TW200538437A - (2S)-2-[2-oxo-4-propylpyrrolidinyl]butanamides and their uses - Google Patents

Abstract

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

Description

200538437 · 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 62 036 B1 discloses the compound (S) -α-ethyl-2-oxy-1-pyrrolidinacetamidine, which has the international non-exclusive name levetiracetam 〇 Levetiracetam is a L-compound that has been disclosed as a protective agent for the treatment and prevention of hypoxic and ischemic injuries of the central nervous system. This compound is also effective in the treatment of epilepsy, for which the d-enantiomer (R)-α -ethyl-2 -oxy-1 -pyrrolidinacetamidine (also Patent case No. 0 1 65 9 1 9 (B1) is completely lacking in activity (AJ. GOWER et al., European Journal of Pharmacology, 211, (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-pyrrolidinacetamidine derivatives. European Patent No. 0 645 1 39 B1 discloses the anxiolytic activity of levetiracetam. PCT Application No. PCT / EP00 / 11808 discloses the use of levetiracetam for the treatment and / or prophylactic treatment of bipolar disorders, migraine, chronic or neuropathic pain, and levetiracetam with at least one A combination of compounds that induces a neurosuppressive effect by the GABAa receptor mediator. Unexpectedly today, certain levetiracetam analogs, particularly compounds with further substitutions in the pyrrolidone ring, have been shown to significantly improve the treatment. 200538437 [Summary of the Invention] In a feature aspect, the present invention provides a compound having formula I Compound or pharmaceutically acceptable salt thereof

Where X is-CAMW or -CAWR7 or-CA1-!? 8 or CN; A] and A2 are respectively oxygen, sulfur or _NR9; 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, nitroxy 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. R2a, R3a and R4a are the same or different and each is hydrogen, halogen atom, alkyl, alkenyl, alkynyl or aryl; R5, R6, R7 and R9 are the same or different and each is hydrogen, hydroxyl , Alkyl, aryl, heterocyclic or oxygen derivatives; and R8 is hydrogen, hydroxy, fluorenyl, halogen, alkyl, aryl, heterocyclic or fluorene derivatives; but 1,2,1,3,1 ^, 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 methyl 'ethyl Group or propyl, take 200538437 # # on the pyrrolidine ring instead of mono-, di- or tri-methyl or mono-ethyl; and when R ^ RW,! ^, R3a and R4a are each hydrogen, When A2 is oxygen and X is CONR5R6, R3 is not carboxyl, ester, amido, substituted oxy-pyrrolidine, hydroxyl, oxygen derivative, amine, amine derivative, methyl, naphthyl, phenyl selectivity Substituted by an oxygen derivative or substituted by a halogen atom at the para position. In the following definitions, unless otherwise stated, R11 and R13 are the same or different and each is a fluorenylamino, alkyl, alkenyl, alkynyl, fluorenyl, ester, ether, aryl, aralkyl, hetero A cyclic or oxygen derivative, a sulfur derivative, a fluorenyl derivative, an amine derivative, a sulfonyl derivative or a sulfinyl derivative, each optionally substituted with any appropriate group, including but not limited to one or more A moiety selected from a lower alkyl group or other groups described later as alkyl substituents. The term "oxy derivative" is used herein to be defined to include the -0-R11 group, where R11 is as defined above, except for "oxy derivative". Non-limiting examples are alkoxy, alkenyloxy, alkynyloxy, fluorenyloxy, oxyester, oxamino, alkylsulfonyloxy, alkylsulfinyloxy, arylsulfonyloxy Group, arylsulfinyloxy, aryloxy, aralkoxy or heterocyclicoxy such as pentyloxy, φ 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, alkynylthio, and arylthio. The term "amino derivative" as used herein is defined to include -NHR11 or -1214 groups, where 1 ^ 11 and 1 ^ 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 200538437 φ #. This definition includes the formula RU-CO-, where R11 may also be hydrogen as previously defined. Non-limiting examples are methyl, ethyl, propyl, propyl, isobutyl, pentyl, lauryl, heptane difluorenyl, cyclohexanecarbonyl, crotonyl, transbutylene Fluorenyl, allyl fluorenyl, benzyl fluorenyl, naphthyl fluorenyl, furan fluorenyl, nicotinyl fluorenyl, 4-carboxybutyl fluorenyl, oxalyl, acetofluorenyl, cysteamine fluorenyl, oxalophenyl . The term "sulfofluorenyl derivative" is used herein to be defined to include the group -SOyR11, where R11 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 a group of the formula -S02-Rn, where R11 is as defined above, except for "sulfinyl sulfinyl derivative". Non-limiting examples are alkylsulfinylene, alkenylsulfinylene, alkynylsulfinylene and arylsulfinylene. The term "alkyl" is used herein to be defined as having a linear, branched or cyclic moiety or combination thereof and containing from 1 to 20 carbon atoms, preferably from 1 to 6 carbon atoms for acyclic alkyl groups and Cyclofluorenyl is a saturated monovalent hydrocarbon group of 3 to 6 carbon atoms (two of the preferred | examples are referred to as "lower alkyl" unless otherwise stated). The alkyl moiety can be optionally selected from 1 to 5 halogen atoms, hydroxyl groups, mercapto groups, amino groups, nitro groups, cyano groups, thiocyano groups, fluorenyl groups, fluorenyloxy groups, sulfonyl derivatives, and Sulfonyl derivative, alkylamino, carboxyl, ester, ether, sulfonyl, azide, cycloalkyl, sulfonate, sulfonamido, sulfur derivative, oxyester, oxo Amine, heterocyclyl, vinyl, G.5-alkoxy '. Aryloxy and c6.1 (r aryl group substituted by a substituent. Preferred alkyl group is methyl, ethyl, propyl, isopropyl, butyl, iso- or third butyl, And 2,2,2-trimethylethyl, each of which is selectively substituted with at least one 200538437 φ # • substituents selected from the group consisting of halogen atom, hydroxyl group, fluorenyl group, amine group, nitro group and cyano group Substitutions such as trifluoromethyl, trichloromethyl, 2,2,2-tri-chloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl- 2,2,2-trichloroethyl. The term "alkenyl" is used herein to be defined to include having at least one double bond such as vinyl vinyl), 1-methyl-1-vinyl, 2, 2- Dimethyl-1-vinyl, 1-propenyl, 2-propenyl (= allyl), 1-butenyl, 2-butenyl, 3-butenyl, 4-pentenyl, 1 Methyl-4-pentenyl, 3-methyl-1-pentenyl, 1-hexenyl, 2 hexenyl, etc. and optionally selected from at least one halogen atom, hydroxyl group, fluorenyl group Branched and unbranched unsaturated hydrocarbon groups substituted with substituents of the group consisting of amine, amine, nitro, cyano, aryl and heterocyclic groups For example, a - and two - halo vinyl where halo is fluoro, chloro or bromo. The term "alkynyl" is used herein to be defined as containing at least one carbon-carbon reference bond such as ethynyl, 2-propynyl (dipropynyl), etc. and optionally selected by at least one member selected from halogen, hydroxyl, A monovalent branched or unbroken φ branched hydrocarbon group substituted with a substituent of a group consisting of fluorenyl, amine, nitro, cyano, aryl, and heterocyclic groups, such as haloethynyl. When present as a bridging group, alkyl, alkenyl and alkynyl represent straight or branched chains, respectively, cv12 is preferably Ci.4-alkylene or c2. 丨 2-, preferably c2.4-alkenyl or -An alkynyl moiety. -Branch derivatives are known to have bases (such as "n", "second", "iso", etc.) specified by prefixes (such as "n-propyl", "second butyl") unless otherwise stated In positive form. Stomach The term "aryl" as used herein is defined as including an aromatic hydrocarbon consisting of 1 to 3 ring free radicals and containing 6 to 30 carbon atoms via the removal of one hydrogen 200538437

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, amine, carboxyl, ester, ether, amido, azide, sulfonic, sulfoamido, alkylsulfoamido, alkylsulfenyl, alkylthio, oxygen Substituents of ester group, oxamino group, aryl group, C! .6-alkoxy group, c6.1 ()-aryloxy group, CVc alkyl group, and cv6-haloalkyl group are substituted organic groups. The aryl group is preferably $ 瓌 containing 6 to 10 carbon atoms. Preferred aryl groups are phenyl and naphthyl, each of which is selected from the group consisting of treasury, nitro, amine, azido, CV6-alkoxy, CV6-alkylthio, alkyl, and dagger. 6-haloalkyl and phenyl substituted. The term "halogen atom" is used herein to include Cl, Bi, F, I atoms. The term "hydroxy" is used herein to represent the -OH group. The term "锍 base" is used here to express the -SH base. The term "cyano" is used here to express the -CN radical. The term "nitro group" is used in the expression formula -NO at ifcb; the term "nitrooxy group J" is used here: -0N0 The term "amine group" is used here to indicate the formula · NH2 group. The term "azido" is used herein to represent the formula -N3 radical. The term "money base" is used herein to represent the formula -C00H base. The term "sulfonic group" is used herein to represent the formula -S03H group. The term "sulfonamido" is used herein to represent the group -S02NH2. The term "ester group" is used herein to represent a group of the formula -COO-R11. R11 in g is as defined above, except for oxygen derivatives, sulfur derivatives or amine derivatives. The term "ether group" is defined to include a selection. Linear or branched alkyl, or C2_5Q linear or branched alkenyl or alkynyl, or a combination thereof that borrows one or more oxygen atoms -10-

200538437 * The foundation of the sub-chat. The term "amido" is defined to include the formula-[(^ 化 or -⑶ 关!? 11 or -CONRnR12, where RH and R12 are as defined above. The term "heterocyclyl" is used herein to be defined to include as above A defined aromatic or non-aromatic cyclic alkyl, alkenyl, or alkynyl moiety with at least one 0, S, and / or N atomic carbocyclic ring structure, and a selective carbocyclic ring structure One of the carbons may be replaced by a carbonyl group. Non-limiting examples of aromatic heterocycles are pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl φ, imidazolyl, benzimidazolyl, tetrazolyl, quinazole Phenyl, quinolinyl, naphthyridinyl, daphnyl, pyrimidinyl, pyryl, quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl, pyrazolyl, indolyl , Indoloyl, purinyl, isoindolyl, carbazolyl, thiazolyl, 1,2,4-thiadiazolyl, thieno (2,3-b) furanyl, furanopyranyl , Benzofuranyl, benzooxazyl, isoxazolyl, oxazolyl, thiathranyl, benzothiazolyl, or benzoxazolyl, fluorinyl, phthaloyl, quinoxaline Fei Pyridyl, acridinyl, pyridinyl, phenanthroline, phenothiyl, furazanyl, benzodihydropyranyl, indololinyl, xanthenyl, hypothrysin®, pyridin , 5-azacytosinyl, 5-azauridine, triazolopyridyl, imidazopyridyl, pyrrolopyrimidyl, and pyrazolopyrimidyl. These groups are selectively Or substituted as described above for alkyl. Non-limiting examples of non-aromatic heterocycles are tetrahydrofuranyl, tetrahydropyran'yl, hexahydropyridyl, hexahydropyridyl, hexahydropyridyl, Imidazolidinyl, morpholino, morpholinyl, 1-oxaspiro (4.5) dec-2-yl, pyrrolidyl, 2-oxy-pyrrolidinyl, sugar moiety (ie glucose, pentose , Hexose, ribose, fructose may also be substituted) or may optionally be substituted with any appropriate group, including but not limited to one or more selected from lower alkyl groups, or other pre-11-

200538437 Part of the base described in the text for alkyl. The term "heterocyclyl" also includes bicyclic, tricyclic and tetracyclic, spiro groups in which any of the foregoing heterocyclic ring rings are combined to one or two rings, and these ring systems are selected from aromatic rings, cyclohexane rings, A cyclohexene ring, a cyclopentane ring, a cyclopentene ring or other monocyclic heterocyclic ring, or a monocyclic heterocyclic ring here is bridged by an alkyl group such as a quinazidine group, a 7-azabicyclic ring (2 · 2 · 1) heptyl, 7-oxabicyclo (2.2 · 1) heptyl, 8-oxabicyclo (3.2.1) octyl. In the foregoing definition, it must be understood that when a substituent such as R2, R3, R4, R2a, R3a, R4a, R5, R6, R7, Rs is attached to the rest of the molecule through a heteroatom or carbonyl group, the chain is straight or branched Cm is preferred (^ .4 alkylene or C2.12, preferably C2_4 alkenyl or -alkynyl bridge system is selectively inserted between the heteroatom or carbonyl group and the attachment point of the rest of the molecule. X is preferred Examples are-C00R7 or -CONR5R6, where R5, R6 and R7 are preferably hydrogen, Ch4-alkyl, phenyl or alkylphenyl. Preferably X is carboxyl or -C0NR7R6, where R5 and R6 are preferably hydrogen, CV4-alkyl, phenyl or alkylphenyl is particularly -C0NH2. Preferably A1 and A2 are each oxygen. Preferred R1 is hydrogen, alkyl is particularly (^ .12 alkyl is particularly low-carbon alkyl or aryl is particularly benzene Preferred R1 groups are, for example, methyl, ethyl, propyl, isopropyl, butyl, iso- or tertiary butyl, and each of 2,2,2-trimethylethyl selectively penetrates through methylene. The bridge is selectively attached 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. R1 is ethyl R2 and 1-23 are preferably hydrogen, and the halogen atom or alkyl group is particularly a lower alkyl group. 12-200538437 φ #-R2 and R2a groups are each preferably hydrogen, halogen atom, or formaldehyde Methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethyl 'or ethyl substituted with at least one halogen atom', such as trifluoromethyl , Trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloro Ethyl. Especially at least one and most preferably R2 and 1 ^ 3 are hydrogen. Preferably R3a, R4 and R4a * are other hydrogen, especially methyl or ethyl or aryl, especially phenyl or aralkyl, especially Is benzyl. ^ Preferred examples of R3a, R4 and R4a are hydrogen, halogen, or methyl, ethyl, propyl, isopropyl, butyl, iso- or tertiary-butyl, 2, 2,2-, trimethylethyl or substituted with at least one halogen atom, such as trifluoromethyl-yl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl -2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl. Particularly at least one and most preferably both R4 and R4a are hydrogen. 1 ^ 32 special Is hydrogen or an alkyl group, especially a lower alkyl group and most preferably hydrogen. R3 is preferably hydrogen, and Cm-alkyl is particularly (^ .6-alkyl, each of which is selected from one or more selected from hydroxyl groups , Halogen atom, cyano, thiocyano or # alkoxy substituents and are directly or through sulfur, sulfenyl, sulfofluorenyl, carbonyl or oxycarbonyl and selectivity (^ .4-alkylene A bridge, in particular a methylene group is attached to the ring; a C2_6-alkenyl or -alkynyl group, in particular a C2.3-alkenyl or -alkynyl group, each of which is optionally substituted with one or more halogen atoms; an azide group; Cyano group; amine group; condensed group; tri beta group, tetrafluorenyl group, B oxo B fluorenyl, hydrazine Π yl, 1-pyridyloxy, thiomorpholinyl, benzodioxoyl, Furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, or hexahydropyridyl, each of which is selectively selected from one or more halogen atoms, -alkyl, and phenyl Is substituted by a substituent, and is directly or through a carbonyl group 200538437 • a ^ group or -alkylene bridge, especially a methylene group attached to the ring; naphthyl; or phenyl 'phenylalkyl or phenenyl One or more Selected from the group consisting of halogen halide C] · 6 · alkyl, c] .6-haloalkyl, c] .6-alkoxy, c] .6-alkylthio, amine, azide, phenyl, and nitrate The substituents of the group are substituted, and each is attached to the ring directly or through an oxygen group, a sulfofluorenyl group, a sulfofluorenyloxy group, a carbonyl group or a carbonyloxy group and optionally an additional methylene group through an alkylene bridge. It is further preferred that R3 is an alkyl group optionally substituted with one or more substituents selected from the group consisting of a halogen atom, a thiochloric acid group, an azido group, an oxo group, a sulfanyl group, and a phenyl group; Oxy; c2.3-alkenyl or alkynyl are each optionally substituted with one or more halogen atoms or ethenyl; tetrazolyl, pyridyl, furyl, pyrrolyl, thiazolyl or thienyl; or The phenyl or phenylalkane groups are each optionally selected from one or more halogen atoms, 6.6-alkyl, c! .6-haloalkyl, Cj.f alkoxy, amine, azide, The phenyl and nitro substituents are substituted and each is directly or through a sulfonyloxy group and optionally additionally through a Ci.4-alkylene bridge, particularly a methylene group attached to the ring. Other preferred examples of R3 are hydrogen, halogen atom or hydrogen, halogen atom, or methyl, φ ethyl, propyl, isopropyl, butyl, iso- or tertiary-butyl, 2, 2, 2- Trimethylethyl or substituted with at least one halogen atom, such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-di Bromine. Ethyl, 1,1-dimethyl-2,2,2-trichloroethyl. • R3 is especially (^ .4-alkyl optionally substituted by one or more substituents selected from halogen, thiocyanate or azide; C2.5-alkenyl or -alkynyl, each selected It is substituted with one or more halogen atoms; thienyl; or phenyl group optionally substituted with one or more substituents selected from halogen atoms, CV6-alkyl, CV6 haloalkyl or azide.- 14- 200538437 ## Further preferred examples of the R3 group are alkyl and C2.6 haloalkenyl. Preferred R5 and R6 are hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso- Or tertiary-butyl, 2,2,2-trimethylethyl, especially hydrogen or methyl. Especially at least one and most preferably R5 and R6 are both hydrogen. Preferably R7 is hydrogen, methyl, ethyl, propyl Isopropyl, isopropyl, butyl, iso • or tertiary butyl, 2,2,2-trimethylethyl, methoxy, ethoxy, phenyl, benzyl or at least one halogen Atom substitutions are, for example, trifluoromethyl, chlorophenyl. R7 is preferably hydrogen, and methyl or ethyl is particularly hydrogen. R8 is preferably hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso -Or tert-butyl, 2,2,2-trimethylethyl, phenyl, Or a group substituted with at least one halogen atom, such as trifluoromethyl, chlorophenyl. Preferred R8 is hydrogen or methyl. Compositions based on one or more of these preferred compound groups are particularly preferred. Formula I A particularly preferred group of compounds (compound 1A) includes these compounds. Φ A2 is oxygen; X is -CONR5R6 or -C00R7 or -CO-R8 or CN; R1 is hydrogen or alkyl, aryl, halogen atom, hydroxyl , Amine, nitro, chloro; R2, R3, R4 are the same or different and each is a hydrogen or halogen atom, hydroxyl, amine, nitro, cyano, fluorenyl, fluorenyloxy, sulfonyl Derivatives, sulfenyl derivatives, amine derivatives, carboxyl groups, ester groups, ether groups, fluorenylamino groups, sulfonic acid groups, sulfonamido groups, alkoxycarbonyl groups, sulfur derivatives, alkyl groups, and oxo , Oxyester, oxamido, aryl, oxygen derivatives, hetero-15- 200538437 • · Cyclic, vinyl, and R3 can additionally represent C2.5 alkenyl, C2.5 alkynyl or azide Each of them is optionally substituted with one or more halogen atoms, cyano, thiocyano, azido, cyclopropyl, fluorenyl, and / or phenyl; or phenylsulfonyloxy The phenyl moiety may be substituted with one or more halogen atoms, alkyl, haloalkyl, alkoxy, nitro, amino, and / or phenyl groups; most preferably methyl, ethyl, propyl, isopropyl R2a, R3a and R "are hydrogen; R5, R6, R7 are the same or different and each is hydrogen, hydroxy'alkyl, aryl, heterocyclyl or oxygen derivative; And R8 is hydrogen, hydroxy, fluorenyl, halogen, alkyl, aryl, heterocyclyl, or sulfanyl. In these compounds 1A, R1 is preferably methyl'ethyl, propyl ' Isopropyl, butyl or isobutyl; most preferred are 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 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 φ group, and an azide group. Group, alkylthio, cyclopropyl, fluorenyl and / or phenyl; phenyl; phenylsulfonyl; phenylsulfonyloxy, tetrazole, triazole, thienyl, furanyl, pyrrole, pyridine , So any phenyl moiety may be substituted with one or more halogen atoms, alkyl, haloalkyl, alkoxy, nitro, amino 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-

200538437 compounds where X is-CA! NH2,-CA ^ HCh or -CAWiChh; R1 is alkyl or phenyl; R3 is alkyl, alkenyl, alkynyl, cyano, isothiocyanate, ether, carboxyl , Fluorenylamino, aryl, heterocyclyl; or R3 is CH2R1G where R1G is ammonia, cycloalkyl'oxyacetyl, oxygenylsulfonyl, oxyarylsulfonyl, aminoalkylsulfonyl , Amine aryl sulfonyl, nitrooxy, cyano, isothiocyanate, fluorenyl, alkylthio * square thio ', sulfhydryl, fluorenyl, and sulfonium R3a is hydrogen, alkyl or aryl (especially when 1 ^ 3 is hydrogen, R3 is not methyl); or R3R3a forms a cycloalkyl group; and R2 R2a, R4 and R4a are each hydrogen. In the compound of formula I, R1 is preferably an alkyl group, particularly Cl12- is more preferable (^ _6 • alkyl and most preferably ethyl; • 1 ^, 1 ^, 1 ^ 33 and R4a are preferably hydrogen. R3 is preferably selected From hydrogen; (^ .12-alkyl special alkyl, each of which is optionally substituted with one or more substituents selected from hydroxyl, halogen, cyano, thiocyanate or alkoxy, and is directly Or through a thio, sulfinamido, sulfofluorenyl, carbonyl or oxycarbonyl group and optionally additional attachment to the ring via a (4-.4-alkylene bridge, especially methylene; C2.6-alkenyl or -Alkynyl, especially C2_3-alkenyl or -alkynyl, each optionally substituted with one or more halogen atoms; azide; cyano; amido; carboxy; triazolyl, tetrazolyl, pyrrolidinyl , Pyridyl, 1-pyridyloxy, thiomorpholine-17- 200538437 • ·, benzodioxolyl, furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, Thienyl or hexahydropyridyl, each of which is optionally substituted with one or more substituents selected from halogen atoms, c ^ -alkyl, and phenyl, and is directly or through a carbonyl or Cp4-alkylene bridge special Allylidene is attached to the ring; naphthyl; or phenyl, phenylalkyl, or phenylalkenyl each is optionally selected from one or more halogen atoms, alkyl, G.6-haloalkyl, ( : Bu 6-alkoxy, alkylthio, amine, azido, phenyl, and nitro substituents, and each directly or through an oxygen φ, sulfonyl, sulfonyloxy, carbonyl or The carbonyloxy group is optionally attached to the ring through a (4-.4-alkylene bridge, particularly methylene. R3a is preferably hydrogen or (4-.4-alkyl; R4 and R4a_ are preferably hydrogen respectively , Alkyl, phenyl or benzyl. Another preferred group of compounds of formula I (compound 1C) includes compounds in racemic form, where when X is -CONR5R6 and R1 is hydrogen, methyl, ethyl or In the case of 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) includes compounds in racemic form #, where when X When-CONR5R6 and R1 are hydrogen or CV6-alkyl, C2.6-alkenyl or -alkynyl or cycloalkyl (each is unsubstituted), the ring is substituted by alkyl, alkenyl or alkynyl (each For unsubstituted) take A further group of compounds of the formula I (compound 1E) comprises wherein 'X is -CA ^ h; R1 is Η; R3 is azidomethyl, iodomethyl, ethyl is optionally substituted with 1 to 5 halogen atoms , N-propyl selectivity is replaced by 1 to 5 halogen atoms, vinyl selectivity is replaced by 1 or 2 methyl groups and / or 1 to 3 halogen atoms, 'ethyl-18- 200538437 φ # alkynyl selectivity Substituted with c ^ -alkyl, phenyl or halogen atom; R3a is hydrogen or halogen atom, preferably fluorine; and R2, R2a, R4 and R4a are each hydrogen; present as a racemic compound or as an enantiomer The structure is abundant, preferably pure enantiomers. A further particularly preferred group of compounds of formula I (compound 1F) include these compounds, where X is -CA] NH2; • R] is Η; R3 is C ^ -alkyl, C2.6-alkenyl or C2.6- Alkynyl is optionally substituted with azide, oxynitro, and 1 to 6 halogen atoms; R3a is hydrogen or a halogen atom, preferably fluorine; and R2, R2a, R4, and R4a are each hydrogen; Enantiomers or enantiomers are in abundant form, preferably pure enantiomers. In all of the foregoing ranges, when R1 is asymmetrically attached to a carbon atom, it is more preferably an "S" configuration. # "Pharmaceutically acceptable salts" according to the present invention include the therapeutically active non-toxic base and acid salt forms that the 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, ba-19-

