TWI300776B - Novel compounds - Google Patents

Description

1300776 IX. Description of the invention: Technical field of L inventions 3 The present invention relates to novel indoleamine compounds for inhibiting monoamine reabsorption, a preparation method thereof, a pharmaceutical composition containing the same, and the use thereof . I [Prior Art 3 [Summary of the Invention]

The compounds of the present invention exhibit activity as inhibitors of serotonin and/or norepinephrine reuptake and, therefore, have utility in various therapeutic fields. For example, the compounds of the present invention are useful in the treatment of diseases involving modulation of monoamine transporter functions, and more particularly in diseases involving inhibition of serotonin or norepinephrine reuptake. Further, the compounds of the present invention are used for diseases involving inhibition of serotonin and norepinephrine, such as urinary incontinence. Further, the compound of the present invention is used for diseases in which it is desired to preferentially inhibit norepinephrine or serotonin reuptake, such as pain, fibromyalgia, ADHA, and depression. According to a first aspect, the present invention provides a compound of formula (1),

And pharmaceutically and/or veterinary acceptable derivatives thereof, wherein: R1, R2, R3 and R2Q each are individually Η, a, Br, F, I, CF3, OCF3, Me or Et; 1300776 R4 is het or A7 cycloalkyl, optionally with a pure ruthenium of 2 to 4 carbon materials, & Cl.4, a system containing 0 or 1; (cw alkyl); het non-aromatic 4 , 5 or 6 membered heterocyclic rings, heteroatoms, selectively fused to 5 or 6M, at least -N's pure shop 7 to destroy each group or contain at least one hydrazine, hydrazine or from the second, 4, 5 or 6 members of the atom Miscellaneous if | L ^ t chen wherein the het group is selectively selected from at least one selected from the group consisting of Ci8 alkyl, K8-based lactide, OH, i-based, CF" 〇CF3, SCF3, hydroxy-Cl_6 alkyl, c U4 pit Substituted by a substituent of a fluorenyl-Cm alkyl group and a 匕4 alkyl-S-Ci.4 alkyl group; 10 but at least one of R1, R2 and R3 is other than H. In the preferred embodiment of the present invention, And R, R, i, cF3, Me or Et; Each of them is a, 玢, f, I, CF3, Me or Et ' and R3 is H, cn, Br, F, I, CF3, Me or Et. 15 In another preferred embodiment 'R1 is C or Me or CF3; R2 is H, Cl, or F; and R3 is H, Cl or F. According to another embodiment of the present invention, R2 and R20 are Non-H. In this embodiment, each of R2 and R2G may be Cl VF, CF3, Me, or Et. According to another embodiment of the present invention, R1, R2, and R2G are non-hydrogen. In an embodiment, each of R1, R2, and R20 may be Cl, F, CF3, Me, or Et. According to another embodiment of the present invention, R1, R3, and R2G are non-hydrogen. In this embodiment, R1 Each of R3 and R2G may be a, F, CF3, Me, or Et. 1300776 According to the above embodiment of the present invention, R4 may be eh-Wei-based, optionally with Cl. 4 decyloxy, An alkoxyalkyl group containing a hydrazine carbon atom, or a -s-(Cl y) group. According to another embodiment, r4 may be a cycloalkyl group, optionally substituted with Me or Et. In any embodiment of the invention, a may be 〇. According to any of the above embodiments of the invention, the het group may be substituted with _, _ 戋 two substituents selected from the group consisting of nucleus, 0H, Cl.4 and CF3.

- Examples, the het group of the compound as described above in relation to the first aspect of the invention and any particular embodiment may be unsubstituted. In another embodiment, the invention provides a compound selected from the group consisting of: 2,3·dichloro Icyclopentyl-N-[(3S)-pyrrolidine! Benzobenzamide, 2.3-dichloro|cyclopentyl_4H[(3S)_n-rrolidine! Alkylamine, gas-N-cyclopentyl-2-ylindolyl_N_[(3S)-pyrrolidine)] benzoic acid amine, cyclopentyl-3-fluoro-2-methyl county [( 3S)-pyrrolidin-3-yl]pyridylcarboxamide, 15 2-chloro-indole-cyclopentyl-3-fluoro-N-IX3S)-11pyrazole-3-yl]formic acid amine, 2.3- Dichlorocyclohexyl-N-[(3S)-pyrrolidin-3-yl]benzoic acid amine, 2-cyclohexyl! Fluorine-N-[(3S)-pyrrolidin-3-yl] arachidylamine, a group of cyclohexyl groups! Fluor-2-methyl-N-[(3S)-pyrrolidin-3-yl]benzamide, 2.3-dichloro-N-cyclobutyl-N-[(3S)-pyrrolidin-3-yl Benzomethionine, 20 N-cyclobutylmethyl-2,3-digas-N-[(3S)-pyrrolidin-3-yl] alum, amine, 2,3, dichloro (cyclopropyl) -N-[(3S)-pyrrolidinyl]benzamide, 2.3-dichloro-N-[(3S)-pyrrolidin-3-yl]-indole-tetrahydro-2H-pyranium Benzobenzamide, 2-chloro-indole-cyclopentyl-N-[(3S)-pyrrolidin-3-yl]benzamide, 1300776 2-gas-N-cyclohexyl-N-[( 3S)-pyrrolidin-3-yl]benzamide, 2-gas-N-cycloheptyl-N-[(3S)-pyrrolidin-3-yl]benzamide, N-cycloheptyl- N-[(3S)-pyrrolidin-3-yl]-2-(trifluoromethyl)benzamide, N-cyclohexyl-N-[(3S)-pyrrolidin-3-yl]-2- (trifluoromethyl)benzamide, 5 N-cyclopentyl-N-[(3S)-pyrrolidin-3-yl]-2(trifluoromethyl)benzamide, 2,3-di Chloro-N-[(l-methylcyclopropyl)methyl]-N-[(3S)-pyrrolidin-3-yl]benzamide, 3-chloro-2-methyl-N-[( 1-Methylcyclopropyl)methyl]-N-[(3S)-pyrrolidin-3-yl]benzamide, 10 N-(cyclobutylindenyl)-N-[(3S)-pyrrole Alkan-3-yl]-2-(trifluoromethyl)benzoguanamine, or Rheology and / or veterinary acceptable derivatives thereof. A pharmaceutically and/or veterinary acceptable derivative means any pharmaceutically or veterinary acceptable salt, solvate, ester or guanamine of the compound of formula (I), 15 or a salt or solvate of the ester or guanamine, Or any other compound of the compound of formula (I) or its active metabolite or residue can be provided (directly or indirectly) when administered to a recipient. For pharmaceutical or veterinary use, although the above salts are pharmaceutically or veterinary acceptable salts, other salts may be found, for example, for the preparation of the compound of formula (1) 20 and its pharmaceutically or veterinary acceptable salts. The aforementioned pharmaceutically or veterinary acceptable salts include the acid addition salts thereof and the base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, aspartate, benzoate, besylate, bicarbonate / 1300776 carbonate, hydrogen sulfate / sulfate, dextrocamphor, citrate, semi-citric acid Salt, ethanedisulfonate, hemi-ethanedisulfonate, ethanesulfonate, fumarate, glucoheptonate, gluconate, gluconate, citrate, gas-gas® salt Vapor, hydrogen >sour acid salt/>smell, hydroxystearate/e5, hydroxyethyl acid salt, lactate, malate, maleate, malonate, methanesulfonic acid Salt, sulfhydryl sulfate, 2-naphthyl acid salt, nicotinate, nitrate, orotate, pamoate, phosphate/hydrogen phosphate, dihydrogen salt, sugar, hard Fatty acid, succinate, tartrate, and tosylate. 10 Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum, arginine, N,N'-bis-decylethylenediamine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, unloading, Sodium, trimethylamine and zinc salts. For a detailed review of suitable salts, see the "Pharmaceutical Salt Handbook: Properties, Selection, and Use", Stahl & Wermuth (Wiley-VCH, Weinheim, Germany, 2002). The pharmaceutically acceptable salt of the compound of the formula (I) can be easily produced by mixing the compound and the acid of the person or the liquid of the tester (suitable). The salt can be precipitated from the solution, and Collected by filtration, or may be recovered by evaporating the solvent. The degree of salting of the salt may vary from fully ionized to almost non-ionized. The pharmaceutically acceptable solvate according to the invention comprises a hydrate of the compound of formula (1) and Solvate. Also within the scope of the present invention is a complex such as a clathrate comprising a drug - 1300776, a complex of hydrazine, wherein, contrary to the solvate described above, the drug and the host. Partial stoichiometry or non-stoichiometry The present invention is also included in the present invention as a pharmaceutical drug containing one or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts. The complex 5 formed may be ionized, partially ionized, or non-ionized. For a detailed investigation of such complexes, see J Pharm Sci, Bao (8), 12691288, Haleblian (1975 8 φ) The compound of formula (1) can be modified with any functional group of the compound to provide a pharmaceutically or veterinary acceptable derivative thereof. Examples of such derivatives are described in DrUgS 〇f Today. Book 19, No. 9, 1983, pages 499-538, Topics in Chemistry, 31st, pp. 306-316; and "Design of pr〇drugs, Η· Bundgaard, Elsevier '1985 'Chapter 1 (the disclosures of which are incorporated herein by reference) and include: esters, carbonates, half esters, phosphates, lithographs, Sulphuric acid S, sulphate, decylamine, decylamine, amino phthalic acid, azo compound, phosphorus amine, glycoside, ether, shrinkage, and ketal. B Those skilled in the art will learn more about certain departments. (this technique is called "pro-moieties", for example, H. Bundgaard" The design (ibid) can be placed on these suitable functional groups when a functional group is present in the compound of the invention. The compound of formula (I) is due to the asymmetric carbon atom of the pyrrolidin-3-yl moiety. And may have one or more pairs of palm centers by means of another asymmetric carbon atom defined by some meaning of R4. While the 3-position stoichiometry is fixed, any other pair of palm centers can exist in any possible stereoisomer form 1300776. It will be understood that the invention encompasses all isomers of the compounds of the invention, including geometric, tautomeric and optical forms (except for the 3' position of the pyrrole moiety = except for the palm center), and mixtures thereof (eg, a mixture of metameric or racemic compounds).

10 15 The compounds of the invention may exist in one or more tautomeric forms. All tautomers and mixtures thereof are included within the scope of the invention. For example, 2-hydroxypyridine is also contemplated to encompass its tautomeric form, pyridone. It is to be understood that the present invention encompasses radiolabeled compounds of formula (1). The compounds of formula (I) and their pharmaceutically and veterinary acceptable derivatives can also exist in more than one crystalline form, referred to as polymorphic. All such polymorphic patterns ("polymorphs") are included within the scope of the invention. Polymorphisms may occur as a function of temperature or pressure or both, and may also occur as a result of changes in the crystallization process. Polymorphs can be distinguished by various physical properties. Typically, X-ray diffraction patterns, soluble behavior, and chemical secrets can be used to distinguish

Any alkyl group may be straight or branched and is 1 to 8 1 to 6 carbon atoms or fluorene to 4 carbon atoms, for example, unless otherwise indicated by a carbon atom, such as methyl, ethyl, n-propyl. , isopropyl, n-butyl, isobutyl, t-butyl or di-butyl. If the alkyl group contains more than one carbon atom, it may be a sum. Thus, the 'c,6-alkyl group contains the c26 dilute group and the C26 fast group. Similarly, . The alkyl group contains a C2.8 alkenyl group and a C2. humyl group, and the heart-burning group includes a C2-4 alkenyl group and a C2_4 alkynyl group. Nan Su - is used to represent fluorine, chlorine, desert, or iodine. 20 1300776 Unless otherwise indicated, the het-word contains any non-aromatic, unsaturated, unsaturated 4, 5 or 6 members of up to 4 heteroatoms selected from n, q, and s. Examples of such heterocyclic groups include furyl, thienyl, pyrrolyl, oroprolyl, pyrrolidinyl, imidazolyl, dioxolanyl, oxazolyl, indolyl, imidazolyl, imidazoline Base, imidazolidinyl, pyrazolyl, oxazoline, pyrazolidinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, oxadiazolyl, fluorenyl, tetrahydro σ Bisyl, pyridyl, piperidinyl, _. Subunit, morpholinyl, dithiaalkyl, thiomorpholinyl, fluorenyl, pyrimidinyl, pyrazinyl, piperidinyl, sulfolyl, tetradecyl, triazinyl, azepine, 10 Anthraquinone, thiazepine, dioxeine, and thiazolinyl. In addition, the term "heterocyclic ring" includes a fused heterocyclic group, for example, benzimidazolyl, benzoxazolyl, imidazopyridyl, benzepoxy, benzothiazepine, pyridopyridyl, benzo Furanyl, porphyrinyl, oxazoline, anthraquinone, dihydro-π-spin, benzo-saltyl, quinone-indenyl, benzodiazepine, 15吲哚 and Hey. The terms of het, heterocyclic group and heterocyclic ring are similarly explained. For the avoidance of doubt, unless otherwise indicated, the term "substitute" means substituted with one or more defined groups. Where the group may be selected from a plurality of selected groups, the selected groups may be the same or different. Furthermore, individual terms mean that if more than one substituent is selected from several possible substituents, such substituents may be the same or different. Thereafter, the compound of the formula (1), and the pharmaceutically and veterinary acceptable derivative thereof, the above-mentioned radiolabeled analogs, and the above-described polymorphs, are referred to as "the compounds of the present invention". In one embodiment of the invention, the compound of the invention is a pharmaceutically and veterinary acceptable derivative of a compound of formula 1300776, such as a pharmaceutically or veterinary acceptable salt or solvate of a compound of formula (1) (eg, a pharmaceutically or veterinary acceptable salt of a compound of the formula 'I). In another embodiment of the invention, there is provided a compound of the invention which is a serotonin and/or de-ephedrine-ephrine monoamine reabsorbent having a SRI or NRI Ki value of 200 nM or less. In another embodiment, the compound has a SRI and/or NRI Ki value of ΙΟΟηΜ or less. In another embodiment, the compound has an SRI or NRI Ki value of 50 ^ nM or less. In another embodiment, the compound has an SRI or NRI Ki value of 50 nM or less. In another embodiment, the compound has an SRI or NRI Ki value of 25 nM or less. According to Scheme I, a compound of formula (V) (i.e., a compound of formula (1) wherein a is 1) can be reacted with a compound of formula (VI) by reaction with an aldehyde R4CHO followed by an acid or acid halide as indicated The reaction (i.e., X-ray OH or i-group) is prepared by deprotection. A 15 Process 1 13 1300776

Ο VII VII PG

Η广FC In the above scheme, R1, R2, R3, 尺4 and 尺2〇 are as defined above for the 'a system 1' and the PG is a suitable protecting group. (a)-Reductive amine interaction 5 The decylamine (VI) reacts with an aldehyde to form 2. The amine (VII) is a reductive amination reaction in which a dehydrogenation reaction of an amine and an aldehyde is carried out in a suitable solvent and the resulting imine is reduced by a metal hydride reagent or a hydrogenation reaction at room temperature. In this reaction, the molars; the amine and the route of S are typically in a suitable solvent (eg, DCM, THF) and at room temperature with sodium triethoxyborohydride (STAB), 10 NaCN (BH) 3 or NaBHU. Handle for 1 to 24 hours. In addition, an excess of reducing agent (eg, NaBH4, UAIH4, STAB) in a suitable solvent (eg, THF, MeOH, EtOH) is added after the amine and aldehyde have been mixed for a period of one hour, the selectivity being attached to a desiccant (eg, molecular sieve) The water is removed in the presence or using a Dean-Stark apparatus with a suitable solvent (eg, toluene, xylene). Alternatively, 14 1300776 is involved in the presence of a palladium or nickel catalyst (eg, Pd/C, Raney surface) and is selective to high temperatures and pressures in a Η: atmosphere, suitable for dissolution (eg, m〇H) Catalytic hydrogenation reaction. A more specific example of a reductive amination reaction involves the presence of an aldehyde in the presence of 1% pd/c in 5, optionally in the presence of triethylamine in ethanol and at about 415 kPa (about 60 psi) of hydrogen and in the chamber. It was treated with warm amine for 18 hours or treated with excess sodium hydride for 6 hours at room temperature in methanol. It is apparent to those skilled in the art that acid, ketone or other suitable carbonyl containing reagents can be used in the reductive amination step under suitable conditions. The formation of 10 (b)-guanamine forming acid or acid halide and amine (VII) peptide bond can be carried out by using: (i) ii & base halide and amine (VII), Suitable for excess acid acceptor in the solvent, or 15 (indolic acid), optionally with conventional coupling agents, and amine (VII), selective in the presence of a catalyst, and in excess of an acid acceptor in a suitable solvent. Examples of such reactions are as follows: (1) acid gasification (selectively in situ reaction) with excess amine (VII), optionally with an excess of 3 ° amine (such as Et3N, Hunig base or NMM) at 20 DCM In benzene or dioxane, selective for high temperature reaction for 1 to 24 hours; (ii) acid, WSCDI/DCCI/TBTU and HOBT/HOAT with excess amine (VII) and excess NMM, Et3N, Hunig base In THF, DCM or EtOAc, react at room temperature for 4 to 48 hours; or (iii) acid and PYBOP®/PyBrOP®/Mukaiyama reagent with an excess of 15 1300776 amine (VII) and excess NMM, Et3N, Hunig base in THF It is reacted at room temperature for 4 to 48 hours in hydrazine, Dcm or EtOAc. If the acid sulfonate is acid chloride (ie, X = C1), this can be produced in situ by standard methods, then with amine (VII) and triethylamine in dioxane 5 and at 70 ° C reacted for 90 minutes. (cV deprotection effect if PG is a suitable amine protecting group, preferably BOC, trifluoroacetic acid or phenylhydrazine, PG is removed from (VIII) to form unprotected amine (V) by ,,Protective Groups in Organic 10 Synthesis, 3rd edition, TW Greene & PGM Wuts· John Wiley &

The method of selecting a protecting group as detailed in Sons, Inc., 1999, which is incorporated herein by reference, is incorporated. An example of a temple deprotection reaction is as follows: When PG is BOC, deprotection involves making (νπΐ) an excess of strong acid (Example 15 such as Ηα, τρΑ) at room temperature and in a suitable solvent (eg, DCM, EtOAc, II) ° bad burn) treatment. When PG is trifluoroacetate, deprotection involves making (VIII) a base (eg, 'K2C03, Na2CO3, NH3, Ba(OH)2) in an alcohol solvent (eg, MeOH, EtOH), optionally having water and Selective for high temperature processing. 20 When the system is used, deprotection involves the presence of a hydrogen donor (eg, nh4+hccv) in a polar solvent (eg, tetrahydrofuran, ethanol, methanol), selective temperature and/or pressure in the south. Transfer hydrogenation reaction of a transition metal or transition metal salt hydrogenation catalyst (for example, Pd/C, pd(0H)2), or in the presence of Ib or a nickel catalyst (for example, Pd/c, Raney® Ni) Under the H2 atmosphere 16 1300776, it is selective to the temperature and pressure of helium, and is suitable for catalytic hydrogenation in a solvent. More specifically: When PG is BOC, deprotection involves an excess of 4m hydrochloric acid to two. The mixture was treated with decane at room temperature for a period of 4.5 hours or at room temperature with TFA at room temperature for 4.5 hours. When PG is trifluoroacetate, deprotection involves treatment with k2c〇3 in a mixture of methanol:water (5:1 to 1〇:1) and treatment at room temperature for 18 hours. When PG is Bz, deprotection involves treatment with nh4+HC02· and 10% Pd/C in 1 〇 ethanol and under mild reflux for 6 and 2 hrs. Further, the preparation of the secondary amine compound (VII) from the primary amine compound (VI) is described in the following schemes la and lb.

