TW200538436A - (2S)-2-[(4s)-4-(2, 2-difluorovinyl)-2-oxopyrrolidin-1-yl]butanamides and their uses - Google Patents

Abstract

The invention concerns 2-oxo-1-pyrrolidine derives of formula I, wherein the substituents are as defined in the specification, as well as their use as pharmaceuticals. The compounds of the invention are particularly suited for treating neurological disorders such as epilepsy.

Description

200538436 IX. Description of the invention: [Technical field to which the invention belongs] The present invention relates to a 2 · oxy-1 · Pit pyridine derivative, a preparation method thereof, a pharmaceutical composition containing these compounds, and a use thereof as a medicine. [Prior art] European Patent No. 01 62 036 B1 discloses the compound (S) -a-ethyl-2-oxy · 1-pyrrolidinacetamidine, which has the international non-exclusive name levetiracetam ° Levetiracetam is a L-compound that has been disclosed as a protective agent for the treatment and prevention of hypoxic and ischemic injuries of the central nervous system. This compound is also effective in the treatment of epilepsy, for which the d-enantiomer (R)-α -ethyl-2 -oxy-1 -pyrrolidinacetamidine (also Patent case No. 0 1 65 9 1 9 (B1) is completely lacking in activity (AJ GOWER et al., European Journal of Pharmacology, 121, (1 992),: 193-203). Racemic α-ethyl-2-oxy-1 -pyrrolidinacetamidine and its analogs are known from British Patent No. 1 309 692. U.S. Patent No. 3,459,738 discloses 2-oxy-1 -pyrrolidineacetamide derivatives. European Patent No. 0 645 1 39 B1 discloses the anxiolytic activity of levetiracetam. PCT Application No. PCT / EP00 / 1 1 808 discloses the use of levetiracetam for the treatment and / or prophylactic treatment of bipolar disorders, migraine, chronic or neuropathic pain, and levetiracetam and A combination of at least one compound that induces a neurosuppressive effect via a GABAa receptor mediator. Unexpectedly, some levetiracetam analogs, particularly compounds with further substitutions in the pyrrolidone ring, were found to have significantly improved therapeutic properties. 200538436 [Summary of the Invention] In a characteristic aspect, the present invention provides a compound having Formula I or a pharmaceutically acceptable salt thereof

Where X is-CA ^ W or -CAWR7 or -CA1-!? 8 or CN;

A1 and A2 are respectively oxygen, sulfur or -NR9; R1 is hydrogen, alkyl, aryl or -CH2-Rla where Rla is aryl, heterocyclic, halogen atom, hydroxyl, amine, nitro or cyano; R2 R3 and R4 are the same or different and each is hydrogen, a halogen atom, a hydroxyl group, a fluorenyl group, an amine group, a nitro group, a nitroxy group, a cyano group, an azide group, a carboxyl group, a fluorenylamino group, a sulfonic acid, a sulfonic acid, Fluorenylamine, alkyl, alkenyl, alkynyl, ester, ether, aryl, heterocyclic or oxygen derivative, sulfur derivative, amine derivative, fluorenyl derivative, sulfonyl derivative or sulfinyl sulfenyl derivative.

1 ^^ 3 and 1? 43 are the same or different and each is hydrogen, halogen atom, alkyl, alkenyl, alkynyl or aryl; R5, R6, R7 and R9 are the same or different and each is Hydrogen, hydroxy, alkyl, aryl, heterocyclic or oxygen derivatives; and R8 is hydrogen, hydroxy, fluorenyl, halogen atom, alkyl, aryl, heterocyclic or fluorene derivatives; but 1 ^, 1 ~ 3 , At least one of 1-4, 1 ^, 1 ^, and 1 ^ is not hydrogen; and when the compound is a mixture of all possible isomers, X is -CONR5R6, A2 is oxygen, and R1 is hydrogen, and A Group, ethyl or propyl group

200538436 Generation non-mono-, di- or tri-methyl or mono-ethyl; and when R], R2, R'R2a, R3a and R4a are each hydrogen, A2 is oxygen and X is co-NR5R6 R3 is non- Is carboxyl, ester, amido, substituted oxy-pyrrolidine, hydroxy, oxo derivative, amine, amine derivative, methyl, naphthyl, phenyl optionally substituted with oxygen derivative or para Halogen atom substitution. In the following definitions, unless otherwise stated, R11 and R13 are the same or different and each is an acid amine group, an alkyl group, a fast group, an alcohol group, an ester, an ether, an aryl group, an aralkyl group, a heterocyclic group A cyclic or oxygen derivative, a sulfur derivative, a fluorenyl derivative, an amine derivative, a sulfonyl derivative or a sulfinyl sulfonyl derivative, each optionally substituted with any appropriate group, including but not limited to one or more A moiety selected from a lower alkyl group or another group described later as an alkyl substituent. The term "oxy derivative" is used herein to be defined to include the -0-R11 group, where Rn is as defined above, except for "oxy derivative". Non-limiting examples are alkoxy, alkenyloxy, alkynyloxy, fluorenyloxy, oxyester, oxamino, alkylsulfonyloxy, alkylsulfinyloxy, arylsulfonyloxy Aryl, aryleneoxy, quaternary oxy, quaternary oxy or heterocyclic oxy such as pentyloxy, allyloxy, methoxy, ethoxy, phenoxy, benzyloxy, 2 -Naphthyloxy, 2-pyridyloxy, methylenedioxy, carbonate. The term "sulfur derivative" as used herein is defined to include the -S-R11 group, wherein R11 is as defined above, except for "sulfur derivative". Non-limiting examples are alkylthio, alkenylthio, alkynylthio, and arylthio. The term "amino derivative" is used herein to be defined to include the -NHR11 or -1412 group, wherein the broad definition of 1 ^ 2 is as before. Non-limiting examples are one- or di-alkyl-, alkenyl ·, alkynyl- and arylamino or mixed amine. The term "fluorenyl derivative" is used herein to denote a group derived from a carboxylic acid 200538436. This definition includes the formula Rn-C0-group, where R11 may also be hydrogen as previously defined. Non-limiting examples are methyl, ethyl, propyl, propyl, isobutyl, pentyl, lauryl, heptane difluorenyl, cyclohexanecarbonyl, crotonyl, transbutenyl difluorenyl, Allyl, benzyl, naphthyl, furanyl, nicotinyl, 4-carboxybutyryl, oxalyl, acetofluorenyl, cysteamine, oxalyl. The term "sulfofluorenyl derivative" is used herein to be defined to include a group of the formula -S02-Rn, where R11 is as defined above, except for "sulfofluorenyl derivative". Non-limiting examples are alkylsulfonyl, alkenylsulfonyl, alkynsulfonyl and arylsulfonyl. The term "sulfinyl sulfenyl derivative" is used herein to be defined to include a group of the formula -S02-Rn, where R11 is as defined above, except for "sulfinyl sulfinyl derivative". Non-limiting examples are alkylsulfinylene, alkenylsulfinylene, alkynylsulfinylene and arylsulfinylene. The term "alkyl" is used herein to be defined as having a linear, branched or cyclic moiety or combination thereof and containing from 1 to 20 carbon atoms, preferably from 1 to 6 carbon atoms for acyclic alkyl groups and Cycloalkyl is a saturated monovalent hydrocarbon group of 3 to 6 carbon atoms (referred to as "lower alkyl" unless otherwise stated in the two preferred examples). The alkyl moiety may be optionally selected from 1 to 5 halogen atoms, hydroxyl groups, fluorenyl groups, amine groups, nitro groups, cyano groups, thiocyano groups, fluorenyl groups, fluorenyloxy groups, sulfonyl derivatives, Sulfenamidine derivatives, alkylamino, carboxyl, ester, ether, fluorenyl, azide, cycloalkyl, sulfonic, sulfonamido, sulfur derivatives, oxyester, oxygen Substituted by substituents of the group consisting of amido, heterocyclyl, vinyl, CV5-alkoxy, C6_1 ()-aryloxy and C6.1 ()-aryl. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, iso- or third butyl, and 2,2,2-trimethylethyl, each of which is optionally selected by at least one

200538436 Substituent substituents selected from the group consisting of halogen atom, hydroxyl group, fluorenyl group, amine group, nitro group and cyano group, such as trifluoromethyl, trichloromethyl, 2, 2, 2-trichloroethyl , 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl · 2,2,2-trichloroethyl. The term "alkenyl" is used herein to be defined to include having at least one double bond such as vinyl (= vinyl), 1-methyl-1-vinyl, 2,2-dimethyl-1-vinyl, 1-propenyl, 2-propenyl (= allyl), 1-butenyl, 2-butenyl, 3-butenyl, 4-pentenyl, 1-methyl-4-pentenyl 3-methyl-1-pentenyl, 1-hexenyl, 2-hexenyl, etc. and optionally selected by at least one selected from halogen atom, hydroxyl group, fluorenyl group, amine group, nitro group, cyano group, The group consisting of aryl and heterocyclic groups is substituted by branched and unbranched unsaturated hydrocarbon groups, such as mono- and di-halovinyl, where halogen is fluorine, chlorine or bromine. The term "alkynyl" is used herein to be defined as containing at least one carbon-carbon reference bond such as ethynyl, 2-propynyl (= propargyl), etc. and optionally selected by at least one member selected from halogen, hydroxyl, A monovalent branched or unbranched hydrocarbon group substituted with a substituent of a group consisting of a fluorenyl group, an amino group, a nitro group, a cyano group, an aryl group, and a heterocyclic group, such as a haloethynyl group. When present as a bridging group, alkyl, alkenyl, and alkynyl represent straight or branched chains, respectively. CV12 is preferably CV4-alkylene or C2.12-, and preferably C2.4-alkenyl or -alkynyl. Base part. Branch derivatives are known to have bases (such as "n", "second", "iso", etc.) specified by prefixes (such as "n-propyl", "second butyl"), and are positive unless otherwise stated form. The term "aryl" is used herein to be defined as including an aromatic hydrocarbon consisting of 1 to 3 ring free radicals and containing 6 to 30 carbon atoms via the removal of one hydrogen

200538436 For example, phenyl and naphthyl are each selectively selected from 1 to 5 halogen atoms, hydroxyl, fluorenyl, amine, nitro, cyano, fluorenyl, fluorenyloxy, sulfonyl, and sulfenyl Group, alkyl, amine, carboxyl, ester, ether, fluorenyl, azide, sulfonate, sulfonamido, alkylsulfonyl, alkylsulfinyl, alkylthio, Oxyester group, oxamido group, aryl group, C, .6-alkoxy group, C6.] 〇-aryloxy group, (: .1.6 alkyl, -haloalkyl substituted organic group substituted The aryl group is preferably a monocyclic ring having 6 to 10 carbon atoms. The preferred aryl group is a phenyl group and a naphthyl group, each of which is selected from a halogen atom, a nitro group, an amine group, and a hydrogen atom. Substituent substituents for nitrogen, CV6-alkoxy, d-6-alkylthio, 6-alkyl, C! _6-haloalkyl, and phenyl. The term "halogen" is used herein to include C 1 , Br, F, I atoms. The term "hydroxyl" is used here to represent the group -0H. The term "fluorenyl" is used here to represent the group -SH. The term "cyano" is used here to represent A group of formula -CN. The term "nitro" is used herein to represent a group of formula -N02. "Nitrooxy "The word" ono2 "is used herein. The term" amine "is used here to indicate the formula -nh2. The word" azido "is used here to indicate the formula -n3." Carboxy " The term is used here to represent the formula -C00H group. The term "sulfonic acid" is used here to represent the formula -S03H group. The term "sulfonamido" is used to represent the formula -302guanyl group. " The term "ester group" is used herein to represent the formula-C00-R11. Where R11 is as defined above, except for oxygen derivatives, sulfur derivatives, or amine derivatives. The term "ether group" is defined to include a group selected from CbM Linear or branched alkyl, or C2. 50 linear or branched alkenyl or alkynyl, or a combination thereof that borrows one or more oxygen radicals -10-

200538436 The foundation of the child. The term "amido" is defined to include the formula -conh2 or 彳 0guan1 ^] 1 or -CONRnR12, wherein R11 and R12 are as defined above.

The term "heterocyclyl" is used herein to be defined to include an aromatic or non-aromatic cyclic alkyl, alkenyl, or alkynyl moiety as defined above with at least one 0, S, and / or N atomic fork One of the carbons of the carbocyclic ring structure and 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, quinolinyl, naphthyridine Methyl, daphyl, pyrimidinyl, pyrimidinyl, quinolinyl, isoquinolinyl, isobenzofuranyl, benzothienyl, pyrazolyl, indolyl, indolyl, purinyl, isopropyl Indolyl, carbazolyl, thiazolyl, 1,2,4-thiadiazolyl, thieno (2,3-b) furanyl, furanopyranyl, benzofuranyl, benzooxazine Base, isoxazolyl, oxazolyl, thiathranyl, benzothiazolyl, or benzoxazolyl, fluorenyl, phthaloyl, quinoxaline, phenanthryl, acridinyl, pyridinyl , Phenanthroline, phenothenyl, furanyl, benzodihydropyranyl, indololinyl, xanthenyl, hypoxanthinyl, pyridinyl, 5-azacytosinyl, 5- Azauridine, triazolopyridyl, imidazopyridyl, pyrrolopyrimidyl and pyrazolopyrimidyl, these groups are optionally substituted with alkyl groups or as described above for alkyl groups. Non-limiting examples of non-aromatic heterocycles are tetrahydrofuryl, tetrahydropyranyl, hexahydropyridyl, hexahydropyridyl, hexahydropyridyl, imidazolidinyl, morpholino, morpholinyl, _Oxaspiro (4.5) dec-2-yl, P is slightly D-based, 2 · oxy-pyrrolidinyl, sugar moiety (ie glucose, pentose, hexose, ribose, fructose can also be passed Substituted) or optionally substituted with any appropriate group, including but not limited to one or more selected from lower alkyl, or other

200538436 Part of the base described for alkyl in the text. The term "heterocyclyl" also includes bicyclic, tricyclic and tetracyclic, spiro groups in which any of the aforementioned heterocyclic ring rings are fused to one or two rings, and these ring systems are respectively selected from aromatic rings, cyclohexane rings, A cyclohexene ring, a cyclopentadienyl ring, a cyclopentanyl ring, or other monocyclic heterocyclic ring, or a monocyclic heterocyclic ring here is bridged by an alkyl group such as quinaziridinyl, 7_azabicyclo (2.2.1) heptyl, 7-oxabicyclo (2.2.1) heptyl, 8-oxabicyclo (3.2.1) octyl. In the foregoing definition, it must be understood that when a substituent such as R2, R3, R4, R2a, R3a, R4a, R5, R6, R7, R8 is attached to the rest of the molecule through a heteroatom or carbonyl group, the chain is straight or branched, C !. 12 is preferably h.4 alkylene or C2.12 is preferably C2.4 alkenyl or -alkynyl bridge system is selectively interposed between the heteroatom or carbonyl group and the attachment point of the rest of the molecule. Preferred examples of X are -C00R7 or -CONR5R6, wherein R5, R6 and R7 are preferably hydrogen, (^ .4-alkyl, phenyl or alkylphenyl. Preferably X is carboxyl or -CONR7R6, where R5 And R6 is preferably hydrogen,

Cpf alkyl, phenyl or alkylphenyl especially -C0NH2. Preferably, A1 and A2 are each oxygen. Preferably, R1 is hydrogen, and alkyl is particularly (^ .12 alkyl is particularly lower alkyl or aryl is particularly phenyl. Preferred R1 is, for example, methyl, ethyl, propyl, isopropyl, butyl, iso -Or a third butyl, 2,2,2-trimethylethyl, each of which is selectively attached through a methylene bridge or is 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 ethyl R2 and R2a are each preferably hydrogen, and the halogen atom or alkyl group is particularly a lower alkyl group. -12-

200538436 Preferred examples of R2 and R2a groups are hydrogen, halogen atom, or methyl, ethyl, propyl, isopropyl, butyl, iso- or tertiary butyl, 2, 2, 3 Methylethyl or substituted with 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. Particularly at least one and preferably R2 and R2a are both hydrogen. Preferably, R3a, R4 and R4a * are other than hydrogen, particularly methyl or ethyl or aryl, especially phenyl or aralkyl, especially benzyl. Preferred examples of the R3a, R4 and R4a groups are hydrogen, halogen atom, or methyl, ethyl, propyl, isopropyl, butyl, iso- or tertiary-butyl, 2,2,2-tri Methylethyl or substituted with 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. Particularly at least one and preferably both R4 and R4a are hydrogen. 1 ^ 3 is especially hydrogen or alkyl, especially lower alkyl and most preferably hydrogen. Preferably, R3 is hydrogen, and 1.12 alkyl groups are particularly (^ .6-alkyl groups, each of which is optionally substituted with one or more substituents selected from a hydroxyl group, a halogen atom, a cyano group, a thiocyano group, or an alkoxy group. And is directly or through sulfur, sulfenyl, sulfonyl, carbonyl or oxycarbonyl and a selective -alkylene bridge, especially methylene attached to the ring; C2.6 • alkenyl or -alkynyl, especially C2.3-alkenyl or -alkynyl, each of which is optionally substituted with one or more halogen atoms; azide; cyano; amido; carboxy; triazolyl, tetrazolyl, pyrrolidinyl, pyridine , 1-oxide pyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, or hexahydropyracyl Each of them is optionally substituted with one or more substituents selected from a halogen atom, Ci.6-alkyl, and phenyl, and is directly or through carbonyl

200538436 group or h.4-alkylene bridge with special methylene attached to the ring; naphthyl; or phenyl 'phenylalkyl or phenenyl, each optionally selected by one or more halo (V6-haloalkyl, cv6-alkoxy, Ci.6-alkylthio, amine, azido, phenyl, and nitro substituents, and each is directly or through an oxygen, sulfonium Group, sulfonyloxy group, carbonyl or carbonyloxy group and optionally additionally attached to the ring through a Ci.4-alkylene bridge, particularly methylene. Yet more preferably R3 is (^ .6-alkylselective via One or more substituents selected from halogen atom, thiocyano group, azido group, alkoxy group, alkylthio group, phenylsulfonyl group; nitrooxy group; c2.3-alkenyl or -alkyne Each group is optionally substituted with one or more halogen atoms or ethenyl; tetrazolyl, pyridyl'furyl, pyrrolyl, thiazolyl, or thienyl; or phenyl or phenylalkyl, each optionally One or more substituents selected from the group consisting of a halogen atom, a C1-6-alkyl group, a haloalkyl group, a Chf alkoxy group, an amine group, an azido group, a phenyl group, and a nitro group, and each is directly or through a sulfonyloxy group And selectivity A (^ .4-alkylene bridge, especially methylene is attached to the ring through the outside. Preferred examples of other R3 are hydrogen, halogen atom or hydrogen, halogen atom, or methyl, ethyl, propyl, Isopropyl, butyl, iso- or tertiary-butyl, 2,2,2-trimethylethyl 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. R3 is especially (^ .4-Alkyl selectivity is substituted with one or more substituents selected from halogen, thiocyanate, or azide; C2.5-alkenyl or -alkynyl, each optionally selected by one or more Optionally substituted with one halogen atom; thienyl; or phenyl optionally substituted with one or more substituents selected from halogen atom, 1.6-alkyl, h.6 haloalkyl or azide. -14-

Further preferred examples of the 200538436 R3 group are alkyl and c2.6 haloalkenyl. Preferably R5 and R6 are hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso- or di-butyl, 2,2,2-trimethylethyl, especially hydrogen or methyl. . Particularly at least one and preferably R5 and R6 are both hydrogen. Preferably R7 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso- or tertiary-butyl, 2,2,2-trimethylethyl, methoxy, ethoxy , Phenyl, benzyl or substituted with at least one halogen atom such as trifluoromethyl, chlorophenyl. R7 is preferably hydrogen, and methyl or ethyl is particularly hydrogen. Preferably R8 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso- or tertiary-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 compounds are particularly preferred. A particularly preferred group of compounds of formula I (compound 1A) includes these compounds. A2 is oxygen, X is -CONR5R6 or -C00R7 or -C0-R8 or CN; R1 is hydrogen or a radical, an aryl group, a halogen atom, a radical, an amino group, a nitro group, a cyano group; R2, R3, R4 are Identical or different and each is hydrogen or halogen atom, hydroxyl, amine, nitro, cyano, fluorenyl, fluorenyl'sulfonyl derivative, sulfinyl derivative, amine derivative, carboxyl , Ester group, ether group, amido group, sulfonate group, sulfonamide group, alkoxycarbonyl 'sulfur derivative, alkyl group, alkoxy group, oxyester group, oxamino group, aryl' oxygen derivative , Miscellaneous -15-

200538436 Ring, vinyl, and R3 may additionally represent C2.5 alkenyl, C2.5 alkynyl, or azide, each of which is optionally selected by one or more halogen atoms, cyano, thiocyano, and azido , Cyclopropyl, fluorenyl and / or phenyl; or phenylsulfonyloxy and any phenyl moiety may be substituted with one or more halogen atoms, alkyl, haloalkyl, alkoxy, nitro, Amine and / or phenyl substitution; preferably methyl, ethyl, propyl, isopropyl, butyl or isobutyl; R2a, R3a and R4a are hydrogen; R5, R6, R7 are the same or different And each is hydrogen, hydroxy, alkyl, aryl, heterocyclyl or oxygen derivative; and R8 is hydrogen, hydroxy, alkynyl, halogen atom, alkyl, aryl, heterocyclyl, alkylthio or sulfur derivative. Among these compounds 1A, R1 is preferably methyl, ethyl, propyl, isopropyl, butyl or isobutyl; most preferably, it is methyl, ethyl or n-propyl. R2 and R4 are preferably hydrogen or a halogen atom or methyl, ethyl, propyl, isopropyl, butyl or isobutyl, respectively; and most preferably each is hydrogen. R3 is preferably a Ch alkyl group, a C2.5 alkenyl group, a C2_5 alkynyl group, a cyclopropyl group, and an azido group, each of which is optionally Thio, cyclopropyl, fluorenyl, and / or phenyl substitution; phenyl; phenylsulfonyl; phenylsulfonyloxy, tetrazole, triazole, thienyl, furyl, pyrrole, pyridine, so any The phenyl moiety may be substituted with one or more halogen atoms, alkyl, haloalkyl, alkoxy, nitro, amine, and / or phenyl; most preferably methyl, ethyl, propyl, isopropyl Base, butyl or isobutyl. X is preferably -C00H or -COOMe or -COOEt or -C0NH2; most preferably -C0NH2. A further particularly preferred group of compounds of formula I (compound 1B) comprises the following compounds

200538436 compounds where X is -CAMh, -CA ^ HCl or -CA] N (CH3) 2; R1 is alkyl or phenyl; R3 is alkyl, alkenyl, alkynyl, cyano, isothiocyanate, Ether group, carboxyl group, amido group, aryl group, heterocyclic group; or R3 is CH2RI () where R1Q is hydrogen, cycloalkyl, oxyester, oxyalkylsulfonyl, oxyarylsulfonyl, amine Alkylalkylsulfonyl, aminoarylsulfonyl, nitrooxy, cyano, isothiocyanate, fluorenylamino, alkylthio, arylthio, alkylsulfinyl, alkyl Sulfonyl, heterocyclyl, aryloxy, alkoxy or trifluoroethyl; R3a is hydrogen, alkyl or aryl (especially when 1 ^ 3 is hydrogen, R3 is not methyl); or R3R3a is formed Cycloalkyl; and R2, R2a, R4 and R4a are each hydrogen. In the compound of formula I, R1 is preferably an alkyl group, particularly CV12- is more preferred (^ .6-alkyl and most preferably ethyl; R2, R2a, R3a and R4a are preferably hydrogen. R3 is preferably selected from hydrogen; Cl .12-alkyl, especially Cl_6-alkyl, each of which is optionally substituted with one or more substituents selected from hydroxyl, halogen, cyano, thiocyanate or alkoxy, and is directly or through one Thio, sulfenyl, sulfenyl, carbonyl or oxycarbonyl and optionally additionally attached to the ring through a <^ 4-alkylene bridge, especially methylene; C2.6 • alkenyl or -alkyne Is particularly c2.3-alkenyl or -alkynyl, each optionally substituted with one or more halogen atoms; azide; cyano; amido; carboxy; triazolyl, tetrazolyl, pyrrolidinyl , Pyridyl, 1_pyridyl oxide, thiomorpholine

200538436, benzodioxoyl, furanyl, oxazolyl, pyrimidinyl, pyrrolyl'thiadiazolyl, thiazolyl, thienyl, or hexahydropyridyl, each of which is optionally selected by one or more Substituted with a substituent selected from a halogen atom, (^ .6-alkyl and phenyl), and attached to the ring directly or through a carbonyl or (^ _4-alkylene bridge, especially methylene; naphthyl; or benzene , Phenylalkyl or phenylalkenyl are each optionally selected from one or more halogen atoms, cv6-alkyl, (^ .6 · haloalkyl, C! .6-alkoxy, CV6-alkane Substituted by substituents of thio, amine, azide, phenyl, and nitro, and each directly or through an oxy, sulfonyl, sulfonyloxy, carbonyl or carbonyloxy group, and optionally through an additional- An alkylene bridge, especially methylene is attached to the ring. R3a is preferably hydrogen or Ci_4-alkyl; R4 and 1 ^ 43 are preferably hydrogen, C, .4-alkyl, phenyl or benzyl, respectively. A further preferred group of compounds of formula I (compound 1C) comprises compounds in racemic form, wherein when X is -CONR5R6 and R1 is hydrogen, methyl, ethyl or propyl, a non-substituted pyrrolidine ring For one- Di- or tri-methyl or monoethyl. Another group of compounds of formula I (compound 1D) comprises compounds in racemic form where X is -CONR5R6 and R1 is hydrogen or <^. 6-alkane When the group is C2_6-alkenyl or -alkynyl or cycloalkyl (each is unsubstituted), the ring is not substituted by alkyl, alkenyl or alkynyl (each is unsubstituted). Another group of compounds of the formula I (Compound 1E) includes, X is -CAWHa;

Ri is Η; R3 is azidomethyl, iodomethyl, ethyl is selectively substituted by 1 to 5 halogen atoms, n-propyl is selectively substituted by 1 to 5 halogen atoms, and vinyl is selectively substituted by 1 or 2 methyl and / or 1 to 3 halogen atoms substituted for 'B-18-

200538436 Alkynyl is optionally substituted with c ^ -alkyl, phenyl or halogen atom; R3a is hydrogen or halogen atom, preferably fluorine; and R2, R2a, R4 and R4a are each hydrogen; present as racemic compounds Or in enantiomerically abundant form, preferably pure enantiomers. A further particularly preferred group of compounds of formula I (compound 1F) include these compounds, where X is -CA] NH2; R 丨 is Η; R3 is C ^ -alkyl, C2.6-alkenyl or C2.6-alkyne The radical selectivity is substituted by azido, oxynitro, 1 to 6 halogen atoms; R3a is hydrogen or a halogen atom, preferably fluorine; and R2, R2a, R4 and R4a are each hydrogen; Compounds or enantiomers are in abundant form, preferably pure enantiomers. In all of the foregoing ranges, when R1 is asymmetrically attached to a carbon atom, it is more preferably an "S" configuration. "Pharmaceutically acceptable salts" according to the present invention include therapeutically active non-toxic base and acid salt forms that compounds of formula I can form. The acid addition salt form of the compound of formula I (which appears as a base in its free form) can be obtained by treating the free base with an appropriate acid, such as an inorganic acid such as a hydrohalic acid such as hydrochloric acid or hydrobromic acid, sulfuric acid , Nitric acid, phosphoric acid, etc .; or organic acids such as acetic acid, glycolic acid, propionic acid, lactic acid, pyruvate, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methane Sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cicamic acid (eye 1 ami c), salicylic acid, p-aminosalicylic acid, Bar-19-

200538436 · Mother acid (p amo i c), etc. The compounds of formula I containing acidic protons can be converted to their therapeutically active non-toxic base addition salt forms, such as metal salts or amine salts, by treatment with appropriate organic and inorganic bases. Suitable alkali salt forms include, for example, ammonium salts, alkali and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, calcium salts, etc., salts with organic bases such as N-methyl-D-glucosamine, hydrobarmin salt ( hydrabamine salts) and salts with amino acids such as arginine and lysine. Conversely, such salt forms can be converted to the free form by treatment with a suitable base or acid. # The compound of formula I and its salt may be solvates, and solvates are included in the scope of the present invention. Such solvates include, for example, hydrates, alcoholates, and the like. Many compounds of formula I and some intermediates have at least one stereogenic center in the structure. The stereogenic center can exist in the R or S configuration, and the R and S labeling methods follow the rules described in Pure Applied Chemistry 45 (1 976) 1 1-30. The invention also relates to all stereo forms of the compounds of formula I, such as enantiomeric and diastereomeric forms or mixtures thereof (including all possible mixtures of φ stereoisomers). In addition &apos; certain compounds of formula I may contain susceptible groups in the form of Z (zusammen) or E (entgegen) isomers. In each case, the present invention includes mixtures and individual isomers. The multiple substituents of the pyrrolidine ring may represent a cis or inverse relationship with each other with respect to the plane of the pyrrolidone ring. Some compounds of formula I may exist as tautomers. These forms, although not explicitly indicated in the above formula, are intended to be included in the scope of the present invention. When referring to compounds, the present invention is intended to include various isoforms of the compounds and mixtures thereof, unless specifically mentioning a particular isoform. The scope of the present invention also includes prodrug forms of the compounds of formula I and their various subranges and groups.

