TW200538435A - (2S)-2-[4-(2, 2-difluorovinyl)-2-oxopyrrolidin-1-yl]butanoic acids 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

200538435 IX. Description of the invention: [Technical field to which the invention belongs] The present invention relates to 2-oxy-1-pyrrolidine derivatives, a method for preparing the same, a pharmaceutical composition containing these compounds, and uses thereof as medicines. [Prior art] European Patent No. 021 62 03 6 B1 discloses the compound (S) -a-ethyl-2-oxy-1 -pyrrolidinacetamidine, which has the international non-exclusive name levetiracetam ) ° Levetiracetam is a levorotide 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, 2i2, (1 992), 1 93-203). 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 pyrrolidinone ring, have been found to unexpectedly improve the therapeutic properties. 200538435 [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 -CAiNR5!? 6 or -CAWR7 or -CA ^ R8 or CN; A1 and A2 are oxygen, sulfur or -NR9 respectively; R1 is hydrogen, alkyl, aryl or -CH2-Rla where Rla is aryl , Heterocyclic ring, halogen atom, hydroxyl group, amine group, nitro group or cyano group; R2, R3 and R4 are the same or different and each is hydrogen, halogen atom, hydroxyl group, fluorenyl group, amine group, nitro group, nitrate group Group, cyano, azide, carboxyl, amido, sulfonic acid, sulfonamide, alkyl, alkenyl, alkynyl, ester, ether, aryl, heterocyclic or oxygen derivative, sulfur derivative, amine Derivatives, fluorenyl derivatives, sulfonyl derivatives or sulfinyl derivatives. Only 23,! ^ 3 and 1? Are the same or different and each is hydrogen, halogen, alkyl, alkenyl, alkynyl or aryl; R5, R6, R7 and R9 are the same or different and each Are hydrogen, hydroxy, alkyl, aryl, heterocyclic or oxygen derivatives; and R8 is hydrogen, hydroxy, fluorenyl, halogen, alkyl, aryl, heterocyclic or fluorene derivatives; but {^, 1 ^, 1 ^, 1 ^, 1 ^, and 1 ^ are 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, the pyrrolidine ring is taken as 200538435 · φ is not mono-, di- or tri-methyl or mono-ethyl; and when R3a and R4a are each hydrogen and A2 is oxygen And when 乂 is conr5r6, r3 is not a carboxyl group, an ester, a fluorenyl group, a substituted oxy-pyrrolidine, a hydroxyl group, an oxo derivative, an amine group, an amine group derivative, a methyl group, a naphthyl group, or a phenyl group. The oxygen derivative is substituted or substituted by a halogen atom in the para position. In the following definitions, unless otherwise stated, R11 and R13 are the same or different and each is amidino, alkyl, alkenyl, alkynyl, fluorenyl , Ester, ether, aryl, aralkyl, heterocyclic or oxygen derivative, sulfur derivative, B fluorenyl derivative, amino derivative, sulfofluorenyl derivative or sulfinyl sulfenyl derivative, each selective Substitution with any appropriate group, including but not limited to one or more moieties selected from lower alkyl groups or other groups described later as alkyl substituents. * The term "oxy derivative" is used herein to define as Including -0-R11 group, where R11 is as defined above, except "oxy derivative". Non-limiting examples are alkoxy, alkoxy, alkynyloxy, fluorenyloxy, oxyester, oxamino, alkylsulfonyloxy, alkylsulfinyloxy, arylsulfonyloxy Group, arylsulfinyloxy, aryloxy, aralkyloxy or heterocyclicoxy such as pentyloxy, B 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, pseudothio, fastthio, and arylthio. The term "amino derivative" as used herein is defined to include the -NHR11 or -NR11R12 group, wherein R11 and R12 are as defined above. 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 200538435. This definition includes the formula R11-C0-, 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 acryl, benzamyl 'naphthyl amidyl, furan amidyl, nicotinyl amidino, 4-carboxybutyridinyl, oxalyl, acetofluorenyl, cysteamine, oxalanyl. The term "sulfofluorenyl derivative" is used herein to be defined to include the group -S02-Rn, where Ri 1 is as defined above, except for "sulfofluorenyl derivatives". Non-limiting examples are alkylsulfonyl, alkenylsulfonyl, alkynsulfonyl and arylsulfonyl. The term "sulfinyl sulfenyl derivative" is used herein to be defined to include the group -S02-RM, wherein 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 can be optionally selected from 1 to 5 by halogen, hydroxy, fluorenyl, amine, nitro, cyano, thiocyano, fluorenyl, fluorenyl, sulfonyl derivatives, Sulfenamidine derivatives, alkylamino, carboxyl, ester, ether, fluorenyl, azide, cycloalkyl, sulfonic, sulfonamido, sulfur derivatives, oxyester, oxygen Amido, heterocyclyl, vinyl, Ci.5-alkoxy, C6.1Q-aryloxy and Cn. -Substituent substitution of the group consisting of aryl groups. 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

200538435 Substituted by 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, and the like 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 selected from a halogen atom, a hydroxyl group, 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, and CV12 is preferred (V4-alkylene or C2.12_, and preferably C2.4-alkylene or -alkylene The base part. Conventional bases (such as "n-propyl" and "second butyl") specified by prefixes (such as "n", "second", "iso", etc.) unless otherwise stated Otherwise, it is in the positive 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 by removing one hydrogen

200538435

For example, phenyl and naphthyl are each selectively selected from 1 to 5 halogen atoms, hydroxyl, fluorenyl, amine, nitro, cyano, fluorenyl, fluorenyl, sulfonyl, and sulfinyl. , Alkyl, amino, carboxyl, ester, ether, amido, azide, sulfonic, sulfoamido, alkylsulfoamido, alkylsulfinamido, alkylthio, oxygen Ester group, oxamino group, aryl group, -alkoxy group. -Aryloxy, Cm-Chenyl, (^ .6-haloethynyl substituted organic groups. The aryl group is preferably a monocyclic ring having 6 to 10 carbon atoms. The preferred aryl group is Phenyl and naphthyl are each selected from 1 to 5 by halogen, nitro, amine, azido, C ^ 6-alkoxy, alkylthio, Ci_6-alkyl, (^ .6 -Haloalkyl and phenyl substituent substitution. The term "halogen atom" is used herein to include C1, Br, F, and I atoms. The term "hydroxyl" is used herein to represent the group -0H. "锍The term "radical" is used herein to represent the formula -SH group. The term "cyano" is used herein to represent the formula -CN group. The term "nitro" is used herein to represent the formula -N02 group. "Nitrooxy The term "radical" is used herein to represent the formula-(^ 02 radical. The term "amine" is used herein to represent the formula -NH2 radical. The term "azido" is used herein to represent the formula -N3 radical. " The term "carboxyl" is used herein to represent the formula -COOH group. The term "sulfonic acid" is used here to represent the formula -S03H group. The term "sulfonamido" is used here to represent the formula -S02NH2 group. " The term "ester group" is used herein to represent the formula-C00-R11. Where R11 is as defined above, but Derivatives, sulfur derivatives, or amine-based derivatives are excluded. "Acid group" ~ * The word meaning is to include a group selected from Ci · 5. A straight or branched alkyl group, or <: 2.50 a linear or branched alkenyl or An alkynyl group or a combination thereof borrows one or more oxygen radicals -10-200538435 · # The branch of the radical. The term "amido" is defined to include the formula -C0NH2 or -C0NHR11 or -C0NRMR12, where R11 and R12 are defined as 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, bearing at least one 0, S, and / or N A bifurcated carbocyclic ring structure and one of the carbons in a selective carbocyclic ring structure can be replaced by a carbonyl group. Non-limiting examples of aromatic heterocycles are pyridyl, furyl, pyrrolyl, thienyl, isothiazole |, Imidazolyl, benzimidazolyl, tetrazolyl, quinazolinyl, quinolinyl, naphthyridinyl, daquatyl, pyrimidinyl, pyrazolyl, quinolinyl, isoquinolinyl, isopropyl Benzofuryl, benzothienyl, pyrazolyl, indolyl, indolyl, purinyl, isoindolyl, carbazolyl, thiazolyl, 1, 2 , 4-thiadiazolyl, thieno (2,3-b) furanyl, furanopyranyl, benzofuranyl, benzooxafluorenyl, isoxazolyl, oxazolyl, thiathranyl , Benzothiazolyl, or benzoxazolyl, fluorenyl, phthaloyl, quinoline, phenanthryl, acridine, pyridinyl, phenanthroline, phenothiyl, furanyl , Benzodihydropyranyl, indololinyl, xanthenyl, hypoxanthinyl, pyridinyl, 5-azacytosinyl, 5-azauridine, triazolopyridyl, imidazo Pyridyl, pyrrolopyrimidyl and pyrazolopyrimidyl 'are optionally substituted with an alkyl group or as described above for an alkyl group. Non-limiting examples of non-aromatic heterocycles are tetrahydrofuryl, tetrahydropyranyl, hexahydropyridyl, hexahydropyridyl, hexahydropyridyl, imidazolidinyl, morpholino, morpholinyl, 1 -Oxaspiro (4.5) dec-2-yl, pyrrolidinyl, 2 · oxy-pyrrolidinyl, sugar moiety (ie glucose, pentose, hexose, ribose, fructose which can also be substituted) Or optionally substituted with any suitable group, including but not limited to one or more selected from lower alkyl, or other pre-11-

200538435 The part of the foundation described by Wenfeng Yuanji. The term "heterocyclyl" also includes bicyclic, tricyclic and tetracyclic, spiro groups in which any of the foregoing heterocyclic ring rings are fused to one or two rings. These ring systems are selected from aromatic rings, cyclohexane rings, A cyclohexyl ring, a cyclopentane ring, a cyclopentene ring or other monocyclic heterocyclic ring, or here a monocyclic heterocyclic ring is bridged by a radical such as quininine, a 7-aza Bicyclo (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, Rh, R4a, R5, R6, R7, R8 is attached to the rest of the molecule through a heteroatom or carbonyl group, straight or branched, CV12 is preferred (^ .4 alkylene or C 2 _ 1 2 is preferably C 2 _ 4 alkyl or -radyl bridge system is selectively inserted between the heteroatom or carbonyl group and the attachment point of the rest of the molecule. Preferred examples of X are -COOR7 or -C0NR5R6, wherein R5, R6 and R7 are preferably ammonia, Ci.4-Cyclo'phenyl or Cryptophenyl. Preferred X is carboxyl or -C0NR7R6, where R5 and R6 is preferably hydrogen, alkyl, phenyl, or alkylphenyl, especially -CONH2. Preferably, A1 and A2 are each oxygen. Preferred R1 is hydrogen, and alkyl is particularly (^ .12 alkyl is particularly lower alkyl or Aryl is particularly phenyl. Preferred R1 groups are, for example, methyl, ethyl, propyl, isopropyl, butyl, iso- or tertiary butyl, and each of 2, 2, 2-trimethylethyl is selective. Selectively attached through a methylene bridge or substituted with at least one halogen atom, such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2, 2-dibromoethyl1, budimethyl-2,2,2-trichloroethyl. Ethyl is preferred. R2 and R2a are each preferably hydrogen, and the halogen atom or alkyl group is particularly a lower alkyl group. -12-

200538435 Preferred examples of R2 and R2a groups are hydrogen, halogen atom, or methyl, ethyl, propyl, isopropyl, butyl, iso- or tertiary-butyl, 2,2,2-trimethyl Ethyl or substituted with at least one halogen atom, such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl Radical, 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 each 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-tris 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. 1-33 is especially hydrogen or alkyl, especially lower alkyl and most preferably hydrogen. Preferably, R3 is hydrogen, and C12-alkyl is particularly Ci_6-alkyl, each of which is optionally substituted with one or more substituents selected from hydroxyl, halogen, cyano, thiocyano, or alkoxy, and Is directly or through sulfur, sulfenyl, sulfofluorenyl, carbonyl or oxycarbonyl and selectivity < ^ 4-alkylene bridge, especially methylene is 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, pyrrole Pyridyl, pyridyl, 1-pyridylyl, thiomorpholinyl, benzodioxoyl, furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, or hexamethylene Hydropyridyl is each optionally substituted with one or more substituents selected from halogen atoms, (^ .6-alkyl and phenyl), and is directly or through a carbonyl-13-200538435 group or Ci.4- The alkylene bridge is particularly methylene attached to the ring; naphthyl; or phenyl, phenalkyl, or phenenyl, each of which is optionally selected from one or more selected from the group consisting of halo Ci_6-fluorenyl, Ci.6-halo Yuanji, C ^ .6-Methoxy,-垸Substituted by substituents of thio, amine, azide, phenyl, and nitro, and each directly or through an oxygen, sulfonyl, sulfonyloxy, carbonyl, or carbonyloxy group and optionally through Cp4- The alkyl bridge is particularly a methylene group attached to the ring. Still more preferably R3 is Ci. 6-alkyl optionally via one or more selected from a halogen atom, a thiocyano group, an azido group, an alkoxy group, an alkane Substituted by thio and phenylsulfonyl substituents; nitrooxy; C2.3-alkenyl or -alkynyl each optionally substituted with one or more halogen atoms or ethenyl; tetrazolyl, pyridine Group, furyl, pyrrolyl, thiazolyl, or thienyl; or phenyl or phenylalkyl, each of which is optionally selected from one or more halogen atoms, Cl_6-alkyl, CV6-haloalkyl, 1.6-alkane Oxy, amine, azido, phenyl, and nitro substituents, and each directly or through a sulfonyloxy group and optionally through a < ^ 4-4-alkylene bridge, especially methylene Is attached to the ring. Preferred examples of other R3 are hydrogen, halogen atom or hydrogen, halogen atom, or methyl, ethyl, propyl, isopropyl, butyl, iso- or tertiary-butyl Group, 2,2,2-trimethylethyl or substituted with at least one halogen atom, such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-di Methyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl. R3 is especially -alkyl optionally selected from one or more halogen atoms, Substituted by a thiocyanate or azide substituent; C2_5-alkenyl or -alkynyl, each optionally substituted with one or more halogen atoms; thienyl; or phenyl optionally substituted with one or more selected Substituted from a halogen atom, a Ci.6-alkyl group, a 1-6 haloalkyl group, or an azide substituent. -14-200538435 · Further preferred examples of the R3 group are a C ^ 6 alkyl group and a C2_6 haloalkenyl group. Preferably R5 and R6 are hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso- or tertiary-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 φ, 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. Φ A2 is oxygen; X is -CONR5R6 or -C00R7 or -C0-R8 or CN; R1 is hydrogen or alkyl, aryl, halogen atom, hydroxyl, amine, nitro, cyano; R2, R3, R4 are Identical or different and each is hydrogen or halogen atom, hydroxyl, amine, nitro, cyano, fluorenyl, fluorenyloxy, sulfonyl derivative, sulfinyl derivative, amine derivative, carboxyl , Ester group, ether group, amido group, sulfonate group, sulfonamide group, alkoxycarbonyl group, sulfur derivative, alkyl group, alkoxy group, oxyester group, oxamido group, aryl group, oxygen derivative , Miscellaneous -15-

200538435 Cyclic, vinyl, and R3 may additionally represent C2_5 alkenyl, C2_5 alkynyl, or azido, each of which is optionally selected from one or more halogen atoms, cyano, thiocyano, azido, and cyclopropyl Substituted with fluorenyl and / or phenyl; or phenylsulfonyloxy and any phenyl moiety may be substituted with one or more halogen atoms, alkyl, haloalkyl, alkoxy, nitro, amino 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 derivatives; and R8 is hydrogen, hydroxy, fluorenyl, halogen atom, alkyl, aryl, heterocyclyl, alkylthio or sulfur derivatives. Among these compounds 1A, Ri is preferably fluorenyl, ethyl, propyl, isopropyl, butyl or isobutyl; most preferably, 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 CV5 alkyl group, a C2.5 alkenyl group, a C2.5 alkynyl group, a cyclopropyl group, and an azido group, each of which is optionally selected from one or more halogen atoms, a cyano group, a thiocyano group, and an azido group. , Alkylthio, cyclopropyl, fluorenyl, and / or phenyl; phenyl; phenylsulfonyl; phenylsulfonyloxy, tetrazole, triazole, thienyl, furanyl, pyrrole, pyridine, Therefore any phenyl moiety may be substituted with one or more halogen atoms, alkyl, haloalkyl, alkoxy, nitro, amine and / or phenyl; most preferably methyl, ethyl, propyl, Isopropyl, 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 -16-

200538435 · In which X ^-CA1NH2, -CA1NHCH3 ^ -CA1N (CH3) 2; R1 is alkyl or phenyl; R3 is alkyl, alkenyl, alkynyl, cyano, isothiocyanate, ether, Carboxyl, amido, aryl, heterocyclic; or R3 is CH2R1 () where R1 () is hydrogen, cycloalkyl, oxyester, oxyalkylsulfonyl, oxyarylsulfonyl, amine Alkylsulfonyl, aminoarylsulfonyl 'nitrooxy' cyano, isothiochloro, acid amine, sulfanyl, arylthio, alkylsulfinyl, alkylsulfonyl Fluorenyl, heterocyclyl, aryloxy, alkoxy or trifluoroethyl; R3a is hydrogen, alkyl or aryl (especially when 1 ^ 33 is hydrogen, R3 is not methyl); or R3R3a forms a ring Alkyl; and R2, R2a, R4 and R4a are each hydrogen. In the compound of the formula I, R1 is preferably alkyl, particularly 1.12, more preferably -alkyl and most preferably ethyl; 1-2, 1 ^ 23, 1 ^ and R4a are preferably hydrogen. R3 is preferably selected from hydrogen; C ^ .u-alkyl, and especially C ^ -alkyl, each of which is optionally selected from one or more selected from hydroxyl, halogen, cyano, thiocyanate, or alkoxy Substituent substitution, and is directly or through a thio, sulfenyl, sulfonyl, carbonyl or oxycarbonyl group and optionally additionally attached to the ring via a < 4-4-alkylene bridge; C2_6-alkenyl or -alkynyl, in particular C2.3-alkenyl or -alkynyl, each optionally substituted with one or more halogen atoms; azide; cyano; amido; carboxy; triazolyl, Tetrazolyl, pyrrolidinyl, pyridyl, 1-oxypyridyl, thiomorpholine-17-200538435 • ·, phenylhydrazone, furanyl, oxazolyl, pyrimidinyl, pyrrolyl, thio Diazolyl, thiazolyl, thienyl, or hexahydropyridyl, each of which is optionally substituted with one or more substituents selected from a halogen atom, Ci_6-alkyl, and phenyl, and is directly or through a carbonyl or Ci_4-alkylene bridges are particularly methylene attached to the ring; naphthyl; or phenyl, phenylalkyl, or phenylalkenyl, each of which is optionally selected from one or more halogen atoms, CV6- Alkyl, C ^ -haloalkyl, C ^ -alkoxy, (^ .6-alkylthio, amine, azido, phenyl, and nitro substituents, and each is directly or through an oxygen Sulfo, sulfofluorenyl, sulfofluorenyloxy, carbonyl or carbonyloxy and optionally additionally through a (4-.4-alkylene bridge, especially methylene is attached to the ring. R3a is preferably hydrogen or alkyl; R4 and 1 ^ 43 are preferably hydrogen, alkyl, phenyl or benzyl, respectively. Another preferred group of compounds of formula I (compound 1C) comprises compounds in racemic form, where when X is -CONR5R6 and When R1 is hydrogen, methyl, ethyl or propyl, the substitution on the pyrrolidine ring is not mono-, 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-alkyl, C2.6-alkenyl or -alkynyl or cycloalkyl (each is unsubstituted), the ring is substituted Not substituted by alkyl, alkenyl or alkynyl (each is unsubstituted). Another group of compounds of special formula I (compound 1E) includes, where X is -CA ^ h; R1 is Η; R3 is azidomethyl, Iodomethyl, ethyl choice After being substituted with 1 to 5 halogen atoms, n-propyl is selectively substituted with 1 to 5 halogen atoms, vinyl is selectively substituted with 1 or 2 methyl and / or 1 to 3 halogen atoms, and B- 18 ·

200538435 Alkynyl is optionally substituted with a Crr alkyl, phenyl or halogen atom; R3a is a hydrogen or halogen atom, preferably fluorine; and R2, R2a, R4 and R4a are each hydrogen; present as a racemic compound or as Enantiomerically abundant forms, preferably pure enantiomers. A further particularly preferred group of compounds of formula I (compound 1F) include these compounds, where X is -CA ^ h; R1 is Η; R3 is Ci.6-alkyl, C2.6 alkenyl or C2.6-alkynyl Optionally substituted by azide, oxynitro, 1 to 6 halogen atoms; R3a is hydrogen or a halogen atom, preferably fluorine; and R2, R2a, R4 and R4a are each hydrogen; present as a racemic compound Or enantiomerically abundant forms, 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, cyClamic acid, salicylic acid, p-aminosalicylic acid, PA-19-200538435 • · pamo ic, 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, these salt forms can be converted to free form by treatment with a suitable base or acid. Compounds of formula I and their salts may be solvates, and solvates are included within 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. The R and S notations 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 stereoisomers). In addition, certain compounds of formula I which contain alkenyl groups may exist as 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-naphthalenylmethyl), alkoxycarbonyl (eg ethoxycarbonyl), trialkylsilyl (eg dimethyl- and triethylsilyl), monoesters with dicarbonic acid (eg butadienyl ), 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. Used for this

For the definition of substituents in 200538435, "=" 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 Qi 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.