17 1300776 wherein PG is a suitable protecting group and R4 is as defined above. According to the scheme la, the compound of the formula VII can be prepared from the compound of the formula vi by reacting with the rhodium chloride, then subjecting the formation to the thiolation reaction with the base amide, and then removing the sulfonyl moiety. 5 Preparation of guanamines, such as molar amines (vi) and chlorinated chlorine (such as '2,4-disuccinylbenzenesulfonyl chloride) in a suitable solvent (such as dcM, THF, or stupid) Reacting in the presence of an organic base (such as pyridine or 2,6-lutidine) or an inorganic base (such as a carbonate) for up to 24 hours to provide a sulfonyl decylamine (XAA) 〇 10 ^ 1 rim Alkylation of the base amine XAA The sulfonyl decylamine of the formula XAA uses the active alkylating agent XBB, wherein the X-based leaving group (such as a halogen such as iodine, bromine or gas) or a sulfonyl ester The alkylation reaction (such as, for example, mesylate) is carried out in an organic or inorganic assay in a suitable solvent such as DMF or THF. In addition, the alkylation reaction of the chemical formula XAA can be carried out by using alcohol XBB (wherein X-based OH), lining (such as triphenylphosphorus) and azodicarboxylate compounds (such as DHDA). This is achieved in a solvent such as THF at a temperature between -20 ° C and 45 ° C for up to 24 hours. The sulfonyl group is transferred to a compound of the formula XCC in an organic solvent (such as triethylamine) or an inorganic base (such as a carbonate or hydroxide) in a suitable solvent (such as DCM, THF or lower alcohol). And with a thiol (such as thioglycolic acid), selectively treated at temperatures of up to 24 hours. , flow lb 18 1300776

AAA (X=OH or *base)

(y) BH,

In the above scheme, R4 is as defined above, and PG is a protecting group. Thiolation-cyclic Reaction According to Scheme lb, the compound of formula (VII) can be from the chemical formula (VI) 15 . The amine is reacted with a carboxylic acid or acid halide AAA (optionally prepared in situ) of R4COX (wherein X-based OH or a halogen group), followed by reaction with a reducing agent (e.g., shed). The formation of a peptide bond between (X)-guanamine forming acid or acid halide and decylamine (VI) can be carried out by using 10 as follows: (1) Mercapto halide and amine (VI) In the presence of an excess of acid acceptor and in a suitable solvent, or (ii) an acid, a selective conventional coupling agent, and an amine (VI), optionally in the presence of a catalyst, in an excess of acid acceptor and in a suitable solvent. 19 1300776 Examples of this reaction are as follows: (iv) acid chloride (selectively in situ reaction) with excess amine (VI), optionally with an excess of 3 ° amine (such as Et3N, Hunig base or NMM) In DCM or dioxane, selective for high temperature reaction for 1 to 24 hours; 5 (ii) acid, WSCDI/DCCI/TBTU and HOBT/HOAT with excess amine (VI) and excess NMM, Et3N, Hunig base Reaction in THF, DCM or EtOAc at room temperature for 4 to 48 hours; or (iii) acid and 1-propylphosphonate cyclic anhydride/PYBOP®/PyBrOP®/Mukaiyama reagent with excess amine (VI) A quantity of NMM, Et3N, Hunig base was reacted in THF, DCM or EtOAc at room temperature for 4 to 24 hours. A more specific example of the formation of the guanamine involves the treatment of the acid in the presence of an amine in the presence of 1-propylphosphonate cyclic anhydride in DCM in the presence of triethylamine and at room temperature for 1 hour. 15 If the acid halide is an acid gasification (ie, x = ci), this can be produced in situ by standard methods, then with amine (VI) and triethylamine in dichloromethane at 70 ° c Reaction for 90 minutes. (V) - Cyclic reaction The reaction (y) is, for example, by a hydride reducing agent under suitable conditions. Conveniently, the reduction of the indoleamine is carried out in the presence of borane and refluxed in THF for 2 hours, after which time the addition of methanol and aqueous gasification is carried out for 4 hours. According to Scheme 2, the compound of formula (IX) can be obtained from a compound of formula (VI) by reacting with R4-(CH2)aL (wherein a is as defined above, and l is from 20 1300776 base), under suitable conditions. Prepared by reaction. The resulting compound of formula (ι) can then be converted to the compound of formula (I) by guanamine formation and deprotection similar to that described above with respect to Scheme 1. Process 2

In the above scheme, R!, R2, R3, R4, R2 and a are as defined above, PG is a suitable protecting group, and L is a leaving group, the meaning of which depends on the nature of the reaction and the particular reaction conditions used. . Suitable leaving groups are apparent to those skilled in the art and are described in many standard organic chemistry textbooks, for example, "Advanced Organic Chemistry", Jerry March, 3rd edition, Wiley (1985), page 587, incorporated herein by reference; it contains a halogen (for example, Br) and a sulfonate (for example, methanesulfonate or trifluoromethanesulfonate). According to Scheme 3, a compound of formula (IX) can be prepared from a ketone 21 13 〇〇 776 of formula (XII) by reaction with a primary amine R4-(CH2)a-NH2 under suitable conditions. However, the resulting compound of formula (IX) can be converted to the compound of formula (I) by formation and deprotection of the guanamine similar to that described above for Flow Cake 1. Process 3

(X=OH or halo)

In the above scheme, R1, R2, R3, R4, R2G and a are as defined above, and a true PG is a suitable protecting group. The reaction of the primary amine R4-(CH2)a-NH2 with a ketone (oxime) is conveniently carried out to reduce the oximation reaction, wherein the dehydrogenation of the amine and the ketone is followed by the formation of a hydrazine, for example, by a metal hydride. The reagent or hydrogenation reaction is carried out under suitable reaction conditions. Conveniently, the reaction of the amine and the ketone is carried out in the presence of titanium tetraisopropoxide (IV) in THF at room temperature, after which it is reacted with an excess of sodium hydride in 曱22 1300776 alcohol at room temperature for 5 hours. Those skilled in the art will be able to select the most suitable synthetic route for the desired compound of formula (I). The above described process can of course be suitably modified in accordance with the general knowledge known to those skilled in the art. 5 Those skilled in the art will recognize that one or more of the sensitive functionalities may be protected and deprotected during the synthesis of the compound of formula (I). This can be achieved by conventional techniques, for example, the protective group of organic synthesis, (Pr〇tective

Groups m Organic Synthesis), 3rd edition, TW Greene & PGM Wuts. John Wiley & Sons, Inc., 1999 (which is hereby incorporated by reference), which also describes the removal The method of these groups. It will be apparent to those skilled in the art that certain protected derivatives of the compounds of the invention (which may be before the final deprotection stage) may or may not possess pharmacological activity, but in some instances may be administered orally or enterally. The drug is administered exogenously and thereafter metabolized in the body to form a pharmacologically active compound of the invention. Therefore, such a 15 derivative can be described as a prodrug. Furthermore, certain compounds of the invention may be used as a precursor to other compounds of the invention. Thus, in accordance with another aspect of the present invention, there is provided a compound of formula (1) which comprises a compound of formula (IX)

20, wherein 'R and a are as defined above and the protecting group reacts with the acid or sulfhydryl complex of formula (9), 23 1300776

Among them, X is an OH or a halogen group, and is deprotected.

If a is 1, the compound of formula (IX) can be prepared by reacting a compound of formula (VI) with an aldehyde R4CHO.

NM

Further, a compound of the formula (IX) can be produced by reacting a compound of the formula (VI) with a compound R4-(CH2)aL, wherein the L is a leaving group, optionally selected from the group consisting of a halide and a yellow stone. The acid S is intended to be the same as trifluoromethane sulphate. Further, a compound of the formula (IX) can be produced by reacting the compound of the formula (XII) with the compound R4(CH2)aNH2.

Some of the intermediates described above are novel compounds and it is believed that all novel intermediates herein are further aspects of the invention. The racemic compound can be isolated by preparative HPLC and a tube having a palmitic static phase of 24 1300776 or by re-dissolving to produce individual enantiomers by methods known to those skilled in the art. Further, the palmitic intermediate compound can be redissolved and used to prepare the antagonistic compound of the present invention. According to another aspect of the invention, one or more metabolites of a compound of the invention formed in vivo are provided. The compounds of the present invention may have more potency than the compounds of the prior art, have a longer duration of action, have a broader range of activities, are more stable, have less field J action, are more selective, and have better spin-on properties. Or have other more useful properties. The compound of the present invention is useful for its pharmacological activity in mammals (including humans). Therefore, it can be used for the treatment or prevention of diseases involving the regulation of monoamine transporter function, more particularly, a disease involving inhibition of serotonin or norepinephrine reuptake, and in particular, inhibition of serotonin and norepinephrine Sudden disease. 15 Accordingly, the compounds according to the invention are used for the treatment of urinary incontinence, such as true stress incontinence (GSI), stress urinary incontinence (SUI) or urinary incontinence in the elderly; overactive bladder (OAB), including spontaneous purulent muscles Unstable, neurological diseases (10) such as Parkinson's disease, township sclerosis, ridge injury and towel wind secondary to detrusor overactivity, and bladder outlet obstruction (eg, good 20 (10) H), urethral stricture or change Narrow) secondary detrusor overactivity; nocturnal bedwetting; urinary incontinence due to mixing of the above conditions (for example, the application of bladder hyperactivity disorder, such as frequent urinary tract and urgency. 〇a B 辞 欲 Ο AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB Symptoms, miscellaneous syndrome, cancer patients' worries, painfulness in the disease, painfulness after myocardial infarction, depression in children, child-induced depression, infertile women's camp Symptoms, postpartum anxiety # , premenstrual malaise, and _ 5 vindictive symptoms. Based on its aforementioned pharmacological activities, the compounds of the present invention are also used to treat cognitive diseases, such as dementia, especially degenerative dementia (including senile dementia, sputum Hammer's disease, Pick's disease, Huntington's disease, Parkinson's disease, and Cremzfeldt-Jakob's disease, and vascular dementia 1 (including multiple infarct dementia) Symptoms, and dementia associated with intracranial space-occupying lesions, trauma, infection and related conditions (including HIV infection), metabolism, toxins, anoxia, lack of vitamins; mild dysfunction associated with aging, In particular, age-related memory impairment (AAMI), amnestic disease, and age-related cognitive decline (ARCD), mental illness, such as schizophrenia and 15 madness; anxiety disorders, such as generalized anxiety disorder , phobia (eg, place • phobia, social phobia and simple phobia), panic disorder, obsessive-compulsive disorder, post-traumatic ink syndrome, anxiety and depression syndrome; personality disorder, such as avoidance personality disorder and note Insufficient hyperactivity disorder (ADHD); sexual dysfunction, such as premature ejaculation, male erectile dysfunction (MED) and female sexual dysfunction 20 (FSD) (eg, female sexual dysfunction (FSAD)); premenstrual syndrome; Seasonal affective disorder (SAD); dietary disorders, such as anorexia nervosa and bulimia nervosa; obesity; appetite suppression; due to drug or substance abuse into sputum (blocking such as 'to nicotine, alcohol, Chemical dependence of coca test, heroin, phenobarbital and phenoxybenzamine; withdrawal syndrome, 26 1300776 as a result of chemical dependence; head pain, such as , migraine, cluster headache, chronic paroxysmal hemiparesis, headache associated with vascular disease, headache associated with chemical dependence or withdrawal syndrome due to chemical dependence, and nervous headache; Pain; Parkinson's disease, 5 such as 'Pardinson's disease dementia, antipsychotic-induced Parkinson's disease and tardive dyskinesia; endocrine diseases, such as high lactation; cerebrovascular cancer, such as Yu Da Vascular; cerebellar ataxia; proper terminal disease; trichotillomania; kleptomania; emotional disturbance; pathological crying; sleep disorder (cataplexy); and shock. 10 From the above situation, ADHD is of particular interest. The diagnosis of ADHD is based on clinical evaluation (M. Dulcan et al.

Psychaitry^ 1997#-10^ ? 36(10 Suppl) ^ 85S-121S ; TVai/ona/ /η如〇///like/recognition, 1998). "The basic characteristics of ADHD are the lack of concentration and/or hyperactivity-impulsiveness of the continuous pattern, which is more frequent and severe than that observed by 15 individuals who are typically at a comparative level of development. (Diagnosis and statistical manual for mental illness) (Diagnostic and Statistical Manual of Mental Disorders) (DSM-IV) 'American Psychiatric Association (American pSyChiatric

Assocciation, Washington, D.C., 1994)). For the diagnosis of ADHD, the patient is required to demonstrate ADHD symptoms that cause damage before the age of seven, and the symptoms need to be at least two settings (eg, school [or work] and home) for more than 6 months. Based on the foregoing pharmacological activities, the compounds of the invention may also be used in the treatment of several other conditions or diseases, including hypertension; gastrointestinal system diseases (involving changes in exercise and secretion), such as intestinal irritation (IBS), intestinal plugs (eg , postoperative intestinal congestion and intestinal congestion during sepsis), gastroparesis (eg, diabetic gastroparesis), 27 1300776. Peptic ulcer, stomach food # reflux disease (GORD, or its synonym GERD), gastro-intestinal gas Zhang and other intestinal functional diseases, such as 彳 如 _ _, non-ulcerative dyspepsia (face) and non-cardiac chest pain (NCCP); and muscle fiber - pain syndrome. 5 This hair (4) is a clearing agent and/or a de-adrenalin reuptake inhibitor, and is effectively used to treat a wide range of diseases, including pain. Physiological pain is an important protective mechanism designed to warn of dangers that may be harmful to the external environment. This system is operated via a special sensory neuron group and is activated by a noxious stimulus by a peripheral transduction mechanism (see Millan, 1999, Prog. Neur 0bil 0, 57, 1 164 to examine these sensory fibers). It is called a damage receptor and features a small diameter shaft column with a slow conduction rate. The injury receptor encodes the strength, time and traits of the hazardous position, and projects its topological tissue to the spinal cord, the location of the stimulus. The crying system is the painful nerve fiber, which has two main types, m-cis (myelin) 15 and C non-myelin). The complex treatment within the dorsal horn of the spinal cord by the injury receptor is transferred directly or via the brainstem transfer nucleus to the thalamic ventral base and then to the cortex, during which a painful sensation is produced. %, the knife can be acute or chronic. The acute pain system begins and is short-term (: 12 weeks or less). It is generally associated with special causes (such as special injuries) and is generally severe and severe. It occurs after a special injury caused by surgery, dental treatment, strain or sprain. Acute pain causes any permanent physiological response. Conversely, chronic pain & pain typically lasts for more than three months and results in significant physiology and morbidity. A common example of sexual pain is neuropathic pain (eg, pain 28 1300776 painful diabetic neuropathy, money neuralgia), carpal tunnel syndrome, back pain, headache, cancer pain, joint pain, and chronic postoperative pain. When a major injury occurs in the body tissue (via disease or trauma), the activation characteristics of the injury receptor are changed, and allergies are caused around it, in the center of the injury or the end of the body. These effects lead to an increase in pain sensation. For acute pain, these institutions are useful for promoting protective behavior and better enable the repair process to occur. It is generally expected that the sensitivity will return to normal once the injury has healed. However, in many chronic pain states, an allergic reaction causes the healing process to become longer and is generally due to a nervous system injury. This injury generally results in sensory nerve fiber disorders associated with maladaptive and abnormal activity (Woolf & Salter, 2000, Science, 288, 1765-1768). Clinical pain is present when the discomfort and abnormal allergies are 4 inches of the patient's syndrome. Patients tend to be quite different and appear with a variety of different pain symptoms. This special case contains 1) spontaneous pain, which may be dark pain, burning or stinging; 15 2) excessive pain response to noxious stimuli (hyperalgesia); and 3) pain caused by general stimuli (Different pain - Meyer et al., 1994, Textbook of Pain, 13-44). Although patients suffering from various types of acute and chronic pain may have similar symptoms, the underlying institutions may be different and, therefore, different treatment strategies may be required. Therefore, pain can be divided into different subtypes according to 20 different physiology and pathology, including nociceptive, inflammatory and neuropathic pain. Nociceptive pain is caused by organizing a party injury or intensive stimuli that may cause injury. Pain afferents are activated by the stimuli transmitted by the injury at the site of injury and activate the neurons within the ridges at the end of their degree. Then, 29 1300776 is transferred to the brain via the spinal cord. The pain is felt during it (Meyer et al., 1994, Pain Textbook, 13-33). The activation of the injury receptor activates both of the transmitted nerve fibers.镛鞠A-delta fibers are delivered quickly and respond to severe and tingling pain, while non-myelinated C fibers are delivered at a lower rate and deliver dark pain 5 or® pain. k and severe acute painful pain are caused by trauma, sprain/strain, burning, myocardial infarction and acute pancreatitis pain, postoperative pain (pain after any type of surgical procedure), trauma Significant features of post-pain, renal colic, cancer pain and back pain. Cancer pain may be a pain in the skin, such as pain associated with the tumor (for example, collateral pain, palpebral pain or visceral pain), or pain associated with cancer treatment (eg, post-chemotherapy syndrome, Chronic postoperative pain syndrome or after radiation therapy = waiting for fresh). Cancer/pain can also occur in response to chemotherapy, treatment, Hor I treatment or radiation therapy. Back pain may be due to rupture or prolapse of the sacral or lumbar facet joints, ankle joints, paraspinal muscles, or posterior longitudinal ligaments. Pain can be dissipated naturally, but in some patients, if it lasts for more than 12 weeks, it will change (4) and it will be particularly weak. / Li, 〖〗 〖Life pain is defined as the initial damage caused by early damage in the nervous system. Nerve damage may be caused by trauma or disease, and the term "neurological pain" includes many diseases with various causes. This π heart, double-constrained peripheral neuropathy, diabetic neuropathy, and herpes Neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, HIV_transformation, hallucinal limb pain, carpal tunnel syndrome, central stroke and post-stroke pain; and with anti-alcoholism, hypothyroidism, uremia, multiple snoring, Spinal injury, Parkinson's disease, epilepsy, and vitamin deficiency have 30,1300,776 pains. Neuropathic pain is morbid because it has no protective role. It usually remains after the initial cause has dissipated, generally lasting for several years. Selectively reduce the quality of life of patients (Woolf & Mannion, 999, Lancet, 353, 1959-1964). The symptoms of neuropathic pain are difficult to treat because they are generally different among patients with the same disease (Woolf & Decosterd, 1999, Pain Sup·, 6, S141-S147; Woolf & Mannion, 1999, Lancet, 353, 1959-1964). These include spontaneous pain (which can be Persistence), and paroxysmal or abnormally induced pain, such as hyperalgesia (increased sensitivity to noxious stimuli)' and abnormal pain (sensitivity to general harmless stimuli). 10 Inflammatory process is a complex system Biochemical and cellular events, activated in response to tissue damage or the presence of foreign substances, cause swelling and pain (Levine & Taiwo, 1994, Textbook for Pain (Textb〇〇kofPain 45_56). Joint pain is the most common inflammatory pain. Rheumatoid Sexually transmitted diseases have developed one of the most common inflammatory conditions in the country, and rheumatoid arthritis is a common cause of disability. The correct pathogen of rheumatoid arthritis is unknown, but today's hypothesis suggests that genetic and microbiological factors may Important (Grennan & Jayson, 1994, Pain Textbook, 397-407). It has been estimated that nearly 16 million Americans have symptomatic arthritis (〇A) or degenerative joint disease, most of which are It has been 60 years old and is expected to reach 40 million with the age of the population, making it a major health problem for 4 people (Houge & Mersfelder, 2002, Ann