The term "prodrug" is used herein to include rapid transformations in vivo, such as rapid conversion to parental compounds according to the invention, by hydrolysis in blood. Prodrugs are compounds that have groups that can be removed by bioconversion before they exert their pharmacological effects. These groups include portions that are conveniently cleaved and removed by a compound bearing such groups in a living test, and the compound can retain or become pharmacologically active after cleaving the portion. Metabolizable bases form a group of well-known groups in the industry. Including but not limited to, for example, alkylsulfenyl (ie, ethylsulfonyl, propionyl, butylfluorenyl, etc.), unsubstituted or substituted carbocyclic arylfluorenyl (such as benzamyl, substituted benzamyl and 1-and 2-naphthylfluorenyl), alkoxycarbonyl (such as ethoxycarbonyl), trialkylsilyl (such as dimethyl- and triethylsilyl), monoesters formed with dicarbonic acid (such as butanefluorenyl) ), Phosphate, sulfate, sulfonate, sulfonyl, sulfinyl and the like. An advantage of a compound with a metabolizable cleavable group is that it provides improved solubility and / or absorption rate to the parent compound due to the presence of the metabolizable cleavable group, resulting in improved bioavailability. T. Higuchi and V. Ste 1 1 a, "Prodrugs as Novel Delivery Systems", A. C. S. Seminar Series; "Bioreversible Reloading Agents for Drug Design" Issue 14, Edward B. Roche Editor, American Pharmaceutical Association and Pergamon Press, 1987. Compounds of formula I according to the present invention, such as those skilled in the art of synthetic organic chemistry, are known to be prepared in a similar manner. The following method descriptions illustrate certain synthetic pathways by way of illustration. Other alternatives and / or similar methods will be apparent to those skilled in the art. For this

For the definition of substituents at 200538436, "=" means "yes" and "#" means "not". A. Cyclization of amino esters. In formula I, when A2 = 0, the amine ester of formula AA-II is cyclized, wherein Q1 together with the oxygen to which it is attached is a leaving group, especially Qi is an alkyl group, and especially has 1 to 4 carbon atoms. Straight or branched alkyl.

Q1 = methyl or ethyl. The reaction is known and convenient at room temperature to 150 ° C in the presence or absence of a catalyst such as acetic acid, hydroxybenzotriazole or 2-hydroxypyridine.

Q] #Methyl or ethyl. The ester of formula AA-11 is hydrolyzed under acidic or basic conditions, and then cyclized using a coupling agent such as dicyclohexylmethyldiimine under conventional peptide synthesis conditions (Bodanszky, M., Bodanszky, A., "Peptide Synthetic Practice ", Springer Verlag, 1984). A.1 Synthesis of AA-II by addition to itaconic acid salt derivative. Compounds of formula AA-II where R2a = R3a = H and R3 = COOQ2, where Q2 represents a selective optically active linear or branched alkyl group, via a compound of formula AA-III and an itaconic acid salt derivative of formula AA-IV according to the following The reaction yields: -22-

200538436

This reaction is based on: Street, L. J., B ake e., R., B ο 〇k, T., Kneen, C.O., ManLeod, A. M., Merchant, K.J.,

Showell, G.A., Saunders, J., Herbert, R.H., Freedman, S.B., Harley, E.A., Journal of Medicinal Chemistry (1990), 33, 2690-2697.

A. 2 Synthesis of AA-II through reductive amination. Compounds of formula AA-II can be prepared by reducing compounds of formula A A-V using compounds of formula AA-III according to the reaction formula:

This reaction uses Abdel_Magid, A.F., Harris, B.D.,

The conditions described in Mar yanoff, C.A., Synlett (1994), 81-83 are performed. In addition, when X represents CONR5R6, the amine AA-III can be bonded to a solid support (for example, Rink resin) through the amine moiety. Compounds of formula AA-V can be prepared by one of the following methods: -23- 200538436

(AA-V) A. 2 · 1 · Aldehydes of formula AA-VI are alkylated with alkyl haloacetates of formula AA-VII, where X represents a halogen atom, and intermediate enamines are used in the reaction, such as described in Whitessell, JK, Whitessell, MA ·, Synthesis, (1983), 517-536 or using hydrazones as described in Corey, EJ, Enders, D., Tetrahedral Letter (1 976), 11-14 followed by ozone decomposition reaction preparation. A.2.2 · Nitro esters of formula AA-VII.I can be converted to compounds of formula AA-V by treating their conjugate base with sulfuric acid in methanol and hydrolyzing intermediate dimethyl acetals (Nef reaction as described in Urpi, F., Vilamsa, J., Tetrahedral Letter (1990), 31, 7499-7500). Nitroesters of the formula AA-VIII are known from Horni, A., Hubacek, I., Hesse, M., Helv. Chim. Acta (1 994), 77,579. A.2.3. The ester AA-X is alkylated with an allyl halide AA-IXUk halogen atom) in the presence of a strong base (such as lithium diisopropylamidide), followed by a reduction ozonolysis reaction of the unsaturated ester. In Am ruta Reddy P., Hsiang B. C. Η., La tifi Τ.Ν., ΗΠΙ M. W., Woodwa rd KE, Rothman SM, Ferrende11i JA ,, Covey DF, -24-

200538436 Journal of Medicinal Chemistry (1 996), 39, 1 898-1 906.

A. 3. Synthesis of AA-II by alkylating r-haloesters. Compounds of formula AA-11 where X = CONR5R6, C00R7 or CN can be alkylated with 7-haloesters AA-XI via amine AA-I II, where X2 represents halogen. Atomic system

This reaction is performed using the conditions described in the patent application GB2225322 A. The synthesis of esters AA-XI is described in Part B. A.4. Synthesis of AA-II by reductive amination of 5-hydroxylactone derivatives. Compounds of formula AA-11 in which X = CONR5R6, C00R7 or CN, Q1 = Η and R2a = Η can be prepared by the reductive amination of amines of formula AA-III according to the following: 5.hydroxylactone of formula AA-XII:

(ΑΑ-ΙΙΙ)

ΟΗ 5-hydroxylactones of the formula AAA-XIII can be synthesized as described in B.I. Β. Condensation of amine with 7 · halic acid derivative in formula I, when A2 = 0, X = CONR7R8, C00R7 or CN and R2a = H, the compound of formula AA-XIII reacts with the amine of formula AA-III according to the following formula : -25-

200538436 wherein X3 represents a halogen atom, preferably an iodine or chlorine atom, and X4 represents a halogen atom, preferably a chlorine atom. This reaction can be performed as described in patent application GB2225322 A ^

Compounds of formula AA-XIII can be obtained by opening a lactone of formula AA-XIV in the presence of a halogenating agent such as TMSI, SOCl2 / ZnCl2 according to the following formula (then the halogenation reaction of the resulting halogen acid (× 4 = 0Η) is performed if necessary):

Lactone AA-XIV can be turned on according to the following procedures: Mazzini, C., Lebreton,], Alphand, V., Furstoss, R., tetrahedral letter

(1998), 38, 1195-1196 and 01 ah, G.A., Nai * ang, S.C., Gupta, B.G.B., Malhotra, R., Journal of Organic Chemistry (1 979), 44, 1247-1250. The halogenated (X4 = halogen atom) or quenched (X4 = 0Q1) of the obtained halogen acid (χ4 = 0Η) can be carried out under any conditions known to those in the industry. Formulas AA-XIV lactones can be prepared by one of the following methods: : B.1. Hydrogenation or conjugate addition of organometals. Compound AA-XIV where R2a = R4a = Η can be obtained by hydrogenation of formula AA-χν $ α, yS-unsaturated lactone, or via organic addition of conjugate addition formula R3M (where M represents Li, Na, Mg or Zn) Metal derivative to compound Aa -26-

200538436 XV was finally obtained by copper (I) salt catalysis.

(AA-XV) R3M, Cul or H2, PdC (R3 = H)

This reaction can be performed according to the following procedures: 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 35 1-1 358 or any method known to the industry. B. 2 Reduction of succinate derivatives. In the formula AA-XIV, when R2 = R2a = H: the reduction system of carboxylic acid AA-XVI is performed on the borohydride according to the following formula, preferably LiBH4 or Ca (BH4) 2 is performed in an alcohol solvent =

φ (AA-XVI) where Q3 is methyl or ethyl, G1 is 0 or S, and Q4 is a hydrogen atom or a straight or branched alkyl group containing 1 to 4 carbon atoms, but when GkS, Q4 = alkyl And when GLO, Q4 = H. C. Alkylation of lactam derivatives. In Formula I, when A2 = 0 and X = C00R7, the compound of formula AA-XVII and the compound of formula AA-XVIII react according to the following formula: -27-

200538436 where X5 represents a halogen atom and M is an alkali metal. Such a reaction may be performed in accordance with the procedure of the patent application GB (case number 15-09). Compounds of formula AA-XVII can be performed according to the procedures described by Horni, A., Hubacek, I., Hesse, M., Helv. Chim. Acta (1 994), 77, 579.

D. Transformation of ester derivatives. In formula I, when A2 = 0 and X = CONR5R6, none of the R2, R2a, R3, R3a, R4 and R4a groups is substituted by carboxyl, ester or sulfonic acid, corresponding to the ester of formula I

Where R7 represents a hydrogen atom or a linear or branched alkyl group containing 1 to 4 carbon atoms, and an amine and a coupling agent such as alkyl chloroformate or dicyclohexyl formyl are used in a direct ammonia decomposition reaction or under conventional peptide synthesis conditions The hydrazone is converted into an amine. E. Reduction of α, fluorene-unsaturated lactam. In formula I, when A2 = 0 and R2a = R3a = R4a = H, the compound of formula I can be obtained by reduction of unsaturated lactam AA-XIX:

-28-

200538436

Ε · 1 alkylated / ring 7 seven

'R2 ° AA-XX

(ΑΑ-ΙΙΙ) ------- &gt; Reductive amination / cyclization

The ΑΑ-χΙχ reduction step can be performed under typical conditions known to those skilled in the art, such as hydrogen in the presence of Pd / C or optionally 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 selectivity of the olefin mixture can be reduced using NaBH4M CoCl2. Compound AA-XIX can be prepared by one of the following methods: E.1 Alkylation Compounds of formula AA-III Compounds of formula AA-XX (where Q5 represents a linear or branched alkyl group containing 1 to 4 carbon atoms) And cyclization. The alkylation step can be performed in an inert solvent such as tetrahydrofuran, dimethylformamide, or dichloromethane at 0 to 5 ° C in the presence of a tertiary amine. The cyclization reaction can be performed spontaneously or according to the method described in Section A. E.2 Reductive amination of compounds of formula AA-XXI with compounds of formula AA-III under reductive amination conditions. The first step of this reaction can be in an inert solvent such as toluene at 0 to 50 ° C in a reducing agent such as NaBH3CN. And in the presence of an acid such as acetic acid. The synthesis of compounds AA-XXI is described in Bou r gu i gnon, J. J. et al., Journal of Medicinal Chemistry (1 988), 31, 893-897. -29-

200538436 F. Branched functional group transformation. F. 1 vinegar is reduced to alcohol. Compound of formula I (where A2 = 0, X = CONR5R6 or C00R7, R7 is the third academy and one of R2, R2a, R3, R3a, R4 and R4a represents G2-C00Q6, G2 is a bonded or extended alkyl group And Q6 is a key synthetic intermediate of a linear or branched alkyl group containing 1 to 4 carbon atoms, which is a corresponding compound (wherein one of R2, R2a, R3, R3a, R4, and R4a represents G2-CH20H). These changes can be made under any of the conditions known to the industry. F. 2 alcohol activation and oxidation. The compound of formula 1 (where human 2 = 0 and 1-2, 1 ^, 1 ^, 1 ^, 1 ^, and 1 ^ represents -G2-CH20H, G2 is a bonded or extended alkyl group) is the corresponding compound (where One of R2, R2a, R3, R3a, R4 and R4a represents -G, CH2X6 or -G2-CH0 where X6 represents a chlorine, bromine or iodine atom or a group of the formula -0-S02-Q7 or -0-Q8, and Q7 is an alkane Group or aryl group and Q8 is an alkyl) key synthetic intermediate. These changes can be made under any of the conditions known to the industry. F.3 Nucleophilic substitution of activated alcohols. Compound of formula I (where A2 = 0 and one of R2, R2a, R3, R3a, R4 and R4a represents -G2-CH2X6, G2 is a bonded or extended alkyl group and X6 is a chlorine, bromine or iodine atom or formula -0 The -S02-Q7 group is defined as F.2) as the corresponding compound (wherein one of R2, R2a, R3, R3a, R4, and R4a represents -G2_CH2X7, where X7 represents an azide group, a halogen atom, a nitro group, an amine group, Amine derivatives, sulfur derivatives and heterocyclic groups) are the key synthetic intermediates. These transitions can occur under any of the conditions known to those skilled in the art. F.4 Olefination by aldehyde. -30- 200538436 • · Compound of formula I (where A2 = 0, X = C0NR5R6 or C00R7 or CN and one of R2, R2a, R3, R3a, R4 and R4a represents -G2-CH0, G2 is a bond or an alkylene Group) is the corresponding compound (where R2, R2a, R3, R3a, R4 and R4a2—represents —G2-Q9, where Q9 represents unsubstituted vinyl, and the halogen atom is mono- or di-substituted vinyl or alkyl group) The key synthetic intermediate. These changes can be made under any of the conditions known to the industry. In addition, the compound -G2-CN can be obtained from the corresponding aldehyde by the reaction of its oxime with Se02 (described in Earl, R.A., Vollhai 'dt, K.P.C., Journal of Organic Chemistry (1984), 49, 4786). F.5 The acid derivative is converted into a heterocyclic ring. Compound of formula I (where A2 = 0 and R2, R2a, R3, R3a, R4 and R4a2 represent -G2-CN or -G2-C0Q1 (), G2 is a bonded or extended alkyl group and QI () is an alkoxy group Group, aryloxy or amine group, halogen atom or amine group derivative, but -C0Q1 () is not X) is the corresponding compound [where R2, R2a, R3, R3a, R4 and R4a2 — represents -G2-QM where Q11 Represents (i) -CO-aryl / heterocyclyl, which is carried out via a palladium-catalyzed coupling reaction between fluorenyl chloride-G2-C0C1 and an aryl / heterocyclic organic metal such as trimethyl-pyridyl-stannate or ( ii) heterocyclic groups such as thiazole (Friedman, BS, Spark s, M., Adams, R., Journal of the American Chemical Society (1933), 55,2262 or Iroka, N ,, Hamada, Y., Shiori, T ·, Tetrahedron (1 992), 48,725 1), feeding mouth sitting (Street, LJ ·, Baker, R ·, Castro, JL, Clamber, RS, Guiblin, AR, Hobbs, SC, Metasa, VG ·, Reeve, AJ, Beer, MS, Middlemis, DN, Noble, AJ, Stanton, J.A., Scholey, K., Hargreaves, RJ., Journal of Medicinal Chemistry (1 993), 36, 1529), Triazole ( Ainsworth, C., beauty

-31-

200538436 · Journal of the Chinese Chemical Society (195S), 77.1 1 48), tetrazole started from rhenium (Goer litze r, K., Kogt, R ·, Proceedings of Pharmacy (1990), 323, 847) Lamattina, JL, Mularski, CJ, Journal of Organic Chemistry (1 984), 49, 4800)]. F. 6 Synthesis of ketone derivatives. Compound of formula I (where A2 = 0 and one of R2, R2a, R3, R3a, R4 and R4a represent-G2-CH = CQ] 2QU or-G2-CQ13 = CHQ12, G2 is a bonded or alkylene group, Q12 and Q13 are hydrogen atoms or alkyl groups, but none of the other R2, R2a, R3, R3a, R4, and R4a carry functional groups sensitive to oxidation conditions. The corresponding compounds (where R2, R2a, R3, One of R3a, R4 and 1? "Represents the key synthetic intermediates of -〇2 彳 〇-0: 印 12〇13 or -〇2- (: 印 13-〇〇- (312). These transformations can be in Any suitable conditions known to those in the industry, such as at 0 and PdCI2 in an inert solvent such as dimethylformamide or N-methylpyrrolidine at 0 to 50 ° C (Bird, transition metal intermediate for organic synthesis) Materials, Academic Press, New York (1 967), 88-111). F.7 Ketone derivatives. Compounds of formula I (where A2 = 0, X = CONR5R6 or C00R7 and R2, R2a, R3, R3a, R4 and R4a2— represents -G2-C0-Q14, where G2 is a bonded or extended alkyl group and Q14 represents an alkyl group) is a synthetic (i) alcohol-G2-CH0H-Q14, which is reduced using a hydrogenating agent (March, Advanced Journal of Mechanochemistry, Third Edition, John Wiley & Sons (1 985), 809), (ii) Fluorinated Branched Chains-G2-CF2-Q14 Uses described in Lai, GS, Pez, GP, Pesaresi, RJ, Prozonic , FM ·, Chemical Communications (1999), Key Intermediate of Conditions 215-216. F.8. Synthesis of Alkynyl Derivatives. -32-

200538436 Compound of formula I (where A2 = 0 and one of R2, R2a, R3, R3a, R4 and R4a represents -G2-C = C (X8) 2, G2 is a bonded or extended alkyl group and X8 is a halogen atom, but Others and none of R4a carry functional groups sensitive to strong bases are corresponding compounds (where R2, R2a, R3, R3a, R4, and 1? "Represent -G2-C C-Q15, where Q15 is a key synthetic intermediate for hydrogen, halogen, alkyl, or aryl). These transformations are performed in the following way: • A base-induced cold-elimination reaction (eg, 1 equivalent of t-BuOK at low temperature, described in Michel, P. , Rassat, A., tetrahedral letter (1 999), 40,8579-8581) into haloalkyne derivatives (Q15 = halogen atom), and then metal-catalytic substitution of halogen atoms by organometallic species (for example, MeZnCl in CuCN In the presence of LiCl, as described 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 the use of alkane Alkyl halide or carbonyl derivative alkylation (described in (: 117). Plant,? 110 ?,?,., Tetrahedral letter 1 972), 36, 3769-3772). F.9 Synthesis of alkanes. Compounds of formula I (where A2 = 0 and one of R2, R2a, R3, R3a, R4 and R4a represent-G2-C = C-Q16QI7, G2 is a bonded or extended alkyl group, and Q16 and Q17 are alkyl or fluorine groups. The corresponding compounds (where R2, R2a, R3, R3a, R4, and R4a represent the key synthetic intermediates of ^^-⑶ ...) The reduction step can be performed under typical conditions known to those in the industry, such as using hydrogen in the presence of Pd / C (March, J., Advanced Journal of Organic Chemistry, Third Edition, 'John Wiley & Sons (1 985), 1101 -1102). -33-

200538436 F. Synthesis of 10 (halo) azidoaryl derivatives. Compound of formula I (where A2 = 0, X = C0NR5R6 or C00R7 or CN and one of the R2, R3, R4 groups is G2-Q18, where Q18 represents a nitroaryl group or a triple-arylene group, and G2 is a bond or an alkylene Group) is the key intermediate for the synthesis of corresponding compounds (where one of the R2, R3 or R4 groups is G-Q19, Q19 is an azidoaryl group optionally substituted with one or more halogen atoms, preferably Br or F atoms) Thing. The transformation is carried out by any means known to those in the industry via partial reduction to aniline through nitro or triphenene, and the selective introduction of one or more halogen atoms (e.g. Xing-teng, D ·, Gu 〇-bi η, L., Synthetic Communications (1 989), 19, 1 26 1) and transamines to azides by well-known methods. F. 11 Synthesis of heterocycles from amines. Compounds of formula I (where A ^ O, χβΟΝ ^ or COOR7 or CN and one of R2, R3 or R4 are G2-Q2G, where G2 is a bonded or extended alkyl group and Q2G is C00H, COH2, or CN) are synthetic Key intermediate of the corresponding compound (where one of the R2, R3 or R4 groups is G2-NH2 or G2-CH2-NH2), resulting in the corresponding compound (where 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 substituted with one or more halogen atoms). • In the case where X = CONR5R6, CN or COOR7, R7 is not Η and R2, R3 or R4 is G2-C00H, the transformation is performed by Curtius rearrangement (such as diphenyl phosphoazide and Triethylamine action and borrowing in situ; alcohol quenching, described in Kim, D., Weinreb, S.M., Journal of Organic Chemistry (1 978), 43, 12S), using hydrogen known to the industry Solution or any condition to deprotect the amine functional group to obtain R2, R3 or R4 = G2-NH2, and then obtain a heterocyclic ring such as pyrrole by ring synthesis (for example, described in 6); [〇1 '(1, (]. What., Ding &amp; £ 11, 0, 2 &amp; 51〇1 ^, person., Journal of the American Chemical Society 34-200538436 (1991), 113, 3 5 1 3-3 5 1 8), and selectivity Introduce one or more halogen atoms to the ring (as described in Gilow, HM, Burt on, DE, Journal of Organic Chemistry (1981), 46, 2221-2225). • where X = CONR5R6, C00R7 or CN and R2, One of the R3 or R4 groups is G2-CONH2, X is not an example of CONR5R6 or G2-CN, and X is not an example of CN. The conversion is through selective reduction of amidine under any of the conditions well known in the industry. Nitrile become aminomethyl moiety, and heterocyclic ring such as to obtain a synthetic triazole (described in example 1 e s, R M i.

W., Samano, V., Robins, M .: T ·, Journal of the American Chemical Society (1995), 117,595 1-5957) ° F. 1 2 three-mile synthesis. The compound of formula I (where A2 = 0 and one of the groups R2, R2a, R3, R3a, R4 and R4a represents -G2-CH2N3, G2 is a bonded or extended alkyl group) is the corresponding compound (wherein one of the r4 groups represents- G2_CH2-triazole) is a key synthetic intermediate. This transformation can be carried out by heating for a long time in the presence of a 1 (triphenylphosphonidene) -one derivative (for example, described in Hammerschmidt, F., Polsterer, J.P., Zbiral, Synthesis (1995), 415). F. 1 3 Optical segmentation. When a compound of formula I has one or more stereogenic centers and the use of non-stereoselective synthetic methods, the optical segmentation of a mixture of stereoisomers is best performed in one or more steps, usually involving diastereoisomers The material mixture is separated into its racemic mixture in sequence. The separation method is preferably used for non-image phase or image phase in reverse mode or better than direct mode for chromatographic separation. The combined phase is chromatographically separated in reverse phase or preferably in direct mode, and -35-200538436 separates each racemic mixture into its enantiomers as the final optical segmentation step. In addition, when using a partially stereoselective synthesis method, the final step is to separate the diastereomers by performing chromatographic separation in a non-image-combined phase or in a reverse-phase or better than direct mode. Certain of the foregoing intermediate compounds, particularly compounds of formula AA-11, in which each substituent has the foregoing definition as a novel compound and also forms part of the present invention. These novel intermediates, when the leaving group is pharmaceutically acceptable, have the same use as described later for the compound of formula I. % Today the compounds of formula I and their pharmaceutically acceptable salts are found to be useful in a variety of medical indications. For example, the compounds according to the invention can be used for the treatment of epilepsy, epilepsy, seizure disorders and convulsions. These compounds are also useful in the treatment of other neurological disorders including bipolar disorders, mania, depression, anxiety, migraine, trigeminal neuralgia and other neuralgia, chronic pain, neuropathic pain, cerebral ischemia, arrhythmia, myotonia, Cocaine abuse, stroke, myoclonus, idiopathic tremor, and other sports disorders' Neonatal cerebral hemorrhage, amyotrophic lateral sclerosis, spasticity, Parkinson's disease, and other degenerative diseases. In addition, the compounds of the present invention are useful in the treatment of bronchial asthma, asthma and allergic bronchitis, asthma, bronchial hyperactivity and bronchospasm, as well as allergic and vasomotor rhinitis and nasal conjunctivitis. As such, the present invention is, in yet another aspect, related to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a drug for treating neurological and other disorders (as described above). In particular, the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof. Used to make epilepsy, bipolar disorder, chronic pain or neuropathy -36-

200538436 Treatment of pain, migraine, bronchial-, asthma- or allergic conditions ° Activity and properties of active compounds, oral utilization and stability in test tubes or in vivo between optical isomers of the disclosed compounds Significant change. In a preferred embodiment, the active compound is administered in an enantiomerically abundant form, i.e., essentially as a single isomer. For example, in the compound of formula I, where R1 is ethyl, X is -CONH2, and A2 is oxygen. 'When R3 is propyl and the remaining substituents are hydrogen, S (butanamine) R (ring) enantiomer When R3 is 2,2-difluorovinyl and the other substituents are all hydrogen, S (butamidamide) and S (ring) enantiomers are more preferable. The invention also relates to a method for treating epilepsy, migraine, bipolar disorder, chronic pain or neuropathic pain or bronchial-, asthmatic- or allergic conditions in a mammal in need of treatment, 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 compound according to the present invention to a mammal (preferably a human) suffering from the aforementioned condition or condition, in an amount sufficient to ameliorate or prevent the condition or condition. The compound is conventionally administered in any suitable unit dosage form, including but not limited to containing 5 to 1,000 mg, preferably 25 to 500 mg of active ingredient per unit dosage form. The term "treatment" is used herein to include both therapeutic and prophylactic treatments. The term "treatment" refers to the current symptoms of a disorder or condition. "Prevention" means preventing the occurrence or recurrence of a disease or condition. The term `` epilepsy '' is used here to indicate brain dysfunction, with regular and -37-

200538436 Unexpected seizures are characterized. The seizures were induced as "non-epileptic" seizures when treated with electric shock or chemical convulsants in the normal brain, without authoritative evidence of seizures. The term "seizure" is used here to indicate temporary behavioral changes due to the barrier, synergy, and rhythmic emission of the brain neuron population. The term "migraine" is used here to indicate a condition characterized by recurrent headaches, which can vary widely in intensity, frequency, and duration. Seizures are usually 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. The duration of migraine headaches ranges from 4 hours to about 72 hours. The International Headache Association (IHS, 1988) classifies migraines as aura with migraine (typical non-migraine) and migraine without aura (common migraine) as the main types of migraine. Aura with migraine includes characteristic visual, sensory, speech, or motor symptoms before the headache period. A headache without this symptom is called aura without migraine. The term "bipolar disorder" is used to indicate classification as an emotional disorder according to the 4th Edition of the Diagnostic and Statistical Manual of Mental Disorders (Diagnosis and Statistical Manual of Mental Disorders (DSM-IV TM), American Psychiatric Association, Washington, DC, 1994) Of illness. Bipolar disorders are generally characterized by the automatic triggering of repetitive (in other words, at least two) episodes. At the time of the episode, the patient's high excitability, activity, and mood are markedly impaired. Such disorders are in some cases elevated mood and increased energy and mobility (Manic or hypomanic) and, in some cases, reduced mood and decreased energy and activity (depression). Bipolar disorders can be divided into four categories in DSM-IV (bipolar I disorders, bipolar 11 disorders, circulatory bipolar disorder, and bipolar disorders that are not specifically classified). The term "manic episode" is used here to indicate a period of abnormal and persistent mood -38- 200538436 sexually elevated, dilated or irritable with symptoms such as compulsive speech and mental agitation. The term "hypomanic" is used here to indicate a less severe episode of less extreme manic episodes. The term "major depressive episode" is used here to mean a period of at least 2 weeks, emotional depression, or loss of interest or pleasure in almost all activities, with impaired attention and mental retardation. The term "mixed seizures" is used here to mean that for a period of time (at least 1 week), the criteria for seizures are consistent with manic episodes and almost daily with major depressive episodes. The term "chronic pain" is used here to indicate a condition in which the progression of the disease is different from acute pain. Knownness is defined as pain that persists beyond the normal healing time, and can also be considered chronic pain when an individual feels that the pain will continue to experience part of their life for the foreseeable future. It is likely that most chronic pain syndromes involve neuropathic components, which are generally more difficult to manage than acute somatic pain. The term "neuropathy pain" is used here to mean pain induced by neuropathological changes, which means that there are harmful stimuli, and when there is no stimulus that can identify φ, it causes a false pain. In other words, it is clear that the pain system is turned on and cannot be turned off. The activity of a compound of formula I or a pharmaceutically acceptable salt thereof as an anticonvulsant can be measured in auditory seizure patterns. The purpose of this test was to evaluate the anticonvulsant ability of compounds by using auditory-induced seizures in sound-sensitive mice (animal models with reflex seizures). In this type of primary generalized epilepsy, seizures are not induced by electrical or chemical stimulation, and at least part of the clinical symptoms are similar to human seizures (Loscher W. & Schmidt D., Epilepsy Research (1 998), 2, ρ · 145-181; Buchhal ter • 39-

