CN1898198A - Alpha-hydroxy amides as bradykinin antagonists or inverse agonists - Google Patents

Abstract

alpha-Hydroxy amide derivatives of the general formula (I) are bradykinin B1 antagonists or inverse agonists useful in the treatment or prevention of symptoms such as pain and inflammation associated with the bradykinin B1 pathway. R<2a> is selected from (1) a group selected from R<a>. (2) (CH2)nNR<b>C(O)R<a>. (3)(CH2)nNR<b>SO2R<d>.(4)(CH2)nNR<b>CO2R<a>.(5)(CH2)k-heterocycle optionally substituted with 1 to 3 groups independently selected from halogen.nitro, cyano.OR<a>.SR<a>.C1-4 alkyl and C1-3 haloakyl wherein said heterocycle is (a) a 5-membered heteroaromatic ring having a ring heteroatom selected from N.O and S. and optionally having up to 3 additional ring nitrogen atoms wherein said ring is optionally benzo-fused; or(b) a 6-membered heteromatic ring containing from 1 to 3 ring nitrogen atoms and N-oxydes thereof. Wherein said ring is optionally benzo-fused. (6)(CH2)kCO2R<a>.and (7)(CH2)C(O)NR<b>R<c>. R<2b> is OH or a group selected from R<2a>; or R<2a> and R<2b> together with the carbon atom to which they are attached form a 3-to 7-membered carbocyclic ring optionally substituted with 1 to 4 groups independently selected from halogen, OR<a>, C1-4 alkyl and C1-4 haloalkyl.

Description

Alpha-hydroxy acid amides as brad ykinin antagonists or inverse agonist

Background of invention

The present invention relates to the Alpha-hydroxy amide compound.Especially, the present invention relates to Alpha-hydroxy amide compound as brad ykinin antagonists or inverse agonist.

Bradykinin (" BK ") is a kind of kassinin kinin, and it plays an important role in the pathologic, physiologic process that is attended by acute and chronic pain and inflammation.Bradykinin (BK) is similar to other kassinin kinin, is the autacoid peptide that produces by in blood plasma and the katalysis of organizing the kallikrein that is called prokinin on the precursor.The biological action of BK mediates by the BK acceptor that at least two kinds of main G albumen-link coupled are called B1 and B2.Generally believe, B2 acceptor, rather than B1 acceptor, at normal tissue expression, and inflammation, tissue injury or infectation of bacteria can cause the B1 expression of receptor apace.This makes the B1 acceptor become attractive especially drug target.Kassinin kinin, the particularly BK supposition effect in pain management and inflammation provides and has developed effectively and the power of selectivity BK antagonist.In recent years, expectation has this effort that analgesia and effective therapeutical agent of anti-inflammatory performance can alleviate the receptor-mediated disease of BK and has obtained enhancing (referring to for example, M.G.Bock and J.Longmore, Current Opinion in Chem.Biol., 4:401-406 (2000)).Therefore, need new compound, its activity for blocking-up or reverse bradykinin receptor is effective.This compound pain management and inflammation and treatment or the prevention bradykinin is disease mediated and illness in be effective; And described compound also can be used as research tool (body is interior and external).

Summary of the invention

The invention provides Alpha-hydroxy amide derivatives, contain the pharmaceutical composition of this compound and they usage as therapeutical agent as brad ykinin antagonists or inverse agonist.

Detailed description of the invention:

The invention provides compound and its pharmacologically acceptable salts of formula (I)

Wherein

Y is CH or N;

R ¹Be

R ^2aBe selected from (1) and be selected from R ^aGroup, (2) (CH ₂) _nNR ^bC (O) R ^a, (3) (CH ₂) _nNR ^bSO ₂R ^d, (4) (CH ₂) _nNR ^bCO ₂R ^a, (5) are optional independently to be selected from (the CH that following group replaces by 1-3 ₂) _k-heterocycle: halogen, nitro, cyano group, OR ^a, SR ^a, C _1-4Alkyl and C _1-3Haloalkyl, wherein said heterocycle are that (a) has the ring hetero atom that is selected from N, O and S and optionally have a 5-unit hetero-aromatic ring of 3 extra loop nitrogen-atoms at the most, and wherein said ring is optional benzo condensed; Or the first hetero-aromatic ring of the 6-that (b) contains 1 to 3 theheterocyclic nitrogen atom and its N-oxide compound, wherein said ring is optional benzo condensed, (6) (CH ₂) _kCO ₂R ^aAnd (7) (CH ₂) _kC (O) NR ^bR ^c, R ^2bBe OH or be selected from R ^2aGroup; Or

R ^2aAnd R ^2bForm 3-to 7-unit carbocyclic ring with the carbon atom that they connected, this carbocyclic ring is optional to be independently selected from halogen, OR by 1 to 4 ^a, C _1-4Alkyl and C _1-4The group of haloalkyl replaces;

R ^3aAnd R ^3bBe independently selected from hydrogen, C _1-4Alkyl and C _1-4Haloalkyl;

R ^4aAnd R ^4bBe independently selected from hydrogen and halogen;

R ⁶It is optional by 1-5 C1-8 alkyl that is independently selected from the following groups replacement to be selected from (1): halogen, nitro, cyano group, COR ^a, CO ₂R ^a, C (O) NR ^bR ^c, OR ^a, OC (O) R ^a, SR ^a, SO ₂R ^d, S (O) R ^d, NR ^bR ^c, NR ^bC (O) R ^a, NR ^bSO ₂R ^d, and NR ^bCO ₂R ^a, (2) C _3-8Cycloalkyl, (3) are optional by CO ₂R ^aThe C that replaces _2-8Thiazolinyl, (4) halogen, (5) cyano group, (6) nitro, (7) NR ^bR ^c, (8) NR ^bC (O) R ^a, (9) NR ^bCO ₂R ^a, (10) NR ^bC (O) NR ^bR ^c, (11) NR ^bC (O) NR ^bCO ₂R ^a, (12) NR ^bSO ₂R ^d, (13) CO ₂R ^a, (14) COR ^a, (15) C (O) NR ^bR ^c, (16) C (O) NHOR ^a, (17) C (=NOR ^a) R ^a, (18) C (=NOR ^a) NR ^bR ^c, (19) OR ^a, (20) OC (O) R ^a, (21) S (O) _vR ^d, (22) SO ₂NR ^bR ^c(23) optional substituted heterocycle, wherein heterocycle is that (a) has the ring hetero atom that is selected from N, O and S and optionally have a 5-unit hetero-aromatic ring of 3 extra loop nitrogen-atoms at the most, (b) have the 6-unit hetero-aromatic ring of 1 to 3 ring N atom, (c) 4,5-dihydro- azoles base or (d) 4,5-dihydro-1,2,4- di azoly, wherein said substituting group are 1 to 3 and are independently selected from C _1-4The group of alkyl, C _1-4Alkyl is optional by 1 to 5 halogen atom, OR ^aOr OC (O) R ^aReplace (24) optional phenyl that independently is selected from following group replacement: halogen, nitro, cyano group, OR ^a, SR ^a, C _1-4Alkyl and C _1-4Haloalkyl and (25) OSO ₂R ^d

R ⁷Be selected from hydrogen and halogen;

R ⁸And R ⁹Be independently selected from hydrogen and R ⁶Group; Condition is R ⁶, R ⁸And R ⁹In at the most one be heterocycle;

R ^aBe selected from (1) hydrogen, (2) are optional by 1 to 5 halogen atom, OH, SH, O-C _1-4Alkyl or S-C _1-4The C that alkyl replaces _1-7Alkyl, (3) are optional to be independently selected from halogen, cyano group, nitro, OH, C by 1 to 3 _1-4Alkyl oxy, C _3-6Cycloalkyl, C _1-4Alkyl and C _1-4(the CH that the group of haloalkyl replaces ₂) _k-phenyl and (4) C _3-6Cycloalkyl;

R ^bAnd R ^cBe independently selected from: (1) hydrogen, (2) are optional to be independently selected from halogen, amino, CO by 1 to 5 ₂R ^a, OR ^a, list-C _1-4Alkylamino and two-C _1-4The C that the group of alkylamino replaces _1-4Alkyl, (3) are optional to be independently selected from halogen, cyano group, nitro, OR by 1 to 3 ^a, CO ₂R ^a, C _3-6Cycloalkyl, C _1-4Alkyl and C _1-4(the CH that the group of haloalkyl replaces ₂) _k-phenyl and (4) C _3-6Cycloalkyl, or

R ^bAnd R ^cAnd the nitrogen-atoms that their connect forms 4-, 5-or 6-unit ring together, and this ring randomly contains and is selected from NR ^e, O, S, S (O) and S (O) ₂Extra heteroatoms;

R ^dBe selected from (1) C _1-4Alkyl, (2) C _1-4Haloalkyl, (3) C _1-4Alkyl oxy, (4) are optional to be selected from halogen, cyano group, nitro, OR by 1 to 3 ^a, CO ₂R ^a, C _3-6Cycloalkyl, C _1-4Alkyl and C _1-4(the CH that the group of haloalkyl replaces ₂) _k-phenyl, (5) pyridyl and (6) pyridyl N-oxide compound;

R ^eBe selected from hydrogen, C _1-4Alkyl, C _1-4Haloalkyl, C (O) H and C (O) C _1-4Alkyl;

N is 1,2 or 3;

K is 0,1,2,3 or 4; With

V is 0,1 or 2.

R ^2aAnd R ^2bExample include, but are not limited to: hydrogen, methyl, ethyl; n-propyl, sec.-propyl, normal-butyl, sec-butyl; isobutyl-, the tertiary butyl, n-pentyl, neo-pentyl; n-hexyl, n-heptyl, trifluoromethyl, 2; 2,2-trifluoroethyl, 1,1-two fluoro ethyls; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; suberyl, phenyl, benzyl, neighbour; between or right-tolyl; xylyl, (trifluoromethyl) phenyl, cyano-phenyl, bromophenyl; chloro-phenyl-, dichlorophenyl, fluorophenyl, difluorophenyl; hydroxy phenyl, dihydroxyphenyl, p-methoxy-phenyl, Dimethoxyphenyl; (hydroxyl) (methoxyl group) phenyl, 3-indyl methyl, pyrryl, thiazolyl;  azoles base, imidazolyl, 2-benzothienyl, different  azoles base; isothiazolyl, quinolyl, 2-(acetylamino) ethyl, (sulfonyloxy methyl amino)-methyl; carboxyl, carbamyl ylmethyl, and 2-(methoxycarbonyl amino) ethyl.R ^2a, R ^2bThe carbon that is connected with them can form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or suberyl together, and each can be chosen wantonly by 1 to 4 and be selected from for example following group replacement: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, chlorine, fluorine, bromine, chloromethyl, trifluoromethyl, 1-chloroethyl, hydroxyl, methoxyl group, and oxyethyl group.

R ^3aAnd R ^3bExample include, but are not limited to: hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, chloromethyl, methyl fluoride, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2-two fluoro ethyls, 1,1,2,2, the 2-pentafluoroethyl group, or the like.

R ⁶Example comprise: methyl, ethyl, 1-methylethyl; the 1-hydroxyethyl, carboxyl, methoxycarbonyl; ethoxycarbonyl, 2-fluorine ethoxycarbonyl, the different third oxygen carbonyl; carbobenzoxy, cyclopentyloxy carbonyl, ring butoxy carbonyl; encircle the third oxygen carbonyl, 2,2; 2-trifluoro ethoxycarbonyl, 4-trifluoromethyl carbobenzoxy, methoxyl group aminocarboxyl; the methoxycarbonyl methyl, formyl radical, hydroxyl; the 5-methyl isophthalic acid, 2,4- diazole-3-base; the 3-methyl isophthalic acid, 2,4- diazole-5-base; 1-methyl-5-tetrazyl, 2-methyl-5-tetrazyl, cyano group; methoxyl group, oxyethyl group, difluoro-methoxy; trifluoromethoxy, 2, the 2-difluoroethoxy; 1,3-difluoro propoxy-, 2; 2,2-trifluoro ethoxy, trifluoromethyl; chlorine, fluorine, methylamino alkylsulfonyl; the dimethylamino alkylsulfonyl, methoxyl group-carbonylamino, ethoxy carbonyl amino; 2-fluorine ethoxycarbonyl amino, methylamino carbonylamino, dimethylamino; the methylamino carbonyl, isopropyl amino-carbonyl, B aminocarbonyl; the cyclopropyl aminocarboxyl; the cyclobutyl aminocarboxyl, dimethylamino carbonyl, and aminocarboxyl.R ⁸Example comprise hydrogen, chlorine, fluorine and methoxycarbonyl; R ⁹Example comprise hydrogen, chlorine, fluorine and methyl.

The subgroup compound of formula I is R wherein ^2a, R ^2bThe carbon atom that is connected with them forms 3-to 7-unit carbocyclic ring, described ring is optional is independently selected from halogen, OR by 1 to 4 ^a, C _1-4Alkyl and C _1-4The compound that the group of haloalkyl replaces.In one embodiment, carbocyclic ring is replaced by methyl or halogen.

Second subgroup of formula I is R wherein ^3aAnd R ^3bIn one be hydrogen, another is the compound of hydrogen or methyl.

The 3rd subgroup of formula I is R wherein ¹It is the compound of following formula.

In the embodiment in this subgroup, compound is R wherein ⁶Be selected from following compound: (1)-CO ₂-C _1-4Alkyl, (2) C _1-4Alkoxyl group and (3) have the ring hetero atom that is selected from N, O and S and optionally have a 5-unit hetero-aromatic ring of 3 extra loop nitrogen-atoms at the most, and described ring is optional by C _1-4Alkyl replaces.In one embodiment, R ⁶Be selected from methoxycarbonyl, oxyethyl group, optional, 4- di azoly and optional by methyl substituted tetrazyl by methyl substituted 1,2.In another embodiment in this subgroup, compound is R wherein ⁸It is the compound of hydrogen or 3-halogen.In another embodiment in this subgroup, compound is R wherein ⁸Be hydrogen or 3-halogen and R ⁹It is the compound of hydrogen or 5-halogen.

