CN103833730A

CN103833730A - Benzo five-membered nitrogen-containing heterocycle-based piperazine derivative and preparation method as well as application thereof

Info

Publication number: CN103833730A
Application number: CN201210486619.9A
Authority: CN
Inventors: 周延; 张丽荣; 周杰; 周欣
Original assignee: LIAONING BEILEI BIOLOGICAL PHARMACEUTICAL Co Ltd
Current assignee: Original Pharmaceutical Port Life Science Research Liaoning Co ltd
Priority date: 2012-11-26
Filing date: 2012-11-26
Publication date: 2014-06-04
Anticipated expiration: 2032-11-26
Also published as: CN103833730B

Abstract

The invention relates to an application of a benzo five-membered nitrogen-containing heterocycle-based piperazine derivative shown in the specification as well as a pharmaceutically acceptable salt and a preparation method thereof, and further relates to a medicine composition containing the derivative and an application thereof in preparation of a vasodilatation medicine, wherein R1, R2, Y, A and B are defined as the specification.

Description

Benzo five-membered Azacyclyl piperidine derivative, Its Preparation Method And Use

Technical field

The present invention relates to a kind of benzo five-membered Azacyclyl piperidine derivative and pharmacy acceptable salt thereof, its preparation method, also relate to the pharmaceutical composition that comprises this derivative with and in the purposes of preparing in vasodilator drug.

Background technology

Exist clinically at present the multiclass can vasodilatory medicine, for example, α ₁receptor blocking agent class medicine, comprises Prazosin, Doxazosin, terazosin etc., and these medicines have obvious first dosage effect or postural hypotension, thereby have limited the widespread use clinically of such medicine; Ca ²⁺channel blocker, existing medicine comprises amlodipine, nifedipine, felodipine etc., the widespread use clinically at present of this class medicine, but also there is the risk that suppresses heart in it simultaneously.

Therefore, still need to develop new vasodilator drug, to improving drug effect, reduce resistance or make its toxic side effect less, to meet different patients' needs clinically as far as possible.

Summary of the invention

The invention provides the benzo five-membered Azacyclyl piperidine derivative of formula (I) or its pharmacy acceptable salt:

Wherein:

R ₁representative is by R ₃monosubstituted or polysubstituted aromatic group or aliphatics cyclic group, wherein

R ₃for H, halogen, CN, C ₁-C ₆alkyl, C ₁-C ₆alkoxyl group, CHO, CO (C ₁-C ₆alkyl), COO (C ₁-C ₆alkyl), NO ₂, NH ₂, NH (C ₁-C ₆alkyl), SH, S (C ₁-C ₆alkyl) ,-SO (C ₁-C ₆alkyl) or-SO ₂(C ₁-C ₆alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms; Work as R ₃during for polysubstituted group, R ₃independently selected from H, halogen, CN, C ₁-C ₆alkyl, C ₁-C ₆alkoxyl group, CHO, CO (C ₁-C ₆alkyl), COO (C ₁-C ₆alkyl), NO ₂, NH ₂, NH (C ₁-C ₆alkyl), SH, S (C ₁-C ₆alkyl) ,-SO (C ₁-C ₆alkyl) or-SO ₂(C ₁-C ₆alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms;

A, B independently represent respectively CH or N;

R ₂represent H, halogen, CN, C ₁-C ₆alkyl, C ₁-C ₆alkoxyl group, CHO, CO (C ₁-C ₆alkyl), COO (C ₁-C ₆alkyl), NO ₂, NH ₂, NH (C ₁-C ₆alkyl), SH, S (C ₁-C ₆alkyl) ,-SO (C ₁-C ₆alkyl) or-SO ₂(C ₁-C ₆alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms; Work as R ₂during for polysubstituted group, R ₂independently selected from H, halogen, CN, C ₁-C ₆alkyl, C ₁-C ₆alkoxyl group, CHO, CO (C ₁-C ₆alkyl), COO (C ₁-C ₆alkyl), NO ₂, NH ₂, NH (C ₁-C ₆alkyl), SH, S (C ₁-C ₆alkyl) ,-SO (C ₁-C ₆alkyl) or-SO ₂(C ₁-C ₆alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms;

Saturated or the undersaturated straight or branched hydrocarbyl chain that contains 2-8 carbon atom that Y representative is optionally replaced by 1-3 halogen atom, the heteroatoms that wherein one or more carbon are optionally selected from oxygen, sulphur and nitrogen substitutes.