200538436 J.R., Epilepsy (1993), 34, S31-S41). The results obtained for compounds of formula I indicate potent medicinal effects. Another assay that indicates possible anticonvulsant activity is binding to Levetiracetam binding site (LBS), described in detail later. The activity of a compound of formula I or a pharmaceutically acceptable salt thereof for chronic neuropathic pain can be determined in animal models. For example, chronic neuropathic pain can be modeled by pharmacologically induced diabetes in rats. In this model, animals show progressive hyperalgesia in response to harmful stimuli. This symptom is common in patients with painful peripheral neuropathy (Courteix C, Eschalier, A. and Lavai · enne «I ·, Pain, 53 ,, (1993) 81-88). This model is highly pharmacologically predictive (Courteix C, Bardin M., Chan t e 1 auz e C., Lavarenne J and Eschalier, A., Pain, 57 (1 994) 1 53-1 60). The activity of a compound of formula I or a pharmaceutically acceptable salt thereof for a bipolar disorder can be assessed in animal models. For example, bipolar disorder, particularly manic disorder, can be modeled in rats by pharmacologically-induced hyperactivity and evaluating its performance in a Y-shaped maze. In this case, effective therapeutic agents for humans such as lithium and sodium valproate can reduce the activity charge, thus confirming that the model is predictive (Cao B.]., And Peng N; A; European Journal of Pharmacology 237 (1993) 1 77-1 81. Vale AL and Ratcliffe F. Psychopharmacology, 91 (1987) 352-355). Possible anti-asthmatic properties of a compound of formula I or a pharmaceutically acceptable salt thereof can be tested in an animal model of allergic asthma, in which guinea pigs sensitized to ovalbumin use antigens to challenge and investigate changes in lung function and the content of inflammatory cells in the respiratory tract (Yamada et al. (1 992) The development of animal models of late allergic reactions in guinea pigs and the effects of antiallergic drugs. -40-200538436 Prostaglandin, 43.507-52 1). The activity of any of the foregoing indications may of course be appropriately clinically tested in a manner known to those skilled in the art for a particular indication and / or the design of a clinical trial. For the treatment of a disease, the 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. Therefore, 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 compounds of formula I or a pharmaceutically acceptable salt thereof are mixed with a pharmaceutical diluent or carrier according to pharmaceutical mixing techniques known to those skilled in the art. Appropriate diluents and carriers can take a wide variety of forms depending on the route of administration, such as oral, rectal or parenteral. A pharmaceutical composition comprising a compound according to the invention can be administered, for example, orally or parenterally, i.e. intravenously, intramuscularly or subcutaneously, intrathecally. Drugs suitable for oral administration may be solid or liquid, such as in the form of lozenges, nine-dose, sugar-coated tablets, gelatin capsules, solutions, syrups, and the like. To achieve this, the active ingredient is mixed with an inert diluent or a non-toxic pharmaceutically acceptable carrier such as starch or lactose. Optionally, the pharmaceutical composition may also contain binders such as microcrystalline cellulose, tragacanth or gelatin, disintegrating agents such as alginic acid, lubricants such as magnesium stearate, slip agents such as colloidal silica, and sweeteners. Such as sucrose or saccharin or colorants or flavoring agents such as menthol or methyl salicylate. The invention also encompasses compositions which can release the active substance in a controlled manner. Pharmaceutical compositions useful for parenteral administration may be in conventional dosage forms such as aqueous or -41 ·

200538436 Oily solutions or suspensions are usually contained in ampoules, disposable syringes, glass or plastic vials or infusion containers. In addition to the active ingredients, these solutions or suspensions may optionally contain sterile diluents such as water for injection, physiological saline, oils, polyethylene glycols, glycerol, propylene glycol or other synthetic solvents, and antibacterial agents such as benzyl alcohol Antioxidants such as ascorbic acid or sodium bisulfite, chelating agents such as ethylenediamine-tetraacetic acid, buffers such as acetates, citrates or phosphates, and osmotic pressure regulators such as sodium chloride or glucose. These pharmaceutical dosage forms are prepared using methods routinely used by pharmacists. The content of the active ingredient in the pharmaceutical composition may fall within a wide concentration range and depends on a number of factors, such as the patient's last name, age, weight, medical condition, and method of administration. As such, the content of the compound of formula I in the oral administration composition may be at least 0.5% by weight and up to 80% by weight relative to the total weight of the composition. It has also been found according to the present 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 these additional compounds that may be used in combination with the compounds of the present invention are anticonvulsants (e.g. baclofen), antiemetics, anti-manic mood stabilizers, analgesics (e.g. aspirin Lin, i bup ro fen, Paracetam (Paracetam ο 1)), narcotic analgesics, local anaesthetics, aphid analgesics, lithium salts, antidepressants (such as Mianxi Forest (mianserin), fluoxetine, trazpdone), anti-depressants (e.g. i imi free i ρ amine), desipramine )), Anticonvulsants (such as valproic acid, carbamazepine, Pheny-toin), antipsychotics (such as risperidone, -42 -200538436

Haloperidol), nerve agents, benzodiazepines (such as diazepam, clonazepam), phenothizones (such as colopomer Chlorpromazine), calcium channel blocker, amphetamine, cionidine, lidocaine, mexiletine, capsaicin, Caffeine, quetiapi ne, angiotensin antagonist, / 3-blocker, antiarrhythmic agent, triptans, ergot derivatives. Of particular interest according to the present invention is a combination of at least one compound of formula I or a pharmaceutically acceptable salt thereof and at least one compound that induces a neurosuppressive effect on the GABAa receptor mediator. Compounds of formula I have potential effects on compounds that induce neurosuppressive effects via GABAa receptor mediators, and in many cases, effective treatment of the condition and disorder can be obtained with less risk of adverse reactions. Compounds that induce neurosuppressive effects via GABAa receptor mediators include, for example, the following: benzodiazepines, barbiturates, steroids, and anticonvulsants such as vanproate, microgabacil ( viagabatrine), tiagabine or a pharmaceutically acceptable salt thereof. The benzodiazepines include 1,4 benzodiazepines such as Didizone and Kronazpan and 1,5 benzodiazepines such as clobazam. The preferred compound is Kronazpan. Barbiturates include Phenobarbital and Pentobarbital. The preferred compound is phenylbarbitur. Steroids include adrenocortical hormones such as tetracosactide acetate and the like. Anti-convulsants include hydantoin (Fenidone, ethotoin -43- 200538436, etc.) 'Mouth 嗤' (trimethadione, etc.), succinimide Genus (ethosuximide, etc.), phenacemides (phenacemides, acetylphene-11111〇 ^, etc.), sulfonamides (Suson (51111} 1 丨 &amp; 11 ^), astroxol (acet 〇a ζ〇Um ide, etc.), aminobutyric acid (for example, 7-amino-fluorene · hydroxybutyric acid, etc.), vanproic acid Sodium and its derivatives, Kabamaz Equal. Preferred compounds include valproic acid, valpromide, piproxil Pi voxil, sodium valproic acid, hemi-vanprotic acid, and divalprox. Ronazepine, phenobarbital, microgabacin, dirubin. For preferred oral compositions, the daily dosage ranges from 5 to 1000 milligrams (mg) of a compound of formula I. In a parenteral pharmaceutical composition, the compound of formula I 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 5 mg to 1000 mg of the compound of formula I. Each daily dose falls within a broad range of dosage units of the compound of formula I and is typically # 5 to 1000 mg. However, it is important to understand that specific dosages can be adjusted to suit specific cases at the discretion of the physician based on individual needs. The amount of the active ingredients (compound I and compounds capable of inducing a neurosuppressive effect by the GABAa receptor mediator) of the pharmaceutical composition of the present invention will depend on the mammal to be administered, the disease to be treated, and other active agents. Generally, for a given composition and dosage form, the amount of the compound which induces the neurosuppressive effect of the GABAa receptor mediator and the amount of the compound I can be conveniently determined by routine procedures. The following examples are provided for illustration only and are not limiting, nor are they to be considered as limiting in any way -44- 200538436 The scope of the invention. Those skilled in the art understand that the following examples can be routinely changed and modified without departing from the spirit and scope of the present invention. Unless otherwise stated in the examples, the characteristics of the compounds are determined according to the following methods:

The spectrum is recorded in Bruker &quot; 401,08 € 2 50 Fourier Transform Off 1? Spectrometer with an Aspect 3000 computer and a 5 mm 1H / 13C dual probe, or Bruker DRX 400 FT NMR is equipped with SG indigo computer and 5 mm reverse geometry W / nc / UN triple probe. The compounds were studied in DMSO-d6 (or CDC13) solution at a probe temperature of 313 ° C and a concentration of 20 mg / ml. The instrument is locked to the DMSO-d6 (or CDC13) deuterium signal. Chemical shifts are expressed in ppm of TMS Shimo, a distance used as an internal standard. Mass spectrometry measurement in LC / MS mode was performed as follows: HPLC condition analysis was performed using WATERS Al 1 iance HPLC system set up with INERTSIL ODS 3, DP 5 microns, 250 X 4.6 mm column. The gradient is from 100% Solvent A (acetonitrile, water TFA (10/90 / 0.1, v / v / 〇) to 100% Solvent 3 (acetonitrile, water, butane (90/10 / 0.1 ^^^)) in Changed within 7 minutes and maintained at 100% B for 4 minutes. The flow rate was set to 2.5 ml / min. Bifurcation of 1/10 was used just before the API source. Chromatography was performed at 30 ° C. MS conditions The sample was dissolved in Acetonitrile / water 70/30 v / v, with a concentration of about 250 // gr / ml. API spectroscopy (+ or-) uses a FINN I GAN (San Jose, California) LCQ ion trap mass spectrometer APCI is derived from 450 ° C operation, capillary heater is operated at 160 ° C. ESI source is 3.5 kV-45- 200538436 # # Operation and capillary heater is operated at 2 10 ° C. In DIP / EI mode The mass spectrometry measurement was performed as follows: The sample was heated from 50 ° C to 250 ° C for 5 minutes while the sample was vaporized. The EI (electron impact) spectrum system was connected to the quadrupole using a Fenegan (San Jose, California) TSQ 700. Recorded by mass spectrometer. Source temperature was set at 150 ° C. Specific rotation was recorded on Perkin-Elmer MC241 or 341 polarimeter. Rotation angle was recorded at 25 ° C in 1% methanol solution. Some points Due to the solubility problem, the solvent was measured using dichloromethane or DMS0. Φ The water content was measured using a Me tr ohm micro-coulometry meter Kar 1 F ischer titrator. Preparative chromatography Separation is carried out on 60 silicone Merck, particle size 15-40 microns, reference number 1.1 5 1 1 1.902 5, using Job in Yvon type axial compression tubing modified in the room (inside Diameter 80 mm), flow rate 70 to 150 ml / min. The amount of silica gel and solvent mixture is as described in the individual procedures. Preparative chromatographic separation was performed at DAICEL Chiralpak AD 20 microns , 100 * 500mm column used in the room. • The instrument is built with various low-carbon alcohols and C5 to C8 linear, branched or cyclic alkanes in the soil 3 50 ml / min. The solvent mixture is as described in the individual procedures. Melting point Measured on a Buchi 53 5 Totol i type melting meter, without correction or by using a starting temperature correction at Bergin Emma DSC 7. The powder X-ray diffraction pattern is based on ambient temperature and Atmosphere, computer controlled Philip PW 1710 is equipped with PW3710 mpd control The control unit uses a single color layer analyzer, Cu κα radiation (test tube at 40 kV, 35 mA operation) and scintillation counter. The data is in continuous scanning mode using a scanning speed of 0.02 2 0 / s at 4 degrees to 50 degrees 2 0 angle range collection. -46- 200538436

The following abbreviations are used in the examples: AcOE t ethyl acetate AcOH BuLi n-butyllithium n-Bu3P tri-n-butylphosphine CICOOEt or ClC〇2Et ethyl chloroformate DCE 1,2 dichloroethane DIC diisopropyl Methylenediamine DMSO Dimethylammonium DSC Differential Scanning Calorimetry DMF N, N-Dimethylformamide Et3N Triethylamine E120 Ether EtOH Ethanol FMOC Lithylmethoxycarbonyl LDA Diisopropylamidamine lithium MeCOCl Acetyl chloride MeCN Acetonitrile MeOH Methanol MTBE Methyl tertiary butyl ether NMP N-methylpyrrolidone PhMe Toluene Pre pLC Preparative liquid chromatography i-Pr20 Diisopropyl ether i-PrOH Isopropanol TFA trifluoroacetic acid-47-

200538436 THF tetrahydrofuran TM0F trimethyl orthoformate TMSCI chlorotrimethylsilane TMSI iodotrimethylsilane Unless otherwise stated in the examples, compounds are obtained in free form (non-salt). [Embodiment] Example 1. Synthesis of 4-substituted 2-oxy-pyrrolidinamine by reductive amination reaction of an aldehyde ester. 1.1. Synthesis of 3-substituted-4-oxy · butyrate 1.1.1.1. Route A: 5,5-dimethyl-3-methylamidino-hexanoic acid methyl ester by alkylation reaction of enamines The synthesis of ester 361 can be expressed as

362 Diisobutylamine 1 BrCH2C02CH3, PhCH3, CH3CN &quot; 18RT, 90o, .i hours then h2O (30%)

361 Diisobutylamine (4.62 ml from Acros), 4,4-dimethylvaleraldehyde in a three-necked flask equipped with a Dean-Stark device under nitrogen A solution of 362 (2.5 g, 0.021 mol) in toluene (20 ml) was heated at 130 ° C for 2 hours and extracted with water. The yellow solution was cooled to room temperature and methyl bromoacetate (3.7 g, 0.024 mol) was added in one portion. The peach-colored solution was stirred at room temperature overnight and at 9 (TC for 1 hour. Water (10 ml) was added at this temperature and the solution was cooled to room temperature after 1 hour. The organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution, and Dehydration, filtration and evaporation of magnesium sulfate -48-

200538436 Oil was obtained, and the oil was distilled under reduced pressure (1 mm Hg) to obtain 5,5-dimethyl-3 · methylmethyl-hexanoic acid methyl ester 361 as a liquid (1.1 g, 0.05 mole, Teb (1 mm Hg): 69-7 1 ° C). The aldehyde ester is then used in a reductive amination step. In addition, the alkylation reaction using ethyl bromoacetate can be performed in the presence of toluene-acetonitrile 1/1 (v / v) as a solvent. The resulting aldehyde was also distilled and left under reduced pressure. 1.1.2. Other synthetic routes Aldehydes can also be obtained by (i) alkylation with bromoacetate derivatives. For example, 5- (phenylphenyl 3-methylfluorenyl-pentanoic acid 2,2-dimethyl-ethyl ester is based on N- (4-phenyl) -propylene-N, N-dimethylphosphonium and bromine The reaction between the third butyl acetate and LDA is followed by an ozonolysis reaction of alkylated europium. (^) Nitromethane addition to,) 5-Unsaturated esters. 3- (3-Bromo-phenyl) -4-oxo-butyric acid ethyl ester was added to nitrodicyclo [5.4.0] undec-7-ene via nitromidine in the presence of 3- (3-Bromo-phenyl) -ethyl acrylate, obtained by oxy-nitro derivative under the condition of Nef and controlled hydrolysis of methyl-acetal by hydrochloric acid. (iii) Ozone decomposition reaction of 4-pentenoic acid derivatives. 2-Benzyl-4-oxy-butyric acid ethyl ester is alkylated with 3-phenyl-butyric acid ethyl ester and allyl bromide using lithium diisopropylammonium lithium, followed by ozonolysis and reduction of odor oxides by PPh3 obtain. 1 2..2. Reductive amination of 3-substituted-4-oxy-butyrate and cyclization to pyrrolidine-2 -one 1. 2 · 1. Reductive amination 4-{[((lS) -l- The synthesis of aminocarbonyl) propyl] amino} methyl butyrate 36 3 is representative. -49-

200538436

2 (S) -Aminamine MeOH, 45 ° C, 0.75h 2. NaBH4, 20eC, 4h t-Bu

(s) k 363

In a three-necked flask equipped with a reflux condenser under argon, aldehyde 361 (1.7 g, 0.09 mol), (S) -2-amino-butylamidine (1.58 g, 0.15 mol) and molecular sieve (3 A suspension of Aldrin (A 1 d 1 · i ch) in methanol was heated at 60 ° C. for 0.5 hours. The suspension 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, dehydrated with magnesium sulfate, filtered and evaporated to obtain a yellow oil. 4-{[(lS) -1-aminocarbonyl) propyl] amino} Methyl butyrate 363 was used directly in the next step without further purification. In addition, reductive amination can be performed under the same conditions using a reducing agent such as NaBH3CN or NaBH (0Ac) 3 (1.4 mole equivalents with respect to the aldehyde ester). 1 · 2. 2. Stereolysis of two (2S) -2- (4-neopentyl-2-oxy-1-pyrrolidinyl) butylamidines in cyclization of butyric acid (methyl or ethyl) esters The synthesis of isomers 149 and 148 is representative

-50-

200538436 In a three-necked flask equipped with a reflux condenser, under argon, an oil 363 was dissolved in toluene and 1,2-di in the presence of hydroxybenzotriazole (2.05 g, obtained from Alexidin). A 1/1 mixture of ethyl chloride (25 ml each), the solution was heated at 90 ° C for 2 hours and cooled to room temperature. The organic phase was washed successively with a saturated aqueous sodium hydrogen carbonate solution, water, dehydrated with magnesium sulfate, filtered and evaporated to obtain a brown solid (1.8 g), which was purified by silica gel column chromatography (eluent: CH2Cl2 / MeOH 95/05 (Wv)) to obtain (2S) -2- (4-neopentyl-2-oxy-1-pyrrolidinyl) butanamide (0.89 g, 0.0036 mole) as a diastereomer Of 1/1 mixture. Separation of the two isomers was achieved by isostatic chromatography (ethanol-hexane 1/1 (v / v)) and two stereoisomers (0.35 g and 0.35 g, respectively) after recrystallization from toluene. 0.37 g). The stereochemical properties are described in the table. In addition, the cyclization of the amino ester can be performed using an agent other than hydroxy-benzotriazole such as acetic acid (as a solvent) or 2-hydroxy-pyridine (1 equivalent). When acetic acid is used as the cyclization solvent, the reaction mixture is evaporated to dryness in vacuo, diluted with dichloromethane and worked up as before. 1.2. 3. Other cyclization reactions In addition, cyclization can be performed in two steps by (i) acid or base hydrolysis of the ester and (ii) activated ester under the usual conditions described in peptide synthesis. 1.3. Solid-phase synthesis of pyrrolidone 1. 3. 1 FMOC-protected amino acids are attached to the boronamine resin. \ 铃 gram resin Λ. .

DIC, DMF .NHFmoc • γ- -51-

200538436 4 g of linacamide resin (0.51 meq / g, 100-200 mesh) was placed in a glass container and stirred at 20% v / v hexahydropyridine / DMF (40 ml for 30 minutes. The resin was drained, The entire deprotection was repeated. The resin was filtered, washed (6XDMF) and dehydrated. The resin was suspended in DMF (40 ml) and treated with N-Fmoc-2-aminobutyric acid (3.02 g, 9.28 mmol), followed by Treated with a solution of 1,3-dicyclohexylmethyldiimine (1.4 g, 11.13 mmol) in DMF (20 ml). The reaction was stirred at room temperature for 1 hour and then filtered, washed (DMF) and repeated coupling. Treatment. The resin was filtered, washed (6X DMF, 6XCH2C12), dehydrated and used as such in the next steps.

1.3.2. Reductive amination and cyclization by adding 5-hydroxy-4-propyl-furan-2-one

100 mg of N-Fmoc-2-aminobutyramine resin (0.051 mmol) was contained in a frosted polypropylene syringe. Removal of the Fmoc group was achieved in DMF using 20% hexahydropyridine. To the amino resin was added 5-hydroxy-4-propyl-furan-2-one (36.72 mg, 0.25 mmol) to DCE (2 ml). The resin was then treated with acetic acid (15 µl) 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 the following solvents: H20 / DMF (1: 1), DMF, CH2Cl2, MeOH and dehydrated. The resin was suspended in a trifluoroacetic acid / dichloromethane mixture (1/1) by vortex stirring for 4 hours, then filtered and washed (dichloromethane X 2). The filtrate was concentrated and the residue was dissolved in dichloromethane (2 ml) and concentrated again. Desired -52- 200538436 · · The compound was purified by LC-MS (Micromass Gilson, LCZ platform, RP-18 column, gradient elution 'CH3CN / H20 / TFA 1%). 1.3. 3. Reductive amination and cyclization by adding aldehyde esters.

150 mg of N-Fmoc-2 · aminobutyramine resin (0.087 mmol) was contained in a frosted polypropylene syringe. Removal of the Fmoc group was achieved in DMF using 20% hexahydropyridine. An aldehyde (0.5 mmol) was added to the amine ester to TM0F (2 ml). The reaction was stirred at room temperature for 18 hours and then filtered and washed (dichloromethane). The resin was swelled with dichloromethane, and then treated with sodium triacetoxyborohydride (22 mg, 0.104 mmol). The reaction was stirred at room temperature for another 18 hours. Then the resin was washed sequentially with the following solvents: H20X6, Me0HX6, CH2Cl2 X6 and dehydrated. The resin was suspended in a trifluoroacetic acid / water mixture (95 / S) for 1 hour with orbital agitation, then filtered and washed (dichloromethane X2). The filtrate was concentrated and the residue was dissolved in dichloromethane (2 ml) and concentrated again. The desired compound was purified by LCNMS micro mass Gilson, LCZ platform, RP-18 column, gradient elution, CH3CN / H20 / TFA 1%). Example 2. Synthesis of 4-substituted 2-oxopyrrolidine butyramine by ring-opening reaction of 4-substituted lactones. 2.1. Synthesis of lactones 2 · 1 · 1 · Route A: via alkylation of 2,3-furanone The synthesis of 4-n-butyl-butyrolactone 365 as a representative: -53-

200538436

In a three-necked flask under argon, n-butyllithium (1.6 M in hexanes, 75 ml, 0.12 mol) was added to Cu 1 (11.42 g, 0.06 mol) and cooled in anhydrous THF (80 ml) to -3 (TC suspension. After 0.5 hours, the solution was cooled to -78 ° C, TMSC1 (4.75 g, 0.04 mole) was added dropwise, followed by 2,3-furanone 364 (from Arylene, 3.36 g Mol), dissolved in anhydrous THF. The suspension was warmed to room temperature and hydrolyzed with saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate (3 times), washed with water, dehydrated with magnesium sulfate and Evaporate to dryness. Crude lactone is purified by distillation (1 mm Hg; 73-80 ° C) to obtain 2.7 g of 4-n-butyl-butyrolactone 365. In addition, the copper acid reactant can be prepared by replacing organic lithium with organic magnesium Organomagnesium can be obtained by reacting alkyl halides with magnesium sulphate under the usual conditions of this conversion reaction. THF can be replaced by ether (for general information please refer to: Lipshutz, BH; Sengupta, S. Organic reactions 1991, 41, 135 ). 2.1.2. Other routes In addition, lactones can also be obtained by (i) reduction of succinate through the following routes. 4- (cyclopropyl) methyl-butane Lactones are alkylated with monomethyl succinate by cyclopropylmethyl bromide with lithium diisopropylammoniumamine, and then 2- (cyclopropyl) methyl-butane is reduced by NaBH4 &amp; CaCl2 Acid 1-methyl ester. (Ii) Reduction of 1-alkyl succinate 4-alkyl thioester. 4-Allyl-butyrolactone is derived from ethyl 4-pentenoic acid thioester (derived from 4-pentenoic acid and ethyl mercaptan-54- 200538436 # · Synthesized in the presence of dicyclohexylmethamine aldimine). Ethyl 4-pentenoic acid thioester with diisopropylhydrazone by ethyl bromoacetate Lithium amine alkylation to obtain 2-allyl · succinate 1-methyl 4-ethylthioester, which is then converted to 4-allyl-butyrolactone by sequentially reacting with Li BH4 and sulfuric acid. 2.2. Synthesis of pyrrolidone 2.2.1.1. Alkylation / alkylation of butamidamide (2S) -2- (4-allyl-2-oxy-1-pyrrolidinyl) butanamine 228 The synthesis of two isomers of 224 and 224 is representative:

-Step 1: Open the lactone in a three-necked flask under argon, and add TMSI (51 ml, Acrylate) to the crude 4-allyl-butyrolactone 3 66 (refer to procedure §2.1.3., 22.9 G, 0.181 mole) solution cooled to 0 ° C. The solution was stirred at room temperature for 2 hours and hydrolyzed with 1N hydrochloric acid (300 ml). The aqueous layer was extracted with dichloromethane, and the organic phase was washed with brine, dried over magnesium sulfate, and concentrated in vacuo to obtain crude 3- (iodo) methyl-5-hexenoic acid 367 (44.5 g). NMR (250MHz, CDC13) · 1.80-2.05 (m, 2H), 2.20 (t, 2H), 2.40-2.60 (t, 2H), 5.10-5.20 (m, 2H), 5. 15-5.80 (m, lH). -Step 2: Chlorinated iodic acid in a three-necked flask equipped with a reflux condenser under argon, sulfenyl chloride (25.5 ml) and crude iodic acid 367 (44.5 g, 0.175 mol) in benzene (90 ml The solution was stirred at room temperature for 24 hours. The solvent was removed by vacuum evaporation to obtain crude 3- (iodo) methyl-5_hexenefluorenyl chloride 368 (47 g), which was used without further -55-

200538436 Purification was used in the next step. Level 4: 250! ^ 2,00013): 1.90-2.05 (m, 2H), 2.15 (t, 2H), 2.90-3.10 (m, 2H), 3.25 (dd, lH), 3.35 (dd, 1H), 5.10-5.20 (m, 2H), 5.15-5.80 (m, 1H). -Step 3: Formaldehyde-alkylation of 5-2-amino-butylamidine in a three-necked flask under argon, crude chlorochloride 368 (47 g, 0.172 mole) in dichloromethane (300 ml ) Dropwise added to molecular sieve (29 grams), powdered potassium hydroxide (22.3 grams), anhydrous sodium sulfate (28.8 grams), 4-n-butylammonium bromide (2.8 grams, 0.0086 moles) and S-2-Aminobutyramine (U) 25d =

+ 19 · 35 degrees; 26.3 grams, 0.26 moles) in methylene chloride (470 ml) by mechanical stirring and cooling to 0 ° C suspension. The solution was stirred at -5 ° C for 5 hours. Powdered potassium hydroxide (6.2 g) was added and stirring was continued at -5 ° C for 3 hours. The reaction mixture was filtered over hefrocil (hy f 1 oce 1) and the solvent was evaporated in vacuo. The crude reaction mixture was purified by silica gel chromatography (ethyl acetate / isopropanol: 97/03 (v / v)) and preparative chromatography (hexane / ethanol) to obtain (2S) -2- ( Two isomers of 4-allyl-2-oxy-1-pyrrolidinyl) butyramine (6.0 g (228) and 5.48 g (224) respectively; 16% and 15%) Two small amounts of impurities were also separated after chromatography, namely (2S) -2- [4- (2-iodopropyl-2-oxy-1-pyrrolidinyl) butanamine 225 (0.22 g) and The two stereoisomers of 226 (0.27 g) showed a white solid after recrystallization. 2.2.2. Alkylation / Hydration of Butanamide (2S)-2- (5-nonyl-2-oxy Synthesis of the two isomers of propyl-1 -pyrrolidinyl) butanamide are as follows: Step 1: T-nononolactone (0.32 ml, 2 mmol) of lactone in sulfenyl chloride (164 Microliter-56-

200538436′2. 25 millimoles) was added to the solution at room temperature, and zinc chloride (2 mg, 0.88 millimoles) was added and the mixture was stirred for 24 hours. An excess of methanol was added, and the reaction mixture was stirred for 10 minutes and then concentrated under reduced pressure to obtain methyl 4-chloro-nonanoate, which was used as such.

Step 2: A solution of alkylated in methyl 4-chloro-nonanoate (2 mmol) in DMF (2 ml) was added with 2-aminobutyramine (1 g '10 mmol) in sequence, 300 mg of sodium iodide (2 mmol) and 276 mg of potassium carbonate (2 mmol). The mixture was stirred at 60 ° C overnight. The solid was filtered and washed with dichloromethane (2 x 2 ml). The filtrate was concentrated under reduced pressure to obtain an ester derivative, which was then used in the cyclization reaction. ^ 2

Synthesis of 2 · 3 · keto-pyrrolidin-2-one The synthesis of (2S) -2- [2-oxy- 4- (2-oxypropylpyrrolidinyl) butanamide 230 is represented by:

• 57-

200538436

In a three-necked flask, oxygen was passed through a solution of PdCl2 (0.68 g, 0.00 3 9 mol), CuC12 (1.68 g, 0.0098 mol) in N-methyl-2-pyrrolidone (NMP, 40 ml), Add (2S) -2- [2-oxy-4- (2-oxypropyl) -1-pyrrolidinyl] butanamine 224 (4.13 g, 0.020 mole) to NMP (40 ml) dropwise. Solution (addition time: 1 · 2 hours). The solution was stirred under aeration for 0.75 hours' and filtered through celite (ce1ite) and evaporated under vacuum (1mm Hg). The crude ketone was purified by silica gel chromatography (dichloromethane / methyl · third butyl ether / isopropanol 9/0 · 9/0 · 1 (ν / ν)) to obtain (2S) -2- [2- Oxy-4- (2-oxypropyl) -1-pyrrolidinyl] butanamine 230, which was a white solid after recrystallization from ethyl acetate. 2.4. Derivation of ketone 230 2.4.1. Synthesis of alcohol (2S) -2-[(4S) -4- (2-hydroxypropyl) -2-oxypyrrolidinyl] butanamine 233 as a representative :

-Step 1: Reduction In a three-necked flask under argon, NaBH4 * was added in several portions to a solution of 230 (9 g, 0.012 mol) in ethanol (14 ml) cooled to -5 ° C. The solution was stirred at this temperature for 4 hours, quenched with saturated ammonium chloride and evaporated to dryness. The solid was dissolved in methanol / dichloromethane, filtered and concentrated in vacuo. Residue at -58-

200538436 Purification by silica gel chromatography (methanol / dichloromethane: 90/10 (v / v)) gave an alcoholic mixture of 69 and 69 (2.2 g, 79%) as an oil. The crude mixture was directly acetylated in the next step. 1H NMR (400MHz, (CD3) 2SO): 0.70 (t, 3H), 1.05 (d, 3H), 1.30-1.45 (ι, 1Η), 1.70-1.80 (m, 1H), 1.80-2.05 (m, 1 Η), 2.20-2.40 (m, 2H, partially overlapping with the solvent), 3.00-3.20 (π, 1 Η), 3.30-3.3 5 (m, 2H, partially overlapping with the solvent), 3.50-3.6 5 (m 1H), 4.30 (111,111), 4.45 (111,1) 1), 7.10 (5 (width), 11〇.7.20 (s (width) 1H).

