TWI297682B - 2-oxo-1-pyrrolidine derivatives, processes for preparing them and their uses - Google Patents

Description

1297682 A7 B7 V. INSTRUCTION DESCRIPTION OF THE INVENTION (1) 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. European Patent No. 621 62 036 B1 discloses the compound (S)-a-ethyl-2-oxy-1-pyrrolidinium, having the international non-exclusive name levetiracetam (left vetirace) Tan is a levorotatory compound that reveals a protective agent for the treatment and prevention of hypoxia and ischemic injury as the central nervous system. This compound is also effective in 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-N pyrrolidineacetamide 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/EP00/11808 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 one A combination of compounds that induce neuroinhibition by GABAa receptor mediators. It has unexpectedly been found that certain levetiracetam analogs, particularly those with a further substitution of the pyrrolidone ring, have demonstrated significantly improved therapeutic properties. In a characteristic aspect, the present invention provides a compound having the formula I or a pharmaceutically acceptable salt thereof. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). Please read the back note S ( Write this pageThe Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed clothing 1297682 A7 B7 RJa R4a

A2 RX i, invention description (2) (I) wherein X is - CAiNW or - CAWR7 or - CA^R8 or CN; A1 and A2 are respectively oxygen, sulfur or _nr9; R1 is hydrogen, alkyl, aryl or -CH2-Rla wherein Rla is aryl, heterocyclic 'halogen, hydroxy, amine, nitro or cyano; R2, R3 and R4 are the same or different and each are respectively hydrogen, halogen atom, thiol, hydrazine Base, amine group, nitro group, nitroxide group, cyano group, azido group, carboxyl group, decylamino group, sulfonic acid, sulfonamide, alkyl group, alkenyl group, alkynyl group, ester, ether 'aryl group, heterocyclic ring Or an oxygen derivative, a sulfur derivative, an amine derivative, a mercapto derivative 'sulfonyl derivative or a sulfinyl derivative. 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 hydrazine; but 1?2,1^,1? At least one of 4,1^,1^, and 8^ 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, B. When the base or propyl is used, the substitution on the D ring is not mono-, di- or tri-methyl or mono-ethyl; and when the -4- paper scale is applicable to the Chinese National Standard (CNS) A4 specification ( 210 x 297 mm) Zero Sweatshirt--------Book--------· (Please read the notes on the back and fill out this page) Printed by the Intellectual Property Office of the Ministry of Economic Affairs 1297682 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperatives Printed V. Inventions (), R3a & R4a are each hydrogen, A2 is oxygen and X is CONR5R6, R3 is not carboxyl, ester, guanamine, substituted oxy -pyrrole , a hydroxyl group, an oxygen derivative, an amine group, an amine derivative, a methyl group, a naphthyl group, a phenyl group optionally substituted by an oxygen derivative or substituted at a para position by a halogen atom. In the following definitions, unless otherwise stated, R11 And R13 are the same or different and each are amidino, alkyl, alkenyl, alkynyl, decyl, ester, ether, aryl, aralkyl, heterocyclic or oxygen derivative, sulfur derivative, hydrazine a base derivative, an amino derivative, a sulfonyl derivative or a sulfinyl derivative, each of which is optionally substituted with any suitable group, including but not limited to one or more selected from the group consisting of lower alkyl or other A moiety which is a group of an alkyl substituent. The term "oxygen derivative" is used herein to include a radical -R-R11, wherein RU is as defined above, except for "oxygen derivative". Non-limiting examples are alkoxylation. , alkenyloxy, alkynyloxy, nonyloxy, oxyester, oxoamine, alkylsulfonyloxy, alkylsulfinyloxy, arylsulfonyloxy, arylsulfin Oxyl, aryloxy, aralkyloxy or heterocyclic oxy group such as pentyloxy, allyloxy, methoxy, ethoxy, phenoxy Benzyloxy, 2-naphthyloxy, 2-pyridyloxy, methylenedioxy, carbonate. The term "sulfur derivative" is used herein to include the radical -S-R11, wherein R11 is as defined Except for "sulfur derivatives", non-limiting examples are alkylthio, olefinylthio, alkynylthio and arylthio. The term "amino derivative" is used herein to mean -NHR11 or -NRUR12 a group wherein R11 and R12 are as defined above. Non-limiting examples are a- or di-alkyl-, alkenyl-, alkynyl- and arylamine-based or mixed amine groups. This paper scale applies to the Chinese National Standard (CNS). A4 size (210 X 297 mm) ▼Install -----------------. (Please read the notes on the back and fill out this page) 1297682 A7 B7 i, invention description () (Please read the note on the back first? Further information on this page. The term "mercapto derivative" is used herein to mean a group derived from a carboxylic acid. The definition thus includes the formula R1 LCO- group, 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 the formula -SCh-R11, wherein R11 is as defined above, with the exception of "sulfonyl derivative". Non-limiting examples are alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl and arylsulfonyl. The term "sulfinyl derivative" is used herein to include a radical of the formula -S〇2-Ru, wherein R11 is as defined above, except for "sulfinyl derivative". Non-limiting examples are alkyl sulfinylene, alkenylsulfinyl, alkynylsulfinyl and arylsulfinyl. The term "alkyl" printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economics is defined herein as having a linear, branched or cyclic moiety or a combination thereof and containing from 1 to 20 carbon atoms, preferably acyclic. A saturated monovalent hydrocarbon group in which the alkyl group is 1 to 6 carbon atoms and the cycloalkyl group is 3 to 6 carbon atoms (two preferred examples are referred to as "lower alkyl groups" unless otherwise stated). 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 decyl group, an amine group, a nitro group, a cyano group, a thiocyanate group, a decyl group, a decyloxy group, a sulfonyl group derivative, Sulfosyl derivative, alkylamino group, carboxyl group, ester group, ether group, decylamino group, azido group, cycloalkyl group, sulfonic acid group, sulfonylamino group, sulfur derivative, oxyester group, oxygen Amidoxime, heterocyclic group, vinyl, this paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1297682 V. Invention description (5)

a Cm-alkoxy group, a substituent of a group consisting of (V!-aryloxy group and Cn.-aryl group). Preferred alkyl groups are methyl group, ethyl group, propyl group, isopropyl group, butyl group, Iso- or tert-butyl, and 2,2,2-trimethylethyl each 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, and a cyano group. Substituted by a substituent such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1- Dimethyl-2,2,2-trichloroethyl. The term "dilute" is used herein to include having at least one double bond such as vinyl (=vinyl), 1-methyl-1 -ethylene. Base, 2,2-dimethyl-1-vinyl, 1-propenyl, 2-propenyl (=allyl), 1-butenyl, 2-butenyl, 3-butenyl, 4 a pentenyl group, a 1-methyl-4-pentenyl group, a 3-methyl-1-pentenyl group, a 1-hexenyl group, a 2-hexenyl group, and the like, and optionally at least one selected from a halogen atom a substituent substituted with a substituent of a group consisting of a hydroxyl group, a thiol group, an amine group, a nitro group, a cyano group, an aryl group and a heterocyclic group, and an unbranched unsaturated hydrocarbon group, Such as mono- and di-halovinyl, where the halo is fluoro, chloro or bromo. The term "alkynyl" is used herein to define a radical containing at least one carbon-carbon such as ethynyl, 2-propynyl (= a propargyl group or the like and optionally substituted by a monovalent branch substituted with at least one substituent 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 group or Unbranched hydrocarbyl group, such as haloethynyl. When present, the alkyl, alkenyl and alkynyl groups respectively represent a straight or branched chain, and Cl-丨2 is preferably a C4-alkylene group or a C2-丨2 group. -, preferably C2 + -7- 1297682 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description () extending alkenyl or - alkynyl moiety. Branch derivatives are known by prefix (eg "positive" The basis for the definition of "second", "different", etc. (eg "n-propyl", "second butyl") unless otherwise stated otherwise is in a positive form. The term "aryl" is used here. It is defined to include an aromatic hydrocarbon derived from 1 to 3 ring compositions and having 6 to 30 carbon atoms by removing a hydrogen such as a phenyl group. Each of the naphthyl groups is 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 sulfinyl group, an alkyl group, Amine, carboxyl, ester, ether, decyl, azide, sulfonate, sulfonylamino, alkylsulfonyl, alkylsulfinyl, alkylthio, oxyester, oxygen An organic group substituted with a substituent of a decylamino group, an aryl group, a C6-alkoxy group, a C6.10-aryloxy group, a Cl_6-homo-based group, and a Cl-6-halogen-based group. The aryl group is preferably a group. a monocyclic ring having 6 to 10 carbon atoms. Preferably, the aryl group is a phenyl group and a naphthyl group, and each of 1 to 5 is independently selected from a halogen atom, a nitro group, an amine group, an azide group, and a C丨-6 group. Substituted by alkoxy, Ci-6-alkylthio, CVi alkyl, Cr6-haloalkyl and phenyl substituents. The term "halogen atom" is used herein to include C1, Br, F, I atoms. The term "base" is used herein to describe the -OH group. 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 describe the formula -N 0 2 group. The term "nitrooxy" is used herein to mean the formula -ON〇2. The term "amino" is used herein to mean the formula -NH2. The term "K-nitrogen" is used herein to refer to the formula -N3. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) ----Book.-------- 1297682 A7 B7 V (Invention) (7) The term "mercapto" is used herein to describe the formula -COOH. The term "sulfonic acid group" is used herein to mean the formula - S〇3H group. The term "denylamine" is used herein to describe the radical -S02NH2. The term "ester group" is used herein to mean the formula - COO-R11 group. Wherein R11 is as defined above, except for oxygen derivatives, sulfur derivatives or amine-based derivatives. The term "ether group" is defined to include a moiety selected from Cr5. A linear or branched alkyl group, or a C2.50 linear or branched alkenyl or alkynyl group or a combination thereof is interrupted by one or more oxygen atoms. The term "amylamine" is defined to include the formula -CONH2 or -CONHR11 or -CONRHR12, where 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, quinolinol, naphthyridine , hydrazine, pyrimidinyl, pyridyl, quinolyl, isoindole quinolyl, isobenzofuranyl, benzothienyl, pyrazolyl, fluorenyl, hydrazine, sulfhydryl, Isoindolyl, carbosazolyl, thiazolyl, 1,2,4-thiadiazolyl, thieno(2,3-b)furanyl, furopyranyl, benzofuranyl, benzoxazepine Base, isoxazolyl, carbazolyl, thioxyl, benzothiazolyl, or benzoxazolyl, porphyrinyl, fluorenyl, quinoxalinyl, phenanthryl, acridinyl, anthracene Acridine, phenanthryl, phenothiphenyl, -9- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) ---- Order--------- Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1297682 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description () furzanyl, benzene Dihydropyranyl, porphyrinyl, xanthenyl, hypoxanthyl 'acridinyl' 5-azacytidine, 5-azopenidine group, triazolopyridyl, imidazopyridyl, The pyrrolopyrimidinyl and pyrazolopyrimidinyl groups are optionally substituted with a court base or as described above for a deuteromeric group. Non-limiting examples of non-aromatic heterocycles are tetrahydrofuranyl, tetrahydropyranyl 'hexahydropyridinium methyl' hexahydro-n-d-decyl, hexahydro-strong cultivating, imi-n-butyl-morpholine , morpholinyl, 1-oxaspiro(4 · 5 )indole-2-yl, pyrrolidinyl, 2-oxy-pyrrolidinyl, sugar moiety (ie glucose, pentose, hexose, ribose, fructose) It may also be substituted or 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 previously described for alkyl groups. The term "heterocyclyl" also includes bicyclic, tricyclic, and tetracyclic, spiro groups wherein any of the foregoing heterocyclic rings are fused 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 or branched chain, Preferably, Cu2 is C4 alkyl or C12. Preferably, the Cr4 extended alkenyl or -exynyl bridge is selectively interposed between the heteroatom or carbonyl group and the remainder of the molecule. A preferred example of X is -COOR7 or -CONR5R6, wherein R5, R6 and R7 are preferably hydrogen, Cr4-alkyl, phenyl or alkylphenyl. -10- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm). 5 Clothes---- (Please read the notes on the back and fill in this page) -- Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printed 1297682 A7 B7 V. Description of Invention (9) Preferably X is a carboxyl group or -CONR7R6, wherein R5 and R6 are preferably hydrogen,

Ci. 4-alkyl, phenyl or alkylphenyl, especially -conh2. Preferably, each of A1 and A2 is oxygen. Preferably, R1 is hydrogen, and the alkyl group is particularly alkyl, particularly lower alkyl or aryl, particularly phenyl. Preferably, the R1 group is, 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, 1,1-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. Preferred examples of the R2 and R2a groups are hydrogen, halogen, or methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethyl. Ethyl or its substituted with at least one halogen atom, such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl 1,1-dimethyl-2,2,2-trichloroethyl. Particularly at least one and the best R2 and 1-23 are all hydrogen. Preferably, R3a, R4 and 1?" are respectively hydrogen, especially methyl or ethyl or aryl, especially phenyl or aralkyl, especially benzyl. Preferred examples of R3a, R4 and R4a are hydrogen, respectively. , halogen atom, or methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl or substituted by at least one halogen atom , for example, trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromo-11- This paper scale applies to China National Standard (CNS) A4 size (210 X 297 mm) -----------Package--------Book--------- (Please read the notes on the back and fill in this Page 1297682 V. INSTRUCTIONS () Ethyl, 1,1-dimethyl-2,2,2-trichloroethyl. Particularly at least one and most preferably both R4 and R4a are hydrogen. Is hydrogen or an alkyl group, especially a lower alkyl group and most preferably hydrogen. Preferably, R 3 is hydrogen, and C 1 . 1 2 -the hospital base is particularly C 1 . Substituting a plurality of substituents selected from a hydroxyl group, a halogen atom, a cyano group, a thiocyano group or an alkoxy group and directly or through a sulfur, a sulfinyl group, a sulfonyl group, a carbonyl group or a carbonyl group and a selective CVe alkylene bridge, particularly a methylene group attached to the ring; a C2_6-alkenyl group or an alkynyl group, particularly a c2.3-alkenyl group or an alkynyl group, each optionally having one or more halogens Atom substitution; azido group; cyano group; decylamino group; carboxyl group; triazolyl, tetrazolyl, pyrrolidinyl, pyridyl, 1-oxypyridyl, thiomorpholinyl, benzodioxoyl, A furyl group, a carbazolyl group, a pyrimidinyl group, a pyrrolyl group, a thiadiazolyl group, a thiazolyl group, a thienyl group or a hexahydropyridinyl group, each of which is optionally selected from one or more selected from the group consisting of a halogen atom, a +alkyl group and a phenyl group. a substituent substituted, and attached directly or through a carbonyl group or a Ci.4-alkylene bridge, a particular methylene group attached to the ring; a naphthyl group; or a phenyl group, a phenylalkyl group or a phenylalkenyl group, each optionally A plurality of selected from the group consisting of a halogen atom, a C-6-alkyl group, a C丨-haloalkyl group, a C丨6-alkoxy group, a C-6-alkylthio group, an amine group, an azide group, a phenyl group, and a nitrate Substituents substituted, and each attached directly or through an oxygen, sulfonyl, sulfonyloxy, carbonyl or carbonyloxy group and optionally additionally through a Cu-extension alkyl bridge to a particular methylene group attached to the ring. Good 1^3 is C 6-alkyl-selectively substituted with one or more substituents selected from the group consisting of a halogen atom, a thiooxy acid group, a gas-rich group, an alkoxy group, a thiol group, a phenyl acid group; ; C2. 3-alkenyl or - alkynyl each selected -12- 1297682 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives printed five, invention description (sexual replacement by one or more halogen atoms or acetyl groups; four An azolyl, pyridyl, furyl, pyrrolyl, thiazolyl or thienyl group; or a phenyl or phenylalkyl group, each optionally having one or more selected from the group consisting of a halogen atom, a Cr6-alkyl group,

Substituted with a substituent of Ci-6-haloalkyl, C!-6-alkoxy, amine, azide, phenyl and nitro, and each directly or through a sulfonyloxy group and optionally additionally passed through a Cm - an alkyl bridge, especially a methylene attached to the ring. Preferred examples of other R3 are hydrogen, halogen or hydrogen, halogen atom, or methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-tri Methyl ethyl group or substituted by at least one halogen atom, such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromo Ethyl, 1,1-dimethyl-2,2,2-trichloroethyl. R3 is particularly preferably Ci-4-alkyl-substituted with one or more substituents selected from a halogen atom, a thiocyanate group or an azide group; an alkenyl group or an alkynyl group, each optionally having one or more halogens Atom substituted; thienyl; or phenyl is optionally substituted with one or more substituents selected from a halogen atom, a Cl-6-alkyl group, a C!-6 halogen alkyl group or an azide group. Further preferred examples of the R3 group are a Cm alkyl group and a C2.6 haloalkenyl group. Preferably, R5 and R6 are respectively hydrogen, methyl, ethyl, propyl, isopropyl 'butyl, iso- or tert-butyl, 2,2,2-trimethylethyl-hydrogen or methyl . 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 , -13 - This paper size is applicable to China National Standard (CNS) A4 specification (210 x 297 mm). Zero-loading---- (Please read the notes on the back and fill in this page) tr------- -- 1297682 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 B7 Description of Invention (12) Phenyl, benzyl or its substitution with at least one halogen atom such as trifluoromethyl, chlorophenyl. Preferably R7 is hydrogen, and the thiol 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 1 A) comprises 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, The heterocyclic group, the vinyl group, and R3 may additionally represent a C2"alkenyl group, and the C2"alkynyl group or the azide group may each optionally have one or more halogen atoms, a cyano group, a thiocyano group, an azide group, and a ring. Propyl, fluorenyl and / or phenyl substituted; or phenylsulfonyloxy and any phenyl moiety can be applied to one or more halogen atoms, alkyl-14- this paper scale applicable to China National Standard (CNS) A4 Specifications (210 X 297 mm) v ·ϋ el· mmmt nn 1·-·« iBi ^ i ^§0 eMMmw tet emmf emt ·ϋ I . (Please read the notes on the back and fill out this page) !297682 V , Description of the invention (13, 'halogen compound, alkoxy, nitro, amine and/or phenyl substituted; most preferably methyl 'ethyl' propyl, isopropyl, butyl or isobutyl;

Pf and widely hydrogen; K5, R6, R7 are the same or different and each is hydrogen, hydroxy, alkyl 'aryl 'heterocyclic or oxygen derivative; and R8 is hydrogen 'hydroxyl, fluorenyl, halogen atom , alkyl, aryl, heterocyclyl 'alkylthio or sulfur derivatives. In these compounds 1A, R1 is preferably a methyl group, an ethyl group, a propyl group, an isopropyl '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 C2" 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 thiocyano 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 -C0NH2; most preferably C_2. Further preferred compound group I (Compound 1 B) comprises the following compounds wherein X is -CA^Nh, -CAWHCh or -CA!N(CH3)2; -15- This paper scale applies to Chinese National Standard (CNS) A4 size (210 χ 297 mm) ------------ Recording clothing (please read the notes on the back and fill out this page) Order---------· Ministry of Economics Property Bureau Staff Consumer Cooperative Printed 1297682 V. Description of Invention (14) R1 is alkyl or phenyl; R3 is alkyl, alkenyl, alkynyl, cyano, isothiocyanate, ether, carboxyl, decylamine a aryl group, an aryl group, or a heterocyclic group; or R3 is CH2R1() wherein R1. Is hydrogen, cycloalkyl, oxy ester, oxyalkylsulfonyl, oxyarylsulfonyl, aminoalkylsulfonyl 'aminoarylsulfonyl, nitrooxy, cyano, different Thiocyanate group, decylamino group, alkylthio group, arylthio group, alkylsulfinyl group, alkylsulfonyl group, heterocyclic group, aryloxy group, or dichloroethyl; Rh is hydrogen An alkyl group or an aryl group (particularly when R3a is hydrogen, 'R3 is not a methyl group); 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 a Cu2-more preferred Ci talkyl group, and most preferably an ethyl group; 1?2,1^,1^ and R4a are preferably hydrogen. R3 is preferably selected from the group consisting of hydrogen; Cm-alkyl specific alkyl groups, each of which is optionally substituted with one or more substituents selected from the group consisting of a hydroxyl group, a halogen atom, a cyano group, a thiocyanate group or an alkoxy group, and Directly or through a thiol, sulfinyl, sulfonyl, carbonyl or oxycarbonyl group and optionally additionally through a C!_4-alkylene bridge, a special methylene group attached to the ring; Cm-alkenyl or -alkyne a particularly C 2 + alkenyl or - alkynyl group, each of which is optionally substituted with one or more halogen atoms, a dimethyl group; a fluorenyl group; a stilbene group; a benzyl group; a π s-based group, a tetradecyl group, a pyridyl group D-based, pyridyl D-based, 1-oxidized pyridyl D, thiomorpholine