Embodiment

Wherein:

A, B independently represent respectively CH or N;

Preferably, the R in formula of the present invention (I) ₂for example, for monosubstituted or polysubstituted group, R on described benzo five-membered nitrogen heterocyclic ₂for monosubstituted, two replacements, three substituted radicals etc.; R ₂the group connecting on any carbon atom for benzo five-membered nitrogen heterocyclic, for example, in the time that A (or B) is C, R ₂also can be coupled.

The implication of term used herein " aromatic group " is interpreted as the C that wherein at least one ring is aromatic nucleus _5-12monocyclic hydrocarbon ring or dicyclic hydrocarbon ring, the heteroatoms that wherein one or more carbon are optionally selected from oxygen, sulphur and nitrogen substitutes.The example of aromatic group comprises aryl and heteroaryl, for example phenyl, naphthyl, benzothiazolyl, benzisothiazole base, benzoxazolyl, benzoisoxazole base, benzimidazolyl-, benzopyrazoles base, benzofuryl, benzo pyrimidyl, benzo pyridyl, quinoxalinyl, furyl, pyridyl or pyrimidyl.

The implication of term used herein " aliphatics cyclic group " is interpreted as C ₄- ₁₂monocycle saturated cyclic or dicyclo saturated cyclic, the heteroatoms that wherein one or more carbon are optionally selected from oxygen, sulphur and nitrogen substitutes.The example of aliphatics cyclic group comprises cyclobutyl, cyclopentyl, cyclohexyl, suberyl, tetrahydrofuran base, piperidyl or piperazinyl etc.

Unless specifically noted in addition, term as used herein " halogen " refers to fluorine, chlorine, bromine or iodine.

Term used herein " alkyl " comprises straight or branched alkyl.Described " C ₁-C ₆alkyl " example of group comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl, isohexyl etc.

Refer to-O-of term used herein " alkoxyl group " alkyl, wherein alkyl comprises straight or branched alkyl.Described " C ₁-C ₆alkoxyl group " example of group comprises methoxyl group, oxyethyl group, propoxy-, butoxy, pentyloxy and hexyloxy etc.

In a specific embodiments, the invention provides the benzo five-membered Azacyclyl piperidine derivative of formula (I) or its pharmacy acceptable salt:

Wherein:

Described aromatic group is preferably phenyl, naphthyl, heteroatoms and is selected from benzo five-membered heterocycle or the hexa-member heterocycle of N, S, O, or five yuan or hexa-atomic unsaturated heterocycle; More preferably phenyl, benzothiazolyl, benzisothiazole base, benzoxazolyl, benzoisoxazole base, benzimidazolyl-, benzopyrazoles base, benzofuryl, benzo pyrimidyl, benzo pyridyl, quinoxalinyl, furyl, pyridyl or pyrimidyl; More preferably phenyl, benzoisoxazole base, benzisothiazole base, benzopyrazoles base, benzofuryl, naphthyl, furyl, pyridyl, pyrimidyl Huo quinoxalinyl again; Be particularly preferably phenyl, benzoisoxazole base; Preferably, in the time that described aromatic group is benzoisoxazole base, A is N;

Described aliphatics cyclic group is preferably five yuan or hexa-atomic saturated cyclic, or heteroatoms is selected from five yuan or the hexa-atomic saturated heterocyclyl of N, S, O; More preferably cyclopentyl, cyclohexyl, tetrahydrofuran base, piperidyl or piperazinyl; More preferably cyclohexyl, piperidyl or piperazinyl again; Be particularly preferably cyclohexyl;

