TWI295286B

TWI295286B - (2s)-2-[(2-oxo-4-propylpyrrolidinyl)butanamides and their uses

Info

Publication number: TWI295286B
Application number: TW95112076A
Authority: TW
Inventors: Edmond Differding; Benoit Kenda; Benedicte Lallemand; Alain Matagne; Philippe Michel; Patrick Pasau; Patrice Talaga
Original assignee: Ucb Sa
Priority date: 2001-03-13
Filing date: 2001-03-13
Publication date: 2008-04-01

Description

1295286 f 九忽螫明說明：【發明所屬之技術領域】本發明係有關2 -氧基-1 -吡咯啶衍生物，其製法，含有此等化合物之醫藥組合物及其用作爲藥物之用途。【先前技術】歐洲專利第〇 1 62 036 B1號揭示化合物（S)-a-乙基-2-氧基-1-吡咯啶乙醯胺，具有國際非專屬名稱左堤拉西坦 (levetiracetam) 0 左堤拉西坦是左旋化合物，揭示用作爲中樞神經系統之缺氧及缺血型傷害的治療及預防用保護劑。此種化合物也可有效用於治療癲癇，對此種治療適應症其右旋對映異構體（R) - α -乙基-2 -氧基-1 -吡咯啶乙醯胺（亦由歐洲專利案第0 1 65 9 1 9 Β1號已知）完全缺乏活性（A.J .GOWER等人，歐洲藥理期刊，211,( 1 992 ) ,1 93 -203 )。外消旋α -乙基-2 -氧基-1 -吡咯啶乙醯胺及其類似物由英國專利第1 309 692號爲已知。美國專利第3 459 738 號揭示2 -氧基-1 -吡咯啶乙醯胺衍生物。歐洲專利第 0 645 1 39 Β1號揭示左堤拉西坦之解焦慮活性。PCT申請案第PCT/EP00/ 1 1808號揭示左堤拉西坦用於兩極性病症、偏頭痛、慢性或神經病變疼痛之治療及/或預防性處理之用途，以及左堤拉西坦與至少一種可誘生藉GABAa受體媒介的神經抑制作用的化合物的組合。今曰出乎意外地發現某些左堤拉西坦類似物，特別吡咯啶酮環帶有進一步取代之化合物驗證顯著改良的治療 1295286 【發明内容】就一特徵方面’本發明提供一種具有式I之化合物或其醫藥可接受性鹽 R3a R4a1295286 f 九忽螫明说明: [Technical Field to Which the Invention Is Along] The present invention relates to a 2-oxy-1-pyrrolidine derivative, a process for the preparation thereof, a pharmaceutical composition containing the same, and use thereof as a medicament. [Prior Art] European Patent No. 1 62 036 B1 discloses the compound (S)-a-ethyl-2-oxy-1-pyrrolidinium, having the international non-exclusive name levetiracetam (levetiracetam) 0 Levetiracetam is a left-handed compound that reveals a protective agent for the treatment and prevention of hypoxia and ischemic injury in the central nervous system. This compound is also effective for the treatment of epilepsy, a therapeutic indication for its right-handed enantiomer (R) - α -ethyl-2-oxy-1-pyrrolidinium (also from Europe) Patent No. 0 1 65 9 1 9 Β1 is completely lacking in activity (AJ. GOWER et al., European Journal of Pharmacology, 211, (1 992), 193-203). Racemic α-ethyl-2-oxy-1-pyrrolidinium and its analogs are known from British Patent No. 1,309,692. U.S. Patent No. 3,459,738 discloses 2-oxy-1 -pyrrolidinium derivatives. European Patent No. 0 645 1 39 Β1 reveals the anxiolytic activity of levetiracetam. PCT Application No. PCT/EP00/1 1808 discloses the use of levetiracetam for the treatment and/or prophylactic treatment of bipolar disorders, migraine, chronic or neuropathic pain, and levetiracetam and at least A combination of compounds that induce neuroinhibition by a GABAa receptor vector. It has unexpectedly been found that certain levetiracetam analogs, particularly pyrrolidone rings with further substitutions, have been shown to significantly improve the treatment of the compound 1295286. [Inventive content] In terms of a feature, the present invention provides a formula I Compound or a pharmaceutically acceptable salt thereof R3a R4a

其中 X 爲- CA】NR5R6 或-CAWR7 或-CA1 -R8 或 CN ; A1及A2分別爲氧、硫或-NR9 ; R1爲氫，烷基，芳基或-CH2-Rla其中Rla爲芳基、雜環、鹵原子、羥基、胺基、硝基或氰基； R2，R3及R4爲相同或相異且各自分別爲氫，鹵原子，羥基，毓基、胺基，硝基，硝氧基，氰基，疊氮基，羧基，醯胺基，磺酸，磺醯胺，院基，條基，炔基，酯，醚，芳基，雜環或氧衍生物，硫衍生物，胺基衍生物，醯基衍生物，磺醯基衍生物或亞磺醯基衍生物。 R2a，R3a及R4a爲相同或相異且各自分別爲氫，鹵原子，烷基，烯基，炔基或芳基； R5，R6，R7及R9爲相同或相異且各自分別爲氫，羥基，烷基，芳基，雜環或氧衍生物；以及 R8爲氫，羥基，毓基，鹵原子，烷基，芳基，雜環或巯衍生物；但1?2，1?3，1?4，1^，1^，及1^中之至少一者非爲氫；以及當化合物爲全部可能的異構物混合物時，X爲-CONR5R6，A2 爲氧以及R1爲氫，甲基，乙基或丙基時則吡咯啶環上的取 1295286 * 代非爲一-、二-或三-甲基或一-乙基；以及當，1^及R4a各自爲氫，A2爲氧及X爲CONR5R6時R3非爲羧基，酯，醯胺基，取代氧基-吡咯啶，羥基，氧衍生物，胺基，胺基衍生物，甲基，萘基，苯基選擇性藉氧衍生物取代或於對位由鹵原子取代。下述定義中，除非另行陳述，否則R11及R13爲相同或相異且各自分別爲醯胺基，烷基，烯基，炔基，醯基，酯，醚，芳基，芳烷基，雜環或氧衍生物，硫衍生物，醯基衍生物，胺基衍生物，磺醯基衍生物或亞磺醯基衍生物，各自選擇性以任何適當基取代，包括但非限於一或多個選自低碳烷基或其它後文說明爲烷基取代基之基的部分。「氧衍生物」一詞用於此處定義爲包括-Ο-R11基，其中R11定義如前，「氧衍生物」除外。非限制性實例有烷氧基，烯氧基，炔氧基，醯氧基，氧酯基，氧醯胺基，烷基磺醯氧基，烷基亞磺醯氧基，芳基磺醯氧基，芳基亞磺醯氧基，芳氧基，芳院氧基或雜環氧基如戊氧基、烯丙氧基、甲氧基、乙氧基、苯氧基、苄氧基、2-萘氧基、2 -吡啶氧基、亞甲基二氧基、碳酸基。「硫衍生物」一詞用於此處定義爲包括-S-R11基，其中R11定義如前，「硫衍生物」除外。非限制性實例有烷硫基、嫌硫基、快硫基及芳硫基。「胺基衍生物」一詞用於此處定義爲包括-NHRH或-NRUR12基，其中R11及R12定義如前。非限制性實例有一-或二-烷基-、烯基-、炔基-及芳基胺基或混合胺基。「醯基衍生物」一詞用於此處表示衍生自羧酸之基團 1295286 ，如此定義包括式Rn-CO-基，其中R11定義如前也可爲氫。非限制性實例有甲醯基，乙醯基，丙醯基，異丁醯基，戊醯基，月桂醯基，庚烷二醯基，環己烷羰基，巴豆醯基，反丁烯二醯基，丙烯醯基，苯甲醯基，萘甲醯基，呋喃醯基，菸鹼醯基，4-羧丁醯基，草醯基，乙草醯基，半胱胺醯基，草胺醯基。「磺醯基衍生物」一詞用於此處定義爲包括式-S02-Rn 基，其中rh定義如前，但「磺醯基衍生物」除外。非限制性實例有烷基磺醯基，烯基磺醯基，炔基磺醯基及芳基擴醯基。「亞磺醯基衍生物」一詞用於此處定義爲包括式· S02-Rn基，其中R11定義如前，但「亞磺醯基衍生物」除外。非限制性實例有烷基亞磺醯基，烯基亞磺醯基，炔基亞磺醯基及芳基亞磺醯基。「烷基」一詞用於此處定義爲帶有直鏈、分支或環狀部分或其組合以及含有1至20個碳原子，較佳對非環狀烷基爲1-6個碳原子以及環烷基爲3-6個碳原子（兩種較佳例中除非另行陳明否則稱作「低碳烷基」）之飽和一價烴基。烷基部分可選擇性經以1至5個分別選自鹵原子、羥基、巯基、胺基、硝基、氰基、硫氰酸基、醯基、醯氧基、磺醯基衍生物、亞磺醯基衍生物、烷基胺基、羧基、酯基、醚基、醯胺基、疊氮基、環烷基、磺酸基、磺醯胺基、硫衍生物、氧酯基、氧醯胺基、雜環基、乙烯基、（^_5-烷氧基，C6.1()-芳氧基及芳基組成的組群之取代基取代。較佳烷基爲甲基，乙基，丙基，異丙基，丁基，異-或第三丁基，及2,2,2-三甲基乙基其各自選擇性經以至少一 1295286 * 個選自鹵原子、羥基、酼基、胺基、硝基及氰基組成的組群之取代基取代，例如三氟甲基，三氯甲基，2,2,2-三氯乙基，1，1-二甲基-2,2-二溴乙基，1，1-二甲基-2,2,2-三氯乙基。「烯基」一詞用於此處定義爲包括具有至少一個雙鍵例如乙烯基（=乙烯基），1-甲基-1-乙烯基，2,2-二甲基 -1-乙烯基，卜丙烯基，2-丙烯基（=烯丙基），1-丁烯基，2-丁烯基，3-丁烯基，4-戊烯基，1-甲基-4-戊烯基， 3-甲基-1-戊烯基，1-己烯基，2-己烯基等以及選擇性經以至少一個選自鹵原子、羥基、锍基、胺基、硝基、氰基、芳基及雜環基組成的組群之取代基取代的分支及未分支未飽和烴基，例如一-及二-鹵乙烯基，此處鹵爲氟、氯或溴。「炔基」一詞用於此處定義爲含有至少一個碳-碳參鍵例如乙炔基、2-丙炔基（=炔丙基）等且選擇性經以至少一個選自鹵原子、羥基、锍基、胺基、硝基、氰基、芳基及雜環基組成的組群之取代基取代的一價分支或未分支烴基，例如鹵乙炔基。當存在爲架橋基時，烷基、烯基及炔基分別表示直鏈或分支鏈，CV12較佳CV4-伸烷基或C2.I2-，較佳C2.4-伸烯基或-伸炔基部分。分支衍生物習知以字首（例如「正」、「第二」、「異」等）加以規定的基（例如「正丙基」、「第二丁基」）除非，另行陳述否則係呈正形式。「芳基」一詞用於此處定義爲包括衍生自由1至3個_ 組成，且含有6至30個碳原子之芳族烴經由去除一個氮 1295286Wherein X is -CA]NR5R6 or -CAWR7 or -CA1 -R8 or CN; A1 and A2 are respectively oxygen, sulfur or -NR9; R1 is hydrogen, alkyl, aryl or -CH2-Rla wherein Rla is aryl, a heterocyclic ring, a halogen atom, a hydroxyl group, an amine group, a nitro group or a cyano group; R2, R3 and R4 are the same or different and each are respectively hydrogen, a halogen atom, a hydroxyl group, a decyl group, an amine group, a nitro group, a nitro group , cyano, azido, carboxy, decyl, sulfonic acid, sulfonamide, aryl, benzyl, alkynyl, ester, ether, aryl, heterocyclic or oxy derivative, sulfur derivative, amine Derivatives, mercapto derivatives, sulfonyl derivatives or sulfinyl derivatives. R2a, R3a and R4a are the same or different and each are respectively hydrogen, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or an aryl group; R5, R6, R7 and R9 are the same or different and each are respectively a hydrogen group, a hydroxyl group , alkyl, aryl, heterocyclic or oxygen derivative; and R8 is hydrogen, hydroxy, decyl, halogen, alkyl, aryl, heterocyclic or anthracene derivatives; but 1?2,1?3,1 At least one of 4, 1^, 1^, and 1^ is not hydrogen; and when the compound is a mixture of all possible isomers, X is -CONR5R6, A2 is oxygen, and R1 is hydrogen, methyl, In the case of ethyl or propyl, 1295286* on the pyrrolidine ring is not mono-, di- or tri-methyl or mono-ethyl; and when 1^ and R4a are each hydrogen, A2 is oxygen and X For CONR5R6, R3 is not a carboxyl group, an ester, a decyl group, a substituted oxy-pyrrolidine, a hydroxyl group, an oxygen derivative, an amine group, an amine derivative, a methyl group, a naphthyl group, a phenyl-selective oxygen-substituted derivative. Or in the para position substituted by a halogen atom. In the following definitions, unless otherwise stated, R11 and R13 are the same or different and each are respectively amidino, alkyl, alkenyl, alkynyl, decyl, ester, ether, aryl, aralkyl, hetero a ring or an oxygen derivative, a sulfur derivative, a mercapto derivative, an amino derivative, a sulfonyl derivative or a sulfinyl derivative, each optionally substituted with any suitable group, including but not limited to one or more It is selected from a lower alkyl group or other moiety which is hereinafter described as a group of an alkyl substituent. The term "oxygen derivative" is used herein to define a radical -R-R11, wherein R11 is as defined above, with the exception of "oxygen derivatives". Non-limiting examples are alkoxy, alkenyloxy, alkynyloxy, decyloxy, oxyester, oxoamine, alkylsulfonyloxy, alkylsulfinyloxy, arylsulfonyloxy , arylsulfinyloxy, aryloxy, aryloxy or heterocyclic oxy such as pentyloxy, allyloxy, methoxy, ethoxy, phenoxy, benzyloxy, 2 -naphthyloxy, 2-pyridyloxy, methylenedioxy, carbonate. The term "sulfur derivative" is used herein to define a radical -S-R11, wherein R11 is as defined above, with the exception of "sulfur derivative". Non-limiting examples are alkylthio, thiol, fast thio and arylthio. The term "amino derivative" is used herein to define a radical comprising -NHRH or -NRUR12, wherein R11 and R12 are as defined above. Non-limiting examples are mono- or di-alkyl-, alkenyl-, alkynyl- and arylamino or mixed amine groups. The term "mercapto derivative" is used herein to mean a radical derived from a carboxylic acid 1295286 and is thus defined to include a radical of the formula Rn-CO-, wherein R11 is as defined above as hydrogen. Non-limiting examples are methyl, ethyl, propyl, isobutyl, pentylene, lauryl, heptanediyl, cyclohexanecarbonyl, crotonyl, antibutenyl, Propylene fluorenyl, benzamidine, naphthylmethyl, furyl sulfhydryl, nicotine sulfhydryl, 4-carboxybutyl fluorenyl, oxalyl, acetoinyl, cysteamine sulfhydryl, oxalyl thiol. The term "sulfonyl derivative" is used herein to include a radical of the formula -S02-Rn, wherein rh is as defined above, with the exception of "sulfonyl derivative". Non-limiting examples are alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl and arylalkyl. The term "sulfinyl derivative" is used herein to define a radical of the formula S02-Rn, wherein R11 is as defined above, except for "sulfinyl derivative". Non-limiting examples are alkyl sulfinylene, alkenylsulfinyl, alkynylsulfinyl and arylsulfinyl. The term "alkyl" as used herein is defined as having a straight chain, branched or cyclic moiety or a combination thereof and having from 1 to 20 carbon atoms, preferably from 1 to 6 carbon atoms for a non-cyclic alkyl group and The cycloalkyl group is a saturated monovalent hydrocarbon group of 3 to 6 carbon atoms (referred to as "lower alkyl group" unless otherwise stated in the two preferred examples). The alkyl moiety may be optionally selected from 1 to 5, respectively, selected from the group consisting of a halogen atom, a hydroxyl group, a thiol group, an amine group, a nitro group, a cyano group, a thiocyanate group, a decyl group, a decyloxy group, a sulfonyl group derivative, and a sub Sulfhydryl derivative, alkylamino group, carboxyl group, ester group, ether group, decylamino group, azide group, cycloalkyl group, sulfonic acid group, sulfonylamino group, sulfur derivative, oxyester group, oxonium group Substituted by a substituent of a group consisting of an amino group, a heterocyclic group, a vinyl group, a (^-5-alkoxy group, a C6.1()-aryloxy group and an aryl group. Preferred alkyl groups are methyl groups, ethyl groups, a propyl group, an isopropyl group, a butyl group, an iso- or a tert-butyl group, and a 2,2,2-trimethylethyl group each having at least one 1,295,286 * selected from a halogen atom, a hydroxyl group, a fluorenyl group Substituted by a group consisting of an amine group, a nitro group and a cyano group, such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2, 2-Dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl. The term "alkenyl" is used herein to include having at least one double bond such as vinyl (=ethylene). Base), 1-methyl-1-vinyl, 2,2-dimethyl-1-vinyl, propylene 2-propenyl (=allyl), 1-butenyl, 2-butenyl, 3-butenyl, 4-pentenyl, 1-methyl-4-pentenyl, 3-methyl 1-pentenyl, 1-hexenyl, 2-hexenyl, etc. and optionally via at least one selected from the group consisting of a halogen atom, a hydroxyl group, a thiol group, an amine group, a nitro group, a cyano group, an aryl group and a heterocyclic ring. Substituent substituted group of branched and unbranched unsaturated hydrocarbon groups of the group consisting of, for example, mono- and di-halovinyl groups, wherein the halogen is fluorine, chlorine or bromine. The term "alkynyl" is used herein to define Containing at least one carbon-carbon bond such as ethynyl, 2-propynyl (=propargyl) and the like and optionally having at least one selected from the group consisting of a halogen atom, a hydroxyl group, a thiol group, an amine group, a nitro group, a cyano group, a monovalent branched or unbranched hydrocarbon group substituted with a substituent of a group consisting of an aryl group and a heterocyclic group, such as a haloethynyl group. When present as a bridging group, an alkyl group, an alkenyl group, and an alkynyl group respectively represent a straight chain or a branched chain. CV12 is preferably CV4-alkylene or C2.I2-, preferably C2.4-alkenyl or -exetylene. Branch derivatives are conventionally prefixed (eg "positive", "second", "Different", etc.) The base (eg "n-propyl", "second butyl") unless otherwise stated otherwise is in a positive form. The term "aryl" is used herein to define a radical free radical consisting of 1 to 3 constituents and containing 6 Aromatic hydrocarbons up to 30 carbon atoms via removal of a nitrogen 1295286

* I 例如苯基及萘基各自選擇性經以1至5個分別選自鹵原子、羥基、锍基、胺基、硝基、氰基、醯基、醯氧基、磺醯基、亞磺醯基、烷基、胺基、羧基、酯基、醚基、醯胺基、疊氮基、磺酸基、磺醯胺基、烷基磺醯基、烷基亞磺醯基、烷硫基、氧酯基、氧醯胺基、芳基、Cp6-烷氧基、。-芳氧基、烷基、1.6-鹵烷基之取代基取代的有機基團。芳基基屬較佳爲含6至10個碳原子之單環。較佳芳基爲苯基及萘基各自經以1至5個分別選自鹵原子、硝基、胺基、疊氮基、CV6-烷氧基、〇ν6-烷硫 > 基、CV6-烷基、CV6-鹵烷基及苯基之取代基取代。「鹵原子」一詞用於此處包括Cl、Bi·、F、I原子。「羥基」一詞用於此處表示式-ΟΗ基。「锍基」一詞用於此處表示式-SH基。「氰基」一詞用於此處表示式-CN基。「硝基」一詞用於此處表示式-Ν02基。「硝基氧基」一詞用於此處表示式-01^02基。「胺基」一詞用於此處表示式-ΝΗ2基。 f 「疊氮基」一詞用於此處表示式-Ν3基。「羧基」一詞用於此處表示式-COOH基。「磺酸基」一詞用於此處表示式-S03H基。「磺醯胺基」一詞用於此處表示式-S02NH2基。「酯基」一詞用於此處表示式-COO-R11基。其中Rn定義如前，但氧衍生物、硫衍生物或胺基衍生物除外。「醚基」一詞定義爲包括選自CU5。直鏈或分支烷基，或C2.5〇直鏈或分支烯基或炔基或其組合藉一或多個氧原 -10- 1295286 子岔斷之基。「醯胺基」一詞定義爲包括式40關2或<0關1^或 -CONRnR12，其中R11及R12定義如前。「雜環基」一詞用於此處定義爲包括如上定義之芳族或非芳族環狀烷基、烯基、或炔基部分，其帶有至少一個0、S及/或N原子岔斷碳環系環結構，以及選擇性碳環系環結構中之一個碳可藉羰基置換。芳族雜環之非限制性實例爲吡啶基，呋喃基，吡咯基，噻吩基，異噻唑基，咪唑基，苯并咪唑基，四唑基，喹唑啉基，喹啉Π井基，萘啶基，嗒畊基，嘧啶基，吡哄基，喹啉基，異喹啉基，異苯并呋喃基，苯并噻吩基，吡唑基，吲哚基，吲哚哄基，嘌呤基，異吲哚基，卡巴唑基，噻唑基，1，2， 4-噻二唑基，噻吩并（2,3-b)呋喃基，呋喃并吡喃基，苯并呋喃基，苯并氧雜萆基，異噚唑基，噚唑基，噻蒽基，苯并噻唑基，或苯并噚唑基，噌啉基，酞畊基，噻噚啉基，菲啶基，吖啶基，啪啶基，菲啉基，吩噻畊基，呋贊基，苯并二氫吡喃基，吲哚啉基，氧雜蒽基，次黃質基，喋啶基，5-氮雜胞啶基，5-氮雜脲啶基，***并吡啶基，咪唑并吡啶基，吡咯并嘧啶基及吡唑并嘧啶基 ’此等基團係選擇性經以烷基或如前文對烷基所述取代。非芳族雜環之非限制性實例有四氫呋喃基，四氫吡喃基，六氫吡啶甲基，六氫吡啶基，六氫吡畊基，咪唑啶基，嗎啉并，嗎啉基，1 -氧雜螺（4 . 5 )癸-2 -基，吡咯啶基，2-氧基-吡咯啶基，糖部分（亦即葡萄糖、戊糖、己糖、核糖，果糖其也可經取代）或可選擇性以任何適當基取代，包括但非限於一或多個選自低碳烷基、或其它前 1295286 r ' 文對院基所述之基之部分。「雜環基」一詞也包括雙環、三環及四環、螺基其中任何前述雜環系環_合至一或二個環，該等環係分別選自芳香環、環己烷環、環己烯環、環戊烷環、環戊烯環或其它單環系雜環族環，或此處單環系雜環基環藉伸烷基橋接例如喹嚀啶基，7-氮雜雙環（2.2.1)庚烷基，7-氧雜雙環（2.2.1)庚烷基，8-氧雜雙環（3 · 2 · 1 )辛烷基。前述定義中，須瞭解當取代基例如R2，R3，R4,R2a，R3a ^ ，R4a，R5，R6, R7，R8透過雜原子或羰基而附接至分子的其 ❿ 餘部分時，直鏈或分支鏈，（^.12較佳伸烷基或 c2.12較佳C2.4伸烯基或-伸炔基橋係選擇性插置於雜原子或羰基與分子其餘部分附接點間。 X之較佳例爲- COOR7或-C0NR5R6，其中R5，R6及R7較佳爲氫，CV4-烷基，苯基或烷基苯基。較佳X爲羧基或-CONR7R6，其中R5及R6較佳爲氫，* I such as phenyl and naphthyl are each optionally selected from 1 to 5 selected from a halogen atom, a hydroxyl group, a decyl group, an amine group, a nitro group, a cyano group, a decyl group, a decyloxy group, a sulfonyl group, a sulfinic group. Sulfhydryl, alkyl, amine, carboxyl, ester, ether, decyl, azide, sulfonate, sulfonylamino, alkylsulfonyl, alkylsulfinyl, alkylthio , oxyester group, oxoamine group, aryl group, Cp6-alkoxy group. a substituent-substituted organic group of an aryloxy group, an alkyl group, or a 1.6-haloalkyl group. The aryl group is preferably a monocyclic ring having 6 to 10 carbon atoms. Preferably, the aryl group is a phenyl group and a naphthyl group, each of which is selected from the group consisting of a halogen atom, a nitro group, an amine group, an azide group, a CV6-alkoxy group, a 〇ν6-alkyl sulfide group, and a CV6- group. Substituted by a substituent of an alkyl group, a CV6-haloalkyl group, and a phenyl group. The term "halogen atom" is used herein to include Cl, Bi, F, I atoms. The term "hydroxy" is used herein to mean the formula - fluorenyl. The term "base" is used herein to mean the -SH group. The term "cyano" is used herein to mean the formula -CN. The term "nitro" is used herein to mean the formula - 02 base. The term "nitrooxy" is used herein to mean the formula - 01^02. The term "amino" is used herein to mean the formula - ΝΗ2 group. f The term "azido" is used herein to mean the formula -Ν3. The term "carboxy" is used herein to mean the formula -COOH group. The term "sulfonic acid group" is used herein to mean the formula -S03H group. The term "sulfonamide" is used herein to denote the radical -S02NH2. The term "ester group" is used herein to mean the formula -COO-R11 group. Wherein Rn is as defined above, except for oxygen derivatives, sulfur derivatives or amine-based derivatives. The term "ether group" is defined to include a selected from CU5. A linear or branched alkyl group, or a C2.5 〇 straight or branched alkenyl or alkynyl group or a combination thereof, borrows one or more oxygen groups. The term "nonylamine" is defined to include the formula 40 off 2 or <0 off 1^ or -CONRnR12, wherein R11 and R12 are as defined above. The term "heterocyclyl" is used herein to define an aromatic or non-aromatic cyclic alkyl, alkenyl, or alkynyl moiety, as defined above, bearing at least one 0, S and/or N atom. The carbon ring ring structure and one of the carbon rings in the selective carbocyclic ring structure may be replaced by a carbonyl group. Non-limiting examples of aromatic heterocycles are pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, quinazolinyl, quinolinium, and naphthalene Pyridyl, hydrazine, pyrimidinyl, pyridyl, quinolyl, isoquinolinyl, isobenzofuranyl, benzothienyl, pyrazolyl, fluorenyl, fluorenyl, fluorenyl, Isoindolyl, carbazolyl, thiazolyl, 1,2,4-thiadiazolyl, thieno(2,3-b)furanyl, furopylopyryl, benzofuranyl, benzoxazepine Sulfhydryl, isoxazolyl, oxazolyl, thiazyl, benzothiazolyl, or benzoxazolyl, porphyrinyl, hydrazine, thiabulinyl, phenanthryl, acridinyl, anthracene Pyridyl, phenanthryl, phenoxyphenyl, furzanyl, benzopyranyl, porphyrin, oxazepine, hypoxanthyl, acridinyl, 5-azacyridinyl, 5 - azaridinyl, triazolopyridyl, imidazopyridyl, pyrrolopyrimidinyl and pyrazolopyrimidinyl groups are optionally substituted with an alkyl group or as described above for an alkyl group. Non-limiting examples of non-aromatic heterocycles are tetrahydrofuranyl, tetrahydropyranyl, hexahydropyridylmethyl, hexahydropyridyl, hexahydropyrryl, imidazolidinyl, morpholine, morpholinyl, 1 - oxaspiro (4.5) 癸-2-yl, pyrrolidinyl, 2-oxy-pyrrolidinyl, sugar moiety (ie glucose, pentose, hexose, ribose, fructose which may also be substituted) Alternatively, it may be optionally substituted with any suitable group including, but not limited to, one or more selected from the group consisting of lower alkyl groups, or other groups described in the preceding paragraphs. The term "heterocyclyl" also includes bicyclic, tricyclic, and tetracyclic, spiro groups, wherein any of the foregoing heterocyclic rings are bonded to one or two rings, each selected from the group consisting of an aromatic ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring or other monocyclic heterocyclic ring, or a monocyclic heterocyclyl ring-extended alkyl bridge herein, such as a quinacridinyl group, a 7-azabicyclo ring (2.2.1) Heptyl, 7-oxabicyclo(2.2.1)heptyl, 8-oxabicyclo(3 · 2 · 1 )octyl. In the foregoing definition, it is understood that when a substituent such as R2, R3, R4, R2a, R3a^, R4a, R5, R6, R7, R8 is attached to the remainder of the molecule through a hetero atom or a carbonyl group, a straight chain or A branched chain, (^.12 preferably alkyl or c2.12 preferably C2.4 extended alkenyl or - ankylosyl bridge is selectively intercalated between a heteroatom or a carbonyl group and the remainder of the molecule. Preferred examples are -COOR7 or -C0NR5R6, wherein R5, R6 and R7 are preferably hydrogen, CV4-alkyl, phenyl or alkylphenyl. Preferably X is carboxy or -CONR7R6, wherein R5 and R6 are preferably hydrogen,

Ci-4-烷基，苯基或烷基苯基特別-C0NH2。較佳A1及A2各自爲氧。 • 較佳R1爲氫，烷基特別1_12烷基特別低碳烷基或芳基特別苯基。較佳R1基例如爲甲基，乙基，丙基，異丙基，丁基，異-或第三丁基，2,2,2-三甲基乙基各自選擇性透過亞甲基橋選擇性附接或經以至少一個鹵原子取代，例如三氟甲基，三氯甲基，2,2,2-三氯乙基，1，卜二甲基-2,2-二溴乙基 1，1-二甲基- 2,2,2·三氯乙基。 R1以乙基爲待佳。較佳R2及R2a分別爲氫，鹵原子或烷基特別爲低碳烷基。 -12· 1295286 R2及R2a基之較佳例分別爲氫，鹵原子，或甲基，乙基，丙基，異丙基，丁基，異-或第三·丁基，2，2,2-三甲基乙基或其經以至少一個鹵原子取代’例如三氟甲基，三氯甲基，2，2,2-三氯乙基，1，卜二甲基-2,2 -二溴乙基，1，1-二甲基-2,2,2-三氯乙基。特別至少一個以及最佳R2及R2a皆爲氫。較佳R3a，R4及R4a分別爲氫，特別爲甲基或乙基或芳基特別爲苯基或芳烷基，特別爲苄基。 R3a，R4及R4a基之較隹例分別爲氫，鹵原子，或甲基，乙基，丙基，異丙基，丁基，異·或第三-丁基，2，2,2· 三甲基乙基或其經以至少一個鹵原子取代，例如三氟甲基，三氯甲基，2,2,2-三氯乙基，1，卜二甲基-2,2-二溴乙基，1，1-二甲基·2,2,2-三氯乙基。特別至少一個且最佳R4及R4a二者皆爲氫。 1^3特別爲氫或烷基，特別爲低碳烷基及最佳爲氫。較佳R3爲氫，Clel2-烷基特別爲（^.6-烷基，各自選擇性經以一或多個選自羥基、鹵原子、氰基、硫氰基或烷氧基之取代基取代且係直接或透過硫、亞磺醯基、磺醯基、羰基或氧羰基及選擇性（^.4-伸烷基橋，特別亞甲基附接至環；C2.6-烯基或-炔基，特別C2.3-烯基或-炔基其各自選擇性經以一或多個鹵原子取代；疊氮基；氰基；醯胺基；羧基；***基，四唑基，吡咯啶基，吡啶基，1-氧化吡啶基，硫嗎啉基，苯并二氧伍圜基，呋喃基，噚唑基，嘧啶基，吡咯基，噻二唑基，噻唑基，噻吩基或六氫吡畊基其各自選擇性經以一或多個選自鹵原子、-烷基及苯基之取代基取代，且係直接或透過羰 -13- 1295286 1 1 基或-伸烷基橋特別亞甲基附接至環；萘基；或苯基，苯烷基或苯烯基各自選擇性經以一或多個選自鹵原 c】-6-烷基、cv6-鹵烷基、cv6-烷氧基、c丨.6-烷硫基、胺基、疊氮基、苯基及硝基之取代基取代，且各自直接或透過一個氧、磺醯基、磺醯氧基、羰基或羰氧基以及選擇性額外透過（^.4-伸烷基橋特別亞甲基附接至環。又較佳R3爲Chf烷基選擇性經以一或多個選自鹵原子、硫氰酸基、疊氮基、烷氧基、烷硫基、苯基磺醯基 0 之取代基取代；硝基氧基；c2.3-烯基或-炔基各自選擇性經以一或多個鹵原子或乙醯基取代；四唑基，吡啶基，呋喃基，吡咯基，噻唑基或噻吩基；或苯基或苯基烷基各自選擇性經以一或多個選自鹵原子、CbP烷基、 C!.6 •鹵烷基、Ci_6-烷氧基、胺基、疊氮基、苯基及硝基之取代基取代，且各自直接或透過一個磺醯氧基以及選擇性額外透過一個Q.4-伸烷基橋，特別爲亞甲基附接至環。其它R3之較佳例爲氫，鹵原子或氫，鹵原子，或甲基， • 乙基，丙基，異丙基，丁基，異·或第三-丁基，2，2,2- 三甲基乙基或其經以至少一個鹵原子取代，例如三氟甲基，三氯甲基，2,2,2 -三氯乙基，1，1-二甲基- 2,2 -二溴乙基，1，1-二甲基-2,2,2-三氯乙基。 R3特別爲（^.4-烷基選擇性經以一或多個選自鹵原子、硫氰酸基或疊氮基之取代基取代；C2.5•烯基或-炔基，各自選擇性經以一或多個鹵原子取代；噻吩基；或苯基選擇性經以一或多個選自鹵原子、烷基、鹵烷基或疊氮基之取代基取代。 -14- 1295286 R3基之進一步較佳例爲（^.6烷基及C2.6鹵烯基。較佳R5及R6分別爲氫，甲基，乙基，丙基，異丙基，丁基，異-或第三-丁基，2,2,2-三甲基乙基特別氫或甲基。特別至少一個且最佳R5及R6皆爲氫。較佳R7爲氫，甲基，乙基，丙基，異丙基，丁基，異 -或第三-丁基，2, 2，2-三甲基乙基，甲氧基，乙氧基，苯基，苄基或其經以至少一個鹵原子取代例如三氟甲基，氯苯基。較佳R7爲氫，甲基或乙基特別爲氫。較佳R8爲氫，甲基，乙基，丙基，異丙基，丁基，異 -或第三-丁基，2,2,2-三甲基乙基，苯基，苄基或其經以至少一個鹵原子取代，例如三氟甲基，氯苯基。較佳R8爲氫或甲基。以一或多個此等較佳化合物基之組合物爲特佳。式I化合物之特佳組群（化合物1A)包含該等化合物其中。 A2爲氧； X 爲-CONR5R6 或-COOR7 或-CO-R8 或 CN ; R1爲氫或烷基，芳基，鹵原子，羥基，胺基，硝基，氰基； R2，R3，R4爲相同或相異且各自分別爲氫或鹵原子，羥基，胺基，硝基，氰基，醯基，醯氧基，磺醯基衍生物，亞磺醯基衍生物，胺基衍生物，羧基，酯基，醚基，醯胺基，磺酸基，磺醯胺基，烷氧羰基，硫衍生物，烷基，烷氧基，氧酯基，氧醯胺基，芳基，氧衍生物，雜 -15- 1295286 τ # 環基，乙烯基，以及R3可額外表示C2.5烯基，C2.5炔基或疊氮基其各自選擇性經以一或多個鹵原子、氰基、硫氰基、疊氮基，環丙基，醯基及/或苯基取代；或苯基磺醯氧基而任何苯基部分可經以一或多個鹵原子、烷基、鹵烷基、烷氧基、硝基、胺基及/或苯基取代；最佳爲甲基，乙基，丙基，異丙基，丁基或異丁基； R2a，R3a 及 R4a 爲氫； R5，R6，R7爲相同或相異且各自分別爲氫，羥基，烷基，芳基，雜環基或氧衍生物；以及 _ R8爲氫，羥基，毓基，鹵原子，烷基，芳基，雜環基，烷硫基或硫衍生物。此等化合物1A中，R1較佳爲甲基，乙基，丙基，異丙基，丁基或異丁基；最佳爲甲基，乙基或正丙基。 R2及R4較佳分別爲氫或鹵原子或甲基，乙基，丙基，異丙基，丁基或異丁基；以及最佳各自爲氫。 R3較佳爲CV5烷基，C2e5烯基，C2.5炔基，環丙基，疊氮基，各自選擇性經以一或多個鹵原子、氰基、硫氰 • 基、疊氮基、烷硫基、環丙基、醯基及/或苯基取代；苯基；苯基磺醯基；苯基磺醯氧基、四唑、***、噻吩基、呋喃基、吡咯、吡啶，因此任何苯基部分可經以一或多個鹵原子、烷基、鹵烷基、烷氧基、硝基、胺基及 /或苯基取代；最佳爲甲基，乙基，丙基，異丙基，丁基或異丁基。 X較佳爲- COOH或- COOMe或-COOEt或- CONH2;最佳爲 -C0NH2。進一步特佳式I化合物組群（化合物1B)包含下述化合 -16- 1295286 τ· * 物其中 X 爲- CA]NH2, - CA】NHCH3 或- CAMiCHsh; R1爲烷基或苯基； R3爲烷基，烯基，炔基，氰基，異硫氰酸基，醚基，羧基，醯胺基，芳基，雜環基；或 R3爲CH2R1()其中R1G爲氫，環烷基，氧酯基，氧烷基磺醯基，氧芳基磺醯基，胺基烷基磺醯基，胺基芳基磺醯基，硝基氧基，氰基，異硫氰酸基，醯胺基，烷硫基，芳硫基，烷基亞磺醯基，烷基磺醯基，雜環基，芳氧 I 基，烷氧基或三氟乙基； R3a爲氫，烷基或芳基（特別當1^33爲氫時，R3非爲甲基）；或R3R3a形成環烷基；以及R2，R2a，R4及R4a各自爲氫。式I化合物中， R1較佳爲烷基特別CV12-更佳（^.6-烷基及最佳爲乙基； > R2，R2a，R3a& R4a 較佳爲氫。 R3較佳選自氫；Cm-烷基特別（^.6-烷基，其各自選擇性經以一或多個選自羥基、鹵原子、氰基、硫氰酸基或烷氧基之取代基取代，且係直接或透過一個硫基' 亞磺醯基、磺醯基、羰基或氧羰基以及選擇性額外透過一個CU4-伸烷基橋特別亞甲基附接至環；C2_6-烯基或 -炔基特別C2.3-烯基或-炔基，各自選擇性經以一或多個鹵原子取代；疊氮基；氰基；醯胺基；羧基；***基，四唑基，吡咯啶基，吡啶基，1 -氧化吡啶基，硫嗎啉 -17- 1295286 1 , » 1 基，苯并二氧伍圜基，呋喃基，曙唑基，嘧啶基，吡咯基’噻二唑基，噻唑基，噻吩基或六氫吡啶畊基，其各自選擇性經以一或多個選自鹵原子、烷基及苯基之取代基取代，且係直接或透過羰基或C;.4-伸烷基橋特別亞甲基附接至環；萘基；或苯基，苯烷基或苯基烯基各自選擇性經以一或多個選自鹵原子、烷基、C^-鹵烷基、烷氧基、烷硫基、胺基、疊氮基、苯基及硝基之取代基取代，且各自直接或透過一個氧基、磺醯基、磺醯氧基、羰基或羰氧基以及選擇性額外透過一個（^.^伸烷基橋，特別亞甲基附接至環。 R3a較佳爲氫或（^.4-烷基； R4及1^43較佳分別爲氫，•烷基，苯基或苄基。式I化合物之又一較佳組群(化合物1C)包含呈外消旋形式之化合物，其中當X爲-CONR5R6及R1爲氫、甲基，乙基或丙基時，吡咯啶環上取代非爲一 ·、二-或三·甲基或一乙基。式I化合物之又一組群（化合物1D)包含呈外消旋形式 > 之化合物其中當X爲- CONR5R6及R1爲氫或Cm-烷基、 C2.6-烯基或-炔基或環烷基（各自爲無取代）時，環之取代非由烷基、烯基或炔基（各自爲無取代）取代。又一組特別式I化合物（化合物1E)包含其中， X 爲-CAiNh ; R1 爲 Η ; R3爲疊氮甲基，碘甲基，乙基選擇性經以1至5個鹵原子取代，正丙基選擇性經以1至5個鹵原子取代，乙烯基選擇性經以1或2個甲基及/或1至3個鹵原子取代’乙 -18- 1295286 1 » 炔基選擇性經以烷基、苯基或鹵原子取代； R3a爲氫或鹵原子，較佳爲氟；以及R2，R2a，R4及R4a各自爲氫；呈其外消旋化合物或呈對映異構物豐富形式，較佳爲純對映異構體。進一步特佳一組式I化合物（化合物1F)包含該等化合物其中， X 爲-CA^NHj ; R】爲Η ; ® R3爲烷基，C2_6-烯基或C2.6-炔基選擇性經以疊氮基、氧硝基、1至6個鹵原子取代； R3a爲氫或鹵原子，較佳爲氟；以及R2，R2a，R4及R4a各自爲氫；呈其外消旋化合物或對映異構物豐富形式，較佳爲純對映異構體。全部前述範圍中，當R1附接至碳原子爲非對稱時，較佳係呈「S」組態。 φ 根據本發明之「醫藥可接受性鹽」包括式I化合物可形成之治療活性無毒性鹼及酸鹽形式。式I化合物（於游離形式時係呈鹼出現）之酸加成鹽形式可經由使用適當酸處理游離鹼獲得，此等酸例如爲無機酸如氫鹵酸如氫氯酸或氫溴酸，硫酸，硝酸，磷酸等 ;或有機酸例如乙酸，羥乙酸，丙酸，乳酸，丙酮酸，丙二酸，丁二酸，馬來酸，反丁烯二酸，蘋果酸，酒石酸，檸檬酸，甲烷磺酸，乙烷磺酸，苯磺酸，對甲苯磺酸，西卡米酸（eye 1 ami c )，水楊酸，對胺基水楊酸，巴 -19· 1295286Ci-4-alkyl, phenyl or alkylphenyl-specific -CONH2. Preferably, each of A1 and A2 is oxygen. • Preferably, R1 is hydrogen, and the alkyl group is particularly 1-12 alkyl, particularly lower alkyl or aryl, particularly phenyl. Preferred R1 groups are, for example, methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl, each selectively passed through a methylene bridge. Sexually attached or substituted with at least one halogen atom, such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,dimethyl-2,2-dibromoethyl 1 , 1-dimethyl-2,2,2·trichloroethyl. R1 is better with ethyl. Preferably, R2 and R2a are each hydrogen, and the halogen atom or alkyl group is especially a lower alkyl group. -12· 1295286 Preferred examples of the R2 and R2a groups are hydrogen, halogen atom, or methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2, 2, 2 -trimethylethyl or substituted by at least one halogen atom 'eg trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,dimethyl-2,2-di Bromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl. Particularly at least one and the best R2 and R2a are all hydrogen. Preferably, R3a, R4 and R4a are each hydrogen, especially methyl or ethyl or aryl, especially phenyl or aralkyl, especially benzyl. The R3a, R4 and R4a groups are respectively hydrogen, halogen, or methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2, 2, 2·3 Methyl ethyl group or substituted by at least one halogen atom, such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,dimethyl-2,2-dibromo Base, 1,1-dimethyl-2,2,2-trichloroethyl. Particularly at least one and most preferably both R4 and R4a are hydrogen. 1^3 is especially hydrogen or an alkyl group, especially a lower alkyl group and most preferably hydrogen. Preferably, R3 is hydrogen, and the Clel2-alkyl group is especially (^.6-alkyl, each of which is optionally substituted by one or more substituents selected from a hydroxyl group, a halogen atom, a cyano group, a thiocyano group or an alkoxy group. And directly or through sulfur, sulfinyl, sulfonyl, carbonyl or oxycarbonyl and selective (^.4-alkyl bridge, especially methylene attached to the ring; C2.6-alkenyl or Alkynyl, especially C2.3-alkenyl or -alkynyl, each of which is optionally substituted with one or more halogen atoms; azide; cyano; amidino; carboxy; triazolyl, tetrazolyl, pyrrole Pyridyl, pyridyl, 1-oxypyridyl, thiomorpholinyl, benzodioxoyl, furyl, carbazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl or hexa Each of the hydrogen pyridyl groups is optionally substituted with one or more substituents selected from the group consisting of a halogen atom, an -alkyl group and a phenyl group, and is directly or through a carbonyl-13-1295286 1 1 group or a -alkyl group bridge. The methylene group is attached to the ring; the naphthyl group; or the phenyl group, the phenylalkyl group or the phenylalkenyl group are each optionally selected from one or more selected from the group consisting of halogeno c]-6-alkyl, cv6-haloalkyl, cv6. -alkoxy, c丨.6-alkyl sulfide Substituted with a substituent of an amine group, an azide group, a phenyl group and a nitro group, and each directly or through an oxygen, a sulfonyl group, a sulfonyloxy group, a carbonyl group or a carbonyloxy group, and optionally an additional permeation (^.4- The alkylene bridge particularly has a methylene group attached to the ring. Further preferably, R3 is a Chf alkyl group selected by one or more selected from the group consisting of a halogen atom, a thiocyanate group, an azide group, an alkoxy group, and an alkylthio group. Substituted with a substituent of phenylsulfonyl group 0; a nitrooxy group; c2.3-alkenyl or -alkynyl group each optionally substituted with one or more halogen atoms or an ethyl fluorenyl group; tetrazolyl, pyridyl group , furyl, pyrrolyl, thiazolyl or thienyl; or phenyl or phenylalkyl, each optionally having one or more selected from the group consisting of a halogen atom, a CbP alkyl group, a C!.6 • haloalkyl group, Ci_6- Substituted with alkoxy, aminyl, azido, phenyl and nitro substituents, each of which is directly or through a sulfonyloxy group and optionally additionally passed through a Q.4-alkylene bridge, especially for methylene The base is attached to the ring. Other preferred examples of R3 are hydrogen, a halogen atom or hydrogen, a halogen atom, or a methyl group, • ethyl, propyl, isopropyl, butyl, iso- or third- a 2,2,2-trimethylethyl group or substituted by at least one halogen atom, such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-di Methyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl. R3 is especially (^.4-alkyl selective by one or more Substituted by a substituent of a halogen atom, a thiocyanate group or an azide group; a C2.5•alkenyl group or an alkynyl group, each of which is optionally substituted with one or more halogen atoms; a thienyl group; or a phenyl selective group Further substituted with one or more substituents selected from a halogen atom, an alkyl group, a haloalkyl group or an azide group. Further preferred examples of the R13 group are (^.6 alkyl and C2.6 haloalkenyl) . Preferably, R5 and R6 are independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl, or hydrogen. . Particularly at least one and most preferably both R5 and R6 are hydrogen. Preferably R7 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2, 2,2-trimethylethyl, methoxy, ethoxy Phenyl, benzyl or substituted by at least one halogen atom such as trifluoromethyl, chlorophenyl. Preferably R7 is hydrogen and the methyl or ethyl group is especially hydrogen. Preferred R8 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl, phenyl, benzyl or Substituted with at least one halogen atom, such as trifluoromethyl, chlorophenyl. Preferably R8 is hydrogen or methyl. Compositions based on one or more of these preferred compound groups are particularly preferred. A particularly preferred group of compounds of formula I (compound 1A) comprises among such compounds. A2 is oxygen; X is -CONR5R6 or -COOR7 or -CO-R8 or CN; R1 is hydrogen or alkyl, aryl, halogen, hydroxy, amine, nitro, cyano; R2, R3, R4 are the same Or different and each being hydrogen or a halogen atom, a hydroxyl group, an amine group, a nitro group, a cyano group, a decyl group, a decyloxy group, a sulfonyl derivative, a sulfinyl derivative, an amine derivative, a carboxyl group, Ester group, ether group, decylamino group, sulfonic acid group, sulfonylamino group, alkoxycarbonyl group, sulfur derivative, alkyl group, alkoxy group, oxyester group, oxonium group, aryl group, oxygen derivative, Hetero-15-1295286 τ# ring group, vinyl group, and R3 may additionally represent C2.5 alkenyl group, C2.5 alkynyl group or azide group, each of which is selectively subjected to one or more halogen atoms, cyano group, sulfur Cyano, azido, cyclopropyl, decyl and/or phenyl substituted; or phenylsulfonyloxy and any phenyl moiety may be substituted with one or more halogen atoms, alkyl, haloalkyl, alkane Oxygen, nitro, amine and/or phenyl substituted; most preferably methyl, ethyl, propyl, isopropyl, butyl or isobutyl; R2a, R3a and R4a are hydrogen; R5, R6, R7 are the same or different and each Respectively hydrogen, hydroxy, alkyl, aryl, heterocyclic or oxy derivative; and _ R8 is hydrogen, hydroxy, decyl, halogen, alkyl, aryl, heterocyclyl, alkylthio or sulphur derived Things. In these compounds 1A, R1 is preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group or an isobutyl group; most preferably a methyl group, an ethyl group or a n-propyl group. R2 and R4 are preferably each hydrogen or a halogen atom or a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group or an isobutyl group; and most preferably each is hydrogen. R3 is preferably a CV5 alkyl group, a C2e5 alkenyl group, a C2.5 alkynyl group, a cyclopropyl group, an azide group, each optionally having one or more halogen atoms, a cyano group, a thiocyanate group, an azide group, Alkenylthio, cyclopropyl, decyl and/or phenyl substituted; phenyl; phenylsulfonyl; phenylsulfonyloxy, tetrazole, triazole, thienyl, furyl, pyrrole, pyridine, Any phenyl moiety may be substituted with one or more halogen atoms, alkyl, haloalkyl, alkoxy, nitro, amine and/or phenyl; most preferably methyl, ethyl, propyl, iso Propyl, butyl or isobutyl. X is preferably -COOH or -COOMe or -COOEt or -CONH2; most preferably -CONH2. Further preferred compound group I (compound 1B) comprises the following compound-16-1295286 τ·* wherein X is -CA]NH2, -CA]NHCH3 or -CAMiCHsh; R1 is alkyl or phenyl; R3 is Alkyl, alkenyl, alkynyl, cyano, isothiocyanate, ether, carboxyl, decyl, aryl, heterocyclyl; or R3 is CH2R1 () wherein R1G is hydrogen, cycloalkyl, oxygen Ester group, oxyalkylsulfonyl group, oxyarylsulfonyl group, aminoalkylsulfonyl group, aminoarylsulfonyl group, nitrooxy group, cyano group, isothiocyanate group, decylamino group , alkylthio, arylthio, alkylsulfinyl, alkylsulfonyl, heterocyclic, aryloxy, alkoxy or trifluoroethyl; R3a is hydrogen, alkyl or aryl ( Particularly when 1^33 is hydrogen, R3 is not methyl); or R3R3a forms a cycloalkyl group; and R2, R2a, R4 and R4a are each hydrogen. In the compound of the formula I, R1 is preferably an alkyl group, particularly CV12-more preferably (^.6-alkyl and most preferably ethyl; > R2, R2a, R3a& R4a is preferably hydrogen. R3 is preferably selected from hydrogen. Cm-alkyl is particularly (^.6-alkyl, each of which is optionally substituted with one or more substituents selected from a hydroxyl group, a halogen atom, a cyano group, a thiocyanate group or an alkoxy group, and is directly Or attached to the ring via a thiol-sulfinyl, sulfonyl, carbonyl or oxycarbonyl group and optionally additionally through a CU4-alkylene bridge; C2_6-alkenyl or -alkynyl C2 . . . alkenyl or - alkynyl, each optionally substituted with one or more halogen atoms; azido; cyano; decylamino; carboxy; triazolyl, tetrazolyl, pyrrolidinyl, pyridyl , 1 - oxidized pyridyl, thiomorpholine-17-1295286 1 , » 1 group, benzodioxanyl, furyl, oxazolyl, pyrimidinyl, pyrrolyl 'thiadiazolyl, thiazolyl, thiophene Or a hexahydropyridine hydration group, each of which is optionally substituted with one or more substituents selected from a halogen atom, an alkyl group and a phenyl group, and is directly or through a carbonyl group or a C; a methylene group attached to a ring; a naphthyl group; or a phenyl group, a phenylalkyl group or a phenylalkenyl group, each optionally having one or more selected from the group consisting of a halogen atom, an alkyl group, a C^-haloalkyl group, an alkoxy group Substituted with alkylthio, amine, azide, phenyl and nitro substituents and each directly or through an oxy, sulfonyl, sulfonyloxy, carbonyl or carbonyloxy group and optionally additionally a (^.^alkylene bridge, especially a methylene group attached to the ring. R3a is preferably hydrogen or (^.4-alkyl; R4 and 1^43 are preferably hydrogen, • alkyl, phenyl Or a benzyl group. A further preferred group of compounds of formula I (compound 1C) comprises a compound in racemic form wherein pyrrolidine is when X is -CONR5R6 and R1 is hydrogen, methyl, ethyl or propyl. The ring is substituted by a mono-, di- or tri-methyl or monoethyl group. A further group of compounds of formula I (compound 1D) comprises a compound in the form of a racemic form > wherein X is - CONR5R6 and R1 When hydrogen or Cm-alkyl, C2.6-alkenyl or -alkynyl or cycloalkyl (each unsubstituted), the substitution of the ring is not replaced by an alkyl, alkenyl or alkynyl group (each unsubstituted) Another A particular compound of formula I (compound 1E) wherein X is -CAiNh; R1 is oxime; R3 is azidomethyl, iodomethyl, ethyl is optionally substituted with from 1 to 5 halogen atoms, n-propyl selectivity Substituted with 1 to 5 halogen atoms, the vinyl group is substituted by 1 or 2 methyl groups and/or 1 to 3 halogen atoms. 'B-18-1295286 1» alkynyl selective via alkyl, benzene Substituted by a halogen atom; R3a is hydrogen or a halogen atom, preferably fluorine; and R2, R2a, R4 and R4a are each hydrogen; in the form of a racemic compound or enantiomerically enriched form, preferably pure Enantiomer. Further particularly preferred compounds of the formula I (compound 1F) comprise the compounds wherein X is -CA^NHj; R] is hydrazine; R3 is alkyl, C2_6-alkenyl or C2.6-alkynyl is selected Substituted with an azide group, an oxynitro group, and 1 to 6 halogen atoms; R3a is hydrogen or a halogen atom, preferably fluorine; and R2, R2a, R4 and R4a are each hydrogen; as a racemic compound or an enantiomer thereof The isomeric rich form is preferably the pure enantiomer. In all of the foregoing ranges, when R1 is attached to a carbon atom that is asymmetric, the preferred system is in an "S" configuration. φ "Pharmaceutically acceptable salt" according to the present invention includes a therapeutically active non-toxic base and acid salt form which can be formed by a compound of formula I. The acid addition salt form of the compound of formula I (which is present as a base in free form) can be obtained by treating the free base with a suitable acid such as a mineral acid such as a hydrohalic acid such as hydrochloric acid or hydrobromic acid, sulfuric acid , nitric acid, phosphoric acid, etc.; or organic acids such as acetic acid, glycolic acid, propionic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methane Sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, sikamic acid (eye 1 ami c ), salicylic acid, p-aminosalicylic acid, Ba-19·1295286

I t 母酸（pamo i c )等。含酸性質子之式I化合物可經由使用適當有機及無機鹼處理而被轉成其治療活性無毒性鹼加成鹽形式，例如金屬鹽或胺鹽。適當鹼鹽形式包括例如銨鹽，鹼及鹼土金屬鹽例如鋰、鈉、鉀、鎂、鈣鹽等，與有機鹼生成之鹽例如N-甲基-D-葡萄糖胺，海卓巴明鹽（hydTabamine salts)以及與胺基酸如精胺酸、離胺酸等生成之鹽。相反地，該等鹽形式可經由使用適當鹼或酸處理而轉成自由態形式。 > 式I化合物及其鹽可呈溶劑合物，溶劑合物係包括於本發明之範圍。此等溶劑合物例如包括水合物、醇合物等。多種式I化合物及部分中間物於結構中至少有一個立體產生中心。立體產生中心可呈R或S組態存在，R及S 標示法遵照純應用化學45( 1976 ) 1 1 -30所述規則。本發明亦係關於式I化合物之全部立體形式，例如對映異構型及非對映異構型或其混合物（包括全部可能的 | 立體異構物混合物）。此外’某些式I化合物其含有嫌基可呈Z(zusammen)或 E(entgegen)異構物形式存在。各例中，本發明包括混合物及個別異構物。吡咯啶環的多個取代基可表示相對於吡略啶酮環平面彼此呈順或反關係。部分式I化合物可呈互變異構物形式存在。此等形式雖然未明白指示於上式但意圖含括於本發明之範圍。本發明涉及化合物時意圖含括化合物之各種異構型及 -20- 1295286 ： , . - 其混合物，除非特別述及某種特定異構型。本發明之範圍內也包括式I化合物之前驅藥形式及其各種子範圍及小組。「前驅藥」一詞用於此處包括於活體內快速轉變例如藉於血液中水解而快速轉變成根據本發明之親代化合物。前驅藥爲帶有基團而可於發揮藥理作用之前藉生物轉換去除之化合物。此等基包括於活體試驗中方便由帶有該等基之化合物割裂去除之部分，該化合物於割裂該部分後能保持或變成具有藥理活性。代謝可割裂基構成一類 > 業界眾所周知的基之組群ι包括但非限於例如烷醯基（亦即乙醯基，丙醯基，丁醯基等），無取代或經取代之碳環芳醯基（例如苯甲醯基，取代苯甲醯基及1-及2-萘甲醯基），烷氧羰基（例如乙氧羰基），三烷基矽烷基（例如二甲基-以及三乙基矽烷基），與二碳酸形成之單酯（例如丁二醯基），磷酸基，硫酸基，磺酸基，磺醯基，亞磺醯基等。帶有代謝可割裂基之化合物之優點爲由於存在有代謝可割裂基而對親代化合物提供提高溶解度及/或吸 > 收速率結果具有改良之生物利用率。T.Higuchi及V. S t e 1 1 a，「前驅藥作爲新穎輸送系統」，A . C . S .硏討會系列；「藥物設計之可生物逆轉載劑」第14期，Edward B.Roche編輯，美國藥學會及波加瑪（Peirgamon)出版社， 1 987 年。根據本發明之式I化合物如合成有機化學業界人士已知可以類似習知方法製備。以下方法說明係以舉例說明方式陳述某些合成途徑。其它替代及/或類似方法對業界人士顯然易知。用於此 -21· 1295286 處有關取代基之定義，「=」表示「是」以及「#」表示「非爲」。 A .胺基酯之環化。式I中，當A2 = 0時，式AA-II之胺基酯經環化，其中 Q1連同其附接之氧爲離去基，特別Q1爲烷基，特別爲含 1至4個碳原子之直鏈或分支烷基。I t mother acid (pamo i c ) and the like. The compound of formula I containing an acidic proton can be converted to its therapeutically active non-toxic base addition salt form, e.g., a metal salt or an amine salt, by treatment with a suitable organic and inorganic base. Suitable base salt forms include, for example, ammonium salts, alkali and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases such as N-methyl-D-glucosamine, hydrabaramine salts ( hydTabamine salts) and salts formed with amino acids such as arginine, lysine, and the like. Conversely, the salt forms can be converted to the free form by treatment with a suitable base or acid. > The compound of the formula I and its salt may be in the form of a solvate, and the solvate is included in the scope of the present invention. Such solvates include, for example, hydrates, alcoholates and the like. A plurality of compounds of formula I and a portion of the intermediates have at least one stereogenic center in the structure. The stereogenic center can exist in an R or S configuration, and the R and S markings follow the rules described in Pure Applied Chemistry 45 (1976) 1 1-30. The invention also relates to all stereoisomeric forms of the compounds of formula I, such as enantiomeric and diastereomeric forms or mixtures thereof (including all possible | stereoisomer mixtures). Furthermore, certain compounds of formula I which contain a stimulating group may be present as Z(zusammen) or E(entgegen) isomers. In each case, the invention includes mixtures and individual isomers. The plurality of substituents of the pyrrolidine ring may represent a cis or inverse relationship with respect to the plane of the pyrrolidone ring. Some of the compounds of formula I may exist in tautomeric forms. Such forms are not intended to be included in the above formula but are intended to be included within the scope of the invention. The present invention relates to compounds which are intended to include various isomeric forms of the compound and -20-1295286:, - mixtures thereof, unless a particular specific isomeric form is specifically recited. Also included within the scope of the invention are pre-drug forms of the compounds of formula I and their various sub-ranges and groups. The term "precursor" is used herein to include rapid conversion in vivo, e.g., by hydrolysis in blood, to rapidly convert to a parent compound according to the present invention. A prodrug is a compound with a group that can be removed by biological conversion prior to exerting pharmacological effects. Such bases include those which are conveniently removed by cleavage of a compound bearing such a group in a living assay which retains or becomes pharmacologically active upon cleavage of the moiety. Metabolically cleavable groups constitute a class> Groups of groups well known in the art include, but are not limited to,, for example, an alkano group (i.e., an ethyl group, a propyl group, a butyl group, etc.), an unsubstituted or substituted carbocyclic aryl group. (eg, benzamidine, substituted benzamidine and 1- and 2-naphthylmethyl), alkoxycarbonyl (eg ethoxycarbonyl), trialkylalkyl (eg dimethyl- and triethyldecane) a monoester formed with dicarbonic acid (for example, butyl fluorenyl), a phosphate group, a sulfate group, a sulfonic acid group, a sulfonyl group, a sulfinyl group or the like. An advantage of a compound having a metabolically cleavable group is the improved bioavailability of the parent compound due to the presence of a metabolically cleavable group to provide improved solubility and/or absorption of the parent compound. T. Higuchi and V. S te 1 1 a, "Precursor as a Novel Delivery System", A. C. S. Chastity Series; "Bioreversible Carrier for Drug Design", Issue 14, Edward B. Roche Editor, American Pharmaceutical Association and Peirgamon Press, 1987. Compounds of formula I according to the invention are known in the art of synthetic organic chemistry and can be prepared analogously to conventional methods. The following method descriptions illustrate some synthetic routes by way of illustration. Other alternatives and/or similar methods are readily apparent to those skilled in the art. For the definition of substituents in this -21· 1295286, "=" means "yes" and "#" means "not". A. Cyclization of the amino ester. In formula I, when A2 = 0, the amino ester of formula AA-II is cyclized, wherein Q1 together with the oxygen to which it is attached is a leaving group, particularly Q1 is an alkyl group, particularly having from 1 to 4 carbon atoms Straight or branched alkyl.