The 4th subgroup of formula I is compound and its pharmacologically acceptable salts of formula (Ia):

Wherein m is 1 to 5; Y is N or CH; R ^3aAnd R ^3bIn one be hydrogen, another is hydrogen or methyl; R ⁷Be hydrogen or fluorine; R ⁶Be selected from: (1)-CO ₂-C _1-4Alkyl, (2) optional C that is replaced by 1 to 5 halogen atom _1-4Alkoxyl group and (3) have the ring hetero atom that is selected from N, O and S and optionally have a 5-unit hetero-aromatic ring of 3 extra loop nitrogen-atoms at the most, and described ring is optional to be replaced by the C1-4 alkyl; R ⁸And R ⁹Be hydrogen or halogen independently.

The 5th subgroup of formula I compound is R wherein ¹It is the compound of following formula.

In the embodiment in this subgroup, R ^aBe H.In another embodiment, R ^4aAnd R ^4bEach is halogen naturally, illustrates by fluorine.

The 6th subgroup of formula I compound is compound and its pharmacologically acceptable salts of formula (Ib):

R wherein ^3a, R ^3b, R ⁶, R ⁷, R ⁸And R ⁹Define suc as formula I.R ^{2a '}And R ^{2b '}Be independently selected from: (1) hydrogen, (2) are optional by 1 to 5 halogen atom, SH, OH, S-C _1-4Alkyl or OC _1-4The C that alkyl replaces _1-7Alkyl, (3) are optional to be independently selected from halogen, cyano group, nitro, OH, C by 1 to 3 _1-4Alkyl oxy, C _3-6Cycloalkyl, C _1-4Alkyl and C _1-4(the CH that the group of haloalkyl replaces ₂) _k-phenyl, (4) C _3-6Cycloalkyl, (5) (CH ₂) _k-pyridyl and (6) (CH ₂) _k-indyl.In the embodiment in this subgroup, be R wherein ^{2a '}And R ^{2h '}Be the optional C that is replaced by 1 to 5 halogen atom independently _1-7The compound of alkyl.In another embodiment, be the compound that meets following condition: R wherein ^3aAnd R ^3bIn one be hydrogen, another is hydrogen or methyl; R ⁷Be hydrogen, chlorine or fluorine; R ⁶Be selected from: (1)-CO ₂-C _1-4Alkyl, (2) optional C that is replaced by 1 to 5 halogen atom _1-4Alkoxyl group and (3) have the ring hetero atom that is selected from N, O and S and optionally have a 5-unit hetero-aromatic ring of 3 extra loop nitrogen-atoms at the most, and described ring is optional by C _1-4Alkyl replaces; R ⁸And R ⁹Be hydrogen or halogen independently.

The 7th subgroup of formula I compound is compound and its pharmacologically acceptable salts of formula Ic:

Wherein Y is N or CH; R ⁷Be H, chlorine or fluorine; R ^3aBe H or methyl; R ⁶Be selected from: (1)-CO ₂-C _1-4Alkyl, (2) C _1-4Alkoxyl group, (3) C _1-4Halogenated alkoxy and (4) have the ring hetero atom that is selected from N, O and S and optionally have a 5-unit hetero-aromatic ring of 3 extra loop nitrogen-atoms at the most, and described ring is optional by C _1-4Alkyl replaces; R ⁸And R ⁹Be hydrogen or halogen independently.In one embodiment, R ⁸Fluorine or chlorine.In another embodiment, R ⁸And R ⁹Each is fluorine or chlorine independently.In another embodiment, R ⁶Randomly be methyl substituted tetrazyl or optional methyl substituted 1,2,4- di azoly.In another embodiment, R ⁷Be chlorine or fluorine, R ⁶Be optional methyl substituted tetrazyl or optional methyl substituted 1,2,4- di azoly, R ⁸Be fluorine or chlorine, R ⁹Be H, chlorine or fluorine.

A second aspect of the present invention provides pharmaceutical composition, comprises compound or its pharmacologically acceptable salts and the pharmaceutically acceptable carrier of the formula (I) for the treatment of significant quantity.

The 3rd aspect of the present invention provides formula I compound or its pharmacologically acceptable salts to be used to prepare the purposes that the treatment bradykinin b 1 receptor mediates the medicine of illness.A subgroup of described illness is a pain, comprises acute, struvite and neuropathic pain.

The 4th aspect of the present invention provides treatment bradykinin b 1 receptor mediation treatment of conditions method in Mammals, comprises compound or its pharmacologically acceptable salts of the formula (I) that gives described Mammals treatment significant quantity.

Except as otherwise noted, following term has following indicated implication:

" thiazolinyl " is meant can be straight or branched or its combination and carbochain that contain at least one C=C key.The example of thiazolinyl comprises allyl group, crotyl, and the 3-butenyl, 1-methyl-2-propenyl, or the like.

" alkyl " and other groups with prefix " alkane ", for example alkoxyl group, alkyloyl or the like are meant it can is straight chain, side chain or or the carbochain of its combination.The example of alkyl comprises methyl, ethyl, and propyl group, sec.-propyl, butyl, secondary-and the tertiary butyl, amyl group, hexyl, heptyl or the like.

" cycloalkyl " be meant and do not comprise heteroatomic carbocyclic ring, comprises list, two and the trinucleated saturated carbon ring, and the condensed ring system.This condensed ring system can comprise a partially or completely undersaturated ring, and phenyl ring for example is to form condensed ring system, for example benzo-fused carbocyclic ring.Cycloalkyl comprises this condensed ring system of picture spiral shell condensed ring system.The example of cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, perhydronaphthalene, diamantane, indanyl, indenyl, fluorenyl, 1,2,3,4-naphthane or the like.

" haloalkyl " is meant alkyl as defined above, wherein at least one and at the most all hydrogen atoms replaced by halogen.The example of this haloalkyl comprises chloromethyl, 1-bromotrifluoromethane, methyl fluoride, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or the like.

" halogen " is meant fluorine, chlorine, bromine and iodine.

" 5-unit hetero-aromatic ring " and " benzo-fused 5-unit hetero-aromatic ring " includes, but are not limited to: pyrroles, imidazoles, pyrazoles, 1,2,3-triazoles, 1,2,4-triazole, tetrazolium, furans, thiophene, thiazole,  azoles, isothiazole, different  azoles, 1,2,4- diazole, 1,2,5- diazole, 1,2, the 4-thiadiazoles, 1,2,5-thiadiazoles, cumarone, thionaphthene, indoles, benzoglyoxaline, benzothiazole, benzoxazol, benzisothiazole and benzisoxa  azoles.

" 6-unit hetero-aromatic ring " and " benzo-fused 6-unit hetero-aromatic ring " includes, but are not limited to: pyridine, pyrimidine, pyridazine, pyrazine, triazine, quinoline, isoquinoline 99.9 and quinoxaline.

Optically active isomer-diastereomer-geometrical isomer-tautomer

Compound described herein can contain asymmetric center, and can exist with enantiomeric form thus.If have two or more asymmetric centers according to The compounds of this invention, they can exist with the diastereomer form in addition.The present invention includes all this possible steric isomers that exist with pure substantially fractionation enantiomorph, its racemic mixture and non-enantiomer mixture form.Above-mentioned formula I does not show the stereochemistry of determining of some position.The present invention includes all steric isomers and its pharmacologically acceptable salts of formula I.The diastereomer of enantiomorph is to separating by for example carrying out fractional crystallization with suitable solvent, thus obtained enantiomorph is to being separated into independent steric isomer by ordinary method, for example by utilizing optically active acid or alkali to separate as resolution reagent or on chirality HPLC post.Further, optically pure starting raw material that any enantiomorph of compound of Formula I or diastereomer can be by using configuration known or reagent carry out stereospecificity and synthesize and obtain.

Compounds more described herein contain the two keys of alkene, and unless otherwise detailed instructions, it means and comprises E and two kinds of geometrical isomers of Z.

Can there be the hydrogen with different point of connection in compounds more described herein, are called tautomer.This example can be ketone and its enol form that is called as the keto-enol tautomerism body.

The compound of formula I comprises single tautomer and its mixture.

Salt

Term " pharmacologically acceptable salts " is meant the salt by acceptable nontoxic alkali of pharmacy or acid preparation.When compound of the present invention was acidity, its corresponding salt can comprise that by the acceptable nontoxic alkali of pharmacy mineral alkali and organic bases prepare easily.The salt that comprises aluminium, ammonium, calcium, copper (ic and ous), iron, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc or the like derived from the salt of this mineral alkali.Preferably ammonium, calcium, magnesium, potassium and sodium salt.By the salt of the acceptable organic nontoxic alkali of pharmacy preparation comprise derived from naturally occurring and synthetic source primary, secondary and tertiary ammonium salt.Can comprise by the acceptable organic nontoxic alkali of the salifiable pharmacy of shape, for example, arginine, trimethyl-glycine, caffeine, choline, N, N-dibenzyl-ethylenediamin, diethylamine, 2-diethyl-monoethanolamine, 2-dimethylaminoethanol, thanomin, quadrol, N-ethylmorpholine, N-ethylpiperidine, glycosamine, glucosamine, Histidine is breathed out amine (hydrabamine), Isopropylamine, dicyclohexylamine, Methionin, meglumine, morpholine, piperazine, piperidines, polyamide resin, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine, tromethane or the like.

When compound of the present invention was alkalescence, its corresponding salt can be easily prepared by the acceptable nontoxic inorganic and organic acid of pharmacy.This acid comprises for example acetate, Phenylsulfonic acid, M-nitro benzoic acid, camphorsulfonic acid, citric acid, ethyl sulfonic acid, fumaric acid, glyconic acid, L-GLUTAMICACID, Hydrogen bromide, hydrochloric acid, isethionic acid, lactic acid, toxilic acid, oxysuccinic acid, amygdalic acid, methylsulfonic acid, glactaric acid, nitric acid, pamoic acid (pamoic acid), pantothenic acid, phosphoric acid, succsinic acid, sulfuric acid, tartrate, tosic acid, or the like.Preferably citric acid, Hydrogen bromide, hydrochloric acid, toxilic acid, phosphoric acid, sulfuric acid and tartrate.

Prodrug

The present invention comprises the prodrug of The compounds of this invention in its scope.Usually, this prodrug is the functional derivatives of The compounds of this invention, and it changes needed compound in vivo easily into.Thus, in methods of treatment of the present invention, term " gives " to comprise with concrete disclosed compound or with the various illnesss that do not have concrete disclosed compounds for treating, but it is transformed into specific compound in vivo after giving the patient.The selection of suitable precursor medicaments derivative and the ordinary method of preparation be at for example " Design of Prodrugs ", ed.H.Bundgaard, and Elsevier has made description in 1985.The metabolite of these compounds comprises the active specy that The compounds of this invention is incorporated in the coenocorrelation to be produced.

Pharmaceutical composition.

Another aspect of the present invention provides pharmaceutical composition, and it comprises compound or its pharmacologically acceptable salts and the pharmaceutically acceptable carrier of formula I.Term in the pharmaceutical composition " composition " is meant the product that comprises the inert component (the acceptable vehicle of pharmacy) that comprises active ingredient and form carrier and by combination, complexing or the gathering of any two or more components or by the decomposition of one or more components or the product that obtained directly or indirectly by other type reaction of one or more components or interaction.Therefore, pharmaceutical composition of the present invention comprises any composition of making by with the compound of formula I, extra active ingredient and the acceptable mixed with excipients of pharmacy.

Pharmaceutical composition of the present invention comprises that the compound (or its pharmacologically acceptable salts) of formula I representative is as active ingredient, pharmaceutically acceptable carrier and other optional treatment component or auxiliary agent.Composition comprises and is suitable for the composition that oral, rectum, part and parenteral (comprising subcutaneous, intramuscular and intravenously) give, although only approach will depend on the concrete host and the character and the severity of illness that active ingredient gives under any given situation.Pharmaceutical composition can exist with unit dosage easily, and can be by the method preparation of generally acknowledging in any pharmaceutical field.

In the reality, compound or its pharmacologically acceptable salts of formula I of the present invention representative can be used as active ingredient and mix nearly with pharmaceutical carriers according to the pharmacy compounding technique of routine.According to the desired dosage form that gives, for example oral or parenteral (comprising intravenously) can adopt the carrier of various ways.Thus, pharmaceutical composition of the present invention can provide to be suitable for oral discrete units form, for example capsule, cachet or tablet, and each contains the active ingredient of pre-determined quantity.Further, composition can provide with the form of the suspension in powder, granule, solution, the waterborne liquid, on-aqueous liquid, oil-in-water emulsion or water-in-oil liquid emulsion.Except that the common formulation of stating above, compound or its pharmacologically acceptable salts of formula I representative also can give by the method and/or the e Foerderanlage of sustained release.Composition can be by any method of pharmacy preparation.Usually, this method comprises active ingredient and the carrier-bound step that constitutes one or more necessary component.Usually, by evenly and closely being mixed, the solid carrier of active ingredient and liquid vehicle or pulverizing or both prepare composition.Can make product form needed outward appearance easily then.

Thus, pharmaceutical composition of the present invention can comprise compound or its pharmacologically acceptable salts of pharmaceutically acceptable carrier and formula I.The compound of formula I or its pharmacologically acceptable salts also can be included in the pharmaceutical composition that makes up with one or more other therapeutical active compound.

The pharmaceutical carriers that adopts can be for example solid, liquid or gas.The example of solid carrier comprises lactose, terra alba, sucrose, talcum powder, gel, agar, pectin, gum arabic, Magnesium Stearate, and stearic acid.The example of liquid vehicle is a syrup, peanut oil, sweet oil, and water.The example of gaseous carrier comprises carbonic acid gas and nitrogen.

