toluene (12 mL) and excess sodium azide (600 mg, 9.2 mmol) was added, catalyzed with tetrabutyl chloride (203⁄4 g, 〇. 〇 9 mM) and water (3) ML) and the mixture was stirred vigorously. The progress of the reaction was traced by IR by tracking the disappearance of coci carbonyl stretching at 1752 cm. Typically, the reaction system takes less than 6 minutes to complete. The aqueous layer was removed, the toluene layer was washed with water, and dried with MgSO 4 . The toluene solution of this intermediate azide b was heated to 1 〇 yc until the release of gas ceased. The progress of the reaction was again monitored by IR by measuring the CO-N3 carbonyl stretching at 1688 cm-1 and the disappearance of 2137 cm-1. In the toluene solution of the obtained isocyanate, followed by the addition of my sensation 123505 -234 - 200815422 interesting alcohol (such as MeOH or t-BuOH), and the reaction is heated until completion (for MeOH to 8 (TC, for t-BuOH) Up to 110 t), as indicated by the disappearance of NCO carbonyl stretching at 2253 cm 1 in the melon spectrum. The solution was evaporated, the residue was dissolved in MeOH and 1 mL aqueous NaOH solution was added. The mixture was heated at 60 ° C for 2 hours. The MeOH was evaporated and the solution was acidified with iM EtOAc (4 mL). The product was extracted in a DCM-EtOAc mixture. EtOAc (EtOAc)

3-第三-丁基_5_(甲氧羰基胺基）苯甲酸甲酯^_a) (R「R2=Me)· ifi-NMR (500 MHz，CDC13) 5 (ppm) 7·81 (s，2H)，7·75 (s，1H)，6.66 (bs，1H)，3.93 (s，3H)，3·81 (s，3H)，1.36 (s，9H). 3_第二-丁基-5_(甲氧羰基胺基）苯甲酸(N-b) (RfMe，R2=H). iH-NMR (500 MHz，DMSO_d6) 5 (ppm) 7.88 (s，1H)，7.84 (s，1H)，7.28 (s，1H)，6·78 (bs，1H)，3.83 (s5 3H)，1.38 (s，9H). 3-(第二-丁氧幾基胺基第三-丁基苯甲酸（n_c)⑻斗如， R2=H). ^-NMR (500 MHz, CDC13) (5 (ppm) 7.87 (s5 1H)? 7.84 (s3 1H)，了.74 (bs，1H)，6.64 (bs，1H)，1.56 (s，9H)，1.37 (s，9H).3-Terti-butyl_5_(methoxycarbonylamino)benzoic acid methyl ester^_a) (R"R2=Me)·ifi-NMR (500 MHz, CDC13) 5 (ppm) 7·81 (s, 2H),7·75 (s,1H),6.66 (bs,1H),3.93 (s,3H),3·81 (s,3H),1.36 (s,9H). 3_Second-Butyl- 5_(methoxycarbonylamino)benzoic acid (Nb) (RfMe, R2=H). iH-NMR (500 MHz, DMSO_d6) 5 (ppm) 7.88 (s, 1H), 7.84 (s, 1H), 7.28 ( s,1H),6·78 (bs,1H),3.83 (s5 3H), 1.38 (s,9H). 3-(2nd-butoxymethylamino-tert-butylbenzoic acid (n_c)(8)斗如, R2=H). ^-NMR (500 MHz, CDC13) (5 (ppm) 7.87 (s5 1H)? 7.84 (s3 1H), .74 (bs, 1H), 6.64 (bs, 1H), 1.56 (s, 9H), 1.37 (s, 9H).

3·胺基-5-第三-丁基苯甲酸甲酯·使3-(第三-丁氧羰基胺 基）-5-第三-丁基苯甲酸甲酯（中間物A_C)(U4克，3·71毫莫耳） 容於TFA中，並在室溫下攪拌1〇分鐘。蒸發溶劑，並使中 間物懸浮於最少量之水中。添加硫酸（25〇微升），且使混合 123505 -235 - 2008154223. Amino-5-tris-butylbenzoic acid methyl ester·Methyl 3-(t-butoxycarbonylamino)-5-tert-butylbenzoate (intermediate A_C) (U4 g , 3.71 millimoles) is contained in TFA and stirred at room temperature for 1 minute. The solvent was evaporated and the intermediate was suspended in a minimum amount of water. Add sulfuric acid (25 〇 microliters) and mix it 123505 -235 - 200815422

物在冰/水浴中冷卻。逐滴添加亞硝酸鈉水溶液（14.15毫莫 耳，已溶於最少量之水中），並將反應物在0°C下混合30分 鐘。將反應混合物添加至沸騰之10%硫酸水溶液（4〇毫升， 47.27毫莫耳）中，歷經1〇分鐘，並於20分鐘後，使反應物冷 卻下來。將產物在DCM中萃取。使一半之溶液於矽膠上， 在DCM-5% MeOH中藉層析純化，而造成兩個溶離份。第一 個溶離份僅含有標的酚（產量150毫克），然而第二個溶離份 含有標的酚與苯胺中間物之混合物（產量：n〇毫克）。i Ή NMR (500 MHz，CDC13) ά (ppm) 7.68 (t，1Η)，7.34 (dd，1Η)，7.10 (t，1Η)， 3.92 (s，3H)，1·34 (s，9H). 3-第三-丁基-5-羥苯甲酸（〇)·使3-第三-丁基-5-羥基苯甲 酸甲酯B (140毫克，0.672毫莫耳）溶於Me〇H (3毫升）中，並 添加lMNaOH水溶液（1毫升，丨毫莫耳）。將反應混合物於卯 °C下加熱75分鐘，然後，將其在室溫下攪拌過夜。以1ΜΗα 水溶液（2毫升）使混合物酸化，且將產物於DCM中萃取。分 離DCM層’賴奶〇4脫水乾燥，及蒸發，而產生9〇毫克標的 化合物。1 H NMR (500 MHz，DMF) δ ①㈣ 13 〇6 扣，ih)，9 75 &amp; 1H), 7.57 (t, 1H), 7.35 (t, 1H), 7.15 (t, 1H), 1.30 (s, 9H) 3-第三-丁基冬甲氧基苯甲酸甲輯·使3-第三_丁基冰經 基苯甲酸甲醋B(190毫克，_毫莫耳）、K2C〇3(糊毫克， 遍毫莫耳）及廳（456毫克，3.213毫莫耳）溶於丙嗣（5毫升） 中’並在8GX：下加熱24小時。使反應混合物蒸發，並以乙 醚研製殘留物。蒸發喊溶液，而得標的錢，為紅色油， 將其制於下—步财，無需純化。1H NMR ( MHz，CDCl3) 123505 -236- 200815422 5 (ppm) 7.71 (t，1H)，7.39 (dd，1H)，7.16 (dd，1H)，3.93 (s，3H)，3.87 (s， 3H)，1_35 (s，9H). 3-第三-丁基-5-甲氧基苯甲酸（P). 使上文獲得之化合物The material was cooled in an ice/water bath. An aqueous solution of sodium nitrite (14.15 mmol, dissolved in a minimum amount of water) was added dropwise, and the reaction was mixed at 0 ° C for 30 minutes. The reaction mixture was added to a boiling 10% aqueous solution of sulfuric acid (4 mL, 47.27 m.m.) for one minute and after 20 minutes, the reaction was allowed to cool. The product was extracted in DCM. Half of the solution was made on silica gel and purified by chromatography in DCM-5% MeOH to yield two fractions. The first fraction contained only the target phenol (yield 150 mg), whereas the second fraction contained a mixture of the indicated phenol and aniline intermediate (yield: n 〇 mg). i Ή NMR (500 MHz, CDC13) ά (ppm) 7.68 (t, 1 Η), 7.34 (dd, 1 Η), 7.10 (t, 1 Η), 3.92 (s, 3H), 1·34 (s, 9H). 3-Terti-butyl-5-hydroxybenzoic acid (〇)·Methyl 3-tert-butyl-5-hydroxybenzoate B (140 mg, 0.672 mmol) dissolved in Me〇H (3) In ml), add 1M NaOH aqueous solution (1 ml, 丨mole). The reaction mixture was heated at 卯 ° C for 75 min and then stirred at room temperature overnight. The mixture was acidified with 1 mL aqueous solution (2 mL) and the product was extracted from DCM. The DCM layer was separated from the dried milk, and evaporated to give 9 mg of the title compound. 1 H NMR (500 MHz, DMF) δ 1 (four) 13 〇6 buckle, ih), 9 75 &amp; 1H), 7.57 (t, 1H), 7.35 (t, 1H), 7.15 (t, 1H), 1.30 (s , 9H) 3-Terve-butyl methoxy benzoic acid A series · 3- 3- butyl butyl benzoic acid methyl vinegar B (190 mg, _ millimoles), K2C 〇 3 (paste Milliliter, all milliliters and hall (456 mg, 3.213 mmol) were dissolved in propionate (5 ml) and heated at 8 GX: for 24 hours. The reaction mixture was evaporated and the residue was crystallised from ethyl ether. Evaporate the solution, and the winning money is red oil, which is made into the next-step, without purification. 1H NMR (MHz, CDCl3) 123505 -236- 200815422 5 (ppm) 7.71 (t,1H), 7.39 (dd,1H), 7.16 (dd,1H),3.93 (s,3H),3.87 (s, 3H) , 1_35 (s, 9H). 3-Terti-butyl-5-methoxybenzoic acid (P). The compound obtained above

溶於MeOH (3毫升）中，添加1M NaOH水溶液（1毫升），並將 混合物加熱至80°C。反應完成係藉TLC監控。蒸發溶劑，以 1M HC1水溶液使殘留物酸化，且將產物於DCM中萃取。使 DCM溶液以MgS04脫水乾燥，過濾，及蒸發，而產生105毫 克標的化合物。1 H NMR (500 MHz，CDC13) 5 (ppm) 7.79 (t，1H)， 7.45 (dd，1H)，7.21 (dd，1H)，3.89 (s，3H)，1.36 (s，9H).Dissolved in MeOH (3 mL), 1M aq. The completion of the reaction was monitored by TLC. The solvent was evaporated, the residue was crystallised eluted eluted eluted The DCM solution was dehydrated to dryness with MgS04, filtered, and evaporated to yield 105 mg of the title compound. 1 H NMR (500 MHz, CDC13) 5 (ppm) 7.79 (t, 1H), 7.45 (dd, 1H), 7.21 (dd, 1H), 3.89 (s, 3H), 1.36 (s, 9H).

5-第三-丁基-3-氰基-2-(2-曱氧基_2_酮乙氧基）苯甲酸甲酯· 在50毫升圓底燒瓶中，放置5-第三-丁基-3-氰基-2-甲氧基苯 甲酸甲酯（3.16克，12.8毫莫耳）（按上述獲得）與DCM (10毫 升），伴隨著磁攪拌。於其中添加DCM中之1M BBr3溶液（12.3 毫升），並將反應物於室溫下攪拌1小時，以水使反應淬滅， 及分離有機層。以DCM萃取水層，並使合併之液層以Na2S04 脫水乾燥。移除溶劑，使粗製物質溶於丙酮中，並以溴醋 123505 -237 - 200815422 酸甲酯（3·85毫升，42毫莫耳）、K2C03 (5.80克，42毫莫耳）處 理，且將反應混合物在回流下加熱1小時。於真空中移除溶 劑，並使殘留物在矽膠上純化，以0-30% EtOAc/己烷溶離， 而付1.552克（40%產率）5-第三-丁基-3-氣基-2-(2-甲氧基-2-酉同 乙氧基）苯甲酸甲酯。1H NMR (500 MHz，CDC13) 5 (ppm) 8.04 (d， J = 2·5 Hz，1H)，7.74 (d5 J = 2.5 Hz，1H)，4.79 (s，2H)，3·93 (s，3H)，3·83 (s，3H)，1.33 (s，9H). 5_第二-丁基-3-氣基-2-(2-經乙氧基）苯甲酸甲S旨· 於冰浴 中’在250毫升圓底燒瓶内，放置上文獲得之化合物（L55 克，5.08毫莫耳）、THF (10毫升）及MeOH (10毫升）。於此經 攪拌混合物中，添加2M NaOH (2·80毫升，5.59毫莫耳）。在 30分鐘後，添加2Μ HC1 (1.53毫升），並於真空中移除溶劑。 將殘留物在THF (100毫升）中稀釋，及添加另外之2Μ HC1 (1.27毫升）。使溶劑濃縮，以致只有水留下。添加Et〇Ac (5〇 毫升），並分離有機層，及以Na2S04脫水乾燥，而得1.56克 5-第二-丁基各氰基-2-(2-甲氧基-2-酮乙氧基）苯甲酸。在250毫 升圓底燒瓶中，使此酸溶於THF (70毫升）中，且以羰基二咪 嗤（1.05克，6.5毫莫耳）處理。將反應物於室溫下攪拌2小 時’於此段時間後，將其添加至硼氫化鈉（756毫克，2〇毫 莫耳）在水（50毫升）中之溶液内，於冰浴中，在5〇()毫升圓底 燒瓿中攪拌。在真空中移除有機溶劑，1小時後，於冰浴中 授拌。以DCM萃取水層，並使合併之有機層以Na2S〇4脫水 乾燥’在真空中移除溶劑，並使殘留物於矽膠上純化，以 〇·50% EtOAc/己烷溶離，而得364毫克5-第三·丁基_3_氰基冬(2_ 123505 -238 - 200815422 經乙氧基）苯甲酸甲醋（26%產率）。lHNMR(500 MHz，cDa3) (5 (ppm) 8.04 (d, J = 3.0 Hz, 1H)} 7.74 (d, J = 3.0 Hz, 1H), 4.45 (t, J = 4.0, 2H)，3.94 (s，3H)，3_93 (t，J = 4.0 Hz，2H)，1.33 (s 9H) 5-第二-丁基各氰基-2-(2-(4-甲基六氫吡畊小基）乙氧基）苯 甲酸甲酯·在50毫升圓底燒瓶中，放置5-第三-丁基-3-氰基 -2-(2-羥乙氧基）苯甲酸甲酯（364毫克，ι·3ΐ毫莫耳）與DCM (3 毫升）。於此反應物中，添加Dess-Martin試劑（668毫克，1.58 毫莫耳）。將反應物加蓋，並於室溫下攪拌25分鐘。將反應 混合物以飽和NaHC〇3 (5毫升）與1M Na2 S2 03 (5毫升）處理，並 攪拌15分鐘。以DCM (20毫升）稀釋反應物，及以DCM萃取。 使合併之有機層以Na] SO#脫水乾燥。移除溶劑，及濃縮至 〜8毫升。將一半溶液放置在16毫米試管中，並以醋酸（728 j政升’ 13.1宅莫耳）’接著以N-甲基六氫p比p井（131微升，ι·3ΐ 耄莫耳）’然後以三乙醯氧基硼氫化納（277毫克，1.31毫莫 耳）處理。於攪拌18小時後，添加另外之三乙醯氧基硼氫化 鈉（277毫克，1.31毫莫耳）。於再攪拌5小時後，以飽和Na2c〇3 使反應淬滅’並以DCM (20宅升）稀釋混合物。將水層以dcm (5毫升）萃取，並使合併之有機層以Na2S〇4脫水乾燥。蒸發 溶劑，並使殘留物於矽膠上純化，以〇_2〇% MeOH/DCM溶離， 而得76毫克（32%產率）5-第三-丁基-3-氰基-2-(2-(4-甲基六氫 吡畊-1-基）乙氧基）苯甲酸甲酯（計算之質量·· 359·2 ;發現之 質量·· 359·0)。 5_第三·丁基-3-氰基-2·(2_(4-甲基六氫吡啡·1-基）乙氧基）苯 甲酸（Q)·於冰浴中，在50毫升圓底燒瓶内，放置5-第三_ 123505 -239 - 200815422 丁基-3-氰基-2-(2-(4-甲基六氫吡畊_1_基）乙氧基）苯曱酸甲酯 (76毫克，0.21毫莫耳）與他〇11(3毫升），接著為2MNa〇H(189 微升，0.38毫莫耳）。在冰浴中攪拌2·5小時後，將反應物加 熱至60 C，歷經1.5小時，於此段時間内，蒸發溶劑。使殘 留物懸浮於THF (5毫升）中，並以2Ν HC1 (189微升）處理，及 蒸發溶劑，而得標的化合物，使用之而無需進一步純化（計 算之質量：345.2 ;發現之質量：345.0)。5-Tris-butyl-3-cyano-2-(2-decyloxy-2-ketoethoxy)benzoic acid methyl ester · Place 5-tri-butyl in a 50 ml round bottom flask Methyl 3-cyano-2-methoxybenzoate (3.16 g, 12.8 mmol) (obtained as above) and DCM (10 mL) with magnetic stirring. A 1 M solution of BBr3 in DCM (12.3 mL) was added and the mixture was stirred at room temperature for 1 hour, quenched with water and organic layer. The aqueous layer was extracted with DCM, and the combined liquid layers were dried over Na2SO. Remove the solvent, dissolve the crude material in acetone, and treat with bromoacetate 123505 -237 - 200815422 methyl ester (3 · 85 ml, 42 mmol), K2C03 (5.80 g, 42 mmol), and The reaction mixture was heated under reflux for 1 hour. The solvent was removed in vacuo and the residue was purified eluted eluted elut elut elut elut elut elut elut Methyl 2-(2-methoxy-2-indenyloxy)benzoate. 1H NMR (500 MHz, CDC13) 5 (ppm) 8.04 (d, J = 2·5 Hz, 1H), 7.74 (d5 J = 2.5 Hz, 1H), 4.79 (s, 2H), 3·93 (s, 3H),3·83 (s,3H), 1.33 (s,9H). 5_Second-butyl-3-yl-2-(2-ethoxy)benzoic acid A In a 250 ml round bottom flask, the compound obtained above (L 55 g, 5.08 mmol), THF (10 mL) and MeOH (10 mL) were placed. After stirring the mixture, 2M NaOH (2·80 mL, 5.59 mmol) was added. After 30 minutes, 2 Μ HCl (1.53 mL) was added and solvent was evaporated in vacuo. The residue was diluted in THF (100 mL) and EtOAc (1. The solvent is concentrated so that only water remains. Add Et 〇Ac (5 〇 ml), and separate the organic layer, and dehydrated with Na2S04 to give 1.56 g of 5-di-butyl-cyano-2-(2-methoxy-2-one ethoxylate) Benzoic acid. This acid was dissolved in THF (70 mL) in a 250 mL EtOAc EtOAc (EtOAc). The reaction was stirred at room temperature for 2 hours. After a period of time, it was added to a solution of sodium borohydride (756 mg, 2 mM hexanes) in water (50 mL) Stir in a 5 〇 () ml round bottom crucible. The organic solvent was removed in vacuo and after 1 hour, it was stirred in an ice bath. The aqueous layer was extracted with EtOAc (EtOAc) (EtOAc m. 5-Third-butyl_3_cyano winter (2_123505 -238 - 200815422 ethoxy)benzoic acid methyl vinegar (26% yield). lHNMR (500 MHz, cDa3) (5 (ppm) 8.04 (d, J = 3.0 Hz, 1H)} 7.74 (d, J = 3.0 Hz, 1H), 4.45 (t, J = 4.0, 2H), 3.94 (s , 3H), 3_93 (t, J = 4.0 Hz, 2H), 1.33 (s 9H) 5-second-butyl cyano-2-(2-(4-methylhexahydropyrazine) Ethyloxymethyl benzoate. In a 50 ml round bottom flask, place methyl 5-tert-butyl-3-cyano-2-(2-hydroxyethoxy)benzoate (364 mg, ι· 3 mM with DCM (3 mL). To this reaction was added Dess-Martin reagent (668 mg, 1.58 mmol). The reaction was capped and stirred at room temperature for 25 min. The mixture was treated with EtOAc (3 mL) (EtOAc m. #脱水干燥干燥。 Remove the solvent, and concentrate to ~ 8 ml. Place half of the solution in a 16 mm tube and use acetic acid (728 j liter ' 13.1 house Moer) ' followed by N - methyl hexahydro p ratio p well (131 μl, ι·3ΐ 耄莫耳)' then with triethoxy borohydride (277 mg, 1 After treatment for 18 hours, another sodium triethoxysulfonate (277 mg, 1.31 mmol) was added. After stirring for another 5 hours, the reaction was quenched with saturated Na2c3. The mixture was diluted with DCM (20 liters). The aqueous layer was extracted with EtOAc (EtOAc). 〇 2〇% MeOH/DCM was dissolved to give 76 mg (32% yield) of 5-tris-butyl-3-cyano-2-(2-(4-methylhexahydropyrazole-1- Ethyl ethoxy) methyl benzoate (calculated mass · · 359 · 2 ; quality found · · 359 · 0) 5_ third · butyl-3-cyano-2 · (2_(4- Methylhexahydropyrrolidin-1-yl)ethoxy)benzoic acid (Q)·in an ice bath, placed in a 50 ml round bottom flask, placed 5-third_123505-239-200815422 butyl-3- Methyl cyano-2-(2-(4-methylhexahydropyrazine-1-yl)ethoxy)benzoate (76 mg, 0.21 mmol) with the oxime 11 (3 mL), then 2MNa〇H (189 μl, 0.38 mmol). After stirring for 2.5 hours in an ice bath, the reaction was heated to 60 C. 1.5 hours, within which time the solvent was evaporated. The residue was suspended in THF (5 mL) EtOAc (EtOAc (EtOAc) ).

3_第三-丁基_5_(氣基續醯基）苯甲酸·於室溫下，使3,5-二-第三-丁基苯甲酸（1273克，5_43毫莫耳）溶於C1S03H (5毫升， 75.22毫莫耳）中。將混合物於l〇〇°C下攪拌150分鐘，傾倒在 冰上’並使所形成之混合物離心。將水層傾析，以水洗滌 固體，並乾燥，而得標的化合物（L3克）。 3-第三·丁基_5_(N_甲基胺磺醯基）苯甲酸（R=H，Me) (R-a)· 在室溫下，使中間化合物（〇·26克，〇·94毫莫耳）溶於甲胺在 THF (4毫升，8毫莫耳）中之2M溶液内（或者，胺之EtOH溶液 可被添加至中間化合物之THF溶液中）。將混合物攪拌30分 鐘’並蒸發。使殘留物溶於DCM中，將其以1M HC1水溶液 洗務’並以無水MgS04脫水乾燥，過濾，及蒸發，而得標的 產物，220 毫克產量。1H NMR (500 MHz，CDC13) 5 (ppm) 8.31 (m， 2H)，8.13 (m，ih)，7.56 (m，lH〇, 2.57 (s，3H)，1.40 (s，9H)· 第三-丁基·5-(Ν，Ν_:甲基胺磺醯基）苯甲酸（R=Me，Me) 123505 -240- 200815422 (R-b)·在室溫下，使3-第三-丁基-5-(氯基磺醯基）苯甲酸（0.26 克’ 0.94毫莫耳）溶於二甲胺在THF (4毫升，8毫莫耳）中之 2M溶液内。將混合物攪拌3〇分鐘，並蒸發。使殘留物溶於 DCM中’將其以iM HC1水溶液洗滌，並以無水MgS〇4脫水乾 燥，過濾，及蒸發，而得標的產物，22〇毫克產量。3_Third-butyl _5_(gas-based fluorenyl)benzoic acid · 3,5-di-t-butylbenzoic acid (1273 g, 5_43 mmol) dissolved in C1S03H at room temperature (5 ml, 75.22 mmol). The mixture was stirred at l ° C for 150 minutes, poured onto ice and the resulting mixture was centrifuged. The aqueous layer was decanted, the solid was washed with water, and dried to give the title compound (L). 3-Third-butyl _5_(N-methylamine sulfonyl)benzoic acid (R=H,Me) (Ra)· At room temperature, intermediate compound (〇·26 g, 〇·94 毫Mole) was dissolved in a 2 M solution of methylamine in THF (4 mL, 8 mmol) (or a solution of the amine EtOH can be added to the intermediate compound in THF). The mixture was stirred for 30 minutes&apos; and evaporated. The residue was dissolved in DCM, washed with EtOAc EtOAc EtOAc. 1H NMR (500 MHz, CDC13) 5 (ppm) 8.31 (m, 2H), 8.13 (m, ih), 7.56 (m, lH〇, 2.57 (s, 3H), 1.40 (s, 9H)· Butyl·5-(Ν,Ν_:methylaminesulfonyl)benzoic acid (R=Me,Me) 123505 -240- 200815422 (Rb)·3-tri-butyl-5 at room temperature -(Chlorosulfonyl)benzoic acid (0.26 g, <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; The residue was dissolved in DCM <RTI ID=0.0>: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt;

3-疊氮基-5-第三-丁基_2_甲氧基苯甲酸甲酯·使3_胺基冰 第二-丁基-2-甲氧基苯甲酸甲酯（〇·387毫克，16毫莫耳）溶於 10% H2S〇4(10毫升）中，並冷卻至。於此混合物中，添加Methyl 3-azido-5-t-butyl-2-methoxybenzoate · Methyl 2-aminobutyl-2-methoxybenzoate as a base , 16 mmol) dissolved in 10% H2S 4 (10 mL) and cooled. In this mixture, add

NaN〇2(159耄克’ 2.31毫莫耳）與NaN3(2〇2毫克，3·ΐι毫莫耳）， 並使反應混合物溫熱至室溫。3〇分鐘後，以DCM萃取混合 物，並使有機層以NasSO4脫水乾燥，過濾，及蒸發，而得 0.361 克標的化合物。！ η nmr (5〇〇 MHz，CDCl3)占（ppm) 7 % ⑷】 i, = 2·5, 1H)，7.18 (d，J = 2·5, 1H)，3·93 (s，3H)，3.89 (s，3H)，1.31 (s，9H). 3-疊氮基-5-第三-丁基-2-甲氧基苯甲酸⑻·使上文獲得 之化合物（0.264耄克，l.oo毫莫耳）溶於Me〇H (3毫升）中。添 加NaOH之2N溶液（0·6毫升，u〇毫莫耳），並將反應物加熱 至50°C，歷經90分鐘。蒸發溶劑，並使殘留物以挪稀釋， 且以2NHC1(0.6毫升）處理。蒸發溶劑，使殘留物溶於 中，並以Na2S〇4/MgS〇4脫水乾燥。 123505 •241 · 200815422NaN 2 (159 g ' 2.31 mmol) and NaN 3 (2 〇 2 mg, 3·ΐι mmol), and the reaction mixture was allowed to warm to room temperature. After 3 minutes, the mixture was extracted with DCM, and then evaporated. ! η nmr (5〇〇MHz, CDCl3) occupies (ppm) 7 % (4)] i, = 2·5, 1H), 7.18 (d, J = 2·5, 1H), 3·93 (s, 3H), 3.89 (s, 3H), 1.31 (s, 9H). 3-azido-5-t-butyl-2-methoxybenzoic acid (8) · The compound obtained above (0.264 g, l. Oo millimolar) was dissolved in Me〇H (3 ml). A 2N solution of NaOH (0.6 mL, EtOAc) was added and the mixture was warmed to 50 &lt;0&gt;C over 90 min. The solvent was evaporated and the residue was diluted and taken &lt;RTI ID=0.0&gt; The solvent was evaporated, the residue was dissolved in water and dried over Na.sub.2.sub.4/. 123505 •241 · 200815422

OH 〇OH 〇

ΟΟ

OH :雜環基異終驗酸醋衍生物(τ)·㈣12氣基異於驗酸第 曰於2氯基異菸鹼酸(2.36克，15毫莫耳）在DCM (4〇 毫升mTHF(10毫升）t之溶液内’添加氯化草醯(65毫升）， 接I添加-滴廳。將混合物於室溫下授掉日夺，然後蒸 發溶劑。使剛製成之氯化醯溶於THF(40毫升）中，並冷卻至 4°C。於添加第三-丁醇鉀（3·4克，3〇毫莫耳）在毫升） 中之浴液後，使反應混合物慢慢溫熱至室溫，並攪拌過夜。 蒸發深紅色懸浮液，且使殘留物於DCM與水之間作分液處 理。以碳酸氫鈉水溶液洗滌有機相。將DCM相以Nh s〇4脫 水乾燥，及蒸發，而得1.658克2·氯基異菸鹼酸第三—丁酯， 為紅色油（純度約90%)，將其使用於下一步驟，無需進一步 U 純化。1H NMR (500 MHz，DMSO-d6) (5 (ppm) 8.62 (d，1H)，7·81 (S， 1H)，7.79 (d，1H)，1·52 (s，9H). 步驟2· 2-嗎福啉基異菸鹼酸第三-丁酯·將2-氯基異菸鹼 酸第三-丁酯（427毫克，2毫莫耳）與嗎福啉（5.2毫升，60毫莫 耳）在DMSO (1毫升）中之溶液於80°C下加熱60小時。蒸發嗎 福啉，並使殘留物溶於EtOAc/NaHC03水溶液中。以EtOAc萃 取水相。將合併之有機相以水洗滌，並以Na2S04脫水乾燥。 蒸發後，使粗產物接受矽膠管柱層析（40克矽膠管柱），使 123505 -242- 200815422 用DCM/EtOAc作為溶離劑。2-嗎福啉基異菸鹼酸第三汀醋係 以浪稠褐色油單離（525毫克，純度&gt;95%)。1H NMR (5〇〇 MHz， DMSO-d6) 5 (ppm) 8.24 (d，1H)，7.18 (s，1H)，7.00 (d，1Η)，3·74 (t，4H)， 3.52 (t，4H)，1.54 (s，9H)· 步驟3· 2_嗎福啉基異菸鹼酸（T_a)·將2-嗎福啉基異菸鹼 酉文苐二-丁酯（525宅克）在4N HC1二氧陸圜溶液（3毫升）與水 (〇_5毫升）中之混合物於室溫下攪拌過夜。於蒸發二氧陸圜 f I與水後，使固體殘留物於80〇C及真空下乾燥，而得淡黃色 固體（421毫克）。LC-MS顯示標的化合物為主要成份（純度 &gt;90/。）。使用此粗產物’無需進一步純化（計算之質量·· Mg， 發現之質量：209)。 使用如關於T-a之製備所示之類似程序，製備下列化合 物： 2_(四氫吡咯小基）異菸鹼酸(T_b)·計算之質量：192，發 現之質量·· 193. 0 2_(六氫说啶小基）異菸鹼酸(T-c)·計算之質量：206，發現 之質量：207. 苯胺中間物OH: Heterocyclic heteroassay acid vinegar derivative (τ) · (IV) 12 gas base is different from acid test 曰 in 2 chloro-isonicotinic acid (2.36 g, 15 mmol) in DCM (4 mL ml mTHF ( Add 10 ml of t in the solution of 'chlorinated grass mash (65 ml), then add I to drop the chamber. The mixture is allowed to be removed at room temperature, then the solvent is evaporated. The freshly prepared barium chloride is dissolved. THF (40 ml) and cooled to 4 ° C. After adding a bath of potassium tert-butoxide (3.4 g, 3 〇 mmol) in ML), the reaction mixture was slowly warmed. Bring to room temperature and stir overnight. The dark red suspension was evaporated and the residue was partitioned between DCM and water. The organic phase was washed with an aqueous solution of sodium hydrogencarbonate. The DCM phase was dried over Nh s 〇 4 and evaporated to give 1.658 g of &lt;RTI ID=0.0&gt;&gt; No further U purification is required. 1H NMR (500 MHz, DMSO-d6) (5 (ppm) 8.62 (d, 1H), 7·81 (S, 1H), 7.79 (d, 1H), 1·52 (s, 9H). Step 2· 2-hoprofenyl isonicotinic acid tert-butyl ester · 2-chloroisonicotinic acid tri-butyl ester (427 mg, 2 mmol) with morphine (5.2 ml, 60 mmol) The solution in DMSO (1 mL) was heated at 80 ° C for 60 h. The EtOAc was evaporated and the residue was taken from EtOAc /EtOAc. Washed and dehydrated and dried with Na2SO4. After evaporation, the crude product was subjected to silica gel column chromatography (40 g of silica gel column) to make the use of DCM/EtOAc as the dissolving agent for the s. Alkaline acid third vinegar is isolated as a dark brown oil (525 mg, purity &gt; 95%). 1H NMR (5 〇〇 MHz, DMSO-d6) 5 (ppm) 8.24 (d, 1H), 7.18 ( s,1H), 7.00 (d,1Η),3·74 (t,4H), 3.52 (t,4H),1.54 (s,9H)· Step 3· 2_Norfolinyl isonicotinic acid (T_a) ) · 2-Isofolinyl isonicotinic acid bismuth di-butyl ester (525 house) in 4N HC1 dioxane solution (3 ml) and water (〇_ The mixture was stirred at room temperature overnight. After evaporation of EtOAc (EtOAc) &EtOAc. MS showed the title compound as the main component (purity &gt; 90%.) This crude product was used without further purification (calculated mass · · Mg, mass found: 209). A similar procedure as shown for the preparation of Ta was used. Preparation of the following compounds: 2_(tetrahydropyrrole small) isonicotinic acid (T_b) · Calculated mass: 192, found mass · 193. 0 2_(hexahydropyridinyl) isonicotinic acid (Tc ··Qualification of calculation: 206, quality found: 207. Aniline intermediate

AA 3-胺基-5-第三-丁基·2-甲氧基苯甲腈（AA)·於5-第三叮基 ’添加 -2-甲氧基-3-硝基苯甲醯胺（按US20050107399中所述製成） (125毫克，〇·5毫莫耳）在4毫升氯仿中之懸浮液内 123505 -243 - 200815422AA 3-Amino-5-tertiary-butyl-2-methoxybenzonitrile (AA)·Addition of 2-methoxy-3-nitrobenzamide to 5-tridecyl (Prepared as described in US20050107399) (125 mg, 〇·5 mmol) in a suspension of 4 ml of chloroform 123505 -243 - 200815422

POCI3 (69微升，〇·75宅莫耳）在〇·5毫升氣仿中之溶液。於室 溫下擾拌3小時後，使反應混合物冷卻至，並添加TEA (500微升）。將所形成之混合物在室溫下攪拌過夜，並倒入 20毫升IN HC1中。於氯仿中萃取化合物。在以水洗滌後， 使有機相濃縮，而得160毫克粗製中間物，為褐色固體。將 此中間物與氯化錫（II)二水合物（678毫克，3毫莫耳，6當量） 在4毫升DMF中，於室溫下一起攪拌過夜。預備之逆相HPLC 純化’獲得標題產物（98毫克），為褐色固體（計算之質量： 204.3 ;發現之質量：245.9 (M+41))(純度 &gt;95%)。POCI3 (69 μl, 〇·75 house Mo) in a solution of 5 ml of gas. After 3 hours of stirring at room temperature, the reaction mixture was cooled to and TEA (500 μL) was added. The resulting mixture was stirred at room temperature overnight and poured into 20 mL of EtOAc. The compound was extracted in chloroform. After washing with water, the org. This intermediate was stirred with tin(II) chloride dihydrate (678 mg, 3 mmol, 6 eq.) in 4 mL of DMF overnight. The title product (98 mg) was obtained as a brown solid (yield: 204.3; mass found: 245.9 (M+41)) (purity &gt; 95%).

步驟1· 3-第三-丁基_5_氰基苯基胺基甲酸第三-丁酯·於3- 第二-丁基-5-氰苯甲酸Η (1.0克，4.9毫莫耳，按上述製成）在 t-BuOH中之溶液内，添加DPPA (1·4毫升，6,4毫莫耳）與ΝΜΜ (稍微過量）。將混合物於回流下攪拌過夜，以DCM萃取， 以鹽水洗滌有機層，脫水乾燥（MgS〇4)，及蒸發。使殘留物 於石夕膠上藉層析純化（梯度液：在己烷中之5至1〇〇% EtOAc) (計算之質量：274.4，發現之質量：275.1)。 步驟2· 3·胺基-5-第三-丁基苯曱腈（BB)·於上文獲得之化 合物在DCM中之溶液（1〇毫升）内，添加tfa (1.5毫升），並將 混合物在室溫下攪拌過夜。蒸發溶劑，並將殘留物使用於 下一步驟，無需進一步純化（計算之質量：Π4·2，發現之質 ΐ · 215.8 (M+AcN)+)。 123505 -244- 200815422Step 1· 3-Terve-butyl_5-cyanophenylaminocarbamic acid tert-butyl ester·3-(2-butyl-butyl-5-cyanobenzoate) (1.0 g, 4.9 mmol, DPPA (1.4 ml, 6, 4 mmol) and hydrazine (slightly excess) were added to the solution in t-BuOH as described above. The mixture was stirred at rt over EtOAc (EtOAc)EtOAc. The residue was purified by chromatography on EtOAc (EtOAc:EtOAc:EtOAc:EtOAc Step 2·3·Amino-5-t-butylbenzonitrile (BB)·In a solution of the compound obtained above in DCM (1 mL), add tfa (1.5 mL) and mixture Stir at room temperature overnight. The solvent was evaporated, and the residue was applied to the next step without further purification (calc. mass: Π4·2, found ΐ · 215.8 (M+AcN)+). 123505 -244- 200815422

=嗎福啉基,Y= CN CC =六氫吡啶，Y=CN DD =四氫吡咯，Y= CONH2 EE= morpholinyl, Y = CN CC = hexahydropyridine, Y = CN DD = tetrahydropyrrole, Y = CONH2 EE

3-胺基-5-嗎福啉基苯甲腈（cc)·將3_氟基_5_硝基苯甲腈 (350宅克，2.11耄莫耳）以嗎福啉（1毫升）在4〇毫升小玻瓶中 處理。將反應物加蓋，並於7〇〇c下攪拌過夜。蒸發溶劑， 並將殘留物以MeOH研製兩次。使殘留物懸浮於DMF (〇 5毫 升）中，以氣化錫二水合物（2·38克，1〇·5毫莫耳）處理，並在 75C下加熱40分鐘。以飽和Na2C〇3(7毫升）與固體Na2C〇^3 克）使反應淬滅。將有機層以DCM稀釋，過濾，以飽*Na2C〇3 洗滌，及以固態無水Na〗SO4脫水乾燥。移除溶劑，並使殘 留物於石夕膠上純化’而得標的化合物（282毫克，65%)。1Η NMR (500 ΜΗζ，丙酮-d6) 5 (ppm) 6·53 (s，1Η)，6·52 (s，1Η)，6.45 (s， 1Η)，3·75 (t，J = 5.0 Ηζ，4Η)，3.123 (t，J = 5.〇 Ηζ，4Η)，2·73 (s，2Η)· 3_胺基_5-(六氫吡啶-1-基）苯甲腈(dd)係在如上述之相同條 件下’使用六氫吡啶作為胺成份而製成。1H NMR (5〇〇 ΜΗζ， 10% CD30D/CDC13) 5 (ppm) 6·47 (dd，J = 2.5 與 1·〇 Ηζ，1Η)，6.34 (t，J =2.0 Hz，1H)，6·30 (t，J = 1.5 Hz，1H)，3.40 (bs，2H)，3.05 (t，J = 11 Hz， 4H)，1.58 (q，J = 6.0 Hz，4H)，1.50 (m，2H)· 3-胺基_5_(四氫p比洛-1_基）苯甲醯胺（ee)·如上述之相同條 件，自作為胺成份之四氫吡咯開始，造成其相應四氫吡咯 苯甲醯胺衍生物之形成。1 H NMR (500 MHz，C：D3 〇D/0)C：13 &gt; 5 (ppm) 6.37 (t，J = 1.5 Hz, 1HX 6.34 (t，J = 1.5 Hz, 1H)，3·5 (bs，4H)，3·19 (q，J = 3·5 Hz，4H)，1.91 (q，J = 3·5 Hz，4H). 123505 -245 · 200815422 中央核心中間物3-amino-5-morpholinebenzonitrile (cc)·3_Fluoro-5-nitrobenzonitrile (350 oz, 2.11 耄mol) in morphine (1 ml) 4 cc in a small glass bottle for processing. The reaction was capped and stirred at 7 ° C overnight. The solvent was evaporated and the residue was taken twice with MeOH. The residue was suspended in DMF (〇 5 mL), treated with vaporized tin dihydrate (2·38 g, 1 〇·5 mmol) and heated at 75 C for 40 minutes. The reaction was quenched with saturated aqueous Na.sub.2.sub.3 (s. The organic layer was diluted with DCM, filtered, washed with sat. Na.sub.2 C.sub.3, and dried over anhydrous Na? The solvent was removed and the residue was purified on EtOAc (yield: 282 mg, 65%). 1Η NMR (500 ΜΗζ, acetone-d6) 5 (ppm) 6·53 (s, 1Η), 6·52 (s, 1Η), 6.45 (s, 1Η), 3·75 (t, J = 5.0 Ηζ, 4Η), 3.123 (t, J = 5.〇Ηζ, 4Η), 2·73 (s, 2Η)· 3_Amino_5-(hexahydropyridin-1-yl)benzonitrile (dd) It was prepared by using hexahydropyridine as an amine component under the same conditions as described above. 1H NMR (5〇〇ΜΗζ, 10% CD30D/CDC13) 5 (ppm) 6·47 (dd, J = 2.5 and 1·〇Ηζ, 1Η), 6.34 (t, J = 2.0 Hz, 1H), 6· 30 (t, J = 1.5 Hz, 1H), 3.40 (bs, 2H), 3.05 (t, J = 11 Hz, 4H), 1.58 (q, J = 6.0 Hz, 4H), 1.50 (m, 2H)· 3-Amino-5-(tetrahydro-p-l-l-yl)benzamide (ee). The same conditions as described above, starting from the tetrahydropyrrole as an amine component, resulting in its corresponding tetrahydropyrrole benzamidine Formation of amine derivatives. 1 H NMR (500 MHz, C: D3 〇 D/0) C: 13 &gt; 5 (ppm) 6.37 (t, J = 1.5 Hz, 1HX 6.34 (t, J = 1.5 Hz, 1H), 3·5 ( Bs,4H),3·19 (q,J = 3·5 Hz, 4H), 1.91 (q, J = 3·5 Hz, 4H). 123505 -245 · 200815422 Central core intermediate

2_甲基-5-硝基各(4,4,5,5_四甲基^:^工氧硼伍圜_2_基）峨咬 鹽（a)·於40耄升小玻瓶中，放置雙（品吶可基）二蝴（687毫 克，2.72毫莫耳）、Pd(dppf)2(94毫克，0.115毫莫耳）、3-溴基 ’ 甲基-5-确基峨淀（5〇〇毫克，2.30毫莫耳）及無水醋酸鉀（733毫 克，7_48毫莫耳）。添加DMSO (7毫升），將小玻瓶以氮沖洗， 加蓋，並於80°C下磁攪拌3小時。使反應混合物於DCM與水 之間作分液處理，且過濾混合物，以移除固體。以DCM洗 滌固體，並收集有機層，以硫酸鈉脫水乾燥，及在真空中 移除溶劑。使殘留物於矽膠上純化，以0-30% EtOAc/己烧溶 離’而付336毫克（37%產率）2-甲基-5-石肖基-3-(4,4,5,5_四甲基 -1，3,2-二氧侧伍圜-2-基风咬，為二經基侧烧鹽。1h NMR (500 t、 MHz) 5 (ppm) 9.32 (d，J = 3·0 Hz，1H)，8.80 (d，J = 3·0 Hz，1H)，2.88 (s, 3H)，1.38 (s，6H)，1·27 (s，6H)5 1·26 (s，6H)，1·24 (s，6H)·2_Methyl-5-nitro each (4,4,5,5-tetramethyl^:^Oxyborin 2圜) base biting salt (a)·in 40 liters small glass bottle , placed double (Pinyl ketone) two butterflies (687 mg, 2.72 mmol), Pd (dppf) 2 (94 mg, 0.115 mmol), 3-bromo-methyl-5-deposited (5 〇〇 mg, 2.30 mmol) and anhydrous potassium acetate (733 mg, 7_48 mmol). DMSO (7 ml) was added, the vial was rinsed with nitrogen, capped, and magnetically stirred at 80 ° C for 3 hours. The reaction mixture was partitioned between DCM and water and the mixture was filtered to remove solid. The solid was washed with DCM, and the organic layer was collected, dried over sodium sulfate and evaporated. The residue was purified on silica gel eluting with 0-30% EtOAc / hexanes to afford 336 mg (37% yield) of 2-methyl-5-s. Methyl-1,3,2-dioxo side, 圜-2-yl wind bite, distillate salt on the dibasic side. 1h NMR (500 t, MHz) 5 (ppm) 9.32 (d, J = 3·0 Hz, 1H), 8.80 (d, J = 3·0 Hz, 1H), 2.88 (s, 3H), 1.38 (s, 6H), 1·27 (s, 6H) 5 1·26 (s, 6H) ,1·24 (s,6H)·

3-疊氮基-2-曱基-5-硝基吡啶（b).將2-甲基-5-硝基吡咬-3- 基胺基甲酸第三-丁酯（2.03克，8.00毫莫耳），或者，2_甲基 123505 -246- 200815422 -5-硝基吡啶各胺（123克，8 〇〇毫莫耳），與12Μ Ηα水溶液（5 84 宅升）’於室溫下攪拌10分鐘。添加Η20 (29·2毫升），並使 黃色溶液冷卻至〇°c。逐滴添加亞硝酸鈉（662毫克，9·6〇毫 莫耳’ 1.2當量）在112〇(2 66毫升）中之溶液，並將混合物在〇 C下擾拌8分鐘。然後，於下逐滴添加疊氮化鈉（572毫 克’ 8.8毫莫耳，U當量）毫升）中之溶液，並使 混合物在4小時内溫熱至室溫。藉過濾移除固體，將濾液以 飽和NaHC〇3水溶液中和，及以DCM萃取產物。使有機層脫 水乾燥（Na2S〇4)，及濃縮，而得3-疊氮基-2-甲基冰硝基吡啶 (1.335克，93%產率，97%純，藉LC-MS-未偵測到物質），為 揮發性黃色液體，其在冷卻時結晶。1H—NMR (5〇〇 MHz， DMSO-d6) (5 (ppm) 9.03 (d5 J = 2.3 Hz? 1H)? 8.36 (d? J = 2.3 Hz, 1H)5 2.48 (s，3H)·3-azido-2-indenyl-5-nitropyridine (b). 2-Methyl-5-nitropyridin-3-ylaminocarbamic acid tert-butyl ester (2.03 g, 8.00 m Moer), or, 2_methyl 123505 -246- 200815422 -5-nitropyridylamine (123 g, 8 〇〇 millimolar), with 12 Μ Ηα aqueous solution (5 84 liters) 'at room temperature Stir for 10 minutes. Add Η20 (29·2 ml) and allow the yellow solution to cool to 〇°c. A solution of sodium nitrite (662 mg, 9.6 mmol) was added dropwise in 112 Torr (2 66 mL), and the mixture was stirred at 〇 C for 8 min. Then, a solution of sodium azide (572 mg "8.8 8.8 mmol") was added dropwise, and the mixture was allowed to warm to room temperature over 4 hours. The solid was removed by filtration, the filtrate was neutralized with saturated aqueous NaHC.sub.3, and the product was extracted with DCM. The organic layer was dried (Na2SO4), and concentrated to give 3-[pi][pi][pi][pi][rho The substance was detected as a volatile yellow liquid which crystallized upon cooling. 1H-NMR (5 〇〇 MHz, DMSO-d6) (5 (ppm) 9.03 (d5 J = 2.3 Hz? 1H)? 8.36 (d? J = 2.3 Hz, 1H) 5 2.48 (s, 3H)·

5·疊氮基-6-甲基於驗酸乙酯（c)·將5-(第三-丁氧羰基胺 基）-6·曱基菸鹼酸乙酯（按國際申請案pCT/us〇6/〇42679獲得） (643毫克，2.29毫莫耳，1.0當量）與12M HC1水溶液(2·〇毫升） 之混合物於室溫下攪拌30分鐘。添加水（ι〇·〇毫升），並使溶 液冷卻至〇°C。逐滴添加亞硝酸鈉（194毫克，2.81毫莫耳，1 2 當量）在水（783微升）中之溶液，並將混合物在〇°C下擾拌7 分鐘。然後，於0°C下逐滴添加疊氮化鈉（168毫克，2.58毫 莫耳，1.1當量）在水（783微升）中之溶液，且使混合物在3 123505 -247- 200815422 時内溫熱至室溫。藉過濾移除固體，使濾液以飽和NaHC03 水溶液中和，及以DCM萃取產物。使有機層脫水乾燥(Na2S04)， 及濃縮，而得c (460毫克，97%產率，90%純，藉LC-MS)，為 油狀物，將其使用在下一步驟中，無需純化（計算之質量·· 206，發現之質量：192)。iHNMRpOOMHz’DMSO-cy 5 (ppm) 8.75 (d，1H，J = 1.8 Hz)，7.99 (d，1H，J = 1·8 Hz)，4.38 (q5 2H，J = 7·1 Hz),5. Azido-6-methyl in acid ethyl ester (c) · 5-(T-butoxycarbonylamino)-6-mercapto nicotinic acid ethyl ester (according to international application pCT/us混合物6/〇42679 was obtained) (643 mg, 2.29 mmol, 1.0 eq.) and a mixture of 12M aqueous HCl (2·ml) was stirred at room temperature for 30 min. Add water (ι〇·〇 ml) and allow the solution to cool to 〇 °C. A solution of sodium nitrite (194 mg, 2.81 mmol, 12 equivalents) in water (783 [mu]L) was added dropwise and the mixture was stirred at &lt Then, a solution of sodium azide (168 mg, 2.58 mmol, 1.1 equivalents) in water (783 μl) was added dropwise at 0 ° C, and the mixture was allowed to have an internal temperature of 3 123505 -247 - 200815422 Heat to room temperature. The solid was removed by filtration, the filtrate was neutralized with saturated aqueous NaHC03, and the product was extracted with DCM. The organic layer was dried (Na2SO4), EtOAc (EtOAc (EtOAc) The quality of the calculation·· 206, the quality of the discovery: 192). iHNMRpOOMHz'DMSO-cy 5 (ppm) 8.75 (d, 1H, J = 1.8 Hz), 7.99 (d, 1H, J = 1·8 Hz), 4.38 (q5 2H, J = 7·1 Hz),

2.44 (s? 3H)5 1.35 (t5 3H5 J = 7.1 Hz).2.44 (s? 3H)5 1.35 (t5 3H5 J = 7.1 Hz).

5-胺基-6-甲基菸鹼酸乙酯·將5-(第三-丁氧羰基胺基）-6-甲基菸鹼酸乙酯（841毫克，3毫莫耳）添加至TFA (9.5毫升） 與水（0.5毫升）之溶液中，並將溶液於室溫下攪拌65分鐘。 於真空中移除溶劑，並使殘留物在HV中乾燥。添加飽和 NaHC〇3水溶液（30毫升），並以DCM萃取水溶液。分離有機 層，以Na2 SO4脫水乾燥，過濾，及在真空中濃縮。使殘留 物於HV中乾燥，而產生551毫克標的化合物（計算之質量： 180.2，發現之質量：181)。iH-NMR (DMSO-d6) 5 (ppm) 8·21 (d，1H， J = 1.9 Hz)，7.44 (d，1H，J = 1.9 Hz)，5.39 (bs，2H)，4.29 (q，2H，J = 7.15-Amino-6-methylnicotinic acid ethyl ester·Addition of ethyl 5-(t-butoxycarbonylamino)-6-methylnicotinate (841 mg, 3 mmol) to TFA (9.5 ml) with water (0.5 ml) and the solution was stirred at room temperature for 65 minutes. The solvent was removed in vacuo and the residue was dried in HV. A saturated aqueous solution of NaHC 3 (30 mL) was added and the aqueous was extracted with DCM. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo. The residue was dried in HV to give 551 mg of the title compound (mass: 180.2, mass found: 181). iH-NMR (DMSO-d6) 5 (ppm) 8·21 (d, 1H, J = 1.9 Hz), 7.44 (d, 1H, J = 1.9 Hz), 5.39 (bs, 2H), 4.29 (q, 2H) , J = 7.1

Hz)，2.33 (s，3H)，1.31 (t，3H，J = 7.1 Hz)· 5-蛾基-6-甲基於驗酸乙酯⑼·於室溫下，使上文獲得之 化合物溶於濃H2S〇4(195微升）與水（3毫升）之溶液中。使亞 硝酸鈉（217毫克，3.15毫莫耳）個別溶於水（450微升）中，且 使碘化鉀（598毫克，3.6毫莫耳）與碘化銅（81·6毫克，·428毫 123505 -248- 200815422 莫耳）溶於水（600微升）中，並音振。使化合物溶液於冰浴中 冷卻至0 C ’並在3分鐘内’逐滴添加亞硝酸鈉溶液。將混 合物於0°C下攪拌8分鐘，然後添加更多濃h2S〇4(60微升， 1.103毫莫耳）。將混合物逐滴添加至冷填化卸溶液（〇它，激 烈撥拌）中’且形成暗色沉殿物。使所形成之混合物溫熱至 室溫’音振’並迅速溫熱至6〇°C (10分鐘）。將混合物以飽和 NaHC〇3水溶液中和，並添加Na2S〇3，以移除碘。過濾已沉 澱之固體，以水、DCM洗滌，及以DCM萃取濾液。將有機 層以Nas SO3水溶液洗滌，以SO#脫水乾燥，在真空中濃 縮’並於HV中乾燥，而產生681.7毫克暗色固體，使其藉石夕 膠層析純化（梯度液：0-20% EtOAc/DCM)，而得標的產物， 為白色結晶性固體（計算之質量：291.09，發現之質量：292)。 ^-NMR (DMSO-d6) δ (ppm) 8.92 (d5 1H5 J = 1.9 Hz)? 8.55 (d, 1H? J， 1.9 Hz)，4.34 (q，2H，J = 7.1 Hz)，2·72 (s，3H)，1.34 (t，3H，J = 7.1 Hz)· 實例1 :式I標的化合物之合成 途徑A :經由G-C(0)0H之偶合至經保護核心模板Hz), 2.33 (s, 3H), 1.31 (t, 3H, J = 7.1 Hz) · 5-Moth-6-methyl in acid ethyl ester (9) · dissolve the compound obtained above at room temperature In a solution of concentrated H2S 4 (195 μL) and water (3 mL). Sodium nitrite (217 mg, 3.15 mmol) was dissolved in water (450 μl), and potassium iodide (598 mg, 3.6 mmol) and copper iodide (81·6 mg, · 428 mA 123505) -248- 200815422 Moer) is soluble in water (600 μl) and is vibrating. The compound solution was cooled to 0 C ' in an ice bath and sodium nitrite solution was added dropwise over 3 minutes. The mixture was stirred at 0 °C for 8 minutes and then more concentrated h2S4 (60 [mu]L, 1.103 mmol). The mixture was added dropwise to the cold-filling solution (in it, vigorously) and formed a dark color. The resulting mixture was allowed to warm to room temperature &quot;sound&apos; and rapidly warmed to 6 °C (10 minutes). The mixture was neutralized with a saturated aqueous NaHC 3 solution, and Na 2 S 〇 3 was added to remove iodine. The solid which had been precipitated was filtered, washed with water, DCM, and filtered with DCM. The organic layer was washed with aq. Na.sub.2SO.sub.3. EtOAc/DCM), mp. mp. ^-NMR (DMSO-d6) δ (ppm) 8.92 (d5 1H5 J = 1.9 Hz)? 8.55 (d, 1H? J, 1.9 Hz), 4.34 (q, 2H, J = 7.1 Hz), 2·72 ( s, 3H), 1.34 (t, 3H, J = 7.1 Hz) · Example 1: Synthesis of a compound of formula I A: Coupling via GC(0)0H to a protected core template

N-(5-澳基-6-甲基p比咬-3·基）-3•第三·丁基_5_氣基苯曱醯胺 123505 -249- 200815422 於DCM中之氯化醯F(15毫升）内，添加2_甲基劣溴基·5_硝基 吡啶（164·4毫克，〇·6毫莫耳）與DIEA (0.4毫升，5當量）。將 混合物於室溫下攪拌過夜，過濾，以％ 〇洗滌，脫水乾燥（以 MgS〇4 )’及濃縮。將所形成之產物使用於下一步驟，無需 進一步純化。1H-NMR (500 MHz，CDC13) 5 (ppm) &amp;72 (d，J Hz，1H)，8·55 (d5 J = 2·21 Hz，1H)，8.26 (t，J = 1.79 Hz，1H)，8.10 (t，J = 1.54 Hz，1H)，7.83 (t，J = 1·61，1H)，2.65 (s，3H)，1.37 (s5 9H)· 3-(5-(3-第三-丁基_5_氱基苯甲醯胺基甲基吡啶各基）苯 甲酸甲醋（2)·將N-(5-溴基-6-甲基吡啶-3-基）-3-第三_丁基-5_ 氰基苯曱醯胺（135毫克，〇.4毫莫耳）、甲苯(2·7毫升）、DMf (〇·3 毫升）、K：2C〇3(284 毫克，2 毫莫耳）、Pd(dppb)Cl2(8.2 毫克， 0.01毫莫耳）及3-(甲氧羰基）苯基二羥基硼烷（1〇〇毫克，〇·6毫 莫耳）之混合物在微波照射下，於150°C下加熱10分鐘。將 此懸浮液過濾（矽藻土），並以DCM洗滌固體。濃縮濾液， 並使殘留物藉RP-HPLC純化（30至99% AcN在H2〇中之梯度 液）。藉RP-HPLC進行第二次純化（35至50% AcN在H：2〇中之梯 度液）’以足夠純度產生標的化合物（計算之質量：428，發 現之質量：428)。 3·(5_(3_第二-丁基·5-氰基苯甲醯胺基）_2_甲基〃比咬_3·基）苯 甲酸·於上文所獲得之苯曱酸酯（129毫克，0.3毫莫耳）在 THF/MeOH (10耄升，1 : 1)中之溶液内，添加2Ν NaOH (4毫 升）。將混合物在室溫下攪拌過夜，以1N HC1中和，並蒸發。 將所獲得之產物使用於下一步驟，無需進一步純化（計算之 質量：414，發現之質量：414)。 123505 -250- 200815422 3-第三_丁基_5_氰基-N_(6_f基各沙(新戊基胺甲醯基）苯基)_ 吡啶各基）苯曱醯胺·於上述酸（85毫克，〇·2毫莫耳）在 DCM/DMF (6毫升，1 · 1)中之溶液内，添加新戍基胺（〇15毫 升，1.3毫莫耳）、PyB0P (245 4毫克，〇5毫莫耳）及〇正八（〇2 毫升，1.2毫莫耳）。將混合物於室溫下攪拌，並藉lc_ms監 測，直到完成為止。蒸發溶劑，並使殘留物接受处-j^LC (梯 度液：在氏0中之35至50% AcN)，獲得產物（24.8毫克），為N-(5-Alkyl-6-methyl-p-Bitter-3·yl)-3•Third-butyl _5_-phenhydrinamine 123505 -249- 200815422 Barium chloride F in DCM Within (15 ml), 2_methyl-bromo-5-nitropyridine (164·4 mg, 〇·6 mmol) was added with DIEA (0.4 mL, 5 eq.). The mixture was stirred at room temperature overnight, filtered, washed with EtOAc EtOAc (EtOAc) The resulting product was used in the next step without further purification. 1H-NMR (500 MHz, CDC13) 5 (ppm) &amp; 72 (d, J Hz, 1H), 8·55 (d5 J = 2·21 Hz, 1H), 8.26 (t, J = 1.79 Hz, 1H ), 8.10 (t, J = 1.54 Hz, 1H), 7.83 (t, J = 1.61, 1H), 2.65 (s, 3H), 1.37 (s5 9H) · 3-(5-(3-third -butyl _5_mercaptobenzamide aminopyridyl) benzoic acid methyl ketone (2) · N-(5-bromo-6-methylpyridin-3-yl)-3- Tri-butyl-5-cyanobenzamine (135 mg, 〇. 4 mmol), toluene (2.7 ml), DMf (〇·3 ml), K: 2C〇3 (284 mg, 2 a mixture of Pm), Pd(dppb)Cl2 (8.2 mg, 0.01 mmol) and 3-(methoxycarbonyl)phenyldihydroxyborane (1 mg, 〇6 mmol) in a microwave The mixture was heated for 10 minutes at 150 ° C. The suspension was filtered (diatomaceous earth) and the solid was washed with DCM. The filtrate was concentrated and the residue was purified by RP-HPLC (30 to 99% AcN in H? Gradient in the middle). Purification by RP-HPLC for a second purification (35 to 50% AcN gradient in H: 2 )) to yield the title compound in sufficient purity (calculated mass: 428, mass found: 42 8) (5_(3_2nd-butyl-5-cyanobenzamide)_2_methylpyrene than biting _3·yl)benzoic acid·benzoic acid obtained above Ester (129 mg, 0.3 mmol) in THF / MeOH (10 mL, 1:1), 2 EtOAc (4 mL). And the product obtained was used in the next step without further purification (calculated mass: 414, mass found: 414). 123505 - 250 - 200815422 3-third_butyl_5-cyano- N_(6_f-based sulphate (neopentylamine-methyl)phenyl)-pyridyl)benzidine in the above acid (85 mg, 〇·2 mmol) in DCM/DMF (6 mL, In the solution of 1 · 1), add neodecylamine (〇15 ml, 1.3 mmol), PyB0P (245 4 mg, 〇5 mmol) and 〇正八 (〇 2 ml, 1.2 mmol) . The mixture was stirred at room temperature and monitored by lc_ms until completion. Evaporate the solvent and allow the residue to stand at -j^LC (gradient: 35 to 50% AcN in 0) to give the product (24.8 mg) as

淡黃色I固體（計算之質量：483，發現之質量·· 484)Light yellow I solid (calculated quality: 483, found quality · 484)

N-(5-(4•(卞氧基）苯基）冬甲基〃比咬各基）_3_第三·丁基氰基 苯曱醯胺·於小玻瓶中，添加N-(5-溴基-6-甲基吡啶斗基）_3· 第三-丁基-5-氰基苯甲醯胺（2〇毫克，〇·〇5毫莫耳）（按上述獲 付）、4-(卞氣基）苯基二經基硼烧（ΐ2·3毫克，〇·〇5毫莫耳）、 κ2 C03 (20 毫克，〇·15 毫莫耳）及 pd(dppb)cl2 (1·5 毫克，〇 〇〇25 毫 莫耳）。然後添加無水甲苯（1毫升）與無水DMF (1毫升）。將 反應合物以氮滌氣，接著密封。將密封管加熱至， 並攪拌12小時。濃縮反應物，並使殘留物經由LC_MS純化， 而產生11毫克標的產物（計算之質量·· 475，發現之質量：N-(5-(4•(卞oxy)phenyl)methylenemethyl hydrazine is a bit of each base)_3_Third-butyl cyanobenzamide. In a small glass bottle, add N-(5 -Bromo-6-methylpyridyl)_3· Third-butyl-5-cyanobenzamide (2 mg, 〇·〇 5 mmol) (paid as above), 4- (helium-based) phenyl dipyridyl boron (ΐ2·3 mg, 〇·〇 5 mmol), κ2 C03 (20 mg, 〇·15 mmol) and pd(dppb)cl2 (1.5 mg, 〇〇〇25 millimoles). Anhydrous toluene (1 mL) was then added with dry DMF (1 mL). The reaction mixture was purged with nitrogen and then sealed. The sealed tube was heated to and stirred for 12 hours. The reaction was concentrated and the residue was purified EtOAc EtOAc EtOAc EtOAc

123505 -251 - 200815422 3-第二-丁基-5-氦基_N-(5_(4-(3,3_二甲基_2_嗣基丁氧基）苯 基)-6-甲基吡啶-3_基）苯甲醯胺於小玻瓶中，添加N-(5-溴基 -6-曱基叶1： α定-3-基）各第 三- 丁基-5-氰基苯甲醯胺（2〇毫克，〇.05 毫莫耳）、3,3-二甲基-i_(4-(4,4,5,5-四甲基-153,2_二氧硼伍圜冬 基）苯氧基）丁-2-酮（16毫克，0.05毫莫耳）、K2C03 (20毫克，0.15 毫莫耳）及Pd(dppb)Cl2(1.5毫克，0_0025毫莫耳）。然後添加無 水甲苯（1毫升）與無水DMF (1毫升）。將反應混合物以氮滌 氣，接著密封。將密封管加熱至80°C，並攪拌12小時。濃 縮反應物，並使殘留物經由LC-MS純化，而產生8毫克標的 產物（計算之質量：427，發現之質量：428)。123505 -251 - 200815422 3-Second-butyl-5-mercapto_N-(5_(4-(3,3-dimethyl-2-indolylbutoxy)phenyl)-6-methyl Pyridine-3-yl)benzamide in a small glass bottle, adding N-(5-bromo-6-fluorenylleaf: α-1,3-yl) each of the third-butyl-5-cyano group Benzamidine (2 mg, 〇.05 mmol), 3,3-dimethyl-i_(4-(4,4,5,5-tetramethyl-153,2-dioxaborin) Phenyloxy)butan-2-one (16 mg, 0.05 mmol), K2C03 (20 mg, 0.15 mmol) and Pd(dppb)Cl2 (1.5 mg, 0_0025 mmol). Then, water-free toluene (1 ml) and anhydrous DMF (1 ml) were added. The reaction mixture was purged with nitrogen and then sealed. The sealed tube was heated to 80 ° C and stirred for 12 hours. The reaction was concentrated and the residue was purified EtOAc EtOAc EtOAc EtOAc

醋酸4-(5_(5_第三_丁基_2_甲氧基苯甲醯胺基）-2-甲基吡啶-3- 基）苯酯· 於小玻瓶中，添加N-(5-溴基-6_甲基p比唆-3-基）-5-第三-丁基_2_甲氧基苯甲醯胺（19毫克，0.05毫莫耳）、4-乙醯 氧基苯基二羥基硼烷（9毫克，0·05毫莫耳）（經由上述方法獲 得）、K2CO3(20 毫克，0.15 毫莫耳）及 Pd(dppb)Cl2(1.5 毫克，0.0025 毫莫耳）。然後添加無水甲苯（1毫升）與無水DMF (1毫升）。 將反應混合物以氮滌氣，接著密封。將密封管加熱至8〇°c， 並攪拌12小時。使反應物濃縮，並經由LC-MS純化，而產 生13毫克產物（計算之質量：432，發現之質量：433)。 途徑B :經由L2-Q之交叉偶合至經保護核心模板 123505 -252 - 2008154224-(5_(5_Third-butyl-2-methoxybenzylamino)-2-methylpyridin-3-yl)phenyl acetate · In a small glass bottle, add N-(5 -bromo-6-methyl p-p--3-yl)-5-tris-butyl-2-methoxybenzamide (19 mg, 0.05 mmol), 4-ethyloxyl Phenyldihydroxyborane (9 mg, 0.055 mmol) (obtained via the above procedure), K2CO3 (20 mg, 0.15 mmol) and Pd (dppb) Cl2 (1.5 mg, 0.0025 mmol). Anhydrous toluene (1 mL) was then added with dry DMF (1 mL). The reaction mixture was purged with nitrogen and then sealed. The sealed tube was heated to 8 ° C and stirred for 12 hours. The reaction was concentrated and purified via LC-MS to yield 13 mg (yield: 432, mass: 433). Path B: Cross-coupling via L2-Q to a protected core template 123505 -252 - 200815422

3-(4-甲氧苯基)2-甲基_5_硝基吡啶·將2_甲基_3_溴基净硝 基说°疋（115.3毫克’ 〇·5毫莫耳）、2-甲基-4-甲氧苯基-二羥基 硼烷(91·2毫克，0.5毫莫耳）、pd(dppb)cl2(16 3毫克，〇 〇3毫莫 耳）及K：2C〇3 (359毫克，2.6毫莫耳）在甲苯/DMF (4毫升，9 : f 丨）中之混合物，於微波照射下，在150°C下加熱10分鐘。將 混合物過濾（矽藻土），以DCM洗滌固體，及濃縮濾液。使 殘留物於石夕膠上層析，使用己烷/^OAc (梯度液：〇至8〇% EtOAc)作為溶離劑，而得標的化合物。i H_NMR (5〇〇 MHz， CD3〇D) 5 (ppm) 9.27 (d，J = 2·59 Hz，1H)，8.28 (d，J = 2.62 Hz, 1H)， 7·〇9 (d，J = 8·37 Hz，1H)，6·94 (d，J : 2.56 Hz，1H)，6.89 (dd，卜 2.64 與 8·00 Hz，1H)，3_85 (s，3H)，2·41 (s，3H)，2.07 (s，3H). 5-(4-甲氧基_2-甲基苯基)_6_甲氧基吡啶_3_胺·於上文所獲 ( 得之硝基吡啶在Me〇H中之溶液内，添加一刮勺之pd/c (1〇 重量°/。），並將此懸浮液於室溫及氐大氣下攪拌過夜。將混 合物過濾（矽藻土），以Me0H洗滌固體，並蒸發濾液，而得 標的化合物，將其使用於下一步驟，無需進一步純化。 3_第三-丁基_5_氰基·队(5_(φ&gt;甲氧基_2_甲基苯基)甲基吡啶 _3_基）苯甲醯胺·將上文獲得之化合物（85·6毫克，〇2毫莫 耳）、3_第三-丁基_5·氰苯甲酸Ε (4〇 6毫克，〇 2毫莫耳）、 (2當ΐ )及DIEA (5當量）在DCM中之溶液於室溫下攪拌過 123505 -253 - 200815422 夜。濃縮混合物，並使殘留物於矽膠上層析（己烷/EtOAc， 梯度液：0至100%)，接著為RP—HPLC (梯度液：AcN/H2〇，10 至95%) ’獲得標的產物，為淡黃色固體（5.9毫克）（計算之質 量：414，發現之質量·· 414)。3-(4-methoxyphenyl)2-methyl-5-nitropyridine·2_methyl_3_bromomethylnitro group 疋°疋(115.3 mg '〇·5 mmol), 2 -methyl-4-methoxyphenyl-dihydroxyborane (91.2 mg, 0.5 mmol), pd(dppb)cl2 (16 3 mg, 〇〇3 mmol) and K:2C〇3 A mixture of (359 mg, 2.6 mmol) in toluene/DMF (4 mL, 9: f) was heated at 150 ° C for 10 min under microwave. The mixture was filtered (celite), the solid was washed with DCM, and the filtrate was concentrated. The residue was chromatographed on celite using hexane / EtOAc (eluent: EtOAc: EtOAc) i H_NMR (5〇〇MHz, CD3〇D) 5 (ppm) 9.27 (d, J = 2.59 Hz, 1H), 8.28 (d, J = 2.62 Hz, 1H), 7·〇9 (d, J = 8·37 Hz, 1H), 6.94 (d, J: 2.56 Hz, 1H), 6.89 (dd, Bu 2.64 and 8·00 Hz, 1H), 3_85 (s, 3H), 2·41 (s , 3H), 2.07 (s, 3H). 5-(4-methoxy-2-methylphenyl)_6-methoxypyridine _3-amine · obtained above (the nitropyridine is obtained) In a solution of Me〇H, a spatula of pd/c (1 〇 weight/%) was added, and the suspension was stirred at room temperature under a helium atmosphere overnight. The mixture was filtered (diatomaceous earth) to The solid was washed with Me0H, and the filtrate was evaporated to give the title compound, which was used in the next step without further purification. 3_T-butyl-5-cyano group (5_(φ&gt;methoxy-2) Methylphenyl)methylpyridine-3-yl)benzamide The compound obtained above (85·6 mg, 〇2 mmol), 3_T-butyl-5-cyanobenzoic acid Ε (4〇6 mg, 〇2 mmol), (2 ΐ) and DIEA (5 eq.) in DCM were stirred at room temperature for 123505 -253 - 200815422 nights. Chromatography on ruthenium (hexane/EtOAc, gradient: 0 to 100%), followed by RP-HPLC (gradient:AcN/H2 s, 10 to 95%). Mg) (calculated quality: 414, quality found 414).

4-(2•甲基冬硝基吡啶-3_基）苯甲酸甲酯· 方法A· 於具 有磁攪拌棒之40毫升小玻瓶中，放置4-羧甲基苯基二羥基 糊烧（414毫克，2.30毫莫耳）、3-溴基-2-甲基-5-硝基吡啶（5〇〇 毫克’ 2.30毫莫耳）及肆（三苯膦）鈀⑼（664毫克，〇·58毫莫 耳）。添加二甲氧基乙烷（18毫升甲苯（2毫升）及Et〇H (2 毫升），並使溶液音振，直到固體溶解為止。添加2M Na2C〇3 溶液（3·6毫升），同時於n2下迅速攪拌。將小玻瓶加蓋，並 於90 C下檀拌7小時。在真空中移除溶劑，並使殘留物於 H2 ◦與DCM之間作分液處理。以DCM萃取有機層，並以 Na] SO#脫水乾燥。移除溶劑，並使殘留物於石夕膠上層析純 化，以0-50% EtOAc/己烷溶離，而得381毫克（61%產率）4_(2_ 甲基-5-硝基吡啶-3-基）苯甲酸甲酯（計算之質量：272，發現 之質量：314 (M+AcN)+)。 方法B· 將3-溴基-2-甲基-5-硝基吡啶（100毫克，〇·5毫莫 123505 -254- 200815422 耳）、4-羧甲基苯基二羥基硼烷（9〇毫克，〇·5毫莫耳）、4-(2•Methyl-N-nitropyridin-3-yl)benzoic acid methyl ester · Method A· Place 4-carboxymethylphenyl dihydroxy paste in a 40 ml vial with a magnetic stir bar ( 414 mg, 2.30 mmol, 3-bromo-2-methyl-5-nitropyridine (5 〇〇 mg ' 2.30 mmol) and hydrazine (triphenylphosphine) palladium (9) (664 mg, 〇· 58 millimoles). Add dimethoxyethane (18 ml of toluene (2 ml) and Et〇H (2 ml) and shake the solution until the solids are dissolved. Add 2M Na2C〇3 solution (3·6 ml) while Stir rapidly under n2. Cap the vial and mix for 7 hours at 90 C. Remove the solvent in vacuo and allow the residue to separate between H2 ◦ and DCM. And dehydrated with Na.sub.SO#. The solvent was removed and the residue was purified eluting eluting eluting eluting Methyl 2-methyl-5-nitropyridin-3-yl)benzoate (mass calculated: 272, mass found: 314 (M+AcN)+). Method B· 3-bromo-2-yl 5--5-nitropyridine (100 mg, 〇·5 mmol 123505-254-200815422 ears), 4-carboxymethylphenyldihydroxyborane (9 〇 mg, 〇·5 mmol),

Pd(dppb)Cl2 (10 莫耳0/〇)及 K2 C03 (3 當量）在甲苯 /dmf (2 毫升， 9 : 1)中之混合物，於微波照射下，在135t下加熱5小時。 將混合物過濾（矽藻土），以DCM洗滌固體，及濃縮濾液。 使殘留物於石夕膝上層析，以EtOAc/己烧（梯度液：〇_5〇%)溶 離’而得標的化合物（計算之質量：272，發現之質量：314 (M+AcN)+) 〇 4-(5•胺基-2_曱基吡啶-3_基）苯甲酸甲酯·於40毫升小玻 瓶中，放置4-(2-甲基·5-硝基吡啶-3-基）苯甲酸曱酯（38〇毫克， 1·40 毫莫耳）、EtOAc (10 毫升）及 SnCl2 · 2Η20 (1.58 克，7 毫莫 耳）。將小玻瓶加蓋，並將混合物於6(rc下磁攪拌丨小時。 以飽和NaHC〇3與EtOAc使反應淬滅。以iM NaOH使有機層鹼 化至pHll ’並以扮〇八0萃取水層。使合併之有機層以Na2S〇4 脫水乾燥，移除溶劑，且使用孓(5-胺基冬甲基吡啶各基）苯 甲酸甲酯殘留物（369毫克），無需進一步純化（計算之質量： 242，發現之質量：243)。 4-(5-(3-第三-丁基氰基苯甲醯胺基）_2_甲基吡啶：基）苯 甲酸甲S曰·於5〇毫升圓底燒瓶中，放置已懸浮於DCM (2毫 升）與DMF (—滴）中之3_第三_丁基_5_氰苯甲酸£(95毫克，44〇 微莫耳）。添加氯化草醯（2毫升2M溶液），並使反應物靜置 過夜。於真空中移除溶劑，並使殘留物自DCM與THF共蒸 發。將已溶於DCM中之所獲得氯化醯Γ添加至4_(5_胺基冬甲 基吡°疋-3-基）苯甲酸甲酯（149毫克，〇·61毫莫耳）與(87 微升）在DCM (總體積，15毫升）中之溶液内。2小時後，移 123505 -255 - 200815422 除洛劑’並使殘留物於石夕膠上純化，以〇_1⑻％醋酸乙酯/己 烧浴離’而得177毫克（95%產率）標的產物。1H NMR (500 MHz， CDC13) (5 (ppm) 8·78 (s，1H)，8·36 (bs，1H)，8·28 (s，1H)，8·23 (s，1H)， 8.15 (dd，J = 2.5, 8 Hz，2H)，8.03 (s5 1H)，7.87 (s，1H), 7.47 (dd，J = 2.5, 8 Hz，2H)，3.98 (s，3H)，2.53 (s，3H)，1.39 (s，9H). 4-(5-(3-第三-丁基_5-氰基苯曱醯胺基）：甲基吡啶各基）苯 甲酸·使上文獲得之化合物（177毫克，0.41毫莫耳）溶於 MeOH (2毫升）與THF (2毫升）中，並以固體Na〇H (48 3毫克， 1.2毫莫耳）處理。將溶液加熱至5〇它，歷經3小時，然後， 將其在室溫下攪拌過夜，於真空中移除溶劑，及以THF稀 釋殘邊物。將〉谷液以1M HC1 (1.20毫升）處理，並在真空中移 除溶劑。使用所獲得之化合物，無需進一步純化（計算之質 量：413，發現之質量：414)。 3-第三-丁基_5·氰基_]\[-(6_甲基-5-(4-(新戊基胺甲醯基）苯基)_A mixture of Pd(dppb)Cl2 (10 mol 0/〇) and K2 C03 (3 eq.) in toluene /dmf (2 mL, 9:1) was heated at 135 Torr for 5 hours under microwave irradiation. The mixture was filtered (diatomaceous earth), the solid was washed with DCM, and the filtrate was concentrated. The residue was chromatographed on EtOAc, eluting with EtOAc / hexane (gradient: 〇 〇 〇 ) ) ) 而 而 而 而 梯度 梯度 梯度 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( 272 272 272 272 272 272 272 〇 4-(5•Amino-2-pyridinyl-3-yl)benzoic acid methyl ester·In a 40 ml small glass bottle, place 4-(2-methyl·5-nitropyridine-3- Ethyl benzoate (38 mg, 1.40 mmol), EtOAc (10 mL) and SnCl2 · 2 Η 20 (1.58 g, 7 mM). The vial was capped and the mixture was magnetically stirred at 6 rc for hr. The reaction was quenched with saturated NaHC EtOAc & EtOAc. &lt;RTI ID=0.0&gt; The aqueous layer was dried over Na 2 S 〇 4, solvent was removed, and EtOAc (5-amino-t-methyl-methylpyridyl)-methyl benzoate residue (369 mg) was used without further purification. Quality: 242, found mass: 243) 4-(5-(3-Tertiary-butylcyanobenzamide)_2-methylpyridine: yl)benzoic acid methyl sulfonate at 5〇 In a milliliter round bottom flask, place 3_T-butyl-5-cyanobenzoic acid (95 mg, 44 〇 micromolar) suspended in DCM (2 ml) and DMF (-drip). Add chlorine The grasshopper (2 ml of 2M solution) was allowed to stand and the reaction was allowed to stand overnight. The solvent was removed in vacuo and the residue was evaporated from DCM and THF. To 4_(5-Amino-m-methylmethylpyridin-3-yl)benzoic acid methyl ester (149 mg, 〇·61 mmol) and (87 μL) in DCM (total volume, 15 mL) Within the solution. 2 hours , transfer 123505 -255 - 200815422 remover 'and the residue was purified on Shishi gum, 〇_1 (8)% ethyl acetate / hexane bath to get '177 mg (95% yield) of the target product. 1H NMR (500 MHz, CDC13) (5 (ppm) 8·78 (s, 1H), 8.36 (bs, 1H), 8·28 (s, 1H), 8.23 (s, 1H), 8.15 ( Dd, J = 2.5, 8 Hz, 2H), 8.03 (s5 1H), 7.87 (s, 1H), 7.47 (dd, J = 2.5, 8 Hz, 2H), 3.98 (s, 3H), 2.53 (s, 3H), 1.39 (s, 9H). 4-(5-(3-Tertiary-butyl-5-cyanobenzoguanamine):methylpyridinyl)benzoic acid (177 mg, 0.41 mmol) dissolved in MeOH (2 mL) EtOAc (EtOAc) After 3 hours, it was stirred at room temperature overnight, the solvent was removed in vacuo and the residue was diluted with THF. &lt;&quot;&gt; The obtained compound was used without further purification (calculated mass: 413, mass found: 414). 3-third- _ _5-cyano-yl] \ [- (6_ methyl-5- (4- (neopentyl acyl carbamoyl) phenyl) _

吡啶各基）苯甲醯胺·使得自前一步驟之化合物溶於DMF (1毫升）中，並以PyBOP (487毫克，0·94毫莫耳）與HOBt (144 宅克’ 0·94宅莫耳）處理。將反應物以(171微升，I % 毫莫耳）在DCM (3毫升）中之溶液處理，接著添加新戊基胺 (72微升，〇·61毫莫耳）。將溶液於室溫下攪拌4小時，在此 段時間内’溶液係從不均勻至均勻。於真空中移除溶劑， 並使殘留物在矽膠上純化，以0_70〇/〇 EtOAc/己烷溶離。使殘 留物自二氧陸圜况2〇凍乾，而得9〇毫克（46%產率，歷經兩 個步驟）3·第三-丁基-5-氰基-N_(6-甲基_5-(4-(新戊基胺甲醯基） 苯基 &gt;比°定-3-基）苯甲醯胺，為白色絨毛狀粉末（計算之質 123505 -256- 200815422 量：482 ;發現之質量：484)。Pyridyl)benzamide The compound from the previous step was dissolved in DMF (1 mL) and taken with PyBOP (487 mg, 0·94 mmol) with HOBt (144 克克' 0·94 house Ear) processing. The reaction was treated with (171 mL, 1% EtOAc) in DCM (3 mL). The solution was stirred at room temperature for 4 hours, during which time the solution was from uneven to homogeneous. The solvent was removed in vacuo and the residue was purified eluting eluting eluting The residue was lyophilized from dioxane to 2 mM (46% yield over two steps). 3·th-butyl-5-cyano-N-(6-methyl_ 5-(4-(neopentylaminomethane)phenyl]&lt;t-but-3-yl)benzamide as a white fluffy powder (calculated quality 123505-256-200815422 Amount: 482; found Quality: 484).