-Step 2: Acetate in a three-necked flask under argon. Acetyl chloride (0.91 g, 0.011 mole) is added to 4-N, N-dimethylaminopyridine (0.11 g, 0.001 mole) at room temperature. Ear), pyridine (0.86 ml) and alcohol in dichloromethane (90 ml). The solution was stirred for 5 hours, quenched with saturated ammonium chloride, and the aqueous layer was extracted with dichloromethane (3 times), dehydrated with magnesium sulfate and concentrated in vacuo to obtain the crude acetate, which was purified by column chromatography on the image phase (Hexane / ethanol) two kinds of epimers acetate 370 and 371 (1.143 g and 1.17 g, respectively) were obtained. 1/1 mixture of 370 and 371 before image chromatography: 沱 NMR (400MHz, CD3SOCD3): 0.9O (t, 3Η), 1.2 · 1 · 1 · 28 (ιι, 4Η), 1.51 82 (m, 4H), 1.89-1.98 (m, lH), 1.80-2.05 (m, lH), 2.04 (s, 3H), 2.16 (dd, lH), 2.38 (m, lH), 2.62 (dd , LH), 3.11 (dd, lH); 3.49 (dd, lH), 4.39-4.49 (m, lH), 4.89-4.99 (111, 111), 5.43 (5 (width), 111), 6.24 (8 ( Wide), 111). -Step 3: Deacetylation in a three-neck flask under argon, a single enantiomer of acetate 37 1 (1.11 g, 0.0042 mole) and a suspension of potassium carbonate in ethanol at 0 ° C was stirred for 20 hours, evaporated to dryness, and the crude alcohol was purified by chromatography on silica gel (methanol / dichloro-59- 200538436 φ # 甲 院 ·· 85/15 (ν / ν)) to obtain (2S) -2- [ (4S) -4- (2-Trans-propyl) -2-oxypyrrolidinyl] butanamine 233 (0.67 g, 72%), after recrystallization from acetonitrile, showed a white solid. 2.4.2. Fluorination of 230 Ketone 230 is fluorinated for the synthesis of 2-[(4S) -4- (2,2-difluoropropyl) · 2-oxypyrrolidinyl] butanamine 265.

-Step 1: Win in a Teflon bottle under argon (MeOCH2CH2) NSF3 (1.86 g, 0.009 mol) and divide into 230 (0.389 g, 0.0017 mol) in dichloromethane solution in 80 parts. ° C for 4 hours. The solution was stirred at this temperature for 4 hours, quenched with sodium carbonate, extracted with dichloromethane, washed with 1N hydrochloric acid, dehydrated with magnesium sulfate, filtered and concentrated in vacuo to obtain a third amine 372 (1.2 g) LC / MS: 3 65 ( MH +). The crude mixture was used directly in the next step. -Step 2: Hydrolysis and ammonialysis. In a three-necked flask under argon, a solution of crude 372 (0.28 g) in 6N hydrochloric acid was heated at 6 ° C for 22 hours, cooled to room temperature, and the aqueous solution was evaporated to dryness. The solid was made from acetonitrile, filtered and dehydrated in vacuo to obtain the acid (1.2 g) as a white solid. The crude mixture was amidated under standard conditions to obtain (2S) and (2R) -2-[(4S) -4 as described in § 6.3.1. (Step 2). -(2,2-difluoropropyl) -2-oxypyrrolidinyl] butanamide mixture (87% and 13% respectively). -60-

200538436 2.5. Synthesis of (2S) -2- (2-oxy-4-Ruiyl-1-pyrrolidinyl) butanamine I58 and 159

2.5.1 · Step 1 · Reductive aminated stomach in a three-necked flask under argon, 4-n-propyl-hydroxyfuranone 373 (35.5 g '0.25 mol by Bourguignon et al., Journal of Medicinal Chemistry' 1988, 31 , 893-897) was added at 18 ° C to a solution of S-2 aminobutyramide (28.1 g, 0.275 moles) 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 the addition of an aqueous solution of NaBH4 (6.2 g, 0.16 mol) in water (62 ml). After 1 hour, the reaction mixture was carefully quenched with acetic acid (30 mL), heated to 50 ° C for 3 • hours and cooled to room temperature overnight. 50% w / w sodium hydroxide (20 ml) was added and the aqueous phase was extracted with toluene (twice). The organic phases were combined, washed with brine and concentrated in vacuo to obtain crude unsaturated pyrrolidone 374 (43.4 g) as an orange oil, which was used in the next step without further purification. It can be recrystallized into a white solid (DSC, starting point: melting point = 72.9 ° C). 2.5. 2. Step 2: Hydrolysis in a three-necked flask under argon. Aqueous solution of NH4C00H (8 g, 0.126 mol) was divided into several parts and added to crude 374 (22 g, 0.105 mol) and 10%. Suspension of pd / c (1.1g) in water (220ml) heated at 5 ° C. The suspension was stirred at -61-200538436 50 ° C for 3 hours, cooled to room temperature and stirred overnight. After 18 hours,

The suspension was heated at 50 ° C, and NH4C00H aqueous solution (8 g '0.126 mol) was added in several portions. After 1.5 hours, a third portion of NH4C00H aqueous solution (8 g '0.126 mol) was added. The suspension was stirred at 50 ° C for 0.5 hours and 10% Pd / C (1.1 g) was added. The suspension was stirred at this temperature for 5 hours and allowed to stand at room temperature overnight without stirring. The reaction mixture was filtered through Celite, washed with water (30 ml), and the aqueous layer was extracted with ethyl acetate (3 times). The combined organic phase was washed with brine and concentrated in vacuo to obtain crude pyrrolidone as white crystals (18 · 1 g). The two diastereomers were separated by preparative HPLC on the image phase (ethanol / heptane: 1/1). After recrystallization from isopropyl ether, two kinds of pyrrolidone 158 (9.5 g) and 159 ( 7.2 g) as a white solid. Two solid forms 159 were observed, namely Form A and Form B. Form A is typically characterized by diffraction peaks at 8.8, 9.8, 14.9, 15.0, 17.0, 17.1, 21 · 2, 21 · 4, 24 · 8 (20 degrees). Form B is typically characterized by diffraction peaks at 6.50: 11.25, 19.22, 23.44, 28 · 47, 29.94 (20 degrees). Synthesis of 2 · 5 · 3 · 5-hydroxy-4-propyl-furan-2-one

5.Hydroxy-4-propyl-5'-furan-2-one 373 (15 g, 0.1 mol), ethyl acetate (260 ml) and Pd / C 5% were placed in a Bal device. The mixture was degassed and hydrogen was introduced into it at 35 psi. The mixture was then stirred vigorously at 25 ° C for 2 hours. After filtration through Celite, the solvent was removed at 50 ° C under reduced pressure to obtain 5-hydroxy-4-propyl-furan-2-one as a crude product (100% yield). LC / MS ·· 145 (MH +). -62- 200538436 • Example 3. Synthesis of 4-substituted 2-oxy-pyrrolidine butyrimidine by alkylating 2-oxy-pyrrolidine with 2-bromo-butyric acid ethyl ester. Synthesis of 3 · 1.4 -Substituted 2-oxy-pyrrolidine 3.1 · 1.a.1. Preparation of 3- (3-chlorophenyl) -2-acrylate 37 5 ··

In a 2 liter three-necked flask equipped with a mechanical stirrer and a dropping funnel under an inert atmosphere, 106.2 g (755 millimoles, 1 equivalent) of 3-chlorobenzaldehyde was dissolved in 1 liter of THF and cooled to 0 ° C. 341.9 g (9 80 mmol, 1.3 eq) of ethyl (triphenylphosphonyl) acetate were then added with effective stirring, and the temperature was raised to HTC. 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 suspended in ether, filtered to remove triphenylphosphine oxide, and the filtrate was concentrated to dryness. The residue was purified by preparative LC (1 kg of silica gel, petroleum ether / ethyl acetate, 75.35) to obtain 191.8 g of pure 375,92% yield.沱 NMR (250MHz, (CD3) 2SO) · 1.30 (t, 3H), 4.25 (q, 2H), 6.70 (d, 1H), 7.40 (m, 2H), 7.50-7 · 70 (π, 2Η), 7.85 (s (width), 1H). 2 · 1.. 1. A. 2. Other methods:

In addition, cinnamate derivatives are also synthesized by palladium-catalyzed formazan metallization of acrylic derivatives. For example, (2E)-3-(5 -pyrimidinyl) -2 -acrylate. Ethyl 376 is via ethyl acrylate and 5-bromopyrimidine in the presence of palladium acetate. -63-

200538436 obtained. 3.l.l.b. Preparation of 3- (3-chlorophenyl) -4-nitrobutyric acid ethyl ester 377:

In a 500 ml three-necked flask equipped with a reflux condenser, magnetic stirrer and dropping funnel in an inert atmosphere, 100 g (447 mmol, 1 equivalent) of 3- (3-chlorophenyl) -2-acrylic acid Ethyl 375 was dissolved in 127 ml (2.37 moles, 5 equivalents) of nitromethane. While maintaining the temperature below 25 ° C (ice / water bath) under effective stirring, add 70.9 ml (447 millimoles, 1 equivalent) of diazabicycloundecene dropwise. The dark red mixture was stirred at room temperature overnight. The mixture was diluted with ether, washed with 1N hydrochloric acid, and the aqueous phase was extracted twice with ether again. The combined organic phase was dehydrated with magnesium sulfate, filtered and concentrated to dryness to obtain 128.5 g of crude 377 in a 99% yield, which was used in the next step. 1H NMR (250MHz, (CD3) 2SO): 1.10 (t, 3H), 2.70 (dd, 1H), 2.75 (dd, 1H), 3.95 (q, 2H), 4.95 (m, 2H), 7.20- 7.45 ( m, 4H). 3.1.1.C: Preparation of 4-amino ethyl 3- (3-chlorophenyl) butyrate 378:

In a 2 liter pressure bottle under an inert atmosphere, 196 g (733 mmol) of 3- (3-chlorophenyl) -4-nitrobutyric acid ethyl ester 377 was dissolved in 200 ml of ethanol. Add 200 g of pre-dried (3 times, ethanol) suspension of Raney Nickel in 700 ml of ethanol and the mixture to hydrogenation in a Bar hydrogenator at a maximum hydrogen pressure of 20 psi -64-

200538436 (strong exothermic reaction, requires ice / water cooling). The mixture was degassed, filtered through a Celite / Norite pad, and the filtrate was concentrated in vacuo to give 13 6.7 g of crude 378 in 78% yield, which was used in the next step. 3_l.l.d: Preparation of 4- (3-chlorophenyl) -2-pyrrolidone 379 ··

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) butyric acid ethyl ester 3 78 was dissolved in 200 ml of toluene The mixture was refluxed for 30 minutes. The solution was concentrated to dryness, and the residue was purified by preparative LC (1 kg of silica gel, dichloromethane / ethanol, 98: 2 to 95: 5) to obtain 54.4 g of pure 379 (49.2%). GC / MS: 197 / 197M +. Preparation of 2- [4- (3-chlorophenyl) -2-oxy-1-pyrrolidinyl] butyric acid ethyl ester 380

379 geo 0 ci C 丨 In a 2 liter three-necked flask equipped with a reflux condenser, magnetic stirrer and dropping funnel, in an inert atmosphere, 54.4 g (278 mmol, 1 equivalent) 4- (3-chloro Phenyl) -2-pyrrolidone 379 was dissolved in 1.4 liters of acetonitrile. 64 ml (100.7 g, 556 mmol, 2 equivalents) of methyl 2-bromobutyrate were added and the temperature was raised to 50 ° C. Add 22.24 g (556 mmol, 2 equivalents) of sodium hydride in portions and raise the temperature to 65 ° C. The mixture was stirred for an additional hour at 50 ° C. The mixture was concentrated to dryness and the residue was suspended in ethyl acetate and washed with water -65 ·

200538436, the aqueous phase was extracted again with ethyl acetate. The combined organic phase was dehydrated with magnesium sulfate, filtered and concentrated to dryness. The residue was purified by preparative LC (1 kg of silica gel, petroleum ether / ethyl acetate, 70:30) to obtain 56.7 g of pure 380,69%. ^ NMR (250MHz, (CD3) 2SO) · 0.80 »1.0.00 (m, 3H), 1.60-1.90 (2H, m), 2.35-2.55 (ra, 1H: partially overlapping with solvent), 2.60 -2.90 (111,1} 1: Partial overlap with solvent), 3.70 (5,3) 1), 3.50-3.80 (m, 3H), 4.50 (m, lH), 7.20-7.50 (m, 4H) · 3. 1. 1. G: 2- [4- (3 -chlorophenyl) -2-oxy-1 · pyrrolidinyl] butyridine

Preparation of amine 381:

381 In a 1-liter three-necked flask equipped with a reflux condenser and a magnetic stirrer, 56 · 7 g (192 mmol) 2- [4- (3-chlorophenyl) -2-oxy-1-pyrrolidine Ethyl] butyrate 380 was dissolved in 600 ml of methanol. Gaseous ammonia passed through the solution, and the saturated solution was maintained at room temperature for 5 days, while occasionally being saturated again with ammonia. After the reaction was completed, the solution was concentrated to dryness. The residue was purified by preparative LC (1 kg of silica gel, dichloromethane / ethanol, 97: 3) to obtain 50 g of pure 38 1,97.8%, and 82.2 g of diastereomeric mixtures were separated by preparative LC ( Image combination pad AD, gasoline / ethanol, 50:50), each pair of enantiomers is optically separated by image preparation preparative LC (image combination pad AD, gasoline / ethanol, 50:50). Four compounds were crystallized from toluene to obtain 16.79 g, 13.9 g, 15.84 g, and 14.84 g of 202,203,204 and 205,72% total yields, respectively. Example 4. Alkylation / Cyclation of 4-Bromo-3-Substitution via 2-Amino-Butylamine -66-

200538436-But-2-enoate to synthesize 4-substituted 2-oxy-pyrrolidine butanamine. 4.1. Synthesis, alkylation and reduction of 4-bromo-3-substituted-but-2-enoate 4.1.1. Bromination of 3-substituted crotonic acid ethyl ester 4-mo-3- (2-thiobenzyl ) -Ding-2 · Synthesis of ethyl acetate 382

383

φ In a 2-liter three-neck flask under argon, mechanically stir the 2-thiophenyl-3-yl-but-2-ene-acid ethyl ester 383 (32.88 g, 0.211 mol), N-bromobutane Reflux solution of arsenimide (37.56 g, 0.211 mole) and 2,2, -aza-fluorene-isobutyronitrile (3.46 g '0.021 mole) in carbon tetrachloride (600 ml) 6 Hours, cooled to room temperature and stirred for 20 hours. The suspension was filtered and concentrated in vacuo to obtain the crude bromide. The crude product was purified by chromatography on silica gel (hexane / dichloromethane: 65/35 (v / v)) to obtain 4-bromo-3- (2-thiobenzene). Ethyl) -but-2-enoate 382 (36.72 g, 78%).沱 NMR (250MHz, (CDC13): 3.80 (s, 3H), 4.95 (s, 2H), 6.25 (s, 1H), 7.10 Φ (dd, lH), 7.35 (d, lH) , 7.45 (d, 1H) 4. ····························································································································································· The synthesis of pyramine 71 is represented by: -67-

200538436

4.1, 2.1. Step 1: Alkylation-Cyclopeptide in a 1 liter three-necked flask under argon, 4-bromo-2 · thiophen-3-yl-but-2-ene-acid methyl ester 382 (36.72 G, 0.134 moles), (S) -2-amino-butylamidine ([a] 25D: 19.09 degrees; 31.6 g, 0.270 moles) in THF (350 ml) in the chamber Stir for 20 hours. The suspension was filtered and concentrated in vacuo to obtain crude unsaturated pyrrolidone 384 and 385 (43.47 g), which were used in the next step without further purification. Crude pyrrolidone is separable and is usually a mixture of double bond isomers (3, 4 and 4, 5 olefins, the former being the main isomer).沱 NMR (250MHz, (CD3) 2SO): 0.80 (t, 3H), 1.30-1.90 (m, 2H), 4.40 (d, 1H), 4.45 (ni, 1H), 4.70 (d, 1H), 6.30 ( 5, 211), 7.0 (8 (width), 111), 7.15 ((1 (1,11 ^), 7.40 (8 (width), 1 ^ 〇, 7.50 (d, lH), 7.85 (d, lH) U.2. 2. Step 2: In a 0.5-liter three-necked flask under argon, divide NaBH4 (1.75 g, 0.044 mole) into crude unsaturated pyrrolidone 384/385 (1 4 G, 0.044 mol), COC1 2 (0.062 g, 0.0005 mol) in ethanol (100 ml) · Diethylene glycol dimethyl ether (65 ml) cooled to 0 ° C. Over 0.75 hours After that, the reaction mixture was heated under reflux for 48 hours. During this period, three portions of NaBH4 (1.75 g '0.045 mole) and cOCl 2 (0.062 -68- 200538436 φ # g') were sequentially added every 10 hours. 0.0005 mole) until the disappearance of the starting material. The reaction mixture was cooled to room temperature, hydrolyzed with saturated ammonium chloride, extracted with ethyl acetate, dehydrated with magnesium sulfate, and concentrated in vacuo to obtain crude pyrrolidone, which was borrowed from mortar Purification by column chromatography (dichloromethane / methanol: 9 7/0 3 (ν / ν)) gives 4. 1 5 G of 2- [2 · oxy-4- (2-thienyl) -1 · pyrrolidinyl] butamidamine (38%). The stereoisomer mixture was purified by column chromatography in an image-combining phase ( Hexane / ethanol) to obtain two diastereomers (2S) -2- [2-oxy- 4- (2-thienyl) -1 -pyrrolidinyl] butanamine 7 1 (in ethyl acetate Ester recrystallized) and 72 (recrystallized from acetic acid &gt; ethyl acetate). In this particular example, two small amounts of impurities were also obtained during purification, namely (2R) -2- [2-oxy-4- (2 -Thienyl) -1-pyrrolidinyl] butylamidine 84 (0.25 g, recrystallized from ethyl acetate) and 85 (0.44 g, recrystallized from ethyl acetate) two diastereomers. 4.2 · Synthesis of azidophenylpyrrolidinone (2S) -2- [4- (3-azidophenyl) -2-oxy-1-pyrrolidinyl] butanamine 86 single enantiomer The synthesis of things is represented by:

4.2.1. Synthesis of aniline • 69- 200538436 4.2. 1 · 1 · Step 1: Alkylation of 4-bromo-3- (3-nitrophenyl) -but-2-ene-acid methyl ester 386 (S The synthesis of -2-aminobutyramine 3 86 was performed as described in § 4.1.1.1. ] H NMR (25 0MHz, (CD3) 2SO): 1.30 (t, 3H), 4.20 (q, 2H), 5.15 (s, 2H), 6.45 (s, 1H), 7.75 (dd, 1H), 8. · 10 (dd, lH), 8.25 (dd'lH), 8.45 (d, lH). Alkylation was performed in accordance with the experimental procedure of § 4.1.2 · 1 (59%). LC / MS: 290 (MH +). ^ 4.2.1.2. Step 2: Reduction in a 2.5-liter pressure bottle under an inert atmosphere, 7.22 g (0.025 mol) 387 and palladium / charcoal (10% w / w, 0.2 g) Dissolved in ethanol (1 liter) and the mixture was hydrogenated in a Bar hydrogenator at a maximum hydrogen pressure of 20 psi. After 1 hour, the mixture was degassed, filtered through a celite / nolite pad, and the filtrate was concentrated in vacuo to obtain crude pyrrolidone, which was purified by silica gel column chromatography (dichloromethane / methanol: 93/07 (v / v)) Obtaining a mixture of diastereomers, which is obtained after purification by column chromatography (hexane / ethanol) and hydrochloric acid in ethanol (for the synthesis of the hydrochloride salt) (2S) -2- [4- (3-Aminophenyl) -2- # oxy-1-pyrrolidinyl] butanamine 90 (0.800 g, recrystallized in ethanol) and 91 (1.21 g, recrystallized in ethanol ) Two diastereoisomers, synthesized as HCl 4.2.2. Phenylazide 86. In a three-necked flask under argon, a solution of sodium nitrite (0.232 g, 0.0037 mol) in water (1.5 ml) was added dropwise to (2S) _2-[4_ (3-aminophenylphenyl) ) -2-oxy-1-pyrrolidinyl] butanamide 90 free state base (0.8 g, 0.0031 mole) was cooled to a solution of (TC) in 10 M hydrochloric acid (6.5 ml). After 0.5 hours, add NaN3 (0.2 20 g, 0.0037 mol) to -70-

200538436 water (2 ml), the resulting solution was stirred at 0 ° C for 0.5 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 obtain crude pyrrolidone, which was purified by silica column chromatography (dichloromethane / methanol: 97/03 (v / v)) and obtained after recrystallization from acetonitrile. 0.42 g of (2S) -2- [2-oxy-4- (3-azidophenyl) -1-pyrrolidinyl] butanamine 86 as a single enantiomer 86 (48%).

Synthesis of 4 · 3 · (2S) -2- [4- (3-Amino-2,4,6-tribromophenyl) -2-oxy-1-pyrrolidinyl] butanamine 107

In a three-necked flask under argon, a solution of Ph3PCH2PhBr3 (2.870 g, 0.048 mol) and 90 (0.420 g, 0.0016 mol) in dichloromethane (10 ml) and methanol (5 ml) and sodium bicarbonate ( 0.407 g, 0.048 mol) and stirred at room temperature for 4 hours (orange solution). The reaction mixture was filtered and concentrated in vacuo to obtain crude aniline, which was purified by silica gel column chromatography (ethyl acetate / ethanol 98/02 (v / v)) to obtain 0.38 g of expected aniline 107 (47%, recrystallized from ether). . 4.4. (2S) Synthesis of 2- [4-methyl-2-oxy-1-pyrrolidinyl] butanamine 35 and 36 -71-

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35 and 36 were obtained by purifying racemic mixture 389 in a stationary phase using ethanol and hexane as solvents. The 35 series was obtained as white crystals after recrystallization from i-Pr20Et. 36 was obtained as white crystals after recrystallization from ether. Example 5. Derivation of 4-substituted 2-oxy-pyrrolidine butyrimidine via derivatization with methylamino) propyl] -5-oxy-3-pyrrolidine carboxylic acid methyl ester 1 1. 5.1. Synthesis of 1- [1- (aminocarbonyl) propyl] -5 -oxy-3-pyrrolidinecarboxylic acid methyl ester 11/12

This transformation is described in § 7 · 0 · 1 to produce two esters 11 and 12. 5.2. Synthesis of 1- [2S-1- (aminocarbonyl) propyl] -5-oxy-3-pyrrolidinecarboxylic acid 48

In a three-necked flask under argon, a solution of 1N sodium hydroxide (126 ml) was added to a solution of the enantiomerically pure ester 1 1 (22.62 g, 0.1 mol) in methanol. After 1.5 hours at this temperature, the reaction was acidified by 1 n hydrochloric acid (109-72-200538436 liters), the solvent was removed by evaporation in vacuo, the residue was extracted with isopropanol, filtered and the filtrate was concentrated in vacuo to obtain the crude acid. (17.82 g), recrystallized from acetonitrile to obtain enantiomerically pure 1- [2S-1- (aminocarbonyl) propylb 5-oxo-3-pyrrolidinecarboxylic acid 48. 5.3. Synthesis of (23) -2- [4- (1,3,4-fluorenediazole-octyl) -2-oxy-1-pyrrolidinyl] butanamide 50

Step 1: Reaction with tritium In a three-necked flask under argon, a solution of the ester 11 (3 g, 0.013 mol) and the dehydrated compound (0.7 ml) was stirred in ethanol (3 ml) for 24 hours. The yellow solution was then concentrated to obtain crude hydrazine 391, which crystallized upon standing (2.37 g, 79%). GC / MS ·· 228 (M +). Step 2: Synthesis of Esotriazole • In a three-necked flask under argon, crude hydrazine 391 (this patent, 3 g, 0.013 mole), triethyl orthoformate (2 ml) and p-toluenesulfonic acid (0.010 g) ) The solution was heated at 110 ° C for 24 hours. The reaction mixture was cooled to room temperature, and concentrated in vacuo to obtain crude oxadiazole, which was purified by silica gel chromatography (dichloromethane / methanol · 95/05 (v / v)) to obtain (2S) -2- [4- (l, 3,4-fluorenediazol-2-yl) -2-oxy-1-pyrrolidinyl] butanamide 50 (0.312 g) was in oil. 5.4. Synthesis of 1,3,4-bisoxazole derivatives In addition, 1,3,4-bisoxazole derivatives were obtained from hydrazine 391. For example, 2- [2-oxy-4-(5-sulfanyl-1,3,4-fluorenediazole-2 -yl) -1 -pyrrolidinyl] butan-73- 200538436 · # amine 5 1 It was obtained through the reaction of 胼 39 1 with CS2 and potassium hydroxide in ethanol. 5.5. Synthesis of 4-amino-pyrrolidin-2-one 392

5.5.1. Step 1: Synthesis of carbamate 393

Enantiomerically pure 1- [2S-1- (aminocarbonyl) propyl] -5-oxy-3-pyrrolidincarboxylic acid 48 (19.06 g, 0.089 mole) in a three-necked flask under argon A solution of diphenylphosphonium azide (26.9 g, 0.097 mol) and triethylamine (π.5 ml) in acetamidine (225 ml) was heated at 55 t with nitrogen to form nitrogen. The temperature was maintained at 55 ° C for 0.5 hours, and maintained at 70 ° C for 2 hours and cooled to room temperature. Add benzyl alcohol (9.25 ml) and reflux the solution for 4 hours, cool to room temperature and concentrate in vacuo. The crude carbamate was purified by silica gel chromatography (ethyl acetate / methanol / ammonium hydroxide · 95/04/01 (v / v)) to obtain two diastereomeric carbamates 394 (2.64 g, 9.3%) and 393 (11.9 g, 42%). As for 393: 沱 NMR (250MHz, (CDC13): 0.90 (t, 3H), 1. 30 -74- 200538436 · -1.90 (ι, 2Η), 2.35 (dd, 1H), 2.75 (dd, 1H) , 3.30 (dd, lH), 3,75 (m, lH), 4.30-4.50 (m, 2H), 5.10 (s, 2H), 5.35 (s, (width), lH), 5.11 (s (width) , 1H), 60.40 (s (width), 1H), 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 under an inert atmosphere, 11.9 g (0. 037 mmol) of 393 and palladium / charcoal (10% w / w, 0.2 g) were dissolved in ethanol (300 ml). And the mixture was hydrogenated in a Barr hydrogenator at a maximum hydrogen pressure of 20 psi. After 20 hours, the mixture was degassed, filtered on a Celite / Nolette pad and the filtrate was concentrated in vacuo to obtain the crude amine, which was recrystallized from toluene to give 2- [4-amino-2-oxy-1 · pyrrolidine Methyl] butylamidine 392 (6.99 g, quantitative yield). 5.6. Synthesis of 4-pyrrolidin-2-one 223

In a three-necked flask under argon, 2- [4-amino-2-oxy-1-pyrrolidinyl] butanamine 393 (6.99 g, 0.037 mole), dimethoxytetrahydrofuran (5.53 g, 0 · 041 mol), 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 by silica gel chromatography (dichloromethane / methanol: 95/05 (Wv)) to give 223 as an oil (2.67 g, 30 1%) 0 5.7. 4-Pyrrolyl-pyrrolidin-2-one 223 bromide-75-

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2S-4-pyrrole-pyrrolidin-2-one 223 is a single enantiomer (1.18 g, 0.0049 mole) in THF (35 ml) in a 0.25 liter three-necked flask under magnetic stirring under argon. The degassed solution was cooled to -78 ° C and N-bromosuccinimide (0.877 g, 0.005 mole) was added in portions. The reaction mixture was stirred for 0.5 hours, and sodium thiosulfate (0.9 g) was added to quench the NBS. The reaction mixture was warmed to room temperature, concentrated in vacuo and purified by silica gel chromatography (ethanol / dichloromethane · 05/95 (v / v)). (2S) -2- [4 was obtained after recrystallization from acetonitrile. -(2-Bromo-1H-pyrrole-1-yl) -2-oxy-1-pyrrolidinyl] butanamine 234 (1.05 g, 67%) as a white solid. In addition, using the same experimental procedure and 2 equivalents of N-bromo-succinimide, dibromopyrrole 237 was obtained. 5.8. Synthesis of Tetrazolyl Derivatives In addition to §5.6, 2- [4-amino-2-oxy-1-pyrrolidinyl] butanamide and triethyl orthoformate, sodium azide and The acetic acid reaction gave 2- [2-oxy- 4- (1fluoren-tetrazol-1-yl) -1-pyrrolidinyl] butanamide 67. 5.9. Synthesis of (4H-1,2,4-tetrazol-4-yl) derivatives. In addition to §5.6, 2- [4-Amino-2_oxy-1-pyrrolidinyl] butanidine Amine reacts with pyridine and 1,2-fluorene (dimethylamino) methylene) hydrazine to obtain 2- [2-oxy- 4- (4H-1,2,4-triazol-4-yl)- 1-pyrrolidinyl] butamidamine 65 and 66. Example 6. Synthesis of 4-Substituted 2-oxy-pyrrolidine butyrimidine via the alkylation of 1- [1- (third butoxycarbonyl) propyl] -5-oxy-3-pyrrolidinylcarboxaldehyde 396. 6.1. 1-[1- (Third-butoxycarbonyl) propyl] -5 -oxy-3 · pyrrolidinecarboxaldehyde -76-

200538436 396 Synthesis Step 1: Condensation of 2-aminobutyrate with methyl itaconate

In a 1 liter three-necked flask under argon, 2,2-dimethylethyl (s) -2-aminobutyrate (commercially available, 46.6 g, 0.26 8 mol) and dimethyl itaconic acid ( 83 ml, 0.59 mol) solution was refluxed in methanol (400 ml) for 20 hours. The mixture was stirred at room temperature for 20 hours, and concentrated in vacuo. The residue was purified by chromatography on silica gel (dichloromethane / methanol: 97/3 () ^)) to obtain 1-[(13) -1- (third butyl Oxycarbonyl) propyl] -5-oxy-3-pyrrolidinecarboxylic acid methyl ester 397 (81.6 g, quantitative yield). Analysis of a 1/1 mixture of l-[(lS) -l- (third butoxycarbonyl) propyl] -5-oxy-3-pyrrolidinecarboxylic acid methyl ester 397: 4 NMR (250MHz, (CD3) 2SO ): 1.05 (t, 3H), 1.44 (s, 9H), 1.60 -1.65 (m, lH), 1.65-1.90 (m, lH), 2.40-2. 65 (m, 2H and solvent part signal overlap ), 3.30-3.65 (m, 3H), 3.70 (s, 3H), 4.40 (dd, 1H "In addition, the reaction can also use racemic 2,2-dimethylethyl-2-amino-butyric acid The ester was obtained to obtain racemic butylamine with similar yields. Step 2: Synthesis of 醯 396.