In the composition process of preparation oral dosage form, can adopt any pharmaceutical media easily.For example, water, glycol, oils, alcohol, seasonings, sanitas, tinting material or the like can be used for forming oral liquid preparation, suspension for example, elixir and solution; For example starch, sugar, Microcrystalline Cellulose, thinner, granulating agent, lubricant, tackiness agent, disintegrating agent or the like can be used for forming oral solid preparation, for example powder, capsule and tablet to carrier simultaneously.Because tablet and capsule are easy to give, they are preferred oral dosage units, adopt the solid pharmaceutical carriers thus.Randomly, tablet can by the moisture of standard or not aqueous techniques carry out dressing.

The tablet that contains the present composition can be by optional with one or more Synergist S-421 95 or auxiliary agent compresses or molding prepares.Compressed tablet can be by with for example active ingredient, the compacting preparation in suitable machinery of powder or granule of free-flowing form, randomly with binding agent, lubricant, inert diluent, surface-active or dispersant.Molded tablet can be by in suitable machine, with the mixture of pulverous humidification compound and inert liquid diluent molded preparation in addition.Each tablet preferably contains the 0.1mg that has an appointment to about 500mg active ingredient, and each cachet or capsule preferably contain the 0.1mg that has an appointment to about 500mg active ingredient.

The pharmaceutical composition of the present invention that is suitable for administered parenterally can prepare with the solution or the form of suspension of the active compound in the water.Can comprise suitable tensio-active agent, for example hydroxypropylcellulose.Dispersion can also prepare in glycerine, liquid macrogol and their mixtures in oil.Further, can comprise sanitas, to prevent the unfavorable breeding of microorganism.

Be suitable for injecting the pharmaceutical composition of the present invention of use, comprise the aseptic aqueous solution or dispersion.In addition, composition can be the form of sterilized powder, is used for the instant preparation of this sterile injectable solution or dispersion.With regard to all situations, final injectable forms must be aseptic, and must be the effective liquid that is easy to inject.Pharmaceutical composition must be stable under preparation and storage requirement; Therefore, preferably stoping microorganism for example to preserve under the condition of the contamination of bacterium and fungi.Carrier can be solvent or dispersion medium, contains for example water, ethanol, polyvalent alcohol (for example glycerine, propylene glycol and liquid macrogol), vegetables oil and its suitable mixture.

Pharmaceutical composition of the present invention can be to be suitable for the local form of using, for example aerosol, ointment, ointment, lotion, fine powder or the like.Further, composition can be the form that is suitable for transdermal device.These preparations can use formula I of the present invention representative compound or its pharmacologically acceptable salts, prepare by ordinary method.For instance, have required conforming ointment or ointment, water wetted material and water and about 5wt% can be prepared ointment or ointment to the compound of about 10wt% in order to produce.

Pharmaceutical composition of the present invention can be to be suitable for the form that rectum gives, and wherein carrier is a solid.Preferred this mixture forms unitary dose suppository.Suitable carrier comprises normally used other material of theobroma oil and this area.Suppository can be by at first composition being mixed with carrier softening or that melt postcooling and form easily in die for molding.

Except that above-mentioned carrier component, aforesaid pharmaceutical formulations can comprise one or more additional carrier component according to circumstances, for example thinner, buffer reagent, seasonings, binding agent, tensio-active agent, thickening material, lubricant, sanitas (comprising antioxidant) or the like.In addition, in order to make preparation and intended recipient's blood isoosmotic pressure, can comprise other auxiliary agent.The composition that contains the described compound of formula I or its pharmacologically acceptable salts also can be prepared into powder or liquid concentrate form.

Following is the representational pharmaceutical dosage form example of formula I compound:

Injectable suspensions (I.M.)	mg/mL	Tablet	The mg/ sheet	Capsule	The mg/ capsule
						Compound methylcellulose Tween 80 phenmethylol benzalkonium chloride water for injection to the 1 ml cumulative volumes of formula I	10 5.0 0.5 9.0 1.0	The compound Microcrystalline Cellulose Polyvinylpyrolidone (PVP) pregelatinized starch Magnesium Stearate of formula I	25 415 14.0 43.5 2.5 500	The compound lactose powder Magnesium Stearate of formula I	25 573.5 1.5 600

Practicality

Therefore compound of the present invention is the especially antagonist or the inverse agonist of bradykinin b 1 receptor of bradykinin receptor, and can be effective to treat and prevent disease and illness by the mediation of bradykinin receptor path, for example pain and inflammation.This compound can effectively be treated or prevent irritation comprises, for example visceral pain (pancreatitis for example, interstitial cystitis, renal colic, prostatitis, chronic pelvic pain), neuropathic pain (neurodynia behind for example banded blister shape, acute herpes zoster pain, neural injury, " dynias ", for example chronic private parts pain, phantom limb pain, root is trodden on and is torn, radiculopathy, the traumatic mononeuropathy of painful, painful is detained neuropathy, carpal tunnel syndrome, the ulna nerve disease, tarsal tunnel syndrome, painful diabetic neuropathy, painful polyneuropathy, trigeminal neuralgia), the central pain syndromes (potential may causing by any focus on neural any level, including, but not limited to apoplexy, multiple cerebral sclerosis, Spinal injury), with postoperative pain syndromes (for example, postmastectomy syndromes, syndromes after the throacotomy, stump pain)), bone and arthralgia (osteoarthritis), spinal pain (for example, acute and chronic low back pain, neck pain, spine is narrow), shoulder pain, repeatability motion pain, toothache, throat pain, cancer pain, the pain of burning, muscular fascia pain (muscular injuries, fibromyalgia), after the operation, postoperative epidural pain and preemptive analgesia (including, but not limited to general surgery, plastic surgery, and gynaecology), chronic pain, dysmenorrhoea (elementary and secondary), and the pain relevant with pharyngalgia, with the inflammatory pain that changes the source (osteoarthritis for example, rheumatoid arthritis, rheumatism, nodular tenosynovitis and gout, ankylosing spondylitis, bursitis).

Further, compound of the present invention can also be used to the struvite effect relevant with respiratory tract disease with treatment of therapeutic response over-drastic respiratory tract, and for example asthma comprises atopic asthma (atopic or ergotropy) and tempers bronchoconstriction, occupational asthma, virus or the bacterial asthma aggravation cause, other anallergic asthma and " panting-baby comprehensive disease ".Compound of the present invention also can be used for treating chronic obstructive pulmonary disease and comprise pulmonary emphysema, adult respiratory distress syndrome, bronchitis, pneumonia, allergic rhinitis (season and chronicity) and vasomotor rhinitis.They also can effectively stop Pneumonoconiosis, comprise aluminosis, anthracosis, asbestosis, silicosis, ptilosis, siderosis disease, silicosis, tobacco poisoning and byssinosis.

Compound of the present invention also can be used for the treatment of inflammatory bowel, comprise Crohn disease and ulcerative colitis, irritable bowel syndrome, pancreatitis, ephritis, urocystitis (interstitial cystitis), uveitis, struvite tetter is psoriasis and eczema for example, rheumatoid arthritis and by with burn, sprain or edema that the relevant wound of fracturing causes, cerebral edema and angioedema (angioedema that comprises hereditary angiodysplasia and medicine-cause, for example angioedema that causes by angiotensin converting enzyme (ACE) or ACE/ neutral endopeptidase inhibitor, for example omepatrilat).They can be used for diabetogenous vascular lesion, diabetic neuropathy, diabetic retinopathy, back capillary vessel tolerance, or the diabetic symptom relevant (for example hyperglycemia, diuresis, the nitrous acid ester of proteinuria and increase and the homaluria of kallikrein) with insulitis.They can be used as smooth muscles relaxants, be used for the treatment of gi tract or uterus spasm.In addition, they can effectively stop hepatic diseases, multiple cerebral sclerosis, cardiovascular disorder, atherosclerosis for example, congestive heart failure, myocardial infarction; Neurodegenerative disease, for example Parkinson's disease and alzheimer's disease, epilepsy, the for example anti-circulating blood volume of septic shock reduces and/or anti-hypotensive agent, headache comprises that cluster headache, migraine comprise prevention and acute purposes, apoplexy, the stopping property injury of head, cancer, septicemia, gingivitis, osteoporosis, benign prostatauxe and hyperactivity bladder.The animal model of disease and illness generally is well known in the art, and can be suitable for assessing the possible applicability of The compounds of this invention.At last, compound of the present invention also can be used as research tool (in vivo with external).

By giving tablet, cachet or capsule, compound of the present invention can be effective to treat pain and inflammation, each tablet, cachet or capsule contain for example The compounds of this invention of 0.1mg, 0.5mg, 1mg, 3mg, 5mg, 10mg, 25mg, 50mg, 100mg, 125mg, 250mg or 500mg, per three to four hours once, once a day, twice or three times, or (in prolonging delivery formulations) weekly, twice or three times.

By giving tablet, cachet or capsule, this compound can effectively be treated or prevent irritation, comprise for example bone and arthralgia (osteoarthritis), the repeatability motion pain, toothache, cancer pain, muscular fascia pain (muscular injuries, fibromyalgia), perioperative pain (general surgery, oral surgery, gynaecology), neuropathic pain (the herpetic neurodynia in back) and chronic pain, each tablet, cachet or capsule contain for example 0.1mg, 0.5mg, 1mg, 3mg, 5mg, 10mg, 25mg, 50mg, 100mg, 125mg, the The compounds of this invention of 250mg or 500mg, per three to four hours once, once a day, twice or three times, or (in prolonging delivery formulations) is weekly, twice or three times.

Especially, by giving tablet, cachet or capsule, can treat for example struvite respiratory tract disease of struvite pain (chronic obstructive pulmonary disease) effectively by compound of the present invention, each tablet, cachet or capsule contain for example 0.1mg, 0.5mg, 1mg, 3mg, 5mg, 10mg, 25mg, 50mg, 100mg, 125mg, 250mg, or the The compounds of this invention of 500mg, per three to four hours are once, once a day, twice or three times, or (in prolonging delivery formulations) weekly, twice or three times.

Further, by giving tablet, cachet or capsule, compound of the present invention can be used for the treatment of asthma in addition, inflammatory bowel, rhinitis, pancreatitis, urocystitis (interstitial cystitis), uveitis, struvite tetter, rheumatoid arthritis and by with burn, sprain or edema that the relevant wound of fracturing causes, each tablet, cachet or capsule contain for example 0.1mg, 0.5mg, 1mg, 3mg, 5mg, 10mg, 25mg, 50mg, 100mg, 125mg, 250mg, or the The compounds of this invention of 500mg, per three to four hours once, once a day, twice or three times, or (in prolonging delivery formulations) is weekly, twice or three times.

By giving tablet, cachet or capsule, they can use and treat the inflammatory pain (osteoarthritis for example in variation source afterwards in surgical operation (for example as postoperative anodyne), rheumatoid arthritis, rheumatism, nodular tenosynovitis and gout), and be used for the treatment of and pharyngalgia, the pain of menstruation or related to cancer, each tablet, cachet or capsule contain for example 0.1mg, 0.5mg, 1mg, 3mg, 5mg, 10mg, 25mg, 50mg, 100mg, 125mg, the The compounds of this invention of 250mg or 500mg, per three to four hours are once, once a day, twice or three times, or (in prolonging delivery formulations) is weekly, twice or three times.

By giving tablet, cachet or capsule, they can be used for the treatment of diabetogenous vascular lesion, postcapillary tolerance or the diabetic symptom relevant (hyperglycemia for example with insulitis, diuresis, the nitrous acid ester of proteinuria and increase and kallikrein homaluria), each tablet, cachet or capsule contain for example 0.1mg, 0.5mg, 1mg, 3mg, 5mg, 10mg, 25mg, 50mg, 100mg, 125mg, the The compounds of this invention of 250mg or 500mg, per three to four hours once, once a day, twice or three times, or (in prolonging delivery formulations) is weekly, twice or three times.

By giving tablet, cachet or capsule, compound of the present invention can be effective to treat inflammatory skin case such as psoriasis and eczema, each tablet, cachet or capsule contain for example The compounds of this invention of 0.1mg, 0.5mg, 1mg, 3mg, 5mg, 10mg, 25mg, 50mg, 100mg, 125mg, 250mg or 500mg, per three to four hours once, once a day, twice or three times, or (in prolonging delivery formulations) weekly, twice or three times.

By giving tablet, cachet or capsule, they can be as the smooth muscles relaxants of treatment gi tract or hysterospasm, or be used for the treatment of Crohn disease, ulcerative colitis or pancreatitis, each tablet, cachet or capsule contain for example 0.1mg, 0.5mg, 1mg, 3mg, 5mg, 10mg, 25mg, 50mg, 100mg, 125mg, the The compounds of this invention of 250mg or 500mg, per three to four hours are once, once a day, twice or three times, or (in prolonging delivery formulations) weekly, twice or three times.

By giving tablet, cachet or capsule, this compound can be used for the treatment of to therapeutic hyperreactive respiratory tract and treatment and for example relevant struvite effect of asthma of respiratory tract disease, and be used for controlling, restriction or the respiratory response that reverses in the asthma are excessive, each tablet, cachet or capsule contain for example 0.1mg, 0.5mg, 1mg, 3mg, 5mg, 10mg, 25mg, 50mg, 100mg, 125mg, the The compounds of this invention of 250mg or 500mg, per three to four hours are once, once a day, twice or three times, or (in prolonging delivery formulations) is weekly, twice or three times.

By giving tablet, cachet or capsule, they can be used for treating internality and extrinsic asthma, comprise atopic asthma (atopic or ergotropy) and temper the bronchoconstriction that causes, occupational asthma, the asthma that virus or bacterium are increased the weight of, other anallergic asthma and " panting-baby comprehensive disease ", each tablet, cachet or capsule contain for example 0.1mg, 0.5mg, 1mg, 3mg, 5mg, 10mg, 25mg, 50mg, 100mg, 125mg, the The compounds of this invention of 250mg or 500mg, per three to four hours are once, once a day, twice or three times, or (in prolonging delivery formulations) is weekly, twice or three times.