4-(2-甲基-5-硝基吡唆-3-基）苯甲酸(γ)·於4-(2-甲基-5·硝基 吡啶-3-基）苯甲酸甲酯（132毫克，〇·5毫莫耳）（按上述獲得） 在THF/MeOH (20毫升，1 : 1)中之溶液内，添加2N NaOH (2當 量），並將混合物在室溫下攪拌過夜。以1N HC1使混合物中 和，濃縮，且使用於下一步驟，無需進一步純化（計算之質 量：258，發現之質量：300 (M+AcN)+)。 4-(2-甲基_5_确基〃比咬-3-基）-N-新戊基苯甲醯胺· 於上文 獲得之化合物（130毫克，0·5毫莫耳）在DCM中之溶液内，添 加新戊基胺（過量）、PyBOP (2當量）及DIEA (5當量）。將混合 物在室溫下攪拌過夜，以Η2 Ο洗滌，脫水乾燥（MgS04)，並 蒸發。使殘留物於矽膠上層析，使用EtOAc/己烷（梯度液： 〇·1〇〇%)作為溶離劑（計算之質量：327，發現之質量：369 (M+AcN)+) 〇 4-(5-胺基-2-甲基吡啶-3-基）-N-新戊基苯甲醯胺·於得自 前一步驟之化合物（160毫克，0.5毫莫耳）在MeOH中之溶液 内，添加一刮勺之Pd/C (10重量0/〇)，並將此懸浮液於室溫及 吒大氣下攪拌過夜。將混合物過濾（矽藻土），以Me〇H洗滌 123505 -257- 200815422 固體’使合併之有機物貝》辰，並將殘留物使用於下^ 一步 驟，無需進一步純化（計算之質量：297，發現之質量·· 298)。 3_氟-Ν-(6_甲基-5-(4-(新戊基胺曱醯基）苯基）,比啶各基）冬嗎 福淋基苯甲醯胺· 於上述化合物在DCM (3.5毫升）中之溶 液内，添加3-氟基-5-嗎福琳基苯甲酸；[_a (24·ι毫克，〇·ΐ毫莫 耳）、數滴DMF、PyBOP (2當量）及DIEA (5當量），並將混合 物於40°C下攪拌過夜。將混合物以h20洗滌，脫水乾燥 (MgS〇4)，及蒸發溶劑。使殘留物藉rp-hplc純化（梯度液： 在H2〇中之10-70。/。AcN)，接著於矽膠上層析（梯度液：〇-1〇〇0/〇4-(2-Methyl-5-nitropyridin-3-yl)benzoic acid (γ)·methyl 4-(2-methyl-5.nitropyridin-3-yl)benzoate (132 </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The mixture was neutralized with 1N HCl, concentrated and used in the next step without further purification (quality: 258, mass found: 300 (M+AcN)+). 4-(2-Methyl_5_ determinyl hydrazide than -3-yl)-N-neopentyl benzamide · Compound obtained above (130 mg, 0.55 mmol) in DCM In the solution, neopentylamine (excess), PyBOP (2 equivalents) and DIEA (5 equivalents) were added. The mixture was stirred at room temperature overnight, washed with EtOAc, dried (MgSO.sub.) and evaporated. The residue was chromatographed on silica gel using EtOAc / hexane ( gradient: 〇··························· (5-Amino-2-methylpyridin-3-yl)-N-neopentylbenzamide. In a solution of the compound from the previous step (160 mg, 0.5 mmol) in MeOH. A spatula of Pd/C (10 wt. 0 / 〇) was added and the suspension was stirred at room temperature under a helium atmosphere overnight. The mixture was filtered (diatomaceous earth), and the solids of the mixture of &lt;RTI ID=0.0&gt;&gt; The quality of discovery·· 298). 3_Fluoro-hydrazine-(6-methyl-5-(4-(neopentyl)indolyl)phenyl), pyridine group), flufenyl benzoguanamine, in the above compound in DCM 3-Fluoro-5-moffinyl benzoic acid was added to the solution in (3.5 ml); [_a (24·ι mg, 〇·ΐ mmol), a few drops of DMF, PyBOP (2 equivalents) and DIEA (5 eq.) and the mixture was stirred at 40 ° C overnight. The mixture was washed with h20, dried (MgSO.sub.4), and evaporated. The residue was purified by rp-hplc (gradient: 10-70% in H.sub.2), followed by chromatography on silica gel (gradient: 〇-1〇〇0/〇)

EtOAc/己烷），而產生最後產物（計算之質量：5〇5，發現之 質量：505)。EtOAc/hexanes gave the final product (mass calculated: 5 〇 5, found mass: 505).

‘(5_(3_第三·丁基_5_氰基苯甲醯胺基）：甲基吡啶各基）苯 甲酸甲酯·於3-第三-丁基-5-氰苯甲酸E (12〇毫克，〇.6毫莫 耳）與4-(5-胺基-2-甲基吡啶-3-基）苯甲酸甲酯（126毫克，〇·5亳 莫耳）（按上述獲得）在！)〇^中之溶液内，添加數滴dmf、 PyB〇p (2當量）及DIEA (3當量），並將混合物在室溫下攪拌過 ^將此a物以％ 〇洗務，脫水乾燥（MgS〇4)，並蒸發溶劑。 123505 -258 - 200815422 使殘留物於矽膠上層析，使用Et0Ac/己烷（梯度液：〇-1〇〇%) 作為溶離劑（計算之質量：428，發現之質量：428)。 4_(5_(3_第三-丁基_5_氰基苯甲醯胺基）_2•甲基吡啶各基）苯 甲酸·於得自前一步驟之化合物（no毫克，〇·3毫莫耳）在 THF/MeOH (4毫升，1 ·· u中之溶液内，添加2N Na〇H (2當量）， 並將混合物於室溫下攪拌2天。以1NHC1使混合物中和，蒸 發’且使用於下一步驟，無需進一步純化（計算之質量： 414，發現之質量：414)。 4_(5-(3-第三-丁基_5_氰基苯甲醯胺基甲基吡啶_3•基）苯 甲酸曱酯·於得自上文之化合物（20毫克，〇·〇5毫莫耳）在 DCM (2爱升）中之溶液内，添加四氫旅喃冰胺（2當量）、 數滴DMF、PyBOP(2當量）及0正八（3當量），並將混合物在室 恤下攪拌過仪。將混合物以H2 〇洗務，脫水乾燥（Mgs〇4)， 及蒸發溶劑。使殘留物於矽膠上層析，使用Et〇Ac/己烷（梯 度液：0-100%)作為溶離劑（計算之質量：497，發現之質量··'(5_(3_Third-butyl-5-cyanobenzamide): methylpyridinyl)methyl benzoate·3-3-tert-butyl-5-cyanobenzoic acid E ( 12 mg (〇6 mol) and methyl 4-(5-amino-2-methylpyridin-3-yl)benzoate (126 mg, 〇·5亳 Mo) (obtained as above) in! In the solution of 〇^, add a few drops of dmf, PyB〇p (2 equivalents) and DIEA (3 equivalents), and stir the mixture at room temperature to wash the a substance in % ,, dehydrated and dried ( MgS〇4) and evaporate the solvent. 123505 -258 - 200815422 The residue was chromatographed on silica gel using Et0Ac/hexane (gradient: 〇-1 〇〇%) as the dissolving agent (calculated mass: 428, mass found: 428). 4_(5_(3_T-Butyl-5-cyanobenzamide)_2•methylpyridinyl)benzoic acid·Compound from the previous step (no mg, 〇·3 mmol) 2N Na〇H (2 eq.) was added to a solution of THF / MeOH (4 mL, EtOAc), and the mixture was stirred at room temperature for 2 days. The mixture was neutralized with 1NHC1, evaporated and used In the next step, no further purification was carried out (calculated mass: 414, mass found: 414). 4_(5-(3-Terti-butyl-5-cyanobenzamidemethylpyridine_3• Ethyl benzoate. In a solution of the above compound (20 mg, 〇·〇 5 mmol) in DCM (2 liters), tetrahydroglycolide (2 equivalents), A few drops of DMF, PyBOP (2 equivalents) and 0 plus eight (3 equivalents), and the mixture was stirred under a chamber. The mixture was washed with H2, dehydrated (Mgs 〇 4), and the solvent was evaporated. Chromatography on tannin using Et〇Ac/hexane (gradient: 0-100%) as the dissolving agent (calculated mass: 497, quality found)

3-氟·Ν-(5-(4-曱氧苯基)_6_甲基吡啶各基)_5•嗎福啉基苯甲醯 胺·將5_(4_甲氧苯基）-6-甲基吡啶-3-胺（按上述獲得）（3〇毫 克，〇·14毫莫耳）（經由上述方法製成）、3_氟基冰嗎福啉基 苯甲酸I-a (37毫克，0.14毫莫耳）、PyB〇p (2當量）及〇ΐΕΑ(5 123505 -259 - 200815422 當量）在DCM/DMF(3.5毫升，6: 1)中之溶液在室溫下擾拌過 夜。濃縮混合物，並使殘留物接受RP-HPLC (梯度液：在h2 〇 中之5至90% AcN) ’接著於石夕膠上層析（己燒，梯度 液·· 0至100%)，獲得10·1毫克最後化合物（計算之質量：422， 發現之質量：422)。3-fluoro-indole-(5-(4-indolylphenyl)_6-methylpyridinyl)_5•morpholinobenzamide·5_(4-methoxyphenyl)-6-A Pyridyl-3-amine (obtained as described above) (3 mg, 〇14 mmol) (made by the above method), 3-fluoro-colsoforphthylbenzoic acid Ia (37 mg, 0.14 mmol) A solution of PyB〇p (2 equivalents) and hydrazine (5 123505 -259 - 200815422 equivalents) in DCM/DMF (3.5 mL, 6:1) was scrambled overnight at room temperature. The mixture was concentrated, and the residue was subjected to RP-HPLC (gradient: 5 to 90% AcN in h.sub.2) and then chromatographed on the saponin (hexane, gradient 0 to 100%). 10.1 mg of the last compound (calculated mass: 422, found quality: 422).

6-溴基於驗酸甲酯· 於1〇〇毫升圓底燒瓶中，放置6-溴基 於驗酸（540毫克，2.7毫莫耳）、DCM (20毫升）及DMF (1滴）。 添加氯化草醯（1毫升），而造成激烈氣體釋出。將反應物檀 拌1小時，然後於真空中移除溶劑。將殘留物以MeOH處理， 並在真空中移除溶劑。使殘留物於DCM與飽和NaHC03之間 作分液處理，並使有機層以Na2S04脫水乾燥。移除溶劑， 而得369毫克（55%產率）6-溴基於驗酸甲酯。1 H NMR (500 MHz) 5 (ppm) 9.00 (dd，J = 2.0, 0·5 Ηζ，1Η)，8.25 (dd，J = 8.5, 2.5 Ηζ， 1Η)，7·42 (dd，J = 8.5, 0·5 Ηζ，1Η)，3.96 (s，3Η). 2’-甲基-5’-破基-2,3’-聯吡啶-5-羧酸曱酯· 於2達蘭小玻瓶 中，放置2-甲基-5-硝基-3-(4,4,5,5-四甲基-1，3,2-二氧硼伍圜-2-基）吡啶品吶可基二羥基硼烷鹽a (130毫克，0.33毫莫耳）、6-溴基菸鹼酸甲酯（按上述製成）（80毫克，0·37毫莫耳）、鈀肆 123505 -260- 200815422 (三苯膦）（38毫克，0.03毫莫耳）、DME (4·5毫升）、乙醇（〇·5 毫升）及甲苯（0·5毫升）。添加飽和Na2C〇3(0.5毫升），同時迅 速地攪拌。將反應物以氮沖洗，並緊密地加蓋，接著加熱 至80°C，歷經8.5小時。在真空中移除溶劑，並使殘留物於 矽膠上純化，而得68毫克（75%產率）2’-甲基-5’-破基·2,3，-聯，比 咬-5-叛酸甲酉旨。1H NMR (500 MHz) 5 (ppm) 9.39 (s，1Η)，9.352 (s 1H)，8.57 (s，1H)，8.47 (d，J = 8.0 Hz，1H)，7.61 (d，J = 8·0 Hz，1H)，4.02 (s，3H)，2·75 (s，3H)· 2’-甲基-5f-琐基-N-((四氫呋喃_2-基）甲基）-2,3，-聯吡啶j幾醯 胺·於100毫升圓底燒瓶中，放置2，-甲基-5，-琐基-2,3，-聯咐咬 -5-羧酸甲酯（67毫克，0.25毫莫耳）、THF (4毫升）、甲醇（4毫 升）及2N氮乳化納（184微升’ 368微莫耳）。於室溫下檀拌2 小時後，將反應物加熱至50°C過夜。移除溶劑，並使殘留 物懸浮於THF中，以2MHC1(184微升，368微莫耳）處理，及 在真空中移除溶劑。使殘留物溶於DMF (0.5毫升）中，並以 PyBOP (312毫克，0.6毫莫耳）與N-甲基嗎福啉（82微升，〇.75 耄莫耳）處理。20分鐘後，將此溶液之三分之一以吱喃甲基 胺（152微升）處理，並加熱至4〇。(；過夜。使殘留物於石夕膠上 純化，以0-100% EtOAc/己烷溶離，而得2，_甲基-5，-硝基-N-((四 氫吱喃-2-基）甲基）-2,3’-聯吡啶-5-羧醯胺（計算之質量·· 342， 發現之質量：343)。 5 (3_第二-丁基_5_氣基本甲醯胺基)_2,_甲基_]^_((四氫咳喘_2_ 基）曱基)-2,3’-聯吡啶-5-羧醯胺·在2達蘭小玻瓶中，使2，_曱 基-5’-硝基氫呋喃基）甲基&gt;2,3，_聯吡啶净羧醯胺溶於 123505 -261 · 2008154226-Bromo based on methyl acetate. In a 1 liter round bottom flask, 6-bromo groups were placed for acid (540 mg, 2.7 mmol), DCM (20 mL) and DMF (1 drop). Chlorinated mash (1 ml) was added, causing intense gas release. The reaction was sanded for 1 hour and then the solvent was removed in vacuo. The residue was taken up in MeOH and solvent was evaporated in vacuo. The residue was partitioned between DCM and sat. NaHC.sub.3, and then evaporated. The solvent was removed to give 369 mg (55% yield) of 6-br. 1 H NMR (500 MHz) 5 (ppm) 9.00 (dd, J = 2.0, 0·5 Ηζ, 1 Η), 8.25 (dd, J = 8.5, 2.5 Ηζ, 1 Η), 7·42 (dd, J = 8.5 , 0·5 Ηζ,1Η), 3.96 (s,3Η). 2'-Methyl-5'-degradoyl-2,3'-bipyridyl-5-carboxylic acid oxime ester in 2 dalan glass bottle Place 2-methyl-5-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)pyridine Hydroxyborane salt a (130 mg, 0.33 mmol), methyl 6-bromonicotinate (made as above) (80 mg, 0·37 mmol), palladium rhodium 123505-260-200815422 ( Triphenylphosphine) (38 mg, 0.03 mmol), DME (4.5 mL), ethanol (〇·5 mL) and toluene (0.5 mL). Saturated Na2C〇3 (0.5 mL) was added while stirring rapidly. The reaction was flushed with nitrogen and tightly capped, then heated to 80 ° C for 8.5 hours. The solvent was removed in vacuo and the residue was purified on silica gel to afford &lt;RTI ID=0.0&gt;&gt; The treason is a purpose. 1H NMR (500 MHz) 5 (ppm) 9.39 (s, 1 Η), 9.352 (s 1H), 8.57 (s, 1H), 8.47 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8· 0 Hz, 1H), 4.02 (s, 3H), 2·75 (s, 3H)· 2'-methyl-5f-triki-N-((tetrahydrofuran-2-yl)methyl)-2,3 ,-bipyridyl j-amine amide in a 100 ml round bottom flask, place 2,-methyl-5,-trityl-2,3,-binidine-5-carboxylic acid methyl ester (67 mg, 0.25 Millol), THF (4 mL), methanol (4 mL), and 2N nitrocellulose (184 liters &lt; 368 micromoles). After 2 hours at room temperature, the reaction was heated to 50 °C overnight. The solvent was removed and the residue was suspended in THF, taken &lt;RTI ID=0.0&gt;&gt; The residue was dissolved in DMF (0.5 mL) and EtOAc (EtOAc &lt;RTIgt; After 20 minutes, one third of this solution was treated with decylmethylamine (152 μL) and heated to 4 Torr. (; Overnight. The residue was purified on EtOAc (EtOAc) elute elute Base) methyl)-2,3'-bipyridyl-5-carboxamide (calculated mass · 342, quality found: 343) 5 (3_ second-butyl _5_ gas basic formazan Amino)_2,_methyl_]^_((tetrahydrocoughchuan_2_yl)indolyl)-2,3'-bipyridyl-5-carboxamide in 2 dalan small glass bottle 2,_Mercapto-5'-nitrohydrofuranylmethyl]&gt;2,3,-bipyridylethylcarboxamide dissolved in 123505 -261 · 200815422

EtOAc (2 毫升）與 MeOH (0.5 毫升）中，以 SnCl2 · 2h2〇 (9〇 毫 克，0.4毫莫耳）處理，並於7(rc下加熱丨小時。蒸發溶劑， 並使殘留物於DCM與飽和N^CO3之間作分液處理。使有機 層乾燥，且過濾溶液。將溶液以氯化3_氰基_5_第三-丁基苯 甲醯F(160微莫耳）與NMM(240微莫耳）處理。蒸發溶劑，並 使殘留物於RP-HPLC上純化，而得2.5毫克5，-(3-第三-丁某-5· 氰基苯甲醯胺基）-2f-甲基-N-((四氫呋喃_2_基）曱基）_2,3»_聯吡 σ定-5_羧醯胺（計算之質量：497，發現之質量499)。 5’-(3-第三丁基_5·氰基苯甲醯胺基)_2，_曱基具((四氫呋喃_2_ 基）曱基）-3,3f-聯吡啶-6-羧醯胺基本上係藉由相同方法製成 (計算之質量·· 497，發現之質量499)。Treated with EtOAc (2 mL) and MeOH (0.5 mL) EtOAc (EtOAc) (EtOAc) The liquid phase was treated between saturated N^CO3, the organic layer was dried, and the solution was filtered. The solution was chlorinated with 3-cyano-5_t-butylbenzamide F (160 micromoles) and NMM ( Treatment with 240 micromoles. The solvent was evaporated and the residue was purified EtOAc EtOAc EtOAc EtOAc Methyl-N-((tetrahydrofuran-2-yl)indenyl)_2,3»_bipyridin-5-carboxyguanamine (calculated mass: 497, mass found 499). 5'-(3- The third butyl _5. cyanobenzamide amino) 2, 曱 曱 ((tetrahydrofuran-2-yl) fluorenyl)-3,3f-bipyridyl-6-carboxamide is basically the same Method made (calculated quality · 497, found quality 499).

&gt;第二-丁基-5-氰基_N-(6_甲基-5-(4-(六氫ρ比咬-1_基胺甲醯 〇 基）苯基）吡啶-3-基）苯曱醯胺·將4-(5-(3-第三-丁基-5-氰基苯 甲醯胺基）-2-甲基吡啶-3-基）苯曱酸(26毫克，0.06毫莫耳）、 1-胺基六氫吡啶（13微升，2當量）、BOP (41毫克，1.5當量） 及DIEA (42微升）在1毫升DMF中之混合物於室溫下攪拌過 夜。以DMF稀釋反應混合物，並使其接受預備之LC-MS純化 (20-50% AcN/H2〇)，提供12.1毫克標題化合物（計算之質量： 496，發現之質量497)。 123505 -262- 200815422&gt;Second-butyl-5-cyano-N-(6-methyl-5-(4-(hexahydro-peptidyl-1-ylaminocarbamoyl)phenyl)pyridin-3-yl Benzoylamine 4-(5-(3-tert-butyl-5-cyanobenzamide)-2-methylpyridin-3-yl)benzoic acid (26 mg, 0.06) A mixture of 1-aminohexahydropyridine (13 μL, 2 eq.), BOP (41 mg, 1.5 eq.) and DIEA (42 μL) in 1 mL of DMF was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc) 123505 -262- 200815422

4-溪-N-新戊基苯確醯胺· 於氣化績酸（4克，1.6毫莫耳） 與DIEA (3當量，0.048莫耳）在50毫升DCM中之溶液内，添加 新戊基胺（1_3當量，2.13毫莫耳）。將溶液在室溫下攪拌2小 時，然後添加至200毫升水（pH 2.0)中。以DCM萃取所形成之 混合物。合併有機離份，脫水乾燥（MgS04)，過濾，及在真 空中濃縮，而產生5.6克標的化合物。1 H NMR (500 MHz，CDC13 ；) 5 (PPm) 7.73 (d，J = 8.0 Hz，2H)，7.66 (d，J = 8·0 Hz，2H)，4.63 (t，J = 7.0 Hz，1H)，2.69 (d，J = 7·0 Hz，2H)，0.89 (s，9H)· N-新戊基_4_(4,4,5,5-四甲基-i，3,2_二氧硼伍圜基）苯磺醯胺· 使上文獲得之化合物（〇·5克，0.0016莫耳）、雙品吶可基二硼 (1.5 當量，0.62 克）、醋酸鉀（3 當量，〇·48 克）及 PdCl2dppf (10 莫耳％，120毫克）溶於3毫升DMSO中。將溶液於80°C及氮 氣下攪拌2小時。將混合物添加至水中，並以DCM萃取。 合併有機離份，脫水乾燥（MgS04)，過濾，及濃縮。管柱層 析（Si02 ; 1 : 1，DCM : EtOAc)，產生 0.415 克標的化合物。1 Η NMR (500 MHz, CDC13) δ (ppm) 7.94 (d5 J - 7.5 Hz? 2H), 7.83 (d? J = 8·0 Hz，2H)，4·37 (bt5 1H)，2.67 (d，J = 6·0 Hz，2H)，1.36 (s，12H)，0.87 (s， 123505 -263 - 200815422 9H). 4-(2-甲基-5-硝基吡啶-3·基）_N-新戊基苯績醯胺·使上文 獲得之化合物（30毫克，0·085毫莫耳）、3-溴基-5-硝基-2-甲基 吡啶（1.0當量，18毫克）、K2C03(3當量，35毫克）及 Pd(PPh3 )4 (10 莫耳。/〇，10 毫克）溶於 3 毫升 DME: EtOH (9 : 1)中。 將〉谷液於80 C及氣氣下稅摔24小時。使混合物在直空中濃 縮。管柱層析（Si02 ; 3 : 1，己烷·· EtOAc)，產生20毫克標 的化合物（計算之質量：364，發現之質量364)。 f &quot;i： 、 ‘(5-胺基-2_甲基吡啶-3-基）-N-新戊基苯磺醯胺·將上文 獲得之化合物（20毫克，0.055毫莫耳）與1〇% Pd/C (10毫克）添 加至3毫升MeOH中。將溶液於室溫及1大氣壓之h2下授拌2 小時。過濾混合物，及在真空中濃縮，而產生18毫克標的 化合物（計算之質量·· 334，發現之質量334)。 &gt;第二丁基-5-象基-Ν-(6·甲基-5-(4-(]&gt;^_新戊基胺續醯基）苯 基）-吡啶-3-基）苯甲醯胺·將上文獲得之化合物（20毫克， # 0·06毫莫耳）與過量DIEA (0.2毫升）添加至氯化3-氰基-5-第三4-brook-N-neopentyl phenyl decylamine · Add a new pentane to a gasification acid (4 g, 1.6 mmol) and DIEA (3 eq., 0.048 mol) in 50 mL DCM Base amine (1 - 3 equivalents, 2.13 millimoles). The solution was stirred at room temperature for 2 hours and then added to 200 ml of water (pH 2.0). The resulting mixture was extracted with DCM. The organic fractions were combined, dried (MgSO4), filtered, and concentrated in vacuo to yield 5.6 g of the title compound. 1 H NMR (500 MHz, CDC13 ;) 5 (PPm) 7.73 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 8·0 Hz, 2H), 4.63 (t, J = 7.0 Hz, 1H ), 2.69 (d, J = 7·0 Hz, 2H), 0.89 (s, 9H)· N-neopentyl_4_(4,4,5,5-tetramethyl-i,3,2_two Oxyfluoride, phenylsulfonamide, the compound obtained above (〇·5 g, 0.0016 mol), diterpene diboron (1.5 eq, 0.62 g), potassium acetate (3 eq, 〇 48 g) and PdCl2dppf (10 mol%, 120 mg) were dissolved in 3 ml of DMSO. The solution was stirred at 80 ° C for 2 hours under nitrogen. The mixture was added to water and extracted with DCM. The organic fractions were combined, dried (MgSO.sub.4), filtered and concentrated. Column chromatography (SiO 2 ; 1 : 1, DCM: EtOAc) yielded 0.415 g of the title compound. 1 Η NMR (500 MHz, CDC13) δ (ppm) 7.94 (d5 J - 7.5 Hz? 2H), 7.83 (d? J = 8·0 Hz, 2H), 4·37 (bt5 1H), 2.67 (d, J = 6·0 Hz, 2H), 1.36 (s, 12H), 0.87 (s, 123505 -263 - 200815422 9H). 4-(2-methyl-5-nitropyridin-3-yl)_N-new Amyl phthalocyanine · The compound obtained above (30 mg, 0. 085 mmol), 3-bromo-5-nitro-2-methylpyridine (1.0 eq, 18 mg), K2C03 ( 3 equivalents, 35 mg) and Pd(PPh3)4 (10 mol./〇, 10 mg) were dissolved in 3 ml of DME: EtOH (9:1). The gluten liquid will fall for 24 hours under the 80 C and gas. Allow the mixture to concentrate in the direct air. Column chromatography (SiO 2 ; 3 : 1, hexane·EtOAc) gave 20 mg of the title compound (mass: 364, mass 364 found). f &quot;i: , '(5-Amino-2-methylpyridin-3-yl)-N-neopentylbenzenesulfonamide · The compound obtained above (20 mg, 0.055 mmol) and 1% Pd/C (10 mg) was added to 3 mL of MeOH. The solution was mixed for 2 hours at room temperature and 1 atmosphere of h2. The mixture was filtered and concentrated in vacuo to give &lt;RTI ID=0.0&gt;&gt;&gt;Secondbutyl-5-yl-yl-hydrazine-(6.methyl-5-(4-()&gt;^_neopentylamine fluorenyl)phenyl)-pyridin-3-yl)benzene Formamide · Add the compound obtained above (20 mg, #0·06 mmol) and excess DIEA (0.2 mL) to 3-cyano-5-chloride

丁基本甲醯F (1.0當量，13毫克）在3毫升DCM中之溶液内。 將溶液於室溫下攪拌1小時，然後在真空中濃縮。RP—fjPLC 純化（10至90% AcN，在H20中，具有0·1% TFA)，產生7.0毫克 標的化合物（計算之質量：519，發現之質量：519)。iHNMR (500 MHz，CD3 OD) 6 (ppm) 〇5 (s，1H)，8·32 (s，1H)，8·16 (m，2H)，7.99 (m? 3H)? 7.63 (d5 J = 7.5 Hz3 2H)? 2.67 (s5 2H)5 2.48 (s3 3H)? 1.42 (s5 9H)? 0.91 (s，9H). 123505 -264- 200815422 途徑c :經由吡啶中央核心之形成D. Basic formazan F (1.0 eq, 13 mg) in 3 mL of DCM. The solution was stirred at room temperature for 1 hour and then concentrated in vacuo. RP-fjPLC purification (10 to 90% AcN, with 0.1% TFA in H20) yielded 7.0 mg of the title compound (mass calculated: 519, mass found: 519). iHNMR (500 MHz, CD3 OD) 6 (ppm) 〇5 (s,1H),8·32 (s,1H),8·16 (m,2H),7.99 (m? 3H)? 7.63 (d5 J = 7.5 Hz3 2H)? 2.67 (s5 2H)5 2.48 (s3 3H)? 1.42 (s5 9H)? 0.91 (s,9H). 123505 -264- 200815422 Route c: Formation through the central core of pyridine

步驟1· 4-(2-甲基-5-硝基吡啶：基）苯甲腈·於4-(2-_基丙 基）苯甲腈（162毫克，1.0毫莫耳，α當量）、2-硝基丙二醛（按Step 1· 4-(2-Methyl-5-nitropyridinyl)benzonitrile·4-(2--propylpropyl)benzonitrile (162 mg, 1.0 mmol, α equivalent), 2-nitromalonaldehyde

Org· Synth· Coll·，4, 844, 1963 製成）（210 毫克，1.5 毫莫耳，U 當 量）及醋酸銨（395毫克，5.1毫莫耳，當量）之混合物中， 添加50% EtOH水溶液（2毫升），並將混合物在6〇°C下攪拌過 夜。將反應混合物以水稀釋，並於DCM中萃取產物。使有 機層脫水乾燥（MgS〇4)，蒸發，且使殘留物於矽膠上藉層析 純化，使用0-3% MeOH/DCM作為溶離劑，提供75毫克（30%產 率）標的產物。1H-NMR (500 MHz，DMSO-d6)5 (ppm) 9.33 (d，1H)， 8.42 (d，1H)，8.02 (d，2H)，7.75 (d5 2H)，2.57 (s，3H). 1H-NMR (500 MHz， CDC13) 6 (ppm) 9.40 (d，1H)，8.34 (d，1H)，7·85 (d，2H)5 7.52 (d，2H)， 2_65 (s，3H).(計算之質量：239.1，發現之質量：280.9 (M+AcN+H+)). ‘(2-曱基-5-硝基吡啶-3_基）苯甲酸(Y)·使4-(2-甲基-5_硝基 吡啶-3-基）苯甲腈（55毫克，0.23毫莫耳）溶於EtOH (1.2毫升） 中’並添加6M HC1水溶液（2.5毫升）。將混合物於11〇。〇下授 拌過夜。蒸發反應混合物，提供59毫克（100%產率）產物。 ^-NMR (500 MHz? DMSO-d6) δ (ppm) 10.34 (s5 1H)? 9.31 (d5 1H)5 8.39 (d，1H)，8.08 (d，2H)，7.65 (d，2H)，2.58 (s，3H)·(計算之質量：258.1， 發現之質量：299.9 (M+AcN+H+))· 123505 •265 - 200815422 中間物Y係使用上述方法進一步衍化。 ΟAdd 50% EtOH in a mixture of Org· Synth· Coll·, 4, 844, 1963 (210 mg, 1.5 mmol, U equivalent) and ammonium acetate (395 mg, 5.1 mmol, equivalent) (2 ml) and the mixture was stirred at 6 ° C overnight. The reaction mixture was diluted with water and the product was extracted in DCM. The organic layer was dehydrated and dried (MgSO.sub.4), evaporated, and the residue was purified by chromatography eluting with EtOAc EtOAc (EtOAc) 1H-NMR (500 MHz, DMSO-d6) 5 (ppm) 9.33 (d, 1H), 8.42 (d, 1H), 8.02 (d, 2H), 7.75 (d5 2H), 2.57 (s, 3H). 1H -NMR (500 MHz, CDC13) 6 (ppm) 9.40 (d,1H), 8.34 (d,1H),7·85 (d,2H)5 7.52 (d,2H), 2_65 (s,3H).( Calculated mass: 239.1, found mass: 280.9 (M+AcN+H+)). '(2-indolyl-5-nitropyridin-3-yl)benzoic acid (Y) · 4-(2-A The benzyl-5-nitropyridin-3-yl)benzonitrile (55 mg, 0.23 mmol) was dissolved in EtOH (1. The mixture was taken at 11 Torr. Underarms are allowed to mix overnight. The reaction mixture was evaporated to give 59 mg (100% yield). ^-NMR (500 MHz? DMSO-d6) δ (ppm) 10.34 (s5 1H)? 9.31 (d5 1H)5 8.39 (d,1H), 8.08 (d,2H), 7.65 (d,2H), 2.58 ( s, 3H)·(Calculated mass: 258.1, quality found: 299.9 (M+AcN+H+))·123505 •265 - 200815422 Intermediate Y was further derivatized using the above method. Ο

途徑D:醯胺鏈結之替代取向 Ν-新戊基-冬(4,4,5,5_四甲基_1，3,2_二氧硼伍圜-2_基）苯曱醯胺· 使4-(4,4,5,5-四甲基]，3,2-二氧硼伍圜-2-基）苯甲酸（339毫克， 1.366毫莫耳）溶於DCM (3毫升）中。添加氯化草醯（3毫升）， 接著為催化量之DMF，並將混合物於室溫下攪拌過夜。在 真空中濃縮混合物，並使殘留物在ΗΥ中乾燥。使淡黃色固 體溶於DCM (3耄升）中，並添加至新戊基胺（丨31〇毫克，15〇3 毫莫耳）與飽和NaHC〇3水溶液之混合物中。將反應物於室溫 下激烈擾拌45分鐘。分離有機層，並以DCM洗滌水層。使 合併之有機層以Na2 SO#脫水乾燥，過濾，在真空中濃縮， 並使殘留物在HV中乾燥。使粗製化合物藉管柱層析純化 (石夕膠’ 0_50% EtOAc/DCM) ’而得純標的產物（計算之質量： 317.23，發現之貝篁 318)。^-NMR (DMSO-d0)占（ppm) 8.41 (t，1H, J - 6.4 Hz)，7.86 (d，2H，J = 8·2 Ηζ)，7·75 (d，2H，J = 8·2 Hz), 3·11 (d，2H， 123505 -266- 200815422 J = 6·4 Hz)，1.32 (s，12H)，0.91 (s，9H). 6-甲基-5-(4-(新戊基胺甲醯基）苯基）菸鹼酸乙酯·將中間 物d (117.4毫克，0.403毫莫耳）與得自上文之化合物（153.5毫 克’ 0.484耄莫耳）、碳酸铯（394.2毫克，1.21毫莫耳）、三苯 胂（18.5毫克，〇·〇6毫莫耳）在二氧陸圜（96毫升）與水（〇.4毫 升）中之混合物脫氣。添加固體Pdcl2(phCN)2(7J毫克，〇 〇2 耄莫耳），並將混合物再一次脫氣。將反應物於7(rc及氮氣 下攪拌135分鐘。使反應物於矽藻土與MgS〇4上過濾，並使 慮液康乾。將殘留物藉管柱層析純化（石夕膠，梯度液· 〇_5〇% EtOAc/DCM)，獲得純標的產物（計算之質量：354 4，發現之 質量：355)。Route D: Alternative orientation of the guanamine linkage Ν-neopentyl-Winter (4,4,5,5-tetramethyl-1,3,2-dioxanthene-2-yl)benzamide · Dissolve 4-(4,4,5,5-tetramethyl),3,2-dioxaboron-2-yl)benzoic acid (339 mg, 1.366 mmol) in DCM (3 mL) in. Chlorohydrazine (3 ml) was added followed by a catalytic amount of DMF and the mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue was dried in EtOAc. The pale yellow solid was dissolved in DCM (3 liters) and added to a mixture of neopentylamine (31 〇 mg, 15 〇 3 mM) and saturated aqueous NaHC 〇3. The reaction was vigorously stirred at room temperature for 45 minutes. The organic layer was separated and the aqueous layer was washed with DCM. The combined organic layers were dried over Na2SO~, filtered, concentrated in vacuo and dried. The crude compound was purified by column chromatography elution elution elution elution elution elution elution elution elution elution elution elution ^-NMR (DMSO-d0) occupies (ppm) 8.41 (t, 1H, J - 6.4 Hz), 7.86 (d, 2H, J = 8·2 Ηζ), 7·75 (d, 2H, J = 8· 2 Hz), 3·11 (d, 2H, 123505 -266- 200815422 J = 6·4 Hz), 1.32 (s, 12H), 0.91 (s, 9H). 6-methyl-5-(4-( Neopentylaminomethyl hydrazinyl) phenyl) nicotinic acid ethyl ester. Intermediate d (117.4 mg, 0.403 mmol) and the compound obtained above (153.5 mg '0.484 耄mol), cesium carbonate ( 394.2 mg, 1.21 mmol, triphenylsulfonium (18.5 mg, 〇·〇 6 mmol) was degassed in a mixture of dioxane (96 ml) and water (〇. 4 ml). Solid PdCl2 (phCN) 2 (7 J mg, 〇 2 耄 Moule) was added and the mixture was again degassed. The reaction was stirred at 7 (rc and MeOH) for 135 min. The reaction was filtered on celite and EtOAc (methanol), and the residue was purified by column chromatography. Liquid·〇_5〇% EtOAc/DCM) gave the title product (mass calculated: 354 4, mass found: 355).

6·甲基_5_(4_(新戊基胺甲醯基）苯基）終鹼酸·將2N Na〇H 水溶液（212微升，〇·424毫莫耳）與水（212微升）添加至上文獲 得之化合物在THF-EtOH中之溶液（2毫升/2毫升）内。將混合 物於50 C下攪拌6·5小時，並濃縮，及在真空中乾燥。添加 1NHC1水溶液（424微升，0.424毫莫耳）與水（3毫升），使混合 物音振’及過滤。將固體以水洗務，風乾，並於Ην中乾燥， 而產生42.8耄克標的化合物（計算之質量·· 326.4，發現之質 量·· 327)。 Ν-(3-第二_丁基冬氰基苯基)_6_甲基-5-(4_(新戊基胺甲醯基)_ 苯基）菸鹼醯胺·將上文之粗製化合物（20毫克，0 061毫莫 耳）、中間物ΒΒ (19·4毫克，0.092毫莫耳）、Β0Ρ (54·2毫克， 0·123耄莫耳）、νμμ (26·9微升，〇 245毫莫耳）及dmf (丨毫升） 之混合物於室溫下攪拌3小時30分鐘，然後加熱至5(rc過 123505 -267- 200815422 夜。使粗製化合物藉RPLC-MS純化（梯度液：3〇·8〇% AcN/ 水），而得標的化合物，24.4毫克產量（計算之質量：4826， 發現之質量：483)。 實例2 :式II標的化合物之合成 進展中間物之合成6·Methyl _5_(4_(neopentylcarbinyl)phenyl) decanoic acid · Add 2N Na〇H aqueous solution (212 μl, 〇·424 mmol) and water (212 μl) To a solution of the compound obtained above in THF-EtOAc (2 mL / 2 mL). The mixture was stirred at 50 C for 6.5 hours, concentrated and dried in vacuo. An aqueous solution of 1NHC1 (424 μl, 0.424 mmol) and water (3 mL) were added, and the mixture was sonicated and filtered. The solid was washed with water, air-dried, and dried in Ην to give 42.8 g of the compound (calculated mass · 326.4, mass found 327). Ν-(3-second-butyl-t-butylcyanophenyl)_6-methyl-5-(4-(p-pentylamine-methylhydrazino)-phenyl)nicotinamide · the above crude compound ( 20 mg, 0 061 mM), intermediate ΒΒ (19.4 mg, 0.092 mmol), Β0 Ρ (54. 2 mg, 0·123 耄 Mo), νμμ (26·9 μl, 〇245 Mix a mixture of millimolar and dmf (丨 ml) at room temperature for 3 hours and 30 minutes, then heat to 5 (rc over 123505 -267-200815422 nights. Purify the crude compound by RPLC-MS (gradient: 3〇) · 8 % AcN / water), and the obtained compound, 24.4 mg yield (calculated mass: 4826, mass found: 483). Example 2: Synthesis of the compound of formula II Progressive intermediate synthesis

b Z 1-(2-甲基·5_靖基ρ比咬·3_基）-1Η_1，2,3-三嗤-4·叛酸第三-丁醋 (Z)·將3·璺氮基-2-甲基-5-石肖基p比唆b (1.12克，6.25毫莫耳） 與丙炔酸第三-丁酯（1·72毫升，12·5毫莫耳，2·〇當量）在 AcN/H2 0 (1〇 : 1，23毫升）中之溶液在銅線存在下，於8〇。〇下 攪拌過夜。使溶液濃縮，並在HV中乾燥，而得粗產物z (1.918 克，定量產率，&gt;90%純度），為褐色固體。管柱層析（矽膠， 在DCM中之(M〇% MeOH或在DCM中之0-50% EtOAc)，產生產 物Z ’為白色固體（1.861克，97%產率，&gt;99%純，藉LC-MS)(計 算之質量：305，發現之質量：291 (MH-tBu+AcN)+)。b Z 1-(2-methyl·5_Jingji ρ than bite·3_ base)-1Η_1,2,3-three 嗤-4· retinoic acid third-butyl vinegar (Z)·3·璺N-based -2-Methyl-5-Shishokiki p is 唆b (1.12 g, 6.25 mmol) and third-butyl propionate (1·72 ml, 12·5 mmol, 2·〇 equivalent) The solution in AcN/H2 0 (1 〇: 1, 23 ml) was at 8 Torr in the presence of a copper wire. Knead under stirring overnight. The solution was concentrated and dried in EtOAc to give a crude material (yield: s. Column chromatography (gelatin, in MeOH (M EtOAc MeOH) EtOAc EtOAc (EtOAc) By LC-MS) (calculated quality: 305, quality found: 291 (MH-tBu+AcN)+).

3-甲基小(1_(2_甲基-5-硝基吡啶_3-基）-1Η-1，2,3·三唑-4-基）丁 1·醇（R=CH(OH)CH2CH(CH3)2)·將 b (97.5 毫克，0.544 毫莫 耳，1.0當量）與5-甲基-1-己炔-3-醇（244毫克，2.18毫莫耳，4.0 123505 -268 - 200815422 當量）在AcN/水（10 : 1，4毫升）中之溶液於80°C下，在銅線存 在下攪拌過夜。使溶液濃縮，並在HV中乾燥，而得粗製標 的產物（118毫克，80%純，藉LC-MS)，將其使用於下一步驟， 無需進一步純化（計算之質量：291，發現之質量：206, 246)。 上述方法亦用於合成2-甲基-2-(1-(2-甲基-5-硝基吡啶-3-基）_1H-1，2,3-三唑-4·基）丙酸苄酯（R=C(CH3)2COOBn)(計算之 質量：381，發現之質量：382)。3-Methyl small (1_(2-methyl-5-nitropyridin-3-yl)-1Η-1,2,3·triazol-4-yl)butanol (R=CH(OH) CH2CH(CH3)2)·b (97.5 mg, 0.544 mmol, 1.0 eq.) with 5-methyl-1-hexyn-3-ol (244 mg, 2.18 mmol, 4.0 123505 -268 - 200815422 Equivalent) A solution in AcN/water (10:1, 4 mL) was stirred at 80 ° C overnight in the presence of copper wire. The solution was concentrated and dried in EtOAc to give EtOAc (EtOAc: EtOAc (EtOAc) :206, 246). The above method is also used for the synthesis of 2-methyl-2-(1-(2-methyl-5-nitropyridin-3-yl)_1H-1,2,3-triazol-4yl)propionic acid benzyl Ester (R = C(CH3)2COOBn) (calculated mass: 381, mass found: 382).

Γ Η〇 〇κ 〇H 丙炔酸· 將3-羧基丙炔酸鉀（200克，1.32莫耳）添加至550 毫升水中。將混合物加熱至回流，歷經4小時，然後冷卻至 室溫（NH4)2S04(25克），及添加IN HC1 (100毫升）。以EtOAc萃 取混合物，並使合併之有機層以MgS04脫水乾燥，及濃縮。 使殘留物在真空[90_100°C /100毫米Hg]中蒸餾，提供標的化合 物（24 克，26% 產率），為無色液體。1H-NMR (CDC13，300 MHz) (5 (ppm) 9.59-9.64 (d，1H)，3.02 (s，1H). I N-新戊基丙炔醯胺· 於上述化合物（11.2克，0.16莫耳）與 DCC (41克）在DCM (650毫升）中之混合物内，在〇°c下，逐滴 添加2,2-二甲基丙-1-胺之溶液（13克，在20毫升DCM中）。將 混合物攪拌1小時，然後，使其溫熱至室溫1小時。過濾混 合物，並蒸發濾液。使殘留物藉管柱層析純化（PE : EtOAc = 2 ·· 1)，而得標的化合物V (17.6克，84.4%產率），為油狀物。 ^-NMR (CDCl33〇〇 MHz) δ (ppm) 6.66 (s5 1H)5 3.01-3.03 (d3 2H)? 2.79 (s，1H)，0.84 (s5 9H). 123505 -269- 200815422Γ Η〇 〇κ 〇H propiolic acid · Potassium 3-carboxypropynoate (200 g, 1.32 mol) was added to 550 ml of water. The mixture was heated to reflux for 4 h then cooled to rt (NH.sub.4) &lt;RTI ID=0.0&gt;&gt; The mixture was extracted with EtOAc. The residue was distilled in vacuo [90-100 ° C / 100 mm Hg] to afford the title compound (24 g, 26% yield) as a colourless liquid. 1H-NMR (CDC13, 300 MHz) (5 (ppm) 9.59-9.64 (d, 1H), 3.02 (s, 1H). I N-Pentylpropynylamine · The above compound (11.2 g, 0.16 Mo A solution of 2,2-dimethylpropan-1-amine (13 g in 20 ml DCM) was added dropwise to a mixture of DCC (41 g) in DCM (650 mL). The mixture was stirred for 1 hour, then it was allowed to warm to room temperature for 1 hour. The mixture was filtered, and the filtrate was evaporated. The residue was purified by column chromatography (PE: EtOAc = 2 ···1) The title compound V (17.6 g, 84.4% yield) was obtained as an oil. NMR (CDCl33 〇〇MHz) δ (ppm) 6.66 (s5 1H)5 3.01-3.03 (d3 2H)? 2.79 (s, 1H ), 0.84 (s5 9H). 123505 -269- 200815422

途徑A :經由G-C(0)0H之偶合至經保護核心模板Route A: coupling to a protected core template via G-C(0)0H

H5-胺基_2_曱基吡啶各基）_1H-1，2,3-三唑_4_羧酸第三_丁 _ . 將阮尼鎳（〜3〇〇毫克）添加至Z (682毫克，2.23毫莫耳）在MeOH (55毫升）中之溶液内。將混合物於大氣及室溫下攪拌過 仪’並經過矽藻土過濾。濃縮濾液，並使產物在Η V中，於 8〇°C下乾燥3小時，而得標的化合物，為白色固體泡沫物（465 毫克’ 75%產率，&gt;99%純，藉LC-MS)(計算之質量·· 275， 發現之質量：191 (M-tBu-N2)+)。 1(5-(3-氟基-5-嗎福啉基苯甲醯胺基）_2-甲基吡啶各 基）·1Η_1，2,3-三唑_4_羧酸第三·丁酯·步驟L將3_氟基_5_嗎 福啉基苯曱酸I_a(762毫克，3.38毫莫耳，2〇當量）、氯化草 醯（10毫升）、DCM (5毫升）及DMF (〜10微升）之混合物於40〇c 下攪拌2_3小時。使透明溶液濃縮，並在80°C下，在HV中乾 燥’而得固體氣化氟基_5_嗎福啉基苯甲醯。 步驟2·將此化合物（3.38毫莫耳，2·〇當量）在1〇^ (5毫 升）中之/谷液逐滴添加至1_(5·胺基_2_甲基？比σ定各基）_ιη-1，2,3_ 123505 -270- 200815422 一哇-4-羧酸弟二-丁酯（465毫克，169毫莫耳）、DIEA (1.77毫 升，10.13毫莫耳，6當量）及DCM (1〇毫升）之經攪拌溶液中。 將混合物於室溫下攪拌過夜，然後添加Na〇H水溶液（25%， 50耄升）’並以DCM萃取產物。使有機層脫水乾燥（N% go#)， 及濃縮。將粗產物使用管柱層析純化（矽膠梯度液：在dcm 中之0 3/。MeOH)，而付標的化合物（749毫克，91%產率，98% 純，藉LC-MS)，為褐色固體泡沫物（計算之質量·· 4幻，發 現之質量：399, 483)。 氟基-5_嗎福啉基苯甲醯胺基）_2_甲基吡啶各 基）-1Η-1，2,3-三唑斗羧酸·將得自上文之化合物（749毫克， 1_55毫莫耳）在TFA-H2〇 (95 : 5，10毫升）中之溶液於室溫下 攪拌2小時，並濃縮。使殘留物溶於AcN (1〇毫升）中，濃縮， 且使所獲得之殘留物在HV中乾燥。將粗產物與乙驗（4〇毫 升）一起攪拌，藉過濾分離固體，以乙醚洗滌，並在^中 乾燥，而得標的化合物（582毫克，88%產率，&gt;99%純，藉 LC-MS)，為褐色固體（計算之質量·· 426，發現之質量：355 (MH-C02-N2)+) 〇 1-(5_(3-氟基_5_嗎福啉基苯甲醯胺基&amp;甲基吡啶； 基）-Ν·((四氫呋喃_2_基）甲基）qjj-y少三唑冬羧醯胺·將四 虱呋喃甲基胺（93微升，〇·9〇毫莫耳，2·4當量）添加至36(162 毫克，0·38毫莫耳）、Β0Ρ (531毫克，12〇毫莫耳，3·2當量） 及DCM (5耄升）之混合物中，接著添加微升，2仙 笔莫耳，6.3當量）。將混合物於室溫下攪拌3小時，然後添 加TFA(46毫升，0.60毫莫耳，u當量）、Η2〇(ι〇〇微升）及撕〇11 123505 -271 - 200815422 以使過量BOP水 度液·H5-Amino-2-pyridylpyridinyl)_1H-1,2,3-triazole_4_carboxylic acid ____ Add 阮Ni Nickel (~3〇〇mg) to Z (682 Mg, 2.23 mmoles in MeOH (55 mL). The mixture was stirred in the atmosphere at room temperature and filtered through celite. The filtrate was concentrated and the product was dried in EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc (Quality of calculation · 275, quality found: 191 (M-tBu-N2)+). 1(5-(3-Fluoro-5-morphobolinylbenzimidyl)_2-methylpyridine each)·1Η_1,2,3-triazole_4_carboxylic acid tert-butyl ester· Step L: 3_Fluoro-5-homofolinylbenzoic acid I_a (762 mg, 3.38 mmol, 2 〇 equivalent), chlorinated hydrazine (10 ml), DCM (5 ml), and DMF (~ A mixture of 10 μl) was stirred at 40 ° C for 2 to 3 hours. The clear solution was concentrated and dried in HV at 80 ° C to give a solidified vaporized fluoro-5-norfosyl benzamidine. Step 2· Add this compound (3.38 mmol, 2·〇 equivalent) in 1 〇^ (5 mL)/mL solution dropwise to 1_(5·Amino_2_methyl? Base)_ιη-1,2,3_ 123505 -270- 200815422 a butyl 4-carboxylic acid di-butyl ester (465 mg, 169 mmol), DIEA (1.77 ml, 10.13 mmol, 6 equivalents) and DCM (1 mL) in a stirred solution. The mixture was stirred at room temperature overnight, then aqueous Na.sub.2H (25%, 50 liters) was then taken and the product was extracted with DCM. The organic layer was dried (N% go#) and concentrated. The crude product was purified using column chromatography (EtOAc: EtOAc: EtOAc: EtOAc, EtOAc, EtOAc Solid foam (calculated quality · 4 illusion, found quality: 399, 483). Fluoro-5-morpholinobenzimidino)_2-methylpyridinyl)-1Η-1,2,3-triazole carboxylic acid·The compound obtained from above (749 mg, 1-55) The solution in TFA-H2 (95: 5, 10 mL) was stirred at room temperature for 2 hr and concentrated. The residue was dissolved in AcN (1 mL), concentrated, and the obtained residue was dried in HV. The crude product was stirred with EtOAc (4 mL). EtOAcjjjjjjjjjjjjjjjjjjj -MS), as a brown solid (calculated mass · 426, found mass: 355 (MH-C02-N2)+) 〇 1-(5-(3-fluoroyl_5_morpholinobenzamide) Base &methylpyridine; yl)- Ν·((tetrahydrofuran-2-yl)methyl)qjj-y-triazol winter carboxamide 将tetrahydrofuranmethylamine (93 μl, 〇·9〇 Millol, 2.4 eq) added to a mixture of 36 (162 mg, 0·38 mmol), Β0Ρ (531 mg, 12 〇 mmol, 3.2 eq) and DCM (5 liters) Then add microliters, 2 centimeters, 6.3 equivalents). The mixture was stirred at room temperature for 3 hours, then TFA (46 mL, 0.60 mmol, u eq), Η 2 〇 (ι 〇〇 升), and 〇 11 123505 -271 - 200815422 were added to allow excess BOP hydration liquid·

(2毫升）’並將混合物於室溫下攪拌過夜，以使過量B〇p水 解。浪縮混合物，並將殘留物使用預備之RP-HPLC純化（梯 度液·在H2〇中之30-50% AcN)。使經濃縮之溶離份以2M k：2C〇3水溶液（50毫升）中和，及DCM萃取，提供標的產物之 自由悲驗（137毫克，70%產率，&gt;99%純，藉LC-MS)(計算之 質量·· 510，發現之質量：482, 51〇)。 使用類似方法，製成下列化合物： Ν_(5·(4-第三-丁基_ih_1，2,3-三唑-1_基）-6_甲基外b咬_3_基）-3-氟 基-5·嗎福啉基苯甲醯胺（計算之質量：439 ;發現之質量： 411，439); 3-氟-N-(6_甲基-5-(4-(吡啶-2-基）-1Η_1，2,3-三唑小基风啶-3- 基）·5_嗎福啉基苯甲醯胺（計算之質量：459·5 ;發現之質量： 432, 460); 氟-Ν-(5_(4·(曱氧基甲基）_ιη_1，2,3·三唑_1_基）_6_甲基咕咬各 基)_5_嗎福淋基苯甲醢胺（計算之質量·· 426 ;發現之質量·· 399, 427). 途徑Β ··經由L2-Q之偶合至經保護核心模板(2 ml)' and the mixture was stirred at room temperature overnight to allow excess B〇p to be hydrolyzed. The mixture was stirred in a wave and the residue was purified using preparative RP-HPLC (gradient solution: 30-50% AcN in H2). The concentrated fractions were neutralized with 2 M k: 2 C 3 aqueous solution (50 mL) and extracted with DCM to afford the free product of the product (137 mg, 70% yield, &gt; 99% pure, by LC- MS) (quality of calculation · 510, quality found: 482, 51 〇). Using a similar method, the following compounds were prepared: Ν_(5·(4-Terve-butyl_ih_1,2,3-triazol-1-yl)-6-methyl external b-bit_3_yl)-3 -Fluoro-5-morpholinobenzamide (calculated mass: 439; mass found: 411, 439); 3-fluoro-N-(6-methyl-5-(4-(pyridine- 2-yl)-1Η_1,2,3-triazole small oxaridin-3-yl)·5_morpholinebenzamide (calculated mass: 459·5; quality found: 432, 460) Fluorine-Ν-(5_(4·(曱oxymethyl)_ιη_1,2,3·triazole_1_yl)_6_methyl 咕 各 ) ) ) ) _ ( ( ( ( ( Quality of Calculation·· 426; Quality of Discovery·· 399, 427). Route Β ··Coupling to protected core template via L2-Q

123505 -272- 200815422 1·(2_甲基_5·破基吡啶-3_基三唑斗羧酸·將z (843 笔克，2.76耄莫耳）在TFA-H2 Ο (95 ·· 5，10毫升）中之溶液在 至溫下攪拌2小時，濃縮，溶於acN (1〇毫升）中，濃縮，及 在HV中乾燥。將粗產物與乙醚（4〇毫升）一起攪拌，藉過濾 分離固體，以乙醚洗滌，並於HV中乾燥，而得標的化合物 (639毫克，92%產率，&gt;95%純，藉LC-MS-未偵測到物質）， 為褐色固體。1H-NMR (500 MHz，DMSO-d6) 5 (ppm) 13_42 (bs，1H)， 9.48 (d，J = 2·5 Hz，1H)，9.24 (s，1H)，8·89 (d，J = 2·5 Hz，1H)，2·54 (s， 3H). ， M2甲基-5-石肖基峨咬_3·基）_N-新戊基_lH_l，2,3i唾_4邊醯 私·將新戊基胺（358微升，3.00毫莫耳，2.1當量）添加至上 述化合物（363毫克，1.46毫莫耳）、ΒΟΡ (1.77克，4.00毫莫耳， 2.7當量）及DCM (12毫升）中之混合物内，接著添加DIEA (139 毫升’ 8.00毫莫耳，5.5當量）。將混合物於室溫下授拌3〇分 鐘，然後添加2M NaOH水溶液（20毫升），以DCM萃取產物， 使有機層脫水乾燥（NasSO4)，及濃縮。將粗產物使用管柱層 析純化（矽膠，梯度液：在DCM中之0_10% MeOH)。為移除 殘留之BOP，使經純化之產物懸浮於熱Me〇H (2〇毫升）中， 並添加醋酸銨（2.0克）在(5毫升）中之溶液。於室溫下擾 拌1小時後，藉過濾分離固體，以H20洗滌，風乾，並在HV 中乾燥，而得純標的化合物（377毫克，81%產率，&gt;99%純， 藉LC-MS)，為白色固體（計算之質量：318，發現之質量： 291 (MH-N2)+, 360 (MH+AcN)+) 〇 1-(5-胺基-2-甲基吡啶-3-基）_N_新戊基-1H-1，2,3-三唑-4·羧醯 123505 -273 - 200815422 fe ·將阮尼鎳（〜300毫克）添加至上述化合物（375毫克，i.i8 毫莫耳）在EtOAc (40毫升）與EtOH (40毫升）之混合物中之溶 液内。將混合物在Η?大氣及室溫下攪拌過夜，並經過石夕藻 土過濾。濃縮濾液，並使產物在HV中乾燥，而得標的化合 物，為白色固體（284毫克，83%產率，&gt;99%純，藉LC-MS)(計 算之質量：288，發現之質量：261，289, 330, 352)。 1-(5-(3-第二-丁基_5_氣基苯甲酿胺基）-2-甲基ί»比唆-3-基）-N_ 新戊基·1Η-1，2,3-三唑-4-叛醯胺·將氣化3-第三-丁基-5-氰基 苯曱醯F (0.60毫莫耳，1.5當量）在DCM (5毫升）中之溶液， 逐滴添加至上述化合物（115毫克，〇·4〇毫莫耳）、DIEA (279 微升，1.60毫莫耳，4.0當量）及DCM (5毫升）之經攪拌溶液 中。將混合物於室溫下攪拌過夜，然後添加2Μ NaOH水溶 液（50毫升），並以DCM萃取產物。將有機層以h2〇 (1〇〇毫升） 洗滌’脫水乾燥（N&amp;2 SO4 )，及濃縮。將粗產物使用預備之 RP-HPLC純化（梯度液：在H2〇中之50-80% AcN)。使經濃縮之 溶離份以2M &amp; CO3水溶液（50毫升）中和，及DCM萃取，提 供標的產物之自由態鹼（118毫克，62%產率，&gt;99%純，藉 LC-MS)(计异之質量：474，發現之質量：446, 474)。123505 -272- 200815422 1·(2_Methyl_5·pyridylpyridin-3-yltriazole carboxylic acid·Z (843 gram, 2.76 耄mol) in TFA-H2 Ο (95 ·· 5 The solution was stirred at room temperature for 2 hours, concentrated, dissolved in EtOAc (1 mL), concentrated, and dried in HV. The crude product was stirred with diethyl ether (4 mL). The solid was isolated, washed with diethyl ether and dried EtOAc EtOAcjjjjjjjjjj NMR (500 MHz, DMSO-d6) 5 (ppm) 13_42 (bs, 1H), 9.48 (d, J = 2·5 Hz, 1H), 9.24 (s, 1H), 8·89 (d, J = 2 · 5 Hz, 1H), 2·54 (s, 3H). , M2 methyl-5-Shi Xiaoji bite _3· base)_N-neopentyl _lH_l, 2, 3i salivation _4 side privately Neopentylamine (358 μL, 3.00 mmol, 2.1 equivalents) was added to the above compound (363 mg, 1.46 mmol), hydrazine (1.77 g, 4.00 mmol, 2.7 eq.) and DCM (12 mL) In the mixture, DIEA (139 ml '8.00 mmol, 5.5 equivalents) was added. The mixture was stirred at room temperature for 3 hrs, then aq. EtOAc (EtOAc)EtOAc. The crude product was purified by column chromatography (gluent, gradient: 0-10% MeOH in DCM). To remove residual BOP, the purified product was suspended in hot MeH (2 mL) and a solution of ammonium acetate (2.0 g) in (5 mL) was added. After 1 hour of stirring at room temperature, the solid was isolated by filtration, washed with H20, dried, and dried in HV to give the pure compound (377 mg, 81% yield, &gt;99% pure, by LC- MS) as a white solid (mass calculated: 318, found mass: 291 (MH-N2)+, 360 (MH+AcN)+) 〇 1-(5-Amino-2-methylpyridine-3- Base)_N_neopentyl-1H-1,2,3-triazole-4·carboxylate 123505-273 - 200815422 fe ·Addition of sini Nickel (~300 mg) to the above compound (375 mg, i.i8 Milliol) in a solution of a mixture of EtOAc (40 ml) and EtOH (40 mL). The mixture was stirred overnight at room temperature and at room temperature and filtered through celite. The filtrate was concentrated and the product was dried in EtOAc EtOAc (EtOAc: EtOAc: 261, 289, 330, 352). 1-(5-(3-Second-butyl_5_ylbenzoylamino)-2-methyl ί»比唆-3-yl)-N_neopentyl·1Η-1,2, a solution of 3-tris-butyl-5-cyanobenzoquinone F (0.60 mmol, 1.5 eq.) in DCM (5 mL) A dropwise addition to the above compound (115 mg, 〇·4 mmol), DIEA (279 μL, 1.60 mmol, 4.0 eq.) and DCM (5 mL) was applied. The mixture was stirred at room temperature overnight, then aq. The organic layer was washed with EtOAc (1 mL) and dried (N & The crude product was purified using preparative RP-HPLC (gradient: 50-80% AcN in H.sub.2). The concentrated fractions were neutralized with aq. EtOAc (EtOAc) (EtOAc) (The quality of the difference: 474, the quality found: 446, 474).

甲基-1-(1-(2-甲基-5-硝基吡啶-3-基）-1Η_1，2,3-三唑_4_基）丁 •1-酮· 將Dess-Martin過峨烷（167毫克，0.398毫莫耳，1_2當量） 123505 -274- 200815422 添加至3-甲基小(1-(2·曱基-5-硝基吡啶各基）-1Η-1，2,3_三嗤-4-基）丁小醇W_a (99毫克，0.340毫莫耳，1.0當量）在DCM (5毫 升）中之溶液内，並將混合物於室溫下攪拌過夜。添加乙喊 (50毫升），並將有機層以Na2S203水溶液（2M，50毫升）、k2C03 水溶液（2M，50毫升）及水（50毫升）洗滌。使合併之有機層 脫水乾燥（Na2S〇4)，在真空中濃縮，並於HV中乾燥，而得 粗製標的產物（96毫克，94%純，藉LC-MS)(計算之質量： 289，發現之質量：206)。4 NMR (500 MHz，DMSOd6) δ (ppm) 9.48 (d，J = 2·4 Hz，1H)，9.31 (s，1H)，8.90 (d，J = 2·4 Hz，1H)，2.97 (d，J =7.0 Hz，2H)，2.55 (s，3H)，2.26 (m，1H)，0.97 (d，J = 6·7, 6H)· 1-(1-(5-胺基_2-甲基外I;咬_3-基）-lH-l，2,3_三嗤-4·基）·3·»甲基丁 小酮·將阮尼鎳（〜300毫克）添加至上文獲得之化合物（96 毫克，0.332毫莫耳）在MeOH (4毫升）中之溶液内。將混合物 於H2大氣及室溫下攪拌2小時，並經過矽藻土過濾。使滤 液濃縮，並在HV中乾燥，而得標的產物（75毫克，94%純， 藉LC-MS)(什异之質量：259，發現之質量：232)。 3-第二·丁基 _5_氰基-Ν-(6·甲基 _5_(4_(3_ 甲基 丁醯基）4Η-1，2,3-二唑-1-基）吡啶·3-基）苯甲醯胺·將氣化3-第三_丁基_5·氰基 苯甲醯F(70.5毫克’ 〇·318毫莫耳，u當量）添加至上文獲得 之化合物（75毫克，0.289毫莫耳，L〇當量）與DffiA(i2i微升， 0.694笔莫耳，2.4當量）在DCM (2毫升）中之經授拌溶液内。 將混合物於室溫下攪拌2小時，接著添加2MK2C〇3水溶液（5 毫升）’並以DCM(50毫升）萃取產物。將有機層以水（ι〇〇毫 升）洗滌，脫水乾燥（N^SO4)，及濃縮。將粗產物使用預備 123505 -275 - 200815422 之RP-HPLC純化（在Ο中之40-80% AcN) ’而得純產物（31 7毫 克，99%純，藉LC-MS)(計算之質量：444，發現之質量：417Methyl-1-(1-(2-methyl-5-nitropyridin-3-yl)-1Η_1,2,3-triazole-4-yl)butan-1-one · Dess-Martin Alkane (167 mg, 0.398 mmol, 1_2 equivalent) 123505 -274- 200815422 Add to 3-methyl small (1-(2·indolyl-5-nitropyridine)-1Η-1,2,3 _Trisin-4-yl) Butanol W_a (99 mg, 0.340 mmol, 1.0 eq.) After the addition of EtOAc (50 mL), EtOAc (EtOAc m. The combined organic layers were dried (Na2SO4), concentrated in vacuo, and dried in EtOAc to give the crude product (96 mg, 94% pure, by LC-MS) (calculated quality: 289) Quality: 206). 4 NMR (500 MHz, DMSOd6) δ (ppm) 9.48 (d, J = 2·4 Hz, 1H), 9.31 (s, 1H), 8.90 (d, J = 2·4 Hz, 1H), 2.97 (d , J = 7.0 Hz, 2H), 2.55 (s, 3H), 2.26 (m, 1H), 0.97 (d, J = 6·7, 6H)· 1-(1-(5-Amino-2-A) Extra-base I; bite_3-yl)-lH-l,2,3_tris--4.yl)·3·»methylbutanone·Febrication of sulphonic nickel (~300 mg) Compound (96 mg, 0.332 mmol) in MeOH (4 mL). The mixture was stirred at room temperature under H2 for 2 h and filtered over Celite. The filtrate was concentrated and dried in HV to give the title product (75 mg, 94% pure, by LC-MS) (small mass: 259, mass found: 232). 3-Secondylbutyl-5-cyano-indole-(6.methyl_5_(4_(3-methylbutenyl)4Η-1,2,3-oxadiazol-1-yl)pyridine-3-yl Benzoguanamine · Gasification of 3-tris-butyl-5 cyanobenzamide F (70.5 mg '〇·318 mmol, u equivalent) was added to the compound obtained above (75 mg, 0.289) Millol, L 〇 equivalent) and DffiA (i2i microliter, 0.694 moles, 2.4 equivalents) in a stirred solution in DCM (2 mL). The mixture was stirred at room temperature for 2 hr then EtOAc (EtOAc)EtOAc. The organic layer was washed with water (m.sub.1 liter), dried (N^SO4), and concentrated. The crude product was purified using RP-HPLC (40-80% AcN in EtOAc) from &lt;RTI ID=0.0&gt;&&&&&&&&&&&&&&& 444, the quality of the discovery: 417

2-(1_(5_胺基-2-甲基p比唆-3-基）-1Η_1，2,3-三唾-4_基）_2_甲基丙 /2-(1_(5-Amino-2-methylp is indole-3-yl)-1Η_1,2,3-tris-7-yl)_2-methylpropane /

酸· 將絶/碳（1〇%，〜500毫克）添加至2-甲基-2-(1-(2-甲基-5· 石肖基说0定-3-基）-1Η-1，2,3_三唾-4-基）丙酸爷酯W-b (277毫克， 0.726毫莫耳）在MeOH (7毫升）中之溶液内。將混合物在％ 大氣及50 C下擾拌3天，並經過石夕藻土過濾。使濾液濃縮， 並在HV中乾無，而得標的產物（ho毫克）（計算之質量： 261，發現之質量：234)。 2-(1-(5-胺基-2-甲基吡啶_3_基）_ih-1，2,3_三唑_4_基）_2_甲基 新戊基丙醯胺·將新戊基胺（478微升，4.00毫莫耳，9.5當 量）添加至上文獲得之化合物（H0毫克，0.421毫莫耳，1〇當 K )、BOP (442毫克，ΐ·〇〇毫莫耳，2 4當量）及DCM (5毫升） 之混合物中。將混合物於室溫下攪拌15小時，然後在真空 中濃縮’以移除過量胺。為移除殘留之Bop，使殘留物溶 於DCM (5毫升）中，並添加醋酸銨（1·26克）在水（5毫升）中之 123505 -276- 200815422 溶液。於室溫下攪拌30分鐘後，將有機層以水洗務，脫水 乾燥（N^SO4)，濃縮，並在HV中乾燥，而得標的產物（116 毫克’ 93%純’藉LC-MS)(計异之質量：330，發現之質量： 303 (MH-N2)+)。 3_第二-丁基_5_氰基_Ν·(6·甲基_5_(4_(2_甲基小(新戊基胺 基）-1_酮基丙烧_2_基）_111-1，2,3_三唑_1_基）峨咬I基）苯甲醯胺 將氯化3-第三-丁基-5-氰基苯甲醯F (56毫克，0·250毫莫耳， 1·4 ¥里）添加至上文獲得之化合物（58毫克，ο」％毫莫耳， ( 1·〇當量）、DIEA (87微升，0.500毫莫耳，2·8當量）及DCM (5 宅升）之經攪拌溶液中。將混合物於室溫下攪拌過夜，然後 添加2M K：2C〇3水溶液（20毫升），並以DCM (5〇毫升）萃取產 物。將有機層以水（1〇〇毫升）洗滌，脫水乾燥（N々s〇4 )，及 濃縮。將粗產物使用預備之RP丄C_MS純化（在h2〇中之 50-60% AcN)，而得純標的產物（3〇·6毫克，98%純，藉lc_ms) (計异之質量：515，發現之質量·· 488 (MH-N2)+)。Acid · Add absolute/carbon (1〇%, ~500mg) to 2-methyl-2-(1-(2-methyl-5·石肖基说0定-3-yl)-1Η-1,2 , 3_Trisept-4-yl)propionate Wb (277 mg, 0.726 mmol) in MeOH (7 mL). The mixture was scrambled at % atmosphere and 50 C for 3 days and filtered through Shixia. The filtrate was concentrated and dried in HV to yield the title product (ho s) (mass calculated: 261, mass found: 234). 2-(1-(5-Amino-2-methylpyridine-3-yl)_ih-1,2,3-triazole-4-yl)_2-methyl-p-pentylpropanamine The amine (478 μl, 4.00 mmol, 9.5 equivalent) was added to the compound obtained above (H0 mg, 0.421 mmol, 1 〇K), BOP (442 mg, ΐ·〇〇 mmol, 2 Mixture of 4 equivalents) and DCM (5 ml). The mixture was stirred at room temperature for 15 hours and then concentrated in vacuo to remove excess amine. To remove the residual Bop, the residue was dissolved in DCM (5 mL) and EtOAc (EtOAc) After stirring at room temperature for 30 minutes, the organic layer was washed with water, dried and dried (N^SO4), concentrated, and dried in HV to give the product (116 mg '93% pure' by LC-MS) The quality of the difference: 330, the quality found: 303 (MH-N2) +). 3_Second-butyl_5_cyano_Ν·(6·methyl_5_(4_(2_methyl small (neopentylamino)-1 ketopropenyl-2-yl)_111 -1,2,3_triazol_1_yl) bite I base) benzamide will chlorinate 3-tris-butyl-5-cyanobenzamide F (56 mg, 0. 250 m Moore, 1·4 ¥)) added to the compound obtained above (58 mg, ο"% millimolar, (1·〇 equivalent), DIEA (87 μl, 0.500 mmol, 2.8 equivalent) and The mixture was stirred at room temperature overnight. The mixture was stirred at room temperature overnight, then 2M K: 2 C 3 aqueous solution (20 ml) was added and the product was extracted with DCM (5 mL). Wash the water (1 ml), dehydrate dry (N々s〇4), and concentrate. Purify the crude product using the preparative RP丄C_MS (50-60% AcN in h2〇) to give the pure product. (3〇·6 mg, 98% pure, borrowed lc_ms) (Quality of the difference: 515, quality found 488 (MH-N2)+).