-16- !297682 hP __ _ Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Β7 Β7 Description of invention (5) Base, benzodioxoyl, furyl, carbazolyl, pyrimidinyl, pyridyl, thia An oxadiazolyl, thiazolyl, thienyl or hexahydropyridinyl group, each of which is optionally substituted with one or more substituents selected from the group consisting of a halogen atom, a C 1 · 6 -yard group, and a phenyl group, and is directly or a particular methylene group attached to the ring through a carbonyl or Cm-alkylene bridge; a naphthyl group; or a phenyl group, a phenylalkyl group or a phenylalkenyl group, each optionally having one or more selected from a halogen atom, a CV6-alkane Substituted by a substituent of a Cm-haloalkyl group, a Ci-6-alkoxy group, a C!-6-alkylthio group, an amine group, an azide group, a phenyl group, and a nitro group, and each directly or through an oxy group, The sulfonyl, sulfonyloxy, carbonyl or carbonyloxy group and optionally additionally pass through a C!.-alkylene bridge, particularly a methylene group attached to the ring. R3a is preferably hydrogen or Cm-alkyl; R4 and 1? "preferably hydrogen, Cm-alkyl, phenyl or benzyl, respectively. A further preferred group of compounds of formula I (compound 1C) comprises a racemic form of a compound wherein when X is -CONR5R6 and R1 is hydrogen, methyl, ethyl or propyl, the pyrrolidine ring is substituted by a mono-, di- or tri-methyl or monoethyl group. A further group of compounds I (compound 1D) comprises a compound in racemic form wherein when X is -CONR5R6 and R1 is hydrogen or Ci.e-alkyl, C2_6-alkenyl or -alkynyl or cycloalkyl ( Wherein each is unsubstituted) the 'ring substitutions are not substituted by alkyl, alkenyl or alkynyl groups (each being unsubstituted). Another group of particular compounds of formula I (compound 1E) comprises wherein 'X is -CA1·〗; R1 Η ; R3 is azidomethyl, iodomethyl, ethyl selective by 1 to 5 halogenogen-17- This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) - loaded --------Book---------- (Please read the notes on the back and fill out this page) 1297682 A7 B7 V. Invention Description (b (Please read the notes on the back first) Fill in this page) Substitution The n-propyl group is substituted with 1 to 5 halogen atoms, the vinyl group is substituted with 1 or 2 methyl groups and/or 1 to 3 halogen atoms, and the ethynyl group is selectively substituted with an alkyl group or a phenyl group. Or 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 pair Further preferred group of compounds of formula I (compound 1F) comprises such compounds wherein X is -CA丨NH2; R1 is Η; R3 is Ch6-alkyl, C2_6-alkenyl or C2 + alkynyl Selectively substituted with an azide group, an oxynitro group, and 1 to 6 halogen atoms;

Rd is a gas or a halogen atom, preferably fluorine; and R2, R2a, R4 and R4a are each hydrogen; in the form of a racemic compound or an enantiomer-rich form thereof, preferably a pure enantiomer. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumers' Cooperatives. In all of the foregoing ranges, when R1 is attached to a carbon atom that is asymmetric, the better system is in an "S" configuration. A "pharmaceutically acceptable salt" according to the invention includes a therapeutically active non-toxic base and acid salt form which the compound of formula I can form. 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. -18- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1297682 A7 B7 V. Invention description (); or organic acids such as acetic acid, glycolic acid, propionic acid, lactic acid ,pyruvate,malonic acid,succinic acid,maleic acid,fumaric acid,malic acid,tartaric acid,citric acid,methanesulfonic acid,ethanesulfonic acid,benzenesulfonic acid,p-toluenesulfonic acid,Sika Eye acid (eye 1 ami c ), salicylic acid, p-aminosalicylic acid, pamoic acid, 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, and salts formed with organic bases such as N-methyl-D-glucosamine 'Hydopamine salt ( Hydrabannne sa 1 ts ) and a salt formed with an amino acid such as arginine or lysine. Conversely, the salt forms can be converted to the free form by treatment with a suitable base or acid. The compounds of formula I and salts thereof may be in the form of a solvate, and solvates are included within the scope of the 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 stereo generation center can exist in an R or S configuration, and the R and S indications follow the rules described in Pure Applied Chemistry 45 (1 976) 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 mixtures of stereoisomers). Furthermore, certain compounds of formula I which contain alkenyl groups may exist in the form of Z(zu s ammen ) or E (entgegen) isomers. In each case, the invention includes mixing -19- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) - Packing.i (Please read the back note first and then fill in this page) Order -- ------- Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives printed 1297682 5, invention description (18) compounds and individual isomers. The plurality of substituents of the pyrrolidine ring may be expressed in 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. When the present invention relates to a compound, it is intended to include various isomeric forms of the compound and mixtures thereof unless a specific specific isomer is specifically mentioned. 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.

"Drive" 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 bases - a group of groups well known in the industry. Including, but not limited to, for example, a sulfhydryl group (ie, an ethyl group, a propyl group, a butyl group, a butyl group, etc.), an unsubstituted or substituted carbocyclic aryl group (eg, a benzylidene group, a substituted benzoyl group, and a fluorene group). 2_naphthylmethyl), a hospital oxycarbonyl (eg ethoxycarbonyl), a trivalent decyl group (eg dimethyl- and triethyldecyl), a monoester formed with dicarbonic acid (eg butyl sulfhydryl) ) 'phosphoric acid group, sulfuric acid group, acid extended group, expanded sulfhydryl group, sub-zinc group and the like. An advantage of a compound having a metabolically cleavable group is an improved bioavailability resulting in increased solubility and/or rate of absorption of the parent compound due to the presence of a metabolically cleavable group. Τ · H i g u c h i and V • 20- A7

1297682 ___B7__ κ 19, V. Description of invention () S te 1 1 a '"Precursor as a novel delivery system", A. c. S. Begging series; "Bioreversible carrier for drug design" No. 14 , edited by Edward B. Roche, American Pharmaceutical Association and Pergamon 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 the substituents used herein, "=" means "yes" and "#" means "not". A. Cyclization of the amino ester. In the formula I, when A2 = 0, the amino ester of the formula AA-II is cyclized, wherein Q1 together with the oxygen to which it is attached is a leaving group, in particular Q1 is an alkyl group, in particular having 1 to 4 carbon atoms Straight or branched alkyl.

Q1 = methyl or ethyl. The reaction is known and is 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. Q1 #methyl or ethyl. The ester of formula AA-11 is hydrolyzed under acidic or basic conditions, and then a coupling agent such as dicyclohexylmethaneimine is used in the conventional-21- paper scale for the Chinese National Standard (CNS) A4 specification (210 X). 297 mm) -------------------Booking·-------1 (Please read the notes on the back and fill out this page) Ministry of Economics Intellectual Property Bureau employee consumption cooperative printed 1297682 A7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed five? π invention description () cyclization under peptide synthesis conditions (Bodanszky, M., Bodan s zky, A., "peptide synthesis practice", Springer Verlag, 1984). A.l is added to the itaconate derivative to synthesize AA_n. A compound of formula AA-II wherein R2a = R3a = H and R3 = COOQ2, wherein Q2 represents a non-selective optically active linear or branched alkyl group, via a compound of formula AA-III and a formula of formula AA-IV based on itaconate The following reaction is obtained: nh2 R1"^X (AA-III)

〇, Q1

〇λ R1' X 〇, (AA-II) This reaction is based on: Street, L.]., Baker, R., Book, T., Kneen, CO, ManLeod, AM·, Merchant, KJ· , Showel 1 , GA , Saunders , J. , Herbert, RH, Freedman, S, B., Harley, E_A_, Journal of Medicinal Chemistry (1 990), 33, 269 0- 26 97. A. 2 Synthesis of aa-II by reductive amination reaction The compound of formula AA-II can be prepared according to the reaction formula using the formula ΑΑ π π i compound or aminating formula A A - V compound: X (AA-III)

, Q· α -22- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page)

R2 into NH〇 (AA-II) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1297682 A/ B7 V. Invention Description (This reaction uses Abdel-Magid, A.F., Harris, B.D.,

Mar y anof f ' C · A ·, Synlett (1 994 ), 8 1 - 83 The conditions are carried out. When X represents CONR5R6, the amine AA-III can be bonded to the solid support via the guanamine moiety (for example, (R i nk ) resin). The compound of formula AA-V can be prepared by one of the following methods:

(AA-IX) (AA-X) A.2.1·Formula AA-VI aldehyde is alkylated using an alkyl haloacetate of the 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), 5 1 7 - 536 or using anthraquinones as described in Corey, EJ., Enders, D., Tetrahedron Letters (1 976), 11-14 followed by ozonolysis. A · 2.2 · The formula AA-VIII nitro ester can be converted to the compound of formula AA-V by treating its conjugate base with sulfuric acid in methanol and hydrolyzing intermediate dimethyl acetal (Nef reaction as described in Urpi, F. , Vi larrasa, J ·, tetrahedral letter (1990), 31, 7499-7500). Formula AA-VIII Nitroester -23- This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) W-------------- (Please read the note on the back and fill out this page.) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1297682 Α7 Β7 22, V. Invention Description () Known by Ho rni, A., Hubacek, I., Hesse, Prepared as described by M., Helv. Chim. Acta (1 994), 77, 579. A.2.3. The ester AA-X is alkylated with an allyl halide AA-IX (X, a halogen atom) in the presence of a strong base (such as lithium diisopropylamide), followed by reduction ozonolysis of the unsaturated ester For example, in Ann·uta Reddy P., Hsiang B. C. Η . , La tifi Τ.Ν., ΗΠΙ M . W . , Woodwa rd KE, Rothman SM, Ferrendelli JA,, Covey DF, Journal of Medicinal Chemistry ( 1 996 ) , 39,1 898 - 1 906.

A. 3. Synthesis of AA-I I compound of formula AA-II by alkylation of 7-haloester wherein X = C〇NR5R6, COOR7 or CN can be alkylated by using amine AA-III to convert the r-haloester AA-XI, wherein X2 Indicates the preparation of a halogen atom. Nh2

R1x^X (AA-III)

a R\ ,R4 3a r4\ 尸 4 r3< R3O^0., R3- Ylf - one 2 X2 person 2 0 R NH (AA-XI) R1/XX (AA-II) This reaction uses the patent application The conditions described in GB2225322 A are carried out. The synthesis of the ester AA-XI is described in Part B. Α································ A compound of the formula 其中-ΙΙ wherein X = c 〇 NR5R6, COOR7 or CN, = Η and R2a = Η can be prepared according to the following formula AA-III amine reductive aminating quinone-quinone 5-hydroxylactone: -24- (Please read the notes on the back and fill out this page again)

1207682 A7 B7 V. Description of invention (23, nh2 R1^"X (AA-lll) +

(AA-XII)

The 5-hydroxylactone of the formula AA-XII can be synthesized as described in B.1. B. Condensation of an amine with an r-halic acid derivative In the formula I, when A2=0, X=C0NR7R8, C00R7 or CN and R2a = H, the compound of the formula AA-XIII reacts with the amine of the formula AA-III according to the following formula:

Nh2 R1^"X (AA-lll)

Ο (I) ft---- (Please read the note on the back and fill out this page) The Ministry of Economic Affairs, Intellectual Property Office, employee consumption cooperative, prints where X3 represents a halogen atom, preferably an iodine or chlorine atom, and X4 represents a halogen atom. A preferred chlorine atom. This reaction can be carried out as described in the patent application GB22253 22 A. The compound of the formula AA-XIII can be obtained by opening the lactone of the formula AA-XIV in the presence of a halogenating agent such as TMSI, S〇Cl2/ZnCl2 according to the following formula (subsequent halogenation reaction of the obtained halogen acid (Χ4=0Η) if necessary) ):

R2, \χ3 (AA-XIII) -25- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm). Order --------- 1297682 A7 B7 V. Description of invention (24 The opening of the lactone AA-XIV can be carried out according to the following procedure: Mazzlni, c. > Lebreton, 】, Alphand, V., Fur stoss, R., Tetrahedron (1998), 38, 1195-1196 and 〇lah, GA·, Na rang, SC Gupta, BGB, Malhot ra, R., Journal of Organic Chemistry (1 979), 44, 1 247 - 1 250. Halogenation of the resulting halogen acid (X4 diOH) (X4 = halogen atom) or cooling (X4 2Q1) can be carried out under any of the conditions known to those skilled in the art. The AA-XIV lactone can be prepared by one of the following methods. : B · 1 · Hydrogenation or conjugate addition of organometallics. Compound AA-XIV wherein R2a = = Η can be obtained via hydrogenation of the α,/3-unsaturated lactone of 4A-XV, or via conjugate addition of the formula R3M (wherein Μ represents Li, Na, Mg or Zn) The metal derivative to the compound AA-XV is ultimately catalyzed by a copper (I) salt. (Please read the notes on the back and fill out this page)

R3M, Cul or H2, PdC (R3=H)

(AA-XIV) The Ministry of Economic Affairs' Intellectual Property Office employee consumption cooperative prints this response according to the following procedure: Alexakis, A., Berlan, J., Besace, Y., Tetrahedron Letter (1986), 27, 1047 -1050; Lipshutz, BH, Ellsworth, EL, Siahaan, T., American Chemical Society Journal (1 989), 111, 1 3 5 1 - 1 3 58 or any method known to the industry. B.2 Reduction of succinate derivatives. In the formula AA-XIV, when R2 = R2\H: the reduction of the carboxylic acid AA-XVI is based on the following formula in the borohydride agent, preferably LiBH4 or Ca (BH〇2 on the alcohol-26- paper scale) China National Standard (CNS) A4 Specification (210 X 297 mm) 25. 1297682 A/ B7 V. Description of the Invention (Solvent: R3a R4a

(AA-XIV) 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 = alkane Base and when G, 0, Q4 = H. C. Alkylation of indoleamine derivatives. In formula I, when A2=0 and X=COOR7, the compound of formula AA-XVII reacts with the compound of formula AA-XVIII according to the following formula: (Please read the note on the back and fill out this page)

R1 V Ο (AA-XVIII)

(I) R wherein X5 represents a halogen atom and hydrazine is an alkali metal. This reaction can be carried out in accordance with the procedure of Patent Application GB (Case No. 15-09). The Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Printed AA-XVII compound can be carried out according to the procedure described by Horni, A., Hubacek, I., Hesse, M., Helv. Chim. Acta (1994), 77, 579. D · Conversion of ester derivatives. In the formula ί, when A2=〇 and X=C〇NR5R6, none of the R2, R2a, R3, R3a R4 and R4d groups are substituted by a thiol, ester or acid extension, corresponding to the ester I of the formula I - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1297682 A/ B7 V. Invention Description (26)

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. Ε. Reduction of α, /3-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 endoamine AA-XIX: R4