By giving tablet, cachet or capsule, they also can effectively stop Pneumonoconiosis, comprise aluminosis, anthracosis, asbestosis, silicosis, ptilosis, siderosis disease, silicosis, tobacco poisoning and byssinosis and adult respiratory distress syndrome, the lung of chronic obstruction or respiratory tract disease, bronchitis, allergic rhinitis and vasomotor rhinitis, each tablet, cachet or capsule contain for example 0.1mg, 0.5mg, 1mg, 3mg, 5mg, 10mg, 25mg, 50mg, 100mg, 125mg, the The compounds of this invention of 250mg or 500mg, per three to four hours are once, once a day, twice or three times, or (in prolonging delivery formulations) is weekly, twice or three times.

In addition, by giving tablet, cachet or capsule, they can effectively stop hepatic diseases, multiple cerebral sclerosis, atherosclerosis, Alzheimer, septic shock, for example reduce and/or anti-hypotensive agent as anti-circulating blood volume, cerebral edema, headache comprises cluster headache, migraine comprises prevention and acute use, the stopping property injury of head, irritable bowel syndrome and ephritis, each tablet, cachet or capsule contain for example 0.1mg, 0.5mg, 1mg, 3mg, 5mg, 10mg, 25mg, 50mg, 100mg, 125mg, the The compounds of this invention of 250mg or 500mg, per three to four hours once, once a day, twice or three times, or (in prolonging delivery formulations) is weekly, twice or three times.

Combination therapy.

The compound of formula I can be used for the treatment of with other/prevent/suppressing or improving in the combination of other medicine of disease that formula I compound is used for and illness and using.Can give this other medicine simultaneously or sequentially by certain approach and with normally used quantity and formula I compound.When the compound of formula I and one or more other medicine used simultaneously, it was preferred containing the pharmaceutical composition that also contains this other medicine except that formula I compound.Therefore, except the compound of formula I, pharmaceutical composition of the present invention comprises that those also contain the pharmaceutical composition of one or more other active ingredient.Can be individually dosed or can in same pharmaceutical composition, give, with the example of other active ingredient of formula I compound bonded including, but not limited to: (1) morphine and other opioid receptor agonist comprise that morphine monomethyl ether, hydroxyl can treat ketone, third oxygen sweet smell (Darvon) and the U-26225A; (2) NSAID (non-steroidal anti-inflammatory drug) (NSAIDs) comprises for example propanoic derivatives (alminoprofen, benzene  Lip river sweet smell, bucloxic acid of cox 2 inhibitor, carprofen, fenbufen, fenoprofen, R.D. 17345, flurbiprofen, Ibuprofen BP/EP, indoprofen, Ketoprofen, miaow Luo Puluofen, Naproxen Base, Ao Shapu piperazine, pirprofen, Y-8004, sutoprofen, tiaprofenic acid, with sulphur  Lip river sweet smell), acetogenin (INDOMETHACIN, acemetacin, Warner-Lambert), clidanac, diclofenac, dichlorphenoxyacetic acid, fenclozic acid, fragrant thiazole acid, Furofenac, Dytransin, Isoxepac, oxpinac, sulindac, thiophene flat sour, Tolmetin, zidometacin, and zomepirac), fenamic acid derivatives (Tecramine, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid), xenyl carboxylic acid derivative (diflunisal and flufenisal), former times health class (isoxicam, piroxicam, sudoxicam and tenoxicam), salicylate (acetylsalicylic acid, sulfasalazine) and Phenylbutazone class (Azapropazone, bezpiperylon, Zentinic, Reumatox, Visubutina, Phenylbutazone) and former times dry goods (celecoxib, valecoxib, rofecoxib and etoricoxib); (3) corticosteroid Betamethasone Valerate for example, budesonide, cortisone, dexamethasone, hydrocortisone, medrat, prednisolone, prednisone and triamcinolone; (4) histamine H 1 receptor antagonist Parabromdylamine (bromopheniramine) for example, chlorphenamine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, Bristaline, promethazine, nedeltran, azatadine, plug pyridine in heptan, Antazol, pheniramine, Pyrilamine, astemizole, terfenadine, Loratadine, alerlisin, delotadine, fexofenedine and levocetirizine; (5) histamine H ₂Receptor antagonist is Cimitidine Type A/AB for example, famotidine and Ranitidine HCL; (6) proton pump inhibitor omeprazole for example, pantoprazole and esomeprazole; (7) leukotriene antagonist and 5-lipoxidase inhibitor Zafirlukast for example, Singulair, pranlukast and zileuton; (8) medicine that is used for pharyngalgia, myocardial ischemia comprises nitric acid fat, for example nitroglycerine and Isosorbide nitric acid fat, and Beta receptor blockers is atenolol USP 23 for example, metoprolol, Propranololum, acebutolol, betaxolol, bisoprolol, carteolol, Trandate, nadolol, Trasicor, penbutolol, pindolol, sotalol and timolol and calcium channel blocker be Odizem for example, verapamil, nifedipine, Bepridil, felodipine, flunamic, Isrodipine, nicardipine and nimodipine; (9) incontinence medicine antimuscarinic drug for example, for example, tolterodine and oxybutinin); (10) gastrointestinal antispasmodic medicine (for example coromegine, scopolamine, Wyovin, Antimuscarinic drugs, and diphenoxylate); Skeletal muscular relaxant (prohe tatriene, Somalgit, Aero-Mycil, chlorzoxazone, Metaxolone, methocarbamol, baclofen, dantrolene, stable, or orphenadinum); (11) gout medicine Zyloric for example, benemid and colchicine; (12) medicine that is used for rheumatoid arthritis methotrexate for example, auranofin, Gold Thioglucose and disodium aurothiomalate; (13) for example diphosphonate and Reynolds former times phenol of the medicine that is used for osteoporosis; (14) for example pseudo-ephedrine and Phenylpropanolamine of decongestant; (15) local anesthetic; (16) herpes medicine acyclovir for example, valacyclovir and Famciclovir; (17) for example ondansetron and granisetron of anti-vomitive; (18) the migraine medicine is for example for smooth class (triptans) (for example laser for smooth, sumatriptan), Ergotamine, dihydroergotamine, the CGRP antagonist, (19) thymoleptic are (for example, tricyclic antidepressant (P-3693A for example, clomipramine hydrochloride, imipramine, amitriptyline, maprotiline, nortriptyline), thrombotonin-optionally/thrombotonin and NRI (paroxetine for example, fluoxetine, duloxetine, vanlafexine), beta-adrenergic blocker; (20) VR1 antagonist; (21) anticonvulsive agent (for example, gabapentin, Pregabalin, lamotrigine, topiramate, Carbamzepine, oxcarbazepine, Phenytoin Sodium Salt); (22) glutaminate antagonist (for example, ketamine and other nmda antagonist, NR2B antagonist); (23) paracetamol; (24) CCR2 antagonist; (25) PDE4 antagonist roflumilast for example; (26) Tegaserod (tegaserod); (27) A Luosiqiong; (28) topiramate; (29) cathepsin K inhibitor; (30) ACE/NEP inhibitor omepatrilat for example.

Biological assessment

(a) the affinity evaluation of selected compounds and bradykinin Bl or B2 receptors bind

The Chinese hamster ovary celI that but use comes from the Chinese hamster ovary celI of the B1 acceptor of the stably express mankind, rabbit, rat or dog, maybe can express human B2 acceptor carries out radioligand in conjunction with test.For all acceptor types, from culturing bottle, be captured in the cell among the PBS/1mM EDTA, and under 1000xg centrifugal 10 minutes.The cell spherolite is used the polytron homogenizing in ice-cold 20mM HEPES, 1mMEDTA, pH 7.4 (dissolving buffer reagent), and 20, under the 000xg centrifugal 20 minutes.With top layer spherolite homogenizing again in the dissolving damping fluid,, centrifugal under the 000xg once more 20, and final spherolite is resuspended in test damping fluid (120mMNaCl, 5mM KCl, 20mM HEPES with 5mg protein/ml, pH value 7.4) in, replenish with 1%BSA, and freezing at-80 ℃.

On the same day of test, 14, under the 000xg centrifugal 5 minutes, and resuspending is to needed protein concn in the test damping fluid, the test damping fluid contained 100nM enaliprilat, 140 μ g/mL bacitracin and 0.1%BSA with film.3H-des-arg10, leu9 pancreokinin are the radioligands that is used for the mankind and rabbit B1 acceptor, and the 3H-des-arg10 pancreokinin is used for rat and dog B1 acceptor, and the 3H-bradykinin is used for the mark mankind's B2 acceptor.

For all tests, 4 μ l DMSO stock solutions are joined in the developmental tube, with diluted compounds, the final DMSO concentration to 2%.Then add 100 μ l radioligands and 100 μ l film suspension.Use 1 μ M des-arg10 pancreokinin to measure the non-specific binding of secondary receptor binding assays, measure the non-specific binding of B2 acceptor with 1 μ M bradykinin.To manage (22 ℃) cultivation at room temperature 60 minutes, and then use Tomtec 96-hole acquisition system to filter.Use the dull and stereotyped scintillometer of Wallac Beta-to calculate the radioactivity that keeps by strainer.

In above-mentioned test, compound of the present invention has affinity for the B1 acceptor, and is illustrated less than the result of 5 μ M as passing through.Test-results less than 1 μ M has advantage, has superiority more less than the result of 0.5 μ M.Further advantageously, compound of the present invention has the affinity to bradykinin b 1 receptor, but not for the affinity of bradykinin b 2 receptor; More advantageously, be for the B2 receptor affinity at least 10 times for the affinity of B1 acceptor, and preferably above 100 times.

(b) for the test of bradykinin Bl antagonists

Use fluorescence imaging plate reader (FLIPR) to monitor the calcium reactivity that the B1 agonist causes.The Chinese hamster ovary celI of expressing the B1 acceptor is coated on the 96 or 384 hole plates, and in the DMEM that Iscove ' s regulates overnight incubation., cultivated one hour with 4 μ M Fluo-3 at 37 ℃ then the hole washed twice with the physiology buffer salt solution.Join in each hole then with buffer salt solution washing plate twice, and with 100 μ l damping fluids.Plate is placed in the FLIPR unit, and balance two minutes.The test compound that adds 50 μ l volumes then after five minutes, adds 50 μ l agonists (des-argl pancreokinin).With not existing and relative fluorescence peak height when having antagonist calculates the inhibition degree of B1 receptor stimulant for the test compound response.Typically assess the test compound of eight to ten concentration, suppress curve to set up, and use four-parametrical nonlinearity regression curve fit procedure to measure IC ₅₀Value.

(c) test of bradykinin inverse agonist

Use the HEK293 cell of of short duration transfection to assess inverse agonist activity in the human B1 acceptor.After the transfection one day, use 6uCi/ml[ ³H] inositol spends the night cell bottle mark.On the same day of test, remove medium, and the phosphate-buffered saline of attached cell with 2x20ml rinsed out lightly.Add test damping fluid (HEPES damping fluid physiology salt, pH value 7.4), and cell is removed by rapping bottle.Under 800xg with cell centrifugation five minutes, and with 1 * 10 ⁶Individual cell/ml is resuspended in the test damping fluid that is supplemented with the 10mM lithium chloride.After at room temperature 10 minutes, the aliquot sample of half milliliter is dispensed to contains in test compound or the vectorial test tube.After adding 10 minutes, test tube changed in 37 ℃ the water-bath over to 30 minutes.Stop cultivating by adding 12% perchloric acid solution, and test tube was placed on 30 minutes on ice.With KOH acid is neutralized then, and test tube is centrifugal to the spherolite thing that forms sediment occurring.[by standard ionomer exchange chromatography technology will form [ ³H] inositol monophosphate reclaims, and measures by liquid scintillation counting(LSC).By test compound will [ ³H] degree that reduces of inositol monophosphate cumulative substrate (using the vehicle cultured cells) level measures the inverse agonist activity.

The abbreviation of using

In specification sheets, following abbreviation has specified implication, except as otherwise noted: the Ac=ethanoyl; The Boc=tertbutyloxycarbonyl; The Cat.=catalyzer; The DCM=methylene dichloride; The DMF=dimethyl formamide; DMADMA=N,N-DIMETHYLACETAMIDE dimethyl-acetal; The DMSO=methyl-sulphoxide; EDCI=1-(3-dimethylaminopropyl)-3-ethyl carbon imide; The Et=ethyl; The EtOAc=ethyl acetate; The HOBT=1-hydroxybenzotriazole; The LAH=lithium aluminium hydride; LDA=di-isopropyl amination lithium; LiHMDS=hmds lithium; The Me=methyl; The NBS=N-bromo-succinimide; The Ph=phenyl; The Rt=room temperature; Tf=trifiyl (trifyl); The THF=tetrahydrofuran (THF).

Synthetic method

The compound of formula I can prepare by reaction scheme 1 described general method.Use to form the standard reagent and the reaction conditions of amido linkage, EDCI/HOBt for example, alpha-hydroxy carboxylic acid compounds (1) and aryl methylamine (2) coupling.

Reaction scheme 1

Carboxylic acid (1) can commercial be bought, and maybe can use conventional chemical reaction well-known in the art, by preparing by the commercial reagent of buying.Amine (2) can prepare according to the method that reaction scheme 2 to 6 is listed.In reaction scheme 2, triaryl phosphine for example triphenylphosphine and metal catalyst for example acid chloride in the presence of, use fragrant boric acid derivatives (3) or suitable boron ester derivative and the reaction of the Suzuki between the aromatic halide (4), synthetic biaryl derivatives (5).Use for example Raney nickel of hydrogen and metal then, in suitable solvent, the cyanobiphenyl base intermediate (5) that obtains is catalysed and reduced into dibenzyl sulfonamide derivatives (2a).

Reaction scheme 2

Perhaps, as the diagram in reaction scheme 3, with suitable protecting group for example after the Boc protection primary amine, use palladium catalyst, for example in the methyl-sulphoxide, sulfonamide derivatives (6) made tetramethyl ethylene ketone boron ester (8) at suitable solvent.After the deprotection, adopt the Suzuki reaction conditions, this boron ester (8) and aryl halide derivative (4) coupling obtain (2a).