Pharmacother 36, 679686; Me Carthy et al., 1994, Pain Textbook, 387-395). Most patients with arthritis seek medical treatment for related pain. Arthritis has a major impact on psychosocial and physical function and is known to be the leading cause of disability in later life. Ankylosing spondylitis is also a genital rheumatic disease that causes arthritis of the spine and ankle joints. It varies from intermittent back pain that occurs throughout the body to severe chronic diseases that attack the spine, surrounding joints, and other body organs. Another type of inflammatory pain is visceral pain, which involves pain associated with inflammatory bowel disease. Visceral pain is the pain associated with the internal organs (organs that contain the abdominal cavity). These organs contain parts of the sex organs, spleen and digestive system. The pain associated with the internal organs can be distinguished as pain in the digestive viscera and pain in the non-digestive visceral. Commonly encountered gastrointestinal (GI) diseases that cause pain include functional bowel disease (IBD) and inflammatory bowel disease (IBD). These GI diseases include a wide range of disease states that are only moderately controlled today. The FBD system includes gastroesophageal reflux, dyspepsia, irritable bowel syndrome (IBS), and functional abdominal pain syndrome (FAPS), and contains about grams of IBD. Ron's disease. Ileitis and ulcerative colitis, which regularly produce visceral pain. Other types of visceral pain include pain and platular pain associated with menstrual pain, cystitis, and pancreatitis. 15 It is important to note that certain types of pain have multiple pathologies and, therefore, can be classified into more than one area, for example, back pain and cancer pain are both harmful and neurological components. Other types of pain include: • Pain caused by muscle and bone diseases, including muscle soreness, fibromyalgia, spondylitis, seronegative (non-rheumatic) joint disease, non-articular rheumatism, dystrophinopathy, liver Glycolysis, polymyositis and multiple pyomyelitis; • Cardiac and vascular pain, including angina pectoris, myocardial infarction, mitral stenosis, pericarditis. Raynaud's phenomenon, scleroderma and skeletal muscle ischemia; 32 1300776 • Headaches, such as migraine (including migraine with precursors), cluster headaches, tight headaches, headaches related to official diseases, and migraine And no precursory mixed headache and blood and oral and maxillofacial pain, including toothache, earache, and muscle spasm pain. Burning mouth syndrome and temporomandibular

10 15

Ah (10) (4) (The disease includes urinary incontinence flying, muddy type of forest loss, wealth, such as, (4) obsessive-compulsive disorder and post-traumatic stress disorder, personality abnormalities, such as, ^, AUHD, sexual dysfunction; According to a further aspect, the present invention provides: i) a compound of the invention for use in human or animal (four) products; u) for the treatment of diseases involving modulation of monoamine transporter function, urine Incontinence, the compound of the present invention,, 110 uses a banming compound to manufacture a drug for treating a disease involving a monoamine transporter function; n〇 is used for the treatment of a disease involving serotonin or norepinephrine regulation The compound of the present invention, such as 20 V, uses the compound of the present invention to produce a medicament for treating a disease involving serum norepinephrine regulation; VI) a serum involved in serotonin and norepinephrine regulation during / σ therapy Or a compound of the present invention; VII) using the compound of the present invention to produce a medicament for treating a disease involving serotonin and norepinephrine regulation; VIII) The invention of the invention of invigorating chemotherapy (Zhu, GSJ and USI) 33 1300776; ix) using the compound of the invention to manufacture a medicament for the treatment of urinary incontinence (such as GSI and USI); X) during the treatment involving a monoamine A method for the transporter-mediated disease comprising administering a therapeutically effective amount of a compound of the invention to a patient in need of such treatment; xi) a method of treating a disease involving serotonin or norepinephrine regulation therebetween, comprising Administering a therapeutically effective amount of a compound of the invention to a patient in need of such treatment; 10 xii) a method of treating a disease involving serotonin and norepinephrine modulation therebetween, comprising administering a therapeutically effective amount of a compound of the invention to the need thereof A patient treated; and xiii) a method of treating urinary incontinence (such as GSI or USI) comprising administering a therapeutically effective amount of a compound of the invention to a patient in need of such treatment. 15 It is important to understand that all treatments described herein include curative, palliative and prophylactic treatments unless otherwise stated. The compounds of the invention may be administered alone or in combination with a portion of the drug. If a mixture of therapeutic agents is administered, the active ingredient may be administered sequentially or simultaneously in separate or mixed pharmaceutical compositions. 20 Examples of suitable agents for adjunctive therapy include: • Opioid analgesics, for example, morphine, heroin, hydromorphone, oxymorphone, levofloxacin, levalprofen, methadone _, billi bite, phenanthrene Nicotine, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, naltrexone, naprofen, naloxone, quetiapine, butylmorphine, 34 1300776 metoprolol, nabufen, or panta 0 new; • non-steroidal anti-inflammatory drugs (NSAID), for example, aspirin, diclofenac, cesinocin, itodorite, phenylbufen , fenoprofen, flubenzol, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketoproic acid, 5 meclofenamic acid, mefenamic acid, meloxicam, nai Dingmeiketone, naproxen, nimesulide, nitroflurifeprofen, olsalazine, oxaprozine, ketata, piroxicam, sulfasalazine p 17 , sulindac , toluene, or acid; or barbiturate, for example, barbital, pentobarbital Prostaglandol, mesobarbital, pentobarbital, phenobarbital, sevobarbital, tadone, simiram or thiopental; • benzodiazepine with sedative effects, for example, chlorinated Nitrogen, gas nitrogen salt, diazepam, flurazepam, lorazepam, oxyzepine, temazapod, 15 or triazolam; • sedative antagonists, for example, diphenhydramine, Biramine, Promethazine, Chlorpheniramine, or Clonacycline; • Sedatives such as glutamide, acetophenone, fluorenone, or diclofenac; 20 • Skeletal muscles Relaxing agents, for example, baclofen, isopropylpyrazine, oxazolidine, amphetamine, mesobarimo, or omeprinadine; • NMDA receptor antagonists, for example, right iliac Norm ((+)-3-hydroxy-N-methylmorphinane) or its metabolite dextromethorphan ((+)-3-hydroxy N-methylmorphinane), ketamine, memantine, pyrrole Porphyrin, cis-4-(phosphonium decyl)-2-35 1300776 氐疋Wei 酉文布布口口, EN-3231 (MorphiDex®, a mixture of morphine and dextromethorphan), tobex ester , Naramson, or Piperfine, Containing an NR2B antagonist, for example, due to fenprovir, Trafalprosine, or (0(R)-6-{2-[4-(3-fluorophenyl) glacial hydroxypiperidinyl] Hydroxyethyl 5- 3,4-dihydro-2(1Η)-σ奎琳酉; • α-adrenalin, for example, doxazosin, tamsulosin, clonidine, pulse, new Metoprolidine, modafinil, tiaramin, terrapin, or 4-month-female-6,7-dimethoxy-2-carcinogen Diphenylphenol pyridyl)oxazoline; 1〇•Tricyclic antidepressant, for example, demethylated, propylene, or nortriptyline; • antiepileptic drugs, for example, carbamazepine, lamo嗉, tobyremet, or valproate; • tachykinin (NK) antagonists, particularly sNK_3, NK_2 or NK_1 antagonists, for example, (aR, 9R) l [3,5-double ( Trifluoromethyl)benzyl]-8,9,10,11-tetrahydroindolylmethyl_5|methylphenyl)711_[1,4]diphthoquinone[2,lg][l ,7]-naphthyridine 6_13-dione (tak 637), 5-[[(2r,3s)-2-[(irm-[3,54g gas fluorenyl)] ethoxy]_3_(4_fluoro Phenyl)-4-morpholinylmethylhydrazine; dihydro·3Η1,2,4 triazole_3• Ketone 20 (ΜΚ-869), alibidine, rupiatan, darbitan, or 3 [[2 methoxyl (trifluoromethoxy)phenyl]-methylamino]-2-benzene Gibberidine (2S, 3S); . Cholesterol antagonists such as 'oxybutynin, tolterodine, C. Devilin, ticlopril, anaphysone, dafenazone, solifenacin, telmivirin, and anti-acetylation test; 36 1300776. (10) Spreading inhibitors, for example, Parecoxib 'valdecoxib, de _ = simiramib; 曰布, or Lu 5

10

• Coal tar analgesics, especially self-inflammation. • Antipsychotics, such as chlorhexidine, thiophene, thiosamine, mesodar. Qin, Sanqi Peila chlorofluoropine, olanzapine, Li _, Qila (four), (four) Ping = Naijing, Ali (four), pine (10), Bronan sarin, Iloperidone, ^ =, LeCl Bili, Yiping, _Plujos, Arsenal Ping ^ Long, Ammonia, Bella, Perlin, Elysin, Osa = Xiqiao, Monaban, McLinantan, Miraxion@, or Sha Liruo 垣 垣, 利如, Spicy = receptor agonist (such as 'Rising Flatoxin) or antagonizing Lai./5-adrenalin, such as Propranol; , such as, mexiletine; • corticosteroids, such as dexamethasone; • 5-HT receptors or antagonists, especially 5_HTib/id, such as eletriptan, sumatriptan, Norastatin, zolmitriptan, or rizatriptan; • 5-HT2A receptor antagonists, such as R(+)_a_(2,3-dimethoxy-phenyl) small 0 ( 4-fluorophenylethyl)]-4^ acetazinyl alcohol (MDL-100907); • Cholinestere (nicotine) analgesic, such as estropone (TC-1734), (E)- N-methyl ice (3_pyridyl)-3_butene small amine (RJR-24〇3), (R)-5-(2-azetidine Methoxychloropyridine 63 1300776 (ΑΒΤ-594), or nicotine; • Tramadol®; • PDEV inhibitor, such as 5-[2-ethoxy·5·(4-methyl-I) -hemeyl)phenyl]small methyl-3·n-propyl-i,6-dihydropyridinium 5 [4,3_d]. pyridine ketone (cidanto), (6艮12) - 2,3,6,7,12,12 heart hexahydro-1 methyl-6-(3,4-methylenedioxyphenyl)-pyridinopyrido[3,4-b]indole-i , 4-dione (IC-351 or Cialis), 2-[2_ethoxy-5-(4-ethyl-°-indol-1-yl-1-fluorenyl)-phenyl]-5- Methyl-7-propyl-311-flavored salic[5,1<|[1,2,4]triazin-4-one (vadinafil), 5-(5-ethinyl-2-) Butoxy-3-10. Ratio to base) _3·ethyl-2-(1-ethyl-3-indole) II,6-dihydropyrene ϋ[4,3-(1 ]|1 flute °-7--, 5-(5-ethyl-bromo-2-propoxy-3-^ ratio. base)_3-ethyl-2-(1-isopropyl-3-indole Ding))-2,6-dihydrogen ratio. Sit and [4,3-dp-biti 7-ketone, 5-[2-ethoxy-5-(4-ethylpiperidinylsulfonyl) Π-pyridyl-3-yl]Ethylethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-u than salido[4,3-d]^- Τ-Τι5 ketone 4-[(3-chloro-4-methoxy) Methyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylindenyl)-l-pyridin-5-nonylamine, 3- (1-methyl•7-oxa-3-propyl-6,7-dihydro-1H-port ratio saliva[4,3-d] ♦ σ定-5-yl)-Ν-[2- (1-methylηpyroxy-2-yl)ethyl]-4-propoxysulfonamide; • α-2-6 ligand, such as gabapentin, pregabalin, 3-曱2〇 Kigapapine, (1α, 3α, 5α) (3-amino-methyl-bicyclo[3.2.0]heptan-3-yl)-acetic acid, (3S-5R)-3-aminoindenyl-5- Methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (2S,4S)-4 -(3·chlorophenoxy)proline, (2S,4S>4-(3-fluorobenzyl)-proline, [(1R,5R,6S) winter (aminomethyl) bicyclic [3·2·0]hept-6-yl]acetic acid, 3-(1-amine 38 1300776-methyl)-cyclohexylmethyl)-4Η-[1,2,4]oxadiazol-5-one , C-[1-(1H-tetrazol-5-ylindenyl)-cycloheptyl]-mercaptoamine, (3S,4S)-(1-aminomethyl-3,4-didecyl- Cyclopentyl)-acetic acid, (3S,5R)-3-aminomethyl-5-mercapto-octanoic acid, (3S,5R)-3-amino-5-methyl-decanoic acid, (3S,5R )-3-amino-5- Benzyl-octanoic acid, (3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid, and (3R,4R,5R)-3-amino-4,5-diindole Base-octanoic acid; • marijuana; • metabotropic glutamate subtype 1 receptor (mGluRl) antagonists; • serotonin reuptake inhibitors, such as sertraline, estimated koji metabolism 10 Lin, Qixi > Ding, Dejiaqixi > Ding (Fluorine &West; D-Methyl Metabolite), Fluvoxamine, Paroxet, Ding, Citalopram, Citalopram Metabolite To thiocarbazepam, escitalopram, d,l-fenfluramine, femtenstin, iveroxetine, cyandoshupin, ritoxetine, dapoxetine, nanofabricol, Western chloramine, and Chardonnay; 15 • norepinephrine (norepinephrine) reuptake inhibitors, such as maprotiline, lofapamine, mirtazapine, hydroxypropetin, fenazolamin , tomoxetine, mesaline, bupropion, bupropion metabolite hydroxy bupropion, nomifen, and vivalan® (especially selective norepinephrine) Resorbing inhibitors, such as reboxetine, especially (S, S)-Rip 20 Westing; • Dual serotonin-norepinephrine reuptake inhibitors, such as venlafaxine, venlafaxine metabolites, genomic venlafaxine, clomipramine, clomipramine metabolites Methyl clomipramine, duloxetine, milnacipran, and imipenem; 39 1300776 • Inducible nitric oxide synthase (iNOS) inhibitors, such as S-[孓[(l-imino) Ethyl)amino]ethyl]-L-isocysteine, S-[2-[(l-iminoethylamino)ethyl]-4,4-dioxocysteine, S -[2-[(l-iminoethyl)amino]ethyl]-2-methyl-L-cystamine, (2S,5Z)-2-amino-2-methyl-5imine Ethylethyl)amino]-5-heptenoic acid, 2-[[(lR,3S)-3-aminol light base small (5-sodium)-butyl]thio]-5-chloro -3" ratio ° 甲甲青; 2-[[(ir,3s)_3·» Amino-4-hydroxy-: 1-(5-soxazolyl)butyl]thio]-4-indole Cyan, (2S,4R)-2-aminocarb[[2-chloro-5-(trifluoromethyl)phenyl]thio]5, succinol, 2-pp(lR,3S)-3 -amino 4-hydroxy-1-(5-soxazolyl)butyl]sulfenyl 10 -yl](trifluoromethyl)-3-pyridinemethyl, 2-[[(lR,3S)-3-amine Base ice-based-H5-pyrazolyl)butyl]thio]- 5-Chlorobenzoic, N-[4-[2-(3-chlorophenylhydrazino)ethyl]phenyl]cephen-2-pyrazine, or carboxyethyl disulfide; • Ethyl chloroesterase inhibitors, such as, for example, Donna η chenqi; • Prostaglandin 亚 2 subtype 4 (ΕΡ4) antagonists, such as Ν-[(丨2-[4-〇15 ethyl-4, 6-Dimethyl-1 oxime-imidazo[4,5-cp-pyridin-1-yl)phenyl]ethyl}amino)-Weiyl M-methyl benzoic acid amine, or 4-[(lS -l-({[5H(3-fluorophenoxy)pyridin-3-yl)carbonyl}amino)ethyl]benzoic acid; • leukotriene B4 antagonist; for example, 1-(3-linked Benz-4-ylmethyl-4-hydroxy-benzodihydrofuran-7-yl)-cyclopentanecarboxylic acid (CP-l〇5696), 5-[2-(2-20-carboxyethyl)! [6-(4-Methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valeric acid (ONO-4057), or DPC-11870; • 5-lipoxygenase inhibitor, such as Qi Retention, 6-[(3_fluoro-5-[4-methoxy-3,4,5,6-tetra-mole-2Η-σ-pyran-4-yl]phenoxymethylmethyl-one 2_ porphyrinone (ZD-2138), or 2,3,5-trimethyl-6-(3^pyridylmethyl), i,4-benzene 40 1300776 fluorenone (CV6504); Blockers, such as lidocaine; • 5-HT3 antagonists, such as ondansetron, glastron, tricepillon, azaxion, dorasian, or alosedron; 5 • estrogen or selective estrogen receptor modulators (eg, HRT treatment or laxoxifene); • alpha-adrenergic receptors such as phenylpropanolamine, or R-450; • Dopamine receptor agonists (eg, apomorphine, which is found in US-A-5,945, 117 as a pharmacy 10), and contains dopamine D2 receptor agonists (eg, Philipcia Upjohn, Pharmacia Upjohn) Compound No. PNU95666; or Rosicillo); • PGE1 excimer (eg, alprostadil); and its pharmaceutically acceptable The present invention thus provides, in another aspect, a composition comprising a compound of the invention in combination with an additional therapeutic agent. For human use, the compounds of the invention may be administered separately, but in human therapy, generally in relation to The pharmaceutical route, the diluent, or the carrier selected by the standard pharmaceutical administration may be administered by mixing. 2〇 For example, the compound of the present invention may be used as a tablet, a capsule (including a soft capsule), a weight d, a tincture, The type of solution or suspension (which may contain a taste or colorant) administered orally, buccally or sublingually, for immediate, delayed, modified, continuous, dual, controlled, released or Pulsating delivery applications. The compounds of the invention may also be administered by injection into the body of the sponge. The compound of the invention 41 1300776 may also be administered via a rapidly dispersing or fast dissolving dosage form. Such troches may contain excipients such as microcrystalline Cellulose, lactose sodium citrate, carbon _, dibasic phosphorus _, glycine, and Sakizawa corn, potato, or tapioca starch), disintegrants, such as Powdered ethanol = 5 sodium, cross-linked methyl cellulose sodium, and some miscible acid salts, and teaching knots = agents, such as polyvinyl, Bi (4), propyl propyl methyl 1 ( HPMC), domain shouting cellulose (HpQ, Yu, gelatin, and Aji Boshu gum) In addition, lubricants (such as stearic acid, stearic acid, Gan / from the day, and talc) can also be The solid composition of the present invention may also be used as a filler in gelatin capsules. Preferred excipients thereof include lactose, starch, cellulose, lactose, or high molecular weight polyethylene glycol. For aqueous suspensions and/or _, the present dimeric compounds and pharmaceutically acceptable salts thereof can be combined with various sweeteners or flavoring agents, materials or materials, and emulsified and/or suspended reagents and diluents (such as 5 water: alcohol, propylene glycol, and glycerin), and mixtures of such mixtures. The modified release and boiled release may contain excipients such as those described in detail for the release dosage form and release dosages as modified release external excipients (which are applied to the body of the device) And/or included in the release. The release rate modifier is not limited to excipiently containing carbaryl, methylcellulose, sodium ketone, ethyl cellulose Acetic acid vinegar, polyethoxylate oxygen, xanthan gum, carbomer, methyl propyl 1 ammonium copolymer, hydrogenated castor oil, palm glutinous rice, stone can, cellulose 7 acid 酉 1 1 propyl methyl cellulose s too acid vinegar, methyl acrylate acid = 軚 and mixtures thereof. Modified release and turbulent release dosage form can be 42 1300776 release rate modified excipients or mixtures thereof. Release rate modified shape The agent may be present in the dosage form (i.e., within the matrix) and/or on the dosage form (i.e., on the surface or coating).

