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TWI285641B - Quinoline and quinoxaline compounds - Google Patents

Quinoline and quinoxaline compounds Download PDF

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Publication number
TWI285641B
TWI285641B TW093108314A TW93108314A TWI285641B TW I285641 B TWI285641 B TW I285641B TW 093108314 A TW093108314 A TW 093108314A TW 93108314 A TW93108314 A TW 93108314A TW I285641 B TWI285641 B TW I285641B
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TW
Taiwan
Prior art keywords
compound
ethyl
group
acid
trifluoromethyl
Prior art date
Application number
TW093108314A
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Chinese (zh)
Other versions
TW200508222A (en
Inventor
George Chang
Mary Theresa Didiuk
Jari Ilmari Finneman
Ravi Shanker Garigipati
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Pfizer Prod Inc
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Publication of TW200508222A publication Critical patent/TW200508222A/en
Application granted granted Critical
Publication of TWI285641B publication Critical patent/TWI285641B/en

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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
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    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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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Abstract

Quinoline and quinoxaline compounds, pharmaceutical compositions containing such compounds and the use of such compounds to elevate certain plasma lipid levels, including high density lipoprotein-cholesterol and to lower certain other plasma lipid levels, such as LDL-cholesterol and triglycerides and accordingly to treat diseases which are exacerbated by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases in some mammals, including humans.

Description

1285641 玖、發明說明： 【發明所屬之技術領域】 本發明係關於峻淋與p奎嗅琳化合物，含有此種抑制劑之醫 藥組合物，及在某些哺乳動物（意即在其血漿中具有CETP者） ，包括人類中，使用此種抑制劑以提高某些血漿脂質含量 ，包括高密度脂蛋白（HDL)-膽固醇，並降低某些其他血漿脂 質含量，譬如低密度脂蛋白（LDL)-膽固醇與甘油三酯，且因 此，治療受低含量HDL膽固醇及/或高含量LDL-膽固醇與甘 油三酯所影響之疾病，譬如動脈粥瘤硬化與心血管疾病。 【先前技術】 動脈粥瘤硬化及其有關聯之冠狀動脈疾病（CAD)係為工業 化世界之主要死亡原因。儘管嘗試改變次要危險因素（抽煙 、肥胖、缺少運動），並以飲食修正與藥療法治療脂血症障 礙，但在美國，冠狀心臟疾病（CHD)仍然是最常見之死亡原 因，其中心血管疾病係構成全部死亡之44%，其中53%係與 動脈粥瘤硬化性冠狀心臟疾病有關聯。 此症狀發展之危險已被証實係強烈地與某些血漿脂質含量 有關聯。雖然提高之LDL-C可能是脂血症障礙之最被認知之 形式，但其絕非是CHD之唯一顯著與脂質有關聯之助長因素 。低HDL-C亦為CHD之一種危險因素（Gordon, D.J.等人·· π高密 度脂蛋白膽固醇與心血管疾病n，Circulation，（1989)，79 : 8-15)。 高LDL-膽固醇與甘油三酯含量係為正關聯，然而HDL-膽 固醇之高含量係與發展心金管疾病之危險為負關聯。因此 ，脂血症障礙並非CHD之單一危險形態，但可能包含一或多 92199 1285641 種脂質迷亂。 在控制此等疾病依賴要素之血漿含量之許多因素中，膽固 醇酯轉移蛋白質（CETP)活性係影嚮全部三者。已在許多動物 種類包括人類中發現之此70,000道爾吞血漿糖蛋白之角色， 係在脂蛋白粒子之間轉移膽固醇酯與甘油三酯，該粒子包 括高密度脂蛋白（HDL)、低密度脂蛋白（LDL)、極低密度脂蛋 曰（VLDL)及乳糜微粒。CETp活性之淨結果為HDL膽固醇之降 低人LDL膽固醇之增加。此種對於脂蛋白分佈形態之作用， 咸認係為致粥瘤前的，尤其是在其脂質分佈形態係構成增 加CHD危險之病患中。 現今在市場上，沒有任何真正令人滿意之提高^^匕療法。 菸鹼酸可顯著地增加HDL，但具有嚴重容許性問題，其會降 低順應性。纖維酸酯與HMGCoA還原酶抑制劑會提升 ，但在—些病患中，其結果是適度比例（〜1042%)之增加。 因此，對於會提高血漿含量，葬诘 。里精以史轉或減緩動脈粥瘤 硬化進展之被認可治療劑，有未達到之醫療需求。 因此，雖然有多種抗動脈粥瘤硬㈣法在此技藝領域 中，對於替代療法有持續需求與持續搜尋。 【發明内容】 本發明係針對根據式I之化合物1285641 玖, the invention description: [Technical field of the invention] The present invention relates to a rinsing and p-quinegrin compound, a pharmaceutical composition containing the same, and in some mammals (ie, having in its plasma) In CETP, including humans, the use of such inhibitors to increase certain plasma lipid levels, including high-density lipoprotein (HDL)-cholesterol, and to lower certain other plasma lipid levels, such as low-density lipoprotein (LDL)- Cholesterol and triglycerides, and therefore, diseases that are affected by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascular disease. [Prior Art] Atherosclerosis and its associated coronary artery disease (CAD) are the leading causes of death in the industrialized world. Despite attempts to change secondary risk factors (smoking, obesity, lack of exercise) and treatment of lipid disorders with dietary correction and medication, coronary heart disease (CHD) remains the most common cause of death in the United States, including cardiovascular The disease system constitutes 44% of all deaths, of which 53% are associated with atherosclerotic coronary heart disease. The risk of developing this condition has been shown to be strongly associated with certain plasma lipid levels. Although elevated LDL-C may be the most recognized form of lipemia disorder, it is by no means the only significant contributing factor to CHD. Low HDL-C is also a risk factor for CHD (Gordon, D.J. et al. π High Density Lipoprotein Cholesterol and Cardiovascular Diseases n, Circulation, (1989), 79: 8-15). High LDL-cholesterol is positively associated with triglyceride levels, whereas high HDL-cholesterol levels are inversely associated with the risk of developing cardiovascular disease. Therefore, lipemia disorder is not a single dangerous form of CHD, but may contain one or more 92199 1285641 lipid disorders. Of the many factors controlling the plasma levels of these disease dependent factors, cholesterol ester transfer protein (CETP) activity affects all three. The role of this 70,000 Dolby plasma glycoprotein found in many animal species, including humans, is the transfer of cholesterol esters and triglycerides between lipoprotein particles, including high density lipoprotein (HDL), low density lipids. Protein (LDL), very low density lipoprotein (VLDL) and chylomicrons. The net result of CETp activity is a decrease in HDL cholesterol and an increase in human LDL cholesterol. This effect on the distribution of lipoproteins is preceded by atheroma, especially in patients whose lipid profile forms a risk of increasing CHD. There is no truly satisfactory improvement in the market today. Nicotinic acid can significantly increase HDL, but has serious tolerance problems that reduce compliance. Fibric acid esters and HMGCoA reductase inhibitors are elevated, but in some patients, the result is a modest proportion (~1042%). Therefore, for the increase in plasma content, funeral. Lijing has been recognized as a therapeutic agent for the progression or slowing of atherosclerosis progression, and there are unmet medical needs. Therefore, although there are a variety of anti-atheroma hard (four) methods in this field of art, there is a continuing need for continuous therapy and continuous search. SUMMARY OF THE INVENTION The present invention is directed to a compound according to formula I

式I 92199 l28564i 其中 C3為碳； j為氮或碳’其中若】為< ’則。與】間之鍵結為單或雙鍵 ’而若J為氮’則C3與J間之鍵結為單鍵· 一 R1為Y、W_X或W-Yl;其中W為羰基、硫代羰基、亞㊃ 基或輕基；X為_αΥ、·3·Υ ' ·Ν(Η)·Υ或·N_⑺2 ; γ對各存在 處係獨立為Ζ，或完全飽和、部份不飽和或完全不飽和一至 十員直鏈或分枝狀碟鏈，其中各個硬，惟連接後除外，可 硯情況被-或兩個獨立選自氧、硫及氮之雜原子置換，且 該碳係視情況獨立被齒基單_、二或三_取代，該碳係視情 被幾基單取代，該碳係視情況被酮基單取代，該硫係視 情況被酮基單-或二取代，該氮係視情況被酮基單-或二取 代，且該錢係視情況被Ζ單取代；且¥1對各存在處係獨立 為Ζ，或$全飽和、部份不飽和或完全不飽和一至十員直鏈 或分枝狀碳鏈，其中各個碳，惟連接碳除外，可視情況被 —或兩個獨立選自氧、硫及氮之雜原子置帛，且該竣係視 h況獨工被齒基單’、二·或三_取代，該碳係視情況被經基 早取代’該碳係視情況被酮基單取代，該硫係視情況被酮 基早-或二取代，該氮係視情況被酮基單-或二取代，且該 竣鏈係’視情況被Z單取代；其中z為部份飽和、完全飽和或 π全不飽和二至八員環，視情況具有一至四個獨立選自氧 八及氮之4原子，或雙環狀環，包含兩個獨立採用之稠 。部伤飽和、元全飽和或完全不飽和三至六員環，視情況 具有一至四個獨立選自氮、硫及氧之雜原子；且該ζ取代基 92199 1285641 係視情況獨立被鹵基、（c2-C6)烯基、（Ci-c6)烷基、羥基、（Ci-C6) '兄氧基、（Ci -C4)fe硫基、胺基、硝基、氰基' _基、竣基、 (Ci-C6)垸氧羰基、單或二·Ν，Ν·((：ι<：6)烷胺基單-、二-或 一取代’其中該（C〗_c6)燒基取代基係視情況獨立被鹵基、 罗二基、（C〗-C6)：fe氧基、（q -Q)娱:硫基、胺基、硝基、氰基、 酮基、羧基、（(VC6)烷氧羰基、單或二-N，N-(Cl_c6)烷胺基 單…二-或三-取代，該（(VC6)烷基或（CrC6)燒氧基取代基亦 視情況被一至九個氟取代； R2為部份飽和、完全飽和或完全不飽和一至六員直鏈或分 枝狀碳鏈，其中各個碳，惟連接碳除外，可視情況被一或 兩個獨立選自氧與硫之雜原子置換，且該碳係視情況獨立 被鹵基單-、二-或三-取代，該碳鏈係視情況被酮基單取代 ’該碳係視情況被羥基單取代，該硫係視情況被酮基單-或 一取代，或该R2為部份飽和、完全飽和或完全不飽和三至 七員環，視情況具有一至二個獨立選自氧與硫之雜原子， 其中該R2環係視情況經過（Ci-Q)烷基連接；其中該R2環係視 情況獨立被i基、（c2-c6)烯基、（(ν(：6)燒基、#f基、（q-Q) $元乳基、（Ci -C4 )纟元硬基、胺基、硝基、氣基、嗣基、幾基、 (Ci -C6)烷氧羰基、單或二-Ν,Ν-Α -C6)烷胺基單-、二-或三 -取代，其中該（Ci -C6)烷基取代基係視情況獨立被鹵基、經 基、（Q -C6)坑氧基、（Q -C4)fe硫基、酮基或（q -Q)燒氧羰基 單-、二-或三-取代； R3為完全飽和、部份不飽和或完全不飽和一至六員直鏈或 分枝狀碳鏈’含有C4a，其中C4a為連接至J之碳原子，其中 199 1285641 竣鏈中之各個竣可視情況被一個選自氧、硫及氮之雜原子 置換’且該碳係視情況被函基單-、二-或三-取代，該碳係 視情況被輕基單取代，該碳係視情況被酮基或氮單取代， 該硫係視情況被酮基單-或二取代，該氮係視情況被氫或酮 基單-或二取代，且該碳鏈係在C4a或鄰近C4a之R3碳處，被 V單-、二-或三_取代；其條件是，在R3中，當：為碳時，其 不為視情況被一個雜原子置換之C4a ;且其條件是，在R3中 ’當J為氮時，其不為視情況被雜原子置換之C4a，且其不 _ 為視情況被羥基或氮單取代之C4a ;其中v為部份飽和、完 全飽和或完全不飽和三至八員環，視情況具有一至四個獨 立選自氧、硫及氮之雜原子，以致V不為咪唑基或完全飽和Formula I 92199 l28564i wherein C3 is carbon; j is nitrogen or carbon 'where 】 is < ’. The bond between the bond is a single or double bond 'and if J is nitrogen', then the bond between C3 and J is a single bond. · R1 is Y, W_X or W-Yl; where W is a carbonyl group, a thiocarbonyl group, Subtetrakis or light groups; X is _αΥ, ·3·Υ ' ·Ν(Η)·Υ or ·N_(7)2 ; γ is independent of each existing system, or is fully saturated, partially unsaturated or fully unsaturated. One to ten members of straight or branched disc chains, each of which is hard except except after the connection, may be replaced by - or two heteroatoms independently selected from oxygen, sulfur and nitrogen, and the carbon system is independently The dentate group is mono-, di- or tri-substituted, and the carbon is optionally substituted by a singular group which is optionally monosubstituted by a keto group which is optionally mono- or disubstituted by a ketone group, the nitrogen system Depending on the case, it is mono- or disubstituted by a ketone group, and the money is replaced by hydrazine as the case may be; and ¥1 is independently Ζ for each existing unit, or $1 to 10 full saturated, partially unsaturated or fully unsaturated. a linear or branched carbon chain in which each carbon, except for the carbon of the connection, may be placed by - or two heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, and the Single ', di- or tri-substituted, the carbon system is replaced by a long-radical basis as the case may be. 'The carbon system is optionally monosubstituted by a ketone group, which is optionally replaced by a keto group, which is optionally or disubstituted. The situation is mono- or disubstituted by a keto group, and the oxime chain 'are replaced by Z as appropriate; wherein z is partially saturated, fully saturated or π-unsaturated two to eight membered rings, optionally one to four independent It is a 4-atom selected from oxygen octa and nitrogen, or a bicyclic ring containing two independently used viscosities. a three- to six-membered ring of saturated, fully saturated or fully unsaturated, optionally having one to four heteroatoms independently selected from nitrogen, sulfur, and oxygen; and the oxime substituent 92199 1285641 is independently halogenated, (c2-C6) alkenyl, (Ci-c6)alkyl, hydroxy, (Ci-C6) 'tertyloxy, (Ci-C4)fethio, amine, nitro, cyano'-yl, hydrazine , (Ci-C6) anthraceneoxycarbonyl, mono or di-anthracene, Ν·((:ι<:6) alkylamine mono-, di- or monosubstituted' wherein the (C _c6) alkyl substituent Depending on the situation, it is independently halogenated, ruthenyl, (C-C6): fe oxy, (q -Q) entertainment: thio, amine, nitro, cyano, keto, carboxy, ((VC6) Alkoxycarbonyl, mono- or di-N,N-(Cl_c6)alkylamino-...di- or tri-substituted, the ((VC6)alkyl or (CrC6) alkoxy substituent is also optionally one to nine Fluorine substitution; R2 is a partially saturated, fully saturated or fully unsaturated one to six member straight or branched carbon chain, wherein each carbon, except for the attached carbon, may be optionally selected from oxygen and sulfur by one or two Heteroatom substitution, and the carbon system is independently halogenated by the single - , di- or tri-substituted, the carbon chain is optionally monosubstituted by a ketone group. The carbon system is optionally monosubstituted by a hydroxy group, which is optionally mono- or mono-substituted by a ketone group, or the R2 is a moiety a saturated, fully saturated or fully unsaturated three to seven membered ring, optionally having one to two heteroatoms independently selected from the group consisting of oxygen and sulfur, wherein the R2 ring is optionally attached via a (Ci-Q) alkyl group; wherein the R2 The ring system is independently i-based, (c2-c6) alkenyl, ((ν(:6) alkyl, #f-based, (qQ) $-membered, (Ci-C4)), amine, amine a nitro group, a nitro group, a fluorenyl group, a fluorenyl group, a aryl group, a (Ci-C6) alkoxycarbonyl group, a mono- or di-anthracene, a fluorene-fluorene-C6 alkylamine group, a mono-, a di- or a tri-substitution, wherein (Ci-C6)alkyl substituents are optionally independently substituted by halo, thiol, (Q-C6) phenoxy, (Q-C4)fethio, keto or (q-Q) oxycarbonyl -, di- or tri-substituted; R3 is a fully saturated, partially unsaturated or fully unsaturated one to six member straight or branched carbon chain 'containing C4a, wherein C4a is a carbon atom attached to J, of which 199 1285641 Each of the 竣 chains may be selected from oxygen, The hetero atom substitution of sulfur and nitrogen 'and the carbon system is optionally substituted by a mono-, di- or tri---, the carbon system is optionally monosubstituted by a light base, which is optionally substituted by a keto group or a nitrogen atom. The sulfur is optionally mono- or disubstituted by a keto group which is optionally mono- or disubstituted by hydrogen or a keto group, and the carbon chain is at C4a or adjacent to the R3 carbon of C4a, and is mono-V- a two- or three-substituted; provided that, in R3, when it is carbon, it is not C4a which is optionally replaced by a hetero atom; and the condition is that in R3, when J is nitrogen, It is not C4a which is optionally replaced by a hetero atom, and it is not C4a which is optionally monosubstituted by a hydroxyl group or nitrogen; wherein v is a partially saturated, fully saturated or fully unsaturated three to eight membered ring, as the case may be One to four heteroatoms independently selected from oxygen, sulfur, and nitrogen such that V is not imidazolyl or fully saturated

雜裱族含氮環，其中該環之氮係連接至R3基團；雙環狀環 ，包含兩個獨採用之稠合部份飽和、完全飽和或完全不 飽和二至7T員環，視情況具有一至四個獨立選自氮、硫及 氧之雜原子，或三環狀環，包含三個獨立採用之稠合部份 飽和、完全飽和或完全不飽和三至六員環，視情沉具有一 至四個獨選自氮、硫及氧之雜原子；且該v取代基係視情 況獨 jl 被 v1、-c6)烷基、qco-v1、a(C(rC6)烷基·νι、(Cl<：6) 烷基-αν、c(〇>·單-π或二-N并(CVC6)烷基今i、函基、（CrC6) 烷基、（c2-c6)烯基、羥基、（(VC6)统氧基、硫基、％ k基亞％醯基、（q -q)烷基磺醯基、單·队或二-N，N-(Ci<：6)烷 基磺醯基、胺基、硝基、氰基、酮基、羧醯胺基、單I或 、（crC6)烷氧羰基、單-N-三-、四-或五取代，其中 二-N’N-A -C：6)燒基羧醯胺基 '羧基 或二-N，N-(Ci -(：6)垸胺基單-、二-、a heterocyclic family containing a nitrogen ring in which the nitrogen of the ring is attached to the R3 group; a bicyclic ring comprising two separately fused portions saturated, fully saturated or fully unsaturated 2 to 7 T ring, as appropriate Has one to four heteroatoms independently selected from nitrogen, sulfur, and oxygen, or a tricyclic ring, comprising three independently fused, partially saturated, fully saturated, or fully unsaturated three to six-membered rings. One to four heteroatoms independently selected from nitrogen, sulfur, and oxygen; and the v substituents are optionally v1, -c6)alkyl, qco-v1, a(C(rC6)alkyl·νι, ( Cl<:6) alkyl-αν, c(〇>·mono-π or di-N-(CVC6)alkyl, i, functional, (CrC6)alkyl, (c2-c6)alkenyl, hydroxy , ((VC6) oxy, thio, % k hydrazino, (q -q) alkyl sulfonyl, mono- or di-N, N-(Ci<:6) alkyl sulfonate Sulfhydryl, amine, nitro, cyano, keto, carboguanamine, mono-I or (crC6) alkoxycarbonyl, mono-N-tri-, tetra- or penta-substituted, wherein di-N'NA -C: 6) alkyl carboxy amide amino group 'carboxy or di-N, N-(Ci - (: 6) decyl mono-, di-,

Q91QQ -10- 1285641 該（Q-C6)烷基或（CyC6)晞基取代基係視情況獨立被羥基、 (C「C6)垸氧基、（(VC4)燒硫基、胺基、硝基、氰基、酮基、 複基、（Ci -Q)燒氧幾基、單或二-Ν,Ν-Α -c6)燒胺基單_、 二-或三-取代，其中各（CrC6)垸基、（CrC6)垸氧基、（C「C4) 烷硫基、（Ci-C4)烷基磺醯基或（c^c：6)烯基取代基，亦視情況 被一至九個氣取代，其中V1為部份飽和、完全飽和或完全 不飽和三至六員環’視情況具有一至二個獨立選自氧、硫 及氮之雜原子，或雙環狀環，包含兩個獨立採用之稠合部 份飽和、完全飽和或完全不飽和三至六員環，視情況具有 一至四個獨立選自氮、硫及氧之雜原子；且該vl取代基係 視情況獨立被鹵基、（Ci-Q)烷基、（Cl-C6)烷氧基、羥基、酮 基、胺基、硝基、氰基、（(VQ)烷氧羰基、單I或二_N，队(Ci-C6) 烷胺基單-、二-、二-、四-或五取代，其中該烷基取 代基係視情況被酮基單取代，該（Cl-C6)烷基或（Ci_C6)烷氧基 取代基亦視情況被一至九個氟取代；且 各R、R、R及R係獨互為氫、一個鍵結、硝基或鹵基， 其中S鍵結係被T或部份飽和、完全飽和或完全不飽和 (CrC!2)直鏈或分枝狀碳鏈取代，其中全碳鏈之各竣可視情 況被一或兩個雜原子置換，其中雜原子係獨立選自氧、硫 及氮，其中該碳係視情況獨立被鹵基單-、二-或三_取代， 該竣係視情況被羥基單取代，該碳係視情況被酮基或氮單 取代，該硫係視情況被酮基單-或二取代，該氮係視情況被 氫或酮基單-或二取代，且該竣鏈係視情沉被丁單取代；其 中T為部份飽和、完全飽和或完全不飽和三至十二員環，視Q91QQ -10- 1285641 The (Q-C6) alkyl or (CyC6) fluorenyl substituent is independently hydroxy, (C "C6) decyloxy, ((VC4) thiol, amine, nitro) , cyano group, keto group, complex group, (Ci-Q) alkoxy group, mono- or di-anthracene, Ν-Α-c6) acryl mono-, di- or tri-substituted, wherein each (CrC6) Sulfhydryl, (CrC6) decyloxy, (C"C4)alkylthio, (Ci-C4)alkylsulfonyl or (c^c:6)alkenyl substituent, also optionally one to nine gases Substituted, wherein V1 is a partially saturated, fully saturated or fully unsaturated three to six membered ring 'as the case has one to two heteroatoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring, comprising two independent uses a fused, partially saturated, fully saturated or fully unsaturated three to six membered ring, optionally having one to four heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; and the vl substituent is independently halogenated, (Ci-Q)alkyl, (Cl-C6) alkoxy, hydroxy, keto, amine, nitro, cyano, ((VQ) alkoxycarbonyl, mono- or di-N, team (Ci- C6) an alkylamino group mono-, di-, di-, tetra- or penta-substituted, wherein the alkane The substituent is optionally substituted by a keto group, and the (Cl-C6)alkyl or (Ci_C6) alkoxy substituent is optionally substituted by one to nine fluorines; and each of R, R, R and R is independently Is hydrogen, a bond, a nitro group or a halogen group, wherein the S bond is replaced by a T or partially saturated, fully saturated or fully unsaturated (CrC! 2) linear or branched carbon chain, wherein the full carbon chain Each of the hydrazines may be replaced by one or two heteroatoms, wherein the heteroatoms are independently selected from the group consisting of oxygen, sulfur, and nitrogen, wherein the carbon is independently substituted by a mono-, di-, or tri-halogen, which is optionally substituted. Optionally, the hydroxy group is monosubstituted, and the carbon is optionally monosubstituted by a keto group or a nitrogen, which is optionally mono- or disubstituted by a keto group, which is optionally mono- or disubstituted by a hydrogen or keto group, And the 竣 chain is replaced by a single singularity; wherein T is a partially saturated, fully saturated or fully unsaturated three to twelve ring, depending on

09 10Q 1285641 情二具有~至四個獨立選自氧、硫及氮之雜原+，或雙環 狀環’包含兩個獨立採用之稠合部份飽和、完全飽和或完 全不飽和三至六員，視情況具有一至四個獨立選自氮、 石凡及氧（雜原子，且琢丁取代基係視情況獨立被自基、％句 烷基、（CVC6)晞基、羥基、（〇VC6)^氧基、（C「Q)燒硫基、 胺基、硝基、氰基、酮基、羧基、（C1-C6)燒氧羰基 ' 單| 或二#1心((：「(：6)垸胺基單_、二_或三_取代，其中該（(：；1<：6)统 基取代基係視情況獨立被羥基、（C1 <6)烷氧基、（q<4)烷硫 基、胺基、硝基、氰基、酮基、羧基、（q <6)烷氧羰基、 單I或二-N，N_(C1 _C6)燒胺基單·、二-或三-取代，該（Q -C6) 烷基或（Ci -C：6)烷氧基取代基亦視情況具有一至九個氟； R4與R5、R5與R6及/或R6與R7可視情況一起採用，且可形 成至少一個環，其係為部份飽和或完全不飽和四至八員環 ’視情況具有一至三個獨立選自氮、硫及氧之雜原子；其 中藉由R4與R5或R5與R6及/或R6與R7形成之各環，係視情況 獨立被_基、（CVC6)烷基、（(VQ)烷基磺醯基、（C2-C6)烯基 、羥基、（C! -C6)烷氧基、-C4)烷硫基、胺基、硝基、氰基 、酮基、羧基、（C「C6)烷氧羰基、單或二烷胺 基單-、二-或三-取代，其中該（q -C6)烷基取代基係視情況 獨立被藉基、（Q )燒氧基、（Ci -C4)燒硫基、胺基、硝基、 氰基、酮基、羧基、（Ci -C6)烷氧羰基、單或二-Ν,Ν-Α -C6) 烷胺基單-、二-或三-取代，該-C6)烷基取代基亦視情況 具有一至九個氟； 或其藥學上可接受之鹽或前體藥物； 09 1 Q0 -12- 1285641 具有下列附帶條件： ^當在C3與】之間有單鍵，且r3為完全飽和—至六員直鍵或 :枝狀碳鏈’於C4a上被V取代時，則r1不為視情況被画基 早-、二-或三-取代之C(〇MCi_C4)烷基，且R1不為c(〇)_單環狀 芳族環；或 b)當在〇3與_1之間有單鍵，且r34_c(〇)_〇_v，及以笨基時 ’則Rl不為（CrC4)烷基；及 )田在C3 μ j之間有雙鍵，且R2為甲基時，則R3不為 v、-CH2-V 或胃CH2-CH2-V。 再者本發明係針對根據式II之化合物 R4 R309 10Q 1285641 情二 has ~ to four independently selected from oxygen, sulfur and nitrogen, or double-ringed ring containing two independently used fused parts saturated, fully saturated or fully unsaturated three to six Depending on the situation, one to four are independently selected from the group consisting of nitrogen, sulphate and oxygen (heteroatoms, and the sulfhydryl substituents are independently derived from the base, the amino group, the (CVC6) thiol group, the hydroxy group, (〇VC6). ) oxy, (C "Q) thiol group, amine group, nitro group, cyano group, keto group, carboxyl group, (C1-C6) pyroxycarbonyl group 'single| or two #1 heart ((: "(: 6) amidino-mono-, di- or tri-substituted, wherein the ((:; 1 <:6) allyl substituent is optionally independently hydroxy, (C1 <6) alkoxy, (q< 4) alkylthio, amine, nitro, cyano, keto, carboxyl, (q < 6) alkoxycarbonyl, mono- or di-N, N-(C1 _C6) acrylamine mono-, di- Or a tri-substitution, the (Q-C6)alkyl or (Ci-C:6) alkoxy substituent optionally has from one to nine fluorines; R4 and R5, R5 and R6 and/or R6 and R7 may be optionally used. Used together, and can form at least one ring, which is partially saturated or not at all And four to eight member rings 'as the case has one to three heteroatoms independently selected from nitrogen, sulfur and oxygen; wherein each ring formed by R4 and R5 or R5 and R6 and/or R6 and R7 is independently —(CVC6)alkyl, ((VQ)alkylsulfonyl, (C2-C6)alkenyl, hydroxy, (C!-C6)alkoxy, -C4)alkylthio, amine, nitrate a cyano group, a cyano group, a keto group, a carboxyl group, a (C"C6) alkoxycarbonyl group, a mono- or dialkylamino group, a mono-, di- or tri-substituted group, wherein the (q-C6)alkyl substituent is optionally independent Borden group, (Q) alkoxy group, (Ci-C4) thiol group, amine group, nitro group, cyano group, ketone group, carboxyl group, (Ci-C6) alkoxycarbonyl group, mono- or di-anthracene, fluorene -Α-C6) an alkylamino group mono-, di- or tri-substituted, the -C6)alkyl substituent optionally having from one to nine fluorines; or a pharmaceutically acceptable salt or prodrug thereof; 09 1 Q0 -12- 1285641 has the following conditions: ^When there is a single bond between C3 and 】, and r3 is fully saturated—to a six-member straight bond or: a dendritic carbon chain is replaced by V on C4a, then r1 C (〇MCi_C4) alkyl, which is not pre-exposed as a case, and is substituted with R1, and R1 Not c(〇)_monocyclic aromatic ring; or b) when there is a single bond between 〇3 and _1, and r34_c(〇)_〇_v, and when stupid is used, then Rl is not (CrC4)alkyl; and the field has a double bond between C3 μ j and R2 is a methyl group, then R3 is not v, -CH2-V or stomach CH2-CH2-V. Compound R4 R3 according to formula II

其中 R1 為 w-x; W為幾基； X 為-0-Y ; y對各存在處係獨立為（q _c6)垸基，該（Ci_c6)烷基視情況 具有一至九個氟，或該（C1-Q)烷基視情況被2單取代； 其tz為部份飽和、完全飽和或完全不飽和三至六員環， 視情況具有一至二個獨立選自氧、硫及氮之雜原子； 其中孩Z取代基係視情況獨立被画基、（c^cj烷基、（c〖 烷氧基、（Ci-C：4)烷硫基、硝基、氰基、酮基4(Ci-C4)烷氧羰 0^100 -13 - 1285641 該（q -C4)垸基，視情況被一至九個 基單_、二-或三-取代 氟取代； R2為部份飽和、完全飽和或完全不飽和（q-co直鏈或分枝 狀碳鍵’其中各個碳，惟連接碳除外，可視情況被一個獨 ϋ·選自氧與硫之雜原子置換，其中該碳係視情況獨立被鹵 基單-、二-或三-取代，該碳鏈係視情況被酮基單取代，該 硬係視情況被經基單取代，該硫係視情況被酮基單-或二取 代，或該R2為邵份飽和、完全飽和或完全不飽和三至五員 籲 每’視情況具有一個獨立選自氧與硫之雜原子； 其中该R2壞係視情況獨立被鹵基或烷氧基單_、二_ 或三-取代； 其中 R3 為-CH2 NR8 R9 或 _c(〇)NR8 R9 ; 其中R8與R9係獨立為氫或（Ci_C2)直碳鏈，其中圮與圮中至 少一個不為氫，且其中該碳係視情況獨立被自基單·、二_ 或二-取代，該碳，惟連接碳除外，係視情沉被羥基單取代 ，該碳係視情況被酮基單取代，且該碳鏈係視情況被π單_ · 、二-或三-取代，其中任一個圮或圮係被π取代，或rs與妒 兩者均被V3取代； 其中V3為部份飽和、完全飽和或完全不飽和三至六員環， 則青況具有-至二個獨立選自氧、硫及氮之雜原子，或雙 環狀環，包含兩個獨立採用之稠合部份飽和、完全飽和= 完全不飽和三至六員環，視情況具有一至四個獨立選自= 、石尼及氧之雜原子； 其中該V3取代基係視情況獨立被V4、烷基、 -14 - 1285641 c(〇)-v4、a(c0-c6)燒基-v4、（c「c6)燒基-αν4、画基、（Cl-c6) 烷基、（Ci -C6)燒氧基、羥基、酮基、胺基、硝基、氰基、（c「c4) 烷硫基、（Ci-C4)烷基亞磺醯基、（q-Q)烷基磺醯基、單養或 二-N，N-(Ci -C6)烷基磺醯基、（Cl -c6)烷氧羰基、單善或二-N，N- (crc6)烷胺基單-、二-、三-、四-或五取代，其中該（CrC6) 烷基取代基係視情況被酮基單取代，其中該（q -c6)烷基取代 基係視情況被羥基單取代，該（q -c6)烷基或-c6)烷氧基取 代基亦視情況被一至九個氟取代； 其中V4為部份飽和、完全飽和或完全不飽和三至六員環， 視情沉具有一至二個獨立選自氧、硫及氮之雜原子，或雙 環狀環’包含兩個獨立採用之稠合部份飽和、完全飽和或 充全不飽和三至六員環，視情況具有一至四個獨立選自氮 、硫及氧之雜原子；其中該V取代基係視情況獨立被_基、 (Cl-C6)燒基、（Cl-C6)烷氧基、羥基、酮基、胺基、硝基、氰 基、〇^-(：6)燒氧羰基、單|或二-;^，叫(：;「(：6成胺基單-、二- 、二-或四取代，其中該（Ci -c6)烷基取代基係視情況被酮基 早取代’該（C^C6)烷基或（Ci-Cj烷氧基取代基亦視情況被一 至九個氟取代； 4/、中R與R係一起採用而形成部份飽和、完全飽和或完 王不飽和二至八員環，視情況具有一至四個獨立選自氧、 石I及氮足雜原子，或雙環狀環，包含兩個稠合部份飽和、 A王飽和或完全不飽和三至六員環，包含獨立選自氮、硫 及氧之雜原子； R4為氫； -15 - 1285641 R5與R6各獨立為氫、鹵基、Τ、（q -C6 >完氧基或（Q -Q)坑基 ，該（Ci-C6)烷氧基或（Ci-CJ烷基取代基視情況具有一至九個 氟，或該（q -C6)烷氧基或（Ci -C6)烷基取代基視情況被T單取 代； 其中T為部份飽和、完全飽和或完全不飽和五至六員環， 視情況具有一至二個獨立選自氧、硫及氮之雜原子；其中 該丁取代基係視情況獨立被自基、（Ci -Cg )、虎基、喪基、（Ci七6) 燒氧基、（Ci-C4)燒硫基 '胺基、酮基、複基、（crC6)挺氧羰 基、單-N-或二-Ν,Ν-Α -C6)烷胺基單-、二-或三-取代，其中 該-C6)烷基取代基，視情況具有一至九個氟； R7為氫； 或其藥學上可接受之鹽或前體藥物。 此外’本發明係提供式III化合物Wherein R1 is wx; W is a group; X is -0-Y; y is independently (q _c6) fluorenyl for each of the existing groups, and the (Ci_c6) alkyl group has from one to nine fluorines as the case may be, or the (C1) -Q)alkyl is optionally substituted by 2; its tz is a partially saturated, fully saturated or fully unsaturated three to six membered ring, optionally having one or two heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen; The Z-substituent is independently drawn by the group, (c^cj alkyl, (c alkoxy, (Ci-C: 4) alkylthio, nitro, cyano, keto 4 (Ci-C4) Alkoxycarbonyl 0^100 -13 - 1285641 The (q -C4) fluorenyl group is optionally substituted by one to nine singly-, di- or tri-substituted fluoro groups; R2 is partially saturated, fully saturated or not at all Saturated (q-co linear or branched carbon bond 'where each carbon, except for the attached carbon, may optionally be replaced by a hetero atom selected from oxygen and sulfur, wherein the carbon is independently halogenated Mono-, di- or tri-substituted, the carbon chain being optionally monosubstituted by a keto group, which is optionally substituted by a radical, which is optionally mono- or disubstituted by a keto group, or the R2 Saturated for Shao, Fully saturated or fully unsaturated, three to five members are said to have a hetero atom independently selected from oxygen and sulfur, as the case may be; wherein the R2 is independently a halogen or alkoxy group, _, or _ Substituting; wherein R3 is -CH2 NR8 R9 or _c(〇)NR8 R9; wherein R8 and R9 are independently hydrogen or (Ci_C2) straight carbon chains, wherein at least one of ruthenium and osmium is not hydrogen, and wherein the carbon system Depending on the situation, it is independently substituted from the base, the second or the second, except for the carbon attached, which is monosubstituted by the hydroxy group, which is optionally substituted by a ketone group, and the carbon chain is optionally treated. The situation is replaced by π-mono-, di- or tri-, wherein either 圮 or 圮 is substituted by π, or both rs and 妒 are replaced by V3; wherein V3 is partially saturated, fully saturated or fully unsaturated. To the six-membered ring, the green condition has - to two heteroatoms independently selected from oxygen, sulfur and nitrogen, or a double-ringed ring, comprising two independently used fused portions saturated, fully saturated = fully unsaturated Up to a six-membered ring, optionally having one to four heteroatoms selected from the group consisting of =, sini and oxygen; wherein the V3 substituent is Independently by V4, alkyl, -14 - 1285641 c(〇)-v4, a(c0-c6)alkyl-v4, (c"c6)alkyl-αν4, benzyl, (Cl-c6) alkyl (Ci-C6) alkoxy, hydroxy, keto, amine, nitro, cyano, (c "c4) alkylthio, (Ci-C4) alkylsulfinyl, (qQ) alkyl Sulfonyl, mono- or di-N,N-(Ci-C6)alkylsulfonyl, (Cl-c6) alkoxycarbonyl, mono- or di-N,N-(crc6)alkylamino- a di-, tri-, tetra- or penta-substituted group wherein the (CrC6)alkyl substituent is optionally monosubstituted by a keto group, wherein the (q-c6)alkyl substituent is optionally monosubstituted with a hydroxy group, The (q-c6)alkyl or -c6) alkoxy substituent is also optionally substituted with from one to nine fluorines; wherein V4 is a partially saturated, fully saturated or fully unsaturated three to six membered ring, One to two heteroatoms independently selected from oxygen, sulfur, and nitrogen, or bicyclic rings containing two independently fused portions that are saturated, fully saturated, or fully unsaturated, three to six-membered rings, as appropriate Four heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; wherein the V substituent is independently _ group, (Cl-C6) alkyl group, (Cl-C6) alkoxy group, hydroxyl group, keto group, amine group, nitro group, cyano group, 〇^-(:6) alkoxycarbonyl group, single|| -;^,called (:; "(: 6 to an amine-mono-, di-, di- or tetra-substituted, wherein the (Ci-c6) alkyl substituent is replaced by a keto group as appropriate] ^C6)alkyl or (Ci-Cj alkoxy substituents are also optionally substituted with one to nine fluorines; 4/, intermediate R and R are used together to form partially saturated, fully saturated or unsaturated unsaturation An eight-membered ring, optionally having one to four heteroatoms selected from the group consisting of oxygen, rock I and nitrogen, or a bicyclic ring containing two fused portions saturated, A-star saturated or fully unsaturated three- to six-membered rings Containing heteroatoms independently selected from nitrogen, sulfur and oxygen; R4 is hydrogen; -15 - 1285641 R5 and R6 are each independently hydrogen, halo, hydrazine, (q -C6 > oxy or (Q -Q) a pit group, the (Ci-C6) alkoxy group or (Ci-CJ alkyl substituent optionally having from one to nine fluorines, or the (q-C6) alkoxy group or (Ci-C6) alkyl substituent The situation is replaced by T; where T is partially saturated, fully saturated or fully unsaturated. a six-membered ring, optionally having one or two heteroatoms independently selected from the group consisting of oxygen, sulfur, and nitrogen; wherein the butyl substituent is independently derived from the group, (Ci-Cg), tiger base, sulfhydryl, (Ci-7) 6) Alkoxy, (Ci-C4) thiol' amine group, keto group, complex group, (crC6) methoxycarbonyl group, mono-N- or di-anthracene, Ν-Α-C6) alkylamine group a -, di- or tri-substituted, wherein the -C6)alkyl substituent, optionally having from one to nine fluorines; R7 is hydrogen; or a pharmaceutically acceptable salt or prodrug thereof. Further, the present invention provides a compound of formula III

其中 C3為碳； J為竣，其中在C3與J間之鍵結為單或雙鍵； η為零，若C3與J間之鍵結為雙鍵時，或為一，若C3及J間 之鍵結為單鍵時； R2為（q 烷基、環丙基或環丁基； 92199 -16- 1285641 R5 為 cf3 ; R6為氫；Wherein C3 is carbon; J is 竣, wherein the bond between C3 and J is a single or double bond; η is zero, if the bond between C3 and J is a double bond, or one, if C3 and J When the bond is a single bond; R2 is (q alkyl, cyclopropyl or cyclobutyl; 92199 -16-1285641 R5 is cf3; R6 is hydrogen;

Rl0為完全飽和（CrC4)直鏈或分枝狀碳鏈； R11為鹵基、羥基、-c(0)(〇(c厂c4)烷基）、-C(〇)C(〇)(〇(C「C4) 烷基）、-CCC^NH^Xq -c4)烷基）或 _c(〇)N((Cl -c4)烷基）(〇(Ci _c4)烷 基）；Rl0 is a fully saturated (CrC4) linear or branched carbon chain; R11 is a halogen group, a hydroxyl group, -c(0) (〇(c)c4)alkyl), -C(〇)C(〇)(〇) (C "C4) alkyl), -CCC^NH^Xq -c4)alkyl) or _c(〇)N((Cl-c4)alkyl)(〇(Ci_c4)alkyl);

Rl2為氫或鹵基，其中當R12為鹵基時，Ru不為_基；Rl2 is hydrogen or a halogen group, wherein when R12 is a halogen group, Ru is not a group;

或RU與R12 一起採用而形成酮基或K ; 或其藥學上可接受之鹽或前體藥物。 此外’本發明係提供在哺乳動物中治療動脈粥瘤硬化、冠 狀動脈疾病、冠狀心臟疾病、冠狀血管疾病、末梢血管疾 病月曰血症障礙、高万脂蛋白症、低α脂蛋白症、高膽固醇 血症、、血甘油三醋過多 '家族性高膽固醇血症或心肌梗塞 、方会/、方式疋對需要此種治療之哺乳動物投予動脈粥Or RU is used together with R12 to form a keto group or K; or a pharmaceutically acceptable salt or prodrug thereof. Furthermore, the present invention provides for the treatment of atherosclerosis, coronary artery disease, coronary heart disease, coronary vascular disease, peripheral vascular disease, hemorrhagic disorder, valvalin, low alpha lipoprotein, high in mammals. Cholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, or myocardial infarction, prescription, and sputum, administration of atherosclerosis to mammals in need of such treatment

瘤更化4狀動脈疾病、冠狀心臟疾病、冠狀血管疾病、 末梢皿&疾病血症障礙、高沒脂蛋白症、低㈣旨蛋白症 、高膽固醇血症、血甘油三§旨過多、家族性高膽固醇血症Tumor-like 4th artery disease, coronary heart disease, coronary vascular disease, deciduous & disease disorder, high-lipoproteinemia, low (four) protein, hypercholesterolemia, blood glycerol Hypercholesterolemia

或心肌梗塞治痒|乏太I RE1 p A •、 發月化合物，或該化合物之藥學.上 可接受形式。 此外，本發明係提供醫蘿 奮毛、，且3物，其包含治療上有效量之 本發明化合物，或該化合物 物足樂學上可接受形式，及藥學 上可接受之媒劑、稀釋劑或載劑。 此外，本發明係提供在哺 、、 礼動物中治療動脈粥瘤硬化、冠 狀動脈疾病、冠狀心臟在症 緘疾涡、甩狀血管疾病、末梢血管疾 92199 > 17- 1285641 病、知血症障礙、鬲召脂蛋白症、低α脂蛋白症、高膽固醇 血症、血甘油三酯過多、家族性高膽固醇血症或心肌梗塞 之醫藥組合物，其包含治療上有效量之本發明化合物，或 該化合物之藥學上可接受形式，及藥學上可接受之媒 稀釋劑或載劑。 1 再者，本發明係提供醫藥組合之組合物，其包含：治療上 有效量之組合物，其包含 第-種化合物’該第一種化合物為本發明之化合物，或該 化合物之藥學上可接受形式； ’ 第一種化合物，孩第二種化合物為刪還原酶抑制劑 、ΜΤΡ/ΑροΒ分泌、抑制劑、職調制劑、膽汁酸再攝取抑制 ，、膽固醇吸收抑制劑、膽固醇合成抑制劑、纖維酸酉旨、 於驗I、缓慢釋出於驗酸、於驗酸與洛伐制菌素⑼赠㈣之 組合 '離子交換《'抗氧化劑、ACAT抑制劑或膽汁酸多 價螯合劑（較佳為HMG-COA還原酶抑制劑、職調制劑、洛 伐制菌素（lovasiatm)、辛伐制菌素（如^她〕、普拉伐制菌素鲁 一ln)、弗伐制菌素(一n)、阿托瓦制菌素(at0__ 、菌素（nv_m)、洛蘇伐制菌素（r〇suvastatm)或皮塔伐 制菌素（pitavastatin));及 醫藥媒劑、稀釋劑或載齊卜此組合物可用以治療前文所提 及之疾病，包括動脈粥瘤硬化。 丰發明亦提供一種在哺乳動物φ 6人 同孔勁物中達成治潦作用之套件，其 匕含一起包裝之第一種治療劑，Α Μ_ 其包括治潦上有效量之根 據申請專利範圍第1、8、12哎13項 > 於人 戈13項 < 化合物，其前體藥物 92199 -18 - 1285641 ’或琢化合物或該前體藥物之藥學上可接受鹽，及藥與上 可接受之載劑，第二種治療劑，其包括治療上有效且之 HMG CoA還原酶抑制劑、ppAR調制劑、膽固醇吸收抑制, 膽固醇合成抑制劑、纖維酸酯、菸鹼酸、緩慢釋出菸鲶酸 於驗酸與洛伐制菌素（lovastatin)之组合、離子交換樹俨”= 氧化釗、ACAT抑制劑或膽汁酸多價螯合劑，及藥學上可、Or myocardial infarction itch | lack of I RE1 p A •, a compound of the moon, or a pharmaceutically acceptable form of the compound. Further, the present invention provides a therapeutically effective amount of a compound of the present invention, or a compound of the present invention, and a pharmaceutically acceptable vehicle, diluent, and the like. Or carrier. In addition, the present invention provides for the treatment of atherosclerosis, coronary artery disease, coronary heart disease, stenosis, sickle vascular disease, peripheral vascular disease 92199 > 17-1285641 disease, azotemia in feeding and ceremonial animals. A pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, a disorder, arachnoid, low alpha lipoprotein, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia or myocardial infarction, Or a pharmaceutically acceptable form of the compound, and a pharmaceutically acceptable vehicle diluent or carrier. Further, the present invention provides a pharmaceutical composition comprising: a therapeutically effective amount of a composition comprising a first compound, wherein the first compound is a compound of the invention, or the compound is pharmaceutically acceptable Accepted form; 'The first compound, the second compound is a de-reductase inhibitor, ΜΤΡ/ΑροΒ secretion, inhibitor, occupational modulator, bile acid reuptake inhibition, cholesterol absorption inhibitor, cholesterol synthesis inhibitor, Fibric acid, in the test I, slowly released from the acid test, in the combination of acid test and locomycin (9) gift (four) 'ion exchange' 'antioxidant, ACAT inhibitor or bile acid sequestrant (more Good for HMG-COA reductase inhibitors, occupational modulators, lovastatin (lovasiat), simvastatin (such as ^ her), pravastin ruthenium ln), fluin bacteriocin (a), Atowa bacteriocin (at0__, bacteriocin (nv_m), rosuvastatin (r〇suvastatm) or pitavastatin); and pharmaceutical agents, thinners Or the composition may be used to treat the diseases mentioned above, Including an atheroma hardening. The invention also provides a kit for achieving a therapeutic effect in a mammalian φ 6 person, which contains a first therapeutic agent packaged together, Α Μ _ According to the scope of the patent application No. 1, 8, 12, 13 > in the human < compound, its prodrug 92199 -18 - 1285641 ' or a guanidine compound or a pharmaceutically acceptable salt of the prodrug, And a pharmaceutically acceptable carrier, a second therapeutic agent comprising a therapeutically effective HMG CoA reductase inhibitor, a ppAR modulator, cholesterol absorption inhibition, a cholesterol synthesis inhibitor, a fiber ester, a niacin Slow release of nicotinic acid in combination with acid and lovastatin, ion exchange tree 俨" = cerium oxide, ACAT inhibitor or bile acid sequestrant, and pharmaceutically acceptable,

受之載劑，以及關於投予該第一種與第二種藥劑以1 = 療作用之指示。 成/D 的是，前文-般說明及下文詳細說明兩者係僅為舉 例與钟釋，而非所請求本發明之限制。 發明詳述 本發明可參考下文本發明列舉具體實施例之詳細說明及包 含於其中之實例，而更容易地明瞭。 在，示並描述本發明之化合物、组合物及方法之前，應明 瞭的是，本發明並不限於製造之特定合成方法，其當㈣ 又了應明瞭的疋’本文中所用之術語係僅為達成描 争疋具體實施例之目的’並非意欲成為限制。 本發明亦關於本發明化合物之藥學上可接受之酸加成鹽類 :用以製備可文所提及本發明鹼性化合物之藥學上可接兵 叙加成鹽類之酸類，係袅 > 又 ’ ^>成典母叙加成鹽者，意即各有 藥理學上可接受陰離子之蹄，链 ^ P。有 風 $如鹽鉍鹽、氳溴酸鹽、氫 琪鹽、硝酸鹽、硫酸職、 ^ 鉍性^鉍鹽、磷酸鹽、酸性磷 &鹽、醋酸鹽、乳酸鹽 ^ 知彳豕鲛鹽、酸性檸檬酸鹽、酒石 叙鹽、酸性酒石酸鹽走 &風號轴酸鹽、順丁缔二酸鹽、反丁缔 92199 -19- 1285641 二酸鹽、葡萄糖酸鹽、蔗線舻睡一田么 、乙燒磺酸睡、笨η、、…ο奴鹽，磺酸鹽 九…鹽、對-甲苯磺 (意即1，广亞甲基_雔门,甘 又匕奈馱鹽 又（-理基-3-莕$酸鹽））0 本發明亦關於本發明化合物之驗加成鹽 ，以製備本性上為酸性、h τ作為相使用 鹽之化學鹼，係為 1明化合物之藥學上可接受驗 無毒驗鹽，包括^限=化合物形成無毒驗鹽者。此種 離子，譬如驗金屬陽離子::生自此種樂理學上可接受之陽 ί)者，銨或水溶性胺加成鹽，譬如N_f基 萄糖胺⑶甲胺）與低碳料铵 :基葡 之其他鹼鹽。 ㈣&头干上可接文有機胺類 一般熟練化學師辦：日3拉α θ ,^ ^ 字月瞭的疋，本發明某些化合物將含有一 或多個可呈特定立骹仆與 二化學或幾何型態之 構物與組態異構物。所古心搞田a ,,± 斤有此種異構物及其混合物均被包括 在本發明内。本發人、 β <水合物與溶劑合物亦被包本 在内。 d 在本發明化合物且右 …、 物具有兩個或多個立體原中心，且絕對或相 對立體化學係示於2殺Φ、 、％中< ^況下，名稱R與S係根據習用 IUPAC 數字體 # ，α ^ 4 & 、 、 ^ 升數字順序（1、2、3等），個別指稱 二 、各上原中心。在本發明之化合物具有一或多個 a原中 且乂體化學並未示於名稱或結構中之情況下 ’應明瞭的是，名溢七纟士 4盆 私或〜構係意欲涵蓋化合物之所有形式 ，包括外消旋形式。 本發明化合物可各古γ ,一 。有似~ fe之雙鍵。當此種鍵結存在時， 92199 -20- !285641 Λ 化&物係以順式與反式組態及其混合物存在。，，順式，， -司係彳曰兩個取代基參照彼此與環平面之取向（無論是兩者 均為"上"或兩者均為，，下"）。同樣地，”反式"一詞係指兩個 弋土 > 彼此與環平面之取向（取代基係在環之相反側上）。 〃冷係札取代基參照環平面之取向。沒係在環平面上方， 而α係在環平面下方。 天、亦包括以同位素方式標識之化合物，其係與藉由式 與Π所述者相同’惟以下事實除外，一或多個原子係被一 有特定原子量或質量數之原子置換。 氟及氣之η:: ’包括氫、竣、氮、氧、硫、 素，譬如個別為2H、3H、uC、uc、，、1S 、7(^^UFM36 η ^ 〇 化H 。本發明之化合物’其前體藥物，及該 化口物或珂體藥物之藥 之同位素及/或…/上了接又鹽，其含有前文所提及 4/、他原子之其他同位去 圍内。本發明之某些 ；’、 '明《範 摻入放射性同位素4 =万式‘識…物，例如被 質組織分转Μ \ 者，可使㈣藥物及/或受 位素二=:(意即、與-(意，之同 被較重質同位辛取Γϊ 易性與可偵測性。再者， 代身女疋性所造成之某此 」设仵由於較大 生期或降低之劑量需要點’例如增加之活體内半 同位素方式標識之二明：：在一些情況中係為較佳。以 行下文圖式及/或實例：斤：物及其前體藥物，可經由進 以同位素方式標識之u ’經由以易於取得之 92199 你取代未以同位素方式標識之試 '21 - 1285641 劑，一般性地進行製備。 在本專利說明書及隨後之啦社 Μ專利範圍中，可參考許多將 被定義成具有下述意義之術語· 於本文中使用之哺乳動物— ^ 巧，係意欲指稱所有在其血漿 中含有CETP之哺乳動物，例 ： Κ 兔子與靈長類動物，譬如猴 子與人類，包括雄性與雌柯 " 某些其他哺乳動物，例如狗 、雜、牛、山羊、绵羊及氣 …’在其血漿中未含有CETP，因 此未被包括在此處。 於本文中使用之’f進行治療"、，，▲ *、 '心療或"治療處理’，術語 ，係包括防止（例如預防）與舒減治療。 所謂"藥學上可接受"，係指載劑、稀釋劑、賦形劑及厂戈 鹽必須可與配方之其他成份μ，且不會對其接受者有害。 當於本文中使用時，"化合物"包括任何藥學上可接受之衍 生物或變f，包括構形異構物(例如順式與反式異構物)與 所有光學異構物（例如對裳里错札 對旱異構物與非對映異構物），此種 異構物之外消旋、非對映異構物及其他混合物，以及溶劑 合物、水合物、類質同晶型體、多晶型物、互變異構物、 醋類、鹽形式及前體藥物。所謂”互變異構物"，係意謂化 學化合物，其可以呈平衡之不同結構（異構物）之兩種或多 種形式存在，冑形式通常係在氫原子之位置上相異。可出 現互變異構現象之各種類型，包括嗣基·締醇、環_鍵及環_ 環互變異構現象。"前體藥物”之措辭，係指藥物先質化衣合 物，其在投藥後會於活體内經由一些化學或生理過程釋: 該藥物（例如前體藥物在被帶至生理阳值或經過酶作用時， 92199 -22- 1285641 係被轉化成所要之藥物形式）。舉例之前體藥物係於分裂時 釋出其相應之自由態酸，且本發明化合物之此種可水解可 形成酯之殘基，包括但不限於具有羧基部份基團者，其中 自由態氫係被（(^<：4瓞基、（eve?)烷醯氧基甲基、具有4至9 個後原子之1-(燒醯氧基）乙基、具有5至1〇個竣原子之卜甲基. 1-(烷醯氧基）-乙基、具有3至6個碳原子之烷氧羰基氧基甲基 、具有4至7個碳原子之丨-(烷氧羰基氧基）乙基、具有5至8個 碳原子之1-甲基-1-(¾氧羰基氧基）乙基、具有3至9個碳原子 足N-〇fe氧羰基）胺基甲基、具有4至丨〇個碳原子之丨_肝後氧 羰基）胺基）乙基、3-酞基、4-巴豆内酯基、丁内酯斗基、 一 -Ν,Ν-% -C2 )燒胺基（c：2 -C3)燒基（譬如石-二甲胺基乙基）、胺 甲醒基瓜-Q)垸基、N，Nc (Cl必)燒基胺甲醯基瓜必)燒基 及六氫吡啶基-、四氫吡咯基-或嗎福啉基（(：2<：3)烷基置換。 下逑段落係描述關於本文所含有之一般性環描述之舉例環 視情況具有一或兩個獨立選自氧、氮及硫之雜原子之舉例 五至六員芳族環，係包括苯基、呋喃基、噻吩基、吡咯基 、哼唑基、嘍唑基、咪唑基、吡唑基、異咩唑基、異噻唑 基、峨啶基、吡啶畊基、嘧啶基及吡畊基。 視情況具有-至四個獨立選自氧、硫及氮之雜原子之舉例 部份飽和、完全飽和或完全不飽和五至八員環，係包括環 戊基、環己基、環庚基、環辛基及苯基。進一步舉例之五 員環，包括2H-,比咯基、3H-吡咯基、2-二氫吡咯基、3_二氫 吡咯基、四氫吡咯基、1,3-二氧伍圜基、嘮唑基、噻唑基、 咪唑基、2H-咪唑基、2-二氫咪唑基、四氫咪唑基、吡唑基 92199 •23- 1285641 、2-二氫吡唑基、四氫吡唑基、異哼唑基、異噻唑基、1> 二硫伍圜基、1,3-二硫伍圜基、3H-1，2-氧硫伍圜基、1，2,3-哼 二唑基、1，2,4 j号二唑基、1，2,5-噚二唑基、1，3,4-嘮二唑基、1，2,3-三唑基、1，2,4-三唑基、1，3,4-噻二唑基、1，2,3,4-噚三唑基、1，2,3,5-吟三唑基、3H-1，2,3-二哼唑基、1，2,4-二噚唑基、1，3,2-二噚唑 基、1，3,4-二呤唑基、5H-1，2,5-吟噻唑基及1，3-氧硫伍圜基。 進一步舉例之六員環，包括2H-哌喃基、4H-哌喃基、吡啶 基、六氫吡啶基' 1，2-二氧陸圜烯基、1，3-二氧陸圜烯基、l，4-二氧陸圜基、嗎福啉基、1，4-二硫陸圜基、硫代嗎福啉基、 哈p井基、喊淀基、p比味基、六氫说畊基、1，3,5_三呼基、ι，2,4_ 二畊基、1，2,3-三畊基、l，3,5-三硫陸圜基、4H-1，2-崎畊基、2H_ U-嘮畊基、6H-1，3-噚畊基、6H-1，2-呤畊基、1，4-嘮畊基、2H-1，2-4畊基、4Η-1，4^号啩基、ι，2,5-嘮嘍畊基、丨，4- α号畊基、鄰-異 呤畊基、對_異嘮畊基、H5-噚嘍畊基、丨，2芥噚嘍畊基、m 呤二畊基及1，3,5,2-噚二啡基。 進-步舉例之七員環包括一氮七圜埽基、氧七園缔基及硫 七圜烯基。 進-步舉例之人員環包括環辛基、環辛晞基及環辛二缔基。 •雙％狀壞，包含兩個獨立採用之稠合部份飽和、完全飽和 或完全不飽和五或六員冑，視情況具有一至四個獨立選自 氮、硫及氧之雜原+，其舉例包括十井基、十朵基、異哨 哚基、3Η-吲哚基、1Η-昱⑷唼其、一与？丨凡甘 4衣基、一虱啕咪基、環戊⑻吡啶 基、Μ基（洲心基、苯并唉喃基、異苯并吱喃基、苯 并幅吩基、苯并（c)4吩基、1Η_啕唑基、啕哚呤畊基、苯 92199 -24- 1285641 并呤唑基、苯并咪唑基、苯并嘍唑基、嘌呤基、4H-,奎P井基 、喳啉基、異喹啉基、唓啉基、呔畊基、喹唑啉基、峻嗓 4基、1，8-喑啶基、喋啶基、茚基、異茚基、萘基、四氫萘 基、十氫莕基、2H-1-苯并喊喃基、吡啶并（3,4-b)-吡啶基、外匕 啶并（3,2-b)-吡啶基、吡啶并（4,3-b)-吡啶基、2H-1，3-苯并吟畊基 、2H-1，4-苯并吟畊基、iH-2,3-苯并吟啡基、4H-3J-苯并呤呼基 、2H-1，2-苯并嘮畔基及4Η-1，4-苯并呤呼基。 所謂”次烷基”，係意謂飽和烴（直鏈或分枝狀），其中氫原 子係自兩個相鄰碳之每一個中移除《此種基團之舉例（假設 所指稱之長度係涵蓋特定實例），係為亞甲基、次乙基、次 丙基、次丁基、次戊基、次己基、次庚基。 所明_基或_素” ’係意謂氯基、溴基、琪基或氟基。 所咕纟元基，係思彡胃直鍵飽和fe或分枝鍵飽和煙。此種燒 基之舉例（假設所指定之長度係涵蓋特定實例），係為甲基 、乙基、丙基、異丙基、丁基、第二-丁基、第三丁基、戊 基、并戊基、新戊基、第三戊基、；μ甲基丁基、2-甲基丁基 、3-甲基丁基、己基、異己基、庚基及辛基。 於本文中所指稱之”烯基”可為線性或分枝狀，且其亦可為 環狀（例如環丁烯基、環戊缔基、環己烯基）或雙環狀，或 含有環狀基團。其係含有1-3個可為順式或反式之碳-碳雙鍵。 所謂π烷氧基”，係意謂經過氧基結合之直鏈飽和烷基或分 枝鏈飽和烷基。此種烷氧基之舉例（假設所指定之長度係涵 蓋特定實例），係為甲氧基、乙氧基、丙氧基、異丙氧基、 丁氧基、#Τ氧基、第三丁氧基、戊氧基、異戊氧基、新 92199 -25- 1285641 戊乳基、第三戊氧基、己氧基、異己氧基、庚氧基及辛氧 基。 於本又中使用單_N’或二蝴呢烷基"術語，係指 獨立採用之（Cl _Cx)垸基部份基團，當其係為二_ν，ν·Α _c^完 基（X係指整數）時。 ，在'’該，碳係視情況獨立被齒基單-、：-或三-取代，該碳係 視^況被先基單取代’該碳係視情況被酮基單取代”措辭中 ’對於，，該竣”之指稱（例如中請專利範圍第！項），係指竣鏈 中之各個碳，包括連接碳。 、本文中氮...被酮基二_取代”之指稱（例如申請專利 圍第1項）’係指構成硝基官能基之末端氮^ 〃 應明瞭的是，若碳環妝十 或雖環狀部份基團可經過不同環原 子，結合或者連接至所指 .、 火 < 爻貝，而未表示出特定連接 點’則係意欲所有可能之 ^ 一、 技 “’·έ ’典論是經過碳原子或例如三 仏氮原子。例如，’％比淀其，， a 一詞係意謂2-、或4-吡啶基， π嗜吩基”一詞係意謂2_或The carrier, as well as instructions for administering the first and second agents with a 1 = therapeutic effect. It is to be understood that the foregoing general description and the following detailed description are merely illustrative and not restrictive. DETAILED DESCRIPTION OF THE INVENTION The invention will be more readily apparent from the following detailed description of the embodiments of the invention, Before the present invention is shown and described, it is to be understood that the invention is not limited to the particular method of manufacture, and that the term used herein is only Achieving the purpose of the specific embodiments is not intended to be limiting. The invention also relates to pharmaceutically acceptable acid addition salts of the compounds of the invention: for the preparation of pharmaceutically acceptable extender salts of the basic compounds of the invention which may be mentioned herein, "袅> Also, '^> is a mother who adds salt to the salt, meaning that each has a pharmacologically acceptable anion hoof, chain ^ P. Windy such as salt, barium salt, barium bromide, hydrogen salt, nitrate, sulfate, ^ 铋 salt, phosphate, acid phosphorus & salt, acetate, lactate Acid citrate, tartar salt, acid tartrate & wind oleate, cis-butane, anti-Button 92199 -19-1285641 diacid salt, gluconate, sugar cane line sleep Yitian, B-sulfonic acid, sleep, stupid η,, ... ο slave salt, sulfonate nine... salt, p-toluene (meaning 1, 1, methylene _ 雔 ,, 甘 匕 匕 驮 salt (-Licyl-3-indole acid salt)) The present invention also relates to an additive salt of the compound of the present invention, to prepare a chemical base which is acidic in nature and h τ as a phase-using salt, which is a compound of 1 The pharmaceutically acceptable non-toxic salt test, including the limit = compound formation of non-toxic salt testers. Such ions, such as metal cations: from such ethically acceptable cations, ammonium or water-soluble amine addition salts, such as N_f glucosamine (3) methylamine) and low carbon ammonium: Other alkali salts of the base. (4) & heads can be attached to the organic amines of the general skilled chemist: day 3 pull α θ, ^ ^ word month of the 疋, some compounds of the invention will contain one or more can be a specific servant and two Chemical or geometric structures and configuration isomers. It is common to understand the presence of such isomers and mixtures thereof in the present invention. The present inventors, β < hydrates and solvates are also included. d in the compound of the present invention and the right ..., the object has two or more stereogenic centers, and the absolute or relative stereochemistry is shown in 2 kill Φ, , % in the case, the name R and S are based on the conventional IUPAC Digital body #, α ^ 4 & , , ^ l number order (1, 2, 3, etc.), individual reference two, each Uehara center. In the case where the compound of the present invention has one or more a-origins and the steroidal chemistry is not shown in the name or structure, it should be understood that the name of the seven-person gentleman or the four-system is intended to cover the compound. All forms, including racemic forms. The compounds of the invention may each have an ancient gamma, a. There are double keys like ~ fe. When such a bond is present, the 92199 -20-!285641 Λ & system is present in both cis and trans configurations and mixtures thereof. , cis,, - 司 彳曰 two substituents refer to each other and the orientation of the ring plane (whether both are " upper " or both, lower "). Similarly, the term "trans" refers to the orientation of two bauxites with respect to the plane of the ring (the substituents are on the opposite side of the ring). The orientation of the ring-based substituents is referenced to the plane of the ring. Above the ring plane, and α is below the plane of the ring. Days, including the compounds identified by isotope, are the same as those described by ', except for the fact that one or more atomic systems are Atomic substitution with a specific atomic mass or mass number. Fluorine and gas η:: 'Includes hydrogen, helium, nitrogen, oxygen, sulfur, and sulphur, such as 2H, 3H, uC, uc, , 1S, 7 (^^ UFM36 η ^ 〇化H. The compound of the present invention is a prodrug thereof, and an isotope and/or a salt of the drug of the phlegm or steroid drug, which contains the aforementioned 4/, Others of his atom are encircled. Some of the inventions; ', 'Ming's "incorporating radioisotope 4 = 10,000" knowledge, such as being transferred to the plasty, can make (4) drugs and / Or the receptor 2 =: (meaning, and - (meaning, by the same heavy symplectic symplectic susceptibility and detectability. One of the reasons for the virginity of the virginity is that it is required to be marked by a larger or shorter dose, such as an increased half-isotopic identification in vivo: in some cases it is preferred. The following diagrams and / or examples: kg: the substance and its prodrugs, can be identified by the isotope method of u ' via the easily available 92199 you replace the not isotically labeled test '21 - 1285641 agent, generally Preparations are made sexually. In the scope of this patent specification and the subsequent patents, reference may be made to a number of terms that will be defined in the following senses. The mammals used herein are intended to refer to all of them. Mammals containing CETP in plasma, for example: 兔子 Rabbits and primates, such as monkeys and humans, including males and females " Certain other mammals, such as dogs, miscellaneous, cattle, goats, sheep, and qi...' It does not contain CETP in its plasma and is therefore not included here. The treatment used in this article is 'f,',, ▲*, 'cardiac treatment or "therapeutic treatment', terminology, It includes prevention (such as prevention) and treatment of relief. The so-called "pharmaceutically acceptable" means that the carrier, diluent, excipient and plant salt must be compatible with the other ingredients of the formulation, and will not It is harmful to the recipient. As used herein, "compound" includes any pharmaceutically acceptable derivative or variant f, including conformational isomers (eg, cis and trans isomers) and all optics. Isomers (eg, pairs of isomers and diastereomers), racemic, diastereomeric and other mixtures of such isomers, as well as solvates, hydration Substance, isomorphs, polymorphs, tautomers, vinegars, salt forms and prodrugs. The term "tautomer" refers to a chemical compound which may exist in two or more forms of different structures (isomers) in equilibrium, and the oxime form usually differs in the position of a hydrogen atom. Various types of tautomerism, including thiol-actinol, ring-bond, and ring-cyclic tautomerism. The word "prodrug" refers to a drug-producing composition that is administered after administration. It will be released in vivo through some chemical or physiological process: The drug (for example, when the prodrug is brought to physiological positivity or enzymatically, 92199-22-1285941 is converted into the desired drug form). For example, a prodrug is released upon cleavage of its corresponding free acid, and such a hydrolyzable compound of the present invention can form an ester residue, including but not limited to those having a carboxyl moiety, wherein the free hydrogen is By ((^<:4 fluorenyl, (eve?) alkoxymethyl, 1 to 9 post-atoms of 1-(anthraceneoxy)ethyl, having 5 to 1 竣 a 竣 atom a methyl 1-(alkyloxy)-ethyl group, an alkoxycarbonyloxymethyl group having 3 to 6 carbon atoms, an anthracene-(alkoxycarbonyloxy)ethyl group having 4 to 7 carbon atoms, 1-methyl-1-(3⁄4 oxycarbonyloxy)ethyl group having 5 to 8 carbon atoms, N-〇fe oxycarbonyl)aminomethyl group having 3 to 9 carbon atoms, having 4 to 丨〇 One carbon atom 丨 _ post-hepatic oxycarbonyl) amino) ethyl, 3-mercapto, 4-crotonolide, butyrolactone, mono-, Ν-% -C2 ) :2 -C3)alkyl (such as stone-dimethylaminoethyl), amine methyl ketone-Q) sulfhydryl, N, Nc (Cl must) alkylamine carbamide) and six Hydropyridyl-, tetrahydropyrrolyl- or morpholinyl ((:2<:3) alkyl substitution. An example five- to six-membered aromatic ring having one or two heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur, including phenyl, furanyl, thiophene, as exemplified by the general ring descriptions contained herein. , pyrrolyl, oxazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, acridinyl, pyridinyl, pyrimidinyl and pyridinyl. Depending on the case - to four Exemplary partially saturated, fully saturated or fully unsaturated five to eight membered rings independently selected from the group consisting of oxygen, sulfur and nitrogen include cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and phenyl. Further example five-membered rings, including 2H-, pyrrolyl, 3H-pyrrolyl, 2-dihydropyrrolyl, 3-dihydropyrrolyl, tetrahydropyrrolyl, 1,3-dioxosulfonyl, anthracene Azyl, thiazolyl, imidazolyl, 2H-imidazolyl, 2-dihydroimidazolyl, tetrahydroimidazolyl, pyrazolyl 92199 •23-1285641, 2-dihydropyrazolyl, tetrahydropyrazolyl, iso Carbazolyl, isothiazolyl, 1> disulfanthyl, 1,3-disulfanyl, 3H-1,2-oxothiol, 1,2,3-oxadiazolyl, 1 , 2, 4 J oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1, 3,4-thiadiazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,5-triazolozolyl, 3H-1,2,3-dicarbazolyl, 1, 2,4-dicarbazolyl, 1,3,2-dicarbazolyl, 1,3,4-dicarbazolyl, 5H-1,2,5-oxathiazolyl and 1,3-oxosulfuryl Further examples of the six-membered ring include 2H-piperidyl, 4H-piperidyl, pyridyl, hexahydropyridyl ' 1,2-dioxo-decenyl, 1,3-dioxane Alkenyl, 1, 4-dioxanthracene, morpholinyl, 1,4-dithiolylhydrazyl, thiomorpholine, haf, ylide, p-taste, six Hydrogen says cultivating base, 1,3,5_three-heck, ι, 2,4_ two tillage, 1,2,3-three tillage, l,3,5-trithiorepine, 4H-1, 2-Saki cultivating base, 2H_ U-唠 ploughing base, 6H-1,3-噚 ploughing base, 6H-1, 2-呤 ploughing base, 1,4-唠 ploughing base, 2H-1, 2-4 cultivating base , 4Η-1,4^ 啩 base, ι, 2,5-唠喽 基 基, 丨, 4-α cultivating base, o-iso ploughing, _ 唠 唠 、, H5-噚喽Base, 丨, 2 mustard cultivating base, m 呤 two tillage and 1,3,5,2- Two brown base. The seven-membered ring of the further example includes a nitrogen heptyl group, an oxygen seven-base group, and a sulfur heptaenyl group. The human ring of the further example includes cyclooctyl, cyclooctyl and cyclooctadienyl. • Double % bad, containing two independently used fused parts saturated, fully saturated or fully unsaturated, five or six members, optionally with one to four heterogenes selected from nitrogen, sulfur and oxygen. Examples include ten wells, ten bases, different sentinel bases, 3Η-吲哚 bases, 1Η-昱(4)唼, one and one?丨凡甘4, 1, 虱啕, Cyclopentyl (8) pyridyl, fluorenyl (Crystal, benzofuranyl, isobenzopyranyl, benzo fluorenyl, benzo (c) 4 pheno, 1 Η oxazolyl, hydrazine, benzene 92199 -24-1285641 and oxazolyl, benzimidazolyl, benzoxazolyl, fluorenyl, 4H-, quinone P well, 喳Polinyl, isoquinolyl, porphyrin, hydrazine, quinazolinyl, fluorenyl, 1,8-acridinyl, acridinyl, fluorenyl, isodecyl, naphthyl, tetrahydrogen Naphthyl, decahydroindenyl, 2H-1-benzopyranyl, pyrido(3,4-b)-pyridyl, azulidine (3,2-b)-pyridyl, pyrido(4) ,3-b)-pyridyl, 2H-1,3-benzofluorene, 2H-1,4-benzopyrene, iH-2,3-benzoxanthyl, 4H-3J-benzene And oxime, 2H-1,2-benzoindole and 4Η-1,4-benzoindole. The so-called "secondary alkyl" means saturated hydrocarbon (straight or branched), Wherein the hydrogen atom is removed from each of two adjacent carbons. "An example of such a group (assuming the length is referred to as a specific example) is a methylene group, a hypoethyl group, a propyl group, Butyl, pentylene, hexyl, or heptyl. The _ _ or _ 素 " ' is a chloro, bromo, thio or fluoro group. Fe or branched bond saturated smoke. Examples of such a base (assuming the specified length covers a specific example) are methyl, ethyl, propyl, isopropyl, butyl, second-butyl, Tertiary butyl, pentyl, pentyl, neopentyl, third amyl, μmethylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl, isohexyl, heptyl and "Alkenyl" as referred to herein may be linear or branched, and may also be cyclic (eg, cyclobutenyl, cyclopentyl, cyclohexenyl) or bicyclic, Or a cyclic group containing 1-3 carbon-carbon double bonds which may be cis or trans. The so-called π alkoxy group means a linear saturated alkyl group or a group which is bonded through an oxy group. Branched chain saturated alkyl group. Examples of such alkoxy groups (assuming the specified length covers a specific example) are methoxy, ethoxy, propoxy, isopropoxy, butoxy, #Τ Oxygen, third Base, pentyloxy, isopentyloxy, new 92199 -25-1285641 pentyl, third pentyloxy, hexyloxy, isohexyloxy, heptyloxy and octyloxy. N' or damperane" term refers to a group of (Cl _Cx) thiol groups independently used, when the system is _ν, ν·Α _c^ complete (X is an integer) In the case of ''the carbon system, the carbon system is independently substituted by the dentate mono-, :- or tri-, and the carbon system is monosubstituted by the primordial 'the carbon system is monosubstituted by the keto group as appropriate.' The reference to 'yes, the 竣 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( For example, the patent application section 1) refers to the terminal nitrogen constituting the nitro functional group. It should be understood that if the carbocyclic makeup or the cyclic moiety can pass through different ring atoms, it is bonded or attached to the Refers to . , fire < mussels, but does not indicate a particular connection point 'is intended to be all possible ^, technology "'·έ' is a theory of passing carbon atoms or for example three Atoms. For example, '% is more than a salt, a, the meaning of 2-, or 4-pyridyl, π phenoxy, means 2_ or

At嚯吩基等等。 DTT係思彡胃二硫基蔽择酸At嚯 嚯 and so on. DTT is a disulfide-based acid

、 ”·· ° ^。dms〇係意謂二甲亞颯。EDTA 係意謂乙二胺四醋酸。”··° ^.dms〇 means dimethyl hydrazine. EDTA means ethylenediaminetetraacetic acid.

於本文中使用之，，對反雇D ^ 題王惰性之溶劑，，與，，惰性溶劑，，措 辭’係指不會與起始物質、 丄a ^二 忒劑、中間物或產物，以不利 地影響所要產物產率之方式交互作用之溶劑或其混合物。 於本發明式1化合物之1具體實施例中’ J為碳； R1 為 W-x ; 92199 ' 26 - 1285641 w為羰基； X為-〇-γ ; Υ對各存在處係獨立為（Ci -C6)烷基，該（Ci -C6)烷基視情況 具有一至九個氟，或該（Ci -C6)烷基視情況被Z單取代； /、中Z為σ卩彳刀飽和、完全飽和或完全不飽和三至六員環， 視情況具有一至二個獨立選自氧、硫及氮之雜原子； 其中該Ζ取代基係視情況獨立被自基、（Ci -C4)烷基、（Ci -c4) 纪氧基、（Q-C4)烷硫基、硝基、氰基、酮基或烷氧羰 基單·、二-或三-取代，該（Cl -c4)烷基或（Ci -c4)烷氧基係視情 況被一至九個氟取代； R2為召，且為部份飽和、完全飽和或完全不飽和（q-ao直 鍵或分枝狀碳鏈，其中各個碳，惟連接碳除外/可視情況 被一個獨立選自氧與硫之雜原子置換，其中該碳係視情沉 獨立被卣基單-、二-或三-取代，該碳鏈係視情沉被酮基或 羥基單取代，該硫係視情況被酮基單-或二取代；或該R2為 部份飽和、完全飽和或完全不飽和三至五員環，視情沉具 有一個獨立選自氧與硫之雜原子； 其中該R2環係視情況獨立被鹵基、羥基、-C6)烷氧基、 胺基、硝基、（Ci-C4)烷氧羰基或羧基單-、二-或三-取代； 其中R3為完全飽和、部份不飽和或完全不飽和一至六員直 鏈或分枝狀竣鏈’其中各個竣’惟C4a除外’可視情況被一 個選自氧、硫及氮之雜原子置換’且該後係視情況獨立被 画基單-、二-或三-取代，該碳係視情況被經基單取代，該 碳係視情況被氰基單取代’該碳係視情況被酮基或氮單取 92199 -27- 1285641 代，該硫係視情況被酮基單-或二取代，該氮係視情況被氫 或酮基單-或二取代，且該碳鏈係視情況在C4a或鄰近C4a之 R3碳處’被V單-、二-或三-取代；V為三、四、五或六員 部份飽和、完全飽和或完全不飽和環，視情況具有一至三 個獨立選自氧、硫及氮之雜原子，以致V不為咪唑基或完全 飽和雜環族含氮環，其中該環之氮係連接至R3基團； 其中該V環係視情況獨立被自基、（Cl -c6)烷基、羥基、 (Ci-C：6)烷氧基、（(：厂(：6)烷氧羰基、硝基、氰基或酮基單-、 二-、三·、四-或五取代，其中該（Ci-C6)烷基或（CrC6)烷氧基 取代基，視情況具有一至九個氟； R4為氫； R5與R6各獨立為氫、鹵基、T、（(VC6)烷氧基或（cvc6)烷基 ’該（Cl -C6)烷氧基或（c! -c6)烷基取代基，視情況具有一至九 個氟’或該（Ci-CJ烷氧基或（q-cj烷基取代基，視情況被丁 單取代； 其中T為部份飽和、完全飽和或完全不飽和五至六員環， 視情 >兄具有一至二個獨立選自氧、硫及氮之雜原子； 其中該T取代基係視情沉獨立被鹵基、（c! -C6)燒基、輕基 、（C1'C6)烷氧基、（Ci-Q)垸硫基、胺基、酮基、幾基、 燒氧羰基、單-N-或二-c6)燒胺基單-、二-或三-取代 ’其中該（cvc6)燒基或（(VQ)燒氧基取代基，視情況具有一 至九個氟；且 R7為氣。 於本發明式I化合物之另一項具體實施例中， 92199 •28, 1285641 Y為（c! -c4)烷基，其中該（q -c4)烷基取代基，視情況具有 一至九個氟； R2為（Ci -C4)烷基、環丙基或環丁基； R3 為-((Q -C4)烷基）(NH2 )(V)、-((C! -C3)烷基）_((：! -C2)烷基）)〇0 、-(((VQ)烷基）(〇H)(V)、-((CrC4)烷基）(F)(V)、-((CrC2)烷基 XO-qoxcvQ^sxvp-qco-v'-cpHXcoDxxcvCs^sxv) 、-CF2(V)、-((CVC2)烷基）(NHC(0)((VC2)烷基）(V)、-CH2(V)、 -((q -c2)烷基 xqopcCi -c2)烷基）(v)、-((Ci -c4)烷基）(c(〇)nh2 )(V) _ 、-((CrC4)燒基）(CN)(V)或-((Ci -C3)烷基）(((：! -C3)烷氧基 XV)， V為苯基，視情沉獨立被鹵基、（Ci -c6)烷基、羥基、-c6) 烷氧基、硝基、氰基或酮基單-、二-或三-取代，其中該 (Ci -C6)烷基或（Ci -c6)烷氧基取代基，視情況具有一至九個氟； R5與R6各獨立為氫、鹵基、-C3)烷氧基或（Ci -C6)烷基， 該（Ci-CJ烷氧基視情況具有一至七個画基，該（Ci-CJ烷基視 情況具有一至九個||基。 於本發明式I化合物之進一步具體實施例中， β Υ為甲基、乙基、1-丙基、2-丙基或第三-丁基； R2為甲基、乙基、2-丙基、環丙基或環丁基； R3 為-C(〇)-V、-C(〇H)(C(〇)OCH3)(V)、-CH(F)(V)、-CF2(V)、 -CH(OCH3 )(V)、-CH(C(〇)OCH3 )(V)、-CH(CN)(V)、-CH(OH)(V)、-CH2 (V)As used herein, the solvent, and, the inert solvent, the term "inert solvent", which is inert to the anti-employment, does not refer to the starting material, 丄a^dioxin, intermediate or product. A solvent or mixture thereof that interacts adversely in the manner in which the desired product yields. In a specific embodiment of the compound of the formula 1 of the present invention, 'J is carbon; R1 is Wx; 92199' 26 - 1285641 w is a carbonyl group; X is -〇-γ; Υ is independent of each existence (Ci - C6) Alkyl, the (Ci-C6)alkyl group optionally has from one to nine fluorines, or the (Ci-C6)alkyl group is optionally substituted by Z; /, Z is saturated, fully saturated or completely An unsaturated three to six membered ring, optionally having one or two heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen; wherein the hydrazine substituent is independently derived from the group, (Ci-C4)alkyl, (Ci- C4) oxime, (Q-C4)alkylthio, nitro, cyano, keto or alkoxycarbonyl mono-, di- or tri-substituted, (Cl-c4)alkyl or (Ci-c4 The alkoxy group is optionally substituted by one to nine fluorines; R2 is a moiety and is partially saturated, fully saturated or fully unsaturated (q-ao direct bond or branched carbon chain, wherein each carbon, but carbon is attached) Except/visually replaced by a hetero atom independently selected from the group consisting of oxygen and sulfur, wherein the carbon is independently substituted by a thiol-, di- or tri-, which is precipitated as a keto or hydroxy group. Single substitution The sulfur is optionally mono- or disubstituted by a ketone group; or the R2 is a partially saturated, fully saturated or fully unsaturated three- to five-membered ring, optionally having a hetero atom independently selected from oxygen and sulfur; The R2 ring is independently substituted by halo, hydroxy, -C6)alkoxy, amine, nitro, (Ci-C4) alkoxycarbonyl or carboxy-mono-, di- or tri-substituted; wherein R3 is completely a saturated, partially unsaturated or fully unsaturated one to six member straight or branched scorpion chain 'where each 竣' except C4a 'may be replaced by a hetero atom selected from oxygen, sulfur and nitrogen' and the latter Optionally, the substrate is mono-, di- or tri-substituted, and the carbon is optionally replaced by a radical, which is optionally monosubstituted by a cyano group. The carbon is optionally taken by a ketone or a nitrogen. 92199 -27- 1285641, the sulfur is optionally mono- or disubstituted by a ketone group, which is optionally mono- or disubstituted by hydrogen or a ketone group, and the carbon chain is optionally in C4a or adjacent to C4a. R3 carbon is 'substituted by V-, di- or tri--; V is a three-, four-, five- or six-membered partially saturated, fully saturated or fully unsaturated ring. a case having one to three heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen such that V is not an imidazolyl group or a fully saturated heterocyclic nitrogen-containing ring wherein the nitrogen of the ring is attached to the R3 group; wherein the V ring system Optionally, independently from the group, (Cl-c6)alkyl, hydroxy, (Ci-C:6) alkoxy, ((: (6) alkoxycarbonyl, nitro, cyano or keto-mono- , a di-, tri-, tetra- or penta-substituted group, wherein the (Ci-C6)alkyl or (CrC6) alkoxy substituent has from one to nine fluorines as appropriate; R4 is hydrogen; R5 and R6 are each independently Hydrogen, halo, T, ((VC6) alkoxy or (cvc6)alkyl 'the (Cl-C6) alkoxy or (c!-c6) alkyl substituent, optionally having from one to nine fluorines Or the (Ci-CJ alkoxy or (q-cj alkyl substituent, optionally substituted by butyl; wherein T is partially saturated, fully saturated or fully unsaturated, five to six-membered ring, as appropriate) Having one to two heteroatoms independently selected from the group consisting of oxygen, sulfur, and nitrogen; wherein the T substituent is independently a halo group, a (c!-C6) alkyl group, a light group, a (C1 'C6) alkoxy group. , (Ci-Q) thiol, amine, keto, several groups An alkoxycarbonyl, mono-N- or di-c6) acryl mono-, di- or tri-substituted 'wherein the (cvc6) alkyl or ((VQ) alkoxy substituent, optionally from one to nine Fluorine; and R7 is gas. In another embodiment of the compounds of Formula I of the present invention, 92199 • 28, 1285641 Y is (c! -c4)alkyl, wherein the (q-c4)alkyl substituent, optionally having from one to nine fluorines R2 is (Ci-C4)alkyl, cyclopropyl or cyclobutyl; R3 is -((Q-C4)alkyl)(NH2)(V),-((C!-C3)alkyl)_ ((:! -C2)alkyl))〇0,-((VQ)alkyl)(〇H)(V),-((CrC4)alkyl)(F)(V),-((CrC2 Alkyl XO-qoxcvQ^sxvp-qco-v'-cpHXcoDxxcvCs^sxv), -CF2(V), -((CVC2)alkyl)(NHC(0)((VC2)alkyl)(V),- CH2(V), -((q-c2)alkylxqopcCi-c2)alkyl)(v),-((Ci-c4)alkyl)(c(〇)nh2)(V) _,-(( CrC4) alkyl (CN) (V) or - ((Ci - C3) alkyl) (((:: -C3) alkoxy XV), V is a phenyl group, depending on the situation, is independently halogenated, Ci-c6)alkyl, hydroxy, -c6) alkoxy, nitro, cyano or keto mono-, di- or tri-substituted, wherein the (Ci-C6)alkyl or (Ci-c6) alkane An oxy substituent, optionally having one to nine fluorines; R5 and R6 are each independently hydrogen, halo, -C3)alkoxy or (Ci-C6)alkyl, which (Ci-CJ alkoxy optionally has One to seven bases, (Ci-CJ alkyl optionally has one to nine || groups. In a further embodiment of the compound of formula I of the invention, β Υ is methyl, ethyl, 1-propyl, 2-propyl or the third -butyl; R2 is methyl, ethyl, 2-propyl, cyclopropyl or cyclobutyl; R3 is -C(〇)-V, -C(〇H)(C(〇)OCH3)(V ), -CH(F)(V), -CF2(V), -CH(OCH3)(V), -CH(C(〇)OCH3)(V), -CH(CN)(V), -CH (OH)(V), -CH2 (V)

、-CH(NH2)(V)、-CH(NH(CH3))(V)、-CH(C(〇)NH2)(V)、-CH(CH2OH)V 、-ch(ch2och3)v、-ch(ch2oc(〇)ch3)v、-ch(ch2f)v 或 -CH(CH2NH2)V;且 V為苯基，視情況獨立被鹵基、硝基或（Ci -c2)烷基單-、二 92199 -29· 1285641 -或三-取代，其中該（Ci_C2)烷基視情況具有一至五個氟； R5與r6各獨立為氫m氧基或氯基；該甲氧基視情 況具有一至二個氟，該甲基視情況具有一至三個氟。 於本發明之另—項具體實施例中，式I化合物包含取代基 ，其中 Y為乙基； R2為乙基或甲基； R為（3,5K二氟甲基）-苯基 >羥基-甲氧羰基-甲基；（3,5-雙-三氟甲基-苯基 > 甲氧羰基-甲基；（3,5-雙-三氟甲基-笨基）_氰基 甲基3,5-雙-二氟甲基_苯甲醯基；〇,5_雙_三氟甲基-苯基）·藉 基-f基，（3,5-雙-三氟甲基苯基）_氟_甲基；（3,5•雙_三氟甲基_ 苯基)-一氟-甲基；（3,5-雙_(三氟甲基）_芊基）；〇,5_雙_三氟甲基一 冬胺甲醯基）-甲基；胺基_(3,5_雙·(三氟甲基）_苯基）_甲基； 雙 <三氟甲基 >苯基）_甲胺呷基；：K3,5-雙-(三氟甲基）_苯基）： 胺基-乙基；^(3,5-雙三氟甲基）_苯基）-2ϋ基；WV·雙·(三 鼠甲基)-苯基)士甲氧基-乙基；μ(3,5Κ三氟f基)_苯基从幾 基-乙基；或2-乙醯氧基-l-(3,5-雙-(三氟甲基 >苯基卜乙基； R5為甲氧基或三氟甲基；且 R6為氫或甲氧基。 於式I化合物之另一項具體實施例中，在〇3與；間之鍵結 為單鍵。 ° 於式I化合物之又另一項具體實施例中’在〇與】間之鍵 結為雙鍵。 於另一項具體實施例中，式I化合物係選自包括： 92199 -30- 1285641 (R，R，S)-4-[胺基-(3,5·雙-三氟甲基-苯基基]乙基冬三氟甲 基-3,4-二氫-2H-喹啉小羧酸乙酯； (R，S，S)-4-[胺基-(3>雙-三氟甲基-苯基）_甲基]-2_乙基冬三氟甲 基-3,4-二氫-2H-喹啉+羧酸乙酯； (11，11)斗(3,5-雙-二氟甲基；基）1乙基各三氟甲基_3，‘二氫-纽_ 4啉小羧酸乙酯； (R，R，S)-4-[(3,5-雙-三氟甲基_苯基 > 甲胺基甲基]乙基各三氟 甲基-3,4-二氫-2H-喹啉+羧酸乙酯； (R，S，S)-4-[(3,5-雙-三氟甲基-苯基 > 甲胺基甲基乙基各三氟 甲基-3,4-二氫奎啉-1-羧酸乙酯； 取和冬哎义雙-三氟甲基-苯基卜羥基-甲氧羰基-甲基^:二甲 氧基-2-甲基-2H-^淋-1-幾酸乙g旨； (R，S)-4-[(3,5-雙-三氟甲基-苯基羥基-甲氧羰基_甲基风7-二甲 氧基-2-甲基-2H-喹啉小羧酸乙酯； (R，S，R)-4-[(3,5-雙-三氟甲基-苯基）-羥基-甲氧羰基_甲基]-6，'二 曱氧基-2-甲基-3,4-二氫奎琳-1-幾酸乙酯； (R，S，S)-4-[(355-雙-三氟甲基-苯基）-羥基-甲氧羰基-甲基]-6,7-二 曱氧基-2-甲基-3,4-一氣-2H-0奎淋-1-幾酸乙§旨； (氏1^)-4-[(3,5-雙-三氟甲基-苯基）-羥基-甲氧羰基-甲基>6,7_二 甲氧基-2-甲基-3,4-二氫-2H-p奎琳小幾酸乙酯； (氏11，11)-4-[(3,5-雙-二氣甲基-苯基）-輕基-甲氧羰基_甲基]_6,7-二 甲氧基-2-甲基-3,4-二氫-2H-峻淋小幾酸乙酯； (R，S，R)-4-[(3,5-雙-三氟甲基-苯基）-羥基-甲氧羰基岬基]-2-乙基 -6-三氟甲基二氫-2Η”奎4小致酸乙酯； 92199 -31 - 1285641 (11，3办4-[(3,5-雙-三氟甲基-苯基）-羥基-甲氧羰基呷基]1乙基 -6-三氣甲基-3,4-一氣-2H-0奎淋小致酸乙醋； (R，R，S)-4-[(3,5-雙-三氟甲基-苯基）-羥基-f氧羰基呷基]:乙基 -6-三氟甲基-3,4-二氫-2H-喳啉小羧酸乙酯； (R，R，R)-4-[(3,5-雙-二氟甲基-苯基）_經基-甲氧幾基·甲基]，2_乙基 -6-三氟《甲基-3,4_二氫-2Hw奎淋小叛酸乙S旨； (R，R，S)-4-[(3,5-雙-二鼠甲基-苯基）_甲氧幾基_甲基]_6,7*·二〒氧 基-2-甲基-3,4-二氫淋小致酸乙酉旨； (氏民3)-4-[(3,5-雙-三氟甲基-苯基）4氧基-甲基]_2_乙基冬三氟 甲基-3,4-二氫-2H-喹啉-1-羧酸乙酯； (R，R)-4-[(3,5-雙-三氟基甲基-苯基）_經基-甲氧羰基_甲基]_2•乙 基-6-三氟甲基-2H-峻琳-1-幾酸乙酯； (R，S)-4-[(3,5-雙-三氟甲基-苯基）邊基-甲氧羧基·甲基]乙基-6-三氟》甲基-2H-峻淋-1-叛酸乙g旨； (R，R，S)-4-[l-(3,5-雙-三氟甲基-苯基）-2-幾基乙基]_2_乙基冬三氣 甲基-3,4-二氮-2H-峻琳-1-幾酸乙@旨； (R，S，S)_4-〇(3,5-雙-三氟甲基-苯基）_2-羥基-乙基]1乙基^三氟 甲基-3,4-二氫-2H-喹啉-1-羧酸乙酯； (R，R，S)-4-[2-乙醯氧基-1-(3,5-雙-三氟甲基-苯基）_乙基]_2•乙基各 三氟甲基-3,4-二氫-211^奎ρ林小叛酸乙g旨； (R，S，S)-4-〇乙醯氧基小(3,5-雙-三氟甲基·笨基乙基]乙基各 三氟甲基-3,4-二鼓-211-峻林小叛酸乙g旨； (氏1^)-4-[1-(3,5-雙-三氟〒基-苯基）-2-甲氧基_乙基]_2_乙基_6_三 氟> 甲基-3,4-二氫17林小叛酸乙g旨； 92199 -32- 1285641 (R，S，S)-4-[l-(3,5-雙-三氟甲基-苯基>2_甲氧基_乙基]_2_乙基* 氟甲基-3,4-二氫-2H-4：琳-1-幾酸乙醋； 基-6-三氟甲 (R，R，S)-4-[l-(3,5-雙-二氟甲基-苯基）_2_氟_乙基]_2_乙 基-3,4-二氲-2Η-ρ奎淋小幾酸乙g旨； (R，S，S)-4-[l-(3,5-雙-三氟甲基-苯基>2•氟·乙基]·2·乙基士三氟甲 基-3,4-二氫奎淋-1-幾酸乙酉旨； (民；^)-4-〇(3,5-雙-三氟甲基-苯基峰胺基_乙基]_2_乙基4:氣 甲基-3,4-二氫-2Η-峻4 -1-幾酸乙酯； (R，S，S)-4-[l-(3,5-雙-二氟甲基·苯基）-2-胺基-乙基]乙基:氣 甲基-3,4-二氫-2Η-Ϊ1奎淋-1-幾酸乙|旨； (R，R)-4-[(3,5-雙-二氟曱基-木基）-甲氧羰基_甲基]乙基二氟 甲基-2Η-喹啉小羧酸乙酯； (似)-4-[(3,5-雙-三氟甲基-苯基）-甲氧羰基-甲基]-2_乙基冬三氣 甲基-2Η-喹啉-1-羧酸乙酯； (以，3)_4-[(3,5-雙-三氟甲基-苯基）-甲氧羰基-甲基]-2-乙基冬： 氟甲基-3,4-二氫-2Η-喹啉小羧酸乙酯； (^办4-[(3,5-雙-三氟甲基-苯基）-甲氧羰基，甲基]1乙基4三 氟甲基-3,4-二氫-2Η-喹啉-1-羧酸乙酯； (R，S，S>4-[(3,5-雙-三氟甲基-苯基）-氰基-甲基]-2-乙基各三敦甲 基-3,4-二氫-2H-喳啉小羧酸乙酯； (R，S，R)-4-[(3,5-雙-三氟曱基-苯基）-氰基-甲基]-2-乙基各三氣甲 基-3,4-二氫-2H-喳啉小羧酸乙酯； (R，R，S)_4-[(3,5-雙-三氟甲基-苯基）-氰基-甲基]-2-乙基各三氟甲 基-3,4-二氫-2H-喳啉-1-羧酸乙酯； 92199 -33- 1285641 (R，R，R)-4-[(3,5-雙-三氟T基-苯基）-氰基-甲基]_2-乙基-6-三氟甲 基-3,4-二鼠-2H-^ °林-1-幾酸乙g旨； (R，S)-4-[(3,5-雙-三氟甲基-笨基）-氰基-甲基奸乙基各三氟甲基 -2H-喹啉小羧酸乙酯； (R，R)-4-[(3,5-雙-三氟甲基-苯基）-氰基-甲基於乙基各三氟甲基 -2H-喹啉小羧酸乙酯； (R，S)-4-(3,5-雙-三氟甲基-苯〒g產基）_6,7-二甲氧基基-3,4-二 氫-2Η-ρ奎琳_1-叛酸乙@旨； (R，R)-4-[(3,5-雙-三氟甲基-苯甲醯基）_6,7-二甲氧基甲基-3,4-二氫-2H-喳啉小羧酸乙酯； (氏民幻冰^^-雙-二氣甲基-冬基卜氟-甲基^义二甲氧基^甲 基-3,4-二氫-2H-峻17林-1-複酸乙g旨； (11，11，3>4-[(3,5-雙-二氟甲基-苯基）_氟_甲基]-6,7_二甲氧基_2_甲 基-3,4-二氫-2H-峻淋-1-叛酸乙g旨； (11，3，11)-4-[(3,5-雙-二氟甲基-苯基）_氟_甲基]_6,7_二甲氧基_2_甲 基-3,4-二氫-2H-^ ?林-1-瘦酸乙@旨； (尺”为冬的义雙-二氟甲基-苯基^氟-甲基“：二甲氧基冬甲 基-3,4-二氫-2H-p奎淋-1-複酸乙g旨； (R，R)-4-(3,5-雙-三氟甲基-苯甲醯基）_2_乙基各三氟甲基从二 氫-2H-喹啉+羧酸乙酯； 〇^，3)-4-(3,5-雙-三氟甲基-苯甲酶 基乙基各三氟甲基-3,4-二 氫-2H-喹啉小羧酸乙酯； -甲基]-6,7-二甲氧基-2- (R，R，R)-4-[(3,5-雙-三氟甲基-苯基）、罗里其 甲基-3,4-二氫-2Η-ρ奎π林小幾酸乙g旨； 92199 -34- 1285641 基]-6,7-二甲氧基冬 (R，R，S)-4-[(3,5-雙-三氟甲基-苯基）_羥基 甲基-3,4-二氫-2H-喹啉小羧酸乙酯； (^^別各旧^-雙-二氟甲基-苯基卜羥基’基^:二甲氧基·] 甲基-3,4-二氫-2H-喹啉_丨_羧酸乙酯； (^^⑸冬旧义雙-三氟甲基-苯基卜羥基-甲基^’^二甲氧基^ 甲基-3,4-二氫-2H-峻琳小複酸乙酯； (R，S，S)-4-[(3,5-雙-三氟甲基-苯基）_幾基_甲基]1乙基各三氟甲 基-3,4-二氫-2H-喹啉+羧酸乙酯； (R，S，R)-4-[a5-雙-三氟甲基-苯基)_幾基_曱基]_2_乙基冬三氣甲 基-3,4-二氫-2H-4：p休+幾酸乙酯； 氟甲 氟甲 (民1^)-4_[(3,5-雙_三氟甲基-苯基）-羥基呷基]1乙基各 基-3,4-二氫-2H-如林，1-羧酸乙酯；及 (R，R，R)-4-[(3,5-雙-三氟甲基_苯基）_羥基-甲基]1乙基4 基-3,4-二氫-2H-喹啉+羧酸乙酯； 或其藥學上可接受之鹽或前體藥物。 於本發明式I化合物之進一步具體實施例中， J為氮； 在C3與J間之鍵結為單鍵； R1 為 w-x ; w為羰基； X為; υ對各存在處係獨立為（Ci_C6)烷基，該（Ci_C6)燒基視情況 /、有至九個氟’或該（C! -C：6)燒基視情況被Z單取代； 其中Z為部份飽和、完全飽和或完全不飽和三至六員環， 92199 -35 - 1285641 視情況具有一至二個獨立選自氧、硫及氮之雜原子；其中 該Z取代基係視情況獨立被_基、（CrQ)烷基、％ 燒氧 基、（C「C4)燒硫基、硝基、氰基、酮基或（q -c4)淀氧羰基單-、二-或三-取代，該（q 烷基或（q -c4)烷氧基視情況被一 至九個氟取代； R2為部份飽和、完全飽和或完全不飽和（Ci<4)直鏈或分枝 狀竣鏈，其中各個碳，惟連接碳除外，可視情況被一個獨 三選自氧與硫之雜原子置換，其中該碳係視情況獨立被自 基單-、二·或三-取代，該碳鏈係視情沉被酮基單取代，該 碳係視情況被羥基單取代，該硫係視情沉被酮基單_或二取 代’或違R為邵份飽和、完全飽和或完全不飽和三至五員 環’視情況具有一個獨立選自氧與硫之雜原子；其中該R2 環係視情況獨立被自基、羥基、（Cl_C6)统氧基、胺基、硝基 、（Ci -Q)统氧羰基或幾基單-、二-或三-取代； 其中R3為完全飽和、部份不飽和或完全不飽和一至六員直 鏈或分枝狀碳鏈，其中各個碳，惟C4a或鄰近C4a之R3碳除 外，可視情沉被一個選自氧、硫及氮之雜原子置換，且該 碳係視6 ;兄獨1被_基單_、二-或三-取代，該碳，惟c4a除 外，係視情況被羥基單取代，該碳係視情況被氰基單取代 ，該碳係視情況被酮基或氮單取代，該硫係視情沉被酮基 單-或二取代，該氮係視情況被氫或酮基單-或二取代，且 該碳鏈係在C4a或鄰近C4a之R3碳處，視情況被v單-、二-或 三-取代； V為五或rr員部份飽和、完全飽和或完全不飽和環，視情 92199 -36- 1285641 况具有一至二個獨立選自氧、硫及氮之雜原子，以致v不為 味唆基或完全飽和雜環族含氮環，其中該環之氮係連接至R3 土團’其中泫v環係視情況獨立被鹵基、（q -C6)统基 '經基 、（Ci-C6)燒氧基、（(：1<6)烷氧羰基、硝基、氰基或酮基單-、 一-、二_、四-或五取代，其中該（Cl <6)烷基或（C^C6)烷氧基 取代基，視情況具有一至九個氟； R4為氯； R5與R6各獨立為氫、鹵基、T、（CrC6)烷氧基或（CrC6)烷基 ’違（ci <：6)烷氧基或（q -c6)烷基取代基，視情況具有〆至九 個氟’或該（C! -C0)烷氧基或（Cl <6)烷基取代基，視情沉被τ 單取代； 其中T為部份飽和、完全飽和或完全不飽和五至六員環， 视情況具有一至二個獨立選自氧、硫及氮之雜原子； 其中該T取代基係視情況獨立被齒基、（Ci _c6)烷基、羥基 (Ci Cg)》元氧基、（Ci -C4)fe硫基、胺基、§同基、叛基、（Ci 燒氧羰基、單-N-或二-N，N-((VC6)^胺基單-、二-或三-取代 ’其中該（Ci -C：6)烷基或（Ci -c6)烷氧基取代基，視情沉鼻有一 至九個氟； R7為氫。 於本發明式I化合物之進一步具體實施例中， γ為-c4)烷基，其中該（Ci -c4)烷基取代基，視情沉具有 至九個氣， R2為（C^Q)烷基、環丙基或環丁基； R3 為-q〇)-v、-01((:(0)0((^ -c3)垸基）(v)或-ch(cn)(v); 92199 -37- 1285641 V為笨基，視情況獨立被函基、（Ci <6)烷基、羥基、（CrCj k氧基、硝基、氰基或酮基單—、二-或三-取代，其中該 (C^C0)燒基取代基，視情況具有一至九個氟； R5與R6各獨立為氫、（CrO烷氧基或（C「C6)烷基，該 燒氧基視情況具有一至九個氟，該（Ci )烷基視情況具有一 至七個氟； 或其藥學上可接受之鹽。 於本發明式I化合物之進一步具體實施例中， Y為甲基、乙基、1-丙基、2-丙基或第三-丁基； R2為曱基、乙基、2-丙基、環丙基或環丁基； R3為3,5-雙-三氟甲基-苯甲醯基、（3,5-雙-三氟曱基-苯基）-氰 基··曱基或（3,5-雙-三氟甲基-苯基)_甲氧羰基呷基； R5為甲基或三氟甲基； R6為氫或甲基。 於式I化合物之又另一項具體實施例中，化合物係選自包 括： ⑻Μ3,5-雙-三氟甲基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H^奎喏4小幾酸乙酯； (R，R)-4-[(3,5-雙-三氟甲基·苯基）_氰基呷基]_2•乙基二甲基_ 3,4-二氫-2H-P奎喏淋-1-幾酸乙酯； (R，S)-4-[(3,5-雙-三氟甲基-苯基）_氰基·甲基>2_乙基〇二甲基_ 二氫奎喏啦小複酸乙酯； (R，R)-4-[(3,5-雙-三氟甲基-苯基）_甲氧羰基-甲基]乙基-6,7-二 甲基-3,4-二氫-2H·。奎喏淋-1-幾酸乙酯； 92199 -38 - 1285641 雙-三氟曱基-笨基）_甲氧羰基_甲基]^乙基41 一 曱基-3,4-二氫-2H<奎喏4小幾酸乙醋； (R，R)-4-[(3,5-雙-三氟甲基-苯基）_曱氧基碳_甲基]_2_乙基7 _ 甲基-3,4-一氮奎p若淋-1-幾酸甲酉旨； (R，S) 4 [(3,5-雙-二氟甲基-苯基）_甲氧羰基-甲基]·2_乙美$ 7 一 甲基·3,4-一氫-2Hw奎嗔淋-1-幾酸甲酉旨； (R，R)-4-[(3,5-雙-三氟甲基-苯基）_甲氧羰基_甲基]^乙基< 7 一 甲基-3,4-二氫-2H-喹喏啉-1-羧酸異丙酯； (R，SH-[(3,5-雙-三氟甲基.笨基）_甲氧碳基_甲基峰乙基分二 甲基-3,4-二氫-2H-喹喏啉-1-羧酸異丙酯； (R，R)-4-[(3,5·雙三氟甲基.苯基>f氧馥基·甲基碎乙基^三及 甲基-3Λ二氫-2H-喳喏啉-1-羧酸乙酯，·及 虱 (卵-[㈤-雙-三氟曱基-苯基)_甲氧羰基_甲基]·2·乙基^三友 甲基-3,4-二氫-2Η-喹喏啉-1-羧酸乙酯； 鼠 或其藥學上可接受之鹽或前體藥物。 再者，本發明之一項具體實施例包括在哺乳動物中治療動 脈粥瘤硬化、冠狀動脈疾病、冠狀心臟疾病、冠狀血管疾 病、末梢血管疾病、脂血症障礙、高则白症、低_蛋 白症、高膽固醇血症、血甘油三酿過多、家族性高膽固醇 血症或：肌梗塞之方法，其方式是對需要此種治療之哺乳 動物投予動脈粥瘤硬化、蘇姑知& 、 社狀動脈疾祸、冠狀心臟疾病、 私狀血管疾病、末梢血管疾病、脂血症障礙、高娜蛋白症 、低⑽旨蛋白症、高膽輯血症、血甘油過多、家族性 南膽固醇血症或心肌梗塞治療量之式如化合物，並前許 92199 -39- 1285641 藥物，或該化合物或兮‘ _ 一 ^ 次逐別體樂物之藥學上可接受之鹽 係治療動脈粥瘤硬化。 於另一項具體實施例中 於另一項具體實施例中 於另一項具體實施例中 於另一項具體實施例中 於另一項具體實施例中 於另一項具體實施例中 於另一項具體實施例中 於另一項具體實施例中 係冶療末梢血管疾病。 係治療脂血症障礙。 係治療高yS脂蛋白症。 係治療低α脂蛋白症。 係治療家族性高膽固醇血症 係治療冠狀動脈疾病。 係治療心肌梗塞。 再者本發明包括—種醫藥組合物，其包含, -CH(NH2)(V), -CH(NH(CH3))(V), -CH(C(〇)NH2)(V), -CH(CH2OH)V, -ch(ch2och3)v,- Ch(ch2oc(〇)ch3)v, -ch(ch2f)v or -CH(CH2NH2)V; and V is phenyl, optionally independently a halo, nitro or (Ci-c2)alkyl--, 292199 -29· 1285641 - or a tri-substitution wherein the (Ci_C2)alkyl group optionally has one to five fluorines; R5 and r6 are each independently a hydrogen moxy group or a chloro group; the methoxy group optionally has one to two Fluorine, the methyl group optionally has one to three fluorines. In another embodiment of the invention, the compound of formula I comprises a substituent wherein Y is ethyl; R2 is ethyl or methyl; R is (3,5K difluoromethyl)-phenyl > hydroxy -methoxycarbonyl-methyl; (3,5-bis-trifluoromethyl-phenyl) methoxycarbonyl-methyl; (3,5-bis-trifluoromethyl-phenyl)-cyano 3,5-bis-difluoromethyl-benzylidene; hydrazine, 5_bis-trifluoromethyl-phenyl)-l-fyl, (3,5-bis-trifluoromethylbenzene ())-fluoro-methyl; (3,5•bis-trifluoromethyl-phenyl)-monofluoro-methyl; (3,5-bis-(trifluoromethyl)-indenyl); 5-_bis-trifluoromethyl-aspartamide-mercapto)-methyl; amine-(3,5-bis(trifluoromethyl)phenyl)methyl; double <trifluoromethyl >Phenyl)-methylamino group; K3,5-bis-(trifluoromethyl)phenyl): Amino-ethyl; ^(3,5-bistrifluoromethyl)phenyl -2 fluorenyl; WV · bis (trimethyl)-phenyl) methoxy-ethyl; μ (3,5 Κtrifluorofyl)-phenyl from a few-ethyl; or 2- Ethyloxy-l-(3,5-bis-(trifluoromethyl)phenylphenyl; R5 is methoxy or trifluoromethyl; and R6 is hydrogen or methoxy In another embodiment of the compound of Formula I, the bond between 〇3 and ; is a single bond. ° In yet another embodiment of the compound of Formula I, the bond between 〇 and 为 is In another embodiment, the compound of formula I is selected from the group consisting of: 92199 -30- 1285641 (R,R,S)-4-[amino-(3,5·bis-trifluoromethyl) -Phenyl]ethyl-t-trifluoromethyl-3,4-dihydro-2H-quinolinecarboxylic acid ethyl ester; (R,S,S)-4-[amino-(3>bis-three Fluoromethyl-phenyl)-methyl]-2-ethyl-t-trifluoromethyl-3,4-dihydro-2H-quinoline+carboxylic acid ethyl ester; (11,11) bucket (3,5- Bis-difluoromethyl; yl) 1 ethyl each trifluoromethyl _3, 'dihydro-neu- 4- phenyl carboxylic acid ethyl ester; (R, R, S) -4- [(3, 5- Bis-trifluoromethyl-phenyl> methylaminomethyl]ethyl trifluoromethyl-3,4-dihydro-2H-quinoline + ethyl carboxylate; (R,S,S)- 4-[(3,5-bis-trifluoromethyl-phenyl)methylaminomethylethyltrifluoromethyl-3,4-dihydroquinoline-1-carboxylic acid ethyl ester;哎 哎 bis-trifluoromethyl-phenyl hydroxy-methoxycarbonyl-methyl ^: dimethoxy-2-methyl-2H-^ lysyl-1-acid acid g; (R, S )-4-[(3,5- -Trifluoromethyl-phenylhydroxy-methoxycarbonyl-methyl wind 7-dimethoxy-2-methyl-2H-quinoline small carboxylic acid ethyl ester; (R,S,R)-4-[ (3,5-bis-trifluoromethyl-phenyl)-hydroxy-methoxycarbonyl-methyl]-6,'dimethoxy-2-methyl-3,4-dihydroquinine-1- (E, S, S)-4-[(355-bis-trifluoromethyl-phenyl)-hydroxy-methoxycarbonyl-methyl]-6,7-dimethoxy-2 -methyl-3,4-one gas-2H-0 quinolate-1-acid acid § §; (1^)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxyl -methoxycarbonyl-methyl>6,7-dimethoxy-2-methyl-3,4-dihydro-2H-p-quineminic acid ethyl ester; (11,11)-4- [(3,5-Bis-dimethyl-phenyl)-carbyl-methoxycarbonyl-methyl]_6,7-dimethoxy-2-methyl-3,4-dihydro-2H- (R,S,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methoxycarbonylindenyl]-2-ethyl-6 -trifluoromethyldihydro-2Η"Quino 4 small acid ethyl ester; 92199 -31 - 1285641 (11,3,4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-- Oxycarbonylcarbonyl]1ethyl-6-trimethylmethyl-3,4-one gas-2H-0 quinomic acid vinegar; (R,R,S)-4-[(3,5-double -trifluoromethyl-phenyl -hydroxy-f-oxycarbonyl fluorenyl]: ethyl-6-trifluoromethyl-3,4-dihydro-2H-carboline small carboxylic acid ethyl ester; (R,R,R)-4-[(3 ,5-bis-difluoromethyl-phenyl)-trans-methoxy-methoxymethyl], 2-ethyl-6-trifluoromethyl-3,4-dihydro-2Hw (R,R,S)-4-[(3,5-bis-dimethylmethyl-phenyl)-methoxybenzyl-methyl]_6,7*·didecyloxy -2-methyl-3,4-dihydro-sodium chlorate; (Mer. 3)-4-[(3,5-bis-trifluoromethyl-phenyl)-4-oxy-methyl] _2_Ethylethyltrifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (R,R)-4-[(3,5-bis-trifluoromethylmethyl) -Phenyl)-yl-methoxycarbonyl-methyl]_2•ethyl-6-trifluoromethyl-2H-junolin-1-carboxylic acid ethyl ester; (R,S)-4-[(3 , 5-bis-trifluoromethyl-phenyl) aryl-methoxycarboxymethyl]ethyl-6-trifluoromethyl-2H-Junlin-1-Resin B; (R, R,S)-4-[l-(3,5-bis-trifluoromethyl-phenyl)-2-ylethyl}_2-ethyl-tertylmethyl-3,4-diaza- 2H-Junlin-1-acid B@; (R,S,S)_4-〇(3,5-bis-trifluoromethyl-phenyl)_2-hydroxy-ethyl]1 ethyl^3 Ethyl fluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate; (R,R,S)-4-[2-Ethyloxy-1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]_2•ethyltrifluoromethyl-3 , 4-dihydro-211^ 奎ρ林小小酸乙乙的; (R,S,S)-4-〇Ethyloxyl small (3,5-bis-trifluoromethyl·stupylethyl Ethyl trifluoromethyl-3,4-di-battery-211-junlin small rebel acid B g; (1^)-4-[1-(3,5-bis-trifluorodecyl- Phenyl)-2-methoxy-ethyl]_2_ethyl_6_trifluoro] methyl-3,4-dihydro 17 lincoln acid B; 92199 -32-1285641 (R, S,S)-4-[l-(3,5-bis-trifluoromethyl-phenyl>2-methoxy-ethyl]_2-ethyl* fluoromethyl-3,4-dihydro -2H-4: lin-1-carboxylic acid ethyl acetonate; -6-trifluoromethyl(R,R,S)-4-[l-(3,5-bis-difluoromethyl-phenyl)_2 _Fluoro-ethyl]_2_ethyl-3,4-diindole-2Η-ρ奎淋小酸乙乙的; (R,S,S)-4-[l-(3,5-double- Trifluoromethyl-phenyl>2•fluoro·ethyl]·2·ethyl-trifluoromethyl-3,4-dihydroquinone-1-acid acid 酉; (Min; ^)-4 -〇(3,5-bis-trifluoromethyl-phenyl amidoamino-ethyl)_2_ethyl 4: methoxymethyl-3,4-dihydro-2Η-Jun 4 -1-acid B (R,S,S)-4-[l-(3,5-bis-difluoromethylphenyl)-2-amino-ethyl ]ethyl: gas methyl-3,4-dihydro-2Η-Ϊ1 quinolate-1-acid B; (R,R)-4-[(3,5-bis-difluoroindolyl- Methyl)-methoxycarbonyl-methyl]ethyldifluoromethyl-2-indole-quinolinecarboxylic acid ethyl ester; (like)-4-[(3,5-bis-trifluoromethyl-phenyl) -Methoxycarbonyl-methyl]-2-ethyl ternary trimethylmethyl-2-indole-quinoline-1-carboxylic acid ethyl ester; (3, 4-)-[[3,5-bis-trifluoromethyl -Phenyl)-methoxycarbonyl-methyl]-2-ethyl winter: ethyl fluoromethyl-3,4-dihydro-2-indole-quinolinecarboxylic acid; (^4-4-((3,5 - bis-trifluoromethyl-phenyl)-methoxycarbonyl, methyl]1 ethyl 4-trifluoromethyl-3,4-dihydro-2-indole-quinoline-1-carboxylic acid ethyl ester; (R, S,S>4-[(3,5-bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-distributyl-3,4-dihydro-2H-indole Ethyl carboxylic acid ethyl ester; (R,S,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl each trimethylmethyl -3,4-Dihydro-2H-carboline ethyl carboxylic acid ethyl ester; (R, R, S) 4-[(3,5-bis-trifluoromethyl-phenyl)-cyano-methyl] Ethyl 2-ethyltrifluoromethyl-3,4-dihydro-2H-porphyrin-1-carboxylate; 92199 -33- 1285641 (R,R,R)-4-[(3,5 -bis-trifluoro-T-phenyl)-cyano- ]]2-ethyl-6-trifluoromethyl-3,4-di-rho-2H-^ °-lin-1-acid C g; (R,S)-4-[(3,5-double -trifluoromethyl-phenyl)-cyano-methyl-ethylethyl trifluoromethyl-2H-quinoline small carboxylic acid ethyl ester; (R,R)-4-[(3,5-double- Trifluoromethyl-phenyl)-cyano-methyl to ethyl each trifluoromethyl-2H-quinoline small carboxylic acid ethyl ester; (R,S)-4-(3,5-bis-trifluoro Methyl-benzoquinone g) _6,7-dimethoxy-3,4-dihydro-2 Η-ρ quinion _1-rebel acid@@; (R,R)-4-[( 3,5-bis-trifluoromethyl-benzhydryl)-6,7-dimethoxymethyl-3,4-dihydro-2H-carboline ethyl carboxylic acid ethyl ester; ^-Bis-di-gasmethyl-winter-based fluoro-methyl^yidimethoxy^methyl-3,4-dihydro-2H-jun 17-lin-1-reacid B g; (11, 11,3>4-[(3,5-bis-difluoromethyl-phenyl)-fluoro-methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro- 2H-Junlin-1-Resin acid B; (11,3,11)-4-[(3,5-bis-difluoromethyl-phenyl)-fluoro-methyl]_6,7_2 Methoxy-2-methyl-3,4-dihydro-2H-^?lin-1-skinic acid@@; (foot) is winter bis-difluoromethyl-phenyl fluoro-- "" Dimethoxybutyl-3,4-dihydro-2H-p-quinone-1- (R,R)-4-(3,5-bis-trifluoromethyl-benzylidene)-2-ethyl trifluoromethyl from dihydro-2H-quinoline + carboxy Ethyl acetate; 〇^,3)-4-(3,5-bis-trifluoromethyl-benzoylethyl-trifluoromethyl-3,4-dihydro-2H-quinoline carboxylic acid Ethyl ester; -methyl]-6,7-dimethoxy-2-(R,R,R)-4-[(3,5-bis-trifluoromethyl-phenyl), roric acid -3-3,4-dihydro-2Η-ρ奎π林小酸酸乙格; 92199 -34- 1285641 base]-6,7-dimethoxy winter (R,R,S)-4-[ (3,5-bis-trifluoromethyl-phenyl)-hydroxymethyl-3,4-dihydro-2H-quinoline small carboxylic acid ethyl ester; (^^ each old ^-bis-difluoromethyl Ethyl-phenyl-hydroxyl-yl^:dimethoxy-]methyl-3,4-dihydro-2H-quinoline-indole-carboxylic acid ethyl ester; (^^(5) winter old double-trifluoromethyl -Phenyl-hydroxy-methyl^'^dimethoxy^methyl-3,4-dihydro-2H-junolin small acid ethyl ester; (R,S,S)-4-[(3 ,5-bis-trifluoromethyl-phenyl)-benzyl-methyl]1 ethyl-trifluoromethyl-3,4-dihydro-2H-quinoline + ethyl carboxylate; (R, S ,R)-4-[a5-bis-trifluoromethyl-phenyl)-monomethyl-indenyl]_2-ethyl ternary trimethyl-3,4-dihydro-2H-4:pH a few acid ethyl esters; Meffluent (Min 1^)-4_[(3,5-bis-trifluoromethyl-phenyl)-hydroxyindenyl]1 ethylyl-3,4-dihydro-2H- as a forest, 1 -ethyl carboxylate; and (R,R,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]1 ethyl 4-yl-3,4-di Hydrogen-2H-quinoline + ethyl carboxylate; or a pharmaceutically acceptable salt or prodrug thereof. In a further embodiment of the compound of Formula I of the present invention, J is nitrogen; the bond between C3 and J is a single bond; R1 is wx; w is a carbonyl group; X is; υ is independent of each existing (Ci_C6) An alkyl group, the (Ci_C6) alkyl group, as the case /, up to nine fluorine ' or the (C! - C: 6) alkyl group is optionally substituted by Z; wherein Z is partially saturated, fully saturated or completely Unsaturated three to six membered rings, 92199 -35 - 1285641 optionally having one or two heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen; wherein the Z substituent is independently a _ group, a (CrQ) alkyl group, % alkoxy, (C "C4) thiol, nitro, cyano, keto or (q -c4) oxycarbonyl mono-, di- or tri-substituted, (q alkyl or (q - C4) alkoxy is optionally substituted by one to nine fluorines; R2 is partially saturated, fully saturated or fully unsaturated (Ci<4) linear or branched hydrazone chain, wherein each carbon, except attached carbon, is visible The situation is replaced by a hetero atom selected from oxygen and sulfur, wherein the carbon system is independently substituted from the mono-, di- or tri-, which is optionally substituted by a ketone group. The carbon system is optionally monosubstituted by a hydroxy group which is mono- or di-substituted by a ketone group or a saturated, fully saturated or fully unsaturated three- to five-membered ring of the R as the case has an independent a hetero atom selected from the group consisting of oxygen and sulfur; wherein the R2 ring is independently selected from the group consisting of a hydroxyl group, a hydroxyl group, a (Cl_C6)oxy group, an amine group, a nitro group, a (Ci-Q) oxycarbonyl group or a mono-mono-, Di- or tri-substituted; wherein R3 is a fully saturated, partially unsaturated or fully unsaturated one to six member straight or branched carbon chain, wherein each carbon, except C4a or R3 carbon adjacent to C4a, Substituted by a hetero atom selected from the group consisting of oxygen, sulfur and nitrogen, and the carbon system is 6; the brother is 1 replaced by _ base _, di- or tri-, except for c4a, which is singly Alternatively, the carbon system is optionally monosubstituted by a cyano group which is optionally monosubstituted by a ketone group or a nitrogen which is mono- or disubstituted by a ketone group which is optionally hydrogen or a ketone. Mono- or di-substituted, and the carbon chain is at C4a or adjacent to the R3 carbon of C4a, optionally by v-, di- or tri--; V is a five or rr member a saturated, fully saturated or fully unsaturated ring, having one or two heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, as the case is 92199-36-1285641, such that v is not a miso base or a fully saturated heterocyclic nitrogen-containing ring Wherein the nitrogen of the ring is attached to the R3 earth mass 'wherein the 泫v ring system is independently independently halogenated, (q-C6)-based, and (Ci-C6) alkoxy, ((:1< 6) an alkoxycarbonyl, nitro, cyano or keto group mono-, mono-, di-, tetra- or penta-substituted, wherein the (Cl <6) alkyl or (C^C6) alkoxy substituent , as the case may have one to nine fluorine; R4 is chlorine; R5 and R6 are each independently hydrogen, halo, T, (CrC6) alkoxy or (CrC6) alkyl 'vio (ci <: 6) alkoxy Or a (q-c6)alkyl substituent, optionally having up to nine fluoro' or the (C!-C0) alkoxy or (Cl <6) alkyl substituent, optionally substituted by τ Wherein T is a partially saturated, fully saturated or fully unsaturated five to six membered ring, optionally having one or two heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen; wherein the T substituent is independently a dentate basis , (Ci _c6) alkyl, hydroxy (C i Cg)"Polyoxy, (Ci-C4)fethio, amine, § synthyl, rebel, (Ci oxycarbonyl, mono-N- or di-N,N-((VC6)) a mono-, di- or tri-substituted 'wherein the (Ci-C:6)alkyl or (Ci-c6)alkoxy substituent, optionally having from one to nine fluorines; R7 is hydrogen. In a further embodiment of the compound of formula I of the present invention, γ is -c4)alkyl, wherein the (Ci-c4)alkyl substituent has up to nine gases and R2 is (C^Q) alkane. a group, a cyclopropyl group or a cyclobutyl group; R3 is -q〇)-v, -01((:(0)0((^-c3) fluorenyl)(v) or -ch(cn)(v); 92199 -37- 1285641 V is a stupid base, optionally a functional group, (Ci <6) alkyl, hydroxy, (CrCj koxy, nitro, cyano or keto mono-, di- or tri-- Substituted, wherein the (C^C0) alkyl substituent has from 1 to 9 fluorines as appropriate; R5 and R6 are each independently hydrogen, (CrO alkoxy or (C"C6) alkyl, the alkoxy group as appropriate Having from one to nine fluorines, the (Ci)alkyl group optionally having from one to seven fluorines; or a pharmaceutically acceptable salt thereof. In a further embodiment of the compound of formula I of the invention, Y is methyl, ethyl, 1-propyl, 2-propyl or tert-butyl; R2 is decyl, ethyl, 2-propyl, cyclopropyl or cyclobutyl; R3 is 3,5-bis-trifluoromethyl- Benzyl fluorenyl, (3,5-bis-trifluoromethyl-phenyl)-cyano·indenyl or (3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl fluorenyl R5 is methyl or trifluoromethyl; R6 is hydrogen or methyl. In yet another embodiment of the compound of formula I, the compound is selected from the group consisting of: (8) Μ3,5-bis-trifluoromethyl-benzene Ethyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H^quine 4 small acid ethyl ester; (R,R)-4-[(3,5-double -trifluoromethyl·phenyl)-cyanoindenyl]_2•ethyldimethyl_3,4-dihydro-2H-Pquinone--1-acid ethyl ester; (R,S)- 4-[(3,5-bis-trifluoromethyl-phenyl)-cyanomethyl]>2_ethyl 〇 dimethyl _ dihydro quinone oxime acid ethyl ester; (R, R )-4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]ethyl-6,7-dimethyl-3,4-dihydro-2H·. Ethyl phthalic acid ethyl ester; 92199 -38 - 1285641 bis-trifluoromethyl-phenyl) methoxycarbonyl _ methyl] ^ ethyl 41 - fluorenyl-3,4-dihydro-2H < Quercetin 4 small acid vinegar; (R,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-nonyloxy carbon_methyl]_2_ethyl 7 _ methyl -3,4-mononitroquinone p-reo-1-carboxylic acid methyl hydrazine; (R,S) 4 [(3,5-bis-difluoromethyl-phenyl)-methoxycarbonyl-methyl] · 2_乙美$ 7 monomethyl·3,4-monohydro-2Hw quinine-l-acid acid (R,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]^ethyl<7-monomethyl-3,4-dihydro-2H - quinoxaline-1-carboxylic acid isopropyl ester; (R, SH-[(3,5-bis-trifluoromethyl. phenyl)-methoxycarbyl_methyl-peak ethyl dimethyl- (3,4-dihydro-2H-quinoxaline-1-carboxylic acid isopropyl ester; (R,R)-4-[(3,5·bistrifluoromethyl.phenyl)>f oxonyl· Methyl Ethyl Ethyl 3- and Methyl-3 O-Dihydro-2H-Porphyrin-1-Ethyl Ethyl Ester, ···虱(Egg-[(5)-Bis-Trifluoromethyl-phenyl)-Methoxy Carbonyl-methyl]·2·ethyl^Sanyoumethyl-3,4-dihydro-2-indole-quinoxaline-1-carboxylic acid ethyl ester; rat or a pharmaceutically acceptable salt or prodrug thereof. Furthermore, a specific embodiment of the present invention includes treatment of atherosclerosis, coronary artery disease, coronary heart disease, coronary vascular disease, peripheral vascular disease, lipemia disorder, high white matter, and low in a mammal. Protein disease, hypercholesterolemia, hyperglycemia, familial hypercholesterolemia, or a method of infarction of the muscle by administering atherosclerosis to a mammal in need of such treatment, Su Guzhi & , Coronary artery disease, Coronary heart disease, Vascular vascular disease, Peripheral vascular disease, Lipidemia, Gonna protein, Low (10) protein, Hypercholestericemia, Hyperglycemia, Familial Southern Cholesterol The amount of treatment for hemorrhage or myocardial infarction is as a compound, and the drug is administered to the medicinal salt of 92199 -39-1285641, or the pharmaceutically acceptable salt of the compound or 兮' _ . In another specific embodiment, in another specific embodiment, in another specific embodiment, in another specific embodiment, in another specific embodiment, another In a specific embodiment, in another embodiment, a peripheral vascular disease is treated. It is a treatment for lipemia disorders. It treats high yS lipoproteinosis. It treats low alpha lipoproteinosis. Treatment of familial hypercholesterolemia for the treatment of coronary artery disease. Department of treatment of myocardial infarction. Furthermore, the invention includes a pharmaceutical composition comprising