The AA-XXI reduction step can be carried out under typical conditions known to those skilled in the art, such as 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 NaBH4 in the presence of COCl2. Compound AA-XIX can be prepared by one of the following methods: -28- This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) π装·-------Book----- ----· (Please read the note on the back and then fill out this page) 1297682 V. INSTRUCTIONS (27) E. 1 Alkylated AA-III compound by AA-XX compound (where Q5 means 1 to A linear or branched alkyl group of 4 carbon atoms is alkylated and cyclized. The alkylation step can be carried out in an inert solvent such as tetrahydrofuran, dimethylformamide or dichloromethane at 0 to 5 (TC in the presence of a tertiary amine. The cyclization can be carried out spontaneously or according to the method described in Part A). E. 2 by reductive amination of a compound of formula AA-XXI and a compound of formula AA-III under reductive amination conditions. The first step of the reaction can be in an inert solvent such as toluene at 0 to 50 ° C in a reducing agent such as NaBH; The presence of CN is carried out in the presence of an acid such as acetic acid. The synthesis of compound AA-XXI is described in Bourgiugnon, J. J. et al., J. Med. Chem. (1 988), 3 1,893-897. F. Base conversion. F. 1 ester reduction to alcohol. Compound of formula I (wherein A2 = 0, X = C0NR5R6 or COOR7, R7 is the third alkyl group and one of R2, R2a, R3, R3a, R4 and R4a represents 02 -C〇〇Q6, G2 is a bonded or alkylene group and Q6 is a linear or branched alkyl group having 1 to 4 carbon atoms) as a corresponding compound (wherein R2, R2a, R3, R3a, R4 and R4a) One of them represents a key synthetic intermediate of G2-CH2〇H). These transformations can be carried out under any of the conditions known to the industry. F. 2 Alcohol And oxidation. Compounds of formula I (wherein A2 = 0 and R2, R2a, R3, R3a, one of R4 and R4a represents -G2-CH2〇H, and G2 is a bonded or alkylene group) is a corresponding compound (where -29 - 1297682 V. INSTRUCTION DESCRIPTION (28) One of R2, R2a, R3, R'R4 and Rh represents -G2-CH2X6 or -G, CHO wherein X6 represents a chlorine, bromine or iodine atom or formula-0-S0b Q7 or - a key synthetic intermediate of -Q-Q8, qi is alkyl or aryl and y is alkyl. These transformations can be carried out under any of the conditions known to the industry. F.3 Nucleophilic substitution of activated alcohols. The compound of formula 1 (wherein 八 2 = 〇 and ^, 1^, 1?3, 1^1, 1?4 and ]^ represents -G2-CH2X6, G2 is a bond or alkyl group and X6 is chlorine Or a bromine or iodine atom or a formula of the formula -〇-S〇2-Q7, as defined in F.2), is a corresponding compound (wherein one of R2, R2a, R3, R3il, R4 and R4a represents -G2-CH2X7, wherein X7 represents A key synthetic intermediate of an azide group, a halogen atom, a nitro group, an amine group, an amine derivative, a sulfur derivative, and a heterocyclic group. These transformations can be carried out under any of the conditions known to the industry. The olefination reaction of aldehydes. a compound (wherein A2 = 0, X = CC) NR5R6 or COOR7 or CN and R2, R2a, R3, R3a, R4 and R4a represent -G2 - CHO, G2 is a bond or alkyl group) as a corresponding compound (wherein R2, R2i', V, R3a, R4 and R4a2 - represent -G2-Q9, wherein Q9 represents an unsubstituted vinyl group, a halogen-atom- or a di-substituted vinyl or alkyl group) Things. 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 Se〇2 (described in Earl, R.A., Vollhardt, K.P.C., Journal of Organic Chemistry (1 984), 49, 4786). -30- 1297682 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperatives Printing Agriculture 29 V. Inventions () F. 5 Acid derivatives are converted into heterocyclic rings. a compound of formula 1 (wherein 8 2 2 0 and 2, 1 ^, 1 3 , 1 ^ ^ and 1 ^ represent - G, CN or -G 2 -COQl (), G 2 is a bond or alkylene group And Q1() is an alkoxy group, an aryloxy group or an amine group, a halogen atom or an amine derivative, but -COQIQ is not X) is a corresponding compound [wherein R2, R'R3, R3a, R4 and R4a2-represented - G2-Qu wherein Q11 represents (U-CO-aryl/heterocyclic group, palladium-catalyzed coupling between chloro-G2-C0C1 and an aryl/heterocyclic organometallic such as trimethyl-pyridyl-stannate The reaction proceeds or (i 1 ) a heterocyclic group such as thiazole (Friedman, BS, Spark s, Μ., Adams, R., Journal of the American Chemical Society (1933), 55, 2262 or Iroka, Ν·, Hamada, Υ·, Shiori, T., Tetrahedron (1992), 48, 7251), 曙 1Φ (Street, LJ, Baker, R., Castro, JL, Clamber, RS, Guiblin, AR, Hobbs, SC, Metassa, VG·, Reeve, AJ, Beer, MS, Middlemis, DN, Noble, AJ, Stanton, J.A., Scholey, K., Hargreaves, RJ, Journal of Medicinal Chemistry (1993), 36, 1529), Ainsworth, C·, Journal of the American Chemical Society (195S), 77.1 1 48), four The azole begins with nitrile (Goerlitzer, K., Kogt, R., Proceedings of the Proceedings (1990), 323, 847) or thiadiazole (Lamat t ina, J.L., Mularski, C. J., Journal of Organic Chemistry) (1 984), 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 II CQ12Q13 or -G2-CQ13 = CHQ12, G2 is a bond or alkyl group, Q12 and Q13 are hydrogen atoms or alkyl groups, but other R2, -31- paper scales are applicable to China National Standard (CNS) A4. Specifications (210 X 297 public) —---------------- Order --------- (Please read the notes on the back and fill out this page) !297682 A7 B7 i, description of the invention (3()) (please read the precautions on the back and fill out this page) R2\ R3 , R3a , R4 and R4a none of them have functional groups sensitive to oxidative conditions) Corresponding compounds (wherein R2, R2a, R3, R3a, R4 and broadly represent - G2-CO-CHQ12Q" or -G2-CHQ13-CO-Q12, respectively) are key synthetic intermediates. These transformations can be carried out under any suitable conditions known to the industry, for example, in 〇2 and PdCl2M inert solvents such as dimethylformamide or N-methylindole D at 0 to 50 °C ( B ird, Transition Metal Intermediate for Organic Synthesis, Academic Press, New York (1 9 6 7 ), 8 8 - 11 1 ). F. 7 Derivatives of ketones. A compound of formula I (wherein Α2=0, Χ2 CONR5R6 or COOR7 and R2, R2a, 尺3,1^,1?4 and 1^ represent -02-(:0-(^4, where 〇2 is a bond) The knot or alkyl group and Q14 represent an alkyl group) is a synthetic (1) alcohol - G2-CHOH-Q14, which is reduced using a hydrogenating agent (M arch, Journal of Advanced Organic Chemistry, Third Edition, John Wiley & Sons (1 983) ), 809 ), ( Π ) fluorinated branch - G2-CF2-Q14 using the conditions described in Lal, GS, Pez, GP, Pesaresi, RJ, Prozonic, FM, Chemical Communication (1999), 215 -2 1 6 The key intermediates. F.8. Synthesis of alkynyl derivatives. The Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, printed compound of formula I (where A2 is divalent and one of R2, R2il, R3, R'R4 and R" -G2-C=C(X8)2, G2 is a bond or alkyl group and X8 is a halogen atom, but other 乂, 1^,1?2, {^,1^,1^,1?4 and 8 Any of the functional groups which are not sensitive to strong bases are corresponding compounds (wherein R2, R2a, R3, R3a, R4 and one of the broad ones represent - G2-CEC-Q15, wherein Q15 is hydrogen, halogen Key synthetic intermediate of atom, alkyl or aryl) -32- paper ruler Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) A7 1297682 B7_____ V. Description of invention (31) How these changes are carried out: (Please read the notes on the back and fill out this page) • Via base Inducing a cold-elimination reaction (eg 1 equivalent of t-BuOK at low temperature, described in Michel, P., Rassat, A., tetrahedral letter (1 999), 40, 8579 - 858 1 ) to a halo alkyne derivative (Q1) a halogen atom), followed by metal-catalyzed substitution of a halogen atom by an organometallic species (for example, by MeZnCl in the presence of CuCN.LiCl, as described, for example, in Micouin, L., Knochel, P., Synlett (1 997), 327) ^ • via direct conversion to a metal acetylenic compound (for example using 2 equivalents of n-butyllithium) and alkylation using an alkyl halide or a carbonyl derivative (described in (]〇1^7, £..,?11(:118 , ?.1., tetrahedral letter (1972), 36, 3769 - 3772). F.9 Synthesis of alkane. Compound of formula I (where A2 = 0 and one of R2, R2a, R3, R3a, R4 and R" Representing -G2-C = C-Q16Q17, G2 is a bond or alkyl group, and Q16 and Q17 are alkyl or fluoro) are corresponding compounds (where 1?2, ^, 1^3, ^, 84 and One of the ^ represents a key synthetic intermediate of -G2-CH-CH-Q16R17). The printing and reduction steps of the Ministry of Economic Affairs' Intellectual Property Bureau employees' consumption cooperatives can be carried out under the typical conditions known to the industry, for example, using hydrogen in the presence of Pd/C (March, 〗. Advanced Organic Chemistry Journal, Third Edition, John Wei Li & Son (1 985), 1101-1102). F. Synthesis of a (halo) azidoaryl derivative. a compound of formula I (wherein A2 = 0, X = C0NR5R6 or C00R7 or CN and R2, R3, one of R4 groups is G2-Q18 wherein Q18 represents a nitroaryl group or a triterpene aryl group 'G2 is a bond or a stretch of alkane Base) for the synthesis of the corresponding compound (where r2, r3 or -33- this paper scale applies the Chinese National Standard (CNS) A4 specification (210 X 297 public f 1297682 V. Invention description (32) One of the R4 bases is G-Q19, Q19 is a key intermediate for the azidoaryl group to be selectively substituted with one or more halogen atoms, preferably Br or F atoms. The conversion is via a nitro or tridecene by any means known to the industry. Partial reduction to aniline, selective introduction of one or more halogen atoms (eg 乂1112-16112, 0., 〇11〇-13111, 1., Synthetic Communications (1989), 19, 1261) and by well-known methods Conversion of amine to azide F. 11 Synthesis of heterocyclic ring from amine. Compound of formula I (wherein Α^Ο, ΧβΟΝΙ^6 or COOR7 or CN and one of R2, R3 or R4 groups is G2-Q2°, where G2 is a bond a knot or alkyl group and Q2() is C00H, C0NH2, or CN) to synthesize a corresponding compound (wherein one of R2, R3 or R4 is 02- Guan 2 or G2-CH2-NH2) The bond intermediate results in a corresponding compound (wherein one of the R2, R3 and R4 groups is G2-Het or G2-CH2-Het, where Het is a heterocyclic ring bonded by a nitrogen atom, optionally via one or more Halogen substituted) • In the case where X = CONR5R6, CN or COOR7, R7 is not Η and R2, R3 or R4 is G2-C00H, the transformation is carried out via Curtius rearrangement (eg phosphorus azide) The action of diphenyl ester with triethylamine and quenching with benzyl alcohol in situ is described in K 1 m, D . , We 1 nreb, S . Μ ., Journal of Organic Chemistry (1 978 ), 43,12S) R2, R3 or R4 = G2-NH2 is obtained by dehydrogenation of an amine functional group by hydrogenolysis or any conditions known to those skilled in the art, followed by ring synthesis to obtain a heterocyclic ring such as pyridine (for example, described in Jeff rd, CW, Tang, Q., Zasl〇na, A., Journal of the American Chemical Society (1991), 1 1 3, 3 5 1 3 - 3 5 1 8 ), and the selective introduction of one or more halogen atoms to the ring (for example, In GU〇w, H. Μ., Bur ton, -34- 1297682 V. Ming said ^ Ming (33) DE, Journal of Organic Chemistry (1981), 46, 222 1 - 2225). • Among them X two CONR5R6, COOR7 or CN And one of the R2, R3 or R4 groups is G2-CONH2, X is not CONRf or G, CN, and X is not an example of CN. The conversion is via selective reduction of guanamine or nitrile by any of the conditions well known to the industry. An aminomethyl moiety, and a ring synthesis to obtain a heterocycle such as a triazole (for example, in M i es, R. W., Samano, V., Robins, M. J., Journal of the American Chemical Society (1) 995 )

, 117, 595 1 - 5957 ). F. 12 Synthesis of triazole.

a compound of formula I (wherein A2 = 0 and R2, R2a, R3, R3a, one of R4 and R4a represents one of -G2-CH2N3, and G2 is a bonded or alkylene group) is a corresponding compound (wherein R2, R2a, R3, One of R3a, one of R4 and R4 represents a key synthetic intermediate of -G2-CH2-triazole). Such a transformation can be carried out by prolonged heating in the presence of a 1-(triphenylphosphinoalkyl)-one derivative (for example, as described in Hammerschmidt, F., Polsterer, JP, Zbiral, Synthesis (1 995), 415). . 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 its constituent racemic mixture. The separation method is preferably used in non-image-phase or image-phase-in-phase mode or preferably in direct mode for chromatographic separation; Combining in reverse phase or preferably in direct mode for chromatographic separation, and -35- 1297682 A7 B7 V_I___ Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Printing Instructions (34) Separating each racemic mixture into its The final optical segmentation step of the enantiomer. Further, the 'final step' is used when the partial stereoselective synthesis method is used to separate the diastereomers by non-image-phase or image-phase-phase in reverse phase or better in direct mode for chromatographic separation. Some of the foregoing intermediate compounds, particularly the compounds of formula A A - I I, wherein each substituent has the aforementioned definition as a novel compound and also form part of the present invention. Such novel intermediates have the same utility as described hereinafter for the compounds of formula I when the leaving group is pharmaceutically acceptable. 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 (as described above). -36- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -----------________^--------1 (Please read the back Note: Please fill out this page again. 1297682 Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Printed Clothing A7 B7 I, Invention Description (35) In particular, the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of epilepsy, A therapeutic drug for bipolar disorder, chronic pain or neuropathic pain, migraine, broncho-, asthma, or allergic conditions. The activity and properties of the active compound vary significantly between the oral isocidity and stability in the test tube or in vivo between the optical isomers of the disclosed compounds. In a preferred embodiment, the active compound is administered in enantiomerically enriched form, i.e., substantially as a single isomer. For example, in the compound of formula I wherein R1 is ethyl, X is -CONH2, and A2 is oxygen. When R3 is propyl and the remaining substituents are hydrogen, the S (butyridamine) R (ring) enantiomer Preferably, when R3 is 2,2-difluorovinyl and the rest of the substituents are hydrogen, the S (butanamine), S (cyclo) enantiomer is preferred. The invention also relates to a method of treating epilepsy, migraine, bipolar disorder, chronic pain or neuropathic pain or bronchial, asthmatic or allergic condition in a mammal in need thereof, comprising administering to the patient at least a therapeutic dose A compound of formula I or a pharmaceutically acceptable salt thereof. The method of the present invention comprises administering a mammal according to the present invention to a mammal (preferred human) having the aforementioned condition or disorder, and the amount administered is sufficient to ameliorate or prevent the condition or condition. The compounds are conventionally administered in any suitable unit dosage form including, but not limited to, from 5 to 1,000 mg, preferably from 25 to 500 mg, of active ingredient per unit dosage form. -37- This paper size applies to Chinese National Standard (CIvJS) A4 specification (210 X 297 mm) -----------€--------Book------- --砉 (Please read the notes on the back and fill out this page) 1297682 A7 B7 , 3 6. V. INSTRUCTIONS () The term “treatment” is used here to include therapeutic treatment and preventive treatment. The term "treatment" refers to the current symptoms that can treat a condition or condition. (Please read the back of the note first and then fill out this page.) "Prevention" means preventing the occurrence or recurrence of a disease or condition. The term "epilepsy" is used herein to mean brain dysfunction and is characterized by regular and unpredictable epilepsy. When a normal brain is treated with an electric shock or a chemical convulsion, it is induced as a "non-epileptic" episode, and the non-stimulus syndrome is referred to as "seizure." The term "seizure" is used herein to mean a temporary change in behavior due to impediment, synergy, and rhythmic firing of the brain neuron population. The term "migraine" is used here to mean a condition characterized by recurrent headache, with a wide range of intensity, frequency and duration of headache. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperatives. Attacks are often unilateral and are often associated with anorexia, nausea, vomiting, phobia and/or photophobia. Some cases have previously been associated with or associated with neurological and emotional disorders. Migraine headaches last from 4 hours to about 72 hours. The International Headache Association (IHS, 1 988) classified migraine as a predatory migraine (typically non-migraine) and no premature 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 classification of mental disorders according to the Diagnostic and Statistical Manual of Psychiatric Disorders, 4th Edition (DSM-IV TM, American Psychiatric Association, Washington, DC, 1994). Illness. Bipolar disorders are generally characterized by an automatic triggering of repetitive (in other words at least two episodes) episodes of high excitability, activity, and mood in the episode -38 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1297682 A7 B7 V. INSTRUCTIONS (37) Obstacles, which in some cases are elevated in mood and increased energy and mobility (sickness or snoring), and in some cases emotions Reduced and reduced energy and activity (depression). Bipolar disorders can be divided into four categories in DSM-IV (bipolar I disorders, bipolar II disorders, circulatory mental depression, and bipolar disorders not specifically classified) > "The snoring episode j is used here to express emotions a period of abnormal and persistent elevation, dilatation or susceptibility, and compulsive speech and psychomotor stimuli. The term "palatosis" is used here to describe a non-extreme snoring episode. The severity is low. 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 (for at least 1 week) whose seizure criteria are consistent with seizures and almost daily for major depressive episodes. The term "chronic pain" is used here to mean disease. Progress is different from acute pain. Conventional definition is pain that lasts longer than normal healing time, when an individual feels that the pain will continue to experience part of it for the foreseeable future Lifetime can also be considered as chronic pain. Most chronic pain syndromes may involve neuropathic components, which are usually more difficult to treat than acute physical pain. The term "neuropathic pain" is used here to mean pain induced by neuropathological changes. There are noxious stimuli that cause a false pain when there is no identifiable stimuli. In other words, it is clear that the paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ( Please read the notes on the back and fill out this page.) --------Book ·------- Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Ϊ 297682 A7 B7__ 3 8 V. Description of Invention () The pain system is turned on and cannot be turned off. (Please read the precautions on the back and fill out this page.) The activity of the compound of formula I or its pharmaceutically acceptable salt as an anticonvulsant can be measured in the pattern of auditory seizures. The ability of the compound to assess the seizure-evoking ability of the mouse by sound-sensitive mice (animal mode with reflex episodes). In this primary systemic epilepsy, epilepsy The 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 (LKs che !· W . & Schmidt D·, Epilepsy (1998), 2, p.l45- 181; Bu chhalter JR, epilepsy (1 993), 34, S31-S41). The results obtained with the compounds of formula I indicate potent efficacy. Another assay that indicates possible anti-convulsive activity is bound to levetiracetam Combined with the location (LBS), detailed later. The Ministry of Economic Affairs Intellectual Property Office employee consumption cooperative printed compound of formula I or its pharmaceutically acceptable salt for chronic neuropathic pain activity can be determined in animal models. For example, chronic neuropathic pain It can be modeled by inducing diabetes by pharmacokinetics in rats. In this model, animals show progressive hyperalgesia to noxious stimuli, which are common in patients with painful peripheral neuropathy (Courteix C, Eschalier, A. and Lavarenne J., Pain, 53, (1 993) ) 8 1 - 88 ). This model has a high degree of pharmacological predictive power (Courteix C, BarcHn M., Chantelauze C., Lavarenne J and Eschalier, 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, bipolar disorder, especially snoring, can be induced by pharmacologically induced activity in rats and evaluated for its performance in gamma-shaped labyrinth. Model-40- This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm). A7 1297682 B7 _ — 39 V. INSTRUCTIONS () (Please read the precautions on the back and fill out this page). In this case, therapeutic agents for humans such as lithium and sodium valproat e can reduce hyperactivity, thus confirming that the model is predictive (Cao B .)., and Peng N; A; European Journal of Pharmacology 237 ( 1 99 3 ) 1 77 - 1 8 1.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. (1992) Development of animal models of allergic symptoms in guinea pigs and effects of antiallergic drugs. Prostaglandins, .1: 507 · 521). 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. 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 a pharmaceutically acceptable diluent or carrier. . To prepare a pharmaceutical composition according to the present invention, one or more of the 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. -41- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1297682 A7 B7 40 V. Invention Description () Medicine containing the compound according to the present invention The composition can be administered, for example, orally or parenterally, i.e., intravenously, intramuscularly or subcutaneously, intrathecally. The drug suitable for oral administration may be in the form of a solid or a liquid such as a tablet, a nine-dose, a sugar-coated tablet, a gelatin capsule, a solution, or a syrup. 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 can be in the form of conventional dosage forms such as aqueous or oily solutions or suspensions, usually 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 a pharmacist. The amount of the active ingredient in the pharmaceutical composition may fall within a broad range and depending on a number of factors, such as the patient's family name, age, weight, and medical condition' and administration method. Thus, the compound of formula I is administered orally in combination-42- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) ------------------- Order·------- (Please read the note on the back and then fill out this page) 1297682 5 'Invention Description (41) The content of the substance may be at least 〇. 5% by weight relative to the total weight of the composition Up to 80% by weight. 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 that can be combined with the compounds of the present invention are anti-caries agents (e.g., baclofen), antiemetics, anti-caries mood stabilizers, analgesics (e.g., aspirin). Lin, ibuprof en, paracetamol, anesthetic analgesic, local anesthetic, flavonoid analgesic, lithium salt, anti-depressant (eg mianserin) ' fluoxetine (trazpdone) 'Sentence anti-depressant (such as Umipr amine), desipra mi ne), anti-convulsant (eg VA 1 pr 〇ic acid, carbamazepine, fentanyl (?1^117-toi η)) antipsychotic (eg risperid 〇ne), Haloperidol, a neuroleptic, benzodiazepines (eg diazepam, clonazepam) phenothiazines (eg Coropium) Chlorpromazine, jin channel interrupting agent, amphetamine, coroniidine Cion lcline), lidocaine, mexiletine, capsaicin, caffeine, quetiapine, angiotensin antagonist, /S-interrupter, Anti-arrhythmia, Tupper (tr 1 p ta ns ), ergot derivatives. Particularly interesting according to the invention are at least one compound of the formula I or a pharmaceutically acceptable salt thereof and at least one inducible GABAa receptor vector -43-A7 1297682 B7 42 , V. Description of the invention () Neurosuppressive effect a combination of compounds. 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 a pharmaceutically acceptable salt thereof. Benzodiazepines include 1,4 benzodiazepines such as dized and konaznapan and 1,5 benzodiazepines such as clobazam. A preferred compound is ronnazap. Barbiturates include phenylbarbital (Phenobarbi tal) and pentobarbital (P e n t 〇 b a r b 1 t a 1 ). A preferred compound is phenyl barbital. Steroids include adrenocortical hormones such as tetracosactide acetate and the like. Anti-twitching agents include carbendazim (fenidon, ethotom, etc.) '曙π sitting π determinate (trimethadione, etc.), butyl bismuth imidate Ethosuximide, etc., phenacemides (phenacetamides, acetylphene-turide, etc.), sulphide (sulthiame), Yass卓卓麦(3〇6 1(^2〇12〇1丨(10), etc.), aminobutyric acid (eg 7-amino-/3-hydroxybutyric acid, etc.), sodium citrate and derivatives, Kabamaz is equal. Preferred compounds include vanadium, va 1 pr om i de, Pi vox i 1 , sodium phenoxide, sodium sulfamate ,代-44- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ------------------- --- (Please read the notes on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Ministry of Printing and Economy Ministry Intellectual Property Bureau Staff Consumer Cooperatives Printed 1297682 A7 B7 43 V. Inventions () Van Pukes (divalproex), konazidine, phenyl For the preferred oral compositions, the daily dosage is from 5 to 1 000 mg (mg) of the compound of formula I. In the composition for parenteral fungus, the compound of formula I It is present in an amount of at least 0.5% by weight and up to 33% by weight relative to the total weight of the composition. As for the preferred parenteral composition, the dosage unit is in the range of from 5 mg to 1 000 mg of the compound of formula I. The dosage unit range of the broad formula I compound is usually from 5 to 1000 mg. It is to be understood that the specific dosage can be adjusted according to the individual requirements by a physician's decision. The active ingredient of the pharmaceutical composition of the present invention (Compound I and The amount of the compound which induces the neuroinhibitory effect of the GABAa receptor vector will depend on the mammal to be administered, the disease to be treated, other active agents, etc. Generally, the GABAa receptor is induced for the specified composition and dosage form. The amount of the compound for the neuroleptic action of the vehicle and the amount of the compound I can be conveniently determined by routine procedures. The following examples are for illustrative purposes only and are not to be construed as limiting the invention. Variations and modifications of the following examples can be made without departing from the spirit and scope of the invention. Unless otherwise stated in the examples, the characteristics of the compounds are determined according to the following methods:

The _R spectrum is recorded on the BRUKER AC 2 50 Fourier transform NMR spectrometer in conjunction with the Aspen 3,000 computer and the 5 mm 1H/13C -45- paper scale for the Chinese National Standard (CNS) A4 specification ( 210 X 297 mm) -----------Installation--------Settings--------I (Please read the notes on the back and fill out this page) 1297682 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 44 V. Invention Description () Dual probe, or Bruker 4〇〇 equipped with SG靛 computer and 5mm reverse geometry 1/1^/1^ triple probe. The compound was applied to DMSO-d6 (or CDCIO solution at a probe temperature of 313 °K and a concentration of 20 mg/ml. The instrument was locked to DMSO-cU (or CDC10氘 signal. The chemical shift was measured as the internal standard of TMS in the distance). The mass spectrometry in LC/MS mode was followed by the following: HPLC condition analysis was performed using the WATERS A 1 1 1 an ce HPLC system with INERTSIL ODS 3, DP 5 micron, 250 x 4.6 mm column. Gradient consists of 100% solvent A (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 1 000% B for 4 minutes. The flow rate was set to 2.5 ml/min just before the API source using a fraction of a minute. The reaction was carried out at 30 ° C. The MS condition sample was dissolved in acetonitrile / water 70 / 30 v / v at a concentration of about 250 / / gr / ml. API spectroscopy (+ or _) using Finnigan (FINNIGAN) (San Jose, Calif.) LCQ ion trap mass spectrometer. APCI is derived from 45 (TC operation 'capillary heater operating at 160 ° C. ESI source is based on 3.5 kV operation and capillary The heat exchanger is operated at 2 1 (TC operation. The mass spectrometry in DIP/EI mode is as follows: the sample is heated from 50 ° C to 25 by 5 minutes (TC and gasification EI (electron impact) spectrum system uses phenanthrene Nigen (San Jose, Calif.) TSq 700 Connected Quadrupole Mass Spectrometer -46- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ------------- --------------- (Please read the notes on the back and fill out this page) 1297682 a7 B7 45 V. Invention description () Record. The source temperature is set at 150 ° C. It was recorded on a Pekingo Emma (Pe rk i η-E 1 me r ) MC24 1 or 341 polarimeter. The rotation angle was recorded at 25 t in 1% methanol solution. For some molecules, solvent is used due to solubility problems. Dichloromethane or DMSO The water content was determined using a Metro hm microcoulometer Karl Fischer titrator. The preparative chromatography was performed on a silicone 60 gram (Merck). , the particle size of 15-40 micron '爹 编 编 5 tiger 1.15111.9025, use the field to modify the correction of the Ivan (J 〇bi η Y v ο η) type axial compression column (inner diameter of 80 ), A flow rate of 70 to 150 ml / min. The amount of sand and solvent mixture is as described in the individual procedures. Preparative image chromatography was performed on DA ICEL, Chiralpak AD 20 μm, 100*500 mm column using field built-in instrumentation with various low alcohols and C 5 to C 8 Straight key, branch or ring yard is carried out in soil at 350 ml/min. The solvent mixture is as described in the individual procedures. The melting point is measured by a Bifch i 5 3 5 Tot ο 1 ! type melt meter and is uncorrected or corrected by the starting temperature of 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 Κ α radiation (tube at 40 kV, 3 5 mAh) Operation) and the scintillation counter is obtained. Data were collected in continuous scan mode using a scan speed of 0.02 20/s over a range of 4 to 50 degrees. The following abbreviations are used in the examples:

AcOEt Ethyl Acetate-47- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) IT--------- Economy Ministry of Intellectual Property Bureau employee consumption cooperative printed clothing 1297682 A7 B7 V. Invention Description ( 46 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

AcOH BuLi η - BusP CICOOEt or DCE DIC DMSO DSC DMF EtsN Et2〇EtOH FMOC LDA MeCOCl MeCN MeOH MTBE NMP PhMe P r epLC i -Pr2〇l_Pr〇H TFA n-butyl lithium acetate tri-n-butylphosphine CIC〇2Et chlorine Ethyl formate 1, 2 -dichloroethane diisopropylcarbodiimide dimethyl hydrazine differential scanning calorimetry N,N-dimethylformamide triethylamine diethyl ether ethanol thiol methoxycarbonyl Diisopropylamine acetonitrile chloroacetonitrile methanol methyl tert-butyl ether N-methylpyrrolidone toluene preparative liquid chromatography diisopropyl ether isopropanol trifluoroacetic acid-48- -- ------Settings-------- (Please read the notes on the back and fill out this page) This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1297682 A7 B7 47 V. Description of the invention (THF tetrahydrofuran TMOF trimethyl orthoformate TMSCI chlorotrimethyl decane TMSI iodine trimethyl decane Unless otherwise stated in the examples, the compounds are obtained in free (non-salt) form. Synthesis of 4 by the reductive amination reaction of aldehyde esters, substituted 2-oxyl _ _ _ _ _ 醯 醯 。 。 。 1 1 1 1 Synthesis of -4 -oxy-butyric acid ester 1 · 1. 1. Route A: alkylation of enamines 5,5-dimethyl_3_methylindolyl-hexanoic acid methyl ester 361 Expressed as

(Please read the notes on the back and fill out this page) Diisobutylamine, PhMe·110. .

BrCH2C02CH3, PhCH3> CH3CN 18RT, 90X, 1 hour then H2〇 (30%) 362 361 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative printed in a three-necked bottle equipped with a Dean-Sta rk device A solution of 4*4-isobutyl female (4.62 ml from Acros), 4,4-dimethylvaleraldehyde 362 (2.5 g, 0.021 mol) in toluene (20 ml) under nitrogen Heat at 30 ° C for 2 hours and extract with water. The yellow solution was cooled to room temperature and methyl bromoacetate (3.7 g, 0. 024 m) was added in one portion. The peach solution was stirred overnight at room temperature and stirred at 90 ° C for 1 hour. Water (1 毫升 ml) was added at this temperature and the solution was cooled to room temperature after 1 hour. The organic layer is washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution, dehydrated with magnesium sulfate, filtered and evaporated -49- The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ^___________ Ministry of Economics Intellectual Property Bureau employee consumption cooperative printed 1297682 A7 B7 invention description (48) Obtained oil, oil distilled under reduced pressure (1 mmHg) to obtain 5,5-dimethyl-3-methylmercapto-hexanoic acid methyl ester 361 Liquid (1.1 g, 〇.〇5 mol, Teb (1 mm Hg): 69 - 7 1 °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-acetonitrile 1 /! (v / v) as a solvent. The resulting aldehyde was also distilled under reduced pressure. 1.1.2. Other synthetic routes Aldecan esters can also be obtained by the following methods including (i) alkylation with a bromoacetate derivative. For example, 5 -(phenyl)-3-methylindolyl valerate 2,2-dimethyl-ethyl ester via N-(4-phenyl)-propylene-N,N-dimethylhydrazine The reaction with the third butyl bromoacetate and LDA is followed by an ozonolysis reaction of the alkyl arsenide. (1 i ) Nitromethane is added to α,/?-unsaturated esters. 3-(3-Bromo-phenyl)-4-oxy-butyric acid ethyl ester is added via nitromethane in the presence of 1,3-diazabicyclo[5.4.0]undec-7-ene To 3-(3-bromo-phenyl)-ethyl acrylate, obtained by oxygenating a nitro derivative under Nef conditions and controlling hydrolysis of methyl-acetal by hydrochloric acid. (Π ! ) Ozonolysis of 4-pentenoic acid derivatives. Ethyl 2-benzyl-4-oxy-butyrate is obtained by alkylation of ethyl 3-phenyl-butyrate with allyl bromide using lithium diisopropylamide, followed by ozonolysis and by PPh; Obtained. Reductive amination of 1,3-substituted 4-ethoxy-butyrate and cyclization to pyrrolidin-2-one 1. 2 · 1 . Reductive amination - 50 - This paper scale applies to Chinese national standards ( CNS)A4 size (210 X 297 mm) βϋ I ϋ ϋ ·ϋ ϋ ·ϋ ·ϋ ·ϋ « n II ϋ ϋ ϋ ϋ .vrJfl n ϋ nna- ·ϋ ϋ I (Please read the notes on the back first) Fill in this page) 1297682 Α7 Β7 V. Description of the invention (49 4-{[((lS)-l-Aminocarbonyl)propyl]amino}butyrate methyl ester 363 is synthesized as a representative.

MeOH, 45 ° C, 0.75 h 2. NaBHif 20 ° C, 4 h 1 2 (S)-aminobutyric acid t-Bu

Printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative (30%) The total yield is in a three-necked flask equipped with a reflux condenser under argon, aldehyde 36 1 (1.7 g '0.09 mol), (S)- 2-Amino-butanamine (1.58 g, 0.15 mol and molecular sieve (3 angstroms from a hydrazine (A 1 d I· i ch ) in methanol suspension heated at 60 ° C. 5 hours. Suspension The liquid was cooled to 0 ° C and sodium borohydride (0.55 g) was added in portions. 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 yellow oil. 4-{[(IS)-1-Aminocarbonyl)propyl]amino}butyric acid methyl ester 363 was used in the next step without further purification. Further 'reductive amination can be reduced under the same conditions. An agent such as NaBlCN or NaBH(0Ac)3 (1.4 moles equivalent to aldehyde ester) is used. 1. 2 · 2 · cyclization of butyric acid (methyl or ethyl) esters (2S)-2 -(4-Pentyl-2-oxy-1-pyrrolidinyl)butanamine is synthesized as stereoisomers 149 and 148 to represent r V(8, Lt

-51- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) ------------------- Order -------- - (Please read the notes on the back and fill out this page) 1297682 Α7 Β7 V. INSTRUCTIONS () In a three-necked flask equipped with a reflux condenser, under argon, oil 363 is hydroxybenzotriazole ( 2 . 05 g, obtained from the mixture of toluene and 1,2-dichloroethane (25 ml each) in the presence of hydrazine, solution at 9 〇t: heating for 2 hours and cooling to room temperature . The organic phase was washed successively with saturated aqueous sodium hydrogen carbonate solution and water, dried over magnesium sulfate, filtered and evaporated to give a brown solid (1·8 g), which was purified by silica gel column chromatography (eluent: (^ 2〇12/^^〇[1 95 /05 卜^)) Obtained (23)-2-(4-neopentyl-2-oxy-1-pyrrolidinyl)butanamine (0 · 89 g, 0.0036 moles is a 1:1 mixture of diastereomers. The separation of the two isomers was obtained by solid phase chromatography (ethanol hexane 1 / 1 (V / V)) and two stereoisomers after recrystallization from toluene (0.35 g, respectively). And 0.37 g). 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, the cyclization can be carried out in two steps by (1) acid or base hydrolysis of the ester and (Π) activation of the ester under cyclization under normal conditions of peptide synthesis. 1.3. Solid phase synthesis of pyrrolidone 1.3.1 FMOC protected amino acid is attached to butyl amide resin. NHFmoc

DIC , DMF : 铃克树脂-52- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) ------------ Clothes (please read the back note first) Fill in this page) Order — .0 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1297682 A7 B7 V. Description of Invention (51) 4 grams of ketamine resin (0.51 meq/g, 1 00-200 mesh) Place in a glass container and stir in 20% v/v hexahydropyridine/DMF (40 ml for 30 minutes. The resin is drained and the entire deprotection is repeated. The resin is filtered, washed (6x DMF) and dehydrated. The resin is suspended in DMF (40 ml) and treatment with 1^?111?(:-2-aminobutyric acid (3.02 g, 9.28 mmol) followed by 1,3-dicyclohexylmethyleneimine (1.4 g, 11.13 mmol) solution in DMF (20 mL). The reaction was stirred at room temperature for 1 hour then filtered, washed (DMF) and re-coupled. The resin was filtered, washed (6x DMF, 6x CH2CI2), dehydrated and dried Used in the next steps. 1.3.2. Reductive amination and cyclization by adding 5-hydroxy-4-propyl-furan-2-one-----------(Please read first Note to fill out the back of this page)

1T---------· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 100 mg of N-Fmoc-2-aminobutyric acid (0.051 mmol) is contained in a frosted polypropylene syringe. Removal of the Fmoc group was achieved using 20% hexahydropyridine in DMF. To the amine resin was added 5-hydroxy-4-propyl-furan-2-one (36.72 mg '0.25 mmol) in DCE (2 mL). The resin was then treated with acetic acid (15 [mu]L) and sodium triacetoxyborohydride (54 mg, 0.25 mmol). The reaction was stirred at room temperature for 18 hours and then filtered and washed sequentially with H2 EtOAc / DMF (1:1), DMF, CH2Cl2, MeOH and dehydrated. Resin by vortex stirring suspension in trifluoroacetic acid / dichloromethane mixture (1 / 1) experienced 4 small -53- This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) Ministry of Economic Affairs Intellectual Property Bureau The employee consumption cooperative printed 1297682 A7 B7 ^, 52, V, invention instructions (), 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/H2O/TFA 1%). 1 . 3 . 3 . Reductive amination and cyclization by adding whole vinegar.

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% hexahydrodrolidine in DMF. An aldehyde (〇 · 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 trisodium borohydride (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: H 2 〇 x 6, MeOH x 6, CH 2 C 12 x 6 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 was dissolved in dichloromethane (2 mL) and concentrated again. The desired compound was purified by LC-MS micromass Gilson, LCZ platform, RP-18 column, gradient elution, CH3CN/H2 〇/TFA 1%). Example 2. 4-Substituted 2-oxypyrrolidinobutamines were synthesized by ring-opening reaction of 4-substituted lactones. -54- This paper size applies to China National Standard (CNS) A4 specification (21G X 297 public hair) "' -----------Install--------Set---- ----I (Please read the note on the back and then fill out this page) 1297682 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 53. Invention description () 2. The synthesis of lactone 2. 1 . 1. Route A: Synthesis of alkylated 4-n-butyl-butyrolactone 365 via 2,3-furanone as representative: 364 1. fvBu2CuLi (1.5 equivalents), TMSC丨 (2 equivalents) Et20, -78° C to 20 ° C, 3 h 2. NH4CI 4 (74%) n-Bu

0 365 in a three-necked flask under argon, n-butyllithium (1.6 M in hexanes, 75 ml, 0 · 12 mol) was added to Cul (1 1.42 g, 0.06 mol) in anhydrous THF (80 ml) a suspension cooled to -30 °C. After 5 hours, the solution and liquid were cooled to -78 ° C, TMSC1 (4.75 g, 0.04 mol) was added dropwise, followed by 2,3-咲 awake 364 (from Yali 胥 ' 3.36 g ' 〇· 〇4 molar dissolved in anhydrous THF. The suspension was warmed to room temperature and hydrolyzed with saturated chlorin. The aqueous layer was extracted with ethyl acetate (3 times), washed with water, and then evaporated and evaporated. The crude lactone is purified by distillation (1 mmHg; 73-80 ° C) to obtain 2.7 g of 4-n-butyl-butyrolactone 365. In addition, the copper acid reagent can be prepared by replacing organic lithium with organomagnesium. , a few magnesium can be obtained by reacting an alkyl halide with magnesium swarf under the usual conditions of such a conversion reaction. THF can be replaced by diethyl ether (for general information, please refer to: Lipshutz, BH; Sengupta, S. Organic Reaction 1991, 41 , 135). 2 . 1 . 2 . Other routes Other lactones can also be obtained via the following route: Reduction of succinates ◦ 4-(cyclopropyl)methyl-butyrolactone by diisopropyl Lithium propyl methyl bromide of lithium decylamine is monomethyl succinate-55- (please read the notes on the back and fill out this page) · — I----订·- ------ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1297682 A7 B7 54 V. Description of the invention (), followed by NaBH4 and CaCh reduction 2-(cyclopropyl) Methyl-succinic acid 1-methyl ester obtained. (i i ) Reduction of 1-alkyl succinate 4-alkyl thioester. 4-Allyl-butyrolactone is obtained from ethyl 4-pentenoic acid thiolate (synthesized from 4-pentenoic acid and ethanethiol in the presence of dicyclohexylmethylamine aldehyde imine). Ethyl 4-pentenoic acid thioester is alkylated with ethyl bromoacetate with lithium diisopropyl decylamine to obtain 2-ethyl thioester of 2-allyl-succinic acid 1-methyl thiolate, followed by sequential It is converted to 4-allyl-butyrolactone by reaction with UBH4 and sulfuric acid. 2 . 2. Synthesis of pyrrolidone 2. 1 . Deuteration / alkylation of (2S )-2-(4-allyl-2-oxy-1-pyridyl)butane via butaline The synthesis of two isomers of amines 228 and 224 is representative: (Please read the notes on the back and fill out this page)

Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperatives - Step 1: The lactone is opened in a three-necked flask under argon, and TMS 1 (51 ml, ylide) is added to the crude 4-allyl-butyrolactone 366. (Refer to Procedure § 2.1.3., 22.9 g, 0.181 mol) Cool the solution to 0 °C. The solution was stirred at room temperature for 2 hours and hydrolyzed with 1 N hydrochloric acid (300 mL). The aqueous layer was extracted with methylene chloride. EtOAc (EtOAc m.)屮NMR (250MHz, CDCl〇: 1.80-2.05(m, 2H), 2.20(t, 2H), 2.40- 2.60(t, 2H), 5. 10-56- This paper scale applies to Chinese national standards ( CNS) A4 size (210 X 297 mm) 1297682 V. Description of invention (55) 5·20 (m, 2H), 5·15-5 · 80 (m, 1H) - Step 2: Chlorination of iodic acid In a three-necked flask equipped with a reflux condenser, sulfinium chloride (25.5 ml) and crude iodic acid 367 (44.5 g, 0.175 mol) in benzene (90 ml) were stirred at room temperature under argon. The solvent was evaporated in vacuo to give EtOAcqqqqqqqqqqqqqQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQ _ 2.05(m,2H),2·15(t,2Η),2·90-3.10(m,2H), 3.25(dd, lH), 3.35(dd, lH), 5.10-5.20(m,2H) , 5.15-5.80 (m, lH) - Step 3: Aldehyde-alkylation using 5 - 2 -amino-butylimine in a three-necked flask under argon, crude chlorobenzene 368 (47 g, 0.172 mol) Dichloromethane (300 ml) was added dropwise to molecular sieves (29 g), powdered potassium hydroxide (22.3 g), anhydrous sodium sulfate (28. 8 g), 4-bromobutyl bromide (2.8 g, 0.0086 mol) and S-2-aminobutylide ([α] 2% di + 19.35 °; 26.3 g, 0.26 mol) in dichloromethane (470 ml) by mechanical stirring and cooling to The suspension of 〇 ° C. The solution was stirred at -51 for 5 hours', added powdered potassium hydroxide (6.2 g) and stirred continuously for -3 hours at -51. The reaction mixture was in the sea float Rosier (hy f 1 〇ce 1) Filtration and evaporation of the solvent in vacuo. The crude reaction mixture was purified by chromatography (ethyl acetate / isopropyl alcohol: 97 / 03 ( v / v) and preparative chromatography (hexane / ethanol) Purification afforded two isomers of (2S)-2-(4-allyl-2-oxy-1-pyrrolidinyl)butanamine (6.0 g (228) and 5.48 g (224), respectively; 16% and 15%). Two small impurities were also separated after image chromatography, ie (2 S ) - 2 - -57- 1297682 A7 B7 56 V. Description of invention () [4_( 2-iodine Two stereoisomers of propyl-2-oxy-1-pyrrolidinyl)butanamine 225 (0.22 g) and 226 (0.27 g) were white solid after recrystallization. 2.2.2. Synthesis of two isomers via alkylation of butaamine (2S) - 2 - (5-fluorenyl-2-ethoxy-1 -pyrrolidinyl)butanamine : Step 1: Open lactone by adding r-decalactone (0.32 ml, 2 mmol) to sulfinium chloride (164 μl, 2.25 mmol) at room temperature with zinc chloride (12 mg) , 0.088 mmol) and the mixture was stirred for 24 hours. Excess methanol was added, and the reaction mixture was stirred for 10 minutes and then concentrated under reduced pressure to give &lt 1. SOCI2, ZnCI2 (please read the notes on the back and fill out this page) Printed by the Intellectual Property Office of the Ministry of Economic Affairs