123505 •277- 200815422 途徑c :經由吡啶環之形成123505 •277- 200815422 Route c: formation via a pyridine ring

方法Α· 1-疊氮基丙I醇·將2_甲基環氧乙烷(4.5毫升，3.2 克’ 55毫莫耳，〇·7當量）添加至疊氮化鈉（5.15克，79毫莫耳， 1·〇當量）之溶液中，並將混合物攪拌40分鐘。添加另一份2_ 甲基環氧乙烧（1.0毫升，0.7克，12毫莫耳，0·16當量），並 ( 將溶液於室溫下留置過夜。然後，將產物於EtOAc中萃取， 脫水乾燥（MgSCU)，及蒸發，提供3.7克（55%產率）濃稠油， 其在靜置時固化。1H-NMR (500 MHz，DMSO_d6) 5 (ppm) 498 (d， 1H)，3·79 (m，1H)，3.14 (dd，1H)，3.09 (dd，1H)，1·〇6 (d，3H) ; iH-NMR (CDC13) 3 (ppm) 3.97 (m，1H)，3.35 (dd，1H)，3.23 (dd，1H)，1.23 (d，3H)· 1-(2-經丙基）-1Η-1，2,3·三嗤_4_叛酸甲酯· 使1-疊氮基丙-2- 醇（2.81克，28毫莫耳，1.0當量）溶於AcN (40毫升）與水（8毫 升）中。以二份添加丙炔酸甲酯（90%最初及10。/〇在2小時下） 123505 -278 - 200815422 (3·〇克，36毫莫耳，1.3當量），並將混合物於6〇°c下，在Cu 線存在下攪拌。4小時後，反應已完成。移除Cu線，並使 殘留物蒸發，而產生3.63克（70%)綠色油，將其使用於下一 反應，無需進一步純化。1 H_NMR (500 MHz，DMSO-d6 ) 5 (ppm) 8.64 (s，1H)，5.07 (d5 1H)，4.40 (dd，1H)，4.26 (dd，1H)，4.02 (m，1H)，3·83 (d，3H)，1.07 (d，3H). 1-(2-經丙基）·Ν-新戊基-1H-1，2,3-三嗤-4·叛醯胺·使1-(2-經 丙基）-1Η_1，2,3-三唑_4_羧酸甲酯（3.63克，20毫莫耳，ΐ·〇當量） 溶於MeOH (12毫升）中。添加新戊基胺（2」克，24毫莫耳， 1.2當量）’並將混合物在密閉管件中，於ι〇〇^下加熱過夜。 藉LC-MS監測反應，且此時完成。蒸發反應混合物，並在 咼真空中乾燥，而產生4.53克（96%)綠色油，將其使用於下 一反應，無需進一步純化。iH-NMR (500 MHz，DMSO-d6) 5 (ppm) 8.42 (s，1H)，8·24 (t，1H)，5.08 (bs，1H)，4.38 (dd，1H)，4.25 (dd，1H)，4·〇2 (bs，1H)，3·08 (d，2H)，1·07 (d，3H)，0.88 (s，9H)· N-新戊基小(2-酮基丙基）_ih_1，2,3-三哇-4_竣醯胺·使1-(2-經丙基）-N_新戊基-1H-1，2,3-三唾-4-羧醯胺（600毫克，2.5毫莫 耳，1.0當量）溶於DCM (8毫升）中。添加Dess Martin過碘烷 (1·Π克，2·8毫莫耳，L1當量），並將混合物攪拌直到反應 已完成（〜2小時）為止。藉TLC監控反應，且於此時完成。將 反應混合物以EtOAc稀釋，並以25毫升1MNa2S2〇3與飽和水 溶液NaHC〇3之混合物〇 ··丨）、飽和水溶液NaHC〇3，及以鹽 水洗滌，脫水乾燥（jy[gS〇4)，蒸發，並在高真空中乾燥，而 產生 390 毫克（66%)產物。1H-NMR (500 MHz，DMSO-d6 ) 5 (ppm) 123505 -279- 200815422 8·38 (s，1H)，8.29 (t，1H)，5.54 (s，2H)，3.31 (s，2H)，3·09 (d，2H)，1.98 (s， 3H)，0.88 (s，9H). 方法Β· 1-吞氮基丙-2-嗣係根據報告程序，製自氯丙自同。 參閱 J· Chem. Soc. 1908, 93, 72 或 Eur. J. 〇rg. Chem. 2005, 4141。於 疊氮化鈉之經濃縮水溶液（78克，1.2莫耳）中，在〇°C下添加 氯丙酮（74克，0.8莫耳）與數滴冰醋酸。將所形成之混合物 於室溫下攪拌24小時。在反應完成後，以乙醚萃取混合物。 使合併之醚層以無水Na2S〇4脫水乾燥，並蒸發，提供粗製 標的產物（64克，81%)，為油狀物，將其使用於下一步驟， 無需進一步純化。1H NMR (500 MHz，CD2C12) 5 (ppm) 3.97 (s， 2H)，2.19 (s，3H). 13C NMR (CD2C12) (5 (ppm) 202.1，58.1，27.2. N_新戊基-1-(2-酮基丙基）-1Η-1，2,3·三嗤-4-敌醯胺· 將上述 化合物（46.5克，47毫莫耳）與N-新戊基丙炔醯胺V (51克，36 毫莫耳）在AcN (1200毫升）與水（120毫升）之混合物中之溶 液’於催化量之Cu粉末存在下加熱至回流，歷經6小時。 在反應完成後’過遽反應混合物。蒸發濾、液，並將殘留物 藉管柱層析純化，經由EtOAc : PE = 1 : 1溶離，提供標的化 合物，為白色固體（70克，82%)。 1-(2-甲基-5-頌基p比唆_3-基）_N_新戊基-1H-1，2,3_三唾·4_叛醯 胺·將得自前一步驟之化合物（84克，0.353莫耳）、$肖基丙 二醛鈉鹽（88克，0.635莫耳）、醋酸銨（244克，3莫耳）、Et〇H (1200毫升）及水（1200毫升）之混合物加熱至8〇°C，並攪拌18 小時。在反應完成後，過濾混合物，以收集固體。蒸發遽 液，以移除EtOH，並將殘留物以EtOAc萃取。使合併之扭〇Ac 123505 •280- 200815422 層以無水Nassef脫水乾燥，及蒸發。使殘留物與所獲得之 固體藉官柱層析純化，以EtOAc : PE = 1 : 3溶離，提供標的 化合物，為白色固體（33克，3〇%)。 胺基I甲基吡啶基）)(1，2,3-三唑-4-基）】-N-(2,2-二曱基 丙基）叛酿胺·於得自前一步驟之化合物（33克，0.104莫耳） 在Me〇H (1·2升）中之溶液内，添加10% Pd/C (16克）。使混合 物在％大氣及室溫下反應3小時。在反應完成後，過濾混 合物。蒸發濾液，提供粗製標的化合物（28.8克，96%)，將 其使用於下一步驟，無需進一步純化。 1-(5-(3_第三·丁基_七氰基苯甲醯胺基）_2_甲基吡啶各基）_Ν· 新戊基-1Η_1，2,3_三唑_4_羧醯胺·於化合物Ε (20.7克，102毫 莫耳）在DCM (400毫升）中之溶液内，在〇°c下逐滴添加氯化 草醯（48.7毫升）與催化量之DMF。將混合物於室溫下攪拌2 小時，然後蒸發。使殘留物再一次溶於DCM (200毫升）中， 並在0°C下添加至上文獲得之化合物（28.8克，100毫莫耳）與 DIEA (87毫升）在DCM (400毫升）中之混合物内。將混合物於 室溫下攪拌3小時。於真空中移除溶劑，並將殘留物藉管柱 層析純化（PE ·· EtOAc=4 : 1)，而得標的化合物（30.5克，64%)， 為黃色固體。1H NMR (CDC13，300 MHz) 5 (ppm) 8.86-8.90 (d，2H)， 8.45-8.46 (d，1H)，8.26-8.28 (m，2H)，8.13-8.14 (t，1H)，7·85-7·86 (t，1H)， 7.35-7.40 (t，1H)，3.26-3.28 (d，2H)，2·45 (s，3H)，1·36 (s，9H)，0.98 (s，9H)· (計算之質量：473.6，發現之質量·· 474.2). 方法C·甲苯磺酸丙酮醇酯·在500毫升燒瓶中，使丙酮 醇（6.86毫升，7.41克，0.100莫耳，1.0當量）與吡啶（30毫升） 123505 -281 - 200815422 之混合物於冰鹽浴中冷卻至&lt;〇°C。將氣化對-甲苯磺醯（20.74 克，0.109莫耳’ 1.1當量）在吡唆（7〇毫升）中之溶液，在内部 溫度&lt;〇°C下逐滴添加至燒瓶中，歷經〜2小時。將混合物於 &lt;〇°C下攪拌30-40分鐘，然後添加冷水（25〇毫升）與6M HC1水 溶液（250 4:升）。以DCM萃取混合物，將合併之有機層以iM H2S〇4、水洗滌，脫水乾燥（Na2S04)，及在真空中濃縮。粗 產物（9.281克’ 41%產率）（96%純，藉LC_MS 1H NMR)為琥珀 色油，其係於靜置時，在室溫下變暗色，且其可藉真空蒸 ί 餾純化。1 H NMR (500 MHz，CD2 Cl2 ) 5 (ppm) 7·82 (d，J = 8 Ηζ，2Η)， 7.42 (d，J = 8 Hz，2H)，4.52 (s，2H)，2.48 (s，3H)，2.18 (s，3H)· 1-疊氮基丙-2-酮·製備兩種溶液如下：溶液A:甲苯磺酸 丙酮醇酯（4.71克，20·6毫莫耳，ΐ·〇當量）在Et〇H (21毫升）與 醋酸（2.36毫升，41.3毫莫耳，2.0當量）中，與溶液b :疊氮 化鈉（2.68克，41_3毫莫耳，2.0當量）在水（8·2毫升）中。使溶 液Α與Β冷卻至0°C，合併，並在〇它（於冷藏室）中保持3天。 起始物質之消失係藉由分析LC-MS追蹤。添加水（500毫 v 升），並以乙醚萃取產物。將合併之有機層以飽和NaHC03 水溶液洗滌，脫水乾燥（Na〗SO4)，及在真空中濃縮。使粗產 物於50°C下，使用高真空，在矽藻土蒸餾裝置中蒸顧。使 用丙酮-乾冰混合物，使收集球冷卻。純產物（〇·791克，39% 產率，&gt;95%純，藉1HNMR)，為揮發性無色至琥珀色液體。 lR NMR (500 MHz5 CD2C12) δ (ppm) 3.97 (s? 2H)? 2.19 (s? 3H) 13CNMR (CD2C12) 5 (ppm) 202.1，58.1，27.2. N-新戊基小(2-酮基丙基）_1H-1，2,3-三唑_4_羧醯胺·將上文 123505 -282 - 200815422 獲得之1-疊氮基丙-2-酮（442毫克，4.47毫莫耳，ι ·2當量）鱼 Ν-新戊基丙醯胺（500毫克，3.59毫莫耳，1.〇當量）在八咖 毫升）與水（1.0毫升）之混合物中之溶液攪拌，並在密閉〗、玻 瓶中，於銅線存在下加熱至60°C，歷經4小時。於冷卻 v 1主室 溫後，移除銅，使混合物在真空中濃縮，並在PJV中乾於 而得粗產物，為灰白色固體（907毫克，定量產率，&gt;95%純， 藉LC-MS與1H NMR)(計算之質量：238，發現之質量：211 239)。1h NMR (500 MHz，DMSO-d6) 5 (ppm) 8.38 (s5 1Η)，8.29 (t j = 6.6 Hz，1H)，5·54 (s，2H)，3.09 (d，J = 6·6 Hz，2H)，2.23 (s，3H)，〇.88 (s 9H). lH NMR (500 MHz, CD2C12) δ (ppm) 8.11 (s5 1H)5 7.25 (bs5 1H) 5·3〇 (s，2H)，3_26 (d，J = 6.6 Hz，2H)，2.30 (s，3H)，1·〇〇 (s，9H). i3 C 難以 (CD2C12) (5 (ppm) 198.6, 160.0, 144.0, 127·0, 58·9, 50.3, 32.3, 27.2。粗 產物含有微量疊氮基丙酮（1H NMR)，其可藉由在hv中，於 高溫下長期乾燥或藉由結晶化作用移除。 1-(2-甲基_5_硝基吡啶_3_基）具新戊基-m-l，2,3-三唑_4_幾醯 胺·將上文獲得之化合物（106毫克，0.445毫莫耳，ι·〇當 量）、補基丙二醛鈉鹽（按上述製成）（62毫克，〇·445毫莫耳， 1.0當量）、醋酸銨（171毫克，2.224毫莫耳，5.0當量）、EtOH (0.5 耄升）及水（0.5毫升）之混合物攪拌，並於8〇^下，在密閉小 玻瓶中加熱8小時。形成深紅色溶液，且固體產物沉澱。於 冷卻至〇°c後，將已沉澱之固體過濾，以冷段〇11_水（1:丨）、 MeOH洗滌，風乾，及在hv中乾燥。灰色固體為純標的產 物（30·8宅克，22%產率，&gt;98%純，藉LC-MS與1H NMR)。或 者，使用1.5當量之硝基丙二醛鈉鹽，且反應係於⑼它下進 123505 200815422 行過夜。於冷卻後，將反應混合物以水（50毫升）稀釋，及 以DCM萃取產物。使合併之有機層脫水乾燥（Nas S04)，在真 空中濃縮，且將殘留物藉管柱層析純化（Si〇2，mo% EtOAc/DCM)，而得純產物，為淡黃色固體。產物亦可自Me〇H 或MeOH/水’精結晶純化（計鼻之質量：318，發現之質量： 204, 219, 245, 262)。1H NMR (500 MHz，DMSO-dg) (ppm) 9.47 (d，J =2.4 Hz，1H)，9·11 (s，1H)，8.88 (d，J = 2·4 Hz，1H)，8.53 (t，J = 6.6 Hz， 1H)，3.14 (d，J = 6·6 Hz，2H)，2.56 (s，3H)，0·92 (s，9H)· 1-(5-(3-第三-丁基-5_氣基苯甲醯胺基）-2-甲基p比咬_3_基）_n_ 新戊基·1Η-1，2,3_三嗤-4_致醯胺以前述方式合成。 途徑D:醯胺鏈結之替代取向Method Α·1-azidopropanol·2-methyloxirane (4.5 ml, 3.2 g '55 mmol, 〇·7 equivalent) was added to sodium azide (5.15 g, 79 m) Moore, 1·〇 equivalent) of the solution, and the mixture was stirred for 40 minutes. Add another portion of 2-methylepoxyacetone (1.0 mL, 0.7 g, 12 mmol, 0·16 eq.) and leave the solution at room temperature overnight. Then, the product is extracted in EtOAc, dehydrated Dry (MgSCU), and evaporated to provide 3.7 g (55% yield) of a thick oil that solidified upon standing. 1H-NMR (500 MHz, DMSO_d6) 5 (ppm) 498 (d, 1H), 3· 79 (m,1H), 3.14 (dd,1H), 3.09 (dd,1H),1·〇6 (d,3H); iH-NMR (CDC13) 3 (ppm) 3.97 (m,1H),3.35 ( Dd,1H), 3.23 (dd,1H), 1.23 (d,3H)· 1-(2-propyl)-1Η-1,2,3·三嗤_4_ oxic acid methyl ester · make 1- Azido propan-2-ol (2.81 g, 28 mmol, 1.0 eq.) was dissolved in AcN (40 mL) and water (8 mL). Methylpropynate was added in two portions (90% initially and 10) /〇 under 2 hours) 123505 -278 - 200815422 (3·〇克, 36 mmol, 1.3 equivalent), and the mixture was stirred at 6 ° ° C in the presence of Cu wire. After 4 hours, the reaction Completed. Remove the Cu line and allow the residue to evaporate to yield 3.63 g (70%) of green oil which was used in the next reaction without further purification 1 H_NMR (500 MHz, DMSO-d6) 5 (ppm) 8.64 (s, 1H), 5.07 (d5 1H), 4.40 (dd, 1H), 4.26 (dd, 1H), 4.02 (m, 1H), 3 ·83 (d,3H),1.07 (d,3H). 1-(2-propyl)-indole-neopentyl-1H-1,2,3-triterpene-4·treazone ·1 -(2-propyl)-1Η_1,2,3-triazole-4-carboxylic acid methyl ester (3.63 g, 20 mmol, ΐ·〇 equivalent) dissolved in MeOH (12 mL). Base amine (2 grams, 24 mmol, 1.2 equivalents)' and the mixture was heated in a closed tube under ι 〇〇 overnight. The reaction was monitored by LC-MS and completed at this time. Drying in a dry vacuum gave 4.53 g (yield: 96%) of green oil which was used in the next reaction without further purification. iH-NMR (500 MHz, DMSO-d6) 5 (ppm) 8.42 (s, 1H) ,8·24 (t,1H),5.08 (bs,1H), 4.38 (dd,1H), 4.25 (dd,1H),4·〇2 (bs,1H),3·08 (d,2H), 1·07 (d,3H),0.88 (s,9H)·N-neopentyl small (2-ketopropyl)_ih_1,2,3-three wow-4_decylamine ·1-(2) -propyl)-N_neopentyl-1H-1,2,3-tris-s-s-carboxamide (600 mg, 2.5 mmol) 1.0 equiv.) Was dissolved in DCM (8 mL). Dess Martin periodinane (1 gram, 2·8 mmol, L1 equivalent) was added and the mixture was stirred until the reaction was completed (~2 hours). The reaction was monitored by TLC and completed at this time. The reaction mixture was diluted with EtOAc and washed with 25 mL of 1M Na.sub.2.sub.3.sub.3 and saturated aqueous NaH.sub.3.sub.3. And dried under high vacuum to yield 390 mg (66%) of product. 1H-NMR (500 MHz, DMSO-d6) 5 (ppm) 123505 -279- 200815422 8·38 (s, 1H), 8.29 (t, 1H), 5.54 (s, 2H), 3.31 (s, 2H), 3.09 (d, 2H), 1.98 (s, 3H), 0.88 (s, 9H). Method Β 1- 1-Phenylpropan-2-indole is produced from chloropropene according to the reporting procedure. See J. Chem. Soc. 1908, 93, 72 or Eur. J. 〇rg. Chem. 2005, 4141. Chloroacetone (74 g, 0.8 mol) and a few drops of glacial acetic acid were added to a concentrated aqueous solution of sodium azide (78 g, 1.2 mol) at 〇 °C. The resulting mixture was stirred at room temperature for 24 hours. After the reaction was completed, the mixture was extracted with diethyl ether. The combined ether layers were dried <RTI ID=0.0></RTI> <RTI ID=0.0> 1H NMR (500 MHz, CD2C12) 5 (ppm) 3.97 (s, 2H), 2.19 (s, 3H). 13C NMR (CD2C12) (5 (ppm) 202.1, 58.1, 27.2. N_nepentyl-1- (2-ketopropyl)-1Η-1,2,3·tris-4-indoleamine· The above compound (46.5 g, 47 mmol) and N-neopentylpropynylamine V ( 51 g, 36 mmol) solution in a mixture of AcN (1200 ml) and water (120 ml) was heated to reflux in the presence of a catalytic amount of Cu powder for 6 hours. After the reaction was completed, the reaction was carried out. The mixture was evaporated, EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -5-颂基p比唆_3-yl)_N_neopentyl-1H-1,2,3_three saliva·4_trepromide·The compound from the previous step (84 g, 0.353 mol) ), a mixture of $Succinil malondialdehyde sodium salt (88 g, 0.635 mol), ammonium acetate (244 g, 3 mol), Et〇H (1200 ml) and water (1200 ml) heated to 8 ° ° C, and stirred for 18 hours. After the reaction was completed, the mixture was filtered to collect a solid. To remove EtOH, and the residue was extracted with EtOAc. EtOAc EtOAc EtOAc EtOAc. The title compound was obtained as a white solid (33 g, 3%). Amino Imethylpyridyl)) (1,2,3-triazol-4-yl) 】-N-(2,2-dimercaptopropyl) apoein · added to the compound from the previous step (33 g, 0.104 mol) in a solution of Me〇H (1.2 liter) 10% Pd/C (16 g). The mixture was allowed to react at room temperature and room temperature for 3 hours. After the reaction was completed, the mixture was filtered. The filtrate was evaporated to give the title compound (28.8 g, 96%). 1-(5-(3_Third-butyl-heptacyanobenzamide)_2-methylpyridyl)_Ν·neopentyl-1Η_1,2,3_triazole_4_carboxylate Amine·In a solution of the compound hydrazine (20.7 g, 102 mmol) in DCM (400 ml), chlorinated hydrazine (48.7 ml) and a catalytic amount of DMF were added dropwise at 〇 °c. The mixture was stirred at room temperature for 2 hours and then evaporated. The residue was taken up in EtOAc (2 mL) (EtOAc) Inside. The mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo and EtOAc EtOAc m. 1H NMR (CDC13, 300 MHz) 5 (ppm) 8.86-8.90 (d, 2H), 8.45-8.46 (d, 1H), 8.26-8.28 (m, 2H), 8.13 - 8.14 (t, 1H), 7· 85-7·86 (t,1H), 7.35-7.40 (t,1H), 3.26-3.28 (d,2H),2·45 (s,3H),1·36 (s,9H),0.98 (s , 9H)· (Calculated mass: 473.6, found quality · 474.2). Method C·Phenyl alcohol tosylate · In a 500 ml flask, make acetol (6.86 ml, 7.41 g, 0.100 mol, 1.0 The mixture of the equivalent) and pyridine (30 ml) 123505 -281 - 200815422 was cooled to &lt; 〇 ° C in an ice salt bath. A solution of gasified p-toluenesulfonate (20.74 g, 0.109 mol '1.1 equivalent) in pyridinium (7 ml) was added dropwise to the flask at an internal temperature &lt; 〇 ° C, after ~2 hour. The mixture was stirred at &lt; 〇 ° C for 30-40 minutes, then cold water (25 〇 ml) and 6 M HCl aqueous solution (250 4 : liter) were added. The mixture was extracted with EtOAc (EtOAc)EtOAc. The crude product (9.281 g &lt;RTI ID=0.0&gt;&gt;&gt;&gt; 1 H NMR (500 MHz, CD 2 Cl 2 ) 5 (ppm) 7·82 (d, J = 8 Ηζ, 2 Η), 7.42 (d, J = 8 Hz, 2H), 4.52 (s, 2H), 2.48 (s , 3H), 2.18 (s, 3H)· 1-azidopropan-2-one. Two solutions were prepared as follows: Solution A: Pyruvate tosylate (4.71 g, 20·6 mmol, ΐ· 〇 equivalent) in Et〇H (21 ml) and acetic acid (2.36 ml, 41.3 mmol, 2.0 eq.), and solution b: sodium azide (2.68 g, 41_3 mmol, 2.0 eq.) in water ( 8·2 ml). The solution was cooled to 0 ° C with hydrazine, combined, and held in a freezer (for freezer) for 3 days. The disappearance of the starting material was followed by analysis of LC-MS. Water (500 mA) was added and the product was extracted with diethyl ether. The combined organic layers were washed with aq. EtOAc EtOAc (EtOAc) The crude product was steamed in a diatomaceous earth distillation apparatus at 50 ° C using a high vacuum. The acetone-dry ice mixture was used to cool the collection ball. The pure product (〇·791 g, 39% yield, &gt;95% pure, by 1H NMR) was a colorless to amber liquid. lR NMR (500 MHz5 CD2C12) δ (ppm) 3.97 (s? 2H)? 2.19 (s? 3H) 13CNMR (CD2C12) 5 (ppm) 202.1,58.1,27.2. N-neopentyl small (2-ketopropyl) Base)_1H-1,2,3-triazole_4_carboxyguanamine· 1-azidopropan-2-one obtained from 123505-282 - 200815422 (442 mg, 4.47 mmol, ι · 2 equivalents of a solution of surimi-nepentylpropionamide (500 mg, 3.59 mmol, 1. 〇 equivalent) in a mixture of eight cc) and water (1.0 ml), and in a sealed, glassy The bottle was heated to 60 ° C in the presence of a copper wire for 4 hours. After cooling the main room temperature of v1, the copper was removed, the mixture was concentrated in vacuo and dried in EtOAc EtOAc (EtOAc) LC-MS and 1H NMR) (mass calculated: 238, mass found: 211 239). 1h NMR (500 MHz, DMSO-d6) 5 (ppm) 8.38 (s5 1 Η), 8.29 (tj = 6.6 Hz, 1H), 5·54 (s, 2H), 3.09 (d, J = 6·6 Hz, 2H), 2.23 (s, 3H), 〇.88 (s 9H). lH NMR (500 MHz, CD2C12) δ (ppm) 8.11 (s5 1H)5 7.25 (bs5 1H) 5·3〇(s, 2H) , 3_26 (d, J = 6.6 Hz, 2H), 2.30 (s, 3H), 1 · 〇〇 (s, 9H). i3 C is difficult (CD2C12) (5 (ppm) 198.6, 160.0, 144.0, 127·0 , 58·9, 50.3, 32.3, 27.2. The crude product contains a trace of azidoacetone (1H NMR) which can be removed by long-term drying at high temperature or by crystallization in hv. 1-(2 -Methyl _5_nitropyridine _3_yl) with neopentyl-ml, 2,3-triazole _4_ octadecylamine. The compound obtained above (106 mg, 0.445 mmol, ι · 〇 equivalent), supplemental malondialdehyde sodium salt (made as above) (62 mg, 〇·445 mmol, 1.0 eq.), ammonium acetate (171 mg, 2.224 mmol, 5.0 eq.), EtOH ( A mixture of 0.5 liters of water and water (0.5 ml) was stirred and heated in a closed vial for 8 hours at 8 ° C. A deep red solution was formed and the solid product precipitated. After 〇°c, the precipitated solid was filtered, washed with cold section _11_water (1: 丨), MeOH, air dried, and dried in hv. Gray solid was pure product (30·8 克, 22 % yield, &gt;98% pure, by LC-MS and 1H NMR. Alternatively, 1.5 equivalents of sodium nitromalonate was used, and the reaction was carried out at (9) it was passed into 123505 200815422 overnight. After cooling, The reaction mixture was diluted with water (50 mL) and EtOAc (EtOAc)EtOAc. % EtOAc/DCM) gave the product as a pale-yellow solid. The product was purified from Me 〇H or MeOH/water </ br </ br </ </ </ 1H NMR (500 MHz, DMSO-dg) (ppm) 9.47 (d, J = 2.4 Hz, 1H), 9·11 (s, 1H), 8.88 (d, J = 2·4 Hz, 1H), 8.53 (t, J = 6.6 Hz, 1H), 3.14 (d, J = 6·6 Hz, 2H), 2.56 (s, 3H), 0·92 (s, 9H)· 1-(5-(3- Tertiary-butyl-5-carbobenzylideneamino)-2-methylp ratio bite_3_yl)_n_neopentyl 1Η-1,2, 3_Triterpene-4_carbamide is synthesized in the manner described above. Route D: Alternative orientation of the indoleamine chain

5_(4-(第三-丁氧羰基）_1Η-1，2,3-三唑+基）-6_甲基菸鹼酸乙 S曰·將c (458宅克，2.22宅莫耳，當量）與丙炔酸第三_ 丁酯（458微升，3.33毫莫耳，1.5當量）在AcN/水（1〇 :丨，8 8毫 升）中之溶液’於80°C下’在密閉小玻瓶中，於銅線存在下 攪拌過夜。濃縮溶液，在HV中乾燥，及使粗產物藉管柱層 析純化（Si〇2 ’ 0-50% EtOAc/DCM)，而得純標的化合物（665毫 123505 -284- 200815422 克，90%產率，99%純，藉LC-MS)，為暗色油（計算之質量： 332，發現之質量：318)。iHNMRpoOMHz，丙酮-d6) 5(PPm) 9.21 (d，J = 2·0 Hz，1H)，8.91 (s，1H)，8.45 (d，J = 2.0 Hz，1H)，4.44 (q，J =7·1 Hz，2H)，2·55 (s，3H)，1.63 (s，9H)，1.41 (t，J = 7.1，3H). 1-(5-(乙氧羰基）-2-甲基吡啶-3-基）-1Η·1，2,3-三唑-4-羧酸·將5_(4-(Third-butoxycarbonyl)_1Η-1,2,3-triazole+yl)-6-methylnicotinic acid B S曰· will c (458 house, 2.22 house mole, equivalent And a solution of the third-butylic acid (458 μl, 3.33 mmol, 1.5 equivalent) in AcN/water (1 〇: 丨, 8 8 mL) at 80 ° C in a small closed In a glass bottle, stir overnight in the presence of copper wire. The solution was concentrated, dried in HV, and the crude product was purified by column chromatography (Si </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Rate, 99% pure, by LC-MS), dark oil (calculated quality: 332, quality found: 318). iHNMRpoOMHz, acetone-d6) 5(PPm) 9.21 (d, J = 2·0 Hz, 1H), 8.91 (s, 1H), 8.45 (d, J = 2.0 Hz, 1H), 4.44 (q, J = 7 · 1 Hz, 2H), 2·55 (s, 3H), 1.63 (s, 9H), 1.41 (t, J = 7.1, 3H). 1-(5-(ethoxycarbonyl)-2-methylpyridine -3-yl)-1Η·1,2,3-triazole-4-carboxylic acid·

上文獲得之化合物（664毫克，2·00毫莫耳）在TFA-水（95 : 5， 10毫升）中之溶液於室溫下攪拌1小時，濃縮，溶於AcN (10 毫升）中，濃縮，及在HV中乾燥。將粗產物與乙醚（4〇毫升） 一起攪拌，藉過濾分離固體，以乙醚洗滌，並在HV中乾燥， 而得標的化合物（523毫克，94%產率，99%純，藉LC-MS)， 為淡褐色固體（計算之質量·· 276，發現之質量·· 277)。iHNMR (500 MHz5 DMSO«d6) δ (ppm) 9.23 (s5 1H)5 9.17 (d5 J = 2.0 Hz5 1H)? 8.45 (d，J = 2.0 Hz，1H)，4.39 (q，J = 7.1 Hz，2H)，2.49 (s，3H)，1.36 (t，J = 7.1The solution obtained above (664 mg, 1.00 mmol) was stirred at room temperature for 1 hour, concentrated and dissolved in AcN (10 mL). Concentrate and dry in HV. The crude product was stirred with EtOAc (EtOAc) (EtOAc). , is a light brown solid (calculated quality · 276, found quality · 277). iHNMR (500 MHz5 DMSO«d6) δ (ppm) 9.23 (s5 1H)5 9.17 (d5 J = 2.0 Hz5 1H)? 8.45 (d, J = 2.0 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H ), 2.49 (s, 3H), 1.36 (t, J = 7.1)

Hz，3H). 6甲基新戍基lie甲酿基)-111-1，2,3_三唾小基）終驗酸乙 酯·將新戊基胺（239微升，2.00毫莫耳，2.〇當量）添加至上 文獲得之化合物（276毫克，1.00毫莫耳，} 〇當量）、B〇p (885 毫克，2.00毫莫耳，2·0當量）及DCM(5O毫升）之混合物中， 接著添加DIEA (697微升，4.00毫莫耳，4·〇當量）。將混合物 於室溫下攪拌3小時，然後添加應身水溶液㈤克，在⑴ 毫升水），並將混合物在室溫下攪拌2小時，以使過量Β〇ρ 水解。濃縮混合物，於HV中乾燥，並使粗產物藉管柱層析 純化（SK)2，在DCM巾之〇福Me〇H)，而得純標的化合物_ 毫克，95%產率，99。/“屯，藉職s)，為灰白色固體(計算 123505 •285 - 200815422 之質量：345，發現之質量：318 (MH+-N2)，346 (MH+), 387 (MH++AcN)，409 (MNa++AcN)) 〇 6_甲基-5_(4_(新戍基胺甲醯基）-1H-1，2,3·三唑小基）終驗酸· 將2M NaOH水溶液（1·〇毫升，2·〇〇毫莫耳，2·1當量）添加至上 文獲得之化合物（326毫克，0.942毫莫耳，1.0當量）在Et0H (5 〇 毫升）與THF (5.0毫升）中之溶液内。將混合物於室溫下搜拌 2小時，在真空中濃縮，及以iM HC1水溶液（3 〇毫升）中和。 使已沉澱之固體音振，過濾，以水洗務，風乾，並在Ηγ中 乾燥’而付標的化合物（271毫克，90%產率，99%純，藉 LC-MS)，為白色固體。（計算之質量：317，發現之質量： 176, 202, 243, 262, 289, 318, 359). 4 NMR (500 MHz，DMSO-d6)占 (ppm) 13.72 (s，1H)，9.15 (d，J = 2·0 Hz，1H)，9.09 (s5 1H)，8.50 (t，J = 6.6 Hz，1H)，8·38 (d，J = 2·0 Hz，1H)，3_15 (d，J = 6.6 Hz，2H)，2·49 (s，3H)， 0.93 (s，9H). N_(3·第三-丁基-5·氰基苯基）_6•甲基冬(4_(新戊基胺曱醯 基）_1H-1，2,3-三唑小基）於鹼醯胺·將上文獲得之化合物 (31.7毫克，0.100毫莫耳，1〇當量）、3_胺基_5_第三_丁基苯曱 腈(34_8 毫克，0.200 毫莫耳，2.0 當量）、BOP (88.5 毫克，0.200 毫莫耳，2.0當量）、DIEA (70微升，〇·4〇〇毫莫耳，4.0當量） 及DCM (1.0毫升）之混合物於室溫下攪拌2小時，然後在密 閉小玻瓶中加熱至5〇°C，歷經0.5小時。於冷卻後，以DCM (50 笔升）稀釋混合物，並將有機層以水洗滌，脫水乾燥 (Na2 SO*)，在真空中濃縮，及於中乾燥。使粗產物藉管 柱層析純化（Si〇2，在DCm中之〇_50% Et0Ac)，而得純標的化 123505 200815422 合物（42·1笔克，88%產率，88_97%純，藉L(&gt;MS)，為白色固 體（計异之負ΐ · 473，發現之質量· 446 (mh+_n2)，474 (MH+》。 實例3 其他衍化反應Hz,3H). 6-methyl fluorenyl lie-enyl)-111-1,2,3_tris-small base) final acid ethyl ester · neopentylamine (239 μl, 2.00 mmol) , 2. 〇 equivalent) added to the compound obtained above (276 mg, 1.00 mmol, 〇 equivalent), B〇p (885 mg, 2.00 mmol, 2.0 eq) and DCM (5O mL) In the mixture, DIEA (697 μl, 4.00 mmol, 4·〇 equivalent) was added. The mixture was stirred at room temperature for 3 hours, then an aqueous solution of the body (five) was added in (1) ml of water), and the mixture was stirred at room temperature for 2 hours to hydrolyze excess Β〇ρ. The mixture was concentrated, dried in EtOAc and EtOAc EtOAc (EtOAc) / "屯, 任s s), as an off-white solid (calculated 123505 • 285 - 200815422 quality: 345, found quality: 318 (MH+-N2), 346 (MH+), 387 (MH++AcN), 409 ( MNa++AcN)) 〇6_methyl-5_(4_(sinodecylaminomethane)-1H-1,2,3·triazole small group) final acid · 2M NaOH aqueous solution (1·〇 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The mixture was stirred at room temperature for 2 hours, concentrated in vacuo, and neutralized with aqueous iM HCl (3 mL). The precipitated solid was shaken, filtered, washed with water, air dried, and in Ηγ Dry 'and the compound of the title (271 mg, 90% yield, 99% pure, by LC-MS) as a white solid. (Computed mass: 317, found quality: 176, 202, 243, 262, 289, 318, 359). 4 NMR (500 MHz, DMSO-d6) (ppm) 13.72 (s, 1H), 9.15 (d, J = 2·0 Hz, 1H), 9.09 (s5 1H), 8.50 (t, J = 6.6 Hz, 1H), 8·38 (d, J = 2·0 Hz, 1H), 3_15 (d, J = 6. 6 Hz, 2H), 2·49 (s, 3H), 0.93 (s, 9H). N_(3·T-butyl-5·cyanophenyl)_6•methyl winter (4_(neopentyl) Amidino)1H-1,2,3-triazole small group) Compound obtained above (31.7 mg, 0.100 mmol, 1 〇 equivalent), 3-amino group _5_ Third _butylbenzonitrile (34_8 mg, 0.200 mmol, 2.0 eq.), BOP (88.5 mg, 0.200 mmol, 2.0 eq.), DIEA (70 μL, 〇·4 〇〇 millimolar, A mixture of 4.0 eq.) and DCM (1.0 mL) was stirred at room temperature for 2 hours, then heated to 5 ° C in a closed vial for 0.5 hour. After cooling, the mixture was diluted with DCM (50 liters) And the organic layer was washed with water, dried (Na2SO*), concentrated in vacuo, and dried in vacuo. The crude product was purified by column chromatography (Si〇2, DC50% Et0Ac in DCm) ), but the pure standard 123505 200815422 compound (42. 1 gram, 88% yield, 88_97% pure, by L (&gt; MS), as a white solid (calculated different ΐ · 473, the quality found · 446 (mh+_n2), 474 (MH+). Example 3 Other Derivation Reactions

3-(胺基甲基）冬第三_丁基邻(4 (1-經甲基）苯基)6甲基吡 唆_3_基）-2_甲氧基苯甲酿胺將一刮勺之罐（ι〇重量添 加至Ν·(5_(4·乙醯基苯基）_6_ f基❹縣）_5_第三.丁基趟 基冬甲氧基苯甲醯胺(10亳克，咖毫莫耳)(經由上述方法 獲得）在EtOH (2毫升彳φ夕、〜v + 笔开）中之浴液内。將混合物在氏大氣及室 溫下攪拌過夜，並經過矽芦 ^ y ’术土過濾。》辰縮濾液，並將殘留 物使用預備之RP-HPLC純化（描痄、广·士 、电化（梯度液.在H20中之10-95%3-(Aminomethyl) Winter Third-Butyl-(4 (1-Methyl)phenyl)6-methylpyridinyl-3-yl)-2-methoxybenzoic acid will be a spatula Can (Im weight added to Ν·(5_(4·Ethylphenyl)_6_ f ❹ ❹)_5_third. Butyl fluorenyl methoxy benzyl carbamide (10 gram, coffee Mohr) (obtained by the above method) in a bath of EtOH (2 ml 彳 夕 〜, ~ v + pen open). The mixture was stirred overnight at room temperature and at room temperature, and passed through a cucurbit Soil filtration. The filtrate was condensed, and the residue was purified by preparative RP-HPLC (descriptive, broad, and electrochemical (gradient solution. 10-95% in H20).

AcN) ’而得標題化合 LC-MS)，為灰白色固體 448)。 版1〇卞才之貝里· 448，發現之質量：AcN) was titled LC-MS as an off-white solid 448). Version 1 of the Berry · 448, the quality of the discovery:

屮.δ笔兄，67%產率，&gt;95%純，難 123505 -287- 200815422 5_第三_丁基各(4-(經甲基）-1Η-1，2,3_三唑小基）_2_甲氧基_N_(卜 甲基_5_(4-(新戊基胺甲醯基）苯基）ρ比唆-3·基）苯甲醯胺·使3·« 豐氮基-5-第三-丁基-2-甲氧基-N-(6-甲基-5-(4-(新戊基胺曱醯 基）苯基 &gt;比σ定各基）苯甲酸胺（使用本文中所述之方法，得自 中間物S) (0.226克，0.43毫莫耳）溶於AcN (2毫升）中。添加丙 -2-炔-1-醇（0.24克，4.28毫莫耳）、銅線及水（2〇〇微升），並將 小玻瓶加蓋，且加熱至ioo°C過夜。將混合物在Et0Ac與鹽 水之間分配’並使有機層以Na] SO#脫水乾燥，過濾，及蒸 發。將殘留物使用矽膠層析純化，獲得標的化合物，125毫 克產量（計算之質量：584_7，發現之質量：585.幻。 5_第二·丁基 _3_(4·甲醯基 _111-1，2,3_三唑-1-基）_2_ 甲氧基 _Ν·(6-甲基-5-(4_(新戊基胺甲醯基）苯基）吡啶各基）苯甲醯胺·使 得自前一步驟之化合物（0.125克，〇·21毫莫耳）溶於dcm(5* 升）中，並添加Dess-Martin試劑（0.136克，〇·32毫莫耳）。將反 應物攪拌48分鐘，並添加飽和NaHC〇3水溶液（2毫升）與1〇% Na2S2〇3(2耄升）。持續攪拌20分鐘，及分離液層。以DCM 萃取水層，並將含有中間物醛之合併DCM相區分成2毫升 液份（8液份），使其接受還原胺化作用，如下文所舉例。 5第一-丁基_2_甲氧基以-(6-曱基-5-(4-(新戊基胺甲醯基）苯 基）_峨啶丨基）各(4-(四氫吡咯小基曱基&gt;1&amp;1，2,3_三唑小基体 甲醯胺（R=h，四氫，比哈基）·於得自±文之^夜中，添 加醋酸(30微升，〇·534毫莫耳），接著為四氫吡咯（24微升， 0.27毫莫耳）與恤611(〇仏)3(57毫克，〇27毫莫耳）。使混合物 123505 - 288 · 200815422 音振，然後於室溫下振盪過夜。蒸發溶劑，並使殘留物經 由預備之HPLC純化，產生8.7毫克標的化合物（計算之質 量：637.8，發現之質量：638.2)。屮.δ笔兄,67% yield, &gt;95% pure, difficult 123505 -287- 200815422 5_third_butyl each (4-(methyl)-1Η-1,2,3_triazole Small base)_2_methoxy_N_(bu methyl_5_(4-(neopentylcarbinyl)phenyl)ρ than 唆-3·yl)benzamide ·3·« nitrogen-rich 5-t-butyl-2-methoxy-N-(6-methyl-5-(4-(neopentylamino)phenyl)&gt; sigma-based benzoic acid amine ( Using the procedure described herein, the intermediate S) (0.226 g, 0.43 mmol) was dissolved in AcN (2 mL). &lt;RTI ID=0.0&gt; ), copper wire and water (2 〇〇 microliters), and cover the vial and heat to ioo ° C overnight. Distribute the mixture between Et0Ac and brine 'and dehydrate the organic layer with Na] SO# Dry, filter, and evaporate. Purify the residue using silica gel chromatography to obtain the title compound, yield of 125 mg (calculated mass: 584_7, found mass: 585. illusion. 5_second·butyl_3_(4· Methionyl_111-1,2,3-triazol-1-yl)_2_methoxy-Ν·(6-methyl-5-(4-(p-pentylaminomethyl)phenyl)pyridine Benzene The guanamine was dissolved in dcm (5* liter) from the compound from the previous step (0.125 g, 〇 21 mmol), and Dess-Martin reagent (0.136 g, 〇·32 mmol) was added. Stir for 48 minutes, and add a saturated aqueous solution of NaHC 3 (2 mL) and 1% Na 2 S 2 〇 3 (2 liters). Stirring for 20 minutes, and separating the layers. The aqueous layer was extracted with DCM and containing intermediates The combined aldehydes of the aldehyde were divided into 2 ml parts (8 parts) to accept reductive amination, as exemplified below. 5 First-butyl-2-methoxyl-(6-fluorenyl- 5-(4-(neopentylcarbinyl)phenyl)-acridinyl) each (4-(tetrahydropyrroleinyl)&gt;1&amp;1,2,3-triazole small matrix A Indoleamine (R = h, tetrahydrogen, Bihaki) · Added from acetic acid (30 μl, 〇·534 mmol), followed by tetrahydropyrrole (24 μL, 0.27) Mol) with 611 (〇仏) 3 (57 mg, 〇 27 mmol). Mix the mixture 123505 - 288 · 200815422 and then shake at room temperature overnight. Evaporate the solvent and allow the residue to pass through HPLC purification, yielding 8.7 m Subject compound (the quality of the calculated: 637.8, found the mass: 638.2).

N-(5-(4-(2-胺基-2-甲基丙基胺曱醯基）苯基）_6-甲基吡啶_3_ 基）各第三·丁基-5-氱基苯曱醯胺·使4_(5_(3_第三-丁基氰 基本甲醯胺基）-2-甲基p比咬-3-基）苯甲酸（按實例1中所述獲 得）（74毫克，0·18毫莫耳）溶於DCM(3毫升）中。添加氯化草 醯（〇·16毫升，1_79毫莫耳）與DMF(2滴），並將反應物攪拌8〇 分鐘。以MeOH使反應淬滅，移除溶劑，且使殘留物在^ 中乾燥。使2-甲基丙烷-1，2_二胺（63毫克，〇·72毫莫耳）溶於Thf (3耄升）與DIEA (0124毫升）中。添加上文獲得之化合物在 THF中之溶液（3毫升），並將反應物檀拌9〇分鐘。蒸發溶劑， 及使殘留物藉預備之HPLC純化。使合併之離份於dCM與少 里飽和NasCO3之間作分液處理。使有機層以Na2c〇3乾燥， 過渡’及蒸發，而產生13·7毫克自由態鹼（計算之質量·· 483·6，發現之質量：484.1)。 3-第二-丁基-5_氰基_Ν-(5-(4_(2_(二甲胺基）_2_甲基丙基_胺甲 123505 200815422 醯基）苯基）-6-曱基外b唆-3-基）苯曱醢胺·使上文獲得之化人 物（6毫克，0.01毫莫耳）溶於DCM(0.5毫升）中。添加甲酸（37% 水溶液，L3微升，0.02毫莫耳），並將混合物檀拌15分鐘。 添加醋酸(20微升）與NaBH(OAc)3(10毫克，0.47亳莫耳），並持 續攪拌70分鐘。蒸發反應混合物，並使殘留物經由預備之 HPLC純化（計算之質量：511.7，發現之質量：。N-(5-(4-(2-Amino-2-methylpropylamino)phenyl)-6-methylpyridine-3-yl) each of the third butyl-5-mercaptophenylhydrazine Indole · 4_(5_(3_Terve-butyl cyanamide) is methyl benzyl)-2-methyl p benzo-3-yl)benzoic acid (obtained as described in Example 1) (74 mg, 0·18 mmoles dissolved in DCM (3 mL). Chlorinated hydrazine (〇·16 ml, 1_79 mmol) and DMF (2 drops) were added and the reaction was stirred for 8 min. The reaction was quenched with MeOH, solvent was removed and residue was dried. 2-Methylpropane-1,2-diamine (63 mg, 〇·72 mmol) was dissolved in Thf (3 liters) and DIEA (1,024 liters). A solution of the compound obtained above in THF (3 mL) was added and the mixture was stirred for 9 min. The solvent was evaporated and the residue was purified by preparative HPLC. The combined fractions were subjected to liquid separation between dCM and less saturated NasCO3. The organic layer was dried over Na 2 c 〇 3, and then allowed to undergo &lt;RTI ID=0.0&gt;&gt; 3-second-butyl-5-cyano-indole-(5-(4_(2-(dimethylamino))-2-methylpropyl-amine-A-123505 200815422 fluorenyl)phenyl)-6-fluorenyl Exo b唆-3-yl)benzamine The above-obtained person (6 mg, 0.01 mmol) was dissolved in DCM (0.5 mL). Formic acid (37% in water, L3 microliters, 0.02 mmol) was added and the mixture was sanded for 15 minutes. Acetic acid (20 μL) and NaBH(OAc) 3 (10 mg, 0.47 mmol) were added and stirring was continued for 70 minutes. The reaction mixture was evaporated, and the residue was purified by preparative HPLC (yield mass: 511.7, mass found: .

3_第三-丁基-5-(異噚唑-4_基）-N-(6-甲基-5-(4-(新戊基胺甲醯 基）-苯基）峨咬_3_基）苯甲醯胺· 使3-溴基_5_第三-丁基-甲 氧基-N-(6-甲基-5-(4_(新戊基胺甲醯基）苯基 &gt;比π定各基）苯甲酸 胺（經由本文中所述之方法獲得）（19毫克，〇·03毫莫耳）與異 气唾-4-基二羥基硼烷（6毫克，〇·〇5毫莫耳）溶於DME (45〇微 升）' EtOH (50微升）及甲苯（50微升）中，並添加pd(pph3 )4(4 毫克，0.003毫莫耳）與飽和％(：03水溶液（34微升）。將反應 物以N2沖洗’並將小玻瓶加蓋。將混合物加熱，並於8〇〇c 下祝摔過仪。使反應物冷卻至室溫’並於N2氣流下蒸發溶 劑。將殘留物使用石夕膠層析純化，產生標的產物，2.3毫克 產量（計算之質量：556.7，發現之質量：557 1)。3_T-butyl-5-(isoxazol-4-yl)-N-(6-methyl-5-(4-(neopentylcarbinyl)-phenyl) 峨3 _ base) benzamide · 3-bromo-5_t-butyl-methoxy-N-(6-methyl-5-(4_(neopentylcarbinyl)phenyl> ; specific ratio of π) benzoic acid amine (obtained by the method described herein) (19 mg, 〇·03 mmol) and isogaso-4-yldihydroxyborane (6 mg, 〇·〇 5 mmoles dissolved in DME (45 μL) ' EtOH (50 μL) and toluene (50 μL) with pd(pph3)4 (4 mg, 0.003 mmol) and % saturated ( :03 aqueous solution (34 μl). The reaction was flushed with N2' and the vial was capped. The mixture was heated and baptized at 8 °c. The reaction was allowed to cool to room temperature. The solvent was evaporated under N2. The residue was purified using EtOAc (EtOAc) elute

N+ 0· 123505 -290- 200815422 5-(3_第三-丁基·5_氰基苯甲醯胺基）_2_甲基各(心(新戊基胺 甲醯基）苯基㈣啶1-氧化物·於3_第三-丁基净氰基善(卜甲 基-5-(4-(新戊基胺甲醯基）苯基）吡啶基）苯甲醯胺（％」毫 克，0.11笔莫耳）在AcN/MeOH (2毫升，1 : 1)中之溶液内，添 加吒〇2(1毫升，30%)，並將混合物於室溫下攪拌，1〇分鐘 後，形成沉澱物，並添加MeOH，直到混合物透明為止。將 所形成之溶液於室溫下攪拌2天，蒸發溶劑，並使殘留物接 受RP-HPLC (梯度液：玛0中之25至95%AcN)，而得標的產物 (8.0毫克，15%)，為白色結晶性固體（計算之質量：498 6， 發現之質量：501.1)。 5_第三-丁基-3.羥基碳胺基亞胺基）界(5_(4-(1_(羥亞胺基） 乙基）苯基）-6-曱基吡啶各基）：甲氧基苯甲醯胺·將ν_(5·(4_ 乙醯基苯基）-6-甲基吡啶各基）-5-第三-丁基_3-氰基-2-甲氧基 苯甲醯胺（10毫克，〇·〇23毫莫耳）、羥胺鹽酸鹽（4·8毫克，〇 〇69 毫莫耳，3.0當量）及吡啶（2滴）在Et〇H(1毫升）中之溶液於％ °C下攪拌過夜。濃縮透明溶液，並將殘留物使用預備之 RP-HPLC純化（梯度液：在氏〇中之1〇_95% AcN)，而得標題化 合物（1·5 t克，14%產率，&gt;95%純，藉LC_MS)，為灰白色固 體（計异之質量：490，發現之質量·· 491)。N+ 0·123505 -290- 200815422 5-(3_T-Butyl-5-cyanobenzamide)_2-methyl each (heart (neopentylaminomethyl) phenyl(tetra)pyridine 1 -Oxide·3_Third-Butyl cyanocyanosyl (Methyl-5-(4-(neopentylcarbinyl)phenyl)pyridyl)benzamide (%) mg, 0.11 In a solution of AcN/MeOH (2 mL, 1:1), EtOAc (1 mL, 30%) was then weighed, and the mixture was stirred at room temperature. Add MeOH until the mixture is clear. The resulting solution is stirred at room temperature for 2 days, the solvent is evaporated, and the residue is subjected to RP-HPLC (gradient: 25 to 95% AcN in MeOH). The title product (8.0 mg, 15%) was obtained as a white crystalline solid (calc. mass: 498, mass found: 501.1). 5_tris-butyl-3. hydroxycarbaminoimido) 5_(4-(1_(hydroxyimino)ethyl)phenyl)-6-fluorenylpyridine): methoxybenzamide · ν_(5·(4_ethenylphenyl)- 6-methylpyridine)-5-tert-butyl-3-cyano-2-methoxybenzamide (10 mg, 〇·〇 A solution of 23 mmoles, hydroxylamine hydrochloride (4.8 mg, 〇〇69 mmol, 3.0 eq.) and pyridine (2 drops) in Et EtOAc (1 mL) . The clear solution was concentrated, and the residue was purified using EtOAc EtOAc--------- 95% pure, by LC_MS), as an off-white solid (the quality of the difference: 490, the quality found 491).

123505 -291 - 200815422 1-(2-甲基_5-(3-(4_曱基·1H-咪唑小基三氟甲基)_苯甲醯胺 基 &gt;比咬_3_基）-N-新戊基-1H-1，2,3-三嗅冬叛醯胺與1-(2-甲基 _5-(3_(5-甲基-1H-咪唑_1_基）-5·(三氟曱基）苯甲醯胺基）吡啶_3_ 基）_N-新戊基-111_1，2,3-三唑-4-羧醯胺·將1-(5-(3-氟基-5-(三氟 甲基）苯甲醯胺基）-2_曱基p比咬-3_基新戊基-111-1，2,3-三峻-4-羧醯胺（38.4毫克’ 0.08毫莫耳）與‘甲基咪唑（65.9毫克，0.8 毫莫耳）在DMF (2毫升）中之溶液，在微波中，於22〇〇c下加 熱3小時。以DMF稀釋溶液，並使用預備之pjpLc純化，提 供兩種異構物之混合物，其並未進一步分離（計算之質量·· 540.5，發現之質量：541.0)。123505 -291 - 200815422 1-(2-methyl_5-(3-(4-decyl·1H-imidazolyltrifluoromethyl)-benzamide amino group> than bite_3_yl)- N-neopentyl-1H-1,2,3-trisole winter tetamine and 1-(2-methyl_5-(3_(5-methyl-1H-imidazol-1-yl)-5· (Trifluoromethyl)benzamide amino)pyridine_3_yl)_N-neopentyl-111_1,2,3-triazole-4-carboxamide A 1-(5-(3-fluoro)- 5-(Trifluoromethyl)benzhydrylamino)-2_fluorenyl p than bit-3-yl neopentyl-111-1,2,3-trisyl-4-carboxamide (38.4 mg' 0.08 mmol) and a solution of 'methylimidazole (65.9 mg, 0.8 mmol) in DMF (2 mL), heated in a microwave for 3 h at 22 ° C. Dilute the solution with DMF and use The preparative pjpLc was purified to provide a mixture of two isomers which were not further separated (calculated mass · 540.5, mass found: 541.0).

3_第三-丁基-5-氰基具(5_(4-(1-(羥亞胺基）各甲基丁 基）-1Η-1，2,3_三嗤.1-基）-6曱基吡啶_3_基）苯甲醯胺·將上述 ( 化合物（18·9宅克’ 42.5微莫耳’ ι·〇當量）、經胺鹽酸鹽（69.5 *克，1.00毫莫耳，23.5當量）及EtOH (1毫升）之溶液於室溫 下攪拌2天。於反應期間形成白色沉澱物，將其藉過濾收 集，以冷EtOH與水洗滌。使固體在Ηγ中乾燥，而得純標的 產物（10.9毫克，99%純，藉LC-MS)(計算之質量：459，發現 之質量：432, 460)。 生物學測試 實例1 ··在THP細胞中TNFa生產之抑制 細胞素生產之抑制可藉由度量TNFa在脂多糖刺激之 123505 -292- 200815422 THP-1細胞中之抑制而發現（參閱Prichett等人J· Inflammation， 1995, 45, 97)。在 37°C，5% C02 下，將 THP-1 細胞（ATCC TIB 202, 美國培養物類型收集處，Rockville，MD)保持於具有10%牛胎 兒血清、10 mM Hepes、1 mM丙酮酸鈉、4.5克/升葡萄糖及0.05 mM 2_靆基乙醇之RPMI 164〇培養基中，如ATCC所建議。關於 此項檢剛，係將細胞與化合物在上文培養基中稀釋，惟使 用1%牛胎兒血清（檢測培養基）。將DMSO中之待測化合物 M # _於檢測培養基中稀釋至6x最後檢測濃度，在該檢測 中具有最後DMSO濃度低於0.3%。將THP-1細胞在1 X 105/井 下’覆蓋於96井組織培養板中。添加經稀釋之化合物（或 DMS〇對照組），並在添加LPS (Sigma)達最後濃度為1微克/ 宅升之前，使其在37°C，5% C02下，以細胞預培養30分鐘。 然後’將細胞在37°C下/5%C02下培養18-20小時。經由將板 在室通下離心10分鐘，使檢測停止。移除上層清液，以清 洗培養板，並移除液份，藉由市購可得之ELISA套件（R&amp;D 糸統# C)Y210, Minneapolis，MN)分析TNFa。數據係藉由非線性 回歸’使用得自Graphpad軟體（San Diego, CA)之PRISM 4軟體分 析。麵計算之IC5G係為會造成最大TNFa生產之50%降低之待 測化合物濃度。 &amp;凊單1中之各化合物係在TNFa ELISA檢測中測試，且發 中具有活性，其中大部份化合物在此項檢測中具有 IC5〇 低於 10 。 實例2 :發炎模式 &amp; &amp;易感染之老鼠中用於測試系統性紅斑狼瘡（SLE)之 123505 -293 - 200815422 方法係為此項技藝中已知（Knight等人，J. Exp. Med.，1978, 147, 1653 ; Reinersten 等人，New Eng· J· Med” 1978, 299, 515)。重症肌 無力（MG)係經由以得自另一物種之可溶性AchR蛋白質引致 疾病’在SJL/J雌性老鼠中測試（Lindstrom等人，Adv. Immunol.， 1988, 42, 233)。關節炎係在容易感染之老鼠品種中，藉由注 射類型 II 膠原而引致（Stuart 等人，Ann. Rev. Immunol·，1984, 42, 233)。在容易感染之大白鼠中，藉由注射分枝桿菌熱震蛋 白質引致佐劑關節炎之模式已被描述（Van Eden等人，Nature， 1988, 331，171)。甲狀腺炎係在老鼠中藉由投予如所述之甲狀 腺球蛋白而引致（Maron 等人，J. Exp· Med.，1980, 152, 1115)。胰 島素依賴性糖尿病（IDDM)係自然地發生，或可在某些老鼠 品種中引致，譬如由 Kanasawa 等人，Diabetologia，1984, 27, 113 所 述者。在老鼠與大白鼠中之實驗性自身免疫腦脊髓炎（EAE) 係充作人類中之MS模式。在此模式中，髓鞘脫失病係藉由 投予體填脂鹼性蛋白質而引致（參閱Paterson，Immuopathology 之教科書，Mischer 等人編著，Grune 與 Stratton，New York，1986，第 179-213 頁；McFarlin 等人，Science，1973, 179, 478 ··及 Satoh 等人，1 Immunol·，1987, 138, 179)。實例係更詳細地描述於下文。 在老鼠中之膠原所引致之關節炎模式· 例如，DBA/1老 鼠以老鼠類型II膠原之免疫作用，會引致慢性復發多關節 炎，其係提供一種關於人類自身免疫關節炎之強模式。此 模式係由例如 Courtenay 等人，Nature，1980, 282, 666 ; Kato 等人， Ann. Rheum. Dis·，1996, 55, 535 ;及 Myers 等人，Life Sci·，1997, 61， 1861-1878描述，其每一件均併於本文供參考。簡言之，係 123505 -294- 200815422 將老鼠檢疫至少三天。於第0天’將老鼠稱重，並分隔成多 個/〇療、’且未患病之對照組動物並未接受佐劑〇〇隻老 鼠）’與患病老鼠（2〇隻老鼠/治療組）對照。使老鼠麻醉， 在尾巴之底部刮毛，並以佐劑注射（皮内）（5〇微升/老鼠，· 100微克/老鼠膠原；·微克/老鼠結核分枝桿菌H37Ra)，使 用裝有26G針頭之！毫升注射器。於第21天，佐劑係經由使 膠原與結核分枝桿菌H37Ra21: i組合乳化（在均化器中） 而衣成。佐劑係使用裝有26G針頭之i毫升注射器注射（皮 内）(50微升/老鼠；100微克/老鼠膠原；100微克/老鼠結核分 枝桿菌臟a)。於第助天，將關節炎之巨觀跡象每日評 分。各足掌係接受評分：〇 =無可見之關節炎作用十一個 足趾之水腫及/或發紅；2 =兩個關節之水腫及/或發紅；3 = 超過兩個關節之水腫及/或發紅；或4=全部足掌與足趾之 嚴重關節《。關節炎指數係藉由所有個別足掌評分之相加 計算而得，並記錄（最高關節炎指數=16)。於第以天，記錄 老鼠體重’並將關節炎之巨觀跡象評分。將老鼠以其關節 炎指數為基礎，分類成多個治療組（1〇隻老鼠/組）。各治療 系一又汁Μ具有同樣平均關節炎指數與同樣關節炎指 數之範圍。起始藉由π腔途徑之服藥使用法。於第29_42天， 使老鼠服藥，並記錄試驗藥劑投藥之任何不利作用。關於 各^之關節炎之巨觀跡象，係每日評分。於第43天，將 關即九之巨：跡象评分’將老鼠除血，並將其血液收集在 肝‘月曰化式s中。將後肢及/或前肢移除，並浸沒在四體積 之1〇%經緩衝福馬林中。評估關於U之脫㈣用與組織 123505 -295 - 200815422 學。移除肝臟，並記錄其重量。3_Terti-butyl-5-cyano has (5-(4-(1-(hydroxyimino)methylbutyl)-1Η-1,2,3_三嗤.1-yl)- 6-mercaptopyridine_3_yl)benzamide. The above (compound (18·9 housew' 42.5 micromoles ι·〇 equivalent), amine hydrochloride (69.5 * gram, 1.00 millimolar) A solution of 23.5 eq.) and EtOH (1 mL) was stirred at room temperature for 2 days. A white precipitate formed during the reaction, which was collected by filtration and washed with cold EtOH and water. Pure standard product (10.9 mg, 99% pure, by LC-MS) (calculated mass: 459, mass found: 432, 460). Biological test example 1 · Inhibition of cytokine production by TNFa production in THP cells Inhibition can be found by measuring inhibition of TNFa in lipopolysaccharide-stimulated 123505-292-200815422 THP-1 cells (see Prichett et al. J. Inflammation, 1995, 45, 97). At 37 ° C, 5% C02 Next, THP-1 cells (ATCC TIB 202, American Culture Type Collection, Rockville, MD) were maintained with 10% fetal fetal serum, 10 mM Hepes, 1 mM sodium pyruvate, 4.5 g/L glucose, and 0.05 m. M 2_mercaptoethanol in RPMI 164 〇 medium, as recommended by the ATCC. For this assay, cells and compounds were diluted in the above medium, using 1% fetal fetal serum (test medium). The test compound M # _ was diluted to 6x final detection concentration in the test medium, and the final DMSO concentration was less than 0.3% in the test. THP-1 cells were covered in 96 wells at 1 X 105/well. In the plate, add the diluted compound (or DMS〇 control group), and pre-culture the cells at 37 ° C, 5% CO 2 before adding LPS (Sigma) to the final concentration of 1 μg / house liter. 30 minutes. Then 'culture the cells for 18-20 hours at 37 ° C / 5% CO 2 . Stop the assay by centrifuging the plate for 10 minutes under the chamber. Remove the supernatant to wash the plate, and The lysate was removed and analyzed for TNFa by a commercially available ELISA kit (R&amp;D 糸# C) Y210, Minneapolis, MN). Data was analyzed by nonlinear regression&apos; using PRISM 4 software from Graphpad software (San Diego, CA). The surface IC5G is the concentration of the test compound that will cause a 50% reduction in maximum TNFa production. Each of the compounds in &lt;1&gt; was tested in a TNFa ELISA assay and was active in the assay, with most of the compounds having IC5〇 below 10 in this assay. Example 2: Inflammatory Mode &amp;&amp;&amp; Infected Rats for Testing Systemic Lupus Erythematosus (SLE) 123505 - 293 - 200815422 Methods are known in the art (Knight et al., J. Exp. Med. , 1978, 147, 1653; Reinersten et al., New Eng J. Med" 1978, 299, 515). Myasthenia gravis (MG) is caused by a soluble AchR protein from another species' in SJL/J Tested in female mice (Lindstrom et al., Adv. Immunol., 1988, 42, 233). Arthritis is caused by injection of type II collagen in susceptible mouse strains (Stuart et al., Ann. Rev. Immunol). ·, 1984, 42, 233). In the susceptible white rats, the pattern of adjuvant arthritis induced by injection of mycobacterial thermal shock proteins has been described (Van Eden et al, Nature, 1988, 331, 171). Thyroiditis is caused in mice by administration of thyroglobulin as described (Maron et al., J. Exp. Med., 1980, 152, 1115). Insulin-dependent diabetes mellitus (IDDM) occurs naturally Or may be caused in certain mouse breeds, such as by Kanasawa Human, Diabetologia, 1984, 27, 113. The experimental autoimmune encephalomyelitis (EAE) system in mice and rats is used as an MS model in humans. In this model, the myelin lost disease system Caused by the administration of body fat-filled basic proteins (see Paterson, textbook of Immuopathology, edited by Mischer et al., Grune and Stratton, New York, 1986, pp. 179-213; McFarlin et al., Science, 1973, 179, 478 ·· and Satoh et al, 1 Immunol, 1987, 138, 179). Examples are described in more detail below. Arthritis patterns caused by collagen in mice · For example, DBA/1 mice are mouse type II The immunological effects of collagen can lead to chronic recurrent polyarthritis, which provides a strong pattern of autoimmune arthritis in humans. This model is for example by Courtenay et al, Nature, 1980, 282, 666; Kato et al., Ann. Rheum. Dis., 1996, 55, 535; and Myers et al., Life Sci., 1997, 61, 1861-1878, each of which is incorporated herein by reference. In short, the system is quarantined for at least three days by 123505 -294- 200815422. On day 0, the mice were weighed and separated into multiple/sputum treatments, and the control animals that did not have disease did not receive adjuvants and mice. 'With the diseased mice (2 mice/treatment) Group) control. The rats were anesthetized, shaved at the bottom of the tail, and injected with adjuvant (intradermal) (5 〇 microliters / mouse, · 100 μg / mouse collagen; · microgram / mouse Mycobacterium tuberculosis H37Ra), using 26G Needle! Ml syringe. On the 21st day, the adjuvant was emulsified by combining the collagen with M. tuberculosis H37Ra21: i (in a homogenizer). The adjuvant was injected (intradermal) with an i ml syringe containing a 26G needle (50 μl/mouse; 100 μg/mouse collagen; 100 μg/mouse M. tuberculosis dirty a). On the help day, the giant signs of arthritis are scored daily. Each foot receives a rating: 〇 = no visible arthritis, eleven toe edema and / or redness; 2 = edema and / or redness of two joints; 3 = edema of more than two joints and / or redness; or 4 = all joints of the soles of the feet and toes. The arthritis index was calculated by summing all individual foot scores and recorded (maximum arthritis index = 16). On the first day, the mouse weight was recorded and the giant signs of arthritis were scored. The mice were classified into multiple treatment groups (1 mouse/group) based on their arthritis index. Each treatment line has a range of the same average arthritis index and the same arthritis index. The method of administration by the π-cavity pathway is initiated. On day 29_42, the rats were given medication and any adverse effects of the test drug administration were recorded. Regarding the giant signs of arthritis, the daily score. On the 43rd day, the squad will be turned off: the sign scores 'The mice are removed from the blood and their blood is collected in the liver's sputum s. The hind limbs and/or forelimbs were removed and submerged in four volumes of 1% buffered formalin. Evaluation of the use of U (four) and organization 123505-295 - 200815422. Remove the liver and record its weight.

在大白鼠中之膠原所引致之關節炎模式· 將雌性路易 士大白鼠（查理士河（Charles River)參考#7218419)，於抵達時體 重為125-15〇克（8隻/組供關節炎用，4隻/組供正常對照組 用），以4隻/籠子收容，並於抵達後使其適應環境4_8天。 使經適應ί衣境之動物以異弗烧（Isoflurane)麻醉，並給予膠原 注射（D0)。於第6天，使其再一次麻醉，以供第二次膠原注 射。製備膠原，其方式是在0.01N醋酸中製成4毫克/毫升溶 液。使等體積之膠原與Freund氏不完全佐劑以手混合而乳 化，直到此物質之珠粒當被置於水中時，仍保持其形式為 止。每隻動物每次係接受300微升混合物，擴展於其背部之 3個皮下位置。於第9天，收集正常（患病前）右與左腳踝關 節之直控度量值。於第10-11天，關節炎之展開係發生，並 將大白鼠隨機分成多個治療組。將欲被給予媒劑或化合物 劑量之動物登記，並起始每天（qd) (24小時間隔）服藥，歷經 第1-6天，使用5毫升/公斤之體積用於口服溶液。將大白鼠 於關節炎之第1-7天稱重；每天取得腳踝之直徑度量值。於 關節炎之第7天收集最後體重。於第7天，使動物麻醉供全 血液抽出，以除血（血清可用於臨床化學），然後使其安樂 死。將兩隻後足掌與膝部移除，稱重後足掌，然後（與膝部&quot;) 置於福馬林中，並處理以用於顯微鏡術。在固定劑中Μ天 及在脫㈣中4-5天後，將腳躁關節以縱 將膝部在前沿平面中切成兩，，處理，包埋，切片兩:以 甲苯胺藍染色。對關節炎腳躁與膝部之發炎、血管醫形成 123505 -296- 200815422 及骨質耗損，給予〇 (正當彳 (正㊆）-5 (嚴重作用）之評分。足 量與AUC之抑制百分比係使用下式計算： % 抑制=A - Β/Α X 1〇〇 其中A =(平均疾病對照組_平均正常組卜與 B =(平均經治療組-平均正常組） 炎性腸與克隆氏病模式· 4評估待測化合物在克隆氏Arthritis pattern caused by collagen in rats · Female Louise white rats (Charles River reference #7218419), weighing 125-15 grams on arrival (8/group for arthritis) For use, 4/group for the normal control group), 4/cage, and adapted to the environment for 4-8 days upon arrival. The animals adapted to the environment were anesthetized with Isoflurane and injected with collagen (D0). On day 6, he was anesthetized again for a second collagen injection. Collagen was prepared by making a 4 mg/ml solution in 0.01 N acetic acid. An equal volume of collagen is emulsified by mixing with Freund's incomplete adjuvant until the beads of this material remain in their form when placed in water. Each animal received 300 microliters of the mixture each time, extending to three subcutaneous locations on the back. On day 9, collect direct control metrics for normal (pre-affected) right and left ankle joints. On days 10-11, the development of arthritis occurred and the rats were randomly divided into multiple treatment groups. Animals to be dosed with vehicle or compound doses were enrolled and started daily (qd) (at 24 hour intervals), and over the first 1-6 days, a volume of 5 ml/kg was used for the oral solution. The rats were weighed on days 1-7 of arthritis; the diameter measurements of the ankles were taken daily. The final weight was collected on the 7th day of arthritis. On day 7, the animals were anesthetized for total blood withdrawal to remove blood (serum for clinical chemistry) and then euthanized. The two hind paws and the knees were removed, the hind paws were weighed, then (with the knees &quot;) placed in the formalin and processed for microscopy. After 4-5 days in the fixative and 4-5 days in the de-(4), the ankle joint was cut into two in the leading plane plane, treated, embedded, and sliced: dyed with toluidine blue. For arthritis ankle and knee inflammation, angiogenesis 123505 -296- 200815422 and bone loss, give 〇 (正正彳(正七)-5 (severe effect) score. The percentage of inhibition of sufficient amount and AUC is used The following formula is calculated: % inhibition = A - Β / Α X 1 〇〇 where A = (mean disease control group - mean normal group and B = (mean treated group - mean normal group) inflammatory bowel and Crohn's disease pattern · 4 evaluation of test compounds in Clone

病中之有效性’故使用克隆氏病之_咖轉基因老鼠模式 (最初由 K〇nt〇yiannis 等人，Immunity，1999, 1〇, 387 描述）（亦可以 類似方式使用DSS (葡聚醣硫酸鈉）模式）。此等動物會發展 出與克隆氏病具有類似性之!BD表現型，在4與8週大之間 開始。待測化合物係在無論是3週大（以測試疾病之預防） 或6週大（以測試疾病徵候之安定化作用，防止進展或逆轉） 時投予，並將動物藉由體重及如本文中所述以組織學方式 評分。待測組合物係無論是每週或每週兩次投予，或可例 如使用滲透泵連續地投予。或者，亦可施用口服傳輸配方。 研究一旦起始，即持續至高7週或更久。動物可根據如 Kontoyiannis等人，2002，同前文出處中所述之標準尺度監控 腸疾病。迴腸之石蠟包埋腸組織切片，係以盲目方式根據 下列尺度進行組織學上評估：急性與慢性發炎係按下述在 最少8種高功率場（hpf)中個別地評估―急性炎性評分：〇 = 每 hpf (0-1)多形核（PMN)細胞（PMN/hpf) ; 1 ==在黏膜内（2_1〇) PMN/hpf ; 2 =在黏膜内（11-20) ΡΜΝ/hpf ; 3 =在黏膜内（21_3〇) PMN/hpf，或（11-20) PMN/hpf，具有低於肌層黏膜之延伸；及 4 =在黏膜内&gt;30 PMN/hpf，或&gt;20 P_/hpf，具有低於肌層黏 123505 •297- 200815422 膜之延伸。慢性炎性評分·· ο =在黏膜内每hpf (0_10)單核白 血球（ML) (ML/hpf) ; 1 =在黏膜内（11-20) ML/hpf ; 2 =在黏膜内 (21-30) ML/hpf，或（11-20) ML/hpf，具有低於肌層黏膜之延伸； 3 -在黏膜内（31_40) ML/hpf，或（21_30) ML/hpf，具有低於肌層 黏膜或毛囊增生之延伸，·及4 =在黏膜内&gt;4〇 ML/hpf，或&gt;30 ML/hpf，具有低於肌層黏膜或毛囊增生之延伸。每隻老鼠 之總疾病評分係藉由對每隻老鼠之急性炎性或慢性炎性評 分之合計計算而得。 在克隆氏病之TNFA ARE模式中之功效，係藉以下之任一 項証實：1)當在3週大開始對動物投藥時，不會發展疾病徵 候；ii)當在3週大開始投藥時，相對於對照動物，出現減輕 之疾病徵候嚴重性；iii)當在6週大開始投藥時，相對於對 知動物，不會進展成較嚴重疾病，或在較低速率下進展； IV)當在6週大開始對動物投藥時，於任何7, 8, 9, 1〇,丨丨，或 14週犄之彳政候逆轉。特定言之，若平均組織病理學評分在 經治療之動物中（藉由統計學上有意義之量）比媒劑對照組 之-平刀低，則治療係被認為是有效。若相對於只有媒劑之 對照組，平均組織病理學評分係較低達至少〇·5單位，至少 1·0早位，至少L5單位，至少2 〇單位，至少2·5單位，至少 3.0單位或達至少3·5單位，則治療亦被認為是有效。或者， 若平均組織病S學評分在整個治療服用》去之過程中保持在 於或降到0至〇·5，則治療係為有效。 IBD之其他模式包括例如在balb/c老鼠中之慢性結腸炎 之DSS模式。DSS椒式最初係由Okayasu等人，胃腸病學，199〇 123505 200815422 98, 694 描述，而由 Kojouharoff 等人，Clin Exp. lmmun〇i 1997, 107, 353修改（亦參閱WO 2004/041862，併於本文供參考）。將體重 21-22克之BALB/c老鼠處理以引致慢性結腸炎，其方式是在 其飲用水中，於5% w/v下投予DSS，在7天治療與12天未使 用DSS之恢復間隔之循環中。第4個恢復期間可自12天延伸 至21天，以表示慢性發炎狀態，而非藉由較短恢復所塑造 之急性狀態。於最後恢復期間後，係起始以本發明化合物， 視情況伴隨著一或多種成份A之治療。首先建議每週投 藥，但可由熟諳此藝者按需要調整。在治療期間之間隔下， 將動物殺死，解剖腸，並評估組織病理學評分，如本文中 所述或如Kojouharoff等人，戰同前文出處中所述。炎性腸 -三硝基苯磺酸之直腸滴The effectiveness of the disease's use of Crohn's disease in the coffee-transgenic mouse model (originally described by K〇nt〇yiannis et al., Immunity, 1999, 1〇, 387) (DSS (dextran sulfate) can also be used in a similar manner Sodium) mode). These animals develop a similarity to Crohn's disease! BD phenotype, starting between 4 and 8 weeks old. The test compound is administered whether it is 3 weeks old (to prevent the disease) or 6 weeks old (to test the stability of the disease sign, prevent progression or reversal), and the animal is weighed and The scores were scored in a histological manner. The composition to be tested is administered either weekly or twice a week, or can be administered continuously, for example, using an osmotic pump. Alternatively, an oral delivery formulation can also be administered. Once the study begins, it continues for up to 7 weeks or more. Animals can be monitored for intestinal diseases according to standard standards as described in Kontoyiannis et al., 2002, supra. The ileal paraffin-embedded intestinal tissue sections were histologically evaluated in a blind manner according to the following scales: acute and chronic inflammatory lines were individually evaluated in a minimum of 8 high power fields (hpf) as described below - acute inflammatory scores: 〇 = per hpf (0-1) polymorphonuclear (PMN) cells (PMN/hpf); 1 == in the mucosa (2_1〇) PMN/hpf; 2 = in the mucosa (11-20) ΡΜΝ/hpf; 3 = PMN/hpf in the mucosa (21_3〇), or (11-20) PMN/hpf, with an extension below the mucosal mucosa; and 4 = in the mucosa &gt;30 PMN/hpf, or >20 P_ /hpf, which has an extension of the membrane below the muscle viscosity of 123505 • 297-200815422. Chronic inflammatory score·· ο = per hpf (0_10) mononuclear leukocyte (ML) (ML/hpf) in the mucosa; 1 = in the mucosa (11-20) ML/hpf; 2 = in the mucosa (21- 30) ML/hpf, or (11-20) ML/hpf, with an extension below the mucosal mucosa; 3 - within the mucosa (31_40) ML/hpf, or (21_30) ML/hpf, with a lower than muscular layer Extension of mucosal or hair follicle hyperplasia, and 4 = in the mucosa &gt; 4 〇 ML / hpf, or > 30 ML / hpf, with an extension below the muscular mucosa or hair follicle hyperplasia. The total disease score for each mouse was calculated by summing the acute inflammatory or chronic inflammatory scores for each mouse. The efficacy of the TNFA ARE model in Crohn's disease is confirmed by any of the following: 1) When the animal is administered at the beginning of 3 weeks, the disease sign is not developed; ii) when the drug is started at 3 weeks old Relative to the control animal, the severity of the symptom of the disease is reduced; iii) when the drug is started at 6 weeks, it does not progress to a more serious disease, or progresses at a lower rate than the known animal; IV) At the beginning of the 6-week period, when the animals were administered, they were reversed at any of the 7, 8, 9, 1 〇, 丨丨, or 14 weeks. In particular, the treatment system is considered to be effective if the mean histopathological score is lower (by statistically significant amount) in the treated animals than in the vehicle control group. The mean histopathological score is as low as at least 〇5 units, at least 1·0 early, at least L5 units, at least 2 〇 units, at least 2.6 units, at least 3.0 units, relative to a vehicle-only control group. Or at least 3.5 units, the treatment is also considered effective. Alternatively, the treatment regimen is effective if the average tissue disease S-score score remains or falls to 0 to 〇5 throughout the course of treatment. Other modes of IBD include, for example, the DSS pattern of chronic colitis in balb/c mice. The DSS pepper type was originally described by Okayasu et al., Gastroenterology, 199 〇 123505 200815422 98, 694, and modified by Kojouharoff et al., Clin Exp. lmmun〇i 1997, 107, 353 (see also WO 2004/041862, and For reference in this article). Treatment of BALB/c mice weighing 21-22 grams to induce chronic colitis by administering DSS at 5% w/v in their drinking water, at 7 days of treatment and 12 days without DSS recovery interval In the loop. The fourth recovery period can be extended from 12 days to 21 days to indicate a chronic inflammatory state rather than an acute state created by a shorter recovery. Following the final recovery period, the compound of the invention is initiated, optionally with the treatment of one or more ingredients A. It is recommended to administer drugs weekly, but it can be adjusted as needed by those skilled in the art. At intervals between treatments, the animals were sacrificed, the intestines were dissected, and histopathological scores were assessed as described herein or as described by Kojouharoff et al., supra. Inflammatory bowel - rectal drops of trinitrobenzene sulfonic acid

疾病之其他動物模式包括藉由2,4,6-三 實例3 :臨床炎性疾病評估Other animal models of disease include 2,4,6-three Example 3: Clinical inflammatory disease assessment

123505 -299- 200815422 文中所述之化合物係在不同劑量下以經口方式投予人 颏〜、願者。於丨至24小時後，血液試樣係經由靜脈穿刺收集 至真空容器管件中，並使其肝燐脂化。在刺激檢測之前， 係針對各個別之未經稀釋、肝燐脂化之全血液試樣（Cell Dyn 3500 SL)進行單細胞計數。對此項目的而言，係將小體積 (100-200微升）自全血液試樣直接抽吸至分析器中。關於各試 樣係對各病患進行下列刺激檢測：a·未經刺激之對照組 (只有媒劑）與13•經刺激：1〇毫微克/毫升LPS (最後濃度）。 刺激私測係於抽取全血液試樣後一小時内進行。刺激檢測 程序係如下述。 h 將全血液試樣1+1以RPMI-1640培養基稀釋；藉由倒 置溫和地混合。 2·將經稀釋之全血液以吸量管吸取至兩個各別無菌 官件之每一個中（對各條件各一個管件）。 3·對各管件添加200微升適當LPS儲備液（或空白試 驗）以產生上文列示之最後LPS濃度。藉由倒置溫 和地混合。 自各s件，以每井〇·5毫升，溫和地添加至多個（例 如八個）母板塊井中。 5·任何空井應以0_5毫升PBS緩衝劑充填。 6·以其特定覆蓋物覆蓋母板塊。 7·於37 ◦與5% c〇2下培養24小時。 8·於培養期結束時，將板塊在室溫下，於1000χ克下離 心1〇分鐘。 123505 -300- 200815422 9·收集上層清液，並將適當井匯集至其適當聚丙烯管 件中（在1+1全血液稀釋丁之預期產率· 40-60。/〇體 積）。 10·此合，並为成數液份至個別管件中；對於欲被分析 之各細胞素各一個管件（每液份之標的上層清液體 積：0.5毫升）。 η·將試樣在-7〇°c下儲存，直到分析為止。 TNF- a、IL-1冷、IL-6或其他細胞素係使用經確認有效之 ELISA方法分析。 風濕性關節炎疾病評估·風濕性關節炎係以數種臨床 上所接X之尺度為基準，以臨床方式評分，譬如在美國專 利5,698，195 (其係併於本文供參考）與Aletaha等人，Εχρ Rheumatol· 2005,23 (補充39)，S 100中所述者。疾病活性及以治 療所達成之改變可使用疾病活性評分（DAS)及/或慢性關節 炎系統指數（CASI)評估，參閱 Carotti 等人，2002, Ann. Rheum. Dis. 61 · 877_882 與 Salaffi 等人，2〇〇〇, Rheumatology 39: go %。簡言之， 臨床回應研究可評估下列參數·· Α ·觸痛關節之數目；Β ·腫 脹關節之數目（對各關節個別地評估觸痛與腫脹兩者）；及 C·視覺類比疼痛尺度（0_10公分）。臨床回應係使用主觀報告 系統評估，如下述：毫無任何困難，有一些困難，有許多 困難，或無法進行。關於疼痛之視覺類比尺度為一直線， 其中該線之左端表示沒有疼痛，而該線之右端表示最差之 疼痛。病患被要求在其認為其疼痛所在之線上作記號。 此外’血液化學分析係測定CRp之含量、類風濕因子、 123505 -301 - 200815422 細胞素及其他生物標記物。 克隆氏病評估：克隆氏病活性指數· CDAI為納入客觀與 主觀兩訊息之病患評估形式。醫師係使用經建立之標準計 算CDAI評分。CDAI評分&gt;150係表示具有比評分&lt;150較差預 後之活性疾病（參閱 Best WR，Becktel JM，Singleton JW，Kem F Jr· 克隆氏病活性指數之發展，國家共同克隆氏病研究.胃腸 病學，1976 ; 70 ·· 439-444 ; Winship DH，Summers RW，Singleton JW 等 人，國家共同克隆氏病研究：研究設計與研究進行.胃腸病 1 學，1979 ; 77 : 829-842)。 牛皮癖疾病評估· 牛皮癖治療之功效可藉由疾病之臨 床跡象與徵候之變化進行監控，包括病患之牛皮癖面積與 嚴重性指數、（PASI)評分、醫師之總體評估（PGA)，與基線 症狀比較。於PASI評分上之降低係表示治療作用。牛皮癖 疾病活性亦可以整體損害嚴重性（OLS)尺度、被牛皮癣所影 響之全身表面積（BSA)之百分比及牛皮癣斑點厚度為基礎 進行測定。研究皮膚生物檢體，關於藥物對牛皮癬損害内 X 之淋巴細胞之作用。可進行皮膚生物檢體之組織學分析， 以尋找表皮厚度與T-細胞浸潤之降低及病理學表皮增生之 逆轉。免疫學活性可藉由測試治療對於細胞所媒介之免疫 反應（遲發過敏性）、破傷風抗體回應及淋巴細胞亞個體群 (流動細胞計數法）之作用進行監控。 實例4 :心血管與代謝疾病模式 脂質測定· 化合物之抗動脈粥瘤硬化活性可藉由測定 改變某些動物血漿中之血漿脂質含量，例如HDL膽固醇含 123505 -302- 200815422 1、LDL膽固醇含量、VLDL膽固醇含量或三酸甘油自旨，所 需要藥劑之量而証實，該動物例如狨（Crook等人，動脈硬化 10, 625, 1990)或金色敘利亞大頰鼠（Goulinet等人，j. Upid 34, 943，1993)及具有類似人類之血漿脂蛋白分佈形態之其他 動物。 在狨中之血液化學評估·將成年狨指定至治療組，以致 使各組具有總計、HDL及/或LDL血漿膽固醇濃度之類似平 均+Λ SD。於組別指定後，使狨每日服用化合物，作成食物 混合物或藉由胃内插管法，歷經一至八天。對照狨僅接受 服藥媒劑。血漿總計、LDL、VLDL及HDL膽固醇值可在研 究期間之任何時點，以下述方式測定，自肘前靜脈獲得血 液，並藉由密度梯度離心，將血漿脂蛋白分離至其個別亞 組中，且如前文所述度量膽固醇濃度（Crook等人，動脈硬化 10, 625, 1990)。 在獮猴屬猴子中之血液化學評估·將十六隻公與16隻 母獮猴屬猴子指定至四個劑量組。化合物係在適#媒劑 中於低+及㈤/辰度下調酉己。三種劑量之化合物及單獨 媒劑係藉由Π腔灌食法，每日_次投予相應劑量組中之所 有公與母狼子，歷經連續90天。血液試樣(4至6毫升)係在 第〇, 28及90天收集自股血管。將血液試樣處理以提供血 /月且臨床化學值，包括例如膽固醇、三酸甘油酷及 總膽紅素含量，係藉由標準方法測定。 在跑狀大白鼠中之血液化學評估.將八十隻雄性與80 隻雌性WiStar大白鼠指定至四個劑量組。化合物係在適當媒 123505 303 - 200815422 劑中，於低、中及冑濃度下調配。z種劑量之化合物及單 獨媒劑係藉由口腔灌食法’ #日—次❹相應劑量組中之 所有雄性與雌性大白鼠，歷經連續90天。血液試樣（2至3 毫升)係在第0,28及90天’經由眶竇收集。將血液試樣處理 以提供血清，且臨床化學值，包括例如1£〇1^膽固醇含量， 係藉由標準方法測定。 在金色敘利亞大頰鼠中之血液化學評估·將雌性金色 敘利亞大頰鼠（6-8週大）檢疫72小時，然後指定至治療組。 血液試樣係在服藥之前，於第〇天藉由後眶採血取得，並在 預冷卻之EDTA處理過之管件中處理成丨毫升血清。將各血 清試樣分成數液份至0.5毫升與0.3毫升體積，並儲存於_2〇 °C下’直到運輸為止。接著’將待測化合物或媒劑以經口 方式投予（對30宅克/公斤之劑量，典型上為5毫升/公斤）。 於第1-13天，#續在此等劑量下之每日一次服藥。於第2 天、第6或13天，末端採企係於最後口服劑量後數小時取 得，並處理血清，分成數液份’且以前述方式儲存。脂質 分析與臨床化學試驗名單分析係在所有血液試樣上進行。 兔子動脈粥瘤硬化檢測.化合物之抗動脈粥瘤硬化作 用可藉由降低兔子主動脈中之脂質沉積所需要之化合物量 測定。雄性紐西蘭白兔係被儀食含有Q·2%膽固醇與腦椰子 油之腾食’歷經4天（每天—讀飲餵食）。將兔子從邊緣耳 朵靜脈採血，且總血漿膽固醇值係測定自此等試樣。然後， 將兔子指定至治療組’以致使各組具有總血漿膽固醇濃 度、HDL膽固醇濃度、三酸甘油醋濃度及/或膽固醇醋轉移 123505 -304- 200815422 蛋白質活性之類似平均+/- SD。於組別指定後，使兔子每曰 服用化合物，以食物混合物或以小片之明膠為基料之糖劑 給予。對照兔子僅接受服藥媒劑，其為食物或明膠糖劑。 持續膽固醇/椰子油膳食，在整個研究中，伴隨著化合物投 藥。血漿膽固醇值可在研究期間之任何時點下，藉由從邊 緣耳朵靜脈獲得血液進行測定。於3-5個月後，使兔子犧 牲，並移除主動脈，從胸廓弓至骼動脈之分枝。將主動脈 清除動脈外膜，以縱向方式打開，然後未經染色或以Sudan IV 染色進行分析，如由 Holman 等人（Lab· Invest· 1958，7，42-47) 所述。經損害表面積之百分比係藉由光密度度量法，使用 Optimas影像分析系統（影像處理系統）定量。在與對照兔子 比較下，經降低之脂質沉積係藉由接受化合物組群中之經 損害表面積百分比上之降低顯示。 環帶所引致之加速動脈粥瘤硬化· 化合物係在老鼠模 式中測試再狹窄與加速動脈粥瘤硬化，以ApoE3 Leiden老鼠 中環繞股動脈之環帶安置為基礎（Lardenoye等人，Circ Res. 2000, 87(3) : 248-53)。此模式係藉由炎性因子高度地調節（Pires 等人，Cardiovasc Res，68(2005) 415-424)，包括 TNFa (Monraats 等人 FASEB J 2005 ; 19 : 1998-2004)與 MCP_1，如已被 Egashira 等人（Circ Res 2002 ; 90 : 1167-72)所証實者。在接受溫和血膽固醇過多 膳食之ApoE3 Leiden老鼠中之環帶安置，會造成單細胞之快 速黏連與浸潤，接著為新血管内膜形成之快速誘發，且會 在加環帶血管節段内造成泡沫細胞蓄積之誘發。 簡言之，在手術環帶安置之前，將雄性ApoE3 Leiden老鼠 123505 -305 - 200815422 ^年齡12週）餵食溫和&amp;膽固醇過多腊食，歷經3週。於 :::老鼠區分成3個組群，配合血漿膽固醇含量。老鼠無 ΤΙ?曰(從第1天開始)接受對照灌食法溶液或含有：測 /之灌食法溶液（典型上在30毫克/公斤之濃度下）。於 第0天進仃手術’意即將非挾縮性環帶（2-3毫米長度）環繞 ，鼠之兩條股動脈放置。於2天後，使老鼠犧牲，以供分： 早細胞黏連與浸潤，並於2週後，使其他老鼠犧牲，以供組123505 -299- 200815422 The compounds described herein are administered orally to humans at different doses. After 24 hours, the blood sample was collected into the vacuum vessel tube by venipuncture and the liver was deflated. Single cell counts were performed on individual undiluted, hepatic lipidated whole blood samples (Cell Dyn 3500 SL) prior to stimulation testing. For this project, a small volume (100-200 μl) was pumped directly from the whole blood sample into the analyzer. For each patient, the following stimulation tests were performed on each patient: a. unstimulated control group (media only) and 13 • stimulation: 1 〇 nanogram/ml LPS (final concentration). The stimulating private test is performed within one hour after the whole blood sample is taken. The stimulation test procedure is as follows. h Whole blood sample 1+1 was diluted in RPMI-1640 medium; gently mixed by inversion. 2. Draw the diluted whole blood into each of the two separate sterile parts by pipette (one tube for each condition). 3. Add 200 microliters of the appropriate LPS stock solution (or blank test) to each tube to produce the last LPS concentration listed above. Mix gently by inversion. From each s piece, 5 ml per well, gently added to multiple (for example, eight) mother plate wells. 5. Any empty well should be filled with 0_5 ml PBS buffer. 6. Cover the mother panel with its specific cover. 7. Train at 37 ◦ and 5% c〇2 for 24 hours. 8. At the end of the incubation period, the plate was centrifuged at 1000 gram for 1 minute at room temperature. 123505 -300- 200815422 9. Collect the supernatant and collect the appropriate wells into its appropriate polypropylene tubing (expected yield of 40 +1. / 〇 volume in 1 +1 whole blood dilution). 10. This combination is a fraction of the liquid to individual tubes; one tube for each cytokine to be analyzed (the upper supernatant per liquid: 0.5 ml). η· Store the sample at -7 ° C until analysis. TNF-a, IL-1 cold, IL-6 or other cytokines were analyzed using a validated ELISA method. Rheumatoid arthritis disease assessment · Rheumatoid arthritis is based on several clinically accepted X scales and is scored clinically, for example, in US Patent 5,698,195 (which is incorporated herein by reference) and Aletaha et al. , Εχρ Rheumatol· 2005, 23 (Supplement 39), as described in S 100. Disease activity and treatment-altered changes can be assessed using the Disease Activity Score (DAS) and/or the Chronic Arthritis System Index (CASI), see Carotti et al., 2002, Ann. Rheum. Dis. 61 · 877_882 and Salaffi et al. , 2〇〇〇, Rheumatology 39: go %. In short, the clinical response study can evaluate the following parameters: · Α · the number of tender joints; Β · the number of swollen joints (both assessment of tenderness and swelling for each joint individually); and C · visual analog pain scale ( 0_10 cm). The clinical response was assessed using a subjective reporting system, as described below: without any difficulty, with some difficulties, with many difficulties, or unable to proceed. The visual analog scale for pain is a straight line, where the left end of the line indicates no pain and the right end of the line indicates the worst pain. The patient is asked to mark the line on which he believes the pain is. In addition, the blood chemical analysis measures CRp content, rheumatoid factor, 123505 -301 - 200815422 cytokines and other biomarkers. Crohn's disease assessment: Crohn's disease activity index · CDAI is a form of patient assessment that incorporates both objective and subjective messages. The physician calculates the CDAI score using established criteria. CDAI score &gt; 150 indicates an active disease with a poor prognosis than score &lt; 150 (see Best WR, Becktel JM, Singleton JW, Kem F Jr. Development of Crohn's Disease Activity Index, National Common Crohn's Disease Study. Gastrointestinal Disease Xue, 1976; 70 ·· 439-444 ; Winship DH, Summers RW, Singleton JW, et al., National Common Crohn's Disease Research: Research Design and Research. Gastrointestinal Diseases 1 , 1979 ; 77 : 829-842 ). Psoriasis Assessment • The efficacy of psoriasis treatment can be monitored by changes in the clinical signs and symptoms of the disease, including the patient's psoriasis area and severity index, (PASI) score, and physician's overall assessment (PGA), and Baseline symptom comparison. The decrease in the PASI score indicates a therapeutic effect. Psoriasis disease activity can also be determined based on the overall severity of injury (OLS) scale, the percentage of body surface area (BSA) affected by psoriasis, and the thickness of the psoriasis spot. Study skin biopsies for the effects of drugs on lymphocytes in X lesions of psoriasis. Histological analysis of skin biopsies can be performed to find a reduction in epidermal thickness and T-cell infiltration and a reversal of pathological epidermal hyperplasia. Immunological activity can be monitored by testing the effects of cellular immune responses (late allergic), tetanus antibody responses, and lymphocyte subpopulations (flow cytometry). Example 4: Cardiovascular and Metabolic Disease Pattern Lipid Assays The anti-atherosclerotic activity of a compound can be determined by altering the plasma lipid content of plasma in certain animals, such as HDL cholesterol containing 123505-302-200815422 1, LDL cholesterol content, The VLDL cholesterol content or triglyceride is confirmed by the amount of the desired agent, such as sputum (Crook et al., arteriosclerosis 10, 625, 1990) or golden Syrian cheek (Goulinet et al., j. Upid 34). , 943, 1993) and other animals with a similar distribution pattern of plasma lipoproteins in humans. Blood Chemistry Assessment in Sputum • Adult sputum was assigned to the treatment group such that each group had a similar mean + Λ SD of total, HDL and/or LDL plasma cholesterol concentrations. After the group is designated, the compound is administered daily for a food mixture or by intragastric intubation for one to eight days. The control sputum only received the medicated vehicle. Plasma total, LDL, VLDL, and HDL cholesterol values can be determined at any point during the study, by obtaining blood from the anterior cubital vein and separating the plasma lipoprotein into individual subgroups by density gradient centrifugation, and Cholesterol concentrations were measured as previously described (Crook et al., Arteriosclerosis 10, 625, 1990). Blood Chemistry Assessment in Colobus Monkeys Sixteen males and 16 female monkeys were assigned to four dose groups. The compound is adjusted in low- and (five)/times in the medium. The three doses of the compound and the vehicle alone were administered to the male and female wolves in the corresponding dose group daily for 30 consecutive days by intra-oral feeding. Blood samples (4 to 6 ml) were collected from the femoral vessels on the third, 28 and 90 days. Blood samples are processed to provide blood/month and clinical chemical values, including, for example, cholesterol, triglyceride, and total bilirubin content, as determined by standard methods. Blood chemistry assessment in running rats. Eighty males and 80 female WiStar rats were assigned to four dose groups. The compounds are formulated in low, medium and hydrazine concentrations in the appropriate medium 123505 303 - 200815422. The z doses of the compound and the individual vehicle were administered to all male and female rats in the corresponding dose group by oral gavage for 90 consecutive days. Blood samples (2 to 3 ml) were collected on the 0th, 28th and 90th days via the sinus. Blood samples are processed to provide serum, and clinical chemical values, including, for example, 1 〇 1 ^ cholesterol content, are determined by standard methods. Blood Chemistry Assessment in Golden Syrian Bugs Rats were quarantined for 72 hours in female golden Syrian cheeks (6-8 weeks old) and assigned to the treatment group. Blood samples were taken on the third day by post-mortem blood collection and processed into pre-cooled EDTA-treated tubing into sputum milliliters of serum. Each serum sample was divided into several portions to a volume of 0.5 ml and 0.3 ml and stored at _2 ° C until the shipment. The compound or vehicle to be tested is then administered orally (for a dose of 30 kg/kg, typically 5 ml/kg). On days 1-13, # continued to take the drug once daily at these doses. On day 2, day 6, or day 13, the end of the harvest was obtained several hours after the last oral dose, and the serum was processed, divided into several portions&apos; and stored as previously described. Lipid analysis and clinical chemistry test list analysis were performed on all blood samples. Rabbit atherosclerosis detection. The anti-atherosclerosis effect of the compound can be determined by reducing the amount of compound required for lipid deposition in the aorta of rabbits. Male New Zealand white rabbits were eaten with Q. 2% cholesterol and brain coconut oil for a period of 4 days (daily-reading and feeding). Rabbits were bled from the marginal ear veins and total plasma cholesterol values were determined from these samples. The rabbits were then assigned to the treatment group&apos; so that each group had a similar mean +/- SD of total plasma cholesterol concentration, HDL cholesterol concentration, triglyceride concentration, and/or cholesterol vinegar transfer 123505 - 304-200815422 protein activity. After the group is designated, the rabbit is administered with the compound per meal, and is administered as a food mixture or as a small piece of gelatin-based sugar. Control rabbits received only the drug vehicle, which was a food or gelatin saccharide. A sustained cholesterol/coconut oil diet was administered along with the compound throughout the study. Plasma cholesterol values can be determined by obtaining blood from the marginal ear veins at any point during the study period. After 3-5 months, the rabbit was sacrificed and the aorta was removed, from the thoracic arch to the branch of the iliac artery. The aorta was removed from the adventitia, opened in a longitudinal manner and then analyzed without staining or staining with Sudan IV as described by Holman et al. (Lab·Invest 1958, 7, 42-47). The percentage of damaged surface area is quantified by optical density measurement using an Optimas image analysis system (image processing system). The reduced lipid deposition is shown by the decrease in the percentage of damaged surface area in the receiving compound group compared to the control rabbit. Accelerated atherosclerosis caused by the annulus. Compounds tested restenosis and accelerated atherosclerosis in a rat model, based on the placement of a ring around the femoral artery in ApoE3 Leiden mice (Lardenoye et al., Circ Res. 2000) , 87(3) : 248-53). This pattern is highly regulated by inflammatory factors (Pires et al, Cardiovasc Res, 68 (2005) 415-424), including TNFa (Monraats et al. FASEB J 2005; 19: 1998-2004) and MCP_1, if As confirmed by Egashira et al. (Circ Res 2002; 90: 1167-72). Placement in the annulus of ApoE3 Leiden mice receiving a mild hypercholesterol diet results in rapid adhesion and infiltration of single cells, followed by rapid induction of neovascular intimal formation and can be caused in the vascular segment of the vascular band Induction of foam cell accumulation. Briefly, male ApoE3 Leiden mice 123505 -305 - 200815422 ^ age 12 weeks were fed mild &amp; cholesterol overdose for 3 weeks prior to surgical ring placement. ::: The mice are divided into 3 groups to match the plasma cholesterol level. The mice were devoid of sputum? 曰 (from day 1) received a control solution or contained a test solution (typically at a concentration of 30 mg/kg). On the 0th day, the operation was performed. The intention was to surround the non-collapsed annulus (2-3 mm length), and the two femoral arteries of the mouse were placed. After 2 days, the rats were sacrificed for the purpose of: early cell adhesion and infiltration, and after 2 weeks, other mice were sacrificed for the group.