Methyl or ethyl. The reaction is known and convenient at room temperature to 15 ° C in the presence or absence of a catalyst such as acetic acid, hydroxybenzotriazole or 2-hydroxypyridine.

Q1 Ancient methyl or ethyl. The ester of formula AA-II 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 AA-I I was synthesized by addition to an 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 derivative of formula AA-IV according to The reaction yields: -22-

200538435 This reaction is based on: Street, L.J., Baker, R., Book, T., Kneen, C.0.5 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 is synthesized by reductive amination reaction to AA-II. The compound of formula AA-II can be prepared by reducing the compound of formula AA-V using the compound of formula AA-III according to the reaction formula:

This reaction was performed using the conditions described in Abdel-Magid, AF, Hai: ris, BD ·, Maryanoff, CA, Synlett (1994), 81-83. In addition, when X represents CONR5R6, the amine AA-III can pass through the amidine moiety Bonded to a solid support (such as Rink resin) ° AA-V compounds can be prepared by one of the following methods: • 23-

200538435

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, ( 1 983), 517-536 or using glands as described in Corey, EJ, Enders, D., Tetrahedral Letter (1 976), 11-14 followed by ozone decomposition reaction. A.2.2 Nitro esters of formula AA-VIII 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. Vilarrasa, J., Tetrahedron Letter (1 990), 3 1, 7499-7500). Nitroesters of 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-IXUL halogen atom) in the presence of a strong base (such as lithium diisopropylamidide), followed by a reduction ozone decomposition reaction of the unsaturated ester, as described in In Amr uta Reddy P., Hsiang BCH, Latifi Τ.Ν., ΗΙΙ MW, Woodward KE, Rot hman SM, Ferrende11i J. A ,, Covey D. F., -24-

200538435 · Journal of Medical Chemistry (1996), 39, 1898-1906. A. 3. Synthesis of AA-11 by alkylating r-haloesters. Compounds of formula AA-11 where X = CONR5R6, C00R7 or CN can be alkylated via the use of amines AA-1-11 11 where r2 is halogen Atomic preparation.

This reaction is performed using the conditions described in the patent application GB2225322 A. The synthesis of ester AA-XI is described in Part B. A.4. Synthesis of AA-II by reductive amination of 5-hydroxylactone derivatives. Compound of formula AA-11 where X = CONR5R6, COOR7 or CN,

Qi = H and R2a = H can be prepared according to the following reductive amination using an amine of formula AA-III: 5-hydroxylactone of formula AA-XII:

(AA-III)

The 5-hydroxylactone of formula AA-XII can be synthesized as described in B.I. B. Condensation of amine and r-halic acid derivative in formula I, when A2 = 0, X = CONR7R8, C00R7 or CN and R2a = H, the compound of formula AA-XII and amine of formula AA-III react according to the formula : -25-

200538435

Wherein X3 represents a halogen atom, preferably an iodine or chlorine atom, and χ4 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 opened according to the following procedures: Mazzini, C., Lebreton, J., Alphand, V., Furstoss, R., Tetrahedral Letter (1 998), 38, 1 1 95-1 1 96 and 01 ah, GA, Na rang, SC, Gupt a, B.G. B., Malhot ra, R., Journal of Organic Chemistry (1 979), 44, 1 247-1 250. The halogenation (X4 = halogen atom) or esterification (X4 = 0Q1) of the obtained halogen acid (χ4 = 0Η) can be performed under any conditions known to those in the industry. Formulas AA-XIV lactones can be prepared by one of the following methods: : Hydrogenation or conjugate addition of BI organometals. Compound AA-XIV where R2y = η can be obtained by hydrogenation of α, meso-unsaturated lactone of formula AA-XV, or derivatization by organometallic of conjugate addition formula r3m (where M represents Li, Na, Mg or Zn) Compound to compound AA- -26-

200538435 · χν was finally obtained by copper (i) salt catalysis.

R3M, Cul or H2> PdC (R ^ H) (AA-XV)

(AA-XIV)

This reaction can be performed according to the following procedures: Alexakis, A., Berlan, J., Besace, Y., Tetrahedron Letter (1986), 27, 1047-1050; Lipshutz, BH, Ells worth, EL, Siahaan, T., Journal of the American Chemical Society (1989), 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 in an alcohol solvent:

(AA-XVI) where Q3 is methyl or ethyl, G1 represents 0 or S and Q4 represents a hydrogen atom or a linear or branched alkyl group containing 1 to 4 carbon atoms, but when G] = S, 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- 200538435 ·

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, / 3 -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-

200538435

AA-XXI Ε · 1

/ Cyclization

The reduction step can be carried out 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. Compounds 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 and 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 the compound AA-XXI is described in Bour gu i gnon, J. J. et al., Journal of Medicinal Chemistry (1 988), 31, 89 3-897. -29-

200538435 · F. Branched functional group transformation. F. 1 ester is reduced to alcohol. Compound of formula I (where A2 = 0, X = CONR5R6 or COOR7, R7 is a third alkyl group 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 straight or branched alkyl group containing 1 to 4 carbon atoms) as the corresponding compound (where R2, R2a, R3,

, One of R3a, R4 and R4a represents a key synthetic intermediate of G2-CH2OH). These changes can be made under any of the conditions known to the industry. F. 2 alcohol activation and oxidation. The compound of formula I (where A2 = 0 and R2, R2a, R3, R3a, R4 and 1? "Represents -G2-CH2OH, G2 is bonded or alkylene) is the corresponding compound (where R2, R2a, R3, One of R3a, R4 and 1-43 represents -G2-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 alkyl group or an aryl group And Q8 is an alkyl) key synthetic intermediate. These transformations can be performed under any of the conditions known to those in the industry. F.3 nucleophilic substitution of activated alcohols. Compounds of formula I (where A2 = 0 and R2, R2a, One of 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 the formula -0-S02-Q7 group is defined as F.2) corresponding to 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, an amine group derivative, a sulfur derivative, and a heterocyclic ring Key) synthetic intermediates. These transformations can be performed under any of the conditions known to the industry. F. 4 Alkenization by aldehydes. -30 ·

200538435 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 bonded or alkylene group) is the corresponding compound (Where R2, R2a, R3, R3a, R4 and R4a2-represents -G2-Q9, where Q9 represents unsubstituted vinyl, mono- or di-substituted vinyl or alkyl by halogen atom) 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 reacting its oxime with Se02 (described in Earl, R.A., Vollhardt, 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 (wherein A2 = 0 and R2, R2a, R3, R3a, R4, and R4a2 represent -G2-CN or -G2-C0Q1G, G2 is a bonded or extended alkyl group, and Q1 () is an alkoxy group, Aryloxy or amine, halogen atom or amine derivative, but -C0Q1Q is not X) is the corresponding compound [where R2, R2a, R3, R3a, R4 and R4a2 — represents -G2-Qu, where Q11 represents (i) -CO-aryl / heterocyclyl, via a palladium-catalyzed coupling reaction between ammonium chloride-G2-C0C1 and an aryl / heterocyclic organic metal such as trimethyl-pyridyl-stannate or (ii) a heterocycle Examples such as Wow (Friedman, BS, Sparks, M., Adams, R., Journal of the American Chemical Society (1 933), 55, 2262 or Iroka, 1 ^., 1 ^ 11 ^ (1 &, yah ,, 31 ^ 〇14, 7 \, Tetrahedron (1992), 48, 7251), Mouth sitting (Street, LJ, Baker, R., Castro, J.L., Chamber, RS, Guiblin, AR, Hobbs, SC, Metasa, VG, Reeve, AJ, Beer, MS, Middlemis, DN, Noble, AJ, Stanton,] Α, Scholey, K., Hargreaves, RJ, Journal of Medicinal Chemistry (1 993), 36, 1 529), oxadiazole (Ainsworth, C., US-31-

200538435 Journal of the Chinese Chemical Society (195S), 77.1 1 48), tetrazole started from gadolinium (Goer 1 tzer, K ·, Kogt, R., Proceedings of Pharmacy (1 990), 323, 847) or thiazolium ( Lamattina, JL, Mularski, CJ., Key synthetic intermediates of the 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 = CQ12Q13 or-G2-CQ13 = CHQ12, G2 is a bonded or alkylene group, Q12 and Q13 Is a hydrogen atom or an alkyl group, but none of the other R2, R2a, R3, R3a, R4, and R4a carry a functional group sensitive to oxidation conditions is a corresponding compound (where R2, R2a, R3, R3a, R4 And one of R4a represents a key synthetic intermediate of -G2-CO-CHQ12Q13 or -G2-CHQ13-CO-Q12), respectively. These transformations can be performed under any suitable conditions known to those skilled in the art, for example, in 0 and PdCl2K inert solvents such as dimethylformamide or N-methylpyridine at 0 to 50 ° C (Bird, organic synthesis Transition Metal Intermediate, Academic Press, New York (1 967), 88-111). F.7 Ketone derivatives. Compound of formula I (where A2 = 0, X = C0NR5R6 or C00R7 and one of R2, R2a, 1 {3, 1 ^, 1? 4 and 1 ^ represent -02- (: 0-(^ 14, where 02 is a bond The alkyl group or alkylene group and Q14 represents an alkyl group) are synthetic (i) alcohols-G and CH0H-Q14, which are reduced using hydrogenating agents (March, Journal of Advanced Organic Chemistry, Third Edition, John Wiley & Sons (1 985) , 809), (ii) fluorinated branched chain-G2-CF2-Q14 use described in Lal, GS, Pez, GP,? 688 1131, 1?.].,?]: 02111 (:,?. 1 \ 1., Chemical Communications (1999), 215 • 216 The key intermediate of the conditions. F.8. Synthesis of alkynyl derivatives. -32-

200538435 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 The other and none of them carry functional groups sensitive to strong bases are corresponding compounds (where R2, R2a, R3, R3a, R4 and R4a represent-G2-C C-Q15, where Q15 is hydrogen , Halogen atom, alkyl or aryl). How these transformations proceed: • Via a base-induced 々-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 a haloalkyne derivative (Q15 = halogen atom), followed by metal-catalytic substitution of the halogen atom by an organometallic species (for example, by MeZnCl in the presence of CuCN.LiCl, as described in Micouin, L., Knochel, P., Synlett (1 997), 327), via direct conversion to metal acetylenic compounds (eg using 2 equivalents of n-butyllithium) and alkylation using alkyl halides or carbonyl derivatives (described in Corey, EJ, Fuchs, PL · , Tetrahedron Letter (1972), 36, 3769-3772). F.9 Synthesis of alkanes. A compound of formula 1 (wherein one of 820, 1,2, 1, 23, 1, 3, 3 ^, and 1 ^ represents -G2-C = C-Q16Q17, G2 is a bonded or extended alkyl group, Q16 And Q17 is an alkyl group or fluorine) is a key synthetic intermediate of the corresponding compound (where one of R2, R2a, R3, R3a, R4W & R4a represents -G2-CH-CH-Q16R17). 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, 〖., Advanced Organic Chemistry Journal, Third Edition, John Wiley & Sons (1 985), 1101- 1102). -33- 200538435 · · F. 10 Synthesis of (halo) azidoaryl derivatives. Compound of formula I (where A2 = 0, X = C0NR5R6 or C00R7 or CN and one of the groups R2, R3, R4 is G2-Q18, where Q18 represents a nitroaryl or triple well and aryl group, and G2 is a bond or an alkylene Group) is the key to the synthesis of corresponding compounds (wherein 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 B r or F atoms) Intermediate. 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 • (eg Xing-teng, D., Guo-bin, L., Synthetic communication (1 989), 19, 1 26 1) and transamines to azides by well-known methods. F. 11 Synthesis of heterocycles from amines. A compound of formula I (wherein A ^ O, XβΟΝ ^ or COOR7 or CN and one of R2, R3 or R4 groups is G2-Q2C), wherein G2 is a bonded or extended alkyl group and Q2G is C00H, CON2, or CN) is Synthesis of the 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 in situ borrowing; alcohol quenching, described in Kiin, D., Weinreb, S.M., Journal of Organic Chemistry (1 978), 43, 12S), known to the industry Deprotection of the amine functional group by hydrogenolysis or any conditions to obtain R2, R3 or R4 = G2-NH2, followed by ring synthesis to obtain heterocycles such as pyriole (for example, described in Jefford, CW, Tang, Q., Zaslona, A ., Journal of the American Chemical Society-34-200538435 (1991), 113, 35 1 3-35 1 8), and the selective introduction of one or more halogen atoms to the ring (for example, described in Gi low, HM, Burt on, DE , Journal of Organic Chemistry (1981), 46, 2221-2225). • where X = CONR5R6, C00R7 or CN and one of the R2, R3 or R4 groups is G2-C0NH2, X is not CONR5R6 or G2-CN, X is not an example of CN, the transformation is through any of the well-known in the industry Under the conditions of selective reduction of amidine or nitrile to amino methyl moiety, and ring synthesis to obtain heterocycles such as triazole (for example, described in Miles, R.

W., Samano, V., Robins, M. J., Journal of the American Chemical Society (1 995), 117, 5951-5957). F. 12 Synthesis of triazole.

The compound of formula I (where A2 = 0 and one of the groups of R2, R2a, R3, R3a, R4 and R4a represents -G2-CH2N3, G2 is a bonded or extended alkyl group) is the corresponding compound (where 1? 2, 1 ^ One of the 1, 1 ^, 1 ^, 1? 4 and 1 ^ 4 groups represents a key synthetic intermediate of -02-(: [12-triazole). This transformation can be via 1- (triphenylphosphorane Keto) -keto derivative in the presence of prolonged heating (for example, described in Haerschmidt, F., Polsterer, JP, Zbiral, Synthesis (1 995), 415). F. 1 3 optical division. Multiple stereogenic centers, and when using non-stereoselective synthetic methods, the optical segmentation of a stereoisomer mixture is optimally performed in one or more steps, usually involving the sequential separation of the diastereomeric mixture into its composition For racemic mixtures, the separation method is preferably used for non-image phase or image phase in reverse mode or better than direct mode for chromatographic separation; then it is best used in image phase for reverse phase or more Better than chromatographic separation in direct mode, and -35-

200538435 The final optical segmentation step that separates each racemic mixture into its enantiomers. 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, wherein 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. The compounds of formula I and their pharmaceutically acceptable salts have been 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 diseases, 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. Thus, the present invention relates, in a further aspect, to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the manufacture of a drug for the treatment of neurological and other conditions (as described above). In particular, the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of epilepsy, bipolar disorders, chronic pain or neuropathy -36-

200538435 Treatment for 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, for a compound of formula I in which R1 is ethyl, X is -CONH2, and A2 is oxygen, when R3 is propyl and the remaining substituents are hydrogen, S (butamidamide) R (ring) enantiomer When R3 is 2,2-difluorovinyl and the other substituents are all hydrogen, S (butamidamide) and S (ring) enantiomers are preferred. 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 5 to 1000 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 and is characterized by regular and unexpected epilepsy. 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 those classified as emotional disorders according to the 4th Edition of the Diagnostic and Statistical Manual of Mental Disorders 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 abnormal and persistent mood -38-

200538435 A period of sexual elevation, expansion or irritation with symptoms such as compulsive speech and irritability. 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, the presence of harmful stimuli, and the absence of any identifiable stimulus causing a false sense of 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 of the seizures are similar to human seizures (Loscher W. & Schmidt D., Epilepsy Research (1998 ), 2, p.l45-181; Buchhalter -39-

200538435 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), which will be 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 Lavarenne J., Pain, 53, (1 993 ) 81-88). This model has high pharmacological prediction capabilities (Courteix C, Bardin Μ., Chan te 1 auz e C., Lava r enne J and Es cha 1 ier, 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 activity progression, thus confirming that the model is predictive (Cao BJ., And Peng N; A; European Pharmacology Journal 237 (1 993) 1 77-1 8 1. Vale AL and Rat cl if fe F. Psychopharmacology, 9 1 (1 987) 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 inflammatory cell content in the respiratory tract (Yamada et al. (1 99 2) Development of animal models of late allergic reactions in guinea pigs and effects of antiallergic drugs. -40-

200538435 Prostaglandin, 4 3: 5 0 7-5 2 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 can be solid or liquid such as in the form of lozenges, nine-dose, dragees, 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-

200538435 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 can fall within a wide range of concentrations 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 such additional compounds that may be used in combination with the compounds of the present invention are anticonvulsants (e.g., baccofen), antiemetics, anti-manic mood stabilizers, analgesics ( For example, aspirin, ibuprofen, Paracetam (Paracetam ο 1)), narcotic analgesics, local anaesthetics, aphid analgesics, lithium salts, antidepressants (such as rice Ansilin (mianserin), fluoxetine, trazpdone), ring antidepressants (such as imipramine, de sipr ami ne) , Anticonvulsants (such as va 1 pr0ic acid, carbamazepine, fenidone (? 1 ^ 11: / -toi η)), antipsychotics (such as Lispi瑞 冬 （risperid ο ne）, • 42-

200538435 ha lope r idol), nerve agent, benzodiazepines (such as diazepam, clonazepam), phenothiculture (such as Ch lor promazine), calcium channel blocker, amphetamine, cion idine, lidocaine, mexiletine, cassine (capsaicin), caffeine, quetiapine, 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 Didizom and Kronazpan, and 1,5 benzodiazepines such as c 1 obazam. 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. Anticonvulsants include hydantoin (Fenidone, ethotoin -43- 200538435, etc.), oxazolidines (Trimi Sadeoan 〇1 ^ 11 ^ 1 ^ 仏 01 ^), etc.) , Succinic imines (ethosuximide, etc.), phenacemides (fenaceme, asirfinnet) (& 0017101 ^ 116-turi de ), Etc.), sulfonamides (su 1 thi ame, acetoazolamide, etc.), aminobutyric acid (such as amino-/ 3-hydroxybutyric acid, etc.), vanproic acid Sodium and its derivatives, Kabamaz Equal. Preferred compounds include vapronic acid, valpromide, valpromide, Pivoxil, sodium vapromide, sodium quaproven, diproprox, clona Zippin, Phenylbarbital, Microgabacin, Tirubin. 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. The daily dose falls within a broad dosage unit range of the compound of Formula I and is usually 5 to 1,000 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 by way of illustration and not limitation, and are by no means considered restrictive -44-

200538435 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: NMR spectra are recorded on a Bruker AC 250 Fourier Transform NMR spectrometer with an Aspect 3000 computer and 5 mm 1H / 13C The dual probe, or Bruker DRX 400 FT NMR, is equipped with a SG indigo computer and a 5 mm reverse geometry 咜 / 1 ^ / 1% 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. The mass spectrometry measurement in LC / MS mode was performed as follows: HPLC condition analysis was performed using WATERS Al 1 iance HPLC system with INERTSIL ODS 3, DP 5 microns, 250 X 4.6 mm tubing. Gradient range from 100% solvent A (acetonitrile, water TFA (10/90 / 0.1, v / v / v)) to 100% solvent B (acetonitrile, water, TFA (90/10 / 0.1, v / v / v)) ) Changed within 7 minutes and maintained at 100% B for 4 minutes. The flow rate was set to 2.5 ml / min. Bifurcation was used at a rate of 10 just before the API source. Chromatography was performed at 30 ° C. MS conditions The sample was dissolved in acetonitrile / water 70/30 v / v at a concentration of about 250 // gr / ml. API spectroscopy (+ or-) was performed using a FINNIGAN (San Jose, California) LCQ ion capture mass spectrometer. APCI is derived from 450 ° C operation and capillary heaters are operated at 160 ° C. ESI source is at 3.5 kV -45-