R ₃for H, halogen, CN, C ₁-C ₆alkyl, C ₁-C ₆alkoxyl group, CHO, CO (C ₁-C ₆alkyl), COO (C ₁-C ₆alkyl), NO ₂, NH ₂, NH (C ₁-C ₆alkyl), SH, S (C ₁-C ₆alkyl) ,-SO (C ₁-C ₆alkyl) or-SO ₂(C ₁-C ₆alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms; Preferably, R ₃for H, F, Cl, Br, CN, moieties are optionally by the C of 1-3 halogen atom replacement ₁-C ₆alkyl or C ₁-C ₆alkoxyl group, CHO, COCH ₃or COOCH ₃; More preferably, R ₃for H, F, Cl, COCH ₃, the C that optionally replaced by 1-3 halogen atom of moieties ₁-C ₄alkyl or C ₁-C ₄alkoxyl group; Again more preferably, R ₃for H, F, Cl, CN, CF ₃, CH ₃, OCH ₃or COCH ₃; Work as R ₃during for polysubstituted group, R ₃independently selected from the above group;

A, B independently represent respectively CH or N; Preferably, A, B all represent N;

R ₂represent H, halogen, CN, C ₁-C ₆alkyl, C ₁-C ₆alkoxyl group, CHO, CO (C ₁-C ₆alkyl), COO (C ₁-C ₆alkyl), NO ₂, NH ₂, NH (C ₁-C ₆alkyl), SH, S (C ₁-C ₆alkyl) ,-SO (C ₁-C ₆alkyl) or-SO ₂(C ₁-C ₆alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms; Preferably, R ₂for H, F, Cl, Br, CN, moieties are optionally by the C of 1-3 halogen atom replacement ₁-C ₆alkyl or C ₁-C ₆alkoxyl group, CHO, COCH ₃or COOCH ₃; More preferably, R ₂for H, F, Cl, CN, CHO, COCH ₃, COOCH ₃or the C that moieties is optionally replaced by 1-3 halogen atom ₁-C ₄alkyl or C ₁-C ₄alkoxyl group; Again more preferably, R ₂for H, F, Cl, CN, CF ₃, CH ₃, OCH ₃, CHO, COCH ₃or COOCH ₃; Work as R ₂during for polysubstituted group, R ₂independently selected from the above group;

Saturated or the undersaturated straight or branched hydrocarbyl chain that contains 2-8 carbon atom that Y representative is optionally replaced by 1-3 halogen atom, the heteroatoms that wherein one or more carbon are optionally selected from oxygen, sulphur and nitrogen substitutes; Preferably, Y is the unsubstituted saturated hydrocarbyl containing 2-8 carbon, or wherein 1 carbon atom for example, by oxygen or the alternative unsubstituted saturated hydrocarbyl containing 2-8 carbon of sulphur ,-C _1-7alkylidene group-O-; More preferably Y is methylene radical, ethylidene, propylidene, butylidene, pentylidene, hexylidene, sub-heptyl, octylene, oxygen methylene, oxygen base ethylidene, oxygen base propylidene, oxygen base butylidene, oxygen base pentylidene, oxygen base hexylidene, the sub-heptyl of oxygen base, methylene radical oxygen base, ethyleneoxy group, propylidene oxygen base, butylene oxide base, pentylidene oxygen base, hexylidene oxygen base or sub-heptyl oxygen base; Again more preferably, Y is methylene radical, ethylidene, propylidene, butylidene, pentylidene, hexylidene, sub-heptyl, octylene, methylene radical oxygen base, ethyleneoxy group, propylidene oxygen base, butylene oxide base, pentylidene oxygen base, hexylidene oxygen base or sub-heptyl oxygen base; Be particularly preferably ethylidene, propylidene, butylidene, ethyleneoxy group or propylidene oxygen base.

In another embodiment, the invention provides the benzo five-membered Azacyclyl piperidine derivative of formula (I) or its pharmacy acceptable salt:

Wherein:

R ₁representative is by R ₃mono-substituted aromatic group, wherein

Described aromatic group is preferably phenyl or benzoisoxazole base; Preferably, in the time that described aromatic group is benzoisoxazole base, A is N;

R ₃for H, F, Cl, CF ₃, CH ₃or OCH ₃;

R ₂represent H, F, Cl, CN, CH ₃, OCH ₃or CHO;

Y represents ethylidene, propylidene, butylidene or propylidene oxygen base.