Q1=甲基或乙基。反應爲已知且方便於室溫至150°C 於有或無催化劑例如乙酸，羥苯并***或2-羥吡啶存在下進行。 Q] #甲基或乙基。式AA-11之酯於酸性或鹼性條件下水解，然後使用偶合劑例如二環己基甲二醯亞胺於習知肽合成條件下環化（6〇〇1&11821^，11.，8〇(1&1182]^，八.，「肽合成實務」，Springer Verlag，1984 年）。 A . 1藉加成於衣康酸鹽衍生物合成AA -1 I。式AA-II化合物其中R2a=R3a = H及R3=COOQ2，其中 Q2表示選擇性旋光性直鏈或分支烷基，係經由式AA-III化合物與式AA-IV衣康酸鹽衍生物根據下式反應獲 -22- 1295286Q1 = methyl or ethyl. The reaction is known and conveniently carried out at room temperature to 150 ° C in the presence or absence of a catalyst such as acetic acid, hydroxybenzotriazole or 2-hydroxypyridine. Q] #methyl or ethyl. The ester of formula AA-11 is hydrolyzed under acidic or basic conditions and then cyclized using a coupling agent such as dicyclohexylmethyleneimine under conventional peptide synthesis conditions (6〇〇1&11821^,11.,8) 〇(1&1182]^, VIII., "Peptide Synthesis Practice", Springer Verlag, 1984. A. 1 Synthesis of AA-1I by addition of an itaconate derivative. Formula AA-II compound wherein R2a = R3a = H and R3 = COOQ2, wherein Q2 represents a selective optically active linear or branched alkyl group, which is obtained by reacting a compound of the formula AA-III with a formula AA-IV itaconate derivative according to the following formula: -22 - 1295286

此種反應係根據述於：Street，L.：i.，Baker，R.，Book， T.，Kneen，C.O.，ManLeod， A.M·，Merchant， K.J·，Such a reaction is described in: Street, L.: i., Baker, R., Book, T., Kneen, C.O., ManLeod, A.M., Merchant, K.J.,

Showell，G.A.，Saunders，J·，Herbert，R.H.，Free dm an ， S.B· ,Harley，E.A，，醫藥化學期刊（ 1 990)，33,2690-2697 之程序進行β Α.2藉還原胺化反應合成ΑΑ-ΙΙ 式ΑΑ-ΙΙ化合物可根據反應式使用式ΑΑ-ΙΙΙ化合物還原胺化式AA-V化合物製備：Showell, GA, Saunders, J., Herbert, RH, Free dm an, SB·, Harley, EA, Journal of Medicinal Chemistry (1 990), 33, 2690-2697 for β Α.2 by reductive amination The synthesis of ruthenium-iridium ruthenium-ruthenium compounds can be prepared according to the reaction formula using a hydrazine-hydrazine compound reductively aminated AA-V compound:

此項反應係使用 Abdel-Magid，A.F.，Harris，B.D·， Maryanoff，C.A.，Synlett(1994)，81-83 所述條件進行另外當X表示CONR5R6時，胺AA -111可透過醯胺部分鍵聯於固體撐體（例如鈴克（Rink)樹脂上）。式AA-V化合物可藉下列方法之一製備： -23- 1295286This reaction was carried out using the conditions described by Abdel-Magid, AF, Harris, BD, Maryanoff, CA, Synlett (1994), 81-83. In addition, when X represents CONR5R6, the amine AA-111 can be linked through the indoleamine moiety. On a solid support (such as Rink resin). The compound of formula AA-V can be prepared by one of the following methods: -23- 1295286

(AA-V)(AA-V)

Α.2· 1 ·式AA-VI醛使用式AA-VII鹵乙酸烷酯烷化，其中X表示鹵原子，反應中使用中間烯胺例如述於 Whitessell，J.K.，Whitessell，M.A·，合成，（1983)， 517-536 或使用腙類如述於 Corey，E.J.，En ders，D.，四面體函件（ 1976 )，11-14接著進行臭氧分解反應製備。 A..2.2 ·式AA-VIII硝基酯可經由使用硫酸於甲醇處理其共軛鹼以及水解中間二甲基乙縮醛而被轉成式AA-V 化合物（Nef反應如述於1113：[，？.，\^1&1：113&，】.，四面體函件（1990)，31 ,7499-7500)。式 AA-VIII 硝基酯可知於 Horni，A.，Hubacek，I.，Hesse，M.，Helv.Chim.Acta ( 1 994 )，77,579 所述製備。 Α·2·3·酯AA-X係藉烯丙基鹵AA-IX(X】 =鹵原子）於強鹼（例如二異丙醯胺鋰）存在下烷化，接著進行未飽和酯之還原臭氧分解反應，例如述於Amruta Reddy P.， Hsiang B . C . Η . , La t i f i Τ.Ν.,ΗΠΙ M . W . , Woodwa r d K.E.,Rothman S.M. ,Ferrende1 1 i J.A,,Covey D.F., -24- 1295286 醫藥化學期刊（ 1 996 ) ,39,1 898- 1 906。Α.2·1 · Formula AA-VI aldehyde is alkylated using an alkyl halide of formula AA-VII, wherein X represents a halogen atom, and an intermediate enamine is used in the reaction, for example, as described in Whitessell, JK, Whitessell, MA, Synthesis, ( 1983), 517-536 or using anthraquinones as described in Corey, EJ, En ders, D., Tetrahedron Letter (1976), 11-14 followed by ozonolysis. A..2.2 The nitro ester of formula AA-VIII can be converted to the compound of formula AA-V by treatment of its conjugate base with sulfuric acid in methanol and hydrolysis of intermediate dimethyl acetal (Nef reaction as described in 1113: [ ,?.,\^1&1:113&,]., tetrahedral letter (1990), 31, 7499-7500). The nitroester of formula AA-VIII is known as described in Horni, A., Hubacek, I., Hesse, M., Helv. Chim. Acta (1 994), 77, 579. Α·2·3·ester AA-X is alkylated with allylic halide AA-IX (X) = halogen atom in the presence of a strong base such as lithium diisopropylamide, followed by reduction of unsaturated ester Ozonolysis reactions, for example, in Amruta Reddy P., Hsiang B. C. Η., La tifi Τ.Ν., ΗΠΙ M. W., Woodwa rd KE, Rothman SM, Ferrende 1 1 i JA,, Covey DF, - 24- 1295286 Journal of Medicinal Chemistry (1 996), 39, 1 898-1 906.

A.3.藉烷化r -鹵酯合成AA-II 式AA-II化合物其中X=CONR5R6，COOR7或CN可經由使用胺AA-III烷化7 •鹵酯AA-XI，其中X2表示鹵原子製A.3. Synthesis of AA-II by alkylating r-haloesters Compounds of formula AA-II wherein X=CONR5R6, COOR7 or CN can be alkylated via the use of amine AA-III. 7. Haloester AA-XI, wherein X2 represents a halogen atom system

此項反應係使用專利申請案GB2225322 A所述條件進行。酯AA-XI之合成述於部分B。 A.4.藉還原胺化5-羥內酯衍生物合成AA-II。式 AA-11 化合物其中 X= CONR5R6，COOR7 或 CN， (^=Η及R2a=H可根據下述使用式AA-III胺還原胺化式AA-XII之5-羥內酯製備：This reaction was carried out using the conditions described in patent application GB2225322 A. The synthesis of the ester AA-XI is described in Part B. A.4. Synthesis of AA-II by reductive amination of 5-hydroxy lactone derivatives. Compounds of formula AA-11 wherein X = CONR5R6, COOR7 or CN, (^=Η and R2a=H can be prepared according to the following 5-Ahydroxylactone of formula AA-XII by reductive amination of formula AA-III:

nh2 R1x^X (AA-II!)Nh2 R1x^X (AA-II!)

OH 式AA-XII之5-羥內酯可如Β·1·所述合成。 B J安與r ·鹵酸衍生物之縮合於式 I 中，當 A2=0，X=C0NR7R8，C00R7 或 CN 及 R2a = H 時，式AA-XIII化合物與式AA-III胺根據下式反應： -25- 1295286The 5-hydroxylactone of the OH formula AA-XII can be synthesized as described in Β·1·. Condensation of BJ An with r·halic acid derivative in Formula I, when A2=0, X=C0NR7R8, C00R7 or CN and R2a = H, the compound of formula AA-XIII reacts with the amine of formula AA-III according to the formula: -25- 1295286

R2入 X3 〇 (ΑΑ-Χ1Ι!)R2 into X3 〇 (ΑΑ-Χ1Ι!)

+ r1 x -^ R (AA-III)+ r1 x -^ R (AA-III)

其中X3表示鹵原子，較佳碘或氯原子，X4表示鹵原子，較佳氯原子。此項反應可如專利申請案GB2225322 A所述進行。· 式AA-XIII化合物可經由根據下式於鹵化劑例如TMSI， SOCl2/ZnCl2存在下打開式AA-XIV之內酯獲得（接著若有所需進行所得鹵酸（X4=OH)之鹵化反應）：Wherein X3 represents a halogen atom, preferably an iodine or a chlorine atom, and X4 represents a halogen atom, preferably a chlorine atom. This reaction can be carried out as described in the patent application GB2225322 A. · A compound of the formula AA-XIII can be obtained by opening a lactone of the formula AA-XIV in the presence of a halogenating agent such as TMSI, SOCl 2 /ZnCl 2 according to the following formula (subsequent halogenation reaction of the obtained halogen acid (X4=OH) if necessary) :

(AA-XIV) (AA-XIII) 內酯AA-XIV之開啓可根據下述程序進行：Mazzini，C.， Lebreton，J ·，Alphand，V.，Fur stoss，R.，四面體函件 ( 1 998 )，38，1 1 95 - 1 1 96 以及 01ah，G· A.，Narang，S.C.， Gupta，B.G.B.，Malhotra，R.，有機化學期刊（ 1 979 )，44， 1247 - 1 250。所得鹵酸（X4=0H)之鹵化（X4 =鹵原子）或酯化（X4 = 0Q1)可於任一種業界人士已知條件下進行式AA-XIV內酯可藉下述方法之一製備： B . 1 .有機金屬之氫化或共軛加成。化合物AA-XIV其中R2a= R4a= Η可經由氫化式AA-XV之 α，未飽和內酯獲得，或經由共軛加成式R3M(其中 Μ表示Li，Na，Mg或Zn)之有機金屬衍生物至化合物AA- -26- 1295286 χν最終藉銅（i)鹽催化獲得。(AA-XIV) (AA-XIII) The opening of the lactone AA-XIV can be carried out according to the following procedure: Mazzini, C., Lebreton, J ·, Alphand, V., Fur stoss, R., Tetrahedron Letter (1 998), 38, 1 1 95 - 1 1 96 and 01ah, G. A., Narang, SC, Gupta, BGB, Malhotra, R., Journal of Organic Chemistry (1 979), 44, 1247 - 1 250. Halogenation (X4 = halogen atom) or esterification (X4 = 0Q1) of the resulting halogen acid (X4 = 0H) can be carried out under any of the conditions known to those skilled in the art for the preparation of the formula AA-XIV lactone by one of the following methods: B. 1. Hydrogenation or conjugate addition of organometallics. Compound AA-XIV wherein R2a = R4a = Η can be obtained via α, an unsaturated lactone of the hydrogenated formula AA-XV, or an organometallic derivative via a conjugate addition formula R3M (wherein Μ represents Li, Na, Mg or Zn) Compound to compound AA- -26- 1295286 χν is finally obtained by copper (i) salt catalysis.

R3M· Cul 或 H2> PdC (R3=H) O (AA-XV)R3M·Cul or H2> PdC (R3=H) O (AA-XV)

0 0 (AA-XIV) 此種反應可根據下述程序進行：A 1 ex ak i s，A .，Be r 1 an ，J·，Be sace，Y.，四面體函件（1986)，27, 104 7-1050; Lipshutz，B.H.，Ellsworth，E.L.，Siahaan，T.，美國化學會期刊（ 1 989 )，111 ,1351- 1 358或業界人士已知之任一種方法。 B.2 丁二酸鹽衍生物之還原。於式AA-XIV中，當R2 = R2a=H時：羧酸AA-XVI之還原係根據下式於硼氫化劑，較佳LiBH4或Ca(BH4)2於醇系溶劑進行：0 0 (AA-XIV) This reaction can be carried out according to the following procedure: A 1 ex ak is, A ., Be r 1 an , J·, Be sace, Y., tetrahedral letter (1986), 27, 104 7-1050; Lipshutz, BH, Ellsworth, EL, Siahaan, T., Journal of the American Chemical Society (1 989), 111, 1351- 1 358 or any method known to those skilled in the art. B.2 Reduction of succinate derivatives. In the formula AA-XIV, when R2 = R2a = H: the reduction of the carboxylic acid AA-XVI is carried out according to the following formula in a borohydride agent, preferably LiBH4 or Ca(BH4)2 in an alcoholic solvent:

0 (AA-XVI) 其中Q3爲甲基或乙基，G1表示0或S及Q4表示氫原子或含1至4個碳原子之直鏈或分支烷基，但當G] = S時， Q4 =烷基以及當GLO時，Q4=H。 C . 內醯胺衍生物之烷化。於式I中，當A2=0及X=C00R7，式AA-XVII化合物與式 AA-XVIII化合物根據下式反應： 1295286 D^a D40 (AA-XVI) wherein Q3 is methyl or ethyl, G1 represents 0 or S and Q4 represents a hydrogen atom or a straight or branched alkyl group having 1 to 4 carbon atoms, but when G] = S, Q4 = alkyl and when GLO, Q4 = H. C. Alkylation of an intrinsic amine derivative. In formula I, when A2 = 0 and X = C00R7, the compound of formula AA-XVII reacts with the compound of formula AA-XVIII according to the formula: 1295286 D^a D4

00

其中X5表示鹵原子及M爲鹼金屬。此種反應可遵照專利申請案GB(案號15-09)之程序進行。式 AA-XVII 化合物可根據 Horni，A·，Hubacek，I.，Hesse ，M.，Helv. Chim.Acta( 1 994 )，77,579 所述程序進行。Wherein X5 represents a halogen atom and M is an alkali metal. This reaction can be carried out in accordance with the procedure of Patent Application GB (Case No. 15-09). The compound of formula AA-XVII can be carried out according to the procedure described by Horni, A., Hubacek, I., Hesse, M., Helv. Chim. Acta (1 994), 77, 579.

D . 酯衍生物之轉變。式 I 中，當 A2= 0 及 X = CONR5R6 時，R2，R2a，R3，R3a， R4及R4a基中並無任一者係藉羧基、酯或磺酸取代，對應式I酯D. Conversion of ester derivatives. In the formula I, when A2= 0 and X = CONR5R6, none of the R2, R2a, R3, R3a, R4 and R4a groups are substituted by a carboxyl group, an ester or a sulfonic acid, and the corresponding ester of the formula I

其中R7表示氫原子或含1至4個碳原子之直鏈或1支烷基，於直接氨分解反應或於習知肽合成條件下使用胺及偶合劑如氯甲酸烷酯或二環己基甲二醯亞胺轉變成胺。 E . α，0-未飽和內醯胺之還原。於式I中，當Α2=0及R2a = R3a=R4a=H時，式I化合物可經由未飽和內醯胺AA-XIX之還原獲得： -28- 1295286 • ·Wherein R7 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, and is used in a direct ammonia decomposition reaction or under conventional peptide synthesis conditions using an amine and a coupling agent such as an alkyl chloroformate or a dicyclohexyl group. Diimine is converted to an amine. E. Reduction of α,0-unsaturated decylamine. In Formula I, when Α2=0 and R2a = R3a=R4a=H, the compound of formula I can be obtained via reduction of the unsaturated internal guanamine AA-XIX: -28- 1295286 •

Ε·1 烷化 NH.Ε·1 alkylation NH.

AA-XXI R1 、X E.2 (AA-III)AA-XXI R1, X E.2 (AA-III)

ΑΑ-ΧΙΧ ΌΑΑ-ΧΙΧ Ό

還原胺化 /環化還原步驟可於業界人士已知之典型條件下進行，例如氫於Pd /C存在下或選擇性於旋光性催化劑存在下進行。當 R2，R3，或R4對低壓條件下之氫化反應例如使用Pd/C作爲催化劑之氫化反應敏感時，烯烴混合物之雙鍵可選擇性使用NaBH4M CoCl2存在下還原。化合物AA_ XIX可藉下列方法之一製備： E . 1藉烷化式AA-III化合物藉式AA-XX化合物（其中Q5表示含1 至4個碳原子之直鏈或分支烷基）烷化及環化。烷化步驟可於惰性溶劑如四氫呋喃、二甲基甲醯胺或二氯甲烷於0至50°C於第三級胺存在下進行。環化反應可自發進行或根據部分A所述方法進行。 E.2藉還原胺化式AA-XXI化合物與式AA-III化合物於還原胺化條件下反應。此反應之第一步驟可於惰性溶劑如甲苯於0至 50°C於還原劑如NaBH3CN存在下以及於酸如乙酸存在下進行。化合物AA-XXI之合成述於Bourguignon，J. J.等人，醫藥化學期刊（ 1 988 )，31，893 - 897。 -29· 1295286 « * F·支鏈之官能基轉變。 F.1酯還原成爲醇。式I化合物（其中A2=0，X=C0NR5R6或COOR7，R7爲第三烷基以及R2，R2a，R3，R3a，R4及R4a中之一者表示G2-COOQ6，G2爲鍵結或伸烷基以及Q6爲含1至4個碳原子之直鏈或分支烷基）爲對應化合物（其中R2，R2a，R3，，R3a，R4以及R4a中之一者表示G2-CH2OH)之關鍵合成中間物。此等轉變可於業界人士已知之任一種條件進行。 > F . 2醇之活化及氧化。式I化合物（其中A2 = 0及R2，R2a，R3，R3a，R4及R4a之一表示-G2 - CH2OH，G2爲鍵結或伸烷基）爲對應化合物（其中 R2，R2a，R3，R3a，R4 及 R4a2— 表示 -G2-CH2X6或-G2-CH0其中X6表示氯、溴或碘原子或式 -0-S02-Q7或-0-Q8基，Q7爲烷基或芳基以及Q8爲烷基）之關鍵合成中間物。此等轉變可於業界人士已知之任一種條件下進行。 | F.3 活化醇之親核取代。式I化合物（其中A2=0以及R2，R2a，R3，R3a，R4以及R4a 之一者表示-G2-CH2X6，G2爲鍵結或伸烷基以及X6爲氯、溴或碘原子或式-0-S02-Q7基定義如F.2)爲對應化合物（其中R2，R2a，R3，R3a，R4以及R4a之一者表示 -G2-CH2X7，其中X7表示疊氮基、鹵原子、硝基、胺基、胺基衍生物、硫衍生物及雜環基）之關鍵合成中間物。此等轉變可於業界人士已知之任一種條件下進行。 F . 4 藉醛之烯烴化反應。 -30- 1295286 ： ! 式I化合物（其中A2 = 0，X=CONR5R6或COOR7或CN以及R2， R2a，R3，R3a，R4以及R4a之一者表示- G2-CHO，G2爲鍵結或伸烷基）爲對應化合物（其中R2，R2a，R3，R3a，R4 以及R4a2—表示-G、Q9，其中Q9表示無取代之乙烯基，藉鹵原子一-或二-取代之乙烯基或烷基）之關鍵合成中間物。此等轉變可於業界人士已知之任一種條件下進行。另外，化合物-G2-CN可藉其肟與Se02反應而得自對應醛（述於 Earl，R.A/，Vol lhardt，K.P.C.，有機化學期 # 刊（1984)，49,4786)。 F.5 酸衍生物轉變成雜環。式I化合物（其中A2 = 0及R2，R2a，R3，R3a，R4以及R4a之一者表示-G2-CN或-G2-C0QIQ，G2爲鍵結或伸烷基以及Q1()爲烷氧基、芳氧基或胺基、鹵原子或胺基衍生物，但-C0Q1()非爲X)爲對應化合物[其中R2，R2a，R3，R3a ，R4以及R4a2—表示-G2-Qn其中Q11表示（i)-CO-芳基/雜環基，係經由醯氯-G2-C0C1與芳基/雜環有機金 φ 屬例如三甲基-吡啶基-錫酸酯間之鈀催化偶合反應進行或（i i )雜環基例如噻唑（Friedman，B.S.，Sparks，M.，八(1&1118，1，美國化學會期刊（1 933 )，55,22 62 或11*〇1^， Ν·，Ham ada，Y.，Sh iori，T.，四面體（1992)，48，7251 )，曙口坐（Street，L.J·，Baker，R·，Castro,J.L·，Clamber ，R.S· ，Guiblin，A.R. ，Hobbs，S.C.，Metassa， V.G.， Reeve，A.J.，Beer，M.S·，Middleniis，D.N·，Noble，A.J·， Stanton，】·Α·，Scholey，K.，Hargreaves，R.J ·，醫藥化學期刊（ 1 993 )，36，1 529 )，噚二唑（Ainsworth，C.，美 -31- 1295286 國化學會期刊（195S) ,77.1 1 48 )，四唑始於腈 (Goerl i tzer，K.，Kogt，R·，藥學論文集（1990 )，323， 847)或噻二卩坐（1^111&11丨]1&，】.1^.，1\5111^]^，(].1.，有機化學期刊（ 1984 )，49,4800)]之關鍵合成中間物。 F.6 酮衍生物之合成。式I化合物（其中A2=0以及R2，R2a，R3，R3a，R4以及 R4a 之一者表示- G2-CH = CQ12Q13 或- G2-CQ】3=CHQU，G2 爲鍵結或伸烷基，Q12及Q13爲氫原子或烷基，但其它R2， R2a，R3，R3a，R4以及R4a中並無任一者帶有對氧化條件敏感 ^ 的官能基）爲對應化合物（其中R2，R2a，R3，R3a，R4以及R“之一分別表示-G2-CO-CHQI2Q13 或-G2-CHQ13-C0-Q12)之關鍵合成中間物。此等轉變可於業界人士已知之任一種適當條件下進行，例如於02及PdCl2M惰性溶劑如二甲基甲醯胺或N-甲基吡咯啶於0至50°C進行（Bird，有機合成之過渡金屬中間物，學術出版社，紐約（ 1 967 ) ,88 - 1 1 1 )。 F.7 酮之衍生物。 φ 式 I 化合物（其中 A2=0，X=C0NR5R6 或 C00R7 以及 R2，R2a，尺3，1^，1?4以及1?“之一表示-02-00-〇14，其中02爲鍵結或伸烷基以及Q14表示烷基）爲合成（i )醇- G2-CH0H-Q14，係使用氫化劑還原（March，先進有機化學期刊，第三版，約翰威利父子公司（ 1 985 )，809 )，（ii)氟化支鏈-G2-CF2-Q14 使用述於 Lal，G.S.，Pez，G.P.， Pesaresi，R.J.，Prozonic，F.M·，化學通訊（1999)，215 -2 1 6之條件之關鍵中間物。 F.8. 炔基衍生物之合成。 -32- 1295286 式I化合物（其中A2 = 0以及R2，R2a，R3，R3a，R4以及R4a之一表示- G、C = C(X8)2，G2爲鍵結或伸烷基以及X8爲鹵原子，但其它X，Rl，R2，R2a，R3，R3a，R4以及中之任一者皆未帶有對強鹼敏感的官能基）爲對應化合物（其中R2， R2a，R3，R3a，R4 以及 R“之一表示- G2-C C-Q15，其中 Q15 爲氫、鹵原子、烷基或芳基）之關鍵合成中間物。此等轉變之進行方式： •經由鹼誘發冷-消去反應（例如1當量t-BuOK於低溫，述於Michel，P.，Rassat，A.，四面體函件 (1 999 )，40,85 79-8581 )成爲鹵炔衍生物（Q15 =鹵原子），接著藉有機金屬物種進行鹵原子之金屬催化取代（例如藉MeZnCl於CuCN.LiCl存在下進行，例如述於 M i c 〇 u i η，L .，Κ η 〇 c h e 1，P .，S y η 1 e 11 ( 1 997 )，327 )， •經由直接轉成金屬炔屬化合物（例如使用2當量正丁基鋰）以及使用烷基鹵或羰基衍生物烷化（述於匸〇117』.；[.，？11〇118，？.1^，四面體函件（1972)，36 ,3769-3772)。 F.9 烷之合成。式I化合物（其中A2 = 0以及R2，R2a，R3，R3a，R4以及R4a 之一表示-02-(：=0：-(^6(^17,02爲鍵結或伸烷基，016及（^7 爲烷基或氟）爲對應化合物（其中R2，R2a，R3，R3a，R4以及R4a 之一表示- G2-CH-CH-Q16R17)之關鍵合成中間物。還原步驟可於業界人士已知之典型條件下進行，例如使用氫於Pd/C存在下進行（March，】·，先進有機化學期刊，第三版，約翰威利父子公司（ 1 985 )，1101-1102)。 -33- 1295286 1 « F. 10 (鹵）疊氮基芳基衍生物之合成。式I化合物（其中A2 = 0，X=C0NR5R6或COOR7或CN以及 R2，R3，R4基之一爲G2-Q18其中Q18表示硝基芳基或三哄并芳基，G2爲鍵結或伸烷基）爲合成對應化合物（其中R2，R3 或R4基之一爲G-Q19，Q19爲疊氮基芳基選擇性經以一或多個鹵原子，較佳Br或F原子取代）之關鍵中間物。轉變係藉業界人士已知之任一種手段經由通過硝基或三哄烯部分還原成爲苯胺進行，選擇性引進一或多個鹵原子 (例如 Xing-teng，D.，Guo-bin， L·，合成通訊 ® ( 1 989 )，19，1261)以及藉眾所周知的方法將轉胺成疊氮。 F.11 由胺合成雜環。式I化合物（其中AkOJrzCONW或COOR7或CN以及R2 ，R3或R4基之一爲G2-Q2()，其中G2爲鍵結或伸烷基以及Q2()爲C00H，C0NH2，或CN)爲合成對應化合物（其中R2 ，R3或R4基之一爲02-_2或G2-CH2-NH2)之關鍵中間物，結果導致對應化合物（其中R2，R3及R4基之一爲G2· Het或G2-CH2-Het，此處Het爲藉氮原子鍵結的雜環， • 選擇性經以一或多個鹵原子取代）。 •於其中 X=CONR5R6，CN 或 C00R7，R7 非爲 Η 以及 R2，R3 或R4爲G2-C00H之例，轉變係經由柯堤斯（Curtius) 重排進行（例如磷疊氮酸二苯酯與三乙基胺作用以及於原位藉苄醇淬熄，述於Kim，D.，Weinreb，S.M.，有機化學期刊（ 1 978 ),43，12S)，藉業界人士已知之氫解或任何條件將胺官能基脫去保護獲得R2，R3或 R4=G2-NH2,接著藉環合成而獲得雜環如吡咯（例如述於 Jefford，C.W.，Tang，Q.，Zaslona，A.，美國化學 • 34 - 129528.6 會期刊（1991)，113，35 1 3 - 35 1 8 )，以及選擇性引進一或多個鹵原子至環（例如述於Gilow，H.M.，Burton， D.E.，有機化學期刊（1981)，46,2221 - 22 25 )。 •於其中X=CONR5R6，C00R7或CN以及R2，R3或R4基之一爲 G2-C0NH2，X 非爲 CONR5R6 或 G2-CN，X 非爲 CN 之例，轉變係經由於業界人士眾所周知之任一種條件下經由選擇性還原醯胺或腈成爲胺基甲基部分，以及環合成而獲得雜環如***進行（例如述於Mi les，R. 0 W·,Samano，V·，Robins，M.J·，美國化學會期刊（1995) ，117，595 1 - 5957 )。 F. 12 ***之合成。式I化合物（其中A2 = 0以及R2，R2a，R3，R3a，R4及R4a之基之一表示-G2-CH2N3，G2爲鍵結或伸烷基）爲對應化合物（其中1?2，1^，尺3，1^，1^及r4基之一表示_g2-CH2-***）之關鍵合成中間物。此種轉變可經由於1 ·(三苯基亞磷烷基）-酮衍生物存在下長時間加熱進行（例如述於 Hammerschmidt，F.，Polsterer，J.P.，Zbiral，合成 _ ( 1995 ) ,41 5 )。 F . 1 3光學分割。當式I化合物存在有一或多個立體產生中心，以及使用非立體選擇性合成方法時，立體異構物混合物之光學分割最佳係以一或數個步驟進行，通常涉及將非對映異構物混合物循序分離成其組成之外消旋混合物，分離方法較佳係使用於非像合相或像合相於反相模式或較佳於直接模式進行層析分離；接著爲最佳使用於像合相於反相或較佳於直接模式進行層析分離，而 -35- 1295286 將各外消旋混合物分離成爲其對映異構物之最終光學分割步驟。另外，當使用部分立體選擇性合成方法時，最終步驟係使用於非像合相或像合相於反相或較佳於直接模式進行層析分離而分離非對映異構物。某些前述中間化合物，特別式AA-II化合物，其中各個取代基具有前述定義爲新穎化合物且也構成本發明之一部分。此等新穎中間物當離去基爲醫藥可接受性诗，具有後文對式I化合物所述之相同用途。今曰發現式I化合物及其醫藥可接受性鹽可用於多種醫藥適應症。例如根據本發明之化合物可用於治療癲癇、癲癇發生、癲癇發作病症及抽搐。此等化合物也可用於治療其它神經病症包括兩極性病症、躁症、鬱症、焦慮、偏頭痛、三叉神經痛及其它神經痛、慢性疼痛、神經病變疼痛、腦缺血、心律不整、肌強直、古柯鹼濫用、中風、肌陣攣、特發性震顫以及其它運動疾病、新生兒腦出血、肌萎縮性脊側索硬化、痙攣狀態、巴金森氏病及其它退化疾病。此外，本發明化合物可用於治療支氣管氣喘、氣喘狀態及過敏性支氣管炎、氣喘症候群 '支氣管活性過高以及支氣管痙攣症候群以及過敏性及血管運動性鼻炎以及鼻結膜炎。如此，本發明於又一方面係有關式I化合物或其醫藥可接受性鹽用以製造神經及其它病症治療用藥（如前述P 特別’本發明係有關使用式I化合物或其醫藥可接受性鹽用以製造癲癇、兩極性病症、慢性疼痛或神經病變 -36· 1295286 , · 疼痛、偏頭痛、支氣管-、氣喘-或過敏性情況之治療用藥0 活性化合物之活性及性質，於試管或於活體之口服利用率及安定性於所揭示之化合物之光學異構物間有顯著變化。較佳具體實施例中，活性化合物係以對映異構物豐富形式，亦即實質爲單一異構物形式投藥。例如於式I化合物其中R]爲乙基，X爲- CONH2，A2爲氧之例，當R3爲丙基而其餘取代基爲氫時，以S(丁醯胺） R(環）對映異構物爲較佳；以及當R3爲2，2·二氟乙烯基及其餘取代基皆爲氫時，以S ( 丁醯胺），S (環）對映異構物爲較佳。本發明亦係關於一種於需要治療的哺乳動物治療癲癇、偏頭痛、兩極性病症、慢性疼痛或神經病變疼痛或支氣管-、氣喘-或過敏性病情之方法，包含對病人投予治療劑量之至少一種式I化合物或其醫藥可接受性鹽。本發明方法包含對患有前述病情或病症之哺乳類（較 • 佳人類）投予根據本發明化合物，而投藥量係足夠改善或預防該病症或病情。化合物習知係以任何適當單位劑型投藥，包括但非限於每單位劑型含有5至1 000毫克，較佳25至500毫克活性成分。「治療」一詞用於此處包括治療性處理及預防性處理。「治療」一詞表示可處理病症或病情的目前症狀。「預防」表示防止病症或病情的發生或復發。「癲癇」一詞用於此處表示腦功能障礙而以定期以及 -37- 1295280 ^ · 無法預期的癲癇發作爲特徵。發作於正常腦使用電擊或化學抽搐劑處理時誘發爲「非癲癇」發作，而無刺激證據發作者爲「癲癇發作」。「發作」一詞用於此處表示由於腦神經元族群之障礙性、協同性以及韻律性發射而造成暫時性行爲改變。「偏頭痛」一詞用於此處表示以復發性頭痛發作爲特徵的病症，頭痛之強度、頻率以及持續時間有寬廣變化。發作常見爲單側，且通常關聯有厭食、噁心、嘔吐、畏聲及/或畏光。某些病例先前有或關聯有神經及情緒障礙 t 。偏頭痛性頭痛持續時間由4小時至約72小時。國際頭痛協會（IHS，1 988年）將偏頭痛分類成有預兆性偏頭痛(典型非偏頭痛）及無預兆性偏頭痛（常見偏頭痛）作爲偏頭痛的主要類型。有預兆性偏頭痛包含頭痛期之前有特徵性視覺、感覺、語言或運動症狀。無此種症狀的頭痛稱作無預兆性偏頭痛。「兩極性病症」一詞用以表示根據精神病症診斷及統計手冊第4版（精神病症診斷及統計手冊（DSM-IV TM)，美 > 國精神科學會，華盛頓特區，1 994年）分類爲情緖障礙的病症。兩極性病症一般特徵爲自動促發重複（換言之至少兩次）發作，發作時病人的高度興奮性、活動及情緒有顯著障礙，此種障礙於某些情況爲情緒升高以及能量及活動力增加（躁症或輕躁症），而於某些情況爲情緒降低以及能量及活動的減少（鬱症）。兩極性病症於DSM -1V可分成四類（兩極性I病症，兩極性11病症，循環性精神躁鬱以及未特別歸類的兩極性病症）。「躁症發作」一詞用於此處表示情緒出現異常且持續 -38- 1295286 , » 'The reductive amination/cyclization reduction step can be carried out under typical conditions known to those skilled in the art, for example, in the presence of hydrogen in the presence of Pd/C or in the presence of an optically active catalyst. When R2, R3, or R4 is sensitive to hydrogenation under low pressure conditions such as hydrogenation using Pd/C as a catalyst, the double bond of the olefin mixture can be selectively reduced using the presence of NaBH4M CoCl2. Compound AA_XIX can be prepared by one of the following methods: E. 1 alkylation of a compound of formula AA-III by a compound of formula AA-XX wherein Q5 represents a straight or branched alkyl group having from 1 to 4 carbon atoms Cyclization. The alkylation step can be carried out in an inert solvent such as tetrahydrofuran, dimethylformamide or dichloromethane at 0 to 50 ° C in the presence of a tertiary amine. The cyclization reaction can be carried out spontaneously or according to the method described in Section A. E.2 Reductive Amination The compound of formula AA-XXI is reacted with a compound of formula AA-III under reductive amination conditions. The first step of this reaction can be carried out in an inert solvent such as toluene at 0 to 50 ° C in the presence of a reducing agent such as NaBH 3CN and in the presence of an acid such as acetic acid. The synthesis of the compound AA-XXI is described in Bourguignon, J. J. et al., J. Med. Chem. (1 988), 31, 893-897. -29· 1295286 « * F· Branching functional group transition. The F.1 ester is reduced to an alcohol. a compound of formula I (wherein A2 = 0, X = C0NR5R6 or COOR7, R7 is a third alkyl group and one of R2, R2a, R3, R3a, R4 and R4a represents G2-COOQ6, and G2 is a bond or alkylene group And Q6 is a linear or branched alkyl group having 1 to 4 carbon atoms) as a key synthetic intermediate of the corresponding compound (wherein one of R2, R2a, R3, R3a, R4 and R4a represents G2-CH2OH). These changes can be made under any of the conditions known to the industry. > F. 2 Alcohol activation and oxidation. a compound of formula I (wherein A2 = 0 and R2, R2a, R3, R3a, one of R4 and R4a represents -G2 - CH2OH, and G2 is a bonded or alkylene group) is a corresponding compound (wherein R2, R2a, R3, R3a, R4 and R4a2—representing -G2-CH2X6 or -G2-CH0 wherein X6 represents a chlorine, bromine or iodine atom or a formula -0-S02-Q7 or -0-Q8 group, Q7 is an alkyl or aryl group and Q8 is an alkyl group. ) a key synthetic intermediate. These changes can be made under any of the conditions known to the industry. | F.3 Nucleophilic substitution of activated alcohols. a compound of formula I (wherein A2 = 0 and one of R2, R2a, R3, R3a, R4 and R4a represents -G2-CH2X6, G2 is a bonded or alkylene group and X6 is a chlorine, bromine or iodine atom or formula-0 -S02-Q7 is defined as F.2) as the corresponding compound (wherein R2, R2a, R3, R3a, R4 and R4a represent -G2-CH2X7, wherein X7 represents an azide group, a halogen atom, a nitro group, an amine A key synthetic intermediate of a base, an amine derivative, a sulfur derivative, and a heterocyclic group. These changes can be made under any of the conditions known to the industry. F. 4 Alkenylation reaction by aldehyde. -30- 1295286 : ! A compound of formula I (wherein A2 = 0, X = CONR5R6 or COOR7 or CN and one of R2, R2a, R3, R3a, R4 and R4a represents - G2-CHO, G2 is a bond or alkylene The base is a corresponding compound (wherein R2, R2a, R3, R3a, R4 and R4a2 - represent -G, Q9, wherein Q9 represents an unsubstituted vinyl group, a halogen-atom- or di-substituted vinyl or alkyl group) The key synthetic intermediate. These changes can be made under any of the conditions known to the industry. Further, the compound -G2-CN can be obtained from the corresponding aldehyde by reacting it with Se02 (described in Earl, R.A/, Vollhardt, K.P.C., Organic Chemistry# (1984), 49, 4786). F.5 Conversion of an acid derivative to a heterocyclic ring. a compound of formula I (wherein A2 = 0 and R2, R2a, R3, R3a, R4 and R4a represent -G2-CN or -G2-C0QIQ, G2 is a bonded or alkylene group and Q1() is an alkoxy group An aryloxy or amine group, a halogen atom or an amine derivative, but -C0Q1() is not a corresponding compound [wherein R2, R2a, R3, R3a, R4 and R4a2 - represent -G2-Qn wherein Q11 represents (i) a -CO-aryl/heterocyclic group via a palladium catalyzed coupling reaction between chloro-G2-C0C1 and an aryl/heterocyclic organogold genus such as trimethyl-pyridyl-stannate (ii) Heterocyclic groups such as thiazole (Friedman, BS, Sparks, M., VIII (1 & 1118, 1, Journal of the American Chemical Society (1 933), 55, 22 62 or 11*〇1^, Ν·, Ham Ada, Y., Sh iori, T., tetrahedron (1992), 48, 7251), Sakaguchi (Street, LJ, Baker, R., Castro, JL, Clamber, RS, Guiblin, AR, Hobbs, SC, Metassa, VG, Reeve, AJ, Beer, MS, Middleniis, DN, Noble, AJ, Stanton, Α·, Scholey, K., Hargreaves, RJ ·, Journal of Medicinal Chemistry (1 993 ), 36,1 529 ), oxadiazole (A Insworth, C., US-31- 1295286 Journal of the National Chemical Society (195S), 77.1 1 48), tetrazole starting from nitrile (Goerl i tzer, K., Kogt, R., Proceedings of Medicine (1990), 323, 847) or thiadipine (1^111&11丨]1&,].1^.,1\5111^]^, (].1., Journal of Organic Chemistry (1984), 49, 4800)] Key synthetic intermediates. F.6 Synthesis of ketone derivatives. Compounds of formula I (where A2 = 0 and one of R2, R2a, R3, R3a, R4 and R4a represent - G2-CH = CQ12Q13 or - G2-CQ) 3=CHQU, G2 is a bond or alkyl group, Q12 and Q13 are a hydrogen atom or an alkyl group, but none of the other R2, R2a, R3, R3a, R4 and R4a are sensitive to oxidation conditions. The functional group) is a key synthetic intermediate of the corresponding compound (wherein one of R2, R2a, R3, R3a, R4 and R" represents -G2-CO-CHQI2Q13 or -G2-CHQ13-C0-Q12, respectively. These transformations can be carried out under any suitable conditions known to the industry, for example, in 02 and PdCl2M inert solvents such as dimethylformamide or N-methylpyrrolidine at 0 to 50 ° C (Bird, organic synthesis) Transition Metal Intermediates, Academic Press, New York (1 967), 88 - 1 1 1 ). F.7 Derivatives of ketones. φ Formula I compound (where A2 = 0, X = C0NR5R6 or C00R7 and R2, R2a, Ruler 3, 1^, 1?4 and 1?" means that -02-00-〇14, where 02 is a bond or Alkyl and Q14 represent an alkyl group for the synthesis of (i) alcohol-G2-CH0H-Q14, which is reduced using a hydrogenating agent (March, Journal of Advanced Organic Chemistry, Third Edition, John Wiley & Sons (1 985), 809 ), (ii) Fluorinated Branch-G2-CF2-Q14 is used as the key to the conditions described in Lal, GS, Pez, GP, Pesaresi, RJ, Prozonic, FM, Chemical Communications (1999), 215-2. Intermediate F.8. Synthesis of alkynyl derivatives. -32- 1295286 Compound of formula I (wherein A2 = 0 and one of R2, R2a, R3, R3a, R4 and R4a represents - G, C = C(X8) 2, G2 is a bond or an alkyl group and X8 is a halogen atom, but the other X, R1, R2, R2a, R3, R3a, R4 and any of them have no functional group sensitive to a strong base) Corresponding compounds (wherein one of R2, R2a, R3, R3a, R4 and R represents - G2-C C-Q15 wherein Q15 is hydrogen, a halogen atom, an alkyl group or an aryl group) is a key synthetic intermediate. How these transitions proceed: • Inducing a cold-elimination reaction via an alkali (eg 1 equivalent t-BuOK at low temperature, described in Michel, P., Rassat, A., Tetrahedron (1 999), 40, 85 79- 8581) to be a haloalkyne derivative (Q15 = a halogen atom), followed by metal-catalyzed substitution of a halogen atom by an organometallic species (for example, by using MeZnCl in the presence of CuCN.LiCl, for example, in Mic 〇ui η, L., η η 〇che 1,P .,S y η 1 e 11 ( 1 997 ), 327 ), • via direct conversion to a metal acetylenic compound (eg using 2 equivalents of n-butyl lithium) and derivatization with an alkyl halide or carbonyl group Alkylation (described in 匸〇117).; [.,?11〇118,?.1^, tetrahedron letter (1972), 36, 3769-3772). F.9 Synthesis of alkane. A compound of formula I (wherein A2 = 0 and one of R2, R2a, R3, R3a, R4 and R4a represents -02-(:=0:-(^6(^17,02 is a bonded or alkylene group, 016 and (^7 is alkyl or fluoro) is a key synthetic intermediate of the corresponding compound (wherein one of R2, R2a, R3, R3a, R4 and R4a represents -G2-CH-CH-Q16R17). The reduction step can be used by the industry. Under typical conditions, for example, using hydrogen in the presence of Pd/C (March, 】, Advanced Organic Chemistry Journal, Third Edition, John Wiley & Sons (1 985), 1101-1102) -33- 1295286 1 « Synthesis of F. 10 (halo) azidoaryl derivative. Compound of formula I (wherein A2 = 0, X = C0NR5R6 or COOR7 or CN and R2, one of R3, R4 is G2-Q18 where Q18 represents a nitroaryl or a tri-indenyl group, G2 is a bond or an alkyl group) to synthesize a corresponding compound (wherein one of the R2, R3 or R4 groups is G-Q19, and Q19 is an azidoaryl group) a key intermediate of one or more halogen atoms, preferably substituted by Br or F. The conversion is by partial reduction of the nitro group or triterpene to benzene by any means known to the industry. Carrying out the selective introduction of one or more halogen atoms (eg Xing-teng, D., Guo-bin, L., Synthetic Communications® (1 989), 19, 1261) and the transfer of amines to azide by well-known methods F.11 Synthesis of heterocyclic rings from amines. Compounds of formula I (wherein AkOJrzCONW or COOR7 or CN and one of R2, R3 or R4 groups are G2-Q2(), wherein G2 is a bond or alkylene group and Q2() is C00H, C0NH2, or CN) is a key intermediate for the synthesis of the corresponding compound (wherein one of the R2, R3 or R4 groups is 02-_2 or G2-CH2-NH2), resulting in the corresponding compound (wherein R2, R3 and R4 are One is G2·Het or G2-CH2-Het, where Het is a heterocyclic ring bonded by a nitrogen atom, • the selectivity is substituted by one or more halogen atoms) • where X=CONR5R6, CN or C00R7, R7 is not Η and R2, R3 or R4 is an example of G2-C00H, and the transformation is carried out by Curtius rearrangement (for example, the action of diphenyl phosphate and triethylamine and the in situ benzylation) Alcohol quenching, described in Kim, D., Weinreb, SM, Journal of Organic Chemistry (1 978), 43, 12S), amine functional groups by hydrogenolysis or any conditions known to the industry Deprotection affords R2, R3 or R4=G2-NH2, followed by ring synthesis to obtain a heterocycle such as pyrrole (for example, as described in Jefford, CW, Tang, Q., Zaslona, A., American Chemicals • 34 - 129528.6) 1991), 113, 35 1 3 - 35 1 8 ), and the selective introduction of one or more halogen atoms to the ring (for example, in Gilow, HM, Burton, DE, Journal of Organic Chemistry (1981), 46, 2221-22 25). • where X=CONR5R6, C00R7 or CN and R2, one of R3 or R4 is G2-C0NH2, X is not CONR5R6 or G2-CN, and X is not CN. The transformation is either known to the industry. The reaction is carried out by selectively reducing a guanamine or a nitrile to form an aminomethyl moiety, and ring synthesis to obtain a heterocyclic ring such as a triazole (for example, in Mi les, R. 0 W·, Samano, V., Robins, MJ· , American Chemical Society Journal (1995), 117, 595 1 - 5957). F. 12 Synthesis of triazole. a compound of formula I (wherein A2 = 0 and R2, R2a, R3, R3a, one of the groups of R4 and R4a represents -G2-CH2N3, and G2 is a bonded or alkylene group) is a corresponding compound (wherein 1?2, 1^) One of the 3, 1^, 1^ and r4 groups represents a key synthetic intermediate of _g2-CH2-triazole. Such a transformation can be carried out by heating for a long time in the presence of a 1,3-(triphenylphosphinyl)-one derivative (for example, as described in Hammerschmidt, F., Polsterer, JP, Zbiral, Synthesis _ (1995), 41 5 ). F. 1 3 optical segmentation. When one or more stereogenic centers are present in a compound of formula I, and the use of a non-stereoselective synthesis method, the optical separation of the mixture of stereoisomers is preferably carried out in one or several steps, usually involving the diastereoisomerization The mixture is sequentially separated into a racemic mixture of its composition, and the separation method is preferably used for non-image-phase or image-phase-in-phase mode or preferably in direct mode for chromatographic separation; The phase separation is carried out in reverse phase or preferably in direct mode for chromatographic separation, while -35-1295286 separates each racemic mixture into the final optical segmentation step of its enantiomer. Further, when a partial stereoselective synthesis method is used, the final step is carried out by separating the diastereomers by non-image-phase or image-phase-phase-inverted or better-directed mode for chromatographic separation. Some of the foregoing intermediate compounds, particularly the compounds of formula AA-II, wherein each substituent has the aforementioned definition as a novel compound and also form part of the present invention. These novel intermediates are the same as those described for the compounds of formula I when the leaving group is a pharmaceutically acceptable poem. It has now been discovered that the compounds of formula I and their pharmaceutically acceptable salts are useful in a variety of medical indications. For example, the compounds according to the invention are useful in the treatment of epilepsy, epileptogenesis, seizure disorders and convulsions. These compounds are also useful in the treatment of other neurological disorders including bipolar disorders, snoring, depression, anxiety, migraine, trigeminal neuralgia and other neuralgia, chronic pain, neuropathic pain, cerebral ischemia, arrhythmia, myotonia, Cocaine abuse, stroke, myoclonus, essential tremors and other motor diseases, neonatal cerebral hemorrhage, amyotrophic lateral sclerosis, spasticity, Parkinson's disease and other degenerative diseases. Furthermore, the compounds of the present invention are useful for the treatment of bronchial asthma, asthmatic and allergic bronchitis, asthmatic syndrome, bronchial hyperactivity and bronchospasm syndrome, as well as allergic and vasomotor rhinitis and rhinoconjunctivitis. Thus, in another aspect, the invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the manufacture of a therapeutic agent for neurological and other disorders (such as the aforementioned P, in particular, the invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof For the treatment of epilepsy, bipolar disorder, chronic pain or neuropathy -36· 1295286 , · Pain, migraine, bronchial -, asthma - or allergic conditions of treatment 0 The activity and properties of the active compound, in vitro or in vivo The oral availability and stability vary significantly between the optical isomers of the disclosed compounds. In preferred embodiments, the active compound is in enantiomerically enriched form, i.e., substantially as a single isomer form. For example, in the case of a compound of formula I wherein R] is ethyl, X is -CONH2, and A2 is oxygen, when R3 is propyl and the remaining substituents are hydrogen, S(butyramine) R(ring) pair Preferably, the imide is preferred; and when R3 is 2,2.difluorovinyl and the remaining substituents are all hydrogen, the S (butanamine), S (cyclo) enantiomer is preferred. The invention also relates to a need for treatment Mammalian for treating epilepsy, migraine, bipolar disorder, chronic pain or neuropathic pain or bronchial-, asthmatic or allergic condition, comprising administering to a patient a therapeutic dose of at least one compound of formula I or a pharmaceutically acceptable amount thereof Sexual salt. The method of the invention comprises administering a compound according to the invention to a mammal (more preferably a human) having the aforementioned condition or disorder, and the amount administered is sufficient to ameliorate or prevent the condition or condition. The compound is conventionally in any suitable unit. Dosage form administration, including but not limited to 5 to 1000 mg, preferably 25 to 500 mg of active ingredient per unit dosage form. The term "treatment" is used herein to include therapeutic treatment and prophylactic treatment. It can treat the current symptoms of a condition or condition. "Prevention" means preventing the occurrence or recurrence of a disease or condition. The term "epilepsy" is used here to mean a brain dysfunction with regular as well as -37-1295280 ^ · Unexpected seizures As a feature, when a normal brain is treated with an electric shock or a chemical convulsion, it is induced as a "non-epileptic" episode without stimulation. According to the author, “seizures.” The term “seizures” is used here to mean temporary behavioral changes due to impedimental, synergistic, and rhythmic emissions of the brain neuron population. The term “migraine” is used here. It refers to a condition characterized by recurrent headache, and the intensity, frequency, and duration of headache vary widely. Attacks are often unilateral and are often associated with anorexia, nausea, vomiting, phobia, and/or photophobia. The case was previously associated with or associated with neurological and emotional disorders. The duration of migraine headaches ranged from 4 hours to approximately 72 hours. The International Headache Association (IHS, 1 988) classified migraine as having a premature migraine (typically non-biased) Headache) and no premeditative migraine (common migraine) as the main type of migraine. Predictive migraine includes characteristic visual, sensory, linguistic or motor symptoms before the headache period. A headache without such symptoms is called a no-pregnancy migraine. The term "bipolar disorder" is used to refer to the 4th edition of the Diagnostic and Statistical Manual of Psychiatric Disorders (DSM-IV TM, US > National Psychiatric Association, Washington, DC, 994) A condition that is a mood disorder. Bipolar disorders are generally characterized by an automatic triggering of repeated (at least twice) episodes of a patient's high excitability, activity, and mood that are associated with increased mood and increased energy and mobility in some cases. (sickness or snoring), and in some cases a decrease in mood and a decrease in energy and activity (depression). Bipolar disorders can be classified into four classes in DSM-1V (bipolar I disorder, bipolar 11 disorder, circulatory encephalopathy, and bipolar disorder not specifically categorized). The term "sickness episode" is used here to indicate an abnormal mood and persistence -38 - 1295286 , » '