Step 2: alkylation of 2-aminobutylinamine (1 g, 10 mmol) in a solution of methyl 4-chloro-decanoate (2 mmol) in DMF (2 mL), 300 Mg sodium iodide (2 mmol) and 276 mg potassium carbonate (2 mmol). The mixture was stirred overnight at EtOAc (EtOAc) eluted eluted eluted eluted eluted eluted

K2C03, Nal, DMF

• 58_ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1297682 A7 B7 57 V. Description of invention () Step 3: Cyclization: Refer to § 1 · 2 · 2 . and § 1. 2 3. The conditions. 2. 3. Synthesis of keto-pyrrolidin-2-one (please read the note on the back and fill out this page) (2S)-2-[2-oxy- 4- (2-oxypropyl) The synthesis of 1_pyrrolidinyl]butanamine 230 is representative:

Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed in three-necked bottles, oxygen through PdC 12 (0.68 g, 0.0039 mol), CuCl2 (1.68 g ' 0.0098 旲 ear) in N-methyl-2-port ratio D a solution of ketone (NMP, 40 mL) which was added dropwise (2S)-2-[2-oxy-4-(2-oxypropyl)-1-pyrrolidinyl]butanamine 224 (4.13 g) , 0.020 mol) in NMP (40 ml) solution (addition time: 1.2 hours). The solution was stirred under a venting time 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 (ν/ν)) to obtain (2S)-2-[2-oxyl 4-(2-Ethoxypropyl)-1 -pyrrolidinyl]butanamine 230 was obtained as a white solid after recrystallization from ethyl acetate. 2.4. Derivatization of ketone 230 2.4.1. Synthesis of alcohol (2S) Synthesis of 2-[(4S)-4-(2-hydroxypropyl)-2-oxypyrrolidinyl]butanamine 2 3 3 For the representative ··-59- This paper scale applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1297682 A7 B7 58 V. Invention description ()

233 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed - Step 1: Restore to a three-necked flask under argon, add NaBH4 in several portions to 230 (9 g, 0.012 mol) in ethanol (14 ml) and cool in - 5 ° C solution. 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: 90/1 0 (v/v)) to afford the mixture of alcohol 369 (2.2 g, 79%) as oil. The crude mixture was directly acetabulized in the next step. 1H NMR (400MHz, (CD3)2SO): 0.70 (t, 3H), 1.05 (d, 3H), 1.30-1.45 (m, lH), 1.70-1.80 (m, lH), 1.80-2·〇5 ( m, 1H), 2. 20-2 · 40 (m, 2H, partially overlapping with the solvent), 3. 00-3 . 2 〇 (m, lH), 3. 30 - 3.3 5 (m, 2H, with solvent Partially overlapping), 3.50-3.65 (m, lH), 4.30 (〇1, 111), 4.45 (111, 1 [1), 7.10 (5 (wide), ^), 7.20 (s (width) 1H). - Step 2: Acetate in a three-necked flask under argon, and add acetonitrile (0.91 g, 0.011 mol) to 4-N,N-dimethylaminopyridine (0.11 g, 0.001 Mo) at room temperature. A solution of pyridine (0.86 ml) and alcohol in dichloromethane (90 ml). Dissolved -60- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) Order ---------ΜΨ. 1297682

5 'Inventive Description (59) The liquid was stirred for 5 hours, quenched with saturated ammonium chloride, and the aqueous layer was extracted with dichloromethane (3 times). Dehydrated with magnesium sulfate and concentrated in vacuo to give crude acetate. Purification by column chromatography (hexane/ethanol) gave the two epimers, s. 370 and 371 (1.143 g and 1.17 g, respectively). 1/1 mixture at 370 and 371 before image chromatography: 屮NMR (400MHz, 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, lH), 2.04 (s, 3H), 2.16 (dd, 1H), 2.38 (m, 1H), 2.62 (dd, lH) , 3.11 (dd, 1H); 3 . 49 (dd, 1H), 4.39-4·49 (m, 1H), 4'89-4 · 99 (m, lH), 5.43 (s (width), lH) , 6.24 (s (wide), 1H). - Step 3: Deacetylation in a three-necked flask under argon, a single enantiomer of acetate 37 1 (1.1 g, 0.0042 mol) and a suspension of potassium carbonate in ethanol. c Stir for 20 hours, evaporate to dryness and crude alcohol in EtOAc (methanol / methylene chloride: 85/15 (v/v)) to obtain (2S)-2-[(4S)-4-(2) -Phenyl)-2-oxypyrrolidinyl]butanamine 23 3 (0.67 g, 72%) - as a white solid after recrystallization from acetonitrile. 2.4.2. Fluorination of 230 The fluorination of ketone 230 was used to synthesize 2-[(4S)-4-(2,2-dichloropropyl)_2 oxypyrrolidinyl]butanamine 265.

-61- 1297682 A7 B7 V. INSTRUCTIONS (°) - Step 1: Fluorine 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 heated at 80 ° C for 4 hours. The solution was stirred at this temperature for 4 hours, quenched with sodium carbonate, extracted with dichloromethane, washed with EtOAc EtOAc EtOAc EtOAc. 3 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 dried in vacuo to give acid (1.2 g) as a white solid. The crude mixture is amided under standard conditions as described in § 6 · 3 · 1 (Step 2) to obtain (23) and (21〇-2-[(43)-4-(2,2-difluoropropyl) a mixture of -2-oxypyrrolidinyl]butanamine (87% and 13%, respectively). 2.5. (2S)-2-(2-oxy-4-propyl-1-pyrrolidinyl) Synthesis of butylamine 158 and 1 59--------------------- Order i (please read the notes on the back and fill out this page) .i. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

-62- This paper scale applies to China National Standard (CNS) A4 specification (210 297 297 mm) Printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs Ϊ 297682 A7 V. Description of the Invention (61) 2 · 5 . 1 · Step 1: Reductive amination in a three-necked flask under argon, 4-n-propyl-hydroxyfuranone 3 73 (3 5.5 g, 0.25 mol by Bourguignon JJ et al; Journal of Medicinal Chemistry, 1988 '31,89 3 - 897 ) at 18T: a solution of S-2 aminamide (28.1 g '0.275 mol) in PhMe (355 ml). 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 a solution of NaBH4 (6.2 g, EtOAc) in water (EtOAc). After 1 h, the reaction mixture was quenched carefully with acetic acid (30 mL) and warmed to 50 EtOAc. 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 NH4COOH (8 g, 0.126 mol) was added in portions to a coarse 374 (22 g, 0.95 m) and 1 〇% Pd/C (1 · 1 g) in water (220 ml) at 50 ° C heated suspension. The suspension was stirred at 50 ° C for 3 hr, cooled to room temperature and stirred overnight. After 18 hours, the suspension was heated at 50 ° C and a portion of aq. NH4C00H (8 g <RTIgt; After 1.5 hours, a second portion of NH4COOH in water (8 g, 0 · 1 26 m) 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, and the reaction mixture was filtered in celite without stirring. The -63- paper scale was applied to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). ----------------- (Please read the notes on the back and fill out this page) 1297682 V. Description of invention (62) Wash with water (30 ml), water layer with acetic acid Ester extraction (3 times). The combined organic phase was washed with brine and concentrated in vacuo to give crude pyrrolidone as white crystals (1······ The two diastereomers were obtained by preparative HPLC separation (ethanol/heptane: 1:1) after recrystallization 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, 1 5.0, 1 7.0, 17.1, 21.2, 21.4, 24·8 (2 degrees). Form B is typically characterized by a diffraction peak at 6.50, 11.25, 19.22' 23.44, 28.47, 29.94 (20 degrees). 2.5.3. Synthesis of 5-hydroxy-4-propyl-furan-2-one

f==\ H2 , Pd/C 5% H0 乂〇Χ〇 EtOAc 5 _ hydroxy-4 propyl - 5H-furan-2-one 373 (15 g, 0.1 mol), ethyl acetate ( 260 ML) and Pd/C 5% were placed in the Barr device. The mixture was degassed and oxygen was introduced at a pressure of 3 5 p s i . The mixture was then stirred vigorously at 2 5 °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+). Example 3. Synthesis of 4-substituted 2-oxy-pyrrolidinobutamine by alkylation of 2-oxy-pyrrolidine using ethyl 2-bromo-butyrate. Synthesis of 3 . 1 -4-substituted 2-oxy-pyrrolidine 3.1.1.a.1. Preparation of 3-(3-chlorophenyl)-2-propane acid vinegar 375 · -64- 1297682 A7 B7 V. Description of invention (63

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-chloro; the aldehyde 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 (EtOAc)屮NMR (250MHz, (CD, small SO): 1.30 (t, 3H) ^ 4.25 (q, 2H), 6.70 (d, 1H), 7.40 (m, 2H), 7.50 - 7.70 (m, 2H), 7.85 ( S (wide), 1H). 2.1.1.a.2. Other methods: -------- order --------- (please read the notes on the back and fill out this page) Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printed 376

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. 3.1.1.b. Preparation of ethyl 3-(3-chlorophenyl)-4-nitrobutanoate 3 77 -65- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1297682 A7 B7 Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 5, Inventions (64)

Equipped with a reflux condenser, a magnetic stirrer and a dropping funnel in a 500 ml three-necked flask under an inert atmosphere, 1 g (447 mmol, 1 equivalent) of 3-(3-chlorophenyl)-2 - Ethyl acrylate 375 was dissolved in 127 ml (2.37 mol, 5 equivalents) of nitromethane. 70.9 ml (447 mmol, 1 equivalent) of diazabicycloundecene was added dropwise while maintaining the temperature below 2 rc (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 aqueous HCl and brine and then twice twice. The combined organic phase was dried over magnesium sulfate, filtered and concentrated to dryness to afford 1 2 8 . 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. llc: Preparation of 4-amino 3-(3-chlorophenyl)butyric acid ethyl ester 378:

196 g (733 mmol) of 3-(3-chlorophenyl)-4-nitrobutyric acid ethyl ester 377 was dissolved in 200 ml of ethanol in a 2-liter pressure flask under an inert atmosphere. Add 200g of pre-dried (3 times, ethanol) Raney nickel in 700ml of ethanol and mix it in a hydrogenation reactor at a maximum hydrogen pressure of 20pS1 (strong-66- this paper scale applies to China National Standard (CNS) A4 Specifications (210 X 297 mm) ------------------- Order --------- (Please read the notes on the back and fill out this page) 1297682 Printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative

A7 B7 Description of invention (65) Strong exothermic reaction, requiring ice/water cooling) ° The mixture is degassed and filtered in a Celite/Nor He pad filter. The filtrate is concentrated in vacuo to obtain 1 36. 7 g thick 3 78 , 78% yield' was used for the next step. 3. 1 .1 .d: Preparation of 4-(3-chlorophenyl)-2-pyrrolidone 379:

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)butanoic acid ethyl ester 3 7 8 was dissolved in 2 0 0 ml of toluene, the mixture was refluxed for 30 minutes. The solution was concentrated to dryness. EtOAc m. GC/MS : 1 97 / 1 97M+· 3 . 1 . 1 . f · Preparation of 2-[4-(3-chlorophenyl)-2-oxy-1-pyrrolidinyl]butanoic acid ethyl ester 380

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 3 79 was dissolved in 1.4 liters of acetonitrile. 64 ml (100.7 g, 556 mmol, 2 equivalents) of methyl 2-bromobutanoate was added and the temperature was raised to 50 °C. Divided into 22. 24 g (556 mmol, 2 when -67- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the phonetic on the back? page)

1297682 A7 B7 V. INSTRUCTIONS (66) Amount of sodium hydride, the temperature is raised to 65 °C. The mixture was stirred at 50 ° C for an additional hour. The mixture was concentrated to dryness. The combined organic phases were dehydrated with magnesium sulfate, filtered and concentrated to dryness. The residue was purified by preparative LC (1 kg of EtOAc, petroleum ether / ethyl acetate ' 70: 30) to afford 56.7 g. !H NMR (250MHz, (CD3)2SO) : 0.80 - 1.〇〇(m,3H), 1.60 -1. 90( 2H, m) ' 2.35 - 2. 55 ( m,lH : partially overlapping with solvent) , 2.60 - 2.90 (m, 1H: partially overlapping 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: Preparation of 2-[4-(3-chlorophenyl)-2-oxy-1-pyrrolidinyl]butanamine 381:

CI

(Please read the notes on the back and fill out this page.) The Ministry of Economic Affairs, the Intellectual Property Office, the employee consumption cooperative, printed a 1 liter three-necked bottle equipped with a reflux condenser and a magnetic stirrer, 56.7 grams (192 millimoles). Ethyl 2-[4-(3-chlorophenyl)-2-oxy-1-pyrrolidinyl]butanoate 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 afford 50 g of pure 381, 97.8%, 82.2 g of mixture of diastereomers 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). -68-

This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public H 1297682 A7 B7 5. Invention description (67) (Please read the back note and then fill out this page) Four compounds are obtained from toluene crystals respectively 6. 79 g, 13.79 g, 15.84 g and 14.84 g 202,203, 204 and 205, 7 2% total yield. Example 4: alkylation/cyclization of 4-bromo via the use of 2-amino-butylimamine Synthesis of 4-substituted 2-oxo-pyrrolidinium butylide with -3-substituted-but-2-enoate. Synthesis of 4 . 4 -bromo-3 -substituted-but-2-enoate , alkylation and reduction 4 · 1 · 1 . 3 - substituted ethyl crotonate ethyl bromide 4-bromo-3-(2-thiophenyl)-but-2-enoic acid ethyl ester 382 synthesis represented

Ministry of Economic Affairs, Intellectual Property Office, Staff and Consumers Cooperative, printed in 2-liter three-necked flasks with mechanical stirring of 2-thiophenyl-3-yl-but-2-en-ethyl ester 383 (32.88 g, 0.211) Mole), N-bromosuccinimide (37, 56 g, 0.211 mol) and 2,2^ aza-indole-isobutyronitrile (3.46 g, 0.021 mol) in carbon tetrachloride (600 The degassed solution of cc) was refluxed for 6 hours, cooled to room temperature and stirred 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: 6 5 / 3 5 ")) to obtain 4-bromo-3-(2-sulfur Ethyl phenyl)-but-2-enoate 382 (36.72 g, 78%). 4 NMR ( 2 50MHz, (CDC13) : 3.80 ( s, 3H), 4.95 (s, 2H), 6 · 25 (s, lH), 7 · 10 (dd, 1H), 7.35 (d, 1H) , 7.45 (d, 1H). 4.1.2. Alkylation with 2-amino-butylimamine to 2-[2-oxy-4-(2-thiophenyl)-1-pyrrolidinyl] The synthesis of indoleamine 71 is representative: -69- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1297682 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

V. Description of the invention (

4 . 1 . 2 . 1 . Step 1: alkylation-cyclization in a 1 liter three-necked flask under argon, 4-bromo-2-thiophenyl-3-yl-but-2-3⁄4, methyl 382 ( 36.72 g '0.134 mol), (S)-2-amino-butylimamine ([α] 2 5d: 19.09 °; 31.6 g, 0.270 mol) in THF (3 50 mL) 20 hours. The suspension was filtered and concentrated in vacuo to give crude crude ethylpyrrolidone 384 and 385 (43.47 g) which was used in the next step. The crude pyridone can be isolated and usually a mixture of double bonds (3, 4 and 4, 5 olefins, the former being the main isomer).屮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. 0 (s (width), 1H), 7 · 15 (dd, 1H), 7 · 40 (s (width), 1H), 7 · 50 (d, 1H), 7 · 85 (d,1H). 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 (1 4 g, 0.044 mol), CoCM 〇. 〇 62 g '0.0005 mol) in ethanol (100 ml) - diethylene glycol dimethyl ether (65 ml) cooled to 0 ° C solution. After 0.75 hours -70- This paper scale applies Chinese National Standard (CNS) A4 specification (21〇X 297 mm) --------^--------- (Please read the back first Note: Please fill out this page again) 1297682 A7 B7 V. INSTRUCTIONS () 'The reaction mixture is heated under reflux for 48 hours. During this period, three portions of NaBH4 (1.75 g '0.045 m) and c are added sequentially every hour. 〇Cl2 (0.062 g, 0.0005 mol) until the disappearance of the starting material. The reaction mixture was cooled to room temperature, then hydrolyzed with saturated ammonium chloride, extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo to give crude pyrrolidone, which was purified by silica gel column chromatography (dichloromethane/methanol) :9 7 / 0 3 ( v / v )) Obtained 4.15 g of 2-[2-oxy-4-(2-cyanophenyl)-1-Pit π-decyl]butanamine (38%) . The stereoisomer mixture was purified by image-phase-by-column column chromatography (Hsin/ethanol) to obtain two diastereomers (2S) - 2 - [ 2 -oxy-4 - ( 2 -thienyl) Isopyrrolidinyl]butanamine 71 (recrystallized from ethyl acetate) and 72 (recrystallized from 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 Gram, recrystallized from ethyl acetate) and 85 (0.44 g, recrystallized from ethyl acetate) of two diastereomers. 4.2. Synthesis of azidophenylpyrrolidone--------^--------- (Please read the notes on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Office staff consumption Co-production of (2S)-2-[4-(3-azidophenyl)-2-oxy-1-pyrrolidinyl]butanamine 86 as a single enantiomer is represented by:

A7

1297682 70 V. INSTRUCTIONS () 4.2. 1. Synthesis of aniline 4 · 2 · 1 · 1 · Step 1: Borrowing 4-bromo-3 -( 3 -nitrophenylbutan-2-ene-acid methyl ester The synthesis of 386 alkylated (S)-2-aminobutylideamine 386 was carried out as described in § 4.1.1. 1H NMR (250 MHz, (CD3) 2SO): 1 · 30 (t, 3H), 4.20 ( q, 2H), 5.15 (s, 2H), 6.45 (s, lH), 7.75 (dd, 1H), 8.10 (dd, lH), 8.25 (dd, lH), 8.45 (d, 1H). Follow the experimental procedure in § 4. 1.2.1. (59%) LC/MS: 290 (MH+). 4 · 2 · 1 · 2 . Step 2: Reductive in a 2.5 liter pressure bottle under an inert atmosphere, 7.22 Grams (0.025 mol) 3 87 and palladium/charcoal (10% w/w, 〇. 2 g) are dissolved in ethanol (1 liter) and the mixture is hydrogenated at a hydrogen pressure of up to 20 ps in a bar hydrogenator. After 1 hour, the mixture After degassing, it was filtered on a Celite/Nollet pad, and the filtrate was concentrated in vacuo to obtain crude pyrrolidone, which was purified by silica gel column chromatography (dichloromethane/methanol: 93 s (v/v)). a mixture of diastereomers, which is purified by a phase-by-column column chromatography (hexane/ethanol) and hydrochloric acid in ethanol (using After synthesizing the hydrochloride salt, (2S) - 2 - [ 4 - ( 3 • aminophenyl b 2-oxy-1-pyrrolidinyl]butanamine 90 (0.88 g, recrystallized from ethanol) was obtained. And 9 1 (1 · 2 1 g, recrystallized from ethanol) two diastereomers, which are hydrochloride. 4.2.2. Synthesis of phenyl azide 86. Under a argon in a three-necked flask , sodium nitrite (0.232 g, 0.0037 mol) in water (1.5 ml) solution is added dropwise to (2S) - 2 - [ 4 - ( 3 -amino benzene - 72 - this paper scale applies to China Standard (CNS) A4 specification (210 X 297 mm) Packing -------- set--------- (Please read the notes on the back and then fill out this page) Ministry of Economic Affairs Intellectual Property Bureau Employee Consumption Cooperative Printed 1297682 A7 B7