200538437 Mother acid (pamo i c) and so on. 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 sa 1 ts) and salts with amino acids such as spermine and lysine. Conversely, such salt forms can be converted to the 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, and the R and S labeling methods follow the rules described in Pure Applied Chemistry 45 (1 976) 1 1-30. The invention also relates to all stereo forms of the compounds of formula I, such as the 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 (z u s ammen) 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 the present invention relates to a compound, it is intended to include various isoforms of the compound and -20-

200538437 mixtures, unless a specific isoform is specifically mentioned. 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-naphthylmethyl), alkoxycarbonyl (such as ethoxycarbonyl), trialkylsilyl (such as dimethyl- and triethylsilyl), and monoesters formed with dicarbonic acid (such as butanefluorenyl) ), Phosphate, sulfate, sulfonate, sulfonyl, sulfinyl and the like. An advantage of a compound with a metabolizable cleavable group is that it provides improved solubility and / or absorption rate to the parent compound due to the presence of the metabolizable cleavable group, resulting in improved bioavailability. T. Higuchi and V. Ste 1 1 a, "Prodrugs as Novel Delivery Systems", A. C. S. Seminar Series; "Bioreversible Reloading Agents for Drug Design" Issue 14, Edward B. Roche Editor, American Pharmaceutical Association and Pergamon Press, 1987. Compounds of formula I according to the present invention, such as those skilled in the art of synthetic organic chemistry, are known to be prepared in a similar manner. The following method descriptions illustrate certain synthetic pathways by way of illustration. Other alternatives and / or similar methods will be apparent to those skilled in the art. For this -21-

For the definition of substituents at 200538437, "=" means "yes" and "#" means "not for". A. Cyclization of amino esters. In formula I, when A2 = 0, the amine ester of formula AA-II is cyclized, wherein Q1 together with the oxygen to which it is attached is a leaving group, especially Qi is an alkyl group, and especially has 1 to 4 carbon atoms. Straight or branched alkyl.

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

Q1 #Methyl or ethyl. The ester of formula AA-11 is hydrolyzed under acidic or basic conditions, and then cyclized using a coupling agent such as dicyclohexylmethyldiimine under conventional peptide synthesis conditions (Bodanszky, M., Bodanszky, A., "Peptide Synthetic Practice ", Springer Verlag, 1984). A.1 Synthesis of AA-II by addition to itaconic acid salt derivative. Compounds of formula AA-11 where R2a = R3a = H and R3 = COOQ2, where Q2 represents a selective optically active linear or branched alkyl group, via a compound of formula AA-III and an itaconic acid salt derivative of formula AA-IV according to the following The reaction yields: -22-

200538437

This type of reaction is based on Street, L · J ·, B ake e ·, R.

Showell, G.A., Saunders, J., Herbert, R.H., Freedman, S.B., Harley, E. A. 5 Journal of Medical Chemistry (1 990), 3 3, 2 690-2697.

A.2 Synthesis of AA-II by reductive amination reaction AA-II compound of formula AA-II can be prepared according to the reaction formula using a compound of formula AA-III to reduce amination compound of formula AA-V:

This reaction is performed using the conditions described in Abdel-Magid, AF, Harris, BD, Maryanoff, CA, Synlett (1994), 81-83. In addition, when X represents CONR5R6, the amine AA-III can be bonded to the amine moiety Solid support (for example on Rink resin). Compounds of formula AA-V can be prepared by one of the following methods: • 23- 200538437

0v A. 2.1. Aldehydes of formula AA-VI are alkylated with alkyl haloacetates of formula AA-VII, where X represents a halogen atom, and intermediate enamines are used in the reaction, such as described in Whitessell, JK, Whitessell, MA, Synthesis, (1983) , (AA-V)

5 1 7-536 or using 腙 as described in Corey, E.J., Endei: s, D., tetrahedral letter (1 976), 11-14 followed by ozone decomposition reaction preparation. 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 ., Vilai: rasa, J., Tetrahedral Letter (1990), 31, 7499-7500). Nitroesters of the formula AA-VIII are known from Horni, A., Hubacek, I., Hesse, M., Helv. Chim. Acta (1 994), 77,579. Α · 2 · 3 · ester AA-X is alkylated with an allyl halide AA-IXU ^ halogen atom) in the presence of a strong base (such as lithium diisopropylamide), followed by a reduction ozone reaction of unsaturated esters. , As described in Amruta Reddy P., Hsiang B. C. .., La tifi Τ.Ν., ΗΠΙ M. W., Woodwa rd KE, Rothman SM, Ferrendelli J. A,, Cov ey D. F., -twenty four-

200538437 Journal of Medical Chemistry (1996), 39, 1898-1906. A · 3 · Synthesis of AA-11 by alkylating 7-haloesters. Compounds of formula AA-11 where X = c0NR5R6, C00R7 or CN can be alkylated via the use of amine AA-III 7-haloesters ΑΑ-χΙ, where X2 represents Preparation of halogen atoms.

νη2 R 乂 X (Μ-ΙΙΙ)

Ο

Q1 〇 This reaction was performed using the conditions described in patent application GB2225322 A. The synthesis of esters A A-XI is described in Section B. A. 4 · Synthesis of AA-11 by reductive amination of 5-hydroxylactone derivatives. Compounds of formula AA-11 where X = CONR5R6, C00R7 or CN, Q1 == Η and R2a = Η can be prepared by the reductive amination of amines of formula AA-III according to the following: 5-hydroxylactones of formula AA-XIII

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

200538437

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

Compounds of formula AA-X111 can be obtained by opening a lactone of formula AA-XIV in the presence of a halogenating agent such as TMS I, S0C1 "ZnCl 2 according to the following formula (then the halogenation reaction of the resulting halogen acid (X4 = 0Η) is performed if necessary ):

(AA-XIV)

The opening of X4 r2 ^ \ x3 (AA-XIII) lactone AA.-XIV can be performed according to the following procedures: Mazzini, C., Lebreton, J., AIphand, V., Fur stoss, R., tetrahedral letter ( 1998), 38, 1195-1196 and 01ah, GA, Narang, SC ·, Gupta, BGB, Malhotra, R., Journal of Organic Chemistry (1979), 4 4, 1247-1250. The halogenated (X4 = halogen atom) or acetic acid (X4 = 0Q1) of the obtained halogen acid (X4 = 0H) can be carried out under any conditions known to those in the industry. Formulas AA-XIV lactone can be prepared by one of the following methods: : B · 1. Hydrogenation or conjugate addition of organometals. Compound AA-XIV where R2a = R4a = Η can be obtained by hydrogenation of α, / 3-unsaturated lactone of formula AA-XV, or via conjugate addition of r3m (where M represents Li, Na, Mg or Zn) Organometallic derivatives to compounds AA_ -26-

200538437 XV finally obtained by copper (I) salt catalysis

R3M, Cul or H2i PdC (R3 = H) (AA-XV) 疒 R4

(AA-XIV)

This reaction can be performed according to the following procedures: Alexakis, A., Berlan, J., Be sace, Y., Tetrahedron Letter (1986), 27, 1 04 7-1050; Lipshutz, BH, Ellsworth, EL, Siahaan , T., Journal of the American Chemical Society (1 989), 111, 1 35 1-1 358 or any method known to the industry. B.2 Reduction of succinate derivatives. In the formula AA-XIV, when R2 = R2a = H: the reduction system of carboxylic acid AA-XVI is performed on a borohydride according to the following formula, preferably LiBH4_Ca (BH4) 2 is performed in an alcohol solvent.

Where Q3 is methyl or ethyl, G1 represents 0 or S and Q4 represents hydrogen atom or a straight or branched alkyl group containing 1 to 4 carbon atoms, but when GLS, Q4 = alkyl and when GkO, 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-

〇 200538437 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, θ-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-

200538437

Alkylation / cyclization

AA-XXI

Reductive amination / cyclization

AA-X1X

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 50 ° C in the presence of a tertiary amine. The cyclization reaction can be carried out spontaneously or according to the method described in Section A. E.2 Reductive amination A compound of formula AA-XXI reacts with a compound of formula AA-III under reductive amination conditions. The first step of this reaction can be performed in an inert solvent such as toluene at 0 to 50 ° C in the presence of a reducing agent such as NaBH3CN and in the presence of an acid such as acetic acid. The synthesis of compounds AA-XXI is described in Bou r gu i gnon, J. J. et al., Journal of Medicinal Chemistry (1 988), 31, 89 3-89 7. -29- 200538437 F. Branched functional group conversion. F. 1 ester is reduced to alcohol. Compound of formula I (where A2 = 0, X = CONR5R6 or COOR'R7 is a third alkyl group and one of R2, R2a, R3, R3a, R4 and R4a represents 02-COOQ6, G2 is a bonded or extended alkyl group And Q6 is a linear 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-CH20H). These changes can be made under any of the conditions known to the industry. F. 2 alcohol activation and oxidation. The compound of formula I (where A2 = 0 and one of R2, R2a, R3, R3a, R4 and R4a represents -G2-CH20H, G2 is bonded or alkylene) is the corresponding compound (where R2, R2a, R3, R3a, R4 and R4a2—representing -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, Q7 is an alkyl or aryl group, and Q8 is an alkyl group ) The key synthetic intermediate. These changes can be made under any of the conditions known to the industry.

F.3 Nucleophilic substitution of activated alcohols. Compound of formula I (wherein A2 = 0 and one of R2, R2a, R3, R3a, R4 and R4a represents -G2-CH2X6, G2 is a bonded or extended alkyl group and X6 is a chlorine, bromine or iodine atom or formula -0 -S02-Q7 group is defined as F.2) as the corresponding compound (wherein one of R2, R2a, R3, R3a, R4 and R4a represents -G2-CH2X7, where X7 represents azide, halogen atom, nitro, amine Groups, amino derivatives, sulfur derivatives and heterocyclic groups). These transitions can occur under any of the conditions known to those skilled in the art. F.4 Olefination by aldehyde. -30- 200538437 # # Compound of formula I (where A2 = 0, X = C0NR5R6 or C00R7 or CN and one of R2, R2a, R3, R3a, R4 and R4a means-G2-CHO, G2 is bonded or extended Group) is the corresponding compound (where one of R2, R2a, R3, R3a, R4, and R4a represents-G2-Q9, where Q9 represents unsubstituted vinyl, and 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 p-alloy by reacting its oxime with Se02 (described in Earl, R.A., Vollhardt, K.P.C., Journal of Organic Chemistry (1 984), 49, 4786). F.5 The acid derivative is converted into a heterocyclic ring. Compound of formula I (wherein A2 = 0 and 1 ^, 1? 23, 1? 3, 1? 33, 1? 4 and 1 ^ represent -G2-CN or -G2-C0Q1 (), G2 is a bond Or alkylene and Q1G are alkoxy, aryloxy or amine, halogen atom or amine derivative, but -COQ1Q is not X) is the corresponding compound [where R2, R2a, R3, R3a, R4 and R4a2— Represents -G2-Qn where Q11 represents (i) -CO-aryl / heterocyclyl, via fluorene chloride-G2-C0C1 and an aryl / heterocyclic organic metal • Metals such as trimethyl-pyridyl-stannate The palladium-catalyzed coupling reaction proceeds or (ii) a heterocyclic group such as thiazepine (Friedman, BS, Sparks, M., Adams, R., Journal of the American Chemical Society (1933), 55, 2262 or Iroka, Ν ·, Ham ada, Y., Shiori, T., tetrahedron (1992), 48, 7251), humiliation ^ (Street, LJ, Baker, R., Castro, JL, Clamber, RS, Guiblin, AR, Hobbs, SC, Metasa, VG., Reeve, AJ, Beer, MS, Middlemis, DN, Noble, AJ, Stanton, J. A., Scholey, K., Hargreaves, RJ., Journal of Medical Chemistry (1 993), 36, 1 529), oxadiazole (Ainsworth, C., US 31-200538 437 • · Journal of the Chinese Chemical Society (195S), 77.1 1 48), tetrazole starts from rhenium (Goerlitzer, K., Kogt, R., Proceedings of Pharmacy (1 990), 323, 847) or thiadiazole (Lamattina, L., Mularski, CJ., Journal of Organic Chemistry (1 984), 49, 4800)] is a key synthetic intermediate. 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, φ R2a, R3, R3a, R4, and R4a carry a functional group sensitive to oxidation conditions is a corresponding compound (where R2, R2a, R3, R3a, One of R4 and R4a represents a key synthetic intermediate of -G2-CO-CHQ12Q13 or -G2-CHQ13-CO-Q12). These transformations can be performed under any suitable conditions known to those skilled in the art, such as at 02 and PdC 12 in an inert solvent such as dimethylformamide or N-methylpyridine at 0 to 50 ° C (Bird, organic Synthetic Transition Metal Intermediate, Academic Press, New York (1 967), 88-1 1 1). F.7 Ketone derivatives. Compounds of formula I (where A2 = 0, X = C0NR5R6 or C00R7 and one of R2, R2a, R3, R3a, R4 and R4a represents -G2-C0-Q14, where G2 is a bonded or alkylene group and Q14 represents an alkane Group) is a synthetic (i) alcohol-G2-CH0H-Q14, which is reduced using a hydrogenating agent (March, Advanced Organic Chemistry, Third Edition, John Wiley & Sons (1 985), 809), (ii) fluorination Branch-G2-CF2-Q14 uses key intermediates described under conditions of Lal, GS, Pez, GP, Pesaresi, RJ, Prozonic, FM ·, Chemical Communications (1999), 215-2 16. F.8. Synthesis of alkynyl derivatives. -32-

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 other X, RI, R2, R2a, R3, R3a, R4 and none of them carry functional groups sensitive to strong bases are the corresponding compounds (where R2, R2a, R3, R3a, R4 and only one of them Represents -G2-C C-Q15, where Q15 is a key synthetic intermediate of hydrogen, halogen atom, alkyl or aryl. 200538437 The way these transformations are performed: • via base-induced / 3-elimination reactions (eg 1 equivalent t-BuOK at low temperature, described in Michel, P., Rassat, A., tetrahedral letter (1,999), 40,8579-8581) into haloalkyne derivatives (Q15 = halogen atom), and then borrowed the organometal Species perform metal-catalyzed substitution of halogen atoms (for example, by the use of MeZnCl in the presence of CuCN.LiCl, as described in Micouin, L., Knochel, P., Synlett (1 997), 327), via direct conversion to metal acetylenes Compounds (eg using 2 equivalents of n-butyllithium) and alkylation using alkyl halides or carbonyl derivatives (described in (: 117, £ .; [.,? 11 ( :} 18,?., Tetrahedral Letter (1972), 36 Φ, 3769-3772). F.9 Synthesis of alkanes. Compounds of formula I (where A2 = 0 and 1-2, feet 23, 1-3, One of 1? 33, 1 ^ 4 and 1? "Means _G2-C = C-Q16QI7, G2 is a bonded or extended alkyl group, Q16 and Q17 are an alkyl group or fluorine) are the corresponding compounds (where R2, R2a, One of R3, R3a, R4, and R4a represents a key synthetic intermediate of -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 , JT., Journal of Advanced Organic Chemistry, Third Edition, John Wiley & Sons (1 985), 1101-1102). -33-

200538437 · F. 10 Synthesis of (halo) azidoaryl derivatives. Compound of formula I (where A2 = 0, X = C0NR5R6 or C00R7 or CN and one of R2, R3, R4 is G2-Q18, where Q] 8 represents a nitroaryl or triple well and aryl group, and G2 is a bonded or (Alkylene) is the synthesis of corresponding compounds (wherein one of the R2, R3 or R4 groups is G-QI9, Q19 is an azidoaryl group optionally substituted with one or more halogen atoms, preferably Br or F atoms) The key intermediate. The transformation is performed 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 φ (e.g. Xing-teng, D ·, Guo-bin, L., Synthetic Communications (1 989), 19, 1 261) and transamines to azides by well-known methods. F. 11 Synthesis of heterocycles from amines. A compound of formula I (where AkCKX ^ CONR5!? 6 or COOR7 or CN and one of R2, R3 or R4 groups is G2-Q2Q, where G2 is a bonded or extended alkyl group and Q2Q is C00H, CON2, or CN) is synthetic The key intermediate of the corresponding compound (where one of the R2, R3 or R4 groups is 02-H2 or G2-CH2-NH2), which results in the corresponding compound (where one of the R2, R3 and R4 groups is G2 · Het or G2- CH2-Het, where Het is a heterocyclic ring bonded by a nitrogen atom, ® optionally substituted with one or more halogen atoms). • In the case where X = CONR5R6, CN or COOR7, R7 is not Η and R2, R3 or R4 is G2-C00H, the transformation is performed by Curtius rearrangement (such as diphenyl phosphoazide and Triethylamine action and borrowing in situ; alcohol quenching, described in Kim, D., Weinreb, SM, Journal of Organic Chemistry (1 978), 43, 12S), by hydrogenolysis or any conditions known to the industry Deprotection of the amine functional group to obtain R2, R3 or R4 = G2-NH2, followed by ring synthesis to obtain a heterocyclic ring such as pyrrole (for example, described in Jefford, CW ·, Tang, Q., Zaslona, A., American Chemistry-34 -

200538437 Journal (1991), 113, 3 5 1 3-3 5 1 8), and the selective introduction of one or more halogen atoms to the ring (eg described in Gilow, HM, Bimun, DE, Journal of Organic Chemistry ( 1981), 46,222 1-22 25). • In which 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, selective reduction of amidine or nitrile to an aminomethyl moiety, and ring synthesis to obtain a heterocyclic ring such as triazole (eg, described in Miles, R. ^ W., Samano, V., Robins, MJ, Journal of the American Chemical Society (1995), 117, 5951-5957). F. 12 Synthesis of triazole. The compound of formula 1 (wherein 8 = 2 and 1 ^ 2, 1 ^, 1 ^ 3, 1 ^ '1 ^ 4 and 1 ^ represents -G2-CH2N3, G2 is a bonded or extended alkyl group) is The key synthetic intermediate of the corresponding compound (wherein one of the groups 1, 2 ^, 1 ^, 1 ^, 1 ^ and 1 ~ 4 represents -02-〇 ^ -triazole). This transformation can be carried out by heating for a long time in the presence of 1- (triphenylphosphinoalkylene) -one derivatives (as described in Hammer schmidt, F., Polsterer, JP, Zbiral, Synthesis • (1 995), 415). F. 1 3 Optical segmentation. When a compound of formula I has one or more stereogenic centers and the use of non-stereoselective synthetic methods, the optical segmentation of a mixture of stereoisomers is best performed in one or more steps, usually involving diastereoisomers The material mixture is separated into its racemic mixture in sequence. The separation method is preferably used for non-image phase or image phase in reverse mode or better than direct mode for chromatographic separation. Chromatographic separation in reversed phase or better than direct mode, and -35-

200538437 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 used to separate diastereoisomers 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, especially compounds of formula AA-1I, in which each substituent has the foregoing definition as a novel compound and also forms part of the present invention. These novel intermediates, when the leaving group is pharmaceutically acceptable, have the same use as described later for the compound of formula I. 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, in another aspect, the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the manufacture of a drug for treating neurological and other disorders (as described above). In particular, the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of epilepsy, bipolar disorder, chronic pain or neuropathy. 36-200538437 pain, migraine, bronchial-, asthmatic- or allergic conditions Treatment medication. The activity and properties of the active compounds vary significantly between the optical isomers of the disclosed compounds and their oral utilization and stability in test tubes or in vivo. In a preferred embodiment, the active compound is administered in an enantiomerically abundant form, i.e., essentially as a single isomer.