CiCi

C 性升高、擴張或易受刺激且帶有強迫性言語以及精神運動激躁等症狀的時期。「輕躁症」一詞用於此處表示較非極端的躁症發作，嚴重程度較低。「重大鬱症發作」一詞用於此處表示持續時間至少2 週，情緒抑鬱或幾乎對所有的活動皆喪失興趣或愉快，且帶有注意力受損以及精神運動遲滯現象。「混合型發作」一詞用於此處表示一段時間（至少持續 1週）其發作標準符合躁症發作以及幾乎每日皆符合重大 > 鬱症發作。「慢性疼痛」一詞用於此處表示疾病的進展與急性疼痛不同的情況。習知定義爲持續超過正常癒合時間的疼痛，當個人感覺該疼痛將於可預見的未來持續經歷其部分生命時也可視爲慢性疼痛。可能大部分慢性疼痛症候群涉及神經病變成分，其通常比急性軀體疼痛更難處理。「神經病變疼痛」——詞用於此處表示因神經病理變化誘發的疼痛，表示存在有有害刺激，當並無任何可辨識 ► 的刺激存在時則造成一種錯誤的疼痛感。換言之，顯然疼痛系統被打開而無法關閉。式I化合物或其醫藥可接受性鹽作爲抗抽搐劑的活性可於聽覺產生發作模式測定。本試驗目的係利用對聲音敏感的小鼠（帶有反射發作之動物模式）藉聽覺誘發發作而評估化合物之抗抽搐能力。此種原發性全身性癲癇中，癲癇的發作並無電或化學刺激而誘發，發作的類別至少有部分之臨床現象係類似人類的發作（Los che r W . & Schmidt D·，癲癇硏究（ 1 998 )，2，ρ· 145-181 ;Buchhal ter -39- 1295286 J .R·，癲癇（ 1 993 )，34，S31-S41)。式I化合物所得結果指示具有強力藥效。另一項指示可能的抗抽搐活性之檢定分析係結合至左堤拉西坦結合位置（LBS)，容後詳述。式I化合物或其醫藥可接受性鹽用於慢性神經病變疼痛之活性可於動物模式測定。例如慢性神經病變疼痛可經由於大鼠藉藥理誘發糖尿病而模式化。此種模式中，動物對有害刺激顯示漸進式痛覺反應過高，此種症狀常 I 見於帶有疼痛性周邊神經病變病人（Courteix C，A period in which C is elevated, dilated, or susceptible to irritation and has symptoms such as compulsive speech and mental motor irritation. The term "palatosis" is used here to mean a less extreme snoring episode with a lower severity. The term "significant depression" is used here to mean a duration of at least 2 weeks, emotional depression or loss of interest or pleasure for almost all activities, with impaired attention and mental retardation. The term "mixed seizures" is used here to mean a period of time (at least 1 week) whose seizure criteria are consistent with snoring episodes and almost daily compliance with major > seizures. The term "chronic pain" is used here to indicate a condition in which the progression of the disease is different from acute pain. Conventional definition is a pain that lasts longer than normal healing time and can also be considered chronic pain when the individual feels that the pain will continue to experience part of his life for the foreseeable future. It is likely that most chronic pain syndromes involve neuropathic components, which are usually more difficult to treat than acute physical pain. "Neuropathic Pain" - The term used herein to refer to pain induced by neuropathological changes indicates the presence of noxious stimuli that cause a false pain when there is no identifiable stimulus. In other words, it is clear that the pain system is turned on and cannot be turned off. The activity of a compound of formula I or a pharmaceutically acceptable salt thereof as an anticonvulsant can be measured in an auditory seizure pattern. The purpose of this study was to evaluate the anticonvulsing ability of a compound by using a sound-sensitive mouse (an animal model with reflex episodes) by auditory evoked episodes. In this type of primary systemic epilepsy, seizures are not induced by electrical or chemical stimuli, and at least some of the clinical manifestations of the seizures are similar to human seizures (Los che r W . & Schmidt D·, epilepsy studies) (1 998 ), 2, ρ· 145-181; Buchhal ter -39-1295286 J.R., epilepsy (1 993), 34, S31-S41). The results obtained with the compounds of formula I indicate potent pharmacological effects. Another assay that indicates possible anti-convulsive activity is coupled to the left-tiracetam binding site (LBS), which is detailed later. The activity of a compound of formula I or a pharmaceutically acceptable salt thereof for use in chronic neuropathic pain can be determined in an animal model. For example, chronic neuropathic pain can be modeled by the rat's pharmacologically induced diabetes. In this model, animals show progressive hyperalgesia to noxious stimuli, which is often seen in patients with painful peripheral neuropathy (Courteix C,

Eschalier，A.及 Lavarenne J.，疼痛，53，（1993)81·88) 。此種模式具有高度藥理預測能力（Courteix C，Bardin Μ . , Chan t e 1 auze C . , Lava r enne J 及 Es cha 1 i e r，A ·，疼痛，57(1994)153-160)。式I化合物或其醫藥可接受性鹽用於兩極性病症的活性可於動物模式評估。例如兩極性病症特別躁症可於大鼠藉藥理誘發活性過高且評估其於Y字形迷宮的表現而模式化。此種情況下，用於人類有效的治療劑例如鋰及凡 • 普酸鈉（Sod i um va 1 pr oa t e )可降低活動性宄進，如此證實該模式具有預測性（Cao B.J .，及Peng N;A;歐洲藥理期刊 237( 1 993 ) 1 77 - 1 81.Vale A.L.及 Ratcliffe F·精神藥理學，9 1 ( 1 987 ) 352- 355 )。式I化合物或其醫藥可接受性鹽可能之抗氣喘性質可於過敏性氣喘的動物模式試驗，該模式中對卵白蛋白敏化的天竺鼠使用抗原挑釁且硏究肺功能變化以及呼吸道的發炎細胞含量（Yamada等人（ 1 992 )於天竺鼠之晚期過敏症狀反應之動物模式之發展以及抗過敏藥物之效果。 -40- 129528,6 r « ***素，43:507 - 52 1 )。前述任一種適應症的活性當然可以業界人士已知方式對特定適應症及/或對臨床試驗的設計進行適當臨床試驗。用於治療疾病，式I化合物或其醫藥可接受性鹽可以有效每日劑量且以醫藥組合物形式投藥。因此本發明之另一具體實施例係有關一種醫藥組合物 ’包含有效量之式I化合物或其醫藥可接受性鹽組合醫藥 > 可接受性稀釋劑或載劑。爲了製備根據本發明之醫藥組合物，一或多種式I化合物或其醫藥可接受性鹽根據業界人士習知的醫藥混合技術混合醫藥稀釋劑或載劑。適當稀釋劑及載劑依據投藥途徑例如經口、直腸或腸外而定可呈寬廣多變的形式。包含根據本發明之化合物之醫藥組合物例如可經口或腸外亦即靜脈、肌肉或皮下、鞘內投藥。適合經口投藥之藥物可爲固體或液體例如呈錠劑、九 > 劑、糖衣錠、明膠膠囊劑、溶液劑、糖漿劑等劑型。爲達此項目的，活性成分混合惰性稀釋劑或無毒醫藥可接受性載劑例如澱粉或乳糖。選擇性地，醫藥組合物也可含有黏結劑例如微晶纖維素、西黃耆膠或明膠、崩散劑如褐藻酸、潤滑劑如硬脂酸鎂、滑動劑如膠體二氧化矽、甜味劑如蔗糖或糖精或著色劑或矯味劑如薄荷腦或水楊酸甲酯。本發明也包含可以控制方式釋放活性物質之組合物。可用於腸外投藥之醫藥組合物可呈習知劑型例如水性或 -41- 1295286 . 油性溶液劑或懸浮液劑通常含於安瓿、拋棄式注射器、玻璃或塑膠小瓶或輸注容器。除了活性成分外，此等溶液劑或懸浮液劑也可選擇性含有無菌稀釋劑例如注射用水、生理食鹽水、油、聚乙二醇類、甘油、丙二醇或其它合成溶劑、抗菌劑如苄醇，抗氧化劑如抗壞血酸或亞硫酸氫鈉，螯合劑如伸乙基二胺-四乙酸，緩衝劑如乙酸鹽類，檸檬酸鹽類或磷酸鹽類以及滲透壓調節劑例如氯化鈉或葡萄糖。 > 此等醫藥劑型係使用藥師例行使用的方法製備。活性成分於醫藥組合物之含量可落入寬廣濃度範圍且依據多項因素而定，例如病人姓別、年齡、體重以及醫療病情，及投藥方法。如此，式I化合物於口服投藥組合物之含量相對於組合物總重可爲至少0.5%重量比而高達 80%重量比。根據本發明也發現式I化合物或其醫藥可接受性鹽可單獨或組合其它醫藥活性成分投藥。此等可與本發明化合物合倂使用之額外化合物之非限制性實例有抗痙攣劑 >(例如北克芬（baclofen))，止吐劑，抗躁症情緒穩定劑，止痛劑（例如阿斯匹林，衣布普芬（i b u p r 〇 f e η )，帕拉西特莫（parace t amol ))，麻藥性止痛劑，局部麻醉劑，雅片類止痛劑，鋰鹽，抗鬱劑（例如米安西林（mianserin) ，浮羅撒汀（fluoxetine) ，翠兹冬（trazpdone)) ，參環抗鬱劑（例如衣米普拉明（imipramine)，迪斯普拉明（des i pr ami ne ))，抗抽搐劑（例如凡普酸（va 1 ρ ι·ο i c acid)，卡巴瑪兹平（carbamazepine)，芬尼通（？1^11：/-t o i η ))，抗精神病劑（例如麗斯皮瑞冬（r i spe r i done )， -42- 1 129528.6 i * 賀羅皮瑞多（h a I op e r i do l·))，神經作用劑，苯并二氮雜卓類（例如迪兹潘（d i a z e p a m)，可羅那兹潘（c 1 ο n a z e p a m )) ’吩噻哄類（例如可羅普瑪晶（chlorpromazine))，釣通道遮斷劑，安非它命，可羅尼定（clonidine)，力度卡因 (lidocaine)，米西勒汀（mexiletine)，卡撒辛 (capsaicin)，咖啡因，魁堤亞平（quetiapine)，血管張力素拮抗劑，/3-遮斷劑，抗心律不整劑，翠普堂 (t r i p t a n s )，麥角衍生物® > 根據本發明特別令人感興趣者爲至少一種式I化合物或其醫藥可接受性鹽與至少一種可誘生GABAa受體媒介的神經抑制作用之化合物的組合。式I化合物對誘生藉GABAa 受體媒介之神經抑制作用的化合物具有潛在效果，於許多病例可於較少不良反應風險下獲得病情及病症的有效' 治療。誘生藉GABAa受體媒介的神經抑制作用之化合物例如包括下列：苯并二氮雜萆類，巴比妥酸鹽類，類固醇類及抗抽搐劑類例如凡普酸鹽、微加巴春（viagabatrine) > ，堤加賓（tiagabine)或其醫藥可接受性鹽。苯并二氮雜萆類包括1，4苯并二氮雜罩類例如迪茲播及可羅那茲潘以及1，5苯并二氮雜萆類例如可羅巴戰 (c lob a z am)。較佳化合物爲可羅那茲潘。巴比妥酸鹽類包括苯基巴比妥（Phenoba r b i t a 1 )以及戊基巴比妥（Pentobarbital)。較佳化合物爲苯基巴比妥。類固醇類包括腎上腺皮質激素例如堤叉可撒泰 (tetracosactide)乙酸鹽等。抗抽搐劑包括乙內醯脲類（芬尼通，衣索通（etho to in) -43- 12.95286 , » · 等）’卩亏嗤11定類（翠米撒代翁（trimethadione)等），丁二醯亞fee類（衣索撒西麥（ethosuximide)等），芬那西麥類 (phenacemides)(芬那西麥，亞西爾芬內圖（acetylphene-turide)等），磺醯胺類（蘇森（suithiame)，亞斯妥卓麥 (&061〇32〇1&11^(^)等），胺基丁酸（例如7-胺基-)5-羥丁酸等），凡普酸鈉及衍生物，卡巴瑪茲平等。較佳化合物包括凡普酸，凡普麥（valpromide)，凡普酸鹽皮瓦西爾（Pivoxil)，凡普酸鈉，半凡普酸鈉，代 > 凡普克斯（divalproex)，可羅那茲平，苯基巴比妥，微加巴春，堤如賓。用於較佳口服組合物，每日劑量爲5至1000毫克（mg) 式I化合物之範圍。腸外投藥用組合物中，式I化合物之存在量相對於組合物總重至少爲0.5%重量比而可高達33%重量比。至於較佳腸外組合物，劑量單位係於.5毫克至1000毫克式I化合物之範圍。每曰劑量落入寬廣式I化合物之劑量單位範圍且通常 > 爲5至1000毫克。但須瞭解特定劑量可依據個別需求由醫師的裁決調整配合特定病例。本發明之醫藥組合物之活性成分（化合物I以及可誘生藉GABAa受體媒介的神經抑制作用之化合物）之用量將隨欲投藥之哺乳動物、欲治療的疾病、其它活性劑等決定。通常對指定組合物及劑型而言，誘生GABAa受體媒介之神經抑制作用之化合物用量以及化合物I用量可方便採用例行程序決定。下列實例僅供舉例說明而非限制性，也絕非視爲囿限 -44- 1295286 r ' 本發明之範圍。業界人士瞭解可未悖離本發明之精髓及範圍對下列實例做出例行的變化及修改。除非於實例中另行載明，否則化合物之特徵係根據下列方法測定： NMR光譜係記錄於布魯克（BRUKER)AC 250傅麗葉轉換NMR 分光計配合亞斯沛克（Aspect)3000電腦以及5毫米1H/nC 雙重探頭，或布魯克DRX 400 FT NMR配備有SG靛電腦以及5毫米反向幾何4/13(：/15!^三重探頭。化合物係於DMSO- > d6(或CDC13)溶液於探頭溫度313度K以及濃度20毫克/ 毫升硏究。儀器鎖定於DMSO-d6(或CDC13)氘信號。化學位移係以距離作爲內部標準的TMS下野之ppm表示。於LC/MS模式之質譜測量進行如後： HPLC條件分析係使用瓦特氏（WATERS )艾麗恩斯（A 1 1 i an c e ) HPLC 系統架設有英那西爾（INERTSIL)ODS 3，DP 5微米，250 Χ4·6^米管柱。梯度係由 100%溶劑 Α(乙腈，水 TFA(10/90/0.1，v/v/v)) > 至 100%溶劑 B(乙腈，水，TFA(90/10/0.1，v/v/v))於 7 分鐘內變化，於100% B維持4分鐘。流速設定爲2.5毫升/分鐘恰在API來源之前使用10分之一分岔。層析術係於3(TC進行。 MS條件試樣溶解於乙膪/水70/ 30 v/v，濃度爲約250 //gr/ml 。API光譜術（+或·）係使用菲尼根（FINNIGAN)(美國加州聖荷西）LCQ離子捕捉質譜儀進行。APCI來源於450°C操作，毛細管加熱器於160°C操作。ESI來源係於3.5千伏 -45- 1295286 . » * 操作及毛細管加熱器於210°C操作。於DIP / EI模式之質譜測量進行如下··試樣係藉5分鐘將探針由50°C加熱至250°C而氣化EI (電子衝擊)光譜係使用菲尼根（美國加州聖荷西）TSQ 700銜接四極質譜儀記錄。來源溫度設定於150°C。比旋係記錄於伯京艾瑪（Perkin-Elmer)MC241或341極化計。旋轉角度係於25°C於1%甲醇溶液記錄。對某些分子由於溶解度問題而溶劑係使用二氯甲烷或DMSO。 φ 水含量係使用美充姆（Me t r ohm)微庫侖計量卡爾費雪 (K a r 1 F i s c h e r)滴定計測定。製備性層析術分離係於矽膠60莫克（Merck)進行，粒徑15-40微米，參考編號1.15111.9025，使用場房內修改糾賓伊凡（Jobin Yvon)型軸向壓縮管柱（內徑80毫米），流速70至150毫升/分鐘進行。矽膠及溶劑混合物用量係如個別程序所述。. 製備性像合層析分離係於代西爾（DAICEL)開羅帕克 (Chiralpak)AD 20微米，100*500毫米管柱使用場房內 # 建儀器以各種低碳醇與C5至C8直鏈、分支或環狀烷於土 3 50毫升/分鐘進行。溶劑混合物係如個別程序所述。熔點係於布奇（Buch i ) 53 5托妥利（To t ο 1 i )型熔化計測量，且未經校正或於伯京艾瑪DSC 7藉起點溫度校正。粉未X光繞射圖樣係於周圍溫度及氣氛，於電腦控制菲利浦PW 1710配備有PW3710 mpd控制單元使用單一色層分析儀，Cu Κα輻射（試管於40千伏，35毫安操作）以及閃爍計數器獲得。資料係於連續掃描模式使用掃描速度0.02 2 0 / s於4度至50度20角度範圍收集。 -46 - 129528.6Eschalier, A. and Lavarenne J., Pain, 53, (1993) 81·88). This model has a high degree of pharmacological predictive power (Courteix C, Bardin Μ . , Chan t e 1 auze C . , Lava r enne J and Es cha 1 i e r, A ·, Pain, 57 (1994) 153-160). The activity of a compound of formula I or a pharmaceutically acceptable salt thereof for use in a bipolar disorder can be assessed in an animal model. For example, a bipolar disorder with special hysteria can be modeled by the over-activity of the hamstring in the rat and its assessment of the performance of the Y-shaped maze. In this case, therapeutic agents for humans such as lithium and sodium sulphate (Sod i um va 1 pr oa te ) can reduce hyperactivity, thus confirming that the model is predictive (Cao BJ ., and Peng N; A; European Journal of Pharmacology 237 (1 993) 1 77 - 1 81. Vale AL and Ratcliffe F. Psychopharmacology, 9 1 (1 987) 352-355). The anti-asthmatic properties of a compound of formula I or a pharmaceutically acceptable salt thereof may be tested in an animal model of allergic asthma, in which ovale-sensitized guinea pigs are challenged with antigen and examined for changes in lung function and inflammatory cells in the respiratory tract. (Yamada et al. (1 992) developed an animal model of allergic symptoms in guinea pigs and the effects of antiallergic drugs. -40- 129528, 6 r « prostaglandins, 43:507 - 52 1 ). The activity of any of the aforementioned indications can of course be appropriately clinically tested for specific indications and/or for the design of clinical trials in a manner known to those skilled in the art. For use in the treatment of a disease, a compound of formula I or a pharmaceutically acceptable salt thereof can be administered in an effective daily dose and in the form of a pharmaceutical composition. Thus, another embodiment of the present invention relates to a pharmaceutical composition comprising an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof in combination with an acceptable diluent or carrier. To prepare a pharmaceutical composition according to the present invention, one or more compounds of formula I or a pharmaceutically acceptable salt thereof are mixed with a pharmaceutical diluent or carrier according to pharmaceutical mixing techniques well known to those skilled in the art. Suitable diluents and carriers may be in a broad and varied form depending on the route of administration, for example, orally, rectally or parenterally. The pharmaceutical composition comprising the compound according to the invention can be administered, for example, orally or parenterally, i.e. intravenously, intramuscularly or subcutaneously, intrathecally. The drug suitable for oral administration may be a solid or a liquid such as a tablet, a ninth package, a sugar-coated tablet, a gelatin capsule, a solution, a syrup, or the like. For this purpose, the active ingredient is mixed with an inert diluent or a non-toxic pharmaceutically acceptable carrier such as starch or lactose. Alternatively, the pharmaceutical composition may also contain a binder such as microcrystalline cellulose, tragacanth or gelatin, a disintegrating agent such as alginic acid, a lubricant such as magnesium stearate, a slip agent such as colloidal cerium oxide, or a sweetener. Such as sucrose or saccharin or a coloring or flavoring agent such as menthol or methyl salicylate. The invention also encompasses compositions which release the active substance in a controlled manner. Pharmaceutical compositions which can be used for parenteral administration may be in the form of conventional formulations such as aqueous or -41 to 1295286. Oily solutions or suspensions are usually contained in ampoules, disposable syringes, glass or plastic vials or infusion containers. These solutions or suspensions may optionally contain sterile diluents such as water for injection, physiological saline, oil, polyethylene glycols, glycerol, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol, in addition to the active ingredient. An antioxidant such as ascorbic acid or sodium hydrogen sulfite, a chelating agent such as ethyldiamine-tetraacetic acid, a buffer such as an acetate, a citrate or a phosphate, and an osmotic pressure adjusting agent such as sodium chloride or glucose. > These pharmaceutical dosage forms are prepared by routine use by pharmacists. The amount of the active ingredient in the pharmaceutical composition may fall within a broad range of concentrations and may depend on a number of factors, such as the patient's family name, age, weight, and medical condition, and the method of administration. Thus, the level of the compound of formula I in the oral administration composition can be at least 0.5% by weight and up to 80% by weight relative to the total weight of the composition. It has also been found in accordance with the invention that the compound of formula I or a pharmaceutically acceptable salt thereof can be administered alone or in combination with other pharmaceutically active ingredients. Non-limiting examples of such additional compounds which may be combined with the compounds of the present invention are anti-caries agents > (e.g., baclofen), antiemetics, anti-caries mood stabilizers, analgesics (e.g. Sprin, ibupr 〇fe η, parace t amol, anesthetic analgesic, local anesthetic, flavonoid analgesic, lithium salt, anti-depressant (eg rice Mianserin, fluoxetine, trazpdone, ginseng antidepressant (eg imipramine, des i pr ami ne ) ), anti-convulsant (such as va 1 ρ ι·ο ic acid, carbamazepine, fentanyl (?1^11:/-toi η)), antipsychotic (such as Ri spe ri done, -42- 1 129528.6 i * ha I op eri do l·), neurological agents, benzodiazepines (eg Dizzi) Diazepam, c 1 ο nazepam ) phenothiazines (eg chlorpromazine) ), fishing channel interrupting agent, amphetamine, clonidine, lidocaine, mexiletine, capsaicin, caffeine, quetiapine (quetiapine), angiotensin antagonist, /3-interrupting agent, antiarrhythmic agent, triptans, ergot derivative® > particularly interesting according to the invention is at least one formula I A combination of a compound or a pharmaceutically acceptable salt thereof and at least one compound that induces a neuroinhibitory effect of a GABAa receptor vector. The compounds of formula I have potential effects on compounds that induce neuroinhibition by GABAa receptor mediators, and in many cases, effective treatment of conditions and conditions can be achieved with less risk of adverse reactions. Compounds that induce neuroinhibition by GABAa receptor media include, for example, the following: benzodiazepines, barbiturates, steroids, and anticonvulsants such as fenpropionate, micro-gaibachun ( Viagabatrine) >, tiagabine or its pharmaceutically acceptable salt. Benzodiazepines include 1,4 benzodiazepines such as dized and konaznapan and 1,5 benzodiazepines such as c lob az am . A preferred compound is ronnazap. Barbiturates include Phenoba r b i t a 1 and Pentobarbital. A preferred compound is phenyl barbital. Steroids include adrenocortical hormones such as tetracosactide acetate and the like. Anti-twitching agents include beta-urea urea (fenidon, etho to in -43- 12.95286, » ·, etc.) '卩 deficit 嗤 11 categorization (trimethadione, etc.), Ding Erya Fee (ethosuximide, etc.), phenacemides (phenacetamides, acetylphene-turide, etc.), sulfonamides (suithiame, Astor Zhuo Mai (&061〇32〇1&11^(^), etc.), aminobutyric acid (eg 7-amino-) 5-hydroxybutyric acid, etc.) Sodium citrate and derivatives, Kabamaz equal. Preferred compounds include phenpromide, valpromide, Pivoxil, sodium phenoxide, sodium sulfamate, and > divalproex, Ronazpin, phenyl barbital, micro-gaibachun, embankment. For use in a preferred oral composition, the daily dosage is from 5 to 1000 milligrams (mg) of the compound of formula I. In parenteral pharmaceutical compositions, the compound of formula I is present in an amount of at least 0.5% by weight and up to 33% by weight, based on the total weight of the composition. For preferred parenteral compositions, the dosage unit will range from .5 mg to 1000 mg of the compound of formula I. Each dose falls within the broad range of dosage units of the compound of formula I and is typically > from 5 to 1000 mg. However, it is important to understand that a particular dose can be adjusted to match a particular case by a physician's decision based on individual needs. The active ingredient of the pharmaceutical composition of the present invention (compound I and a compound which induces neuroleptic action by the GABAa receptor vector) will be determined depending on the mammal to be administered, the disease to be treated, other active agents and the like. Generally, for a given composition and dosage form, the amount of the compound that induces the inhibition of the GABAa receptor vector and the amount of Compound I can be conveniently determined by routine procedures. The following examples are intended to be illustrative and not limiting, and are not to be construed as limiting the scope of the invention. Those skilled in the art will appreciate that the following examples can be routinely changed and modified without departing from the spirit and scope of the invention. Unless otherwise stated in the examples, the characteristics of the compounds were determined according to the following method: NMR spectra were recorded on a Bruker AC 250 Fourier transform NMR spectrometer with an Assex 3000 computer and 5 mm 1H/nC Dual probe, or Bruker DRX 400 FT NMR equipped with SG靛 computer and 5 mm reverse geometry 4/13 (:/15!^ triple probe. Compound in DMSO- > d6 (or CDC13) solution at probe temperature 313 ° K and the concentration of 20 mg / ml. The instrument is locked to the DMSO-d6 (or CDC13) 氘 signal. The chemical shift is expressed as the ppm of the TMS field in the distance as the internal standard. The mass spectrometry in the LC/MS mode is performed as follows: HPLC condition analysis was performed using an WATERS A 1 1 i an ce HPLC system with INERTSIL ODS 3, DP 5 μm, 250 Χ 4·6 ^ m column. Made from 100% solvent hydrazine (acetonitrile, water TFA (10/90/0.1, v/v/v)) > to 100% solvent B (acetonitrile, water, TFA (90/10/0.1, v/v/v )) Changed within 7 minutes and maintained at 100% B for 4 minutes. The flow rate was set to 2.5 ml/min just before the API source. One-point bifurcation. Chromatography is performed at 3 (TC). MS condition sample is dissolved in acetonitrile/water 70/30 v/v at a concentration of about 250 //gr/ml. API spectroscopy (+ or · The system was performed using FINNIGAN (San Jose, Calif.) LCQ ion trap mass spectrometer. APCI was operated at 450 ° C, capillary heater was operated at 160 ° C. ESI source was at 3.5 kV -45- 1295286 . » * Operation and capillary heater operation at 210 ° C. Mass spectrometry in DIP / EI mode is as follows: · The sample is heated from 50 ° C to 250 ° C for 5 minutes to gasify EI ( The electron impact) spectroscopy was recorded using a Fingen (San Jose, Calif.) TSQ 700 coupled quadrupole mass spectrometer. The source temperature was set at 150 ° C. The specific rotation was recorded on a Perkin-Elmer MC241 or 341 pole. The rotation angle was recorded in a 1% methanol solution at 25 ° C. For some molecules, the solvent used was dichloromethane or DMSO due to solubility problems. φ Water content was measured using Me tr ohm microcoulomb Determination by Karl Fischer titration. Preparative chromatography is based on silicone 60 gram (Merc) k) Carrying, particle size 15-40 microns, reference number 1.15111.9025, using the modified room in the room to modify the Jobin Yvon axial compression column (inner diameter 80 mm), flow rate 70 to 150 ml / min get on. The amount of silicone and solvent mixture is as described in the individual procedures. Preparative image chromatography separation is based on Dairyl (DAICEL) Chiralpak AD 20 micron, 100*500 mm column used in the field. Built with various low alcohols and C5 to C8 linear, Branch or cyclic alkane is carried out in soil 3 50 ml/min. The solvent mixture is as described in the individual procedures. The melting point is measured by a Buch i 53 5 Tot ο 1 i type melt meter and is uncorrected or corrected by the starting temperature at the Bering Emma DSC 7. The powder is not X-ray diffraction pattern is attached to the ambient temperature and atmosphere. The computer controlled Phillips PW 1710 is equipped with PW3710 mpd control unit using a single color layer analyzer, Cu Κα radiation (tubes at 40 kV, 35 mA operation) And the scintillation counter is obtained. Data were collected in continuous scan mode using a scan speed of 0.02 2 0 / s at 4 to 50 degrees 20 angular range. -46 - 129528.6

實例中使用下列縮寫： AcOE t 乙酸乙酯 AcOH 乙酸 BuLi 正丁基鋰 η -Bu3P 三-正丁基膦 CICOOEt 或 ClC02Et 氯甲酸乙酯 DCE 1，2 -二氯乙烷 DIC 二異丙基甲二醯亞胺 DMSO 二甲亞楓 DSC 差異掃描熱量計量術 DMF * N，N -二甲基甲醯胺 Et3N 三乙基胺 Et 20 *** EtOH 乙醇 FMOC 芴基甲氧羰基 LDA 二異丙醯胺鋰 MeCOCl 乙醯氯 MeCN 乙腈 MeOH 甲醇 MTBE 甲基第三丁基醚 NMP N-甲基吡咯啶酮 PhMe 甲苯 PrepLC 製備性液相層析術 i-Pr2〇二異丙基醚 i-PrOH 異丙醇 TFA 三氟乙酸 -47- 1295286 THF 四氫呋喃 TMOF 原甲酸三甲酯 TMSCI 氯三甲基矽烷 TMSI 碘三甲基矽烷除非於實例中另行載明，否則化合物係以自由態（非鹽）形式獲得。【實施方式】實例1 ·藉醛酯之還原胺化反應合成4 -取代2 -氧基-吡咯啶丁醯胺。 1.1. 3-取代-4-氧基-丁酸酯之合成 1 . 1 . 1 .途徑A :藉烯胺類之烷化反應 5, 5-二甲基-3-甲醯基-己酸甲酯361之合成可表示爲The following abbreviations are used in the examples: AcOE t ethyl acetate AcOH acetic acid BuLi n-butyllithium η -Bu3P tri-n-butylphosphine CICOOEt or ClC02Et ethyl chloroformate DCE 1,2-dichloroethane DIC diisopropylcarbamate醯iamine DMSO dimethyl sulfoxide DSC differential scanning calorimetry DMF * N,N-dimethylformamide Et3N triethylamine Et 20 diethyl ether EtOH ethanol FMOC fluorenyl methoxycarbonyl LDA diisopropyl hydrazide lithium MeCOCl Acetyl chloride MeCN acetonitrile MeOH methanol MTBE methyl tert-butyl ether NMP N-methylpyrrolidone PhMe toluene PrepLC preparative liquid chromatography i-Pr2 〇 diisopropyl ether i-PrOH isopropanol TFA three Fluoroacetic acid - 47 - 1295286 THF Tetrahydrofuran TMOF Trimethyl orthoformate TMSCI Chlorotrimethyl decane TMSI Iodotrimethyl decane The compound is obtained in free (non-salt) form, unless otherwise stated in the examples. [Examples] Example 1 - Synthesis of 4-substituted 2-oxy-pyrrolidinium by reductive amination of an aldehyde ester. 1.1. Synthesis of 3-substituted-4-oxy-butyrate 1.1.1. Route A: alkylation of enamines 5, 5-dimethyl-3-methylindenyl-hexanoic acid The synthesis of ester 361 can be expressed as

362 i 二異丁基胺，phMe,1l(TC BrCH2C02CH3, PhCH3, CH3CN" WRTWd小時然後h2〇 (30%)362 i diisobutylamine, phMe, 1l (TC BrCH2C02CH3, PhCH3, CH3CN" WRTWd hour then h2〇 (30%)

361 於配備有丁史塔克（Dean-Stark)裝置之三頸瓶內於氮下，二異丁基胺（4.62毫升得自阿可羅斯（ACros))，4,4-二甲基戊醛362( 2.5克，0.021莫耳）於甲苯（20毫升）之溶液於1 3 0 °C加熱2小時及以水萃取。黃色溶液冷卻至室溫及一次加入溴乙酸甲酯（3 · 7克，0.024莫耳）。桃色溶液於室溫攪拌隔夜及於90°C攪拌1小時。於此溫度加水（1〇毫升）及於1小時後溶液冷卻至室溫。有機層以1 N鹽酸、飽和碳酸氫鈉水溶液洗滌，以硫酸鎂脫水，過濾及蒸發 -48- 1295286 , I ' 獲得油，油於減壓（1毫米汞柱）下蒸餾獲得5，5-二甲基 -3-甲醯基-己酸甲酯361呈液體（1.1克，0.05莫耳’ Teb (1毫米汞柱）：69-71 °C)。然後醛酯用於還原胺化步驟。另外，使用溴乙酸乙酯之烷化反應可於甲苯·乙膪1 /1 (v/v)作爲溶劑存在下進行。最終所得醛亦係於減壓下蒸 1.1.2. 其它合成途徑醛酯也可藉下列方法獲得包括 (i)腙藉溴乙酸酯衍生物烷化。例如5-(苯基）-3-甲醯 > 基-戊酸2,2-二甲基-乙酯係經由N-(4-苯基）-亞丙基-N， N-二甲基腙與溴乙酸第三丁酯及LDA反應接著進行烷化腙之臭氧分解反應獲得。 (i i )硝基甲烷加成至α，/3 -未飽和酯類。3 · ( 3 -溴-苯基）-4 -氧基-丁酸乙酯係經由硝基甲烷於1 . 8 -二氮雜雙環[5.4.0]十一碳-7-烯存在下加成至3-(3-溴-苯基）-丙烯酸乙酯，於尼夫（Nef)條件下.氧合硝基衍生物以及藉鹽酸進行甲基·縮醛之控制水解反應獲得。 > (iii)4-戊烯酸衍生物之臭氧分解反應。2-苄基-4-氧基-丁酸乙酯係經由使用二異丙基醯胺鋰烷化3-苯基-丁酸乙酯以及烯丙基溴接著進行臭氧分解及藉PPh3還原臭氧化物獲得。 1.2. 3-取代-4-氧基-丁酸酯之還原胺化以及環化成爲吡咯啶-2 -酮 1.2.1.還原胺化 4-{[((IS )-1-胺基羰基）丙基]胺基）丁酸甲酯363之合成作爲代表。專 12,95286 t-Bu361 Diisobutylamine (4.62 ml from ACros), 4,4-dimethylvaleraldehyde in a three-necked flask equipped with a Dean-Stark apparatus under nitrogen A solution of 362 (2.5 g, 0.021 mol) in toluene (20 mL) was then evaporated. The yellow solution was cooled to room temperature and methyl bromoacetate (3 · 7 g, 0.024 mol) was added in one portion. The peach solution was stirred overnight at room temperature and stirred at 90 ° C for 1 hour. Water (1 ml) was added at this temperature and the solution was cooled to room temperature after 1 hour. The organic layer was washed with 1 N hydrochloric acid and a saturated aqueous solution of sodium hydrogen sulfate, dried over magnesium sulfate, filtered and evaporated, and evaporated, and evaporated, Methyl methyl-3-methylindenyl-hexanoate 361 was a liquid (1.1 g, 0.05 mol' Teb (1 mm Hg): 69-71 ° C). The aldehyde ester is then used in the reductive amination step. Further, the alkylation reaction using ethyl bromoacetate can be carried out in the presence of toluene·acetam 1 /1 (v/v) as a solvent. The resulting aldehyde is also distilled under reduced pressure. 1.1.2. Other synthetic routes The aldehyde ester can also be obtained by the following methods: (i) alkylation with a bromoacetate derivative. For example, 5-(phenyl)-3-carboindole> 2,2-dimethyl-ethyl valerate is via N-(4-phenyl)-propylene-N,N-dimethyl The reaction of hydrazine with the third butyl bromoacetate and LDA is followed by an ozonolysis reaction of cerium alkyl halide. (i i ) Nitromethane is added to α,/3-unsaturated esters. 3 · (3-Bromo-phenyl)-4-oxy-butyric acid ethyl ester is added via nitromethane in the presence of 1.8-diazabicyclo[5.4.0]undec-7-ene To 3-(3-bromo-phenyl)-ethyl acrylate, obtained under Nef (Nef) conditions, oxygenated nitro derivative and controlled hydrolysis of methyl acetal by hydrochloric acid. > (iii) Ozonolysis of 4-pentenoic acid derivatives. Ethyl 2-benzyl-4-oxy-butyrate is obtained by alkylating 3-phenyl-butyric acid ethyl ester with allyl isopropylamine and allyl bromide followed by ozonolysis and reduction of ozonide by PPh3 obtain. 1.2. Reductive amination and cyclization of 3-substituted-4-oxy-butyrate to pyrrolidin-2-one 1.2.1. Reductive amination of 4-{[((IS)-1-aminocarbonyl) The synthesis of methyl propyl]amino)butyrate 363 is representative. 12,95286 t-Bu

於配備有回流冷凝器之三頸瓶內於氬下，醛361(1.7 克，0.09莫耳），（S)-2-胺基-丁醯胺（1·58克，〇·15莫耳）以及分子篩（3埃得自亞力胥（Aldrich)於甲醇之懸浮液於6(TC加熱〇 . 5小時。懸浮液冷卻至〇°C及分成數份加入硼氫化鈉（0.5 5克）。於室溫經歷1小時後，反應混合物以醛稀釋，以水洗滌，以硫酸鎂脫水，過濾及蒸發獲得黃色油。4-{[(13)-1-胺基羰基）丙基]胺基}丁酸甲酯363 未經進一步純化即直接用於次一步驟。另外，還原胺化可於相同條件下使用還原劑例如 NaBH3CN或NaBH(OAc)3(相對於醛酯使用1 .4莫耳當量）進行0 1·2·2· 丁酸（甲基或乙基）酯之環化兩種（2 S )· 2 - ( 4 -新戊基-2 -氧基-1 ·吡咯啶基）丁醯胺之立體異構物149及148之合成爲代表In a three-necked flask equipped with a reflux condenser under argon, aldehyde 361 (1.7 g, 0.09 mol), (S)-2-amino-butymidine (1·58 g, 〇·15 mol) And a molecular sieve (3 angstroms from a suspension of Aldrich in methanol at 6 (TC heating 〇. 5 hours. The suspension is cooled to 〇 ° C and divided into several portions to add sodium borohydride (0.5 5 g). After 1 hour at room temperature, the reaction mixture was diluted with aldehyde, washed with water, dried over magnesium sulfate, filtered and evaporated to give a yellow oil. 4-{[(13)-1-aminocarbonyl)propyl]amino] Methyl ester 363 was used directly in the next step without further purification. Alternatively, reductive amination can be carried out under the same conditions using a reducing agent such as NaBH3CN or NaBH(OAc)3 (1.4 mole equivalents relative to the aldehyde ester) Cyclization of 2 1 ·2·2· Butyric Acid (Methyl or Ethyl) Ester (2 S )· 2 - ( 4 -N-Pentyl-2-ethoxy-1 ·pyrrolidinyl) The synthesis of the stereoisomers 149 and 148 of the amine is representative

-50--50-

1295286 於配備有回流冷凝器之三頸瓶內，於氬下，油狀物363 於羥苯并***（2.05克，得自亞力胥）存在下溶解於甲苯及1,2·二氯乙烷（各25毫升）之1/1混合物，溶液於90°C 加熱2小時及冷卻至室溫。有機相連續以飽和碳酸氫鈉水溶液、水洗滌，以硫酸鎂脫水，過濾及蒸發獲得褐色固體（1 · 8克），其係於矽膠藉管柱層析術純化（洗提劑： CH2Cl2/MeOH 95/05(v/v))獲得（2S)-2-(4-新戊基-2-氧基-1 -吡咯啶基）丁醯胺（0· 89克，0.0036莫耳）呈非對映異構物之1 /1混合物。兩種異構物之分開係藉由於像合靜相層析術（乙醇-己院1 /1 ( v / v ))以及於甲苯再結晶後獲得兩種立體異構物（分別爲0 · 3 5克及0 · 3 7克）。立體化學性質述於表。另外，胺基酯之環化可使用羥-苯并*** 以外之作用劑例如乙酸（作爲溶劑）或2-羥-吡啶（1當量）進行。當乙酸用作爲環化溶劑時，反應混合物係於真空蒸發至乾，以二氯甲烷稀釋及如前述後續處理。 1.2.3.其它環化反應另外，環化可藉（i )酯之酸或鹼水解以及（i i )活化酯於肽合成所述尋常條件下環化而以二步驟進行。 1 · 3 ·吡咯啶酮類之固相合成 1 . 3 · 1 FMOC保護胺基酸附接於鈴克醯胺樹脂。 s鈴克樹脂· Λ001295286 Dissolved in toluene and 1,2·dichloroethane in the presence of hydroxybenzotriazole (2.05 g from ylide) in a three-necked flask equipped with a reflux condenser under argon. A 1/1 mixture of alkane (25 mL each) was heated at 90 °C for 2 hours and cooled to room temperature. The organic phase was washed successively with saturated aqueous NaH.sub.sub.sub.sub.sub.sub.sub.ssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss 95/05(v/v)) obtained (2S)-2-(4-neopentyl-2-oxy-1 -pyrrolidinyl)butanamine (0·89 g, 0.0036 mol) was non-pair a 1 / 1 mixture of the isomers. The separation of the two isomers was obtained by a combination of static phase chromatography (ethanol-hexa-1 / v (v)) and recrystallisation of toluene to obtain two stereoisomers (0 · 3 5 grams and 0 · 3 7 grams). The three-dimensional chemical properties are described in the table. Further, the cyclization of the amino ester can be carried out using an agent other than hydroxy-benzotriazole such as acetic acid (as a solvent) or 2-hydroxy-pyridine (1 equivalent). When acetic acid was used as the cyclization solvent, the reaction mixture was evaporated to dryness in vacuo, diluted with dichloromethane and subsequently worked up. 1.2.3. Other cyclization reactions Alternatively, cyclization can be carried out in two steps by (i) acid or base hydrolysis of the ester and (i i ) activation of the ester under cyclization under normal conditions of peptide synthesis. Solid Phase Synthesis of 1 · 3 · Pyrrolidone 1. 3 · 1 FMOC Protected Amino Acid Attached to Cyclohexylamine Resin. s 铃克克树脂· Λ00

DIC, DMF -51- 1295286 , 4克鈴克醯胺樹脂（0.51毫當量/克，100- 200篩目）置於玻璃容器及於20% v/v六氫吡啶/DMF( 40毫升攪拌30分鐘。樹脂經排乾，整個脫去保護重複進行。樹脂經過濾，洗滌（6XDMF)及脫水。樹脂懸浮於DMF(40毫升）及使用 N-Fmoc-2-胺基丁酸（3.02克，9.28毫莫耳）處理，接著使用1，3-二環己基甲二醯亞胺（1.4克，11.13毫莫耳）於 DMF(20毫升）之溶液處理。反應於室溫攪拌1小時然後過濾，洗滌（DMF)及重複偶合處理。樹脂經過濾，洗滌（6X > DMF，6XCH2C12)，脫水以及就此用於其次各步驟。 1.3.2.藉添加5-羥-4-丙基-呋喃-2-酮進行還原胺化及環化反應 1. 六氫吡啶 2. NaBH(OAc)3/CHaCI, NHFmoc 籲，錄克.樹脂. 3. TFA/CHaCI2 100毫克N-Fmoc-2-胺基丁醯胺樹脂（0.051毫莫耳）容納於磨砂聚丙嫌注射器。Fmoc基的去除係使用20%六氫口比 Π定於DMF達成。胺基樹脂內加入5 ·經-4 -丙基-呋喃-2 -酮 (36·72毫克，0.25毫莫耳）於DCE(2毫升）。然後樹脂使用乙酸（15微升）及三乙醯氧硼氫化鈉（54毫克，0.25毫莫耳）處理。反應於室溫攪拌1 8小時然後過濾，以下列溶劑順序洗滌：H20/DMF(1 : 1)，DMF，CH2Cl2，MeOH 及脫水。樹脂藉渦旋攪拌懸浮於三氟乙酸/二氯甲烷混合物（丨/丨）經歷 4小時，然後過濾，洗滌（二氯甲烷X 2)。濾液經濃縮，殘餘物溶解於二氯甲烷（2毫升）及再濃縮一次。所需化 -52- 1295286 ' 合物藉LC-MS(微質量吉爾森（Micromass Gilson),LCZ平台，RP-18管柱，梯度洗提，CH3CN/H20/TFA 1%)純化。 1 . 3 . 3 .藉添加醛酯進行還原胺化以及環化。DIC, DMF -51- 1295286, 4 g of ketamine resin (0.51 meq/g, 100-200 mesh) placed in a glass container and stirred in 20% v/v hexahydropyridine/DMF (40 ml for 30 minutes) The resin was drained and the entire deprotection was repeated. The resin was filtered, washed (6×DMF) and dehydrated. Resin was suspended in DMF (40 mL) and N-Fmoc-2-aminobutyric acid (3.02 g, 9.28 m) Treatment with moth) followed by treatment with a solution of 1,3-dicyclohexylmethylenediamine (1.4 g, 11.13 mmol) in DMF (20 mL). The reaction was stirred at room temperature for 1 hour then filtered and washed DMF) and repeated coupling treatment. The resin was filtered, washed (6X > DMF, 6XCH2C12), dehydrated and used for the next steps. 1.3.2. Add 5-hydroxy-4-propyl-furan-2-one Reductive amination and cyclization 1. Hexahydropyridine 2. NaBH(OAc)3/CHaCI, NHFmoc, gram. Resin. 3. TFA/CHaCI2 100 mg N-Fmoc-2-aminobutyric acid (0.051 millimolar) is contained in a frosted polyacrylic syringe. The removal of the Fmoc group is achieved by using a 20% six-hydrogen port ratio in DMF. The amine-based resin is added with 5 · by -4 - Base-furan-2-one (36.72 mg, 0.25 mmol) in DCE (2 mL). The resin then used acetic acid (15 μl) and sodium triethyl sulfonate (54 mg, 0.25 mmol) The reaction was stirred at room temperature for 18 hours and then filtered and washed in the following solvent sequence: H20/DMF (1:1), DMF, CH2Cl2, MeOH and dehydrated. Resin was suspended in trifluoroacetic acid/dichloride by vortexing. The methane mixture (丨/丨) was subjected to 4 hours, then filtered and washed (dichloromethane <RTI ID=0.0></RTI> </RTI> <RTIgt; The compound was purified by LC-MS (Micromass Gilson, LCZ platform, RP-18 column, gradient elution, CH3CN/H20/TFA 1%). 1. 3 . Reductive amination and cyclization are carried out.

150毫克N-Fmoc-2-胺基丁醯胺樹脂（ 0.087毫莫耳）容納於磨砂聚丙烯注射器。Fmoc基的去除係使用20%六氫吡啶於DMF達成。胺基酯內加入醛（0.5毫莫耳）於TM0F(2毫升）。反應於室溫攪拌1 8小時然後過濾及洗滌（二氯甲烷）。樹脂使用二氯甲烷溶脹，然後以三乙醯氧硼氫化鈉（22 毫克，0. 104毫莫耳）處理。反應又於室溫攪動18小時。然後樹脂以下列溶劑循序洗滌：H20X6，Me0Hx6，CH2Cl2 X 6及脫水。樹脂懸浮於三氟乙酸/水混合物（9 5 / S )經歷 1小時伴以軌道式攪動，然後過濾，洗滌（二氯甲烷X 2 ) 。濾液經濃縮，殘餘物溶解於二氯甲烷（2毫升）及再次濃縮。所需化合物係藉LC-MS微質量吉爾森，LCZ平台，RP-18管柱，梯度洗提，CH3CN/H20/TFA 1%)純化。實例2. 4-取代2-氧基吡咯啶丁醯胺類藉4-取代內酯類之開環反應合成。 2 . 1 .內酯之合成 2 . 1 · 1 ·途徑A :經由2，3 -呋喃酮之烷化 4-正丁基·丁內酯365之合成作爲代表·· -53- 1295286 1 · rvBu2CuU (1 ·5 當量),TMSCI (2 當纛) —----150 mg of N-Fmoc-2-aminobutyric acidamine resin (0.087 mmol) was contained in a frosted polypropylene syringe. Removal of the Fmoc group was achieved using 20% hexahydropyridine in DMF. An aldehyde (0.5 mmol) was added to the amine ester in TM0F (2 mL). The reaction was stirred at room temperature for 18 hours then filtered and washed (dichloromethane). The resin was swollen with dichloromethane and then treated with sodium tris-sulfonium hydride (22 mg, 0. 104 mmol). The reaction was again stirred at room temperature for 18 hours. The resin was then washed sequentially with the following solvents: H20X6, Me0Hx6, CH2Cl2X6 and dehydrated. The resin was suspended in a trifluoroacetic acid/water mixture (9 5 /s) for 1 hour with orbital agitation, then filtered and washed (dichloromethane X 2 ). The filtrate was concentrated and the residue dissolved in dichloromethane (2 mL). The desired compound was purified by LC-MS micromass Gilson, LCZ platform, RP-18 column, gradient elution, CH3CN/H20/TFA 1%). Example 2. 4-Substituted 2-oxypyrrolidinobutamines were synthesized by ring-opening reaction of 4-substituted lactones. 2.1. Synthesis of lactones 2. 1 · 1 · Route A: Synthesis of 4-n-butyl-butyrolactone 365 via 2,3-furanone as a representative ·· -53- 1295286 1 · rvBu2CuU (1 · 5 equivalents), TMSCI (2 when 纛) —----

Et20, -780C至έΟ0。，3 h 2.，丨（74%)Et20, -780C to έΟ0. , 3 h 2., 丨 (74%)

於三頸瓶內於氬下，正丁基鋰（1·6Μ於己烷類，75毫升，0· 12莫耳）添加至Cul ( 11 .42克，〇 . 〇6莫耳）於無水 THF(80毫升）冷卻至- 30°C之懸浮液。〇·5小時後，溶液冷卻至-78°C，逐滴加入TMSC1(4.75克，〇·〇4莫耳）接著加入2,3-呋喃酮364(得自亞力胥，3.36克，〇.〇4莫耳）溶解於無水THF。任懸浮液溫熱至室溫及使用飽和氯化銨水解。水層以乙酸乙酯萃取（3次），以水洗滌，以硫酸鎂脫水及蒸發至乾。粗內酯藉蒸餾（1毫米汞柱；73 - 80°C)純化獲得2.7克4-正丁基-丁內酯365。Add n-butyllithium (1·6 Μ to hexanes, 75 ml, 0·12 mol) to Cul (11.42 g, 〇. 〇6 mol) in anhydrous THF under argon in a three-necked flask. (80 ml) was cooled to a suspension at -30 °C. After 5 hours, the solution was cooled to -78 ° C, TMSC1 (4.75 g, 〇·〇 4 mol) was added dropwise followed by 2,3-furanone 364 (from ylide, 3.36 g, 〇. 〇4 mol) Dissolved in anhydrous THF. The suspension was allowed to warm to room temperature and hydrolyzed using saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate (3×), washed with water, dried over magnesium sulfate and evaporated. The crude lactone was purified by distillation (1 mm Hg; 73 - 80 ° C) to give 2.7 g of 4-n-butyl-butyrolactone 365.

ο 364 另外，銅酸反應劑可藉有機鎂置換有機鋰製備，有機鎂可經由烷基鹵化物與鎂璇屑於此種轉化反應之尋常條件下反應獲得。THF可以***替代（一般資訊請參考： Lipshutz，B.H. ;Sengupta，S.有機反應 1991，41，135)。 2 . 1 . 2 .其它途徑另外內酯也可經由下列途徑獲得 (i) 丁二酸酯之還原。4-(環丙基）甲基-丁內酯係藉帶有二異丙基醯胺鋰之環丙基甲基溴進行一甲基丁二酸酯之烷化，接著藉NaBH4& CaCl2還原2-(環丙基）甲基-丁二酸1 -甲酯獲得。 (ii) 丁二酸卜烷酯4-烷基硫酯之還原。4-烯丙基·丁內酯係得自乙基4-戊烯酸硫酯（係由4-戊烯酸以及乙硫醇 -54- 1295286 於二環己基甲胺醛亞胺存在下合成）。乙基4·戊烯酸硫酉旨藉溴乙酸乙酯帶有二異丙基醯胺鋰烷化獲得2-烯丙基·Τ 二酸1-甲酯4-乙基硫酯，然後經由依序與Li ΒΗ4以及硫酸反應而轉變爲4-烯丙基-丁內酯。 2.2.吡咯啶酮之合成 2.2.1.經由丁醯胺之醯化/烷化 (2S)-2-(4-烯丙基-2-氧基-1-吡咯啶基）丁醯胺228及 224之兩種異構物之合成爲代表：ο 364 In addition, the cupric acid reactant can be prepared by replacing the organolithium with organomagnesium, which can be obtained by reacting an alkyl halide with magnesium swarf in the usual conditions of such a conversion reaction. THF can be replaced by ether (for general information, please refer to: Lipshutz, B.H.; Sengupta, S. Organic Reaction 1991, 41, 135). 2.1.2. Other routes Further lactones can also be obtained by (i) reduction of succinate by the following route. 4-(cyclopropyl)methyl-butyrolactone is alkylated with monomethylsuccinyl bromide with lithium diisopropylamide, followed by NaBH4 & CaCl2 reduction 2 - (Cyclopropyl)methyl-succinic acid 1-methyl ester obtained. (ii) Reduction of the alkyl 4-alkyl succinate. 4-allyl-butyrolactone is obtained from ethyl 4-pentenoic acid thiolate (synthesized from 4-pentenoic acid and ethanethiol-54- 1295286 in the presence of dicyclohexylmethylamine aldehyde imine) . Ethyl 4-pentenoic acid thioindole is obtained by alkylation of ethyl bromoacetate with lithium diisopropyl guanamine to obtain 2-ethyl thioester of 1-allyl·decanedioic acid, followed by The sequence is converted to 4-allyl-butyrolactone by reaction with Li ΒΗ 4 and sulfuric acid. 2.2. Synthesis of pyrrolidone 2.2.1. Deuteration/alkylation of (2S)-2-(4-allyl-2-oxy-1-pyrrolidinyl)butanamine 228 via butaline The synthesis of two isomers of 224 is representative:

-步驟1 :內酯的打開於三頸瓶內於氬下，TMSI(51毫升，亞力胥）添加至粗 4-烯丙基-丁內酯3 66 (參考程序§2.1.3.，22.9克，0.181 莫耳）冷卻至0°C之溶液。溶液於室溫攪拌2小時及以 1N鹽酸（ 300毫升）水解。水層以二氯甲烷萃取，合倂有機相以鹽水洗滌，以硫酸鎂脫水及真空濃縮獲得粗3 -(碘）甲基-5-己烯酸 367( 44.5 克）。沱 NMR( 2 50MHz，CDC13): 1.80-2.05(m,2H),2.20(t,2H),2.40-2.60(t,2H),5.1〇- 5.20(m ， 2H)，5.15-5.80(m，lH)。 -步驟2 :碘酸之氯化於配備有回流冷凝器之三頸瓶內於氬下，亞磺醯氯 (25.5毫升）及祖碘酸367( 44.5克，0· 175莫耳）於苯（90 毫升）之溶液於室溫攪拌24小時。真空蒸發去除溶劑獲得粗3-(碘）甲基-5-己烯醯氯368( 47克），其未經進一步 -55- 1295286 . • * 純化即用於次一步驟。4關以2501^2,00(：13):1.90-2 ·05(πι，2H)，2 · 15( t，2H)，2· 90-3 · 10(m，2H)，3 · 25(dd， 1H)，3·35(dd，1H)，5·10-5.20(m，2H)，5·15-5·80(m，1H)。 -步驟3 :使用5-2-胺基·丁醯胺之醛化-烷化於三頸瓶於氬下，粗醯氯368( 47克，0. 172莫耳）於二氯甲烷（ 300毫升）逐滴添加至分子篩（29克）、粉狀氫氧化鉀（22.3克）、無水硫酸鈉（28.8克），溴化4-正丁基銨（2.8克，0.0086莫耳）及S*2-胺基丁醯胺（[a ]25d= • +19.35度；26·3克5 0.26莫耳）於二氯甲烷（ 470毫升）藉機械攪拌且冷卻至0°C之懸浮液。溶液於-5°C攪拌5小時，加入粉狀氫氧化鉀（6.2克）及於-5°C持續攪拌3小時。反應混合物於海浮羅西爾（hy f 1 oce 1 )過濾及溶劑經真空蒸發。粗反應混合物依次於矽膠層析（乙酸乙酯/異丙醇 :97 /03 (v/v)及於像合靜相製備性層析（己烷/乙醇）純化獲得（2S ) - 2 - ( 4 -烯丙基-2 -氧基-卜吡咯啶基）丁醯胺之兩種異構物（分別爲6.0克（ 228 )及5.48克（ 224); 16%及 15%)。 # 於像合層析術後也分離兩種小量雜質，亦即（2S)-2-[4-(2-碘丙基-2-氧基-1-吡咯啶基）丁醯胺22 5(0.22克）及226( 0.27克）之兩種立體異構物，於再結晶後呈白色固體。 2.2.2.經由丁醯胺之烷化/醯化 (2S)-2-(5 -壬基-2-氧基-1-毗咯啶基）丁醯胺之兩種異構物之合成爲代表：步驟1 :內酯之打開 7-壬內酯（0.32毫升，2毫莫耳）於亞磺醯氯（164微升 -56- 1295286 ，2.25毫莫耳）之溶液內於室溫加入氯化鋅（1 2毫克， 0.088毫莫耳）及混合物攪拌24小時。加入過量甲醇，反應混合物攪拌1 0分鐘然後於減壓下濃縮獲得4 -氯·壬酸甲酯，供就此使用。- Step 1: Opening of the lactone in a three-necked flask under argon, TMSI (51 ml, ylide) was added to the crude 4-allyl-butyrolactone 3 66 (refer to Procedure § 2.1.3., 22.9) Gram, 0.181 mole) solution cooled to 0 °C. The solution was stirred at room temperature for 2 hours and hydrolyzed with 1N hydrochloric acid (300 mL). The aqueous layer was extracted with methylene chloride. EtOAc (EtOAc m.).沱NMR ( 2 50 MHz, CDC 13 ): 1.80-2.05 (m, 2H), 2.20 (t, 2H), 2.40-2.60 (t, 2H), 5.1 〇 - 5.20 (m, 2H), 5.15-5.80 (m, lH). - Step 2: Chlorination of iodic acid in a three-necked flask equipped with a reflux condenser under argon, sulfinium chloride (25.5 ml) and ou iodate 367 (44.5 g, 0·175 mol) in benzene ( The solution of 90 ml) was stirred at room temperature for 24 hours. Removal of the solvent in vacuo gave crude 3-(iodo)methyl-5-hexenepyridinium chloride 368 (47 g), which was used without further -55 - 1295286. 4Off to 2501^2,00(:13):1.90-2 ·05(πι,2H), 2 · 15( t,2H), 2· 90-3 · 10(m,2H),3 · 25( Dd, 1H), 3·35 (dd, 1H), 5·10-5.20 (m, 2H), 5·15-5·80 (m, 1H). - Step 3: Aldehyde-alkylation with 5-2-aminobutanamine in a three-necked flask under argon, crude chlorobenzene 368 (47 g, 0.172 m) in dichloromethane (300 ml) ) was added dropwise to molecular sieves (29 g), powdered potassium hydroxide (22.3 g), anhydrous sodium sulfate (28.8 g), 4-n-butylammonium bromide (2.8 g, 0.0086 mol) and S*2- Amidine butyrate ([a ] 25d = • +19.35 degrees; 26.3 g 5 0.26 mol) was suspended in dichloromethane (470 ml) with mechanical stirring and cooled to 0 °C. The solution was stirred at -5 ° C for 5 hours, and powdered potassium hydroxide (6.2 g) was added and stirring was continued at -5 ° C for 3 hours. The reaction mixture was filtered over a sea of celite (hy f 1 oce 1 ) and the solvent was evaporated in vacuo. The crude reaction mixture was purified by silica gel chromatography (ethyl acetate/isopropanol: 97/03 (v/v) and purified by preparative chromatography (hexane/ethanol) to afford (2S) - 2 - ( Two isomers of 4-Allyl-2-oxo-pyrrolidinylbutyramine (6.0 g (228) and 5.48 g (224); 16% and 15%, respectively). Two small impurities were also separated after chromatography, ie (2S)-2-[4-(2-iodopropyl-2-oxy-1-pyrrolidinyl)butanamine 22 5 (0.22 g) And 226 (0.27 g) of two stereoisomers, which are white solid after recrystallization. 2.2.2. Alkylation/deuteration via butaamine (2S)-2-(5-fluorenyl-2 Synthesis of two isomers of -oxy-1-pyrrolidyl)butanamine as representative: Step 1: Opening of lactone to 7-decalactone (0.32 ml, 2 mmol) to sulfin A solution of chlorine (164 μl - 56 - 1295286, 2.25 mmol) was added with zinc chloride (1 2 mg, 0.088 mmol) at room temperature and the mixture was stirred for 24 hours. Excess methanol was added and the reaction mixture was stirred 1 0 After a minute, it was concentrated under reduced pressure to give methyl 4-chloro-decanoate for use.