200538435 Operation and capillary heaters are operated at 210 ° C. The mass spectrometry measurement in DIP / EI mode was performed as follows: The sample was heated from 50 ° C to 250 ° C for 5 minutes while the EI (electron impact) spectrum was measured using Finigan (San Jose, California, USA) The TSQ 700 is connected to a quadrupole mass spectrometer record. The source temperature is set at 15CTC. The specific rotation system is recorded in Perk in-Elmer MC241 or 341 polarimeter. The rotation angle was recorded at 25 ° C in a 1% methanol solution. For some molecules the solvent is dichloromethane or DMSO due to solubility issues. The water content was determined using a Metr ohm micro-coulomb metered Karl Fischer (K a r 1 F i s c h e r) titrator. Preparative tomographic separation was performed on a silica gel 60 Merck, with a particle size of 15-40 microns, reference number 1.1 5 1 1 1.9025, which was modified in the room using Job in Yvon type axial compression Column (80 mm id), flow rate 70 to 150 ml / min. The amount of silicone and solvent mixture is as described in the individual procedures. Preparative chromatographic separation was performed at DA ICEL Chiralpak AD 20 micron, 100 * 500 mm tubing column. The built-in instrument was used in the field room to use various low-carbon alcohols and C5 to C8 linear Branching or cyclic alkanes are carried out at 350 ml / min. The solvent mixture is as described in the individual procedures. Melting points are measured on a Buchi 535 Totol i melting meter and are uncorrected or calibrated at the starting temperature using the Birkin Emma DSC 7. The powder X-ray diffraction pattern is based on ambient temperature and atmosphere. The Phillips PW 1710 is equipped with a PW3710 mpd control unit using a single color layer analyzer and Cu κα radiation (test tube at 40 kV, 35 mA). As well as a flicker counter. Data were collected in continuous scan mode using a scan speed of 0.02 20 / s over a range of 4 to 50 degrees and 20 angles. -46- 200538435

The following abbreviations are used in the examples: AcOE t ethyl acetate AcOH BuLi n-butyllithium n-Bu3P tri-n-butylphosphine CICOOEt or ClC02Et ethyl chloroformate DCE 1,2-dichloroethane DIC diisopropylmethylene dichloride醯 Imine DMSO dimethyl isocyanate DSC differential scanning calorimetry DMF N, N-dimethylformamide Et3N triethylamine E120 ether EtOH ethanol FMOC fluorenylmethoxycarbonyl LDA diisopropylamidamine lithium MeCOCl acetamidine Chlorine MeCN Acetonitrile MeOH Methanol MTBE Methyl Tertiary Butyl Ether NMP N-Methyl Pyrrolidone PhMe Toluene PrepLC Preparative Liquid Chromatography i-Pr20 Diisopropyl Ether i-PrOH Isopropanol TFA Trifluoroacetic Acid- 47-

200538435 · THF tetrahydrofuran TMOF trimethyl orthoformate TMSCI chlorotrimethylsilane TMSI iodotrimethylsilane Unless otherwise stated in the examples, compounds are obtained in free (non-salt) form. [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-butyric acid ester 1.1.1.1. Route A: alkylation reaction by enamines 5,5-dimethyl-3-formamyl-hexanoic acid The synthesis of ester 361 can be expressed as

! Diisobutylamine, PhMe, 110eC BrCH2C02CH3, PhCH3 > CH3CN 18RT, mv! Hours then h2〇 (30%)

361 362

In a three-necked flask equipped with a Dean-Stark device under nitrogen, diisobutylamine (4.62 ml from ACroS), 4,4-dimethylvaleraldehyde 3 A solution of 62 (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 solution was stirred at room temperature overnight and at 90 ° C 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 and a saturated aqueous sodium hydrogen carbonate solution, dehydrated with magnesium sulfate, quenched and evaporated. -48-

200538435 Oil was obtained. 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 mol, Teb (1 mm Hg): 69-71 ° C). The aldehyde ester is then used in a reductive amination step. Alternatively, 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 under reduced pressure. 1.1.2. Other synthetic routes Aldehydes can also be obtained by (i) alkylation with bromoacetate derivatives. For example, 5- (phenyl) -3-methylfluorenyl-valeric acid 2,2-dimethyl-ethyl ester is obtained through N- (4-phenyl) -propylene-N, N-dimethylfluorene and The reaction between tert-butyl bromoacetate and LDA is followed by an ozonolysis reaction of alkylated europium. (ii) Addition of nitromethane to α, unsaturated esters. 3- (3-Bromo-phenyl) -4-oxy-butyric acid ethyl ester is added to 3 via nitromethane in the presence of 1.8-diazabicyclo [5.4.0] undec-7-ene -(3-Bromo-phenyl) -ethyl acrylate, obtained by oxidizing a nitro derivative under Nef conditions and carrying out a controlled hydrolysis reaction of methyl-acetal with 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. Reductive amination of 3-substituted-4-oxy-butyrate and cyclization to pyrrolidin-2-one 1.2.1, reductive amination of 4-{[(((1S) -1-aminocarbonyl)) Synthesis of propyl] amino methyl butyrate 363 is representative. -49-

200538435

In a three-necked flask equipped with a reflux condenser under argon, aldehyde 361 (1.7 g '0.09 mole), (s) _2-amino-butyramine (1.58 g, 0.15 mole) ® and molecular sieve (3 A suspension of Aldrich (A1 dri ch) in methanol was heated at 60 ° C. for 0.5 hours. The suspension was cooled to 0 t: and sodium borohydride (0.55 g) was added in portions. At room temperature After 1 hour, the reaction mixture was diluted with hydrazone ', washed with water, dehydrated with magnesium sulfate, filtered and evaporated to obtain a yellow oil. 4-{[((1S) -1-aminocarbonyl) propyl] amino} butanoic acid methyl Ester 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). Stereotacticity of two (2S) -2- (4-neopentyl-2-oxy-1-pyrrolidinyl) butylamidines cyclized with butyric acid (methyl or ethyl) esters The synthesis of isomers 149 and 148 is representative

-50-

200538435 In a three-necked flask equipped with a reflux condenser, oil 363 was dissolved in toluene and 1,2-dichloroethyl in the presence of hydroxybenzotriazole (2.05 g, obtained from arylene) under argon. A 1/1 mixture of alkane (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 saturated aqueous sodium bicarbonate 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 (v / v)) Obtained (2S) -2- (4-neopentyl-2 · oxy-1-pyrrolidinyl) butanamide (0.89 g, 0.0036 mole) as diastereomer 1/1 mixture of isomers. Separation of the two isomers was achieved by isostatic chromatography (ethanol-hexane 1/1 (Wv)) and two stereoisomers (0.35 g and 0,5, respectively) after recrystallization from toluene. 37 grams). 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.

• 51-

200538435 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 and the whole 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 use A solution of 1,3-dicyclohexylmethyldiimine (1.4 g, 11.13 mmol) in DMF (20 mL) was treated. The reaction was stirred at room temperature for 1 hour, then filtered, washed (DMF), and repeated coupling treatment. The resin was filtered, washed (6x DMF, 6XCH2C12), dehydrated and used in the next steps. 1 · 3. 2. Reductive amination and cyclization by adding 5 -hydroxy-4-propyl-furan-2 -one reaction

100 mg of N-Fmoc-2-aminobutyramine resin (0.051 mol) 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- 200538435 · 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. Hexahydropyridine

NHFmoc 2. TMOF 3.NaBH (OAc) 3 / CH2Cl2 · = Suzuki resin 4TF / WH2Q

φ150 mg 1 ^ 邛 111〇 (:-2-Aminobutyramine resin (0.087 mmol) is housed in a frosted polypropylene syringe. Fmoc group removal is achieved using 20% hexahydropyridine in DMF. Amine Add aldehyde (0.5 mmol) to TMF (2 ml) into the base ester. The reaction was stirred at room temperature for 18 hours and then filtered and washed (dichloromethane). The resin was swollen with dichloromethane and then triethylboron oxide Treated with sodium hydride (22 mg, 0.14 mmol). The reaction was stirred at room temperature for another 18 hours. The resin was then washed sequentially with the following solvents: H20 × 6, MeOHX6, CH2Cl2 X 6 and dehydrated. The resin was suspended in trifluoroacetic acid. / Water mixture (95 / S) for 1 hour with orbital agitation, then filtered, 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 LC-MS micro mass Gilson, LCZ platform, RP-18 column, gradient elution, CH3CN / H20 / TFA 1%). Example 2. 4-Substituted 2-oxypyrrolidine butyridamines were synthesized by the 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-

200538435 ·

In a three-necked flask under argon, n-butyllithium (1.6 M in hexanes, 75 ml, 0.12 mol) was added to Cul (11.42 g, 0.06 mol) in anhydrous THF ( 80 ml) of the suspension cooled to -30 ° C. After 0.5 hours, the solution φ was cooled to -78 ° C, and TMSC1 (4.75 g, 0.04 mole) was added dropwise, followed by 2,3-furanone 364 (available from Alexis, 3.36 g, 0.04 mole). ) Dissolved in anhydrous THF. The suspension was allowed to warm to room temperature and was hydrolyzed using saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate (3 times), washed with water, dried over magnesium sulfate and evaporated to dryness. The crude lactone was purified by distillation (1 mm Hg; 73-80 ° C) to obtain 2.7 g of 4-n-butyl-butyrolactone 365. In addition, the cupric acid reactant can be prepared by replacing organolithium with organomagnesium, which can be obtained by reacting an alkyl halide with magnesium shavings under the usual conditions of such a conversion reaction. THF can be replaced by ether (for general information please refer to: Lu Lipshutz, B.H .; Sengupta, S. Organic Reactions 1991, 41, 135). 2.1.2. Other routes In addition, lactones can also be obtained via (i) reduction of succinate. 4- (Cyclopropyl) methyl-butyrolactone is alkylated with monomethylsuccinate by cyclopropylmethyl bromide with lithium diisopropylammoniumamine, and then reduced by NaBH4 & CaCl2 -(Cyclopropyl) methyl-succinic acid 1-methyl ester. (ii) Reduction of 1-alkyl succinate 4-alkylthioester. 4-Allyl-butyrolactone is derived from ethyl 4-pentenoic acid thioester (based on 4-pentenoic acid and ethyl mercaptan-54- 200538435 · · in the presence of dicyclohexylmethamine aldimine synthesis). Ethyl 4-pentenoate thioester is obtained by alkylation of ethyl bromoacetate with lithium diisopropylamide to obtain 2-allyl-succinate 1-methyl 4-ethyl thioester. Reacts with Li BH4 and sulfuric acid to convert to 4-allyl-butyrolactone. 2.2 Synthesis of pyrrolidone 2.2.1.1. Alkylation / alkylation of (2S) -2- (4-allyl-2-oxy-1-pyrrolidinyl) butyl via butyridamine The synthesis of the two isomers of amidine 228 and 224 are representative:

-Step 1: Open the lactone in a three-necked flask under argon, add TMSI (51 ml, Acrylic) to the crude 4-allyl-butyrolactone 3 66 (refer to the 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 combined organic phase was washed with brine, dehydrated with magnesium sulfate and concentrated in vacuo to obtain crude 3- (iodo) methyl-5-hexenoic acid 367 (44.5 g). NMR (2 50MHz, CDC13): 1.80 -2.05 (m, 2H), 2.20 (t, 2H), 2.40-2.60 (t, 2H), 5. 10-5 · 20 (ιώ, 2H), 5. 15- 5.80 (m, lH). -Step 2: Chlorinated iodic acid in a three-necked flask equipped with a reflux condenser under argon, sub-dichloromethane (25. 5 ml) and crude iodic acid 367 (44. 5 g, 0.175 mol ) A solution in benzene (90 ml) was stirred at room temperature for 24 hours. Removal of the solvent by vacuum evaporation gave crude 3- (iodo) methyl-5-hexylsulfonium chloride 368 (47 g), which was used in the next step without further purification. Level 4 25 (^ [12,0〇 (: 13): 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 (in, 2H), 5. 15-5.80 (m, 1H).-Step 3: Aldolization with 5-2 · amino · butyramine-alkylation at three Under an argon flask, crude chloroform 368 (47 g, 0.172 mol) in methylene chloride (300 ml) was added dropwise to molecular sieve (29 g), powdered potassium hydroxide (22.3 g), Anhydrous sodium sulfate (28.8 grams), 4-n-butylammonium bromide (2.8 grams, 0.0086 moles) and S-2-aminobutyramide ([a] 25D = + 19. 35 degrees; 26.3 grams (26.26 mol) in methylene chloride (470 ml) by mechanical stirring and cooled to a suspension. The solution was stirred at -5 ° C for 5 hours, powdered potassium hydroxide (6.2 g) was added and -5 ° C. Stirring was continued for 3 hours. The reaction mixture was filtered through Hyfluxil (hy f 1 oce 1) and the solvent was evaporated in vacuo. The crude reaction mixture was subjected to silica gel chromatography (ethyl acetate / isopropanol: 97/03 (v / v) and purified by stationary phase preparative chromatography (hexane / ethanol) to obtain (2S) -2- (4-allyl-2-oxy-1-pyrrolidinyl) butanamide Two isomers (6.0 g (228) and 5.48 g (224); 16% and 15%). Two small amounts of impurities were also separated after the imaging chromatography, namely (2S) -2- [4- (2-iodopropyl-2-oxy-1-pyrrolidinyl) butyramine 225 (0.22 g) and 226 (0.27 g) are two stereoisomers, which appear as a white solid after recrystallization 2.2.2. Synthesis of two isomers of (2S) -2- (5-nonyl-2-oxy-1-pyrrolidinyl) butanamide via alkylation / halfation of butanamide as Representative: Step 1: 7-nononolactone (0.32 ml, 2 mmol) of lactone in sulfenyl chloride (164 μl -56-

200538435 · ′ 2.25 mmoles) was added to the solution at room temperature and zinc chloride (12 mg, 0.088 mmoles) 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 for use as it is.

Step 2: alkylation

To a solution of 4-chloro-nonanoic acid methyl ester (2 mmol) in DMF (2 ml) was sequentially added 2-aminobutyramide (1 g, 10 mmol), 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.

Step 3: Cyclization: refer to the conditions in § 1.2.2.2 and §1.2.3.

2.3. Synthesis of keto-pyrrolidin-2-one Synthesis of (2S) -2- [2-oxy-4- (2-oxypropyl) -1-pyrrolidinyl] butanamine 230 :

-57-

200538435 ·

In a three-necked flask, oxygen was passed through PdCl2 (0.68 g, 0.0039 moles), CuCl 2 (1.68 g, 0.009 moles), and N-methyl-2-pyrrolidone (nmp, 40 ml). Solution, which was added dropwise (2S) -2- [2-oxy-4- (2-oxypropyl) -pyrrolidinyl] butanamine 224 (4.13 g, 0.020 mole) to NMP (40 Ml) solution (addition time: 1 · 2 hours). The solution was stirred for 0.775 hours under aeration, filtered through celite and evaporated under vacuum (1 mmHg). 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] butanamide 230, as 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 (140 ml) cooled at -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. The residue was purified by -58- 200538435 · Shixijia chromatography (methanol / dichloromethane: 90/10 (v / v)) to obtain an alcoholic 369 differential mixture (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) j 1.30-1.45 (m, 1H), 1.70-1.80 (m, 1H), 1.80- 2.05 (m, lH), 2.20-2 · 40 (π, 2Η, partially overlapping with solvent), 3.00-3.20 (m, lH), 3.30- 3.35 (m, 2H, partially overlapping with solvent ), 3.50-3.6 5 (m, 1H), 4.30 (m, 1H), 4.45 (m, 1H), 7.10 (sm), 1H), 7.20 (s (width) 1H). Step 2: Acetate in a three-necked flask under argon, and add acetamidine (0.91 g, 0.011 mole) to 4-N, N-dimethylaminopyridine (0.11 g, 0.001 mole), pyridine (0.86 ml) and an alcohol in dichloromethane (90 ml). The solution was stirred for 5 hours, quenched with saturated ammonium chloride, and the aqueous layer was extracted with dichloromethane (3 times), 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: 4 NMR (400 MHz, CD3SOCD3): 0.90 (t ^ 3H), 1.21-1.28 (m, 4H), 1.51-1.82 (m, 4H), 1.89-1.98 (m, lH), 1.80-2.05 (m, lH), 2.04 (s, 3H), 2.16 (dd, 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 (claw, 111), 5.43 (8 (width), 111), 6.24 (8 (width), 1). -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. Stir at 20 ° C for 20 hours, evaporate to dryness and purify the crude alcohol by silica gel chromatography (methanol / dichloro-59-

200538435 Methane: 85/15 (Wv)) Obtained (2S) -2-[(4S) -4- (2-hydroxypropyl) -2-oxyzirdinyl] butanamine 233 (0.67 g, 72 %) As a white solid after recrystallization from acetonitrile. 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: Fluoride 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 the third amine 372 (1.2 g) • LC / MS: 36 5 (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 60 ° 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 an acid (1.2 g) as a white solid. The crude mixture was aminated under standard conditions to obtain (23) and (21〇-2-[(43) -4- (2,2-difluoropropyl)-as described in § 6.3.1. (Step 2). A mixture of 2-oxypyrrolidinyl] butanamide (87% and 13%, respectively). -60- 200538435 • · 2.5. (2S) -2- (2-oxy-4-propyl-1- Synthesis of pyrrolidinyl) butanamine 丨 58 and 159

Φ 2 · 5.1 · Step 1 · · Reductive amination in a three-necked flask under argon, 4-n-propyl-hydroxyfuranone 373 (35.5 g, 0.25 mol by Bourguignon JJ et al .; Journal of Medical Chemistry, 1988 '31, 89 3-897) 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 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 I hours, and cooled to room temperature overnight. 50% w / w (20 ml) of sodium hydroxide 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 NH4COOH (8 g, 0.126 mol) is divided into several parts and added to crude 374 (22 g, 0.105 mol) and i. A suspension of 0% Pd / C (1.1 g) in water (220 ml) heated at 50 ° C. The suspension was stirred at 200538435 at 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 mole) was added in several portions. After 1.5 hours, a third aqueous NH4C00H 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 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), and two pyrrolidone 158 (9.5 g) and 159 were obtained after recrystallization from isopropyl ether. (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 8 is typically characterized by diffraction peaks at 6.50, 11.25, 19.22, 23.44, 28.47, 29.94 (20 degrees). 2.5.3. Synthesis of 5-hydroxy-4-propyl-furan-2-one

5-Hydroxy-4-propyl-5H-furan-2-one 373 (15 g, 0.1 mol), ethyl acetate (260 ml) and Pd / C 5% were placed in 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- 200538435 · Example 3 · Synthesis of 4-substituted 2-oxo-pyrrolidine butyrimidine by alkylation of 2-oxy-pyrrolidine with 2-bromo-butyric acid ethyl ester 3.1. Synthesis of 4-substituted 2-oxy-pyrrolidine 3.1.l.a.l. Preparation of 3- (3-chlorophenyl) -2-acrylic acid ethyl ester 375:

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. Then, 341.9 g (9 80 mmol, 1.3 eq) of ethyl (triphenylphosphine) acetate was added with effective stirring, and the temperature was raised to 10 ° C. The mixture was maintained at 0 ° C with stirring for 1 hour, and then stirred at room temperature overnight. The mixture was concentrated to dryness, the residue was 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, 75.3 5) to obtain 191.8 g of pure 375,92% yield. NMR (250MHz, (CD3) 2SO): 1.30 (t, 3H), 4.25U, 2H), 6.70 (d, 1H), 7.40 (m, 2H), 7.50-7.70 (m, 2H), 7.85 (s ( Wide), 1H) · 2.1.1.a.2. Other methods:

In addition, cinnamate derivatives are also synthesized by palladium-catalyzed formazan metallization of acrylic derivatives. For example, (2E) -3- (5-pyrimidinyl) -2-acrylic acid ethyl ester 376 is obtained by reacting ethyl acrylate with 5-bromopyrimidine in the presence of palladium acetate -63- 200538435 φ. 3.1.1.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 3 75 was dissolved in 127 ml (2.37 mole '5 equivalents) of nitromethane. While maintaining the temperature below 251 (ice / water bath) with effective stirring, 70.9 ml (447 mmol, 1 equivalent) of diazabicycloundecene was added 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, lH), 2.75 (dd, 1H), 3.95 (q, 2H), 4.95 (m, 2H), 7. 20- 7.45 (m, 4H). 3.llc: 378 Preparation of 4-amino 3- (3-chlorophenyl) butyric acid ethyl ester 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-