量之式I或II化合物，戈前髀 A /、則《庄头物，或菘化合物或該前體3 物足藥學上可接受鹽’及藥學 ’ 載劑。 子上可接文（媒劑、稀釋费“ 於-項具體實施例中，本發明為一種在哺乳動物中治療動 脈粥瘤硬化'冠狀動脈疾病、冠狀心臟疾病、冠狀血管疾 病、末梢血管疾病、脂血症障礙、高抑旨蛋白症、低_蛋 白症、高膽固醇血症、血甘油三醋過多、家族性高膽固醇 血症或心肌梗塞之醫藥組合物，纟包含治療上有效量之式工 或II化合物，其前體藥物，或該化合物或該前體藥物之藥學 上可接焚鹽’及藥學上可接受之媒劑、稀釋劑或載劑。 於另-項具體實施例中，本發明為一種在哺乳動物中治療 動脈粥瘤硬化之醫藥組合物，其包含動脈粥瘤硬化治療量 《式I或II化Μ ’其冑體藥&，或該化合物或該前體藥物 之藥學上可接受鹽，及藥學上可接受之媒劑稀釋劑或載劑。 92199 -40- 1285641 於另一項具體實施例中，本發明包括一種醫藥組合之組合 物，其包含：治療上有效量之組合物，其包含：第一種化 合物，該第一種化合物為式I或II化合物，其前體藥物，或 該化合物或該前體藥物之藥學上可接受鹽；第二種化合物 ，該第二種化合物為HMG CoA還原酶抑制劑、MTP/Apo B分 泌抑制劑、PPAR調制劑、膽汁酸再攝取抑制劑、膽固醇吸 收抑制劑、膽固醇合成抑制劑、纖維酸酯、菸鹼酸、緩慢 釋出於驗酸、於驗酸與洛伐制菌素（lovastatin)之組合、離子交 換樹脂、抗氧化劑、AC AT抑制劑或膽汁酸多價螯合劑；及 醫藥媒劑、稀釋劑或載劑。 於另一項具體實施例中，本發明包括一種醫藥組合之組合 物，其中第二種化合物為HMG-CoA還原酶抑制劑或PPAR調 制劑。 於另一項具體實施例中，本發明包括一種醫藥組合之組合 物，其中第二種化合物為洛伐制菌素（lovastatin)、辛伐制菌素 (simvastatin)、普拉伐制菌素(pravastatin)、弗伐制菌素（fluvastatin) 、阿托瓦制菌素（atorvastatin)、利伐制菌素（rivastatin)、洛蘇伐 制菌素（rosuvastatin)或皮塔伐制菌素（pitavastatin)。 於另一項具體實施例中，本發明包括一種醫藥組合之組合 物，其進一步包含膽固醇吸收抑制劑。於另一項具體實施 例中，此膽固醇吸收抑制劑為也吉提麥伯（ezetimibe)。 本發明之一項進一步具體實施例包括一種在哺乳動物中治 療動脈粥瘤硬化之方法，其包括對需要治療之哺乳動物投 予：第一種化合物，該第一種化合物為式（I)化合物，其前 92199 -41 - 1285641 體藥物，或該化合物或該前體藥物之藥學上可接受鹽；與 第二種化合物，該第二種化合物為HMG CoA還原酶抑制劑、 PPAR調制劑、膽固醇吸收抑制劑、膽固醇合成抑制劑、纖 維酸i旨、於驗酸、緩慢釋出If驗酸、於驗酸與洛伐制菌素 (lovastatin)之組合、離子交換樹脂、抗氧化劑、ACAT抑制劑 或膽汁酸多價螯合劑；其中第一種與第二種化合物之量會 造成治療作用。 於另一項具體實施例中，本發明包括一種治療動脈粥瘤硬 化之方法，其中第二種化合物為HMG-CoA還原酶抑制劑或 PPAR調制劑。 於另一項具體實施例中，本發明包括一種治療動脈粥瘤硬 化之方法，其中第二種化合物為洛伐制菌素（lovastatin)、辛伐 制菌素（simvastatin)、普拉伐制菌素（pravastatin)、弗伐制菌素 (fluvastatin)、阿托瓦制菌素（atorvastatin)、利伐制菌素（rivastatin) 、洛蘇伐制菌素（rosuvastatin)或皮塔伐制菌素（pitavastatin)。 於另一項具體實施例中，本發明包括一種治療動脈粥瘤硬 化之方法，其中此方法進一步包括投予膽固醇吸收抑制劑 。於另一項具體實施例中，膽固醇吸收抑制劑為也吉提麥 伯（ezetimibe) 〇 本發明之進一步具體實施例包括一種在哺乳動物中達成治 療作用之套件，其包含一起包裝之第一種治療劑，其包含 治療上有效量之根據申請專利範圍第1、8、12或13項之化 合物，其前體藥物，或該化合物或該前體藥物之藥學上可 接受鹽，及藥學上可接受之載劑，第二種治療劑，其包含 92199 -42- 1285641 治療上有效量之HMG CoA還原酶抑制劑、PPAR調制劑、膽固 醇吸收抑制劑、膽固醇合成抑制劑、纖維酸酯、菸鹼酸、 緩k釋出於鹼酸、菸鹼酸與洛伐制菌素（1〇vastatm)之組合、離 子父換樹脂、抗氧化劑、ACAT抑制劑或膽汁酸多價螯合劑 ，及藥學上可接受之載劑，以及關於投予該第一種與第二 種藥劑以達成治療作用之指示。 於另一項具體實施例中，本發明包括-種套件，其中該第 二種化合物為HMG-CoA還原酶抑制劑或ppAR調制劑。 於進-步具體實施例中，本發明包括一種套件，其中該第 一=化合物為洛伐制菌素（bastatin)、辛伐制菌素（simvastatin) 二4戈制菌素（pravastatin)、弗伐制菌素（fjuvastatin)、阿托瓦 菌素（atorvastatm)、利伐制菌素（士沾拉此）、洛蘇伐制菌素 (r〇SUVaStatin)或皮塔伐制菌素（pitaVastatin)。 於另一項具體實施例中，本發明包括一種套件，其進一步 包含膽固醇吸收抑制劑。於另-項具體實施例巾，膽固醇 吸收抑制劑為也吉提麥伯（ezetimibe)。 特定式III化合物包括： 2-乙基斗碘基各三氟甲基·2H_邊啉小羧酸乙酯； 乙基4琪基各二氟甲基·2Η♦林小瘦酸乙酯； 4氯基2·乙基各二氟甲基部·二氫撒4琳]•羧酸乙酿； 4溴基-2-乙基各三氟甲基_3,4_二氫】·喹啉小羧酸乙酯； Μ氮基士乙基各三氟甲基*二氫-2Η-喹啉小羧酸乙酯； 4虱基-2-乙基各三氟甲基私二氫善奎啉飞‘二羧酸小乙酯 92199 1285641 」/爲酸-1 -乙醋-4-甲g旨； 2·乙基各三氟甲基_3,4·二氫-2H-喳卩林-Μ-〆後 2-乙基冬(甲氧基-甲基-胺甲醯基）-6-三氟甲基丨-3,4_二氫-2H-喳 啉-1-羧酸乙酯； 2-乙基-6-三氟甲基-2H-喳啉-1，4-二羧酸小乙酯冬甲酯； 4-氯基-2-乙基-4-甲氧基碳羰基-6-三氟甲基-3,4-二氫-2H-喹啉-1-羧酸乙酯； 2-乙基斗甲氧基碳羰基-6-三氟甲基-2H-喹啉-1-羧酸-乙酯； 4-重氮基-6,7-二甲氧基-2·甲基_3,4_二氫-2H-喹啉小羧酸乙酯； 6,7-二甲氧基-4-曱氧基碳羰基-2-甲基-2H-喹啉-1-羧酸-乙酯； 6,7_二甲氧基-2-甲基_3,4_二氯-2H-^ p林-1，4-二叛酸小乙酉旨-4-甲 酯； 6,7-二甲氧基斗(甲氧基-甲基-胺甲醯基）-2-甲基-3,4-二氫-2H-喹啉小羧酸乙酯； 2-乙基-4-¾基-6-三氟甲基-3,4_二氫奎淋-1-幾酸乙酉旨； 2-乙基冬酮基-6-三氟甲基-3,4-二氫-2H-喹啉小羧酸乙酯； 2-乙基-4-羥基-6-三氟甲基-3,4-二氫-2H-喹啉-1-羧酸甲酯； 2-乙基-4-酮基-6-三氟甲基-3,4-二氫-2H-喹淋-1-羧酸甲酯； 2-乙基冰羥基各三氟甲基-3,4-二氫-2H-喹啉小羧酸1-丙酯； 2-乙基酮基-6-三氟甲基-3,4-二氫-2Η^奎淋小幾酸1-丙酯； 2-乙基-4-羥基-6-三氟甲基-3,4-二氫-2Η-喹啉小羧酸2-丙酯； 2-乙基冬酮基-6-三氟甲基-3,4-二氫-2Η-喳啉小羧酸2-丙酯； 2-乙基冰羥基-6-三氟甲基-3,4-二氫-2Η-喹啉小竣酸第三-丁酯； 2-乙基-4-酮基-6-三氟甲基-3,4-二氫-2Hw奎淋-1-叛酸第三-丁酉旨 :及 92199 -44- 1285641 ^乙基-6-三㈣基_3,4_二氫抓奎#从二幾酸小乙醋冬甲醋。 1而言’本發明之化合物可藉由一些方法製造，其包括 力貝似化學技藝中已夺， 、 /,特別是在明白本文所含有之 =後。㈣製造本發明化合物之某些方法係被提供作為 發明之進一步特徵’且藉由下列反應圖式說明。其他方 ^係被描料實驗段落中。類似方法係揭示於下列美國專 •中’其係據此以全文料本文供參考·· 4國專利6，140,342 ，吴國專利6,362，198 ;美國專利6，147,〇9〇 ;美國專利6列5 751 , 美國專利6，147,089 ;美國專利6,310,075 ;美國專利6，所，786 ;美 國專利6，140,343 ;美目專利6,489,478 ,·及國際公報w〇 〇〇/ΐ7ΐ64。 此處所述之反應圖式係意欲提供許多所 ^ ^ 叮了貝例之製備上所 採用操作法之一般描述。但是，從實驗 谷甲所丁〈詳細 說明得以明白，所採用之製備模式係比本 ’又〒所逑之一般 程序更加擴大。特定言之，^主意的是’根據此等圖式製 成之化合物可經進一步修改，以提供本發 、、4貧明範圍内之新穎 實例。例如，酯官能基可使用熟諳此藝者河 叮白知〈程序進 一步反應，而得另一種酯、醯胺、甲醇或_。 1 -45- 92199 1285641 R4 0A compound of formula I or II, a pharmaceutically acceptable salt of pharmaceutically acceptable salt and a pharmaceutically acceptable carrier. In the specific embodiment, the present invention is a method for treating atherosclerosis in a mammal, coronary artery disease, coronary heart disease, coronary vascular disease, peripheral vascular disease, A pharmaceutical composition comprising a lipid-lowering disorder, a high-lowering protein disease, a low-protein disorder, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia or myocardial infarction, and a therapeutically effective amount of a laboratories Or a compound of II, a prodrug thereof, or a pharmaceutically acceptable incineration salt of the compound or the prodrug, and a pharmaceutically acceptable vehicle, diluent or carrier. In another embodiment, The invention relates to a pharmaceutical composition for treating atherosclerosis in a mammal, comprising an atheroma sclerotherapy therapeutic amount "Formula I or II phlegm", a steroid thereof & remedy, or a pharmaceutics of the compound or the prodrug An acceptable salt, and a pharmaceutically acceptable vehicle diluent or carrier. 92199 - 40 - 1285641 In another embodiment, the invention comprises a pharmaceutical combination comprising: therapeutically effective A composition comprising: a first compound, which is a compound of formula I or II, a prodrug thereof, or a pharmaceutically acceptable salt of the compound or the prodrug; a second compound, The second compound is an HMG CoA reductase inhibitor, an MTP/Apo B secretion inhibitor, a PPAR modulator, a bile acid reuptake inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fiber ester, a nicotinic acid, Slow release from acid testing, combination of acid and lovastatin, ion exchange resin, antioxidant, AC AT inhibitor or bile acid sequestrant; and pharmaceutical vehicle, diluent or carrier In another embodiment, the invention includes a pharmaceutical combination composition wherein the second compound is an HMG-CoA reductase inhibitor or a PPAR modulator. In another embodiment, the invention A composition comprising a pharmaceutical combination wherein the second compound is lovastatin, simvastatin, pravastatin, fluvastatinAtorvastatin, rivastatin, rosuvastatin or pitavastatin. In another specific embodiment, the invention A composition comprising a pharmaceutical combination further comprising a cholesterol absorption inhibitor. In another specific embodiment, the cholesterol absorption inhibitor is ezetimibe. A further embodiment of the invention includes A method of treating atherosclerosis in a mammal comprising administering to a mammal in need of treatment: a first compound, which is a compound of formula (I), which is pre-92199 - 41 - 1285641 Or a pharmaceutically acceptable salt of the compound or the prodrug; and the second compound, which is an HMG CoA reductase inhibitor, a PPAR modulator, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fiber Acid, acid test, slow release of Acid test, combination of acid test and lovastatin, ion exchange resin, antioxidant, ACAT inhibitor or gallbladder A juice acid sequestrant; the amount of the first and second compounds will cause a therapeutic effect. In another embodiment, the invention includes a method of treating atheroma hardening wherein the second compound is an HMG-CoA reductase inhibitor or a PPAR modulator. In another specific embodiment, the invention includes a method of treating atherosclerosis, wherein the second compound is lovastatin, simvastatin, and platamycin Pravastatin, fluvastatin, atorvastatin, rivastatin, rosuvastatin or pitavamycin ( Pitaavastatin). In another specific embodiment, the invention includes a method of treating atheroma hardening, wherein the method further comprises administering a cholesterol absorption inhibitor. In another specific embodiment, the cholesterol absorption inhibitor is ezetimibe. Further embodiments of the invention include a kit for achieving a therapeutic effect in a mammal comprising the first package packaged together A therapeutic agent comprising a therapeutically effective amount of a compound according to claim 1, 8, 12 or 13 of the invention, a prodrug thereof, or a pharmaceutically acceptable salt of the compound or the prodrug, and a pharmaceutically acceptable The carrier to be received, the second therapeutic agent comprising 92199 -42-1285941 therapeutically effective amount of HMG CoA reductase inhibitor, PPAR modulator, cholesterol absorption inhibitor, cholesterol synthesis inhibitor, fiber ester, nicotine Acid, slow-k release from alkali acid, a combination of niacin and lovastatin (1〇vastatm), ion parent resin, antioxidant, ACAT inhibitor or bile acid sequestrant, and pharmaceutically acceptable Accepted carrier, and instructions for administering the first and second agents to achieve a therapeutic effect. In another specific embodiment, the invention includes a kit wherein the second compound is an HMG-CoA reductase inhibitor or a ppAR modulator. In a specific embodiment, the invention includes a kit wherein the first compound is bastatin, simvastatin, pravastatin, flu Fjuvastatin, atorvastatm, rivastigmine, sulphate sputum (r〇SUVaStatin) or pita vaginin (pitaVastatin) . In another specific embodiment, the invention includes a kit further comprising a cholesterol absorption inhibitor. In another embodiment, the cholesterol absorption inhibitor is ezetimibe. The specific compound of the formula III includes: 2-ethyl fluoroiodoyl trifluoromethyl 2H- porphyrin small carboxylic acid ethyl ester; ethyl 4 yl yl difluoromethyl 2 Η ♦ lin small acid ethyl ester; 4 Chloro 2,ethyl difluoromethyl moiety · dihydropropane 4 Lin] • Carboxylic acid ethyl; 4 bromo-2-ethyltrifluoromethyl_3,4_dihydro]quinoline Ethyl carboxylate; Μ 基 基 乙基 ethyl trifluoromethyl * dihydro - 2 Η - quinoline small carboxylic acid ethyl ester; 4 fluorenyl-2-ethyl trifluoromethyl private dihydro cyproline fly 'Diethyl carboxylic acid ethyl ester 92199 1285641 ′/ is acid-1 - acetoacetate-4-methyl ke; 2 · ethyl each trifluoromethyl _3,4 · dihydro-2H-喳卩林-Μ- 2-ethyl winter (methoxy-methyl-aminocarbamimidyl)-6-trifluoromethylindole-3,4-dihydro-2H-indololin-1-carboxylic acid ethyl ester; 2- Ethyl-6-trifluoromethyl-2H-carboline-1,4-dicarboxylic acid small ethyl ester winter methyl ester; 4-chloro-2-ethyl-4-methoxy carboncarbonyl-6-three Ethyl fluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate; 2-ethylidenemethoxycarbonylcarbonyl-6-trifluoromethyl-2H-quinoline-1-carboxylic acid -ethyl ester; 4-diazo-6,7-dimethoxy-2.methyl-3,4-dihydro-2H-quinolinecarboxylic acid ethyl ester; 6,7-dimethoxy- 4-decyloxycarboncarbonyl- 2-methyl-2H-quinoline-1-carboxylic acid-ethyl ester; 6,7-dimethoxy-2-methyl_3,4-dichloro-2H-^p-lin-1,4-two Resin acid small acetamidine-4-methyl ester; 6,7-dimethoxy oxo (methoxy-methyl-amine carbaryl)-2-methyl-3,4-dihydro-2H-quinoline Small carboxylic acid ethyl ester; 2-ethyl-4-3⁄4yl-6-trifluoromethyl-3,4-dihydroquinone-1-acid acid; 2-ethyloxanyl-6-three Ethyl fluoromethyl-3,4-dihydro-2H-quinolinecarboxylate; 2-ethyl-4-hydroxy-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 - methyl carboxylate; methyl 2-ethyl-4-keto-6-trifluoromethyl-3,4-dihydro-2H-quinolin-1-carboxylate; 2-ethyl glacial hydroxy 1-propyl fluoromethyl-3,4-dihydro-2H-quinoline carboxylic acid; 2-ethyl ketone-6-trifluoromethyl-3,4-dihydro-2 Η^ 奎 淋1-propyl acid; 2-ethyl-4-hydroxy-6-trifluoromethyl-3,4-dihydro-2-indole-quinoline small carboxylic acid 2-propyl ester; 2-ethyloxanyl-6 2-trifluoromethyl-3,4-dihydro-2-indole-porphyrin small carboxylic acid 2-propyl ester; 2-ethyl glacial hydroxy-6-trifluoromethyl-3,4-dihydro-2 fluorene-quinoline Tri-butyl citrate; 2-ethyl-4-keto-6-trifluoromethyl-3,4-dihydro-2Hw quinine-1-retribution third- ting: and 92199 - 44- 1285641 ^Ethyl- 6-three (four) base _3,4_ dihydro grab quinone # from a few acid small vinegar winter vinegar. 1' The compounds of the present invention can be made by a number of methods, including those that have been taken from the chemical arts, and/or especially after the inclusion of the = contained herein. (d) Certain methods of making the compounds of the present invention are provided as further features of the invention' and are illustrated by the following reaction schemes. Others are drawn in the experimental paragraph. A similar method is disclosed in the following U.S. specials, which are hereby incorporated by reference in its entirety for reference. 4 Patent No. 6,140,342, Wu Guo Patent 6,362,198; US Patent 6,147, 〇9〇; US Patent 6 U.S. Patent No. 6, 751, 089, U.S. Patent No. 6,310,075, U.S. Patent No. 6, 786, U.S. Patent No. 6,140,343, U.S. Patent No. 6,489,478, and International Publication No. The reaction schemes described herein are intended to provide a number of general descriptions of the methods of operation employed in the preparation of the examples. However, from the experiment, the detailed description of the grain is better than the general procedure of this book. In particular, it is intended that the compounds made according to such figures may be further modified to provide novel examples within the scope of the present invention. For example, the ester functional group can be further reacted using the formula, and another ester, guanamine, methanol or _ can be obtained. 1 -45- 92199 1285641 R4 0

R4 N2R4 N2

KCOLKCOL

ΚΛ1 根據反應圖式1，所要之化合物，其中了為碳，選用之雙 键不存在，R3為基團CH(V)(L)，其中L為（(VC6)烷氧羰基，且 V、R1 ' R2、R4、R5、R6及R7均如上文所述（在圖式丨中描繪 為式II化合物），可自其相應圖式丨式0化合物，藉由雙鍵之 還原作用被製成非對映異構物之混合物，或L為如本文中定 義之R3。這可在對反應為惰性之溶劑中’譬如甲醇、乙 92199 -46- 1285641 或醋酸，使用觸媒，譬如 ^ 一丄 乂錄/妷，於虱壓力等於15-50 psi 卜，楮由氫化2-24小時間夕Α叫 期間，或藉由轉移氫化作用，使 用甲&叙，在回流甲醇中， T於觸媒存在下，譬如鈀/碳，在 對反應為惰性之溶劑中，孽 • « π Τ知或乙醉，在〇艺至8(rc間 <溫度下，典型上為25〇c 人1 C下達成。製備此等特定式J化 θ物之此種方法，i刑 /、土 係奴先奐供其申R2與R3基團對彼 此為順式之非對映異構物。 所要《式III化合物，其中L、v、R1、r2、R4、R5、尺6及尺7 均如上述’可自其相應之式仅化合物，藉由移除羥基，被 製成非對映異構物之混合物。這可經由以氯化劑，譬如氯 化磷(III)或二氯化亞硫醯’在對反應為惰性之溶劑中，譬如 二氯f燒或氯仿，視情況含有驗，譬如峨咬、二異丙基乙 胺或2,6-二-第三-丁基冬甲基吨咬，在叱至贼間之溫度下， 典型上為環境溫度’在丨至24小時間之期間處理而達成。然 後’將如此形成之氯衍生物，以細分金屬譬如鋅，於酸或 酸混合物譬如醋酸或鹽酸存在下，在適當溶劑或溶劑混合 物中，譬如甲醇、水或四氫呋喃，於乃它至仞^間之溫度下 ’典型上為環境溫度下處理，提供所要之式產物。 所要之式IV化合物，其中L為（Ci_C6)烷氧羰基，且v、Rl 、R2、R4、R5、R6及R7均如上述，可自其相應之式v化合物 ’被製成非對映異構物之混合物，其方式是與V基困之適當 有機金屬衍生物反應，譬如鎂或鋰衍生物，其係依次製自 化合物V-Hal，其中Hal表示氯、溴或碘原子，使用熟諳此藝 者所習知之方法，例如按L.A· Paquette (編著），有機合成詖劑百 92199 -47- 1285641 全書，John Wiley & Sons，Chichester，England，1995 中所述者。此反 應係在對反應為惰性之適當溶劑中，譬如四氫吱喃咬乙趟 ，在-78°C至25T：間之溫度下，典型上為-78t下進行，提供所 要之式IV產物。 所要之式V化合物，其中L為（Q -C6)烷氧羰基，且Rl、r2 、R4、R5、W及R7均如上述，可製自其相應之式％化合物， 其方式是與醯基化合物KCOL反應，其中K為脫離基，譬如 氯或溴，在0°C至25°C間之溫度下，典型上為環境溫度，於 對反應為惰性之溶劑中，譬如乙腈或甲苯，視情況於驗存 在下’譬如二異丙基乙胺或三乙胺，以移除可能存在之微 量HK。依式VI化合物上之取代基性質，及l之性質而定， 式V化合物可以具有其相應式VII化合物之混合物獲得。 所要之式VI化合物，其中R1、R2、R4、R5、R61R7均如上 述，可製自其相應之式VIII化合物，其方式是與適當氧化劑 反應，典型上為氧化錳(IV)，在對反應為惰性之適當溶劑中 ’譬如乙醚’於0°C至25 C間之溫度下，典型上為環境溫度 。由於此反應會產生一當量水，其可能有害於後續步驟， 故其可視情況以下述方式被移除，添加適合不一反應之溶 劑’譬如乙腈或甲苯，及蒸發此溶劑混合物，至體積稍微 低於所添加之溶劑，但未達乾涸。 所要之式VIII化合物’其中R1、R2、R4、R5、於及^均如 上述，可製自其相應之式IX化合物，其方式是與肼水合物 反應，在對反應為惰性之適當溶劑中，譬如乙醇或甲苯， 在25t至18(TC間之溫度下，典型上為80。(：至17〇。(：。此腙形成 92199 -48- 1285641 可藉助於水之連續移除，譬如利用Dean-Stark裝置，或藉由在 在、閉容器中加熱至溫度超過溶劑之沸點，譬如藉由微波爐。 所要之式II化合物’其中L為（C! )燒氧羰基，且v、ri、 R2、R4、R5、R6及R7均如上述，其一種替代製備法可自其相 應之式X化合物，經由以氯化劑，譬如氯化磷（ΙΠ)或二氯化 亞硫S盈處理而達成’在對反應為惰性之溶劑中，聲如_氯 甲^元或氣仿’視情況含有驗’譬如Ρ比淀、二異丙基乙胺咬2 6 二-第三-丁基斗甲基吡啶，在ot：至6(TC間之溫度下，典型上 為環境溫度，歷經1至24小時間之期間。然後，將如此以非 對映:異構物之混合物形成之氣衍生物，以細分金屬處理， 譬如鋅，於酸或酸混合物4在下，譬如醋酸或鹽酸，在適 當溶劑或溶劑混合物中，譬如曱酵、水或四氫呋喃，在25<>c 至6(TC間之溫度下，典型上為環境溫度，提供所要之式11產 物。 所要之式X化合物，其中L為（Ci -c6)烷氧羰基，且v、R1、 R2、R4、R5、R6及R7均如上述，可自其相應之式沿化合物， 被製成非對映異構物之混合物，其方式是與v基團之適當有 機金屬衍生物反應，譬如鎂或鋰衍生物，其係依次製自化 。物V-Hal，其中Hal表不氯、溴或碘原子，使用熟諳此藝者 所白知又方法，例如按L.A· Paquette (編著），有機合成試劑 复复 John Wiley & Sons，Chichester，England, 1995 中所述者。此反應 係在對反應為惰性之適當溶劑中進行，譬如四氩呋喃或乙 醚在-78 C至25 C間之溫度下，典型上為n，提供所要之 式X產物。 92199 -49- 1285641 所要之式XI化合物’其中L為(CVQ)烷氧羰基，且R1 ' r2 R R及R均如上述，可自其相應之式V化合物，藉 _之還原，被製成非對映異構物之混合物。這可藉由 氫化作用’在對反應為惰性之溶劑中，譬如甲帛、乙醇或 醋酸’使用㈣，譬如免或錄/竣，在氯壓力等㈣5〇胛 下’歷經2-24小時之期間，或藉由轉移氫化作用，使用^酸 銨，在回流甲醇中，於觸媒存在下，譬如免/碳，在對反應 為惰性之溶劑中’譬如甲醇或乙醇，於〇°C至8〇t間之溫度 下’典型上為25t至6〇t下達成。 2所要之式X化合物，其中L4(Ci_C6)燒氧幾基，且ν、^、 m4、r5、r6及r7均如上述，其—種替代製備法可自其相 應之式XII化合物’被製成非對映異構物之混合物，其中K 為脫離基，譬如氯或漠，其方式是氫化作$，在對反應為 f月f生之’合Μ中’譬如甲醇、乙醇或醋酸，使用觸媒，孽如 把或錄/後’在氫壓力等於15_5()psi下，歷經2-24小時間之期 間，或藉由轉移氫化作用，使用甲酸銨，在回流曱醇中， 於觸媒存在下’譬如飽/竣，在對反應為惰性之溶劑中，蓉 如〒醇或乙醇’在叱至航間之溫度下，典型上為说至^ 1下，提供所要之式X產物。 所要之式X化合物，其中L為（Ci_C6)院氧羰基，且v、R1、 R、R4、R5、R6及R7均如上述，其另_種替代製備法可自其 相應之式IV化合物，藉由雙鍵還原，被製成非對畋異構物 之混合物。這可藉由氫化作用，在對反應為惰性之溶劑中 ，譬如甲醇、乙醇或醋酸，使用觸媒，譬如鈀或铑/碳，在 92199 -50- 1285641 氫壓力等於15-50 psi下，歷經2-24小時間> ^ 』足朋間，或藉由轉移 氫化作用，使用甲酸銨，在回流甲醇中，认總w + 、 於觸媒存在下， 譬如鈀/碳，在對反應為惰性之溶劑中，譬如曱醇或乙醇， 於〇°c至8〇t間之溫度下’典型上為25。0至6〇。(：下達成，提供 所要之式X產物。還原之-種替代方法係涉及以二醯亞胺處 理’其係在對反應呈惰性之溶劑中，於式W化合物存在下 ’藉由熟諳此藝者已知之多種方法當場產生，譬如在 L.A. Paquette (編著），有_機„舍成試劑耳Wiley & Sons, Chichester，England，1995 中所述者。 所要之式XII化合物，其中L為（q <：6)烷氧羰基，K為脫離 基，譬如氯或溴，且V、Ri、R2、R4、r5、“及^均如上述 ，可自其相應之式VII化合物，經由與V基團之適當有機金 屬衍生物反應，被製成非對映異構物之混合物，譬如鎂或 鐘衍生物，其係依次製自化合物V-Hal，其中Hal表示氯、溴 或琪原子。此反應係在對反應為惰性之適當溶劑中進行， 譬如四氫呋喃或乙醚，在-78°C至25t：間之溫度下，典型上為 -78°C ’提供所要之式XII產物。 正如上文所指，所要之式VII化合物，其中L為（Cl-C6)烷氧 羰基，K為脫離基，譬如氣或溴，且、R2、R4、、R6及 R7均如上述，可自其相應之式V!化合物，被製成非對映異 構物之混合物，其方式是與醯基化合物KC〇L反應，在0°c至 25°C間之溫度下，典型上為環境溫度，在對反應為惰性之溶 劑中’譬如乙腈或甲笨，視情況於鹼存在下，譬如二異丙 基乙胺或三乙胺，以移除可能存在之微量HK。依式VI化合 92199 -51 - 1285641 物上之取代基性質，及L之性質而定，式νπ化合物可以具 有其相應式V化合物之混合物獲得。 所要之式XIII化合物，其中Μ為充氧基，且Rl、R2 、R、R5、R6及R7均如上述，可自其相應之式VI化合物，被 製成非對映異構物之混合物，其方式是與光氣反應，在Ot 至25°C間之溫度下，典型上為環境溫度，在對反應為惰性之 心％彳中’譬如乙腈或甲苯，於鹼存在下，譬如二異丙基乙 胺或二乙胺。然後，於過量鹼存在下，添加所要之醇MOH 至氣化醯，係提供所要之式化合物。 所要 < 式xiv化合物，其中M為（Ci-C6)烷氧基，且Rl、R2 、R、R5、R0及R7均如上述，可自其相應之式XIII化合物， 藉由氫解作用，被製成非對映異構物之混合物。這可藉由 氯化作用，在對反應為惰性之溶劑中，譬如甲醇、乙醇或 醋酸’使用觸媒，譬如鈀或鍺/碳，在氫壓力等於15-5〇psi 下，歷經2-24小時間之期間，或藉由轉移氫化作用，使用甲 酸銨，在回流甲醇中，於觸媒存在下，譬如鈀/碳，在對反 應為惰性之溶劑中，譬如甲醇或乙醇，在〇°C至80°C間之溫 度下，典型上為25。(：至60T：下達成。或者，式χπΐ化合物可 以細分金屬處理，譬如鋅，於酸或酸混合物存在下，譬如 醋酸或鹽酸，在適當溶劑或溶劑混合物中，譬如甲醇、水 或四氯咬喃，在25°C至60°C間之溫度下，典型上為環境溫度 ’以提供所要之式XIV化合物。 所要之式XV化合物，其中R1、R2、R4、R5、R6&R?均如 上述，可藉由式XIV化合物之酯基水解作用，使用熟諳此項 92199 -52- 1285641 技藝者習知之方法製成，譬如可參閱L.A. Paquette (編著），有機 合成試劑百科全書，John Wiley & Sons，Chichester，England，1995，例 如經由以含水驗處理，較佳為氫氧化链、鈉或钾，於極性 溶劑中，較佳為二氧陸圜，在〇°C與丨⑻它間之溫度下（較佳為 室溫），歷經1至20小時之間，以提供所要之式XV化合物。 圖式2ΚΛ1 According to the reaction scheme 1, the desired compound, wherein it is carbon, the selected double bond is absent, and R3 is a group CH(V)(L), wherein L is ((VC6) alkoxycarbonyl group, and V, R1 'R2, R4, R5, R6 and R7 are all as described above (depicted in the formula 为 as a compound of formula II), and can be made from the corresponding formula of the compound of formula 0 by reduction of a double bond. a mixture of enantiomers, or L is R3 as defined herein. This may be in a solvent inert to the reaction, such as methanol, E 92199 -46-1285641 or acetic acid, using a catalyst such as ^ Recorded / 妷, 虱 虱 pressure equals 15-50 psi Bu, 楮 by hydrogenation 2-24 hours during the squeaking, or by transfer hydrogenation, using A &, in reflux methanol, T in the presence of catalyst Underneath, such as palladium/carbon, in a solvent inert to the reaction, 孽• « π Τ or E drunk, in the art to 8 (rc room temperature, typically 25 〇c person 1 C) Such a method for preparing these specific J-thetas, i.e., is used to make the R2 and R3 groups cis-is diastereomers. The compound of the formula III, wherein L, v, R1, r2, R4, R5, 尺6 and 尺7 are all as described above, can be made from their corresponding formula, by removing the hydroxyl group, and making diastereomeric a mixture of structures. This may be carried out by using a chlorinating agent such as phosphorus (III) chloride or sulfite dichloride in a solvent inert to the reaction, such as dichloro-f- or chloroform, as appropriate. For example, biting, diisopropylethylamine or 2,6-di-t-butyl-m-methyl methyl ton bite, at temperatures between thieves and thieves, typically ambient temperature 'in 丨 to 24 hours The treatment is carried out during the process. Then the chlorine derivative thus formed is subdivided into a metal such as zinc in the presence of an acid or an acid mixture such as acetic acid or hydrochloric acid in a suitable solvent or solvent mixture such as methanol, water or tetrahydrofuran. It is typically treated at ambient temperature to provide the desired product. The desired compound of formula IV, where L is (Ci_C6) alkoxycarbonyl, and v, Rl, R2, R4, R5, R6 and R7 are as described above, and can be made into diastereomers from their corresponding compounds of formula v a mixture obtained by reacting with a suitable organometallic derivative of a V group, such as a magnesium or a lithium derivative, which is sequentially produced from the compound V-Hal, wherein Hal represents a chlorine, bromine or iodine atom, and is used by the artist. Conventional methods are described, for example, in LA·Paquette (eds.), Organic Synthetic Tinctures, pp. 92199 - 47-1285641, John Wiley & Sons, Chichester, England, 1995. This reaction is inert to the reaction. The desired product of formula IV is provided in a suitable solvent, such as tetrahydroanthracene, at a temperature between -78 ° C and 25 T:, typically at -78 t. A compound of the formula V, wherein L is a (Q-C6) alkoxycarbonyl group, and R1, r2, R4, R5, W and R7 are as defined above, and may be prepared from the corresponding compound of the formula % in the form of a fluorenyl group. Compound KCOL reaction wherein K is a leaving group, such as chlorine or bromine, at a temperature between 0 ° C and 25 ° C, typically at ambient temperature, in a solvent inert to the reaction, such as acetonitrile or toluene, as appropriate In the presence of the test, such as diisopropylethylamine or triethylamine, to remove trace amounts of HK that may be present. Depending on the nature of the substituents on the compound of formula VI, and the nature of 1, the compound of formula V can be obtained as a mixture of its corresponding compound of formula VII. The desired compound of formula VI, wherein R1, R2, R4, R5, R61R7 are as defined above, may be prepared from their corresponding compounds of formula VIII by reaction with a suitable oxidizing agent, typically manganese (IV) oxide, in the reaction. In a suitable solvent which is inert, such as diethyl ether, at temperatures between 0 ° C and 25 C, is typically ambient temperature. Since this reaction produces one equivalent of water which may be detrimental to the subsequent steps, it may be removed in the following manner, by adding a solvent suitable for the non-reaction, such as acetonitrile or toluene, and evaporating the solvent mixture to a slightly lower volume. The solvent was added but not dried. The desired compound of the formula VIII wherein R1, R2, R4, R5, and R are as defined above, may be prepared from the corresponding compound of the formula IX by reacting with hydrazine hydrate in a suitable solvent inert to the reaction. For example, ethanol or toluene, at 25 to 18 (temperature between TC, typically 80. (: to 17 〇. (:. This 腙 forms 92199 -48-1285641 can be continuously removed by means of water, such as utilization Dean-Stark device, or by heating in a closed vessel to a temperature above the boiling point of the solvent, such as by a microwave oven. The desired compound of formula II wherein L is (C!) is an oxygenated carbonyl group, and v, ri, R2 , R4, R5, R6 and R7 are all as described above, and an alternative preparation method can be achieved from the corresponding compound of formula X by treatment with a chlorinating agent such as phosphorus chloride or sulfinium chloride. 'In a solvent inert to the reaction, the sound such as _chloromethyl or gas-like 'contains as appropriate' such as Ρ, Ρ, 二, diisopropylethylamine bites 2 6 di-third-butyl fluoromethyl Pyridine, at ot: to 6 (temperature between TC, typically ambient temperature, over a period of 1 to 24 hours. Then, A gas derivative formed by diastereomeric: a mixture of isomers, treated with a finely divided metal, such as zinc, in an acid or acid mixture 4, such as acetic acid or hydrochloric acid, in a suitable solvent or solvent mixture, such as fermentation , water or tetrahydrofuran, at a temperature between 25 <>c to 6 (typically ambient temperature, providing the desired product of formula 11. The desired compound of formula X wherein L is (Ci-c6) alkoxycarbonyl And v, R1, R2, R4, R5, R6 and R7 are all as described above, and may be prepared as a mixture of diastereomers from the corresponding formula, in such a manner as to be appropriately organic with the v group. The reaction of a metal derivative, such as a magnesium or a lithium derivative, is sequentially produced by a compound V-Hal, wherein the Hal represents a chlorine, bromine or iodine atom, and the method is known to the artist, for example, according to LA· Paquette (ed.), Organic Synthesis Reagents, as described in John Wiley & Sons, Chichester, England, 1995. This reaction is carried out in a suitable solvent inert to the reaction, such as tetrahydrofuran or diethyl ether at -78 C. At a temperature of 25 C, typically n, The desired product of formula X. 92199 -49- 1285641 The desired compound of formula XI wherein L is a (CVQ) alkoxycarbonyl group, and R1 'r2 RR and R are as defined above, and may be derived from the corresponding compound of formula V, Reduction, is made into a mixture of diastereomers. This can be used by hydrogenation 'in a solvent inert to the reaction, such as formazan, ethanol or acetic acid' (4), such as exemption or recording Chlorine pressure, etc. (4) under 5 ' ' during 2-24 hours, or by transfer hydrogenation, using ammonium sulphate, in refluxing methanol, in the presence of a catalyst, such as free/carbon, inert to the reaction In a solvent such as methanol or ethanol, it is typically at a temperature between 〇 ° C and 8 ° t, typically 25 t to 6 〇 t. 2 desired compound of the formula X, wherein L4 (Ci_C6) is an alkoxy group, and ν, ^, m4, r5, r6 and r7 are as described above, and an alternative preparation method can be prepared from the corresponding compound of the formula XII. a mixture of diastereomers, wherein K is a leaving group, such as chlorine or desert, in the form of hydrogenation for $, in the reaction of the reaction of the month, such as methanol, ethanol or acetic acid, used Catalyst, for example, to record or record / after 'hydrogen pressure equal to 15_5 () psi, for a period of 2-24 hours, or by transfer hydrogenation, using ammonium formate, in refluxing methanol, in the catalyst In the presence of 'sufficient/sufficient, in a solvent inert to the reaction, a sulphur-like alcohol or ethanol' is typically at a temperature of from 叱 to 航, providing a desired product of formula X. A compound of the formula X, wherein L is a (Ci_C6) oxycarbonyl group, and v, R1, R, R4, R5, R6 and R7 are as defined above, and another alternative preparation method may be derived from the corresponding compound of formula IV, By double bond reduction, a mixture of non-isomers is prepared. This can be accomplished by hydrogenation, in a solvent inert to the reaction, such as methanol, ethanol or acetic acid, using a catalyst such as palladium or rhodium/carbon, at a pressure of 921.9 -50 - 1285641 hydrogen equal to 15-50 psi. 2-24 hours> ^ 』 between the feet, or by transfer hydrogenation, using ammonium formate, in reflux methanol, the total w + , in the presence of a catalyst, such as palladium / carbon, in the reaction is inert The solvent, such as decyl alcohol or ethanol, is typically 0.25 to 6 Torr at temperatures between 〇 °c and 8 〇t. (Available below, providing the desired product of formula X. The alternative method of reduction involves treatment with diimine, which is in a solvent inert to the reaction, in the presence of a compound of formula W. A variety of methods are known to be produced on the spot, as in LA Paquette (eds.), as described in Wiley & Sons, Chichester, England, 1995. The desired compound of formula XII, where L is (q) <: 6) alkoxycarbonyl group, K is a leaving group, such as chlorine or bromine, and V, Ri, R2, R4, r5, "and ^ are as described above, may be derived from their corresponding compounds of formula VII, via a V group The appropriate organometallic derivative of the group is reacted to form a mixture of diastereomers, such as magnesium or a bell derivative, which are sequentially prepared from the compound V-Hal, wherein Hal represents chlorine, bromine or a chi atom. The desired product of formula XII is provided in a suitable solvent which is inert to the reaction, such as tetrahydrofuran or diethyl ether, at a temperature between -78 ° C and 25 t:, typically -78 ° C. , the desired compound of formula VII, wherein L is (Cl-C6) alkoxylate a group, K is a leaving group, such as gas or bromine, and R2, R4, R6 and R7 are all as described above, and can be made into a mixture of diastereomers from the corresponding compound of formula V! It is reacted with the mercapto compound KC〇L, at a temperature between 0 ° C and 25 ° C, typically at ambient temperature, in a solvent inert to the reaction, such as acetonitrile or stupid, as the case may be in the presence of a base , such as diisopropylethylamine or triethylamine, to remove trace amounts of HK that may be present. According to the nature of the substituents on the compound of formula 9299 -51 - 1285641, and the nature of L, the compound of formula νπ may have A mixture of the corresponding compounds of the formula V. The compound of the formula XIII wherein ruthenium is an oxygen group, and R1, R2, R, R5, R6 and R7 are as defined above, can be prepared from the corresponding compound of the formula VI. a mixture of diastereomers in a manner which reacts with phosgene, at a temperature between 0 and 25 ° C, typically at ambient temperature, in a concentration of 彳, such as acetonitrile or toluene, which is inert to the reaction. In the presence of a base, such as diisopropylethylamine or diethylamine. Then, in the presence of excess base Next, adding the desired alcohol MOH to the gasification hydrazine, providing the desired compound. The compound of the formula xiv, wherein M is a (Ci-C6) alkoxy group, and R1, R2, R, R5, R0 and R7 As described above, a mixture of diastereomers can be prepared from the corresponding compound of formula XIII by hydrogenolysis, which can be chlorinated in a solvent inert to the reaction, such as methanol. , ethanol or acetic acid 'use catalyst, such as palladium or rhodium / carbon, at hydrogen pressure equal to 15-5 psi psi, over a period of 2-24 hours, or by transfer hydrogenation, using ammonium formate, reflux methanol In the presence of a catalyst, such as palladium on carbon, in a solvent inert to the reaction, such as methanol or ethanol, at a temperature between 〇 ° C and 80 ° C, typically 25 . (: to 60T: to achieve. Or, the formula χπΐ compound can be subdivided metal treatment, such as zinc, in the presence of an acid or acid mixture, such as acetic acid or hydrochloric acid, in a suitable solvent or solvent mixture, such as methanol, water or tetrachlorine bite Ic, at ambient temperature between 25 ° C and 60 ° C, typically ambient temperature 'to provide the desired compound of formula XIV. The desired compound of formula XV, wherein R1, R2, R4, R5, R6 & R? The above can be prepared by the esterification of the compound of the formula XIV using a method known to those skilled in the art, for example, in LA Paquette (eds.), Encyclopedia of Organic Synthesis Reagents, John Wiley & Sons, Chichester, England, 1995, for example by treatment with an aqueous test, preferably a chain of hydroxide, sodium or potassium, in a polar solvent, preferably dioxane, at a temperature between 〇 ° C and 丨 (8) Lower (preferably room temperature), between 1 and 20 hours, to provide the desired compound of formula XV.

92199 -53- 128564192199 -53- 1285641

XX

2 R 2 R2 R 2 R

XVIXVI

VV

XXIXXI

XXIXXI

XXVIIXXVII

XXVIII 圖式2 根據反應圖式2，所要之化合物，其中J為碳，選用之雙 -54- 92199 1285641 鍵不存在，R3為基團CH(V)(L),其中：為％七6)烷氧羰基或氰 基，且V、Rl、R2、R4、R5、R6及R7均如上述（被描繪為式XVI 化合物），可自其相應之式xvii化合物，被製成非對映異構 物之混合物，其方式是與化合物VCH2L反應，於適當鹼存在 下，譬如1，8-二氮雙環并[5A0]十一孓烯、二異丙基乙胺、三 乙胺或氫化鈞，在對反應為惰性之溶劑中，譬如N，N_二甲基 甲醯胺、二甲亞職、乙腈或甲苯，在〇〇c至6(rc間之溫度下 ’典型上為環境溫度。 所要之式XVII化合物，其中Q為脫離基，譬如氯、溴、甲 统績酸氧基或對-甲苯磺醯氧基，且R1、R2、R4、R5、以及反7 均如上述，可自其相應之式χνπΐ化合物，被製成非對映異 構物之混合物，其方式是與適當試劑反應，譬如氯化甲烷 磺醯或氯化甲苯磺醯，於適當鹼存在下，譬如二異丙基乙 胺或三乙胺，在對反應為惰性之溶劑中，譬如Ν，队二甲基甲 胺、二甲亞颯、氯仿、二氯甲烷或甲苯，在〇。〇至間 之溫度下，典型上為環境溫度。用於形成式化合物之其 他適當試劑，包括氯化磷（III)、溴化磷（m)及二氯化亞硫醯 ’視情況在對反應為惰性之溶劑中，譬如氯仿、二氯f燒 、吡啶或甲苯，在0°C至60°C間之溫度下，典型上為環境溫 度。 所要之式XVIII化合物，其中R1、R2、R4、r5、&6及r7均如 上述’可自其相應之式IX化合物，被製成非對映異構物之 混合物，其方式是羰基之還原，使用熟諳此項技藝者所習 知之方法與試劑’譬如可參閱L.A. Paquette (編著），㈣j成‘詰 92199 -55- 1285641 gj 百科全書，John Wiley & Sons，Chichester，England，1995，例如使用 硼氫化鈉，在醇溶劑中，譬如甲醇、乙醇，在〇t至6〇它間 之溫度下，典型上為環境溫度，或使用三-第二-丁基硼氣化 鉀（K-Sdectnde®)，在對反應為惰性之溶劑中，譬如四氫呋喃 或乙鍵’在-78°C至25°C間之溫度下，典型上為。 在一種替代程序中，所要之式ΧΥΠΙ化合物，其中Ri、y、 R4、R5、R6及R7均如上述，可以下述方式獲得，於酸存在下 ，較佳為醋酸，以亞硝酸鈉處理其相應之式XJX化合物，接 著以適當鹼水解，譬如氫氧化鋰、鈉或鉀，較佳為氫氧化 鈉，在適當羥基溶劑中，譬如乙醇，而得所要之式χιχ化合 物。製備式XIX化合物之方法，係描述於美國專利6197786與 國際申請案W0 0140190中。 所要之式IX化合物，其中Ri為烷氧羰基，且R2、圮、r5、 R6及R7均如上述，可製自其相應之式:^孓甲氧基喳啉化合 物’其方式是以R2基團之有機鎂衍生物，與醯化劑譬如氯 甲酸乙酯一起處理，在-l〇〇°C至7〇。〇間之溫度下，典型上為_78 °C，在對反應為惰性之溶劑中，譬如四氫呋喃，接著溫熱至 溫度介於(TC與約7(TC之間（較佳為環境溫度），歷經〇1與24 小時之間，較佳為1小時，接著在含水酸中水解，較佳為別 鹽酸，而得所要之式IX化合物，按美國專利6197786中所述。 在一種替代程序中，所要之式IX化合物，其中Rl、WW 、R5、R6及R7均如上述，可經由其相應式化合物之氧 化而獲得，使用熟諳此項技藝者所習知之多種方法與試劑 ，譬如可參閱L.A· Paquette (編著），有一機合成詖科全書，J〇hn 92199 -56- 1285641XXVIII Scheme 2 According to the reaction scheme 2, the desired compound, wherein J is carbon, the selected double-54-92199 1285641 bond is absent, and R3 is a group CH(V)(L), wherein: % is seven 6) Alkoxycarbonyl or cyano, and V, R1, R2, R4, R5, R6 and R7 are all as described above (depicted as a compound of formula XVI) and can be made diastereoisomers from their corresponding compounds of formula xvii a mixture of compounds in the form of a reaction with the compound VCH2L in the presence of a suitable base such as 1,8-diazabicyclo[5A0]undecene, diisopropylethylamine, triethylamine or hydrazine hydride. In a solvent inert to the reaction, such as N,N-dimethylformamide, dimethylidene, acetonitrile or toluene, at 温度c to 6 (temperature between rc 'typically ambient temperature. A compound of the formula XVII, wherein Q is a leaving group, such as chloro, bromo, methic acid or p-toluenesulfonyloxy, and R1, R2, R4, R5, and trans 7 are as described above, respectively a compound of the formula χνπΐ, which is prepared as a mixture of diastereomers by reaction with a suitable reagent such as methanesulfonate or toluene chloride. In the presence of a suitable base, such as diisopropylethylamine or triethylamine, in a solvent inert to the reaction, such as hydrazine, dimethyl dimethylamine, dimethyl hydrazine, chloroform, dichloromethane or toluene At temperatures between 〇 and 〇, typically ambient temperature. Other suitable reagents for forming compounds, including phosphorus (III) chloride, phosphorus bromide (m), and sulfite In the case of a solvent inert to the reaction, such as chloroform, dichloro-f-burn, pyridine or toluene, typically at ambient temperature between 0 ° C and 60 ° C. The desired compound of formula XVIII, wherein R 1 R2, R4, r5, & 6 and r7 are each as described above from the corresponding compound of formula IX, as a mixture of diastereomers by way of reduction of a carbonyl group, using the skilled artisan Known methods and reagents can be found in, for example, LA Paquette (ed.), (iv) j Cheng '诘92199 -55-1285641 gj encyclopedia, John Wiley & Sons, Chichester, England, 1995, for example using sodium borohydride in an alcohol solvent , such as methanol, ethanol, between 〇t to 6〇 At ambient temperature, typically ambient temperature, or using potassium tri-t-butylboron (K-Sdectnde®), in a solvent inert to the reaction, such as tetrahydrofuran or ethyl bond 'at -78 ° C Typically at temperatures between 25 ° C. In an alternative procedure, the desired compound of the formula, wherein Ri, y, R 4 , R 5 , R 6 and R 7 are as defined above, may be obtained in the following manner, in the presence of an acid Preferably, acetic acid is treated with sodium nitrite to treat its corresponding compound of formula XJX, followed by hydrolysis with a suitable base such as lithium hydroxide, sodium or potassium, preferably sodium hydroxide, in a suitable hydroxy solvent, such as ethanol. And get the desired formula χιχ compound. A process for the preparation of a compound of formula XIX is described in U.S. Patent No. 6,1977,986 and International Application No. WO 0140190. The desired compound of the formula IX, wherein Ri is an alkoxycarbonyl group, and R 2 , 圮, r 5 , R 6 and R 7 are as defined above, and can be prepared from the corresponding formula: 孓 methoxy porphyrin compound 'in a manner of R 2 The organomagnesium derivative of the group is treated with a hydrating agent such as ethyl chloroformate at -10 ° C to 7 Torr. The temperature at the daytime is typically _78 ° C, in a solvent inert to the reaction, such as tetrahydrofuran, followed by warming to a temperature between (TC and about 7 (between TC (preferably ambient temperature), Between 1 and 24 hours, preferably 1 hour, followed by hydrolysis in an aqueous acid, preferably other hydrochloric acid, to give the desired compound of formula IX as described in U.S. Patent 6,1977,86. In an alternative procedure, The desired compound of the formula IX, wherein R1, WW, R5, R6 and R7 are as defined above, can be obtained by oxidation of the corresponding compound thereof, and various methods and reagents known to those skilled in the art can be used, for example, see LA· Paquette (ed.), has a synthetic syllabus, J〇hn 92199 -56-1285641

Wiley & Sons，ChlcheSter’England，1995 ’ 例如氯鉻酸吡錠、次氣酸 納水溶液，於催化量之2,2,6,6-四曱基小六氫吨唉基氧基（τΕΜρ〇) 自由基及催化用溴化鉀存在下，在對反應為惰性之適當溶 劑中，譬如二氯甲烷，或者，使用醋酸酐與二曱亞颯。 所要之式XXI化合物，其中R1、R2、R4、R5、R6、R7均如 上述，可製自其相應之式IX化合物，其方式是以氰化三甲 基矽烷處理，於惰性溶劑中，譬如芳族烴（例如苯、甲苯、 二曱苯），在催化量之路易士酸存在下，較佳為碘化鋅，於 約25 c至約14(TC之溫度下，較佳為約8〇°c至约1〇〇它，歷經丨_12 小時，較佳為5小時。使所形成之溶液濃縮至乾涸，且無需 進一步純化，直接添加至極性溶劑（例如甲醇、乙醇）中。 將酸（較佳為鹽酸）在極性非質子性溶劑（較佳為二氧陸圜）中 之洛液，添加至孩溶液中，並將混合物在溫度為〇。〇至約 °C ,較佳為室溫下，攪拌1至24小時，較佳為12小時，而產 生式XXI化合物。 所要之式XXII化合物，其中R1、R2、R4、R5、R6、R7均如 上述，可製自其相應之式）〇α化合物，其方式是以還原劑處 理’譬如侧氫化鈉或氰基硼氫化鈉，在對反應為惰性之溶 劑中，譬如甲醇或乙醇，較佳為乙醇，在約0^至約1〇〇。〇(較 佳為回流溫度）之溫度下，歷經0.1至5小時（較佳為〇75小時） ’以提供所要之式XXII化合物。 或者，所要之式χχΠ化合物，其中Ri、r2、r4、r5、r6、 R7均如上述，可製自其相應之式xvn化合物，其中Q為如上 述之脫離基，其方式是以氰化物鹽處理，譬如鋰、鈉、_ 92199 -57- 1285641 或四烷基銨之氰化物，在對反應為惰性之溶劑中，譬如二 甲基甲醯胺，在0°C至loot間之溫度下，歷經1至12小時， 以提供式XXII化合物。 、 所要之式XXIII化合物，其中R1、R2、R4、R5、R6、r7均如 上述，可製自其相應之式XXII化合物，其方式是溶解在含有 五當量水之濃硫酸中，於溫度為ot至loot (較佳為室溫）下 ，歷經1至20小時。然後，使所形成之醯胺溶解於極性溶劑 (較佳為二氣甲烷）中，並以三甲基鑌四氟硼酸鹽處理，在 溫度為0°c至100°C (較佳為室溫）下，歷經1-20小時（較佳為12 小時）。接著，將所形成之亞胺基酯以含水鹼處理，較佳為 氫氧化鋰、鈉或鉀，於極性溶劑中，較佳為二氧陸園，在〇 C與100°C間之溫度下（較佳為室溫），歷經丨至2〇小時之間， 以提供式XXIII化合物。 所要之式XXIV化合物，其中Rl、R2、R4、R5、R6、r7、r8 及妒均如上述，可製自其相應之sxxm化合物，其方式是 在對反應為惰性之溶劑（較佳為二氯甲烷）中，以其相應之 胺（NHR8R9)處理該酸，於;U羥基苯并三唑水合物（1108丁）與1〇 一甲胺基丙基）-3-乙基碳化二亞胺鹽酸鹽（EDCI)存在下，在〇 C至100°c間之溫度下（較佳為環境溫度），歷經丨至24小時 (較佳為12小時）。 所要之式XXV化合物，其中Rl、r2、R4、r5、r6、r7均如 上述’且乂2為基團wCH2v，其中乂係如上述，可製自其相 應之式XXIV化合物，當尺8為甲基且汉9為甲氧基（,,Wemreb，，酿 胺）時’經由以多種V2Met化合物處理，其中Met為金屬，較 92199 -58- 1285641 佳為鎂或鋰，以產生所要之式mv化合物。 所要（式 XXVI 化合物，其中 Rl、r2、r4、r5、r6、r7、r8 及R9(其係在本發明之範圍内)均如上述，可製自其相應之式 IV化3物，其方式是以氫化物來源還原，較佳為硼氫化 鋼，於酸存在下，譬如三氟醋酸，在對反應為惰性之溶劑 (較佳為四氫呋喃）中，於0°c與100°c間之溫度下，歷經1至20 小時（較佳為12小時）。當R8及/或R9為H時，此胺可使用熟 諳此藝者已知之標準醯胺偶合條件進行醯基化，譬如在 L.A· Paquette (編著），百科全書，John Wiley & Sons,Wiley & Sons, ChlcheSter 'England, 1995 ' For example, pyridinium chlorochromate, aqueous sodium hypochlorite, in a catalytic amount of 2,2,6,6-tetradecyl hexahydro ton decyloxy (τΕΜρ〇 Free radicals and catalyzed in the presence of potassium bromide in a suitable solvent inert to the reaction, such as dichloromethane, or with acetic anhydride and diterpenoids. A compound of the formula XXI wherein R1, R2, R4, R5, R6, and R7 are as defined above, which may be prepared from the corresponding compound of formula IX by treatment with trimethyldecane cyanide in an inert solvent such as The aromatic hydrocarbon (e.g., benzene, toluene, diphenyl) is preferably zinc iodide in the presence of a catalytic amount of Lewis acid at a temperature of from about 25 c to about 14 (TC, preferably about 8 Torr). From °c to about 1 Torr, it is 丨12 hours, preferably 5 hours. The resulting solution is concentrated to dryness and added directly to a polar solvent (eg methanol, ethanol) without further purification. (preferably hydrochloric acid) in a polar aprotic solvent (preferably dioxane), added to the child solution, and the mixture is at a temperature of 〇. 〇 to about ° C, preferably a chamber Heating, stirring for 1 to 24 hours, preferably 12 hours, to produce a compound of the formula XXI. The compound of the formula XXII, wherein R1, R2, R4, R5, R6, R7 are as defined above, can be prepared from the corresponding formula a compound of 〇α in a manner that is treated with a reducing agent such as sodium hydride or sodium cyanoborohydride, Among the solvents inert to the reaction, such as methanol or ethanol, preferably ethanol, is from about 0 to about 1 Torr. The compound of formula XXII is provided at a temperature of 〇 (preferably at reflux temperature) for 0.1 to 5 hours (preferably 〇75 hours). Or a desired compound of the formula wherein Ri, r2, r4, r5, r6 and R7 are as defined above, and may be prepared from the corresponding compound of the formula xvn, wherein Q is a leaving group as described above, in the form of a cyanide salt. Treating, for example, lithium, sodium, _ 92199 -57-1285641 or a tetraalkylammonium cyanide in a solvent inert to the reaction, such as dimethylformamide, at a temperature between 0 ° C and loot, The compound of formula XXII is provided over a period of from 1 to 12 hours. The compound of the formula XXIII, wherein R1, R2, R4, R5, R6 and r7 are as defined above, can be prepared from the corresponding compound of the formula XXII by dissolving in concentrated sulfuric acid containing five equivalents of water at a temperature of Ot to loot (preferably room temperature) for 1 to 20 hours. Then, the formed guanamine is dissolved in a polar solvent (preferably di-methane) and treated with trimethylsulfonium tetrafluoroborate at a temperature of 0 ° C to 100 ° C (preferably room temperature). ), after 1-20 hours (preferably 12 hours). Next, the formed imido ester is treated with an aqueous alkali, preferably lithium hydroxide, sodium or potassium, in a polar solvent, preferably dioxere, at a temperature between 〇C and 100 ° C. (preferably room temperature), after hydrazine to between 2 hours, to provide a compound of formula XXIII. A compound of the formula XXIV, wherein R1, R2, R4, R5, R6, r7, r8 and hydrazine are as defined above, may be prepared from the corresponding sxxm compound by way of a solvent inert to the reaction (preferably two) In methyl chloride), the acid is treated with its corresponding amine (NHR8R9); U hydroxybenzotriazole hydrate (1108 butyl) and 1 〇 monomethylaminopropyl)-3-ethylcarbodiimide In the presence of hydrochloride (EDCI), at a temperature between 〇C and 100 ° C (preferably ambient temperature), it is subjected to enthalpy to 24 hours (preferably 12 hours). The desired compound of the formula XXV, wherein R1, r2, R4, r5, r6, and r7 are as defined above and 乂2 is a group wCH2v, wherein the lanthanide is as described above, and can be prepared from the corresponding compound of the formula XXIV, when the ruler 8 is Methyl and Han 9 is a methoxy (,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Compound. A compound of the formula XXVI wherein R1, r2, r4, r5, r6, r7, r8 and R9, which are within the scope of the invention, is as defined above, may be prepared from the corresponding formula IV, in a manner It is reduced by a hydride source, preferably a hydroborated steel, in the presence of an acid, such as trifluoroacetic acid, in a solvent inert to the reaction (preferably tetrahydrofuran) at a temperature between 0 ° C and 100 ° C. Next, after 1 to 20 hours (preferably 12 hours). When R8 and/or R9 is H, the amine can be thiolated using standard guanamine coupling conditions known to the artist, such as in LA·Paquette. (ed.), Encyclopedia, John Wiley & Sons,

Chlchester，England，1995中所述者，以產生其他式XXVI化合物。 所要足式XXVI化合物，其中Ri、R2、R4、R5、以6及R7均如 上述，且R8與R9為Η，其替代製備法係涉及其相應式χχπ化 合物之還原，使用熟諳此藝者已知之程序，譬如在 L.A· Paquette (編著），m 百科全書，J〇hn Wiley & s〇ns，Chlchester, England, 1995 to produce other compounds of formula XXVI. The compound of the formula XXVI, wherein Ri, R2, R4, R5, 6 and R7 are as defined above, and R8 and R9 are oxime, and the alternative preparation method relates to the reduction of the corresponding χχπ compound. Knowing procedures, such as in LA· Paquette (eds.), m encyclopedia, J〇hn Wiley & s〇ns,

Chichester，England，1995中所述者，例如使用硼烷_四氫呋喃複 合物，在對反應為惰性之溶劑中。可接著使此等一級胺類 轉化成如上述之醯胺類，以產生本發明範圍内之其他化合 物。所要之式XXVII化合物，其中Rl、r2、r4、r5、r6 ' r7 及V2均如上述，且χΐ為OH、F或η，可製自其相應之式xxy 化合物’其方式是以還原劑處理，譬如硼氫化鈉，於極性 溶劑中，譬如甲醇或乙醇，在約〇它至約l〇(rc之溫度下，歷 經1至10小時（較佳為1小時），以產生式化合物，其中 X1 為 OH。 式XXVII化合物，當X1 = N時，可製自其相應之醇（Χι =〇H) 92199 -59- 1285641 ，其係被轉化成f料酸I旨，並以疊氮錢置換。使疊氣 化物氫化成NH2。熟諳此藝者可藉標準還原胺化條件，使用 其相應之醛與還原劑，譬如硼氫化鈉或氰基硼氫化鈉，使 轉化成NR1H。NR1H可被轉化成njor2 ,其係使用還原胺化 作用之相同條件，以產生NRi R2。 再者，當X1為NH2時，其相應之醇（χ1 = 〇Η)可被轉化成甲 烷磺酸酯，以疊氮化物置換，及以氫還原，以產生單一非 對映異構物。當XI為NHR1(RUMe)時，其相應之一級胺 可經由以甲酸乙酯處理，被轉化成NHRi，在〇。〇至丨⑻。C間之 溫度下，歷經1，24小時之間（較佳為12小時）。無需進一步純 化，將所形成之甲醯胺直接添加至非極性溶劑（例如苯、甲 苯，較佳為甲苯）與還原劑譬如硼烷硫化甲烷複合物中，在〇 C至100 c間之溫度下，歷經丨_24小時之間（較佳為12小時）， 提供所要之單甲胺產物。當力為胃^時，其相應之一級胺 可藉標準還原胺化條件，被轉化成NHR1 ’其方式是以醛Ri 處理’於極性落劑中，譬如甲醇或乙醇，於硼氫化鈉或氰 基调氫化納存在下，在01至l〇(rc間之溫度下，歷經丨_24小 時之間（較佳為12小時）。當χΐ為NR1 R2時，其相應之二級胺 NHR1可藉如上述之標準還原，被轉化成R2。化合物 亦可藉由標準還原胺化條件，使用如上述之相應醛或酮， 被轉化成NH2、NHR1及NRiR2 V·此方法係產生胺非對映異構 物之混合物，其可藉矽膠層析分離。 可使其轉化成相應之式XXVII化合物，其中X1為F，其方 式是以IL化劑處理，譬如三氟化二乙胺基硫（DAST)或 92199 -60- 1285641 [雙（2- T氧基乙基）胺基]三氟化硫（Deoxyfluor)，在對反應為惰 性之溶劑中，譬如二氣甲烷或1，2二氣乙烷，在-78°c至約· °C間之溫度下（較佳為環境溫度），歷經〇.1至10小時（較佳為 1小時）。可使其轉化成相應之式XXVII化合物，其中χ1為H ，其方式是以適當氫化物來源還原，譬如氫化二異丁基链 ，在對反應為惰性之溶劑中，譬如四氫呋喃，在至約1〇〇 °C間之溫度下，較佳為約〇艺，歷經01至1〇小時。 所要之式XXVIII化合物，其中R1、r2、R4、R5、、r7均 如上述，且V2為基團V或C^V，其中V係如上述，可製自其 相應之式xxv化合物，其方.式是以氟化劑處理，譬如三氟 化二乙胺基硫（DAST)或[雙（2_甲氧基乙基）胺基心氣:: (Deoxyfliioi·)，在對反應為惰性之溶劑中，譬如二氯甲烷戋^ 二氯乙mn：至約航間之溫度下（較佳為環^溫^ ，歷經0.1至24小時（較佳為12小時）。 又 圖式3 R6As described in Chichester, England, 1995, for example, a borane-tetrahydrofuran complex is used in a solvent inert to the reaction. These primary amines can then be converted to the guanamines as described above to produce other compounds within the scope of the invention. A compound of the formula XXVII, wherein R1, r2, r4, r5, r6' r7 and V2 are as defined above, and hydrazine is OH, F or η, which may be prepared from the corresponding compound of formula xxy' in a manner which is treated with a reducing agent , for example, sodium borohydride, in a polar solvent, such as methanol or ethanol, at a temperature of about 〇 to about 1 Torr (rc, for 1 to 10 hours (preferably 1 hour) to produce a compound of the formula, wherein X1 OH. The compound of the formula XXVII, when X1 = N, can be prepared from its corresponding alcohol (Χι = 〇H) 92199 - 59 - 1285641, which is converted to the acid I and replaced with azide. Hydrogenation of the gasside to NH2. The formula can be converted to NR1H by standard reductive amination conditions using its corresponding aldehyde and reducing agent, such as sodium borohydride or sodium cyanoborohydride. NR1H can be converted to Njor2, which uses the same conditions of reductive amination to produce NNi R2. Further, when X1 is NH2, its corresponding alcohol (χ1 = 〇Η) can be converted to methane sulfonate to azide Substitution, and reduction with hydrogen to produce a single diastereomer. When XI is NHR1 (RUMe), its phase The primary amine can be converted to NHRi by treatment with ethyl formate, between 1 and 24 hours (preferably 12 hours) at a temperature between 〇.〇 to 丨(8) C. Without further purification, The formed formamide is directly added to a non-polar solvent (for example, benzene, toluene, preferably toluene) and a reducing agent such as a borane vulcanized methane complex at a temperature between 〇C and 100 c, after 丨24 Between hours (preferably 12 hours), the desired monomethylamine product is provided. When the force is gastric, the corresponding monoamine can be converted to NHR1 by standard reductive amination conditions. The mode is aldehyde Ri The treatment is carried out in a polar primer such as methanol or ethanol in the presence of sodium borohydride or cyanohydrin at a temperature between 01 and 10 Torr (between 丨24 hours (preferably 12 hours) When hydrazine is NR1 R2, its corresponding secondary amine NHR1 can be converted to R2 by standard reduction as described above. The compound can also be converted by standard reductive amination conditions using the corresponding aldehyde or ketone as described above. Converted to NH2, NHR1 and NNiR2 V. This method produces an amine non-pair a mixture of isomers which can be separated by chromatography. It can be converted to the corresponding compound of formula XXVII wherein X1 is F in a manner which is treated with an acylating agent such as diethylamine trifluoride (DAST). Or 92199 -60-1285641 [bis(2-Toxyethyl)amino]desulfide (Deoxyfluor) in a solvent inert to the reaction, such as di-methane or 1,2 di-ethane , at a temperature between -78 ° C and about ° ° C (preferably ambient temperature), after 1 to 10 hours (preferably 1 hour). It can be converted to the corresponding compound of formula XXVII wherein χ1 is H in a manner which is reduced by a suitable hydride source, such as a diisobutyl hydride chain, in a solvent inert to the reaction, such as tetrahydrofuran, to about 1 Torr. At a temperature between ° C, it is preferably about 至, after 01 to 1 hour. A compound of the formula XXVIII, wherein R1, r2, R4, R5, and r7 are as defined above, and V2 is a group V or C^V, wherein the V system is as defined above, and can be prepared from the corresponding compound of the formula xxv, The formula is treated with a fluorinating agent, such as diethylamine disulfide (DAST) or [bis(2-methoxyethyl)amine-based:: (Deoxyfliioi), a solvent inert to the reaction. For example, methylene chloride 戋^ dichloroethylene mn: to the temperature of the space (preferably ring temperature ^, after 0.1 to 24 hours (preferably 12 hours). Figure 3 R6

NH: NH, XXXNH: NH, XXX

〜丨 Λ R、~丨 Λ R,

.Cl.Cl

R X 1R X 1

XXIX XXXIXXIX XXXI

-6l - 92199-6l - 92199

XXXIVXXXIV

XXXV 1285641 圖式3 根據圖式3，所要之式XXIX化合物，其中J為氮，選用之 雙鍵不存在，且R2、R4、R5、R6及R7均如上述，可製自其相 應之式XXX化合物，其方式是與α-酮基羧酸R2C〇C〇2H反應 ，在質子性溶劑中，譬如乙醇或甲醇，於高溫下。此等溫 度可合宜地·且安全地使用熟諳此藝者熟悉之微波裝置達成 ，譬如 Emrys Optimizer (Personal 化學，Uppsala，Sweden)或 Milestone 微 波（Milestone實驗室，Sorisole，Italy)。使所形成之反應混合物濃 縮至乾涸，且經常可使式XXIX化合物結晶，或者，可在矽 膠上藉急驟式層析純化。 所要之式XXXI化合物，其中R2、R4、R5、R6及R7均如上述 ，可製自其相應之式XXIX化合物，其方式是以氣化劑處理 ，譬如氯化磷（III)、氧氯化磷（V)、二氯化亞硫醯或三苯膦/ 四氯化碳。典型上，係使式XXIX化合物溶於過量氯化磷醯 中，並將混合物加熱至約l〇〇°C，歷經12-18小時。於冷卻後 ，蒸餾出過量氧氯化磷（V)，並以飽和NaHC〇3小心地使殘留 物淬滅。將所形成之含水懸浮液以適當有機溶劑萃取，較 佳為二氣甲烷。 所要之式XXXII化合物，其中R2、R4、R5、R6及R7均如上 述，可藉催化性氫化，於熟諳此藝者所習知之標準觸媒存 在下，製自其相應之式XXXI化合物，例如按L.A. Paquette (編 著），有機合成試劑百科全書，John Wiley & Sons, Chichester, England, 1995中所述。典型上，係使化合物溶於有機溶劑中，較佳為 極性溶劑，譬如酷酸。經常添加添加劑，譬如錯酸鈉，以 92199 -62- 1285641 改良反應速率。適當觸媒係經選擇，譬如鈀/碳。氫化作用 係於高壓下，在適當裝置中進行，較佳為約6小時。濾出觸 媒，產生式XXXII化合物，其典型上係於矽膠上層析後被分 離。 所要之式XXXIII化合物，其中R2、R4、R5、R6及R7均如上 述，可製自其相應之式XXXII化合物，其方式是與boc-酐反應 ，按 T.W.Greene 與 G.M. Wuts,有機合成之保護基，Wiley Interscience， 1991中所述。典型上，反應係在溶劑中進行，譬如二氯甲烷 ，於-78°C至〇°C下，典型上為-40°C。一般而言，在此程序中 ，式XXXII化合物上之較不受阻氮，有選擇性官能基化。式 XXXIII化合物若需要可藉標準矽膠層析純化。 所要之式XXXIV化合物，其中R1、R2、R4、R5、R6及R7均 如上述，可製自其相應之式XXXIII化合物，其方式是引進醯 基、胺甲醯基、亞磺醯基或磺醯基R1。這可經由以適當試 劑處理而達成，例如氯甲酸乙酯或氯甲酸異丙酯，在對反 應為惰性之適當溶劑中，譬如二氯甲烷或氯仿，視情況含 有鹼，譬如吡啶、二異丙基乙胺、4-二甲胺基吡啶或2,6-二-第三-丁基斗甲基吡啶，在0°C至60°C間之溫度下，典型上為 環境溫度，歷經1至24小時之期間。有時，此反應係在作為 溶劑之吡啶中進行。產物係經常藉由標準萃取處理及於矽 膠上急驟式層析進行分離。 所要之式XXXV化合物，其中R1、R2、R4、R5、R6及R7均 如上述，可以酸處理，製自其相應之式XXXIV化合物，按 T. W, Greene 與 G. M· Wuts，有機合成之保護基，Wiley Interscience, 92199 -63 - 1285641 1991中所述。在一典型程序中，係將雙胺基甲酸酯以三氟醋 酸處理，於環境溫度下，歷經1-24小時，典型上為3小時。 於完成時，藉由蒸發移除此酸，並使殘留物於有機溶劑幸交 佳為二氯甲烷與碳酸氫鈉水溶液之間作分液處理。蒸發有 機溶劑獲得所要之式XXX V化合物。 圖式4XXXV 1285641 Figure 3 According to the formula 3, the desired compound of the formula XXIX, wherein J is nitrogen, the selected double bond is absent, and R2, R4, R5, R6 and R7 are all as described above, and can be prepared from the corresponding formula XXX A compound which is reacted with an α-ketocarboxylic acid R2C〇C〇2H in a protic solvent such as ethanol or methanol at a high temperature. These temperatures can be conveniently and safely achieved using microwave devices familiar to those skilled in the art, such as Emrys Optimizer (Personal Chemistry, Uppsala, Sweden) or Milestone Microwave (Milestone Laboratories, Sorisole, Italy). The resulting reaction mixture is concentrated to dryness and the compound of formula XXIX can often be crystallized or purified by flash chromatography on silica gel. The desired compound of the formula XXXI, wherein R2, R4, R5, R6 and R7 are as defined above, may be prepared from the corresponding compound of the formula XXIX by a gasifying agent such as phosphorus (III) chloride, oxychlorination Phosphorus (V), sulfinium dichloride or triphenylphosphine / carbon tetrachloride. Typically, the compound of formula XXIX is dissolved in an excess of phosphonium chloride and the mixture is heated to about 10 ° C for 12-18 hours. After cooling, excess phosphorus oxychloride (V) was distilled off and the residue was carefully quenched with saturated NaHC. The resulting aqueous suspension is extracted with a suitable organic solvent, preferably dihalomethane. The desired compound of formula XXXII, wherein R2, R4, R5, R6 and R7 are all as described above, by catalytic hydrogenation, in the presence of a standard catalyst known to those skilled in the art, from the corresponding compound of formula XXXI, for example According to LA Paquette (ed.), Encyclopedia of Organic Synthetic Reagents, John Wiley & Sons, Chichester, England, 1995. Typically, the compound is dissolved in an organic solvent, preferably a polar solvent such as a succinic acid. Additives such as sodium sulphate are often added to improve the reaction rate with 92199 -62-1285941. Suitable catalysts are selected, such as palladium/carbon. The hydrogenation is carried out under elevated pressure in a suitable apparatus, preferably about 6 hours. The catalyst is filtered off to yield a compound of formula XXXII which is typically isolated after chromatography on silica gel. The desired compound of the formula XXXIII, wherein R2, R4, R5, R6 and R7 are as defined above, can be prepared from the corresponding compound of the formula XXXII by reaction with boc-anhydride, by TW Greene and GM Wuts, protection by organic synthesis Base, described in Wiley Interscience, 1991. Typically, the reaction is carried out in a solvent such as dichloromethane at -78 ° C to 〇 ° C, typically -40 ° C. In general, in this procedure, the compound of formula XXXII is less resistant to nitrogen and is selectively functionalized. The compound of formula XXXIII can be purified by standard gel chromatography if desired. A compound of the formula XXXIV, wherein R1, R2, R4, R5, R6 and R7 are as defined above, may be prepared from the corresponding compound of the formula XXXIII by introducing a thiol group, an amine carbaryl group, a sulfinyl group or a sulfonate.醯基R1. This can be achieved by treatment with a suitable reagent, such as ethyl chloroformate or isopropyl chloroformate, in a suitable solvent inert to the reaction, such as dichloromethane or chloroform, optionally containing a base such as pyridine or diisopropyl. Ethylethylamine, 4-dimethylaminopyridine or 2,6-di-t-butylidene chloropyridine, typically at ambient temperature between 0 ° C and 60 ° C, after 1 to During the 24-hour period. Sometimes, this reaction is carried out in pyridine as a solvent. The product is often isolated by standard extraction treatment and flash chromatography on silica. The compound of the formula XXXV, wherein R1, R2, R4, R5, R6 and R7 are all as described above, can be acid-treated, from the corresponding compound of the formula XXXIV, according to T. W, Greene and G. M· Wuts, organic synthesis The protecting group is described in Wiley Interscience, 92199-63-1285641 1991. In a typical procedure, the bis-carbamate is treated with trifluoroacetic acid at ambient temperature for a period of from 1 to 24 hours, typically 3 hours. Upon completion, the acid was removed by evaporation and the residue was partitioned between organic solvent and methylene chloride and aqueous sodium bicarbonate. The organic solvent is evaporated to obtain the desired compound of formula XXX V. Figure 4

OHOH

R2 OMeR2 OMe

XXXVIIIXXXVIII

R4 R3 R5 R6R4 R3 R5 R6

N^R2 92199 -64- 1285641 根據圖式4，所要之化合物，並 存在，R1、R2、R4、r5、R 又鍵不 及R均如上述，且R3係如上述， 其中連接碳係經酮基取代（被騎為式XXXM合物），可製 自其相應之式XXXV化合&’其方式是與氯化醯反應，在溶 劑中，譬如二氯甲烷或素长 κ主、 :、，視h況含有驗，譬如Ρ比淀、 二異丙基乙胺、4-二甲胺基吡 疋Λ 2,6-一-罘二-丁基冬甲基峨 啶，在0°C至60°C間之溫度下，血刑 〆、土上為J衣境〉皿度’歷經1至 24小時心期間。在反應完成時，將混合物以含水酸與鹽水 洗務，於珍膠層析後，獲得式XXXVI化合物。若需要，、i化 酿可當場產生自其相應之羧酸與三苯膦，並搭配作用劑， 譬如四氯化碳、六氯乙燒或三氯乙腈。此後述程序可以樹 脂結合之三苯膦進行，這使其《於接受自動化化學。過滤 樹脂，接著蒸發及於矽膠上純化，產生所需要之式XXXVHt 合物。 所要之式XXXVII化合物，其中Ri、R2、R4、R5、R6及R7均 如上述，且R3係如上述，其中基團V係連接至連接碳，可經 由以適當烷基溴化物進行烷基化作用，製自其相應之式 XXX V化合物。此等烷基化作用典型上係於極性溶劑中，譬 如二甲基甲驢胺、二甲亞礙、N-甲基四氫吡哈酮等，於鹼 存在下（例如後酸钾、三乙胺、P比咬、4-二甲胺基u比咬、二 甲基吡啶），在25°C至200°C間之溫度下，典型上為i5〇°c下進 行。由於喳喏啉之非反應性，故在微波中，於適當溫度T 之加熱，係特別適合此程序。烷基化作用可以多種烷基溴 92199 -65 - 1285641 化物進行，譬如芳基甲基溴化物或α取代之芳基甲基溴化物 。利用適當微波設備，譬如Emrys Optimizer (Personal化學，Uppsala， Sweden)或 Milestone 微波（Milestone 實驗室，Sorisole，Italy)有助於此 等反應。 所要之式XXXVIII化合物，其中R1、R2、R4、R5、R6、R7及 V均如上述，可製自其相應之α-溴基酯VCHBi*C〇2Me化合物 。此等烷基化作用典型上係於極性溶劑中進行，譬如二甲 基甲醯胺、二甲亞戚' N-甲基四氫叶I：洛酮等，於驗存在下 (例如碳酸鉀、三乙胺、吡啶、4-二甲胺基吡啶、二甲基吡 啶），在25°C至200°C間之溫度下，典型上為150°C。由於喹喏 4之非反應性，故在微波中，於適當溫度下加熱，係特別 適合此程序。利用適當微波設備，譬如Emrys Optimizer (Personal 化學，Uppsala，Sweden)或 Milestone 微波（Milestone 實驗室，Sorisole， Italy)有助於此等反應。 所要之式XXXIX化合物，其中R1、R2、R4、R5、R6、R7及 V均如上述，可製自其相應之式XXXVIII化合物，其方式是 使用熟諳此藝者所習知之試劑與條件，使酯官能基還原。 例如，可將式XXXVIII化合物以氫化鋰鋁，在無水含醚溶劑 中，譬如四氫呋喃與醚，於溫度範圍介於-78°C與〇°C之間處 理。典型上，以硫酸鈉六水合物或矽膠/氯仿處理反應混合 物，及藉過濾移除固體，獲得粗產物，式XXXIX化合物典型 上係自其藉矽膠層析分離。 所要之式L化合物，其中R1、R2、R4、R5、R6、R7及V均 如上述，可製自其相應之式XXXIX化合物，其係利用適當烷 92199 -66- 1285641 基化劑，譬如應化物或漠化物，及驗，譬如氫化鋼， 在對反應為惰性（落劑t ’譬如四氫吱喃或二甲基甲酿胺 ，以獲得所要之式L化合物。 所要之式U化合物’其中Ri、r2、r4、r5、r6、r7&^_ 如上述，且Ac為醯基（其係在本發明之範圍内），可製自其 相應之式XXXIX化合物’其係利用適當氯化醯，及驗，譬如 叶匕呢、三乙胺或4-二甲胺基吡啶，在無水溶劑中，譬如二氯 〒垸。依氯化醯之反應性而定，吾人可利用鹼，譬如吡啶 ’作為溶劑。產物通常可經由使反應混合物濃縮，及藉矽 膠層析純化產物而被分離。 圖式5 92199 -6Ί - 1285641N^R2 92199 -64- 1285641 According to the formula 4, the desired compound is present, and R1, R2, R4, r5, and R are less than R as described above, and R3 is as defined above, wherein the carbon is bonded via a ketone group. Substituted (ridden as a compound of formula XXXM), can be prepared from its corresponding formula XXXV compound &' in a manner that is reacted with cesium chloride in a solvent such as methylene chloride or a long κ main, :,, h conditions include, for example, bismuth, diisopropylethylamine, 4-dimethylaminopyridinium 2,6-mono-p-butyl-butanylmethyl acridine, at 0 ° C to 60 ° At the temperature between the C, the blood is smashed, and the soil is J clothing> the degree of the dish's period of 1 to 24 hours. Upon completion of the reaction, the mixture is washed with aqueous acid and brine, and after chromatography, the compound of formula XXXVI is obtained. If desired, the i-brew can be produced on the spot from its corresponding carboxylic acid and triphenylphosphine, together with an agent such as carbon tetrachloride, hexachloroethane or trichloroacetonitrile. The procedure described below can be carried out with a resin-bound triphenylphosphine, which allows it to undergo automated chemistry. The resin was filtered, then evaporated and purified on silica gel to give the desired compound of formula XXXVHt. A compound of the formula XXXVII, wherein Ri, R2, R4, R5, R6 and R7 are as defined above, and R3 is as defined above, wherein the group V is attached to a linking carbon and can be alkylated via a suitable alkyl bromide. Function, made from its corresponding compound of formula XXX V. Such alkylation is typically carried out in a polar solvent such as dimethylformamide, dimethoprim, N-methyltetrahydropyrone, etc. in the presence of a base (eg post-acid potassium, triethyl) The amine, P ratio bite, 4-dimethylamino group u bite, lutidine) is carried out at a temperature between 25 ° C and 200 ° C, typically i5 ° ° c. Due to the non-reactivity of the porphyrins, heating in the microwave at an appropriate temperature T is particularly suitable for this procedure. The alkylation can be carried out with a variety of alkyl bromide 92199 - 65 - 1285641 compounds such as aryl methyl bromide or alpha substituted aryl methyl bromide. These reactions are facilitated by the use of appropriate microwave equipment such as Emrys Optimizer (Personal Chemistry, Uppsala, Sweden) or Milestone Microwave (Milestone Laboratories, Sorisole, Italy). The desired compound of the formula XXXVIII wherein R1, R2, R4, R5, R6, R7 and V are as defined above, can be prepared from the corresponding α-bromo ester VCHBi*C〇2Me compound. Such alkylation is typically carried out in a polar solvent such as dimethylformamide, dimethyl hydrazine 'N-methyltetrahydroleaf I: naloxone, etc., in the presence of (eg potassium carbonate, Triethylamine, pyridine, 4-dimethylaminopyridine, lutidine), typically between 150 ° C and 200 ° C, is typically 150 ° C. Due to the non-reactivity of quinone 4, heating in a microwave at a suitable temperature is particularly suitable for this procedure. These reactions are facilitated by the use of appropriate microwave equipment such as Emrys Optimizer (Personal Chemistry, Uppsala, Sweden) or Milestone Microwave (Milestone Laboratories, Sorisole, Italy). The desired compound of the formula XXXIX, wherein R1, R2, R4, R5, R6, R7 and V are as defined above, may be prepared from the corresponding compound of the formula XXXVIII by using the reagents and conditions known to those skilled in the art. Reduction of the ester functional group. For example, the compound of formula XXXVIII can be treated as lithium aluminum hydride in an anhydrous ether-containing solvent such as tetrahydrofuran and ether at a temperature ranging from -78 °C to 〇 °C. Typically, the reaction mixture is treated with sodium sulphate hexahydrate or sulphuric acid/chloroform, and the solid is removed by filtration to give the crude product which is typically isolated from the sulphuric acid chromatography. The desired compound of the formula L, wherein R1, R2, R4, R5, R6, R7 and V are as defined above, may be prepared from the corresponding compound of the formula XXXIX, which utilizes the appropriate alkane 92199-66-1285641 baseing agent, for example a compound or a desert material, such as a hydrogenated steel, which is inert to the reaction (injection t' such as tetrahydrofuran or dimethylamine to obtain the desired compound of formula L. Ri, r2, r4, r5, r6, r7 & ^_ as described above, and Ac is a fluorenyl group (which is within the scope of the invention), which can be prepared from its corresponding compound of formula XXXIX' which utilizes appropriate ruthenium chloride And test, such as leaf mites, triethylamine or 4-dimethylaminopyridine, in an anhydrous solvent, such as dichloropurine. Depending on the reactivity of ruthenium chloride, we can use alkali, such as pyridine As a solvent, the product can usually be isolated by concentrating the reaction mixture and purifying the product by gel chromatography. Figure 5 92199 -6Ί - 1285641

RR

XXXVXXXV

圖式5係描述並他化八物甘φ 立 也化口物具中J為氮，且選用之雙鍵不 子在（意即喹喏啉），使用類似由V. Krchnak等人，及加&办⑽Z脱 42,2443-2446(2001)所述之固相化學之製備，且其係提供數項 優點。此化學亦可在溶液相中進行，其方式是以富含電子 之芳基甲基，譬如‘甲氧基芊基或2，1二甲氧基芊基取代樹 92199 -68- 1285641 脂，且類似保護基使用之，及在適當條件下分裂，按 T, W· Greene 與 G· M· Wuts，透:機合成之保譜基，wilev Interscience, 1991中所述。特足s之，此圖式係提供由對掌性胺基醇製備 對掌性喳喏啉之方法，該胺基醇係容易地使用熟諳此藝者 所習知之方法與試劑，製自可廣泛取得之對掌性胺基酸。 樹脂結合之式UI化合物，其中R2、R4、R5、R6及R7均如上 述，可製自其相應之胺基醇R2CH(CH2〇H)NH2，其係首先藉由 V. Krchnak 等人，批 42, 2443-2446 (2001)所述之方法紝 合至樹脂。然後，將其以相應之式Lin化合物處理，典型上 在極性溶劑中，譬如二甲亞颯、二甲基甲醯胺、N_甲基四 氫说洛酮或二甲基乙醯胺，正如熟諳此藝者所已知，其能 夠允許聚苯乙烯為基料之樹脂膨潤。反應係進行12·36小時， 然後將樹脂洗滌，以單離所要之樹脂結合之式Ln化合物。 所要之樹脂結合之式LIV化合物，其中R2、R4、R5、反6及R7 均如上述’可製自其相應之樹脂結合之式LII化合物醇，其 方式是如熟諳此藝者所熟悉之方式，使醇官能基活化。此 係涉及醇轉化成磺酸酯（譬如甲烷磺酸酯或甲苯磺酸酯）、 #化物（譬如氯化物或溴化物）或醋酸酯。反應較佳係經由 乂氟化甲燒確酿處理樹脂結合之式LII化合物，於驗存在下 ’譬如吡啶、4-二甲胺基吡啶或質子海绵，在溶劑中進行， 譬如二氯甲烷或二氯乙烷，於此種情況中，反應典型上係 進行1-5小時。將所形成之樹脂結合之磺酸酯洗除所有試劑 ’且确基可藉由熟諳此藝者所習知之多種還原劑還原，例 如桉L.A· Paquette (編著），有機合成試劑百科+書J〇hnW〜y & 92199 .69- 1285641Figure 5 is a description of the genus of Physcomitrium sinensis. J is nitrogen, and the double bond is selected (meaning quinoxaline), similar to that used by V. Krchnak et al. & (10) Z De 42, 2443-2446 (2001) for the preparation of solid phase chemistry, and which provides several advantages. This chemistry can also be carried out in a solution phase by replacing the tree 92199-68-1285641 with an electron-rich arylmethyl group such as a 'methoxy fluorenyl group or a 2,1 dimethoxy fluorenyl group, and Similar to the use of protecting groups, and splitting under appropriate conditions, according to T, W· Greene and G·M· Wuts, through the synthesis of the spectrum, Wilev Interscience, 1991. In particular, this figure provides a method for preparing a palmitic porphyrin from a palmitic amine alcohol, which is readily available from a variety of methods and reagents known to those skilled in the art. Obtained the palmitic amino acid. A resin-bound U compound of the formula wherein R 2 , R 4 , R 5 , R 6 and R 7 are as defined above, and may be prepared from the corresponding amino alcohol R 2 CH(CH 2 〇 H)NH 2 , which is first approved by V. Krchnak et al. The method described in 42, 2443-2446 (2001) is incorporated into a resin. It is then treated with the corresponding compound of the formula, typically in a polar solvent such as dimethyl hydrazine, dimethylformamide, N-methyltetrahydro-loxaprofen or dimethylacetamide, as It is known to those skilled in the art that it is capable of allowing polystyrene-based resin to swell. The reaction was carried out for 12.36 hours, and then the resin was washed to separate the compound of the formula Ln from the desired resin. The desired resin-bound LIV compound, wherein R2, R4, R5, trans 6 and R7 are as described above in the form of a compound of the formula LII which can be prepared from the corresponding resin, in a manner familiar to those skilled in the art. To activate the alcohol functional group. This involves the conversion of an alcohol to a sulfonate (such as a methanesulfonate or tosylate), a # (such as a chloride or bromide) or an acetate. Preferably, the reaction is carried out by treating the resin-bound compound of the formula LII via hydrazine fluorinated methane, in the presence of a reagent such as pyridine, 4-dimethylaminopyridine or a proton sponge, in a solvent such as dichloromethane or two. Ethyl chloride, in which case the reaction is typically carried out for 1-5 hours. The formed resin-bound sulfonate is washed out of all reagents' and the substrate can be reduced by various reducing agents known to those skilled in the art, for example, 桉LA· Paquette (eds.), Organic Synthesis Reagents Encyclopedia+Book J〇 hnW~y & 92199 .69- 1285641

Sons, CWchester’ England, 〖995中所述。例如’吾人可使用氯化錫⑻ 於極性溶劑中，譬如N_甲基四氣吡咯酮或二甲基甲醯胺， 其能夠使聚苯乙烯為基料之樹脂膨潤。反應典型上係進行 1-5小時，將試劑洗離，且所形成之—級胺係進行分子Z閉 環作用，而得樹脂結合之式LIV化合物。若吾人使用如上述 甲烷磺酸酯以外之活化基團，則正如熟諳此藝者所已知， 閉環作用之反應時間或許會較久。 樹脂結合之式LV化合物，其中、r4、r5、r6、及γ均 如上述’彳製自纟相應之式LIV化合物’纟方式{與氯化酿 V0C1反應，在溶劑中’譬如二氯甲烷或氯仿，視情況含有 鹼，譬如吡啶、二異丙基乙胺、4_二甲胺基吡啶或2,6_二-第 三-丁基冬甲基吡啶，在〇。(；至6(rc間之溫度下，典型上為環 境溫度，歷經1至24小時之期間。接著將樹脂結合之式Lv化 合物過濾，並以溶劑重複洗滌，譬如二氯甲烷、甲醇及水 ’以移除過量試劑。 所要之式LVI化合物，其中r2、R4、R5、R6、R7及v均如上 述’可製自其相應之樹脂結合之式LV化合物，其方式是以 熟諳此藝者所習知之強酸處理，譬如三氟醋酸或氫氟酸， 視情況在對反應呈惰性之溶劑中，譬如二氯甲烷或二氯乙 烷。典型上，可將所要之式LVI化合物藉過濾分離，並以適 當有機溶劑洗滌樹脂，譬如二氯甲烷、二氣乙烷或四氫呋 喃。若必要，式LVI化合物可在標準條件下，進一步藉矽膠 層析純化。 所要之式LVII化合物，其中R1、R2 ' R4、R5、R6、r7及v 92199 -70- 1285641 均如上述，可製自其相應之式LVI化合物，其方式是以適當 試劑處理，例如氯甲酸乙酯或氣甲酸異丙酯，在對反應為 θ f生之’容贫彳中，4如一氯p燒或氯仿，視情況含有驗，擘 如吡哫、二異丙基乙胺、冬二甲胺基吡啶或2,6_二·第三·丁基 I甲基吡啶，在（TC至6(rc間之溫度下，典型上為環境溫度 ，歷經1至24小時之期間。有時，反應係在作為溶劑之吡啶 中進行。在其中Ri為胺基甲酸酯或脲之特定情況下，產物 可I由以光氣在甲苯中處理式LVI化合物而獲得，視情況含 有鹼，譬如吡啶、二異丙基乙胺、4_二甲胺基吡啶或2,6•二-罘三-丁基斗甲基吡啶，在〇t至6(rc間之溫度下，接著個別 以酵或胺處理，而得所要之式1^11胺基甲酸酯或脲。產物經 常藉由標準萃取處理，並於矽膠上急驟式層析而被單離。 所要之樹脂結合之式Lvm化合物，其中Rl、R2、R4、r5、 R6及R7均如上述，且r3係如上述，其中基團v係連接至連接 反 了象自其相應之樹脂結合之式LIV化合物，其方式是以 適當燒基溴化物或碘化物進行烷基化作用。此等烷基化作 用典型上係在極性溶劑中進行，譬如二甲基曱醯胺、二甲 亞職或N-甲基四氫吡咯酮，於鹼存在下（三乙胺、吡啶、 4-二甲胺基吡啶、二甲基吡啶）。被使用於此反應中之溶劑 正如热淆此蟄者所熟悉，係能夠允許聚苯乙烯樹脂膨潤 。此等反應經常在環境溫度至約150°C下進行。由於喹喏琳 之非反應性，故在微波爐中，於適當溫度下加熱為較佳。 烷基化作用可以多種烷基溴化物進行，譬如芳基甲基溴化 物或α取代之芳基甲基溴化物。若將溴化物以α拉電子基取 92199 -71 - 1285641 代（譬如在圖式4中，於製備式xxxvm化合物時）’則烷基化 反應典型上係以更良好產率進行。 式LIX喹嗓啉化合物，其中R1、R2 ' R4、R5、R6及R7均如 上述，可製自其相應之樹脂結合之式LVln化合物，其方式 是以熟諳此藝者所習知之強酸處理，譬如三氟醋酸或氫氟 酸，使用或未使用其他溶劑（譬如二氯甲垸或二氯乙烷）。 典型上，式LIX喹喏啉化合物可藉過濾，並以適當有機溶劑 洗滌樹脂而被分離，譬如二氯甲烷、二氯乙烷或四氳呋喃 。蒸發溶劑經常提供純淨所要之式Lix化合物，若必要則經 單離之產物可在標準條件下進一步藉矽膠層析純化。 所要之式LX化合物，其中Ri、R2、R3、R4、R5、汉6及r7均 如上述，可製自其相應之式ux化合物，其方式是以醯化/ 磺化劑溶劑處理，例如氯甲酸乙酯或異丙酯，在對反應呈 惰性之溶劑中，譬如二氯甲烷或氯仿，視情況含有鹼，譬 如吡啶、二異丙基乙胺、本二甲胺基吡啶或2，卜二-第三-丁基 斗甲基吡啶，在（TC至6(rc間之溫度下，典型上為環境溫度 ，歷經1至24小時之期間。有時，反應係在作為溶劑之吡啶 中進行。在R1為胺基甲酸酯或脲時之特定情況中，產物可 ，，二由以光氣在甲苯中處理式LX化合物而獲得，視情況含有 鹼，譬如吡啶、二異丙基乙胺、4_二甲胺基吡啶、2,卜二_第 三-丁基斗甲基吡啶，在至6〇r間之溫度下，接著個別以 醇或胺處理，而得所要之SLX化合物之胺基甲酸酯或脲。 產物經常藉由標準萃取處理，及於矽膠上急驟式層析而被 單離。 92199 -72- 1285641 所要之式LVI化合物，並 冲·甘# . 其中R、R4、R5、R6、R7及v均如上 U ,其替代製備法可自Α ,,^ 〃、相應（式xxxv化合物，經由與醯 化剤譬如氣化醯V〇C1 ,.反應，在落劑中，譬如二氣甲烷或氣 仿，視饧況含有鹼，譬如 _ 、 疋一兴丙基乙胺、4-二甲胺某 Μ或2,6-二-第三_丁基_4_甲基一，在忙至6忙間之溫度； ’典型上為環境溫度，歷經丨至24小時之期間而達成。典型 上，在此等條件下，當R2不為氫時’L林之較不受阻氮 原子係優先地進行㈣作用，而得所要之式W化合物。所 要之式圓化合物，其中r1、r2、r4、r5、r6、r7^m ，且R3係如上述’其中基團V係連接至連接碳，可自其相應 之式LVI化合物’藉由垸基化仙或_化作用，使用如上述 之程序達成。 所要之式LIX化合物，其中r2、R4、R5、R6、R7均如上述 ，且R3係如上述，其中基團V係連接至連接碳，其替代製備 法可自其相應之式XXXV化合物，經由式LIX化合物，藉由 以適當烷基溴化物或碘化物進行烷基化作用而達成。此等 坑基化作用典型上係在極性溶劑中進行，譬如二甲基甲辦 胺、二甲亞颯及N-甲基四氫吡咯酮，於鹼存在下（例如三乙 胺、p比咬、4-二甲胺基吡淀、二甲基叶(：淀）。此等反應經常 在環境溫度至約150°C下進行。由於喳喏啉之非反應性，故 在微波爐中，於適當溫度下加熱為較佳。烷基化作用可以 多種烷基溴化物進行，譬如芳基甲基溴化物、α取代之芳基 甲基溴化物。典型上，在此等條件下，當R2不為氫時，邊 喏啉之較不受阻之氮原子係優先地進行烷基化作用，而得 92199 -73 - 1285641 所要之式LIX化合物。 所要之式XXXV化合物，其中R2、R4、R5、R6及R7均如上 述，可製自其相應之樹脂結合之式LIV化合物，其方式是以 熟諳此藝者所習知之強酸處理，譬如三氟醋酸或氫氟酸， 視情況在對反應為惰性之溶劑中，譬如二氯甲燒或一 ^ ^ 4 4氟乙 圖式6Sons, CWchester’ England, 〖995. For example, 'we can use tin chloride (8) in a polar solvent such as N-methyltetrapypyrrole or dimethylformamide, which is capable of swelling the polystyrene-based resin. The reaction is typically carried out for 1-5 hours, the reagent is washed away, and the resulting amine is subjected to molecular Z ring closure to give a resin-bound LIV compound. If we use an activating group other than the above methane sulfonate, as is known to those skilled in the art, the reaction time of the ring closure may be longer. a resin-bound compound of the formula LV, wherein r4, r5, r6, and γ are all the same as described above for the corresponding compound of the formula LIV compound '纟 method {reacted with chlorinated V0C1 in a solvent such as dichloromethane or Chloroform, if appropriate, contains a base such as pyridine, diisopropylethylamine, 4-dimethylaminopyridine or 2,6-di-t-butyl-m-methylpyridinium. (; to 6 (at a temperature between rc, typically ambient temperature, for a period of 1 to 24 hours. The resin-bound Lv compound is then filtered and washed repeatedly with solvent such as dichloromethane, methanol and water' To remove excess reagents. The desired compound of the formula LVI, wherein r2, R4, R5, R6, R7 and v are as described above, can be prepared from their corresponding resin-bound LV compounds by way of familiarity with the artist. A strong acid treatment, such as trifluoroacetic acid or hydrofluoric acid, optionally in a solvent inert to the reaction, such as dichloromethane or dichloroethane. Typically, the desired compound of formula LVI can be isolated by filtration and The resin is washed with a suitable organic solvent, such as dichloromethane, di-hexane or tetrahydrofuran. If necessary, the compound of formula LVI can be further purified by gel chromatography under standard conditions. The desired compound of formula LVII, wherein R1, R2' R4 R5, R6, r7 and v 92199 -70- 1285641, all as described above, may be prepared from the corresponding compound of the formula LVI by treatment with a suitable reagent, such as ethyl chloroformate or isopropyl formate, in the reaction. for θ f raw 'tolerant sputum, 4 such as a chlorine p-burn or chloroform, as the case may be included, such as pyridinium, diisopropylethylamine, dimethylaminopyridine or 2,6_2·third Butyl I methylpyridine, at (TC to 6 (temperature between rc, typically ambient temperature, for a period of 1 to 24 hours. Sometimes the reaction is carried out in pyridine as a solvent. Among them Ri In the particular case of urethane or urea, the product can be obtained by treating a compound of formula LVI with phosgene in toluene, optionally containing a base such as pyridine, diisopropylethylamine, 4-dimethylamine. Pyridine or 2,6•di-tris-tri-tert-methylpyridinium, at a temperature between 〇t and 6 (rc, followed by treatment with yeast or amine, to obtain the desired formula 1^11 amine group A The acid ester or urea. The product is often isolated by standard extraction and flash chromatography on silica gel. The desired resin is combined with a compound of the formula Lvm, wherein R1, R2, R4, r5, R6 and R7 are as described above. And r3 is as defined above, wherein the group v is attached to a compound of the formula LIV which is bonded to the corresponding resin, in a manner which is suitably brominated Alkylation of the substance or iodide. Such alkylation is typically carried out in a polar solvent such as dimethyl decylamine, dimethyl sub- or N-methyltetrahydropyrrolidone, in the presence of a base Lower (triethylamine, pyridine, 4-dimethylaminopyridine, lutidine). The solvent used in this reaction is familiar to those skilled in the art and is capable of allowing polystyrene resin to swell. The reaction is usually carried out at ambient temperature to about 150 ° C. Because of the non-reactivity of quinoxaline, it is preferred to heat it at a suitable temperature in a microwave oven. The alkylation can be carried out by various alkyl bromides, such as aryl. a methyl bromide or an α-substituted aryl methyl bromide. If the bromide is taken as an α-electron group, 92199 -71 - 1285641 (as in the case of Figure 4, when preparing a compound of the formula xxxvm) The basic reaction is typically carried out in a better yield. A compound of the formula LIX quinoxaline wherein R1, R2'R4, R5, R6 and R7 are as defined above, and can be prepared from the corresponding resin-bound LVln compound by treatment with a strong acid known to those skilled in the art. For example, trifluoroacetic acid or hydrofluoric acid, with or without other solvents (such as methylene chloride or dichloroethane). Typically, the quinazoline compound of the formula LIX can be isolated by filtration and washing the resin with a suitable organic solvent such as dichloromethane, dichloroethane or tetrahydrofuran. Evaporation of the solvent often provides the desired compound of the formula Lix, and if necessary, the isolated product can be further purified by gel chromatography under standard conditions. A compound of the formula LX, wherein Ri, R2, R3, R4, R5, Han 6 and r7 are as defined above, may be prepared from their corresponding formula ux compounds by treatment with a deuteration/sulfonating agent solvent, such as chlorine. Ethyl formate or isopropyl ester, in a solvent inert to the reaction, such as dichloromethane or chloroform, optionally containing a base such as pyridine, diisopropylethylamine, dimethylaminopyridine or 2, - Third-butyl chloromethylpyridine, at (TC to 6 (temperature between rc, typically ambient temperature, for a period of from 1 to 24 hours. Sometimes the reaction is carried out in pyridine as a solvent). In the specific case where R1 is a urethane or urea, the product may be obtained by treating the compound of formula LX with phosgene in toluene, optionally containing a base such as pyridine or diisopropylethylamine. 4_Dimethylaminopyridine, 2, bis-tertiary-butyl-tert-methylpyridinium, at a temperature of up to 6 Torr, followed by treatment with an alcohol or an amine alone to obtain the desired amine group of the SLX compound Formate or urea. The product is often isolated by standard extraction and flash chromatography on silica gel. -72- 1285641 The desired LVI compound, and Chong·Gan#. wherein R, R4, R5, R6, R7 and v are all as above U, and the alternative preparation method can be self-purifying, ^^, corresponding (formula xxxv compound, By reacting with a hydrazine, such as gasification 醯V〇C1, in a falling agent, such as di-methane or gas, depending on the condition, a base, such as _, 疋-propyl propylamine, 4-dimethyl A certain amine or 2,6-di-third-butyl_4_methyl one, in the busy to 6 hours of temperature; 'typically ambient temperature, reached after a period of 24 hours. Typically Under these conditions, when R2 is not hydrogen, the L-lin is preferentially subjected to the (4) function, and the desired compound of the formula W is obtained. The desired compound is round, wherein r1, r2, r4, R5, r6, r7^m, and R3 are as described above, wherein the group V is attached to a linking carbon, and can be obtained from the corresponding formula LVI compound by thiolation or crystallization, using the procedure described above A compound of the formula LIX, wherein r2, R4, R5, R6, and R7 are as defined above, and R3 is as defined above, wherein the group V is attached to a linking carbon, and the alternative preparation method From its corresponding compound of formula XXXV, via a compound of formula LIX, by alkylation with an appropriate alkyl bromide or iodide. Such pitification is typically carried out in a polar solvent such as dimethyl Azide, dimethyl hydrazine and N-methyltetrahydropyrrolone in the presence of a base (eg triethylamine, p-bite, 4-dimethylaminopyridinium, dimethyl leaf (: lake) These reactions are often carried out at ambient temperatures up to about 150 C. Due to the non-reactivity of the porphyrins, it is preferred to heat them at a suitable temperature in a microwave oven. The alkylation can be carried out with various alkyl bromides. For example, an arylmethyl bromide or an α-substituted arylmethyl bromide. Typically, under these conditions, when R2 is not hydrogen, the more unobstructed nitrogen atom of the porphyrin is preferentially alkylated to give the compound of formula LIIX of the formula 92199 - 73 - 1285641. The desired compound of the formula XXXV, wherein R2, R4, R5, R6 and R7 are as defined above, may be prepared from the corresponding resin-bound LIV compound by a strong acid treatment known to those skilled in the art, such as trifluoroethylene. Acetic acid or hydrofluoric acid, as appropriate, in a solvent inert to the reaction, such as methylene chloride or a ^ 4 4 fluoroethylene pattern 6

根據反應圖式6，所要之化合物，其中j為碳，選用之雙 鍵係存在，R3為基團COV，且V、R1、R2、R4、r5、r6及r7 均如上述（被描繪為式LXIII化合物），可藉由醇之氧化作用 ，製自其相應之式LXII化合物。這可藉由熟諳此藝者所習知 之極多種方法達成，例如按L.A· Paquette (編著），^試劑 t John Wiley &amp; Sons，Chichester，England，1995 中所述。例々 ，式LXII化合物可以經活化之氧化錳（IV)處理，在對反應: 惰性之適當溶劑中，譬如四氫，夫喃、乙趟或二氯甲燒 92199 -74- 1285641 C至25°C間之溫度下，典型上為環境溫度，提供所要之式Lxni 產物。 所要之式LXII化合物，其中v、R1、圮、R4、r5、r6及r7 均如上述’可自其相應之式LXI化合物，被製成非對晚異構 物之混合物，其方式是以適當金屬交換劑處理，譬如烷某 鋰化合物，譬如正-丁基鋰或第二·丁基鋰，或烷基鎂_化物 ’譬如異丙基氯化鎂，在對反應為惰性之適當溶劑中，嬖 如四氫呋喃或乙醚，在-i2〇t至〇°c間之溫度下，典型上為_78 C，以提供乙烯基鋰物種，其係接著與式VCH〇適當醛反應 ，在-120°c至CTC間之溫度下，典型上為-78°c至，提供所 要之式LXII產物。在一些情況中，係合宜地添加金屬交換作 用劑於醛與碘化物之混合物中。 所要之式LXI化合物，其中Ri、R2、R4、R5、以及R7均如 上述，可t自其相應之式VIII化合物（按圖式I中所述製成） ，使用 D.H.R. Barton 等人（Tetrahedron Letters 1983 24, 1605)所述之一 般程序’其中係使腙與碘反應，於適當受阻鹼存在下，嬖 如1，1，3,3-四曱基胍’在對反應為惰性之適當溶劑中，譬如四 氫呋喃，在25°C至100°C間之溫度下，典型上為25°C至85°C， 在反應過程中移除溶劑，提供所要之式LXI產物。 所要之式IV化合物，其中L為（Ci &lt;6)烷氧羰基，且v、Rl 、R、R、R、R6及R7均如上述，其替代製備法可以類似關 於自相應式LXI化合物製備式lxii化合物所述之方式達成， 其方式疋以適當金屬交換劑處理，譬如、j；完基經化合物，嬖 如正-丁基鋰或第二-丁基鋰，或烷基鎂鹵化物，譬如異丙基 92199 -75 - 1285641 氯化鎖：’在對反應為惰性之適當溶劑中，譬如四氫咬喃或 乙酸’在-120°C至0°C間之溫度下，典型上為-78。〇，以提供乙 烯基鋰物種，其係接著與適當式VCOL酮反應，在-120°C至0 °C間之溫度下，典型上為-78°C至-23t，提供所要之式IV產物 。在一些情況中，係合宜地添加金屬交換作用劑於酮與碘 化物之混合物中。 作為最初注意事項，在製備化合物時，應注意的是，可用 於製備本文中所述化合物之一部份製備方法，可需要遠距 _ T能基保護（例如，在中間物中之一級胺、二級胺、羧基） 。對於此種保護之需求，係依遠距官能基之性質及製備方 法之條件而改變。對於此種保護之需求，很容易由熟諳此 蟄者決定。此種保護/去除保護方法之利用，亦在此項技藝 之技術範圍内。關於保護基及其利用之一般描述，可參閱 T.W. Greene，直機合成之保護基,John Wiley &amp; Sons，New York 1991。 例如’在反應圖式中，某些化合物含有一級胺類或羧酸官 能基’若保留未經保護，則其可能會干擾分子其他位置處籲 (反應。因此，此種官能基可被適當保護基保護，其可在 後績步驟中被移除。對胺與羧酸保護之適當保護基，包括 常用於肽合成之保護基（譬如，對胺類為N-第三-丁氧羰基、 爷氧羰基及9-苐基亞甲氧基羰基，而對羧酸類為低碳烷基或 +基g旨）’其在所述之反應條件下，通常不具化學反應性， 且典型上可被移除，而不會於化學上改變化合物中之其他 官能基。 本發明化合物之前體藥物可根據熟諳此藝者已知之方法製 92199 -76- 1285641 備。舉例之方法係描述於下文。 其中在化合物羧酸中之羧基係被酯置換之本發明前體藥物 ，可經由使羧酸與適當烷基函化物結合而製成，於鹼存在 下，譬如碳酸鉀，於惰性溶劑中，譬如二甲基甲醯胺，在 約0至100°c之溫度下，歷經約丨至約24小時。或者，使酸與 作為溶劑之適當醇結合，於催化量之酸存在下，譬如濃硫 酸’在約20至100 C之溫度下，較佳係在回流下，歷經約丨小 時至、24小時。另一種方法為酸與化學計量之醇反應，於 催化K酸存在下，在惰性溶劑中，譬如甲苯或四氫呋喃 且伴Ik著藉由物理（例如Dean_Stark集氣瓶）或化學（例如分 子篩）方式移除被產生之水。 ”中醇έ犯基已被行化成醚之本發明前體藥物，可經由使 該醇與適當垸基漠化物或琪化物結合而製成，於驗存在下 ’譬如碳酸_ ’於惰性溶劑中’譬如二甲基甲碰，在約〇 至100°c之溫度下，歷經則至㈣小時。燒賴基f基酸類 可I由醇與雙-(烷醯胺基）甲烷之反應而獲得，於催化量之酸 存在下，於惰性落劑中，譬如四氫呋喃，根據us 中 所述足方法。或者，此等化合物可藉由Hoffoian等人在 1〇rg_ Chem· 1994, 59, 3530中所述之方法製備。 糖甞類係經由該醇與碳水化合物，於惰性溶劑中，譬如甲 苯，於酸存在τ反應而製成。典型上，在反應中形成之水 ，如上述，當其正被形成時，係被移除。一種替代程序為 該醇與纟k適§保護之糖基自化物，於鹼存在下之反應，接 著去除保護。 92199 -77- 1285641 ^㈣細胺類，N__基姆氧羰基） 可經由母體醯胺與適當醛之反應， ， ， ^ 中性或鹼性條件（例如 氧其每内，在乙醇中）’於25與7〇。〇間之溫度下製成。N_垸 =?基或叫貌氧錄基衍生物，可經未經取代化合 而獲得。 ^在下’在惰性溶劑中反應 本發明化合物亦可搭配其他藥劑（例如咖膽固醇降低劑 。、甘油三酯降低劑）使用，以治療本文中所述之疾病/症狀 、例如：其可與祕c〇A還原酶抑制劑、膽固醇合成抑制劑 &amp;固醇吸收抑制劑、Μτρ/Αρ〇 B分泌抑制劑、概尺調制劑 及其他膽固醇降低劑（譬如纖維酸自旨）、Μ酸、離子交換 樹脂、抗氧化劑、ACAT抑制劑及膽汁酸多價整合劑合併使 用。其他藥劑亦包括下列··膽汁酸再攝取抑制劑、迴腸膽 汁酸運輸子抑制劑、ACC抑制劑、抗高血壓藥（譬如N〇RvAs。 、選擇性雌激素受體調制劑、選擇性雄激素受體調制劑、 ，生素、抗糖尿病劑（譬如二〒雙胍（metf〇mun)、ppAR 了活化 劑、％醯脲、胰島素、醛糖還原酶抑制劑（ARI)及花楸醇脫 气-每抑制剑（SDI))及阿斯匹靈（乙醯柳酸）。菸鹼酸之緩慢釋 弋係為了彳于’且被稱為尼阿斯潘例哪如）。於驗酸亦可 ^、/、他療劑合併，譬如制菌素，意即洛伐制菌素（lovastatin) 其係為HMG-CoA還原酶抑制劑，並在下文進一步描述。此 一療去係被稱為八£)VIC〇R® (k〇s醫藥公司）。於組合療法治 療中本發明化合物與其他藥物療法兩者，係藉習用方法 才又予哺礼動物（例如人類，男性或女性）。 92199 -78- 1285641 任何HMG-CoA還原酶抑制劑均可用於本發明之組合方面中 。HMG-CoA還原酶抑制劑一詞，係指化合物會抑制羥甲基戊 二醯基-輔酶A生物轉化成藉由酵素HMG-CoA還原酶所催化之 甲經戊酸。此種抑制係容易地由熟諳此藝者，根據標準檢 測法測得（例如Meth. Enzymol· 1981 ; 71 : 455-509及其中引述之 參考資料）。多種此等化合物係被描述並引用於下文中，但 是，其他HMG-CoA還原酶抑制劑係為熟諳此藝者所已知。美 國專利4,231，938 (其揭示内容係據此併於本文供參考）揭示某 些化合物，其係在歸屬於曲霉屬之微生物培養後經單離， 譬如洛伐制菌素（lovastatin)。美國專利4,444,784 (其揭示内容係 據此併於本文供參考）亦揭示前文所提及化合物之合成衍生 物，譬如辛伐制菌素（simvastatin) ^美國專利4,739,073 (其揭示 内容係併於本文供參考）亦揭示某些經取代之吲嗓，譬如弗 伐制菌素（fluvastatin)。美國專利4,346,227 (其揭示内容係併於 本文供參考）亦揭示ML-236B衍生物，譬如普拉伐制菌素 (pravastatin)。EP-491226A (其揭示内容係併於本文供參考）亦揭 示某些吡啶基二經基庚烯酸，譬如些利伐制菌素（cerivastatin) 。此外，美國專利5,273,995 (其揭示内容係併於本文供參考） 揭示某些6-[2-(取代—比咯小基）烷基]哌喃-2-酮，譬如阿托瓦制 菌素（atorvastatin)，及其任何藥學上可接受之形式（意即 LIPITOR®)。另外之HMG-CoA還原酶抑制劑，包括洛蘇伐制 菌素（rosuvastatin)與皮塔伐制菌素（pitavastatin)。 任何PPAR調制劑可用於本發明之組合方面中。PPAR調制 劑一詞，係指在哺乳動物特別是人類中調制過氧化物酶體 92199 -79- 1285641 增生物活化劑受體（PPAR)活性之化合物。此種調制係容易地 由熟諳此藝者，根據文獻上已知之標準檢測測得。咸認此 種化合物會經由調制PPAR受體，調節涉及脂質與葡萄糖新 陳代謝作用之關键基因之轉錄，譬如在脂肪酸氧化作用中 以及涉及高密度脂蛋白（HDL)组裝者（例如，載脂蛋白AI基因 轉錄），因此降低全身脂肪，並增加HDL膽固醇。由於其活 性，故此等化合物亦可在哺乳動物特別是人類中降低甘油 三酯、VLDL膽固醇、LDL膽固醇及其有關聯成份，譬如載 脂蛋白B之血漿含量，以及增加HDL膽固醇與載脂蛋白AI。 因此，此等化合物可用於治療並矯正經發現與動脈粥瘤硬 化及心血管疾病之發展與發生率有關聯之各種脂血症障礙 ，包括低α脂蛋白症與血甘油三醋過多。多種此等化合物係 被描述並引用於下文中，但是，其他係為熟諳此藝者所已 知。國際公報W0 02/064549與02/064130，及2003年11月24日提 出申請之美國專利申請案10/W0942 (其揭示内容均據此併於 本文供參考），揭示某些PPARa活化劑之化合物。 任何MTP/Apo B (微粒體甘油三酯轉移蛋白質及/或載脂蛋 白B)分泌抑制劑可用於本發明之組合方面中。MTP/Apo B分 泌抑制劑一詞，係指會抑制甘油三酯、膽固醇基酯及磷脂 分泌之化合物。此種抑制係容易地由熟諳此藝者，根據標 準檢測法測得（例如 Wetterau，J.R· 1992 ; Science 258 : 999)。多種 此等化合物係被描述並引用於下文中，但是，其他MTP/Apo B 分泌抑制劑係為熟諳此藝者所已知，包括因普達來得 (imputapride)(Bayer)及其他化合物，譬如在W〇96/40640與 92199 -80- 1285641 W〇98/23593中所揭示者（兩種舉例之公報）。 例如，下列MTP/Apo B分泌抑制劑特別有用： 4'二氟甲基-聯苯基-2-複酸[2-(11^[1，2,4，]三吐&gt;-3-基甲基）-1，2,3,4-四氫-異喳啉-6-基]-醯胺； 三氟甲基-聯苯基-2-羧酸[2-(2-乙醯胺基-乙基）-l，2,3,4-四氫-異喹啉-6-基]-醯胺； (2]6-[(4’-三氟甲基-聯苯基丨羰基 &gt;胺基&gt;3,‘二氫-1H-異喹啉-2-基卜乙基 &gt;胺甲基酸曱酯； 4-二氟甲基-聯苯基_2_羧酸[2-(ih-咪唑-2-基甲基）-1，2,3,4-四氫-異喳啉冬基]-醯胺； 4’_二氟甲基-聯苯基-2-羧酸[2-(2,2-二苯基-乙基）W-四氫異 口奎淋-6_基]-酿胺；及 4-二氟甲基-聯苯基-2-羧酸[2-(2-乙氧基乙基）-i，2,3,4-四氫-異 峻淋-6-基]-騷胺。 任何HMG-CoA合成酶抑制劑均可用於本發明之組合方面中 。HMG-CoA合成酶抑制劑一詞，係指化合物會抑制羥甲基戊 二醯基-輔酶A自藉由酵素hmg-Coa合成酶催化之乙醯基_輔 酶A與乙醯乙醯基-輔酶A之生物合成。此種抑制係容易地由 熟讀此藝者，根據標準檢測法測得（Meth Εη^〇1·丨975 ;乃： 155-160 : Meth· EnzymoL 1985，· 110 ·· 19_26 及其中引述之參考資料） 。多種此等化合物係被描述並引用於下文，但是，其他 HMG-CoA合成酶抑制劑係為熟諳此藝者所已知。美國專利 5，120,729 (其揭示内容係據此併於本文供參考）揭示某些牟内 酿胺衍生物。美國專利5,064,856 (其揭示内容係據此併^本文 92199 -81 - 1285641 供參考）揭示某些經由培養微生物（MF5253)所製成之螺内酯 衍生物。美國專利4,847,271 (其揭示内容係據此併於本文供參 考）揭示某些環氧丙烷化合物，譬如U-(3-羥〒基斗_基_2_環 氧丙燒基）-3,5,7-三甲基-2,4-十一-二烯酸衍生物。 任何會降低HMG-CoA還原酶基因表現之化合物，均可用於 本發明之組合方面中。此等藥劑可為hmg—Coa還原酶轉綠抑 制劑，其會阻斷DNA之轉錄，或轉譯抑制劑，其會預防或 降低對HMG-CoA還原酶進行編碼之轉譯至蛋白質中。 此種化合物可無論是直接影響轉錄或轉譯，或可在膽固醇 生物合成階式反應中，被一或多種酵素生物轉變成具有前 又所提及活性之化合物，或可導致具有前文所提及活性之 異戊二烯新陳代謝產物之蓄積。此種化合物可經由降低 SREBP(固醇受體結合蛋白質)含量，經由抑制位置·i蛋白酶 (sip)之活性，或抗拮歐吉真諾（〇xzgenal)受體或scAp，造成此 作用。此種調節係容易地由熟諳此藝者，根據標準檢測法 測得陶L En聊。!·聰；UQ ·· 9_19)。數種化合物係被描述並φ ㈣於下X ’但是’觀⑽八還原酶基因表現之其他抑制劑 係為熟諳此藝者所已知。美國專利5,〇41，432 (其揭示内容係併 於本又供參考）揭示某些15♦代之羊毛留醇衍生物。會壓抑 MG CoA遂原g每合成〈其他氧化固醇，係經m而(pr〇g· Up·According to the reaction scheme 6, the desired compound, wherein j is carbon, the selected double bond is present, R3 is a group COV, and V, R1, R2, R4, r5, r6 and r7 are as described above (depicted as The LXIII compound) can be prepared from its corresponding compound of formula LXII by oxidation of an alcohol. This can be achieved by a variety of methods known to those skilled in the art, for example as described in L.A. Paquette (eds.), ^Reagents t John Wiley &amp; Sons, Chichester, England, 1995. For example, the compound of formula LXII can be treated with activated manganese (IV) in a suitable solvent for the reaction: inert, such as tetrahydro, phoranyl, acetamidine or methylene chloride 92199 -74-1268941 C to 25°. The temperature between C, typically ambient temperature, provides the desired Lxni product. The desired compound of the formula LXII, wherein v, R1, 圮, R4, r5, r6 and r7 are each as a mixture of the corresponding LXI compounds, which are prepared as a mixture of non-isomers, in a manner appropriate Metal exchanger treatment, such as a lithium compound, such as n-butyl lithium or a second butyl lithium, or an alkyl magnesium compound such as isopropyl magnesium chloride, in a suitable solvent inert to the reaction, such as Tetrahydrofuran or diethyl ether, typically at a temperature between -i2 〇t and 〇 °c, typically _78 C to provide a vinyl lithium species which is then reacted with an appropriate aldehyde of the formula VCH, at -120 ° C to CTC The temperature of the mixture is typically -78 ° C to provide the desired product of the formula LXII. In some cases, it is convenient to add a metal exchange aid to the mixture of aldehyde and iodide. A compound of the formula LXI, wherein Ri, R2, R4, R5, and R7 are as defined above, may be prepared from their corresponding compound of formula VIII (as described in Scheme I) using DHR Barton et al. (Tetrahedron Letters) 1983 24, 1605) The general procedure 'in which the hydrazine is reacted with iodine in the presence of a suitable hindered base such as 1,1,3,3-tetradecyl hydrazine in a suitable solvent inert to the reaction. For example, tetrahydrofuran, at a temperature between 25 ° C and 100 ° C, typically 25 ° C to 85 ° C, removes the solvent during the reaction to provide the desired product of the formula LXI. The desired compound of the formula IV, wherein L is (Ci &lt; 6) alkoxycarbonyl, and v, R1, R, R, R, R6 and R7 are as defined above, and the alternative preparation method can be similarly prepared from the corresponding compound of the formula LXI. The manner of the compound of formula lxii is achieved in such a manner that it is treated with a suitable metal exchanger, such as, for example, a compound, such as n-butyllithium or a second-butyllithium, or an alkylmagnesium halide, For example, isopropyl 92199 -75 - 1285641 Chlorination lock: 'In a suitable solvent inert to the reaction, such as tetrahydroanthracene or acetic acid' at temperatures between -120 ° C and 0 ° C, typically - 78. 〇 to provide a vinyl lithium species which is then reacted with a suitable VCOL ketone to provide the desired product of formula IV at a temperature between -120 ° C and 0 ° C, typically between -78 ° C and -23 t. . In some cases, it is convenient to add a metal exchange agent to the mixture of the ketone and the iodide. As a preliminary precaution, in the preparation of compounds, it should be noted that a method of preparation for the preparation of one of the compounds described herein may require remote _T-energy protection (eg, a primary amine in the intermediate, Secondary amine, carboxyl). The need for such protection varies depending on the nature of the remote functional groups and the conditions of the preparation process. The need for such protection is easily determined by the person skilled in the art. The use of such protection/removal protection methods is also within the skill of the art. For a general description of protecting groups and their use, see T.W. Greene, Protection Group for Direct Synthesis, John Wiley & Sons, New York 1991. For example, 'in the reaction scheme, certain compounds contain a primary amine or a carboxylic acid functional group'. If left unprotected, it may interfere with other positions of the molecule (reactions. Therefore, such functional groups may be suitably protected Base protection, which can be removed in the subsequent steps. Suitable protecting groups for amine and carboxylic acid protection, including protecting groups commonly used for peptide synthesis (for example, N-tertiary-butoxycarbonyl for amines, An oxycarbonyl group and a 9-fluorenylmethoxycarbonyl group, and a carboxylic acid group is a lower alkyl group or a + yl group) which is generally not chemically reactive under the reaction conditions described, and is typically removable In addition, it does not chemically alter other functional groups in the compound. The prodrugs of the compounds of the present invention can be prepared according to methods known to those skilled in the art, and the methods are exemplified below. The prodrug of the present invention in which the carboxyl group in the carboxylic acid is replaced by an ester can be prepared by combining a carboxylic acid with a suitable alkyl group in the presence of a base such as potassium carbonate in an inert solvent such as dimethyl. Formamide, at about 0 At a temperature of 100 ° C, from about 丨 to about 24 hours. Alternatively, the acid is combined with a suitable alcohol as a solvent, in the presence of a catalytic amount of an acid, such as concentrated sulfuric acid, at a temperature of about 20 to 100 C. The best system is under reflux for about 丨hours to 24 hours. Another method is to react an acid with a stoichiometric alcohol in the presence of a catalytic K acid in an inert solvent such as toluene or tetrahydrofuran with Ik by physics. (eg Dean_Stark gas cylinders) or chemical (eg molecular sieves) removal of the water produced. "The prodrugs of the invention which have been converted to ethers by the alcohols and the appropriate sulfhydryl deserts Or a combination of kiwis, in the presence of 'such as carbonic acid _ 'in an inert solvent' such as dimethyl keb, at a temperature of about 〇 to 100 ° C, after a period of up to (four) hours. The base acid I can be obtained by the reaction of an alcohol with bis-(alkylguanidino)methane in the presence of a catalytic amount of an acid in an inert bulking agent, such as tetrahydrofuran, according to the method described in us. Compounds available by Hoffoian et al. at 1〇r Prepared by the method described in g_Chem. 1994, 59, 3530. The glycoside is prepared by reacting the alcohol with a carbohydrate in an inert solvent such as toluene in the presence of τ in the acid. Typically, it is formed in the reaction. The water, as described above, is removed as it is being formed. An alternative procedure is the reaction of the alcohol with the glycosyl-protected glycan-based compound, in the presence of a base, followed by removal of protection. 92199 -77 - 1285641 ^(4) The fine amines, N__kim oxycarbonyl) can be reacted with the parent amide and the appropriate aldehyde, , , ^ neutral or basic conditions (eg oxygen per internal, in ethanol) 'at 25 7〇. Made at the temperature of the day. N_垸=? base or morpho-derivative derivatives, can be obtained by unsubstituted compound. ^The reaction of the present invention in an inert solvent can also be used in combination with other agents (for example, a cholesterol lowering agent, a triglyceride lowering agent) to treat the diseases/symptoms described herein, for example, 〇A reductase inhibitor, cholesterol synthesis inhibitor & sterol absorption inhibitor, Μτρ / Αρ〇B secretion inhibitor, sizing agent and other cholesterol lowering agents (such as fiber acid), citric acid, ion exchange Resins, antioxidants, ACAT inhibitors and bile acid multivalent integrators are used in combination. Other agents include the following · Bile acid reuptake inhibitors, ileal bile acid transporter inhibitors, ACC inhibitors, antihypertensives (such as N〇RvAs., selective estrogen receptor modulators, selective androgens). Receptor modulators, vitamins, anti-diabetic agents (such as metformin, ppAR activator, % guanidine, insulin, aldose reductase inhibitor (ARI) and saponin degassing - Every Sword (SDI) and Aspirin (Acetrine). The slow release of niacin is based on 'and is known as Niaspan'. The acid can also be combined with a therapeutic agent such as bacteriocin, meaning lovastatin, which is an HMG-CoA reductase inhibitor and is further described below. This treatment is called eight £) VIC〇R® (k〇s pharmaceutical company). In combination therapy, both the compound of the present invention and other drug therapies are administered to the animal (e.g., human, male or female) by a conventional method. 92199 - 78 - 1285641 Any HMG-CoA reductase inhibitor can be used in the combination aspect of the invention. The term HMG-CoA reductase inhibitor means that the compound inhibits the biotransformation of hydroxymethylpentyl-coenzyme A to mevalonic acid catalyzed by the enzyme HMG-CoA reductase. Such inhibition is readily detectable by the skilled artisan according to standard assays (e.g., Meth. Enzymol. 1981; 71: 455-509 and references cited therein). A variety of such compounds are described and cited below, but other HMG-CoA reductase inhibitors are known to those skilled in the art. U.S. Patent No. 4,231,938, the disclosure of which is hereby incorporated by reference in its entirety in its entirety in the entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire all U.S. Patent No. 4, 444, 784, the disclosure of which is hereby incorporated by reference in its entirety in its entirety in its entirety in its entirety in its entirety in its entirety in the the the the the the the the Reference) also reveals certain substituted mites, such as fluvastatin. Also disclosed in U. EP-491226A, the disclosure of which is hereby incorporated by reference, also discloses certain pyridyl di-heptenoenoic acids, such as cerivastatin. In addition, U.S. Patent No. 5,273,995, the disclosure of which is incorporated herein by reference in its entirety, the disclosure of the disclosure of the disclosure of the the the the the the the the the the the Atorvastatin), and any pharmaceutically acceptable form thereof (meaning LIPITOR®). Further HMG-CoA reductase inhibitors include rosuvastatin and pitavastatin. Any PPAR modulator can be used in the combined aspects of the invention. The term PPAR modulator refers to a compound that modulates the activity of the peroxisome 92199-79-1285841 bioactivating agent receptor (PPAR) in mammals, particularly humans. Such modulation is readily detectable by those skilled in the art and based on standard detection known in the literature. It is recognized that this compound modulates the transcription of key genes involved in the metabolism of lipids and glucose via modulation of PPAR receptors, such as in fatty acid oxidation and in high-density lipoprotein (HDL) assemblers (eg, apolipoproteins). The AI gene is transcribed), thus reducing systemic fat and increasing HDL cholesterol. Due to their activity, these compounds can also reduce triglycerides, VLDL cholesterol, LDL cholesterol and its related components, such as plasma levels of apolipoprotein B, and increase HDL cholesterol and apolipoprotein AI in mammals, especially humans. . Thus, these compounds are useful in the treatment and correction of various lipid disorders known to be associated with the development and incidence of atheroma hardening and cardiovascular disease, including low alpha lipoproteinemia and hypertriglyceridemia. A variety of such compounds are described and cited below, but others are known to those skilled in the art. U.S. Patent Application Serial No. 10/W094, filed on Nov. 24, 2003, the entire disclosure of which is hereby incorporated by reference inco . Any MTP/Apo B (microsomal triglyceride transfer protein and/or apolipoprotein B) secretion inhibitor can be used in the combination aspect of the present invention. The term MTP/Apo B secretion inhibitor refers to a compound that inhibits the secretion of triglycerides, cholesterol esters, and phospholipids. Such inhibition is readily determined by the skilled artisan according to standard assays (e.g., Wetterau, J. R. 1992; Science 258: 999). A variety of such compounds are described and cited below, however, other MTP/Apo B secretion inhibitors are known to those skilled in the art, including imputapride (Bayer) and other compounds, such as W〇96/40640 and 92919-80-1283541 W〇98/23593 (two examples of publications). For example, the following MTP/Apo B secretion inhibitors are particularly useful: 4' difluoromethyl-biphenyl-2-reacid [2-(11^[1,2,4,]triple &gt;-3-yl) Methyl)-1,2,3,4-tetrahydro-isoindoline-6-yl]-nonylamine; trifluoromethyl-biphenyl-2-carboxylic acid [2-(2-acetamido) -ethyl)-l,2,3,4-tetrahydro-isoquinolin-6-yl]-nonylamine; (2)6-[(4'-trifluoromethyl-biphenylindolecarbonyl) Amine Group&gt;3, 'Dihydro-1H-isoquinolin-2-ylethyl} 胺-aminomethyl methacrylate; 4-difluoromethyl-biphenyl-2-carboxylic acid [2-(ih- Imidazol-2-ylmethyl)-1,2,3,4-tetrahydro-isoporphyrin-m-yl]-decylamine; 4'-difluoromethyl-biphenyl-2-carboxylic acid [2-( 2,2-diphenyl-ethyl)W-tetrahydroiso-hydroxypyridin-6-yl]-bristamine; and 4-difluoromethyl-biphenyl-2-carboxylic acid [2-(2- Ethoxyethyl)-i,2,3,4-tetrahydro-isoindol-6-yl]-sodium amide. Any HMG-CoA synthetase inhibitor can be used in the combination aspect of the present invention. HMG- The term "CoA synthetase inhibitor" refers to a compound which inhibits hydroxymethylpentadienyl-CoA from acetyl-coenzyme A and acetophenone-coenzyme A catalyzed by the enzyme hmg-Coa synthetase. Biosynthesis Ex situ is measured by the standard test method (Meth Εη^〇1·丨975; is: 155-160: Meth· EnzymoL 1985, · 110 ·· 19_26 and references cited therein). Such compounds are described and referenced below, but other HMG-CoA synthetase inhibitors are known to those skilled in the art. U.S. Patent No. 5,120,729, the disclosure of which is hereby incorporated by reference herein Certain intrinsic amine derivatives are disclosed in U.S. Patent No. 5,064,856, the disclosure of which is hereby incorporated by reference in its entirety by reference in its entirety in the entire disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the entire disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of (The disclosure of which is hereby incorporated by reference herein in its entirety by reference in its entirety herein in its entirety in its entirety in in in in in in in in in in in in in in in in in in in in Methyl-2,4-undecenoic acid derivatives Any compound which reduces the expression of the HMG-CoA reductase gene can be used in the combination aspect of the present invention. These agents can be hmg-Coa reductase. a green inhibitor that blocks the transcription of DNA, or a translation inhibitor, which Prevents or reduces the translation of HMG-CoA reductase into a protein. This compound can directly affect transcription or translation, or can be converted to one by one enzyme organism in a cholesterol biosynthesis step reaction. Also mentioned are active compounds which may result in the accumulation of isoprene metabolites having the activities mentioned above. Such a compound can cause this effect by reducing the SREBP (sterol receptor binding protein) content, by inhibiting the activity of the site i-protease (sip), or by the anti-aliasing xzgenal receptor or scAp. This type of adjustment is easily detected by the artist, according to the standard test method. !·聪; UQ ·· 9_19). Several compounds are described and φ(d) are known to those skilled in the art of the lower X', but other (10) eight reductase gene expression. U.S. Pat. Will suppress MG CoA 遂 original g per synthesis <other oxidative sterols, through m (pr〇g· Up·

Res. 1993； 32： 357-416)#^ 〇 任何角㈣合成酶抑制劑均可用於本發明之組合方面中。 1二·希口成酶抑制劑一詞，係指化合物會抑制焦磷酸法呢 “ 2個分子精由酵素角㈣合成酶所催化之縮合以形成角 92199 -82- !285641 i烯。此種抑制係容易地由熟諳此藝者，根據標準檢測法 測得 _h. Enzymol.丨 969 ; 15 : 393-454，與 Meth. Enzymol.丨 985 ; 11〇 :359-373，及其中所含有之參考資料）。多種此等化合物係 被描述並引用於下文，但是，其他角鯊缔合成酶抑制劑係 為熟諳此藝者所已知。美國專利5,〇26,554 (其揭示内容係併於 本文供參考）揭示微生物MF5465 (ATCC74〇11)之發酵產物，包Res. 1993; 32: 357-416) #^ 〇 Any of the angles (4) synthetase inhibitors can be used in the combination aspect of the present invention. 1 2 · Xikou Cheng enzyme inhibitor term, refers to the compound will inhibit the pyrophosphate method "two molecules refined by the enzyme angle (four) synthetase catalyzed condensation to form the angle 92199 -82- !285641 iene. The inhibition system is easily determined by the skilled person, according to the standard test method _h. Enzymol. 丨 969; 15: 393-454, and Meth. Enzymol. 丨 985; 11 〇: 359-373, and contained therein A variety of such compounds are described and cited below, however, other squalal synthase inhibitors are known to those skilled in the art. U.S. Patent 5, 〇26,554 (the disclosure of which is incorporated herein by reference) For reference) to reveal the fermentation product of the microorganism MF5465 (ATCC74〇11), package

括札拉郭吉（zarag0zlc)酸。其他取得專利之角鯊晞合成酶抑制 焚1J 之摘述已被收集（CuiT 〇p pantents (1993) 8614)。Accompanied by the zarag0zlc acid. A summary of other patented horn shark quinone synthase inhibition incinerates 1J has been collected (CuiT 〇p pantents (1993) 8614).