In another specific embodiments, the invention provides the benzo five-membered Azacyclyl piperidine derivative of formula (I) or its pharmacy acceptable salt:

Wherein:

R ₁representative is by R ₃mono-substituted aromatic group, wherein

R ₃for H or CF ₃;

R ₂represent H or OCH ₃;

Y represents propylidene or butylidene.

Wherein: in the time that A, B are N,

R ₁the benzoisoxazole base not replacing for 6-fluorine;

R ₂be not H or Cl; And

Y is not ethyleneoxy group or propylidene oxygen base.

Wherein: in the time that A, B are C,

R ₁the benzoisoxazole base not replacing for 6-fluorine;

R ₂be not H, F, CN, COOCH ₃or Cl; And

Y is not ethylidene, propylidene, butylidene, pentylidene, ethyleneoxy group or propylidene oxygen base.

Wherein: when only one of A, B are C, when another is N,

R ₁the benzoisoxazole base not replacing for 6-fluorine;

R ₂be not H, F or CN; And

Y is not propylidene or butylidene.

Described benzo five-membered Azacyclyl piperidines comprises:

I-1 N-(4-(1H-benzoglyoxaline-1-yl) butyl)-4-(3-chloro-phenyl-) piperidines,

I-2 N-(4-(1H-benzotriazole-1-yl) butyl)-4-(3-chloro-phenyl-) piperidines,

I-3 N-(4-(1H-benzoglyoxaline-1-yl) butyl)-4-(3-trifluoromethyl) piperidines,

I-4 N-(4-(1H-benzotriazole-1-yl) butyl)-4-(3-trifluoromethyl) piperidines,

I-5 N-(4-(1H-benzoglyoxaline-1-yl) butyl)-4-(3-fluorophenyl) piperidines,

I-6 N-(4-(1H-benzoglyoxaline-1-yl) butyl)-4-(2-p-methoxy-phenyl) piperidines,

I-7 N-(4-(the fluoro-1H-benzotriazole-1-of 6-yl) butyl)-4-(3-trifluoromethyl) piperidines,

I-8 N-(4-(6-methoxyl group-1H-benzotriazole-1-yl) butyl)-4-(3-trifluoromethyl) piperidines,

I-9 N-(4-(6-cyano group-1H-benzotriazole-1-yl) butyl)-4-(3-trifluoromethyl) piperidines,

I-10 N-(4-(1H-benzotriazole-1-yl) propoxy-)-4-(3-trifluoromethyl) piperidines,

I-11 N-(4-(1H-benzoglyoxaline-1-yl) propoxy-)-4-(3-trifluoromethyl) piperidines,

I-12 N-(3-(1H-benzotriazole-1-yl) propyl group)-4-(3-(6-methyl benzoisoxazole)) piperidines,

I-13 N-(3-(1H-benzotriazole-1-yl) propyl group)-4-(3-(6-methoxyl group benzo isoxazole)) piperidines,

I-14 N-(3-(the fluoro-1H-benzotriazole-1-of 6-yl) propyl group)-4-(3-(6-fluorine benzoisoxazole)) piperidines,

I-15 N-(3-(the chloro-1H-benzotriazole-1-of 6-yl) propyl group)-4-(3-(6-fluorine benzoisoxazole)) piperidines,

I-16 N-(3-(6-methyl isophthalic acid H-benzotriazole-1-yl) propyl group)-4-(3-(6-fluorine benzoisoxazole)) piperidines,

I-17 N-(3-(6-methoxyl group-1H-benzotriazole-1-yl) propyl group)-4-(3-(6-fluorine benzoisoxazole)) piperidines,

I-18 N-(3-(6-formyl radical-1H-benzotriazole-1-yl) propyl group)-4-(3-(6-fluorine benzoisoxazole)) piperidines,

I-19 N-(3-(6-methoxyl group benzo triazol radical) propyl group)-4-(3-benzoisoxazole) piperidines,

I-20 N-(2-(1-benzotriazole base) ethyl)-4-(3-(6-fluorine benzoisoxazole)) piperidines,

I-21 N-(4-(1-benzotriazole base) butyl)-4-(3-(6-fluorine benzoisoxazole)) piperidines,

I-22 N-(4-(6-cyano group benzotriazole base) butyl)-4-(3-(6-fluorine benzoisoxazole)) piperidines,