V. Description of the invention (yl)-2-oxo-1 -pyrrolidinyl]butanthine 90 free base (〇. 8 g, 0.003 1 mol) was cooled to i〇M (6.5 ml) 0 ° C solution. After 0.5 hours at room temperature, NaN3 (0.220 g, 0.003 7 m) was added to water (2 ml), and the mixture was stirred at 0 ° 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 was dehydrated with magnesium sulfate and concentrated in vacuo to give crude EtOAc (EtOAc: EtOAc (MeOH): After obtaining 0.42 g of (2S)-2-[2-oxy-4-(3-azidophenyl)-1-pyrrolidinyl]butanamine 86 as the single enantiomer 86 (48%) . 4.3 · Synthesis of (2S )-2-[4-(3-Amino-2,4,6-tribromophenyl)-2-oxo-1-pyrrolidinyl]butanamine 107

A solution of Ph3PCH2PhBr3 (2870 g, 0.048 mol) and 90 (0.420 g, 0.0016 mol) in dichloromethane (1 ml) and methanol (5 ml) in a three-necked flask under argon with sodium bicarbonate ( 0.407 g, 0.048 mol) was stirred for 4 hours (orange solution) at room temperature. The reaction mixture was filtered and concentrated in vacuo tolululululululululululululululululululululu ). -73- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) —---------------------- f Please read the notes on the back first. Fill in this page) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1297682 A7 B7 V. Description of Invention (72. 4.4. (2S)-2-[4-Methyl-2-oxy-1-pyrrolidinyl] Synthesis of guanamine 35 and 36

The 35 and 36 series were obtained by using a racemic mixture 389 in a stationary phase using ethanol and a solvent as a solvent. 3 5 is obtained by white crystal after recrystallization from i - P r 2〇E t . The 36 series was obtained as white crystals after recrystallization from diethyl ether. Example 5. Derivatization of 4-substituted 2-oxy-pyrrolidinium via 1 - [ 1 -(aminoalkyl)propyl]-5-oxy-3 -indolepyridylcarboxylate 11 amine. 5 . 1 . 1 - [1 -(Aminocarbonyl)propyl]-5-oxy-3-pyrrolidinecarboxylate 1 1 / 1 2 Synthesis CV^CCX>M· MeOOC _rY——Humble ----------Install--------Book--------- (Please read the notes on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative The printing of this transition is described in § 7.0. 1 to make two esters 1 1 and 12 . 5 . 2 . 1 - [ 2S - 1 -(Aminocarbonyl)propyl]-5-oxy-3-pyrrolidinecarboxylic acid 48

I. MeOH, NaOH nhj 2. HCI 48 in a three-necked flask under argon, IN sodium hydroxide (126 ml) solution was added to -74- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) )

1297682 A7 _ B7 V. INSTRUCTIONS (73) Enantiomerically pure ester 1 1 (22 · 62 g, 0 · 1 mol) was cooled in methanol to 彳c. After 5 hours at this temperature, the reaction was acidified with EtOAc (1 mL, EtOAc). (g), recrystallized from acetonitrile to give enantiomerically pure 1 - [ 2 S - 1 -(aminoalkyl)propyl]-5-oxy-3-pyrrolidinecarboxylic acid 48. 5 · 3 . Synthesis of ( 2S ) - 2 _ [ 4 - ( 1,3,4 -oxadiazol-2-yl)-2-yloxy-1 -pyrrolidinyl]butanamine 50

Step 1: Reacting with hydrazine in a three-necked flask under argon, a solution of ester 1 1 (3 g, 0. 01 mol) and hydrazine hydrate (0.7 ml) was stirred in ethanol (3 ml). hour. The yellow solution was then concentrated to give a crude EtOAc (yield: 372 g, 79%). GC/MS: 228 (M+). Step 2: Synthesis of oxadiazole in a three-necked flask under argon, crude 醯肼 39 1 (this patent, 3 g, 〇. 0 1 3 mol), triethyl orthoformate (2 ml) and p-toluene A solution of the acid (0.010 g) was heated at 110 ° C for 24 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to give crude oxadiazole, which was purified by chromatography on silica gel (dichloromethane/A-75- paper scale applicable to Chinese National Standard (CNS) A4 specification (210 X 297 mm) ) ------------------- Order --------- (Please read the notes on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Bureau staff consumption Co-operatives printed 1297682 A7 B7 V. Description of invention (74. Alcohol: 95 / 05 (v/\〇) obtained (2S)-2-[4-(l,3,4-oxadiazol-2-yl) - 2-oxo-1 -pyrrolidinyl]butanamine 50 (0.32 g) is an oil. 5 . 4 . Synthesis of 1,3,4-dicarbazole derivatives 1 , 3, 4 - The carbazole derivative is derived from 肼391. For example, 2-[2-oxy-4-(5-sulfanyl-1,3,4-oxadiazol-2-yl)-1-pyrrolidinyl] Indoleamine 51 is obtained by reacting 肼391 with CS2 and potassium hydroxide in ethanol. 5.5. Synthesis of 4-amino-pyrrolidin-2-one 392

+

394 〇 (S'

H2, Pd/C h2n’

-----------Install.-------Set--------- (Please read the notes on the back and fill in this page) Ministry of Economic Affairs Intellectual Property Bureau staff consumption Co-operative printing 5.5.1. Step 1: Synthesis of carbamate 39 3 in a three-necked flask under argon, enantiomerically pure 1-[2S-1-(aminocarbonyl)propyl]-5 -oxy-3-pyrrolidinecarboxylic acid 48 (19.06 g, 0.089 mol), diphenylphosphonium azide (26.9 g, 0.097 mol) and triethylamine (π. 5 ml) in acetonitrile (225 The solution of cc) was heated at S5 ° 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 is purified by silica gel chromatography (acetic acid B-76- This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1297682 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7

7 S V. INSTRUCTIONS () Ester/Methanol/Ammonium Hydroxide: 95 /04/0 1 (v/v)) Obtained two diastereomeric urethane 394 (2.64 g, 9 3%) and 393 (11.9g, 42%). As for 393: NMR (250MHz, (CDCl3): 0.9 〇 (t, 3H), 1.30 - 1.90 (m, 2H), 2.35 (dd, lH), 2.75 (dd, lH), 3.30 (dd, lH), 3,75(m,lH) ^ 4.30 - 4 . 50(m , 2H), 5.10(s,2H), 5.35(s, (width), 1[1), 5.11(5(width), 1[1 ), 60.40 (3 (width), 1 [1), 7.30-7.45 (m, 5H). 5.5.2. Step 2: Synthesis of 4-amino-pyrrolidin-2-one 392 in a 0.25 liter pressurized bottle In an inert atmosphere, 11.9 g (0. C37 mmol) of 393 and palladium/charcoal (10% w/w, 0.2 g) were dissolved in ethanol (300 ml) and the mixture was subjected to a hydrogen pressure of up to 20 pS1 in a Bar hydrogenator. Hydrogenation. After 20 hours, the mixture was degassed, filtered on a pad of Celite/Nollet, and the filtrate was concentrated in vacuo to give crude amine, which was recrystallized from toluene to give 2-[4-amino-2-oxy-1- Pyrrolidinyl]butanamine 392 (6.99 g, quantitative yield) 5.6. Synthesis of 4-pyrrolidin-2-one 223

2-[4-Amino-2-oxo-1-pyrrolidinyl]butanamine 393 (6.99 g, 0_037 mol), dimethoxytetrahydrofuran (5.53 g ' 0.041 in a three-necked flask under argon A suspension of pyridine (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 room temperature, concentrated in vacuo and the crude product was purified on silica gel by chromatography -77-. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). --------^ -------11 (Please read the notes on the back and fill out this page) 1297682 A7 B7 V. Description of invention (76) (dichloromethane / decyl alcohol: 95 /05 (v/v)) obtained 223 oil (2. 67 g 30.1%). (Please read the notes on the back and fill out this page) 5.7. Bromination of 4-pyrrolyl-pyrrolidin-2-one 223

The 0.25 liter three-necked flask was magnetically stirred with '2S-4-pyrrole-pyrrolidin-2-one 223 as a single enantiomer (1.8 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 234 (1.05 g, 67%) as a white solid. Further, dibromopyrrole 237 was obtained using the same experimental procedure and 2 equivalents of N-bromo-butanediamine. 5.8. Synthetic Department of Tetrazolyl Derivatives Ministry of Intelligence, Intellectual Property Office, Staff Consumer Cooperatives Printed separately for § 5.6, 2-[4-Amino-2-oxy-1-pyrrolidinyl]butanamine and original Triethyl formate, sodium azide and acetic acid are reacted to obtain 2-[2-oxy-4-(1Η-tetrazol-1-yl)-1-pyrrolidinyl]butanamine 67. 5.9. Synthesis of (4H-1,2,4-tetrazol-4-yl) derivatives Further to § 5.6, 2-[4-amino-2-oxy-1-pyrrolidinyl]butane Amine reacts with pyridine and 1,2-anthracene (dimethylamino)methylene) oxime to obtain -78- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) Ministry of Economic Affairs Intellectual Property Bureau Employees' Consumption Cooperatives Printed 1297682 A7 B7 77 V. INSTRUCTIONS () 2_[2-Oxo- 4-(4Η-1,2,4-triazol-4-yl)-1-pyrrolidinyl]butanamine 65 and 66. Example 6. Synthesis of 4-substituted 2-oxy-pyrrolidinobutamine by olefination of a third butoxycarbonyl)propyl]-5-oxy-3-pyrrolidinecarboxaldehyde 396. 6.1. Synthesis of 1-[1-(Tertidinoxycarbonyl)propyl]-5-oxy-3-pyrrolidinium Carboxaldehyde 396 Step 1: 2 -Aminobutyrate Condensate with Methyl Itaconate NH ,

rVV

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 (83) A solution of cc, 0.59 mol) was refluxed in methanol (400 mL) for 20 h. The mixture was stirred at room temperature for 20 hr, then concentrated in vacuo. EtOAc mjjjjjjjjjj Methyl butyloxy)propyl]-5-oxy-3-pyrrolidinecarboxylate 397 (81.6 g, quantitative yield). 1/1 mixture analysis of l-[(lS)-l-(2nd-butoxycarbyl)propyl]-5-oxy-3-pyrrolidinecarboxylate 397: 4 NMR (250 MHz, (CD3) 2SO): l.〇5(t,3H), 1.44(s,9H),1.6〇-1 .65( m,1H), 1.65-1 .90( m,1H) , 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). In addition, the reaction can also be used with racemic 2,2-dimethylethyl-2-amino--79- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 public) ---- ----Book-------- (Please read the note on the back and then fill out this page) 1297682 V. Description of the invention (μ) Butyrate to obtain racemic butylamine, the yield is similar. Step 2: Synthesis of 醯396.

396 Reduction of ester 397 to alcohol 398 is carried out using the procedure described in § 7.0.2. Using 397 as a single enantiomer, a mixture of two enantiomers or 1 / 1 / 1 / 1 of 4 stereoisomers The mixture is carried out. As for the 1/1 diastereomer mixture of (2S)-2-[4-(hydroxymethyl)-2-oxy-1-pyrrolidinyl]butyrate tert-butyl ester 398: GC/MS: 257 M+ oxime is oxidized to aldehyde 396 in a three-necked flask under argon, (2S)-2-[4-(hydroxymethyl)-2-oxy-1-pyrrolidinyl]butyric acid tert-butyl ester 398 ( </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; </RTI> </RTI> <RTIgt; The suspension was stirred at room temperature. 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) Obtained 2.03 g of 1-[(lS)-l-(t-butoxycarbonyl)propyl]-5-oxy-3-pyrrolidinecarboxaldehyde 396 (41%). Alternatively, the racemic ester can be used to obtain the racemic aldehyde with similar yields. 1 - [( 1 S ) -1 -(t-butoxycarbonyl)propyl]-5-oxy-80- 1297682 V. Description of the invention (79) 1/1 mixture of -3-pyrrolidinecarboxaldehyde 396 Analysis: 4 NMR (250MH, (CDC13): 0.91 (t, 3H), 1.44 (s, 8H), 1. 55-1.77 (m, 1H), 1.9〇-2.15 (m, lH), 2.63-2.82 (m, 2H), 3.47-3.61 (m, lH), 3. 65 - 3.79 (m, 1 H), 3.83 - 3.94 (m, one of the diastereomers), 4.48- 4.62 (m, lH), 9.74 (s (width), 1 Η) 6.2· l-[(lS)-l-(t-butoxycarbonyl)propyl]-5-oxy-3-pyrrolidinecarboxaldehyde 396 Alkylation reaction 6.1.2. Synthesis of olefinic derivatives. Substituting § 6 . 2 · 3 ·, olefinic derivatives may be via 1 - [ ( 1 S ) - 1 -(t-butoxycarbonyl) Keb 5-oxy-3-pyrrolidinium carboxaldehyde 396 is obtained by performing Wit tig olefination reaction in the presence of a strong base. For example, (2S)-2-(2-oxy-4- 2,2-(Dimethyl)ethyl vinyl-1-pyrrolidinyl)butyrate is obtained by reacting aldehyde 396 with PhPChBr and n-BuLi in THF. 6.2.2. Via using Ph3P/CBi*4 olefin Alternative to § 6 · 2 · 3 ., halovinyl derivatives can be via 1 - [ ( 1 S ) - 1 - ( Butoxycarbonyl)propyl]-5-oxy-3-pyrrolidinecarboxyaldehyde 396 is obtained by the Wittite reaction in the presence of a phosphine and a halomethane. For example, (2S)-2-(2-oxy-4- (2,2-Dibromovinyl)-1 -pyrrolidinyl)butyric acid 2,2-(dimethyl)ethyl ester is obtained from CB η of aldehyde 396 in the presence of triphenylphosphine. . By using (Me2N)3P/CF2Br2 olefination

9M -81- Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1297682 A7 B7 Ο Λ V. Invention Description () (2S )-2-(2-Oxo- 4-(2,2-difluorovinyl)- The synthesis of two diastereomers of 2,2-(dimethyl)ethyl 399 of 1-pyrrolidinyl)butyrate is representative. In a three-necked flask under argon, (Me2N; hP (89.8 g, 0.55 mol) was added to a solution of CF2Br*2 (58 g, 0.25 mol) in THF (280 mL) at -78 ° C (white appeared) Precipitate) and warm to room temperature. Aldehyde 396 is added dropwise to a pre-formed scale salt as a 1/1 mixture of diastereomers (35.2 g, 0.138 mol) in THF. After the reaction mixture was filtered through celite and concentrated in vacuo. The reaction mixture was diluted with hexanes, washed with brine, dried over magnesium sulfate and concentrated in vacuo to give crude hexanes. 99/01 (v/v)) obtained 34.6 g of (2S)-2-(2-oxy-4-(2,2-difluorovinyl)-1-pyrrolidinyl)butyric acid 2,2-( a 1/1 mixture of diastereomers of dimethyl)ethyl ester 399 (87%). 4 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 , 2H partially overlaps with solvent), 3.00 - 3.35 (m, 2H), 3.45 - 3.5 5 (m, lH), 4.20-4.40 (m, lH), 4.60 (ddd, lH - diastereomeric Construct), 4.75 (ddd, lH another diastereomer). 6.2.4· Using (nBu)3P/CChF olefination instead of § 6.2.3. The halovinyl derivative may be via 1 - [ ( 1 S ) - 1 -(t-butoxycarbonyl)propyl]- 5-Oxo-3-pyrrolidinium Carboxaldehyde 396 is obtained by the Wittite olefination reaction in the presence of a phosphine and a halomethane. 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 η-ΒιηΡ are reacted, followed by sodium hydroxide to dephosphorylate the intermediate ethylene-based iron. -82- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) -n an nn —Bi 一口·· tat emmmm l MW. 1297682 V. INSTRUCTIONS INSTRUCTION (81) 6.2.5. 4 - Synthesis of a ketone-stranded n-butanone In addition, a 4-cyano-pyrrolidone derivative can be via 1 - [( 1 S ) - 1- (third The butoxycarbonyl)propyl]-5-oxy-3-pyrrolidinium carboxaldehyde 396 is reacted with hydroxylamine and then reacted with selenium oxide. 6. 3 · 2 · 2 -Dimethyl-ethyl ester amination 6 · 3 · 1 · Deprotection with trifluoroacetic acid and aminolysis. (2S) - 2- (2-oxy- 4-(2) , 2-difluorovinyl)-1 -pyrrolidinyl) The synthesis of two diastereomers of butanamine 213 and 222 is representative:

Step 1: 2. 2 -(Dimethyl)ethyl ester is deprotected in a three-necked bottle, stupid, (23)-2-(2-oxy-4-(2,2-difluorovinyl) 1-1-(2-methyl)ethyl butyrate 399 (3 1.8 g, 0.110 mol) in trifluoroacetic acid (170 ml) and dichloromethane (500 ml) The /1 mixture of diastereomers was stirred at room temperature for 20 hours. The reaction mixture was evaporated to dryness. The residue was taken up in toluene and evaporated to dryness eluting eluting eluting eluting eluting of LC/MS: 234 (MH+) Step 2: Activation and Ampholysis _ Add ClCOOEt (23 mL, -83- 1297682 V, inventor (82) 0.24 旲) to a three-necked flask under mechanical stirring with argon to The acid mixture (25.6 g '0.11 mol) was cooled to a solution of -irc in dichloromethane (250 mL) and triethylamine (33.7 ml). The reaction mixture was stirred at -1 Torr: for 1.5 hours, and then gaseous ammonia was passed through the solution while maintaining the temperature below 0 °C. The suspension was stirred at 0 ° C for 1 hour, warmed to rt. filtered and filtered. Purification of crude decylamine on silica gel by column chromatography (dichloromethane/ethanol 99/01 (v/v)) afforded 23 g (2S)-2-(2-oxy-4-(2,2-) Fluorine-vinyl)-1-pyrrolidine []-based) butyric acid 2,2-(dimethyl) ethyl ester 1:1 mixture of diastereomers Purification (hexane/ethanol) gave the two diastereomers 2 1 3 (1 〇. 1 g recrystallized from isopropyl ether) and 222 (1 1 · 2 g, recrystallized from isopropyl ether). 6 . 3 . 2 · Deprotection can also be carried out using bromocatechol borane. The four diastereoisomers of 2-(2-oxy-4-(2,2-dimethylvinyl)-1-pyrrolidinyl)butanamine 1 6 3 via 2 - ( 2 - 1 / 1 / 1 / 1 diastereomer of 2,2-(dimethyl)ethyl oxy-4 - (2,2-dimethylvinyl)-1 -pyrrolidinyl)butyrate The mixture is reacted with bromocatechol borane to obtain an acid, which is then aminated under the conditions described in § 6 · 3 · 1 (step 2). 6.4. Synthesis of acetylenic derivatives 6.4 · 1 · 2 - ( 4 -ethynyl-2-methoxy-1 -pyrrolidyl)butanamine 206 / 207

-84- 1297682 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 B7 83 V. Invention Description () In a three-necked flask under argon, n-butyllithium (1.6 M in hexanes, 1 16 ml) was added to a 1:1 mixture of two diastereomers of 2-[4-(2,2-dibromovinyl)-2-oxy-1-pyrrolidinyl]butanamine (stereochemistry undecided, 10.95 A solution of gram '0.031 mol) cooled to -7 8 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 0 /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-oxo-1-pyrrolidinyl)butanamine 206 (0.84 g, from toluene) was obtained by sequential purification by conjugation 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-Pyryryridinyl] Butanamine 47 is obtained by reacting 2 equivalents of potassium tert-butoxide in THF at a low temperature (-5 ° C to 0 ° C). 6.4.2. Synthesis of 2-(4-propyn-1-yl-2-oxo-1-pyrrolidinyl)butanamine 2 80