The fast dispersing or dissolving agent composition (FDDF) may contain the following 5 wounds, aspartame, acesulfame potassium, citric acid, croscarmellose sodium, paternal poly- _, ascorbic acid Ethyl acrylate, ethyl cellulose, gelatin, hydroxypropyl methylcellulose, magnesium stearate, mannitol, mercapto acrylate, mint flavor, polyethylene glycol, smoky stone , sulphur dioxide, '/, and ^ ethanol | ^, sodium stearyl fumarate, sorbitol, xylitol. The phrase "1" or "bath" is used to describe the FDDF depending on the solubility of the drug used. That is, if the drug is insoluble, a rapidly dispersing dosage form can be prepared, and when the right music system is soluble, A fast dissolving dosage form can be prepared. 15

20 This compound may also be administered parenterally, for example, intravenously, transarterally, transabdominally, intrathecally, intracerebroventricularly, transurethral, transsacral, or intrauterine. Subcutaneous, or can be administered by injection techniques. 1; these non-intestinal techniques 'best in a sterile water solvent type 1, which may contain other substances, such as (10) salt or glucose to make the fluid isotonic with blood [aqueous solution when needed Need to be properly buffered by Huaijia = 3 to 9). Preparation of a suitable parenteral composition under sterile conditions is accomplished by (4) the know-how of the skilled artisan (4). For oral and parenteral administration to a human patient, the daily dose of the compound of the invention or its salt or solvate is generally gamma to milligrams (single or separate agents). Thus, for example, a compound of the present invention or a salt or solvate lozenge thereof may contain from 5 mg to 25 g mg of the active compound for appropriate administration per unit or - or household. The actual dose that is most suitable for any individual patient can be determined to vary depending on the age, weight and response of the particular patient. An example of the average dose solution. This may be a paste having a higher or lower slit therebetween, and the second grade is within the scope of the present invention. Those skilled in the art will be able to understand that in the treatment of certain conditions (including hydrazine), the compounds of the invention may, if desired, be based on (ie, upon need)

10

Or a single agent if desired. IL Tablet Compositions Generally, the (4) composition typically contains between about _mg and 500 mg of the compound (or a salt thereof) according to the present invention, and the tablet filler weight may range from 50 mg to gram mg. 1G mg tablets of hemp %w/w 10.000* 64.125 21.375 3.000 1.200 and based on the weight of the free base - the free base of the compound or the salt lactose starch parent-linked cellulose-based sodium nanostearate * This amount is typically Depending on the activity of the drug, the compound of the invention may also be administered intranasally or by inhalation, and may be in the form of a knife inhalation or a self-pressurizing container, pump, sprinkler or nebulizer and using a suitable propellant (eg , dichlorodifluoromethane, trichloro-fluoromethane, di-tetrafluoroethane, hydrofluorocarbon, such as U, l, 2-tetrafluoroethane (HFA 134A [business not] or 1,1 1,1,3,3,3-heptafluoropropane (HFA 227EA [trademark], carbon dioxide 20 or other suitable gas) is conveniently delivered by aerosol spray. The unit can be borrowed in the pressurized gas system. It is determined by the provision of a valve to deliver a meter. 44 1300776 A pressurized container, pump, sprinkler or spray may contain a solution or suspension of the active compound, for example, using a mixture of ethanol and a propellant as a solvent, which may additionally Contains a lubricant, for example, sorbitol trioleate. For inhalers or blows The capsules and crucibles (for example, made of gelatin) can be formulated into a powder mixture comprising 5 of the compound of the invention and a suitable powder base material such as lactose or starch. The composition of the spray or dry powder is preferably It is configured such that each metered dose or "blowing" contains 1 to 50 mg of a compound of the invention delivered to a patient. The total daily dose range by spraying is from 1 to 50 mg, which may be 10 single doses or More generally, the drug is administered in divided doses throughout the day. The compounds of the invention may also be formulated for delivery via a nebulizer. The composition for the nebulizer device may contain the following ingredients as a co-solvent, emulsifier or Suspending agent: water, ethanol, glycerin, propylene glycol, low molecular weight polyethylene glycol, sodium vaporized gas, fluorocarbon, polyethylene glycol ether, sorbitol trioleate, oil 15 acid. In addition, the compound of the present invention can Suppository or ring-type administration, or may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dust powder. The compounds of the invention may also be administered by skin or skin penetration, for example, by Use a skin patch. It can also be administered by eye, lung or rectal route. For ophthalmic use, the compound can be formulated as a suspension in isotonic, pH-adjusted sterile physiological saline, or preferably. A solution in isotonic, pH-adjusted sterile physiological saline, optionally mixed with a preservative such as benzylketone chloride. Alternatively, it can be formulated as an ointment (eg, 45 1300776 Vaseline) ).

When applied to the skin, the compound of the present invention can be formulated into a suitable ointment containing a suspension of the active ingredient in a mixture of _ or more of the following: mineral oil, liquid petroleum jelly, white Vaseline, propylene, alcohol ♦ oxyethylene polyoxypropylene compound, emulsified butterfly and water. Alternatively, a silk or ritual cream may be prepared which is suspended or dissolved, for example, a mixture of one or more of the following: table oil, yam turntable monostearate, polyacetal liquid stone worm, polysorbate 6〇, hexadecanic acid vinegar, butterfly, worm, alcohol, 2-octyldodecanol, benzyl alcohol and water. 1 〇 ^ Ming compounds can also be mixed with cyclodextrin. Cyclodextrins are known to form inclusion and non-inclusion complexes using L, drug knives. The formation of a drug cyclodextrin alpha can improve the solubility, dissolution rate, bioavailability and/or stability properties of the drug molecule. The drug-cyclodextrin complex is generally used in most dosage forms and routes of administration. In addition to being directly mismatched with the drug, the cyclodextrin can also act as a 15 auxiliary additive, for example, as a carrier, diluent or co-solvent. α -, point one and? - Cyclodextrins are most commonly used, and suitable examples are described in WO-A-98/55148. WO-A-91/11172, WO-A-94/02518 For the oral or intravenous administration of human patients, the parental dose of the compound of formula (1) and its pharmaceutically acceptable salt is 〇01 to% mg/kg (single 20 Or a separate agent)' and preferably in the range of 0. 01 to 5 mg/kg. Thus, the agent will contain from 13⁄4 grams to 0.4 grams of the compound for appropriate single or- or more administrations per dose. In any case, the doctor can determine the optimal dosage for any particular patient, and it will change depending on the age, weight and response of the particular patient. The above agents are of course only exemplified on the average, and may be in the range of the examples in which the higher or lower dose ranges are to be obtained in the present invention. Oral administration is preferred. 5 For veterinary use, the compounds of the present invention are administered in accordance with a general veterinary practice, and the veterinarian may determine the mode of administration and route of administration that is most suitable for the particular animal. Accordingly, in accordance with still another aspect, the present invention provides a pharmaceutical composition comprising a pharmaceutical composition of the present invention and a pharmaceutically acceptable adjuvant, diluent or carrier. The above mixture may also be conveniently presented for use in the form of a pharmaceutical composition of formula 10, and thus, the pharmaceutical composition comprising the mixture as described above and a pharmaceutically acceptable adjuvant, diluent or carrier together comprises another of the invention on the one hand. The individual components of such mixtures may be administered sequentially or simultaneously in separate or mixed pharmaceutical compositions. When the compound of the present invention is used in combination with the second therapeutic agent, the dose per _ compound 15 may be different from when the compound is used alone. The appropriate dosage can be easily understood by those skilled in the art. The invention is illustrated by the following non-limiting examples in which the following abbreviations and definitions can be used: APC1 atmospheric pressure chemical ionization

Arbacel® filler J Br wide BOC third butoxycarbonyl CDI rim base. Sitting △ chemical shift D double △ heat DCCI dicyclohexylcarbodiimide DCM dichloromethane

47 1300776

DMF DMSO ES+ ES' H HOAT HOBT HPLC M/z min MS NMM NMR Q s T TBTU Tf TFA THF TLC TS+ WSCDI N,N-dimethylformamide dimethyl sulphite wind-electric spray ionization positive scan electric spray Ionization negative scan hour 1-hydroxy-7-azobenzotriazole 1-hydroxybenzotriazole high pressure liquid chromatography mass spectrometry peak minute mass spectrometry

N-methylmorphine NMR quadruple single triple 2-(1 benzotriazol-1-yl)-indole, iota, 3,3-tetramethyluronium tetrahydroborate trifluoromethanesulfonyl Trifluoroacetic acid tetrahydrofurfuryl thin layer chromatography hot spray ionization positive scanning 1-(3-dimethylaminopropyl)_3_ethylcarbodiimide hydrochloride The following preparations and examples The invention is illustrated, but is not intended to limit the invention in any way. All temperatures are based on. C meter. Flash column chromatography was performed using Merck Meteorite 60 (9385). Solid phase extraction (SPE) chromatography was performed using a Varian Mega Bond Elut (Si)® (Anachem) under a vacuum of 15 mmHg. Thin layer chromatography (TLC) was performed on Merck vermiculite gel 60 (5729). Melting points were determined using a Gallenkamp MPD350 apparatus and were uncorrected. NMR was performed using a Varian-Unity Inova 400 MHz nmr spectrometer or a Varian Mercury 400 MHz nmr spectrometer. Mass spectrometry was performed using a Finnigan Navigator single quadrupole electrospray mass spectrometer or a Finnigan aQa 48 1300776 APCI mass spectrometer. Conveniently, the compound of the present invention is a pharmaceutically acceptable acid addition salt of the compound according to the operation of the free base form. The solvate of the compound of the present invention can be used in the aforementioned treatment steps. The 5 is formed during the operation. ^5 When the system is prepared in the manner described in the previous examples, those skilled in the art know that the reaction time, the equivalent number of reagents, and the reaction temperature can be modified for each special reaction. However, it may require or desire to make soil. Different operating or purification conditions. [Details of the preferred embodiment] Preparation of 1 cyclopentylamino)pyrrolidine small carboxylate

% pentyl 1 (12.7 ml, 143 mmol) was added to the third butyl (3S)-3-aminopyrrolidine-1-carboxylate in a mixture of methanol:toluene 3.1 (6003⁄4 liter: 2 〇〇ml) 26.6 g, 143 mmoles, and the reaction mixture was stirred at room temperature under nitrogen for 1.5 h. Then, the mixture was evaporated to 5 mL, and then azeotroped three times with methanol·toluene 3:1 (600 ml: 200 ml), and was reduced in vacuo to a concentration of 49 1300776. The reaction mixture was taken up in methanol (250 ml), cooled to EtOAc, and sodium borohydride (7.5 g, 200.2 mmol) was added in one portion. After the reaction was completed, water (50 ml) was added and solvent was evaporated. The residue was diluted with more water (150 liters) and extracted three times with dichloromethane (250 mL). The organic phase was combined, dried over MgSO4, and concentrated in vacuo to afford the compound as a gel, 36.1 g (99.4%). !HNMR (CDC13? 400MHz) 5 : 1.18 (brs, 1H), 1.28 (m, 2H), 1.44 (s, 9H), 1.52 (m, 2H), 1.67 (m, 3H), 1.83 (m, 2H) , 2.05(m, 1H), 2.98(m, 1H), 3.08(m, 1H)? 3.30(m9 2H), 3.45(m, 1H), 10 3.58(m, 1H) MS APC1+ m/z 255 [MH ]+ Preparation 2 Complex tributyl (3S)-3-f cyclopentyl (2,3-dichlorobenzamide) amino ipyrrolidine _·[_ carboxylic acid ester

Triethylamine (24 ml, 170 mmol) was added to a solution of the title compound (36.1 g, 142 mM) of amine in chloroformane (350 ml). The reaction mixture was cooled to 〇 ° C, and 2,3 - 2 gas - benzoic acid chloride (29.8 g, 142 mmol) in dichloromethane was maintained at a temperature below 5. And dripping 50 1300776 into. Then, the reaction mixture was stirred for 6 hours. Water (200 ml) was added and the organic phase was collected. The aqueous layer was extracted with dichloromethane (250 mL). The combined organic phases were washed with 2M aqueous sodium hydroxide and 10% EtOAc. The crude product is purified by column chromatography on a vermiculite gel eluted with ethyl acetate: cyclohexane (1:6 to 1:4 to 1:2 to 1:1 by volume). The target product, 50 g (82.4%). iHNMRCDCls, 400 MHz, rotamer 1.43-1.47 (d,

9H), 1.56-1.66 (m, 5H), L79 (m, 0·5Η), 1.98 (m, 3H), 2.37 (m, 1Η), 2.92 (m, 〇·5Η), 3.15 (m, 0·) 5Η), 3.40(m,1Η), 3.58(m, 10 3.74(m, 2H), 3.97(m, 1H), 7.1〇(m, 1H)9 7.24(m, 1H), 7.46(d, 1H) MS APC1+ m/z 427[MH]+ and m/z 327 [MH-Boc]+

Preparation 3

p each burning 1-carboxylic acid ester

2,3-dichloro-4-fluorobenzoic acid (4·25 g) of turmeric (2.13 ml, 24.4 mmol) added to a dry dichloromethane (41 ml) at room temperature under nitrogen , 2 〇 · 33 mmol (see ΕΡ 0600317, Example 15) suspension. Add 51 1300776 plus dimethyl dimethylformate (10) #1, 1 mmol), and the reaction mixture was stirred for 1 hour. The solvent was removed by evaporation under reduced pressure to give a yellow solid which was dissolved in methylene chloride (2 mL) and then evaporated to <RTIgt; · 72 ml, 33 9 mmoles and a solution of 咐^5 g, I6·95*mol). After stirring at room temperature for 18 hours, the resulting mixture was diluted with dichloromethane (100 mL) &amp; The organic phase was dried over magnesium sulfate, filtered, and solvent was removed from evaporation from vacuo. The residue was dissolved in a minimum amount of methylene chloride and was changed to ethyl acetate by a solvent gradient of pentane on a vermiculite gel: pentane (2 〇:8 Torr, by volume) 10 elution chromatography Purification 'produced the title compound as a white foam, 6.6 (73%).

WnMRCCDsODJOOMHz, rotamer) 5: 1.43-1.47 (d, 9H), 1.62 (m, 1.5H), 1.72 (m, 3H), 1.88 (m? 1.5H), 1.97 (m, 0.5H), 2.13 (m, 1.5H), 2.32 (m, 0.5H), 2.74 (m, 1H), 2.74 (m, 15 1H), 3.40 (m, 1H), 3.51-3.59 (m, 1.5H), 3.76 (m) , 2H), 3.88 (m, 1H), 4.05 (m, 1H), 7.33 (m, 2H) Preparation 4 Third butyl (3S)-3-(cyclohexylamino)pyrrolidine-1-carboxylic acid Ji

H3c 52 1300776 tert-butyl(3S)-3-(cyclohexylamino)pyrrolidine small carboxylic acid ester using a third butyl(3S)-3-aminopyrrolidine by a method similar to that described in Preparation 1. Preparation of the 1-carboxylic acid ester and cyclohexanone gave the desired product, 5.9 g (82%). ^NMRCCDCls, 400MHz) δ : l.〇9(m, 2H)9 1.24(m, 3H), 1.45(s,9H),1.62(m, 2H), 1.72(m, 2H),1.88(m,2H) ), 2.06 (m, 1H), 2.48 (m, 1H), 3.01 (m, 1H), 3.30 (m, 1H), 3.45 (m, 2H), 3.55-3.62 (m, 1H)

Preparation 5 Di-dibutyl (3S)-3- "cyclohexyl (2,3-dioxa) amino group &quot;|ppiroxime-1-carboxylate

The third butyl-(3S)-3-[cyclohexyl(2,3·dichlorobenzylidene)amino]pyrrolidine-1-carboxylate is prepared by a method similar to that of Preparation 2; The amine and 2,3-one gas methylformyl chloride were prepared to give the desired product, 514 g (%). HNMR (CDC13, 400MHz,

1H), 7.23 (m, 1H), 7.47 (d, 1H). 53 1300776 LCMS ELSD/APC1+ m/z 441[MH]+ Preparation 6 succinyl butyl (3S)-3 j% hexyl (2-gas-3-gas benzoic acid) amine group &quot;jp than p each burning - 1-acid ester

The second butylhexyl (2- gas-3-gas benzoate)amino]upyrrolidine-1-carboxylate is prepared by a method similar to that described in Preparation 3, using the amine of Preparation 4 and 2 -Chloro-3-fluorobenzoic acid was prepared to give the desired product, 158 mg (29%). hNMRCCDCls, 400 MHz, rotamer) 5: 0.98-1.06 (m, 10 2·5 Η), 1.29 (m, 1.5 Η), 1.47 (d, 9 Η), 1.57 (m, 3 Η), 1.73 (m, 2 Η) ), 1.87 (m, 2H), 2.66 (m, 0.5H), 2.89 (m, 1H), 3.11 (m, 1H), 3.38 (m, 1H), 3.53 (m, 1H), 3·69 (πι ,0·5Η),3·91(πι,2H), 6.99(m,1H),7.15(t,1H),7·28(ιη,1H) MS APC1+ m/z 425[MH]+ and m/ z 325[MH-Boc]+ 15 Preparation 7 Third butyl (3S)-3-[cyclohexyl(3-fluoro-2-methylbenzomethyl)amino-1pyrrolidin-1-carboxylate 54 1300776

The third butyl (3S)-3-[cyclohexyl(3-fluoro-2-methylbenzylidene)amino]pyrrolidine-1-carboxylate is similar to that described in Preparation 3. Method using the amine of Preparation 4 and 3-fluoro-2-indolyl-benzoic acid to prepare the desired product, 63 mg 5 (12%) 〇iHNMRCCDCls, 400 MHz, rotamer) 5: i.〇2 (m) , 2.5H), 1.30 (m, 2·5Η), 1.47 (d, 9H), 1.57 (m, 1H), 1.62 (m, 4H), 1.73 (m, 1H), 1.91 (1X1, 1H), 2.20 (s, 3H), 2.71 (m, 0.5H), 2.91 (m, 1H), 3.18 (m, 1H), 3.39 (m, 1H), 3.49 (m, 0.5H), 10 3.68 (m, 0.5) , 3.85-3.93(m, 1.5H) 6.87(d,1H),7.01(t,1H), 7.17(q,lH) 〇MS APC1+ m/z 405[MH]+ and m/z 305[MH-Boc ]+ Preparation 8 Third butyl (3SH cyclobutylamino) pyrrolidine-1-carboxylate