織形態測定分析’以定量經加速動脈粥瘤硬化性損傷盥新 血管内膜形成（之抑制）。 實例5 ·臨床心血管與代謝疾病評估 抗肥胖檢測· &amp;合物造成體重減輕之能力可在具有身 體貝里指數(BMI) - 30公斤/平方米之肥胖人類病患中評 估。抑制劑之劑量係經投予，其足以造成膽固醇含量 上一 15/。之牦加。BMI與體脂肪分佈，被定義為腰部（|)對 髖部⑻比例（WHR) ’係在3_6個月研究過程期間監測，且將 治療組之結果與接受安慰劑者比較。 關於葡萄糖與胰島素病症之診斷方法· 口服葡萄糖容 許度測試(OGTT)·纟葡萄糖容許度試驗期^，其可用以診 斷糖尿病，經斷食之病患係服用75克口服劑量之葡萄糖。 然後，在接著2小時内度量血糖含量。說明係以_〇指引 為基礎，但在2小時下血糖過多係大於或等於1]L1毫莫耳/ 升，或大於或等於7·0毫莫耳/升斷食，係被診斷為糖尿病。 OGTT在單純胰島素抗藥性中可為正常或溫和異常。在早期 度1中經常有升高之葡萄糖含量，反映出在胰島素生產中 123505 -306 - 200815422 之鲁後（用餐後）尖峰之損失。測試之延長（歷經再數小時） 可顯現出血糖過少之”急降後上升”，其料生理學餐後騰 島素回應失敗後，於胰島素生產中之㈣之結果。 j島素過多血糖正常之夾持·關於研究與定量胰島素 f ί 抗杂性之標準係為”胰島素過多金橋正常之夾持”，如此稱 呼係因其係度量補償增加之胰島素含量而不會造成低血糖 所必須之葡萄糖量。此程序係花費約2小時。經過末梢靜 將胰島素在每平方米每分鐘1(M2〇 下灌注。為補償 胰島素灌注，係灌注葡萄糖2〇%以保持血糖含量在5與Μ 也莫耳/升之間。葡萄糖灌注之速率係藉由每分鐘確認 糖a里而測知。低劑量胰島素灌注係較可用於評估肝臟 之回應’然而局劑量騰島素灌注可用於評估末梢（意即肌肉 與脂肪）胰島素作用。在試驗之最後3〇分鐘期間，葡萄糖灌 注之速率係測定胰島素敏感性。若需要高含量(7·5毫克/分 里或較南），則病患為胰島素敏感性。極低含量（4·〇毫克/ 分鐘或較低）係表示身體對胰島素作用具抗藥性。在4.0與 b毫克/分鐘間之含量並不明確，且暗示”減弱之葡萄糖容 許度’其為胰島素抗藥性之早期跡象。 在夾持技術之複雜性質（與在一些病患中低血糖之潛 在危險）下，已尋找替代方式，以簡化胰島素抗藥性之度 弟種為專穩模式評估（HOMA) [Matthews DR，Hosker JP， ki AS’ Naylor BA，Treacher DF，Turner RC·等穩性模式評 估·知自人類中之斷食血漿葡萄糖與胰島素濃度之胰島素 抗藥性與尽細胞功能· Diabetologia 1985 ; 28 ·· 412-9]，而較最近 123505 -307- 200815422 之方法為QUICKI (定量胰島素敏感性確認指數）。兩者均採 用斷食胰島素與葡萄糖含量，以計算胰島素抗藥性，且兩 者均與夾持研究之結果合理地產生關聯。 使用斷食血液試樣，胰島素抗藥性（IR)係利用下式定量： IR =葡萄糖（毫克/公合））X胰島素（//U/毫升）/ 405 在此方程式中，若葡萄糖以毫莫耳/升作報告，則吾人應 使用常數22.5代替405。此模式係與使用血糖正常夾持方法 之估計值良好地關聯。 在1.7與2.5間之HOMA IR值係在具有正常葡萄糠容許度之 病患中被發現[Tripathy D，Carlsson M，Almgren P，Isomaa Bo, Taskinen MR，Tuomi T，Groop LC :關於葡萄糖容許度之胰島素分 泌與胰島素敏感性：來自Botnia研究之課程·糠尿病49 : 975-980, 2000 ； Bonora E? Kiechl S? Willeit J, Oberhollenzer F? Egger G? Targher G，Alberiche M，Bonadonna RC，Muggeo M :胰島素抗藥性在 代謝病症中之普及：Bruneck研究·糖尿病47: 1643-1649, 1998 ; Juan F. Ascaso，MD，Susana Pardo，MD，Jose T. Real，MD，Rosario I· Lorente，MD，Antonia Priego, MD 及 Rafael Carmena，MD 藉由簡易定 量方法在具有正常葡萄糖新陳代謝作用之病患中診斷胰島 素抗藥性，Diabetes Care 26 : 3320-3325, 2003]。 實例6:臨床試樣中之生物標記物之分析 具有低HDL_C與高TG含量之病患，使用或未使用共存降 低脂質療法（例如制菌素、膽汁酸多價螯合劑或膽固醇吸收 抑制劑），係以如本文中所述之化合物治療，每日一次以經 口方式投藥，歷經6週。斷食脂質試驗名單（總膽固醇、 123505 -308 - 200815422 HDL-C、LDL-C、TG)、CRP及一般實驗室參數（CBC、一般化 學试驗名單）係在基線下、服藥期間之每兩週及服藥結束後 之4週評估。在第1週，病患具有經評估之-般化學試驗名 單。體重及腰部與髖部圓周係在第丨週以外之每次探訪時評 估月曰貝/代身乂性及血栓形成前生物標記物係在基線 下、第2週、第4週、第6週及追蹤評估。尿分析法與凝血 參數係在基線下與服藥結束時評估。 實例7 :癌症模式 增生檢測·人類非小細胞肺癌細胞A549 (ATCC# CCL-185) 係於37 C +/·0·5 C與5% C〇2下，在經補充1〇% FBS、2福麩醯 胺、1%青黴素及1%鏈黴素之DMEM中生長。抗增生檢測係 在384-井板中進行。將6·6微升1〇χ儲備化合物溶液，添加至 檢測井中之40微升培養基内。腫瘤細胞係使用〇·25%胰蛋白 酶之溶液自培養燒瓶釋出。將細胞在培養基中稀釋，以致 使3000或6000個細胞在2〇微升培養基中釋放至各檢測井 中。將檢測板在37 C +/-0.5°C與5% C〇2下培養72-80小時。在 培養期之後，將已溫熱至3η：^0·5^之二十微升2〇%八丨啦虹 Blue添加至各檢測井中。AlamarBlue新陳代謝作用係於添加 後3.5-5.0小時，藉由螢光強度之量定量。使用〇1^_他 讀取器（LJLBi〇Systems)之定量，係在井之中間取得，使用高 衰減，励毫秒讀取時間，在53G毫微米下之激發濾光鏡， 及在575毫微米下之發射濾光鏡。對於一些實驗，定量係使 用Wallac Victor^讀取器進行。度量值係在井之頂部取得，使 用經安定化之能量燈控制；1〇〇毫秒讀取時間，在53〇毫微 123505 -309- 200815422 米下之激發濟#拉Ώ 先鏡及在590毫微米下之發射 取器之間，未度量出顯著差異。 先鏡在“ ❶關於各井之抑制百分比(%1)係使用下式計算： 。单Μι 缝處理之井_經處理之井)/(平均未經處理之井)】χ 100 ^ 經處理之井值（平均未經處理之井）係為得自單獨 以媒』處理之相同檢測板之4G個井之算術平均。當與未經 處里之井比較時，負抑制值係由於經處理井中之局部偏差 所造成。 °Weaving morphology assays 'to quantify accelerated atherosclerotic lesions and new intimal formation (inhibition). Example 5 • Clinical Cardiovascular and Metabolic Disease Assessment The ability of anti-obesity testing &&amp; composition to cause weight loss can be assessed in obese human patients with a body Bile Index (BMI) - 30 kg/m2. The dose of the inhibitor is administered, which is sufficient to cause a cholesterol level of 15/. After that. The BMI and body fat distribution, defined as the waist (|) versus hip (8) ratio (WHR) was monitored during the 3-6 month study period and the results of the treatment group were compared to those receiving the placebo. Diagnostic methods for glucose and insulin disorders • Oral glucose tolerance test (OGTT) • Glucose tolerance test period ^, which can be used to diagnose diabetes, and patients who are fasted take 75 grams of oral dose of glucose. Then, the blood sugar level was measured over the next 2 hours. The instructions are based on the _〇 guidelines, but the hyperglycemia at 2 hours is greater than or equal to 1] L1 millimoles per liter, or greater than or equal to 7·0 millimoles per liter of fasting, which is diagnosed as diabetes. OGTT may be normal or mildly abnormal in insulin resistance alone. Elevated glucose levels are often present in early stage 1 and reflect the loss of peaks after meals (after meals) between 123505 - 306 and 200815422 in insulin production. The extension of the test (after a few hours) can show the hypoglycemia "rise after a sudden drop", which is the result of (4) in insulin production after the response to the failure of the physiology meal. j 素 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多 过多The amount of glucose necessary for hypoglycemia. This program takes about 2 hours. Insulin is perfused at a rate of 1 (M2) per minute per minute. To compensate for insulin perfusion, 2% of glucose is perfused to maintain a blood glucose level between 5 and Μ 莫 / liter. It is detected by confirming the sugar a every minute. The low-dose insulin perfusion system can be used to evaluate the liver response. However, the local dose of Tengdasu perfusion can be used to evaluate the insulin action of the distal (ie muscle and fat). At the end of the experiment. During the 3 minute period, the rate of glucose perfusion is determined by insulin sensitivity. If high levels (7.5 mg/min or south) are required, the patient is insulin sensitive. Very low content (4·〇 mg/min) Or lower) indicates that the body is resistant to insulin. The content between 4.0 and b mg/min is not clear and implies "attenuated glucose tolerance" which is an early indication of insulin resistance. The complex nature (and the potential risk of hypoglycemia in some patients) has been sought as an alternative to simplifying insulin resistance to the degree of stability model assessment (HOMA) [Mat Thews DR, Hosker JP, ki AS' Naylor BA, Treacher DF, Turner RC·Equilibrium model evaluation · Insulin resistance and cell function in fasting plasma glucose and insulin concentrations in humans · Diabetologia 1985 ; 28 · · 412-9], and the more recent method of 123505 -307- 200815422 is QUICKI (Quantitative Insulin Sensitivity Confirmation Index). Both use fasting insulin and glucose content to calculate insulin resistance, and both are sandwiched. The results of the study were reasonably correlated. Using a fasting blood sample, insulin resistance (IR) was quantified using the following formula: IR = glucose (mg/m)) X insulin (//U/ml) / 405 In this equation, if glucose is reported in millimoles per liter, we should use a constant of 22.5 instead of 405. This pattern is well correlated with estimates using normal blood glucose clamping methods. HOMA IR values between 1.7 and 2.5 It was found in patients with normal vine tolerance [Tripathy D, Carlsson M, Almgren P, Isomaa Bo, Taskinen MR, Tuomi T, Groop LC: Islet on glucose tolerance Secretion and Insulin Sensitivity: Courses from Botnia Research · Diarrhea 49: 975-980, 2000; Bonora E? Kiechl S? Willeit J, Oberhollenzer F? Egger G? Targher G, Alberiche M, Bonadonna RC, Muggeo M: The spread of insulin resistance in metabolic disorders: Bruneck Research Diabetes 47: 1643-1649, 1998; Juan F. Ascaso, MD, Susana Pardo, MD, Jose T. Real, MD, Rosario I Lorente, MD, Antonia Priego , MD and Rafael Carmena, MD Diagnose insulin resistance in patients with normal glucose metabolism by simple quantitative methods, Diabetes Care 26: 3320-3325, 2003]. Example 6: Analysis of biomarkers in clinical samples Patients with low HDL_C and high TG levels, with or without coexistence, reduced lipid therapy (eg, bacteriocin, bile acid sequestrant or cholesterol absorption inhibitor) It is treated with a compound as described herein and administered orally once a day for 6 weeks. The list of fasting lipid tests (total cholesterol, 123505 -308 - 200815422 HDL-C, LDL-C, TG), CRP and general laboratory parameters (CBC, general chemical test list) are at baseline and every two days during the medication period. Week and assessment 4 weeks after the end of medication. In the first week, the patient had a list of evaluated chemical tests. Body weight and lumbar and hip circumference were evaluated at each visit outside the third week of the month of mussel/generation and prethrombotic biomarker at baseline, week 2, week 4, week 6. And tracking assessment. Urinalysis and coagulation parameters were assessed at baseline and at the end of dosing. Example 7: Detection of cancer pattern hyperplasia · Human non-small cell lung cancer cell A549 (ATCC# CCL-185) is lined with 37 C +/·0·5 C and 5% C〇2, supplemented with 1% FBS, 2 Glucosamine, 1% penicillin and 1% streptomycin were grown in DMEM. The anti-proliferation assay was performed in a 384-well plate. 6.6 μl of a 1 〇χ stock solution was added to 40 μl of the medium in the well. Tumor cell lines were released from the culture flask using a solution of 25% trypsin. The cells were diluted in culture medium so that 3000 or 6000 cells were released into each well in 2 μl of medium. The assay plates were incubated at 37 C +/- 0.5 ° C with 5% C 〇 2 for 72-80 hours. After the culturing period, twenty microliters of 2 〇% octagonal rainbow blue, which had been warmed to 3 η: ^0·5^, was added to each of the detection wells. AlamarBlue metabolism is quantified by the amount of fluorescence intensity after 3.5-5.0 hours of addition. Quantification using 〇1^_他读器 (LJLBi〇Systems), taken in the middle of the well, using high attenuation, excitation millisecond read time, excitation filter at 53G nm, and at 575 nm Under the launch filter. For some experiments, quantification was performed using a Wallac Victor(R) reader. The metric is obtained at the top of the well, using a stabilized energy lamp control; 1 〇〇 millisecond reading time, at 53 〇 nano 123505 -309- 200815422 meters under the stimulus #拉Ώ Ώ and at 590 millimeters No significant differences were measured between the emitters under the micrometer. The prosthesis is calculated as follows: ❶ Percentage of inhibition (%1) for each well is calculated using the following formula: . Μ Μ 处理 处理 _ _ 经 ( ( ( ( ( ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ The well value (average untreated well) is the arithmetic mean of 4G wells from the same test plate treated with the media alone. When compared to the well without the well, the negative inhibitor value is due to the treated well Caused by local deviations.

可以本文所指之腫瘤細胞系証實之抗癌作用，可以類似 方式使用其他癌細胞系証實，例如NSC肺癌、MCF7乳房腺 癌、PA—1卵巢畸胎癌、HT29結腸直腸腺癌、H1299大細胞癌、 U-2 OS成骨質肉瘤、u_373 MG神經膠質母細胞瘤、MG 神經膠質母細胞瘤、UL138 MG神經膠質母細胞瘤、LN-229 神經膠質瘤、Hep-3B肝細胞癌、BT-549乳房癌、T-24膀胱癌、 C-33A子宮頸癌、HT-3轉移性子宮頸癌、SiHa鱗狀子宮頸癌、 CaSki表皮樣子宮頸癌、NCI-H292黏膜表皮樣肺癌、 NCI-2030、非小細胞肺癌、HeLa、子宮頸腺癌、KB上皮口 癌、HT1080上皮纖維肉瘤、Saos-2上皮成骨質肉瘤、PC3上 皮前列腺腺癌、SW480結腸直腸癌、CCL-228、MS-751表皮 樣子宮頸癌、LOX IMVI黑色素瘤、MALME-3M黑色素瘤、 M14黑色素瘤、SK-MEL-2黑色素瘤、SK-MEL-28黑色素瘤、 SK-MEL-5黑色素瘤、UACC-257黑色素瘤或UACC-62黑色素瘤 細胞系。專一性可利用細胞測試’譬如NHLF肺臟纖維母細 胞、NHDF皮膚纖維母細胞、HMEC乳房上皮細胞、PrEC前 123505 -310- 200815422 列腺上皮細胞、HRE腎上皮細胞、NHBE枝氣管上皮細胞、 CoSmC結腸平滑肌細胞、CoEC結腸内皮細胞、ΝΗΕΚ表皮角 質細胞及骨髓細胞作為對照細胞。 正如熟諳此藝者所明瞭，更多種癌細胞系，譬如可得自 美國培養物類型收集處（ATCC)(郵政信箱1549 Manassas，VA 20108, USA)者，可以類似方式使用。， 實例8 / 表5係列出使用實例1-2方法所製成之本發明化合物。各 化合物係藉由LC-MS分析，且顯示預期之分子離子。本發 明化合物可藉一或多種上述方法檢測，且在一或多種上述 才欢測中具有或預期具有活性。例如，表5中之各化合物係在 腿EUSA檢測（實例3)中測試，且發現於其中具有活性， 其中一些化合物在此項檢測中具有^低於1〇 _。 編號 1 — —--- 表 5· ^ ^ --~~~--__ _ 化合物名稱 3-第三-丁基-5-氰基 -Ν-(6-甲基-5-(3-(新戊基 胺甲醯基）苯基 &gt;吡啶 各基）苯甲醯胺 2 N-(5-(4-(爷氧基）苯 基）各甲基吡啶-3-基）· 3-第三-丁基-5-氰基苯 甲醯胺 3 —-—— ~--~~——__ 3-第三-丁基―5·氰基 -Ν·(5-(4-(3,3·二甲基-2- 酮基丁氧基）苯基）-6-甲基吡啶-3-基）苯甲 醯胺 123505 -311 - 200815422 f 編號 結構 化合物名稱 4 5 6 7 8 9 10The anti-cancer effect confirmed by the tumor cell line referred to herein can be confirmed in a similar manner using other cancer cell lines, such as NSC lung cancer, MCF7 breast adenocarcinoma, PA-1 ovarian teratoma, HT29 colorectal adenocarcinoma, H1299 large cell. Carcinoma, U-2 OS osteosarcoma, u_373 MG glioblastoma, MG glioblastoma, UL138 MG glioblastoma, LN-229 glioma, Hep-3B hepatocellular carcinoma, BT-549 Breast cancer, T-24 bladder cancer, C-33A cervical cancer, HT-3 metastatic cervical cancer, SiHa squamous cervical cancer, CaSki epidermoid cervical cancer, NCI-H292 mucosal epidermoid lung cancer, NCI-2030, non Small cell lung cancer, HeLa, cervical adenocarcinoma, KB epithelial carcinoma, HT1080 epithelial fibrosarcoma, Saos-2 epithelial osteosarcoma, PC3 epithelial prostate adenocarcinoma, SW480 colorectal cancer, CCL-228, MS-751 epidermoid cervix Cancer, LOX IMVI melanoma, MALME-3M melanoma, M14 melanoma, SK-MEL-2 melanoma, SK-MEL-28 melanoma, SK-MEL-5 melanoma, UACC-257 melanoma or UACC-62 Melanoma cell line. Specificity can be measured by cell assays such as NHLF lung fibroblasts, NHDF dermal fibroblasts, HMEC mammary epithelial cells, PrEC pre-123505-310-200815422 glandular epithelial cells, HRE renal epithelial cells, NHBE branch tracheal epithelial cells, CoSmC colon Smooth muscle cells, CoEC colonic endothelial cells, sputum epidermal keratinocytes and bone marrow cells were used as control cells. As is well known to those skilled in the art, more cancer cell lines, such as those available from the American Type Culture Collection (ATCC) (Post Office Box 1549 Manassas, VA 20108, USA), can be used in a similar manner. Example 8 / Table 5 Serialize the compounds of the invention prepared using the procedures of Examples 1-2. Each compound was analyzed by LC-MS and showed the expected molecular ion. The compounds of the present invention can be detected by one or more of the above methods and have or are expected to be active in one or more of the above. For example, each of the compounds in Table 5 was tested in the leg EUSA test (Example 3) and found to be active therein, some of which have ^ less than 1 〇 in this assay. No. 1 — — — — — Table 5· ^ ^ --~~~--__ _ Compound name 3-T-butyl-5-cyano-indole-(6-methyl-5-(3-( Neopentylamine indenyl)phenyl&gt;pyridinyl)benzamide 2 N-(5-(4-(yloxy)phenyl)methylpyridin-3-yl)· 3- Tri-butyl-5-cyanobenzamide 3 ————— ~--~~——__ 3-Terti-butyl-5·cyano-Ν·(5-(4-(3, 3·Dimethyl-2-ketobutoxy)phenyl)-6-methylpyridin-3-yl)benzamide 123123505 -311 - 200815422 f No. Structure Compound Name 4 5 6 7 8 9 10

醋酸4-(5-(5-第三-丁基 -2-甲氧基苯甲醯胺 基）-2-甲基口比σ定-3-基） 苯酉旨4-(5-(5-Third-butyl-2-methoxybenzylideneamino)-2-methyl-hydroxypyrene-3-yl)acetate

3-第二-丁基-5-氣基 _Ν-(5-(4-甲氧基-2-甲基 苯基&gt;6-甲基吡啶-3-基）苯甲醯胺3-second-butyl-5-carbyl Ν-(5-(4-methoxy-2-methylphenyl&gt;6-methylpyridin-3-yl)benzamide

3-第二-丁基-5-鼠基 -N-(6-甲基-5-(4-(新戊基 胺甲醯基）苯基）-吡啶 -3-基）苯甲醯胺3-second-butyl-5-murine-N-(6-methyl-5-(4-(neopentylcarbinyl)phenyl)-pyridin-3-yl)benzamide

3-氣-N-(6-甲基-5-(4-(新 戊基胺甲醯基）苯基）-外匕咬-3-基）-5-嗎福淋基 苯甲醯胺3-gas-N-(6-methyl-5-(4-(neopentylaminocarbyl)phenyl)-outer guan-3-yl)-5-morphine-based benzylamine

3-第二-丁基-5-鼠基 -N-(6-甲基-5-(4-(四氫 -2H-哌喃-4-基胺甲醯 基）苯基）吡啶-3-基）苯 甲醯胺3-Second-butyl-5-muro-N-(6-methyl-5-(4-(tetrahydro-2H-piperidin-4-ylaminocarbamoyl)phenyl)pyridine-3- Benzomamide

3-氟-N-(5-(4-甲氧苯 基）-6-甲基吡啶-3-基）-5- 嗎福啉基苯甲醯胺3-fluoro-N-(5-(4-methoxyphenyl)-6-methylpyridin-3-yl)-5-morpholinobenzamide

N-(5-(4-乙醯基苯基）-6- 甲基17比σ定-3-基）-5-弟二 -丁基-3-氮基-2-甲氧基 苯甲醯胺 123505 -312- 200815422 編號 結構 化合物名稱 11 OH 3-(胺基甲基）-5-第二_ 丁基-N-(5-(4-(l-經乙基） 苯基）-6-甲基吡啶-3-基）-2-甲氧基苯甲醯胺 12 Η0^ν HO, 〇\ 0 I人 5-弟二-丁基-3-(N-|^ 基 碳胺基亞胺基）&quot;Ν» (5-(4-(1-(羥亞胺基） 乙基）苯基）-6-甲基吡 0定-3-基）-2-曱氧基苯曱 隨胺 13 \ 5’-(3-第三-丁基-5-氰基 苯甲醯胺基）-7-甲基 -N-((四氮咬喃-2-基） 曱基）-2,3’-聯吡啶-5-羧 醯胺 14 \ 5*-(3-第二-丁基-5-鼠基 苯甲醯胺基）-2’-甲基 -N·((四氮咬喃-2-基） 甲基）-3,3f-聯吡啶-6-羧 醯胺 15 3-第三-丁基_5_亂基 -]^-(6-甲基-5-(4-(六鼠口比 啶小基胺曱醯基） 苯基）吡啶-3-基）苯甲 醯胺 16 W^H 3-第三-丁基-5-鼠基 -N-(6_ 甲基-5-(4-(N-新戊 基胺績酸基）苯基）p比 啶-3-基）苯甲醯胺 17 0 y£^ 1-(5-(3-氟基-5-嗎福琳 基苯甲醯胺基）-2-甲基 外匕淀-3-基）-N-((四氫吱 喃-2-基）甲基）-1Η-1，2,3-三唑-4-羧醯胺 123505 -313- 200815422 編號 結構 化合物名稱 18 0 V 〇 人 N-(5-(4-第三·丁基 -1H-1，2,3-三唑-1-基）-6-甲基说。定-3-基）-3-氣基 -5-嗎福淋基苯甲醯胺 19 3-氟-N-(6-甲基-5-(4-(吡 啶-2-基）_1H-1，2,3-三唑 -1-基）p比σ定-3-基）-5-嗎福 啉基苯甲醯胺 20 0 / Λ H rC° 3-氟-N-(5-(4-(甲氧基甲 基）-1Η-1，2,3-三唑-1-基）-6-甲基说σ定-3-基）-5- 嗎福啉基苯甲醯胺 21 &quot;V νΝ(Γ^ ，為 hxxn;n 1-(5-(3-第三-丁基-5-氰 基苯曱醯胺基）-2-甲基 口比咬-3-基）-N-新戍基 -1Η-1，2,3·三唑-4-羧醯胺 22 + v&gt; n^Vxx‘n 3-第二-丁基-5-氮基 -Ν-(6-甲基-5-(4-(3-甲基 丁醯基）-1Η-1，2,3-三唑 -1-基）口比咬-3-基）苯甲 醯胺 23 + H〇，yV n^Vxx‘N (Z)-3-第二-丁基-5-氣基 -N-(5-(4-(l-(羥亞胺 基）-3-曱基丁 基）-1Η-1，2,3-三唑小 基）-6-甲基吡啶-3·基） 苯甲醯胺 123505 314- 200815422 編號 結構 化合物名稱 24 3-弟二-丁基-5-氣基 -Ν-(6-甲基-5-(4-(2-曱基 -1_(新戍基胺基）_1-酉同 基丙烷-2-基）-1Η-1，2,3-三唑-1-基）吡啶-3-基） 苯甲醯胺 25 士 N-(3-第二-丁基-5·氰基 苯基)·6-曱基-5-(4-(新戍 基胺甲醯基）-lH-l，2,3-三 ϋ坐 -1-基）於 驗醯胺 26 0 , Νόν〆 w Ν-(6-甲基-5-(4-(新戊基 胺甲醯基）-1Η-1，2,3-三 唑-1-基）吡啶-3-基&gt;2-嗎 福琳基異於驗酸胺 27 0 , hniX'n，n N-(6-甲基-5-(4-(新戊基 胺甲醯基）-1Η-1，2,3-三 ϋ坐-1-基）p比σ定-3-基）-2-(六鼠咕咬-1-基） 異菸鹼醯胺 28 〔N〕 。了0&lt; 3-氣-N-(6-甲基-5-(3-(新 戊基胺甲醯基）苯基） 叶匕唆基）-5-嗎福p林基 苯曱醯胺 29 Λ^?° 3_第三-丁基-5-氣基 -N-(5-(3-(二甲基胺曱醯 基）苯基&gt;6-曱基吡啶 -3-基）苯甲醯胺 123505 -315 - 200815422 編號 結構 化合物名稱 30 1-(5-(5-第三-丁基-2-曱 氧基苯曱酸胺基）-2-甲 基吡啶-3-基）-N·新戊基 -1H-1，2,3-三唑-4-羧醯胺 31 ◦ A 1-(5-(3-氟基-5-嗎福啉 基苯甲醯胺基）-2-甲基 叶匕°定-3-基）-N-新戊基 -1Η·1，2,3-三唑-4-羧醯胺 32 C 5-第三·丁基-2-甲氧基 -Ν-(5-(6-甲氧基莕-2-基）-6-甲基ρ比σ定-3-基） 苯甲醯胺 33 / 3-第三-丁基-5-氰基 -Ν-(5-(3-(3,3-二甲基丁 醯胺基）苯基）-6-曱基 吡啶_3·基）苯甲醯胺 34 〇 N-(2,6f-二甲基-3,4f-聯口比 唆-5-基）-3-氣基-5-嗎福 啉基苯甲醯胺 35 W6 3-第二-丁基-5-乳基 -N-(2,6’-二甲基-3,4’-聯 吡啶-5-基）苯甲醯胺 36 0 3-說·Ν-(5-(4·曱氧基-3-甲基苯基）-6-甲基吡啶 -3-基）-5-嗎福14木基苯甲 醯胺 123505 -316- 200815422 編號 結構 化合物名稱 37 Ν-(5-(4-乙醯基苯基）-6-曱基吡啶-3-基）-5-第三·丁基-2-曱氧基苯 甲醯胺 38 N-(5-(4-乙醯基苯基）-6-甲基吡啶_3_基）-5-第三 -丁基-2-甲氧基-3-(甲 基磺醯胺基）苯甲醯胺 39 0 。 N-(5-(4-乙醯基苯基）-6-甲基被唆-3-基）-3-敗基 -5-嗎福p林基苯甲醯胺 40 \ ζ ^V〇 N-(5-(4-(芊基胺甲醯基） 苯基&gt;6-甲基吡啶-3-基）-5·第三-丁基-2-甲 氧基苯甲醯胺 41 ς /〇 5-第三-丁基-N-(5-(4-(3,4-二甲氧基苄基 胺甲醯基）苯基）-6-曱 基的b。定_3_基）-2-甲氧基 苯甲醯胺 42 /( 5-第三-丁基-2-甲氧基 _Ν-(5-(4-(3·甲氧基苄基 胺甲醯基）苯基）-6-甲 基吡啶-3-基）苯甲醯胺 43 〇 。 N-(5-(4-(苄基胺曱醯基） 苯基）-6-甲基吡啶-3-基）-3-氣基-5-嗎福淋基 苯甲醯胺 123505 -317- 200815422 編號 結構 化合物名稱 44 0 。 Ν-(5-(4-(3,5-二甲氧基芊 基胺甲酷基）苯基）-6-甲基峨唆-3-基）-3·氟基 -5-嗎福啉基苯曱醯胺 45 〇 。 0 3·氟-N-(5-(4-(3-甲氧基 苄基胺甲醯基）苯 基）-6-甲基^比σ定-3-基）-5_ 嗎福啉基苯甲醯胺 46 0 。 3-氟-Ν-(5-(4-(4-曱氧基 苄基胺甲醯基）苯 基）-6-甲基吡啶-3-基）-5- 嗎福啉基苯甲醯胺 47 0 。 N-(5-(4-(苯并[d][l，3]二 氧伍圜烯-5-基曱基胺 甲醯基）苯基）-6-甲基 叶匕σ定-3-基）-3-氣基-5-嗎 福啉基苯甲醯胺 48 0 &gt;Ν^ 為Vx^ 1-(5-(3-氟基-5-嗎福琳 基苯甲醯胺基）-2-甲基 口比σ定-3-基）-N-(p比咬-3-基甲基）-1Η_1，2,3-三唑 -4-羧醯胺 49 0 〆 為Vi^ 1-(5-(3-氣基-5-嗎福p林 基苯甲醯胺基）-2-甲基 口比。定-3-基）-N-異丁基 -1H-1，2,3-三唑-4-羧醯胺 123505 318- 200815422 編號 結構 化合物名稱 50 0 Ν~(ί哀丙基甲基）-1-(5-(3_ 氣基-5-嗎福淋基苯曱 醯胺基）-2-甲基吡啶-3-基）-lH_l，2,3-三唑-4-羧 醯胺 51 〔°〕 r^f Y Vnh 1-(5-(3-氟基-5-嗎福淋 基苯甲醯胺基）-2-甲基 吡啶各基）-N-(3,3,3-三 氟丙基）-1Η-1，2,3-三唑 -4-羧醯胺 52 0 。 3-氟-N-(6_ 甲基-5-(4-((四 氫-2H-哌喃-4-基）甲基 胺甲醯基）苯基）叶b唆 -3·基）-5-嗎福啉基苯甲 醯胺 53 0 。 3-氟-N-(6-甲基-5-(4-((四氫咬喃-2-基）甲基 胺甲醯基）苯基）吡啶 -3-基）-5-嗎福4木基苯甲 酿胺 54 &lt; 0、 5-第三-丁基-N-(5-(4-(3,5-二甲氧基芊基 胺甲醯基）苯基）-6-甲 基外b咬-3-基）-2-甲氧基 苯甲醯胺 55 \ C W°H N-(5-(4-(苯并[d][l，3]二 氧伍圜烯-5-基甲基胺 甲醯基）苯基）-6-甲基 口比 °定-3-基）-5-第二丁 基-2-甲氧基苯甲醯胺 56 、 C 5-第二-丁基-2-曱氧基 -N-(6-甲基-5-(4-(口比 σ定-3- 基甲基胺甲醯基） 苯基）口比啶各基） 苯甲醯胺 123505 -319- 200815422 編號 結構 化合物名稱 57 C 、/ 0 1^0 5·第三-丁基-2-甲氧基 -Ν-(6-甲基-5-(4·(四氫 -2Η-哌喃-4-基胺曱醯 基）苯基）ρ比σ定-3-基）苯 甲醯胺 58 ς 0 VyyO^ 、〇 5·第三-丁基-2-甲氧基 -Ν-(6-甲基-5-(4-((四氫 -2H-哌喃-4-基）甲基胺 甲醯基）苯基）吡啶-3-基）苯甲醯胺 59 \ ς C 5-第三-丁基-2-甲氧基 -N-(6-甲基-5-(4-((四鼠 呋喃-2-基）甲基胺甲醯 基）苯基 &gt;比淀-3-基）苯 甲醯胺 60 0 。 N-(5-(4-(3,4-二曱氧基芊 基胺甲醯基）苯基）-6-甲基峨ϋ定-3-基）-3-亂基 -5-嗎福啉基苯甲醯胺 61 〇 。 3-氟-Ν-(6·甲基-5-(4-(吡 啶-3_基甲基胺甲醯基） 苯基）^比咬-3-基）-5-嗎 福啉基苯甲醯胺 62 〇、〇 0 4-((4-(5·(5-第三-丁基 _2-甲氧基苯甲醯胺基）-2-曱基吡啶-3-基）苯甲醯 胺基）甲基）苯甲酸曱酯 63 0 。Γ。 0 3-氣-N-(6-曱基 _5-(4-(四 氫-2H_哌喃-4-基胺甲 酿基）苯基)说σ定-3-基)-5-嗎福啉基苯甲醯胺 123505 -320- 200815422 編號 結構 化合物名稱 64 0 。 4-((4-(5-(3-氟基-5-嗎福 淋基苯甲酿胺基）-2-甲 基吡啶-3-基）苯甲醯胺 基）甲基）苯甲酸曱酯 65 3-第二-丁基-5-亂基 -N-(6-甲基-5-(4-((四氫 呋喃-2-基）甲基胺甲醯 基）苯基比17定-3-基）苯 甲醯胺 66 3-第二-丁基-5-氣基 -N-(6-甲基-5-(4-((四氫 -2H-哌喃-4-基）甲基胺 甲醯基）苯基）吡啶-3-基）苯甲醯胺 67 N-(5-(4-(苄基胺甲醯基） 苯基）-6-甲基吡啶-3-基）-3·第二-丁基-5-氣 基苯甲醯胺 68 〇 v&lt; 1-(5-(3-氟基-5-嗎福淋 基苯甲醯胺基）-2-甲基 吡啶-3-基）-N，N-二甲基 -1H-1，2,3-三唑-4-羧醯胺 69 O' 〆 ΛκΧΧν；，ν 1-(2-甲基-5-(3-嗎福啉 基-5-(三氟甲基）苯甲 酿·胺基）口比σ定-3-基）-N-新戊基-1Η-1，2,3-三唑-4- 羧醯胺 70 ο. r^T Ν V-NH 1-(2-甲基-5-(3-(四鼠口比 咯-1-基）-5-(三氟甲基）-苯甲醯胺基）吡啶-3-基）-N-新戊基-1H-1，2,3-三唑-4-羧醯胺 123505 -321 - 200815422 編號 結構 化合物名稱 71 1-(5-(3-氟基-5-(六氮p比 啶-1-基）苯甲醯胺 基）-2-甲基峨咬-3-基）-N-新戊基-1H-1，2,3-三唑-4-羧醯胺 72 〇 1-(5-(3-氟基-5-(四氫吡 咯小基）苯曱醯胺 基）-2-甲基吡啶-3· 基）-N-新戊基-1H-1，2,3-三唑_4-羧醯胺 73 0 。〆 ^ V-NH fy η Γν 〇 ‘A 1-(5-(3-氟基-5-嗎福p林 基苯甲醯胺基）-2-甲基 吡啶-3-基）_N-(2-曱基丁 基）-1Η·1，2,3_三唑-4- 羧醯胺 74 〇 〇vrO f|] Η Γ^ν 〇、人 Ν-(環己基甲基）-1-(5-(3-氟基-5-嗎福啉基苯甲 酷胺基）-2-甲基p比唆-3-基）_lH-l，2,3-三唑-4- 羧醯胺 75 〔n〕 〇vrO° fjC)y^yn;n 〇、人 1-(5-(3-氟基-5-嗎福琳 基苯曱醯胺基）-2-甲基 外匕口定-3-基）-N-((四鼠 -2H-哌喃-4-基）甲基）-1H-1，2,3-三唑-4-羧醯胺 76 〔。〕 rP Y Vnh oh fJC^n^^nT/ 0 ‘人 1-(5-(3-敗基-5-嗎福琳 基苯甲酿胺基）-2-曱基 口比 °定-3-基）-1^-(2-¾ 基-2-苯基乙基）-1Η-1,2,3-三 唑-4-羧醯胺 123505 -322 - 200815422 編號 結構 化合物名稱 77 0 ^ \ \ Η Γ^Ν 〇 ‘A 1-(5-(3-氟基-5-嗎福啉 基苯甲醯胺基）-2-甲基 吡啶-3-基）-N-(l-羥基-3-甲基丁-2-基）-1Η-1，2,3-三唑-4-羧醯胺 78 0 彳 y-NH 7 \ \ Η Γ^Ν 〇 A N-((l-乙基四氮卩比略-2-基）甲基）-1-(5-(3-氟基-5-嗎福啉基苯甲醯胺 基）-2-甲基ρ比17定-3-基）-1H-1，2,3-三唑-4-羧醯胺 79 /{ 5-第二-丁基-3-氣基 -N-(5-(4-((l-乙基四氫吡 咯-2-基）甲基胺甲醯 基）苯基）-6-甲基吡啶_3_ 基)-2-曱氧基苯甲醯胺 80 / 〇 r〆 άΗ^ 5_第二-丁基-3-氣基-2-甲氧基-N-(6-甲基 -5-(4-(1-甲基六氫说唆 -4-基胺甲醯基）苯基） 吡啶-3-基）苯曱醯胺 81 5-第三-丁基-3-氰基-2-甲氧基-N-(6-甲基 -5-(4-((1-甲基六氫咕咬 -4-基）曱基胺甲醯基）-苯基）外1： σ定-3-基）苯甲 醯胺 82 Ο 0 3-氣-Ν-(6-甲基-5-(4-(1- 甲基六氮p比°定-4-基胺 甲醯基）苯基）外1： 11 定-3-基）-5-嗎福啉基苯曱 醯胺 123505 - 323 - 200815422 編號 結構 化合物名稱 83 0 。 3-氟-N-(6-甲基-5-(4-((1-甲基六氫吡啶-4-基）甲 基胺甲醯基）苯基）吡 °定-3-基）-5-嗎福p林基苯 甲醯胺 84 5_第二-丁基-3-氣基-2_ 甲氧基-N-(6-甲基 -5-(4七比啶-3-基甲基胺 曱醯基）苯基）吡啶_3_ 基）苯甲醯胺 85 0 vP ρ/όγΜγ^γΝΓ/ ◦ ‘A 1-(5-(3-氟基-5-嗎福琳 基苯甲酿胺基）-2-甲基 吡啶-3-基）·Ν-(四氫-2H-哌喃-4_基）-1Η·1，2,3_三 唑-4-羧醯胺 86 〇 VP 〇 ‘A Ν-環己基-1-(5-(3-亂基 -5-嗎福啉基苯甲醯胺 基）-2-甲基p比0定-3_ 基）-1Η-1，2,3-三唑-4-羧 醯胺 87 〇 VP ^ y-NH 0、人 N-環戍基-1-(5-(3-氟基 -5-嗎福啉基苯甲醯胺 基）-2-甲基外匕σ定-3_ 基）-1Η-1，2,3-三唑-4-羧 醯胺 88 〇 〇νΛ f/〇y^yn;，n 0 A 1-(5-(3-氟基-5-嗎福琳 基苯甲醯胺基）-2-甲基 叶匕啶-3-基）-N-(3-羥基 -2,2-二甲基丙基）-1H-1，2,3-三唑-4-羧醯胺 123505 324 - 200815422 編號 結構 化合物名稱 89 4- νΝ(Γ^ n^«Xxn^n 1-(5-(3-第三-丁基-5-氰 基苯甲醯胺基）-2·甲基 口比唆-3-基）-Ν-((四風口夫 喃-2-基）甲基）-1Η-1，2,3- 三唑-4-羧醯胺 90 1-(5-(5-第二-丁基-3-氣 基-2-甲氧基苯甲醯胺 基）-2-甲基π比σ定-3-基）-111-1，2,3-三唑-4-羧 酸第三-丁酯 91 Vn(T^ n^Vxx‘n 1-(5-(3-氰基-5-嗎福啉 基苯甲酿胺基）-2-甲基 外匕咬-3-基）-N-((四鼠口失 喃-2-基）甲基）-1Η-1，2,3-三唆-4-羧醯胺 92 〇 Vn(T^ 1-(5-(3-氣基-5-(六鼠口比 啶-1-基）苯甲醯胺 基）-2-曱基ρ比唆-3-基）-N-((四氮咬喃-2-基） 甲基）-1Η-1，2,3-三唑-4-羧醯胺 93 又 Vn(T^ n^Vxx‘n 1-(5-(3-氣基-5-(四氮ρ比 咯-1-基）苯曱醯胺 基）-2-甲基吡啶-3-基）-N-((四氫呋喃-2-基） 曱基）-1Η·1，2,3-三唑-4-羧醯胺 94 Ν-(5-(4-((1·乙基四氫吡 咯_2_基）甲基胺甲醯 基）苯基）-6-甲基说咬 -3-基）-3-氣基-5-嗎福琳 基苯曱醯胺 123505 -325 - 200815422 f \ \ 編號 結構 95 96N-(5-(4-Ethylphenyl)-6-methyl17-pyridin-3-yl)-5-di-di-butyl-3-nitro-2-methoxybenzamide Amine 123505 -312- 200815422 No. Structure Compound Name 11 OH 3-(Aminomethyl)-5-Second-Butyl-N-(5-(4-(l-ethyl)phenyl)-6- Methylpyridin-3-yl)-2-methoxybenzimidamide 12 Η0^ν HO, 〇\ 0 I human 5-di-di-butyl-3-(N-|^-carbamidoimidate Base)&quot;Ν»(5-(4-(1-(hydroxyimino)ethyl)phenyl)-6-methylpyridin-3-yl)-2-decyloxybenzoquinone with amine 13 \ 5'-(3-Terve-butyl-5-cyanobenzamide)-7-methyl-N-((tetrazole-2-yl)indenyl)-2,3 '-Bipyridyl-5-carboxyguanamine 14 \ 5*-(3-second-butyl-5-murine benzhydrylamino)-2'-methyl-N·((tetrazole) 2-yl)methyl)-3,3f-bipyridyl-6-carboxamide 3-15 3-tri-butyl_5_乱基-]^-(6-methyl-5-(4-(six口 小 小 小 ) ) ) ) ) ) ) ) ) ) 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 (4-(N-Pentylamino acid) phenyl)p-pyridin-3-yl)benzamide 17 0 y£^ 1-(5-(3- 5--5-wfolinyl benzalkonium)-2-methylexodecyl-3-yl)-N-((tetrahydrofuran-2-yl)methyl)-1Η-1,2 ,3-triazole-4-carboxyguanamine 123505 -313- 200815422 No. Structure Compound name 18 0 V Deuterium N-(5-(4-Tervenyl-1H-1,2,3-triazole- 1-yl)-6-methyl. 1,4--3-)-3-yl-5-moffylbenzamide 19 3-fluoro-N-(6-methyl-5-(4 -(pyridin-2-yl)_1H-1,2,3-triazol-1-yl)p than sigma-3-yl)-5-morpholinebenzamide 20 0 / Λ H rC° 3-Fluoro-N-(5-(4-(methoxymethyl)-1Η-1,2,3-triazol-1-yl)-6-methyl σσ-3-yl)-5 - morpholinyl benzamide 21 &quot;V νΝ(Γ^ , hxxn; n 1-(5-(3-t-butyl-5-cyanobenzoguanamine)-2-methyl) Base mouth ratio -3-yl)-N-inoindol-1Η-1,2,3·triazole-4-carboxyguanamine 22 + v&gt; n^Vxx'n 3-second-butyl-5 -N-yl-indole-(6-methyl-5-(4-(3-methylbutylidene)-1Η-1,2,3-triazol-1-yl) aceto-3-yl)benzamide Indole 23 + H〇, yV n^Vxx'N (Z)-3-second-butyl-5-carbyl-N-(5-(4-(l-(hydroxyimino))-3- Mercaptobutyl)-1Η-1,2,3-three Oxazol)-6-methylpyridin-3-yl)benzamide 123505 314- 200815422 No. Structure Compound name 24 3-di-di-butyl-5-carbyl-indole-(6-methyl-5 -(4-(2-mercapto-1_(indanylamino)_1-indolylpropan-2-yl)-1Η-1,2,3-triazol-1-yl)pyridin-3-yl Benzalamine 25 N-(3-second-butyl-5.cyanophenyl)·6-fluorenyl-5-(4-(sinodecylcarbinyl)-lH-l, 2,3-triterpenoid-1-yl) in the test of guanamine 26 0 , Νόν〆w Ν-(6-methyl-5-(4-(neopentylcarbinyl)-1Η-1,2 , 3-triazol-1-yl)pyridin-3-yl&gt;2-isofenyl is different from acid test amine 27 0 , hniX'n, n N-(6-methyl-5-(4-( Neopentylamine methyl hydrazino)-1Η-1,2,3-tris-l-yl)p ratio sigma-3-yl)-2-(six-biten-1-yl) isonianicine Indoleamine 28 [N]. 0-gas-N-(6-methyl-5-(3-(neopentylcarbinyl)phenyl) sulfonyl)-5-morphin p-linylbenzamine 29 Λ^?° 3_Third-butyl-5-carbyl-N-(5-(3-(dimethylaminoindenyl)phenyl>6-decylpyridin-3-yl)benzene Indoleamine 123505 -315 - 200815422 No. Structure Compound Name 30 1-(5-(5-Terve-butyl-2-decyloxybenzoic acid amino)-2-methylpyridin-3-yl)-N · Neopentyl-1H-1,2,3-triazole-4-carboxyguanamine 31 ◦ A 1-(5-(3-Fluoro-5-morpholinebenzimidamide)-2- Methyl yttrium yttrium-3-yl)-N-neopentyl-1 oxime 1,2,3-triazole-4-carboxamide guanamine 32 C 5-t-butyl-2-methoxy- Ν-(5-(6-methoxyindol-2-yl)-6-methylρ than sigma-3-yl) benzamide 33 / 3-tris-butyl-5-cyano- Ν-(5-(3-(3,3-dimethylbutylamido)phenyl)-6-mercaptopyridine-3-yl)benzamide 35 〇N-(2,6f-dimethyl Base-3,4f-linked 唆-5-yl)-3-carbyl-5-morpholinebenzamide 35 W6 3-second-butyl-5-lacyl-N-(2 ,6'-dimethyl-3,4'-bipyridin-5-yl)benzamide 36 0 3-say·Ν-(5-(4·曱oxy-3-methyl) Phenyl)-6-methylpyridin-3-yl)-5-?-fu 14-phenyl-benzamide 123505 -316- 200815422 No. Structure Compound Name 37 Ν-(5-(4-Ethylphenyl) -6-Mercaptopyridin-3-yl)-5-t-butyl-2-oxoylbenzamide 38 N-(5-(4-Ethylphenyl)-6-methylpyridine _3_yl)-5-tert-butyl-2-methoxy-3-(methylsulfonylamino)benzamide 39 0 . N-(5-(4-ethenylphenyl) )-6-methyl-indole-3-yl)-3-aryl-5-fopasyl-p-phenylbenzamide 40 \ ζ ^V〇N-(5-(4-(decylamine) Base) phenyl &gt; 6-methylpyridin-3-yl)-5·t-butyl-2-methoxybenzamide 41 ς /〇5-tris-butyl-N-(5 -(4-(3,4-Dimethoxybenzylaminemethanyl)phenyl)-6-fluorenyl b. D. _3_yl)-2-methoxybenzamide 42 / ( 5-tert-butyl-2-methoxy-oxime-(5-(4-(3.methoxybenzylaminecarbamimidyl)phenyl)-6-methylpyridin-3-yl)benzene Methionine 43 〇. N-(5-(4-(benzylaminoindolyl)phenyl)-6-methylpyridin-3-yl)-3-yl-5-moffylbenzophenone Guanamine 123505 -317- 200815422 No. Structure Compound Name 44 0. Ν-(5-(4-(3,5-Dimethoxydecylamine) phenyl)-6-methylindol-3-yl)-3·fluoro-5-morpholine Benzimidamide 45 〇. 0 3 ·Fluoro-N-(5-(4-(3-methoxybenzylaminecarbamimidyl)phenyl)-6-methyl^pyrazine-3-yl)-5-morpholinoylbenzene Formamide 46 0 . 3-fluoro-indole-(5-(4-(4-decyloxybenzylaminomethyl)phenyl)-6-methylpyridin-3-yl)-5-morpholinebenzamide 47 0 . N-(5-(4-(4-benzo[d][l,3]dioxosulphone-5-ylmercaptoalkylguanidinyl)phenyl)-6-methylazuron sigma-3- ))-3-气基-5-morpholinebenzimidamide 48 0 &gt; Ν^ is Vx^ 1-(5-(3-fluoro-5-moffene-based benzylamino) -2-methyl-port ratio σ- -3-yl)-N-(p than -3-ylmethyl)-1Η_1,2,3-triazole-4-carboxyguanamine 49 0 〆 is Vi^ 1 -(5-(3-carbyl-5-morpho-p-linylbenzamide)-2-methylpyrazine. Benz-3-yl)-N-isobutyl-1H-1,2, 3-triazole-4-carboxyguanamine 123505 318- 200815422 No. Structure Compound name 50 0 Ν~(ί哀propylmethyl)-1-(5-(3_气基-5-? Amino)-2-methylpyridin-3-yl)-lH-1,2,3-triazole-4-carboxyguanamine 51 [°] r^f Y Vnh 1-(5-(3-fluoro--5 -Nalofylbenzamide)-2-methylpyridinyl)-N-(3,3,3-trifluoropropyl)-1Η-1,2,3-triazole-4-carboxylate Guanamine 52 0 . 3-Fluoro-N-(6-methyl-5-(4-((tetrahydro-2H-pyran-4-yl)methylaminemethanyl)phenyl)leaf b唆-3·yl)-5 - morpholinyl benzamide 53 0 . 3-Fluoro-N-(6-methyl-5-(4-((tetrahydromethane-2-yl)methylaminemethanyl)phenyl)pyridin-3-yl)-5-? Wood-based benzoic acid 54 &lt; 0, 5-tri-butyl-N-(5-(4-(3,5-dimethoxydecylaminomethyl)phenyl)-6- Extrabasic b--3-yl)-2-methoxybenzamide 55 \ CW°H N-(5-(4-(benzo[d][l,3]dioxosperidine-5 -ylmethylamine-methyl hydrazino)phenyl)-6-methyl-portion -3-yl)-5-t-butyl-2-methoxybenzamide 56, C 5-second -butyl-2-decyloxy-N-(6-methyl-5-(4-(orylpyridin-3-ylmethylaminemethyl fluorenyl) phenyl) phenanthyl) benzoyl Indoleamine 123505 -319- 200815422 No. Structure Compound Name 57 C , / 0 1^0 5 · Third-butyl-2-methoxy-oxime-(6-methyl-5-(4·(tetrahydro-) 2Η-piperazin-4-ylaminoindenyl)phenyl)ρ ratio sigma-3-yl)benzamide 58 ς 0 VyyO^, 〇5·T-butyl-2-methoxy- Ν-(6-Methyl-5-(4-((tetrahydro-2H-pyran-4-yl)methylaminemethane)phenyl)pyridin-3-yl)benzamide 59 \ ς C 5-Terti-butyl-2-methoxy-N-(6-methyl-5-(4-((tetrazofuran-2-) Methylaminomethylmercapto)phenyl>pyramid-3-yl)benzamide 60 0 . N-(5-(4-(3,4-didecyloxydecylamine) Phenyl)-6-methylindazol-3-yl)-3-ranyl-5-morpholinebenzimidamide 61 〇. 3-fluoro-Ν-(6·methyl-5- (4-(pyridin-3-ylmethylaminemethanyl)phenyl)^Bist-3-yl)-5-morpholinebenzamide 62 〇, 〇0 4-((4-( 5·(5-Terve-butyl-2-methoxybenzoguanamine)-2-decylpyridin-3-yl)benzhydrylamino)methyl)benzoate oxime 63 0 . 0 3-Gas-N-(6-fluorenyl_5-(4-(tetrahydro-2H-pyran-4-ylamine)-phenyl) succin-3-yl)-5- Morpholine benzoguanamine 123505 -320- 200815422 No. Structure compound name 64 0 . 4-((4-(5-(3-Fluoro-5-moffofylbenzamide)-2- Methylpyridin-3-yl)benzhydrylamino)methyl)benzoate oxime 65 3-second-butyl-5-ranyl-N-(6-methyl-5-(4-(( Tetrahydrofuran-2-yl)methylamine-mercapto)phenyl- 17-but-3-yl)benzamide 66 3-second-butyl-5-yl-N-(6-methyl-5 -(4-((tetrahydro-2H-piperazin-4-yl)methylamine) Mercapto)phenyl)pyridin-3-yl)benzamide 67 N-(5-(4-(benzylaminecarbamimidyl)phenyl)-6-methylpyridin-3-yl)-3 ·Second-butyl-5-carbobenzamide 68 〇v&lt; 1-(5-(3-fluoro-5-m-fluentylbenzamide)-2-methylpyridine-3 -yl)-N,N-dimethyl-1H-1,2,3-triazole-4-carboxyguanamine 69 O' 〆ΛκΧΧν;,ν 1-(2-methyl-5-(3-? Florinyl-5-(trifluoromethyl)benzoic acid amine group mouth ratio sigma-3-yl)-N-neopentyl-1Η-1,2,3-triazole-4-carboxylate Amine 70 ο. r^T Ν V-NH 1-(2-methyl-5-(3-(tetra-n-butyrrol-1-yl)-5-(trifluoromethyl)-benzimidamide Pyridin-3-yl)-N-neopentyl-1H-1,2,3-triazole-4-carboxyguanamine 123505 -321 - 200815422 No. Structure Compound Name 71 1-(5-(3-Fluoro) -5-(hexanitropyridin-1-yl)benzamideamino)-2-methylindole-3-yl)-N-neopentyl-1H-1,2,3-triazole- 4-carboxyguanamine 72 〇 1-(5-(3-fluoro-5-(tetrahydropyrrolidinyl)phenylhydrazino)-2-methylpyridine-3·yl)-N-neopentyl -1H-1,2,3-triazole_4-carboxyguanamine 73 0 . 〆^ V-NH fy η Γν 〇'A 1-(5-(3-Fluoro-5-?-fu-p-linylbenzylamino)-2-methylpyridin-3-yl)_N-(2 -mercaptobutyl)-1Η·1,2,3_triazole-4-carboxycarboxamide 74 〇〇vrO f|] Η Γ^ν 〇, human Ν-(cyclohexylmethyl)-1-(5 -(3-Fluoro-5-morphobolinylbenzamide)-2-methylp-p--3-yl)-lH-l,2,3-triazole-4-carboxycarboxamide 75 [ n] 〇vrO° fjC)y^yn;n 〇, human 1-(5-(3-fluoro-5-norfosylphenyl phenylamino)-2-methyl oxime -3- Base)-N-((tetra-mound-2H-piperidin-4-yl)methyl)-1H-1,2,3-triazole-4-carboxydecylamine 76 [. 〕 rP Y Vnh oh fJC^n^^nT/ 0 'People 1-(5-(3-Acety-5-moffene-based benzoylamino)-2-hydrazinyl group ratio -3- Base)-1^-(2-3⁄4-yl-2-phenylethyl)-1Η-1,2,3-triazole-4-carboxyguanamine 123505 -322 - 200815422 No. Structure Compound Name 77 0 ^ \ \ Η Γ^Ν 〇'A 1-(5-(3-Fluoro-5-morpholinebenzimidino)-2-methylpyridin-3-yl)-N-(l-hydroxy-3 -Methylbutan-2-yl)-1Η-1,2,3-triazole-4-carboxyguanamine 78 0 彳y-NH 7 \ \ Η Γ^Ν 〇A N-((l-ethyl four Aziridine/pyridyl-2-yl)methyl)-1-(5-(3-fluoroyl-5-morpholinebenzimidyl)-2-methylρ ratio 17--3-yl) -1H-1,2,3-triazole-4-carboxyguanamine 79 /{ 5-second-butyl-3-yl-N-(5-(4-((l-ethyltetrahydropyrrole) -2-yl)methylamine-mercapto)phenyl)-6-methylpyridine-3-yl)-2-nonyloxybenzamide 80 / 〇r〆άΗ^ 5_second-butyl- 3-oxo-2-methoxy-N-(6-methyl-5-(4-(1-methylhexahydroindole-4-ylaminecarbamoyl)phenyl)pyridin-3-yl Benzoylamine 81 5-tris-butyl-3-cyano-2-methoxy-N-(6-methyl-5-(4-((1-methylhexahydropurine)-4 -base) Mercapto)-phenyl)exyl 1: sigma-3-yl)benzamide 82 Ο 0 3-oxo-oxime-(6-methyl-5-(4-(1-methylhexanitro)p比定-4--4-aminocarbamoyl)phenyl)exyl 1:11 -3-yl)-5-morpholine phenyl hydrazine 123505 - 323 - 200815422 No. Structure Compound Name 83 0 . 3-fluoro-N-(6-methyl-5-(4-((1-methylhexahydropyridin-4-yl)methylaminemethanyl)phenyl)pyridin-3-yl)- 5-Fo-P-Linylbenzamide 84 5_Second-Butyl-3-Alkyl-2_Methoxy-N-(6-Methyl-5-(4-7-pyridin-3-yl) Amino-5-phenyl)pyridinyl-3-yl)benzamide 85 0 vP ρ/όγΜγ^γΝΓ/ ◦ 'A 1-(5-(3-fluoro-5-moffene-based benzoyl) Amino)-2-methylpyridin-3-yl)·Ν-(tetrahydro-2H-piperidin-4-yl)-1Η·1,2,3-triazole-4-carboxamide 〇VP 〇'A Ν-cyclohexyl-1-(5-(3-ranyl-5-morphobolinylbenzamide)-2-methyl p ratio 0--3)-)-1Η-1,2 ,3-triazole-4-carboxyguanamine 87 〇VP ^ y-NH 0, human N-cyclodecyl-1-(5-(3-fluoro-5-morpholinebenzimidamide) -2-Methyl-purine 匕 定 -3 - yl) -1 Η -1,2,3-triazole-4-carboxy oxime 88 〇〇νΛ f /〇y^yn;, n 0 A 1-(5- (3-Fluoro-5-moffinylbenzimidyl)-2-methylsulfan-3-yl)-N-(3-hydroxy-2,2-dimethylpropyl)- 1H-1,2,3-triazole-4-carboxyguanamine 123505 324 - 200815422 No. Structure compound name 89 4- νΝ(Γ^ n^«Xxn^n 1-(5-(3 -Third-butyl-5-cyanobenzylidinium)-2.methyl-methylpyrimidin-3-yl)-indole-((四风口夫喃-2-yl)methyl)-1Η- 1,2,3-triazole-4-carboxyguanamine 90 1-(5-(5-second-butyl-3-yl-2-methylbenzylamino)-2-methyl π ratio σ-3-yl)-111-1,2,3-triazole-4-carboxylic acid tert-butyl ester 91 Vn(T^ n^Vxx'n 1-(5-(3-cyano) -5-morpholinylbenzamideamino-2-methylisoindole-3-yl)-N-((tetramethyl-n-but-2-yl)methyl)-1Η-1,2 ,3-triterpene-4-carboxyguanamine 92 〇Vn(T^ 1-(5-(3-carbyl-5-(hexamethylpyridin-1-yl)benzamide)-2-曱基ρ比唆-3-yl)-N-((tetrazole-2-yl)methyl)-1Η-1,2,3-triazole-4-carboxyguanamine 93 and Vn(T^ n^Vxx'n 1-(5-(3-Alkyl-5-(tetrazo-p-pyrrol-1-yl)phenylhydrazino)-2-methylpyridin-3-yl)-N-( (tetrahydrofuran-2-yl) fluorenyl)-1Η·1,2,3-triazole-4-carboxyguanamine 94 Ν-(5-(4-((1·ethyltetrahydropyrrole_2-yl)) Methylamine-mercapto)phenyl)-6-methyl-n--3-yl)-3-yl-5-moffinylbenzamide 123505-325 - 200815422 f \ \ No. Structure 95 96

化合物名稱 1-(5-(5-第二-丁基-3-鼠 基-2-甲氧基苯甲醯胺 基）-2-甲基外匕。定-3-基）-N-新戊基-1H-1，2,3_ 三唑-4-羧醯胺 1-(5-(5-第二-丁基-3-氣 基_2_甲氧基苯甲醯胺 基）-2-甲基π比σ定-3-基）-N-(V比σ定-3-基甲 基）-1Η-1，2,3-三唑-4-羧The compound name 1-(5-(5-second-butyl-3-murly-2-methoxybenzamide)-2-methylindole. D--3-yl)-N-new pentyl-1H-1,2,3_triazole-4-carboxyguanamine 1-(5-(5-second-butyl-3-yl-2-methoxybenzoguanamine)-2 -Methyl π ratio sigma-3-yl)-N-(V ratio sigma-3-ylmethyl)-1Η-1,2,3-triazole-4-carboxylate

醯胺 1-(5-(3-第三-丁基-5-氰 基苯甲醯胺基）-2-曱基 外匕唆-3-基）-N-((l-乙基 四氮卩比洛-2-基）曱 基）-1Η-1，2,3-三唑-4-羧 醯胺 98Indoleamine 1-(5-(3-Terve-butyl-5-cyanobenzamide)-2-mercaptopurin-3-yl)-N-((l-ethyltetrazine) Indoprofen-2-yl)hydrazino)-1Η-1,2,3-triazole-4-carboxyguanamine 98

9999

3-第二-丁基-5-氣基 -N-(6-甲基-5-(4-(4-甲基 六氫吡畊-1-羰 基)-1Η-1，2,3-三唑-1-基） 吡啶-3-基）苯甲醯胺 1-(5-(5-第三-丁基-3-氰 基-2-甲氧基苯甲醯胺 基）-2-甲基p比σ定-3-基）-Ν-((四氫呋喃-2-基） 甲基）-111-1，2,3-三唑-4· 1003-second-butyl-5-carbyl-N-(6-methyl-5-(4-(4-methylhexahydropyramide-1-carbonyl)-1Η-1,2,3-three Zin-1-yl)pyridin-3-yl)benzamide-1(5-(5-tris-butyl-3-cyano-2-methoxybenzamide)-2-methyl Base p ratio σ-3-yl)-Ν-((tetrahydrofuran-2-yl)methyl)-111-1,2,3-triazole-4·100

羧醯胺 3-第三-丁基-5-氣基 -]^-(6-甲基-5-(4-(嗎福'?林 -4-羰基）-1Η-1，2,3_三唑 -1-基）吡啶-3-基）苯曱 驢胺 123505 -326· 200815422Carboxylamamine 3-tert-butyl-5-carbyl-]^-(6-methyl-5-(4-(TM)- -4-phenyl)-1Η-1,2,3_ Triazol-1-yl)pyridin-3-yl)benzamide 123505 -326· 200815422