Reaction scheme 3

The third method of preparation dibenzyl vulkacit H derivative is described in the reaction scheme 4.Use palladium catalysis with (9) and aryl zn cpds (10) coupling, at first make dibenzyl part (11), as shown in the figure.According to the nucleophilic displacement and three steps of the reductive order of halogenation, halogen and trinitride, the methyl of dibenzyl (11) is processed then, formed corresponding amine intermediate (2a).Perhaps, in the 4th kind of method, dibenzyl vulkacit H (2a) can also begin preparation by aryl nitrile of discussing in advance (13) and aryl zn cpds (10).Use hydrogen with dibenzyl nitrile (5) reduction that obtains then, form (2a).

Reaction scheme 4

The 5th kind of method of preparation dibenzyl vulkacit H derivative is described in the reaction scheme 5.Known pyridine (14) (nitroreduction 2042-2046) and nitrile hydrolysis, follow by the conversion of gained amine to fluorochemical, obtains (15) by J.Chem.Soc, (1952).With 3 steps order acid amides is converted into aldehyde (16).Form imines, then add the methyl Grignard reagent with tertiary butyl sulfinyl amine, produce (17), it further can be processed to form aforesaid dibenzyl vulkacit H.

Reaction scheme 5

The for example clear wherein R for preparing of reactions steps in the reaction scheme 6 ¹It is formula (I) compound of benzisothiazole part.Reaction scheme 6 has been described the preparation of particular compound simultaneously, and this method can be used for preparing other similar formula (I) compound.

Reaction scheme 6

Reference example

Provide the following examples to illustrate the preparation of starting raw material dibenzyl methylamine.Can prepare other dibenzyl methylamine similarly.

I.2-[6-(aminomethyl)-5-fluorine pyridin-3-yl]-6-fluorobenzoic acid methyl ester

(5.0g 40.9mmol) handles to use the 2-cyano group in the 50ml THF-3-fluorine pyridine that dropwise adds at-78 ℃ of 200ml THF solution with LDA (40.9mmol is by the Diisopropylamine of 11.4ml and the 2.5M n-Butyl Lithium of 16.4ml/hexane preparation).After 10 minutes, add iodine (10.4g, 10mL THF solution 40.9mmol).After 30 minutes, will react with the 40mL shrend and go out, then handle with sodium thiosulfate solution.Mixture is diluted with ether, use the salt water washing, use Na ₂SO ₄Drying is filtered and vacuum concentration.Resistates is carried out the silica gel chromatography purifying, with 0-20% ethyl acetate/hexane wash-out, obtain 3-fluoro-4-iodo pyridine-2-nitrile, it produces and theoretical consistent proton NMR spectrum.

At-78 ℃, the 200ml THF solution of LDA (16.9mmol) is used the above-mentioned nitrile in 50ml THF that dropwise adds, and (4.2g 16.9mmol) handles.After 2 hours, will react the water cancellation, and be warming up to room temperature.Mixture is diluted with ether, use the salt water washing, use Na ₂SO ₄Drying is filtered and vacuum concentration.Resistates is carried out silica gel chromatography handle, with 0-20% ethyl acetate/hexane wash-out, obtain 3-fluoro-5-iodo pyridine-2-nitrile, it produces and theoretical consistent proton N MR spectrum.

Pass through sleeve pipe, with above-mentioned nitrile (1.08g, 3.87mmol) 10ml THF solution and tetra-triphenylphosphine palladium (0.18g 0.16mmol) joins in the 20ml THF solution of [3-fluoro-2-(methoxyl group-carbonyl) phenyl] (iodo) zinc (by the preparation of 2-fluoro-6-iodobenzoic acid methyl ester and Reike zinc).Mixture heating up to refluxing one hour, is cooled off, and distributed between ethyl acetate and water.With organic extraction salt water washing, use MgSO ₄Drying is filtered and vacuum concentration.Resistates is carried out silica gel chromatography handle, with 0-20% ethyl acetate/hexane wash-out, obtain 2-(6-cyano group-5-fluorine pyridin-3-yl)-6-fluorobenzoic acid methyl ester, it obtains and theoretical consistent proton N MR spectrum.

(0.75g, (5ml 2.0M) adds Raney2800 nickel (slurries in the water) to NH3/MeOH 2.7mmol) in the stirred solution to above-mentioned ester.With mixture at H ₂Under (balloon) atmosphere, at room temperature stirred 6 hours.Then by glass filter paper filtering mixture, with extra MeOH washing.With the solution for vacuum concentration that obtains, and with methylbenzene azeotropic three times, obtain the crude product title compound (0.65g, 2.34mmol).

II. (1R)-1-{5-[3,5-two chloro-2-(methoxycarbonyl) phenyl]-3-fluorine pyridine-2-yl } second ammonium muriate.

With 2, (5.00g, 125ml methanol solution 26.18mmol) is cooled to 0 ℃ to 4-two chloro-6-hydroxy benzaldehydes.(70%, 1.47ml 16.23mmol), and stirred this solution 10 minutes to add perchloric acid.At 0 ℃, with vanadium oxide (V) (0.190g, 1.05mmol) join superoxol in the independent flask (30%, in water, 11.90mL, 104.7mmol) in.Stir this solution,, produce the orange solution of clarification, it dropwise is added in the methanol solution until catalyst dissolution.To react and be warming up to room temperature at leisure, and stir and spend the night.Vacuum concentrated solution, and resistates is dissolved in the ethyl acetate.With sodium bicarbonate aqueous solution and salt water washing organic extraction, all Na ₂SO ₄Drying is filtered and is concentrated.Resistates is filtered by silicagel pad,, obtain 2 with 10% ethyl acetate/hexane wash-out, 4-two chloro-6-hydroxy-benzoic acid methyl ester, it obtains and theoretical consistent proton N MR spectrum.

With above-mentioned ester (4.64g, 20.99mmol) and pyridine (1.87ml, 100mlCH 23.09mmol) ₂Cl ₂Solution is cooled to 0 ℃.(4.94ml 29.39mmol), and stirred this solution 2 hours to add trifluoromethanesulfonic acid.With sodium bicarbonate aqueous solution, copper sulfate solution and salt solution washing reaction mixture, use Na ₂SO ₄Drying is filtered and is concentrated, and obtains 2,4-two chloro-6-{[(trifluoromethyls) alkylsulfonyl] the oxygen base } benzoic acid methyl ester, it obtains and theoretical consistent proton N MR spectrum.

At N ₂Under the atmosphere, to 5-bromo-3-nitropyridine-2-nitrile (4.71g, add in MeOH 20.7mmol) (319ml) solution tin chloride (II) dihydrate (27.97g, 123.9mmol).Reaction is heated to 40 ℃, kept vacuum concentration, and and methylbenzene azeotropic 40 minutes.Resistates is dissolved in the ethyl acetate, and adds 10% sodium bicarbonate aqueous solution, be alkalescence up to solution.Use CHCl ₃Extract water layer 3 times, and with the organism Na that merges ₂SO ₄Drying is filtered and vacuum concentration, obtains 3-amino-5-bromopyridine-2-methane amide, and it obtains 218.2 M+H ⁺(81Br) mass ion (ES+).

To above-mentioned methane amide (40.0g, CH 185.2mmol) ₂Cl ₂Adding Tetrafluoroboric acid nitrous  (nitrosonium tetrafluoroborate) in the solution (22.71g, 191.4mmol).To react and at room temperature stir 4.5 hours, then vacuum concentration and and methylbenzene azeotropic.Resistates is suspended in the toluene (1100ml), and is heated to 100 ℃, kept 2 hours.To react vacuum concentration, and resistates will be suspended in CH ₂Cl ₂In.Collect solid, obtain 5-bromo-3-fluorine pyridine-2-carboxamide, it obtains and theoretical consistent proton N MR spectrum and 219.1 M+H ⁺(79Br) mass ion (ES+).

(40.50g, (6.472mol) solution is heated to 120 ℃ to HCl 184.9mmol) for 12N, 539.4ml, keeps 1 hour with above-mentioned crude product methane amide.To react cool to room temperature, and add NaOH (20%) at leisure to pH value～6.Vacuum concentrated solution, and with methylbenzene azeotropic 3 times.With resistates 40%MeOH/CHCl ₃Extract up hill and dale, and filter.Repeat this process three times.The filtrate that merges is concentrated, and with methylbenzene azeotropic 3 times, obtain 5-bromo-3-fluorine pyridine-2-carboxylic acids, it obtains 218.1 M+H ⁺(79Br) mass ion (ES+).

With above-mentioned crude carboxylic acid slurry (40.65g, 184.8mmol), O, N-dimethyl hydroxyl-amine hydrochlorate (21.63g, 221.7mmol), 1-ethyl-(3-dimethylaminopropyl)-carbodiimide hydrochloride (70.85g, 369.6mmol), 1-hydroxyl-7-azepine benzotriazole (2.497g, 18.48mmol) and triethylamine (16.48ml, 200ml DMF solution 118.3mmol) is in stirred overnight at room temperature.With solution vacuum concentration partly, and between ethyl acetate and 10% sodium bicarbonate aqueous solution, distribute.With water layer ethyl acetate extraction 4 times, and, use Na with the organism water and the salt water washing that merge ₂SO ₄Drying is filtered and vacuum concentration, and 5-bromo-3-fluoro-N-methoxyl group-N-picoline-2-methane amide is provided, and it obtains and theoretical consistent proton N MR spectrum and 263.01 M+H ⁺(79Br) mass ion (ES+).

At-78 ℃, to above-mentioned crude product methane amide (27.94g, dropwise add in THF 106.2mmol) (350ml) solution LAH (1M in THF, 45.67ml, 45.67mmol).To be reflected at-78 ℃ and stir 2 hours down, add H then ₂O (100mL) and salt solution (100mL).Mixture is warming up to room temperature, and vacuum concentration, with the ethyl acetate dilution, pass through diatomite filtration.With water layer ethyl acetate extraction 4 times.With the organism salt water washing that merges, use Na ₂SO ₄Drying is filtered and vacuum concentration.Resistates is filtered by silica filler, with 10% ethyl acetate/hexane wash-out, obtain 5-bromo-3-fluorine pyridine-2-formaldehyde, it obtains and theoretical consistent proton N MR spectrum.

To (R)-(+)-2-methyl-2-propane sulfinyl amine (9.898g, CH 81.67mmol) ₂Cl ₂(160ml) add in the solution 5-bromo-3-fluorine pyridine-2-formaldehyde (16.66g, 81.67mmol), tosic acid pyridine  (1.026g, 4.08mmol) and sal epsom (49.15g, 408.3mmol).To react at room temperature to stir and spend the night, then by diatomite filtration and vacuum concentration.Resistates is carried out silica gel chromatography to be handled, with 0 to 10% ethyl acetate/hexane wash-out, obtain N-[(1E)-(5-bromo-3-fluorine pyridine-2-yl) methyne (methylidene)]-2-methylpropane-2-sulfinyl amine, it obtains and theoretical consistent proton N MR spectrum and 307.0 M+H ⁺(81Br) mass ion (ES+).

At N ₂Under the atmosphere, with above-mentioned sulfinyl amine (18.63g, CH 60.65mmol) ₂Cl ₂(375ml) solution is cooled to-50 ℃.(3M, in THF, 30.32ml 90.97mmol), will react and stir 1 hour dropwise to add methylmagnesium-chloride.After 30 minutes, (5.0ml 15.0mmol), finishes so that react to add extra methylmagnesium-chloride.Add entry (200ml) and salt solution (200ml), and make reaction be warming up to room temperature.With water layer CH ₂Cl ₂Extract 4x, and with the organism Na that merges ₂SO ₄Drying is filtered and vacuum concentration.Resistates is carried out silica gel chromatography handles,, obtain N-[(1R with 10-40% ethyl acetate/hexane wash-out)-1-(5-bromo-3-fluorine pyridine-2-yl) ethyl]-2-methylpropane-2-sulfinyl amine, it obtains and theoretical consistent proton N MR spectrum and 325.0 M+H ⁺(81Br) mass ion (ES+).

At N ₂Under the atmosphere, with above-mentioned sulfinyl amine (0.500g, 1.55mmol), two (tetramethyl ethylene ketone base (pinacolato)), two boron (0.412g, 1.62mmol), potassium acetate (0.456g, 4.64mmol) and [1,1 '-two (diphenylphosphino) ferrocene]-(0.030g 0.041mmol) in the mixture heating up to 90 of 5ml DMF ℃, kept 4 hours palladium chloride (II).Add extra two (tetramethyl ethylene ketone base (pinacolato)), two boron (0.295g, 1.16mmol) and the 3-chloroperoxybenzoic acid (861mg, 4.99mmol) and [1,1 '-two (diphenylphosphino) ferrocene] palladium chloride (II) (0.030g, 0.041mmol), reaction is finished.This reaction mixture is cooled to room temperature; and add 2; 4-two chloro-6-{[(trifluoromethyls) alkylsulfonyl] the oxygen base } benzoic acid methyl ester (0.546g; 1.55mmol), yellow soda ash (2M; 2.32ml; 4.64mmol) and [1,1 '-two (diphenylphosphino) ferrocene] palladium chloride (II) (0.003g, 0.041mmol).Reaction mixture is heated to 90 ℃, kept 1.5 hours, be cooled to room temperature then, and between ethyl acetate and water, distribute.Water and salt water washing organic extraction are used Na ₂SO ₄Drying is filtered and vacuum concentration.Resistates is carried out silica gel chromatography to be handled; with 0-30% ethyl acetate/hexane wash-out; obtain 2-(6-{ (1R)-1-[(tertiary butyl sulfinyl) amino] ethyl }-5-fluorine pyridin-3-yl)-4,6-dichlorobenzoic acid methyl ester, it obtains and theoretical consistent proton N MR spectrum.

Adding HCl/ two  alkane solution in methyl alcohol (1.2ml) solution of above-mentioned product (4M, 1.2ml, 4.6mmol).This solution was at room temperature stirred 30 minutes, and vacuum concentration obtains title compound then, M+H ⁺(ES+) 343.01.