55 1300776 tert-butyl(3S)-(cyclobutylamino)pyrrolidine small carboxylic acid ester using a third butyl (3S)-3-aminopyrrolidine by a method similar to that described in Preparation 1. 1-carboxylic acid ester and cyclobutanone (15 equivalents: 10 equivalents added first, 5 equivalents added before the second azeotropic removal of water), but the crude product was subjected to 5-column chromatography on a vermiculite gel. Purification afforded the title compound, 542 mg (28%). 'HNMRCCDsOD, 400MHz) 5 : 1.45(s, 9H), 1.70(m? 3H), 1.81(m,3H), 2.05(m,1H), 2.21(m,2H),3·03(Μ,1H) , 3.26(m, 2H), 3.47(m,2H) MS APC1+ m/z 241 [MH]+ 10 Preparation 9 Third butyl (3SV3-" butyl butyl (2,3-dichloro-molybdenum) Face base &gt;pyrrolidine

1-carboxylic acid ester

Third butyl (3S) each [cyclobutyl (2,3-dioxa-benzimidyl)amino]pyr 15-rrolidine-1-carboxylate by a method similar to that described in Preparation 2 Prepared using the amine of Preparation 8 and 2,3-dichlorobenzhydryl group to give the desired product, 370 mg (79%). ^NMRCCDsOD, 400MHz) (5: 1.43(m, 1H), 1.48(s, 9H), 1.66(m, 1H), 1.95(m, 1H), 2.12-2.27(m, 4H), 2.72(m, 1H ), 56 1300776 3.42 (m, 1H), 3.61 (m, 1H), 3.69 (m, 1H), 3.86 (m, 1H), 3.98 (m, 1H), 4.45 (m, 1H), 7.24 (dd, 1H), 7.40(t,1H), 7.62(d,1H) MS APC1+ m/z 313 [MH-Boc]+ Preparation 10 5 1^.11 base (35)_3-{『(2,4-dinitrogen笨基基) 醯1 1 aminopyrrolidine-1: carboxylate

Tributyl(3S)-3-aminopyrrolidine-1-carboxylate (5 g, 27 mmol) added to a 2,6-dimethyl group in dichloromethane (150 mL). A solution of pyridine 10 (6.2 mL, 54 mmol). The reaction mixture was cooled to zero. (:, and a solution of 2,4-dinitrobenzenesulfonyl chloride (7.15 g, 27 mmol) in dichloromethane (100 mL) was added slowly (TC) over 15 min. The reaction mixture was stirred at room temperature for 48 hours under nitrogen. Water (1 mL) was added, and then 2N aqueous hydrogen chloride was added to the aqueous layer to pH 2. Then, the 15 layers were separated and the aqueous layer was More dichloromethane (100 ml) was extracted. The organic layer was mixed, washed twice with water (1 mL), dried over magnesium sulfate and concentrated in vacuo to give the title compound as a gel, 10 g (89%) 'HNMRCCDCIb, 400MHz) 1.42(s, 9H), 1.88(m, 1H), 2.15(m,1H),3·18(ηι,1H),3.37-3_44(m,2H),4.07 (m,1H), 57 1300776 5.58(d,1H), 8.40(d,1H), 8.57(d,1H), 8.68(s, 1H), Preparation 11 di-dibutyl __QS)_3_(obtained ^ Base mercaptoamine group

20 cyclobutane methanol (0.2 ml, 211 mmol) followed by triphenylphosphine (465 mg ' 2.33⁄4 mol) added to tetrahydrofuran (4 mL) of compound 10 (under nitrogen) A solution of 0.8 g, ι·92 mmol. The reaction mixture was cooled to 0 ° C, and a solution of diisopropyl azodicarboxylate (0. 45 mL, 2.3 mmol) in tetrahydrofuran (15 mL) was kept at a temperature below 3 〇c. In. The reaction mixture was stirred at 0 ° C for 5 hours and then at room temperature for 18 hours. Tetranitrofuran was evaporated and the residue was taken up in dioxane (2 mL). Diethylamine (0.53 ml, 3.84 mmol) and thioglycolic acid (16 ml, 2.33⁄4 mol) were added and the mixture was stirred at room temperature for 2 h. Then, it was washed with 2N aqueous hydrogenated hydrogen. The aqueous layer was assayed to pH 11 with 2 m sodium hydroxide and extracted three times with ethyl acetate. The organic phase was then concentrated in vacuo to give the title compound (151 mg, 31%). ^NMRCCDCls, 400MHz) (5: 1.44 (s, 9H), 1.65 (m, 3H), 1.87 (m, 2H), 2.05 (m, 3H), 2.45 (m, 1H), 2.62 (d, 1H), 3.05 (m, 1H), 3.28-3.51 (m, 5H). Method 58 1300776 borane tetrahydrofuran complex (1M in tetrahydrofuran, 100 mL, 100 mmol) was added to anhydrous tetrahydrofuran under nitrogen ( A solution of the compound of Preparation 27 (9 g, 33.54 mmol) was taken in 100 mL. The reaction mixture was refluxed for 2 hr. The reaction mixture was cooled to room temperature, quenched with methanol and concentrated in vacuo. The methanol was azeotroped, then redissolved in methanol (200 mL) and heated under reflux for 18 hours then concentrated in vacuo. Chromatography on a vermiculite gel with dichloromethane: decyl alcohol 0.88 ammonia (95 :5:0.5, by volume), the residue was purified by elution to give the title compound (7.67 g, 90%) as a gel. 10 iHNMR (10 MHz, CD3OD) (5: 1.44 (s, 9 Η), 1· 70 (ιη, 3Η), 1.90 (m, 2Η), 2.08 (m, 3Η), 2·47 (ιη, 1Η), 2.62 (m, 2Η), 3.06 (m, 1H), 3.27 (m, 2H) , 3.45 (m, 1H), 3.54 (m, 1H) MS APC1 m/z 255 [MH] + system 12 15 tert-butyl (35) each [cyclobutylmethyl (2,3-gas - Mo acyl methyl) amine in a 1 duh pyrrolidine-1-carboxylate

The third butyl (3S) winter [cyclobutylmethyl (2,3-dioxa-o-methane)amino]pyrrolidine-1-carboxylate is produced by a method similar to that described in Preparation 2.

59 1300776 Prepare the desired product, 94 mg (37%) of the amine of the 11 and the 2,3-dibenzophenone. LCMS ELSD/APC1+ m/z 427 [MH]+ Preparation 13 tert-butyl(3S)-3-(cyclopropylmethylamino)pyrrolidine-1-indole ginyl ester

The third butyl (3S)-3-(cyclopropyldecylamino)pyrrolidine-1-carboxylate is a third butyl (3S)-3-amine by a method similar to that described in Preparation 1. Preparation of pyrrolidine-1-carboxylate and cyclopropanecarbaldehyde, but the crude product was changed by a color spectrum analysis on a vermiculite gel with a solvent gradient of di-methane to methane: methanol: 0.88 ammonia ( Purification by elution at 90:10:1 by volume gave the title compound, 5.2 g (81%). 'HNMRCCDCls, 400ΜΗζ) ά : 0.15(m, 2H), 0.48(m, 2H), 0·97(ιη,1H), 1.43(s,9H), 1.75(m,1H),2.05(m, 1H) , 2.50 (d, 15 2H), 3.10 (m, 1H), 3.47 (m, 2H), 3.50 (m, 2H) MS APC1+ m/z 241 [MH]+ Preparation 14 Third butyl (3S)-3彳tetrahydro-2H-pyran-4-ylamino)pyrrolidine small ^^ 60 1300776

a solution of tetrabutyl(3S)-3-aminopyrrolidine-1-carboxylate added to tetrahydro-4H-pyran-4-one in ethanol and 10% Pd/C (300 mg), and The reaction mixture was left under about 415 kPa (about 60 pis) of hydrogen for 18 hours. The reaction mixture was filtered through Arbocel® and washed thoroughly with ethyl acetate. The filtrate was concentrated in vacuo, and the crude material was purified by column chromatography eluting with silica gel to yield desired product, 6.7 g (61%). ^NMR^DCls, 400MHz) 5: 1.39 (m9 2H), 1.46 (s, 9H), 1.67 (m, 1H), 1.82 (m, 2H), 2.07 (m, 1H), 2.72 (m, 1H), 10 3.02(brm,1H),3.31-3.39(m,5H),3.59(brm, 1H),3.96(m, 2H) MS S+ m/z 271 [MH]+ Preparation 15 Third butyl (3SV3-K2 , 3-dioxabenzoyl) (tetrahydro-2H-pyran-4-yl) 15 Aminopyrrolidine-1-carboxylate 61 1300776

Second butyl (3S) winter [Ο dichlorobenzhydryl) (tetrahydro-: 2 Η-pyran-4-yl)amino]17 piroxicam-1-carboxylate by and preparation 2 The method similar to the above (using Ν-methylmorphine as a base) was prepared from the preparation of μ amine and 2,3-dibenzobenzene 5 oxime to give the desired product, 200 mg (31%). 'HNMRCCDsOD, 400MHz) 5 : 1.43-1.47(d, 9H), 1.58(m, 1·5Η), 1.76(m,0.5H), 1.94(m,2H),1H), 2.76(m, 0.5H) , 2.98 (m, 0.5H), 3.13 (m, 2H), 3·4-3·58 (ιη, 4H), 3.69 (m, 0.5H), 3.9 (m, 2.5H), 4.04 (m, 0) · 5 Η), 4.2 (m, 0.5H), 7.29 (d, 10 1H), 7.43 (t, 1H), 7.62 (d, 1H) rotamer. MS APC1+ m/z 443 [MH]+ and 343 [MH-Boc]+ Preparation 16 tert-butyl (3SV3-K2-chloro adenyl) (cyclo-) amino 1 pyrrolidine-l-carboxylic acid Decree

62 15 1300776 tert-butyl (3S)-3-[(2-chlorobenzylidene)(cyclopentyl)amino]π-pyrrolidine-1-carboxylate by the preparation described in A similar method (using toluene as a solvent, hydrazine-hydrazinomorpholine as a base, and the reaction mixture was prepared at 6 (rc heating for 18 hours) using the amine of Preparation 1 and 2-chlorophenylhydrazinyl chloride to produce the desired product. 5, 1.16 g (75%). WNMI^ChOD, 400 MHz, rotamer) 5: 1.42-1.47 (d, 11H), 1.62 (m, 1H), 1.71 (m, 3H), 1.89 (m, 1H), 1.99 (m, 1H), 2·13 (ιη, 1H), 2.33 (m, 0·5Η), 2.77 (m, 1H), 3.07 (m, 0·5Η), 3.46 (m, 1H) , 3.60 (m, 0.5H), 3.70 (m, 1H), 3.78 (m, 1H), 10 3.90 (m, 0.5H), 4.04 (m, 1H), 7.30 (m, 1H), 7.41 (m, 2H), 7.48(m,1H) MS APC1+ m/z 393[MH]+ and m/z 293 [MH-Boc]+ Preparation 17 Third butyl (3SV3-K2-acetomethyl) (cyclohexyl) Amino 1 pyrrolidine-l-carboxyl 15 acid ester

Tert-butyl (3S)-3-[(2-chlorobenzylidenyl)(cyclohexyl)amino]pyrrolidine-1-carboxylate by a method similar to that described in Preparation 2 (using toluene) As a solvent, N-mercaptomorpholine was used as a base, and the reaction mixture was heated at 60 ° C for 18 63 1300 776 hours) using the amine of Preparation 4 and 2-chlorophenyl hydrazine chloride to give the desired product, 1.09 g (72 %). b^nVIRCCDsOD, 400MHz, rotamer: 〇97(m,1Η), 1.09(m,1Η), 1.43-1.47(d,9Η),1·55-1·87(ιη,8Η),2.07( m, 5 1H), 2 76 (m, 1H), 3.16 (m, 1H), 3.39 (m, 1H), 3.54 (m, 1H), 3·68 (χη, 1H), 3.88 (m, 1H) , 4.146(m,1H), 7.30(d,1H), 7.41(m, 2H), 7.48(m,1H) LCMS APC1+ m/z 407[MH]+ and m/z 307 [MH-Boc]+ Preparation 18 士士工基(3 S)-3 -(cycloheptylamino Vth p each burning -1 - acid cool

The third butyl (3S)-3-(cycloheptylamino)u ratio is slightly calcined with the 1-weiler ester. The third butyl (3S)-3- is used by a method similar to that described in Preparation 14. Preparation of the aminopyrrole-1-carboxylate and cycloheptanone gave the desired product, 4.54 g (100%). 'HNMRCCDaOD, 400MHz) 5 : 1.45(s, 12H), 1.57(m, 5H), ΐ·69(πι, 3H), 1.89(m, 2H), 2·12(ιη, 1H), 2.71(m, 1H), 3.〇2(m,1H), 3.26(m,1H), 3.45(m,2H),3.59(m,1H) MS APCl+m/z 283[MH]+ Preparation 19 64 1300776 Third Butyl (3SV3-K2-acetomethyl) (cycloheptyl)amino 1 -pyrrolidine-1-carboxylate

The third butyl (3S)-3-[(2-chlorophenylindenyl)(cycloheptyl)amino]aminopyrrolidine-1-carboxylate is by a method similar to that described in Preparation 2 ( Using decene as a solvent, N-methylmorpholine as a base, and heating the reaction mixture at 60 ° C for 18 hours) using the amine of Preparation 18 and 2-chlorobenzhydrin chloride to give the desired product, 1.27 g ( 90%). MS APC1+ m/z 421 [MH]+ and m/z 321 [MH-Boc]+ tert-butyl (3SV3-indolecycloheptyl "2-(trifluoromethyl)) adenyl 1 aminopyrrole Alkane-1-carboxylate

H3c tert-butyl-(3S)-3-{cycloheptyl[2-(trifluoromethyl)phenylindenyl]amino} 65 1300776 pyrrolidine-1-carboxylate by preparation with 2 A similar method (using benzene as a solvent, N-methylmorpholine as a base, and heating the reaction mixture at 6 ° C for 18 hours) using the amine of Preparation 18 and 2-(trifluoromethyl)benzamide Gas preparation 'produces the desired product, 910 mg (57%). MS APC1+ m/z 455 [MH]+^m/z 355 [MH-Boc]+ Preparation 21 is butyl butyl (3S)-3]cyclohexyldifluoromethyl)benzimidyl 1amine p Hyun-1-acid cool

Tert-butyl-(3S)-3-{cyclohexylindole (trifluoromethyl)benzylidene]amino} each of the 1-carboxylic acid esters is a method similar to that described in Preparation 2 ( Using methyl bromide as a solvent, N-methylmorpholine as a base, and heating the reaction mixture at 6 ° C for 18 hours) using the amine of Preparation 4 and 2-(trifluoromethyl)benzhydrin chloride, For product, 860 mg (52%). MS APC1+ m/z 441 [MH]+ and m/z 341 [MH-Boc]+ Preparation 22 丨 丨 戊 『 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- Carboxylic ester 66 1300776

Tert-butyl-(3S)-3-{cyclopentyl[2-(trifluoromethyl)phenylhydrazinyl]amino}pyrrolidine-1-carboxylate is similar to that described in Preparation 2. The method (using benzene as a solvent, N-methylmorpholine as a base, and heating the reaction mixture at 6 ° C for 18 hours) using the amine of Preparation 1 and 2-(trifluoromethyl)benzhydrazide chloride Prepared to give the desired product, 910 mg (54%). 'HNMRCCDCls, 400MHz, rotamer) 5: 1.43-1.47 (brd, 11H), 1.55 (m, 2H), 1.65 (m, 1H), 1.76 (m, 2H), 1.99 (m, 2H), 2.35 (m,0·5Η), 2.89 (m, 0.5H), 3.05 (m, 0·5Η), 10 3.19 (m, 0·5Η), 3.39 (m, 1H), 3.57 (m, 1H), 3.69 (m, 2H), 3·96 (πι, 1H), 7·24 (πι, 1H), 7.50 (m, 1H), 7.57 (m, 1H), 7.69 (d, 1H) MS APC1+ m/z 427 [MH]+ and m/z 327 [MH-Boc]+ Preparation 23 15 Third butyl (3SV3-mi-methylcyclo)carbonyl 1 Aminopyrrolidine-1-#醢67 1300776

1-Mercaptocyclopropanecarboxylic acid (2·96 g, 29.54 mmol) was added to the third butyl (3S)-3-aminopyrazine in di-methane (135 mL) at room temperature. A solution of 1-carboxylic acid ester (5 g, 26.85 mmol). Then, triethylamine 5 (9.4 ml, 67.13 mmol) was added. The reaction was cooled to 〇 ° C and 2,4,6 propyl-1,3,5,2,4,6-tri was added. Ethylene triphosphonate was calcined with 2,4,6-trioxide (50% in ethyl acetate, 17.4 ml, 29.54 mmol). The mixture was stirred at room temperature for a few hours and then concentrated under reduced pressure. The residue was diluted in dichloromethane (100 mL), and a 20% aqueous acid-bromine solution (80 mL) was added. The mixture was stirred at room temperature for 18 hours and the layers were separated. The organic layer was dried with EtOAc (EtOAc)EtOAc. %). ^NMRCCDCla, 400MHz) 5 : 0.52-0.54(m9 2H), 1.16-L19(m,2H), 1.29(s,3H), 1.45(s,9H),1.81(brs,1H), 15 2.14(m, 1H), 3.14 (brs, 1H), 3.42 (brs, 2H), 3.64 (m, 1H), 4.44 (m, 1H), 5.73 (brs, 1H). MS APC1+ m/z 269[MH]+ _Preparation of 24 m 棊(3s)-3-{"(u-cyclopropyl)methyl-i-amino hydrazine P is less than calcined 68 1300776 acid ester

A shed (1 M 'in tetrahydrofuran, 75 ml, % mmol) was slowly added to a solution of compound 23 (6.815 g &apos; 25.39 house Moule) of Preparation 23 in tetrahydrofuran (75 mL) under nitrogen. The mixture was heated at reflux for 2 hours and then stirred at room temperature for 18 hours. small. The reaction mixture was quenched by the addition of MeOH and then the mixture was concentrated in vacuo. The residue was taken up in methanol (12 mL) and heated at reflux for 3 h. Then, aqueous ammonium chloride was added, and the reaction mixture was heated under reflux for 4 hours. Then, the reaction was concentrated in vacuo, residue 10 was partitioned between EtOAc &lt;RTI ID=0.0&gt;&gt; . The crude product was purified by column chromatography eluting with EtOAc EtOAc (EtOAc:EtOAc) 15 ^ NMR CCDbOD, 400 ΜΗζ) δ : 〇.55-〇.58 (m, 2H), 〇.62-0.64 (m, 2H), 1.22 (s, 3H), 1.46 (s, 9H), 2.08 (m, 1H), 2.36(m,1H), 2.94(q,2H), 3.36-3.41(m,2H),3.56(m,1H), 3.74-3.86(m, 2H) 0 MS APC1+ m/z 255[MH ]+ Preparation 25 69 1300776 •^Χ^(35)-3-{(2,3-Dioxybenzhydryl)丨(1_甲埤丐芊埤丐芊)甲肀1 If the base is p than Haha- 1 - a few acid