The reduction of ester 397 to alcohol 398 -77- 200538436 was carried out using the method described in § 7.0.2. Using 397 as a single enantiomer, a mixture of two enantiomers or one of four stereoisomers 1/1 mixture was performed. As for (2S) -2- [4- (hydroxymethyl) -2-oxy-1 -pyrrolidinyl] butyric acid third butyl 398-1 / 1 diastereomer mixture: GC / MS: 257 M + 〇 oxidation to aldehyde 396 in a three-necked flask under argon, (2S) -2- [4- (hydroxymethyl) -2-oxy-1 · pyrrolidinyl] butyric acid third butyl ester 398 ( A solution of 4.0 g, 0.016 mol) in dichloromethane (8 ml) was added to Ci: 03 (6.2 g, 0.062 mol) in pyridine (1 1.3 ml) / dichloromethane (80 ml) 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. The filtrate was washed with 1N hydrochloric acid, brine, dehydrated with magnesium sulfate and concentrated in vacuo to obtain crude aldehyde. The aldehyde was purified by silica gel column chromatography (hexane / acetone 70/30 (v / v). ) 2.03 g of l-[(lS) -l- (third butoxycarbonyl) propyl] -5-oxy-3-pyrrolidinecarboxaldehyde 396 (41%) was obtained. Alternatively, racemic esters can be used to obtain racemic aldehydes with similar yields. Analysis of a 1/1 mixture of l-[(lS) -l- (third butoxycarbonyl) propyl] -5-oxy • -3-pyridinecarboxaldehyde 396: 屮 NMR (250MH, (CDC13) : 0 · 91 (t, 3H), 1.44 (s, 8H), 1.55-1 · 77 (m, 1H), 1.90-2.15 (m, 1H), 2.63-2.82 (m, 2H), 3.47-3.61 (m, lH), 3.65-3.79 (m, lH), 3.83-3.94 (m, 1H of one of the diastereomers), 4.48-4.62 (111, 1 ^ 1), 9.74 (8 (Wide), 110.2.1. Alkylation reaction of l-[(lS) -l- (third butoxycarbonyl) propyl] -5-oxy-3 · pyrrolidinecarboxaldehyde 396 6.2.1. Ethylene Synthesis of derivatives. Instead of § 6.2.3, olefinic derivatives can be passed through 1-[(1 S) -1-(Third-78-200538436 · Butoxycarbonyl) propyl] -5-oxy-3 -Pyrrolidine carboxaldehyde 3 96 and money salt in the presence of a strong base by Witti (wi 11 ig) alkylation reaction. For example (2 S)-2-(2-oxy-4-vinyl · 1- Pyrrolidyl) butyric acid 2,2- (dimethyl) ethyl ester is obtained through the reaction of aldehyde 396 with Ph3PCH3Br and n-BuLi in THF. 6.2.2. Through alkylation using Ph3P / CBr4

Instead of § 6.2.3, halovinyl derivatives may be passed through 1-[(1 S) -1-(third butoxycarbonyl) propyl] -5-oxy-3-pyrrolidinecarboxaldehyde 3 96 It is obtained by carrying out Wittig reaction in the presence of phosphine and methyl halide. For example, (2S) -2- (2-oxy-4- (2,2-dibromovinyl) -1-pyrrolidinyl) butyric acid 2,2- (dimethyl) ethyl ester is based on triphenyl CBr4 from aldehyde 396 in the presence of phosphono. 6.2.3_ Through the use of ("^ 21 ^) 3? / 0? 231 * 2 alkylene

(2S) -2- (2-oxy-4- (2,2-difluorovinyl) -1-pyrrolidinyl) butyric acid 2,2- (dimethyl) ethyl ester 399 The synthesis of enantiomers is representative. In a three-necked flask under argon, (Me2N) 3P (89.8 g, 0.55 moles) was added to a solution of CF2Br2 (58 g, 0.25 moles) in THF (280 ml) at -78 ° C (white appears Precipitation) and warm to room temperature. Aldehyde 396 was added dropwise to a previously prepared scale salt as a solution of a 1/1 mixture of diastereomers (35.2 g, 0.138 mol) in THF. After 1 hour, the reaction mixture was filtered through Celite and concentrated in vacuo. The reaction mixture was diluted with hexane, washed with brine, dehydrated with magnesium sulfate and concentrated in vacuo to obtain crude olefins. The olefins were purified by silica gel column chromatography (dichloromethane / methanol 99/01 (v / v)) to obtain 34.6 g (2S) -2- (2-oxy- 4- (2,2-difluorovinyl) -1-pyrrolidinyl) butanoic acid-79- 200538436 · 2,2- (dimethyl) ethyl 1/1 diastereomer mixture of ester 399 (87%). NMR (250MHz, (CD3) 2S〇): 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 and solvent partially overlap), 3.00-3.35 (m, 2H), 3.45-3.55 (m, 1H), 4.20-4.40 (m, 1H), 4.60 (ddd , 1H—a diastereomer), 4.75 (ddd, 1H another diastereomer). 6.2.4. Using (nBu) 3P / CCl3F alkylation instead of § 6.2.3 ·, halovinyl derivatives may be passed through 1-[(1 S) -1-(gth tributoxycarbonyl) propyl] -5-oxy-3-pyrrolidinecarboxaldehyde 3 96 was obtained by carrying out a Wittmann alkylation reaction in the presence of phosphine and methyl halide. For example, 2- (2-oxy-4- (2- (Z) -fluorovinyl) -1-pyrrolidinyl) butanoic acid is derived from aldehyde 396, CFC13 and n-Bu3P were reacted, followed by sodium hydroxide to dephosphorylate the intermediate ethylene scale. 6.2.5. Synthesis of 4-cyano-pyrrolidone In addition, 4-cyano-pyrrolidone derivatives can be passed through 1-[(1 s) -1-(third butoxycarbonyl) propyl] -5 -Oxy-3-pyrrolidinecarboxaldehyde 396 is obtained by reaction with hydroxylamine followed by reaction with selenium oxide. • 6.3. 2.2 Amination of dimethyl-ethyl esters 6. 3. 1. Deprotection and ammonolysis using trifluoroacetic acid (23) -2- (2-oxy-4- (2,2-di The synthesis of two diastereomers of fluorenylbutyryl) butylamine 213 and 222 is represented by: -80-

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Step- 丄 "__2 ^ 1 Dimethyl) ethyl ester is removed in a three-necked flask under argon, (2S) -2- (2-oxy-4 · (2,2-difluoroethylene) ) -1 · pyrrolidinyl) butyric acid 2,2- (dimethyl) ethyl ester 399 (31.8 g '0.110 mole) in trifluoroacetic acid (170 ml) and methylene chloride (500 ml) The / 1 diastereomeric mixture solution was stirred at room temperature for 20 hours. The reaction mixture was evaporated to dryness. The residue was dissolved in toluene and evaporated to dryness again to remove trifluoroacetic acid to obtain 32 g of crude acid, which was used in the next step without further purification. LC / MS: 234 (MH +) Step 2: Activation and ammonolysis In a three-necked flask, add ClCOOEt (23 mL, 0.24 mol) to the acid mixture (25.6 g, 0.11 mol) by mechanical stirring under argon. The solution was cooled to -15 ° C in dichloromethane (250 ml) and triethylamine (33.7 ml). The reaction mixture was stirred at -1 (TC for 1.5 hours, then gaseous ammonia was passed through the solution while maintaining the temperature below 0 ° C. The suspension was stirred for 1 hour, warmed to room temperature, filtered, and the filtrate was evaporated in vacuo. Crude Amine was purified by silica gel column chromatography (dichloromethane / ethanol 99/01 (v / v)) to obtain 23 g of (2S) -2- (2-oxy- 4- (2,2 · difluoroethylene) ) -1-pyrrolidinyl) butyric acid 2,2- (dimethyl) ethyl ester 1/1 diastereomeric mixture, which was purified by column chromatography (hexane / Ethanol) to obtain two diastereomers 213 (10.1 g recrystallized from isopropyl ether) and 222 (1 1.2 g recrystallized from isopropyl ether). 200538436 · 6. 3.2 Tea phenol borane is deprotected. Four diastereoisomeric systems of 2- (2-oxy- 4- (2,2-dimethylvinyl) -1-pyrrolidinyl) butanamine 163 Via 2- (2-oxy-4- (2,2-dimethylvinyl) -1-pyrrolidinyl) butanoic acid, 1/1/1/1/1 The diastereomeric mixture is reacted with bromocatecholborane to obtain an acid, which is then obtained by amination under the conditions described in §6.3.1 (step 2). 6. 4. Synthesis of acetylenic derivatives 6.4.1. Synthesis of 2- (4-ethynyl-2-oxy-pyrrolidinyl) butanamine 206/207

In a three-necked flask under argon, n-butyllithium (1.6 M in hexanes, 116 ml) was added to 2- [4 · (2,2 · dibromovinyl) -2-oxy-1 -Pyrrolidinyl] butamidamine, a 1/1 mixture of two diastereomers (stereochemistry indeterminate, 10.95 g, 0.031 mole) was cooled in THF to -78C. The white suspension was stirred at this temperature for 1.5 hours, quenched with methanol (120 ml), warmed to room temperature and concentrated in vacuo. The crude alkyne was dissolved in ethanol / dichloromethane (10./90 v / v), filtered through Celite, and concentrated in vacuo. The obtained solid was subjected to silica gel chromatography (ethanol / dichloromethane: 10/90 (v / v )) And sequential purification by chromatographic chromatography (ethanol / hexane) to obtain 2 · (4-ethynyl-2-oxy-1-pyrrolidinyl) butanamide 206 (0.84 g, from toluene Recrystallisation) and 207 (0.44 g 'recrystallisation from toluene) two diastereomers. In addition, the 2- (4-bromo-ethynyl-2-oxy-1_pyrrolidinyl) butanamide 267 is passed through the 2-[4 · (2,2-dibromovinyl) -2-oxy- 1-pyrrolidinyl] -82- 200538436 · Butylamidine 47 was obtained by reacting 2 equivalents of potassium tert-butoxide in THF at low temperature (-5 ° C to 0 ° C). 6 · 4 · 2. Synthesis of 2- (4 · propyne-1 -yl-2-oxy-1 -pyrrolidinyl) butanamine 280

In a three-necked flask under argon, methyl zinc chloride (prepared from methyl lithium (1.5 in ether, 6.14 ml) and zinc chloride (1.25 g) in THF (15 ml)) was added to CuCN (0.82 g) and A solution of LiCl (0.78 g) in THF (10 mL) at -10 ° C. In another three-necked flask under argon, NaH (80% in oil, 0.097 g) was added to 2- (4-bromo-ethynyl-2-oxy-1 -pyrrolidinyl) butanamide (1 g, 0.0036 moles) in THF (20 ml) at -10 ° C, followed by zinc chloride (0.50 g). The amidine solution was then added dropwise to the organic copper salt cooled at -78 ° C. The reaction mixture was stirred at this temperature for 3 hours and allowed to warm to room temperature overnight. After hydrolysis with a saturated ammonium chloride aqueous solution, the aqueous layer was extracted with dichloromethane, dehydrated with magnesium sulfate, filtered and concentrated in vacuo to obtain crude alkyne. The crude alkyne was purified by chromatography (ethanol / hexane) to obtain -(4-propyn-1-yl-2-oxy-1-pyrrolidinyl) butanamide 280. 6.5. Hydrogenation of olefinic pyrrolidone by 4- [4- (2,2-difluoroethyl) · 2 · oxy-1-pyrrolidinyl] butanamine 1 5 7 The synthesis of a mixture of enantiomers 1/1/1/1 is represented by: -83-

200538436 ·

In a 0.25 liter pressure bottle under an inert atmosphere, 1 g (0.0043 mmol) of 156 and palladium / charcoal (10% w / w, 0.2 g) were dissolved in ethanol (50 ml), and the mixture was hydrogenated in a Bal hydrogenator. . After 20 hours, the mixture was degassed,

Filtered on a Celite / Nolite pad, the filtrate was concentrated in vacuo to obtain crude fluoroalkane, and the fluoroalkane was recrystallized from toluene to obtain 2- [4- (2,2-difluoroethylbuth 2-oxy-1 -pyrrolidine). [1]] Butamidine 1 57 A 1/1/1 mixture of the four diastereoisomers as a white solid (0.75 g). 6.6.2 2- [4- (5-methyl-1,3-oxazole Synthesis of 2--2-yl) -2-oxy-1-pyrrolidinyl] butanamine 62 and 63

Step 1: Hydrolysis of the ester in a three-necked flask under argon, 1N sodium hydroxide (39 ml) was added to 1- [1- (third butoxycarbonyl) propyl] -5-oxy-3-pyrrolidine Methyl carboxylate 397 is a 1/1/1/1 mixture of 4 stereoisomers (10 g, 0.035 mole) in methanol (100 ml) in a solution of 20 t. The solution was stirred for 0.5 hours, evaporated to -84- 200538436 dry and acidified to pH = 1 with 1 N hydrochloric acid. The aqueous layer was extracted with ethyl acetate, dehydrated with magnesium sulfate, filtered and concentrated in vacuo to obtain crude acid 400 (8.45 g) as a white solid, which was used in the next step without further purification. 1H NMR (250MHz, (CD3) 2SO): 0.80 (t, 3H), 1.44 (s, 9H), 1.55-1.60 (m, 1H), 1.70-1.95 (111, 111), 2.40- 2.55 (111, 21 ^ Overlaps with solvent part), 3.10-3. 55 (m, 1H overlaps with solvent part), 4.45 (dd, 1H). Step 2: Synthesis of ammonium 401 $ In a three-necked flask under argon, add ethyl chloroformate (0.50 ml, 0.005 mole) to acid 400 (0.678 g, 0.0025 mole) in dichloromethane (10 ml) and Triethylamine (0.77 ml) was cooled at -20 ° C. The reaction mixture was stirred at -10 ° C for 1.5 hours, and then propargylamine (0.36 ml) was added to the solution while maintaining the temperature below 0 ° C. The suspension was stirred at 0 ° C for 1 hour, warmed to room temperature, filtered and the filtrate was evaporated in vacuo. The crude amidine was purified by silica gel column chromatography (dichloromethane / methanol 98/02 (v / v)) to obtain 0.8 g of propynamide 40 1 as one of four diastereomers. 1/1 mixture.

] H NMR (250MHz »(CD3) = SO): 0.80 (t, 3H), 1.44 (s, 9H) φ, 1.55-1.65 (m, lH), 1.70-1.95 (m, lH), 2.40- 2.55 (m, lH and solvent partially overlap), 3.0-3.70 (m, 3H and solvent partially overlap), 3.70-3.90 (π, 2Η), 4.45 (m, lH), 8.45 ( m, lH). Step 3: Synthesis of oxazole 402 in a three-necked flask under argon, osmium 402 (0.77 g, 0.0025 mol) in acetic acid (40 ml) and Hg (OAc) 2 (0.048 g, 0.0001 5 mol The solution was refluxed for 1 hour, the reaction was cooled to room temperature, concentrated in vacuo and hydrolyzed with saturated sodium carbonate. The aqueous layer was extracted with dichloromethane and the organic phase was washed with brine. Dehydrated with magnesium sulfate, filtered and concentrated in vacuo to obtain the crude compound. The crude -85 · 200538436 compound was purified by silica gel chromatography (hexane / ethyl acetate 5 0/50 (v / v) to obtain pure oxazole 402 (0.15 g, 20%). GC / MS: 308 (M +) can be similar to 6.3.1. Conversion to 62 and 63 by ammonia hydrolysis 6.7. Synthesis of tetrazole 6.7.1. Synthesis of unsubstituted tetrazole

In a three-necked flask under argon, a solution of racemic nitrile 403 (2.66 g, 0.011 mol), and a solution of hydrazine (4.8 g, 0.073 mol) and triethylamine hydrochloride (10.12 g) was prepared. 110 ° C was heated in DMF (60 ml) for 2 hours. Cool to room temperature and evaporate in vacuo. The crude product was purified by silica gel chromatography (dichloromethane / methanol / acetic acid: 90/08/02 (v / v)) to obtain racemic tetrazolate 404 (3.42 g, 0.010 mole) as diastereomers. 1/1/1/1 mixture of structures. LC / MS: 295 (MH +). 6.7.2. Alkylation of tetrazole

Racemic tetrazole 404 (5.6 g, 0.019 mol), potassium carbonate (2.88 g) and methyl iodide (1.3 ml) in a three-necked flask under argon under argon -86- 200538436 The suspension was stirred at room temperature for 29 hours and evaporated in vacuo. The crude mixture was purified by silica gel chromatography (MTBE / hexane 50/50 (v /) to obtain two regioisomers, tetrazolium 405 (1.98 g, 34%) and 406 (1.03 g, 17%). Oil. LC / MS: 309 (MH +). 6.8. Synthesis of thiazole 6.8.8. Synthesis of thiamine

6.8.1.1. 397 ammonolysis In a 0.5-liter three-neck flask equipped with a reflux condenser and a magnetic stirrer addition tube, 10 g (0.035 mmol) of 397 was dissolved in 100 ml of methanol. Gaseous ammonia passed through the solution, and the saturated solution was maintained at room temperature for 1 day, while occasionally being saturated with ammonia again. After the reaction was completed, the solution was concentrated in vacuo to obtain crude amidine 407 (9.6 g, 100%). NMR (250MHz, (CD3) 2S0): 0.85 (t, 3H), 1.44 (s, 9H), 1.55-1.60 (m, lH), 1.70-1.95 (m, lH), 2.40-2.60 (m, 2H and Solvent partially overlap), 3.0- 3.70 (m, 1H and solvent partially overlap), 4.35-4.45 (〇1, 1 ", 6.95 (8 (width), 1} 1), 7.40 (8 (width), 1Η) 〇6.8. 1 · 2 · Synthesis of thioxamine 408 in a three-neck flask under argon, crude amine 407 (6 g, 0.022 mol), P4S1Q (4.93 g, 0.011 mol) and sodium bicarbonate ( 3.73 g) in acetonitrile (100 ml), and the valley solution was stirred at 5 C for 6 hours. The reaction mixture was filtered, concentrated in vacuo, and the crude thiamine was purified by silica gel chromatography (ethyl acetate / -87-200538436). Hexane: 50/50 (v / v)) was recrystallized from ethyl acetate to obtain thiamine 408 (3.7 g, 60%). GC / MS: 286 (M +). 6.8.2. Substituted thiazole synthesis

In a three-necked flask under argon, thiamine 408 was a 1/1/1/1/1 mixture of 4 diastereomers (this patent, 1.5 g, 0.005 mole), and alumina (12 g ) And a solution of 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 concentrated in vacuo to obtain crude thiazole 409 (0.5 g, 30%), which was used in the next step without further purification. GC / MS: 324 (M +). 6.8.3. Synthesis of unsubstituted thiazole. In addition, unsubstituted thiazole can be generated via thiamine 408, aluminum oxide and bromo-acetamidine (in-situ from bromine-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 sequentially connected with N, N- Dimethyl-acetamidodimethyl acetal is obtained by subsequent cyclization in the presence of pyridine. 6.9. Synthesis of 2- [2-oxy- 4 · (3-pyridylcarbonyl) -1-pyrrolidinyl] butyric acid 2,2 · dimethyl ethyl ester 410 -88 · 200538436

In a three-necked flask under argon, soci2 (0.56 ml) was added to a solution of acid 400 (1.90 g of '〇.〇07〇mol) in toluene (20 ml) at room temperature. The reaction mixture was refluxed for 1.5 hours to turn yellow. After cooling to room temperature, PdCl2 (PPh3) 2 (0.25 g, 0,00035 mol) and 3-trimethylstannyl-pyridine (1.7 g, 0.07 mol) were added in one portion and reacted. The mixture was refluxed for 0.5 hours, cooled to room temperature, and quenched with water. The aqueous layer was extracted with dichloromethane, and the combined organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo (3.2 g). The crude ketone was purified by column chromatography (dichloromethane / methanol 97/03 (v / v)) to obtain 1.3 g of ketone 410 as 1 of 1 diastereomers. 1 mixture. LC / MS: 3 33 (MH +). Example 7 Synthesis of 2- (4-substituted-2-oxy-pyrrolidinyl) -butanamide via substitution of activated 2- (4-hydroxymethyl-2-oxy-pyrrolidinyl) -butanamine 7.0. Synthesis of starting alcohol 7.0.1. Synthesis of esteramine 7.0.1.a. l-[(lS) -l- (aminocarbonyl) propyl] -5 -oxy-5-pyrrolidinylcarboxylate Synthesis of Methyl Ester 11/12

In a 10-liter three-necked flask equipped with a mechanical stirrer and a reflux condenser, under an argon atmosphere, 1226 g (12 moles, 1 equivalent) of (2S) -2-aminobutane-89 · 200538436 amidine And 1912 ml (2150 g, Π.2 moles, 1.1 equivalents) of dimethyl itaconic acid was dissolved in 6.1 l of methanol. The mixture was adjusted to reflux for 10 hours and slowly cooled to 201 over a period of 4 hours. Filtration, washing the precipitate with methanol, and concentrating the organic phase to dryness gave 3.283 g of crude intermediate 74%. In a 20-liter three-necked flask equipped with a mechanical stirrer, Rashi g column and distillation arm, in an inert atmosphere, crude intermediate and 84.7 g (891 millimoles, 0.1 equivalent) octahydroxy Pyridine was dissolved in 1 1.6 liters of toluene. The mixture was adjusted to reflux and the formed methanol was removed by distillation for 8 hours until 480 ml was collected. The temperature inside the reaction bottle reached 11 2 ° C. The mixture was cooled and concentrated to dryness to obtain 2,187 g of crude amidine ester in a 57.5 / 42.5 ratio of diastereomers. The two diastereomers were separated by preparative liquid chromatography in the image synthesizer (image synthesizer AD 100 * 500 mm, ethanol / water 99.9: 0.1), and the fractions were concentrated to dryness to obtain 968 g. Crude 12 (first elution) and 1,052 g of crude 11 (second elution). The crude 12 was not crystallized, it was dissolved in 1.5 liters of ethanol and was used there for further use. The crude 11 was recrystallized from 2 liters of ethyl acetate to obtain 676 g of pure 11. In addition, 1-[(1S) _2 -amino-1-methyl-2-oxyethyl] -5 -oxy-3-pyrrolidinecarboxylic acid methyl ester, l-[(lS) -l- ( Aminocarbonyl) butyl] -5 -oxy-3 -pyrrolidinecarboxylic acid methyl ester, 1 · {(1 s) -1-[(methylamino) carbonyl] propyl}-5 -oxy- Methyl 3-pyrrolidinate is prepared in a similar manner. 7.2.2 Synthesis of Alcohol-Amidoamine 7.0. 2.a. Synthesis of (2S) -2- [4- (residual methyl) -2-oxy-1 · B than slightly B adenyl] butamidine 6 .