任何角鯊浠環氧酶抑制劑均可用於本發明之組合方面中。 角黨婦環氧酶抑制劑一詞，係指化合物會抑制藉由酵素角 f缔環氧酶催化之K晞與分子氧之生物轉化成角f缔-2,3. 環氧化物。此種抑制係容易地由熟諳此藝者，根據標準檢 測法測得（B10chlm. Bl0phys杨腦；別：466·47ι)。多種I等 化合物係被描述並引㈣下《，但是，其他角^希環氧酶 抑制劑係為熟諳此藝者所已知。美國專利柳，⑽與讽输 (其揭示内容係併於本文供參考)揭示角！稀之某些氟基類 似物嗜公報395,768A(其揭示内容係料本文供參考）揭示 某一 ’·.:取代《缔丙基胺衍生物。pcT公報恥93i2〇69A (其揭 示内容係據此併於本文供參考）揭示某些胺基醇衍生物了美 此二^ /5 U34 (其W内容係據此併於本文供參考）揭示某 些裱丙基氧基-角鯊埽衍生物。 任何角！缔環化酶抑制劑均可在本發明之組合方面中，作 ::二種成份使用。角f缔環化酶抑制劑一詞，係指化合 4制猎由酵素角，“環化酶催化之角笑埽-2&gt;環氧化物 92199 -83- 1285641 (生物轉化成手毛留醇。此種抑制係容易地由熟諸此藝者 ，根據標準檢測法測得（FEBS Lett· 1989; 244: 347_35〇)。此外 下文所描述並引用之化合物係為角鯊烯環化酶抑制劑， 但是，其他角鯊烯環化酶抑制劑亦為熟諳此藝者所已知。％丁 公報W〇9410150 (其揭示内容係據此併於本文供參考）揭示某 些l，2,3,5,6,7,8,8a-八氫-5,5,8(奶―三甲基各異喹啉胺衍生物，譬如 N- |L 6 SI ^ -l,25355?657,858a-A ^ ^ ^ f ^ 異喳啉胺。法國專利公報πάκο(其揭示内容係據此併於本 文供參考）揭示某些反仏二〒基斗六氫吡啶乙醇衍生物，孽 如丨-(1，5,9-三〒基癸基二平基冰六氫吡啶乙醇。 β 任何合併之角鯊烯環氧酶/角鯊晞環化酶抑制劑，均可在 本發明之組合方面中，作為第二種成份使用。合併之角業 缔環氧酶/角鯊烯環化酶抑制劑一詞，係指化合物會抑制角 鯊烯經由角鯊烯-2,3-環氧化物中間物之生物轉化成羊毛留醇 。在一些檢測中，不可能在角笑烯環氧酶抑制劑與角^烯 環化酶抑制劑之間作區別，但是，此等檢測係為熟諳2藝 者所明瞭。因此，藉由合併之角鯊烯環氧酶 抑制敲抑制，係容易地由熟諳此藝者，根據前 關於角農烯環化酶或角鯊缔環氧酶抑制劑之標準檢測而測 知°多種此等化合物係被描述並引用於下文， —丨—疋，具他 用鯊烯環氧酶/角鯊烯環化酶抑制劑係為熟諳此藝者所已知 。美國專利5,084,461與5,278，Π1 (其揭示内容係併於本文供參 考）揭示某些氮十氫莕衍生物。ΕΡ公報468,434 (其揭示内容係 併於本文供參考）揭示某些六氫吡啶基醚與硫基醚衍生物， 92199 -84- 1285641 譬如氫吡啶基）戊基異戊基亞砜與2-(1-六氫吡啶基）乙基 乙硫醚。PCT公報W〇94〇14〇4(其揭示内容係據此併於本文供 參考）揭示某些醯基-六氫吡啶類，譬如Hl_酮基戊基_5_苯硫 基）-4-(2-羥基-l_甲基）·乙基）六氫吡啶。美國專利5，丨〇2,915 (其揭 示内容係據此併於本文供參考）揭示某些環丙基氧基_角鯊烯 衍生物。 本發明化合物亦可與用以降低血漿膽固醇含量之天然生成 化口物口併投藥。此等天然生成之化合物一般稱為保健食 且G括例如大蒜萃取物與於驗酸。於驗酸之緩慢釋出 形式係為可得，且被稱為尼阿斯潘_鄉如）。菸鹼酸亦可與 其他治療劑合併，譬如洛伐制菌素（1〇vastatin)，或另一種為 HMG-CoA還原酶抑制劑。此種與洛伐制菌素之組合療法係被 稱為ADVIC〇RTM(K〇s醫藥公司）。 任何膽固醇吸收抑制劑可在本發明之組合方面中，作為另 一種藥劑使用。膽固醇吸收抑制一詞，係指化合物防止被 包含在腸腔内之膽固醇進入腸細胞中，及/或從腸細胞内通 過進入淋巴系統及/或進入血流中之能力。此種膽固醇吸收 抑制活性係容易地由熟諳此藝者，根據標準檢測法測得㈠列 如J4ld Res· (1993) 34 : 3?㈣）。膽固醇吸收抑制劑係為熟諸 此蟄者所已知，且係描述於例如PCT w〇94/〇〇48〇中。最近認 可之膽固醇吸收抑制劑之實例為zetiaTM(也吉提麥伯 (ezetimibe))(Schering-Pl〇ugh/Merck)。 任何ACAT抑制劑均可用於本發明之組合療法方面中。 ACAT抑制劑’係指化合物會抑制飲食膽固醇被酵素酿 92199 -85 - 1285641 基CoA ♦膽固醇酿基轉移酶之胞内g旨化。此種抑制可容易地 由熟諳此藝者，根據標準檢測法測得，譬如Heider等人在廢 ’妤宏痨办，24 : 1127 (1983)中所述之方法。多種此等化合物 係為熟諳此藝者所已知，例如美國專利5,510,379揭示某些叛 基磺酸酯，而W〇96/26948與W0 96/10559兩案係揭示具有ACa丁 抑制活性之脲衍生物。AC AT抑制劑之實例包括一些化合物 ’譬如亞發西米貝（avasimibe)(Pfizer)、CS-505 (Sankyo)及伊弗西 米貝（Eflucimibe)(Eli Lilly 與 Pierre Fabre)。 脂肪酶抑制劑可用於本發明之組合療法方面中。脂肪酶抑 制劑為一種會抑制飲食甘油三醋或血漿磷脂之代謝分裂成 為自由態脂肪·酸及其相應甘油g旨（例如EL、HL等）之化合物 。於正常生理條件下，脂肪分解係經由兩步騾過程發生， 該過程係涉及脂肪酶之經活化絲胺酸部份基團之酸化作用 。這會導致脂肪酸-脂肪酶半縮醛中間物之產生，然後，其 會被分裂以釋出甘油二酯。在進一步脫醯基作用之後，脂 肪酶-脂肪酸中間物會被分裂，而造成自由態脂防酶、甘油 醋及脂肪酸。在腸中，所形成之自由態脂肪酸與甘油單酯 係被摻入膽汁酸-磷脂微胞中，其係隨後在小腸刷狀緣之層 次下被吸收。微胞最後會以乳糜微粒進入末梢循環中。此 種脂肪酶抑制活性係容易地由熟諳此藝者，根據標準檢測 法測得（例如 Methods Enzymol. 286 : 190-231)。 胰脂肪酶係媒介脂肪酸類在1-與3-碳位置處，自甘油三酉旨 代謝分裂。經攝食脂肪類新陳代謝作用之主要位置，係在 十一指腸與近^空細中藉由膜心肪&quot;酶，其通常係以脂肪類 92199 -86- 1285641 分解所必須之非常過量，分泌於較上方小腸中。由 _係為吸收飲食甘油三醋所需要之主要酵素，故抑制； =台療肥胖及其他相關症狀上，具有利錄。此種騰脂肪 “舌性係谷易地由熟諳此藝者，根據標準檢測法測得 (例如 Methods Enzymol. 286 : 190-231)。 胃脂肪酶為免疫學上3®娃&gt; % 予上獨特之脂肪酶，其係負責大約10至40 %之飲食脂肪類消化。胃脂肪酶係經分泌以回應機械刺激 ，食物之攝食，脂肪餐飲之存在，或藉由交感神經劑分泌 。經攝食脂肪類之胃脂防分解，在觸發腸中胰脂㈣活性 所需要&amp;脂肪酸類提供上’具生理學重要性，且亦對於與 胰機能不全有關聯之多種生理學與病理學症狀中之脂肪吸 收’具重要性。參閱，例如C K. Abrams等人，冢摩肩學， 92, 125 (1987)。此種胃脂肪酶抑制活性係容易地由熟讀此藝 者，根據標準檢測法測得（例如Meth〇ds Enzym〇1· 286 : 19〇_231): 多種胃及/或胰脂肪酶抑制劑係為一般熟諳此藝者所已知 。較佳脂肪酶抑制劑為選自包括制脂菌素、四氫制脂素（奥 麗斯特（orlistat))、威利内酯（valilact〇ne)、酯拉史汀（城咖3如）、 、.’勺必内酉曰（ebelactone) A及約必内酉旨（ebelactone) B之抑制劑。化合 物四氫制脂素為尤佳。脂肪酶抑制劑三氟甲基苯基种冬 氯基-4’-三氟甲基苯基脲，及其相關之各種脲衍生物，係揭 示於美國專利4,405,644中。脂肪酶抑制劑酯拉新（esteracin)係 揭示於美國專利4，189,438與4,242,453中。脂肪酶抑制劑環-〇，〇，_ [(1，6-己烷二基）-雙-(亞胺基羰基）]二肘，及其相關之各種雙（亞 92199 -87- 1285641 229 (1949)中所述製備。 多種胰脂月方酶抑制劑係描述於下文中。胰脂肪酶抑制劑制 脂菌素，（2S，3S，5S，7Z，10Z)-H⑸1 f醯胺基冰f基_戊醯基氧 基]-2-己基-3-羥基-7，10-十六酸内酯，與四氫制脂素（奥麗斯特 (orhstat)) ’（2S，3S，5S)-5-[(S)-2-甲醯胺基-4-f 基-戊醯基氧基]-2•己 基冬羥基-十六酸1，3酸内酯，及其種種經取代之n_甲醯基白 胺酸衍生物與立體異構物，係揭示於美國專利4,598,〇89中。 例如，四氫制脂素係按例如美國專利5,274，143 ; 5,420,305 ; 5,540,917 ;及5,643,874中所述製成。胰脂肪酶抑制劑孔_386 , 1-[4-(2-甲基丙基）環己基&gt;2·[(苯磺醯基）氧基 &gt; 乙酮，及其相關 之種種經取代之磺酸酯衍生物，係揭示於美國專利4,452,813 中。胰脂肪酶抑制劑WAY-121898，4-苯氧基苯基斗甲基六氫 吡啶小基-羧酸酯，及其相關之各種胺基甲酸酯類與藥學上 可接受之鹽，係揭示於美國專利5,512,565 ; 5,391，571及5,6〇2，151 中。胰脂肪酶抑制劑威利内酯（valilact〇ne)及其藉由放線菌菌 種MG147-CF2之微生物培養之製備方法，係揭示於Kitahaia等 人，/也版加也4〇 (11)，1647-1650 (1987)中。胰脂肪酶抑制劑約必 内酯（ebelactone) A與約必内酯（ebelactone) B，及其藉由放線菌菌 種MG7-G1之微生物培養之製備方法，係揭示於Umezawa等人， / 如版加认 33, 1594-1596 (1980)中。約必内酯（ebelactone) A 與 B 在 壓抑甘油單醋形成上之用途，係揭示於1996年6月4日公告 之曰本公開專利案08-143457中。 針對包括高膽固醇血症之血脂肪過多所銷售，且意欲幫助 預防或治療動脈粥瘤硬化之其他化合物，包括膽汁酸多價 92199 -88- 1285641 螯合劑，譬如 Welchol®、Colesdd®、LoCholest® 及 Questran® ;以及 纖維鉍衍生物，譬如Atromid®、Lopid®及丁ricor®。 糖尿病可經由對具有糖尿病（尤其是第㈣）' 胰島素抗藥 性、減弱之葡萄糖容許度、代謝徵候蔟或其類似病症或任 何糖尿病併發症譬如神經病、腎病、視網膜病或白内障之 病患’投予治療上有效量之本發明化合物，且併用可用以 治療糖尿病之其他藥劑（例如胰島素），而加以治療。這包 括本文中所述抗糖尿病劑（及特定藥劑）之種類。 g 任何肝糖磷酸化酶抑制劑可作為第二種藥劑，與本發明化 合物合併使用。肝糖鱗酸化酶抑制劑一詞，係指會抑制藉 由酵素肝糖磷酸化酶所催化之肝糖生物轉化成葡萄糖錢 叙酉旨之化合物。此種肝糖磷酸化酶抑制活性係容易地由孰 讀此藝者’根據標準檢測法測得（例如舰^.仰_ 293棚卜多種肝糖磷酸化酶抑制劑係為熟諳此藝者所已 知，包括W0 96/39384與W0 96/39385中所述者。 任何《還原酶抑制劑均可與本發明化合物併用。 原酶抑制劑一詞，係指會抑 ^ — ^抑制精由酵素醛糖還原酶催化之 匍苟糖生物轉化成花楸醇之化合物。駿糖還原酶抑制係容 易地由熟諳此藝者，根櫨俨、、佳 ^ 贫根據&amp;準檢測法測得（例如】 ML卿賢紅血球花楸醇…㈣尿病㈣之^ 標I多㈣糖還原酶抑制劑係為熟諳此藝者所已知。9 任何花楸醇脫氫酶抑制夺丨於Any of the hornblenon epoxidase inhibitors can be used in the combination aspect of the present invention. The term "party epoxidase inhibitor" refers to a compound that inhibits the conversion of K 晞 and molecular oxygen catalyzed by an enzyme horn b epoxidase to an angole-2,3. epoxide. Such inhibition is easily measured by a person skilled in the art according to standard detection methods (B10chlm. Bl0phys Yang brain; other: 466.47ι). A variety of I compounds have been described and referred to (4), however, other angles of cyclooxygenase inhibitors are known to those skilled in the art. U.S. Patent Liu, (10) and Satirical (the content of which is disclosed in this article) reveals the corner! Some of the fluoro-like analogs, 395, 768A (the disclosure of which is incorporated herein by reference), discloses a &apos;. pcT Communiqué 93i2〇69A (the disclosure of which is hereby incorporated by reference herein in its entirety by reference in its entirety in its entirety herein in its entirety in its entirety in the entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire disclosure Some propyl propyl-squalene derivatives. Any corner! The cyclase inhibitor can be used in the combination of the invention as a two-component. The term f-ring cyclase inhibitor refers to the compound 4 hunted by the enzyme horn, "cyclase-catalyzed horned 埽-2" epoxide 92199-83-1285641 (biotransformation into chlorhexidine). Such inhibition is readily determined by those skilled in the art according to standard assays (FEBS Lett. 1989; 244: 347_35). Furthermore, the compounds described and referenced below are squalene cyclase inhibitors, However, other squalene cyclase inhibitors are also known to those skilled in the art. % Ding K. No. 9410150 (the disclosure of which is hereby incorporated by reference) ,6,7,8,8a-octahydro-5,5,8 (milk-trimethylisoquinolinamine derivatives, such as N- |L 6 SI ^ -l, 25355?657,858aA ^ ^ ^ f ^Isomorpholinamine. The French Patent Gazette πάκο (the disclosure of which is hereby incorporated by reference herein) discloses certain certain bismuthyl hydrazine hexahydropyridine ethanol derivatives, such as 丨-(1,5,9- Trimethyl sulfhydryl-dipyridyl hexahydropyridine ethanol. β Any combined squalene epoxidase/squalene cyclase inhibitor can be used as a second component in the combination aspect of the present invention. The term "bonded epoxidase/squalene cyclase inhibitor" means that the compound inhibits the conversion of squalene to lanolin alcohol via the squalene-2,3-epoxide intermediate. In some tests, it is not possible to distinguish between a cryptoene epoxidase inhibitor and a horn ene cyclase inhibitor, but these tests are known to those skilled in the art. Therefore, by merging Squalene epoxidase inhibits knock inhibition, which is readily detected by the skilled person, based on previous standards for the detection of hornine cyclase or squalene epoxidase inhibitors. It is described and cited below, 丨-疋, which is known to those skilled in the art of squalene epoxidase/squalene cyclase inhibitors. U.S. Patents 5,084,461 and 5,278, Π1 (Disclosed The disclosure of certain nitrogen decahydroquinone derivatives is disclosed in U.S. Pat. No. 468,434, the disclosure of which is incorporated herein by reference in its entirety in its entirety in its entirety in its entirety in 1285641 such as hydrogen pyridyl) amyl isoamyl sulfoxide and 2-(1-hexahydropyridyl) Ethyl ethene ether. PCT Bulletin W〇94〇14〇4, the disclosure of which is hereby incorporated by reference, discloses certain s s s s s s s s s s s s s s s s s s 4-(2-hydroxy-l-methyl)-ethyl)hexahydropyridine. U.S. Patent No. 5, 丨〇 2, 915, the disclosure of which is hereby incorporated by reference herein Base squalene derivatives. The compounds of the invention may also be administered in combination with a naturally occurring mouthwash for lowering plasma cholesterol levels. Such naturally occurring compounds are generally referred to as health foods and include, for example, garlic extracts and Acid test. The slow release form of acid testing is available and is known as Niaspan_乡如). Niacin can also be combined with other therapeutic agents, such as lovastatin (1 vastatin) or the other as an HMG-CoA reductase inhibitor. This combination therapy with lovastatin is called ADVIC® RTM (K〇s Pharmaceuticals). Any cholesterol absorption inhibitor can be used as another agent in the combination aspect of the present invention. The term cholesterol absorption inhibition refers to a compound that prevents the cholesterol contained in the intestinal lumen from entering the intestinal cells and/or the ability to pass through the intestinal lymphocytes into the lymphatic system and/or into the bloodstream. Such cholesterol absorption-inhibiting activity is easily measured by a person skilled in the art according to a standard test method (i) as listed in J4ld Res (1993) 34: 3 (4). Cholesterol absorption inhibitors are known to those skilled in the art and are described, for example, in PCT w〇94/〇〇48〇. An example of a recently recognized cholesterol absorption inhibitor is zetiaTM (ezetimibe) (Schering-Pl〇ugh/Merck). Any ACAT inhibitor can be used in the combination therapy aspect of the present invention. An ACAT inhibitor means that the compound inhibits the intracellular g of cholesterol in the diet by the enzyme 92199 -85 - 1285641-based CoA ♦ cholesterol-based transferase. Such inhibition can be readily determined by those skilled in the art, as measured by standard assays, such as those described by Heider et al., Recycling, 24: 1127 (1983). A variety of such compounds are known to those skilled in the art, for example, U.S. Patent 5,510,379 discloses certain thiol sulfonates, while W 〇 96/26948 and WO 96/10559 disclose urea derivatives having ACa inhibitory activity. Things. Examples of AC AT inhibitors include compounds such as avasimibe (Pfizer), CS-505 (Sankyo), and Eflucimibe (Eli Lilly and Pierre Fabre). Lipase inhibitors can be used in the combination therapy aspect of the invention. The lipase inhibitor is a compound which inhibits the metabolism of dietary triglyceride or plasma phospholipids into free fatty acids and acids and their corresponding glycerols (e.g., EL, HL, etc.). Under normal physiological conditions, lipolysis occurs via a two-step process involving the acidification of the activated serine moiety of the lipase. This results in the production of a fatty acid-lipase hemiacetal intermediate which is then cleaved to release the diglyceride. After further deamination, the lipase-fatty acid intermediate is split, resulting in free lipid defense enzymes, glycerol vinegar and fatty acids. In the intestine, the free fatty acids and monoglycerides formed are incorporated into the bile acid-phospholipid micelles which are subsequently absorbed at the layer of the small intestine brush border. The micelles will eventually enter the peripheral circulation with chylomicrons. Such lipase inhibiting activity is readily determined by the skilled artisan according to standard assays (e.g., Methods Enzymol. 286: 190-231). Pancreatic lipase-mediated vector fatty acids are metabolized from the triglyceride at the 1- and 3-carbon positions. The main position of the metabolism of fat-feeding is in the eleven-neck and near-empty, by the membrane heart fat &quot; enzyme, which is usually a very large excess of the decomposition of fat 92199 -86-1285641, secretion In the upper small intestine. _ is the main enzyme needed to absorb dietary glycerin, so it is inhibited; = Taiwanese obesity and other related symptoms have a good record. This kind of fat is "developed by the artist, according to the standard test method (for example, Methods Enzymol. 286: 190-231). Gastric lipase is immunologically 3® baby&gt;% A unique lipase that is responsible for about 10 to 40% of dietary fat digestion. The gastric lipase is secreted in response to mechanical stimuli, food intake, fat catering, or secretion by sympathetic agents. The anti-decomposition of gastric lipids, which is required to trigger the activity of pancreatic lipids in the intestines, and the provision of fatty acids, is also physiologically important, and is also associated with a variety of physiological and pathological symptoms associated with pancreatic insufficiency. Absorption is of importance. See, for example, C K. Abrams et al., 肩 肩, 92, 125 (1987). This gastric lipase inhibitory activity is easily read by the artist, according to standard test methods. (e.g., Meth〇ds Enzym〇1·286: 19〇_231): A variety of gastric and/or pancreatic lipase inhibitors are known to those skilled in the art. Preferred lipase inhibitors are selected from the group consisting of Lactin, tetrahydrolipid (Orlista) t)), valilactine (valilact〇ne), ester lacastine (city coffee 3), , ''ebelactone' A and ebelactone B inhibitor The compound tetrahydrolipid is particularly preferred. The lipase inhibitor trifluoromethylphenyl amyl chloride-4'-trifluoromethylphenylurea, and various urea derivatives thereof, are disclosed in the United States. Patent 4,405,644. The esterase inhibitor esteracin is disclosed in U.S. Patent Nos. 4,189,438 and 4,242,453. Lipase inhibitors ring-oxime, oxime, _[(1,6-hexanediyl)-double -(Iminocarbonyl)] II elbow, and its associated various bis (described in 921 99 - 87 - 1285641 229 (1949). A variety of pancreatic lipase inhibitors are described below. Pancreatic lipase Inhibitor lipophyllin, (2S, 3S, 5S, 7Z, 10Z)-H(5)1 f guanylamine ice f-based-pentyloxy]-2-hexyl-3-hydroxy-7,10-hexadecanoic acid Lactone, with tetrahydrolipin (orhstat) '(2S,3S,5S)-5-[(S)-2-carbamido-4-fyl-pentanyloxy Base]-2•hexyl winter hydroxy-hexadecanoic acid 1,3 acid lactone, and its various substitutions The n-methionyl leucine derivatives and stereoisomers are disclosed in U.S. Patent No. 4,598, filed to Mar. 89. For example, the tetrahydrolipids are described, for example, in U.S. Patent Nos. 5,274,143; 5,420,305; 5,540,917; and 5,643,874. Prepared. Pancreatic lipase inhibitor pore _386, 1-[4-(2-methylpropyl)cyclohexyl>2·[(phenylsulfonyl)oxy&gt; ethyl ketone, and related A variety of substituted sulfonate derivatives are disclosed in U.S. Patent 4,452,813. Pancreatic lipase inhibitor WAY-121898, 4-phenoxyphenylidenemethylhexahydropyridine small-carboxylate, and various related urethanes and pharmaceutically acceptable salts thereof, are disclosed in U.S. Patents 5,512,565; 5,391,571 and 5,6,2,151. The preparation method of pancreatic lipase inhibitor valilactine and its microbial culture by actinomycetes MG147-CF2 is disclosed in Kitahia et al., / also in addition to 4 〇 (11), 1647-1650 (1987). The preparation method of the pancreatic lipase inhibitor ebelactone A and ebelactone B, and the microorganism culture thereof by the actinomycetes MG7-G1, is disclosed in Umezawa et al. The edition is added 33, 1594-1596 (1980). The use of ebelactone A and B for the inhibition of the formation of glycerol monoacetate is disclosed in Japanese Patent Laid-Open Publication No. 08-143457, filed on Jun. 4, 1996. Other compounds sold for hyperlipidemia, including hypercholesterolemia, and intended to help prevent or treat atherosclerosis, including bile acid polyvalent 92199 -88-1285641 chelating agents such as Welchol®, Colesdd®, LoCholest® and Questran®; and fiber 铋 derivatives such as Atromid®, Lopid® and butyl ricor®. Diabetes can be administered via a disease in patients with diabetes (especially (4)) insulin resistance, impaired glucose tolerance, metabolic syndrome or the like or any diabetic complications such as neuropathy, nephropathy, retinopathy or cataract A therapeutically effective amount of a compound of the invention is administered in combination with other agents (e.g., insulin) that can be used to treat diabetes. This includes the types of anti-diabetic agents (and specific agents) described herein. g Any hepatose phosphorylase inhibitor can be used as a second agent in combination with the compound of the present invention. The term hepatic glucoamylase inhibitor refers to a compound which inhibits the conversion of glycogen biosynthesis to glucose by the enzyme hepatic glycophosphorylase. Such hepatic glycophosphorylase inhibitory activity is easily detected by the artist's method according to standard assays (eg, ^ . 仰 293 shed buds, various hepatic glycophosphorylase inhibitors are known to those skilled in the art) It is known to include those described in WO 96/39384 and WO 96/39385. Any "reductase inhibitor" can be used in combination with the compound of the present invention. The term "proenzyme inhibitor" means inhibiting the essence of the enzyme. A saccharide reductase-catalyzed biotransformation of a glycoside into a compound of sterol. The glycoside reductase inhibitor is readily detectable by the skilled person, the root sputum, and the poorly based &amp; quasi-detection method (eg 】 ML Qingxian red blood cell saponin ... (four) urinary disease (four) ^ standard I (four) sugar reductase inhibitors are known to those skilled in the art. 9 Any sterol dehydrogenase inhibition

&gt; 』&quot;彳均可與本發明化合物併用。花M 醇脫氩S母抑制劑一詞，係p合&amp; ^ 係彳日會抑制藉酵素花楸醇 化之花楸醇生物轉化成果㈤風酶催 &lt;化合物。此種花楸醇脫氫酉每 92199 -89 - 1285641 抑制劑活性係容易地由熟諳此藝者’根據標準檢測法測得 (例如Analyt. Bl0chem (2_卻：329·33丨）。多種花楸醇脫氫酶抑 制劑係為已知，例如美國專利5,72S，7〇4與5,866,578揭示藉由抑 制酵素花楸醇脫氫酶，治療或預防糖尿病併發症之化合物 與方法。&gt;』&quot;彳 can be used in combination with the compound of the present invention. Flower M alcohol de-argon S-suppressant term, the term "p- & ^" will inhibit the biosynthesis of alfalfa by alcoholic alfalfa (5) wind enzymatic &lt; compound. This phytosterol dehydrogenation enthalpy per 92199 -89 - 1285641 inhibitor activity is readily determined by the skilled artisan's according to standard assays (eg Analyt. Bl0chem (2_: 329·33丨). The sterol dehydrogenase inhibitors are known, for example, in U.S. Patent Nos. 5,72,7,7,4,5,866,578, which disclose compounds and methods for treating or preventing diabetic complications by inhibiting enzyme phytosterol dehydrogenase.

任何葡萄糖苷酶抑制劑均可與本發明化合物併用。葡萄糖 苷酶抑制劑會抑制複合碳水化合物藉由糖苷水解酶（例如澱 卷酶或麥芽糖酶）之酶促水解成為生物可利用單純糖，例如 ^萄糖。葡萄糖甞酶之迅速代謝作用，特別是在攝取高含 量之碳水化合物後，會造成一種消化高血糖狀態，其在： 肪或糖尿病患者中’會導致增強之胰島素分泌，增加之脂 肪合成，及降低之脂肪降解^此種高血糖之後，經常^ 出現低血糖，此係由於增大之胰島素含量存在所致。此外 ---&amp;工，升潢5丨赞Any glucosidase inhibitor can be used in combination with the compound of the present invention. Glucosidase inhibitors inhibit the enzymatic hydrolysis of complex carbohydrates by glycoside hydrolases (e. g., lake enzymes or maltase) into bioavailable simple sugars, such as saccharide. The rapid metabolism of glucose chymase, especially after ingesting high levels of carbohydrates, causes a state of hyperglycemia that causes increased insulin secretion, increased fat synthesis, and lowering in: patients with diabetes or diabetes. Fat degradation ^ After this high blood sugar, hypoglycemia often occurs due to the increased insulin content. In addition ---&amp; work, upgrade 5 praise

利於《炎或十二指腸潰瘍之發展。因此，已知葡萄糖 酶抑制劑在加速碳水化合物通過胃及抑制葡萄糖自腸级 上’具有利用性。再者，竣水化合物之轉化成為脂防紐 足脂質’及消化脂肪之^|後併人脂防組織沉積物中，倍 此被降低或延遲，具有降低或預防自其所形成有害異奪 伴隨利益。此種葡萄糖料抑制活性㈣易地由熟請丑 者，根據標準檢測法測得（例如Bl〇chemistry (1969) δ :幻;。 -般較佳葡萄糖《抑制劑係包括澱粉酶抑制劑。澱彩 :制劑為-種葡萄糖甞酶抑制劑，其會抑制澱 酵素降解成麥芽糖。此種殿粉酶抑制活性係容易地㈣ 92199 -90- 1285641 此藝者，根據標準檢測法測得（例如Me_s Enzymd (ΐ955) κ i49) 。此種酵素降解之抑制，在降低生物可利用糖類之量，包 括葡萄糖與麥芽糖’及自其所形成之伴隨有害症狀上，是 有益的。 多種葡萄糖甞酶抑制劑係為一般熟諳此藝者所已知，且實 例係提供於下《。較佳葡萄糖#酶抑制劑為以下抑制劑， ^ I ^ ^ ^ ^ (acarbose) ^ . ^ g #l] ^ (y〇gllb〇se) ^ ^ 葛利妥__、約米葛利特㈣幽則、卡蜜葛利糖（觀_^ 、天達米斯特（tendamistate)、特端制菌素（trestatin)、普拉地米 辛(pmdmncn^Q及沙破制菌素（salb〇statm)。葡萄糖菩酶抑制劑 阿卡糖（acarbose)及其相關之各種胺基糖衍生物，係個別揭示 於美國專利4，G62,95G與4，174,439中。葡萄料酶㈣劑脂解素 ’係揭示於美國專利4,254,256中。葡萄糖:y：酶抑制劑沃葛利 糖（V〇gllb〇Se)，3,4_二去氧嚓基-1.甲基）乙基]胺基&gt;2心 (¾甲基）-D-表-肌醇，及其相關之各種N_取代之擬胺基糖類 ，係揭示於美國專利4,701，559中。葡萄糖甞酶抑制劑米葛利 女（miglitol) ’陣风斗砂:^分經乙基峰腾甲基阳义六氫吡啶 三醇，及其相關之各種3,4,5-三羥基六氫吡啶，係揭示於美 國專利4,639,436中。葡萄糖苷酶抑制劑約米葛利特㈣ ，對-[2-[(211，311，411，53)-3,4,5-三羥基-2-(羥甲基）六氫吡啶基]乙氧 基]-苯甲酸乙酯，其相關之各種衍生物，及其藥學上可接受 之酸加成鹽，係揭示於美國專利5，192,772中。葡萄糖甞酶抑 制劑MDL-25637，2,6-二去氧孚〇仏仏哌喃葡糖基_2,6_亞胺基七一 甘油基-1-葡萄糖基-庚糖醇，其相關之各種均二醣，及其藥 92199 -91 - 1285641 學上可接受之酸加成鹽，係揭示於美國專利4,634,765中。葡 萄糖甞酶抑制劑卡蜜葛利糖（camigiibose)，甲基6-去氧-6-[(211，311，411，53)-3,4,5-三羥基-2-(羥甲基）六氫吡啶基]-1〇-哌喃葡 糖苷倍半水合物，其相關之脫氧諾吉利霉素（nojinmycm)衍生 物，各種其藥學上可接受之鹽及其製備合成方法，係揭示 於美國專利5，157，116與5,504,078中。糖苷酶抑制劑沙玻制菌素 及其相關之各種擬醣，係揭示於美國專利5,091，524中。 多種澱粉酶抑制劑係為一般熟諳此藝者所已知。殿粉酶抑 制劑天達米斯特（tendamistat)及其相關之各種環狀肽，係揭示 於美國專利4,451，455中。澱粉酶抑制劑AI-3688及其相關之各 種環狀多肽，係揭示於美國專利4,623,714中。澱粉酶抑制劑 特瑞制菌素（trestatin)，包括特瑞制菌素（trestatin) A、特瑞制菌 素（trestatin) B及特瑞制菌素（trestatin) C之混合物，及其相關之 各種含海藻糖胺基糖類，係揭示於美國專利4,273,765中。 可作為第二種藥劑，與本發明化合物合併使用之其他抗糖 尿病化合物，包括例如下列：雙縮胍類（例如二甲雙胍 (metformin))、胰島素促分泌素（例如續酿基脲類與胍類）、葛 塔宗（glitazone)、非葛塔宗、PPARt^動劑、PPAR冷催動劑、DPP-IV 之抑制劑、PDE5之抑制劑、GSK-3之抑制劑、胰增血糖素拮 抗劑、f-l，6-BPase 之抑制劑（Metabasis/Sankyo)、GLP-1 / 類似物 (AC 2993，亦稱為乙先素（exendin)-4)、胰島素與胰島素擬似物 (Merck天然產物）。其他實例包括PKC- /5抑制劑與AGE破碎劑。 本發明化合物可與其他抗肥胖劑併用。任何抗肥胖劑可在 此種組合中作為第二種藥劑使用，且實例係提供於本文中 92199 -92- 1285641 。此種抗肥胖活性係容易地由熟諳此藝者，根據此項技藝 中已知之標準檢測法測得。 適當抗肥胖劑，包括苯丙醇胺、麻黃鹼、假麻黃鹼、吩特 明（phentermme)、馬腎上腺素能受體催動劑、載脂蛋白·B分泌 物/微粒眼甘油二g旨轉移蛋白質⑽丁p)抑制劑、 傕動劑、縮膽囊肽-A (CCK-A)催動劑、單胺再吸收抑制劑（例 如希布拉胺（S1bmramme))、擬交感劑、5_羥色胺能劑、類大蔴 甘文體拮抗劑（例如利夢那班（rim〇nabant)(SR441，716A))、多巴 胺催動劑（例如溴麥角環肽）、促黑細胞激素受體類似物、 5HT2c催動劑、黑色素聚集激素拮抗劑、勒帕茄鹼（〇B蛋白 質）、勒帕茄鹼類似物、勒帕茄鹼受體催動劑、高良薑黃素 ^ ^ ^纟曰肪酶抑制劑（例如四氫制脂素，意即奥麗斯特 (〇rllStat))、朋貝辛O^mbesin)催動劑、減食慾劑（例如朋貝辛 (bombesin)催動劑）、神經肽拮抗劑、甲狀腺素擬甲狀腺劑 、脫氯表雄留嗣或其類似物、類皮質糖受體催動劑或拮抗 劑、奥瑞辛（orexin)受體拮抗劑、尿可體素結合蛋白質拮抗劑 、似胰咼血糖激素肽-丨受體催動劑、睫狀神經營養因子（例 如AxokmeTM)、人類刺鼠相關蛋白質（AGRp)、葛瑞林（ghrdin) 文體拮抗劑、組織胺3受體拮抗劑或逆催動劑、神經激素u 受體催動劑等。 任何擬甲狀腺劑可作為第二種藥劑，與本發明化合物合併 使用。此種擬甲狀腺活性係容易地由熟諳此藝者，根據標 準檢測法測得（例如，動脈粥瘤硬化（丨996) 126 : 53_63)。多種 擬甲狀腺劑係為熟諳此藝者所已知，例如美國專利4,766，121 92199 -93 - 1285641 ；4,826,876 ； 4,910,305 ； 5,061,798 ； 5,284,971 ； 5,401,772 ； 5,654,468 :及5,569,674中所揭示者。其他抗肥胖劑包括希布拉胺 (sibutramine)，其可按美國專利4,929,629中所述製成，與溴麥角 環肽，其可按美國專利3,752,814與3,752,888中所述製成。 本發明化合物亦可與其他抗高血壓劑合併使用。任何抗高 血壓劑均可在此種組合中作為第二種藥劑使用，且實例係 提供於本文中。此種抗高血壓劑活性係容易地由熟諳此藝 者，根據標準檢測法測得（例如血壓度量法）。 目前市售含有抗高血壓劑之產物實例，包括鈣通道阻斷劑 ，譬如 Cardizem®、Adalat®、Calan®、Cardene®、Covera®、Dilacor® 、DynaCirc®、Procardia XL®、Sular®、Tiazac®、Vascor®、Verelen® 、Isoptin®、Nimotop®、Norvasc® 及 Plendil® ;血管收縮素轉化酶（ACE) 抑制劑，譬如 Accupril®、Altace®、Captopril®、Lotensin®、Mavik® 、Monopril®、Prinivil®、Univasc®、Vasotec® 及 Zestril®。 骨質疏鬆症為一種系統性骨骼疾病，其特徵為低骨頭質量 與骨頭組織退化，伴隨著骨頭脆度與對骨折易感受性之繼 起增加。在美國，此症狀每年影響超過2千5百萬人，且造 成超過1百30萬件骨折，包括每年500,000件脊椎，250,000件 髖部，及240,000件手腕骨折。髖部骨折為骨質疏鬆症之最嚴 重結果，其中5-20%之病患係在一年内瀕臨死亡，且超過50 %之存活者為殘障。 年長者係處於骨質疏鬆症之最大危險下，因此，預測此問 題會隨著人口老化而顯著地增加。預測全世界之骨折發生 率，在下一個60年内會增加三倍，且一項研究已估計在2050 92199 -94- 1285641 年全世界將有4百50萬件髖部骨折。 女性係比男性處於骨質疏鬆症之較大危險下。女性係在斷 經後五年期間，經歷激烈加速之骨質耗損。增加此危險之 其他因素，包括抽煙、酒精濫用、久坐工作生活型態及低 爹弓攝取。 熟諳此藝者將明瞭抗耗損劑（例如黃體製劑、多膦酸鹽、 雙膦酸鹽、雌激素催動劑/拮抗劑、雌激素、雌激素/黃體 製劑組合、Premarin®、雌酮、雌三醇或17 α-或17 /3-乙決雌二 醇），可搭配本發明之化合物使用。 舉例之黃體製劑可得自商業來源，且包括：阿皆斯酮 (algestone)乙酿苯、阿瑞謹傑特（altrenogest)、19-去甲氯地孕酮 酷酸鹽、安那傑斯酮（anagestone)錯酸鹽、氯馬地農（chlormadinon) 醋酸鹽、異炔諾、可若傑斯酮（clogestone)醋酸鹽、甲氯地孕 酮、迪馬定酮（delmadinone)醋酸鹽、地索傑斯瑞（desogestrel)、 二甲炔睪g同、地卓傑斯酮（dydrogesterone)、乙諾酮（ethynerone) 、雙酯決諾酮、乙通傑斯瑞（etonogestrel)、氟傑斯酮（flurogestone) 醋酸鹽、傑斯塔可酮（gestaclone)、傑斯托定（gestodene)、傑斯 托諾酮（gestonorone)己酸鹽、傑斯三嗣（gestrinone)、鹵基黃體酮 、己酸經孕酮、左旋甲基決諾酮、來臬史催醇（lynestrenol)、 美卓傑斯酮（medrogestone)、甲孕酮酷酸鹽、甲連孕酮（melengestrol) 醋酸鹽、甲諾二醇（methynodiol)二醋酸鹽、炔諾酮、醋炔諾酮 、異块諾酮、語傑斯美特（norgestimate)、諾傑斯托美（norgestomet) 、曱基決語酮、嗣基傑斯酮（oxogestone)苯丙酸鹽、黃體酮、 環戊決諾酮、奎傑斯酮（quingestrone)及提傑斯醇（tigestol)。 92199 -95 - 1285641 較佳黃體製劑為甲孕酮、炔諾酮及異炔諾酮。 舉例之骨質耗損抑制多膦酸鹽，包括揭示於美國專利 3,683,080中之多膦酸鹽類型，其揭示内容係併於本文供參考 。較佳多膦酸鹽為孿二膦酸鹽（亦被稱為雙—膦酸鹽）。太魯 宗酸鹽（tHudronate)二制為尤佳多膦酸鹽。愛邦宗（ibandr〇mc)酸 為尤佳多膦酸鹽。阿連宗酸鹽（alendronate)與瑞辛宗酸鹽 (resmdronate)為尤佳多膦酸鹽。卓列宗（z〇ledr〇mc)酸為尤佳多膦 酸鹽。其他較佳多膦酸鹽為6番基小羥基_亞己基·雙膦酸與 1-¾基-3-(甲基戊基胺基亞丙基_雙膦酸。多膦酸鹽可以酸或 可溶性驗金屬鹽或驗土金屬鹽之形式投藥。多騰酸鹽之可 水解酯類係同樣地被包括。特殊實例包二 膦酸、甲燒二騰酸、戊燒·^基_u_二膦酸、甲燒二氯1膦 鉍、T U基二騰酸、乙垸々·胺基•二膦酸、乙燒_2·胺基_ 1，1-—膦酸、丙烷各胺基4•羥基_丨山二膦酸、 如一騰酸、丙一基 -膦酸、苯基胺基甲燒二膦酸、Ν，Ν•二f胺基甲垸二膦酸、 Ν彻乙基）胺基？垸二膦酸、丁统趙基+經基^二膊酸 △戊乂士胺基+超基从二膦酸、己垸谷胺基小經基十^二膦 酸及其藥學上可接受之酯類及鹽類。 士丄。之本發明之化合物可與哺乳動物雌激素催動劑/ 全人、彳&quot;併任何雌激素催動劑/拮抗劑均可用於本發明之 、且&quot;万面中。雌激素催動劑/拮抗劑-詞，係指會與雌激素 =體=合，抑制骨質轉換，及/或防止骨質耗損之化合物:、 -〈雌激素催動劑係於本文中被定義為能夠在哺乳 92199 -96- 1285641 動物組織中結合至雌激素受體部位，並模仿雌激素在一或 多種組織中之作用之化學化合物。雌激素拮抗劑係於本文 中被定義為能夠在哺乳動物組織中結合至雌激素受體部位 ’並阻斷雌激素在一或多種組織中之作用之化學化合物。 此種活性係容易地藉由熟諳此藝者，根據標準檢測法測得 ，包括雌激素受體結合檢測，標準骨頭組織形態測定與光 密度計方法，及EnksenRF·等人，骨頭組織形態測定法，Raven 出版社，New Y〇rk，1994,第1-74頁；GnerS.J,等人，雙能量乂·射線 吸光測定法在動物中之用途，Inv· Radi〇L，1996, 31⑴：5〇_62 ; Wahner H.W.與Fogelman I”骨質疏鬆症評估：臨床實務上之雙能 畺X射，·泉吸光測足法，Martin Dunitz公司，London，1994,第1-2%頁） 。多種此等化合物係被描述並引用於下文。 另一種較佳雌激素催動劑/拮抗劑為3-(4屮义二苯基-丁小 烯基）-苯基）-丙烯酸，其係揭示於wms〇n等人，内分泌學， 1997，138, 3901-3911 中。 另一種較佳雌激素催動劑/拮抗劑為他摩西吩（tam〇xifen): (乙胺，2-(-4-(1，2-二苯基小丁烯基）苯氧基）-N，N-二甲基，⑺士，羥 基1，2,3-丙纟元二竣酸鹽（丨·· 1))及其相關化合物，其係揭示於 美國專利4,536,5丨6中，其揭示内容係併於本文供參考。 另一種相關化合物為4-羥基他摩西吩（tam〇xifen)，其係揭示 於美國專利4,623,660中，其揭示内容係併於本文供參考。 幸乂佳雌激素催動劑/拮抗劑為端洛西吩（也^丨制e):(甲_，（6_ 趙基1(4-羥苯基）苯并问嘍吩各基）(4-(2_(1·六氫吡啶基）乙氧基） 苯基）-鹽酸鹽），其係揭示於美國專利4,4丨8,〇68中，其揭示内 92199 -97- 1285641 容係併於本文供參考。 另一種較佳雌激素催動劑/拮抗劑為托里米吩（t〇remifene): (乙胺，2-(4-(4-氯基_1，2_二苯基小丁缔基）苯氧基）-N，N-二甲基_， (ZK2-羥基-丨，2,3-丙烷三羧酸鹽（丨：1))，其係揭示於美國專利 4,996,225中，其揭示内容係併於本文供參考。 另一種較佳雌激素催動劑/拮抗劑為先特咣（centchr〇man): 1-(2-((4-(-甲氧基-2,2-二甲基-3-苯基-咬冬基苯氧基乙基 &gt;四氫 吡咯，其係揭示於美國專利3,822,287巾，其揭示㈣係併於 本文供參考。亦較佳者為列弗滅西吩（lev〇nnd〇xi_。 另一種較佳雌激素催動劑/拮抗劑為愛多西吩（id〇xifene): (E)+(2-(4-(H4-碘笨基&gt;2_苯基叮+缔基）_苯氧基）_乙基 &gt;四氫说 咯酮，其係揭示於美國專利4,839，155中，其揭示内容係併於 本文供參考。 另:種較佳雌激素催動劑/括抗劑為2_(4_甲氧基_苯基^卜 (2-穴虱吡呢-1-基-乙氧基）_苯氧基]_苯并间嚙吩各醇，立係揭 示於美國專利5,卿58中，其揭示内容係併於本文供參考。 、另/種較料激素催_ /拮抗劑為6·_基.苯基）邻_(2_ -虱峨m-乙乳基)_字I)_茶_2_醇，其係揭示於美國專利 5,484,795中，其揭示内容係併於本文供參考。· ^ #] ^ (4_(2_(2_^ ^ ^ ^ ^ 庚-2-基)-乙氧基)_苯基)_(崎基邻名基_苯基)_苯并_吩冬 基）甲酮，其伴心著製備方法被揭示於歸屬於时取公司之％丁 公報 W0 95/10513 中。 其他較佳雌激素催動劑/结抗劑，包括化合物TSE_ 92199 -98- 1285641 424 (Wyeth-Ayerst 實驗室）與阿唑西吩（araz〇xlfene)。 其他較佳雌激素催動劑/拮抗劑包括如共同歸屬之美國專 利5,552,412中所述之化合物，其揭示内容係併於本文供參考 。其中所述之尤佳化合物為： 順式-6-(4-氟苯基）-5-(4-(2-六氫吡啶小基-乙氧基）_苯基）-5,6,7,8-四氫-莕-2-醇； (·)-順式各笨基-5-(4-(2-四氫吡咯小基_乙氧基）_苯基）-5,6,7,8-四 氲-秦-2-醇（亦稱為拉素西吩（ias〇£〇xifene)); 順式-6-苯基-5-(4-(2-四氫吡咯_ι·基-乙氧基苯基）-5,6,7,8-四氫_ 奈-2-醉； 順式小(6’-四氫吡咯乙氧基1吡啶基）-2-苯基+羥基-丨^洚四 氫萘； 四氫吡咯乙氧基苯基）_2-(4，L轨苯基）各經基义2,3头四氫 異口奎淋； 順式各(4-羥苯基）々(4-(2-六氫吡啶小基-乙氧基）-苯基）-5,6,7,8-四氫莕-2-醇；及 四氫吡咯乙氧基苯基&gt;2•苯基各羥基义2,3头四氫異喳啉。 其他雌激素催動劑/拮抗劑係描述於美國專利4，133,8丨4 (其 揭示内容係併於本文供參考）中。美國專利4，133,814揭示2•苯 基各万醯基-苯并噻吩與2-苯基·3_芳醯基苯并噻吩+氧化物之 衍生物。 可作為第二種藥劑，與本發明化合物合併使用之其他抗骨 質疏鬆劑，包括例如下列：甲狀旁腺激素（pTH)(骨頭合成代 謝劑）；甲狀旁腺激素（PTH)促分泌素（參閱，例如美國專利 92199 -99- 1285641 6,132,774) ’特別是鈣受體拮抗劑；降血鈣素；及維生素〇與 維生素D類似物。 任何選擇性雄激素受體調制劑（SARM)均可與本發明化合物 併用。選擇性雄激素受體調制劑（SARM)為一種具有雄激素 活性且會施加組織選擇性作用之化合物。SARM化合物可充 作雄激素党體催動劑、部份催動劑、部份拮抗劑或拮抗劑 。適當SARM之實例，包括一些化合物，譬如環丙氯地孕酮 醋酸鹽、氯馬地農（chlormadinon)、弗如醯胺（flutamide)、羥基 弗如酸胺（hydroxyflutamide)、二卡如驢胺（bicalutamide)、尼如醯 胺(nilutamide)、螺甾内酯、4-(三氟甲基）-2(lH)-四氫吡咯基[3,2-g] 峡淋衍生物、1，2-二氫吡啶并[5,6-g]4啉衍生物及六氫吡啶基 [3,2-g]口奎口林酮衍生物。 西普特酮(cypterone)，亦稱為（ib，2b)-6-氯基-1，2-二氫-17-羥基-3 H-環丙[1，2]孕-1，4,6-三缔-3,20-二酮，係揭示於美國專利3,234,093 中。氯馬地農（chlormadinon)，亦稱為17-(乙醯氧基）-6-氯基孕-4,6-二烯-3,20-二酮’呈其醋酸鹽形式，係充作抗雄激素，且係 揭示於美國專利3,485,852中。尼如酸胺（nilutamide)，亦稱為5,5_ 二甲基_3-[4-硝基各(三氟甲基）苯基]-2,4-四氫咪唑二酮，且商 標名為Nilandron®，係揭示於美國專利4,097,578中。弗如醯胺 (flutamide)，亦稱為2-甲基-N-[4-硝基-3-(三氟甲基）苯基]丙醯胺 ，且商標名為Eulexin®，係揭示於美國專利3,847,988中。二卡 如醯胺（bicalutamide)，亦稱為4’-氰基-a，，a，，a，-三氟-3-(4-氟苯基磺 醯基）-2-經基-2-甲基戊酮-間-甲苯胺，且商標名為Casodex®， 係揭示於EP-100172中。二卡如醯胺之對掌異構物係由Tucker 92199 -100- 1285641 與 Chesterton，tWW. CT^m, 1988, 31，885-887 討論。經基弗如酿胺 (hydroxyflutamide)為一種在大部份組織中之已知雄激素受體拮 抗劑，已被指出充作SARM，藉由成骨細胞，提供對於IL-6 生產之作用，如在H〇ft&gt;auer等人乂及天以.丨999, 14, 1330-1337中所揭示者。其他SARM已揭示於美國專利6,017,924 ; W〇 01/16108、W〇 01/16133、W〇 01/16139、W〇 02/00617、W0 02/16310 、美國專利申請案US 2〇02/0099096、美國專利申請案公報 US 2003/0022868、W0 03/011302 及 W0 03/011824 中。所有上述參 考資料均據此併於本文供參考。 上述化合物之起始物質與試劑，亦易於取得或可容易地由 熟諳此藝者使用有機合成之習用方法合成。例如’許多本 文中使用之化合物係關於或衍生自其中有很大科學重要性 與商業需求之化合物，且因此許多此種化合物係為市購可 得或被報告於文獻中，或容易地藉由文獻上所報告之方法 ，製自其他一般可取得之物質。 本發明之一些化合物或在其合成上之中間物’係具有不對 稱碳原子，因此係為對掌異構物或非對映異構物。非對峡 異構混合物可以其物理化學差異為基礎’藉本質上已知之 方法，例如藉層析及/或分級結晶，被分離成其個別非對峡 異構物。對掌異構物可以下述方式分離，例如對掌性HPLC 方法，或使對掌異構混合物經由與適當光學活性化合物（例 如醇）反應而被轉化成非對映異構混合物，將非對映異構物 分離，並使個別非對映異構物轉化（例如水解）成其相應之 純對掌異構物。化合物或在其合成上之中間物之含有酸性 92199 -101 - 1285641 或鹼性部份基團之對掌里M，，曰 田 構此合物，亦可被分離成其相應 、屯好旱兴構物，其方式是形成Α井與 ,1 疋/风，、先學上純對掌性鹼或酸（例 二二基-乙胺或酒石酸)之非對映異構物鹽，並藉由分級結 …非對映異構物，接著是中和作用，以使鹽分解，因 2提供其相應之純對掌異構物。所有此種異構物，包括非 ^映^構物、對掌異構物及其混合物，對所有本發明化合 π ’均被認為是本發明之—部份’包括本發明之化合 兹一本發明（一些化合物亦為非向性異構物(例如經取代之 耳外万基類）’且被認為是本發明之一部份。 更明確言之，本發明化合物可以對掌異構上富含形式獲得 ’其方式是將最後化合物或其合成上中間物之外消旋物解 析，於不對稱樹脂（較佳為㈤细頂⑽或〇D(得自對掌性技 術’EXt〇n’Pennsylvania))上採用層析（較佳為高壓液相層析法 [HPLC])，具有包含烴(較佳為庚烷或己烷)之流動相，含有〇 與塌間之異丙醇（較佳係在2與職之間），及〇與洸間之 坭基胺（較佳為〇·1%二乙胺）。使含產物之溶離份濃縮，獲 得所要之物質。 本發明 &lt; 一些化合物為酸性，且其係形成與藥學上可接受 :離子之鹽。本發明之一些化合物為鹼性，且其係形成與 樂學上可接受陰離子之鹽。所有此種鹽均在本發明之範圍 内且其可藉習用方法製備，譬如將酸性與鹼性本體，通 常以化學計量比，在無論是水性、非水性或部份水性媒質 中^按適當方式合併。此等鹽係無論是藉由過濾，藉由與 非落劑疋沉澱作用，接著過濾，藉由蒸發溶劑，或在水溶 92199 -102- 1285641 液之情況中，藉由；東乾，按適當方式回收。化合物可經由 溶解於適當溶劑中，譬如乙醇、己炫*或水/乙醇混合物，以 結晶形式獲得。 此外，當本發明化合物形成水合物或溶劑合物時，其亦在 本發明之範圍内。 本發明之化合物、其前體藥物及此種化合物與前體藥物之 鹽，均適合治療用途，作為在哺乳動物特別是人類中抑制 膽固醇酯轉移蛋白質活性之藥劑。因此，本發明之化合物 會在哺乳動物特別是人類中，提高血漿HDL膽固醇、其有關 聯成份及藉由彼等所表現之功能。由於其活性，故此等藥 劑亦會在哺乳動物特別是人類中，降低甘油三酯、VLDL膽 固醇、Apo-B、LDL膽固醇及其有關聯成份之血漿含量。再 者，此等化合物可用於使LDL膽固醇與HDL膽固醇均衡化。 因此，此等化合物可用於治療並矯正經發現與動脈粥瘤硬 化及心血管疾病之發展與發生率有關聯之各種脂血症障礙 ，包括冠狀動脈疾病、冠狀心臟疾病、冠狀血管疾病、末 梢血管疾病、低α脂蛋白症、高/3脂蛋白症、血甘油三醋過 多、高膽固醇血症、家族性高膽固醇血症、低HDL及有關聯 之成份、提高之LDL及有關聯之成份、提高之Lp⑻、提高之 小稠密LDL、提高之VLDL及有關聯之成份，及正餐後脂血 症。 再者，將功能性CETP基因引進缺乏CETP之動物（老鼠）中 ，會造成降低之 HDL 含量（Agellon，L.B·等人：/· 5幻/. (1991) 266 : 10796-10801)，及對動脈粥瘤硬化之增加易感染性（Marotti， 92199 -103 - 1285641 K.R.等人：Mziwre (1993) 364 : 73-75)。以抑制性抗體抑制 CETP 活性，亦在大頰鼠（Evans，G.F.等人：腐：T砑究廣办（1994) 35 : 1634-1645)與兔子（Whitlock，M.E.等人：/ C/z&gt;z. /πν如·（1989) 84 : 129-137)中提升HDL-膽固醇。使用針對CETP mRNA之反有意義寡 脫氧核苷酸，藉由靜脈内注射以壓抑增加之血漿CETP，會 在經餵食膽固醇之兔子中降低動脈粥瘤硬化（Sugano, M.等人 :/· C/zem. (1998) 273 ·· 5033-5036)。重要的是，由於基因突 變而缺乏血漿CETP之人類病患，係具有顯著提高之血漿HDL-膽固醇含量與載脂蛋白A-I，其係為HDL之主要脫輔基蛋白 成份。此外，大部份係展示顯著減少之血衆LDL膽固醇與載 脂蛋白B (LDL之主要載脂蛋白成份（Inazu，A.，Brown，M.L.，Hesler， C.B·等人：J· MM. (1990) 323: 12344238))。 在具有心血管、腦血管及末梢血管疾病發展之血液中，於 HDL膽固醇與HDL有關聯脂蛋白含量間之負相關，及甘油三 酯、LDL膽固醇及其有關聯載脂蛋白間之正相關之下，本發 明化合物、其前體藥物及此種化合物與前體藥物之鹽，由 於其藥理學作用，故可用於動脈粥瘤硬化及其有關聯疾病 狀態之預防、遏制及/或退化。其包括心血管病症（例如絞 痛、絕血、心臟絕血及心肌梗塞）、由於心血管疾病療法所 致之併發症（例如再灌注損傷與血管母細胞再狹窄）、高血 壓、與高血壓有關聯之經提高心血管危險、中風、與器官 移植有關聯之動脈粥瘤硬化、腦血管疾病、認知力機能障 礙（包括但不限於動脈粥瘤硬化續發之癡呆症、短暫腦絕血 發作、神經變性、神經元缺乏及阿耳滋海默氏疾病之延遲 92199 -104- 1285641 展開或行進）、提高含量之氧化性壓力、提高含量之c-反應 性蛋白質、代謝徵候簇及提高含量之HbAlC。 由於廣泛地與提高之HDL含量有關聯之有利作用，故一種 因其HDL增加能力而在人類中抑制CETP活性之藥劑，亦在 許多其他疾病領域中提供有價值之治療手段。 因此，在本發明化合物、其前體藥物及此種化合物與前體 藥物之鹽，經由膽固醇酯轉移之抑制而改變脂蛋白組合物 之能力下，其可用於治療與糖尿病有關聯之血管併發症， 與糖尿病有關聯之脂蛋白異常，及與糖尿病及血管疾病有 關聯之性機能障礙。血脂肪過多係存在於患有糖尿病之大 部份病患中（Howard，B.V· 1987. J_ Lipid Res· 28, 613)。即使是在正 常脂質含量存在下，糖尿病患者係經歷心血管疾病之較大 危險（Kannel W.B.與 McGee，D.L. 1979.糖尿病護理，2, 120)。已知 CETP所媒介之膽固醇基酯轉移在胰島素依賴性（Bagdade，J.D·， Subbaiah，P.V.與 Ritter，M.C. 1991. Eur. J. Clin. Invest. 21，161)與非胰島 素依賴性糖尿病（Bagdade· J.D.，Ritter，M.C·，Lane，J·及 Subbaiah· 1993· 動脈粥瘤硬化104, 69)兩者中異常增加。已有人指出膽固醇轉 移之異常增加會造成較具致粥瘤性之脂蛋白組成上之改變 ’特別是 VLDL 與 LDL (Bagdade，J.D.，Wagner，J.D.，Rudel，L丄·及 Clarkson, T.B. 1995. J. Lipid Res. 36, 759)。此等變化未必會在例行 脂質篩檢期間發現。因此，本發明可用於降低由於糖尿病 症狀所造成之血管併發症之危險。 所述之藥劑可用於治療肥胖及與肥胖有關聯之高心血管危 險。在人類（Radeau，T·，Lau，P·，Robb，M·，McDonnell，M·，Ailhaud，G,及 92199 -105 - 1285641Conducive to the development of inflammation or duodenal ulcer. Therefore, it is known that glucosidase inhibitors have utility in accelerating the passage of carbohydrates through the stomach and inhibiting glucose from the intestinal level. Furthermore, the conversion of hydrophobic compounds into fat-resistant lipids and digestive fats is followed by reduction or delay in the deposition of human lipids, which has the effect of reducing or preventing the formation of harmful impurities. interest. Such glucose inhibitory activity (IV) is easily measured by a standard test method (for example, Bl〇chemistry (1969) δ: illusion; - generally preferred glucose "inhibitors include amylase inhibitors. Color: The preparation is a glucose chymase inhibitor, which inhibits the degradation of the enzyme to maltose. This inhibitory activity of the enzyme is easily (4) 92199 -90 - 1285641. This artist measured according to the standard test method (for example, Me_s Enzymd (ΐ955) κ i49). This inhibition of enzyme degradation is beneficial in reducing the amount of bioavailable sugars, including glucose and maltose, and the accompanying harmful effects formed by them. It is known to those skilled in the art, and examples are provided below. The preferred glucose #enzyme inhibitor is the following inhibitor, ^ I ^ ^ ^ (acarbose) ^ . ^ g #l] ^ (y 〇 gllb〇se) ^ ^ Glitto __, 约米格利特(四) 幽,卡蜜葛糖 (view _^, tendamistate, trestatin, Pratimisine (pmdmncn^Q and sputum sputum (salb〇statm). The inhibitor acarbose and its related various amino sugar derivatives are disclosed in U.S. Patent Nos. 4, G62, 95G and 4,174,439. The grape enzyme (tetra) leptin' system is disclosed in the US patent. 4,254,256. Glucose: y: enzyme inhibitor wagril (V〇gllb〇Se), 3,4-dideoxyindolyl-1.methyl)ethyl]amine&gt;2 heart (3⁄4 methyl -D-table-inositol, and its various N-substituted pseudo-amino sugars, are disclosed in U.S. Patent 4,701,559. Glucose chymase inhibitor Migitol's gusty sand :^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Glit (4), p-[2-[(211,311,411,53)-3,4,5-trihydroxy-2-(hydroxymethyl)hexahydropyridinyl]ethoxy]-benzoic acid Esters, their various derivatives, and their pharmaceutically acceptable acid addition salts are disclosed in U.S. Patent 5,192,772. Glucosidase inhibitor MDL-25637, 2,6-dideoxyfluorene Gentamicin glucosyl 2,6_ Aminos-seven glyceryl-1-glucosyl-heptitol, the related various saccharides, and the pharmaceutically acceptable acid addition salts thereof, 92199-91 - 1285641, are disclosed in U.S. Patent 4,634,765. Glucosidase inhibitor camigiibose, methyl 6-deoxy-6-[(211,311,411,53)-3,4,5-trihydroxy-2-(hydroxymethyl) Hexahydropyridyl]-1 〇-glucopyranoside sesquihydrate, related to nojinmycm derivatives, various pharmaceutically acceptable salts thereof, and methods for their preparation and synthesis, disclosed in the United States Patent Nos. 5,157,116 and 5,504,078. The glycosidase inhibitor, spirulina and its related various saccharides, are disclosed in U.S. Patent 5,091,524. A variety of amylase inhibitors are known to those skilled in the art. Tendamistat and its related cyclic peptides are disclosed in U.S. Patent 4,451,455. The amylase inhibitor AI-3688 and its associated various cyclic polypeptides are disclosed in U.S. Patent 4,623,714. Amylase inhibitor trestatin, including a mixture of trestatin A, trestatin B, and trestatin C, and related Various trehalose-containing saccharides are disclosed in U.S. Patent 4,273,765. Other anti-diabetic compounds which can be used as a second agent in combination with the compounds of the present invention include, for example, the following: bifolds (e.g., metformin), insulin secretagogues (e.g., continuation ureas and terpenoids) , glitazone, glitazone, PPARt^, mobilizer, PPAR cold agonist, inhibitor of DPP-IV, inhibitor of PDE5, inhibitor of GSK-3, glucagon antagonist, Fl, an inhibitor of 6-BPase (Metabasis/Sankyo), GLP-1 / analogue (AC 2993, also known as exendin-4), insulin and insulin mimics (Merck natural product). Other examples include PKC-/5 inhibitors and AGE breakers. The compounds of the invention may be used in combination with other anti-obesity agents. Any anti-obesity agent can be used as a second agent in such a combination, and examples are provided herein in 92199 - 92 - 1285641. Such anti-obesity activity is readily measured by those skilled in the art, according to standard assays known in the art. Suitable anti-obesity agents, including phenylpropanolamine, ephedrine, pseudoephedrine, phentermme, equine adrenergic receptor agonist, apolipoprotein B secretion/microparticle glycerol Transferring protein (10) butyl p) inhibitor, mobilizing agent, cholecystokinin-A (CCK-A) priming agent, monoamine reuptake inhibitor (such as sbmramme), sympathomimetic, 5 - serotonergic agents, cannabinoids (such as rim〇nabant (SR441, 716A)), dopamine agonists (such as bromocriptine), melatonin receptor analogues , 5HT2c agonist, melanin-concentrating hormone antagonist, leptin (〇B protein), leptin analogue, leptin receptor agonist, galangin, ^ ^ 纟曰 酶Agents (eg, tetrahydrolipids, meaning 奥rllStat), ponsin O^mbesin) agonists, anorectic agents (eg, bombesin mobilizers), neuropeptides Antagonist, thyroxine thyroid stimulant, dechlorinated episode or its analog, corticosteroid receptor agonist or antagonist, Oresin Orexin) receptor antagonist, urinary voxel binding protein antagonist, pancreatic glycohormone peptide-丨 receptor agonist, ciliary neurotrophic factor (eg AxokmeTM), human squirrel-associated protein (AGRp), grelin (ghrdin) Stimulant antagonist, histamine 3 receptor antagonist or inverse agonist, neurohormone u receptor agonist, and the like. Any thyroid agent can be used as a second agent in combination with the compounds of the present invention. Such a pseudothyroid activity is readily measured by standard methods (e.g., atherosclerosis (丨 996) 126: 53_63). A variety of thyroid stimulating agents are known to those skilled in the art, for example, as disclosed in U.S. Patent Nos. 4,766,121, 92,199, 199, 218, 046, 4, 826, 876, 4, 910, 305, 5, 061, 798, 5, 284, 971, 5, 401, 772, 5, 654, 468, and 5, 569, 674. Other anti-obesity agents include sibutramine, which can be made as described in U.S. Patent No. 4,929,629, and to bromo ergoline, which can be prepared as described in U.S. Patent Nos. 3,752,814 and 3,752,888. The compounds of the invention may also be combined with other antihypertensive agents. Any anti-hypertensive agent can be used as a second agent in such a combination, and examples are provided herein. Such antihypertensive agent activity is readily measured by standard methods (e. g., blood pressure measurements) by those skilled in the art. Examples of products containing antihypertensive agents currently available, including calcium channel blockers such as Cardizem®, Adalat®, Calan®, Cardene®, Covera®, Dilacor®, DynaCirc®, Procardia XL®, Sular®, Tiazac® , Vascor®, Verelen®, Isoptin®, Nimotop®, Norvasc® and Plendil®; angiotensin-converting enzyme (ACE) inhibitors such as Accupril®, Altace®, Captopril®, Lotensin®, Mavik®, Monopril®, Prinivil ®, Univasc®, Vasotec® and Zestril®. Osteoporosis is a systemic skeletal disorder characterized by low bone mass and bone tissue degradation, accompanied by increased bone brittleness and subsequent susceptibility to fracture. In the United States, this condition affects more than 25 million people each year and causes more than 1.3 million fractures, including 500,000 spines per year, 250,000 hips, and 240,000 wrist fractures. Hip fractures are the most serious result of osteoporosis, with 5-20% of patients dying within one year and more than 50% of survivors being disabled. The elderly are at the greatest risk of osteoporosis, so it is predicted that this problem will increase significantly as the population ages. The incidence of fractures worldwide is predicted to triple in the next 60 years, and a study has estimated that there will be 4.5 million hip fractures worldwide in 2050 92199 -94 - 1285641. Women are at greater risk of osteoporosis than men. Females experienced intensely accelerated bone loss during the five years following menstruation. Other factors that increase this risk include smoking, alcohol abuse, sedentary work and life, and low sacral ingestion. Those skilled in the art will be aware of anti-wear agents (eg, corpus luteum preparations, polyphosphonates, bisphosphonates, estrogen agonists/antagonists, estrogens, estrogen/luteal preparations, Premarin®, estrone, females). Triol or 17 alpha- or 17/3-ethylestradiol) can be used in conjunction with the compounds of the invention. Exemplary corpus luteum preparations are available from commercial sources and include: algestone, arsenic, altenogest, 19-demethylprednisolone, anazesone (anagestone) acid salt, chlormadinon acetate, isolino, clogestone acetate, clopidogrel, delmadinone acetate, ground Desogestrel, dimethyl alkyne g, dydrogesterone, ethynerone, diesterolone, etonogestrel, fluorojesone ( Fluoragestone) acetate, gestaclone, gestodene, gestonorone hexanoate, gestrinone, haloprogesterone, caproic acid Progesterone, L-methyl quinolone, lynestrenol, medrogestone, medroxyprogesterate, melengestrol acetate, carnotol Methynodiol) diacetate, norethisterone, norethisterone, iso-nolone, norgestimate ), norgestomet, thioglycol ketone, oxogestone phenylpropionate, progesterone, cyclopentanone, quingestrone and tigels Alcohol (tigestol). 92199 -95 - 1285641 The preferred corpus luteum preparations are medroxyprogesterone, norethisterone and norethisterone. Exemplary bone depletion inhibiting polyphosphonates, including the polyphosphonate type disclosed in U.S. Patent No. 3,683,080, the disclosure of which is incorporated herein by reference. Preferred phosphinates are phosphonium diphosphonates (also known as bis-phosphonates). Thudronate is a eupolyphosphonate. Ibandr 〇mc acid is a particularly good polyphosphonate. Alendronate and resmdronate are particularly preferred polyphosphonates. The acid of z〇ledr〇mc is a good polyphosphonate. Other preferred polyphosphonates are hexanyl small hydroxy-hexylene bisphosphonic acid and 1-3⁄4yl-3-(methylpentylamino propylene bisbisphosphonic acid. The polyphosphonate may be acid or It can be administered in the form of a soluble metal salt or a soil-measuring metal salt. The hydrolyzable esters of the dodecanoate are similarly included. Special examples include diphosphonic acid, carbaryl, pentane ketone _u_ Phosphonic acid, toluene dichloride, 1 phosphine, TU-based sulphate, acetoin-amino-diphosphonic acid, ethion-2, amine _ 1,1-phosphonic acid, propane, amine 4 Hydroxy 丨 二 bisphosphonic acid, such as a nicotinic acid, propyl-based-phosphonic acid, phenylamino-methyl bisphosphonate, hydrazine, hydrazine, bis-aminomethyl bisphosphonate, decyl ethylamine ? Bismuth diphosphonic acid, butyl sulphate + sulphate succinyl acid △ 乂 乂 胺 + 超 超 超 超 超 超 超 超 超 从 及其 及其 及其 及其 及其 及其 及其 及其 及其 及其 及其 及其 及其 及其 及其 及其 及其Esters and salts. Gentry. The compounds of the present invention can be used in conjunction with mammalian estrogen agonists/whole humans, 彳&quot; and any estrogen agonist/antagonist can be used in the present invention. Estrogen agonist/antagonist-word refers to a compound that binds to estrogen = body, inhibits bone turnover, and/or prevents bone loss: - The estrogen agonist is defined herein as A chemical compound that binds to the estrogen receptor site in mammalian 92199-96-1285941 animal tissue and mimics the action of estrogen in one or more tissues. An estrogen antagonist is defined herein as a chemical compound that binds to the estrogen receptor site in mammalian tissues and blocks the action of estrogen in one or more tissues. Such activity is readily measured by standard methods, including estrogen receptor binding assays, standard bone histomorphometry and densitometer methods, and EnksenRF et al., bone histomorphometry. , Raven Press, New Y〇rk, 1994, pp. 1-74; GnerS. J, et al., Dual Energy X-ray Absorption Spectrometry for Use in Animals, Inv· Radi〇L, 1996, 31(1): 5 〇_62 ; Wahner HW and Fogelman I” Assessment of Osteoporosis: Dual-energy X-rays in Clinical Practice, Spring Absorbing Method, Martin Dunitz, London, 1994, 1-2%). Such compounds are described and cited below. Another preferred estrogen agonist/antagonist is 3-(4屮diphenyl-butenyl)-phenyl)-acrylic acid, which is disclosed in wms 〇n et al., Endocrinology, 1997, 138, 3901-3911. Another preferred estrogen agonist/antagonist is tam〇xifen: (ethylamine, 2-(-4-() 1,2-diphenyls-butenyl)phenoxy)-N,N-dimethyl, (7), hydroxy 1,2,3-propanoid dicaprate (丨·· 1)) Its related compounds are disclosed in U.S. Patent No. 4,536,5, the disclosure of which is incorporated herein by reference. 4, 623, 660, the disclosure of which is incorporated herein by reference. Fortunately, the estrogen agonist/antagonist is leucine (also known as e): (A_, (6_Zhaoji 1 (4-hydroxyl) Phenyl)benzophenanyl)(4-(2-(1·hexahydropyridinyl)ethoxy)phenyl)-hydrochloride), which is disclosed in U.S. Patent 4,4,8, In 68, it discloses the contents of 92199-97-1285841 and is incorporated herein by reference. Another preferred estrogen agonist/antagonist is tormimethomate: (ethylamine, 2-(4) -(4-Chloro-1,2-diphenylbutylbutanyl)phenoxy)-N,N-dimethyl-, (ZK2-hydroxy-indole, 2,3-propane tricarboxylate (丨: 1)), which is disclosed in U.S. Patent No. 4,996,225, the disclosure of which is incorporated herein by reference. 2-((4-(-methoxy-2,2-dimethyl-3-phenyl-t-butyl benzene) Ethylethyl&gt;tetrahydropyrrole, which is disclosed in U.S. Patent No. 3,822,287, the disclosure of which is incorporated herein by reference in its entirety in its entirety in its entirety in its entirety in its entirety in its entirety. The estrogen agonist/antagonist is id〇xifene: (E)+(2-(4-(H4-iodophenyl)&gt;2_phenylindole+conazole)-phenoxy _Ethyl&gt; tetrahydrofuranone, which is disclosed in U.S. Patent 4,839,155, the disclosure of which is incorporated herein by reference. Another: a preferred estrogen stimulant / antagonist is 2_(4-methoxy-phenyl^b (2-azepine-1-yl-ethoxy)-phenoxy]-benzene In the case of singularity, the singularity is disclosed in U.S. Patent No. 5, PCT, the disclosure of which is incorporated herein by reference. </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; · ^ #] ^ (4_(2_(2_^ ^ ^ ^ ^ hept-2-yl)-ethoxy)-phenyl)_(akisaki ortho-phenyl)_benzo-phenyl-phenyl) The ketone, which is accompanied by the preparation method, is disclosed in the publication of the company Ding K. Other preferred estrogen agonists/resistances include the compounds TSE_92199-98-1285641 424 (Wyeth-Ayerst Laboratories) and arazox xlfene. Other preferred estrogen agonists/antagonists include those described in U.S. Patent No. 5,552,412, the disclosure of which is incorporated herein by reference. The preferred compound described therein is: cis-6-(4-fluorophenyl)-5-(4-(2-hexahydropyridine small-ethoxy)phenyl)-5,6,7 , 8-tetrahydro-indole-2-ol; (·)-cis-styl-5-(4-(2-tetrahydropyrrole small group-ethoxy)-phenyl)-5,6,7 , 8-tetramethyl-Qin-2-ol (also known as ias〇£〇xifene); cis-6-phenyl-5-(4-(2-tetrahydropyrrole_ι·) -Ethyloxyphenyl)-5,6,7,8-tetrahydro-naphthalene-inducible; cis-small (6'-tetrahydropyrroleethoxyl pyridyl)-2-phenyl+hydroxyl -丨^洚tetrahydronaphthalene; tetrahydropyrroleethoxyphenyl)_2-(4,L- orbital phenyl) each having 2,3 heads of tetrahydroiso-hydroxyquinone; cis-form (4-hydroxybenzene) (々)(4-(2-hexahydropyridine small-ethoxy)-phenyl)-5,6,7,8-tetrahydroindol-2-ol; and tetrahydropyrroleethoxyphenyl&gt; 2 phenyl hydroxy group 2, 3 tetrahydroisoindoline. Other estrogen agonists/antagonists are described in U.S. Patent 4,133,8, the disclosure of which is incorporated herein by reference. U.S. Patent No. 4,133,814 discloses the disclosure of 2,phenyl benzyl benzyl benzothiophene and 2-phenyl·3 aryl benzothiophene + oxide. Other anti-osteoporosis agents which can be used as a second agent in combination with the compounds of the present invention include, for example, the following: parathyroid hormone (pTH) (bone anabolic agent); parathyroid hormone (PTH) secretagogue (See, for example, U.S. Patent No. 92,199 -99 - 12,856, 421, 6, 134, 774) 'In particular, calcium receptor antagonists; calcitonin; and vitamin bismuth and vitamin D analogs. Any selective androgen receptor modulator (SARM) can be used in combination with the compound of the present invention. The selective androgen receptor modulator (SARM) is a compound that has androgenic activity and exerts a tissue selective action. SARM compounds can act as androgen motility agents, partial agonists, partial antagonists or antagonists. Examples of suitable SARMs include compounds such as cyproterone acetate, chlormadinon, flutamide, hydroxyflutamide, bis-carbamide ( Bicalutamide), nilutamide, spirolactone, 4-(trifluoromethyl)-2(lH)-tetrahydropyrrolidin[3,2-g] gorcose derivative, 1,2- Dihydropyrido[5,6-g]4 morphine derivatives and hexahydropyridyl [3,2-g] quinone derivatives. Cypterone, also known as (ib, 2b)-6-chloro-1,2-dihydro-17-hydroxy-3 H-cyclopropene [1,2]pregnant-1,4,6 Tris--3,20-dione is disclosed in U.S. Patent 3,234,093. Chlormadinon, also known as 17-(acetoxy)-6-chloropregna-4,6-diene-3,20-dione, is in the form of its acetate Androgen, and is disclosed in U.S. Patent 3,485,852. Nilutamide, also known as 5,5-dimethyl-3-[4-nitro(trifluoromethyl)phenyl]-2,4-tetrahydroimidazoledione, and trade name Nilandron® is disclosed in U.S. Patent 4,097,578. Flutamide, also known as 2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]propanamide, and trade name Eulexin®, is disclosed in the United States. Patent 3,847,988. Bicalutamide, also known as 4'-cyano-a, a, a, -trifluoro-3-(4-fluorophenylsulfonyl)-2-yl-2- Methyl pentanone-m-toluidine, under the trade name Casodex®, is disclosed in EP-100172. The ruthenium of ruthenium ruthenium is discussed by Tucker 92199 -100-1285641 and Chesterton, tWW. CT^m, 1988, 31, 885-887. Hydroxyl fluoride, a known androgen receptor antagonist in most tissues, has been identified as a SARM, providing osteoblasts for IL-6 production, such as H〇ft&gt;auer et al., et al., 丨999, 14, 1330-1337. Other SARMs are disclosed in U.S. Patent No. 6,017,924; W〇01/16108, W〇01/16133, W〇01/16139, W〇02/00617, W0 02/16310, U.S. Patent Application US 2〇02/0099096, USA Patent application publications US 2003/0022868, WO 03/011302 and WO 03/011824. All of the above references are hereby incorporated by reference. The starting materials and reagents of the above compounds are also readily available or can be readily synthesized by conventional methods of organic synthesis by those skilled in the art. For example, 'many of the compounds used herein are related to or derived from compounds in which there is significant scientific importance and commercial need, and thus many such compounds are commercially available or reported in the literature, or readily by The methods reported in the literature are made from other generally available materials. Some of the compounds of the present invention or intermediates in their synthesis have an asymmetric carbon atom and are therefore a para-isomer or diastereomer. Non-isotropic complexes can be separated into their individual non-isotropic isomers by methods known per se, such as by chromatography and/or fractional crystallization, on the basis of their physicochemical differences. The palmomers may be separated in the following manner, for example, by a palmitic HPLC method, or by converting a palm-isomeric mixture to a diastereomeric mixture by reaction with a suitable optically active compound (e.g., an alcohol). The isomers are separated and the individual diastereomers are converted (e.g., hydrolyzed) to their corresponding pure palmomers. The compound or the intermediate in its synthesis contains acidic 92199 -101 - 1285641 or the basic part of the pair of palms M, the composition of the field, can also be separated into their corresponding, good haze a structure in which a well is formed, 1 疋/wind, and a diastereomeric salt of pure palmitic acid or acid (such as bis-ethylamine or tartaric acid) is first learned by Fractionation ... diastereomers, followed by neutralization to decompose the salt, as 2 provides its corresponding pure palmomer. All such isomers, including non-images, palmomerisomers and mixtures thereof, are considered to be part of the invention for all combinations of the invention π' including a combination of the invention Invention (Some compounds are also non-tropisomers (e.g., substituted otic bases)' and are considered to be part of the invention. More specifically, the compounds of the invention may be heterogeneous for palm The inclusion form is obtained by analyzing the final compound or its synthetic intermediate racemate, in an asymmetric resin (preferably (5) fine top (10) or 〇D (from the palm technology 'EXt〇n' Pennsylvania)) using chromatography (preferably high pressure liquid chromatography [HPLC]) with a mobile phase comprising a hydrocarbon (preferably heptane or hexane) containing hydrazine and isopropyl alcohol Preferably, the product is between 2 and 2, and the mercaptoamine (preferably 1% diethylamine) between the hydrazine and the hydrazine. The dissolved fractions of the product are concentrated to obtain the desired substance. The present invention &lt;some The compound is acidic and is formed into a pharmaceutically acceptable: ionic salt. Some of the compounds of the invention are bases. Sexually, and which forms a salt with a grammatically acceptable anion. All such salts are within the scope of the invention and may be prepared by conventional methods, such as acidic and basic bodies, usually in stoichiometric ratios, Whether in aqueous, non-aqueous or partially aqueous media, combined in a suitable manner, whether by filtration, by precipitation with a non-dropping agent, followed by filtration, by evaporation of the solvent, or in water, 92199 -102- 1285641 In the case of liquid, it is recovered in an appropriate manner by means of Donggan. The compound can be obtained in a crystalline form by dissolving in a suitable solvent such as ethanol, hexahydrogen or water/ethanol mixture. When the compound of the invention forms a hydrate or solvate, it is also within the scope of the invention. The compounds of the invention, prodrugs thereof and salts of such compounds and prodrugs are suitable for therapeutic use, as in mammals It is an agent that inhibits the activity of cholesterol ester transfer proteins in humans. Therefore, the compounds of the present invention increase plasma HDL cholesterol in mammals, especially humans, Associated ingredients and functions exhibited by them. Due to their activity, these agents also reduce plasma levels of triglycerides, VLDL cholesterol, Apo-B, LDL cholesterol and their related components in mammals, especially humans. Further, these compounds can be used to equalize LDL cholesterol and HDL cholesterol. Therefore, these compounds can be used to treat and correct various lipids found to be associated with the development and incidence of atherosclerosis and cardiovascular disease. Diabetes disorders, including coronary artery disease, coronary heart disease, coronary vascular disease, peripheral vascular disease, low alpha lipoprotein, high / 3 lipoproteinemia, hypertriglyceridemia, hypercholesterolemia, familial hypercholesterolemia Symptoms, low HDL and associated components, elevated LDL and associated components, improved Lp(8), improved small dense LDL, improved VLDL and associated components, and post-meal lipemia. Furthermore, introduction of a functional CETP gene into animals lacking CETP (mouse) results in a reduced HDL content (Agellon, LB et al.: / 5 illusion / (1991) 266: 10796-10801), and Increased atherosclerosis is susceptible to infection (Marotti, 92199 - 103 - 1285641 KR et al.: Mziwre (1993) 364: 73-75). Inhibition of CETP activity by inhibitory antibodies is also observed in large cheeks (Evans, GF et al.: Corruption: T. (1994) 35: 1634-1645) and rabbits (Whitlock, ME et al.: / C/z > z. /πν如·(1989) 84 : 129-137) promotes HDL-cholesterol. Using anti-significant oligodeoxynucleotides against CETP mRNA, by intravenous injection to suppress increased plasma CETP, reduces atherosclerosis in rabbits fed cholesterol (Sugano, M. et al.: /· C/ Zem. (1998) 273 ·· 5033-5036). Importantly, human patients lacking plasma CETP due to gene mutations have significantly increased plasma HDL-cholesterol levels and apolipoprotein A-I, which is the major apoprotein component of HDL. In addition, most of the lines show a significant reduction in blood LDL cholesterol and apolipoprotein B (the main apolipoprotein component of LDL (Inazu, A., Brown, ML, Hesler, CB. et al.: J. MM. (1990) ) 323: 12344238)). In blood with cardiovascular, cerebrovascular and peripheral vascular disease development, there is a negative correlation between HDL cholesterol and HDL-related lipoprotein content, and a positive correlation between triglyceride, LDL cholesterol and its associated apolipoprotein. The compounds of the present invention, prodrugs thereof and salts of such compounds and prodrugs, because of their pharmacological action, are useful for the prevention, containment and/or degradation of atherosclerosis and its associated disease states. It includes cardiovascular disorders (such as colic, blood loss, cardiac arrhythmia, and myocardial infarction), complications due to cardiovascular disease therapy (such as reperfusion injury and restenosis of hemangioblasts), hypertension, and hypertension Associated with increased cardiovascular risk, stroke, atherosclerosis associated with organ transplantation, cerebrovascular disease, cognitive dysfunction (including but not limited to dementia with atherosclerotic sequelae, transient cerebral seizures) , neurodegeneration, neuronal deficiency and delay of Alzheimer's disease 92199 -104-1285641 development or progression), increased levels of oxidative stress, increased levels of c-reactive protein, metabolic syndrome and increased content HbAlC. Because of the beneficial effects associated with increased HDL levels, an agent that inhibits CETP activity in humans due to its increased ability to HDL also provides valuable therapeutics in many other disease areas. Therefore, the compound of the present invention, a prodrug thereof, and a salt of such a compound and a prodrug can be used for the treatment of vascular complications associated with diabetes by the ability to alter the lipoprotein composition via inhibition of cholesteryl ester transfer. , lipoprotein abnormalities associated with diabetes, and sexual dysfunction associated with diabetes and vascular disease. Hyperlipidemia is present in most patients with diabetes (Howard, B.V. 1987. J_ Lipid Res. 28, 613). Diabetes patients experience greater risk of cardiovascular disease, even in the presence of normal lipid levels (Kannel W. B. and McGee, D.L. 1979. Diabetes Care, 2, 120). It is known that CETP-mediated cholesteryl ester transfer is insulin dependent (Bagdade, JD·, Subbaiah, PV and Ritter, MC 1991. Eur. J. Clin. Invest. 21, 161) and non-insulin dependent diabetes (Bagdade· JD, Ritter, MC·, Lane, J. and Subbaiah 1993. Atherosclerosis 104, 69) An abnormal increase in both. It has been suggested that an abnormal increase in cholesterol metastasis will result in a change in the composition of the more atherogenic lipoproteins - particularly VLDL and LDL (Bagdade, JD, Wagner, JD, Rudel, L丄· and Clarkson, TB 1995. J). Lipid Res. 36, 759). These changes are not necessarily found during routine lipid screening. Therefore, the present invention can be used to reduce the risk of vascular complications due to symptoms of diabetes. The agents described can be used to treat obesity and the high cardiovascular risk associated with obesity. In humans (Radeau, T., Lau, P., Robb, M., McDonnell, M., Ailhaud, G, and 92199-105-1285641

McPherson，R·, 1995·腐：T 蛘芜廣办.36 (12) : 2552-61)與非人類靈 長類動物（Quinet，E.，Tall, A” Ramakrishnan，R·及 Rudel，L·，1991·蕊居 哿究癀τΥ . 87 (5) : 1559-66)兩者中，對於CETP之mRNA係在高 程度下表現於脂肪組織中。脂肪信息係隨著脂肪進食 (Martin，L. J·，Connelly，P. W·，Nancoo, D.，Wood, N·，Zhang，Z· J·，Maguire，G.， Quinet，E.，Tall，A. R·，Marcel，Y. L·及 McPherson，R” 1993.廢貧好龙廣 办.34 (3) : 437-46)而增加，且係被轉譯至功能性轉移蛋白質 中，並經過分泌，顯著地幫助血漿CETP含量。在人類脂肪 細胞中，大多數膽固醇係由血漿LDL與HDL提供（Fong, B· S·與 Angel，A·，1989·及1004(1): 53-60)。HDL 膽 固醇基酯之吸收大部份係視CETP而定（Benoist，F·，Lau，P·， McDonnell，M·，Doelle，H·，Milne，R·及 McPherson，R·，1997·立# 必學廣 疗.272 (38) ·· 23572-7)。CETP刺激HDL膽固醇基吸收之此種能 力，在肥胖患者中，與HDL之增強結合至脂肪細胞相結合 (Jimenez，I G·，Fong，B·，Julien, P.，Despres，J· P·，Rotstein，L.及 Angel，A·，1989· 鐵縻粑犀廣办· 13 (5) : 699-709)，指出對於CETP之角色，不僅 是在此等病患中產生低HDL表現型，亦經由促進膽固醇蓄積 而發展肥胖本身。因此，會阻斷此過程之CETP活性抑制劑 ，係充作會造成體重減少之飲食療法之有用佐劑。 CETP抑制劑可用於治療由於革蘭陰性敗血病與敗血性休 克所致之發炎。例如，革蘭陰性敗血病之系統毒性大部份 係由於内毒素所致，其為一種自細菌外部表面釋出之脂多 糖（LPS)，其會造成廣泛之炎性回應。脂多糖可形成與脂蛋 白之複合物（Ulevitch，R.J.，Johnston，A.R·及 Weinstein，D.B·，1981. J· Clin. 92199 -106- 1285641McPherson, R., 1995·Corruption: T 蛘芜 广.36 (12): 2552-61) and non-human primates (Quinet, E., Tall, A) Ramakrishnan, R· and Rudel, L· 87 (5): 1559-66) In both cases, the mRNA of CETP is expressed in adipose tissue at a high degree. The fat information system is fed with fat (Martin, L. J., Connelly, P. W., Nancoo, D., Wood, N., Zhang, Z. J., Maguire, G., Quinet, E., Tall, A. R., Marcel, Y. L. And McPherson, R" 1993. Apocalypse Leung Long Guang. 34 (3): 437-46) increased, and was translated into functional transfer proteins, and secreted, significantly help plasma CETP content. In human adipocytes, most cholesterol is provided by plasma LDL and HDL (Fong, B. S. and Angel, A., 1989 and 1004(1): 53-60). Most of the absorption of HDL cholesterol esters depends on CETP (Benoist, F·, Lau, P·, McDonnell, M·, Doelle, H., Milne, R. and McPherson, R·, 1997·立# Learn to treat.272 (38) ·· 23572-7). This ability of CETP to stimulate HDL cholesterol-based absorption is combined with enhanced adhesion of HDL to adipocytes in obese patients (Jimenez, IG., Fong, B., Julien, P., Despres, J.P., Rotstein). , L. and Angel, A·, 1989 · Shoji Hosei, 13 (5): 699-709), pointing out that the role of CETP is not only to produce low HDL phenotypes in these patients, but also Promote the accumulation of cholesterol and develop obesity itself. Therefore, the inhibitor of CETP activity, which blocks this process, is a useful adjuvant for diet therapy that causes weight loss. CETP inhibitors can be used to treat inflammation due to Gram-negative septicemia and septic shock. For example, most of the systemic toxicity of Gram-negative septicemia is due to endotoxin, a lipopolysaccharide (LPS) released from the external surface of bacteria that causes a wide range of inflammatory responses. Lipopolysaccharide forms a complex with lipoproteins (Ulevitch, R.J., Johnston, A.R. and Weinstein, D.B., 1981. J. Clin. 92199 -106-1285641

Invest· 67, 827-37)。活體夕卜研究已証實LPS對HDL之結合，會實 質上降低發炎介體之產生與釋出（Ulevitch，R.J.，Johhston，A.R.，1978. J. Clin· Invest. 62, 1313-24)。活體内研究已顯示表現人類apo-AI與 高HDL含量之轉基因老鼠，係被保護而免於敗血性休克 (Levine，D.M.，Parker，T.S.，Donnelly，T.M.，Walsh，A.M.及 Rubin，A.L. 1993. Proc. Natl. Acad. Sci. 90, 12040-44)。重要的是，對於以内毒素激發 之人類投予重配之HDL，會造成降低之炎性回應（Pajkrt，D.， Doran，J.E·，Koster，F·, Lerch，RG·，Amet，B·，van der Poll，T” ten Cate，J.W.及 van Deventer，S.J.H· 1996. J. Exp. Med. 184, 1601-08)。由於其提升 HDL 含量之事實，故CETP抑制劑會減弱發炎與敗血性休克之發 展。此等化合物亦可用於内毒血症、自身免疫疾病及其他 系統疾病適應徵、器官或組織移植排斥及癌症之治療。 本發明化合物、其前體藥物及此種化合物與前體藥物之鹽 作為醫藥劑，在哺乳動物（例如人類，男性或女性）中治療 上述疾病/症狀之利用性，係藉由本發明化合物在習用檢測 與下述活體内檢測中之活性証實。活體内檢測（具有此藝技 術内之適當修正）可用以測定其他脂質或甘油三酯控制劑以 及本發明化合物之活性。下述之組合擬案可用於証實本文 中所述脂質與甘油三酯劑（例如本發明化合物）組合之利用 性。此種檢測亦提供一種方式，其中可將本發明化合物、 其前體藥物及此種化合物與前體藥物之鹽（或本文中所述之 其他藥劑）之活性互相比較，並與其他已知化合物之活性比 較。此等比較之結果，可用於決定在哺乳動物包括人類中 治療此種疾病之劑量程度。 92199 -107 - 1285641 下述擬案當然可由熟諳此藝者改變。 化合物之高α膽固醇血症活性可經由評估此等化人物對、、 膽固醇基酯轉移蛋白質作用之影響而測得，其方式是产曰 脂蛋白部份間之經放射性標識脂質之相對轉移 w，基本 上如先别由 Morton 在 J_ Biol· Chem. 256, 11992 1981 Φ ，n η. 5 τ 次Dias在Invest· 67, 827-37). In vivo studies have demonstrated that the binding of LPS to HDL substantially reduces the production and release of inflammatory mediators (Ulevitch, R.J., Johhston, A.R., 1978. J. Clin. Invest. 62, 1313-24). In vivo studies have shown that transgenic mice exhibiting human apo-AI and high HDL levels are protected from septic shock (Levine, DM, Parker, TS, Donnelly, TM, Walsh, AM and Rubin, AL 1993. Proc) Natl. Acad. Sci. 90, 12040-44). Importantly, a reconstituted HDL is administered to humans challenged with endotoxin, resulting in a reduced inflammatory response (Pajkrt, D., Doran, JE, Koster, F., Lerch, RG., Amet, B., Van der Poll, T" ten Cate, JW and van Deventer, SJH. 1996. J. Exp. Med. 184, 1601-08). CETP inhibitors attenuate inflammation and septic shock due to the fact that it increases HDL content. Developments. These compounds are also useful in endotoxemia, autoimmune diseases and other systemic disease indications, organ or tissue transplant rejection, and cancer treatment. Compounds of the invention, prodrugs thereof, and such compounds and prodrugs The use of the salt as a pharmaceutical agent for the treatment of the above-mentioned diseases/symptoms in a mammal (e.g., human, male or female) is confirmed by the activity of the compound of the present invention in the conventional test and the following in vivo test. Suitable modifications within the art can be used to determine the activity of other lipid or triglyceride control agents as well as the compounds of the invention. The combination of the following can be used to demonstrate the lipids described herein. The utility of a combination of triglyceride agents (e.g., compounds of the invention). Such assays also provide a means in which the compounds of the invention, prodrugs thereof, and salts of such compounds with prodrugs (or described herein) The activities of other agents are compared with each other and compared to the activity of other known compounds. The results of such comparisons can be used to determine the extent of the treatment of the disease in mammals, including humans. 92199 -107 - 1285641 The case can of course be changed by those skilled in the art. The high alpha cholesterol activity of the compound can be measured by assessing the effect of such a pair of characters, cholesteryl ester transfer proteins, by the production of lipoprotein partial The relative transfer of radioactively labeled lipids is essentially as follows by Morton in J_Biol. Chem. 256, 11992 1981 Φ, n η. 5 τ times Dias

Clin. Chem. 34, 2322, 1988 中所述者。 CETP活體外檢測 下述為在97% (完整）或經稀釋人類血漿（活體外）及動物血 漿（活體外）中膽固醇基酯轉移檢測之簡略描述··於藥物存 在或不存在下之CETP活性，係藉由測定3沁標識之油酸膽固 醇基酯（CO)之轉移進行檢測，其係於人類血漿中，個別從外 源TF蹤劑HDL或LDL至非HDL或HDL脂蛋白部份，或於動物 血漿中，從3H-標識之LDL至HDL部份。經標識之人類脂蛋 白受質係以類似由MortonK述之方法製成，其中係採用血漿 中足内源CETP活性，以在血漿中使3H-C〇從磷脂微脂粒轉移 至所有脂蛋白部份。接著，個別藉由相繼超離心分離，於 1·〇19-1·〇63與U0-L21克/毫升之密度離份下，將3沁標識之 LDL與HDL單離。 對97/^或元整血漿活性檢測，係將3h_標識之，於⑺·乃 毛微莫耳CO / ί:升下’添加至血漿中，並使試樣在沉下培 養2.5〇小時。然後，藉由添加等體積之顺（重量/體積）聚 =:醇8000 (DiaS)，使非HDL脂蛋白沉澱。使試樣離心750克X 20 刀叙並藉由液體閃爍計數測定被包含在含HDL之上層清液 中之攻射活性。在添加經放射性標識之油酸膽固醇基酯之 92199 1285641 前，將不同量之本發明化合物’以在二甲亞礙中之溶液， 引進人類血漿中，並將所轉移之放射性標識量與未含有抑 制劑化合物之培養物比較，（許膽固醇基醋轉移抑:活性 得以被測得。 當需要更具敏感性之檢測時，係利用一種使用經稀釋之人 類血漿之活體外檢測。對於此項檢測，係將3h_栌熾之 ，於5〇毫微莫耳⑺/毫升下’添加至血㈣，並:樣在37 t下培養7小時，然後’藉由將磷酸㈣加至⑽壤最後濃 度，接著將二氯化錳添加至2〇11^最後濃度，使非hdl脂蛋 白沉澱。於旋滿後，使試樣離心75〇克χ2〇分鐘，並藉=液 體閃爍計數測被包含在含HDL之上層清液中之放射二性。 添加經放射性標識之油酸膽固醇基酯之前，將不同量之本 發明化合物，以在二甲亞財之溶液，引進經稀釋之人類 血漿中，並將所轉移之放射性標識量與未含有抑制劑化人 物之培養物比#，允許膽固醇基g旨轉移抑制活性得以被； 得。此項檢測已被修改，以在微滴定板格式中進行’並使 用Wallac板讀取器達成液體閃爍計數。 内檢測 此等化合物在活體内之活性，可藉由在活體外’於不同時 間點’欲被投予（相對於對照組）以抑制膽固醇g旨轉移活性 達50%，或在含CETP之動物種類中，提高狐膽固醇達特a 百分比，戶斤需要之藥劑量而測得。表現人類咖與人^ ^ ^ Μ ^ ^ ^ # ^ . (Charles ^ B〇st〇^ ma) ^ ^ 體内用以評估化合物。欲被檢驗之化合物係藉由口腔灌舍 92199 ' 109 &lt; 1285641 法，在含有20% (v:v)橄欖油與80%牛磺膽酸鈉（〇 5% )之乳化 液媒劑中投予。若需要服藥前血液試樣，則在服藥之前， 自老鼠後眶抽取血液。於服藥後之不同時間下，涵蓋從4小 時至24小時之範圍’使動物犧牲，藉由心臟穿刺獲得血液 ，並度量脂質參數，包括總膽固醇、HDL與LDL膽固醇及甘 油三酯。CETP活性係藉由類似上述之方法測定，惟含有3 油酸膽固醇酯之LDL係作為供體來源使用，與肋乙不同。將 關於脂質與轉移活性所獲得之數值’與’服藥之前所獲得者 · 及/或仔自早獨接受媒劑之老氣者進行比較。 血漿脂皙檢測 此等化合物之活性，亦可在某些哺乳動物例如狨之血槳中 ，其具有CETP活性，及類似人類之血漿脂蛋白分佈形態， 藉由測定改變血漿脂質含量所需要之劑量而証實，例如 膽固醇έ i、LDL膽固醇含量、yldL·膽固醇含量或甘油三 酯（Crook等人，動脈硬化1〇, 625, 199〇)。將成年狨分派為數治療 組，以致使各組具有對總體、及/或LD]L血漿膽固醇濃· 度之類似平均± SD。於組群分派後，使狨每日以食物混合 物服用化合物，或藉由胃内插管法，歷經一至八天。對照 狨只接文配藥媒劑。血漿總體、LDL、VLDL及膽固醇 值’可在研冗期間之任何時點，經由從肘前靜脈獲得血液 並將血水爿曰蛋白’藉密度梯度離心，分離成其個別亞組 ’及經由如先前所述度量膽固醇濃度（Crook等人，動脈硬化 10, 625, 1990)進行測定。 動脈粥瘤硬化檢測 92199 -110- 1285641 化合物…脈粥瘤硬化作用，可藉由降低脂質沉積於兔 子王動脈中所需要之化合物量測定。將雄性紐西蘭白兔銀 食含有0.2%膽固醇與_耶子油之膳食，歷經4天（銀食之餐 飲^天一次）。使兔子自邊緣耳部靜脈失血，並自此等試樣 刺得總血漿膽固醇值。然後，將兔子分派為數治療組，以 致使各崎總血㈣固醇濃度、胍膽料濃度、甘油三醋 濃度及/或膽固醇基g旨轉移蛋白質活性，具有類似平均地 。於組群分派後，&lt;吏兔子每曰服用化合物，以食物混合物 或在-小片明膠為基料之糖劑上給予。對照兔子只接受配 樂媒劑’其係為食物或明膠糖劑。膽固醇/椰子油膳食係伴 隨著化合物投藥’在整個研究中持續著。▲漿膽固醇值盥 膽固醇基㈣移蛋白質活性’可在研究期間之任何時/，、 經由從邊緣耳㈣脈獲得之血液進㈣〇於3_5個月後， 使兔子犧牲，並將從胸靡弓至腸骨動脈支管之主動脈移除 。將主動脈清除動脈外膜’以縱向方式打開，然後分析， 未染色或以Sudan IV染色，按Η〇1_等人所述進行㈣上赠 1958, 7, 42·47)。損傷表面積之百分比係藉由光密度分析法， 使用Optimas影像分析系統(影像處理系統)定量。降低之脂質 沉積係藉由在接受化合物之組群中，經由與對照兔子比較 下之損傷表面積百分比之降低表示。 技肥 CETP抑制劑造成體重減輕之能力’可在具有身體質量指 數_1)230公斤/平方米之肥胖人類病患中評估。抑制劑 (劑I係以足夠造成HDL膽固醇含量增加g25%投予。飞吣 92199 111 - 1285641 與體脂肪分佈，被定義為腰部（W)對髖部（Η)比例（WHR)，係 在3-6個月研究之過程期間監測，且將治療組之結果與接受 安慰劑組比較。 适__體内敗血病檢測 活體内研究証實，表現人類apo_AI與高HDL含量之轉基因 老鼠’係被保護而免於敗血性休克。因此，CETP抑制劑保 護以免敗血性休克之能力，可在表現人類ap〇-AI與人類CETP 轉基因兩者之轉基因老鼠中証實（L^in^D.MiP^kAT.S.，Clin. Chem. 34, 2322, 1988. CETP In Vitro Assay The following is a brief description of the detection of cholesteryl ester transfer in 97% (intact) or diluted human plasma (in vitro) and animal plasma (in vitro) · CETP activity in the presence or absence of drug By detecting the transfer of the oleic acid cholesteryl ester (CO) of the 3沁 mark, which is in human plasma, individually from the exogenous TF tracer HDL or LDL to the non-HDL or HDL lipoprotein fraction, or In animal plasma, from 3H-labeled LDL to HDL fraction. The labeled human lipoprotein receptors were made in a manner similar to that described by Morton K, using endogenous CETP activity in plasma to transfer 3H-C〇 from phospholipid vesicles to all lipoproteins in plasma. Share. Then, by successive ultracentrifugation separation, the LDL of the 3沁 mark was separated from the HDL under the density separation of 1·〇19-1·〇63 and U0-L21 g/ml. For the detection of 97/^ or elemental plasma activity, the marker was labeled 3h_, and (7) was added to the plasma, and the sample was incubated for 2.5 hours. Then, non-HDL lipoprotein was precipitated by adding an equal volume of cis (weight/volume) poly =: alcohol 8000 (DiaS). The sample was centrifuged at 750 g X 20 and the attack activity contained in the HDL-containing supernatant was determined by liquid scintillation counting. Different amounts of the compound of the present invention are introduced into human plasma prior to the addition of the radiolabeled oleic acid cholesteryl ester 92199 1285641, and the transferred radioactive labeling amount is not contained. Comparison of cultures of inhibitor compounds (Cholesterol-based vinegar transfer: activity can be measured. When more sensitive tests are required, an in vitro test using diluted human plasma is used. , 3h_栌火之, at 5〇 nanomole (7) / ml 'added to blood (four), and: sample cultured at 37 t for 7 hours, then 'by adding phosphoric acid (four) to the final concentration of (10) soil Then, the manganese chloride was added to the final concentration of 2〇11^ to precipitate the non-hdl lipoprotein. After the spin-up, the sample was centrifuged for 75 χ 2 〇 2 minutes, and the liquid scintillation count was included in the inclusion. Radiation in the supernatant of the HDL. Before adding the radiolabeled oleic acid oleate, different amounts of the compound of the invention are introduced into the diluted human plasma in a solution of the dimethyl sulfonate, and Transferred The amount of radioactive labeling compared to the culture without the inhibitory person allows the cholesterol-based g-transfer inhibitory activity to be obtained; this test has been modified to perform in the microtiter plate format and read using the Wallac plate. The liquid scintillation count is achieved by the extractor. The activity of these compounds in vivo can be detected by injecting (in comparison with the control group) in vitro to inhibit the cholesterol g transfer activity by 50%. Or, in the animal species containing CETP, increase the percentage of fox cholesterol Dat, measured by the amount of drug required by the household. Show human coffee and human ^ ^ ^ Μ ^ ^ ^ # ^ . (Charles ^ B〇st〇 ^ ma) ^ ^ The body is used to evaluate the compound. The compound to be tested is made by oral cavity 92199 ' 109 &lt; 1285641, containing 20% (v:v) olive oil and 80% sodium taurocholate (〇5%) is administered in an emulsion vehicle. If a blood sample is required before taking the drug, blood is taken from the back of the mouse before taking the drug. It covers from 4 hours to 24 hours at different times after administration. Range 'to make animals sacrifice, obtained by cardiac puncture Liquid, and measure lipid parameters, including total cholesterol, HDL and LDL cholesterol, and triglycerides. CETP activity is determined by a method similar to the above, except that LDL containing 3 oleic acid cholesteryl ester is used as a donor source, with Rib The value obtained for the lipid and transfer activity is 'compared with the one obtained before the administration of the drug and/or the older one who received the vehicle alone. The plasma lipid oxime test can also detect the activity of these compounds. Certain mammals, such as the blood plasma of sputum, have CETP activity, and similar human lipoprotein profiles, as evidenced by the dose required to alter plasma lipid levels, such as cholesterol έ i, LDL cholesterol content, yldL • Cholesterol content or triglycerides (Crook et al., arteriosclerosis 1 〇, 625, 199 〇). Adult ticks were assigned to several treatment groups such that each group had a similar mean ± SD for total, and/or LD]L plasma cholesterol concentration. After the group has been assigned, the compound is administered daily as a food mixture or by intragastric intubation for one to eight days. The control 狨 only received the drug. Plasma total, LDL, VLDL, and cholesterol values may be obtained at any point during the study, by obtaining blood from the anterior elbow vein and by centrifugation of the blood sputum protein into a subset of its individual subgroups' and via previous The measurement of cholesterol concentration (Crook et al., Arteriosclerosis 10, 625, 1990) was performed. Atherosclerosis detection 92199 -110- 1285641 Compound... The atheroma hardening effect can be determined by reducing the amount of compound required for lipid deposition in the rabbit king artery. The male New Zealand white rabbit silver food contains a diet of 0.2% cholesterol and _Yellow oil, which lasts for 4 days (the food of the silver food is once a day). The rabbit was given blood loss from the marginal ear vein and the total plasma cholesterol value was obtained from the samples. Then, the rabbits were assigned to a number of treatment groups such that the total blood (tetra) sterol concentration, sputum concentration, triglyceride concentration, and/or cholesteryl-g transfer protein activity of each saki had a similar average. After the group was assigned, &lt;吏 rabbits were given a compound per dose, administered on a food mixture or on a small piece of gelatin-based sugar. The control rabbits received only the hormonal mediator's which were food or gelatin saccharides. The cholesterol/coconut oil diet was accompanied by the administration of the compound's throughout the study. ▲Pulp cholesterol value 盥Cholesterol-based (IV) MMO activity can be made at any time during the study period, via blood obtained from the marginal ear (four) veins (4) After 3 to 5 months, the rabbit is sacrificed and will be bowed from the chest Remove the aorta from the intestinal branch. The aorta was removed from the adventitia of the artery and opened in a longitudinal manner, then analyzed, unstained or stained with Sudan IV, as described by Η〇 1_ et al. (iv) 1958, 7, 42·47). The percentage of the damaged surface area was quantified by optical density analysis using an Optimas image analysis system (image processing system). Reduced lipid deposition is indicated by a decrease in the percentage of damaged surface area compared to control rabbits in the group receiving the compound. The ability of CETP inhibitors to cause weight loss can be assessed in obese human patients with a body mass index of _1) 230 kg/m2. Inhibitor (agent I was administered in an amount sufficient to cause an increase in HDL cholesterol content by g25%. The distribution of the body fat was defined as the waist (W) to hip (Η) ratio (WHR), at 3 During the course of the -6 month study, the results of the treatment group were compared with those in the placebo group. __ In vivo septicemia testing in vivo studies confirmed that transgenic mice expressing human apo_AI and high HDL content were Protected from septic shock. Therefore, the ability of CETP inhibitors to protect against septic shock can be demonstrated in transgenic mice that exhibit both human ap〇-AI and human CETP transgenes (L^in^D.MiP^kAT .S.,

Donnelly，Τ·Μ·，Walsh，Α·Μ·及 Rubin，a.L” 1993· Proc· Natl· Acad· Sci· 90, Π040-44)。衍生自大腸桿菌之Lps係於3〇毫克/公斤下，藉 由腹膜腔内注射投予已在適當劑量下投予CETp抑制劑以造 成HDL升咼足動物中^存活老鼠數係在Lps注射後高達牝小 時（時間下測足，並與只被投予媒劑（減去CETp抑制劑）之 老鼠比較。 本發明化合物之投藥，可經由任何以系統及/或局部方式 傳輸本發明化合物之方法。此等方法包括口服途徑、非經 腸 '十二指腸内途徑等。-般而t，本發明化合物係以經 口方式投藥，但可利用非經腸投藥（例如靜脈内、肌内、皮 下或髓内），例如，在口服投藥對標的為不適當之情況下， 或在病患無法攝食藥物之情況下。 般而3，係、使用足以達成所要治療作用（例如hdl升高） 之本發明化合物量。 一般而言，本發明化合物之有效劑量係為約〇〇〇1至丨〇〇毫 克/公斤/天之化合物、其前體藥物或該化合物或該前體藥 92199 -112- 1285641 物之藥學上可接受之鹽。尤佳 、 尤佳劑I為約0.01至10毫克/公斤 /天之化合物、其前體藥物或兮仆人a A Μ化合物或該前體藥物之藥學 上可接受之鹽。 欲被搭配CETP抑制劑佶用 &gt; 〜人 〗使用 &lt; 组合藥劑之劑量，係以對於 被治療之適應徵有效之量使用。 例如，典型上，HMG-CoA i曼届綠#山 遂原峰抑制劑之有效劑量係在〇 〇1Donnelly, Τ·Μ·, Walsh, Α·Μ· and Rubin, aL” 1993· Proc· Natl· Acad· Sci· 90, Π040-44). The Lps derived from Escherichia coli is at 3〇mg/kg. The CETp inhibitor has been administered by intraperitoneal injection to induce HDL to increase the number of surviving mice in the pedigree. The number of viable mice is up to 牝 hours after Lps injection (the time is measured and only administered Comparing with a vehicle (minus CETp inhibitor). Administration of a compound of the invention may be by any method of systemic and/or topical delivery of a compound of the invention. These methods include oral route, parenteral 'duodenal route And, generally, the compound of the present invention is administered orally, but may be administered parenterally (for example, intravenously, intramuscularly, subcutaneously or intramedullaryly), for example, when the oral administration is inappropriate. Next, or in the case where the patient is unable to take the drug. Typically, the amount of the compound of the invention sufficient to achieve the desired therapeutic effect (e.g., elevated hdl). In general, the effective dose of the compound of the invention is about 〇〇〇1丨〇〇 mg / kg / day of the compound, its prodrug or the pharmaceutically acceptable salt of the compound or the prodrug 92199 - 112 - 1285641. More preferably, the preferred agent I is about 0.01 to 10 mg /kg/day of the compound, its prodrug or servant a A Μ compound or a pharmaceutically acceptable salt of the prodrug. To be used with CETP inhibitors &gt; ~ people use &lt; combination agent The dose is administered in an amount effective for the indication being treated. For example, typically, the effective dose of HMG-CoA i Mann Green #Hawthorn inhibitor is in 〇〇1

至100毫克/公斤/天之苑圍肉 A 4圍内—般而言，PPAR調制劑之 有效劑量係在0.01至100毫克/公斤/天之範圍内。 本發明化合物一般係以醫藥組合物之形式投藥，該組合物 包含至少-種本發明化合物’伴隨著如下述之藥學上可接 受之媒劑、稀釋劑或載劑。因此， 4 u此，本發明化合物可個別或 一起以任何f用口服、非經腸、直腸或經皮劑型投藥。 對於口服投藥，醫藥組合物可採取溶液、懸浮液、片劑、 丸劑、膠囊、粉末等之形式。人女々仏， s有各種賦形劑譬如檸檬酸 鈉、碳酸鈣及磷酸鈣之片劑，仿往P.左— A d 係伴隨耆各種崩解劑，蓉如 殿粉，且較佳為馬鈴薯或木薯殿粉，Λ某些複合麥酸二， 伴隨著黏合劑’譬如聚乙稀基四氫㈣酮、㈣、明膠及 阿拉伯膠-起採用。此外，、潤滑劑，譬如硬脂酸鎂、月桂 基硫酸鈉及滑叾’經常極可用於壓片目的。類似型式之固 體組合物，亦被採用作為軟與硬填充明膠膠囊中之填料； 畎此而論之較佳物質亦包括乳糖或牛奶糖，以及高分子量 聚乙二醇。較佳配方係為油中之溶液或懸浮液，該：例： 植物油’譬爾油；甘油三酷，譬如以MlglyolTM為名銷售 者，或甘油早酯或二酯，譬如以CapmulTM為名銷售者，例如 92199 113 - 1285641 在軟明膠膠囊中。可按適當方式添加抗氧化劑，以防止長 期降解。當口服投藥需要含水懸浮液及/或酏劑時，可將本 發明化合物與各種增甜劑、绩味劑'著色劑、乳化劑及/或 懸浮劑，以及一些稀釋劑，譬如水、乙醇、丙二醇、甘、、由 及其各種類似組合合併。 包含膽固醇基酯轉移蛋白質（CETP)抑制劑與提高濃度聚合 體之固態非晶質分散體之醫藥組合物，係描述於國際公報 w〇_〇中，細此併於本文供參考。膽固醇基酉旨轉移 蛋白質（CETP)抑制劑之自行乳化配方，係描述於國際公報 W003/000295中，其係據此併於本文供參考。使小藥物結 譬如在J. Pharm. 沉積於賦形劑上之方法，係在文獻中提出To 100 mg / kg / day of the court meat A 4 - generally, the effective dose of PPAR modulator is in the range of 0.01 to 100 mg / kg / day. The compounds of the present invention are generally administered in the form of a pharmaceutical composition comprising at least one compound of the invention' accompanied by a pharmaceutically acceptable vehicle, diluent or carrier as described below. Thus, 4 u, the compounds of the invention may be administered, either individually or together, in any of the oral, parenteral, rectal or transdermal dosage forms. For oral administration, the pharmaceutical compositions may take the form of solutions, suspensions, tablets, pills, capsules, powders, and the like. A female sputum, s has a variety of excipients such as sodium citrate, calcium carbonate and calcium phosphate tablets, imitation to P. left-A d is accompanied by various disintegrants, Rongrudian powder, and preferably potato Or cassava powder, some of the complex malic acid II, accompanied by binders such as polyethylene tetrahydrotetracyclone, (four), gelatin and gum arabic. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and slipper are often used for tabletting purposes. Solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules; preferred materials for this purpose also include lactose or milk sugar, as well as high molecular weight polyethylene glycols. The preferred formulation is a solution or suspension in oil, such as: vegetable oil 'Mulberry oil; glycerol three cool, such as the seller of MlglyolTM, or glycerol early ester or diester, such as the name of CapmulTM seller For example, 92199 113 - 1285641 in soft gelatin capsules. Antioxidants can be added in a suitable manner to prevent long-term degradation. When aqueous administration requires aqueous suspensions and/or elixirs, the compounds of the invention may be combined with various sweetening agents, sizing agents, colorants, emulsifiers and/or suspending agents, as well as some diluents such as water, ethanol, Propylene glycol, glycerol, and their various similar combinations are combined. A pharmaceutical composition comprising a cholesteryl ester transfer protein (CETP) inhibitor and a solid amorphous dispersion of a concentration-enhancing polymer is described in International Publications, incorporated herein by reference. A self-emulsifying formulation of a cholesterol-based transfer protein (CETP) inhibitor is described in International Publication No. W003/000295, which is incorporated herein by reference. The method of depositing a small drug such as J. Pharm. on an excipient is proposed in the literature.