Dibutyl (3S)-3-{(2,3-dioxaphenyl)[(^-decylcyclopropyl)-5-yl]amino}pyrrolidine-1-carboxylate Prepared in a similar manner to that described in Preparation 2 using the amine of Preparation 24 and 2,3-dichlorobenzoquinone chloride to give the desired product (448 mg, 85%). 1H NMR (DMSO-D6, 400MHz, rotamer): 〇·15-0·18(ιη,1·5Η), 0·26-0·31(ιη, 1.5H), 0.42 (m, 0.5H) ), 10 〇.53(m,1H), 0.88(d,2H), 1.07(s,1.5H), 1.33(s,4H), 1.39(s,

5H), 2.05 (m, 1H), 2.55 (m, 0.5H), 2.88 (m, 0.5H), 2.96 (m, 0.5H), 3.10-3.22 (m, 2H), 3.31 (m, 1H), 3.49-3.56 (mv 1.5H), 3.65 (m, 0.5H), 4.23 (m, 0·5 Η), 7.35 (m, 1H), 7.42 (m, 1H), 7.66 (m, 1H). 15 MS APC1+ m/z 427 [MH]+ Preparation 26 篦 Tributyl (3SV3-K3-Nitro-2-methyl jasmonylmethylcyclopropyl)methyl 1 Aminopyrrolidin-1-carboxylate Acid ester 70 1300776

Indole dibutyl (3S)-3-{(3-chloro-2-methylbenzoate)[(lmethylcyclopropyl)methyl]amino Kb-rrolidine-1-carboxylate Prepared using the amine of Preparation 24 and 3-chloro-2-methylbenzoic acid in a similar manner to that described in Preparation 3 to give the desired product (300 mg, 60%). WNMR (DMSO-D6, 400MHz, rotamer) (5: 〇18(m, 1H), 0·24-0·32 (ιη, 2H), 0.51 (m, 1H), 0.83 (s, 2H) , l.〇6(s,1H), 1.32(s,4H), 1.39(s,5H),1.85(m,0.5H),2.04(m,1H),2.18(s, 2H), 2.22(s , 1H), 2.56 (m, 1H), 2.95 (m, 1H), 3.09 (m, 1H), 10 3.18-3.22 (m, 2H), 3.48-3.55 (m, 1.5H), 3.66 (m, 0.5) H), 4.22 (m, 0.5H), 7.15 (m, 1H), 7.26 (t, 1H), 7.45 (d, 1H) MS APC1+ m/z 407 [MH]+ Preparation 27 Third butyl (3SV3) -f(cyclobutylcarbonyl)amino ipyrrolidine-l-carboxylate

71 15 1300776 Cyclobutanecarbonyl chloride (9 g, 76 mmol) added to a solution of triethyl (12.5 mL, 89.7 mmol) in dichloromethane (385 mL) A solution of butyl (3S)-3-aminopyrrolidine-1-carboxylate (12.87 g, 69 mmol). After stirring at room temperature for 18 hours, the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ hNMRGOOMHz, CDC13)5: 1.45 (S, 9H), 1.75-2.00 (m, 3h), 2.07-2.30 (m, 5H), 2.95 (m, 1H), 3.15 (m, 1H), 3.40 (m, 2H) ), 3.60 (m, 1H), 4.44 (m, 1H), 5.40 (brs, 1H) 10 Preparation 28 capping butylmethyl) trifluoromethyl, benzoyl hydrazino

Ν” 0=ζ H3C—^ch3 ch3 The third butyl (3s)_3_[(cyclobutylmethyl)amine-based weiwei acid _·8 gram in a jiaben (ca liter), 3 ls millimol It was treated with 2_(Sandunmethyl)benzene δ helium (0.55 liter, 3.78 Φ molar) and triethylamine (G 88 mL, 63 mM). The solution was allowed to stand at room temperature for 18 hours, and the solvent was removed under reduced pressure. The crude product was converted to pentane: ethyl acetate (1:1 by volume) using a gradient of pentane 72 15 1300776 alkane: ethyl acetate (4:1 by volume) on a column chromatography gel. Purified to provide a colorless compound (1.40 g, crude) which was used directly in the next step. MS APC1+ m/z [ΜΗ]+,371 {ΜΗ·isobutyl dilute 5 327 [MH-BOC]+ Example 1 2,3-di-gas-N-cyclopentylpyrrolidin-3-yl 1 mo醢面半.7'- taraxanthin

10 Preparation of Boc-protected product (46 g, 107 mmol) dissolved in di-methane (85 mL) under nitrogen, and the reaction mixture was added dropwise tri-acetic acid (85 ml, 1 at 〇 ° C) Moore) processing. After the reaction mixture was stirred at room temperature for 4 hrs, then evaporated, evaporated. The residue was taken up in a methane (400 ml) and washed with 1M aqueous sodium hydroxide 15 (2 mL). The organic phase was separated, dried over magnesium sulfate and concentrated in vacuo. The residue was azeotroped with ethyl acetate (10x) then dried in vacuo to yield the title compound as the title compound, One part of this compound (24 g, 70 mmol) in isopropanol (4 mL) in isopropyl-disulfonic acid hydrate (6.65 g, 35) 20 ml solution of millimolar. The solvent was removed in vacuo and the residue was taken from ethyl acetate to afforded EtOAc EtOAc (EtOAc: EtOAc: The solid was recrystallized from isopropanol / decyl alcohol (700 ml of isopropyl alcohol and the minimum amount of methanol required to afford solubility) and dried under high vacuum to afford compound (13.94 g) as a white solid. 5 !HNMR (CD3OD, 400MHz) (5: 1.40-1.74 (m, 7H), 1.92 (m, 1H), 2.52 (m, 2H), 3.24 (s, 2H), 3.30 (m, 1H), 3.56 ( m,1H), 3.78(m,3H), 4.33(m,1H),7.35(dd,1H), 7.42(t,1H), 7.63(d, 1H) MS APC1+ m/z 327 [MH+] LC= MS ELSD m/z 327 100% 0 microanalysis: found C, 47.37; H, 5.59; N, 6.47. C16H20Cl2N2O· 〇.5C2H606S2. 0·5Η2Ο requires C, 47·34; H, 5.61; N, 6.49%. Example 2 1 Dichloro-N-cyclononyl-4-fluoro-N-"(3SVpyrrolidin-3-one 1 meglumine hydrogenated product

Hydrogenated hydrogen (4M in 1,4-dioxane, 37 mL, 148 mmol) was added to a product of Preparation 3 (6.65 g, 14.93 mmol) in di-methane (40 mL) . After stirring at room temperature for 18 hours, the solvent was removed by evaporation under reduced pressure to give a solid. HNMR (CD3OD, 400MHz) 5 : 1.54 (m, 4H), 1.73 (m, 3H), 74 1300776 1.92 (m, 1H), 2.52 (m, 2H), 3.25 (m, 1H), 3.52 (m, 1H), 3.78 (m, 3H), 4.32 (m, 1H), 7.37 (m, 2H) MS APC1 + m/z 345 [M] + Example 3 5 UN-cyclopentyl-2-methyl-N- |~(3S)·^Biluo-3-ylcarboxamide hydrogenation

The third butyl (3S)-3-[cyclopentyl (3-oxa-2-mercaptobenzylidene)amino]pyrrolidine-1-carboxylate is similar to that described in Preparation 3. The procedure was prepared using mp. MS APC1+ m/z 407 [MH]+ 3-chloro-N-cyclopentyl-2-methyl-N-[(3S)-pyrrolidinyl]phenylhydrazine hydrochloride is derived from the aforementioned compound Prepared in a similar manner to that described in Example 2 to give the product as a solid, 199 mg (47%). !HNMR (CD3OD9 400MHz) 5 : 1.44-1.60 (m, 4H), 1.79 (m, 4H), 2.33 (d, 3H), 2·44-2·54 (πι, 2H), 3.24 (m, 1H) , 3.54 (m, 1H), 3.72 (m, 1H), 3.80 (m, 2H), 4.31 (m, 1H), 7.16 (dd, 1H), 7.28 (t, 1H), 7.47 (d, 1H) 20 LCMS ELSD/APC1+ m/z 307 [MH]+ 100% 75 1300776

Microanalysis: found: C, 58·25; H, 7.20; N, 7.92%. Calculated for C17H23C1N20· Ηα·0·4Η2Ο: c, 58.26; Η, 7·13; N Ί.99%. Example 4_ N-cyclodecyl-3-fluoro-2-methyl-N-[Y3SVpyrrolidin-3-antimony

Tert-butyl (3S)-3-[(3-fluoro-2-methylbenzylidene)(cyclopentyl)amino]debornrol-l-carboxylate by preparation with 3 A similar method was used to prepare the desired product, 639 mg (crude), using the amine 1 and 3-fluoro-2-methylbenzoic acid. MS APC1+ m/z 391 [MH]+ N-%-pentyl-3-fluoro-2-methyl-N-[(3S)·^ ratio p-s--3-yl]benzamide-hydrochloride Prepared from the above compound by a method similar to that described in Example 2 to give the product as a solid, 182 mg (46%). 2H NMR (CD3OD, 400MHz) (5: 1.49-1.63 (m, 4H), 1.78 (m, 4H), 2.22 (d, 3H), 2.49 (m, 2H), 3.25 (m, 1H), 3.55 ( m,1Η), 3.74(m,1H),3.87(m,2H),4.31(m,1H),7.03(dd,1H),7.14(t, 1H),7.31(q,1H) 20 MS APC1+ m /z 291 [MH]+ 76 1300776 LCMS ELSD/APC1+ m/z 291 [MH]+ 100% microanalysis: found: C, 61.18; H,7·51; N, 8.25%. For C17H23FN20· HC1.0.39H2O Calculated: c, 61·16; H, 7.48; N, 8.39%. Example 5 1: Tomb-ring fluorenyl-fluoro-N-K3SV-rrolidine-3-one 1 scorpion scorpion face

Tertiary butyl (3S)-3-[(2-fluoro-3-fluorobenzylidinyl)(cyclopentyl)amino]pyryl 10 11 each of the pyridin-1-decanoate was prepared by the preparation of A similar method is prepared using the amine of Preparation 1 and 2-ox-3-fluoro-benzoic acid to give the desired product. 2-Gas-N-cyclopentyldi-N-[(3S)-pyrrolidin-3-yl]benzamide amine hydrochloride was prepared from the aforementioned compound by a method similar to that described in Example 2. The product was obtained as a solid, 62 mg (15%). 15 HNMR (CD3OD, 400MHz) 5 : 1.44-1.63 (m, 4H), 1.73 (m 3H), 1.92 (m, 1H), 2.52 (m, 2H), 3.24 (m, 1H), 3.58 (m, 1H) ), 3.80 (m, 3H), 4.32 (m, 1H), 7.19 (dd, 1H), 7.35 (t, 1H), 7.45 (m, 1H). LCMS ELSD/APC1+ m/z 311 [MH] + 100% 20 microanalysis: found: C, 53.68; H, 6.30; N, 7. 7 %. Calculation for 77 1300776 C16H2〇C1FN20· Ηα·0·6Η2Ο: C, 53·67; Η, 6.25; N, 7.82%. Example 6 2,3-Dichloro-N-cyclohexyl-N-((3S)-pyrrolidin-3-yl 1 benzoic acid hydrochloride hydrochlorination

2,3-Dichloro-N-cyclohexyl-N-[(3S)-pyrrolidin-3-yl]benzamide hydrochloride is a compound of Preparation 5 which is similar to that described in Example 2. The method was prepared to give the product as a solid, 3.95 g (yield: 89%). ^NMR (CD3OD, 400MHz) δ: 1.02-1.10 (m, 3H), 1.56-1.81 (m, 7H), 2.46 (m, 2H), 3.13 (m, 1H), 3.25 (m, 1 Η), 3.48 ( m, 1H), 3.73 (m, 1H), 3.81 (m, 1H), 4.45 (m, 1H), 7.32 (dd, 1H), 7.43 (t, 1H), 7.66 (d, 1H). MS APC1+ m/z 341 [MH]+ Example 7 Hydrogenation of 2-Nitro-N-cyclohexyl-3-fluoro-N-K3S)-pyrrolidin-3-yl 1 acesulfame 78 1300776

2-Chloro-N-cyclohexyl-3-fluoro-N-[(3S)-pyrrolidin-3-yl]benzamide hydrochloride is a compound from Preparation 6 which is similar to that described in Example 2. Prepared by the method to give the product as a solid, 118 mg (88%). 5 !HNMR (CD3OD, 400MHz) 5 : 0.99-1.12 (m, 3H), 1.56-1.91 (m, 7H), 2.47 (m, 2H), 3.15-3.22 (m, 2H), 3.50 (m, 1H) , 3.71 (m, 1H), 3.81 (m, 1H), 4.45 (m, 1H), 7.21 (dd, 1H), 7.37 (t, 1H), 7.46 (m, 1H). MS APC1+ m/z 325 [MH] + 10 NMR: Found: C, 54.87; H, 6.55; N, 7.30%. Calculated for C17H22C1FN20· HC1.0.6H2O: C, 54·88; H, 6.56; N, 7.53%. Example 8 N-cyclohexyl-3-fluoro-2-methyl-N-K3S)-pyrrolidin-3-yl 1 cumamine hydrogen 15

79 1300776 N-cyclohexyl-3-fluoro-2-indenyl-N-[(3S)-17 to 0 benzyl-3-yl]benzamide amines from the compound of Preparation 7 by way of Examples 2 The same procedure was used to produce the product as a solid, 45 mg (85%). 'HNMR (CD3OD, 400MHz) 5:0·99-1·17(ιη,3H), 5 1·54-1·77(ιη,7Η), 2.20(d,3Η), 2.47(m, 2Η), 3.23(m,2Η), 3.48(m,1H), 3.70(m,1H),3.81(m,1H),4.43(m,1H),7.03(dd, 1H), 7.16(t,1H),7.31 (q, 1H). MS APC1+ m/z 305 [MH]+LCMS ELSD m/z 305 [MH]+ 100% 10 microanalysis: found C, 60·87; H, 7.80; N, 7.59%. Calculated for C18H25FN20· HC 1.0.79H2O: C, 60.88; H, 7.83; N, 7.89%. Example 9 2,3-digas-N-cyclobutyl-N-((3S)-pyrrolidin-3-yl 1 molybdenum face servant 15

2,3-digas-N-cyclobutyl-N-[(3S)-pyrrolidine! The benzylideneamine hydrogenate from the compound of Preparation 9 was prepared by a procedure similar to that described in Example 2 to give the product as a solid, 311 mg (99%). 20] HNMR (CD3OD, 400MHz) 5 : 1.56 (m, 1H), 1·70 (ιη, 1H), 2.00 (m, 1H), 2.13 (m, 1H), 2.23-2.30 (m, 2H), 2.46 (m, 1H), 80 1300776 2.54 (m, 1H), 3.26 (m, 1H), 3.54 (m, 1H), 3.73-3.81 (m, 2H), 4.00 (m, 1H), 4.71 (m, 1H) ), 7.31 (m, 1H), 7.43 (t, 1H), 7.66 (d, 1H). MS APC1+ m/z 313 [MH]+ Example 10 N-cyclobutylmethyl-2,3-diaza-N-K3S)-pyrrolidin-3-yl 1-indolecarboxamide Hydrogenated product

N-Cyclobutylmethyl-2,3-dichloro-N-[(3S)-pyrrolidin-3-yl]phenylhydrazine hydrochloride is a compound of Preparation 12 which is similar to that described in Example 1. The method was prepared to give the product as a gel, 55 mg (68%). ^NMR (CD3OD, 400MHz) 5 : 1.55-1.70 (m, 3H), 1.85-2.03 (m, 3H), 2.54 (m, 3H), 3.15 (m, 1H), 3.26 (m, 2H), 3.50 ( m, 1H), 3.76 (m, 2H), 4.30 (m, 1H), 7.38 (m, 1H), 7.43 (t, 1H), 7.66 (d, 1H). <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> Calculated for C16H20Cl2N2O. HC 1.0.75H2O: C, 50.94; H, 6·01; N, 7. 43%. Example 11 2,3-digas-N-(cyclopropylindenyl)-N4 (3SV pyrrolidine-3-1 benzoic acid amine chlorophyll 81 1300776 chloride

The third butyl (3S)-3-[cyclopropylindenyl (2,3-dichlorophenylhydrazino)amino]pyrrolidine-1-carboxylate is similar to that described in Preparation 1. The method was prepared by using a compound of Ammonium 13 and 2,3-dibenzophenone to produce the desired product (crude). MS APC1+ m/z 413 [MH]+ and m/z 313 [MH-Boc]+ 2,3-dioxo-N-(cyclopropylindenyl)-N-[(3S)-pyrrolidin-3- The benzoylamine hydrochloride is prepared from the above compound by a method similar to that described in Example 1, purified by chromatography, and formed into a hydrogenate salt to give the product as a 10 gel, 393 mg. (77%). 2ΗΝΜΚ (CD3OD5 400MHz) 5 : 0.09 (m, 2H), 0.502 (m, 2H), 0.88 (m, 1H), 2.47-2.54 (m, 2H), 3.01 (m, 2H), 3.21 (m, 1H) , 3.50 (m, 1H), 3.76 (m, 2H), 4.42 (m, 1H), 7.36 (m, 2H), 7.59 (d, 1H). </ RTI> <RTIgt; Calculated for C15H18C12N20. HC1.0.78H2O: C, 49·53; H, 5.70; N, 7.70%. Example 12 20 2,3-digas-N4(3S)-pyrrolidin-3-yl 1-N-tetrahydro-2H-pyridin-4-yl benzoate 82 1300776 decylamine

2,3-digas-N-[(3S)·pyrrolidine! a compound of the formula 15 is prepared by a method similar to that of the second embodiment (the free test system is performed by column chromatography). Gradient two-gas methane·· sterol on the Shi Xishi gel: aqueous ammonia (100:0:0, by volume) changed to dichloromethane: methanol: aqueous ammonia (100:10:1, by volume Prepared to provide the title compound as a colorless oil to give the product as a gel, 120 mg (77%). 10 W NMR (CD3OD, 400 MHz) 5 : 1.58 (m, 1H), 1.74 (m, 1H), L89-1.97 (m, 2H), 2.28 (m, 2H), 2.96 (m, 1.5 Η), 3.11-3.20 (m, 3H), 3.45-3.53 (m, 3H), 3.92 (m, 1.5H), 4.03(m, 0.5H), 4.20(m, 0.5H), 7.32(dd,1H), 7.42(t,1H), 7.64(d,1H) 〇MS APC1+ m/z 343 [MH] + 15 Example 13 2-Gas-N- sulphide-N-"(3S)-Pl; b-carbo-3-yl 1benzamide 1300776 2-chloro-N-cyclopentyl-N-[ (3S)-Pyrrolidin-3-yl]benzamide The compound from Preparation 16 was prepared by a procedure similar to that described in Example 1 to give the title product, 640 mg (74%). 400MHz) 5 : 1.43 (m, 2H), L61 (m, 2H), 5 1.72 (m, 3H), 1.92 (m, 2H), 2.38 (m, 2H), 3.09 (q, 1H), 3.57-3.65 (m, 2H), 3.79 (m, 1H) , 4.15 (m, 1H), 7.33 (m, 1H), 7.43 (m, 2H), 7.49 (m, 1H) MS APC1 + m/z 293 [MH] + Example 14 ίο 2- gas _N-cyclohexyl -N-"(3S)-pyrrolidin-3-yl 1benzimidazole