For example, in the compound of formula I, in which R1 is ethyl, X is -CONH2, and A2 is oxygen, when R3 is propyl and the remaining substituents are hydrogen, S (butamidine) R (ring) enantiomer When R3 is 2,2-difluorovinyl and the remaining substituents are all hydrogen, S (butylammonium) and S (ring) enantiomers are preferred. The present invention also relates to a method for treating epilepsy, migraine, bipolar disorder, chronic pain or neuropathic pain or bronchial, asthma or allergic conditions in a mammal in need of treatment, comprising administering to the patient at least a therapeutic dose A compound of formula I or a pharmaceutically acceptable salt thereof. The method of the present invention comprises administering a compound according to the present invention to a mammal (preferably a human) suffering from the aforementioned condition or condition, in an amount sufficient to ameliorate or prevent the condition or condition. The compound is conventionally administered in any suitable unit dosage form, including but not limited to containing 5 to 1,000 mg, preferably 25 to 500 mg of active ingredient per unit dosage form. The term "treatment" is used herein to include both therapeutic and prophylactic treatments. The term "treatment" refers to the current symptoms of a disorder or condition. "Prevention" means preventing the occurrence or recurrence of a disease or condition. The term "epilepsy" is used here to indicate brain dysfunction and is characterized by regular and -37- 200538437 # # unpredictable seizures. 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 Illness" is used to denote the classification according to the 4th Edition of the Diagnostic and Statistical Manual of Mental Disorders (Diagnosis and Statistical Manual of Mental Disorders (DSM-IV TM) Emotional disorders. 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-

200538437 'Sexually elevated' period of 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 indicate 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 φ 1 week), the seizure criteria meet a manic episode and a major depressive episode almost daily. 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 refer to pain induced by neuropathological changes, to indicate the presence of harmful stimuli, and to cause a false sense of pain when no identifiable stimulus is present. 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 electricity or chemical stimulation, and at least part of the clinical symptoms of the seizures are similar to human seizures (Los che 1 · W. &Amp; Schmidt D., Study on Epilepsy (1998), 2, p.l45-181; Buchhalter -39-

200538437 J.R., Epilepsy (1993), 34, S31-S41). The results obtained for compounds of formula I indicate potent medicinal effects. Another assay that indicates possible anticonvulsant activity is binding to Levetiracetam binding site (LBS), described in detail later. The activity of a compound of formula I or a pharmaceutically acceptable salt thereof for chronic neuropathic pain can be determined in animal models. For example, chronic neuropathic pain can be modeled by pharmacologically induced diabetes in rats. In this model, animals show progressive hyperalgesia in response to harmful stimuli. This symptom is often seen in patients with painful peripheral neuropathy (Coimeix C,

Eschaliei, A., and Lavarenne J., Pain, 53, (1993) 81-88). This model has high pharmacological prediction capabilities (Courteix C, Bardin M., Chan t e 1 auze C., Lavarenne J, and Es cha 1 e r, A., Pain, 57 (1994) 153-160). 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 hyperactivity, thus confirming that the model is predictive (Cao BJ, and Peng N; A; European Journal of Pharmacology 237 (1 993) 1 77-1 8 1. Vale AL and Ratcliffe 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. (1 992) Development of animal models of late allergic reactions in guinea pigs and effects of antiallergic drugs. -40-

200538437 Prostaglandin, 43: 507-521). 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 -41-200538437 oily solutions or suspensions, which 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 these additional compounds that may be used in combination with the compounds of the present invention are anticonvulsants (e.g. baclofen), antiemetics, anti-manic mood stabilizers, analgesics (e.g. aspirin Lin, ibuprofen, paracet amo 1), narcotic analgesics, local anaesthetics, apioid analgesics, lithium salts, antidepressants (e.g. Miancillin (Mianserin), fluoxetine, trazpdone), anti-ring anti-love agents (such as i in i p amine, desipramine) ), Anticonvulsants (such as valproic acid, carbamazepine, fenidone (? 1 ^ 1 ^ -t 〇i η)), antipsychotics (such as Lispiredon (Rispe 1 · id ο ne), -42- 200538437

Ha loperi dol)), a neuroactive agent, benzodiazepines (eg diazepam, cionazepam) 'phenothiazine ( For example, Covitma crystal (ch 1 ο ι · pr omazine), 1¾ channel blocker, amphetamine, clonidine, lidocaine, micilitine ( mexiletine), capsaici η, caffeine, quet 丨 ap 丨 ne, angiotensin antagonists, Θ-blockers, antiarrhythmic agents, Tripipangs (11 · iptans ), 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, microgabazone (Viagabatrine), Tigabin ("& £ 313 丨 1 ^) or a pharmaceutically acceptable salt thereof. Benzodiazepines include 1,4 benzodiazepines such as Dizbe and Kolo Nazpan and 1,5 benzodiazepines such as clobazam. The preferred compound is kronazapan. Barbiturates include phenobarbital and Pentobarbital. The preferred compound is phenylbarbital. Steroids include adrenocortical hormones such as tetracosactide acetate and the like. Anticonvulsants include hydantoin (finney) Through, ethotoin -43- 200538437, etc.) 'p Qinwa Π categorized (Trimei Sadei (tr 丨 India ethadi ο ne), etc.), succinimide (Ethososimide (Ethosuximide, etc.), phenacemides (phenacemides, yacilfinnet (206171) 1: ^ 116-11114 06), etc.) 'sulfonamides (Sueson (51111} 1 丨 & 11 ^), ace toazol amide, etc.), aminobutyric acid (such as r- Amino · / 3 · Hydroxybutyric acid, etc.), sodium vanproate and its derivatives, Kabamaz et al.

Preferred compounds include vanproic acid, valpromide, Pi voxil, sodium vanproxide, sodium hemi-vanproxil, divalproex, colo Nazpine, phenobarbital, microgabatine, dirubin. For preferred oral compositions, the daily dosage ranges from 5 to 1,000 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 for illustration only and are not limiting, nor are they to be considered as limiting in any way -44- 200538437 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 were recorded on a Bruker AC 250 Fourier Transform NMR spectrometer with an Aspect 3000 computer and a 5 mm 1H / 13C dual probe, or a Bruker DRX 400 FT NMR equipped with an SG indigo computer and a 5 mm reflection Directional Geometry W / UC / 1 ^ Triple Probe. The compounds were studied in DMS0-d6 (or CDC13) solution at a probe temperature of 313 degrees K and a concentration of 20 mg / ml. The instrument is locked to the DMSO-d6 (or CDC13) deuterium signal. Chemical shifts are expressed in ppm of TMS Shimo, a distance used as an internal standard. Mass spectrometry measurement in LC / MS mode was performed as follows: HPLC condition analysis was performed using WATERS Aliiance HPLC system with INERTSIL ODS 3, DP 5 microns, 250 X 4.6 mm tubing. The gradient is from 100% solvent A (acetic acid, water TFA (10/90 / 0.1, v / v / v)) to 100% solvent 8 (acetonitrile, water, butyl? Eight (90/10 / 0.1, \ ^^ / 乂)) 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 ν / ν 'at a concentration of about 250 // gi: / ml. API spectroscopy (+ or-) was performed using a FINNI GAN (San Jose, California) LCQ ion capture mass spectrometer. APCI is derived from 450 ° C operation and capillary heaters are operated at 160 ° C. The ESI source was operated at 3.5 kV -45-200538437 and the capillary heater was operated at 21 ° 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 was set at 150 ° C. The specific rotation system is recorded in Perkin's Emma (Pe r k i η-E1 m e r) MC24 1 or 3 4 1 polarimeter. The rotation angle is recorded at 25 ° C in a 1% methanol solution. For some molecules, the solvent is dichloromethane or DM SO due to solubility problems. The water content was measured using a Metcoil microcoulomb metered Karl Fischer (Ka ·· 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, using a modified Jobin Yvon type in the room Axial compression of the tubing (80 mm id) is performed at a flow rate of 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 DAICEL's Chiralpak AD 20 micron, 100 * 500 mm column using a built-in instrument in the field room to use various low-carbon alcohols with C5 to C8 linear, branched or The cycloalkane was performed at 350 ml / min. The solvent mixture is as described in the individual procedures. Melting points are measured on a Buchi 5 3 5 Totoli type 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 was collected in continuous scan mode using a scan speed of 0.02 2 0 / s at an angle ranging from 4 to 50 degrees and 20 degrees. 200538437

The following abbreviations are used in the examples

AcOE t

AcOH

BuLi

η -Bu3P CICOOEt or ClC〇2Et

DCE

DIC

DMSO

DSC

DMF

Et3N E12〇

EtOH

FMOC

LDA

MeCOCl MeCN MeOH MTBE NMP PhMe PrepLC i-Pr2〇i-PrOH TFA ethyl acetate n-butyllithium acetate tri-n-butylphosphine ethyl chloroformate 1,2-dichloroethane diisopropylmethylene diimide Dimethylarsine differential scanning calorimetry N, N-dimethylformamide triethylamine ether ethanol fluorenyl methoxycarbonyl diisopropylamide lithium ethane chloroacetonitrile methanol methyl third butyl ether N- Methylpyrrolidone toluene preparative liquid chromatography diisopropyl ether isopropanol trifluoroacetic acid-47- 200538437 # THF tetrahydrofuran TM0F trimethyl orthoformate TMSCI chlorotrimethylsilane TMSI iodotrimethylsilane It is stated separately in the examples, otherwise the compounds are obtained in free form (non-salt). [Embodiment] Example 1. Synthesis of 4-substituted 2-oxypyrrolidimidine 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 · methylmethyl-hexanoic acid The synthesis of ester 361 can be expressed as diisobutylamine, PhMe, 11 (TO BrCH2C02CH3 f PhCH3 > CH3CN " 18RT, 90 ° C, 1. hour and then off (30%)

361

362 Dinitrobutylamine (4.62 ml from ACros;), 4,4-dimethylpentane in a three-necked flask equipped with a Dean-Stark device under nitrogen A solution of aldehyde 362 (2.5 g, 0.021 mol) in toluene (20 ml) was heated at 130 ° C for 2 hours and extracted with water. The yellow solution was cooled to room temperature and methyl bromoacetate (3.7 g, 0.024 mol) was added in one portion. The peach 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, filtered and evaporated. -48-

200538437 Oil was obtained, and the oil was distilled under reduced pressure (1 mm Hg) to obtain 5,5-dimethyl-3-methylfluorenyl-hexanoic acid methyl ester 361 as a liquid (1.1 g, 0.05 mole, Teb (1 mm Hg): 69-7 1 ° C). The aldehyde ester is then used in a reductive amination step. In addition, the alkylation reaction using ethyl bromoacetate can be performed in the presence of toluene-acetonitrile 1/1 (v / v) as a solvent. The resulting aldehyde was also distilled under reduced pressure. 1.1.2. Other synthetic routes Aldehydes can also be obtained by the following methods including (i) alkylation with bromoacetate derivatives. For example, 5- (phenyl) -3 -methylamidino-valeric acid 2,2-dimethyl-ethyl ester is connected via N- (4-phenyl) -propylene · N, Ν-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, / 3-unsaturated esters. 3- (3-Bromo-phenyl) -4-oxy-butyric acid ethyl ester is added via nitromethane in the presence of 1.8-diazabicyclo [5.4.0] undec-7-ene To 3- (3-bromo-phenyl) -ethyl acrylate, obtained under Nef conditions. Oxynitro derivatives and controlled hydrolysis of methyl-acetals by hydrochloric acid. (Iii) 4 -Ozone decomposition reaction of pentenoic acid derivatives. 2-Benzyl-4-oxy-butyric acid ethyl ester is alkylated with ethyl 3-phenyl-butyrate and allyl via lithium diisopropylamidamine Bromine is then decomposed by ozone and reduced by PPh3. 1.2 · Reductive amination of 3-substituted-4-oxy-butyric acid ester and cyclization to pyrrolidine-2 -one 1. 2. 1. Reductive amination The synthesis of methyl 4-{[((lS) -l-aminocarbonyl) propyl] amino) butyrate 363 is representative. -49-

200538437

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 angstroms) A suspension of Aldrich (A1 drich) in methanol was heated at 60 ° C. for 0.5 hours. The suspension was cooled to 0 ° C. and sodium borohydride (0.55 g) was added in portions. At room temperature After 1 hour, the reaction mixture was diluted with aldehyde ', washed with water, dehydrated with magnesium sulfate, filtered and evaporated to obtain a yellow oil. 4-{[((lS) -1 -aminocarbonyl) propyl] amino} 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 NaBHsCN or NaBH (0Ac) 3 (1.4 mol equivalents with respect to the aldehyde ester). Cyclization of 1 · 2 · 2 · butyric acid (methyl or ethyl) esters Two kinds of (2S) -2- (4-neopentyl-2-oxy-l-pyridyl) The synthesis of the stereoisomers 149 and 148 is representative

-50-

200538437 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 a saturated sodium bicarbonate aqueous 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: 邙 2 ( : 12/1 ^ 〇} 1 95/05 "^)) Obtained (23 1 2- (4-neopentyl-2-oxy-1 -pyrrolidinyl) butanamide (0.89 g, 0.0036 mole) It is a 1/1 mixture of diastereoisomers. The separation of the two isomers is achieved by image static phase chromatography (ethanol-hexane 1/1 (v / v)) and after recrystallization from toluene. Two stereoisomers were obtained (0.35 g and 0.37 g respectively). The stereochemical properties are described in the table. In addition, the cyclization of the amino ester can use 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 subsequently treated as previously described. 1.2. 3. Other cyclizations In addition, the cyclization can be performed in two steps by (i) acid or base hydrolysis of the ester and (ii) activation of the ester under the usual conditions described in peptide synthesis. 1.3 Solid-phase synthesis of pyrrolidone 1. 3. 1 FMOC-protected amino acid is attached to boronamine resin.

Lingke resin -51- 200538437 #

4 g of linkoamide (0.51 meq / g, 100-200 mesh) was placed in a glass container and stirred at 20% v / v hexahydropyridine / DMF (40 ml for 30 minutes. The resin was drained, The entire deprotection was repeated. The resin was filtered, washed (6 XDMF) and dehydrated. The resin was suspended in DMF (40 ml) and treated with N-Fmoc-2-aminobutyric acid (3.02 g, 9.28 mmol). It was then treated with a solution of 1,3-dicyclohexylmethyldiimine (1.4 g, 11.13 mmol) in DMF (20 ml). The reaction was stirred at room temperature for 1 hour, 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 NHFmoc 1_hexahydropyridine 2. NaBHtOAc ^ / CHaClj

3. TFA / CHjCIj

Difficulty. Resin. 100 mg of N-Fmoc-2-aminobutyramine resin (0.051 mmol) is housed 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- 200538437 # # The compound was purified by LC-MS (Micromass Gilson, LCZ platform, RP-18 column, gradient elution, CH3CN / H20 / TFA 1%). 1.3. 3. Reductive amination and cyclization by adding aldehyde esters.

150 mg of N-Fmoc-2.-aminobutyramine resin (0.087 mmol) was contained in a frosted polypropylene syringe. Removal of the Fmoc group was achieved in DMF using 20% hexahydropyridine. To the amine ester was added aldehyde (0.5 mmol) to TMF (2 ml). The reaction was stirred at room temperature for 18 hours and then filtered and washed (dichloromethane). The resin was swollen with dichloromethane, and then treated with sodium triacetoxyborohydride (22 mg, 0.14 mmol). The reaction was stirred at room temperature for another 18 hours. Then the resin was washed sequentially with the following solvents: 20 × 6, 1 ^ 0Η × 6, € 2 (12 × 6 and dehydration. The resin was suspended in a trifluoroacetic acid / water mixture (95 / S) for 1 hour with orbital agitation, and then filtered , Washed (dichloromethane χ 2). The filtrate was concentrated, the residue was dissolved in dichloromethane (2 ml) and concentrated again. The desired compound was obtained by LCNMS micro mass Gilson, LCZ platform, RP-18 column, gradient Elution and CH3CN / H20 / TFA 1%) purification. Example 2. Synthesis of 4-Substituted 2-Oxypyrrolidine Butamidines by Ring-Opening Reaction by Boron 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-

200538437

364 1n-Bu2CuLI (1.5 equivalent), TMSCI (2 equivalent :) Et2〇, -78 ° C ^ 20eC, 3 h

2. NH4CI

365 (74%)

In a three-necked flask under argon, n-butyllithium (1.6 M in hexanes, 75 ml, 0.12 mol) was added to Cul (1 1.42 g, 0.06 mol) in anhydrous THF (80 Ml) of the suspension cooled to -30 ° C. After 0.5 hours, the solution was cooled to -78 ° C, and TMSCU 4.75 g, 0.04 mole was added dropwise, followed by 2,3-furanone 364 (from Arylene, 3.36 g, 0.04 mole) and 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: 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 monomethyl succinate by cyclopropylmethyl bromide with lithium diisopropylammoniumamine, and then by NaBH4 & CaCl2 Obtained by reduction of 2- (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- 200538437 # # in the presence of dicyclohexylmethamine aldimine synthesis). Ethyl 4-pentenoic acid thioester is obtained by alkylation of ethyl bromoacetate with lithium diisopropylamide to obtain 2-ethyl succinic acid 1-methyl 4-ethyl thioester, and then sequentially Reacts with Li BH4 and sulfuric acid to convert to 4-allyl-butyrolactone. 2.2. Synthesis of pyrrolidone 2.2.1. Alkylation / alkylation of butamidine (2S) -2- (4-allyl-2-oxy-1 -pyrrolidinyl) butyramine 228 and The synthesis of two isomers of 224 is represented:

-Step 1: Open the lactone in a three-necked flask under argon, and add TMSI (51 ml, Acrylate) to the crude 4-allyl-butyrolactone 3 66 (refer to the procedure § 2.1.3. , 22.9 g, 0.181 mol) cooled to 0 ° C solution. 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). 4 Li 2 5 (^) ^, 00 (: 13) ... 1.80-2.05 (m, 2H), 2.20 (t, 2H), 2.40-2.60 (t, 2H), 5.10-5.20 (m, 2H) , 5.15-5.80 (m, lH)-Step 2: Chlorination of iodic acid in a three-necked flask equipped with a reflux condenser under argon, sulfenyl chloride (2 5.5 ml) and crude iodic acid 367 (44.5 g, 0.175 mol) in benzene (90 ml) was stirred at room temperature for 24 hours. The solvent was removed by evaporation in vacuo to obtain crude 3- (iodo) methyl-5-hexenesulfonium chloride 368 (47 g) , Which was used in the next step without further -55-200538437 purification. 4 off !? (25 (^) ^, [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, lH), 5.10-5.20 (m, 2H), 5.15-5.80 (m, lH)-Step 3: Use 5-2 -Amine-Butylamine formaldehyde-alkylation in a three-necked flask under argon, crude chloroform 368 (47 g, 0.172 mol) in dichloromethane (300 ml) was added dropwise to molecular sieve (29 g) , Powdered potassium hydroxide (22.3 g), anhydrous sodium sulfate (28.8 g), 4-n-butylcopper bromide (2.8 g '0.0086 旲) and S-2 -aminobutyramine ([a] 25D = φ +19. 35 degrees; 26.3 grams, 0.26 Ear) mechanical suspension in methylene chloride (470 ml) and cooled to 0 ° C suspension. The solution was stirred at -5 ° C for 5 hours, powdered potassium hydroxide (6.2 g) was added and the temperature was -5 ° C. Stirring was continued for 3 hours. The reaction mixture was filtered through Hyfluxil (hy f 1 oc e 1) and the solvent was evaporated in vacuo. The crude reaction mixture was subjected to silica gel chromatography (ethyl acetate / isopropanol: 97/03 ( Wv) 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%, respectively). Φ also separates two small amounts of impurities after image chromatography, which is (2S)- 2-[4- (2-iodopropyl-2-oxy-1-pyrrolidinyl) butanamine 225 (0.22 g) and 226 (0.27 g) are two stereoisomers, which appear after recrystallization White solid. 2.2.2. Alkylation / halfation of (2S) -2- (5-nonyl-2-oxy-1-pyrrolidinyl) butyramine through butyridamine Synthesis as a representative: Step 1: Opening of lactone 7-nononolactone (0.32 ml, 2 mmol) Chlorine (164 μl -56-

200538437 ′ 2.25 mmol) was added to the solution at room temperature, and zinc chloride (12 mg, 0.088 mmol) 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 iodine Sodium (2 mmol) and 276 mg of potassium carbonate (2 mmol). The mixture was stirred at 60 ° C overnight. The solid was filtered and washed with dichloromethane (2 × 2 mL). The filtrate was concentrated under reduced pressure to obtain an ester derivative, which was then used in the cyclization reaction.

Step 3: Cyclization: Refer to the conditions in § 丨 .2 · 2 · and § 1.2. 3 ·. Synthesis of 2 · 3 · Keto-pyrrolidin-2-one Synthesis of (2S) -2- [2-oxy-4- (2-oxypropyl) -1_pyrrolidinyl] butanamide 230 to represent:

-57- 200538437 #

In a three-necked bottle, oxygen was passed through PdCl2 (0,68 g, 0.039 mol), CnCl2 (1.68 g, 0,098 mol) in N-methyl-2-pyrrolidone (NMP, 40 ml) ) Solution, (2S) -2- [2-oxy-4- (2-oxypropyl) -1 -pyrrolidinyl] butanamide 224 (4.13 g, 0 · 020 mol) in NMP (40 ml) (addition time: 1.2 hours). The solution was stirred under aeration for 0.75 hours, 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] butanamine 230, which was a white solid after recrystallization from ethyl acetate. 2.4. Derivation of ketone 230 2.4.1. Synthesis of alcohol (2S) -2-[(4S) -4- (2-hydroxypropyl) -2-oxypyrrolidinyl] butanamine 233 as a representative :

-Step 1: Reduction In a three-necked flask under argon, NaBH4 * was added in portions to a solution of 230 (9 g, 0.012 mol) in ethanol (140 ml) cooled to -5 ° C. The solution was stirred at this temperature for 4 hours, quenched with saturated ammonium chloride and evaporated to dryness. The solid was dissolved in methanol / dichloromethane, filtered and concentrated in vacuo. Residue at -58-

200538437 Purification by silica gel chromatography (methanol / dichloromethane: 90/10 (ν / ν)) 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), 1.30-1.45 (m, 1H), 1.70-1.80 (m, 1H), 1.80-2.05 (m, 1H ), 2.20-2 · 40 (π, 2Η, partially overlapping with the solvent), 3.00-3.20 (m, 1H), 3.30 · 3 · 35 (2ώ, 2Η, partially overlapping with the solvent), 3 50-3.6 5 (m, lH), 4.30 (111, 110, 4.45 (111 ,: ^), 7.10 (8 (width), 111), 7.20 (s (width) 1H). • Step 2: B Tritiated in a three-necked flask under argon, acetamidine chloride (0.91 g, 0.011 mol) was added at room temperature to 4-N, N-dimethylaminopyridine (0.11 g, 0.001 mol), pyridine ( 0.86 ml) and alcohol in dichloromethane (90 ml). The solution was stirred for 5 hours, quenched with saturated ammonium chloride, and the aqueous layer was extracted with dichloromethane (3 times), dehydrated with magnesium sulfate and concentrated in vacuo to obtain The crude acetate was purified by column chromatography (hexane / ethanol) on the image phase to obtain two epimers 370 and 371 (1.143 g and 1.17 g, respectively). 1/1 mixture of 370 and 371 before image chromatography: 4 NMR (40 MHz, CD3SOCD3): 0.9O (t, 3Η), 1.21 · 1.28 (ιι, 4Η), 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, 1Η); 3.49 (dd, lH), 4.39-4.49 (m, 1H), 4.89-4.99 (111, 11 ^, 5.43 (8 (width), 11 ^), 6.24 (8 (wide), 1} 1).-Step 3: Deacetylation of a single enantiomer of acetate 371 in a three-necked flask under argon (1.11 g, 0.0042 mole) The suspension of potassium carbonate and ethanol was stirred at 0 ° C for 20 hours, evaporated to dryness and the crude alcohol was purified by silica gel chromatography (methanol / dichloro-59-200538437. Methane: 85/15 (\ ^ / ¥) ) (23) -2-[(43) -4- (2-hydroxypropyl) -2-oxypyrrolidinyl] butanamine 233 (0.67 g, 72%) was obtained after recrystallization from acetonitrile It is a white solid. 2.4.2. The fluorinated ketone of 230 is used to synthesize 2-[(4S) -4- (2,2-difluoropropyl) -2-oxypyrrolidinyl] butyrate Amine 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 a third amine 372 (1.2 g) LC / MS: 365 (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 amidated under standard conditions to obtain (2S) and (2R) -2-[(4S) -4- (2,2-difluoropropyl)- A mixture of 2-oxypyrrolidinyl] butyramine (87% and 13%, respectively). -60- 200538437