Pharmacol. 1987, 39 : 769-773中，其係據此併於本文供參考。 對非經腸投藥之目的而言，在芝麻或花生油中或在丙二醇 水溶液中之溶液，以及其相應水溶性鹽之無菌水溶液，均 可採用。m ’可將此種水溶液適當地緩衝，且液體稀 釋劑係先以足量鹽水或葡萄糖成為等渗。此等水溶液尤其 適用於靜脈内、肌内、皮下及腹膜腔内注射目白卜就此而 論，所採用之無菌水性媒質均易於藉熟諳此藝者所習知之 標準技術獲得。 對經皮（例如局部）投藥之目的而言，係製備其他方面類似 上述非經腸溶液之稀釋無菌水溶液或部份水溶液（通常在約 0.1%至5%濃度下）。 製備具有某-數量活性成份之各種醫藥組合物之方法係為 熟諳此藝者所已知’或在明白此揭示内容之後，將顯而易 92199 -114- 1285641 見。關於製備醫藥組合物之方法實例，可參閱Remington氏醫 iUii，Mack 出版公司，Easter，Pa·，第 15 版（1975)。 根據本發明之醫藥組合物可含有〇,丨％ -95%本發明化合物 較佳為1% -70%。無論如何，欲被投予之組合物或配方將含 有某數里之根據本發明化合物’其量可有效治療被治療 病患之疾病/症狀，例如動脈粥瘤硬化。 由於本發明具有一方面係關於以可個別投藥之活性成份之 組合治療本文中所述之疾病/症狀，故本發明亦關於將個別 醫藥組合物合併成套件形式。此套件包含兩種個別醫藥組 口物·本發明化合物、其前體藥物或此種化合物或前體藥 物之鹽，與如上述之第二種化合物。&amp;套件包括含有個別 組合物之裝置，譬如容器，分隔瓶或分隔箔袋。典型上， 此套件包含關於個別成份投藥之指示。當個別成份較佳係 以不同劑型（例如口服與非經腸）投藥，係在不同劑量間隔 下投藥時，或當組合之個別成份需要由指 ' 此套件形式係特別有利。 純嘗1千疋貫例為所謂之氣泡包裝。氣泡包裝為包裝工 上所習知，且正被廣泛地使用於醫藥單位劑量形 膠囊等)之包裝。氣泡包裝通常包括以强覆蓋之相對幹: 材料：片，較佳為透明塑膠材料。在包裝製程期間； 塑=中形成凹陷。凹陷具有欲被裝填之片劑或膠囊々 小與形狀。接著’將片劑或膠囊置於凹陷中 硬挺材：薄片對著塑㈣密封，在與其中形成凹 相反表面±。因此，將片劑或膠囊密封在介於塑屑 92199 -Π5 - 1285641 =片間之凹陷中。薄片之強度較佳係、致使片劑或膠囊可 &lt;由手動方式施加壓力於凹陷上’於是在凹陷位 薄片上形成開口 ’而被移離氣泡包裝。然後二二 口移除片劑或膠囊。 α由琢開 —般可能期望在套件上提供〆種記憶辅助， 劑或膠囊之數目形★，而其中數目係與如片 =囊應被攝取之服用法日期相應。此種記憶辅助之== 貫例，為被印刷於卡片μ 士 Ρ蘇，Μ』γ 、 、丁片上夂日曆，例如按下述，，第一週 了他交型將疋顯而易見的。&quot;日服劑量，，可為特定日欲服 用之單—片劑或膠囊或數粒丸劑或膠囊。而且，本發明化 合物之日服劑量可包含一個片劑或膠囊，然而第二種化人 物之曰服劑量可包含數個片劑或膠囊，且反之亦然。記： 辅助應反映此情況。 思 在本發明之另一項特殊具體實施例中，係提供—種分配器 ’經設計以分配日服劑量’依其所意欲 ： -個。此分配器較佳係裝有記憶辅助，以進―步： 力二 用法m此餘憶輔助之—項實例為機械計數哭， 其：顯示已被配藥之日服劑量數目。此種記憶辅助之另一 =例為與液晶示值讀數或可聽見提醒信號聯結之電池供 、 ，、θ铋不上一次日服劑量已被服用 之曰期，及/或在要服用下一劑量時提醒吾人。 本發明化合物無論單獨或與彼此或其他化合物合併，一般 係在合宜配方中投藥。下列配方實例僅為說明，&amp;，並不意 Π6- 92199 1285641 欲限制本發明之範圍。 在隨後之配方中，π活性成份π係意謂本發明化合物。 配方1 :明膠膠囊 硬明膠膠囊係使用下列製成： 成备 量（毫克/膠囊） 活性成份 0.25-100 殿粉，NF 0-650 澱粉可流動粉末 0-50 聚矽氧流體350厘史 0-15 片劑配方係使用下述成份製成： 配方2 :片劑 成份 量（毫克/片劑） 活性成份 0.25-100 微晶性纖維素 200-650 煙霧狀二氧化矽 10-650 硬脂酸 5-15 將諸成份摻合，並壓縮以形成片劑。 或者，各含有0.25-100毫克活性成份之片劑係按下述構成： 配方3 :片劑 成份 量（毫克/片劑） 活性成份 0.25-100 澱粉 45 微晶性纖維素 35 聚乙烯基四氫吡咯酮（為水中之10%溶液） 4 羧甲基纖維素鈉 4.5 硬脂酸鎂 0.5 滑石 1 92199 -117 - 1285641 使活性成份、澱粉及纖維素通過45號網目美國篩網，並充 分地’扣σ將聚乙烯基四氫吡咯酮溶液與所形成之粉末混 合尤：後’使其通過14號網目美國篩網。使因此製成之顆 粒於50-60 C下乾燥，並通過18號網目美國篩網。使羧甲基澱 粉鈉、硬脂酸鎂及滑石預先通過60號美國篩網，接著添加 至顆粒中，於混合後，使其在片劑機上壓縮，而產生片劑。 每5 ΐ升劑量各含有〇 25-1〇〇毫克活性成份之懸浮液，係按 下述製成： 配方4 :懸浮液Pharmacol. 1987, 39: 769-773, which is incorporated herein by reference. For the purpose of parenteral administration, solutions in sesame or peanut oil or in aqueous propylene glycol solution, as well as sterile aqueous solutions of the corresponding water-soluble salts, may be employed. The aqueous solution can be suitably buffered with m ', and the liquid diluent is first rendered isotonic with sufficient saline or glucose. Such aqueous solutions are especially useful for intravenous, intramuscular, subcutaneous, and intraperitoneal injections of the target, and the sterile aqueous media employed are readily available by standard techniques known to those skilled in the art. For the purpose of transdermal (e.g., topical) administration, a dilute sterile aqueous solution or a portion of an aqueous solution (usually at a concentration of about 0.1% to 5%) which is otherwise similar to the parenteral solution described above is prepared. Methods of preparing various pharmaceutical compositions having a certain amount of active ingredient are known to those skilled in the art, or will be apparent from the disclosure of this disclosure, as will be apparent from the disclosure of 92199-114-1285641. For examples of methods for preparing pharmaceutical compositions, see Remington's iUii, Mack Publishing Company, Easter, Pa., 15th Edition (1975). The pharmaceutical composition according to the present invention may contain hydrazine, 丨% - 95% of the compound of the present invention is preferably from 1% to 70%. In any event, the composition or formulation to be administered will contain a certain amount of a compound according to the invention in an amount effective to treat the disease/symptom of the patient being treated, such as atheroma. Since the present invention has, on the one hand, the treatment of the diseases/symptoms described herein with a combination of the individual active ingredients, the present invention also relates to the incorporation of individual pharmaceutical compositions into a kit form. This kit comprises two individual pharmaceutical compositions, a compound of the invention, a prodrug thereof, or a salt of such a compound or prodrug, and a second compound as described above. & kits include devices containing individual compositions, such as containers, separate bottles or separate foil pouches. Typically, this kit contains instructions for administering the individual ingredients. It is particularly advantageous when the individual ingredients are administered in different dosage forms (e.g., orally and parenterally) at different dosage intervals, or when the individual components of the combination need to be referred to by the kit. Purely tasted a thousand cases of so-called bubble packaging. Bubble wrap is well known in the packaging industry and is being widely used in the packaging of pharmaceutical unit dosage capsules, etc.). Bubble wraps typically include relatively dry, strong coverage: Material: Sheet, preferably a clear plastic material. During the packaging process; a depression is formed in the plastic =. The depression has a tablet or capsule to be filled and has a small shape. Next, the tablet or capsule is placed in the depression. The stiffener: the sheet is sealed against the plastic (four), forming a concave opposite surface ± with it. Therefore, the tablet or capsule is sealed in a depression between the sheets 92199 - Π 5 - 1285641. Preferably, the strength of the sheet is such that the tablet or capsule can be removed from the bubble wrap by applying pressure to the recess manually&apos; thereby forming an opening&apos; on the recessed sheet. Then remove the tablets or capsules two or two. α 琢 — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — This memory-assisted == example, for the calendar to be printed on the card, Μ γ, 、, 丁, 丁, 例如, for example, as follows, the first week of his symmetry will be obvious. &quot;Daily dosage, which may be a single-use tablet or capsule or a few pills or capsules. Moreover, the daily dose of the compound of the present invention may comprise one tablet or capsule, however, the second dose of the human may comprise several tablets or capsules, and vice versa. Note: Auxiliary should reflect this. In another particular embodiment of the invention, a dispenser is provided that is designed to dispense a daily dose as desired. Preferably, the dispenser is equipped with a memory aid for further stepping: Force 2 Usage m. This example of the memory is a mechanical count crying, which: displays the number of daily doses that have been dispensed. Another example of such memory assistance is a battery supply that is coupled to a liquid crystal display reading or an audible alert signal, and θ is not in the last period in which the daily dose has been taken, and/or is to be taken. Remind me when the dose. The compounds of the invention, whether alone or in combination with each other or other compounds, are generally administered in a convenient formulation. The following formulation examples are merely illustrative, &amp;, and are not intended to limit the scope of the invention. In the subsequent formulation, the π active ingredient π means the compound of the present invention. Formulation 1: Gelatin Capsules Hard gelatin capsules are prepared using the following: Preparation (mg/capsule) Active ingredient 0.25-100 Temple powder, NF 0-650 Starch flowable powder 0-50 Polyoxane fluid 350% history 0- 15 Tablet Formulations are prepared using the following ingredients: Formulation 2: Tablet Ingredient (mg/tablet) Active Ingredient 0.25-100 Microcrystalline Cellulose 200-650 Smoked Ceria 10-650 Stearic Acid 5 -15 The ingredients are blended and compressed to form a tablet. Alternatively, tablets containing from 0.25 to 100 mg of active ingredient are formulated as follows: Formulation 3: tablet ingredient (mg/tablet) active ingredient 0.25-100 starch 45 microcrystalline cellulose 35 polyvinyl tetrahydrogen Pyrrolidone (10% solution in water) 4 Carboxymethylcellulose sodium 4.5 Magnesium stearate 0.5 Talc 1 92199 -117 - 1285641 The active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and fully ' The sigma σ mixes the polyvinylpyrrolidone solution with the formed powder: it is then passed through a No. 14 mesh U.S. sieve. The pellets thus produced were dried at 50-60 C and passed through a No. 18 mesh U.S. sieve. Sodium carboxymethyl starch, magnesium stearate and talc were previously passed through a No. 60 U.S. sieve, then added to the granules which, after mixing, were compressed on a tablet machine to yield tablets. Each 5 liters of a suspension containing 〇 25-1 mg of the active ingredient is prepared as follows: Formulation 4: Suspension

成份 〇·25-1〇〇 毫克 5〇毫克 1.25毫克 〇·1〇毫升 適量 適量 5毫升 活性成份 羧甲基纖維素鈉 糖漿 苯甲酸溶液 矯味劑 著色劑 純水至 使活性成份通過45號網目美國篩網，並與羧甲基纖維素I 與糖漿混合，以形成平滑糊劑。將苯甲酸溶液、矯味劑及 著色劑以一些水稀釋，並添加，及攪拌。然後，添加足量 水，以產生所需要之體積。 氣溶膠溶液係被製成含有下列成份： 92199 -118 - 1285641 配方5 :氣溶膠Ingredients 〇·25-1〇〇mg 〇5〇mg 1.25mg 〇·1〇ml Appropriate amount 5ml Active ingredient Carboxymethylcellulose sodium syrup Benzoic acid solution Flavoring agent Coloring agent Pure water to make the active ingredient through the 45th mesh US Screen and mix with carboxymethylcellulose I and syrup to form a smooth paste. The benzoic acid solution, flavor, and color are diluted with some of the water, added, and stirred. Then, add enough water to produce the required volume. The aerosol solution is formulated to contain the following ingredients: 92199 -118 - 1285641 Formulation 5: Aerosol

活性成份 量（重量&amp; 0.25Active ingredient amount (weight &amp; 0.25

乙醇 推進劑22 (氯基 將活性成份與乙醇混合，並將混合物添加至一部份推進劑 22中，冷卻至30°C，及轉移至裝填裝置中。然後，將所需要 之量餵至不銹鋼容器中，並以其餘推進劑稀釋。接著，將 閥單元安裝至容器。 栓劑係按下述製成： 配方6 :栓劑 成份 量（毫克/栓杳η 活性成份 250 飽和脂肪酸甘油酯 2,000 使活性成份通過60號網目美國篩網，並懸浮於預先使用最 小必要熱所熔解之飽和脂肪酸甘油酯中。然後，將混合物 倒入額定2克容量之栓劑模具中，並使其冷卻。 靜脈内配方係按下述製成： 配方7 ··靜脈内溶液Ethanol propellant 22 (chlorine-based mixing of the active ingredient with ethanol, adding the mixture to a portion of propellant 22, cooling to 30 ° C, and transferring to a filling device. Then, feeding the required amount to stainless steel The container is diluted with the rest of the propellant. Next, the valve unit is mounted to the container. The suppository is prepared as follows: Formulation 6: Suppository component (mg/plug 杳 active ingredient 250 saturated fatty acid glyceride 2,000 active ingredient Pass through a No. 60 mesh U.S. sieve and suspend it in a saturated fatty acid glyceride previously melted with the minimum necessary heat. The mixture is then poured into a suppository mold of nominal 2 gram capacity and allowed to cool. Made as follows: Formulation 7 ··Intravenous solution

溶於乙醇中之1%活性成份 Intralipid7 M 乳化液1% active ingredient in ethanol Intralipid7 M emulsion

込成Ϊ/7之/公液係在每分鐘約丨毫升之速率下，以靜脈内 方式投予病患。 軟明膠膠囊係使用下列製成 92199 -119- 1285641 配方8 :具有油配方之軟明膠膠囊 成份 量（毫克/膠囊） 活性成份 10-500 橄欖油或MiglyoF'ij 500-1000 上述活性成份亦可為藥劑之組合。 【實施方式】 一般實驗程序 提出下述實例以對一般熟諳此藝者提供如何製造及評估本 文所請求之化合物、組合物及方法之揭示内容與說明，且 意欲純粹為本發明之舉例，而非意欲限制本發明人所認為 其本發明之範圍。除非另有指明，否則百分比係為所予成 份重量對組合物總重量之百分比，溫度係以°C表示，或在環 境溫度下，而壓力係在於或接近大氣壓。利用市售試劑， 無需進一步純化。室溫或環境溫度係指20-25°C。為了方便， 且使產率達到最大程度，所有非水性反應均在氮大氣下進 行。於真空中濃縮，係意謂使用迴轉式蒸發器。本發明化 合物之名稱，係藉由得自Beilstein Informationssysteme GmbH之 Autonom 2.0 PC-批次版本（ISBN 3-89536-976-4)產生。所描繪之化 學結構可能僅為一般結構或有限異構物之舉例，並未包括 如在化學名稱中列舉之特定立體化學。 NMR光譜係於環境溫度下，被記錄在Varian Unity 400 (Varian 公司，Palo Alto, CA) NMR光譜儀上。化學位移係以相對於外標 準物（四甲基矽烷）之每百萬份之份數（5 )表示。吸收峰形狀 係按下述表示：s,單重峰；d，二重峰，t，三重峰，q，四重峰 92199 -120- 1285641 ，m，多重峰，其中字首br表示變寬之信號。所予之偶合常數 (J)數據具有最大誤差為± 0.41 Hz，此係由於所獲得光譜之數 字化所致。質譜係藉由以下方式獲得，（1)大氣壓力化學電 離（APCI)，在交替陽與陰離子模式中，使用Fisons Platformll光 譜儀，或 Micromass MZD 光譜儀（Micromass，Manchester，UK)上，或 ⑺電噴霧離子化作用，在交替陽與陰離子模式中，使用具 有 Gilson LC-MS 界面（Gilson 儀器，Middleton，WI)之 Micromass MZD 光譜儀（Micromass，Manchester，UK)，或（3) QP-8000 質譜儀（Shimadzu 公司，Kyoto, Japan)，在陽或陰單離子監測模式中操作，利用 電噴霧離子化作用或大氣壓力化學電離。在描述含氣或溴 離子強度之情況下，觀察所預期之強度比例（對含有35C1/37C1 之離子為大約3 ·· 1，而對含有79Br/81Br之離子為1 : 1)，且 僅給予較低質量離子之位置。 管柱層析係以無論是Baker矽膠（40微米）(J.T. Baker，Phillipsburg， N.J·)或矽膠 60 (40-63 微米）(EM 科學，Gibbstown，N.J·)進行。急驟 式層析係使用急驟式12或急驟式40管柱（Biotage，Dyar公司 ，Charlottesville，VA)進行。預備之 HPLC 純化係於 Shimadzu 10A 預 備 HPLC 系統（Shimadzu 公司，Kyoto, Japan)上，使用 SIL-10A 型自 動取樣器與8A型HPLC泵進行。預備之HPLC-MS係於相同系 統上進行，以QP-8000質譜儀修改，在陽或陰單離子監測模 式中操作，利用電噴霧離子化作用或大氣壓力化學電離。 溶離係使用含有無論是0.1%甲酸或氫氧化銨作為改變劑之 水/乙腈梯度液進行。在酸性模式中，所使用之典型管柱包 括 Waters 對稱性 C8, 5 微米，19x50 毫米或 30x50 毫米，Waters XTerra 92199 -121 - 1285641 018,5微米，50\50(1&amp;1€1*3公司，]\4沉〇1*(1，]\4入）或？11611〇11^11以3&gt;^啦 Max-RP 4 微米，50x50 毫米（Phenomenex 公司，Torrance，CA)。在驗 性模式中’係使用Phenomenex Synergi Max-RP 4微米，21.2x50毫米 或 30x50 毫米管拄（Phenomenex 公司，Torrance，CA)。 旋光度係使用Jasco P-1020旋光計(Jasco公司，Easton，MD)測得。 二甲基甲醯胺、四氫呋喃、甲苯及二氯甲烷為無水等級， 由Aldrich化學公司（Milwaukee，WI)供應。除非另有指明，否則 試劑係以得自商業來源時之情況使用。&quot;濃縮”與π蒸發”兩 術語，係指於1-200毫米水銀壓力下，在迴轉式蒸發器上， 以低於45°C之浴溫移除溶劑。縮寫nminn表示’’分鐘π，而nh π 或nhr”表示π小時π。縮寫ngm”或ngn表示克。縮寫π //Γ或n //Ln 表示微升。 製備1 (R，S)-2-乙基-4-羥基-6-三氟甲基-3,4-二氫-2H-喹啉-1-羧酸乙酯 (方法1) 於（R，S)斗胺基-2-乙基-6-三氟甲基-3,4-二氫-2H-喹啉小羧酸乙 酯（1294克，4.09莫耳，根據W00140190中所述之程序製成）在 冰醋酸（3882毫升）中之溶液内，添加亞硝酸鈉（582克，8.18莫 耳）在水（1618毫升）中之溶液，保持溫度為20至25°C。於真空 下移除溶劑，使殘留物溶於二氯甲烷（2006毫升）中，並以飽 和碳酸氫鈉溶液洗滌該溶液。在大氣壓力下藉蒸餾移除溶 劑，並使殘留物溶於無水乙醇（2688毫升）中，及以氫氧化鈉 水溶液（62.2克，1.55莫耳）處理。在真空下移除溶劑，使殘 留物溶於二氣甲烷（2000毫升）中，以水洗滌，以無水硫酸鎂 92199 -122- 1285641 脫水乾燥，並在真空下蒸發至乾酒 ’獲得標題化合物，為The sputum/7/public solution is administered intravenously to the patient at a rate of about one milliliter per minute. Soft gelatin capsules are prepared using the following formula 92199 -119-1268941 Formulation 8: Soft gelatin capsules with oil formula (mg/capsule) Active Ingredients 10-500 Olive Oil or MiglyoF'ij 500-1000 The above active ingredients can also be Combination of pharmacy. [Embodiment] The following examples are provided to provide a general description of how to make and evaluate the disclosures and descriptions of the compounds, compositions, and methods claimed herein, and are intended to be purely illustrative of the invention, rather than It is intended that the inventors consider the scope of the invention. Unless otherwise indicated, the percentage is the percentage of the total weight of the composition to the total weight of the composition, the temperature is expressed in ° C, or at ambient temperature, and the pressure is at or near atmospheric pressure. Commercially available reagents were used without further purification. Room temperature or ambient temperature means 20-25 °C. For convenience, and to maximize yield, all non-aqueous reactions were carried out under a nitrogen atmosphere. Concentration in a vacuum means the use of a rotary evaporator. The name of the compound of the invention was generated by Autonom 2.0 PC-batch version (ISBN 3-89536-976-4) from Beilstein Informationssysteme GmbH. The chemical structure depicted may be merely an example of a general structure or a finite isomer, and does not include the specific stereochemistry as listed in the chemical name. NMR spectra were recorded on a Varian Unity 400 (Varian, Palo Alto, CA) NMR spectrometer at ambient temperature. The chemical shift is expressed in parts per million (5) relative to the external standard (tetramethyl decane). The shape of the absorption peak is expressed as follows: s, singlet peak; d, doublet, t, triplet, q, quartet 92199 -120-1285641, m, multiplet, where the prefix br indicates broadening signal. The coupling constant (J) data has a maximum error of ± 0.41 Hz due to the digitization of the obtained spectrum. Mass spectra were obtained by (1) atmospheric pressure chemical ionization (APCI), in alternating positive and anion modes, using a Fisons Platformll spectrometer, or a Micromass MZD spectrometer (Micromass, Manchester, UK), or (7) electrospray ionization. For the alternate cation and anion modes, use a Micromass MZD spectrometer (Micromass, Manchester, UK) with Gilson LC-MS interface (Gilson Instruments, Middleton, WI), or (3) QP-8000 mass spectrometer (Shimadzu Corporation) , Kyoto, Japan), operating in a positive or negative single ion monitoring mode, using electrospray ionization or atmospheric pressure chemical ionization. In the case of describing the gas or bromide ion intensity, observe the expected intensity ratio (about 3 ··1 for ions containing 35C1/37C1 and 1:1 for ions containing 79Br/81Br), and only give The location of lower mass ions. Column chromatography was performed either Baker Silicone (40 microns) (J.T. Baker, Phillipsburg, N.J.) or Silicone 60 (40-63 microns) (EM Science, Gibbstown, N.J.). The flash chromatography was carried out using a flash 12 or a flash 40 column (Biotage, Dyar, Charlottesville, VA). The preparative HPLC purification was carried out on a Shimadzu 10A preparative HPLC system (Shimadzu Corporation, Kyoto, Japan) using a SIL-10A type autosampler and an 8A type HPLC pump. Prepared HPLC-MS was performed on the same system, modified with a QP-8000 mass spectrometer, operated in a positive or negative single ion monitoring mode, using electrospray ionization or atmospheric pressure chemical ionization. The dissolution was carried out using a water/acetonitrile gradient containing either 0.1% formic acid or ammonium hydroxide as a modifier. In acid mode, typical columns used include Waters symmetry C8, 5 microns, 19x50 mm or 30x50 mm, Waters XTerra 92199 -121 - 1285641 018, 5 microns, 50\50 (1&amp;1 €1*3 companies ,]\4 sinking 1*(1,]\4 into) or ?11611〇11^11 to 3&gt;^Max-RP 4 micron, 50x50 mm (Phenomenex, Torrance, CA). In the experimental mode 'The Phenomenex Synergi Max-RP 4 micron, 21.2 x 50 mm or 30 x 50 mm tube (Phenomenex, Torrance, CA) was used. The optical rotation was measured using a Jasco P-1020 polarimeter (Jasco, Inc., Easton, MD). Methylformamide, tetrahydrofuran, toluene and dichloromethane are anhydrous grades supplied by Aldrich Chemical Company (Milwaukee, WI). Unless otherwise indicated, reagents are used when available from commercial sources. &quot;Concentration&quot; The term "vaporization with π" refers to the removal of solvent at a bath temperature of less than 45 ° C on a rotary evaporator at a pressure of 1-200 mm mercury. The abbreviation nminn means ''minute π, and nh π or Nhr" means π hours π. Abbreviation ngm" or ngn means gram. Abbreviation π //Γ or n //Ln for microliters. Preparation 1 (R,S)-2-ethyl-4-hydroxy-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1- Ethyl Carboxylic Acid (Method 1) Ethyl (R,S)-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinolinecarboxylic acid (1294 g, 4.09 mol, according to the procedure described in W00140190) in a solution of glacial acetic acid (3882 ml), a solution of sodium nitrite (582 g, 8.18 mol) in water (1618 ml) was added to maintain the temperature. The solvent was removed under vacuum, the residue was dissolved in dichloromethane (2006 mL), and the solution was washed with saturated sodium hydrogen carbonate solution. The solvent was removed by distillation under atmospheric pressure and The residue was taken up in dry EtOAc (2 EtOAc (EtOAc) Washed with water, dried over anhydrous magnesium sulfate 9299-122-1228641, and evaporated to dryness in vacuo to give the title compound as

製備2Preparation 2

加2,2,6,6-四甲基-1-六氫吡啶基氧基（TEMp〇）、自由基（61克， 〇·〇38莫耳）及已溶於水（191毫升）中之溴化鉀溶液（45 8克， 0.381莫耳）。於〇至5°C下，慢慢添加已經以固體碳酸氫鈉（78 克）緩衝至pH 8.6到9.5之6%次氯酸鈉水溶液（7748毫升）。以 二氯甲燒（1208耄升）洗條水層。將合併之有機層以其中已添 加琪化鉀（12.8克，0.076莫耳）之L4N鹽酸（1493毫升）洗滌，然 後是已溶於水（1208毫升）中之硫代硫酸鈉溶液（6〇·8克，〇 381 莫耳），及最後是水（1691毫升）。使有機層以無水硫酸鎂脫 水乾燥，並於真空下蒸發至乾涸，而得標題化合物，為黃 色油（1193克）。 1 H-NMR (DMSO-d6) δ 8.03 (m3 2H), 7.91 (dd, J=9.12, 2.49Hz, 1H), 4.79 (m, 1H), 4.23 (q5 J=7.05Hz, 2H), 3.25 (dd5 J=17.423 5.81Hz, 1H)3 2.61 (dd, J= 17.42, 1.66Hz，1H)，1.42 (m，2H)，1·25 (t，J=7.05Hz，3H)，0.76 (t，J=7.05Hz， 製備3與4 (R)-2-乙基-4-酮基-6-三氟甲基-3,4-二氫-2H-喳啉-1-羧酸乙酯（3) 與（S)-2-乙基-4-酮基-6-三氟甲基-3,4-二氫-2H-喹啉小羧酸乙酯（4) 使（RS)-2-乙基-4-酮基-6-三氟甲基-3,4-二氫-2H-喳啉小羧酸乙 92199 -123 - 1285641 酯於1 〇公分X 25公分以Chlralcel 〇D裝填之管柱(對掌性技術八 司，Extort)上，藉對掌性層析解析。將甲醇（_毫升）中2 外消旋嗣（300毫克）注射至管柱上，並以庚燒：異丙醇％ ，於275耄升/分鐘流率下溶離，而得標題化合物： (R) -2-乙基-4-酮基·6_三說甲基_3,4_二氮_2H_如林小複酸乙酉旨⑺ ，滯留時間了及分鐘^办：心犯㈣顿’氣仿）。 (S) -2-乙基-4-酮基冬三氟甲基_3,4_二氫_2H_喳啉小羧酸乙酯⑷ ，滯留時間 8.93分鐘，[a]D = +139.7〇(c==〇4i，氯仿）。 製備5 4-亞肼基-6,7-二甲氧基-2·甲基-3,4_二氫-2H-喳啉-1-羧酸乙酯 將6,7-二甲氧基-2-甲基-4-酮基_3,4-二氫-2H_喹啉小羧酸乙醋 (1.00克’ 3.41毫莫耳，根據德國專利DE 2461〇5〇中所述之程序 製成）、肼水合物（330微升，6·80毫莫耳）及乙醇（4.5毫升）之 混合物’在捲曲頂部小玻瓶中，於150°c下，在微波爐 (Emrys Optimizer，Personal 化學，Uppsala，Sweden)中，一起加熱 30 分 鐘。在真空下移除溶劑，使殘留物溶於乙醇（4.5毫升）中， 添加肼水合物（330微升，6·80毫莫耳），並將溶液以前述方式 ，在150°C下加熱30分鐘。在真空下蒸發溶劑，而得標題化 合物，為淡黃色固體。 MS : 308.2 [M+H]+實測值 1H-NMR (CDC13) δ 7.39 (s5 1H), 7.03 (brs, 1H), 5.21 (s, 2H), 5.04 (m3 1H), 4.27 (m，1H)，4.15 (m，1H)，3.88 (s，3H)，3.85 (s，3H)，2,61 (dd，J=17, 5·81Ηζ，1H)， 2.53 (dd，J=17, 1·66Ηζ，1Ή)，1.28 (t，J=7.47Hz，3H)，1.08 (d，J=6.64Hz，3H)· 製備6 92199 -124- 1285641 (R)-2-乙基-4-亞胼基-6-三氟甲基_3,4_二氫-2Η-σ奎啉小羧酸乙酯 將（R)-2-乙基-4-酮基-6-三氟甲基-3,4_二氫-2Η…奎啉小羧酸乙酯 (製備3，1.13克，3.58毫莫耳）、肼水合物（348微升，7.16毫 莫耳）及乙醇（10愛升）之混合物，在De^-Stark裝置中，於允 终缓慢蒸餾溶劑之條件下加熱。5小時後，已經收集大約5 毫升館出物。將溶液以等體積甲苯稀釋，並於真空下蒸發 〉谷劑’獲得淡綠色固體，將其研製，並以少量己烷沖洗， 而得標題化合物，為幾乎無色固體（1〇7克）。 MS : 330.2 [M+H]+實測值 1 H^NMR (CDC13) S 8.23 (s, 1H), 7.62 (brd, J=8.30Hz, 1H), 7.46 (dd, J=8.30, 1.66Hz, 1H), 5.45 (brs5 2H), 4.82 (m, 1H), 4.28 (m, 1H), 4.24 (m, 1H), 2.64 (m, 2H)，1.36 (m，2H)，1.31 (t，J=7.47Hz，3H)，0.84 (t，J=7.47Hz，3H)· 製備7 4重氮基-6,7-一甲氧基-2-甲基-3,4-二氫-2H-峻淋小羧酸乙醋 於4-亞肼基-6,7-二甲氧基-2-甲基-3,4-二氫-2H-喳啉小羧酸乙 醋（製備5，200毫克，〇·65毫莫耳）在乙醚（2〇毫升）中之溶液 内’添加氧化錳（IV)(400毫克，已活化，〜85%，Aldrich化學 公司，Milwaukee，WI)。將此懸浮液於環境溫度及氮氣下，在黑 暗中攪拌30分鐘，然後經過Celite®，藉過濾移除固體，而得 才右越化合物’為帶唐紅色溶液，其典型上係立即使用。 製備8 (R&gt;4-重氮基-2-乙基-6-三氟甲基-3,4-二氫-2H-喹淋-1-羧酸乙酯 於⑻-2-乙基-4-亞肼基-6-三氟甲基-3,4-二氫-2H-峻4 -1-叛酸乙 酯（製備6，317毫克，0,962毫莫耳）在乙醚（6毫升）中之溶液 92199 -125- 1285641 内’添加氧化4孟（IV)(1.1克，已活化，〜85%，Aldrich化學公司， Milwaukee，WI)。將此懸浮液於環境溫度及氮氣下，在黑暗中 搜拌1.5小時，然後經過celite⑧，藉過濾移除固體。於蒸發至 大約10毫升（絕不至乾涸）之最後體積前，以甲苯（15毫升）稀 釋/慮液’而彳于標題化合物，為帶唐紅色溶液，其典型上係 立即使用。 製備9與10 ⑻+氯基-2-乙基斗〒氧基碳羰基各三氟甲基-3,4-二氫-2H-喹啉 •1-叛酸乙g旨（9)與⑻-2-乙基-4-甲氧基碳羰基各三氟甲基-2H-4 啉小羧酸乙酯（10) 於如上述製自製備6之（R)-4-重氮基-2-乙基-6-三氟甲基-3,4-二 氫沁喹啉-1-羧酸乙酯（製備8)(317毫克，0.962毫莫耳）在甲苯 中作成溶液之溶液内，添加N，N-二異丙基乙胺（335微升，1.92 愛莫耳），接著是逐滴之氯基酮基醋酸甲酯（〇·962毫莫耳，88·4 微升）。將混合物於室溫及氮氣下攪拌。在約1〇分鐘内，發 現氣體釋出’且唐紅色改變成黃橘色。將溶液以醋酸乙酯 稀釋’以飽和碳酸氫鈉溶液，然後以水洗滌，以無水硫酸 鈉脫水乾燥，及蒸發至乾涸。使殘留物於矽膠上層析，以 己院：酷酸乙酯梯度液19 ·· 1至4 : 1溶離，獲得標題化合物： ⑻-4-氣基-2-乙基斗甲氧基碳羰基各三氟甲基召，4_二氫-2如奎 淋-l-幾酸乙酯（較早溶離出之非對映異構物，82毫克） MS : 422.0 [Μ+Η]+ 實測值 1H-NMR (CDC13) (5 7.72 (d5 J=9.13Hz, 1H), 7.58 (m5 1H), 7.54 (s, 1H), 4.57 (m，1H)，4.27 (m，1H)，4.25 (m，1H)，3.95 (s，3H)，2.85 (dd，J=14.11，6.64Hz， 92199 -126- 1285641 1H)，2.77 (dd，J=14.11，6·92Ηζ，1H)，1.61 (m，1H)，1.52 (m，1H)，1.30 (t，J=7.47 Hz，3H)，0.87 (t，J=7.47Hz，3H). ⑻-4-氯基-2-乙基-4-T氧基碳羰基-6-三氟基-3,4-二氫-2H-p奎 啉-1-羧酸乙酯（稍後溶離出之非對映異構物，73毫克） MS : 422.0 [M+Hf 實測值 1H-NMR (CDC13) 5 7.88 (s，1H)，7.60 (m，2H)，7·54 (s，1H)，4.57 (m，1H)， 4.22 (m，1H)，4.20 (m，1H)，3.73 (s，3H)，3.26 (dd，J=13.8, 7.47Hz，1H)，2·23 (dd，J=13.8, 6.75Hz，1H)，1.65 (m，1H)，1·53 (m，1H)，1·27 (t，J=7.47Hz，3H)， 0.89 (t，J=7.47Hz，3H)· (R)-2-乙基-4-甲氧基碳幾基-6-三氟甲基-2H-p奎琳小叛酸乙酉旨 ，133毫克 MS : 384.1 [M-Η]-實測值 1H-NMR (CDC13) 5 8.27 (s, 1H), 7.71 (brd, J=8.30Hz, 1H), 7.56 (dd? J=8.30? 1·66Ηζ，1H)，7·20 (d，J=6.64Hz，1H)，5·21 (m，1H)，4.28 (m，2H)，3.95 (s，3H), 1·57 (m，1H)，1.41 (m，1H)，1.32 (t，J=7.47Hz，3H)，0.91 (t，J=7.47Hz，3H). 製備11 2-乙基-4-羥基-6-三氟甲基二氫-2H-喹啉-1-羧酸乙酯（方法2) 於2-乙基-4-酉同基-6-三氟甲基-3,4-二氫_2H-p奎淋-1-複酸乙醋 (0.89克，2.83毫莫耳）在甲醇（2〇毫升）中之溶液内，添加固體 硼氫化鈉（102毫克，2·8毫莫耳）。10分鐘後，添加丙酮以使 反應淬滅’並將混合物攪拌2小時，然後於真空下蒸發溶劑 。使殘留物溶於二氣甲烷中，並以〇·〇5 Ν鹽酸洗滌溶液。使 有機層以無水硫酸鈉脫水乾燥，以甲苯稀釋，及蒸發至乾 涸’而得標題化合物，為非對映異構物之混合物，其係繼 92199 -127 - 1285641 續進行而未被分離。 MS : 318.0 [M+Hf 實測值 (反式異構物-較少）1 H-NMR (CDC13) 5 7.80 (d，J=8.30Hz，1H)，7·69 (s，1Η)，7.49 (dd，J=8.30, 1.66Hz，1Η)，4.86 (m5 1Η)，4.58 (m，1Η)，4.25 (m，2Η)， 2.16 (m，2H)，1.60 (m，1H)，1.50 (m，1H)，1·32 (t，J=7.47Hz，3H)，0.90 (t, J=7.47 Hz，3H)· MS : 318·0[Μ+Η]+實測值 (順式異構物-主要）1H-NMR (CDC13) 5 7.73 (s，1H)，7.58 (d，J=9.13 Hz，1H)，7·50 (dd，J=9.13, 1·66Ηζ，1H)，4.55 (m，1H)，4.41 (m，1H)，4.24 (m， 2H)，2.52 (ddd，JN13.28, 7.47, 4·98Ηζ，1H)，1.67 (m，1H)，1·60 (m，1H)，1·48 (m， 1H)5 1.30 (t? J=7.47Hz, 3H), 0.85 (t, J=7.47Hz, 3H). 製備12 4鼠基-2-乙基-6-二氟甲基-3,4_二氫奎4木小叛酸乙醋（方法1) 使得自前述製備之產物（製備U，2·83毫莫耳）溶於無水二 氣甲烷（30毫升）中，冷卻至〇它，並添加三乙胺（1〇毫升，7.口 t莫耳），接著是氯化甲烷磺醯（245微升，316毫莫耳）。2小 時後，添加另一液份三乙胺（1〇毫升，717毫莫耳），並將混 合物於環境溫度下攪拌15小時，然後以含有21^鹽酸之水（ι〇 耄升）洗滌。使有機層以無水硫酸鈉脫水乾燥，蒸發至乾涸 ，並於矽膠上藉層析純化，以己烷：丙酮25: 1溶離，獲得 標題化合物，為非對映異構物之不均句混合物(59〇毫克卜 其典型上係繼續進行而未被分離。 非對峡異構物丨（主要） MS · 336.0 [M+H]+ 實測值 92199 * 128 - 1285641 1 H-NMR (CDC13) 5 7.69 (d, J=8.29Hz, 1H), 7.60 (s5 1H), 7.63 (d, J=8.29Hz, 1H)，5.12 (dd，J=6.64, 4.98Hz，1H)，4.60 (m，1H)，4.27 (m，2H)，2.60 (ddd，J= 14.11，6.64, 6.64Hz，1H)，2.13 (ddd，J=14.11，6.64, 4·98Ηζ, 1H)，1.64 (m，1H), 1.54 (m，1H)，1.31 (t，J=7.47Hz，3H)，0.89 (t，J=7.47Hz，3H)· 非對映異構物2 (較少） MS : 336.0 [M+Hf 實測值 1 H-NMR (CDC13) 5 7.82 (s，1H)，7.68 (d，J=8.30Hz，1H)，7.51 (dd，J=8.30, 1.66Hz，1H)，5.08 (dd，J=5.81，5.81Hz，1H)，4.55 (m，1H)，4.25 (m，2H)，2·71 (ddd, J=14.11, 5.81, 5.81Hz, 1H), 2,18 (ddd, J=14.11, 5.81, 5.81Hz? 1H), 1.74 (m，1H)，1.60 (m，1H)，1·31 (t，J=7.47Hz，3H)，0.91 (t，J=7.47Hz，3H)· 製備13 (R，S)-2-乙基-4-羥基-6-三氟甲基-3,4-二氫-2H-喹啉小羧酸乙酯 (方法3) 於⑻-2-乙基-4-酮基-6-三氟甲基-3,4-二氫-2H-喹啉小羧酸乙酯 (1.1克’ 3.49耄莫耳）在無水四氫呋喃中之溶液内，在〇。〇及氮 氣下’添加二異丁基硼氫化卸（K-Selectride®，1M，在四氫吱 喃中’ 8.0愛升’ 8毫莫耳）。於15小時後，使混合物溫熱至 環境溫度，攪拌16小時，然後添加另一液份K-Sdectride® (3,49 毫升，3.49 φ莫耳）。丨.5小時後，在真空下移除溶劑，使殘 留物溶於醋酸乙醋（50毫升）中，並將此溶液以21^氫氧化納 溶液（20毫升），接著以過氧化氫（3〇%，15毫升）洗滌，以無 水硫酸鎂脫水乾燥，及濃縮至低體積。使殘留物溶於乙腈 中，並詻發至乾涸（x3)以移除殘留水，而得標題化合物（1〇〇 % )’與上迷產物之順式異構物（製備u)相同。 92199 -129 - 1285641 製備14 ()4氯基-2-乙基-6-三氟甲基·3,4-二氫·2Η^奎，林小羧酸乙酯 (方法2) 使（R，S&gt;2•乙基斗羥基各三氟甲基-3,4-二氩-2Η-喹啉小羧酸乙Add 2,2,6,6-tetramethyl-1-hexahydropyridyloxy (TEMp〇), free radical (61 g, 〇·〇38 mol) and dissolved in water (191 ml) Potassium bromide solution (45 8 g, 0.381 mol). A 6% aqueous solution of sodium hypochlorite (7748 ml) which had been buffered to pH 8.6 to 9.5 with solid sodium hydrogencarbonate (78 g) was slowly added at 5 °C. The aqueous layer was washed with methylene chloride (1208 liters). The combined organic layers were washed with L4N hydrochloric acid (1493 mL), which had been added with potassium (12.8 g, 0.076 mol), followed by sodium thiosulfate solution (6 〇·) dissolved in water (1208 ml) 8 grams, 〇381 莫), and finally water (1691 ml). The organic layer was dried with EtOAc EtOAc EtOAcjjjjjj 1 H-NMR (DMSO-d6) δ 8.03 (m3 2H), 7.91 (dd, J=9.12, 2.49 Hz, 1H), 4.79 (m, 1H), 4.23 (q5 J=7.05 Hz, 2H), 3.25 ( Dd5 J=17.423 5.81Hz, 1H)3 2.61 (dd, J= 17.42, 1.66Hz, 1H), 1.42 (m, 2H), 1·25 (t, J=7.05Hz, 3H), 0.76 (t, J =7.05 Hz, Preparation of 3 and 4 (R)-2-ethyl-4-keto-6-trifluoromethyl-3,4-dihydro-2H-indolinoline-1-carboxylic acid ethyl ester (3) Ethyl (S)-2-ethyl-4-keto-6-trifluoromethyl-3,4-dihydro-2H-quinolinecarboxylic acid (4) (RS)-2-ethyl 4-keto-6-trifluoromethyl-3,4-dihydro-2H-carboline small carboxylic acid B 92199 -123 - 1285641 ester in 1 〇 cm X 25 cm packed with Chlralcel 〇D ( On the palm of the palm technology, Extort), by palm chromatography, 2 racemic oxime (300 mg) in methanol (_ml) was injected onto the column and burned with glucan: isopropanol% Dissolved at a flow rate of 275 liters per minute to obtain the title compound: (R) -2-ethyl-4-keto- 6-three-methyl _3,4-diaza 2H_ B. (7), staying in time and minutes ^ do: heart off (four) Dun 'mim imitation. (S) 2-Ethyl-4-keto-t-trifluoromethyl_3,4-dihydro-2H_carboline small carboxylic acid ethyl ester (4), retention time 8.93 minutes, [a] D = +139.7〇 (c==〇4i, chloroform). Preparation 5 4-Amidino-6,7-dimethoxy-2.methyl-3,4-dihydro-2H-indolinoline-1-carboxylic acid ethyl ester 6,7-dimethoxy- 2-methyl-4-keto-3,4-dihydro-2H-quinoline carboxylic acid ethyl vinegar (1.00 g ' 3.41 mmol), made according to the procedure described in German Patent DE 2461〇5〇 ), a mixture of hydrazine hydrate (330 μl, 6.80 mmol) and ethanol (4.5 ml) 'in a curly top glass vial at 150 ° C in a microwave oven (Emrys Optimizer, Personal Chemistry, Uppsala) ,Sweden), heat together for 30 minutes. The solvent was removed under vacuum, the residue was dissolved in ethanol (4.5 mL), hydrazine hydrate (330 liters, 6. 80 mM) was added, and the solution was heated at 150 ° C in the manner described above. minute. The solvent was evaporated in vacuo to give crystall MS : 308.2 [M+H] + found 1H-NMR (CDC13) δ 7.39 (s5 1H), 7.03 (brs, 1H), 5.21 (s, 2H), 5.04 (m3 1H), 4.27 (m,1H) , 4.15 (m, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 2, 61 (dd, J=17, 5.81Ηζ, 1H), 2.53 (dd, J=17, 1.66Ηζ) ,1Ή), 1.28 (t, J=7.47Hz, 3H), 1.08 (d, J=6.64Hz, 3H)· Preparation 6 92199 -124- 1285641 (R)-2-Ethyl-4-indenyl- Ethyl 6-trifluoromethyl_3,4-dihydro-2Η-σ quinolate small carboxylic acid (R)-2-ethyl-4-keto-6-trifluoromethyl-3,4_ a mixture of dihydro-2Η...quinoline carboxylic acid ethyl ester (preparation 3, 1.13 g, 3.58 mmol), hydrazine hydrate (348 μl, 7.16 mmol) and ethanol (10 liters) in De In the ^-Stark apparatus, it is heated under conditions of slow distillation of the solvent. After 5 hours, approximately 5 ml of the museum has been collected. The solution was diluted with an equal volume of toluene and evaporated in vacuo to give a pale green solid. MS : 330.2 [M+H] + found 1 H NMR (CDC13) S 8.23 (s, 1H), 7.62 (brd, J = 8.30 Hz, 1H), 7.46 (dd, J = 8.30, 1.66 Hz, 1H ), 5.45 (brs5 2H), 4.82 (m, 1H), 4.28 (m, 1H), 4.24 (m, 1H), 2.64 (m, 2H), 1.36 (m, 2H), 1.31 (t, J = 7.47 Hz, 3H), 0.84 (t, J = 7.47 Hz, 3H) · Preparation of 7 4 Diazo-6,7-monomethoxy-2-methyl-3,4-dihydro-2H-Jun Ethyl acetate to 4-mercapto-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-carboline small carboxylic acid ethyl acetate (preparation 5,200 mg, 〇· Add 65 mg of manganese oxide (IV) (400 mg, activated, ~85%, Aldrich Chemical Company, Milwaukee, WI) in a solution of diethyl ether (2 ml). The suspension was stirred in the dark at ambient temperature under nitrogen for 30 minutes and then filtered through Celite® to remove solids, and the compound of the right-right was taken as a red solution, which was typically used immediately. Preparation 8 (R>4-diazo-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester in (8)-2-ethyl-4 - fluorenyl-6-trifluoromethyl-3,4-dihydro-2H-jun 4-1--1-oxoethyl ester (preparation 6,317 mg, 0,962 mmol) in diethyl ether (6 mL) Solution 92199 -125-1285941 within the 'addition of oxidation 4 Meng (IV) (1.1 g, activated, ~ 85%, Aldrich Chemical Company, Milwaukee, WI). This suspension was mixed in the dark at ambient temperature and under nitrogen. After 1.5 hours, the solid was removed by filtration through celite 8 and diluted with toluene (15 ml) before evaporation to a final volume of about 10 ml (never dry). Red solution, which is typically used immediately. Preparations 9 and 10 (8) + chloro-2-ethylindoleoxycarbocarbonyl trifluoromethyl-3,4-dihydro-2H-quinoline•1-rebel Ethyl acetate (9) and (8)-2-ethyl-4-methoxycarbocarbonylethyl trifluoromethyl-2H-4 porphyry small carboxylic acid ethyl ester (10) as prepared above from the preparation of 6 (R Ethyl 4-diazo-2-ethyl-6-trifluoromethyl-3,4-dihydroquinolinol-1-carboxylate (Preparation 8) (317 mg 0.962 mmol) in a solution of toluene as a solution, N,N-diisopropylethylamine (335 μl, 1.92 Amol), followed by dropwise chloropropyl ketoacetate (〇) · 962 mmol, 88·4 μL. The mixture was stirred at room temperature under nitrogen. Within about 1 minute, the gas was released and the red color changed to yellow orange. The solution was ethyl acetate. Dilute 'with saturated sodium bicarbonate solution, then washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was chromatographed on silica gel. 4:1 dissolving, the title compound was obtained: (8) 4-oxyl-2-ethyl fluoromethoxycarbonyl, trifluoromethyl, 4-dihydro-2, such as quinolate-l-acid ethyl ester ( The earlier diastereoisomers, 82 mg) MS: 422.0 [Μ+Η]+ found 1H-NMR (CDC13) (5 7.72 (d5 J=9.13 Hz, 1H), 7.58 (m5 1H) , 7.54 (s, 1H), 4.57 (m, 1H), 4.27 (m, 1H), 4.25 (m, 1H), 3.95 (s, 3H), 2.85 (dd, J = 14.11, 6.64 Hz, 92199 -126 - 1285641 1H), 2.77 (dd, J=14.11, 6.92Ηζ, 1H), 1.61 (m, 1H), 1.52 (m, 1H), 1.30 (t, J = 7.47 Hz, 3H), 0.87 (t, J = 7.47 Hz, 3H). (8)-4-Chloro-2-ethyl-4 -T-oxycarbonylcarbonyl-6-trifluoro-3,4-dihydro-2H-p-quinoline-1-carboxylic acid ethyl ester (diastereoisomers later eluted, 73 mg) MS: 422.0 [M+Hf found 1H-NMR (CDC13) 5 7.88 (s, 1H), 7.60 (m, 2H), 7·54 (s, 1H), 4.57 (m, 1H), 4.22 (m, 1H) , 4.20 (m, 1H), 3.73 (s, 3H), 3.26 (dd, J = 13.8, 7.47 Hz, 1H), 2·23 (dd, J = 13.8, 6.75 Hz, 1H), 1.65 (m, 1H) ),1·53 (m,1H),1·27 (t,J=7.47Hz,3H), 0.89 (t,J=7.47Hz,3H)·(R)-2-ethyl-4-methoxy Carbocyclyl-6-trifluoromethyl-2H-p-quinein, small oxetine, 133 mg MS: 384.1 [M-Η]-measured 1H-NMR (CDC13) 5 8.27 (s, 1H), 7.71 (brd, J=8.30Hz, 1H), 7.56 (dd? J=8.30?1·66Ηζ,1H),7·20 (d,J=6.64Hz,1H),5·21 (m,1H), 4.28 (m, 2H), 3.95 (s, 3H), 1·57 (m, 1H), 1.41 (m, 1H), 1.32 (t, J = 7.47 Hz, 3H), 0.91 (t, J = 7.47 Hz) , 3H). Preparation 11 ethyl 2-ethyl-4-hydroxy-6-trifluoromethyldihydro-2H-quinoline-1-carboxylate (Method 2) 2-ethyl-4-indolyl-6-trifluoromethyl-3,4-dihydro-2H-p-quinone-1-acid vinegar (0.89 g, 2.83 mmol) in methanol (2 Solid sodium borohydride (102 mg, 2·8 mmol) was added to the solution in 〇ml). After 10 minutes, acetone was added to quench the reaction' and the mixture was stirred for 2 hours, then the solvent was evaporated in vacuo. The residue was dissolved in di-methane and the solution was washed with hydrazine hydrazine. The organic layer was dried over anhydrous sodium sulfate (MgSO4). MS: 318.0 [M+Hf calcd. (.s.s.ss.sssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss Dd, J = 8.30, 1.66 Hz, 1 Η), 4.86 (m5 1 Η), 4.58 (m, 1 Η), 4.25 (m, 2 Η), 2.16 (m, 2H), 1.60 (m, 1H), 1.50 (m, 1H),1·32 (t, J=7.47Hz, 3H), 0.90 (t, J=7.47 Hz, 3H)· MS : 318·0[Μ+Η]+ measured value (cis isomer - mainly 1H-NMR (CDC13) 5 7.73 (s, 1H), 7.58 (d, J = 9.13 Hz, 1H), 7·50 (dd, J = 9.13, 1.66 Ηζ, 1H), 4.55 (m, 1H) , 4.41 (m, 1H), 4.24 (m, 2H), 2.52 (ddd, JN13.28, 7.47, 4.98Ηζ, 1H), 1.67 (m, 1H), 1·60 (m, 1H), 1· 48 (m, 1H)5 1.30 (t? J = 7.47 Hz, 3H), 0.85 (t, J = 7.47 Hz, 3H). Preparation of 12 4 -Methyl-2-ethyl-6-difluoromethyl-3 , 4_Dihydroquino-4-mucold acid vinegar (Method 1) The product prepared as described above (Preparation U, 2.83 mmol) was dissolved in anhydrous di-methane (30 mL), cooled to 〇 And added triethylamine (1 mL, 7. t-mole) followed by chlorinated methanesulfonate (245 μL, 316 mmol). After 2 hours, another portion of triethylamine (1 mL, 717 mmol) was added and the mixture was stirred at ambient temperature for 15 hours and then washed with water containing &lt;RTIgt; The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness eluting eluting eluting eluting 59 〇 mg is typically continued without separation. Non-isomer isomer 丨 (main) MS · 336.0 [M+H]+ Measured 92199 * 128 - 1285641 1 H-NMR (CDC13) 5 7.69 (d, J = 8.29 Hz, 1H), 7.60 (s5 1H), 7.63 (d, J = 8.29 Hz, 1H), 5.12 (dd, J = 6.64, 4.98 Hz, 1H), 4.60 (m, 1H), 4.27 (m, 2H), 2.60 (ddd, J = 14.11, 6.64, 6.64 Hz, 1H), 2.13 (ddd, J = 14.11, 6.64, 4.98 Ηζ, 1H), 1.64 (m, 1H), 1.54 (m ,1H),1.31 (t,J=7.47Hz,3H),0.89 (t,J=7.47Hz,3H)· diastereomer 2 (less) MS : 336.0 [M+Hf measured 1 H - NMR (CDC13) 5 7.82 (s, 1H), 7.68 (d, J = 8.30 Hz, 1H), 7.51 (dd, J = 8.30, 1.66 Hz, 1H), 5.08 (dd, J = 5.81, 5.81 Hz, 1H), 4.55 (m, 1H), 4.25 (m, 2H), 2·71 (ddd, J=14.11, 5.81, 5.81Hz, 1H), 2,18 (ddd, J=14.11, 5.81, 5.81Hz? 1H), 1.74 (m,1H), 1.60 (m,1H),1·31 (t, J = 7.47 Hz, 3H), 0.91 (t, J = 7.47 Hz, 3H). Preparation 13 (R,S)-2-ethyl-4-hydroxy-6-trifluoromethyl-3,4 - Dihydro-2H-quinoline small carboxylic acid ethyl ester (Method 3) to (8)-2-ethyl-4-keto-6-trifluoromethyl-3,4-dihydro-2H-quinoline carboxylate Ethyl acetate (1.1 g ' 3.49 Torr) in a solution of anhydrous tetrahydrofuran, added with diisobutylborohydride (K-Selectride®, 1 M in tetrahydrofuran) under hydrazine and nitrogen. '8.0 AiLeng' 8 mM. After 15 hours, the mixture was allowed to warm to ambient temperature, stirred for 16 hours, then another portion of K-Sdectride® (3,49 mL, 3.49 φ Moule) was added. After 5 hours, the solvent was removed in vacuo and the residue was dissolved in ethyl acetate ethyl acetate (50 mL). Wash ,%, 15 ml), dehydrate dry over anhydrous magnesium sulfate, and concentrate to a low volume. The residue was dissolved in acetonitrile and taken to dryness (x3) to remove residual water to give the title compound (1%) as the cis isomer (preparation u). 92199 -129 - 1285641 Preparation 14 () 4 chloro-2-ethyl-6-trifluoromethyl 3,4-dihydro 2 Η ^ Kui, Lin small carboxylic acid ethyl ester (Method 2) S&gt;2•ethyl hydroxy-hydroxytrifluoromethyl-3,4-diar-argon-2 quinone-quinoline small carboxylic acid

Ml備13 ’ U克’ 3·47毫莫耳)在環境溫度及氮氣下溶於二 氯化亞瓴醯（20毫升）中。於i小時後，添加Ν，Ν-二甲基甲醯 胺（2滴），並將混合物在環境溫度下攪拌丨5小時。在減壓下 多除岭浏，並使殘留物於矽膠上層析，以醋酸乙酯-己烷％ • 1 /合離，獲得標題化合物，為黃色油（4〇5毫克），具有極類 似關於製備12所獲得之質子光譜，惟混合物之主要與 較小成份逆轉。 實例1Ml was prepared at 13 ‘U gram '3·47 mmol) and dissolved in hydrazine dichloride (20 mL) at ambient temperature under nitrogen. After i hours, hydrazine, hydrazine-dimethylformamide (2 drops) was added, and the mixture was stirred at ambient temperature for 5 hours. The residue was purified by EtOAc (EtOAc m. Regarding the proton spectrum obtained in Preparation 12, only the mixture was mainly reversed with the smaller component. Example 1

4-(3,5-雙-三氟甲基-苯甲醯基）-6义二甲氧基甲基_2η-喹啉+羧 酸乙酯 將按上述在乙醚中製成溶液之4·重氮基_6,7_二甲氧基丨甲 基-3,4-二氫-2Η-喹啉小羧酸乙酯（製備7，〇·65毫莫耳）之溶液 ’添加至氣化335-雙三氟甲基苯甲醯（18〇毫克，〇·65毫莫耳） 與Ν，Ν-二異丙基乙胺（12〇微升，0.65毫莫耳）在乙醚⑴毫升） 中之溶液内，並將其在室溫及氮氣下，於黑暗中攪拌丨5 92199 -130- 1285641 時。在真空下移除溶劑’並使殘留物於硬膠上層析，以己 烷：醋酸乙酯3 : 1溶離，獲得部份純化之產物，使其藉逆 相層析進一步純化（線性乙腈：水梯度液，55%至100%乙腈 ，兩相均含有甲酸）’而得標題化合物，為檸檬黃固體（9〇 毫克）。 MS : 518.1 [M+H]+實測值 1H-NMR (CDC13) (5 8·26 (s，2H)，8.07 (s，1H)，7·25 (brs，1H)，7.04 (s，1H)， 6·32 (d，J=6.64Hz，1H)，5·31 (m，1H)，4.33 (m，1H)，4·23 (m，1H)，3.91 (s，3H)， 3.80 (s，3H)，1.33 (t，J=7.47Hz，3H)，L20 (d，J=6.64Hz，3H). 實例24-(3,5-Bis-Trifluoromethyl-benzylidene)-6-yidimethoxymethyl 2 η-quinoline + ethyl carboxylate will be prepared as a solution in diethyl ether as described above. A solution of diazo- 6,7-dimethoxyindole methyl-3,4-dihydro-2-indole-quinoline carboxylic acid ethyl ester (Preparation 7, 〇·65 mmol) was added to gasification. 335-bistrifluoromethylbenzamide (18 mg, 〇·65 mmol) with hydrazine, hydrazine-diisopropylethylamine (12 〇 microliters, 0.65 mmol) in diethyl ether (1 mL) The solution was stirred at room temperature under nitrogen at 丨5 92199 -130 - 1285641 in the dark. The solvent was removed under vacuum and the residue was chromatographed on EtOAc EtOAc (EtOAc) elute A water gradient (55% to 100% acetonitrile, both phases containing formic acid) afforded the title compound as a yellow solid (9 mg). MS : 518.1 [M+H] + found 1H-NMR (CDC13) (5 8·26 (s, 2H), 8.07 (s, 1H), 7·25 (brs, 1H), 7.04 (s, 1H) , 6·32 (d, J=6.64Hz, 1H), 5·31 (m, 1H), 4.33 (m, 1H), 4·23 (m, 1H), 3.91 (s, 3H), 3.80 (s , 3H), 1.33 (t, J = 7.47 Hz, 3H), L20 (d, J = 6.64 Hz, 3H). Example 2

⑻-4-[(3,5-雙-三氟甲基-苯基)-羥基-甲氧羰基-甲基]-2-乙基-6_三 氟甲基-2Η-喹啉小羧酸乙酯 3,5-雙（三氟甲基苯基）溴化鎂之溶液，係於35。〇下，經由將3,5-雙三氟甲基溴苯（0.818毫升，4.74毫莫耳）在無水四氫呋喃（〇.7 毫升）中之溶液，逐滴添加至鎂粉（116毫克，4.74毫莫耳）在 無水四氫呋喃（4.7毫升）中之經攪拌懸浮液内而製成。然後 ’將混合物於回流下加熱1小時’獲得暗色溶液。於-78°C下 ，將此溶液之一部份（1.5毫升）逐滴添加至（R)-2-乙基-4-甲氧基 碳談基-6-三氣甲基-2Η-^ 17林小致故乙®旨（製備1〇，133毫克， 92199 -131 - 1285641 0.345耄莫耳）在無水四氫呋喃（4毫 、 ^ ; T &lt;落液内。於30分# 後’使混合物溫熱至〇°c ,並倒入 、 、， 甲，及以醋酸乙酯萃取 ’添加數滴2N鹽酸，以幫助液厣 η , 不力及層刀離。使有機層以無水硫 鉍鈉脫水乾燥，並蒸發至乾酒。 孔口 以疋全類似之方式重複此 程序，使用無水四氫咬喃（5毫升）中之齡乙基冰甲氧基碳 窥基-6-三氟甲基-2Η+林-㈣酸乙酷（製備1〇，235毫克，讀 毫莫耳），並添加3,5-雙（三氟甲基笨基）漠化鎮溶液(2毫升）。 使合併之粗產物於碎膠上層析’以醋酸乙醋-己燒梯度液， 從5%至30%溶離，獲得標題化合物，為非對映異構物之混 合物（463毫克），其係繼續進行而未被分離。 MS : 597·9 [Μ-ΗΓ 實測值 非對映異構物 1 : 1H-NMR (CDC13) (5 7·92 (s，2Η)，7·75 (s，1Η)，7.67 (s，1Η)，7.65 (d，J=8.30Hz，1Η)，7·34 (dd，J=8.30, 1,66Hz，1Η)，5·97 (d，J=6.64 Hz，1H)，5.04 (m5 1H)，4.53 (s，1H)，4·27 (m，2H)，3.87 (s，3H)，1.47 (m，1H)， 1.35 (m，1H)，1.28 (t，J=7.47Hz，3H)，0.85 (d，J=6.64Hz，3H). MS : 597.9 [M-H]·實測值 非對映異構物 2 ·· 1 H-NMR (CDC13) 5 8.16 (s，2H)，7.90 (s，1H)，7·65 (d，J=8.30，1H)，7.63 (s，1H)，7.45 (dd，J=8.30, 1·66Ηζ，1H)，5.82 (d，J=6.42Hz， 1H)，4.96 (m，1H)，4_34 (s，1H)，4.27 (m，2H)，3.78 (s，3H)，1.47 (m，1H)，1.35 (m, 1H), 1.33 (t, J=7.47Hz5 3H), 0.83 (d, J=7.47Hz, 3H). 實例3與4 92199 -132- 1285641 (R，R)斗[(3,5-雙-三氟(8)-4-[(3,5-Bis-Trifluoromethyl-phenyl)-hydroxy-methoxycarbonyl-methyl]-2-ethyl-6-trifluoromethyl-2Η-quinolinecarboxylic acid A solution of ethyl 3,5-bis(trifluoromethylphenyl)magnesium bromide, at 35. Under the armpit, a solution of 3,5-bis-trifluoromethylbromobenzene (0.818 ml, 4.74 mmol) in anhydrous tetrahydrofuran (〇.7 ml) was added dropwise to magnesium powder (116 mg, 4.74 m). Mol) was prepared in a stirred suspension in anhydrous tetrahydrofuran (4.7 mL). Then, the mixture was heated under reflux for 1 hour to obtain a dark solution. One part (1.5 ml) of this solution was added dropwise to (R)-2-ethyl-4-methoxycarboyl-6-trimethylmethyl-2Η-^ at -78 °C. 17 Lin Xiaozhi et al. (preparation 1 〇, 133 mg, 92199-131 - 1285641 0.345 耄 Mo) in anhydrous tetrahydrofuran (4 mM, ^; T &lt; falling solution. After 30 minutes # after 'make the mixture Warm to 〇 °c, and pour in, and, and extract with ethyl acetate. Add a few drops of 2N hydrochloric acid to help the liquid 厣 η, weak and layer knife. The organic layer is dehydrated and dried with anhydrous sodium sulphate. And evaporate to dry wine. The procedure is repeated in a similar manner, using an anhydrous tetrahydrocarbamate (5 ml) in the age of ethyl ice methoxy carbonyl 6-trifluoromethyl-2 hydrazine. + Lin-(iv) acid B (prepared 1 〇, 235 mg, read millimolar), and added 3,5-bis(trifluoromethylphenyl) desertification solution (2 ml). The title compound was obtained as a mixture of diastereomers (463 mg) eluting with EtOAc EtOAc. Separation. MS : 597 ·9 [Μ-ΗΓ measured value diastereomer 1 : 1H-NMR (CDC13) (5 7·92 (s, 2Η), 7·75 (s, 1Η), 7.67 (s, 1Η), 7.65 (d, J = 8.30 Hz, 1 Η), 7·34 (dd, J = 8.30, 1, 66 Hz, 1 Η), 5.97 (d, J = 6.64 Hz, 1H), 5.04 (m5 1H), 4.53 ( s, 1H), 4·27 (m, 2H), 3.87 (s, 3H), 1.47 (m, 1H), 1.35 (m, 1H), 1.28 (t, J = 7.47 Hz, 3H), 0.85 (d , J = 6.64 Hz, 3H). MS: 597.9 [MH]···································· · 65 (d, J = 8.30, 1H), 7.63 (s, 1H), 7.45 (dd, J = 8.30, 1.66 Ηζ, 1H), 5.82 (d, J = 6.42 Hz, 1H), 4.96 (m, 1H), 4_34 (s, 1H), 4.27 (m, 2H), 3.78 (s, 3H), 1.47 (m, 1H), 1.35 (m, 1H), 1.33 (t, J = 7.47Hz5 3H), 0.83 (d, J = 7.47 Hz, 3H). Examples 3 and 4 92199 -132 - 1285641 (R,R) bucket [(3,5-bis-trifluoro)

甲基-笨基）-甲氧羰基-甲基]-2-乙 基三氟 甲基-2H-喹啉-1-幾酸乙酯Methyl-phenyl)-methoxycarbonyl-methyl]-2-ethyltrifluoromethyl-2H-quinoline-1-carboxylic acid ethyl ester

(R，S)-4-[(3&gt;雙-三氟甲基-苯基甲氧羰基呷基碎乙基·卜三氣甲 基-2H-4：淋-1-幾酸乙酯 於⑻-4-[(3&gt;雙、三氟甲基.苯基）_經基_甲氧幾基-甲基於乙基 6-三氟m嗜琳领酸乙酯（實例2，125毫克，〇·观毫莫 耳）與2,6_二第三-丁基斗甲基吡啶（256毫克，1·248毫莫耳）在 氯仿(7毫升)中之溶液内’添加二氯化亞硫醯(30·4微升，0.417 毫莫耳）。於環境溫度下攪拌1δ小時後，將混合物以二氯甲 烷稀釋，以水洗滌，並以無水硫酸鈉脫水乾燥。在真空下 移除溶劑彳4，使殘留物於謂上層#，以醋酸乙§旨_己燒梯 度液，從0%至40%溶離，獲得4_[(3,5_雙_三氟甲基·苯基）_氯_ 曱氧羰基-甲基]-2-乙基-6-三氟甲基-2Η-喹啉-1-羧酸乙酯，為非 對映異構物之混合物。使此物質（128毫克）溶於四氫呋喃（2 92199 -133- 1285641 。添加鋅粉（200毫克，3.05 I酸（1.5毫升）。將此懸浮液於環境溫度 、二氣甲烷稀釋，並以水洗滌。使有機 乾燥，並於真空下蒸發至乾涸。使殘 以二氯甲烷-己烷梯度液，從60%至80 毫升）與醋酸（2毫升）之混合物中。 宅莫耳），接著是2N鹽酸（L5毫升）。 下攪拌3小時，然後以二氣甲烷稀釋 層以無水硫酸鈉脫水乾燥，並於真 留物於矽膠上層析，以二f甲惊-? %溶離，獲得標題化合物： 非對映異構物1 : 44毫克 MS: 584.0 [M+Hf實測值 1H-NMR (CDC13) δ 7.79 (s3 1H), 7.76 (s5 2H), 7.74 (d, J=8.30Hz3 1H), 7.47 (d，J=8.30Hz，1H)，7.41 (s，1H)，6.02 (d，J=6.64Hz，1H)，5·12 (s，1H)，5.01 (m， 1H)，4.26 (m，2H)，3.82 (s，3H)，1·53 (m，1H), 1·40 (m，1H)，1.30 (t，J=7.47Hz， 3H)，0.87 (d，J=7.47Hz，3H). 非對映異構物2: 16毫克 MS: 584.0 [M+Hf實測值 1 H-NMR (CDC13) 5 7.88 (s，2H)，7.87 (s，1H)，7.77 (d，J=8.30Hz，1H)，7.49 (d，J=8.30Hz，1H)，7.33 (s，1H)，5.96 (d，J=5.81Hz，1H)，5·07 (s，1H)，5.00 (m， 1H)，4.29 (m，2H)，3·74 (s，3H)，1.47 (m，1H)，1.36 (m5 1H)，1.34 (t，J=7.47Hz， 3H)，0,84 (d，J=7.47Hz，3H). 實例5與6(R,S)-4-[(3&gt; bis-trifluoromethyl-phenylmethoxycarbonyl sulfhydrylethyl)-tris-methyl-2H-4: leu--1-acid ethyl ester (8) -4-[(3&gt; bis, trifluoromethyl.phenyl)-trans-methoxy-methoxy-methyl-ethyl-6-trifluorom-ethyl ester (Example 2, 125 mg, hydrazine) · Viewing millimolar and adding 2,6-di-t-butyl-tert-methylpyridine (256 mg, 1.248 mmol) in chloroform (7 ml) (30·4 μL, 0.417 mmol). After stirring at ambient temperature for 1δ hours, the mixture was diluted with dichloromethane, washed with water and dried over anhydrous sodium sulfate. The residue is dissolved in a gradient of 0% to 40% with a gradient of acetic acid to obtain 4_[(3,5-bis-trifluoromethylphenyl)_chloro- 曱Ethyloxymethyl-methyl]-2-ethyl-6-trifluoromethyl-2-indole-quinoline-1-carboxylate as a mixture of diastereomers. This material (128 mg) was dissolved. Tetrahydrofuran (2 92199 -133-1285641. Add zinc powder (200 mg, 3.05 I acid (1.5 ml). This suspension is at ambient temperature, two Methane was diluted and washed with water. The organics were dried and evaporated in vacuo to dryness eluting with methylene chloride-hexane gradient from 60% to 80 <RTIgt; Moer), followed by 2N hydrochloric acid (L5 ml). Stir for 3 hours, then dilute the layer with di-methane to dryness with anhydrous sodium sulfate, and chromatograph on the solid residue on the tannin extract. The title compound was obtained as the title compound: diastereomer 1 : 44 mg MS: 584.0 [M+Hf </ RTI> NMR (CDC13) δ 7.79 (s3 1H), 7.76 (s5 2H), 7.74 (d, J =8.30Hz3 1H), 7.47 (d, J=8.30Hz, 1H), 7.41 (s,1H), 6.02 (d,J=6.64Hz,1H),5·12 (s,1H),5.01 (m, 1H), 4.26 (m, 2H), 3.82 (s, 3H), 1·53 (m, 1H), 1·40 (m, 1H), 1.30 (t, J = 7.47 Hz, 3H), 0.87 (d , J = 7.47 Hz, 3H). Diastereomer 2: 16 mg MS: 584.0 [M+Hf found 1 H-NMR (CDC13) 5 7.88 (s, 2H), 7.78 (s, 1H), 7.77 (d, J = 8.30 Hz, 1H), 7.49 (d, J = 8.30 Hz, 1H), 7.33 (s, 1H), 5.96 (d, J = 5.81 Hz, 1H), 5·07 (s, 1H) ), 5.00 (m, 1H), 4.29 (m, 2H), 3·74 (s, 3H), 1.47 (m, 1H), 1.36 (m5 1H), 1.34 (t, J = 7.47 Hz, 3H), 0, 84 (d, J = 7.47 Hz , 3H). Examples 5 and 6

92199 -134- 1285641 (1^11，；^)-4-[(3,5-雙-二氟甲基-苯基）-甲氧羰基_甲基]_2_乙基各 二氟甲基-3,4-二氫-2H”奎#木-1-羧酸乙酯92199 -134- 1285641 (1^11,;^)-4-[(3,5-bis-difluoromethyl-phenyl)-methoxycarbonyl-methyl]_2-ethyldifluoromethyl- 3,4-Dihydro-2H" Kui #木-1-carboxylic acid ethyl ester

(RS，SR，SR)-4-[(3,5-雙-三氟甲基_苯基 &gt; 甲氧羰基-甲基]-2_乙基各 二氣甲基-3,4-二氫-2H…奎淋小叛酸乙酯 於4-氯基-2-乙基各三氟甲基二氫-2沁喹啉小羧酸乙酯（製 備12，275毫克，〇·82毫莫耳）與3,5_雙（三氟甲基苯基）醋酸甲 酯（286毫克，1毫莫耳）在無水二甲基甲醯胺（2毫升）中之溶 液内，添加1，8-一氮雙環并[5.4.0]十一 +晞（DBU，〜100毫克）。 將混合物於環境溫度下攪拌24小時，然後在5(rCT15小時。 將/把合物倒入水中’藉由添加少量2N鹽酸酸化，並以二氯 曱烷萃取（x3)。使萃液以無水硫酸鈉脫水乾燥，蒸發至乾涸 ’並使殘留物首先藉逆相層析，且最後於矽膠上藉層析純 化，以己烷-醋酸乙酯6 : 1溶離，獲得標題化合物。 (RS，SR，RS)-4-[(3,5-雙-三氟甲基-苯基甲氧羰基_甲基]-2•乙基各 三氟甲基-3,4-二氫-2H-喹啉-1-羧酸乙酯（ns毫克，第一個溶離 出之非對映異構物） MS · 586·0 [M+H]+ 實測值 1H-NMR (CDC13) 5 7.90 (s, 2H), 7.87 (s5 1H)5 7.59 (d, J=8.30Hz, 1H), 7.62 (d, J=8.30Hz, 1H), 7.61 (s5 1H), 4.39-4.27 (m, 2H), 4.27-4.18 (m, 1H), 3.78 (d, 92199 -135 - 1285641 J=11.61Hz，1H)，3.59 (m，1H)，3.48 (s，3H)，1.76 (ddd，J=14.10, 8.30, 3·30Ηζ， 1H), 1.61-1.55 (m, 1H), 1.57-1.50 (m, 1H), 1.48-1.40 (m, 1H), 1.35 (t, J=7.47Hz, 3H), 0.73 (t, J=7.47Hz, 3H). (1^，31^11&gt;4-[(3,5-雙-三氟甲基-苯基）-甲氧羰基-曱基]-2-乙基-6-三氟甲基-3,4-二氫-2H-喹啉-1-羧酸乙酯（33.7毫克，第二個溶離 出之非對映異構物） MS: 586.0 [Μ+ΗΓ實測值 1H-NMR (CDC13) 5 7·66 (s，1H)，7.42 (d，J=8.30Hz，1H)，7.40 (s，2H)，7.33 (dd, J=8.30, 1·66Ηζ，1H)，6.47 (d，J=1.66Hz，1H)，4·55-4·47 (m，1H)，4.34 (m， 1H)3 4.32 (m5 1H)3 3.83 (d, J=11.61Hz5 1H)5 3.80 (s5 3H), 3.43 (ddd5 J=1L61, 4.98, 2.49Hz，1H)，2.44 (ddd，J=14.11，8.30, 2.49Hz，1H)，1·81 (ddd，J=14.10， 8.30, 4.98Hz，1H)，1.67 (m，1H)，1.51 (m，1H)，1.33 (t，J=7.47Hz，3H)，0.85 (t， J=7.47Hz, 3H). 實例7與8(RS, SR, SR)-4-[(3,5-bis-trifluoromethylphenyl) methoxycarbonyl-methyl]-2-ethyldimethyl-3,4-di Hydrogen-2H...Querone small acid-depleted ethyl ester in 4-chloro-2-ethyl-trifluoromethyldihydro-2沁quinoline small carboxylic acid ethyl ester (preparation 12,275 mg, 〇·82 mmol) To the solution of 3,5-bis(trifluoromethylphenyl)acetate (286 mg, 1 mmol) in anhydrous dimethylformamide (2 mL), add 1,8- Azabicyclo[5.4.0]11+晞 (DBU, ~100 mg). Stir the mixture at ambient temperature for 24 hours, then at 5 (rCT for 15 hours. Pour / pour into water) by adding Acidified with a small amount of 2N hydrochloric acid, and extracted with dichloromethane (x3). The extract was dried over anhydrous sodium sulfate, evaporated to dryness, and the residue was purified by reverse phase chromatography, and finally purified by chromatography on silica gel. The title compound was obtained by hexane-ethyl acetate 6:1. (RS,SR,RS)-4-[(3,5-bis-trifluoromethyl-phenylmethoxycarbonyl-methyl)- 2•Ethyl ethyltrifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (ns mg, the first dissolution is not correct Isomers) MS · 586·0 [M+H]+ found 1H-NMR (CDC13) 5 7.90 (s, 2H), 7.87 (s5 1H)5 7.59 (d, J = 8.30 Hz, 1H), 7.62 (d, J=8.30Hz, 1H), 7.61 (s5 1H), 4.39-4.27 (m, 2H), 4.27-4.18 (m, 1H), 3.78 (d, 92199 -135 - 1285641 J=11.61Hz, 1H ), 3.59 (m, 1H), 3.48 (s, 3H), 1.76 (ddd, J=14.10, 8.30, 3.30Ηζ, 1H), 1.61-1.55 (m, 1H), 1.57-1.50 (m, 1H) , 1.48-1.40 (m, 1H), 1.35 (t, J=7.47Hz, 3H), 0.73 (t, J=7.47Hz, 3H). (1^,31^11&gt;4-[(3,5- Ethyl bis-trifluoromethyl-phenyl)-methoxycarbonyl-indenyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate ( 33.7 mg, the second diastereomeric diastereomer) MS: 586.0 [Μ+ΗΓ measured 1H-NMR (CDC13) 5 7·66 (s, 1H), 7.42 (d, J = 8.30 Hz, 1H), 7.40 (s, 2H), 7.33 (dd, J=8.30, 1.66Ηζ, 1H), 6.47 (d, J=1.66Hz, 1H), 4·55-4·47 (m, 1H), 4.34 (m, 1H)3 4.32 (m5 1H)3 3.83 (d, J=11.61Hz5 1H)5 3.80 (s5 3H), 3.43 (ddd5 J=1L61, 4.98, 2.49Hz, 1H), 2.44 (ddd, J =14.11, 8.30, 2.49 Hz, 1H), 1·81 (ddd, J=14.10, 8.30, 4.98 Hz, 1H), 1.6 7 (m, 1H), 1.51 (m, 1H), 1.33 (t, J = 7.47 Hz, 3H), 0.85 (t, J = 7.47 Hz, 3H). Examples 7 and 8

阳，1^，311)-4-[(3,5-雙-三氟甲基-苯基）-曱氧羰基-甲基设乙基各 三It甲基-3,4-二氫-2H-p奎淋小叛酸乙|| 92199 -136- 1285641阳,1^,311)-4-[(3,5-bis-trifluoromethyl-phenyl)-oximeoxycarbonyl-methyl-ethyl-ethyl each three-It-methyl-3,4-dihydro-2H -p奎淋小叛酸乙|| 92199 -136- 1285641

阳邮^^叫阳-雙-王氟甲基-苯基^甲氧羰基-甲基峰乙基各 二氟甲基-3,4-二氫-2H-p奎淋-1-羧酸乙酉旨 使(RS，RS)-4-[(3,5-雙-三氟甲基-苯基 &gt;甲氧羰基，基•乙基冬 二氟甲基-2H-喹啉小羧酸乙酯與⑽，SR)冬[(3,5-雙_三氟甲基·苯 基）-甲氧羰基-甲基]-2-乙基-6-三氟甲基-2H-喹啉-1-羧酸乙酯 (藉由完全類似關於實例3與4所述之程序製成，惟使用外消 旋起始物質，且所產生之非對映異構物之混合物未被分離） (20耄克，0.0342毫莫耳）在含有氫氧化鈀（2〇% /碳，2〇毫克） 足乙醇（5毫升）中之混合物，在帕爾振盪器（帕爾儀器公司， Molme，Illinols)中，於40 psi下氫化5小時。經過Celite®，藉過濾 移除觸媒，並於真空下移除溶劑。使殘留物於矽膠上層析 ，以醋酸乙酯-己烷梯度液，從0%至1〇%溶離，獲得標題化 合物。 (RS，RS，SR)-4-[(3,5-雙-三氟甲基-苯基甲氧羰基_甲基]_2_乙基奍 二氟甲基-3,4-二氫-2H-4啉-1-羧酸乙酯（第一個溶離出之非對 映異構物，8毫克） MS: 586.0 [M+H]+實測值 1H-NMR (CDC13) 5 7.89 (s，1H)，7.88 (s，2H)，7.53 (m，2H)，7·39 (s，1H)， 92199 -137- 1285641 4.55-4.47 (m，1H)，4.34-4.24 (m，2H)，4.24-4.18 (m，1Η)，4·03 (d，J= 11.62Hz， 1H)，3.77 (s，3H)，3.38 (m，1H)，1.75 (m，1H)，1.49 (m，1H)，1.38 (m, 1H)，1.31 (t，J=7.47Hz，3H)，0.96 (m，1H)，0.71 (t，J=7.47Hz，3H). (113，义3，113)-4-[(3,5-雙-三氟1甲基-苯基）-甲氧羰基-甲基]-2-乙基4 三氟甲基-3,4-二氫-2H-喹啉小羧酸乙酯（第二個溶離出之非對 映:異構物，5毫克） MS : 586.0 [M+Hf 實測值 1H-NMR (CDC13) 5 7.93 (s，2H)，7.84 (s，1H)，7.53 (d，J=8.29Hz，1H)，7.43 (dd5 J=8.29Hz, 1H), 7.07 (s, 1H)? 4.42 (m, 1H), 4.27 (d, J=9.96Hz3 1H), 4.26 (m3 2H)，4.32 (m，1H)，3.76 (s，3H)，3.28 (m，1H)，2.36 (m，1H)，1.65 (m，1H)，1.62 (m，1H)，1.45 (m，1H)，1.31 (t，J=7.47Hz，3H)，0·84 (t，J=7.47Hz，3H)· 實例9與10阳邮^^叫阳-双-王fluoromethyl-phenyl^methoxycarbonyl-methyl peak ethyldifluoromethyl-3,4-dihydro-2H-p-quinone-1-carboxylic acid acetam RS(RS,RS)-4-[(3,5-Bis-Trifluoromethyl-phenyl]methoxycarbonyl, yl-ethyl-t-butyl difluoromethyl-2H-quinoline carboxylic acid ethyl ester And (10), SR) Winter [(3,5-bis-trifluoromethylphenyl)-methoxycarbonyl-methyl]-2-ethyl-6-trifluoromethyl-2H-quinoline-1- Ethyl carboxylate (prepared by procedures analogously to those described in Examples 3 and 4 except that the racemic starting material was used and the resulting mixture of diastereomers was not isolated) (20 gram) , 0.0342 millimolar) in a mixture containing palladium hydroxide (2% by weight / carbon, 2 mg) of ethanol (5 ml) in a Parr oscillator (Pal Instrument, Molme, Illinols) Hydrogenation at 40 psi for 5 hours. After removal through Celite®, the catalyst is removed by filtration and the solvent is removed under vacuum. The residue was chromatographed on EtOAc (EtOAc) elute (RS,RS,SR)-4-[(3,5-bis-trifluoromethyl-phenylmethoxycarbonyl-methyl]_2-ethyl fluorene difluoromethyl-3,4-dihydro-2H Ethyl 4-linoline-1-carboxylate (first dissociated diastereomer, 8 mg) MS: 586.0 [M+H] + found 1H-NMR (CDC13) 5 7.89 (s, 1H ), 7.88 (s, 2H), 7.53 (m, 2H), 7·39 (s, 1H), 92199 -137- 1285641 4.55-4.47 (m, 1H), 4.34 - 4.24 (m, 2H), 4.24 4.18 (m,1Η),4·03 (d,J= 11.62Hz, 1H), 3.77 (s,3H), 3.38 (m,1H), 1.75 (m,1H), 1.49 (m,1H),1.38 (m, 1H), 1.31 (t, J = 7.47 Hz, 3H), 0.96 (m, 1H), 0.71 (t, J = 7.47 Hz, 3H). (113, sense 3, 113)-4-[( 3,5-bis-trifluoro-1methyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl 4 trifluoromethyl-3,4-dihydro-2H-quinoline small carboxylic acid ethyl ester (Second dissolved diastereoisomer: isomer, 5 mg) MS: 586.0 [M+Hf found 1H-NMR (CDC13) 5 7.93 (s, 2H), 7.84 (s, 1H), 7. d, J=8.29 Hz, 1H), 7.43 (dd5 J=8.29 Hz, 1H), 7.07 (s, 1H)? 4.42 (m, 1H), 4.27 (d, J=9.96Hz3 1H), 4.26 (m3 2H ), 4.32 (m, 1H), 3.76 (s, 3H), 3.28 (m, 1H), 2.36 (m, 1) H), 1.65 (m, 1H), 1.62 (m, 1H), 1.45 (m, 1H), 1.31 (t, J = 7.47 Hz, 3H), 0·84 (t, J = 7.47 Hz, 3H)· Examples 9 and 10

(R，S，S)-4-[(3,5-雙-三氟甲基-苯基）-氰基-甲基]-2-乙基-6-三氟甲基- 3,4-二氫奎淋小瘦酸乙酯(R,S,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6-trifluoromethyl-3,4- Dihydroquinone small acid ethyl ester

92199 -138- 1285641 (R，S，R)-4-[(3,5-雙 •三氟甲基-苯基）-氰基呷基]:乙基各三氟甲基 3,4-二氫-2H-峻淋-1-幾酸乙酯 水-甲基曱SS胺(2毫升）中之溶液。將混合物於環境溫度下 攪拌16小時，然後倒入水(2〇毫升)中，並以乙醚⑽毫升) 萃取。使萃液以無水硫酸鈉脫水乾燥，並於真空下移除溶 劑。使此物質於矽膠上藉層析純化’首先以醋酸乙酯-己烷 將氣化鈉（礦油中之60%分散液，34毫克，0.85毫莫耳）添 加至3,5-雙（三氟甲基苯基）乙赌(212毫克，⑽4毫莫耳）在無水 :甲基：醯胺(L5毫升)中之溶液内。於氮氣下攪拌3〇分鐘 後，在環境溫度下，添加⑻领基_2_乙基冬三氣〒基从二 氫-2H-喹啉小羧酸乙醋（製備14，1δ8毫克’ 〇56毫莫耳）在無 (1 : 19)溶離，獲得所要化合物之一種非對映異構物，呈不 純形式，使其藉逆相層析進一步純化，獲得標題化合物實 例9，為透明油（69毫克）。以醋酸乙酯·己烷（1 :句進一步溶 離矽膠管柱，提供標題化合物實例10，為黃色油（54毫克）。 (R，S，S)-4-[(3,5-雙-三氟甲基-苯基）_氰基_甲基]_2_乙基各三氟甲 基-3,4-二氫-2H-喹啉小羧酸乙酯 MS : 553 [M+Hf 實測值 1H-NMR (CDC13) δ 7.80 (s, 1H), 7.60 (d, J=8.30Hz, 1H), 7.49 (dd, J=8.30, 1·66Ηζ，1H)，7.40 (s，2H)，6.60 (d，J=1.66Hz，1H)，4·59 (m，1H)，4·33 (m，2H)， 4·06 (d，J=9.96，1H)，3.20 (m，1H)，2·78 (m，1H)，1.89 (m，1H)，L65 (m，1H)， 1.53 (m，1H)，1.34 (t，J=7.47Hz，3H)，0.96 (m，1H)，0.88 (t，JN7.47Hz，3H). (R，S，R)-4-[(3,5-雙-三氟甲基-苯基）-氣基-甲基]-2-乙基-6-三氟甲 基-3,4-二氫-2H-喹啉小羧酸乙酯 92199 -139- 1285641 MS : 553 [M+H]+ 實測值 1 H-NMR (CDC13 ) (5 7.89 (s，1H)，7·62 (s，2H)，7.62 (d，J=8.30Hz，1H)，7.55 (d，J=8.30Hz，1H)，7.38 (s，1H)，4·41 (m，1H)，4.24 (m，2H)，4.16 (m，1H)，4.15 (d，J=8.30Hz，1H)，3.48 (m，1H)，2.01 (m，1H)，1.95 (m，1H)，1.48 (m，1H)， 1.41 (m，1H)，1.29 (t，J=7.47Hz，3H)，0.77 (t，J=7.47Hz，3H). 製備1592199 -138- 1285641 (R,S,R)-4-[(3,5-Bis-trifluoromethyl-phenyl)-cyanoindolyl]:ethyl each trifluoromethyl 3,4-di A solution of hydrogen-2H-furan-1-acid ethyl ester water-methyl hydrazine SS amine (2 mL). The mixture was stirred at ambient temperature for 16 hours then poured into water (2 mL) andEtOAc The extract was dried over anhydrous sodium sulfate and the solvent was removed in vacuo. This material was purified by chromatography on silica gel. First, sodium sulphate (60% dispersion in mineral oil, 34 mg, 0.85 mmol) was added to 3,5-bis (three) with ethyl acetate-hexane. Fluoromethylphenyl) B. (212 mg, (10) 4 mmol) in a solution of anhydrous: methyl: decylamine (L5 mL). After stirring for 3 minutes under nitrogen, (8) tertyl 2 - ethyl ternary trimethyl sulfonate was added from dihydro-2H-quinoline carboxylic acid ethyl acetate at an ambient temperature (preparation 14, 1 δ 8 mg ' 〇 56 Mellow in the absence of (1:19) to obtain a diastereomer of the desired compound, which was obtained in an impure form, which was further purified by reverse phase chromatography to give the title compound as Example 9 as a transparent oil (69). Mg). Ethyl acetate and hexane (1: further elution of the ruthenium tube column provided the title compound Example 10 as yellow oil (54 mg). (R,S,S)-4-[(3,5-bis-three) Ethyl fluoromethyl-phenyl)-cyano-methyl]_2-ethyl each trifluoromethyl-3,4-dihydro-2H-quinoline carboxylic acid MS : 553 [M+Hf found 1H -NMR (CDC13) δ 7.80 (s, 1H), 7.60 (d, J = 8.30 Hz, 1H), 7.49 (dd, J = 8.30, 1.66 Ηζ, 1H), 7.40 (s, 2H), 6.60 (d , J=1.66Hz, 1H), 4·59 (m, 1H), 4·33 (m, 2H), 4·06 (d, J=9.96, 1H), 3.20 (m, 1H), 2.78 (m, 1H), 1.89 (m, 1H), L65 (m, 1H), 1.53 (m, 1H), 1.34 (t, J = 7.47 Hz, 3H), 0.96 (m, 1H), 0.88 (t, JN7.47Hz,3H). (R,S,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-carbyl-methyl]-2-ethyl-6-trifluoro Ethyl methyl-3,4-dihydro-2H-quinoline carboxylic acid 92199-139- 1285641 MS : 553 [M+H]+ found 1 H-NMR (CDC13) (5 7.89 (s, 1H) ,7·62 (s,2H), 7.62 (d, J=8.30 Hz, 1H), 7.55 (d, J=8.30 Hz, 1H), 7.38 (s, 1H), 4·41 (m, 1H), 4.24 (m, 2H), 4.16 (m, 1H), 4.15 (d, J = 8.30 Hz, 1H), 3.48 (m, 1H) , 2.01 (m, 1H), 1.95 (m, 1H), 1.48 (m, 1H), 1.41 (m, 1H), 1.29 (t, J = 7.47 Hz, 3H), 0.77 (t, J = 7.47 Hz, 3H). Preparation 15

[(R，S)，(S，R)]與[(民11)，(3,3)]-4-氰基-6,7-二甲氧基-2-甲基-4-三甲基碎 烷基氧基-3,4-二氫-2H·喳啉小羧酸乙酯 於氮大氣下，將[(R，S)]-6,7-二甲氧基-2-甲基斗酮基-3,二氫-2H”奎啉-1-羧酸乙酯（8.02克，27.3毫莫耳，1當量）與碘化鋅（0.43 克，1.37毫莫耳，0.05當量）添加至裝有磁攪拌棒與回流冷凝 管之乾燥圓底燒瓶中。將甲苯(20毫升）添加至燒瓶中，接著 是氰化三甲基矽烷（4.40毫升，33.0毫莫耳，1,2當量）^將反 應物加熱至80°C。於5小時後，使反應混合物濃縮至乾酒， 而得標題化合物（10.7克，27.2毫莫耳，100%產率），使用之 而無需進一步純化。 LCMS(ESI+)： 393 (MH+). 製備16[(R,S),(S,R)] and [(Min 11), (3,3)]-4-cyano-6,7-dimethoxy-2-methyl-4-trimethyl Ethyl succinyloxy-3,4-dihydro-2H·carboline carboxylic acid ethyl ester under nitrogen atmosphere, [(R,S)]-6,7-dimethoxy-2-methyl Ethyl ketone-3,dihydro-2H"quinoline-1-carboxylate (8.02 g, 27.3 mmol, 1 eq.) was added to zinc iodide (0.43 g, 1.37 mmol, 0.05 eq.) to In a dry round bottom flask equipped with a magnetic stir bar and a reflux condenser. Toluene (20 mL) was added to the flask followed by trimethyldecane cyanide (4.40 mL, 33.0 mmol, 1, 2 equivalents)^ The reaction was warmed to <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> <RTIgt; ESI+): 393 (MH+). Preparation 16

92199 -140- 1285641 (R，S)-4-夜基-6,7-二甲氧基-2-甲基-2H-峻琳小叛酸乙酉旨 將[(R，S)，(S，R)]與[(氏幻必⑺^-氨基^了-二—氧基^-甲基-木三甲 基石夕燒基氧基-3,4-二氫-2H-0奎#木-1-幾酸乙醋（1〇·7克，27.37毫莫 耳）放置在100 4:升圓底燒瓶中，並溶於乙醇（25毫升）中。將 二氧陸圜中之鹽酸（21.0毫升，4·0 Μ溶液）添加至混合物中。 於室溫下12小時後，使反應混合物濃縮，以飽和碳酸氫鋼 水溶液使反應淬滅，並以醋酸乙酯萃取3次。使合併之有機 層以無水硫酸鈉脫水乾燥，過濾，及濃縮。急驟式層析， 以80/20己烷/醋酸乙酯溶離，標題化合物（5.49克，18.1毫莫 耳，67%產率）。 LCMS (ESI+) : 303 (ΜΗ+). 1H-NMR (CDC13) : 5 U3 (d5 3Η)，1.33 (t，3Η)，3·90 (s，3Η)，3.92 (s，3Η)， 4·30 (m，2Η)，5·25 (m，1Η)，6.65 (d，1Η)，6·91 (s，1Η)，7·24 (brs，1Η). 製備17與1892199 -140- 1285641 (R,S)-4-Night-6,7-Dimethoxy-2-methyl-2H-Junlin Small Resin Ethylene ([R,S),(S, R)] and [(氏氏必(7)^-amino^-di-oxy^-methyl-xytrimethyl sulphateoxy-3,4-dihydro-2H-0 奎#木-1- A few acid vinegar (1 〇·7 g, 27.37 mmol) was placed in a 100 4: liter round bottom flask and dissolved in ethanol (25 ml). Hydrochloric acid in dioxane (21.0 ml, 4 0 Μ solution) was added to the mixture. After 12 hours at room temperature, the reaction mixture was concentrated, the reaction was quenched with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate three times. The title compound (5.49 g, 18.1 mmol, 67% yield) was obtained eluted eluted eluted eluted eluted (ΜΗ+). 1H-NMR (CDC13): 5 U3 (d5 3Η), 1.33 (t, 3Η), 3·90 (s, 3Η), 3.92 (s, 3Η), 4·30 (m, 2Η) , 5·25 (m, 1Η), 6.65 (d, 1Η), 6.91 (s, 1Η), 7·24 (brs, 1Η). Preparations 17 and 18

[(R，S)，((S，R)]與[(氏幻，(3,3)]冬氰基-6,7-二甲氧基-2-曱基-3,4_二氫-2Η-ρ奎淋-1-叛酸乙酉旨 將（R，S)-4-氰基-6,7-二甲氧基-2-甲基-2H-喹啉-1-羧酸乙酯（4.99 克’ 16.5毫莫耳）放置在裝有磁撥拌棒之圓底燒瓶中，溶於47 毫升乙醇中，並與硼氫化鈉（3.18克，84·3毫莫耳，5.1當量） 合併。於回下加熱45分鐘後，使混合物濃縮至乾酒，以 水使反應淬滅，並以醋酸乙酯萃取3次。收集有機層，以硫 92199 - 141 - 1285641 酸鈉脫水乾燥，過濾，及濃縮，而得標題化合物（4.91克，16.1 毫莫耳，98%產率）。 順式異構物： LCMS (ESI+) ： 305 (MH+). (R，S)與（S，R)1H-NMR (CDC13 )·· 51·23 (d，3H)，1.29 (t，3H)，1·78 (m，1H)， 2·65 (m，1H), 3.74 (m，1H)，3.86 (s，3H)，3·90 (s，3H)，4.22 (m，2H)，4·61 (m， lH)，6.92(s，lH)，7.10(s，1H)· 反式異構物： LCMS (ESI+) : 305 (MH+). (R，R)與（S，S)1H-NMR (CDC13): 51.16 (d，3H)，L32 (t，3H)，2.03 (m，1H)， 2.42 (m，1H)，3.87 (s，3H)，3.88 (s，3H)，3.94 (m，1H)，4·26 (m，2H)，4.86 (m， lH)，6.77(s，lH)，7.30(s，1H)· 製備19與20[(R,S),((S,R)] and [(Crystal, (3,3)] Winter Cyano-6,7-Dimethoxy-2-indolyl-3,4-dihydrogen -2Η-ρ奎淋-1- 叛 酸 酉 酉 酉 酉 ( ( ( ( ( ( ( ( ( ( ( R R R R R R R R R (4.99 g ' 16.5 mmol) placed in a round bottom flask equipped with a magnetic stir bar, dissolved in 47 ml of ethanol and combined with sodium borohydride (3.18 g, 84·3 mmol, 5.1 equivalent) After heating for an additional 45 minutes, the mixture was concentrated to dryness and the mixture was evaporated to dryness eluting with ethyl acetate. The organic layer was collected and dried over sodium sulfate s s s s s s. The title compound (4.91 g, 16.1 mmol, 98% yield). </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; -NMR (CDC13)·· 51·23 (d,3H), 1.29 (t,3H),1·78 (m,1H), 2·65 (m,1H), 3.74 (m,1H),3.86 ( s,3H),3·90 (s,3H), 4.22 (m,2H),4·61 (m, lH), 6.92(s,lH),7.10(s,1H)·trans isomer: LCMS (ESI+): 305 (MH+). (R, R) and (S,S)1H-NMR (CDC13): 51.16 (d, 3H), L 32 (t,3H),2.03 (m,1H), 2.42 (m,1H),3.87 (s,3H),3.88 (s,3H),3.94 (m,1H),4·26 (m,2H) , 4.86 (m, lH), 6.77 (s, lH), 7.30 (s, 1H) · Preparation 19 and 20

[(R，S)，(S，R)]與[(11，11)，(3,3)]-4-胺甲醯基-6,7-二甲氧基-2-甲基-3,4-二 氫-2H-p奎琳小幾酸乙酉旨 使[(R，S)，(S，R)]與[取尺⑽別冬氰基令^二甲氧基么甲基召+二 氫-2H^奎淋小叛酸乙酯（2.22克，7·32毫莫耳，1當量）溶於濃 硫酸（12毫升）與水（0.66毫升，36.6毫莫耳，5當量）中。於環 境溫度下12小時後’使反應於固態碳酸氫鈉中淬滅，溶於 水中，並以醋酸乙酯萃取3次。收集有機層，以無水硫酸鈉 脫水乾燥，過濾，及濃縮，提供標題化合物（2 25克，6·98毫 92199 -142- 1285641 莫耳，95%產率）。 LCMS (ESI+) : 323 (MH+)· [(R，S)，(S，R)]: 1 H-NMR (CDC13): ά 1.20 (d，3H)，1.30 (t，3H)，1.89 (m，1H)， 2.41 (m，1H), 3.37 (m，1H)，3.84 (s，3H)，3·86 (s，3H)，4.22 (m，2H)，4.55 (m， 1H)，5.70 (s，1H)，5.80 (s，1H)，6.70 (s，1H)，7.21 (s，1H). LCMS (ESI+) : 323 (MH+).[(R,S),(S,R)] and [(11,11),(3,3)]-4-aminecarboxamido-6,7-dimethoxy-2-methyl-3 , 4-dihydro-2H-p-quineline acid, [ 酉 [ [R, S), (S, R)] and [take the ruler (10) other winter cyano group ^ dimethoxy methyl call + Dihydro-2H^quinidine small acid methyl ester (2.22 g, 7.32 mmol, 1 eq.) was dissolved in concentrated sulfuric acid (12 mL) and water (0.66 mL, 36.6 mmol, 5 eq.). After 12 hours at ambient temperature, the reaction was quenched in solid sodium bicarbonate, dissolved in water and extracted three times with ethyl acetate. The organic layer was collected, dried over EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj LCMS (ESI+): 323 (MH+)· [(R,S), (S,R)]: 1 H-NMR (CDC13): ά 1.20 (d, 3H), 1.30 (t, 3H), 1.89 (m) , 1H), 2.41 (m, 1H), 3.37 (m, 1H), 3.84 (s, 3H), 3·86 (s, 3H), 4.22 (m, 2H), 4.55 (m, 1H), 5.70 ( s, 1H), 5.80 (s, 1H), 6.70 (s, 1H), 7.21 (s, 1H). LCMS (ESI+): 323 (MH+).

[(R，R)，(S，S)]: 1H-NMR (CDC13): 51.17 (d，3H)，1·30 (t，3H)，1·74 (m，1H)5 2.67 (m，1H)，3.55 (m，1H)，3.86 (s，3H)，3.87 (s，3H)，4.21 (m，2H)，4.58 (m， 1H)，5·36 (s，1H)，5.49 (s，1H)，6·65 (s，1H)，7.15 (s，1H). 製備21與22[(R,R),(S,S)]: 1H-NMR (CDC13): 51.17 (d,3H),1·30 (t,3H),1·74 (m,1H)5 2.67 (m, 1H), 3.55 (m, 1H), 3.86 (s, 3H), 3.87 (s, 3H), 4.21 (m, 2H), 4.58 (m, 1H), 5·36 (s, 1H), 5.49 (s , 1H), 6·65 (s, 1H), 7.15 (s, 1H). Preparation 21 and 22

[(R，s)，(s，r)]與[(氏幻办別'?-二甲氧基 基-3,4-二氫-2H_4 啉 _ 1，4-二羧酸小乙酯-4-甲酯 將[(R，S)，((S，R)]與[(11，11)，(3,3)]-4-胺甲醯基_6,7-二甲氧基冬甲基_ 3,4-二氫-2H-喹啉-μ幾酸乙酯（2.24克，6.95毫莫耳，1當量）放 置在裝有攪拌棒之1〇〇毫升圓底燒瓶中，並溶於二氯曱垸（565 笔升）中。將三甲基鑌四氟硼酸鹽（1.29克，8.76毫莫耳，i 26 當量）添加至溶液中，接著是12.2毫升較多二氯甲烷。於環 境服度下12小時後，使反應混合物濃縮至乾涸，並使用之 而無需進一步純化。使產物（2·84克，6.95毫莫耳，丨當量）溶 於水(20毫升）中，並在室溫下揽拌數小時。以氣化納溶液使 混合物飽和，以醋酸乙酯萃取3次，以硫酸鈉脫水乾燥，過 92199 -143 - 1285641 濾，及濃縮至乾涸。急驟式層析，以80/20己烷/醋酸乙酯 溶離，提供標題化合物（1.65克，4.88毫莫耳，70%產率）。 LCMS (ESI+) : 338 (MH+).[(R, s), (s, r)] and [(氏幻别别'?-Dimethoxy-3,4-dihydro-2H_4 porphyrin _ 1,4-dicarboxylic acid small ethyl ester - 4-Methyl ester will [(R,S),((S,R)] with [(11,11),(3,3)]-4-aminemethylamino]6,7-dimethoxy winter Methyl 3,4-dihydro-2H-quinoline-μ-acid ethyl ester (2.24 g, 6.95 mmol, 1 eq.) was placed in a 1 liter round bottom flask equipped with a stir bar and dissolved. In dichloropurine (565 liters), trimethylsulfonium tetrafluoroborate (1.29 g, 8.76 mmol, i 26 equivalents) was added to the solution followed by 12.2 mL of more dichloromethane. After 12 hours of environmental service, the reaction mixture was concentrated to dryness and used without further purification. The product (2·84 g, 6.95 mmol, 丨 equivalent) was dissolved in water (20 mL) and The mixture was stirred at room temperature for several hours. The mixture was saturated with a gasified sodium solution, extracted with ethyl acetate three times, dried over sodium sulfate, filtered, filtered, and concentrated to dryness. The title compound (1.65 g, 4.88 mmol, 70% yield). CMS (ESI+) : 338 (MH+).

[(R，S)(S，R)] 1 H-NMR (CDC13): 5 1.17 (d，3H)，1.29 (t，3H), 1·81 (m，1H)， 2.46 (m，1Η)，3·56 (m，1Η)，3.81 (s，3Η)，3.83 (s，3Η)，3.85 (s，3Η)，4.21 (m，2Η)， 4.55 (m，1H)，6.60 (s，1H)，7.11 (s，1H). LCMS (ESI+) ： 338 (MH+).[(R,S)(S,R)] 1 H-NMR (CDC13): 5 1.17 (d,3H), 1.29 (t,3H), 1·81 (m,1H), 2.46 (m,1Η) ,3·56 (m,1Η),3.81 (s,3Η),3.83 (s,3Η),3.85 (s,3Η), 4.21 (m,2Η), 4.55 (m,1H),6.60 (s,1H) ), 7.11 (s, 1H). LCMS (ESI+): 338 (MH+).

[(R，R)(S，S)]: 1H-NMR (CDC13): 51.13 (d，3H)，1.29 (t，3H)，1.78 (m，1H)， · 2.54 (m，1H)，3.67 (s，3H)，3.71 (m，1H)，3.84 (s，3H)，3_85 (s，3H)，4.21 (m，2H)， 4.74 (m5 1H)，6.66 (s，1H)，7.13 (s，1H). 製備23與24[(R,R)(S,S)]: 1H-NMR (CDC13): 51.13 (d,3H), 1.29 (t,3H), 1.78 (m,1H), · 2.54 (m,1H), 3.67 (s, 3H), 3.71 (m, 1H), 3.84 (s, 3H), 3_85 (s, 3H), 4.21 (m, 2H), 4.74 (m5 1H), 6.66 (s, 1H), 7.13 (s , 1H). Preparation 23 and 24

[(R，S)，(S，R)]與[(R，R)，(S，S)]-6,7^ 甲氧基-2-曱基-3,4-二氫-2H-喳啉- 1，4-二羧酸小乙酯 在具有磁攪拌棒之圓底燒瓶中，使[取习必太)]與[(民R)，(s，s)]_ 6,7-一甲氧基甲基-3,4-二氫-2H…奎#木-1，4邊酸乙酯冬甲酯（ο; 克，1,73耄莫耳，1當量）溶於二氧陸圜（12毫升）與水（12毫升） 中。添加氫氧化鈉（0·13克，3.48毫莫耳，2當量），並於室溫 下攪拌。於12小時後，使反應混合物濃縮，並在1〇N氫氧 化鈉水落液與乙醚之間作分液處理。收集水層，以濃鹽酸 酸化，並以醚萃取。收集有機層，以硫酸鎂脫水乾燥，過 濾，及濃縮，提供標題化合物（〇·536克，丨65毫莫耳，9〇%產 92199 -144 - 1285641 率），為非對映異構物之混合物。 LCMS (ESI+) : 324 (MH+).[(R,S),(S,R)] and [(R,R),(S,S)]-6,7^methoxy-2-mercapto-3,4-dihydro-2H- Small phthalocyanine-1,4-dicarboxylic acid ethyl ester in a round bottom flask with a magnetic stir bar, [[Xi Bi Bi]] and [(Min R), (s, s)] _ 6, 7-A Oxymethylmethyl-3,4-dihydro-2H... Kui #木-1, 4-acid ethyl ester methyl ester (ο; gram, 1,73 耄mol, 1 equivalent) is soluble in dioxane ( 12 ml) with water (12 ml). Sodium hydroxide (0.13 g, 3.48 mmol, 2 eq.) was added and stirred at room temperature. After 12 hours, the reaction mixture was concentrated and partitioned between 1N aqueous sodium hydroxide and diethyl ether. The aqueous layer was collected, acidified with concentrated hydrochloric acid and extracted with ether. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated to give the title compound ((··············· mixture. LCMS (ESI+): 324 (MH+).

[(R，S)，(S，R)]: 1 H-NMR(CDC13): 5 1.18 (d，3H)，1.30 (t，3H)，1.89 (m，1H)， 2.48 (m，1H)，3.61 (m，1H)，3.84 (s，3H)，3.85 (s，3H)，4_21 (m，2H)，4.60 (m， 1H)，6.75 (s，lH), 7.15 (s，1H)· LCMS (ESI+) ： 324 (MH+).[(R,S),(S,R)]: 1 H-NMR(CDC13): 5 1.18 (d,3H), 1.30 (t,3H), 1.89 (m,1H), 2.48 (m,1H) , 3.61 (m, 1H), 3.84 (s, 3H), 3.85 (s, 3H), 4_21 (m, 2H), 4.60 (m, 1H), 6.75 (s, lH), 7.15 (s, 1H)· LCMS (ESI+): 324 (MH+).

[(R，R)，(S，S)]: 1 H-NMR (CDC13): ¢51.14 (d，3H)，1.29 (t，3H)，1.83 (m，1H)， 2.56 (m，1H)，3.74 (m，1H)，3.85 (s，6H)，4.21 (m，2H)，4.76 (m，1H)，6·70 (s， lH)，7.14(s，1H)· 實例11與12[(R,R),(S,S)]: 1 H-NMR (CDC13): ¢51.14 (d,3H), 1.29 (t,3H), 1.83 (m,1H), 2.56 (m,1H) , 3.74 (m, 1H), 3.85 (s, 6H), 4.21 (m, 2H), 4.76 (m, 1H), 6.70 (s, lH), 7.14 (s, 1H) · Examples 11 and 12

[(R，S)，(S，R)]與[供，11)，(3,3)]-4-(3,5-雙-三氟甲基-爷基胺甲醯基)-6,7-二甲氧基-2-甲基-3,4-二氩-2H-喹啉小羧酸乙酯 將[(R，S)，(S，R)]與[(民11)，(3,3)]-6,7-二〒氧基-2-甲基-3,4-二氫-211-喹 啉-1，4-二羧酸小乙酯（0.229克，0.710毫莫耳）放置在裝有攪拌 棒之25毫升圓底燒瓶中。添加二氯甲烷（7.0毫升），接著添 加3,5-雙（三氟甲基）；胺（〇·519克，2.14毫莫耳，3.0當量）。於 此反應物中，添加1-羥基苯并三唑水合物（0.022克，0.146毫 莫耳，0.2當量）與1-(3-二甲胺基丙基）-3-乙基碳化二亞胺鹽酸 鹽（0.232克，1.21毫莫耳，1.7當量）。將反應混合物於室溫下 擾拌。12小時後，以水使反應淬滅，並以醋酸乙酯萃取3次 92199 -145 - 1285641 。收集有機層，以硫酸鈉脫水乾燥，過濾，濃縮，提供標 題化合物（0.1225克，0.223毫莫耳，58%產率），為非對映異 構物之混合物。 LCMS (ESI+) : 549 (MH+). 1.80 (m，1H)，2.66 (m，1H)，3.64 (m，1H)，3.81 (s，3H)，3·86 (s，3H)，4.11 (m，2H )，4.29 (m，1Η)，4.56 (m，2Η)，4·70 (m，2Η)，6·05 (m，1Η)，6·40 (m，1Η)，6·65 (s， 1H)? 6.60 (s5 1HX 7.13 (s5 1H), 7.66 (s, 2H)? 7.75 (s3 1H), 7.80 (s5 1H). LCMS (ESI+) ： 549 (MH+). 製備25與26 [(R，S)，(S，R)]與[(民!1)，(3,3)]-6,7-二甲氧基-4-(甲氧基甲基-胺甲醯基） -2-甲基-3,4-二氫-2H-0奎淋小幾酸乙酉旨 將[(R，S)，(S，R)]與[(民11)，(8,3)]-6,7-二甲氧基-2-甲基-3,4-二氫-21^奎 啉-1，4-二羧酸小乙酯（〇·536克，1·55毫莫耳）放置在裝有攪拌棒 之25毫升圓底燒瓶中，並溶於二氯甲燒（1〇毫升）中。使反應 混合物冷卻至0°C，並添加二-異丙基乙胺（0.18克，2.0毫莫耳 ，1.3當量），接著添加N，〇-二-甲基羥胺鹽酸鹽（ι·ι當量）、 4-二甲胺基吡啶（〇·ΐ當量）及1-(3-二甲胺基丙基）—3_乙基碳化二 亞胺鹽酸鹽（1.2當量）。將反應混合物於室溫下攪拌。12小 時後’以水使反應混合物淬滅，並以酷酸乙酯萃取3次。收 集有機層，脫水乾燥，過濾及濃縮，提供標題化合物（0.56克 ，1.52毫莫耳，98%產率），使用之而無需進一步純化。 LCMS (ESI+) : 367 (MH+).[(R,S),(S,R)] and [supply,11),(3,3)]-4-(3,5-bis-trifluoromethyl--ylylaminomethyl)-6 , 7-dimethoxy-2-methyl-3,4-diar argon-2H-quinoline small carboxylic acid ethyl ester [[R, S), (S, R)] and [(Min 11), (3,3)]-6,7-Dimethoxy-2-methyl-3,4-dihydro-211-quinoline-1,4-dicarboxylic acid small ethyl ester (0.229 g, 0.710 mmol) The ear was placed in a 25 ml round bottom flask equipped with a stir bar. Dichloromethane (7.0 ml) was added followed by 3,5-bis(trifluoromethyl)amine (amine 519 g, 2.14 mmol, 3.0 eq.). To this reaction, 1-hydroxybenzotriazole hydrate (0.022 g, 0.146 mmol, 0.2 equivalent) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide were added. Hydrochloride (0.232 g, 1.21 mmol, 1.7 eq.). The reaction mixture was stirred at room temperature. After 12 hours, the reaction was quenched with water and extracted with EtOAc EtOAc EtOAc EtOAc EtOAc. The organic layer was collected, dried over sodium sulfate, filtered and concentrated to afford titled compound (0.1225 g, 0.223 m LCMS (ESI+): 549 (MH+). 1.80 (m,1H), 2.66 (m,1H), 3.64 (m,1H), 3.81 (s,3H),3·86 (s,3H),4.11 (m) , 2H ), 4.29 (m, 1Η), 4.56 (m, 2Η), 4·70 (m, 2Η), 6·05 (m, 1Η), 6·40 (m, 1Η), 6·65 (s , 1H)? 6.60 (s5 1HX 7.13 (s5 1H), 7.66 (s, 2H)? 7.75 (s3 1H), 7.80 (s5 1H). LCMS (ESI+): 549 (MH+). Preparation 25 and 26 [(R ,S),(S,R)] and [(Min!1),(3,3)]-6,7-Dimethoxy-4-(methoxymethyl-aminecarbamyl)-2 -Methyl-3,4-dihydro-2H-0 quinine oxime acid [(R,S),(S,R)] and [(Min 11), (8,3)]-6 , 7-Dimethoxy-2-methyl-3,4-dihydro-21^-quinoline-1,4-dicarboxylic acid small ethyl ester (〇·536 g, 1.55 mmol) placed in It was placed in a 25 ml round bottom flask equipped with a stir bar and dissolved in dichloromethane (1 mL). The reaction mixture was cooled to 0 ° C and di-isopropylethylamine (0.18 g, 2.0 Mohr, 1.3 equivalents), followed by the addition of N, 〇-di-methylhydroxylamine hydrochloride (1⁄2 eq.), 4-dimethylaminopyridine (〇·ΐ equivalent) and 1-(3-dimethylamine) Propyl)-3-ethylcarbodiimide salt Salt (1.2 eq.). The reaction mixture was stirred at room temperature. After 12 hours, the mixture was quenched with water and extracted with EtOAc EtOAc. Compound (0.56 g, 1.52 mmol, 98% yield).

[(R，R)，(S，S)] 1 H-NMR (CDC13): 5 1.10 (d，3H)，1.28 (t，3H)，1.83 (m，1H)， 92199 -146- 1285641 2.41 (m，1Η)，3·16 (s，3H)，3.38 (s，3H)，3.80 (s，3H)，3.82 (s，3H)，4.06 (m，1H)， 4.21 (m，2H)，4.84 (m，1H)，6.55 (s，1H)，7.16 (s，1H). LCMS (ESI+) : 367 (MH+).[(R,R),(S,S)] 1 H-NMR (CDC13): 5 1.10 (d,3H), 1.28 (t,3H), 1.83 (m,1H), 92199 -146- 1285641 2.41 ( m,1Η),3·16 (s,3H),3.38 (s,3H),3.80 (s,3H),3.82 (s,3H),4.06 (m,1H), 4.21 (m,2H),4.84 (m, 1H), 6.55 (s, 1H), 7.16 (s, 1H). LCMS (ESI+): 367 (MH+).