2-Gas-N-Lomohexyl-N-fGS)-11-pyrrol-3-yl]benzoquinone-based amines were prepared from a compound of Preparation 17 by a method similar to that described in Example 1, to give the title product. , 685 mg (83%). 15 'HNMR (CD3OD, 400MHz) (5: 0.98-1.13 (brm, 3H), 1.54-1.88 (brm, 7H), 2.44 (m, 2H), 3.19 (m, 2H), 3.44 (q, 1H), 3.66 (m, 1H), 3.78 (m, 1H), 4.41 (m, 1H), 7.34-7.52 (brai, 4H) MS APC1+ m/z 307 [MH]+ Example 15 2〇2-Ga-N -cycloheptane-Nr (3SV pyrrolidine-3-some 1 benzamidine 84 1300776

2-Chloro-N-cycloheptane-N-[(3S)-pyrrolidin-3-yl]benzamide is prepared from the compound of Preparation 19 by a method similar to that described in Example 1, to give the target Product, 785 mg (81%). Lu 5 ^ NMR (CD3OD, 400MHz) 5 : 1.27(m, 3H), 1.44(m, 3H), 1.62(m,1H),1·75-1·92(ιη,5H), 2.49(m,2H ), 3.22 (m, 2H), 3.49 (q, 1H), 3.70 (m, 1H), 3.81 (m, 1H), 4.36 (m, 1H), 7.35-7.52 (brm, 4H). MS APC1+ m/z 321 [MH]+ 10 Example 16

N-cycloheptyl-N-[(3S)-p-pyrrolidin-3-yl1-2-(trifluoromethyl) abbreviated amine F

N-cycloheptyl-N-[(3S)-pyrrolidin-3-yl]-2-(trifluoromethyl)benzamide is a compound of Preparation 20 which is similar to that described in Example 1. Method 15 was prepared to give the title product, 502 mg (72%). HNMR (CD3OD, 400MHz) 5 : 1.19 (m, 2H), 1.32 (m, 1H), 85 1300776 1.42 (m, 3H), 1.65-1.81 (m, 6H), 2.45 (m, 2H), 3.24 ( m, 2H), 3.48 (t, 1H), 3.56 (m, 0.5H), 3.76 (m, 1.5H), 4.35 (m, 1H), 7.49 (dd, 1H), 7.69 (m, 1H), 7.75 (m, 1H), 7.81 (m, 1H). MS APC1+ m/z 355 [MH]+ Example 17 N-cyclohexyl-N-K3S)-pyrrolidin-3-yl1-2-(trifluoromethyl)methaneamine

N-cyclohexyl-N-[(3S)-pyrrolidin-3-yl]-2-(trifluoromethyl)benzoguanamine is a compound similar to that described in Example 1 from the compound of Preparation 21. 10 Preparation, producing the target product, 460 mg (69%). !HNMR (CD3OD, 400MHz) (5: 0.95-1.08 (m, 3H), 1.52-1.73 (m, 7H), 2.08 (m, 1H), 2.20 (m, 1H), 2.79 (m, 1H), 2.96 (m, 1H), 3.06 (m, 1H), 3.21 (dd, 0.5H), 3.37 (m, 1.5 Η), 4.06 (m, 1H), 7.42 (dd, 1H), 7.65 (m, 1H) , 7.72 (m, 1H), 7.79 (m, 15 1H) MS APC1 + m/z 341 [MH] + Example 18 N- sulphonyl-N- "(3S)-p|; -yl 1-2-(trifluoromethyl)benzamide 86 1300776

N-cyclopentyl-N-[(3S)-pyrrolidin-3-yl]-2-(trifluoromethyl)benzamide is a compound of Preparation 22 which is similar to that described in Example 1. The method was prepared to give the title product 690 mg (99%). 5 WnMR (CD3OD, 400MHz) 5 : 1.44 (m, 2H), 1.59 (m, 2H), L73 (m, 4H), 2.47 (m, 2H), 3.24 (m, 1H), 3.53 (m, 1 · 5Η), 3.76 (m, 2.5H), 4.29 (m, 1H), 7.46 (dd, 1H), 7.66 (m, 1H), 7.74 (m, 1H), 7.80 (m, 1H). MS APC1+ m/z 327 [MH] + 10 Example 19 2,3-dioxo-indole-indole-methylcyclopropyl)methyl 1-N-IY3S)-pyrrolidin-3-yl 1

Methionine hydrochloride

2,3-di-gas-N-[(l-methylcyclopropyl)methyl]-N-[(3S)-pyrrolidin-3-yl]benzamide amine hydrochloride from the preparation of 25 The compound was prepared by a method similar to that described in Example 2 to give the product as a solid (269 亳 87 1300 776 g, 100%) 〇^NMR (CD3OD, 400 MHz) δ: 0.25-0.32 (m, 2H), 0.44(m, 1H), 0.50 (m, 0·5Η), 0.60 (m, 0·5Η), 0.98 (s, 3H), 2.50-2.61 (m, 2H), 2.95 (dd, 1H), 3.24- 3.36 (m, 2H), 3.57 (m, 1H), 3.75-3.87 (m, 2H), 4.52 (m, 1H), 7·36-7·45 (πι, 2H), 7.63 (d, 1H). MS APC1+ m/z 327 [MH]+ Example 20

3-nitro-2-mercaptomethylcyclopropyl)methylpyrrolidin-3-yl 1 acesulfame hydrogenated product

3-Chloro-2-methyl-N-[(l-methylcyclopropyl)methyl]-N-[(3S)-pyrrolidin-3-yl]benzamide amine hydrochloride from self-preparation 26 The compound was prepared in a similar manner to that described in Example 2 to give the product as a solid (310 mg, 90%). ^NMR (CD3OD, 400 ΜΗζ) δ: 0.29-0.42 (m9 3.5 Η), 0.51 (m, 0·5 Η), 0.96 (s, 3H), 2.31 (d, 3 Η), 2.50 (m, 1 Η), 2.59 ( m, 1H), 3.02 (d, 0·5Η), 3.15 (q, 1H), 3.25-3.32 (m, 1.5H), 3.59 (m, 1H), 3.78-3.83 (m, 2H), 4.51 (brs) , 1H), 7.21 (m, 1H), 7.29 (t, 1H), 7.47 (d, 1H). 88 1300776

MS APC1+ m/z 307 [ΜΗ] Example 21 ϋcyclobutylmethyl)-N-"(3SVpyrrolidine winter 1-2-(tripamethionine&gt;&gt;

F

Preparation 28 of the third butyl (3S)-3-{(cyclobutylmethyl)[2-(trimethyl)benzylidenyl]amino}pyrrolidine-1-carboxylate (1·4〇) Gram, 3.3 millimoles) 4N hydrogenated hydrogen dissolved in dimethane. The solution was stirred for 1 hour and the solvent was removed under reduced pressure. The residue was dissolved in water and the solution was washed with ether. The aqueous phase was basified by the addition of aqueous NaOH and extracted with ether. The ether phase was dried over MgSO.sub.4, filtered, and solvent was evaporated and evaporated to dryness eluting with EtOAc EtOAc EtOAc EtOAc Compound. ]ΗΝΜΚ(400ΜΗζ, CD3OD) δ :1.6M.72(m, 3jj) 1.92-2·03(ιη,3H), 2.45(m,1H), 2.59(m,2H), 3.14(m,ih 3.26(m, 2H), 3.55(m, 1H), 3.68-3.82(m, 2H), 4.34(m, 13⁄4) 7.54(m,1H), 7.72(m,1H), 7.80(m,1H) , 7.85 (m, 1H). LCMS APC1 + m/z 327 [MH] + Example 22 NRI Ki and SRI Ki of the compounds of Examples 1 to 21 are determined as follows. The choice of results is shown in Table 1 below. All of the compounds of the examples exhibited less than 100 nM of NRI Ki and SRI Ki. Biologically active compounds were tested for bioactivity using the Scintillation Proximity Assay (SPA) technique by their ability to inhibit selective radiation ligand binding in human 5 serotonin and norepinephrine transporters (individual lines SERT and NET). The SPA binding system was prepared using a cell membrane preparation (hSERT, hNET) prepared from a cell line expressing human cDNA encoding SERT or NET using the radioligands 3H-tetrapatium and 3H-nisoldipine. 10 i) Cell culture method The human embryonic kidney cells (HEK-293) expressing each transporter were continuously cultured using standard cell culture techniques in a 225 cm 2 flask (at 37 ° C and in a humidified atmosphere with 5% C 〇 2 The presence of 50 ml of growth medium (see Media and Buffer for composition) is maintained. The fine 15 cell line is passed through a 90% monolithic monolayer at a ratio of 1:3-1:4. For cell collection, the growth medium is removed from this monolayer and the cells are cultured in cell dissociation (Sigma) until dissociation information is revealed. The cells are subsequently knocked down from the bottom of the flask and pelletized by centrifugation for further use. Storage (freezing at -80 ° C). 20 ϋ) Preparation of Cell Membrane Cell pellets are melted on ice and resuspended in a membrane preparation buffer of 3 liters per liter of volume (see composition medium) In the buffer, night, the cell pellet was dispersed using a vortex mixer. After culturing for 1 minute on ice, the suspension was homogenized four times using a hand-held homogenizer for a period of 90 1300776 for 1 second. The homogenate was then centrifuged at 1075 g for 2 minutes at 4 °C. The upper layer is then collected and retained. The starting cells and nuclear pellets (P1) were then homogenized and centrifuged using the above-mentioned strip, and the supernatant was collected and mixed with the first rotation retainer. The upper layer of k ό was centrifuged at 35,000 X g for 3 minutes at 4 C, and the upper layer was discarded. Then, the pellet (P2) was resuspended in 1 ml of the original packed cell volume per ml of membrane preparation buffer. Then, the protein concentration was measured, and the number of membrane suspensions was frozen in a set volume aliquot and stored at -80 °C before being used for analysis. 10 iii) Analytical method A· stationary _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ (YSi WGA) SPA beads were used for hSERT and WGA coated polyvinyl toluene (PVT WGA) spA beads were used for 15 hNET analysis. For each batch of film used, the optimum concentration of beads and film is determined.

Radiation ligands specific to each transporter (for hSERT line 3H_tetrapatium, and for hNET nisoldipine) were used. The analysis of the concentration of the non-radiative ligand was expressed as a percentage of the total concentration of the non-radiative ligand 20 to produce an estimate of the depletion of the radioligand. The light carrier ligand depletion system of the second transporter is less than 3〇% to ensure that there is sufficient radiation ligand T for the towel a ligand depletion value and also when using the new batch of membrane Choose the best analysis conditions. The affinity for a particular radioligand for an individual transporter is determined by the protein and bead concentration of 91 1300776 selected for each membrane batch. This can be achieved by determining the KD (the concentration of the free-radiating ligand when 50% of the transporter binding sites are occupied). The average KD of the radiation ligands of a batch of membranes is determined from the data of the smallest of the three individual analyses. Thereafter, the average KD was used to determine the relationship between the inhibitory constants (κ i) of Cheng YC and Pnisoff W Η and the inhibitor concentration of 50% inhibition of the enzymatic reaction using the method determined by Cheng and Prussoff. , Biochem Pharmacol 1973; 22: 2098-3018) All analyses of membrane batches described by the Ki values of the compounds studied. B. Analytical Methods 10 Preparation of Bead/Film Composite The desired amount of membrane is melted on ice and added to a predetermined volume of the bead suspension in the assay buffer. The beads were then pre-coupled by culturing the predetermined protein amount per milligram of beads on a 4 °C shaker for 2 hours. Thereafter, the bead/film composite was spun at 865 g for 5 minutes. The formed pellet 15 is resuspended in the analysis buffer, and then this rotation/washing step is repeated. The final pellet is then resuspended in assay buffer at the specific concentration required for the final assay. Preparation of Ligand 3 [H] - An aliquot of the starting ligand material is diluted in assay buffer, 20 yielding a predetermined final assay concentration that is less than the equilibrium dissociation constant (KD) value. All test compounds were prepared from dried samples at a concentration of 4 mM in 100% dimethylarsine (DMSO). Compound in ddH2〇

The 0.75% DMS was diluted and the appropriate concentration was generated on a 384-well plate to yield a final volume of 2 〇&quot;L. 92 1300776 The same volume of assay buffer is added to the specific well of the plate for subsequent detection of total light-light ligand binding. Further, a specific 20//L·South concentration compound for each transporter is then added to the predetermined well to determine the non-specific binding (NSB). Fluoxil &gt; D (1〇//)^ final analysis concentration) was used for hSERT, 5 and normipropionate (4〇 // Μ last analyzed concentration) was used for hNET. For each individual transporter analysis, 2 Å//] L of the specific radiation ligand prepared was added to each well of the final assay plate (containing the compound solution). Thereafter, 20//L of the corresponding bead/membrane complex was added to each well of the final assay plate to ensure that the suspension was thoroughly mixed. The plates were then sealed and incubated, 10 and shaken at temperature for 1 hour. These plates were then additionally conditioned for 6 hours prior to reading. The analysis window (specific combination) of each plate is calculated from the average of the total combined readings η minus the average NSB reading (the number per minute, or ah). The cpm reading (and the subtracted average NSB) for each subsequent hole is determined by the percentage of the plate window to determine the amount of light-emitting ligand bound to the transporter. These values are plotted against the concentration of the test compound, and the s-type inhibitory concentration is used as follows: the curve uses a four-parameter logistic equation and free-fit parameters and data to produce an IC50 value (with a specific name of the neurotransmitter suppressed by 卩20) Concentration of the desired compound). Then, the suppression dissociation constant (6) is calculated from the 仏 value using the Cheng p_^ program. After determining the individual &amp; values of the test compound, the overall geometric mean is calculated as 95% confidence interval and _value_, where the total number of read _ values is 93 1300776. The formation &amp; values of the compounds of Examples 1-18 can be found in the second table. Iv) medium and buffer hSERT cell growth medium DMEM, 10% (w/v) dialysis FCS 5 2 mM L-glutamine (diluted from 200 mM material) 25 mM HEPES (diluted from 1 M material) 250 // g /mL of gemstone (genetecin) hNET cell growth medium DMEM, 10% (w / v) FCS 10 2mL of L-glutamine (diluted from 200 mM raw material) 25mM HEPES (diluted from 1M raw material) 250 / /g/mL of Genitalin membrane preparation buffer 20 mM HEPES (diluted from 1 M material in ddHA), 15 PH 7.4 at room temperature, stored at 4 °C. A complete protease inhibitor ingot was dissolved in 50 ml of buffer prior to use. Analytical buffer (1.5 X final analysis 澧Tang) 30 mM HEPES (diluted from 1 M material in ddH20) and 180 mM NaCl (diluted from 5M material in ddH20), pH 7.4 at room temperature, stored at 4 ° C 20 . Compound No. 1 SRI Ki(nM) NRI Ki(nM) 1 5 15 6 9 11 14 11 9 &quot;20 3 14 94 1300776 The e-form can also be tested for disease patterns, such as the pain pattern described below: The activity of a neuropathic pain compound in the treatment of neuropathic pain can be measured according to the following test 5 method.

Animals and male Sprague Dawley rats were housed in groups of appropriate size. All animals were maintained on a 12-hour light/black cycle (at 7 o'clock ^) ^ and food and water were free to feed. All experiments were performed by observers who were unaware of the treatment and were based on H〇me 〇ffice Animals (Scientific 10 Procedures) Act 1986. The CCI system of the sinusoidal injury (cci), such as Bennett and Xie, was performed as described previously (Bennett GJ [, Xie γκ• rat peripheral neuropathy, which is produced as a human Painful disease of the person seen, Pain: 33:87 1〇7, 1988). Animals were anesthetized with a mixture of di/fluoroether 02. After the right hind thigh was shaved and rubbed with 1% iodine, the animal was transferred to the thermostat blanket during the treatment and anesthetized to the surgery and maintained by the nasal vertebra. The skin is cut along the thigh bone line. The total sciatic nerve = ^, the other part of the head muscles in April was dissected and exposed in the middle of the thigh. By the recording of the nerve and gently raising the nerve from the thigh, about 7mm is applied to the escaping trigeminal point. Use tweezers to pull the suture through the nerves ^. And the shackles of the singularity of the singularity felt a little resistance, and then hit the double knot. The sequence was repeated until 4 sutures (4-quilt lines) were tied around the nerves and spaced about 1 mm apart. The incision is layer by layer, and the wound is treated with topical antibiotics. 0 95 1300776 too fkii's shop, singer, singer, stagnation, stagnation, diabetes, diarrhea, diarrhea, diarrhea, diarrhea Physiology • Induced by streptozotocin (50 mg/kg) in saline. Injection of streptozotocin induces regenerative mechanical pain in 3 weeks for at least 7 weeks • 5 (Chen and Pan, rat ridge auditory microstem neurons associated with diabetic neuropathic pain) Hypersensitivity 〇f Spinothalamic Tract Neurons Associated With Diabetic • Neuropathic Pain in Rats ^ J Neurophysiol 87:2726-2733, 2002) Evaluation of Static and Dynamic Touch Pain Electrostatic Touch Pain Animals Before Assessment of Touch Pain Let it tame in the test cage at the bottom of the wire. Static touch pain is by von Frey hair (Stoelting, Wood 15 Dale, by the power of ascending order (0.6, 1,1.4, 2, 4, 6, 8, 10, 15 and 26 grams) Illinois, USA) was applied to the toe of the hind paw and evaluated. Each Frey's hair system is applied to the sole of the foot for up to 6 seconds, or until a retraction reaction occurs. Once the reversal reaction to Frey's hair is established, the foot is tested again, starting with the filaments under the retractor, and then with the remaining filaments in descending order of force to no retraction. occur. The highest force of 26g makes the foot lift and gives a response, thus representing the cut-off point. Each animal tested the second hind paw in this way. The minimum force required to elicit a response is recorded as the paw retraction threshold (PWT) in grams. If the animal responds to 4g (or less) of the stimulus (which is harmless to the rat that was first used as a naive), static touch pain is defined as being present (Field MJ, Bmmwell S, Hughes J, Singh L. Neuropathy) 96 1300776 Detection of static and dynamic components of mechanical pain in the atmospheric pattern of pain • Does it produce signals by individual major sensory neurons? Pain, 1999; 83: 303-11). Dynamic Touch 痼 5 Dynamic Touch Pain is estimated by gently tapping the underside of the foot of the foot with a cotton swab. To avoid recording general activity activities, care must be taken to perform this procedure on inactive, fully paid rats. At least two measurements were taken at each time point, the average of which represents the palm condensation latency (PWL). If no reaction occurs within 15 seconds, the procedure is terminated and the animal is scheduled for this retraction time. Pain 10 Retracted response - the general system is accompanied by repeating the contraction of the foot or tongue paper. If the animal responds to cotton swab stimuli within 8 seconds of the start of the tap, dynamic touch pain is considered to be present. Nociceptive Pain The activity of chemotherapeutic agents for chemosensory pain can be measured according to the following test 15 procedure. Hot plate. Experimental procedure: Male Sprague Dawley rats were placed at 55 ± 5 . (The hot plate kiss is measured on the hot plate and the time between the front or the back of the tongue, the shaking, or the beating on the surface. The baseline is measured and the animal is The drug was re-evaluated after administration of the drug. The deadline for the incubation period of the hot plate was set to 20 seconds to avoid tissue damage. Egg-Cavity Uterine Removal Street Experimental Procedure: Female Sprague Dougly rats were placed in an anesthesia chamber, and 2% 贱_2 mixture was anesthetized. During the operation, the anesthesia was maintained by the nasal vertebra 97!3〇〇776. The ονχ was performed in the abdominal white line through the middle incision (length 2 cm), and the animal was attached to the thermal blanket. The ovarian ligament And the cervix was prepared with a single hook technique using a 5_ quilting thread. Then, the ovaries and uterus were removed. The abdominal wall was closed with 4 simple interrupted sutures, and the skin was closed with 4 wound clips. 5 animals immediately after the operation. Placed in an individual plexiglass chamber. Once the animal recovers from anesthesia, the abdominal body amnesia is recorded at various time points in 30 min bins. The marked posture is the position of the hunchback, abdominal muscle contraction related to the inward movement of the hind limb, and body stretching. , The lower abdomen is pressed against the floor. Each of these acts is marked as a gesture. 10 Buchanan iBrennan) Experimental procedure · Male Sprague Dawley rats are placed in an anesthesia room and are 2% different Anesthetize the mixture of fluoroether oxime 2 . During the operation, the anesthesia is maintained via the nasal vertebrae. The bottom of the right hind paw was cleaned with 50% ethanol. Longitudinal incision of 1 cm The No. 11 knife is used for the skin and sarcolemma at the base of the foot, starting from 0. 5 cm from the proximal edge of the heel and extending to the toe. The sclerosing muscles are lifted and cut longitudinally using forceps, and the muscles begin and stop intact. After hemostasis with gentle compression, the skin is sutured with two simple braided nylon sutures. Acetate (MIA) reading 〇A槿 Male 6-week-old Sprague Dougly (SD, Japai^charles River 20 JaPan) rats were anesthetized with pentobarbital. The injection site was shaved and cleaned with 70% ethanol. A 25//1 MIA solution or saline was injected into the right knee joint using a 29G needle. On days 7, 14, 19 and 20 after MIA injection, a series of rats were tested for weight-bearing (WB) without stress. 21 days after the injection of MIA, \^2 on each of the hind paws was measured, and WB deficiency was calculated. Define the WB deficiency value, first value, ,. Exam 98 1300776 pre-dose and pre-previous values and evenly arrange the experimental group. After administration of the test compound or vehicle, the WB on each of the hind paws was measured. Cancer Pain Patterns These experiments used adult male C3H/HeH mice (Nihon SLC, 5 Shizuoka, Japan). The mouse is based on the National Health Association (Nati〇nal