I-23 N-(4-(6-cyano group benzotriazole base) butyl)-4-(3-(6-methoxyl group benzo isoxazole)) piperidines,

I-24 N-(2-(6-methoxyl group benzo triazol radical) oxyethyl group)-4-(3-benzoisoxazole) piperidines,

I-25 N-(2-(1-benzotriazole base) oxyethyl group)-4-(3-fluorine benzoisoxazole) piperidines,

I-26 N-(3-(6-methoxyl group benzo triazol radical) propyl group)-4-(3-(6-fluorine benzisothiazole)) piperidines,

I-27 N-(3-(6-methoxyl group benzo triazol radical) propyl group)-4-(3-(6-fluorine benzopyrazoles)) piperidines,

I-28 N-(3-(6-methoxyl group benzo triazol radical) propyl group)-4-(3-(6-fluorine cumarone)) piperidines,

I-29 N-(4-(1H-benzimidazolyl--1-yl) butyl)-4-(2-furyl) piperidines,

I-30 N-(4-(1H-benzimidazolyl--1-yl) butyl)-4-(4-pyridyl) piperidines,

I-31 N-(4-(1H-benzimidazolyl--1-yl) butyl)-4-(2-pyrimidyl) piperidines,

I-32 N-(4-(1H-benzotriazole-1-yl) butyl)-4-cyclohexyl piperidines,

I-33 N-(4-(1H-benzotriazole-1-yl) butyl)-4-(1-naphthyl) piperidines,

I-34 N-(4-(1H-benzotriazole-1-yl) butyl)-4-(2-quinoxalinyl) piperidines.

Particular chemical formula is as shown in the table:

In specific embodiment of the invention scheme, more preferably following compound or its pharmacy acceptable salt:

I-1 N-(4-(1H-benzoglyoxaline-1-yl) butyl)-4-(3-chloro-phenyl-) piperidines,

I-2 N-(4-(1H-benzotriazole-1-yl) butyl)-4-(3-chloro-phenyl-) piperidines,

I-3 N-(4-(1H-benzoglyoxaline-1-yl) butyl)-4-(3-trifluoromethyl) piperidines,

I-4 N-(4-(1H-benzotriazole-1-yl) butyl)-4-(3-trifluoromethyl) piperidines,

I-10 N-(4-(1H-benzotriazole-1-yl) propoxy-)-4-(3-trifluoromethyl) piperidines,

I-23 N-(4-(6-cyano group benzotriazole base) butyl)-4-(3-(6-methoxyl group benzo isoxazole)) piperidines.

In specific embodiment of the invention scheme, particularly preferably following compound or its pharmacy acceptable salt:

I-3 N-(4-(1H-benzoglyoxaline-1-yl) butyl)-4-(3-trifluoromethyl) piperidines,

I-4 N-(4-(1H-benzotriazole-1-yl) butyl)-4-(3-trifluoromethyl) piperidines,

I-19 N-(3-(6-methoxyl group benzo triazol radical) propyl group)-4-(3-benzoisoxazole) piperidines.

The pharmacy acceptable salt of formula of the present invention (I) compound is preferably hydrochloride, hydrogen bromide salt, vitriol, trifluoroacetate, mesylate, tartrate, malate, succinate, maleate, Citrate trianion, phosphoric acid salt, lactic acid salt, pyruvate salt, acetate, fumarate, oxaloacetate, esilate, oxalate, benzene sulfonate or isethionate.Pharmacy acceptable salt of the present invention, preferably containing crystal water, more preferably contains the crystal water of 0.5-3 molecule.

The invention still further relates to the purposes in formula of the present invention (I) compound and pharmaceutically acceptable disease or the illness relevant to the contraction of continuous vessel pathologic or vasospasm prevention, alleviation or treatment experimenter.Described formula (I) compound and pharmacy acceptable salt thereof can be used in particular for prevention, alleviate or treatment hypertension heart failure, stenocardia, coronary heart disease etc.; For the cerebral ischemia diseases being caused by vasospasm, myocardial ischemia disease, shock etc.; The poor kidney and the periperal vascular spasm that be used for renal ischaemia, are caused by kidney vasospasm.

Experimenter's preferred mammal described herein, particularly preferably people.