Synthesis of (2S) -2- (2-oxy-4-oxo 2.5. Pyrrolidinyl) butanamine 1 5 8 and 159

hcoonh4 Pd / C H20

2.5.1. Step 1: Reducing limbs in a three-necked flask, 4-n-propyl-transfuranone 373 (35.5 g, 0.25 mol by Bourgignon Π et al .; Journal of Medicinal Chemistry, 1988, 31, 893-897) was added at 18 ° C to a solution of S-2 aminobutyramide (28.1 g, 0.275 moles) in PhMe (355 ml). The solution was stirred at this temperature for 0.5 hours and precipitation occurred. The reaction mixture was stirred for 2 hours and 4N sodium hydroxide (37.5 ml) was added dropwise to the suspension, followed by the addition of an aqueous solution of NaBH4 (6.2 g, 0.16 mol) in water (62 ml). After 1 hour, the reaction mixture was carefully quenched with acetic acid (30 mL), heated to 50 ° C for 3 hours and cooled to room temperature overnight. 50% w / w sodium hydroxide (20 ml) was added and the aqueous phase was extracted with toluene (twice). The organic phases were combined, washed with brine and concentrated in vacuo to obtain crude unsaturated pyrrolidone 374 (43.4 g) as an orange oil, which was used in the next step without further purification. It can be recrystallized into a white solid (DSC, starting point: melting point = 72.9 ° C). 2. 5. 2. Step 2: Hydrolyze in a three-necked flask under argon. Add an aqueous solution of NΗβ〇〇8 (8 g, 0.126 mol) in several portions to crude 374 (22 g, 0.105 mol) and 1 A suspension of 0% pd / c (1.1 g) in water (220 ml) heated at 50 ° C. The suspension was stirred at -61 · 200538437 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 mol) was added in several portions. After 1.5 hours, a third aqueous NH4C00H solution (8 g '0.126 mole) was added. The suspension was stirred for s hours and 10% Pd / C (1.1 g) was added. The suspension was stirred at this temperature for 5 hours and allowed to stand at room temperature overnight without stirring. The reaction mixture was filtered through Celite, washed with water (30 ml), and the aqueous layer was extracted with ethyl acetate (3 times). The combined organic phase was washed with brine and concentrated in vacuo to obtain crude pyrrolidone as white crystals (18 · 1 g). The two diastereomers were separated by preparative hPlc (ethanol / heptane: 1/1) on the image phase, and two pyrrolidone 158 (9.5 g) and 159 ( 7.2 g) as a white solid. Two solid forms 159 were observed, namely Form A and Form B. Form A is typically characterized by diffraction peaks at 8.8, 9.8, 14.9, 15.0, 17.0, 171, 21.2, 21.4, 24.8 (20 degrees). Form B is typically characterized by diffraction peaks at 6.50, 11.25, 19.22, 23 · 44, 28 · 4 7, 29.94 (20 degrees). 2.5.3. Synthesis of 5-hydroxy-4-propyl-furan-2 · one

5-Hydroxy-4-propyl-5'-furan-2-one 373 (15 g, 0.1 mol), ethyl acetate (260 ml) and Pd / C 5% were placed in a Bal device. The mixture was degassed and hydrogen was introduced into it at 35 psi. Then mix at 25. 〇 · Stir vigorously 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 +). Good 200538437

Example 3. Synthesis of 4-substituted 2-oxy-pyrrolidine butyrimidine by alkylating 2-oxy-pyrrolidine with 2-bromo-butyric acid ethyl ester. Synthesis of 3 · 1 · 4-substituted 2-oxy-pyrrolidine 3.1.1.a.1. Preparation of 3- (3-chlorophenyl) -2-acrylate 3 75:

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, 75.35) to obtain 191.8 g of pure 375,92% yield. Bandit 1 ^ (2501 ^ 1 ^, (003) 23〇): 1.30 (t, 3H), 4.25 (q, 2H), 6.70 (d, 1H), 7.40 (m, 2H), 7.50-7.70 (m , 2H), 7.85 (s (width), 1H) · 2.1.1.a.2. Other methods:

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

200538437 obtained. 3.1.1.b · Preparation of 3- (3-chlorophenylb 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 moles, 5 equivalents) of nitromethane. While maintaining the temperature below 25 ° C (ice / water bath) under effective stirring, add 70.9 ml (447 millimoles, 1 equivalent) of diazabicycloundecene dropwise. The dark red mixture was stirred at room temperature overnight. The mixture was diluted with ether, washed with 1N hydrochloric acid, and the aqueous phase was extracted twice with ether again. The combined organic phase was dehydrated with magnesium sulfate, filtered and concentrated to dryness to obtain 128.5 g of crude 377 in a 99% yield, which was used in the next step. 1H NMR (250MHz, (CD3) 2SO): 1.10 (t, 3H), 2.70 (dd, 1H), 2.75 (dd, 1H), 3.95 (q, 2H), 4.95 (m, 2H), 7.20-7.45 ( m, 4H). 3.1.1.C ·· 4-amino 3- (3-chlorophenyl) butyric acid ethyl ester 378 preparation:

In a 2 liter pressure bottle under an inert atmosphere, 196 g (7.33 mmol) of 3- (3-chlorophenyl) -4-nitrobutyric acid ethyl ester 377 was dissolved in 200 ml of ethanol. Add 200 g of previously dried (3 times, ethanol) suspension of Raney Nickel in 700 ml of ethanol and the mixture to hydrogenation in a Bar hydrogenator under a maximum hydrogen pressure of 20 p s i -64-

200538437 (strong exothermic reaction, requires ice / water cooling). The mixture was degassed, filtered through a Celite / Norite pad, and the filtrate was concentrated in vacuo to obtain 136.7 g of crude 378, 78% yield, which was used in the next step. 3.1.1.d: Preparation of 4- (3-chlorophenyl) -2-pyrrolidone 379

In a 500 ml flask equipped with a reflux condenser and a magnetic stirrer, 135.7 g (561 mmol) of 4-amino-3- (3-chlorophenyl) butyric acid ethyl ester 3 78 was dissolved in 200 ml of toluene, The mixture was refluxed for 30 minutes. The solution was concentrated to dryness and the residue was purified by preparative LC (1 kg of silica gel, dichloromethane / ethanol, 98: 2 to 95: 5) to obtain 54.4 g of pure 379 (49.2%). GC / MS: 197 / 197M +. Preparation of 2- [4- (3-chlorophenyl) -2-oxy-1-pyrrolidinyl] butyric acid ethyl ester 380

5 In a 2 liter three-necked flask equipped with a reflux condenser, magnetic stirrer, and dropping funnel, 54.4 g (27.8 mmol, 1 equivalent) 4- (3-chlorophenyl)- 2-Pyrrolidone 379 was dissolved in 1,4 liters of acetonitrile. Add 64 ml (100.7 g, 556 mmol, 2 equivalents) 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, and the residue was suspended in ethyl acetate and washed with water.

200538437, 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%. ] Η NMR (250MHz, (CD3) 2SO): 0.80 -1. 00 (m, 3H), 1.60 -1 · 90 (2Η, η), 2.35-2.55 (m, 1H: partially overlap with solvent), 2.60- 2. 90 (m, 1H: partially overlapping with the solvent), 3.70 (s, 3H), 3.50-3.80 (m, 3H), 4.50 (m, 1H), 7.20-7.50 (m, 4H ). 3.1.1.g: 2- [4- (3-chlorophenyl) -2-oxy-1-pyrrolidinyl] butanyl

Preparation of amine 381:

56.7 g (192 mmol) 2_ [4- (3-chlorophenyl) -2-oxy-1-pyrrolidinyl] butanoic acid in a 1 liter three-necked flask equipped with a reflux condenser and a magnetic stirrer Ethyl 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 381, 97.8%, and 82.2 g of diastereomeric mixtures. Adhesive gasket AD, gasoline / ethanol, 50:50), each pair of enantiomers is optically separated by synthesizing preparative LC (image gasket 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- via alkylation / cyclization of 4-bromo-3-substituted-66- 200538437 # # -but-2-enoate with 2-amino-butamidamine Pyrrolidine butamidine. 4.1. Synthesis, alkylation and reduction of 4-bromo-3-substituted-but-2-enoate 4.1.1. 4-bromo-3- (2-thiophenyl) bromide of 3-substituted crotonic acid ethyl ester ) -But-2-enoic acid ethyl ester 382 as a representative

383

φ In a 2-liter three-neck flask under argon, mechanically stir 2-thiophenyl-3-yl-but-2-ene-2-acrylic acid ethyl ester 383 (32.88 g, 0.211 mole), N-bromobutane The degassed solution of hydrazone (37.56 g, 0.211 mole) and 2,2 · -aza-fluorene-isobutyronitrile (3.46 g, 0.021 mole) in carbon tetrachloride (600 ml) was refluxed for 6 hours. Cool 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) -but-2-enoate ethyl ester 382 (36.72 g, 78%). ⑴ NMR (250JiHz, (CDC13): 3.80 (s, 3H) 5 4.95 (s, 2H), 6.25 (s, 1H), 7.10 ® (dd, lH), 7.35 (d, lH), 7.45 (d, lH ). 4 · 1 · 2 · The synthesis of 2- [2-oxy- 4- (2-thienyl) -fluorene · pyrrolidinyl] butanamine 71 using 2-amino-butyramine alkylation as Representative: -67-

200538437

4.1.2.1. Step 1: Alkylation-cyclization ^ In a 1 liter three-necked flask under argon '4-bromo-2-thiophen-3-yl-but-2-ene-acid methyl ester 382 (36,72 g '0.134 mole), a solution of (s) _2-amino-butyramine ([a] 25D: 19.09 degrees; 31.6 g, 0.270 mole) in THF (350 ml) Stir at room temperature for 20 hours. The suspension was filtered and concentrated in vacuo to obtain the crude unsaturated stilbene ketones 3 8 4 and 3 8 5 (4 3.4 7 g), which were used in the next step without further purification. Crude pyrrolidone is separable and is usually a mixture of double bond isomers (3, 4 and 4, 5 olefins, the former being the main isomer).沱 NMR (250MHz, (CD3) 2SO): 0.80 (t, 3H), 1.30-1.90 (m, 2H), 4.40 (d, 1H), 4.45 (m, 1H), 4.70 (d, 1H), 6.30 (5; Φ 21 ^), 7.0 (8 (width), 111), 7.15 ((1 (1, 11 {), 7.40 (8 (width), 11 ^, 7.50 (d, 1H), 7.85 (d, lH) 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, 0.044 mole) to crude unsaturated pyrrolidone 384/385 ( 14 g, 0.044 mol), COC1 2 (0.062 g, 0.0005 mol) in ethanol (100 ml). Diethylene glycol dimethyl ether (65 ml) was cooled to 0 ° C. After 0.75 After 4 hours, the reaction mixture was heated at reflux for 48 hours. During this period, three portions of NaBH4 (1.75 g, 0.045 mol) and coCl2 (0.062 • 68- 200538437 g '0.0005 mol) were sequentially added every 10 hours to the beginning. The material disappeared. The reaction mixture was cooled to room temperature, hydrolyzed with saturated ammonium chloride, extracted with ethyl acetate, dehydrated with magnesium sulfate and concentrated in vacuo to obtain crude pyrrolidone, which was purified by silica gel column chromatography (two Chloromethane / methanol: 97/03 (v / v)) to obtain 4.15 g of 2- [2-oxy- 4- (2-Thienyl) -1-pyrrolidinyl] butyramine (38%). The stereoisomer mixture was purified by column chromatography (hexane / ethanol)

Two diastereoisomers (2S) -2- [2-oxy- 4- (2-thienyl) -1_pyrrolidinyl] butanamide 7 1 (recrystallized from ethyl acetate) 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] butanamine 84 (0.25 G, recrystallized from ethyl acetate) and 85 (0.44 g, recrystallized from ethyl acetate) two diastereomers. 4.2. Synthesis of azidophenylpyrrolidone A single enantiomer of (2S) -2- [4- (3-azidophenyl) -2-oxy-1-pyrrolidinyl] butanamine 86 The synthesis of isomers is represented by:

4.2.1. Synthesis of aniline-69-200538437 · 4.2 · 1 · 1 · Step 1: borrow 4-bromo-3- (3-nitrophenyl) -but-2-ene-acid methyl ester 386 alkane The synthesis of (S) -2-aminobutyramine 3 86 was carried out as described in § 4.1.1. 1H NMR (250MHz, (CD3) 2SO): 1.30 (t, 3H), 4.20 (q, 2H), 5.15 (s, 2Η), 6.45 (s, 1H), 7.75 (dd, 1H ), 8.10 (dd, lH), 8.25 (dd, lH), 8.45 (d, lH). The alkylation was performed according to the experimental procedure of § 4. 1.2.1 · (59%). LC / MS: 290 (MH +). 4.2.1.2. Step 2: Reduce in a 2.5-liter pressure bottle under an inert atmosphere, dissolve 7.22 g (0.025 mol) of 387 and palladium / charcoal (10% w / w, 0.2 g) in ethanol (1 liter) and the mixture was hydrogenated in a Bal 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 (Crystalline) Two diastereomers as the hydrochloride. 4.2.2. Synthesis of Phenylazido 86. In a three-necked flask under argon, a solution of sodium nitrite (0.232 g, 0.0037 mol) in water (1.5 ml) was added dropwise to (2S) -2- [4- (3-aminophenylphenyl) A solution of 2-oxy-1-pyrrolidinyl] butanamine 90 free state base (0.8 g, 0.0031 mole) in 10 M hydrochloric acid (6.5 ml) was cooled to 0 ° C. After 0.5 hours at room temperature, add NaN "0.220 g, 0.0037 mol) at -70 ·

200538437 · 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 gel column chromatography (dichloromethane / methanol: 97/03 (v / v)) and obtained after recrystallization from acetonitrile. 0.42 g of (2S) -2- [2-oxy-4- (3-azidophenyl) -1-pyrrolidinyl] butanamine 86 as a single enantiomer 86 (48%).

4.3 · Synthesis of (2S) -2- [4- (3-Amino-2,4,6-tribromophenyl) -2-oxy-1-pyrrolidinyl] butanamide 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) Stir together 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 1 07 (47%, recrystallized from ether). ). Synthesis of 4 · 4 · (2S) -2- [4-methyl-2-oxy-1-pyrrolidinyl] butanamine 35 and 36 -71-

200538437 _

Series 3 5 and 3 6 were obtained by racemic mixture 3 8 9 and purified by image synthesis using ethanol and Kojima as a solvent in the static phase. ° 3 5 series was obtained after recrystallization from i-Pr 20E t as white crystals. 36 was obtained as white crystals after recrystallization from ether. Example 5-Derivation of 4-substituted 2-oxy-pyrrolidine butyrimidine via methyl- (aminocarbonyl) propyl] -5 -oxy-3 -pyrrolidine carboxylic acid 11 derivatization. 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 1 1 and 12. 5.2. 1- [2S-1- (Aminocarbonyl) propyl] -5 -oxy-3-pyrrolidinecarboxylic acid

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 and cooled to 0 ° C. After 1.5 hours at this temperature, the reaction was acidified by hydrochloric acid (109 mmol-72-200538437 · · liter), the solvent was removed by vacuum evaporation, the residue was extracted with isopropanol, filtered and the filtrate was concentrated in vacuo to obtain the crude acid (1 7 82 g), recrystallized from acetonitrile to obtain enantiomerically pure 1-[2S · 1-(aminocarbonyl) propyl] · 5 -oxy-3-pyrrolidinecarboxylic acid 48. Synthesis of 5 · 3 · (23) -2- [4- (1,3,4-fluorenediazol-2-yl) -2-oxy-1-pyrrolidinyl] butanamine 50

Step 1: react with hydrazine

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-neck flask under argon, crude hydrazine 391 (this patent, 3 g, 0.013 mole), triethyl orthoformate (2 ml) and p-toluenesulfonic acid (0.010 g) The solution was heated at 110 ° C for 24 hours. The reaction mixture was cooled to room temperature, and concentrated in vacuo to obtain crude oxadiazole, which was purified by silica gel chromatography (dichloromethane / methanol: 95/05 (Wv)) to obtain (2S) -2- [4- (l, 3,4-fluorenediazole-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 · oxadiazol-2 -yl)-1 -pyrrolidinyl] butan-73 · 200538437 · · amine The 51 series was obtained by reacting hydrazine 39 1 with CS2 and potassium hydroxide in ethanol. 5.5. Synthesis of 4-amino-pyrrolidin-2-one 392

5.5.1. Step 1: Synthesis of carbamate 393

Enantiomerically pure 1- [2S-1- (aminocarbonyl) propyl] -5-oxy-3-pyrrolidincarboxylic acid 48 (19.06 g, 0.089 in a three-necked flask under argon Mol), a solution of diphenylphosphonium azide (26.9 g, 0.097 mol) and triethylamine (13.5 ml) in acetamidine (225 ml) was heated at 55 ° C with nitrogen formation. The temperature was maintained at 55 ° C for 0.5 hours, and maintained at 70 ° C for 2 hours and cooled to room temperature. Benzyl alcohol (9.25 ml) was added and the solution was refluxed for 4 hours, cooled to room temperature and concentrated in vacuo. The crude carbamate was purified by silica gel chromatography (ethyl acetate / methanol / ammonium hydroxide: 95/04/01 (Wv)) to obtain two diastereomeric carbamates 394 (2.64 G '9.3%) and 393 (11.9 g, 42%). As for 393: 4 NMR (250MHz, (CDCl3): 0.90 (t, 3H), 1.30 -74- 200538437 · reference-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. Synthesis of 4-amino-pyrrolidin-2-one 392 in a 0.25 liter pressurized bottle Under an inert atmosphere, 11.9 g (0.037 mmol) of 393 and palladium / charcoal (10% ^, 0.2 g) were dissolved in ethanol (300 ml) and the mixture was hydrogenated in a Bar hydrogenator at a maximum hydrogen pressure of 20 psi. After 20 hours, the mixture was degassed, filtered on a Celite / Nolette pad and the filtrate was concentrated in vacuo to obtain the crude amine, which was recrystallized from toluene to give 2- [4-amino-2-oxy-1-pyrrolidine Propyl] 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] • Butylamine 393 (6.99 g, 0.03 7 mol), dimethoxytetrahydrofuran (5.53 g , 0.041 mole), 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 g , 30.1%). 5.5.7 Bromination of 4-pyrrolyl-pyrrolidin-2-one 223 -75-

200538437 ·

In a 0.25 liter three-neck flask under magnetic stirring under argon, 2S_4-pyrrole-pyrrolidin-2 · one 223 was present as a single enantiomer (1.18 g, 0.049 mole) in THF (35 ml). The degassed solution was cooled to -78 ° C 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-pyrrol-1-yl) -2-oxy-1-pyrrolidinyl] butanamine 2 34 (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] butanidine and triethyl orthoformate, sodium azide and Acetic acid reaction gave 2- [2-oxy- 4- (1H-tetrazol-1-yl) -1-pyrrolidinyl] butanamide 67. Synthesis of 5 · 9 · (4H-1,2,4-tetrazol-4-yl) derivative In addition to §5.6, S '2- [4 -amino-2-oxy-1-B is better than B Amine] Butamidine reacts with pyrimidine and 1,2-fluoren (dimethylamino) methylene) hydrazine to obtain 2- [2-oxy-4- (4 Hong1,2,4-triazole- 4-yl) -1-pyrrolidinyl] butamidamine 65 and 66. Example 6. Synthesis of 4 -Substituted 2-oxy-pyrrolidine butyrimidine via alkylenelation of third butoxycarbonyl) propyl] -5 -oxy-3-pyrrolidinecarboxaldehyde 3 9 6. 6 · 1 · [1-(Third-butoxycarbonyl) propyl] -5 -oxy-3 -pyrrolidinecarboxaldehyde -76-

200538437 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 mole) 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 a 1/1 mixture of l-[(lS) -l- (third butoxycarbonyl) propyl] -5-oxy-3-pyrrolidinecarboxylic acid methyl ester 397: 4 NMR (250MHz, (CD3) 2SO ): 1.05 (t, 3H), 1.44 (s, 9H), 1.60 -1.65 (m, lH), 1.65-1.90 (m, lH), 2.40-2.65 (m, 2H and solvent part signal overlap), 3.30- 3.65 (m, 3H), 3.70 (s, 3H), 4.40 (dd

, 1H). In addition, the reaction can also use racemic 2,2-dimethylethyl-2-amino-butyric acid ester to obtain racemic butylamidine with similar yields. Step 2: Synthesis of 醯 396.