-90-

200538436 In a 2 liter three-necked flask equipped with a mechanical stirrer and a reflux condenser under an inert atmosphere, 133 g (583 mmol, 1 equivalent) (2S) -2- (4-methoxycarbonyl-2-oxyl 1-pyrrolidinyl] butanamine 1 1 in 200 ml of ethanol was added to 300 ml of ethanol, and the mixture was cooled to 0 ° C. Then 66.2 g (1.74 moles, 12 equivalents) were added in portions over a period of 1.5 hours. ) Solid NaBH4, while maintaining the temperature at 2 to 4 ° C. After 2 hours the temperature rises to 12 ° C for 1 hour and then again to 2-4 ° C. 240 ml of ammonia chloride is added dropwise over 1 hour Saturated solution, then added 120 ml of acetone, and the mixture was left at room temperature overnight. The mixture was filtered, the precipitate was washed with 3 × 70 ml of ethanol, and the combined organic portion was concentrated to dryness to obtain 148 g of crude 6. Suspended in 300 ml of dichloromethane and stirred for 30 minutes. Minutes, filtered, washed with 2 × 100 ml of dichloromethane and dehydrated to obtain 114 g of pure 6,98%. In addition, (2S) -2- [4- (hydroxymethyl) -2-oxy-1-pyrrolidinyl ] Propanamide, (2S) -2- [4- (hydroxymethyl) -2-oxy-1-pyrrolidinyl] pentamidine, (2S) -2- [4- (hydroxymethyl)- 2-oxy-1 -Pyrrolidinyl] -N-methylbutanidine is prepared in a similar manner. 7.1. Using triphenylphosphine to directly convert to synthesis 7.1.1. (2S) -2- [4- (iodomethyl) ) -2-oxy-pyrrolidinyl] butanamine 10 synthesis

A 100 liter 3-necked flask equipped with a mechanical stirrer and a reflux condenser under an inert atmosphere, 400 g (2 mol, 1 equivalent) (2S) -2-[4- (hydroxymethyl) -2-oxo -Pyrrolidinyl] butanamine 6 was dissolved in 3 liters of acetonitrile. Added 629g -91-

200538436 (2.4 moles, 1.2 equivalents) of triphenylphosphine, then 608 g (2.4 moles, 1.2 equivalents) of iodine were added in three portions over 5 minutes. The mixture was heated to 60 ° C for 30 minutes and stirred at this temperature for 5 hours. After cooling, the mixture was concentrated to dryness, and the residue was suspended in a solution of 750 g of sodium thiosulfate in 10 liters of water and stirred at 50 ° C for 4 hours. The precipitate was filtered and washed with 3 × 1 liters of water. The combined aqueous phase was treated with 1 kg of sodium chloride and extracted with 6 X 1 liter of dichloromethane. The combined organic phase was dehydrated with magnesium sulfate, filtered and concentrated to dryness to obtain 482 g of crude 10. Crystallized from toluene. Several harvests were recrystallized from ethyl acetate to obtain 425 g of pure 10, 68%. In addition, (2S) -2- [4- (iodomethyl) -2-oxy-1-pyrrolidinyl] -N-methylbutanamide 146, (23b 2- [4- (iodomethyl) ) -2-oxy-1-pyrrolidinyl] propanilamine 110, (2S) -2- [4- (iodomethyl) -2-oxy-1-pyrrolidinyl] pentamidine 105, ( 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. ···· (2S) -2- [2-oxy-4 · (phenoxymethyl) -1-pyrrolidinyl] butane Synthesis of Amidine 1 8

In a 50 ml three-necked flask equipped with a magnetic stirrer and a dropping funnel in an inert atmosphere, 1 g (5 mmol, 丨 equivalent) (23) -2- [4- (hydroxymethyl) -92- 200538436 -2-oxy-1-pyrrolidinyl] butanamine 6 was dissolved in 20 ml of THF and cooled to 0 ° C. 517 mg of phenol, 0.87 ml (960 mg) of diethyl azodicarboxylate and 1.44 g of triphenylphosphine (5.5 mmol, 1.1 equivalents) were added sequentially and the mixture was stirred for 2 hours. The mixture was concentrated to dryness and purified by preparative LC (500 kg of silica gel, dichloromethane / ethanol, 97.5: 2.5) to obtain 1.1 g of pure 18,80%, which was crystallized from ethyl acetate. 7.2. Synthesis via Substituted Methane Sulfonate 7.2.1. {L-[(lS) -1- (aminocarbonyl) propyl] -5-oxy-3-pyrrolidinyl} methylmethanesulfonate Synthesis of Ester 37

In a 4-liter three-necked flask equipped with a mechanical stirrer, a dropping funnel, and a reflux condenser, in an inert atmosphere, 1 14 g (569 mmol, 1 equivalent) (2S) -2- [4- ( Hydroxymethyl) -2-oxy-1-pyrrolidinyl] butanamine 6 was dissolved in 2 liters of dichloromethane and cooled to 0 ° C. 158.5 ml (1 15 g, 2 eq) of anhydrous triethylamine was added thereto at once, followed by dropwise addition of a solution of 66.3 ml (96.2 g, 1.5 eq) of methanesulfonyl chloride in 190 ml of dichloromethane over 1 hour, Keep the temperature below 4 ° C. After 4 hours, 7.5 ml of methanesulfonyl chloride and 15 ml of triethylamine and the mixture were added to the refrigerator overnight. The mixture was filtered, the residue was washed with dichloromethane and the combined organic phases were concentrated to dryness to give 2 16 g of crude 37. Purification by preparative LC (1 kg of silica gel, dichloromethane / ethanol, 100: 0 to 96: 4) was divided into several batches to obtain 109 g of pure 37,69%. In addition, {1-[(1 S) -1-(aminocarbonyl) propyl] -5 -oxy-3 -pyrrole-93- 200538436 · pyridyl) methyl-4-methylbenzenesulfonate 31 Prepared in a similar manner. 7.2.2. Synthesis of (2S) -2- [4- (azidomethyl) -2-oxy · 1 · pyrrolidinyl] butanamine 32

In a 3 liter three-necked flask equipped with a mechanical stirrer and a reflux condenser under an inert gas atmosphere, 89 · 7 g (322 mmol, 1 equivalent) {1 [(is) -l-(aminocarbonyl) Propyl] -5 -oxy-3 -pyrrolidinyl} methylmethanebenzenesulfonate 37 was dissolved in 300 ml of acetonitrile. Add 27.3 g (419 mmol, 1.3 eq) of sodium azide and 150 ml of acetonitrile in one portion. The mixture was adjusted to reflux over 20 minutes and stirred overnight. Add 3.1 grams (48 millimoles, 0.2 equivalents) of sodium azide and continue refluxing for a total of 44 hours. After cooling to 10 ° C, the mixture was filtered, the precipitate was washed with 3 × 50 ml of acetonitrile, and the combined organic portion was concentrated to dryness to obtain 77.3 g of crude 32. Crystallization from 150 ml of ethyl acetate at 10 ° C gave 60 g of pure 32,82%. Φ In addition, (2S) -2- [4- (fluoromethyl) -2-oxy-1-pyrrolidinyl] butanamine 44 and (2S) -2- [2-oxy-4- (1Η) -Tetrazol-1-ylmethyl) -1-pyrrolidinyl] butanamine 39, (2S) -2 · [2-oxy- 4- (1H-tetrazol-1-ylmethyl) -1 _Pyrrolidinyl] butanamine 40, (2S) -2- [2-oxy- 4-UH-1,2,4-triazol-1-ylmethylbutan-1-pyrrolidinyl] butanamine 55, (23) -2- [2 · oxy- 4- (1Η-1,2,3-triazol-1-ylmethyl) -1-pyrrolidinyl] butanamine 56, (2S)- 2- (4-[(isopropylsulfanyl) methyl] -2-oxy-1-pyrrolidinyl} butanamine 24, (23) -2- [2-oxy-4- (1 -Pyrrolidinylmethyl) -1-pyrrolidinyl] butyramine 1 5, (2S)-2 · [2 -oxy-4-(4-thiomorpholinylmethyl-94-

200538436)) 1-pyrrolidinyl] butanamine 17 is prepared in a similar manner from activated alcohol derivatives such as methanesulfonate, tosylate or halide. 7.3. Other Synthesis 7.3.1. Synthesis of {l-[(lS) -l- (aminocarbonyl) propyl] -5-oxy-3-pyrrolidinyl} methyl nitrate 38

\ Λ ^ νη2 7.3.1.

In a 500 ml 3-necked flask equipped with a mechanical stirrer and reflux condenser and in an inert atmosphere, 8.10 g (26 mmol, 1 equivalent) (2S) -2- [4- (iodomethyl)- 2-oxy-1-pyrrolidinyl] butyramine 10 was dissolved in 250 ml of dinitrile. 4.86 g (28.6 mmol, 1.1 equivalents) of silver nitrate were added and the mixture was adjusted to reflux. After 2 hours, add 440 mg (2.8 millimoles,

0.1 equivalent) and reflux for a total of 4 hours. After cooling, the mixture was concentrated to dryness and purified by preparative LC (200 g of silica gel, dichloromethane / methanol / ammonium hydroxide, 96: 5.4: 0.6) to obtain 5.7 g of crude 3.8. Recrystallization from 50 ml of ethyl acetate gave 4.13 g of pure 38,65%. 7.3.2. Synthesis of 2- {4-[(benzyloxy) methyl] -2 -oxy-1-pyrrolidinyl butylamine 1 5 3/1 54

7.3.2.a Synthesis of (2S) -2- {4-[(benzyloxy) methyl] -2-oxy-pyrrolidinyl) butyric acid tert-butyl ester -95- 200538436

In a 100 ml 3-necked flask equipped with a magnetic stirrer and a reflux condenser under an inert atmosphere, 1.1 g (60%, 27.5 mmol, 1.1 equivalents) of sodium hydride was suspended in 60 ml of DMF The mixture was cooled to 0 ° C, and 6.37 g (24.8 mmol, 1 equivalent) of (2S) -2- [4- (hydroxymethyl) -2-oxy-1-pyrrolidinyl] butanoic acid was carefully added Tributyl 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 and the residue was suspended in brine / dichloromethane, decanted and extracted with dichloromethane. The combined organic phase was dehydrated with magnesium sulfate, concentrated to dryness and the residue was purified by preparative LC (1 kg of silica gel, hexane / MTBE, 40:60 to 0: 100) to obtain 3.2 g of a mixture of tert-butyl ester and benzyl ester in Second elution, 37% overall yield. This is used in the next step 7.3. L.b. ! H NMR (250MHz &gt; (CDC13): 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, 1H), 3.45-3.55 (m, 1H), 4.40 (dd, 1H), 4.55 (s, 2H), 7.20-7.40 (m, 5H).

7.3.2.b. Synthesis of 2- {4-[(benzyloxy) methyl] -2-oxy-1-pyrrolidinyl} butanamine 1 5 3 is equipped with a magnetic stirrer and a reflux condenser and In a 50 ml 3-necked flask under an inert atmosphere, 1.75 g of benzyl ester-rich eluent was dissolved in 20 ml of methanol. Gaseous ammonia was then maintained at room temperature for 24 hours through the solution and saturated solution, while occasionally being saturated again with ammonia. After the reaction was completed, the solution was concentrated to dryness and purified by preparative LC (1 kg of silica gel, dichloromethane / methanol, 98: 2 to 90:10) to obtain two diastereomers. In a 25 ml 3-necked flask equipped with a magnetic stirrer and a reflux condenser under an inert atmosphere, 1.24 g of the third butyl ester-rich elution fraction was dissolved in 16-96-

200538436

Ml of a 1: 1 mixture of dichloromethane / trifluoroacetic acid and maintained at 0-5t for 24 hours. The solution was concentrated to dryness and the residue was dissolved in 10 ml of dichloromethane. Add 1.2 ml (2.2 theoretical equivalents) and cool the mixture to -20 ° C. 780 μl of ethyl chloroformate was added dropwise, and the mixture was allowed to slowly warm to −10 ° C. over a period of 1.5 hours. Gaseous ammonia was passed through the solution for 0.5 hours, and the mixture was maintained at room temperature overnight. After filtration, the precipitate was washed with dichloromethane, and the combined organic fractions were concentrated to dryness and purified by preparative LC (1 kg of silica gel, dichloromethane / methanol, 98: 2 to 90:10) to obtain two diastereomers. Isomers. The first and second diastereoisomers obtained from the two rounds were condensed and crystallized from toluene to obtain 305 mg of pure 153 and 480 mg of pure 154, respectively, with a total yield of 11%. 7.3.3 · (2S) -2- {4-[(5-methyl-1fluorene-1,2,3-triazol-1-yl) methyl] -2-oxy-1-pyrrolidinyl} butanidine Synthesis of amine 52

In a 50 ml 3-neck flask equipped with a magnetic stirrer and a reflux condenser under an inert atmosphere, 1 g (4.44 millimoles' 1 equivalent) (23) -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 _ (triphenylphosphinoalkylene) 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 silica gel, dichloromethane / methanol / ammonium hydroxide, 94.5: 5: 0.5). Suspended in 15 ml of water and lyophilized to obtain 240 mg of pure 52 Cheng Cheng oil ’42% ° -97-

200538436 7. 3 · 4. (2S)-Synthesis of 2- [4- (isothiocyanatomethyl) -2-oxy-1-pyrrolidinyl] butanamine 49

In a 500 ml pressure bottle under an inert atmosphere, 900 mg of 10% palladium was adsorbed on charcoal and suspended in 100 ml of ethanol. Add 8.7 g (38 mmol) of φ (2S) -2- [4- (azidomethyl) _2-oxy-1-pyrrolidinyl] butanamide 32 in 150 ml of ethanol and The mixture was hydrogenated in a Bar hydrogenator at a maximum hydrogen pressure of 30 psi for 2 hours. The mixture was degassed and filtered on a Celite / Nolite pad. The residue was washed with 2 × 100 ml of ethanol and the filtrate was concentrated to dryness to give 7.93 g of crude 412, 100% yield, which was used in the next step. GC / MS: 199 (M +). 7.3.4.a. Synthesis of (2S) -2- [4- (isothiocyanatomethyl) -2-oxy-1-pyrrolidinyl] butanamine 49 on a magnetic stirrer and reflux In a 100 ml 3 neck flask with a condenser and in an inert atmosphere, 4.5 g (22.7 mmol, 1 equivalent) of thiocarbonylimidazole was dissolved in 25 ml of DMF, and the mixture was cooled to 0 ° C. 4.53 g (22.7 mmol, 1 equivalent) of (2S) -2- [4- (aminomethyl) -2-oxo-1-pyrrolidine, butanylamine was added dropwise over a period of 30 minutes. 412 in 25 ml DMF, the mixture was stirred at room temperature for 3 hours and left overnight. The mixture was concentrated to dryness and the residue was dissolved in 20 ml of toluene and concentrated to dryness again. The residue was purified by preparative LC (350 g of silica gel, dichloromethane / methanol / ammonium hydroxide, 9 3.4: 6: 0.6 ) To obtain 3.1 grams of crude 49. Prepared in 20 ml of ether, filtered and the residue (1.9 g) was crystallized from 15 ml of acetonitrile to obtain 1.2 g of pure 49 (22%). -98- 200538436 The compounds of the formula shown in the table below can be prepared in a similar manner or as described elsewhere herein. In the table, stereochemical information is contained in two columns with the header "Configuration Data". The second column indicates whether the compound does not have a stereogenic center (non-photographic). Pure enantiomers (pure) 'racemic mixtures (racemic) or two or more stereoisomers may be in unequal proportions. Of mixtures (mixtures). The first column contains the stereochemical labels of the centers that have been identified, followed by the IUPAC number used in the previous column. Separate numbering means that both configurations exist ^ in the center. The number followed by "R" or "S" indicates an absolute configuration known to the center. The number followed by "§" indicates that there is only one but unknown absolute configuration at the center. The preceding letters (A, B, C, D) distinguish each enantiomer or racemic mixture 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) melting point is marked, this 値 is shown in parentheses. In the table, the column "synthesis number" indicates the synthesis actually used for the most important compounds. Slight changes may be required to obtain similar compounds. These modifications are within the skill of those in the organic synthesis industry. -99- 200538436

RMN! H Γ-1 Ξ LC / MS MH + Melting point (° C) (127-128) 143.0 (116-120) (106-107) (146-150) 144.3 116.0 181.3 91.4 104..0 Synthesis • • 7.1. 1. 7.1.1. 7.1.1. • Configuration data racemic racemic racemic mixture non-image m 窠 窠 m 窠 窠 m inch inch inch 9 \ A-2S, 4§ C00 inch 6 00 CS A-2S, 4§ 〇0) inch Λ CO &lt; N PQ Pi gas αΓ CN 000 m C / T * -1 1 &lt; B-1S, 3 § IUPAC chemical name 狴 m ΰ mm acne swallow 1 Η m 浒1 11 (N Free K3 I 1 &lt; Ν m N3 ϊ η 1 1-Η m 浒 1 m 嫲 κ I &lt; N 2_ (4-methyl-2-oxy-1-pyrrolidinyl) acetamidine Amine 2- (4-methyl-2-oxy-1-pyrrolidinyl) propanilamine 2- (4,4-dimethyl-2-oxy-1-pyrrolidinyl) propanilamine (2S ) -2- [4- (hydroxymethyl) -2-oxy-1-pyrrolidinyl] butanamine (2S) -2- [4- (hydroxymethyl) -2-oxy-1-pyrrole Pyridyl] butanamine (2S) -2- [4- (bromomethyl) -2-oxy-1-pyrrolidinyl] butanidine (2S) -2- [4- (bromomethyl)- 2-oxy-1-pyrrolidinyl] butyramine (2S) -2-[(4R) -4- (iodomethyl) -2-oxypyrrolidinyl] butanidine 1 ro mm 1 supplement g Slightly ki g, ΠΓ ®®I 7 fr G 氍 二 惣 • t ^ ΤΠν two slightly n 1 cn m 1 5 gm ki hair am ya®I 7 ffi- 1 1 &gt; ΓΠν two slightly compound number τ-Η (N m inch Ό 00 〇 \ 〇 (N

One 100 one 200538436

Ξ r—1 189.0 202.0 (99.3-100.4) 120.0 124.4 93.2 144.9 〇 \ 00 • • 1.1.1 then 1.2.1. Then 1.2.2 窠 mmmm 窠 窠 m 窠 锾 000 m ζ / ί CN &lt; 000 gas c / i CN FREE A-2S, 4§ GO) inch, &gt; C / 3 &lt; N free coo gas CN &lt; coo gas CO &lt; N &lt; B-2S, 4§ A-2S, 4§ coo inch Λ c / T CD A-2S, 4§ fflr m glycoside 1 rH Λ 浒 punishment sm 4 tm ^ «锃 acac r ^ &lt; N 1 1—1 1 C / D '~' 3« S 'glycoside m &lt; \ T— (m roll 狴 im 4 H slightly butterfly 1 secret pan a ac rs &lt; N · 1 iH 1 i C / J 1 ~ 1 CL slightly 1 1 slightly H- slightly η r1 r * H 1 «铿λ mvh Dou Jizhi blanket I swallow 1 1 slightly B- swallow 1 rH 1 c; m ^ «d η swallow 1 iH 1 i ®- m 荖 m 1 1 m secret ^ mvh ^ doug slightly. dn (2S) -2- [2-oxy-4- (phenoxymethyl) -1-pyrrolidinyl] butanamine 1 rH m Hf 1 (N slightly fr 1 2) ^ g l_l * iiaxia CL 砮 m H 3 ml s 1 rH Λ m 1 H Λ 1 1 &lt; N CO-: 2S) -2- (4-benzyl-2-oxy-1-pyrrolidinyl) butanamide) k2S) -2- ( 2-oxy-4-phenyl-1-pyrrolidinyl) butanamide m inch rH νο 〇〇Os (N (N 200538436

ίο * 92.4 103.8 I _i 98.1 107.7 211.4 1- 142.8 120.3 111.7 84.8 134.8 "&lt; N — ^ 1 • ^ _; 1—t 1—H r &quot; H rH rH 7.2.1. 7.2.2 6 · 2 · 2 · Then 6.3.1. M 窠 窠 窠 racemic racemic 窠 窠 m mixture coo gas czT &lt; s FREE A-2S, 4§ coo inch. 00 CN &lt;: C00 gas CN FREE coo gas CO CN FREE A-2,4 B-2,4 000 Gas 00 (N &lt; 000 m αΓ ^ Η 1 &lt; Inch X ι / Γ cs Inch CN (2S) -2- (2-oxy-4-benzene Yl-1-pyrrolidinyl) butanamide slightly &lt; N 5 El · slightly Sg 撵 狴 κ ϊ 晡 (— ν 械 1 s η a ^ Λ ^ m, has 7 (2S) -2- (4 -Isopropyl-2-oxy-1-pyrrolidinyl) butanamine! (2S) -2- (4-isopropyl-2-oxy-1-pyrrolidinyl) butanamine (2S) -2- [4- (iodomethyl) -2-oxy-1-pyrrolidinyl] butanamine 2- (4 · amino-2-oxy-1-¾soridine) butanamine 2 -(4-cyano-2-oxy-1-pyrrolidinyl) butanamine 1 (2S) -2- [4- (chloromethyl) -2-oxy-1-pyrrolidinyl] butanidine Amine ancestor CO secret 1 wo ν) πι 1 ΉΙ δ 1 ΙΕ 征 S rolls «« 4 shopping · V «: El ·-« ^ η swallow secrets (N m a- paste β {| ι {ί ^ S Η 1—Ϊ η—1 1 r—Η Λ Base 1 CN 载 载 Κ) Goose 1 I chain CS bite crocodile 4 t A «m (N (N v〇 (N $ 00 (N 〇 \ &lt; N (N mmm-* 1 〇2- ° 200538436

S r ~ n 202.8 73.9 56.9 135.0 181.9 82.3 120.5 138.1 4.4. I _ί 7.3.1. 7.2.1. 6.2.1 · then 6.3.1. 7.2.2. M 窠 mm 窠 mixture 窠 mmm αΓ rH 1 &lt; A -2S, 4§ B-2S, 4§ _i 000 CO CO &quot; 1 &lt; A-1S, 3 § A-2S, 4§ 1 A-2S, 4 § &lt; N A-2S, 4§ coo CO · CN &lt; 1 m 1 E i slightly ^ v hall g s ^ diacryl (2S) -2- (4-methyl-2-oxy-1-¾ slightly D fluorenyl) butylamine (2S) -2- (4-Methyl-2-oxy-1-pyrrolidinyl) butanilamide 1 ΓΟ m Na 1 1 5 Ε: distillate _ w If quasi £ 7 fr-«rn 1 m W) Na 1 1 Ϊ g Ϊ anr s ^ right s ^ 2 vm ^ l · -m diac1 1—1 i Bl · «I rH ia 1 ffi T ^ Ilf H • Free S cj n 1 fH 1 m 1 rH im 1 ffi 1— (Inch plate i αχζ Complement _ Jiff Η S 2 (2-oxy-4-vinyl-1-pyrrolidinyl) butanamine sulfur 1 TH secret 1 slightly m minus 4 ^ V ^ Ϊ h 00 '~' Swallow 1 rH 1 ϊ Slightly mm «S 4 ^ ip mti tip arvn m VO Γ〇 00 m ON m ο 1— (m -103- 200538436

Ξ S r—4 oo 00 On 〇rH m τ · Η rH ο Os 1-Η ^ Η inch CN Ό rH VO On CO rH 00 &lt; N ττ-Η &lt; N 00 CN tH rl 心 vd &lt; Ν ^ 〇J heart vd inch CO r &gt; m 窠 窠 窠 m &lt; ίπ m 窠 &lt; ln m A-2S, 4§ 000 CO οΓ rH 1 gas CO CN gas CO &lt; N coo m 00 1—H 1 &lt; 000 CO &lt; N &lt; coo gas 00 CS &lt; &lt; N 〇〇〇οΓ CN &lt; ri (2S) -2- [4-(^ ylmethyl) -2-oxy-1-¾ ΠΠ a base 1 butylamine amine A Hff 1 V &quot;) 1 s E: s ® ΠΤ m this s ^ 7 fr -wvn diacyl_ m 1 cs s KK] 郏 11 1 &lt; N S slightly secret 1 (N i Μ 1 &lt; N t ^^ ^ m 1 rn secret 1 1 Wfl E ϊ mm T ^ S n two interpretations 1 tH 〇i slightly l · m 趑 4ir2 033 i S c; n ^ Already 1 rH Λ 嫲 1 &lt; N s 1 CN έ 11 Up .You inch 1333 ^ m 二 卜 i 5 &&lt; N II ip 1 cn rH FREE i ^ &quot; 1 mh &lt; N —: Right ffi η Slightly swallowed & λ «4 ^ rc;" ^ E- m Secret 1 &lt; N i 1 U ^) II m, .M inch 0x2 ^ m ^ t SlightlyElig d 5 4 砮 u_) 1 (N &quot; 7 vo r- inch 00 C \ &lt; N m -10 A-- 200538436

r ~ i 〇m U ^ l 117.3 Ό CN inch r &gt; H CN 00 CN CS r〇dv〇iH CN ON V £ &gt; rH inch rH 00 CN ON rH t &gt; 00 o rH 00 VO rH mixture tap 4n m Mm 墀 墀 B t: 墀 m 遐 mmm '墀 m inch Λ CN coo inch Λ CO &lt; s &lt; coo inch, CN &lt; ri &lt; &lt;: qi ri &lt; ci FREE ri &lt;: cs Royalty Free 1 rH Λ 1 CN i 1 &lt; N m rA ^ »h ^ aiplastic a 砮 ffl- tip 1 rH HI 1 inch Λ ci 5 m? t ¥ 5 &lt; NSV ^" 二 / ^ N 1 00 i s -m 1 ^ H Hi 1 cn 〇TV ^ ffi _ V h 5w | Ilf ^ 1 1 CN — 1 ▼ -H Hi & m 1 ▼ -H Ξ 1 ffi 4 Learn Wi ^ mt ^ m 砮 I iH m ni »(N Ϊ 1 m 1 ttd« 1 让 ¢-H ά S in A ^ 1 m 11 &lt; N Ϊ 1 ΜΊ a 1 ffi — like 1 ΠΧ »mm ffi- H i S ina ^ 砮 1 τ-Η A Ilf CN Slightly 1 a a * 经 1 cxz wm fr H ά 5 i AA acne I ii secret 1 CS m I s 1 three trends mm B- H i WA acne 1 m 嫲 1 &lt; N s 1 &s; sg 辛 cA YOU # \ LLCt ^ m}}-7 ί s 1 τ-Η mm 1 1 1 CN i •• ITT ^ h A5 ^ ni nia 砮 in 00 v〇ON S CN Ό m &quot; 105- 20053843 6

[10] 94.3 d rH v〇00 rH r—1 00 O inch ΓΟ inch rH m 〇 \ VO d &lt; N rH 6 · 8 · 3 and then 6.3.1.-^ "Inch · 鲦 Η inch · mixture m yammm &lt; nmm 窠 inch • # Ν CN &lt; inch office &lt; s inch inch office CN PQ COQ inch ^ Γ / Γ &lt; N &lt; 000 inch Λ 00 cs inch inch · CN coo gas αΓ cs &lt; : 000 gas οΓ CN m 2- [2-oxy-4- (1,3-thiazol-2-yl) -1-pyrrolidinyl] butanamine 1 ▼ -H 1 i 1 ά ill 1 inch 9 \ τ-Η 1 KV ^ t epilepsy b secret _ i η a acne swallow 1 1 i 1 111 1 inch rv CN rH WV t dart slightly H secret 5 ά η a acne 砮 1 rH 1 5 9 τ-Η m Κ rH 1 mm secret ab ^ 5 η swallow 1 rH secret 1 CN 1 Ϊ roll secret fr 4 ^ Μ 00 '~~ »1 1—1 m if f &lt; N s 枨 Ilf ffi- 4 ^ vm 1 h GO '' C complement n swallow 1 r * H 1 5 賧 mn 砮 1 m 1 At ίΓ «swallow 1 tH 1 i sound • 1 vm 1 Η C / DI—1 dwm Sheng I swallow 1 ^ H 1 s sound 1 1 nf 铿 铿 Η 00 1 ~ 1 Cl W v〇v〇VO 〇〇 \ 〇ON Ό O τ-Η CS -1 〇6-200538436

112.0 150.2 91.3 146.5 73.7 115.0 129.0 100.2. ^ ^ • ^ ^ — · You— · “— · You—.d Two · inch ·;: Ning · inch · 2 Lier 4 窠 m 窠 窠 mmm &lt; Π m 000 inches "000 inches do 000 gas cw gas coo 乂 m gas coo gas CO 1 / Γ CS CO CN c / Γ cs C / T (N &lt; s C / T CN inch CN &lt;: &lt;; FREE SHOP &lt; PQ &lt; η η m 痤 · 砮 1 1 1 1 砮 1 1 1 1 τ-Η 1 Λ «Λ mi—Η m FREE Royalty Free 5 • Δρ · 11 秘 1 | | m if 嫲 2S κΐ (ΝΝΝΙ CN / —Ν, &lt; N &lt; N CN (Ν 1 nJ Slight weight slightly lake m 3 roll 1; &lt; N m slightly secret slightly slightly 1 £ B- mm fr El · HM u_i CS 1 inch 1 ΓΟ 1 1 m 1 &lt; N 1 S 4 ^ 4 ^ 4 狴 4 ^ 4 ^ 4 ^ 4 锴 _ i: m 3 _ 3 _ ί; m = _ domain: Η Ren Bu 7 ζ /) Γ-—Ι Λ hr /) p—n Λ Η ζ / ^ r ~ i Λ Η rf \ f _ «\ Ah Γ f · η Λ h T f \ f—η Λ h Α has been slightly cs m 2 slightly yyj 1 · ci m \ JJ 1 1 yJJ 1 'Pasted C / D r ~ 1 Cl slightly a η m inch ν〇Ό 卜 00 s

200538436

r—ι ί ~ 1 rH k_J r—! (N 1-HU ^ J rH ON Ό vd Os / —Ν ΟΝ I m has ο inch 00 inch d cs rH Os o 00 Os &lt; N Η Η — · — “ Inch · CA cvj Inch · CN H 狯 Η-勹 "Inch ·. — CN — · 鹚“ 鹚 “β Inch 窠 窠 窠 窠 窠 m 窠 窠 m coo Gas GO CN &lt; 000 Gas C / ί CN PQ 0C0, \ 00 CN &lt; coo qiαΓ CN free coo inch office οΓ &lt; Ν &lt; coo inch • N GO CS &lt;: coo qioT cs ￥ 000 CO CO PQ COD inch Λ αΤ &lt; N trophy 1 r— ί m Secret 1 CN s Roll m Smell 4 m 孑 t Sheng I 砮 1 rH m 嫲 1 &lt; N Slightly decrease slightly • 1 i ^ 4 m γΡΡ—, has been sunned T—1 1 5宓 m 1 m 1 can be secret: t _ Λ Η 00 '~~ &2; 2 «η swallow I 1-Η 5 ring 1 &lt; N 1 secret:? Ρ Λ Η ζη' ~~ '2 slightly η general I Swallow 1 S sound 1 Cl 1 «Secret 狴 :: ^ Λ Η 00 '· ~-' d« Swallow 1 tH m Secret 1 CN Slightly e $ d | ά ^ 4 mv μ ^ 斗 ει n Swallow 1 1— Η mm 1 CN 枨 _ Dirty i made 4 m γ Bu has 砮 1 rH 1 Slightly m 1 ΓΟ 1 ma 袈 Η CO '~' η Swallow 1 rH m \ $ 1 CN i Rolling 4 ^ Λ h 00 '~ · S. CS 〇〇 m oo 00 v〇 oo 5 00 00 ON OO -108- 200538436

[13] [14] 226.4 79.0 68.3 129.4 165.4 104.3 217.4 6.2.1 · Then 6.3.1. 6.2.1. Then 6.3.1. ^ Η "q H — τ-Η tH 3.1.1.a S 3.1.1 .g 鹚 黎 2 H ^ inch · inch 1 m 窠 mm 窠 mixture mixture m A-2S, 4 § B-2S, 4§ (1HC1) DO inch 00 &lt; N Pi gas 00 CN A-2S, 4§ 1 1_ CO) inch Λ CO cs free gas CN inch CN A-2S, 4§ (2S) -2- [4- (3-aminophenyl) -2-oxy-1-pyrrolidinyl 1 butanidine Pan Sheng I swallow 1 rH m CN ϊ roll. 1 m 4 ^ vm Λ h 00 '~' (2S) -2-[(4S) -2-oxy-4-vinylpyrrolidinyl] butanamine (2S) -2-[(4R) -2-oxy-4-vinylpyrrolidinyl] butanamine 2- [4- (bromophenyl) -2-oxy-1-pyrrolidinyl] butyl Amidamine l2- [4- (2-bromophenyl) -2-oxy-1-pyrrolidinyl] butamidamine 2-[(2-oxy-4- (3-pyridyl) -1-pyrrole Pyridyl) butanamine 1 lli 1 &lt; N m η 1 1 CO ni mit I _ ^ m 砮 1 H iil if 1 CN «1 r—i-d: 鳔 4 h ^ Ϊ (N 〇 \ Os s; 〇〇σ \ -109- 200538436