200538435 (strong exothermic reaction, requires ice / water cooling). The mixture was filtered through a degassing pad on a Celite / Norite pad, and the filtrate was concentrated in vacuo to obtain 136.7 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:

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 + · 3.1.1.1.f · 2- [4- (3-chlorophenyl) -2-oxy · 1-pyrrolidinyl] butanoic acid

In a 2-liter three-necked flask equipped with a reflux condenser, magnetic stirrer, and dropping funnel, 54.4 g (278 mmol, 1 equivalent) of 4- (3-chlorophenyl) -2- Pyrrolidone 379 was dissolved in 1.4 liters of acetonitrile. Add 64 ml (100.7 g, 5 56 mmol, 2 eq.) Of methyl 2-bromobutyrate and raise the temperature to 50 ° C. Add 22.24 g (556 millimoles, 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, the residue was suspended in ethyl acetate, washed with water -65- 200538435, and 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%. ] H NMR (250MHz, (CD3) 2SO): 0.80-1.00 (m, 3H), 1.60-1.90 (2H, m), 2.35-2.55 (m, lH: partly overlap with solvent), 2.60 -2.90 ( m, 1H: partially overlapped with the solvent), 3.70 (s, 3H), 3.50-3.8 0 (m, 3H), 4.50 (m, 1H), 7.20-7.50 (m, 4H). g: 2- [4- (3-chlorophenyl) -2-oxy-1 · pyrrolidinyl] butyrium

Preparation of amine 381:

In a 1-liter three-neck flask equipped with a reflux condenser and a magnetic stirrer, 56.7 g (192 mmol) of 2- [4- (3-chlorophenyl) -2 · oxy-1-pyrrolidinyl 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%, 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. Synthesis of 4-substituted 2-oxy-pyrroles via alkylation / cyclization of 4-bromo-3-substitution with 66-200538435-butane-2-enoate using 2-amino-butyramide Pyridoxamine. 4.1. Synthesis, alkylation and reduction of 4-bromo-3--substituted-but-2-enoate Synthesis of phenyl) -but-2-enoic acid ethyl ester 382 as representative

383

# In a 2-liter three-necked flask under argon, mechanically stir the 2-thiophenyl-3 -yl-but-2-ene-enoic acid ethyl ester 383 (32.88 g, 0.211 mole), N-bromobutane The degassed solution of arsenimide (37.56 g, 0.211 mole) and 2,2f-aza-fluorene-isobutyronitrile (3.46 g, 0.021 mole) in carbon tetrachloride (600 ml) was refluxed for 6 hours and cooled. Warm to room temperature and stir for 20 hours. The suspension was filtered and concentrated in vacuo to obtain the crude bromide. The crude product was purified by silica gel chromatography (hexane / dichloromethane: 65/35 (v / v)) to obtain 4-bromo-3- (2-thiobenzene). Ethyl) -butan-2-ethylacetate 382 (36.72 g, 78%). 4 NMR (250MHz, • (CDC13): 3.80 (s, 3H), 4.95 (s, 2H), 6.25 (s, 1H), 7.10 (dd, 1H), 7.35 (d, 1H), 7.45 (d, 1H). 4 · 1 · 2 · Alkylation with 2-amino-butyramide to 2- [2-oxy- 4- (2-thienyl) -1-pyrrolidinyl ] The synthesis of butanamine 71 is represented by: -67 ·

200538435

4. 1. 2. 1. Step 1: Alkylation-Cyclation • 4-Bromo-2-thiobenzene-3 -yl-but-2-ene-acid methyl ester in a 1 liter three-neck flask under argon 382 (36.72 g, 0.134 mole), (s) -2-aminobutymidine ([a] 25D: 19.09 degrees; 31.6 g, 0.2 70 mole) 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).屮 NMR (250MHz, (CD3) 2SO): 0.80 (t, 3H), 1.30-1.90 (m, 2H), 4.40 (d, 1H), 4.45 (m, 1H), 4.70 (d, 1H), 6.30 ( 5, • 2 old, 7.0 (in width), 11 (), 7.15 (〇1 (1, 1) 0, 7.40 (8 (width), 111), 7.50 (d, 1 Η), 7.8 5 (d, 1Η) · 4.1.2.2. Step 2: Reduce in a 0.5 liter three-necked flask under argon and divide into several portions of NaBH4 (1.75 g, 0.004 mole) to the crude unsaturated pyrrolidone 384/385 (14 g, 0.044 mol), COC 1 2 (0.062 g, 0.0005 mol) in ethanol (100 ml) _ Diethylene glycol dimethyl ether (65 ml) cooled to 0 ° C After 0.75 hours, 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- 200538435 g, 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 Purified by silica gel column chromatography (dichloromethane / methanol: 97/03 (v / v)). 4 · 15 g of 2- [2-oxy- 4- (2-thienylb-1-pyrrolidinyl] butamidamine (38%). Stereoisomer mixtures were imaged by column chromatography Purification (hexane / ethanol) to obtain two diastereoisomers (2S)-2-[2 -oxy-4-(2 -thienyl) -1-pyrrolidinyl] butanamide 71 (in acetic acid Ethyl ester recrystallized) and 72 (recrystallized from 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] butyramine 84 (0.25 g, recrystallized from ethyl acetate) and 85 (0.44 g, recrystallized from ethyl acetate) two diastereomers. 4.2. Synthesis of Aminophenyl Pyrrolidone A Single Enantiomer of (2S) -2- [4- (3-Azidophenyl) -2-oxy-1-pyrrolidinyl] butanamine 86 The synthesis is represented by:

4,2. 1. Synthesis of aniline • 69 · 200538435 · 4.2.1.1 · Step 1: Alkylation of 4-bromo-3- (3-nitrophenyl) -but-2-ene-acid methyl ester 386 ( S) Synthesis of 2-aminobutyramine 3 86 was performed as described in § 4.1.1.1. 1H NMR (250MHz, (CD3) 2SO): 1 · 30 (t, 3H), 4 · 20U, 2H), 5 · 1 5 (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 according to the experimental procedure of § 4. 1.2.1. (59%). LC / MS: 290 (MH +). 4.2.1.2. Step 2: Reduction in a 2-5 liter pressure bottle under an inert atmosphere. 7.22 g (0.025 mol) 3 87 and palladium / charcoal (10% w / w, 0.2 g) are 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, re-ethanol Crystallization) Two diastereomers, tcte ψM ο 4.2.2. Synthesis of phenyl azide 86. In a three-necked flask under argon, sodium nitrite (0.232 g, 0. 0037 moles :) in water (1.5 ml) was added dropwise to (2S)-2-[4-(3 -Aminophenyl) -2 -oxy-1 -pyrrolidinyl] butanamide 90 free state base (0.8 g, 0.00 31 mole) was cooled to 10 M in hydrochloric acid (6.5 ml). ° C solution. After 0.5 hours at room temperature, add NaN3 (0.220 g, 0.003 7 mol) to -70-

200538435 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 (ν / ν)) 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. Synthesis of (2S) -2- [4-methyl-2-oxy-1-pyrrolidinyl] butanamine 35 and 36

200538435 ·

35 and 36 were obtained by purifying racemic mixture 389 in the static phase of the image using ethanol and hexane as a solvent. The 3 5 series was obtained as white crystals after recrystallization from i-p r 2 OE t. 36 was obtained as white crystals after recrystallization from ether. Example 5. Derivation of 4-Substituted 2-oxy-pyrrolidine butyrimidine via derivation of 1-II- (aminoamino) 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 conversion is described in §7.0.1 to produce two esters and 12.

5.2. Synthesis of 1- [2S-1- (aminocarbonyl) propyl] -5-oxy-3-pyrrolidine

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 to 0 × :. After 1.5 hours at this temperature, the reaction was acidified by hydrochloric acid (109-72-200538435 · # 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 enantiomeric pure 1- [2S-1- (aminocarbonyl) propyl] -5-oxy-3-pyrrolidinecarboxylic acid 48. 5.3. Synthesis of (2S) -2- [4- (l, 3,4-fluorenediazole-2 · yl) -2-oxy-1-pyrrolidinyl] butanamine 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, a solution of crude hydrazine 391 (this patent, 3 g, 0.013 mole), triethyl orthoformate (2 ml) and p-toluenesulfonic acid (0.010 g) was heated at 110 ° C for 24 hours. hour. 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) as an oil. 5.4. Synthesis of 1,3,4-bisoxazole derivatives In addition, 1,3,4-bisoxazole derivatives are derived from hydrazine 391. For example, 2- [2-oxy-4-(5-sulfanyl-1,3,4-fluorenediazole-2 -yl) -1 -pyrrolidinyl] butanidine-73- 200538435 · · amine 51 series It is obtained by reacting hydrazine 391 with 0 2 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-pyridinecarboxylic acid 48 (19.06 g, 0.089 in a three-necked flask under argon Mol), a solution of diphenylphosphonium azide (26.9 g, 0.097 mole) and triethylamine (13.5 ml) in acetonitrile (225 ml) was heated at 55 t with nitrogen formation. The temperature was maintained at 55 ° C for 0.5 hours, maintained at 7 (TC for 2 hours and cooled to room temperature. Benzyl alcohol (9.2 5 ml) was added and the solution was refluxed for 4 hours, cooled to room temperature and concentrated in vacuo. Crude carbamate 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 (1 1.9 g, 42%). As for 393:! H NMR (250 MHz, (CDCl3): 0.90 (t, 3H), 1.30 -74- 200538435,-1.90 (m, 2H), 2.35 ( dd, lH), 2.75 (dd, lH), 3.30 (dd, lH), 3,75 (m, lH), 4.30-4.50 (m, 2H), 5.10 (s, 2H), 5.35 (s, (width ), LH), 5.11 (s (width), lH), 60.40 (s (width), 11 ^), 7.30-7.45 (m, 5H). 5.5.2. Step 2: 4-amino-pyrrolidine- Synthesis of 2-ketone 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 mixed in a Bar hydrogenator at the highest Hydrogenated at 20 psi hydrogen pressure. 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 Moore), 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 (v / v)) to obtain 223 as an oil (2. 67 grams, 30.1%). 5.7. Bromination of 4-pyrrolyl-pyrrolidin-2-one 223 -75-

200538435

2S-4 -pyrrole-pyrrolidin-2-one 223 was 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 -78t and N-bromobutanediimide (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 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- (2-Bromo-1H.pyrrole-1-yl) -2-oxy-1-pyrrolidinyl] butanamine 234 (1.05 g, 67%) was a white solid. In addition, using the same experimental procedure and 2 equivalents of N-bromo-succinimide, dibromopyrrole 23 7 was obtained. 5.8. Synthesis of Tetrazolyl Derivatives In addition to §5.6, 2- [4-amino-2-oxy-1-.pyrrolidinyl] butanamide and triethyl orthoformate, azide The reaction of sodium chloride and acetic acid gives 2- [2-oxy-4- (1fluoren-tetrazol-1-yl) -1-pyrrolidinyl] butanamide 67. Synthesis of 5 · 9 · (4H-1,2,4-tetrazol-4-yl) derivatives. In addition to §5.6, 2- [4-amino-2-oxy-1-pyrrolidine Group] Butamidamine reacts with pyridine and 1,2-fluorene (dimethylamino) methylene) hydrazine to obtain 2- [2-oxy-4- (4 [1-1,2,4-triazole -4-yl) -1-pyrrolidinyl] butamidamine 65 and 66. Example 6. Synthesis of 4-Substituted 2-oxy-pyrrolidine butyrimidine via the alkylation of a third butoxycarbonyl) propyl] -5-oxy-3-pyrrolidincarboxaldehyde 396. 6.1. 1 · [1 · (Third Butoxycarbonyl) propyl] -5-oxy-3_pyrrolidinecarboxaldehyde -76-

200538435 396 Synthesis Step 1: Condensation of 2-aminobutyrate with methyl itaconic acid

In a 1-liter three-necked flask under argon, 2,2-dimethylethyl (s) -2-aminobutyrate (commercially available, 46.6 g, 0.268 mol) and dimethyl itaconic acid (83 Ml, 0.59 mol) 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 silica gel chromatography (dichloromethane / methanol: 97/3 (v / v)) to obtain 1-[(1S) -1- (third Butoxycarbonyl) propyl] -5-oxy-3-pyrrolidinecarboxylic acid methyl ester 397 (81.6 g, quantitative yield). Analysis of l-[(lS) -l- (third butoxycarbonyl) propyl] -5-oxy-3-pyrrolidinecarboxylic acid methyl ester 397 in a 1/1 mixture ·· 屮 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 overlap with the solvent part ), 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-butyrate was used to obtain racemic butylamidine with similar yields. Step 2: Synthesis of 醯 396.

Reduction of ester 397 to alcohol 398 -77- 200538435 · The method described in § 7.0.2. Uses 397 as a single enantiomer, a mixture of two enantiomers or one of four stereoisomers / 1/1 mixture. As for (2S) -2- [4- (hydroxymethyl) -2-oxy-1-pyrrolidinyl] tertiary butyl butyrate 398 diastereomer mixture: GC / MS: 257 M + oxidized 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 Cr03 (6.2 g, 0.062 mol) in pyridine (11.3 ml) / dichloromethane (80 ml) and stirred at room temperature. suspension. The temperature was raised to 30t and the suspension was stirred for 0.2 hours. The suspension was filtered through Celite, and 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-pyrrolidinecarboxaldehyde 396: 沱 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 (ι, 1Η), 3.65-3.79 (m, 1H), 3.83-3.94 (m, 1H of one of the diastereomers), 4.48-4.62 (m, lH), 9.74 (sm), lH) 6.2. The alkylation reaction of l-[(lS) -l- (third butoxycarbonyl) propyl] -5-oxy-3-pyrrolidinecarboxaldehyde 396 6.2. 1. Synthesis of olefinic derivatives. Instead of § 6 · 2 · 3 ·, olefinic derivatives can be substituted via Carboxaldehyde 396 is obtained by carrying out Wit tig alkylation reaction with scale salt in the presence of a strong base. For example, (2S) -2- (2-oxy-4-vinyl-1-pyrrolidinyl) butyric acid 2,2- (dimethyl) ethyl ester is via aldehyde 396 with Ph3PCH3Br and n-BuLi in THF. The reaction was obtained. 6.2.2. Through alkylation using Ph3P / CBr4

Instead of § 6.2.3, halovinyl derivatives can be obtained via 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) butanoic acid 2,2- (dimethyl) ethyl ester is based on triphenyl CBr4 from aldehyde 396 in the presence of phosphono. 6.2. 3. Alkylation via (Me2N) 3P / CF2Br2

Two kinds of (2S) -2- (2-oxy- 4- (2,2-difluoro.vinyl) -1-pyrrolidinyl) butyric acid 2,2- (dimethyl) ethyl ester 399 The synthesis of diastereomers is representative. (Me2N) 3P (89.8 g, 0.55 mol) in a three-necked flask under argon was added to a solution of CF2Br2 (58 g, 0.25 mol) 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 99/0 l (v / v)) to obtain 34.6. G (2S) -2- (2-oxy- 4- (2,2-difluorovinyl) -1-pyrrolidinyl) butanoic acid-79- 200538435 · 2,2- (dimethyl) ethyl Ester 3 99/1/1 diastereomeric mixture 87%). 4 NMR (250MHz, (CD3) 2SO): 0.81-0.91 (m, 3H), 1.44 (s, 9H), 1.50-1.75 (m, lH), 1.80-1.95 (m, lH), 2.30-4.40 (m, 2H and solvent partially overlap), 3.00-3.35 (m, 2H), 3.45-3.55 (m, 1Η), 4.20-4.40 (ιι, 1Η), 4.60 (ddd, lH-a diastereomer), 4.75 (ddd, lH another diastereomer). 6.2.4. Use (nBu) 3P / CCl3F for alkylation instead of § 6.2.3. Halogenated vinyl derivatives may be substituted via -Oxy-3-pyrrolidinecarboxaldehyde 396 is 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 obtained via l-[(lS) -l- (third butoxycarbonyl) propyl] -5- Oxy-3--3-pyrrolidinecarboxaldehyde 396 is obtained by reaction with hydroxylamine followed by reaction with selenium oxide. • 6.3. 2.2-Dimethyl-ethyl amination 6. 3 · 1 · Deprotection with trifluoroacetic acid and ammonolysis of (2S) -2- (2-oxy- 4- (2,2-di Fluorovinyl) · 1-pyrrolidinyl) The synthesis of two diastereomers of butylamine 213 and 222 are representative: • 80-

200538435

Step-to-step, deprotection of 2.2 "dimethylformate" ethyl ester

(2S) -2- (2-oxy-4- (2,2-difluorovinyl) -1-pyrrolidinyl) butanoic acid 2,2- (dimethyl in a three-necked flask under argon ) Ethyl ester 399 (31.8 g '0.110 mol) in a 1/1 diastereomeric mixture solution of trifluoroacetic acid (170 ml) and dichloromethane (500 ml) 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 -10 ° C for 1.5 hours, and then gaseous ammonia was passed through the solution while maintaining the temperature below 0 ° C. The suspension was stirred at 0 ° C for 1 hour, warmed to room temperature, filtered, and the filtrate was evaporated in vacuo. Crude amidine 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-di Fluorovinyl) _1-pyrrolidinyl) butyric acid 1,2- (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 (11. 2 g recrystallized from isopropyl ether). -81-200538435 · 6.3.2. In addition, bromocatechol borane can be used for deprotection. The four diastereomers of 2- (2-oxy- 4- (2,2-dimethylvinyl) -1-pyrrolidinyl) butanamine 1 6 3 are via 2-(2- 1/1/1/1/1 diastereomers of oxy-4-(2,2-dimethylvinyl) -1-pyrrolidinyl) butyric acid 2,2- (dimethyl) ethyl ester The 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-1-pyrrolidinyl) butanamine 206/207

BuUUHF

In a three-necked flask under argon, n-butyllithium (1.6M in hexanes, 116 ml) was added to 2- [4- (2,2-dibromovinyl) -2-oxy-1-pyrrole A 1/1 mixture of two diastereomers of pyridyl] butylamidine (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 image chromatography (ethanol / hexane) to obtain 2- (4-ethynyl-2-oxy-1-pyrrolidinyl) butanamide 206 (0.84 g, recrystallized from toluene ) And 207 (0.44 g, recrystallized from toluene) as two diastereomers. In addition, the 2- (4-bromo-ethynyl-2-oxy-1 -pyrrolidinyl) butanamide 267 is passed through 2- [4- (2,2-dibromovinyl) -2-oxy- 1-pyrrolidinyl] -82- 200538435 # # Butamidamine 47 is obtained by reacting 2 equivalents of third potassium butoxide in THF at low temperature (-5 ° C to 0 ° C). Synthesis of 6 · 4 · 2 · 2- (4-propyn-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 (.25 g) in THF (15 ml)) was added to A solution of CuCN (0.82 g) and LiCl (0.78 g) in THF (10 mL) at -10 ° C. 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 with four diastereomers of 2- [4- (2,2-difluoroethyl) -2-oxy-1-pyrrolidinyl] butanamine 1 57 The synthesis of the 1/1/1/1/1 mixture is represented by: -83-

200538435 ·

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 Bal器 hydride. After 20 hours, the mixture was degassed, filtered through a Celite / Nolette pad, and the filtrate was concentrated in vacuo to obtain crude fluoroalkane, which was recrystallized from toluene to obtain 2- [4- (2,2-difluoroethyl) ) -2-oxy • 1-pyrrolidinyl] butyramine 1 57 A 1/1/1/1/1 mixture of the four diastereomers as a white solid (0.75 g). 6.6. Synthesis of 2- [4- (5-methyl-1,3-oxazol-2-yl) -2-oxy-1-pyrrolidinyl] butanamine 62 and 63

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-pyrrolidinylcarboxylate Methyl Ester 397 is a 1/1/1/1/1 mixture of 4 stereoisomers (10 g, 0.035 mol) in methanol (100 ml) at 20 ° C. The solution was stirred for 0.5 hours and evaporated to -84- 200538435 ·