Adding -85- paper to 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)) The scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ----------------- (Please read the notes on the back and fill out this page) 1297682 A7 B7 -r- 84 V. INSTRUCTIONS () to CuCN (0.82 g) and LiC1 (0.78 g) in THF (10 ml) in -1 (TC solution. Another three-necked flask under argon, NaH (80%) In oil, 0.097 g) was added to 2-(4-bromo-ethynyl-2-yloxy-1-pyrrolidinyl)butanamine (1 g, 0.0036 mol) in THF (20 mL) at -10. A solution of C was then added with zinc chloride (0.50 g). The guanamine solution was then added dropwise to the -781 cooled organic cuprate. The reaction mixture was stirred at this temperature for 3 hours and allowed to warm to room temperature overnight. After the aqueous solution of saturated ammonium chloride is hydrolyzed, the aqueous layer is extracted with dichloromethane, dehydrated with magnesium sulfate, filtered and concentrated in vacuo to give crude alkyne, and crude acetylene is obtained by phase-by-phase chromatography (ethanol/hexane) to obtain 2- (4-C Alkyn-1-yl-2-oxy-1-pyrrolidinyl)butanamine 280. 6.5. Hydrogenation of olefinic pyrrolidone with 2 - [ 4 - ( 2,2-difluoroethyl)-2 - The synthesis of 1 / 1 / 1 / 1 mixture of four diastereomers of oxy-1 -pyrrolidinyl]butanamine 1 57 is representative: (Please read the notes on the back and fill out this page)

The Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative is printed in a 0.2 liter pressure bottle under an inert atmosphere, 1 gram (0.0043 mmol) 156 and palladium/charcoal (10% w/w, 0.2 gram) dissolved in Ethanol (50 ml), 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 fluorohexane, which was recrystallized from toluene to give 2-[4-(2,2-difluoroethyl) -2-oxy-1 -pyrrolidinyl]butanamine 1 57 4 diastereomers 1 /1 /1 /1 mixed-86- This paper scale applies to China National Standard (CNS) A4 specification ( 210 X 297 public interest) 1297682 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives printed A7 B7 85 I, invention description () compound, white solid (0.75 g). 6 . 6 · 2 - [ 4 - ( 5 -methyl - 1 , 3 - 坐 _ 2 _ yl ) _ 2 _ oxy _ 丨 _ pyrrolidine yl] butyl amide 62 and 63 synthesis

Step 1: Hydrolysis of the ester In a two-necked flask, add 1 N sodium hydroxide (39 ml) to 丨_[

Methyl (t-butoxycarbonyl)propyl]-5-oxy-3-pyrrolidinecarboxylate 397 is a 1/1/1/1 mixture of 4 stereoisomers (10 g, 0.035 mol) A solution of methanol (100 ml) at 20 °C. The solution was stirred for 5 hours, evaporated to dryness and acidified to pH = 1 using 1N hydrochloric acid. The aqueous layer was extracted with EtOAc EtOAc (EtOAc)EtOAc. 1H NMR (250MHz, (CD3) 2S 〇): 0.80 (t, 3H), 1.44 (s, 9H), 1.55-1.60 (m, lH) '1.70-1.95 (m, lH), 2.40-2. 55 ( m, 2H partially overlaps with the solvent), 3.10 - 3 . 55 (m , 1 H partially overlaps with the solvent), 4.45 (dd, 1H). Step 2: Synthesis of indoleamine 401 in a three-necked flask under argon, ethyl chloroformate (0.50 ml, 0.005 mol) was added to acid 400 (0.678 g, 0.0025 mol) in dichloromethane (1 mL and Triethylamine (0.77 ml) solution cooled at -20 ° C. Reaction Mix -87- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) ------- ----衣--------Book--------- (Please read the note on the back and fill out this page) 1297682 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 * v 86 I, invention instructions () Stir at -1 °C for 1 · 5 hours, then propargylamine (Ο. 36 ml) was added to the solution while maintaining the temperature below 0 ° C. Suspension at 0 ° C was stirred for 1 hour, warmed to room temperature 'filtered and the filtrate was evaporated in vacuo. The crude amine was purified on silica gel eluting with column chromatography (dichloromethane / methanol 98 s (v / v)). The indoleamine 40 1 is a 1 / 1 / 1 / 1 mixture of four diastereomers. *H NMR ( 250 MHz ^ (CDb) = SO) : Ο . 80 (t, 3H), 1.44 (s, 9H) ), 1.55-1.65 (m, lH), 1.70-1.95 (m, lH), 2.40-2.55 (m, lH partially overlaps with solvent) , 3 . 0 - 3 . 70 (m, 3H partially overlaps with solvent), 3.70-3.90 (m, 2H), 4.45 (m, lH), 8.45 (m, lH). Step 3: Synthesis of oxazole 402 A solution of decylamine 402 (0.77 g, 0.002 5 mol) in acetic acid (40 ml) and Hg (OAc) 2 (0 · 048 g, 0.000 1 5 m) was refluxed for 1 hour under argon. The reaction was cooled to room temperature, concentrated in vacuo and purified with EtOAc EtOAc EtOAc.EtOAc. Purification by HPLC (hexane/ethyl acetate 50 / 50 (v / v) to obtain pure carbazole 402 (0.15 g, 20%). GC/MS: 308 (M+) can be similar to 6.3. Conversion to 62 and 63. 6.7. Synthesis of tetrazole 6.7.1. Synthesis of unsubstituted tetrazole

This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ---------------I---------- (Please read the back first Note: Please fill in this page) 4. 1297682 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed V. Invention Description (87) In a three-necked flask under argon, racemic 膪40 3 ( 2.66 g, 0.011 Mo A solution of NaN3 (4.8 g, 0.07 3 mol) and triethylamine hydrochloride (10.12 g) was heated in DMF (60 mL) at 110 °C for 2 hr. Cool to room temperature and evaporate in vacuo. The crude product was purified by chromatography on silica gel (dichloromethane / methanol / acetic acid: &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&&&&& A 1/1/1/1 mixture of constructs. LC/MS : 295 (MH+) ◦ 6 . 7 . 2 . Alkylation of tetrazole

A suspension of racemic tetrazole 404 (5.6 g, 0.019 mol), potassium carbonate (2.88 g) and methyl iodide (1.3 ml) in DMF (60 mL) at room temperature under argon Stir for 29 hours and evaporate in vacuo. The crude mixture was purified by chromatography on silica gel (MTBE / hexane: 50 / 50 (v / v)) to afford two res. Oiled. LC/MS: 309 (MH+). 6. 8. Synthesis of thiazole 6.8.1. Synthesis of thioindole-69. This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm). ---- (Please read the notes on the back and fill in this page) 4 1297682 V. Description of invention (88)

6.8.1.1. Ammonia solution of 397 In a 5 liter three-necked flask equipped with a reflux condenser and a magnetic stirrer, add 10 g (0.035 mmol) of 397 dissolved in 1 ml of methanol. Gaseous ammonia was maintained at room temperature for 1 day through the solution of the solution, while occasionally saturated with ammonia. After the reaction was completed, the solution was concentrated in vacuo to give crude EtOAc (EtOAc, EtOAc)屮NMR (250MHz, (CD〇2S0): 0.85 (t, 3H), 1.44 (s, 9H), 1.55-1.60 (m, lH), 1.70-1.95 (ιη, 1Η), 2.40-2.60 (〇 1,21*1 partially overlaps with the solvent), 3.00-3.70 (111,1[] partially overlaps with the solvent), 4.35-4.45 (111,1[1), 6.95 (8 (wide), 11^), 7.40〇 (wide), 1 Η). 6.8.1.2. Synthesis of thioguanamine 408 in a three-necked flask under argon, crude amide 407 (6 g, 0.022 mol), P4Sn) (4.93 g, 0.011 mol) and sodium bicarbonate (3.73 g) The solution in acetonitrile (100 ml) was stirred at 5 ° C for 6 hours. The reaction mixture was filtered, concentrated with EtOAc EtOAc (EtOAc) · 7 grams '60%). GC/MS: 286 (M+). 6.8.2. Synthesis of substituted thiazoles -90- 1297682 A7 B7 89 V. Description of invention ()

The Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs printed in a three-necked flask under argon. Thioamine 408 is a mixture of four diastereomers of 1 /1 /1 /1 (this patent, 1.25 grams, 0· 005 mol), a solution of aluminum oxide (12 g) and 1-bromo-2-dimethoxyprop-2-ene (0.85 ml) in toluene (100 ml) was refluxed for 3 hours. The reaction mixture was cooled to room temperature, filtered and evaporated in vacuo tolulululululululu GC/MS: 3 24 (M+). 6.8.3. Synthesis of unsubstituted thiazoles Additional unsubstituted thiazoles can be formed via thioguanamine 408 with alumina and bromo-acetamidine (formed in situ from bromo-2,2-dimethoxyethane under acidic conditions). The reaction is obtained. 6.8.4. Synthesis of 1,2,4-thiadiazol-5-yl derivatives In addition, 1,2,4-thiadiazol-5-yl derivatives can be sequenced with N,N_ via thioguanamine 408 The reaction of dimethyl-acetamide dimethyl acetal is followed by cyclization in the presence of pyridine. 6.9. 2-[2-Oxo-4-(3-pyridylcarbonyl)-1-pyridolidinyl]butyric acid Synthesis of 2,2-dimercaptoethyl ester 410

-91- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) r Pack--------Book·--- -----· 1297682 V. INSTRUCTIONS (9()) In a three-necked flask under argon, 'S0C12 (0.56 ml) was added to acid 400 (1.90 g, 0.007 mol) to toluene (20) ML) solution at room temperature. The reaction mixture turned yellow for 1 hour to reflux. After cooling to room temperature, PdCl 2 (PPh small (0.25 g, 0.00035 mol) and 3-trimethylstannyl-pyridine (1.7 g, 0·007 mol) was added in one step. After chilling to room temperature, it was quenched with water. The aqueous layer was extracted with dichloromethane, and the organic phase was washed with brine. The mixture was dehydrated with magnesium sulfate, filtered and concentrated in vacuo (3·2 g). Purification by column chromatography (dichloromethane/methanol 9 7 / 0 3 ( v / v )) to obtain 1 · 3 g of ketone 4 1 0 as a mixture of 4 diastereomers / 1 / 1 / 1 / 1 mixture LC/MS: 333 (MH+). Example 7 · 2 -( 4 -substituted-2-ethoxy-pyrrolidinyl)-butanamine via activation of 2-(4-hydroxymethyl-2-oxo-pyrrole Substituted synthesis of pyridine bupholamine 7. 0. Synthesis of starting alcohol 7.0.1 Synthesis of ester decylamine 7.0.1.a. l-[(lS)-l-(amino forging) Synthesis of methyl propyl]-5-oxy-5-3⁄4 succinylcarboxylate 1 1 /1 2

In a 10 liter three-necked flask equipped with a mechanical stirrer and a reflux condenser, under an argon atmosphere, 1 226 g (1 2 mol, 1 equivalent) of (2S)-2-aminobutylide and 1912 ML (2150 g, 13.2 mol, 1.1 equivalent) of dimethyl itaconate was dissolved in 6 · 13 liters of methanol. The mixture was adjusted to reflux for 1 hour and slowly cooled to 20 °C over 4 hours. Filtration, precipitation with methanol wash-92- 1297682 Α7 Β7 Description of the invention (91 Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, concentrated organic phase to dry to obtain 3 · 28 3 grams of crude intermediate 74%. The 20 liter three-necked flask of the R ashig column and the steamed I arm is in an inert atmosphere, the crude intermediate and 84.7 g (89 1 mmol, 0.1 equivalent) The 2-hydroxypyridine was dissolved in 1 升.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 in the reaction flask reached 112 ° C. The mixture was cooled and concentrated to dryness. 2, 187 g of crude decylamine is obtained as a ratio of 57.5/ 42.5 of diastereomers. The two diastereomers are separated by preparative liquid chromatography like phasing (like padding AD 100) *500 mm, ethanol/water 99.9:0.1), the extract was concentrated to dryness to obtain 968 g of crude 12 (first elution) and 1,05 2 g of crude 11 (second elution). Crude 1 2 was not crystallized, It was dissolved in 1.5 liters of ethanol and used for further use. Crude 11 was recrystallized from 2 liters of ethyl acetate to give 676 g of pure 11. Methyl l-[(lS)-2-amino-1-methyl-2-oxyethyl]-5-oxy-3-pyrrolidinecarboxylate, 1 - [( 1 S ) - 1 - ( Methylaminocarbonyl)butyl]-5-oxy-3-pyrrolidinecarboxylate, b{( 1 S ) - 1 -[(methylamino)carbonyl]propyl b 5-oxy-3 Methyl pyrrolidinecarboxylate was prepared in a similar manner. 7.0. 2. Synthesis of alcohol-decylamine 7.0. 2.a·(2S)-2-[4-(hydroxymethyl)-2-oxy-1 -Pyridylpyridyl]butanamine 6 synthesis °V- 〇7.02 a. 〇β in a 2-liter three-necked flask equipped with a mechanical stirrer and a reflux condenser at -93- This paper scale applies to Chinese national standards ( CNS) A4 size (210 X 297 mm) Please read the note on the back first

921297682 Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing A7 Description (In an inert atmosphere, 133 g (583 mmol), 1 equivalent) (2S)-2-(4-methoxycarbonyl-2-oxy-1 - Pyrrolidinyl] Butyridinium oxime in 200 ml of ethanol was added to 300 ml of ethanol, and the mixture was cooled to 〇. (:. Then divided into several portions of 6.6 cc (1. 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, again reduced to 2 - 41. Add 240 to 1 hour A saturated solution of 1 ml of ammonium chloride was added, followed by the addition of 1 20 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 x 70 ml of ethanol, and the organic portion was concentrated to dryness to obtain 1 48 g of crude 6. suspended in 300. Methylene chloride was stirred for 30 minutes, filtered, washed with 2 x 100 ml of dichloromethane and dehydrated to give 141 g of pure 6,98%. In addition, (2S)-2-[4-(hydroxymethyl)-2 -oxy-1-pyrrolidinyl]propanamine, (2S)-2-[4-(hydroxymethyl)-2-oxy-1-pyrrolidinyl]pentanylamine, (2 S) - 2-[4-(hydroxymethyl)-2-oxy-1-pyrrolidinyl N-methylbutyramine is prepared in a similar manner. 7.1. Direct conversion to synthesis using triphenylphosphine 7.1.1. Synthesis of (2S)-2-[4-(iodomethyl)-2-oxy-1-pyrrolidinyl]butanamine 10 is equipped with a mechanical stirrer and a reflux condenser of 10 liters In a 3-necked flask, 400 g (2 mol, 1 equivalent) of (2S)-2-[4-(hydroxymethyl)_2-oxy-1-pyrrolidinyl]butanamine 6 was dissolved in 3 under an inert atmosphere. Acetonitrile. Add 62 9 g-94- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -----------*装-------- Order --------- (Please read the note on the back and fill out this page) 1297682 A7 B7 93 V. Invention Description (Please read the note on the back and fill in this page) (2.4旲耳' 1.2 equivalents of triphenylphosphine, followed by 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 that, 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 The precipitate was filtered and washed with 3 x 1 L of water. The combined aqueous phase was treated with 1 kg of sodium chloride and extracted with 6 x 1 L of dichloromethane. The organic phase was dried over magnesium sulfate, filtered and concentrated to dryness 482. Gram 1 0. Crystallized from toluene. A number of harvests were recrystallized from ethyl acetate to obtain 4 2 5 g of pure 1 0, 68%. , (2S)-2-[4-(iodomethyl)-2-oxy-1-pyrrolidinyl]-N-methylbutyramine 146 , (2S)-2-[4-(iodine Methyl)-2-oxo-1 -pyrrolidinyl]propanamide 110,(2S)-2-[4-(iodomethyl)-2-oxy-1-pyridinyl]pentanamide 1 05,( 2S ) - 2 - [ 4 -(Bromomethyl)-2-oxy-1-pyrrolidinyl] Butanamine 8, (2S)-2-[4-(chloromethyl)-2 -oxy-1-pyrrolidinyl]butanamine 30 was prepared in a similar manner. 7.1.2. Synthesis of (2S)-2-[2-oxy-4-(phenoxymethyl)-i-u ratio succinyl] butylamine 1 8

Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives are printed in a 5 〇 ml three-necked flask equipped with a magnetic stirrer and a dropping funnel in an inert atmosphere, 1 gram (5 mM, 1 equivalent) (2S) _ 2 _ [Heart (hydroxymethyl)-2-oxo-1-pyrrolidinyl]butanamine 6 dissolved in 20 ml of THF and cold-95- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 Public Love) 1297682 A7 B7 94 V. INSTRUCTIONS () (Please read the notes on the back and fill out this page) but go to 0 °C. 5 1 7 mg of phenol, 〇. 87 ml (960 mg) of diethyl azodicarboxylate and 1.44 g of triphenylphosphine (5.5 mmol, ΐ·ι equivalent) were added thereto 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 a substituted methanesulfonate 7. 2·1. U-[(lS)-l-(aminocarbonyl)propyl]oxy-3-pyrrolidinyl}methylmethanesulfonate 37 synthesis

In a 4-liter three-necked flask equipped with a mechanical stirrer, a dropping funnel and a reflux condenser, in an inert atmosphere, 141 g (569 mmol, 1 equivalent) printed by the Ministry of Economic Affairs Intellectual Property Office Staff Cooperatives (2S) - 2 - [ 4 -(Hydroxymethyl)-2-oxy-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 equivalents) of methanesulfonium chloride in 190 ml of dichloromethane over 1 hour. 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 was washed with methylene chloride and EtOAc evaporated Prepared by preparative LC purification (1 kg of decidant 'dichloromethane/ethanol, 1 〇〇 ·· 〇 to 96:4) to obtain 109 g of pure 37, 69%. -96- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1297682 Α7 Β7 95 5. Inventive Note () In addition, { 1 - [( 1 s ) - 1 -(aminocarbonyl) Propyl 5 _oxy-3 _pyrrolidinyl}methyl-4-methylbenzenesulfonate 3 1 was prepared in a similar manner. Synthesis of 7 · 2 · 2 · ( 2S ) - 2 - [ 4 -(azidomethyl)· 2 -oxy-1 ·pyrrolidinyl]butanamine 32

(Please read the notes on the back and fill out this page.) In a 3-liter three-necked flask equipped with a mechanical stirrer and reflux condenser, under an inert atmosphere, 89.7 g (322 mAh, 1 equivalent) {iris) , Aminocarbonyl)propyl]-5-oxy-3-pyrrolidinylmethylmethanesulfonate 37 was dissolved in 300 ml of acetonitrile. 27.3 g (419 mmol, 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. Add 3 · 1 g (48 mmol, 0.2 equivalents) of sodium azide and continue to reflux 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%. (2S )-2-[4-(fluoromethyl)-2-oxy-1-pyrrolidinyl]butanamine 44, (2S) - 2- [ 2-oxy-4-(1H-tetrazol-1-ylmethyl)-1-pyrrolidinyl]butanamine 3 9,( 2 S ) - 2 - [ 2 -oxy-4 - ( 1 Η -tetrazole-1 -ylmethyl)-1-pyrrolidinyl]butanamine 40,(2S)-2-[2-oxy-4-(1Η-1,2,4-triazole-1 - Methyl)-1 -pyrrolidinyl]butanamine 5 5,( 2S ) - 2 - [ 2 -oxy-4 - ( 1 Η - 1,2,3 -triazol-1-ylmethyl) -1 -pyrrolidinyl]butanamine-97- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1297682 V. Invention description (96) 56,(2S)-2-{4 -[(isopropylsulfanyl)methyl]-2-oxy-1-pyrrolidinyl agmatine 24,(2S)-2- [2-oxy-4-(1-pyrrolidinyl) Methyl)-1 -pyrrolidinyl]butanamine 1 5,( 2S ) - 2 - [ 2 -oxy-4 -( 4 -thiomorpholinylmethyl)-1 -pyrrolidinyl]butanamine 1 7 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 ·{ 1 - [( 1 S ) - 1 -(Aminocarbonyl)propyl]-5-oxy-3-pyrrolidinyl}methyl nitrate 38