III.4 '-[(1R)-the 1-aminoethyl]-3-fluoro-1,1 '-xenyl-2-carboxylate methyl ester hydrochloride

Can carry out the BOC protection by commercial (1R)-1-(4-bromophenyl) ethamine of buying, use standard method well known by persons skilled in the art, produce (1R)-1-(4-bromophenyl) ethyl-carboxylamine tertiary butyl ester.

At room temperature, at N ₂In the atmosphere, to above-mentioned carbamate (7.6g, 25.3mmol) DMSO (20ml) solution in add two (tetramethyl ethylene ketone base (pinacolato)), two boron (7.07g, 27.9mmol), dichloro [1,1 '-two (diphenylphosphino) ferrocene] palladium (II) methylene dichloride adducts (2.06g, 2.53mmol) and potassium acetate (7.45g, 76.0mmol).The mixture that obtains was heated 1 hour at 80 ℃.React by adding the EtOAc cancellation, and pass through diatomite filtration.Wash organic extraction with water three times,, use MgSO with saturated NaCl washing ₄Drying is filtered and vacuum concentration.With resistates purifying on silica gel,, form (1R)-1-[4-(4 with 0-20% ethyl acetate/hexane wash-out, 4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl] ethyl carbamic acid tertiary butyl ester clarification light yellow oil, have 333 mass ion (ES+).

To above-mentioned carbamate (1.0g, 2.9mmol) and 2-fluoro-6-iodobenzoic acid methyl ester (1.2g, 4.32mmol) at 5: 1 THF of 25ml: add salt of wormwood (1.2g in the stirred solution in the water mixture, 8.64mmol), tri-o-tolyl phosphine (350mg, 1.15mmol), add at last acid chloride (65mg, 0.29mmol).Sealed reaction vessel then, and be placed in 90 ℃ of oil baths and spend the night, also heating stirred.After about 18 hours, reaction mixture is cooled to room temperature, dilutes with EtOAc then.Organism with salt solution (x4) washing, is used dried over sodium sulfate, filter and concentrating under reduced pressure, obtain oil.This oil is carried out silica gel chromatography to be handled, with 10-60%EtOAc/ hexane wash-out, obtain 4 '-(1R)-the 1-[(tertbutyloxycarbonyl) amino] ethyl }-3-fluoro-1,1 '-xenyl-2-carboxylic acid methyl ester (205mg) finds that by LC/MS and proton N MR it is pure.

(205mg 0.60mmol) is dissolved among the MeOH (15ml), and is cooled to 0 ℃ with above-mentioned carboxylicesters.This homogeneous phase solution is saturated with anhydrous HCl, and shelved 20 minutes.In solution, blasted drying nitrogen then about 30 minutes.Removal of solvent under reduced pressure obtains the oiliness resistates then.Then oil is dissolved among the DCM, and removes and desolvate.Repeat this process, until obtaining the solid amine hydrochloride.

IV.N-[(1R)-and 1-(5-bromo-3-fluorine pyridine-2-yl) ethyl] ethanamide.

Step 1.2,5-two bromo-3-nitropyridines

2-hydroxyl-3-nitro-5-bromopyridine (1 equivalent) is suspended in the toluene (3vol), and adds N, dinethylformamide (0.1 equivalent).Mixture is kept in Dark Place.At about 90 ℃, join in this pyridine mixtures with 1.5 hours toluene (2vol) solution, and will react aging about 14 hours at 90 ℃ with bromine phosphorus oxide (1.2 equivalent).With the reaction mixture cool to room temperature, and add entry (10vol) and toluene (5vol).Each layer separately, and with organic layer usefulness 1NNaOH (2 * 10vol) and H ₂O (5vol) washing.This batch of material of concentrating under reduced pressure obtains needed product.

Step 2.5-bromo-3-nitropyridine-2-nitrile

The compound (1 equivalent) of step 1 is suspended in the propionitrile (3vol).Add cupric cyanide (1.1 equivalent), and with mixture heating up to 90 ℃, aging about 17 hours.With the reaction mixture cool to room temperature, and add isopropyl acetate (12vol) and saturated brine (8vol).Mixture was stirred 15 minutes, and separate each layer.With the salt solution (organic layer of 4 * 6vol) washing upper ends.This batch of material of concentrating under reduced pressure obtains needed product.

Step 3.5-bromo-3-fluorine pyridine-2-nitrile

Sulfuric acid (0.02 equivalent) is joined in DMF (5vol) solution of tetrabutylammonium fluoride (3 equivalent), and this mixture is cooled to-40 ℃.DMF (2vol) solution that adds step 2 compound (1eq) keeps temperature＜-35 ℃.Add 2N HCl (3vol) after about 20 minutes, then add 1NHCl (15vol).Filter the collecting precipitation product, obtain needed product.

Step 4.N-[1-(5-bromo-3-fluorine pyridine-2-yl) vinyl] ethanamide

The compound (1eq) of step 3 is dissolved in the toluene (10vol).This batch of material is cooled to-10 ℃, and adds MeMgCI (1.5eq), keep temperature＜0 ℃.With mixture ageing 1h, add diacetyl oxide with about 30 minutes, keep temperature＜0 ℃.To be reflected at-10 ℃ wore out 18 hours down.Use half saturated NaHC0 ₃(6vol) cancellation mixture, and aging 30 minutes at 20-25 ℃.Separate each layer, and with separating machine layer water (5vol), 10%Na ₂SO ₄The aqueous solution (2 * 5vol) and water (2 * 5vol) washing.This batch of material of vacuum concentration obtains title compound.

Step 5.N-[(1R)-and 1-(5-bromo-3-fluorine pyridine-2-yl) ethyl] ethanamide

At a glove box (＜10ppm O who fills nitrogen ₂) in, (S, S, R, R)-Tangphos (1.05 equivalents are with respect to Rh) with (COD) ₂RhBF ₄In conjunction with, and be dissolved in the methyl alcohol, make the solution that calculates 0.107M with Rh.This catalyst solution was worn out 1 hour.

In a glove box that fills nitrogen, with this catalyst solution (((S, S, R, R)-(Tangphos) Rh (COD) BF ₄, 0.00284 equivalent S/C=352) changes in the stainless steel cylinder, with washed with methanol (1 volume).In an independent stainless steel cylinder, add the methyl alcohol (1 volume) that additionally feeds intake.These two cylinders connect by a ball valve.The enamine (54wt% is in MeOH) of step 4 is introduced in the reactor of band stirring by vacuum unit, then used methyl alcohol (10mL/g enamine) flushing.Use nitrogen (3X) with this solution degassing then.The stainless steel vessel that will contain catalyst solution leads to by flexible pipe and reactor.Reactor is placed in parital vacuum, and catalyst solution is introduced in the reactor, then wash with MeOH.With this solution H ₂(100psig) degassing 3X, and regulate resulting pressure to 20psig.Temperature of reaction is arranged on 25 ℃, and begins to stir.After 20 minutes, reaction pressure is increased to 98psig.With the extra hydrogenation of mixture 4 hours.Enantiomeric excess is 99.5%.

From reactor, remove this batch of material, vacuum concentration, and solvent is transformed into isopropyl acetate (IPAc), to the final concn of 10mL/g.Filter IPAc solution by silica gel (300wt%), and wash with the IPAc of 1 volume.Add Darko KB-B (50wt%), and mixture was worn out 16 hours at 20-25 ℃.This batch of material is filtered by Solka Floc, and with IPAc (1.1 volume) washing leaching cake.This batch of material of vacuum concentration obtains title compound.

V.3-(2-bromo-4-chloro-6-fluorophenyl)-5-methyl isophthalic acid, 2,4- diazole.

In room temperature, in 2 liters of round-bottomed flasks that are equipped with bubbler, (25.0g, (14.3g 123mmol) handles the anhydrous DCM solution of 200ml 111mmol) with Tetrafluoroboric acid nitrous  with 2-bromo-4-chloro-6-fluoroaniline.After 1 hour, observe aniline and all consume.This reaction mixture is cooled to 0 ℃, then add potassium cyanide (14.5g, 223mmol).Under stirring fast, add the aqueous solution of copper sulfate hexahydrate (55.6g, 223mmol is in 125ml water) at leisure, produce a large amount of gas.After stirring 40 minutes, remove ice bath, and make reaction be warming up to room temperature.After at room temperature 1 hour, with extra DCM diluted reaction mixture, then by adding saturated sodium bicarbonate aqueous solution cancellation at leisure, until no longer observing extra gas evolution.Then the non-homogeneous mixture that obtains is filtered by big diatomite liner, if desired, wash with DCM.Wash organic filtrate twice with saturated brine then, then use dried over sodium sulfate.Filter and remove and desolvate, form material, it is carried out silica gel chromatography handle, with 0-25%DCM/ heptane wash-out.Collection contains the product of fraction, and removes and desolvate, and obtains the 2-bromo-4-chloro-6-fluorobenzene and the nitrile of 9.76 grams, and it obtains and theoretical consistent LC/MS and proton N MR spectrum.

(5.00g 21.3mmol), then adds excessive azanol (the 50% azanol aqueous solution of 21ml) to add above-mentioned nitrile in the ethanol of 21ml.Then with this mixture heating up to 60 ℃, simultaneously to atmosphere opening.1.5 after hour, finish by the reaction of LC/MS analysis and judgement.Mixture is cooled to room temperature, then with ether and water dilution.With extra water washing ether layer, use the saturated brine washed twice then.Use the dried over sodium sulfate organic layer, filter then and concentrate the unpurified azanol complex compound of acquisition 5.5g.With of the unpurified hydroxyl-amine complex combination of this material, obtain～total mass of 11.1g with the monovalent quantity of parallel preparation.With this material of 11.1g be dissolved in DMA (38.7g, 290mmol) in, and stirring at room 30 minutes.Use the ether diluted reaction mixture then, and water, half saturated brine, salt water washing then, dried over sodium sulfate then used.Filter and remove and desolvate, form material, it is carried out silica gel chromatography handle, with 40-85%DCM/ hexane wash-out.Collection contains the product of fraction, removes and desolvates, and obtains the title compound of 5.08g, and it obtains and theoretical consistent LC/MS and proton N MR spectrum.

Provide the following examples to illustrate the present invention, it should be interpreted as the scope that limits claim by any way.

Embodiment 1

4 '-({ [(1-hydroxyl cyclopropyl) carbonyl] amino } methyl) xenyl-2-carboxylic acid methyl ester

4 '-(aminomethyl) xenyl-2-carboxylic acid methyl ester (0.325g, 1.35mmol), 1-hydroxyl cyclopropane-carboxylic acid (0.151g, 1.48mmol) and I-hydroxybenzotriazole hydrate (0.248g, 1.62mmol) be suspended in the mixture of THF/DCM (DCM of the THF/6.5ml of 13ml), then add 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.336g, 1.75mmol).This solution changes homogeneous solution apace into, but reverts to heterogeneous mixture after 5 minutes.After 3 hours, solvent mixture is converted to pure DCM,,, forms title compound with 1-5% methyl alcohol/DCM wash-out then by the silica gel chromatography purifying.

LRMS(ES，M+H ⁺)：326.1H NMR(400MHz，CDCl ₃)：δ7.84(dd，J＝8.0，1.2Hz，1H)，7.53(td，J＝7.6，1.6Hz，1H)，7.41(td，J＝7.6，1.2Hz，1H)，7.34(m，3H)，7.29(bd，J＝8.4Hz，2H)，7.19(bs，1H)，4.55(d，J＝6.0Hz，2H)，3.69(s，3H)，2.55(bs，1H)，1.43(m，2H)，1.07(m，2H).

Embodiment 2

(2R)-N-((1R)-1-{5-[5-chloro-3-fluoro-2-(5-methyl isophthalic acid, 2,4- diazole-3-yl) phenyl]-3-fluorine pyridine-2-yl } ethyl)-3,3,3-three fluoro-2-hydroxy-2-methyl propionic acid amides

(20.6g, the anhydrous MeOH solution of 210ml 79.1mmol) is cooled to 0 ℃, then uses anhydrous hydrogen chloride saturated with the compound of reference example IV.Connect condenser and oily bubbler then, and solution is heated to 85 ℃, kept 5 hours.After being cooled to room temperature, removal of solvent under reduced pressure obtains yellow solid.With this solid be dissolved in the DCM of 200mL and 210mL aqueous sodium hydroxide solution (1M, 210mmol) in.Add then the Boc-acid anhydrides (23g, 105mmol), and stirring reaction 16 hours.Separate each layer then, and organic layer is extracted once with DCM.The organism that merges is washed with saturated brine, then use dried over sodium sulfate.Filter and remove and desolvate, form material, it is carried out silica gel chromatography handle, with 5-30%EtOAc/ hexane wash-out.Collection contains the product of fraction, removes to desolvate, and obtains [(1R)-1-(5-bromo-3-fluorine pyridine-2-yl) ethyl] carboxylamine tertiary butyl ester of 25.1g, and it obtains composing with theoretical consistent LC/MS and proton N MR.

With potassium acetate (3.43g, 35.0mmol), above-mentioned carbamate (3.72g, 11.7mmol) and 4,4,4 ', 4 ', 5,5,5 ', 5 '-prestox-2,2 '-two-1,3, (3.85g, mixture 15.2mmol) is dissolved among the DMSO of 24mL in a sealing tubular reactor vessel that is stamped rubber septum 2-two oxa-boron heterocycle pentanes.Then with this heterogeneous mixture exhaust, and with nitrogen purging three times, then introduce [1,1 '-two (diphenylphosphino) ferrocene] two chloro-palladiums (II) and DCM (1: 1) complex compound (0.426g, 0.583mmol).Then with the heterogeneous mixture exhaust, and with nitrogen purging twice, then with the alternative partition of tetrafluoroethylene spiral cover sealing.Sealed vessel is heated to 90 ℃ then, kept 1.5 hours.Be cooled to after the room temperature, add salt of wormwood (3.22g, 23.3mmol), (3.74g, 12.8mmol) (0.426g 0.583mmol), and seals this reaction once more with extra palladium catalyst for the compound of water (3ml), reference example V.After being heated to 80 ℃ 3 hours, will react cooling, then water and EtOAc cancellation.Water layer is extracted once with EtOAc.The organic layer that merges with extra water, use the salt water washing then, is then used dried over sodium sulfate.Filter and remove and desolvate, form material, it is carried out silica gel chromatography handle, with 10-35%EtOAc/ hexane wash-out.Collection contains the product of each fraction, removes to desolvate, obtain 3.62g ((1R)-1-{5-[5-chloro-3-fluoro-2-(5-methyl isophthalic acid, 2,4- diazole-3-yl) phenyl]-3-fluorine pyridine-2-yl ethyl) the carboxylamine tertiary butyl ester.