Dry and acidify 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. 1 H NMR (250MHz, (CD3) 2S〇): 0.80 (t, 3H), 1.44 (s, 9H), 1.55-1.60 (m, 1H), 1.70-1.95 (m, 1H) 2.40-2.55 (m, 2H and solvent partially overlap), 3.10-3.55 (m, 1H and solvent partially overlap), 4.45 (dd, 1H). Step 2: Synthesis of amidine 401 in a three-necked flask under argon, ethyl chloroformate (0.50 ml, 0.005 mole) was added to acid 400 (0,678 g, 0.0025 mole) in dichloromethane (10 ml) and three A solution of ethylamine (0.77 ml) 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 for 1 hour, warmed to room temperature, filtered and the filtrate was evaporated in vacuo. Crude amidine was purified by silica gel column chromatography (dichloromethane / methanol 98/02 (v / v)) to obtain 0.8 g of propynamidamine 40 1 as one of four diastereomers. 1/1 mixture. NMR (250MHz, (CD3) = SO): 0.80 (t, 3H), 1.44 (s, 9H), 1.55-1.65 (m, lH), 1.70-1.95 (m, lH), 2.40-2.55 (m, lH Partially overlap with solvent), 3.0-3.7 0 (m, 3H partially overlaps with solvent), 3.70-3.90 (ιη, 2η), 4.45 (m, 1H), 8.45 (m, 1H). Step 3: Synthesis of oxazole 402 in a three-necked flask under argon, amine 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 -85-200538435 · The compound was purified by silica gel chromatography (hexane / ethyl acetate). 50/50 (Wv) to obtain pure oxazole 402 (0.1 5 g, 20%). GC / MS: 308 (M +) can be similar to 6.3.1. It can be converted to 62 and 63 by ammonia hydrolysis. Synthesis 6.7.1. Synthesis of unsubstituted tetrazole

In a three-neck flask under argon, a solution of racemic nitrile 403 (2.66 g, 0.011 mol), NaN3 (4.8 g, 0.07 3 mol) and triethylamine hydrochloride (10.12 g) was prepared at 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. 1 ^ / ^^:

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- 200538435 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 / v)) to obtain two regioisomers, tetrazolium 405 (1.98 g, 34%) and 406 (1.03 G, 17%) was oily. LC / MS: 309 (MH +). 6.8. Synthesis of thiazole 6.8.8. Synthesis of thiamine

6.8.1. 1. 397 Ammonialysis In a 0.5 liter three-necked flask equipped with a reflux condenser and a magnetic stirrer addition tube, 10 g (0.0 3 5 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%).咜 NMR (250MHz, (CD3) 2SO): 0.85 (t, 3H), 1.44 (s, 9H), 1.55-1.60 (m, 1H), 1.70-1.95 (m, 1H), 2.40-2.60 (m, 2H Partially overlapped with the solvent), 3.0 (K3.70 (m, 1H partially overlapped with the solvent), 4.35-4.45 (111, 111), 6.95 (5 (width), 110.7.40 (3 (width), 1H). 6.8.1.2. Synthesis of thiamine 408 in a three-neck flask under argon, crude amine 407 (6 g, 0.022 mol), P4S1G (4.93 g, 0.011 mol) and sodium bicarbonate (3.73 G) A solution in acetamidine (100 ml) was stirred at 5 ° C for 6 hours. The reaction mixture was filtered, concentrated in vacuo and the crude thiamine was purified by chromatography on silica gel (ethyl acetate / -87-200538435 hexane). : 50/50 (v / v)) Thiamine 408 (3.7 g, 60% "GC / MS: 286 (M +) after recrystallization from ethyl acetate. 6.8. 2 Synthesis of substituted thiazole

In a three-necked flask under argon, thiamidine 408 was a 1/1/1/1/1 mixture of 4 diastereomers (this patent, 1-5 g, 0.005 mole), and aluminum trioxide (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 with aluminum oxide and bromo-acetamidine (bromo-2,2-dimethoxyethane in situ 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-

200538435

In a three-necked flask under argon, SOC12 (0.56 ml) was added to a solution of acid 400 (1.90 g, 0.007 mol) in toluene (20 ml) at room temperature. 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, 0.007 mol) were added in one portion, and the reaction mixture was refluxed for 0.5 hours. , Cooled to room temperature, 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 silica gel column chromatography (dichloromethane / methanol 97/03 (v / v)) to obtain 1.3 g of ketone 410 as a 1/1/1/1/1 mixture of 4 diastereomers. LC / MS 333 (MH +). Example 7 Synthesis of 2- (4-substituted-2-oxy-pyrrolidinyl) -butanamide via substitution of activated 2- (4-hydroxymethyl-2-oxy-pyrrolidinyl) -butanamide 7.0. Synthesis of starting alcohol 7.0.1. Synthesis of esteramine 7.0.1.a. l-[(lS) -l- (aminocarbonyl) propyl] -5_oxy-5-pyrrolidinecarboxylate Synthesis of Methyl Ester 11/12

In a 10-liter three-necked flask equipped with a mechanical stirrer and a reflux condenser, under the argon atmosphere, 12 26 g (12 mol, 1 equivalent) (2S) -2-aminobutane-89- 200538435 φ Amidine and 1912 ml (2150 g, 13.2 moles, 1.1 equivalents) of dimethyl itaconic acid were dissolved in 6.1 l of methanol. The mixture was adjusted to reflux for 10 hours and slowly cooled to 20 ° C over 4 hours. It was filtered, the precipitate was washed with methanol, and the combined organic phase was concentrated to dryness to obtain 3.283 g of crude intermediate 74%. In a 20 liter three-necked flask equipped with a mechanical stirrer, Rashig column and distillation arm, in an inert atmosphere, crude intermediate and 8 4.7 g (889 mM, 0.1 equivalent) ) 2-Hydroxypyridine was dissolved in 11.6 liters of toluene. The mixture was adjusted to reflux and the formed methanol was removed by distillation for 8 hours until 480 ml was collected. The temperature inside the reaction flask reached 1 12 ° 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 (image AD 100 * 500 mm, ethanol / water 99.9: 0.1), and the fractions were concentrated to dryness to obtain 968 g of 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, l-[(lS) -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-{(1S) -1-[(methylamino) carbonyl] propyl 5-oxo-3 -Methyl pyrrolidinecarboxylate is prepared in a similar manner. 7.0. 2. Synthesis of Alcohol-Amidine 7.0. 2. Synthesis of a. (2S) -2- [4- (hydroxymethyl) -2-oxy-1-pyrrolidinyl] butanamine 6.

-90- 200538435

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) of (2S) -2- (4-methoxycarbonyl-2-oxy -1-Pyrrolidinyl] butamidin was added to 300 ml of ethanol in 200 ml of ethanol, and the mixture was cooled to 00c. Then, 6 · 2 g was added in several portions over a period of 1.5 hours ( 1. 7 Moore, 12 equivalents) solid NaBH4, while maintaining the temperature at 2 to 4 ° C. After 2 hours the temperature rose to 12 ° C for 1 hour, and again dropped to 2-4 ° C. Take 1 240 ml of a saturated solution of ammonia chloride was added dropwise over an hour, followed by 20 ml of acetone, and the mixture was left at room temperature overnight. The mixture was filtered, the precipitate was washed with 3 X 70 ml of ethanol, and the combined organic portion was concentrated to dryness to obtain 1 48 g of crude 6. Suspended in 300 ml of dichloromethane and stirred for 30 minutes, filtered, washed with 2X 100 ml of dichloromethane and dehydrated to obtain 14 g of pure 6,98%. In addition, (2S) -2- [4- (Hydroxymethyl) -2-oxy-1-pyrrolidinyl] propanamide, (2S) -2- [4- (hydroxymethyl) -2-oxy-1-pyrrolidinyl] pentanamine , (2S) -2- [4- (hydroxymethyl ) -2 -oxy-1-pyrrolidinyl] -methylbutyramine is prepared in a similar manner. 7.1 · Using triphenylphosphine by direct conversion to the synthesis 7.1.1 · (2S) -2- [ Synthesis of 4- (iodomethyl) -2-oxy-1-pyrrolidinyl] butanamine 10

10 liter 3-neck flask equipped with a mechanical stirrer and reflux condenser under an inert atmosphere '400 g (2 mol, 1 equivalent) (2S) -2-[4- (hydroxymethyl) -2 · oxygen -Pyrrolidinyl] butanamine 6 was dissolved in 3 liters of acetonitrile. Add 629 grams of • 91-200538435 · (2.4 moles, 1.2 equivalents) triphenylphosphine, and then add 608 grams (2.4 moles, 1.2 equivalents) of iodine in three portions over a period of 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 3X 1 liter of water. The combined aqueous phase was treated with 1 kg of sodium chloride and extracted with 6 X 1 liter of dichloromethane. The combined organic 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-methylbutanidine 146, (2S) -2- [4- (iodine Methyl) -2-oxy-1-pyrrolidinyl] propanilamine 110, (2S) -2- [4- (iodomethyl) -2-oxy-1-pyrrolidinyl] pentamidine 1 〇5, (2S) -2- [4- (Bromomethyl) -2-oxy-1-pyrrolidinyl] Butanamine 8, (2S) -2- [4- (chloromethyl) -2 · Oxy-1-pyrrolidinyl] butanamine 30 was prepared in a similar manner. 7.1.2. Synthesis of (2S) -2- [2-oxy- 4- (phenoxymethyl) -1-pyrrolidinyl] butanidine 18

In a 50 ml three-necked flask equipped with a magnetic stirrer and a dropping funnel in an inert atmosphere, 1 g (5 mmol, 1 equivalent) (2S) -2- [4- (hydroxymethyl) -92-

200538435 -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-pyrrole

Synthesis of pyridyl} methanesulfonate 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 (115 g, 2 eq) of anhydrous triethylamine was added at once, followed by dropwise 66 · 3 ml (96.2 g, 1.5 eq) of methanesulfonyl chloride in 190 ml of two A solution of methyl chloride while maintaining the temperature below 4 ° C. After 4 hours, add 7.5 ml of methanesulfonyl chloride and 15 ml of triethylamine and the mixture 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, {l-[(lS) -l- (aminocarbonyl) propyl] -5-oxy-3-pyrrole-93- 200538435 · pyridyl} methyl-4-methylbenzenesulfonate 3 1 Prepared in a similar manner. 7.2.2. Synthesis of (2S) -2- [4- (azidomethyl) -2 -oxy-1 · pyrroleπyl] Butamidine 32

In a 3 liter three-necked flask equipped with a mechanical stirrer and a reflux condenser under an inert atmosphere, 89.7 g (322 millimoles, 1 equivalent) U [(lS) -1- (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%. In addition, (2S) -2- [4- (fluoromethyl) -2-oxy-1-pyrrolidinyl] butanamine 44 and (2S) -2- [2-oxy- 4- (1Η- Tetrazol-1-ylmethyl) -1-pyrrolidinyl] butanamide 39, (2S) -2- [2-oxy- 4- (1H-tetrazol-1-ylmethyl) -1- Pyrrolidinyl] butyramine 40, (2S) -2- [2-oxy- 4- (1Η-1,2,4-triazol-1-ylmethyl) -1-pyrrolidinyl] butyridine Amine 55, (2S) -2- [2-oxy- 4- (1H-1,2,3-triazol-1-ylmethyl) -1-pyrrolidinyl] butanamine 56, (2S) -2- (4-[(isopropylsulfanyl) methyl] -2-oxy-1-pyrrolidinyl} butanamine 24, (2S) -2- [2-oxy- 4- ( 1-pyrrolidinylmethyl) -1-pyrrolidinyl] butyramine 15, (2S) -2- [2-oxy- 4- (4-thiomorpholinylmethyl-94- 200538435 φ group)- 1-pyrrolidinyl] butylamidine 17 is prepared in a similar manner from activated alcohol derivatives such as methanesulfonate, tosylate or halide. 7.3. Other Synthesis 7.3.1. {L-[(lS)- Synthesis of l- (aminoamino) propyl] -5 -oxy-3-pyridinyl} methyl nitrate 38

In a 500 ml 3-necked flask equipped with a mechanical stirrer and a reflux condenser and in an inert atmosphere, 8.10 g (26 mmol, 1 equivalent) (2S) -2- [4- (iodomethyl) -2 -Oxy-1-pyrrolidinyl] butamidamine 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, 440 mg (2.8 mmol, 0.1 equivalent) was added and reflux was continued 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 53/1 54

7.3.2.a · (2S) -2- {4-[(Benzyloxy) methyl] · 2-oxy-1-pyrrolidinyl} Synthesis of tert-butyl butyrate -95-200538435 _ In the equipment In a 100 ml 3-necked flask 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, and the mixture was cooled to 0 ° C. Carefully add 6.37 g (24.8 mmol, 1 equivalent) of (23) -2- [4- (hydroxymethyl) -2-oxy-1 -pyrrolidinyl] butyric acid tert-butyl ester 398 in 10 ml 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.屮 NMR (250MHz, (CDCl3): 0.85 (t, 3H), 1.44 (s, 9H), 1.55 -1.95 (m, 2H), 2.10 (dd, lH), 2.45 (dd, lH), 2.55-2.70 ( m, 1Η), 3.45-3.55 (ιη, 1Η), 4.40 (dd, 1H), 4.55 (s, 2H), 7.20-7.40 (m, 5H). 7.3.2.b · 2- { Synthesis of 4-[(benzyloxy) methyl] -2 -oxy-1-pyrrolidinyl 丨 butyrate # amine 153 in a 50 ml 3-neck flask equipped with a magnetic stirrer and reflux condenser under an inert atmosphere Within 1.75 grams of benzyl ester-rich extracts were dissolved in 20 ml of methanol. Then gaseous ammonia was passed through the solution and saturated solution at room temperature for 24 hours, and occasionally saturated with ammonia again. After the reaction was completed, the solution was concentrated to dryness and preparative LC (1 kg of silica gel, dichloromethane / methanol, 98: 2 to 90:10) was purified to obtain two diastereomers. In 25 ml of an inert atmosphere equipped with a magnetic stirrer and a reflux condenser 3 In the flask, 1.24 grams of the third butyl ester-rich eluate was dissolved in 16-96-200538435 _ · ml of a 1: 1 mixture of dichloromethane / trifluoroacetic acid and maintained at 0- for 24 hours. The solution was concentrated To dryness, the residue was dissolved in 10 ml of dichloromethane. 1.2 ml (2 2 theoretical equivalents), and the mixture was cooled to -20 ° C. 780 microliters of ethyl chloroformate was added dropwise, and the mixture was allowed to slowly warm to -10 ° C for 1.5 hours. Gaseous ammonia passed through the solution for 0.5 hours The mixture was maintained at room temperature overnight. After filtration, the precipitate was washed with dichloromethane, and the combined organic extracts were concentrated to dryness and purified by preparative LC (1 kg of silica gel, dichloromethane / methanol, 98: 2 to 90: 10) Two kinds of diastereomers were obtained. The first and second diastereoisomers obtained in two rounds were combined and crystallized from toluene to obtain 305 mg pure 153 and 480 mg pure 154, 11 respectively. % Total yield. 7.3.3. (2S) -2- {4-[(5-methyltriazol-1-yl) methylbutoxy-2-pyrrolidinyl} butanamine 52 synthesis

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 millimoles' I · 1 equivalent = phenylphosphinoalkylene) 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 sand gum, dichloromethane / methanol / ammonium hydroxide, 94 · 5: 5: 0.5), suspended in 15 ml of water and lyophilized to obtain 240 mg of pure 52 was clarified oil '42% ° -97- 200538435 · 7.3.4. (2S) -2- [4- (isothiocyanatomethyl) -2-oxy-1-pyrrolidinyl Synthesis of 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 (2S) -2- [4- (azidomethyl) -2-oxy-1-pyrrolidinyl] butanamide 32 in 150 ml of ethanol and the mixture to The Barr hydrogenator was hydrogenated at a maximum hydrogen pressure of 30 psi for 2 hours. The mixture was degassed, filtered through a Celite / Nolette pad, the residue was washed with 2 x 100 ml ethanol and the filtrate was concentrated to dryness to obtain 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-necked 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-oxy-1-pyrrolidinyl] butanamine 412 was added dropwise over a period of 30 minutes. 25 ml of 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, 93.4: 6: 0.6) to obtain 3. 1 gram thick 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- 200538435 · The compounds of formula I shown in the table below can be prepared in a similar manner or as described elsewhere herein. In the table, 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 identification of each identified center, followed by the IUPAC number used in the previous column. Separate numbering indicates that both configurations exist in the center. The number followed by "R" or "S" indicates the absolute configuration known to the center. The number followed by "§" indicates that there is only one but unknown absolute configuration at the center. The 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- 200538435 · • · RMN] H Ξ LC / MS MH + -1 melting point 〇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. TH τ-Η 7.1.1. • Configuration Information Racemic Racemic Racemic Mixture Non-Photon m 窠 窠 mm 窠 m Inch inch Office CN A-2S, 4§ B- 2S, 4§ A-2S, 4§ B-2S, 4§ j Pi gas αΓ; A-1S, 3§ B-1S, 3 § IUPAC chemical name I 铿 m surgery I swallow 1 rH free snow Λ if 1 CN m Κ] 1-CS-2 (2-oxy-4-phenyl-1-pyrrolidinyl) acetamidamine 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] butamidamine (2S) -2- [4- (bromomethyl) -2-oxy-l-ftpyridinyl] butamidamine PS) -2- [4- (bromomethyl)- 2-oxy-1-pyrrolidinyl] butyramine (2S) -2-[(4R) _4- (iodomethyl) -2-oxypyrrolidinyl] butanidine 1 mm nf 1 1 i E imv ® " T fr ^ m w 1 1 J ^ ΓΤΤχ two paste n 1 cn m l! f 1 1 5 g ϊ m s ^: E-G 氍 C you two paste compound number τ-Η Γ〇 inch VO 00 Ον 〇 1—ί cs —100 — 200538435

Ξ Γ-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 mm 窠 窠 窠 窠 窠 m A-2S, 3 § B-2S, 4§ coo gas 00 CS < 000 CO cs free A-2S, 4§ A-2S, 4§ 000 gas C / T CN PQ coo inch Λ CO CN < OOO inch Λ 00 cs CQ A-2S, 4§ m 隹 < 1 1-H m 浒 狴 sm 4 h saurian ^ < N 1 tH / ^ N 1 C / D i ~ 'fr s glycoside_ * κ 1 iH m 浒 狴 im 4 h slightly Butterfly 1 «ア ac ^^ / 1 S 1 C / D '~ 1 has swallowed 1 TH 1 5 El · _ Pan 1 rH 1 I " m secret c; m ^ tdn 砮 1 1—ί 1 ϊ m η junction I r1 rH 1 m 嫲 铿 ^ mg slightly ei m swallow 1 1-HI i & m incense mm 1 1 iil secret ^ mvh 'g slightly. cixia (2S) -2- [2-oxyl -4- (phenoxymethyl) -1-pyrrolidinyl] butylamidine 1 T-amylol 1 CN 5 6 3 5g 怀 S ® ii CL # (2S) -2- (4-benzyl-1 -Oxy-1-pyrrolidinyl) butanamide: 2S) -2- (4-benzyl-2-oxy-1-pyrrolidinyl) butanamine] (2S) -2- (2-oxo 4-Phenyl-1-pyrrolidinyl) butanamine 1! M inch VO 00 On < N CN -101- 200538435

Ξ 92.4 103.8 98.1 107.7 211.4! 142.8 120.3 111.7 84.8 134.8 Two-H 7.1.1. RH Bu 7.2.1. I! _ 7.2.2 6 · 2 · 2 · Then 6.3.1. M Μ 窠 窠 窠 elimination Racemic 窠 窠 m mixture 000 gas GO CN FREE coo gas C / T- CS < A-2S, 4§ coo inch 00 < N FREE 000 inch Λ 00 < Ν FREE and ri < inch office < N ries A-2S, 4§ A-1S, 3 § | Pi inch αΓ CN inch office CS (2S) -2- (2-oxy-4-phenyl-1-pyrrolidinyl) butanamide slightly Domain: 1 CN 5 ϊ κ η Βϋ (C / D 1 (2S) -2- (4-isopropyl-2-oxy-1-pyrrolidinyl) butanamide (2S) -2- (4-isopropyl-2-oxy-1-pyrrolidinyl) butanamine (2S) -2- [4- (iodomethyl) -2-oxy-1-pyrrolidinyl] butanamine 2- (4-cyano-2-oxy-1-pyrrolidinyl) butanilamine 2- (4-cyano-2-oxy-1-pyrrolidinyl) butanil (2S) -2- [4- (chloromethyl) -2-oxy-1-pyrrolidinyl] Butanamide 醯 1 ΓΟ η ii ag κ | 1 «« ϊ V «v fr -W vm 苕. Slightly m 1 < N 5 &-shout iSH T ^ 2 _ SH 1 τ-Η Secret 1 (NS Award K) 鹓 〇; _ Ϊ b AW m CN < N VO (N 00 (N 〇 \ CN m ro cn -102- 200538435