Γ—1 rH 1—1 VO tH U—J [17] 255 172.7 135.7 171.1 166.6 161.7 119.4 7.2.2. RH rH 窠 窠 窠 m mixture mixture 窠 mm racemic coo inch office 00 CN PQ A-2S, 4 § A-2S, 4§ coo gas 00 &lt; N FREE CN inch ^ CN A-2S, 4R A-2S, 4S A-2S, 4§ inch ts CN &lt; swallow 1 t—Η 11 &lt; Ν ii 1 · ^ j · i—n 罃: £ Hall 4 Η &lt; N ^ 1 rH FREE Secret 1 (N m &amp; S is similar? M £ hii cj n (2S) -2- [4- (l-naphthalene ) -2-oxy-1-pyrrolidinyl] butanamine (2S) -2- [4- (l-naphthyl) -2-oxy-1-pyrrolidinyl] butanamine 2- [ 4- (iodomethyl) -2-oxy-1-pyrrolidinyl] butanamine 2- [4- (chloromethyl) -2-oxy-1-pyrrolidinyl] butanamine 1 Λ 1 (Ν Slightly Bl · 1 inch handle plate stone sci ci η 1 rH m shout 1 CN Slightly 1 l · ^ sm ^ s Secret 1 &lt; N 郏 郏 HI 1 ¥ 铿 ^ m slightly hd {M i 都t-1 00 · ci slightly (2S) -2- (4-hexyl-2-oxy-1-pyrrolidinyl) butanamine 〇 \ 〇 100 101 J 102 103 104 105 106 107 108 -110- 200538436

255 241 241 395 395 i 283 269 297 199 269 241 147 _! 116.3 ▼ -H BU ^ iH 3.1.1.a ^ 3.1.1.g &lt; π Rose bet mm inch λ Pi Pi Gas inch office inch · N inch office (N inch inch rv &lt; N CN &lt; N 〇Γ CN CN inch inch # s rsJ inch inch Λ rsi FREE CN CN &lt; CQ &lt;: PQ &lt; FREE VN v N m η mm Η-|-= T m Μ 铿铿 锴 铿 w mm Ξ Ξ 1 m 鳔 mm 鳔 m slightly. ΛΙ «&gt; gg 太 Ε« g St It) 11® 1 · 1 3 fi mm ϊ s SS ϊ 砮 1 (N &lt; N mm ig η ig η n fH 1 / ^ N Butterfly N m blanket I I I ac. M l ™ ffi- swallow 1 swallow 1 rH砮 1 1-H swallow 1 1 — swallow 1 rH swallow 1 tH 1 swallow 1 i-Η face τ »Η 1 (N hee 1 綦 'w ^ mmmmm Λ m Λ Λ Λ Λ 1 Hf κ Ε Ε 〇] S &quot; / ^ NC / D cs (N (N CN 1 (N 1 cs 1 CS III s 狴 * ~ j J13H s 铿 UJri Λ ά mmmmm) m W 1 CN 1 —r 1 U7-? fi] fll 〇] ri] R] ru m Ilf Secrets / —N 00 / ^-NV ^ L ·. 00 1 ~ 1 λ m 〇〇 '~~ 1 Soil inch inch 1 1 1 1 cs 1 I (Ν ει m 1 CN 1 (N 3 pack 1 &lt; N 1 (N 1 &lt; N 1 CN 1 (NI CN 109 110 111 112 113 114 115 116 117 118 119 120 121 -111- 200538436

241 227 227 255 255 213 185 i- 261 261 381 297 297 269 134.5 3.1.1.a $ 3.1.1.g Xia &lt; ίπ &lt; n 4π &lt; ίπ mmmmmmmmm inch coo inch inch inch inch CN &lt; s CN气 cs &lt; Ν 〇Γ inch 00 of of inch (N &lt; N &lt; N (N &lt; CN &lt;: ώ &lt; rent &lt; &lt; 1 rH 1 N3 K) m 锴 铿 锴 铿铿 铿Slightly It i Slightly mm 铿 mmmmmmmm Secret 1 Roll 1 m Radium mm K mm Η S CN nn CN / ^ • N (N Zhai St K Paste i S slightly imwm Tip S slightly S η η nm yamm &amp; n η m knot I 普 I blanket I / ^-N m acne 1 1 1 1 swallow 1 砮 1 砮 1 m 1 苕. 1 砮 I rH 1 swallow 1 1 m ή mmm ή mmim «mm τ-Η m ▼ -H m Ε: | κ 1 Ε: K IE? jm 45 η T τ tr ^ \ may 1 1 may 1 Λ m Λ Λ ώ msmmmmm secret mmmm if secret cj n secret secret (N &gt; w, d ^ ά ^ 1 &lt; N 1 (N V- ^ 1 CN 1 CN 1 CN 1 &lt; N 1 CN «CN 1 CN 1 CN 1 (N 1 (N ^ m must A Kai 1 &lt; N 1 (N 1 CN 122 123 124 125 126 127 128 129 130 131 132 133 134 135 called 12-200538436

269 255 255 284 289 241 241 213 291 1 53.8 94.8 66.6 3.1.1.a $ 3.1.1.g 7.1.1. Racemic racemic racemic mixture. 1 Mixture racemic racemate mmm mixture B-2,4 inch office &lt; s &lt; B-2,4 inch &lt; N A-2,4 〇Γ PQ inch Pi gas.οΓ (Ν Ρύ inch ^ t / Γ CN Ρύ 气 αΓ CN Inch &lt; N 狴 m K Slightly 1 τ-Η Λ 1 Secret 1 (N I &lt; N 狴 m S. Slightly swallow 1 rH Λ 1 A 嫲 1 d 1 &lt; N 2- (2-oxyl -4-pentyl-1-pyrrolidinyl) pentanamine 2- (2-oxy-4-pentyl-1-pyrrolidinyl) heptanamine 2- (2-oxy-4-pentyl- 1-¾Lyridyl) -2-benzylacetamidinyl 2-P-oxy-4-pentyl-1-pyrrolidinyl) butanylamine 2- (2-oxy-4-pentyl- 1-¾ Succinyl) butanamine [2- (2-oxy-4-pentyl-1-pyrrolidinyl) acetamidine m 嫲. 1 slightly noodles «h 4» Λ fr ^ 11 IV of / ^ s 1 ⑺ 1 ~ i η slightly iii 1 CN f fr i Han h Ϊ m 1 η- ^ 1] 1 V ^ 1 C / D i ~ i εί, «Pan slightly Jlfii 1 CN I 5 6 smvm 1 H ^ mv El · 1 C /} '~ &gt; 3 W 1 rH mm 1 CN i 1 in 1 Wake 丨 1 狴 ft ^ Whip t Λ W c η ± ^ CN Swallow 136 137 138 139 140 141 142 143 144 145 146 147 -113- 200538436 m 9

[18] [19] [20] [21] 187.0 155.7 101.8 119.1 1 丄 1 then 1.2.1. Then 1.2.2. ^ ^ Η: —: ~ · 1 &lt; N · — ^ -Η 1-Η 1.1 .1. Then 1.2 丄 then 1.2.2. 窠 窠 窠 mm racemic racemic 窠 coo inch 00 &lt; N 〇00 inch inch CO free A-2S, 4§ A-2S, 4§ coo inch € \ 00 CN free 乂 &lt; inch, &gt; 00 gas CO &lt; N (28) -2_ (4-neopentyl-2-oxy-1-zolopyridyl) butanamide (2S) -2- (4-neopentyl-2-oxy-1-pyrrolidinyl) butanamine 1 (NS i 鲡 «Η 苎 砮 slightly 砮 00 1 (N 1-H 1 (2S) -2- (4 -Ethyl-2-oxy-1-pyrrolidinyl) butanilamine (2S) -2- (4-ethyl-2-oxy-1-pyrrolidinyl) butanamine 1 2- {4- [(Benzyloxy) methyl] -2-oxy-l-pyrrolidinyl} Butanamine 2- {4-[(lethoxyl) methyl] -2-oxy-1-¾ slightly steeper} Butamidine ig Slightly Jiff 1 CN i &amp; 綦 铿 4 m Λ Η IC / D 11 148 149 150 151 152 153 154 155 ~ 11A— 200538436

127.2 136.8 82.1 74.3 121.3 180.3 105.0 118.1 108.8 6 · 2 · 3 · Then 6.3.1. 2.5 CN 6 · 2 · 4 · Then 6.3.1 · 3.2.1. Then 6.3.2 · 2.1.1. Then 2.2. Mixture Mixture i 窠 racemic racemic mixture mixture mixture Λ c ^ T 00 orT &lt; s 00 inch Λ 00 (Ν (N &lt; 'inch r \ CS free gas (N c ^ T η 1 ^ -Η m CN Ϊ K1 base 11 A 铿 cr m Ϊ ba «2- [4- (2,2-difluoroethyl) -2-oxy-1-pyrrolidinyl] butanamine (2S) -2- [(4S) -2-oxy-4-propylpyrrolidinyl] butanamine (2S) -2-[(4R) -2-oxy-4-propylpyrrolidinyl] butanamine 2- [2-oxy-4- (trifluoromethyl) -1-pyrrolidinyl] butanamine 2- [2-oxy-4- (trifluoromethyl) -1-pyrrolidinyl] butanamine η 1 Λ Secret 1 Load Μ Jii N IXQ Baguan 4 Η Swallow 1 1—Η 1 &lt; N m install E 1 rH 1 m ^ η- m CS] ~ &gt; -1 1 ~~ 1 A PAN 2- (4 -Butyl-2-oxy-1-pyrrolidinyl) butanamine 156 157 158 1 1 1 159 160 161 162 163 164 -115- 200538436

r-i &lt; N 299/301 297 281 315 261 120.2 _1 b〇% C &lt; i &lt; NH CN 6. ···········: 6.3.1 ^ — · "·- m 3.1.1.a 3.1.1 'of — · —:-— · m 3.1.1.a 3.1.1., Rongsong &lt; ίπ πτ * Ρ 4α 4n &lt; π &lt; □ &lt; ίπ &lt; n &lt; n Si 魃 m mil SI m anger ri CvT qi cs inch office cs inch ψ \ CN inch office CN inch # \ inch Λ CN inch, C &gt; T m 铿 nm Η 1 1 H s nm nm Swallow 1 5 blanket I Η 1 5 η τ-Η Flat Γ—1 η # m 1 m Sheng I 砮 TH 1 m Acoustic t 1 τ * Η Slightly acne 1 § τ-Η 1 1 r «H 1 S Λ 1 Taste Secret I # 1 (N ^ Η 1 幡 «l · m slightly &lt; N rH 1 1 \ / a 5 _ mm Maple 1 CN Jiff slightly domain: Secret 1 1 &lt; N / ^ s 1 &lt; N / —N HI i 1 / ^ \ 1 嘁 I CN / —N ttl t CN 枨 Slightly A Ό 1 »Rolling juice becomes slightly rolled} E) -1 domain 锴 U u 4 _ &amp; shout s ^ 罐 cn m 1 1 1 mmti ^ 1 i _ 1 1 t 1 inch i _ CN H 1 (N a slightly A simplified ^ n (NH 165 166 i 1! 167 168 169 170 171 172 173 -116— 200538436

311 283 269 89.5 100.2 j 1 99.6 116.9 97.2 3.1.1.a $ 3.1.1 g 1.1.2. Then 1.2.1. Then 1.2.3. 1.1.2. Then 1.2.1. Then 1.2.3 Pseudo "Η (N 3 · 1 c · -s ^ 3.1.1.a · to 3.1.1.g. Mixture 窠 · Mixture racemic 1 racem mm 窠 C &T; T 000 〇〇 &quot; CN FREE A-2S, 4§ &lt; N inch (N FREE CS &lt; coo gas CO &lt; N &lt; coo 00 &lt; N FREE A-2 §, 4 § 2- [4- (3-methylphenyl) -2-oxy-1-¾ slightly steep group] Butanidine η 砮 1 t—H 1 m Κ] 浒 1 1 Λ mam 7: p human H • 00 '—' 3 slightly η swallow 1 rH 1 m 浒1 1 Λ Λ Η m '&gt; ci m 2- (4-hexyl-2-oxy-1-pyrrolidinyl) octylamine 2- (4-hexyl-2-oxy-1-pyrrolidine Hexylamine 2- (4-hexyl-2-oxy-1-pyrrolidinyl) pentamidine m Swallow 1 τ-Η mm 1 CN Slightly 1 m 4 S Λ H 00 '~' n Swallow 1 1— (m Secret CN Quan Bian m 4 ^ Λ Η GO '~~' 1 r »H m Secret 1 &lt; N ϊ si Bl · alkali 狴 111 i ¥ t Λ« &amp; PAN s cs swallow 174 175 176 177 178 179 180 181 182 -117- 200538436

97.2 148.6 148.6 1 _1 177.9 177.9 154.7 178.7 201.4 138.0 137.4 3.1.1.a S 3.1.1.g 3.1.1.a M 3.1.1.g 3.1.1.a S 3.1.1.g 3-lla to 3.1 .1.g 窠 m 窠 mm racemic ^ racemic 窠 窠 B-2§, 4§ C-2 §, 4 § D-2 §, 4 § A-2 §, 4 § B-2§, 4§ Inch CN &lt; CN FREE 000 Gas CO CS PLUS A-2 §, 4 § B-2§, 4§ 1 vH m secret 1 CS 5 s- maple plate !! li ¥ t Λ msaccs swallow 1 secret 1 &lt; N 5 ft S E- Alkaline ill S $ Acetate &lt; N Swallow 1 rH Λ m 1 (N 5 ft ia · Alkaline 111 Dust Λ mzwa 翌 2- [4- (3,4-dichlorobenzene ) -2-oxy-1-pyrrolidinyl] butanamine 2- [4- (3,4-dichlorophenyl) -2-oxy-1-pyrrolidinyl] butanamine 2- [ 4- (2,4-monobenzyl) -2-¾yl-1-¾ slightly D-aminyl] butanamine 2- [4- (2,4- ^ chlorophenyl) -2-oxy-1- tft slightly steep base] Butylamine 砮 1 1— (ά m I CN 5 郏 11 1 6 ^ 4 m ^ bg slightly dmsmmmi «£ 111 fi _ 4- n ά | nf ^ X slightly si double 5 Er ^ s in ®; ti slightly 's • ^ w — AW 183 184 185 186 187 188 189 190 191 192 -118- 200538436

[23] [24] 84.4 83.8 92.5 118.6 153.8 154.4 99.8 3.1.1.a S 3.1.1.g 3.1.1.a S 3.1.1.g ^ —: (N — 1.1.2.Π then 1.2 · 1 · Then 1.2.2. 3.1.1.a S 3.1.1.g 3.1.1. A to, 3.1.1. G 窠 racemic racemic mixture m 窠 m mixture C-2 §, 4 § D-2§, 4§ A-2,4 _1 B-2,4 inch 00 (N A-2S, 4§ C-2 §, 4 §, D-2 §, 4 § inch Λ CN 5 遁 i a -ili couple 111 l ά 4 η m 1 mf ϊί ^ HS 赃 盘 HI 5 ft _ bismuth £ mf Si 2- [4- (2-furanyl) -2-oxy-1-pyrrolidinyl] but Amidamine 2- [4- (2-furanyl) -2-oxy-1-pyrrolidinyl] butamidamine η 1 1—Η i 1 1 1 free of charge mam OQ i ~ i 3 slightly cautious 1 τ-Η Free Jii 1 (N Ϊ 鹅 Goose II 1 U ^) 6 ^ 4 m 孑 tg slightly cl n 2- [4- (3,4-dichlorophenyl) -2-oxy-1-pyrrolidinyl] Ding Amidinamine 2- [4- (3,4-dichlorophenyl) -2-oxy-1-pyrrolidinyl] butanamine 2- (2-oxy-4-propyl-1-pyrrolidinyl ) Butamidine 193 194 195 196 丨 1.1 .1 197 198 199 200 201 -119- 9

200538436

-120- 200538436

[25] [26] [27] 76.1 120.9 115.9 84.26 79.4 i 93.9 1_ 104 1 60 6 · 2.3 · Ran 6.3.1. Scale I · &lt; N τ-Η &lt; N 2 · 1 · 1 · Ran 2.2 Λ "-" • ^ m $ dq CM · rH &lt; N 6 · 2 · 3 · Ran 6.3.1. 窠 窠 mm 锾 锾 &lt; π 窠 mm COO coo coo 000 coo 000 coo CO气 寸 办 气 气 气 Ρύ in coo coo coo 000 coo 000 cs 000 rr \ CN CN &lt; N &lt; N CN CN &lt; N yyj CN &lt; PQ &lt; ό PQ Q FREE Slightly 1 «tr? Swallow 1 Swallow 1 i Ϊ 5 Η mm rH 1 / ^ S rH 1 nn η slightly swallowed 1 secret 1 CN slightly acne η—τ 1 (N / —N s E: swallowed slightly m li ii 1 1 1 rH 1 1 rH 1 1 rH 1 砮 密 铿 K] in Hi erm I τ-Η 1 cs N] 赃 1 1 mr〇m cn m 1 ¥ 1 secret 1 獬 1 ms maple 1 1 1 1 1 cs cn (N / —N &lt; N /-• N (N (Ν 迤 ffi- 1 1 1 CS d; 狴 1 1 Complement slightly mw 1 4 mmm «S 浒 浒) E tm ^ H 嫲 Crocodile secret hall slightly m 1 酹 铿SS ht—J r—i (NH * —J 1—1 1 fr 1 ε- 1 1 »Ϊ 譲 U—J 4 s s… AW &lt; N K + | m ^ t 2ya i m i m i m i m i Cl Cls cs H &lt; N H (N H CS Η ^ m g, n 213 i 214 215 216 217 218 219 220 221 222 121- 200538436

[28] Ι: 29] CN Os inch 1-H ▼ -H tH l &gt; rH m 00 »n VO d 〇 \ 〇 \ CN rH inch CO rH &lt; N vd 〇00 Li.… Cs • VH · &lt; N ^ &lt; N 狯.… CN • fH · &lt; N Li.… (N •, H · CS Li.… &lt; N • rH · csi ^ CN cn (N 窠 mmm 窠 窠 窠 窠 B- 2S, 4§ ooo gas oT cs PQ coo gas 00 CN &lt; coo inch office 00 CN PQ coo inch one CO &quot; (N PQ ooo gas c / T &lt; N &lt; coo and 00 (N &lt; coo inch office 00 &lt; N PQ 00 &quot; Gas C / T CS-COD CO Gas.CO) ^ (N PQ 砮 1 τ-Η 1 1 ▼ —Η 1 1 ffi τ—Η 1 Λ Secret A _ V ^ cl n Ϊ swallow 1 rH Λ 娜 1 &lt; Ν Λ equipment I 1 CN ά ^ ci mn 结 I daddy 1 rH m secret 1 CN m No. »(N 4 ^ vm 1 h C / Q '~~ ci mn 砮 1 v-rH 嫲1 &lt; N Slightly IE 綦 ά 4 锴 Λ h 00 I ~~ 'Cl «砮 1 rH — Secret 1 (Ν s fr Secret B- 4 ^ m · 1 ei m Ϊ Swallow 1 ι—1 Na 1 CN« Line I 1 CS looks like in = d 3 ya n Shen 1 rH 1 mr Secret 1 1 «Secret A 铿 *; p Λ Η CO 1-1 weighted m swallow 1 ι-H 1 slightly} E slightly Secret I m Secret a铿 Λ Η CO '~~' Slightly Hf CN ir Min 1 1 00 s 铿 ^ m cs ^ AH 00 '~ · n Slightly Hf 1 CN s EH 1 1 / ^ S xn s 鲢 ⑺v 鲢 ⑺ I ~~ I 223 inch &lt; N CS (N (N Ό (Ν CN <N CS 00 (N CS C \ CN (S 〇r〇 (N rH CN &lt; N CO (N 22- 200538436

[31] [32] [33] [34] 133.0 74.9 84.8 137.2 137.3 112 窠 racemic racemic 窠 窠 窠 窠 窠 inch. COD GO ^ (N ￥ 000 inch office co &quot; &lt; N ώ inch λ CN &lt; rr 1 CQ COD C / T &lt; N PQ CO gas Pi &lt; N Pi 乂 Pi CN A-2 §, 4 § B-2 §, 4 § C-2 §, 4 § (2S) -2- [(4R) -4- (2-Hydroxypropyl) -2-oxypyrrolidinyl] Butanamine (1) (N i 1 1 'Μ Φ Φ S &lt; N 3 3 Secret 1 (N 1 ΠΙ 1 inch plate ^ m «h 2 5 V i A 2m secret 1 &lt; N Ϊ roll in in 1 \ 〇 inch plate ^ m SS τ ig r 5 2L 砮 1« (N 1— * m &lt; N Ϊ 1 rH 1 Μ t A _ ci m clay t — 1 00 (2R) -2-[(4S) -2-oxy-4-propylpyrrolidinyl] butylamine (2R) -2- [(4R) -2-oxy-4-propylpyrrolidinyl] butanamine 2- (4-ethyl-2-oxy-4-phenyl-1-pyrrolidinyl) butanamine 2- (4-Ethyl-2-oxy-4-phenyl-1-¾lodinyl) butanamide 2- (4-ethyl-2-oxy-4-phenyl-1-¾lodinyl ) Butamidine 233 234 235 236 237 238 239 240 241 242 -123- 200538436

361 i- 361 229 112.2 73.5 1 _1 58.6 59.7 133.3 68.2 96.4 2 · 1.2 · then 2.2. 6.2.2. Then 6.3.1. 6 · 2 · 2 · then 6.3.1. M 窠 mm mixture mixture mm 窠 D- 2 §, 4 § m Gas Pi CN &lt;: A-2 §, 4 § B-2§, 4§ Inch CS CS in &lt; N Λ Pi 乂 CO CN, &lt; N A-2S, 4§ A -2S, 4§ 〇〇〇c / T &lt; N-2- (4-ethyl-2-oxy-4-phenyl-1-pyrrolidinyl) butanidine η chain I 砮 1 rH nf ( N 5 Bl · Mi l · ^ ^ ^ t 2- [4- (methoxymethyl) -2-oxy-1-pyrrolidinyl] butanamine 2- [4- (methoxymethyl) -2 -Oxy-1-pyrrolidinyl] butyramine 1 TH Λ 1 1 (N 1 S base-A 狴 «S 4¾ Η V« A 砮 1 m 1 1 &lt; N slightly El · base 1 inch A Zhao «S m -vm ^ mi plastic a 砮 n knot I slightly secret 1 &lt; N i E: m ^ TTJ \ 1 cs ^ 1 inch sέί: g Λ Η 00 I ~~ '53« swallow 1 rH m E 1 m Secret 1 &lt; N ml · 4 · 狴 in ^ 3 slightly 1 tH A Secret 1 &lt; N s Pack K) u 11 Must be d: _ 4 H ^ s swallow I rH m 1 &lt; N 1 i K) Alkali II Λ sd: m 4 H ^ s S '. Pan 243 244 i 1-: ~ 1 245 246 247 248 249 250 251 252 12 ^-

200538436 261 66.4 127.6 116.6 100 100.8! 84.2 ί 87.8 65.1 53.5 m 窠 窠 窠 m 窠 mm 窠 m A-2S, 4§ 000 inch office 00 &quot; (N ￥ 00 Α-2 §, 4 § B-2§, 4 § C-2§, 4§ 1 D-2§, 4§ GOO inch C / T cs free A-2S, 4§ B-2S, 4§ 2- (4-ethyl-4-methyl-2- Oxy-1-pyrrolidinyl) butanilamine 2- (4-ethyl-4-methyl-2-oxy-1-pyrrolidinyl) butanyl! Hydrazone (2S) -2- (2-oxo -4,4-dipropyl-1-pyrrolidinyl) Butanidine amine. 1 r &quot; H m T1 T m base 1 CN η ^ 'm 2 t hire 1 — (m roll 1 may m secret I (N m X δ Panton 1 τ-Η 1 mm 1 CN &amp; such as | | == 1 'm ^ t 1 1-H m 浒 1 τ m Secret 1 &lt; N m fr 1 1 013 Si 1 Λ 1 Λ secret 1 (N «ffi- 4 狴 Λ Η 00 ^ has» 1 GS) -2- (3-benzyl-2-oxy-1-pyrrolidinyl) butanamine (2 R) -2- ( 3-Pentyl-2-oxy-1- (¾: pyridinyl) butylamine 253 255 256 ί 257 258 259 '260 261 262 263 -125- 200538436

418/420 / 422 227 275 173.2 110.9 _I 103.9 87.4 146.6 118 56.8 6.4.1. 2.4.2. 6.4.1. I 6.4.1. Mixture mixture 窠 窠 mm Mixture mixture m 2,4 § 00 inch λ coo ικΓ CN &lt;; A-2S, 4§ coo inch office C / T CN FREE A-2S, 4§ i_ 00 CN 〇0) m (N &lt; 000 m c &lt; T FREE A-2S, 4§ 2- [4 -(Bromoethynyl) -2-oxy-1-pyrrolidinyl] butanamine η Hf 1 (N ϊ Ε ii 11 1 &lt; N &lt; Ν 4 ^ ά ^ 5 Η ^ S slightly 1 &lt; N Ϊ goose Π I inch m μ. B b ϊ i η 〇〇. CN is called 1 η 砮 1 rH m base 1 &lt; N slightly Λ Η 00 1 ~~ 1 C slightly m. CN s N] Huan II Y Bu 2L-cj «00 · (2S) -2- (4-ethynyl-2-oxy-1-pyrrolidinyl) butanamine (2S) -2- (3,3-diethyl-2-oxy Yl-1-pyrrolidinyl) butanidine 2- (3-1 ^ yl-3-methyl-2-oxy-1-¾pyrryl) butanidine 2- (3-amyl-3- (Methyl-2-oxy-1-¾). Butanidine Η l Ml Secret 1 CN «! CO cA 狴 ：: J Λ Η 00 ^ 264 265 j 266 267 268 269 270 270 271 272 273 -126- 200538436

Swallow 1 tH m secret 1 &lt; N s ring 1 CN ii ^ &amp; m ιΛ H »Ϊ ^ ^ n 砮 1 tH trophy Hff 1 rs 5 宓 m 1 (N slightly 狴! \) H ά 5 ina τ-Η w Hf 1 &lt; N slightly m 1 CN m ^ alkali painting un f— »Yadou 21 slightly ^ nm 1 iH Jiff 1 &lt; N 1 m ring 1 &lt; N cA m 4 ta slightly 砮 1 y— {«Secret 1 &lt; N slightly m 1 (N 1 1fr _ it i ^ λ n slightly E 1 τ-Η ιΐ in 1 cn md: ^ 4 mwt Secret butterfly 1 ^ n Consortium CN rH 1 m 砮 1 τ-Η i κ 1 r &quot; H mm Λ Η / C / D '· 1 1—Η m 1 CN s hO m storage 狴 w 5 »t cs m 1 vH 51 &lt; N 5 Η1 vH 1 狴 狴 E- mi 卜 i _ c; n ά ^ swallow 1 rH «Hf 1 CN s H · 4 ^ Λ H &gt; 〇0 '~~' cm 274 l &gt; CN v〇 卜 (N 卜卜 &lt; N 00 r- &lt; N Os bu CN 〇00 (NT-t oo cs CN oo CN m 00 (N -Ί 2 7 ~ 200538436 ·

259 284 257 丨 _1 355 265 276 I 281 319 305 229 1.3.1. Then 1.3.2. 1.3.1. Then i 1.3.2. 1.3.1. Then 1.3.2. 1.3.1. Then 1.3.2 1.3.1 · then 1.3.2. 1.3.1. Then 1.3.2. 1.3.1. Then 1.3.2. I 1.3.1. Then 1.3.2. 1.3.1. Then 1.3.2. Γ 1.3. 1. Then 1.3.2. Mixture mixture mixture mixture mixture mixture mixture mixture mixture mixture λ cn &quot; inch office CN inch (N inch office (N CN CN 乂 (Ν 气 (N ΛΛ (Ν A Λη η 1 ν 1 i Λ Ε: I “π ¥ ϊ ά Ρ… slightly El · tii cA rA m 嫲 1 d 1 &lt; N 5 ^ g S slightly em Min slightly mm — 铿 butterfly) inch 1 1 can m 嫲 嫲 ^ m slightly g Ning Mi 1 Tonic. Pushing — Tonic E- 4 LI Λ 4 Mi 1 1 1 Price 1 1 (N S inch m S1 硭 一 硭 ig m ^ 1 1 rH 1 ^ m 砮 1 K: 1 m mite 1 CS ^ 1 (N s ^ inch 0X5 w anti-E «cn Aacquiescence 1 m hire ro 1 1 inch you 1 CECI slightly _ Λ £ ά slightly ^ sound 1 m 1 rn sm swallow 1 rH inch you 1 ™ c &gt; Slightly «gi _ a 宓 3- (benzyloxy) -2- (2-oxy-4-propyl-1-pyrrolidinyl) butanidine 3- (benzyloxy) -2- (2-oxo Propyl-4-propyl -1-pyrrolidinyl) propanilamine 4-hydroxy-2- (2-oxy-4-propyl-1-pyrrolidinyl) butyramine 284 285 286 287 j ________1 288 289 290 291 292 293 -128 -200538436