[(R，S)，(S，R)] 1 H-NMR (CDC13): 5 1.32 (d，3H)，1.65 (t，3H)，1.75 (m，1H)， 2.39 (m，1H)，3.16 (s，3H)，3.35 (s，3H)，3.80 (s，3H)，3.82 (s，3H)，4.06 (m，1H)， 4.21 (m，2H)，4.84 (m，1H)，6.45 (s，1H)，7.05 (s，1H). 實例13與14[(R,S),(S,R)] 1 H-NMR (CDC13): 5 1.32 (d,3H), 1.65 (t,3H), 1.75 (m,1H), 2.39 (m,1H), 3.16 (s, 3H), 3.35 (s, 3H), 3.80 (s, 3H), 3.82 (s, 3H), 4.06 (m, 1H), 4.21 (m, 2H), 4.84 (m, 1H), 6.45 (s, 1H), 7.05 (s, 1H). Examples 13 and 14

[(R，S)，(S，R)]與[(1^)，(3,3)]-4-(3,5-雙-三氟基甲基-苯甲醯基)-6,7-二 甲氧基-2-甲基-3,4-二氫-2H-喳啉小羧酸乙酯 在裝有磁攪拌棒之圓底部燒瓶中，使[(R，S)，(S，R)]與 [(11，11)，(3,3)]-6,7-二甲氧基冬(甲氧基-甲基-胺甲醯基）-2-甲基-3,4-二氫-2H-喹啉-1-羧酸乙酯（0.56克，1.45毫莫耳，1當量）溶於 四氫呋喃（12毫升）中。使反應物冷卻至〇°C。逐滴添加3,5-雙 (二氟甲基）+基 &gt;臭化錢（13.6愛升0.5 Μ溶液）’並將反應混合 物於室溫下攪拌。丨2小時後，以氯化銨水溶液使反應混合 物淬滅，進一步以NaCl飽和，並以醋酸乙酯萃取3次。收集 有機層，以硫酸鈉脫水乾燥，過濾，及濃縮至乾涸。急驟 式層析，以90/10己烷/醋酸乙酯溶離，提供標題化合物（0.556 克，1.07毫莫耳，73%產率）。 LCMS (ESI+) : 520 (MH+). -M7 - 1285641 [(R,S)，(S，R)]: lHNMR(CDCl3): 5 1.24(d，3H)，1.35(t，3H)，1.81 (m，1H)， 2.52 (m5 1H)，3.63 (s，3H), 3.88 (s，3H)，4.29 (m，2H)，4.42 (m5 1H)，4·57 (m， 1H)，6.21 (s，1H)，7.15 (s，1H)，8.13 (s，1H)，8·45 (s，2H)· LCMS (ESI+) : 520 (MH+).[(R,S),(S,R)] and [(1^),(3,3)]-4-(3,5-bis-trifluoromethyl-benzhydryl)-6, Ethyl 7-dimethoxy-2-methyl-3,4-dihydro-2H-carbolinecarboxylate in a round bottom flask equipped with a magnetic stir bar to give [(R,S),(S ,R)] and [(11,11),(3,3)]-6,7-dimethoxy winter (methoxy-methyl-amine-mercapto)-2-methyl-3,4 Ethyl dihydro-2H-quinoline-1-carboxylate (0.56 g, 1.45 mmol, 1 eq.) was dissolved in THF. The reaction was allowed to cool to 〇 ° C. 3,5-bis(difluoromethyl)+ group &gt; stinky money (13.6 liters of 0.5 Μ solution) was added dropwise and the reaction mixture was stirred at room temperature. After 2 hours, the reaction mixture was quenched with aqueous ammonium chloride, and further saturated with NaCI. The organic layer was collected, dried over sodium sulfate, filtered and concentrated to dryness. The title compound (0.556 g, 1.07 mmol, 73% yield). LCMS (ESI+): 520 (MH+). -M7 - 1285641 [(R,S), (S,R)]: lHNMR (CDCl3): 5 1.24 (d, 3H), 1.35 (t, 3H), 1.81 ( m,1H), 2.52 (m5 1H), 3.63 (s,3H), 3.88 (s,3H), 4.29 (m,2H), 4.42 (m5 1H),4·57 (m, 1H), 6.21 (s , 1H), 7.15 (s, 1H), 8.13 (s, 1H), 8·45 (s, 2H)· LCMS (ESI+): 520 (MH+).

[(R，R)，(S，S)]: 1 H NMR (CDC13 )·· 51.18 (d，3H)，1.28 (t，3H)，1.88 (m，1H)， 2.67 (m，1H)，3·79 (s，3H)，3.84 (s，3H)，4,21 (m，2H)，4·45 (t，1H)，4.88 (m，1H)， 6.59 (s，1H)，7.07 (s，1H)，7.97 (s，1H)，8.25 (s，2H)· 實例15[(R,R),(S,S)]: 1 H NMR (CDC13 )·· 51.18 (d,3H), 1.28 (t,3H), 1.88 (m,1H), 2.67 (m,1H), 3·79 (s,3H), 3.84 (s,3H),4,21 (m,2H),4·45 (t,1H),4.88 (m,1H), 6.59 (s,1H),7.07 ( s, 1H), 7.97 (s, 1H), 8.25 (s, 2H)· Example 15

[取別必別-^^义雙-三氟甲基-苯基卜二氟-甲基降曱基义卜二曱 氧基-3,4-二氫奎淋小複酸乙醋 在裝有磁攪拌棒之小玻瓶中，使[(R，R)，(S，S)]-4-(3,5U‘T 基-苯甲醯基）-2-甲基-6,7-二甲氧基-3,4-二氫-2H-p奎。林小幾酸乙 酯（0.062克，〇·12〇毫莫耳）溶於二氣甲烷（〇·25毫升）中。將[雙（2· 甲氧基乙基）胺基]三氟化硫（〇·22毫升，1.20毫莫耳，10當量） 添加至此溶液中，並於室溫下攪拌反應混合物。12小時後 ，以飽和氯化銨水溶液使反應混合物淬滅，並以醋酸乙醋 萃取3次。收集有機層，以硫酸鎂脫水乾燥，過濾，濃縮， 並於石夕膠上藉層析純化’以90/10己燒/醋酸乙g旨溶離，提 供標題化合物（0.045克，0.08毫莫耳，66%產率）。 LCMS (ESI+) ·· 542 (ΜΗ+)· 92199 -148 - 1285641 [(R?R)?(S?S)]： {HNMR(COChy δ 1.10 (d,3H), 1.22 (t,3H), 1.95 (m, 1H), 2.45 (m，1H)，3.55 (m，1H)，3.75 (s，3H)，3.87 (s，3H)，4.00 (m，1H)，4.19 (m， 1H)，4.60 (m，1H)，6.45 (s，1H)，6.99 (s，1H)，7.6 (s，2H)，7_90 (s，1H)· 實例16與17[取别别别-^^ bis-trifluoromethyl-phenyldifluoro-methylnorbornyl iodide dimethoxy-3,4-dihydroquinone small acid vinegar in the In a small glass bottle with a magnetic stir bar, make [(R,R),(S,S)]-4-(3,5U'T-based-benzylidene)-2-methyl-6,7-di Methoxy-3,4-dihydro-2H-p-quine. Lin Xiaoji acid ethyl ester (0.062 g, 〇·12 〇 millimol) was dissolved in di-methane (〇·25 ml). [Bis(2·methoxyethyl)amino]sulfur trifluoride (〇·22 ml, 1.20 mmol, 10 equivalents) was added to this solution, and the reaction mixture was stirred at room temperature. After 12 hours, the reaction mixture was quenched with saturated aq. The organic layer was collected, dried with EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 66% yield). LCMS (ESI+) ·· 542 (ΜΗ+)· 92199 -148 - 1285641 [(R?R)?(S?S)]: {HNMR(COChy δ 1.10 (d,3H), 1.22 (t,3H), 1.95 (m, 1H), 2.45 (m, 1H), 3.55 (m, 1H), 3.75 (s, 3H), 3.87 (s, 3H), 4.00 (m, 1H), 4.19 (m, 1H), 4.60 (m, 1H), 6.45 (s, 1H), 6.99 (s, 1H), 7.6 (s, 2H), 7_90 (s, 1H)· Examples 16 and 17

[(R，R，R)，(S，S，S)]與[(11，1^)，(3,3，11)]-4-[(3,5-雙-三氟甲基-苯基)-羥基-甲基]-6,7-二甲氧基-2-甲基-3,4-二氫-2H-喳啉小羧酸乙酯 將[(11，11)，(3,3)]-4-(3,5-雙-三氟甲基-苯甲醯基）-6,7-二甲氧基-2-甲 基-3,4-二氫-2H-喹啉小羧酸乙酯(0.302克，0.58毫莫耳，1當量） 放置在裝有磁攪拌棒之圓底燒瓶中。於室溫下添加甲醇（12 毫升），接著添加硼氫化鈉（0.131克，3.48毫莫耳，6當量）。 1小時後，以鹽水溶液使反應混合物淬滅，以醋酸乙酯萃取 3次，並以硫酸鈉脫水乾燥。使此物質藉急驟式層析純化， 以75/25己烷/醋酸乙酯溶離，提供標題化合物（0.271克，0.52 毫莫耳，89%產率）。 非對映異構物1 (29%產率） LCMS (ESI+) ·· 522 _+)· 1H NMR (CDC13): 51.12 (d，3H)，1.29 (t，3H)，1.39 (m，1H)，2·52 (m，1H)， 2.81 (brs，1H)，2.94 (m，1H)，3.65 (s，3H)，3·83 (s，3H)，4.21 (m，2H)，4.67 (m， 1H)，5·04 (d，1H)，6.18 (s，1H)，7.02 (s，1H)，7.64 (s，2H)，7·72 (s，1H), 非對映異構物2 (60%產率） 92199 -149- 1285641 LCMS (ESI+) ： 522 (MH+). lHNMR(CDCl3)： (5 1.14 (d53H)J34(t,3H)5 1.56 (m,lH), 1.86 (m,lH)? 2.97 (m，1H)，3.87 (s，3H)，3.88 (s，3H)，4.26 (m，2H)，4·49 (m，1H)，4.77 (d， 1H)，6.70 (s，1H)，7.09 (s，1H)，7.84 (s，3H)· 實例18與19[(R,R,R),(S,S,S)] and [(11,1^),(3,3,11)]-4-[(3,5-bis-trifluoromethyl- Ethyl phenyl)-hydroxy-methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-carboline small carboxylic acid [[11,11), (3 ,3)]-4-(3,5-bis-trifluoromethyl-benzhydryl)-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline Ethyl carboxylic acid (0.302 g, 0.58 mmol, 1 eq.) was placed in a round bottom flask equipped with a magnetic stir bar. Methanol (12 mL) was added at room temperature followed by sodium borohydride (0.131 g, 3.48 mmol, 6 eq.). After 1 hour, the reaction mixture was quenched with brine, EtOAc (EtOAc) The material was purified by flash chromatography eluting elut elut elut elut elut elut elut Diastereomer 1 (29% yield) LCMS (ESI+) ·· 522 _+)· 1H NMR (CDC13): 51.12 (d,3H), 1.29 (t,3H), 1.39 (m,1H) ,2·52 (m,1H), 2.81 (brs,1H), 2.94 (m,1H), 3.65 (s,3H),3·83 (s,3H),4.21 (m,2H),4.67 (m , 1H),5·04 (d,1H), 6.18 (s,1H), 7.02 (s,1H), 7.64 (s,2H),7·72 (s,1H), diastereomer 2 (60% yield) 92199 -149 - 1285641 LCMS (ESI+): 522 (MH+). lHNMR (CDCl3): (5 1.14 (d53H)J34(t,3H)5 1.56 (m,lH), 1.86 (m, lH)? 2.97 (m, 1H), 3.87 (s, 3H), 3.88 (s, 3H), 4.26 (m, 2H), 4·49 (m, 1H), 4.77 (d, 1H), 6.70 (s , 1H), 7.09 (s, 1H), 7.84 (s, 3H) · Examples 18 and 19

[(R，R，R)，(S，S，S)與（氏民孙^么即-‘既^雙-三氟甲基-苯基卜氟-甲基] -6,7-二甲氧基-2-甲基-3,4-二氫-2Η&quot;·ρ奎淋小叛酸乙酯 將[(R，R，R)，(S，S，S)與（民民3)，(3么11)]-4-[(3,5-雙-三氟甲基-苯基）_羥 基-甲基]-6,7-二甲乳基-2-甲基-3,4-二氯-211-峻p林-1-幾酸乙g旨（〇.〇6 克，0.115毫莫耳）放置在含有磁攪拌棒之小圓底燒瓶中，並 溶於二氯甲烷（〇·25毫升）中。於此反應物中，在室溫下，逐 滴添加（二乙胺基）三氟化硫（0.152毫升）。2小時後，藉由添加 氯化銨水溶液使反應淬滅，並以EtOAc萃取3次。收集有機 物質，以Na2S〇4脫水乾燥，過濾，及濃縮，而得標題化合物 ，40%單離產率（0.024克，0.046毫莫耳）。 LCMS (ESI+) ： 524 (MH+). lHNMR(CDCl3)： 5 1.19(^3¾ 1.30 (t, 3H), 2.02 (m5 1H), 2.95 (m5 1H), 3.95 (s3 3H), 3.97 (s5 3H), 4.26 (m? 2H)? 4.49 (m, 1H), 6.40 (s, 1H), 6.9 (s5 1H), 7.1(s，lH)，7.8(s，3H)，7.95(s，lH)· 製備27 92199 .150- 1285641 〇[(R,R,R),(S,S,S) and (氏民民^^ ie-'^^-trifluoromethyl-phenyl-fluoro-methyl]-6,7-dimethyl Oxy-2-methyl-3,4-dihydro-2Η&quot;·ρ奎淋小叛酸酯[[R,R,R),(S,S,S) and (民民3), (3 11)]-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-6,7-dimethyllacyl-2-methyl-3,4- Dichloro-211-Jun plin-1-carboxylic acid B g (〇.〇6 g, 0.115 mmol) was placed in a small round bottom flask containing a magnetic stir bar and dissolved in dichloromethane (〇· In 25 ml), in this reaction, (diethylamino)sulfur trifluoride (0.152 ml) was added dropwise at room temperature. After 2 hours, the reaction was quenched by the addition of aqueous ammonium chloride. This was extracted with EtOAc (3 mL), EtOAc (EtOAc) (MH+). lHNMR(CDCl3): 5 1.19(^33⁄4 1.30 (t, 3H), 2.02 (m5 1H), 2.95 (m5 1H), 3.95 (s3 3H), 3.97 (s5 3H), 4.26 (m? 2H ) 4.49 (m, 1H), 6.40 (s, 1H), 6.9 (s5 1H), 7.1 (s, lH), 7.8 (s) 3H), 7.95 (s, lH) · Preparation 2,792,199 1,285,641 square .150-

Me \工 to&quot;6 n C02Et [(R，S)與（R’RM-氯基-2-乙基冬三氟f基_3,4_二氫_2H_喹啉_丨，木二 羧酸-1-乙酯-4-甲酯 將⑻-2-乙基-4-亞肼基-6-三氟甲基-3,4-二氫_2H•喹啉小羧酸乙 酯（製備6，1.22克，3.70毫莫耳）放置在裝有攪拌棒之25〇毫 升圓底燒瓶中。添加乙酸（100毫升），接著添加^02(222毫 莫耳’ 6當f )。保遵反應物以隔離光線，並於室溫下撥掉％ 分鐘。經過Celite®過濾溶液，並濃縮至30毫升之最後體積。 添加另外之甲苯（100毫升），並濃縮至4〇毫升。於此溶液中 ’添加二-異丙基乙胺（3.25毫升，ΐ8·5毫莫耳），接著添加甲 冬中之20%光氣7谷液（7.5愛升）。在添加無水甲醇（丨〇毫升）之 前，將反應混合物攪拌45分鐘。2小時後，使反應物濃縮降 至20毫升，萃取於二氯甲烷中，並以〇·ι νHC1洗滌。收集有 機層，以硫酸鍰脫水乾燥，過滤，及濃縮至乾涸，獲得標 題化合物（1.43克，3.66毫莫耳，98%產率）。 LCMS (ESI+) : 394 (ΜΗ+), (R，S)，(R，R): 1H NMR (CDC13) ·· $ 〇·95 (t，3Η), 1,25 (m, 2Η)，1.30 (t，3Η)， 2.60 (dd, 1H)，2.79 (dd，1H)，3.99 (s，3H)，4.23 (m，2H)，4·62 (MH)，7.61 (d，1H)， 7.70 (d，1H). 製備28與29Me \工to&quot;6 n C02Et [(R,S) and (R'RM-chloro-2-ethyl-t-trifluorofyl_3,4_dihydro-2H_quinoline 丨, xylocarboxylate Acid-8-ethyl ester-4-methyl ester (8)-2-ethyl-4-indenyl-6-trifluoromethyl-3,4-dihydro-2H•quinoline small carboxylic acid ethyl ester (preparation 6,1.22 g, 3.70 mmol) placed in a 25 liter round bottom flask equipped with a stir bar. Add acetic acid (100 mL), then add ^02 (222 mAh '6 when f). The material was isolated and allowed to shake off at room temperature for 1 minute. The solution was filtered through Celite® and concentrated to a final volume of 30 mL. Additional toluene (100 mL) was added and concentrated to 4 mL. 'Add di-isopropylethylamine (3.25 ml, ΐ8·5 mmol), then add 20% phosgene 7 solution (7.5 liters) in the winter. Before adding anhydrous methanol (丨〇 ml) The reaction mixture was stirred for 45 minutes. After 2 hours, the reaction was concentrated to 20 mL, EtOAc (EtOAc)EtOAc. To dry up, get the mark Compound (1.43 g, 3.66 mmol, 98% yield). LCMS (ESI+): 394 (ΜΗ+), (R,S), (R,R): 1H NMR (CDC13) ·· $ 〇·95 (t,3Η), 1,25 (m, 2Η), 1.30 (t,3Η), 2.60 (dd, 1H), 2.79 (dd,1H), 3.99 (s,3H), 4.23 (m,2H), 4·62 (MH), 7.61 (d, 1H), 7.70 (d, 1H). Preparations 28 and 29

92199 -151 - 1285641 使[(R，S)與（R，R)]-2-乙基各 三氟甲基-3,4-二氫-2H-喳啉- Μ-二羧92199 -151 - 1285641 [[R,S) and (R,R)]-2-ethyl each trifluoromethyl-3,4-dihydro-2H-carboline-indole-dicarboxylate

莫耳）溶於30毫升甲醇中， 然後添加0·15克10% Pd/C，並使混 合物於45 pS1下，在par振盪器上氫化2小時。使反應混合物 經過矽澡土過濾’並濃縮。接著，使粗製混合物溶於二氯 甲燒中’並收集有機物質，以硫酸鎂脫水乾燥，及濃縮。 藉管柱層析純化，以9〇 : 1〇己烷·丙酮溶液溶離後，分離產 物，而產生83% (2.98毫莫耳）標題化合物。 (R,S) ： 1H NMR (CDC13) : δ 0.84 (t, 3H), 1.30 (t, 3H), 1.40 (m, 2H)5 1.95 (m，1H)，2.47 (m，1H)，3.61 (m，1H)，3.80 (s，3H)，4.3 (m，2H)，4·42 (m5 1H)， 7.40 (s，1H)，7.60 (d，1H)，7.70 (d，1H)· LCMS (ESI+) ： 360 (MH+) (R，R): 1H NMR (CDC13 )·· (5 0.86 (t，3H)，1·28 (t，3H)，L38 (m，2H)，2·1 (m， 1H)，2.56 (m，1H)，3.69 (s，3H)，3.90 (t，1H)，4.30 (m，2H)，4,58 (m，1Η)·7·46 (s， 1H)，7.50 (d，1H)，7.70 (d，1H) LCMS (ESI+) ： 360 (MH+) 製備30Mol) was dissolved in 30 ml of methanol, then 0. 15 g of 10% Pd/C was added, and the mixture was hydrogenated on a par shaker at 45 pS1 for 2 hours. The reaction mixture was filtered through a pad of water and concentrated. Next, the crude mixture was dissolved in methylene chloride and the organic material was collected, dried over magnesium sulfate, and concentrated. Purification by column chromatography, eluting with 9:1 hexanes-hexanes, and the product was isolated to give the title compound (83%). (R,S) : 1H NMR (CDC13) : δ 0.84 (t, 3H), 1.30 (t, 3H), 1.40 (m, 2H)5 1.95 (m,1H), 2.47 (m,1H), 3.61 ( m,1H),3.80 (s,3H),4.3 (m,2H),4·42 (m5 1H), 7.40 (s,1H), 7.60 (d,1H),7.70 (d,1H)· LCMS ( ESI+) : 360 (MH+) (R,R): 1H NMR (CDC13 )·· (5 0.86 (t,3H),1·28 (t,3H), L38 (m,2H),2·1 (m , 1H), 2.56 (m, 1H), 3.69 (s, 3H), 3.90 (t, 1H), 4.30 (m, 2H), 4, 58 (m, 1Η)·7·46 (s, 1H), 7.50 (d,1H), 7.70 (d,1H) LCMS (ESI+): 360 (MH+) Preparation 30

[(R，S)與（R，R)]-2-乙基-6-三氟甲基-3,4-二氫-2H-喹啉-1，4·二羧酸小 乙酉旨 使[(R,S)與（R，R)]-2-乙基各三氟甲基-3,4-二氫-2H-喳啉-1，4-二羧 92199 -152· 1285641 酸-1-乙酯-4-甲酯（製備28與29，0.070克，0.195毫莫耳，！當 量）溶於具有磁攪拌棒且含有二氧陸圜（1.5毫升）與水G .5毫升） 之圓底燒瓶中。添加氫氧化鈉（0.016克，0.409毫莫耳，2.1當 f )，並於立k下邊掉。12小時後，使反應混合物濃縮至最 小體積，並於1.0 N氫氧化鈉水溶液與乙醚之間作分液處理 。收集水層’以濃鹽酸酸化，並以酷酸乙酯萃取。收集有 機層，以硫酸鎂脫水乾燥，過濾，及濃縮，提供標題化合 物（0.067克，0.194毫莫耳，99%產率）。 LCMS (ESI+) ： 346 (MH+).[(R,S) and (R,R)]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1,4·dicarboxylic acid (R,S) and (R,R)]-2-ethyl each trifluoromethyl-3,4-dihydro-2H-carboline-1,4-dicarboxy 92199-152· 1285641 acid-1- Ethyl 4-methyl ester (preparations 28 and 29, 0.070 g, 0.195 mmol, ! equivalent) was dissolved in a round bottom with a magnetic stir bar containing dioxane (1.5 mL) and water G. 5 mL) In the flask. Sodium hydroxide (0.016 g, 0.409 mmol, 2.1 when f) was added and dropped off the vertical k. After 12 hours, the reaction mixture was concentrated to a minimum volume and partitioned between 1.0N aqueous sodium hydroxide and diethyl ether. The aqueous layer was collected and acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated to give the title compound (0.067 g, 0.194 mmol, 99% yield). LCMS (ESI+): 346 (MH+).

[(R，S)，(R，R)]: 1H-NMR (CDC13): 5 〇·84 (t，3H)，1·23 (t，3H)，1.39 (m，2H)， 1·94 (m，1H)，2·59 (m，1H)，3.84 (t，1H)，4·19 (m，2H)，4·62 (m，H)，7·49 (m， 2H)，7·63 (d，1H)· 製備31[(R,S),(R,R)]: 1H-NMR (CDC13): 5 〇·84 (t,3H),1·23 (t,3H), 1.39 (m,2H), 1·94 (m,1H),2·59 (m,1H),3.84 (t,1H),4·19 (m,2H),4·62 (m,H),7·49 (m, 2H),7 ·63 (d,1H)· Preparation 31

[(R，S)與（R，R)]-2-乙基-4-(甲氧基-甲基-胺甲醯基）各三氟甲基-3,4_ 二氫-2H-喹淋-1-幾酸乙酯 將[(R，S)與（R，R)]-2-乙基-6-三氟甲基-3,4-二氫-2H_4 啉-1，4_二羧 酸-1-乙醋（0.066克，0.239毫莫耳）放置在裝有攪拌棒之5毫升 圓底燒瓶中。添加一氯曱fe (3愛升）。使反應混合物冷卻至〇 °C。添加二-異丙基乙胺（0.032克，〇·248毫莫耳，1.3當量）， 接著添加Ν，〇-二甲基經基胺HC1鹽（0.239毫莫耳）、4-二甲胺基 92199 -153- 1285641 p比咬（0.019愛莫耳）及1-(3-二甲胺基丙基）-3-乙基碳化二亞胺鹽 酸鹽（0.210毫莫耳）。將反應物於室溫下攪拌。12小時後，以 水使反應淬滅，並以醋酸乙酯萃取3次。收集有機層，以硫 酸鈉脫水乾燥，過濾，濃縮，提供標題化合物（〇〇65克，0.167 毫莫耳，88%產率）。 LCMS (ESI+) : 389 (MH+).[(R,S) and (R,R)]-2-ethyl-4-(methoxy-methyl-aminecarboxy) each trifluoromethyl-3,4-dihydro-2H-quinoline Ethyl-1-carboxylic acid to [(R,S) and (R,R)]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H_4 porphyrin-1,4-dicarboxylate Acid-1-ethyl vinegar (0.066 g, 0.239 mmol) was placed in a 5 mL round bottom flask equipped with a stir bar. Add chloranthene fe (3 liters). The reaction mixture was allowed to cool to 〇 °C. Di-isopropylethylamine (0.032 g, 〇·248 mmol, 1.3 eq.) was added followed by hydrazine, hydrazine-dimethyl-methylamine HCl salt (0.239 mmol), 4-dimethylamino group 92199 - 153 - 1285641 p bite (0.019 Amor) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.210 mmol). The reaction was stirred at room temperature. After 12 hours, the reaction was quenched with water and extracted three times with ethyl acetate. The organic layer was collected, dried with EtOAc EtOAcjjjjjjj LCMS (ESI+): 389 (MH+).

[(R，S)，(R，R)]: 1 H-丽R (CDC13): 5 0.90 (t，3H)，1.33 (t，3H)，1.39 (m，2H)， 2.0 (m，1H)，2·55 (m，1H)，3.20 (s，3H)，3·40 (s，3H)，4·19 (m，2H)，4.62 (m，1H)， 7,21 (s，1H)，7.40 (s，2H)，7.62 (d，2H)· 實例20與21[(R,S),(R,R)]: 1 H-Li R (CDC13): 5 0.90 (t,3H), 1.33 (t,3H), 1.39 (m,2H), 2.0 (m,1H) ), 2·55 (m, 1H), 3.20 (s, 3H), 3·40 (s, 3H), 4·19 (m, 2H), 4.62 (m, 1H), 7, 21 (s, 1H) ), 7.40 (s, 2H), 7.62 (d, 2H) · Examples 20 and 21

[(R，S)]與[(R，R)]_4-(3,5-雙-三氟甲基-苯T醯基&gt;2-乙基各三氟甲基 -3,4-二氫-211-4：淋-1-羧酸乙酯 在裝有擾拌棒之圓底燒瓶中，使[(R，S)，(R，R)]-2-乙基冰(甲氧 基-甲基-胺甲醯基）-6-三氟甲基-3,4-二氫_2H-4淋-1-複酸乙g旨 (0.564克1.45毫莫耳，1當量）溶於四氫呋喃（12毫升）中。使反 應物冷卻至0°C。逐滴添加3,5-雙（三氟甲基）苯基溴化鎂（13.6 耄升’ 0.5 Μ溶液），並將反應混合物於室溫下搅拌。I]小時 後，以氯化銨水溶液使反應混合物淬滅，進一步以NaC1飽和 ’並以醋酸乙酯萃取3次。收集有機層，以硫酸鈉脫水乾燥 ，過濾，及濃縮至乾涸。急驟式層析，以90/10己燒/醋酸 92199 -154- 1285641 乙酯溶離，提供標題化合物(0.556克，1.02毫莫耳，70%產率）。 反式異構物： LCMS (ESI+) ： 542 (MH+). (R，R): iH-NMRCCDCl;): 5 0.98(t，3H)，1.29 (t，3H)，1.52 (m，2H)，2.05 (m，1H)，2·64 (m5 1H)，4.24 (m，2H)，4.66 (m，2H)，7.40 (s，1H)，7·55 (d，1H)， 7.60 (d，1H)，8.05 (s，21¾ 8.24 (s，1H)· 順式異構物： LCMS (ESI+) ： 542 (MH+). 參 (R，S): 1H-NMR (CDC13) : (5 0·91 (t，3H)，1.39 (t，3H)，1.43 (m，2H)，1·78 (m，1H)，1·99 (m，1H)，2.60 (m，1H)，4.34 (m，2H)，4.56 (m，2H)，7.05 (s，1H)， 7.55 (d，1H)，7.65 (d，1H)，8·20 (s，1H)，8.44 (s，2H)· 實例 22、23、24 及 25[(R,S)] and [(R,R)]_4-(3,5-bis-trifluoromethyl-benzene T-decyl>2-ethyl-trifluoromethyl-3,4-di Hydrogen-211-4: Ethyl l-carboxylate in a round bottom flask equipped with a stir bar to give [(R,S),(R,R)]-2-ethyl ice (methoxy -Methyl-aminomethylmercapto)-6-trifluoromethyl-3,4-dihydro-2H-4 lyl-formate B g (0.564 g 1.45 mmol, 1 equivalent) dissolved in tetrahydrofuran (12 ml). The reaction was cooled to 0 ° C. 3,5-bis(trifluoromethyl)phenylmagnesium bromide (13.6 liters of '0.5 Μ solution) was added dropwise, and the reaction mixture was placed in the chamber. After stirring for 1 hour, the reaction mixture was quenched with aqueous EtOAc (aq. EtOAc) EtOAc (EtOAc)EtOAc. The title compound (0.556 g, 1.02 mmol, 70% yield) was obtained eluted elute elute : 542 (MH+). (R, R): iH-NMRCCDCl;): 5 0.98 (t, 3H), 1.29 (t, 3H), 1.52 (m, 2H), 2.05 (m, 1H), 2· 64 (m5 1H), 4.24 (m, 2H), 4.66 (m, 2H), 7.40 (s, 1H), 7·55 (d, 1H), 7.60 (d, 1H), 8.05 (s, 213⁄4 8.24 (s, 1H)· Isomers: LCMS (ESI+): 542 (MH+). s (R,S): 1H-NMR (CDC13): (5 0·91 (t,3H), 1.39 (t,3H), 1.43 (m) , 2H),1·78 (m,1H),1·99 (m,1H), 2.60 (m,1H), 4.34 (m,2H), 4.56 (m,2H),7.05 (s,1H), 7.55 (d,1H), 7.65 (d,1H),8·20 (s,1H),8.44 (s,2H)· Examples 22, 23, 24 and 25

[(R，R，R)]，[(R,R，S)]，[(R，S，S)]及[(民3，11)]冬(3,5-雙-三氟甲基-苯基）-羥 基-甲基]-2-乙基-6-二氣〒基-3,4-二氮-2H-^ 12林-1-叛故乙S曰 92199 -155 - 1285641 將[(R，S)]與[(R，R)]-4-(3,5-雙-三氟甲基-苯甲醯基）-2-乙基-6-三氟 甲基-3,4-二氫-2H_喹啉小羧酸乙酯（0.182克，0.34毫莫耳，1當 量）放置在裝有磁攪拌棒之圓底燒瓶中。於室溫下添加甲醇 (6.8毫升），接著添加（0.077克，2.05毫莫耳，6當量）硼氫化鈉 。1小時後，以鹽水溶液使反應混合物淬滅，以醋酸乙酯萃 取3次，並以硫酸鈉脫水乾燥。使物質藉急驟式層析純化， 以90/10己烷/醋酸乙酯溶離，以三份溶離份提供標題化合 物〇 (R，S，R): LCMS (ESI+) ： 544 (MH+). 1H-NMR (CDC13 )·· 5 0.81 (t，3H)，1.27 (t，3H)，2·04 (m，1H)，4.22 (m，3H)， 7.86 (s，1H)，7.90 (s，1H). (R，S，S): LCMS (ESI+) ： 544 (MH+). 1H-NMR (CDC13 )·· 5 0·73 (t，3H)，1.09 (m，1H)，1.27 (t，3H)，1.43 (m，2H)， 1.67 (m, 1H)，2.44 (d，1H)，2·87 (m，1H)，4.24 (m，3H)，5.17 (dd，1H)，7.26 (s， 1H)，7.50 (m，2H)，7.90 (s，2H)，7.92 (s，1H)· (R，R，R)與（R，R,S):此混合物係於10公分x 50公分Chiralpak AD 管拄上分離，在庚烷/IPA 98//2中，於275毫升/分鐘之流率下 溶離。 (R,R,R): ^-NMRCCDC^)： (5 0.77 (t,3H), 1.31 (ζ 3H), 1.41 (m,2H)32.21 (d，1Η)，3.19 (m，1Η)，4.23 (m，2Η)，4·37 (m，1Η)，4.83 (d，1Η)，7·65 (s，2Η)， 7.79(s，lH)· LCMS (ESI+) ： 544 (MH+). 92199 -156- 1285641 (R，R，S): 1 H-NMR (CDC13): (5 0.81 (t，3H)，1.33 (t，3H)，1.6 (m，2H)，2.22 (d，1H)，3.05 (m，1H)，4.30 (m，2H)，4.62 (m，1H)，5.19 (d，1H)，7.01 (s，1H)， 7.40 (s，2H)，7.85 (s，1H)· LCMS (ESI+) ： 544 (MH+). 製備32與33 [(R，R)，(S，S)]與昭，11)，(11，3)]-4-胺基甲基-6,7-二甲氧基-2-甲基-3,4-二 氫-2H-喹淋-1-羧酸乙酯 在裝有攪拌棒之乾燥50毫升圓底燒瓶中，使硼氫化鈉（〇 828 克’ 21.9耄莫耳）懸浮於四氫吱喃（13.5毫升）。在另一個燒瓶 中，使三氟醋酸（1.68毫升，2L8毫莫耳）溶於四氫呋喃（5毫升） 中。使50愛升反應燒瓶冷卻至〇 C ’並慢慢添加三氟酷酸溶 液。將反應物於室溫下攪拌。30分鐘後，將四氫唉喃（5毫升） 中之[(R，R)，(S，S)]與[(3，11)，(11，3)]斗氰基-6,7-二甲氧基-2-甲基-3,4-二 氫-2H-喹啉小羧酸乙酯（1.33克，4.37毫莫耳）逐滴添加至反應 物中。12小時後，使反應物冷卻回復至〇。〇，並小心地以水 使反應淬滅。以醋酸乙酯將水層萃取2次。將有機層合併， 以硫酸鎂脫水乾燥，過濾，及濃縮。使粗產物藉急驟式層 析純化，以97/2/1二氣甲烷/甲醇/三乙胺溶離，而得標題 化合物（0.982克，3.18毫莫耳，73%產率）。 LCMS (ESI+) : 309 (MH+)· [(R，S)，(S，R)] 1 H-NMR(CDC13): 5 1.18 (d，3H)，1·27 (t，3H)，2·47 (m, 2H)， 2·92 (m，1Η)，3·29 (m，1Η)，3.84 (s，3Η)，3·86 (s，3Η)，4.19 (m，2Η)，4·47 (m， 1H)，6.69 (s，1H)，7.02 (s，1H). LCMS (ESI+) : 309 (MH+). 92199 -157- 1285641 [(R，R)，(S，S)] 1 H-NMR(CDC13): 51.15 (d，3H)，1·31 (t，3H)，1·76 (m，1H)， 2·18 (m，1H)，2.94 (m，3H)，3·85 (s，3H)，3.86 (s，3H)，4.22 (m，2H)，4.61 (m， 1H)，6.69 (s，1H)，7.12 (s，1H). 實例26[(R,R,R)],[(R,R,S)],[(R,S,S)] and [(Min 3,11)] Winter (3,5-bis-trifluoromethyl) -phenyl)-hydroxy-methyl]-2-ethyl-6-diazinyl-3,4-diaza-2H-^ 12-lin-1 renegade B S曰92199 -155 - 1285641 will [ (R,S)] and [(R,R)]-4-(3,5-bis-trifluoromethyl-benzylidenyl)-2-ethyl-6-trifluoromethyl-3,4 Ethyl dihydro-2H-quinolinecarboxylate (0.182 g, 0.34 mmol, 1 eq.) was placed in a round bottom flask equipped with a magnetic stir bar. Methanol (6.8 ml) was added at room temperature followed by (0.077 g, 2.05 mmol, 6 eq.) sodium borohydride. After 1 hour, the reaction mixture was quenched with EtOAc (EtOAc)EtOAc. The title compound 〇(R,S,R): LCMS (ESI+): 544 (MH+). 1H- NMR (CDC13)········ (R,S,S): LCMS (ESI+): 544 (MH+). 1H-NMR (CDC13)·· 5 0·73 (t,3H), 1.09 (m,1H), 1.27 (t,3H) , 1.43 (m, 2H), 1.67 (m, 1H), 2.44 (d, 1H), 2·87 (m, 1H), 4.24 (m, 3H), 5.17 (dd, 1H), 7.26 (s, 1H) ), 7.50 (m, 2H), 7.90 (s, 2H), 7.92 (s, 1H) · (R, R, R) and (R, R, S): This mixture is 10 cm x 50 cm Chiralpak AD The tube was separated and dissolved in heptane/IPA 98//2 at a flow rate of 275 ml/min. (R, R, R): ^-NMRCCDC^): (5 0.77 (t, 3H), 1.31 (ζ 3H), 1.41 (m, 2H) 32.21 (d, 1Η), 3.19 (m, 1Η), 4.23 (m,2Η),4·37 (m,1Η),4.83 (d,1Η),7·65 (s,2Η), 7.79(s,lH)· LCMS (ESI+) : 544 (MH+). 92199 - 156- 1285641 (R, R, S): 1 H-NMR (CDC13): (5 0.81 (t, 3H), 1.33 (t, 3H), 1.6 (m, 2H), 2.22 (d, 1H), 3.05 (m, 1H), 4.30 (m, 2H), 4.62 (m, 1H), 5.19 (d, 1H), 7.01 (s, 1H), 7.40 (s, 2H), 7.85 (s, 1H)· LCMS ( ESI+): 544 (MH+). Preparation 32 and 33 [(R,R),(S,S)] and Zhao,11),(11,3)]-4-aminomethyl-6,7-di Ethyl methoxy-2-methyl-3,4-dihydro-2H-quinolin-1-carboxylate in a dry 50 ml round bottom flask equipped with a stir bar to give sodium borohydride (〇828 g) 21.9 耄mol) was suspended in tetrahydrofuran (13.5 ml). In a separate flask, trifluoroacetic acid (1.68 mL, 2 L 8 mmol) was dissolved in tetrahydrofuran (5 mL). Cool to 〇C ' and slowly add the trifluoro acid solution. Stir the reaction at room temperature. After 30 minutes, tetrahydrofuran (5 [(R,R),(S,S)] in [ml] and [(3,11),(11,3)]cyano-6,7-dimethoxy-2-methyl-3 , 4-Dihydro-2H-quinoline carboxylic acid ethyl ester (1.33 g, 4.37 mmol) was added dropwise to the reaction. After 12 h, the reaction was cooled and returned to hydrazine. The reaction was quenched with water, and the aqueous layer was extracted twice with ethyl acetate. The organic layer was combined, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography to 97/2/1 The title compound (0.982 g, 3.18 mmol, 73% yield) was obtained from m.p. )] 1 H-NMR(CDC13): 5 1.18 (d,3H),1·27 (t,3H),2·47 (m, 2H), 2·92 (m,1Η),3·29 (m , 1Η), 3.84 (s, 3Η), 3·86 (s, 3Η), 4.19 (m, 2Η), 4·47 (m, 1H), 6.69 (s, 1H), 7.02 (s, 1H). <RTIgt; ),1·76 (m,1H), 2·18 (m,1H), 2.94 (m,3H),3·85 (s,3H),3.86 (s,3H),4.22 (m , 2H), 4.61 (m, 1H), 6.69 (s, 1H), 7.12 (s, 1H). Example 26

[(R，S)，(R，R)]與[(3,3)，(3，11)]-4-[(3,5-二氟-苯甲醯胺基)-甲基]_6,7-二甲 氧基-2-甲基-3,4-二氫-2H-峻淋小叛酸乙酉旨 於[(R，S)，(R，R)]與[(3,3)，(3，11)]-4-胺基甲基-6,7-二甲氧基_2-甲基-3,4-二氫-2H-喹啉-1-羧酸乙酯（0.012克，0.039毫莫耳）在二氣甲 烷（1.0毫升）中之溶液内，添加3,5-二氟苯甲酸（0.0065克，0.041 毫莫耳，1.0當量），接著是1-(3-二甲胺基丙基）-3-乙基碳化二 亞胺鹽酸鹽（0.012克，0.065毫莫耳，1.6當量）與1-羥基苯并三 唑水合物（0.005克，0.039毫莫耳，1當量）。於環境溫度下將 反應物攪拌12小時。使混合物濃縮，溶於二甲亞風中，並 藉HPLC純化，提供標題化合物（〇·〇〇8克，〇·〇19毫莫耳）。 LCMS (ESI+) ·· 449 (ΜΗ+)· [(11，3)，(11，11)]與[(3,3)，(3，11)]:11^]\汉(〇〇(：13):(5 1.15((1，311)，1.30 (t，3Η)，1.79 (m，1Η)，2.16 (m，1Η)，3.16 (m，1Η)，3.63 (m，2Η)，3.82 (s，3Η)， 3.87 (s，3H)，4.22 (m，2H)，4.63 (m，1H)，6·13 (m，1H)，6·63 (s，1H)，6·92 (m, 1H)，7.13 (s，lH)，7.19(m，2H). 實例27與28 92199 -158- 1285641[(R,S),(R,R)] and [(3,3),(3,11)]-4-[(3,5-difluoro-benzamide)-methyl]_6 ,7-dimethoxy-2-methyl-3,4-dihydro-2H-Junlin small acid-reducing acetamidine for [(R,S),(R,R)] and [(3,3) ,(3,11)]-4-aminomethyl-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (0.012 g , 0.039 mmol; in a solution of di-methane (1.0 mL), 3,5-difluorobenzoic acid (0.0065 g, 0.041 mmol, 1.0 eq.), followed by 1-(3-dimethyl Aminopropyl)-3-ethylcarbodiimide hydrochloride (0.012 g, 0.065 mmol, 1.6 equivalents) and 1-hydroxybenzotriazole hydrate (0.005 g, 0.039 mmol, 1 equivalent) ). The reaction was stirred at ambient temperature for 12 hours. The mixture was concentrated, taken up in EtOAc EtOAc (EtOAc) LCMS (ESI+) ·· 449 (ΜΗ+)· [(11,3),(11,11)] and [(3,3),(3,11)]:11^]\汉(〇〇(: 13): (5 1.15 ((1,311), 1.30 (t,3Η), 1.79 (m,1Η), 2.16 (m,1Η), 3.16 (m,1Η), 3.63 (m,2Η), 3.82 ( s,3Η), 3.87 (s,3H), 4.22 (m,2H), 4.63 (m,1H),6·13 (m,1H),6·63 (s,1H),6·92 (m, 1H), 7.13 (s, lH), 7.19 (m, 2H). Examples 27 and 28 92199 -158- 1285641

F3CF3C

[(R，S)，(S，R)]與职和办別叫㈨-雙-三氟甲基彳胺基^甲基从^ —：甲氧基-2-甲基-3,4-二氫-2H-p奎琳小致酸乙酉旨 在裝有攪拌棒之10毫升圓底燒瓶中，使|j；R，S从S，R)]與 [(33)，(11，11)]-4-胺基甲基-6,7-二甲氧基-2-甲基-3,4-二氫-211-喹啉小 羧酸乙酯（0.131克，0.428毫莫耳）溶於二氯乙烷（2·〇毫升）中。 於此溶液中，添加3,5-雙（三氟甲基）苯甲醛（0.071毫升，0.431 毫莫耳），接著是三乙醯氧基硼氫化鈉（〇·272克，1.28毫莫耳） 。於環境溫度下攪拌12小時後，以1.〇 Ν氫氧化鈉水溶液使 反應混合物淬滅，並以醋酸乙酯萃取3次。收集有機層，以 硫酸鈉脫水乾燥，過濾，及濃縮。藉急驟式層析純化，以80/20 己：/醋乙I旨落離’提供標題化合物（〇·〇63克，0.12毫莫耳 ，28%產率）。 LCMS (ESI+) ： 535 (ΜΗ+).[(R, S), (S, R)] and the job and do not call (n) - bis-trifluoromethyl decyl group ^ methyl from ^ -: methoxy-2-methyl-3,4- Dihydro-2H-p-quinein acid acetate is intended to be used in a 10 ml round bottom flask equipped with a stir bar to give |j;R,S from S,R)] and [(33),(11,11) ] 4-Aminomethyl-6,7-dimethoxy-2-methyl-3,4-dihydro-211-quinolinecarboxylic acid ethyl ester (0.131 g, 0.428 mmol) is soluble Dichloroethane (2·〇 ml). To this solution, 3,5-bis(trifluoromethyl)benzaldehyde (0.071 ml, 0.431 mmol) was added followed by sodium triethyloxyborohydride (〇·272 g, 1.28 mmol). . After stirring at ambient temperature for 12 hours, the reaction mixture was quenched with EtOAc EtOAc. The organic layer was collected, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography eluting with EtOAc / EtOAc (EtOAc: EtOAc) LCMS (ESI+): 535 (ΜΗ+).

[(R，S)(S，R)] 1 H-NMR (CDC13): 5 1.09 (m，1Η)，1.17 (d，3Η)，1.28 (t，3Η)， 2·47 (m，1H)，2·61 (m，1H)，2·83 (m，1H)，3.16 (m，1H)，3·83 (s，3H)，3·84 (s， 3H)，4.02 (s，2H)，4.20 (m，2H)，4.47 (m，1H)，6.81 (s，1H)，7.01 (s，1H)，7·82 (s， 1H)，7.87 (s，2H)· LCMS (ESI+) : 535 _+)· [(R，R)(S，S)] 1 H-NMR (CDC13): 5 1.14 (d，3H)，1.28 (t，3H)，1·74 (m，1H)， 2.21 (m，1H)，2.79 (m，2H)，2.93 (m，1H)，3.83 (s，3H)，3.84 (s，3H)，3.88 (s，2H)， 92199 -159- 1285641 4·20 (m，2H)，4·56 (s，1H)，6,69 (s，1H)，7.11 (s，1H)，7.75 (s，1H)，7.79 (s，2H)· 實例29與30[(R,S)(S,R)] 1 H-NMR (CDC13): 5 1.09 (m,1Η), 1.17 (d,3Η), 1.28 (t,3Η), 2·47 (m,1H) ,2·61 (m,1H),2·83 (m,1H), 3.16 (m,1H),3·83 (s,3H),3·84 (s, 3H), 4.02 (s,2H) , 4.20 (m, 2H), 4.47 (m, 1H), 6.81 (s, 1H), 7.01 (s, 1H), 7·82 (s, 1H), 7.87 (s, 2H)· LCMS (ESI+): 535 _+)· [(R,R)(S,S)] 1 H-NMR (CDC13): 5 1.14 (d,3H), 1.28 (t,3H),1·74 (m,1H), 2.21 (m,1H), 2.79 (m,2H), 2.93 (m,1H),3.83 (s,3H),3.84 (s,3H),3.88 (s,2H), 92199 -159- 1285641 4·20 ( m, 2H), 4·56 (s, 1H), 6, 69 (s, 1H), 7.11 (s, 1H), 7.75 (s, 1H), 7.79 (s, 2H) · Examples 29 and 30

[(R，S)，(S，R)]與[(11，11)，(3,3)]-4-[(3,5-雙-三氟甲基-宇基）-甲氧羰基-胺 基]-6,7-二甲氧基-2-甲基-3,4-二氫-2H-喳啉-1-羧酸乙酯 在裝有攪拌棒之10毫升圓底燒瓶中，使[(R，S)，(S，R)]與 邸，3)，(11，11)]-4-[(3,5-雙-三氟甲基-爷胺基)-甲基]-6,7-二甲氧基-2-甲 基_3,4-二氫-2H-喹啉小羧酸乙酯（0.020克，0.037毫莫耳）溶於四 氫呋喃（2.0毫升）中。於此溶液中，添加碳酸鉀（0.134克，0.972 毫莫耳），接著添加氯甲酸甲酯（0.030毫升，0.388毫莫耳）。 將反應混合物於室溫下攪拌。12小時後，以1·0 N氫氧化鈉 水溶液使反應混合物淬滅，並以醋酸乙酯萃取3次。收集有 機層，以硫酸鈉脫水乾燥，過濾，及濃縮。藉急驟式層析 純化，以65/35己烷/醋酸乙酯溶離，提供標題化合物（0.005 克，0.008毫莫耳，30%產率）。 LCMS (ESI+) ： 593 (MH+).[(R,S),(S,R)] and [(11,11),(3,3)]-4-[(3,5-bis-trifluoromethyl-ylidene)-methoxycarbonyl -Amino]ethyl 6,7-dimethoxy-2-methyl-3,4-dihydro-2H-indolinoline-1-carboxylate in a 10 ml round bottom flask equipped with a stir bar, [[R, S), (S, R)] with hydrazine, 3), (11, 11)] -4-[(3,5-bis-trifluoromethyl--arylamino)-methyl] Ethyl-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinolinecarboxylate (0.020 g, 0.037 mmol) was dissolved in tetrahydrofurane (2.0 mL). To this solution, potassium carbonate (0.134 g, 0.972 mmol) was added followed by methyl chloroformate (0.030 mL, 0.388 mmol). The reaction mixture was stirred at room temperature. After 12 hours, the reaction mixture was quenched with EtOAc EtOAc. The organic layer was collected, dried over sodium sulfate, filtered, and concentrated. Purify by flash chromatography eluting with EtOAc EtOAc (EtOAc) LCMS (ESI+): 593 (MH+).

[(R，S)(S，R)] 1H-NMR (CDC13): 5 1·17 (d，3H)，1.29 (t，3H)，2.30 (m，1H)， 2·75 (m，1H)，3·60 (m，1H)，3·78 (s，3H)，3·83 (s，3H)，3.85 (s，3H)，4·22 (m，2H)， 4.39 (m, 1H), 7.03 (s, 1H). LCMS (ESI+) ： 593 (MH+).[(R,S)(S,R)] 1H-NMR (CDC13): 5 1·17 (d,3H), 1.29 (t,3H), 2.30 (m,1H), 2·75 (m,1H) ),3·60 (m,1H),3·78 (s,3H),3·83 (s,3H),3.85 (s,3H),4·22 (m,2H), 4.39 (m, 1H) ), 7.03 (s, 1H). LCMS (ESI+): 593 (MH+).

[(R，R)(S，S)] 1 H-NMR(CDC13): 5 1.15 (d，3H)，1.24 (m，3H)，1.63 (m，1H)， 92199 -160- 1285641 2.15 (m, IH), 3.78 (s, 3H), 3.83 (s, 3H), 3.86 (s, 3H), 4.17 (τη, 2H), 4.53 (m, 1H), 7.06 (s, 1H). 下述實例係使用類似上文實例中所述之方法，製自類似起 始物質： 實例31[(R,R)(S,S)] 1 H-NMR(CDC13): 5 1.15 (d,3H), 1.24 (m,3H), 1.63 (m,1H), 92199 -160 - 1285641 2.15 (m , IH), 3.78 (s, 3H), 3.83 (s, 3H), 3.86 (s, 3H), 4.17 (τη, 2H), 4.53 (m, 1H), 7.06 (s, 1H). Similar starting materials were prepared using methods similar to those described in the examples above: Example 31

[(11，3)，(3，11)]-4-[(3,5-雙_三氟甲基-苯甲醯基）-6,7-二甲氧基-2-甲基- 3,4-二氫-2H-喹啉-1-羧酸乙酯 1H-NMR (CDC13) ： 5 1.2 (d, 3H), 1.35 (t, 3H), 1.95 (m, 1H), 2.55 (m, 1H), 3.60 (s，3H)，3.97 (s，3H)，4.20 (m，1H)，4.22 (m，1H)，4·40 (m，1H)，4.62 (m， 1H)，6.2 (s，1H)，7,1 (s，1H) 8.19 (s，1H)，8·45 (s，2H)· LCMS (ESI+) ： 522 (MH+). 實例32[(11,3),(3,11)]-4-[(3,5-bis-trifluoromethyl-benzylidenyl)-6,7-dimethoxy-2-methyl- 3 , 4-Dihydro-2H-quinoline-1-carboxylic acid ethyl ester 1H-NMR (CDC13): 5 1.2 (d, 3H), 1.35 (t, 3H), 1.95 (m, 1H), 2.55 (m, 1H), 3.60 (s, 3H), 3.97 (s, 3H), 4.20 (m, 1H), 4.22 (m, 1H), 4·40 (m, 1H), 4.62 (m, 1H), 6.2 (s ,1H),7,1 (s,1H) 8.19 (s,1H),8·45 (s,2H)· LCMS (ESI+) : 522 (MH+). Example 32

[(1^，3)，(3，11，11)，(11，3，11)，(3，民3)]-4-[(3,5-雙-三氟甲基-苯基）-羥基-甲基 ]-6,7-二甲氧基-2-曱基-3,4-二氫-2H-喳啉-1-羧酸乙酯 1 H-NMR (CDC13): 5 1.13 (d，3H)，1.34 (t，3H)，（m，1H)，2.97 (m, 1H)，3.87 (s，3H)，3.88 (s，3H)，4.26 (m，2H)，4·40 (m，1H)，5·05 (d，1H)，6.89 (s，1H)， 92199 • 16卜 1285641 6.99(s，lH)，7.84(s，3H). LCMS (ESI+) : 522 (MH+). 實例33[(1^,3),(3,11,11),(11,3,11),(3,Min 3)]-4-[(3,5-bis-trifluoromethyl-phenyl) -Hydroxy-methyl]-6,7-dimethoxy-2-indolyl-3,4-dihydro-2H-indolinoline-1-carboxylic acid ethyl ester 1 H-NMR (CDC13): 5 1.13 ( d,3H), 1.34 (t,3H), (m,1H), 2.97 (m, 1H), 3.87 (s,3H), 3.88 (s,3H), 4.26 (m,2H),4·40 ( m,1H),5·05 (d,1H),6.89 (s,1H), 92199 • 16 卜1285641 6.99(s,lH),7.84(s,3H). LCMS (ESI+) : 522 (MH+). Example 33

C02Et (R，S)-4-(3,5-雙-三氟甲基-苯甲醯基）-2-乙基·6-三氟甲基-3,4_二氫- 2H-喹啉小羧酸乙酯 (R，S)]-順式：1 H-NMR (CDC13 )·· 5 0.91 (t，3H)，1.39 (t，3H)，1·43 (m，2H)， 1·78 (m，1Η)，1·99 (m，1Η)，2.60 (m，1Η)，4·34 (m，2Η)，4.56 (m，2Η)，7.05 (s， 1H)，7.55 (d，1H)，7.65 (d，1H)，8.20 (s，1H)，8.44 (s，2H). LCMS (ESI+) ： 542 (MH+). 實例34C02Et (R,S)-4-(3,5-bis-trifluoromethyl-benzylidenyl)-2-ethyl·6-trifluoromethyl-3,4-dihydro-2H-quinoline Ethyl carboxylic acid (R,S)]-cis: 1 H-NMR (CDC13 )·· 5 0.91 (t,3H), 1.39 (t,3H),1·43 (m,2H), 1· 78 (m,1Η),1·99 (m,1Η), 2.60 (m,1Η),4·34 (m,2Η),4.56 (m,2Η),7.05 (s, 1H),7.55 (d, 1H), 7.65 (d, 1H), 8.20 (s, 1H), 8.44 (s, 2H). LCMS (ESI+): 542 (MH+). Example 34

[(11，11，3)，(3,3，11)，(11,11，11)，(3,3,3)]-4-[乙醯氧基-(3,5-雙-三氟甲基-苯基)-甲基]-6,7-二甲氧基-2-甲基-3,4-二氫-2Ημ奎啉小羧酸乙酯 1H-NMR (CDC13 )· 5 1.10 (d, 3H), 1.29 (t? 3H), 1.62 (m, 1H), 1.87 (m, 1H), 2·00 (s，3H)，3.22 (m，1H)，3.84 (s，3H)，3·86 (s，3H)，4.21 (m，2H)，4.47 (m，1H)， 5.89 (d，1H)，6.62 (s，1H)，7.03 (s，1H)，7.66 (s，2H)，7.80 (s，1H). LCMS (ESI+) ： 564 (MH+). 92199 -162- 1285641 實例35[(11,11,3),(3,3,11),(11,11,11),(3,3,3)]-4-[acetoxy-(3,5-bis-three Ethyl fluoromethyl-phenyl)-methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2Ημ quinine carboxylic acid 1H-NMR (CDC13 )· 5 1.10 (d, 3H), 1.29 (t? 3H), 1.62 (m, 1H), 1.87 (m, 1H), 2·00 (s, 3H), 3.22 (m, 1H), 3.84 (s, 3H), 3·86 (s, 3H), 4.21 (m, 2H), 4.47 (m, 1H), 5.89 (d, 1H), 6.62 (s, 1H), 7.03 (s, 1H), 7.66 (s, 2H) , 7.80 (s, 1H). LCMS (ESI+): 564 (MH+). 92199 -162 - 1285641 Example 35

[(R，R，R) (S，S，S)與（R，R，S)與（S，S，R)]-4-[(3,5-雙-三氟甲基-苯基 &gt;•氟-甲 基]-6,7-二甲氧基-2-曱基-3,4-二氫-2H-p奎11林-1-幾酸乙酷 1H-NMR (CDC13): 5 U9 (d，3H)，1.30 (t，3H)，2.02 (m，1H)，2.95 (m，1H)， 3.95 (s，3H)，3·97 (s，3H)，4.26 (m，2H)，4.49 (m，1H)，6.40 (s，1H)，6.9 (s，1H)， 7·1 (s，1H)，7.8 (s，3H)，7.95 (s，1H)· LCMS (ESI+) ： 524 (MH+). 實例36[(R,R,R) (S,S,S) and (R,R,S) and (S,S,R)]-4-[(3,5-bis-trifluoromethyl-phenyl) &gt;•Fluoro-methyl]-6,7-dimethoxy-2-indolyl-3,4-dihydro-2H-p-quinone-11-lin-1-acidic acid 1H-NMR (CDC13): 5 U9 (d, 3H), 1.30 (t, 3H), 2.02 (m, 1H), 2.95 (m, 1H), 3.95 (s, 3H), 3.97 (s, 3H), 4.26 (m, 2H) ), 4.49 (m, 1H), 6.40 (s, 1H), 6.9 (s, 1H), 7·1 (s, 1H), 7.8 (s, 3H), 7.95 (s, 1H) · LCMS (ESI+) : 524 (MH+). Example 36

C02Et [(R，R)，(S，S)，(R，S)，(S，R))-4-(#i 基-二苯基-甲基）-6,7-二甲氧基-2-甲基· 3,4-二氫-2H-喹啉小羧酸乙酯 1H-NMR (CDC13) ： 5 1.0 (d，3H)，L32 (t, 3H)，2·2 (m，1H)，3·90 (s，3H)， 3·95 (s，3Η)，4.26 (m，2Η)，4·6 (m，1Η)，6·60 (s，1Η)，6·9 (s，1Η)，7.0 (s，1Η)， 7.2-7.4(m，10H)· LCMS (ESI+) : 444 (MH+)(減去 17 OH 基）· 實例37 92199 -163 - 1285641C02Et [(R,R),(S,S),(R,S),(S,R))-4-(#i-diphenyl-methyl)-6,7-dimethoxy Ethyl 2-methyl-3,4-dihydro-2H-quinolinecarboxylate 1H-NMR (CDC13): 5 1.0 (d,3H), L32 (t, 3H), 2·2 (m, 1H),3·90 (s,3H), 3·95 (s,3Η), 4.26 (m,2Η),4·6 (m,1Η),6·60 (s,1Η),6·9 ( s,1Η), 7.0 (s,1Η), 7.2-7.4(m,10H)· LCMS (ESI+) : 444 (MH+) (minus 17 OH group)· Example 37 92199 -163 - 1285641

羧酸乙酯 [(11，11)，(3,3)斗苯甲醯基-6,7-二甲氧基-2-甲基-3,4-二氫-211-喳啉小 lH-NMR(CDCl3) ： 5 1.19 (d，3H)，1.25 (t，3H)，2.4 (m，1H)，3.75 (s，3H)， 3.85 (s，3H)，4·30 (m，2H)，4·6 (m，1H)，4.9 (m，1H)，6.50 (s，1H)，7.2 (s，1H)， 7·4 (m，2H)，7.5 (t，1H)，7.9 (d，2H). LCMS (ESI+) : 384 (MH+). 實例38Ethyl carboxylate [(11,11),(3,3) piperidinyl-6,7-dimethoxy-2-methyl-3,4-dihydro-211-carboline small lH- NMR (CDCl3): 5 1.19 (d,3H), 1.25 (t,3H), 2.4 (m,1H), 3.75 (s,3H), 3.85 (s,3H),4·30 (m,2H), 4·6 (m, 1H), 4.9 (m, 1H), 6.50 (s, 1H), 7.2 (s, 1H), 7·4 (m, 2H), 7.5 (t, 1H), 7.9 (d, 2H). LCMS (ESI+): 384 (MH+). Example 38

[(1^，3)，(1^，11)，(3，11，11)，(3，11，3)]4-(羥基-苯基-甲基）-6,7-二甲氧基-2-甲基-3,4-二氫-2H-喳啉小羧酸乙酯 LCMS (ESI+) ： 386 (MH+) 表A中之實例39-169係使用類似如上述之方法，製自適當 起始物質，為外消旋混合物’並具有下列結構：[(1^,3),(1^,11),(3,11,11),(3,11,3)]4-(hydroxy-phenyl-methyl)-6,7-dimethoxy Ethyl 2-methyl-3,4-dihydro-2H-carbolinecarboxylic acid ethyl ester LCMS (ESI+): 386 (MH+). A suitable starting material is a racemic mixture 'and has the following structure:

92199 -164- 1285641 表A 實例 R3 ( ·表示連結至結 構） 化合物 LCMS ESI+ (MH+) 39 F— r^(_,=0 \ (4-[(3,5-雙-三氟甲基-爷基）-甲基-胺甲醯基]-6,7-二甲 氧基-2-甲基-3,4-二氫-2H-峻p林-1-複酸乙酯） 563 40 〇=( F F 4-{[(3,5-雙-三氟甲基-芊基 )-甲氧羰基-胺基]-甲基}-6,7-二甲氧基-2-甲基-3,4-二 氫-2H-喹啉小羧酸乙酯 593 41 〇 ch2· 、一N 。如 —F 4-[(3,5-雙·三氟基甲基-苯 基）-甲氧基-羰基-胺基]-甲 基}-6,7-二甲氧基-2-甲基-3,4-二氫-2H-喹啉小羧酸乙 m 579 42 -/Ν f Γ 4-{[(3,5-雙-三氟甲基-芊基 )-甲氧基-談基-胺基]-甲基 }-6,7-二曱氧基-2-甲基-3,4-二鼠-2H-^ p林-1-複酸乙酉旨 593 43 F— x—NH •c=o 4-(3,5-雙-三氟甲基4基胺 甲醯基）-6,7-二甲氧基-2-甲 基-3,4-二氫-2H-喹啉小羧 酸乙醋 549 92199 -165 - 1285641 實例 R3 ( ·表示連結至結 構） 化合物 LCMS ESI+ (MH+) 44 //°92199 -164- 1285641 Table A Example R3 (· indicates linkage to structure) Compound LCMS ESI+ (MH+) 39 F— r^(_,=0 \(4-[(3,5-bis-trifluoromethyl--) ))-Methyl-amine-mercapto]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-Jun Pulin-1-Ethyl Ethyl Ester) 563 40 〇= (FF 4-{[(3,5-bis-trifluoromethyl-indenyl)-methoxycarbonyl-amino]-methyl}-6,7-dimethoxy-2-methyl-3, 4-Dihydro-2H-quinoline small carboxylic acid ethyl ester 593 41 〇ch2· , a N. such as —F 4-[(3,5-bis-trifluoromethyl-phenyl)-methoxy- Carbonyl-amino]-methyl}-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline small carboxylic acid ethyl m 579 42 -/Ν f Γ 4-{ [(3,5-Bis-Trifluoromethyl-indenyl)-methoxy-ne-amino-amino]-methyl}-6,7-dimethoxy-2-methyl-3,4-二鼠-2H-^ p Lin-1-Fuic acid B. 593 43 F— x—NH • c=o 4-(3,5-bis-trifluoromethyl 4 ylaminomethylcarbenyl)-6,7 -Dimethoxy-2-methyl-3,4-dihydro-2H-quinoline carboxylic acid acetate 549 92199 -165 - 1285641 Example R3 (· indicates linkage to structure) Compound LCMS ESI+ (MH+) 44 / /°

HN—C· 6,7-二甲氧基-2-甲基斗(4-三氟甲基-爷基胺甲醯基）-3,4-二氩-2H-喹啉小羧酸乙 酯 481 45HN-C· 6,7-dimethoxy-2-methylidene (4-trifluoromethyl-glycosylcarbamimidyl)-3,4-diar-argon-2H-quinoline small carboxylic acid ethyl ester 481 45

•C—NH• C-NH

4-(2-氟基-4-三乳甲基-爷基 胺甲醯基）-6,7-二甲氧基-2-甲基-3,4-二氫-2H-喹啉小 羧酸乙酯 499 464-(2-Fluoro-4-tris-methyl--ylaminomethylmercapto)-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline carboxy Ethyl acetate 499 46

4-(2-氟-芊基胺甲醯基）-6,7-二甲氧基-2-甲基-3,4-二氫-2H-4啉小羧酸乙酯 431 474-(2-Fluoro-indolylcarbamimidyl)-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-4oline small carboxylic acid ethyl ester 431 47

4-(3-氟-爷基胺甲醯基）-6,7-二甲氧基-2-甲基-3,4-二氮-2H-喳啉小羧酸乙酯 431 484-(3-Fluoro-glycosylcarbamimidyl)-6,7-dimethoxy-2-methyl-3,4-diazo-2H-carboline ethyl carboxylic acid 431 48

、NH I 4-(4-氟-芊基胺甲醯基）-6,7-二甲氧基-2-甲基-3,4-二氮_ 2H-喹啉-1-羧酸乙酉旨 431 49, NH I 4-(4-fluoro-indolylcarbamimidyl)-6,7-dimethoxy-2-methyl-3,4-diaza-2H-quinoline-1-carboxylic acid 431 49

4-(2-氯-爷基胺甲醯基）-6,7-二甲氧基-2-甲基-3,4-二氮-2H-p查4木小致酸乙酯 447 504-(2-Chloro-glycosylcarbamoyl)-6,7-dimethoxy-2-methyl-3,4-diaza-2H-p, 4 wood small acid ethyl ester 447 50

4-(3-氯-爷基胺甲醯基）-6,7-二甲氧基-2-甲基-3,4-二氫-2H-喹啉小羧酸乙酯 4474-(3-Chloro-glycosylcarbamimidyl)-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinolinecarboxylic acid ethyl ester 447

4-(4-氣-爷基胺甲醯基）-6,7- 447 二甲氧基-2-曱基-3,4-二氩-2H-喹啉小羧酸乙酯 92199 -166- 12856414-(4-Gas-glycosylcarbamoyl)-6,7-447 Dimethoxy-2-indolyl-3,4-diar-argon-2H-quinolinecarboxylic acid ethyl ester 92199-166- 1285641

化合物 4-(2,4-二氯-芊基胺甲醯基 )-6,二甲氧基-2-甲基-3,4-二氫-2H-喹啉小羧酸乙酯 LCMS ESI+ (MH+) 481 4-(2,5-二氣-爷基胺甲醯基 )-6,7-二甲氧基-2-甲基-3,4-二氫-2H-喹啉-1-羧酸乙酯 4-(3,4-二氯-芊基胺甲醯基 )-6,7-二甲氧基-2-甲基-3,4-二氮-2Η-ρ奎g林-1-幾乙酉旨 4-(3,5-二氟-苄基胺甲醯基 )-6,7_二甲氧基-2-f7 基-3,4-二氫-2H-喳啉小羧酸乙酯 4-(2,4-二氟-爷基胺甲縫基 )-6,7-二甲氧基-2-甲基-3,4-二氫-2H-喹啉小羧酸乙酯 6,7-二甲氧基-2-甲基-4-(4-三氟甲氧基-爷基胺甲酿 基）-3,4-二氫-2H-喹啉小羧 酸乙醋 4-(3,5-雙-三氟甲基-爷基胺 甲醯基）-6,7-二甲氧基-2-甲 基-3,4-二氫-2H-喹啉-1-羧 酸乙酯 481 481 449 449 497 549 92199 -167- 1285641 實例 R3 ( ·表示連結至結 構） 化合物 LCMS ESI+ (MH+) 59 0γ Cl 4-(3,5-二氣-芊基胺甲醯基 )-6,7-二甲氧基-2-甲基-3,4-二氫-2H-喹啉小羧酸乙酯 481 60 6,7-二甲氧基-2-甲基-4-(3· 三氟甲氧基-芊基胺甲醯 基）-3,4-二氫-2Η-喳啉小羧 酸乙醋 497 61 〇 H vN、c々〇 曹 4-(3,4-二氣-卞基胺甲酸基 )-6,7-二甲氧基-2-甲基-3,4-二氮-2Η-口奎淋-1-瘦乙酉旨 449 62 6 H \^N、C々〇 • 6,7-二甲氧基-2-甲基-4-(3,4,5-三氟-芊基胺甲醯基 )-3,4-二氫-2H-喹啉小羧酸 乙醋 467 63 F、 F〆 c (F ·‘〇 6,7-二甲氧基-2-甲基斗 (2,4,5-三氟-爷基胺甲酉1：基 )-3,4-二氫-2H-喳啉小羧酸 乙醋 467 64 H · cfljr、 4-〇(1Η-啕哚-3-基）-乙基胺 甲醯基]-6,7-二甲氧基-2-甲 基-3,4-二氫-2H-喹啉小羧 酸乙酯 466 65 Xo 6,7-二甲氧基-2-甲基-4-[(噻 吩-2-基甲基&gt;胺甲醯基]-3,4-二氫-2H-口奎。林-1-複酸乙 酯 419 92199 -168 - 1285641 實例 R3 ( ·表示連結至結 構） 化合物 LCMS ESI+ (ΜΗ+) 66 6,7-二甲氧基-2-甲基-4-[(5-甲基-味喃-2-基甲基）-胺甲 驢基]-3,4-二氮-2H-^ 57林-1·* 羧酸乙酯 417 67 〇\ HN 'JO 4-[(呋喃-2-基甲基）-胺甲醯 基]-6,7-二甲氧基-2-甲基-3,4-二氫-2H-喹啉-1-羧酸乙 403 68 0 6,7-二甲氧基-2-甲基-4-[(四 氫-17夫喃-2-基甲基）-胺甲酿 基]-3,4-二鼠-2Η-ρ奎淋-1-竣 酸乙酯 407 69 H2C 4-{[(3&gt;雙-三氟甲基-爷基 )-甲氧基-藏基-胺基]-甲基 }-6,7-二甲乳基-2-甲基-3,4-二鼠-211-0奎淋-1-幾酸乙画旨 593 70 F- HN-C* \ 4-(3,5-雙-三氟甲基-苯胺甲 醯基）-6,7-二甲氧基-2-甲基 -3,4-二氫-2Η-喹啉小羧酸 乙酉旨 535 71 1 F 4-[(2,4-雙-三氟甲基-苯甲 醯胺基）-甲基]-6,7-二甲氧 基-2-甲基-3,4-二氫-2Η-喳 啉小羧酸乙酯 549 92199 -169- 1285641 實例 R3 ( ·表示連結至結 構） 化合物 LCMS ESI+ (MH+) 72 HN 一/ f F 4-[(3,5-雙-三氟甲基-苯甲 醯胺基）-甲基]-6,7-二甲氧 基-2-甲基-3,4-二氮-2Η-^ 啉小羧酸乙酯 549 73 Cl y\) •H2C-NH xU 4-[(2-氯-苯甲醯胺基）-甲基 ]-6,7-二甲氧基-2-甲基-3,4-二氫-2H-喹啉小羧酸乙酯 447 74 •H2c-NH Nf 4-[(2,4-二氯-苯甲醯胺基）-甲基]-6,7-二甲氧基-2-甲基 -3,4-二氫-2H-喹啉小羧酸 乙酯 481 75 Cl °H $ •H2c——NH -Y Cl 4-[(3,5-二氯-苯甲醯胺基）-甲基]-6,7-二甲氧基-2-甲基 -3,4-二氫·2Η-喹啉-1-羧酸 乙酉旨 ：481 76 •H2C-NH N-' 4-[(2,4-二氟-苯甲醯胺基）-甲基]-6,7-二甲氧基-2-甲基 -3,4-二氫-2Η-喹啉小羧酸 乙酉旨 449 77 •H2c——NH 乂-&lt; F 4-[(3,5-二氟-苯甲醯胺基）-甲基&gt;6,7-二甲氧基-2-甲基 -3,4-二氫-2Η-喹啉-1-羧酸 乙醋 449 78 Wh 0 ch2. 4-{[(2,4-雙-三氟f基-芊基 )-甲氧羰基-胺基]-甲基}-6,7-二甲氧基-2-甲基-3,4-二 氫-2H-喹啉小羧酸乙醋 593 92199 &gt; 170- 1285641 實例 R3 ( ·表示連結至結 構） 化合物 LCMS ESI+ (MH+) 79 •H〇C 〇 CI 4-{[(2-氯-芊基）-甲氧羰基-胺基]-甲基卜6,7-二甲氧基-2-甲基-3,4-二氫-2H-喹啉-1-羧酸乙酯 491 80 〇 CH，· F \ F 4-{[(3,5-二氟-爷基）-甲氧羰 基-胺基]-甲基卜6,7-二甲氧 基-2-甲基-3,4-二氫-2H-喹 啉小羧酸乙酯 493 81 〇 ~F 4-{[(2,4-二氟-字基）-甲氧羰 基-胺基]-甲基}-6,7-二甲氧 基-2-甲基-3,4-二氫-2H-喹 啉小羧酸乙酯 493 82 〇 CH2· / 4-{[(3,5-二甲基-異噚唑斗 基甲基）-甲氧羰基-胺基]-甲基}-6,7-二甲氧基-2-甲 基-3,4-二氫-2H-喳啉-1-羧 酸乙酯 476 83 1 ·、 4-爷基胺甲酿基-6,7-二甲 氧基-2-甲基-3,4-二氫-2H- 喹啉小羧酸乙酯 413 84 F^r〇 •C=〇 4-[爷基-(3,5-雙-三敦曱基-芊基）-胺甲醯基]-6,7-二甲 氧基冬甲基-3,4-二氫-2H_ 喹啉-1-羧酸乙酯 639 92199 -171 - 1285641 實例 R3 ( ·表示連結至結 構） 化合物 LCMS ESI+ (ΜΗ+) 85 vC F 4-[(3,5-雙-三氟甲基-爷基）-(3,5-二甲基-異哼唑斗基甲 基）-胺甲醯基]-6,7-二甲氧 基-2-甲基-3,4-二氫-2H-4 淋複故乙S旨 658 86 •H2C—NH ^^ F 6,7-二f氧基-2-甲基斗 [(3,4,5-三氟-苯甲醯胺基）_ 甲基]-3,4-二氫-2H-喹啉小 羧酸乙酯 467 87 •H2c—NH ^~~J 4-[(3,4-二氟-苯甲醯胺基）-甲基]-6,7-二甲氧基-2-甲基 -3,4-二氣-2H-11 奎 σ林-1-竣酸 乙醋 449 88 F\ F \ H •H2C—NH、~( F 6,7-二甲氧基-2-曱基-4-[(2,3,5-三氟-苯甲醯胺基）-甲基]-3,4-二鼠-2Η-17奎 17林-1_ 羧酸乙酯 467 89 :办 •Hi ”F 6,7-二甲氧基-2-曱基-4_ [(2,3,4,5,6-五氟苯甲醯基胺 基）-甲基]-3,4-二氫-2Η-喳 啉-1-羧酸乙酯 503 90 F F rS ?H2* ^γΝΗ 〇 4-[(3-氟基-5-三氟甲基-苯 甲醯胺基）-曱基]-6,7-二甲 氧基-2-甲基-3,4-二氫-2Η-4啉小羧酸乙酯 499 92199 -172- 1285641 實例 R3 ( ·表示連結至結 構） 化合物 LCMS ESI+ (ΜΗ+) 91 〇 ΗΝ^γ-γΡ CH2· F 4-[(3-氟基-4-三氟甲基-苯 甲醯胺基）-甲基]-6,7-二甲 氧基-2-甲基-3,4-二氫-2H-喹啉小羧酸乙酯 499 92 个。 4-[(5-氟基-2-三氟甲基-苯 甲醯胺基）-甲基]-6,7-二甲 氧基-2-甲基-3,4-二氫-2H-ΪΤ奎琳-1-瘦酸乙酉旨 499 93 0，如 6,7-二甲氧基-2-甲基-4-[(3-三氟甲氧基-苯甲醯胺基）-甲基]-3,4-二氫-2H-喹啉-1-羧酸乙酯 497 94 •H2C—NH ^~^ ‘{[(4-氟-茶-1-羰基）-胺基]-甲基}-6,7-二甲氧基-2-甲 基-3,4-二氫-2H-喳啉小羧 酸乙醋 481 95 /°~fF nh X0 F •H2C^N γ^Ν 〇 6,7-二甲氧基-2-甲基-4-{[(5-三氟甲氧基-1H-啕哚-2-羰 基）-胺基]-甲基]-3,4-二氫-2H-喹啉-1-羧酸乙酯 536 96 ΑΌ1，. 〇 Cl 4-[(2-氯基-4-甲烷磺醯基-苯甲醯胺基）-甲基]-6,7-二 甲氧基-2-甲基-3,4-二氫-2Η-4淋-1-幾酸乙@旨 525 97 ΝΗχχ^ 〇 4-[(3-氟基-4-三氟甲基-苯 甲醯胺基）-甲基]-6,7-二甲 氧基-2-甲基-3,4-二氫-2Η- 喹啉小羧酸乙酯 499 92199 -173 - 1285641 實例 R3( ·表示連結至結 構） 化合物 LCMS ESI+ (ΜΗ+) 98 〇 ΧΗ2· \ΧΧ^Η 〇 / 4-[(2,4-二甲氧基-苯甲醯胺 基）-甲基]-6,7-二甲氧基-2-甲基-3,4-二氫-2Η-喳啉小 羧酸乙酯 473 99 4-[(4-氟-苯甲醯胺基）-甲基 ]-6,7-二甲氧基-2-甲基-3,4-二氫-2Η-喹啉小羧酸乙酯 431 100 r&gt;^NHCH2* % 6,7-二甲氧基-2-甲基-4-[(2-三氟甲基-苯甲醯胺基）-甲 基]-3,4-二氫-2Η-喹啉小羧 酸乙醋 481 101 xci 4-[(2-氯基冬氟-苯甲醯胺 基）-甲基]-6,7-二甲氧基-2-甲基-3,4-二氩-2Η-喹啉-1- 羧酸乙酯 465 102 6,7-二甲氧基-2-甲基-4-[(4-三氟甲氧基-苯甲醯胺基）-甲基]-3,4-二氫-2Η-喹啉-1-羧酸乙酯 497 103 F F 4-[(2-氟基-4-三氟甲基-苯 甲醯胺基）-甲基]-6,7-二甲 氧基-2-甲基-3,4-二氫-2Η_ 喹啉小羧酸乙酯 499 104 F 6,7-二甲氧基冬甲基斗 [(2,3,6-三氟-苯甲酿胺基）-甲基]-3,4-二氩-2Η-喹啉小 羧酸乙酯 467 92199 -174 - 1285641 實例 R3 ( ·表示連結至結 構） 化合物 LCMS ESI+ (ΜΗ 十） 105 F 4-[(2-氟基-3-三氟甲基-苯 甲醯胺基）-甲基]-6,7-二甲 氧基-2-甲基-3,4-二氣-2Η-喹啉小羧酸乙酯 499 106 Cl 〇 Ιί χη2· F 4-[(2-氯基-4,5-二氟-苯甲醯 胺基）-甲基]-6,7-二甲氧基-2-甲基-3,4-二氫-2Η-喹啉-1-羧酸乙酯 483 107 rV^NHCH2* 4-[(4-氟基-2-三氟甲基-苯 甲醯胺基）-甲基]-6,7-二甲 氧基-2-甲基-3,4-二氮-2Η-喹啉小羧酸乙酯 499 108 〇 /^\ JL xh2· 4-[(4-氟基-3-三氟甲基-苯 甲醯胺基）-甲基]-6,7-二甲 氧基-2-甲基-3,4-二鼠-2Η_ 喹啉小羧酸乙酯 499 109 v 〇 4-[(3,5-二甲基-苯甲醯胺基 )-甲基]-6,7-二甲氧基-2-甲 基-3,4-二氫-2Η-喹啉小羧 酸乙醋 441 110 F 4-[(3-氟基-4-甲基-苯甲醯 胺基）-甲基]-6,7-二甲氧基-2-甲基-3,4-二氫-2Η-喹啉-1-羧酸乙酯 445 111 h 〇 4-[(3-氟-苯甲醯胺基）-甲基 ]-6,7-二甲氧基-2-甲基-3,4-二氮-2Η-^淋-1-複酸乙S旨 431 92199 -175 - 1285641 實例 R3 ( ·表示連結至結 構） 化合物 LCMS ESI+ (MH+) 112 °\ 6,7-二甲氧基-4-[(3-甲氧基-4-甲基-苯甲醯胺基）-曱基 ]-2-甲基-3,4-二氫-2H-喹啉-1-羧酸乙酯 457 113 CI 4-[(3-氯基-2-氟-苯甲醯胺 基）-甲基]-6,7-二甲氧基-2-甲基-3,4-二氣-2H-p奎淋-1-羧酸乙酯 465 114 Q^NHCH2* F 6,7-二甲氧基-2-甲基4-[(2-三氟甲氧基-苯甲醯胺基）-甲基]-3,4-二氫-2H-喹啉小 羧酸乙酯 497 115 ( ‘[(3-乙氧基苯甲醯胺基）-甲基]-6,7-二甲氧基-2-甲基 -3,4-二氫-2H-喹啉-1-羧酸 乙酉旨 457 116 〇 ]1 χη2· x〇^i ΝΗ Cl 4-[(3-氯基-4-甲氧基-苯甲 醯胺基）-甲基]-6,7-二甲氧 基-2-甲基-3,4-二氫-2H-喹 淋小叛酸乙醋 477 117 \^0 〇 Y?Xy^^ 4-[(3-異丙氧基-4- f7氧基_ 苯甲醯胺基）-甲基]-6,7-二 甲氧基-2-甲基-3,4-二氫-奎淋-1-癸复酸乙酉旨 501 92199 -176- 1285641 實例 R3 ( ·表示連結至結 構） 化合物 LCMS ESI+ (MH+) 118 ffY •H2c—NH ^~f 0一 6,7-二甲氧基-4-{[5-甲氧基-2-(2,2,2-三氟-乙氧基）-苯甲 醯胺基]-甲基卜2-甲基-3,4-二氫-2H-喹啉小羧酸乙ί旨 541 119 ^pr^NH瑪. VF F 4-[(3-二氟f氧基-苯甲醯 胺基）-甲基]-6,7-二甲氧基-2-甲基-3,4-二氫-2H-喹啉小 羧酸乙酯 479 120 'io^. 〇 4-[(4-二丙基胺績S盈基-本 甲醯胺基）-甲基]-6,7-二甲 氧基-2-甲基-3,4-二氫-2H-喹啉-1-羧酸乙酯 576 121 ry^mCH29 V〆 4-{〇(2-第三-丁氧羰基胺 基-乙基）-苯甲醯胺基]-甲 基}-6,7-二甲乳基-2-甲基-3,4-二氫-2H-喳啉-1-羧酸乙 酯 556 122 /^N V-N 〇 yy^NHcH2&lt; 6,7-二甲氧基-2-甲基-4-[(3-吡唑-1-基-苯甲醯胺基）-甲 基]-3,4-二氫-2H-喹啉小羧 酸乙酯 479 123 4-[(4-甲烷磺醯基-苯甲醯 胺基）-甲基]-6,7-二甲氧基-2-甲基-3,4-二氫-2H-喹啉小 羧酸乙酯 491 92199 -177- 1285641 實例 R3 ( ·表示連結至結 構） 化合物 LCMS ESI+ (MH+) 124 0 4-{[3-(3,5-二甲基-说唑小基 )-苯甲醯胺基]-甲基}-6,7-二甲氧基-2-甲基-3,4-二氫-2H-4啉小羧酸乙酯 507 125 4-{[(3f氟-聯苯基冰談基）-胺基]-甲基}-6,7-二甲氧基-2-甲基-3,4-二氫-2H-喹啉小 羧酸乙酯 507 126 ry^NHCH2· 4-{[(2’-氟-聯苯基-3-談基）_ 胺基]-甲基}-6,7-二甲氧基-2-甲基-3,4-二氩-2H-喹啉-1-羧酸乙酯 507 127 ry^NHcH2- X 4-{[(3’-氟-聯苯基-3-談基）-胺基]-甲基}-6；7-二甲氧基-2-甲基_3,4_二氫-2H-喹啉-1-羧酸乙酯 507 128 ^y^NHXH2· F 4-{[(4^氟-聯苯基-3-談基）-胺基]-甲基}-6,7-二曱氧基-2-甲基-3,4-二氫-2H-喳啉-1-羧酸乙酯 507 129 d1，. 'Cl 4-[(2,6-二氯-苯甲驢胺基）-甲基]-6,7-二甲氧基-2-甲基 -3,4-二鼠-2Η-ρ奎淋-1-複 fe 乙酉旨 481 92199 -178 - 1285641 實例 R3 ( ·表示連結至結 構） 化合物 LCMS ESI+ (MH+) 130 〇 /^\ JL χη2· F 6,7-二甲氧基-2-甲基-4-[(3-三氟甲基-苯甲醯胺基）-甲 基]-3,4-二氫-2H-喹啉小羧 酸乙醋 481 131 y〇 〇 〇/ 4-[(3-f烷磺醯基-苯甲醯 胺基）-曱基]-6,7-二甲氧基-2-甲基-3,4-二氫-2H-喹啉-1-羧酸乙酯 491 132 〇 xh2· 6,7-二甲氧基-4-[(3-甲氧基-苯甲醯胺基）-甲基]-2-甲基 -3,4-二氫-2H-喹啉小羧酸 乙醋 443 133 Cl 4-[(3,4-二氣-苯甲醯胺基）-甲基]-6,7-二甲氧基-2-甲基 -3,4-二氫-2H-喳啉-1-羧酸 乙酉旨 481 134 r^\ Jl XH2- Cx^ Cl 4-[(2-氯基-6-氣-苯甲驢胺 基）-甲基]-6,7-二甲氧基-2-甲基-3,4-二氫-2H-喹啉-1-羧酸乙酯 465 135 Ft^&quot;CH2' F 4-[(2,5-二氟-苯甲醯胺基）-甲基]-6,7-二甲氧基-2-甲基 -3,4-二氫-2H-喹啉小羧酸 乙酉旨 449 136 F 4-[(2,3-二氟-苯甲醯胺基）-甲基]-6,7-二甲氧基-2-甲基 -3,4-二氫-2H-喹啉-1-羧酸 乙酉旨 449 92199 -179 - 1285641 實例 R3 ( ·表示連結至結 構） 化合物 LCMS ESI+ (MH+) 137 •H2c-Ny 〇 V F 4-[(2,4-二氟-苯甲醯胺基）-甲基]-6,7-二甲氧基-2-甲基 -3,4-二氫-2H-喳啉小羧酸 乙i旨 449 138 •H，V 〇 ά 4-[(3&gt;二氟-苯甲醯胺基）-甲基]-6,7-二甲氧基-2-甲基 -3,4-二氫-2H-喹啉小羧酸 乙酉旨 449 139 F 〇 V 4-[(2,5-雙-三氟甲基-苯甲 醯胺基）-甲基]-6,7-二甲氧 基-2-甲基-3,4-二氫-2H-喹 啉-1-羧酸乙酯 449 140 F F 6,7-二甲氧基-2-甲基-4-[(2,4,5-三氟-苯甲醯胺基）-甲基]-3,4-二氫-2H-喹啉小 羧酸乙酯 467 141 勞。H2· 4-[(2-氟基-6-三氟甲基-苯 甲醯胺基）-甲基]-6,7-二甲 氧基-2-甲基-3Λ二氫-2H-口奎4 -1-複酸乙酉旨 499 142 F 6,7-二甲.氧基-2- f基斗 [(2,3,4-二氟-苯甲驗胺基）-甲基]-3,4-二氫-2H-喹啉小 羧酸乙酯 467 92199 -180- 1285641 實例 R3 ( ·表示連結至結 構） 化合物 LCMS ESI+ (ΜΗ+) 143 〇 〇^. 6,7-二甲氧基-2-甲基冬 {[(恥三氟甲基-聯苯基-2-羰基）-胺基]-甲基卜3,4-二 氫-2Η-。奎淋-1-敌酸乙醋 557 144 〇 11 χη2· F 4-[(3-氟基-4-甲氧基-苯甲 醯胺基）-甲基]-6,7-二甲氧 基-2-甲基-3,4-二氫-2Η-喹 啉小羧酸乙酯 461 145 〇 r^\ J1 ΧΗ2· Cl 4-[(3-氯基-4-氟-苯甲醯胺 基）-甲基]-6,7-二甲氧基-2-甲基-3,4-二氫-2Η-喹啉小 羧酸乙酯 465 146 jfS 〇 4-[(3-氟基-5-三氟甲基-苯 甲醯胺基）-甲基]-6,7-二甲 氧基-2-甲基-3,4-二氫_2Η-口奎淋-1-幾酸乙酯 499 147 4-[(4-二氟甲氧基-苯甲醯 胺基）-甲基]-6,7-二甲氧基-2-甲基-3,4-二氫-2Η-喹啉小 羧酸乙酯 479 148 〇 丄 ΧΗ2· ^ΝΗ CI 4-[(3-氯-苯甲醯胺基）-甲基 ]-6,7-二甲氧基-2-甲基-3,4-二氫-2Η-喹啉小羧酸乙酯 447Compound 4-(2,4-Dichloro-indolylcarbamimidyl)-6,dimethoxy-2-methyl-3,4-dihydro-2H-quinolinecarboxylic acid ethyl ester LCMS ESI+ ( MH+) 481 4-(2,5-diox-glycosylcarbamoyl)-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Ethyl ethyl ester 4-(3,4-dichloro-indolylmethionyl)-6,7-dimethoxy-2-methyl-3,4-diaza-2Η-ρ奎克林-1 - 乙乙酉 4-(3,5-Difluoro-benzylaminecarbazyl)-6,7-dimethoxy-2-f7-yl-3,4-dihydro-2H-carboline small carboxylic acid Ethyl 4-(2,4-difluoro-glycosylmethyl)-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinolinecarboxylic acid ethyl ester 6,7-Dimethoxy-2-methyl-4-(4-trifluoromethoxy-l-arylamine)-3,4-dihydro-2H-quinoline small carboxylic acid ethyl vinegar 4 -(3,5-bis-trifluoromethyl-glycosylcarbamimidyl)-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Ethyl acrylate 481 481 449 449 497 549 92199 -167- 1285641 Example R3 (· indicates linkage to structure) Compound LCMS ESI+ (MH+) 59 0 γ Cl 4-(3,5-di-methane-mercaptocarbamyl)- 6,7-Dimethoxy-2-methyl-3,4-dihydro-2H-quinolinecarboxylic acid ethyl ester 481 60 6,7-dimethoxy-2-methyl-4-(3 · three Methoxy-decylamine-mercapto)-3,4-dihydro-2-indole-porphyrin small carboxylic acid vinegar 497 61 〇H vN, c々〇Cao 4-(3,4-digas-fluorenyl Aminocarboxylic acid)-6,7-dimethoxy-2-methyl-3,4-diaza-2Η-hydroxyquinone-1-skinny 449 62 6 H \^N, C々〇• 6 ,7-Dimethoxy-2-methyl-4-(3,4,5-trifluoro-decylamine-methylhydrazino)-3,4-dihydro-2H-quinolinecarboxylic acid acetoacetate 467 63 F, F〆c (F · '〇6,7-dimethoxy-2-methylindole (2,4,5-trifluoro-glycosylcarbazide 1: base)-3,4-di Hydrogen-2H-porphyrin small carboxylic acid vinegar 467 64 H · cfljr, 4-anthracene (1Η-indol-3-yl)-ethylaminemethanyl]-6,7-dimethoxy-2- Ethyl methyl-3,4-dihydro-2H-quinoline carboxylic acid 466 65 Xo 6,7-dimethoxy-2-methyl-4-[(thiophen-2-ylmethyl) amine Methyl hydrazide]-3,4-dihydro-2H-hydroxyl. Lin-1-carboxylic acid ethyl ester 419 92199 -168 - 1285641 Example R3 (· indicates linkage to structure) Compound LCMS ESI+ (ΜΗ+) 66 6, 7-Dimethoxy-2-methyl-4-[(5-methyl-mum-2-ylmethyl)-aminecarbamyl]-3,4-diaza-2H-^ 57- 1·* Ethyl carboxylate 417 67 〇 \ HN 'JO 4-[(furan-2-ylmethyl)-amine carbaryl ]-6,7-Dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid B 403 68 0 6,7-dimethoxy-2-methyl- 4-[(tetrahydro-17f-amyl-2-ylmethyl)-amine-methanol]-3,4-dimur-2Η-ρ 奎 竣-1-decanoic acid ethyl ester 407 69 H2C 4-{[ (3&gt; bis-trifluoromethyl-aryl)-methoxy-salt-amino]-methyl}-6,7-dimethyllacto-2-methyl-3,4-dimur- 211-0 Querine-1-acid B. 593 70 F-HN-C* \ 4-(3,5-bis-trifluoromethyl-anilinecarbamyl)-6,7-dimethoxy -2-methyl-3,4-dihydro-2-indole-quinoline carboxylic acid 535 535 71 1 F 4-[(2,4-bis-trifluoromethyl-benzoguanidino)-methyl ]-6,7-Dimethoxy-2-methyl-3,4-dihydro-2-indole-porphyrin small carboxylic acid ethyl ester 549 92199 -169- 1285641 Example R3 (· indicates linkage to structure) Compound LCMS ESI+ (MH+) 72 HN a / f F 4-[(3,5-bis-trifluoromethyl-benzamide)-methyl]-6,7-dimethoxy-2-methyl-3 , 4-Diazin-2-indole-carboxylic acid ethyl carboxylate 549 73 Cl y\) • H2C-NH xU 4-[(2-chloro-benzamide)-methyl]-6,7-di Ethyl methoxy-2-methyl-3,4-dihydro-2H-quinoline carboxylic acid 447 74 •H2c-NH Nf 4-[(2,4-dichloro-benzamide) -Methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinolinecarboxylic acid ethyl ester 481 75 Cl °H $ •H2c——NH -Y Cl 4 -[(3,5-dichloro-benzamide)-methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2-indolyl-1-carboxylate Acid 酉: 481 76 • H2C-NH N-' 4-[(2,4-difluoro-benzamide)-methyl]-6,7-dimethoxy-2-methyl-3 , 4-dihydro-2-indole-quinoline small carboxylic acid acetonitrile 449 77 •H 2c——NH 乂-&lt; F 4-[(3,5-difluoro-benzamide)-methyl&gt;6 ,7-Dimethoxy-2-methyl-3,4-dihydro-2-indole-quinoline-1-carboxylic acid ethane 449 78 Wh 0 ch2. 4-{[(2,4-bis-trifluoro F-yl-fluorenyl)-methoxycarbonyl-amino]-methyl}-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline carboxylic acid 593 92199 &gt; 170- 1285641 Example R3 (· indicates linkage to structure) Compound LCMS ESI+ (MH+) 79 •H〇C 〇CI 4-{[(2-Chloro-indolyl)-methoxycarbonyl-amino]-A Ethyl 6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester 491 80 〇CH,· F \ F 4-{[(3, 5-difluoro-aryl)-methoxycarbonyl-amino]-methyl b 6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quin Ethyl phthalate small carboxylic acid 493 81 〇~F 4-{[(2,4-difluoro-yl)-methoxycarbonyl-amino]-methyl}-6,7-dimethoxy-2- Ethyl methyl-3,4-dihydro-2H-quinoline carboxylic acid 493 82 〇CH2· / 4-{[(3,5-dimethyl-isoxazole)methylcarbonyl-methoxycarbonyl -Amino]-methyl}-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-indololin-1-carboxylic acid ethyl ester 476 83 1 ·, 4-loyyl Aminomethyl-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline small carboxylic acid ethyl ester 413 84 F^r〇•C=〇4-[Germanyl -(3,5-bis-triptanyl-fluorenyl)-amine-mercapto]-6,7-dimethoxybutyryl-3,4-dihydro-2H-quinoline-1-carboxylic acid Ethyl ester 639 92199 -171 - 1285641 Example R3 (· indicates linkage to structure) Compound LCMS ESI+ (ΜΗ+) 85 vC F 4-[(3,5-bis-trifluoromethyl-yl)-(3,5 -Dimethyl-isoxazinylmethyl)-amine-methylmethyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-4 658 86 •H2C—NH ^^ F 6,7-di-f-oxy-2-methylindole [(3,4,5-trifluoro-benzamide)-methyl]-3,4-di Hydrogen-2H-quinoline small carboxylic acid ethyl ester 467 87 •H2c—NH ^~~J 4-[(3,4-difluoro-benzamide)- Methyl]-6,7-dimethoxy-2-methyl-3,4-dioxa-2H-11 quinoxaline-1-decanoic acid vinegar 449 88 F\ F \ H • H2C-NH, ~( F 6,7-Dimethoxy-2-indolyl-4-[(2,3,5-trifluoro-benzylidinium)-methyl]-3,4-dimur-2Η- 17 Kui 17 Lin-1_ Ethyl Carboxylate 467 89 : Do•Hi ”F 6,7-Dimethoxy-2-indolyl-4_ [(2,3,4,5,6-pentafluorobenzidine) Ethylamino)-methyl]-3,4-dihydro-2-indole-porphyrin-1-carboxylic acid ethyl ester 503 90 FF rS ?H2* ^γΝΗ 〇4-[(3-fluoro-5-trifluoro Methyl-benzylaminoamido)-indolyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2indole-4 carboxylic acid ethyl ester 499 92199 -172- 1285641 Example R3 (· indicates linkage to structure) Compound LCMS ESI+ (ΜΗ+) 91 〇ΗΝ^γ-γΡ CH2· F 4-[(3-Fluoro-4-trifluoromethyl-benzamide)-A There are 499 92 ethyl acetate-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline. 4-[(5-fluoro-2-trifluoromethyl-benzamide)-methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H- ΪΤ奎琳-1-Skin acid 酉 499 93 0, such as 6,7-dimethoxy-2-methyl-4-[(3-trifluoromethoxy-benzamide)-methyl ]-3,4-Dihydro-2H-quinoline-1-carboxylic acid ethyl ester 497 94 •H2C—NH ^~^ '{[(4-fluoro-tea-1-carbonyl)-amino]-methyl }-6,7-Dimethoxy-2-methyl-3,4-dihydro-2H-carboline small carboxylic acid acetate 481 95 /°~fF nh X0 F •H2C^N γ^Ν 〇6 ,7-dimethoxy-2-methyl-4-{[(5-trifluoromethoxy-1H-indole-2-carbonyl)-amino]-methyl]-3,4-dihydro -2H-quinoline-1-carboxylic acid ethyl ester 536 96 ΑΌ1.. 〇Cl 4-[(2-chloro-4-methanesulfonyl-benzamide)-methyl]-6,7- Dimethoxy-2-methyl-3,4-dihydro-2Η-4-lead-1-acid B @ 525 97 ΝΗχχ^ 〇4-[(3-fluoro-4-trifluoromethyl- Benzylguanidino)-methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2-indole-quinoline carboxylic acid ethyl ester 499 92199 -173 - 1285641 Example R3 ( · indicates linkage to structure) Compound LCMS ESI+ (ΜΗ+) 98 〇ΧΗ2· \ΧΧ^Η 〇/ 4-[(2,4-dimethoxy-benzamide) )-Methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2-indole-porphyrin small carboxylic acid ethyl ester 473 99 4-[(4-fluoro-benzamide) Ethyl)-methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2-indole-quinoline carboxylic acid ethyl ester 431 100 r&gt;^NHCH2* % 6,7-II Methoxy-2-methyl-4-[(2-trifluoromethyl-benzoguanidino)-methyl]-3,4-dihydro-2-indole-quinoline carboxylic acid acetate 481 101 xci 4-[(2-Chlorotoluene-benzylidinium)-methyl]-6,7-dimethoxy-2-methyl-3,4-diar-2-quinoline-1- Ethyl carboxylate 465 102 6,7-dimethoxy-2-methyl-4-[(4-trifluoromethoxy-benzoguanidino)-methyl]-3,4-dihydro- 2Η-Quinolin-1-carboxylic acid ethyl ester 497 103 FF 4-[(2-Fluoro-4-trifluoromethyl-benzoguanidino)-methyl]-6,7-dimethoxy- Ethyl 2-methyl-3,4-dihydro-2-indole_quinoline carboxylic acid 499 104 F 6,7-dimethoxy-m-methyl benzene [(2,3,6-trifluoro-benzamide) Ethyl)-methyl]-3,4-diar-2-quinolinecarboxylic acid ethyl ester 467 92199 -174 - 1285641 Example R3 (· indicates linkage to structure) Compound LCMS ESI+ (ΜΗ 十) 105 F 4-[ (2-Fluoro-3-trifluoromethyl-benzylidinium)-methyl]-6,7-dimethoxy- 2-methyl-3,4-dioxa-2Η-quinoline carboxylic acid ethyl ester 499 106 Cl 〇Ιί χη2· F 4-[(2-chloro-4,5-difluoro-benzamide) )-Methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2-indole-quinoline-1-carboxylic acid ethyl ester 483 107 rV^NHCH2* 4-[(4- Fluoro-2-trifluoromethyl-benzylideneamino)-methyl]-6,7-dimethoxy-2-methyl-3,4-diaza-2Η-quinoline small carboxylic acid Ester 499 108 〇/^\ JL xh2· 4-[(4-Fluoro-3-trifluoromethyl-benzylidinium)-methyl]-6,7-dimethoxy-2-methyl -3,4-dimur-2Η_quinoline small carboxylic acid ethyl ester 499 109 v 〇4-[(3,5-dimethyl-benzamide)-methyl]-6,7-dimethoxy Benzyl-2-methyl-3,4-dihydro-2-indole-quinoline carboxylic acid ethane vinegar 441 110 F 4-[(3-fluoro-4-methyl-benzhydrylamino)-methyl] Ethyl-6,7-dimethoxy-2-methyl-3,4-dihydro-2-indole-quinoline-1-carboxylate 445 111 h 〇4-[(3-fluoro-benzamide) )-Methyl]-6,7-dimethoxy-2-methyl-3,4-diaza-2Η-^-l-hexa-acid B. 431 92199 -175 - 1285641 Example R3 ( · indicates Link to Structure) Compound LCMS ESI+ (MH+) 112 °\ 6,7-Dimethoxy-4-[(3-methoxy-4-methyl-benzamide) - mercapto]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester 457 113 CI 4-[(3-chloro-2-fluoro-benzamide) -methyl]-6,7-dimethoxy-2-methyl-3,4-dioxa-2H-p-quinone-1-carboxylic acid ethyl ester 465 114 Q^NHCH2* F 6,7-II Methoxy-2-methyl 4-[(2-trifluoromethoxy-benzoguanidino)-methyl]-3,4-dihydro-2H-quinolinecarboxylic acid ethyl ester 497 115 ( '[(3-ethoxybenzamide)-methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid acetamidine 457 116 〇]1 χη2· x〇^i ΝΗ Cl 4-[(3-Chloro-4-methoxy-benzamide)-methyl]-6,7-dimethoxy-2 -Methyl-3,4-dihydro-2H-quinoline small acid vinegar 477 117 \^0 〇Y?Xy^^ 4-[(3-isopropoxy-4-f7oxy_benzol Amidino)-methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-quinone-1-indole acid 酉 501 92199 -176- 1285641 Example R3 ( Indicates that the structure is attached to the compound) LCMS ESI+ (MH+) 118 ffY •H2c—NH ^~f 0—6,7-dimethoxy-4-{[5-methoxy-2-(2,2,2- Trifluoro-ethoxy)-benzylaminoamido]-methyl-2-methyl-3,4-dihydro-2H-quinolinecarboxylic acid B. 541 119 ^pr^NH玛. VF F 4-[(3-Difluorofoxy-benzamide)-methyl]-6,7-dimethoxy-2-methyl-3,4-di Hydrogen-2H-quinoline small carboxylic acid ethyl ester 479 120 'io^. 〇4-[(4-dipropylamine S-sodium-methionine)-methyl]-6,7-dimethyl Ethyl oxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate 576 121 ry^mCH29 V〆4-{〇(2-T-butoxycarbonylamino-B Ethyl benzylamino]-methyl}-6,7-dimethyllacyl-2-methyl-3,4-dihydro-2H-indololin-1-carboxylic acid ethyl ester 556 122 /^ N VN 〇yy^NHcH2&lt;6,7-dimethoxy-2-methyl-4-[(3-pyrazol-1-yl-benzamide)-methyl]-3,4-di Hydrogen-2H-quinoline small carboxylic acid ethyl ester 479 123 4-[(4-methanesulfonyl-benzhydrylamino)-methyl]-6,7-dimethoxy-2-methyl-3 , 4-dihydro-2H-quinoline small carboxylic acid ethyl ester 491 92199 -177- 1285641 Example R3 (· indicates linkage to structure) Compound LCMS ESI+ (MH+) 124 0 4-{[3-(3,5-II Methyl-thrazole small group)-benzylaminoamido]-methyl}-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-4 phenyl small carboxylic acid ethyl ester 507 125 4-{[(3fFluoro-biphenylyl)-amino]-methyl}-6,7-dimethoxy-2-methyl-3,4- Hydrogen-2H-quinoline small carboxylic acid ethyl ester 507 126 ry^NHCH2· 4-{[(2'-fluoro-biphenyl-3-yl)-amino]-methyl}-6,7-di Ethyl methoxy-2-methyl-3,4-diar argon-2H-quinoline-1-carboxylate 507 127 ry^NHcH2- X 4-{[(3'-fluoro-biphenyl-3- Ethyl)-amino]-methyl}-6;7-dimethoxy-2-methyl_3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester 507 128 ^y^NHXH2 · F 4-{[(4^Fluoro-biphenyl-3-indolyl)-amino]-methyl}-6,7-dimethoxy-2-methyl-3,4-dihydro- Ethyl 2H-porphyrin-1-carboxylate 507 129 d1,. 'Cl 4-[(2,6-Dichloro-benzylidinium)-methyl]-6,7-dimethoxy-2 -Methyl-3,4-dimur-2Η-ρ奎淋-1-复fe 酉 481 92199 -178 - 1285641 Example R3 ( · indicates linkage to structure) Compound LCMS ESI+ (MH+) 130 〇/^\ JL Χη···6,6-dimethoxy-2-methyl-4-[(3-trifluoromethyl-benzoguanidino)-methyl]-3,4-dihydro-2H-quinoline Small carboxylic acid ethyl vinegar 481 131 y〇〇〇 / 4-[(3-f alkanesulfonyl-benzamide)-fluorenyl]-6,7-dimethoxy-2-methyl-3 , 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester 491 132 〇xh2· 6,7-dimethoxy-4-[(3-methoxy-benzamide)- 4-methyl-3,4-dihydro-2H-quinolinecarboxylic acid ethyl acetoacetate 443 133 Cl 4-[(3,4-dioxa-benzamide)-methyl]-6 ,7-Dimethoxy-2-methyl-3,4-dihydro-2H-porphyrin-1-carboxylic acid ethyl ester 481 134 r^\ Jl XH2- Cx^ Cl 4-[(2-chloro group -6-gas-benzamide amino)-methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester 465 135 Ft^&quot;CH2' F 4-[(2,5-Difluoro-benzamide)-methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro- 2H-quinoline small carboxylic acid 449 449 136 F 4-[(2,3-difluoro-benzylidinium)-methyl]-6,7-dimethoxy-2-methyl-3, 4-Dihydro-2H-quinoline-1-carboxylic acid ethyl acetate 449 92199 -179 - 1285641 Example R3 (· indicates linkage to structure) Compound LCMS ESI+ (MH+) 137 • H2c-Ny 〇VF 4-[(2, 4-Difluoro-benzhydrylamino)-methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-carboline small carboxylic acid il 449 138 • H,V 〇ά 4-[(3&gt;Difluoro-benzamide)-methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline Small carboxylic acid 449 449 139 F 〇V 4-[(2,5-bis-trifluoromethyl-benzamide)-methyl]-6,7-di Ethyl oxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate 449 140 FF 6,7-dimethoxy-2-methyl-4-[(2,4 , 5-trifluoro-benzylaminoamido)-methyl]-3,4-dihydro-2H-quinoline small carboxylic acid ethyl ester 467 141 labor. H2·4-[(2-Fluoro-6-trifluoromethyl-benzoguanidino)-methyl]-6,7-dimethoxy-2-methyl-3-indole dihydro-2H-port奎 4 -1-Fuic acid acetate 499 142 F 6,7-dimethyl oxy-2-f base hopper [(2,3,4-difluoro-benzhydryl)-methyl]-3 , 4-dihydro-2H-quinoline small carboxylic acid ethyl ester 467 92199 -180- 1285641 Example R3 (· indicates linkage to structure) Compound LCMS ESI+ (ΜΗ+) 143 〇〇^. 6,7-dimethoxy -2-Methyl winter {[(shurium trifluoromethyl-biphenyl-2-carbonyl)-amino]-methyl b 3,4-dihydro-2 fluorene-.奎 -1--1-Ethyl acetate 557 144 〇11 χη2· F 4-[(3-Fluoro-4-methoxy-benzamide)-methyl]-6,7-dimethoxy Ethyl 2-methyl-3,4-dihydro-2-indole-quinoline carboxylic acid 461 145 〇r^\ J1 ΧΗ2· Cl 4-[(3-chloro-4-fluoro-benzamide) )-Methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2Η-quinolinecarboxylic acid ethyl ester 465 146 jfS 〇4-[(3-fluoro--5 -trifluoromethyl-benzhydrylamino)-methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2Η-hydroxyquinone-1-carboxylic acid ethyl ester 499 147 4-[(4-Difluoromethoxy-benzimidamide)-methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2Η-quinoline Ethyl carboxylic acid 479 148 〇丄ΧΗ2· ^ΝΗ CI 4-[(3-chloro-benzamide)-methyl]-6,7-dimethoxy-2-methyl-3,4 -Dihydro-2Η-quinoline small carboxylic acid ethyl ester 447

92199 -181 - 1285641 實例 R3 ( ·表示連結至結 構） 化合物 LCMS ESI+ (MH+) 149 °\ 6,7-二甲氧基-2-甲基-4-[(3,4,5-三甲氧基-苯甲醯胺 基）-甲基]-3,4-二氫-2H-4 啉小羧酸乙酯 503 150 / 〇 F^y^NHcH2* 4-[(4-氟基！甲氧基-苯甲 醯胺基）-甲基]-6,7-二甲氧 基-2-甲基-3,4-二氫-2H-喹 啉小羧酸乙酯 461 151 Cl 4-[(5-氯基-2-甲基-苯甲醯 胺基）-甲基]-6,7-二甲氧基-2-甲基-3,4-二氫-2H-喹啉-1-羧酸乙酯 461 152 〇/ ο J^y^NHCH2* °\ 4-[(3,5-二甲氧基-4-甲基-苯 甲醯胺基）-甲基]-6,二甲 氧基-2-甲基-3,4-二氫-2H-喹啉小羧酸乙酯 487 153 4-[(2-氯基-3,4-二甲氧基-苯 甲醯胺基:l·甲基]-6,7-二甲 氧基-2-甲基-3Λ·二氫-2H-喹啉小羧酸乙醋 507 154 4-[(3-壞戊氧基-4-甲氧基-苯甲醯胺基）-甲基]-6,7-二 甲氧基-2- T基-3,4-二氯_ 2H—奎淋-1-複酸乙酉旨 527 92199 -182 - 1285641 實例 R3 ( ·表示連結至結 構） 化合物 LCMS ESI+ (MH+) 155 &gt;° 6,7-二甲氧基-4-[(4-甲氧基-3-丙氧基-苯甲醯胺基）-甲 基]-2-甲基-3,4-二氫-2H-喹 淋小叛酸乙酯 501 156 CI 4-[(2-氯基-4,5-二甲氧基-苯 甲醯胺基）-甲基]-6,7-二甲 氧基-2-甲基-3,4-二氫-2H-喹啉小羧酸乙酯 507 157 6,7-二T氧基斗[(4-甲氧基-3-甲基-苯甲醯胺基）-甲基 ]-2-甲基-3,4-二氫-2H-喹啉-1-羧酸乙酯 457 158 H /-° •H2C—NH ^~’J ‘{[(苯并[1，3]二氧伍圜烯-5-羰基）-胺基]-甲基卜6,7-二 甲氧基-2-甲基-3,4-二氫-2Η-ρ奎淋-1-竣故乙酉旨 457 159 〇 4_{[φ·(1-第三-丁氧羰基-四 氫吡咯-3-基氧基）-苯甲醯 胺基l·甲基}-6,7-二甲氧基-2-甲基-3,4-二氫-2H-喹啉-1-羧酸乙基 498 160 ^^^^YN、ch2· 6,7-二甲氧基-2-甲基-4-{[3-(2-嗣基-四鼠p比-1-基l )-冬 甲醯胺基]-甲基卜3,4-二氫-2Η^奎淋-1-幾酸乙酯 496 161 •h2c 0 1 H、N^y_A 4-{[3-(3,5-二甲基-说唑小基 甲基）-苯甲醯胺基]-甲基Ιό，?-二 甲氧基-2-甲基-3,4-二 氫-2H-峻淋-1-竣酸乙酉旨 521 92199 -183 - 1285641 實例 R3 ( ·表示連結至結 構） 化合物 LCMS ESI+ (MH+) 162 vo^o \ 4-{〇(1-第三-丁氧藏基-六 氫叶1：淀-4-基）-苯甲贐胺基 ]-甲基}-6,7-二甲氧基-2-甲 基-3,4-二氫-2Η-4 啉-1-羧 酸乙醋 496 163 4-{[(聯苯基-3-談基）-胺基]-甲基}-6,7-二甲氧基-2-甲 基-3,4-二氫-2Η-喹啉小羧 酸乙酯 489 164 4-{[(3f，4f-二氯-聯苯基冰談 基）·胺基]-甲基卜6,7-二甲 氧基-2-甲基-3,4-二氮-2H-喹啉小羧酸乙酯 557 165 •h2c p HN—/ 6,7-二甲乳基-2-甲基-4-{[3-(5-甲基-[1，2,4]噚二唑各基）· 苯甲醯胺基]-甲基卜3,4-二 氫-2H-喹啉小羧酸乙酯 495 166 •h2c p .hW 4-{[3-(5-乙基-[1，2,4]吟二唑-3-基）-苯甲醯胺基]-甲基}-6,7-二甲氧基-2-甲基-3,4-二 鼠-2H·^奎淋-1-致酸乙画旨 509 167 (Γ^ N)&gt;==\ HN—CH〇· N切。 4-{[(冬并違σ坐-6-談基）-胺 基]-甲基}-6,7-二1f7氧基-2-甲基-3,4-二氫-2H-喹啉小 羧酸乙酯 470 168 Cl Vri~ •h2c-nh ^ 4-[(3-氣基-4-甲基-苯甲醯 胺基）-甲基]-6,7-二甲氧基-2-甲基-3,4-二氫-2H-喹啉小 羧酸乙酯 461 92199 -184 - 1285641 實例 R3 ( ·表示連結至結 構） 化合物 LCMS ESI+ (ΜΗ+) 169 Λ •h2c—nh n~ 4-[(2-氯-苯甲醯胺基）-甲基 ]-6,7-二甲氧基-2-f 基-3,4-一氮-2Η-Ρ奎57林-1-幾酸乙酉旨 447 製備34 3-乙基·6,7-二甲基-3,4-二氫-lH-p奎嗓淋-2-酮 使5,6-二甲胺基苯胺（22.45克，165毫莫耳，1當量）、2- 丁酿1 酸（16.83克，165毫莫耳’ 1當量）及乙醇（75毫升）之混合物， 在 Milestone 微波（Milestone 實驗室，Sorisole，Italy)中，於 180°C 下照 射5分鐘。於冷卻時過濾固體產物，並以乙醇洗滌。濃縮濾 液，及進一步結晶化，提供所要之喹喏啉-2-酮（18.45克，55.2 %)。 1H-NMR (DMS〇-d6): (H.17 (t，J=7.05Hz，3H)，2.25 (s，3H)，2.26 (s，3H)， 2·74 (q，J=7.05Hz，2H)，7.00 (s，1H)，7.48 (s，1H)，12.15 (brs，1H)· ESI-MS ： 203 (MH+). 製備35 3-氯基-2-乙基-6,7-二甲基-1，2-二氫^奎喏啉 使3-乙基_6,7-二甲基-3,4-二氫-1H-喳喏啉丨酮（18Λ5克，91·2毫 莫耳）溶於180毫升氯化磷醯中，並將混合物在裝有氫氧化鉀 與Dnente®之乾燥管下，於u〇t：下加熱過夜。於冷卻後，小 心悉館出氧氯化磷（V)，並小心地以冰’接著以飽和碳酸氫 納使殘留物淬滅。以二氣曱烷將含水懸浮液萃取數次。將 合併之’機物質以鹽水洗滌1次，以無水硫酸鈉脫水乾燥， 92199 • 185 - 1285641 過濾’及蒸發，而得標題化合物（19·3克81%)，其係繼續進 行而無需進一步純化。 1 H-NMR (DMS0-d6) ： 5 1.30 (t, J=7.47Hz? 3H), 3.04 (q5 J=7.47Hz? 2H)? 7.74，(s，1H)，7.83 (s，1H), 製備36 2-乙基-6,7-二甲基-i，2,3,4-四氫-喹喏啉 使含有氣基-2-乙基-6,7-二甲基-1，2-二氮-峻?若淋之殘留物〉谷 於200毫升醋酸中，並添加18 2克醋酸鈉（222毫莫耳，3當量） 。以氮沖洗後，於容器中添加鈀/碳（10%，7.86克，0.1當量 Pd，7.39毫莫耳）。使反應物在45 psi下接受氫化5小時，此時 氫吸收停止。使反應物經過Celite®過濾，並蒸發。使殘留物 與庚:fe共沸3次，以移除較多醋酸。然後，使殘留物於醋酸 乙醋與飽和碳酸氫鈉水溶液之間作分液處理。將有機層以 飽和瑗酸氫鈉水溶液洗滌3次，以鹽水1次，以無水硫酸鈉 脫水乾燥’過濾，及蒸發。急驟式層析，以2〇-5〇%醋酸乙酯 /己院梯度液溶離，提供所要之喳喏啉（1〇.56克，63%產率） ’為蓬怒略帶粉紅色固體。 1H-NMR (DMS〇-d6): 6 0·89 (t，J=7.46Hz，3H)，1.35 (m，2H)，1.89，(s，3H)， 1.94 (s，3H)，2.75 (m，1H)，2.96 (m，1H)，3.14 (m，1H)，6.12,（s，1H)，6.17 (s，1H)· 製備37 3-乙基-6,7'二甲基-3,4-二氫-2H-p奎每淋-1-羧酸第三-丁 g旨 使2-乙基-6,7-二甲基-1，2,3,4-四氫-喹喏啉（ΐ〇·56克，55.6毫莫耳 ’ 1當量）溶於無水二氣曱烷中，並在乙二醇/乾冰浴中冷 卻至-30 C。逐滴添加二後酸二-第三·丁酯（丨2.丨3克，55.6毫莫 92199 -186- 1285641 耳’ 1當量）在二氯〒燒（50毫升）中之溶液，並使反應物慢慢 溫熱至室溫過夜。使反應物蒸發至乾涸，並於醋酸乙酯與 0.1 M HC1之間再作分液處理。將有機層以〇.丨μ HC1洗滌3次， 以飽和碳酸氫鈉1次，以鹽水1次，以無水硫酸鈉脫水乾燥 ’過遽’及蒸發。矽膠層析，以醋酸乙酯/己烷溶離， 提供所要之化合物（10.35克，64%)。 1 H-NMR (DMS〇-d6): 5 0.90 (t，J=7.47Hz，3Η)，1·34 (m，2Η)，1.41 (s，9Η)， 2.02 (s? 6H), 3.09 (τη, 1H), 3.24 (m5 1H), 3.58 (m5 1H), 5.74 (s, 1H), 6.34 (s? 1H), 7.05 (brs5 1H). ESI-MS : 290 (M+)，235 (MH+ -異丁締）. 製備38 2-乙基-6,7-二甲基-2,3-二氫-P奎喏啉-丨，4_二羧酸4_第三叮酯^乙酯 使3-乙基-6,7-一甲基-3,4-二氫-2Η-峻喏淋-1-叛酸第三-丁酯 (10.35克’ 35.7耄莫耳，1當量）與4-二甲胺基吡啶（436毫克，357 笔莫耳，0.1當量）在無水吡啶（25〇毫升）中之溶液冷卻至〇。〇 ，並逐滴添加氯甲酸乙酯（17.〇毫升，178·3毫莫耳，5當量） 。使反應物溫熱至室溫過夜。於真空下蒸發溶劑，並與庚 烷共沸3次。於真空下乾燥後，使殘留物在醋酸乙酯與 0.1 M HC1之間作分液處理。以〇1 μ HC1萃取有機層，直到萃 液呈酸性為止，然後以飽和碳酸氫鈉水溶液洗滌丨次，以水 1次，以鹽水1次。使有機層以無水硫酸鈉脫水乾燥，過濾 ’及蒸發，提供所要之化合物（100% )。 1 H-NMR (DMS〇-d6) : 5 0.77 (t，J=7.05Hz，3Η)，1.20 (t，J=7.〇5Hz，3Η)， 1.25 (m，2H)，1.44 (s，9H)，2.13 (s，6H)，3.55 (dd，&gt;13.35, 4.98Hz，1H), 3·78 92199 -187 - 1285641 (dd，J=13.1，3.32Hz，1Η)，4·12 (m，2H)，4.39 (m，1H)，7.41 (s，1H)，7.44(s，1H)· ESI-MS : 307 (MH+ -異丁烯），263 (MH+ - boc). 製備39 2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏啉小羧酸乙酯 於2-乙基-6,7-二甲基，2,3-二氫^奎喏啉-1，4-二羧酸4-第三-丁酯 1-乙酯（12.93克）中，添加三氟醋酸（2〇〇毫升）’將混合物攪掉 直到溶液已形成為止，然後在真空下蒸發至乾涸。使殘留 物與庚烷共沸3次，並於真空下乾燥。接著，使殘留油於二 氯甲烷與飽和竣酸氫鈉水溶液之間作分液處理。以二氯甲 fe將水層萃取3次。合併之二氯甲烷萃液以無水硫酸鈉脫水 乾燥’過濾，及蒸發，獲得所要之P奎喏淋（1QQ%)。 1H-NMR (DMS0-d6)： 5 0.77 (t5 J=7.47Hz, 3H), 1.19 (t? J=7.05Hz, 3H), 1.24 (m，2H)，2.02 (s，6H)，3.14 (m，2H)，4.08 (m，2H)，4·24 (m，1H)，5.72 (m，1H)， 7.11 (brs，1H)· ESI-MS : 263 (MH+). 使此外消旋4喏淋接受預備之對掌性分離，使用 ClnmlcdOD 10x25公分對掌性預備管柱。溶離劑為庚烷中之5 /6乙醇’其流率為275毫升/分鐘，於3〇〇毫微米下觀察。將 試樣裝填於管柱上，使用2 :丨甲醇/二氯甲烷。孓對掌異構 物之滯留時間為16分鐘，R•對掌異構物為22分鐘。使乃克 試樣接受此等條件，而造成丨〇克[對掌異構物，99.4%ee， 與11克S-對掌異構物，95.1% ee。 實例 170、171、172 及 173 92199 -188- 128564192199 -181 - 1285641 Example R3 (· indicates linkage to structure) Compound LCMS ESI+ (MH+) 149 °\ 6,7-Dimethoxy-2-methyl-4-[(3,4,5-trimethoxy) -Benzylguanidino)-methyl]-3,4-dihydro-2H-4 porphyry carboxylic acid ethyl ester 503 150 / 〇F^y^NHcH2* 4-[(4-fluoro! methoxy -benzimidamide)-methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinolinecarboxylic acid ethyl ester 461 151 Cl 4-[(5 -Chloro-2-methyl-benzhydrylamino)-methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid Ethyl ester 461 152 〇 / ο J^y^NHCH2* °\ 4-[(3,5-dimethoxy-4-methyl-benzamide)-methyl]-6,dimethoxy Ethyl 2-methyl-3,4-dihydro-2H-quinolinecarboxylate 487 153 4-[(2-Chloro-3,4-dimethoxy-benzamide:l· Methyl]-6,7-dimethoxy-2-methyl-3-indole-dihydro-2H-quinoline carboxylic acid acetate 507 154 4-[(3-d-pentyloxy-4-methoxy -benzimidamide)-methyl]-6,7-dimethoxy-2-T-yl-3,4-dichloro-2H-quinone-1-reacid acetate 527 92199 -182 - 1285641 Example R3 (· indicates linkage to structure) Compound LCMS ESI+ (MH+) 155 &gt;° 6,7 -dimethoxy-4-[(4-methoxy-3-propoxy-benzylamino)-methyl]-2-methyl-3,4-dihydro-2H-quinoline Tetraic acid ethyl ester 501 156 CI 4-[(2-Chloro-4,5-dimethoxy-benzylidinium)-methyl]-6,7-dimethoxy-2-methyl- Ethyl 3,4-dihydro-2H-quinolinecarboxylate 507 157 6,7-di-T-oxy chloro[[4-methoxy-3-methyl-benzylamino)-methyl] Ethyl 2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate 457 158 H /-° •H2C—NH ^~'J '{[(benzo[1,3] Oxyzolidine-5-carbonyl)-amino]-methyl b 6,7-dimethoxy-2-methyl-3,4-dihydro-2Η-ρ奎淋-1-竣457 159 〇4_{[φ·(1-Third-butoxycarbonyl-tetrahydropyrrole-3-yloxy)-benzylideneamine l·methyl}-6,7-dimethoxy-2 -Methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl 498 160 ^^^^YN, ch2· 6,7-dimethoxy-2-methyl-4-{[ 3-(2-mercapto-tetra-m-p-pyr-1-1-yl l)-glymeaminoglycol]-methyl b 3,4-dihydro-2-indole quinidine-1-carboxylic acid ethyl ester 496 161 • H2c 0 1 H, N^y_A 4-{[3-(3,5-dimethyl-s-azolidinemethyl)-benzimidamide]-methylhydrazine, ?-dimethoxy-2 -methyl-3,4-dihydro-2H-jun -1- 竣 酉 521 521 92199 -183 - 1285641 Example R3 ( · indicates linkage to structure) Compound LCMS ESI+ (MH+) 162 vo^o \ 4-{〇(1-Third-butoxy-s-hexahydro Leaf 1: Depot-4-yl)-benzylaminoamido]-methyl}-6,7-dimethoxy-2-methyl-3,4-dihydro-2Η-4-phenyl-1-carboxylate Acid vinegar 496 163 4-{[(biphenyl-3-indolyl)-amino]-methyl}-6,7-dimethoxy-2-methyl-3,4-dihydro-2Η - quinoline small carboxylic acid ethyl ester 489 164 4-{[(3f,4f-dichloro-biphenylyl yl)-amino]-methyl b 6,7-dimethoxy-2-methyl -3,4-Diazin-2H-quinolinecarboxylic acid ethyl ester 557 165 •h2c p HN—/ 6,7-dimethyllacyl-2-methyl-4-{[3-(5-methyl) -[1,2,4]oxadiazoleyl)·benzimidamide]-methyldiethyl 3,4-dihydro-2H-quinolinecarboxylic acid ethyl ester 495 166 •h2c p .hW 4- {[3-(5-Ethyl-[1,2,4]oxadiazol-3-yl)-benzylideneamino]-methyl}-6,7-dimethoxy-2-methyl -3,4-two mice-2H·^ 奎淋-1-致酸乙画 509 167 (Γ^ N)&gt;==\ HN—CH〇· N cut. 4-{[(冬和违σ坐-6-谈基)-Amino]-methyl}-6,7-di 1f7oxy-2-methyl-3,4-dihydro-2H-quinoline Ethyl carboxylic acid 470 168 Cl Vri~ • h2c-nh ^ 4-[(3-carbyl-4-methyl-benzamide)-methyl]-6,7-dimethoxy-2 -ethyl-3,4-dihydro-2H-quinoline small carboxylic acid ethyl ester 461 92199 -184 - 1285641 Example R3 (· indicates linkage to structure) Compound LCMS ESI+ (ΜΗ+) 169 Λ •h2c—nh n~ 4-[(2-Chloro-benzylamino)-methyl]-6,7-dimethoxy-2-fyl-3,4-nitroso-2Η-Ρ奎57林-1-乙乙酉 447 Preparation of 34 3-ethyl·6,7-dimethyl-3,4-dihydro-lH-p-quinone-one-2-one 5,6-dimethylaminoaniline (22.45 g, a mixture of 165 millimolar, 1 equivalent), 2-butane 1 acid (16.83 grams, 165 millimoles '1 equivalent) and ethanol (75 ml) in Milestone Microwave (Milestone Laboratories, Sorisole, Italy), Irradiation at 180 ° C for 5 minutes. The solid product was filtered while cooling and washed with ethanol. The filtrate was concentrated and further crystallized to afford the desired quinoxaline-2-one (18.45 g, 55.2 %). 1H-NMR (DMS〇-d6): (H.17 (t, J=7.05 Hz, 3H), 2.25 (s, 3H), 2.26 (s, 3H), 2·74 (q, J=7.05 Hz, 2H), 7.00 (s, 1H), 7.48 (s, 1H), 12.15 (brs, 1H). ESI-MS: 203 (MH+). Preparation 35 3-chloro-2-ethyl-6,7- Methyl-1,2-dihydro^quinoxaline makes 3-ethyl-6,7-dimethyl-3,4-dihydro-1H-porphyrinone (18Λ5 g, 91·2 mmol) The ear is dissolved in 180 ml of chlorinated phosphonium chloride, and the mixture is heated under a drying tube containing potassium hydroxide and Dnente® overnight at u〇t: After cooling, carefully observe the phosphorus oxychloride (V), and carefully quench the residue with ice' followed by saturated sodium bicarbonate. The aqueous suspension was extracted several times with dioxane. The combined 'mechanical material was washed once with brine to anhydrous sulfuric acid. Sodium dehydration, EtOAc (EtOAc: EtOAc: EtOAc: EtOAc (EtOAc) , J=7.47Hz? 3H), 3.04 (q5 J=7.47Hz? 2H)? 7.74, (s,1H), 7.83 (s,1H), Preparation 36 2-ethyl-6,7-dimethyl- i,2,3,4-tetrahydro-quin The porphyrin contains a residue containing a gas-based 2-ethyl-6,7-dimethyl-1,2-diaza- ruthenium salt in 200 ml of acetic acid, and 18 2 g of sodium acetate (222) is added. Millol, 3 equivalents. After rinsing with nitrogen, palladium on carbon (10%, 7.86 g, 0.1 equivalents Pd, 7.39 mmol) was added to the vessel. The reaction was hydrogenated at 45 psi for 5 hours. Hydrogen absorption ceased. The reaction was filtered through Celite® and evaporated. The residue was azeotroped three times with hept:fe to remove more acetic acid. The residue was then taken in ethyl acetate and saturated aqueous sodium hydrogen carbonate. The organic layer was washed three times with a saturated aqueous solution of sodium hydrogencarbonate, brine, dried over anhydrous sodium sulfate, filtered, and evaporated. Ethyl acetate / hexanyl gradient solution was dissolved to provide the desired porphyrin (1.56 g, 63% yield) as a phoenix pink solid. 1H-NMR (DMS 〇-d6): 6 0 · 89 (t, J = 7.46 Hz, 3H), 1.35 (m, 2H), 1.89, (s, 3H), 1.94 (s, 3H), 2.75 (m, 1H), 2.96 (m, 1H), 3.14 (m,1H), 6.12, (s, 1H), 6.17 (s, 1H)· Preparation 37 3-ethyl-6,7'-dimethyl-3,4-dihydro-2H-p-quine-l-carboxylic acid tert-butyr to 2-ethyl-6,7-di Methyl-1,2,3,4-tetrahydro-quinoxaline (ΐ〇·56 g, 55.6 mmoles 1 equivalent) is dissolved in anhydrous dioxane and in an ethylene glycol/dry ice bath Cool to -30 C. A solution of di-tert-butyl succinate (丨2.丨3 g, 55.6 mM 92199-186-1285641 ears 1 equivalent) in dichlorohydrazine (50 ml) was added dropwise and the reaction was allowed to proceed. The mixture was slowly warmed to room temperature overnight. The reaction was evaporated to dryness and partitioned between ethyl acetate and 0.1 M EtOAc. The organic layer was washed three times with EtOAc EtOAc (EtOAc) EtOAc (EtOAc) The title compound (10.35 g, 64%) was obtained eluted elut elut elut elut 1 H-NMR (DMS〇-d6): 5 0.90 (t, J = 7.47 Hz, 3 Η), 1·34 (m, 2 Η), 1.41 (s, 9 Η), 2.02 (s? 6H), 3.09 (τη , 1H), 3.24 (m5 1H), 3.58 (m5 1H), 5.74 (s, 1H), 6.34 (s? 1H), 7.05 (brs5 1H). ESI-MS : 290 (M+), 235 (MH+ - different Preparation of 38 2-ethyl-6,7-dimethyl-2,3-dihydro-P quinoxaline-indole, 4-dicarboxylic acid 4_tridecyl ester ethyl ester 3- Ethyl-6,7-monomethyl-3,4-dihydro-2-indole-Jun-Lin-1-Resin-T-butyl ester (10.35 g '35.7 耄mol, 1 equivalent) and 4-dimethyl A solution of the aminopyridine (436 mg, 357 moles, 0.1 equivalent) in anhydrous pyridine (25 mL) was cooled to hydrazine. 〇 and add ethyl chloroformate (17. liters, 178·3 mmol, 5 equivalents) dropwise. The reaction was allowed to warm to room temperature overnight. The solvent was evaporated under vacuum and azeotroped three times with heptane. After drying under vacuum, the residue was partitioned between ethyl acetate and 0.1 M EtOAc. The organic layer was extracted with 〇1 μl of HCl until the extract was acidic, and then washed with a saturated aqueous solution of sodium bicarbonate, once with water, once with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to give the desired compound (100%). 1 H-NMR (DMS 〇-d6) : 5 0.77 (t, J = 7.05 Hz, 3 Η), 1.20 (t, J = 7. 〇 5 Hz, 3 Η), 1.25 (m, 2H), 1.44 (s, 9H) ), 2.13 (s, 6H), 3.55 (dd, &gt; 13.35, 4.98 Hz, 1H), 3·78 92199 -187 - 1285641 (dd, J = 13.1, 3.32 Hz, 1 Η), 4·12 (m, 2H), 4.39 (m, 1H), 7.41 (s, 1H), 7.44 (s, 1H). ESI-MS: 307 (MH+-isobutene), 263 (MH+ - boc). Preparation 39 2-ethyl-6 , 7-Dimethyl-3,4-dihydro-2H-quinoxaline small carboxylic acid ethyl ester in 2-ethyl-6,7-dimethyl, 2,3-dihydro quinoxaline-1 4-Dicarboxylic acid 4-tris-butyl ester 1-ethyl ester (12.93 g), trifluoroacetic acid (2 mL) was added. The mixture was stirred until the solution was formed, and then evaporated under vacuum. Dry up. The residue was azeotroped 3 times with heptane and dried under vacuum. Next, the residual oil was subjected to liquid separation treatment between methylene chloride and a saturated aqueous solution of sodium hydrogencarbonate. The aqueous layer was extracted 3 times with methylene chloride. The combined dichloromethane extracts were dried over anhydrous sodium sulfate, dried and filtered, and evaporated to give the desired crystals (1QQ%). 1H-NMR (DMS0-d6): 5 0.77 (t5 J=7.47Hz, 3H), 1.19 (t? J=7.05Hz, 3H), 1.24 (m, 2H), 2.02 (s, 6H), 3.14 (m , 2H), 4.08 (m, 2H), 4·24 (m, 1H), 5.72 (m, 1H), 7.11 (brs, 1H)· ESI-MS : 263 (MH+). Accept the preparatory pair of palms, use ClnmlcdOD 10x25 cm to prepare the column for palmarity. The leaching agent was 5/6 ethanol in heptane. The flow rate was 275 ml/min and was observed at 3 Torr. The sample was loaded onto a column using 2: methanol/dichloromethane. The residence time of the palmosome is 16 minutes, and the R• palmomer is 22 minutes. The gram sample was subjected to these conditions, resulting in a gram [yield of palmar isomer, 99.4% ee, and 11 g of S-ply isomer, 95.1% ee. Examples 170, 171, 172 and 173 92199 - 188 - 1285641

(R，R，R，S，S，R及S，S)-4-[(3,5j _三氟甲基-苯基）_甲氧羰基_甲基峰 乙基-6,7-二甲基-3,4-二氫-2H&gt;奎喏琳小瘦酸乙酯 方法A :將（R，S)-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏啉-1-羧酸 乙酯（652毫克，1當量，2·5毫莫耳）、溴基冰(3,5-雙-三氟甲基 -苯基）-酷酸甲酯（1.0克，1.1當量，2.74毫莫耳）及2,6-二甲基 吡啶（0.87毫升，3當量，7.47毫莫耳）在二甲基甲醯胺（3毫升） 中之混合物’於140 C下’在Emrys Optimizer (Personal化學 ，Uppsala，Sweden)中，藉由微波照射加熱20分鐘。使混合物於 一氯甲燒與水之間作分液處理，並分離液相。以二氯甲燒 將水相萃取3次，並將合併之有機萃液以水洗滌2次，以鹽 水1次，以無水硫酸鈉脫水乾燥，過濾，及蒸發。於♦膠上 層析’使用己烷中之10%醋酸乙酯作為溶離劑，提供標題化 合物，為兩種非對映異構物之混合物（9〇〇毫克，的％ )。 方法B :將（R，S)-2-乙基-6,7-二甲基-3,4-二氫-2H-喳喏啉-1·羧酸 乙酯（652毫克，1當量，2.5毫莫耳）、溴基-4-(3,5-雙-三氟甲基 -苯基）-醋酸甲酯（1.0克，U當量，2/74毫莫耳）及2,6-二甲基 吡啶（0.87毫升，3當量，7.47毫莫耳）在二甲基甲醯胺（3毫升） 中之混合物，於室溫下攪拌24小時。使混合物於二氯甲境 與水之間作分液處理，並分離液相。以二氯甲烷將水相萃 取3次’並將合併之有機萃液以水洗滌2次，以鹽水1次，以 92199 -189- 1285641 無水硫酸鈉脫水乾燥，過〉慮，及蒸發。於碎膠上層析，使 用己烷中之10%醋酸乙酯作為溶離劑，提供標題化合物，為 兩種非對映異構物之混合物（900毫克，66% )。 非對映異構物 1 : 1 H-NMR (CDC13) : (5 0.71 (t，J=7.57Hz，3H)，1.30 (t，J=7.05Hz，3H)，1.46 (m，2H)，2.18 (s，3H)，2·20 (s，3H)，2.77 (dd，J=9.54, 2.0 8Hz，1H)，3.37 (dd，J二 11.38, 3.32Hz，1H) 3.82 (s，3H)，4,20 (m，2H)，4.26 (m， 1H)，5.82 (s，1H)，6·58 (s，1H)，7.49 (brs，1H) 7.75 (s，2H)，7.88 (s，1H).(R, R, R, S, S, R and S, S)-4-[(3,5j _trifluoromethyl-phenyl)-methoxycarbonyl_methylphenethyl-6,7-di Methyl-3,4-dihydro-2H&gt; quetiapine small ethyl ester ethyl ester Method A: (R,S)-2-ethyl-6,7-dimethyl-3,4-dihydro- Ethyl 2H-quinoxaline-1-carboxylate (652 mg, 1 eq., 2.5 mM), bromo ice (3,5-bis-trifluoromethyl-phenyl)-succinic acid methyl ester (1.0 g, 1.1 eq., 2.74 mmol) and a mixture of 2,6-lutidine (0.87 ml, 3 eq., 7.47 mmol) in dimethylformamide (3 mL). C under 'In Emrys Optimizer (Personal Chemistry, Uppsala, Sweden), heated by microwave irradiation for 20 minutes. The mixture was subjected to a liquid separation treatment between monochloromethane and water, and the liquid phase was separated. The aqueous phase was extracted three times with methylene chloride, and the combined organic extracts were washed twice with water, brine, dried over anhydrous sodium sulfate, filtered, and evaporated. The title compound was obtained as a mixture of two diastereomers (9 mg, %). Method B: Ethyl (R,S)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-carboline-1·carboxylate (652 mg, 1 eq, 2.5 Millol), bromo-4-(3,5-bis-trifluoromethyl-phenyl)-acetic acid methyl ester (1.0 g, U equivalent, 2/74 mmol) and 2,6-dimethyl A mixture of pyridine (0.87 ml, 3 eq., 7.47 mmol) in dimethylformamide (3 mL) was stirred at room temperature for 24 hours. The mixture was partitioned between methylene chloride and water, and the liquid phase was separated. The aqueous phase was extracted 3 times with methylene chloride. The combined organic extracts were washed twice with water, brine, and dried over anhydrous sodium sulfate (s). Chromatography on EtOAc (EtOAc: EtOAc) Diastereomer 1 : 1 H-NMR (CDC13) : (5 0.71 (t, J = 7.57 Hz, 3H), 1.30 (t, J = 7.05 Hz, 3H), 1.46 (m, 2H), 2.18 (s, 3H), 2·20 (s, 3H), 2.77 (dd, J = 9.54, 2.0 8 Hz, 1H), 3.37 (dd, J 2, 11.38, 3.32 Hz, 1H) 3.82 (s, 3H), 4 ,20 (m,2H), 4.26 (m, 1H), 5.82 (s,1H),6·58 (s,1H),7.49 (brs,1H) 7.75 (s,2H),7.88 (s,1H) .