The invention provides formula (I) compound or its pharmacy acceptable salt and be particularly preferred for prevention, alleviate or for example treat, hypertension, stenocardia, heart failure, coronary heart disease, cerebral ischemia and periperal vascular spasm are as thromboangiitis obliterans, Raynaud disease etc.

The invention still further relates to the pharmaceutical composition that comprises formula of the present invention (I) compound or its pharmacy acceptable salt, it is for oral administration, administered parenterally, by sucking administration in spray delivery, rectal administration, intranasal administration, sublingual administration, cheek, transdermal administration or through drug delivery implant, that described administered parenterally comprises is subcutaneous, in intracutaneous, intravenously, intramuscular, intraarticular, synovial membrane, in breastbone, in sheath, intralesional and intracranial injection administration or drip infusion technique.Formula of the present invention (I) compound or its pharmacy acceptable salt preferred oral administration, sublingual administration, intravenously, intramuscular, subcutaneous injection administration.Described pharmaceutical composition can comprise one or more conventional pharmaceutically acceptable carrier, auxiliary agent or medium, for example: thinner, vehicle are as water etc.; Tackiness agent is as derivatived cellulose, gelatin, polyvinylpyrrolidone etc.; Weighting agent is as starch etc.; Burst apart agent as calcium carbonate, sodium bicarbonate; Lubricant is as calcium stearate or Magnesium Stearate etc.; And other auxiliarys are as flavouring agent and sweeting agent.

The described pharmaceutical composition that comprises formula of the present invention (I) compound or its pharmacy acceptable salt can be the form of aseptic injection, for example, as sterile aqueous or oil suspension.This suspension can for example, according to the suitable dispersion agent of utilization known in the art or wetting agent (Tween 80) and suspension agent preparation.Aseptic injection also can be aseptic injectable solution or the suspension in the nontoxic thinner or the solvent that can be used for administered parenterally, for example, as the solution in 1,3 butylene glycol.Spendable usable medium and solvent are N.F,USP MANNITOL, water, Ringer ' s solution and isotonic sodium chlorrde solution.In addition, aseptic expressed oil routine can be used as solvent or suspension medium.For this purpose, the expressed oil of any gentleness be can use, synthetic monoglyceride or triglyceride comprised.Lipid acid, for example oleic acid and glyceride derivative thereof can be used in injectable formulation, and natural pharmaceutically useful oil also can be used for wherein, for example sweet oil or Viscotrol C, especially its polyoxyethylene form.Described oil solution or suspension also can comprise long-chain alcohol thinner or dispersion agent (be for example described in Ph.Helv those) or similar alcohol.

The pharmaceutical composition that comprises formula of the present invention (I) compound or its pharmacy acceptable salt can any formulation oral administration that can be oral, described formulation includes but not limited to, capsule, tablet, pulvis, granule and aqueous suspension agent and solution.Described formulation is to make according to known technology in field of pharmaceutical preparations.For the tablet orally using, normally used carrier comprises lactose and W-Gum.Also conventionally add lubricant (for example Magnesium Stearate).To the oral administration of capsule form, available thinner comprises lactose and dry W-Gum.When aqueous suspension agent is during by oral administration, active ingredient can be combined with emulsifying agent and suspension agent.If need, can add some sweeting agent and/or seasonings and/or tinting material.

The pharmaceutical composition that comprises formula of the present invention (I) compound or its pharmacy acceptable salt can be by nose gaseous solvents or inhalation.This based composition can be according to known technology preparation in field of pharmaceutical preparations, and absorption enhancer, fluorocarbon and/or other solubilizing agent known in the art or the dispersion agent that can use phenylcarbinol or other suitable sanitass, raising bioavailability, be prepared as the solution in salt solution.

The pharmaceutical composition that comprises formula of the present invention (I) compound or its pharmacy acceptable salt can also be used for the suppository form administration of rectal administration.Described composition can be by the compounds of this invention and suitable non-stimulated mixed with excipients are made, and described vehicle is at room temperature solid but is liquid under rectal temperature, therefore in rectum, will dissolve to discharge active ingredient.This class material includes but not limited to, theobroma oil, beeswax and polyoxyethylene glycol.