步驟2 :烷化於4 -氯-壬酸曱酯（2鼋莫耳）於DMF ( 2毫升）之溶液內依序加入2 -胺基丁醯胺（1克，1〇毫莫耳），3〇〇毫克碘化鈉 (2毫莫耳）及276毫克碳酸鉀（2毫莫耳）。混合物於60 °C 攪拌隔夜。固體經過濾，藉二氯甲烷洗滌（2 X 2毫升）。濾液於減壓下濃縮獲得酯衍生物，其就此用於環化反應。〇步驟3 :環化：參考§ 1 · 2 · 2 ·及§ 1 . 2.3 ·之條件。 2.3.酮基-吡咯啶-2-酮之合成 (2S)-2-[2 -氧基- 4- (2 -氧基丙基吡咯π定基]丁醯胺230之合成爲代表：Step 2: alkylation of 2-aminobutylinamine (1 g, 1 mmol) in a solution of 4-chloro-decanoate (2 mol) in DMF (2 mL). 3 mg of sodium iodide (2 mmol) and 276 mg of potassium carbonate (2 mmol). The mixture was stirred at 60 ° C overnight. The solid was filtered and washed with dichloromethane (2×2 mL). The filtrate was concentrated under reduced pressure to give an ester derivative which was used for the cyclization. 〇 Step 3: Cyclization: Refer to the conditions of § 1 · 2 · 2 · and § 1.2.3. 2.3. Synthesis of keto-pyrrolidin-2-one The synthesis of (2S)-2-[2-oxy-4-(2-oxypropylpyrrole π-decyl)butanamine 230 is represented by:

-57- 1295286 於三頸瓶，氧氣通過PdCl 2(0.68克，0.0039莫耳）， CuCl2( 1 · 68克，0 · 0098莫耳）於N -甲基-2·吡咯η定酮（關p ，40毫升）之溶液，其逐滴加入（2S)-2-[2-氧基-4-(2·氧基丙基）-1-吡咯啶基]丁醯胺224( 4.1 3克，0.020莫耳）於NMP(40毫升）之溶液（添加時間：1 . 2小時）。溶液於通氣下攪拌0.75小時，經西萊特（cel ite)過濾及真空（1毫米汞柱）蒸發。粗酮於矽膠層析術純化（二氯甲烷/甲基_ 第三丁基醚/異丙醇9/0.9/0.1( v/v))獲得（2S)-2-[2·氧基-4-(2-氧基丙基）-1 -吡咯啶基]丁醯胺230，於乙酸乙酯再結晶後呈白色固體。 2.4.酮230之衍生 2.4 . 1 .醇之合成 (2S)-2-[(4S)-4-(2-羥丙基）-2-氧基吡咯啶基]丁醯胺233之合成爲代表：-57- 1295286 In a three-necked flask, oxygen is passed through PdCl 2 (0.68 g, 0.0039 mol), CuCl 2 (1 · 68 g, 0 · 0098 mol) to N-methyl-2·pyrrole n-butanone (off p , 40 ml) solution, which was added dropwise (2S)-2-[2-oxy-4-(2-oxypropyl)-1-pyrrolidinyl]butanamine 224 (4.1 g, 0.020) Mole) A solution of NMP (40 ml) (addition time: 1.2 hours). The solution was stirred under agitation for 0.75 hours, filtered over celite and evaporated in vacuo (1 mmH). The crude ketone was purified by silica gel chromatography (dichloromethane/methyl_t-butyl ether/isopropanol 9/0.9/0.1 (v/v)) to give (2S)-2-[2. -(2-Ethoxypropyl)-1 -pyrrolidinyl]butanamine 230, as a white solid after recrystallization from ethyl acetate. 2.4. Derivation of ketone 230 2.4. Synthesis of alcohol (2S)-2-[(4S)-4-(2-hydroxypropyl)-2-oxypyrrolidinyl]butanamine 233 :

-步驟1 :還原於三頸瓶內於氬下，NaBH4*成數份添加至230( 9克， 0.012莫耳）於乙醇（140毫升）冷卻於-5°c之溶液。溶液於此溫度攪拌4小時，以飽和氯化銨淬熄及蒸發至乾。固體溶解於甲醇/二氯甲烷，過濾及真空濃縮。殘餘物於 -58- 1295286 . , * 矽膠層析純化（甲醇/二氯甲烷：9 Ο /1 Ο ( v / v ))獲得醇3 6 9之差向混合物（2.2克，79%)呈油。粗混合物於次一步驟直接乙醯化。1H NMR( 400MHz，（CD3)2SO):0.70(t，3H)，l.〇5 (d，3H)，1·30- 1.45(m，1H)，1·70-1·80(m，1H)，1·80-2.05 (m，lH)，2.20-2.40(m，2H，與溶劑部分重疊），3.00-3.20 (m，lH)，3·30-3·35(πι，2Η，與溶劑部分重疊），3.50-3.6 5 (m，lH)，4.30(m，lH)，4.45(m，lH)，7.10(sJ)，lH)，7.20 (s(寬）1H)。 ι -步驟2 :乙醯化於三頸瓶內於氬下，乙醯氯（0.91克，0.011莫耳）於室溫添加至4-N，N-二甲基胺基吡啶（0· 11克，0· 〇〇1莫耳），吡啶（0.86毫升）及醇於二氯甲烷（90毫升）之溶液。溶液攪拌5小時，以飽和氯化銨淬熄，及水層以二氯甲烷萃取（3次），以硫酸鎂脫水及真空濃縮獲得粗製乙酸鹽，其於像合相藉管柱層析術純化（己烷/乙醇）獲得兩種差向異構物乙酸酯370及371 (分別爲1 · 143克及1 · 17克）。於像合層析前於370及371之1/1混合物：卬NMR( 400MHz， I CD3SOCD3) :0.90(t » 3H),1.21-1.28(m,4H),1.51-1.82 (m,4H),1.89-1.98(m,lH),1.80-2.05(m,1H),2.04 (s,3H),2.16(dd,lH),2.38(m,lH) » 2.62(dd,lH),3.11 (dd，lH);3.49(dd，lH)，4.39-4.49(m，lH) ， 4.89-4.99 (111，111)，5.43(8(寬），11^)，6.24(8(寬），1}〇。 -步驟3 :去乙醯化於三頸瓶於氬下，乙酸酯371之單一對映異構物（1.11 克，0.0042莫耳）及碳酸鉀於乙醇之懸浮液於0°C攪拌20 小時，蒸發至乾及粗醇於矽膠藉層析術純化（甲醇/二氯 -59- 1295286 . I 擊甲烷：85/15(v/v))獲得（2S)-2-[(4S)-4-(2-羥丙基）·2-氧基吡咯啶基]丁醯胺233 ( 0.67克，72%)，於乙腈再結晶後呈白色固體。 2.4.2. 230之氟化酮230之氟化用於合成2-[(4S)-4-(2,2-二氟丙基卜2-氧基吡咯啶基]丁醯胺265。- Step 1: Reduction In a three-necked flask under argon, NaBH4* was added in portions to a solution of 230 (9 g, 0.012 mol) in ethanol (140 ml) cooled at -5 °C. The solution was stirred at this temperature for 4 hours, quenched with saturated aqueous ammonium chloride and evaporated to dryness. The solid was dissolved in methanol / dichloromethane, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (methanol / methylene chloride: 9 Ο /1 Ο (v / v)) to give the mixture of the mixture of alcohol (3 </ br> . The crude mixture was directly acetabulized in the next step. 1H NMR (400MHz, (CD3)2SO): 0.70 (t, 3H), l. 〇5 (d, 3H), 1·30- 1.45 (m, 1H), 1·70-1·80 (m, 1H) ),1·80-2.05 (m,lH), 2.20-2.40 (m, 2H, partially overlapping with solvent), 3.00-3.20 (m, lH), 3·30-3·35 (πι, 2Η, with solvent Partially overlapping), 3.50-3.6 5 (m, lH), 4.30 (m, lH), 4.45 (m, lH), 7.10 (sJ), lH), 7.20 (s (width) 1H). Ip - Step 2: Acetate in a three-necked flask under argon, add acetonitrile (0.91 g, 0.011 mol) to 4-N,N-dimethylaminopyridine (0·11 g) at room temperature , 0· 〇〇1 mol), a solution of pyridine (0.86 ml) and an alcohol in dichloromethane (90 ml). The solution was stirred for 5 hours, quenched with saturated ammonium chloride, and the aqueous layer was extracted with dichloromethane (3 times), dried over magnesium sulfate and concentrated in vacuo to give crude acetate, which was purified by column chromatography. (Hexane/ethanol) Two epimer acetates 370 and 371 were obtained (1·143 g and 1.7 g, respectively). 1/1 mixture at 370 and 371 before image chromatography: NMR (400 MHz, I CD3SOCD3): 0.90 (t » 3H), 1.21-1.28 (m, 4H), 1.51-1.82 (m, 4H), 1.89-1.98 (m, lH), 1.80-2.05 (m, 1H), 2.04 (s, 3H), 2.16 (dd, lH), 2.38 (m, lH) » 2.62 (dd, lH), 3.11 (dd, lH); 3.49 (dd, lH), 4.39-4.49 (m, lH), 4.89-4.99 (111, 111), 5.43 (8 (wide), 11^), 6.24 (8 (wide), 1} 〇. - Step 3: Deacetylation in a three-necked flask under argon, a single enantiomer of acetate 371 (1.11 g, 0.0042 mol) and a suspension of potassium carbonate in ethanol at 0 ° C for 20 hours. Evaporation to dry and crude alcohol in phthalocyanine by chromatography (methanol / dichloro-59- 1295286. I methane: 85/15 (v/v)) to obtain (2S)-2-[(4S)-4 -(2-Hydroxypropyl)-2-oxypyrrolidinyl]butanamine 233 (0.67 g, 72%) as a white solid after recrystallization from acetonitrile 2.4.2. For the synthesis of 2-[(4S)-4-(2,2-difluoropropyl-2-oxypyrrolidinyl)butanamine 265.

-步驟1 :氟化於鐵氟龍瓶內於氬下（MeOCH2CH2)NSF3(1.86克，0.009 莫耳）分成數份添加至230( 0.389克，0.0017莫耳）於二氯甲烷之溶液及於80°C加熱4小時。溶液於此溫度攪拌4小時，以碳酸鈉淬熄，以二氯甲烷萃取，以1N鹽酸洗滌，以硫酸鎂脫水，過濾及真空濃縮獲得第三胺372( 1 .2克） LC/MS : 3 65 (MH+)。粗混合物直接用於次一步驟。 -步驟2 :水解及氨解。於三頸瓶內於氬下，粗372(0.28克）於6N鹽酸之溶液於60°C加熱22小時，冷卻至室溫，水溶液蒸發至乾。固體於乙腈硏製，過濾及真空脫水獲得酸（1 · 2克）呈白色固體。粗混合物如§6.3.1·(步驟2)所述於標準條件下醯胺化獲得（2S)及（21〇-2-[(43)-4-(2,2-二氟丙基卜2-氧基口比略U定基]丁醯胺之混合物（分別爲8 7 %及1 3 %)。 -60- 1295286 . < · 2.5· (2S)-2-(2-氧基-4-丙基-1-吡咯啶基）丁醯胺158及 159之合成- Step 1: fluorination in a Teflon bottle under argon (MeOCH2CH2) NSF3 (1.86 g, 0.009 mol) was added in portions to 230 (0.389 g, 0.0017 mol) in dichloromethane and at 80 Heat at °C for 4 hours. The solution was stirred at this temperature for 4 hours, quenched with sodium carbonate, extracted with methylene chloride, washed with EtOAc EtOAc EtOAc EtOAc. 65 (MH+). The crude mixture was used directly in the next step. - Step 2: Hydrolysis and aminolysis. A solution of crude 372 (0.28 g) in 6N hydrochloric acid was heated at 60 ° C for 22 hours in a three-necked flask, cooled to room temperature, and evaporated to dryness. The solid was tritonated in acetonitrile, filtered and vacuum dehydrated to give the acid (1.2 g) as a white solid. The crude mixture is obtained by hydrazylation under standard conditions as described in § 6.3.1 (Step 2) to obtain (2S) and (21〇-2-[(43)-4-(2,2-difluoropropyl b 2) a mixture of -oxyl groups to a little more than a base of butylamine (8 7 % and 13 %, respectively) -60 - 1295286 . < · 2.5 · (2S)-2-(2-oxy-4- Synthesis of propyl-1-pyrrolidyl)butanamine 158 and 159

1£ 2 · 5 . 1 ·步驟丨：還原胺化於三頸瓶內於氬下，4-正丙基-羥呋喃酮373 ( 35.5克， 0.25旲耳由Bourguignon JJ等人；醫藥化學期刊，1988 ’ 31，893 - 897合成）於18°C添加至S-2胺基丁醯胺（28.1 克’ 〇·275莫耳）於PhMe( 355毫升）之溶液。溶液於此溫度攪拌0 · 5小時及出現沉澱。反應混合物攪拌2小時及4N 氫氧化鈉（37.5毫升）逐滴添加至懸浮液，接著加入NaBH4 (6.2克，〇·16莫耳）於水（62毫升）之水溶液。1小時後，反應混合物小心使用乙酸（30毫升）淬熄，加熱至50°C歷3 小時及冷卻至室溫隔夜。加入氫氧化鈉50% w/w( 20毫升） ’水相以甲苯萃取（2次）。有機相經合倂，以鹽水洗滌及真空濃縮獲得粗未飽和吡咯啶酮374( 43.4克）呈橙色油，其未經進一步純化即用於次一步驟。可再結晶成白色固體（DSC，起點：熔點=72.9°C)。 2.5.2.步驟2:氫解於三頸瓶內於氬下，NH4C00H(8克，0.126莫耳）之水溶液分成數份添加至粗374(22克，0.105莫耳）及pd/c (1 · 1克）於水（ 220毫升）於50°C加熱之懸浮液。懸浮液於 1295286 50°C攪拌3小時，冷卻至室溫及攪拌隔夜。18小時後，懸浮液於50°C加熱，分成數份加入NH4COOH水溶液（8克，0.126莫耳）。1.5小時後又加入第三份NH4COOH水溶液 (8克，0.126莫耳）。懸浮液於50°C攪拌0.5小時及加入 10% Pd/C(l.l克）。懸浮液於此溫度攪拌5小時，任其於室溫放置隔夜未經攪拌。反應混合物於西萊特過濾，以水（30毫升）洗滌，水層以乙酸乙酯萃取（3次）。合倂有機相以鹽水洗滌及真空濃縮獲得粗吡咯啶酮呈白色晶體 (1 8 . 1克）。兩種非對映異構物係於像合相藉製備性HPLC 分離（乙醇/庚烷：1 /1 )，於異丙醚再結晶後獲得兩種吡咯啶酮158(9.5克）及159(7.2克）呈白色固體。觀察得兩種固體形式1 59，亦即形式A及形式B。形式 A之典型特徵爲繞射峰於8.8,9.8,14.9 ,15.0, 17.0, 17.1， 21 ·2,21 ·4,24.8(20度）。形式B典型係以繞射峰於6.50 ，11.25，19.22，23.44，28.47，29.94 (20 度）爲特徵。 2.5.3. 5 -羥-4-丙基·呋喃-2-酮之合成1 £ 2 · 5 . 1 · Step 丨: Reductive amination in a three-necked flask under argon, 4-n-propyl-hydroxyfuranone 373 (35.5 g, 0.25 旲 ear by Bourguignon JJ et al; Journal of Medicinal Chemistry, 1988 '31,893 - 897 synthesis) was added to a solution of S-2 aminamide (28.1 g of '〇·275 mol) in PhMe (355 ml) at 18 °C. The solution was stirred at this temperature for 0.5 hours and precipitation occurred. The reaction mixture was stirred for 2 hours and 4N sodium hydroxide (37.5 mL) was added dropwise to the suspension, followed by aqueous NaBH4 (6.2 g, 〇16 mole) in water (62 mL). After 1 hour, the reaction mixture was quenched carefully with acetic acid (30 mL), warmed to 50 <0>C for 3 hours and cooled to room temperature overnight. Sodium hydroxide 50% w/w (20 mL) was added and the aqueous phase was extracted with toluene (2 times). The organic phase was combined with EtOAc (EtOAc m. It can be recrystallized into a white solid (DSC, starting point: melting point = 72.9 ° C). 2.5.2. Step 2: Hydrogenolysis in a three-necked flask under argon, an aqueous solution of NH4C00H (8 g, 0.126 mol) was added in portions to a coarse 374 (22 g, 0.105 m) and pd/c (1) · 1 g) A suspension of water (220 ml) heated at 50 °C. The suspension was stirred at 1295286 at 50 ° C for 3 hours, cooled to room temperature and stirred overnight. After 18 hours, the suspension was heated at 50 ° C and a portion of aqueous NH.sub.4COOH (8 g, 0.126 moles). After a further 1.5 hours, a third portion of aqueous NH4COOH (8 g, 0.126 mol) was added. The suspension was stirred at 50 ° C for 0.5 hours and 10% Pd/C (1.1 g) was added. The suspension was stirred at this temperature for 5 hours, allowed to stand at room temperature overnight without stirring. The reaction mixture was filtered with EtOAc (EtOAc) The combined organic phase was washed with brine and concentrated in vacuo to give crude pyrrolidone as white crystals (18.1 g). The two diastereomers were separated by preparative HPLC (ethanol/heptane: 1:1), and recrystallized from isopropyl ether to give two pyrrolidone 158 (9.5 g) and 159 ( 7.2 g) is a white solid. Two solid forms 1 59 were observed, namely Form A and Form B. Typical characteristics of Form A are diffraction peaks at 8.8, 9.8, 14.9, 15.0, 17.0, 17.1, 21 · 2, 21 · 4, 24.8 (20 degrees). Form B is typically characterized by diffraction peaks at 6.50, 11.25, 19.22, 23.44, 28.47, 29.94 (20 degrees). 2.5.3. Synthesis of 5-hydroxy-4-propylfuran-2-one

5-羥-4-丙基-5Η-呋喃-2-酮373(15克，0·1莫耳），乙酸乙酯（ 260毫升）及Pd/C 5%置於巴爾裝置。混合物經除氣，氫氣於35 psi壓力下導入其中。然後混合物於25°C 激烈攪拌2小時。於西萊特過濾後溶劑於50°C於減壓下去除獲得5-羥-4-丙基-呋喃-2-酮呈粗產物（100%產率）。 LC/MS : 145(MH+)。 1295286 實例3.經由使用2-溴-丁酸乙酯烷化2-氧基-吡咯啶而合成4-取代2-氧基-吡咯啶丁醯胺。 3.1. 4-取代2-氧基-吡咯啶之合成 3·1·1·&·1· 3·(3·氯苯基）-2-丙烯酸乙酯37 5之製備：5-Hydroxy-4-propyl-5-furan-2-one 373 (15 g, 0.1 mol), ethyl acetate (260 ml) and Pd/C 5% were placed in a bar apparatus. The mixture was degassed and hydrogen was introduced at a pressure of 35 psi. The mixture was then stirred vigorously at 25 ° C for 2 hours. After filtration in celite, the solvent was removed under reduced pressure at 50 ° C to give 5-hydroxy-4-propyl-furan-2-one as crude product (100% yield). LC/MS: 145 (MH+). 1295286 Example 3. Synthesis of 4-substituted 2-oxy-pyrrolidinobutamine by alkylation of 2-oxy-pyrrolidine using ethyl 2-bromo-butyrate. 3.1. Synthesis of 4-substituted 2-oxy-pyrrolidinium 3·1·1·&·1·3·(3·Chlorophenyl)-2-ethyl acrylate 37 5 Preparation:

於配備有機械攪拌器及滴液漏斗於惰性氣氛下之2升三頸瓶內，106.2克（ 755毫莫耳，1當量）3-氯苄醛溶解於1升THF及冷卻至0°C。然後於有效攪拌下加入341 .9 克（ 980毫莫耳，1.3當量）（三苯基亞磷烷基）乙酸乙酯，溫度升高至10°C。混合物於0°C於攪拌下維持1小時，然後於室溫攪拌隔夜。混合物濃縮至乾，殘餘物懸浮於 ***，過濾去除氧化三苯基膦及濾液濃縮至乾。殘餘物藉製備性LC純化（1千克矽膠，石油醚/乙酸乙酯，75.35 ) 獲得 191.8 克純 375,92%產率。4 NMR( 250MHz，（CD3)2SO)In a 2 liter three-necked flask equipped with a mechanical stirrer and a dropping funnel under an inert atmosphere, 106.2 g (755 mmol, 1 equivalent) of 3-chlorobenzylaldehyde was dissolved in 1 liter of THF and cooled to 0 °C. Then, 341.9 g (980 mmol, 1.3 equivalents) of (triphenylphosphinoalkyl)acetic acid ethyl ester was added under effective stirring, and the temperature was raised to 10 °C. The mixture was maintained at 0 ° C with stirring for 1 hour and then stirred at room temperature overnight. The mixture was concentrated to dryness. The residue was purified by preparative LC (1 g, EtOAc (EtOAc) 4 NMR (250MHz, (CD3) 2SO)

:1.30(t，3H) ， 4.25(q，2H)，6.70(d，lH)，7.40(m，2H)， 7_50 - 7.70(m，2H)，7.85(s(寬），111)· 2.1.1.a.2.其它方法：:1.30(t,3H) , 4.25(q,2H), 6.70(d,lH), 7.40(m,2H), 7_50 - 7.70(m,2H), 7.85(s(width),111)· 2.1. 1.a.2. Other methods:

另外，桂皮酸酯衍生物也藉鈀催化丙烯酸衍生物之甲醯金屬化反應合成。例如（2E)-3-(5-嘧啶基）-2-丙烯酸乙酯376係經由丙烯酸乙酯與5-溴嘧啶於乙酸鈀存在下 -63- 1295286 r , * 反應獲得。 3.1 .l.b. 3-(3-氯苯基）-4-硝基丁酸乙酯377之製備：Further, the cinnamate derivative is also synthesized by a rhodium metallation reaction of a palladium-catalyzed acrylic acid derivative. For example, (2E)-3-(5-pyrimidinyl)-2-ethyl acrylate ethyl ester 376 is obtained by the reaction of ethyl acrylate with 5-bromopyrimidine in the presence of palladium acetate -63- 1295286 r, *. 3.1.l.b. Preparation of 3-(3-chlorophenyl)-4-nitrobutyric acid ethyl ester 377:

於配備有回流冷凝器、磁力攪伴器及滴液漏斗於惰性氣氛下於500毫升三頸瓶，100克（ 447毫莫耳，1當量）3-(3_氯苯基）-2-丙烯酸乙酯375溶解於127毫升（2.37莫耳 ’ 5當量）硝基甲烷。於有效攪拌下維持溫度低於25°C(冰 /水浴）逐滴加入70.9毫升（ 447毫莫耳，1當量）二氮雜雙環十一烯。深紅色混合物於室溫攪拌隔夜。混合物以乙醚稀釋，以1N鹽酸洗滌，水相再度以***萃取兩次。合倂有機相以硫酸鎂脫水，過濾及濃縮至乾獲得128.5克粗 377，99%產率，就此用於次一步驟。1H NMR( 250MHz， (CD3)2SO):1.10(t,3H),2.70(dd,1H),2.75(dd,1H),3.95 (q,2H),4.95(m,2H),7.20-7.45 (m,4H). 3.1.1.〇:4-胺基3-(3-氯苯基）丁酸乙酯之378製備：Equipped with a reflux condenser, a magnetic stirrer and a dropping funnel in a 500 ml three-necked flask under an inert atmosphere, 100 g (447 mmol, 1 equivalent) of 3-(3-chlorophenyl)-2-acrylic acid Ethyl 375 was dissolved in 127 mL (2.37 moles of '5 equivalents) of nitromethane. 70.9 ml (447 mmol, 1 equivalent) of diazabicycloundecene was added dropwise while maintaining the temperature below 25 °C (ice/water bath) with effective stirring. The dark red mixture was stirred overnight at room temperature. The mixture was diluted with diethyl ether, washed with 1N hydrochloric acid and then twice twice with diethyl ether. The combined organic phase was dried over magnesium sulfate, filtered and concentrated to dryness to afford 128.5 g of crude 377, 99% yield, which was used for the next step. 1H NMR (250MHz, (CD3)2SO): 1.10 (t, 3H), 2.70 (dd, 1H), 2.75 (dd, 1H), 3.95 (q, 2H), 4.95 (m, 2H), 7.20-7.45 ( m, 4H). 3.1.1. Preparation of 378: 4-amino 3-(3-chlorophenyl)butanoic acid ethyl ester:

於2升壓力瓶內於惰性氣氛下，196克（ 733毫莫耳）3. (3-氯苯基）-4·硝基丁酸乙酯377溶解於200毫升乙醇。加入200克預先乾燥（3次，乙醇）阮尼鎳於700毫升乙醇之懸浮液及混合物於巴爾氫化器於最高20psi氫壓下氫化 -64- 1295286 i (強烈放熱反應，需要冰/水冷卻）。混合物經除氣，於西萊特/諾萊特（Norite)襯墊過濾，濾液經真空濃縮獲得 136.7克粗378，78%產率，就此用於次一步驟。 3.1.1.(1:4-(3-氯苯基）-2-吡咯啶酮379之製備：196 g (733 mmol) of 3-(3-chlorophenyl)-4. nitrobutyrate ethyl ester 377 was dissolved in 200 ml of ethanol in a 2-liter pressure bottle under an inert atmosphere. Add 200 g of pre-dried (3 times, ethanol) Raney nickel in 700 ml of ethanol and mix the mixture in a Baler hydrogenator at a hydrogen pressure of up to 20 psi - 64 - 1295286 i (strong exothermic reaction, ice/water cooling required) . The mixture was degassed and filtered on a pad of Celite/Norite. The filtrate was concentrated in vacuo to afford 136.7 g of crude 378, 78% yield, which was used for the next step. 3.1.1. Preparation of (1: 4-(3-chlorophenyl)-2-pyrrolidone 379:

於500毫升配備有回流冷凝器及磁力攪拌器之燒瓶內 ’ 135.7克（561毫莫耳）4-胺基-3-(3-氯苯基）丁酸乙酯 378溶解於200毫升甲苯，混合物回流30分鐘。溶液濃縮至乾，殘餘物藉製備性LC純化（1千克矽膠，二氯甲烷/ 乙醇，98:2 至 95: 5)獲得 54.4 克純 379(49.2%)。 GC/MS ： 197/197M+. 3. 1 . 1 . f · 2-[4-(3·氯苯基）-2·氧基-1-吡咯啶基]丁酸乙酯380之製備In a 500 ml flask equipped with a reflux condenser and a magnetic stirrer, '135.7 g (561 mmol) of 4-amino-3-(3-chlorophenyl)butyric acid ethyl ester 378 was dissolved in 200 ml of toluene. Reflux for 30 minutes. The solution was concentrated to dryness. EtOAc m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m v GC/MS : 197/197M+. 3. 1 . 1 . f · Preparation of 2-[4-(3·chlorophenyl)-2.oxy-1-pyrrolidinyl]butanoic acid ethyl ester 380

於配備有回流冷凝器、磁力攪拌器及滴液漏斗之2升三頸瓶內，於惰性氣氛下，54.4克（ 278毫莫耳，1當量） 4-(3-氯苯基）-2-吡咯啶酮379溶解於1 .4升乙腈。加入64 毫升（100.7克，556毫莫耳，2當量）2-溴丁酸甲酯，溫度升高至50°C。分成數份加入22.24克（ 556毫莫耳，2當量）氫化鈉，溫度升高至65°C。混合物於50°C又攪拌1小時。混合物濃縮至乾，殘餘物懸浮於乙酸乙酯，以水洗 -65- 1295286 滌，水相再度以乙酸乙酯萃取。合倂有機相以硫酸鎂脫水，過濾及濃縮至乾。殘餘物藉製備性LC純化（1千克矽膠，石油醚/乙酸乙酯，70:30)獲得56.7克純380,69%。 ]H NMR( 250MHz,(CD3)2SO) ： 0.80 - 1.00(m,3H),1.60 -1 .90(2H，m)，2.35 - 2.55 (m，lH :與溶劑部分重疊），2.60 -2.90(m，1H··與溶劑部分重疊），3.70(s，3H)，3.50-3.80 (m，3H)，4.50(m，lH)，7.20-7.50(m，4H). 3.1.1.g: 2-[4-(3 -氯苯基）-2 -氧基-1-吡咯啶基]丁醯In a 2-liter three-necked flask equipped with a reflux condenser, a magnetic stirrer and a dropping funnel, under an inert atmosphere, 54.4 g (278 mmol, 1 equivalent) 4-(3-chlorophenyl)-2- Pyrrolidone 379 was dissolved in 1.4 liters of acetonitrile. 64 ml (100.7 g, 556 mmol, 2 equivalents) of methyl 2-bromobutyrate was added and the temperature was raised to 50 °C. 22.24 g (556 mmol, 2 equivalents) of sodium hydride was added in portions and the temperature was raised to 65 °C. The mixture was stirred at 50 ° C for an additional hour. The mixture was concentrated to dryness. EtOAc EtOAc m. The combined organic phases were dehydrated with magnesium sulfate, filtered and concentrated to dryness. The residue was purified by preparative LC (1 kg EtOAc,EtOAcEtOAcEtOAcEtOAc ]H NMR (250MHz, (CD3)2SO): 0.80 - 1.00 (m, 3H), 1.60 -1 .90 (2H, m), 2.35 - 2.55 (m, lH: partially overlap with solvent), 2.60 - 2.90 ( m,1H·· partially overlaps with the solvent), 3.70 (s, 3H), 3.50-3.80 (m, 3H), 4.50 (m, lH), 7.20-7.50 (m, 4H). 3.1.1.g: 2 -[4-(3-chlorophenyl)-2-oxy-1-pyrrolidinyl]butane

胺381之製備：Preparation of amine 381:

配備有回流冷凝器、磁力攪拌器之1升三頸瓶內，56.7 克（192毫莫耳）2-[4-(3-氯苯基）-2-氧基-1-吡咯啶基]丁酸乙酯380溶解於600毫升甲醇。氣態氨通過溶液，飽和溶液於室溫維持5日，同時偶爾再度使用氨飽和。反應完成後，溶液濃縮至乾。殘餘物藉製備性LC純化（1千克矽膠，二氯甲烷/乙醇，97:3)獲得50克純381，97.8%，82.2 克非對映異構物混合物係藉像合製備性LC分離（像合襯墊 AD，汽油/乙醇，50:50 )，各對對映異構物係藉像合製備性LC做光學分隔（像合襯墊AD，汽油/乙醇，50:50 )。四種化合物由甲苯結晶分別獲得1 6 . 79克、1 3 . 9克、 15.84克及14.84克 202,203,204 及 205,72%總產率。實例4·經由使用2-胺基-丁醯胺烷化/環化4-溴-3·取代 -66 - 1295286 •丁-2-烯酸酯而合成4-取代之2-氧基-吡咯啶丁醯胺。 4 · 1 · 4 -溴-3 -取代-丁 - 2 -烯酸酯之合成，烷化及還原 4.1.1. 3-取代巴豆酸乙酯之溴化 4-溴- 3-( 2-硫苯基）·丁 -2-烯酸乙酯382之合成爲代表56.7 g (192 mmol) 2-[4-(3-chlorophenyl)-2-oxy-1-pyrrolidinyl] Ethyl acetate 380 was dissolved in 600 ml of methanol. Gaseous ammonia was passed through the solution, and the saturated solution was maintained at room temperature for 5 days while occasionally using ammonia saturation again. After the reaction was completed, the solution was concentrated to dryness. The residue was purified by preparative LC (1 kg EtOAc, methylene chloride/ethanol, 97:3) to yield 50 g of pure 381, 97.8%, and 82.2 g of diastereomer mixture was prepared by preparative LC separation (like Pad AD, gasoline/ethanol, 50:50), each pair of enantiomers was optically separated by preparative LC (image pad AD, gasoline/ethanol, 50:50). The four compounds were crystallized from toluene to give 16.79 g, 13.79 g, 15.84 g, and 14.84 g of 202, 203, 204 and 205, 72% total yield, respectively. Example 4: Synthesis of 4-substituted 2-oxy-pyrrolidine via alkylation with 4-amino-butyridamine/cyclization of 4-bromo-3.-substituted-66 - 1295286 • but-2-enoate Butylamine. Synthesis, alkylation and reduction of 4 · 1 · 4 -bromo-3-substituted-but-2-butenoic acid esters 4.1.1. 3-Bromo-bromo acid ethyl bromide 4-bromo-3-(2-sulfuric acid Synthesis of phenyl)-but-2-enoic acid ethyl ester 382 is representative

383383

於2升三頸瓶內於氬下藉著機械攪拌將2 -硫苯基-3 -基 -丁-2-烯-酸乙酯 383(32.88 克，0.211 莫耳），N-溴丁二醯亞胺（37.56克，0.211莫耳）及2,21-氮雜-貳-異丁腈 (3·46克，0.021莫耳）於四氯化碳（ 600毫升）之除氣溶液回流6小時，冷卻至室溫及攪拌20小時。懸浮液經過濾及真空濃縮獲得粗溴化物，粗產物於矽膠藉層析術純化 (己烷/二氯甲烷：65/35(ν/ν))獲得4 -溴- 3- (2 -硫苯基）-丁- 2-烯酸乙酯 382(36.72 克，78%)。4 NMR( 250MHz， (CDC13):3.80(s，3H) ， 4.95(s，2H)，6.25(s，lH)，7.10 (dd，lH)，7.35(d，lH)，7·45 (d，lH” 4.1.2.使用2-胺基-丁醯胺烷化以2-[2 -氧基- 4- (2 -噻吩基）-1-吡咯啶基]丁醯胺71 之合成爲代表： -67- 129528,62-Hydroxyphenyl-3-yl-but-2-ene-acid ethyl ester 383 (32.88 g, 0.211 mol), N-bromobutane, in a 2-liter three-necked flask under mechanical stirring with argon The imine (37.56 g, 0.211 mol) and 2,21-aza-indole-isobutyronitrile (3·46 g, 0.021 mol) were refluxed in a degassing solution of carbon tetrachloride (600 ml) for 6 hours. Cool to room temperature and stir for 20 hours. The suspension is filtered and concentrated in vacuo to give the crude bromide. The crude product is purified by chromatography (hexane/dichloromethane: 65/35 (v/v)) to give 4-bromo-3-(2-thiobenzene) Ethyl 4-butenoate ethyl ester 382 (36.72 g, 78%). 4 NMR (250MHz, (CDC13): 3.80 (s, 3H), 4.95 (s, 2H), 6.25 (s, lH), 7.10 (dd, lH), 7.35 (d, lH), 7·45 (d, lH" 4.1.2. Alkylation with 2-amino-butylimamine is represented by the synthesis of 2-[2-oxy-4-(2-thiophenyl)-1-pyrrolidinyl]butanamine 71: -67- 129528,6

4 . 1 . 2 . 1 .步驟1 :烷化-環化_ 於1升三頸瓶於氬下，4-溴-2-硫苯-3-基-丁-2·烯-酸 ® 甲酯382( 36.72克，0.134莫耳），（S)-2-胺基-丁醯胺 ([a ]25D : 19.09 度；31 . 6 克，0· 270 莫耳）於 THF( 350 毫升）之溶液於室溫攪拌20小時。懸浮液經過濾及真空濃縮獲得粗未飽和吡咯啶酮3 84及385 ( 43.47克），其未經進一步純化即用於次一步驟。粗吡咯啶酮可分離且通常爲雙鍵異構物混合物（呈3，4及4,5之烯烴，以前者爲主要異構物）。沱 NMR( 250MHz，（CD3)2SO):0.80(t，3H)，1.30-1.90 (m，2H) ， 4.40(d，lH)，4.45(m，lH)，4.70(d，lH)，6.30(5， _ 2H)，7.〇(s(寬），1Η)，7·15(dd，lH)，7.40(s(寬），1Η)，7·50 (d，lH)，7.85 (d，lH)· 4.1.2.2.步驟2:還原於0 · 5升三頸瓶內於氬下，分成數份NaBH4( 1 · 75克， 0.044莫耳）至粗未飽和吡咯啶酮384/ 385( 14克，0.044 莫耳），C〇C1 2( 0.062克，0.0005莫耳）於乙醇（100毫升二乙二醇二甲醚（6 5毫升）冷卻至0 °C之溶液。經〇 . 7 5小時後，反應混合物回流加熱48小時，於該段期間每1〇小時依序加入三份NaBH4(l_75克，0.045莫耳）及c〇C12(0.062 -68- 1295286 * 克，0.0005莫耳）至起始物料的消失爲止。反應混合物冷卻至室溫，以飽和氯化銨水解，以乙酸乙酯萃取，以硫酸鎂脫水及真空濃縮獲得粗吡咯碇酮，其於矽膠藉管柱層析術純化（二氯甲烷/甲醇：97 /03 (v/v))獲得4.15克 2-[2 -氧基- 4- (2-噻吩基）-1-吡咯啶基]丁醯胺（38%)。立體異構物混合物於像合相藉管柱層析術純化（己烷/乙醇）獲得兩種非對映異構物（2S)-2-[2 -氧基- 4·(2 -噻吩基）· 1-吡咯啶基]丁醯胺71 (於乙酸乙酯再結晶）及72(於乙酸 > 乙酯再結晶）。此特定例中於純化期間也獲得兩種小量雜質，亦即（2R)-2-[2-氧基-4-(2-噻吩基）-1-吡咯啶基]丁醯胺84( 0.25.克，於乙酸乙酯再結晶）及85( 0.44克，於乙酸乙酯再結晶）兩種非對映異構物。 4.2 .疊氮基苯基吡咯啶酮之合成 (2S)-2-[4-(3-疊氮基苯基）-2-氧基-1·吡咯啶基]丁醯胺86之單一對映異構物之合成爲代表：4 . 1 . 2 . 1 . Step 1: alkylation-cyclization _ 4-bromo-2-thiophenyl-3-yl-but-2-ene-acid® methyl ester in a 1-liter three-necked flask under argon 382 (36.72 g, 0.134 mol), (S)-2-amino-butylimamine ([a]25D: 19.09 degrees; 31.6 g, 0·270 mol) in THF (350 mL) Stir at room temperature for 20 hours. The suspension was filtered and concentrated in vacuo to give crude crude br. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The crude pyrrolidone is separable and usually a mixture of double bonds (3, 4 and 4, 5 olefins, the former being the main isomer).沱NMR (250MHz, (CD3)2SO): 0.80 (t, 3H), 1.30- 1.90 (m, 2H), 4.40 (d, lH), 4.45 (m, lH), 4.70 (d, lH), 6.30 ( 5, _ 2H), 7. 〇 (s (width), 1 Η), 7·15 (dd, lH), 7.40 (s (width), 1 Η), 7·50 (d, lH), 7.85 (d, lH)· 4.1.2.2. Step 2: Reduction in a 0.5 liter three-necked flask under argon, divided into several portions of NaBH4 (1 · 75 g, 0.044 mol) to crude unsaturated pyrrolidone 384/ 385 (14克, 0.044 摩尔), C〇C1 2 (0.062 g, 0.0005 mol) in ethanol (100 ml of diethylene glycol dimethyl ether (65 ml) cooled to 0 ° C solution. 〇. 7 5 hours Thereafter, the reaction mixture was heated under reflux for 48 hours, and three portions of NaBH4 (1 - 75 g, 0.045 mol) and c〇C12 (0.062 - 68 - 1295286 * g, 0.0005 mol) were sequentially added every 1 hour during the period. The reaction mixture was cooled to room temperature, hydrolyzed with saturated ammonium chloride, extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo to give crude pyrrolone, which was purified by silica gel column chromatography ( Methylene chloride/methanol: 97 /03 (v/v)) 4.15 g of 2-[2-oxy-4-(2-thiazide) Benzyl-1-pyrrolidyl]butanamine (38%). The mixture of stereoisomers was purified by enzymatic phase column chromatography (hexane/ethanol) to obtain two diastereomers (2S). 2-[2-Oxo-4(2-thienyl)·1-pyrrolidinyl]butanamine 71 (recrystallized from ethyl acetate) and 72 (recrystallized from acetic acid & ethyl acetate). In this particular example, two minor impurities were also obtained during the purification, namely (2R)-2-[2-oxy-4-(2-thienyl)-1-pyrrolidinyl]butanamine 84 (0.25 .g, recrystallized from ethyl acetate) and 85 (0.44 g, recrystallized from ethyl acetate) of two diastereomers. 4.2. Synthesis of azidophenylpyrrolidone (2S)-2- The synthesis of a single enantiomer of [4-(3-azidophenyl)-2-oxy-1.pyrrolidinyl]butanamine 86 is representative:

4.2 . 1 .苯胺之合成 -69- 1295286 . 4.2.1.1.步驟1:藉4-溴-3-(3-硝基苯基）-丁-2-烯-酸甲酯386烷化（S)-2-胺基丁醯胺 386之合成係如§4.1.1.所述進行。1H NMR( 250MHz， (CD3)2SO):1·30(t，3H)，4.20(q，2H)，5·15(s，2Η)，6·45 (s，1H)，7.75(dd，1H)，8.10(dd，lH)，8·25(dd，lH)，8.45 (d,lH). 烷化係遵照§4.1·2· 1·之實驗程序進行（59%)。 LC/MS : 290(MH+)。 ^ 4.2.1.2.步驟2:還原於2 · 5升壓力瓶內於惰性氣氛下，7.2 2克（0 · 0 2 5莫耳） 387及鈀/木炭（10% w/w，0.2克）溶解於乙醇（1升）及混合物於巴爾氫化器於最高20psi氫壓氫化。1小時後，混合物經除氣，於西萊特/諾萊特襯墊過濾，濾液經真空濃縮獲得粗吡咯啶酮，於矽膠藉管柱層析術純化（二氯甲烷/ 甲醇：93 /07(v/v))獲得非對映異構物混合物，其係於像合相藉管柱層析術純化（己烷/乙醇）與鹽酸於乙醇反應 (用於合成鹽酸鹽）後獲得（2S)-2-[4-(3-胺基苯基）-2-• 氧基-1-吡咯啶基]丁醯胺90( 0.800克，於乙醇再結晶）及 91(1 .21克，於乙醇再結晶）兩種非對映異構物，呈鹽酸鹽0 4.2.2·苯基疊氮基86之合成。於三頸瓶內於氬下，亞硝酸鈉（ 0.232克，0.0037莫耳）於水（1 .5毫升）之溶液逐滴添加至（2S)-2-[4-(3_胺基苯基）-2-氧基-1-吡咯啶基]丁醯胺90自由態鹼（0.8克， 0.0031莫耳）於鹽酸10M(6.5毫升）冷卻至〇°c之溶液。於室溫經0.5小時後，加入NaN3 ( 0.220克，0.0037莫耳）於 -70- 1295286 水（2毫升），所得溶液於〇°C攪拌Ο · 5小時。反應混合物以氫氧化鈉（33% w/w)淬熄及藉乙酸乙酯稀釋。水相酸化至PH5 - 6及以乙酸乙酯萃取。合倂有機相以硫酸鎂脫水及真空濃縮獲得粗吡咯啶酮，其於矽藉管柱層析術純化（二氯甲烷/甲醇：97/03 (v/v))，於乙腈再結晶後獲得0.42 克（2S)-2-[2 -氧基- 4- (3 -疊氣基苯基）-1-卩比咯n定基]丁釀胺86之單一對映異構物86( 48%)。4.2. 1. Synthesis of aniline -69- 1295286 . 4.2.1.1. Step 1: alkylation of 4-bromo-3-(3-nitrophenyl)-but-2-ene-acid methyl ester 386 (S) The synthesis of 2-aminobutylinamide 386 is carried out as described in § 4.1.1. 1H NMR (250MHz, (CD3)2SO): 1·30 (t, 3H), 4.20 (q, 2H), 5·15 (s, 2Η), 6·45 (s, 1H), 7.75 (dd, 1H) ), 8.10 (dd, lH), 8·25 (dd, lH), 8.45 (d, lH). The alkylation was carried out according to the experimental procedure of §4.1.2·1· (59%). LC/MS: 290 (MH+). ^ 4.2.1.2. Step 2: Reduction in a 2 liter pressure bottle under an inert atmosphere, 7.2 2 g (0 · 0 2 5 m) 387 and palladium / charcoal (10% w/w, 0.2 g) dissolved The ethanol (1 liter) and the mixture were hydrogenated at a hydrogen pressure of up to 20 psi in a Bar hydrogenator. After 1 hour, the mixture was degassed, filtered over a pad of Celite/Nollet, and the filtrate was concentrated in vacuo to give crude pyrrolidone, which was purified by column chromatography (methylene chloride / methanol: 93 s. /v)) Obtaining a mixture of diastereomers obtained after purification by means of phase-separated column chromatography (hexane/ethanol) and hydrochloric acid in ethanol (for synthesis of hydrochloride) (2S) -2-[4-(3-Aminophenyl)-2-•oxy-1-pyrrolidinyl]butanamine 90 (0.800 g, recrystallized from ethanol) and 91 (1.21 g, in ethanol Recrystallization) The two diastereomers are synthesized as the hydrochloride 0.2.2. Phenyl azide 86. Add a solution of sodium nitrite (0.232 g, 0.0037 mol) in water (1.5 ml) to (2S)-2-[4-(3-aminophenyl) in a three-necked flask under argon. -2-oxo-1-pyrrolidinyl]butanamine 90 free base (0.8 g, 0.0031 mol) was cooled to a solution of EtOAc (EtOAc) EtOAc. After 0.5 hours at room temperature, NaN3 (0.220 g, 0.0037 mol) was added to -70-1295286 water (2 ml), and the resulting solution was stirred at 〇 ° C for 5 hours. The reaction mixture was quenched with sodium hydroxide (33% w/w) and diluted with ethyl acetate. The aqueous phase was acidified to pH 5-6 and extracted with ethyl acetate. The combined organic phase is dehydrated with magnesium sulfate and concentrated in vacuo to give crude pyrrolidone, which is purified by column chromatography (dichloromethane/methanol: 97/03 (v/v)). 0.42 g (2S)-2-[2-oxy-4-(3-pyrimidinylphenyl)-1-indolyl n-based] butylamine 86 single enantiomer 86 (48%) .