S r—i 202.8 73.9 56.9 135.0 181.9 82.3 120.5 138.1 — inch 4.4. 7.3.1. 7.2.1. 6.2.1. Then 6.3.1. 7.2.2. 窠 mm 窠 窠 m 窠 mixture 窠 m coo ΓΛ c / Γ 1 C 000 gas 00 04 < 00Q gas 00 < N FREE 000 m ζΛ r— ^ yan &co; COo CO 00 τ-Η 1 < A-2S, 4§ 000 gas 00 < N < inch Office ri 1 A-2S, 4§ A-2S, 4§ 砮 1 rn mm 1 1 m ES Attack V ^ 彳 娘 S η 铿 铿 j (2S) -2- (4-methyl- 2-oxy-1-pyrrolidinyl) butanamine (2S) -2- (4-methyl-2-oxy-1-pyrrolidinyl) butanamine 1 m Λ secret 1 1 5 E distillate 5 By S ii If 2 m 二 accent rn Λ Secret 1 1 s E Slightly as 1¾ ™ «1 v ™ V ffi- -mvm 1 rH 1 i & 1 ύ s 1 KJ _ Ilf H ά s ^ n 砮 1 ▼ -H 1 i B- Complement 1 P a 1 ffi 1—H 4 狴 1 M < Slightly _ 嫲 dsn 2- (2-oxy-4-vinyl-1-pyrrolidinyl) butanamine • Swallow 1 m Jlf CN s BB- Slightly 4 ^ 3 J Λ HK / l '~~' Swallow 1 i—Η 1 5 ji crocodile ft 4 ^ «p ά w ro VO m $ OO mmor—4 _1〇3_ 200538435

SS 87.1 00 〇rH cn rH rH TH ο On τ-Η inch CN rH Ό ON cn rH 00 cvi bu < N 00 CN Csi ^ v〇 (N ^ vd ct — r〇ϊ > mm 窠 m 锾 窠 Μ < π mm € coo inch 00 CN <: 000 m • οΓ r—l 1 < ί Pi gas (zT < N gas (A < N coo mc / Γ rH 1 < C0Q gas czT CN < 000 gas αΓ < N <; inch λ CN coo inch t / T CS <: CN (2S) -2- [4- (fluoromethyl) -2-oxy-1-pyrrolidinyl] Butanimine 1 CO price secret 1 1 s IE ϊ l UL · paste this one v v slightly ^ ffi- two slightly vn slightly secret 1 < N slightly linked ΚΙ 郏 II I < N τ m Pi t S «έ ^ Slightly m 1 CS hO 11 1 < N tm 2s t δ «λ m 1 mm hire ^ Τ) 1 5 (E s -ΤΤ > \ wi warp S ^ 2 淦 1 TH ¥ 1 < N slightly fr m 鍫^ 1? 巨 ^ η has been 砮 1 τ-Η m secret 1 CS S 1 < N i II g $ >. You inch m ^ m 二 卜 i WA ί 基 ά 你 1 < N i II 1 qicn Η m it can be slightly yaa 芰 ^ «i 1 rH m qi f-cs —: slightly ffixia slightly swallowed 1-Λ im 4 w 1 ^ 2 has been fr ml! F 1 < N Ϊ 1 i li town inch ⑽ csT 观 ^ t 机 1 slightly ffl- ig cA 4 ^ U-U 1 A 7 $ 00 α \ CN m -104- 200538435

[3〇] 117.3 Ό cs inch 1—H CN 00 < N CN m 〇VO rH (N Ον νο rH 1 ^ -H inch ▼ -H 00 CN C \ rH Bu 00 〇 r—Η oo r > vo rH Mixture m < n crane k: yaxia m yamm yam inch CN " coo gas00 < N <: coo gasγ ^ Γ < inch a 〇r < inch and CN <: (N < Inch. OT ώ Inch Office (N 1 PQ Gas (N <: rjT PQ 1 V—Η ml outside the inch! F 1 CN 1 < N m #s D, T4 ^ m slightly h call S smiplastic a 砮 Bl · Paste 1 r »H deg m 1 gas CN 5 m 4 twg ^ S CN * 1 t—1 1 00 ^ has been slightly Λ _ ffi- slightly 1 rH im 1 m CN« m V h ^ 5 «| Secret I i # 1 1 < N rH Swallow 1 i—Η 1 i & slightly 1 a 1 ffi 4 ^ Hf t ^ m 1 ι ^ Η FREE Secret 1 (N slightly 1 a * ^ Λ _ Ε- άά S i ^ 砮 1 m Jiff 1 (N 3 1 ia 1 mm ffl- H i S i AA 砮. 1 τ · Η m Hf 1 (N Ϊ 1 a I vxxz «m BE- H ά 5 in A ^ 1 ▼ • H m Secret Words (N s 1 a 1 * ^ lil _ ffi- H i S in Aac 1 m Secret 1 CN i 1 cs ά w —i 卜布》 · S i 塑 < N swallow 1 m ni 1 (N «1 CN Up m pan〒imh ^ n ± ^ a 砮 in oo ON WO S Ό CN vo cn vo -105- 200538435

[10] 1 I 94.3 'On 〇rH i—H vd 00 τ-Η fH 00 tH O m inch ΓΟ inch τ-Η m 〇 \' O yr \ 〇CN »-H 6. · 8.3 and then 6.3.1 Two — two inch · inch · ^ — — ^ inch · mixture _1 yaxiam ya 窠 窠 m 窠 m inch office < Ν inch Λ < N < inch office CN FREE < N OQ COD 气 CO Cjl <: coo gas 00 CN PQ < N 000 gas ζ / ί < coo gas 00 CN FREE m 1 1 5 1 (N m 1 m rH 1 A t swallow 1 τ-Η 1 slightly 1 k HI 1 〇T 1—H 1 ffi V ^ tm slightly h Hi S ina acne swallow 1 1-H 1 slightly 1 k in 1 inch cn 1 KV st _ slightly him 丨 ac m 砮 1 rH 1 complement 1 r—1 s 1 ffi 1- H 1 Tj- butterfly 1 铿 ^ »1 m base 1 (N 3 roll E- 4 S ： P Λ HX / l '~~' dw (2S) -2- [4- (4-methoxy Phenyl) -2-oxy-1-pyrrolidinyl] butanamine 'xia1 ^ -H 1 5 m η 砮 1 cn 1 inch m ^ 嘁 ^ t 7 slightly m swallow 1 τ-Η 1 ϊ m 1 1 m Ilf A 铿 Ϊ h KM i ~ 'Cl weight m swallow 1? -H Zu Shouxiang 1 1 secret a 铿 Λ Η GO' ~~ 'v〇00 v〇Os O τ-Η < N -106 -200538435

112.0 Ί 1 _1 150.2 m rH ON 1 146.5 73.7 115.0 129.0 100.2 1 • ^ ^. ^ ^. Li 2 — · You —. · — · 鹚 勹 d ί ^-ί ^-寸 :: inch · inch · 鹚Inch · Silver inch · 鹚 窠 mm 窠 窠 窠 m < n Crane coo Inch Λ coo Inch office 000 Inch Λ coo Gas coo Inch office coo Inch office 000 Inch office C / Γ CN οΓ CS 00 CS CO < N ικΓ ( N 1 CO CN 1 C / T (N (N < < FREE PQ < PQ < 智. Mm Sheng I 1 1 1 1 砮 1 1 1 I 1 p—n iii «A mmm H mm • AB 嫲| I Hi Secret 嫲 Ilf $ Kl < N (N 1 / ^ \ < N < N (N CN < N 1 nj slightly m slightly Ϊ slightly 浒 浒 浒 擗 浒 擗 浒 擗 浒 擗 1) & < N 秘Slightly m Slightly E- m El · m fr »-s L—1 CN 1 1 m 1 inch 1 cn 1 CN I i Ning 4 ^ 4 ^ 4 ^ 4 S 4 S 4 ^ 4 锴 A _ 3 wine:娘 ^ m ^ m X Hall m ^ m ig. Bu 7 Λ h in '· Λ h (/)' ~ '1 b C / J' — ~ 1 Λ h C /) '' Λ h 〇0 ι— ι Λ h C /! D 'i Λ h C / Q' ~~ 'Hip bucket i has been slightly 3 has been slightly supplemented and has been slightly supplemented ^ η mv〇VO oo Os -107 ^ 200538435

[11] 1 [12] 1 1 91.4 Ό vd ON Os co ο inch · 00 inch _ d < Ν i ο 00 ○ 4.2.2. Two-two inch Tj- < N < N inch ri Η inch · 黎 -I ”— two inch inch • • — CN; ^ Η ^ Η 1 inch inch 窠 mm 窠 窠 mm 窠 锾 A-2S, 4§ COD qi go " < N CQ ooo qi c / ί CN <; coo Inch Office 00 < N free coo Inch Office οΓ CN < coo Inch CO CS < coo 00 CS PQ COO Gas GO CN PQ 000 Gas 00 " CN 1 PQ Swallow 1 r— < m 峥 CS S Roll slightly reduced] | Turn i S 4 m ν Η G slightly dn »rH m secret 1 < S 1 Ϊ 喊 喊 i number 4 喊 vh” 1 ~ ^ η 1 1 5 ring CO 1 «secret AS 3:? Λ Η 00 11 Already 1 ^ Η 1 m 1 < N 1 Λ ί: Ρ Λ Η 0Q 'ι 3 slightly 1 ^ Η 艺 Ϊ Ϊ1 1 inch «ma η A ^ Λ Η 00 1 ~~' ει m Dad1 τ-Ή m Hi 1 CN Slightly shout i ^ 4 m 孑 t has swallowed up 1 τ-Η m Secret 1 < N 1 Slightly dirty d | d | 趋 4 waking up ^ temm 砮 1 rH 1 im 1 1 mma 狴 Λ Η 00 '~~' has been a little η Sheng I swallowed 1 y— ^ m 1 CN i rolling right Ning 4 S *: g Λ Η 00 '~~' s. < N oo m 00 ^ Τ) 00 VO 00 oo 00 〇 \ 00 -108- 200538435

[13] [Η] 1 226.4 79.0 68.3 129.4 1 1 165.4 104.3 217.4 6 · 2 · 1 · then 6.3.1 · 6 · 2 · 1 · then 6.3.1. ^ ^ Η ^ CS;-rH 1—Η 3.1 .la Μ 3.1.lg% 窠 m 窠 m mixture mixture coo gas GO CN < B-2S, 4§ (1HC1) 2S, 4S Pi inch 00 CS A-2S, 4§ 000 gas CO < N PQ inch and Inch A-2S, 4§ η shall be τ-Η mw 1 (NS 浒 Right 1 m is Λ Η 00 < —1 has been a little bit I 1 swallow 1 rH Λ secret 1 < N 3 Ν slightly 狴. 1 m 4 ^ vm 1 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] butanamine 2- [4- (2-bromophenyl)- 2-oxy-1-pyrrolidinyl] butyramine 1__ 2-[(2-oxy-4- (3-pyridinyl) -1-pyrrolidinyl) butyramide 1 1-H m Secret 1 (N 5 swallow 1 ΓΛ 1 Secret _ two h I 5 ^ m swallow 1 tH mm 1 (N m 1 r—η thin d: m 4 Η ^ ϊ% CS On σ \ Os VO Os 〇〇σ \- 109- 200538435

r—1 L_J t—nv〇r— (l_l [17] 255 172.7 1 ί 1 135.7 171.1 166.6 161.7 119.4 7.2.2. 7.1.1. 7.1.1. 窠 mixture mixture 窠 窠 窠 racemic coo gas αΓ ( N 1 PQ CO) Inch Office αΓ < N < A-2S, 4§ 1 1 ί 000 Inch C / T ί Inch Office Inch Λ ri A-2S, 4R 00 Inch Office CO CS <: 000 Gas οΓ < N < and rjT < swallow 1 rH 1 < N m 1. r—i 4 Η 孑 ϊ 1 Λ secret 1 CN slightly fr W 5S Huai like _ s rob ii must be 3 砮 (2S) -2- [4- (l-naphthyl) -2-oxypyrimidinyl] butamidamine (2S) -2- [4- (l-naphthyl) -2-oxy-1-pyridinyl Pyrrolidinyl] butanamine 2- [4- (iodomethyl) -2-oxy-1-pyrrolidinyl] butanidine 2- [4- (chloromethyl) -2-oxy-1- ¾ pyridinyl] butylamine 1 ί—Η 11 (NS ffl- 綦 Ϊ, sm ^ S 着 r— ^ m 11 (N 5 1 ά ^ sm ^ S m 1 (N 5 枨 m 1 彳 画Co-h 4 ^^ / ^ N rH 00 1 C Slightly (2S) -2- (4-hexyl-2-oxy-1-pyrrolidinyl) butanamide On ON 100 ί 101 102 103 104 105 106 107 108 -110- 200538435

255 241 241 395 395 283 269 297 199 269 241 147 1 116.3 rH 7.1.1. 3.1.1.a S | 3.1.1.g Xia Xia Xia Xia Xia Songsong 窠 mmm 4n < Π <! □ < ίπ Si mm Crane Pi inch inch inch inch inch inch inch r / \ inch rr \ CN 1 ri CN CN ri (N inch CN inch < N inch cs inch cs ￥ \ JA CN w J < N < FREE <; FREE & <: FREE mmm. ϋ m η 铿铿 遁 m tar 铿铿 铿铿 ϊ mmss dart mmmmm ya paste g £ + y ^ NKS jit; tQii E 5t E blanket I secret l * 3 i slightly Slightly s Slightly S Slightly 1 (N < N η η nnm η rH I / ^ S jrrji) / ^ N m Interpretation l Lake lif l · ml · rH Zu r-4 1 砮 1 rH 1 ▼ -H砮 1 rH 砮 1 i-Η 砮 1 砮 1 τ-Η Swallow 1 τ-Η 1 (N 1 綦 'w / m «Λ« «mm« Λ m «m inch 1 Secret Secret Secret m Secret llff m KK 〇 ] 着 / ^ N 00 CN CN CN CN (N 1 1 CN < N 1 ^ j- 艿 1 s punishment t -— / iijtd s 铿 1—J t ^ 3 | d Λ Λ Λ slightly m Λ m «Λ 1 (N 4 r Γΰ 〇] 〇] 〇] 01 a] 〇] Alkali / * N in / —s | K-CO '~ 1 C / D 11 inch < N < N Like v / Π33 Has been slightly < N 1 < N 1 CN 1 < N 1 (N 1 CN i (N 1 CS 109 110 111 112 113 114 115 116 117 118 119 120 121 -111- 200538435

Call 12- 200538435

269 255 255 284 289 1 1 _1 241 241 213 291 1-! 53.8 94.8 66.6 3.1.1.a to 3.1.1.g, _H racemic racemic racemic mixture mixture: 1 _1 racemate II racemic 窠 mixture inch 〇Γ I A-2,4 B-2,4 inch rv CS 乂 (N B-2,4 inch Ρύ C C / T (N CC / T (N Pi 0000 CN ri 鳔 SS ηac # 1 rH «4¾ 1 Secret 1 Dagger 1 (N 鳔 S Μ η 1« 1 m Secret 1 already 1 (N 鳔 S η blanket I # 1 m 4 ¾ I m Secret 1 cs 1 < N 2- (2-oxy-4-pentyl-1-zolinidinyl) heptanamine ^ 2- (2-oxy-4-pentyl-1-¾zolidine) -2-phenylethyl Hydrazine 2- (2-oxy-4-pentyl-1-pyrrolidinyl) butylamine (2-oxy-4-pentyl-1-¾ slightly D-based) ethyl amine supplement m 1 (N 5 ^ th η 4 «Λ fr 窆 丨 1 1 1 in i ~ 1 ci m tonic 1 1 S -m let h 4 «Λ fr ^ II 1 1 0Q 1 ~ 'supplemented 1 CN 1 5 a- the second hall H7 $ mv 1 GO» ~' cl m 1 irH A m 1 < N s 1 1 awake U 铿 #: P 埤 t A right two plastics swallow 136 137 138 139 140 142 143 144 145 146 147 -113- 200538435

[18] [19] [20] ί. [21] 1_ 187.0 155.7 119.1 1 丄 1 then 1.2 丄 then 1.2.2. 1.1.1. Then 1.2.1. Then 1.2.2. ^ ^ Η "Η Two ί —Η τ-Η mmm Racem 丨 racem 窠 000 gas GO CM 1 < 000 gas ο Γ CN ￥ 000 inch Λ 〇〇 <: oco gas C / T CN < B-2S? 4§ inch office < Inch ^ PQ 00 Gas CO CN (2S) -2- (4-neopentyl-2-airyl-1-¾roflidine) Butanidine (2S) -2- (4-neopentyl- 2-oxy-1-pyrrolidinyl) butanidine wm 1 CN 1 sm 狴 ml ffi- Ning slightly S pan A acne 砮 00. ≪ N rH s— ^ 1 (2S) -2- (4 -Ethyl-2-oxy-1-pyrrolidinyl) butanilamine 1 1-l (2S) _2- (4-ethyl-2-oxy-1-pyrrolidinyl) butanamine 1_ 2- { 4-[(benzyloxy) methyl] -2-oxy-1-pyrrolidinyl} Butanamine 2- {4-[(benzyloxy) methyl] -2-oxy-1-pyrrolidinyl} Butylamine «Domain: 1 CS 1 Ϊ _ Λ h7 ^« 1 C / D 1 ~ 1 148 149 150 151 152 153 154 155 —11 A—

200538435

127.2 136.8 1 82.1 74.3 121.3 180.3 105.0 118.1 108.8 i 6. · 2 · 3 · then 丨 6.3.1. CN yn k2.4. Then 6.3.1. 3 · 2 · 1. Then 6.3.2. 2.1.1. Then 2.2. Mixture mixtures 窠 窠 Racemic racemic mixtures | mixtures · CN inch csT χΠ gas CN CO inch 0 (N < inch (N PQ gas inch · CN CN 2-[4- (2, 2-diethylenyl) -2-oxy-l-strongly acryl] butanamide 2- [4- (2,2-digasethyl) -2-oxy-1-¾ slightly steep Yl] butanamine (2S) -2-[(4S) -2-oxy-4-propylpyrrolidinyl] butanamine (2S) -2-[(4R) -2-oxy-4- Propylftrolidinyl] butanylamine 2 ^ 2-oxy-4- (trifluoromethyl) -1-pyrrolidinyl] butanidine 2- [2-oxy-4- (trifluoromethyl) Group) -1-pyrrolidinyl] butyramine disk chain I swallow 1 1— * Λ 嫲 1 1 5 link KK) ”” your UXZ darts τ η? Ϊ swallow 1 τ-Η m 嘁 1 (N m E: 1 1 glutamate fr epi CN Η η 2- (4-butyl-2-oxy-1-pyrrolidinyl) butanamine 1 156 1-! 157 1 158 159 160 161 162 163 164 -115- 200538435

[22] 299/301 297 281 315 261 120.2 j _1 ^ ^. Just bn just tic cut W Kft H (N 6.2.1 · 6.5. Ran 4 6.3.1. 3.1.1.a 3.1.1.] 3.1 .1.a 3.1.1. 丨 3.1.1 .a 3.1.1.] 1 3.1.1.a 3.1.1.] Loose < n m43 loose < π < 1π < π < jn 4〇 < □ Si m lll «u 蜉 m Si Inch Office Out of CN Inch ri of Inch Inch Inch ri ci Inch CN Inch Office (N s 铿 mm bu『 Ac 5 nm nm -I-\ " 1 5 5 S swallow 1 5 Η 1 5 η τ—Η 1 r—ϊ 砮 5 rH 1 then I slightly 1 τ—Η 1 m swallow # t 1 lumpy I ilff 1 1 rH 1 1 rH 1 s 1 1 ; N rH 1 Slightly El. Secret tip < N I r—Η 1 s Slightly m screaming 1 CN U Slightly secretive alkaloid 1 1 < N /-* N 1 (N / ^-N HI 'w ^ Ϊ 1 (N fr 1 < Ν 基 1 (N / ^ N slightly 1 CN 1 ^ _1 rolling up for free 1 supplementing 浒 ΤΤνΙ 1 ~ ^ alkaline 铿 uw _ li g 挺 看 am V 1 1 CN 1 1 mmts ^ 1 im 1 st 1 inch i is im < Ν A _ A 简 ^ n (NH ^ m 165 166 1 i 167 168 169 170 171 172 173 -116- 200538435