The material of above-mentioned BOC-protection is dissolved among the MeOH of 100ml, is cooled to 0 ℃ then.In solution, blasted anhydrous HCl gas then 3 minutes.Make reaction mixture after 0 ℃ leaves standstill 30 minutes, remove and desolvate.Add extra MeOH, under vacuum, remove then, then add and remove DCM (twice), obtain the amine hydrochlorate spumescence solid of 3.10g.

In a 200ml round-bottomed flask, to above-mentioned amine hydrochlorate (4.54g adds anhydrous DCM (31ml), (2R)-3,3 in 11.7mmol), 3-three fluoro-2-hydroxy-2-methyl propionic acid (2.78g, 17.6mmol), HOBt.H ₂O (0.898g, 5.86mmol), triethylamine (2.97g, 29.3mmol), add at last EDCI (3.60g, 18.8mmol).This reaction mixture was at room temperature stirred 16 hours.After judging that by LC/MS reaction is finished, to reaction mixture (without aftertreatment or remove and desolvate) carry out silica gel chromatography and handle, with 20-60%EtOAc/ hexane wash-out.Collection contains the product of each fraction, removes and desolvates, and obtains the title compound spumescence solid of 3.61g.By LCMS (ES MS, M+H ⁺Measured value: 491) and proton N MR (400MHz, CD3OD: δ 8.208,8.204,7.569,7.564,7.558,7.546,7.541,7.537,7.533,7.518,7.515,7.513,7.510,5.381,5.366,5.363,5.349,5.346,5.331,2.546,1.576,1.468,1.451) and determine purity.

The general method that provides according to embodiment 1 and 2 prepares following compound.The starting raw material alpha-hydroxy carboxylic acid compounds can commercial be bought, and perhaps can use popular response well-known in the art, by preparing by the commercial reagent of buying.Starting raw material dibenzyl methylamine can be by providing in reference example part and the popular response route method, use maybe can using popular response well-known in the art, preparing of can commercially buying by the reagent of reagent preparation that can commercial purchase.

Table 1

Embodiment	R 2a	R 2b	*	LRMS(M+H+)
					3	CH 3	CH 3	-	364
4	H	H	-	336
					5	CH 2CH 3	CH 2CH 3	-	392
6	3-(OCH 3)-Ph	H	±	442
					7	CHCH 3	CH 3	±	378
8	CH(CH 3) 2	H	±	378
					9	CH 3	H	S	350
10	Ph	Cyclopentyl	±	480
					11	4-Br-Ph	H	±	490
12	4-(CF 3)-Ph	H	±	480
					13	Ph	H	S	412
14	4-(OCH 3)-Ph	H	±	442
					15	CH 2Ph	H	±	426
16	Cyclohexyl	H	R	418
					17	3-(OH)-4-(OCH 3)-Ph	H	±	458
18	3，4-diOH-Ph	H	±	444
					19	CF 3	CF 3	-	472
20	CH 2CH(CH 3) 2	H	±	392
					21	Ph	CH 3	±	426
22	(the methyl of 1H-indoles-3-y1)	H	±	465
					23	CH 2(CH 2) 4CH 3	H	±	420
24	3，5-diF-Ph	H	±	448
					25	CF 3	H	±	404
26	CF 3	CH 3	S	418

Embodiment	R 2a	R 2b	*	LRMS(M+H+)
					27	CF 3	CH 3	R	418
28	CH 3	H	R	350
					29	(CH 2) 3CH 3	H	±	392
30	Cyclohexyl	H	S	418
					31	CH 2CH(CH 3) 2	H	S	392
32	CH(CH 3) 2	H	R	378
					33	CH(CH 3) 2	H	S	378
34	CH(CH 3)CH 2CH 3	H	S	392
					35	C(CH 3) 3	H	S	392
36	CF 3	H	S	404
					37	CH 2CH 2SCH 3	H	±	410
38	CH 2CH(CH 3) 21	H	R	392
					39	(pyridin-3-yl) methyl	H	±	427
40	OH	CF 3	-	420
					41	CF 2CF 3	CH 3	-	468
42	CF 2H	CH 3	±	400

Table 2

Embodiment	m	R 3a	Y	*	R 6	R 7	R 8	R 9	LRMS (M+H+)
										43	1	H	CH	-	CO 2CH 3	F	F	H	362
44	2	H	CH	-	CO 2CH 3	F	F	H	376
										45	1	CH 3	N	R	CO 2CH 3	F	Cl	Cl	427
46	5	H	CH	-	CO 2CH 3	F	F	H	418

Embodiment	m	R 3a	Y	*	R 6	R 7	R 8	R 9	LRMS (M+H+)
										47	1	CH 3	N	R	OCH 2CH 3	F	Cl	Cl	413
48	1	CH 3	CH	R	CO 2CH 3	F	Cl	H	392
										49	1	CH 3	CH	R	CO 2CH 3	H	F	H	358
50	1	CH 3	CH	S	CO 2CH 3	F	F	H	376
										51	1	CH 3	N	R	OCH 2CHF 2	F	Cl	Cl	449
52	1	CH 3	CH	R	CO 2CH 3	Cl	Cl	H	408
										53	1	CH 3	CH	R	OCH 2CHF 2	F	Cl	Cl	448
54	1	CH 3	CH	R	2-CH 3-2H-tetrazolium-5-base	F	F	H	400
										55	1	CH 3	CH	R	CO 2CH 3	F	Cl	Cl	426
56	2	CH 3	N	R	CO 2CH 3	F	Cl	Cl	441
										57	1	CH 3	N	R	2-CH 3-2H-tetrazolium-5-base	F	F	H	401

Table 3

Embodiment	Y	*	R 6	R 7	R 8	R 9	LRMS (M+H+)
								58	CH	R	CO 2CH 3	F	Cl	H	448
59	N	R	CO 2CH 3	F	F	Cl	467
								60	N	R	2-CH 3-2H-tetrazolium-5-base	F	F	H	457
61	N	R	CO 2CH 2CH 3	F	F	Cl	481
								62	N	R	CO 2CH 3	F	Cl	Cl	483
63	N	R	OCH 2CHF 2	F	Cl	Cl	505
								64	N	R	OCH 2CH 3	F	Cl	Cl	469
65	CH	R	2-CH 3-2H-tetrazolium-5-base	F	F	H	456
								66	CH	±	Ph	F	H	H	432

Embodiment	Y	*	R 6	R 7	R 8	R 9	LRMS (M+H+)
								67	CH	R	CO 2CH 3	F	Cl	Cl	482
68	N	R	CN	F	Cl	Cl	450
								70	CH	R	OCH 2CF 3	F	F	Cl	504
71	CH	R	3-CH 3-1,2,4- diazole	F	H	Cl	470
								72	N	R	OCH 2CF 3	F	F	Cl	505
73	CH	R	OCH 2CHF 2	F	Cl	Cl	504
								74	CH	R	2-CH 3-2H-tetrazolium-5-base	F	H	F	456
75	CH	R	CF 3	F	H	H	424
								76	CH	R	5-CH 3-1,2,4- diazole	F	H	F	456
77	N	R	OCH 2CF 3	Cl	Cl	Cl	539
								78	N	R	2-CH 3-2H-tetrazolium-5-base	Cl	F	H	471
79	N	R	OCH(CH 3) 2	F	Cl	Cl	483
								80	N	R	2-CH 3-2H-tetrazolium-5-base	F	Cl	Cl	507
81	CH	R	3-CH 3-1,2,4- diazole	F	F	H	456
								82	CH	R	2-CH 3-2H-tetrazolium-5-base	F	Cl	Cl	506
83	CH	R	OCH 2CF 3	F	Cl	Cl	522
								84	CH	R	OCH(CH 3) 2	F	Cl	Cl	482
85	CH	R	CO 2CH 3	F	F	H	432
								86	N	R	CONH 2	F	Cl	Cl	468
87	N	R	SCH 2CH 3	F	Cl	H	449
								88	N	R	OCH 2CF 3	F	Cl	Cl	523
89	N	R	5-CH 3-1,2,4- diazole	F	Cl	Cl	507
								90	N	R	CO 2CH 3	Cl	F	H	447
91	CH	R	2-CH 3-2H-tetrazolium-5-base	F	Cl	H	470
								92	CH	R	OCH(CH 2CH 3) 2	F	Cl	Cl	510
93	CH	R	OCH 2CH 2CH 3	F	Cl	Cl	482
								94	CH	R	OCH 2CHF 2	F	F	F	472
95	CH	R	CO 2CH 2CH 3	F	Cl	H	460
								96	N	R	2-CH 3-2H-tetrazolium-5-base	Cl	Cl	H	489
97	N	R	OCH 2CHF 2	F	F	Cl	487
								98	N	R	CO 2CH 3	Cl	Cl	Cl	499

Embodiment	Y	*	R 6	R 7	R 8	R 9	LRMS (M+H+)
								99	N	R	OCH 2CH(CH 3) 2	F	Cl	Cl	497
100	N	R	CO 2CH 2CH 3	F	Cl	H	461
								101	N	R	CO 2CH 2CH 3	F	Cl	Cl	497
102	N	R	CO 2CH 3	F	Cl	H	447
								103	N	R	2-CH 3-2H-tetrazolium-5-base	F	Cl	H	471
104	N	R	S(O)CH 2CH 3	F	Cl	H	465
								105	N	R	CO 2CH 2CH 3	Cl	Cl	H	479
106	CH	R	CO 2CH 3	H	F	H	414
								107	N	R	5-CH 3-1,2,4- diazole	F	F	H	457
108	CH	R	CO 2CH 2CH 3	F	Cl	Cl	496
								109	N	R	2-CH 3-2H-tetrazolium-5-base	Cl	Cl	Cl	521
110	N	R	5-CH 3-1,2,4- diazole	Cl	Cl	Cl	521
								111	N	R	2-CH 3-2H-tetrazolium-5-base	F	F	Cl	489
112	N	R	3-CH 3-1,2,4- diazole	F	F	H	457
								113	N	R	5-CH 3-1,2,4- diazole	F	Cl	H	471
114	N	R	3-CH 3-1,2,4- diazole	F	F	Cl	489
								115	CH	R	2-CH 3-2H-tetrazolium-5-base	F	F	Cl	488
116	N	R	3-CH 3-1,2,4- diazole	Cl	F	H	471
								117	N	R	3-CH 3-1,2,4- diazole	Cl	F	Cl	507
118	N	R	5-CH 3-1,2,4- diazole	Cl	Cl	H	489
								119	CH	R	5-CH 3-1,2,4- diazole	F	F	Cl	488
120	N	R	5-CH 3-1,2,4- diazole	Cl	F	H	471
								121	N	R	2-CH 3-2H-tetrazolium-5-base	Cl	F	Cl	507
122	CH	R	CO 2CH 3	Cl	Cl	H	464
								123	N	R	3-CH 3-1,2,4- diazole	F	Cl	H	471
124	N	R	5-CH 3-1,2,4- diazole	F	Cl	F	489
								125	N	R	2-CH 3-2H-tetrazolium-5-base	F	Cl	F	489
126	N	R	CO 2CH 2CH 3	Cl	Cl	Cl	511
								127	N	R	5-CH 3-1,2,4- diazole	Cl	F	Cl	507
128	N	R	3-CH 3-1,2,4- diazole	F	Cl	Cl	507
								129	CH	R	5-CH 3-1,2,4- diazole	F	F	Me	470

Embodiment	Y	*	R 6	R 7	R 8	R 9	LRMS (M+H+)
								130	CH	R	1-CH 3-2H-tetrazolium-5-base	F	F	Cl	488
131	CH	R	2-CH 3-2H-tetrazolium-5-base	Cl	F	Cl	506
								132	N	R	3-CH 3-1,2,4- diazole	Cl	Cl	Cl	521
133	N	R	2-CH 3-2H-tetrazolium-5-base	F	F	F	475
								134	N	R	CO 2CH 3	H	Cl	Cl	465
135	CH	R	2-CH 3-2H-tetrazolium-5-base	F	F	Me	470
								136	N	R	5-CH 3-1,2,4- diazole	Cl	Cl	Me	503
137	N	R	2-CH 3-2H-tetrazolium-5-base	Cl	Cl	Me	503
								138	CH	R	OCH 2CH 2CF 3	F	Cl	Cl	536
139	CH	R	5-CH 3-1,2,4- diazole	F	Cl	CF 3	538
								140	CH	R	5-CH 3-1,2,4- diazole	F	H	H	438
141	CH	R	2-CH 3-2H-tetrazolium-5-base	F	Cl	CF3	538
								142	N	R	5-CH 3-1,2,4- diazole	F	F	F	475
143	N	R	5-CH 3-1,2,4- diazole	Cl	F	F	489
								144	N	R	2-CH 3-2H-tetrazolium-5-base	Cl	F	F	489
145	N	R	SO 2CH 2CH 3	F	Cl	H	481
								146	N	R	5-CH(CH 3) 2-1,2,4- diazole	F	Cl	Cl	534
147	CH	R	NH(CH 2CF 3)	F	Cl	Cl	503
								148	CH	R	2-CH 3-2H-tetrazolium-5-base	F	Cl	OCF 3	554
149	N	R	3-CH 3-1,2,4- diazole	F	Cl	F	489
								150	N	R	3-CH 3-1,2,4- diazole	Cl	F	F	489
151	N	R	3-CH 3-1,2,4- diazole	F	F	F	475
								152	N	R	5-CH 3-1,2,4- diazole	F	F	F	451
153	CH	R	5-CH 3-1,2,4- diazole	F	Cl	SO 2Me	548
								154	CH	R	Cyclopropyl	F	Cl	Cl	464
155	CH	R	The 5-pyrimidyl	F	Cl	Cl	502
								156	CH	R	2-CH 3-2H-tetrazolium-5-base	F	Cl	CO 2CH 3	528