/ V 編號 結構 101/ V number structure 101

102 103 104 105 106 107102 103 104 105 106 107

化合物名稱 1-(5-(3-第二丁基-5-氣 基苯甲酸胺基）-2-甲基 口比咬-3-基）-N-(l-甲基六 氫吡啶·4_基）-1Η-1，2,3-三唑-4-羧醯胺 1-(5-(3-第二-丁基-5-氣 基苯甲醯胺基）-2-甲基 口比口定-3-基）·Ν_(2-(四氣 叶匕洛-1-基）乙基）_ 1Η-1，2,3·三唑-4-羧醯胺 1-(5-(3-第三-丁基-5-氰 基苯甲酿胺基）-2-甲基 口比 σ定-3-基）-N-(2-(二甲 胺基）乙基）-1Η-1，2,3-三 唑-4-羧醯胺 1-(5-(3-第三-丁基-5-氰 基苯甲醯胺基）-2-甲基 p比σ定-3-基）-N-(2-甲氧基 乙基）-111-1，2,3-三唑-4· 羧醯胺 1-(5-(3第三-丁基-5-氰 基苯甲醯胺基）-2-甲基 口比0定-3-基）-N-(。昆σ定-3_ 基）-111-1，2,3_三唑-4-羧 醯胺 1-(5-(3-第三-丁基-5-氰 基苯甲酿胺基）-2-甲基 口比σ定-3-基）-N-(六氮口比 啶-4-基）_1Η-1，2,3-三唑 -4-羧醯胺 1-(5-(3-第二-丁基-5-氣 基苯甲酿胺基）-2-曱基 口比σ定-3-基）(六鼠口比 啶-3-基）-1Η-1，2,3-三唑 -4-羧醯胺 123505 -327 - 200815422 編號 結構 化合物名稱 108 〇人' 入OH 1-(5-(3-第二-丁基-5-氣 基苯甲酸胺基）-2-甲基 p比σ定-3-基）-N-(2-經丙 基）-1Η-1，2,3-三唑-4-羧 醯胺 109 0 Vn^ 1-(5-(3-氟基-5-(l，4-氧氮 七圜-4-基）苯甲醯胺 基）-2-甲基叶匕咬-3-基）-N-((四氮咬喃-2-基） 甲基）-1Η-1，2,3-三唑-4-羧醯胺 110 父 Vn^ 0 ‘N人 1-(5-(3-1基-5-(四氫叶匕 咯小基）苯曱醯胺 基）-2-甲基口比咬-3-基）-N-((iz3氮咬喃-2-基） 甲基）-1Η-1,2,3-三唑-4-羧醯胺 111 n^^Xxn^n 1-(5-(3-氰基-5-(四氫口比 咯-1-基）苯甲醯胺 基）-2-甲基吡啶-3-基）-N-新戊基-1H-1，2,3-三唑-4-羧醯胺 112 Q X-£^ n^Vtx‘n 1-(5-(3-氣基-5-(六鼠外匕 啶-1-基）苯甲醯胺 基）-2·甲基吡啶各 基）-N-新戊基-1H-1，2,3-三唑-4-羧醯胺 113 ^VNXXN》 1-(5-(3-氰基-5-嗎福啉 基苯甲酿胺基）-2-甲基 p比σ定-3-基）-N-新戍基 -1Η-1，2,3-三唑-4-羧醯胺 123505 -328 - 200815422 /' 編號 結構 化合物名稱 114 Q Vn(T^ 1-(5-(3-氟基-5-硫代嗎 福啉基苯甲醯胺基）-2-曱基1^比咬-3-基）-N-新戍 基-1H-1，2,3-三唑-4· 羧醯胺 115 \ \ H /n 1-{5-[3-氟基-5-(1-酮基-lλ4-硫代嗎福p林-4-基）-苯甲驢胺基]-2-甲 基-吡啶-3-基}-1Η-[1，2,3] 三唑-4-羧酸（2,2_二曱 基·丙基）-酿胺 116 、 \ 1-(5-(3-第二-丁基-5-鼠 基苯甲驢胺基）-2-甲基 口比咬-3-基）-N-((l-甲基 六氮外b σ定-4-基）甲基）-1Η_1，2,3-三唑-4-羧醯胺 117 \一 .Λ 3-第二-丁基-5-氣基 -Ν-(5-(4-(4-(2-經乙基）六 氫吡畊小羰基）-1Η-1，2,3-三唑-1-基）-6-甲 基吡啶-3-基）苯甲醯胺 118 1-(5-(3-第三-丁基-5-氰 基苯甲醯胺基）-2-甲基 口比唆-3-基）-N-(2,2,6,6-四 甲基六氯p比咬-4-基）-1Η·1，2,3-三唑-4-羧 醯胺 119 Q / F&gt;^O^Y〇 n^n FT hX^k。 1-(2-甲基-5-(3-(四氫吡 咯-1-基）-5-(三氟曱基） 苯甲醯胺基）-吡啶-3-基）-N-(吡啶-2-基甲 基）-1Η-1，2,3-三唑-4-羧 醯胺 123505 -329- 200815422 編號 結構 化合物名稱 120 〇、、/ 1-{5-[3-(1，1-二嗣基 _ 1 λ 6 -硫代嗎福p林-4· 基）-5-氣-苯甲酷胺 基]-2-曱基-^比0定-3-基}-111-[1，2,3]三唑-4-羧 酸（2,2-二曱基-丙基）-酿胺 121 、/ ^γ° ν^Η ΗΝχχ^^0 1-(5-(3-第二-丁基-5-氣 基苯甲酿胺基）-2-甲基 p比0定-3-基）-N-(外匕σ定-2-基甲基）-1Η-1，2,3-三唑 -4_羧醯胺 122 叶 5-第三-丁基-3-氛基_2_ 甲氧基-Ν-(6-甲基 -5-(4-(新戊基胺甲醯 基）苯基）吡啶-3-基）苯 甲醯胺 123 3-&gt;臭基-5-第二-丁基-2_ 甲氧基-N-(6-甲基 -5-(4-(新戊基胺甲醯 基）苯基）说啶-3-基）苯 甲醯胺 124 Vtx0^ (R)-5-第三-丁基-3-氰基 -Ν-(5·(4-((1-乙基四氫外匕 咯-2-基）曱基胺甲醯 基）苯基&gt;6-甲基吡啶-3-基)-2-甲氧基苯甲醯胺 125 Q / 為 1-(5-(3-氰基-5-(六鼠P比 啶小基）苯甲醯胺基）-2-甲基峨唆-3-基）-Ν-(外匕 啶-2-基甲基）-1Η-1，2,3-三唑-4-羧醯胺 123505 -330 - 200815422 編號 結構 化合物名稱 126 / 3-弟二-丁基-5-氣基-Να—甲基-5-(4 七比啶-2-基 甲基胺甲醯基）苯基） 吡啶各基）苯甲醯胺 127 N-(6-甲基-5-(4-(吡啶-2-基甲基胺甲醯基）苯 基）卩比ϋ定-3-基）-3-(四氮 吡咯-1-基）_5-(三氟甲 基）苯曱醯胺 128 / 3-第二-丁基-5-氣基 -N-(6-甲基-5-(4-((1-甲基 六氮口比17定-2-基）甲基胺 甲醯基）苯基）吡啶-3-基）苯甲醯胺 129 N-(6-甲基-5-(4-((1-甲基 六氫吡啶-2-基）甲基胺 甲醯基）苯基）吡啶-3-基）-3-(四鼠卩比洛-1-基）-5-(三氟曱基）苯甲 醯胺 130 /( / 5-第三-丁基-3-氰基-2_ 甲氧基-N-(6-甲基 -5-(4-((1-甲基六氫？比0定 -2-基）甲基胺曱醯基）-苯基）吡啶-3-基）苯甲 醯胺 131 (R)-3-第二-丁基-5-氣基 -Ν-(5-(4-((1·乙基四氫吡 咯-2-基）甲基胺甲醯 基）苯基）-6-甲基吡啶 -3-基）苯甲酿胺 123505 -331 - 200815422 編號 結構 化合物名稱 132 0 。&gt; (R)-N-(5-(4-((l-乙基四氫 吡咯-2-基）甲基胺甲醯 基）苯基）-6·甲基7比咬 -3-基）-3-嗎福p林基-5-(二 氟甲基）苯甲醯胺 133 〇 、 F ° (R)-N_(5-(4-((l-乙基四氫 吡咯-2-基）甲基胺甲醯 基）苯基）-6-甲基吡啶 -3-基）-3-(四氫卩比咯-1-基）-5-(三氟甲基）苯甲 S&amp;胺 134 0 。&gt; (R)-N-(5-(4-((1-乙基四氮 吡咯-2-基）甲基胺甲醯 基）苯基）-6-甲基吡啶 -3-基）-3-(六氮p比σ定-1-基）-5-(三氟甲基）苯甲 醯胺 135 \〆 ΗΝχχΝ^^° 1-(5-(3-第三-丁基 _5_氰 基苯甲醯胺基）-2-甲基 吡啶-3-基）-N-((l-曱基 六氮p比17定-2-基）甲基）-1H-1，2,3-三唑-4-羧醯胺 136 /〇 / ^Y〇 TX 0 1-(5-(5-第三丁基-3-氰 基-2-甲氧基苯甲醯胺 基）-2-甲基吡啶-3_ 基）-N-((l-甲基六氫吡 啶-2-基）甲基）-1Η-1，2,3-三吐-4-羧醯胺 137 〇vP y^NH ^^τχΝ:/Ν 1-(5-03-第三-丁基-5-氰 基苯曱醯胺基）-2-甲基 吡啶-3_基）-N-環己基 -1H-1，2,3-三唑-4-羧醯胺 123505 - 332 - 200815422The compound name 1-(5-(3-t-butyl-5-carbylbenzoic acid amine)-2-methyl-p-but-3-yl)-N-(l-methylhexahydropyridine·4 _ base)-1Η-1,2,3-triazole-4-carboxyguanamine 1-(5-(3-second-butyl-5-carbylbenzamide)-2-methyl比 口定-3-基)·Ν_(2-(Tetraxanthene-1-yl)ethyl)_ 1Η-1,2,3·triazole-4-carboxyguanamine 1-(5-( 3-Terti-butyl-5-cyanobenzoylamino-2-methylpyrazine sigma-3-yl)-N-(2-(dimethylamino)ethyl)-1Η- 1,2,3-triazole-4-carboxyguanamine 1-(5-(3-tris-butyl-5-cyanobenzamide)-2-methyl p-sigma-3- -N-(2-methoxyethyl)-111-1,2,3-triazole-4·carboxycarboxamide 1-(5-(3 tert-butyl-5-cyanobenzoic acid) Amidino)-2-methyl-port ratio 0--3-yl)-N-(. σσ定-3_yl)-111-1,2,3-triazole-4-carboxyguanamine 1-( 5-(3-Terti-butyl-5-cyanobenzoylamino)-2-methylpyrazine sigma-3-yl)-N-(hexanitropyridin-4-yl)_1Η -1,2,3-triazole-4-carboxyguanamine 1-(5-(3-second-butyl-5-ylphenylbenzylamino)-2-hydrazinoyl ratio sigma-3 -yl)(six-rhodopyridin-3-yl)-1Η-1,2,3-triazole-4 - Carboxylamidine 123505 -327 - 200815422 No. Structure Compound Name 108 Deaf Person's OH 1-(5-(3-Second-Butyl-5-ylbenzoic acid amine)-2-methyl p ratio σ Ding-3-yl)-N-(2-propyl)-1Η-1,2,3-triazole-4-carboxyguanamine 109 0 Vn^ 1-(5-(3-fluoro-5-- (l,4-oxo-7-indolyl-4-yl)benzhydrylamino)-2-methylanthracepin-3-yl)-N-((tetrazole-2-yl)methyl) -1Η-1,2,3-triazole-4-carboxyguanamine 110 parent Vn^ 0 'N human 1-(5-(3-1--5-(tetrahydroanthracene small) phenylhydrazine) Amino)-2-methyl-n-butyl-3-yl)-N-((iz3azepin-2-yl)methyl)-1Η-1,2,3-triazole-4-carboxyguanamine 111 n^^Xxn^n 1-(5-(3-Cyano-5-(tetrahydropyrano-1-yl)benzimidamide)-2-methylpyridin-3-yl)-N - Neopentyl-1H-1,2,3-triazole-4-carboxyguanamine 112 Q X-£^ n^Vtx'n 1-(5-(3-gasyl-5-(six-mouse)啶-1-yl)benzhydrylamino)-2·methylpyridinyl)-N-neopentyl-1H-1,2,3-triazole-4-carboxyguanamine 113 ^VNXXN 1- (5-(3-Cyano-5-morphobolinylbenzamide)-2-methylp-pyridyl-3-yl)-N-neindyl-1Η-1,2,3- Triazole-4-carboxyguanamine 123505 -328 - 200815422 /' No. Structure Compound Name 114 Q Vn(T^ 1-(5-(3-Fluoro-5-thio-morpholinobenzoylamino)-2-mercapto 1^ bite -3-yl)-N-nonindolyl-1H-1,2,3-triazole-4·carboxycarboxamide 115 \ \ H /n 1-{5-[3-fluoro-5-(1- Ketoyl-lλ4-thiodoffene-p--4-yl)-benzylaminoamido]-2-methyl-pyridin-3-yl}-1Η-[1,2,3] triazole-4- Carboxylic acid (2,2-diindolyl propyl)-bristamine 116, \ 1-(5-(3-second-butyl-5-murine benzhydryl)-2-methyl咬-3-yl)-N-((l-methylhexanitro-b σ -4--4-yl)methyl)-1Η_1,2,3-triazole-4-carboxyguanamine 117 \一.Λ 3-second-butyl-5-carbyl-indole-(5-(4-(4-(2-ethyl)hexahydropyridinium carbonyl)-1Η-1,2,3-triazole- 1-yl)-6-methylpyridin-3-yl)benzamide 118 1-(5-(3-Terti-butyl-5-cyanobenzamide)-2-methyl Than 唆-3-yl)-N-(2,2,6,6-tetramethylhexachloro-p-buty-4-yl)-1Η·1,2,3-triazole-4-carboxamide 119 Q / F&gt;^O^Y〇n^n FT hX^k. 1-(2-Methyl-5-(3-(tetrahydropyrrol-1-yl)-5-(trifluoromethyl)benzhydrylamino)-pyridin-3-yl)-N-(pyridine- 2-ylmethyl)-1Η-1,2,3-triazole-4-carboxyguanamine 123505 -329- 200815422 No. Structure Compound name 120 〇,, / 1-{5-[3-(1,1- Dimercapto-based _ 1 λ 6 -thiodoxime p--4 -yl)-5-gas-benzylideneamino]-2-indolyl-^ is 0--3-yl}-111-[1 , 2,3] triazole-4-carboxylic acid (2,2-dimercapto-propyl)-bristamine 121, / ^γ° ν^Η ΗΝχχ^^0 1-(5-(3- second -butyl-5-carbylbenzamide)-2-methyl p is 0-but-3-yl)-N-(exoquinolidine-2-ylmethyl)-1Η-1,2, 3-triazole-4_carboxyguanamine 122 leaves 5-tris-butyl-3-yl-2-_2methoxy-indole-(6-methyl-5-(4-(nepentylamine) Phenyl)pyridin-3-yl)benzimidamide 123 3-&gt;Smelly-5-Second-Butyl-2-yloxy-N-(6-methyl-5-(4-( Neopentylamine-methyl indenyl)phenyl)rsyn-3-yl)benzamide 124 Vtx0^(R)-5-tris-butyl-3-cyano-oxime-(5·(4- ((1-Ethyltetrahydrofurfuryl-2-yl)decylaminecarbinyl)phenyl&gt;6-methylpyridin-3-yl)-2-methoxybenzamide 1 25 Q / is 1-(5-(3-cyano-5-(six-pulp-p-pyridyl)-benzamide)-2-methylindol-3-yl)-indole- Pyridin-2-ylmethyl)-1Η-1,2,3-triazole-4-carboxyguanamine 123505 -330 - 200815422 No. Structure Compound name 126 / 3-di-di-butyl-5-carbyl-Να —Methyl-5-(4-7-pyridin-2-ylmethylaminemethane)phenyl)pyridinyl)benzamide 127 N-(6-methyl-5-(4-(pyridine- 2-ylmethylamine-mercapto)phenyl)indole-p-but-3-yl)-3-(tetraapyridin-1-yl)_5-(trifluoromethyl)benzoguanamine 128 / 3- Second-butyl-5-carbyl-N-(6-methyl-5-(4-((1-methylhexanitro) 17-but-2-yl)methylamine-methyl) phenyl) Pyridin-3-yl)benzamide 129 N-(6-methyl-5-(4-((1-methylhexahydropyridin-2-yl)methylaminemethanyl)phenyl)pyridine -3-yl)-3-(tetrazolium biro-1-yl)-5-(trifluoromethyl)benzamide 130 /( / 5-tris-butyl-3-cyano-2_ Methoxy-N-(6-methyl-5-(4-((1-methylhexahydro)? 0-0-2-yl)methylamine decyl)-phenyl)pyridin-3-yl)benzamide 131 (R)-3-second-butyl-5-carbyl-indole-( 5-(4-((1·ethyltetrahydropyrrol-2-yl)methylaminemethane)phenyl)-6-methylpyridin-3-yl)benzamide 125505 -331 - 200815422 Structural compound name 132 0 . &gt; (R)-N-(5-(4-((l-ethyltetrahydropyrrol-2-yl)methylaminemethanyl)phenyl)-6-methyl-7 is more than -3-yl )-3-福福 p-Linyl-5-(difluoromethyl)benzamide 133 〇, F ° (R)-N_(5-(4-((l-ethyltetrahydropyrrole-2-) Methyl)methylaminomethylmercapto)phenyl)-6-methylpyridin-3-yl)-3-(tetrahydroindolepyr-1-yl)-5-(trifluoromethyl)benzene S&amp; Amine 134 0 . &gt; (R)-N-(5-(4-((1-Ethyltetraapyridin-2-yl)methylaminemethanyl)phenyl)-6-methylpyridin-3-yl)- 3-(hexanitrogen p sigma-1-yl)-5-(trifluoromethyl)benzamide 135 \〆ΗΝχχΝ^^° 1-(5-(3-Terti-butyl_5_ Cyanobenzoguanidino)-2-methylpyridin-3-yl)-N-((l-fluorenylhexanitrogen p to 17-but-2-yl)methyl)-1H-1,2,3 -triazole-4-carboxyguanamine 136 /〇/ ^Y〇TX 0 1-(5-(5-t-butyl-3-cyano-2-methoxybenzamide)-2- Methylpyridin-3-yl)-N-((l-methylhexahydropyridin-2-yl)methyl)-1Η-1,2,3-trivo-4-carboxamide 137 〇vP y^NH ^^τχΝ: /Ν 1-(5-03-Third-butyl-5-cyanobenzoguanamine)-2-methylpyridin-3-yl)-N-cyclohexyl-1H-1, 2,3-triazole-4-carboxyguanamine 123505 - 332 - 200815422

編號 結構 化合物名稱 138 〇 νΝΓ 1-(5-(3-第二-丁基-5-氣 基苯甲醯胺基）-2-曱基 口比17定-3-基）-N-(六氮p比 啶-1-基）-1Η-1，2,3-三唑 -4-羧醯胺 139 3-第二-丁基-5-氣基 -Ν·(6-甲基-5-(4-((6-甲基 吡啶-2-基）甲基胺甲醯 基）苯基）被咬-3-基）苯 甲醯胺 140 5-第二-丁基-3_氣基-2-甲氧基-N-(6-甲基 -5-(4-((6-甲基批咬-2-基） 甲基胺甲醯基）苯基） 吡啶-3-基）苯甲醯胺 141 〇&gt; N-(6-甲基-5-(4-((6-甲基 吡啶-2-基）甲基胺甲醯 基）苯基）批唆-3-基）-3-(四鼠^比洛-1-基）-5-(二 氟甲基）苯曱醯胺 142 3-第三-丁基-5-(6-曱基 -5-(4-(新戍基胺甲酿 基）-苯基）说咬-3-基胺 甲醯基）苯甲酸曱酯 143 ΗΟγί 3-第三-丁基-5-(6-甲基 -5-(4-(新戊基胺甲醯 基）-苯基）批咬-3-基胺 甲醯基）苯甲酸 144 0 。 叶 N-(6-甲基-5-(4-(新戊基 胺甲酸基）苯基 &gt;比咬 -3-基）-2-(六鼠卩比°定-1- 基）異菸鹼醯胺 123505 - 333 - 200815422 編號 結構 化合物名稱 145 5-第三-丁基-:^-(2-(二 甲胺基）乙基）-N3 -(6-甲 基-5-(4-(新戊基胺甲醯 基）苯基）比σ定-3-基）間 苯二甲醯胺 146 Λ V ν，οη 3-氟-Ν-(5·(4-(1-(羥亞胺 基）乙基）苯基&gt;6-曱基 外匕。定-3-基）-5-嗎福ρ林基 苯甲醯胺 147 a〆 4-(5-(3-第三-丁基-5-氣 基苯甲酿胺基）-2-甲基 吡啶-3-基）苯甲酸甲酯 148 n,n 〇_/ XX 1-(5-(3-第三-丁基-5-氰 基苯甲醯胺基）-2-甲基 吡啶·3·基）-1Η-1，2,3-三 唑-4-羧酸乙酯 149 3c p n^：^Nv- XX 1-(5-(3-第二-丁基-5-氣 基苯甲醯胺基）-2-甲基 口比厂定-3-基）-N-(2-(二乙 胺基）乙基）-1Η·1，2,3-三 唑-4-羧醯胺 150 1-(5-(3-第二丁基-5-鼠 基苯甲醯胺基）-2-甲基 吡啶-3·基）·Ν-(2-(二異 丙基胺基）乙基）-1Η-1，2,3-三唑-4-羧醯胺 123505 334 - 200815422 編號 結構 化合物名稱 151 XX。 1-(5-(3-第二-丁基-5-氣 基苯甲醯胺基）-2-甲基 吡啶-3-基）-N-(2-甲基 -2-(六氮ρ比17定-1-基）丙 基）-1沁1，2,3-三唑-4-羧 醯胺 152 1-(5-(3-弟二-丁基-5-氣 基苯甲醯胺基）-2-甲基 外匕ϋ定-3-基）-N-((l-(六氮 吡啶-1-基）環己基）曱 基）-1Η-1，2,3-三唑-4-羧 醯胺 153 0 。 6^^叶 N-(6-甲基_5-(4-(新戊基 胺甲酸基）苯基）-外1： ϋ定 -3-基）-2-嗎福琳基異於 驗酸胺 154 0 3-氰基-N-(6-甲基 -5-(4-((6-甲基说咬-2-基） 甲基胺甲醯基）苯基） 吡啶各基）-5_嗎福啉基 苯甲醯胺 155 φ 3-氰基-N-(6-甲基 -5-(4-((6-甲基说咬-2-基） 甲基胺甲醯基）苯基） 叶匕σ定-3-基）-5-(四鼠外匕 咯-1-基）苯甲醯胺 156 0 3-氰基-N-(6-甲基 -5-(4-((6-甲基吡啶-2·基） 甲基胺甲醯基）苯基） 外匕咬-3-基）-5-(六鼠口比 啶小基）苯曱醯胺 123505 - 335 - 200815422 編號 結構 化合物名稱 157 4-(5-(5_第三-丁基各氰 基-2-甲氧基苯甲醯胺 基）-2-甲基吡啶-3-基） 苯甲酸甲酯 158 3-第三-丁基-5-氣基 -N-(5-(4-(環己基胺甲醯 基）苯基）-6-甲基吡啶 -3-基）苯甲醯胺 159 3-第三-丁基-5·鼠基 -N-(5-(4-(2-(二乙胺基） 乙基胺甲醯基）-苯 基）-6-甲基外匕唆-3-基） 苯甲醯胺 160 3-第二-丁基-5-氣基 -N-(5-(4-(2-(二異丙基胺 基）乙基胺甲醯基）苯 基）-6_甲基吡啶-3-基） 苯甲醯胺 161 3-第三-丁基-5-亂基 -N-(6-甲基-5-(4-(2-甲基 -2-(六氮。比^定-1_基）丙 基胺甲醯基）苯基）吡 啶-3-基）苯甲醯胺 162 Λ^λ古 3-第三-丁基-5-氣基 -N-(6-甲基-5-(4-((1-(六 氮峨σ定-1-基）¾己基） 甲基胺甲醯基）苯基） 吡啶-3-基）苯甲醯胺 123505 336- 200815422 編號 結構 化合物名稱 163 C 3-第三-丁基-5-(((2-甲氧 基乙基）(曱基）胺基）甲 基）-N-(6-甲基-5-(4-(新 戊基胺甲醯基）苯基）-吡啶-3-基）苯甲醯胺 164 3-第三-丁基-N-(6-甲基 -5-(4-(新戊基胺甲醯 基）苯基）说啶-3-基）-5-(四鼠卩比洛-1-基 甲基）苯甲醯胺 165 0 3-第三-丁基-N-(6-甲基 -5-(4-(新戊基胺甲醯 基）苯基 &gt;比啶-3-基）-5-(六鼠说咬-1-基 甲基）苯甲醯胺 166 0 ΟΗ 3-氟-N-(5-(4-(l-羥乙基） 苯基&gt;6-甲基吡啶-3-基）-5-嗎福啉基苯甲醯 胺 167 XX 1-(5-(3-第二-丁基-5_氣 基苯甲醯胺基）-2-甲基 吡啶-3-基）-N-嗎福啉基 -1Η·1，2,3-三唑-4-羧醯胺 168 XX 1-(5-(3-第三-丁基-5-氣 基苯甲醯胺基）-2-甲基 p比σ定-3-基）-N-(四氮-2H-哌喃-4-基）-1Η-1，2,3-三 唑-4-羧醯胺 123505 - 337 - 200815422 編 結構 化合物名稱 169 5-弟二-丁基-3-氣基 -N-(5-(4-(環己基胺甲醯 基）苯基）-6-甲基说唆 -3-基）-2-甲氧基苯甲醯 胺 170 5-第二-丁基-3-氣基-2-甲氧基-N-(6-甲基 -5-(4-(六氮ρ比σ定-1-基胺 曱酸基）苯基）ρ比咬-3-基）苯甲醯胺 171 5-第二-丁基-3-氰基-2-甲氧基-Ν-(6-甲基 -5-(4-(四氫-2Η·口瓜喃-4-基胺甲醯基）苯基）吡 啶-3-基）苯甲醯胺 172 5-第三-丁基-3-氣基-2-甲乳基-N-(6-甲基 -5-(4-(嗎福啉基胺甲醯 基）苯基比σ定-3-基）苯 甲醯胺 173 1 3·第二-丁基-Ν~(6-甲基 -5-(4-(新戊基胺甲醯 基）苯基）吡啶-3-基）-5-((4-曱基六氫吡畊-1-基）曱基）苯甲醯胺 174 C0 3-第二-丁基-N_(6-甲基 -5-(4-(新戊基胺甲醯 基）苯基）比唆-3-基）-5-(((四氫呋喃-2-基）甲胺 基）甲基）苯甲醯胺 123505 -338 - 200815422 編號 結構 化合物名稱 175 \ Λ ΝΗ II 3-第三-丁基-N-(6-甲基 -5-(4-(新戊基胺甲醯 基）苯基）-峨咬-3-基）-5-((丙-2-快基胺基） 甲基）苯甲醯胺 176 0 w°^ 3-第三-丁基-N-(6-甲基 -5-(4-(新戊基胺甲醯 基）苯基）·吡啶-3-基）-5-(嗎福啉基甲基） 苯甲醯胺 177 α Η W0^ ) 3-第二-丁基-Ν-(6·甲基 -5-(4-(新戊基胺甲醯 基）苯基）比ϋ定-3-基）-5-((3-嗣基六鼠被p井-1-基）甲基）苯甲醯胺 178 玉。^ 3-第二-丁基-N-(5-(4-(2-第三-丁基耕獄基）-1H-1，2,3-三唑 _1_基）-6-甲 基说唆-3-基）-5-氣基苯 甲醯胺 179 五。〇 N^W：MN、NH XX。 3·第二-丁基-5·乳基 -N-(5-(4-(2-環己基肼羰 基）-1Η-1，2,3-三唑-1-基）-6-甲基^比σ定-3-基） 苯甲醯胺 180 1-(5-(3-第二-丁基-5-氧 基苯甲醯胺基）_2_甲基 外匕σ定基）-N-(2,6-二甲 基六氮p比11定_1-基）-1H-1，2,3-三唑-4-羧醯胺 181 N-(6-甲基-5-(4-(新戊基 胺甲醯基）苯基）-吡啶 基）異菸鹼醯胺 123505 - 339 - 200815422 編號 結構 化合物名稱 182 、s/^nh o ilN人 3-第三-丁基-N-(6-甲基 -5-(4-(新戊基胺甲醯 基）苯基）比。定-3-基）-5-((2-(甲硫基）乙胺 基）甲基）-苯甲醯胺 183 、〜 1 3-第三-丁基-5-(((2-(二 甲胺基）乙基）(甲基）胺 基）甲基）-N-(6-甲基 -5-(4-(新戊基胺甲醯 基）苯基）-0比0定-3·基）苯 甲醯胺 184 又。r^0 3-第二-丁基-5-氣基 -1^-(6-甲基-5-(4-(嗎福1?林 基胺甲酿基）苯基）-1[7比 啶-3-基）苯甲醯胺 185 3-第二-丁基-N-(5-(4-(2_ 第三·丁基肼羰基）苯 基）-6-甲基p比σ定-3-基）-5- 氰基苯甲醯胺 186 3-第二-丁基-5-氧基 -N-(5-(4-(2-環己基肼羰 基）·苯基）-6-甲基吡啶 -3-基）苯甲醯胺 187 5·第三-丁基-N-(5-(4-(2· 第三-丁基肼羰基）苯 基）-6-甲基吡啶-3-基）-3-氰基-2-甲氧基苯甲 醯胺 123505 340 - 200815422 編號 結構 化合物名稱 188 1-(5-(3-氟基-2-曱氧基 -5-嗎福啉基苯甲醯胺 基）-2-甲基吡啶-3-基）-N-新戊基-1H-1，2,3-三唑 -4-羧醯胺 189 Λ Η ^ F 人Ν 丫γ Ν、Ν’ /0 0、人 1-(5-(3-氟基-2-曱氧基 -5-嗎福啉基苯甲醯胺 基）-2-甲基口比唆-3-基）-N-((四氫呋喃-2-基）甲 基）-1沁1，2,3-三唑斗羧 醯胺 190 Λ Η 1-(5-(3-氟基-2-曱氧基 -5-嗎福啉基苯甲醯胺 基）-2-甲基p比ϋ定-3-基）· Ν-(口比口定-3-基曱基）-1Η-1，2,3-三唑-4-羧醯胺 191 0 。 F么 3-氣基-2-甲氧基-Ν-(6_ 甲基-5-(4-(吡啶-3-基甲 基胺甲醯基）苯基）吡 啶各基）-5-嗎福啉基苯 甲醯胺 192 0 。彳 3-氟基-2-曱氧基-N-(6-甲基-5-(4-((四氮咬喃-2-基）甲基胺甲醯基）苯 基）吡啶-3-基）-5-嗎福 啉基苯甲醯胺 193 0 。 3-1基-2-甲氧基-N-(6-甲基-5-(4-(新戊基胺甲 醯基）苯基）·吡啶-3-基）-5-嗎福啉基苯曱醯胺 123505 -341 - 200815422 編號 結構 化合物名稱 194 3-第二-丁基-5-鼠基 -N-(5-(4-(2,6-二甲基六 鼠口比咬-1-基胺甲酿基） 苯基&gt;6-甲基吡啶-3-基）苯甲醯胺 195 5-第二-丁基-3-乳基 -N-(5-(4-(2,6-二甲基六 氫说唆-1-基胺甲酸基） 苯基）-6-甲基^比咬-3-基）-2-甲氧基苯甲醯胺 196 1-(5-(5-第三-丁基-3-氰 基-2-甲氧基苯甲酿胺 基）-2-甲基吡啶-3-基）-N-(2,6-二甲基六鼠 吡啶-1-基）-1Η-1，2,3-三 唑-4-羧醯胺 197 ：^：0 1-(5-(5-第二丁基-3-氣 基-2-甲氧基苯甲醯胺 基）-2-甲基吡啶-3-基）-N-(六鼠p比σ定-1-基）-1Η-1，2,3·三唑-4-羧 醯胺 198 5- 第二-丁基-Ν-(5-(4-(2_ 第三-丁基肼羰 基)-1Η-1，2,3-三唑-1-基)- 6- 甲基吡啶-3-基）-3-氰 基-2-甲氧基苯甲醯胺 199 〇 ° lA。 1-(5-(3-第三-丁基-5-(嗎 福啉基甲基）苯甲醯胺 基）-2-甲基外匕0定-3-基）-N-新戊基-1H-1，2,3_ 三唑-4-羧醯胺 123505 -342 - 200815422 編號 結構 化合物名稱 200 /〇 ΗΝΤχΝ^^ 5-第三-丁基-3-氰基 -N-(5-(4-(2-環己基肼羰 基）-1Η-1，2,3-三唑-1-基）-6-曱基^比咬-3-基）-2_ 甲氧基苯甲醯胺 201 ^ 〇 ΙΑ 〇 1 1-(5-(3第三-丁基 _5_((4-甲基六氫吡畊-1-基）甲 基）苯甲醯胺基）-2-甲 基吡啶-3-基）-N-新戊基 -1H-1，2,3-三唑-4·羧醯胺 202 0 。 3-氰基-N-(6-甲基 -5-(4-(新戊基胺甲醯 基）苯基）-吨咬-3-基）-5- 嗎福啉基苯甲醯胺 203 士 Ν-(5·第二-丁基-3-乳基 -2-甲氧苯基）-6-甲基 -5-(4-(新戊基胺甲醯 基）-1Η-1，2&gt;三唑-1-基） 於驗酿胺 204 Φ N-(3-氰基-5-嗎福啉基 苯基)-6-甲基-5-(4-(新戍 基胺甲醯基）-1Η-1，2,3-三唑-1-基）菸鹼醯胺 205 0 VnC^ ^hVtn^n %入 Ν·(3·氟基-5-嗎福啉基 苯基)-6-甲基-5-(4-(新戍 基胺甲醯基）-1Η-1，2,3-三唑-1-基）菸鹼醯胺 123505 - 343 - 200815422 編號 結構 化合物名稱 206 N-(3-第三-丁基-1·甲基 -1H-吡唑-5-基）-6-曱基 -5-(4-(新戊基胺甲醯 基）-1Η·1，2,3-三唑小基） 菸鹼醯胺 207 l-(5-(3-((lS，5R)-8-氧-3-氮 -雙環并[3.2.1]辛-3-基）-5-氣基苯甲驢胺 基）-2-甲基t7比σ定-3-基）-N-新戊基-1Η-1，2,3· 三唑-4-羧醯胺 208 0 。 3-乳基-Ν-(6-甲基 -5-(4-((四氯咬喃-2-基） 甲基胺f醯基）苯基） 吡啶-3-基）-5-嗎福啉基 苯甲醯胺 209 0 。 3-氣基-N-(6-甲基-5-(4_ (吡啶-3-基甲基胺甲醯 基）苯基）比ϋ定-3-基）-5- 嗎福啉基苯甲醯胺 210 士 όί,Α^Ο N-(3-弟二-丁基苯基）-6· 甲基-5-(4-(新戍基胺甲 醯基）-1Η-1，2,3-三唑-1- 基）菸鹼醯胺 211 士 N-(5-第三-丁基，2-甲氧 苯基）-6-甲基-5-(4-(新戍 基胺甲醯基）-1Η-1，2,3-三唑-1-基）菸鹼醯胺 212 \〆 2-(3-第三-丁基-5-(6-曱 基-5-(4-(新戍基胺甲酿 基）-1Η-1，2,3-三唑-1-基） 吡啶-3-基胺曱醯基）苄 胺基）醋酸第三-丁酯 123505 -344- 200815422 / i 編號 結構 化合物名稱 213 2-(3-第三 _丁基-5-(6-曱 基-5-(4-(新戊基胺甲醯 基）苯基）-说唆-3-基胺 甲醯基）爷胺基）醋酸 第三·丁酯 214 〇Α/ΝΗ 0 2-(3-第二-丁基-5-(6-甲 基-5-(4-(新戊基胺甲醯 基）苯基）-咐ϋ定-3-基胺 甲醯基）爷胺基）醋酸 215 Ν-(5-(4-(8-氧-3-氮-雙壞 并[3·2·1]辛烷-3-羰基）苯 基）-6-甲基吡啶各基）-3-第二-丁基-5-氣基苯甲 醯胺 216 N-(5-(4-(8-氧-3-氮-雙壞 并[3.2.1]辛烷-3-羰基）-1H-1，2,3-三唑-1-基）-6-甲 基p比σ定-3-基）-5-弟二-丁基-3-鼠基-2-甲氧基 苯甲醯胺 217 A^〇v 3-弟二-丁基-5-氣基 -N-(6-甲基-5-(4-(2,2,6,6-四甲基嗎福啉-4-羰基） 苯基）吡啶各基）苯甲 醯胺 218 Ν^^Τ° /〇 ην^^ν^&lt;〇 5-第三-丁基-3-氮基-2· 甲氧基-N-(6-甲基 -5-(4-(2,2,6,6-四甲基嗎 福 p林-4-緣基）-1Η-1，2,3-二σ坐-1-基）p比σ定-3-基） 苯甲醯胺 123505 -345 _ 200815422 編號 結構 化合物名稱 219 n^n Ν-(5-(4-(8-氧-3-氮-雙環 并[3.2.1]辛烷-3-羰基）-1Η_1，2,3_三唑 _1_基）_6_ 甲 基吡啶-3-基）-3-第三-丁基-5-氣基苯甲酿胺 220 3： &gt; ν^ν Ν XX 3-第二·丁基-5-乳基 -N-(6-甲基-5-(4-(2,2,6,6-四甲基嗎福啉-4-羰 基）-1Η·1，2,3-三唑-1-基） 吡啶-3-基）苯甲醯胺 221 Η2Ν^ Ν-(5-第三-丁基-3-胺甲 酿基-2-甲氧苯基）-6-甲 基-5-(4-(新戊基胺甲醯 基）-1Η-1，2,3-三唑-1-基） 菸鹼醯胺 222 J- νΝΓ^ N-(5-第三-丁基-3-(環丙 基胺甲醯基）-2-甲氧苯 基）-6-甲基-5-(4-(新戍基 胺甲醯基）-1Η-1，2,3-三 σ坐·1-基）於驗酸胺 223 ^\χύμ Ν-(5-第三-丁基-2_甲氧 基-3-(甲基磺醯胺基） 苯基)-6-甲基-5-(4-(新戍 基胺甲醯基）-1Η-1，2,3-三唑小基）菸鹼醯胺 224 Ν-(5-(4-(8-氧-3-氮-雙環 并[3·2·1]辛烷-3-羰基）苯 基）-6-曱基峨σ定-3-基）-5-第三-丁基-3-氰基-2·甲 氧基苯甲酿胺 225 5-第三-丁基-3·鼠基-2· 甲氧基-N_(6-曱基 -5-(4-(2,2,6,6-四甲基嗎 福琳-4-魏基）苯基 &gt;比 啶-3-基）苯甲醯胺 123505 -346- 200815422No. Structure Compound Name 138 〇νΝΓ 1-(5-(3-Second-Butyl-5-ylbenzobenzylamino)-2-hydrazylylation ratio 17--3-yl)-N-(six Nitrogen p-pyridin-1-yl)-1Η-1,2,3-triazole-4-carboxamide 139 3-second-butyl-5-carbyl-indole·(6-methyl-5- (4-((6-Methylpyridin-2-yl)methylaminemethanyl)phenyl) benzyl-3-yl)benzamide 140 5-second-butyl-3_ayl- 2-methoxy-N-(6-methyl-5-(4-((6-methyl-Butyl-2-yl)methylamine-methyl)phenyl)pyridin-3-yl)benzene Indoleamine 141 〇&gt; N-(6-methyl-5-(4-((6-methylpyridin-2-yl)methylaminemethanyl)phenyl)-indol-3-yl)-3 -(四鼠^比洛-1-yl)-5-(difluoromethyl)benzoguanamine 142 3-Terti-butyl-5-(6-mercapto-5-(4-(新戍胺 甲 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) Amylamine methyl hydrazino)-phenyl) tribend-3-ylaminocarbamoyl)benzoic acid 144 0 . Leaf N-(6-methyl-5-(4-(neopentylcarbamic acid)phenyl)&gt; than -3-yl)-2-(six sputum than dec-1-yl) isoniazid Basic guanamine 123505 - 333 - 200815422 No. Structure Compound name 145 5-Terti-butyl-:^-(2-(dimethylamino)ethyl)-N3 -(6-methyl-5-(4- (neopentylamine carbaryl)phenyl)pyrazine-3-yl)m-xylylenediamine 146 ΛV ν,οη 3-fluoro-Ν-(5·(4-(1-(hydroxy) Amino)ethyl)phenyl&gt;6-fluorenyl fluorene. Benz-3-yl)-5-morpho-p-phenylbenzamide 147 a〆4-(5-(3-third-butyl) Methyl-5-carbylbenzimidyl)-2-methylpyridin-3-yl)benzoic acid methyl ester 148 n,n 〇_/ XX 1-(5-(3-tri-butyl-5 -Cyanobenzoguanamine)-2-methylpyridine·3·yl)-1Η-1,2,3-triazole-4-carboxylic acid ethyl ester 149 3c pn^:^Nv- XX 1-( 5-(3-second-butyl-5-carbobenzylideneamino)-2-methylpyrazine-form-3-yl)-N-(2-(diethylamino)ethyl) -1Η·1,2,3-triazole-4-carboxyguanamine 150 1-(5-(3-secondbutyl-5-murine benzhydryl)-2-methylpyridine-3· Base)·Ν-(2-(diisopropylamino)ethyl)-1Η-1,2,3-triazole-4- Carboxyguanamine 123505 334 - 200815422 No. Structure Compound name 151 XX. 1-(5-(3-Second-butyl-5-carbobenzylideneamino)-2-methylpyridin-3-yl)- N-(2-methyl-2-(hexanitro-p- 17-den-1-yl)propyl)-1沁1,2,3-triazole-4-carboxamide 152 1-(5-(3) -Di-tert-butyl-5-ylbenzobenzylamino)-2-methylexidine-3-yl)-N-((l-(hexazapyridin-1-yl)cyclohexyl) Mercapto)-1Η-1,2,3-triazole-4-carboxyguanamine 153 0. 6^^Leave N-(6-methyl-5-(4-(neopentylcarbamic acid)phenyl) )-External 1: ϋ定-3-yl)-2-isofanyl is different from acid test amine 154 0 3-cyano-N-(6-methyl-5-(4-((6-methyl)) Said bit-2-yl) methylamine-mercapto)phenyl)pyridinyl)-5-morpholinobenzamide 155 φ 3-cyano-N-(6-methyl-5-( 4-((6-Methyl-n-butyl-2-yl)methylamine-mercapto)phenyl) yttrium s--3-yl)-5-(tetra-mole-pyrene-1-yl)benzene Indoleamine 156 0 3-cyano-N-(6-methyl-5-(4-((6-methylpyridin-2-yl)methylaminemethanyl)phenyl) Base)-5-(six-rhamnosylpyridinyl)benzamide 123505 - 335 - 200815422 Structural Compound Name 157 4-(5-(5_Third-butylcyano-2-methoxybenzoguanidino)-2-methylpyridin-3-yl)methylbenzoate 158 3- Tert-Butyl-5-yl-N-(5-(4-(cyclohexylaminemethyl)phenyl)-6-methylpyridin-3-yl)benzamide 159 3-third -butyl-5.murino-N-(5-(4-(2-(diethylamino)ethylaminemethanyl)-phenyl)-6-methyl-indol-3-yl) Benzylamine 160 3-second-butyl-5-carbyl-N-(5-(4-(2-(diisopropylamino)ethylaminemethanyl)phenyl)-6_ Methylpyridin-3-yl) benzamide 161 3-tert-butyl-5-ranyl-N-(6-methyl-5-(4-(2-methyl-2-(hexanitro) . ^定-1_yl)propylamine carbyl)phenyl)pyridin-3-yl)benzamide 162 Λ^λ古3-Third-butyl-5-gas-N-(6 -Methyl-5-(4-((1-(hexanitroindole-1-yl)3⁄4-hexyl)methylamine-methane)phenyl)pyridin-3-yl)benzamide 123505 336- 200815422 No. Structure Compound name 163 C 3-Terti-butyl-5-(((2-methoxyethyl)(indolyl)amino)methyl)-N-(6-methyl-5-( 4-(neopentylaminomethane)phenyl)-pyridin-3-yl)benzamide 164 3-tert-butyl-N-(6-methyl-5-(4-(neutyl) Hydrazinyl)phenyl)rsyn-3-yl)-5-(tetra-p-pyrrolidino-1-ylmethyl)benzamide 165 0 3-tri-butyl-N-(6 -Methyl-5-(4-(neopentylcarbinyl)phenyl&gt;pyridin-3-yl)-5-(six-spin-1-ylmethyl)benzamide 166 0 ΟΗ 3-Fluoro-N-(5-(4-(l-hydroxyethyl)phenyl)&gt;6-methylpyridin-3-yl)-5-morpholinebenzamide 167 XX 1-( 5-(3-second-butyl-5-ylbenzobenzylamino)-2-methylpyridin-3-yl)-N-morpholinyl-1Η·1,2,3-triazole -4-carboxyguanamine 168 XX 1-(5-(3-tri-butyl-5-carbyl) Methionine)-2-methyl p-pyridyl-3-yl)-N-(tetrazol-2H-pyran-4-yl)-1Η-1,2,3-triazole-4-carboxylate Indoleamine 123505 - 337 - 200815422 The structural compound name 169 5-di-di-butyl-3-yl-N-(5-(4-(cyclohexylaminomethyl)phenyl)-6-methyl Ind-3-yl)-2-methoxybenzamide 170 5-second-butyl-3-yl-2-methoxy-N-(6-methyl-5-(4-( Hexanitro-p-ratio sigma-l-ylamine decanoic acid)phenyl)pyrhyl-3-yl)benzamide 171 5-second-butyl-3-cyano-2-methoxy- Ν-(6-Methyl-5-(4-(tetrahydro-2Η·口瓜喃-4-ylamine)methyl)phenyl)pyridin-3-yl)benzamide 172 5-Third- Butyl-3-yl-2-methyllacyl-N-(6-methyl-5-(4-(morpholinylcarbinyl)phenyl)pyridin-3-yl)benzamide Amine 173 1 3·Second-butyl-indole~(6-methyl-5-(4-(neopentylcarbenyl)phenyl)pyridin-3-yl)-5-((4-曱) Hexahydropyrrol-1-yl)mercapto)benzamide 174 C0 3-second-butyl-N_(6-methyl-5-(4-(neopentylcarbinyl)phenyl) ) 唆-3-yl)-5-(((tetrahydrofuran-2-yl)methylamino)methyl)benzamide 1235 05 -338 - 200815422 No. Structure Compound Name 175 \ Λ ΝΗ II 3-Terve-butyl-N-(6-methyl-5-(4-(neopentylcarbinyl)phenyl)-bite 3-yl)-5-((propan-2-ylamino)methyl)benzamide 176 0 w°^ 3-tert-butyl-N-(6-methyl-5-( 4-(neopentylaminomethane)phenyl)pyridin-3-yl)-5-(morpholinomethyl)benzamide 177 α Η W0^) 3-second-butyl- Ν-(6·methyl-5-(4-(neopentylcarbinyl)phenyl)pyridin-3-yl)-5-((3-mercapto-six-mouse) Base) methyl) benzamide 178 jade. ^ 3-Second-butyl-N-(5-(4-(2-Third-butyl Prison)-1H-1,2,3-triazol-1-yl)-6-methyl Said 唆-3-yl)-5-carbobenzamide 179 five. 〇 N^W: MN, NH XX. 3. Second-butyl-5-lactyl-N-(5-(4-(2-cyclohexylcarbonyl)-1Η-1,2,3-triazol-1-yl)-6-methyl ^比σ定-3-yl) Benzylamine 180 1-(5-(3-second-butyl-5-oxybenzamide)_2_methylpyridinium s-dentate)-N- (2,6-Dimethylhexanitrogen p to 11 1-1-yl)-1H-1,2,3-triazole-4-carboxyguanamine 181 N-(6-methyl-5-(4- (neopentylamine carbaryl)phenyl)-pyridyl)isonicotinamine decyl 123505 - 339 - 200815422 No. Structure Compound Name 182, s/^nh o ilN 3-3-tert-butyl-N-( 6-methyl-5-(4-(neopentylcarbinyl)phenyl)pyr.-3-yl)-5-((2-(methylthio)ethylamino)methyl)- Benzamide 183, ~ 1 3-tri-butyl-5-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)-N-(6-methyl -5-(4-(neopentylaminomethane)phenyl)-0 to 0--3-yl)benzamide 184 again. r^0 3-second-butyl-5-carbyl-1^-(6-methyl-5-(4-(i-flo- 1?-linylamine)-phenyl)-1) Pyridin-3-yl)benzamide 185 3-second-butyl-N-(5-(4-(2_3d-butyl fluorenylcarbonyl)phenyl)-6-methyl p ratio σ- 3-yl)-5-cyanobenzamide 186 3-second-butyl-5-oxy-N-(5-(4-(2-cyclohexylcarbonyl)phenyl)-6- Methylpyridin-3-yl)benzamide 187 5·T-butyl-N-(5-(4-(2·tris-butylphosphonyl)phenyl)-6-methylpyridine- 3-yl)-3-cyano-2-methoxybenzamide 123505 340 - 200815422 No. Structure Compound Name 188 1-(5-(3-Fluoro-2-oxo-5-morpholine Benzobenzamide)-2-methylpyridin-3-yl)-N-neopentyl-1H-1,2,3-triazole-4-carboxyguanamine 189 Λ Η ^ F Human Ν 丫 γ Ν,Ν' /0 0, human 1-(5-(3-fluoro-2-indolyl-5-morpholinebenzimidyl)-2-methylpyryl-3-yl-3-yl )-N-((tetrahydrofuran-2-yl)methyl)-1沁1,2,3-triazole carboxy carbamide 190 Λ Η 1-(5-(3-fluoroyl-2-decyloxy- 5-morpholinebenzimidamide)-2-methylp-pyridin-3-yl)·Ν-( 口比口定-3- Base ))-1Η-1,2,3-triazole-4-carboxyguanamine 191 0 . 3-M-yl-2-methoxy-indole-(6-methyl-5-(4-(pyridin-3-ylmethylamine-methyl)phenyl)pyridine)-5-? Polinylbenzamide 192 0 . 3-Hydroxy-2-indolyl-N-(6-methyl-5-(4-((tetrazole-2-yl)methylaminemethanyl)phenyl)pyridine-3- Base)-5-morpholinyl benzamide 193 0 . 3-1-yl-2-methoxy-N-(6-methyl-5-(4-(neopentylcarbenyl)phenyl)pyridin-3-yl)-5-morpholinyl Phenylguanamine 123505 -341 - 200815422 No. Structure Compound Name 194 3-Second-butyl-5-murine-N-(5-(4-(2,6-dimethylhexaquivalent) bite-1 -ylamine methyl phenyl)phenyl&gt;6-methylpyridin-3-yl)benzamide 195 5-second-butyl-3-lacyl-N-(5-(4-(2, 6-Dimethylhexahydroindol-1-ylaminecarboxylic acid)phenyl)-6-methyl^biten-3-yl)-2-methoxybenzamide 196 1-(5-( 5-t-butyl-3-cyano-2-methoxybenzoylamino)-2-methylpyridin-3-yl)-N-(2,6-dimethylhexapyridine) 1-yl)-1Η-1,2,3-triazole-4-carboxamide 197 :^:0 1-(5-(5-t-butyl-3-yl-2-methoxybenzene) Methionido)-2-methylpyridin-3-yl)-N-(six-mouse p-sigma-l-yl)-1Η-1,2,3·triazole-4-carboxamide 198 5 - Second-butyl-indole-(5-(4-(2_th-tert-butylindolecarbonyl)-1Η-1,2,3-triazol-1-yl)-6-methylpyridine-3- 3-(cyano-2-methoxybenzamide 199 〇° lA. 1-(5-(3-Terti-butyl-5-(morpholinemethyl)benzene) Amino)-2-methylindole quinone-3-yl)-N-neopentyl-1H-1,2,3_triazole-4-carboxyguanamine 123505 -342 - 200815422 No. Structure Compound Name 200 / 〇ΗΝΤχΝ^^ 5-Tris-butyl-3-cyano-N-(5-(4-(2-cyclohexylcarbonyl)-1Η-1,2,3-triazol-1-yl)- 6-曱基^比咬-3-yl)-2_methoxybenzamide 201 ^ 〇ΙΑ 〇1 1-(5-(3 tert-butyl_5_((4-methylhexahydropyridyl) Till-1-yl)methyl)benzimidamide)-2-methylpyridin-3-yl)-N-neopentyl-1H-1,2,3-triazole-4·carboxyguanamine 202 0. 3-cyano-N-(6-methyl-5-(4-(neopentylcarbinyl)phenyl)-ton-3-yl)-5-morpholinebenzamide Amine 203 g.-(5·Second-butyl-3-lacyl-2-methoxyphenyl)-6-methyl-5-(4-(neopentylcarbamoyl)-1Η-1 , 2&gt; Triazol-1-yl) in the presence of the amine 204 Φ N-(3-cyano-5-morpholineylphenyl)-6-methyl-5-(4-(xindecylamine) Mercapto)-1Η-1,2,3-triazol-1-yl)nicotinium 205 0 VnC^ ^hVtn^n % Ν·(3·Fluoro-5-morpholinylphenyl) -6-Methyl-5-(4-(indanylaminomethyl)-1Η-1,2,3-triazol-1-yl)nicotine 123505 - 343 - 200815422 No. Structure Compound name 206 N-(3-Terti-butyl-1·methyl-1H-pyrazol-5-yl)-6-mercapto-5-(4-(neopentyl) Aminomethylmercapto)-1Η·1,2,3-triazole small group) Nicotinamide 207 l-(5-(3-((lS,5R)-8-oxo-3-nitro-bicyclo[ 3.2.1] Oct-3-yl)-5-ylbenzobenzylamino)-2-methyl t7 than sigma-3-yl)-N-neopentyl-1Η-1,2,3· Triazole-4-carboxyguanamine 208 0 . 3-lacyl-indole-(6-methyl-5-(4-((tetrachloromethane-2-yl)methylamine)-phenyl)phenyl)pyridin-3-yl)-5-? Polinylbenzamide 209 0 . 3-oxyl-N-(6-methyl-5-(4-(pyridin-3-ylmethylaminecarbamimidyl)phenyl)pyridin-3-yl)-5-morpholine-based benzoyl醯amine 210 士όί,Α^Ο N-(3-di-di-butylphenyl)-6·methyl-5-(4-(sindecylaminomethane)-1Η-1,2,3 -Triazol-1-yl)nicotinamide 211 N-(5-tris-butyl, 2-methoxyphenyl)-6-methyl-5-(4-(indanylamine) Base)-1Η-1,2,3-triazol-1-yl)nicotinate guanamine 212 \〆2-(3-t-butyl-5-(6-mercapto-5-(4-( Neodecylamine aryl)-1Η-1,2,3-triazol-1-yl)pyridin-3-ylaminoindenyl)benzylamino)acetic acid tert-butyl ester 123505 -344- 200815422 / i number structure compound name 213 2-(3-tert-butyl-5-(6-fluorenyl-5-(4-(neopentylcarbinyl)phenyl)- 唆-3-ylamine Methyl hydrazide) arylamino) acetic acid third butyl ester 214 〇Α / ΝΗ 0 2-(3-second-butyl-5-(6-methyl-5-(4-(neopentylamine)醯))phenyl)-indole-3-ylaminocarbamoyl)-amino-amino)acetic acid 215 Ν-(5-(4-(8-oxo-3-nitrogen-double bad and [3·2· 1] Octane-3-carbonyl)phenyl)-6-methylpyridinyl)-3-second-butyl-5- Benzobenzamide 216 N-(5-(4-(8-oxo-3-nitro-bis-benzo[3.2.1]octane-3-carbonyl)-1H-1,2,3-triazole- 1-yl)-6-methyl p-pyridin-3-yl)-5-di-di-butyl-3-murly-2-methoxybenzamide 217 A^〇v 3-different -butyl-5-carbyl-N-(6-methyl-5-(4-(2,2,6,6-tetramethylmorpholine-4-carbonyl)phenyl)pyridinyl)benzene Formamide 218 Ν^^Τ° /〇ην^^ν^&lt;〇5-Third-butyl-3-nitro-2-methoxy-N-(6-methyl-5-(4 -(2,2,6,6-tetramethyl- orb-pylinyl-4-yl)-1Η-1,2,3-di-sigma-1-yl)p-pyridyl-3-yl)benzene Methionine 123505 -345 _ 200815422 No. Structure Compound name 219 n^n Ν-(5-(4-(8-oxo-3-nitro-bicyclo[3.2.1]octane-3-carbonyl)-1Η_1, 2,3_Triazole_1_yl)_6_methylpyridin-3-yl)-3-tert-butyl-5-ylbenzobenzamide 220 3: &gt; ν^ν Ν XX 3- Dibutyl-5-lacyl-N-(6-methyl-5-(4-(2,2,6,6-tetramethylmorpholine-4-carbonyl)-1Η·1,2, 3-triazol-1-yl)pyridin-3-yl)benzamide 221 Η2Ν^ Ν-(5-Third-butyl-3-amine-mercapto-2-methoxyphenyl)-6- Methyl-5-(4-(neopentylamine) Base)-1Η-1,2,3-triazol-1-yl) Nicotinamide 222 J- νΝΓ^ N-(5-Third-butyl-3-(cyclopropylaminemethanyl)- 2-methoxyphenyl)-6-methyl-5-(4-(indicylaminocarbazyl)-1Η-1,2,3-tris-sigma-1 -yl) in acid amine 223 ^ \χύμ Ν-(5-Third-butyl-2-methoxy-3-(methylsulfonylamino)phenyl)-6-methyl-5-(4-(indoxylamine) Base)-1Η-1,2,3-triazole small group) Nicotinamide 224 Ν-(5-(4-(8-oxo-3-nitro-bicyclo[3·2·1]octane- 3-carbonyl)phenyl)-6-fluorenylindole-3-yl)-5-tris-butyl-3-cyano-2.methoxybenzoic acid 225 5-third-butyl -3-3·murine-2·methoxy-N_(6-fluorenyl-5-(4-(2,2,6,6-tetramethyl-wufolin-4-weiry)phenyl]&gt; Pyridin-3-yl)benzamide 123505 -346- 200815422

編號 結構 化合物名稱 226 5-第二-丁基-3-乳基-2_ 曱氧基-N-{6-甲基 -5·[4-(10-氧-4-氮三環 并[5.2.1.02,6]癸烷斗羰 基）-苯基]-吡啶-3-基}-苯甲醯胺 227 In人 5-第三-丁基-3-亂基-2-甲氧基-Ν-{6-甲基 -5-[4-(10-氧-4-氮-三環 并[5.2.1.02,6]癸烷-4-羰 基）-[1，2,3]三唑-1-基]-吡 啶-3-基}-苯甲醯胺 228 n^n N hT 3-第二-丁基-5-乳基 -Ν-{6·甲基-5-[4-(10-氧-4-氮-三環并[5.2.1.02,6]癸 烷斗羰基）-[1，2,3]三唑 -1-基]•吡啶-3-基卜苯甲 醯胺 229 3-第三-丁基-5-氰基 -Ν-{6-甲基-5-[4-(10·氧-4-氮-三環并[5.2.1.02,6]癸 烧-4-搂基）-苯基]比0定 -3-基}-苯曱醯胺 230 〇 3-第二-丁基-Ν-(6-甲基 -5-(4-(新戊基胺曱醯 基）苯基）-吨咬-3-基）-5-((2-(甲基亞磺醯 基）乙胺基）甲基）苯甲 醯胺 231 r^NH ° 人 0々、0 3-第三-丁基-N-(6-甲基 -5-(4-(新戊基胺甲醯 基）苯基）-说咬-3-基）-5-((2-(甲續驢基）乙 胺基）甲基）苯甲醯胺 123505 - 347 - 200815422No. Structure Compound name 226 5-second-butyl-3-lacyl-2_decyloxy-N-{6-methyl-5.[4-(10-oxo-4-nitrotricyclo[[. 1.02,6]nonane carbonyl)-phenyl]-pyridin-3-yl}-benzamide 227 In human 5-tri-butyl-3-ranyl-2-methoxy-oxime-{ 6-Methyl-5-[4-(10-oxo-4-nitro-tricyclo[5.1.2.02,6]decane-4-carbonyl)-[1,2,3]triazol-1-yl ]-pyridin-3-yl}-benzamide 228 n^n N hT 3-second-butyl-5-lactyl-indole-{6·methyl-5-[4-(10-oxo- 4-Nitro-tricyclic [5.2.1.02,6]decane carbonyl)-[1,2,3]triazol-1-yl]•pyridin-3-ylbenzamide 229 3-third -butyl-5-cyano-indole-{6-methyl-5-[4-(10.oxo-4-nitro-tricyclo[5.1.2.02,6]pyrene-4-yl)- Phenyl]pyrene-3-yl}-benzoguanamine 230 〇3-second-butyl-indole-(6-methyl-5-(4-(neopentylamino)phenyl) )-Teng-3-yl)-5-((2-(methylsulfinyl)ethylamino)methyl)benzamide 231 r^NH ° Human 0々, 0 3-Third - Butyl-N-(6-methyl-5-(4-(neopentylcarbinyl)phenyl)--n--3-yl)-5-((2-(methyl)-yl) Amino)methyl)benzamide 123 505 - 347 - 200815422

編號 結構 232 233 234 235 236 237No. Structure 232 233 234 235 236 237

化合物名稱 N-(3-第二-丁基-5-亂基 苯基）-6-甲基-5-(4-(六鼠 吡啶-1-基胺甲醯 基）-1Η-1，2,3-三唑-1-基） 菸鹼醯胺 N-(5-第三-丁基-2-甲氧 基-3-(曱基磺醯胺基） 苯基）-6-甲基-5-(4-(六氫 吡啶-1_基胺甲醯 基）-1Η·1，2,3-三唑-1-基） 菸鹼醯胺The compound name N-(3-second-butyl-5-ranylphenyl)-6-methyl-5-(4-(hexorpyridin-1-ylaminecarbamyl)-1Η-1,2 , 3-triazol-1-yl) Nicotinamide N-(5-tert-butyl-2-methoxy-3-(decylsulfonylamino)phenyl)-6-methyl- 5-(4-(hexahydropyridine-1_ylaminocarbamimidyl)-1Η·1,2,3-triazol-1-yl) Nicotinamide

N-(5-第三-丁基-3-鼠基 -2-甲氧苯基）-6-甲基 -5-(4-(六氮p比咬-1-基胺 甲醯基）-1Η-1，2,3·三唑 -1-基）於驗酿胺 1-(5-(5-第三-丁基-3-氰 基-2-(2-(4-甲基六氫吡 畊-1-基）乙氧基）苯甲 酸胺基）-2-曱基口比σ定-3-基 &gt;^_新戊基-1Η-1，2,3-三唑-4-羧醯胺 5-第三-丁基-3-氰基 -Ν-(6-甲基-5-(4-(新戊基 胺甲醯基）苯基）-p比咬 -3-基）-2-(2-(4-甲基六氫 口比喷-1-基）乙乳基）苯 甲醯胺N-(5-Third-butyl-3-murly-2-methoxyphenyl)-6-methyl-5-(4-(hexanitro-p-butyr-1 -ylaminocarbamoyl)- 1Η-1,2,3·Triazol-1-yl) in the presence of 1-(5-(5-tri-butyl-3-cyano-2-(2-(4-methyl)hexahydro) Pyridin-1-yl)ethoxy)benzoic acid amino)-2-hydrazinol ratio sigma-3-yl group&gt;^_neopentyl-1Η-1,2,3-triazole-4- Carboxylamidine 5-tris-butyl-3-cyano-indole-(6-methyl-5-(4-(neopentylcarbinyl)phenyl)-p is a benzyl-3-yl) -2-(2-(4-methylhexahydropyranylpyran-1-yl)ethylidyl)benzamide

3-氰基-N-(6-曱基 -5-(4-(N-新戊基胺磺醯 基）苯基）吡啶-3-基）-5-嗎福啉基苯甲醯胺 123505 -348 - 200815422 編號 結構 化合物名稱 238 A， 、〆 3-氰基-N-(6-甲基 -5-(4-(N-新戍基胺績S篮 基）苯基）说咬-3-基）-5-(四氮卩比咯-1-基） 苯甲醯胺 239 4 、〆 5-第二-丁基-3-乳基-2· 甲氧基-N-(6-甲基 -5-(4-(N-新戊基胺磺醯 基）苯基）说。定-3-基）苯 甲醯胺 240 叶 N-(6-甲基-5-(4-(新戍基 胺甲醯基）苯基 &gt;吡啶 -3-基）異嘮唑-3-羧醯胺 241 3_第三-丁基-1-甲基 _N-(6-甲基-5-(4-(新戊基 胺甲醯基）苯基）-吡啶 -3-基）-1Η-吡唑-5- 羧醯胺 242 寸 5-第二-丁基-2·甲基 -N-(6-甲基-5-(4-(新戊基 胺甲醯基）_苯基 &gt;比啶 -3-基）呋喃-3-羧醯胺 243 彳 3-第三-丁基-N-(6-甲基 -5-(4-(新戊基胺甲醯 基）苯基）吡啶-3-基）-1Η-外匕。坐-5-魏醯胺 244 〇 、人 5-第三-丁基-N-(6-甲基 -5-(4-(新戊基胺甲醯 基）苯基）-吡啶各基）異 噚唑-3-羧醯胺 245 / 1-(5-(3-第二-丁基-5-鼠 基苯甲醯胺基）-2-乙基 吡啶-3-基）-N-新戊基 -1H-1，2,3-三唑-4-羧醯胺 123505 - 349 - 200815422 編號 結構 化合物名稱 2463-cyano-N-(6-fluorenyl-5-(4-(N-neopentylamine sulfonyl)phenyl)pyridin-3-yl)-5-morpholinebenzimidamide 123505 -348 - 200815422 No. Structure Compound name 238 A, 〆 3-cyano-N-(6-methyl-5-(4-(N-neinylamine) S-base) phenyl) -yl)-5-(tetraziniumpyrrol-1-yl)benzamide 239 4 ,〆5-second-butyl-3-lacyl-2·methoxy-N-(6-A 5-O-(4-(N-Pentylamine sulfonyl)phenyl). Benz-3-yl)benzamide 240 leaves N-(6-methyl-5-(4-(new Mercaptoaminemethanyl)phenyl&gt;pyridin-3-yl)isoxazole-3-carboxamide 241 3_Third-butyl-1-methyl-N-(6-methyl-5- (4-(neopentylaminomethane)phenyl)-pyridin-3-yl)-1Η-pyrazole-5-carboxamide 242 inch 5-second-butyl-2.methyl-N- (6-Methyl-5-(4-(neopentylcarbamoyl)-phenyl]pyridin-3-yl)furan-3-carboxamide 243 彳3-third-butyl-N -(6-Methyl-5-(4-(neopentylcarbinyl)phenyl)pyridin-3-yl)-1Η-pyrene. Sodium-5-Weiamine 244 人, human 5- Tri-butyl-N-(6-methyl-5-(4-(neopentylaminomethyl) benzene) )-pyridyl)isoxazole-3-carboxamide 245 / 1-(5-(3-second-butyl-5-murine benzhydryl)-2-ethylpyridine-3- -N-neopentyl-1H-1,2,3-triazole-4-carboxyguanamine 123505 - 349 - 200815422 No. Structure Compound Name 246

247247

5-第三·丁基-N1-甲基 -N3-(6-甲基-5-(4-(新戊 基胺甲醯基）苯基）吡 啶-3-基）間苯二甲醯胺 5-第三-丁基-N1-環丙 基-N3-(6-甲基-5-(4-(新戊基胺甲醯基）苯 基）吡啶-3-基）間苯二 甲醯胺 2485-Third-butyl-N1-methyl-N3-(6-methyl-5-(4-(neopentylcarbenyl)phenyl)pyridin-3-yl)m-xylylenediamine 5-Terti-butyl-N1-cyclopropyl-N3-(6-methyl-5-(4-(neopentylcarbenyl)phenyl)pyridin-3-yl)m-xylylene hydrazide Amine 248

5-第三-丁基-N1-(環丙 基曱基）-N3 -(6-甲基 -5-(4-(新戊基胺甲醯 基）苯基）吡啶-3-基）間 苯二甲醯胺 2495-Terti-butyl-N1-(cyclopropylindenyl)-N3-(6-methyl-5-(4-(neopentylaminomethyl)phenyl)pyridin-3-yl) Benzoguanamine 249

5-第二-丁基-Ni -(6-甲 基-5-(4-(新戊基胺曱醯 基）苯基）吡啶-3-基）間 苯二甲醯胺 2505-Second-butyl-Ni-(6-methyl-5-(4-(neopentyl)indolyl)phenyl)pyridin-3-yl)m-xylylenediamine 250

1-(5-(3-氟基·5-嗎福琳 基苯甲醯胺基&gt;2-甲基 吡啶-3-基）-1Η-1，2,3-三 唑-4-羧酸乙酯 2511-(5-(3-Fluoro-5-hhofolinylbenzamide)&gt;2-methylpyridin-3-yl)-1Η-1,2,3-triazole-4-carboxylic acid Ethyl ester 251

3-第二-丁基-5-(6-曱基 -5-(4-(新戊基胺甲醯 基）-1Η·1，2,3_三唑-1-基） 吡啶-3-基胺甲醯基）苯 甲酸甲酯 2523-second-butyl-5-(6-fluorenyl-5-(4-(neopentylcarbamoyl)-1Η·1,2,3-triazol-1-yl)pyridine-3- Methylaminomethyl benzoate 252

1-(5-(3-氟基-5-(二氟1 甲 基）苯甲醯胺基）-2-甲 基吡啶-3-基）-N-新戊基 -1H-1，2,3-三唑_4_羧醯胺 123505 -350 - 200815422 〆 編號 結構 2531-(5-(3-Fluoro-5-(difluoromethyl)benzylamino)-2-methylpyridin-3-yl)-N-neopentyl-1H-1,2, 3-triazole_4_carboxyguanamine 123505 -350 - 200815422 〆Number structure 253

254 255254 255

256256

化合物名稱 3-第三-丁基-5-(6-甲基 -5-(4-(新戊基胺甲醯 基）-1Η·1，2,3-三唑-1-基） 吡啶-3-基胺甲醯基）苯 甲酸 5-(3-第二-丁基-5-氣基 苯甲醯胺基）-2-甲基 -3-(4-(新戊基胺甲醯 基）苯基）吡啶1-氧化物 5-(3-第二-丁基-5-鼠基 苯甲醯胺基）-2-甲基 -3-(4-(新戊基胺甲醯 基）·1Η·1，2,3-三唑-1-基） 口比淀1-氧化物 5·第三-丁基-Ν1-(環丙 基曱基）-Ν3 -(6· 甲基-5-(4-(新戍基胺甲 醯基）-1Η-1，2,3-三唑-1-基）1?比咬-3-基）間苯二 257Compound name 3-Terti-butyl-5-(6-methyl-5-(4-(neopentylcarbenyl)-1Η·1,2,3-triazol-1-yl)pyridine- 5-(amino-carbamoyl)benzoic acid 5-(3-second-butyl-5-carbobenzylideneamino)-2-methyl-3-(4-(neopentylamine) Phenyl)pyridine 1-oxide 5-(3-second-butyl-5-murtobenzamide)-2-methyl-3-(4-(neopentylcarbamyl) ·1Η·1,2,3-triazol-1-yl) lat. 1-oxide 5·t-butyl-Ν1-(cyclopropylindenyl)-Ν3 -(6·methyl-5 -(4-(indanylaminocarbazinyl)-1Η-1,2,3-triazol-1-yl)1? than -3-yl)isophthalic 257

甲醯胺 1-(5-(2,5-二甲氧基笨甲 酿胺基）-2-甲基批唆-3-基）-N-新戊基-1Η-1，2,3- 258Methionamine 1-(5-(2,5-dimethoxyphenylamino)-2-methyl-triazin-3-yl)-N-neopentyl-1Η-1,2,3- 258

三唑-4-羧醯胺 5-第三-丁基-N1-甲基 -N3-(6-甲基-5-(4-(新戊 基胺甲醯基）-1Η-1，2,3· 二坐-1-基）p比ϋ定-3-基） 間苯二甲醯胺 259Triazole-4-carboxyguanamine 5-tri-butyl-N1-methyl-N3-(6-methyl-5-(4-(neopentylcarbamyl)-1Η-1,2, 3·二坐-1-yl)p than ϋ定-3-yl) m-xylyleneamine 259

3-氰基-5-(4-甲基-1Η-咪唑-1-基）-N-(6-曱基 -5-(4-(新戊基胺甲醯 基）苯基）峨咬-3_基）苯 曱醯胺 123505 -351 - 200815422 \ 編號 結構 化合物名稱 260 F ΗΝγνΝ^Ν 1-(2-甲基-5-(3-(4-甲基 -1H-咪唑-1-基）-5-(三氟 甲基）苯甲醯胺基）外匕 啶-3-基）-N-新戊基 -1H-1，2,3-三唑-4-羧醯胺 261 tS ΗΝχχ&quot; 1-(5-(3-氰基-5-(4甲基 -1H-咪唑-1-基）苯曱醯 胺基）-2-甲基p比ϋ定-3-基）-Ν-新戊基-1Η-1，2,3- 三唑-4-羧醯胺 262 ^ H 1-(5-(3-第二-丁基-5-氣 基苯甲醯胺基）-2-甲基 口比咬-3-基）-Ν-(3·經基 -2,2-二甲基丙基）-1Η-1，2,3-三唑-4-羧醯胺 263 (R)-l-(5-(3•第三-丁基-5-氰基苯甲醯胺基）-2-甲 基叶b °定-3-基）~N-((四氮 咬喃-2-基）甲基）-1H-1,2,3-三唑-4-羧醯胺 264 (S)-l-(5-(3-第三-丁基-5-氰基苯甲醯胺基）-2-甲 基外b °定-3-基）-N-((四氣 呋喃-2-基）甲基）-1H-1，2,3-三唑-4-羧醯胺 265 〇H /0 ΗΝγ^Ν、/ 1-(5-(5-第三-丁基各氰 基-2-甲氧基苯甲醯胺 基）-2-曱基p比咬-3-基）-Ν-((1·羥基環丙基）曱 基）-1Η-1，2,3-三唑-4-羧醯胺 123505 352 - 2008154223-cyano-5-(4-methyl-1Η-imidazol-1-yl)-N-(6-fluorenyl-5-(4-(neopentylcarbinyl)phenyl)-bite- Benzeneamine 123505 -351 - 200815422 \ No. Structure Compound name 260 F ΗΝγνΝ^Ν 1-(2-methyl-5-(3-(4-methyl-1H-imidazol-1-yl) -5-(trifluoromethyl)benzamideamino)- acridin-3-yl)-N-neopentyl-1H-1,2,3-triazole-4-carboxamide 261 tS ΗΝχχ&quot; 1-(5-(3-Cyano-5-(4methyl-1H-imidazol-1-yl)phenylhydrazinyl)-2-methylp-pyridin-3-yl)-indole-new pentyl-1Η-1,2,3-triazole-4-carboxamide 262 ^ H 1-(5-(3-second-butyl-5-carbylbenzamide)-2-methyl Base mouth ratio bit-3-yl)-Ν-(3·transyl-2,2-dimethylpropyl)-1Η-1,2,3-triazole-4-carboxyguanamine 263 (R)- L-(5-(3•Third-butyl-5-cyanobenzamide)-2-methylleaf b °-3-yl)~N-((tetrazole-2- Methyl)-1H-1,2,3-triazole-4-carboxamide 264 (S)-l-(5-(3-Terti-butyl-5-cyanobenzamide) -2-methyl-external b ° -3-yl)-N-((tetrafluorofuran-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide 265 〇 H /0 ΗΝγ^Ν, / 1- (5-(5-Terve-butyl cyano-2-methoxybenzylamino)-2-indolyl p-biti-3-yl)-indole-((1.hydroxycyclopropyl) ) mercapto)-1Η-1,2,3-triazole-4-carboxyguanamine 123505 352 - 200815422

編號 結構 化合物名稱 266 267 268 269 270 271 272No. Structure Compound name 266 267 268 269 270 271 272

1-(5-(3,5-雙三甲基乙醯 胺基苯甲醯胺基）-2-甲 基外b咬-3-基）-N-新戍基 -111-1，2,3-三〇坐-4-魏酸胺1-(5-(3,5-bistrimethylacetamidobenzylidinium)-2-methylexyl b--3-yl)-N-neindyl-111-1,2, 3-triterpenoid-4-weis acid amine

N-(3-第三-丁基-5-氰基 苯基）-6-甲基-5-(4-(新戍 基胺甲醯基）苯基）菸 驗醯胺N-(3-Terve-butyl-5-cyanophenyl)-6-methyl-5-(4-(indicylaminomethyl)phenyl) acetonide

N-(5-第二-丁基-3-氣基 -2-甲氧苯基）-6-甲基 -5-(4-(新戊基胺甲醯 基）苯基）柊驗酸胺N-(5-Second-butyl-3-oxyl-2-methoxyphenyl)-6-methyl-5-(4-(neopentylaminomethyl)phenyl) hydrazide

5-第三-丁基-3-氣基 -N-(5-(4-(3-羥基-2,2-二 甲基丙基胺甲醯基）苯 基）-6-甲基π比咬-3-基）-2_ 甲氧基苯甲醯胺5-Terti-butyl-3-yl-N-(5-(4-(3-hydroxy-2,2-dimethylpropylamine)methyl)phenyl)-6-methyl π ratio Bite-3-yl)-2_methoxybenzamide

5-第三-丁基-3-乳基 -N-(5-(4-((l-羥基環丙 基）甲基胺甲醯基）苯 基）-6·甲基吡啶各基）-2- 曱氧基苯甲醯胺5-Terti-butyl-3-lacyl-N-(5-(4-((l-hydroxycyclopropyl)methylaminemethanyl)phenyl)-6-methylpyridine)- 2-decyloxybenzamide

1-(5-(5-弟二-丁基-3-氣 基_2-曱氧基苯曱醯胺 基）-2-曱基口比ϋ定-3-基）-Ν-(3-羥基-2,2-二甲 基丙基）-1Η-1，2,3-三唑 -4-羧醯胺1-(5-(5-di-di-butyl-3-yl-2-hydroxyphenylamino)-2-mercapto-pyrrolidine-3-yl)-indole-(3- Hydroxy-2,2-dimethylpropyl)-1Η-1,2,3-triazole-4-carboxyguanamine

1-(5-(3-第二-丁基-5-(正 丙基胺磺醯基）苯甲醯 胺基）-2-甲基外Is σ定-3-基）-Ν-新戊基 _1Η-1，2,3-三唑-4-羧醯胺 123505 - 353 - 200815422 編號 結構 化合物名稱 273 t l-(5-(3,5-雙（新戊氧基） 苯甲醯胺基）-2-甲基吡 咬-3-基）-N-新戊基 -1H-1，2,3-三唑-4-羧醯胺 274 ^0^Η〇&lt;Γ〇Η 3-第二-丁基-5-亂基 -N-(5-(4-(3-羥基-2,2-二 曱基丙基胺曱醯基）苯 基）-6-甲基p比淀-3-基） 苯甲醯胺 275 / 3-第二-丁基-5-氣基 -Ν-(5-(4-((1·羥基環丙 基）甲基胺甲醯基）苯 基）各甲基吡啶-3-基） 苯甲醯胺 276 \ V 〇 5-第三-丁基-Ν'Ν1-二 甲基-Ν3-(6-甲基 -5-(4-(新戊基胺甲醯 基）苯基）吡啶-3-基）間 苯二甲醯胺 111 N-(5-(4-(2-胺基-2-甲基 丙基胺曱醯基）苯 基）-6-甲基吡啶-3-基）-3-第三-丁基-5-氣基苯甲 酸胺 278 〇 vv 1-(2-甲基-5-(3-三甲基 乙醯胺基苯曱醯胺基） 外匕°定-3-基）-N_新戍基 _1H-1，2,3-三唑-4-羧醯胺 123505 354 - 200815422 f 編號 結構 化合物名稱 279 280 281 283 2841-(5-(3-second-butyl-5-(n-propylaminesulfonyl)benzamide)-2-methylexido Is sigma-3-yl)-indole-neopent Base_1Η-1,2,3-triazole-4-carboxyguanamine 123505 - 353 - 200815422 No. Structure Compound name 273 t l-(5-(3,5-bis(neopentyloxy)benzamide ))-2-methylpyridin-3-yl)-N-neopentyl-1H-1,2,3-triazole-4-carboxamide 274 ^0^Η〇&lt;Γ〇Η 3- Second-butyl-5-ranyl-N-(5-(4-(3-hydroxy-2,2-dimercaptopropylamino)phenyl)-6-methylp-precipitate- 3-yl)benzamide 275 / 3-second-butyl-5-carbyl-indole-(5-(4-((1)hydroxycyclopropyl)methylamine-methyl)phenyl) Each methylpyridin-3-yl)benzamide 276 \ V 〇5-tris-butyl-Ν'Ν1-dimethyl-indole 3-(6-methyl-5-(4-(neopentyl) Aminomethyl)phenyl)pyridin-3-yl)m-xylylenediamine 111 N-(5-(4-(2-Amino-2-methylpropylamino)phenyl)- 6-methylpyridin-3-yl)-3-tert-butyl-5-ylbenzoic acid amine 278 〇vv 1-(2-methyl-5-(3-trimethylethylguanidinylbenzene)曱醯 基 ) 匕 -3- -3- 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基-4- 2carboxamide 123505 354 - 200815422 f Compound Structure Name No. 279,280,281,283,284

5-第三-丁基-N1-(6·曱 基-5-(4-((四鼠咬喃-2-基）甲基胺甲醯基）苯 基）口比咬-3-基）-N3 _ (ρ比σ定-3-基甲基）間苯5-Terti-butyl-N1-(6. fluorenyl-5-(4-((tetramethylpyran-2-yl)methylaminemethanyl)phenyl)) is more than -3-yl) -N3 _ (ρ ratio σ--3-methyl) benzene

二甲醯胺 1-(5-(5-第三-丁基-2-甲 氧基-3-石肖基苯甲酿胺 基）-2-甲基峨唆-3-基）-N·新戊基-1H-1,2,3_ 三唑-4-羧醯胺Dimethylamine 1-(5-(5-tert-butyl-2-methoxy-3-stone succinylamino)-2-methylindol-3-yl)-N·neutyl Base-1H-1,2,3_triazole-4-carboxyguanamine

5-第三-丁基-2-甲氧基 -N-(6-甲基-5-(4-(新戊基 胺甲醯基）苯基）吡啶 -3-基）-3-石肖基本甲酿胺5-Terti-butyl-2-methoxy-N-(6-methyl-5-(4-(neopentylcarbenyl)phenyl)pyridin-3-yl)-3-shi Xiao Basic amide

(R)-1-(5-(5-第二-丁基-2-甲氧基-3-(四氮π比嘻-2-羧醯胺基）苯甲醯胺 基）-2-甲基吡啶-3-基）新戊基-1H-1，2,3-三唑-4-羧醯胺(R)-1-(5-(5-second-butyl-2-methoxy-3-(tetrazoπ-pyrene-2-carboxyguanidino)benzamide)-2-methyl Pyridin-3-yl)neopentyl-1H-1,2,3-triazole-4-carboxyguanamine

(R)-N-(5-第三-丁基-2-曱 氧基-3-(6-甲基-5-(4-(新 戊基胺甲醯基）苯基） 吡啶-3_基胺甲醯基）苯 基）四氫吡咯-2-羧醯胺(R)-N-(5-Third-butyl-2-oxooxy-3-(6-methyl-5-(4-(neopentylcarbinyl)phenyl)pyridine-3_ Hydrazinyl)phenyl)tetrahydropyrrole-2-carboxyguanamine

5-第二-丁基-N1 -(6-甲 基-5-(4-(新戊基胺甲醯 基）苯基）吡咬-3-基）· N3-(吡啶各基甲基）間 苯二甲醯胺 123505 - 355 - 200815422 編號 結構 化合物名稱 285 〇 N-(5-第三-丁基-2-甲氧 基-3-(6-甲基-5-(4-(新戍 基胺甲醯基）苯基）吡 啶-3-基胺甲醯基）苯 基）-5-酮基四氫卩比嘻-2·» 羧醯胺 286 〆 5-第三-丁基-3-(1Η-咪 唑-1-基）-2-曱氧基-N-(6-甲基-5-(4-(新戊基胺甲 酉盘基）苯基）批σ定-3-基） 苯甲醯胺 287 \ 3 ΗΝΥΎΝ、Ν 1-(5-(5-第三·丁基-3-(1Η-咪唑-1-基）-2-甲氧基苯 甲醯胺基）-2-甲基吡啶 -3-基）-N-新戍基 -1H-1，2,3-三唑-4-羧醯胺 288 3-第三-丁基-5-(6-甲基 -5-(4-((四氮咬喃-2-基） 甲基胺甲醯基）苯基） 吡啶-3-基胺甲醯基）苯 甲酸甲酯 289 Λ^° 3-第三·丁基-5-鼠基 -N-(6-甲基-5-(4-(2-(六鼠 叶匕唆-1-基）乙酿基） 苯基）吡啶-3-基）苯曱 醯胺 290 、為 1-(5-(3-第三-丁基-5-甲 氧基苯甲醯胺基）-2-甲 基外b唆-3-基）-N-新戍基 -1H-1，2,3-三唑-4-羧醯胺 291 、為 3-第三-丁基-5-曱氧基 -N-(6-甲基-5-(4-(新戊基 胺甲醯基）苯基）吡啶 -3-基）苯甲醯胺 123505 - 356 - 200815422 編號 結構 化合物名稱 292 HC^X 〇 3-弟二-丁基-5-(6-甲基 -5-(4-((四氫咬喃-2-基） 甲基胺甲醯基）苯基） 吡啶-3-基胺甲醯基） 苯甲酸 293 \ 〇 5-第三丁基-N^N1-二 甲基-N3-(6-甲基-5-(4-((四氮咬喃-2-基）甲基 胺甲醯基）苯基）吡啶 -3-基）間苯二曱醯胺 294 〇 5-第三-丁基-N1-甲氧 基-N1-甲基-N3-(6-甲基-5-(4-((四氮咬喃-2-基）甲基胺甲醯基）苯 基比σ定-3-基）間苯二 甲醯胺 295 寸 5 3-第二-丁基-Ν-(6-甲基 -5-(4-(新戊基胺甲醯 基）苯基）说咬-3-基）-5·(2-嗎福啉基乙氧 基）苯甲醯胺 296 叶 5-第三-丁基-2-甲氧基 -3-(4-曱基-1Η-咪唑-1-基)-N-(6-甲基-5-(4-(新 戊基胺甲醯基）苯基） 吡啶-3-基）苯曱醯胺 297 尸/〇ηνΤ又Ν、ν 1_(5_(5·第三-丁基-2-甲 氧基-3-(4-甲基-1H-咪 唑-1-基）苯甲醯胺 基）-2-甲基外1：唆-3-基）-N-新戊基-1H-1，2,3-三唑-4-羧醯胺 123505 - 357 - 200815422 ί 編號 結構 化合物名稱 298 299 300 301 302 303 3045-second-butyl-N1 -(6-methyl-5-(4-(neopentylcarbinyl)phenyl)pyridin-3-yl)·N3-(pyridylmethyl) Meta-xyl phthalamide 123505 - 355 - 200815422 No. Structure compound name 285 〇N-(5-T-butyl-2-methoxy-3-(6-methyl-5-(4-(新戍)胺 - ) ) ) ) -3- -3- 基 · · · · · · · · · · · · · · · - - - - - - - - - - - -(1Η-imidazol-1-yl)-2-decyloxy-N-(6-methyl-5-(4-(neopentylaminocarboxanyl)phenyl)batch sigma-3-yl Benzoamide 287 \ 3 ΗΝΥΎΝ, Ν 1-(5-(5-Third-butyl-3-(1Η-imidazol-1-yl)-2-methoxybenzimidamide)-2 -methylpyridin-3-yl)-N-nonindolyl-1H-1,2,3-triazole-4-carboxamide 288 3-Terti-butyl-5-(6-methyl-5 -(4-((tetrazole-2-yl)methylaminemethanyl)phenyl)pyridin-3-ylaminecarbazyl)benzoic acid methyl ester 289 Λ^° 3-third·butyl -5-murine-N-(6-methyl-5-(4-(2-(hexamethylpyridin-1-yl)ethenyl)phenyl)pyridin-3-yl)benzamide 290 is 1-(5-(3-tert-butyl-5-methoxy) Benzylamino)-2-methyl-exo-b唆-3-yl)-N-neinyl-1H-1,2,3-triazole-4-carboxyguanamine 291, 3-3- Butyl-5-decyloxy-N-(6-methyl-5-(4-(neopentylcarbenyl)phenyl)pyridin-3-yl)benzamide 99505 - 356 - 200815422 Structural Compound Name 292 HC^X 〇3-Di-di-butyl-5-(6-methyl-5-(4-((tetrahydromethane-2-yl)methylaminemethanyl)phenyl) Pyridin-3-ylaminocarbamoyl)benzoic acid 293 \ 〇5-tert-butyl-N^N1-dimethyl-N3-(6-methyl-5-(4-((tetrazo) 2-yl)methylamine-mercapto)phenyl)pyridin-3-yl)isophthalamide 294 〇5-tris-butyl-N1-methoxy-N1-methyl-N3-( 6-Methyl-5-(4-((tetrazole-2-yl)methylaminemethanyl)phenylpyrimidine-3-yl)m-xylyleneamine 295 inch 5 3- Di-butyl-indole-(6-methyl-5-(4-(neopentylcarbinyl)phenyl)-n--3-yl)-5-(2-morpholinoethoxy) Benzoguanamine 296 leaves 5-tris-butyl-2-methoxy-3-(4-mercapto-1Η-imidazol-1-yl)-N-(6-methyl-5-(4) -(neopentylaminomethane)phenyl)pyridin-3-yl)phenylhydrazine 297 尸/〇ηνΤ又Ν, ν 1_(5_(5·Third-butyl-2-methoxy-3-(4-methyl-1H-imidazol-1-yl)benzamide)- 2-Methyl Exo: indole-3-yl)-N-neopentyl-1H-1,2,3-triazole-4-carboxyguanamine 123505 - 357 - 200815422 ί No. Structure Compound Name 298 299 300 301 302 303 304