8.10 g (26 mmol, 1 equivalent) (2S)-2-[4-(iodomethyl)-2 in a 500 ml 3-neck flask equipped with a mechanical stirrer and reflux condenser under an inert atmosphere. -oxy-1 -pyrrolidinyl]butanamine 1 oxime is dissolved in 25 ml of dinitrile. 4.86 g (28.6 mmoles, 1.1 equivalents) of silver nitrate was added and the mixture was adjusted to reflux. After 2 hours, 4,400 mg (2.8 mmol, 0. 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. Recrystallization from 50 ml of ethyl acetate gave 4.13 g of pure 358. 7 · 3 · 2 . 2 - { 4 -[(benzyloxy)methyl]_ 2 -oxy-indole-pyrrolidinyl} Butanamine 1 53 / 1 54 Synthesis -98- 1297682 A7 B7 97 V. Description of the invention ()

7 · 3 . 2 . a . ( 2S ) - 2 -丨 4 -[(benzyloxy)methyl]-2-oxy-1-pyrrolidinyl}butyric acid tert-butylate synthesized with magnetic stirring And a reflux condenser and a 100 ml 3-necked flask under an inert atmosphere, 1.1 g (60%, 27.5 mmol, 1.1 equivalents) of sodium hydride suspended in 60 ml of DMF, and 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]butyric acid tert-butyl ester 398 in 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) to give a mixture of butyl butyl ester and benzyl ester. Two wash points, 37% total yield. This is used for the next step 7 . 3 . 1 . b. 4 NMR (250MHz, (CDCl3): 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) 7.3.2.b· 2-(4-[( Synthesis of benzyloxy)methyl]-2-oxo-1-pyrrolidinyl}butanamine 153-99- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (please read first) Precautions on the back side Fill in this page) - Pack---- · 11111 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1297682 A7 B7 V. Invention Description (^) (Please read the note on the back and fill out this page) In a 50 ml 3-neck flask equipped with a magnetic stirrer and a reflux condenser under an inert atmosphere, 1.75 g of the benzyl ester rich elution fraction was dissolved in 20 ml of methanol, then the gaseous ammonia was passed through the solution and the saturated solution at room temperature. Maintained for 24 hours, and occasionally saturated with ammonia again. After the reaction is completed, the solution is concentrated to dryness and purified by preparative LC (1 kg oxime, dichloromethane/methanol, 98:2 to 90:10) to obtain two kinds of diastereomers. Isomers. Ministry of Economic Affairs Intellectual Property Office employees The consumer cooperative was printed in a 25 ml 3-neck flask equipped with a magnetic stirrer and a reflux condenser under an inert atmosphere, and 1. 24 g of the third butyl ester rich elution fraction was dissolved in 16 ml of dichloromethane/trifluoro a 1:1 mixture of acetic acid, and maintained at 〇-5 ° C for 24 hours. The solution was concentrated to dryness and the residue was dissolved in dichloromethane (1 ml). To -20 ° C. Add 780 μl of ethyl chloroformate dropwise, and let the mixture slowly warm to -1 (TC) for 1.5 hours. Gaseous ammonia is passed through the solution for 5 hours. The mixture is maintained at room temperature. After filtration, the precipitate was washed with dichloromethane, and the combined organic extracts were concentrated to dryness and purified by preparative LC (1 kg EtOAc, methylene chloride/methanol, 98:2 to 90:10). The enantiomers were obtained by combining the first and second eluting diastereomers obtained in two rounds and crystallization from toluene to obtain 305 mg of pure 153 and 480 mg of pure 154, 11% of the total yield, respectively. (2S)-2-{4-[(5-Methyl-1H-1,2,3-triazol-1-yl)-

-100-

Synthesis of benzyl]-2-oxo-1-pyrrolidinyl)butanamine 52 nW:n· 32々 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1297682 A7 B7 Ministry of Economic Affairs Printed by the Intellectual Property Office Staff Consumer Cooperative 99 V. INSTRUCTIONS () 1 g (4.44 mmol, 1 eq.) in a 50 ml 3-neck flask equipped with a magnetic stirrer and reflux condenser under an inert atmosphere ( 2S)-2-[4-(Azidomethyl)-2-oxy-1-pyrrolidinyl]butanamine 32 was suspended in 20 ml of toluene. 1.55 g (4.88 mmol, 1.1 equivalents) 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 EtOAc, methylene chloride/methanol / ammonium hydroxide, 94. 5: 5: 0. 5). Suspended in 15 ml of water and lyophilized to obtain 240 mg of pure 52 cumin oil, 42%. 7.3.4. Synthesis of (2S)-2-[4-(isothioacylmethyl)-2-yl-1-ylidene-1 D-pyridyl]butanamine 49

In a 500 ml pressure bottle, under an inert atmosphere, 900 mg of 10% ginseng and attached to charcoal were suspended in 100 ml of ethanol. Add 8.7 g (38 mmol) of (2S)-2-[4-(azidomethyl)-2-oxy-1-pyrrolidinyl]butanamine 32 in 150 ml of ethanol and a mixture of The Bar hydrogenator was hydrogenated for 2 hours at a hydrogen pressure of up to 30 ps 1 . The mixture was degassed, filtered over a pad of Celite/Nollet, and the residue was washed with 2×100 ml of ethanol and the filtrate was concentrated to dryness to obtain 7·9 3 g of crude 4 1 2 , 100% yield. The next step. GC/MS: 199 (M+). 7.3.4.a. Synthesis of (2S)-2-[4-(isothiocyanatomethyl)-2-oxy-1-pyrrolidinyl]butanamine 49 -101- This paper size applies to China National Standard (CNS) A4 Specification (210 X 297 mm) ----------------- (Please read the notes on the back and fill out this page) A7 1297682 ____B7__ 100 V. DESCRIPTION OF THE INVENTION () In a 100 ml 3-necked flask equipped with a magnetic stirrer and a reflux condenser under an inert atmosphere, 4 · 5 g (22.7 mmol, 1 equivalent) of thiocarbonyl imidazole was dissolved in 25 ml DMF, the mixture is cooled to Ot:. 4.53 g (22.7 mmol, 1 equivalent) of (2S)-2-[4-(aminomethyl)-2-ethoxy-1 -pyrrolidinyl]butanamine 4 was added dropwise over 30 minutes. 1 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 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 Obtained 3. 1 g of crude 49. 2 g of pure 49 (22%) was obtained by crystallization from 15 ml of ether, filtration and residue (1·9 g) from 15 ml of acetonitrile. 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 known to 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. -102- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) --------^--------- (Please read the notes on the back and fill in On this page) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1297682 A7 B7 V. INSTRUCTIONS (1()i In the table, the column "Synthesis Number" indicates the actual synthesis for the most important compounds. It may take a slight change to obtain a similar Compounds. These modifications are within the skill range of the organic synthesis industry. (Please read the notes on the back and fill out this page.) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed -103- This paper scale applies to Chinese National Standards (CNS) )A4 size (210 X 297 mm)

Claims (1)

1 细 82 VI. Patent application No. 901 05824 "2-oxy-1-pyrrolidine derivative, its preparation method and use" patent case (amended in March 2008) VI. Patent application scope 1 with formula I Compound, Wherein X is -C〇NR5R6; R2, R2a, R4 and R4a are each hydrogen; A2 is oxygen; R1 is hydrogen; Ci-6 yard or -CH2-Rla where the ruler is "aryl"; R3 is Cl-6 Base, C2.6 cantyl, C2.6 fast radical, phenyl, sulfhydryl, thienyl, furyl, pyrrolyl, pyridyl, Cw alkylthio, arylsulfonyloxy, arylsulfonyl R3a is hydrogen or Cm alkyl; R5 and R6 are hydrogen; and wherein Cm alkyl may be independently selected from halo, tetrazolyl, phenyl, vinyl, nitroxyl, decyl, iso Substituted by a group of thiocyanate groups; 1297682 VI. Scope of Application The group may be substituted by one or more substituents selected from halogen, benzyl, decyloxy, benzyl or azide; C2 -6 alkenyl and C2·6 alkynyl may be substituted with at least one halogen; and when the compound is a mixture of isomers, x is -C〇NR5R6, and R1 is hydrogen, methyl, ethyl or propyl , the substitution on the batch of the pyridyl ring is not a mono-, di-methyl or mono-ethyl; and when R1 and R31 are hydrogen and X is -CONR5R6, R3 is not methyl or in the para position by a halogen atom Substituted phenyl; and the combination of formula I Not: (2S)-2-[(4R)-2-oxy-4-propylpyrrolidinyl]butanamine; and (2S)-2-[(4S)-2-oxy-4- Or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, wherein Ri is hydrogen or a C.6 alkyl group. And a compound of claim 1, wherein R3a is hydrogen. 5. A compound according to claim 1, wherein R3 is selected from the group consisting of G-6-alkyl and a substituent of a haloalkenyl group. 6. The compound of claim 1 which is a pure enantiomer. 7. The compound of claim 1 wherein R1 is attached to a carbon atom In the case of asymmetry, it is in the "S" configuration. 8. The compound of claim 1 is selected from the group 1927682. Patent application (2S)-2-[4-(bromomethyl)-2-oxy-1-pyrrolidinyl] (2S)-2-[(4R)-4-(iodomethyl)-2-oxypyrrolidinyl]butanamine; (2S)-2-(2-oxy-4-phenyl- (2S)-2-[4-(iodomethyl)-2-oxy-1-pyrrolidinyl]butanamine; (23)-2-[4-(chlorine) Methyl)-2-oxo-1-pyrrolidinyl]butanamine; {1-[(1S)-1_(aminocarbonyl)propyl]-5-oxy-3-pyrrolidinyl}methyl -4-methylbenzenesulfonate; (2S)-2-[(4R)-4-(azidomethyl)-2-oxypyrrolidinyl]butanamine; 2-[4-(2 ,2-dibromovinyl)-2-oxo-1-pyrrolidinyl]butanamine; {l-[(lS)-l-(aminocarbonyl)propyl]-5-oxy-3- Pyrrolidinyl}methyl nitrate; (2S) -2· [2-oxy-4-(1H-tetrazole-; l-ylmethyl)· 1 -pyrrolidinyl]butanamine; 2 - ( 2-ethoxy-4-vinyl-:1-pyrrolidinyl)butanamine; 2-{2-oxy-4-[(phenylsulfonyl)methyl]-1-pyrrolidinyl} Guanidine; (2S)-2-[(4R )-4-(2,2-dibromovinyl)-2-oxypyrrolidinyl]butanamine; (2S) - 2- [(4S) - 4-(2,2-dibromovinyl)-2-oxypyrrolidinyl]butanamine; (2S) - 2 ·[ 4 -(isothiocyanate) Methyl)-2-oxy-1-pyrrolidinyl] 1297682 VI. Patent application: Butylamine; 2-[2-Oxo-4-(1,3-thiazol-2-yl)-1pyrrole (2S)-2-[2-oxy-4-(2-thienyl)-1-pyrrolidinyl]butanamine; (2S)-2-[4-(2- Methoxyphenyl)-2-oxo-pyrrolidyl]butanamine; (2S)-2-[4-(3-methoxyphenyl)-2-oxy-pyrrolidinyl]butane (2S)-2-[4-(4-azidophenyl)-2-oxy-1-pyrrolidinyl]butanamine; (%)-2-[2-oxy-4- (3-thienyl)-1-pyrrolidinyl]butanamine; (2S)-2_[4-(3-azidophenyl)-2-oxy-pyrrolidinyl]butanamine; 2S)-2-[2-oxy-4-(3-thienyl)-1-pyrrolidinyl]butanamine; (23)-2-[(43)-2-oxy_4-vinyl Pyrrolidinyl]butanamine; (2S)-2-[(4R)-2-oxo-4-vinylpyrrolidinyl]butanamine; 2-[4-(2-bromophenyl)_2 Oxy-1-pyrrolidinyl]butanamine; 2-[(2-oxy-4-(3.pyridyl)-1-pyrrolidyl)butanamine; (2S) - 2 - ( 4 - [ 1,r -biphenyl]-4-yl-2-oxo-1 -pyrrolidinyl)butanamine; (2S)-2-{4-[(methylsulfanyl)methyl]-2-oxy- 1-pyrrolidinyl}butanamine; 1 2 -[ 4 -(iodomethyl)-2-oxy-; 1-pyrrolidinyl]butanamine; (2S)-2_ [(4R)-4- (Iodomethyl)-2.oxy-1-pyrrolidinyl]pent-4 - 1297682 VI. Patent application range of decylamine; (2S)-2-[(4R)-4-(iodomethyl)-2 -oxypyrrolidinyl]propanamine; 2·(2-oxy-4-propyl, 1-pyrrolidinyl)propanamine; 2-(2-oxy-4-propyl-1-pyrrole Butyryl)butanamine; 2 -(2-oxy-4-pentyl-1-pyrrolidinyl)butanamine; (23)-2-[(41〇-4-(iodomethyl)-2 -oxypyrrolidinyl]-1^methylbutyramine; (2S)-2-(4-pentopent-2-yloxy-1-pyrrolidinyl)butanamine; (2S)-2- (4-ethyl-2-oxy-1-pyrrolidinyl)butanamine; 2-[4-(2,2-difluoroethyl)-2-oxy-1-pyrrolidinyl]butane Amine; 2-{4-[(2)-2-fluorovinyl]-2-oxy-1-pyrrolidinyl}butanamine; 2-[4-(2.methyl-1-propenyl) -2-oxy-1·pyrrolidinyl]butanamine; 2 -( 4 -butyl-2-oxy-1 -pyrrolidinyl)butanamine; 2 - [4-(cyclopropylmethyl)-2-oxy-1-pyrrolidinyl]butanamine; 2-(4-isobutyl-2-yl-1-yl-l-l-butyryl) Amine, 2-[4-(4-chlorophenyl)-2-oxy-1-pyrrolidinyl]butanamine; 2-[4-(3-chlorophenyl)-2-oxy-1 -pyrrolidinyl]butanamine; 2-{2-oxy-4-[2-(trifluoromethyl)phenyl]-pyrrolidinyl}butanamine; 2-[4-(2-fluoro Phenyl)·2-oxy-1-pyrrolidinyl]butanamine; 2 _[ 4 -( 3 -methylphenyl)-2-oxy-1-pyrrolidinyl]butanamine; (2S )-2-[2-oxy-4-(2-phenylethyl)-1-pyrrolidinyl]butyl 1297682 6. Patent application range of decylamine; (2S)-2-[4-(3-bromo) Phenyl)-2-oxo-1-pyrrolidinyl]butanamine; 2-{4-[3,5-fluorenyl(trifluoromethyl)phenyl]-2-oxy-pyrrolidinyl} Butylamine; 2-[4-(3,4-dichlorophenyl)-2-oxy-1-pyrrolidinyl]butanamine; 2-[4-(2,4-dichlorophenyl) -2-oxo-1-pyrrolidinyl]butanamine; 2-[4-(2-furyl)-2-oxy-1-pyrrolidinyl]butanamine; (2S)-2- [2.oxy-4-(3-phenylpropyl)-1-pyrrolidinyl]butanamine; (2S)-2-[4-(3,5-dibromophenyl)-2-oxo Base-1-pyridyl Butyryl]butanamine; 2-[4-(3,4-dichlorophenyl)-2-oxy-1-pyrrolidinyl]butanamine; 2 - (2-oxy-4-propyl) -1-卩β11 base) butylamine; 2 ·[ 4 -( 3 -chlorophenyl)-2-oxy-1-pyrrolidinyl]butanamine; 2 - ( 4 -ethynyl-2 -oxy-pyrrolidyl)butanamine; 2-[4-(2-fluorophenyl)-2-oxy-1.pyrrolidinyl]butanamine; 2 - [ 4 - ( 2 -fluoro Phenyl)·2-oxy-1-pyrrolidinyl]butanamine; (2S)-2-[4-(cyclopropylmethyl)-2-oxy-1-pyrrolidinyl]butanamine (2S)-2-[(4S)-4-(2,2-difluorovinyl)-2-oxypyrrolidinyl]butanamine, (23)-2-[2-oxy-4 -(3,3,3-trifluoropropyl)-1-pyrrolidinyl]butanamine; 1297682 VI. Patent application 2-[4-(3-methylphenyl)_2-oxy-1- (2S)-2-[4-(cyclopropylmethyl)-2-oxy-1-pyrrolidinyl]butanamine; (2S)-2-[(4R )-4-(2,2-difluorovinyl)-2-oxypyrrolidinyl]butanamine; (2S) - 2-[2-oxy-4-(1H-pyrrole-1-yl) -1 -pyrrolidinyl]butanamine; (2S)-2-(4-allyl-2-oxy-pyrrolidyl)butanamine (2S)-2-[4-(2-Iodopropyl)-2-oxy-1-pyrrolidinyl]butanamine; (2S)-2-(4-allyl-2-oxy- 1-pyrrolidinyl)butanamine; (23)-2-[2-oxy-4-(2-oxypropyl)-1-pyrrolidinyl]butanamine; (23)-2-[ 4-(2-bromo-111-pyrrol-1-yl)-2-oxy-1-pyrrolidinyl]butanamine; (2S)-2-(4-methyl-2-oxy-4- Propyl-1-pyrrolidyl)butanamine; (21〇-2-[4-(2,2-dichlorovinyl)-2-oxy-1-pyrrolidinyl]butanamine; 2 - [4-(Bromoethynyl)·2-oxy-1-pyrrolidinyl]butanamine; 2-[(4S)-4-(2,2-difluoropropyl)-2-oxypyrrolidine Butylamine; (2S)-2-[4-(bromoethynyl)-2-oxy-1-pyrrolidinyl]butanamine; * 2-(2-oxy-4-propyl- 1-pyrrolidinyl)pentaamine; 3-cyclopropyl-2-(2-oxy-4-propyl-1-pyrrolidinyl)propanamine; 2 - (2-oxy-4-propane) Benzyl-1 -pyrrolidinyl-3 - ( 1,3 -thiazol-4 - Ϊ 297682 ^, the base of the patent application) acrylamide; and 2 - ( 2 · oxy-4 · propyl - 1 - pyrrolidine (4-)-pentenylamine; includes all isomeric forms and mixtures thereof or pharmaceutically acceptable salts thereof. 9. A mammalian body in need of treatment for epilepsy, seizures, seizure disorders, convulsions and other neurological disorders including bipolar disorder, snoring, depression, anxiety, migraine, trigeminal neuralgia, chronic pain, neuropathic pain A pharmaceutical composition comprising at least one of the compounds of claims 1 to 8. The pharmaceutical composition of claim 9, wherein the compound of the formula I is a compound as in claim 8 of the patent application. 11. A pharmaceutical composition according to claim 9 or 10 for use in the treatment of epilepsy, dysmenorrhea, bipolar disorder or migraine. 12·—a compound of the formula AA-II, Wherein X, Ri, R2, R3, R4, R2a, and R4a are as defined in the first item of the patent application range and Q1 is a C.6 alkyl group. A compound according to claim 12, which is selected from the group consisting of ethyl 3-({[(ια-ι-(aminocarbonyl)propyl)amino)methyl)hexanoate hydrochloride, 3 -({[(1 幻_1-(aminocarbonyl)propyl)amino}methyl) butyl hexanoate 1297682 6. Patentized range of hydrochloride and 3-({[(15&gt;1-(amine) Group of carbonylcarbonyl)propyl]amino}methyl)hexanoic acid isopropyl esters, including all isomeric forms and mixtures thereof or pharmaceutically acceptable salts thereof.