Table 4

Embodiment	Y	*	R 6	R 7	R 8	R 9	LRMS (M+H+)
								157	CH	R	CONHCH 3	F	F	H	417
158	N	R	CO 2CH 3	Cl	F	H	433
								159	CH	R	2-CH 3-2H-tetrazolium-5-base	Cl	F	Cl	492
160	N	R	2-CH 3-2H-tetrazolium-5-base	F	Cl	Cl	493
								161	N	R	2-CH 3-2H-tetrazolium-5-base	F	F	Cl	475
162	N	R	2-CH 3-2H-tetrazolium-5-base	Cl	F	Cl	493
								163	CH	R	5-CH 3-1,2,4- diazole	Cl	F	Cl	492
164	N	R	5-CH 3-1,2,4- diazole	Cl	F	Cl	493
								165	N	R	2-CH 3-2H-tetrazolium-5-base	Cl	Cl	Cl	507
166	N	R	3-CH 3-1,2,4- diazole	Cl	F	Cl	493
								167	N	R	2-CH 3-2H-tetrazolium-5-base	Cl	F	H	457
168	N	R	2-CH 3-2H-tetrazolium-5-base	F	F	F	461
								169	N	R	5-CH 3-1,2,4- diazole	F	F	Cl	475
170	N	R	2-CH 3-2H-tetrazolium-5-base	F	F	H	443
								171	CH	R	CO 2CH 3	Cl	Cl	Cl	482
172	N	R	2-CH 3-2H-tetrazolium-5-base	Cl	F	F	475
								173	N	R	2-CH 3-2H-tetrazolium-5-base	Cl	Cl	H	475
174	N	R	3-CH 3-1,2,4- diazole	Cl	Cl	Cl	507
								175	N	R	5-CH 3-1,2,4- diazole	Cl	F	F	475
176	N	R	3-CH 3-1,2,4- diazole	Cl	F	F	475
								177	N	R	2-CH 3-2H-tetrazolium-5-base	Cl	Cl	F	493
178	N	R	3-CH 3-1,2,4- diazole	Cl	Cl	F	493
								179	N	R	CO 2CH 3	Cl	F	Cl	468

Embodiment	Y	*	R 6	R 7	R 8	R 9	LRMS (M+H+)
								180	N	R	5-CH 3-1,2,4- diazole	Cl	Cl	Cl	507
181	N	R	5-CH 3-1,2,4- diazole	F	Cl	Cl	493
								182	N	R	3-CH 3-1,2,4- diazole	Cl	Cl	H	475
183	N	R	5-Ch 3-1,2,4- diazole	Cl	Cl	F	493
								184	N	R	3-CH 3-1,2,4- diazole	F	F	Cl	476

Claims (18)

1. the compound of formula (I) and its pharmacologically acceptable salts

Wherein

Y is CH or N;

R ¹Be

R ^2aBe selected from (1) and be selected from R ^aGroup, (2) (CH ₂) _nNR ^bC (O) R ^a, (3) (CH ₂) _nNR ^bSO ₂R ^d, (4) (CH ₂) _nNR ^bCO ₂R ^a, (5) are optional independently to be selected from (the CH that following group replaces by 1-3 ₂) _k-heterocycle: halogen, nitro, cyano group, OR ^a, SR ^a, C _1-4Alkyl and C _1-3Haloalkyl, wherein said heterocycle are that (a) has the ring hetero atom that is selected from N, O and S and optionally have a 5-unit hetero-aromatic ring of 3 extra loop nitrogen-atoms at the most, and wherein said ring is optional benzo condensed; Or the first hetero-aromatic ring of the 6-that (b) contains 1 to 3 theheterocyclic nitrogen atom and its N-oxide compound, wherein said ring is optional benzo condensed, (6) (CH ₂) _kCO ₂R ^aAnd (7) (CH ₂) _kC (O) NR ^bR ^c,

R ^2bBe OH or be selected from R ^2aGroup;

Or R ^2aAnd R ^2bForm 3-to 7-unit carbocyclic ring with the carbon atom that they connected, this carbocyclic ring is optional to be independently selected from halogen, OR by 1 to 4 ^a, C _1-4Alkyl and C _1-4The group of haloalkyl replaces;

R ^3aAnd R ^3bBe independently selected from hydrogen, C _1-4Alkyl and C _1-4Haloalkyl;

R ^4aAnd R ^4bBe independently selected from hydrogen and halogen;

R ⁶Be selected from: (1) is optional to be independently selected from the C that following group replaces by 1-5 _1-8Alkyl: halogen, nitro, cyano group, COR ^a, CO ₂R ^a, C (O) NR ^bR ^c, OR ^a, OC (O) R ^a, SR ^a, SO ₂R ^d, S (O) R ^d, NR ^bR ^c, NR ^bC (O) R ^a, NR ^bSO ₂R ^d, and NR ^bCO ₂R ^a, (2) C _3-8Cycloalkyl, (3) are optional by CO ₂R ^aThe C that replaces _2-8Thiazolinyl, (4) halogen, (5) cyano group, (6) nitro, (7) NR ^bR ^c, (8) NR ^bC (O) R ^a, (9) NR ^bCO ₂R ^a, (10) NR ^bC (O) NR ^bR ^c, (11) NR ^bC (O) NR ^bCO ₂R ^a, (12) NR ^bSO ₂R ^d, (13) CO ₂R ^a, (14) COR ^a, (15) C (O) NR ^bR ^c, (16) C (O) NHOR ^a, (17) C (=NOR ^a) R ^a, (18) C (=NOR ^a) NR ^bR ^c, (19) OR ^a, (20) OC (O) R ^a, (21) S (O) _vR ^d, (22) SO ₂NR ^bR ^c(23) optional substituted heterocycle, wherein heterocycle is that (a) has the ring hetero atom that is selected from N, O and S and optionally have a 5-unit hetero-aromatic ring of 3 extra loop nitrogen-atoms at the most, (b) have the 6-unit hetero-aromatic ring of 1 to 3 ring N atom, (c) 4,5-dihydro- azoles base or (d) 4,5-dihydro-1,2,4- di azoly, and wherein said substituting group is 1 to 3 and is independently selected from C _1-4The group of alkyl, C _1-4Alkyl is optional by 1 to 5 halogen atom, OR ^aOr OC (O) R ^aReplace (24) optional phenyl that independently is selected from following group replacement: halogen, nitro, cyano group, OR ^a, SR ^a, C _1-4Alkyl and C _1-4Haloalkyl and (25) OSO ₂R ^d

R ⁷Be selected from hydrogen and halogen;

R ⁸And R ⁹Be independently selected from hydrogen and R ⁶Group; Condition is R ⁶, R ⁸And R ⁹In at the most one be heterocycle;

R ^aBe selected from (1) hydrogen, (2) are optional by 1 to 5 halogen atom, OH, SH, O-C _1-4Alkyl or S-C _1-4The C that alkyl replaces _1-7Alkyl, (3) are optional to be independently selected from halogen, cyano group, nitro, OH, C by 1 to 3 _1-4Alkyl oxy, C _3-6Cycloalkyl, C _1-4Alkyl and C _1-4(the CH that the group of haloalkyl replaces ₂) _k-phenyl and (4) C _3-6Cycloalkyl;

R ^bAnd R ^cBe independently selected from: (1) hydrogen, (2) are optional to be independently selected from halogen, amino, CO by 1 to 5 ₂R ^a, OR ^a, list-C _1-4Alkylamino and two-C _1-4The C that the group of alkylamino replaces _1-4Alkyl, (3) are optional to be independently selected from halogen, cyano group, nitro, OR by 1 to 3 ^a, CO ₂R ^a, C _3-6Cycloalkyl, C _1-4Alkyl and C _1-4(the CH that the group of haloalkyl replaces ₂) _k-phenyl and (4) C _3-6Cycloalkyl, or

R ^bAnd R ^cThe nitrogen-atoms that connects with their forms 4-, 5-or 6-unit ring, and this ring randomly contains and is selected from NR ^e, O, S, S (O) and S (O) ₂Extra heteroatoms;

R ^dBe selected from (1) C _1-4Alkyl, (2) C _1-4Haloalkyl, (3) C _1-4Alkoxyl group, (4) are optional to be selected from halogen, cyano group, nitro, OR by 1 to 3 ^a, CO ₂R ^a, C _3-6Cycloalkyl, C _1-4Alkyl and C _1-4(the CH that the group of haloalkyl replaces ₂) _k-phenyl, (5) pyridyl and (6) pyridyl N-oxide compound;

R ^eBe selected from hydrogen, C _1-4Alkyl, C _1-4Haloalkyl, C (O) H and C (O) C _1-4Alkyl;

N is 1,2 or 3;

K is 0,1,2,3 or 4; With

V is 0,1 or 2.

2. the compound of claim 1, wherein R ^2a, R ^2bThe carbon atom that is connected with them forms 3-to 7-unit carbocyclic ring together, described ring is optional is independently selected from halogen, OR by 1 to 4 ^a, C _1-4Alkyl and C _1-4The group of haloalkyl replaces.

3. the compound of claim 1, wherein R ¹Be

R wherein ⁶, R ⁸And R ⁹As defined in claim 1.

4. the compound of claim 3, wherein R ⁶Be selected from (1)-CO ₂-C _1-4Alkyl, (2) C _1-4Alkoxyl group and (3) have the ring hetero atom that is selected from N, O and S and optionally have a 5-unit hetero-aromatic ring of 3 extra loop nitrogen-atoms at the most, and described ring is optional by C _1-4Alkyl replaces.

5. the compound of claim 4, wherein R ⁸Be hydrogen or 3-halo and R ⁹Be hydrogen or 5-halo.

6. the compound of claim 1, wherein R ¹Be

R wherein ^4a, R ^4bAnd R ^aAs defined in claim 1.

7. the compound of claim 6, wherein R ^4aAnd R ^4bEach is fluorine naturally.

8. compound and its pharmacologically acceptable salts of having the claim 1 of formula (Ia):

Wherein m is 1 to 5; Y is N or CH; R ^3aAnd R ^3bIn one be hydrogen, another is hydrogen or methyl; R ⁷Be hydrogen or fluorine; R ⁶Be selected from: (1)-CO ₂-C _1-4Alkyl, (2) optional C that is replaced by 1 to 5 halogen atom _1-4Alkoxyl group and (3) have the ring hetero atom that is selected from N, O and S and optionally have a 5-unit hetero-aromatic ring of 3 extra loop nitrogen-atoms at the most, and described ring is optional by C _1-4Alkyl replaces; R ⁸And R ⁹Be hydrogen or halogen independently.

9. compound and its pharmacologically acceptable salts of having the claim 1 of formula Ib:

R wherein ^3a, R ^3b, R ⁶, R ⁷, R ⁸And R ⁹Such as claim 1 definition, R ^{2a '}And R ^{2b '}Be independently selected from: (1) hydrogen, (2) are optional by 1 to 5 halogen atom, SH, OH, SC _1-4Alkyl or OC _1-4The C that alkyl replaces _1-7Alkyl, (3) are optional to be independently selected from halogen, cyano group, nitro, OH, C by 1 to 3 _1-4Alkoxyl group, C _3-6Cycloalkyl, C _1-4Alkyl and C _1-4(the CH that the group of haloalkyl replaces ₂) _k-phenyl, (4) C _3-6Cycloalkyl, (5) (CH ₂) _k-pyridyl and (6) (CH ₂) _k-indyl.

10. the compound of claim 9, wherein R ^{2a '}And R ^{2b '}Be the optional C that is replaced by 1 to 5 halogen atom independently _1-7Alkyl.

11. the compound of claim 10, wherein R ^3aAnd R ^3bIn one be hydrogen, another is hydrogen or methyl; R ⁷Be hydrogen, chlorine or fluorine; R ⁶Be selected from: (1)-CO ₂-C _1-4Alkyl, (2) optional C that is replaced by 1 to 5 halogen atom _1-4Alkoxyl group and (3) have the ring hetero atom that is selected from N, O and S and optionally have a 5-unit hetero-aromatic ring of 3 extra loop nitrogen-atoms at the most, and described ring is optional by C _1-4Alkyl replaces; R ⁸And R ⁹Be hydrogen or halogen independently.

12. have compound and its pharmacologically acceptable salts of the claim 1 of formula Ic:

Wherein Y is N or CH; R ⁷Be H, chlorine or fluorine; R ^3aBe H or methyl; R ⁶Be selected from: (1)-CO ₂-C _1-4Alkyl, (2) C _1-4Alkoxyl group, (3) C _1-4Halogenated alkoxy and (4) have the ring hetero atom that is selected from N, O and S and optionally have a 5-unit hetero-aromatic ring of 3 extra loop nitrogen-atoms at the most, and described ring is optional by C _1-4Alkyl replaces; R ⁸And R ⁹Be hydrogen or halogen independently.

13. pharmaceutical composition comprises the compound and the pharmaceutically acceptable carrier of the claim 1 for the treatment of significant quantity.

14. the method for the illness of treatment or the mediation of prevention bradykinin b 1 receptor in Mammals, this method comprises the compound of the claim 1 that gives described Mammals treatment significant quantity.

15. the method for treatment or prevent irritation in Mammals, this method comprise the compound of the claim 1 that gives described Mammals treatment significant quantity.

16. treatment or prevention are selected from the method for the pain of acute pain, inflammatory pain and neuropathic pain in Mammals, this method comprises the compound of the claim 1 that gives described Mammals treatment significant quantity.

17. the compound of claim 1 or its pharmacologically acceptable salts are used for the treatment of or prevent purposes in the medicine of the disease of bradykinin b 1 receptor mediation or illness in preparation.

18. the purposes of claim 17, wherein said disease or illness are acute pain, inflammatory pain and neuropathic pain.