HO 5-第三-丁基-N1-((1-羥 基環丙基）甲基）-N3-(6-甲基-5-(4-((四氮咬喃-2-基）甲基胺甲醯基）苯 基）说啶-3-基）間苯二 甲醯胺HO 5-Terti-butyl-N1-((1-hydroxycyclopropyl)methyl)-N3-(6-methyl-5-(4-((tetrazolan-2-yl)methyl) Amidinomethyl)phenyl)rsyn-3-yl)m-xylylenediamine

5-第二-丁基-3-氣基 _N-(5-(4-(環戊基胺甲醯 基）苯基）-6·甲基p比σ定-3-基）-2-曱氧基苯甲醯胺5-second-butyl-3-yl-yl-N-(5-(4-(cyclopentylaminomethyl)phenyl)-6-methyl p-pyridyl-3-yl)-2- Decyloxybenzamide

5-第三-丁基-3-氰基 -N-(5-(4-(4,4-二氟環己 基胺甲酿基）苯基）-6-甲基外匕σ定-3·基）-2-甲乳 基苯甲醯胺 5-第二-丁基-3-乱基 -N-(5-(4-(異丙基胺甲醯 基）苯基）-6-甲基p比σ定-3-基）-2_甲氧基苯曱醯胺 5_第三-丁基-3-氰基 -Ν-(5-(4-(異丁基胺甲醯 基）苯基）-6-甲基吡啶-3-基）-2-甲氧基苯曱醯胺 5-第二-丁基-3-乳基 -N-(5-(4-(環丙基胺甲醯 基）苯基）-6-甲基吡啶-3-基）-2-甲氧基苯甲醯胺 5-第三-丁基-3-氣基-2-甲氧基-N-(6-曱基 _5-(4-(2-(六鼠说咬-1-基） 乙醯基）苯基）吡啶-3_ 基）苯甲醯胺 123505 - 358 - 200815422 /5-Terti-butyl-3-cyano-N-(5-(4-(4,4-difluorocyclohexylamine)-phenyl)-6-methyl-indole sigma-3 Benzyl-2-methyllactobenzamide 5-second-butyl-3-ranyl-N-(5-(4-(isopropylaminomethyl)phenyl)-6-methyl p ratio σ-3-yl)-2-methoxybenzoin 5_t-butyl-3-cyano-indole-(5-(4-(isobutylamine)methyl)benzene 5-(methylpyridin-3-yl)-2-methoxybenzoguanamine 5-second-butyl-3-lacyl-N-(5-(4-(cyclopropylamine) Mercapto)phenyl)-6-methylpyridin-3-yl)-2-methoxybenzimidamide 5-tris-butyl-3-yl-2-methoxy-N-(6 - mercapto _5-(4-(2-(six rats) bit -1-yl) ethenyl)phenyl)pyridin-3-yl)benzamide 123123505 - 358 - 200815422 /

編號 結構 化合物名稱 305 Η 〇VNH ^ 〇N 〜 VJ 0 ΗΝγ^Ν^Ν 5-弟二-丁基-Ni -(6-甲 基-5-(4-(新戊基胺甲醯 基）-1Η·1，2,3-三唑-1-基） 口比唆-3-基）-Ν3 -(2-(四氮 吡咯-1-基）乙基）間苯 二甲醯胺 306 0 ηντ^ν、ν〜 5-第三-丁基-N1-(6-甲 基-5-(4-(新戍基胺甲酸 基）-1Η-1，2,3-三唑小基） 吡啶-3·基）-N3-((l-甲基 六氫吡啶_2_基）甲基） 間苯二甲醯胺 307 /° 〆 0 f&quot;T〇H 5-第三-丁基-3-氣基 -N-(5-(4-((lr，4r)-4-羥基環 己基胺甲醯基）-苯 基）-6-甲基p比咬-3-基）-2- 甲氧基苯甲醯胺 308 \ / ίχ^ N_(5-(4-((lR，2R，4S)-雙環 并[2.2.1]庚-2-基胺曱醯 基）苯基）-6-甲基吡啶 -3-基）-5-弟二-丁基-3-氣 基-2-甲氧基苯甲醯胺 309 5-第二-丁基-3-鼠基 -N-(5-(4-(3-羥丙基胺甲 醯基）苯基）-6-甲基吡 啶-3-基&gt;2-甲氧基苯甲 醯胺 310 / 〜。H 5-第三-丁基-3·氣基 -N-(5-(4-(2-羥乙基胺甲 醯基）苯基）-6-甲基吡 啶-3-基）-2-甲氧基苯甲 醯胺 123505 -359 - 200815422 編號 結構 化合物名稱 311 、 、/ 叶 5-弟二-丁基-Ni -(6-甲 基-5-(4-(新戊基胺甲醯 基）苯基）p比σ定-3-基）-N3-(2-(四氫吡咯-1-基） 乙基）間苯二甲醯胺 312 1 0 / 叶 5-第三-丁基-N1-(6-甲 基-5-(4-(新戊基胺甲醯 基）苯基）?比唆-3-基）-Ν3-((1-甲基六氫吡啶 -2·基）甲基）間苯二甲 醯胺 313 1-(5-(3-第三-丁基 -5-(N，N-二甲基胺磺醯 基）苯甲醯胺基）·2-曱 基比11 定-3-基）-Ν-新戊基 -1Η-1，2,3-三唑-4-羧醯胺 314 、A^°^ 3-第二-丁基-5-(Ν，Ν-二 曱基胺磺醯基）-Ν-(6-甲 基-5-(4-(新戊基胺甲醯 基）苯基）吡啶-3-基）苯 甲醯胺 315 寸 3-第三-丁基-5-(5-甲基 -1，2,4-哼二唑-3-基）-N-(6-曱基-5-(4-(新戊基 胺甲醯基）苯基 &gt;比啶 -3-基）苯甲醯胺 316 y^H V众乂 ΗΝΤΧ'&quot; 1-(5-(3-第三-丁基-5-(5-甲基-1，2,4-喝二唑-3-基） 苯曱醯胺基）-2-甲基吡 啶-3-基）-N-新戊基 -1Η-1，2,3-三唑-4-羧醯胺 123505 -360- 200815422 編號 結構 化合物名稱 317 Vt^、 3-弟二-丁基-5-乳基 -N-(5-(4-(2-(二甲胺 基）-2-甲基丙基胺甲醯 基）苯基）-6-甲基吡啶 -3-基）苯甲醯胺 318 5-第三-丁基-N1-(3-羥 基-2,2-二甲基丙基）-N3-(6-甲基-5-(4-(新戊基 胺甲醯基）苯基Η啶 -3-基）間苯二甲醯胺 319 5-第二-丁基-3-乳基 -Ν-(5-(4-(2,2-二甲基環 己基胺曱醯基）苯基）-6-甲基峨。定-3-基）-2-甲 氧基苯甲醯胺 320 ^01¾ N-(5-(4-((lR,2S，4R)·雙環 并[2.2.1]庚-2-基胺甲醯 基）苯基）-6-甲基吡啶 -3-基）-5•第二-丁基-3-氣 基-2-甲氧基苯甲醯胺 321 1-(5-(3-第三-丁基-5-(N-甲基胺磺醯基）苯甲醯 胺基）-2-甲基吡啶-3_ 基）-N-新戊基-1H_1，2,3-三唑-4_羧醯胺 322 3-第二-丁基-N-(6-甲基 -5-(4-(新戊基胺甲醯 基）苯基）说σ定-3-基）-5-(Ν-甲基胺磺醯 基）苯曱醯胺 323 、 5-第三-丁基-3-(異'^号唾 _4_基）-2-甲氧基-N-(6-甲 基-5-(4-(新戊基胺甲醯 基）苯基）吡啶-3-基）苯 甲醯胺 123505 •361 - 200815422No. Structure Compound name 305 Η NHVNH ^ 〇N 〜 VJ 0 ΗΝγ^Ν^Ν 5-di-butyl-Ni-(6-methyl-5-(4-(neopentylcarbamyl)- 1Η·1,2,3-triazol-1-yl) 唆-唆-3-yl)-Ν3 -(2-(tetrazirpyrrolidin-1-yl)ethyl)m-xylylenediamine 306 0 ηντ ^ν, ν~ 5-Terve-butyl-N1-(6-methyl-5-(4-(sinodecylcarbamic acid)-1Η-1,2,3-triazole small) pyridine- 3·yl)-N3-((l-methylhexahydropyridin-2-yl)methyl) m-xylyleneamine 307 /° 〆0 f&quot;T〇H 5-tri-butyl-3- Gas-N-(5-(4-((lr,4r)-4-hydroxycyclohexylaminecarboxamyl)-phenyl)-6-methyl p-bit-3-yl)-2-methoxy Benzobenzamide 308 \ / ίχ^ N_(5-(4-((lR,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)phenyl)-6-A Pyridin-3-yl)-5-di-dibutyl-3-yl-2-methoxybenzamide 309 5-second-butyl-3-murine-N-(5-( 4-(3-Hydroxypropylaminecarbamimidyl)phenyl)-6-methylpyridin-3-yl&gt; 2-methoxybenzamide 310 / 〜H 5-tri-butyl- 3. Gas-N-(5-(4-(2-hydroxyethylamine)methyl)phenyl)-6-methyl Pyridin-3-yl)-2-methoxybenzimidamide 123505 -359 - 200815422 No. Structure Compound name 311 , , / Leaf 5 - di-butyl-Ni -(6-methyl-5-(4 -(neopentylaminomethane)phenyl)p than sigma-3-yl)-N3-(2-(tetrahydropyrrol-1-yl)ethyl)m-xylamine 312 1 0 / Leaf 5-tris-butyl-N1-(6-methyl-5-(4-(neopentylcarbinyl)phenyl)? 唆-3-yl)-Ν3-((1-A) Hexahydropyridin-2-yl)methyl)m-xylylenediamine 313 1-(5-(3-tri-butyl-5-(N,N-dimethylaminesulfonyl)benzamide Amidino)·2-indenyl ratio 11-3-yl)-indole-neopentyl-1Η-1,2,3-triazole-4-carboxyguanamine 314, A^°^ 3- second -butyl-5-(anthracene, fluorene-didecylamine sulfonyl)-fluorene-(6-methyl-5-(4-(neopentylaminomethyl)phenyl)pyridin-3-yl Benzalamide 315 inch 3-tris-butyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)-N-(6-mercapto-5-(4) -(neopentylaminomethane)phenyl&gt;pyridin-3-yl)benzamide 316 y^HV乂ΗΝΤΧ'&quot; 1-(5-(3-Terti-butyl-5 -(5-methyl-1,2,4-dioxazol-3-yl)phenylhydrazinyl)-2- Pyridin-3-yl)-N-neopentyl-1Η-1,2,3-triazole-4-carboxyguanamine 123505 -360- 200815422 No. Structure Compound Name 317 Vt^, 3-Di-Butyl-Butyl -5-lactyl-N-(5-(4-(2-(dimethylamino)-2-methylpropylaminemethanyl)phenyl)-6-methylpyridin-3-yl)benzene Methionamine 318 5-Terti-butyl-N1-(3-hydroxy-2,2-dimethylpropyl)-N3-(6-methyl-5-(4-(neopentylamine) Phenyl acridine-3-yl) m-xylylenediamine 319 5-second-butyl-3-lacyl-indole-(5-(4-(2,2-dimethylcyclohexylamine) Mercapto)phenyl)-6-methylindole. D--3-yl)-2-methoxybenzamide 320 ^ 013⁄4 N-(5-(4-((lR,2S,4R)·bicyclo[2.2.1]hept-2-ylamine A Mercapto)phenyl)-6-methylpyridin-3-yl)-5•second-butyl-3-yl-2-methylbenzamide 321 1-(5-(3- Tri-butyl-5-(N-methylaminesulfonyl)benzamide)-2-methylpyridin-3-yl)-N-neopentyl-1H_1,2,3-triazole-4 Carboxyxylamine 322 3-second-butyl-N-(6-methyl-5-(4-(neopentylcarbinyl)phenyl) sigma-3-yl)-5-( Ν-Methylamine sulfonyl) benzoguanamine 323, 5-tris-butyl-3-(iso-^-salt-4-yl)-2-methoxy-N-(6-methyl -5-(4-(neopentylaminomethane)phenyl)pyridin-3-yl)benzamide 99505 •361 - 200815422

編號 結構 324 325 326 327 328 329 330No. Structure 324 325 326 327 328 329 330

化合物名稱 5-第三-丁基-3-(2,3-二 氫異噚唑-4-基）-2-甲氧 基-N-(6-甲基-5-(4-(新戍 基胺甲醯基）苯基）吡 啶-3-基）苯曱醯胺The compound name 5-tri-butyl-3-(2,3-dihydroisoxazol-4-yl)-2-methoxy-N-(6-methyl-5-(4-(new 戍) Amidoxime)phenyl)pyridin-3-yl)benzamide

3-弟二-丁基-5-(5-J哀丙 基-1，2,4-嘮二唑-3-基）_N-(6-甲基-5-(4-(新 戊基胺甲醯基）苯基） 吡啶-3-基）苯甲醯胺3-di-dibutyl-5-(5-J propylpropyl-1,2,4-oxadiazol-3-yl)-N-(6-methyl-5-(4-(neopentylamine) Mercapto)phenyl)pyridin-3-yl)benzamide

3-第二-丁基-5-(5-(甲氧 基甲基）-1，2,4-噚二唑-3-基）-N-(6-甲基-5-(4-(新 戊基胺甲醯基）苯基） 吡啶-3-基）苯甲醯胺 3-第二-丁基-N_(5-(4-(3_ 羥基-2,2-二甲基丙基 胺甲醯基）苯基）-6-甲 基π比σ定-3-基）-5-(N-曱基 胺磺醯基）苯甲醯胺3-second-butyl-5-(5-(methoxymethyl)-1,2,4-oxadiazol-3-yl)-N-(6-methyl-5-(4-( Neopentylamine, decyl)phenyl)pyridin-3-yl)benzamide-3,2-butyl-N-(5-(4-(3-hydroxy-2,2-dimethylpropylamine) Methyl fluorenyl)phenyl)-6-methyl π-pyridyl-3-yl)-5-(N-nonylaminosulfonyl)benzamide

3-第三·丁基 _N-(5-(4-(4,4-二氟環己 基胺甲醯基）苯基）-6-甲基吡啶-3-基）-5-(N-甲 基胺磺醯基）苯曱醯胺3-Third-butyl-N-(5-(4-(4,4-difluorocyclohexylamine)methyl)phenyl)-6-methylpyridin-3-yl)-5-(N- Methylamine sulfonyl)benzamide

3-第二-丁基-5-(5-弟二-丁基-1，2,4-呤二唑-3-基）-N-(6-甲基-5-(4-(新 戊基胺甲醯基）苯基） 吡啶-3-基）苯甲醯胺3-second-butyl-5-(5-di-di-butyl-1,2,4-oxadiazol-3-yl)-N-(6-methyl-5-(4-(neutyl) Hydrazinyl)phenyl)pyridin-3-yl)benzamide

5-第三-丁基-2-甲氧基 -Ν·(6-甲基-5-(4-(新戊基 胺甲醯基）苯基 &gt;比啶 -3-基）-3-(1Η-吡唑-1-基） 苯甲醯胺 123505 -362 - 2008154225-tert-butyl-2-methoxy-oxime (6-methyl-5-(4-(neopentylcarbenyl)phenyl]pyridin-3-yl)-3- (1Η-pyrazol-1-yl) benzoguanamine 123505 -362 - 200815422

編號 結構 化合物名稱 331 332 333 334 335 336No. Structure Compound name 331 332 333 334 335 336

5-第三-丁基-3-氰基 -N-(5-(4-(2,2-二甲基 -3-(四鼠卩比嗜&gt; -l-基^)丙 基胺甲酿基）苯基）-6_ 甲基吡啶-3-基）-2-甲氧 基苯甲醯胺5-Terti-butyl-3-cyano-N-(5-(4-(2,2-dimethyl-3-(tetrazolium))-l-yl^propylamine Styrene)phenyl)-6-methylpyridin-3-yl)-2-methoxybenzamide

5-第二-丁基-3-亂基 -N-(5-(4_(2,2-二甲基 _3-(4-甲基六氮p比呼-1-基）丙基胺甲醯基）苯 基）-6-甲基^比ϋ定-3 _基）-2-甲氧基苯甲醯胺5-second-butyl-3-ranyl-N-(5-(4-(2,2-dimethyl-3-(4-methylhexanitro-p-heptan-1-yl)propylamine) Mercapto)phenyl)-6-methyl^bendidine-3 _yl)-2-methoxybenzamide

5-第二-丁基-3-氣基 -N-(5-(4-(2,2-二甲基-3-嗎福啉基丙基胺甲醯 基）苯基）-6-甲基吡啶-3-基）-2-甲氧基苯甲醯胺 N-(5-(4_(3-胺基-2,2-二甲 基丙基胺甲醯基）苯 基）-6-甲基吡啶-3-基）-5-第三-丁基-3-氰基-2-曱 氧基苯甲醯胺 5-第二-丁基-3-鼠基 -N-(5-(4-(3-(二甲胺 基&gt;2,2-二甲基丙基胺 甲醯基）苯基）-6-甲基 外匕ϋ定-3-基）-2-甲氧基苯 甲醯胺 5-第三_丁基-3-(4-⑽甲 基）-1Η·1，2,3-三唑-1-基）-2-甲氧基-Ν-(6»•甲基 -5-(4-(新戊基胺甲醯 基）苯基）吡啶-3-基）苯 甲醯胺 123505 •363 - 2008154225-second-butyl-3-yl-N-(5-(4-(2,2-dimethyl-3-oxafolinylpropylamine)methyl)phenyl)-6-A Pyridin-3-yl)-2-methoxybenzimidamide N-(5-(4-(3-amino-2,2-dimethylpropylamine)methyl)phenyl)-6- Methylpyridin-3-yl)-5-tris-butyl-3-cyano-2-nonyloxybenzamide 5-second-butyl-3-murine-N-(5-( 4-(3-(Dimethylamino)&gt;2,2-dimethylpropylaminemethanyl)phenyl)-6-methyl-exoquinol-3-yl)-2-methoxybenzene Methionamine 5-tris-butyl-3-(4-(10)methyl)-1Η·1,2,3-triazol-1-yl)-2-methoxy-oxime-(6»•甲5-(4-(neopentylcarbinyl)phenyl)pyridin-3-yl)benzamide 505123505 •363 - 200815422

編號 結構 337 338 339No. Structure 337 338 339

ΟΟ

化合物名稱 5-弟二-丁基-2-甲氧基 -N-(6-甲基-5-(4-(新戊基 胺甲醯基）苯基）毗啶 -3-基）-3-(4-(四氫p比洛-1-基甲基）-1Η-1，2,3-三唑 -1-基）苯甲醯胺 5-第二-丁基-2-甲氧基 -N-(6-甲基-5-(4-(新戊基 胺甲醯基）苯基Η啶 -3-基）-3-(4-(六氮吨σ定-1-基甲基）-1Η-1，2,3-三唑 -1-基）苯甲醯胺 5-第三-丁基-2-曱氧基 -Ν-(6-甲基-5-(4-(新戍基 胺甲醯基）苯基）说啶 -3-基）-3-(4-((4-甲基六鼠 外匕畊-1-基）甲基)-1H-1，2,3-三峻-1-基）苯甲 醯胺The compound name 5-di-dibutyl-2-methoxy-N-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl)pyridin-3-yl)-3 -(4-(tetrahydrop-pyrrol-1-ylmethyl)-1Η-1,2,3-triazol-1-yl)benzamide-5-t-butyl-2-methoxy -N-(6-methyl-5-(4-(neopentylcarbamoyl)phenyl acridine-3-yl)-3-(4-(hexanitrox sigma-1-ylmethyl) )-1Η-1,2,3-triazol-1-yl)benzamide-5-t-butyl-2-oxo-oxime-(6-methyl-5-(4-(new Hydrazinylmethyl hydrazino)phenyl)rsyn-3-yl)-3-(4-((4-methylhexahydroquinone-1-yl)methyl)-1H-1,2,3 -Sanjun-1-yl)benzamide

5-第三-丁基-2-甲氧基 -N-(6-甲基-5-(4-(新戍基 胺甲醯基）苯基 &gt;比啶 -3-基）-3-(4-(嗎福啉基甲 基)-1Η-1，2,3-三唑-1-基） 苯甲醯胺 5-第二-丁基-3-(4-((二乙 胺基）甲基）_1H-1，2,3-三 唑-1-基）-2-甲氧基-N-(6-甲基-5-(4-(新戊基胺甲 醯基）苯基）吡啶-3-基） 苯甲醯胺 123505 -364- 200815422 \5-Terti-butyl-2-methoxy-N-(6-methyl-5-(4-(indanylaminomethyl)phenyl]&gt;pyridin-3-yl)-3- (4-(morpholinemethyl)-1Η-1,2,3-triazol-1-yl)benzamide-5-second-butyl-3-(4-((diethylamino) )methyl)_1H-1,2,3-triazol-1-yl)-2-methoxy-N-(6-methyl-5-(4-(neopentylcarbinyl)phenyl) Pyridin-3-yl) benzamide 123505 -364- 200815422 \

正如热請此藝者所明瞭，對於任何與所有目的而言，特 別疋以提供經書寫說明文觀之，於本文中所揭示之所有範 圍亦涵蓋任何與所有可能之亞範圍及其亞範圍之組合。任 何列示之範圍可容易地被認為是充分地描述，且使得相同 範圍能夠被分解成至少相等二等分、三等分、四等分、五 等分、十等分等。作為非限制性實例，本文中所討論之各 範圍可容易地被分解成較低三分之一、中間三分之一及較 化合物名稱 第三-丁基-3-(4-((二甲 胺基）曱基）-1Η_1，2,3-三 唑·1-基）-2·甲氧基-N-(6-甲基-5-(4-(新戊基胺曱 醯基）苯基）吡啶-3-基） 苯曱醯胺 5-第三-丁基-3-(4-((異丙 基胺基）甲基&gt;1Η-1，2,3· 唑-1-基&gt;2-甲氧基 -Ν-(6-甲基-5-(4-(新戊基 胺甲醯基）苯基）吡啶 -3-基）苯曱醯胺 5-第三-丁基-3-(4-((環丙 胺基）甲基&gt;1Η-1，2,3-三 唑_1_基&gt;2-甲氧基-N-(6_ 甲基-5-(4-(新戊基胺曱 醯基）苯基）吡啶-3-基） 笨曱醮胺 5-第三-丁基-3_氰基 -N-(5-(4-(l-(二曱胺 基）-2-曱基丙-2-基胺曱 醢基）笨基）-6_甲基外匕 啶-3-基）-2-曱氧基苯甲 醯胺 123505 -365 - 200815422 尚二分之—#。正如熟諳此藝 至高，，、，·至少，，、&quot;大於”,瞭所有語文，譬如&quot; 目，且孫扣、專’係包括所敘述之數 目且係“可接著被分解成如上文 田祕T » J 4卿亞乾圍之範圍。 取後，正如熟諳此藝者所明瞭，_ s乾圍係包括各個別成員。 =例如，具有Μ個原子之基團係指具有U或3個原子 :基團。同樣地，具有“個原子之基圏係指具有U 3, 4 或5個原子之基團，等等。 f κ 雖然某些具體實施例已被說明與描述，但應明瞭的是， 在未偏離如下述請求項中所定義之本發明下 方面内，可根據此項技藝之一般拮扩 八 为技衡’於其中施行改變與 修正。 在本專利說明書中所引述之所有公報、專利中靖案、已 頒予之專利及其他文件’均併於本文供參考，猶如各個別 公報、專利申請案、已頒予之專利或其他文件係被明確且 個別地顯示以其全文併於本文供參考_般。被包含在併入 供參考之原文中之定義係被排除在外，至其與本揭示内容 中之定義矛盾之程度。 123505 366-As the enthusiasm is known to the artist, for all and all purposes, in particular to provide written descriptions, all ranges disclosed herein also cover any and all possible sub-ranges and sub-ranges thereof. combination. Any of the listed ranges can be readily considered to be sufficiently described, and the same range can be decomposed into at least equal halving, three equal, four equal, five equal, ten equal, and the like. As a non-limiting example, the ranges discussed herein can be readily broken down into lower one-third, middle third, and the compound name third-butyl-3-(4-((dimethyl) Amino)mercapto)-1Η_1,2,3-triazole·1-yl)-2.methoxy-N-(6-methyl-5-(4-(neopentyl)indolyl)benzene Pyridin-3-yl) benzoguanamine 5-tri-butyl-3-(4-((isopropylamino)methyl&gt;1Η-1,2,3·oxazol-1-yl &gt;2-methoxy-indole-(6-methyl-5-(4-(neopentylcarbinyl)phenyl)pyridin-3-yl)phenylamine 5-tert-butyl -3-(4-((cyclopropylamino)methyl)&gt;1Η-1,2,3-triazol-1-yl>2-methoxy-N-(6-methyl-5-(4- (neopentylamine fluorenyl)phenyl)pyridin-3-yl) abbreviated amine 5-tris-butyl-3-cyano-N-(5-(4-(l-(diamine) ))-2-mercaptopropan-2-ylamine fluorenyl) phenyl)-6-methyl acridin-3-yl)-2-decyloxybenzamide 123505 -365 - 200815422 -#. As familiar with this art, the highest,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, The number and "can be subsequently broken down into the range of the above-mentioned Takuya T » J 4 Qing Yawei. After taking it, as is familiar to the artist, the _ s trunk system includes individual members. = For example, there are A group of atoms means having U or 3 atoms: a group. Similarly, a group having "one atom" means a group having U 3, 4 or 5 atoms, etc. f κ although some specific The embodiment has been illustrated and described, but it should be understood that within the scope of the invention as defined in the following claims, the invention can be modified according to the general skill of the art. Amendments. All publications, patents, patents and other documents cited in this patent specification are hereby incorporated by reference in their entirety as if each of the publications, patent applications, issued patents or otherwise The documents are expressly and individually shown in their entirety and are hereby incorporated by reference in their entirety in their entirety in their entireties in the the the the the the the 366-

Claims (1)