311 283 269 89.5 100.2 99.6 116.9 i… I 97.2 3.1.1.a Μ 3.1.1.g 1. · 1.2 · then 1.2.1. Then 1 1.2.3. 1.1.2. Then 1.2.1 · then 1.2 .3. 1.1 · 2 · ϋ then 1.2 丄 and then 1.2 · 2 · j 1.1.2 · β · 1.2 and 1 · βM 1.2.2. 1 3.1.1.a · to 3.1.1.g. Mixture 1 m mixture racemic racem m 窠 m ri coo inch co " CS PQ A-2S, 4§ gas inch · (N FREE inch (N < coo inch office < coo gas C / Γ (N PQ A-2 §, 4 § 1 2- [4- (3-methylphenyl) -2-oxy-1-pyrrolidinyl] Butanidine η 1 1 3 Slightly rolled 1 1 Λ Η in ' — 'Cl, «Swallow 1 i-Η 1 3 κ) Slightly 1 < N 1 铿 A 铿 *:? Λ Η ΟΟ 11 Cl« 2- (4-hexyl-2-oxy-1-pyrrolidinyl) Octylamine 2- (4-hexyl-2-oxy-1-pyrrolidinyl) hexamidineamine 2- (4-hexyl-2-oxy-1-pyrrolidinyl) pentanidine η 1 μm if 1 ϊ 郏 1 CO 4 ^ Λ h Z / l 1 ~~ > n 1 m 1 (N 5 goose 1 4 ^ Λ HC / 0 1 ~ 1 supplemented 1 tHά secret 1 Οί 5 ft slightly 6 shouting trend mi a _ a 砮 174 175 i 1 176 177 178 179 180 181 182 -117- 200538435

97.2 148.6 148.6 177.9 177.9 154.7 178.7 201.4 138.0 137.4 3.1.1.a M 3.1.1.g 3.1.1.a M 3.1.1.g 3.1.1.a M 3.1.lg 3.1.1.a M 3.1.lg m 窠 窠 mm racemic racem m 窠 B-2§, 4§ C-2 §, 4 § D-2§, 4§ A-2 §, 4 § B-2§, 4§ A-2 , 4 PQ 000 inch Λ C / Γ cs FREE A-2 §, 4 § i_ B-2§, 4§ 1 m secret 1 cs 5 ft 5 6 maple ill S redundant ta 砮 1 vH Λ secret 1 cs 5 t ϊ El · 铿 ΰ 1 1 «ta slightly a 砮 1 tH Λ 嫲 1 (N 1 slightly ft s fr maple 铿 111 ϋ tt t A slightly i ^ (N swallow 2- [4- (3,4-dichloro Phenyl) -2-oxy-1-pyrrolidinyl] butanamine 2- [4- (3,4-dichlorophenyl) -2-oxy-1-pyrrolidinyl] butanamine 2 -[4- (2,4-dichlorophenyl) -2-oxy-1-pyrrolidinyl] butanamine 2- [4- (2,4-dichlorophenyl) -2-oxy- 1-pyrrolidinyl] Butanidine 1 rH Secret I (N i 枨 11 1 d ^ 4 m ^ t 2 slightly d η s 5 遁 mi Eh li gm ® vt ά slightly 4 η «1 if. 1:丄 A «5 遁 m S Bl · Alkali attack in J d tip 4 n Λ I m ®, ^ 183 184 185 186 187 188 189 190 191 192 -118- 200538435

[23] [24] 84.4 83.8 92.5 118.6 153.8 154.4 99.8 1 1 3.1.1.a ng 3.1.1.g 1 3.1.1.a Μ 1 3.1.1.g Η —: ^ — (Ν: — r— (1 · 1 · 2 · ϋ then 1 · 2 · 1 · then 1 · 2 · 2 · 3.1.1.a Μ 3.1.1.g 3.1.1. A to, 3.1.1. Gm 窠 racemic racem Racemic mixture 窠 m mixture 000 乂 coo CN 6 coo gas 000 (NQ A-2,4 free gas 00 CN coo inch ^ CO CN < C-2§, 4§, 1 D-2§, 4§ inch office CN s 5 sg X 5 El · 经 经 III 5 ά m 4 nw | w. »A a« S 5 遁 m 5 η- in pvti slightly w S Secret a slightly 2- [4- (2-furanyl) -2-oxy-1-pyrrolidinyl] butyramine 2- [4- (2-furanyl) -2-oxy-1-pyrrolidinyl] butanidine η 砮 1 rH 1 roll 1 m 1 Secret Λ Η C / D i ~ i C slightly swallow 1 r · im nf 1 CN 1 Ϊ goose Π 1 ^ T) 6 ^ 4 m 孑 t 2- [4- (3,4-dichlorophenyl) -2 -Oxy-1-pyrrolidinyl] butanamine 2- [4- (3,4-dichlorophenyl) -2-oxy-1-pyrrolidinyl] butanamine 2- (2-oxy -4-propyl-1-pyrrolidinyl) butanamine 193 194 195 1 -1 196 197 198 199 200 201 H19- 200538435

111.8 113.2 113.4 113.4 147 115.2 120.7! | 123.7 I 154.26 150.9 1 1____ 104.4 3.LI.a S 3.1.1.g 3.1.1.a Μ 3.1.1.g inch vd 3.1.1.a S; 3.1.1 .g 3.1.1.a S 1 3.1.1.g 2.1.2. then 2.2. 窠 窠 窠 窠 窠 窠 C-2 §, 4 § 1 B-2§, 4§ A-2 §, 4 § D -2 §, 4 § A-2 §, 4 § B-2§, 4§ A-2 §, 4 § 000D 00D < N ό B-2§, 4§ ί D-2§, 4§ 000 inches Λ 000 (N < 2- [4- (3-chlorophenyl) -2-oxy-1-pyrrolidinyl] butanimidine 2- [4- (3-chlorophenyl) -2 -Oxy-1-pyrrolidinyl] butanamine 2- [4- (3-chlorophenyl) -2-oxy-1-pyrrolidinyl] butanamine 2- [4- (3-chlorobenzene ) -2-oxy-1-pyrrolidinyl] butanylamine 2- (4-ethynyl-2-oxy-1-pyrrolidinyl) butanidine 2- (4-ethynyl-2-oxy Yl-1-pyrrolidinyl) butanilamine 2- [4- (2-fluorophenyl) -2-oxy-1-pyrrolidinyl] butanilamine 2- [4- (2-fluorophenyl) -2-oxy-1-pyrrolidinyl] butanamine 2- [4- (2-fluorophenyl) -2-oxy-1-pyrrolidinyl] butanamine 2- [4- (2- Fluorophenyl) -2-oxy-1-¾pyridinyl] butamidamine 1 m 2 1 CN m η- slightly fermented 4 m V)-. ”R—. 3 Pan 202 203 1 204 1 20 5 206 207 208 209 210 211 212 • 120- 200538435

-121 — 200538435

ρ—-π 〇〇 (NU ~ J r-η 〇 \ CN 〇Ί 寸 inch v〇tH TH tH r rH m 00 VO d 〇 > »n 6s < N rH VO inch On m rH (N vd 〇 rH 00 Li.… CN • fl · Two · 鹚 < N 狯. — CS • F- < · csi ^ — 鹚 cs Li.… CN • fH # csi ^ oi 狯.… < N < N m r > im 窠 mm 窠 窠 窠 窠 coo gas CN free coo 乂 < N PQ 000 gas CO CN < 〇〇〇oT (N Royalty free coo gas C / T < N PQ coo inch one (yT CN < 000气 αΓ cs < 000 inch office CO free go " qi C / T (N CO ^ 000 PQ swallow 1 r—4 1 i 1 rH 1 1 K 1 Λ secret plate a ν η ^ 1— * & slightly Pan sn swallow 1 τ * Η «Secret Mist < N m outfit 1 1 &N; N person you 〇Q m ^ mn swallow 1 rH m 嫲 1 < N s E first» CS 4 S Λ OO OO '~' 3 Weight n 砮 1 i-rH m Ilf (N Ϊ E: 綦 1 cs 4 ^ C / D 1—-1 m 砮 1 ι * · Η «I (N lake ffi- ii s- 4 mvm 1 h C / D '~~' d weight H Ϊ m is I swallow 1 i— (Secret 1 < N Λ IE 嫂 1 1 < N 譲 c 譲 η Swallow 1 τ-Η 1 Ϊ Secret »cs ^ 1 Λ *: l Λ Η in 1— '3 slightly pan 砮 1 rH 1 m κ slightly nf 1 m ilff a 狴 Λ Η GO 1--1 3 slightly alkaline 1 CS 毅 yi) 1 1 00 inch you Λ Η GO 1 ~ 'Cl «n slightly Hi 1 < N i E m -tHs 1 1 rf /-> v 00 sm ^ 5 Λ H 00 '1 cn CN (N inch CN < N CN (N Ό CS < N CN < N OO CN (N (N CS Ο m CN rH m CN < N m < N -122-

200538435 m

[31] [32] [33] [34] 1 1 133.0 74.9 84.8 137.2 137.3 112 窠 m racemic racem m 窠 窠 m 窠 窠 Pi inch. Coo ζ / Γ ^ (Ν I PQ coo 气 00 CN FREE A-2,4 Qi < N CQ coo and αΓ < N FREE00 Qi Pi < N Ρύ Qi < s A-2 §, 4 § B-2§, 4§ C-2§, 4 § (2S) -2-[(4R) -4- (2-hydroxypropyl) -2-oxypyrrolidinyl] butanamine Λ Na I CN 5 1 Η 1 Plastic < N »> w / r ~ l Λ m 1 CN s minus HI 1 \ 〇inch plate ^ mmh? Iv ^ i 砮 1 1 CN it m Hi 1 < NS roll n in 1 inch trend__ Wi Η S 5 ig v Ϊ 2: 砮 Second Secret 1 cs i 1 rH i ώw 7 狴 Squat inlaid il ts Lake has been intelligent / ^ S rH 00 · (2R) -2-[(4S) -2-oxy Methyl-4-propylpyrrolidinyl] butanamine (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-pyrrolidinyl) butanamine 2- (4- Ethyl-2_oxy-4-phenyl-1-pyrrolidinyl) butyramine! 233 234 j 235 236 237 238 239 240 240 241 242 -123- 200538435

361 I 361 229 1 112.2 73.5 58.6 59.7 133.3 68.2 96.4 2 · 1 · 2 · then 1 2.2. 6.2 · 2 · then 6.3.1. 6 · 2 · 2 · then 6.3.1. Mm 窠 mixture mixture 窠 m 窠 D -2§, 4§ A-2R, 4 § A-2 §, 4 § B-2§, 4§ CN inch office (N Pi gas C / Γ CN A-2S, 4§ 1 000 gas • C / Γ CN < coo 气 GO CN PQ 2- (4-ethyl-2-oxy-4-phenyl-1-pyrrolidinyl) butanamine η 1 rH m Secret 1 (N ϊ Secret fr it 2- [4- (methoxymethyl) -2-oxy-1-¾pyridinyl] butanilamine 2- [4- (methoxymethyl) -2-oxy-1-pyrrolidinyl] butanyl Amine 1 rH Λ m 1 (N s Se El · t ^ S 1 ¾ H v «^ mi blanket 1 A 砮 1 rH Λ Se 1 (N 5 EE- Se B- 1 inch person embedded« S ^ h V «Ba ya i 塑 a 砮 n Slightly secret 1 (N ϊturn II inch s 铿 Λ Η Ιίΐ 1 ~~ 1 1 r—Η m IE 1 m nf 1 Λ fr X Mod Η Η OQ ^ swallow 1 rH Λ Hf I (N 3 Pack κι u II Α 狴 d: m it 孑 H gya swallow 1 tH m Hff 1 CN 1 m Pack K) Alkali 11 A 铿 d ϋ 4 hr—i Broken slightly 2 243 244 245 246 247 248 249 250 251 252 -124- 200538435 m

261 66.4 i I _I 127.6 116.6 100 100.8 84.2 [1 1 87.8 r— < vo 53.5 1 i 窠 窠 mmmmmm 窠 A-2S, 4§ II _I B-2S, 4§ 1 _1 00 CN A-2 §, 4 § B-2§, 4§ C-2§, 4§ D-2§, 4§ I! Coo gas αΓ < N FREE A-2S, 4§ COD gas CO CN FREE ------ I 2 -(4-ethyl-4-methyl-2-oxy-L.pyrrolidinyl) butanyl I Imidamine i 2- (4-ethyl-4-methyl-2-oxy-1-pyrrole Pyridinyl) butanylamine (2S) -2- (2-oxy-4,4-dipropyl-1-pyrrolidinyl) butanidine amine. Swallow 1 rH roll 1 mm 1 < N m Η- 11 mm swallow 1 τ-Η m 浒 1 can m secret 1 (N E " 11 m 丨 · 丨 _ 31 Λ w 1 m 浒 1 m secret 1 < N Λ 'm ^ t ίί m 1 ίΐ roll 1 can m Secret 1 CN m fr 1 1 ^ t ίί «m swallow 1 τ · Η m κ 1 m na 1 CN Λ fr 4 铿 Λ h 00 C slightly (2S) -2- (3-benzyl-2-oxy- 1-pyrrolidinyl) butyramine (2R) -2- (3-benzyl-2-oxy-1-pyrrolidinyl) butyramine 253 255 256 j 257 258 259 260 261 262 263 -125- 200538435

418/420 / 422 227 1____________ 275 1_ 173.2 110.9 103.9 87.4 146.6 56.8 6.4.1. 2.4.2. 6.4.1. 6.4.1. Mixture mixture mmm: Mixture mixture 窠 coo inch office < N gas CN A-2S , 4§ A-2S, 4§ 000 inch office ot CN PQ coo gas CO CN <; 00 1 Α-2,3 § | B-2,3§ 000 gas GO CN <: 2- [4- ( Molybdenyl) -2-oxy-1-zirconyl) Butanidine m chain I slightly (NSK Jii II 1 S Η Α slightly secret 1 CN 1 ϊ goose Π I inch < N class window Ε〇 5 darts fi 4 η a ^ 会 专 (Ν I— * 1 η 砮 1 rH FREE m 1 < N i N] Λ H 00 1 ~ 1 knot I 砮 slightly 嫲 1 CN 1 3 install N3 Huan 11 it CN W / —NO) dn (2S) -2- (4-ethynyl-2-oxy-1-pyrrolidinyl) butanamine (2S) -2- (3,3-diethyl-2- Oxy-1-pyrrolidinyl) butanamine 2- (3-benzyl-3-methyl-2-oxy-1-pyrrolidinyl) butanamine 2- (3-benzyl-3-methyl Yl-2-oxy-1-pyrrolidinyl) butanamide 1 Λ 嫲 1 (N m s- 1 Γ〇 «rA 狴 ί: g Λ Η C / D ^ C weight 264 265 1. .1 266 267 268 269 270 271 272 273 _126- 200538435

Swallow 1 r—H m Hf 1 rs 5 宓 m 1 CN n ^ fr m; bu 1 ▼ < m secret 1 < N 5 m 1 (N paste mm K) H i 5 ina acne swallow 1 rH m secret 1 < N 5 Zem 1 CS base _ i Η »i WA Panm swallow 1 m Secret 1 cs S Zem 1 1 < N cA _ Ϊ t A slightly 1 m Secret 1 (N 5 m 1 (N EB- m 4 hi W ^ mm QI K 1 ▼ -H 1 m HI 1 mmd; ^ mtw _ ^ m (N t—i 1 n — S 11 r " H 1 free 嫲 ^ m Λ HC / D '— ·' d «1 rH mk € 1 (N i 琪 K)« nf S mhn 塑 塑 1 rH m Jiff 1 < N s H 1 rH 1 Just a little. Hall ti _ A Aά ^ n. Swallow 1 r—H Secret 1 (N h- Λ H 00 '~' Added 274 < n t > CN VO t > (N N 卜 &N; OO t- »CN 〇 \ r > oa o 00 (N rH 00 CN CN 00 (N m 00 cs -127-200538435

259 284 257 355 I 1 265 | 276 281 319 305 229 1.3 丄 then 1.3.2. 1.3.1. Then 1.3.2. 1.3.1. Then 1.3.2. 1.3.1. Then 1.3.2. 1.3.1 Then 1.3.2. 1.3.1. Then 1.3.2. 1.3.1. Then 1.3.2. 1.3.1. Then 1.3.2. 1.3 丄 then 1.3.2. 1.3.1. Then 1.3.2. Mixture mixture mixture mixture mixture mixture mixture mixture mixture (N inch ri inch · CN ri inch "(N (N CS CN A m η acne 1 f— < m E: 1 5 ivh " slightly W fig fr 撵 1 1 mmm Secret 1 1 (NS radium slightly ΓΓΤ ^ £ m «Ban i — 狴 slightly ... inch 1 1 m Secret _« g ning_w — 铿 slightly m te fr 4! im 4 Secret E 1 Price 1 < Ν I CN inch ^ 4 mother W a ^ ig two v X m swallow 1 rH Λ 1 m secret I (N ^ 1 CN s T inch 1: 1X1 A \ _ 31 \ rp C ^ rAAc砮 1 m 1 m 1 in 砮 1 i-Η Λ E inch {cup 1 CEU w £ i slightly ^ nm 1 m 1 m 1 im swallow 1 tH Λ r inch you 1 ΠΧΙ w £ dwa 宓 3- (flat oxygen) -2- (2-oxy-4-propyl-1-¾ slightly steep) butanamine 3- (benzyloxy) -2- (2-oxy-4-propyl-1-pyrrolidinyl) Propylamine 4-hydroxy-2- (2-oxo 4-propyl-1-pyrrolidinyl-piperidinyl) butoxy Amides 284,285,286,287,288 289,290,291,292,293 -128-200538435

215 On them (N rH (N CO tH r〇On r-H m BU 00 cs BU & N ON CN (N 〇rH 00 CN 1.3.1. Then 1.3.2. 狯 Η cn "▼ -H tH 黎cs: ▼ -H two ^ ΓΛ ^ cn-狯 Η — · ^ -i — · T ^ i rJ cn “tH Ban- ^ ro — rH — · -i — rH 1 mixture i < Π < Π m loose 4Π m < Π 蜉. M < Π m < Π < n 蛑 < Π m inch office < N and (N CN inch office CN CNλλ CN inch economy < N 乂 inch office CN inch office ΓνΓ Inch Office (N Inch CN 3-hydroxy-2- (2-oxy-4-propyl-1-pyrrolidinyl) propanamide IrH Λ Ε: I m Na 1 (N 1 CS slightly 铿 sg mm ιέ, ϊ N ig X i swallow 1 Λ K 1 m surface 1 CN butterfly 1 铿 遁 铿 遁 Jf S IX i κ 1 m secret 1 1 (N Sg ™ fe y ^ t «s {g 鹏 逆 El · 运έ — cA m slightly 1 m 1 1 CS ϊ 撵 ja ii! £ slightly h η m ^ 濉 苕 1 ΓΟ 1 m K 1 Secret 1 already 1 (S a little you; ^ s ί Ϊ 1 paninac S # 1 1 CO tH 1 r—H m K 1 mm 1 d 1 CN / — · N mb ^ im ig frac 4 ^ Swallow 1 T—t) Ε I m secret 1 < N 1 CN ϊ _ 狴 m μ _ h 5: Slightly 4 Λ. M 1 1 CN ^ i tii S r—i fCi. «S 5: n Slightly m ^! 2 Λ ^ IE 1 1 m inch sn swallow 1 τ- ^ Η Λ E 1 w Ilf 1 CS 1 CN n [Ώ punish brewer rA E: 294 〇 \ CN v〇ON CN bu Cs < N 00 ON Cn Ch < NO om rH O cn (N 〇cn m 〇m -129- 200538435