215 〇 \ CN TH &lt; N m rH CO Os rH m BU 00 (Ν t &gt; CN tH Os (N (N 〇r〇r—H 00 CS 1.3.1. Then 1.3.2. Li Li cn “rH — ^ m ^ tH 黎 H rn — τ · Η 狯 cs: rn — 鹚 鲦 Η “° Ί cn — tH“ ° Ί cn — c〇— i—H 黎 H 2 ^ &lt; rj — leigh H ΓΠ ^ ^- H mixture_ί 蜉 &lt; ίπ m 松 &lt; Π m &lt; ίπ m &lt; Π m · &lt;! Π gambling &lt; ίπ &lt; Π Si &lt; ίπ C &gt; T inch office (N 乂 CN Gas CN inch ci (N gas CN inch Λ CN 3-hydroxy-2- (2-oxy-4-propyl-1.pyridinyl) propanamide 砮 1 Λ κ: I m Hf 1 (N 1 &lt; N Slightly Tan Tan, s M to; X 5 葚 1 rH m K 嫲 嫲 1 1 (N / ^ N 遁 厅 池 IE ff ig air 1 Jlf 1 CS ^ 1 CS 5 ^ s s s ffi -砮 i — «(E 1 m Secret 1 ci t &lt; N s π Μ _ 11 K mihn 111 Acne 1 rA 7 FREE Ι I Secret 1 1 CS WYou 5g S _ E ^ a 丨 丨 plastic S 2 1 rH m κ 1 m Na 1 CS I (N / ^ s olive 铿 mmmh ^ ϊ 磐 El · 4 4 4 S swallow 1 τ-Η Λ ΙΕ I m secret 1 1 &lt; N i _ 狴 _ Η 5 : S 4 遐 m 嫲 1 1 (N 1 i «s 5; n 痤 m ^ (S« 1 I m 3 η 砮 1 τ-Η W Ε I ή 1 d 1 CN 03¾ Old 譲 rA IE 294 to &lt; N VO C \ &lt; N Bu C \ CN 00 〇 \ CS C \ ON &lt; NO om rH Ο m CN 〇mm 〇m -129_

200538436 227 267 1 239 239 255 241 316 331 320 289 1.3 丄 then 1.3.2. 1.3.1. Then i 1.3.2. 1 1.3.1. Then 1.3.2. 1.3.1. Then 1.3.2. 1.3 .1. Then 1.3.2. 1.3.1. Then 1 1.3.2. 1.3.1. Then 1.3.2. 1.3.1. Then 1.3.2. 1.3.L then 1.3.2. 1.3.1. Then 1.3 .2. Mixture Mixture Mixture Mixture Mixture Mixture I 1 Mixture Mixture Mixture Mixture Inch r \ Inch CN (N Inch Inch CN Inch.rs CS Inch #s CS Inch λ c &lt; T CN Inch e \ CN 2- (2-oxy- 4-propyl-1-pyrrolidinyl) pentamidine 2-cyclohexyl-2- (2-oxy-4-propyl-1-pyrrolidinyl) acetamidin 3-cyclopropyl-2- (2-oxy-4-propyl-1-pyrrolidinyl) 1 Propylamine Λ 砮 砮 1 τ-Η I mm Ύ ^ ^ m Slightly avoid &amp; call 1 1 inch inch 5-methyl-2- ( 2-oxy-4-propyl-1-pyrrolidinyl) hexamidineamine 2- (2-oxy-4-propyl-1-¾pyridinyl) hexamidineamine | i i1 rH 1E 1 m Secret 1 1 (N is 浒 _ κ5Μ S i ^ m κ 1 m Secret 1 CJ / 1 &lt; N »i base S ii ^ m% I 1 I ΓΠ T— * swallow 1 τ-Η m K 1 Secret 1 1 (N i ^ 浒 譲 _ IE Ϊ i ^ 2- (2-oxy-4-propyl-1-pyrrolidinyl) -4- Phenylbutyramine 304 305 306 I 307 1 .-1 308 309 310 311 312 313 -130- 200538436

379 .I ▼ -H ON &lt; N o rH cn CN cn On 00 &lt; S m 〇 \ cs cn Os CN m Ch &lt; s ^ H rH m 1.3 丄 then 1.3.2. Rn — TH rn 1—1 cn — rH &lt; η — rH 狯 H-^ cn — rH — ^ ΓΟ ^ H hide Η rn — ^ Η — ^ ro — tH 0 Li H CO H rH mixture pine &lt; nm &lt; Π &lt; Π m &lt; π m _ &lt; nm &lt; Π m &lt; Π m loose &lt; ίπ &lt; nm CN &lt; N gas &lt; N gasci gas cs gas ci inch office &lt; N gas r &lt; T inch 〇Γ gas &lt; N mr 1 FREE 1 1 &lt; N slightly} E 1 s age are i ^ 1 1 ΓΟ 1— &lt; 1 m E: 1 m Hf 1 1 &lt; N slightly 狴 m K i W; 1 tH m E 1 m 娜 1 (N ^ t (N 1 5 ^ 揪 观 nf ga · slightly in Shisu 1 tH m IE 1 mm L am roll K -s two nd ^ c; 砮 m swallow 1 rH m κ 1 嫲 1 ci 1 &lt; N Complement 2 E: w ^ r; m swallow 1 rH K: 1 m Jii 1 CN ^ 1 (N s ^ pepper_ mg fr command 1 in rA 漥 1 f— &lt; me 1 Hf CN ^ CN i ^ 浒 Crocodile Ιί K i W r; η swallow 1 tH trophy I m secret 1 d 1 1 m ^ 浒 li ^ i slightly c; pan swallow 1 rH m κ: 1 m Hff 1 &lt; N 1 CN Ϊ ^ roll_ «gi W c; n 1 me 1 m secret 1 1 CN 5 ® li S 11 ^ 4 辎 d: ya rA 漥 314 in t-H m Ό r-H m r r-H m 〇〇 r-H cn T-H rO ο CS m i—H &lt; s m CA CN rO m cn m 131- 200538436

354 rH o inch C \ o ro 〇 \ 〇〇 \ 〇o os CN 00 (N CN ON 00 inch »〇00 CN 1.3.1. Then 1.3.2. Rn — i—H —, CO; — rH co- rH cn — r—H cn-rH 狯 H m — rH 狯 Η-, rn — ΓΛ 1-1 ^ H mixture Rong 4n m pine &lt; π m meal mm &lt; Π m rongm pine 4π mm CnT inch a ri &lt; N &lt; N gas &lt; N gas CN inch C &lt; T inch ^ CN inch &lt; N swallow 1 Η Λ IE 1 嫲 1 1 (N slightly 铿 i _ rA n 1 τ ^ Η m IE 1 m nf CN ^ (N 1 5 ^ Ling Rao ES ES «rA n 砮 1 Η m κ 1 m W 1 CN ^ 1 CN 5 s 浒 鲡 u £ i slightly c; n 砮 1 f—Η 1 m secret 1 1 (N s ^ Jg gi slightly cA n 1 ^ H mr 1 m ni 1 1 CN i ^ u_ u £ i __ rA n swallow 1 rH m κ 1 mm 1 1 (N i ^ roll Jane mg tingϊ in H m swallow 1 1-H me 1 m Ilf 1 &lt; N 1 &lt; N m 铿铿 4 m 锴 女 i K epilepsy 1 m {m 5% move TI 1-HJ m ffi)} E ^ 4 f W n ^ v ^ / CN 1 Bar A 1 J s ® 1 iH m IE 1 Λ Secret 1 1 &lt; N -m complement 4¾ «g 324 &lt; T) &lt; N cn Ό CN m BU CN cn 00 &lt; N ma \ &lt; N m O cn cn rH m co (N m cn -132- 9 200538436 9

299 352 338 348 595 242 348 326 329 424 1.3.1. Then 1.3.2. 1 · 3 · 1 · then 1.3.2. 1.3.1. Then 1.3.2. 1.3.1. Then 1.3.2. 1.3. 1.then 1.3.2. 1.3.1.then 1.3.2. Llΐ3 · 1 · then 1.3.2. 1.3 · 1.then 1.3.2. 1.3.1.then 1.3.2. 1.3.1 . Then mixture mixture mixture mixture mixture mixture mixture mixture mixture mixture 2,4,4 2,4,4 inch &quot; 3a, 4,6, a, 2,4 CN inch (N inch Λ inch Λ inch · CN inch office » λΓ 1 m IE 1 m 1 1 &lt; N s ^ -m lake [US m «sac νthion 2,5- 贰 (2 · oxy-4-propyl-1-pyrrolidinyl) pentanamine 2,4-fluorenyl (2-oxy-4-propyl-1-pyrrolidinyl) butyramine 1 m κ, I * S i 5 r—il * T ^ r—ι 4 W Μ. CO ^ ra i ~ 1 0X1 目 目 5 ^ til 11 ® 械 1 FREE Eya «2 ά ^ S r ά-1-Αhm A rt nf S ^ i 1 meaning 1 VO West CN 5-amino-2- (2 -Oxy-4-propyl-1-pyrrolidinyl) pentamidine 1 rH m κ 1 ¥ ^ fr cA W 1 UT7 rA η Sheng I swallow 1 r—1 m κ I mg fr _ slightly secret you Λ S tends to be a little bit ^ 4 ^ 7 w S fr slightly 2Ϊ 023 to m τ a complement 1] τρ Α i Zheng CCQ | Η Ϊ ί ^ 6- -6- amino-5- (2-oxo-4-propyl-1-pyrrolidinyl 333,334,335,336,337 338,339,340,341,342 -133-200538436?

298 352 482 1 243 I- 325 339 297 282 225 1.3.2. 1 · 3 · 1 · Ran 1.3.2. 1 · 3 · 1 · Ran 1.3.2. 1 · 3 · 1 · Ran 1.3.2. 1 · 3 · 1 · Ran 1.3.2. 1 · 3 · 1 · Ran 1.3.2. 1 · 3 · 1 · Ran 1.3.2. 1 · 3 · 1 · Ran 1.3.2. 1.3 · 1 · Ran 1.3. 2. TH m 1—t &lt; π &lt; in &lt; ίπ &lt;! □ &lt; ίπ &lt; ίπ &lt; π 4π &lt; i〇mm crane mm 鹧 mm crane gas r &lt; T gas c inch λ CN inch Outside ΓΠ inch office CO inch # &inch; inch inch gas (N inch office CnT ii # m chain I Pu 1 mm Dad HI ^ Dad daddy 1 cn Post 1 1—Η 1 U—1 1 ^ t 1 rH 1 1 rH 1 1 1-Ή 1 1 1 Ό 1 NS «« _ slightly 1 rn m J Hff E 1 E: 1 1E 1 | fi can = 1 CN sugar V nm Λ η m Sheng I m 1 bUf secret | 嫲 1 Ililf 砮? CN 1 CS v 狴 _ 狴 s cs ^ (N 1 tH 1 rH 1 Bl · 1 CN Paste JC ^ M 1 m 1 T ® τ, m ^ W slightly 1 / ^ s κ E «1 ™ W Tli \ Jgd / ^ N _ Γΰ _ it) Butterfly 1 E IE | E «g« Secret Jiff m Secretly Dressed IT 狴 骟 Marrying Swan 4 Sutra 4 ^; 趑 iT) ^ 1 Ut7 ^-mm Π3 .η ^ Secret rights mt W t S «s secret_ secret Wi ά m 5 tf 狴« 狴 狴 狴 »铿 ά 升 1 1 &lt; N \ &lt; mmy m vi ^ AK] A 鄯 spoon 4 m 4 m &lt; N 31 1 (N 343 344 345! 346 347 348 349 350 351

200538436 314 229 259 _1 275 381 1 256 1.3.2. 1.3.1. Then 1.3.2. 1.3.1. Then 1.3.2. 1.3.1. Then! 1.3.2. 1.3.1. Then 1.3.2. 1.3.1. Then 1.3.2. 1.3.1. Then 1.3.2. Mixture mixture mixture 1 mixture mixture mixture inch CN 3R, 2,4 _1 inch Λ C ^ T inch ^ ci inch &lt; N CvT swallow 1 τ- Η m K: 1 m secret 1 d 1 CN cA ^ i slightly C ^ cA ac m Sheng I swallow 1 rH slightly 1E 1 T slightly secret 1 has 1 (N Α 厅 έ t C 补 砮 1 yim κ 1 &quot; Τ η 嫲 1 1 weight 狴 is mmh JS 4 i 2- (2-oxy-4-propyl-1-¾pyridinyl) -3-phenylpropanamine 砮 1 rH mr 1 iil il1 d 1 CN ϊ ft S sec} E Ul ^ W 6-amino-2- (2-oxy-4-propyl-1-pyrrolidinyl) hexamidine 1 rH domain: 1 CN slightly K) Base Π1 d 4 Η slightly ^ η 1 m Jii slightly K) ii 11 1 (N Φ ti _ cj m 3 砮 IH Λ m 1 &lt; N s K) minus 11 1 &lt; N «m &lt; N \ -n ί a cj m 352 353 354 355 356 357 358 359 360 1〆) 5 ~ 200538436

Solvent DMSO DMSO DMSO DMSO DMSO I- DMSO DMSO DMSO DMSO W NMR Description 0.80 (t, 3H); 1.40-1.60 (m, lH); 1.75-1.95 (m, lH); 2.10 (dd, lH); 2.45 (dd , LH, partially overlapping with the solvent); 2.8 (m, 1H); 3.05 (dd, lH); 3.60 (m, 3H); 4.45 (dd, lH); 6.90 (s (width), 1H); 7.30 (s (Width), 1H). 0.80 (t, 3H); 1.45-1.70 (m, lH); 1.75-1.95 (m, lH); 2.50 (m, lH, partially overlapping with the solvent); 3.40 (πι , 1Η); 3.50-3.70 (m? 5H, 4.45 (dd, lH); 6.90 (s (E) 51H); 7.30 (s (E) 51H). 0.80 (t, 3H); 1.40-1.90 (m, 6H); 2.10 (dd, lH); 2.30-2.60 (m, 6H); 3.05 (dd, lH); 3.60 (dd, lH); 3.60 (dd, lH); 4.30 (dd, lH); 6.90 (s (Width), 1H); 7.30 (s (width), 1H) 0.80 (t, 3H); 1.20 (d, 6H); 1.404.60 (m, lH); 1.70-1.85 (m, lH); 2.45 (dd, lH); 2.35-2.55 (m, lH, partially overlapping with the solvent); 2.55 (m, 2H); 2.90 (s, lH); 3.00 (m, lH); 3.60 (m, lH); 4.30 ( dd, lH); 6.90 (s (width), 1H); 7.30 (s (width), 1H). 0.80 (t53H); 1.20 (d, 6H); 1.40-1.65 (m, lH); 1.75-1.90 ( m, lH); 2.15 (dd, lH); 2.35-2.55 (m, lH); 2.55 (d, 2H); 2.95 (s, lH); 3.30 (m, lH, overlap with solvent); 3.45 (m, lH); 4.45 ( dd, lH); 6.90 (s (width), 1H); 7.30 (s (width), 1H). 0.80 (t, 3H); 1.40-1.65 (m, lH); l_75-1.95 (m, lH); 2.10 (dd, lH); 2.45 (dd, lH, partially overlapping with the solvent); 2.75 (m, 1H); 3.20-3 · 50 (π, 5Η, overlapping with the solvent); 4.30 (d, 2H) 4.45 (dd, lH); 6.90 (s (width), 1H); 7.35 (s (width), 1H). 0.80 (t, 3H); 1.40-1 · 60 (ηι, 1Η); L70- 1.90 (m, lH); 2.20 (dd, lH); 2.45 (dd, lH); 2.60 (m, lH); 3.25 (m, lHjS | solvent overlap); 3.45 (dd, lH); 3.60 (d, 2H ); 4.30 (dd, lH); 6.90 (s (width), 1H); 7.30 (s (width), 1H); 7.60-8.00 (m, 5H). 0.85 (t, 3H); 1.55-1.70 ( m, lH); 1.80-1.95 (m, lH); 2.65 (dd, lH); 2.85 (dd, lH); 3.45 (dd, lH); 3.80 (m, 2H), 4.05 (m, lH); 4.50 (dd, lH); 6.80 (s (width), 1H); 7.40 (s (width), 1H); 9.20 (s, 1H) · 0.65 (t, 3H); 1.40-1.60 (m, lH); 1.75-1.90 (m? LH); 2.15 (dd, lH); 2.30 (s, 3H); 2.45 (dd, lH); 2.80-2.95 'HNMR No. r—i Ξ Ξ Ξ r—1 r—π ss- 136- 200538436

DMSO DMSO DMSO DMSO 1! DMSO DMSO CDC13 CDCI3 rH • r \ rH fi o &quot; rH 8 o 'reference c \ inch · inch · CN ^ o' cn &lt; N rn ffi rH 5 ~ g Exercise 1 3 wthera ^ ^ ^ ffiH (^ Alley: 芑 g Yiqin TS fit and 00 00 Den 弋 g. 2 5 1 Si 1 s 5 5 County stupid g ^ 71 tlmil Qin | pg 5 g Hi Bu m 〇2 g 5 inch h ^ 1 f | id Βϋ \ ^ 6 ^ X .φ 5 5 5 0.75 (t, 3H); 1.55-1.70 (m, lH); 1.80-1.95 (m, lH); 2.50 (dd, lH, overlap with solvent ); 2.70 (dd, lH); 3.30 (m, lH, overlap with dissolved! 1); 3.70 (m, lH); 3.90 (dd, lH); 4.50 (dd, lH); 6.90 (s (width) , 1H); 7.10 (d, lH); 7.20-7.40 (m, 2H); 7.50 (d, lH) · 0.80 (t, 3H); L50-1.75 (m, lH); 1.80-1.95 (m, lH) ); 2.45 (dd, lH, overlapping with solvent); 2.75 (dd, lH); 3.40-3.80 (m, 3H), 4.45 (dd, lH); 6.90 (s (width), 1H); 7.20-7.25 ( m, 5H). 0.80 (t, 3H); 1.50-1.75 (m, lH); 1.80-1.90 (m, lH); 2.45 (dd, lH, overlap with solvent); 2.75 (dd, lH) ;, 3.15 (dd, lH); 3.65 (m, lH); 3.95 (dd, lH); 4.45 (dd, lH); 6.90 (s (width), 1H); 7.10-7.25 (m, 3H), 7.30-7.50 ( m, 2H). 0.80 (t, 3H); 1.55-1.70 (m, lH); 1.80-1.95 (m , LH); 2.55 (dd, lH, overlap with solvent); 2.75 (d (UH); 3.30 (m, lH ,, overlap with solvent); 3.70 (dd, lH); 4.50 (dd, lH); 6.95 ( s (width 7.30-7.70 (m, 10H). 0.85 (t, 3H); 1.60-1.75 (m, lH); 1.75-1.95 (m, lH); 2.55 (m, lH, overlap with dissolved U); 2.75 (dd, lH); 3.30 (m, lH ,, partially overlapping with the solvent); 3.50-3.85 (m, 1H); 4.40 (dd, lH); 6.95 (s (width), 1H); 7.30-7.80 ( m, 10). 0.90 (t, 3H); 1.20 (s, 3H); 1.60-1.80 (m, lH); 1.80-2.10 (m, lH); 2.40 (dd, lH); 2.50-2.60 (m, 3H, | a ^ lM stack); 3.20 (m, lH); 3.50-3.70 (m, 3H); 4.45 (dd, lH); 5.45 (s (width), 1H); 6.30 (s (width), 1H ) 1.05 (t, 3H); 1.6 (M.75 (m, lH); 1.90-2.20 (m, lH); 2.70 (dd, lH); 3.80 (m, 2H); 4.45-4.50 (m, 2H ); 5.30 rH L—J r—i rH T—1 S1 L · —J π rH 1-1 L_J Γη rH L ^ I r—1 r—1 -137- 200538436

〇00 P osiAta OC / DSQ 〇 • 00 s QO 00 Q ss Q ss Q fp QU έ 1—Η ffi R v CO vd ffi rH s ffi, (NO as 〇 om °) Inch (N • Office • Decay ffi 5 s ～ 田 _ 3 View irT ^ ι S. S 豸 CS inch N 0? I 异 • · »&>; WO ®bM iimil. ^ S ό 〆hang® ξ m 7k d '^ N ^ Dan ^ ss« Poor S 亘 弋 rn 〇r-ί CO ^ 2 3: S Ο O wo 00 (N Ch o cn vd • r \ K t CN • # \ (N o 'cs ό y— &lt; CN § έ s, gg 3 t »— ·… • # \ 广 一 、 S S g g V °) O v〇 • 办 ffi s § ° 〇§ 〇 CO» n 1-H cn iH # \ s JTi r4 • # \ rH 芎CN 旮 1—H s «S l &gt; § ^ 3 ^ Bu · W 1-HW 〇 \ 2 s &gt;? • # \ 3 a • Inch tga ^ qa 殳 5 § ^ 〇s •, \ &amp; tH go 'cn • * \ rH (N: • * \ aj〇 &lt; N • · Ν ϊέ rH g § ^ b · 6 * ^ a, inch day ¥ va $ s ^ a ^ π 3 o' w 00 inch dd 2 ^ • a white ffi &amp; Γ〇— # \ 〇〇g ΐή β s § ffi ^ rl β rn § 91 ^ ® 9 ^ Sdan d 沄 乂 s' SS Poor ί s ^ s 2 | ξ § ^ § RunH &amp; C / D… g ^ ^ 跸 丹 i ffi s ^ 5 3 i〇 ^ O inch 〇 .... S get s § i soap s cn tH s. Ffi ffi ffi ^ ι-H a? ^ § den ^ ^ * S § ® 2 ^ Dan ^ 〇 ^ 5 wi ^ — cx ύ a fist # \ · s 巨 la § rn 0 r • r \ r \ poor 3 5 § once tm i-η g S ^ 2 ^ g 00 3 suitable II VO, n fi ^ § fi ± 〇rH tH 琴 3 i ~ H 〇 ... V〇 Tian inch · agi〇cn §SOί S § ffi CO CO ^ 2 ^ 〇§ ffi CN ^ minister g ^ 〇VW ^ CO § ^ CN ^ swallow S ffi〆3 «&Lt; N ^ • 5 ς? ^ G 2 3 3 2 Os inch • · * \ | a 1 ^ t &gt; ΓΟ s 营 二 莒 ffi ^. S ^ ffi ssa 5? I—l U ^ J r—i CN U ^ J a Γ-1 a L- ^ J g -138- 200538436

CDC13 DMSO CDC13 DMSO DMSO I CDC13 DMSO DMSO CDC13 0.90 (t, 3H); 1.60-1.70 (m, lH); 1.85-2.10 (m, lH); 2.25 (s, 3H); 2.55 (dd, lH); 2.85 (dd, lH); 3.30-3.60 (m, 2H), 3.75 (dd, lH); 3.80 (dd, lH); 4.50 (dd, lH); 5.50 (s (width), 1H); 6.30 (s ( Width), 1H); 6.90-7.10 (m, 3H), 7.20 (dd, lH). '0.70-0.90 (m, 3H); 1.50-1.75 (m, lH); 1.80-1 · 95 (πχ, 1Η ); 2.50-2.90 (m, 2H); 3.20-3.40 (m, lH, overlap with solvent); 3.50-3 · 80 (ιη, 3Η); 3.95 (dd, one of the diastereomers 1H); 4.45 (dd, 1H); 6.90 (s (width), 1H); 7.30 (s (width), 1H); 8.70 (d, 2H); 9.15 (d, 1H). 0.95 ( t, 3H); 1.60, 1.70 (m, lH); 1.85-2.10 (m, lH); 2.80 (dd, lH); 3.05 (dd, lH); 3.55 (dd, lH); 4.00 (dd, lH) 4.55 (dd, lH); 4.8 (m, lH); 5.60 (s (width), 1H); 6.25 (d, 2H); 6.30 (s (width), lH); 6.75 (d, 2H) .0.75 (t? 3H); 1.45-1.60 (m, lH); 1.75-1.90 (m, lH); 2.05 (dd, lH); 2.40 (dd, lH); 2.60 (m, lH); 3.05 (dd , lH); 3.25 (s, 3H); 3.30 (m, 2H, partially overlapping with the solvent); 3.55 (dd, lH); 4.30 (d (UH); 7.05 (s (width 7.40 (s (width 0.80 (t 3H); 1.4M.63 (m, lH); 1.71- 1.86 (m, lH); 2.12 (dd, lH); 2.43 (dd, lH), 2.82 (m? LH); .3.2-3.4 (m, 2H); 4.23 (d, 2H), 4.31 (dd, lH) ), 6.97 (s (width), 1H), 7.31 (s (width), 1H), 7.94 (s, lH), 8.5 (s, lH). 1 ---- 0.84 (t, 3H); 1.60-1.72 (m, lH); 1.86-1.98 (m, lH); 2.78 (dd, lH); 3.0 (dd, lH); 3.42 (dd, lH) 5 3.98 (dd, lH) 4.53 (dd, lH ), 5.08 (m, lH), 5.58 (s (width), 1H), 6.21 (s, 2H), 6.25 (s (width), 1H), 6.73 (s, lH). 0.83 (t, 3H); 1.52-1.70 (m, lH); 1.70-1.84 (m, lH); 2.5 (m, overlap with DMSO), 2.72 (dd, lH), 3.64 (m, 2H), 3.84 (m, lH); 4.39 ( dd, lH); 7.05. (s (width), 1H); 7.42 (m, 2H) · 0.81 (t, 3H); 1.48-1.51 (m, lH); 1.80-1.94 (m, lH); 2.5 ( m, overlap with DMSO), 2.72 (dd, lH), 3.78 (m, H), 3.95 (m, lH), 4.38 (m, lH), 7.05 (s (width), 1H), 7.42 (m, 2H ). 1.02 (t53H); 1.63-1.82 (m, lH); 1.91-2.08 (m, lH); 2.86 (dd, lH); 3.22 (dd, lH)? 3.83 (dd, lH), 3.98 (dd, lH), 4.44 (dd, lH), 5.3-5.5 (m, 2H); 6.13 (s (width), 1H), 6.21 (s, 2H). · &lt; N 5? &lt; NL · —J CN mi r—1 rH rnt • CO, rni -139- 200538436

_π GC / M Μ + 286 I LC / M ΜΗ + 259 Os (N m On m 273 Configuration data mm Racem Racem Racem 00 rH 〇〇〇 &lt; 00 τ— &co; PQ (N TH χη rH 00 TH CO IUPAC Chemical name 1 3-({(((lS) -l- (aminocarbonyl) propyl] amino} methyl) hexanoic acid ethyl ester hydrochloride 3-((((lS) -l- (aminocarbonyl) propyl] amino} methyl) hexanoic acid ethyl ester hydrochloride 鍫 K m &amp; ϊ g S g Η 3-({[((lS) -l- (aminocarbonyl) propyl] amino} methyl) butylhexanoate hydrochloride l3-({[((lS) -l- (aminocarbonyl) propyl [Amino] amino} methyl) isopropylhexanoate hydrochloride TΓ Γ Compound No. AA1 -1 AA2 1 ΑΑ3 AA4 AA5 —1A-O &quot; »

Claims (1)

200538436 X. Scope of patent application No. 90105824 "(2S) -2- [4- (2,2-difluorovinyl) · 2-oxypyrrolidin-1 -yl] butanoic acid and its use" Patent Division Application (2) Application Patent Scope (Amended in July 1994) 1. A compound which is (2S) -2-[(4S) -4- (2,2-difluorovinyl) -2-oxypyrrolidin-1-yl ] Butamidine or a pharmaceutically acceptable salt thereof. 2 · —Used in mammals in need to treat epilepsy, epilepsy, seizures, convulsions and other neurological conditions including bipolar disorders, mania, depression, anxiety, migraine, trigeminal neuralgia and other neuralgia, chronic Pain, neuropathic pain, cerebral ischemia, arrhythmia, myotonia, cocaine abuse, stroke, myoclonus, idiopathic tremor and other dyskinesias, neonatal cerebral hemorrhage, amyotrophic lateral sclerosis, spasm State, Parkinson's disease and other degenerative diseases, bronchial asthma, asthma, and allergic asthma, asthma, bronchial hyperactivity and bronchospasm, and allergic and vasomotor rhinitis and conjunctivitis The compound includes the compound or the pharmaceutically acceptable salt thereof as the active ingredient in the scope of application for the patent, and the combined pharmaceutically acceptable diluent or carrier. 3. The medicinal composition of item 2 of the patent application, wherein the disease to be treated is epilepsy, neuropathic pain, bipolar disorder or migraine. -141-