4·3· (2S)-2-[4-(3-胺基-2,4,6-三溴苯基）-2-氧基-l-吡咯啶基]丁醯胺107之合成Synthesis of (2S)-2-[4-(3-Amino-2,4,6-tribromophenyl)-2-oxo-l-pyrrolidinyl]butanamine 107

107107

於三頸瓶內於氬下，Ph3PCH2PhBr3( 2.870克，0.048 旲耳）及90(0.420克，0.0016莫耳）於二氯甲院（1〇毫升）及甲醇（5毫升）之溶液與碳酸氫鈉（〇 · 407克，〇 · 048莫耳）於室溫共同攪拌4小時（橙色溶液）。反應混合物經過濾及真空濃縮獲得粗製苯胺，於矽膠藉管柱層析術純化（乙酸乙酯/乙醇98/02(v/v))獲得〇·38克預期苯胺1〇7(47%，由***再結晶）。 4.4· (2S)-2-[4-甲基-2-氧基-1-吡咯啶基]丁醯胺35及 36之合成 -71- 129528,6In a three-necked flask under argon, Ph3PCH2PhBr3 ( 2.870 g, 0.048 旲 ear) and 90 (0.420 g, 0.0016 mol) in a solution of dichlorocarbyl (1 ml) and methanol (5 ml) with sodium bicarbonate (〇·407 g, 〇·048 mol) Stir for 4 hours (orange solution) at room temperature. The reaction mixture was filtered and concentrated in vacuo to give EtOAc EtOAc (EtOAc) Recrystallization of ether). 4.4·(2S)-2-[4-Methyl-2-oxy-1-pyrrolidyl]butanamine 35 and 36 Synthesis -71- 129528,6

389 35389 35

35及36係藉外消旋混合物389於像合靜相使用乙0?及己烷做溶劑藉像合純化獲得。35係於i-Pr2〇Et再結晶# 呈白色晶體獲得。36係於***再結晶後呈白色晶體獲得1 ° 實例5.經由1-[1-(胺基羰基）丙基氧基_3-卩比咯D定羧酸甲酯11衍生合成4-取代2-氧基-吡咯陡丁醯胺° 5. 1 . 1- [1-(胺基羰基）丙基]-5-氧基-3-吡咯啶羧酸甲酯11/12之合成The 35 and 36 were obtained by the racemic mixture 389 in the form of a stationary phase using ethyl acetate and hexane as a solvent. The 35 series was obtained by recrystallizing i-Pr2〇Et# in white crystals. 36 is obtained as white crystals after recrystallization from diethyl ether to obtain 1 °. Example 5. Derivatization of 4-substituted 2 via 1-[1-(aminocarbonyl)propyloxy-3-pyrrole-D-carboxylic acid methyl ester 11 -oxy-pyrrolethromidium ° 5. 1. Synthesis of methyl 1-methyl 1-[1-(aminocarbonyl)propyl]-5-oxy-3-pyrrolidinecarboxylate 11/12

此種轉變係述於§7.0.1而製造兩種酯11及12。 5.2. 1-[2S-1-(胺基碳基）丙基]-5 -氧基-3-卩比略H定殘酸 48之合成This conversion is described in § 7.0.1 for the manufacture of two esters 11 and 12. 5.2. Synthesis of 1-[2S-1-(aminocarbyl)propyl]-5-oxy-3-indole ratio H-reserved acid 48

於三頸瓶於氬下，1N氫氧化鈉（126毫升）溶液添加至對映異構純質酯1U22.62克，〇.丨莫耳）於甲醇冷卻至〇。〇之溶液。於此溫度經i.5小時後’反應藉1N鹽酸（1〇9毫 -72- 129528.6 , r ' 升）酸化，真空蒸發去除溶劑，殘餘物以異丙醇萃取，過濾及濾液經真空濃縮獲得粗酸U 7 · 82克），由乙膪再結晶獲得對映異構純質W2S-1-(胺基羰基）丙基]氧基 -3-吡咯啶羧酸48。 5.3. (23)-2-[4-(1，3,4-噚二唑-2-基）-2-氧基-1-吡咯啶基]丁醯胺50之合成A three-necked flask was added to a solution of 1N22.62 g of enantiomerically pure ester under argon, 1N sodium hydroxide (126 mL), and then cooled to hydr. 〇 Solution. After i.5 hours at this temperature, the reaction was acidified with 1N hydrochloric acid (1 </ br> <RTI ID=0.0></RTI> </RTI> <RTIgt; Crude acid U 7 · 82 g), recrystallized from acetamidine to give enantiomerically pure W2S-1-(aminocarbonyl)propyl]oxy-3-pyrrolidinecarboxylic acid 48. 5.3. Synthesis of (23)-2-[4-(1,3,4-oxadiazol-2-yl)-2-oxy-1-pyrrolidinyl]butanamine 50

步驟1 :與肼反應於三頸瓶內於氬下，酯11(3克，0.013莫耳）及脫水合物（0.7毫升）之溶液於乙醇（3毫升）攪拌24小時。然後黃色溶液濃縮獲得粗醯肼391，於放置時結晶（2.37克，79%)。 GC/MS ·· 228(M+)。步驟2:曙二唑之合成於三頸瓶於氬下，粗醯肼391(本專利，3克，0.013莫耳），原甲酸三乙酯（2毫升）及對甲苯磺酸（0.010克）之溶液於110°C加熱24小時。反應混合物冷卻至室溫，真空濃縮獲得粗噚二唑，其於矽膠藉層析術純化（二氯甲院/甲醇：95 / 05 (v/v))獲得（2S)-2-[4-(l，3,4-噚二唑-2-基） -2-氧基-1-吡咯啶基]丁醯胺50(0.312克）呈油。 5·4· 1，3,4-二噚唑衍生物之合成另外1，3,4-二噚唑衍生物係得自肼391。例如2•[八氧基- 4- (5-硫烷基-1，3，4·噚二唑-2-基）-1·吡咯啶基]丁醯 -73- 129528,6 胺5 1係經由肼39 1與CS2及氫氧化鉀於乙醇反應獲得。 5.5. 4-胺基-吡咯啶·2·酮392之合成Step 1: Reaction with hydrazine A solution of ester 11 (3 g, 0.013 mol) and dehydrated compound (0.7 ml) was stirred in ethanol (3 ml) in a three-necked flask under argon for 24 hours. The yellow solution was then concentrated to give crude 391, which crystallised (2.37 g, 79%). GC/MS ·· 228 (M+). Step 2: Synthesis of oxadiazole in a three-necked flask under argon, crude 醯肼391 (this patent, 3 g, 0.013 mol), triethyl orthoformate (2 ml) and p-toluenesulfonic acid (0.010 g) The solution was heated at 110 ° C for 24 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to give the crude succinimide, which was purified by chromatography (dichlorobenzene/methanol: 95 / 05 (v/v)) (2S)-2-[4- (l,3,4-oxadiazol-2-yl)-2-oxo-1-pyrrolidinyl]butanamine 50 (0.312 g) is an oil. Synthesis of 5·4· 1,3,4-dicarbazole derivatives The other 1,3,4-dicarbazole derivatives were obtained from 肼391. For example, 2•[octaoxy-4-(5-sulfanyl-1,3,4·oxadiazol-2-yl)-1·pyrrolidinyl]butane-73- 129528,6 amine 5 1 It is obtained by reacting 肼39 1 with CS2 and potassium hydroxide in ethanol. 5.5. Synthesis of 4-amino-pyrrolidin-2-one 392

5.5. 1 .步驟1 ··胺基甲酸酯39 3之合成於三頸瓶於氬下，對映異售純質1-[2S-1-(胺基幾基）丙基]-5-氧基-3-吡咯啶羧酸48 ( 1 9.06克，0·089莫耳），二苯基磷醯疊氮（26.9克，0.097莫耳）及三乙基胺（13.5 毫升）於乙膪（ 225毫升）之溶液於55°C加熱伴以形成氮氣。溫度於55°C _持0 · 5小時，於70°C維持2小時及冷卻至室溫。加入苄醇（9.2 5毫升）及溶液回流4小時，冷卻至室溫及真空濃縮。粗胺基甲酸酯於矽膠藉層析術純化（乙酸乙酯/甲醇/氫氧化銨：95/04/01 ( v/v))獲得兩種非對映異構物胺基甲酸酯394( 2.64克，9.3%)及393 ( 1 1 .9克，42%) 。至於 393 : !H NMR( 250MHz，（CDCl3):0.9O(t，3H)，1.30 •74- 奶5286 1 1 .90(m,2H) ^ 2.35(dd, 1H),2.75(dd,1H),3.30(dd,1H) ，3,75(m，lH) ， 4.30-4.50(m，2H)，5.10(s，2H)，5.35(s, (寬），111)，5.11(8(寬），11^)，60.40(8(寬），111)，7.30-7·45(ιη，5Η)。 5·5·2·步驟2:4-胺基-吡咯啶-2-酮392之合成於0.25升加壓瓶內於惰性氣氛下，11 .9克（0.037毫莫耳）3 93及鈀/木炭（10% w/w，0.2克）溶解於乙醇（ 300毫升）及混合物於巴爾氫化器於最高20psi氫壓下氫化。經20 小時後混合物經除氣，於西萊特/諾萊特襯墊過濾及濾液 b 經真空濃縮獲得粗製胺，其由甲苯再結晶獲得2-[ 4-胺基 -2·氧基-1-¾咯π定基]丁醯胺392(6.99克，定量產率）。 5.6· 4-吡咯啶-2-酮223之合成5.5. 1. Step 1. · Synthesis of carbamate 39 3 in a three-necked flask under argon, enantiomerically sold pure 1-[2S-1-(amino)propyl]-5- Oxy-3-pyrrolidinecarboxylic acid 48 (1 9.06 g, 0·089 mol), diphenylphosphonium azide (26.9 g, 0.097 mol) and triethylamine (13.5 ml) in acetamidine ( A solution of 225 ml) was heated at 55 ° C to form nitrogen. The temperature was maintained at 55 ° C for 0 · 5 hours, maintained at 70 ° C for 2 hours and cooled to room temperature. Benzyl alcohol (9.25 ml) was added and the solution was refluxed for 4 hr then cooled to room temperature and concentrated in vacuo. The crude urethane was purified by chromatography on silica gel (ethyl acetate / methanol / ammonium hydroxide: 95/04/01 (v / v)) to afford two diastereomers carbazides 394 ( 2.64 g, 9.3%) and 393 (1 1. 9 g, 42%). As for 393 : !H NMR ( 250MHz, (CDCl3): 0.9O (t, 3H), 1.30 • 74- milk 5286 1 1 .90 (m, 2H) ^ 2.35 (dd, 1H), 2.75 (dd, 1H) , 3.30 (dd, 1H), 3, 75 (m, lH), 4.30-4.50 (m, 2H), 5.10 (s, 2H), 5.35 (s, (width), 111), 5.11 (8 (width) , 11^), 60.40 (8 (width), 111), 7.30-7·45 (ιη, 5Η). 5·5·2·Step 2: Synthesis of 4-amino-pyrrolidin-2-one 392 In a 0.25 liter pressurized bottle under an inert atmosphere, 11.9 g (0.037 mmol) of 3 93 and palladium/charcoal (10% w/w, 0.2 g) dissolved in ethanol (300 ml) and mixture in a bar hydrogenator Hydrogenation at a hydrogen pressure of up to 20 psi. After 20 hours, the mixture was degassed, filtered on a Celite/Nollet pad and the filtrate b was concentrated in vacuo to give a crude amine which was recrystallized from toluene to give 2-[4-amino- 2·oxy-1-3⁄4 π 定】 butylamine 392 (6.99 g, quantitative yield) 5.6· Synthesis of 4-pyrrolidin-2-one 223

於三頸瓶內於氬下，2· [4-胺基-2-氧基-1 -吡咯啶基] 丁醯胺393(6.99克，0.03 7莫耳），二甲氧四氫呋喃（5.53 克’ 0.041吴耳），卩比卩定（50.6毫升）及乙酸（36毫升）之懸浮液溫熱至70°C及進行溶解。於此溫度經2小時後，反應冷卻至室溫，經真空濃縮及粗產物於矽膠藉層析術純化（二氯甲烷/甲醇：95/05(v/v))獲得223呈油（2.67克， 30.1%) 0 5 · 7 · 4-吡咯基-吡咯啶-2-酮223之溴化 -75- 1295286 1 * 1In a three-necked flask under argon, 2·[4-amino-2-oxy-1-pyrrolidinyl]butanamine 393 (6.99 g, 0.03 7 mol), dimethoxytetrahydrofuran (5.53 g' 0.041 ul), a suspension of hydrazine (50.6 ml) and acetic acid (36 ml) was warmed to 70 ° C and dissolved. After 2 hours at this temperature, the reaction was cooled to rt. EtOAc (EtOAc) , 30.1%) 0 5 · 7 · 4-pyrrolyl-pyrrolidin-2-one 223 bromination -75 - 1295286 1 * 1

於0.25升三頸瓶於氬下以磁力攪拌，2S-4-吡咯-吡咯啶-2-酮223呈單一對映異構物（1· 18克，0.0049莫耳）於 THF(35毫升）之除氣溶液冷卻至- 78°C及分成數份加入N-溴丁二醯亞胺（ 0.877克，0.005莫耳）。反應混合物攪拌〇.5 小時，硫代硫酸鈉（0 · 9克）加入其中而淬熄NBS。反應混合物溫熱至室溫，真空濃縮及於矽膠藉層析術純化（乙醇/ 二氯甲烷：05 / 95 (v/v))，於乙腈再結晶後獲得（2S)-2-[4-(2-溴-1H-吡咯-1-基）-2·氧基-1·吡咯啶基]丁醯胺 2 34( 1.05克，67%)呈白色固體。另外使用相同實驗程序及2當量Ν-溴-丁二醯亞胺，可獲得二溴吡咯237。 5.8. 四唑基衍生物之合成另外對§5.6而言，2-[ 4-胺基-2-氧基-1-吡咯啶基] 丁醯胺與原甲酸三乙酯、疊氮化鈉及乙酸反應獲得2 - [ 2 _ 氧基- 4-( 1Η-四唑-1-基）-1-吡咯啶基]丁醯胺67。 5.9. (4H-1，2,4-四唑-4-基）衍生物之合成另外對§5.6而言，2·[4-胺基-2-氧基-1-吡咯啶基] 丁醯胺與吡啶及1，2 -貳（二甲基胺基）亞甲基）肼反應獲得 2-[2-氧基-4-(41^1，2,4-***-4-基）-1-吡咯啶基]丁醯胺65及66 。實例6.經由卜[1-(第三丁氧羰基）丙基卜5-氧基-3-吡咯啶羧醛396之烯化合成4-取代2-氧基-吡咯啶丁醯胺。 6 . 1 . 1 - [ 1 -(第三丁氧羰基）丙基5 -氧基-3 -吡咯啶羧醛 •Ί6- 1295286 . 396之合成步驟1 : 2 ·胺基丁酸酯與衣康酸甲酯縮合The 0.25 liter three-necked flask was magnetically stirred under argon. The 2S-4-pyrrole-pyrrolidin-2-one 223 was obtained as a single enantiomer (1·18 g, 0.0049 mol) in THF (35 mL). The degassing solution was cooled to -78 ° C and N-bromobutaneimine (0.877 g, 0.005 mol) was added in portions. The reaction mixture was stirred for 5 hours, and sodium thiosulfate (0.9 g) was added thereto to quench NBS. The reaction mixture was warmed to room temperature, concentrated in vacuo and purified by EtOAc (EtOAc/EtOAc (EtOAc/EtOAc) (2-Bromo-1H-pyrrol-1-yl)-2.oxy-1.pyrrolidinyl]butanamine 2 34 (1.05 g, 67%) as a white solid. Further, dibromopyrrole 237 was obtained using the same experimental procedure and 2 equivalents of ruthenium-bromo-butanediamine. 5.8. Synthesis of tetrazolyl derivatives Further, for § 5.6, 2-[4-amino-2-oxy-1-pyrrolidinyl]butanamine and triethyl orthoformate, sodium azide and The acetic acid reaction gave 2 -[ 2 _oxy-4-(1Η-tetrazol-1-yl)-1-pyrrolidinyl]butanamine 67. 5.9. Synthesis of (4H-1,2,4-tetrazol-4-yl) Derivatives In addition to §5.6, 2.[4-Amino-2-oxy-1-pyrrolidinyl]butane The amine is reacted with pyridine and 1,2-anthracene (dimethylamino)methylene) hydrazine to give 2-[2-oxy-4-(41^1,2,4-triazol-4-yl)- 1-pyrrolidinyl]butanamine 65 and 66. Example 6. Synthesis of 4-substituted 2-oxy-pyrrolidinobutamine by olefination of [1-(t-butoxycarbonyl)propyl 5-methoxy-3-pyrrolidinecarboxaldehyde 396. 6 . 1 . 1 - [ 1 -(Tertidinoxycarbonyl)propyl 5-oxy-3-pyrrolidinecarboxaldehyde • Ί6- 1295286 . Synthesis of 396 Step 1: 2 · Aminobutyrate and itacon Acid methyl ester condensation

於1升三頸瓶於氬下，2,2·二甲基乙基（s)-2_胺基丁酸酯（市售，46.6克，0.268莫耳）及衣康酸二甲酯（8 3毫升，0·59莫耳）之溶液於甲醇（400毫升）回流20小時。混合物於室溫攪拌20小時，經真空濃縮，殘餘物於矽膠藉層析術純化（二氯甲烷/甲醇：97/3(ν/ν))獲得1-[(1S) -1-(第三丁氧羰基）丙基]-5-氧基-3-吡咯啶羧酸甲酯397 (81.6克，定量產率）。l-[(lS)-l-(第三丁氧羰基）丙基] -5-氧基-3-吡咯啶羧酸甲酯397之1/1混合物分析：沱 NMR(250MHz ，（CD3)2SO) : 1.05(t，3H)，1.44(s，9H)，1.60 -1 .65(m，lH)，1 .65- 1.90( m，lH) ,2.40-2.65( m，2H 與溶劑部分信號重疊），3.30 - 3.65 (m，3H)，3.70(s，3H)，4.40(dd ，1H)。另外，反應也可使用外消旋2,2·二甲基乙基-2-胺基_ 丁酸酯進行獲得外消旋丁醯胺，產率類似。步驟2 : 醯396之合成。In a 1 liter three-necked flask under argon, 2,2·dimethylethyl(s)-2-aminobutyrate (commercially available, 46.6 g, 0.268 mol) and dimethyl itaconate (8) A solution of 3 ml, 0·59 mol) was refluxed in methanol (400 ml) for 20 hours. The mixture was stirred at room temperature for 20 hr, then concentrated in vacuo. EtOAc mjjjjjjjjj Methyl butyloxy)propyl]-5-oxy-3-pyrrolidinecarboxylate 397 (81.6 g, quantitative yield). 1/1 mixture analysis of methyl 1-[(lS)-l-(t-butoxycarbonyl)propyl]-5-oxy-3-pyrrolidinecarboxylate 397: 沱NMR (250MHz, (CD3)2SO ) : 1.05(t,3H), 1.44(s,9H), 1.60 -1 .65(m,lH), 1.65- 1.90( m,lH) , 2.40-2.65 ( m,2H overlaps with the solvent part signal) ), 3.30 - 3.65 (m, 3H), 3.70 (s, 3H), 4.40 (dd, 1H). Alternatively, the reaction can also be carried out using racemic 2,2·dimethylethyl-2-amino-butyrate to obtain the racemic butyzanamine in a similar yield. Step 2: Synthesis of 醯396.

酯397還原成爲醇398 -77- 129528,6 係使用§ 7·0·2·所述方法使用397爲單一對映異構物，兩種對映異構物混合物或4種立體異構物之1 /1 /1 /1混合物進行。至於（2S ) - 2 - [ 4 -(羥甲基）-2 -氧基-1-吡咯啶基] 丁酸第三丁酯398之1/1非對映異構物混合物·· GC/MS:25 7 M+ 〇氧化成爲醛396 於三頸瓶內於氬下，（2S)-2-[4-(羥甲基）-2-氧基-1-吡咯啶基]丁酸第三丁酯398( 4.0克，0.016莫耳）於二氯 | 甲烷（8毫升）之溶液添加至Cr03 (6.2克，0.062莫耳）於吡啶（11 · 3毫升）/二氯甲烷（8〇毫升）於室溫攪拌之懸浮液。溫度升高至30°C，懸浮液攪拌0.2小時。懸浮液經西萊特過濾，濾液依次以1N鹽酸、鹽水洗滌，以硫酸鎂脫水及真空濃縮獲得粗醛，醛於矽膠藉管柱層析術純化（己烷/ 丙酮70 /30(v/v))獲得2.03克l-[(lS)-l-(第三丁氧羰基）丙基]-5-氧基·3-吡咯啶羧醛396(41%)。另外反應也可使用外消旋酯進行獲得外消旋醛，具有類似產率。l-[(lS)-l-(第三丁氧羰基）丙基卜5-氧基 φ -3-吡咯啶羧醛396之1/1混合物之分析：沱NMR( 25 0MH， (CDC13) : 0.91(t，3H)，1.44(s，8H)，1.55-1.77(m，lΗ)， 1.90-2.15(m，lH)，2.63-2.82(m，2H)，3.47-3.61(m，lH)， 3.65 - 3.79 (m，lH)，3.83-3.94(m，非對映異構物之一之 1H)，4.48-4.62(m，lH)，9.74(s(寬），1H) 6·2· l-[(lS)-l-(第三丁氧羰基）丙基]-5 -氧基-3·吡咯啶羧醛396之烯化反應 6 · 2 · 1 .烯屬衍生物之合成。替代§ 6 · 2 · 3 ·，烯屬衍生物可經由1 - [ ( 1 S ) -1 -(第三 -78- 1295286 丁氧羰基）丙基卜5-氧基·3-吡咯啶羧酸396與鱗鹽於強鹼存在下進行威堤氏（Wit tig)烯化反應獲得。例如（2S)-2-(2 -氧基-4-乙烯基-1-吡咯啶基）丁酸2，2-(二甲基）乙基酯係經由醛396與Ph3PCH3Br及n-BuLi於THF反應獲得。 6.2.2.經由使用Ph3P/CBr4烯化Reduction of ester 397 to alcohol 398-77-129528, 6 using 397 as a single enantiomer, a mixture of two enantiomers or four stereoisomers using the method described in § 7.0.2. 1 / 1 / 1 / 1 mixture was carried out. As for (2S)-2-(4-hydroxymethyl)-2-oxy-1-pyrrolidinyl]butyric acid tert-butyl ester 398 1/1 diastereomeric mixture·· GC/MS :25 7 M+ 〇 oxidized to aldehyde 396 in a three-necked flask under argon, (2S)-2-[4-(hydroxymethyl)-2-oxy-1-pyrrolidino]butyric acid tert-butyl ester A solution of 398 (4.0 g, 0.016 mol) in dichloromethane (8 mL) was added to EtOAc (EtOAc, EtOAc (EtOAc) Warmly stir the suspension. The temperature was raised to 30 ° C and the suspension was stirred for 0.2 hours. The suspension was filtered through celite, and the filtrate was washed successively with 1N hydrochloric acid and brine, dried over magnesium sulfate and concentrated in vacuo to give crude aldehyde. The aldehyde was purified by silica gel column chromatography (hexane/acetone 70 / 30 (v/v) 2.03 g of 1-[(lS)-l-(t-butoxycarbonyl)propyl]-5-oxy-3-pyrrolidinium carboxaldehyde 396 (41%) was obtained. Alternatively, the racemic ester can be used to obtain the racemic aldehyde with similar yields. Analysis of a 1/1 mixture of l-[(lS)-l-(t-butoxycarbonyl)propyl 5-oxoφ-3-pyrrolidinecarboxaldehyde 396: 沱NMR (25 0MH, (CDC13): 0.91(t,3H), 1.44(s,8H),1.55-1.77(m,lΗ), 1.90-2.15(m,lH),2.63-2.82(m,2H),3.47-3.61(m,lH), 3.65 - 3.79 (m, lH), 3.83-3.94 (m, 1H of one of the diastereomers), 4.48-4.62 (m, lH), 9.74 (s (width), 1H) 6·2·l -[(lS)-l-(Tertidinoxycarbonyl)propyl]-5-oxy-3. Pyrrolidine Carboxaldehyde 396 olefination reaction 6 · 2 · 1. Synthesis of olefinic derivatives. 6 · 2 · 3 ·, the olefinic derivative can be via 1 - [ ( 1 S ) -1 - (Third -78-1295286 Butoxycarbonyl) propyl 5-methoxy-3-pyrrolidine 396 The scale salt is obtained by Wit tig olefination reaction in the presence of a strong base. For example, (2S)-2-(2-oxy-4-vinyl-1-pyrrolidinyl)butyric acid 2,2- (Dimethyl)ethyl ester is obtained by reacting aldehyde 396 with Ph3PCH3Br and n-BuLi in THF. 6.2.2. Ethylation via the use of Ph3P/CBr4

替代§6·2·3·，鹵乙烯基衍生物可經由l-[(lS)-l-( 第三丁氧羰基）丙基]-5-氧基-3-吡咯啶羧醛396於膦及鹵甲烷存在下進行威堤氏反應獲得。例如（2S )-2-( 2-氧基 -4-(2，2-二溴乙烯基）-1-吡咯啶基）丁酸2,2-(二甲基）乙基酯係於三苯基膦存在下得自醛396之CBr4。 6.2. 3 .經由使用（Me2N)3P/CF2Bi:2 烯化Substituting §6·2·3·, the halovinyl derivative can be passed through 1-[(lS)-l-(t-butoxycarbonyl)propyl]-5-oxy-3-pyrrolidinium carboxaldehyde 396 to phosphine Obtained by the Wittite reaction in the presence of halomethane. For example, (2S)-2-(2-oxy-4-(2,2-dibromovinyl)-1-pyrrolidinyl)butyric acid 2,2-(dimethyl)ethyl ester is based on triphenyl CBr4 from aldehyde 396 in the presence of a phosphine. 6.2. 3. By using (Me2N)3P/CF2Bi:2 olefination

(2S)-2-(2-氧基-4·(2,2-二氟乙烯基）-1-吡咯啶基）丁酸2,2·(二甲基）乙基酯399之兩種非對映異構物之合成爲代表。於三頸瓶內於氬下，（Me2N)3P(89.8克，0.55莫耳）添加至CF2Br2(58克，0.25莫耳）於THF( 280毫升）於-78°C 之溶液（出現白色沉澱）及溫熱至室溫。醛396呈非對映異構物（35.2克，0.138莫耳）之1/1混合物於THF之溶液逐滴添加至預先製成之鳞鹽。1小時後，反應混合物經西萊特過濾及真空濃縮。反應混合物以已烷稀釋，以鹽水洗滌，以硫酸鎂脫水及真空濃縮獲得粗烯烴，烯烴於矽膠藉管柱層析術純化（二氯甲烷/甲醇99/01( v/v))獲得34.6克 (2S )-2-(2-氧基-4-(2，2-二氟乙烯基）-1-吡咯啶基）丁酸 -79- 1295286 , 2,2 -(二甲基）乙基酯399之1 /1非對映異構物混合物87%) 。NMR(250MHz，（CD3)2SO):0.81-0.91(m，3H)，1.44(s ，9H)，1.50-1.75(m，lH)，l.80- 1.95(m，lH)，2.30-4·40(m ，2 H 與溶劑部分重疊），3.0 0 - 3 · 3 5 ( m，2 H )，3 . 4 5 - 3 · 5 5 ( m， 1H)，4· 20-4.40( m，lH)，4.60( ddd，lH—種非對映異構物），4.75(ddd，lH另一種非對映異構物）。 6·2·4·使用（nBu)3P/CCl3F 烯化替代§ 6 . 2 · 3 ·，鹵乙烯基衍生物可經由1 - [ ( 1 S ) -1 -(第三丁氧羰基）丙基]-5-氧基-3-吡咯啶羧醛3 96於膦及鹵甲 > 烷存在下進行威堤氏烯化反應獲得。例如2-(2-氧基-4-(2-(Z)-氟乙烯基）-1-吡咯啶基）丁酸2,2·(二甲基）乙酯係由醛396，經由循序與CFC13以及n-Bu3P反應，接著氫氧化鈉將中間物乙烯系鐵脫磷酸化獲得。 6.2.5. 4-氰基-吡咯啶酮之合成另外，4 -氰基-吡咯啶酮衍生物可經由1 - [(1 s ) -1 -(第三丁氧羰基）丙基]-5-氧基-3-吡咯啶羧醛396與羥胺反應接著與氧化硒反應獲得。 > 6.3. 2.2-二甲基-乙酯之胺化 6 . 3 · 1 .使用三氟乙酸脫去保護以及氨解 (2S )-2-(2-氧基- 4·(2,2-二氟乙烯基）-1_吡咯啶基）丁醯胺213及222之兩種非對映異構物之合成爲代表： -80- 1295286Two kinds of (2S)-2-(2-oxy-4·(2,2-difluorovinyl)-1-pyrrolidinyl)butyric acid 2,2·(dimethyl)ethyl ester 399 The synthesis of enantiomers is representative. (Me2N)3P (89.8 g, 0.55 mol) was added to a solution of CF2Br2 (58 g, 0.25 m) in THF (280 mL) at -78 ° C (white precipitate) in a three-necked flask under argon. And warm to room temperature. Aldehyde 396 was added dropwise to a pre-formed scale salt as a 1/1 mixture of diastereoisomers (35.2 g, 0.138 mol) in THF. After 1 h, the reaction mixture was filtered with EtOAc EtOAc. The reaction mixture was diluted with hexanes, washed with brine, dried over magnesium sulfate and evaporated tolululululululululululululululululululululululu (2S)-2-(2-oxy-4-(2,2-difluorovinyl)-1-pyrrolidinyl)butyric acid-79- 1295286 , 2,2- (dimethyl)ethyl ester 399 of 1:1 mixture of diastereomers (87%). NMR (250MHz, (CD3)2SO): 0.81-0.91 (m, 3H), 1.44 (s, 9H), 1.50-1.75 (m, lH), 1.80- 1.95 (m, lH), 2.30-4· 40 (m , 2 H partially overlaps with solvent), 3.0 0 - 3 · 3 5 ( m, 2 H ), 3 . 4 5 - 3 · 5 5 ( m, 1H), 4 · 20-4.40 ( m, lH ), 4.60 (ddd, lH - diastereomer), 4.75 (ddd, lH another diastereomer). 6·2·4· Using (nBu)3P/CCl3F olefination instead of § 6 . 2 · 3 ·, halovinyl derivatives via 1 - [ ( 1 S ) -1 -(t-butoxycarbonyl)propyl ]-5-Oxo-3-pyrrolidinium Carboxaldehyde 3 96 was obtained by performing a Witteth olefination reaction in the presence of a phosphine and a halo amyl group. For example, 2-(2-oxy-4-(2-(Z)-fluorovinyl)-1-pyrrolidinyl)butyric acid 2,2.(dimethyl)ethyl ester is derived from aldehyde 396, CFC13 and n-Bu3P are reacted, followed by sodium hydroxide to dephosphorylate the intermediate ethylene-based iron. 6.2.5. Synthesis of 4-cyano-pyrrolidone In addition, the 4-cyano-pyrrolidone derivative can be via 1-[(1 s ) -1 -(t-butoxycarbonyl)propyl]-5 The reaction of -oxy-3-pyrrolidinecarboxaldehyde 396 with hydroxylamine is followed by reaction with selenium oxide. > 6.3. Amination of 2.2-dimethyl-ethyl ester 6. 3 · 1. Deprotection with trifluoroacetic acid and aminolysis (2S)-2-(2-oxy- 4·(2,2- Synthesis of two diastereomers of difluorovinyl)-1_pyrrolidinyl)butanamine 213 and 222 is represented by: -80- 1295286

步驟1 : 2.2 -(二甲基）乙酯之脫去保護於三頸瓶內於氬下，（2S)-2-(2-氧基-4-(2,2-二氟乙烯基卜1-吡咯啶基）丁酸2,2-(二甲基）乙基酯399 ( 3 1.8 克，0.110莫耳）於三氟乙酸（170毫升）及二氯甲烷（500 毫升）之1 /1非對映異構物混合物溶液於室溫攪拌20小時。反應混合物蒸發至乾。殘餘物溶解於甲苯，再度蒸發至乾而去除三氟乙酸獲得32克粗酸，其未經進一步純化即用於次一步驟。LC/MS:234(MH+) 步驟2 : 活化及氣解於三頸瓶內於氬下藉機械攪拌將ClCOOEt(23毫升， 0.24莫耳）添加至酸混合物（25.6克，0.11莫耳）於二氯甲烷（ 250毫升）及三乙基胺（33 .7毫升）冷卻至-15°C之溶液。反應混合物於-10°C攪拌1.5小時，然後氣態氨通過溶液同時將溫度維持低於0°C。懸浮液於攪拌1小時，溫熱至室溫，過濾，濾液經真空蒸發。粗醯胺於矽膠藉管柱層析術純化（二氯甲烷/乙醇99/01(Wv))獲得23克（2S)-2-(2-氧基- 4- (2,2-二氟乙烯基）-1-吡咯啶基）丁酸2,2·(二甲基）乙酯之1 /1非對映異構物混合物，其於像合相藉管柱層析術純化（己烷/乙醇）獲得兩種非對映異構物213(10.1克由異丙醚再結晶）及222( 1 1 .2克，由異丙醚再結晶）。 1295286 6 · 3 · 2 .另外可使用溴兒茶酚硼烷進行脫保護。 2-(2 -氧基-4- (2,2-二甲基乙烯基）-1-吡咯啶基）丁醯胺163之四種非對映異構物係經由2-(2-氧基-4-(2,2-二甲基乙烯基卜1-吡咯啶基）丁酸2,2-(二甲基）乙酯之1/1 /1 /1非對映異構物混合物與溴兒茶酚硼烷反應獲得酸，接著於§6.3.1 (步驟2)所述條件下進行胺化獲得。 6 · 4 ·炔屬衍生物之合成6.4 · 1 . 2 · ( 4 ·乙炔基-2 -氧基-；1 -吡咯啶基）丁醯胺206 /207之合成Step 1: 2.2-(Dimethyl)ethyl ester was deprotected in a three-necked flask under argon, (2S)-2-(2-oxy-4-(2,2-difluorovinyl b) - pyrrolidinyl)butyric acid 2,2-(dimethyl)ethyl ester 399 (3 1.8 g, 0.110 mol) in 1 / 1 of trifluoroacetic acid (170 ml) and dichloromethane (500 ml) The mixture of the enantiomers was stirred at room temperature for 20 hr. The reaction mixture was evaporated to dryness. One step. LC/MS: 234 (MH+) Step 2: aq. a solution of methylene chloride (250 ml) and triethylamine (33.7 ml) cooled to -15 ° C. The reaction mixture was stirred at -10 ° C for 1.5 hours, then gaseous ammonia was passed through the solution while maintaining the temperature low. The mixture was stirred at 0 ° C for 1 hour, warmed to room temperature, filtered, and the filtrate was evaporated in vacuo. 99/01(Wv)) Obtained 23 g of (2S)-2-(2-oxy-4-(2,2-difluorovinyl)-1-pyrrolidinyl)butyric acid 2,2·(dimethyl a 1/1 mixture of diastereomers of ethyl ester which was purified by column chromatography (hexane/ethanol) to afford two diastereomers 213 (1. Ether recrystallized) and 222 (11.2 g, recrystallized from isopropyl ether). 1295286 6 · 3 · 2 . Further deprotection using bromocatechol borane 2-(2-oxy-4 - Four diastereomers of (2,2-dimethylvinyl)-1-pyrrolidinyl)butanamine 163 via 2-(2-oxy-4-(2,2-di) a 1/1 /1 /1 diastereomeric mixture of 2,2-(dimethyl)ethyl 2,2-(dimethyl)ethyl butyrate is reacted with bromocatechol borane to obtain an acid, This is followed by amination under the conditions described in § 6.3.1 (Step 2). 6 · 4 · Synthesis of acetylenic derivatives 6.4 · 1. 2 · (4 · ethynyl-2-oxy-; 1-pyrrole Synthesis of pyridine)butanamine 206 /207

於三頸瓶於氬下，正丁基鋰（1.6M於己烷類，116毫升）添加至2 - [ 4 - ( 2，2 -二溴乙烯基）· 2 -氧基-1 -吡咯D定基]丁醯胺之兩種非對映異構物之1 / 1混合物（立體化學未定， 10.95克，0.031莫耳）於THF冷卻至- 78C之溶液。白色懸浮液於此溫度攪拌1 . 5小時，使用甲醇（1 20毫升）淬熄，溫熱至室溫及真空濃縮。粗炔溶解於乙醇/二氯甲烷（1 〇 /90 v/v)，經西萊特過濾，真空濃縮，所得固體於矽膠藉層析術（乙醇/二氯甲烷：10/90(v/v))以及於像合相藉層析術（乙醇/己烷）循序純化而獲得2 - ( 4 -乙炔基-2 -氧基-1 -吡咯啶基）丁醯胺206( 0.84克，由甲苯再結晶）及 207 ( 0.44克，由甲苯再結晶）兩種非對映異構物。另外，2 - ( 4 -溴-乙炔基-2 -氧基-1 -吡咯啶基）丁醯胺 267係經由2 - [4-(2，2·二溴乙烯基）-2·氧基-1 -吡咯啶基] -82- 1295286 丁醯胺47與2當量第三丁氧化鉀於THF於低溫（- 5°C至Ο °C)反應獲得。 6.4.2. 2-(仁丙炔-1-基-2-氧基-1-吡咯啶基）丁醯胺280 之合成In a three-necked flask under argon, n-butyllithium (1.6M in hexanes, 116 ml) was added to 2 - [ 4 - ( 2,2-dibromovinyl)-2-oxy-1-pyrrole D A 1 / 1 mixture of two diastereomers of butylamine (stereochemical undetermined, 10.95 g, 0.031 mol) was cooled to -78 C in THF. The white suspension was stirred at this temperature for 1.5 hours, quenched with methanol (1 20 mL), warm to room temperature and concentrated in vacuo. The crude alkyne was dissolved in ethanol/dichloromethane (1 〇/90 v/v), filtered through celite and concentrated in vacuo. The obtained solid was purified by chromatography (ethanol/dichloromethane: 10/90 (v/v) And 2-[(4-ethynyl-2-oxy-1-pyrrolidinyl)butanamine 206 (0.84 g, from toluene) was purified by sequential purification by chromatography (ethanol/hexane). Crystallized) and 207 (0.44 g, recrystallized from toluene) of two diastereomers. Further, 2-(4-bromo-ethynyl-2-ethoxy-1-pyrrolidinyl)butanamine 267 is via 2-[4-(2,2·dibromovinyl)-2.oxy- 1-Pyrrolidinyl] -82- 1295286 Butanamine 47 is obtained by reacting 2 equivalents of potassium tert-butoxide in THF at a low temperature (-5 ° C to Ο ° C). 6.4.2. Synthesis of 2-(propargin-1-yl-2-oxy-1-pyrrolidinyl)butanamine 280

於三頸瓶於氬下，甲基氯化鋅（由甲基鋰（1 . 5於醚， 6. 14毫升）及氯化鋅（1 .25克）於THF( 15毫升））製備添加至 CuCN(0.82 克）及 LiCl(0.78 克）於 THF(10 毫升）於-10°C 之溶液。另一三頸瓶內於氬下，NaH( 80%於油，0.097克）添加至2 - ( 4 -溴-乙炔基-2 -氧基-1 -吡咯啶基）丁醯胺（1 克，0.0036莫耳）於THF(20毫升）於-10°C之溶液，接著添加氯化鋅（0.50克）。然後醯胺溶液逐滴添加至於-78°C 冷卻之有機銅酸鹽。反應混合物於此溫度攪拌3小時及任其溫熱至室溫隔夜。使用飽和氯化銨水溶液水解後，水層以二氯甲烷萃取，以硫酸鎂脫水，過濾及真空濃縮獲得粗炔，粗炔係於像合相藉層析術純化（乙醇/己烷）獲得 2-(4-丙炔-1·基-2-氧基-1-吡咯啶基）丁醯胺280。 6 . 5 .烯屬吡咯啶酮之氫化以2-[4-(2,2-二氟乙基）-2-氧基-1-吡咯啶基]丁醯胺 1 57之四種非對映異構物之1 /1 /1 /1混合物之合成爲代表： -83- 1295286In a three-necked flask under argon, methyl zinc chloride (from methyl lithium (1.5 in ether, 6. 14 ml) and zinc chloride (1.25 g) in THF (15 ml)) was added to A solution of CuCN (0.82 g) and LiCl (0.78 g) in THF (10 mL) at -10 °C. Another three-necked flask was added with argon, NaH (80% in oil, 0.097 g) to 2-(4-bromo-ethynyl-2-ethoxy-1-pyrrolidinyl)butanamine (1 g, A solution of 0.0036 moles in THF (20 mL) at -10 ° C followed by zinc chloride (0.50 g). The guanamine solution was then added dropwise to the organic copperate cooled at -78 °C. The reaction mixture was stirred at this temperature for 3 hours and allowed to warm to room temperature overnight. After hydrolysis with a saturated aqueous solution of ammonium chloride, the aqueous layer was extracted with dichloromethane, dried over magnesium sulfate, filtered, and concentrated in vacuo to give crude acetylene. The crude acetylene was purified by chromatography (ethanol/hexane). -(4-propyne-1·yl-2-oxy-1-pyrrolidinyl)butanamine 280. 6.5. Hydrogenation of olefinic pyrrolidone with four kinds of diastereomers of 2-[4-(2,2-difluoroethyl)-2-oxy-1-pyrrolidinyl]butanamine 1 57 The synthesis of the 1 / 1 / 1 / 1 mixture of isomers is represented by: -83- 1295286

於0.25升壓力瓶內於惰性氣氛下，1克（ 0.0043毫莫耳） 156及鈀/木炭（10% w/w，0.2克）溶解於乙醇（50毫升），混合物於巴爾氫化器氫化。20小時後，混合物經除氣，於西萊特/諾萊特襯墊過濾，濾液經真空濃縮獲得粗氟烷，氟烷由甲苯再結晶獲得2-[4-(2,2 -二氟乙基）-2 -氧基 _1-吡咯啶基]丁醯胺157四種非對映異構物之1/1/1/1混合物，呈白色固體（0·75克）。 6.6. 2-[4-(5 -甲基-1，3 -噚唑-2-基）-2·氧基-1-吡咯啶基]丁醯胺62及63之合成1 g (0.0043 mmol) of 156 and palladium/charcoal (10% w/w, 0.2 g) were dissolved in ethanol (50 ml) in a 0.25 liter pressure bottle under an inert atmosphere, and the mixture was hydrogenated in a bar hydrogenator. After 20 hours, the mixture was degassed, filtered over a pad of Celite/Nollet, and the filtrate was concentrated in vacuo to give crude hexanes, which was recrystallized from toluene to give 2-[4-(2,2-difluoroethyl) -1 - 1 - 1 / 1 / 1 mixture of four diastereomers of -2 -oxy-1 -pyrrolidinyl]butanamine 157 as a white solid (0·75 g). 6.6. Synthesis of 2-[4-(5-methyl-1,3-oxazol-2-yl)-2.oxy-1-pyrrolidinyl]butanamine 62 and 63

步驟1 : 酯之水解於三頸瓶內於氬下，1Ν氫氧化鈉（39毫升）添加至1-[1· (第三丁氧羰基）丙基]-5-氧基-3-吡咯啶羧酸甲酯397呈4 種立體異構物之1/1/1/1混合物（10克，0.035莫耳）於甲醇（1 00毫升）於20°C之溶液。溶液攪拌〇 · 5小時，蒸發至 -84- J295286 / * "Step 1: Hydrolysis of the ester in a three-necked flask under argon, 1 Ν sodium hydroxide (39 ml) was added to 1-[1·(t-butoxycarbonyl)propyl]-5-oxy-3-pyrrolidine Methyl carboxylate 397 was a 1/1/1/1 mixture of 4 stereoisomers (10 g, 0.035 mol) in methanol (100 mL) at 20 °C. Stir the solution for 5 hours, evaporate to -84- J295286 / * "

乾及使用IN鹽酸酸化至PH=1。水層以乙酸乙酯萃取，以硫酸鎂脫水，過濾及真空濃縮獲得粗酸400( 8.45克）呈白色固體，其未經進一步純化即用於次一步驟。iH NMR (250MHz，（CD3)2SO):0.80(t，3H)，1.44(s，9H)，1.55-1.60(m，lH)，1.70-1·95(ιώ，1Η)，2·40-2.55(ιώ，2Η 與溶劑部分重疊），3.10-3.55(m，lH與溶劑部分重疊），4.45(dd， 1H” 步驟2 : 醯胺401之合成於三頸瓶於氬下，氯甲酸乙酯（〇.5〇毫升，0·005莫耳） • 添加至酸400( 0.678克，0·0025莫耳）於二氯甲烷（10毫升）及三乙基胺（0 · 77毫升）於-20°C冷卻之溶液。反應混合物於-l〇°C攪拌1.5小時，然後丙炔胺（0.36毫升）添加至溶液同時將溫度維持低於0°C。懸浮液於〇°C攪拌1小時，溫熱至室溫，過濾及濾液經真空蒸發。粗醯胺於矽膠藉管柱層析術純化（二氯甲烷/甲醇98/02( v/v))獲得0.8 克丙炔醯胺401呈四種非對映異構物之丨/丨μ/1混合物。 NMR(250MHz ，（CD3)=SO): 0.80(t，3H)，1.44(s，9H) • ,1.55-1.65(m,lH),l.70-1.95(m,lH),2.40-2.55(m,lH 與溶劑部分重疊），3 · 0 - 3 . 70 (m，3H與溶劑部分重疊）， 3.70-3.90(m，2H)，4.45 (m，lH)，8.45(m，lH)。步驟3 : 噚唑402之合成於三頸瓶內於氬下，醯胺402( 0.77克，0.0025莫耳）於乙酸（40毫升）及Hg(OAc)2(0.048克，0.00015莫耳）之溶液回流1小時，反應冷卻至室溫，經真空濃縮及以飽和碳酸鈉水解。水層以二氯甲烷萃取及有機相以鹽水洗滌 ’以硫酸鎂脫水，過濾及真空濃縮獲得粗化合物，粗化 -85- 1295286 合物於矽膠藉層析術純化（己烷/乙酸.乙酯50 / 50( W v )獲得純噚唑 402( 0.1 5 克，20%)。GC/MS :308 ( M+)可類似 6.3. 1 .藉氨解而轉成62及63。 6.7.四唑之合成 6.7.1.無取代四唑之合成Dry and acidify to pH = 1 using IN hydrochloric acid. The aqueous layer was extracted with EtOAc EtOAc EtOAc m. iH NMR (250MHz, (CD3)2SO): 0.80 (t, 3H), 1.44 (s, 9H), 1.55-1.60 (m, lH), 1.70-1.95 (ιώ, 1Η), 2·40-2.55 (ιώ, 2Η partially overlaps with solvent), 3.10-3.55 (m, lH partially overlaps with solvent), 4.45 (dd, 1H) Step 2: Synthesis of indoleamine 401 in a three-necked flask under argon, ethyl chloroformate 〇5〇mL, 0·005 mol) • Add to acid 400 (0.678 g, 0·0025 mol) in dichloromethane (10 ml) and triethylamine (0 · 77 ml) at -20 ° C. The cooled solution was stirred at -10 ° C for 1.5 hours, then propargylamine (0.36 ml) was added to the solution while maintaining the temperature below 0 ° C. The suspension was stirred at 〇 ° C for 1 hour, warming To room temperature, filtration and evaporation of the filtrate in vacuo. The crude amide was purified by silica gel column chromatography (dichloromethane/methanol 98/02 (v/v)) to obtain 0.8 g of propynamide 401 as four non-丨/丨μ/1 mixture of enantiomers NMR (250MHz, (CD3)=SO): 0.80(t,3H), 1.44(s,9H) • ,1.55-1.65(m,lH),l .70-1.95 (m, lH), 2.40-2.55 (m, lH partially overlaps with solvent), 3 · 0 - 3. 70 (m, 3H and solvent parts Overlap), 3.70-3.90 (m, 2H), 4.45 (m, lH), 8.45 (m, lH). Step 3: Synthesis of oxazole 402 in a three-necked flask under argon, decyl 402 (0.77 g, A solution of acetic acid (40 ml) and Hg (OAc) 2 (0.048 g, 0.00015 mol) was refluxed for 1 hour, the reaction was cooled to room temperature, concentrated in vacuo and hydrolyzed with saturated sodium carbonate. The methyl chloride extraction and the organic phase were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give a crude compound. The crude-85- 1295286 compound was purified by chromatography (hexane/acetic acid ethyl ester 50 / 50 ( W v ) Obtained pure carbazole 402 (0.1 5 g, 20%). GC/MS: 308 (M+) can be similar to 6.3.1. Converted to 62 and 63 by aminolysis. 6.7. Synthesis of tetrazole 6.7.1 . Synthesis of unsubstituted tetrazole

於三頸瓶於氬下，外消旋腈403 ( 2.66克，0.011莫耳），NaN3 (4.8克，0.07 3莫耳）及三乙基胺鹽酸鹽（10.12克）之溶液於ll〇°C於DMF(60毫升）加熱2小時。冷卻至室溫及真空蒸發。粗產物於矽膠藉層析術純化（二氯甲烷/甲醇 /乙酸：90/08/02(v/v))獲得外消旋四唑酯404( 3.42克， 0.010莫耳）呈非對映異構物之1/1/1/1混合物。LC/MS : 295(MH+)。A solution of racemic nitrile 403 ( 2.66 g, 0.011 mol), NaN3 (4.8 g, 0.07 3 mol) and triethylamine hydrochloride (10.12 g) in a three-necked flask under argon C was heated in DMF (60 mL) for 2 h. Cool to room temperature and evaporate in vacuo. The crude product was purified by chromatography on silica gel (dichloromethane / methanol / acetic acid: <RTI ID=0.0>>&&&&&&&&&&&&&&& A 1/1/1/1 mixture of constructs. LC/MS: 295 (MH+).

6 . 7 . 2 .四唑之烷化6 . 7 . 2 . Alkylation of tetrazole

於三頸瓶內於氬下，外消旋四唑404( 5.6克，0.019莫耳），碳酸鉀（2.88克）及甲基碘（1 .3毫升）於DMF( 60毫升） -86- 1295286 , 之懸浮液於室溫攪拌29小時及真空蒸發。粗混合物於矽膠藉層析術純化（MTBE/己烷50/ 50(v/\〇)獲得兩種區域異構物四唑405( 1.98克，34%)及406 ( 1.03克，17%)呈油。 LC/MS : 309(MH+)。 6.8 .噻唑之合成 6.8.1.硫醯胺之合成Racemic tetrazole 404 (5.6 g, 0.019 mol) in a three-necked flask under argon, potassium carbonate (2.88 g) and methyl iodide (1.3 ml) in DMF (60 ml) -86 - 1295286 The suspension was stirred at room temperature for 29 hours and evaporated in vacuo. The crude mixture was purified by silica gel chromatography (MTBE/hexane 50/50 (v/\〇) to obtain two regioisomers of tetrazole 405 ( 1.98 g, 34%) and 406 (1.03 g, 17%). LC/MS: 309 (MH+) 6.8. Synthesis of thiazole 6.8.1. Synthesis of thiolamine

6.8.1.1. 397 之氨解於配備有回流冷凝器，磁攪拌器添加管之0.5升三頸瓶內，10克（ 0.035毫莫耳）397溶解於100毫升甲醇。氣態氨通過溶液，飽和溶液於室溫維持1日，同時偶爾再度以氨飽和。反應完成後，溶液經真空濃縮獲得粗醯胺407( 9.6 克，100%)。沱 NMR( 250MHz，（CD3)2SO) : 0.85( t，3H)， 1·44(s，9H)，1·55-1·60(m，1H)，1·70 - 1.95 (m，1H)，2·40-2·60(ιη，2Η與溶劑部分重疊），3·00 - 3.70(m，1H與溶劑部分重疊），4.35-4.45(111，111)，6.95(8(寬），11^)，7.40(8( 寬），1H)。 6.8. 1 .2.硫醯胺408之合成於三頸瓶於氬下，粗醯胺407 ( 6克，0.022莫耳）， P4S1G(4.93克，0.011莫耳）及碳酸氫鈉（3·73克）於乙腈 (100毫升）之溶液於5°C攪拌6小時。反應混合物經過濾，真空濃縮及粗硫醯胺於矽膠藉層析術純化（乙酸乙酯/ -87- 1295286 . 1 己烷：50 / 50(ν/ν))由乙酸乙酯再結晶後獲得硫醯胺4〇8 (3 ·7 克，60% )。GC/MS ·· 286(M+)。 6 · 8 · 2 ·取代噻唑之合成6.8.1.1. Ammonia solution of 397 In a 0.5 liter three-necked flask equipped with a reflux condenser and a magnetic stirrer addition tube, 10 g (0.035 mmol) of 397 was dissolved in 100 ml of methanol. Gaseous ammonia passes through the solution and the saturated solution is maintained at room temperature for 1 day while occasionally being saturated with ammonia again. After the reaction was completed, the solution was concentrated in vacuo to give crude succinamine 407 ( 9.6 g, 100%).沱NMR (250MHz, (CD3)2SO) : 0.85( t,3H), 1·44(s,9H),1·55-1·60(m,1H),1·70 - 1.95 (m,1H) , 2·40-2·60 (ιη, 2Η partially overlaps with solvent), 3·00 - 3.70 (m, 1H partially overlaps with solvent), 4.35-4.45 (111, 111), 6.95 (8 (wide), 11 ^), 7.40 (8 (wide), 1H). 6.8.1.2. The synthesis of thioguanamine 408 in a three-necked flask under argon, crude amide 407 (6 g, 0.022 mol), P4S1G (4.93 g, 0.011 mol) and sodium bicarbonate (3·73) A solution of acetonitrile (100 ml) was stirred at 5 ° C for 6 hours. The reaction mixture was filtered, dried with EtOAc EtOAcjjjjjjjjjj Thioamine 4〇8 (3 · 7 g, 60%). GC/MS ·· 286 (M+). 6 · 8 · 2 · Synthesis of substituted thiazole

於三頸瓶內於氬下，硫醯胺408呈4種非對映異構物之 1/1/1/1混合物（本專利，1 ·5克，0.005莫耳），三氧化 —•銘（12克）及1-漠-2- —*甲氧丙-2-嫌（0.85毫升）於甲苯 (1 00毫升）之溶液回流3小時。反應混合物冷卻至室溫，過濾及真空濃縮獲得粗噻唑409( 0.5克，30%)其未經進一步純化即用於次一步驟。GC/MS ·· 324(Μ+)。 6.8· 3·無取代噻卩坐之合成另外無取代噻唑可經由硫醯胺408與三氧化二鋁及溴-乙醯（於原位由溴-2，2 ·二甲氧乙烷於酸性條件下生成）反應獲得。 6.8.4. 1，2,4 -噻二唑-5-基衍生物之合成另外，1，2,4-噻二唑-5-基衍生物可經由硫醯胺408循序與Ν，Ν -二甲基-乙醯胺二甲基縮醛反應，接著於吡啶存在下環化獲得。 6.9. 2-[2-氧基- 4-(3-吡啶基羰基）-1-吡咯啶基]丁酸 2,2-二甲基乙酯410之合成 -88 - 1295286Thioamine 408 is a 1/1/1/1 mixture of 4 diastereomers in a three-necked flask under argon (this patent, 1.25 g, 0.005 m), trioxide-• Ming A solution of (12 g) and 1-yiel-2--*methoxypropan-2-yt (0.85 ml) in toluene (100 mL) was refluxed for 3 hr. The reaction mixture was cooled to room temperature, filtered and evaporated in vacuo tolulululululululu GC/MS ·· 324 (Μ+). 6.8·3·Unsubstituted thiazide-synthesis of an additional unsubstituted thiazole via thiolamine 408 with alumina and bromo-acetamidine (in situ from bromo-2,2.dimethoxyethane in acidic conditions) Generated under the reaction. 6.8.4. Synthesis of 1,2,4-thiadiazole-5-yl derivatives In addition, 1,2,4-thiadiazol-5-yl derivatives can be sequentially and via thiolamine 408, The reaction of dimethyl-acetamide dimethyl acetal is followed by cyclization in the presence of pyridine. 6.9. Synthesis of 2-[2-oxy-4-(3-pyridylcarbonyl)-1-pyrrolidinyl]butanoic acid 2,2-dimethylethyl ester 410 -88 - 1295286

於三頸瓶內於氬下，SOC12(0.56毫升）添加至酸400 (1 ·90克，0.007莫耳）於甲苯（20毫升）於室溫之溶液。反應混合物回流1 · 5小時變黃。冷卻至室溫後，一次加入 PdCl2(PPh3)2(0.25 克，0.00035 莫耳）及 3·三甲基錫烷基-吡啶（1 · 7克，0 · 007莫耳），反應混合物回流〇 . 5小時，冷卻至室溫，以水淬熄。水層以二氯甲烷萃取，合倂有機相以鹽水洗滌，以硫酸鎂脫水，過濾及真空濃縮 (3 · 2克）。粗酮於矽膠藉管柱層析術純化（二氯甲烷/甲醇97 / 03 ( Wv))獲得1.3克酮410呈4種非對映異構物之 1/1/1/1 混合物。LC/MS : 333 (MH+)。實例7. 2-(4-取代-2-氧基-吡咯啶基）-丁醯胺經由活化 2-(4 -羥甲基-2-氧基-吡咯啶基）-丁醯胺之取代合成 7.0. 起始醇之合成 7.0. 1.酯醯胺之合成 7.0. 1.a. l-[(lS)-l-(胺基羰基）丙基]-5 -氧基-5-吡咯啶羧酸甲酯11/12之合成SOC12 (0.56 mL) was added to a solution of acid 400 (1·90 g, 0.007 mol) in toluene (20 mL) at room temperature under argon in a three-necked flask. The reaction mixture turned yellow for 1 hour to reflux. After cooling to room temperature, PdCl2(PPh3)2 (0.25 g, 0.00035 mol) and 3·trimethylstannyl-pyridine (1.7 g, 0·007 mol) were added in one portion, and the reaction mixture was refluxed. After 5 hours, it was cooled to room temperature and quenched with water. The aqueous layer was extracted with EtOAc (EtOAc). The crude ketone was purified by silica gel column chromatography (dichloromethane/methanol 97 / 03 (Wv)) to afford 1.3 g of ketone 410 as a 1/1/1/1 mixture of 4 diastereomers. LC/MS: 333 (MH+). Example 7. 2-(4-Substituted-2-oxo-pyrrolidinyl)-butanamine was synthesized by activation of 2-(4-hydroxymethyl-2-oxo-pyrrolidinyl)-butanamine 7.0. Synthesis of the starting alcohol 7.0. 1. Synthesis of the ester decylamine 7.0. 1.a. l-[(lS)-l-(aminocarbonyl)propyl]-5-oxy-5-pyrrolidinecarboxylate Synthesis of methyl ester 11/12

於配備有機械擾件益及回流冷凝器之1 〇升二頸瓶內，於氬氣氣氛下，1226克（12莫耳，1當量）（2S)-2-胺基丁 -89- 1295286 醯胺及1912毫升（21 50克，13.2莫耳，1.1當量）衣康酸二甲酯溶解於6 . 1 3升甲醇。混合物調整至回流歷1 0小時，以4小時時間緩慢冷卻至20°C。過濾，沉澱以甲醇洗滌，合倂有機相濃縮至乾獲得3.283克粗中間物74%。In a 1 liter two-necked flask equipped with a mechanical scrambler and a reflux condenser, under an argon atmosphere, 1226 g (12 mol, 1 equivalent) (2S)-2-aminobutyrate-89-1295286 醯The amine and 1912 ml (21 50 g, 13.2 mol, 1.1 equivalent) of dimethyl itaconate were dissolved in 6.13 liters of methanol. The mixture was adjusted to reflux for 10 hours and slowly cooled to 20 °C over 4 hours. Filtration, the precipitate was washed with methanol, and the combined organic layers were concentrated to dryness to afford 3.283 g of crude intermediate 74%.

於配備有機械攪拌器及拉西格（Rashi g )管柱及蒸餾臂之20升三頸瓶內於惰性氣氛下，粗中間物及84.7克（891 毫莫耳，0. 1當量）2-羥吡啶溶解於11 .6升甲苯。混合物調整至回流，形成的甲醇經蒸餾去除8小時，直到收集480 毫升爲止。反應瓶內溫度到達112°C。混合物經冷卻及濃縮至乾獲得2,187克粗醯胺酯呈非對映異構物之57.5/ 42.5比例獲得。兩種非對映異構物於像合相藉製備性液相層析術分離 (像合襯墊AD 100*500毫米，乙醇/水99.9:0.1)，洗提分濃縮至乾獲得968克粗12(第一洗提）及1，052克粗11(第二洗提）。粗1 2未結晶，其溶解於1 . 5升乙醇且就此供進一步使用。粗11由2升乙酸乙酯再結晶獲得676克純11。另外，l-[(lS)-2-胺基-1-甲基-2-氧基乙基]-5-氧基 •3-吡咯啶羧酸甲酯，l-[(lS)-l-(胺基羰基）丁基]-5-氧基·3·吡咯啶羧酸甲酯，1-{(1S)-1-[(甲基胺基）羰基] 丙基卜5-氧基-3-吡咯啶羧酸甲酯係以類似方式製備。 7.0. 2.醇-醯胺之合成 7.0. 2.a. (2S)-2-[4-(羥甲基）-2-氧基-1-吡咯啶基]丁醯胺6之合成。In a 20 liter three-necked flask equipped with a mechanical stirrer and a Rashi g column and a distillation arm, under an inert atmosphere, a crude intermediate and 84.7 g (891 mmol, 0.1 equivalent) 2- Hydroxypyridine was dissolved in 11.6 liters of toluene. The mixture was adjusted to reflux and the formed methanol was removed by distillation for 8 hours until 480 mL was collected. The temperature inside the reaction flask reached 112 °C. The mixture was cooled and concentrated to dryness to give 2,187 g of crude dec. The two diastereomers were separated by preparative liquid chromatography (such as padding AD 100*500 mm, ethanol/water 99.9:0.1), and the extract was concentrated to dryness to obtain 968 g thick. 12 (first elution) and 1,052 grams thick 11 (second elution). The crude 12 is not crystallized, it is dissolved in 1.5 liters of ethanol and is used for further use. The crude 11 was recrystallized from 2 liters of ethyl acetate to afford 676 g. Further, methyl l-[(lS)-2-amino-1-methyl-2-oxyethyl]-5-oxy•3-pyrrolidinecarboxylate, l-[(lS)-l- Methyl (aminocarbonyl)butyl]-5-oxy-3' pyrrolidinecarboxylate, 1-{(1S)-1-[(methylamino)carbonyl]propyl 5-methoxy-3 Methyl pyrrolidinecarboxylate was prepared in a similar manner. 7.0. 2. Synthesis of alcohol-decylamine 7.0. 2.a. Synthesis of (2S)-2-[4-(hydroxymethyl)-2-oxy-1-pyrrolidinyl]butanamine 6.