227 267 _1 239 239 255 241 316 331 320 289 i 1.3.1. Then 1.3.2. 1 · 3 · 1. Then 1.3.2. 1 丄 1. then 1.3.2. 1.3.1. Then 1.3.2 1.3.1. Then 1.3.2. | Ϊ́.3 · 1. Then 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 i Mixture Mixture Mixture Mixture 1 1_ Mixture Mixture Mixture Mixture 1 Gas CN (N inch office CN inch CN inch << CN inch office &lt; N inch office gas CS gas cs CN --j 2- (2-oxy-4-propyl-1-pyrrolidinyl) pentamidine 1 1 2-cyclohexyl-2- (2-oxy-4-propyl-1-pyrrolidinyl) acetamidine 3-cyclopropyl-2- (2-oxy-4-propyl-1-pyrrolidinyl) propanamide Λ weighting τ-Η m 1 ^ m butterfly 1 terminal B- ^ 1 1 inch inch 5- Methyl-2- (2-oxy-4-propyl-1-pyrrolidinyl) hexamidineamine 2- (2-oxy-4-propyl-1-pyrrolidinyl) hexamidine 1 swallow 1 τ-Η m 1 11 1 &lt; N 1 5 ^ 浒 _ S s η K 1 m 11 1 &lt; NS ^ »i slightly IE base 2 1177 m SI 1 1 T-1 砮 1 rH ii E: 1 m base 1 1 &lt; N 1 s ^ 揪 譲 mg mg 饀 butterfly 1 i cA ^ 2- (2-oxy-4-propyl-l- strong (Deepyl) -4-phenylbutanamide 304 305 i 306; ί 1 307 308 309 310 311 312 313 -130- 200538435

379 τ-Η On CM 〇rH m (N m 〇 \ 00 &lt; N m C \ CA m OS CN m Os CN rH r * H m 1.3.1. And then 1.3.2. Avoid T—H carbonyl H cn — RH CO-r »H I · ^ cn ^ T—H rn — m two ^ cn — cn-i &quot; H two ^ CO-iH m -r &lt; T) — mixture 蜉 &lt; nm &lt; ίπ 松 m · Loose 4π m &lt; □ &lt; Π &lt; ia &lt; Π betting gas CS gas ci ci ri gas cs inch CN gas ci and cs gas cN gas cs gas &lt; N m 1 secret 1 1 &lt; N slightly _ Complement E | S Wang · Take s ^ 1 1 m τ— * 砮 1 1—Η m κ 1 m Na 1 d 1 (N s ^ _ m IE i paste c; m # 1 rH ώ IE 1 m domain ： 1 CL 1 CS S s mg a-slightly im 1 1-H 1 m secret 1 1 &lt; N «^-^ 1 m 浒 IE -g two nd ^ cA swallow n knot I daddy 1 rH K 1 m Alkali 1 CN ^ 1 CN Slightly dish two K a 3 葚 1 rH Wl K 1 m Secret 1 1 &lt; N s ^ Rolling crocodile slightly ggin cAacin I swallow 1 rH κ 1 FREE u 1 d 1 CS 5 ^ 浒 濶ϋ j ^ s ^ an swallow 1 rH m K 1 m secret 1 rj ^ 1 &lt; N 5 ^ 枨 _ i W cA mf 1— &lt; mr 1 m 嫲 i CN 1 (N 1 butterfly 1 铿Wu d slightly c; η 砮 1 τ—Η m ε 1 ii m 1 1 (N fm tT \ trip «s 11 4« d: Pan 314 H cn VO t—H cn BU r—Η c〇 00 r-H CO 〇 \ t-H m O CS ro t-H (N CO CS CN m cn CN m 131- 200538435

354 Ο inch ON 〇CO a \ 〇ΓΛ On 〇〇〇 \ CS 00 CN CS 〇 \ 00 inch 00 &lt; N 1.3.1.then 1.3.2. Li Li-^ cn — ^ Η 狯 H cn ^ rH &lt; rj — vH rn ^ tH m ^ τ-Η class — · ^ m: — rH 狯 Η — · ^ -i two r—ί rn H mixture &lt; Π m &lt; ίπ Si &lt; ίπ m &lt; Π m &lt; ίπ 松 4π m 松 赖 气 CN 气 eNinch λ ri &lt; N qiri inch ri inch &lt; N qi CS inch cn CN swallow 1 τ-Η me 1 m Secret 1 1 &lt; N 枨 _ M gi 械 cA η swallow 1 r «H Λ ΙΕ I can m secret 1 d 1 CN is 浒 娘 f E s _ cA m swallow 1 τ * Η ίΐ 1 m secret 1 1 (N 5 ^ 浒 娘 i slightly cA m dad 1 rH m K 1 Kem Secret window 1 (N 1 i ^ i_ iw cA m swallow 1 r »H κ 1 Kem Secret I 1 &lt; N is g gd supplement cA m # 1 rH m K 1 T mm I 1 &lt; N 1 5 ^ mg_ mg plate supplement sn cA acne. i η II daddy 1 1—Η FREE κ 1 m 嫲 1 CS 1 CN m 铿 狴 4 m 锴 顦 ϊ w _ wm {m 5 gmt 1 iH person_ slightly} E 狴 4 f «n« w CN 1 B A flat Z mm 1 ^ H ή 1 Λ 1 (Ν I &lt; N 5 Zn ^ -m slightly ^ «2; swallow 324 cs m ν〇cs (N CO 00 CN m Os (N cn O m cn i—H cn m CN m m -132- 200538435

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. 1.3.1.1. Then 1.3.2. 1.3.1. Then 1.3.2. Ι.3.1. Then 1.1.3.2. 1.3.1.1. Then 1.3.2.1.3. 1. Then the mixture mixture mixture 1 _i mixture 1 _i mixture mixture mixture mixture mixture inch r \ CN 2,4,4 2,4,4 inch inch &quot; 3a, 4,6, a, 2,4 &lt; N Inch, &gt; CN inch λ CN inch r \ IT »1 m E: 1 Λ secret 1 1 &lt; N S ^ you TO ^ m slightly ru 鼷 S m ™ S _ vi da 2,5- 贰 (2- oxygen -4-propyl-1-pyrrolidinyl) pentamidine amine 丨 2,4-fluorenyl (2-oxy-4-propyl-1-pyrrolidinyl) butanamine 1 rH m 1 «1 ¥ i ¥ S «S ^ 5 r—ι i ^ i— * 4 m ^ (^ 你 TO r ^ jg £ w ra I ^ s FREE E ^-slightly 逵 1 _ 铿 _ m« g K ά-t 佥 — _ rt iif d i i vo cs 5-Amino-2- (2-oxy-4-propyl-1-pyrrolidinyl) pentamidine • Acetone 1 FH m κ 1 d 饀 CN K-赃 盘 cA W '117 ^ «S 狴 W c; η swallow 1 rH m can be stolen, and 4 fr paste; a little S SS fr frSi m τ a slightly 1 | 17 ^ ^ m ϊ Cape CCCJ I 冏 "6-amino-6-oxy-5- (2-oxy-4-propyl-1-pyrrole 1 333 334 1 335 336 337 338 339 340 341 342 -133- 200538435

298 352 482 243 325 339 297 282 225 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. 1.3.1. Then 1.3.2. 1.3.1. Then 1.3.2. 1.3.1. Then 1.3.2. 1 1.3.1. Then mixture mixture mixture mixture Mixture mixture mixture mixture mixture gas CN cs inch Nm inch gas inch inch gas CN gas &lt; N pyridyl) hexylaminomethyl 2-chlorobenzyl ester 1 rH 1 secret 1 1 (N slightly 锴 mg! SS vi n in u_t 1 VO 1 二 盘 r Ε Α 发 嫲 略 ά m Λ κι # my IE inch · tg «Φ cs mv T &lt; N a 丄 3 mfgi« «〇]« g «7 -4-Oxy-3- (2-oxy-4-propyl-1-brazoridinyl) butyric acid I swallow 1 Λ E: 1 can be secreted 1 m nj carboxaldehyde 4 via 4 η swallowed 1 rH m κ 1 FREE m 1 T ® Slightly 03 Jif m; S «S 狴 Swallow up 1 1—1 1 Secret 1 T distilling slightly E ui 2 A 氍« S _ Slightly ^ 1m 1 ro ϊ Swallow 1 rH m ^ 4 ^ 1 U? 7 m ^ Secrets τ 1 ^ $ 4 &lt; NW 2- (2-oxy-4-propyl-1-¾pyridinyl) -4-pentene 醯 343 344 345 346 347 348 349 350 3 51 -134- 200538435

314 1 229 _ί 259 275 381! 256 1.3.2. 1 · 3 · 1 · then 1.3.2. 1.3.1. Then 1.3.2.! 1.3.1. Then 1.3.2. 1.3.1. Then 1.3. 2. 1.3.1. Then i 1.3.2. 1 · 3 · 1 · then 1.3.2 mixture mixture mixture mixture mixture i mixture inch Λ 3R, 2,4 _ί inch r \ CN ri CN cs swallow 1 τ-Η m E: 1 m 1 CL 1 CN f disk free C ^ 砮 1 rH m E 1 m 11 1 (S ΐ ® 砮 tc 湖 砮 1 1-H m K 1 mw 1 1 CN h _ ϊ 4 ^ 2- (2-oxy-4-propyl-l-strongly steep group) -3-benzylpropanamide 砮 1 m κ 1 m 1 1 (N slightly you ft s Ul ^ C Slightly im 6-amino-2- (2-oxy-4-propyl-1-¾pyrryl) hexylamine 1 1-H Secret I (NS M li HI d _ 4 Η Α slightly 1 τ- Η A m window cs i K) Huan II 1 (N 彳 disc mm φ H i _ ^ n ά ^ 1 τ-Η mm 1 &lt; N s Kl minus II 1 CN goose_ i slightly 蛉 352 353 1 354 355 356 357 358 359 360 -135- 200538435

Solvent DMSO DMSO DMSO DMSO DMSO DMSO i- 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 (m, lH ); 3.50-3.70 (m, 5H, partially overlapping with the solvent); 4.45 (dd, lH); 6.9G (s (width), 1H); 7.3G (s (width), 1H) · 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); 1.4 (M.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 (t? 3H); 1.20 (d, 6H); 1.40-1.65 (m, lH); 1.75-1.90 (m, lH); 2.15 (dd, lH); 2.35-2.55 (m, lH); 2.55 (d, 2H); 2.95 (s, lH); 3.30 ( m, lH, and Agent overlap); 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); 1.75-1.95 (m, lH); 2.10 (dd, lH); 2.45 (dd, lH, partially overlapping with the solvent); 2.75 (m, 1H); 3.20-3 · 50 (ιη, 5Η , And the solvent partially overlap); 4.30 (d, 2H); 4.45 (dd, 1H); 6.90 (s (width), 1H); 7.35 (s (width), 1H) · 0.80 (t, 3H); 1.40- 1.60 (m, lH); 1.70-1.90 (m, lH); 2.20 (dd, lH); 2.45 (dd, lH); 2.60 (m, lH); 3.25 (m, lH, J | 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), lH); 9.20 (s, lH) ... 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 number r-i Ξ Ξ gs -136- 200538435

DMSO DMSO DMSO DMSO DMSO DMSO CDC13 CDCI3 τ—Η ι &lt; • «\ κ WV ο &quot; see rs ffi rH fi o 'rH BU • • #s ΓΠΛ 1 inch · § &lt; N o' CO cn 5? Τ · Η ， W fi SI § 1 s ιώ ^ ό 1 g ^ 1 T i fit inch Λ OO 00 once 5 g. S ^ &amp; ΐ i | * ® * # i § 2 atri ilmll § 1 P 5 3 Q 111 bu ro O 2 ^ 2 inch S 4 V go! gt Hi ά ^ χ.φ 〇5 ^ 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 solvent! f); 3.70 (m, lH); 3.90 (dd, lH); 4.50 (dd, lH); 6.90 (s (width), 1H); 7.10 (d, lH); 7.20-7.40 (m, 2H); 7.50 (d, lH). 0.80 (t, 3H); 1.50-1.75 (m, lH); 1.80- 1.95 (m, lH); 2.45 (dd, lH, ffl ^! Lfi #); 2.75 (dd, lH); 3.40-3.80 (m, 3H), 4.45 (dd, lH); 6.90 (s (1;) 51H); 7.20-7.25 (m, 5H). 0.80 (t, 3H); 1.50-1.75 (m, lH); 1.80-L90 (m, lH); 2.45 (dd, lH, overlap with solvent); 2.75 ( dd, lH) ;, 3.15 (dd, lH); 3.65 (m, lH); 3.95 (dd, lH); 4.45 (dd, lH); 6.90 (s (width), 1H); 7.10-7.25 (m, 3H), 7.30-7.50 (m, 2H) · 0.80 (t, 3H); L55-1.70 (m, lH); 1.80-1.95 (m, lH ); 2.55 (dd, lH, overlap with solvent); 2.75 (dcUH); 3.30 (m, lH ,, overlap with solvent); 3.70 (dd, lH); 4.50 (dd, lH); 6.95 (s (wide) , 1H); 7.30-7.70 (m, 10H). 0.85 (t, 3H); 1.60-1.75 (m, lH); 1.75-1.95 (m, lH); 2.55 (m, lH, overlap with solvent); 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) · i 0.90 (t, 3H); 1.20 (s, 3H); 1.60-1.80 (m, lH); 1.80-2.10 (m, lH); 2.40 (dd, lH); 2.50-2.60 (m, 3H, overlap with solvent); 3.20 (m, lH); 3.50-3.70 (m, 3H); 4.45 (dd, lH); 5.45 (s (width), 1H); 6.30 (s (width), 1Η) · 1.05 (t, 3H); 1.60-1.75 (m, lH); 1.90-2.20 (m, lH); 2.70 (dd, lH); 3.80 (m, 2H); 4.45-4 · 50 (π, 2Η); 5.30 r ^ n L—1 r—i TH rH S 'tH rjn 51 U ~ l 137- 200538435

DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO 1 cdci3 Ο Κ τ · Η ® tH R 0.80 (t53H); 1.50-1.65 (m, lH); 1.75-1.90 (m, lH); 2.25 (dd, lH); 2.55 (s , 3H); 2.75 (m, lH); 2.90 (m, 2H); 3.20 (d, 2H); 3.3 (m, 3H, 3.5 (dd, lH); 4.05 (dd, 1 ^ 1H); 4.35 (dd3lH ), 1 6.95 (s (width), 1H); 7.35 (s (width), 1H) · 0.80 (t53H); 0.90 (t, 3H); 1.30-1.70 (m, 3H); 1.70-2.00 (m , 2H); 2.10-2.40 (m, 2H); 2.90 (dd, lH); 3.60 (dd, lH); 4.30 (dd, lH); 6.90 (s (width), 1H); 7.30 (s (width) 1H) ·. 0.80 (t, 3H); 0.85 (t, 3H); 1.30-1.70 (m, 3H); 1.70-1.90 (m, lH); 2.00 (dd, lH); 2.20 (m, lH) ; 2.45 (dd, lH); 3.15 (dd, lH); 3.45 (dd, lH); 4.30 (dd, lH); 6.90 (s (width), lH); 7.30 (s (width), 1H). 0.80 (t, 3H); 1.45-1.55 (m5lH); 1.60-1.95 (m, lH); 2.1 (dd, lH); 2.45 (dd5lH) ;, 2.55 (m, lH); 3.0 (dd, lH); 3.4 (dd, 2H); 3.6 (dd, lH); 4.30 (dd, lH); 7.80 (s (width), 1H) ·· 0 · 00-0 · 005 (m, 2H, overlap with TMS); 0.40- 0.55 (m, 2H); 0.55-0.70 (m, lH); 0.85-1.00 (t, 3H); 1.25-1.55 (m52H); 1.60-1.85 (m, lH); 1.85-2.05 (m, lH); 2.05-2.30 (m, lH); 2.35-2.70 (m, 2H); 3.10 (m, lH); 3.55 (m, lH); 4.45 (dd, lH); 5.45 (s (width), lH); 6.20 (s (width), 1H) · 0.95 (t, 3H); 1.60-1.80 (m, lH); 1.90-2.10 (m, lH); 2.60-2.70 (m , 2H); 3.45 (dd, lH); 3.65 (m, lH), 3.80 (dd, lH); 4.50 (dd, 1H); 5.40 6.00-6.20 (m, 2H); 6.30 (d, lH); 7.45 (d, lH). 0.95 (t, 3H); 1.60-1.70 (ιχι51Η); 2.00-2.10 (m, lH); 2.60 (dd, lH); 2.85 (dd, lH); 3.40 (m, lH); 3.40-3.80 (m, 3H); 4.50 (dd, lH); 5.40 (s (width), 1H); 6.10 (s (width), 1H); 6.15 (d, lH); 6.35 (d, lH); 7.40 (d, lH) ·, 0.80 (t, 3H); 1.60-1.70 (m, lH); 1.90-2.10 (m, lH); 2.25 (s, 3H); 2.60 (dd, lH); 2.80 (dd , LH); 3.30-3.60 (m, 2H), 3.75 (dd, lH); 3.95 (dd, lH); 4.50 (dd, lH); 5.50 (s (width), 1H); 6.30 (s ( Width), 1H); 6.90-7.10 (m, 3H), 7.20 (dd, lH) ·! So rH L * _t L ^ —J r ^ i (Nr r—ί p—n CN &lt; N. P— 1 m CN, ryn (Ni r-1 (N -138- 200538435

CDC13 DMSO cdci3 DMSO DMSO CDC13 DMSO DMSO CDC13 0.90 (t, 3H); 1.60-1.70 (m5lH); 1.85-2.10 (m3lH); 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 (m, lH); 2.50-2.90 (m, 2H); 3.20-3.40 (m, lH, overlapping with the solvent); 3.50-3.80 (m, 3H); 3.95 (dd, 1H of one of the diastereomers); 4.45 (dd, lH); 6.90 ( s (width), 1H); 7.30 (s (width), 1H); 8.70 (d, 2H); 9.15 (d, lH). 0.95 (t, 3H); 1.60-1.70 (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 (dcUH); 2.40 (dcUH); 2.60 (m, lH); 3.05 (dcUH); 3.25 (s, 3H); 3.30 (m, 2H), and solvent part Overlapping); 3.55 (dd, 1H); 4.30 (dcUH); 7.05 (s (width 7.40 (s (width 0.80 (t53H); 1.41-1.63 (m5lH); 1.71-L86 (m, lH); 2.12 ( dd, lH); 2. 43 (dd, lH), 2.82 (m, lH); .3.2-3.4 (m52H); 4.23 (d, 2H), 4.31 (dd5lH), 6.97 (s (1;) 51H), 7.31 (s®, lH ), 7.94 (s, lH), 8.5 (s, lH). 0.84 (t, 3H); 1.60-1.72 (m5lH); 1.86-1.98 (m, lH); 2.78 (dd, lH); 3.0 (dd, lH); 3.42 (dd, lH), 3.98 (dd, lH) 4.53 (dd, lH), 5.08 (m, lH), 5.58 (s (width), 1H), 6.21 (s, 2H), 6.25 (s (Width), 1H), 6.73 (s, lH). 0.83 (t, 3H); 1.52-1.70 (m, lH); 1.70-1.84 (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, 1H); 1.80-1.94 (m, lH); 2.5 (mM DMSO MS), 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 (t, 3H); 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) ... (N l—lr ^ i (N gr—n On r〇ir—-i cni r—i CO rnt -139- 200538435 ·

GC / M M + 286 LC / M MH + 259 259 mm mm COO rH 〇〇〇 &lt; N 1-H OQ 00 — PQ &lt; ^ T CO rn distillation κ K] K] &lt; N (趑 氍 氍 饀 m ra s K Ε 03 Ϊ s Ϊ Slightly &amp; l · l · fr EE- ii ii r · r—n 簦 g —r—1 瞾 slightly 5 S slightly 5 £ ggturn gg OSS w 氍s S pLi 鼷 鼷 kt kt slightly feed HH § mg S g § 1 rH 1 tH II slightly 1 rH 1 r— * 4 1 K / l 1 / ^ N CO 1 C / D ^ Si cm C -® II Jumping DTI? Three Classics, Three Classics ^ 4 ^ 1 1 Three Classics, π cA mc; ® 着 — ΓΟ c; a cA distillation &lt; n ^ iH &lt; &lt; 1 ί -140-

Claims (1)

200538435 · X. Scope of patent application: No. 90 1 05 824 "(2S) -2- [4- (2,2-difluorovinyl) -2-oxypyrrolidin-1 -yl] butanoic acid and "Use" application for patent division (1) Patent application scope (Amended in July 1994) 1. A compound, which is (2S) -2- [4- (2,2-difluorovinyl) -2-oxo Pyrrolidin-1-yl] butanoic acid and its stereoisomers. 2. The compound of the scope of application for item 1, which is a (4R) diastereomer. 3. The compound according to item 1 of the scope of patent application, which is a (4S) diastereomer.黍 — * 141 — i