Reduction of ester 397 to alcohol 398 -77- 200538437

§ 7 · 0 · 2 was used. The method was performed using 397 as a single enantiomer, a mixture of two enantiomers, or a 1/1/1/1/1 mixture of 4 stereoisomers. As for (2S) -2- [4- (hydroxymethyl) -2-oxy-1 -pyrrolidinyl] butyric acid third butyl 398-1 / 1 diastereomer mixture: GC / MS: 257 M + 〇 Oxidation to aldehyde 396 In a three-necked flask under argon, (2S) -2- [4- (hydroxymethyl) -2-oxy-1-pyrrolidinyl] butyric acid third butyl ester 3 98 (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 Of suspension. The temperature was raised to 30 ° C and the suspension was stirred for 0.2 hours. The suspension was filtered through Celite. The filtrate was washed with 1N hydrochloric acid, brine, dehydrated with magnesium sulfate and concentrated in vacuo to obtain crude aldehyde. The aldehyde was purified by silica gel column chromatography (hexane / acetone 70/30 (v / v). ) 2.03 g of l-[(lS) -l- (third butoxycarbonyl) propyl] -5-oxy-3-pyrrolidinecarboxaldehyde 396 (41%) was obtained. Alternatively, racemic esters can be used to obtain racemic aldehydes with similar yields. Analysis of a 1/1 mixture of l-[(lS) -l- (third butoxycarbonyl) propyl] -5-oxy • _3_pyrrolidincarboxaldehyde 396: 4 NMR (25 0MH, (CDC13): 0 · 91 (t, 3H), 1.44 (s, 8H), 1. 55-1 · 77 (m, 1H), 1.90-2 · 15 (ιη, 1Η), 2.63-2.82 (m, 2H) , 3.47-3.61 (m, 1H), 3.65-3.79 (m, 1H), 3.83-3.94 (m, 1H of one of the diastereomers), 4.48-4.62 (m, 1H), 9.74 (sm) , LH) 6.2. Alkylation reaction of l-[(lS) -l- (third butoxycarbonyl) propyl] -5 -oxy-3 · pyrrolidinecarboxaldehyde 396 6.2.1. Of olefinic derivatives synthesis. Instead of § 6 · 2 · 3 ·, olefinic derivatives may be passed through 1-[(1 S)-1-(third -78-

200538437 Butoxycarbonyl) propyl] -5 -oxy-3 -pyrrolidinecarboxaldehyde 3 9 6 and squamous salt in the presence of a strong base by a WUtig alkylation reaction. 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

In lieu of § 6.2.3, halogenated vinyl derivatives may be substituted with 1-[(1S) -1- (third-butoxycarbonyl) propyl] -5-oxy-3-pyrrolidinecarboxaldehyde 396 in phosphine and It is obtained by carrying out Wittig reaction in the presence of methyl halide. For example, (2S) -2- (2-oxy-4- (2,2-dibromovinyl) -1-pyrrolidinyl) butyric acid 2,2- (dimethyl) ethyl ester is based on triphenyl CBr4 from aldehyde 396 in the presence of phosphono. 6 · 2 · 3. Alkylation by using (Me2N) 3P / CF2Br2

(2S) -2- (2-oxy- 4- (2,2-difluorovinyl) -1-pyrrolidinyl) butyric acid 2,2- (dimethyl) ethyl ester 399 The synthesis of enantiomers is representative. In a three-necked flask under argon, (Me2N) 3P (8 9.8 g, 0.55 mol) was added to a solution of CF2Br2 (58 g, 0.25 mol) in THF (280 mL) at -78 ° C (white precipitate appeared). ) And warm to room temperature. Aldehyde 396 was added dropwise to a previously prepared scale salt as a solution of a 1/1 mixture of diastereomers (35.2 g, 0.138 mol) in THF. After 1 hour, the reaction mixture was filtered through Celite and concentrated in vacuo. The reaction mixture was diluted with hexane, washed with brine, dehydrated with magnesium sulfate and concentrated in vacuo to obtain crude olefins. The olefins were purified by silica gel column chromatography (dichloromethane / methanol 99/01 (v / v)) to obtain 34. 6 g (2S) -2- (2-oxy-4 · (2,2-difluorovinyl) · 1-pyrrolidinyl) butanoic acid-79- 200538437 · 2,2- (dimethyl) ethyl 1% diastereomer mixture of the base ester 399 (87%). 4 NMR (250MHz, (CD3) 2SO): 0.81-0.91 (m, 3H), 1.44 (s, 9H), 1.50-1.75 (m, lH), 1.80-1.95 (m, lH), 2.30-4.40 (m , 2H and solvent partially overlap), 3.00-3.3 5 (m, 2H), 3.45-3.55 (m, 1H), 4.20-4.40 (m, 1H), 4.60 (ddd, lH — diastereomers ), 4.75 (ddd, 1H another diastereomer). 6.2.4. Using (nBu) 3P / CCl3F alkylation instead of §6.2.3., Halovinyl derivatives can be passed through l-[(lS) -l- (φtributoxycarbonyl) propyl 5-oxo Acyl-3-pyrrolidinecarboxaldehyde 3 96 was obtained by carrying out a Wittmann alkylation reaction in the presence of phosphine and methyl halide. For example, 2- (2-oxy-4- (2- (Z) -fluorovinyl) -1-pyrrolidinyl) butyric acid 2,2- (dimethyl) ethyl ester is derived from aldehyde 396, CFC13 and η-Bι3P reaction, followed by sodium hydroxide to dephosphorylate the intermediate ethylene scale. 6.2.5. Synthesis of 4-cyano-pyrrolidone In addition, 4-cyano-pyrrolidone derivatives can be passed through 1-[(1 S) -1-(third butoxycarbonyl) propyl] -5 -Oxy-3-pyrrolidinecarboxaldehyde 396 is obtained by reaction with hydroxylamine followed by reaction with selenium oxide. # 6.3. 2.2 Amination of dimethyl-ethyl ester 6.3. 1. Deprotection with trifluoroacetic acid and ammonolysis of (2S) -2- (2-oxy- 4- (2,2-di The synthesis of two diastereomers of fluorovinyl) -1-pyrrolidinyl) butylamine 213 and 222 is represented by: -80 ·

200538437 φ

Step 1: Deprotection of 2.2 (dimethyl) 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 mole) in a 1/1 diastereomeric mixture 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 argon decomposition. 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. A solution of methyl chloride (250 ml) and triethylamine (33.7 ml) cooled to -15 ° C. The reaction mixture was stirred at -1 (TC for 1.5 hours, then gaseous ammonia was passed through the solution while maintaining the temperature below 0 ° C. The suspension was stirred 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- Difluorovinyl) · 1-pyrrolidinyl) butyric acid 1/1 diastereomeric mixture of 2,2- (dimethyl) ethyl ester, which was purified by column chromatography using image conjugation ( Hexane / ethanol) gave two diastereomers 213 (10.1 g recrystallized from isopropyl ether) and 222 (1 1.2 g recrystallized from isopropyl ether).

200538437 · 6. 3. 2. In addition, debromocatechol borane can be used for deprotection. The four diastereomers of 2- (2-oxy- 4- (2,2-dimethylvinyl) -1-pyrrolidinyl) butanamine 163 are via 2- (2 · oxy _4- (2,2-Dimethylvinyl) -1-pyrrolidinyl) butanoic acid 1/1/1/1/1 diastereomeric mixture with Bromocatechol borane is reacted 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 (1.2- (4-ethynyl-2-oxy-1-pyrrolidinyl) butanamide 206/207

In a three-necked flask under argon, n-butyllithium (1.6 M in hexanes, 116 ml) was added to 2- [4- (2,2 · dibromovinyl) · 2-oxy-1 -Pyrrolidinyl] butamidamine, a 1/1 mixture of two diastereomers (stereochemistry indeterminate, 10.95 g, 0.031 mole) was cooled in THF to -78C. The white suspension was stirred at this temperature for 1.5 hours, quenched with methanol (120 ml), warmed to room temperature and concentrated in vacuo. The crude alkyne was dissolved in ethanol / dichloromethane (10/90 ν / ν), filtered through Celite, and concentrated in vacuo. The obtained solid was subjected to silica gel chromatography (ethanol / dichloromethane: 10/90 (ν / \ 〇)). And sequential purification by image chromatography (ethanol / hexane) to obtain 2-(4- ethynyl-2-oxy-pyrrolidinyl) butanamide 206 (0.84 g, recrystallized from toluene) And 207 (0.44 g, recrystallized from toluene) two diastereoisomers. In addition, 2- (4-bromo-ethynyl-2-oxy-1.pyrrolidinyl) butanamide 267 is via 2 -[4- (2, 2-Dibromovinyl) -2-oxy-1-pyrrolidinyl] -82- 200538437 · Butamidamine 47 and 2 equivalents of potassium third butoxide in THF at low temperature (-5 ° C to 0 ° C). 6.4 · 2 · 2- (4 · propyn-1-yl-2-oxy-1-pyrrolidinyl) butanamide 280 Synthesis

• In a three-neck flask under argon, methyl zinc chloride (from methyl lithium (1.5 in ether, 6.14 ml) and zinc chloride (1.25 g) in THF (15 ml)) was added. To a solution of CuCN (0.82 g) and LiCl (0.88 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 2 -(4-propynyl-oxo-2-oxo-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-

200538437 ·

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, φ 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] butanamine 1 57 A 1/1/1/1/1 mixture of the four diastereoisomers 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- [!. (third butoxycarbonyl) propyl] -5-oxy-3-pyrrolidine Methyl carboxylate 397 is a 1/1/1/1/1 mixture of 4 stereoisomers (10 g, 0.03 5 mol) in methanol (100 ml) at 20 ° C. The solution was stirred for 0.5 hours, evaporated to -84- 200538437 · dried and acidified to pH = 1 with IN hydrochloric acid. The aqueous layer was extracted with ethyl acetate, dehydrated with magnesium sulfate, filtered, and concentrated in vacuo to obtain the crude acid 40 0 (8.45 g) as a white solid, which was used in the next step without further purification. 1H NMR (250MHz, (CD3) 2SO): 0.80 (t, 3H), 1.44 (s, 9H), 1.55-1.60 (m, lH), 1.70-1.95 (m, lH), 2.40-2.55 (in, 2H Partially overlap with solvent), 3. 10-3.55 (m, lH and solvent partially overlap), 4.45 (dd, 1H "Step 2: Synthesis of ammonium 401 in a three-necked flask under argon, ethyl chloroformate (0.50 ml , 0.005 moles) was added to a solution of acid 400 (0.678 g, 0.0025 moles) in dichloromethane (10 ml) and triethylamine (0.77 ml) at -20 ° C. The reaction mixture was at -10 ° C. Stir for 1.5 hours, then add propargylamine (0.36 ml) to the solution while maintaining the temperature below 0 ° C. The suspension is stirred at 0 ° C for 1 hour, warmed to room temperature, filtered and the filtrate is evaporated in vacuo. The crude amidine was purified by silica gel column chromatography (dichloromethane / methanol 98/02 (v / v)) to obtain 0.8 g of propynamide 40 1 as one of four diastereomers. 1/1 mixture. 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 and solvent partially overlap), 3.0-3.70 (m, 3H and solvent partially overlap), 3.70-3.90 (m, 2 H), 4.45 (m, 1H), 8.45 (m, 1H). Step 3: Synthesis of oxazole 402 in a three-necked flask under argon, fluoramine 402 (0.77 g, 0.0025 mol) in acetic acid (40 ml ) And Hg (OAc) 2 (0. 048 g, 0. 0001 5 mol) 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- 200538437 · compound was purified by silica gel chromatography (hexane / ethyl acetate 50/50 (v / v) Pure oxazole 402 (0.1 5 g, 20%) was obtained. GC / MS: 308 (M +) was similar to 6.3.1. It was converted to 62 and 63 by ammonia hydrolysis. 6.6.7. Synthesis of tetrazole 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. LC / MS: 295 (MH +) 〇 6. 7. 2. Alkylation of tetrazolium

Racemic tetrazole 404 (5.6 g, 0.019 mol), potassium carbonate (2.88 g) and methyl iodide (1.3 ml) in DMF (60 ml) in a three-necked flask under argon • 86- 200538437 · · 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 (1.998 g, 34%) and 406 (1.03 G, 17%) was oily. LC / MS: 309 (MH +). 6.8. Synthesis of thiazole 6.8. 1. Synthesis of thiamidine

6.8.1. 1. 397 Ammonia hydrolysis In a 0.5 liter three-necked flask equipped with a reflux condenser and a magnetic stirrer addition tube, 10 g (0.035 mmol) of 397 was dissolved in 100 ml of methanol. Gaseous ammonia 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%).沱 NMR (250MHz, (CD3) 2SO): 0.85 (t, 3H), # 1.44 (s, 9H), 1.55-1.60 (m, lH), 1.70-1.95 (m, lH), 2.40-2.60 ( m, 2H and solvent partially overlap), 3.00-3.70 (m, 1H and solvent partially overlap), 4.35-4.45 (m, lH), 6.95 (s (width), lH), 7.40 (s (width), 1Η). 6.8.1. 2 Synthesis of Thioamine 408 in a three-necked flask under argon, crude amine 407 (6 g, 0.022 mol), P4S1G (4.93 g, 0.011 mol) and sodium bicarbonate (3.73 g) The solution in acetonitrile (100 ml) was stirred at 5 ° C for 6 hours. The reaction mixture was filtered, concentrated in vacuo and the crude thiosalamine was purified by silica gel chromatography (ethyl acetate / -87-200538437 hexane: 50/50 (v / v)). The thiosulfone was recrystallized from ethyl acetate. Amine 408 (3.7 g, 60%). GC / MS · 286 (M +). 6. 8.2. Synthesis of Substituted Thiazole

In a three-necked flask under argon, thiamine 408 was a 1/1/1/1/1 mixture of 4 diastereomers (this patent, 1.5 g, 0.005 mole), and alumina ( 12 g) and a solution of 1-bromo-2-dimethoxyprop-2-ene (0.85 ml) in toluene (100 ml) were 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. Synthesis of 6 · 8 · 4 · 1,2,4-thiadiazol-5-yl derivatives In addition, 1,2,4 · thiadiazol-5-yl derivatives can be sequentially linked with N through thiamine 408, It is obtained by the reaction of N-dimethylacetamide dimethyl acetal, followed by cyclization in the presence of pyridine. 6 · 9 · Synthesis of 2- [2-oxy- 4- (3-pyridylcarbonyl) -1_pyrrolidinyl] butanoic acid 2,2-dimethyl ethyl ester 410 -88-

200538437 ·

In a three-necked flask under argon, SOCl2 (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, 0.000 3 5 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 hour. , 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 1/1/1/1 of 4 diastereomers. mixture. LC / MS: 33 3 (MH +). Example 7 Synthesis of 2- (4-substituted-2-oxy-pyrrolidinyl) -butanamide via substitution of activated 2- (4-hydroxymethyl-2-oxy-pyrrolidinyl) -butanamine 7.0. Synthesis of starting alcohol 7.0.1. Synthesis of esteramine 7.0.1.a. l-[(lS) -l- (aminocarbonyl) propyl] -5_oxy-5-pyrrolidinecarboxylic acid Synthesis of methyl ester 11/12

12/11 In a 10-liter three-necked flask equipped with a mechanical stirrer and a reflux condenser, under an argon atmosphere, 1226 g (12 moles, 1 equivalent) (2S) -2-aminobutane-89- 200538437 · # Phenylamine 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. Filtration, washing the precipitate with methanol, concentrating the organic phase to dryness gave 3.283 g of crude intermediate 74%. In a 20 liter three-necked flask equipped with a mechanical stirrer, Rashi g column and distillation arm, in an inert atmosphere, crude intermediate and 84.7 g (891 millimoles, 0.1 equivalent) 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 φ 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 diastereoisomers were separated by preparative liquid chromatography on image syntheses (image synthesizer AD 1 00 * 500 mm, ethanol / water 99.9: 0.1), and the fractions were concentrated to dryness to obtain 968 g. Coarse 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) -1 -(Aminocarbonyl) butyl] -5 -oxy-3-pyrrolidinecarboxylic acid methyl ester, 1-{(1S) -b [(methylamino) carbonyl] propylb 5-oxo-3- Methyl pyrrolidine carboxylate is prepared in a similar manner. 7.0. 2. Synthesis of Alcohol · Ammoniumamine 7.0. 2. Synthesis of a · (2S) -2- [4- (hydroxymethyl) -2-oxy-1-pyrrolidinyl] butanamine 6.

• 90- 200538437 · 133 g (583 mmol, 1 equivalent) (2S) -2- (4-methoxycarbonyl) in a 2 liter three-necked flask equipped with a mechanical stirrer and a reflux condenser under an inert atmosphere A solution of -2-oxy-1-pyrrolidinyl] butyramine 11 in 200 ml of ethanol was added to 300 ml of ethanol, and the mixture was cooled to 0 ° C. Then, 66.2 g (1 · 74 mols, 12 equivalents) solid NaBH4, while maintaining the temperature at 2 to. After 2 hours the temperature rises to 12 ° C for 1 hour, then again to 2-4 ° C. 240 is added dropwise over 1 hour. Ml of a saturated ammonia chloride solution, followed by the addition of 120 ml of acetone, and the mixture was left at room temperature overnight. The mixture was filtered, the precipitate was washed with 3 × 70 ml of ethanol, and the combined organic portion was concentrated to dryness to obtain 148 g of crude 6. Suspended in 300 ml of two Chloromethane and stirred for 30 minutes, filtered, washed with 2 × 100 ml of dichloromethane and dehydrated to obtain 114 g of pure 6,98%. In addition, (2S) -2- [4- (hydroxymethylbuthoxy-2-oxy-1- Pyrrolidinyl] propanamide, (2S) -2- [4- (hydroxymethyl) -2-oxy-1-pyrrolidinyl] pentanamine, (2S) _2- [4- (hydroxymethyl )-2 -Oxy-1-pyrrolidinyl] -N-methylbutyramine is prepared in a similar manner. 7.1. Using triphenylphosphine to convert directly to synthesis • 7 · 1 · 1 · (2S) -2- [ Synthesis of 4- (iodomethyl) -2-oxy_1-pyrrolidinyl] butanamine 10

A 10 liter 3-necked flask equipped with a mechanical stirrer and a reflux condenser under an inert atmosphere, 400 g (2 moles, 1 equivalent) (2S) -2- [4- (hydroxymethyl) -2-oxyl -Pyrrolidinyl] butyramine 6 was dissolved in 3 liters of acetonitrile. 629 grams of -91-200538437 (2.4 moles, 1.2 equivalents) triphenylphosphine was added, followed by 608 grams (2.4 moles, 1.2 equivalents) of iodine in three portions over 5 minutes. The mixture was heated to 60 ° C for 30 minutes and stirred at this temperature for 5 hours. After cooling, the mixture was concentrated to dryness, and the residue was suspended in a solution of 750 g of sodium thiosulfate in 10 liters of water and stirred at 50 ° C for 4 hours. The precipitate was filtered and washed with 3 × 1 liters of water. The combined aqueous phase was treated with 1 kg of sodium chloride and extracted with 6 X 1 liter of dichloromethane. The combined organic phase was dehydrated with magnesium sulfate, filtered and concentrated to dryness to obtain 482 g of crude 10. Crystallized from toluene. Several harvests were recrystallized from ethyl acetate to obtain 425 g of pure 10,68%. In addition, (2S) -2- [4- (iodomethyl) · 2-oxy-1-pyrrolidinyl] -N · methylbutanidine 146, (2S) -2- [4- (iodomethyl) ) -2-oxy-1-pyrrolidinyl] propanamine 110, (2S) -2- [4- (iodomethyl) -2-oxy-1-pyrrolidinyl] pentamylamine 105, (2S) -2- [4- (Momethyl) -2 -oxy-1-pyrrolidine group] Butylase 8 '(2S) -2- [4- (chloromethyl) -2- The oxy-l-zirconyl] butamidine 30 line was prepared in a similar manner. 7.1.2. Synthesis of (2S) -2- [2-oxy- 4- (phenoxymethylpyrrolidinyl) butanamide 18

In a 5 Q ml three-necked flask equipped with a magnetic interference companion and a dropping funnel, in an inert atmosphere, 1 g (5 millitorles, 1 equivalent of methylol) • 92- 200538437 · # -2-oxy-1 -Pyrrolidyl] butamidamine 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 of substituted methanesulfonate 7.2 · 1 · {l-[(lS) -1- (aminocarbonyl) propyl] -5 -oxy-3-pyrrolidinyl} methylmethanesulfonate Synthesis of Ester 37

In a 4 liter three-necked flask equipped with a mechanical stirrer, a dropping funnel and a reflux condenser, in an inert atmosphere, 114 g (569 mmol, 1 equivalent) (2 S) · 2 · [4- (Methyl) -2-oxy-1-π than slightly B amidyl] butamidamine 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 a dropwise addition of 66.3 ml (96 · 2 g, 1.5 eq) of methanesulfonyl chloride in 190 ml of dichloromethane over 1 hour. , 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 obtain 216 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- (amino group) propyl] -5 -oxy-3 -P ratio slightly -93- 200538437 · pyridyl} methyl-4 -methylbenzenesulfonic acid Esters 31 are prepared in a similar manner. 7.2.2. Synthesis of (2S) -2- [4- (azidomethyl) -2-oxy-l-p-pyridyl] Butamidine 32

In a 3 liter three-necked flask equipped with a mechanical stirrer and a reflux condenser, under a φ inert atmosphere, 89.7 g (322 mmol, 1 equivalent) UU1S) -1- (aminocarbonyl) propyl] -5-oxy-3-pyrrolidinyl} methylmethanebenzenesulfonate 37 was dissolved in 300 ml of acetonitrile. Add 27.3 grams (419 millimoles, 1.3 equivalents) of sodium azide and 150 ml of acetonitrile in one portion. The mixture was adjusted to reflux over 20 minutes and stirred overnight. Add 3.1 grams (48 millimoles, 0.2 equivalents) of sodium azide and continue refluxing for a total of 44 hours. After cooling to 10 ° C, the mixture was filtered, the precipitate was washed with 3 × 50 ml of acetonitrile, and the combined organic portion was concentrated to dryness to obtain 77.3 g of crude 32. Crystallization from 150 ml of ethyl acetate at 10 ° C gave 60 g of pure 32,82%. Φ In addition, (2S) -2- [4- (fluoromethyl) -2-oxy-1-pyrrolidinyl] butanamine 44 and (2S) -2- [2-oxy-4- (1Η) -Tetrazol-1-ylmethyl) -1-pyrrolidinyl] butyramine 39, (2S) -2- [2-oxy- 4- (1fluorene-tetrazol-1-ylmethyl) -1 -Pyrrolidinyl] butanamine 40, (2S) -2- [2-oxy- 4-UH-1,2,4-triazol-1 -ylmethyl) -pyrrolidinyl] butanamine 55, (2S)-2- [2-oxy- 4- (1,2-1,2,3-triazol-1-ylmethyl) -1-pyrrolidinyl] butanamine 5 6, (2 S ) · 2-{4-[(Isopropylsulfanyl) methyl] -2 -oxy-pyrrolidinyl} butanamine 24, (2S)-2- [2-oxy-4- ( 1-pyrrolidinylmethyl) -1 -pyrrolidinyl] butanamine 15 5, (2S)-2-[2-oxy-4-(4-thiomorpholinylmethyl-94- 200538437) The 1-pyrrolidinyl] butanamine 17 is prepared in a similar manner from activated alcohol derivatives such as methanesulfonate, tosylate or halide. 7.3. Other Synthesis 7.3.1.1. Synthesis of {l-[(lS) -l- (aminocarbonyl) propyl] -5-oxy-3-pyrrolidinyl) methyl nitrate 38

In a 500 ml 3-necked flask equipped with a mechanical stirrer and reflux condenser and in an inert atmosphere, 8.10 g (26 mmol, 1 equivalent) (2S) -2- [4- (iodomethyl ) -2-oxy-1-pyrrolidinyl] butanamide 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 millimoles, 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 · 2-{4-[(Benzyloxy) methyl] -2-oxy-1 · pyrrolidinyl butylamidine 1 5 3/1 54

7.3.2.3. (23) -2- {4-[(Benzyloxy) methyl] -2-oxy-1-pyrrolidinyl} Synthesis of tert-butyl butyrate-95- 200538437 In a 100 ml 3-necked flask with a stirrer and a reflux condenser under an inert atmosphere, 1.1 g (60%, 27.5 millimoles, 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 (2S) -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, 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.咜 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 (η, 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} butylamidine # amine 1 5 3 in 50 ml of an inert atmosphere equipped with a magnetic stirrer and reflux condenser 3 Inside the flask, 1.75 g of benzyl ester-rich extract was dissolved in 20 ml of methanol. Then the 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 borrow Preparative LC (1 kg of silica gel, dichloromethane / methanol, 98: 2 to 90:10) was purified to obtain two diastereomers. 25% in an inert atmosphere equipped with a magnetic stirrer and a reflux condenser In a three-necked flask, 1.24 g of the third butyl ester-rich extract was dissolved in 16-96-200538437 · ml of a 1: 1 mixture of dichloromethane / trifluoroacetic acid, and maintained at 0-5 ° C for 24 hours. The solution was concentrated to dryness and the residue was dissolved in 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 over a 1.5 hour period. Gaseous ammonia passed through the solution. The mixture was maintained at room temperature overnight for 5 hours. 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 diastereoisomers were obtained. The first and second diastereoisomers obtained in the 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-methyl-1fluorene-1,2,3-triazol-1-yl) methyl] -2-oxy-1 Of Pyrrolidinyl} Butanamine 52