-90- 1295286-90- 1295286

於配備有機械攪拌器及回流冷凝器之2升三頸瓶內於惰性氣氛下，133克（583毫莫耳，1當量）（2S)-2-(4-甲氧羰基-2-氧基-1 -吡咯啶基]丁醯胺11於200毫升乙醇之溶液添加至300毫升乙醇，混合物冷卻至〇°c。然後以 1 · 5小時時間分成數份加入66 · 2克（1 · 74莫耳，1 2當量）固體NaBH4，同時將溫度維持於2至4°C。2小時後溫度升高至12°C歷1小時，再度降至2-4°C。以1小時時間逐滴加入240毫升氯化氨飽和溶液，接著加入120毫升丙酮，混合物於室溫放置隔夜。混合物經過濾，沉澱以3X70毫升乙醇洗滌，合倂有機部分濃縮至乾獲得1 48克粗6。懸浮於300毫升二氯甲烷及攪拌30分鐘，過濾，以2X100 毫升二氯甲烷洗滌及脫水獲得114克純6，9 8%。另外，（2S)-2-[4-(羥甲基）-2-氧基-1-吡咯啶基]丙醯胺，（2S)-2-[4-(羥甲基）-2-氧基-1-吡咯啶基]戊醯胺，（23)-2-[4-(羥甲基）-2-氧基-1-吡略啶基]4-甲基丁醯胺係以類似方式製備。 7·1·使用三苯基膦藉直接轉變成合成In a 2-liter three-necked flask equipped with a mechanical stirrer and reflux condenser, under an inert atmosphere, 133 g (583 mmol, 1 equivalent) of (2S)-2-(4-methoxycarbonyl-2-oxyl -1 -pyrrolidinyl]butanamine 11 was added to 300 ml of ethanol in 200 ml of ethanol, and the mixture was cooled to 〇 ° C. Then, 6 · 2 g (1 · 74 Mo) was added in several portions over 1.5 hours. Ear, 1 2 equivalents) Solid NaBH4 while maintaining the temperature at 2 to 4 ° C. After 2 hours, the temperature was raised to 12 ° C for 1 hour and then lowered again to 2-4 ° C. Add dropwise by 1 hour A saturated solution of 240 ml of ammonium chloride was added, followed by the addition of 120 ml of acetone, and the mixture was allowed to stand overnight at room temperature. The mixture was filtered, and the precipitate was washed with 3×70 ml of ethanol, and the organic portion was concentrated to dryness to obtain 1 48 g of crude 6. suspended in 300 ml. Dichloromethane and stirring for 30 minutes, filtration, washing with 2×100 ml of dichloromethane and dehydration to obtain 114 g of pure 6,9 8%. In addition, (2S)-2-[4-(hydroxymethyl)-2-oxyl -1-pyrrolidinyl]propanamine, (2S)-2-[4-(hydroxymethyl)-2-oxy-1-pyrrolidinyl]pentanylamine, (23)-2-[4- (hydroxymethyl)-2-oxy-1- Slightly piperidinyl] -4-methylbut-acyl amine prepared in a similar manner. 7.1.1 Synthesis of triphenyl phosphine by using converted directly to

7·1·1· (2S)-2-[4-(碘甲基）-2-氧基-1-吡咯啶基]丁醯胺1 0之合成7·1·1·(2S)-2-[4-(iodomethyl)-2-oxy-1-pyrrolidinyl]butanylamine 1 0 Synthesis

配備有機械攪拌器及回流冷凝器之10升3頸瓶內於惰性氣氛下，400克（2莫耳，1當量）（2S )-2-[4-(羥甲基）-2-氧基-卜吡咯啶基]丁醯胺6溶解於3升乙腈。加入629克 -91 - 129528.6 . ) f (2.4莫耳，1.2當量）三苯基膦，接著以5分鐘時間分成三份加入608克（2.4莫耳，1.2當量）碘。混合物於30分鐘時間加熱至60°C，於該溫度攪拌5小時。冷卻後，混合物濃縮至乾，殘餘物懸浮於750克硫代硫酸鈉於10升水之溶液及於50°C攪拌4小時。沉澱經過濾及以3X1升水洗滌。合倂水相以1千克氯化鈉處理及以6 X 1升二氯甲烷萃取。合倂有機相以硫酸鎂脫水，過濾及濃縮至乾獲得482 克粗1 0。由甲苯結晶。若干收穫物共同由乙酸乙酯再結晶獲得425克純10，68%。 ® 另外，（2S)-2-[4-(碘甲基）-2-氧基-1-吡咯啶基]-N- 甲基丁醯胺146，（2S)-2-[4-(碘甲基）-2-氧基-1-吡咯啶基]丙醯胺110，（2S)-2-[4-(碘甲基）-2 -氧基-1-吡咯啶基 ]戊醯胺105,（2S)-2-[4-(溴甲基）-2-氧基-1-吡咯啶基] 丁醯胺8，（2S)-2-[4-(氯甲基）-2-氧基-1-吡咯啶基]丁醯胺30係以類似方式製備。 7.1.2. (2S)-2-[2-氧基- 4-(苯氧甲基）-i-吡咯啶基]丁醯胺1 8之合成A 10 liter 3-neck flask equipped with a mechanical stirrer and reflux condenser in an inert atmosphere, 400 g (2 mol, 1 eq.) (2S)-2-[4-(hydroxymethyl)-2-oxyl -Byryrrolidinyl]butanamine 6 was dissolved in 3 liters of acetonitrile. 629 g -91 - 129528.6 . ) f (2.4 mol, 1.2 equivalents) of triphenylphosphine was added, followed by the addition of 608 g (2.4 mol, 1.2 equivalents) of iodine in three portions over 5 minutes. The mixture was heated to 60 ° C over 30 minutes and stirred at this temperature for 5 hours. After cooling, the mixture was concentrated to dryness, and the residue was suspended in 750 g of sodium thiosulfate in 10 liters of water and stirred at 50 ° C for 4 hours. The precipitate was filtered and washed with 3 x 1 liter of water. The combined aqueous phase was treated with 1 kg of sodium chloride and extracted with 6 X 1 liter of dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated to dryness to afford 482 g. Crystallized from toluene. Several of the harvests were recrystallized from ethyl acetate to give 425 g of pure 10,68%. ® In addition, (2S)-2-[4-(iodomethyl)-2-oxy-1-pyrrolidinyl]-N-methylbutyramine 146, (2S)-2-[4-(iodine Methyl)-2-oxo-1-pyrrolidinyl]propanamine 110,(2S)-2-[4-(iodomethyl)-2-oxy-1-pyrrolidinyl]pentanylamine 105 ,(2S)-2-[4-(bromomethyl)-2-oxy-1-pyrrolidinyl]butanamine 8,(2S)-2-[4-(chloromethyl)-2-oxo The base-1-pyrrolidinyl]butanamine 30 was prepared in a similar manner. 7.1.2. Synthesis of (2S)-2-[2-oxy-4-(phenoxymethyl)-i-pyrrolidinyl]butanamine 1 8

於配備有磁攪拌器及滴液漏斗之5 0毫升三頸瓶內於惰性氣氛下，1克（5毫莫耳，1當量）（2S)·八[4-(羥甲基） -92- 1295286 -2-氧基-1-吡咯啶基]丁醯胺6溶解於20毫升之THF及冷卻至0°C。517毫克酚，0.87毫升（ 960毫克）偶氮二羧酸二乙酯及1.44克三苯基膦（5. 5毫莫耳，1.1當量）循序加入其中及混合物攪拌2小時。混合物濃縮至乾及藉製備性 LC純化（ 500千克矽膠，二氯甲烷/乙醇，97.5 : 2.5)獲得1 · 1克純18，80%，由乙酸乙酯結晶。 7 · 2 ·經由取代甲烷磺酸酯之合成 7 · 2 . 1 · { 1 - [ ( 1 S ) -1 -(胺基羰基）丙基]-5 -氧基· 3 -吡咯啶基）甲基甲烷磺酸酯37之合成In an inert atmosphere of a 50 ml three-necked flask equipped with a magnetic stirrer and a dropping funnel, 1 g (5 mmol, 1 equivalent) (2S)·8 [4-(hydroxymethyl)-92- 1295286 -2-oxo-1-pyrrolidinyl]butanamine 6 was dissolved in 20 mL of THF and cooled to 0 °C. 517 mg of phenol, 0.87 ml (960 mg) of diethyl azodicarboxylate and 1.44 g of triphenylphosphine (5.5 mmol, 1.1 eq.) were added sequentially and the mixture was stirred for 2 hours. The mixture was concentrated to dryness and purified by preparative EtOAc (EtOAc:EtOAc:EtOAc 7 · 2 · Synthesis via substituted methane sulfonate 7 · 2 . 1 · { 1 - [ ( 1 S ) -1 -(aminocarbonyl)propyl]-5-oxy-3-pyrrolidinyl) Synthesis of methanesulfonate 37

於配備有機械攪拌器、滴液漏斗及回流冷凝器之4升之三頸瓶內於惰性氣氛下，114克（ 569毫莫耳，1當量） (2S )-2-[4-(羥甲基）-2-氧基-1-吡咯啶基]丁醯胺6溶解於2升二氯甲烷及冷卻至〇°C。158.5毫升（115克，2當量）無水三乙基胺一次添加入其中，接著以1小時時間逐滴加入66 · 3毫升（96 ·2克，1 · 5當量）甲烷磺醯氯於190毫升二氯甲烷之溶液，同時維持溫度低於4 °C。經4小時後，加入7 · 5毫升甲烷磺醯氯及1 5毫升三乙基胺及混合物於冰箱維持隔夜。混合物經過濾，殘餘物以二氯甲烷洗滌及合倂有機相濃縮至乾獲得216克粗37。分成數批藉製備性LC純化（1千克矽膠，二氯甲烷/乙醇，1〇〇:〇至96:4) 獲得109克純37，69%。另外，{1-[(1S)-1-(胺基羰基）丙基]-5-氧基-3-吡咯 -93- 1295286 , ♦ * Π定基}甲基-4 -甲基苯磺酸酯3 1係以類似方式製備。 7.2.2. (2S)-2-[4-(疊氮基甲基卜2 -氧基-1-吡咯D定基] 丁醯胺32之合成In a 4-liter three-necked flask equipped with a mechanical stirrer, a dropping funnel and a reflux condenser, under an inert atmosphere, 114 g (569 mmol, 1 equivalent) (2S)-2-[4-(hydroxyl) The benzyl)-2-oxo-1-pyrrolidinyl]butanamine 6 was dissolved in 2 liters of dichloromethane and cooled to 〇 °C. 158.5 ml (115 g, 2 equivalents) of anhydrous triethylamine was added thereto in one portion, followed by dropwise addition of 66·3 ml (96·2 g, 1.5 eq.) of methanesulfonium chloride to 190 ml in 1 hour. A solution of methyl chloride while maintaining the temperature below 4 °C. After 4 hours, 7.5 ml of methanesulfonium chloride and 15 ml of triethylamine and the mixture were added to the refrigerator overnight. The mixture was filtered, the residue washed with dichloromethane and EtOAc EtOAc Prepared by preparative LC purification (1 kg of yttrium gel, dichloromethane/ethanol, 1 〇〇: 〇 to 96:4) to afford 109 g of pure 37, 69%. Further, {1-[(1S)-1-(aminocarbonyl)propyl]-5-oxy-3-pyrrole-93- 1295286 , ♦ * Π定基}methyl-4-methylbenzenesulfonate 3 1 was prepared in a similar manner. 7.2.2. Synthesis of (2S)-2-[4-(azidomethyldi-2-oxo-1-pyrrole D-decyl)butanamine 32

>。 Y"° ν^γΝΗ2 -^ 37 〇於配備有機械攪拌器及回流冷凝器之3升三頸瓶內於 ρ 惰性氣氛下，89.7克（ 322毫莫耳，1當量胺基羰基）丙基]-5-氧基-3-吡咯啶基}甲基甲烷苯磺酸酯37溶解於300毫升乙腈。一次加入27 · 3克（419毫莫耳 ’ 1 .3當量）疊氮化鈉及150毫升乙腈。混合物以20分鐘調整至回流及攪拌隔夜。加入3.1克（48毫莫耳，0.2當量）疊氮化鈉及持續回流共計44小時。冷卻至1 〇°C後，混合物經過濾，沉澱以3X50毫升乙腈洗滌，合倂有機部分濃縮至乾獲得77.3克粗32。由150毫升乙酸乙酯於 10°C結晶獲得60克純32，82%。 • 另外，US)-2-[4-(氟甲基）-2-氧基-卜吡咯啶基]丁醯胺44,（2S )-2-[2-氧基- 4-( 1H-四唑-1·基甲基）-1-吡咯啶基]丁醯胺39，（2S)-2-[2-氧基- 4·(1Η-四唑-1-基甲基）-1-吡咯啶基]丁醯胺 40，（2S )-2-[2-氧基- 4-( 1Η·1，2 ，4-***-卜基甲基）-1-吡咯啶基]丁醯胺55，（2S)-2-[2-氧基-4-(1Η-1，2,3-***-1-基甲基）-1·吡咯啶基]丁醯胺 56，（2S)-2-{4-[(異丙基硫烷基）甲基]-2-氧基-1-吡咯啶基）丁醯胺24，（23)-2-[2-氧基-4-(1-吡咯啶基甲基卜1-吡咯啶基]丁醯胺15，（23)-2-[2-氧基-4-(4-硫嗎啉基甲 -94- 1295286 基）-1-吡咯啶基]丁醯胺17係以類似方式由活化醇衍生物例如甲烷磺酸酯，甲苯磺酸酯或鹵化物製備。 7.3.其它合成 7.3.1· {l-[(lS)-l-(胺基羰基）丙基]-5 -氧基-3-吡咯啶基}甲基硝酸酯38之合成>. Y"° ν^γΝΗ2 -^ 37 8In a 3-liter three-necked flask equipped with a mechanical stirrer and reflux condenser, under an inert atmosphere of ρ, 89.7 g (322 mmol, 1 equivalent of aminocarbonyl) propyl] -5-Oxo-3-pyrrolidinyl}methylmethanesulfonate 37 was dissolved in 300 ml of acetonitrile. 27 · 3 g (419 mmoles of 1.3 equivalents) of sodium azide and 150 ml of acetonitrile were added in one portion. The mixture was adjusted to reflux and stirred overnight over 20 minutes. 3.1 grams (48 millimolar, 0.2 equivalents) of sodium azide was added and continuous reflux was carried out for a total of 44 hours. After cooling to 1 〇 ° C, the mixture was filtered, washed with EtOAc EtOAc (EtOAc) Crystallization from 150 ml of ethyl acetate at 10 ° C gave 60 g of pure 32,82%. • In addition, US)-2-[4-(fluoromethyl)-2-oxy-pyrrolidinyl]butanamine 44,(2S)-2-[2-oxy-4-(1H-tetra Oxazol-1·ylmethyl)-1-pyrrolidinyl]butanamine 39,(2S)-2-[2-oxy- 4·(1Η-tetrazol-1-ylmethyl)-1-pyrrole Butyryl]butanamine 40,(2S )-2-[2-oxy-4-(1Η·1,2,4-triazol-buylmethyl)-1-pyrrolidinyl]butanamine 55 ,(2S)-2-[2-oxy-4-(1Η-1,2,3-triazol-1-ylmethyl)-1·pyrrolidinyl]butanamine 56,(2S)-2 -{4-[(isopropylsulfanyl)methyl]-2-oxy-1-pyrrolidinyl)butanamine 24,(23)-2-[2-oxy-4-(1- Pyrrolidinylmethylpyrrolidinopyrrolidinylbutyramine 15,(23)-2-[2-oxy-4-(4-thiomorpholinylmethyl-94- 1295286)-1-pyrrolidine Butylamine 17 is prepared in a similar manner from an activated alcohol derivative such as a methanesulfonate, tosylate or halide. 7.3. Other Synthesis 7.3.1 · {l-[(lS)-l-(amine Synthesis of carbonylcarbonyl)propyl]-5-oxy-3-pyrrolidinyl}methyl nitrate 38

於配備有機械攪拌器及回流冷凝器及於惰性氣氛下之 5 00毫升3頸瓶內，8 · 10克（26毫莫耳，1當量）（2S) - 2-[4-(碘甲基）-2-氧基-1-吡咯啶基]丁醯胺1〇溶解於250 毫升二膪。加入4.86克（28· 6毫莫耳，1 · 1當量）硝酸銀，混合物調整至回流。2小時後，加入440毫克（2.8毫莫耳，〇 . 1當量）及共持續回流4小時。冷卻後混合物濃縮至乾及藉製備性LC純化（ 200克矽膠，二氯甲烷/甲醇/氫氧化銨， 96:5.4 :0.6)獲得5.7克粗3.8。由50毫升乙酸乙酯再結晶獲得4. 13克純38，65%。 7.3.2. 2-{4-[(;氧）甲基]-2 -氧基-1-Π比略η定基）丁醯胺 1 53 / 1 54之合成In a 500 ml 3-neck flask equipped with a mechanical stirrer and reflux condenser in an inert atmosphere, 8 · 10 g (26 mmol, 1 equivalent) (2S) - 2-[4-(iodomethyl) )-2-oxo-1-pyrrolidinyl]butanamine 1 hydrazine was dissolved in 250 ml of diterpene. 4.86 g (28·6 mmol, 1.1 eq.) of silver nitrate was added and the mixture was adjusted to reflux. After 2 hours, 440 mg (2.8 mmol, 〇. 1 equivalent) was added and a total of 4 hours was continuously refluxed. After cooling, the mixture was concentrated to dryness and purified by preparative LC (200 g, methylene chloride/methanol/methanol. Recrystallized from 50 ml of ethyl acetate afforded 4.13 g of pure 38, 65%. 7.3.2. Synthesis of 2-{4-[(;oxy)methyl]-2-oxy-1-indenyl succinyl)butanamine 1 53 / 1 54

7 · 3 · 2 · a · ( 2S ) -2 - { 4·[(苄氧）甲基]-2 -氧基-1 -吡咯啶基丨丁酸第三丁酯之合成 •95- 1295286 於配備有磁攪拌器及回流冷凝器且於惰性氣氛下之 100毫升3頸瓶內，1.1克（60%，27· 5毫莫耳，1.1當量）氫化鈉懸浮於60毫升DMF，混合物冷卻至0°C，小心加入 6.37克（24.8毫莫耳，1當量）（2S)-2-[4-(羥甲基）-2-氧基-1-吡咯啶基]丁酸第三丁酯398於10毫升DMF。10 .分鐘後，加入3.3毫升（4.75克，27.8毫莫耳，1當量）苄基溴於10毫升DMF及於0°C持續攪拌30分鐘，接著於室溫攪拌3小時。混合物濃縮至乾，殘餘物懸浮於鹽水/二氯甲烷，傾析及以二氯甲烷萃取。合倂有機相以硫酸鎂脫水，濃縮至乾及殘餘物藉製備性LC純化（1千克矽膠，己烷/ MTBE，40:60至0:100)獲得3.2克第三丁酯及苄酯混合物於二洗提分，37%總產率。就此用於次一步驟7.3. l.b。 !H NMR( 250MHz » (CDC 13)：0.85 ( t,3H),1.44(s,9H),1.55 -1.95(m，2H)，2· 10 (dd，lH)，2.45(dd，lH)，2.55-2.70(m ，lH)，3.45-3.55(m，lH) ， 4.40(dd，lH)，4.55(s，2H)， 7.20-7.40(m，5H)。 7.|.2.b· 2-{4-[(苄氧）甲基]-2-氧基·1-吡咯啶基}丁醯胺153之合成於配備有磁攪拌器及回流冷凝器且於惰性氣氛下之50 毫升3頸瓶內，1.75克苄酯豐富洗提分溶解於20毫升甲醇。然後氣態氨通過溶液及飽和溶液於室溫維持24小時，同時偶爾再度以氨飽和。反應完成後，溶液濃縮至乾及藉製備性LC(1千克矽膠，二氯甲烷/甲醇，98:2至90:10) 純化獲得兩種非對映異構物。於配備有磁攪拌器及回流冷凝器且於惰性氣氛下之25 毫升3頸瓶內，1 · 24克第三丁酯豐富洗提分溶解於1 6 -96- 1295286 毫升二氯甲烷/三氟乙酸之1:1混合物，及於0-5°C維持24 小時。溶液濃縮至乾，殘餘物溶解於1 〇毫升二氯甲烷。加入1 · 2毫升（2.2理論當量），及混合物冷卻至-20°C。逐滴加入780微升氯甲酸乙酯，任混合物以1 · 5小時時間緩慢溫熱至-10°C。氣態氨通過溶液歷〇·5小時，混合物於室溫維持隔夜。經過濾，沉澱以二氯甲烷洗滌，合倂有機洗提分濃縮至乾及藉製備性LC純化（1千克矽膠，二氯甲烷/甲醇，98:2至90:10)獲得兩種非對映異構物。兩回合所得第一及第二洗提非對映異構物經合倂及由甲苯結Synthesis of 7 · 3 · 2 · a · ( 2S ) -2 - { 4 · [(benzyloxy)methyl]-2 -oxy-1 -pyrrolidinyl indolebutyrate • 95- 1295286 In a 100 ml 3-neck flask equipped with a magnetic stirrer and a reflux condenser under an inert atmosphere, 1.1 g (60%, 27.5 mmol, 1.1 equivalents) of sodium hydride suspended in 60 ml of DMF, the mixture was cooled to 0 °C, carefully added 6.37 g (24.8 mmol, 1 equivalent) of (2S)-2-[4-(hydroxymethyl)-2-oxy-1-pyrrolidinyl]butyrate tert-butyl ester 398 10 ml of DMF. After 10 minutes, 3.3 ml (4.75 g, 27.8 mmol, 1 equivalent) of benzyl bromide was added to 10 ml of DMF and stirring was continued at 0 ° C for 30 minutes, followed by stirring at room temperature for 3 hours. The mixture was concentrated to dryness. The combined organic phase is dehydrated with magnesium sulfate, concentrated to dryness and the residue is purified by preparative LC (1 kg EtOAc, hexane / MTBE, 40:60 to 0:100). Two wash points, 37% total yield. This is used for the next step 7.3. l.b. !H NMR (250MHz » (CDC 13): 0.85 ( t, 3H), 1.44 (s, 9H), 1.55 -1.95 (m, 2H), 2· 10 (dd, lH), 2.45 (dd, lH), 2.55-2.70(m,lH), 3.45-3.55(m,lH), 4.40(dd,lH),4.55(s,2H), 7.20-7.40(m,5H) 7.|.2.b· 2 -{4-[(Benzyloxy)methyl]-2-oxy-1-pyrrolidinyl}butanamine 153 is synthesized in a 50 ml 3-neck equipped with a magnetic stirrer and a reflux condenser under an inert atmosphere In the bottle, 1.75 g of benzyl ester rich elution fraction was dissolved in 20 ml of methanol, then the gaseous ammonia was maintained at room temperature for 24 hours through the solution and the saturated solution, and occasionally saturated with ammonia again. After the reaction was completed, the solution was concentrated to dryness and prepared. Purification of the two diastereomers by LC (1 kg decyl, methylene chloride / methanol, 98:2 to 90:10). 25 ml in an inert atmosphere with a magnetic stirrer and reflux condenser In a 3-necked flask, 1 · 24 g of the third butyl ester-rich extract was dissolved in a 1:1 mixture of 16 - 96 - 1295286 ml of dichloromethane / trifluoroacetic acid and maintained at 0 - 5 ° C for 24 hours. The solution was concentrated to dryness and the residue was dissolved in dichloromethane (1 mL). On the basis of the equivalent), and the mixture was cooled to -20 ° C. 780 μl of ethyl chloroformate was added dropwise, and the mixture was slowly warmed to -10 ° C over a period of 1.5 hours. Gaseous ammonia was passed through the solution for 5 hours. The mixture was maintained at room temperature overnight. After filtration, the precipitate was washed with dichloromethane, and the organic extracts were concentrated to dryness and purified by preparative LC (1 kg hexane, methylene chloride/methanol, 98:2 to 90: 10) Obtaining two diastereomers. The first and second eluting diastereomers obtained in two rounds are combined and combined with toluene

晶分別獲得30 5毫克純153及480毫克純154, 11%總產率。 7.3.3. (2S)-2-{4-[(5 -甲基-1Η-1，2,3-***-1-基）甲基]-2-氧基-1-吡咯啶基}丁醯胺52之合成Crystals obtained 30 5 mg of pure 153 and 480 mg of pure 154, 11% of the total yield, respectively. 7.3.3. (2S)-2-{4-[(5-Methyl-1Η-1,2,3-triazol-1-yl)methyl]-2-oxy-1-pyrrolidinyl} Synthesis of butyric acid 52

於配備有磁攪拌器及回流冷凝器且於惰性氣氛下之50 毫升3頸瓶內，1克（4.44毫莫耳，1當量）（23)-2-[4-(疊氮基甲基）-2 -氧基-1 -吡咯啶基]丁醯胺32懸浮於2〇毫升甲苯。加入1.55克（4· 88毫莫耳，1·1當量）1-(三苯基亞磷烷基）丙酮，及混合物加熱至80°C歷24小時。冷卻後，混合物濃縮至乾及藉製備性LC純化（1千克矽膨，二氯甲烷/甲醇/氫氧化銨，94 · 5 : 5 : 0 · 5 )。懸浮於1 5毫升水及凍乾獲得240毫克純52呈澄淸油’ 42% ° -97- 1295286 7·3·4· (2S)-2-[4·(異硫氰酸基甲基）-2-氧基-1-吡咯啶基]丁醯胺49之合成In a 50 ml 3-neck flask equipped with a magnetic stirrer and a reflux condenser under an inert atmosphere, 1 g (4.44 mmol, 1 equivalent) of (23)-2-[4-(azidomethyl) -2 -oxy-1 -pyrrolidinyl]butanamine 32 was suspended in 2 ml of toluene. 1.55 g (4.98 mmol, 1.1 eq.) of 1-(triphenylphosphinoalkyl)acetone was added, and the mixture was heated to 80 ° C for 24 hours. After cooling, the mixture was concentrated to dryness and purified by preparative LC (1 kg of swell, methylene chloride / methanol / ammonium hydroxide, 94 · 5 : 5 : 0 · 5 ). Suspension in 15 ml of water and lyophilization to obtain 240 mg of pure 52 cumin oil '42% ° -97- 1295286 7·3·4· (2S)-2-[4·(isothiocyanatomethyl) Synthesis of -2-oxo-1-pyrrolidinyl]butanamine 49

於500毫升壓力瓶內於惰性氣氛下，900毫克10%鈀吸附於木炭懸浮於100毫升乙醇。加入8.7克（38毫莫耳） (2S)-2-[4-(疊氮基甲基）-2 -氧基-1-P比咯B定基]丁醯胺 32於150毫升乙醇之溶液及混合物於巴爾氫化器於最高 3Ops i氫壓下氫化2小時。混合物經除氣，於西萊特/諾萊特襯墊過濾，殘餘物以2X100毫升乙醇洗滌及合倂濾液濃縮至乾獲得7.93克粗412 ,100%產率，就此用於次一步驟。GC/MS : 199(M+)。 7.3.4.a. (2S)-2-[4-(異硫氰酸基甲基）-2-氧基-1-吡咯啶基]丁醯胺49之合成於配備有磁攪拌器及回流冷凝器且於惰性氣氛下之丨00 毫升3頸瓶內，4.5克（22 ·7毫莫耳，1當量）硫羰基咪唑溶解於2 5毫升DMF，混合物冷卻至〇。以3 0分鐘時間逐滴加入4.53克（22.7毫莫耳，1當量）（2S)-2-[4-(胺基甲基）-2 -氧基-1 -吡咯啶基]丁醯胺41 2於2 5毫升DMF，混合物於室溫攪拌3小時及放置隔夜。混合物濃縮至乾，殘餘物溶解於20毫升甲苯，再度濃縮至乾，殘餘物藉製備性LC 純化（ 350克矽膠，二氯甲烷/甲醇/氫氧化銨，93.4:6: 0.6)獲得3.1克粗49。於20毫升醚硏製，過濾及殘餘物 (1 .9克）由15毫升乙腈結晶獲得丨·2克純49 ( 22%)。 -98 - 1295286 下表顯示之式I化合物可以類似方式或如此處它處所述方式製備。表中，立體化學資訊含於兩欄標頭爲「組態資料」。第二欄表示化合物是否不具有立體產生中心（非像合），純對映異構物（純），外消旋混合物（外消旋）或兩種或多種立體異構物可能爲不等比例之混合物（混合物）。第一欄含有各個已經被辨識出的中心之立體化學標示，接著爲前一欄使用的IUPAC編號。單獨編號表示兩種組態皆存在於該中心。編號接著爲「R」或「S」表示該中心已知 ® 之絕對組態。編號後面接著「§」表示於該中心僅存在有一個但未知的絕對組態。前方字母（A，B，C，D)係區別同一結構式的各個對映異構物或外消旋混合物。表中，大半熔點係藉DSC曲線起點決定。當標示視覺（熔化計）熔點時，該値以括弧表示。表中，欄「合成編號」表示實際用於最重要化合物之合成。可能需要略微變化才能獲得類似化合物。此等修改係屬於有機合成業界人士之技巧範圍。 -99- 1295286900 mg of 10% palladium was suspended in charcoal in 100 ml of ethanol in a 500 ml pressure bottle under an inert atmosphere. Add 8.7 g (38 mmol) of (2S)-2-[4-(azidomethyl)-2-oxy-1-Ppyrrolidine B]butanamine 32 in 150 ml of ethanol and The mixture was hydrogenated at a maximum of 3Ops i hydrogen pressure for 2 hours in a Bar hydrogenator. The mixture was degassed and filtered on a pad of Celite/Nollet. The residue was washed with 2×100 ml of ethanol and the filtrate was concentrated to dryness to afford 7.93 g of crude 412, 100% yield, which was used for the next step. GC/MS: 199 (M+). 7.3.4.a. Synthesis of (2S)-2-[4-(isothiocyanatomethyl)-2-oxy-1-pyrrolidinyl]butanamine 49 equipped with a magnetic stirrer and reflux In a condenser and under an inert atmosphere in a 00 ml 3-necked flask, 4.5 g (22 · 7 mmol, 1 equivalent) of thiocarbonyl imidazole was dissolved in 25 ml of DMF and the mixture was cooled to hydrazine. 4.53 g (22.7 mmol, 1 equivalent) of (2S)-2-[4-(aminomethyl)-2-oxy-1-pyrrolidinyl]butanamine 41 was added dropwise over 30 minutes. 2 In 25 ml of DMF, the mixture was stirred at room temperature for 3 hours and placed overnight. The mixture was concentrated to dryness. EtOAc EtOAc m. 49. Made in 20 ml of ether, filtered and the residue (1. 9 g) was crystallized from 15 ml of acetonitrile to give y 2 g of pure 49 (22%). -98 - 1295286 The compounds of formula I shown in the table below can be prepared in a similar manner or as described elsewhere herein. In the table, the three-dimensional chemical information is included in the two column headers as "Configuration Data". The second column indicates whether the compound does not have a stereogenic center (non-image), the pure enantiomer (pure), the racemic mixture (racemic) or two or more stereoisomers may be in unequal proportions. a mixture (mixture). The first column contains the stereochemistry of each identified center, followed by the IUPAC number used in the previous column. A separate number indicates that both configurations exist in the center. The number followed by "R" or "S" indicates the absolute configuration of the known ® of the center. The number followed by "§" indicates that there is only one but unknown absolute configuration at the center. The forward letters (A, B, C, D) distinguish between individual enantiomers or racemic mixtures of the same structural formula. In the table, the majority of the melting point is determined by the starting point of the DSC curve. When the visual melting point is indicated, the 値 is indicated by brackets. In the table, the column "Synthesis Number" indicates the actual synthesis for the most important compounds. A slight change may be required to obtain a similar compound. These modifications are within the skill of those in the organic synthesis industry. -99- 1295286

RMN ΓΗ Γ—1 Ξ LC/MS MH+ 熔點(°C) (127-128) 143.0 (116-120) (106-107) (146-150) 144.3 116.0 181.3 91.4 104..0 合成 • 7.1.1. 7.1.1. 7.1.1. • 組態資料外消旋外消旋外消旋混合物非像合 m 窠 m 窠 m 锾寸寸寸寸办 (N 〇〇〇气 CO CN < 000 寸Λ οΓ ώ 000 寸 αΤ (Ν < B-2S，4§ Pi 寸办 C0 <N A-1S,3 § coo CO 1 m IUPAC化學名 2-(4-乙基-2-氧基-4-苯基-1 -¾略陡基）乙酿胺 2-(2-氧基苯基-1-毗咯啶基)乙醯睽 2-(4-甲基-2-氧基-1-吡咯啶基）乙醯胺 2-(4-甲基-2-氧基-1-吡咯啶基)丙醯胺 2-(4,4-二甲基-2-氧基-1-吡咯啶基)丙醯胺 (2S)-2-[4-(羥甲基）-2-氧基-1-吡咯啶基]丁醯胺 I (2S)-2-[4-(羥甲基）_2-氧基-1-吡咯啶基]丁醯胺 1- (2S)-2-[4-(溴甲基）-2_氧基-1-吡咯啶基]丁醯胺 (2S)-2-[4-(溴甲基)-2-氧基-1-吡咯啶基]丁醯胺 (2S)-2-[(4R)-4-(碘甲基)-2-氧基吡咯啶基]丁醯胺 η 遂I 砮 1 rn m 祕 1 m g 糊髮am V m. ^ 扭· C愁 • y -tHS 二 m n 1 cn 嫲 I 5 g 稍藤 ki v ^ v s-^ m » » ^ΤΤΧ\ 二糊化合物編號 r-H <N m 寸 VO 卜 00 〇\ 〇 ?—t <N -100- 1295286RMN ΓΗ Γ—1 Ξ LC/MS MH+ melting point (°C) (127-128) 143.0 (116-120) (106-107) (146-150) 144.3 116.0 181.3 91.4 104..0 Synthesis • 7.1.1. 7.1.1. 7.1.1. • Configuration data racemic racemic racemic mixture non-image m 窠m 窠m 锾 inch inch inch (N 〇〇〇 gas CO CN < 000 inch Λ οΓ ώ 000 Inch αΤ (Ν < B-2S, 4§ Pi inch C0 <N A-1S, 3 § coo CO 1 m IUPAC chemical name 2-(4-ethyl-2-oxy-4-phenyl- 1 -3⁄4 slightly steep base) 2-ethyl 2-(2-oxyphenyl-1-pyrrolidyl)acetam 2-(4-methyl-2-oxy-1-pyrrolidinyl) Indole 2-(4-methyl-2-oxy-1-pyrrolidinyl)propanamide 2-(4,4-dimethyl-2-oxy-1-pyrrolidinyl)propanamide 2S)-2-[4-(hydroxymethyl)-2-oxy-1-pyrrolidinyl]butanamine I (2S)-2-[4-(hydroxymethyl)_2-oxy-1- Pyrrolidinyl]butanamine 1-(2S)-2-[4-(bromomethyl)-2-oxy-1-pyrrolidinyl]butanamine (2S)-2-[4-(bromo (2-oxy-1-pyrrolidinyl)butanamine (2S)-2-[(4R)-4-(iodomethyl)-2-oxypyrrolidinyl]butanamine η 遂I砮1 rn m secret 1 mg Hair am V m. ^ Twist · C愁 • y -tHS Two mn 1 cn 嫲I 5 g 藤藤 ki v ^ v s-^ m » » ^ΤΤΧ\ Two paste compound number rH <N m inch VO 00 〇\ 〇?—t <N -100- 1295286

Ξ r~n 189.0 202.0 (99.3-100.4) '120.0 124.4 _____1 93.2 144.9 ON 〇〇 • 1.1.1 然後 1.2.1. 然後 1.2.2 m m η m 窠窠窠㈣ oco m OQ <N < 〇〇〇 C/T CN PQ m 寸办 00 CN < 〇0) 寸 00 CN PQ A-2S,4§ A-2S，4§ COO CO cs PQ A-2S，4§ 〇〇〇 αΓ <Ν 1 QQ 000 寸Λ 00 (Ν < Ϊ m 苷 _ 1 r-H Λ 擀鏗 s m 4 i-1 — 稍湖祕锃 A銮 T砮 <Ν 1 r-H 1 C/D '» St 補普福 < 1 Λ 擀鍇 i m 爷t Ml w 祕遐 a痤 T砮 CS » 1 ”H ^N 1 K/l 1~» c稍 1 1 fr 稍 η 砮 1 r-H 1 祕狴 ^ m γ卜 ” r-, 糊 e磐普I 砮 1 1 _ Wr 稍 η 吞 1 τ-Η 1 m 狴必應 ^ -cs m 霞 τ·Η 1 i Β- m 香 m m 1 1 m 碱鏗 ^ m 卞卜 7鬥 2稍 .cl η (2S)-2-[2-氧基-4-(苯氧甲基）-1-吡咯啶基]丁醯胺 1 τ-Η Λ 祕 1 CN 補 s iS 嬸 ! g i^j * i S ig 会绝 (2S)-2-(4-苄基-1-氧基-1-吡咯啶基)丁醯胺 :2S)_2-(4-苄基-2-氧基-1-吡咯啶基)丁醯胺 ] i(2S)-2-(2-氧基-4-苯基-1-吡咯啶基)丁醯胺 m 寸 VO *> 00 Os CN (N -101 — 12952.86Ξ r~n 189.0 202.0 (99.3-100.4) '120.0 124.4 _____1 93.2 144.9 ON 〇〇• 1.1.1 then 1.2.1. then 1.2.2 mm η m 窠窠窠(4) oco m OQ <N < 〇〇〇C/T CN PQ m inch 00 CN < 〇0) inch 00 CN PQ A-2S,4§ A-2S,4§ COO CO cs PQ A-2S,4§ 〇〇〇αΓ <Ν 1 QQ 000 inch Λ 00 (Ν < Ϊ m _ _ 1 rH Λ 擀铿 sm 4 i-1 — 略湖秘锃 A銮T砮<Ν 1 rH 1 C/D '» St Bu Puff < 1 Λ im 爷 t Ml w Secret 遐 a痤T砮CS » 1 ”H ^N 1 K/l 1~» c slightly 1 1 fr η η 砮1 rH 1 secret 狴 ^ m γ 卜” r-, paste e磐普I 砮1 1 _ Wr Slightly η swallow 1 τ-Η 1 m 狴必应^ -cs m 霞τ·Η 1 i Β- m 香mm 1 1 m alkali 铿^ m 卞卜7斗2 slightly. Cl η (2S)-2-[2-oxy-4-(phenoxymethyl)-1-pyrrolidinyl]butanamine 1 τ-Η 秘 Secret 1 CN 补 s iS 婶! gi^j * i S ig will be (2S)-2-(4-benzyl-1-oxy-1-pyrrolidinyl)butanamine: 2S)_2-(4-benzyl-2-oxy-1-pyrrolidine Butylamine] i(2S)-2-(2-oxy-4-phenyl-1-pyrrolidinyl)butanamine m-inch VO *> 00 Os CN (N -101 — 12952.86

•Ί 02— 1295286•Ί 02— 1295286

S r—1 202.8 73.9 56.9 135.0 181.9 82.3 120.5 138.1 4.4. 寸：寸· 7.3.1. 7.2.1. 6·2·1·然後 6.3.1. 7.2.2. 窠 m 窠窠混合物 η m m cn 〇〇" 1 < 〇〇0 寸Λ 00 <Ν < 000 气 00 (N ώ A-1S，3§ ! GOO CO 〇〇" r-H 1 c COD 气 00 cs <; A-2S，4§ 寸 r\ <N m 气 00 Οί < A-2S,4§ 1 m m 祕 1 I s E 稍 1¾ 稍 V ^ 2惣 S遐二铿 (2S)-2-(4-甲基-2-氧基-1-吡咯啶基）丁醯胺 (28)-2-(4-甲基-2-氧基-1-啦略11定基)丁釀胺 1 c〇 ώ 祕 1 wo 1 S | S v ™ 7 扭· /-*-N -^ v η 1 m 嫲 1 世 5 E '31^ ΚΠ s ^ 稍s v _ 7 Bl· ^ m 二痤 1 τ—1 1 s fr 補 1 έ Ξ I ffi t-H >w/ 寸您 « i W H .i稍 ^ m 已砮 1 — 1 s El· 補 1 t—1 ύ m 1 ffi r-H 4狴 Λ _ Hff h ά S 2-(2-氧基-4-乙烯基-1-吡咯啶基)丁醯胺爸 1 r-H Jlf 1 CN Ϊ ffl- 4 ^ Λ H 〇0 '~1 吞 1 r-H 1 稍 fr i m m 稍 4 s ώ _ m t ά w a遐 CO Ό ΓΟ $ 00 m ON m ο m -103- 1295286S r—1 202.8 73.9 56.9 135.0 181.9 82.3 120.5 138.1 4.4. Inch: inch · 7.3.1. 7.2.1. 6·2·1· then 6.3.1. 7.2.2. 窠m 窠窠 mixture η mm cn 〇〇" 1 < 〇〇0 inch Λ 00 <Ν < 000 gas 00 (N ώ A-1S, 3§ ! GOO CO 〇〇" rH 1 c COD gas 00 cs <; A-2S, 4§ inch r\ <N m gas 00 Οί < A-2S,4§ 1 mm secret 1 I s E slightly 13⁄4 slightly V ^ 2惣S遐二铿(2S)-2-(4-methyl- 2-oxy-1-pyrrolidinyl)butanamine (28)-2-(4-methyl-2-oxy-1-lalo 11-decyl) butylamine 1 c〇ώ Secret 1 wo 1 S | S v TM 7 Twist · /-*-N -^ v η 1 m 嫲1 World 5 E '31^ ΚΠ s ^ Slightly sv _ 7 Bl· ^ m 二痤1 τ—1 1 s fr 补 1 έ Ξ I ffi tH >w/ inch you « i WH .i slightly ^ m 砮1 — 1 s El· complement 1 t-1 ύ m 1 ffi rH 4狴Λ _ Hff h ά S 2-(2-oxy -4-vinyl-1-pyrrolidyl)butanamine dad 1 rH Jlf 1 CN Ϊ ffl- 4 ^ Λ H 〇0 '~1 swallow 1 rH 1 slightly fr imm slightly 4 s ώ _ mt ά wa遐CO Ό ΓΟ $ 00 m ON m ο m -103- 1295286

S r*H t> 00 00 αί 〇 t—H CO r-H r-H i-H o On t—H y—i 寸 <Ν to r-H VO On m t—H oo CN 卜 r-H <N 00 cs t—< <N ^ csi ^ V〇 m n CN ^ vd 寸· m 窠窠窠 m m <π m m <ίπ m coo 气 C/T <N 1 COD CO •GO" T-H 1 < Pi 寸 C/T CS CO 气 GO <S coo m rs OQ fH 1 C 000 气 oT <N <； coo 气 CO (N <： <N coo 寸·χ C/Γ (Ν < ci m 砮 1 r-H m Jlf <N s fr m Jli鏗 4 i ? t G稍 cs 1 cn 祕 1 1 稍 i 1 EL 糊此 v稍 :B- -« v m m 祕 1 CS 1 稍裝 K] 郏 11 I CN t m ^ h ^ n 稍 Jli 1 CN 補裝 K) 郏 11 I <Ν -r m 2s t S δ a遐砮 1 rn m 祕 1 1 補 s Ϊ 補 7 ^ G澈 S {M 二痤 1 i-H J!f (N 稍補氍 Ιέ你; 柄 TO & m K b i W ^ n g痤 c砮 1 m m 泰 cs S 1 <N il 4鏗 CO' -h i補 ^ n g痤 1 <N i 11 1 气 CO r-H m 攆簡 …i—> V ^ 工S ϊ 1 r-H i m lij _ ^ h CN /-*-n 7稍 a m r-H ._ 1 塑稍砮 l· Λ ά m 4 « r c； ” A G湖 3 fr 稍嫲 1 (N i 1 i II m 寸 ΟΧΙ ci m ^ t 權稍 El· ig d塑 4砮 t—J 1 CSI "7 5 VO 00 0\ <N m ui 1295286S r*H t> 00 00 αί 〇t—H CO rH rH iH o On t—H y—i inch<Ν to rH VO On mt—H oo CN 卜rH <N 00 cs t—<<;N ^ csi ^ V〇mn CN ^ vd 寸 · m 窠窠窠mm <π mm <ίπ m coo gas C/T <N 1 COD CO •GO" TH 1 < Pi inch C/T CS CO gas GO <S coo m rs OQ fH 1 C 000 gas oT <N <; coo gas CO (N <: <N coo inch·χ C/Γ (Ν < ci m 砮1 rH m Jlf <N s fr m Jli铿4 i ? t G slightly cs 1 cn secret 1 1 slightly i 1 EL paste this v slightly: B- -« vmm secret 1 CS 1 slightly loaded K] 郏11 I CN tm ^ h ^ n Slightly Jli 1 CN Supplement K) 郏11 I <Ν -rm 2s t S δ a遐砮1 rn m Secret 1 1 Supplement s Ϊ Complement 7 ^ G Che S {M 二痤1 iH J!f ( N slightly compensates you; handle TO & m K bi W ^ ng痤c砮1 mm Thai cs S 1 <N il 4铿CO' -hi complement ^ ng痤1 <N i 11 1 gas CO rH m 撵 ......i—> V ^工 S ϊ 1 rH im lij _ ^ h CN /-*-n 7 slightly am rH ._ 1 塑砮 l· Λ ά m 4 « rc; ” AG Lake 3 fr嫲1 (N i 1 i II m inch ΟΧΙ ci m ^ t 权略 El· ig d plastic 4砮 t—J 1 CSI "7 5 VO 00 0\ <N m ui 1295286

[30] 117.3 v〇 CN 寸 r-H <N 00 <N CN ro 〇 v〇 r*H <N On VO r-H r-H r—H 00 CN 〇\ ι—H 卜 00 o r-H 00 l> Ό r-H 混合物窠 <n m 遐 m 垲璲 m 遐遐裝. 遐寸 CN coo 气 C/Γ rs < coo <N < 气 rs 〇Γ < 寸ex (N < 寸· <N PQ 寸λ <Ν ώ (N < cs PQ 1 r-H Λ 1 <N 湖 1 <N 響 ^ m « h i i s磐 A砮 fr 梢麻 r—Η HI 1 寸一 οί τ' ^ «翻 Τ t « ^ ¥ 5 <Ν三 CN ι 祖 — » 00 已稍 Λ 稍 Bl· 糊 I ι—Η m in I m <N κ m v H ' i 祕毯I is 1 1 CN r-H 砮 1 r-H 1 S Bl· 稍 1 H m 1 ffi 4 ^ m p m t i稍 ^ m 吞 1 ι—Η m ni CN m 1 •i m 3 ^ m m ¢- H ά 5 i m A痤砮 1 i-H A 骣 I CN s 1 a 1 ffi 1 m m B5- H i S i n a痤 1 A W cs 9 ύ m 1 ffi (N 诞 m m fr H ά 5 i磐 A痤砮 ι ▼—κ Λ 娜 I <Ν I S 審 A _ ffi- H i S i ^ A痤 I ι—1 Hf 1 1 稍 I Cji 〒_ 糊卜7 ί s i皆 A砮 1 m CN i 1 (N ώ A裝〒孃 « h ΐ s ^ m i塑 a吞 κη VO in 〇〇 as ^T) S <N Ό m vo -105- 1295286[30] 117.3 v〇CN 寸rH <N 00 <N CN ro 〇v〇r*H <N On VO rH rH r—H 00 CN 〇\ ι—H 00 o rH 00 l> Ό rH Mixture 窠<nm 遐m 垲璲m armored. 遐CN coo gas C/Γ rs < coo <N < gas rs 〇Γ < inch ex (N < inch · <N PQ inch λ <Ν ώ (N < cs PQ 1 rH Λ 1 <N Lake 1 <N 响^ m « hiis磐A砮fr 麻麻r-Η HI 1 inch οί τ' ^ «翻Τ t « ^ ¥ 5 <Ν三CN ι祖—» 00 已Λ slightly Bl· 糊 I ι—Η m in I m <N κ mv H ' i Secret carpet I is 1 1 CN rH 砮1 rH 1 S Bl · slightly 1 H m 1 ffi 4 ^ mpmti slightly ^ m swallow 1 ι—Η m ni CN m 1 •im 3 ^ mm ¢- H ά 5 im A痤砮1 iH A 骣I CN s 1 a 1 ffi 1 mm B5- H i S ina痤1 AW cs 9 ύ m 1 ffi (N mmmm fr H ά 5 i磐A痤砮ι ▼—κ Λ I I I <Ν IS Review A _ ffi- H i S i ^ A痤I ι—1 Hf 1 1 Slightly I Cji 〒 _ paste 7 ί si all A砮1 m CN i 1 (N ώ A 装〒娘 « h ΐ s ^ mi plastic a κη VO in 〇〇as ^T ) S <N Ό m vo -105- 1295286

r—η Ο τ-Η 94.3 170.9 186.1 185.1 143.0 147.3 69.3 120.5 6·8·3然後 6.3.1. 4.1.1·然後 4.1.2. 4.1.1.然後 4.1.2. 混合物外消旋外消旋外消旋 m 混合物 m m 寸” <N < <N ώ 寸λ of ώ A-2S，4§ GW oT cs ώ 寸外 r<T 000 气 00" CS < GO) 寸办 CO" CN ώ 2-[2-氧基-4-(1，3-噻唑-2-基）-1-吡咯啶基]丁醯胺雄 1 S ! 可 HI 1 <n" r-H 1 ffi 可譲 Η l!f g it； A痤 1 1 5 1 m 1 寸办 CN r-H ffi V ^ 可m W H if稍 i n A痤 2-[2-氧基-4-(lH-四唑-1-基）-1-吡咯啶基]丁醯胺 m 1 τ-Η m 碱 1 CN i 碱 Bl· 4 ^ Λ Η C/0 '—> cl m (2S)-2-[4-(4-甲氧苯基)-2-氧基-1-吡咯啶基]丁醯胺砮 1 τ-Η 1 5 3¾ 稍 m 砮 1 m 1 祕_ At η 1 ^Η 1 S 響 1 1 W 祕 :r鞸 Λ卜 C/D '~' 已稍 η 普I 砮 1 r«H 1 s 響 1 cs 1 m w a鏗 Λ Η CO '~、 3稍寸 in vo vo VO 00 On vo 〇 r-H CN -106 ㈣ 1295286R-η Ο τ-Η 94.3 170.9 186.1 185.1 143.0 147.3 69.3 120.5 6·8·3 then 6.3.1. 4.1.1· then 4.1.2. 4.1.1. then 4.1.2. Race racemic racemization Racemic m mixture mm inch" <N <<N ώ inch λ of ώ A-2S,4§ GW oT cs ώ 外外 r<T 000 gas 00" CS < GO) inch office CO" ώ 2-[2-Oxo-4-(1,3-thiazol-2-yl)-1-pyrrolidinyl]butanamine male 1 S ! HI 1 <n" rH 1 ffi 譲Η l !fg it; A痤1 1 5 1 m 1 inch, CN rH ffi V ^ can be m WH if slightly in A痤2-[2-oxy-4-(lH-tetrazol-1-yl)-1- Pyrrolidinyl]butanamine m 1 τ-Η m base 1 CN i base Bl· 4 ^ Λ Η C/0 '-> cl m (2S)-2-[4-(4-methoxyphenyl) -2-oxy-1-pyrrolidinyl]butanamine 砮1 τ-Η 1 5 33⁄4 slightly m 砮1 m 1 secret _ At η 1 ^Η 1 S ring 1 1 W Secret: r鞸Λ Bu C/ D '~' has been slightly η I 砮1 r«H 1 s ring 1 cs 1 mwa铿Λ Η CO '~, 3 slightly inch in vo vo 00 00 On vo 〇rH CN -106 (4) 1295286

112.0 150.2 91.3 I 146.5 73.7 115.0 129.0 100.2 4.1.1. 然後 4.1.2.1 m 後 4.1.2.2 4.1.1. 然後 4.1.2.1 m ft 4.1.2.2 4.1.1. 然後 4.1.1.1 m it 4.2.1.2 m m 窠窠窠混合物 COD 寸 CO <N < A-2S,4 § coo 寸Λ co" CN ώ 1 B-2S，4§ COO 气 ζ/Γ <Ν < 〇0) 寸 00 CS ώ COD 气 c/Γ cs <; <N (2S)-2-[4-(2-甲氧苯基)-2-氧基-1.咯啶基]丁醯胺 m I ▼"Η m 祕 1 <N s 橄 m 4 ^ Λ Η 00 '~~' ci m 吞 I r-H m m 1 <N 稍祕 ffi- cA 4 ^ Λ H C/D '~~* 已稍 (2S)-2-[4-(4-硝基苯基)-2-氧基小吡咯啶基]丁醯胺 (2S)-2-[4-(3-甲氧苯基)-2-氧基-1-吡咯啶基]丁醯胺 m 1 r-H A 祕 1 s 擀祕 fr 1 CN 4 ^ Λ H 00 '—1 已稍 m 痤_ 吞· 1 r-H m 祕 1 <N I 稍擀稍鏗 1 S 4狴 :r P Λ Η C/0 '~1 已稍眷 1 ^r—j 1 梢態 K] 稍擀 1； <N g «麵 HI t 么稍 ^ m CO JO VO 00 On g -107^ 1295286112.0 150.2 91.3 I 146.5 73.7 115.0 129.0 100.2 4.1.1. Then 4.1.2.1 m after 4.1.2.2 4.1.1. then 4.1.2.1 m ft 4.1.2.2 4.1.1. then 4.1.1.1 m it 4.2.1.2 mm 窠窠窠 mixture COD inch CO <N < A-2S,4 § coo inch Λ co" CN ώ 1 B-2S, 4§ COO gas ζ / Γ < Ν < 〇 0) inch 00 CS ώ COD gas c/Γ cs <;<N (2S)-2-[4-(2-methoxyphenyl)-2-oxy-1.pyridyl]butanamine m I ▼"Η m Secret 1 <N s olive m 4 ^ Λ 00 00 '~~' ci m swallow I rH mm 1 <N slightly secret ffi- cA 4 ^ Λ HC/D '~~* slightly (2S)-2-[ 4-(4-nitrophenyl)-2-oxopyrrolidinyl]butanamine (2S)-2-[4-(3-methoxyphenyl)-2-oxy-1-pyrrolidine Butylamine m 1 rH A secret 1 s 擀 secret fr 1 CN 4 ^ Λ H 00 '-1 has been slightly m 痤 _ swallow · 1 rH m secret 1 <NI later slightly later 1 S 4狴:r P Λ Η C/0 '~1 has been slightly 眷1 ^r-j 1 tip state K] 擀1; <N g «face HI t 么^^ CO CO VO 00 00 On g -107^ 1295286

[11] [12] 寸 ▼—< ON 96.6 (93-95) 84.0 120.4 94.5 98.0 4.2.2. 4.1.1.然後 4.1.2. 4.2.2. 4.2.2. 4.1.1.然後 4.1.2. 4.1.1. 然後 4.2.1.1 然後 4.2.1.2 窠窠窠窠窠窠 m coo 寸· oo" CN < coo 寸办 CO CN PQ coo 气 CO CN < B-2S，4§ A-2S，4§ A-2S,4§ coo 寸办 00 CS ώ B-2S34§ B-2S,4§ 砮 1 t-H m m CN m 擀稍碱 i|d| i幾 4譲 41 2稍已遐痤 1 m 碱 1 (N i 稍 m 翻 is 4 m ^ t (2S)-2-[2-氧基-4-(3-噻吩基）-1-吡咯啶基]丁醯胺 η 砮 1 r-H 1 5 響 1 1 祕 a鏗 ^ ja Λ Η 00 '~~» m _ # 1 r-H 1 m 宓 m 1 1 T 補祕 A狴 Λ H GO '~~·i C稍盛I 砮 1 r-H m m CS s 擀 m K翻 4 m ? b g稍 cl n 砮 1 r-H ώ m 補擀 m iH ά ^ 4 m ? t g梢 m 砮 1 i-Η 1 i m 1 rn^ 1 嫲 Λ h CO 1~1 (2S)-2-[>(4-胺基苯基)-2-氧基小吡咯啶基]丁醯胺 CN 00 m 〇〇 to 00 vo oo OO 00 〇\ 〇〇 -"108— 1295286 ι—i (Τ) r-H U_J [14] 226.4 79.0 68.3 129.4 165.4 104.3 217.4 6·2·1·然後 6.3.1. 6·2·1·然後 6.3.1. “ “ <N —<Ν·— r-H 3.1.1.a S 3.1.1.g 鹚餘2 ^ " <N * . · ”r T--I r-H 寸·寸 1 m m 窠窠窠混合物混合物褰 A-2S，4 § B-2S,4§ (1HC1) 00 寸办 CO CN Pi 寸 00 (N A-2S，4§ COD 气 CO <N PQ 气 CN 寸 CS 000 气 00 CN <： (2S)-2-[4-(3-胺基苯基)-2-氧基-1-吡咯啶基]丁醯胺 η 盛I 菪 1 1-H m • 1 <N ϊ 擀 m 鏗 1 4 ^ S： « Λ Η C/D 'ι 已稍 (2S)-2-[(4S)-2-氧基-4-乙烯基毗咯啶基] 丁醯胺 (2S)-2-[(4R)-2-氧基-4-乙烯基吡咯啶基] 丁醯胺 2-[4-(溴苯基）-2-氧基-1-吡咯啶基]丁醯胺 2_[4-(2-漠苯基）-2-氧基-1-¾略U定基]丁醯胺 2-[(2-氧基-4-(3-吡啶基）-1-吡咯啶基）丁醯胺 1 m m 1 s m 隹 m I 祕瀏 it A磐砮 1 τ—1 m 祕 1 CN ii 1 r—ι 擀 4 h 石s 5? η (N 〇\ 〇\ 〇\ VO OS S；〇〇 σ\ -109- 1295286[11] [12] Inch ▼—< ON 96.6 (93-95) 84.0 120.4 94.5 98.0 4.2.2. 4.1.1. Then 4.1.2. 4.2.2. 4.2.2. 4.1.1. Then 4.1. 2. 4.1.1. Then 4.2.1.1 then 4.2.1.2 窠窠窠窠窠窠m coo inch · oo" CN < coo inch CO CO PQ coo gas CO CN < B-2S, 4§ A-2S , 4§ A-2S, 4§ coo Inch 00 CS ώ B-2S34§ B-2S, 4§ 砮1 tH mm CN m 擀 slightly alkali i|d| i a few 4譲41 2 slightly 遐痤1 m Base 1 (N i slightly m is 4 m ^ t (2S)-2-[2-oxy-4-(3-thienyl)-1-pyrrolidinyl]butanamine η 砮1 rH 1 5 ring 1 1 Secret a铿^ ja Λ Η 00 '~~» m _ # 1 rH 1 m 宓m 1 1 T Secret A狴Λ H GO '~~·i C slightly Sheng I 砮1 rH mm CS s 擀m K flip 4 m ? bg slightly cl n 砮1 rH ώ m complement i m iH ά ^ 4 m ? tg tip m 砮1 i-Η 1 im 1 rn^ 1 嫲Λ h CO 1~1 (2S)-2- [>(4-Aminophenyl)-2-oxypyrrolidinyl]butanamine CN 00 m 〇〇to 00 vo oo OO 00 〇\ 〇〇-"108-1295286 ι-i (Τ rH U_J [14] 226.4 79.0 68.3 129.4 165.4 104.3 217.4 6·2·1· then 6.3.1. 6·2·1· then 6.3.1. “ “ <N —<Ν·— rH 3.1.1.a S 3.1.1.g 鹚 remaining 2 ^ "<N * . ”r T--I rH inch·inch 1 mm 窠窠窠 mixture mixture 褰A-2S,4 § B-2S,4§ (1HC1) 00 inch office CO CN Pi inch 00 (N A-2S, 4§ COD Gas CO <N PQ gas CN inch CS 000 gas 00 CN <: (2S)-2-[4-(3-aminophenyl)-2-oxy-1-pyrrolidinyl]butanamine η盛 I 菪1 1-H m • 1 <N ϊ 擀m 铿1 4 ^ S: « Λ Η C/D 'ι has been slightly (2S)-2-[(4S)-2-oxy-4- Vinylpyridinyl] Butanamine (2S)-2-[(4R)-2-oxy-4-vinylpyrrolidinyl] Butanamine 2-[4-(bromophenyl)-2- Oxy-1-pyrrolidyl]butanamine 2_[4-(2-Molyl)-2-oxy-1-3⁄4 U 定 ]] Butylamine 2-[(2-oxy-4- (3-pyridyl)-1-pyrrolidyl)butanamine 1 mm 1 sm 隹m I Secret itit A磐砮1 τ—1 m Secret 1 CN ii 1 r—ι 擀4 h Stone s 5? η (N 〇\ 〇\ 〇\ VO OS S; 〇〇σ\ -109- 1295286