LCMS (ESI+) ： 547 (MH+) 非對映異構物 2 : 1H-NMR (CDC13) : 5 0·87 (t，JN7.47Hz，3H)，1.28 (t，J=6.64Hz，3H)，1.43 (m，2H)，2.18 (s，3H)，3.11 (dd，J=11.35, 4.98Hz，1H)， 3.22 (dd，J=10.79, 1·66Ηζ，1H)，3.83 (s，3H)，4·19 (m，2H)，4.44 (m，1H)，5.66 (s，1H)，6.41 (s，1H)，7·28 (brs，1H)，7.73 (s，2H)，7.86 (s，1H)· LCMS (ESI+) ： 547 (MH+). 此非對峡異構物之外消旋混合物可進一步於Pirkle共價 (S，S) Whelk-ΟΙ 管柱（Regis 技術公司，Morton Grove，IL)(5 X 25 公分） 上，藉對掌性HPLC解析，在100毫升/分鐘下，以5%乙醇/ · 庚统溶離，提供三份溶離份： 異構物1，滯留時間=18分鐘 異構物2與3，滯留時間=25分鐘 異構物4，滯留時間=37分鐘 實例174與175 92199 -190- 1285641LCMS (ESI+): 495 (MH+), s (2, MH), NMR (CD, NMR) 1.43 (m, 2H), 2.18 (s, 3H), 3.11 (dd, J = 11.35, 4.98 Hz, 1H), 3.22 (dd, J = 10.79, 1.66 Ηζ, 1H), 3.83 (s, 3H), 4·19 (m, 2H), 4.44 (m, 1H), 5.66 (s, 1H), 6.41 (s, 1H), 7·28 (brs, 1H), 7.73 (s, 2H), 7.86 (s, 1H)· LCMS (ESI+): 547 (MH+). This non-isomeric isomer mixture can be further covalent to the Pirkle (S, S) Whelk-ΟΙ column (Regis Technologies, Morton Grove, IL) (5 X 25 cm), by palm chromatography HPLC, dissolved in 5% ethanol / · G. at 100 ml / min, providing three parts of the separation: isomer 1, residence time = 18 minutes Structures 2 and 3, residence time = 25 minutes of isomer 4, residence time = 37 minutes Examples 174 and 175 92199 -190 - 1285641

4-[(3,5-雙-三氟甲基_苯基甲氧&amp; _甲基]士乙基私二〒基· 3,4-二氫-2H-喹喏啉小羧酸甲酯之製備 此化。物係使用如上文關於本[(3,5-雙·三氟甲基·苯基）_甲氧 沒基甲基]2,乙基-6,7-一甲基-3,4-二氫-2Η-ρ奎嘆琳-1-幾酸乙酯 所述足程序製成，但使用氯甲酸甲酯替代氣甲酸乙酯。 非對峡異構物 1 1 H-NMR (CDC13): 5 0·86 (t，J=7.47Hz，3Η)，1·43 (m， 2Η)，2·18 (s，6Η)，3.10 (dd，J=11.48, 4.98Hz，1Η)，3·22 (dd，J=11.17Hz，1·66Ηζ， 1H)，3.75 (s，3H)，4.43 (m，1H)，3.82 (s，3H)，5.66 (s，1H)，6.41 (s，1H)，7.22 (brs， 1H)，7.72 (s，2H)，7.86 (s，1H). LCMS (ESI+) : 532 (M+). 非對映異構物 2 1H-NMR (CDC13) ·· 5 0.71 (t，J=7.47Hz，3H)，1.19 (m， 1H)，1.43 (m，1H)，2.19 (s，3H)，2.20 (s，3H)，2.77 (dd，J=11.47, 1.65Hz，1H)， 3.38 (dd，J=li.30, 3.74Hz，1H)，3.77 (s，3H)，3.81 (s，3H)，4.38 (m，1H)，5.83 (s， 1H)，6,58(s，1H)，7.37(s，1H)，7.75(s，2H)，7.88(s，1H)· LCMS (ESI+) : 532 (M+)· 實例176與1774-[(3,5-bis-trifluoromethyl-phenylmethoxy]amp; methicone] ethyl 2-carbomethoxy 3,4-dihydro-2H-quinoxaline small carboxylic acid methyl ester The preparation was carried out as follows. For the above [(3,5-bis-trifluoromethylphenyl)-methoxymethylmethyl] 2, ethyl-6,7-monomethyl-3 , 4-dihydro-2Η-ρ奎叹琳-1-carboxylic acid ethyl ester, prepared by the foot procedure, but using methyl chloroformate instead of gaseous ethyl formate. Non-isomer isomer 1 1 H-NMR ( CDC13): 5 0·86 (t, J=7.47Hz, 3Η), 1·43 (m, 2Η), 2·18 (s, 6Η), 3.10 (dd, J=11.48, 4.98Hz, 1Η), 3·22 (dd, J=11.17Hz, 1.66Ηζ, 1H), 3.75 (s, 3H), 4.43 (m, 1H), 3.82 (s, 3H), 5.66 (s, 1H), 6.41 (s, 1H), 7.22 (brs, 1H), 7.72 (s, 2H), 7.86 (s, 1H). LCMS (ESI+): 532 (M+). diastereomers 2 1H-NMR (CDC13) ·· 5 0.71 (t, J=7.47Hz, 3H), 1.19 (m, 1H), 1.43 (m, 1H), 2.19 (s, 3H), 2.20 (s, 3H), 2.77 (dd, J=11.47, 1.65Hz , 1H), 3.38 (dd, J=li.30, 3.74Hz, 1H), 3.77 (s, 3H), 3.81 (s, 3H), 4.38 (m, 1H), 5.83 (s, 1H), 6, 58(s,1H), 7.37(s,1H), 7.75( s, 2H), 7.88(s, 1H)· LCMS (ESI+): 532 (M+)· Examples 176 and 177

92199 -191 - 1285641 4-[(3,5-雙-三氟甲基-苯基）·甲氧幾基-甲基]_2·乙基-6,7-二甲基-3,4-二氫-2H-喳喏啉小羧酸異丙酯之製備 此化合物係使用如上文關於化合物4-[(3,5-雙-三氟甲基-苯基 )-甲氧羰基-甲基]-2-乙基-6,7-二甲基-3,4-二氫-2H-喳喏啉小羧酸 乙酯所述之程序製成，但使用氣甲酸異丙酯替代氯甲酸乙 酉旨。 非對映異構物 1 1 H-NMR (CDC13 )·· 5 0.86 (t，J=7.47Hz，3H)，U6 (dd， J=6.22, 6·22Ηζ，3H)，1·26 (dd，JN15.07, 6·22Ηζ，3H)，1.50 (m，2H)，2.17，(s，6H)， 3.10，(m，1H)，3.2 (m，1H)，3.82 (s，3H)，4.42 (m，1H)，5.00 (m，1H)，5·65 (s，1H)， 6.40 (s，1H)，7.31 (brs，1H)，7.64 (s，1H)，7.74 (s，1H). LCMS (ESI+) ： 560 (M+). 非對映異構物 2 1H-NMR (CDC13): 5 0.71 (t，JN7.47, 3H)，1.16 (m，1H)， 1.26 (d，J=6.23Hz)，1.29 (d，J=5.81Hz)，1.44 (m，1H)，2·18 (s，3H)，2.20 (s，3H)， 2·76 (dd，J=11.52, 2·07Ηζ，1H)，3.37 (dd，J=11.52, 3.32Hz)，3.82 (s，3H)，4.38 (m，1H)，5.01 (m，1H)，5.82 (s，1H)，6.58 (s，1H)，7·47 (brs，1H)，7.75 (s，2H)， 7.88 (s，1H)· LCMS (ESI+) ： 561 (MH+). 製備40 (3,5-雙-三氟甲基-苯基H臭-乙腈 於（3,5-雙-三氟甲基-苯基)-乙腈（2·〇克，7·9毫莫耳）在四氯化 碳（20毫升）中之溶液内，添加過氧化二苯甲醯（0.076克，〇.3 毫莫耳）與N-溴基琥珀醯亞胺（L4克，7.9毫莫耳）。使此反應 混合物回流24小時，然後以二氯甲烷稀釋，並以鹽水洗條 。使有機層脫水乾燥，並濃縮，而得粗產物，使其藉咬膠 92199 -192- 1285641 層析純化，使用己烷中之2%醋酸乙酯作為溶離劑，而得標 題化合物（2.0克，75% )。 LCMS (ESI+) ： 333 (MH+). 實例17892199 -191 - 1285641 4-[(3,5-Bis-Trifluoromethyl-phenyl)-methoxybenzyl-methyl]_2·ethyl-6,7-dimethyl-3,4-di Preparation of hydrogen-2H-porphyrin carboxylic acid isopropyl ester This compound was used as described above for the compound 4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]- The procedure described for the ethyl 2-ethyl-6,7-dimethyl-3,4-dihydro-2H-carboline small carboxylic acid was used, but isopropyl carbamic acid was used instead of chloroformic acid. Diastereomer 1 1 H-NMR (CDC13 )·· 5 0.86 (t, J=7.47 Hz, 3H), U6 (dd, J=6.22, 6.22Ηζ, 3H), 1·26 (dd, JN15.07, 6·22Ηζ, 3H), 1.50 (m, 2H), 2.17, (s, 6H), 3.10, (m, 1H), 3.2 (m, 1H), 3.82 (s, 3H), 4.42 ( m,1H), 5.00 (m,1H),5·65 (s,1H), 6.40 (s,1H),7.31 (brs,1H), 7.64 (s,1H),7.74 (s,1H). LCMS (ESI+): 560 (M+). diastereomer 2 1H-NMR (CDC13): 5 0.71 (t,JN7.47, 3H), 1.16 (m,1H), 1.26 (d,J=6.23Hz ), 1.29 (d, J = 5.81 Hz), 1.44 (m, 1H), 2·18 (s, 3H), 2.20 (s, 3H), 2·76 (dd, J=11.52, 2·07Ηζ, 1H ), 3.37 (dd, J=11.52, 3.32Hz), 3.82 (s, 3H), 4.38 (m, 1H), 5.01 (m, 1H), 5.82 (s, 1H), 6.58 (s, 1H), 7 · 47 (brs, 1H), 7.75 (s, 2H), 7.88 (s, 1H)· LCMS (ESI+): 561 (MH+). Preparation 40 (3,5-bis-trifluoromethyl-phenyl H odor - Peracetic acid in a solution of (3,5-bis-trifluoromethyl-phenyl)-acetonitrile (2·5 g, 7. 9 mmol) in carbon tetrachloride (20 mL) Benzophenone (0.076 g, 〇.3 mmol) N-bromosuccinimide (L4 g, 7.9 mmol). The reaction mixture was refluxed for 24 h then diluted with dichloromethane and washed with brine. The title compound (2.0 g, 75%) was obtained. (MH+). Example 178

4-[(3,5-雙-三氟甲基-苯基氰基-甲基]-2-乙基-6,7-二甲基-3,4-二 氫-2H-4:喏4 -1-幾酸乙酯 方法A ··使2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏啉小羧酸乙酯 (1克’ 1當量，3.81毫莫耳）、3,5-雙·(三氟甲基-苯基）-溴-乙腈 (製備40，1.27克，1當量，3.81毫莫耳）及碳酸鉀（1.58克，3 當量’ 11.43毫莫耳）在乙腈（5毫升）中之混合物，在 Emrys Optimizer (Personal 化學，Uppsala，Sweden)中，於140°C 下，接 受微波照射20分鐘。使反應物於醋酸乙酯與水之間作分液 處理，並分離液相。以醋酸乙酯將水相萃取3次，並將合併 足有機萃液以水洗滌2次，以鹽水1次，以無水硫酸鈉脫水 乾燥’過濾，及蒸發。於矽膠上層析，使用己烷中之10-30% 酷酸乙醋之梯度液作為溶離劑，提供所要之腈，為兩種非 對映異構物之混合物（15 :以9〇〇毫克，29% )。 方法B :將2-乙基-6,7_二甲基-3,4-二氫-2H-喹喏啉小羧酸乙酯 (1克，1當量，3.81毫莫耳）、3,5_雙-(三氟甲基_苯基）_溴-乙腈 92199 -193 - 1285641 (製備40，1·27克，1當量，3.81毫莫耳）及2,6-二甲基吡啶 (3當量，11.43毫莫耳）在N，N-二甲基甲醯胺（5毫升）中之混合 物，於室溫下撥拌24小時。使反應物於醋酸乙酯與水之間 作分液處理，並分離液相。以醋酸乙酯將水相萃取3次，並 將合併之有機萃液以水洗滌2次，以鹽水1次，以無水硫酸 納脫水乾燥，過遽，及蒸發。於碎膠上層析，使用己燒中 之10-30%醋酸乙酯之梯度液作為溶離劑，提供所要之亞硝酸 鹽，為兩種非對映異構物之混合物（1.5 : 1)(900毫克，29% )。 LCMS(ESI+)： 514 (MH+) 實例1794-[(3,5-bis-trifluoromethyl-phenylcyano-methyl]-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-4:喏4 Ethyl-1-acetic acid method A ··Ethyl 2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline small carboxylic acid (1 g '1 equivalent, 3.81 Millol), 3,5-bis(trifluoromethyl-phenyl)-bromo-acetonitrile (preparation 40, 1.27 g, 1 eq, 3.81 mmol) and potassium carbonate (1.58 g, 3 eq. A mixture of millimolar in acetonitrile (5 mL) was subjected to microwave irradiation for 20 minutes at 140 ° C in Emrys Optimizer (Personal Chemistry, Uppsala, Sweden). The reaction was between ethyl acetate and water. The liquid phase was separated and the liquid phase was separated. The aqueous phase was extracted 3 times with ethyl acetate, and the combined organic extracts were washed twice with water, once with brine, dried over anhydrous sodium sulfate, filtered, and evaporated. Chromatography on silica gel, using a gradient of 10-30% citric acid in hexane as the eluent to provide the desired nitrile as a mixture of two diastereomers (15: 9 〇〇) Mg, 29%) Method B: 2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline small carboxylic acid Ester (1 g, 1 equivalent, 3.81 mmol), 3,5-bis-(trifluoromethyl-phenyl)-bromo-acetonitrile 92199-193 - 1285641 (preparation 40,1·27 g, 1 equivalent, a mixture of 3.81 mmoles and 2,6-lutidine (3 equivalents, 11.43 mmol) in N,N-dimethylformamide (5 ml), stir at room temperature for 24 hours The reaction mixture was partitioned between ethyl acetate and water, and the liquid phase was separated. The aqueous phase was extracted three times with ethyl acetate, and the combined organic extracts were washed twice with water, 1 time with brine. Drying with anhydrous sodium sulfate, drying, and evaporation. Chromatography on crushed rubber, using 10-30% ethyl acetate gradient in hexane as the dissolving agent to provide the desired nitrite. a mixture of diastereomers (1.5: 1) (900 mg, 29%). LCMS (ESI+): 514 (MH+)

4-[1-(3,5-雙-二氣甲基-冬基）經基-乙基]-2-乙基_6,7-二甲基-3,4-二氫-2H-喹喏琳-丨名酸乙酯之製備 於4-[(3,5-雙-三氟甲基-苯基）·甲氧羰基4基]_2_乙基_6,7_二甲 基-3,4-二氫-2H-喹喏啉小羧酸乙酯（〇14克，〇·26毫莫耳）在四氫 呋喃（5毫升）中之溶液内，在-78。〇下，逐滴添加氫化鋰鋁溶 液（1M，在四氫味喃中，Q.Μ毫升）。此溶液慢慢溫熱至室溫 ，歷經3小時。以硫酸鈉六水合物（2克）使反應混合物淬滅 ，並將混合物攪拌30分鐘。使反應混合物過濾，及濃縮， 而得粗產物（非對映異構物之混合物），使其藉矽膠層析純 92199 -194- 1285641 化，以己烷中之10%醋酸乙酯溶離，而得標題化合物（0.08克 ，70% 卜 1 H-NMR (CDC13) * 5 0.71 (t，J=7.57Hz，3H)，0.95 (t，J=7.05Hz，3H)，1.26 (m，2H)，2.20 (bs，6H)，2.97 (dd，1H)，3·25 (m，1H)，3.37 (m, 1H)，3.85 (m，2H)， 4.15 (m，3H)，4.5 (bm，1H)，4.62 (m，1H)，4.70 (m，1H)，5.82 (s，1H)，6.58 (s， 1H)，7.49 (bi*s，1H) 7.75 (s，2H)，7.88 (s，1H). LCMS (ESI+) ： 518 (MH+) 實例1804-[1-(3,5-bis-dimethylmethyl-winteryl)-carbyl-ethyl]-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quin Preparation of 喏琳-丨名酸ethyl ester in 4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl-4-yl]_2-ethyl_6,7-dimethyl-3 , a solution of 4-dihydro-2H-quinoxaline carboxylic acid ethyl ester (14 g, 〇·26 mmol) in tetrahydrofuran (5 mL) at -78. Under the sputum, a lithium aluminum hydride solution (1 M in tetrahydrofuran, Q. Μ ml) was added dropwise. The solution was slowly warmed to room temperature over 3 hours. The reaction mixture was quenched with sodium sulfate hexahydrate (2 g) and mixture was stirred for 30 min. The reaction mixture was filtered, and concentrated to give a crude material (jjjjjjjjjjjjjjjjjjjjjjjjjj) The title compound was obtained (0.08 g, 70%, 1H-NMR (CDC13), </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 2.20 (bs,6H), 2.97 (dd,1H),3·25 (m,1H), 3.37 (m, 1H), 3.85 (m,2H), 4.15 (m,3H),4.5 (bm,1H) , 4.62 (m, 1H), 4.70 (m, 1H), 5.82 (s, 1H), 6.58 (s, 1H), 7.49 (bi*s, 1H) 7.75 (s, 2H), 7.88 (s, 1H) LCMS (ESI+) : 518 (MH+) Example 180

4-[l-(3&gt;雙-三氟甲基-苯基）-2-甲氧基-乙基]-2-乙基-6,7-二甲基-3,4-二氫奎嘆淋小複酸乙i旨之製備 於4-[1-(3,5_雙-三氟甲基-苯基）_2名基-乙基]-2-乙基_6,7_二甲基 -3,4-二氫-2H-喹喏啉-1-羧酸乙酯（〇 〇44克，0.13毫莫耳）在無水 二曱基甲酸胺（93毫升）中之溶液内，添加氫化鈉（6〇%懸浮液 ’ 0.005克，0.27毫莫耳），並將混合物攪拌20分鐘。添加過 量琪化甲烷’並將反應物攪拌1小時，且以飽和氯化銨使反 應淬滅。將混合物以醚（3χ2〇毫升）萃取，並濃縮。粗產物之 矽膠層析，使用己烷中之1〇-3〇%醋酸乙酯之梯度液作為溶離 劑’提供所要之產物，為油狀物（〇 〇15克，35% )。 1 H-NMR (CDC13) ： 5 0.71 (t5 J=7.57Hz, 3H), 1.30 (t5 J=7.〇5Hz, 3H), 1.46 92199 -195 - 1285641 (m，2H)，2·20 (brs，6H)，2·97 (dd，1Η)，3·25 (m，1H)，3.37 (m，1H)，3.4 (s，3H)， 3.85 (m，2H)，4.26 (m，1H)，4.5 (bm，1H)，4.62 (m，1H)，4.70 (m，1H)，5.82 (s， 1H), 6.58 (s? 1H), 7.49 (brs, 1H)? 7.75 (s? 2H), 7.88 (s, 1H). LCMS (ESI+) ： 532 (MH+). 實例1814-[l-(3&gt; bis-trifluoromethyl-phenyl)-2-methoxy-ethyl]-2-ethyl-6,7-dimethyl-3,4-dihydroquine Preparation of 4-[1-(3,5-bis-trifluoromethyl-phenyl)_2-yl-ethyl]-2-ethyl-6,7-dimethyl -3,4-Dihydro-2H-quinoxaline-l-carboxylic acid ethyl ester (44 g, 0.13 mmol) in anhydrous sodium decanoate (93 mL) (6 〇% suspension '0.005 g, 0.27 mmol) and the mixture was stirred for 20 minutes. The reaction was stirred for 1 hour and the reaction was quenched with saturated ammonium chloride. The mixture was extracted with ether (3 mL 2 mL) and concentrated. The crude product was chromatographed eluting with EtOAc EtOAc EtOAc (EtOAc) 1 H-NMR (CDC13) : 5 0.71 (t5 J=7.57Hz, 3H), 1.30 (t5 J=7.〇5Hz, 3H), 1.46 92199 -195 - 1285641 (m,2H),2·20 (brs ,6H),2·97 (dd,1Η),3·25 (m,1H), 3.37 (m,1H),3.4 (s,3H), 3.85 (m,2H), 4.26 (m,1H), 4.5 (bm, 1H), 4.62 (m, 1H), 4.70 (m, 1H), 5.82 (s, 1H), 6.58 (s? 1H), 7.49 (brs, 1H)? 7.75 (s? 2H), 7.88 (s, 1H). LCMS (ESI+): 532 (MH+). Example 181

4-[2-乙酿氧基-1-(3,5-雙-三氟曱基-苯基）-乙基]-2-乙基-6,7-二甲基 二氫-2H-喹喏啉小羧酸乙酯之製備 使4-[1-(3,5-雙-三氟甲基-苯基）-2-經基-乙基]-2-乙基-6,7-二甲基 -3,4-二氫奎嗔淋-1-幾酸乙酯溶於醋酸纤與p比淀之1 : 1混 合物（4毫升）中，並將混合物在環境溫度下擾拌1〇小時。於 真空中移除溶劑，並使殘留物藉矽膠層析純化，而得所要 之醋酸酯（25毫克，58% ;非對映異構物之混合物） 1H-NMR (CDC13) : (5 0.71 (t，J=7.57Hz，3H)，1.30 (t，J=7.05Hz，3H)，1.46 (m，2H)，1·98 (s，3H) 2·18 (s，3H)，2·20 (s，3H)，2·77 (dd，1H)，3·05 (m，1H)， 3·37 (m，1H)，4.20 (m，2H)，4.26 (m，1H)，4.5 (m，1H)，4·62 (m，1H)，4.70 (m， 1H)，5.82 (s，1H)，6·58 (s，1H)，7.49 (brs，1H)，7,75 (s，2H)，7.88 (s，1H). LCMS (ESI+) ： 560 (MH+) 實例182 92199 -196- 12856414-[2-Ethyloxy-1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-ethyl-6,7-dimethyldihydro-2H-quin Preparation of porphyrin ethyl carboxylic acid ethyl 4-[1-(3,5-bis-trifluoromethyl-phenyl)-2-yl-ethyl]-2-ethyl-6,7-di Methyl-3,4-dihydroquinidine-acetic acid ethyl ester was dissolved in a 1:1 mixture (4 ml) of acetic acid fiber and p-precipitate, and the mixture was turbulent at ambient temperature for 1 hour. . The solvent was removed in vacuo and the residue was purified eluted eluted elut elut elut elut elut elut elut elut elut elut t, J = 7.57 Hz, 3H), 1.30 (t, J = 7.05 Hz, 3H), 1.46 (m, 2H), 1·98 (s, 3H) 2·18 (s, 3H), 2·20 ( s,3H),2·77 (dd,1H),3·05 (m,1H), 3·37 (m,1H), 4.20 (m,2H), 4.26 (m,1H),4.5 (m, 1H),4·62 (m,1H), 4.70 (m, 1H), 5.82 (s,1H),6·58 (s,1H), 7.49 (brs,1H),7,75 (s,2H) , 7.88 (s, 1H). LCMS (ESI+): 560 (MH+) Example 182 92199 -196- 1285641

4-(3,5-雙-二氟甲基-笨甲醯基）_2-乙基-6,7-二甲基，3,4-二氫-2H-喳 喏啉小羧酸乙酯之製備 將2-乙基-6,7-二甲基-3,4-二氫-2H-g奎喏啉小羧酸乙酯（〇·ι克， 1當量，0.38愛莫耳）在5毫升二氯甲烷中之室溫溶液，以經 由將J，5-雙-(二敦甲基）苯甲酸（147毫克，1.5當量，q.57毫莫耳） 、氯化草酿（〇.〇5毫升，L5當量，〇.57毫莫耳）及一滴無水二 甲基甲酿胺合併而形成之氯化醯處理。使反應物於室溫下 攪拌過夜’此時’以飽和後酸氫鈉使反應淬滅，並以二氯 甲烷萃取3次。將合併之有機萃液以iM HC1洗滌1次，以飽 和碳酸氫鈉1次，以鹽水1次，以無水硫酸鈉脫水乾燥，過 濾，及蒸發。於矽膠上層析，使用己烷中之10-20%醋酸乙酯 梯度液，提供4-(3,5-雙-三氟曱基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喳喏啉-1-羧酸乙酯（130毫克，68% )。 1H-NMR (CDC13) ·· ά 0·91 (t，J=7.47Hz，3H)，1.30 (t，J=7.04Hz，3H)，1.50 (m，1H)，1.60 (m，1H)，L94 (s，3H)，2·20 (s，3H)，3.39 (m，1H)，4.26 (q，JN6.22 Hz，2H)，4·68 (m，2H)，6.29 (brs，1H)，7.41 (brs，1H)，7·78 (s，2H)，7.85 (s，1H)· FIA-MS (APCI+) ·· 503 (MH+). 製備41 6-三氟甲基-1，2,3,4-四氫奎每口林 92199 -197- 1285641 此所要之喹喏啉係使用V. Krchnak等人（7^ra/^ran 仏2443-2446 (2001))所述之方法，使用3-(R)-胺基-戊烷小醇與2-氟基-5-三氟甲基-硝基苯製成。 1 H-NMR (DMSO-d6) ： ά 1·06 (t，J=7.48Hz，3H)，1.73(rn，J=7.90Hz，2H)， 3.19 (dd，J=9.96Hz，1H)，3.68 (dd，J=9.55Hz，1H)，3.71 (m，1H)，6·98 (d，J=8.3 Hz, 1H)，7.25 (dd，1H)，7.43 (s，1H)· ESI-MS : 231 (MH+). 實例1834-(3,5-bis-difluoromethyl-benzoamyl)_2-ethyl-6,7-dimethyl, 3,4-dihydro-2H-carboline small carboxylic acid ethyl ester Preparation of 2-ethyl-6,7-dimethyl-3,4-dihydro-2H-g quinoxaline small carboxylic acid ethyl ester (〇·ι克, 1 equivalent, 0.38 Amor) in 5 ml a room temperature solution in dichloromethane to give J,5-bis-(di-methyl)benzoic acid (147 mg, 1.5 equivalents, q.57 mmol), chlorinated grass (〇.〇5 The ruthenium chloride treatment was formed by combining ML, L5 equivalent, 〇.57 mmoles and one drop of anhydrous dimethyl ketoamine. The reaction was allowed to stir at room temperature overnight &lt;RTI ID=0.0&gt;&gt;&gt;&gt; The combined organic extracts were washed once with iM HCl, and then sat. Chromatography on silica gel, using a 10-20% ethyl acetate gradient in hexane affording 4-(3,5-bis-trifluoromethyl-benzhydryl)-2-ethyl-6,7 Ethyl dimethyl-3,4-dihydro-2H-carboline-1-carboxylate (130 mg, 68%). 1H-NMR (CDC13) ·· ά 0·91 (t, J=7.47 Hz, 3H), 1.30 (t, J=7.04 Hz, 3H), 1.50 (m, 1H), 1.60 (m, 1H), L94 (s, 3H), 2·20 (s, 3H), 3.39 (m, 1H), 4.26 (q, JN6.22 Hz, 2H), 4·68 (m, 2H), 6.29 (brs, 1H), 7.41 (brs,1H),7·78 (s,2H), 7.85 (s,1H)· FIA-MS (APCI+) ·· 503 (MH+). Preparation 41 6-Trifluoromethyl-1,2,3 , 4-tetrahydroquine per sulphate 92199 -197- 1285641 The desired quinoxaline system is carried out by the method described by V. Krchnak et al. (7^ra/^ran 仏 2443-2446 (2001)), using 3- (R)-Amino-pentane small alcohol and 2-fluoro-5-trifluoromethyl-nitrobenzene. 1 H-NMR (DMSO-d6) : ά 1·06 (t, J = 7.48 Hz, 3H), 1.73 (rn, J = 7.90 Hz, 2H), 3.19 (dd, J = 9.96 Hz, 1H), 3.68 (dd, J=9.55 Hz, 1H), 3.71 (m, 1H), 6·98 (d, J=8.3 Hz, 1H), 7.25 (dd, 1H), 7.43 (s, 1H)· ESI-MS: 231 (MH+). Example 183

一鼠-211*^奎p若？林-1-幾酸乙g旨 使6-三氟甲基-1，2,3,4-四氫^奎喏啉（製備41，0.01克，〇·〇4毫 莫耳，1當量）、溴化3,5-雙-三氟甲基-苯基）_甲氧羰基-甲烷 (0.017克，0.044毫莫耳，U當量）及2,6_二甲基吡虔（〇〇14克， 0.12毫莫耳，3當量）在二曱基甲醯胺（〇·5毫升）中之溶液，在A mouse-211*^奎普 if? 6-trifluoromethyl-1,2,3,4-tetrahydro-quinoline (preparation 41, 0.01 g, 〇·〇 4 mmol, 1 equivalent), 3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl-methane (0.017 g, 0.044 mmol, U equivalent) and 2,6-dimethylpyridinium (〇〇14 g, 0.12 millimolar, 3 equivalents) in dimercaptocaramine (〇·5 ml) in solution

Milestone 微波（Milestone 實驗室，Sorisole，Italy)中，於 140 °C 下照射 10分鐘。於減壓下移除溶劑，產生暗色油，使用之而無需 進一步純化。 ESI-MS ： 542 (MH+). 將此殘留物與2,6-二甲基吡啶（〇,〇丨8克，0.16毫莫耳，2當量） 92199 -198 - 1285641 及氣甲酸乙酯（0.0175克，0,16毫莫耳，2當量）在二甲基甲醯 胺（0.5毫升）中合併，並於140°C下，在Milestone微波（Milestone 實驗室，Sorisole，Italy)中，藉由照射加熱10分鐘。使溶液藉預 備之HPLC純化，以水0.1% NH4〇H、70-0%具有乙腈、0.1% NH4〇H，6分鐘梯度液時間與8分鐘操作時間溶離，產生標 題化合物。 ESI-MS ： 587 (MH+) 醯胺類平行合成之一般程序： 將所需要之苯甲酸（0.06毫莫耳，1當量）與PS-PPh3 (115毫克 ，1·51毫莫耳/克，3當量，0.18毫莫耳）(Argonaut技術公司 ，Foster City，CA)在隔片罩蓋之2達蘭（dram)小玻瓶中合併。於 此固體混合物中，經由TecanUS (Research Triangle Park，NC)液體 處理器添加二氯乙烷（1毫升）。於此懸浮液中，經由Tecan， 添加三氯乙腈（0.0072毫升，1.2當量，0.07毫莫耳）在二氯乙 烷（1毫升）中之溶液，並利用執道振盪器，將反應物溫和攪 拌3小時。於此溶液中，添加PS-DIPAM (56毫克，3.2毫莫耳/ 克，3當量，0.18毫莫耳）（聚合體實驗室，Amherst，MA)，並經 由Tecan，添加2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏啉-1-羧酸乙 酯（15毫克，〇·〇6毫莫耳，1.0當量）在二氯乙烷（1毫升）中之溶 液。將反應物攪拌過夜。使用Tecan液體處理器，使反應物 經過濾器管件過濾，並以二氣乙烷將樹脂洗滌3次。使用 Genevac Mega660離心蒸發器（Genevac公司，Suffolk, UK)蒸發溶液 ，並使殘留物再溶解於二甲亞颯（0.2毫升）中，且使用Shimadzu 預備之 HPLC 系統（Shimadzu 公司，Kyoto, Japan)純化，以 30-100% 92199 -199 - 1285641 乙腈/水/ 0.1%甲酸梯度液，於19x50毫米Waters對稱性管柱 (Waters公司，Milford，MA)上溶離，8分鐘操作，6分鐘梯度液， 25毫升/分鐘，UV觸發收集，在210毫微米下觀察。使用 Genevac Mega660 離心蒸發器（Genevac 公司，Suffolk，UK)使含產物 之溶離份蒸發至乾涸。 使用適當起始物質，實例184-409係以類似實例183之方式 製成，為外消旋混合物： 實例184Milestone microwaves (Milestone Laboratories, Sorisole, Italy) were irradiated at 140 °C for 10 minutes. The solvent was removed under reduced pressure to give a dark oil which was used without further purification. ESI-MS: 542 (MH+). This residue was combined with 2,6-dimethylpyridine ( 〇, 〇丨 8 g, 0.16 mmol, 2 eq.) 92199 -198 - 1285641 and ethyl formate (0.0175 Gram, 0,16 mmol, 2 eq.) combined in dimethylformamide (0.5 mL) and illuminated at 140 ° C in Milestone Microwave (Milestone Laboratories, Sorisole, Italy) by irradiation Heat for 10 minutes. The solution was purified by preparative HPLC using water 0.1% NH4 〇H, 70-0% with acetonitrile, 0.1% NH?? ESI-MS: 587 (MH+) General procedure for parallel synthesis of guanamine: The desired benzoic acid (0.06 mmol, 1 equivalent) and PS-PPh3 (115 mg, 1.51 mmol/g, 3 Equivalent, 0.18 millimoles) (Argonaut Technologies, Foster City, CA) was combined in a 2 dram small glass vial cover. To this solid mixture, dichloroethane (1 mL) was added via a TecanUS (Research Triangle Park, NC) liquid processor. A solution of trichloroacetonitrile (0.0072 ml, 1.2 eq., 0.07 mmol) in dichloroethane (1 mL) was added to this suspension via Tecan, and the reaction was gently stirred using a running shaker. 3 hours. To this solution, PS-DIPAM (56 mg, 3.2 mmol/g, 3 equivalents, 0.18 mmol) (Polymer Laboratories, Amherst, MA) was added and 2-ethyl-6 was added via Tecan. ,7-Dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester (15 mg, 〇·〇6 mmol, 1.0 eq.) in dichloroethane (1 mL) Solution in the middle. The reaction was stirred overnight. The reactants were filtered through a filter tube using a Tecan liquid handler and the resin was washed 3 times with di-hexane. The solution was evaporated using a Genevac Mega660 centrifugal evaporator (Genevac, Suffolk, UK), and the residue was redissolved in dimethyl hydrazine (0.2 ml) and purified using a Shimadzu preparative HPLC system (Shimadzu Corporation, Kyoto, Japan). , 30-100% 92199 -199 - 1285641 acetonitrile / water / 0.1% formic acid gradient, dissolved on a 19x50 mm Waters symmetry column (Waters, Milford, MA), 8 minutes operation, 6 minutes gradient, 25 ML/min, UV triggered collection, observed at 210 nm. The product-containing dissolved fraction was evaporated to dryness using a Genevac Mega660 centrifugal evaporator (Genevac, Suffolk, UK). Using the appropriate starting materials, Examples 184-409 were prepared in a similar manner to Example 183 as a racemic mixture: Example 184

4-(5-第三-丁基-2-曱基-2H-吡唑-3-羰基）-2-乙基-6,7-二甲基-3,4-二 氫-2H-喹喏啉小羧酸乙酉旨 LC-MS (ESI+) ： 427 (MH+). 實例1854-(5-Terti-butyl-2-mercapto-2H-pyrazole-3-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoline Chlorocarboxylic acid small carboxylic acid LC-MS (ESI+): 427 (MH+). Example 185

2-乙基斗[2-(4-氟-苯氧基）-吡啶-3-羰基]-6,7-二甲基-3,4-二氫-2H- 92199 -200- 1285641 喳喏啉-1-羧酸乙酯 LC-MS (ESI+) ： (MH+). 實例186 h3c h3c2-ethyl phenyl [2-(4-fluoro-phenoxy)-pyridine-3-carbonyl]-6,7-dimethyl-3,4-dihydro-2H- 92199 -200- 1285641 porphyrin 1-carboxylic acid ethyl ester LC-MS (ESI+): (MH+). Example 186 h3c h3c

4-(2-二氟甲氧基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏 琳-1-致酸乙酉旨 LC-MS (ESI+) : 478 (MH+).4-(2-Difluoromethoxy-benzylidene)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-acid acid -MS (ESI+): 478 (MH+).

實例187 F h3c H3CExample 187 F h3c H3C

甲基-3,4-二氫-2H-喹喏 4-(3-二氟甲氧基-苯甲醯基）-2-乙基-6,7-. 啉-1-羧酸乙酯 LC-MS (ESI+) ： 433 (MH+). 實例188 92199 -201 - 1285641Methyl-3,4-dihydro-2H-quinoline 4-(3-difluoromethoxy-benzylidene)-2-ethyl-6,7-. -MS (ESI+): 433 (MH+). Example 188 92199 -201 - 1285641

,C, C

2-乙基-6,7-二甲基-4-(2-三氟l甲基-[1，8]審咬-3_談基）_3,4_二氫-2H- 喹喏啉-1-羧酸乙酯 LC-MS (ESI+) : 487 (MH+)· 實例1892-ethyl-6,7-dimethyl-4-(2-trifluoromethyl-[1,8]-trim-3_Talky)_3,4-dihydro-2H-quinoxaline- 1-Carboxylic acid ethyl ester LC-MS (ESI+): 487 (MH+)· Example 189

h3c HXH3c HX

2-乙基-6,7-二甲基-4-(2-三氟甲基-[1，6]蕃咬-3-羰基）-3,4-二氫-2H- 喹喏啉小羧酸乙酯 LC-MS (ESI+) : 487 (MH+)· 實例1902-ethyl-6,7-dimethyl-4-(2-trifluoromethyl-[1,6]carboxy-3-carbonyl)-3,4-dihydro-2H-quinoxaline small carboxy Acid ethyl ester LC-MS (ESI+): 487 (MH+)· Example 190

h3c HXH3c HX

2-乙基-6,7-二甲基-4-(5-三氟甲基-P塞吩并[3,2_b]p比淀各羰基）-3,4- 二氫-2H-喹喏啉小羧酸乙酯 92199 -202- 1285641 LC-MS (ESI+) : 492 (MH+). 實例1912-ethyl-6,7-dimethyl-4-(5-trifluoromethyl-P-seceno[3,2_b]p ratio carbonyl)-3,4-dihydro-2H-quinoline Ethyl phthalate small carboxylic acid 92199 - 202 - 1285641 LC-MS (ESI+): 492 (MH+).

2-乙基-6,7-二甲基-4-(2-苯基-5-三氣甲基亏嗤-4-談基）-3,4-二氮- 2H-喹喏啉小羧酸乙酯 LC-MS (ESI+) ： 502 (MH+). 實例192 〇、、2-ethyl-6,7-dimethyl-4-(2-phenyl-5-trismethylmethyridin-4-yl)-3,4-diaza-2H-quinoxaline small carboxy Ethyl acetate LC-MS (ESI+): 502 (MH+). Example 192 〇,

4-(4-二丙基胺續驢基-苯甲驗基）-2-乙基-6,7-二甲基-3,4-二氮-2H- 喹喏啉小羧酸乙酯 LC-MS (ESI+) ： 530 (MH+). 實例1934-(4-dipropylamine thiol-benzhydryl)-2-ethyl-6,7-dimethyl-3,4-diaza-2H-quinoxaline small carboxylic acid ethyl ester LC -MS (ESI+): 530 (MH+). Example 193

92199 - 203 - 1285641 4-(2,3-二氫-苯并呋喃-7-羰基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹 喏啉-1-羧酸乙酯 LC-MS (ESI+) : 409 (MH+). 實例19492199 - 203 - 1285641 4-(2,3-Dihydro-benzofuran-7-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline- 1-carboxylic acid ethyl ester LC-MS (ESI+): 409 (MH+).

ch3 4-(3-溴基-4-氯-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏啉- 1-羧酸乙酯 LC-MS (ESI+) : 480 (MH+). 實例195Ch3 4-(3-Bromo-4-chloro-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline- 1-carboxylic acid Ester LC-MS (ESI+): 480 (MH+). Example 195

ch3 4-(2-氣基-3-甲基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏 啉小羧酸乙酯 LC-MS (ESI+) ： 415 (MH+). 實例196 92199 -204 - 1285641Ch3 4-(2-carbo-3-methyl-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline small carboxylic acid ethyl ester LC-MS (ESI+): 415 (MH+). Example 196 92199 -204 - 1285641

h3c H,CH3c H, C

CH3 4-(2-氣基-4-甲烷磺醯基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫- 2H-喹喏啉小羧酸乙酯 LC-MS (ESI+) ： 479 (MH+). 實例197CH3 4-(2-Alkyl-4-methanesulfonyl-benzylidene)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxalinecarboxylic acid Ethyl ester LC-MS (ESI+): 479 (MH+). Example 197

4-(2,6-二氯-苯甲騷基）-2-乙基-6,7-二f基-3,4-二氮-2H-峻嘆3林-1- 羧酸乙酯 LC-MS (ESI+) ： 436 (MH+). 實例1984-(2,6-Dichloro-benzylidene)-2-ethyl-6,7-dif-yl-3,4-diaza-2H-Jun 3lin-1-carboxylic acid ethyl ester LC -MS (ESI+): 436 (MH+). Example 198

'U ^ch3 CHn h3c'U ^ch3 CHn h3c

H,C 2-乙基-4-(4-甲氧基-苯甲醯基）-6,7-二甲基-3,4-二氫-2H-喹喏啉-l· 羧酸乙酯 92199 - 205 - 1285641 LC-MS (ESI+) ： 397 (MH+). 實例199H,C 2-ethyl-4-(4-methoxy-benzylidenyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-l·carboxylate 92199 - 205 - 1285641 LC-MS (ESI+): 397 (MH+). Example 199

2-乙基-4-(2-甲氧基-p比啶冬羰基）-6,7-二甲基二氫-2H-喹喏啉- 1-羧酸乙酯 LC-MS (ESI+) ·· 398 (MH+)· 實例2002-ethyl-4-(2-methoxy-p-pyridylcarbonyl)-6,7-dimethyldihydro-2H-quinoxaline- 1-carboxylic acid ethyl ester LC-MS (ESI+) · 398 (MH+)· Example 200

CH3CH3

2-乙基-6,7-二甲基-4-(1-苯基-5-二氣甲基-lH-p比吐-4-談基）-3,4·二 氫-2Η-4喏啉小羧酸乙酯 LC-MS(ESI+)： 501 (MH+). 實例2012-ethyl-6,7-dimethyl-4-(1-phenyl-5-dimethyl-lH-ppyt-4-yl)-3,4·dihydro-2Η-4 Porphyrin carboxylic acid ethyl ester LC-MS (ESI+): 501 (MH+). Example 201

CH. 92199 - 206 - 1285641 2-乙基-6,7-二甲基-4-(3-甲基-苯并呋喃-2-羰基）-3,4-二氫-2H-喹喏 啉-1-羧酸乙酯 LC-MS(ESI+)： 421 (MH+). .實例202CH. 92199 - 206 - 1285641 2-Ethyl-6,7-dimethyl-4-(3-methyl-benzofuran-2-carbonyl)-3,4-dihydro-2H-quinoxaline- 1-carboxylic acid ethyl ester LC-MS (ESI+): 421 (MH+).

ch3Ch3

2-乙基-4-(2-甲烷磺醯基-苯甲醯基）-6,7-二甲基-3,4-二氫-2H-喹喏 淋-1-瘦酸乙@旨 LC-MS (ESI+) ： 445 (MH+). 實例2032-ethyl-4-(2-methanesulfonyl-benzhydryl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-sodium sulphate -MS (ESI+): 445 (MH+). Example 203

ch3Ch3

2-乙基-4-(9H-第斗羰基）-6,7-二甲基-3,4-二氫-2H-喹喏啉-1-羧酸乙酯 LC-MS (ESI+) ： 455 (MH+). 實例204 92199 - 207 - 1285641Ethyl 2-ethyl-4-(9H-piperidinyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylate LC-MS (ESI+): 455 (MH+). Example 204 92199 - 207 - 1285641

HXHX

ch3 2-乙基-6,7-二甲基-4-(2,3,6-三氟-笨甲醯基）-3,4-二氫-2H-喳喏啉-1 羧酸乙酯 LC-MS (ESI+) ： 421 (MH+). 實例205 αCh3-ethyl 2-ethyl-6,7-dimethyl-4-(2,3,6-trifluoro-phenylmethyl)-3,4-dihydro-2H-carboline-1 carboxylic acid ethyl ester LC-MS (ESI+): 421 (MH+).

ch3 4-(4,5-二氯-異嘧唑-3-羰基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喳喏 啉小羧酸乙酯 LC-MS (ESI+) ： 443 (MH+). 實例206Ch3 4-(4,5-Dichloro-isopyrazole-3-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-carboline small carboxylic acid ethyl ester LC-MS (ESI+): 443 (MH+).

〇、 h3c cr 2-乙基-6,7-二甲基-4-(5-T基冬苯基-2H[1，2,3]三唑-4-羰基）-3,4- 氫-2Η-喹喏啉-1-羧酸乙酯 92199 - 208 - 1285641 LC-MS (ESI+) ： 448 (MH+). 實例207 α〇, h3c cr 2-ethyl-6,7-dimethyl-4-(5-T-t-phenylphenyl-2H[1,2,3]triazole-4-carbonyl)-3,4-hydrogen- 2Η-quinoxaline-1-carboxylic acid ethyl ester 92199 - 208 - 1285641 LC-MS (ESI+): 448 (MH+). Example 207 α

2-乙基-6,7-二甲基斗(2-苯氧基甲基-苯甲醯基）-3,4-二氫-2Η-喹喏 啉小羧酸乙酯 LC-MS (ESI+) : 473 (ΜΗ+). 實例2082-ethyl-6,7-dimethylpipe (2-phenoxymethyl-benzoguanidino)-3,4-dihydro-2-indole-quinoxaline small carboxylic acid ethyl ester LC-MS (ESI+ ) : 473 (ΜΗ+). Example 208

4-(3-氣-苯并[b]噻吩-2-羰基）-2-乙基-6,7-二甲基-3,4-二氫-2Η-喳喏 淋-1-叛酸乙醋 LC-MS (ESI+) ·· 457 (ΜΗ+)· 實例209 92199 - 209 - 12856414-(3-Gas-benzo[b]thiophene-2-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2Η-喳喏--1-Resin B Vinegar LC-MS (ESI+) ·· 457 (ΜΗ+)· Example 209 92199 - 209 - 1285641

ClCl

ch3 4-(3-氯基-4-甲基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹嘆 淋-1-竣乙§旨 LC-MS(ESI+)： 415 (MH+). 實例210Ch3 4-(3-Chloro-4-methyl-benzoguanidino)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoresin-1-竣B § LC-MS (ESI+): 415 (MH+). Example 210

ch3 4-(3-溴基-2,6-二甲氧基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫- 2H-4喏啉小羧酸乙酯 LC-MS (ESI+) : 506 (MH+)· 實例211Ch3 4-(3-bromo-2,6-dimethoxy-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-4 porphyrin Ethyl Carboxylic Acid LC-MS (ESI+): 506 (MH+)· Example 211

o^o CH3 'CH, 4-(2-氣基-3,4-二甲氧基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫- 92199 -210- 1285641 2H-喹喏啉小羧酸乙酯 LC-MS(ESI+) ： 461 (MH+). 實例212O^o CH3 'CH, 4-(2-carbyl-3,4-dimethoxy-benzylidene)-2-ethyl-6,7-dimethyl-3,4-dihydro- 92199 -210- 1285641 2H-quinoxaline ethyl carboxylate LC-MS (ESI+): 461 (MH+).

4-0(4-氯苯基）-5-三氟甲基-1H-吡唑-4-羰基]-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏啉小羧酸乙酯 LC-MS (ESI+) ： 535 (MH+). 實例2134-0(4-chlorophenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-2-ethyl-6,7-dimethyl-3,4-dihydro-2H- Ethyl quinoxaline carboxylic acid LC-MS (ESI+): 535 (MH+).

4-(3-乙氧基噻吩-2-羰基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喳喏啉- 1-羧酸乙酯 LC-MS(ESI+)： 417 (MH+). 實例214 92199 -211 - 1285641Ethyl 4-(3-ethoxythiophene-2-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-carboline-carboxylate LC-MS (ESI+): 417 (MH+). Example 214 92199 -211 - 1285641

4-(5-氯基-4-甲氧基塞吩-3-談基）-2-乙基-6,7-二甲基-3,4-二鼠-2H- 喹喏啉-1-羧酸乙酯 LC-MS (ESI+) : 437 (MH+).4-(5-Chloro-4-methoxysente-3-yl)-2-ethyl-6,7-dimethyl-3,4-dimur-2H-quinoxaline-1- Ethyl Carboxylic Acid LC-MS (ESI+): 437 (MH+).

實例215Example 215

4-[2-(2,3-二氫-苯并[1，4]二氧陸圜烯-2-基）-塞唑-4-羰基]-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏淋小羧酸乙酯 LC-MS (ESI+) ： 508 (MH+). 實例216 ?H34-[2-(2,3-Dihydro-benzo[1,4]dioxolyl-2-yl)-pyrazole-4-carbonyl]-2-ethyl-6,7-dimethyl Ethyl-3,4-dihydro-2H-quinoxaline carboxylic acid ethyl ester LC-MS (ESI+): 508 (MH+). Example 216 ?H3

4-(3-環戊氧基-4-甲氧基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫- 2H-峻诺淋小竣酸乙醋 92199 -212- 1285641 LC-MS(ESI+) : 481 (MH+). 實例217 广4-(3-cyclopentyloxy-4-methoxy-benzylidene)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-junoline Ethyl acetate 92199-212-1285941 LC-MS (ESI+): 481 (MH+). Example 217 wide

CH3 0 CH] 2-乙基-4_(4-甲氧基-3-丙氧基-苯甲驗基）-6,7-二甲基-3,4-二鼠-2H- 喳喏啉小羧酸乙酯 LOMS (ESI+) : 455 (MH+)· 實例218CH3 0 CH] 2-ethyl-4_(4-methoxy-3-propoxy-benzhydryl)-6,7-dimethyl-3,4-dimur-2H-carboline Ethyl Carboxylate LOMS (ESI+): 455 (MH+)· Example 218

2-乙基斗(3-異丙氧基斗甲氧基-苯甲醯基）-6,7-二甲基-3,4-二氫- 2H-喹喏啉小羧酸乙酯 LC-MS (ESI+) ·· 455 (MH+)· 實例2192-ethyl THF (3-isopropoxy oxomethoxy-benzylidene)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline carboxylic acid ethyl ester LC- MS (ESI+) ·· 455 (MH+)· Example 219

92199 -213 - 1285641 4-(3-丁氧基斗甲氧基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H- 峻喏啉小羧酸乙酯 LC-MS (ESI+) : 469 (MH+). 實例220 /CH392199 -213 - 1285641 4-(3-Butoxy-p-methoxy-benzhydryl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H- sucrose Ethyl Carboxylic Acid LC-MS (ESI+): 469 (MH+). Example 220 /CH3

2-乙基-4-(5-甲氧羰基4比啶-2-羰基）-6,7-二甲基-3,4-二氫-2H-喳喏 啉小羧酸乙酯 LC-MS (ESI+) ： 426 (MH+). 實例2212-ethyl-4-(5-methoxycarbonyl 4 -pyridine-2-carbonyl)-6,7-dimethyl-3,4-dihydro-2H-carboline ethyl carboxylate LC-MS (ESI+) : 426 (MH+). Example 221

2-乙基-6,7-二甲基-4-(4-二氣甲基-p比咬-3-談基）-3,4-二鼠-2H-^ p若 啉小羧酸乙酯 LC-MS (ESI+) ： 436 (MH+). 實例222 92199 -214- 12856412-ethyl-6,7-dimethyl-4-(4-dimethyl-p-butyl-3-yl)-3,4-dimur-2H-^ p-morpholine small carboxylic acid Ester LC-MS (ESI+): 436 (MH+). Example 222 92199 -214- 1285641

2-乙基-6,7-二甲基-4-[6-(2,2,2-三氟-乙氧基）-吡啶-3-羰基]-3,4-二氫 -2H-喹喏啉小羧酸乙酯 LC-MS (ESI+) : 466 (MH+). 實例2232-ethyl-6,7-dimethyl-4-[6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-3,4-dihydro-2H-quin Porphyrin small carboxylic acid ethyl ester LC-MS (ESI+): 466 (MH+).

2-乙基冬[5-甲氧基-2-(2,2,2-三氟-乙氧基）-苯甲醯基]-6,7-二甲基- 3,‘二氫-2H-喹喏啉-1-羧酸乙酯 LC-MS (ESI+) ·· 495 (MH+). 實例2242-ethyl winter [5-methoxy-2-(2,2,2-trifluoro-ethoxy)-benzylidenyl]-6,7-dimethyl-3, 'dihydro-2H - quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+) ··495 (MH+). Example 224

2-乙基-6,7-二甲基外(2-甲基-5-苯基-吱喃-3-羰基）-3,4-二氫-2H-喹 92199 -215 · 1285641 喏啉小羧酸乙酯 LC-MS (ESI+) ·· 447 (MH+)_ 實例2252-ethyl-6,7-dimethylexo(2-methyl-5-phenyl-indolyl-3-carbonyl)-3,4-dihydro-2H-quino 92199-215 · 1285641 small porphyrin Ethyl Carboxylic Acid LC-MS (ESI+) ·· 447 (MH+)_ Example 225

ch3 2-乙基-6,7-二T基斗(5-f基冬三氟甲基-呋喃-3-羰基）-3，Φ二氫- 2Η-喹喏啉小羧酸乙酯 LC-MS (ESI+) ： 439 (ΜΗ+). 實例226Ch3 2-ethyl-6,7-di-T-base (5-f-based dimethyl-trifluoromethyl-furan-3-carbonyl)-3, Φ dihydro-2 quinone-quinoxaline small carboxylic acid ethyl ester LC- MS (ESI+): 439 (ΜΗ+). Example 226

2-乙基-4-(2-乙基-5-甲基-2Η-吡唑各羰基）-6,7-二甲基-3,4-二氫-2Η- 邊ρ若57林小幾酸乙酯 LC-MS (ESI+) ： 399 (ΜΗ+). 實例227 92199 -216- 1285641 ch3 ¥人』 人λ 4-(2-第三-丁基-5-甲基-2H-吡唑-3-羰i )-2-乙基-6,7-二甲基-3,4-二 LC-MS (ESI+): 氫-2H-喹喏啉小羧酸乙酯 427 (MH+). 實例228 ch3 Γ) φο 2-乙基-4-[2-(4-乙基-苯甲醯基）-苯甲醯基]-6,7-二甲基-3,4-二氫 LC-MS (ESI+): 2H-喹喏啉小羧酸乙醋 499 (MH+). 實例229 η3、 0η °rVS 。丄。ch3 ^CH, 4-(2-乙氧基莕小羰基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏啉-1 羧酸乙酯 92199 -217- 1285641 LC-MS (ESI+) : 461 (MH+). 實例2302-ethyl-4-(2-ethyl-5-methyl-2-indole-pyrazole each carbonyl)-6,7-dimethyl-3,4-dihydro-2Η- edge ρ if 57 林小Ethyl acetate LC-MS (ESI+): 399 (ΜΗ+). Example 227 92199 -216- 1285641 ch3 ¥人』 Human λ 4-(2-Terti-butyl-5-methyl-2H-pyrazole- 3-carbonyl i)-2-ethyl-6,7-dimethyl-3,4-diLC-MS (ESI+): EtOAc (MH+) Ch3 Γ) φο 2-ethyl-4-[2-(4-ethyl-benzylidene)-benzylidenyl]-6,7-dimethyl-3,4-dihydrol-LC-MS ( ESI+): 2H-quinoxaline small carboxylic acid ethyl acetate 499 (MH+). Example 229 η3, 0η °rVS. Hey. Ch3 ^CH, 4-(2-ethoxyindole carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1 carboxylic acid ethyl ester 92199 - 217- 1285641 LC-MS (ESI+): 461 (MH+). Example 230

BrBr

4-(5-溴基-2,3-二氫-苯并呋喃-7-羰基）-2-乙基-6,7-二曱基-3,4-二氫- 2H-喹喏啉小羧酸乙酯 LC-MS (ESI+) ： 488 (MH+). 實例2314-(5-Bromo-2,3-dihydro-benzofuran-7-carbonyl)-2-ethyl-6,7-dimercapto-3,4-dihydro-2H-quinoxaline Ethyl Carboxylic Acid LC-MS (ESI+): 488 (MH+).

CICI

4-0(4-氣-苯氧基）-吡啶-3-羰基]-2-乙基-6,7-二甲基-3,4-二氫-2H- 喹喏啉小羧酸乙酯 LC-MS (ESI+) ： 494 (MH+). 實例232 γμ4-0(4-Gas-phenoxy)-pyridine-3-carbonyl]-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline small carboxylic acid ethyl ester LC-MS (ESI+): 494 (MH+). Example 232 γμ

ch3 92199 -218 - 1285641 2-乙基-6,7-二甲基-4-(2-對-甲苯氧基^比咬-3-談基）-3,4-二氫-2H-。奎 LC-MS (ESI+): 喏啉小羧酸乙酯 474 (ΜΗ+). 實例233 h3cv^V-nx h]c ηΛΧ 认Λ ch3 2-乙基-4-(5-異丁基-異吟唑-3-羰基）-6,7-二甲基-3,4-二氫-2H-喹喏 LOMS (ESI+): 啉-1-羧酸乙酯 414 (MH+). 實例234 0H v〇r、 。丄0 CH] 2-乙基-4-{4-[(2-羥基-乙基）-甲基-胺基]-苯甲醯基二甲基·3,4- 二氫-2Η-喹喏啉-1-羧酸乙酯 LC-MS (ESI+) : 440 (ΜΗ+). 實例235 92199 -219 - 1285641Ch3 92199 -218 - 1285641 2-Ethyl-6,7-dimethyl-4-(2-p-tolyloxy)-3,4-dihydro-2H-. Kui LC-MS (ESI+): porphyrin small carboxylic acid ethyl ester 474 (ΜΗ+). Example 233 h3cv^V-nx h]c ηΛΧ Λ ch3 2-ethyl-4-(5-isobutyl-iso Oxazol-3-carbonyl)-6,7-dimethyl-3,4-dihydro-2H-quinoline LOMS (ESI+): Ethyl l-carboxylate 414 (MH+). Example 234 0H v 〇 r, .丄0 CH] 2-ethyl-4-{4-[(2-hydroxy-ethyl)-methyl-amino]-benzylidenedimethyl]3,4-dihydro-2Η-quinoline Ethyl l-carboxylate LC-MS (ESI+): 440 (ΜΗ+). Example 235 92199 -219 - 1285641

CH, 4-(3,5-二甲基-1H-4丨哚冬羰基）-2-乙基-6,7-二甲基-3,4-二氫-2H-4 喏啉小羧酸乙酯 LC-MS (ESI+) ： 434 (MH+). 實例236CH, 4-(3,5-Dimethyl-1H-4indolinyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-4 porphyrin carboxylic acid Ethyl ester LC-MS (ESI+): 434 (MH+).

CH. CH, 2-乙基-4-[4-(5-乙基-[1，2,4]吟二唑-3-基）-苯甲醯基]-6,7-二甲基-3,4- 二氫-2H-喹喏啉小羧酸乙酯 LC-MS (ESI+) ： 463 (MH+). 實例237 h3cCH. CH, 2-ethyl-4-[4-(5-ethyl-[1,2,4]oxadiazol-3-yl)-benzylidenyl]-6,7-dimethyl- 3,4-Dihydro-2H-quinoxaline carboxylic acid ethyl ester LC-MS (ESI+): 463 (MH+). Example 237 h3c

2-乙基-6,7-二甲基-4-0(5-甲基-[1，2,4]哼二唑-3-基）-苯甲醯基]-3,4- 二氫-2H-喹喏啉小羧酸乙醋 92199 - 220 - 1285641 LC-MS (ESI+) : 449 (MH+). 實例2382-ethyl-6,7-dimethyl-4-0(5-methyl-[1,2,4]oxadiazol-3-yl)-benzylidene]-3,4-dihydro -2H-quinoxaline small carboxylic acid ethyl acetonate 92199 - 220 - 1285641 LC-MS (ESI+): 449 (MH+). Example 238

ch3 2-乙基-6,7-二甲基-4-(5-丙基-異呤唑-3-羰基）-3,4-二氫-2H-喳喏啉- 1-羧酸乙酯 LC-MS (ESI+)400 (ΜΗ+). 實例239Ch3 2-ethyl-6,7-dimethyl-4-(5-propyl-isoxazol-3-carbonyl)-3,4-dihydro-2H-porphyrin-1-carboxylate LC-MS (ESI+) 400 (ΜΗ+). Example 239

2-乙基-4-(5-異丁基-2-甲基-2H-吡唑-3-羰基）-6,7-二甲基-3,4-二氩- 2H-喹喏啉小羧酸乙酯 LC-MS (ESI+) ·· 427 (MH+)· 實例2402-ethyl-4-(5-isobutyl-2-methyl-2H-pyrazole-3-carbonyl)-6,7-dimethyl-3,4-diargon-2H-quinoxaline Ethyl Carboxylic Acid LC-MS (ESI+) ·· 427 (MH+)· Example 240

CH. 92199 -221 - 1285641 2-乙基-4-(5-甲氧基甲基-吱喃冬羰基）-6,7-二甲基-3,4-二氫-2H-喳 喏啉小羧酸乙酯 LC-MS(ESI+)： 401 (MH+). 實例241CH. 92199 -221 - 1285641 2-Ethyl-4-(5-methoxymethyl-indolylcarbonyl)-6,7-dimethyl-3,4-dihydro-2H-carboline Ethyl Carboxylic Acid LC-MS (ESI+): 401 (MH+).

2-乙基斗(5-異丙基-2H-吡唑-3-羰基）-6,7-二甲基-3,4-二氫-2H-喹喏 啉-1-羧酸乙酯 LC-MS (ESI+) ： 399 (MH+). 實例2422-ethyl phenyl (5-isopropyl-2H-pyrazole-3-carbonyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester LC -MS (ESI+): 399 (MH+). Example 242

2-乙基-6,7-二甲基-4-(4-嗎福啉-4-基-苯甲醯基）-3,4-二氫-2H-喹喏 啉小羧酸乙酯 LC-MS (ESI+) ： 452 (MH+). 實例243 92199 - 222 ^ 1285641Ethyl 2-ethyl-6,7-dimethyl-4-(4-morpholine-4-yl-benzoguanidino)-3,4-dihydro-2H-quinoxalinecarboxylate LC -MS (ESI+): 452 (MH+). Example 243 92199 - 222 ^ 1285641

4-(5-氯基冬甲基-1H-吲哚-2-羰基）-2-乙基-6,7-二甲基-3,4-二氫-2H- 喳喏啉小羧酸乙酯 LC-MS (ESI+) : 454 (MH+). 實例2444-(5-Chloro-t-butyl-1H-indole-2-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-carboline small carboxylic acid Ester LC-MS (ESI+): 454 (MH+). Example 244

4-(3,5-二甲基-1H-吡咯-2-羰基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹 喏啉-1-羧酸乙酯 LC-MS (ESI+) ： 384 (MH+). 實例2454-(3,5-Dimethyl-1H-pyrrol-2-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid Ethyl ester LC-MS (ESI+): 384 (MH+). Example 245

2-乙基-6,7-二甲基-4-(6,7,8,9-四氫-5H-咔唑-3-羰基）-3,4-二氫-2H-喳 92199 - 223 - 1285641 喏啉-1-羧酸乙酯 LC-MS (ESI+) ： 460 (MH+). 實例2462-ethyl-6,7-dimethyl-4-(6,7,8,9-tetrahydro-5H-indazole-3-carbonyl)-3,4-dihydro-2H-喳92199 - 223 - 1285641 Ethyl porphyrin-1-carboxylate LC-MS (ESI+): 460 (MH+).

4-[4-(2,5-二甲氧基-苯甲醯基）-苯甲醯基]-2-乙基-6,7-二甲基-3,4- 二氫-2H-4喏啉小羧酸乙酯 LC-MS(ESI+)： 531 (MH+). 實例2474-[4-(2,5-Dimethoxy-benzylidenyl)-benzylidenyl]-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-4 Ethyl porphyrin carboxylic acid LC-MS (ESI+): 531 (MH+).

C h3c KCC h3c KC

CH, ch3 2-乙基-6,7-二甲基-4-(2-甲基-嘍唑-4-羰基）-3,4-二氫-2H-喹喏啉-1- 羧酸乙酯 LC-MS (ESI+) ： 388 (MH+). 實例248CH, ch3 2-ethyl-6,7-dimethyl-4-(2-methyl-oxazol-4-carbonyl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid Ester LC-MS (ESI+): 388 (MH+). Example 248

CH, 92199 1285641 4-[3-(3,5-二甲基-口比吐-1-基）-苯甲酿基]-2-乙基-6,7-二甲基-3,4-二 氫-2H^奎喏淋小致酸乙醋 LC-MS (ESI+) ： 461 (MH+)· 實例249CH, 92199 1285641 4-[3-(3,5-Dimethyl-mouth-t-but-1-yl)-benzyl]-2-ethyl-6,7-dimethyl-3,4- Dihydro-2H^ quetiapine small acid ethyl acetate LC-MS (ESI+): 461 (MH+)· Example 249

2-乙基-6,7-二甲基-4-(2-對苯基-峻p林-4-藏基）-3,4-二鼠-211-17奎哈 57林-1-複酸乙酉旨 LC-MS (ESI+) : 508 (MH+). 實例2502-ethyl-6,7-dimethyl-4-(2-p-phenyl-Jun plin-4-carving)-3,4-dimur-211-17 quake 57-1-1 Acidic LC-MS (ESI+): 508 (MH+). Example 250

2-乙基-6,7-二甲基斗(5-甲基-1，3-二苯基-1H-吡唑-4-羰基）-3,4«二氫 -2H-喹喏啉-1-羧酸乙酯 LC-MS (ESI+) ·· 523 (MH+)· 實例251 92199 - 225 - 12856412-ethyl-6,7-dimethylpipe (5-methyl-1,3-diphenyl-1H-pyrazole-4-carbonyl)-3,4«dihydro-2H-quinoxaline- Ethyl 1-carboxylate LC-MS (ESI+) ·· 523 (MH+)· Example 251 92199 - 225 - 1285641

2-乙基-6,7-二甲基-4-(4-六氫吡啶小基-苯甲醯基）-3,4-二氫-2H-口奎 喏啉-1-羧酸乙酯 LC-MS (ESI+) : 450 (MH+). 實例2522-ethyl-6,7-dimethyl-4-(4-hexahydropyridine small-benzylidene)-3,4-dihydro-2H-methyl quinoxaline-1-carboxylate LC-MS (ESI+): 450 (MH+).

3,4-二氫-2H-喹喏啉-1-羧酸乙酯 LC-MS (ESI+) ： 475 (MH+). 實例253Ethyl 3,4-dihydro-2H-quinoxaline-1-carboxylate LC-MS (ESI+): 495 (MH+).

2-乙基-6,7-二甲基-4十奎啉-2-羰基）-3,4-二氫-2H-喹喏啉小羧酸乙酉旨 92199 - 226 - 1285641 LOMS(ESI+) : 418(MH+). 實例2542-ethyl-6,7-dimethyl-4tetraquinoline-2-carbonyl)-3,4-dihydro-2H-quinoxaline small carboxylic acid acetazone 92199 - 226 - 1285641 LOMS (ESI+): 418 (MH+). Example 254

ch3 2-乙基-4-(呋喃-3-羰基）-6,7-二甲基-3,4-二氫-2H-喹喏啉小羧酸乙酯 LC-MS (ESI+) ·· 357 (MH+)· 實例255Ch3 2-ethyl-4-(furan-3-carbonyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline small carboxylic acid ethyl ester LC-MS (ESI+) ·· 357 (MH+)· Example 255

CH3 4-(5-溴基-2-氯-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏啉- 1-羧酸乙酯 LC-MS (ESI+) ： 480 (MH+). 實例256 〇CH3 4-(5-Bromo-2-chloro-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline- 1-carboxylic acid Ester LC-MS (ESI+): 480 (MH+). Example 256 〇

ch3 92199 - 227 - 1285641 4-(4-乙醯基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喳喏啉-1- 羧酸乙酯 LC-MS (ESI+) : 409 (MH+)· 實例257Ch3 92199 - 227 - 1285641 4-(4-Ethyl-benzhydryl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-porphyrin-1-carboxylate Acid ethyl ester LC-MS (ESI+): 409 (MH+)· Example 257

4-(2-氯基-6-氟-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏啉- 1-羧酸乙酯 LC-MS(ESI+)： 419 (MH+). 實例258Ethyl 4-(2-chloro-6-fluoro-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline- 1-carboxylate LC-MS (ESI+): 419 (MH+).

‘ch3 2-乙基-6,7-二甲基冬(莕-2-羰基）-3,4-二氫-2H-喹喏啉小羧酸乙酯 LC-MS(ESI+) ： 417 (MH+). 實例259 92199 - 228 - 1285641 h3c h3c'ch3 2-ethyl-6,7-dimethyl-m-(indole-2-carbonyl)-3,4-dihydro-2H-quinoxaline carboxylic acid ethyl ester LC-MS (ESI+): 417 (MH+ Example 259 92199 - 228 - 1285641 h3c h3c

、CH， 4-(3-溴-苯甲醯基）冬乙基-6,7-二甲基-3,4-二氫-2H-喹喏啉小羧酸 乙醋 LC-MS (ESI+) : 446 (MH+). 實例260 h3c h3c,CH, 4-(3-bromo-benzylidene)-t-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline small carboxylic acid ethyl acetate LC-MS (ESI+) : 446 (MH+). Example 260 h3c h3c

2-乙基-6,7-二甲基-4-(2,3,4-三甲氧基-苯甲醯基）-3,4-二氫-2H-喹喏 啉小羧酸乙酯 LC-MS (ESI+) ： 457 (MH+). 實例2612-ethyl-6,7-dimethyl-4-(2,3,4-trimethoxy-benzoguanidino)-3,4-dihydro-2H-quinoxaline small carboxylic acid ethyl ester LC -MS (ESI+) : 457 (MH+). Example 261

、(:K, (:K

CK 2-乙基-4-(4-乙基-苯甲醯基）-6,7-二甲基-3,4-二氫-2H-喹喏啉小羧 酸乙醋 92199 -229 - 1285641 LC-MS (ESI+): 395 (MH+). 實例262 A 〇人〇°^ ^ch3 2-乙基-6,7-二甲基-4-(2-苯基-喹啉-4-羰基）-3,4-二氫-2H-喹喏啉-1 羧酸乙酯 LC-MS (ESI+): 494 (MH+)· 實例263 〇v〇 :職 。人A ^CH, 2-乙基-6,7-二甲基-4-(2-三氟甲基-苯甲醯基）-3,4-二氫-2H-喹喏啉 1-羧酸乙酯 LC-MS (ESI+): 435 (MH+). 實例264 f p 92199 ::職 入1 、h3 - 230 - 1285641 2-乙基-6,7-二甲基斗(4-三氟甲基-苯甲醯基）-3,4-二氫-2H-喹喏啉- 1-羧酸乙酯 LC-MS (ESI+) ： 435 (MH+). 實例265CK 2-ethyl-4-(4-ethyl-benzhydryl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline small carboxylic acid ethyl acetate 92199 -229 - 1285641 LC-MS (ESI+): 395 (MH+). Example 262 A 〇人〇°^^ch3 2-ethyl-6,7-dimethyl-4-(2-phenyl-quinolin-4-carbonyl) -3,4-Dihydro-2H-quinoxaline-1carboxylic acid ethyl ester LC-MS (ESI+): 494 (MH+). Human A ^CH, 2-ethyl-6,7-dimethyl-4-(2-trifluoromethyl-benzylidenyl)-3,4-dihydro-2H-quinoxaline 1-carboxylic acid Ethyl ester LC-MS (ESI+): 435 (MH+). Example 264 fp 92199::1, h3 - 230 - 1285641 2-ethyl-6,7-dimethyl benzene (4-trifluoromethyl- Benzyl hydrazino)-3,4-dihydro-2H-quinoxaline-l-carboxylic acid ethyl ester LC-MS (ESI+): 435 (MH+).

4-[2-(4-氯-苯甲醯基）-苯甲醯基]-2-乙基-6,7-二甲基-3,4-二氫-2H- 喹喏啉小羧酸乙酯 LC-MS (ESI+) ： 506 (MH+). 實例2664-[2-(4-Chloro-benzylidene)-benzylidenyl]-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxalinecarboxylic acid Ethyl ester LC-MS (ESI+): 506 (MH+). Example 266

4-(3,4-二乙氧基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏 啉-1-羧酸乙酯 LC-MS (ESI+) ： 455 (MH+). 實例267 92199 -231 - 1285641Ethyl 4-(3,4-diethoxy-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylate LC-MS (ESI+): 455 (MH+). Example 267 92199 -231 - 1285641

ch3 ‘(2-氯基-5-甲硫基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹Ch3 ‘(2-Chloro-5-methylthio-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quin

喏啉-1-羧酸乙酯 LC-MS (ESI+) ： 448 (MH+). 實例268Ethyl porphyrin-1-carboxylate LC-MS (ESI+): 448 (MH+).

2-乙基-6,7-二甲基-4-(3-甲基塞吩-2-談基）-3,4-二氣-2H-17奎嗓淋-1- 羧酸乙酯 籲 LC-MS (ESI+) ： 387 (MH+). 實例2692-ethyl-6,7-dimethyl-4-(3-methylsecen-2-yl)-3,4-digas-2H-17 quinoxaline-1-carboxylate LC-MS (ESI+): 387 (MH+). Example 269

CH^ I JCH^ I J

ch3 4-(2,5-二甲氧基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏 92199 - 232 - 1285641 啉小羧酸乙酯 LC-MS (ESI+) : 427 (MH+). 實例270Ch3 4-(2,5-dimethoxy-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoline 92199-232-1283041 Ethyl Carboxylic Acid LC-MS (ESI+): 427 (MH+).

ch3 4-(2,4-二氟-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏啉-1 羧酸乙酯 LC-MS (ESI+) ： 403 (MH+). 實例271Ch3-ethyl 2-(2,4-difluoro-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1carboxylate LC- MS (ESI+): 403 (MH+). Example 271

4-(3,4-二氣-苯甲縫基）-2-乙基-6,7-二甲基-3,4-二鼠-2Η-^ % 57林-1 羧酸乙酯 LOMS (ESI+) : 403 _+)· 實例272 92199 - 233 - 12856414-(3,4-dioxa-benzylidene)-2-ethyl-6,7-dimethyl-3,4-dimur-2Η-^ % 57 Lin-1 Ethyl carboxylate LOMS ( ESI+) : 403 _+)· Example 272 92199 - 233 - 1285641

ch3 4-(3-溴基-4-甲基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喳喏 啉-1-羧酸乙酯 LC-MS (ESI+) : 460 (MH+). 實例273 ch3Ch3 4-(3-Bromo-4-methyl-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-porphyrin-1-carboxylic acid Ethyl ester LC-MS (ESI+): 460 (MH+). Example 273 ch3

^ch3 人ch3 2-乙基斗(4_異丙基-苯甲醯基）_6,7-二甲基-3,4-二氫-2H-喹喏啉小 羧酸乙酯 LC-MS (ESI+) ： 409 (MH+)· 實例274 ?H3^ch3 human ch3 2-ethylidene (4-isopropyl-benzhydryl)_6,7-dimethyl-3,4-dihydro-2H-quinoxaline ethyl carboxylate LC-MS ( ESI+) : 409 (MH+)· Example 274 ?H3

ch3 2-乙基-4-(2-甲氧基斗甲硫基-苯甲醯基）-6,7-二甲基-3,4-二氫-2H- 喹喏啉小羧酸乙酯 92199 - 234 - 1285641 LC-MS (TESI+) : 443 (MH+)· 實例275Ch3 2-ethyl-4-(2-methoxypipemethylthio-benzylidene)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline small carboxylic acid ethyl ester 92199 - 234 - 1285641 LC-MS (TESI+) : 443 (MH+)· Example 275

h3c HXH3c HX

ch3 4-(3,5-二氣-禾甲廳:基）-2-乙基-6,7-二甲基-3,4-二鼠-2H-峻令淋-1_ 羧酸乙酯 LC-MS (ESI+) : 403 (MH+)· 實例276 h3c h3cCh3 4-(3,5-diox-he-methyl:yl)-2-ethyl-6,7-dimethyl-3,4-dimur-2H-junling-1-carboxylic acid ethyl ester LC -MS (ESI+) : 403 (MH+)· Example 276 h3c h3c

、CH，, CH,

F 4-(2-氯基-4-氟-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏啉 1-羧酸乙酯 LC-MS(ESI+)： 419 (MH+). 實例277 h3c h3cF 4-(2-Chloro-4-fluoro-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline 1-carboxylic acid ethyl ester LC-MS (ESI+): 419 (MH+). Example 277 h3c h3c

ch3 92199 - 235 - 1285641 2-乙基-6,7-二甲基-4-(9-酮基-9H-第小羰基）-3,4-二氫-2H-喹喏啉小 羧酸乙酯 LC-MS (ESI+) ： 469 (MH+)· 實例278Ch3 92199 - 235 - 1285641 2-ethyl-6,7-dimethyl-4-(9-keto-9H-small carbonyl)-3,4-dihydro-2H-quinoxaline small carboxylic acid Ester LC-MS (ESI+): 469 (MH+)· Example 278

4-(苯并呋喃-2-羰基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏啉小羧 酸乙酿 LC-MS (ESI+) ： 407 (MH+). 實例279 叩、〇4-(benzofuran-2-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline small carboxylic acid ethyl acetate LC-MS (ESI+): 407 (MH+). Example 279 叩, 〇

2-乙基-4-(2-甲氧羰基-苯甲醯基）-6,7-二甲基-3,4-二氫-2H-喹喏啉- 1-羧酸乙酯 LC-MS (ESI+) ： 425 (MH+). 實例280 92199 - 236 - 1285641Ethyl 2-ethyl-4-(2-methoxycarbonyl-benzylidenyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylate LC-MS (ESI+): 425 (MH+). Example 280 92199 - 236 - 1285641

氫-2H-喳喏啉-1- 2-乙基-6,7-二甲基冬(2,4,5-三氟-苯甲醯基）_3,4- 羧酸乙酯 LC-MS(ESI+)： 421 (MH+). 實例281Hydrogen-2H-porphyrin-1-2-ethyl-6,7-dimethyl winter (2,4,5-trifluoro-benzylidene)-3,4-carboxylic acid ethyl ester LC-MS ( ESI+): 421 (MH+). Example 281

人CH] -2H-4喏啉小羧 2-乙基-6,7-二甲基-4-(4-丙基·《苯甲酿基）-3,4-二 酸乙醋 LC-MS (ESI+) ： 409 (MH+). 實例282 h3c h3cHuman CH] -2H-4 porphyrin small carboxy 2-ethyl-6,7-dimethyl-4-(4-propyl·benzoyl)-3,4-diacetic acid ethyl acetate LC-MS (ESI+) : 409 (MH+). Example 282 h3c h3c

ch3 2-乙基-6,7-二甲基-4-(2,3,4-三氟-苯甲醯基）-3,4- 氫-2H-喹喏啉小 92199 - 237 - 1285641 複酸乙酯 LC-MS (ESI+) ： 421 (MH+)· 實例283Ch3 2-ethyl-6,7-dimethyl-4-(2,3,4-trifluoro-benzylidene)-3,4-hydro-2H-quinoxaline small 92199 - 237 - 1285641 Ethyl acetate LC-MS (ESI+): 421 (MH+)· Example 283

〇丄〇〇丄〇

2-乙基-4-(2-氟基-3-二氟甲基-木甲酸基二甲基二氫-识 喹喏啉+羧酸乙酯 LC-MS (ESI+) ： 453 (MH+). 實例2842-ethyl-4-(2-fluoro-3-difluoromethyl-xylformyldimethyldihydro- quinoxaline + ethyl carboxylate LC-MS (ESI+): 453 (MH+). Example 284

〇人 CH] ^ch3 2-乙基-6,7-二甲基斗[2-(4-甲基-苯甲醯基）-苯甲醯基]-3,4-二氫- 2H-。奎嘆琳小複酸乙画旨 LC-MS (ESI+) ： 485 (MH+). 實例285 92199 - 238 - 1285641〇人 CH] ^ch3 2-ethyl-6,7-dimethylpipe [2-(4-methyl-benzylidene)-benzylidenyl]-3,4-dihydro-2H-.奎叹琳小复酸乙画 LC-MS (ESI+) : 485 (MH+). Example 285 92199 - 238 - 1285641

2-乙基-6,7-二甲基-4-(4’-三氟甲基-聯苯基-2-羰基）-3,4-二氫-2H-喹 喏啉-1-羧酸乙酯 LC-MS (ESI+) ： 511 (MH+). 實例2862-ethyl-6,7-dimethyl-4-(4'-trifluoromethyl-biphenyl-2-carbonyl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid Ethyl ester LC-MS (ESI+): 511 (MH+). Example 286

FF

^ch3 人CH3 2-乙基-4-(3-氟基-4-甲氧基-苯甲醯基）-6,7-二甲基-3,4-二氫-2Η-4 喏啉-1-羧酸乙酯 LC-MS (ESI+) ： 415 (ΜΗ+). 實例287^ch3 Human CH3 2-ethyl-4-(3-fluoro-4-methoxy-benzhydryl)-6,7-dimethyl-3,4-dihydro-2Η-4 porphyrin- Ethyl 1-carboxylate LC-MS (ESI+): 415 (ΜΗ+). Example 287

2-乙基斗(4-異丙氧基-苯甲醯基）-6,7-二甲基-3,4-二氫-2Η-喹喏啉- 92199 - 239 - 1285641 1-羧酸乙酯 LC-MS (ESI+) : 425 (MH+). 實例2882-ethylidene (4-isopropoxy-benzylidene)-6,7-dimethyl-3,4-dihydro-2-indole-quinoxaline- 92199 - 239 - 1285641 1-carboxylic acid Ester LC-MS (ESI+): 425 (MH+). Example 288

2-乙基-6,7-二甲基-4-(4-丙氧基-苯甲醯基）-3,4-二氫-2H-喹喏啉-1 羧酸乙酯 LC-MS (ESI+) ： 425 (MH+). 實例289Ethyl 2-ethyl-6,7-dimethyl-4-(4-propoxy-benzylidene)-3,4-dihydro-2H-quinoxaline-1carboxylate LC-MS ( ESI+) : 425 (MH+). Example 289

ch3 4-(3-氣基-4-氟-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏啉 1-羧酸乙酯 LC-MS (ESI+) ： 419 (MH+). 實例290 92199 - 240 - 1285641Ch3 4-(3-Alkyl-4-fluoro-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline 1-carboxylic acid ethyl ester LC-MS (ESI+): 419 (MH+). Example 290 92199 - 240 - 1285641

4-(2,4-雙-三氟曱基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹 喏啉小羧酸乙酯 LC-MS (ESI+) : 503 (MH+). 實例291 ?H3 h3c4-(2,4-bis-trifluoromethyl-benzhydryl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline small carboxylic acid ethyl ester LC-MS (ESI+): 503 (MH+). Example 291 ?H3 h3c

〇、 CHi 、CHn 4-(2,6-二甲氧基—比啶各羰基）-2-乙基-6,7-二甲基-3,4-二氫-2H-4 喏啉小羧酸乙酯 LC-MS (ESI+) ： 428 (MH+). 一實例292〇, CHi, CHn 4-(2,6-dimethoxy-bipyridine carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-4 porphyrin small carboxy Acid ethyl ester LC-MS (ESI+): 428 (MH+). An example 292

、CH， 4-(2-澳基-5-甲氧基-笨甲酿基）-2-乙基-6,7-二甲基-3,4-二氫-2H-^ 喏啉-1-羧酸乙酯 92199 -241 - 1285641 LC-MS (ESI+) : 476 (MH+). 實例293,CH, 4-(2-Amino-5-methoxy-stupyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-^ porphyrin-1 -ethyl carboxylate 92199 -241 - 1285641 LC-MS (ESI+): 476 (MH+). Example 293

2-乙基-4-(2-氟-苯甲醯基）-6,7-二曱基-3,4-二氩-2H-喹喏啉小羧酸 乙酉旨 LC-MS (ESI+) : 385 (MH+)· 實例294 H3Cv^02-ethyl-4-(2-fluoro-benzylidenyl)-6,7-dimercapto-3,4-diar argon-2H-quinoxaline small carboxylic acid acetonitrile LC-MS (ESI+): 385 (MH+)· Example 294 H3Cv^0

4-(2,5-二甲羞-呋喃：羰基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏 啉小羧酸乙酯 LC-MS (ESI+) ： 385 (MH+). 實例2954-(2,5-Dim-furan:carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline carboxylic acid ethyl ester LC-MS ( ESI+) : 385 (MH+). Example 295

92199 - 242 - 1285641 2-乙基-4-(4-氟基-3-三氟甲基-苯甲醯基）-6,7-二甲基-3,4-二氫-2H- 喹喏啉小羧酸乙酯 LC-MS (ESI+) : 453 (MH+). 實例29692199 - 242 - 1285641 2-Ethyl-4-(4-fluoro-3-trifluoromethyl-benzylidene)-6,7-dimethyl-3,4-dihydro-2H-quinoline Ethyl phthalate small carboxylic acid LC-MS (ESI+): 453 (MH+).

4-(2-苯甲醯基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏啉- 1-羧酸乙酯 LC-MS(ESI+)： 471 (MH+). 實例297 〇4-(2-Benzylmercapto-benzylidene)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline- 1-carboxylic acid ethyl ester LC- MS (ESI+): 471 (MH+). Example 297 〇

4-(4-苯曱醯基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏啉- 1-羧酸乙酯 LOMS (ESI+) ·· 471 (MH+)· 實例298 92199 - 243 - 1285641Ethyl 4-(4-phenylhydrazino-benzylidene)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-l-carboxylate LOMS ( ESI+) ·· 471 (MH+)· Example 298 92199 - 243 - 1285641

ch3 4-(聯苯基-2-羰基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喳喏啉小羧酸 乙酯 LC-MS (ESI+) : 443 (MH+). 實例299Ch3- 4-(biphenyl-2-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-carboline ethyl carboxylate LC-MS (ESI+): 443 (MH+). Example 299

4-(聯苯基斗羰基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏啉小羧酸 乙醋 LC-MS (ESI+) ： 443 (MH+). 實例3004-(biphenylyl carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline small carboxylic acid ethyl acetate LC-MS (ESI+): 443 (MH+ ). Example 300

4-(3-氯-苯甲醯基）-2-乙基-6,7-二曱基-3,4-二氫-2H-喹喏啉小羧酸 92199 -244 - 1285641 乙酉旨 LC-MS(ESI+) : 401 (MH+). 實例3014-(3-Chloro-benzylidenyl)-2-ethyl-6,7-dimercapto-3,4-dihydro-2H-quinoxaline small carboxylic acid 92199-244 - 1285641 MS (ESI+): 401 (MH+). Example 301

4-(4-氰基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏啉小複 酸乙酉旨 LC-MS (ESI+) ·· 392 (MH+). 實例3024-(4-Cyano-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline small resulphonate LC-MS (ESI+) ·· 392 (MH+). Example 302

4-(2,3-二甲氧基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏 啉小羧酸乙酯 LC-MS (ESI+) : 427 (MH+). 實例303 92199 - 245 - 12856414-(2,3-Dimethoxy-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline carboxylic acid ethyl ester LC- MS (ESI+): 427 (MH+). Example 303 92199 - 245 - 1285641

4-(2,4-二甲氧基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喳喏 淋-1-幾酸乙酉旨 LC-MS (ESI+) : 427 (MH+)· 實例304 H3C、〇4-(2,4-Dimethoxy-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-indole-1-carboxylic acid LC-MS (ESI+): 427 (MH+)· Example 304 H3C, 〇

4-(3,4-二甲氧基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏 啉-1-羧酸乙酯 LOMS (ESI+) ·· 427 (MH+)· 實例305Ethyl 4-(3,4-dimethoxy-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylate LOMS (ESI+) ·· 427 (MH+)· Example 305

4-(3,5-二曱氧基-冬甲酿基）-2-乙基-6,7-—甲基-3,4-二鼠-2H-口奎％ 啉小羧酸乙酯 92199 - 246 - 1285641 LC-MS (ESI+) ： 427 (MH+). 實例306 h3c h3c4-(3,5-dimethoxy-angelyl)-2-ethyl-6,7-methyl-3,4-dimur-2H-hydroxyquinoline carboxylic acid ethyl ester 92199 - 246 - 1285641 LC-MS (ESI+): 427 (MH+). Example 306 h3c h3c

4-(3,4-二甲基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏啉- 1-羧酸乙酯 LC-MS (ESI+) ： 395 (MH+). 實例3074-(3,4-Dimethyl-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline- 1-carboxylic acid ethyl ester LC -MS (ESI+): 395 (MH+). Example 307

4-(3,5-二甲基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏啉- 1-羧酸乙酯 LC-MS (ESI+) : 395 (MH+). 實例3084-(3,5-Dimethyl-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline- 1-carboxylic acid ethyl ester LC -MS (ESI+): 395 (MH+). Example 308

92199 -247 - 1285641 2-乙基斗(3-氟基斗甲基-苯甲醯基）-6,7-二甲基-3,4-二氫-2H-喳喏 啉小羧酸乙酯 LC-MS (ESI+) : 399 (MH+). 實例30992199 -247 - 1285641 2-ethylidene (3-fluoropiperidinylmethyl-benzylidene)-6,7-dimethyl-3,4-dihydro-2H-carboline small carboxylic acid ethyl ester LC-MS (ESI+): 399 (MH+). Example 309

ch3 2-乙基-4-(呋喃-2-羰基）-6,7-二甲基-3,4-二氫-2H-4喏啉小羧酸乙酯 LC-MS (ESI+) ： 357 (MH+). 實例310Ch3 2-ethyl-4-(furan-2-carbonyl)-6,7-dimethyl-3,4-dihydro-2H-4 porphyrin ethyl carboxylate LC-MS (ESI+): 357 ( MH+). Example 310

ch3 2-乙基斗(3-氟-苯甲醯基）-6,7-二甲基-3,4-二氫-2H-喹喏啉小羧酸 乙酯 LC-MS (ESI+) ： 385 (MH+). 實例311 0^100 - 248 - 1285641 h3c、 h3c h3cCh3 2-ethyl phenyl (3-fluoro-benzylidenyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline carboxylic acid ethyl ester LC-MS (ESI+): 385 (MH+). Example 311 0^100 - 248 - 1285641 h3c, h3c h3c

ch3 2-乙基-4-(3-甲氧基-4-甲基-苯甲醯基）-6,7-二甲基-3,4-二氫-2H哇 口若淋-1-複故乙酉旨 LC-MS(ESI+) : 411 (MH+)· 實例312Ch3 2-ethyl-4-(3-methoxy-4-methyl-benzylidene)-6,7-dimethyl-3,4-dihydro-2H Therefore, LC-MS (ESI+): 411 (MH+)· Example 312

CH, CH, 2-乙基-6,7-二甲基-4-(5-甲基塞吩-2-談基）-3,4-二氮-2H-^ p若淋-1- 羧酸乙酯 LC-MS (ESI+) : 387 (MH+). … 實例313CH, CH, 2-ethyl-6,7-dimethyl-4-(5-methylsecen-2-yl)-3,4-diaza-2H-^p-rule-1-carboxylate Acid ethyl ester LC-MS (ESI+): 387 (MH+).

2-乙基-6,7-二甲基冬(莕小羰基）-3,4-二氫-2H-喳喏啉小羧酸乙酯 LC-MS(ESI+) : 417(MH+). 92199 - 249 - 1285641 實例314Ethyl 2-ethyl-6,7-dimethyl-m-(indole carbonyl)-3,4-dihydro-2H-carbolinecarboxylic acid ethyl ester LC-MS (ESI+): 417 (MH+). 249 - 1285641 Example 314

2-乙基-6,7-二甲 LC-MS (ESI+)： 2-乙基-6,7-二甲 LC-MS (ESI+): 基冬(6-甲基—比啶-2-羰基）-3,4-二氫-2H-喳喏啉小 羧酸乙酯 382 (MH+). 實例315 ?h32-ethyl-6,7-dimethyl LC-MS (ESI+): 2-ethyl-6,7-dimethyl LC-MS (ESI+): carbamide (6-methyl-pyridin-2-carbonyl) -3,4-Dihydro-2H-carboline ethyl carboxylate 382 (MH+). Example 315 ?h3

ch3 基冰(2,4,6-三甲氧基-苯甲醯基）-3,4-二氫-2H-喹喏 啉小羧酸乙酯 457 (MH+). 實例316Ch3 base ice (2,4,6-trimethoxy-benzylidene)-3,4-dihydro-2H-quinoxaline ethyl carboxylate 457 (MH+). Example 316

92199 -250 - 1285641 4-[3-(2-氯苯基）-5-甲基-異哼唑-4-羰基]-2-乙基-6,7-二甲基-3,4-二 鼠奎。若？林-1-致酸乙酉旨 LC-MS (ESI+) ： 482 (MH+). 實例31792199 -250 - 1285641 4-[3-(2-Chlorophenyl)-5-methyl-isoxazole-4-carbonyl]-2-ethyl-6,7-dimethyl-3,4-di Rat Kui. If? LAM-1-acidic acid LC-MS (ESI+): 482 (MH+). Example 317

4-(2-溴基-5-氯-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏啉 1-羧酸乙酯 LC-MS (ESI+) : 480 (MH+). 實例318Ethyl 4-(2-bromo-5-chloro-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline 1-carboxylate -MS (ESI+): 480 (MH+). Example 318

Br h3c h3cBr h3c h3c

CH. 、CH， 4-(3-溴基-4-甲氧基-苯甲醯基）-2-乙基-6,7-二f基-3,4-二氫-2H-4 喏啉-1-羧酸乙酯 LC-MS (ESI+) : 476 (MH+)· 實例319 -251 - 1285641CH., CH, 4-(3-Bromo-4-methoxy-benzylidenyl)-2-ethyl-6,7-di-f--3,4-dihydro-2H-4 porphyrin Ethyl-1-carboxylate LC-MS (ESI+): 476 (MH+)· Example 319 -251 - 1285641

4-(4-芊氧基-苯并）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏啉小羧酸 乙酯 LC-MS (ESI+) : 473 (MH+). 實例320Ethyl 4-(4-decyloxy-benzo)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxalinecarboxylate LC-MS (ESI+): 473 (MH+). Example 320

33

2-乙基-6,7-二曱基-4七塞吩-2-羰基）-3,4-二氫-2H-喹喏啉小羧酸乙酯 LC-MS (ESI+) : 373 (MH+). 實例321 h3c h3cEthyl 2-ethyl-6,7-diamidino-4hepta-2-yl)-3,4-dihydro-2H-quinoxalinecarboxylate LC-MS (ESI+): 373 (MH+ ). Example 321 h3c h3c

2-乙基-6,7-二甲基-4-(2-甲基-苯甲醯基）-3,4-二氫-2H-喹喏啉-1-羧 酸乙醋 92199 - 252 - 1285641 LC-MS(ESI+)： 381 (MH+). 實例3222-ethyl-6,7-dimethyl-4-(2-methyl-benzoguanidino)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl acetate 92199 - 252 - 1285641 LC-MS (ESI+): 381 (MH+). Example 322

ch3 2-乙基-6,7-二甲基-4-(3-甲基-苯甲醯基）-3,4-二氫-2H-喳喏啉-1-羧 Φ 酸乙酯 LC-MS(ESI+)： 381 (MH+). 實例323Ch3 2-ethyl-6,7-dimethyl-4-(3-methyl-benzoguanidino)-3,4-dihydro-2H-indolino-1-carboxypyranate ethyl ester LC- MS (ESI+): 381 (MH+). Example 323

2-乙基-6,7-二甲基-4-(4-甲基-苯甲醯基）-3,4-二氫-2H-喹喏啉小羧 酸乙酯 LC-MS (ESI+) ： (MH+). 實例324 队〇Ethyl 2-ethyl-6,7-dimethyl-4-(4-methyl-benzoguanidino)-3,4-dihydro-2H-quinoxalinecarboxylate LC-MS (ESI+) : (MH+). Example 324 Team 〇

人 CHn 0^0 3 ^ch3 1285641 2-乙基-6,7-二甲基-4-(3,4,5-三甲氧基-苯甲醯基）-3,4-二氫-2H-喳喏 啉-1-羧酸乙酯 LC-MS (ESI+) ： 457 (MH+). 實例325Human CHn 0^0 3 ^ch3 1285641 2-Ethyl-6,7-dimethyl-4-(3,4,5-trimethoxy-benzylidene)-3,4-dihydro-2H- Ethyl porphyrin-1-carboxylate LC-MS (ESI+): 457 (MH+).

2-乙基_4-(異喹啉小羰基）-6,7-二甲基-3,4-二氫-2H-喹喏啉小羧酸 乙酯 LC-MS(ESI+)： 418 (MH+). 實例3262-Ethyl 4-(isoquinoline carbonyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline carboxylic acid ethyl ester LC-MS (ESI+): 418 (MH+ ). Example 326

4-(2,6-二甲基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏啉- 1-羧酸乙酯 LC-MS (ESI+) ： 395 (MH+). 實例327 -Ι^ά _ 12856414-(2,6-Dimethyl-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylate ethyl ester LC -MS (ESI+) : 395 (MH+). Example 327 -Ι^ά _ 1285641

4-(3,5-雙-三氟甲基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹 喏啉-1-羧酸乙酯 LC-MS (ESI+) ： 503 (MH+). 實例3284-(3,5-bis-trifluoromethyl-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid Ethyl ester LC-MS (ESI+): 503 (MH+). Example 328

ch3 4-苯甲醯基-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏啉-1-羧酸乙酯 LC-MS (ESI+) : 367 (MH+). 實例329Ch3 4-Benzylmercapto-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 367 (MH+ ). Example 329

4-(5-氯基-3-苯基-1H-吲哚-2-羰基）-2-乙基-6,7-二甲基-3,4-二氫-2H- 17奎嗅57林小夢复酸乙酉旨 1285641 LC-MS (ESI+) ： 517 (MH+). 實例3304-(5-Chloro-3-phenyl-1H-indole-2-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H- 17 quinolyl 57小梦 复酸乙酉1,285,541 LC-MS (ESI+): 517 (MH+). Example 330

2-乙基-4-(4’-氣-聯苯基-4-藏基）-6,7-二甲基-3,4-二氮-2H-P奎％ p林-1- 羧酸乙酯 LC-MS(ESI+)： 461 (MH+). 實例3312-ethyl-4-(4'-gas-biphenyl-4-carzyl)-6,7-dimethyl-3,4-diazo-2H-P-quine-p-lin-1-carboxylic acid Ethyl ester LC-MS (ESI+): 461 (MH+).

2-乙基-4-(3f-氟-聯苯基-4-羰基）-6,7-二甲基-3,4-二氫-2H-喳喏啉-1- 羧酸乙酯 LC-MS (ESI+) ·· 461 (MH+). 實例3322-ethyl-4-(3f-fluoro-biphenyl-4-carbonyl)-6,7-dimethyl-3,4-dihydro-2H-indolino-1-carboxylic acid ethyl ester LC- MS (ESI+) ·· 461 (MH+). Example 332

h3Ch3C

CK 92199 - 256 - 1285641 2-乙基-4-(2f-氟-聯苯基-3-羰基）-6,7-二甲基-3,4-二氫-2H-喳喏啉小 羧酸乙酯 LOMS(ESI+) : 461 (MH+). 實例333CK 92199 - 256 - 1285641 2-ethyl-4-(2f-fluoro-biphenyl-3-carbonyl)-6,7-dimethyl-3,4-dihydro-2H-carboline small carboxylic acid Ethyl ester LOMS (ESI+): 461 (MH+). Example 333

ch3 2-乙基-4-(3f-氣-聯^基-3-談基）-6,7-二甲基-3,4-二鼠奎哈淋-1- 羧酸乙酯 LC-MS (ESI+) ： 461 (ΜΗ+). 實例334Ch3 2-ethyl-4-(3f-gas-linked yl-3-yl)-6,7-dimethyl-3,4-dimuridine quinolate-1-carboxylate ethyl ester LC-MS (ESI+) : 461 (ΜΗ+). Example 334

2-乙基冰(4·-氟-聯苯基-3-羰基）-6,7_二甲基-3,4-二氫-2Η-喹喏啉小 羧酸乙酯 LC-MS (ESI+) : 461 (ΜΗ+)· 實例335 12856412-ethyl ice (4·-fluoro-biphenyl-3-carbonyl)-6,7-dimethyl-3,4-dihydro-2Η-quinoxaline small carboxylic acid ethyl ester LC-MS (ESI+ ) : 461 (ΜΗ+)· Example 335 1285641

ch3 2-乙基-6,7-二甲基冬([1，2,5]噻二唑-3-羰基）-3,4-二氫-2H-喹喏啉小 羧酸乙酯Ch3 2-ethyl-6,7-dimethyl winter ([1,2,5]thiadiazole-3-carbonyl)-3,4-dihydro-2H-quinoxaline small carboxylic acid ethyl ester

LC-MS (ESI+) : 375 _十). 實例336LC-MS (ESI+): 375 _ _). Example 336

2-乙基-6,7-二甲基-4-(2-吡唑小基-苯甲醯基）-3,4-二氫-2H-喹喏啉- 1-羧酸乙酯 LC-MS (ESI+) ： 433 (MH+). 實例3372-ethyl-6,7-dimethyl-4-(2-pyrazole small-benzylidene)-3,4-dihydro-2H-quinoxaline- 1-carboxylic acid ethyl ester LC- MS (ESI+): 433 (MH+). Example 337

2-乙基-6,7-二甲基-4-(4-吡唑小基-苯甲醯基）-3,4-二氫-2H-喹喏啉- rp 1 0Γ) -958 - 1285641 1-羧酸乙酯 LC-MS (ESI+) ： 433 (MH+). 實例338 H〕C h3c2-ethyl-6,7-dimethyl-4-(4-pyrazole small-benzylidene)-3,4-dihydro-2H-quinoxaline- rp 1 0Γ) -958 - 1285641 1-Carboxylic acid ethyl ester LC-MS (ESI+): 433 (MH+). Example 338 H] C h3c

2-乙基-6,7-二甲基-4-(3-苯基-異吟唑-5-羰基）-3,4-二氫_2H-喳喏啉- 1-羧酸乙酯 LC-MS (ESI+) ： 434 (MH+). 實例339Ethyl 2-ethyl-6,7-dimethyl-4-(3-phenyl-isoxazol-5-carbonyl)-3,4-dihydro-2H-porphyrin-1-carboxylate -MS (ESI+): 434 (MH+). Example 339

2-乙基-4-[5-(4-f氧基-苯基）-呋喃-2-羰基]-6,7-二甲基-3,4-二氫- 2H-喳喏啉-1-羧酸乙酯 LC-MS (ESI+) ： 463 (MH+). 實例340 09100 -7SQ - 12856412-ethyl-4-[5-(4-f-oxy-phenyl)-furan-2-carbonyl]-6,7-dimethyl-3,4-dihydro-2H-porphyrin-1 -Carboxylic acid ethyl ester LC-MS (ESI+): 463 (MH+). Example 340 09100 -7SQ - 1285641

2-乙基-6,7-二甲基-4-(2-曱基-5-丙基-纽-吡唑-3-羰基）-3,4~二氫-211- 。奎嗔4 ·1-複酸乙醋 LC-MS(ESI+)： 413 (MH+). 實例3412-ethyl-6,7-dimethyl-4-(2-indolyl-5-propyl-neu-pyrazole-3-carbonyl)-3,4-dihydro-211-. Kuitun 4 · 1-Resin Ethyl Acetate LC-MS (ESI+): 413 (MH+). Example 341

2-乙基-4-(5-乙基-2-甲基比唆-3-談基）-6,7-二甲基-3,4-二氫-2H- 喹喏啉-1-叛酸乙酯 LC-MS (ESI+) ： 399 (MH+). 實例3422-ethyl-4-(5-ethyl-2-methylpyridin-3-yl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-rebel Ethyl acetate LC-MS (ESI+): 399 (MH+). Example 342

2-乙基-6,7-二甲基-4十比唑并[l，5-a]喹啉·2,羰基）-3,‘二氫_2H-P奎喏 1285641 啉-1-羧酸乙酯 LC-MS (ESI+) : 457 (MH+). 實例3432-ethyl-6,7-dimethyl-4decazolo[l,5-a]quinoline·2,carbonyl)-3,'dihydro-2H-Pquinone 1285641 quinone-1-carboxylate Acid ethyl ester LC-MS (ESI+): 457 (MH+). Example 343

2-乙基-6,7-二甲基-4-(3-苯基-1H-啕哚-2-羰基）-3,4-二氫-2H-喳喏啉 -1-羧酸乙酯 LC-MS (ESI+) ： 482 (MH+). 實例344 0-CH3Ethyl 2-ethyl-6,7-dimethyl-4-(3-phenyl-1H-indole-2-carbonyl)-3,4-dihydro-2H-indololin-1-carboxylate LC-MS (ESI+): 482 (MH+). Example 344 0-CH3

2-乙基-4-[5-(4-甲氧基-苯基）-4吩-2-羰基]-6,7-二甲基-3,4-二氫- 2H-喹喏啉小羧酸乙醋 LC-MS (ESI+) ： 479 (MH+). 實例345 92199 -261 - 12856412-ethyl-4-[5-(4-methoxy-phenyl)-4 phen-2-carbonyl]-6,7-dimethyl-3,4-dihydro-2H-quinoxaline Ethyl acetate acetate LC-MS (ESI+): 479 (MH+). Example 345 92199 -261 - 1285641

ch3 4-(5-&gt;臭基-2-甲氧基比淀-3-談基）-2-乙基-6,7-二甲基-3,4-二氣-2H_ 4 p若17林小癸复酸乙酯 LOMS (ESI+) : 477 (MH+)· 實例346Ch3 4-(5-&gt;Smelly-2-methoxyl-butyl-3-yl)-2-ethyl-6,7-dimethyl-3,4-dialdehyde-2H_ 4 p17 Lin Xiaoyu Ethyl Ester LOMS (ESI+): 477 (MH+)· Example 346

2-乙基-4-(3-甲氧基-苯甲醯基）-6,7-二甲基-3,4-二氫-2H-喹喏啉小 羧酸乙酯2-ethyl-4-(3-methoxy-benzylidenyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline small carboxylic acid ethyl ester

LC-MS (ESI+) ： 397 (MH+). 實例347LC-MS (ESI+): 397 (MH+). 347

ch3 2-乙基斗(4-氟-苯甲醯基）-6,7-二甲基-3,4-二氫-2H-喹喏啉小羧酸 乙酯 - 262 - 1285641 LC-MS (ESI+) : 385 (MH+). 實例348Ch3 2-ethylidene (4-fluoro-benzhydryl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline small carboxylic acid ethyl ester - 262 - 1285641 LC-MS ( ESI+) : 385 (MH+). Example 348

2-乙基-6,7-二甲基-4-(5-甲基-3-苯基-異哼唑斗羰基）-3,4-二氫-2H- # 喹喏啉小羧酸乙酯 LC-MS (ESI+) ： 448 (MH+). 實例3492-ethyl-6,7-dimethyl-4-(5-methyl-3-phenyl-isoxazole carbonyl)-3,4-dihydro-2H-# quinoxaline small carboxylic acid Ester LC-MS (ESI+): 448 (MH+). Example 349

4-(2-氣-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喳喏啉-1-羧酸 乙I旨 LC-MS(ESI+)： 401 (MH+). 實例3504-(2-Gas-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-porphyrin-1-carboxylic acid B-LC (MS-MS) ESI+): 401 (MH+). Example 350

1285641 4-(4-氣-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-4喏啉小羧酸 乙醋 LC-MS (ESI+) ： 401 (MH+)· 實例3511285641 4-(4-Gas-benzylidene)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-4 porphyrin carboxylic acid ethyl acetate LC-MS (ESI+) : 401 (MH+)· Example 351

2-乙基-4-[2-(4-氟-苯甲醯基）-苯甲醯基]-6,7-二甲基-3,4-二氫-2H- 喳喏啉-1-羧酸乙酯 LC-MS (ESI+) ： 489 (MH+). 實例3522-ethyl-4-[2-(4-fluoro-benzhydryl)-benzylidenyl]-6,7-dimethyl-3,4-dihydro-2H-carboline-1- Ethyl Carboxylic Acid LC-MS (ESI+): 489 (MH+).

4-(2-溴-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喳喏啉小羧酸 乙醋 LC-MS (ESI+) ： 446 (MH+). 實例353 92199 - 264 - 12856414-(2-Bromo-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-carboline small carboxylic acid ethyl acetate LC-MS (ESI+): 446 (MH+). Example 353 92199 - 264 - 1285641

ch3 4-(2,4-二氯-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏啉小 羧酸乙酯 LC-MS (ESI+) ： 436 (MH+). 實例354Ch3 4-(2,4-Dichloro-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline small carboxylic acid ethyl ester LC-MS (ESI+) : 436 (MH+). Example 354

ch3 4-(3,4-二氯-苯甲驢基）-2-乙基-6,7-二甲基-3,4-二氮每淋* 1-羧酸乙酯 LC-MS (ESI+) ： 436 (MH+)· 實例355Ch3 4-(3,4-Dichloro-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-diaza perpin * 1-carboxylic acid ethyl ester LC-MS (ESI+ ) : 436 (MH+)· Example 355

ch3 4-(4-乙氧基苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏啉小 92199 - 265 - 1285641 羧酸乙酯 LC-MS(ESI+)： 411 (MH+). 實例356Ch3 4-(4-ethoxybenzimidyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline small 92199 - 265 - 1285641 ethyl carboxylate LC-MS (ESI+): 411 (MH+).

ch3 2-乙基-6,7-二甲基斗(4-甲硫基-苯曱醯基）-3,4-二氫-2H-喹喏啉小 羧酸乙酯 LC-MS (ESI+) ： 413 (MH+). 實例357 ?h3Ch3 2-ethyl-6,7-dimethylpipe (4-methylthio-benzoinyl)-3,4-dihydro-2H-quinoxaline small carboxylic acid ethyl ester LC-MS (ESI+) : 413 (MH+). Example 357 ?h3

ch3 4-(4-氯基-2-甲氧基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-4 喏啉-1-羧酸乙酯 LC-MS(ESI+) ： 431 (MH+). ♦ 實例358 92199 - 266 - 1285641Ch3 4-(4-Chloro-2-methoxy-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-4 porphyrin-1-carboxylate Acid ethyl ester LC-MS (ESI+): 431 (MH+). ♦ Example 358 92199 - 266 - 1285641

4-(2-乙氧基苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏啉小 羧酸乙酯4-(2-ethoxybenzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline small carboxylic acid ethyl ester

LC-MS(ESI+)： 411 (MH+). 實例359LC-MS (ESI+): 411 (MH+).