In a 50 ml 3-neck flask equipped with a magnetic stirrer and a reflux condenser under an inert atmosphere, 1 g (4.44 millimoles' 1 equivalent) (23) -2- [4- (azidomethyl) -2 -oxy · 1-pyrrolidinyl] butanamine 32 was suspended in 20 ml of toluene. Add 1.55 g (4.88 millimoles, 丨 · 1 equivalent) of _ (triphenylphosphonyl) acetone, and heat the mixture to 80 ° C for 24 hours. After cooling, the mixture was concentrated to dryness and purified by preparative LC (1 kg of silica gel, dichloromethane / methanol / ammonium hydroxide, 94.5: 5: 0.5) suspended in 15 ml of water and lyophilized to obtain 240 Mg of pure 52 was Cheng's oil, 42% ° -97- 200538437 · 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 was hydrogenated in a Barr hydrogenator 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 × 100 ml of 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 +) 〇 7.3.4.a. (2S) -2- [4- (isothiocyanatomethyl) -2-oxy-1-pyrrolidinyl] butanamine 49 synthesis

In a 100 ml 3-necked flask equipped with a magnetic stirrer and a reflux condenser under an inert atmosphere, 4.5 g (22.7 mmol, 1 equivalent) of 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 sand gel 'dichloromethane / methanol / ammonium hydroxide, 93.4: 6: 0.6) to obtain 3.1 g 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%). -98-200538437 φ 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 of the center known ®. 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-

200538437

RMN lU Γ-1 Ξ LC / MS MH + Melting point (° c) (127-128) 143.0 (116-120) (106-107) (146-150) 144.3 116.0 181.3 91.4 104..0 Synthesis • • I 7.1. 1. 7.1.1. 7.1.1. • Configuration data racemic racemic racemic mixture_1 non-image i Μ 窠 窠 窠 mmm inch inch inch inch w \ < N coo inch # \ 00 CN < : 000 gas 00 " CN PQ 000 gas C / T (N < 0W inch A czT < N FREE Pi gas οΓ CN A-1S, 3 § B-1S, 3 § IUPAC chemical name 狴 m slightly m 1 rH A I Λ Hf 1 (NAK) 1 1 CN m slightly η 1 rH Λ 擗 擗 1 m 嫲 1 I < N 狴 m NJ n 1 m Secret 1 (N Λ El · 1 1 (N & m K tip m 1 Λ m 1 (N Royalty & 1 1 < N 2- (4,4-dimethyl-2-oxy-1-pyrrolidinyl) propanamide! (2S) -2- [4- (hydroxyl (Methyl) -2-oxy-1-pyrrolidinyl] butanamine (2S) -2- [4- (hydroxymethyl) -2-oxy-1-pyrrolidinyl] butanamine 1- ( 2S) -2- [4- (bromomethyl) -2-oxy-1-pyrrolidinyl] butanamine (2S) -2- [4- (bromomethyl) -2-oxy-1- Pyrrolidinyl] butyramine (2S) -2-[(4R) -4- (iodomethyl) -2-oxypyrrolidinyl] butyridine m 1 cn m Secret 1 slightly g Kiki am ®I: fr G 趑 w worry 1 t -τΓΚ two slightly n 1 cn m 1 s K Ϊ 丫 m m V E-jing tt «^ ιΠΝ two compound number T—ί CN m inch Ό 00 Os 〇 (N -100- 200538437

Ξ 1—1 189.0 1 1 _1 202.0 (99.3-100.4) 120.0 124.4 93.2 144.9 ON 00 • • 1.1.1 then 1.2.1. Then 1.2.2 m 窠 m 窠 mm 窠 n 000 mc / Γ (N <: COT gas c / i CN free coo inch office 〇〇 " CN < COD inch r > 〇〇CN PQ COD gas l / T < N <: A-2S, 4§ 〇〇〇inch "0〇 " CN ries A-2S, 4§ coo c / T CN GQ 000 inch office 00 (N < fr m glycoside_ 1 rH Λ 浒 铿 sm 4 H 1 — T &< N «! Τ-Η 1 m 1 ~ 1 Bl · S 'glycoside_ 1 y ~ i «i dig 4 h slightly T 砮 CS' 1 1 OO '· 3 slightly 苕 1 rH 1 i fr 砮 1 rH sw / 1« 狴 A 鳔 Y 卜 r-1 G 略 ci n ## 1 r ^ H 1 slightly fr slightly n 1 rH 1 m 嫲 铿 ^ m ^ ΰ g weight csxia1 1 i a- slightly 荖 BU 1 1 嫲 铿 ^ m γbu "1 ~~ ' (2S) -2- [2-oxy-4- (phenoxymethyl) -1-pyrrolidinyl] butanamine 1 τ—Η ＊ Secret 1 CN paste t 1 遁 m 2 ^ 1 ® L_l 1 i ^ ^ Nm Η i 1 rH FREE 1 s 1 (N / ^-* N 00 Cl: 2S) -2- (4-benzyl-2-oxy-1-pyrrolidinyl) butanamide] (2S) 2- (2-oxy-4-phenyl-1-pyrrolidinyl) butanamide m inch VO 00 a \ (N (N 1 〇1 a 200538437

Ξ 92.4 103.8 98.1 107.7 211.4 142.8 I 120.3 111.7 84.8 134.8 1 — · < n —Η * — — rH r * H τ-Η 7.2.1. 7.2.2 1 6 · 2 · 2 · and then 6.3.1. 窠窠 窠 窠 窠 racemic racemic 窠 mm 1 mixture ί coo gas CO CN FREE A-2S, 4§ 00Q inch office 00 CN < B-2S, 4§ 000 inch Λ 00 (N PQ A-2, 4 B-2,4 000 inches rx οΓ CN < 00D m 00 1-H 1 < Pi CO < N gas CN (2 S) -2- (2-oxy-4-phenyl-1-¾ (Slightly II fixed base) Butanamine slightly if 1 < N 5 3 sg Λ \ M Πχ »™ m (—V slightly sna Ac A ^ LO. (2S) -2- (4-isopropyl-2-oxy Yl-1-pyrrolidinyl) butyramine (2S) -2- (4-isopropyl-2-oxy-1-pyrrolidinyl) butyramine (2S) -2- [4- (iodine (Methyl) -2-oxy-1-pyrrolidinyl] Butanamine 2- (4-Amino-2-oxy-1-¾ or acryl) Butanamine 2- (4-Amino-2 -Oxy-1-¾tyl) butyramine (2S) -2- [4- (chloromethyl) -2-oxy-1-pyrrolidinyl] Butanidine 1 m Na 1 ό anr • m. H g £ t «4 v _ 7 Sl ·-« Slightly 1 CS Cao i Ε- m annihilate bSM t ^ 2 Jane Sh ^ S Dead Pan CL 1 ▼ -H 1 < N i Kl Goose II . 俶 (N c < r m 4 b cn < N < N Ό (N 00 (N 〇 \ (N r〇 m m 02 — 200538437

2 r—1 202.8 73.9 56.9 _1 135.0 1 181.9 82.3 120.5 138.1 4.4. 4.4. 7.3.1. 7.2.1. 6 · 2 · 1 · and then 6.3.1. 7.2.2. Mm 窠 窠 m 窠 mixture 窠 窠 m ro GO meaning < A-2S, 4§ B-2S, 4§ 000 CO 00 rH 1 < A-1S, 3 § 000 00 CN <; 000 gas oo " < N <; CN A-2S , 4§ 〇0) οΓ · < N <; 1 mm secret 1 1 Ϊ E slightly vm 2 succin η diacryl (2S) -2- (4-methyl-2-oxy-1-pyrrolidine Butyl butyl amine 1 amine (2S) -2- (4-methyl-2-oxy-1-pyrrolidinyl) butyl amine daddy 1 ΟΊ Λ secret 1 meaning K feed Si «ff« 7 5l · rn two Acne 1 cn m secret 1 I sg Ϊ, ra '鼷 s Is hot 雎 V slightly V l · ^ r · ^ two acne 1 rH 1 Ϊ fr slightly 1 rH a 1 ffi supplement_ WH FREE S ^ n 1 rH 1 Wl l · 1 tH s 1 ffi 4 CCC > «Dart_ t A _ Sui Pan 2- (2-oxy-4-vinyl-1-pyrrolidinyl) butanamide 1 rH Secret 1 < N 0l · Slightly Mi 4 S ί: J Λ Η 00-~~ 1 Swallow 1 1-Η 1 5 6 i 鲢 S 4 ^ _ t ά _ VO m $ 00 m ON r〇〇 1-H cn -103 » 200538437

0? S rH r > OO 00 〇 \ 〇 ^ rH CO rH rH rH 〇OS 1-Η inch oi rH VO Os ΓΛ rH 00 CN bu Η N (N 00 CN r * H < N · ^ CS · ^ vd狯 — · CS ν〇 · cd inch · CO bu · m 窠 窠 窠 窠 mm <! □ 窠 松 < n A-2S, 4§ C00 m 00 rH 1 < Pi gas CO CS 00 inch · 00 ( Ν C0D m 〇Γ 1 c coo gas CO " < N <; 000 gas 00 (N < inch ^ CN 000 gas C / T (N < gas 〇Γ (2S) -2- [4- (fluoro Methyl) -2-oxy-1-pyrrolidinyl] butanamine 1 1 CO Λ 嫲 1 WO 1 s IE ^ am «1 ™ I ^ V w 7 B- Wuzhi slightly Jlf 1 < N slightly Installed K) 郏 11 I < N Singular Hall ^ t saint "r; η m 嫲 1 (N 1 KK) 11 1 (N inch_ 2 t SS ^ m swallow 1 m iil secret 1 1 5 E ϊ 3¾ slightly 7 ^ sn 二 ac1 1HH Ji CS Br Slightly _ Sightseeing w w Fighting earth c; η 1 1-H Λ Secret 1 CN ϊ 1 < N II Up. ^ Inch 0x1 (τΓ ££ Hi 通通 < Ν II ϋρ I inch "CO ^ ― < m right 鲡 it may be slightly different a 芰 ^« S 1 tH ύ ^, ', ι mh CN " 7 slightly better ffl- ^ ά m 4 wr ^ ^ Two CS E- Senna 1 (Ν S 1 i 1) m .. your inch to ^ m ^ t & -pan rn you 4 ^ u—1 1 A ^ 5 v0 ν〇 00 On (N r〇 ~ 1 〇4— 200538437

r—1 ο m 1—_J 117.3 Ό (N inch CN od CN CN rd vo tH CN C \ VO rH inch rH 00 CN tH Γ ΟΟ ο τ-Η 00 1 > Ό ▼ -Η Mixture 窠 < Π ya m 垲 垲 m m CN CN coo gas οΓ < N < coo inch office (N < < N < inch office < N <; < s < inch office < N PQ Tt CN FREE (N <: CS CQ 1 rH Secret 1 (Ν I ϊ • (Ν ma 您 r > PJ4: 馑 W Η ί is η i 逆 fr 1 rH m 1 CNCN ® m 4 t «g ¥ i V ^ (N «1 i— (1 〇) ^ ^ m 1 i & Complement 1 r * H i HI 1 m CN κ m V h can 5 secret plastic 1 1 CN — swallow 1 τ-Η 1 i H- m 1 rH a 1 ffi Λ ^ wh ^ m swallow 1 rH Λ 1 CN Ϊ 1 WO. 旮 m | CCd w _ ffi- H ά S i ^ 丨 ac1 ^ Η Λ 密 1 04 I 1 5 I mm Β -Η i S i η aac1 rH m secret 1 CN Ϊ 1 im * ting «m E- H ά 5 iam Aac 1 1 ▼ -H Λ secret 1 < Ν Λ I έ 狴 I-狴 m ϊ l · Η c S i ^ 1 1-Η Λ Secret 1 (Ν 5 1 CS ir〇 ^ ^ 7 _ paste) — 1 ί S ^ η ± ^ (N swallow 1 1-Η m nff 1 < N 5 1 CN S | rA plate ^ i «h ®- S ^ mi 塑 a 砮 κη wo VO in 00 wo ON S VO (Ν Ό m vo 105- 200538437

[10] 94.3 〇 \ d rH v〇00 r * H rH vri 00 rH O CO inch rH m r > inch rH r〇ON Ό d CN rH 6 · 8 · 3 then 6.3.1. You 鲦 Η "— — · Inch · inch 'village “— 1: inch · inch · mixture yaxiam rabbit xia 窠 窠 < nm 锾 锾 inch” < inch rs CN ￥ inch office CN PQ 000 inch "C / Γ CN < 0 〇) gas c / Γ < N PQ gas ri 〇0) C / T < N < 000 gas 00 " CN FREE 2- [2-oxy-4- (1,3-thiazol-2-yl) -1-pyrrolidinyl] butaminidine 1 1—1 1 slightly 1 HI 1 gas < N rH 1 ffi VS t _ K4! H «SA acne 1 ▼ -H 1 5 1 im 1 gas CN TH 1 ffi V disk tm secret_ aac m 砮 1 i—l 1 slightly 1 rH SI 1 ffi rH 1 m ^ secret 譲 ^ b swallow 1 t—Η Λ secret 1 (N i 浒 密 a- 4 ^ 00 '~ ~ 'Already η 砮 1 r—Η Λ l! F 1 CN i Rolling secret a- 4 ^ Λ H 00' ~~ 1 ci mm swallow 1 rH 1 slightly η η1 r〇1 inch secret · ^ h swallow 1 1—ί 1 Ϊ ring 1 1 m Jlf must 铿: ρ Λ h 00 i ~ id «m sheng I swallow 1 r-Ή 1 slightly ring 1 CN ^ 1 mwa 铿 Λ Η GO 1 ~ 1 VO VO 00 v〇 ON VO 〇ϊ—H CN -106 200538437

112.0 ί 150.2 91.3 j 146.5 73.7 115.0 129.0 100.2. ^ S • ^ 2. ^ ^ Ι 雄-“— · 进 $ —.“: · 2 · 4; * ^ ^ ^ ymm ^ f \ J ^ rH * inch · "Inch" · 鹚 窠 窠 m 窠 窠 m 4n m 000 inch Λ 000 inch coo inch · 000 gas oco inch · COD gas coo 00 CN c / Γ CS vA CS CO < NC / Γ < N CO cs 〇T CS inch cs < <; free sale < PQ < η mnn η mn chain I 1 1 1 swallow 1 砮 1 1 swallow 1 1 ^ H 1 Λ ii m τ-Η Λ ^ H Λ τ-Η m τ-Η m 5 > £ lA 1 11 碱 1 base I Ilf 嫲 秘 秘 κΤ CN / ^ S < N CN z ^ -S cs < N (N < N 1 l \ l _ slightly Ϊ ms枨 浒 浒 擀 1; < N m Slightly secret «1 Secret m 1 £ Η- m ffi- m Gl · m lM (N 1 inch 1 1 inch I CO 1 < N 1 inch 4 ^ 4 ^ 4 ^ 4 ^ 4 狴 4 ^ 4 ^ slightly_ 3 譲 3 _ 3 譲 ^ m 3 _ ^ m secret h Λ h GO i ~ i Λ h 00 '-' Λ HC / D i-i Λ Η ΖΠΠ ~~ 1 b 00 1 ~ 1 Λ h 00 1— '1 b C / D' '• wr, »_, slightly ci m already slightly cs m A pan m bu 00 σ \ s -107 ^ 200538437

" * 108 200538437

[13] [14] 226.4 79.0 68.3 129.4 165.4 104.3 217.4 6 · 2 · 1 · then 6.3.1. 6 · 2 · 1 · then 6.3.1. ^ ^ Η ——1 1 csj — τ-Η rH 3.1. 1.a to 3.1.1.g Ning-2 1: 1 — _! 1—4 inch · inch 1 窠 窠 窠 m 窠 m mixture mixture 窠 coo inch • S 00 < B-2S, 4§ (1HC1) 00 inch · 00 CN Pi 00 < N A-2S, 4§ coo gas 00 CN CN inch (N 000 gas czT CN < η Sui I # 1 τ-Η Λ Secret 1 < N slightly 1mm 1 ro Ϊ S Λ H 00 ηη swallow 1 1-Η m 嫲 1 < N s 浒 slightly 铿. 1 m 4 S Λ Η 00 '~' has been slightly (2S) -2-[(4S) -2-oxy- 4-vinylpyrrolidinyl] | * i Butanidine 1 (2S) -2-[(4R) -2-oxy-4-vinylpyrrolidinyl] Butanidine 2- [4- (bromobenzene ) -2-oxy-1-pyrrolidinyl] butanamine 2- [4- (2-bromophenyl) -2-oxy-1-pyrrolidinyl] butanamine 2-[(2- Oxy-4--4- (3-pyridinyl) -1-pyrrolidinyl) butyramine 1 Η ii Secret 1 < N pin η 砮 1 m 1 Cuiji nf m 2 h is a lithium swallow 1 1— < Λ m 1 CN m 1 r—i 枨-£ ^ 4 Η 3 ϊ Huipan CN 〇 \ r〇〇 \ On Ό 〇 \ s; 00 σ \ -109 " * 200538 437

[15] i- \ VO τ-Η [17] 255 172.7 135.7 171.1 166.6 161.7 119.4 7.2.2. 7.1.1. R ^ H t-4 窠 m mixture mixture_ 窠 窠 窠 racemic coo gas go " CN PQ 000 inch Λ C / D CN <: A-2S, 4§ _1 000 gas 00 " < N trophy office < N CN Pi gas οΓ CN < 00 gas CO CN <; A-2S, 4 § CS swallow 1 rH mw 1 CN m 1 r—l roll 4 Η 蛉 城 1 rH m 嫲 1 < N stifi I ϊ n 会 塑 3 # (2S) -2- [4- (l-naphthyl)- 2-oxy-1-pyrrolidinyl] butanamine (2S) -2- [4- (l-naphthyl) -2-oxy-1-pyrrolidinyl] butanamine 2- [4- ( Iodomethyl) -2-oxy-1-pyrrolidinyl] butanamide 2- [4- (chloromethyl) -2-oxy-1-pyrrolidinyl] butanamide 1 m 1 CN fr Ϊ , sm ^ s 砮 I rH m base 1 CN Ϊ Bl · 綦 1 inch person you 00 譲 S 譲 ^ S 3 雅 秘 1 (N 5 ΠΙ 1 寸 inch: 铿 " m ηη 4ac? / ^ \ ϊ --T 00 · (2S) -2- (4-hexyl-2-oxy-1-pyrrolidinyl) butanamide ON ON 1 100 101 102 103 104 105 106 107 108 -11〇 200538437

255 241 241 395 395 283 269 297 199 199 269 241 147 116.3 1— (tH ϊ > 3.1.1.a $ 3.1.1.g yaxia 窠 窠 mm < ίπ < π < ίπ < n crane SI m Compensation inch Pi Pi inch inch office inch inch outside inch office inch · οί inch ζ / ^ inch ζ / ^ CN CN CN 〇Γ (N < N inch # > Λ \ ϊ inchrv rsi inchrsi inchrsi PQ c < \ < N < PQ < FREE < PQ νΝ VNV, < mnwm 鳔 η 铿 狴 m Sg Pi 1 锴 铿铿 铿 mms Ξ simple mmmmmmw tip g jE + / ^ NK nmg Zhai K Sheng I% 1 Secret 1 Secret I i Wi Slightly i ϊ mii Slightly 1 CN 1 (N n η mnnwm 1 / ^ N / ^ N y4j II ww Slightly rKl fr l · 1 rH 砮 1 r ^ i Swallow 1 τ— < Swallow 1 τ-Η Dad 1 1—Η 1 rH 1 rH 砮 砮 1 rH Swallow 1 rH 1 (N 綦 I Λ Λ Λ Λ m Λ Λ Λ m ii 嫲 嫲 秘 嫲 秘 秘 秘 秘 IE IE ΓΏ Ώ / ^ V CO 1 (N 音 1 (Ν I (Ν 1 CN 1 (N 1 (Ν 1 1 (Ν 1 1 1 1 1 sss 狴 J ujri m Μ slightly «Λ slightly m Λ 1 (N 00… r | dangling ^ r Γΰ 〇] R] [TJ r u 〇] Γΰ Secret UI × in * ~ > / ^ N ΐϋ-00 1 ~ 1 土 寸寸 CN 'W ^ m3 has been slightly CL W 1 (N 1 (N Λ ^ 1 (N 1 (Ν 1 1 CN 1 CN 1 < N 109 110 m, 1 112 113 114 115 116 117 118 119 120 121 200538437

241 227 227 255 255 _i 213 185 261 261 381 297 297 269 134.5 3.1.1.a $ 3.1.1.g 1 Songya block pines < π < ίπ < ίπ mm 窠 m in mmm, mouth m coo «^ 4 · inch inch inch inch inch inch rs cs inch ― CN gas CN 乂 cs CN inch GO 9 \ CN < N gas CjT ci 〇Γ <; CN < FREE <: FREE < < 1 rH 1 N ) K) m 狴 装 狴 经 狴 s slightly m 11 im 狴 铿 mmmmmmm I 浒 1 I m epilepsy KKS m / ^ vm / ^ sh < N Γ—1 < N / —N rs / ^ s +世 K mm Slightly i S Complementary S i Weight η η nnm fr n η n η n Sui I Blanket I Acoustics Sheng I Pu I Knot I Acne 1 Swallowing 1 1 1 1 1 1 m 砮 1 # 1 砮 1 tH 砮 1 砮 1 daddy 1 m Λ mm Λ Royalty-free «1 Λ Λ 1—Η» τ-Η τ-Η m κ r 1 | E: 1 1 1 J m η ^ J · i T 4 inch 1 1 Λ «Λ m Λ mmm« ά mm Ilf nf Hff ^ nm KK $ ni ¥¥ CS (N CN —7 < N cs cs ^ ά ^ ά ^ d ^ 1 (Ν 1 1 d 1 CN 'w, 1 CS 1 (N 1 < N 1 CN 1 CN 1 CN 1 CN λ m a m 1 (N 1 CN 1 (N 122 123 124 125 125 126 127 1 128 129 130 131 132 133 134 135 -112- 200538437