200815422 十、申請專利範圍： 1· 一種化合物，其包含： 瞄乾部份基團，™，包含酸胺NH與羧基，此瞒無部份 基團能夠與一種標的蛋白質形成一或多個氫鍵； 袋形擴大部份基團，PEM，經直接連接至瞄靶部份基團 之幾基或NH，此袋形擴大部份基團包含經連接至龐大非 平面狀疏水性部份基團之平面狀部份基團，其中非平面狀 部份基團係能夠與標的蛋白質形成疏水性交互作用； 指向部份基團，OM，包含孓員雜芳基環，且連接至瞄 乾部份基團之NH或幾基，#中指向部份基團係能夠與^ 的蛋白質形成疏水性交互作用； 連結基部份基團’ L，經連接至指向部份基團中愈瞒無 部份基團不同之原子，#中連結基部份基團係包含^員芳 基或雜芳基部份基團；及 …η〜、、、口签邓物、基團L·連接至指 向部份基團，其中錯定部份基團係能夠與該標的蛋白質之 ΑΤΡ-結合袋形成至少1個氫鍵交互作用； 、 其中該化合物為細胞素抑制劑。 ^如請求们之細胞素抑制劑，其中料部份基團為醯胺基。 •，求们之細胞素抑制劑，其中袋形擴大部份基團包含 6貝芳基或雜芳基部份基團，被經取代 η义未經取代之C2 4 &amp;暴環烷基或雜環基取代。 4. ^請求項！之細胞素抑制劑，其中指向部份基團包含 基、_基縣化物或Μ基，㈣素、ψ基或三敗甲基 123505 200815422 取代。 5·如請求項1之細胞素抑制劑，其中錨定部份基團包含醯 胺、胺、羰基、烷氧基、胺基甲酸酯、亞砜、磺醯胺或OC(O) 基團。 6· —種式I化合物 Q 、人 式i 其立體異構物、其互變異構物、其溶劑合物、其前體 藥物及其藥學上可接受之鹽； 其中 X 為 CH、N 或 NO ; Y為CH、N、NO，其條件是，X與Y並非皆為CH或NO ; A為F、Cl、Br、I、见^或心」烷基或·0((ν3烷基），其 中烷基係視情況經部份或完全鹵化； G為芳基或雜芳基，其中G係被一或多個R1，R2或R3取 代； Ar為6-員芳基或雜芳基； L1 為-C(0)NH-; L2 為共價鍵、（CR’2)S、（CR’2)nO(CRf2)t、（CR，2)nNR(CR，2)t、 (CRf2 )n C(NOR) &gt; (CRf2 )n S02 NR(CRf2 )t ^ (CRf2 )n C(0)(CR：2 )t ^ OCCR^ )tC(0)(CRf2)n ^ OCCR^^NRCCR^^ &gt; 0(CRf2 )n C(0)NR(CR'2 )t ^ 0(CRf2)sNRC(0)(CRf2)n &gt; (CR^^C^NRCCR^X ' (CRf2 )n C(0)NRNR- 123505 200815422 (CRf2 )t 或(CR，2 )n NRC⑼0(CR，2 )t ; Q為經取代或未經取代之烷基、環烷基、芳基、雜環基、 壤燒基烧基、芳烷基或雜環基烷基； 各R1係獨立為F、Cl、Br、I、_NR2、_CN，或經取代或 未經取代之烷基、烯基 '炔基、環烷基、環烯基、芳基、 雜環基或雜環基烧基； 各R2係獨立為F ' Cl、Br、I、-CN .、·Ν02、經取代或未 絰取代之烷基或雜環基烷基、_〇R，、-c(〇)R，、_c(〇)〇R，、 C(0)NR2 - -C(NR)NR2 &gt; -C(NR)NROR &gt; -NRf2 ^ -(CR^XNRR1 &gt; NRC(0)R &gt; -NR?C(0)〇R·» . -NRfS02Rff &gt; -NR,C(0)NRf2 - -nr，c(s)nr，2、_s(0)mR，u〇2NR,2 ; 各R係獨立為經取代或未經取代之烷基、烯基或炔基， 或烧基）’其中q _4烧基係視情況經部份或完全齒 化； 各R係獨立為氫’或經取代或未經取代之^ 6烷基； 各R係獨立為氫’或經取代或未經取代之烷基、環烷 基、環烧基職、芳烧基、雜環基或雜環基烧基； 各R，，f獨立為經取代或未經取代之烧基、環烧基、芳 土雜玉衣基' %烧基烧基、芳燒基或雜環基烧基； 各πι係獨立為〇，1或2 ; 11為 〇, 1，或 2 ; s為1，2或3 ;且 各t係獨立為〇, 1或2; 其條件是該化合物不為5_(聯苯_4_基&gt;6_氣·甲氧基峨 123505 200815422 唆-3-基）於鹼醯胺。 7. 如請求項6之化合物，其中Ar為苯基、吡啶基、嘧啶基或 塔p井基。 8. 如請求項7之化合物，其中Ar為苯基、2-吡啶基、3-吡啶基 或4-ρ比唆基。 9. 如請求項6之化合物，其中化合物為200815422 X. Patent application scope: 1. A compound comprising: a target group, TM, comprising an acid amine NH and a carboxyl group, wherein no part of the group can form one or more hydrogen bonds with a target protein. a pocket-shaped enlarged moiety, PEM, directly attached to a group or NH of the target moiety, the pocket-shaped enlarged moiety comprising a moiety attached to the bulky non-planar hydrophobic moiety a planar moiety, wherein the non-planar moiety is capable of interacting hydrophobically with the target protein; pointing to a moiety, OM, comprising a chelating heteroaryl ring, and attached to the target moiety NH or a few groups of the group, the partial group in # can form a hydrophobic interaction with the protein of ^; the linking group 'L, which is linked to the part of the group, has no part a group of different atoms, the linker group in # contains a member of the aryl or heteroaryl moiety; and ... η~,,, the mouth of the Deng, the group L · connected to the partial base a group in which a misidentified part of the group is capable of binding to the target protein The pocket forms at least one hydrogen bond interaction; wherein the compound is a cytokine inhibitor. ^ As the cytokine inhibitor of the request, wherein the moiety of the material is an amidino group. • a cytokine inhibitor, wherein the pocket-shaped enlarged moiety comprises a 6-shell aryl or heteroaryl moiety, substituted by a η-unsubstituted C2 4 & cycloalkyl or Heterocyclic group substitution. 4. ^Requests! A cytokine inhibitor in which a moiety is a group containing a group, a cycline or a thiol group, a (tetra), a thiol or a tri-substituted methyl 123505 200815422. 5. The cytokine inhibitor of claim 1, wherein the anchor moiety comprises a guanamine, an amine, a carbonyl, an alkoxy group, a urethane, a sulfoxide, a sulfonamide or an OC(O) group . a compound of the formula I, a stereoisomer thereof, a tautomer thereof, a solvate thereof, a prodrug thereof, and a pharmaceutically acceptable salt thereof; wherein X is CH, N or NO Y is CH, N, NO, provided that X and Y are not both CH or NO; A is F, Cl, Br, I, see ^ or heart "alkyl or · 0 ((ν3 alkyl), Wherein the alkyl group is partially or completely halogenated as appropriate; G is an aryl or heteroaryl group wherein the G system is substituted by one or more R1, R2 or R3; Ar is a 6-membered aryl or heteroaryl group; Is -C(0)NH-; L2 is a covalent bond, (CR'2)S, (CR'2)nO(CRf2)t, (CR,2)nNR(CR,2)t, (CRf2)n C(NOR) &gt; (CRf2 )n S02 NR(CRf2 )t ^ (CRf2 )n C(0)(CR:2 )t ^ OCCR^ )tC(0)(CRf2)n ^ OCCR^^NRCCR^^ &gt; 0(CRf2 )n C(0)NR(CR'2 )t ^ 0(CRf2)sNRC(0)(CRf2)n &gt; (CR^^C^NRCCR^X ' (CRf2 )n C(0 )NRNR- 123505 200815422 (CRf2 )t or (CR,2 )n NRC(9)0(CR,2 )t ; Q is a substituted or unsubstituted alkyl group, a cycloalkyl group, an aryl group, a heterocyclic group, a ground alkyl group Alkyl, aralkyl or heterocyclylalkyl; each R1 is independently F, Cl, Br, I, _NR2 -CN, or substituted or unsubstituted alkyl, alkenyl 'alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heterocyclyl; each R2 is independently F ' Cl, Br , I, -CN ., ·Ν02, substituted or unsubstituted alkyl or heterocyclylalkyl, _〇R,, -c(〇)R, _c(〇)〇R,, C(0 NR2 - -C(NR)NR2 &gt; -C(NR)NROR &gt; -NRf2 ^ -(CR^XNRR1 &gt; NRC(0)R &gt; -NR?C(0)〇R·» . -NRfS02Rff &gt; -NR, C(0)NRf2 - -nr, c(s)nr, 2, _s(0)mR, u〇2NR, 2 ; each R is independently a substituted or unsubstituted alkyl or alkene Or alkynyl, or alkyl)' wherein the q_4 alkyl group is partially or completely dentated as appropriate; each R is independently hydrogen' or substituted or unsubstituted 6 alkyl; each R is independent Is hydrogen' or substituted or unsubstituted alkyl, cycloalkyl, cycloalkyl, aryl, heterocyclyl or heterocyclyl; each R,,f is independently substituted or unsubstituted a calcined base, a cycloalkyl group, a sulphate base, a sulphur-based alkyl group, an arylalkyl group or a heterocyclic group; each πι system is independently 〇, 1 or 2; 11 is 〇, 1, or 2 ; s is 1,2 3; and each t is independently 〇, 1 or 2; the condition is that the compound is not 5_(biphenyl_4_yl)&gt;6_gas·methoxy oxime 123505 200815422 唆-3-yl) amine. 7. The compound of claim 6 wherein Ar is phenyl, pyridyl, pyrimidinyl or t. 8. The compound of claim 7, wherein Ar is phenyl, 2-pyridyl, 3-pyridyl or 4-p-indenyl. 9. The compound of claim 6 wherein the compound is 10.如請求項6之化合物，其中化合物為10. The compound of claim 6 wherein the compound is 11.如請求項6之化合物，其中化合物為11. The compound of claim 6 wherein the compound is 12.如請求項6之化合物，其中化合物為12. The compound of claim 6 wherein the compound is Y A 13. 如請求項6之化合物，其中A為F、-CH3或-CF3。 14. 如請求項6之化合物，其中G為苯基、嘧啶基、吡啶基、 崎u坐基、異崎嗤基、p比唾基或咬喃基。 15. 如請求項6之化合物，其中G為苯基。 123505 200815422 16.如請求項14之化合物，其中G為Y A 13. The compound of claim 6, wherein A is F, -CH3 or -CF3. 14. The compound of claim 6, wherein G is phenyl, pyrimidinyl, pyridyl, sulphonyl, isosaki, p-salt or cumyl. 15. The compound of claim 6 wherein G is phenyl. 123505 200815422 16. The compound of claim 14, wherein G is 17·如請求項6之化合物，其中L2為共價鍵、Ο、NR、 C(0)(CH2)n、C(NOR)、S02NR、0(CH2)tC(0)、C(0)NR、C(0)NRNR 或NRC(0)0基團。 18.如請求項6之化合物，其中L2為共價鍵、O、OC(O)、 C(NOH)、so2nh、och2c(o)、c(o)、c(o)ch2、C(0)CH2CH2 ' C(0)NHNH 或 C(0)NH 〇 19. 如請求項6之化合物，其中Q為經取代或未經取代之烷 基、環烧基、（CG-4烧基）苯基、（C〇-4烧基比11 定基、（C〇-4烧 基）嘧啶基、（CG-4烷基）嗎福啉基、（CG-4烷基）硫代嗎福啉 基、（CG-4烷基）嗝啶基、（CG_4烷基）(10-氧-4_氮-三環并 [5.2.1.02,6]癸基）、（C〇_4 烷基）(8-氧-3-氮-雙環并[3.2.1]辛烷 基）、（c〇_4烷基）四氫哌喃基、（C〇-4烷基）四氫呋喃基、（c0_4 烷基）四氫吡咯基、（C〇_4烷基）六氫吡啶基或（CG-4烷基）六氫 峨畊基。 20. 如請求項19之化合物，其中Q為經取代或未經取代之甲 基、乙基、正·丙基、異丙基、正-丁基、第三-丁基、第二 -丁基、異丁基、新戊基、環丙基、（CH2)-環丙基、（CH2)2-環丙基、（CH2)3-環丙基、環丁基、（ch2)-環丁基、（ch2)2-環丁基、（ch2)3-環丁基、環戊基、（ch2)-環戊基、（ch2)2-環戊基、（ch2)3-環戊基、環己基、（ch2)-環己基、（ch2)2- 123505 200815422 環己基、（CH2)3·環己基、雙環并[2.21]庚烷基、（CH2)雙環并 [2.2.1]庚烧基、（CHA雙環并[2.2.1]庚烷基、（CH2)3雙環并[2.2J] 庚烷基、環庚基、苯基、芊基、苯乙基、2-吡啶基、（CH2)-2-吡啶基、（CH2 )2冬吡啶基、（CH2 )3 -2-吡啶基、3-吡啶基、（CH2 )各 外匕啶基、（CH2 )2 -3-吡啶基、（CH2 )3 -3-吡啶基、44啶基、（CH2 )-4_ 吡啶基、（CH2)2_4-吡啶基、（CH2)3_4-吡啶基、四氫呋喃基、 (CH2)-四氫呋喃基、（CH2)2-四氫呋喃基、（CH2)3-四氫呋喃 基、四氫哌喃基、（CH2)_四氫哌喃基、（CH2)2-四氫哌喃基、 (CH2)3·四氫哌喃基、四氫吡咯基、（CH2)_四氫吡咯基、（CH2)2_ 四氫峨洛基、（CH2)3·四氫吡洛基、ίο-氧_4_氮-三環并 [5.2.1.02,6]癸基、8_氧斗氮_雙環并[321]辛烷基、六氫吡啶 基、（CH2)-六氫吡啶基、（Ch2)2-六氫吡啶基、（Ch2)3-六氫吡 咬基、六氫吡畊基、（CH2 )-六氫吡啩基、（ch2 )2 -六氫吡畊基、 (CH2)3·六氫吡畊基、嗎福啉基、（CH2)·嗎福啉基' (CH2)2_ 嗎福啉基或（CH2)3-嗎福啉基。 21·如請求項6之化合物，其中R1為F、_CN、，或經取代 或未經取代之Q-4烷基、C3_9環烷基、雜環基或雜環基烷 基。 22·如請求項21之化合物，其中Ri為ρ、-CN、_n(Ch烷基)2， 其中各C^3烷基係獨立為經取代或未經取代；或Ri為經取 代或未經取代之甲基、異丙基、第三_丁基、異丁基、第 一 -丁基、新戊基、環己基、四氫吡咯基、咪唑基、吡唑 基、三唑基、酮基二唑基、異噚唑基、2，&gt;二氫異噚唑基、 六氫吡啶基、六氫吡畊基、氧氮七圜基、嗎福啉基、硫代 123505 -6 - 200815422 嗎福啉基、（ch2)-四氫吡咯基、（ch2)-六氫吡啶基、（ch2)_ 氧氮七圜基、（ch2)-嗎福啉基或（ch2)-六氫吡啡基。 23.如請求項6之化合物，其中R2為經取代或未經取代之（Ch 烷基）或雜環基烷基、F、Cl、-CN、-N02、-OR’、-C(0)0R’、 -C(0)NR，2、-(CH2)tNRR”、-C(NR)NR2、-C(NR)NROR、-NRC(0)R”、 -NRC(0)ORn、-NR，S02Rn、-NR’CXCONE^ 或·802ΝΙΙ，2。 24·如請求項23之化合物，其中R2為F、-CN、-CF3、-N02、-0((：卜6 烷基）、-0(0)0((^-6烷基）、-C(0)NH2、烷基）、 -C(0)NH(C3 _ 6 環烷基）[0]、-C(0)NH(環烷基烷基）[〇]、_C(0)NH(芳 烷基）、-(CHJNHd6 烷基）、-(CH2)NH(芳烷基）、_(CH2)Nh(雜 環基烷基）、-C(NH)NH2、-CXM^NH^ · 6 烷基）、—qnj^nhoh、 -CXM^NHCKCu烷基）、-NHC(0)(CV6烷基）、-nhqq)% 6環 烧基）、-NHC(0)(i哀烧基烧基）、-NHC(〇)(芳基）、_^j|c(〇)(芳 烧基）、-nhso2 (Cb 6 烧基）、-nhso2 (c3 · 6 環燒基）、-NHS〇2 (環 烷基烷基）、_NHS〇2(芳基）、_NHS〇2(芳烷基）、-S〇2NH(Ci 6 烷基）、-S02NH(C3-6環烷基）、4〇2ΝΗ(環烷基烷基）、 -so2nh(芳基）或-so2nh(芳烷基），其中各Ci 6烷基、c3 6環 烷基、環烷基烷基芳基及芳烷基係為經取代或未經取代。 25·如請求項6之化合物，其中R3為經取代或未經取代 烷基或-〇(Α 4烷基），或為經部份或完全幽化之-ο% ·2燒 基）。 26·如請求項6之化合物，其中G為苯基，且R^F、C1、_CN、 -N(Cl_3烷基h，其中各Cl_3烷基係獨立為經取代或未經取 代，或R為經取代或未經取代之嗎福琳基、硫代嗎福啦 123505 200815422 基、四氫吡咯基、咪唑基、吡唑基、三唑基、酮基二唑基、 異吟0坐基、2,3-—氧異p号吐基、六氫咐σ定基、六氫说p井基、 乳氮七圜基、（CH2 )-四氳p比洛基、（CH2 )·六氫p比唆基、（c%) 氧氮七圜基、（CH2)-嗎福啉基、（CH2)_六氫吡畊基、甲基、 異丙基、第三-丁基、異丁基、第二_ 丁基、新戊基或壤已 基。 27·如請求項26之化合物，其中Ri為f ' C1、經取代或未缝取 代之嗎福淋基、四氫咐洛基、咪唆基、峨唾基、三唾基、 酮基二唑基、異唠唑基、2,3-二氫異嘮唑基、六氫吡啶基、 (CH2)-四氫卩比洛基、（CH2)—六氫吡啶基、（CH2y嗎福啉基、 (CH2)-六氫吡畊基、甲基、第三_丁基或環己基。 28. 如請求項26之化合物，其中r2為f、-CN、-CF3、-N02、-0% 烷基）、-c(o)o(cw烷基）、_C(0)NH2、_c(0)NH(Ci_6烷基）、 -C(0)NH(C3 ·6環烧基）[〇]、_C(⑺nh(環烷基烷基 p]、_c(〇)Nh(芳 烷基）、-NHC(0)(Cb 6烷基）、-仰匚⑼％ _ 6環烷基）、-nhC(0)(環 烷基烷基）、-NHC(〇)(芳基）、-(：(〇)(芳烷基）、-(CHJNH% _6 烷基）、-(CH2)NH(芳烷基）、-(CH2)NH(雜環基烷基）、 -nhscmCu烷基）、-nhS〇2(C3-6環炫基）、-nhso2(環燒基烧 基）、-NHS〇2(芳基）、-nhs〇2(芳烷基）、-S〇2NH(Cl_6烧基）、 -S02NH(C3環烷基）、_s〇2NH(環烷基炼基）、_s〇2NH(芳基） 4_so2NH(芳烷基），其中各c1-6烷基、C3-6環烷基、環烷基 烷基芳基或芳烷基係為經取代或未經取代。 29. 如請求項26之化合物，其中r2為f、-CN、-CF3、-C(0)NH2、 _ 6烷基）' _C(0)NH(C3 - 6環烷基）、巧0)1^(環烷基烧 123505 200815422 基）、-(CHJNHCCh 烷基）、-(ch2)nh(雜環基烷基）、 -NHS02(CV6烷基）或-SC^NHCCu烷基），其中各CV6烷基、 c3_6環烷基及環烷基烷基係為經取代或未經取代。 30. 如請求項26之化合物，其中R3為經取代或未經取代之Ci _4 烷基或-cxq-4烷基），或為經部份或完全鹵化之-Ο%_2烷 基）。 31. 如請求項6之化合物，其中L2為Ο、OC(O)、C(O)、C(0)NH、 C(0)NHNH、C(0)NMe、0CH2C(0)、S02NH、CH(OH)或 C(NOH)，17. The compound of claim 6, wherein L2 is a covalent bond, Ο, NR, C(0)(CH2)n, C(NOR), S02NR, 0(CH2)tC(0), C(0)NR , C(0)NRNR or NRC(0)0 group. 18. The compound of claim 6, wherein L2 is a covalent bond, O, OC(O), C(NOH), so2nh, och2c(o), c(o), c(o)ch2, C(0) CH2CH2 'C(0)NHNH or C(0)NH 〇 19. The compound of claim 6, wherein Q is a substituted or unsubstituted alkyl group, a cycloalkyl group, a (CG-4 alkyl) phenyl group, (C〇-4 alkyl group 11 base group, (C〇-4 alkyl) pyrimidinyl group, (CG-4 alkyl) oxabulin group, (CG-4 alkyl) thiotropulin group, (CG -4 alkyl)acridinyl, (CG_4 alkyl) (10-oxo-4_nitro-tricyclo[5.2.1.02,6]decyl), (C〇_4 alkyl) (8-oxo- 3-nitro-bicyclo[3.2.1]octyl), (c〇_4 alkyl)tetrahydropyranyl, (C〇-4 alkyl)tetrahydrofuranyl, (c0-4 alkyl)tetrahydropyrrolyl (C〇_4 alkyl)hexahydropyridyl or (CG-4 alkyl)hexahydroindole. 20. The compound of claim 19, wherein Q is substituted or unsubstituted methyl, B Base, n-propyl, isopropyl, n-butyl, tert-butyl, second-butyl, isobutyl, neopentyl, cyclopropyl, (CH2)-cyclopropyl, (CH2 ) 2-cyclopropyl, (CH2)3-cyclopropyl, cyclobutene , (ch2)-cyclobutyl, (ch2)2-cyclobutyl, (ch2)3-cyclobutyl, cyclopentyl, (ch2)-cyclopentyl, (ch2)2-cyclopentyl, (ch2 3-cyclopentyl, cyclohexyl, (ch2)-cyclohexyl, (ch2)2-123505 200815422 cyclohexyl, (CH2)3·cyclohexyl, bicyclo[2.21]heptyl, (CH2)bicyclo[ 2.2.1] heptyl, (CHA bicyclo[2.2.1]heptyl, (CH2)3bicyclo[2.2J]heptyl, cycloheptyl, phenyl, decyl, phenethyl, 2 -pyridyl, (CH2)-2-pyridyl, (CH2)2 winter pyridyl, (CH2)3-2-pyridyl, 3-pyridyl, (CH2) each aziridine, (CH2)2- 3-pyridyl, (CH2)3-3-pyridyl, 44 pyridine, (CH2)-4_pyridyl, (CH2)2-tetrapyridyl, (CH2)3-tetrapyridyl, tetrahydrofuranyl, (CH2)- Tetrahydrofuranyl, (CH2)2-tetrahydrofuranyl, (CH2)3-tetrahydrofuranyl, tetrahydropyranyl, (CH2)-tetrahydropyranyl, (CH2)2-tetrahydropyranyl, (CH2)3 Tetrahydropyranyl, tetrahydropyrrolyl, (CH2)-tetrahydropyrrolyl, (CH2)2_tetrahydroindolyl, (CH2)3·tetrahydropyrrolyl, ίο-oxo_4_nitrogen- Three rings and [5.2.1.02,6 ] mercapto, 8_oxopipe nitrogen_bicyclo[321]octyl, hexahydropyridyl, (CH2)-hexahydropyridyl, (Ch2)2-hexahydropyridyl, (Ch2)3-hexahydro Pyridyl, hexahydropyridinyl, (CH2)-hexahydropyridinyl, (ch2)2-hexahydropyrrole, (CH2)3·hexahydropyrrole, morpholinyl, (CH2) · Trophosyl '(CH2)2_morpholinyl or (CH2)3-norfosolinyl. The compound of claim 6, wherein R1 is F, -CN, or a substituted or unsubstituted Q-4 alkyl group, a C3-9 cycloalkyl group, a heterocyclic group or a heterocycloalkyl group. 22. The compound of claim 21, wherein Ri is ρ, -CN, _n(Ch alkyl)2, wherein each C^3 alkyl group is independently substituted or unsubstituted; or Ri is substituted or unsubstituted Substituted methyl, isopropyl, tert-butyl, isobutyl, first-butyl, neopentyl, cyclohexyl, tetrahydropyrrolyl, imidazolyl, pyrazolyl, triazolyl, keto Diazolyl, isoxazolyl, 2, &gt; dihydroisoxazolyl, hexahydropyridyl, hexahydropyrrole, oxynitridinyl, morpholinyl, thio 123505 -6 - 200815422 Folinolyl, (ch2)-tetrahydropyrrolyl, (ch2)-hexahydropyridyl, (ch2)-oxyziridine, (ch2)-morpholinyl or (ch2)-hexahydropyramyl . 23. The compound of claim 6 wherein R2 is substituted or unsubstituted (Ch alkyl) or heterocyclylalkyl, F, Cl, -CN, -N02, -OR', -C(0) 0R', -C(0)NR,2, -(CH2)tNRR", -C(NR)NR2, -C(NR)NROR, -NRC(0)R", -NRC(0)ORn, -NR , S02Rn, -NR'CXCONE^ or · 802ΝΙΙ, 2. 24. The compound of claim 23, wherein R2 is F, -CN, -CF3, -N02, -0 ((: 6 alkyl), -0 (0) 0 ((^-6 alkyl), - C(0)NH2, alkyl), -C(0)NH(C3 -6 cycloalkyl)[0], -C(0)NH(cycloalkylalkyl)[〇], _C(0)NH (Aralkyl), -(CHJNHd6 alkyl), -(CH2)NH(aralkyl), _(CH2)Nh(heterocyclylalkyl), -C(NH)NH2, -CXM^NH^ 6 alkyl), -qnj^nhoh, -CXM^NHCKCu alkyl), -NHC(0)(CV6 alkyl), -nhqq)% 6 cycloalkyl), -NHC(0)(i smoldering base Base), -NHC(〇)(aryl), _^j|c(〇)(aryl), -nhso2 (Cb 6 alkyl), -nhso2 (c3 · 6 cycloalkyl), -NHS〇 2 (cycloalkylalkyl), _NHS〇2 (aryl), _NHS〇2 (aralkyl), -S〇2NH(Ci 6 alkyl), -S02NH(C3-6 cycloalkyl), 4〇 2ΝΗ(cycloalkylalkyl), -so2nh(aryl) or -so2nh(aralkyl), wherein each Ci 6 alkyl, c 3 6 cycloalkyl, cycloalkylalkylaryl and aralkyl is Substituted or unsubstituted. The compound of claim 6, wherein R3 is substituted or unsubstituted alkyl or -〇(Α4 alkyl), or is partially or completely decimated - ο% · 2 alkyl). The compound of claim 6, wherein G is phenyl, and R^F, C1, -CN, -N(Cl_3 alkylh, wherein each Cl_3 alkyl group is independently substituted or unsubstituted, or R is Substituted or unsubstituted wheylin, thiophene 123505 200815422, tetrahydropyrrolyl, imidazolyl, pyrazolyl, triazolyl, ketodiazolyl, isoindole 0, 2 , 3--oxyiso-p- thiol, hexahydropurine sigma, hexahydro-p-peptidyl, lacto-nitrazinyl, (CH2)-tetraindole p-l- yl, (CH2)·hexahydro-p-pyrene Base, (c%) oxynitridinyl, (CH2)-morpholinyl, (CH2)_hexahydropyrrole, methyl, isopropyl, tert-butyl, isobutyl, second _ butyl, neopentyl or hexyl. 27. The compound of claim 26, wherein Ri is f 'C1, substituted or unstitched wholfolide, tetrahydrofuranyl, imidinyl, Ruthenyl, trisal, ketodiazolyl, isoxazolyl, 2,3-dihydroisoxazolyl, hexahydropyridyl, (CH2)-tetrahydroindolebiloyl, (CH2)- Hexahydropyridyl, (CH2y morpholine, (CH2)-hexahydropyrrole, methyl, tert-butyl or cyclohexane 28. The compound of claim 26, wherein r2 is f, -CN, -CF3, -N02, -0% alkyl), -c(o)o(cw alkyl), _C(0)NH2, _c (0) NH(Ci_6 alkyl), -C(0)NH(C3 ·6 cycloalkyl)[〇], _C((7)nh(cycloalkylalkylp), _c(〇)Nh(aralkyl) , -NHC(0)(Cb 6 alkyl), -homoxime (9)% _ 6 cycloalkyl), -nhC(0)(cycloalkylalkyl), -NHC(〇)(aryl), -( :(〇)(aralkyl), -(CHJNH% _6 alkyl), -(CH2)NH(aralkyl), -(CH2)NH(heterocyclylalkyl), -nhscmCualkyl), - nhS〇2 (C3-6cyclodecyl), -nhso2 (cycloalkyl), -NHS〇2 (aryl), -nhs〇2 (aralkyl), -S〇2NH (Cl_6 alkyl) -S02NH(C3 cycloalkyl), _s〇2NH (cycloalkyl refinery), _s〇2NH(aryl) 4_so2NH(aralkyl), wherein each c1-6 alkyl group, C3-6 cycloalkyl group, The cycloalkylalkylaryl or aralkyl group is substituted or unsubstituted. 29. The compound of claim 26, wherein r2 is f, -CN, -CF3, -C(0)NH2, -6 alkyl )C'0(0)NH(C3-6 cycloalkyl), 巧0)1^(cycloalkyl burn 123505 200815422 base), -(CHJNHCCh alkyl), -(ch2)n h(heterocyclylalkyl), -NHS02(CV6 alkyl) or -SC^NHCCualkyl), wherein each CV6 alkyl, c3-6 cycloalkyl and cycloalkylalkyl is substituted or unsubstituted. 30. The compound of claim 26, wherein R3 is substituted or unsubstituted Ci_4 alkyl or -cxq-4 alkyl, or partially or fully halogenated -Ο%_2 alkyl). 31. The compound of claim 6, wherein L2 is Ο, OC(O), C(O), C(0)NH, C(0)NHNH, C(0)NMe, 0CH2C(0), S02NH, CH (OH) or C(NOH), 且Q為And Q is 32. 如請求項31之化合物，其中G為苯基。 33. 如請求項6之化合物，其中在10 //M濃度下之化合物會抑制 自細胞所引致之TNFa-釋出，達約50%或大於50%。 123505 200815422 34.—種式II化合物，32. The compound of claim 31, wherein G is phenyl. 33. The compound of claim 6, wherein the compound at a concentration of 10 //M inhibits TNFa-induced release from the cell by up to about 50% or greater than 50%. 123505 200815422 34. - a compound of formula II, 式II 其立體異構物、其互蠻里m ^ ^ 支異構物、其溶劑合物、其丽體 藥物及其藥學上可接受之鹽； 其中 X 為 CH、N 或 NO ; Y 為 CH、N 或 NO ; A為 F、Cl、Br、I、NRptCi-3 烧基或 _〇(Ci3 烷基），其 中烷基係視情況經部份或完全_化； B與D各獨立為CR或N; G為芳基或雜芳基，其中〇係被一或多個Rl，R2或R3取 代； L1 為-C(0)NH-; L2 為共價鍵、CR，20 、 （CR，2)mC(0)(CR，2)t 、 (CR’2)mC(〇)NR(CR，2)t、（CRACXCONRNRXCRU、（CR，2)mC(NOR)-(CR’2 )t 或(CR，2 )mNRC(0)0(CR，2 )t ; Q為經取代或未經取代之烷基、環烷基、芳基、雜環基、 環燒基烷基、芳烷基或雜環基烷基； 各R1係獨立為F、Cl、Br、I、-NR2、-CN，或經取代或 未經取代之烷基、烯基、炔基、環烷基、環烯基、芳基、 雜環基或雜環基烷基； 123505 200815422 各R2係獨立為F、Cl、Br、I、_CN、_N〇2、經取代或未 經取代之烧基或雜環基烷基、-〇R，、_c(〇)R，、_c(〇)〇R，、 -C(0)NR’2、视-2、_(CR,2)tNRR,、胤。(〇)尺，，、视叼⑼⑽， -NR’S02R”、-NR’C(〇)NR，2、 -NR’C(S)NR’2、-S(0)mRn 或-S02NR，2 ; 各R3係獨立為經取代或未經取代之烷基、烯基或炔基， 或_〇%_4烷基），其中CiM烷基係視情況經部份或完全_ 各R係獨立為氫，或經取代或未經取代之烷基； 各R’係獨立為氫，或經取代或未經取代之烷基、環烷 基、環烷基烷基、芳烷基、雜環基或雜環基烷基； 各R係獨立為經取代或未經取代之烷基、環烷基、芳 基雜％基、1 哀烷基烷基、芳烷基或雜環基烷基； 各m係獨立為〇, 1或2 ;且 t為0, 1或2。 35·如請求項34之化合物，其中化合物為a stereoisomer of the formula II, a m ^ ^ branched isomer thereof, a solvate thereof, a lysine thereof, and a pharmaceutically acceptable salt thereof; wherein X is CH, N or NO; Y is CH , N or NO; A is F, Cl, Br, I, NRptCi-3 alkyl or 〇 (Ci3 alkyl), wherein the alkyl group is partially or completely _ as the case may be; B and D are each independently CR Or N; G is aryl or heteroaryl, wherein the lanthanide is substituted by one or more R1, R2 or R3; L1 is -C(0)NH-; L2 is a covalent bond, CR, 20, (CR, 2) mC(0)(CR,2)t , (CR'2)mC(〇)NR(CR,2)t, (CRACXCONRNRXCRU, (CR,2)mC(NOR)-(CR'2 )t or (CR,2 ) mNRC(0)0(CR,2 )t ; Q is substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocyclyl, cycloalkyl, aralkyl or Heterocyclylalkyl; each R1 is independently F, Cl, Br, I, -NR2, -CN, or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Aryl, heterocyclyl or heterocyclylalkyl; 123505 200815422 Each R2 is independently F, Cl, Br, I, _CN, _N〇2, substituted or unsubstituted alkyl or hetero Alkyl group, -〇R,, _c(〇)R,, _c(〇)〇R,, -C(0)NR'2, 视-2, _(CR,2)tNRR, 胤.(〇 ), ruler, (9) (10), -NR'S02R", -NR'C(〇)NR, 2, -NR'C(S)NR'2, -S(0)mRn or -S02NR, 2 ; R3 is independently substituted or unsubstituted alkyl, alkenyl or alkynyl, or _〇%_4 alkyl), wherein the CiM alkyl group is partially or completely _ each R system is independently hydrogen, or Substituted or unsubstituted alkyl; each R' is independently hydrogen, or substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, heterocyclyl or heterocyclyl Alkyl; each R is independently substituted or unsubstituted alkyl, cycloalkyl, arylhetero, 1 sinylalkyl, aralkyl or heterocyclylalkyl; each m is independently 〇, 1 or 2; and t is 0, 1 or 2. 35. The compound of claim 34, wherein the compound is 如凊求項34之化合物，其中化合物為For example, a compound of claim 34, wherein the compound is 37. 如請求項34之化合物 38. 如請求項34之化合物 之化合物，其中B為N。 之化合物，其中D為N。 123505 • 11 - 200815422 39·如明求項34之化合物，其中A為F、-CH3或_CF3 〇 4〇·如明求項34之化合物，其中G為苯基、嘧啶基或吡啶基。 41·如請求項34之化合物，其中G為37. The compound of claim 34. The compound of claim 34, wherein B is N. a compound wherein D is N. The compound of claim 34, wherein A is F, -CH3 or _CF3 〇 4〇. The compound of claim 34, wherein G is phenyl, pyrimidinyl or pyridyl. 41. The compound of claim 34, wherein G is 42.如凊求項34之化合物，其中l2為共價鍵、c(〇)、CH2 Ο、 C(〇)NHNH、c(N〇H)或 c⑼nh 〇 43·如請求項34之化合物，其中q為經取代或未經取代之烷 基、環烷基、10-氧-4-氮-三環并[5·2·1·02,6]癸基、8-氧-3-氮-雙環并[3.2.1]辛烷基、（Q)-4烷基）環烷基、（CG_4烷基）苯基、 (c0·4烧基）吡啶基、（Cg_4烷基）鳴啶基、（Cq_4烷基辦啶基、 (C〇_4烧基）嗎福啉基、（C()-4烷基）硫代嗎福啉基、（Cq_4烷基） 四氫略喃基、（CG_4烷基）四氫呋喃基、（CG-4烷基）四氫吡咯 基、（cG-4烷基）六氫吡啶基或（Cg 4烷基）六氫吡畊基。 44_如請求項34之化合物，其中q為經取代或未經取代之甲 基、乙基、正-丙基、異丙基、正-丁基、第三-丁基、第二 -丁基、異丁基、新戊基、環丙基、（CH2)-環丙基、（CH2)2-環丙基、（CH2)3·環丙基、環丁基、（Ch2)_環丁基、（ch2)2-環丁基、（CH2)3_環丁基、環戊基、（Ch2)—環戊基、（Ch2)2_ 環戊基、（ch2)3_環戊基、環己基、（Ch2)_環己基、（CH2)2-環己基、（CH2)3·環己基、雙環并[2·2_1；^烷基、（Ch2)雙環并 P.2.1]庚烷基、(CH2)2雙環并ρ·21]庚烷基、(ch2)3雙環并[2.2.1] 庚烷基、環庚基、苯基、苄基、苯乙基、2-吡啶基、（CH2)-2- 123505 -12- 200815422 吡啶基、（CH2 )2 -2-吡啶基、（CH2 )3 -2-吡啶基、3-吡啶基、（CH2 )-3-口比 σ定基、（CH〗)2 比 17定基、（CH2 )3 σ定基、4-峨 σ定基、（CH2 )-4- 吡啶基、（CH2)2-4-吡啶基、（CH2)3-4-吡啶基、峴啶基、（CH2)-喵啶基、（CH2 )2 -嗝啶基、（CH2 )3 -喵啶基、10-氧-4-氮-三環并 [5.2.1.02,6]癸基、8-氧-3-氮·雙環并[3.2.1]辛烷基、四氫呋喃 基、（CH2)-四鼠咬σ南基、（CH〗)2 -四氮咬喃基、（CH〗)3 ·四氮咬 喃基、四氮p辰喃基、（CH2 四氮味喃基、（CH2 )2 -四鼠成喃基、 (CH2 )3 -四氫旅喃基、四氫吡洛基、（CH2)-四氫卩比略基、（CH2 )2 - / ^ 四氫卩比洛基、（CH2 )3 -四氫卩比洛基、六氫卩比p井基、（CH2)-六氫 吡畊基、（CH2)2-六氫吡畊基、（CH2)3-六氫吡畊基、六氫吡 啶基、（CH2)·六氫吡啶基、（CH2)2-六氫吡啶基、（CH2)3-六氫 P比σ定基、嗎福淋基、（CH2 )-嗎福琳基、（CH2 )2 -嗎福淋基或 (CH2)3-嗎福啉基。 45. 如請求項34之化合物，其中R1為F、-CN、-NR2 ’或經取代 或未經取代之(^_4烷基、C3_9環烷基、雜環基或雜環基烷 …基。 \ 46. 如請求項45之化合物，其中R1為F、_CN、-Νθ〗·3烷基）2， 其中各(^_3烷基係獨立為經取代或未經取代；或R1為經取 代或未經取代之曱基、異丙基、第三-丁基、異丁基、第 二-丁基、新戊基、環己基、四氫吡咯基、咪唑基、吡唑 基、三σ坐基、闕基二嗤基、異崎唆基、2,3-二氫異崎ϋ坐基、 六氫ρ比σ定基、六氫说ρ井基、氧II七圜基、嗎福ρ林基、硫代 嗎福ρ林基、（CH2)-四氮1^比洛基、（CH〗)-六鼠峨σ定基、（CH2 )-氧氮七圜基、（CH2)-嗎福啉基或（CH2)-六氫吡畊基。 123505 -13- 200815422 47.如請求項34之化合物，其中R2為經取代或未經取代之（Ci -6 烷基）或雜環基烷基、F、Cl、-CN、-N02、-OR’、-C(0)0R’、 _C(0)^2、-(CH2)tNRR，，、-NRC(0)R”、_NRC(0)0R&quot;、-NR’S02R&quot;、 -nr，c(o)nr，2 或 _so2nr，2。 48·如請求項47之化合物，其中R2為F、-CN、-CF3、-N02、-0(C卜6 烷基）、-C(0)0(CV6 烷基）、-C(0)NH2、-C(0)NH(C卜6 烷基）、 -C(0)NH(C3 _ 6 環烷基）[0]、-C(0)NH(環烷基烷基）[0]、-C(0)NH(芳 烷基）、-(CH2 _ 6 烷基）、-(CH2 )NH(芳烷基）、-(CH2 )NH(雜 ί 環基烷基）、-NHCXOXq ·6 烷基）、-NHC(0)(C3 _6 環烷基）、 -NHC(0)(環烷基烷基）、-NHC(0)(芳基）、-NHC(0)(芳烷基）、 -NHSCMCw烷基）、_nhso2(c3_6環烷基）、-NHS02(環烷基烷 基）、-nhso2(芳基）、-NHS〇2(芳烷基）…s〇2NH(Ch烷基）、 -S〇2NH(C3 _6環烷基）、_s〇2NH(環烷基烷基）、_s〇2nh(芳基） 或-S〇2NH(芳烷基），其中各Cu烷基、c3-6環烷基、環烷基 烷基、芳基及芳烷基係為經取代或未經取代。 《49·如請求項34之化合物，其中R3為經取代或未經取代之〇14 烧基或-0(CW烷基），或為經部份或完全鹵化之_〇(Cu烷 基）。 50.如請求項34之化合物，其中g為苯基，且Ri為f、C1、—CN、 -NCq _3烧基h，其中各Q _3烷基係獨立為經取代或未經取 代，或R1為經取代或未經取代之嗎福琳基、硫代嗎福淋 基、四氫吡咯基、咪唑基、吡唑基、三唑基、酮基二唑基、 異$。坐基、2,3-二氫異$。坐基、六氫说唆基、六氫批畊基、 氧氮七圜基、（CH2)-四氫咐洛基、（ch2)-六氫峨唆基、（CH2)- 123505 -14- 200815422 氧氮七圜基、（CH2&gt;嗎福啉基、（CH2&gt;六氫吡畊基、甲基、 異丙基、第三-丁基、異丁基、第二-丁基或環己基。 51. 如請求項50之化合物，其中R1為F、C1、經取代或未經取 代之嗎福琳基、四氫说σ各基、哺σ坐基、峨σ坐基、三唾基、 酮基二唑基、異崎唑基、2,3-二氫異嘮唑基、六氫吡啶基、 (CH2)-四氫吡咯基、（CH2)-六氫吡啶基、（CH2)-嗎福啉基、 (CH2)-六氫峨p井基、甲基、第三-丁基或環己基。 52. 如請求項50之化合物，其中R2為F、-CN、-CF3、-N02、-0(Ch 烷基）、-C(0)0(C卜6 烷基）、&lt;(0)ΝΗ2、-CXCONH% ·6 烷基）、 -C(0)NH(C3 - 6 環烷基）[〇]、_C(0)NH(環烷基烷基）[〇]、-C(0)NH(芳 烷基）、-NHCXOXq - 6 烷基）、-NHQOXq - 6 環烷基）、-NHC(0)(環 烷基烷基）、-NHC(0)(芳基）、-NHC(0)(芳烷基）、-(CH^NH% -6 烷基）、-(CH2)NH(芳烷基）、_(CH2)NH(雜環基烷基）、 NHSCMCu烷基）、-NHS02(C3_6環烷基）、-NHS02(環烷基烷 基）、-nhso2(芳基）、-nhso2(芳烷基）、-S02NH(Ch烷基）、 -S〇2NH(C3 _6環烷基）、-S〇2NH(環烷基烷基）、-S〇2NH(芳基） 或-S〇2NH(芳烷基），其中各q-6烷基、c3_6環烷基、環烷基 烷基、芳基及芳烷基係為經取代或未經取代。 53·如請求項50之化合物，其中R2為F、-CN、_CF3、-C(0)NH2、 ((0)ΝΗ((^_6 烷基）、-C(0)NH(C3_6 環烷基）[〇]、-C(0)NH(環烷 基烧基）[〇] ' -(CHJNHds烷基）、-(CH2)NH(雜環基烷基）、 -NHSCMCh烷基）或-Sc^n^Ch烷基），其中各Cl-6烷基、 環烷基及環烷基烷基係為經取代或未經取代。 54·如請求項50之化合物，其中r3為經取代或未經取代之 123505 -15- 200815422 烷基或-CXCi _4烷基），或為經部份或完全鹵化之-CKCi _2烷 基）。 55.如請求項34之化合物，其中L2為鍵結、CH20、C(O)、C(0)0、 C(0)NH、C(0)NHNH、C(NOR)或 C(CH3)2C(0)NH，且 Q 為42. The compound of claim 34, wherein l2 is a covalent bond, c(〇), CH2 Ο, C(〇)NHNH, c(N〇H) or c(9)nh 〇43. q is a substituted or unsubstituted alkyl, cycloalkyl, 10-oxo-4-nitro-tricyclo[5·2·1·02,6]fluorenyl, 8-oxo-3-nitro-bicyclic ring And [3.2.1] octyl, (Q)-4 alkyl)cycloalkyl, (CG_4 alkyl)phenyl, (c.04 alkyl)pyridyl, (Cg_4 alkyl)peridinyl, Cq_4 alkyl acyl group, (C〇_4 alkyl) oxabulin group, (C()-4 alkyl) thiomorpholine group, (Cq_4 alkyl) tetrahydrofuranyl, (CG_4 alkane a tetrahydrofuranyl group, a (CG-4 alkyl)tetrahydropyrrolyl group, a (cG-4 alkyl)hexahydropyridyl group or a (Cg 4 alkyl)hexahydropyranyl group. 44. The compound of claim 34, Wherein q is substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, second-butyl, isobutyl, neopentyl, Cyclopropyl, (CH2)-cyclopropyl, (CH2)2-cyclopropyl, (CH2)3·cyclopropyl, cyclobutyl, (Ch2)-cyclobutyl, (ch2)2-cyclobutyl , (CH2)3_cyclobutyl, Pentyl, (Ch2)-cyclopentyl, (Ch2)2_cyclopentyl, (ch2)3_cyclopentyl, cyclohexyl, (Ch2)-cyclohexyl, (CH2)2-cyclohexyl, (CH2)3 ·cyclohexyl, bicyclo[2.2_1;^alkyl, (Ch2)bicyclic and P.2.1]heptanyl, (CH2)2bicyclo and ρ21]heptyl, (ch2)3bicyclo[2.2 .1] heptyl, cycloheptyl, phenyl, benzyl, phenethyl, 2-pyridyl, (CH2)-2-123505 -12- 200815422 pyridyl, (CH2)2-2-pyridyl, (CH2)3 -2-pyridyl, 3-pyridyl, (CH2)-3-port ratio σ group, (CH))2 ratio 17 group, (CH2)3 σ group, 4-峨σ group, (CH2 )-4-pyridyl, (CH2)2-4-pyridyl, (CH2)3-4-pyridyl, acridinyl, (CH2)-acridinyl, (CH2)2-acridinyl, (CH2) 3 - acridinyl, 10-oxo-4-nitro-tricyclo[5.2.1.02,6]decyl, 8-oxo-3-nitrobicyclo[3.2.1]octyl, tetrahydrofuranyl, (CH2)- four mouse bites σ Nanji, (CH)) 2 - tetrazole, (CH)) 3 · tetrazole, tetrazinc p-butyl, (CH2 tetrakiromyl, (CH2)2-tetramer-forming thiol, (CH2)3-tetrahydronaphthyl, tetrahydropyridyl Base, (CH2)-tetrahydroindole, (CH2)2 - / ^ tetrahydroindolebiloyl, (CH2)3-tetrahydroindolebiolyl, hexahydropyrene ratio p well base, (CH2) - hexahydropyrrole, (CH2)2-hexahydropyrrole, (CH2)3-hexahydropyrrole, hexahydropyridyl, (CH2)·hexahydropyridyl, (CH2)2-hexahydro Pyridyl, (CH2)3-hexahydroP is more specific than sigma, whiferidin, (CH2)-moffolinyl, (CH2)2-norfosyl or (CH2)3-morpholino. 45. The compound of claim 34, wherein R1 is F, -CN, -NR2' or substituted or unsubstituted (^-4 alkyl, C3-9 cycloalkyl, heterocyclyl or heterocyclyl). 46. The compound of claim 45, wherein R1 is F, —CN, —Νθ”·3 alkyl), wherein each (^-3 alkyl group is independently substituted or unsubstituted; or R1 is substituted or Unsubstituted fluorenyl, isopropyl, tert-butyl, isobutyl, second-butyl, neopentyl, cyclohexyl, tetrahydropyrrolyl, imidazolyl, pyrazolyl, tris-sine , fluorenyl fluorenyl, isosaki fluorenyl, 2,3-dihydroisosaki, hexahydro ρ than sigma, hexahydro ρ well, oxygen II sulphate, ruthenium ruthenium, Thiofolf ruthenyl, (CH2)-tetrazine 1^bi Loki, (CH))-six sputum sigma, (CH2)-oxynitr-7, (CH2)-morpholinyl or (CH2)-hexahydropyranin. 123505 -13- 200815422 47. The compound of claim 34, wherein R2 is substituted or unsubstituted (Ci-6 alkyl) or heterocyclylalkyl, F, Cl, -CN, -N02, -OR', -C(0)0R', _C(0)^2, -(CH2)tNRR,,, -NRC(0)R", _NRC(0)0R&quot;, -NR'S02R&quot;, -nr,c(o)nr,2 or _so2nr, 2. 48. The compound of claim 47, wherein R2 is F, -CN, -CF3, - N02, -0(Cb6 alkyl), -C(0)0(CV6 alkyl), -C(0)NH2, -C(0)NH(Cb6 alkyl), -C(0) NH(C3 _ 6 cycloalkyl)[0], -C(0)NH(cycloalkylalkyl)[0], -C(0)NH(aralkyl), -(CH2_6 alkyl) , -(CH2)NH(aralkyl), -(CH2)NH(heterocycloalkyl), -NHCXOXq ·6 alkyl), -NHC(0)(C3_6 cycloalkyl), -NHC( 0) (cycloalkylalkyl), -NHC(0)(aryl), -NHC(0)(aralkyl), -NHSCMCwalkyl), _nhso2(c3_6cycloalkyl), -NHS02 (cycloalkane) Alkyl), -nhso2(aryl), -NHS〇2(aralkyl)...s〇2NH(Ch alkyl), -S〇2NH(C3_6cycloalkyl), _s〇2NH (cycloalkyl) Alkyl), _s〇2nh(aryl) or -S〇2NH(aralkyl), wherein each Cu alkyl, c3-6 cycloalkyl, cycloalkylalkyl, aryl and aralkyl is Substituted or unsubstituted. 49. The compound of claim 34, wherein R3 is substituted or unsubstituted fluorene or alkyl (CW alkyl), or The _〇 or fully halogenated (Cu alkyl). 50. The compound of claim 34, wherein g is phenyl, and Ri is f, C1, -CN, -NCq _3 alkyl, wherein each Q-3 alkyl is independently substituted or unsubstituted, or R1 It is a substituted or unsubstituted wheylinyl, thiofenofyl, tetrahydropyrrolyl, imidazolyl, pyrazolyl, triazolyl, ketodiazolyl, iso-. Sitting base, 2,3-dihydroisomeric $. Sedentary, hexahydro sulfhydryl, hexahydrogen, oxynitridinyl, (CH2)-tetrahydrofuranyl, (ch2)-hexahydroindenyl, (CH2)- 123505 -14- 200815422 Oxygen nitrogen heptayl, (CH2&gt; morpholinyl, (CH2&gt; hexahydropyrrole, methyl, isopropyl, tert-butyl, isobutyl, second-butyl or cyclohexyl. 51 The compound of claim 50, wherein R1 is F, C1, substituted or unsubstituted wheylinyl, tetrahydron sigma, sigma, sigma, tris, keto Diazolyl, isoxazolyl, 2,3-dihydroisoxazolyl, hexahydropyridyl, (CH2)-tetrahydropyrrolyl, (CH2)-hexahydropyridyl, (CH2)-morpholin a compound of the formula 50, wherein R 2 is F, -CN, -CF3, -N02, -0. (Ch alkyl), -C(0)0(Cb6 alkyl), &lt;(0)ΝΗ2, -CXCONH% ·6 alkyl), -C(0)NH(C3-6 cycloalkyl) [〇], _C(0)NH(cycloalkylalkyl)[〇], -C(0)NH(aralkyl), -NHCXOXq-6 alkyl), -NHQOXq-6-6 cycloalkyl), NHC(0)(cycloalkylalkyl), -NHC(0)(aryl), -NHC(0)(aralkyl), -(CH^NH% -6 alkyl), -(CH2)NH(aralkyl), _(CH2)NH( Heterocyclylalkyl), NHSCMCu alkyl), -NHS02 (C3_6 cycloalkyl), -NHS02 (cycloalkylalkyl), -nhso2 (aryl), -nhso2 (aralkyl), -S02NH (Ch Alkyl), -S〇2NH(C3_6cycloalkyl), -S〇2NH(cycloalkylalkyl), -S〇2NH(aryl) or -S〇2NH(aralkyl), wherein each q The -6 alkyl group, the c3_6 cycloalkyl group, the cycloalkylalkyl group, the aryl group and the aralkyl group are substituted or unsubstituted. 53. The compound of claim 50, wherein R2 is F, -CN, _CF3, -C(0)NH2, ((0)ΝΗ((^_6 alkyl), -C(0)NH(C3_6 cycloalkyl) )[〇], -C(0)NH(cycloalkylalkyl)[〇] '-(CHJNHdsalkyl), -(CH2)NH(heterocyclylalkyl), -NHSCMChalkyl) or -Sc ^n^Ch alkyl) wherein each Cl-6 alkyl, cycloalkyl and cycloalkylalkyl group is substituted or unsubstituted. 54. The compound of claim 50, wherein r3 is substituted or unsubstituted 123505 -15-200815422 alkyl or -CXCi-4 alkyl, or partially or fully halogenated-CKCi _2 alkyl). 55. The compound of claim 34, wherein L2 is a bond, CH20, C(O), C(0)0, C(0)NH, C(0)NHNH, C(NOR) or C(CH3)2C (0)NH, and Q is 56. 如請求項55之化合物，其中B與D為N。 57. 如請求項56之化合物，其中G為苯基。 58. 如請求項34之化合物，其中在10 濃度下之化合物會抑 制自細胞所引致之TNFa-釋出，達約50%或大於50%。 123505 -16- 200815422 59.種組合物，其包含如請求項6或％之化合物，及藥 可接受之載劑。 ”予 6〇·種^睛求項6或34之化合物於藥劑製造上之用途，該单 劑係用於治療藉由細胞素所媒介之病症。 ' 61·^求項6G之用途，其中細胞素所媒介之病症為風濕性關 :炎、骨關節炎、克隆氏病、潰瘍性結腸炎、牛皮癖關節 火外傷性關節炎、風疹關節炎、炎性腸疾病、多發性硬 化、移植物對宿主疾病、系統性紅斑狼瘡、毒性休克徵候 族、刺激性腸徵候簇、肌肉退化、同種移植排斥、胰腺炎、 夷島X 、、糸球體性腎炎、糖尿病患者之腎病、腎纖維變性、 悛性腎衰竭、痛風、麻風、急性滑膜炎、賴透氏徵候簇、 痛ϋΠ生關節炎、Behcet氏疾病、脊椎炎、子宮内膜組織異 位形成、非關節炎性症狀、急性或慢性疼痛、中風、慢性 心臟衰竭、内毒血症、再灌注損傷、絕血再灌注、心肌絕 血、再狹窄、血栓形成、血管生成、冠狀心臟疾病、冠狀 動脈疾病 '急性冠狀徵候簇、Takayasu動脈炎、心力衰竭、 高膽固醇血、相關於血液凝固或血纖維蛋白溶酶作用之疾 病或症狀、動脈粥瘤硬化、過敏性結合膜炎、葡萄膜炎、 青光眼、視神經炎、視網膜絕血、糖尿病患者之視網膜病、 雷射所引致之視覺傷害 '手術或外傷所引致之增生性玻螭 體視網膜病、過敏性鼻炎、氣喘、成人呼吸困難徵候蔟、 慢性肺發炎、慢性阻塞肺病、閉塞性細枝氣管炎、氣腫、 枝氣管炎、黏液過度分泌、矽土沉著病、SARS感染、呼 吸道發炎、牛皮癬、天疱瘡、濕疹、異位性皮炎、接觸性 123505 -17- 200815422 皮膚炎、痤瘡、Guillain-Barre徵候簇、巴金生氏病、亨丁頓 氏病、阿耳滋海默氏病、肌萎縮性側索硬化、多發性硬化、 髓鞘脫失病、病毒腦膜炎、細菌腦膜炎、CNS損傷、脊髓 才貝傷、發作、搐搦、橄欖體橋腦小腦萎縮、AIDS癡呆症複 徵、ME響徵候簇、MELAS徵候簇、氏疾病、偏-氏腦病、Rett徵候簇、高半胱胺酸尿、高脯胺酸血症、血 咼半胱胺酸過多、非酮病高甘胺酸血症、經丁酸胺基酸 (尿、亞硫酸鹽氧化酶缺乏、合併之系統疾病、鉛中毒性腦 病、Tourett氏徵候簇、肝腦病 '藥瘾、藥物耐藥性、藥物 依賴丨生抑營、焦慮、精神分裂症、動脈瘤、癲癇、糖尿 病、系統惡病質、感染或惡性病症之續發性惡病質、惡病 質所續發之後天免疫不全徵候簇、肥胖、神經性厭食、貪 食神經質、骨質耗損疾病、骨質石化病、骨質疏鬆症、敗 血病、HIV感染、HCV感染、瘧疾、感染性關節炎、利什 曼病、Lyme疾病、癌症、Castleman氏疾病或抗藥性。 〔62·如請求項6〇之用途，其中細胞素所媒介之病症為風濕性關 節炎、骨關節炎、克隆氏病、潰瘍性結腸炎、炎性腸疾病、 糖尿病、牛皮癬關節炎、牛皮癬' 天癌瘡、慢性阻塞肺病、 疼痛、動脈粥瘤硬化、絕血再灌注、再狹窄、急性冠狀徵 候鎮、心臟衰竭、多發性骨髓瘤、濾胞淋巴瘤或骨肉瘤。 63·如請求項60之用途，其中細胞素所媒介之病症為嗜中性白 金球所媒介之病症。 64·如請求項63之用途，其中嗜中性白血球所媒介之病症為枝 氣官性氣喘、鼻炎、流行性感冒、中風、心肌梗塞、熱損 123505 -18- 200815422 傷、成人呼吸困難徵候簇（ARDS)、創傷續發之多重器官傷 害、急性絲球體性腎炎、具有急性炎性成份之皮膚病、急 性含膿腦膜炎，血液透析、白血球電泳、粒性血球輸血有 關聯之徵候簇，或壞死性小腸結腸炎。 65·如請求項60之用途，其中細胞素係選自、il-1、IL_6、 IL-8、GM-CSF、IFN- r或其任兩種或多種之組合。 66·如请求項60之用途，其中病症係為或由於以下所造成，異 常出血、膿腫、光化網狀徵候簇、急性混亂偏頭痛、急性 混亂老年癡呆症、急性肝細胞損傷、急性管狀壞死、垂體 腺性部疾病、腺病毒感染、黏連物、黏連囊炎、子宮附件 炎、無7球蛋白血症、過敏反應、禿髮、纖維化肺胞炎、 澱粉樣變性病、血管造形術、狹心症、抗磷脂徵候簇、動 脈硬化癡呆症、顳動脈炎、節肢動物先天性腦炎、窒息、 異位過敏性、心房纖維顫動、海狸熱、膽硬化、骨質耗損、 細枝氣官炎、内分泌腺癌、喉癌、念珠菌病、小細胞肺癌、 心臟肥大、心臟手術、心臟擴大、心臟炎、頸動脈血管造 形術、頸動脈内膜切除術、頸動脈支架、頸動脈潰瘍、腹 腔疾病、肝硬化、結腸炎、結腸炎肉芽腫、冠狀動脈分流 私植、越狀動脈分流手術、皮質白内障、皮質類固醇抗藥 性氣喘、變性關節疾病、皮膚炎、腹瀉 '勃起神經病、勃 起脈官病、眼乾、脂血症障礙、呼吸困難、水腫、末期腎 病、支氏噸-巴爾（Epstein-Barr)病毒感染、發熱、濾胞曱狀腺 癌瘤、月腸炎、心臟病發作、心臟分流手術、心臟手術、 ^臟移植、A型肝炎、b型肝炎、c型肝炎、慢性肝炎、 123505 -19- 200815422 胰島素抗藥性、腎力衰竭、腎臟移植、成人慢性白血病、 肝硬化、肝臟移植、腦膜炎、細菌腦膜炎、骨髓增生病症、56. The compound of claim 55, wherein B and D are N. 57. The compound of claim 56, wherein G is phenyl. 58. The compound of claim 34, wherein the compound at 10 concentrations inhibits TNFa-release from the cell by up to about 50% or greater than 50%. 123505 -16- 200815422 59. A composition comprising a compound of claim 6 or %, and a pharmaceutically acceptable carrier. The use of a compound of the formula 6 or 34 for the manufacture of a medicament for the treatment of a condition mediated by a cytokine. The use of the 6G, wherein the cell The disease of the media is rheumatic: inflammation, osteoarthritis, Crohn's disease, ulcerative colitis, psoriasis joint fire traumatic arthritis, rubella arthritis, inflammatory bowel disease, multiple sclerosis, graft pair Host disease, systemic lupus erythematosus, toxic shock syndrome, irritating intestinal syndrome, muscle degeneration, allograft rejection, pancreatitis, Yidao X, sputum glomerulonephritis, kidney disease in diabetic patients, renal fibrosis, spastic kidney Failure, gout, leprosy, acute synovitis, Reed's syndrome, arthritis, Behcet's disease, spondylitis, ectopic endometrial tissue formation, non-arthritic symptoms, acute or chronic pain, stroke , chronic heart failure, endotoxemia, reperfusion injury, apoplexy reperfusion, myocardial ischemia, restenosis, thrombosis, angiogenesis, coronary heart disease, coronary artery disease 'acute crown Symptoms, Takayasu arteritis, heart failure, hypercholesterolemia, diseases or symptoms associated with blood clotting or plasmin, atherosclerosis, allergic conjunctivitis, uveitis, glaucoma, optic neuritis, Retinal blood vessels, retinopathy of diabetic patients, visual damage caused by laser 'proliferative vitreous retinopathy caused by surgery or trauma, allergic rhinitis, asthma, adult dyspnea syndrome, chronic lung inflammation, chronic obstruction Lung disease, occlusive trochanteric bronchitis, emphysema, bronchitis, excessive mucus secretion, stagnation, SARS infection, respiratory inflammation, psoriasis, pemphigus, eczema, atopic dermatitis, contact 123505 -17- 200815422 Dermatitis, acne, Guillain-Barre syndrome, Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, myelin sheath loss, viral meninges Inflammation, bacterial meningitis, CNS injury, spinal cord injury, seizures, sputum, olive pons cerebellar atrophy, AIDS dementia relapse, ME stagnation Cluster, MELAS syndrome, disease, partial-encephalopathy, Rett syndrome, homocysteine, hyperglutaemia, hyperactivity of cysteine, non-ketotic hyperglycemia, Amino acid butyrate (urine, sulfite oxidase deficiency, combined systemic diseases, lead toxic encephalopathy, Tourett's syndrome, hepatic encephalopathy' drug addiction, drug resistance, drug dependence, inhibition, anxiety , schizophrenia, aneurysm, epilepsy, diabetes, systemic cachexia, recurrent cachexia of malignant disease, cachexia, post-immune insufficiency syndrome, obesity, anorexia nervosa, bulimia, bone loss disease, bone Petrochemical disease, osteoporosis, septicemia, HIV infection, HCV infection, malaria, infectious arthritis, leishmaniasis, Lyme disease, cancer, Castleman's disease or drug resistance. [62. The use of claim 6 wherein the cytokine-mediated condition is rheumatoid arthritis, osteoarthritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, diabetes, psoriatic arthritis, psoriasis' Ascites, chronic obstructive pulmonary disease, pain, atherosclerosis, arrhythmia reperfusion, restenosis, acute coronary syndrome, heart failure, multiple myeloma, squamous lymphoma or osteosarcoma. 63. The use of claim 60, wherein the condition mediated by cytokines is a condition mediated by neutrophils. 64. The use of claim 63, wherein the condition mediated by neutrophils is stagnation, rhinitis, rhinitis, influenza, stroke, myocardial infarction, heat loss 123505 -18- 200815422 injury, adult dyspnea syndrome (ARDS), multiple organ injury with traumatic recurrence, acute spheroid nephritis, skin disease with acute inflammatory components, acute purulent meningitis, hemodialysis, leukocyte electrophoresis, granulocyte hematocrit-related syndrome, or Necrotizing enterocolitis. 65. The use of claim 60, wherein the cytokine is selected from the group consisting of il-1, IL-6, IL-8, GM-CSF, IFN-r, or a combination of any two or more thereof. 66. The use of claim 60, wherein the condition is or due to the following, abnormal bleeding, abscess, actinic reticular syndrome, acute confusion migraine, acute confusion, Alzheimer's disease, acute hepatocyte injury, acute tubular necrosis , pituitary gland disease, adenovirus infection, adhesions, bursitis, uterine annexitis, no 7 globulinemia, allergic reactions, alopecia, fibrotic pulmonary cytoatosis, amyloidosis, angiogenesis Surgery, sciatic syndrome, antiphospholipid syndrome, arteriosclerosis dementia, temporal arteritis, arthropod congenital encephalitis, asphyxia, ectopic hypersensitivity, atrial fibrillation, beaver fever, biliary sclerosis, bone loss, twig gas Guanyan, endocrine adenocarcinoma, laryngeal cancer, candidiasis, small cell lung cancer, cardiac hypertrophy, cardiac surgery, cardiac enlargement, carditis, carotid angioplasty, carotid endarterectomy, carotid stent, carotid ulcer , celiac disease, cirrhosis, colitis, colitis of colitis, coronary artery shunt, vaginal shunt surgery, cortical cataract, corticosteroid resistance Asthma, degenerative joint disease, dermatitis, diarrhea, erectile neuropathy, erectile pulse disease, dry eye, lipodystrophy, dyspnea, edema, end stage renal disease, Epstein-Barr virus infection, fever, Filtered squamous adenocarcinoma, colitis, heart attack, cardiac bypass surgery, cardiac surgery, visceral transplantation, hepatitis A, hepatitis B, hepatitis C, chronic hepatitis, 123505 -19- 200815422 insulin resistance, kidney Depletion, kidney transplantation, adult chronic leukemia, cirrhosis, liver transplantation, meningitis, bacterial meningitis, myeloproliferative disorders, 肌病、肌炎、新生兒展開之多系統炎性疾病、t炎、神經 肌肉病症、神經病、閉塞性細枝氣管炎、口腔癌、經皮冠 狀；|入回周膜骨質耗損、末梢神經病症、神經病、腹膜 參析、胸膜疾病、肺炎、多肌炎、後囊混濁、播疼病、肺 ，截維艾性、腎癌、腎渗析、硬皮病、敗企性關節炎、习〇群邱 2徵候簇、關節黏連脊椎炎、Still氏疾病、交感性眼炎、 毒血症、結核病、蓴麻疹、病毒肝炎或Wegener氏肉芽腫病。 67.-種細胞素抑制劑於藥劑製造上之用途，該藥劑係用於降 低細胞素之含量，相對於投予藥劑前之含量，其中細胞素 抑制劑為如請求項6或34之化合物。 月求貝67之用途，其中細胞素係選自顶…丄 IL-8、GM_CSF、聰_ y或其任兩種或多種之組合^ 69. —種活體外方法，其包 制劑，1係有#^ 曝路至一數置之細胞素抑 人旦： 降低、，、田胞回應預發炎刺激所釋出之細胞素 :::相：於使細胞與細胞素抑制劑接觸前所釋出細胞素 % 一^㈣ΓΓ素抑制劑為如請求項6或34之化合物。 之包括使P38與有效抑制P38活性、- 料“丨《兩者之-數量細胞素抑制劑接觸，其中細 料抑制劑為如請求項6或34之化合物。 … 71· —種細胞素抑制劑於 低預發炎介劑係用於降 ^於技予樂劑前之活性，JL中细 胞素抑制劑為如請求項6或34之化合物。 -中、，田 123505 •20- 200815422 \種細胞素抑制㈣藥劑製造上之用途，該藥劑係在血液 一降低c-反應性蛋白質或類風濕因子或兩者之循環含 f，相對於投予藥劑前之含量，其中細胞素抑制劑為如請 求項6或34之化合物。 3·種如明求項6或34之化合物於藥劑製造上之用途，該藥 ^係用於增加病患之HDL·含量，相對於投予藥劑前之含 f 74.一種如請求項6或34之化合物於藥劑製造上之用途，該藥 劑係在顯示一或多種風濕性關節炎標記之病患中，降低風 “性關即火之至少—種標記至低於投予該藥劑前所存在 之含量。 75. 藥劑製造上之用途，該藥 ’相對於投予藥劑前之含 一種如請求項6或34之化合物於 剤係用於增加病患之Apo-Al-含量 量°Myopathy, myositis, multiple systemic inflammatory diseases, t-inflammatory, neuromuscular disorders, neuropathy, occlusive trochanteric bronchitis, oral cancer, percutaneous coronary; | perimembranous bone loss, peripheral nerve disorders, Neuropathy, peritoneal analysis, pleural disease, pneumonia, polymyositis, posterior capsule opacification, soreness, lung, cut-off, kidney cancer, renal dialysis, scleroderma, septic arthritis, Xi Yuqun 2 syndrome, joint adhesion spondylitis, Still's disease, sympathetic ophthalmia, toxemia, tuberculosis, urticaria, viral hepatitis or Wegener's granulomatosis. 67. Use of a cytokine inhibitor for the manufacture of a medicament for reducing the content of a cytokine relative to the amount prior to administration of the medicament, wherein the cytokine inhibitor is a compound of claim 6 or 34. The use of Bayer 67, wherein the cytokine is selected from the group consisting of 顶IL-8, GM_CSF, Cong_y or a combination of two or more thereof. 69. In vitro method, package preparation, 1 line #^ Exposure to a number of cytokine inhibitors: Reduce,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, The %%-(tetra) quinone inhibitor is a compound as claimed in claim 6 or 34. This includes contacting P38 with an effective inhibitor of P38 activity, which is said to be in contact with a cytokine inhibitor, wherein the fines inhibitor is a compound as claimed in claim 6 or 34. The low pre-inflammatory mediator is used to reduce the activity before the technical agent, and the cytokine inhibitor in JL is the compound of claim 6 or 34. - Zhong, Tian Tian 123505 • 20- 200815422 Inhibiting (4) the use of the medicament for the manufacture of a medicament for reducing the c-reactive protein or rheumatoid factor or both of the blood in the blood, relative to the amount before administration of the medicament, wherein the cytokine inhibitor is as claimed a compound of 6 or 34. 3. The use of a compound according to claim 6 or 34 for the manufacture of a medicament for increasing the HDL content of a patient relative to the pre-administration of the medicament f 74. A use of a compound according to claim 6 or 34 for the manufacture of a medicament for reducing the risk of at least one of the markers of the wind in a patient exhibiting one or more markers of rheumatoid arthritis The amount present before the administration of the agent. 75. The use of a medicament for the manufacture of a medicament comprising a compound according to claim 6 or 34 prior to administration of the medicament for increasing the Apo-Al content of the patient. 76· 一種製備如請求項6之化合物之方法 化合物 此方法包括使式III76. A method of preparing a compound according to claim 6 Compounds This method comprises making Formula III 式III 與（1) G-COOH，於偶合劑與鹼存在下，·或 與⑻G-CO-Z，於驗存在下接觸； ，、〒琢接觸係在適合提供式；!化合物之條件下發生； v g如式I中之定義，且Z 123505 -21 - 200815422 為活化部份基團。 77. 一種製備如請求項6之化合物之方法，此 ⑴使式IIIB化合物 /会包括Formula III and (1) G-COOH, in the presence of a coupling agent and a base, or with (8) G-CO-Z, in contact with the test; and the ruthenium contact system occurs under conditions suitable for providing the compound; ; vg is as defined in formula I, and Z 123505 -21 - 200815422 is an activating moiety. 77. A process for the preparation of a compound of claim 6 wherein (1) a compound of formula IIIB is included ( 與G-NH2，於偶合劑與鹼存在下接觸；或 (ii)使式IIIC化合物(contacting G-NH2 in the presence of a coupling agent with a base; or (ii) bringing a compound of formula IIIC Q 2 &quot; i... 與G-NH2,於驗存在下接觸，其中該接觸係在適合提供 化合物之條件下發生，其中A、X、y、r、L2、q&amp;、g 如式I中之疋義，且Z為活化部份基團。 78. —種製備如請求項34之化合物之方法，此方法包括使式 化合物 2'Q h2nQ 2 &quot; i... is in contact with G-NH2 in the presence of a test, wherein the contact occurs under conditions suitable for providing a compound, wherein A, X, y, r, L2, q&amp;, g are as in Formula I In the meantime, and Z is an activating moiety. 78. A method of preparing a compound of claim 34, which comprises making a compound 2'Q h2n A 式IV 丄π 與（i) G-COOH，於偶合劑與鹼存在下；或 與（11) G-CO-Z，於鹼存在下接觸； 123505 -22- 200815422 /、A、B、D、X、Y、R、L2、Q及G均如式„中之定 義，且Z為活化部份基團。 79·-種製備如請求項34之化 枝 ⑺使式㈣化合物 此方法包括A Formula IV 丄π and (i) G-COOH, in the presence of a coupling agent and a base; or with (11) G-CO-Z, in the presence of a base; 123505 -22- 200815422 /, A, B, D , X, Y, R, L2, Q, and G are all as defined in the formula, and Z is an activating moiety. 79.- Preparation of the compound of claim 34 (7) to make the compound of formula (IV) This method includes 該接觸係在適合提供式11化合物之條件下發生； 式IVB 與 G-NB ’於偶合劑與鹼存在下接觸；或 ⑼使式IVC化合物The contacting occurs under conditions suitable for providing a compound of formula 11; formula IVB is contacted with G-NB' in the presence of a coupling agent with a base; or (9) is a compound of formula IVC 式IVC 與〇姻2,於驗存在下接觸，其中該接觸係在適合提供❹ 化合物之條件下發生；其中a、b、d、x、y、r、g、 Q及G均如式II中之定義，且z為活化部份基團。 8〇·—種製備式V化合物之方法 〇2NV^N^Ar， 式V 此方法包括使式VI化合物 123505 -23 - 200815422 /Ar， 式VI /、硝基丙一醛鈉鹽接觸，其中該接觸係在適合提供式v 化合物之條件下發生；其中 心為5或6-員芳無或雜芳族基團，視情況被L3々取代； 界為&lt;^-6烷基或環烷基； L3 為共價鍵、CH2〇、C(〇)、c(〇)〇、（CR2)mC(〇)NR、 C(0)NRNR、C(NOR)或 ^^(0)0 基團； Q為氫、經取代或未經取代之烷基、環烷基、芳基、雜 環基、芳烷基或雜環基烷基；且 各R係獨立為氫或經取代或未經取代院基。 81· —種式VII化合物Formula IVC is contacted with Amaranth 2 in the presence of a test wherein the contact occurs under conditions suitable for the supply of a hydrazine compound; wherein a, b, d, x, y, r, g, Q and G are as in Formula II Definition, and z is an activating moiety. 8〇· a method for preparing a compound of formula V 2NV^N^Ar, formula V This method comprises contacting a compound of formula VI 123505 -23 - 200815422 /Ar, a salt of formula VI /, nitropropanone, wherein The contact system occurs under conditions suitable for the compound of formula v; the center is a 5 or 6-membered aromatic or heteroaromatic group, optionally substituted by L3?; the boundary is &lt;^-6 alkyl or cycloalkyl L3 is a covalent bond, CH2〇, C(〇), c(〇)〇, (CR2)mC(〇)NR, C(0)NRNR, C(NOR) or ^^(0)0 groups; Q is hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl or heterocyclylalkyl; and each R is independently hydrogen or substituted or unsubstituted base. 81·—Formula VII compound 式VII 其中 Hal 為 Cl、Br 或 I ; T 為 〇 或（CH2)n ; ^為11，或經取代或未經取代之烷基、芳烷基或雜環烷 基；且 η為0，1或2。 82· —種式VIII化合物 123505 •24- 200815422Wherein Hal is Cl, Br or I; T is hydrazine or (CH2)n; ^ is 11, or a substituted or unsubstituted alkyl, aralkyl or heterocycloalkyl group; and η is 0,1 Or 2. 82·—Formula VIII compound 123505 •24- 200815422 V Ο 式 VIII 其中 τ 為 Ο 或（CH2 )η ; U 為 F、Cl、m 比、CN、-S02NR’2、-C(0)NR，2*-NRfS02R，，； ί V 為-〇(Cl-6烷基）； Rm為H ’或經取代或未經取代之烷基、芳烷基或雜環烷 基； 各R係獨立為氫，或經取代或未經取代之烷基、芳烷 基、雜環基或雜環基烷基； 各R”係獨立為經取代或未經取代之烷基、芳基、雜環 基、芳烷基或雜環基烷基；且 η為0, 1或2。 Κ 83· —種式IX化合物V Ο where τ is Ο or (CH2)η; U is F, Cl, m ratio, CN, -S02NR'2, -C(0)NR, 2*-NRfS02R,,; ί V is -〇( Cl-6 alkyl); Rm is H ' or substituted or unsubstituted alkyl, aralkyl or heterocycloalkyl; each R is independently hydrogen, or substituted or unsubstituted alkyl, aryl An alkyl group, a heterocyclic group or a heterocyclic alkyl group; each R" is independently substituted or unsubstituted alkyl, aryl, heterocyclic, aralkyl or heterocyclylalkyl; and η is 0 , 1 or 2. Κ 83· - a compound of formula IX Η 式IX 其中 Τ為（C2-6)烷基或環烷基，視情況經部份或完全_化； U 為-CN、-S〇2NRf2 或-NR，S02R” ； 各R|係獨立為氫’或經取代或未經取代之烷基、芳烷 123505 -25- 200815422 基、雜環基或雜環基烷基； 各R&quot;係獨立為經取代或未經取代 — 之烷暴方基、雜環 基、芳烷基或雜環基烷基；且 ΡΝ為Η或胺保護基。 84· —種化合物，其係選自： 3-第三_丁基_5_氰基具(6·曱基·5_(3·(新戊基胺甲醯基）苯 基比啶-3-基）苯甲醯胺； f Ν_(5-(4-(苄氧基）苯基）各甲基吡啶_3_基）_3_第三·丁 基笨甲醯胺·， 一土…鼠 3-第三-丁基氰基-Ν_(5-(4_(3,3_二甲基_2_酮基丁氧基）苯 基）冬甲基吡啶基）苯曱醯胺； 醋酉文4 (5-(5-第二-丁基-2-甲氧基苯甲醯胺基）-2•甲基吡啶 I基）苯酯； 3-第三-丁基_5_氰基_N_(5_(4_甲氧基_2_甲基苯基甲基吡 唆_3-基）苯甲醯胺； 3-第三-丁基_5_氰基_N-(6-甲基_5_(4_(新戊基胺甲醯基）苯 基比啶-3-基）苯甲醯胺； 3-氟_N-(6-甲基_5_(4_(新戊基胺甲醯基）苯基）_吡啶各基）_5_ 嗎福啉基苯甲醯胺； 3第—'&quot;丁基-5-氰基-N-(6-甲基-5-(4-(四氫-2H_喊喃冰基胺 甲酿基）苯基）吡啶-3-基）苯甲醯胺； 3鼠N-(5-(4-甲氧苯基）_6_甲基u比σ定-3·基）-5-嗎福琳基苯甲 醯胺； N-(5-(4-乙酿基笨基）各甲基吡啶各基&gt;5_第三叮基各氰基 123505 -26- 200815422 -2-甲氧基苯甲醯胺； 3-(胺基f基）-5_第三-丁基-N-(5-(4-(l-羥乙基）苯基）各甲基 吡啶_3_基）-2·甲氧基苯甲醯胺； 5-第三丁基-3-(N-羥基碳胺基亞胺基）-Ν-(5-(4-(1-(羥亞胺 基）乙基）苯基）-6-甲基吡啶-3-基）-2-甲氧基苯甲醯胺； 5 -(3-弟二-丁基-5-氰基苯甲醯胺基）-2’·甲基_N-((四氫吱喃 -2-基）甲基）-2,3’-聯峨唆-5-羧隨胺； 5’-(3-第三·丁基-5-氰基苯甲醯胺基）-2，-甲基((四氫呋喃 -2·基）甲基）-3,31^聯p比咬-6_羧醢胺； 弟二-丁基-5_氰基-N-(6-甲基-5-(4-(六氫π比咬-1-基胺曱醢 基）苯基）吡啶-3-基）苯曱醯胺； 3-第三-丁基-5-氰基_Ν_(6·甲基-5-(4-(N-新戊基胺磺醯基）苯 基）吡啶-3-基）苯甲醯胺； i-(5_(3-氟基-5-嗎福啉基苯甲醯胺基）-2-甲基吡啶-3-基）_N-((四氫呋喃-2-基）曱基）-1Η-1，2,3-三唑-4-羧醯胺； N-(5-(4-第三-丁基-1Η·1，2,3_三唑小基）各甲基吡啶-3-基）-3-氟基-5-嗎福啉基苯甲醯胺； 3-氟-N-(6-曱基-5-(4-(吡啶-2-基）-1Η-1，2,3-三唑-1-基）吡啶-3-基）-5-嗎福啉基苯曱醯胺； 3-氟-N-(5-(4-(甲氧基甲基）-1Η-1，2,3-三唑-1-基）-6-甲基吡啶 -3-基）-5-嗎福啉基苯甲醯胺； H5-(3-第三-丁基-5-氰基苯甲醯胺基）-2-曱基吡啶-3-基）-N-新戊基-1Η-1，2,3·三唑-4-羧醯胺； 3_第三-丁基-5-氰基 _Ν-(6-曱基-5-(4-(3-曱基 丁醯基）_1Η·1，2,3- 123505 -27- 200815422 三唑小基）吡啶-3-基）苯甲醯胺； (Z)-3-第三-丁基-5-氰基-N-(5-(4-(l-(羥亞胺基）-3-曱基丁 基）-111-1，2,3-三°坐-1-基）_6_甲基峨唆-3-基）苯甲酸胺； 3-第三·丁基-5-氰基-N-(6-甲基-5-(4-(2-甲基-1-(新戊基胺 基）-1-8同基丙烧-2-基）-1Η-1，2,3·三唾小基）外1:唆·3-基）苯曱醯胺； Ν-(3-第三-丁基-5-氰基苯基）-6-甲基-5-(4-(新戊基胺甲醯 基）_1H_1，2,3·三α坐_1_基）終驗酿胺； Ν-(6-曱基-5-(4-(新戊基胺甲醯基）-ΐΗ-1，2,3·三唑-1-基）,比啶 -3-基）-2-嗎福琳基異於鹼醯胺； Ν-(6·甲基-5-(4-(新戊基胺甲醯基hh-UJ-三唑-1_基）p比啶 -3-基）-2-(六氫吡啶-1_基）異菸鹼醯胺； 3_氟-N-(6_甲基-W新戊基胺甲醯基）苯基 &gt;比啶·3_基 嗎福啉基苯甲醯胺； 3-第三·丁基-5-氰基1(5-(3-(二甲基胺甲醯基）苯基）冬甲 基吡啶-3_基）苯甲醯胺； 1-(5-(5-第三-丁基1甲氧基苯甲醯胺基）_2_甲基吡啶-3-基）新戊基-1H-1，2,3_三唾_4_羧醯胺； Η5-(3·氟基-5-嗎福啉基苯甲醯胺基）-2-甲基吡啶各基）孙 新戊基-1Η-1，2,3-三唑冰羧醯胺； 5_第三-丁基1甲氧基-Ν-(5-(6-甲氧基莕-2-基）-6-甲基毗啶 -3-基）苯甲醯胺； 3_第三-丁基氰基-Ν_(5_(3·(3,3_二甲基丁醯胺基）苯基）各 甲基p比唆-3-基）苯甲酿胺； N-(2,6fc甲基-3,4’-聯吡啶_5_基&gt;3-氟基-5_嗎福啉基苯甲醯 123505 -28 - 200815422 胺； 3-第三-丁基-5-氰基-N-(2,6，-二甲基-3,4，_聯吡啶_5•基）笨甲 醯胺； 3-氟_N-(5-(4-甲氧基各甲基苯基）冬甲基吡啶_3_基）_5_嗎护 啉基苯曱醯胺； $ N-(5-(4-乙醯基苯基）-6-甲基吡啶-3-基）-5-第三-丁基_2-甲氧 基苯曱醯胺； N-(5-(4-乙醯基苯基）-6-甲基吡啶-3-基）-5-第三-丁基甲氧 基-3-(甲基磺醯胺基）苯甲醯胺； N-(5-(4-乙醯基苯基）-6-甲基吡啶-3_基）-3_氟基净嗎福啉基 苯甲醯胺； N-〇(4_(爷基胺甲醯基）苯基）-6_甲基吡啶_3_基）_5_第三-丁 基-2-甲氧基苯甲醯胺； 5-第三-丁基-Ν-(5·(4-(3,4-二甲氧基苄基胺甲醯基）苯基）各 甲基吡啶-3-基）-2-甲氧基苯甲醯胺； 5-第三-丁基-2-甲氧基·Ν-(5-(4_(3_曱氧基苄基胺甲醯基）苯 基）各甲基吡啶-3-基）苯甲醯胺； Ν-(5-(4-(芊基胺曱醯基）苯基）_6-甲基吡啶|基&gt;3_氟基-5_ 嗎福12林基苯甲酿胺； Ν-(5-(4-(3,5-二甲氧基芊基胺甲醯基）苯基）-6_甲基吡啶各 基）-3-氟基-5-嗎福琳基苯甲醯胺； 3-氟-N-(5-(4-(3-甲氧基苄基胺甲醯基）苯基）冬曱基峨σ定-3-基）-5-嗎福淋基苯甲醯胺； 3-氟-N-(5-(4-(4-甲氧基苄基胺曱醯基）苯基）_6_曱基吡啶冬 123505 -29- 200815422 基）_5_嗎福啉基苯曱醯胺； N-(5-(4-(苯并[d][l，3]二氧伍圜烯_5_基曱基胺曱醯基）苯 基）·6-甲基叶b咬-3-基）·3-氟基-5-嗎福琳基苯曱龜胺； 1-(5-(3-氟基-5-嗎福琳基苯甲醯胺基）_2-曱基吡啶-3-基）-N七比啶斗基甲基）_1Η_1，2,3·三唑斗羧醯胺·， 1-(5-(3_氟基-5-嗎福啉基苯甲醯胺基）_2_甲基吡啶基）-Ν-異丁基-1Η-1，2,3-三唾-4-魏醯胺； Ν-(環丙基甲基）小(5-(3-氟基-5-嗎福啉基苯甲醯胺基）-2-甲 基外1；°定-3-基）-111-1，2,3-三°坐-4_緩醯胺； 1-(5-(3-氟基-5-嗎福啉基苯甲醯胺基甲基吡啶各 基）-队(3,3,3-三氟丙基）-lH-l，2,3-三。坐冰魏醯胺； 3-氟-Ν·(6-曱基-5-(4-((四氫_2Η·哌喃冰基）甲基胺甲醯基）苯 基 &gt;比啶_3_基）-5-嗎福琳基苯甲醯胺； 3-氟-N-(6-甲基-5-(4-((四氫呋喃-2-基）甲基胺甲醯基）苯基） 吡啶-3-基）-5-嗎福啉基苯甲醯胺； 5_第三丁基-N_(5-(4_(3,5-二甲氧基苄基胺甲醯基）苯基）_6-甲基吡啶-3-基）-2-甲氧基苯甲醯胺； N-(5-(4-(苯并[d][l，3]二氧伍圜烯-5-基甲基胺曱醯基）苯 基）-6-曱基吡啶-3-基）-5-第三-丁基冬甲氧基苯甲醯胺； 5-第三-丁基_2_甲氧基-N_(6-甲基-5-(4-〇比咬-3·基甲基胺甲 醯基）苯基）吡啶-3-基）苯甲醯胺； 5·第三-丁基甲氧基_N-(6-甲基-5-(4-(四氫·2Η-哌喃-4-基 胺甲醯基）苯基）吡啶-3-基）苯甲醯胺； 弟二-丁基-2-甲氧基-Ν-(6-甲基-5-(4-((四氫-2Η·喊喃-4-基） 123505 -30- 200815422 甲基胺甲醯基）苯基）吡啶_3_基）苯曱醯胺； 5-第二-丁基-2·甲氧基-Ν·(6-甲基-5-(4-((四氫呋喃-2·基）甲 基胺甲醯基）苯基）吡啶各基）苯甲醯胺； Ν·(5-(4-(3,4-二甲氧基苄基胺甲醯基）苯基）各甲基吡啶冬 基）-3-氟基-5-嗎福啉基苯甲醯胺； 3H(6·甲基·5-(4-〇比啶-3-基甲基胺甲醯基）苯基风啶-3-基）-5-嗎福淋基苯甲醯胺； r 4-((4-(5-(5-第三-丁基-2-甲氧基苯甲醯胺基）-2-甲基吡啶-3- \ 基）苯曱醯胺基）甲基）苯甲酸甲酯； 3- 氟-N_(6_甲基-5-(4-(四氫_2H-哌喃斗基胺甲醯基）苯基）峨 °定-3-基）-5-嗎福淋基苯甲醯胺； 4- ((4-(5_(3-鼠基-5-嗎福p林基苯曱酿胺基）-2-甲基p比咬-3-基） 苯甲醯胺基）甲基）苯甲酸甲酯； 第二·丁基-5-氣基-N-(6-甲基-5-(4_((四氫咬喃_2-基）甲基 胺甲醯基）苯基）吡啶-3-基）苯甲醯胺； I 3-弟二'丁基-5-乱基-Ν-(6·甲基-5-(4-((四氮-2H-喊喃-4-基）曱 基胺甲醯基）苯基）吡啶-3-基）苯甲醯胺； Ν-(5-(4·(苄基胺甲醯基）苯基）-6-甲基吡啶-3-基）各第三·丁 基-5-氰基苯甲醯胺； 1-(5-(3-氟基-5-嗎福啉基苯甲醯胺基）-2-甲基吡啶-3-基）-N，N-二甲基-1H]，2,3-三唑-4-羧醯胺； 1-(2-甲基-5-(3-嗎福啉基-5-(三氟甲基）苯甲醯胺基）吡啶-3-基）-N-新戊基-1Η·1，2,3-三唑-4-羧醯胺； 1-(2-甲基-5-(3-(四氫吡咯-1_基）-5-(三氟甲基）_苯甲醯胺基） 123505 -31 - 200815422 吡啶-3-基）-N-新戊基-1Η-1，2,3-三唑斗羧醯胺； 1-(5-(3-1基-5-(六氫ρ比u定小基）苯甲醯胺基）-2-曱基外b唆-3«· 基）-N·新戊基-1H-1，2,3-三唾-4-叛醯胺； H5-(3-氟基·5-(四氫吡咯小基）苯甲醯胺基）-2-甲基吡啶-3-基）-N-新戊基-1H-1，2,3-三唑-4-羧醯胺； 1-(5-(3-氟基-5-嗎福啉基苯甲醯胺基）-2-甲基吡啶I 基）-N-(2-甲基丁基）-1Η-1，2,3-三唑-4-羧醯胺； N-(環己基甲基）-l_(5-(3-氟基_5_嗎福啉基苯曱醯胺基）-2-甲 基吡啶-3-基）-111-1，2,3-三唑-4-羧醯胺； 1-(5-(3-氟基-5_嗎福p林基苯甲酿胺基）-2-甲基被咬-3·» 基）-N-((四氫-2H-哌喃-4-基）甲基）-1Η-1,2,3-三唑-4-羧醯胺； 1-(5-(3-氟基-5_嗎福啉基苯甲醯胺基）-2-甲基吡啶氺 基）-N-(2-經基-2-苯基乙基）·1Η-1，2,3-三唆-4-叛S&amp;胺； 1-(5-(3-氟基·5-嗎福啉基苯甲醯胺基）-2-甲基吡啶一3_ 基）-N-(l-羥基-3-甲基丁 -2-基）_1H-1，2,3-三唑-4-羧醯胺； N-((l-乙基四氫吡咯-2-基）甲基）-1-(5-(3-氟基-5-嗎福啉基笨 曱醯胺基）-2-甲基吡啶-3-基）-1Η-1，2,3-三唑-4-羧醯胺； 5-第三-丁基-3-氰基-Ν-(5-(4-((1·乙基四氫吡咯-2-基）甲基胺 曱醯基）苯基）-6-甲基吡啶-3-基）-2_甲氧基苯甲醯胺； 5-第三-丁基-3-氰基-2_甲氧基-N_(6-甲基-5-(4-(1-甲基六氫 吡啶-4-基胺甲醯基）苯基）吡啶-3-基）苯曱醯胺； 5·第三-丁基-3_氰基-2-甲氧基-N-(6-甲基-5-(4-((1-甲基六氫 吡啶-4-基）甲基胺曱醯基）-苯基风啶_3_基）苯甲醯胺； 3-氟-N-(6-甲基-5_(4·(1-甲基六氫吡啶-4-基胺甲醯基）苯基） 123505 -32- 200815422 外匕唆_3_基）·5-嗎福琳基苯甲醯胺； 3-氟-Ν_(6-甲基-5-(4-((1-甲基六氫吡啶-4-基）甲基胺甲醯基） 本基）叶1： σ定-3-基）-5-嗎福琳基苯曱酿胺； 5-第三-丁基-3-氰基-2-甲氧基-N-(6-甲基-5-(4-(吡啶-3-基甲 基胺甲醯基）苯基）峨啶·3-基）苯甲醯胺； Η5-(3-氟基-5-嗎福啉基苯甲醯胺基）-2-甲基吡啶-3-基）小1-(四氫-2H-哌喃冬基）-1Η·1，2,3-三唑-4-羧醯胺； Ν-環己基小(5-(3_氟基-5-嗎福啉基苯甲醯胺基）-2-甲基吡 口定各基）-111_1，2,3-三唾-4-叛醯胺； N-環戊基-1-(5-(3-氟基-5_嗎福啉基苯甲醯胺基）冬甲基吡 °定_3_基）-1Η-1，2,3-三唾·4_羧醯胺； 1-(5-(3-氟基-5-嗎福啉基苯甲醯胺基）-2-曱基吡啶-3-基）-Ν·(3-羥基_2,2_二甲基丙基）-1Η-1，2,3-三唑冰羧醯胺； 1-(5-(3-第三-丁基-5-氰基苯曱醯胺基）-2-甲基吡啶各 基）-N_((四氫呋喃-2-基）甲基）-lH-l，2,3-三唑-4-羧醯胺； 1-(5-(5-第三-丁基各氰基-2-甲氧基苯甲醯胺基）_2·甲基吡 啶-3-基）-1Η·1，2,3_三唑-4-羧酸第三-丁酯； Η5-(3-氰基-5-嗎福啉基苯甲醯胺基）-2-甲基吡啶-3-基）-N-((四氫呋喃-2-基）甲基）-1Η-1，2,3-三唑-4-羧醯胺； H5-(3-氰基-5_(六氫吡啶-1-基）苯甲醯胺基）-2-曱基吡啶-3-基）-N-((四氫呋喃-2-基）曱基）-1Η-1，2,3-三唑-4-羧醯胺； 1-(5-(3-氰基-5-(四氫吡咯小基）苯甲醯胺基）-2-甲基吡啶-3-基）-N-((四氫呋喃-2-基）曱基）-1Η_1，2,3-三唑-4-羧醯胺； N-(5_(4-((l-乙基四氫p比洛-2-基）甲基胺甲醢基）苯基）各甲 123505 -33- 200815422 基p比咬-3-基）-3-敦基-5_嗎福琳基苯甲酿胺； 1-(5-(5-第三-丁基-3-氰基-2-甲氧基苯甲醯胺基）-2-甲基吡 啶-3_基）新戊基-1H_1，2,3-三唑-4-羧醯胺； 1-(5-(5-第三-丁基-3-氰基-2-甲氧基苯甲醯胺基）-2-甲基吡 啶-3-基&gt;N_(吡啶-3-基甲基&gt;1Η-1，2,3·三唑-4-羧醯胺； 1_(5-(3-第三-丁基-5-氰基苯甲醯胺基）-2-甲基吡啶-3· 基）-N-((l-乙基四氫吡咯-2-基）曱基）-1Η-1，2,3-三唑-4-羧醯胺； / 弟二-丁基鼠基-N-(6-甲基-5-(4-(4-甲基六氮峨p井-1-罗炭 \ 基）_1H-1，2,3-三唑小基）吡啶-3-基）苯甲醯胺； 1-(5-(5-第三-丁基-3-氰基_2_甲氧基苯甲醯胺基）-2-曱基吡 啶各基）-N-((四氫呋喃-2-基）甲基）_1H-1，2,3-三唑冰羧醯胺； 3-第三-丁基-5-氰基-N-(6-曱基-5-(4-(嗎福啉-4-羰 基）-lH-l，2,3-三唑小基）吡啶-3-基）苯甲醯胺； 1-(5-(3-第三-丁基-5-氰基苯甲醯胺基）-2-甲基吡啶-3-基）-N-(l-甲基六氫吡啶冬基）-1Η-1，2,3-三唑-4-羧醯胺； ( H5-(3-第三-丁基-5-氰基苯甲醯胺基）-2-甲基吡啶-3- 基）-N&lt;2-(四氫吡咯-1-基）乙基）·ιη-1，2,3-三唑斗羧醯胺； M5-(3-第三-丁基-5-氰基苯曱醯胺基）-2-甲基毗啶各 基）-队(2_(二甲胺基）乙基）_1H-1，2,3-三唑冰羧醯胺； 1-(5-(3-第二-丁基-5_氛基苯曱酿胺基）-2-甲基外匕ϋ疋3 基）-Ν-(2-甲氧基乙基）-1Η_1，2,3_三唑-4-羧醯胺； 1·(5-(3-第三-丁基-5-氰基苯甲醯胺基）-2-曱基毗11 定冬 基）&quot;^(喷唆-3-基）-111-1，2,3-三唾-4-叛酿胺； 1-(5-(3-第三-丁基_5_氰基苯曱醯胺基）-2-甲基吡唆士 123505 -34- 200815422 基）-1^-(六氫吡啶-4-基）-111_1，2,3_三唑-4-羧醯胺； 1-(5-(3-第三-丁基-5-氰基苯甲醯胺基）-2•甲基吡啶-3-基）_N-(六氫吡啶-3-基&gt;1H-1，2,3-三唑-4-羧醯胺； 1-(5-(3-第三-丁基-5-氰基苯甲醯胺基）-2-曱基吡啶-3-基）-N_(2-羥丙基）-1Η-1，2,3-三唑斗羧醯胺； 1-(5-(3-氟基-5-(1，4-氧氮七圜冰基）苯甲醯胺基）-2-甲基吡啶 •3-基）-N-((四氫咬喃-2-基）甲基）·1Η·1，2,3-三唾-4-魏酿胺； 1-(5-(3-1基-5-(四氫外t 17各-1-基）苯甲醯胺基）_2-甲基峨咬-3-基）((四氫咬喃-2-基）甲基）-1Η-1，2,3-三嗤-4-魏S篮胺； H5-(3-氰基-5-(四氫吡咯-1-基）苯甲醯胺基）-2-甲基吡啶_3_ 基）-N-新戊基-1H-1，2,3-三唑-4_羧醯胺； 1-(5-(3-氰基-5-(六氫吡啶小基）苯甲醯胺基）-2-甲基吡啶-3-基）新戊基-1H-1，2,3-三唑斗羧醯胺； 1-(5-(3-氰基-5-嗎福啉基苯甲醯胺基）-2-甲基吡啶-3-基）-N-新戊基-1H-1，2,3-三唑-4-羧醯胺； 1-(5-(3-氣基-5-硫代嗎福淋基苯曱酿胺基）-2-曱基ρ比唆-3-基KN-新戊基-1H-1，2,3_三唑斗羧醯胺； 1-{5-[3-氟基-5-(1-酮基-1人4·硫代嗎福啉-4-基）-苯甲醯胺 基]-2-曱基比σ定-3-基}-1Η-[1，2,3]三嗤-4·魏酸（2,2-二甲基-丙基）-醯胺； 1-(5-(3-第三-丁基-5-氰基苯曱酿胺基）-2-甲基1^比°定-3-基）-N-((l-甲基六氫吡啶-4-基）曱基）_1H-1，2,3-三唑-4-羧醯胺； 3-第三-丁基-5-氰基-N-(5-(4-(4-(2-羥乙基）六氫吡畊小羰 基）-1Η-1，2,3-三吐-1-基）-6-甲基p比唆_3_基）苯甲酿胺； 123505 -35- 200815422 1-(5-(3-第二-丁基-5-氰基苯甲醯胺基）_2_甲基吡啶_3_ 基）抓(2,2,6,6-四甲基六氫吡啶_4_基）_1H-1，2,3_s唑斗羧醯胺； H2-甲基-5-(3-(四氫吡咯_1_基&gt;5_(三氟甲基）苯甲醯胺基）_ 外卜定-3·基）-N-0比啶-2-基甲基）]凡1，2,3-三唑斗羧醯胺； 1-{5-[3-(1，1-二酮基-1入6-硫代嗎福琳-4-基）·5-氟-苯甲醯胺 基]_2_甲基-峨啶-3-基}·1Η_[1，2,3]三唑冬羧酸（2,2-二甲基-丙基） 醯胺； 1-(5-(3-第三-丁基-5-氰基苯甲醯胺基）_2_甲基吡啶 基）-N七比啶_2_基甲基）_1H-1，2,3-三唑—4-羧醯胺； 5-第三-丁基-3-氰基-2_甲氧基-N-(6-甲基-5-(4-(新戊基胺甲 醯基）苯基）吡啶-3-基）苯甲醯胺； 3-溴基-5-第三-丁基-2-甲氧基-N-(6-甲基-5-(4-(新戊基胺甲 醯基）苯基）吡啶-3-基）苯甲醯胺； (R)-5-第三-丁基_3·氰基-Ν-(5-(4·((1-乙基四氫吡咯-2-基）甲 基胺甲醯基）苯基）-6-甲基ρ比咬-3-基）-2-甲氧基苯曱醯胺； H5-(3-氰基_5-(六氫吡啶小基）苯甲醯胺基）_2_甲基吡啶； 基）-队〇比啶-2-基甲基）_111_1，2,3_三唑-4-羧醯胺； 3-苐二-丁基-5-氰基-N-(6-甲基-5-(4七比咬_2_基甲基胺曱醯 基）苯基Η啶-3-基）苯甲醯胺； Ν_(6-曱基-5-(4-(吡啶-2-基甲基胺甲醯基）苯基）吡啶_3· 基）各(四氫吡咯-1-基）-5-(三氟曱基）苯甲醯胺； 第二-丁基-5-氰基-N-(6-曱基-5-(4-((1-甲基六氫p比咬-2-基） 甲基胺曱醯基）苯基）吡啶-3-基）苯甲醯胺； Ν·(6-甲基-5-(4-((1-甲基六氫吡啶-2-基）甲基胺甲醯基）苯 123505 •36- 200815422 基 &gt;比啶-3-基）-3-(四氫吡咯-1-基）-5-(三氟曱基）苯甲醯胺； 5-第三-丁基-3-氰基-2-甲氧基-N-(6-曱基-5-(4-((1-甲基六氫 吡啶-2-基）甲基胺曱醯基）_苯基）吡啶各基）苯甲醯胺； (R)-3-第三丁基—5-氰基-N-(5-(4-((l-乙基四氫吡咯基）甲 基胺曱醯基）苯基）-6-甲基吡啶-3-基）苯甲醯胺； (R)-N-(5-(4-((l-乙基四氫吡咯基）甲基胺甲醯基）苯基）-6-甲基吡啶-3-基）-3-嗎福啉基-5-(三氟甲基）苯甲醯胺； (R)-N-(5-(4-((l-乙基四氫吡咯_2_基）甲基胺甲醯基）苯基）-6-甲基吡啶-3-基）_3_(四氫吡咯小基）_5-(三氟甲基）苯甲醯胺； (R)-N-(5-(4-((l-乙基四氫吡咯_2_基）甲基胺曱醯基）苯基）_6_ 甲基吡啶-3-基）-3-(六氫吡啶-1·基）-5-(三氟甲基）苯甲醯胺； 1-(5-(3-第三-丁基_5_氰基苯甲醯胺基）-2-曱基吡啶-3-基）-N-((l-甲基六氫吡啶_2_基）甲基）三唑-4-羧醯胺； 1-(5-(5-第三-丁基-3-氰基-2-甲氧基苯甲醯胺基）-2-甲基吡 淀-3-基）-N-((l-甲基六氫吡啶_2·基）甲基）_ih-1，2,3-三唑-4-羧醯 胺； 1-(5-(3-第三·丁基-5-氰基苯曱醯胺基）-2-甲基吡啶斗基）-N-環己基-1H-1，2,3_三唑-4-羧醯胺； 1-(5-(3-第三-丁基；氰基苯甲醯胺基）-2-曱基吡啶_3· 基）1(六氫吡啶-1_基）_出_1，2,3-三唑_4-羧醯胺； 3-第三_丁基-5-氰基-N-(6-甲基-5·(4_((6-甲基吡啶-2-基）甲基 胺甲醯基）苯基）吡啶-3-基）苯甲醯胺； 5-第三_丁基各氰基甲氧基-Ν-(6-甲基-5-(4-((6-甲基吡咬 -2-基）甲基胺甲醯基）苯基）吡啶净基）苯甲醯胺； 123505 -37- 200815422 N-(6_甲基-5-(4-((6-甲基吡啶-2-基）甲基胺甲醯基）苯基）p比 啶-3-基）-3·(四氫吡咯-1-基）-5-(三氟曱基）苯甲醯胺； 3-第三-丁基-5-(6-甲基-5-(4-(新戊基胺曱醯基）-苯基）咐啶 -3-基胺甲醯基）苯甲酸甲酯； 3-苐二-丁基-5-(6-甲基-5-(4-(新戊基胺甲醯基）-苯基）p比。