[15] |—"ϊ Ό ^Η U~J [17] 255 172.7 135.7 171.1 166.6 161.7 119.4 7.2.2. T-H 7.1.1. 窠窠 m 混合物混合物 m m m 外消旋 B-2S，4§ 000 寸办 αΓ Γ<1 < 000 寸·> CO <N < B-2S，4§ 寸· (N CN A-2S，4R 00 气 CO <s < A-2S,4§ 寸rs CN <： 1 ii 娜 1 <N 1 r—i 浒 _ ：£ _ 4 Η 3 s 1 r-H Λ 嫲 1 <N 稍稍 • ^ ί杯 Γ m £ h i Ϊ ^ n (2S)-2-[4-(l-萘基）-2-氧基-1-吡咯啶基] 丁醯胺 (2S)-2-[4-(l-萘基）-2-氧基小吡咯啶基] 丁醯胺 2-[4-(姚甲基）-2-氧基-1-¾略Π定基]丁釀胺 2-[4-(氯甲基）-2-氧基-1-吡咯啶基]丁醯胺砮 1 r-H m 祕 1 CN 5 El· s m g稍 cs η 1 1-H άι if CN i 藓 1 έ ^ s濯 T s π « d n 祕瞻 Ϊ 浒鹅 m 1 vo ¥狴 7 m 補卜^ ^ i i塑 <N 吞 1 · /—N r—1 00 ' 已摊1 (2 S)-2-(4-己基-2-氣基-1-¾略D定基）丁釀胺 ON ON 100 101 102 103 104 105 106 107 108 -110- 1295286[15] |—"ϊ Ό ^Η U~J [17] 255 172.7 135.7 171.1 166.6 161.7 119.4 7.2.2. TH 7.1.1. 窠窠m mixture mixture mmm racemic B-2S, 4§ 000 inch ΓαΓ Γ<1 < 000 inch·> CO <N < B-2S, 4§ inch · (N CN A-2S, 4R 00 gas CO <s < A-2S, 4§ inch rs CN <: 1 ii Na 1 <N 1 r-i 浒 _ : £ _ 4 Η 3 s 1 rH Λ 嫲 1 <N Slightly ^ ^ ί cup Γ m £ hi Ϊ ^ n (2S) -2- [4-(l-Naphthyl)-2-oxy-1-pyrrolidinyl] Butanamine (2S)-2-[4-(l-naphthyl)-2-oxypyrrolidinyl] Indole 2-[4-(Yaomethyl)-2-oxy-1-3⁄4 Π Π ]] butylamine 2-[4-(chloromethyl)-2-oxy-1-pyrrolidinyl] Amine 砮1 rH m Secret 1 CN 5 El· smg slightly cs η 1 1-H άι if CN i 藓1 έ ^ s濯T s π « dn 秘Ϊ Ϊ 浒 go m 1 vo ¥狴7 m Bu Bu ^ ^ Ii plastic <N swallow 1 · / -N r -1 00 ' has been spread 1 (2 S)-2-(4-hexyl-2-carbyl-1-3⁄4 slightly D-based) butylamine ON ON 100 101 102 103 104 105 106 107 108 -110- 1295286

255 241 241 395 395 1 283 269 297 199 269 241 147 116.3 7.1.1. 7.1.1. 3.1.1.a 至 3.1.1.g 外消旋窠外消旋外消旋外消旋外消旋外消旋外消旋混合物混合物混合物混合物寸办 CN ώ Pi 寸 <N Pi 气 CO ca A-2,4 寸办 ci ώ 气 CN < 〇Γ ώ 寸办 (S < 寸Λ CN • ώ of Γ^Γ ri 寸《 CN (2S)-2-(4-己基-2-氧基-1-吡咯啶基)丁醯胺 m 嫲 1 CS S S- 奮寸 έ S鏗 OQ i~ι 已補 m 结I m. ! <N 1 m r 1 可 00 寸你 ΠΧΙ v m ^ s /^s fH. 00 '1 ^ m 2-(4-己基-2-氧基-1-吡咯啶基)丙醯胺 2-(4·己基-2-氧基-1-吡咯啶基)丙醯胺 2-(4-己基-2-氧基-1-吡咯啶基)十四烷醯胺 2-(4-己基-2-氧基-1-吡咯啶基）十四烷醯胺 2-(4-己基-2-氧基-1-吡咯啶基)己醯胺 2-(4-己基-2-氧基-l-ft咯啶基)戊醯胺 2-(4-己基-2-氧基-1-吡咯啶基)庚醯胺 2-(2-氧基-4-丙基-1-吡咯啶基)丙醯胺 2-(2-氧基-4-丙基-1-毗咯啶基)辛醯胺 2-(2-氧基-4-丙基-1-吡咯啶基)己醯胺 109 110 111 112 113 1 114 | 115 116 117 118 119 120 121 -111 - 1295286 •· 241 227 227 255 255 213 185 261 261 381 297 297 269 134.5 3.1.1.a $ 3.1.1.g 混合物混合物混合物混合物混合物外消'旋外消旋外消旋外消旋混合物外消旋外消旋外消旋寸a ci <N ri ri 寸办 <N <；寸 A-2S,4§ <N < 寸λ CN ώ 寸c ri A-2,4 B-2,4 气 2-(2-氧基-4-丙基-1-毗咯啶基)己醯胺 2-(2-氧基-4-丙基-1-吡咯啶基)己醯胺 2-(2-氧基-4-丙基-1-吡咯啶基)戊醯胺 2^2-氧基-4-丙基-1-吡咯啶基)庚醯胺 2-(2-氧基-4-丙基-1-吡咯啶基)庚醯胺 2-(2-氧基-4-丙基-1-吡咯啶基)丁醯胺 2-(2-氧基-4-丙基-1-吡咯啶基）乙醯胺 1 1-H ά m 1 CN 稍 ii 簡 ? m i Ϊ 已砮 2-(2-氧基-4-丙基-1-毗咯啶基)-2-苯基乙醯胺 2-(2-氧基-4-丙基-1-吡咯啶基）-2-苯基乙醯胺 2^2-氧基-4-戊基-1-吡咯啶基）十四烷醯胺 2-(2-氧基-4-戊基-1-吡咯啶基)辛醯胺 2-(2-氧基-4-戊基-1-吡咯啶基)辛醯胺 2-(2-氧基-4-戊基-1-吡咯啶基)己醯胺 122 123 124 125 126 127 128 _ . . 1 129 130 131 132 133 134 135 -112- 1295286255 241 241 395 395 1 283 269 297 199 269 241 147 116.3 7.1.1. 7.1.1. 3.1.1.a to 3.1.1.g Racemic racemic racemic racemic racemic Racemic mixture mixture mixture mixture CN ώ Pi inch <N Pi gas CO ca A-2, 4 inch office ci ώ gas CN < 〇Γ ώ inch office (S < inch Λ CN • ώ of Γ^Γ ri 寸" CN (2S)-2-(4-hexyl-2-oxy-1-pyrrolidyl)butanamine m 嫲1 CS S S- 奋 inch έ S铿OQ i~ι m 结 I m. ! <N 1 mr 1 can be 00 inch ΠΧΙ vm ^ s /^s fH. 00 '1 ^ m 2-(4-hexyl-2-oxy-1-pyrrolidinyl) propyl hydrazine Amine 2-(4·hexyl-2-oxy-1-pyrrolidinyl)propanamide 2-(4-hexyl-2-oxy-1-pyrrolidinyl)tetradecanedecyl 2-(4- Hexyl-2-oxy-1-pyrrolidinyl)tetradecanedecyl 2-(4-hexyl-2-oxy-1-pyrrolidinyl)hexylamine 2-(4-hexyl-2-oxyl -l-ftrrolidyl)pentaamine 2-(4-hexyl-2-oxy-1-pyrrolidinyl)heptanyl 2-(2-oxy-4-propyl-1-pyrrolidinyl) Propionamide 2-(2-oxy-4-propyl-1-pyrrolidyl)octylamine 2-(2-oxy-4-propyl-1-pyrrolidine Hexylamine 109 110 111 112 113 1 114 | 115 116 117 118 119 120 121 -111 - 1295286 •· 241 227 227 255 255 213 185 261 261 381 297 297 269 134.5 3.1.1.a $ 3.1.1.g Mixture mixture mixture mixture extinction 'spin racemic racemic racemic mixture racemic racemic racemic inch a ci <N ri ri inch<N <; inch A-2S,4 § <N < inch λ CN ώ inch c ri A-2,4 B-2,4 gas 2-(2-oxy-4-propyl-1-pyrrolidyl) hexamethyleneamine 2-( 2-oxy-4-propyl-1-pyrrolidinyl)hexylamine 2-(2-oxy-4-propyl-1-pyrrolidinyl)pentanylamine 2^2-oxy-4- Propyl-1-pyrrolidinyl)heptanyl 2-(2-oxy-4-propyl-1-pyrrolidinyl)heptanyl 2-(2-oxy-4-propyl-1-pyrrole Butyryl)butanamine 2-(2-oxy-4-propyl-1-pyrrolidinyl)acetamide 1 1-H ά m 1 CN simi ii sim? mi Ϊ already 2-(2-oxygen 4--4-propyl-1-pyridyl)-2-phenylacetamide 2-(2-oxy-4-propyl-1-pyrrolidinyl)-2-phenylacetamide 2 ^2-Oxo-4-pentyl-1-pyrrolidinyl)tetradecanedecyl 2-(2-oxy-4-pentyl-1-pyrrolidine Octylamine 2-(2-oxy-4-pentyl-1-pyrrolidinyl)octylamine 2-(2-oxy-4-pentyl-1-pyrrolidinyl)hexylamine 122 123 124 125 126 127 128 _ . . 1 129 130 131 132 133 134 135 -112- 1295286

269 255 255 284 289 241 241 1 213 291 53.8 94.8 66.6 3.1.1.a $ 3.1.l.g 7.1.1. 外消旋外消旋外消旋混合物混合物外消旋I 外消旋外消旋窠混合物寸〇Γ ώ A-2,4 寸办 ώ CS 寸 CA A-2,4 1 ώ 寸 Pi 气 co" CN Ρύ 00" <N Pi 寸办 GO CN 寸 <N 2-(2-氧基-4-戊基-1-吡略啶基)己醯胺 2-(2-氧基-4-戊基-1-吡咯啶基)戊醯胺 2-(2-氧基-4-戊基-1-¾略Π定基)戊釀胺 2-(2-氧基-4-戊基-1-吡咯啶基)庚醯胺 2-(2-氧基-4-戊基-1-¾略D定基）-2-苯基乙醯胺 2-P-氧基-4-戊基-1-吡咯啶基)丁醯胺 | 2-(2-氧基-4-戊基-1-吡咯啶基)丁醯胺 2-(2-氧基-4-戊基-1 - ¾咯卩定基）乙釀胺 m 痤 m w 冊 <N 梢盤 s m b 4 « Λ El· ^ 11 'W/ 1 t CO 11 砮 m nf 1 <N fr i Λ &· ^ 11 I /^N 1 00 «~* 遐盛I 稍祕 1 CS 1 5 6 綦鏗 ^ Η 耷稍 V Β- t C/D *^ c m f Λ 嫲 1 <N 1 i 1 1 醒 II ^ 爷t c ^ 土普 A吞 136 137 138 139 140 141 ί 142 143 144 145 146 147 -113- 1295286 [18] r—1 ON r*H L_l |；20] [21] 187.0 155.7 101.8 119.1 l.i.i mk 1·2·1·然後 1.2.2. 1.1.1. 然後 1.2.1. 然後 1.2.2. 二 “ <N d Η — 窠 m m m 外消旋外消旋窠 A-2S,4§ coo 寸办 00 CN ώ A-2S,4§ ———1 A-2S，4§ i B-2S，4§ A-2,4 B2,4 寸” CN (23)-2-(4-新戊基-2-氧基-1-姐略卩疋基)丁醯胺 (23)-2-(4-新戊基-2-氧基-1-啦咯11定基）丁醯胺祕 1 <N 稍 3 m 胡Μ 苧稍 X磐士眷 00 1 <N T-H S-^ 1 (2S)-2-(4-乙基-2-氧基-1-吡咯啶基）丁醯胺 (2S)-2-(4-乙基-2-氧基-1-吡咯啶基）丁醯胺 2-{4-[(苄氧）甲基]-2-氧基-1-吡咯啶基} 丁醯胺 2-{4_[(爷氧）甲基]-2-氧基-1-¾略Π定基} 丁醯胺 η 稍祕 1 CN 1 i & 了 _ Λ Η ，：έ I 00 11 已權 148 149 150 151 152 153 154 155 —11A— 12952.86269 255 255 284 289 241 241 1 213 291 53.8 94.8 66.6 3.1.1.a $ 3.1.lg 7.1.1. Racemic racemic racemic mixture mixture racemic I racemic racemic mixture 〇Γ ώ A-2, 4 inch office CS inch CA A-2, 4 1 ώ inch Pi gas co" CN Ρύ 00"<N Pi inch GO CN inch <N 2-(2-oxy- 4-pentyl-1-pyridylpyridyl)hexylamine 2-(2-oxy-4-pentyl-1-pyrrolidinyl)pentanylamine 2-(2-oxy-4-pentyl- 1-3⁄4 Π定定) pentylamine 2-(2-oxy-4-pentyl-1-pyrrolidinyl)heptanyl 2-(2-oxy-4-pentyl-1-3⁄4 slightly D 2-phenyl-2-indanyl 2-P-oxy-4-pentyl-1-pyrrolidyl)butanamine | 2-(2-oxy-4-pentyl-1-pyrrolidinyl) Butylamine 2-(2-oxy-4-pentyl-1 -3⁄4 fluorenyl) ethylamine m 痤mw book <N tip plate smb 4 « Λ El· ^ 11 'W/ 1 t CO 11 砮m nf 1 <N fr i Λ &· ^ 11 I /^N 1 00 «~* 遐盛 I 密秘1 CS 1 5 6 綦铿^ Η 耷 slightly V Β- t C/D *^ Cmf Λ 嫲1 <N 1 i 1 1 醒 II ^ 爷 tc ^ 土普A 136 137 138 139 140 141 ί 142 143 144 145 146 147 -113- 1295286 [18] r-1 ON r*H L_l |;20] [21] 187.0 155.7 101.8 119.1 lii mk 1·2·1· then 1.2.2. 1.1.1. then 1.2.1. then 1.2 .2. 2 " <N d Η - 窠mmm racemic racem 窠A-2S, 4§ coo 寸办00 CN ώ A-2S,4§ ———1 A-2S,4§ i B -2S,4§ A-2,4 B2,4 inch" CN (23)-2-(4-neopentyl-2-oxy-1-succinyl)butanamine (23)-2 -(4-neopentyl-2-oxy-1-lol-11) butylamine 1 <N slightly 3 m Μ 苎 slightly X 磐眷 00 1 <N TH S-^ 1 ( 2S)-2-(4-ethyl-2-oxy-1-pyrrolidyl)butanamine (2S)-2-(4-ethyl-2-oxy-1-pyrrolidinyl)butane Amine 2-{4-[(benzyloxy)methyl]-2-oxo-1-pyrrolidinyl}butanamine 2-{4_[(())-oxy]methyloxy]-1-oxy-1-3⁄4 Π定定基丁丁amine η 密密1 CN 1 i & _ Λ Η ,:έ I 00 11 权148 149 150 151 152 153 154 155 —11A— 12952.86

127.2 136.8 82.1 74.3 _i 121.3 180.3 105.0 118.1 108.8 6·2·3·然後 6.3.1. <Ν· <N 6·2·4·然後 6.3.1. 3·2·1·然後 6.3.2. 2.1丄然後 2.2. 混合物混合物窠 m 外消旋外消旋混合物混合物混合物寸λ cs ri C0 寸” ζ/Γ CN 00 寸· χλ CS 寸· CN < 寸办 ώ 寸λ <Ν 寸办 (Ν 〇Γ m 1 Λ m 1 (Ν I 3 载 Κ) 喊 ',1 ^ CN 4 Η ^ 5 2-[4-(2,2-二氟乙基)-2-氧基-1-吡咯啶基] 丁醯胺 (2S)-2-[(4S)-2-氧基-4-丙基吡咯啶基]丁醯胺 (2S)-2-[(4R)-2-氧基-4-丙基吡咯啶基]丁醯胺 2-[2-氧基-4-(三氟甲基）-1-吡咯啶基]丁醯胺 2-[2-氧基-4-(三氟甲基）-1-吡咯啶基]丁醯胺 m 砮 1 r-H ώ Jiff 1 (N 稍敢 ΚΙ Jii tTQ 4 Η IS 1 Η W 娜 1 稍裝 Ε 1 1 稍鏗 fr廳 Η 2-(4-丁基-2-氧基-1-吡咯啶基)丁醯胺 156 157 158 159 160 161 162 163 164 -115-127.2 136.8 82.1 74.3 _i 121.3 180.3 105.0 118.1 108.8 6·2·3· then 6.3.1. <Ν· <N 6·2·4· then 6.3.1. 3·2·1· then 6.3.2. 2.1丄 then 2.2. Mixture mixture 窠m racemic racemic mixture mixture mixture λ cs ri C0 inch” ζ/Γ CN 00 inch · χλ CS inch · CN < inch ώ 寸 λ <Ν inch office ( Ν 〇Γ m 1 Λ m 1 (Ν I 3 Κ) shout ',1 ^ CN 4 Η ^ 5 2-[4-(2,2-difluoroethyl)-2-oxy-1-pyrrolidine Butylamine (2S)-2-[(4S)-2-oxy-4-propylpyrrolidinyl]butanamine (2S)-2-[(4R)-2-oxy-4- Propylpyrrolidyl]butanamine 2-[2-oxy-4-(trifluoromethyl)-1-pyrrolidinyl]butanamine 2-[2-oxy-4-(trifluoromethyl) )-1-pyrrolidyl]butanamine m 砮1 rH ώ Jiff 1 (N slightly dare ΚΙ Jii tTQ 4 Η IS 1 Η W 娜1 slightly Ε 1 1 铿铿 fr hallΗ 2-(4-butyl -2-oxy-1-pyrrolidinyl)butanamine 156 157 158 159 160 161 162 163 164 -115-

1295286 r—ϊ CN (N 299/301 297 ϊ 1 281 315 261 120.2 2·1·2·然後 2.2. 6·2·1·然後 6.5.然後 6.3.1. 3.1.1.a S 3.1.1.g ^ i-I ΓΠ 3.1.1.a 至 3.1.1.g 3.1.1.a S 3.1.1.g 混合物混合物混合物混合物混合物混合物混合物混合物混合物寸办 CN 寸 CN 寸CS <N CN CN 寸 CN 寸 Λ CN 2-[4-(環丙基甲基）-2·氧基-1-吡咯啶基] 丁醯胺 2-(4-異丁基-2-氧基-1-吡咯啶基)丁醯胺 η 盛I . 砮 1 τ-Η m (N 5 擀 1 碱鏗丨m 4 fc A稍 2-[4-(2-萘基）-2-氧基-1-吡咯啶基]丁醯胺丨 2-[4-(4-氯苯基）-2-氧基-1-吡咯啶基]丁醯胺 2-[4-(3-氯苯基）-2-氧基-1-吡咯啶基]丁醯胺 1 ▼-H 睡 5 t S l· ii HI 1 (N T ^ 稍_ m t ^ m 2-[4-(4-甲基苯基）-2-氧基-1-吡咯啶基] 丁醯胺 2-[4-(2-赢苯基）-2-氧基-1-¾略Π定基]丁醯胺 165 166 167 168 j _! 169 170 171 172 173 -116~ 12952861295286 r—ϊ CN (N 299/301 297 ϊ 1 281 315 261 120.2 2·1·2· then 2.2. 6·2·1· then 6.5. then 6.3.1. 3.1.1.a S 3.1.1. g ^ iI ΓΠ 3.1.1.a to 3.1.1.g 3.1.1.a S 3.1.1.g mixture mixture mixture mixture mixture mixture mixture mixture CN inch CN inch CS <N CN CN inch CN inch Λ CN 2-[4-(cyclopropylmethyl)-2.oxy-1-pyrrolidinyl]butanamine 2-(4-isobutyl-2-oxo-1-pyrrolidinyl)醯amine η 盛 I. 砮1 τ-Η m (N 5 擀1 alkali 铿丨m 4 fc A slightly 2-[4-(2-naphthyl)-2-oxy-1-pyrrolidinyl] Amidoxime 2-[4-(4-chlorophenyl)-2-oxy-1-pyrrolidinyl]butanamine 2-[4-(3-chlorophenyl)-2-oxy-1-pyrrole Iridyl]butanamine 1 ▼-H sleep 5 t S l· ii HI 1 (NT ^ _ mt ^ m 2-[4-(4-methylphenyl)-2-oxy-1-pyrrolidine Butylamine 2-[4-(2-winylphenyl)-2-oxy-1-3⁄4 Π Π ]] butyl amide 165 166 167 168 j _! 169 170 171 172 173 -116~ 1295286

311 283 269 89.5 100.2 1 1 99.6 116.9 97.2 3.1.1.a $ 3.1.1.g 1丄2·然後 1·2·1·然後 1.2.3. 1·1·2·然後 1.2.1·然後 1.2.3. 1·1·2·ϋ 然後 1·2·1· 然後1.2.2. 1·1·2·ϋ 然後 1.2.1· 然後1·2·2· 3.1.1.a·至 3.1.1.g. 混合物 m 窠· 混合物外消旋外消旋窠 m 000 寸办 00 ώ 000 寸办 00 (Ν < 气寸办 ώ 寸办 <； 000 气 CO CN < 000 寸Λ CO <N ώ A-2 § ,4 § 2-[4-(3 -甲基苯基）-2-氧基-1-¾略Π疋基] 丁醯胺 (2S)-2-[2-氧基-4-(2-苯基乙基)-1-妣咯啶基]丁醯胺替I 1 1-H 1 S K) 補浒 1 1 Jlf Λ Η C/D '~~' 1(4-己基-2-氧基-1-吡咯啶基)辛醯胺 2-(4 -己基-2-氧基- l- 啦咯陡基）己釀胺 2-(4-己基-2-氧基-1-吡咯啶基)戊醯胺吞 1 νΗ m if I <N s 1 4 ^ Λ Η CO 1~1 m 吞 1 τ-Η m 嫲 1 <N ϊ 浒鹅 1 ΓΟ 4 ^ Λ h C/D '~~1 I τ-Η m 碱 1 CN 5 i 槭盤 111 i ¥ t Aw <N 吞 174 175 176 177 178 179 180 181 182 -117-311 283 269 89.5 100.2 1 1 99.6 116.9 97.2 3.1.1.a $ 3.1.1.g 1丄2· then 1·2·1· then 1.2.3. 1·1·2· then 1.2.1· then 1.2 .3. 1·1·2·ϋ then 1·2·1· then 1.2.2. 1·1·2·ϋ then 1.2.1· then 1·2·2· 3.1.1.a· to 3.1. 1.g. mixture m 窠 · mixture racemic racemization 000 m 000 inch 00 ώ 000 inch office 00 (Ν < gas inch office 寸 office <; 000 gas CO CN < 000 inch Λ CO &lt ;N ώ A-2 § ,4 § 2-[4-(3-methylphenyl)-2-oxy-1-3⁄4 Π疋 Π疋 ]] Butaneamine (2S)-2-[2-oxygen 4-(2-phenylethyl)-1-pyridinyl]butanamine for I 1 1-H 1 SK) 浒1 1 Jlf Λ Η C/D '~~' 1(4- Hexyl-2-oxy-1-pyrrolidinyl)octylamine 2-(4-hexyl-2-yloxy-l-lalocyl)-bristamine 2-(4-hexyl-2-oxy- 1-pyrrolidyl)pentaamine 1 νΗ m if I <N s 1 4 ^ Λ Η CO 1~1 m 吞 1 τ-Η m 嫲1 <N ϊ 浒 1 1 ΓΟ 4 ^ Λ h C /D '~~1 I τ-Η m alkali 1 CN 5 i Maple plate 111 i ¥ t Aw <N 吞174 175 176 177 178 179 180 181 182 -117-

12952861295286

97.2 148.6 148.6 177.9 177.9 154.7 1 i 178.7 201.4 138.0 137.4 3.1.l.a S 3.1.1.g 3.1.1.a S 3.1.1.g 3.1.1.a Μ 3.1.1.g 3.1.1.a $ 3.1.1.g 裳 m 窠外消旋外消旋 m 窠 B-2§,4§ coo 寸Λ COD CN 0 D-2§,4§ coo 寸《 coo CN < B-2§，4§ A-2,4 寸Λ <Ν ώ coo 气 00 cs ώ A-2 § ,4 § B-2§，4§ ! r-H w 雛 I (N 稍 s s fr 碱鏗 111 i ¥ t A稍 x痤 a害 I t-H Λ 嫲 1 CS| 稍稍 sa- ii 鏗 !H S « tz Λ m 巴遐 i塑 a砮 1 H m m 1 (N 5 ft 3 E- 减盤 111 i ¥ t A稍巴® i绝 a # 2-[4-(3,4-二氯苯基)-2-氧基-1-吡咯啶基] 丁醯胺 2-[4-(3,4-二氯苯基)-2-氧基_1-吡咯啶基] 丁醯胺 2-[4-(2,4-一氣苯基)-2-氧基-1-¾略H定基] 丁醯胺 [ 2-[4-(2,4-二氯苯基)-2-氧基-1-吡咯啶基] 丁醯胺篇 Ϋ-Η Λ m (N 稍揪 11 1 d： ^ 4 m 孑t g稍 S 稍 m S &· 槭盤 11] 5 午t i S 4 m «s c； 1 :稍 s 5 遯 H S & 緘裝 111 g ά S 4 m ,: 183 184 185 186 187 188 189 190 191 192 —118— 1295286 [23] [24] 84.4 83.8 92.5 1 1 118.6 153.8 154.4 99.8 Η —: • ^ Γ〇 3.1.1.a S 3.1.1.g <Ν· “ 〜· —<Ν·— r-H r-H I 1·1·2·ϋ 然後 1·2·1· 然後1.2.2. 3.1.1.a $ 3.1.1.g 3.1.1. a 至， 3.1.1. g m 案外消旋外消旋混合物窠混合物 C-2 §，4 § D-2§，4§ Α-2,4 B-2,4 寸办 αΓ rs I 1 A-2S，4§ C-2 §，4 §， coo 寸 000 cs Q #N CN s 5 遯 m 5 6 减趨 111 5 ά S 4 m « | • v w — s 糊 ss m S l· 槭盤 111 p 午t ά m 4 m w S « 7 w — ^ m 2-[4-(2-咲喃基）-2-氧基-1-¾咯Π定基]丁醯胺 2-[4-(2-呋喃基）-2-氧基-1-吡咯啶基]丁醯胺 m # 1 τ-Η 1 i « 擀 1 CO 1 A Ilf 乂惩 v m 1 h C/D '' 砮 1 r-H Λ 祕 1 cs 擀郏 II 1 d ^ ;謹 At 2-[4-(3,4-二氯苯基)-2-氧基-1-吡咯啶基] 丁醯胺 2-[4-(3,4-二氯苯基)-2-氧基-1-吡咯啶基] 丁醯胺 2-(2-氧基-4-丙基-1-吡咯啶基)丁醯胺 193 194 195 196 197 198 199 200 201 -119- 129528697.2 148.6 148.6 177.9 177.9 154.7 1 i 178.7 201.4 138.0 137.4 3.1.la S 3.1.1.g 3.1.1.a S 3.1.1.g 3.1.1.a Μ 3.1.1.g 3.1.1.a $ 3.1 .1.g sm m 窠 racemic racem m 窠 B-2§, 4§ coo inch Λ COD CN 0 D-2§,4§ coo inch "coo CN < B-2§,4§ A -2,4 inch Λ <Ν ώ coo gas 00 cs ώ A-2 § , 4 § B-2 §, 4 § ! rH w Young I (N Slightly ss fr Alkali 铿 111 i ¥ t A slightly x痤a害I tH Λ 嫲1 CS| Slightly sa- ii 铿!HS « tz Λ m 巴遐i塑a砮1 H mm 1 (N 5 ft 3 E- 减盘111 i ¥ t A 巴巴® i absolutely a # 2-[4-(3,4-Dichlorophenyl)-2-oxy-1-pyrrolidinyl]butanamine 2-[4-(3,4-dichlorophenyl)-2-oxyl _1-pyrrolidinyl]butanamine 2-[4-(2,4-a-phenylphenyl)-2-oxy-1-3⁄4 slightly H-butyl] Butanamine [2-[4-(2,4) -dichlorophenyl)-2-oxo-1-pyrrolidinyl]butanamine Ϋ-Η Λ m (N 揪11 1 d: ^ 4 m 孑tg slightly S slightly m S &· Maple plate 11] 5 ti S 4 m «sc; 1 : Slightly s 5 遁HS & Armored 111 g ά S 4 m , : 183 184 185 186 187 188 189 190 191 192 —118 — 1295286 [23] [24] 84.4 8 3.8 92.5 1 1 118.6 153.8 154.4 99.8 Η —: • ^ Γ〇3.1.1.a S 3.1.1.g <Ν· “ 〜· —<Ν·— rH rH I 1·1·2·ϋ Then 1·2·1· then 1.2.2. 3.1.1.a $ 3.1.1.g 3.1.1. a to, 3.1.1. gm case racemic racemic mixture C mixture C-2 §, 4 § D-2§,4§ Α-2,4 B-2,4 inch office αΓ rs I 1 A-2S,4§ C-2 §,4 §, coo inch 000 cs Q #N CN s 5 遁m 5 6 Decrease 111 5 ά S 4 m « | • vw — s paste ss m S l· maple plate 111 p noon t ά m 4 mw S « 7 w — ^ m 2-[4-(2-咲基 )) -2-oxy-1-3⁄4 Π Π ] ] ] ] 2- 2- 2- 2- 2- 2-[4-(2-furyl)-2-oxy-1-pyrrolidinyl]butanamine m # 1 τ-Η 1 i « 擀1 CO 1 A Ilf 乂 v vm 1 h C/D '' 砮1 rH Λ secret 1 cs 擀郏II 1 d ^ ; I would like At 2-[4-(3,4-dichlorophenyl)-2 -oxy-1-pyrrolidinyl]butanamine 2-[4-(3,4-dichlorophenyl)-2-oxy-1-pyrrolidinyl]butanamine 2-(2-oxyl -4-propyl-1-pyrrolidyl)butanamine 193 194 195 196 197 198 199 200 201 -119- 1295286

—120— 1295286—120— 1295286

-121- 1295286-121- 1295286

r—η 00 CN Γ—1 〇\ 69.2 165.4 171.1 58.3 90.6 129.5 139.46 106.2 oo 2.1.2.H 然後 2.2· 2·1·2·ϋ 然後 2.2· 2·1·2·Π 然後 2·2· 2.1.2.H 然後 2·2· m CN m m 窠 m 窠 m 窠. 窠 000 寸e GO <N ώ coo 气 GO CS PQ coo 寸 CO <N < B-2S，4§ coo 寸Λ c/Γ CN ώ 000 寸 r\ 00 <N < 000 气 CO (N < B-2S，4§ ζ/Γ 气 00" CN ^ (Ν B-2S，4S， 2§ 盛I 砮 1 r»H 1 i 1 r-H 1 毯I 菪 1 ffi t-H 1 W Hf ® A譲 ^ t 5Γ W (2S)-2-(4-烯丙基-2-氧基-1-吡咯啶基)丁醯胺 (2S)-2-[4-(2-碘丙基）-2-氧基-1-吡咯啶基]丁醯胺 η 1 t-rH 'm 嫲 1 CS 5 綦 1 <N 4 ^ Λ Η C/3 r~i C補砮 1 τ-Η Λ ϋ 1 cs i 祕 Η- 4 ^ ί： P Λ H CO '—' (2S)-2-(4-燃丙基-2-氧基-1-¾略B定基）丁醯胺 (2 S)-2-[2-氧基-4-(2-氧基丙基)-1-¾略Π定基]丁醯胺 GS)-2-[2-氧基-4-(氧基丙基）-1-吡咯啶基]丁醯胺 η 稍 CN Ϊ Ε m ^ΠΎ\ 1 1 可 00 S狴 Α Η CO '~1 c « m 稍嫲 1 CS S E ^rns 1 1 可 /—N CO 寸似 v—/ TO Λ Η 00 '~、 223 224 225 226 227 228 229 230 231 232 -122- 1295286R—η 00 CN Γ—1 〇\ 69.2 165.4 171.1 58.3 90.6 129.5 139.46 106.2 oo 2.1.2.H then 2.2· 2·1·2·ϋ Then 2.2· 2·1·2·Π Then 2·2· 2.1 .2.H then 2·2· m CN mm 窠m 窠m 窠. 窠000 inch e GO <N ώ coo gas GO CS PQ coo inch CO <N < B < B-2S, 4 § coo inch Λ c /Γ CN ώ 000 inch r\ 00 <N < 000 gas CO (N < B-2S, 4§ ζ/Γ气00" CN ^ (Ν B-2S, 4S, 2§ 盛 I 砮1 r »H 1 i 1 rH 1 blanket I 菪1 ffi tH 1 W Hf ® A譲^ t 5Γ W (2S)-2-(4-allyl-2-oxy-1-pyrrolidyl)butanamine (2S)-2-[4-(2-Iodopropyl)-2-oxy-1-pyrrolidinyl]butanamine η 1 t-rH 'm 嫲1 CS 5 綦1 <N 4 ^ Λ Η C/3 r~i C 砮1 τ-Η Λ ϋ 1 cs i Tips - 4 ^ ί: P Λ H CO '-' (2S)-2-(4-flame propyl-2-oxy -1-3⁄4略乙定基)Butylamine (2S)-2-[2-oxy-4-(2-oxypropyl)-1-3⁄4 Π定定]丁丁胺 GS)-2- [2-oxy-4-(oxypropyl)-1-pyrrolidinyl]butanamine η CNCN Ϊ Ε m ^ΠΎ\ 1 1 00 00 狴Α Η CO '~1 c « m 嫲1 CS SE ^rns 1 1 / / N CO 寸 v v _ _ Λ 00 00 '~, 223 224 225 226 227 228 229 230 231 232 -122- 1295286

[31] [32] [33] [34] 133.0 74.9 84.8 137.2 137.3 112 卜窠 m 外消旋外消旋 m 窠 m m 窠葉 Pi 寸· coo orT ^ CN ώ m 气 co" Γνϊ ώ 寸，\ (N < <N ώ m 气 c/T CN PQ DQ Tt Pi CN Pi 寸办 Pi CA A-2 § ,4 § B-2§,4§ C-2 § ,4 § (2S)-2-[(4R)-4-(2-羥丙基)-2-氧基吡咯啶基]丁醯胺 m Jiff 稍 1 r-H 1 痤 • m ^ - V W ;磐 03 绝 CO ® 已二 m 祕 1 浒 li. 1)1 1 #s LLi 之 ^ m _ 5 « | v 5 A 二 m m 1 <N 3 浒贓. ID 1 VO 寸製彳i m h m | Φ 5 2L砮 1 1 CS — if <N Ϊ 1 r-H 1 淦 ^ m η fc A _ CL w i塑 •芻 t—l CO * 已補 (2R)-2-[(4S)-2-氧基-4-丙基吡咯啶基]丁醯胺 1 (2R)-2-[(4R)-2-氧基-4-丙基吡咯啶基]丁醯胺 2-(4-乙基-2-氧基-4-苯基-1-吡咯啶基）丁醯胺 2-(4-乙基-2-氧基-4-苯基-1-吡咯啶基)丁醯胺 2-(4 -乙基-2-氧基-4-苯基-1-¾略B定基）丁醯胺 233 234 235 236 237 i _1 238 239 240 241 242 一 123· 1295286[31] [32] [33] [34] 133.0 74.9 84.8 137.2 137.3 112 Divination m Racemic race m 窠mm 窠 leaf Pi inch · coo orT ^ CN ώ m gas co" Γνϊ ώ inch, \ ( N <<N ώ m gas c/T CN PQ DQ Tt Pi CN Pi Inch Pi CA A-2 § , 4 § B-2 §, 4 § C-2 § , 4 § (2S) -2- [(4R)-4-(2-hydroxypropyl)-2-oxypyrrolidinyl]butanamine m Jiff slightly 1 rH 1 痤• m ^ - VW ;磐03 COCO ® has two m secret 1 浒Li. 1)1 1 #s LLi^ m _ 5 « | v 5 A 2 mm 1 <N 3 浒赃. ID 1 VO inch 彳imhm | Φ 5 2L砮1 1 CS — if <N Ϊ 1 rH 1 淦^ m η fc A _ CL wi plastic•刍t—l CO * Complemented (2R)-2-[(4S)-2-oxy-4-propylpyrrolidinyl]butanamine 1 (2R)-2-[(4R)-2-oxy-4-propylpyrrolidinyl]butanamine 2-(4-ethyl-2-oxy-4-phenyl-1-pyrrolidinyl Butylamine 2-(4-ethyl-2-oxy-4-phenyl-1-pyrrolidinyl)butanamine 2-(4-ethyl-2-oxo-4-phenyl-1 -3⁄4略乙定基丁丁amine 233 234 235 236 237 i _1 238 239 240 241 242 a 123· 1295286

361 I 361 229 112.2 73.5 58.6 59.7 i _____—_________1 133.3 68.2 96.4 2·1·2·然後 2.2. 6·2·2·然後 6.3.1. 6·2·2·然後 6.3.1. m m m m 混合物混合物 m 窠 D-2§,4§ 〇〇〇寸Λ Pi (N < CO) 寸*x COD CN < B-2§,4§ —1 寸办 ri CN Pi 气 00 CN 、r<i A-2S，4§ A-2S，4§ CO) 气 <Ν ώ 2-(4-乙基-2-氧基-4-苯基-1-吡咯啶基)丁醯胺 m 键I 砮 1 r-H Λ Ilf CN m 嫲 Br έ fc 2-[4-(甲氧甲基）-2-氧基-1-吡咯啶基]丁醯胺 2-[4-(甲氧甲基）-2-氧基-1-吡咯啶基]丁醯胺 1 τ—Η m 1 <N s ffi- Jlff Wr t ^ TgS 稍i Y權衷痤 A砮 1 1—( m Jiff 1 <N 稍 Er 祕 m 3 m -v m v {M s痤 a砮砮 m m 1 (N 1 s IE m WTTN 1 CN^ 1 S狴：t ^ A H CO '' 磐爸 1 r-H m e 1 "T m 祕奮 (N m Β- 4鏗 2： m Α Η 00 ^ C稍砮 1 ι—Η m (Ν ϊ 叢 κ] 喊 11 Α狴 d譲 4 h 蛉蝴) ^ m 砮 I r—1 m Hf 1 1 s K] u 11 A鏗 d M 土 H 碎稍 2s锃 243 244 245 246 247 248 249 250 251 252 —12 A·— 261 66.4 127.6 116.6 100 100.8 84.2 87.8 t—H VO 53.5 窠窠窠窠 m m m 窠 m coo 气 orT <N < 000 寸a 00 ώ 00 CN A-2 § ,4 § B-2§，4§ C-2 §，4 § D-2§，4§ B-2S,4§ A-2S，4§ CW 气 <N ώ 2-(4-乙基-4-甲基-2-氧基-1-¾略陡基)丁醯胺 2-(4-乙基-4-甲基-2-氧基-1-吡咯啶基)丁醯胺 (23)-2-(2-氧基-4,4-__^丙基-1-¾ 咯陡基）丁醯胺 2-(3,3-二甲基-2-氧基-4-苯基-1-吡咯啶基)丁醯胺磐菪 1 T—H 浒 1 m 碱 1 <N Λ fr ^ 1 | 丨譲 3 t 工i m 砮 1 r-H m 浒 1 m 祕 1 « H ^ m 3 t 3 ϊ 磐遂I 砮 1 r-H m 浒 1 m 祕 1 Οί fr ru， 11 ^ .m ^ H n 吞 1 r-H m K 1 祕 1 (N m Bl· 4 ^ Λ ^ Λ卜1 00 ^ (2 S )-2-(3-平基-2-氧基-1-¾略陡基)丁釀胺 (2R)-2-(3-芊基-2-氧基-1-吡咯啶基)丁醯胺 253 255 256 257 258 259 * 260 261 262 263 418/420 /422 227 275 173.2 110.9 103.9 87.4 146.6 118 56.8 6.4.1. 2.4.2. 6.4.1. 6.4.1. 混合物混合物 m 窠窠窠混合物混合物窠 2,4 § 2,4S 000 气 CO <N < A-2S，4§ B-2S，4§ A-2S，4§ 00 CS 〇〇〇 m <N <： B-2,3 § 000 气 00 CN < 2-[4-(溴乙炔基）-2-氧基-1-吡咯啶基]丁醯胺稍嫲 1 CN S 槭 II 1 〇Γ 4 S 人_ 〇0 ™ 5 Η 3 5 稍 .祕鲁 <N i 擀鹅 II 1 <N 热 1 nan 稍_ • ® Η i S 4 η a ^ 合夸 — m 1 t-H 祕 1 <N 稍琪 K) 鹅 Α Η 00 ι~ι 稍 Ilf CN s 联 N3 槭 II w 1 it CN W ^ i~1 m « (2S)-2-(4-乙炔基-2-氧基-1-吡咯啶基）丁醯胺 GS)-2-(3,3-二乙基-2-氧基-1-吡咯啶基）丁醯胺 2-(3-苄基-3-甲基-2-氧基-1-吡咯啶基)丁醯胺 2-(3-茶基-3 -甲基-2-氧基-1-社略0定基)丁醯胺 η 砮 1 1-Η W 祕 1 Cji Bl· 1 m ii cA S ί： p Λ H 264 265 266 267 ι _1 268 269 270 271 272 273 1295286361 I 361 229 112.2 73.5 58.6 59.7 i _______________1 133.3 68.2 96.4 2·1·2· then 2.2. 6·2·2· then 6.3.1. 6·2·2· then 6.3.1 mmmm mixture m窠D-2§,4§ Λ inch Pi (N < CO) inch*x COD CN < B-2§,4§ -1 inch office ri CN Pi gas 00 CN,r<i A- 2S,4§ A-2S,4§ CO) gas <Ν ώ 2-(4-ethyl-2-oxo-4-phenyl-1-pyrrolidinyl)butanamine m bond I 砮1 rH Λ Ilf CN m 嫲Br έ fc 2-[4-(methoxymethyl)-2-oxy-1-pyrrolidinyl]butanamine 2-[4-(methoxymethyl)-2-oxyl -1-pyrrolidyl]butanamine 1 τ—Η m 1 <N s ffi- Jlff Wr t ^ TgS ii Y 权心痤A砮1 1—( m Jiff 1 <N Slightly Er Mi Mi 3 m -vmv {M s痤a砮砮mm 1 (N 1 s IE m WTTN 1 CN^ 1 S狴:t ^ AH CO '' 磐爸爸1 rH me 1 "T m 秘奋 (N m Β- 4铿2: m Α Η 00 ^ C 砮 1 ι—Η m (Ν 丛 κ κ) shouting 11 Α狴d譲4 h 蛉 butterfly) ^ m 砮I r—1 m Hf 1 1 s K] u 11 A铿d M soil H broken slightly 2s锃243 244 245 246 247 248 249 250 251 252 —12 A·— 261 66. 4 127.6 116.6 100 100.8 84.2 87.8 t-H VO 53.5 窠窠窠窠mmm 窠m coo gas orT <N < 000 inch a 00 ώ 00 CN A-2 § , 4 § B-2§, 4§ C- 2 §, 4 § D-2§, 4§ B-2S, 4§ A-2S, 4§ CW gas <N ώ 2-(4-ethyl-4-methyl-2-oxy-1- 3⁄4 slightly steep base) Butanamine 2-(4-ethyl-4-methyl-2-oxy-1-pyrrolidinyl)butanamine (23)-2-(2-oxy-4,4 -__^propyl-1-3⁄4 咯 steep base) Butylamine 2-(3,3-dimethyl-2-oxy-4-phenyl-1-pyrrolidinyl)butanamine 磐菪1 T —H 浒1 m alkali 1 <N Λ fr ^ 1 | 丨譲3 t workim 砮1 rH m 浒1 m secret 1 « H ^ m 3 t 3 ϊ 磐遂I 砮1 rH m 浒1 m Secret 1 Οί fr ru, 11 ^ .m ^ H n 吞 1 rH m K 1 secret 1 (N m Bl· 4 ^ Λ ^ Λ卜 1 00 ^ (2 S )-2-(3-flatyl-2-oxy -1-3⁄4 slightly steep base) butylamine (2R)-2-(3-indolyl-2-oxy-1-pyrrolidinyl)butanamine 253 255 256 257 258 259 * 260 261 262 263 418/ 420 /422 227 275 173.2 110.9 103.9 87.4 146.6 118 56.8 6.4.1. 2.4.2. 6.4.1. 6.4.1. Mixture mixture m 窠窠窠 mixture mixture 窠 2,4 § 2 , 4S 000 gas CO < N < A-2S, 4§ B-2S, 4§ A-2S, 4§ 00 CS 〇〇〇m <N <: B-2,3 § 000 gas 00 CN < 2-[4-(Bromoethynyl)-2-oxy-1-pyrrolidinyl]butanamine 嫲1 CN S Maple II 1 〇Γ 4 S Person _ 〇0 TM 5 Η 3 5 Slightly. Peru <N i 擀 II II 1 <N heat 1 nan slightly _ • ® Η i S 4 η a ^ 合夸—m 1 tH 秘 1 <N 奇琪K) Goose Α 00 ι~ι 略Ilf CN s N3 Maple II w 1 it CN W ^ i~1 m « (2S)-2-(4-ethynyl-2-oxy-1-pyrrolidyl)butanamine GS)-2-( 3,3-Diethyl-2-oxy-1-pyrrolidinyl) Butanamine 2-(3-benzyl-3-methyl-2-oxy-1-pyrrolidinyl)butanamine 2 -(3-Tealyl-3-methyl-2-oxy-1-rea- 0-butyl) Butanamine η 砮1 1-Η W Secret 1 Cji Bl· 1 m ii cA S ί: p Λ H 264 265 266 267 ι _1 268 269 270 271 272 273 1295286

# 1 m m 1 m 響 1 (N s- m :H 2 ϊ 審 m 嫲 1 <N 稍 m 1 <N 稍狴 m m K] H ά δ i n A痤 1 v-H nf CS 補響 I <N m ^ 碱餾 ;H ί i a智磐 1 ϊ—1 m 娜隹 <N 稍 m I <N ;m I t « 砮 1 τ·Η Λ m 1 CS m 1 <N fr m 4 h Si ^ m 補 E 1 t-H li HI 1 rn m 6狴 4 m At 娜_ <N 念专 CN 1-H 1 n 砮 1 r-H 1 稍 Ε 1 r-H 1 嫲 ί:， Λ Η 00 ι~~* 已稍 » m Ilf 1 CN m 遂 κι m «5 A磐 1 r-H 嫲 I CN 卜 I τ-Η 1 fr m φ Η i權 η c # η 吞 1 τ-Η W 祕 1 CN S 卜· 4 ^ 人卜 00 '~' 已稍 274 CN vo 卜 CN 卜 r> cs OO 卜 CN 〇\ 卜 CSJ Ο 00 (Ν r—1 00 (N CN 00 (Ν m 00 (N -127-. 1295286# 1 mm 1 m 响1 (N s- m :H 2 ϊ 审 m 嫲1 <N slightly m 1 <N 狴mm K] H ά δ in A痤1 vH nf CS Reverberation I <N m ^ alkali distillation; H ί ia Zhi 磐 1 ϊ -1 m 隹隹 <N mm I <N ;m I t « 砮1 τ·Η Λ m 1 CS m 1 <N fr m 4 h Si ^ m 补E 1 tH li HI 1 rn m 6狴4 m At _ <N 念专 CN 1-H 1 n 砮1 rH 1 Ε 1 rH 1 嫲ί:, Λ Η 00 ι~~* Slightly » m Ilf 1 CN m 遂κι m «5 A磐1 rH 嫲I CN Bu I τ-Η 1 fr m φ Η i η c # η 吞 1 τ-Η W Secret 1 CN S 卜· 4 ^ 00 '~' has been slightly 274 CN vo 卜CN 卜r> cs OO 卜CN 〇\ 卜 CSJ Ο 00 (Ν r—1 00 (N CN 00 (Ν m 00 (N -127-. 1295286

259 284 257 355 . __________1 265 281 319 305 229 1·3·1·然後 1.3.2. 1.3.1.然後 1.3.2. 1·3·1·然後 1.3.2. 1.3.1.然後 1.3.2. 1.3.1.然後 1.3.2. 1.3.1.然後 1.3.2. 1.3.1.然後 1.3.2. 1.3.1.然後 1.3.2. 1.3.1·然後 1.3.2. 1.3丄然後 1.3.2. 混合物混合物混合物混合物i ——一 1 混合物 1混合物混合物混合物混合物混合物气寸《X <N 寸办寸" 寸办 <N (N 寸λ ΓνΤ 寸*s CN <N 寸《S (N 寸办 t s η 链r 砮 1 E 1 祕s ^ p V h cA rA ή Jiff L s a 補1¾ m ^ 5:稍稍智 5ί 7 鍇秘I ^ E：寸 1 1 祕餾 _ _s 寧_ 磐權3 !ϊ ? •稍7 狴稍稍Κ Ε- 可 U m 4祕 K 1 ώ 域1 1 1 <Ν s ^ 寸 ΒΧΪ # ts ώ稍 m ^ X « 省 1 m E： 1 m 祕 1 1 <N ί ^ 寸 ΠΧί 4 _ My 1^- ώ補 5 η A塑砮 1 m 1 ro 5 m 痤砮 1 1-H E t ^ m g ά稍 n 響 1 m I rn i n 砮 1 r-H E 稍濯 w £ d W <N Φ 3-(苄氧）-2-(2-氧基-4-丙基-1-吡咯啶基）丁醯胺 3-(苄氧）-2-(2-氧基-4-丙基-1-吡咯啶基）丙醯胺 4-羥-2-(2-氧基-4-丙基-1-吡咯啶基)丁醯胺 284 285 286 287 ί 288 289 290 291 292 293 -128- 1295286259 284 257 355 . __________1 265 281 319 305 229 1·3·1· then 1.3.2. 1.3.1. then 1.3.2. 1·3·1· then 1.3.2. 1.3.1. then 1.3.2 1.3.1. Then 1.3.2. 1.3.1. Then 1.3.2. 1.3.1. Then 1.3.2. 1.3.1. Then 1.3.2. 1.3.1· then 1.3.2. 1.3丄 then 1.3 .2. Mixture mixture mixture i - 1 - 1 mixture 1 mixture mixture mixture mixture "X < N inch inch" &inch; inch < N (N inch λ ΓνΤ inch *s CN < N inch S (N inch do ts η chain r 砮1 E 1 secret s ^ p V h cA rA ή Jiff L sa fill 13⁄4 m ^ 5: slightly smart 5ί 7 锴 secret I ^ E: inch 1 1 secret _ _s ning _磐 right 3 !ϊ ? • slightly 7 狴 slightly Κ 可 - can U m 4 secret K 1 ώ domain 1 1 1 <Ν s ^ inch ΒΧΪ # ts ώ slightly m ^ X « province 1 m E: 1 m secret 1 1 <N ί ^ inchΠΧί 4 _ My 1^- ώ5 η A plastic 砮 1 m 1 ro 5 m 痤砮1 1-HE t ^ mg ά slightly n 1 m I rn in 砮1 rH E濯w £ d W <N Φ 3-(benzyloxy)-2-(2-oxy-4-propyl-1-pyrrolidinyl)butanamine 3-(benzyloxy)-2-(2- Oxy-4-propyl-1-pyridyl Piperidinyl) propan-Amides 4-hydroxy-2- (2-4-propyl-1-pyrrolidinyl) butoxy Amides 284 285 286 287 ί 288 289 290 291 292 293 -128- 1295286

215 CN <N m r-H CO On t-H CO 卜 00 CS »〇 CN t-H On CN (Ν Ο m r—H 00 CN 1·3·1·然後 1.3.2. 黎Η 二 ^ -i 一· t—Η cn — r-H T—< 鹚狯H <rj — t-H CO ^ r-H cn 一 CO 1—1 r-H 班 ^ Η 二 -i “ τ-Η 鹚 t-H 混合物 <ίπ <Π 媒 <ίπ m <ίπ m <ίπ m · <ίπ 赌 <ίπ m <π m <n m 寸办 <Ν 寸λ <Ν CN 寸 <N <N 寸Λ (N 寸： CN 寸 #N (N 寸办 CN 气 (N 3-羥-2-(2-氧基-4-丙基-1-姐咯啶基)丙醯胺 ! ▼-Η ώι E： 1 m 祕 1 (N 'w^ 1 (N 越廳 « i N ig X 5 砮 1 τ-Η m E： 1 m 祕 1 1 CN I N 稍鏗 sg廳 fii r * m A i 1 Λ 祕 1 1 <N i m Urt « i fr- ig 祕塑 i Ϊ cA稍糊 K 1 Λ m 喔 CL 看 <N 1 ^ S p 11 s 補· η n ni痤鹕砮 1 rA 7 遄 E： 1 Λ 碱 I ci/ CN 稍i杯 sg 5 «i K * i \ iH 丨11 s g 2 1 1 ΓΟ 1—i 舊 Η m IE 1 A m 1 1 <N 補狴灑廳 m h ^ S 糊磐 ffl· 结I .4 s 菪 1 ι-H m E 1 T m 碱義 • CN 稍翻鏗燬}i _ Η t稍 4 η Λ 祕 1 1 <N 1 i i—i fL·-. « s ^ n 城1痤 ^ m ^ Βζ 1 1 m i n 砮 1 r-H m E： 1 m 祕 1 1 <N R]鏗孵_ cA r 294 <n Os CN \〇 C\ CN 卜 ON CN 00 Os <N ON C\ <N o o cn τ-Η Ο m CN Ο m m 〇 ro •129- 1295286215 CN <N m rH CO On tH CO 00 CS »〇CN tH On CN (Ν Ο mr—H 00 CN 1·3·1· then 1.3.2. Li Wei 2^ -i a·t-Η Cn — rH T—< 鹚狯H <rj — tH CO ^ rH cn a CO 1-1 rH class ^ Η two-i “ τ-Η 鹚tH mixture < ίπ <Π 媒<ίπ m &lt ;ίπ m <ίπ m · <ίπ 赌<ίπ m <π m <nm 寸办<Ν λλ <Ν CN 寸<N <N 寸Λ (N inch: CN inch# N (N-inch CNC gas (N 3-hydroxy-2-(2-oxy-4-propyl-1-stilridinyl)propanamine! ▼-Η ώι E: 1 m Secret 1 (N ' w^ 1 (N Yue Hall « i N ig X 5 砮1 τ-Η m E: 1 m Secret 1 1 CN IN 铿 sg hall fii r * m A i 1 Λ Secret 1 1 <N im Urt « i Fr- ig 秘塑 i Ϊ cA slightly paste K 1 Λ m 喔CL see <N 1 ^ S p 11 s complement · η n ni痤鹕砮1 rA 7 遄E: 1 Λ base I ci / CN slightly i cup Sg 5 «i K * i \ iH 丨11 sg 2 1 1 ΓΟ 1—i old Η m IE 1 A m 1 1 <N 狴厅 m mh ^ S 磐磐 ffl · 结 I .4 s 菪1 ι -H m E 1 T m Basic meaning • CN Slightly smashed}i _ Η t slightly 4 η Λ Secret 1 1 &Lt;N 1 ii—i fL·-. « s ^ n City 1痤^ m ^ Βζ 1 1 min 砮1 rH m E: 1 m Secret 1 1 <NR] 铿 _ cA r 294 <n Os CN \〇C\ CN 卜ON CN 00 Os <N ON C\ <N oo cn τ-Η Ο m CN Ο mm 〇ro •129- 1295286