CICI

入CH] ^CH3 4-(2,3-二氯-苯曱醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏啉小Into CH] ^CH3 4-(2,3-Dichloro-phenylindenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline

羧酸乙酯 LC-MS (ES—I+) : 436 (MH+). 實例360Ethyl Carboxylic Acid LC-MS (ES-I+): 436 (MH+). Example 360

2-乙基-6,7-二甲基-4七塞吩-3-羰基）-3,4-二氫-2Hm音喏啉小羧酸乙酯 92199 - 267 - 1285641 LC-MS (ESI+) : 373 (MH+). 實例361Ethyl 2-ethyl-6,7-dimethyl-4heptaphen-3-carbonyl)-3,4-dihydro-2Hm phonoline small carboxylic acid 92199 - 267 - 1285641 LC-MS (ESI+) : 373 (MH+). Example 361

^ch3 4-(2,3-二氟-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏啉-1- 羧酸乙酯 LC-MS (ESI+) ： 403 (MH+). 實例362^ch3 4-(2,3-Difluoro-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 403 (MH+). Example 362

2-乙基冬(4:氣-莕小羰基）-6,7-二甲基-3,4-二氫-2H-喹喏啉小羧酸 乙酉旨 LC-MS (ESI+) ·· 435 (MH+). 實例3632-ethyl winter (4: gas-hydrazine small carbonyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline small carboxylic acid ethyl acetate LC-MS (ESI+) ·· 435 ( MH+). Example 363

92199 - 268 - 128564192199 - 268 - 1285641

2-乙基-6,7-二甲基-4-(4-三氟甲氧基-苯甲醯基）-3,4-二氫-2H-喹喏 LC-MS (ESI+): 啉小羧酸乙酯 451 (MH+). 實例364 。梦F :錢 〇人A 2-乙基-4-(2-氟基斗三氟曱基-苯曱醯基）-6,7-二甲基-3,4-二氫-2H. LC-MS (ESI+)： 喹喏啉小羧酸乙酯 453 (MH+). 實例365 F — .：xx；V 。人Λ 4-(2,5-雙-三氟甲基-苯甲醯基）冬乙基-6,7-二甲基-3,4-二氫-2Hw奎 LC-MS (ESI+)： 喏啉-1-羧酸乙酯 503 (MH+). 實例366 92199 - 269 - 12856412-ethyl-6,7-dimethyl-4-(4-trifluoromethoxy-benzylidene)-3,4-dihydro-2H-quinoline LC-MS (ESI+): small porphyrin Ethyl carboxylate 451 (MH+). Example 364. Dream F: Qian Qiren A 2-ethyl-4-(2-fluoropiperidinyl-phenylindoleyl)-6,7-dimethyl-3,4-dihydro-2H. LC- MS (ESI+): quinoxaline carboxylic acid ethyl ester 453 (MH+). </RTI> </RTI> </RTI> <RTIgt; 4-(2,5-Bis-trifluoromethyl-benzylidene)-ethyl-ethyl, 7,7-dimethyl-3,4-dihydro-2Hw-yue LC-MS (ESI+): 喏Ethyl phthalate-1-carboxylate 503 (MH+). Example 366 92199 - 269 - 1285641

ch3 2-乙基-4-(2-氣基-6-二氣甲基-本甲驢基）-6,7-二甲基-3,4-二鼠-2H- 喳喏啉小羧酸乙酯 LC-MS (ESI+) ： 453 (MH+). · 實例367Ch3 2-ethyl-4-(2-carbyl-6-dimethyl-methylcarbamoyl)-6,7-dimethyl-3,4-dimur-2H-porphyrin small carboxylic acid Ethyl ester LC-MS (ESI+): 453 (MH+). · Example 367

FF

ch3 2-乙基-4-(3-氟基-2-甲基-苯曱醯基）-6,7-二甲基-3,4-二氫-2H-喹喏Ch3 2-ethyl-4-(3-fluoro-2-methyl-phenylhydrazino)-6,7-dimethyl-3,4-dihydro-2H-quinoline

淋-1-致酸乙酉旨 LC-MS (ES1+) ： 399 (MH+). 實例368LC-MS (ES1+): 399 (MH+). Example 368

FF

CH3 4-(2,4-二氯-5-氟-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喳喏 92199 - 270 - 1285641 啉小羧酸乙酯 LC-MS (ESI+) ： 454 (MH+)· 實例369CH3 4-(2,4-Dichloro-5-fluoro-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-喳喏92199 - 270 - 1285641 Ethyl phthalate small carboxylic acid LC-MS (ESI+): 454 (MH+)· Example 369

ch3 2-乙基-6,7-二甲基-4-(2,4,6-三氟-苯甲醯基）-3,4-二氫-2H-喹喏啉小 羧酸乙酯 LC-MS (ESI+) ： 421 (MH+). 實例370Ch3 2-ethyl-6,7-dimethyl-4-(2,4,6-trifluoro-benzylidenyl)-3,4-dihydro-2H-quinoxaline small carboxylic acid ethyl ester LC -MS (ESI+): 421 (MH+). Example 370

2-乙基-4-(5-氟基-2-甲基-苯曱醯基）-6,7-二甲基-3,4-二氫-2H-喹喏 啉小羧酸乙酯 LC-MS (ESI+) ： 399 (MH+). 實例371 92199 -271 - 12856412-ethyl-4-(5-fluoro-2-methyl-phenylhydrazino)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline small carboxylic acid ethyl ester LC -MS (ESI+): 399 (MH+). Example 371 92199 -271 - 1285641

ch3 2-乙基斗(2-氟基-5-甲基-苯甲醯基）-6,7-二甲基-3,4-二氫-2H-喹喏 p林-1-竣故乙酉旨 LC-MS (ESI+) ： 399 (MH+). 實例372 · h3c h3cCh3 2-ethyl phenyl (2-fluoro-5-methyl-benzoguanidino)-6,7-dimethyl-3,4-dihydro-2H-quinoline p--1- 竣LC-MS (ESI+): 399 (MH+). Example 372 · h3c h3c

4-(5-&gt;臭塞吩-2-藏基）-2-乙基-6,7-二甲基-3,4-二氮p林-1-幾 酸乙酯4-(5-&gt;oxe-2-phenyl)-2-ethyl-6,7-dimethyl-3,4-diaza-p-lin-1-carboxylic acid ethyl ester

LC-MS (ESI+) ： 452 (MH+). — 實例373LC-MS (ESI+): 452 (MH+). - Example 373

4-(4-二氟甲氧基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏 啉小羧酸乙酯 92199 - 272 - 1285641 LC-MS (ESI+) : 433 (MH+). 實例3744-(4-Difluoromethoxy-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline small carboxylic acid ethyl ester 92199 - 272 - 1285641 LC-MS (ESI+) : 433 (MH+). Example 374

ch3 4-(2,6-二甲氧基-苯曱醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏 啉-1-羧酸乙酯 LC-MS (ESI+) ： 427 (MH+). 實例375Ch3 4-(2,6-Dimethoxy-phenylhydrazino)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid Ester LC-MS (ESI+): 427 (MH+). Example 375

2-乙基-6,7-三甲基-4-(4-甲基-莕小羰基）-3,4-二氫-2H-喳喏啉小羧 酸乙酯 LC-MS(ESI+): 431(MH+). 實例376Ethyl 2-ethyl-6,7-trimethyl-4-(4-methyl-indole carbonyl)-3,4-dihydro-2H-carbolinecarboxylate LC-MS (ESI+): 431 (MH+). Example 376

CH 92199 - 273 - 1285641 4-(3-氯基-2,6-二甲氧基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫- 2H-喹喏啉小羧酸乙酯 LC-MS (ESI+) ： 461 (MH+). 實例377CH 92199 - 273 - 1285641 4-(3-Chloro-2,6-dimethoxy-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H - quinoxaline small carboxylic acid ethyl ester LC-MS (ESI+): 461 (MH+).

H3C&gt;V^v^N&gt;“XX CI 0H3C&gt;V^v^N&gt;"XX CI 0

0 人。CH30 people. CH3

4-(3-氣基-2-氣-冬甲驢基）-2-乙基-6,7-二甲基-3,4-二鼠-211-3奎p若琳- 1-羧酸乙酯 LC-MS (ESI+) ： 419 (MH+). 實例3784-(3-carbyl-2-a-methylenemethyl)-2-ethyl-6,7-dimethyl-3,4-dimur-211-3 quinone-l-carboxylic acid Ethyl ester LC-MS (ESI+): 419 (MH+).

4-(3-氯-嘍吩-2-羰基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏啉-1-羧 酸乙酯 LC-MS (ESI+) ： 407 (MH+). 實例379 92199 - 274 - 1285641 H^C h3c4-(3-Chloro-nonyl-2-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester LC-MS (ESI+): 407 (MH+). Example 379 92199 - 274 - 1285641 H^C h3c

2-乙基-6,7-二甲基斗(2-三氟甲氧基-苯甲醯基）-3,4-二氫-2H-喹喏 淋-l-致酸乙酯 LC-MS(ESI+)： 451 (MH+). 實例3802-ethyl-6,7-dimethylpipe (2-trifluoromethoxy-benzylidene)-3,4-dihydro-2H-quinoxaline-l-acid ethyl ester LC-MS (ESI+): 451 (MH+). Example 380

H,CH, C

CH， ch3 2-乙基-6,7-二甲基-4-(5-甲基-異p亏吐-3-談基）-3,4-二鼠奎嘆g林 1-羧酸乙酯 LC-MS (ESl+) ： 372 (MH+). 實例381 h3cCH, ch3 2-ethyl-6,7-dimethyl-4-(5-methyl-iso-p-sodium-3-yl)-3,4-dimurium sin g-lin 1-carboxylic acid Ester LC-MS (ESl+): 372 (MH+). Example 381 h3c

'CHn 2-乙基-6,7-二甲基-4-(3-甲基-呋喃-2-羰基）-3,4-二氫-2H-4喏啉小 92199 - 275 - 1285641 羧酸乙酯 LC-MS(ESR)： 371 (MH+). 實例382'CHn 2-ethyl-6,7-dimethyl-4-(3-methyl-furan-2-carbonyl)-3,4-dihydro-2H-4 porphyrin small 92199 - 275 - 1285641 carboxylic acid Ethyl ester LC-MS (ESR): 371 (MH+). Example 382

ch3Ch3

4-(4-溴基-2-甲基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏 淋-1-幾酸乙S旨 LC-MS (ESI+) ： 460 (MH+). 實例3834-(4-bromo-2-methyl-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-acid B S-LC-MS (ESI+): 460 (MH+). Example 383

4-(4-溴基冬氯-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏啉- 1-羧酸乙酯 LC-MS (ESI+) ·· 480 (MH+). 實例384 92199 - 276 - 12856414-(4-Bromo-tungyl-benzylidene)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline- 1-carboxylic acid ethyl ester LC- MS (ESI+) ·· 480 (MH+). Example 384 92199 - 276 - 1285641

ch3 4-(4-&gt;臭基-3-甲基-苯甲醒基）-2-乙基-6,7-二曱基-3,4-二鼠-2H-^味 ' 你-1-竣酸乙@旨 LC-MS (ESI+) ： 460 (MH+). 實例385Ch3 4-(4-&gt;Smelly-3-methyl-benzamide)-2-ethyl-6,7-dimercapto-3,4-dimur-2H-^味' you-1 - 竣 乙 B @ LC-MS (ESI+): 460 (MH+). Example 385

4-(5-氯-噻吩-2-羰基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏啉小羧 酸乙酯 LC-MS (ESI+) ： 407 (MH+). 實例386Ethyl 4-(5-chloro-thiophene-2-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxalinecarboxylate LC-MS (ESI+) : 407 (MH+). Example 386

4-(3-芊氧基-4-甲氧基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H- 92199 -277 - 1285641 LC-MS (ESI+): 喹喏啉小羧酸乙酯 503 (ΜΗ+). 實例387 ¥、。 〇Α3 :xxV 。人。ch] 4-(3,5-二甲氧基-4-甲基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫- 2H-喹喏啉小羧酸乙酯 LC-MS (ESI+)： 441 (MH+). 實例388 vCP :職 -人 ch3 ch3 4-(苯并[b]p塞吩-2-藏基）-2-乙基-6,7-二甲基-3,4-二氮-2H-p奎％ ρ林-1 LC-MS (ESI+): 羧酸乙酯 423 (MH+). 實例389 92199 -278 - 12856414-(3-decyloxy-4-methoxy-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H- 92199 -277 - 1285641 LC- MS (ESI+): quinoxaline small carboxylic acid ethyl ester 503 (ΜΗ+). 〇Α3 : xxV. people. Ch] 4-(3,5-Dimethoxy-4-methyl-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline Small Carboxylic Acid Ethyl Ester LC-MS (ESI+): 441 (MH+). Example 388 vCP: O-Human ch3 ch3 4-(Benzo[b]p-sept-2-phenyl)-2-ethyl-6 , 7-Dimethyl-3,4-diaza-2H-p-quinion ρ-lin-1 LC-MS (ESI+): carboxylic acid ethyl ester 423 (MH+). Example 389 92199 -278 - 1285641

^ch3 h3c^ch3 h3c

HnC 入 4-(4-氯基-3-甲基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏 淋-1-幾酸乙酯 LC-MS (ESI+) ： 415 (MH+). 實例390HnC into 4-(4-chloro-3-methyl-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1- Acid ethyl ester LC-MS (ESI+): 415 (MH+). Example 390

HXHX

、CH， C! 4-(2-溴基斗氯-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喳喏啉 1-羧酸乙酯 LC-MS (EST+) ： 480 (MH+)· 實例391,CH, C! 4-(2-Bromopiperidinyl-benzylidene)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-carboline 1-carboxylic acid Ethyl ester LC-MS (EST+) : 480 (MH+)· Example 391

h3c HXH3c HX

4-(2-溴基-3-甲基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-4喏 92199 - 279 - 1285641 4 -1-叛酸乙酯 LC-MS (ESI+) : 460 (MH+)· 實例3924-(2-Bromo-3-methyl-benzhydryl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-4喏92199 - 279 - 1285641 4 - 1-Resinic acid ethyl ester LC-MS (ESI+): 460 (MH+)· Example 392

ch3 4-(2-溴基-5-甲基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏 啉-1-羧酸乙酯 LC-MS (ESI+) ： 460 (MH+). 實例393Ch3 4-(2-Bromo-5-methyl-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid Ethyl ester LC-MS (ESI+): 460 (MH+). Example 393

BrBr

^CH3 人CH- 4-(3-溪基-2-甲基-苯甲龜基）-2-乙基-6,7-二甲基-3,4-二氯奎诺 啉-1-羧酸乙酯 LC-MS (ESI+) ： 460 (MH+). 實例394 92199 -280- 1285641^CH3 Human CH- 4-(3-xiry-2-methyl-benzylidene)-2-ethyl-6,7-dimethyl-3,4-dichloroquinolino-1-carboxylate Ethyl acetate LC-MS (ESI+): 460 (MH+). Example 394 92199 -280 - 1285641

CH3 4-(2-氯基-4,5-二甲氧基-苯甲驢基）-2-乙基-6,7-二甲基-3,4-二氯- 2H-喹喏啉小羧酸乙酯 LC-MS (ESI+) ： 461 (MH+). 實例395CH3 4-(2-Chloro-4,5-dimethoxy-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dichloro-2H-quinoxaline Ethyl Carboxylic Acid LC-MS (ESI+): 461 (MH+). Example 395

4-(7-乙氧基苯并呋喃-2-羰基）-2-乙基-6,7-二甲基-3,4-二氫-2H-峻 喏啉-1-羧酸乙酯 LC-MS(ESI+)： 451 (MH+). 實例396Ethyl 4-(7-ethoxybenzofuran-2-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-junphyrin-1-carboxylate -MS(ESI+): 451 (MH+). Example 396

2-乙基-6,7-二甲基斗[2-(1-苯基-乙基胺甲醯基）-苯甲醯基）-3,4-二 92199 -281 - 1285641 LC-MS (ESI+) 氫-2H-喳喏啉小羧酸乙酯 ：514 (MH+). 實例3972-ethyl-6,7-dimethylpipe [2-(1-phenyl-ethylaminemethylmercapto)-benzylidene)-3,4-di 92199-281 - 1285641 LC-MS ( ESI+) Hydrogen-2H-carboline ethyl carboxylic acid ethyl ester: 514 (MH+). Example 397

4-(苯并[1，3]二 LC-MS (ESI+) 氧伍圜烯-5-羰基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹喏啉-1-羧酸乙酯 ：411 (MH+). 實例398 h3c h3c4-(Benzo[1,3]diLC-MS (ESI+) oxolene-5-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quin Ethyl porphyrin-1-carboxylate: 411 (MH+). Example 398 h3c h3c

ch3 4-(4-第三-丁基 LC-MS (ESI+) -苯甲酿基）-2-乙基-6,7-二甲基-3,4-二氮-2H-^诺淋 -1-羧酸乙酯 ：423 (MH+). 實例399 92199 -282- 1285641Ch3 4-(4-Terti-butyl LC-MS (ESI+)-benzyl)-2-ethyl-6,7-dimethyl-3,4-diaza-2H-^Noprine- Ethyl 1-carboxylate: 423 (MH+). Example 399 92199 -282- 1285641

ch3 2-乙基-6,7-二〒基-4-(2-冬氧基-本曱醒基）-3,4-&lt;一鼠哈淋-1- 羧酸乙酯 LC-MS (ESI+) ： 459 (MH+). 實例400Ch3 2-ethyl-6,7-dimercapto-4-(2-butoxy-benzamide)-3,4-&lt;one rat halal-1-carboxylic acid ethyl ester LC-MS ( ESI+) : 459 (MH+). Example 400

4-(3,5-雙-三氟甲基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喹 喏啉小羧酸乙酯 LC-MS (ESI+) ： 503 (MH+). 實例4014-(3,5-bis-trifluoromethyl-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline small carboxylic acid ethyl ester LC-MS (ESI+): 503 (MH+). Example 401

4-(3,5-雙-三氣甲基•苯甲酿基）-2-乙基-6,7-&lt;一甲基-3,4-二氮-2H-口奎 92199 - 283 - 1285641 喏啉小羧酸乙酯 LC-MS (ESI+) : 503 (MH+). 實例4024-(3,5-bis-trimethylmethyl•benzyl)-2-ethyl-6,7-&lt;-methyl-3,4-diaza-2H-mouth kull 92199-283 1285641 Ethyl porphyrin carboxylic acid LC-MS (ESI+): 503 (MH+).

2-乙基-6,7-二甲基-4-(1-甲基-1H-吲哚-2-羰基）-3,4-二氫-2H-喹喏啉 小羧酸乙酯 LC-MS (ESI+) ： 420 (MH+). 實例4032-ethyl-6,7-dimethyl-4-(1-methyl-1H-indole-2-carbonyl)-3,4-dihydro-2H-quinoxaline small carboxylic acid ethyl ester LC- MS (ESI+): 420 (MH+). Example 403

4-(苯并[b]噻吩-3-羰基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喳喏啉小 羧酸乙酯 LC-MS (ESI+) ： 423 (MH+). 實例404 92199 - 284 - 12856414-(Benzo[b]thiophene-3-carbonyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-carboline ethyl carboxylate LC-MS (ESI+ ) : 423 (MH+). Example 404 92199 - 284 - 1285641

〇、 /0〇, /0

2-乙基-4-(2-甲氧基-苯甲醯基）-6,7-二甲基-3,4-二氫-2H-喹喏啉-1· 羧酸乙酯 LC-MS (ESI+) ： 3977 (ΜΗ+). 實例405Ethyl 2-ethyl-4-(2-methoxy-benzylidenyl)-6,7-dimethyl-3,4-dihydro-2H-quinoxaline-1·carboxylate LC-MS (ESI+) : 3977 (ΜΗ+). Example 405

4-(2,3-二甲基-苯甲醯基）-2-乙基-6,7-二曱基-3，4-二氫-2H-喹喏啉- 1-羧酸乙酯 LC-MS (ESI+) : 395 (MH+)· 實例406 92199 - 285 - 12856414-(2,3-Dimethyl-benzylidenyl)-2-ethyl-6,7-diamidino-3,4-dihydro-2H-quinoxaline- 1-carboxylic acid ethyl ester LC -MS (ESI+): 395 (MH+)· Example 406 92199 - 285 - 1285641

4-(2,4-二甲基-苯甲醯基）-2-乙基-6,7-二甲基-3,4-二氫-2H-喳喏啉- 1-羧酸乙酯 LC-MS (ESI+) : 395 (ΜΗ+)· 實例407 #4-(2,4-Dimethyl-benzylidenyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-carboline-carboxylate ethyl ester LC -MS (ESI+) : 395 (ΜΗ+)· Example 407 #

4-(2,5-二甲基•苯甲驢基）-2-乙基-6,7-二甲基-3,4-二鼠-2Η-ρ奎哈淋- 1-羧酸乙酯 LC-MS (ESI+) ： 395 (ΜΗ+). 實例4084-(2,5-Dimethylbenzylidene)-2-ethyl-6,7-dimethyl-3,4-dimur-2Η-ρ 奎a-ethyl 1-carboxylate LC-MS (ESI+): 395 (ΜΗ+). Example 408

2-乙基-4-(4-甲氧基-3-甲基-苯甲醯基）-6,7-二曱基-3,4-二氫-2Η-喹 喏啉-1-羧酸乙酯 Q91QQ - 286 - 1285641 LC-MS(ESI+)： 411 (MH+). 實例4092-ethyl-4-(4-methoxy-3-methyl-benzylidenyl)-6,7-dimercapto-3,4-dihydro-2-indole-quinoxaline-1-carboxylic acid Ethyl ester Q91QQ - 286 - 1285641 LC-MS (ESI+): 411 (MH+). Example 409

4-(3,5-雙-三氟甲基-罕基）-2-乙基-6,7-二甲基-3,4-二氫-2H-峻喏琳、· 1-羧酸乙酯之製備 將2-乙基-6,7-二甲基-3,4-二氫-2H·^奎嗅淋小叛酸乙g旨（0 05克， 1當量，0.19毫莫耳）、3,5-雙-(三氟甲基）溴化苄（〇·038毫升，2.2 當量，0·42毫莫耳）及三乙胺（0.062毫升，3當量，〇·57毫莫耳） 在乙腈（2毫升）中之溶液，以催化用琪化卸處理，並在4-(3,5-bis-trifluoromethyl-hanyl)-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-junine, 1-carboxylic acid B The preparation of the ester will be 2-ethyl-6,7-dimethyl-3,4-dihydro-2H·^ 嗅 嗅 小 小 叛 ( ( (0 05 g, 1 equivalent, 0.19 mmol), 3,5-bis-(trifluoromethyl)benzyl bromide (〇·038 ml, 2.2 eq, 0·42 mmol) and triethylamine (0.062 ml, 3 equivalents, 〇·57 mmol) a solution in acetonitrile (2 ml), which is catalyzed by catalysis, and

Emrys Optimizer (Personal 化學，Uppsala，Sweden)上，於 180〇C 下，使 其接受兩次二十分鐘循環化學微波。使反應物蒸發至乾酒 ，並於Shimadzu公司（Kyoto, Japan)預備之HPLC系統上，使用40· _ 100%乙腈/水純化，6分鐘梯度液，8分鐘總操作時間，提 供標題化合物（0.0045毫克，5% )。 1H NMR (CDC13) ： (5 0.90 (t, J=7.47Hz, 3H), 1.31 (ty J=7.05Hz, 3H), 1.46 (m，2H)，2·11 (s，3H)，2·16 (s，3H)，3.17 (dd，J=1L28, 1·24Ηζ，1H)，3·49 (dd， 11.16, 4.15Hz，1H)，4·19 (m，1H)，4.28 (m，1H)，4·46 (d，J=17.43Hz)，4.52 (m， 1H)，4.66 (d，J=17.01Hz，1H)，6·31 (s，1H)，7.29 (brs，1H)，7.71 (s，2H)，7.78 (s， 1H). LCMS (ESI+) : 489 (MH+). &gt; 287 - 1285641 ^/ 、士所述之方法，藉由解析 預告實例410-427可使用類似本又中所 L + L 士 +仏七甘入★ 士之中間物’製成光學上 所指示之相應外消從物或其合成中&amp; 冨含形式： 實例410 (實例2之立體異構物）Emrys Optimizer (Personal Chemistry, Uppsala, Sweden) was subjected to two twenty minute cycles of chemical microwaves at 180 °C. The reaction was evaporated to dryness and purified eluting with EtOAc EtOAc (EtOAc) Mg, 5%). 1H NMR (CDC13): (5 0.90 (t, J=7.47Hz, 3H), 1.31 (ty J=7.05Hz, 3H), 1.46 (m, 2H), 2·11 (s, 3H), 2·16 (s,3H), 3.17 (dd, J=1L28, 1·24Ηζ, 1H), 3·49 (dd, 11.16, 4.15Hz, 1H), 4·19 (m, 1H), 4.28 (m, 1H) , 4·46 (d, J = 17.43 Hz), 4.52 (m, 1H), 4.66 (d, J = 17.01 Hz, 1H), 6·31 (s, 1H), 7.29 (brs, 1H), 7.71 ( s, 2H), 7.78 (s, 1H). LCMS (ESI+): 489 (MH+). &gt; 287 - 1285641 ^/, the method described by the method, by parsing the notice example 410-427 can be used similar to this L + L 士 + 仏 七 甘 甘 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士 士

供，11)-4-[(3,5-雙-三氟曱基-苯基）-羥基-甲氧羰基-甲基]-2-乙基-6-三氟甲基-2H-喹啉-1-羧酸乙酯； (R，S)-4-[(3,5-雙-三氟甲基-苯基）-羥基-甲氧羰基甲基&gt;2,乙基 6-三氟甲基-2H-喹啉小羧酸乙酯； (S，R)-4-[(3,5-雙-三氟甲基-苯基）-羥基-甲氧基碳呷基]_2-乙基· 6-三氟甲基-2H-喹啉小羧酸乙酯；或 (3,3)冰[(3,5-雙-三氟甲基-苯基)-羥基-甲氧基硬_甲基]_2_乙基_6 三氟甲基-2H-喹啉小羧酸乙酯； 或該化合物之藥學上可接受鹽。 實例411 (實例3與4之立體異構物）,11)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methoxycarbonyl-methyl]-2-ethyl-6-trifluoromethyl-2H-quinoline Ethyl-1-carboxylate; (R,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methoxycarbonylmethyl&gt;2, ethyl 6-trifluoro Methyl-2H-quinoline small carboxylic acid ethyl ester; (S,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methoxycarbenyl]_2-B Ethyl 6-trifluoromethyl-2H-quinoline carboxylic acid ethyl ester; or (3,3) ice [(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methoxy hard _ Methyl]_2-ethyl_6 trifluoromethyl-2H-quinoline small carboxylic acid ethyl ester; or a pharmaceutically acceptable salt of the compound. Example 411 (stereoisomers of Examples 3 and 4)

92199 288 - 1285641 氟 (S，S)冬[(3&gt;雙 '三氟甲基-苯基氧羰基-f基]-2-乙基冬, 甲基酸4 ;或該化合物之藥學上可接受鹽 具例412 (貫例5、6、7及8之立體異構物）92199 288 - 1285641 Fluorine (S,S) winter [(3&gt; bis-trifluoromethyl-phenyloxycarbonyl-fyl]-2-ethyl winter, methyl acid 4; or the pharmaceutically acceptable compound Salt 412 (stereoisomers of Examples 5, 6, 7 and 8)

氟甲基-3,4-二氫-2H-喹啉+羧酸乙g旨； (1^，幻冬[(3,5-雙-三氟甲基-苯基）_甲氧羰基_甲基卜2_乙基_6 氣甲基一氮-2H-p奎啦-1-羧酸乙酉旨； (11，11，3&gt;4-[(3,5-雙-二氟甲基-苯基）-甲氧羰基-甲基]1乙基_6 氟甲基-3,4-二氫-2H·喹啉_1_羧酸乙酯； (R，R，R)冰[(3,5-雙-三氟甲基-苯基）-甲氧羰基呷基碎乙基_6•三 氟甲基-3,4-二氫-2H-喹啉-1-羧酸乙酯； (S，S，R)-4-[(3,5-雙-三氟甲基-苯基）-甲氧羰基砰基碎乙基各三 氟甲基-3,4-二氫-2H-喹啉小羧酸乙酯； (S，S，S)-4-[(3,5-雙-三氟甲基-苯基）-甲氧羰基-甲基]_2_乙基各三 氟甲基-3,4-二氫-2H-喳淋-1-羧酸乙酯； 仏^^冰旧^-雙-王氟甲基-苯基:^甲氧羰基-甲基碎乙基冬三 氟甲基-3,4-二氫-2H-喹啉小羧酸乙酯；或 92199 - 289 - 1285641 (s，R，R)-4-[(3,5-雙-三氟甲基-苯基）-甲氧羰基-甲基]-2_乙基·6 氟甲基-3,4-二氫-2扎喹啉小羧酸乙酯；或 該化合物之藥學上可接受鹽。 實例4丨3 (實例9與10之立體異構物）Fluoromethyl-3,4-dihydro-2H-quinoline + carboxylic acid B g; (1^, Fantasia [(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl] Keb 2_ethyl_6 gas methyl-nitro-2H-p-quile-1-carboxylic acid ethyl ester; (11,11,3&gt;4-[(3,5-bis-difluoromethyl-benzene) (), methoxycarbonyl-methyl]1 ethyl_6 fluoromethyl-3,4-dihydro-2H.quinoline-1-carboxylic acid ethyl ester; (R, R, R) ice [(3, 5-bis-trifluoromethyl-phenyl)-methoxycarbonylmercaptoethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; (S ,S,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonylmercaptoethylidene trifluoromethyl-3,4-dihydro-2H-quinoline Small carboxylic acid ethyl ester; (S,S,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]_2-ethyltrifluoromethyl- 3,4-Dihydro-2H-indole-1-carboxylic acid ethyl ester; 仏^^冰旧^-bis-wang fluoromethyl-phenyl: ^methoxycarbonyl-methyl-ethylidene trifluoromethyl Ethyl-3,4-dihydro-2H-quinolinecarboxylic acid ethyl ester; or 92199 - 289 - 1285641 (s,R,R)-4-[(3,5-bis-trifluoromethyl-phenyl) )-methoxycarbonyl-methyl]-2_ethyl·6 fluoromethyl-3,4-dihydro-2 zaquinoline small carboxylic acid ethyl ester; or pharmaceutics of the compound Acceptable salts. Example 4丨3 (stereoisomers of Examples 9 and 10)

(R，R，R)斗[(3,5-雙-三氟甲基-苯基）-氰基-甲基]-2-乙基士三氣甲 基-3,4-二氫-2H-喹啉小羧酸乙酯； (11，11，3)-4-[(3,5-雙-三氟甲基-苯基）-氰基呷基]-2-乙基各三氣甲 基-3,4-二鼠-2Η-^淋-1-竣fee乙酉旨， (R，S，R)-4-[(3,5-雙-三氟甲基-苯基）-氰基-甲基&gt;2-乙基-6·三氣甲 基-3,4-二氫-2H-喹啉小羧酸乙酯； (R，S，S)-4-[(3,5-雙-三氟甲基-苯基）-氰基-甲基&gt;2-乙基-6_三氣甲 基-3,4-二氫-2H-喳啉小羧酸乙醋； (3,3,3)-4-[(3,5-雙-三氟甲基-苯基）-氰基-甲基]:乙基_6_三氣甲 基-3,4-二氫-2H-喳啉小羧酸乙酯； 92199 - 290 - 1285641 (S，S，R)-4-[(3,5-雙-三氟甲基-苯基）-氰基-甲基]_2_乙基三氣甲 基-3,4-二氮-2H-峻17林-1-叛酸乙醋； 6，11，11)-4-[(3,5-雙-三氟甲基-苯基）-氰基-甲基1二乙其 恭二氟甲基-3,4-二氫-2Η-喹淋-1-羧酸乙酯； (3，11，11)-4-[(3,5-雙-三氟甲基-苯基）-氰基-甲基]-2_乙基_6：:：/^ 一'氣甲 基-3,4-二鼠-2Η-峻琳-1-瘦酸乙|旨； 4-[(3,5-雙-三氟甲基-苯基）-氰基-甲基]-2-乙基 喳啉小羧酸乙酯； 氟甲基-2H- (R，S)-4-[(3,5-雙-三氟甲基-苯基）-氰基-甲基]_2-乙基二 -2H-p奎α林-1 -幾酸乙酉旨； /SL 、 鼠甲基 (R，R)_4-[(3,5-雙-三氟T基-苯基）-氰基岬基]_2_乙基·6•:々 一*氣T基 奎淋-1-幾酸乙酉旨； (S，R)-4-[(3,5-雙-三氟甲基-苯基）-氰基-甲基降乙基·&amp;三 -2H-喳啉-1-羧酸乙酯；或 氟甲基 (S，S)-4-[(3,5-雙-三氟甲基-苯基）-氰基-甲基]-2_乙基_6•三^ '裂》甲基 2Η-喳啉-1-羧酸乙酯； 或該化合-物之藥學上可接受鹽。 實例414 (實例13與14之立體異構物）(R,R,R) bucket [(3,5-bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethylste-trimethyl-3,4-dihydro-2H - quinoline small carboxylic acid ethyl ester; (11,11,3)-4-[(3,5-bis-trifluoromethyl-phenyl)-cyanoindolyl]-2-ethyl each three gas -3-3,4-二鼠-2Η-^淋-1-竣fee 酉, (R,S,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-cyano -methyl&gt;2-ethyl-6.trimethylmethyl-3,4-dihydro-2H-quinolinecarboxylic acid ethyl ester; (R,S,S)-4-[(3,5- Bis-trifluoromethyl-phenyl)-cyano-methyl&gt; 2-ethyl-6-tris-methyl-3,4-dihydro-2H-carboline small carboxylic acid ethyl acetate; (3, 3,3)-4-[(3,5-bis-trifluoromethyl-phenyl)-cyano-methyl]:ethyl_6_trismethyl-3,4-dihydro-2H- Porphyrin small carboxylic acid ethyl ester; 92199 - 290 - 1285641 (S,S,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-cyano-methyl]_2-ethyl Tris-methyl-3,4-diaza-2H-jun 17-lin-1-resinic acid vinegar; 6,11,11)-4-[(3,5-bis-trifluoromethyl-phenyl) -Cyano-methyl 1 diethyl keto difluoromethyl-3,4-dihydro-2-indole-quinoline-1-carboxylic acid ethyl ester; (3,11,11)-4-[(3,5- Bis-trifluoromethyl-phenyl)-cyano-methyl]-2_ethyl_6:::/^ a gas -3-3,4-dimur-2Η-junlin-1-skin acid B; 4-[(3,5-bis-trifluoromethyl-phenyl)-cyano-methyl]-2- Ethyl porphyrin small carboxylic acid ethyl ester; fluoromethyl-2H-(R,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-cyano-methyl]_2-B二2-2H-p-quelin-α-lin-1-mono-acid oxime; /SL, murine methyl (R,R)_4-[(3,5-bis-trifluoro-T-phenyl)-cyanoguanidine (2,5-bis-trifluoromethyl-phenyl); (S,R)-4-[(3,5-bis-trifluoromethyl-phenyl) -Cyano-methyl-lower ethyl·&lt;3-2H-porphyrin-1-carboxylate; or fluoromethyl(S,S)-4-[(3,5-bis-trifluoromethyl) -Phenyl)-cyano-methyl]-2_ethyl_6•3^'cracked methyl 2-indole-quinoline-1-carboxylate; or a pharmaceutically acceptable salt of the compound. Example 414 (stereoisomers of Examples 13 and 14)

(R，S)-4-[(3,5-雙-三氟甲基-苯甲醯基）]·6,7-二甲氧基-2-甲基-3,4_ 二氫-2H-4：啉-1-羧酸乙酯； 92199 -291 - 1285641 (R，R)冬[(3,5-雙-三氟甲基-笨甲醯基）]，6，二甲氧基么甲基·3,4_ 一鼠-2Η-峻17林-1 -幾酸乙g旨； (S，R)-4-[(3,5-雙-三氟甲基-苯甲醯基外6,7-二甲氧基：甲基_3,4· 二氫-2Η-ρ奎淋小幾酸乙g旨；或 (S，S)-4-[(3,5-雙-三氟甲基-苯甲醯基外6,7_二甲氧基冬甲基_3,4_ 二氫奎淋-1-叛酸乙酉旨； 或其藥學上可接受之鹽。 實例415 (實例18、19及35之立體異構物）(R,S)-4-[(3,5-bis-trifluoromethyl-benzylidenyl)]·6,7-dimethoxy-2-methyl-3,4-dihydro-2H- 4: ethyl phthalate-1-carboxylate; 92199 -291 - 1285641 (R, R) winter [(3,5-bis-trifluoromethyl-benzomethyl)], 6, dimethoxy-methyl基·3,4_一鼠-2Η-峻17林-1 -acid acid B; (S,R)-4-[(3,5-bis-trifluoromethyl-benzhydryl group 6, 7-Dimethoxy:methyl_3,4·dihydro-2Η-ρ 淋 小 小 ;; or (S,S)-4-[(3,5-bis-trifluoromethyl) - Benzyl hydrazino, 6,7-dimethoxy-m-methyl-3,4-dihydroquinone-1-Resin, or a pharmaceutically acceptable salt thereof. Example 415 (Examples 18, 19 and 35 stereoisomers)

(11，11，11)斗[(3,5-雙-三氟甲基-苯基）_氟-甲基]_6,7_二甲氧基1? 基-3,4-二氫-2H-喹啉-1-羧酸乙酯； (R，R，S)-4-[a5-雙-三氟甲基-苯基）-氟-甲基]_6,7·二甲氧基士甲 基-3,4-二氫-2H-喳啉-1-羧酸乙酯； (11，3，11)-4-[(3,5-雙-三氟甲基-笨基）-氟-甲基]_6,7-二曱氧基1曱 基-3,4-二氫-2H-喳啉-1-羧酸乙酯； (R，S，S)-4-[(3,5-雙-三氟甲基-笨基）-氟-甲基]二甲氧基-2•曱 基-3,4-二氫-2H-喹啉小羧酸乙酯； (S，R，R)-4-[(3,5-雙-三氟曱基-笨基）-氟-甲基]-6,7_二甲氧基_2-甲 基-3,4-二氫-2H-+啉小羧酸乙酯； (S，R，S)-4-[(3,5-雙-三氟甲基-笨基）-氟-甲基]_6,7-二甲氧基-2-甲 基-3,4-二氫-2H-+ 4 -1-羧酸乙酯； 92199 - 292 - 1285641 (S，S，R)-4-[(3,5-雙-三氟甲基_苯基）_氟_甲基]_6,7_二曱氧基_2_甲 基-3,4-二氫-2H-峻琳-1-羧酸乙酯；或 甲基]-6,7-二〒氧基：甲基 立體異構物） (S，S，S)-4-[(3,5-雙-三氟甲基-笨基）_氟_ -3,4-二氫-211-喹4木-1-複酸乙酯； 或該化合物之藥學上可接受鹽。 實例416(實例20與21之(11,11,11) bucket [(3,5-bis-trifluoromethyl-phenyl)-fluoro-methyl]_6,7-dimethoxy 1?-yl-3,4-dihydro-2H - Quinoline-1-carboxylic acid ethyl ester; (R,R,S)-4-[a5-bis-trifluoromethyl-phenyl)-fluoro-methyl]_6,7·dimethoxymethyl Ethyl-3,4-dihydro-2H-porphyrin-1-carboxylate; (11,3,11)-4-[(3,5-bis-trifluoromethyl-phenyl)-fluoro- Ethylmethyl]_6,7-dimethoxyoxyindolyl-3,4-dihydro-2H-indolinoline-1-carboxylate; (R,S,S)-4-[(3,5- Bis-trifluoromethyl-phenyl)-fluoro-methyl]dimethoxy-2-indolyl-3,4-dihydro-2H-quinolinecarboxylic acid ethyl ester; (S,R,R) -4-[(3,5-bis-trifluorodecyl-phenyl)-fluoro-methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-+ Ethyl carboxylic acid small carboxylic acid; (S,R,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-fluoro-methyl]_6,7-dimethoxy-2- Ethyl methyl-3,4-dihydro-2H-+ 4-1-carboxylate; 92199 - 292 - 1285641 (S,S,R)-4-[(3,5-bis-trifluoromethyl) Phenyl)-fluoro-methyl]_6,7-didecyloxy-2-methyl-3,4-dihydro-2H-junolin-1-carboxylic acid ethyl ester; or methyl]-6,7 -dimethoxyl:methyl stereoisomer) (S,S,S)-4-[(3,5-bis-trifluoromethyl-phenyl)_fluoro_ -3,4 - dihydro-211-quino-4-xy-1-hydroxyethyl ester; or a pharmaceutically acceptable salt of the compound. Example 416 (Examples 20 and 21)

基）]_2_乙基冰三氟曱基·3,4_二 (S，R)-4-[(3,5-雙-三氟甲基-苯甲醯 氫-2H-喹啉小羧酸乙酯；或 (S，SM-[(3,5-雙-三氟甲基-苯甲醯基）]·2-乙基4三氟甲基斗 氫-2H-喹啉小羧酸乙醋； ’ 或該化合物之藥學上可接受鹽。 實例417 (實例16與Π之立體異構物）Base)]_2_Ethyl ice trifluoromethyl 3,4_bis(S,R)-4-[(3,5-bis-trifluoromethyl-benzoguanidine hydrogen-2H-quinoline small carboxy Ethyl acetate; or (S,SM-[(3,5-bis-trifluoromethyl-benzylidene)] 2-ethyl 4-trifluoromethyl-hydrogen-2H-quinoline small carboxylic acid Vinegar; 'or a pharmaceutically acceptable salt of the compound. Example 417 (Example 16 and stereoisomers of hydrazine)

(R，R，R)-4-[(3,5-雙-三氟甲基-笨基Hi基呷基]，6;二甲氧基·2 甲基-3,4-二氫-2H-喳啉小羧酸乙酯； 土 — (R，R，S)-4-[(3,5-雙-三氟甲基-苯基）_羥基-曱基]_6,7_二曱氧基 甲基-3,4-二氩-2H-喹啉-1-羧酸乙酯； 土 92199 - 293 - 1285641 (R，S，R)-4-[(3,5-雙-三氟甲基-苯基）-羥基-甲基]-6,7-二甲氧基-2-甲基-3,4-二鼠奎淋-1-叛乙S旨， (R，S，S)-4-[(3,5-雙-三氟甲基-苯基）-羥基-甲基]-6,7-二甲氧基-2-甲基-3,4-二氫-2H-喳啉小羧酸乙酯； (S，R，R)-4-[(3,5-雙-三氟甲基-苯基）-羥基-甲基]-6,7-二甲氧基-2-甲基-3,4-二氫-2H-喹啉小羧酸乙酯； (3，11,3)斗[(3,5-雙-三氟甲基-苯基）-羥基-甲基]-6,7-二甲氧基-2-甲基-3,4-二鼠-2H-^淋-1-複酸乙酉旨， (S，S，R)-4-[(3,5-雙-三氟甲基-苯基）-羥基-甲基]-6,7-二甲氧基-2-甲基-3,4-二氫-2H-喹啉-1-羧酸乙酯；或 (3,3,3)-4-[(3,5-雙-三氟甲基-苯基）-羥基-甲基]-6,7-二甲氧基-2-甲 基-3,4-二鼠奎淋-1-瘦酸乙酉旨， 或該化合物之藥學上可接受鹽。 實例418 (實例34之立體異構物） cf3(R,R,R)-4-[(3,5-bis-trifluoromethyl-styl Hiyl),6;dimethoxy·2methyl-3,4-dihydro-2H - porphyrin small carboxylic acid ethyl ester; soil - (R,R,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-indenyl]_6,7-dioxane Ethyl methyl-3,4-diar-2H-quinoline-1-carboxylic acid ethyl ester; soil 92199 - 293 - 1285641 (R,S,R)-4-[(3,5-bis-trifluoromethyl) (-Phenyl)-hydroxy-methyl]-6,7-dimethoxy-2-methyl-3,4-di-r-quinone-Nine-Bet-S, S (R, S, S)- 4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-carboline Small carboxylic acid ethyl ester; (S,R,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-6,7-dimethoxy-2- Methyl-3,4-dihydro-2H-quinolinecarboxylic acid ethyl ester; (3,11,3) bucket [(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl] -6,7-Dimethoxy-2-methyl-3,4-di-rho-2H-^-Lin-1 acetate, (S,S,R)-4-[(3,5- Ethyl bis-trifluoromethyl-phenyl)-hydroxy-methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate; Or (3,3,3)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-6,7-dimethoxy-2-methyl-3, 4-diquinone quinone-1-sodium acetoate, or a pharmaceutically acceptable salt of the compound. Example 418 (Stereoisomer of Example 34) cf3

(R，S，S)-4-[乙醯氧基-(3,5-雙-三氟甲基-苯基）-甲基]-6,7-二甲氧 基-2-甲基-3,4-二氫-2H-喹啉小羧酸乙g旨； (R，R，S)-4-[乙醯氧基-(3,5-雙-三氟甲基-苯基）-甲基]-6,7-二甲氧 基-2-甲基-3,4-二氫-2H-喹啉小羧酸乙酯； (R，S，R)-4-[乙醯氧基-(3,5-雙-三氟甲基-苯基）-甲基]-6,7-二甲氧 基-2-曱基-3,4-二氫-2H-喹啉-1-羧酸乙酯； 92199 - 294 - 1285641 (R，R，R)-4-[乙醯氧基-(3,5-雙-三氟甲基·苯基）_甲基]_6,7_二甲氧 基-2-甲基-3,4-二氫-2H-0奎淋小幾酸乙醋； (S，S，S)-4-[乙醯氧基-(3,5-雙-三氟甲基-苯基 &gt;甲基]_6,7_二甲氧 基基-3,4-二氫-2H-峻琳小幾酸乙g旨； (S，R，S)-4-[乙氧基-(3,5-雙·《三氟甲基_苯基 &gt; 甲基]二甲氧 基-2-甲基-3,4-二氫-2H-p奎淋小幾酸乙酯； 甲氧 甲氧 (S，S，R)-4-[乙氧基-(3,5-雙-三氟甲基·苯基）_甲基]_6,7_二 基-2-甲基-3,4-二氫-2H-p奎啦小羧酸乙酉旨；或 (S，R，R)-4-[乙醯氧基-(3,5-雙·三氟甲基-苯基 &gt;甲基'二 基-2-甲基-3,4-二氫奎淋]_幾酸乙酉旨； 或該化合物之藥學上可接受鹽。 實例419 (實例22、23、24及25之立體異構物）(R,S,S)-4-[acetoxy-(3,5-bis-trifluoromethyl-phenyl)-methyl]-6,7-dimethoxy-2-methyl- 3,4-dihydro-2H-quinoline small carboxylic acid, ethyl chloroform; (R, R, S)-4-[ethyloxy-(3,5-bis-trifluoromethyl-phenyl)- Ethyl methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinolinecarboxylic acid; (R,S,R)-4-[ethyloxy -(3,5-bis-trifluoromethyl-phenyl)-methyl]-6,7-dimethoxy-2-indolyl-3,4-dihydro-2H-quinoline-1-carboxylate Ethyl acetate; 92199 - 294 - 1285641 (R,R,R)-4-[acetoxy-(3,5-bis-trifluoromethylphenyl)methyl]_6,7-dimethyl Oxy-2-methyl-3,4-dihydro-2H-0 quinine acid vinegar; (S,S,S)-4-[acetoxy-(3,5-bis-three Fluoromethyl-phenyl&gt;methyl]_6,7-dimethoxy-3,4-dihydro-2H-junolinic acid B; (S,R,S)-4-[ Ethoxy-(3,5-bis-"trifluoromethyl-phenyl]methyl]dimethoxy-2-methyl-3,4-dihydro-2H-p-quinoline acid B Ester; methoxymethoxy(S,S,R)-4-[ethoxy-(3,5-bis-trifluoromethylphenyl)methyl]_6,7-diyl-2-yl a group of 3-,4-dihydro-2H-p-quine carboxylic acid; or (S,R,R)-4-[ethyloxy-( 3,5-bis-trifluoromethyl-phenyl&gt;methyl 'diyl-2-methyl-3,4-dihydroquinine]-acid acetal; or a pharmaceutically acceptable salt of the compound Example 419 (stereoisomers of Examples 22, 23, 24 and 25)

(R，S，S)-4-[(3,5-雙-二氟甲基-苯基）·羥基-甲基]1乙基冬三氟甲 基-3,4-二氫-2H-p奎p林小幾酸乙g旨； (R，S，R)-4-[(3,5-雙-二氟甲基-苯基）_經基-甲基]乙吴 ：^ 土 二氣曱 基-3,4-二氫-2H-p奎淋-1-幾酸乙酉旨； (R，R，S)-4-[(3,5-雙-二氣甲基-冬基）_經基-甲基]乙美·6二# «t· Ό-二氣甲 基-3,4-二氮-2Η-0奎淋小致酸乙g旨； (R，R，R)-4-[(3,5-雙-二氟甲基-冬基）_經基-甲基]乙美 ：^ 土 -Ό-二乱甲 基-3,4-二氫-2Η-喹啉-1-幾酸乙酯； 92199 - 295 - 1285641 (S，S，S)-4-[(3,5-雙-三氟甲基-苯基）-羥基-甲基]-2-乙基-6-三氟甲 基-3,4-二鼠奎17林-1-叛酸乙醋， (S，S，R)-4-[(3,5-雙-三氟甲基-苯基）-羥基-甲基]-2-乙基-6-三氟甲 基-3,4-二氫-2H-喳啉小羧酸乙醋； (S，R，S)-4-[(3,5-雙-三氟甲基-苯基）-羥基-甲基]-2-乙基-6-三氟甲 基-3,4-二氮-2H-^ g林-1-幾乙自旨，或 (S，R，R)-4-[(3,5-雙-三氟甲基-苯基）-羥基-甲基]-2-乙基各三氟曱 基-3,4-二氮-2H-^淋-1-致酸乙酉旨， 或該化合物之藥學上可接受鹽。 實例420(R,S,S)-4-[(3,5-bis-difluoromethyl-phenyl)-hydroxy-methyl]1ethyl-t-trifluoromethyl-3,4-dihydro-2H- p奎奎林小酸酸乙克; (R,S,R)-4-[(3,5-bis-difluoromethyl-phenyl)-carbyl-methyl]ethyl: ^ (R,R,S)-4-[(3,5-bis-dimethylmethyl-winter) _经基-methyl]乙美·6二# «t· Ό-dimethylmethyl-3,4-diaza-2Η-0 quinine small acid B; (R,R,R)- 4-[(3,5-bis-difluoromethyl-winteryl)-trans-yl-methyl]ethylamine:^ Ό-Ό-disorganomethyl-3,4-dihydro-2-indole-quinoline- 1-monoethyl ester; 92199 - 295 - 1285641 (S,S,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl- 6-trifluoromethyl-3,4-dimurium 17-lin-1-deoxyacetate, (S,S,R)-4-[(3,5-bis-trifluoromethyl-phenyl) -hydroxy-methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-carboline small carboxylic acid ethyl acetate; (S,R,S)-4-[(3, 5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6-trifluoromethyl-3,4-diaza-2H-^ g-lin-1-a , or (S,R,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]- 2-Ethyltrifluoromethyl-3,4-diaza-2H-ethyl-1-acid, or a pharmaceutically acceptable salt of the compound. Example 420

4-[(3,5-雙-三氟甲基-苯基）-二氟-甲基]-2-乙基-6-三氟甲基-3,4-二鼠-211-峻淋-1-致乙@旨， (R，S)-4-[(375-雙-三氟甲基-苯基）-二氟-甲基]-2-乙基-6-三氟甲基 -3,4-二氫-2H-喹啉小羧酸乙酯； (R，R)-4-[(3,5-雙-三氟甲基-苯基）-二氟-甲基]-2-乙基-6-三氟甲基 -3,4-二鼠-2Η-ρ奎淋-1-¾ fee 乙 @旨， (S，R)-4-[(3,5-雙-三氟甲基-苯基）-二氟-甲基]-2-乙基-6-三氟甲基 -3,4-二氫-2H-喳啉小羧酸乙酯；或 (S，S)-4-[(3,5-雙-三氟甲基-苯基）-二氟-甲基]-2-乙基-6-三氟甲基-3,4-二氫-2H-喹啉小羧酸乙醋； 92199 - 296 - 1285641 或該化合物之藥學上可接受鹽。4-[(3,5-bis-trifluoromethyl-phenyl)-difluoro-methyl]-2-ethyl-6-trifluoromethyl-3,4-di-r-211-Jun-Lin- 1-致乙@,,(R,S)-4-[(375-bis-trifluoromethyl-phenyl)-difluoro-methyl]-2-ethyl-6-trifluoromethyl-3 , 4-dihydro-2H-quinoline small carboxylic acid ethyl ester; (R,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-difluoro-methyl]-2- Ethyl-6-trifluoromethyl-3,4-dimur-2Η-ρ奎淋-1-3⁄4 fee B @,, (S,R)-4-[(3,5-bis-trifluoromethyl) Ethyl-phenyl)-difluoro-methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-carboline small carboxylic acid ethyl ester; or (S,S)-4 -[(3,5-bis-trifluoromethyl-phenyl)-difluoro-methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline carboxylate Acidic vinegar; 92199 - 296 - 1285641 or a pharmaceutically acceptable salt of the compound.

N Me C02EtN Me C02Et

基二氫-2H-。奎0林小瘦酸乙醋；Dihydrogen-2H-. Kui 0 Lin small soaked acid vinegar;

基-3,4-二氫-2Η-ρ奎琳小幾酸乙酯； (S，R)-4-[(3,5-雙-三氟甲基-苯基）-二氟-甲基]1甲基丨二甲氧 基-3,4-二氫-2H-p奎淋-1-幾酸乙g旨；或 (S，S)-4-[(3,5-雙-三氟甲基-苯基）-二氟_甲基]_2_甲 u，’**—'* Y 氧 基-3,4-二氫-2Η-Ρ奎淋-1-幾酸乙g旨； 或該化合物之藥學上可接受鹽。 實例422 (實例182之立體異構物）Ethyl-3,4-dihydro-2Η-ρ奎琳小酸酸; (S,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-difluoro-methyl ] 1 methyl 丨 dimethoxy-3,4-dihydro-2H-p quinolate-1-acid S, or (S,S)-4-[(3,5-bis-trifluoro Methyl-phenyl)-difluoro-methyl]_2_methylu, '**-'* Y-oxy-3,4-dihydro-2Η-Ρ奎淋-1-酸酸乙格; or A pharmaceutically acceptable salt of the compound. Example 422 (stereoisomer of Example 182)

(R) -4-[(3,5-雙-三氟甲基-笨甲醯基）]-2-乙基-6,二甲基-3,4_二顏 -2H-口奎嘆淋-1-複fe乙SS，或 (S) -4-[(3,5-雙-三氟甲基-笨甲醯基）]-2-乙基-6,7-二甲基_3士二 -^Vi 92199 - 297 - 1285641 2H-喹喏啉小羧酸乙酯； 或該化合物之藥學上可接受鹽。(R) -4-[(3,5-bis-trifluoromethyl-benzomethyl)]-2-ethyl-6, dimethyl-3,4_diyan-2H-mouth snail -1-Fufe B SS, or (S) -4-[(3,5-bis-trifluoromethyl-benzomethyl)]-2-ethyl-6,7-dimethyl_3 2-^Vi 92199 - 297 - 1285641 2H-quinoxaline small carboxylic acid ethyl ester; or a pharmaceutically acceptable salt of the compound.

實例423 (實例178之立體異構物） F PExample 423 (stereoisomer of Example 178) F P

(R，R)-4-[(3,5-雙-三氟甲基-苯基）-氰基-甲基]-2-乙基-6,7-二甲基- 3.4- 二鼠-2H-^ p若17林-1-致乙舀旨， (R，S)-4-[(3,5-雙-三氟甲基-苯基）-氰基-甲基]-2-乙基-6,7-二甲基- 3.4- 二氫-2H-喹喏啉-1-羧酸乙酯； (S，R)-4-[(3,5-雙-三氟甲基-苯基）-氰基-甲基]-2-乙基-6,7-二甲基- 3.4- 二氫-2H-喹喏啉-1-羧酸乙酯；或 (S，S)-4-[(3,5-雙-三氟甲基-苯基）-氰基-甲基]-2-乙基-6,二甲基- 3.4- 二鼠-2^^奎诺淋-1-複故乙酉旨， 或該化合物之藥學上可接受鹽。 實例424 (實例170、171、172及173之立體異構物）(R,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6,7-dimethyl-3.4-di- 2H-^ p if 17 Lin-1-induced ethyl, (R,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl Ethyl-6,7-dimethyl-3.4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester; (S,R)-4-[(3,5-bis-trifluoromethyl-benzene) Ethyl)-cyano-methyl]-2-ethyl-6,7-dimethyl-3.4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester; or (S,S)-4- [(3,5-bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6, dimethyl-3.4-two-rat-2^^quinol-1 Therefore, or a pharmaceutically acceptable salt of the compound. Example 424 (stereoisomers of Examples 170, 171, 172, and 173)

92199 - 298 - 128564192199 - 298 - 1285641

(R，R)-4-[(3,5-雙-三氟甲基-苯基）-甲氧羰基基]乙基_6，'二 甲基-3,4-二氮林-1-叛酸乙g旨； (R，S)-4-[(3,5-雙-三氟甲基-苯基）-甲氧基碳-甲基择乙基_6，?_二 甲基-3,4-二氫-2H-^笔淋-1-叛酸乙g旨； (S，R)-4-[(3,5-f -三氟甲基·苯基）-甲氧羰基-〒基]，2·乙基_6,7_二 甲基-3,4-二氫-2H-p奎嗅琳小幾酸乙酉旨；或 (S，SM-[(3,5-雙-三氟甲基-苯基）_甲氧羰基-甲基抄乙基_6，?-二 甲基-3,4-二氫-2H-喹喏啉小羧酸乙酯； 或該化合物之藥學上可接受鹽。 實例425 (實例174與175之立體異構物）(R,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl]ethyl-6, 'dimethyl-3,4-diazepine-1- (R,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarb-methylethylidene-6,?-dimethyl- 3,4-Dihydro-2H-^Pen-1-Resin acid g; (S,R)-4-[(3,5-f-trifluoromethylphenyl)-methoxycarbonyl- Indenyl], 2·ethyl_6,7-dimethyl-3,4-dihydro-2H-p-quinegrin-succinic acid; or (S,SM-[(3,5-double-) Trifluoromethyl-phenyl)-methoxycarbonyl-methyl-ethyl-ethyl-6,?-dimethyl-3,4-dihydro-2H-quinoxaline small carboxylic acid ethyl ester; or pharmaceutics of the compound Acceptable salts. Example 425 (Stereoisomers of Examples 174 and 175)

(R，R)-4-[(3,5-雙-三氟甲基-苯基）—甲氧羰基-甲基]·2_乙基^ 甲基-3,4-二氫-2H-峻喏琳-1-幾酸甲酯； (R，S)-4-[(3,5-雙-三氟甲基-苯基）_甲氧羰基-甲基]·2•乙基^ 甲基-3,4-二氫-2H-峻喏琳-1-幾酸甲酯； 92199 - 299 - 1285641 (S，R)-4-[(3,5-雙-二氟甲基-苯基）-甲氧基碳-甲基]-2-乙基-6,7-二 曱基-3,4-二氫-2H-喳喏啉小羧酸甲酷；或 (S，S)-4-[(3,5-雙-三氟甲基-苯基）-甲氧羰基-甲基]-2-乙基-6,7-二 甲基-3,4-二氫-2H-喹喏啉小羧酸甲酯； 或該化合物之藥學上可接受鹽。 實例426 (實例176與177之立體異構物）(R,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]·2_ethyl^methyl-3,4-dihydro-2H- (R,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]·2•ethyl^ A Methyl-3,4-dihydro-2H-Junlin-1-carboxylic acid methyl ester; 92199 - 299 - 1285641 (S,R)-4-[(3,5-bis-difluoromethyl-phenyl) )-methoxycarbonyl-methyl]-2-ethyl-6,7-dimercapto-3,4-dihydro-2H-carboline small carboxylic acid methyl; or (S,S)-4 -[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoline a methyl ester of a small carboxylic acid; or a pharmaceutically acceptable salt of the compound. Example 426 (Stereoisomers of Examples 176 and 177)

(R，R)-4-[(3,5-雙-三氟甲基-苯基）-甲氧羰基-甲基]-2-乙基-6,7-二 甲基-3,4-二氫-2H-喹喏啉小羧酸異丙酯； (R，S)-4-[(3,5-雙-三氟甲基-苯基）-甲氧羰基-甲基]-2-乙基-6,7-二 甲基-3,4-二氫-2H-喹喏啉小羧酸異丙酯； (S，R)-4-[(3,5-雙-三氟甲基-苯基）-甲氧羰基-甲基]-2-乙基-6,7-二 甲基-3,4-二鼠奎诺淋-1-複異丙酉旨，或 (S，S)-4-[(3,5-雙-三氟甲基-苯基）-甲氧羰基-甲基]-2-乙基-6,7-二 甲基-3,4-二氫-2Η-喹喏啉小羧酸異丙酯； 或該化合物之藥學上可接受鹽。 實例427 (實例183之立體異構物） 92199 - 300 - 1285641(R,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6,7-dimethyl-3,4- Dihydro-2H-quinoxaline carboxylic acid isopropyl ester; (R,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2- Ethyl-6,7-dimethyl-3,4-dihydro-2H-quinoxaline carboxylic acid isopropyl ester; (S,R)-4-[(3,5-bis-trifluoromethyl) -phenyl)-methoxycarbonyl-methyl]-2-ethyl-6,7-dimethyl-3,4-dimurone quinolone-1-reisopropyl hydrazine, or (S,S) 4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6,7-dimethyl-3,4-dihydro-2Η- Isopropyl quinone carboxylic acid isopropyl ester; or a pharmaceutically acceptable salt of the compound. Example 427 (Stereoisomer of Example 183) 92199 - 300 - 1285641

十 F 三氟 三氟 剛冰[(3,5_雙-三氟甲基_苯基)、甲氧羰基_甲基碎乙基^ 甲基-3,4-二氫K喏琳-i-羧酸乙醋· (R，SH_[(3,5•雙三氟甲基.苯基)_甲氧談基_甲基]1乙基^ 甲基_3,4_二氫-2H-4喏啉-1-羧酸乙醋； •〒基]1乙基-6-三氟 (S，R)-4-[(3,5-雙-三氟甲基-笨基）_甲氧窥基 甲基-3,4-二氫_2H-喹喏啉小羧酸乙酯；或 (S，S)-4-[(3,5-雙-三氟甲基-苯基)_甲氧羰基_甲基於乙基·卜三氣 甲基-3,4-二氫-2H-P奎p若p休小幾酸乙酉旨； 或該化合物之藥學上可接受鹽。 實例428與429Decafluorotrifluoroaluminium [(3,5-bis-trifluoromethyl-phenyl), methoxycarbonyl-methylethylidene]methyl-3,4-dihydro-K-lin-i- Carboxylic acid ethyl acetate · (R, SH_[(3,5• bistrifluoromethyl.phenyl)_methoxy]methyl]1 ethyl^methyl_3,4_dihydro-2H-4 Porphyrin-1-carboxylic acid ethyl acetate; • mercapto]1 ethyl-6-trifluoro(S,R)-4-[(3,5-bis-trifluoromethyl-stupyl)_methoxy Ethyl methyl-3,4-dihydro-2H-quinoxaline small carboxylic acid ethyl ester; or (S,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-methoxy Carbonyl-methyl to ethyl-tris-trimethyl-3,4-dihydro-2H-P-quino- p-succinic acid; or a pharmaceutically acceptable salt of the compound. Examples 428 and 429

(R，S)-4-[(3,5-雙-二氟甲基-苯基）-氰基-甲基]i乙基二甲某 3,4-二氫-2H-4：喏4小叛酸乙酯與 (R，R)-4-[(3,5-雙-三氟甲基-苯基）-氰基-甲基]·2·乙基二甲美 92199 -301 - 1285641 3,4-一氫-2H·^奎嗓淋小幾酸乙醋 將2-乙基-6'二甲基〇,4-二氫-2(RH^奎喏啉小羧酸乙酯〇克 ，1當量，3.81毫莫耳）、3,5_雙-(三氟〒基，苯基）·漠{腈（製 備4〇，1.27克，i當量，3·δ1毫莫耳）及2&gt;二甲基吡啶（3當量 ，11.43毫莫耳）在Ν，Ν-二甲基甲醯胺（5毫升）中之混合物，於 室溫下攪拌24小時。使反應物於醋酸乙酯與水之間作分液 處理，並分離液相。以醋酸乙酯將水相萃取3次，並將合併 之有機萃液以水洗滌2次，以鹽水丨次，以無水硫酸鈉脫水_ 乾燥，過濾，及蒸發。於矽膠上層析，使用己烷中之1〇_3〇% 醋酸乙酯梯度液作為溶離劑，提供所要之腈非對映異構物 (1·5 : 1)(1.0 克與 0.7 克，60%)。 異構物1 : LCMS(ESI+)： 514 (MH+) 1H-NMR (CDC13) 5 0.88 (t5 J=7.5Hz, 3H), 1.29 (ζ J=7.1Hz, 3Η), 1.49 (m5 2H)，2.21 (s，3H)，2·22 (s，3H)，3·03 (dd，&amp; =11·0Ηζ，J2=2.9Hz，1H)，3·19 (dd， J^ll.OHz, J2=5.4Hz, 1H), 4.19 (m, 1H)3 4.27 (m, 1H), 4.50 (brm, 1H), 6.05 (s5 · 1H)，6.59 (s5 iTl)，7.33 (brs，1H)，7·94 (s，1H)，7·97 (s，2H)· 異構物2 : LCMS(ESI+)： 514 (MH+) 1H-NMR (CDCI3) δ 0.76 (t, J=7.48Hz, 3H), 1.31 (t, J=7.06Hz, 3H), 1.52 (m, 2H)，2.21 (s，3H)，2.23 (s，3H)，2.75 (dd，h =11·0Ηζ，J2=2.1Hz，1H)，3.29 (dd， Α=11.0Ηζ，J2=3J3Hz，1H)，4.19-4.30 (m，2H)，4·52 (brm，1H)，6.19 (s，1H)， 6.70 (s，1H)，7.47 (brs，1H)，7.96 (s，1H)，8.00 (s，2H)· 製備42 09 100 .10?- 1285641(R,S)-4-[(3,5-bis-difluoromethyl-phenyl)-cyano-methyl]iethyldimethyl 3,4-dihydro-2H-4:喏4 Small acid-repellent ethyl ester with (R,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-cyano-methyl]·2·ethyl dimethyl mei 99199 -301 - 1285641 3,4-monohydro-2H·^ 奎嗓淋小酸酸乙醋 2-ethyl-6' dimethyl hydrazine, 4-dihydro-2 (RH quinoxaline small carboxylic acid ethyl ester gram , 1 equivalent, 3.81 mmol, 3,5-bis-(trifluoromethyl, phenyl)·independent (nitrile (preparation 4〇, 1.27 g, i equivalent, 3·δ1 mmol) and 2&gt; A mixture of lutidine (3 equivalents, 11.43 mmol) in hydrazine, dimethyl-dimethylcarbamide (5 ml) was stirred at room temperature for 24 hours. The reactant was subjected to liquid separation between ethyl acetate and water, and the liquid phase was separated. The aqueous phase was extracted three times with ethyl acetate, and the combined organic extracts were washed twice with water, brine, and dried over anhydrous sodium sulfate, dried, filtered, and evaporated. Chromatography on ruthenium, using 1 〇 〇 〇 〇 醋酸 醋酸 醋酸 ethyl acetate as a dissolving agent to provide the desired nitrile diastereomer (1·5 : 1) (1.0 g and 0.7 g, 60%). Isomer 1 : LCMS (ESI+): 514 (MH+) 1H-NMR (CDC13) 5 0.88 (t5 J=7.5 Hz, 3H), 1.29 (ζ J=7.1 Hz, 3Η), 1.49 (m5 2H), 2.21. (s, 3H), 2·22 (s, 3H), 3·03 (dd, &amp; =11·0Ηζ, J2=2.9Hz, 1H), 3·19 (dd, J^ll.OHz, J2= 5.4 Hz, 1H), 4.19 (m, 1H)3 4.27 (m, 1H), 4.50 (brm, 1H), 6.05 (s5 · 1H), 6.59 (s5 iTl), 7.33 (brs, 1H), 7.94 (s,1H),7·97 (s,2H)·isomer 2: LCMS (ESI+): 514 (MH+) 1H-NMR (CDCI3) δ 0.76 (t, J=7.48 Hz, 3H), 1.31 ( t, J=7.06Hz, 3H), 1.52 (m, 2H), 2.21 (s, 3H), 2.23 (s, 3H), 2.75 (dd, h =11·0Ηζ, J2=2.1Hz, 1H), 3.29 (dd, Α=11.0Ηζ, J2=3J3Hz,1H), 4.19-4.30 (m,2H),4·52 (brm,1H),6.19 (s,1H), 6.70 (s,1H),7.47 (brs , 1H), 7.96 (s, 1H), 8.00 (s, 2H) · Preparation 42 09 100 .10?- 1285641

'、 由 D.H.R. Barton 等人（Tetrahedron Letters 1983 M 1605)所述之一般 叙私序t成。於碘（3.〇克，91毫莫耳）在無 水四氫呋喃（3〇毫升彳φ 士、—、— 一 开）中足洛硬内，在氮氣下，慢慢添加u，3,3_ 四甲基胍（63·7蒼堇且 Q ^ . Ν ^ 〉谷液。將混合物於 天斗’ 8耄升）在無水四氫呋喃（3〇毫升）中之 直溫下擾掉1〇分鐘，然後添加無水四氫 失南（30毛升）中之⑻么乙基_4_亞肼基各三氟甲基_3,4_二氫-況_ 喹啉小叙酸乙酯（製備6，9」毫莫耳，3克）。於15分鐘後， 在真空下移除落劑’並將殘留物在氮氣及85t下加熱9〇分鐘 。使殘留物洛於醋酸乙酯中，以2N鹽酸、亞硫酸鈉溶液（2 5 /6 )、飽和峡酸氫鈉溶液洗滌，並以無水硫酸鈉脫水乾燥。 使粗產物於矽膠上藉層析純化，以己烷/醋酸乙酯19 :丨至85 • 15溶離’而得標題化合物，為黃色固體（2.8克，72% )。 MS : 426·3 [M+H]+ 實測值· 1H-NMR (CDC13) δ 7.69 (brs, 1H), 7.61 (brd5 J=8.14Hz5 1H)5 7.49 (brd, J= 8·14Ηζ，1H)，6.85 (d，J=6.64Hz，1H)，4.87 (m，1H)，4.27 (m，2H)，4·15 (m，1H)， 1.50 (m，1H)，1.38 (m，1H)，1.32 (t，J=7.47Hz，3H)，0·87 (t，J=7.47Hz，3H)· 實例430 92199 - 303 - 1285641', as described by D.H.R. Barton et al. (Tetrahedron Letters 1983 M 1605). In iodine (3. gram, 91 mM) in anhydrous tetrahydrofuran (3 〇 ml 彳 φ 士, -, - 一 开) in the foot Luo hard, under nitrogen, slowly add u, 3, 3_ four Base 63 (63·7 堇 堇 and Q ^ . Ν ^ 〉 谷液. Mix the mixture in Tiandou '8 liters) in the dry temperature of anhydrous tetrahydrofuran (3 〇 ml) for 1 ,, then add anhydrous (8) in the tetrahydrogen loss (30 liters) of ethyl _4_ fluorenyl trifluoromethyl _3,4 dihydrogen - _ quinoline small acid ethyl ester (preparation 6,9" Moer, 3 grams). After 15 minutes, the drawdown was removed under vacuum and the residue was heated under nitrogen and 85t for 9 min. The residue was taken up in ethyl acetate, washed with 2N hydrochloric acid, sodium sulfite solution (2 5 / 6 ), saturated sodium hydrogen sulfate solution, and dried over anhydrous sodium sulfate. The crude product was purified by chromatography eluting elut elut elut elut elut elut elut elut elut elut elut MS : 426·3 [M+H]+ Measured value · 1H-NMR (CDC13) δ 7.69 (brs, 1H), 7.61 (brd5 J=8.14Hz5 1H)5 7.49 (brd, J= 8·14Ηζ,1H) , 6.85 (d, J = 6.64 Hz, 1H), 4.87 (m, 1H), 4.27 (m, 2H), 4·15 (m, 1H), 1.50 (m, 1H), 1.38 (m, 1H), 1.32 (t, J = 7.47 Hz, 3H), 0·87 (t, J = 7.47 Hz, 3H) · Example 430 92199 - 303 - 1285641

(RS，RS)與（RS，SR)斗[(3,5-雙-三氟甲基-苯基）_羥基-甲基乙基各 二氟甲基奎淋小幾酸乙酉旨 於（RS)-2-乙基斗碘基各三氟甲基-2H-喳啉小羧酸乙酯（814毫 克I.%耄莫耳，按上文關於(R)異構物所述製成，惟使用外 消旋起始物質）在無水四氫呋喃（4毫升）中之溶液内，於氮氣 及-78°C下，逐滴添加正_ 丁基鋰（2·5Μ，在己烷中，2 87毫莫 耳，1· 15毫升）。5分鐘後，逐滴添加3,5_雙（三氟罕基）苯甲醛（6 〇6 耄莫耳，1毫升）。於45分鐘後，在-78°C下，使混合物溫熱 至室溫，並於1小時後，添加水。藉由添加2N鹽酸使混合物 酸化’並以醋酸乙酯萃取。將有機溶液以水洗滌，以無水 硫酸鈉脫水乾燥，並於真空下蒸發。使殘留物於矽膠上藉 層析純化，以己烷/醋酸乙酯9 : 1至4 : 1溶離，然後進一步 於碎膠上藉層析純化，以二氯甲烷溶離，獲得標題化合物 ’為非對映異構物之混合物（6〇毫克）。 MS : 540·3 [M-H]+ 實測值· 實例431 92199 - 304 - 1285641(RS,RS) with (RS,SR) bucket [(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methylethyl each difluoromethyl quinone succinic acid 2-ethylidene iodo-trifluoromethyl-2H-carboline small carboxylic acid ethyl ester (814 mg I.% oxime, prepared as described above for the (R) isomer, Add n-butyllithium (2·5 Torr in hexane, 2 87 mM) in a solution of the racemic starting material in anhydrous tetrahydrofuran (4 mL) under nitrogen and -78 °C. Mohr, 1. 15 ml). After 5 minutes, 3,5-bis(Trifluorohanyl)benzaldehyde (6 〇6 耄mol, 1 mL) was added dropwise. After 45 minutes, the mixture was allowed to warm to room temperature at -78 ° C, and after 1 hour, water was added. The mixture was acidified by the addition of 2N hydrochloric acid and extracted with ethyl acetate. The organic solution was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by chromatography on silica gel eluting with hexane / ethyl acetate 9:1 to 4:1. A mixture of enantiomers (6 mg). MS: 540·3 [M-H]+ Measured value · Example 431 92199 - 304 - 1285641

(RS，RS)與（RS，SR)-4-[(3,5-雙-三氟曱基-苯基）_甲氧基-甲基碎乙美 -6-二氣甲基-2H-p奎17林-1-幾酸乙酯 於非對映異構物混合物（RS，RS)與（RS，SR)斗[(3,5-雙-三氟曱基, 苯基羥基-甲基]-2-乙基各三氟甲基-2H•喹啉小羧酸乙醋（實^ 430，32毫克，0·059毫莫耳）在二甲亞颯（3毫升）中之溶液内 在氮氣下，添加粉末狀氫氧化钾（q.236毫莫耳，η毫克）， 接著立即添加碘甲烷（0·118毫莫耳，7·4微升）。將混合物於室 下搅拌2小時，然後以2Ν鹽酸稀釋。以醋酸乙酯萃取麁合 物’將有機層以水及飽和氯化㈣液洗條，以無水硫酸納 脫水乾燥’並於真$下蒸發。使粗產物於碎膠上藉層析純 化’以己燒’接著是己烷/醋酸乙酯19 : 1，然後9 : 1，接 著85 · 15二離，而得標題化合物（13毫克），為非對映異構物 之混合物二 實例432(RS,RS) and (RS,SR)-4-[(3,5-bis-trifluorodecyl-phenyl)-methoxy-methyl acetamily-6-dimethylmethyl-2H- P-quinone-17--1-acid ethyl ester in diastereomeric mixture (RS, RS) and (RS, SR) bucket [(3,5-bis-trifluoromethyl, phenylhydroxy-methyl) a solution of 2-ethylhexyl trifluoromethyl-2H•quinoline carboxylic acid in ethyl acetate (solid 430, 32 mg, 0·059 mmol) in dimethyl hydrazine (3 ml) in nitrogen Next, add powdered potassium hydroxide (q. 236 millimolar, η mg), then immediately add methyl iodide (0.118 mmol, 7.4 μL). The mixture was stirred under the chamber for 2 hours, then Dilute with 2 Ν hydrochloric acid. Extract the chelate with ethyl acetate. The organic layer was washed with water and saturated chlorinated (iv) solution, dried under anhydrous sodium sulfate, and evaporated under true y. The title compound (13 mg) was obtained as a mixture of diastereomers from hexane/ethyl acetate 19:1, then 9:1, followed by 85·15. Second instance 432

氟甲基-2H-喹啉- (R，S)-4-(3,5-雙、三氟甲基·苯甲醯基）_2•乙基_6 92199 -305 - 1285641 i-羧酸乙酯 於非對映異構物混合物（RS，RS)與（RS，SR)-4-[(3,5-雙-三氟甲基-苯基）-經基-甲基]-2-乙基-6-三氟甲基奎啉小羧酸乙酯（實例 430 ’ 11愛克’ 0.020毫莫耳）在無水乙醚（丨毫升）中之溶液内 ’添加氧化鐘（IV)(22毫克，已活化，〜85%，Aldrich化學公司， Milwaukee，WI)。將此懸浮液於環境溫度下攪拌9〇分鐘。添加 第二份氧化鐘（IV)(20毫克），並再持續擾拌1小時，然後添加 第三份氧化錳（IV)(30毫克）。1〇分鐘後，經過Celite®藉過濾移 除固體，於真空下移除溶劑，並使殘留物在Baker矽膠（1克 ，40 微米）（J.T. Baker, Phillipsburg，N.J,)上層析，以己燒，接著己 烷/醋酸乙酯19 : 1，然後9 : 1，接著85 : 15，然後4 : 1溶 離，獲得標題化合物（6.6毫克）。 MS: 540·3[Μ+Η]+實測值· 1H-NMR (CDC13) (5 8.27 (s，2H)，8·11 (s，1H)，7.79 (brd，J=8.3Hz，1H)， 7·77 (brs，1H)，7.57 (brd，J=8.3Hz，1H)，6·56 (d，J=6.64Hz，1H)，5·18 (m，1H)， 4.31 (m，2H)，1.64 (m，1H)，1.55 (m，1H)，1.33 (t，J=7.47Hz，3H)，0.96 (t，J=7.47 Hz，3H)· 實例433與434Fluoromethyl-2H-quinoline-(R,S)-4-(3,5-bis, trifluoromethyl·benzylidene)_2•ethyl_6 92199 -305 - 1285641 i-carboxylic acid B Ester in a mixture of diastereomers (RS, RS) with (RS,SR)-4-[(3,5-bis-trifluoromethyl-phenyl)-carbyl-methyl]-2-ethyl Ethyl-6-trifluoromethylquinoline carboxylic acid ethyl ester (Example 430 '11 Aike' 0.020 mmol) in a solution of anhydrous diethyl ether (丨 ml) 'Addition of oxidized clock (IV) (22 mg, Activated, ~85%, Aldrich Chemical Company, Milwaukee, WI). The suspension was stirred at ambient temperature for 9 minutes. A second oxidized clock (IV) (20 mg) was added and the scavenging was continued for an additional hour, followed by the addition of a third portion of manganese (IV) oxide (30 mg). After 1 minute, the solid was removed by filtration through Celite®, the solvent was removed in vacuo and the residue was chromatographed on Baker (1 gram, 40 micron) (JT Baker, Phillipsburg, NJ). After the hexane/ethyl acetate 19:1, then 9:1, then 85:15, then 4:1 eluted to give the title compound (6.6 mg). MS: 540·3[Μ+Η]+ measured value·1H-NMR (CDC13) (5 8.27 (s, 2H), 8·11 (s, 1H), 7.79 (brd, J = 8.3 Hz, 1H), 7·77 (brs, 1H), 7.57 (brd, J=8.3Hz, 1H), 6.56 (d, J=6.64Hz, 1H), 5·18 (m, 1H), 4.31 (m, 2H) , 1.64 (m, 1H), 1.55 (m, 1H), 1.33 (t, J = 7.47 Hz, 3H), 0.96 (t, J = 7.47 Hz, 3H) · Examples 433 and 434

〇，〇 g?199 - 306 - 1285641 (11，1^)-4-[(3,5-雙-三氟〒基-笨基）-甲氧羰基_甲基]士乙基各三氟 甲基-3,4_一氫《·2Η&lt;奎淋-1-叛酸乙@旨〇,〇g?199 - 306 - 1285641 (11,1^)-4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-ethene trifluoromethyl Base-3,4_-hydrogen "·2Η&lt;Querlin-1-Resin B

〇人〇 k (S，S，R)-4-[(3,5-雙-三氟甲基-苯基）_甲氧羰基呷基乙基冬三氟 甲基-3,4-一氫-2H”奎琳-1-幾酸乙酯 使（1^，1^，311)斗[(3,5-雙-三氟甲基_苯基）_甲氧羰基_甲基]_2-乙 基-6-三氟甲基-3,4-二氫-2H-喹啉小羧酸乙酯（實例7)再溶解於 P·共價（s，s) Whdk-o 1 管柱（Regls 技術公司，M〇rt〇nGiOve，iL) (5x25公分）上，在100毫升/分鐘下，以5%乙醇/庚烷溶離 ，提供兩份溶離份： 第一個溶離物：佐3，11)-4-[(3,5-雙-三氟甲基_苯基）_甲氧羰基- 甲基]-2-乙基-6-三氟甲基-3,4-二氫-2H-峻淋小幾酸乙酉旨； MS : 585.8 [M+Hf 實測值· 第二個溶離物：（R，R，S)-4-[(3,5-雙-三氟甲基_苯基 &gt; 甲氧羰基_ 甲基]_2_乙基-6-三氟甲基-3,4-二氫-2H-0奎淋-1-羧酸乙酉旨； MS : 586.2 [M+H]+實測值， 實例435與436 92199 - 307 - 1285641〇 human 〇k (S,S,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl decylethyl winter trifluoromethyl-3,4-monohydrogen -2H" quinal-1-carboxylic acid ethyl ester to make (1^,1^,311) bucket [(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl_methyl]_2-B Ethyl 6-trifluoromethyl-3,4-dihydro-2H-quinolinecarboxylic acid ethyl ester (Example 7) redissolved in P·covalent (s,s) Whdk-o 1 column (Regls technology Company, M〇rt〇nGiOve, iL) (5x25 cm), dissolved in 5% ethanol/heptane at 100 ml/min to provide two dissolving fractions: first dissolvate: 3,11)- 4-[(3,5-Bis-Trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-Jun Amino acid; MS: 585.8 [M+Hf Measured value · Second solvate: (R,R,S)-4-[(3,5-bis-trifluoromethyl-phenyl) A Oxycarbonyl-methyl]_2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-0 quinone-1-carboxylic acid acetonitrile; MS: 586.2 [M+H]+, Examples 435 and 436 92199 - 307 - 1285641

(R，R，S)-4-[(3,5-雙-三氟甲基-苯基）_羧基呷基]-2•乙基·卜三氟甲基 3,4-二氫-2H-p奎淋-1-叛酸乙酯(R,R,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-carboxyindenyl]-2•ethyl·trifluoromethyl 3,4-dihydro-2H -p quino-1-deoxyethyl ester

(R，R，R)-4-[(3,5-雙-三氟甲基-苯基）_羧基-甲基]·2_乙基各三氟甲基 -3,4-一氫-2H*^奎p林小幾酸乙酉旨 三氟甲基-3,4-二氫-2H-喳啉小羧酸乙酯（實例433，兕毫克，〇 i67 毫莫耳）、氫氧化鈉水溶液（1N，丨毫升，丨毫莫耳）及無水四 氫吱喃（2.4毫升）之混合物，於室溫下擾掉5天，然後添加2n 鹽酸，以成為酸pH值。以醋酸乙酯萃取混合物，將有機溶 液以水洗滌（x3),並以無水硫酸鈉脫水乾燥。於真空下移除 溶劑，並使殘留物於Baker矽膠上層析（丨克，4〇微米）(JTBaker， Phmlpsburg，n.j.)，以己烷_醋酸乙g旨梯度液，從〇%至8〇%醋酸 92199 • 308 - 1285641 乙酯溶離，而得標題化合物： 第一個溶離物：（R，R，S)-4-[(3,5-雙-三氟甲基-苯基）-羧基-甲基]-2-乙基-6-一氣甲基-3,4-一氮-2H-P奎淋-1-致酸乙醋（67愛克）； MS : 572.4 [M+Hf 實測值· 1H-NMR (CDC13) 5 7_90 (s，1H)，7.89 (s，2H)，7.54 (m，2H)，7.46 (brs，1H)， 4.28 (m，2H)，4.22 (m，1H)，4.08 (d，J=11.2Hz，1H)，3·37 (m，1H)，L76 (m，1H)， 1.48 (m，1H)，L38 (m，1H)，1·31 (t，J=7.05Hz，3H)，0·95 (m，1H)，0·70 (U=7.47 Hz，3H)· 第二個溶離物：（R,R，R)斗[(3,5-雙-三氟甲基-苯基）-羧基-甲基 ]-2-乙基-6-三氟甲基-3,4-二氫_2H·^奎琳-1-幾酸乙酿（29.5毫克） MS : 572.3 [M+H]—實測值 1H-NMR (CDC13) δ 7.94 (s, 2H), 7.83 (s5 1H), 7.50 (d, J=8.14Hz, 1H), 7.41 (brd，J=8.14Hz，1H)，7.01 (brs，1H)，4·42 (m，1H)，4.22 (m，2H)，4.21 (m，1H)， 3·32 (m，1H)，2.45 (m，1H)，1.58 (m，1H)，1.41 (m，1H)，1.41 (m，1H)，1.28 (t， J=7.47Hz，3H)，0.79 (t，J=7.47Hz，3H). 實例437(R,R,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-carboxy-methyl]·2-ethyl-trifluoromethyl-3,4-monohydro- 2H*^奎普林小酸酸乙酉Trifluoromethyl-3,4-dihydro-2H-carboline small carboxylic acid ethyl ester (example 433, 兕mg, 〇i67 millimolar), aqueous sodium hydroxide solution A mixture of (1 N, 丨ml, 丨mole) and anhydrous tetrahydrofuran (2.4 mL) was taken up at room temperature for 5 days, then 2n hydrochloric acid was added to afford acid pH. The mixture was extracted with ethyl acetate, and the organic solution was washed with water (x3) and dried over anhydrous sodium sulfate. The solvent was removed under vacuum and the residue was chromatographed on EtOAc EtOAc (EtOAc) Ethyl acetate 92199 • 308 - 1285641 Ethyl ester was dissolved to give the title compound: first isolate: (R,R,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-carboxyl -Methyl]-2-ethyl-6-monomethyl-3,4-nitroso-2H-P-quinone-1-acidic vinegar (67 gram); MS: 572.4 [M+Hf measured value · 1H-NMR (CDC13) 5 7_90 (s, 1H), 7.89 (s, 2H), 7.54 (m, 2H), 7.46 (brs, 1H), 4.28 (m, 2H), 4.22 (m, 1H), 4.08 (d, J=11.2Hz, 1H), 3·37 (m, 1H), L76 (m, 1H), 1.48 (m, 1H), L38 (m, 1H), 1·31 (t, J= 7.05Hz, 3H), 0·95 (m, 1H), 0·70 (U=7.47 Hz, 3H)· The second dissolvate: (R, R, R) bucket [(3,5-double-three) Fluoromethyl-phenyl)-carboxy-methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H·^ quinolin-1-carboxylic acid (29.5 mg) MS : 572.3 [M+H] - found 1H-NMR (CDC13) δ 7.94 (s, 2H), 7.83 (s5 1H), 7.50 (d, J = 8.14 Hz, 1H), 7.41 (brd, J = 8.14 Hz , 1H ), 7.01 (brs, 1H), 4·42 (m, 1H), 4.22 (m, 2H), 4.21 (m, 1H), 3·32 (m, 1H), 2.45 (m, 1H), 1.58 ( m, 1H), 1.41 (m, 1H), 1.41 (m, 1H), 1.28 (t, J = 7.47 Hz, 3H), 0.79 (t, J = 7.47 Hz, 3H). Example 437

(R，R)與（R，S)-4-[l-(3,5-雙-三氟甲基-苯基基-乙基]-2-乙基-6- 三氟甲基-2H-喳啉小羧酸乙醋 於(R,R)-4-[(3,5-雙-三氟甲基-苯基:l·甲氧羰基-甲基]-2-乙基-6-三 92199 - 309 - 1285641 氟甲基-2H-p奎淋-1-叛酸乙i旨與（R，S)-4-[(3,5-雙-三氟甲基-苯基）· 甲氧羰基-甲基]-2-乙基-6-三氟甲基奎琳小幾酸乙g旨（實例3 與4，以分離前所獲得之混合物使用，329毫克，0.563毫莫 耳）在無水四氫呋喃（6毫升）中之溶液内，在氮氣及-4〇°c下， 逐滴添加氫化鋰鋁溶液（1M，在四氫呋喃中，845微升，〇.845 毫莫耳）。於30分鐘後，添加過量醋酸乙酯，以使反應淬滅 ’並使混合物溫熱至室溫。使混合物與水/醋酸乙g旨振盘， 將有機層以水洗滌，以無水硫酸鋼脫水乾燥，及在真空下 蒸發。使粗產物於矽膠上藉層析純化，以己燒，然後己燒/ 酷酸乙酯9 : 1，接著4 ·· 1，然後7 : 3溶離，而得標題化合 物，為非對映異構物之混合物（243毫克）^ MS : 556.3 [M+H]+實測值· 實例438(R,R) and (R,S)-4-[l-(3,5-bis-trifluoromethyl-phenyl-ethyl]-2-ethyl-6-trifluoromethyl-2H - porphyrin small carboxylic acid ethyl acetoacetate in (R,R)-4-[(3,5-bis-trifluoromethyl-phenyl:l. methoxycarbonyl-methyl]-2-ethyl-6- 92192199 - 309 - 1285641 fluoromethyl-2H-p-quinone-1-repulesate and (R,S)-4-[(3,5-bis-trifluoromethyl-phenyl)· A Oxycarbonyl-methyl]-2-ethyl-6-trifluoromethyl quinione acid B (Examples 3 and 4, used in the mixture obtained before separation, 329 mg, 0.563 mmol) A solution of lithium aluminum hydride (1 M in THF, 845 μL, 〇.845 mmol) was added dropwise to a solution of anhydrous tetrahydrofuran (6 mL) under nitrogen and -4 ° C. Thereafter, an excess of ethyl acetate was added to quench the reaction and the mixture was allowed to warm to room temperature. The mixture was shaken with water/acetic acid, the organic layer was washed with water, dried with anhydrous sulfuric acid steel, and Evaporation under vacuum. The crude product was purified by chromatography on silica gel, hexanes, then hexanes/ethyl succinate 9:1, then 4··1, then 7:3 dissolved, and titled Was diastereomeric mixture of isomers (243 mg) ^ MS: 556.3 [M + H] + Example 438 · Found

人 (R，R，S)-4_[(3,5-雙-三氟甲基-苯基）-胺甲醯基·甲基]·2_乙基各三氟 甲基-3,4-二氫-2H”奎淋-1-竣酸乙酯Human (R,R,S)-4_[(3,5-bis-trifluoromethyl-phenyl)-aminecarboxamylmethyl]2-ethyl-trifluoromethyl-3,4- Dihydro-2H" quinolate-1-decanoic acid ethyl ester

曱基-3,4-二氫-2H-喹啉小羧酸乙酯（實例435 , 11〇毫克，〇193 I吴耳）與一氣化亞硫酿（1¾升）之混合物，於室溫及氣氣下 92199 -310- 1285641 攪拌3天，然後，在真空下移除過量二氣化亞硫醯。於殘留 物中，添加氨在二氧陸圜中之溶液（0.5M，6毫升，3毫莫耳） 。12小時後’將混合物以酷酸乙g旨稀釋，以水洗滌（χ2)，並 使有機層以無水硫酸鈉脫水乾燥，然後於真空下蒸發至乾 酒。使粗產物於矽膠上藉層析純化，以二氯甲烷/醋酸乙酯 39 : 1，接著19 : 1溶離，獲得標題化合物（1〇3毫克）。 MS : 571·3[Μ+Η]+實測值。 1H-NMR (CDC13) 5 7.88 (s，1Η)，7·88 (s，2Η)，7·51 (m，2Η)，7.46 (brs，1Η)， 5.80 (brs，1H)，5.53 (brs，1H)，4.26 (m，1H)，4.26 (m，1H)，4·19 (m，1H)，3.82 (d，J=10.79Hz，1H)，3.45 (m，1H)，1.68 (m，1H)，1.49 (m，1H)，1·39 (m，1H)， 1.29 (t5 J=7.06Hz, 3H), 0.95 (m, 1H), 0.70 (t, J=7.47Hz, 3H). 兩種下列化合物係藉由類似程序，個別利用甲胺與二甲胺 替代氨而製成： 實例439a mixture of decyl-3,4-dihydro-2H-quinoline carboxylic acid ethyl ester (example 435, 11 〇 mg, 〇193 I wuer) and a gasified sulphurized sulphur (13⁄4 liter) at room temperature and Under a gas atmosphere, 92199 -310 - 1285641 was stirred for 3 days, and then excess di-sulfurized sulfite was removed under vacuum. A solution of ammonia in dioxane (0.5 M, 6 mL, 3 mmol) was added to the residue. After 12 hours, the mixture was diluted with citric acid, washed with water (2), and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The crude product was purified by chromatography EtOAcjjjjjjjjj MS: 571·3 [Μ+Η]+ measured value. 1H-NMR (CDC13) 5 7.88 (s, 1Η), 7·88 (s, 2Η), 7·51 (m, 2Η), 7.46 (brs, 1Η), 5.80 (brs, 1H), 5.53 (brs, 1H), 4.26 (m, 1H), 4.26 (m, 1H), 4·19 (m, 1H), 3.82 (d, J = 10.79 Hz, 1H), 3.45 (m, 1H), 1.68 (m, 1H) ), 1.49 (m, 1H), 1·39 (m, 1H), 1.29 (t5 J=7.06Hz, 3H), 0.95 (m, 1H), 0.70 (t, J=7.47Hz, 3H). The following compounds were prepared by similar procedures using methylamine and dimethylamine instead of ammonia: Example 439

(R，R，S)-4-[(3,5-雙-三氟甲基-苯基）_甲基胺〒醯基-甲基]1乙基各 三氟甲基-3,4-二氫奎啉小羧酸乙酯 MS ·· 585.3 [M+H];實測值. 實例440 92199 -311 &lt; 1285641(R,R,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-methylamine fluorenyl-methyl]1 ethyl-trifluoromethyl-3,4- Dihydroquinoline small carboxylic acid ethyl ester MS ·· 585.3 [M+H]; measured value. Example 440 92199 -311 &lt; 1285641

(R，R，S)-4-[(3,5-雙-三氟甲基-苯基）-二甲基胺甲醯基-甲基]-2•乙基 -6-二氣甲基-3,4-二氮奎7林-1-幾酸乙酉旨 MS : 599.3 [M+H]+ 實測值· 實例441與442(R,R,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-dimethylaminecarbazyl-methyl]-2•ethyl-6-dimethylmethyl -3,4-diazepine-7-lin-1-carboxylic acid ethyl hydrazine MS: 599.3 [M+H]+ Measured values · Examples 441 and 442

c Fc F

广。乂〇 (氏1^)_4-[(3,5-雙-三氟基甲基-苯基）-氰基-甲基]-2-乙基各三氟甲 基-3,4-二氫-2H-0奎17林-1-致酸乙@旨wide.乂〇(1^)_4-[(3,5-bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-trifluoromethyl-3,4-dihydro -2H-0 Kui 17 Lin-1-acid B@

(11，11，11)-4-[(3,5-雙-三氟甲基-苯基）-氰基-甲基]-2-乙基-6-三氟甲基 92199 -312 - 1285641 二氫-2H-喹啉小羧酸乙酯 於（R，R，S)-4-[(3,5-雙-二氟甲基-苯基）_胺甲醯基·甲基]乙基； 二氟甲基-3,4-二氫-2H-4淋小幾酸乙酯（實例438，3〇毫克，〇⑹ 毫莫耳）在無水二氯甲烷（1毫升）中之溶液内，添加（甲氧羰 基胺績醯基）二乙基氫氧化铵（Burgess試劑，37毫克，〇 157客 莫耳）。將混合物於室溫及氮氣下攪拌72小時，然後在真空 下蒸發。使粗產物於矽膠上藉層析純化，以己烷溶離，接 著為己烷/醋酸乙酯19 : 1，然後9 ·· 1，獲得標題化合物： 第一個溶離化合物：（民民扣冰⑹^-雙-三氟甲基-苯基^氰基· 甲基]-2-乙基-6-三轨甲基-3,4-二氫-2H-0奎琳-1-複酸乙酯（8毫克）； MS: 553·3[Μ+Η]+實測值； 1H-NMR (CDC13) (5 7.96 (s, 1H), 7.90 (s, 2H), 7.60 (m3 2H), 7.56 (brs, 1H)? 4.88 (d? J=3.32Hz5 1H), 4.28 (m, 1H), 4.22 (m, 1H), 4.22 (m, 1H), 2.93 (m? 1H), 2.22 (m? 1H), 1.63 (m, 1H), 1.62 (m, 1H), 1.51 (m, 1H), 1.27 (t, J=7.47Hz? 3H)5 0.83 (t，J=7.47Hz，3H)· 第二個溶離化合物：（R，R，S)-4-[(3,5-雙-三氟甲基-苯基）-氰基-甲基]-2-乙基-6-三氟甲基-3,4-二氫-2H*^奎淋-1-叛酸乙§旨(20毫克）； MS : 553.3 [M+Hf 實測值； 1 H-NMR (CDC13) 5 7.96 (s，1H)，7.92 (s，2H)，7.59 (brs，1H)，7.57 (m，2H)， 4.36 (m，1H)，4.30 (m，1H)，4.27 (d，J=8.3Hz，1H)，4·22 (m，1H)，3.23 (m，1H)， 2·08 (m，1H)，1.55 (m，1H)，1.43 (m，1H)，1.30 (t，J=7.47Hz，3H)，1.27 (m，1H)， 0.79 (t，J=7.47Hz，3H). 製備43 (R)-4-溴基-2-乙基-6-三氟甲基-3,4-二氫-2H-喹啉小叛酸乙酯 92199 -313 - 1285641 MS : 379, 381 [Μ]·+ 實測值（GC-MS)· 於（R，S&gt;2-乙基领基各三氣曱基从二氮_2h七木小幾酸乙 酉旨（製備D，129克，10.37毫莫耳）在二氣甲院（25毫升）中之 溶液内…衰境溫度及氮氣了 ’添加吡咬(15δ毫升），接2 是逐滴之漠化磷⑽(U毫升）在二氯甲垸（1〇毫升）中之溶^ 。將混合物於環境溫度下授拌15小時，然後在水與二Ζ 燒之間作分液處理。將有機層以飽和錢氫納溶液（η。毫 升）洗滌’以無水硫酸納脫水乾燥，並於減壓下移除溶劑毛 =得標題化合物’為黃色油（3J9克），含有非對吹異構物與 藉由脫除溴化氫所形成之可變量⑻_2•乙基各三氟甲基_2η-邊 啉-1-羧酸乙酯之大約5 : i混合物。直接使用此粗製溴化物 無需進一步純化，或儲存於冷藏室中，以遏制進一步分解。 實例443與444(11,11,11)-4-[(3,5-bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6-trifluoromethyl 92199-312 - 1285641 Ethyl dihydro-2H-quinoline carboxylic acid in (R,R,S)-4-[(3,5-bis-difluoromethyl-phenyl)-amine-methylmethyl]ethyl]ethyl Difluoromethyl-3,4-dihydro-2H-4 leucine ethyl ester (Example 438, 3 〇 mg, 〇 (6) mmol) in anhydrous dichloromethane (1 mL) (Methoxycarbonylamine oxime) diethylammonium hydroxide (Burgess reagent, 37 mg, 〇 157 guest moles) was added. The mixture was stirred at room temperature under nitrogen for 72 hours and then evaporated in vacuo. The crude product was purified by chromatography on silica gel eluting with hexane, then hexane/ethyl acetate: 19:1, then 9··1, to give the title compound: first dissolved compound: ^-Bis-trifluoromethyl-phenyl^cyano·methyl]-2-ethyl-6-tris-methyl-3,4-dihydro-2H-0-quinone-1-acid ethyl ester (8 mg); MS: 553·3[Μ+Η]+ measured value; 1H-NMR (CDC13) (5 7.96 (s, 1H), 7.90 (s, 2H), 7.60 (m3 2H), 7.56 (brs , 1H)? 4.88 (d? J=3.32Hz5 1H), 4.28 (m, 1H), 4.22 (m, 1H), 4.22 (m, 1H), 2.93 (m? 1H), 2.22 (m? 1H), 1.63 (m, 1H), 1.62 (m, 1H), 1.51 (m, 1H), 1.27 (t, J=7.47Hz? 3H)5 0.83 (t, J=7.47Hz, 3H)· Second dissolved compound :(R,R,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-cyano-methyl]-2-ethyl-6-trifluoromethyl-3,4 - dihydro-2H*^ quinine-1-repulsate B (20 mg); MS: 553.3 [M+Hf found; 1 H-NMR (CDC13) 5 7.96 (s, 1H), 7.92 (s , 2H), 7.59 (brs, 1H), 7.57 (m, 2H), 4.36 (m, 1H), 4.30 (m, 1H), 4.27 (d, J = 8.3 Hz, 1H), 4·22 (m, 1H), 3.23 (m, 1H), 2·08 (m, 1H), 1.55 (m 1H), 1.43 (m, 1H), 1.30 (t, J = 7.47 Hz, 3H), 1.27 (m, 1H), 0.79 (t, J = 7.47 Hz, 3H). Preparation 43 (R)-4-bromo Ethyl-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline betulinic acid ethyl ester 92199-313 - 1285641 MS : 379, 381 [Μ]·+ Measured value (GC- MS) · (R, S > 2-ethyl ketone each of the three gas thiol groups from dinitrogen 2h heptachloric acid (preparation D, 129 grams, 10.37 millimoles) in the second gas hospital ( In a solution of 25 ml), the temperature of the aging and the nitrogen were added 'addition of the butyl bite (15 δ ml), followed by the dropwise solution of the desertified phosphorus (10) (U ml) in dichloromethane (1 ml) ^ The mixture was stirred at ambient temperature for 15 hours and then separated between water and bismuth. The organic layer was washed with a saturated aqueous solution of hydrogen (n.sub.1 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give the title compound as a yellow oil (3J 9 g). The construct is a mixture of about 5:1 of a variable amount of (8)_2•ethyltrifluoromethyl-2η-porphyrin-1-carboxylic acid ethyl ester formed by removal of hydrogen bromide. This crude bromide can be used directly without further purification or stored in a cold room to contain further decomposition. Examples 443 and 444

CICI

(R，R，R)-4-[氰基-(3,5-二氯-苯基 &gt;甲基]-2-乙基-6-三氟甲基-3,4-二 氫-2H-喳啉小羧酸乙酯 92199 -314 - 1285641(R,R,R)-4-[cyano-(3,5-dichloro-phenyl)methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H -porphyrin small carboxylic acid ethyl ester 92199 -314 - 1285641

ClCl

(R，R，S)-4-[氣基-(3,5-«_鼠-冬基）-f基]-2-乙基-6-三氣甲基-3,4-二氮 -2H^奎啉小羧酸乙酯 於3,5-二氯苯基乙腈（134毫克，0.72毫莫耳，根據W0 00/58292 中所述之程序製成）在無水N，N-二甲基甲醯胺（1毫升）中之溶 液内，添加氫化鈉（60%礦油分散液，〇·925毫莫耳，37毫克） ，並將混合物在室溫下攪拌30分鐘。添加⑻斗溴基1乙基各 二氟甲基-3,4-一氲-2Η-Ρ奎淋小羧酸乙酯（製備43，250毫克，異 構物之混合物，按上述製成）在無水Ν，Ν_二甲基甲醯胺（1·5毫 升）中之溶液，並將混合物於室溫下攪拌5分鐘。添加水， 並以乙醚（3x20毫升）萃取混合物，且將有機萃液以庚烷稀 釋，並蒸發至乾涸，獲得粗產物，為黃色油（〜4〇〇毫克）。最 初之純化係-藉由在矽膠上藉層析純化，以己烷/醋酸乙醋$ :1溶離而達成。使含有標題化合物之溶離份進一步純化， 使用具有2毫米矽膠轉子之徑向展開層析〜 -' , (挪fe形色顯像 官 7924丁型，Hamson 研究，Palo Alt〇, cA)，以己卢 ^ 、 70 /醋酸乙g旨9 ·· 1 溶離’獲得標題化合物： 第一個溶離化合物： 氟甲基-3,4-二 (R，R，R)_4-[氰基-(3,5·二氯-苯基）_甲基乙基^ 氫-2H-喹淋小羧酸乙酯（丨4毫克）； 92199 -315 - 1285641 1 H-NMR (CDC13) (5 7.59 (s，2H)，7.54 (s，1H)，7.43 (t，J=1.95Hz，1Η)，7·35 (d，J=1.95Hz，2H)，4.69 (d，J=3.52Hz，1H)，4.28 (m，1H)，4·22 (m，1H)，4.22 (m， 1H)，2.90 (m，1H)，2.27 (m，1H)，1.61 (m，1H)，1.50 (m，1H)，1.49 (m，1H)，1,29 (t，J=7.03Hz，3H)，0.84 (t，J=7.42Hz，3H). 第二個溶離化合物： (R，R，S)-4-[氰基-(3,5_二氯-苯基）-甲基]-2-乙基-6-三氟甲基-3,4-二 氫-2H-喳啉-1-羧酸乙酯（5毫克）； MS : 485·2[Μ+Η]+實測值； 1H-NMR (CDC13) 5 7.59 (s，1Η)，7.55 (s，2Η)，7·42 (t，&gt;1·66Ηζ，1Η)，7.33 (d，J=1.66Hz，2Η)，4·34 (m，1Η)，4·27 (m，1Η)，4.22 (m，1Η)，4·01 (d，&gt;9·13Ηζ， 1H)，3.13 (m，1H)，2.07 (m，1H)，1.53 (m，1H)，1·42 (m，1H)，L30 (t，J=7.47Hz， 3H)，1.16 (m，1H)，0.78 (t，J=7.47Hz，3H)· 實例445(R,R,S)-4-[gas-based-(3,5-«_murine-winteryl)-fyl]-2-ethyl-6-tris-methyl-3,4-diaza- 2H^ quinine small carboxylic acid ethyl ester in 3,5-dichlorophenylacetonitrile (134 mg, 0.72 mmol, according to the procedure described in WO 00/58292) in anhydrous N,N-dimethyl Sodium hydride (60% mineral oil dispersion, 〇·925 mmol, 37 mg) was added to the solution of the mesamine (1 ml), and the mixture was stirred at room temperature for 30 minutes. Add (8) bromodiethyldiethyldifluoromethyl-3,4-indan-2-indole-quinone carboxylic acid ethyl ester (preparation 43,250 mg, a mixture of isomers, prepared as described above) A solution of anhydrous hydrazine, hydrazine-dimethylformamide (1.5 ml) was added, and the mixture was stirred at room temperature for 5 minutes. Water was added and the mixture was extracted with EtOAc (EtOAc m. The initial purification was achieved by chromatography on silica gel, eluting with hexane/ethyl acetate $:1. The fractions containing the title compound were further purified using a radial development chromatography with a 2 mm silicone rotor ~-', (Nove Fe color imaging officer 7924 type, Hamson study, Palo Alt〇, cA) Lu ^, 70 / acetic acid ethyl g 9 ·· 1 Dissolution 'obtained the title compound: the first dissolved compound: fluoromethyl-3,4-di(R,R,R)_4-[cyano-(3, 5·Dichloro-phenyl)-methylethyl^ Hydrogen-2H-quinoline small carboxylic acid ethyl ester (丨4 mg); 92199 -315 - 1285641 1 H-NMR (CDC13) (5 7.59 (s, 2H) ), 7.54 (s, 1H), 7.43 (t, J = 1.95 Hz, 1 Η), 7·35 (d, J = 1.95 Hz, 2H), 4.69 (d, J = 3.52 Hz, 1H), 4.28 (m) , 1H), 4·22 (m, 1H), 4.22 (m, 1H), 2.90 (m, 1H), 2.27 (m, 1H), 1.61 (m, 1H), 1.50 (m, 1H), 1.49 ( m,1H),1,29 (t,J=7.03 Hz,3H), 0.84 (t,J=7.42 Hz, 3H). The second solvate compound: (R,R,S)-4-[cyano -(3,5-Dichloro-phenyl)-methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-indololin-1-carboxylic acid ethyl ester (5 mg MS: 485·2[Μ+Η]+ measured value; 1H-NMR (CDC13) 5 7.59 (s, 1Η), 7.55 (s, 2Η), 7.42 (t,&gt;1·66Ηζ,1Η),7.33 (d,J=1.66Hz,2Η),4·34 (m,1Η),4·27 (m,1Η), 4.22 (m,1Η),4 ·01 (d,&gt;9·13Ηζ, 1H), 3.13 (m,1H), 2.07 (m,1H), 1.53 (m,1H),1·42 (m,1H), L30 (t,J= 7.47 Hz, 3H), 1.16 (m, 1H), 0.78 (t, J = 7.47 Hz, 3H) · Example 445

(R，R，S)-4-[(3,5-雙-二氟甲基-苯基）-乙氧羰基-甲基]乙基各三氟 甲基-3,4-二氫-2H—奎淋-1-叛酸乙酯 將（R，R，S)-4-[(3,5-雙·三氟甲基-苯基）-羧基-甲基]乙基各三氟 甲基-3,4-二氫-2Η-ρ奎π林-1-複酸乙g旨（實例435，33毫克，〇 〇58毫 莫耳）在含有濃硫酸（4滴）之無水乙醇（5毫升）中之溶液，於 92199 -316* 1285641 回流下加熱18小時，然後在真空下蒸發溶劑。使殘留物於 水與醋酸乙酯之間作分液處理，將有機層以水洗滌，以無 水硫酸鈉脫水乾燥，及在真空下蒸發。使殘留物於矽膠上 藉層析純化’以己烷，接著己烷/醋酸乙酯梯度液9 : 1至 4: 6溶離，而得標題化合物（17·5毫克），為膠質。 MS : 600·6 [Μ+Η]+ 實測值. 1 H-NMR (CDC13) (5 7.88 (s, 2H), 7.88 (s, 1H)? 7.53 (m, 2H), 7.44 (brs, 1H), 4.35 (m，1H)，4.27 (m，2H)，4.22 (m，1H)，4.06 (m，1H)，4,01 (d，J=lL62Hz，1H)， 3.37 (m，1H)，1.73 (m，1H)，1.48 (m，1H)，L38 (m，1H)，1.30 (t，JM7.06HZ，3H)， 1.27 (t，J=7.06Hz，3H)，0.94 (m，1H)，0.70 (t，J=7.47Hz，3H)· 實例446(R,R,S)-4-[(3,5-bis-difluoromethyl-phenyl)-ethoxycarbonyl-methyl]ethyltrifluoromethyl-3,4-dihydro-2H - quinine-1-o-acid ethyl ester (R,R,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-carboxy-methyl]ethyl each trifluoromethyl -3,4-Dihydro-2 Η-ρ π π lin-1- carboxylic acid B g (example 435, 33 mg, 〇〇58 mmol) in absolute ethanol (4 ml) containing concentrated sulfuric acid (5 ml) The solution was heated under reflux at 92199-316* 1285641 for 18 hours and then the solvent was evaporated in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by chromatography eluting EtOAc EtOAc EtOAc EtOAc MS : 600·6 [Μ+Η]+ Measured value. 1 H-NMR (CDC13) (5 7.88 (s, 2H), 7.88 (s, 1H)? 7.53 (m, 2H), 7.44 (brs, 1H) , 4.35 (m,1H), 4.27 (m,2H), 4.22 (m,1H), 4.06 (m,1H),4,01 (d,J=lL62Hz,1H), 3.37 (m,1H),1.73 (m, 1H), 1.48 (m, 1H), L38 (m, 1H), 1.30 (t, JM7.06HZ, 3H), 1.27 (t, J = 7.06 Hz, 3H), 0.94 (m, 1H), 0.70 (t, J = 7.47 Hz, 3H) · Example 446

⑻斗(3,5-雙-三氟甲基-爷基）-2-乙基-6-三氟甲基-2H-喳啉小羧酸 乙酉旨 於(R，R)-4-[(3,5-雙-三氟甲基-苯基）-甲氧羰基-甲基]乙基-6-三 氟曱基-2H-喹啉-1邊酸乙酯與（R，S)-4-[(3,5-雙-三氟甲基-苯基）_ 甲氧黢基-甲基]-2-乙基-6-三氟甲基奎π林小幾酸乙醋（實例3 與4，以分離前所獲得之混合物使用，148毫克，0.253毫莫 耳）在四氫呋喃（3毫升）中之溶液内，在氮氣下，添加氫氧化 92199 -317- 1285641 鈉水溶液（1M，250微升，0.25毫莫耳）。於室溫下撥拌72小 時後，添加另一液份之氫氧化納溶液（1M，1〇〇微升，〇 1毫 莫耳）。72小時後，藉由添加2N鹽酸使混合物酸化，並以酷 酸乙酯萃取。使有機層以無水硫酸納脫水乾燥，於真空下 蒸發，並使殘留物在硬膠上藉層析純化，以二氯f垸/己燒 1 : 1，然後3 : 1，接著二氯甲燒，然後二氯甲垸/甲醇9 : 1 ，接著己烷/醋酸乙酯梯度液從9 : 1至4 : 6溶離，而得標題 化合物（4.5毫克）。 MS : 526·3 [Μ+ΗΓ 實測值· 1H-NMR (CDCI3) 5 7.76 (s，1Η)，7.74 (m，1Η)，7.68 (s，2Η)，7·48 (m，1Η)， 7.42 (brs，1H)，5·76 (d，J=5.81Hz，1H)，4.93 (m，1H)，4.27 (m，2H)，3·92 (m，1H)， 3.88 (m，1H)，1.48 (m，1H)，1.38 (m5 1H)，1.32 (t，J=7.47Hz，3H)，0.85 (t，J=7.47 Hz, 3H). 實例447(8) Bucket (3,5-bis-trifluoromethyl-yl)-2-ethyl-6-trifluoromethyl-2H-carboline small carboxylic acid acetamidine (R,R)-4-[( 3,5-Bis-Trifluoromethyl-phenyl)-methoxycarbonyl-methyl]ethyl-6-trifluorodecyl-2H-quinoline-1 oleate and (R,S)-4 -[(3,5-bis-trifluoromethyl-phenyl)-methoxymethyl-methyl]-2-ethyl-6-trifluoromethyl quinanyl chlorate (example 3 with 4, using a mixture obtained before the separation, 148 mg, 0.253 mmol, in tetrahydrofuran (3 ml), under a nitrogen atmosphere, adding 9299-317-1268941 sodium hydroxide solution (1 M, 250 μl , 0.25 millimoles). After mixing for 72 hours at room temperature, another aliquot of sodium hydroxide solution (1 M, 1 〇〇 microliter, 〇 1 mmol) was added. After 72 hours, the mixture was acidified by the addition of 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, evaporated in vacuo, and the residue was purified by chromatography on a hard gel, hexane, hexane, 1:1, then 3:1, then dichloromethane. Then, the title compound (4.5 mg) was obtained from the hexane/ethyl acetate gradient from 9:1 to 4:6. MS : 526·3 [Μ+ΗΓ Measured value · 1H-NMR (CDCI3) 5 7.76 (s,1Η), 7.74 (m,1Η), 7.68 (s,2Η),7·48 (m,1Η), 7.42 (brs,1H),5·76 (d,J=5.81Hz,1H), 4.93 (m,1H), 4.27 (m,2H),3·92 (m,1H), 3.88 (m,1H), 1.48 (m, 1H), 1.38 (m5 1H), 1.32 (t, J = 7.47 Hz, 3H), 0.85 (t, J = 7.47 Hz, 3H). Example 447

(11，氏3)-4-[1-(3,5-雙-三氟甲基-苯基）-2-#至基-乙基]-2-乙基-6-三氟 甲基-3,4-二氫-2H-p奎琳-1-複酸乙酉旨 於(R，R，S)-4-[(3,5-雙-三氟甲基-苯基）_羧基-甲基]-2-乙基各三氟 甲基-3,4-二氫-2H-喳啉-1-複酸乙酯（實例435，67毫克，0.117毫 92199 -318- 1285641 莫耳）在四氩吱喃（丨毫升）中之溶液内，在氮氣下，添加硼烷 -硫化二甲烷複合物（22.2微升，0.234毫莫耳）。於24小時後， 添加氲氧化制水溶液（1M，4滴），以使反應淬滅，並將混合 物攪拌1小時。藉由添加2N鹽酸使混合物酸化，攪拌1〇分鐘 ’並以醋酸乙g旨萃取。將有機層以水洗務，以無水硫酸納 脫水乾燥，並於真空下蒸發溶劑。使粗產物於矽膠上藉層 析純化，以己烷，然後己烷/醋酸乙酯19 : 1，接著9 : , 然後4 : 1，接著3 : 7，及最後2 : 3溶離，而得標題化合物（54 毫克）。 MS : 558·3[Μ+Η]+實測值· 1H-NMR (CDC13) 5 7.83 (s，1Η)，7.80 (s，2Η)，7.60 (brs，1Η)，7.52 (m，2Η)， 4.27 (m，1H)，4.24 (m，2H)，4.20 (m，1H)，4·00 (m，1H)，3.54 (m，1H)，2.84 (m， 1H)，1.82 (m，1H)，1·63 (brs，1H)，1·46 (m，1H), 1·32 (m，1H)，1·31 (t，J=7.05Hz， 3H)，0.87 (m，1H)，0.69 (t，J=7.47Hz，3H). 製備44 (3,5-二氣）-苯基醋酸甲酯 將3,5-二t：苯基乙腈（2克，根據WO 00/58292中所述之程序製 成）、乙醇（25毫升）、氫氧化鉀（3.95克）及水（1〇毫升）之混合 物，於回流下加熱4小時，然後在真空下蒸發至乾涸。使殘 留物於水（20毫升）與乙醚之間作分液處理，並藉由添加濃鹽 酸使水層酸化至pH 1。以乙醚（3 X 25毫升）萃取混合物，使有 機層以無水硫酸鈉脫水乾燥，並於真空下蒸發。使幾酸溶 於甲醇（20毫升）中，並慢慢添加三甲基矽烷基重氮甲烷（在 己烷中之2M溶液，30毫升Aldrich化學公司，Milwaukee，WI)。1 92199 -319 - 1285641 小時後’在真空下移除溶劑，使殘留物汝 „,，，、、 各於乙醚中，以碳 鈉水溶液（2M)洗務，以無水硫酸鈉脫水努 乾兔，及蒸發至乾 涸，而得標題化合物（2.1克）。 1 H-NMR (CDC13) 5 7.27 (s，1H)，7.17 (s，2H)，3.71 (s，3H)， 3.57 (s，2H). 實例 448、449、450 及 451 Cl(11, 3)-4-[1-(3,5-bis-trifluoromethyl-phenyl)-2-#-yl-ethyl]-2-ethyl-6-trifluoromethyl- 3,4-Dihydro-2H-p-quine-1-carboxylic acid acetamidine (R,R,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-carboxy-- Ethyl 2-ethyl-trifluoromethyl-3,4-dihydro-2H-carboline-1-hydroxylate (example 435, 67 mg, 0.117 m 92199 -318-1268941 Mo) in four A solution of borane-sulfurized dimethane (22.2 μL, 0.234 mmol) was added to the solution in argon (in liters) under nitrogen. After 24 hours, an aqueous solution of hydrazine oxidation (1M, 4 drops) was added to quench the reaction, and the mixture was stirred for 1 hour. The mixture was acidified by the addition of 2N hydrochloric acid, stirred for 1 min and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The crude product was purified by chromatography on hydrazine eluted with hexanes, then hexane/ethyl acetate 19:1, then 9:, then 4:1, then 3:7, and finally 2:3, and the title was obtained. Compound (54 mg). MS : 558·3[Μ+Η]+ measured value · 1H-NMR (CDC13) 5 7.83 (s, 1Η), 7.80 (s, 2Η), 7.60 (brs, 1Η), 7.52 (m, 2Η), 4.27 (m, 1H), 4.24 (m, 2H), 4.20 (m, 1H), 4·00 (m, 1H), 3.54 (m, 1H), 2.84 (m, 1H), 1.82 (m, 1H), 1·63 (brs,1H),1·46 (m,1H), 1·32 (m,1H),1·31 (t,J=7.05Hz, 3H), 0.87 (m,1H),0.69 ( t, J = 7.47 Hz, 3H). Preparation of 44 (3,5-di-)-phenylacetic acid methyl ester 3,5-di-t:phenylacetonitrile (2 g, as described in WO 00/58292 A mixture of ethanol, (25 mL), potassium hydroxide (3.95 g) and water (1 mL) was then warmed to reflux for 4 hours and then evaporated to dryness under vacuum. The residue was partitioned between water (20 mL) and diethyl ether, and the aqueous layer was acidified to pH 1 by adding concentrated hydrochloric acid. The mixture was extracted with diethyl ether (3×25 mL). Several acids were dissolved in methanol (20 mL) and trimethyldecyl diazomethane (2M solution in hexanes, 30 mL Aldrich Chemical Co., Milwaukee, WI) was added slowly. 1 92199 -319 - 1285641 hours later, the solvent was removed under vacuum, and the residue was washed with EtOAc (2M). The title compound (2.1 g) was obtained from EtOAc (EtOAc: EtOAc). Examples 448, 449, 450 and 451 Cl

(R，S，R&gt;4-[(3,5-二氯-苯基）-甲氧羰基-甲基;μ2_乙基各三氟甲基_3,4_ 二氫-2Η^奎淋-1_幾酸乙酉旨(R,S,R&gt;4-[(3,5-Dichloro-phenyl)-methoxycarbonyl-methyl; μ2_ethyl each trifluoromethyl_3,4_ dihydro-2Η^奎淋- 1_Severe acid

CICI

、ci 〇 (R，R，S)-4-[(3,5-二氯-苯基）-甲氧基碳-甲基]乙基各三氟甲基-3,4-, ci 〇 (R,R,S)-4-[(3,5-Dichloro-phenyl)-methoxycarbonyl-methyl]ethyltrifluoromethyl-3,4-

二氫-2H-p奎淋-1-叛酸乙酉旨 CIDihydro-2H-p-quinone-1-restroy acid

〇 92199 - 320 - 1285641 (R，S，S)-4-[(3,5-二氣-苯基甲氧羰基_f基]冬乙 一氫，2H”奎淋小幾酸乙酯 -甲基]-2-乙基-6-三 二氟甲基-3,4-〇92199 - 320 - 1285641 (R,S,S)-4-[(3,5-di-p-phenylmethoxycarbonyl-f-yl]-glycol-hydrogen, 2H" quinolate-ethyl ester-methyl ]-2-ethyl-6-tridifluoromethyl-3,4-

(民11，11)-4-[(3,5-二氯-苯基）_甲氧基碳-甲基]_2-乙基_6_三氟甲基 於（3,5-二氯）-苯基酷酸甲船⑴^ 3,4_二氫·2Η_α奎淋-μ幾酸乙酯(Nation 11,11)-4-[(3,5-Dichloro-phenyl)-methoxycarbonyl-methyl]_2-ethyl-6-trifluoromethyl (3,5-dichloro) -Phenyl succinic acid boat (1)^ 3,4_Dihydro·2Η_α 奎淋-μ-acid ethyl ester

分鐘。添加水，並以乙醚（3x20毫升）萃取混合物，且將有 獲得粗產物，為黃色 機萃液以庚^完稀釋，並蒸發至乾涸， 油（〜460毫克）^純化係使用具有4毫米矽膠轉子之徑向展開 層析法（柵控彩色顯像管7924T型，Hams〇n研究，pal〇 Alt〇, CA)達 成，以己烷/醋酸乙酯9 :丨溶離，接著使適當溶離份再層析 ，以二氣甲烷/己烷45 : 55溶離，而得標題化合物： (R，S，R)-4-[(3,5-二氯-苯基）_甲氧羰基_甲基]_2_乙基各三氟曱基-3,4-二氫-2H^奎琳幾酸乙酯（1〇毫克）； MS ·· 518·3[Μ+ΗΓ實測值； 92199 -321 - 1285641 1 H-NMR (CDC13) (5 7.55 (brd, J=8.30Hz, 1H), 7.49 (brd, J=8.30Hz, 1H), 7.48 (brs，1H)，7.33 (m，2H)，7.33 (m，1H)，4.33 (m，1H)，4.31 (m，1H)，4.24 (m， 1H)，3.56 (d，J=11.62Hz，1H)，3.52 (m，1H)，3·46 (s，3H)，1.86 (m，1H)，1.53 (m， 1H)，1.47 (m，2H)，1·34 (t，J=7.47Hz，3H), 0.74 (t，J=7.47Hz，3H). (R，R，S)-4-[(3,5-二氯-苯基）-甲氧羰基-甲基]-2-乙基-6-三氟甲基- 3.4- 二氫-2H-喹啉小羧酸乙酯（24毫克）； MS : 518.3 [M+Hf 實測值； 1 H-NMR (CDC13) δ 7·52 (m，1Η)，7.50 (m，1Η)，7.35 (t，J=1.66Hz，1Η)， 7.32 (brs，1H)，7.30 (d，J=1.66Hz，2H)，4.30 (m，1H)，4.27 (m，1H)，4.20 (m，1H)， 3.78 (d，J=11.61Hz, 1H)，3·74 (s，3H)，3.2,8 (m，1H)，1.85 (m，1H)，1.49 (m，1H)， 1.39 (m，1H)，1.30 (U=7.47Hz，3H)，0·91 (m，1H)，0,72 (t，J=7.47Hz，3H). (11，3,3)-4-[(3,5-二氯-苯基）-甲氧羰基-甲基]-2-乙基各三氟甲基- 3.4- 二氫_2H-喳啉小羧酸乙酯（29毫克）； MS : 518.3 [M+H]+實測值； 1 H-NMR (CDC13) 5 7·43 (d，J=8.30Hz，1H)，7.36 (dd，J=8.30, 1.66Hz，1H)， 7·15 (U=1.66，1H)，6·88 (d，J=1.66Hz，2H)，6.69 (brs，1H)，4.45 (m，1H)，4.32 (m，1H)，4.31访1，1H)，3.75 (s，3H)，3·62 (d，J=10.79Hz，1H)，3.40 (m，1H)， 2·88 (m，1H)，1.75 (m，1H)，1.64 (m，1H)，1.48 (m，1H)，1.34 (t，J=7.47Hz，3H)， 0.83 (t，J=7.47Hz，3H). (R，R，R)-4-[(3,5-二氣-苯基）-甲氧談基-甲基]-2-乙基-6-三氟甲基- 3.4- 二氫-211-。奎0林小複酸乙g旨（18毫克）； MS : 518.3 [M+H]+實測值； 1 H-NMR (CDC13) 5 7.51 (brd，J=8.59Hz，1H)，7.43 (brd，J=8.59Hz，1H)， 7.33 (m，2H)，7.31 (m，1H)，7,10 (brs，1H)，4·40 (m，1H)，4.28 (m，1H)，4.23 (m， 92199 - 322 - 1285641 1H)，4.06 (d，J=l〇.15Hz，iH)，3.74 (s，3H)，3.24 (m，1H)，2.32 (m，1H)，i.64 (m， 1H)，1.47 (m，1H)，1.37 (m，1H)，1.32 (t，J=7.02Hz，3H)，0.83 (t，J=7.47Hz，3H)· 實例452minute. Water was added, and the mixture was extracted with diethyl ether (3×20 mL), and a crude product was obtained, which was diluted with EtOAc, evaporated and evaporated to dryness, EtOAc (~ 460 mg). Radial expansion chromatography of the rotor (Gate-controlled color picture tube 7924T, Hams〇n study, pal〇Alt〇, CA) was achieved by hexane/ethyl acetate 9: hydrazine, followed by re-chromatography of the appropriate fraction The title compound was obtained by dissolving with di-methane/hexane 45:55: (R,S,R)-4-[(3,5-dichloro-phenyl)-methoxycarbonyl-methyl]_2_ Ethyl ethyltrifluoromethyl-3,4-dihydro-2H^ quinal acid ethyl ester (1 〇 mg); MS ·· 518·3 [Μ + ΗΓ measured value; 92199 -321 - 1285641 1 H- NMR (CDC13) (5 7.55 (brd, J = 8.30 Hz, 1H), 7.49 (brd, J = 8.30 Hz, 1H), 7.48 (brs, 1H), 7.33 (m, 2H), 7.33 (m, 1H) , 4.33 (m, 1H), 4.31 (m, 1H), 4.24 (m, 1H), 3.56 (d, J = 11.62 Hz, 1H), 3.52 (m, 1H), 3·46 (s, 3H), 1.86 (m, 1H), 1.53 (m, 1H), 1.47 (m, 2H), 1·34 (t, J = 7.47 Hz, 3H), 0.74 (t, J = 7.47 Hz, 3H). (R, R,S)-4-[(3,5-dichloro- Phenyl)-methoxycarbonyl-methyl]-2-ethyl-6-trifluoromethyl-3.4-dihydro-2H-quinolinecarboxylic acid ethyl ester (24 mg); MS: 518.3 [M+Hf Found; 1 H-NMR (CDC13) δ 7·52 (m, 1 Η), 7.50 (m, 1 Η), 7.35 (t, J = 1.66 Hz, 1 Η), 7.32 (brs, 1H), 7.30 (d, J = 1.66 Hz, 2H), 4.30 (m, 1H), 4.27 (m, 1H), 4.20 (m, 1H), 3.78 (d, J = 11.61 Hz, 1H), 3.74 (s, 3H), 3.2,8 (m,1H),1.85 (m,1H), 1.49 (m,1H), 1.39 (m,1H),1.30 (U=7.47Hz,3H),0·91 (m,1H),0 , 72 (t, J = 7.47 Hz, 3H). (11,3,3)-4-[(3,5-Dichloro-phenyl)-methoxycarbonyl-methyl]-2-ethyl each Fluoromethyl- 3.4-dihydro-2H-carboline ethyl carboxylic acid ethyl ester (29 mg); MS: 518.3 [M+H] + found; 1 H-NMR (CDC13) 5 7·43 (d, J =8.30Hz,1H),7.36 (dd,J=8.30, 1.66Hz,1H), 7·15 (U=1.66,1H),6·88 (d,J=1.66Hz,2H),6.69 (brs, 1H), 4.45 (m, 1H), 4.32 (m, 1H), 4.31 visit 1, 1H), 3.75 (s, 3H), 3.62 (d, J = 10.79Hz, 1H), 3.40 (m, 1H) ), 2·88 (m, 1H), 1.75 (m, 1H), 1.64 (m, 1H), 1.48 (m, 1H), 1.34 (t, J = 7.47) Hz,3H), 0.83 (t,J=7.47Hz,3H). (R,R,R)-4-[(3,5-di-phenyl)-methoxy-yl]methyl]-2 -ethyl-6-trifluoromethyl-3.4-dihydro-211-.奎0林小复酸乙g(18mg); MS : 518.3 [M+H]+ Measured; 1 H-NMR (CDC13) 5 7.51 (brd,J=8.59Hz,1H),7.43 (brd,J= 8.59 Hz, 1H), 7.33 (m, 2H), 7.31 (m, 1H), 7, 10 (brs, 1H), 4·40 (m, 1H), 4.28 (m, 1H), 4.23 (m, 92199) - 322 - 1285641 1H), 4.06 (d, J=l〇.15Hz, iH), 3.74 (s, 3H), 3.24 (m, 1H), 2.32 (m, 1H), i.64 (m, 1H) , 1.47 (m, 1H), 1.37 (m, 1H), 1.32 (t, J = 7.02 Hz, 3H), 0.83 (t, J = 7.47 Hz, 3H) · Example 452