定 -3-基胺甲酿基）苯甲酸； N-(6-甲基-5-(4-(新戊基胺甲醯基）苯基 &gt;比啶-3·基）-2-(六氫 峨σ定-1-基）異於驗醯胺； 5-第三·丁基-Ν1 -(2-(二曱胺基）乙基）-N3-(6-甲基-5-(4-(新戊 基胺曱酸基）本基）比σ定-3-基）間苯二甲酿胺； 3- 氟-Ν-(5-(4-(1-(羥亞胺基）乙基）苯基）_6_甲基吡啶-3-基&gt;5- 嗎福啉基苯甲醯胺； 4- (5-(3-第三-丁基-5-氰基苯甲醯胺基）-2-甲基吡啶-3·基）苯 曱酸甲酯； 1-(5-(3-第三-丁基-5-氰基苯甲醯胺基）-2-曱基吡啶-3_ 基）-1Η-1,2&gt;三唑-4·羧酸乙酯； 1-(5-(3-第三-丁基-5-氰基苯甲醯胺基）-2-甲基吡啶_3-基）_N-(2_(二乙胺基）乙基）-iH-l，2,3-三唑-4-羧醯胺； 1-(5_(3-第三-丁基-5_氰基苯曱醯胺基）-2-甲基吡啶各 基）-Ν-(2·(二異丙基胺基）乙基）-ΐΗ-1，2,3·三唑-4-羧醯胺； 1-(5-(3-第三-丁基-5-氰基苯甲醯胺基）-2-甲基吡啶各基）-N-(2-甲基-2-(六氫吡啶-1-基）丙基）-1Η·1，2,3-三唑-4-羧醯胺； 1-(5-(3-第三-丁基-5-氰基苯甲醯胺基）-2-甲基吡啶-3-基）-N-((l-(六氫吡啶小基）環己基）甲基）_ih-1，2,3-三唑-4-羧醯胺； 123505 -38 - 200815422 N-(6-甲基-5-(4-(新戊基胺甲醯基）苯基）_吡啶_3_基）_2_嗎福 琳基異終驗酿胺； 3-氰基-N-(6-曱基-5-(4-((6-甲基外匕淀-2-基）甲基胺甲酿基）苯 基）吡啶-3-基）-5-嗎福啉基苯甲醯胺； 3-氧基-N_(6_甲基-5-(4-((6_甲基外1：咬-2-基）甲基胺甲酿基）苯 基）吡啶-3-基）-5-(四氫吡咯-1-基）苯甲醯胺； 3- 氰基-N-(6-甲基-5-(4-((6-甲基吡啶-2-基）甲基胺甲醯基）苯 基 &gt;比唆-3·基）_5_(六氫ρ比咬_1_基）苯甲醯胺； 4- (5-(5-弟二-丁基-3-氰基-2-曱氧基苯甲醯胺基）_2_甲基p比 °定-3-基）苯甲酸甲醋； 3_弟二-丁基·5_氰基-N-(5-(4-(環己基胺甲醯基）苯基）各甲 基吡啶-3-基）苯甲醯胺； 3-弟二-丁基-5-氰基-N-(5-(4_(2-p乙胺基）乙基胺甲醯基）_ 苯基）_6_甲基u比π定-3-基）苯甲醯胺； 3-第三·丁基·5_氰基-N-(5-(4-(2-(二異丙基胺基）乙基胺曱醯 基）苯基）-6-甲基吡啶-3-基）苯甲醯胺； 3-弟二-丁基-5_氰基-N-(6-甲基_5-(4-(2-甲基-2-(六氫p比咬-1-基）丙基胺甲醯基）苯基）吡啶各基）苯甲醯胺； 3-第三-丁基-5-氰基-N_(6-甲基-5-(4-((1-(六氫吡啶-1-基）環己 基）甲基胺甲醯基）苯基 &gt;比啶-3-基）苯甲醯胺； 3-第三-丁基-5-(((2-甲氧基乙基）(甲基）胺基）甲基）_n-(6-甲 基-5-(4-(新戊基胺甲酸基）苯基）-p比咬各基）苯甲醯胺； 3-第三-丁基-N-(6-曱基-5-(4-(新戊基胺甲醯基）苯基）p比唆 -3-基）_5_(四氫吡咯小基甲基）苯甲醯胺； 123505 -39- 200815422 3-第三-丁基-Ν·(6-甲基-5-(4-(新戊基胺甲醯基）苯基）吨啶 -3-基）-5-(六氫吡啶小基曱基）苯曱醯胺； 3-敦’5-(4-(1-經乙基）苯基）_6_甲基吡啶_3_基）_5•嗎福啉基 苯甲醯胺； 1-(5-(3-第三-丁基_5_氰基苯甲醯胺基）_2_甲基吡啶_3•基）-N_ 嗎福4基-识-1，2,3-三嗤-4-魏酸胺； 1-(5-(3-第三-丁基-5-氰基苯曱醯胺基）_2_甲基吡啶_3_ f 基）_化(四氫-2H-哌喃斗基）-1Η·1，2,3-三唑斗羧醯胺； 5-第三-丁基-3-氰基-Ν-(5-(4·(環己基胺甲醯基）苯基）各甲 基峨咬-3-基）-2-甲氧基苯曱酿胺； 5-第三-丁基-3-氰基_2_甲氧基-N-(6-甲基-5-(4-(六氫吡啶小 基胺甲醯基）苯基）吡啶-3-基）苯甲醯胺； 弟二β丁基-3-氰基-2-甲氧基-N-(6-甲基-5-(4-(四氫-211-旅 喃-4-基胺甲醯基）苯基风咬_3_基）苯甲醯胺； 5-第三-丁基-3-氰基-2-甲氧基-N-(6-甲基-5-(4-(嗎福啉基胺 i ) 甲醯基）苯基）-吡啶-3-基）苯曱醯胺； 弟二-丁基-N-(6-甲基-5-(4-(新戊基胺甲隨基）苯基）说咬 -3·基）-5-((4-甲基六氫吡畊-1-基）甲基）苯甲醯胺； 3-第三-丁基-N-(6-甲基-5-(4-(新戊基胺曱醯基）苯基）_吡啶 _3_基）_5_(((四氫呋喃基）甲胺基）甲基）苯甲醯胺； 3-第三-丁基-N-(6-甲基-5-(4-(新戊基胺甲醯基）苯基）_吡啶 •3-基）_5-((丙-2-炔基胺基）甲基）苯甲醯胺； 3_第二-丁基-N-(6-甲基-5-(4-(新戊基胺甲酿基）苯基比咬 -3-基）-5-(嗎福啉基甲基）苯甲醯胺； 123505 -40- 200815422 3-第三·丁基-N-(6-甲基-5-(4-(新戊基胺甲醯基）苯基）-吡啶 各基）-5-((3-酮基六氫吡畊小基）曱基）苯甲醯胺； 3-第三-丁基-N-(5-(4-(2-第三-丁基肼羰基）-1Η-1,2,3-三唑-1-基）-6-甲基吡啶-3-基）-5-氰基苯甲醯胺； 3-第三-丁基-5-氰基-N-(5_(4-(2-環己基肼羰基）-1Η-1，2,3-三唑 -1-基）-6-曱基吡啶斗基）苯甲醯胺； 1-(5-(3-第三-丁基-5_氰基苯甲醯胺基）-2-甲基吡啶-3-基）-N-(2,6-二甲基六氫吡啶小基）-1Η-1，2,3-三唑冰羧醯胺； N-(6-甲基-5-(4-(新戊基胺甲醯基）苯基）-吡啶-3-基）-2-(四氫 吡咯-1-基）異菸鹼醯胺； 3-第三-丁基-N-(6-甲基-5-(4-(新戊基胺甲醯基）苯基）-吡啶 -3-基）-5-((2-(甲硫基）乙胺基）甲基）-苯甲醯胺； 3·第三丁基-5_(((2-(二甲胺基）乙基）(甲基）胺基）甲基）-N-(6-甲基-5-(4-(新戊基胺曱醯基）苯基）-吡啶-3-基）苯甲醯胺； 3-第三-丁基-5-氰基-N-(6-甲基-5-(4-(嗎福啉基胺甲醯基）苯 基）-吡啶-3_基）苯甲醯胺； 3-第三-丁基-N-(5-(4-(2-第三-丁基肼羰基）苯基）-6-甲基吡 啶-3-基）-5-氰基苯甲醯胺； 3-第三-丁基-5-氰基-N_(5-(4-(2-環己基肼羰基）-苯基）·6_甲 基吡啶-3_基）苯曱醯胺； 5-第三-丁基-Ν-(5-(4-(2_第三-丁基肼羰基）苯基）-6_曱基吡 咬_3_基）-3·氰基-2-曱氧基苯曱醯胺； Η5-(3-氟基-2-曱氧基-5-嗎福啉基苯曱醯胺基）-2-曱基吡 啶·3-基）新戊基-1H-1，2,3-三唑-4-羧醯胺； 123505 -41 - 200815422 ^(5-(3-氟基-2-甲氧基_5_嗎福啉基苯甲醯胺基）_2_曱基吡 啶·3_基）-N-((四氫吱°南-2-基）甲基）·1Η-1,2,3 -三唑-4-羧醯胺； l-〇(3-|L基-2-甲氧基_5_嗎福啉基苯甲醯胺基）_2_甲基吡 咬各基）·Ν-(ίΤ比咬_3_基甲基ΗΗ-1，2,3-三唑斗羧醯胺； 3-氟基-2-曱氧基-Ν-(6-甲基-5-(4-〇比啶-3-基甲基胺曱醯基） 苯基 &gt;比啶-3-基）_5_嗎福啉基苯甲醯胺； 3-氟基-2-曱氧基抓(6_曱基-5_(4_((四氫呋喃_2_基）曱基胺曱 f 酿基）苯基）p比啶基）-5-嗎福琳基苯甲醯胺； 3-氟基-2-甲氧基-N-(6-甲基-5-(4-(新戊基胺甲醯基）苯基）-外匕啶-3-基）-5-嗎福啉基苯甲醯胺； 3-第三·丁基_5·氰基_N_(5_(4-(2,6_二甲基六氫吡啶小基胺甲 醯基）苯基）-6-甲基吡啶各基）苯甲醯胺； 5-第三-丁基_3_氰基-N_(5_(4_(2,6_二甲基六氫吡啶小基胺甲 酿基）苯基）-6-甲基吡啶-3-基）-2-甲氧基苯甲醯胺； 1-(5-(5-第三-丁基_3_氰基冬甲氧基苯甲醯胺基）-2_甲基吡 (; °定I基）_N-(2,6-二甲基六氫吡啶-1-基）-iH-l，2,3-三唑-4-羧醯 胺； M5_(5-第三-丁基-3-氰基-2-甲氧基苯甲醯胺基）-2-甲基吡 唆-3-基）_队(六氫吡啶小基三唑冰羧醯胺； 5 第二·丁基-N-(5-(4-(2-第三-丁基耕魏基）-111-1，2,3-三峻-1-基）七甲基吡啶_3_基）-3·氰基-2-甲氧基苯甲醯胺； 第三-丁基-5-(嗎福啉基甲基）苯曱醯胺基）-2-甲基吡 咬基）-N-新戊基-1H_1，2,3-三唑-4-羧醯胺； 5-第三-丁基_3·氰基-N-(5-(4-(2-環己基肼羰基）-1Η-1，2,3-三唑 123505 -42- 200815422 -1-基）-6•甲基吡啶-3-基）-2-曱氧基苯曱醯胺； 1-(5-(3-第三-丁基_5-((4_甲基六氫吡畊小基）曱基）苯甲醯胺 基）-2-甲基被咬-3-基）新戊基·ιη-1，2,3-三唆-4-羧醯胺； 3-氰基-N-(6-甲基-5-(4-(新戊基胺甲醯基）苯基分吡啶士 基）-5-嗎福淋基苯甲酿胺； N-(5-第三·丁基-3-氰基_2_甲氧苯基)·6_甲基_5普(新戊基胺 甲醯基）-111-1，2,3-三唑+基）於鹼醯胺； Ν-(3_氰基-5-嗎福啉基苯基）各甲基_5_(4_(新戊基胺甲醯 基）-1Η-1，2,3-三吐+基）菸鹼醯胺； Ν-(3-氟基-5-嗎福啉基苯基&gt;6_甲基_5_(4_(新戊基胺甲醯 基）_1Η_1，2,3·三唾士基）菸鹼醯胺； Ν-(3-第一 -丁基七甲基_1Η_吡唑士基&gt;6_甲基_5_(4_(新戊基 胺甲酿基^1，2,3^·基谈驗醯胺； 1-(5-(3舰5够氧_3遺_雙環并[3·21]辛·3_基）_5_氣基苯甲 醯胺基)-2-甲基咐〇定士基叫斤戍基腿办三唾锁酿胺； 3_fl基-N_(6-甲基傳((四氯咬喃絲）甲基胺甲酿基）苯 基Η啶-3-基）_5_嗎福啉基苯甲醯胺； 3氰基Ν (6-甲基_5_(4七比啶冰基甲基胺甲醯基)苯基)_吡 啶-3-基）-5-嗎福啉基苯甲醯胺； N-(3-第二·丁基苯基）冬甲基_5普（新戊基胺甲醯 基）_1H-1，2,3-三。坐七基）菸鹼醯胺； N-(5-第三·丁基·2·甲氧苯基 &gt; 甲基_5例新戊基胺甲酿 基）-1Η-1，2,3-三嗤七基）菸鹼醯胺； (第 丁基·5'(6_甲基-5-(4-(新戊基胺甲醯基） 123505 -43- 200815422 二嗤-1-基）p比啶-3-基胺甲醯基）爷胺基）醋酸第三-丁酯； 2_(3_第三·丁基_5_(6_甲基_5_(4·(新戊基胺甲醯基）苯基）_口比 啶_3_基胺甲醯基）爷胺基）醋酸第三·丁酯； 2-(3-第三-丁基-5-(6-甲基-5-(4-(新戊基胺甲醯基）苯基）-吡 啶-3_基胺甲醯基）爷胺基）醋酸； N-(5-(4-(8-氧-3-氮·雙環并[3·2·ι]辛烷-3-羰基）苯基）各甲基吡 啶-3·基）-3-第三·丁基-5-氰基苯甲醯胺； N-(5_(4-(8-氧-3-氮-雙環并[3·2·1]辛烷-3-羰基）-1Η_1，2,3-三唑 +基）各甲基吡啶-3-基）-5•第三丁基各氰基-2-甲氧基苯甲醯 胺； 3_第三-丁基-5-氰基-N-(6-甲基_5-(4-(2,2,6,6-四甲基嗎福啉-4-羰基）苯基）吡啶-3-基）苯甲醯胺； 5-第三-丁基-3·氰基丨甲氧基·Ν·(6—甲基_5_(4_(2,2,6,6_四甲基 嗎福琳-4-幾基）-1Η_1，2,3_三唑-l-基 &gt;比唆-3-基）苯甲醯胺； Ν-(5-(4-(8-氧-3-氮-雙環并[3.2.1]辛烷-3-羰基）-1Η-1，2,3-三唑 -1-基）_6_甲基吡啶-3-基&gt;3-第三-丁基_5_氰基苯甲醯胺； 3·第三-丁基-5_氰基_Ν-(6-甲基-5-(4-(2,2,6,6-四甲基嗎福啉-4-羰基）-1Η-1，2,3-三唑_1-基风啶_3_基）苯甲醯胺； Ν-(5-第三-丁基-3-胺甲醯基甲氧苯基）-6-甲基-5-(4-(新戊 基胺甲醢基）-1Η-1，2,3·三唑-μ基）辂驗醯胺； Ν-(5-第三_ 丁基-3-(環丙基胺甲醯基甲氧苯基）各甲基 -5-(4-(新戊基胺甲醯基）_ιη·1，2,3-三唑小基）於鹼醯胺； Ν-(5-第三-丁基-2-甲氧基_3-(甲基磺醯胺基）苯基）_6_甲基 -5-(4-(新戊基胺甲醯基三唑-1-基）菸驗醯胺； 123505 -44 - 200815422 N-(5-(4-(8-氧-3-氮-雙環并[3.2.1]辛烷-3-羰基）苯基）-6-甲基吡 咬-3-基）-5-第三-丁基-3-氰基-2-甲氧基苯曱酿胺； 5-第三-丁基各氰基-2-甲氧基-N-(6-甲基-5-(4-(2,2,6,6-四甲基 嗎福啉-4-羰基）苯基）吡啶-3-基）苯甲醯胺； 5-第三-丁基氰基_2_曱氧基_N-{6-甲基-5-[4-(10-氧-4-氮-三 環并[5.2.1.02,6]癸烧-4廣基）-苯基]^比。定_3_基}_苯甲醯胺； 5-第三-丁基-3-氰基-2-甲氧基-Ν·{6-甲基_5_[4-(10-氧-4-氮-三 玉衣弁[5·2·1·02,6]癸烧-4-幾基）-[1，2,3]三吐-1-基]比u定_3_基}-苯甲 醯胺； 3-第三-丁基-5-氰基_Ν-{6-甲基-5_[4_(10-氧-4-氮-三環并 [5·2·1·02,6]癸烧-4-羰基&gt;[1，2,3]三唑-1-基]比啶-3-基}-苯曱醯 胺； 3-第三·丁基-5_氰基-Ν-{6-甲基-5-[4-(10-氧-4-氮-三環并 [5·2.1·02,6]癸烷_4_羰基）-苯基]-吡啶-3-基卜苯甲醯胺； 3-第三-丁基-Ν-(6-甲基-5-(4-(新戊基胺曱醢基）苯基）-ρ比咬 -3-基）-5-((2-(甲基亞磺醯基）乙胺基）甲基）苯甲醯胺； 3-第三-丁基-N-(6-甲基-5-(4-(新戊基胺甲醯基）苯基）_吡啶 -3-基）_5·((2_(曱石黃醯基）乙胺基）甲基）苯甲醯胺； Ν-(3-第三-丁基-5-氰基苯基）-6-甲基-5-(4-(六氫ρ比咬-1-基胺 甲醯基）-111-1，2,3-三唾-1-基）於驗醯胺； N-(5-第三歸丁基-2-甲氧基-3-（甲基磺醯胺基）苯基）-6咖曱基 -5-(4-(六氫峨淀-1-基胺甲醢基）_ih_1，2,3_三嗤小基）於驗醯胺； N-(5-第三-丁基-3-氰基-2-甲氧苯基）-6-甲基-5-(4-(六氫吡咬 -1-基胺甲醯基）-lH_l，2,3·三唾-1_基）於驗醯胺； 123505 -45- 200815422 1-(5-(5-第三-丁基I氰基-2-(2-(4-甲基六氫吡畊+基）乙氧 基）苯甲醯胺基&gt;2-甲基吡啶_3_基）新戊基-1Η-1，2,3-三唑-4-羧醯胺； 5-第二-丁基各氰基-Ν-(6-甲基-5-(4-(新戊基胺甲醯基）苯 基）-吡啶-3·基）-2-(2-(4-甲基六氫吡畊+基）乙氧基）苯甲醯胺； 3-氰基-N-(6-甲基-5_(4-(N-新戊基胺磺醯基）苯基风啶士 基）-5-嗎福啉基苯甲醯胺； 3-氰基-N-(6-甲基-5-(4-(N-新戊基胺磺醯基）苯基）吡啶_3_ 基）_5_(四氣p比洛基）苯甲酿胺； 5·第三-丁基各氰基冬甲氧基_N-(6•甲基_5_(4_(N•新戊基胺 績醯基）苯基）p比唆_3_基）苯甲醯胺； Ν-(6·甲基-5-(4-(新戊基胺甲醯基）苯基）_吡啶斗基）異嘮唑 -3-羧醯胺； 3-第三-丁基小甲基-N_(6_甲基净(4_(新戊基胺甲醯基）苯 基）巧比σ定-3-基）-1Η-峨唾-5-魏醯胺； 5-第三-丁基-2-甲基-N-(6-甲基-5-(4-(新戊基胺甲醯基）_苯 基Η啶_3_基）咬喃_3_羧醯胺； 3-第三-丁基-Ν-(6-甲基-5-(4-(新戊基胺甲醯基）苯基风啶 -3-基）-1Ηπ比唾·5·緩gf胺； 5_第三-丁基.(6_甲基·5_(4_(新戊基胺甲醯基）苯基 &gt;吡啶 -3-基）異呤唑-3-羧醯胺； Η5-(3-第三-丁基_5_氰基苯甲醯胺基）_2_乙基吡啶各基 新戊基-1Η-1，2,3-三唑_4_羧醯胺； 5-第二-丁基-Ν1 -甲基-Ν3 -(6_甲基-5-(4-(新戊基胺甲醯基）苯 123505 -46- 200815422 基）p比啶-3-基）間苯二甲醯胺； 5-第三丁基-N1-環丙基-N3-(6_甲基_5·(4-(新戊基胺甲醯基） 苯基比嗓-3-基）間苯二甲酿胺； 5-第三-丁基-Ν1-(環丙基甲基）·ν3-(6·甲基-5-(4-(新戊基胺 甲醯基）苯基）吡啶-3-基）間苯二甲醯胺； 5*&quot;第二-丁基-N1 -(6-甲基-5-(4-(新戊基胺甲醯基）苯基）p比ϋ定 -3-基）間苯二曱酿胺； 《、 iK3-氟基；嗎福淋基苯甲醯胺基）-2-曱基吡啶各 基HH-1，2,3-三唑-4_羧酸乙酯； 3-第三-丁基-5-(6-甲基_5-(4_(新戊基胺曱醯基 唑小基）吡啶-3-基胺甲醯基）苯甲酸甲酯； ^(5-(3-氟基-5-(三氟甲基）苯甲醯胺基）_2_甲基吡啶彳 基）新戍基-1H-1，2,3-三嗤-4-緩酿胺； 第三-丁基-5_(卜甲基_5-(4-(新戊基胺曱醯基）-1Η-1，2,3-三 哇+基）吡啶-3-基胺甲醯基）苯甲酸； I 5 (3弟二-丁基-5-氣基本甲酿胺基）_2_甲基-3-(4-(新戍基胺 甲酉叔基）笨基比ϋ定1·氧化物； 第三-丁基-5-氰基苯曱醯胺基）_2_曱基_3_(4-(新戊基胺 甲酿基）]H-1，2,3-三唑_1_基）π比咬1-氧化物； 5-第三-丁基-Nl _(環丙基甲基&gt;N3 _(6_曱基净(4_(新戊基胺 曱醯基）-1Η-1，2,3-三唑-l-基 &gt;比啶各基）間苯二曱醯胺； ^ (5-(2,5-一甲氧基本甲醯胺基）-2-甲基u比咬-3-基）-N-新戊 基-1H-1，2,3-三唑-4-羧醯胺； 5-第三-丁基-N1-甲基邾-(6_甲基-5_(4-(新戊基胺甲醯 123505 -47- 200815422 基）-1Η-1，2,3-三唑·1·基风啶！基）間苯二甲醯胺； 3-氰基-5-(4-甲基-1Η-咪唑小基）_Ν-(6·甲基-5-(4-(新戊基胺甲 醯基）苯基&gt;比啶-3-基）苯甲醯胺； H2-甲基-5-(3-(4_曱基-1H·咪唑小基）-5-(三氟甲基）苯甲醯 胺基）p比咬_3_基）-N·新戊基-1H-1，2,3-三峻-4-魏醢胺； H5-(3-氰基-5-(4-甲基-1H-咪唑·1_基）苯甲醯胺基）-2-甲基吡 啶-3-基）_N-新戊基-1Η-1，2,3-三嗤-4-羧醯胺； ξ ^ 苐二_丁基-5-氰基苯甲酸胺基）_2·甲基峨。定-3- 基）1(3_羥基-2,2-二甲基丙基）-1私1，2,3-三唑-4-羧醯胺； (R)-l-(5-(3-第三-丁基-5-氰基苯曱醯胺基）-2-甲基吡啶-3-基）((四氫唉喃-2-基）甲基）_1H_1，2,3_三唾-4-魏醯胺； (8)-1-(5-(3-第三-丁基-5-氰基苯甲醯胺基）_2_甲基吡啶-3-基）-N-((四氫呋喃-2-基）甲基）_1H-1，2,3-三唑-4-羧醯胺； 1-(5-(5-第三-丁基-3-氰基-2_甲氧基苯甲醯胺基）-2-甲基吡 咬-3-基）-N-((l-經基環丙基）甲基）_ih-1，2,3-三唑斗羧醯胺； I) 雙三甲基乙醯胺基苯甲醯胺基）-2-甲基吡啶-3- 基）新戊基-1H-1，2,3-三唑冰羧醯胺； N-(3-第三-丁基-5-氰基苯基）-6-曱基-5-(4-(新戊基胺曱醯 基）苯基）於驗醯胺； Ν-(5·第三-丁基-3-氰基_2_甲氧苯基）各甲基-5-(4-(新戊基胺 甲酿基）苯基）菸鹼醯胺； 5-第三-丁基-3-氰基-Ν·(5-(4-(3-經基-2,2-二甲基丙基胺甲醯 基）苯基）-6-甲基吡啶-3-基）-2-甲氧基苯甲醯胺； 5·弟二-丁基-3-氰基_Ν-(5_(4-((1-經基環丙基）甲基胺曱醯 123505 -48- 200815422 基）苯基&gt;6-甲基吡啶_3_基）_2•甲氧基苯甲醯胺； H5-(5-第三·丁基_3_氰基冬甲氧基苯甲醯胺基）·2_甲基吡 淀-3·基）-Ν·(3-經基_2,2二甲基丙基）-1Η_ΐ52,3-三唑斗羧醯胺； 1-(5_(3-第三·丁基_5_(正_丙基胺磺醯基）苯甲醯胺基）甲 基峨咬-3-基）新戊基]Η-1，2,3-三Κ羧醯胺； 1-(5-(3,5-雙（新戊氧基）苯曱醯胺基）_2_甲基吡啶；基）_Ν_新 戊基·1Η_1，2,3-三唾冬羧醯胺； 3-第二-丁基I氰基_Ν-〇(4-(3-羥基-2,2-二甲基丙基胺甲醯 基）苯基）-6_甲基吡啶各基）苯甲醯胺； 3-第三-丁基_5_氰基_Ν-(5_(4_((μ羥基環丙基）甲基胺甲醯 基）苯基）·6_甲基吡咬_3_基）苯甲醯胺； 5_第三_丁基·Νι，Νι _二甲基冰|甲基_5普(新戊基胺曱醯 基）苯基 &gt;比咬-3-基）間苯二甲醯胺； N-(5-(4-(2-胺基-2-甲基丙基胺甲醯基）苯基）各曱基吡啶_3_ 基）-3-第三-丁基-5-氰基苯甲醯胺； K2-曱基-5-(3-三甲基乙醯胺基苯甲醯胺基）被啶各基 新戊基_1H-1，2,3_三唑-4-羧醯胺； 5-第三-丁基-N1 -(6-甲基-5-(4-((四氫呋喃-2-基）曱基胺曱醯 基）苯基Η啶-3-基）·Ν3 _(吡啶-3_基曱基）間苯二甲醯胺； 1-(5·(5-第三-丁基-2-甲氧基-3-硝基苯甲醯胺基）-2-甲基吡 咬-3·基）新戊基_1Η·1，2,3·三唑-4-羧醯胺； 5-第三丁基-2-曱氧基善(6-甲基-5_(4-(新戊基胺甲醯基）苯 基Η啶-3_基）-3-碗基苯甲醯胺； (RM-(5-(5-第三-丁基·2_曱氧基-3-(四氫吡咯-2-羧醯胺基）苯 123505 -49- 200815422 甲醯胺基）_2-甲基吡啶-3-基）新戊基_1H-1，2,3-三唑冬羧醯 胺； (R)-N-(5_第三-丁基·2-甲氧基_3_(6_甲基-5·(冬(新戊基胺甲醯 基）苯基）峨唆-3-基胺甲醯基）苯基）四氫吡咯羧醯胺； 5·第三-丁基-Ν1 -(6-甲基-5-(4-(新戊基胺甲醯基）苯基风啶 -3-基）-N3 -(吡啶-3-基甲基谓苯二甲醯胺； N-(5_第三-丁基-2-甲氧基-3-(6-甲基-5_(4-(新戊基胺甲醯基） ξ \ 苯基 &gt;比σ定基胺甲醯基）苯基）_5-S同基四氫ρ比嘻-2-魏醯胺； 5·第三丁基_3-(1Η-咪唑小基&gt;2-甲氧基|(6_甲基-5-(4-(新 戊基胺曱酸基）本基）ρ比咬-3-基）苯甲酿胺； 1-(5-(5-第三-丁基-3-(1Η_咪唑小基）-2-甲氧基苯甲醯胺 基）-2-甲基吡啶-3-基）_N_新戊基-1Η·1，2,3 •三唾-4-魏酿胺； 3-第三-丁基-5-(6-甲基-5-(4-((四氫吱喃-2-基）甲基胺甲醯 基）苯基）吡啶-3-基胺甲醯基）苯甲酸甲酯； 3·第三·丁基-5-氰基-N-(6_甲基-5-(4-(2-(六氫峨咬小基）乙醯 (1 基）苯基）吡啶-3-基）苯甲醯胺； 1-(5-(3-第三-丁基-5-甲氧基苯甲醯胺基）_2_甲基吡啶各 基）新戊基-1H_1，2,3-三唑-4-羧醯胺； 3-第三-丁基-5-甲氧基-N-(6-甲基-5-(4-(新戊基胺甲醯基）苯· 基）吡啶-3-基）苯甲醯胺； 3-第三-丁基-5_(6-甲基-5-(4·((四氫呋喃基）甲基胺甲醯 基）苯基）吡啶-3-基胺甲醯基）苯甲酸； 5-第三-丁基-N1 ,Ν1 -二甲基_N3 -(6-曱基-5-(4-((四氫呋喃_2_ 基）甲基胺甲醯基）苯基 &gt;比啶_3_基）間苯二甲醯胺； 123505 -50- 200815422 5-第三-丁基-N1 -甲氧基-N1 -甲基-N3 -(6-甲基-5-(4-((四氫呋 喃-2-基）甲基胺甲醯基）苯基 &gt;比啶_3_基）間苯二甲醯胺； 3-第三-丁基-N-(6-甲基-5-(4-(新戊基胺甲醯基）苯基）峨咬 -3-基）-5-(2-嗎福淋基乙氧基）苯甲醯胺； 5-第三-丁基_2_甲氧基-3-(4-甲基-1H-咪唾-1-基）_ν·(6-甲基 -5-(4-(新戊基胺甲醯基）苯基）吡啶基）苯甲醯胺； H5-(5-第三-丁基-2-甲氧基_3-(4-甲基-1H-咪唑小基）苯甲驢 胺基）1甲基p比咬-3-基）-N-新戊基_1H-1，2,3-三唾-4-魏醯胺； 5-第三-丁基-N1 -((1-羥基環丙基）甲基）-N3 _(6_甲基_5-(4_((四 氫呋喃-2-基）甲基胺甲醯基）苯基）峨啶_3_基）間苯二甲醯胺； 5-第三·丁基-3-氰基-N-(5-(4-(環戊基胺甲醯基）苯基）_6•甲 基叶I：淀-3-基）_2_甲氧基苯甲醯胺； 5-第三-丁基各氰基_N-(5-(4_(4,4-二氟環己基胺甲醯基）苯 基）-6_甲基吡啶-3-基）-2-甲氧基苯甲醯胺； 5-第二-丁基-3-氰基-Ν·(5_(4-(異丙基胺甲醯基）苯基）甲 V 基吡啶各基&gt;2-甲氧基苯甲醯胺； 5-第三-丁基-3-氰基-Ν-(5-(4-(異丁基胺甲醯基）苯基）_6_甲 基吡啶-3-基）-2-甲氧基苯甲醯胺； 5-第二-丁基-3-氰基-N-(5-(4-(環丙基胺甲醯基）苯基）_6_甲 基吡啶-3-基）-2-甲氧基苯甲醯胺； 5_第三-丁基；氰基1甲氧基_N_(6_甲基·5·(4·(2·(六氫吡啶 -1-基）乙si基）苯基风啶_3·基）苯甲醯胺； 5-第三-丁基-N1 -(6-甲基-5-(4_(新戊基胺甲醯基HH_U，3•三 唑-1-基Μ啶-3-基&gt;N3_(2_(W氫吡咯小基）乙基）間苯二甲醯 123505 -51 · 200815422 胺； 5-第三·丁基-N1 -(6-甲基-5-(4-(新戊基胺甲醯基）-1η_1，2,3-三 唑小基）吡啶-3-基）_Ν3 -((1-甲基六氫吡啶-2-基）甲基）間苯二甲 醯胺； 5-第三-丁基-3-氰基-N-(5-(4-((lr，4r)-4-羥基環己基胺甲醯基） 苯基）-6-曱基吡啶-3-基）-2-甲氧基苯甲醯胺； N-(5-(4-((lR，2R，4S)-雙環并[2.2.1]庚·2·基胺甲醯基）苯基)各曱 基ρ比σ定-3-基）-5_第二-丁基-3-氮基-2-曱氧基苯甲酿胺； 5-第三-丁基-3-氰基-Ν-(5-(4_(3-經丙基胺甲醯基）苯基）_6_甲 基吡啶-3-基）-2-曱氧基苯甲醯胺； 5-第三-丁基-3-氰基-N-(5-(4-(2-羥乙基胺甲醯基）苯基）-6-甲 基吡啶-3-基）_2_甲氧基苯甲醯胺； 5-第三-丁基-N1 -(6-甲基-5-(4_(新戊基胺甲醯基）苯基 &gt;比啶 •3-基）-N3 -(2-(四氫外1： 口各_1_基）乙基）間苯二甲醯胺； 5-第三-丁基-N1 -(6-曱基-5-(4_(新戊基胺甲醯基）苯基 &gt;比啶 -3-基）·Ν3 -((1-甲基六氫峨淀-2-基）甲基）間苯二甲醯胺； 1-(5-(3-第三-丁基-5-(N，N-二甲基胺績醯基）苯甲醯胺基）_2_ 甲基外I：咬_3_基）-N-新戊基-1H-1，2,3_三峻-4-紱醯胺； 3_弟二-丁基-5-(N，N-一甲基胺石黃酿基）-N-(6-甲基-5-(4-(新戍 基胺甲δ&amp;基）本基）p比咬_3_基）苯甲酿胺； 3-第三-丁基-5-(5-甲基-1，2,4』号二唑-3-基）-N-(6-甲基-5_(4-(新 戊基胺甲醯基）苯基）峨咬-3_基）苯甲醯胺； 1-(5-(3-第三-丁基-5-(5-甲基·1,2,4-嘮二唑-3-基）苯甲醯胺 基）-2-甲基吡啶_3_基）-Ν-新戊基-1Η-1，2,3-三唑-4-羧醯胺； 123505 -52- 200815422 3-第三_丁基-5-氰基4(5-(4-(2-(二甲胺基）-2-甲基丙基胺甲 醯基）苯基）-6-甲基吡啶-3-基）苯甲醯胺； 5-第三-丁基-N1 -(3-羥基-2,2-二甲基丙基）-N3 -(6-甲基 -5-(4-(新戊基胺甲醯基）苯基）吡啶各基）間苯二甲醯胺； 5-第三-丁基-3-氰基-N-(5-(4-(2,2-二甲基環己基胺甲醯基） 苯基）-6-甲基ττ比咬-3-基）-2-甲氧基苯甲醯胺； N-(5-(4-((lR，2S，4R)-雙環并[2.2.1]庚-2-基胺甲醯基）苯基）·6_甲 ^ 基p比咬I基）-5-第三-丁基-3-氰基冬甲氧基苯甲醯胺； 1-(5-(3-第三-丁基-5-(N-甲基胺磺醯基）苯甲醯胺基）-2-甲基 口比唆_3«基）-N-新戊基-1H-1，2,3-三嗤-4-魏酿胺； 3-第三-丁基-N-(6-甲基-5-(4-(新戊基胺甲醯基）苯基）,比啶 -3-基）-5-(N-甲基胺磺醯基）苯甲醯胺； 5-第三-丁基-3-(異呤唑冰基）-2-甲氧基-N-(6-甲基-5-(4-(新戊 基胺甲醯基）苯基）p比啶-3-基）苯甲醯胺； 5_第二-丁基-3-(2,3-二氫異巧唾-4-基）-2-甲氧基-N_(6-甲基 ij -5-(4-(新戊基胺甲醯基）苯基）吡啶-3-基）苯甲醯胺； 3-第三-丁基_5-(5-環丙基-ΐ，2,4·嘮二唑-3-基）-N-(6-甲基 _5-(4-(新戊基胺甲醯基）苯基）吡啶_3_基）苯甲醯胺； 3第二丁基_5_(5_(甲乳基甲基）-1，2,4-π号二。坐-3-基）-N-(6-甲 基-5-(4-(新戊基胺甲醯基）苯基）吡啶基）苯甲醯胺； 3-第三-丁基-N-(5-(4-(3-羥基-2,2-二甲基丙基胺甲醯基）苯 基）冬曱基峨咬基）_5-(N-甲基胺石黃醯基）苯曱醢胺； 3-第三-丁基|(5-(4-(4,4-二氟環己基胺甲醯基）苯基）_6•甲 基吡啶-3-基）-5-(N-甲基胺磺醯基）苯甲醯胺； 123505 -53 - 200815422 3·第二-丁基-5-(5第三-丁基-ΐ，2,4^号二η坐各基甲基 -5-(4-(新戊基胺甲醯基）苯基 &gt;比淀_3_基）苯甲酸胺； 5-第二-丁基-2-甲氧基-N-(6-甲基-5-(4-(新戊基胺甲醯基）苯 基Η啶基）-3_(1Η-吡唑-1_基）苯甲醯胺； 5-弟二-丁基-3-氰基私(5_(4-(2,2-二甲基-3-(四氫p比口各基） 丙基胺甲醯基）苯基）-6-甲基吡啶-3-基）-2-甲氧基苯甲醯胺； 5-弟二-丁基-3-氰基|(5-(4-(2,2-二甲基-3-(4-甲基六氫峨p井 -1_基）丙基胺甲醯基）苯基）-6-甲基咐唆-3-基）-2-甲氧基苯甲 醯胺； 弟二-丁基-3-氰基-N_(5-(4-(2,2-二甲基-3-嗎福淋基丙基胺 甲醯基）苯基）-6-甲基吡啶-3-基）-2-甲氧基苯甲醯胺； N-(5-(4-(3-胺基-2,2-二甲基丙基胺甲醯基）苯基）各甲基外匕 啶-3-基）·5-第三-丁基-3-氰基_2_甲氧基苯甲醯胺； 5_第三-丁基-3-氰基_N-(5_(4_(3-(二甲胺基）_2,2·二甲基丙基 胺甲醯基）苯基）-6-甲基吡啶-3-基）-2-甲氧基苯甲醯胺； 、 5-第三-丁基-M4-(羥甲基）-1Η-1，2,3-三唑-1-基）_2_甲氧基 -N-(6-甲基-5-(4-(新戊基胺甲醯基）苯基 &gt;比啶；基）苯甲醯胺； 5-第三-丁基-2_甲氧基-N-(6-甲基-5-(4_(新戊基胺甲醯基）苯 基）说啶_3_基）-3-(4-(四氩吡咯-1-基曱基）_ih-1，2,3-三唑小基）苯 甲醯胺； 5-第三-丁基-2-甲氧基-N-(6-曱基-5·(4-(新戊基胺甲醯基）苯 基Η啶-3-基）-3-(4-(六氫吡啶小基甲基）-ΐΗ-1，2,3-三唑-1-基）苯 甲醯胺； 5-第三-丁基-2-甲氧基-Ν-(6-曱基-5_(4-(新戊基胺甲醯基）苯 123505 -54- 200815422 基）吡啶-3-基）-3-(4-((4-甲基六氫吡畊-1-基）曱基）-1Η-1，2,3-三唑 -1-基）苯甲酿胺； 5-弟二-丁基-2-甲氧基-N-(6-甲基-5-(4-(新戊基胺甲酿基）苯 基）吡啶-3-基）-3_(4-(嗎福啉基甲基）-lH_l，2,3-三唑小基）苯甲醯 胺； 5-第三丁基-3-(4-((二乙胺基）甲基）-iH_l，2,3-三唑小基&gt;2_曱 氧基-N-(6-甲基-5-(4-(新戊基胺甲醯基）苯基）吡啶-3-基）苯甲 〆 醯胺； \ 卜 5-第三-丁基-3-(4-((二甲胺基）甲基）_1H-1，2,3_三唑·1_基）-2-曱 氧基-N-(6-曱基-5-(4-(新戊基胺甲醯基）苯基）吡啶氺基）苯甲 醯胺； 5_第三β丁基；(4_((異丙基胺基）甲基）-1Η_1，2,3-三唾-1-基）-2- 甲氧基-N-(6-甲基-5-(4-(新戊基胺甲醯基）苯基风啶各基）苯 甲醯胺； 5-第三-丁基-3-(4_((環丙胺基）甲基）·1Η_ΐ52,3_三唑小基）_2_甲 \ : 氧基-Ν-(6_甲基_5-(4-(新戊基胺甲醯基）苯基）峨啶-3—基）苯甲 醯胺；及 5-第三-丁基-3-氰基-Ν_(5-(4-(2·(二甲胺基甲基丙基胺甲 醯基）苯基&gt;6-甲基吡啶_3_基）·2_甲氧基苯甲醯胺。 123505 -55- 200815422 七、指定代表圖： (一) 本案指定代表圖為：（無） (二) 本代表圖之元件符號簡單說明: 八、本案若有化學式時，請揭示最能顯示發明特徵的化學式：Η Formula IX wherein Τ is (C2-6)alkyl or cycloalkyl, as appropriate partially or completely _; U is -CN, -S〇2NRf2 or -NR, S02R"; each R| is independently Hydrogen' or substituted or unsubstituted alkyl, aralkyl 123505 -25- 200815422, heterocyclyl or heterocyclylalkyl; each R&quot; is independently substituted or unsubstituted - alkane a heterocyclic group, an aralkyl group or a heterocyclic alkyl group; and the hydrazine is a hydrazine or an amine protecting group. 84. A compound selected from the group consisting of: 3-tert-butyl _5-cyano group (6) · mercapto·5_(3·(neopentylaminomethane)phenylpyridin-3-yl)benzamide; f Ν_(5-(4-(benzyloxy)phenyl)methyl Pyridine_3_yl)_3_third·butyl benzylamine, a soil...rat 3-third-butylcyano-Ν_(5-(4_(3,3_dimethyl-2) Ketobutoxy)phenyl)methylenepyridyl)benzamine; vinegar 4 (5-(5-second-butyl-2-methoxybenzamide)-2• Methylpyridine I phenyl) phenyl ester; 3-tert-butyl _5-cyano_N_(5_(4-methoxy-2-methylphenylmethylpyridin-3-yl)benzimidazole Amine; 3-tert-butyl_5-cyanide _N-(6-methyl_5_(4_(neopentylcarbenyl)phenylpyridin-3-yl)benzamide; 3-fluoro_N-(6-methyl_5_(4_( Neopentylaminomethyl)phenyl)-pyridyl)_5_morpholinebenzamide; 3--&quot;butyl-5-cyano-N-(6-methyl-5- (4-(tetrahydro-2H_pyranyl)-phenyl)pyridin-3-yl)benzamide; 3N-(5-(4-methoxyphenyl)_6_A Group 比 比 -3 · · · · -5 -5 - ; ; ; N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N Each cyano group 123505 -26- 200815422 -2-methoxybenzamide; 3-(amino group f)-5_t-butyl-N-(5-(4-(l-hydroxyethyl) Phenyl)methyl picidin-3-yl)-2.methoxybenzylamine; 5-tert-butyl-3-(N-hydroxycarbamimidino)-indole-(5- (4-(1-(hydroxyimino)ethyl)phenyl)-6-methylpyridin-3-yl)-2-methoxybenzimidamide; 5-(3-di-di-butyl) 5-5-cyanobenzylamino)-2'-methyl-N-((tetrahydrofuran-2-yl)methyl)-2,3'-biindole-5-carboxyl with an amine; 5'-(3-Third-butyl-5-cyanobenzamide)-2,-methyl ((tetrahydro) Furan-2·yl)methyl)-3,31^linked p to bite-6-carboxyguanamine; di-butyl-5-cyano-N-(6-methyl-5-(4-( Hexahydropyridinyl-1-ylaminoindenyl)phenyl)pyridin-3-yl)phenylhydrazine; 3-tert-butyl-5-cyano-indole_(6·methyl-5- (4-(N-Pentylamine sulfonyl)phenyl)pyridin-3-yl)benzamide; i-(5-(3-Fluoro-5-morpholinebenylamino) -2-methylpyridin-3-yl)_N-((tetrahydrofuran-2-yl)indolyl)-1Η-1,2,3-triazole-4-carboxamide; N-(5-(4- Third-butyl-1Η·1,2,3_triazole small group) each methylpyridin-3-yl)-3-fluoro-5-morpholinebenzimidamide; 3-fluoro-N -(6-fluorenyl-5-(4-(pyridin-2-yl)-1Η-1,2,3-triazol-1-yl)pyridin-3-yl)-5-morpholinylbenzoquinone Indoleamine; 3-fluoro-N-(5-(4-(methoxymethyl)-1Η-1,2,3-triazol-1-yl)-6-methylpyridin-3-yl)- 5-morpholinebenzamide; H5-(3-t-butyl-5-cyanobenzamide)-2-mercaptopyridin-3-yl)-N-neopentyl- 1Η-1,2,3·triazole-4-carboxyguanamine; 3_T-butyl-5-cyano-indole-(6-fluorenyl-5-(4-(3-mercaptobutyl)) _1Η·1,2,3- 123505 -27- 200815 422 triazole small group pyridin-3-yl)benzamide; (Z)-3-tris-butyl-5-cyano-N-(5-(4-(l-(hydroxyimino)) -3-mercaptobutyl)-111-1,2,3-tris-yl-1-yl)-6-methyl-3-yl)benzoic acid amine; 3-tert-butyl-5 -Cyano-N-(6-methyl-5-(4-(2-methyl-1-(neopentylamino)-1-8-propenylpropan-2-yl)-1Η-1, 2,3·三唾小基)External 1:唆·3-yl)phenylhydrazine; Ν-(3-t-butyl-5-cyanophenyl)-6-methyl-5-( 4-(neopentylaminomercapto)_1H_1,2,3·three α sitting_1_yl) final test amine; Ν-(6-mercapto-5-(4-(neopentylamine) Base)-ΐΗ-1,2,3·triazol-1-yl),pyridin-3-yl)-2-isofenyl-iso-indoleamine; Ν-(6·methyl-5-( 4-(neopentylaminocarbazyl hh-UJ-triazole-1_yl)p-pyridin-3-yl)-2-(hexahydropyridin-1-yl)isonicotinamide amide; 3_fluorine -N-(6-methyl-W-p-amylamine-methylhydrazino)phenyl&gt;pyridinyl-3-carbolinebenzamide; 3-t-butyl-5-cyano-1 (5-(3-(Dimethylamine-methyl)phenyl)phenylmethylpyridin-3-yl)benzamide; 1-(5-(5-tri-butyl-1-methoxybenzene) Methylamino)_2_methyl Pyridin-3-yl)neopentyl-1H-1,2,3_tris-s-_carboxamide; Η5-(3·fluoro-5-morpholinebenzimidyl)-2- Methylpyridinyl) Sundopentyl-1Η-1,2,3-triazole glacial guanamine; 5_Third-butyl 1 methoxy-indole-(5-(6-methoxy oxime) -2-yl)-6-methylpyridin-3-yl)benzamide; 3_Third-butylcyano-oxime_(5_(3·(3,3-dimethylbutyrylamine) )phenyl)methyl p to 唆-3-yl)benzamide; N-(2,6fcmethyl-3,4'-bipyridyl-5-yl)3-fluoro-5-? Florinyl benzamidine 123505 -28 - 200815422 amine; 3-tert-butyl-5-cyano-N-(2,6,-dimethyl-3,4,-bipyridyl-5) Benzomethamine; 3-fluoro-N-(5-(4-methoxymethylphenyl)-t-methylpyridyl-3-yl)-5-oxalinylbenzamide; $N-( 5-(4-Ethylphenyl)-6-methylpyridin-3-yl)-5-tris-butyl-2-methoxybenzoin; N-(5-(4-B Nonylphenyl)-6-methylpyridin-3-yl)-5-tris-butylmethoxy-3-(methylsulfonylamino)benzamide; N-(5-(4-B Nonylphenyl)-6-methylpyridin-3-yl)-3-fluoroethyl morpholine benzoguanamine; N-〇 (4_(Germanidomethylmercapto)phenyl)-6-methylpyridine-3-yl)-5_t-butyl-2-methoxybenzamide; 5-tri-butyl- Ν-(5·(4-(3,4-dimethoxybenzylamine)methyl)phenyl)methylpyridin-3-yl)-2-methoxybenzamide; 5- Tri-butyl-2-methoxyindole-(5-(4-(3-methoxy)benzylamino)phenyl)methylpyridin-3-yl)benzamide; (5-(4-(decylamine decyl)phenyl)-6-methylpyridine|yl group&gt;3_fluoro-5-?? 12 base benzoylamine; Ν-(5-(4- (3,5-dimethoxydecylamine-methylhydrazino)phenyl)-6-methylpyridinyl)-3-fluoro-5-moffinylbenzamide; 3-fluoro-N -(5-(4-(3-methoxybenzylaminecarbamimidyl)phenyl)oxanylindole-3-yl)-5-morphine-based benzamide; 3-fluoro- N-(5-(4-(4-methoxybenzylaminoindolyl)phenyl)_6-mercaptopyridine winter 123505 -29- 200815422 base)_5_homofolinyl benzoguanamine; N- (5-(4-(Benzo[d][l,3]dioxosylene_5-yldecylamine decyl)phenyl)·6-methyl leaf b -3-yl)· 3-fluoro-5-moffinylbenzamide; 1-(5-(3-fluoro-5-? (Linyl benzoguanamine) 2 - decylpyridin-3-yl)-N-7-pyridinylmethyl)_1Η_1,2,3·triazole carboxy guanamine ·, 1-(5-(3_ Fluoro-5-morpholinylbenzimidamide)_2-methylpyridyl)-indole-isobutyl-1Η-1,2,3-tris-s--4-propanosamine; Ν-(ring Propylmethyl)small (5-(3-fluoro-5-homofolinylbenzimidino)-2-methylexyl; °-3-yl)-111-1,2,3 -3° sit-4_ slow oxime; 1-(5-(3-fluoro-5-homofolinylbenzimidylmethylpyridinyl)-team (3,3,3-trifluoro Propyl)-lH-l, 2, 3-tri. Sitting on the ice, sulphate; 3-fluoro-indole (6-fluorenyl-5-(4-((tetrahydro-2-indole))-methyl carbazyl) phenyl &gt; _ base)-5-moffinylbenzamide; 3-fluoro-N-(6-methyl-5-(4-((tetrahydrofuran-2-yl)methylaminemethanyl)phenyl) Pyridin-3-yl)-5-morpholinebenzimidamide; 5_t-butyl-N-(5-(4-(3,5-dimethoxybenzylamine)methyl)phenyl) _6-Methylpyridin-3-yl)-2-methoxybenzimidamide; N-(5-(4-(benzo[d][l,3]dioxosyl-5-yl) Amidino)phenyl)-6-decylpyridin-3-yl)-5-tri-butyl-m-methoxybenzamide; 5-tri-butyl-2-methoxy -N_(6-methyl-5-(4-indolyl-3-aminomethylmercapto)phenyl)pyridin-3-yl)benzamide; 5·Third-butylmethoxy_ N-(6-Methyl-5-(4-(tetrahydro-2-indolyl)-pyridin-4-ylaminocarbamoyl)phenyl)pyridin-3-yl)benzamide; di-butyl- 2-methoxy-indole-(6-methyl-5-(4-((tetrahydro-2Η·)-4-yl) 123505 -30- 200815422 methylamine-mercapto)phenyl)pyridine_ 3_yl)benzamine; 5-second-butyl-2.methoxy-oxime·(6-methyl- 5-(4-((tetrahydrofuran-2.yl)methylaminemethane)phenyl)pyridinyl)benzamide; Ν·(5-(4-(3,4-dimethoxybenzyl) Hydrazinyl)phenyl)methylpyridinyl)-3-fluoro-5-morpholinebenzamide; 3H(6·methyl·5-(4-indolyl-3 -ylmethylamine-methyl hydrazino)phenyl oxazolidine-3-yl)-5-morphine-based benzamide; r 4-((4-(5-(5-tri-butyl-2) -Methoxybenzylaminoamido)-2-methylpyridine-3-(yl)phenylhydrazinyl)methyl)benzoic acid methyl ester; 3-fluoro-N_(6-methyl-5-( 4-(tetrahydro-2H-piperidinylcarbinyl)phenyl)indole-3-yl)-5-morphine-based benzamide; 4-((4-(5_(3) - murine-5-fosfos p-linyl phenyl hydrazone)-2-methyl p butyl-3-yl) benzalkonium)methyl)benzoic acid methyl ester; second butyl- 5-Alkyl-N-(6-methyl-5-(4-((tetrahydro))-2-yl)methylaminemethyl hydrazino)phenyl)pyridin-3-yl)benzamide; I 3-di-di-butyl-5-ranyl-indole-(6.methyl-5-(4-((tetrazo-2H-pyran-4-yl)decylamine)-phenyl)phenyl) Pyridin-3-yl)benzamide; Ν-(5-(4·(benzylaminemethanyl)) )--6-methylpyridin-3-yl) each of the third butyl-5-cyanobenzamide; 1-(5-(3-fluoro-5-morpholinebenzamide) 2-methylpyridin-3-yl)-N,N-dimethyl-1H],2,3-triazole-4-carboxamide; 1-(2-methyl-5-(3) - morpholinyl-5-(trifluoromethyl)benzylidinium)pyridin-3-yl)-N-neopentyl-1Η·1,2,3-triazole-4-carboxamide; 1-(2-Methyl-5-(3-(tetrahydropyrrole-1_yl)-5-(trifluoromethyl)-benzamide) 123505 -31 - 200815422 Pyridin-3-yl)- N-neopentyl-1Η-1,2,3-triazole carboxy guanamine; 1-(5-(3-1--5-(hexahydro-p-but-butoxy)benzamide-based) -2-fluorenyl b唆-3«·yl)-N·neopentyl-1H-1,2,3-tris-s--4-redecylamine; H5-(3-fluoro-based 5-(four Hydropyrrole small) benzhydrylamino)-2-methylpyridin-3-yl)-N-neopentyl-1H-1,2,3-triazole-4-carboxamide; 1-(5 -(3-Fluoro-5-morphobolinylbenzimidyl)-2-methylpyridine I-yl)-N-(2-methylbutyl)-1Η-1,2,3-triazole -4-carboxyguanamine; N-(cyclohexylmethyl)-l-(5-(3-fluoro-5-norfosylphenylindolyl)-2-methylpyridin-3-yl)- 111-1,2,3-triazole-4- Indoleamine; 1-(5-(3-fluoro-5-?-fusino-p-phenylbenzoylamino)-2-methyl-bito-3·»yl)-N-((tetrahydro-2H-) Piperazin-4-yl)methyl)-1Η-1,2,3-triazole-4-carboxamide; 1-(5-(3-fluoro-5-?-morpholinebenzimidamide) -2-methylpyridinyl)-N-(2-yl-2-ylethyl)·1Η-1,2,3-tris--4-re S&amine; 1-(5- (3-fluoro-5-morpholinobenzamide)-2-methylpyridine-3-yl)-N-(l-hydroxy-3-methylbutan-2-yl)_1H-1, 2,3-triazole-4-carboxyguanamine; N-((l-ethyltetrahydropyrrol-2-yl)methyl)-1-(5-(3-fluoro)-5-morpholinyl Alanine amino)-2-methylpyridin-3-yl)-1Η-1,2,3-triazole-4-carboxamide; 5-tris-butyl-3-cyano-oxime- (5-(4-((1)ethyltetrahydropyrrol-2-yl)methylamine decyl)phenyl)-6-methylpyridin-3-yl)-2-methoxybenzimidazole Amine; 5-tris-butyl-3-cyano-2-methoxy-N-(6-methyl-5-(4-(1-methylhexahydropyridin-4-ylaminocarbamoyl) Phenyl)pyridin-3-yl)phenylhydrazine; 5·T-butyl-3-cyano-2-methoxy-N-(6-methyl-5-(4-((1- Methylhexahydropyridin-4-yl)methylamine decyl)-benzene Oleidine _3_yl)benzamide; 3-fluoro-N-(6-methyl-5_(4·(1-methylhexahydropyridin-4-ylaminecarbamoyl)phenyl) 123505 - 32- 200815422 外匕唆_3_基)·5-moffinylbenzamide; 3-fluoro-indole_(6-methyl-5-(4-((1-methylhexahydropyridine-4) -yl)methylamine-methyl fluorenyl) benzyl) leaf 1: sigma-3-yl)-5-moffinyl benzoquinone; 5-tris-butyl-3-cyano-2- methoxy-N-(6-methyl-5-(4-(pyridin-3-ylmethylaminemethane)phenyl)acridin-3-yl)benzamide; Η5-(3- Fluoro-5-morpholine benzylamino)-2-methylpyridin-3-yl) small 1-(tetrahydro-2H-pyranyl)-1Η·1,2,3-three Oxazol-4-carboxyguanamine; Ν-cyclohexyl small (5-(3-fluoro-3-pentanylbenzoylamino)-2-methylpyrrolidine)-111_1,2, 3-tris--4-demethylamine; N-cyclopentyl-1-(5-(3-fluoro-5-?-morpholinebenzimidamide)-methylenemethylpyrazine _3_yl -1Η-1,2,3-tris-s- 4-carboxamide; 1-(5-(3-fluoro-5-homofolinylbenzimidino)-2-mercaptopyridine-3 -yl)-Ν(3-hydroxy-2,2-dimethylpropyl)-1Η-1,2,3-triazole glacial guanamine; 1-(5-(3-third- Butyl-5-cyanobenzoguanamine)-2-methylpyridinyl)-N-((tetrahydrofuran-2-yl)methyl)-lH-l,2,3-triazole-4-carboxylate Indoleamine; 1-(5-(5-tri-butyl-cyano-2-methoxybenzoguanidino)_2·methylpyridin-3-yl)-1Η·1,2,3_ Triazol-4-carboxylic acid tert-butyl ester; Η5-(3-cyano-5-morpholinebenzimidyl)-2-methylpyridin-3-yl)-N-((tetrahydrofuran) -2-yl)methyl)-1Η-1,2,3-triazole-4-carboxamide; H5-(3-cyano-5-(hexahydropyridin-1-yl)benzamide) -2-decylpyridin-3-yl)-N-((tetrahydrofuran-2-yl)indolyl)-1Η-1,2,3-triazole-4-carboxamide; 1-(5-(3) -Cyano-5-(tetrahydropyrrole small)benzimidino)-2-methylpyridin-3-yl)-N-((tetrahydrofuran-2-yl)indolyl)-1Η_1,2,3 - triazole-4-carboxyguanamine; N-(5-(4-((l-ethyltetrahydrop)-methyl-2-methyl)methylamine) phenyl) phenyl) 123505 -33- 200815422 Base p is more than -3-yl)-3-Denyl-5_fofolinylbenzamide; 1-(5-(3-tri-butyl-3-cyano-2-methoxybenzene) Methionido)-2-methylpyridin-3-yl)neopentyl-1H_1,2,3-triazole-4-carboxamide; 1-(5 -(5-Third-butyl-3-cyano-2-methoxybenzimidino)-2-methylpyridin-3-yl&gt;N_(pyridin-3-ylmethyl)&gt;-1,2,3·triazole-4-carboxyguanamine; 1_(5-(3-tris-butyl-5-cyanobenzoguanidino)-2-methylpyridine-3·yl) -N-((l-ethyltetrahydropyrrol-2-yl)indolyl)-1Η-1,2,3-triazole-4-carboxamide; /di-butyl-methyl-N-( 6-Methyl-5-(4-(4-methylhexanitropurine p-well-l-l-carbon\yl)_1H-1,2,3-triazole-based)pyridin-3-yl)benzimidazole Amine; 1-(5-(5-tri-butyl-3-cyano-2-methoxybenzoguanidino)-2-mercaptopyridine)-N-((tetrahydrofuran-2-) Methyl)_1H-1,2,3-triazole glacial guanamine; 3-tert-butyl-5-cyano-N-(6-fluorenyl-5-(4-(morphine) -4-carbonyl)-lH-l,2,3-triazole small group)pyridin-3-yl)benzamide; 1-(5-(3-tri-butyl-5-cyanobenzoic acid) Amidino)-2-methylpyridin-3-yl)-N-(l-methylhexahydropyridyl)-1Η-1,2,3-triazole-4-carboxamide; (H5- (3-tert-butyl-5-cyanobenzamide)-2-methylpyridin-3-yl)-N &lt;2-(tetrahydropyrrol-1-yl)ethyl)·ιη-1,2,3-triazole carboxy guanamine; M5-(3-tert-butyl-5-cyanobenzoquinone Amino)-2-methylpyridinyl)-team (2-(dimethylamino)ethyl)_1H-1,2,3-triazole glacial guanamine; 1-(5-(3- Di-butyl-5-ylaminobenzoylamino)-2-methylindole-3-yl)-indole-(2-methoxyethyl)-1Η_1,2,3_triazole-4 - Carboxylamamine; 1·(5-(3-Terti-butyl-5-cyanobenzylidinium)-2-indolylpyrene-11) )-111-1,2,3-tris-s--4-derivative; 1-(5-(3-tri-butyl-5-cyanobenzoguanamine)-2-methylpyridinium士123505 -34- 200815422 基)-1^-(hexahydropyridin-4-yl)-111_1,2,3-triazole-4-carboxamide; 1-(5-(3-tri-butyl) -5-cyanobenzamideamino)-2•methylpyridin-3-yl)_N-(hexahydropyridin-3-yl)1H-1,2,3-triazole-4-carboxyguanamine 1-(5-(3-Terti-butyl-5-cyanobenzamide)-2-mercaptopyridin-3-yl)-N-(2-hydroxypropyl)-1Η-1, 2,3-triazole carboxy guanamine; 1-(5-(3-fluoro-5-(1,4-oxo-7-yl)-benzylamino)-2-methylpyridine•3 -base)-N- ((tetrahydromethane-2-yl)methyl)·1Η·1,2,3-tris-s--4-propanamine; 1-(5-(3-1-yl-5-(tetrahydro-t-t 17-1-yl)benzamide amino) 2 -methylindole-3-yl)((tetrahydrocarba-2-yl)methyl)-1Η-1,2,3-triterpene- 4-Wei S basket amine; H5-(3-cyano-5-(tetrahydropyrrol-1-yl)benzylidinium)-2-methylpyridine-3-yl)-N-neopentyl-1H -1,2,3-triazole-4_carboxamide; 1-(5-(3-cyano-5-(hexahydropyridinyl)benzamide)-2-methylpyridine-3 -yl) neopentyl-1H-1,2,3-triazole carboxy guanamine; 1-(5-(3-cyano-5-morpholinebenzimidino)-2-methyl Pyridin-3-yl)-N-neopentyl-1H-1,2,3-triazole-4-carboxamide; 1-(5-(3-carbyl-5-thio-norofenylbenzene) Brewed amino)-2-mercaptopurine ρ-indole-3-yl KN-neopentyl-1H-1,2,3-triazole carboxy guanamine; 1-{5-[3-fluoro-5 -(1-keto-1 human 4 thiomorpholine-4-yl)-benzylideneamino]-2-indenyl σ -3--3-}}Η-[1,2,3 Triterpene-4·wei (2,2-dimethyl-propyl)-decylamine; 1-(5-(3-tris-butyl-5-cyanobenzoinyl)-2 -Methyl 1^ is more than -3 -)-N-((l-methylhexahydropyridin-4-yl)indolyl _1H-1,2,3-triazole-4-carboxamide; 3-tert-butyl-5-cyano-N-(5-(4-(4-(2-hydroxyethyl))hexahydro) Pyridinium small carbonyl)-1Η-1,2,3-trit-1-yl)-6-methyl p 唆_3_yl)benzamide; 123505-35- 200815422 1-(5-( 3-second-butyl-5-cyanobenzamide)- 2-methylpyridine-3-yl)(2,2,6,6-tetramethylhexahydropyridine_4_yl)_1H- 1,2,3_s oxazole carboxamide; H2-methyl-5-(3-(tetrahydropyrrole_1_yl)&gt;5-(trifluoromethyl)benzylideneamine)_exudidine-3 ·-)-N-0-pyridin-2-ylmethyl)], 1,2,3-triazole, carboxamide; 1-{5-[3-(1,1-dione--1 6-Thiofolin-4-yl)·5-fluoro-benzimidamide]_2-methyl-acridin-3-yl}·1Η_[1,2,3]triazole carboxylic acid ( 2,2-dimethyl-propyl) decylamine; 1-(5-(3-tris-butyl-5-cyanobenzamide)-2-methylpyridyl)-N-pyridinium _2_ylmethyl)_1H-1,2,3-triazole-4-carboxyguanamine; 5-tris-butyl-3-cyano-2-methoxy-N-(6-methyl -5-(4-(neopentylaminomethyl)phenyl)pyridin-3-yl)benzamide; 3-bromo-5-tri-butyl-2-methoxy-N- (6-methyl-5-(4-(neopentyl) (Indolyl)phenyl)pyridin-3-yl)benzamide; (R)-5-tris-butyl-3-cyanyl-indole-(5-(4.((1-ethyltetra) Hydropyrrolidin-2-yl)methylamine-carbenyl)phenyl)-6-methyl-p-butyl-3-yl)-2-methoxybenzamine; H5-(3-cyano-5 -(hexahydropyridine small group) benzhydryl) 2 -methylpyridine; yl)-indolepyridin-2-ylmethyl)_111_1,2,3-triazole-4-carboxamide; 3 - 苐di-butyl-5-cyano-N-(6-methyl-5-(4-7-bito-2-ylmethylaminoindolyl)phenyl acridine-3-yl)benzimidazole Amine; 6-(6-fluorenyl-5-(4-(pyridin-2-ylmethylaminemethyl fluorenyl)phenyl)pyridine _3·yl) each (tetrahydropyrrol-1-yl)-5-( Trifluoromethyl)benzamide; second-butyl-5-cyano-N-(6-mercapto-5-(4-((1-methylhexahydro-p-but-2-yl)) Methylaminoindenyl)phenyl)pyridin-3-yl)benzamide; Ν·(6-methyl-5-(4-((1-methylhexahydropyridin-2-yl)methyl) Amidylmercapto)benzene 123505 •36- 200815422 base&gt;pyridin-3-yl)-3-(tetrahydropyrrol-1-yl)-5-(trifluoromethyl)benzamide; 5- Tri-butyl-3-cyano-2-methoxy-N-(6-mercapto-5-(4-((1-methyl-6) Pyridin-2-yl)methylamine decyl)-phenyl)pyridinyl)benzamide; (R)-3-tert-butyl-5-cyano-N-(5-(4- ((l-ethyltetrahydropyrrolyl)methylamine decyl)phenyl)-6-methylpyridin-3-yl)benzamide; (R)-N-(5-(4-( (l-Ethyltetrahydropyrrolyl)methylaminemethylene)phenyl)-6-methylpyridin-3-yl)-3-morpholine-5-(trifluoromethyl)benzamide Amine; (R)-N-(5-(4-((l-ethyltetrahydropyrrole-2-yl)methylaminemethane)phenyl)-6-methylpyridin-3-yl)_3_ (tetrahydropyrrole small)_5-(trifluoromethyl)benzamide; (R)-N-(5-(4-((l-ethyltetrahydropyrrole-2-yl)methylamine) Mercapto)phenyl)_6-methylpyridin-3-yl)-3-(hexahydropyridin-1yl)-5-(trifluoromethyl)benzamide; 1-(5-(3- Tri-butyl-5-cyanobenzamide)-2-mercaptopyridin-3-yl)-N-((l-methylhexahydropyridin-2-yl)methyl)triazole-4 - Carboxylamamine; 1-(5-(5-tris-butyl-3-cyano-2-methoxybenzamide)-2-methylpyridin-3-yl)-N- ((l-methylhexahydropyridin-2-yl)methyl)_ih-1,2,3-triazole-4-carboxyguanamine; 1-(5-(3-third·butyl) 5--5-cyanobenzoguanamine)-2-methylpyridyl)-N-cyclohexyl-1H-1,2,3-triazole-4-carboxamide; 1-(5-( 3-tert-butyl; cyanobenzylamino)-2-mercaptopyridine _3·yl) 1 (hexahydropyridine-1_yl)_out_1,2,3-triazole_4 -carboxylamidine; 3-tert-butyl-5-cyano-N-(6-methyl-5.(4-((6-methylpyridin-2-yl)methylaminemethanyl)benzene Pyridin-3-yl)benzamide; 5-tris-butylcyanomethoxy-indole-(6-methyl-5-(4-((6-methylpyrobitone-2) -yl)methylamine-mercapto)phenyl)pyridyl)benzamide; 123505 -37- 200815422 N-(6-methyl-5-(4-((6-methylpyridine-2-) Methylaminomethylmercapto)phenyl)p-pyridin-3-yl)-3.(tetrahydropyrrol-1-yl)-5-(trifluoromethyl)benzamide; 3-third -butyl-5-(6-methyl-5-(4-(neopentyl)indolyl)-phenyl)acridin-3-ylamine-carbenyl)benzoic acid methyl ester; 3-anthracene - Butyl-5-(6-methyl-5-(4-(neopentylcarbinyl)-phenyl)p ratio. N-(6-methyl-5-(4-(neopentylaminomethyl)phenyl]pyridin-3-yl)-2-( Hexahydroquinone sigma-1-yl) is different from prodamine; 5-t-butyl-indole-1 -(2-(didecylamino)ethyl)-N3-(6-methyl-5-( 4-(neopentylamine decanoic acid) ketone) sigma-3-yl)m-xylylene amide; 3-fluoro-indole-(5-(4-(1-(hydroxyimino))) Ethyl)phenyl)_6-methylpyridin-3-yl&gt;5-homofolinylbenzamide; 4-(5-(3-tri-butyl-5-cyanobenzamide) Methyl)-2-methylpyridin-3-ylbenzoate; 1-(5-(3-tert-butyl-5-cyanobenzamide)-2-mercaptopyridine- 3_yl)-1Η-1,2&gt; triazole-4·carboxylic acid ethyl ester; 1-(5-(3-tert-butyl-5-cyanobenzoguanamine)-2-methylpyridine _3-yl)_N-(2-(diethylamino)ethyl)-iH-l,2,3-triazole-4-carboxamide; 1-(5-(3-tri-butyl-5) _Cyanobenzoylamino)-2-methylpyridinyl)-indole-(2.(diisopropylamino)ethyl)-indole-1,2,3·triazole-4-carboxylate Indoleamine; 1-(5-(3-t-butyl-5-cyanobenzylideneamino)-2-methylpyridinyl)-N-(2-methyl-2-(hexahydro) Pyridin-1-yl)propyl)-1Η·1,2,3-triazole-4-carboxyguanamine; 1-(5-(3-tri-butyl-5-cyanobenzamide) -2-methylpyridin-3-yl)-N-((l-(hexahydropyridine small)cyclohexyl)methyl)_ih-1,2,3-triazole-4-carboxamide; 123505 -38 - 200815422 N-(6-Methyl-5-(4-(neopentylcarbinyl)phenyl)-pyridyl_3_yl)_2_isofenyl-based final amine; 3- Cyano-N-(6-fluorenyl-5-(4-((6-methyl-exo-indol-2-yl)methylamine)-phenyl)pyridin-3-yl)-5-? Folinylbenzamide; 3-oxy-N_(6-methyl-5-(4-((6-methylexyl): dimethyl-2-yl)methylamine) Pyridin-3-yl)-5-(tetrahydropyrrol-1-yl)benzamide; 3-cyano-N-(6-methyl-5-(4-((6-methylpyridine-2) -yl)methylamine-methyl fluorenyl)phenyl&gt; 唆-3·yl)_5_(hexahydro ρ than _1 yl)benzamide; 4- (5-(5-di-di-butyl) Benzyl-3-cyano-2-indolylbenzimidamide)_2-methyl p ratio 1,4--3-ylbenzoic acid methyl vinegar; 3_di-butyl-5-cyano-N -(5-(4-(cyclohexylaminemethyl)phenyl)methylpyridin-3-yl)benzamide; 3-dibutyl-butyl 5-5-cyano-N-(5-(4-(2-pethylamino)ethylaminemethyl)-phenyl)-6-methyl-pyrene-pyridyl-3-yl)benzamide; 3-Third-butyl-5-cyano-N-(5-(4-(2-(diisopropylamino)ethyl)indolyl)phenyl)-6-methylpyridine-3 -yl)benzamide; 3-di-butyl-5-cyano-N-(6-methyl-5-(4-(2-methyl-2-(hexahydro-p-bite-1) -yl)propylamine-mercapto)phenyl)pyridinyl)benzamide; 3-tris-butyl-5-cyano-N-(6-methyl-5-(4-((1) -(hexahydropyridin-1-yl)cyclohexyl)methylaminecarboxamido)phenyl&gt;pyridin-3-yl)benzamide; 3-tris-butyl-5-(((2) -Methoxyethyl)(methyl)amino)methyl)_n-(6-methyl-5-(4-(neopentylcarbamate)phenyl)-p ratio base) benzyl Indoleamine; 3-tert-butyl-N-(6-fluorenyl-5-(4-(neopentylcarbinyl)phenyl)p than indol-3-yl)_5_(tetrahydropyrrole small Methyl)benzamide; 123505 -39- 200815422 3-Terti-butyl-oxime (6-methyl-5-(4-(neopentylcarbinyl)phenyl)tonidine- 3-yl)-5-(hexahydropyridine small fluorenyl) benzoguanamine; 3-D'5-(4-(1-ethyl) Base)_6_methylpyridine_3_yl)_5•morpholinobenzamide; 1-(5-(3-tert-butyl-5-cyanobenzamide)_2_A Pyridyl _3•yl)-N_ sulphate 4 yl---1,2,3-trimethyl-4-carboxylic acid amine; 1-(5-(3-tri-butyl-5-cyanobenzene) Amidino) 2 -methylpyridine _3_ f yl) _ (tetrahydro-2H-piperidinyl)-1 Η·1,2,3-triazole carboxy guanamine; 5-third-butyl Benzyl-3-cyano-indole-(5-(4.(cyclohexylaminecarboxylidene)phenyl)methylidene-3-yl)-2-methoxybenzoquinone; 5- Tri-butyl-3-cyano-2-methoxy-N-(6-methyl-5-(4-(hexahydropyridyl)carbinyl)phenyl)pyridin-3-yl)benzene Methionine; di-β-butyl-3-cyano-2-methoxy-N-(6-methyl-5-(4-(tetrahydro-211-l-butan-4-ylamine) Phenyl wind bite _3_yl) benzamide; 5-tris-butyl-3-cyano-2-methoxy-N-(6-methyl-5-(4-() Lolinylamine i) formamyl)phenyl)-pyridin-3-yl)benzamide; di-butyl-N-(6-methyl-5-(4-(neopentylamine) Base) phenyl) said bite-3·yl)-5-((4-methylhexahydropyrrolidin-1-yl)methyl)benzamide; 3-third-butyl --N-(6-methyl-5-(4-(neopentylamino)phenyl)-pyridine-3-yl)-5-(((tetrahydrofuryl)methylamino)methyl)benzene Indoleamine; 3-tert-butyl-N-(6-methyl-5-(4-(neopentylcarbinyl)phenyl)-pyridine-3-yl)_5-((propyl-2) -alkynylamino)methyl)benzamide; 3_second-butyl-N-(6-methyl-5-(4-(neopentylamine)-yl) phenyl-3 -yl)-5-(morpholinylmethyl)benzamide; 123505 -40- 200815422 3-T-butyl-N-(6-methyl-5-(4-(neopentylamine) Methyl fluorenyl)phenyl)-pyridyl)-5-((3-ketohexahydropyrrolidine)indolyl)benzamide; 3-tris-butyl-N-(5-( 4-(2-tert-butylfluorenylcarbonyl)-1Η-1,2,3-triazol-1-yl)-6-methylpyridin-3-yl)-5-cyanobenzamide; 3-Terti-butyl-5-cyano-N-(5-(4-(2-cyclohexylfluorenecarbonyl)-1Η-1,2,3-triazol-1-yl)-6-mercaptopyridine Benzyl)benzamide; 1-(5-(3-tris-butyl-5-cyanobenzamide)-2-methylpyridin-3-yl)-N-(2,6 - dimethyl hexahydropyridine small group) -1 Η-1,2,3-triazole carbaryl amide; N-(6-methyl-5-(4-(neopentylamine) Phenyl)-pyridin-3-yl)-2-(tetrahydropyrrol-1-yl)isonicotinamine amide; 3-tert-butyl-N-(6-methyl-5-(4) -(neopentylamine-methyl)phenyl)-pyridin-3-yl)-5-((2-(methylthio)ethylamino)methyl)-benzamide; 3·3rd 5-(((2-(dimethylamino)ethyl))(methyl)amino)methyl)-N-(6-methyl-5-(4-(neopentylamine) Phenyl)-pyridin-3-yl)benzamide; 3-tris-butyl-5-cyano-N-(6-methyl-5-(4-(morpholinolamine) Phenyl)-pyridin-3-yl)benzamide; 3-tert-butyl-N-(5-(4-(2-tris-butylfluorenyl)phenyl)-6- Pyridin-3-yl)-5-cyanobenzamide; 3-tert-butyl-5-cyano-N-(5-(4-(2-cyclohexylfluorenylcarbonyl)-phenyl)· 6-methylpyridin-3-ylphenylamine; 5-tris-butyl-indole-(5-(4-(2-tris-butylphosphonyl)phenyl)-6-fluorenyl Pyridyl _3_yl)-3 cyano-2-nonyl phenyl hydrazide; Η5-(3-fluoro-2-yloxy-5-morpholinophenyl hydrazino)- 2-mercaptopyridine·3-yl)neopentyl-1H-1,2,3-triazole-4-carboxamide; 123505 -41 - 200815422 ^(5- (3-Fluoro-2-methoxy_5_morpholinobenzamide)_2-mercaptopyridine·3_yl)-N-((tetrahydroanthracene-2-yl)A Base)·1Η-1,2,3-triazole-4-carboxamide; l-〇(3-|L-yl-2-methoxy_5_morpholinobenzamide)_2_ Methyl pyridine bite) · Ν-( Τ Τ _ _ _ _ _ _ methyl ΗΗ , , , , , ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; -methyl-5-(4-indolyl-3-ylmethylamine fluorenyl) phenyl &gt;pyridin-3-yl)-5-norfosfylbenzamide; 3-fluoro- 2-曱oxy-patch (6-mercapto-5-(4_((tetrahydrofuran-2-yl)decylamine 曱f))phenyl)p-pyridyl)-5-moffinylbenzamide ; 3-fluoro-2-methoxy-N-(6-methyl-5-(4-(neopentylcarbinyl)phenyl)-exoazin-3-yl)-5-? Polinylbenzamide; 3-t-butyl-5-cyano_N_(5-(4-(2,6-dimethylhexahydropyridinyl)-phenyl)phenyl)-6 -methylpyridinyl)benzamide; 5-tris-butyl-3-ylcyano-N_(5_(4_(2,6-dimethylhexahydropyridyl)-phenyl)phenyl -6-methylpyridin-3-yl)-2-methoxybenzimidamide; 1-(5-(5-tri-butyl-3-cyanide) Winter methoxybenzimidamide)-2-methylpyridyl; (N,6-dimethylhexahydropyridin-1-yl)-iH-l,2,3- Triazole-4-carboxyguanamine; M5_(5-tris-butyl-3-cyano-2-methoxybenzamide)-2-methylpyridin-3-yl)_team Hexahydropyridine small triazole ice carboguanamine; 5 second · butyl-N-(5-(4-(2-t-butyl) weiwei)-111-1,2,3-three -1-yl) heptamethylpyridine _3_yl)-3 cyano-2-methoxybenzamide; third-butyl-5-(morpholinemethyl)phenyl hydrazide ))-2-methylpyridyl)-N-neopentyl-1H_1,2,3-triazole-4-carboxamide; 5-tris-butyl-3-cyanyl-N-(5 -(4-(2-cyclohexylfluorenylcarbonyl)-1Η-1,2,3-triazole 123505 -42- 200815422-1-yl)-6-methylpyridin-3-yl)-2-decyloxy Benzoylamine; 1-(5-(3-tert-butyl-5-((4-methylhexahydropyridinyl) fluorenyl)benzimidamide)-2-methyl is bitten 3-yl) neopentyl·ιη-1,2,3-trimethyl-4-carboxamide; 3-cyano-N-(6-methyl-5-(4-(neopentylamine) Thiophenyl)phenylpyridinyl)-5-morphine-based benzoic acid; N-(5-tris-butyl-3-cyano-2-methoxy Phenyl)·6_methyl_5 pu (nepentylamine carbhydryl)-111-1,2,3-triazole+yl) in the base amide; Ν-(3-cyano-5-? Phenolinylphenyl)methyl_5_(4_(neopentylcarbamoyl)-1Η-1,2,3-tris-decyl)nicotinium amide; Ν-(3-fluoro-5 - morpholinylphenyl group &gt; 6_methyl_5_(4_(neopentylcarbamyl)_1Η_1,2,3·three-salt) nicotine amide; Ν-(3-first- Butyl heptamethyl-1-indole-3-pyrazolyl group&gt;6_methyl_5_(4_(neopentylamine methyl ketone^1,2,3^· 谈 醯 醯 ;; 1-(5-( 3 ship 5 oxygen enough _3 legacy _ double ring and [3 · 21] 辛 · 3_ base) _5_ gas benzoyl amide amino) -2- methyl 咐〇 士 士 士 士 戍 叫 叫 叫 叫 叫 戍Locking amine; 3_fl-N-(6-methyl-trans((tetrachloro-methane) methylamine methyl) phenyl acridine-3-yl)_5_morpholinebenzamide; 3 Cyano hydrazine (6-methyl_5_(4-7-pyridylsylmethylidenemethyl)methyl)-pyridin-3-yl)-5-morpholinebenzamide; N-(3 -Secondyl butyl phenyl)winter methyl _5 pu (nepentylamine carbaryl)_1H-1,2,3-tri. Nicotine amide; N-(5-Third-butyl-2-methoxyphenyl) methyl 5-5 neopentylamine-based 1-1-1,2,3- Nicotinic acid amide; (tert-butyl·5'(6-methyl-5-(4-(neopentylcarbamyl) 123505-43- 200815422 diin-1-yl)p Bis-butyl-3-ylaminocarbamoyl) arylamino)acetic acid tert-butyl ester; 2_(3_third·butyl_5_(6-methyl_5_(4·(neopentylamine) Base) phenyl) _ 比 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ (4-(neopentylaminomercapto)phenyl)-pyridin-3-ylaminecarboxamido)-amino)acetic acid; N-(5-(4-(8-oxo-3-nitro)bicyclo And [3·2·ι]octane-3-carbonyl)phenyl)methylpyridin-3-yl)-3-t-butyl-5-cyanobenzamide; N-(5_( 4-(8-oxo-3-nitro-bicyclo[3·2·1]octane-3-carbonyl)-1Η_1,2,3-triazole+yl)methylpyridin-3-yl)-5 • tert-butyl cyano-2-methoxybenzamide; 3_tri-butyl-5-cyano-N-(6-methyl_5-(4-(2,2, 6,6-tetramethylmorpholine-4-carbonyl)phenyl)pyridin-3-yl)benzamide; 5-Terti-butyl-3·cyano methoxymethoxy·Ν·(6-methyl_5_(4_(2,2,6,6-tetramethylphenoflavin-4-yl)- 1Η_1,2,3_triazole-l-yl>pyr-3-yl)benzamide; Ν-(5-(4-(8-oxo-3-nitro-bicyclo[3. 2. 1] Octane-3-carbonyl)-1Η-1,2,3-triazol-1-yl)-6-methylpyridin-3-yl&gt;3-tert-butyl-5-cyanobenzoic acid Guanidine; 3·T-butyl-5-cyano-indole-(6-methyl-5-(4-(2,2,6,6-tetramethylmorpholine-4-carbonyl)- 1Η-1,2,3-triazol-1-yloxazin-3-yl)benzamide; Ν-(5-tris-butyl-3-aminecarboxymethylmethoxyphenyl)-6 -methyl-5-(4-(neopentylcarbinyl)-1Η-1,2,3·triazole-μ group) oxime; Ν-(5-third-butyl-3 - (cyclopropylamine-mercaptomethoxyphenyl)methyl-5-(4-(neopentylcarbenyl)-yl) 1,2,3-triazole small group) in the base amide; Ν-(5-Third-butyl-2-methoxy_3-(methylsulfonylamino)phenyl)_6-methyl-5-(4-(neopentylaminocarbazinyltriazole) -1-yl) acetonamine; 123505 -44 - 200815422 N-(5-(4-(8-oxo-3-nitro-bicyclo[3. 2. 1]octane-3-carbonyl)phenyl)-6-methylpyridin-3-yl)-5-tris-butyl-3-cyano-2-methoxybenzoquinone; 5- Third-butyl cyano-2-methoxy-N-(6-methyl-5-(4-(2,2,6,6-tetramethylmorpholine-4-carbonyl)phenyl Pyridin-3-yl)benzamide; 5-tris-butylcyano-2-oxooxy_N-{6-methyl-5-[4-(10-oxo-4-nitrogen- Three rings and [5. 2. 1. 02,6]癸烧-4广基)-Phenyl]^ ratio. _3_基}_benzamide; 5-tris-butyl-3-cyano-2-methoxy-oxime {6-methyl_5_[4-(10-oxo-4- Nitrogen-three jade 弁[5·2·1·02,6] 癸-4-yl)-[1,2,3]tris-1-yl]pyrene _3_yl}-benzene Methionine; 3-tert-butyl-5-cyano-indole-{6-methyl-5_[4_(10-oxo-4-nitro-tricyclo[5·2·1·02,6癸 -4--4-carbonyl>[1,2,3]triazol-1-yl]pyridin-3-yl}-benzoguanamine; 3-t-butyl-5-cyano-oxime -{6-Methyl-5-[4-(10-oxo-4-nitro-tricyclo[5.2. 1·02,6]decane_4_carbonyl)-phenyl]-pyridin-3-ylbenzamide; 3-tert-butyl-hydrazine-(6-methyl-5-(4- (neopentylamine fluorenyl)phenyl)-ρ ratio -3-yl)-5-((2-(methylsulfinyl)ethylamino)methyl)benzamide; 3- Tert-Butyl-N-(6-methyl-5-(4-(neopentylcarbenyl)phenyl)-pyridin-3-yl)-5·((2_(曱石黄醯基)ethylamine) Methyl)benzamide; Ν-(3-tert-butyl-5-cyanophenyl)-6-methyl-5-(4-(hexahydro-p-butyl-1-amine) Mercapto)-111-1,2,3-tris-s-l-yl) in proline; N-(5-tris-butyl-2-methoxy-3-(methylsulfonamide) Phenyl)-6-glycolyl-5-(4-(hexahydroindole-1-ylaminemethyl hydrazino)_ih_1,2,3_triterpenyl) is tested by decylamine; N-(5 -T-butyl-3-cyano-2-methoxyphenyl)-6-methyl-5-(4-(hexahydropyridin-1-ylaminemethyl)-lH-1,2,3 ·Sansal-1_yl) in the test of guanamine; 123505 -45- 200815422 1-(5-(3-tert-butyl I cyano-2-(2-(4-methylhexahydropyrazine +) Ethyloxy)benzhydrylamine&gt;2-methylpyridine-3-yl)neopentyl-1Η-1,2,3-triazole-4-carboxamide; 5- -butyl cyano-indenyl-(6-methyl-5-(4-(neopentylcarbinyl)phenyl)-pyridin-3-yl)-2-(2-(4-methyl) Hexahydropyrazine + yl) ethoxy) benzepidine; 3-cyano-N-(6-methyl-5-(4-(N-neopentylamine sulfonyl)phenyl) -5-morpholinylbenzimidamide; 3-cyano-N-(6-methyl-5-(4-(N-neopentylaminesulfonyl)phenyl)pyridine-3-yl) _5_(four gas p than 洛基基)benzamide; 5·third-butyl cyano methoxymethyloxy_N-(6•methyl_5_(4_(N• neopentylamine) Phenyl)p than 唆_3_yl)benzamide; Ν-(6·methyl-5-(4-(neopentylaminomethyl)phenyl)-pyridyl)isoxazole 3-carboxycarboxamide; 3-tris-butyl small methyl-N_(6-methyl benzyl (4_(neopentylcarbinyl)phenyl)) σ -3-yl)-1Η - 峨 -5 -5-Wilylamine; 5-Terti-butyl-2-methyl-N-(6-methyl-5-(4-(neopentylcarbinyl)-phenyl acridine _3_基) gnaw _3_carboxamide; 3-tert-butyl-hydrazine-(6-methyl-5-(4-(neopentylcarbinyl)phenyl) -Base)-1Ηπ than salivation·5·slow gf amine; 5_third-butyl. (6-methyl·5_(4_(neopentylcarbinyl)phenyl>pyridin-3-yl)isoxazole-3-carboxamide; Η5-(3-tri-butyl-5 _Cyanobenzoylamino)_2-ethylpyridinyl neopentyl-1Η-1,2,3-triazole_4_carboxamide; 5-second-butyl-Ν1-methyl- Ν3 -(6-methyl-5-(4-(neopentylcarbamoyl)benzene 123505 -46- 200815422 yl)p-pyridin-3-yl)m-xylyleneamine; 5-third -N1-cyclopropyl-N3-(6-methyl-5·(4-(neopentylcarbenyl)phenyl)indol-3-yl)m-xylylene amide; 5-third -butyl-Ν1-(cyclopropylmethyl)·ν3-(6·methyl-5-(4-(neopentylcarbenyl)phenyl)pyridin-3-yl)m-xylylene hydrazide Amine; 5*&quot;Second-butyl-N1-(6-methyl-5-(4-(neopentylcarbinyl)phenyl)p-pyridin-3-yl)isophthalene Brewing amine; ", iK3-fluoro; flufenyl benzoguanidino)-2-hydrazinopyridine HH-1,2,3-triazole-4_carboxylic acid ethyl ester; 3-third -butyl-5-(6-methyl-5-(4-(p-pentylaminecarbazole)pyridin-3-ylaminocarbamoyl)benzoic acid methyl ester; ^(5-(3- Fluoro-5-(trifluoromethyl)benzimidamide)_ 2-methylpyridinyl)ne-n-yl-1H-1,2,3-tris--4-chitoamine; third-butyl-5-(dimethyl-5-(4-(neopentylamine) Mercapto)-1Η-1,2,3-triwax+yl)pyridin-3-ylaminemethanyl)benzoic acid; I 5 (3 di-di-butyl-5-gas basic alanine)_2 _Methyl-3-(4-(ne-decylamine-methyl sulfonyl)-p-styl-pyramine-1. Oxide; Tertiary-butyl-5-cyanobenzoguanamine)_2_indenyl_ 3_(4-(neopentylamine)]H-1,2,3-triazole-1-yl)π ratio biting 1-oxide; 5-tris-butyl-Nl _(cyclopropyl Methyl group&gt;N3 _(6_曱基净(4_(neopentylamine fluorenyl)-1Η-1,2,3-triazole-l-yl group&gt;pyridinyl)isophthalene Indoleamine; ^(5-(2,5-monomethoxybenzimidyl)-2-methylu than -3-yl)-N-neopentyl-1H-1,2,3-three Oxazole-4-carboxyguanamine; 5-tris-butyl-N1-methylindole-(6-methyl-5-(4-(neopentylaminecarbamate 123505-47-200815422))-1Η-1 , 2,3-triazole·1·pyrrolidine;yl)m-xylyleneamine; 3-cyano-5-(4-methyl-1indole-imidazolyl)_Ν-(6·methyl- 5-(4-(neopentylaminomethyl)phenyl&gt;pyridin-3-yl)benzamide; H2-methyl-5-(3-(4-mercapto-1H.imidazolyl)-5-(trifluoromethyl)benzamide)p ratio bite_3_yl)-N·neutamide -1H-1,2,3-trisyl-4-propanolamine; H5-(3-cyano-5-(4-methyl-1H-imidazolyl-1-yl)benzamide)- 2-methylpyridin-3-yl)_N-neopentyl-1Η-1,2,3-trimethyl-4-carboxamide; ξ ^ 苐 bis-butyl-5-cyanobenzoic acid amine) _2·methyl oxime. D--3-yl) 1 (3-hydroxy-2,2-dimethylpropyl)-1 private 1,2,3-triazole-4-carboxamide; (R)-l-(5-( 3-tert-butyl-5-cyanobenzoguanamine)-2-methylpyridin-3-yl)((tetrahydrofuran-2-yl)methyl)_1H_1,2,3_3 Salivary-4-propanolamine; (8)-1-(5-(3-t-butyl-5-cyanobenzamide)-2-methylpyridin-3-yl)-N-( (tetrahydrofuran-2-yl)methyl)_1H-1,2,3-triazole-4-carboxamide; 1-(5-(3-tri-butyl-3-cyano-2-methoxy) Benzobenzamide)-2-methylpyridin-3-yl)-N-((l-propylcyclopropyl)methyl)_ih-1,2,3-triazole carboxy guanamine; I) bistrimethylethylammonium benzhydryl)-2-methylpyridin-3-yl)neopentyl-1H-1,2,3-triazole glacial guanamine; N-(3 -Third-butyl-5-cyanophenyl)-6-mercapto-5-(4-(neopentylamino)phenyl) in the test amine; Ν-(5·third- Butyl-3-cyano-2-methoxyphenyl)methyl-5-(4-(neopentylamine)phenyl)nicotiniumamine; 5-tris-butyl-3 -Cyano-anthracene (5-(4-(3-carbazhen-2,2-dimethylpropylaminemethane)phenyl)-6-methylpyridin-3-yl)-2-yl Oxybenzamide; 5·Di-butyl-3-cyano-indole-(5-(4-((1-)-cyclopropyl)methylamine 曱醯123505 -48- 200815422 phenyl)&gt;6-methyl Pyridine_3_yl)_2•methoxybenzamide; H5-(5-Third-butyl_3_cyano-m-methoxybenzamide)·2_methylpyrazine-3 ······(3-carbyl-2,2 dimethylpropyl)-1Η_ΐ52,3-triazole carboxy guanamine; 1-(5_(3-third·butyl_5_(正_ Propylamine sulfonyl)benzhydrylamino)methylindole-3-yl)neopentyl]indole-1,2,3-trimethylcarboxamide; 1-(5-(3,5- Bis(neopentyloxy)phenylhydrazinyl)_2-methylpyridine; yl)-indole_neopentyl-1Η_1,2,3-trisaxylcarboxamide; 3-second-butyl Icyano _Ν-〇(4-(3-hydroxy-2,2-dimethylpropylaminemethane)phenyl)-6-methylpyridinyl)benzamide; 3-tert-butyl _5_Cyano-indole-(5_(4_(((hydroxypropyl)propyl)methylaminemethyl)phenyl)-6-methylpyridyl-3-yl)benzamide; 5_ Tri-butyl Νι, Νι _ dimethyl ice | methyl _5 pu (neopentylamine fluorenyl) phenyl &gt; butyl-3-yl) m-xylyleneamine; N- (5 -(4-(2-Amino-2-methylpropylamine) Mercapto)phenyl)pyridylpyridine-3-yl)-3-tris-butyl-5-cyanobenzamide; K2-mercapto-5-(3-trimethylethylammonium Benzoylamino) is pyridyl neopentyl-1H-1,2,3-triazole-4-carboxamide; 5-tris-butyl-N1-(6-methyl-5-( 4-((tetrahydrofuran-2-yl)decylamine decyl)phenyl acridine-3-yl)·Ν3 _(pyridin-3-ylindenyl)m-xylyleneamine; 1-(5· (5-Terti-butyl-2-methoxy-3-nitrobenzamide)-2-methylpyridin-3-yl) neopentyl_1Η·1,2,3·3 Oxazole-4-carboxyguanamine; 5-tert-butyl-2-decyloxy (6-methyl-5-(4-(neopentylaminomethyl)phenyl acridine-3))- 3-Phenylbenzamide; (RM-(5-(3-tert-butyl-2-indolyloxy-3-(tetrahydropyrrole-2-carboxyguanidino))benzene 123505 -49- 200815422 Methionido)_2-methylpyridin-3-yl)neopentyl-1H-1,2,3-triazole winter carboxamide; (R)-N-(5_third-butyl·2 -methoxy_3_(6-methyl-5.(winter (neopentylcarbinyl)phenyl)indol-3-ylaminecarbinyl)phenyl)tetrahydropyrrolecarboxamide; 5 ·Third-butyl-indole-1 -(6-methyl-5-(4-(neopentylcarbamyl))风 啶 -3--3-yl)-N3 -(pyridin-3-ylmethyl-phthalic acid amide; N-(5-tris-butyl-2-methoxy-3-(6-methyl) -5_(4-(neopentylcarbamoyl) ξ \ phenyl> σ 定 胺 胺 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) Third butyl _3-(1 Η-imidazole small group &gt; 2-methoxy | (6-methyl-5-(4-(neopentyl decanoyl))) ρ ratio -3- Benzoylamine; 1-(5-(5-tris-butyl-3-(1Η-imidazolidinyl)-2-methoxybenzamide)-2-methylpyridine-3 -yl)_N_neopentyl-1Η·1,2,3 •tris-s--4-terenol; 3-tert-butyl-5-(6-methyl-5-(4-((4) Hydroquinol-2-yl)methylamine-methyl indenyl)phenyl)pyridin-3-ylamine-methylmethyl)benzoic acid methyl ester; 3·t-butyl-5-cyano-N-(6) _Methyl-5-(4-(2-(hexahydroindole)) acetamidine (1 yl)phenyl)pyridin-3-yl)benzamide; 1-(5-(3-third -butyl-5-methoxybenzimidino)_2-methylpyridyl) neopentyl-1H_1,2,3-triazole-4-carboxamide; 3-tert-butyl- 5-methoxy-N-(6-methyl-5-(4-(neopentylcarbenyl)phenyl)pyridin-3-yl)benzene Indoleamine; 3-tert-butyl-5-(6-methyl-5-(4.(tetrahydrofuryl)methylaminemethane)phenyl)pyridin-3-ylaminecarboxamido)benzoic acid ; 5-Terti-butyl-N1, Ν1-dimethyl-N3-(6-fluorenyl-5-(4-((tetrahydrofuran-2-yl)methylaminemethanyl)phenyl) _3_yl) m-xylyleneamine; 123505 -50- 200815422 5-tris-butyl-N1-methoxy-N1-methyl-N3-(6-methyl-5-(4-( (tetrahydrofuran-2-yl)methylamine-methyl indenyl)phenyl&gt;pyridinyl-3-yl)m-xylyleneamine; 3-tert-butyl-N-(6-methyl-5- (4-(neopentylaminomercapto)phenyl)indole-3-yl)-5-(2-morpholylethoxy)benzamide; 5-tris-butyl-2- _Methoxy-3-(4-methyl-1H-imidazo-1-yl)_ν·(6-methyl-5-(4-(neopentylcarbinyl)phenyl)pyridinyl) Benzalamine; H5-(5-tert-butyl-2-methoxy-3-(4-methyl-1H-imidazolyl)benzamide)1 methyl p to bite-3 -yl-N-neopentyl-1H-1,2,3-tris-s--4-propanosamine; 5-tris-butyl-N1-((1-hydroxycyclopropyl)methyl)- N3 _(6-methyl_5-(4_((tetrahydrofuran-2-yl)methylamine) Phenyl)acridine_3_yl)m-xylylenediamine; 5-t-butyl-3-cyano-N-(5-(4-(cyclopentylamine)methyl)phenyl _6•methyl leaf I: -3-yl) _2-methoxybenzamide; 5-tri-butyl cyano _N-(5-(4_(4,4-difluorocyclo) Hexylamine carbhydryl)phenyl)-6-methylpyridin-3-yl)-2-methoxybenzamide; 5-second-butyl-3-cyano-oxime (5_(4) -(isopropylaminemethanyl)phenyl)methyl-based pyridine each &gt;2-methoxybenzamide; 5-tris-butyl-3-cyano-oxime-(5-( 4-(isobutylamine carbaryl)phenyl)-6-methylpyridin-3-yl)-2-methoxybenzamide; 5-second-butyl-3-cyano-N- (5-(4-(cyclopropylaminemethanyl)phenyl)-6-methylpyridin-3-yl)-2-methoxybenzamide; 5_T-butyl; cyano 1 methoxy_N_(6-methyl·5·(4·(2·(hexahydropyridin-1-yl)ethyl yl)phenyl oxazide _3·yl)benzamide; 5-third -butyl-N1 -(6-methyl-5-(4_(neopentylaminemethanyl HH_U,3•triazol-1-ylacridin-3-yl)&gt;N3_(2_(W-hydropyrrole small Ethyl)m-xylylenedicarboxylate 123505 -51 · 200815422 Amine; 5-Third -N1-(6-methyl-5-(4-(neopentylcarbinyl)-1η_1,2,3-triazole)pyridin-3-yl)-indole-3-((1-methyl) Hexahydropyridin-2-yl)methyl)m-xylyleneamine; 5-tris-butyl-3-cyano-N-(5-(4-((lr,4r)-4-hydroxyl) Hexylaminocarbazinyl)phenyl)-6-fluorenylpyridin-3-yl)-2-methoxybenzamide; N-(5-(4-((lR,2R,4S)-bicyclo) [2. 2. 1]g·2·ylamine-methyl hydrazino)phenyl) fluorenyl ρ ratio sigma-3-yl)-5-second-butyl-3-nitro-2- methoxybenzoate ; 5-Terti-butyl-3-cyano-indole-(5-(4-(3-propylaminomethyl)phenyl)-6-methylpyridin-3-yl)-2-oxo Benzobenzamide; 5-tris-butyl-3-cyano-N-(5-(4-(2-hydroxyethylamine)methyl)phenyl)-6-methylpyridine-3- 2) methoxybenzamide; 5-tris-butyl-N1 -(6-methyl-5-(4_(neopentylcarbinyl)phenyl> ))-N3 -(2-(tetrahydro-examination 1: 1 yl)ethyl)m-xylyleneamine; 5-tris-butyl-N1 -(6-fluorenyl-5-( 4_(neopentylaminomethane)phenyl&gt;pyridin-3-yl)·Ν3 -((1-methylhexahydroindole-2-yl)methyl)m-xylyleneamine; 1 -(5-(3-Terve-butyl-5-(N,N-dimethylamine decyl)benzamide)_2_methylexo I:bit _3_yl)-N-new pentyl-1H-1,2,3_sanjun-4-decylamine; 3_di-butyl-5-(N,N-monomethylamine stellate)-N-(6- Methyl-5-(4-(ne-decylaminemethyl δ & yl)-based) p-bit _3_yl) benzalkonium; 3-tert-butyl-5-(5-methyl- 1,2,4, oxadiazol-3-yl)-N-(6-methyl-5-(4-(neopentylcarbinyl)phenyl) 峨-3_yl)benzamide ; 1-(5-(3-Terve-butyl-5-(5-methyl·1,2,4-oxadiazol-3-yl)benzimidamide)-2-methylpyridine_ 3_yl)-Ν-neopentyl-1Η-1,2,3-triazole-4-carboxyguanamine; 123505 -52- 200815422 3-third-butyl-5-cyano 4(5-( 4-(2-(Dimethylamino)-2-methylpropylaminecarboxylidene)phenyl)-6-methylpyridin-3-yl)benzamide; 5-tri-butyl- N1 -(3-hydroxy-2,2-dimethylpropyl)-N3 -(6-methyl-5-(4-(neopentylcarbinyl)phenyl)pyridine)m-phenylene Methionamine; 5-tris-butyl-3-cyano-N-(5-(4-(2,2-dimethylcyclohexylaminemethyl) phenyl)-6-methylττ ratio Benz-3-yl)-2-methoxybenzamide; N-(5-(4-((lR,2S,4R)-bicyclo[2. 2. 1]hept-2-ylaminocarbamoyl)phenyl)·6-methyl group p to bit I group)-5-tris-butyl-3-cyano-m-methoxybenzamide; 1 -(5-(3-Terti-butyl-5-(N-methylamine sulfonyl)benzamide)-2-methylpyrazine_3«yl)-N-neopentyl -1H-1,2,3-trian-4-propanol; 3-tert-butyl-N-(6-methyl-5-(4-(neopentylcarbinyl)phenyl) ,bipyridin-3-yl)-5-(N-methylaminesulfonyl)benzamide; 5-tris-butyl-3-(isoxazole ice-based)-2-methoxy -N-(6-methyl-5-(4-(neopentylcarbinyl)phenyl)p-pyridin-3-yl)benzamide; 5_second-butyl-3-( 2,3-Dihydroisocyanyl-4-yl)-2-methoxy-N-(6-methylij-5-(4-(neopentylcarbinyl)phenyl)pyridine-3- Benzobenzamide; 3-tert-butyl-5-(5-cyclopropyl-indole, 2,4.oxadiazol-3-yl)-N-(6-methyl-5-( 4-(neopentylaminomethane)phenyl)pyridine-3-yl)benzamide; 3 second butyl_5_(5-(methyllacylmethyl)-1,2,4-π 2. Ole-3-yl)-N-(6-methyl-5-(4-(neopentylcarbinyl)phenyl)pyridyl)benzamide; 3-tert-butyl- N-(5-(4-(3-hydroxy-2) ,2-dimethylpropylamine-mercapto)phenyl)-indene-based guanidine)_5-(N-methylamine sulphate)benzamine; 3-tri-butyl|(5- (4-(4,4-Difluorocyclohexylamine)methyl)phenyl)-6-methylpyridin-3-yl)-5-(N-methylaminesulfonyl)benzamide; 123505 - 53 - 200815422 3·Second-butyl-5-(5-tert-butyl-indole, 2,4^-di-n-n-ylmethyl-5-(4-(neopentylcarbamyl) Phenyl group > benzyl benzoic acid amine; 5-second-butyl-2-methoxy-N-(6-methyl-5-(4-(neopentylamine) Phenyl acridine)-3_(1Η-pyrazol-1-yl)benzamide; 5-di-butyl-3-cyano private (5_(4-(2,2-dimethyl) -3-(tetrahydro-p-specific group) propylamine-methyl indenyl)phenyl)-6-methylpyridin-3-yl)-2-methoxybenzamide; 5-di-di-butyl Benzyl-3-cyano|(5-(4-(2,2-dimethyl-3-(4-methylhexahydropurine p-l-yl)propylaminemethanyl)phenyl)- 6-methylindol-3-yl)-2-methoxybenzamide; di-butyl-3-cyano-N_(5-(4-(2,2-dimethyl-3) -Folpe propylamine-methyl hydrazino)phenyl)-6-methylpyridin-3-yl)-2-methoxybenzidine Amine; N-(5-(4-(3-amino-2,2-dimethylpropylaminemethyl)phenyl)phenylmethyl acridin-3-yl)·5-third- Butyl-3-cyano-2-methoxybenzylamine; 5_T-butyl-3-cyano_N-(5_(4_(3-(dimethylamino))_2,2· Dimethylpropylamine-mercapto)phenyl)-6-methylpyridin-3-yl)-2-methoxybenzamide; 5-tert-butyl-M4-(hydroxymethyl) )-1Η-1,2,3-triazol-1-yl)_2-methoxy-N-(6-methyl-5-(4-(neopentylcarbinyl)phenyl> ratio Acridine; benzyl benzoguanamine; 5-tris-butyl-2-methoxy-N-(6-methyl-5-(4-(p-pentylaminomethyl)phenyl) pyridine 3-(4-(4-(tetrahydropyrrole-1-ylindenyl)_ih-1,2,3-triazole)-benzamide; 5-tri-butyl-2-methyl oxy-N-(6-fluorenyl-5.(4-(neopentylaminomethyl)phenyl acridine-3-yl)-3-(4-(hexahydropyridylmethyl)- Indole-1,2,3-triazol-1-yl)benzamide; 5-tris-butyl-2-methoxy-oxime-(6-fluorenyl-5-(4-(neopentyl) Amidinomethyl)benzene 123505 -54- 200815422 yl)pyridin-3-yl)-3-(4-((4-methylhexahydropyrrolidin-1-yl)indolyl)-1Η-1,2, 3-triazole -1-yl)benzamide; 5-dibutyl-2-methoxy-N-(6-methyl-5-(4-(neopentylamine)phenyl)pyridine -3-yl)-3_(4-(morpholinylmethyl)-lH-1,2,3-triazole small)benzamide; 5-tert-butyl-3-(4-((2) Ethylamino)methyl)-iH-1,2,3-triazole small group &gt; 2_decyloxy-N-(6-methyl-5-(4-(neopentylcarbinyl)phenyl) Pyridin-3-yl)benzamide; \b 5-tris-butyl-3-(4-((dimethylamino)methyl)_1H-1,2,3_triazole·1 _ yl)-2-decyloxy-N-(6-fluorenyl-5-(4-(neopentylcarbinyl)phenyl)pyridinyl)benzamide; 5_third beta (4_((Isopropylamino)methyl)-1Η_1,2,3-tris-s-l-yl)-2-methoxy-N-(6-methyl-5-(4-( Neopentylamine methyl hydrazino) phenyl anthracenyl) benzamide; 5-tris-butyl-3-(4-((cyclopropylamino)methyl)·1Η_ΐ52,3_triazole small group _2_A\: oxy-oxime-(6-methyl_5-(4-(neopentylcarbenyl)phenyl)acridin-3-yl)benzamide; and 5-position Tri-butyl-3-cyano-indole_(5-(4-(2.(dimethylaminomethylpropylaminemethyl)phenyl)&gt; 6-Methylpyridine_3_yl)·2_methoxybenzamide. 123505 -55- 200815422 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please reveal the characteristics that can best display the invention. Chemical formula: L2—Q X、 、Υ八A 式IL2—Q X, Υ八A I ηη 〆 G〆 G 式IIFormula II 式VII 123505 -6 - 200815422Formula VII 123505 -6 - 200815422 式 VIIIFormula VIII 式IX ，PN 123505Equation IX, PN 123505
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