269 255 255 284 289 241 241 213 291 53.8 94.8 66.6 3.1.1.a to 3.1.1.g rH ^ τ · Η Racemic racemic racemic i Mixture mixture racemic racemic racem mmn Mixture (N Royalty A-2,4 (N Royalty ci 乂 < N < B-2,4 inch Ρύ inch rv CN gas αΓ CN Pi gas 00 (N inch λ < N 2- (2-oxy- 4-pentyl-1-pyrrolidinyl) hexamidine 铿 m S η 砮 1 r-HA 1 d 1 d 1 (N 2- (2-oxy-4-pentyl-1-pyrrolidinyl) pentan Amine 2- (2-oxy-4-pentyl-1-pyrrolidinyl) heptanamine 2- (2-oxy-4-pentyl-1-pyrrolidinyl) -2-phenylacetamidine Amine 2- (2-oxy-4-pentyl-1-pyrrolidinyl) butanamine 2- (2-oxy-4-pentyl-1-pyrrolidinyl) butanamine 2- (2- Oxy-4-pentyl-1-pyrrolidinyl) acetamidine η Sheng I complement m 1 < N slightly fr 5 sh 4 «Λ ffi- ^ II 1 V of 1 00 ί ~ 1 i ci m Sheng I 砮 mw 1 < N 5 ^ m 碁 \ — > 4 «Λ E- ^ II 1 1 00 1 * Secret I Pan slightly Jlf 1 (N. 碁 铿 i 酒 ^ Η ElEl · 1 C / 2 1 ~ 1 ci m V τ-Η m Secret 1 CN i 1 ^ T) 1 Wake up m ^ II ^ ft g Roll out Λ i ia 136 137 138 139 140 141 142 143 144 145 146 147 -113- 200538437

[18] [19] 〇CN k_i [21] 187.0 155.7 101.8 119.1 1.1.1 then 1.2.1. Then 1.2.2. ——: rH < N ^ 1.1 · 1.1. Then 1.2 .2. M 窠 m racemic racemic 窠 A-2S, 4§ C00 and (/ Γ < N 000 000 inch Λ C / T CN < A-2S, 4 § CO) inch (N PQ < N < Inch Λ 03 00 Inch CO < N (23) -2- (4-neopentyl-2-oxy-1-sobrinofluorenyl) butanamide (2S) -2- (4-neopentyl-2-oxy-1-pyrrolidinyl) butanamine Hf 1 < N Suppose m 邂 狴 H mm l_, ffl- U. ^ mz ^ A 砮 00 1 CS rH 1 (2S) -2- (4-ethyl-2-oxy-1-pyrrolidinyl) butanamine f2S) _2- (4-ethyl-2-oxy-1-pyrrolidinyl) butanidine丨 Amine 2- {4-[(benzyloxy) methyl] -2-oxy-1-pyrrolidinyl} Butanamine 2- {heart [(benzyloxy) methyl] oxy-1-pyrrolidinyl } Butamidine η Compensator CN 1 Ϊ El · 菡 狴 4 m Λ Η 匕 1 CZ) '~ 1 148 149 150 1 151 152 153 154 155 — 114— 200538437

127.2 136.8 1 82.1 74.3 121.3 1 180.3 105.0 118.1 108.8 6 · 2 · 3. Then 6.3.1. (N 6 · 2 · 4 · then 6.3.1. 3 · 2 · 1 · then 6.3.2 · 2 · 1 · 1 · Then 2.2. Mixture Mixtures Racemic Racemic Mixture Mixture Gas CN CN 00 inch AC / T < N 00 inch Office 00 (N inch · (N < Γ B-2,4 | Gas CS Inch Office η Swallow 1 rH Λ Hf 1 (N ϊ ΒΝ) JiS 丨. 1 buried < N Ϊ h 1—J Λ w 2- [4- (2,2-difluoroethyl) -2-oxy -Pyrrolidinyl] butanamine (2S) -2-[(4S) -2-oxy-4-propylpyrrolidinyl] butanidine (2S) -2-[(4R) -2-ox Methyl-4-propylpyrrolidinyl] butanylamine 1 2- [2-oxy-4- (trifluoromethyl > bupyrrolidyl] butanylamine 2- [2-oxy-4- (Trifluoromethyl) -1-pyrrolidinyl] butyramine η 1 m Secret 1 (N 5 line N) Huan S tEQ Already 4 Η 砮 1 T—H mm 1 < N Slightly loaded E 1 rH 1 Slightly-m (N Η i slightly m 2- (4-butyl-2-oxy-1-pyrrolidinyl) butanamine 156 157 158 159 丨… 1 160 161 162 163 164-115- 200538437

-116- 200538437

311 [1 283 269 89.5 j 100.2 99.6 116.9 97.2 Wl bo 狯; 躲 hide "Η Μ ^ Λ 二 狯 狯 -i (N · • * fH CN ^. W) — rl: 一 < n — 〇ί — y —I rH CN ^ J < si — rH two_ i 3 swim 1 — · “^ mm yaxia < 1π m 窠 · < π mmm 窠 m medium 000 c t1 000 ^ 4 · inch inch 000 000 000 inch cs αΓ 00 气 Γ \ 1 CN 〇Γ inch CO inch C0 000 < s CN ν Ν ώ <; < N Οί < N troph <; < trophy <; 5 mnn 1 τ-Η η狴 铿 狴 ώ = e Hire 1 mmm Carefully swallow rH 1 / ~ N 1 /-N ΐ: SS 1 rH 1 1 r— (1 1 (N 1 rH 1 «S i slightly S m Jlf K) slightly K] Slight n acne n sacrifice I secret 1 < N ¥ noodle (NS 1 CS 砮 砮 1 / ^ s 1 / —N slightly / —N 1 1 1 rH 1 1 τ—Η slightly l · slightly 1 1 m «Λ IS 铿 揪 m Λ Secret m 111 i Slightly Secret 1 (N | 1 CN 1 (N mm sulfur, t Bl · 1 a 铿 \: j A 铿 1_J UJeJ m Λ 4 狴 4 ^ Λ _« _ CS ~ fl] ΓΠ Γΰ V η im A r7 • 00 1 ~ '〇0 1 ~~' 1 1 I Λ h 00 ' '/ ^ N 1 ~} C / D »~ * Zn ^ (N H 1 CN 1 (N 1 (Μ has been slightly 174 175 176 1 1 1 177 178 179 180 181 182 -117- 200538437

97.2 148.6 148.6 177.9 177.9 154.7 178.7 201.4 138.0 137.4 3.1.1.a S 3.1.1.gi 3.1.1.a Μ 3.1.1.g 1 3.1.1.a Μ 3.1.1.g 3.1.1.a $ 3.1.1.gm 窠 m 窠 racemic racemic m 窠 窠 B-2§, 4§ C-2 §, 4 § D-2§, 4§ coo inch · coo cs < coo gas 000 cs CQ A-2,4 (Ν FREE coo inch Λ οΓ CN FREE A-2 §, 4 § B-2§, 4§ 1 rH 嫲 1 CN Slightly alkaline plate ill SA slightly ^ n Zu ▼ -I m 嫲 1 CS ϊ ft m η- shout 铿 111 S 1iiis blow a little Sac A 砮 1 rH Λ m 1 CN 5 ti minus HI Ϊ A slightly i (N d 2- [4- (3,4-dichlorophenyl)- 2-oxy-1-pyrrolidinyl] butanamine 2- [4- (3,4-dichlorophenyl) -2-oxy-1-pyrrolidinyl] butanamine 2- [4- ( 2,4-dichlorophenyl) -2-oxy-1 · ®pyridinyl] butanamine 2- [4- (2,4-dichlorophenyl) -2-oxy-1-pyrrolidine [Base] Butamidine I rH Λ Secret < N 郏 II 1 4 m ^ h 2 ϊ sg Ϊ m ^ £ in ® V t ά _ 4 n «| ϋ. One 1 ϊ i sg double slightly & * ¢ 1 _ HI ® noon b ά 4 m Ml ^ Ilf ^ 3 slightly 183 184 185 186 "187 188 189 190 191 192 • " 118— 200538437

[23] [24] 84.4 83.8 92.5 118.6 153.8 154.4 99.8 3.1.1.a to 3.1.1.g! 3.1.1.a to 3.1.1.g CS · "… one: (N — 1.1.2.ii Then 1. · 2 · 1 · Then 1.2.2. 3.1.1.a M 3.1.1.g 3.1.1. A to, 3.1.1. G Racem | Racemic mixture 窠 m Mixture C-2 § , 4 § D-2 §, 4 § A-2,4 _i inch office < N 'FREE C / T < N 000 inch ^ α (N < C-2§, 4§, coo inch · coo cs Q inch CN slightly m slightly m P ^ t ά m 4 m «.,: Have two AW sm slightly III 5 ft i slightly 4« «| Ilf» 7 丄 A tip 2- [4- (2-furyl) 2-oxy-1-pyrrolidinyl] butanamine 2- [4- (2-furanyl) -2-oxy-1-pyrrolidinyl] butanamine 1 TH 1 1E 1 m 1 00 11 Has been swallowed 1 rH m 嫲 1 (N Ϊ Goose 11 1 4 Hall ^ t G supplement 2- [4- (3,4-dichlorophenyl) -2-oxy-1-pyrrolidinyl] Butan Amine 2- [4- (3,4-dichlorophenyl) -2-oxy-1-pyrrolidinyl] Butanamine 2- (2-oxy-4-propyl-1-pyrrolidinyl) Butylamine 193 194 195 1 196 197 198 199 200 201 Η19- 200538437

-Ί 20— 200538437

[25] CA Γ-1 [27] vd Bu 120.9 115.9 84.26 1 79.4 93.9 104 _ ΚΛ 6 · 2 · 3. Then 6.3.1. < N Η CN 2.1.1. Ran 2.2. 3.1.1.a; 3.1.1 '' $ d ^ οί rH (N 6.2.3 · Ran 6.3.1. 窠 窠 窠 mm 窠 窠 < π M 窠 m COD 000 coo oco coo coo 000 OQ inch ^ air gas air inch outside air C / T 〇〇〇 CO) COD ooo 000 ooo CN 000 inch r \ rf \ CN < N CN < N CN CN < s cs CN < PQ < 6 PQ Q PQ m 砮 1 砮 1 slightly 5 5 Η ac m m 1 τ Ή 1 r—4 1 / —N nnn 5 51 matter 1 CN 1 / —N slightly η rH 1 CN / ^ N Slightly E: E: Saccharine 1 τ-Η 1 1 rH 1 1 1 1 τ-Η I Hf Loading m 111 Right slightly 1 1 cs K) Shout 1 1 1 cn rn 1 rn Base 1 1 Secret 1 Base 1 S 5 if 1 1 1 1 1 (N rn ^ CO (N / ^ N < N / ^ N (N / ^-N 04 X-S η ffi- 1 1 1 < N < N ^ tcci 1 for 1 T complement 13 1 for tmm ^ 浒 ν— / K: xi hall m ^ __ slightly I aldehyde 狴 Pi HS 5 abu—ir— * (N l · 1 »~ J r— »Ffi- 1 fr 1 fr 1 S- 1« 4 m I-—J 1 S 5 A slightly < N Wf | c 狴 C 铿, H m Huipan imimi hall im 2 slightly ac rlj H (NH (NH & lt N Η r; m 213 214 215 i 216 217 218 219 220 221 222 — 121 — 200538437

R8] [29] < N On v〇inch wo v〇tH ^ H rH r > tH 00 Ό 〇 Os σΊ (N fH Όinch 〇 \ cn rH < N v〇〇 rH 5.8.… ≪ N Reference < N ^ Two · 鹚 < N 狯.… CS • fH · cs * ^ (N Li.… ≪ N CN · — < N • ^ · oi ^ —you CN m (N 窠 m 窠窠 m 锾 窠 ㈣ GOO gas αΤ cs trophy CO) inch office C / T CN free coo gas 00 CN < coo inch office c / i CS PQ COD inch office CO CN 〇00 αΓ < N < coo inch Λ 00 CN < coo inch · CO (N FREE GG 气 CO CN 二 coo * \ 00 'coo ^ (N 普 I swallow 1 rH 1 i 1 1 1 ffi i-Η 1 Λ ilf ^ ^ m γbu · -1 sr slightly i swallow 1 τ—Η na 1 < N m tE equipment 1 1 < N 00 = R c turn n Sheng I swallow 1 rH Λ secret 1 CN 5 moss 1 (N 4 ^ vm 1 h GO i ~~ i cs slightly n knot I 砮 1 rH secret 1 (N slightly hei 1 (S 4 ^ 00 '~' η 砮 1 1- 1 m secret 1 CS nf E- 4 ^ HC / D '' i ΗrH « Domain: 1 < N m K Post 1 1 CN has given m 砮 1 rH 1 s K mm 1 1 Λ secret a 狴 Λ Η CO I " ―1 has been slightly m # 1? * H 1 i E: slightly secret 1 T m Ilf a 狴 V m 1 h 00 '' d «Slightly 1 CS K m ^ ΓΠν 1 (N ^ I, * —, 00 inch 揪 ν ^ / > Πχ > Α C / D 1 ~ 1 G slightly tip 1 (N slightly E m ^ ΓΠ \ 1 Cl / 1 rN 00 Inch you nx > Λ Η 00 bucket 223 Inch (N (N (N (N N cs < N &N; N (N 00 CS CN ON CN CN om < N τ-Η m < N < Ν m (N -122- 200538437

[31] [32] [33] [34] 133.0 74.9 84.8 137.2 137.3 112 mm mm Racemic Racem 窠 Pi Inch. 〇w CO β cs 1 PQ coo Gas CO < N FREE INC < inch ^ 〇Γ ￥ 000 inch Λ 00 CN Free CO inch Pi < N Ρύ Pi CN A-2 §, 4 § B-2§, 4§ C-2 §, 4 § (2S) -2- [ (4R) -4- (2-hydroxypropyl) -2-oxypyrrolidinyl 1 butanidine m ¥ m 1 r— (! 铿 ώ 宁 ά ^ Φ 5 η (N / ^ S, 4J OQ ® Λ secret 1 < Ν 3 Huan in 1 Ό * \ DXI ^ m weight h S 5 v S 1 1 CN η m Hf 1 (N i 浒 nm 1 \ 〇inch 'you rs tCCi slightly h ^ 5 ig r 5 1 1 CN — secret 1 < N 1 i ^ ji ubi plastic tH 00 «(2R) -2-[(4S) -2-oxy-4-propylpyrrolidinyl] butanamine 1 (2R) -2 -[(4R) -2-oxy-4-propylpyrrolidinyl] butanamine 2- (4-ethyl-2-oxy-4-phenyl-1-pyrrolidinyl) butanamine 2 -(4-ethyl-2-carbyl-4-benzyl-1-¾thiol) butanylamine 2- (4-ethyl-2-oxy-4-phenyl-1-pyrrolidine Butylamine 233 234 235 ji | 236 237 238 239 240 241 242 -123- 200538437

361 361 229 112.2 73.5 58.6 59.7 133.3 68.2 96.4 2 · 1 · 2 · then 2.2. 6.2 · 2 · then 6.3.1. 6 · 2 · 2 · and then 6.3.1. 窠 m mixture mixture 窠 窠 窠 m D-2 §, 4 § A-2R, 4 § coo inch coo (N < B-2§, 4§ inch office ri Pi gas CN, < N A-2S, 4§ A-2S, 4§ COD gas 00 (N PQ 2- (4-ethyl-2-oxy-4-phenyl-1-pyrrolidinyl) butanamide η 1 mm (N s B- ilf ffi- 4 ^ Λ ^ έ t 2- [4- (methoxymethyl) -2-oxy-1-pyrrolidinyl] butanamine 2- [4- (methoxymethyl) -2-oxy-1-pyrrolidinyl] butanamine 1 τ-Η m 嫲 1 (N 1 slightly Ώτ 嫲 A ^ slightly S ν mi are all 1 1-H m 嫲 1 < N 5 6 secret η--looks like «5 eg m -vmz ^ a 砮 n slightly secret 1 (N 1 K m ^ ΓΠν 1 Inch S S ^ Λ Η 00 '~~' η Blanket I hire rH m IE 1 «Secret 1 (Νώ Er 4 铿 X, Λ Η 00 ^ d Swallow 1 rH Λ Secret 1 (N 线 line KII II CS ^ d _ 4 H rj _ ^ n swallow 1 m secret 1 < N s linked K1 base II A 铿 d epilepsy 4 ht—1 r—i 243 244 245 246 ——1 247 248 249 250 251 252 —124—

200538437

261 66.4 127.6 116.6 i 100 100.8 84.2! 87.8 rH vn VO 53.5 mmmm 窠 窠 m coo inch # NC / O cs < 000 inch f CO (S PQ 00. CN 000 inch office 000 CN < B-2§, 4 § C-2 §, 4 § 1 D-2 §, 4 § coo gas C / T cs CQ A-2S, 4§ CO) gas orT CN PLUS 2- (4 -ethyl-4-methyl-2- Oxy-1-¾-pyridyl) butanamide 1 2- (4-ethyl-4-methyl-2-oxy-1-pyrrolidinyl) butanidine 1 (2S) -2- ( 2-oxy-4,4-dipropyl-1-pyrrolidinyl) Butamidine. 砮 1 rH m 浒 1 m Secret 1 Bl · 11 丨 Hall St A right 1 m Hf 1 CN m BE -| 1 m ^ ϋ d: t 4 slightly m swallow 1 fH 1 m secret 1 CS m twist " 4ϋν 1 1 13X1 'm 3 t ίί «1 m 浒 1 m 嫲 1 CS twist' Jlb (| I 035 •丨 鳔 ^ tim 1 τ-Η Λ ΙΕ I m Secret 1 (N m XJ Λ h 00 ^ (2S) -2- (3-benzyl-2-oxy-1-pyrrolidinyl) butanamine (2R) -2- (3-benzyl-2-oxy-1-pyrrolidinyl) butanamine 253 255 256 257 1 _ '' 258 259 260 261 262 263 -125- 200538437

418/420 J / 422! 227 275 173.2 110.9 | 103.9 87.4 146.6 118 56.8 6.4.1. 1 2.4.2. 6.4.1. 6.4.1. Mixture mixture i 窠 窠 mmm Mixture mixture 窠 2,4 § 2,4S A-2S, 4§ A-2S, 4§ COD gas czT cs ￥ 000 CO " CN < 00 CN A-2,3 § B-2,3 § 1 A-2S, 4§ 2- [4- ( Bromoethynyl) -2-oxy-1-pyrrolidinyl] butanilamine 1 < NS minus II 1 (N 4 ^ human_ 00, S ^ 5 m • Na 1 CN slightly goose II 1 | CCE3 Slight_ 咢 t ά S 4 已 7 7 η Swallow 1 ▼ —Η mw 1 CN s K] Goose 4 ® Λ Η 00 '~~' ε Secret I CN s K] li 11 ίτ mw 1 it CN ^ / * N ϊ-Η 00 «Hexyl (2S) -2- (4-ethynyl-2-oxy-1-pyrrolidinyl) butanamide (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-2-oxy-1-pyrrolidinyl) butanamide! RH Secret 1 < N Twist > 1 cn w A 狴 vm 1 h in ^ 264 265 266 267 268 269 270 270 271 272 273- 126- 200538437

Swallow 1 τ—Η m 1 CN 5 Zeom I (N ii ® & · Distillation 5 Swallow 1 i-Η FREE Secret 1 CN 5 Ring 1 CN 锴 mit \) Η ά iaAc Swallow 1 rH SECRET 1 < N m 宓 m 1 CN mi u A \ — > i K + i A 砮 砮 1 τ-Η m 1 < N weight m 1 CN cA _ 4 t A «swallow 1 rH m secret 1 CN slightly louder I < N Slightly El · Hall 4 h 2 S r; n Slightly E 1 tH u 111 1 mmd: Slightly 4 m Λ tmw ^ m 1 Slightly E: 1 rH »Secret Λ h 00 '' 1 Secret 1 < Ν ϊ Κ] Slightly nf 3 m η soil W ^ η 1 rH ώ nf cs s bu 1 τ-Η Λ ^ fr 娘 i ii WA 会 会 盛 1 rr * H i 11 (N s .. 4 ^ Μ 00 '~, has been slightly 274 t > CN VO t > CN ϊ > CN 00 < N Os t > < N ο 00 CN rH 00 (N CN 00 CN m 00 (N -127- 200538437

259 284 257 1 1 355 丨 265 276 281 319 305 229 1.3.1. Then 1.3.2. 1.3 丄 then 1.3.2. 1.3 丄 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. 1.3.1. Then 1.3.2. 1.3.1. Then 1.3.2. 1.3 · 1 · then 1.3.2. 1.3.1. Then 1.3.2. Mixture mixture mixture mixture mixture mixture mixture outside rs inch λ ri inch CN CN gas CN CN gas (N CN inch · CN A Sheng I 1 ii E: 1 "π ϋ svh 1 slightly fr mm ro mm L · sm ^ ΓΓΤ ^ 5: m ^ 1E inch 1 1 ^ m slightly. ¾ Ning _ 'Τ) Pan butterfly 1 plastic (f # weight E B- ^ * ϋ «4 W Ε: 1 m secret 1 1 < N s τ like Inch = Q FREE__ My ^ 士 略 m ^ — — ^ ^ Da 1 rH FREE 1 Secret 1 already 1 (Ν δ w Inch TO Qin ΙΙΓ MV 1 ^ FREE Ml C ^ rA ^ 砮 1 m 1 cn 1 slightly m 砮1 τ— (ί inch you 1 ttc > «Μ 福 1 陧 d slightly lambda η m 1 1 m 1 in then I swallow 1 rH Ml r slightly crocodile W £ i _ < N prepare 3- (benzyloxy) -2 -(2-oxy-4-propyl-1-pyrrolidinyl) butanamine 3- (wetoxy) -2- (2-oxy-4-propyl-1-®pyridinyl) propanyl Amine 4-hydroxy-2 -(2-oxy-4-propyl-1-pyrrolidinyl) butyramine 284 285 286 287 j i-i 288 289 290 291 292 293 -128 ”200538437