(R，R，S)-4-[(3,4-一氯-苯基）-甲氧羰基-甲基]-2-乙基-6-三氟甲基4_ 二氫奎啉小羧酸乙酯 於（3,4-二氯）-苯基醋酸甲酯（1·22克，5·57毫莫耳）在無水n，n_ 二甲基甲醯胺（5毫升）中之溶液内，添加氫化鈉（6〇%礦油分 散液’ 7毫莫耳，280毫克），並將混合物在室溫下攪拌5分 鐘。添加（R)-4_溴基-2-乙基各三氟甲基-3,4-二氫-2H-喹啉小羧酸 乙酯（798笔克，異構物之混合物，製備43)在無水n，n•二甲基 甲醯胺（4毫升）中之溶液，並將混合物在室溫下攪拌μ分鐘 。添加水，一並使混合物藉由添加2N鹽酸酸化，然後以二氯 甲烷萃取（x3)，並使有機萃液以無水硫酸鈉脫水乾燥，及蒸 發至乾涸，獲得更色油。使其溶於四氫呋喃（丨〇毫升）與水 (5毫升）中，並添加氫氧化鈉水溶液（2N，1〇毫升）。將混合 物於室溫下攪拌24小時，接著在鹽酸剛與二氯甲烷之間 作分液處理。使有機萃液以無水硫酸鈉脫水乾燥，並蒸庐 至乾涸，而得羧酸類之混合物 純化，以己燒/醋酸乙酯5 : 1 , 。使此物質於矽膠上藉層析 然後4 · 1 A離。將含有第一 92199 - 323 - 1285641 個溶離之羧酸之溶離份（具有所要之R，R，S立體化學）合併， 在真空下蒸發至乾涸，並溶於甲醇（25毫升）中。慢慢添加三 甲基矽烷基重氮甲烷（在己烷中之2M溶液，Aldnch化學公司 ，Milwaukee，WI)，直到停止發泡且黃色持續為止。藉由添加少 量醋酸使其排放，然後，於真空下移除溶劑，並使殘留物 在矽膠上藉層析純化，以己烷/二氯甲烷梯度液2 : 1至1 : 2 溶離。最後之純化係使用逆相HPLC，使用Shimadzu預備之HPLC 系統（Shimadzu 公司，Kyoto, Japan)達成，以 30-100% 乙腈 / 水 / 0.1 %甲酸梯度液溶離，在19x50毫米Waters對稱性管柱上（Waters 公司，Milford，ΜΑ)，8分鐘操作，6分鐘梯度液，25毫升/分 鐘，UV觸發收集，於210毫微米下觀察。使含產物之溶離份 蒸發至乾涸，而得標題化合物（75毫克）。 MS : 518.3 [Μ+Η]+實測值. 1H-NMR (CDC13) δ 7·52 (m，1H)，7.51 (m，1H)，7.50 (m，1H)，7·47 (d， 8.3Hz? 1H), 7.34 (brs? 1H), 7.25 (dd5 J=8.3,2.49Hz5 1H), 4.28 (m, 1H)5 4.27 (m, 1H)，4.20 (m，1H)，3.80 (d，J=11.62Hz，1H)，3.73 (s，3H)，3.29 (m，1H)，1.86 (m， 1H)，L50 (m，TH)，1.37 (m，1H)，1.30 (t，J=7.47Hz，3H)，0.90 (m，1H)，0.71 (t， J=7.47Hz，3H)· 實例453(R,R,S)-4-[(3,4-Chloro-phenyl)-methoxycarbonyl-methyl]-2-ethyl-6-trifluoromethyl 4_dihydroquinoline carboxylic acid Ethyl ester in a solution of methyl (3,4-dichloro)-phenylacetate (1·22 g, 5·57 mmol) in anhydrous n, n-dimethylformamide (5 mL) Sodium hydride (6 〇% mineral oil dispersion '7 mmol, 280 mg) was added, and the mixture was stirred at room temperature for 5 minutes. Add (R)-4-bromo-2-ethyl-trifluoromethyl-3,4-dihydro-2H-quinolinecarboxylic acid ethyl ester (798 pg, mixture of isomers, preparation 43) A solution of anhydrous n, n-dimethylformamide (4 ml) was added, and the mixture was stirred at room temperature for a minute. Water was added, and the mixture was acidified by addition of 2N hydrochloric acid, then extracted with dichloromethane (x3), and the organic extracts were dried over anhydrous sodium sulfate and evaporated to dryness to give a coloured oil. This was dissolved in tetrahydrofuran (ml) and water (5 ml), and aqueous sodium hydroxide (2N, 1 mL) was added. The mixture was stirred at room temperature for 24 hours, then partitioned between hydrochloric acid and dichloromethane. The organic extract was dried over anhydrous sodium sulfate and evaporated to dryness to give a mixture of carboxylic acid to afford hexanes / ethyl acetate 5:1. This material was subjected to chromatography on silica gel and then 4 · 1 A. The fractions containing the first 92199 - 323 - 1285641 dissolving carboxylic acids (having the desired R, R, S stereochemistry) were combined, evaporated to dryness in vacuo and dissolved in methanol (25 mL). Trimethyldecyl diazomethane (2M solution in hexane, Aldnch Chemical Company, Milwaukee, WI) was slowly added until foaming ceased and the yellow color continued. The solvent was removed by adding a small amount of acetic acid, and then the solvent was removed under vacuum, and the residue was purified by chromatography on silica gel eluting with hexane/dichloromethane gradient 2:1 to 1:2. The final purification was achieved by reverse phase HPLC using a Shimadzu preparative HPLC system (Shimadzu Corporation, Kyoto, Japan) eluting with a 30-100% acetonitrile/water/0.1% formic acid gradient on a 19 x 50 mm Waters symmetry column. (Waters, Milford, ΜΑ), 8 min operation, 6 min gradient, 25 mL/min, UV triggered collection, observed at 210 nm. The product-containing fractions were evaporated to dryness to crystall MS : 518.3 [Μ + Η] + measured value. 1H-NMR (CDC13) δ 7·52 (m, 1H), 7.51 (m, 1H), 7.50 (m, 1H), 7·47 (d, 8.3 Hz 1H), 7.34 (brs? 1H), 7.25 (dd5 J=8.3, 2.49Hz5 1H), 4.28 (m, 1H)5 4.27 (m, 1H), 4.20 (m, 1H), 3.80 (d, J= 11.62 Hz, 1H), 3.73 (s, 3H), 3.29 (m, 1H), 1.86 (m, 1H), L50 (m, TH), 1.37 (m, 1H), 1.30 (t, J = 7.47 Hz, 3H), 0.90 (m, 1H), 0.71 (t, J = 7.47 Hz, 3H) · Example 453

92199 - 324 - 1285641 (R，S)與（R，R)-4-[2-乙醯氧基小(3&gt;雙_三氟甲基-苯基 &gt; 乙基乙 基-6-二氟甲基奎琳_丨_叛酸乙酯 於非對映異構物混合物（R，R)與（R，s)冰[1&lt;3,5•雙-三氟甲基-笨 基）基-乙基]-2-乙基-6-三氟甲基-2H•喹啉小羧酸乙酯（實例 437，57笔克，0.102毫莫耳）在二氯甲烷（丨毫升）中之溶液内 在氮氣下，添加三乙胺（43微升，〇·3〇6毫莫耳），接著是氯 化乙睡（9微升’ 〇·132 *莫耳）。3小時後，使混合物於水與 一氯甲烷足間作分液處理，分離有機層，以無水硫酸鈉脫 尺乾燥，及在真空下条發。使殘留物於矽膠上藉層析純化 以己:k，然後己/醋酸乙酯19 :丄，接著9 :丄，然後4 ·· 1，接著3 : 7，及最後2 : 3溶離，而得標題化合物，為非對 映異構物之混合物（51毫克）。 MS : 598·3[Μ+Η]+實測值·92199 - 324 - 1285641 (R,S) and (R,R)-4-[2-acetoxyl small (3&gt;bis-trifluoromethyl-phenyl&gt; ethylethyl-6-difluoro Methylquineline 丨-丨 叛 acid ethyl ester in diastereomeric mixture (R, R) and (R, s) ice [1 &lt; 3,5 • bis-trifluoromethyl- phenyl)- Ethyl ethyl 2-ethyl-6-trifluoromethyl-2H•quinoline carboxylic acid (example 437, 57 gram, 0.102 mmol) in dichloromethane (丨 mL) Triethylamine (43 μl, 〇·3〇6 mmol) was added under nitrogen, followed by chlorinated b (9 μl of '〇·132*mol). After 3 hours, the mixture was partitioned between water and methylene chloride. The organic layer was separated, dried over anhydrous sodium sulfate and evaporated. The residue was purified by chromatography on silica gel to give: k, then hexane / ethyl acetate 19 : oxime, then 9 : oxime, then 4 · · 1, then 3 : 7, and finally 2 : 3 dissolved, The title compound is a mixture of diastereomers (51 mg). MS : 598·3[Μ+Η]+ measured value·

(R，R，S)-4-[2-乙醒氧基-1-(3,5_雙-三氟曱基-苯基）_乙基]乙基各 二氟甲基-3,4-二氫-2H-0奎I -1-叛酸乙|旨 於(R，R，S)-4-[l-(3,5-雙-三氟曱基-苯基）-2-經基-乙基]·2_乙基各三 氟甲基-3,4-二氫-2Η-喹啉小羧酸乙酯（實例447，50毫克，0.0896 92199 - 325 - 1285641 *莫耳）在二氣甲烷（1毫升）中之溶液内，在氮氣下，添加三 乙胺（37微升’ 0.269毫莫耳），接著是氯化乙醯（8 3微升，〇116 毫莫耳）。30分鐘後，使混合物於水與二氯甲垸之間作分液 處理，分離有機層，以無水硫酸鈉脫水乾燥，及在真空下 蒸發。使殘留物於矽膠上藉層析純化，以己烷，然後己垸/ 醋酸乙酯19: 1，接著9: 1，然後4: 1溶離，獲得標題化合 物（41毫克）。 MS : 600.4 [M+Hf 實測值. 1H-NMR (CDCI3) 5 7.88 (s，1H口.85 (s，1H)，7.73 (s，2H)，7.64 (m，1H)， 7.62 (m，1H)，4·80 (dd，J=11.62, 4.15Ηζ，1H)，4.29 (m，1H)，4.25 (m，1H)，4.23 (m，1H)，4.20 (m，1H)，3.72 (ddd，J=9.13, 9.13, 3·32Ηζ，1H)，2.79 (m，1H)，1.97 (s，3H)，1.84 (m，1H)，1.46 (m，1H)，1.32 (m，1H)，1.31 (t，J=7.47Hz，3H)，0.87 (m，1H)，0.69 (t，J=7.47Hz，3H). 實例455(R,R,S)-4-[2-Ethyloxy-1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]ethyldifluoromethyl-3,4 -Dihydro-2H-0 Quelin I-1-Resin B; for (R,R,S)-4-[l-(3,5-bis-trifluorodecyl-phenyl)-2- Ethyl-ethyl]·2-ethyl ethyl trifluoromethyl-3,4-dihydro-2-indole-quinoline carboxylic acid ethyl ester (Example 447, 50 mg, 0.0896 92199 - 325 - 1285641 * Moel) In a solution of di-methane (1 mL), triethylamine (37 [mu]L '0.269 mmol) was added under nitrogen, followed by acetonitrile (8 3 liters, 〇 116 mM). After 30 minutes, the mixture was partitioned between water and methylene chloride. The organic layer was separated, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAcEtOAc: MS : 600.4 [M+Hf found. 1H-NMR (CDCI3) 5 7.88 (s, 1H.85 (s, 1H), 7.73 (s, 2H), 7.64 (m, 1H), 7.62 (m, 1H) ), 4·80 (dd, J=11.62, 4.15Ηζ, 1H), 4.29 (m, 1H), 4.25 (m, 1H), 4.23 (m, 1H), 4.20 (m, 1H), 3.72 (ddd, J = 9.13, 9.13, 3·32Ηζ, 1H), 2.79 (m, 1H), 1.97 (s, 3H), 1.84 (m, 1H), 1.46 (m, 1H), 1.32 (m, 1H), 1.31 ( t, J = 7.47 Hz, 3H), 0.87 (m, 1H), 0.69 (t, J = 7.47 Hz, 3H). Example 455

(R，R，S)-4-[l-(3,5-雙-三氟甲基-苯基）-2-甲氧基-乙基]-2-乙基-6-三 氟甲基-3,4-二氫-2Η-ρ奎琳-1-叛酸乙酉旨 於（民11，3)斗[1-(3,5-雙-三氟甲基-苯基）-2-羥基-乙基]-2-乙基-6-三 氟甲基-3,4-二氫-2H-喹啉小羧酸乙酯（實例447，20毫克，0,035 92199 - 326 - 1285641 t莫耳）在四氫呋喃（1毫升）中之溶液内，在氮氣下，添加氫 化鈉（60%礦油分散液，〇 〇43毫莫耳，17毫克），接著在$分 鐘後，添加碘甲烷（2滴）。攪拌16小時後，添加另一份氫化 鈉（2毫克）與碘甲烷（3滴）。將混合物於室溫下攪拌牝小時， 然後以醋酸乙酯稀釋。以水洗滌混合物，將有機層分離， 以無水硫酸鈉脫水乾燥，及在真空下蒸發。使粗產物於矽 膠上藉層析純化，以己烷，接著己烷/醋酸乙酯19 ·· 1，然 後9 : 1溶離，獲得標題化合物（丨9毫克）。 MS : 572.5 [M+Hf 實測值· 1 H-NMR (CDC13) 5 7.81 (s，1H)，7·76 (s，2H)，7.61 (brs，1H)，7.52 (m，2H)， 4·27 (m，1H)，4·24 (m，1H)，4·21 (m，1H)，3.89 (dd，J=9.96, 3·32Ηζ，1H)，3·74 (dd，J=9.13, 7·47Ηζ，1H)，3.55 (m，1H)，129 (s，3H)，2·85 (m，1H)，1.80 (m，1H)， 1·47 (m，1H)，L32 (m，1H)，1.31 (t，J=7.47Hz，3H)，0.87 (m，1H)，0·69 (t，J=7.47 Hz，3H). 實例456(R,R,S)-4-[l-(3,5-bis-trifluoromethyl-phenyl)-2-methoxy-ethyl]-2-ethyl-6-trifluoromethyl -3,4-Dihydro-2Η-ρ奎琳-1- 叛 酸 酉 酉 酉 ( 民 民 民 民 民 民 (1,3,5-bis-trifluoromethyl-phenyl)-2-hydroxy Ethyl ethyl 2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinolinecarboxylate (Example 447, 20 mg, 0,035 92199 - 326 - 1285641 tm) In a solution of tetrahydrofuran (1 ml), sodium hydride (60% mineral oil dispersion, 〇〇43 mmol, 17 mg) was added under nitrogen, followed by iodomethane (2 drops) after . After stirring for 16 hours, another portion of sodium hydride (2 mg) and methyl iodide (3 drops) were added. The mixture was stirred at room temperature for a few hours and then diluted with ethyl acetate. The mixture was washed with water, the organic layer was separated, dried over anhydrous sodium sulfate and evaporated. The crude product was purified by chromatography eluting EtOAc elut elut elut elut elut elut MS: 572.5 [M+Hf found: 1 H-NMR (CDC13) 5 7.81 (s, 1H), 7·76 (s, 2H), 7.61 (brs, 1H), 7.52 (m, 2H), 4· 27 (m,1H),4·24 (m,1H),4·21 (m,1H),3.89 (dd,J=9.96, 3·32Ηζ,1H),3·74 (dd,J=9.13, 7·47Ηζ,1H),3.55 (m,1H),129 (s,3H),2·85 (m,1H), 1.80 (m,1H), 1·47 (m,1H), L32 (m, 1H), 1.31 (t, J = 7.47 Hz, 3H), 0.87 (m, 1H), 0·69 (t, J = 7.47 Hz, 3H). Example 456

(R，R，S)-4-[l-(3,5-雙-三氟甲基-苯基）-2-氟-乙基]-2-乙基-6-三氟甲 基-3,4-二氫-2H-喹啉-1-羧酸乙酯 於(11，11,3)-4-〇(3,5-雙-三氟甲基-苯基）-2-羥基-乙基]-2-乙基-6-三 92199 - 327 - 1285641 氟甲基-3,4-二氫-2H-喳啉-1-羧酸乙酯（實例糾7 , 2〇毫克，〇 〇35 耄莫耳）在二氣甲烷（：[毫升）中之溶液内，在氮氣下，添加三 氟化二乙胺基硫（47微升，0.358毫莫耳）。將混合物於室溫下 搜拌3小時，然後添加另一份三氟化二乙胺基硫（47微升，〇 358 愛莫耳）。1小時後，使混合物於水與二氯甲烷之間作分液 處理，分離有機層，以無水硫酸鈉脫水乾燥，及在真空下 蒸發。使殘留物首先於石夕膠上藉層析純化，以己垸/酷酸乙 S旨19 · 1 ’然後19 · 1 ’接著9 : 1溶離，且最後藉逆相册乙匸 純化，使用 Shimadzu 預備 HPLC 系統（Shimadzu 公司，Kyoto, Japan) ，以30-100%乙腈/水/ 0.1%甲酸梯度液溶離，在19χ5〇毫米 ，Waters對稱性管柱（Waters公司，Milford，MA)上，8分鐘操作，6 分鐘梯度液，25毫升/分鐘，UV觸發收集，於210毫微米下 觀察。使含產物之溶離份蒸發至乾涸，而得標題化合物（3毫 克）。 MS: 560·3[Μ+Η]+實測值· 1H-NMR (CDC13) 5 7.86 (s，1H)，7.80 (s，2H)，7.55 (m，2Η)，7·54 (s，m)， 4·93 (ddd，JMT6.47, 9.96, 4·14Ηζ，1Η)，4.82 (ddd，JN46.47, 9.96, 6.64Hz，1Η)， 4.28 (m，1H)，4.27 (m，1H)，4·23 (m，1H)，3.72 (m，1H)，2.91 (xn，1H)，1·88 (m， 1H)，1.48 (m，1H)，1.34 (m，1H)，1.32 (t，J=7.47Hz，3H)，0.92 (m，1H)，0.71 (t， J=7.47Hz，3H). 實例457 92199 - 328 - 1285641(R,R,S)-4-[l-(3,5-bis-trifluoromethyl-phenyl)-2-fluoro-ethyl]-2-ethyl-6-trifluoromethyl-3 , 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester in (11,11,3)-4-indole (3,5-bis-trifluoromethyl-phenyl)-2-hydroxy-B Ethyl]-2-ethyl-6-tris 92199 - 327 - 1285641 Ethyl fluoromethyl-3,4-dihydro-2H-porphyrin-1-carboxylate (example correction 7 , 2 〇 mg, 〇〇 35 In a solution of di-methane (: [ml), diethylamine trifluoride (47 μL, 0.358 mmol) was added under nitrogen. The mixture was stirred at room temperature for 3 hours and then another portion of diethylamine trifluoride (47 μL, 358 358 Amor) was added. After 1 hour, the mixture was partitioned between water and methylene chloride. The organic layer was separated, dried over anhydrous sodium sulfate and evaporated. The residue was first purified by chromatography on the saponin, and then dissolved in hexanyl/succinic acid B. 19 · 1 ' then 19 · 1 ' followed by 9:1, and finally purified by reverse album acetonitrile, prepared with Shimadzu HPLC system (Shimadzu Corporation, Kyoto, Japan), eluted with a gradient of 30-100% acetonitrile/water/0.1% formic acid, on a 19 χ 5 〇 mm, Waters symmetry column (Waters, Milford, MA), 8 minutes operation , 6 min gradient, 25 ml/min, UV triggered collection, observed at 210 nm. The product-containing fractions were evaporated to dryness to give crystall MS: 560·3[Μ+Η]+Measured value·1H-NMR (CDC13) 5 7.86 (s,1H), 7.80 (s,2H), 7.55 (m,2Η),7·54 (s,m) , 4·93 (ddd, JMT6.47, 9.96, 4·14Ηζ, 1Η), 4.82 (ddd, JN46.47, 9.96, 6.64Hz, 1Η), 4.28 (m,1H), 4.27 (m,1H), 4·23 (m,1H), 3.72 (m,1H), 2.91 (xn,1H),1·88 (m, 1H), 1.48 (m,1H), 1.34 (m,1H), 1.32 (t, J = 7.47 Hz, 3H), 0.92 (m, 1H), 0.71 (t, J = 7.47 Hz, 3H). Example 457 92199 - 328 - 1285641

(R，R，S)-4-[l-(3,5-雙-三氟T基-苯基）-2-胺基-乙基]-2-乙基_6 _ = •二鼠 甲基-3,4-二氫-2Η-^淋小瘦酸乙酉旨 於（R，R，S)-4-[(3,5-雙-三氟甲基-苯基）-胺甲縫基基]I, J g 暴-6- 三氟甲基-3,4-二氫-2Η-ρ奎4 -1-叛酸乙g旨（實例438，25毫克 0.0438毫莫耳）在四氫吱喃（3毫升）中之溶液内，在氮氣下 添加硼烷-硫化二曱烷複合物（8·3微升，0.0876毫莫耳）。 J。將混 合物於70°C下加熱48小時，然後添加水（2.5毫升）與飽和竣酸 鋼落液（1毫升）。將混合物於70°C下加熱1小時，接著在水與 二氯甲烷之間作分凌處理。在真空下使有機層蒸發至乾酒 ，並使殘留物溶於乙醚（5毫升）中，並添加2N鹽酸（1毫升）。 24小時後，以水稀釋混合物，添加碳酸鈉溶液，並以二氯 甲烷萃取混、合物。使有機層以無水硫酸鈉脫水乾燥，並於 真空下蒸發溶劑。使粗產物於矽膠上藉層析純化，以己垸/ 醋酸乙酯3 : 1，然後醋酸乙酯溶離，獲得標題化合物（185毫 克）。 MS : 557.4 [M+Hf 實測值. 1 H-NMR (CDC13) 5 7.84 (s，1H)，7·77 (s，2H)，7.58 (brs，1H)，7.52 (m，2H)， 4·27 (m，1H)，4,23 (m，1H)，4.22 (m，1H)，3·44 (dd，J=13.28, 3.32Hz，1H)，3·35 (m，1H)，3.09 (dd，J=13.28, 9·13Ηζ，1H)，2.76 (m，1H)，1.76 (m，1H)，1.45 (m， 92199 - 329 - 1285641 1H)，1.34 (m，1H)，1.31 (t，J=7.47Hz，3H)，0.84 (m，1H)，0.69 (t，J=7.47Hz，3H). 實例 458、459、460 及 461(R,R,S)-4-[l-(3,5-bis-trifluoro-T-phenyl)-2-amino-ethyl]-2-ethyl_6 _ = • -3-3,4-Dihydro-2Η-^Lessing Essence of Ethyl Acetate for (R,R,S)-4-[(3,5-Bis-Trifluoromethyl-phenyl)-amine ]], J g 暴-6-trifluoromethyl-3,4-dihydro-2 Η-ρ 奎 4 -1- oxo acid B g (example 438, 25 mg 0.0438 mmol) in tetrahydroanthracene A solution of borane-sulfurized dioxane (8.3 microliters, 0.0876 millimoles) was added to the solution in hexane (3 mL) under nitrogen. J. The mixture was heated at 70 ° C for 48 hours, then water (2.5 mL) and saturated EtOAc (1 mL). The mixture was heated at 70 ° C for 1 hour, followed by a split between water and dichloromethane. The organic layer was evaporated to dryness <RTI ID=0.0> After 24 hours, the mixture was diluted with water, a sodium carbonate solution was added, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The crude product was purified by chromatography eluting elut elut elut elut elut elut elut elut elut MS: 557.4 [M+Hf found. 1 H-NMR (CDC13) 5 7.84 (s, 1H), 7·77 (s, 2H), 7.58 (brs, 1H), 7.52 (m, 2H), 4· 27 (m,1H),4,23 (m,1H), 4.22 (m,1H),3·44 (dd,J=13.28, 3.32Hz,1H),3·35 (m,1H),3.09 ( Dd, J=13.28, 9·13Ηζ, 1H), 2.76 (m, 1H), 1.76 (m, 1H), 1.45 (m, 92199 - 329 - 1285641 1H), 1.34 (m, 1H), 1.31 (t, J = 7.47 Hz, 3H), 0.84 (m, 1H), 0.69 (t, J = 7.47 Hz, 3H). Examples 458, 459, 460 and 461

[(R，S，S)]_4-[(3,5-雙-三氟甲基-苯基）-羥基-甲基]-2-乙基各三氟甲 基-3,4-二氮-2H-峻淋-1-複版乙§旨[(R,S,S)]_4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-trifluoromethyl-3,4-diazepine -2H-Junlin-1-Reissue B

[(R，R，R)]-4-[(3,5j _三氟甲基-苯基）-羥基-甲基]-2-乙基各三氟甲 基-3,4-二氫-2H-喹啉小羧酸乙酯[(R,R,R)]-4-[(3,5j _trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-trifluoromethyl-3,4-dihydro- 2H-quinoline small carboxylic acid ethyl ester

[(11，11，3)]-4-[(3,5-雙-三氟甲基-苯基）-羥基-甲基]-2-乙基-6-三氟甲 基-3,4-二氫-2H-喹啉-1-羧酸乙酯[(11,11,3)]-4-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-2-ethyl-6-trifluoromethyl-3,4 -Dihydro-2H-quinoline-1-carboxylic acid ethyl ester

92199 - 330 - 1285641 [(R，S，R)pK(3,5’ _二氟甲基-苯基）邊基-甲基]_2•乙基各三氟甲 基-3,4-二氫-2H-p奎啉_丨_羧酸乙酯 此等化合物（先前在實例22、23、24及25中製備）係使用類 似本文中所述之方法，藉由解析所指示之相應外消旋物或 其合成中之中間物’製成光學上富含形式。 貫例 462、463、464 及 46592199 - 330 - 1285641 [(R,S,R)pK(3,5' _Difluoromethyl-phenyl))-methyl]_2•ethyltrifluoromethyl-3,4-dihydro -2H-p-quinoline-indole-carboxylic acid ethyl esters These compounds (previously prepared in Examples 22, 23, 24 and 25) were subjected to the methods described herein, by resolution of the corresponding racemic indicated The intermediate in the substance or its synthesis' is made optically rich. Examples 462, 463, 464 and 465

[(R,R，R)]，[(R，R，S)], [(R，S，S)]，及[(R，S，R)]_4-[胺基-(3,5-雙-三氟甲基-苯 基）-甲基]-2-乙基-6-二氟甲基-3,4-二氫奎淋-1-幾酸乙酯之製備 製造胺化合物之一般程序：將雙-三氟甲基-苯 基）-經基·甲基;h2-乙基-6-三氟甲基_3,4-二氫-2H-喹啉小羧酸乙酯 (0.527克’ 〇·971毫莫耳，1當量）放置在裝有磁攪拌棒之圓底 燒瓶中。於室溫下，添加二氯甲烷（2〇毫升），接著添加三乙 胺（0.456毫开’ 3.37毫莫耳，3.37當量）與氯化甲烷磺醯（〇,15〇 毫升’ 1.94毫莫耳，2.0當量），並將反應混合物攪拌過夜。 以水使反應混合物淬滅，以醋酸乙酯萃取4次。將有機層以 CUM HC1 ’接著以飽和重碳酸鹽溶液洗滌，並以硫酸鈉脫水 乾燥。使溶液過濾，濃縮，並在高真空中乾燥，提供 [(RAR)]_4_[(3,5-雙-三氟甲基-苯基）_甲烷磺醯氧基-甲基]-2-乙基_ 6-三氟甲基·3,4-二氫-2H-喳啉小羧酸乙酯（0.599克，99%產率） ，為白色固體，MS(ES+)m/z=622 (M+l). 92199 1285641 將[(尺凡則冰旧义雙-王氟甲基-苯基卜甲烷磺醯氧基-甲基]·〕-乙基各二氟甲基-3,4-二氫-2H-喹啉小羧酸乙酯（〇 3n克，〇 5〇4 毫莫耳，1當量）放置在裝有磁攪拌棒之圓底燒瓶中。添加 DMF (12毫升），接著添加疊氮化鈉（〇 2〇丨克，〇·3 ι〇毫莫耳，6」 當I )。將反應混合物加熱至701，歷經12小時。使反應混 合物冷卻至室溫，稀釋至200毫升Et〇Ac中，並以鹽水及水洗 滌4 /人。收集EtOAc，以硫酸鈉脫水乾燥，過濾，及濃縮。 使物質於Biotage急驟式40s上純化，提供[(R，R，s)]-4-[疊氮基-(3,5- 雙-三氟甲基-苯基）-甲基]-2-乙基各三氟甲基-3,4-二氫-2私喹啉-1-羧酸乙酯（0.202 克，71% 產率）MS (ES+)(M+1), 將[(R，R，S)]-4-[疊氮基_(3,5_雙-三氟甲基—苯基）_甲基]_2•乙基各 三氟甲基-3,4二氫-2H-4：啉-1_羧酸乙酯（〇 2〇2克，〇·356莫耳，1 當量）放置在裝有磁攪拌棒與回流冷凝管之圓底燒瓶中。添 加 NH4C〇2H(0.226 克，3.58 莫耳，ΐ〇·ι 當量）與!)^^^·；^ 克，〇1〇7 莫耳’ 0.30當量），接著添加甲醇與醋酸乙酯之2 :丨溶液（8 8〇 毫升）。使反應混合物回流2小時，然後經過Celite®過濾。濃 縮濾液’但*·並非乾涸，並於醋酸乙酯與碳酸氫鈉水溶液之 間作分液處理。收集有機層，以硫酸鈉脫水乾燥，過濾， 及丨辰縮。使粗製物質於Biotage急驟式40 Μ上純化，提供所要 之化合物[(R，R，S)]，4-[胺基-(3,5-雙-三氟甲基-苯基）_甲基]_2-乙基-卜三氟甲基-3,4-二氫-2H-喹啉-1-羧酸乙酯（0.162克，83%產率 )MS (ES+) m/z=543 (M+1). 1H NMR (CDC13): 5 0·82 (t，3H)，1.32 (t，3H)，1·34-1·57 (m，3H)，2·53 (m， 1H)，3.00 (m，1H)，4.28 (q，2H)，4.50 (d，1H)，4.54 (m，1H)，7.03 (s，1H)，7.42 (d， 92199 - 332 - 1285641 1H)，7.60 (d，1H)，7.66 (s，2H)，7.72 (s，1H). MS (ES+) m/z=543 (M+l). 此等其他化合物係使用類似本文中所述之程序製成：[(R,R,R)],[(R,R,S)], [(R,S,S)], and [(R,S,R)]_4-[Amino-(3,5 Preparation of bis-trifluoromethyl-phenyl)-methyl]-2-ethyl-6-difluoromethyl-3,4-dihydroquinone-1-acid ethyl ester Procedure: bis-trifluoromethyl-phenyl)-trans-methyl group; h2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinolinecarboxylic acid ethyl ester (0.527克 '〇·971 mmol, 1 eq.) was placed in a round bottom flask equipped with a magnetic stir bar. Dichloromethane (2 liters) was added at room temperature followed by triethylamine (0.456 mAh 3.37 mmol, 3.37 eq.) and chloromethane sulfonate (〇, 15 〇 ml ' 1.94 mmol) 2.0 equivalents, and the reaction mixture was stirred overnight. The reaction mixture was quenched with water and extracted with ethyl acetate 4 times. The organic layer was washed with CUM HC1' followed by a saturated bicarbonate solution and dried over sodium sulfate. The solution is filtered, concentrated, and dried under high vacuum to afford [(RAR)]_4_[(3,5-bis-trifluoromethyl-phenyl)-methanesulfonyloxy-methyl]-2-ethyl Ethyl 6-trifluoromethyl-3,4-dihydro-2H-carboline carboxylic acid ethyl ester (0.599 g, 99% yield) mp. +l). 92199 1285641 will [[(2), ruthenium, sulphate, fluoromethyl-phenylmethanesulfonyloxy-methyl]-]-ethyldifluoromethyl-3,4-di Hydrogen-2H-quinoline carboxylic acid ethyl ester (〇3ng, 〇5〇4 mM, 1 eq.) was placed in a round bottom flask equipped with a magnetic stir bar. DMF (12 mL) was added followed by a stack Sodium nitride (〇2 gram, 〇·3 ι〇 mmol, 6). When I), the reaction mixture was heated to 701 for 12 hours. The reaction mixture was cooled to room temperature and diluted to 200 mL of Et. The mixture was washed with brine and water and washed with EtOAc EtOAc EtOAc (EtOAc) [azido-(3,5-bis-trifluoromethyl-phenyl)-methyl]-2-ethyl-trifluoromethyl-3,4-dihydro-2 quinolin-1-one Ethyl acetate (0.202 g, 71% yield) MS (ES+) (M+1), [(R,R,S)]-4-[azido-[3,5-bis-trifluoromethyl] Ethyl-phenyl)-methyl]_2•ethyl each trifluoromethyl-3,4 dihydro-2H-4: porphyrin-1-carboxylic acid ethyl ester (〇2〇2 g, 〇·356 m, 1 eq.) placed in a round bottom flask equipped with a magnetic stir bar and a reflux condenser. Add NH4C〇2H (0.226 g, 3.58 mol, ΐ〇·ι equivalent) and !)^^^·;^ gram, 〇 1 〇 7 Moer '0.30 eq.), followed by the addition of methanol and ethyl acetate 2: hydrazine solution (8 8 mM). The reaction mixture was refluxed for 2 h then filtered over Celite. The concentrated filtrate 'but*' is not dry and is subjected to liquid separation between ethyl acetate and an aqueous solution of sodium hydrogencarbonate. The organic layer was collected, dried over sodium sulfate, filtered, and dried. The crude material was purified on Biotage to give the desired compound [(R,R,S)], 4-[amino-(3,5-bis-trifluoromethyl-phenyl)-methyl Ethyl 2-ethyl-p-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate (0.162 g, 83% yield) MS (ESI) m/z = 543 (M +1). 1H NMR (CDC13): 5 0·82 (t,3H), 1.32 (t,3H),1·34-1·57 (m,3H),2·53 (m, 1H), 3.00 (m, 1H), 4.28 (q, 2H), 4.50 (d, 1H), 4.54 (m, 1H), 7.03 (s, 1H), 7.42 (d, 92199 - 332 - 1285641 1H), 7.60 (d, 1H), 7.66 (s, 2H), 7.72 (s, 1H). MS (ES+) m/z = 543 (M+l). These other compounds were prepared using procedures similar to those described herein:

[(民3,3)]，4-[胺基-(3,5-雙-三氟甲基-苯基）-甲基]-2-乙基各三氟甲 基-3,4-二氫-2H-喹啉小羧酸乙酯： 'HNMRCCDCl.J： (5 0.71 (t, 3H), LOO (m5 1H), L29 (t? 3H), 1.33^1.52(m? 2H)，1·67 (m，1H &amp; H2 〇)，2·70 (m，1H)，4.15-4.31 (m，3H)，4·47 (d，1H)，7.51 (m，2H)，7.84 (s，1H)，7.89 (s，2H)，7·91 (s，1H) MS (ES+) m/z=543 (M+l).[(Min 3,3)], 4-[Amino-(3,5-bis-trifluoromethyl-phenyl)-methyl]-2-ethyl-trifluoromethyl-3,4-di Hydrogen-2H-quinoline carboxylic acid ethyl ester: 'HNMRCCDCl.J: (5 0.71 (t, 3H), LOO (m5 1H), L29 (t? 3H), 1.33^1.52 (m? 2H), 1· 67 (m,1H &amp; H2 〇), 2·70 (m,1H), 4.15-4.31 (m,3H),4·47 (d,1H),7.51 (m,2H),7.84 (s,1H) ), 7.89 (s, 2H), 7·91 (s, 1H) MS (ES+) m/z = 543 (M+l).

N 、 C02Et [(R，R，R)]，4-[胺基-(3,5-雙-三氟甲基·苯基 &gt; 甲基]冬乙基各三氟 甲基-3,4-二氫-2H-喳啉小羧酸乙酯： HNMR (CDC13) ： 5 0.75 (ζ 3Η), 1.33 (t, 3H)5 1.37-1.62 (m, 3H), 1.82 (m, 1H)，2.98 (m，1H)，4.17-4.36 (m，4H)，7.51 (s，1H)，7.53-7.61 (m，2H)，7.83 (s， 1H), 7.86 (s, 2H)； MS (ES+) m/z=543 (M+l). 92199 - 333 - 1285641N, C02Et [(R,R,R)],4-[Amino-(3,5-bis-trifluoromethylphenyl)&gt;methyl]winterethyl each trifluoromethyl-3,4 -Dihydro-2H-carboline small carboxylic acid ethyl ester: HNMR (CDC13): 5 0.75 (ζ 3Η), 1.33 (t, 3H)5 1.37-1.62 (m, 3H), 1.82 (m, 1H), 2.98 (m,1H), 4.17-4.36 (m,4H),7.51 (s,1H),7.53-7.61 (m,2H),7.83 (s, 1H), 7.86 (s, 2H); MS (ES+) m /z=543 (M+l). 92199 - 333 - 1285641

[(11，3，11)]，4-[胺基-(3,5-雙-三氟甲基-苯基）-甲基]-乙基-6-2-三氟 甲基-3,4-二氫_2Η-ρ奎淋-1-叛酸乙g旨： HNMR (CDC13) : 5 0.82 (t，3H)，1.27 (t，3H)，1.40-1.64 (m，3H)，2,07 (m， 1H)，2.76 (m，1H)，4.09-4.27 (m，3H)，5.07 (m，1H)，7.55 (q，2H)，7.66 (s，1H)， 7.83 (s，1H)，7.96 (s，2H); MS (ES+) m/z=543 (M+l). 實例 466、467、468 及 469 下列化合物係製自類似上述，特別是實例18、19及456中 之起始物質及程序。[(11,3,11)],4-[Amino-(3,5-bis-trifluoromethyl-phenyl)-methyl]-ethyl-6-2-trifluoromethyl-3, 4-Dihydro 2 Η-ρ 奎 -1- -1- 叛 叛 : : :: H NMR (CDC13) : 5 0.82 (t, 3H), 1.27 (t, 3H), 1.40-1.64 (m, 3H), 2, 07 (m, 1H), 2.76 (m, 1H), 4.09-4.27 (m, 3H), 5.07 (m, 1H), 7.55 (q, 2H), 7.66 (s, 1H), 7.83 (s, 1H) , 7.96 (s, 2H); MS (ES+) m/z = 543 (M+l). Examples 466, 467, 468 and 469 The following compounds were prepared from similar to the above, especially from Examples 18, 19 and 456. Starting materials and procedures.

[(R，S，R)]-4-(3,5-雙-三氟甲基-苯基）-氟-甲基]冬乙基-6-三氟甲基 -3,4-二氫-21^奎淋小叛酸乙酉旨 1 H-NMR (CDC13) : 5 7.92 (s，1H)，7.83 (s，2H)，7.67 (s，1H)，7.57 (s，2H)， 6·5 (d，1H)，4.24 (m，3H)，2.91 (dd，1H)，2.08 (m，1H)，1.51 (m，3H)，1.27 (t， 3H)，0.80 (t，3H); MS : 546.3 [M+Hf 實測值· 92199 - 334 - 1285641 cf3[(R,S,R)]-4-(3,5-bis-trifluoromethyl-phenyl)-fluoro-methyl]whenyl-6-trifluoromethyl-3,4-dihydro -21^奎淋小叛酸 酉 酉 1 H-NMR (CDC13) : 5 7.92 (s, 1H), 7.83 (s, 2H), 7.67 (s, 1H), 7.57 (s, 2H), 6·5 (d, 1H), 4.24 (m, 3H), 2.91 (dd, 1H), 2.08 (m, 1H), 1.51 (m, 3H), 1.27 (t, 3H), 0.80 (t, 3H); MS: 546.3 [M+Hf measured value · 92199 - 334 - 1285641 cf3

C02Et cf3 [(R，S，S)]-4-(3,5-雙-三氟甲基-苯基）-氟-甲基]-2-乙基各三氟甲基-3,4-二氫-2H^奎琳小幾酸乙酯 1H-NMR (CDC13 )： 5 7.96 (s, 1H)3 7.88 (s3 2H), 7.76 (s? 1H), 7.55 (s51? 2H), 5.86 (dd，J=9.13Hz，1H)，4.25 (m，3H)，3.10 (m，1H)，1.75 (m，1H)，1.47 (m， 2H)，1.29 (t，3H)，U8 (t，3H)，0.77 (t，3H); MS : 546.4 [M+H]+ 實測值· cf3C02Et cf3 [(R,S,S)]-4-(3,5-bis-trifluoromethyl-phenyl)-fluoro-methyl]-2-ethyl-trifluoromethyl-3,4- 1H-NMR (CDC13): 2 7.96 (s, 1H)3 7.88 (s3 2H), 7.76 (s? 1H), 7.55 (s51? 2H), 5.86 (dd , J=9.13Hz, 1H), 4.25 (m, 3H), 3.10 (m, 1H), 1.75 (m, 1H), 1.47 (m, 2H), 1.29 (t, 3H), U8 (t, 3H) ,0.77 (t,3H); MS : 546.4 [M+H]+ Measured value · cf3

[(民民3)]-4-(3,5-雙-二氟甲基-苯基）-氟-甲基]-2-乙基-6-三氟甲基 -3,4-二氫-2H-喹啉-1-羧酸乙酯 1H-NMR (CDC13) : 5 7·8 (s，1H)，7.59 (d，1H)，7.47 (d，1H)，7·43 (s，2H)， 6·86 (s，1H)，5.65 (dd，J=7.88Hz，1H)，4,60 (m，1H)，4.28 (m，2H)，3·21 (m，1H)， 2.65 (m，3H)，1.74 (m，1H)，1.41-1.62 (m，2H)，1.31 (t，3H)，0.86 (t，3H); MS : 546·3 [Μ+Η]+ 實測值 cf3[(民民3)]-4-(3,5-bis-difluoromethyl-phenyl)-fluoro-methyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro -2H-quinoline-1-carboxylic acid ethyl ester 1H-NMR (CDC13): 5 7·8 (s, 1H), 7.59 (d, 1H), 7.47 (d, 1H), 7·43 (s, 2H ), 6·86 (s, 1H), 5.65 (dd, J = 7.88 Hz, 1H), 4, 60 (m, 1H), 4.28 (m, 2H), 3·21 (m, 1H), 2.65 ( m, 3H), 1.74 (m, 1H), 1.41-1.62 (m, 2H), 1.31 (t, 3H), 0.86 (t, 3H); MS: 546·3 [Μ+Η]+ cf3

92199 - 335 - 1285641 [(11，11,11)]-4-[(3,5-雙-三氟甲基-苯基）-氟-甲基]-2-乙基-6-三氟甲 基-3,4-二氫-2H-喹啉-1-羧酸乙酯 1H-NMR (CDC13): 5 7.88 (s，1H)，7.63 (s，d，3H)，7.52 (d，1H)，7.41 (s, 1H)， 5·58 (dd，J=7.47Hz，1H)，4·42 (m，1H)，4.24 (m，2H)，3·40 (m，1H)，1·97 (m，1H)， L74 (m，1H)，1.41 (m，2H)，1.27 (t，3H), 0.79 (t，3H); MS : 546.3 [M+H]+ 實測值· 實例 470、471、472 及 473 下列化合物係製自類似上述之起始物質及如圖式2中所示 之程序，而其中係添加適當有機金屬衍生物，譬如鎂或I里 衍生物，製自化合物烷基-Hal，其中Hal表示氯、溴或琪原 子，至所製成之XXV化合物，示於實例470、471、472及473 中0 將[(反，尺)，(3,3)]-4-[(3,5-雙-二氟甲基-苯甲酿基）]各三氟甲基_2_乙 基-3,4_二氫-2H-4啉-1-羧酸乙酯（〇 〇15克，〇 〇28毫莫耳）放置在 含有磁攪拌棒之小圓底燒瓶中，並溶於〇·5〇毫升四氫呋喃中 。將溴化甲基鎂溶液（0.028毫升，3·〇 Μ，在乙醚中）於室溫下 添加至反葱·混合物中，並攪拌2小時。然後，以飽和氯化銨 落液使反應混合物淬滅，並萃取於醋酸乙酯中。將有機層 以水洗滌，以硫酸鎂脫水乾燥，過濾，及濃縮，提供所要 之產物’為粗製油。料非對晚異構物藉謂層析分離， 提供[(以，彰-[(3,5·雙-三氟甲基-苯基Η•經基_乙基昤乙基^ 三氟曱基-3,4-二氫-2Η+林錢酸乙画旨，與[(r，r，s㈣V·雙 三氟甲基-苯基)领基·乙基]_2_乙基各三說甲基从二氫抓奎 啉小羧酸乙酯。 92199 • 336 - 128564192199 - 335 - 1285641 [(11,11,11)]-4-[(3,5-bis-trifluoromethyl-phenyl)-fluoro-methyl]-2-ethyl-6-trifluoromethyl Ethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester 1H-NMR (CDC13): 5 7.88 (s,1H), 7.63 (s,d,3H), 7.52 (d,1H) , 7.41 (s, 1H), 5·58 (dd, J=7.47Hz, 1H), 4·42 (m, 1H), 4.24 (m, 2H), 3·40 (m, 1H), 1.97 (m,1H), L74 (m,1H),1.41 (m,2H), 1.27 (t,3H), 0.79 (t,3H); MS: 546.3 [M+H]+ Measured Values · Examples 470, 471 472 and 473 The following compounds are prepared from a starting material similar to that described above and the procedure shown in Figure 2, wherein an appropriate organometallic derivative, such as a magnesium or I derivative, is prepared from the compound alkyl group. Hal, wherein Hal represents a chlorine, bromine or qi atom, to the resulting XXV compound, shown in Examples 470, 471, 472 and 473 0 will [(reverse, ruler), (3,3)]-4-[ (3,5-bis-difluoromethyl-benzoyl)]Ethyl trifluoromethyl-2-ethlyl-3,4-dihydro-2H-4-l-carboxylic acid ethyl ester (〇〇 15 g, 〇〇28 mmol) placed in a small round bottom flask containing a magnetic stir bar and dissolved in 〇·5 〇 ml of tetrahydrofuran In. A solution of methylmagnesium bromide (0.028 ml, 3·〇 in diethyl ether) was added to the mixture, and stirred for 2 hours. The reaction mixture was then quenched with saturated aqueous ammonium chloride and extracted in ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated to give the desired product as crude oil. Separation of the non-isomerization of the isomers by chromatography, providing [(,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, -3,4-Dihydro-2Η+linnic acid B, and [(r,r,s(tetra)V·bistrifluoromethyl-phenyl) collaryl·ethyl]_2_ethyl each three methyl Ethyl carboxylic acid ethyl ester from dihydrogen. 92199 • 336 - 1285641

[(11，11，11)]，(11，11，3)]-4-[(3,5-雙-三氟甲基-苯基）小羥基-乙基]-2-乙基 -6-三氣甲基-3,4-二鼠-2Η-^淋-l-複叙乙醋 第一個溶離化合物：1H-NMR (CDC13): 5 7.86 (s，2Η)，7.80 (s，1Η)， 7·53 (dd，2H)，7.34 (s，1H)，4.3 (m，2H)，4.18 (m, 1H)，3.18 (m，1H)，1.95 (m， 1H)，1.80 (s，1H)，1.5-1.63 (m, 4H)，1.24-1.45 (m，5H)，0,70 (t，3H); MS ·· 588.3 [M+H]+實測值. 第二個溶離化合物·· 1H-NMR (CDC13): 5 7.76 (m，3H)，7.53 (d，1H)， 7.42 (d，1H)，7.06 (s，1H)，4.41 (m，1H)，4.2 (q，2H)，3.18 (m，1H)，2·30 (m，1H)， L91 (brs, 1H), 1.62-L74 (m, 4H), 1.24-1.43 (m, 5H), 0.77 (t, 3H)； MS : 588.3 [M+H]+實測值·[(11,11,11)],(11,11,3)]-4-[(3,5-bis-trifluoromethyl-phenyl)hydroxy-ethyl]-2-ethyl-6 - Tri-gas methyl-3,4-di-mouse-2Η-^-l-l-reciting vinegar first dissolved compound: 1H-NMR (CDC13): 5 7.86 (s, 2Η), 7.80 (s, 1Η ), 7·53 (dd, 2H), 7.34 (s, 1H), 4.3 (m, 2H), 4.18 (m, 1H), 3.18 (m, 1H), 1.95 (m, 1H), 1.80 (s, 1H), 1.5-1.63 (m, 4H), 1.24-1.45 (m, 5H), 0, 70 (t, 3H); MS · · 588.3 [M+H] + measured value. Second dissolved compound·· 1H-NMR (CDC13): 5 7.76 (m, 3H), 7.53 (d, 1H), 7.42 (d, 1H), 7.06 (s, 1H), 4.41 (m, 1H), 4.2 (q, 2H), 3.18 (m,1H),2·30 (m,1H), L91 (brs, 1H), 1.62-L74 (m, 4H), 1.24-1.43 (m, 5H), 0.77 (t, 3H); MS: 588.3 [M+H]+ measured value·

[(5^，11)]，(1^，3)]-4-[(3,5-雙-三氟甲基-苯基）-1-羥基-乙基]-2-乙基-6-三氟甲基-3,4-二氫-2H-喳啉-1-羧酸乙酯 第一個溶離化合物：1H-NMR (CDC13): (5 7·86 (s，1H)，7.80 (s，1H)， 7,70 (s，1Η)，7.55 (m，2Η)，7.35 (s，1Η)，4.3 (m，2Η)，4.19 (m，1Η)，3·20 (m，1Η)， 1.91 (m，1H)，1.60 (s，3H)，1·30 (t，3H)，0·70 (t，3H); MS : 556.2 [Μ-ΗΓ 實測值. 92199 - 337 - 1285641 第二個溶離化合物·· iH-NMR(CDCl3): (58.0(s，2H)，7,80(s，iH)， 7.50 (brs, 1H), 7.40 (dd, 2H), 4.4 (br m, 1H), 4.20 (m, 2H), 3.05 (d, 1H), 2.55 (brm，1H)，1.74 (s，3H)，1·63 (m，1H)，1.43 (m，2H)，1.30 (t, 3H)，0.90 (t，3H); MS : 558·3[Μ+Η]+實測值. 實例474與475 下列化合物係製自類似上文圖式1，特別是實例2中所述 之起始物質及程序。[(5^,11)],(1^,3)]-4-[(3,5-bis-trifluoromethyl-phenyl)-1-hydroxy-ethyl]-2-ethyl-6 -Ethyl trifluoromethyl-3,4-dihydro-2H-indolinoline-1-carboxylate First dissolving compound: 1H-NMR (CDC13): (5 7·86 (s, 1H), 7.80 ( s,1H), 7,70 (s,1Η),7.55 (m,2Η),7.35 (s,1Η),4.3 (m,2Η), 4.19 (m,1Η),3·20 (m,1Η) , 1.91 (m,1H), 1.60 (s,3H),1·30 (t,3H),0·70 (t,3H); MS : 556.2 [Μ-ΗΓ measured value. 92199 - 337 - 1285641 second Isolation Compound·································································· , 4.20 (m, 2H), 3.05 (d, 1H), 2.55 (brm, 1H), 1.74 (s, 3H), 1.63 (m, 1H), 1.43 (m, 2H), 1.30 (t, 3H) ), 0.90 (t, 3H); MS: 558·3 [Μ + Η] + measured values. Examples 474 and 475 The following compounds were prepared from a starting material similar to that described above in Scheme 1, in particular Example 2. And procedures.

[取扣]，(1^)]-4-[(3,5-雙-三氟基甲基-苯基）-1-經基-甲氧羰基-〒 基]-6,7-二甲氧基-2-甲基-2H-喹啉-1-羧酸乙酯 非對映異構物 1 : 1H-NMR (CDC13) : 5 7.92 (s，2H)，7.73 (s，1H)， 6.81 (s3 1H), 5.80 (d, 1H), 5.20 (br m, 1H), 4.40 (brs, 1H), 4.30 (m, 1H), 4.20 (br m，1H)，3.84 (s，3H)，3.80 (s，3H)，3.50 (s，3H)，1·34 (m，4H)，1·09 (d，3H); MS: 578·Γ[Μ+Η]+實測值· 非對映異構物 2 : 1H-NMR (CDC13): 5 8.18 (s，2H)，7.87 (s，1Η)，6.67 (s，1H)，5.65 (brs，1H)，5.15 (brs，1H)，4.31 (brm，1H)，4.20 (brm5 1H)，3·86 (s， 3H)，3.80 (s，3H)，3.58 (s，3H)，1.33 (t，3H)，1.09 (d，3H); MS · 578.6 [M+H]+ 實測值· 實例476與477 下列化合物係製自類似上文圖式1，特別是實例7與8中所 述之起始物質及程序。 92199 - 338 - 1285641[Reel], (1^)]-4-[(3,5-bis-trifluoromethyl-phenyl)-1-yl-methoxy-methoxycarbonyl]-6,7-dimethyl Ethyloxy-2-methyl-2H-quinoline-1-carboxylic acid ethyl ester diastereomer 1 : 1H-NMR (CDC13) : 5 7.92 (s, 2H), 7.73 (s, 1H), 6.81 (s3 1H), 5.80 (d, 1H), 5.20 (br m, 1H), 4.40 (brs, 1H), 4.30 (m, 1H), 4.20 (br m,1H), 3.84 (s,3H), 3.80 (s,3H), 3.50 (s,3H),1·34 (m,4H),1·09 (d,3H); MS: 578·Γ[Μ+Η]+ measured value · diastereomer 2: 1H-NMR (CDC13): 5 8.18 (s, 2H), 7.87 (s, 1 Η), 6.67 (s, 1H), 5.65 (brs, 1H), 5.15 (brs, 1H), 4.31 (brm, 1H), 4.20 (brm5 1H), 3·86 (s, 3H), 3.80 (s, 3H), 3.58 (s, 3H), 1.33 (t, 3H), 1.09 (d, 3H); MS · 578.6 [ M+H]+ Measured values. Examples 476 and 477 The following compounds were prepared from starting materials and procedures similar to those described above in Scheme 1, in particular Examples 7 and 8. 92199 - 338 - 1285641

[(R，S，R)，(R，S，S)]冬[(3,5-雙-三氟甲基-苯基：l·羥基-甲氧羰基-甲基]-6,7-二甲氧基-2-甲基-3,4-二氫奎啉小羧酸乙酯 第一個溶離物：1H NMR (CDC13) : (5 8.18 (s，2H)，7.88 (s，1H)，7_03 (brs5 1H), 6.73 (s? 1H), 4.31 (m5 1H)? 4.20 (m5 2H), 3.88 (s, 3H)3 3.86 (s, 3H), 3.81 (s，3H)，3.30 (d，1H)，1.70 (m，2H)，1·21-1·30 (tm，4H)，1.09 (d，3H); MS : 580.6 [M+H]+ 實測值. 第二個溶離物：1H NMR (CDC13) : (5 8·25 (s，2H)，7·84 (s，1H)，6·92 (brs, 1H)5 6.30 (s, 1H), 4.55 (m? 1H), 4.30 (m5 1H)3 4.20 (m, 1H)3 3.88 (s, 3H), 3.80 (s，3Η)3·60 (d，1H)，3.40 (s，3H)，2·03 (m，2H)，1·55 (m，1H)，1·32 (t，3H) 1.09 (d，3H); MS : 580.5 [M+Hf 實測值· 實例478與479 下列化合一物係製自起類似上文，特別是實例448、449、450 及451中所述之始物質及程序。 [(民11，11)]，(民民3)]-4-[(3,5-雙-三氟甲基_苯基）-甲氧羰基-甲基]_6,7- 二甲氧基-2-甲基-3,4-二氫奎淋-1-羧酸乙酯[(R,S,R),(R,S,S)] Winter [(3,5-bis-trifluoromethyl-phenyl:l-hydroxy-methoxycarbonyl-methyl]-6,7- Ethyl dimethoxy-2-methyl-3,4-dihydroquinoline carboxylic acid ethyl ester First dissolving: 1H NMR (CDC13) : (5 8.18 (s, 2H), 7.88 (s, 1H) , 7_03 (brs5 1H), 6.73 (s? 1H), 4.31 (m5 1H)? 4.20 (m5 2H), 3.88 (s, 3H)3 3.86 (s, 3H), 3.81 (s, 3H), 3.30 (d , 1H), 1.70 (m, 2H), 1·21-1·30 (tm, 4H), 1.09 (d, 3H); MS: 580.6 [M+H]+ Measured value. Second solvate: 1H NMR (CDC13) : (5 8 · 25 (s, 2H), 7. 84 (s, 1H), 6.92 (brs, 1H) 5 6.30 (s, 1H), 4.55 (m? 1H), 4.30 ( M5 1H)3 4.20 (m, 1H)3 3.88 (s, 3H), 3.80 (s,3Η)3·60 (d,1H), 3.40 (s,3H),2·03 (m,2H),1 ·55 (m,1H),1·32 (t,3H) 1.09 (d,3H); MS : 580.5 [M+Hf measured value · Examples 478 and 479 The following compounds are similar to the above, especially It is the starting material and procedure described in Examples 448, 449, 450 and 451. [(Min 11, 11)], (民民3)]-4-[(3,5-bis-trifluoromethyl-benzene) ))-methoxycarbonyl-methyl]_6,7-dimethoxy-2-methyl-3,4-dihydroquinone-1-carboxylic acid

92199 - 339 - 1285641 1 H NMR (CDC13) ： (5 7.97 (s, 2H), 7.83 (s5 1H)5 7.0 (brs, 1H), 6.20 (s, 1H), 4.50 (m，1H), 4.30 (m，1H)，4.30 (m，1H)，4.19 (m，1H)，4.17 (d，1H)，3.80 (s， 3H)，3.74 (s，3H)，3.51 (s，3H)，3.32 (m，1H)，2.30 (m，1H)，1,31 (t，3H)，1.20 (d， 3H)； MS : 564.5 [M+Hf 實測值·92199 - 339 - 1285641 1 H NMR (CDC13) : (5 7.97 (s, 2H), 7.83 (s5 1H)5 7.0 (brs, 1H), 6.20 (s, 1H), 4.50 (m,1H), 4.30 ( m,1H), 4.30 (m,1H), 4.19 (m,1H), 4.17 (d,1H), 3.80 (s, 3H), 3.74 (s,3H),3.51 (s,3H),3.32 (m ,1H),2.30 (m,1H),1,31 (t,3H),1.20 (d, 3H); MS : 564.5 [M+Hf measured value·

1H NMR (CDC13): ¢5 7.87 (s，3H)，7.03 (brs，1H)，6·72 (s，1H)，4.31 (m, 2H)， 4,20 (m，1H)，3,98 (d，1H)，3·86 (s，6H)，3.75 (s，3H)，3.32 (t，1H)，1.70 (m，1H)， 1.30 (t，3H)，1.07 (d，3H)，0.80 (m，1H); MS : 564.4 [M+Hf 實測值. 實例480 下列化合物係製自類似上文，特別是實例470、471、472 及473中所述之起始物質及程序。 將[(11，11，11)]，(11，11，3)]-4-[(3,5-雙-三氟甲基-苯基）小輕基-乙基]-乙 基-6-三氟甲基-3,4-二氫-2H-喹# -1-绶酸乙酯（0.079克，0.142毫 莫耳）放置在含有磁攪拌棒之小圓底燒瓶中，並溶於1.5毫升 無水氯仿中。於此反應溶液中添加2,6-二-第三-丁基-4-甲基吡 啶（0.117克，0.568毫莫耳）與二氯化亞硫醯（〇.〇51克，0.425毫 莫耳），並將其在室溫下揽拌四小時。以水使反應混合物淬 滅，並萃取於二氯甲烷中。將有機層以〇1 N HC1洗滌，以硫 92199 -340- 1285641 酸鎂脫水乾燥，過濾，及濃縮，提供 雙-三氟甲基-苯基）小氣-乙基]-2-乙基-6-三氟甲基-3,4-二氫-2H-喹淋小羧酸乙酯，為油狀物，使用之而無需進一步純化。 將[(11，11，11)]，(11，11，3)]-4-1&gt;(3,5-雙-三氟〒基-苯基）小氯-乙基]-2-乙基-6-三氟甲基-3,4-二氫-2H-喹啉小羧酸乙酯（0.085克，0.142毫莫耳） 放置在含有磁攪拌棒之小圓底燒瓶中，並溶於〇 48毫升THF 中。於此溶液中，添加冰醋酸（〇·48毫莫耳）、HC1 (0·80毫莫耳） 及鋅粉（(0.093克，1.42毫莫耳）。將反應混合物於室溫下攪拌 三小時。以水使反應混合物淬滅，並以醋酸乙酯萃取三次 。將有機層以水洗滌，以硫酸鎂脫水乾燥，過濾，及濃縮 ’提供[(R，RH-[l-(3,5-雙-三氟甲基-苯基）-乙烯基]·2-乙基-6-三氟 甲基-3,4- 一鼠奎啦_1_幾酸乙g旨，為油狀物。 將[(R，R)_4-[l-(3,5{ _三氟甲基苯基）_乙烯基]-2-乙基-6-三氟甲 基-3,4-二氫-2H-喹啉小羧酸乙酯（15毫克）放置在小圓底燒瓶中 ’並溶於10毫升甲醇中。於此溶液中，添加1〇毫克PWC 。使反應混合物在45 psi下氫化12小時。然後，經過矽藻土 過濾反應惠·合物，並以T醇洗滌。使漉液濃縮成油，並藉 ♦膠層析純化，提供[(11,11，11)]，(11，^)]-4-[1-(3,5-雙-三氟〒基-苯基 &gt;乙基]-6,7-三氟甲基-3,4-二氫-2H-喹啉小叛酸乙酯，66%產率。1H NMR (CDC13): ¢5 7.87 (s,3H), 7.03 (brs,1H),6·72 (s,1H), 4.31 (m, 2H), 4,20 (m,1H),3,98 (d,1H),3·86 (s,6H),3.75 (s,3H),3.32 (t,1H), 1.70 (m,1H), 1.30 (t,3H),1.07 (d,3H), 0.80 (m, 1H); MS: 564.4 [M+Hf found. </ RTI> </ RTI> </ RTI> The following compounds were prepared from similar starting materials and procedures as described above in Examples 470, 471, 472 and 473. [(11,11,11)],(11,11,3)]-4-[(3,5-bis-trifluoromethyl-phenyl) chlorenyl-ethyl]-ethyl-6 -Trifluoromethyl-3,4-dihydro-2H-quinoethyl-1-acetate (0.079 g, 0.142 mmol) placed in a small round bottom flask containing a magnetic stir bar and dissolved in 1.5 In milliliters of anhydrous chloroform. To this reaction solution was added 2,6-di-tert-butyl-4-methylpyridine (0.117 g, 0.568 mmol) and sulfite dichloride (〇.〇 51 g, 0.425 mmol) ) and mix it for four hours at room temperature. The reaction mixture was quenched with water and extracted in dichloromethane. The organic layer was washed with 〇1N HCl, dried over EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc Ethyl trifluoromethyl-3,4-dihydro-2H-quinoline carboxylic acid as an oil which was used without further purification. [(11,11,11)],(11,11,3)]-4-1&gt;(3,5-bis-trifluoromethyl-phenyl) chloro-ethyl]-2-ethyl Ethyl -6-trifluoromethyl-3,4-dihydro-2H-quinolinecarboxylate (0.085 g, 0.142 mmol) placed in a small round bottom flask containing a magnetic stir bar and dissolved in hydrazine 48 ml of THF. To this solution, glacial acetic acid (〇·48 mmol), HC1 (0·80 mmol) and zinc powder ((0.093 g, 1.42 mmol) were added. The reaction mixture was stirred at room temperature for three hours. The reaction mixture was quenched with water and extracted with EtOAc EtOAc EtOAc EtOAc (EtOAc) Bis-trifluoromethyl-phenyl)-vinyl]·2-ethyl-6-trifluoromethyl-3,4-one quinine _1 _ _ _ acid is an oily substance. [(R,R)_4-[l-(3,5{ _Trifluoromethylphenyl)-vinyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H- Ethyl quinoline small carboxylic acid (15 mg) was placed in a small round bottom flask and dissolved in 10 mL of methanol. To this solution, 1 mM of PWC was added. The reaction mixture was hydrogenated at 45 psi for 12 hours. The reaction mixture was filtered through celite, and washed with T alcohol. The mash was concentrated to an oil and purified by gel chromatography to provide [(11,11,11)], (11,^)] -4-[1-(3,5-bis-trifluoromethyl-phenyl)ethyl]-6,7-trifluoromethyl-3,4-dihydro-2H-quinoline Ester, 66% yield

92199 -341 - 1285641 [(11，3，11)]，(11，3,3)]-4-[1-(3,5_雙-三氟甲基-苯基）-乙基]-2-乙基-6,7-三 氟甲基-3,4-二氫-2H-峻α林-丨_瘦酸乙酯 1 H NMR (CDC13): 5 7.78 (s，1Η)，7.65 (s，2Η)，7.59 (dd，2Η)，7.41 (s，1Η)， 4·30 (m，1H)，4.20 (τη，2H)，2·95 (m，2H)，1.80 (m，1H)，1.58 (m，2H)，1.40 (m， 1H), 1·30 (t，3H)，1·20 (d，3H)，0.72 (t，3H); MS : 542.3 [M+Hf 實測值· 實例481 (實例462、463、464及465之立體異構物）92199 -341 - 1285641 [(11,3,11)],(11,3,3)]-4-[1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2 -ethyl-6,7-trifluoromethyl-3,4-dihydro-2H-jun α-lin-succinate ethyl ester 1 H NMR (CDC13): 5 7.78 (s,1Η), 7.65 (s , 2Η), 7.59 (dd, 2Η), 7.41 (s, 1Η), 4·30 (m, 1H), 4.20 (τη, 2H), 2·95 (m, 2H), 1.80 (m, 1H), 1.58 (m, 2H), 1.40 (m, 1H), 1·30 (t, 3H), 1·20 (d, 3H), 0.72 (t, 3H); MS: 542.3 [M+Hf measured value · example 481 (stereoisomers of Examples 462, 463, 464 and 465)

[(S，R，S)]，4-[胺基-(3,5-雙-三氟甲基-苯基 &gt;曱基]·2_乙基各三氟甲 基二氫-2Η-啥琳-1-羧酸乙I旨； [(S，S，S)]，4-[胺基-(3,5-雙-三氟甲基-苯基）_曱基降乙基各三氟甲 基-3,4-二氫-2H-喹啉-1-複酸乙酯； [(3，11，11)]，4-[胺基-(3,5-雙-三氟甲基-苯基）_甲基]_2_乙基各三氟 甲基-3,4-二1 -2H-喳啉小羧酸乙酯； [(S，S，R)]，4-[胺基-(3,5-雙-三氟甲基-苯基）-甲基]i乙基各三乳甲 基-3,4·二氫-2H-P奎0林小幾酸乙酯； 或該化合物之藥學上可接受鹽。 上述實例462、463、464及465之立體異構物係為預告，且 可使用類似本文中所述之方法，藉由解析所指示相應之外 消旋物或其合成中之中間物，製成呈光學上富各形式。 實例482與483 92199 - 342 - 1285641[(S,R,S)],4-[Amino-(3,5-bis-trifluoromethyl-phenyl)-indenyl] 2-ethyl-trifluoromethyldihydro-2Η-啥琳-1-carboxylic acid ethyl I; [(S, S, S)], 4-[amino-(3,5-bis-trifluoromethyl-phenyl)-fluorenyl-ethylate each Ethyl fluoromethyl-3,4-dihydro-2H-quinolin-1-one; [(3,11,11)],4-[amino-(3,5-bis-trifluoromethyl) -phenyl)-methyl]_2-ethyl each trifluoromethyl-3,4-di-1 -2H-carboline small carboxylic acid ethyl ester; [(S, S, R)], 4-[amino group -(3,5-bis-trifluoromethyl-phenyl)-methyl]iethyl each tris-methyl-3,4·dihydro-2H-P-quinoline acid; or Pharmaceutically acceptable salts of the compounds. The stereoisomers of the above Examples 462, 463, 464 and 465 are foreseen, and the corresponding racemates or their The intermediate in the synthesis, made in optically rich form. Examples 482 and 483 92199 - 342 - 1285641

(R，R)-4-[(3,5-雙-二氟甲基·苯基）_羥基·甲氧羰基-甲基]·2·乙基· 6-三氟甲基-2Η-4：ρ林-1-幾酸乙酯； (R，S)-4-[(3,5-雙-二氟甲基·苯基）_幾基·甲氧羰基·甲基]_2_乙基_ 6_三氟甲基-2Η_4：β林小幾酸乙酯 使兩種非對映異構物之混合物（實例2，1〇克）於矽膠上層 析（急恭式 40Μ 管柱，Biotage，Dyar 公司，Charlottesville，VA)，以二 氯甲燒-己燒梯度液2 : 3至4 : 1溶離，獲得標題化合物，為 白色固體。 第一個溶離出之非對映異構物（並未測得4a立體化學）： MS ·· 597.9 [M-Η]·實測值 1H-NMR (CDC13) 5 7.92 (s5 2H), 7.75 (s, 1H), 7.67 (s, 1H), 7.65 (d, J=8.30 Hz, 1H)，7.34Tdd，J=8.30, 1.66Hz，1H)，5.97 (d，J=6.64Hz，1H)，5.04 (m，1H)， 4·53 (s，1H)，4.27 (m，2H)，3·87 (s，3H)，1.47 (m，1H)，1.35 (m，1H)，1·28 (t，J= 7.47Hz, 3H), 0.85 (d, J=6.64Hz, 3H). 第二個溶離出之非對映異構物（並未測得4a立體化學）： MS : 597.9 [M-Η]·實測值 1H-NMR (CDC13) 5 8.16 (s，2H)，7.90 (s，1H)，7.65 (d，J=8.30，1H)，7·63 (s， 1Η)，7.45 (dd，J=8.30, 1.66Hz，1Η)，5.82 (d，J=6.42Hz，1Η)，4,96 (m，1Η)，4.34 (s，1H), 4.27 (m，2H)，3.78 (s，3H)，1.47 (m，1H)，1.35 (m，1H)，1.33 (t，J=7.47 92199 - 343 - 1285641(R,R)-4-[(3,5-bis-difluoromethylphenyl)-hydroxymethoxycarbonyl-methyl]·2·ethyl·6-trifluoromethyl-2Η-4 : ρ lin-1-carboxylic acid ethyl ester; (R,S)-4-[(3,5-bis-difluoromethylphenyl)phenyl-methoxycarbonylmethyl]_2-ethyl _ 6_Trifluoromethyl-2Η_4: β-linic acid ethyl ester. A mixture of two diastereomers (Example 2, 1 gram) was chromatographed on silica gel. , Dyar Company, Charlottesville, VA), eluted with chloroform-hexanes gradient 2:3 to 4:1 to give the title compound as a white solid. The first dissociated diastereomer (no 4a stereochemistry was measured): MS ·· 597.9 [M-Η]·Measured value 1H-NMR (CDC13) 5 7.92 (s5 2H), 7.75 (s , 1H), 7.67 (s, 1H), 7.65 (d, J=8.30 Hz, 1H), 7.34Tdd, J=8.30, 1.66Hz, 1H), 5.97 (d, J=6.64Hz, 1H), 5.04 ( m,1H), 4·53 (s,1H), 4.27 (m,2H),3·87 (s,3H), 1.47 (m,1H), 1.35 (m,1H),1·28 (t, J = 7.47 Hz, 3H), 0.85 (d, J = 6.64 Hz, 3H). The second eluted diastereomer (no 4a stereochemistry was measured): MS : 597.9 [M-Η] · Measured value 1H-NMR (CDC13) 5 8.16 (s, 2H), 7.90 (s, 1H), 7.65 (d, J = 8.30, 1H), 7·63 (s, 1Η), 7.45 (dd, J= 8.30, 1.66 Hz, 1 Η), 5.82 (d, J = 6.42 Hz, 1 Η), 4, 96 (m, 1 Η), 4.34 (s, 1H), 4.27 (m, 2H), 3.78 (s, 3H), 1.47 (m,1H), 1.35 (m,1H), 1.33 (t,J=7.47 92199 - 343 - 1285641

Hz, 3H), 0.83 (d, J=7.47Hz, 3H). 實例484Hz, 3H), 0.83 (d, J=7.47Hz, 3H). Example 484

(R，R)-4-(3,5-雙-三氟甲基4基）_2-乙基各三氟甲基-3,4-二氫々Η- 喳啉-1-羧酸乙酯 將[(以則叫即-雙-王氟甲基-苯基卜甲烷磺醯氧基呷基降 乙基-6-三氟甲基-3,4-二氫-2H-喳啉小羧酸乙酯（0.045毫莫耳， 0.0278克）放置在5毫升反應燒瓶中，於其中，添加丨.3毫升dmf ，接著是硼氫化鈉（0.526毫莫耳，0.019克）。將反應物加熱至 85°C，歷經十二小時。然後，將反應混合物以醋酸乙酯稀釋 ，並以鹽水溶液洗滌。收集有機層，以硫酸鈉脫水乾燥， 過遽’及濃縮至乾涸。使粗製反應混合物於碎膠上純化層 析，提供18:5毫克所要之產物（R，R)冰(3,5-雙-三氟甲基4基&gt;2_ 乙基-6-三氟甲基-3,4-二氫奎淋-1-複酸乙酉旨，78%產率。 lHNMR(CDCl3) ： 〇.80ppm(t?3H)5 L10(m5lH)5 1.29 (t?3H), 1.41-1.62 (m，2H &amp; H2 0)，2.16 (m，1H)，2.76-2.87 (m，2H)，3·64 (d，1H)，4.15-4.32 (m， 3H)，7.47 (s，1H)，7·51-7.57 (m，2H)，7.70 (s，2H)，7·80 (s，1H). MS (ES+) m/z=528 (M+l). 實例485 92199 -344 - 1285641(R,R)-4-(3,5-bis-trifluoromethyl-4-yl)_2-ethyl-trifluoromethyl-3,4-dihydroindole-porphyrin-1-carboxylic acid ethyl ester Will be [(), ie, ie, bis-terofluoromethyl-phenylmethanesulfonyloxycarbonyl-ethyl-6-trifluoromethyl-3,4-dihydro-2H-carboline small carboxylic acid Ethyl ester (0.045 mmol, 0.0278 g) was placed in a 5 mL reaction flask to which was added &lt;RTI ID=0.0&gt;&gt;&gt; After a period of 12 hours, the reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was collected, dried over sodium sulfate, dried and evaporated to dryness. Purification chromatography to provide 18:5 mg of desired product (R, R) ice (3,5-bis-trifluoromethyl-4-yl)-2-ethyl-6-trifluoromethyl-3,4-di Hydrogen quinone-1-acid acetate, 78% yield. lHNMR(CDCl3) : 〇.80ppm(t?3H)5 L10(m5lH)5 1.29 (t?3H), 1.41-1.62 (m,2H &amp ; H2 0), 2.16 (m, 1H), 2.76-2.87 (m, 2H), 3·64 (d, 1H), 4.15-4.32 (m, 3H), 7.47 (s, 1H), 7·51- 7.57 (m, 2H), 7. 70 (s, 2H), 7·80 (s, 1H). MS (ES+) m/z = 528 (M+l). Example 485 92199 -344 - 1285641

(!1，11，3)4-[(3,5-雙-三氟甲基-苯基&gt;^胺基甲基]-2-乙基各三氟甲 基-3,4-一氮奎琳-1-致酸乙酉旨 將（R，R，S)4-[胺基-(3,5-雙-三氟甲基-苯基甲基]-2·乙基各三氟 甲基_3斗二氫-2H-喳啉小羧酸乙酯（〇·ΐ93克，0·357毫莫耳）放置 在含有7毫升甲酸乙酯之密封管中。密封管件，並於i〇(rc下 加熱十二小時。然後，使反應混合物濃縮，並於矽膠上純 化層析，提供0.165克甲醯胺，81%產率。接著，將此產物放 置在裝有磁攪拌棒之圓底燒瓶中，並溶於7.3毫升甲苯中。 於此溶液中，添加2_92毫升甲苯中之硼烷硫化甲烷複合物 (2·0 M)。將回流冷凝管連接至燒瓶，並將反應物加熱至％ ，歷經十二小時。然後，以甲醇與數滴HC1使反應混合物淬 滅。接著將此混合物加熱1小時。於冷卻至室溫後，以NaHC〇3 水溶液使混^合物反應淬滅，並以醋酸乙酯萃取3次。收集有 機物質，以硫酸#3脫水乾燥，並濃縮至乾涸。使粗製油於 矽膠上純化層析，提供（R，R，S)4-[(3,5-雙-三氟甲基-苯基）-甲胺 基甲基&gt;2-乙基-6-三氟甲基-3,4-二氫-2H-喹啉-1-羧酸乙酯，41% 產率。 1H NMR(CDC13): 0.81 ppm (t，3H)，1.33 (t，3H)，1.36-1.52 (m，3H)，2·25 (s， 3H)，2·52 (m，1H)，2.97 (m，1H)，3.99 (d，1H)，4.28 (m，2H)，4·52 (m，1H)，7.04 (s，1H)，7·41 (m，1H)，7·59-7·61 (m，3H)，7.72 (s，1H)· 92199 - 345 - 1285641 MS(ES+)m/z=557 (M+l)· 實例 486-499 此等化合物係類似實例9、10、433、434、438、443、444 、452、454、457中所述，及圖式2中一般性描述之程序，製 自適當起始物質。於圖式2中稱為式XVII之經適當取代之溴 基中間物，係使用由Matsugi在以2000, 47, 8523中， 與Hardy在美國專利6,288,075中所述之程序製成。 實例486(!1,11,3)4-[(3,5-Bis-Trifluoromethyl-phenyl)-aminomethyl]-2-ethyl-trifluoromethyl-3,4-nitrogen奎琳-1-酸酸乙酉(R,R,S)4-[Amino-(3,5-bis-trifluoromethyl-phenylmethyl]-2·ethyl trifluoromethyl _3 piped dihydro-2H-carboline ethyl carboxylic acid ethyl ester (〇·ΐ 93 g, 0·357 mmol) was placed in a sealed tube containing 7 ml of ethyl formate. Sealed tube, and i〇(rc It was heated for 12 hours. Then, the reaction mixture was concentrated and purified by chromatography on silica gel to afford 0.165 g of carbamide, 81% yield. The product was then placed in a round bottom flask containing a magnetic stir bar. And dissolved in 7.3 ml of toluene. In this solution, add 2 to 92 ml of borane vulcanized methane complex in toluene (2.0 M). Connect the reflux condenser to the flask and heat the reaction to %. Twelve hours. Then, the reaction mixture was quenched with methanol and a few drops of HCl. The mixture was then heated for 1 hour. After cooling to room temperature, the mixture was quenched with NaHC 3 aqueous solution and acetic acid was obtained. Ethyl acetate extraction 3 times. Collect organic matter to sulfuric acid #3 Dry with water and concentrate to dryness. Purify the crude oil on silica gel to afford (R,R,S)4-[(3,5-bis-trifluoromethyl-phenyl)-methylaminomethyl &gt; 2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, 41% yield. 1H NMR (CDC13): 0.81 ppm (t, 3H ), 1.33 (t, 3H), 1.36-1.62 (m, 3H), 2·25 (s, 3H), 2·52 (m, 1H), 2.97 (m, 1H), 3.99 (d, 1H), 4.28 (m, 2H), 4·52 (m, 1H), 7.04 (s, 1H), 7·41 (m, 1H), 7·59-7·61 (m, 3H), 7.72 (s, 1H) ) 92199 - 345 - 1285641 MS(ES+)m/z=557 (M+l)· Examples 486-499 These compounds are similar to Examples 9, 10, 433, 434, 438, 443, 444, 452, 454, The procedure generally described in 457, and generally described in Scheme 2, is prepared from a suitable starting material. The appropriately substituted bromo intermediate of formula XVII in Figure 2 is used by Matsugi at 2000. 47, 8523, made with the procedure described by Hardy in U.S. Patent 6,288,075. Example 486

(RS，RS，SR)-4-[(3,5-雙-三氟甲基-苯基）-甲氧羰基-甲基]-6-氟基-2-甲基-3,4-二氫-2H-喳啉小羧酸異丙酯 GCMS (EI) ： 535 (M+) 1H-NMR (CDC13): 5 0.87 (m, 1H)，1.04 (d，3H)，1.25 (m，3H)，1·32 (d，3H)， 1·69 (m，1H)，3·33 (m，1H)，3.76 (s，3H)，3·92 (d, 1H)，4·29 (m，1H)，5.03 (m， 1H)，6.81 (dd，1H)，6.87 (m，1H)，7.38 (bs，1H)，7.85 (s，2H)，7.87 (s，1H)· 實例487(RS,RS,SR)-4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-6-fluoro-2-methyl-3,4-di Hydrogen-2H-carboline carboxylic acid isopropyl ester GCMS (EI): 535 (M+) 1H-NMR (CDC13): 5 0.87 (m, 1H), 1.04 (d, 3H), 1.25 (m, 3H), 1·32 (d,3H), 1·69 (m,1H),3·33 (m,1H), 3.76 (s,3H),3·92 (d, 1H),4·29 (m,1H) ), 5.03 (m, 1H), 6.81 (dd, 1H), 6.87 (m, 1H), 7.38 (bs, 1H), 7.85 (s, 2H), 7.87 (s, 1H) · Example 487

92199 - 346 - 1285641 (R，R，S)-4-[(3,5-雙-三氟甲基-苯基）·甲氧羰基-甲基]各氟基-2-甲基- 3,4-一氣-2Η-Ϊ7奎淋-丨-竣酸異丙g旨 GCMS (EI) ： 535 (M+) 1 H-NMR (CDC13 )·· 5 0.83 (m，1H)，1.04 (d，3H)，1.26 (d，3H)，1.32 (d，3H)， 1·72 (m，1H)，3·33 (m，1H)，3,77 (s，3H)，3.91 (d，1H)，4·28 (m，1H)，5.03 (m， 1H)，6.82 (dd，1H)，6.95 (m，1H)，7.38 (bs，1H)，7·84 (s，2H)，7·87 (s，lH).92199 - 346 - 1285641 (R,R,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]fluoromethyl-2-methyl- 3, 4-一气-2Η-Ϊ7 奎淋-丨-竣 isopropyl acid g GCMS (EI) : 535 (M+) 1 H-NMR (CDC13 )·· 5 0.83 (m,1H), 1.04 (d,3H) , 1.26 (d, 3H), 1.32 (d, 3H), 1·72 (m, 1H), 3·33 (m, 1H), 3, 77 (s, 3H), 3.91 (d, 1H), 4 · 28 (m, 1H), 5.03 (m, 1H), 6.82 (dd, 1H), 6.95 (m, 1H), 7.38 (bs, 1H), 7.84 (s, 2H), 7·87 (s , lH).

實例488Example 488

(S，S，R)-4-[(3,5-雙-三氟甲基-苯基）-甲氧羰基-甲基]各氟基-2-甲基-(S,S,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]fluoromethyl-2-methyl-

3,4-二氫-2H-峻淋-1-幾酸異丙醋 GCMS (EI) ： 535 (M+) 1H-NMR (CDC13): 5 0.83 (m，1H)，1.04 (d，3H)，1.26 (d，3H)，L32 (d，3H)， 1.69 (m，1H)，3.33 (m，1H)，3.77 (s，3H)，3.91 (d，1H)5 4.28 (m，1H)，5·03 (m， 1H)，6.82 (dd，1H)，6.95 (m，1H)，7.38 (bs，1H)，7.84 (s，2H)，7.87 (s，1H). 實例4893,4-Dihydro-2H-Fluorine-1-acid isopropyl vinegar GCMS (EI): 535 (M+) 1H-NMR (CDC13): 5 0.83 (m, 1H), 1.04 (d, 3H), 1.26 (d,3H), L32 (d,3H), 1.69 (m,1H), 3.33 (m,1H),3.77 (s,3H),3.91 (d,1H)5 4.28 (m,1H),5 · 03 (m, 1H), 6.82 (dd, 1H), 6.95 (m, 1H), 7.38 (bs, 1H), 7.84 (s, 2H), 7.87 (s, 1H). Example 489

92199 - 347 - 1285641 (113，113，113)-4-[(3,5-雙-三氟甲基-苯基）-甲氧羰基-甲基]-6-氟基-2-甲基-3,4-二氫-2H-。奎淋-1-幾酸異丙酉旨 GCMS (ΕΙ) ： 535 (Μ+) 1 H-NMR (CDC13 )·· (5 0.87 (m，1Η)，1.17 (d，3Η)，1.26 (m，3Η)，1.32 (d，3Η)， 2.31 (m，1H)，3.28 (m，1H)，3.74 (s，3H)，4.17 (d，1H)，4.46 (m，1H)，5.04 (m， 1H), 6.44 (dd5 1H), 6.87 (m? 1H)3 7.38 (m? 1H), 7.84 (s, 1H), 7.89 (s5 2H). 實例490 cf392199 - 347 - 1285641 (113,113,113)-4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-6-fluoro-2-methyl- 3,4-Dihydro-2H-.奎 -1- -1- -1- 几 GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC GC 3Η), 1.32 (d, 3Η), 2.31 (m, 1H), 3.28 (m, 1H), 3.74 (s, 3H), 4.17 (d, 1H), 4.46 (m, 1H), 5.04 (m, 1H) ), 6.44 (dd5 1H), 6.87 (m? 1H)3 7.38 (m? 1H), 7.84 (s, 1H), 7.89 (s5 2H). Example 490 cf3

(R，R，S)-4-[(3,5-雙-三氟甲基-苯基）-胺甲醯基-甲基]-6-氟基-2-甲基- 3,4-二氫-2H-喹啉小羧酸異丙酯 GCMS^EI) ： 520 (M+) 1H-NMR (CDC13): 5 0.85 (m，1H)，1.05 (d，3H)，1.25 (d，3H)，1·30 (d，3H)， ® 1.64 (m，1H)，T.38 (m，1H)，3·71 (d，1H)，4.26 (m，1H)，5.01 (m，1H)，5·53 (bs， 1H)，5 J8 (bs，1H)，6·93 (m，2H)，7.37 (m，1H)，7.85 (s，2H)，7.87 (s，1H). 實例491(R,R,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-aminecarbamido-methyl]-6-fluoro-2-methyl- 3,4- Dihydro-2H-quinoline carboxylic acid isopropyl ester GCMS^EI) : 520 (M+) 1H-NMR (CDC13): 5 0.85 (m, 1H), 1.05 (d, 3H), 1.25 (d, 3H) ,1·30 (d,3H), ® 1.64 (m,1H), T.38 (m,1H),3·71 (d,1H), 4.26 (m,1H),5.01 (m,1H), 5·53 (bs, 1H), 5 J8 (bs, 1H), 6.93 (m, 2H), 7.37 (m, 1H), 7.85 (s, 2H), 7.87 (s, 1H). Example 491

92199 - 348 - 1285641 (1^，113，113)-4-[(3,5-雙-三氟甲基-苯基）-氰基-甲基]-6-氟基-2-甲基- 3,4-二氫-2H-喹啉小羧酸異丙酯 LCMS (ESI+) ： 503 (MH+) 1H-NMR (CDC13): 5 1·19 (d，3H)，1.24 (d，3H)，1·28 (d，3H)，1.45 (m，1H)， 2.18 (m，1H)，2·87 (m，1H)，4·31 (m，1H)，4·77 (d，1H)，4·99 (m，1H)，7·04 (bs， 1H)，7.06 (bs，1H)，7.45 (m，1H)，7.90 (s，2H)，7.96 (s，1H). 實例49292199 - 348 - 1285641 (1^,113,113)-4-[(3,5-bis-trifluoromethyl-phenyl)-cyano-methyl]-6-fluoro-2-methyl- 3,4-Dihydro-2H-quinoline carboxylic acid isopropyl ester LCMS (ESI+): 503 (MH+) 1H-NMR (CDC13): 5 1 · 19 (d, 3H), 1.24 (d, 3H), 1·28 (d,3H), 1.45 (m,1H), 2.18 (m,1H),2·87 (m,1H),4·31 (m,1H),4·77 (d,1H), 4·99 (m, 1H), 7·04 (bs, 1H), 7.06 (bs, 1H), 7.45 (m, 1H), 7.90 (s, 2H), 7.96 (s, 1H). Example 492

(耶，113,311)-4-[(3,5-雙-三氟甲基-苯基）-甲氧羧基-甲基]-2-甲基-6-三氟曱基-3,4-二氫-2H-p奎淋小幾酸異丙酯 GCMS (EI) ： 585 (M+) 1H-NMR (CDC13): 5 0·91 (m, 1H)，1·09 (d，3H)，1.29 (d，3H)，1·34 (d，3H)， L75 (m，1H)，3:38 (t，1H)，3.77 (s，3H)，4.02 (d，1H)，4.31 (m，1H)，5.06 (m，1H)， 7.38 (s, 1H), 7.55 (m, 2H), 7.88 (bs5 3H). 實例493(Ye, 113, 311) -4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarboxy-methyl]-2-methyl-6-trifluoromethyl-3,4-di Hydrogen-2H-p-quinone isopropyl ester GCMS (EI) : 585 (M+) 1H-NMR (CDC13): 5 0·91 (m, 1H),1·09 (d,3H), 1.29 ( d,3H),1·34 (d,3H), L75 (m,1H),3:38 (t,1H),3.77 (s,3H),4.02 (d,1H),4.31 (m,1H) , 5.06 (m, 1H), 7.38 (s, 1H), 7.55 (m, 2H), 7.88 (bs5 3H). Example 493

92199 - 349 - 1285641 (113，113，1^&gt;4-[(3,5-雙-三氟甲基-苯基）-甲氧羰基-甲基]-2-甲基-6-三氟甲基-3,4-二氫-2H-喹啉小羧酸異丙酯 LCMS (ESI+) ： 585 (M+) 1H-NMR (CDC13 )·· (5 1.22 (d，3H)，1.28 (d，3H)，1.33 (d，3H)，1.39 (m，1H)， 2.36 (m，1H)，3·27 (m，1H)，3.76 (s，3H)，4·27 (d，1H)，4.46 (m，1H)，5.06 (m， 1H)，7·08 (s，1H)，7·43 (d，1H)，7.57 (d，1H)，7.85 (s，1H)，7.93 (s，2H). 實例49492199 - 349 - 1285641 (113,113,1^&gt;4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2-methyl-6-trifluoro Methyl-3,4-dihydro-2H-quinoline carboxylic acid isopropyl ester LCMS (ESI+): 585 (M+) 1H-NMR (CDC13)·· (5 1.22 (d, 3H), 1.28 (d, 3H), 1.33 (d, 3H), 1.39 (m, 1H), 2.36 (m, 1H), 3·27 (m, 1H), 3.76 (s, 3H), 4·27 (d, 1H), 4.46 (m, 1H), 5.06 (m, 1H), 7·08 (s, 1H), 7·43 (d, 1H), 7.57 (d, 1H), 7.85 (s, 1H), 7.93 (s, 2H) ). Example 494

(RS，RS，SR)斗[(3,5-雙-三氟甲基-苯基）-胺甲醯基-甲基]-2-甲基-6-三氟甲基-3,4-二氫-2H-喹啉-1-羧酸異丙酯 LCMS (ESI+) ： 571 (MH+) 1H-NMR (CDC13 )·· (5 0.91 (m，1H)，1.09 (d，3H)，1·27 (d，3H)，1.33 (d，3H)， _ 1.68 (m，1Η)，—3‘·46 (t，1H)，3.81 (d，1H)，4·28 (m，1H)，5·04 (m，1H)，5.54 (bs， 1H)，5.82 (bs，1H)，7.46 (s，1H)，7.50 (d，1H)，7.56 (d，1H)，7.88 (s，3H)· 實例495(RS,RS,SR) bucket [(3,5-bis-trifluoromethyl-phenyl)-aminecarboxamido-methyl]-2-methyl-6-trifluoromethyl-3,4- Dihydro-2H-quinoline-1-carboxylic acid isopropyl ester LCMS (ESI+): 571 (MH+) 1H-NMR (CDC13)·· (5 0.91 (m,1H), 1.09 (d,3H),1· 27 (d,3H),1.33 (d,3H), _ 1.68 (m,1Η),—3'·46 (t,1H),3.81 (d,1H),4·28 (m,1H),5 · 04 (m, 1H), 5.54 (bs, 1H), 5.82 (bs, 1H), 7.46 (s, 1H), 7.50 (d, 1H), 7.56 (d, 1H), 7.88 (s, 3H)· Example 495

92199 - 350 - 1285641 (R，R，S)斗[(3,5-雙-三氟甲基-苯基）-胺甲醯基呷基]-2-甲基各三氟 甲基-3,4_二氫奎π林-1-複酸異丙酉旨 LCMS(ESI+)： 571 (MH+) 1 H-NMR (CDC13): 5 0.87 (m，1H)，1.09 (d，3H)，1.26 (d，3H)，1·33 (d，3H)， 1.69 (m，1H)，3·45 (t，1H)，3,83 (d，1H)，4.27 (m，1H)，5·03 (m，1H)，5.65 (bs5 1H)，5·99 (bs，1H)，7.46 (s，1H)，7.49 (d，1H)，7.55 (d5 1H)，7.88 (s，3H). 實例49692199 - 350 - 1285641 (R, R, S) Buck [(3,5-bis-trifluoromethyl-phenyl)-amine-mercaptoindolyl]-2-methyl-trifluoromethyl-3, 4_Dihydroquinoline lin-1 - hydroxy acid isopropyl ester LCMS (ESI+): 571 (MH+) 1 H-NMR (CDC13): 5 0.87 (m, 1H), 1.09 (d, 3H), 1.26 ( d,3H),1·33 (d,3H), 1.69 (m,1H),3·45 (t,1H),3,83 (d,1H), 4.27 (m,1H),5·03 ( m, 1H), 5.65 (bs5 1H), 5·99 (bs, 1H), 7.46 (s, 1H), 7.49 (d, 1H), 7.55 (d5 1H), 7.88 (s, 3H). Example 496

(S，S，R)-4-[(3,5-雙-三氟甲基-苯基）-胺甲醯基-甲基]-2-曱基-6-三氟 甲基-3,4-二氫-2H-喹啉小羧酸異丙酯 LCMS (ESI+) : 571 (MH+) 1H-NMR (CDC13 )： δ 0.87 (m, 1H), 1.08 (d, 3H), 1.26 (d3 3H)5 1.32 (d, 3H)? 1·68 (m，1Η)，1·44 (t，1H)，3.84 (d，1H)，4.26 (m，1H)，5.02 (m，1H)，5.69 (bs， 1H)，6.01 (bs，1H)，7.47 (s，1H)，7·49 (d，1H)，7.54 (d，1H)，7·87 (s，3H). 實例497(S,S,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-aminecarbamido-methyl]-2-indolyl-6-trifluoromethyl-3, 4-Dihydro-2H-quinoline carboxylic acid isopropyl ester LCMS (ESI+): 571 (MH+) 1H-NMR (CDC13): δ 0.87 (m, 1H), 1.08 (d, 3H), 1.26 (d3 3H ) 5 1.32 (d, 3H)? 1·68 (m, 1Η), 1.44 (t, 1H), 3.84 (d, 1H), 4.26 (m, 1H), 5.02 (m, 1H), 5.69 ( Bs, 1H), 6.01 (bs, 1H), 7.47 (s, 1H), 7·49 (d, 1H), 7.54 (d, 1H), 7·87 (s, 3H). Example 497

92199 -351 - 1285641 (1^，113，1^)斗[(3,5-雙-三氟甲基-苯基）-胺甲醯基-甲基]-2-甲基-6-三氟甲基-3,4-二氫-2H-喳啉-1-羧酸異丙醋 LCMS (ESI+) ： 571 (MH+) 1 H-NMR (CDC13 )·· 5 0·87 (m，1H)，1.18 (d，3H)，1.24 (d，3H)，1.28 (d，3H)， 2.54 (m，1H)，3.37 (t，1H)，4.00 (d，1H)，4·48 (m，1H)，5.04 (m，1H)，6.02 (bs， 1H)，6.33 (bs，1H)，7.00 (s，1H)，7·36 (d，1H)，7.55 (d，1H)，7.81 (s，1H)，7.98 (s， 2H). 實例49892199 -351 - 1285641 (1^,113,1^) bucket [(3,5-bis-trifluoromethyl-phenyl)-aminecarboxamido-methyl]-2-methyl-6-trifluoro Methyl-3,4-dihydro-2H-inorganoline-1-carboxylic acid isopropyl acetate LCMS (ESI+): 571 (MH+) 1 H-NMR (CDC13)·· 5 0·87 (m,1H), 1.18 (d,3H), 1.24 (d,3H), 1.28 (d,3H), 2.54 (m,1H), 3.37 (t,1H), 4.00 (d,1H),4·48 (m,1H) , 5.04 (m, 1H), 6.02 (bs, 1H), 6.33 (bs, 1H), 7.00 (s, 1H), 7·36 (d, 1H), 7.55 (d, 1H), 7.81 (s, 1H) ), 7.98 (s, 2H). Example 498

(RS，RS，SR)-4-[2-胺基-l-(3,5-雙-三氟甲基-苯基）-乙基]-2_甲基-6-三 氟曱基-3,4-二氫-2H-喹啉小羧酸異丙酯 LCMS (ESI+) ： 557 (MH+) 1H-NMR (CDC13): 5 0.80 (m，1H)，1.04 (d，3H)，1.28 (d，3H)，1,34 (d，3H)， 1.76 (m，1H)，2·75 (t，1H)，3,11 (m，1H)，3·35 (m，1H)，3.46 (m，1H)，4.26 (m， 1H)，5.06 (m，1H)，7·54 (m，3H)，7·77 (s，2H)，7·84 (s，1H)· 實例499(RS,RS,SR)-4-[2-Amino-l-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-methyl-6-trifluorodecyl- 3,4-Dihydro-2H-quinoline carboxylic acid isopropyl ester LCMS (ESI+): 555 (MH+) 1H-NMR (CDC13): 5 0.80 (m, 1H), 1.04 (d, 3H), 1.28 ( d,3H),1,34 (d,3H), 1.76 (m,1H),2·75 (t,1H),3,11 (m,1H),3·35 (m,1H), 3.46 ( m,1H), 4.26 (m, 1H), 5.06 (m, 1H), 7·54 (m, 3H), 7·77 (s, 2H), 7·84 (s, 1H)· Example 499

Q^1QO 1285641 (RS，RS，SR)-4-[2-乙醯胺基小(3,5-雙-三氟甲基-苯基）-乙基]-2-甲基-6-三氣甲基-3,4-二氫-2H-峻淋-1-叛酸異丙酉旨 LCMS (ESI+) ： 599 (MH+) 1H-NMR (CDC13 )·· 5 0·78 (m，1H)，1.04 (d，3H)，1·28 (d，3H)，1.34 (d，3H)， L76 (m，1H)，1·93 (s，3H)，2.68 (s，1H)，3·01 (m，1H)，3,72 (m，1H)，4·26 (m， 1H)，4.37 (m，1H)，5.06 (m，1H)，5.40 (m，1H)，7·53 (s，2H)，7.70 (s，2H)，7.85 (s， 1H)，8.41 (s，1H). 實例500與501Q^1QO 1285641 (RS, RS, SR)-4-[2-acetamidamine small (3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-methyl-6-three Gas methyl-3,4-dihydro-2H-Junlin-1-oxo acid isopropyl ester LCMS (ESI+) : 599 (MH+) 1H-NMR (CDC13)·· 5 0·78 (m,1H) , 1.04 (d,3H),1·28 (d,3H), 1.34 (d,3H), L76 (m,1H),1·93 (s,3H),2.68 (s,1H),3·01 (m,1H),3,72 (m,1H),4·26 (m,1H), 4.37 (m,1H),5.06 (m,1H),5.40 (m,1H),7·53 (s , 2H), 7.70 (s, 2H), 7.85 (s, 1H), 8.41 (s, 1H). Examples 500 and 501

(1^別-4-[(3,5-雙-三氟甲基-苯基）_甲氧羰基-甲基]1乙基各三氟 甲基-3,4_二氫-2Hw奎琳-l-幾酸乙酯(1^- -4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]1 ethyl-trifluoromethyl-3,4-dihydro-2Hw-quine -l-acid acid ethyl ester

(尺”为-^^^-雙-二氟甲基-笨基^曱氧羰基-曱基^^乙基各三氟 甲基-3,4_二氫·2扎喳啉小羧酸乙酯 於3&gt;雙（三氟甲基苯基）酷酸甲酯（141克，4·93毫莫耳）在無 Q9199 ' 353 - 1285641 水N，N-二甲基曱酿胺（3毫升）中之溶液内，添加氫化鈉（6〇% 礦油分散液，6.55毫莫耳，262毫克），並將混合物在室溫下 攪拌60分鐘。添加（R)斗氯基-2-乙基各三氟甲基-3,4-二氫-2H-+ 啉-1-羧酸乙酯（1.10克，3.28毫莫耳，異構物之混合物，製備14) 在無水N，N-二甲基甲醯胺（1.5毫升）中之溶液，並將混合物於 室溫下授拌72小時。添加水（20毫升），並以乙_ (3 &amp; 5〇毫升） 萃取混合物，且將有機萃液以無水硫酸鈉脫水乾燥，及在 真空下移除溶劑，獲得粗產物，為黃色油（〜2克）^純化係使 用具有4毫米矽膠轉子之徑向展開層析法（柵控彩色顯像管 7924T型，Harrison研究，Palo Alto, CA)達成，以己烷/醋酸乙酯 9 : 1溶離，獲得標題化合物： (R,S，R)-4-[(3,5-雙-三氟曱基-苯基）_甲氧羰基-甲基设乙基各三 氟甲基-3,4-二氫-2H^奎淋-1-幾酸乙酯（第一個溶離出之非對映 異構物） MS: 586.0 [M+Hf實測值 1H-NMR (CDC13) (5 7.90 (s3 2H)3 7.87 (s, 1H), 7.59 (d, J=8.30Hz, 1H), 7.62 (d，J=8.30Hz，TH)，7.61 (s，1H)，4.39-4.27 (m，2H)，4.27-4.18 (m，1H)，3.78 (d， J=lL61Hz，1H)，3.59 (m，1H)，3.48 (s，3H)，1.76 (ddd，&gt;14.10, 8.30, 3.30Hz， 1H)，1.61-1.55 (m，1H)，1.57-1.50 (m，1H)，1·48-1·40 (m，1H)，1.35 (t，J=7.47Hz， 3H), 0.73 (t, J=7.47Hz5 3H). (11，3,3)-4-[(3,5-雙-三氟甲基-苯基）-甲氧羰基-甲基]-2-乙基-6-三 氟甲基-3,4-二氫奎淋小幾酸乙酯（536毫克，第二個溶離出 之非對映異構物） MS: 586.0 [M+H]+實測值 92199 - 354 - 1285641 1 H-NMR (CDC13) (5 7.66 (s，1H)，7.42 (d，J=8.30Hz，1H)，7.40 (s，2H)，7.33 (dd，J=8.30, 1·66Ηζ，1H)，6.47 (d，J=1.66Hz，1H)，4.55-4.47 (m，1H)，4.34 (m， 1H)，4.32 (m，1H)，3.83 (d，J=11.61Hz，1H)，3.80 (s，3H)，3.43 (ddd，J=ll.61， 4.98, 2·49Ηζ，1H)，2.44 (ddd，J=14.11，8·30, 2·49Ηζ，1H)，1.81 (ddd，J=14,10， 8.30, 4·98Ηζ，1H)，1.67 (m，1H)，1.51 (m，1H)，1.33 (t，J=7.47Hz，3H)，0.85 (t， J=7.47Hz，3H)_ 實例502與503(尺尺) is -^^^-bis-difluoromethyl-stupyl^曱oxycarbonyl-fluorenyl^^ethyl trifluoromethyl-3,4_dihydro-2 porphyrin small carboxylic acid Ester in 3&gt; bis(trifluoromethylphenyl)carboxylic acid methyl ester (141 g, 4.93 mmol) in the absence of Q9199 ' 353 - 1285641 water N,N-dimethyl anthraquinone (3 ml) In the solution, sodium hydride (6 〇% mineral oil dispersion, 6.55 mmol, 262 mg) was added, and the mixture was stirred at room temperature for 60 minutes. (R) chlorophenyl-2-ethyl each Ethyl trifluoromethyl-3,4-dihydro-2H-+ phenan-1-carboxylate (1.10 g, 3.28 mmol, mixture of isomers, preparation 14) in anhydrous N,N-dimethyl a solution of the meglumine (1.5 ml), and the mixture was stirred at room temperature for 72 hours. Water (20 ml) was added and the mixture was extracted with _ (3 &amp; Dehydrated and dried with anhydrous sodium sulfate, and the solvent was removed under vacuum to obtain a crude product as a yellow oil (~2 g). Purification was carried out using a radial expansion chromatography with a 4 mm silicone rotor (Gate-controlled color picture tube 7924T type) , Harrison Research, Palo Alto, CA) reached The title compound was obtained by hexane/ethyl acetate 9:1 to give the title compound: (R,S,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl Ethyl trifluoromethyl-3,4-dihydro-2H^-quinone-1-carboxylic acid ethyl ester (first dissociated diastereomer) MS: 586.0 [M+Hf found 1H- NMR (CDC13) (5 7.90 (s3 2H)3 7.87 (s, 1H), 7.59 (d, J = 8.30 Hz, 1H), 7.62 (d, J = 8.30 Hz, TH), 7.61 (s, 1H), 4.39-4.27 (m, 2H), 4.27-4.18 (m, 1H), 3.78 (d, J = lL61Hz, 1H), 3.59 (m, 1H), 3.48 (s, 3H), 1.76 (ddd, &gt; 14.10 , 8.30, 3.30Hz, 1H), 1.61-1.55 (m, 1H), 1.57-1.50 (m, 1H), 1·48-1·40 (m, 1H), 1.35 (t, J=7.47Hz, 3H ), 0.73 (t, J = 7.47 Hz 5 3H). (11,3,3)-4-[(3,5-bis-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-2- Ethyl ethyl-6-trifluoromethyl-3,4-dihydroquinoate (536 mg, second diastereomeric diastereomer) MS: 586.0 [M+H]+ Value 92199 - 354 - 1285641 1 H-NMR (CDC13) (5 7.66 (s, 1H), 7.42 (d, J = 8.30 Hz, 1H), 7.40 (s, 2H), 7.33 (dd, J = 8.30, 1 · 66Ηζ, 1H), 6.47 (d, J=1.66Hz, 1H ), 4.55-4.47 (m, 1H), 4.34 (m, 1H), 4.32 (m, 1H), 3.83 (d, J = 11.61 Hz, 1H), 3.80 (s, 3H), 3.43 (ddd, J = Ll.61, 4.98, 2·49Ηζ, 1H), 2.44 (ddd, J=14.11, 8·30, 2·49Ηζ, 1H), 1.81 (ddd, J=14,10, 8.30, 4.98Ηζ, 1H) , 1.67 (m, 1H), 1.51 (m, 1H), 1.33 (t, J = 7.47 Hz, 3H), 0.85 (t, J = 7.47 Hz, 3H) _ Examples 502 and 503

(R，S，R)-4-[(3,5-雙-三氟甲基-苯基）-羧基-甲基]-2-乙基-6-三氟甲基- 3,4-二氫-2H-喹啉小羧酸乙酯(R,S,R)-4-[(3,5-bis-trifluoromethyl-phenyl)-carboxy-methyl]-2-ethyl-6-trifluoromethyl-3,4-di Hydrogen-2H-quinoline small carboxylic acid ethyl ester

(R，S，S)-4-[(3,5-雙-三氟甲基-苯基）-羧基-曱基]-2-乙基-6_三氟曱基一 3,4-二氫-2H-喹啉小羧酸乙酉旨 將（1^办4-[(3,5-雙-三氟曱基-苯基）-甲氧羰基-曱基]-2-乙基各 1285641 二氣甲基-3,4-二氩-2H-喹啉小羧酸乙酯（實例501，100毫克， 0.171愛莫耳）、氫氧化鈉水溶液（2N，〇 512毫升，丨.〇24毫莫耳） 及典水四氫呋喃（2毫升）之混合物，於室溫下攪拌2天，然 後添加2N鹽酸（1·5毫升）。將混合物以乙腈稀釋，並於真空 下条發至乾涸，而得粗產物，為油狀物（128毫克）。純化係 使用具有4耄米石夕膠轉子之徑向展開層析法（栅控彩色顯像 管7924丁型，Harrison研究，pal〇 Alto, CA)達成，以己烷/醋酸乙 酯55 ·· 45溶離，獲得標題化合物： 第一個溶離物：（R，S，R)-4-[(3&gt;雙-三氟甲基-苯基）-羧基-甲基]· 2-乙基-6-二氣甲基-3,4-二氫-2H_峻淋-1-致酸乙酉旨（14毫克）； 1H-NMR (CDC13) 5 7.88 (s，1H)，7.88 (s，2H)，7.55 (m，1H)，7.51 (m，1H)， 7.49 (m，1H)，4·32 (m，1H)，4.27 (m，1H)，4.21 (m，1H)，3·80 (d，J=10.79Hz， 1H),3.57 (m? 1H), 1.78 (m, 1H), 1.55 (m? 2H), 1.43 (m, 1H)5 1.32 (t, J=7.47Hz, 3H)，0.71 (t，J=7.47Hz，3H). 第二個溶離物：（R，S，S)斗[(3,5-雙-三氟甲基-苯基）-羧基-甲基]· 2-乙基-6-三氟甲基-3,4-二氫-2H-喹啉小羧酸乙酯（32毫克） 1H-NMR (CDC13) 5 7.67 (s，1H)，7.45 (s，2H)，7.41 (m，1H)，7,34 (m，1H)， 6.51 (brs，1H)，4·55 (m，1H)，4.32 (m，2H)，3·85 (d，J=10.79Hz，1H)，3·43 (m， 1H)，2.55 (m，1H)，1.81 (m，1H)，1.63 (m，1H)，1.60 (m，1H)，1.31 (t，J=7.47Hz， 3H)，0.84 (t，J=7.47Hz，3H). 實例504與505 92199 - 356 - 1285641(R,S,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-carboxy-indenyl]-2-ethyl-6-trifluoromethyl- 3,4-di Hydrogen-2H-quinoline small carboxylic acid acetamidine (1^4-[(3,5-bis-trifluorodecyl-phenyl)-methoxycarbonyl-indenyl]-2-ethyl each 1285641 Ethyl methyl-3,4-diar-argon-2H-quinoline small carboxylic acid ethyl ester (example 501, 100 mg, 0.171 Amor), aqueous sodium hydroxide solution (2N, 〇 512 ml, 丨.〇24 mmol The mixture was stirred at room temperature for 2 days, then 2N hydrochloric acid (1.5 ml) was added. The mixture was diluted with acetonitrile and evaporated to dryness under vacuum. The product was obtained as an oil (128 mg). Purification was carried out using a radial expansion chromatography (Gate-controlled color picture tube 7924-type, Harrison study, pal〇Alto, CA) with a 4 mil. The title compound was obtained by dissolving hexane/ethyl acetate 55 ··45. The first dissolving product: (R,S,R)-4-[(3&gt; bis-trifluoromethyl-phenyl)-carboxy-methyl 2-ethyl-6-dimethylmethyl-3,4-dihydro-2H_Jinglin-1-acid acetate (14 mg); 1H-NMR (CDC13 5 7.88 (s, 1H), 7.88 (s, 2H), 7.55 (m, 1H), 7.51 (m, 1H), 7.49 (m, 1H), 4·32 (m, 1H), 4.27 (m, 1H), 4.21 (m, 1H), 3·80 (d, J = 10.79 Hz, 1H), 3.57 (m? 1H), 1.78 (m, 1H), 1.55 (m? 2H), 1.43 (m, 1H) ) 5 1.32 (t, J = 7.47 Hz, 3H), 0.71 (t, J = 7.47 Hz, 3H). Second dissolvate: (R, S, S) bucket [(3,5-bis-trifluoro) Methyl-phenyl)-carboxy-methyl] 2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinolinecarboxylic acid ethyl ester (32 mg) 1H-NMR (CDC13 5 7.67 (s,1H), 7.45 (s,2H), 7.41 (m,1H),7,34 (m,1H), 6.51 (brs,1H),4·55 (m,1H),4.32 ( m,2H),3·85 (d,J=10.79Hz,1H),3·43 (m,1H),2.55 (m,1H),1.81 (m,1H),1.63 (m,1H),1.60 (m, 1H), 1.31 (t, J = 7.47 Hz, 3H), 0.84 (t, J = 7.47 Hz, 3H). Examples 504 and 505 92199 - 356 - 1285641

(R，S，RM_[K3,5-雙-三氟甲基-苯基）·.基·乙基择乙基木三氟 甲基-3,4-二氫-2Η^奎淋+幾酸乙酯(R, S, RM_[K3,5-bis-trifluoromethyl-phenyl)·.ylethylethylethyltrifluoromethyl-3,4-dihydro-2Η^quinidine+acid Ethyl ester

(R，S，SH-[l-(3,5-雙-三氟甲基-苯基）_2-幾基-乙基]1乙基冬三氟甲 基一氣琳-1-叛酸乙酉旨 於(R，S，R)-與（R，S，S)-4-[(3,51 -三氟甲基-苯基）_羧基-甲基碎乙 基各三氟甲基-3,4-二氫-2H-喹啉小羧酸乙酯（實例502與503， 按上述製備，但異構物並未分離，143毫克，0.25毫莫耳）在 四氫唉喃（3毫升）中之溶液内，在氮氣下，添加硼烷-硫化二 甲燒複合物（2M，在四氫呋喃，〇·25毫升，〇·5毫莫耳）。於24 小時後’將混合物以甲醇（1毫升）稀釋，並在真空下蒸發至 乾酒。於殘留物中，添加2N鹽酸（3毫升），將混合物攪拌1〇 分鐘，然後以乙醚（3 x 15毫升）萃取。使有機層以無水硫酸 鈉脫水乾燥，並於真空下蒸發溶劑，而得粗產物，為油狀 1285641 物（175毫克）。純化係使用具有丨毫米矽膠轉子之徑向展開層 析法（柵控彩色顯像管7924丁型，Harrison研究，pai〇 Alt0, CA)達成 ，以己烷/醋酸乙酯梯度液4 : 1至7 : 3溶離，獲得標題化合 物·· 第一個溶離物：（R，S，R)-4-[l-(3,5-雙-三氟甲基-苯基）_2_羥基_乙 基]-2-乙基-6-三氟甲基-3,4-二氫-2H-喹啉-1-羧酸乙酯（9毫克） MS : 558·3 [M+H]+實測值· 1H-NMR (CDC13) 5 7.83 (s，1Η)，7.79 (s，2Η)，7.60 (m，1Η)，7·53 (brs，1Η)， 7.52 (m，1H)，4.35 (m，1H)，4.24 (m，1H)，4·16 (m，1H)，3·71 (m，2H)，3·34 (m， 1H)，2.99 (m，1H)，1.78 (m，1H)，1·57 (m, 2H)，1.57 (m，1H)，1.45 (m，1H)，1.33 (t，J=7.47Hz，3H)，0.71 (t，J=7.47Hz，3H)· 第二個溶離物：（113,3&gt;4-[1-(3,5-雙-三氟甲基-苯基）-2-羥基-乙 基]-2-乙基-6-三氟甲基-3,4-二氫-2H-P奎淋小瘦酸乙酉旨（30毫克） MS: 558·5[Μ+Η]+實·測值. 1H-NMR (CDC13) δ 7.63 (s, 1H)5 7.40 (m, 1H)5 7.39 (s, 2H), 7.32 (m3 1H), 6·62 (brs，1Η)4·48 (m，1H)，4·25 (m，2H)，4.15 (m，2H)，3·13 (m，2H)，2·60 (m， 1H)，1.69 (m，3H)，1.50 (m，1H)，1.29 (t，J=7.47Hz，3H)，0.86 (t，J=7.47Hz，3H). 實例506(R,S,SH-[l-(3,5-bis-trifluoromethyl-phenyl)_2-mono-ethyl]ethylidene trifluoromethyl-one-lin--1-reoxazide (R,S,R)- and (R,S,S)-4-[(3,51-trifluoromethyl-phenyl)-carboxy-methyl-ethylidene trifluoromethyl-3, Ethyl 4-dihydro-2H-quinolinecarboxylate (Examples 502 and 503, prepared as above, but the isomer was not isolated, 143 mg, 0.25 mmol) in tetrahydrofuran (3 mL) In the solution, borane-sulfur dimethyl sulphide complex (2M in tetrahydrofuran, 〇·25 ml, 〇·5 mmol) was added under nitrogen. After 24 hours, the mixture was taken up in methanol (1 ml). Dilute and evaporate to dryness in vacuo. EtOAc (3 mL)EtOAc. Dry and evaporate the solvent under vacuum to give a crude material (yield: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> 175 mg). Purification is performed using a radial expansion chromatography with a 丨 矽 矽 转子 rotor (Gate-controlled color picture tube 7924, Harrison study) ,pai〇Alt0, CA) The title compound was obtained by dissolving in a hexane/ethyl acetate gradient from 4:1 to 7:3. The first solvate: (R,S,R)-4-[l-(3,5-double -Trifluoromethyl-phenyl)_2-hydroxy-ethyl]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (9 mg MS : 558·3 [M+H]+Measured value · 1H-NMR (CDC13) 5 7.83 (s,1Η), 7.79 (s,2Η), 7.60 (m,1Η),7·53 (brs,1Η) ), 7.52 (m,1H), 4.35 (m,1H), 4.24 (m,1H),4·16 (m,1H),3·71 (m,2H),3·34 (m, 1H), 2.99 (m,1H), 1.78 (m,1H),1·57 (m, 2H), 1.57 (m,1H), 1.45 (m,1H), 1.33 (t,J=7.47Hz,3H),0.71 (t, J = 7.47 Hz, 3H) · Second dissolvate: (113,3&gt;4-[1-(3,5-bis-trifluoromethyl-phenyl)-2-hydroxy-ethyl] -2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-P-quinone-small acid (30 mg) MS: 558·5[Μ+Η]+ real. 1H-NMR (CDC13) δ 7.63 (s, 1H)5 7.40 (m, 1H)5 7.39 (s, 2H), 7.32 (m3 1H), 6·62 (brs,1Η)4·48 (m,1H) ,4·25 (m,2H), 4.15 (m,2H),3·13 (m,2H),2·60 (m, 1H), 1.69 (m,3H), 1.50 (m , 1H), 1.29 (t, J = 7.47 Hz, 3H), 0.86 (t, J = 7.47 Hz, 3H). Example 506

(R，R，S)-4-[(3,5-雙-三氟甲基-苯基)-甲氧基-甲基]乙基各三氟甲 基-3,4-二氫-2H-0奎淋-1-致&amp;乙酉旨 92199 - 358 · 1285641 將[(尺，氏3)]-4-[(3,5-雙-三氟甲基-苯基）-技基-甲基]-2-乙基-6-二 氟甲基-3,4-二氫-2H-喳啉-1-羧酸乙酯（0.030克，0.055毫莫耳，1 當量）放置在裝有磁攪拌棒之圓底燒瓶中。於室溫下，添加 DMSO (1·0毫升），接著添加（0.012克，0.221毫莫耳，4當量）、 氫氧化鉀及（0.016克，0.110毫莫耳，2當量）碘化甲烷。於1.5 小時後，以1NHC1使反應混合物淬滅，以醋酸乙酯萃取3次 ’並以硫酸鈉脫水乾燥。使粗製物質於矽膠上純化層析， 提供標題化合物。 LCMS(ESI+): 551_+). HNMR(CDC13)： (5 0.95 (t3 3H)5 L31 (t, 3H), 1.41 (m3 1H)3 1.60 (m, 1H), 2.6 (m, 1H), 2.90 (m, 1H), 3.20 (s5 3H), 4.33 (m? 2H)? 4.45 (m, 1H)? 6.60 (s, 1H), U(s，M)，7·30 (d，1H).7.5 (d，1H) 7.70 (s，1H). 在正個本申凊案中，有各種刊物被引用。此等刊物之揭示 内谷係以其全文據此併於本t請案供參考，以提供所有目 的。 ^諳此藝者將顯而易見的是，各種修正與變異可在未偏 之1ί圍或精神下1本發明中施行。本發明之其 “植貫施例，對熟諳此藝者 ^ απ ^ ^ σ 哥自本又中所揭示之 發月專利說明書盘實施田 舍匕― 又考置，而顯而易見。本專利說 田與1例係意欲僅被視為舉 圍與精神1由下中本發明之真實, 係由下述_請專利範圍指示。(R,R,S)-4-[(3,5-bis-trifluoromethyl-phenyl)-methoxy-methyl]ethyl-trifluoromethyl-3,4-dihydro-2H -0奎淋-1-致&amp;乙酉u 92199 - 358 · 1285641 Will [(尺,3)]-4-[(3,5-bis-trifluoromethyl-phenyl)-technical-A Ethyl 2-ethyl-6-difluoromethyl-3,4-dihydro-2H-indololin-1-carboxylate (0.030 g, 0.055 mmol, 1 eq.) Stir the bar in a round bottom flask. DMSO (1.0 mL) was added at room temperature followed by (0.012 g, 0.221 mmol, 4 eq.), potassium hydroxide and (0.016 g, 0.110 mmol, 2 eq.). After 1.5 hours, the reaction mixture was quenched with EtOAc (EtOAc)EtOAc. The crude material was purified by chromatography on silica gel to afford the title compound. LCMS (ESI+): 551_+). HNMR (CDC13): (5 0.95 (t3 3H)5 L31 (t, 3H), 1.41 (m3 1H)3 1.60 (m, 1H), 2.6 (m, 1H), 2.90 (m, 1H), 3.20 (s5 3H), 4.33 (m? 2H)? 4.45 (m, 1H)? 6.60 (s, 1H), U(s,M), 7·30 (d,1H).7.5 (d, 1H) 7.70 (s, 1H). In the case of this application, various publications have been cited. The disclosures of these publications are based on their full texts and are hereby incorporated by reference. All the purposes are provided. ^ This artist will obviously understand that various modifications and variations can be performed in the present invention without the bias or the spirit. The invention is based on the embodiment of the invention. Ππ ^ ^ σ 哥 自 本 本 本 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利The true nature of the invention is indicated by the following _ patent scope.

Claims (1)

拾、年請專利範圍： 1· 一種式III化合物Pick up, year, patent scope: 1. A compound of formula III 其中 C3為碳； J為碳，其中在C3與J間之鍵結為單或雙鍵； 右C3與J間之鍵結為雙鍵則n為零，或若在c3與了間之 键結為單鍵則n為1 ; R2為（C〗-C4)燒基 '環丙基或環丁基； R5 為 CF3 ; R6為氫； R 0為冗全飽和（C〗-C4 )直鏈或分枝狀碳鏈； R11與R12 —起形成酮基或N2 ; 或其藥學上可接受之鹽。Wherein C3 is carbon; J is carbon, wherein the bond between C3 and J is a single or double bond; the bond between the right C3 and J is a double bond, then n is zero, or if the bond between C3 and J3 is For a single bond, n is 1; R2 is (C--C4) alkyl-cyclopropyl or cyclobutyl; R5 is CF3; R6 is hydrogen; R 0 is redundant (C-C4) linear or a branched carbon chain; R11 and R12 together form a keto group or N2; or a pharmaceutically acceptable salt thereof. 之群：Group: 羧酸乙酯；Ethyl carboxylate; 羧酸乙酯； 92199-960511.doc 1285641 (S)-2-乙基-4-酮基-6-三氟甲基-3,4-二氫-2H-喹啉-1- 羧酸乙酯； 2 -乙基-4 -嗣基-6-二氣甲基-3,4 -二氮-211-峻淋-1-棱酸 甲酯； 2 -乙基-4 -嗣基-6-二氣甲基-3,4 -二氮-2 Η -峻淋-1 -竣酸 1 -丙酯； 2-乙基-4-酮基-6-三氟甲基-3,4-二氫-2Η-喳啉-1-羧酸 2 -丙@旨，及 2-乙基-4-酮基-6_三氟甲基-3,4_二氫-2Η_喳啉-1-羧酸 第三丁酯； 或其藥學上可接受之鹽。 92199-960511.docEthyl carboxylate; 92199-960511.doc 1285641 (S) ethyl 2-ethyl-4-keto-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate ; 2 -ethyl-4 -mercapto-6-dimethylmethyl-3,4-diazo-211-trilinium methyl ester; 2 -ethyl-4-mercapto-6-di Gas methyl-3,4-diazo-2 Η-Junlin-1 -propanoic acid 1-propyl ester; 2-ethyl-4-keto-6-trifluoromethyl-3,4-dihydro- 2Η-porphyrin-1-carboxylic acid 2-propyl@, and 2-ethyl-4-keto-6-trifluoromethyl-3,4-dihydro-2Η_porphyrin-1-carboxylic acid Tributyl ester; or a pharmaceutically acceptable salt thereof. 92199-960511.doc
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