227 267 239 239 255 241 316 331 320 289 1·3·1·然後 1.3.2. 1·3·1·然後 1.3.2. 1·3·1·然後 1.3.2. 1.3.1.然後 1.3.2. 1.3.1.然後 1.3.2. .. 1.3.1.然後 1.3.2. 1.3.1.然後 1.3.2. 1·3·1·然後 1.3.2. 1.3.1.然後 1.3.2. 1.3.1.然後 1.3.2. 混合物混合物混合物混合物混合物混合物混合物混合物混合物混合物 Cvf CS 寸^ CN 寸办 CS 寸Λ CsT (N 寸· (N 2-(2-氧基-4-丙基-1-吡咯啶基)戊醯胺 2-環己基-2-(2-氧基-4-丙基-1-吡咯啶基) 乙醯胺 3 -¾丙基-2-(2-氧基-4-丙基-1 - ¾咯Π定基）丙醯胺 1 S 砮 1 r-H m E 1 祕 Φ ^ 稍裝 1 1 寸寸 5-甲基-2-(2-氧基-4-丙基-1-吡略啶基）己醯胺 2-(2-氧基-4-丙基-1-毗咯啶基)己醯胺砮 1 τ-Η m κ 1 m 祕 1 1 (N 1 S ^ 擀翻域K 4i S i η m κ 1 m 祕 1 CL 1 <N 5 ft 1 IE 嘁s π權 8 ϊ a 二砮 1 τ-Η m K 1 m 碱 1 已 1 (N S ^ 浒觀 « g 恶S i m 2-(2-氧基-4-丙基-1-毗咯啶基)-4-苯基丁醯胺 304 305 306 307 _1 308 309 310 311 312 313 -130- 1295286227 267 239 239 255 241 316 331 320 289 1·3·1· then 1.3.2. 1·3·1· then 1.3.2. 1·3·1· then 1.3.2. 1.3.1. then 1.3. 2. 1.3.1. Then 1.3.2. .. 1.3.1. then 1.3.2. 1.3.1. then 1.3.2. 1·3·1· then 1.3.2. 1.3.1. then 1.3.2 1.3.1. Then 1.3.2. Mixture Mixture Mixture Mixture Mixture Mixture Mixture Cvf CS Inch ^ CN Inch CS Inch CsT (N inch · (N 2-(2-oxy-4-propyl-) 1-pyrrolidyl)pentanylamine 2-cyclohexyl-2-(2-oxy-4-propyl-1-pyrrolidinyl)acetamide 3 -3⁄4propyl-2-(2-oxy- 4-propyl-1 - 3⁄4 Π Π ) ) ) r r r r r r r r r r r r r r r r r r ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ 1 1 1 -pyridinyl)hexylamine 2-(2-oxy-4-propyl-1-pyrrolidyl)hexylamine 砮1 τ-Η m κ 1 m Secret 1 1 (N 1 S ^ 擀Turnover domain K 4i S i η m κ 1 m Secret 1 CL 1 <N 5 ft 1 IE 嘁s π weight 8 ϊ a 2砮1 τ-Η m K 1 m Base 1 has 1 (NS ^ 浒 view « g SS im 2-(2-oxy-4-propyl-1-pyrrolidyl)-4-phenylbutyramine 304 305 306 307 _1 308 30 9 310 311 312 313 -130- 1295286

379 ▼-H Ch CS 〇 CO r-H m (N m ON 00 CN m On CN m 〇\ CN m 〇\ cs t-H T-H m 1·3.1·然後 1.3.2. 鹚黎H —^ rn — i-H m 叫 r-H cn — ^H rn — T-H rn — T-H 黎H CO — r-H cn — i-H 餘H cn — r-H 黎H — ⑺· m ^ t-H 混合物鬆鹧 <ίπ m <Π 蓉鹤. 鬆 <Π 赔 <n m <Π m <ία 蜉蓉 4n m ΓνΤ 寸Λ οΓ 气 (N 寸办 <N <N <N 寸λ CN 气 CN 寸办 ri CN m Ε： 1 ii 嫲 1 1 CN 1 蝴1鏗浒灑稍B： 1 s 田' m i吞 1 1 m — 1 t-H m E 1 iil Jiff <N s ^ 揪觀 m K i稍 cA n 砮 · 1 r-H » E： 1 m 碱 1 CS 1 CN 5 ^ 擀譲 Jif £ fr s i智 rA痤 1 t-H ii )E 1 Hf L λ m 枨κ -g 二 n d ^ cA # n 砮 1 v-H m E： 1 "T m 嫲 1 CL 1 CN 1 糊盤觀二}ε a i 1 ▼-Ή m E： 1 T Λ Jlf 1 CL 1 (N 1 5 ^ 枨簡 m e b~稍 i磐 cA 砮 1 vH m E 1 祕 1 CN^ 1 rvj 1 稍鏗擀· iS i W cA n 砮 1 t-H m E 1 可 m m 1 CS I CS 1 i ^ 擀觀 li K i _ cA n 1 r-H m r 1 m 娜 1 CS 1 CN 5 s 擀譲 i稍 rA m 砮 1 f—H m E： • m m 1 CJ/ 1 CN 慮盤 ΤτΓ «歴 II 12; 4 « d遐 314 l〇 CO Ό r-H cn 卜 t-H m 00 r-H m On t-H CO O <N m r—i <N m <N CN m cn CS m 131- 129528.6379 ▼-H Ch CS 〇CO rH m (N m ON 00 CN m On CN m 〇\ CN m 〇\ cs tH TH m 1·3.1· then 1.3.2. 鹚黎H —^ rn — iH m is called rH Cn — ^H rn — TH rn — TH Li H CO — rH cn — iH 余 H cn — rH 黎 H — (7)· m ^ tH Mixture 鹧 ί ί ί ί ί ί ί 松松松松松松松 & &&;nm<Π m <ία 蜉蓉4n m ΓνΤ inchΛ οΓ gas (N inch office <N <N <N inch λ CN gas CN inch office ri CN m Ε: 1 ii 嫲1 1 CN 1 Butterfly 1 chic slightly B: 1 s field ' mi swallow 1 1 m — 1 tH m E 1 iil Jiff < N s ^ 揪 view m K i slightly cA n 砮 · 1 rH » E: 1 m alkali 1 CS 1 CN 5 ^ 擀譲Jif £ fr si 智 rA痤1 tH ii )E 1 Hf L λ m 枨κ -g two nd ^ cA # n 砮1 vH m E: 1 "T m 嫲1 CL 1 CN 1糊盘观二}ε ai 1 ▼-Ή m E: 1 T Λ Jlf 1 CL 1 (N 1 5 ^ 枨 me meb~ slightly i磐cA 砮1 vH m E 1 secret 1 CN^ 1 rvj 1 · iS i W cA n 砮1 tH m E 1 can be mm 1 CS I CS 1 i ^ 擀 li li K i _ cA n 1 rH mr 1 m 娜1 CS 1 CN 5 s 擀譲i slightly rA m 砮1 f —H m E: • mm 1 CJ/ 1 CN 盘盘ΤτΓ «歴II 12; 4 « d遐314 l〇CO Ό rH cn 卜 tH m 00 rH m On tH CO O <N mr—i <N m <N CN m cn CS m 131- 129528.6

-132· 1295286-132· 1295286

299 352 338 348 595 242 348 326 329 424 1·3·1·然後 1.3.2. 1·3·1·然後 1.3.2. 1·3·1·然後 1.3.2. 1.3.1.然後 1.3.2. 1.3.1.然後 1.3.2. 1.3.1.然後 1.3.2. 1.3.1.然後 1.3.2. 1.3丄然後 1.3.2. 1.3.L然後 1.3.2. 1.3.1.然後混合物混合物混合物混合物 1 混合物混合物混合物混合物混合物混合物 CN 2,4,4 2,4,4 寸 3a,4,6, a，2,4 <N 寸寸气 CN 寸 rs 1 r—ί Λ κ I Λ 祕 1 Ci/ i s ^ 你 TO -m 稍fU «g νό 吞 2,5-貳(2-氧基-4-丙基-1-吡咯啶基）戊醯胺 2,4-貳（2-氧基-4-丙基-1-吡咯啶基）丁醯胺鲁 r-H Λ Β： I ώ ι Ml ^ ¥ S « S ^ ifc! ή, 5 ζ ^ r—ι l ^ r—η A *r*tK cn -tW =5 i—j cns 作—® S « Γ0 l S s ώ E n mi ^ ^ « ^ « ^ S κ ά S 4 ώ ί Λ T T祕 S智i ι My ι 。西（N J 5-胺基-2-(2-氧基-4-丙基-1-¾略Π定基）戊醯胺砮 1 τ-Η m κ I if ® ci m rj E5- 祕盤 cA W 1 IIP 稍阪鏗w c； m 雪 r-H ώ ! 稍g ά -^ β- 補糊 ;.補 1议 «ι S 鏗權 ;磐鏗屬 as &稍 Ξ塑 0X3 -1-3 稍T 祕飞 A稍 ^ E： 5 1 A稍 5崢 Π32 | S Z ? « S 6-胺基-6-氧基-5-(2-氧基-4-丙基-1-¾略 333 334 335 336 337 338 339 340 341 342 -133- 1295286299 352 338 348 595 242 348 326 329 424 1·3·1· then 1.3.2. 1·3·1· then 1.3.2. 1·3·1· then 1.3.2. 1.3.1. then 1.3. 2. 1.3.1. then 1.3.2. 1.3.1. then 1.3.2. 1.3.1. then 1.3.2. 1.3 then 1.3.2. 1.3.L then 1.3.2. 1.3.1. then the mixture Mixture mixture mixture 1 mixture mixture mixture mixture mixture CN 2,4,4 2,4,4 inch 3a,4,6, a,2,4 <N inch inch gas CN inch rs 1 r-ί Λ κ I Λ Secret 1 Ci/ is ^ You TO -m slightly fU «g νό 吞 2,5-贰(2-oxy-4-propyl-1-pyrrolidinyl)pentanyl 2,4-anthracene (2-oxyl) -4-propyl-1-pyrrolidyl)butanamine LurH Λ Β: I ώ ι Ml ^ ¥ S « S ^ ifc! ή, 5 ζ ^ r-ι l ^ r-η A *r*tK Cn -tW =5 i—j cns do —® S « Γ0 l S s ώ E n mi ^ ^ « ^ « ^ S κ ά S 4 ώ ί Λ TT Secret S 智 i ι My ι . West (NJ 5-amino-2-(2-oxy-4-propyl-1-3⁄4 4 Π )) pentylamine 砮 1 τ-Η m κ I if ® ci m rj E5- secret disk cA W 1 IIP Sakae 铿wc; m Snow rH ώ ! Slightly g ά -^ β- 补糊;.补1议«ι S 铿权; 磐铿属as & slightly Ξ塑0X3 -1-3 Slightly T Secret A slightly ^ E: 5 1 A slightly 5峥Π32 | SZ ? « S 6-amino-6-oxy-5-(2-oxy-4-propyl-1-3⁄4 333 334 335 336 337 338 339 340 341 342 -133- 1295286

298 · 352 482 243 ! 325 339 297 282 225 1.3.2. 1.3.1.然後 1.3.2. 1.3.1.然後 1.3.2. 1.3.1.然後 1.3.2. 1.3.1.然後 1.3.2. 1.3.1.然後 j 1.3.2. 1.3.1.然後 1.3.2. 1.3.1.然後 1.3.2. 1.3.1.然後 1.3.2. 1.3.1.然後混合物混合物混合物混合物混合物混合物混合物混合物混合物 (S CN 寸 rn CO 寸λ 寸寸 CN 寸办 CN 啶基)己基胺基甲2-氯芊酯葚 1 r-H Λ r 1 m 嫲 1 1 (N s ^ 鏗譲 m g !S S 槭 11] I Ό I i m 稍廳 κ E 兮蝴1 稍髮 ά m Α κ) 卷稍亏Κ 4· t £ « 2 Hf 宓A 響γ . CN κ丄 jl W ^ ^ m m ^] « W « g « a s磐 X w塑匕4砮 —« , 4-胺基-4-氧基-3-(2-氧基-4-丙基-1-吡咯啶基)丁酸砮 1 r-H m κ 扁 m 祕 1 ?.餾 m w 祕醛 4觀 « t 狴稍 4 η 1 ^Η ώ Ε： 1 A Hf 1 CN^ T ® _ Γΰ «酹 ;趑 « s 鏗械i 盛I 砮 1 r-H Λ Ε： I Λ Ilf 1 CL T.餾 _ IE « s 鍇稍 ^ m 響谦 CO r-H 麵 ΓΟ s η 砮 1 r-H 1E狴 4 m 1 U77 i稍 < 1 1 ^<11 CN 曾1 2-(2-氧基-4-丙基-1-吡咯啶基)-4-戊烯醯 343 344 345 346 347 348 349 350 351 —1 jjA·— 1295286298 · 352 482 243 ! 325 339 297 282 225 1.3.2. 1.3.1. then 1.3.2. 1.3.1. then 1.3.2. 1.3.1. then 1.3.2. 1.3.1. then 1.3.2 1.3.1. then j 1.3.2. 1.3.1. then 1.3.2. 1.3.1. then 1.3.2. 1.3.1. then 1.3.2. 1.3.1. then mixture mixture mixture mixture mixture mixture Mixture mixture (S CN inch rn CO inch λ inch inch CN inch for CN pyridine) hexylaminomethyl 2-chlorodecyl ester 葚 1 rH Λ r 1 m 嫲 1 1 (N s ^ 铿譲mg !SS Maple 11] I Ό I im 厅 κ E 兮 1 1 稍 ά κ κ 卷卷卷 Κ · · · · · · · · · · · CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN X w plastic 匕 4砮—«, 4-amino-4-oxy-3-(2-oxy-4-propyl-1-pyrrolidyl)butyric acid 砮1 rH m κ flat m secret 1 ? Distillation mw aldehyde 4 views « t 狴 slightly 4 η 1 ^ Η Ε 1: 1 A Hf 1 CN^ T ® _ Γΰ «酹;趑« s i i i i I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I CL T. Distillation _ IE « s 锴 ^ ^ m 谦 CO CO rH ΓΟ s s η 1 rH 1E 狴 4 m 1 U77 i slightly < 1 1 ^<11 CN 曾1 2-(2-oxy- 4-propyl-1-pyrrole Yl) -4-penten-XI 343 344 345 346 347 348 349 350 351 -1 jjA · - 1295286

314 229 259 _1 275 381 256 1.3.2. 1.3.1.然後 1.3.2. 1·3·1·然後 1.3.2. 1.3.1.然後 1.3.2. 1.3丄然後 1.3.2. 1.3.1.然後 1.3.2. 丨1·3·1·然後 1.3.2. 混合物混合物混合物混合物混合物混合物寸 <Ν 寸λ <Ν 寸办寸 <Ν (N 寸·> ci 狴 1 m κ 1 m 嫲 1 1 CN ¢1 ώ稍 c ϋ c； ^ (3R)-3 -翔-2-(2-氧基-4-丙基-1 - tft 咯 fl定基)丁醯胺砮 1 m κ 1 Jlf 1 1 <N W鏗遯麵 Μ Η _ ϊ fr ifc! 4 ϊ 2-(2-氧基-4-丙基-1 - ¾略卩疋基）-3 -本基丙醯胺砮 1 r-H m E： 1 可 m 祕 1 1 CN s ^ ta m 祕E： Ul ^ tt m i m A诠 1 6 -胺基-2-(2-氧基-4-丙基-1-¾咯B定基）己醯胺砮 1 r-H m \€ 1 CS S K) 槭 11] ίτ ^ d翻 4 Η 4涵匕銮‘ 1 τ-Η m 薷 1 CN K) 槭 11 1 (N m m d Η i稍 a n 1 τ-Η Λ 祕 1 <N s K1 减 11 1 <N 郏_ ά t 2：稍 A智 352 353 354 j 355 356 357 358 359 360 -135- 1295286314 229 259 _1 275 381 256 1.3.2. 1.3.1. then 1.3.2. 1·3·1· then 1.3.2. 1.3.1. then 1.3.2. 1.3丄 then 1.3.2. 1.3.1 Then 1.3.2. 丨1·3·1· then 1.3.2. Mixture mixture mixture mixture mixture inch<Ν inch λ <Ν inch inch<Ν (N inch·> ci 狴1 m κ 1 m 嫲1 1 CN ¢1 ώ slightly c ϋ c; ^ (3R)-3 - Xiang-2-(2-oxy-4-propyl-1 - tft fluorenyl) butylamine 砮1 m κ 1 Jlf 1 1 <NW铿遁面Μ Η _ ϊ fr ifc! 4 ϊ 2-(2-Oxo-4-propyl-1 -3⁄4 fluorenyl)-3 -propenylamine 砮1 rH m E: 1 can be m secret 1 1 CN s ^ ta m secret E: Ul ^ tt mim A 1 6 -amino-2-(2-oxy-4-propyl-1-3⁄4-b-B-based) Hexamine 砮1 rH m \€ 1 CS SK) Maple 11] ίτ ^ d 4 Η 4 匕銮 ' 1 τ-Η m 薷 1 CN K) Maple 11 1 (N mmd Η i slightly an 1 τ- Η 秘 Secret 1 <N s K1 minus 11 1 <N 郏_ ά t 2: slightly A Zhi 352 353 354 j 355 356 357 358 359 360 -135- 1295286

溶劑. DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO W NMR說明 0.80(t，3H); 1.4(M.60(m，lH); 1.75-1.95(m，lH); 2.10(dd，lH); 2.45(dd，lH，與溶劑部分重疊);2.8(m， 1H); 3.05(dd，lH); 3.60(m，3H); 4.45(dd，lH); 6.90(s(寬)，1H); 7.30(s(寬)，1H). 0.80(t，3H); 1.45-1.70(m，lH); 1.75-1.95(m，lH); 2.50(m，lH，與溶劑部分重疊);.3.40(m，lH); 3.50-3.70 (m55H, 4.45(dd,m)； 6.9〇(S(i；),iH)； 7.3〇(S(m),iH). 0.80(t，3H); 1.40-1.90(m，6H); 2.10(dd，lH); 2.30-2.60(m，6H); 3.05(dd，lH); 3.60(dd，lH); 3.60(dd，lH); 4.30(dd，lH); 6.90(s(寬)，1H); 7.30(s(寬)，1H). j 0.80(t53H); 1.20(d56H); 1.40-L60(m,lH); 1.70-1.85(m,lH); 2.45(dd,lH); 2.35-2.55(m,lH5|H^iig|5^ 重疊);2.55(m，2H); 2.90(s，lH); 3.00(m，lH); 3.60(m，lH);4.30(dd，lH); 6.90(s(寬)，1H); 7.30(s(寬)，1H). 0.80(t?3H); 1.20(d,6H); 1.40-1.65(m,lH); 1.75-1.90(m,lH); 2.15(dd,lH); 2.35-2.55(m,lH); 2.55(d,2H) ;2.95(s，lH); 3.30(m，lH，與溶劑重疊);3.45(m，lH); 4.45(dd，lH); 6.90(s(寬)，1H); 7.30(s(寬)，1H). 0.80(t，3H); 1.40-1.65(m，lH); 1.75-1.95(m，lH); 2.10(dd，lH); 2.45(dd，lH，與溶劑部分重疊);2.75(m， 1H); 3.20-3.50(m，5H，與溶劑部分重疊);4.30(d，2H); 4.45(dd，lH); 6.90(s(寬)，1H); 7.35(s(寬)，1H). 0.80(t，3H); 1.40-1.60(m，lH); 1.70-1.90(m，lH); 2.20(dd，lH); 2.45(dd，lH); 2.60(m，lH);3.25(m，lHj§| 溶劑重疊)；3.45(dd，lH); 3.60(d，2H); 4.30(dd，lH); 6.90(s(寬)，1H); 7.30(s(寬)，1H); 7.60-8.00(m，5H)·· 0.85(t，3H); 1.55-1.70(m，lH); 1.80-1.95(m，lH); 2.65(dd，lH); 2.85(dd，lH);3.45(dd，lH);3.80(m，2H)， 4.05(m，lH); 4.50(dd，lH);6.80 (s(寬)，1H); 7.40(s(寬)，1H);9.20(s，1H)·· <N ύ CN 运 τ—I g jo CN rn m s t-H cs t—H 窆 r-H I jn Τ'" 1—< s ώ r—H 贫 v〇 o ]HNMR 編號 r—n s r—n r—i 〇〇 s -136- 1295286Solvent. DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO W NMR: 0.80 (t, 3H); 1.4 (M.60 (m, lH); 1.75-1.95 (m, lH); 2.10 (dd, lH); Dd, lH, partially overlapping with the solvent); 2.8 (m, 1H); 3.05 (dd, lH); 3.60 (m, 3H); 4.45 (dd, lH); 6.90 (s (width), 1H); 7.30 ( s (width), 1H). 0.80 (t, 3H); 1.45-1.70 (m, lH); 1.75-1.95 (m, lH); 2.50 (m, lH, partially overlapping with solvent); 3.40 (m, lH); 3.50-3.70 (m55H, 4.45(dd,m); 6.9〇(S(i;),iH); 7.3〇(S(m),iH). 0.80(t,3H); 1.40-1.90( m,6H); 2.10(dd,lH); 2.30-2.60(m,6H); 3.05(dd,lH); 3.60(dd,lH); 3.60(dd,lH); 4.30(dd,lH); 6.90 (s (width), 1H); 7.30 (s (width), 1H). j 0.80 (t53H); 1.20 (d56H); 1.40-L60 (m, lH); 1.70-1.85 (m, lH); 2.45 ( Dd, lH); 2.35-2.55 (m, lH5|H^iig|5^ overlap); 2.55 (m, 2H); 2.90 (s, lH); 3.00 (m, lH); 3.60 (m, lH); 4.30 (dd, lH); 6.90 (s (width), 1H); 7.30 (s (width), 1H). 0.80 (t? 3H); 1.20 (d, 6H); 1.40-1.65 (m, lH); 1.75-1.90 (m, lH); 2.15 (dd, lH); 2.35-2.55 (m, lH); 2.55 (d, 2H); 2.95 (s, lH); 3.30 (m, lH, overlap with solvent); 3.45(m,lH); 4.45(dd,lH); 6.90(s( ), 1H); 7.30 (s (width), 1H). 0.80 (t, 3H); 1.40-1.65 (m, lH); 1.75-1.95 (m, lH); 2.10 (dd, lH); 2.45 (dd , lH, partially overlapping with the solvent); 2.75 (m, 1H); 3.20-3.50 (m, 5H, partially overlapping with the solvent); 4.30 (d, 2H); 4.45 (dd, lH); 6.90 (s (width) , 1H); 7.35 (s (width), 1H). 0.80 (t, 3H); 1.40-1.60 (m, lH); 1.70-1.90 (m, lH); 2.20 (dd, lH); 2.45 (dd, lH); 2.60 (m, lH); 3.25 (m, lHj§| solvent overlap); 3.45 (dd, lH); 3.60 (d, 2H); 4.30 (dd, lH); 6.90 (s (width), 1H 7.30 (s (width), 1H); 7.60-8.00 (m, 5H) · · 0.85 (t, 3H); 1.55-1.70 (m, lH); 1.80-1.95 (m, lH); 2.65 (dd , lH); 2.85 (dd, lH); 3.45 (dd, lH); 3.80 (m, 2H), 4.05 (m, lH); 4.50 (dd, lH); 6.80 (s (width), 1H); (s(width), 1H); 9.20(s,1H)·· <N ύ CN 运τ—I g jo CN rn ms tH cs t—H 窆rH I jn Τ'"1—< s ώ r—H 〇v〇o ]HNMR No. r—nsr—nr—i 〇〇s -136- 1295286

DMSO DMSO DMSO DMSO DMSO DMSO CDC13 CDCI3 (m，lH); 3.25-3.40(m，2H); 4·30-4·45(πι，3Η); 7.10(s(寬)，1H); 7.40(s(寬)，1H); 7.50(s，lH)·， g ? 1 vS ^ IS _ 3 3 _ I琴 i τ! Ill 寸办 οο οο 旦亡g. ^ g § S ΐ | f p #議g On jlul ιλ <6 W n 2罔5 ^ ® K ||| ^ cn ^ 3 g S d γ莒民^ 1 s鬆。 ^ * 2 ^ ^ Χ.φ 0.75(t，3H); 1.55-1.70(m，lH); 1.80-1.95(m，lH); 2.50(dd，lH，與溶劑重疊);2.70(dd，lH); 3.30(m，lH，與溶劑重疊);3.70(m，lH); 3.90(dd，lH); 4.50(dd，lH); 6.90(s(寬)，1H); 7.10(d，lH); 7.20-7.40 (m，2H); 7.50(d，lH)· 0.80(t,3H); 1.50-L75(m,lH); 1.80-1.95(m,lH); 2.45(dd,lH,ffl'M!lSft)； 2.75(dd,lH); 3.40-3.80 (m，3H)，4.45(dd，lH); 6.90(s(寬)，1H); 7.20-7.25(m，5H). 0.80(t，3H); 1.50-1.75(m，lH); 1.80-1.90(m，lH); 2.45(dd，lH，與溶劑重疊);2.75(dd，lH);，3.15(dd，lH); 3.65(m，lH); 3.95(dd，lH); 4.45(dd，lH); 6.90(s(寬)，1H); 7.10-7.25(m，3H)，7.30-7.50(m，2H). 0.80(t，3H); L55-1.70(m，lH); 1.80-1.95(m，lH); 2.55(dd，lH，與溶劑重疊);2.75(dd5lH); 3.30(m，lH，，與溶劑重疊);3.70(dd，lH); 4.50(dd，lH); 6.95(s(寬)，1H); 7.30-7.70(m，10H)· 0.85(t，3H); 1.60-1.75(m，lH); 1.75-1.95(m，lH); 2.55(m，lH，與溶齊If重疊);2.75(dd，lH); 3.30(m，lH，，與溶劑部分重疊);3·50-3·85(πι，1H); 4.40(dd，lH); 6.95(s(寬)，1H); 7.30-7.80(m，10)· 0.90(t，3H); 1.20(s，3H); 1.60-1.80(m，lH); 1.80-2.10(m，lH);2.40(dd，lH);2.50-2.60(m，3H，與溶劑重疊);3.20(m，lH); 3.50-3.70(m，3H); 4.45(dd，lH); 5.45(s(寬)，1H); 6.30(s(寬)，1H). 〇 cn o' 寸寸· CN g ro T-H g oi • rs T-H o' CS oi S r-H 6? r-H JQ r-H § r-H s r-H ι^~ι r—i t-H r-H S' r—l m r—H rji L—1 r—i r-H r^l r-H L—J -137- 1295286 DMSO DMSO DMSO DMSO DMSO DMSO DMSO CDC13 (s(寬6.30(s(寬)，1H); 7.70(s，lH)· 0.80(t,3H); 1.50-1.65(m5lH); 1.75-1.90(m,lH); 2.25(dd,lH); 2.55(s,3H); 2.75(m,lH); 2.90(m,2H); 3.20(d，2H);3.3(m，3H，與溶劑重疊);3.5(dd，lH); 4.05(dd，非對映異構物之 1 之 1H); 4.35(dd，lH)， 6.95(s(寬)，1H); 7.35(s(寬)，1H)·· 0.80(t,3H); 0.90(t,3H); L30-1.70(m,3H); 1.70-2.00(m,2H); 2.10-2.40(m52H); 2.90(dd3lH); 3.60(dd，lH);4.30(dd，lH); 6.90(s(寬)，1H); 7.30(s(寬)，1H)·· 0.80(t,3H); 0.85(t53H); 1.30-1.70(m,3H); 1.70-1.90(m,lH); 2.00(dd5lH); 2.20(m,lH);2.45(dd5lH);3.15 (dd5lH); 3.45(dd5lH);4.30(dd5lH); 6.90(s(X)51H);7.30(s®51H). 0.80(t,3H); 1.45-1.55(m,lH); 1.60-1.95(m,lH); 2.1(dd,lH); 2.45(dd,lH);,2.55(m,lH); 3.0(dd,lH); 3.4(dd，2H); 3.6(dd，lH); 4.30 (dd,lH); 7.80(s(寬)，1H)·· 0·00-0· 005(m，2H，與 TMS 重疊);0.40-0.55(m，2H); 0.55-0.70(m，lH); 0.85-1.00(t，3H); 1.25-1.55 (m,2H); 1.60-1.85(m,lH); 1.85-2.05(m,lH); 2.05-2.30(m,lH);2.35-2.70(m,2H); 3.10(m,lH); 3.55 (m，lH); 4.45(dd，lH); 5.45(s(寬)，lH);6.20(s(寬)，1H) · 0.95(t33H); 1.60-1.80(m5lH); 1.90-2.10(m,lH); 2.60-2.70(m,2H); 3.45(dd,lH); 3.65(m,lH), 3.80 (dd?lH); 4.50(dd5 1H); 5.40 (s(S)31H); 6.00-6.20(m,2H); 6.30(d5lH); 7.45(d,lH). 0.95(t?3H); 1.60-1.70(m,lH); 2.00-2.10(m5lH); 2.60(dd,lH); 2.85(dd?lH); 3.40(m,lH); 3.40-3.80 (m53H); 4.50(dd5lH); 5.40 (s(1：)51H); 6.10 (s(K),lH); 6.15(d,lH); 6.35(d,lH); 7.40(d,lH)., 0.80(t53H); 1.60-1.70(m,lH); 1.90-2.10(m?lH); 2.25(s,3H); 2.60(dd,lH); 2.80(dd,lH); 3.30-3.60(m, 2H)，3.75(dd，lH); 3.95(dd，lH); 4.50(dd，lH); 5.50 (s(寬)，1H); 6.30 (s(寬)，1H); 6.90-7.10(m，3H)，7.20 (dd，lH)· So t-H CN| r—i r—i (N <CNi r—i ro CS[ r—1 CN> -138- 1295286 ,DMSO DMSO DMSO DMSO DMSO DMSO CDC13 CDCI3 (m, lH); 3.25-3.40 (m, 2H); 4·30-4·45 (πι, 3Η); 7.10 (s (width), 1H); 7.40 (s Width), 1H); 7.50(s,lH)·, g ? 1 vS ^ IS _ 3 3 _ I 琴 i τ! Ill inch οο οο 死死 o. g § S ΐ | fp #议g On jlul Ιλ <6 W n 2罔5 ^ ® K ||| ^ cn ^ 3 g S d γ莒民^ 1 s loose. ^ * 2 ^ ^ Χ.φ 0.75(t,3H); 1.55-1.70(m,lH); 1.80-1.95(m,lH); 2.50(dd,lH,overlap with solvent);2.70(dd,lH) ; 3.30 (m, lH, overlap with solvent); 3.70 (m, lH); 3.90 (dd, lH); 4.50 (dd, lH); 6.90 (s (width), 1H); 7.10 (d, lH); 7.20-7.40 (m,2H); 7.50(d,lH)· 0.80(t,3H); 1.50-L75(m,lH); 1.80-1.95(m,lH); 2.45(dd,lH,ffl'M !lSft); 2.75(dd,lH); 3.40-3.80 (m,3H), 4.45(dd,lH); 6.90(s(width),1H); 7.20-7.25(m,5H). 0.80(t, 3H); 1.50-1.75 (m, lH); 1.80-1.90 (m, lH); 2.45 (dd, lH, overlap with solvent); 2.75 (dd, lH);, 3.15 (dd, lH); 3.65 (m , lH); 3.95 (dd, lH); 4.45 (dd, lH); 6.90 (s (width), 1H); 7.10-7.25 (m, 3H), 7.30-7.50 (m, 2H). 0.80 (t, 3H); L55-1.70 (m, lH); 1.80-1.95 (m, lH); 2.55 (dd, lH, overlap with solvent); 2.75 (dd5lH); 3.30 (m, lH, overlap with solvent); 3.70 (dd, lH); 4.50 (dd, lH); 6.95 (s (width), 1H); 7.30-7.70 (m, 10H) · 0.85 (t, 3H); 1.60-1.75 (m, lH); 1.75- 1.95 (m, lH); 2.55 (m, lH, overlap with dissolve If); 2.75 (dd, lH); 3.30 (m, lH, partially overlap with solvent); 3·50-3·85 (πι, 1H); 4.40 (dd, lH); 6.95 (s (width), 1H); 7.30-7.80 (m, 10) · 0.90 (t, 3H); 1.20 (s, 3H); 1.60-1.80 (m, lH); 1.80 -2.10 (m, lH); 2.40 (dd, lH); 2.50-2.60 (m, 3H, overlap with solvent); 3.20 (m, lH); 3.50-3.70 (m, 3H); 4.45 (dd, lH) ; 5.45 (s (width), 1H); 6.30 (s (width), 1H). 〇cn o' inch inch · CN g ro TH g oi • rs TH o' CS oi S rH 6? rH JQ rH § rH s rH ι^~ι r-i tH rH S' r-lmr-H rji L-1 r-i rH r^l rH L-J -137- 1295286 DMSO DMSO DMSO DMSO DMSO DMSO CDC13 (s (width 6.30 ( s (width), 1H); 7.70(s,lH)·0.80(t,3H); 1.50-1.65(m5lH); 1.75-1.90(m,lH); 2.25(dd,lH); 2.55(s,3H 2.75(m,lH); 2.90(m,2H); 3.20(d,2H);3.3(m,3H, overlapping with solvent); 3.5(dd,lH); 4.05(dd, diastereomer 1H); 4.35 (dd, lH), 6.95 (s (width), 1H); 7.35 (s (width), 1H) · 0.80 (t, 3H); 0.90 (t, 3H); L30 -1.70 (m, 3H); 1.70-2.00 (m, 2H); 2.10-2.40 (m52H); 2.90 (dd3lH); 3.60 (dd, lH); 4.30 (dd, lH); 6.90 (s (width), 1H); 7.30 (s (width), 1H)············· .20(m,lH); 2.45(dd5lH); 3.15 (dd5lH); 3.45(dd5lH); 4.30(dd5lH); 6.90(s(X)51H);7.30(s®51H). 0.80(t,3H) 1.45-1.55(m,lH); 1.60-1.95(m,lH); 2.1(dd,lH); 2.45(dd,lH);,2.55(m,lH); 3.0(dd,lH); 3.4( Dd,2H); 3.6(dd,lH); 4.30 (dd,lH); 7.80(s(width),1H)··0·00-0· 005(m,2H, overlap with TMS); 0.40-0.55 (m, 2H); 0.55-0.70 (m, lH); 0.85-1.00 (t, 3H); 1.25-1.55 (m, 2H); 1.60-1.85 (m, lH); 1.85-2.05 (m, lH) ; 2.05-2.30 (m, lH); 2.35-2.70 (m, 2H); 3.10 (m, lH); 3.55 (m, lH); 4.45 (dd, lH); 5.45 (s (width), lH); 6.20 (s (width), 1H) · 0.95 (t33H); 1.60-1.80 (m5lH); 1.90-2.10 (m, lH); 2.60-2.70 (m, 2H); 3.45 (dd, lH); 3.65 (m , lH), 3.80 (dd?lH); 4.50 (dd5 1H); 5.40 (s(S)31H); 6.00-6.20(m, 2H); 6.30(d5lH); 7.45(d,lH). 0.95(t ?3H); 1.60-1.70(m,lH); 2.00-2.10(m5lH); 2.60(dd,lH); 2.85(dd?lH); 3.40(m,lH); 3.40-3.80 (m53H); 4.50( dd5lH); 5.40 (s(1:)51H); 6.10 (s(K),lH); 6.15(d,lH); 6.35(d,lH); 7.40(d,lH)., 0.80(t53H); 1.60-1.70 (m, lH); 1.90-2.10 (m?lH); 2.25 (s, 3H); 2.60 (dd, lH); 2.80 (dd, lH); 3.30-3.60 (m, 2H), 3.75 ( Dd,lH); 3.95(dd,lH 4.50 (dd, lH); 5.50 (s (width), 1H); 6.30 (s (width), 1H); 6.90-7.10 (m, 3H), 7.20 (dd, lH) · So tH CN| r —ir—i (N <CNi r-i ro CS[ r-1 CN> -138- 1295286 ,

CDC13 DMSO CDCI3 DMSO DMSO cdci3 DMSO DMSO CDC13 0.90(t，3H); 1.6(M.70(m，lH); 1.85-2.10(m，lH); 2.25(s，3H); 2.55(dd，lH); 2.85(dd，lH); 3·30-3·60 (m，2H)，3.75(dd，lH); 3.80(dd，lH); 4.50(dd，lH); 5.50(s(寬)，1H); 6.30(s(寬)，1H); 6.90-7.10(m，3H)， 7.20(dd，lH). 0.70-0.90(m，3H); l，50-1.75(m，lH); 1.80-1.95(m，lH); 2.50-2.90(m，2H); 3.20-3.40(m，lH，與溶劑重疊);3.50-3.80(m，3H); 3.95(dd，非對映異構物之一之 1H); 4.45(dd，lH); 6.90(s(寬)，1H); 7·30 (s(寬)，1H); 8.70(d，2H); 9.15(d，lH). 0.95(t，3H); 1.6(M.70(m，lH); 1.85-2.10(m，lH); 2.80(dd，lH); 3.05(dd，lH); 3.55(dd,lH); 4.00(dd，lH); 4.55(dd，lH);4.8(m，lH); 5.60 (s(寬)，1H); 6.25(d，2H); 6.30 (s(寬)，lH);6.75(d，2H). 0.75(t?3H); L45-1.60(m,lH); 1.75-1.90(m,lH); 2.05(dd,lH); 2.40(dd,lH);2.60(m,lH); 3.05(dd,lH); 3.25(s，3H); 3.30(m，2H，與溶劑部分重疊);3.55(dd，lH); 4.30(dcUH); 7.05 (s(寬7.40 (s(寬 0.80(t,3H); 1.4M.63(m,lH); 1.71-L86(m,lH); 2.12(dd3lH); 2.43(dd,lH), 2.82(m,lH); .3.2-3.4 (m，2H); 4.23(d，2H)，4.31(dd，lH)，6.97 (s(寬)，1Η)，7·31 (s(寬)，1H)，7.94(s，lH)，8.5(s，lH). 0.84(t，3H); 1.60-1.72(m，lH); 1.86-1.98(m，lH); 2.78(dd，lH); 3.0(dd，lH); 3.42(dd，lH)，3.98(dd，lH) 4.53(dd，lH)，5.08(m，lH)，5.58 (s(寬)，1H)，6.21(s，2H)，6.25 (s(寬)，1H)，6.73(s，lH). 0.83(t，3H); 1.52-1.70(m，lH); 1.7(M.84(m，lH); 2.5(m，與 DMSO 電黌)，2.72(dd，lH)，3.64(m，2H)， 3.84(m，lH); 4.39(dd，lH); 7.05.(s(寬)，1H); 7.42(m，2H). 0.81(t，3H^1.48_1.51(m，lH); 1.80-1.94(m，lH); 2.5(m，與 DMSO 重疊)，2.72(dd，lH)，3.78(m，H)，3.95 (m，lH)，438(m，lH)，7.05 (s(寬)，1H)，7.42(m，2H). 1.02(t?3H); 1.63-1.82(m,lH); 1.91«2.08(πι,1Η); 2.86(dd,lH); 3.22(dd,lH), 3.83(dd?lH), 3.98(dd,lH) ，4.44(dd，lH)，5.3-5.5(m，2H); 6.13(s(寬)，1H), 6.21(s，2H)·· g 1—1 〇〇 CO r—1 o\ cnt r—1 r—( pi r—1 CO C〇| -139- 1295286 > / k π GC/M Μ+ 286 LC/M ΜΗ+ 259 J _i Os CN m as m rn (N 組態資料 m 窠外消旋外消旋外消旋 00 r-H coo < B-§，1S 1 <N T-H cn 00 r-H rn 3，1S IUPAC化學名稱 3-({[(lS)-l-(胺基羰基)丙基]胺基}甲基)己酸乙酯臨酸臨 ΓΤΠ· RPC· .iXTL 3-({[(lS)-l-(胺基羰基)丙基]胺基}甲基)己酸乙酯: 鹽酸鹽 (N 氍 ru m & S § 權贮翻 S經鼷颤 A_Jil ^HH m g S 二 m 人遯 00 = c ® 二姻 1 1 τ-Η ΓΟ w 3-({[(lS)-l-(胺基羰基)丙基]胺基}甲基)己酸丁酯鹽酸鹽 3-({[(lS)-l-(胺基羰基)丙基]胺基}甲基)己酸異丙酯鹽酸鹽 Li ΗΗ 化合物編號 AA1 ΑΑ3 AA4 AA5 —1A-0— 1295286 實例8 : LBS結合檢定分析 [LBS表示左堤拉西坦結合位置，參考M.Noyer等人，歐洲藥理期刊，286 ( 1 995 ) 1 37 - 1 46 ]。化合物之抑制常數（K i )係於競爭結合實驗測定，實驗中測量單一放射性配體濃度與多種不同濃度之未加標記的試驗物質結合。試驗物質抑制50%放射性配體之特異性結合之濃度稱作IC50。平衡解離常數Ki係與1C成比例且係使用陳氏及普索夫（Cheng and Prusoff)方程式計算 ® (Cheng Υ·等人，生物化學藥理學 1 972,22,3099 - 3 1 08 )。濃度範圍通常涵蓋6對數單位且帶有可變步驟（〇 . 3至 0 · 5對數値）。檢定分析係以單次或重複進行，各K i之測定係對兩種不同試驗物質樣本進行。得自200-250克雅史伯格拉力大鼠之腦皮質使用波特 (Pot ter )S均化器（10衝程於1，〇0〇rpm ;德國伯恩）於20 毫莫耳/升Tris-HCl(pH7.4)，250毫莫耳/升蔗糖（緩衝液 A)均化；全部操作皆係於4°C進行。均化物於30,000g離 ® 心1 5分鐘。所得粗膜九粒再度懸浮於5 0毫莫耳/升1^丨8-11(：1(?^17.4)，（緩衝液6)及於37°〇培育15分鐘，於3 0,00 0 X g離心1 5分鐘及以相同緩衝液洗兩次。最終九粒再度懸浮於15至25毫克/毫升蛋白質濃度之緩衝液a及儲存於液態氮。膜（ 1 50 - 200微克蛋白質/檢定分析）係於4°C於0.5毫升 50毫莫耳/升Tris-HCl緩衝液（ρΗ7·4)培育，緩衝液中含有2毫莫耳/升二氯化鎂，1至2Χ10·9。莫耳/升[3Η]-2- -141- 1295286 [4-(3 -疊氮基苯基）-2 -氧基-1-吡咯啶基]丁醯胺以及遞增濃度之試驗物質。非特異性結合（NSB )定義爲於可大致結合全部受體之參考物質濃度（例如10·3莫耳/升左堤拉西坦）存在下觀察得的殘餘結合。膜結合的以及游離的放射性配體藉快速通過玻璃纖維過濾膜（相當於瓦特曼 (Wh a t m a n ) GF / C或GF / B ;比利時威爾公司）分離，過濾膜預先浸泡於0 · 1%聚伸乙基亞胺及10·3莫耳/升左堤拉西坦俾減少非特異性結合。樣本及過濾、膜至少藉6毫升5 0毫 ® 莫耳/升丁1^-11(：1(?117.4)緩衝液淸洗。整遇過濾程序對每個試樣不超過1 0秒。捕捉於過濾膜上的放射性係於石-計數器（材卡伯（T]：i-Carb)1900或托普康（TopCount)9206 ，比利時坎伯拉沛克公司或任何相當的計數器）計數。資料分析係藉電腦化非線性曲線匹配法，使用一組方程式進行分析，該組方程式說明多種結合模式，假定獨立非交互作用的受體族群遵循物質法則。根據本發明化合物顯示pKi値爲6.0及以上。顯示特殊 ® 親和力之化合物編號爲：8，9，10，22，23，27，30，3 1，32，33 ，38,40,41，43,46,47,49,64,71，72,73,75,81，83,86,87， 88,92,93,95,96,98, 100,103,105,110,119,127,142,146 ，149,151，152, 156,157,158,159,162,163,164,165,166， 169, 170,171，173, 174,175,176,180,181，185,187,188, 195,196,197,198,200,201,204,206,207,209,211,212, 213,214,215,219,221,222,223,224,225,226,228,229, 234,250,251 ,252,264,265,267,304,306,350 及 351。 -142- 1295286 實例9 : 聲音敏感小鼠之動物樽式本試驗目標係評估化合物用於聲音敏感小鼠之抗抽搐活性，聲音敏感小鼠係屬於一種具有反射性發作之動物模式。於本原發性全面性癲癇模式申，發作係未經電或化學刺激而誘發，發作的類型至少部分類似人類出現的癲癇發作臨床現象（L5scher W.& Schmidt D.，癲癇硏究 (1998)，2，ρ·145-181; Buchhalter J.R·，癲癇（1993)， 34，S31-S41)。 B 雄或雌性聲音敏感小鼠（1 4 - 2 8克；N= 1 0 )係由聲音生理學實驗室巴黎最初由Lehmann博士選出且自1978年以來在UCB藥物園區育種的DBA種系衍生而得。實驗設計由數組組成，一組接受媒劑對照而其它組接受不同劑量的試驗化合物。化合物係於誘生音原性發作之前6 0分鐘腹內投藥。投藥劑量範圍係以對數方式遞增，通常爲1 . 0 X 10_5莫耳千克至1.ΟΧΙΟ·3莫耳/千克，但若有所需可試驗較低或較高劑量。 Β 用於試驗，動物置於小籠內每籠一頭小鼠置於聲音衰減的腔室內。經過30秒的定向期之後開始透過設置於各籠上方的揚聲器傳輸聲音刺激（90分貝，10-20千赫）歷經 30秒時間。此段期間，觀察小鼠，記錄是否出現3期發作活動期亦即狂奔、陣攣性抽搐及強直性抽搐。分別計算可保護不發作狂奔、陣攣性及強直性抽搐的小鼠比例。對活性化合物，使用普拉華特（Probit)分析（SAS/STAT 軟體，6 . 09版，普拉華特程序）計算3期發作活動獲得保 -143- 1295286 護的小鼠比例之ED50値，亦即比較對照組可產生50%保護的劑量。本發明化合物顯示ED 5 0値爲1 . 〇E - 0 4或以下。特別有展望的活性係由下列化合物編號顯示：8，9，1 0，2 2，2 3， 27,30,31，32,33,38,40,41，46,47,64,71，72,81，86,87， 88,92,93,95,96, 100, 105,110,146,151，152,156,158， 159,162, 163, 164, 166, 180,181，187,188,195,196,197 ，198,200,201，204 ,205,207,209,211，212,213,214,215 Φ ，219,221，222,223,224,226,228,229,234,250,251，252， 264,265,267，AA 1，AA 2，AA 3，AA 4 及 AA 5。</ RTI> </ RTI> </ RTI> <RTIgt; 2.85 (dd, lH); 3·30-3·60 (m, 2H), 3.75 (dd, lH); 3.80 (dd, lH); 4.50 (dd, lH); 5.50 (s (width), 1H) ; 6.30 (s (width), 1H); 6.90-7.10 (m, 3H), 7.20 (dd, lH). 0.70-0.90 (m, 3H); l, 50-1.75 (m, lH); 1.80-1.95 (m, lH); 2.50-2.90 (m, 2H); 3.20-3.40 (m, lH, overlapping with solvent); 3.50-3.80 (m, 3H); 3.95 (dd, one of the diastereomers) 1H); 4.45 (dd, lH); 6.90 (s (width), 1H); 7·30 (s (width), 1H); 8.70 (d, 2H); 9.15 (d, lH). 0.95 (t, 3H); 1.6 (M.70 (m, lH); 1.85-2.10 (m, lH); 2.80 (dd, lH); 3.05 (dd, lH); 3.55 (dd, lH); 4.00 (dd, lH) 4.55(dd,lH);4.8(m,lH); 5.60 (s(width),1H); 6.25(d,2H); 6.30 (s(width),lH);6.75(d,2H). 0.75 (t?3H); L45-1.60 (m, lH); 1.75-1.90 (m, lH); 2.05 (dd, lH); 2.40 (dd, lH); 2.60 (m, lH); 3.05 (dd, lH) 3.25(s,3H); 3.30 (m, 2H, partially overlapping with solvent); 3.55 (dd, lH); 4.30 (dcUH); 7.05 (s (width 7.40 (s) (0.80 (t, 3H); 1.4M.63(m,lH); 1.71-L86(m,lH); 2.12(dd3lH) 2.43(dd,lH), 2.82(m,lH); .3.2-3.4 (m,2H); 4.23(d,2H),4.31(dd,lH),6.97 (s(width),1Η),7 · 31 (s (width), 1H), 7.94 (s, lH), 8.5 (s, lH). 0.84 (t, 3H); 1.60-1.72 (m, lH); 1.86-1.98 (m, lH); 2.78(dd,lH); 3.0(dd,lH); 3.42(dd,lH),3.98(dd,lH) 4.53(dd,lH),5.08(m,lH),5.58 (s(width),1H) , 6.21 (s, 2H), 6.25 (s (width), 1H), 6.73 (s, lH). 0.83 (t, 3H); 1.52-1.70 (m, lH); 1.7 (M.84 (m, lH) ); 2.5 (m, with DMSO 黉), 2.72 (dd, lH), 3.64 (m, 2H), 3.84 (m, lH); 4.39 (dd, lH); 7.05. (s (width), 1H) 7.42(m,2H). 0.81(t,3H^1.48_1.51(m,lH); 1.80-1.94(m,lH); 2.5(m, overlapping with DMSO), 2.72(dd,lH),3.78 (m, H), 3.95 (m, lH), 438 (m, lH), 7.05 (s (width), 1H), 7.42 (m, 2H). 1.02 (t? 3H); 1.63-1.82 (m, lH); 1.91 «2.08 (πι, 1Η); 2.86 (dd, lH); 3.22 (dd, lH), 3.83 (dd?lH), 3.98 (dd, lH), 4.44 (dd, lH), 5.3-5.5 (m, 2H); 6.13 (s (width), 1H), 6.21(s, 2H)·· g 1—1〇〇CO r—1 o\ cnt r—1 r—( pi r—1 CO C〇 | -139- 1295286 > / k π GC/M Μ+ 286 LC/M ΜΗ+ 259 J _i Os CN m as m rn (N configuration data m 窠 racemic racemic racemic 00 rH coo < B-§, 1S 1 <N TH cn 00 rH rn 3,1S IUPAC chemical name 3-({[(lS)-l-(Aminocarbonyl)propyl]amino}methyl)hexanoic acid ethyl ester Linyi · RPC · .iXTL 3-({[(lS)-l-( Ethyl carbonyl)propyl]amino}methyl)hexanoic acid ethyl ester: hydrochloride (N 氍ru m & S § 权储 S 鼷鼷 A A A_Jil ^HH mg S 二m 人遁00 = c ® Difedral 1 1 τ-Η ΓΟ w 3-({[(lS)-l-(aminocarbonyl)propyl]amino}methyl)hexanoic acid butyl ester hydrochloride 3-({[(lS)- 1-(Aminocarbonyl)propyl]amino}methyl)hexanoic acid isopropyl ester hydrochloride Li ΗΗ Compound No. AA1 ΑΑ3 AA4 AA5 —1A-0—1295286 Example 8: LBS binding assay analysis [LBS represents left bank The position of lacacetam is described in reference to M. Noyer et al., European Journal of Pharmacology, 286 (1955) 1 37 - 1 46 ]. The inhibition constant (K i ) of the compound is determined by a competitive binding assay in which a single radioligand concentration is measured in combination with a plurality of different concentrations of unlabeled test material. The concentration at which the test substance inhibits the specific binding of 50% of the radioligand is called IC50. The equilibrium dissociation constant Ki is proportional to 1C and is calculated using the Cheng and Prusoff equations (Cheng Υ· et al., Biochemical Pharmacology 1 972, 22, 3099 - 3 1 08 ). The concentration range typically covers 6 log units and has a variable step (〇 . 3 to 0 · 5 log 値). The assay is performed in a single or repeated manner and the determination of each Ki is performed on two different test substance samples. The brain cortex from the 200-250 gram yasberg rat rat uses a Pot ter S homogenizer (10 strokes at 1, 〇0 rpm; Bourne, Germany) at 20 mM/Ls-Tris- HCl (pH 7.4), homogenization at 250 mM sucrose (buffer A); all operations were carried out at 4 °C. The homogenate is at 30,000g from the heart for 1 minute. The obtained crude membrane was resuspended in 50 mmol/L of 1^丨8-11 (:1 (?^17.4), (buffer 6) and incubated at 37 ° for 15 minutes at 3 0,00 0 X g was centrifuged for 15 minutes and washed twice with the same buffer. The final nine pellets were resuspended in 15 to 25 mg/ml protein concentration in buffer a and stored in liquid nitrogen. Membrane (1 50 - 200 μg protein / assay analysis) The system was incubated at 0.5 ° C in 50 ml Moule/L Tris-HCl buffer (ρΗ7·4) containing 2 mmol/L magnesium dichloride, 1 to 2Χ10·9. Molar/L. [3Η]-2-141- 1295286 [4-(3-Azidophenyl)-2-oxy-1-pyrrolidinyl]butanamine and test substances in increasing concentrations. Non-specific binding (NSB) Is defined as residual binding observed in the presence of a reference substance concentration that is substantially conjugated to all receptors (eg, 10·3 mol/L of levetiracetam). Membrane-bound and free radioligands are rapidly passed through the glass. Fiber filter membrane (equivalent to Wh atman GF / C or GF / B; Belgian Weir) Separation, filter membrane pre-soaked in 0 · 1% polyethylenimine and 10 · 3 mol / Levetiracetam reduces the non-specific binding. Samples and filters, membranes are washed with at least 6 ml of 50 mM Mohr / liter of 1 ^ -11 (: 1 (? 117.4) buffer. No more than 10 seconds for each sample. The radioactivity captured on the filter membrane is attached to a stone-counter (Tab: i-Carb) 1900 or TopCount 9206, Campbell, Belgium The company or any equivalent counter is counted. The data analysis is analyzed by a computerized nonlinear curve matching method using a set of equations that illustrate multiple combinations of modes, assuming that the independent non-interactive receptor population follows the laws of matter. The compound according to the present invention shows pKi値 of 6.0 and above. The compound numbers showing the specific® affinity are: 8, 9, 10, 22, 23, 27, 30, 3 1, 32, 33, 38, 40, 41, 43, 46,47,49,64,71,72,73,75,81,83,86,87,88,92,93,95,96,98,100,103,105,110,119,127,142,146,149,151,152,156,157,158,159,162,163,164,165,166, 169, 170,171,173, 174,175,176,180,181,185,187,188, 195,196,197,198,200,201,204,206,207,209,211,212, 213,214,215,219,221,222,223,224,225,226,228,229, 234,250,251, 252,264,265,267,304,306,350 and 351. - 142 - 1295286 Example 9: Animal sputum of sound-sensitive mice The objective of this test was to evaluate the anti-twitch activity of compounds for use in sound-sensitive mice, which belong to an animal model with reflex episodes. In this primary comprehensive epilepsy mode, the seizures are induced by electrical or chemical stimulation, and the type of seizure is at least partially similar to the clinical phenomenon of seizures in humans (L5scher W. & Schmidt D., Epilepsy (1998) ), 2, ρ·145-181; Buchhalter JR·, Epilepsy (1993), 34, S31-S41). B male or female voice-sensitive mice (1 4 - 28 g; N = 10) were selected by the Sound Physiology Laboratory in Paris, originally selected by Dr. Lehmann and have been derived from the DBA lineage of the UCB drug park since 1978. Got it. The experimental design consisted of an array, one group receiving vehicle control and the other group receiving different doses of test compound. The compound was administered intraperitoneally 60 minutes prior to the induction of the oncogenic episode. The dosage range is logarithmically increasing, typically 1.0 X 10_5 moles to 1. ΟΧΙΟ 3 moles/kg, but lower or higher doses may be tested if desired. Β For the test, the animals were placed in a small cage and one mouse per cage was placed in a chamber with reduced sound. After a 30-second orientation period, sound stimuli (90 decibels, 10-20 kHz) were transmitted through the speakers placed above each cage for 30 seconds. During this period, mice were observed to record whether there were 3 episodes of episodes, namely madness, clonic convulsions, and tonic convulsions. Separate calculations can protect the proportion of mice that do not have madness, clonic and tonic convulsions. For the active compound, the Prob analysis (SAS/STAT software, version 6. 09, Prahmat program) was used to calculate the ED50値 of the proportion of mice in which the 3-stage seizure activity was obtained from the protected -143-1295286. That is, the control group can produce a 50% protected dose. The compound of the present invention shows that ED 50 値 is 1. 〇E - 0 4 or less. Particularly promising activities are shown by the following compound numbers: 8,9,1 0,2 2,2 3, 27,30,31,32,33,38,40,41,46,47,64,71,72 , 81,86,87, 88,92,93,95,96,100,105,110,146,151,152,156,158, 159,162, 163, 164, 166, 180,181,187,188,195,196,197,198,200,201,204,205,207,209,211,212,213,214,215 Φ,219,221,222,223,224,226,228,229,234,250,251,252, 264, 265, 267, AA 1, AA 2, AA 3, AA 4 and AA 5.

-144--144-

Claims

1295286 第95112076號「（2S)-2-[2-氧基-4-丙基吡咯啶基]丁醯胺類及其用途」專利案 ( 2008年1月修正）十、申請專利範圍： 1.一種化合物，其係（2S)-2-[2-氧基-4-丙基吡咯啶基]丁醯胺之（4R)或（4S)非對映異構或其醫藥可接受鹽。 2 .如申請專利範圍第1項之化合物，其爲 (2S )-2-[(4R)-2-氧基-4-丙基吡咯啶基]丁醯胺或其醫藥可接受鹽。 3 · —種用於有需要之哺乳動物治療癲癇、偏頭痛、神經病變疼痛、及特發性震顫之醫藥組成物，其包括申請專利範圍第1或2項之化合物或其醫藥可接受鹽作爲活性成分，組合醫藥可接受稀釋劑或載劑。 4 ·如申請專利範圍第3項之醫藥組成物，其中欲治療之疾病爲癲癇。1295286 No. 95112076 "(2S)-2-[2-Oxo-4-propylpyrrolidinyl]butanamine and its use" Patent (amended in January 2008) X. Patent application scope: 1. A compound which is a (4R)-2-[2-oxy-4-propylpyrrolidinyl]butanamine (4R) or (4S) diastereomer or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1 which is (2S)-2-[(4R)-2-oxy-4-propylpyrrolidinyl]butanamine or a pharmaceutically acceptable salt thereof. 3. A pharmaceutical composition for treating epilepsy, migraine, neuropathic pain, and idiopathic tremor in a mammal in need thereof, comprising a compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof as The active ingredient, in combination with a pharmaceutically acceptable diluent or carrier. 4. A pharmaceutical composition as claimed in claim 3, wherein the disease to be treated is epilepsy.