The Institutes of Health guidelines are maintained at 22 ° C and have 12 small

An alternate animal house with bright/dark cycles and free access to food and water. The sarcoma injection pattern used has been described. After systemic anesthesia was induced by inhalation of isoflurane (92%), the surface was cut to cover the skin of the body bone using 10 Mora. Then, the hip ligament is cut to expose the femoral condyle. The 3〇_ gauge needle is inserted into the concave level of the femur and enters the bone chain tube to create the initial nuclear path. After the initial nucleus is produced, a 29 gauge needle is used to bring the final path into the bone. Then, a semicircular drill used in a pneumatic high-speed handle for pneumatics produces a 0.5-mm depression as a mechanically retained dental resin plug 15 plug. Then, Shen #1' minimum amount of basic medium (Sigma; counterfeit injection) or 20//1 § has 1 x 1 〇 2472 osteolytic sarcoma cell medium (American

Type Culture Collection, R0ckville, Maryland; sarcoma injections were injected using a 29-gauge needle and a 25 cc syringe. In order to prevent the cells from leaking out of the bones, the injection site is sealed with a resin for dental use, and then washed thoroughly with filtered water. Knowing the mouth grabs the system using an automatic wound clip (to 〇111:)^1115〇11,5 grab 1 〇, California). The wound clip was removed on day 5 to avoid interference behavior testing. Static for the A1 touch 痼 Static contact Mi animal before the evaluation of the touch pain to make it in the bottom of the test line in the cage test 99 1300776 clothing. Static Touch Pain is by von Frey hair (Stoelting, Wood) by the power of ascending order (0.6, 1,1.4, 2, 4, 6, 8, 10, 15 and 26 grams)

Dale, Illinois, USA) was applied to the toe of the hind paw and evaluated. Each Frey's hair system is applied to the sole of the foot for up to 6 seconds, or until a retraction reaction occurs. Once the reversal reaction of 5 pairs of Frey's hair is established, the foot is tested again, starting with the filaments under the retractor, and then with the remaining filaments in descending order of strength to no shrinkage. Back to happen. The highest force of 26g makes the foot lift and responds, thus representing the cut-off point. Each animal tested the second hind paw in this way. The minimum force required to elicit a response is recorded as the palm retraction threshold 1 — - )), u 克. If the animal is irritated to him or less (which is harmless to the first-time experimental rat) (4) The secret state is defined as the presence (Held paper BmmWe11 S, H_es J, Singh L. Rat model of neuropathic pain) Detection of static and dynamic components of mechanical pain: Does it produce signals by individual major sensory neurons? Pain, 15 1999; 83: 303-11). 'Dynamic touch pain; dynamic touch pain is based on the bottom of the foot of the cotton palm after a slight tapping of the cotton stick - flat estimate (four) free of the δ recorded - the general action activities, need to be careful to the inactive fully paid rats This program. Each time - 20 points, the average value of the palm retraction, both #丁一-人测反庳,Ρ,丨 m period (PWL). If not displayed within 15 seconds?, winter stop And the animal is scheduled to retract this time. The pain is retracted in response to the general system, accompanied by pain in the beginning of the stroke within 8 seconds on the cotton ~ foot 4 or tongue. If the animal believes that there is. New Zealand response, __ The pain was retracted by the 100 1300776 radiant hot foot test procedure: the hot foot retraction was assessed using the rat foot test (Ugo Basile, Italy) and later by the modified method of Hargreaves et al. 1988. The rat was tamed at A high glass table consisting of three separate transparent plastic boxes 5. The mobile radiant heat source is located under the table and gathered on the hind foot pocket, and the foot retraction latency (PWL) is recorded. Automatic with 22.5 seconds Cut off points to avoid tissue damage. PWL is tied to the second hind of each animal 2-3 times, the average value represents the baseline of the right and left hind paws. The device is calibrated to produce a PWL of about 10 seconds. 10 Load-bearing procedure: Animals are used in load-bearing tests, and are not suitable for test. (Linton Instruments, Diss, Norfolk, ϋ·Κ·) detects hypersensitivity reactions. Rats are placed with their forelimbs on a transparent plastic bevel, and the weight of the hind limbs is extended by the force sensor under each hind paw. Measurement. Each movement 15 is placed in the device and is recorded by the load applied by the hind paw. The difference between the weights is calculated by subtracting the ipsilateral (damaged) foot from the contralateral paw, and this The original data may be used. The activity of the inflammatory pain compound in the treatment of inflammatory pain can be measured according to the following test method 20. The CFA-induced C. sinensis in male rats is 7 days old and the SD rats are fasted overnight. [CFA in liquid paraffin (Wako) (300//g of Mycobacterium tuberculosis rib RA (Dif〇 laboratory) was injected into the right hind paw of the rat. After administration of the second, left (ipsilateral) and Right 101 1300776 (opposite side) changes in the weight distribution of the foot after the limb The pain test was measured using a Lint〇n Discommended Tester (Linton Instrumentation, UK). Test compounds suspended in 0.1% MC (Wako) were orally administered in a volume of 1 ml per 1 gram of body weight. It was placed in the device, and the weight of the hind paw was applied to the test. The load was measured before the administration and at 1, 2, and 4 hours after the administration. The carrageenan-induced mechanical pain in rats was abnormally male. The 4-week SD rats were banned overnight. Food. Pain abnormalities were obtained by intraorbital injection; I-carat (0.1 ml in 1% w/v solution in saline, Zushikagaku). The test compound (1 ml of 0.1% thioglycol/1 gram of 10 body weight) was orally administered 5.5 hours after carrageenan injection. The paw withdrawal threshold (g) was measured by a pain meter (Ugo Basile) at 3.5, 4.5, 6 · 5 and 7.5 hours after injection of carrageenan. (Randall L.O. &amp; Selitto 1丄, Arch. Int. harmacodyn. 111, 409-419, 1957). Abnormal thermal pain induced by pull-and-mouse in rats. 15 Thermal pain abnormalities are tested using the rat foot (Ugo Basile, Comerio,

Italy) was evaluated according to the method improved by Hargreaves et al. (1988). Briefly, the rats were tamed to a device consisting of three individual transparent plastic boxes on a glass table. The mobile radiant heat source is located under the table and gathered at the desired foot, and the paw retraction latency (PWL) is recorded for each animal's second hind paw. The average value represents the right and left hind paws. Baseline. This device was calibrated to produce PWL· for about 10 seconds for the first experimental rat. In order to avoid the sparse area, the 22·5 heart is observed at the cutoff. Λ Carrageenan was injected intradermally (10) 〇//1,20 mg/ml) to the right hind paw, and the baseline of pWT was recorded for 2 hours after the fungus. 102 1300776 Visceral Pain The activity of a compound in the treatment of visceral pain can be measured according to the following test procedure. Several modes can be used to determine if a compound is effective in treating visceral disease. These modes include the LPS mode (Eutamene et al, J Pharmal Exp Ther 2000 295 (1): 162-7), TNBS mode (Dip et al, Gastroenterology 1999, 116, 4(2): A986), IBD mode (Clemett D, Markham A, Drugs 2000 Ar; 59(4): 92956), pancreatic pain pattern (Isla AM, Hosp Med 2000 Jun; 61(6): 386-9), and internal 10 non-digestive Pain pattern (Boucher M et al, J Urol 2000 Jul; 164(1): 203-8). Rat TNBS-induced chronic visceral touch 痼 In the colonic expansion test mode of conscious rats, prior injection of trinitrobenzene sulfonic acid (TNBS) reduced the critical value of visceral pain in the proximal colon. 15 Materials and Methods · Male Sprague Dougly rats were used. Animals were fed 3 cages per cage in a regulated environment (20 ± 1 ° C, 50 ± 5% humidity, 8:00 an^8:00 pm). On day 0, under anesthesia (kappa 8 mg/kg ι·ρ·; acetaminophen 12 mg/kg ί·ρ·), the control rats were injected with TNBS (50 mg/kg, In ethanol, 30%) or saline (1.5 ml / 20 kg) was applied to the proximal colon wall (1 cm from the cecum). After the surgery, the animals were individually housed in polypropylene cages and maintained in a regulated environment for 7 days (2 〇 ± 1 C, 50 ± 5% humidity '8:00 am to 8: 〇〇 pm illumination). On day 7, after administration of TNBS, the balloon (5-6 cm long) was inserted through the anus and positioned by catheter based on the base of the tail (the top of the balloon was 5 cm from the anal). The test compound 103 1300776 Oral administration was performed 1 hour before the colonic expansion cycle: the balloon was gradually expanded by 0 to 75 mm Hg and at 5 mm Hg (0.667 kPa), each of which lasted for 30 seconds. Each colon expansion cycle is controlled by a standard gas pressure regulator. The critical value (mm Hg) corresponds to the 5 pressure at which the first abdominal contraction occurs, and then the expansion cycle is interrupted. The colonic threshold was determined after four expansion cycles of the same animal. LPS-induced per-intestinal over-age of the rats The intraperitoneal injection of bacterial lipopolysaccharide (LPD) has been shown to induce abnormal rectal pain in conscious mice. 10 Materials and methods: Animals were surgically prepared for electromyography: rats were anesthetized by intraperitoneal injection of acetaminophen (〇·6 mg/kg) and a meter. Three sets of three electrodes in each of the three groups were implanted into the external oblique muscle system of the abdominal cavity, just above the inguinal ligament. The electrodes are located on the outside of the neck and are protected by a glass tube attached to the skin. Animals were individually housed in polypropylene cages, 15 and maintained in a temperature-controlled room (21. 〇. Food (UAR pellets, Epinay, France) and water systems were free to feed. EMG reading was performed on surgery The last 5 days began. The electrical activity of the abdominal stripe muscles was measured by brainwave meter n (Mini vm A1·, Pads, F_e) and using a short-selling number (0.03 seconds) to remove low-frequency signals and 3·6 cm/min. The speed of the paper was again recorded. The spike was recorded as an index of abdominal contraction. The expansion sequence was placed in a plastic channel (6 cm diameter x 25 cm long), and the rat could not move, escape, or flip. To avoid balloon inflation &amp; expansion in the rectum to allow the animal to adapt to the procedure for 4 days to minimize stress response during the reaction. Balloon for arterial embolectomy for inflation 104 1300776 (Fogarty, Edwards Laboratories Inc. The rectal expansion is made by inserting the balloon (2 mm diameter x 2 cm) into the rectum, 1 cm from the anus, and the catheter is fixed to the base of the tail. In warm water and in a stage of 0.4 ml, from 0 to 1.2 ml, gradually Irrigation, each irrigation step lasts 5 minutes. Measure possible water leakage, 5 The volume of water introduced into the airbag is checked by completely removing the water from the syringe at the end of the expansion period. L diagram simple explanation 3 (none) [Main component symbol description] (none)

105

Claims (1)

&gt;4140922 patent application application ten, the scope of application for patent: 96.12.28 1. A compound of formula (I), And pharmaceutically and/or veterinary acceptable derivatives thereof, wherein: R, R2, R3 and R2G each are individually Η, ci, Br, F, I, CF3, OCF3, Me or Et; R4 is het or C3 a 7-cycloalkyl group optionally substituted with a C 4 alkyl group, a Ci 4 alkoxy group, an alkoxyalkyl group having 2 to 4 carbon atoms, or a _S-(Ci * alkyl group); And het is a non-aromatic heterocyclic ring of 4, 5 or 6 members which contains at least one n, hydrazine or S hetero atom, selectively fused to a 5 or 6 membered carbocyclic group or contains at least one N, a heterocyclic ring of a second 4, 5 or 6 member of a 0 or S hetero atom, wherein the het group is optionally at least one selected from the group consisting of Ci 8 alkyl, Ci 8 alkoxy, hydrazine H, —yl, CF 3 , 〇CF3, SCF3, via a base-Cu alkyl group, a Cm alkoxy-Cw alkyl group, and a substituent of a C 4 alkyl group _s_Ci 4 alkyl; but at least one of R1, R2 and r3 is non-Η . 2. The compound of claim 1, wherein: R1 is Cl, Br, F, I, CF3, Me or Et; and R and R are one of the individual systems, Cl, Br, F, I, CF3 , Me or Et. 3. The compound of claim 2, wherein: each of R1 and R2 is Cl, Br, F, I, Me or Et; and R3 is Η, Cl, Br, F, I, Me or Et . 106-1300776 4. The compound of claim 1 or 2, wherein: • R1 is Cl, Me or CF3; R2 is Η, C or F; and R3 is Η, C1 or F. The compound according to any one of claims 1 to 4, wherein R4 is a C3_7 cycloalkyl group. 6. The compound of any one of claims 1 to 5, wherein a is 0 〇 7. 7. The compound of claim 1 is: 10 2,3-dichloro-N- Cyclopentyl-N-[(3S)-pyrrolidin-3-yl]benzamide, 2.3-di-n-cyclopentyl-4-fluoro-N-[(3S)-pyrrolidin-3- Benzoylamine, 3-oxo-N-cyclopentyl-2-methyl-N-[(3S)-pyrrolidin-3-yl]benzamide, N-cyclopentyl-3-fluoro -2-methyl-N-[(3S)-pyrrolidin-3-yl]phenylguanamine, 15 2-chloro-N-cyclopentyl-3-fluoro-N-[(3S)-pyrrolidine- 3-yl]benzamide, 2.3-diqi-yicyclohexyl-?^-[(33)-pyrrolidin-3-yl]benzamide, 2-oxo-N-cyclohexyl-3- Fluorine-N-[(3S)-pyrrolidin-3-yl]benzamide, N-cyclohexyl-3-fluoro-2-methyl-N-[(3S)-pyrrolidin-3-yl]benzene Formamide, 2.3-di-gas-N-cyclobutyl-N-[(3S)-pyrrolidin-3-yl]benzamide, 20 N-cyclobutylmethyl-2,3-dichloro-N- [(3S)-pyrrolidin-3-yl]benzamide, 2.3-dichloro-N-(cyclopropylmethyl)-N-[(3S)-pyrrolidin-3-yl]benzamide , 2.3- Digas-N-[(3S)-pyrrolidin-3-yl]-N-tetrahydro-2H-pyran-4-ylbenzamide, 107 •1300776 2- -N-cyclopentyl-N-[(3S)-pyrrolidin-3-yl]benzamide, 2-a-N-cyclohexyl-N-[(3S)-pyrrolidin-3-yl]benzene Formamide, 2-chloro-N-cycloheptyl-N-JX3S)-11-pyrrol-3-yl]benzamide, heptyl-N-[(3S)-Ubiluo*-3 -yl]-2-(trimethylmethyl) benzylamine, 5 N-cyclohexyl-N-[(3Sppyrrol-3-yl)-2-(trifluoromethyl)benzamide, N-cyclopentyl-N-[(3S)-pyrrolidin-3-yl]-2(trifluoromethyl)benzamide, 2,3-dichloro-N-[(l-methylcyclopropane)曱)]]N-[(3S)-pyrrolidin-3-yl]phenyl hydrazide, 3-ox-2-indolyl-N-[(l-methylcyclopropyl)methyl]_N_ [(3S)-pyrrolidine_3_10-yl]benzamide, N-(cyclobutylmethyl)-N-[(3S)-pyrrolidin-3-yl]-2-(trifluoromethyl)benzoquinone Indoleamine, or a pharmaceutically and/or veterinary acceptable derivative thereof. 8. A compound of claim 7 which is a 2,3-diox_N_cyclopentyl 15-N-[(3S) - pyrrolidinyl] benzamide, or a pharmaceutically and/or veterinary acceptable derivative thereof. A pharmaceutical composition comprising a compound of any one of the claims (8) and a pharmaceutically acceptable adjuvant, diluent or carrier. 10. The use of a compound according to any one of the claims of claim 4, which is used for the manufacture of a compound according to any one of claims 1 to 8 of the invention. An agent that treats a disease in which a monoamine transporter function is regulated in a mammal. The use of a compound according to any one of the items of claim 18, which is for use in the manufacture of a medicament for the treatment of a disease involving serotonin or a norepinephrine regulation in a mammal. • I 13· The use of the scope of claim 12, which involves the regulation of serotonin and norepinephrine. The use of a compound according to any one of claims 1 to 8 for the manufacture of a medicament for the treatment of urinary diseases, depression, pain, premature ejaculation, ADHD or fibromyalgia in a mammal. 15. The use of claim 14 for the treatment of urinary incontinence in mammals, such as GSI or USI. 10. A method of preparing a compound according to any one of claims 1 to 8, which comprises a compound of formula (IX) PG IX Wherein R4 is as defined in any one of claims 1 to 8 and the PG-based protecting group reacts with the acid or sulfhydryl dentate of the formula (II), Wherein R1, R2, R3 and R2G are as defined in any one of claims 1 to 8 and are X-based OH or a halogen group, and deprotected. 109 15