215 〇 \ CSi H m rH m Os tH m BU 00 CN BU CS rH ON < N < N 〇cn rH 00 CN 1.3.1. Then 1.3.2. 狯 Η rH-;, m 1-1 t— H -q — ^ TH — · ΓΛ ^ — · ^ CO-r—1 "⑺ · < rj — hide H — · ^ rn ^-, ro —-^ ΓΟ-rH mixture loose 4π m loose < ίπ, Spiral < Π Lai < Π m Song 4n bet < am < Π m Song < n < N inch Λ < N inch office (N inch ^ ri < N inch λ inch office CN < sT < N inch CN 3-via-2- (2-oxy-4-propyl-1-pyrrolidinyl) propanamide 砮 1 r * H m κ 1 Λ Hf 1 1 CS ^ mme:, i N {g X Ϊ 砮 1 τ-Η m κ 1 Hf I 1 CN / ^ N butterfly i 铿 ig mm κ * m fr ^ κ I rj- m nf 1 < N ^ 1 CN s ^ Yuei _ S 2 S fr {g Secret l · 萁 έ — r; mm IE 1 m Secret 1 df (N _ ji Μ E m «η n Π1acrylic 砮 v— ^ 1 m T m E: 1 FREE Secret 1 < N 1 paste * t cup | s fe IE f S bu W " t 5 I 1 m 1— * 1 rH m IE 1 Wi secret 1 Cj ^ 1 CN / * N Slightly mmmh ^ 3 ffi ~ 4 • i τ-Η m IE 1 m Secret 1 < N 1 (N _ 铿 邂 譲 Wi H s fi 4 mm Secret 1 d 1 < N Slightly | i & a mp; IE f S £ n slightly acne key — ^ Λ I 1 r〇 inch in swallow 1 r — Η m E: 1 Λ secret shed 1 (N Λ 1U 铿 Utah Hall; r 294 O ^ N (N Ό 〇 \ < N CN Os CN 〇〇C \ CN 〇 \ 〇 \ < N ο ο m rH om CN 〇 mm 〇m «129- 200538437

227 267 _1 239 239 255 1 241 316 331 320 289 1.3.1. Then 1.3.2. 1.3.1. Then 1.3.2. 1.3.1. Then 1.3.2. 1.3.1. Then 1.3.2. 1.3. L then 1.3.2. 1 1.3.1 · then 1.3.2. 1.3.1. Then 1.3.2. 1.3.1. Then 1.3.2. 1.3.1. Then 1.3.2. 1.3 丄 then 1.3.2. Mixture mixture mixture mixture mixture; mixture mixture mixture mixture mixture Λ (Ν and (N inch office CN CN r < T gas CN (N 2- (2-oxy-4-propyl-1-pyrrolidinyl ) Pentamidine 2-cyclohexyl-2- (2-oxy-4-propyl-1-pyrrolidinyl) | Acetylamine 3-cyclopropyl-2- (2-oxy-4-propyl -1-pyrrolidinyl) propylamine Λ slightly η blanket I swallow 1 Τ—Η mr 1 Ilf V ^ mechanical 1 avoid 1 1 inch 5 -methyl-2- (2-oxy-4-propyl-1 -¾ Slightly steep) Hexamidine f- 2- (2-oxy-4-propyl-1-pyrrolidinyl) Hexamidine plug τ-Η 1E 1 m 1 1 5 ^ 浒 _ mgs η cA Ac m κ 1 m 嫲 1 1 CN s ft 1 slightly} e secret U77 ms 1 forget 砮 cA 砮 1 rH IE 1 Τ m 嫲 1 I (NI 5 ^ roll_ slightly g feed butterfly 1 Sr rAAc 2 ^ 2-oxy-4-propyl-1-pyrrolidinyl) -4-phenylbutyramide 304 305 306 307 ______1 308 309 310 311 312 313 -130- 200538437

379 Os cs 〇m rH m < N m 〇 \ 00 CN m 〇 \ < N m os CN cn 〇 \ cs rH rH C <) 1.3.1. Then 1.3.2. Tap H-rn — i- H Xiang Li H rn — co — r — H 鲦 Η —. cn — τ-Η 狯 H cn ^ rH cn-rn — edge oj-rn — r ^ H Li H — ⑺ · cn — tH mixture < ln 蜉 < ίπ m 孬 4π m. < n gambling < Π m < ln Compensation < ίπ m (N 'Qi r &T; T inch office (N < N inch office CN inch office CN inch office CN inch Λ CN CN inch · (N m κ 1 m Hf tt < N 1 / -N Slightly 浒 _ Slightly E Age 5 i Dad 1 1 CO τ ~ Η 砮 1 rH m IE 1 m Secret 1 d 1 < N 1 ϋ ^ Roll _ m IE is called an r; n ttH IE 1 m 1 has 1 (N s ^ 浒 hall mg fr is a r r ac 1 m K 1 m secret 1 < N 1 (N m ^ 4 铿 1 m 浒 K fi 锃 m m m blanket I 砮 1 rH «K The ancestor m 1 d 1 < N 1 is slightly two E: w ^ rA m 砮 1 Η Λ 1 m 嫲 1 d 1 (NS s 枨 濯 mg & slightly 4 稍 ν j j CHI rA 盛 盛 I swallow 1? -H m 雠 li secret 1 d 1 CS butterfly 1 ijij i Wi cA n swallow 1 rH IE 1 m Jii 1 CN ^ 1 (N 5 m m_ li £ i slightly cA n swallow 1 rH m E ： 1 m Hf 1 CN ^ 1 CN 1 City 1 铿 crocodile Hi K ά a little cA η Swallow 1 m E 1 «m 1 1 CN t t11 民 4« rAac314 vn m Ό rH C ^ i τ- Η m 00 rH m Q \ rH o < N m cs c < ^ CN CN r〇m < N m 131- 200538437

354 rH o inch 〇 \ O CO os 〇m ON 〇m O Os < N 00 < N CN On 00 inch 00 < N 1.3.1. Then 1.3.2. Li Li-, cn — τ — 4 cn — RH CO — rH — ^ cn ^ cn — — ^ CO ^ rH Escape ΓΟ — 1—1 — ^ ro ^ rH Blend pine < ίπ < ίπ Laixon < ίπ m < ίπ m < ίπ m Loose < Π m < ίπ m < Π Compensation ^ CN qi CS < N inch outside CN inch office (N qi < N qi ri (N 啰 1— (Λ r 1 Λ secret 1 1 CN 1 5 ^ Gi · gigi cA n 1 rH m κ 1 mw 1 CS ^ 1 < N 1 s ^ __ instead of gi _ cA n 1 τ-Η Κ 1 Λ m 1 has 1 (N 5 ^ 浒 箭 ugi _ c; n swallow 1 1—Η ΙΕ I «Hf I 1 CN 1 S ^ crocodile u £ ά w cA n 1 tH Λ K 1 may m secret 1 d 1 < N 1 Ϊ ^ _ ill £ i cA n砮 1 tH ii k 1 m Secret 1 CL 1 < N s ^ Roll_ mg Pan Secret 1 s ^ cAac 5i m Knot I Swallow 1 t—i FREE K 1 m nf 1 1 < N «4 m 狴 娘5 S mw is n ss m τ 工》 complement (e ^ 4 n ^ CN iw 2 A 1 Z mm 1 rH m) E 1 Λ 嫲 1 1 < N i ^ -m «4¾ Sac; Da 324 ν / Ί (N m Ό < N m l > < N (T) 00 < N m Os < N m O m t-H m ro CN m m -132- 200538437

299 352 338 348 595 1 242 1 348 326 329 424 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 丄Then L3.2. 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. 1.3.1 · then mixture mixture mixture mixture_ί Mixture [-mixture mixture mixture mixture mixture gas 2,4,4 2,4,4 inch rs inch 3a, 4,6, a, 2,4 5 inch gas inch " gas (Ν 1 τ-Η m κ 1 m 11 1 (NL · -m slightly ru is W sac ν d 2,5-2 (2-oxy-4-propyl-1-pyrrolidinyl) pentamidine 2,4- 贰 (2- Oxy-4-propyl-1-pyrrolidinyl) butyramine 1 τ-Η m E: 1 'I ¥ 1 τ λ ¥ S 1¾ «a price 5 rn I ^ r—ί 4 m ^ cn i · ^ tec tons of white white 5 w 〇] ring® commandment 1 FREE S ^ ^ ^ i 5 Λ «SE ά-ί * 厶 《械 1 rt Jii Ό ^ 'Dagger C 1 | No < N 5-amine Yl-2- (2-oxy-4-propyl-1-¾slopyryl) pentanylamine 1 m κ 1 ί c 饀 4 a · right · secret disk cA «1 Ur7 supplementary 1 rH ί wg 11 涯 ά i ηη · m S 狴 器 1 ^ η 铿 送 SS fr 稍 S 磐Pack 3 WT Secret 7 a slightly ^ E:; ΐ A slightly «« CCQ 1 SZ 芝 S 赵 6-amino-6-oxy-5- (2-oxy-4-propyl-1-¾ slightly 333 334 335 336 337 338 339 340 341 342 -133- 200538437

OO 〇 \ CA cs < nm < N 00 inch m inch < N r〇〇 \ mm 卜 〇 \ < N CN 00 CN vn (N (N m cn — i-H rn ^ 狯 Η ΓΟ — rH Condensate rn "^ -H — · ^ CO ^ rH 狯 Η — · ^ m ^ τ-Η hide Η rH cn 1-1 rH 1—H ΟΊ 1-4 < Π 蜉 < ίπ 蜉 < 1π mouth < Π m < Π media < π < ίπ < Π gambling m (S inch · ci 〇ί gas mm inch (S inch λ < N distillate *) < N κ i Sheng I swallow 1 rH m K 1 m 秘 1 1 CN Slightly mmsmmg 丄 Uii in U ^ J 1 VO in — 变 κ Ε 稍 密 稍 butterfly I ά m Α Κ) 6-{[(5- (2-oxyhexahydro-1Η -Thieno [3.4-d] imidazol-4-yl) pentanyl) amino} -2- (2-oxy-4-propyl-1-pyrrolidinyl) hexamidine 1 rH m E: 1 m ϋ 1 (N 1 m «4 watch mt 铿 commandment 1 4 n swallow 1 r * H free κ m m secret 1 < N trophy secret recipe 4« t 狴 slightly 4 pan swallow 1 tH «1« secret 1 CN ^? ® _ Γΰ 嫲 Brewing; 趑 »Negotiation S 铿 Swallow 1 rH Λ Lu m Λ 1 < NT Distillation r Hff Pack; 氍« s 狴 slightly m 1 m 1—H 1 ΓΟ 1 fi n 1 rH | E 铿 4 ^ W ^ ig complement 1 1 1 ^ < iJ (N 31 m installed 4¾ 1 lake n 砮1 r-H m K 1 T Λ secret 1 d 1 CN m inch CO inch inch ΓΛ inch m VO inch m b inch m 〇〇 inch m Os inch m o yn m r-H v〇 m —1) Zf — 200538437

314 229 259 1 _1 275 381 i _____... 256 1.3.2. 1.3.1. Then 1.3.2. 1.3 丄 then 1.3.2. 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. Mixture Mixture Mixture! _Ί Mixture Mixture 1 Mixture Inch 3R, 2, 4 inch ci inch Office < N inch Office CN gas CN # 1 τ-Η Λ Ε ： 1 m Secret 1 1 CS! Buried κ slightly C η (3R) -3-hydroxy-2- (2-oxy-4-propyl-1-pyrrolidinyl 1) butanilamine 1 rH me 1 m Secret eyebrow 1 CS «1 hwg 4 5 2- (2-oxy-4-propyl-1-pyrrolidinyl) -3-phenylpropanamine 砮 1 rH m κ 1 m 1 1 CN s ^ S m Hi e: UL ^ il mi cc; 铿 6-amino-2- (2-oxy-4-propyl-1-¾ acryl) hexylamine τ-Η m 1 1 Οί 5 κι Maple π 4 h lord butterfly 1 π disk has been. 1 m 赃 1 (N 1 Ϊ N3 li 11 I CN nmi _ cj n 1 mm CA s K) Jii II 1 CN mmd fc 2: slightly cs n 352 353 354: 1 355 356 357 358 359 360 135- 200538437

Solvent. DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO W NMR Description 0.80 (t, 3H); 1.4 (M.60 (m, lH); 1.75-1.95 (m, lH); 2.10 (dd, lH); 2.45 ( dd, lH, partially overlapping with 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 overlap with the solvent); 3.40 ( ιη, 1Η); 3.50-3.70 (m, 5H, partially overlapping with the solvent); 4.45 (dd, 1H); 6.9G (s (width), 1H); 7.3G (s (width), 1Η) · 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 7.30 (s (width), 1H) · 0.80 (t, 3H); 1.20 (d, 6H); 1.40-i.60 (m, lH); 1.70- 1.85 (111,111); 2.45 ((1 (1,111); 2.35-2.55 (111,111, with Rong Qi !!) (partial overlap); 2.55 (m, 2H); 2.90 (s, lH); 3.00 ( m, lH); 3.60 (m, lH); 4.30 (dd, lH); 6.90 (s (width), 1H); 7.30 (s (width), 1H). 0.80 (t, 3H); 1.20 (d, 6H); 1.40-1.65 (m5lH); 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 Overlapping with solvents); 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 (π, 5Η, partially overlapping with solvent); 4.30 (d, 2H); 4.45 (dd, lH); 6.90 (s (width), 1H); 7.35 (s (width), 1H) · 0.80 (t, 3H); 1.40 -1.60 (m, lH); 1.70-1.90 (m, lH); 2.20 (dd, lH); 2.45 (dd, lH); 2.60 (m, lH); 3.25 (m, lHj§ | Solvent overlap); 3.45 (dd, lH); 3.60 (d, 2H); 4.30 (dd, lH); 6.90 (s (width), 1H); 7.30 (s (width), 1H); 7.60-8.00 (m, 5H) .. 0.85 (t? 3H); 1.55-1.70 (m, lH); 1.80-1.95 (tn, lH); 2.65 (dd5lH); 2.85 (dd, lH); 3.45 (dd, lH); 3.80 (m, 2H) , 4.05 (m, lH); 4.50 (dd, lH); 6.80 (s (width), 1H); 7.40 (s (width), 1H); 9.20 (s, 1H) · 0.65 (t? 3H); 1.40-1.60 (m5lH); 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 np Ξ sn—! ss -136- 200538437

DMSO DMSO DMSO DMSO DMSO DMSO CDC13 CDCI3 r ^ H ^ Τ) • # \ rH W ο ^ Η β r ^ H • · Ν cn ^ 1 inch · • r \ ffi CO rn ffi r—1 g ^ ILINGof a S § HS 〇II-: I r 1 3 § 2 ^ Γι @ S | • rx Μ: ^ II § Os OIL (Λ 女 M ^ 琴 1 p 5 ig 11 § 3 ^ 2 Zi r—1 • Burnt t ^ 1 denier 2 ^ | 2 o B} j \ ^ d iS ^ 0.75 (t, 3Hkl.55-1.70 (m, lH); 1.8 (M.95 (m, lH); 2.50 (dd, lH, and Solvent overlap); 2.70 (dd, 1H); 3.30 (m, 1H, overlap with solvent); 3.70On, 1H); 3.90Cdd, 1H); 4.50 (dd, 1H); 6.90 (X width yH〇; 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, and solvent overlap); 2.75 (dd, lH); 3.40-3.80 (m, 3H), 4.45 (dd, lH); 6.90 (s (width), 1H); 7.20-7.25 (m, 5H) 0.80 (t, 3H); 1.50-1.75 (m, lH); 1.80-1 · 90 (π, 1Η); 2.45 (dd, lH, overlapping 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) .i0.80 (t, 3H); 1.55-1.70 (m, lH); 1.80-L95 (m, lH); 2.55 (dd , LH, overlap with solvent); 2.75 (dd, lH); 3.30 (m, lH ,, solvent overlap); 3.70 (dd, lH); 4.50 (dd, lH); 6.95 (s (width), 1H) ; 7.30-7.70 (ιη, 10Η) · 0.85 (t, 3H); 1.60-1.75 (m5lH); 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 (π, 1H); 4.40 (dd, lH); 6.95 (s (width), 1H); 7.30- 7.80 (m, 10) · 0.90 (t, 3H); 1.20 (s, 3H); 1.60-1.80 (m, lH); 1.80-2.10 (m, lH); 2.40 (dd, lH); 2.50-2.60 ( m, 3H, overlap with solvent); 3.20 (m, lH); 3.50-3.70 (m, 3H); 4.45 (dd, lH); 5.45 (s (width), 1H); 6.30 (s (width), 1H ). 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 (πι , 2Η); 5.30 r— ^ U ^ J r ~ nr—l TH L—J rH t—J r ^ n CrT fH U ^ J -137- o GO QO CO Q o in% Q osna O 00 Q o 00 QS s Q ^ fO QU τ-Η \ ό R 5? ffi, cn g 3 〇 / ^ oom ^ Tt CN… LSI Tians Tian Han 2g ^ I Fen * ^ | g · 衮 s CN inch SW ffi, T—1 Π3 a 3 vi ^ • · »\ ιό ®turn C ^ \ lrnl |. S§ έ s 差 弋 rn ο rn 2 g ί s V i #N _J § ^ as d rn \ 〇 • 9 \ 6? ^ H < N • »N o '(N C > fH 01 ffi Φ cs W 〇§ g ^ — • decay •« s 〇 旦 《v °) O v〇2 § ^ 5 ° 〇sa § § d > rn ^ T) r—H ΓΟ • r \ lean iH g (N • # \ rH r4 • r > iH | g E 8 Ϊ ^ lean 3 ^ 纲 rl 奋 〇W ON 3 >? ^ r- ^ • r \ 2 a * # \ N • ts • · N · »-H · & ^ 5s ^ 5 sa •, \ tH # \ so 'CO • # \ r—4 cs rs • r \ rH # \ s > n < N • # > ϊ ^ 1-H < NQ g § Xbu · 6 * ^ a ffi n — inch S ^ ίτΤ W »n ^ il; cn 4-Γ Ό ^ s 00 inch O CO» 〇: JQ ^ # \ • # \ White ffi t 〇g S °°. ^ rl l〇dn § 91 * > K 9 ^ $ 旦 έ s ξ J s ® 〇g VO || g iM ιΛ ffi «^ 1 〇 2 v〇g 巨 3 · #N ffi ^ ^ ^ ^ άά〆s 2 3 〇 .... •, ~ · Ν sss § ii § CO 铉 iH S. R—I as 乂 ^ Tian 3 3 VO s Dan Pan s Dan ^ 2 ^ 〇9 iiH • 外 3 Juqin 1 ^ § ffi ύ S-^ 旮 1 ^ a § 1 § rn ό rm * • f \ lean 3 〆 • mi—i —ΓΤ) 2 VO Ig (N ^ ffi ^ S * ® i 2 〇 犮 〇1 d ® i tH i -H 1 ^ ST: ^ g 1 a κ § once i a amm will Ϊ 2 • r \ · 1 ^ a-: § a < N ， g v ^ 〇wm § CN Divination? £ W 〆 2 «< N ^ 0? ^ • So ^ | 2 | α inch · • · r \ 1 aig • #N g & 3 ^ S s 豸 a 5o 1—H 1_ \ 2 CN, Γ—1 < NL ^ J p—is L ^ lr-i

138- 200538437

CDC13 DMSO CDC13 DMSO DMSO CDC13 DMSO DMSO CDCI3 0.90 (t? 3H); L60-1.70 (m, lH); 1.85-2.10 (m, lH); 2.25 (s, 3H); 2.55 (dd, lH); 2.85 ( dd, lH); 3.30-3.60 (m, 2H), 3.75 (dd, lH); 3.80 (dd, lH); 4.50 (dd, lH); 5.50 (s (width), 1H); 6.30 (s (width ), 1H); 6.90-7.10 (m, 3H), 7.20 (dd, 1H). 0.70-0.90 (χη, 3Η); 1.50-1.75 (m, lH); 1.80-1.95 (m, lH); 2.50-2.90 (m, 2H); 3.20-3.40 (m, lH, overlap with 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 (dd, lH); 2.40 (dd, lH); 2.60 (m, lH); 3.05 (dd, lH); 3.25 (s, 3H ); 3.30 (m, 2H, partially overlapping with the solvent); 3.55 (dd, lH); 4.30 (dcUH); 7.05 (s (width 7.40 (s (width 0.80 (t53H)); 1.41-1.63 (in, lH); 1.71-1.86 (m, lH); 2.12 (dd, lH); 2 .43 (dd, lH), 2.82 (m, lH); .3.2-3.4 (m, 2H); 4.23 (d, 2H), 4.31 (dd, lH), 6.97 (s (^), lH), 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 (dd5lH); 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〇; 1.52-1 · 70 (ιη, 1Η); 1.70-1.84 (m, lH); 2.5 (m, with DMSO Overlapping), 2.72 (dd, lH) 3 3.64 (m, 2H), 3.84 (m, lH); 4.39 (dd, lH); 7.05. (S (width), 1H); 7.42 (m, 2H). 0.81 (t, 3H \ 1.48-1.51 (m, lH); 1.80-1.94 (m, lH); 2.5 (m, overlap with DMSO), 2.72 (dd, lH), 3.78 (m, H), 3.95 (m, lH), 4.38 (m, lH), 7.05 (s (width), 1H), 7.42 (m, 2H). 1.02 (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 Γ ~ ϊ rn < r ~ i 1— (FT r—n ro c〇i -139- 200538437 #

GC / M M + 286 LC / M MH + 〇 \ < N 259 mm 1- 273 Configuration data 窠 Racemic racemic racem i 1 ζ / D coo < 00 r—Η r \ 000 ώ (N TH # \ ΓΟ C /) # \ m 00 r " H rv m IUPAC Chemical name 3-(((((lS) small (aminocarbonyl) propyl) amino) methyl) hexanoic acid ethyl ester 3-({[((lS) -l- (aminocarbonyl) propyl] amino} methyl) hexanoic acid ethyl ester hydrochloride < N 繇 S i B- i S £ 1¾ Title g S di m Λ Jg ^ Ξ; 1 • rH m I ^ | 3-({[((lS) -1- (aminocarbonyl) propyl] amino} methyl) butylhexanoate i hydrochloride 3-({[((lS) -1- (aminocarbonyl) propyl] amino) methyl) isopropylhexanoate hydrochloride AA-II ^ Compound No. AA1 AA3 AA4 AA5

Claims (1)

200538437 · · 10. Scope of patent application: No. 90 1 05824 "(2S) -2- [2-oxy-4-propylpyrrolidinyl] butanamides and their applications" Patent Division Application (3) Scope of Patent Application (Amended in July 1994) 1. A compound which is a (2R) -2- [2-oxy-4-propylpyrrolidinyl] butanamine (4R) and (4S) Enantiomers or their pharmaceutically acceptable salts. 2. —A treatment for mammals in need of epilepsy, epilepsy, seizures, convulsions and other neurological conditions including bipolar disorders, mania, depression, anxiety, migraine, trigeminal neuralgia and other neuralgia, chronic Pain, neuropathic pain, cerebral ischemia, arrhythmia, myotonia, cocaine abuse, stroke, myoclonus, idiopathic tremor and other dyskinesias, neonatal cerebral hemorrhage, amyotrophic lateral sclerosis, spasm State, Parkinson's disease and other degenerative diseases, bronchial asthma, asthma and allergic asthma, asthma syndrome, bronchial hyperactivity and bronchospasm syndrome, and allergic and vasomotor rhinitis and conjunctivitis The compound includes the compound or the pharmaceutically acceptable salt thereof as the active ingredient in the scope of application for the patent, and the combined pharmaceutically acceptable diluent or carrier. 3. The pharmaceutical composition according to item 2 of the patent application, wherein the disease to be treated is epilepsy, neuropathic pain, bipolar disorder or migraine. -141-