Infer according to anesthetized rat test-results, dosage every day of formula of the present invention (I) compound should be less than dosage every day of amlodipine.Dosage every day for vasodilator or hypertensive amlodipine is known in the art, for example 10mg/ day.The concrete dosage of formula of the present invention (I) compound can be determined by doctor according to clinical experiment result and patient's the state of an illness, age etc.

The pharmaceutical composition that comprises formula of the present invention (I) compound or its pharmacy acceptable salt can adopt the method for medical field routine to be prepared, wherein the content of activeconstituents is 0.1 % by weight～99.5 % by weight, the characteristic that this depends on the illness of to be treated or prevention and gives the experimenter of described compound.Dosage for given compound can utilize content disclosed herein easily to determine by those skilled in the art.

In a specific embodiments, compound formula (I) compound of the present invention or its pharmacy acceptable salt can with one or more other active medicine component couplings.This coupling medicine can be the form of the single composition that comprises the compounds of this invention or its pharmacy acceptable salt and one or more other active medicine components, or, this coupling medicine can be the cooperative programs of two or more independent compositions, wherein compound of the present invention is included in a kind of composition, and one or more other active medicine components are included in one or more independent compositions.Can to formula of the present invention (I) compound or its pharmacy acceptable salt coupling taking prevention, alleviate or other active medicine components for the treatment of experimenter and the contraction of continuous vessel pathologic or the relevant disease of vasospasm or illness for example as other anti-smooth muscle spasm medicines, preferably from Sertraline, captopril, benazepril, valsartan, Proprasylyte, hydragog(ue).

In another aspect, the invention provides the preparation method of the benzo five-membered Azacyclyl piperidines of formula (I):

Scheme (one)

Comprise

At the temperature of 10-150 DEG C, make compound

With compound

Under the existence of mineral alkali and phase-transfer catalyst in solvent reacting generating compound

Then under refluxing, make itself and compound

Under the existence of organic bases in solvent reacting generating compound

Or

Scheme two

Comprise

At the temperature of 10-150 DEG C, make compound

With compound

Then under refluxing, make itself and compound

Under the existence of organic bases in solvent reacting generating compound

Wherein,

Saturated or the undersaturated straight or branched hydrocarbyl chain that contains 2-8 carbon atom that Y representative is optionally replaced by 1-3 halogen atom, the heteroatoms that wherein one or more carbon are optionally selected from oxygen, sulphur and nitrogen substitutes; Preferably, Y is the unsubstituted saturated hydrocarbyl containing 2-8 carbon, or wherein 1 carbon atom for example, by oxygen or the alternative unsubstituted saturated hydrocarbyl containing 2-8 carbon of sulphur ,-C _1-7alkylidene group-O-; More preferably Y is methylene radical, ethylidene, propylidene, butylidene, pentylidene, hexylidene, sub-heptyl, octylene, oxygen methylene, oxygen base ethylidene, oxygen base propylidene, oxygen base butylidene, oxygen base pentylidene, oxygen base hexylidene, the sub-heptyl of oxygen base, methylene radical oxygen base, ethyleneoxy group, propylidene oxygen base, butylene oxide base, pentylidene oxygen base, hexylidene oxygen base or sub-heptyl oxygen base; Again more preferably, Y is methylene radical, ethylidene, propylidene, butylidene, pentylidene, hexylidene, sub-heptyl, octylene, methylene radical oxygen base, ethyleneoxy group, propylidene oxygen base, butylene oxide base, pentylidene oxygen base, hexylidene oxygen base or sub-heptyl oxygen base; Particularly preferably, Y is ethylidene, propylidene, butylidene, ethyleneoxy group or propylidene oxygen base;

Under the first step each comfortable mineral alkali of reaction of scheme () and scheme (two) and the existence of phase-transfer catalyst, in solvent, carry out, described mineral alkali is preferably sodium hydride, sodium hydroxide, sodium methylate, sodium ethylate, sodium carbonate, sodium bicarbonate, potassium hydride KH, potassium hydroxide, potassium methylate, potassium ethylate, salt of wormwood or saleratus, is more preferably sodium hydride or sodium hydroxide; Described phase-transfer catalyst is preferably Tetrabutyl amonium bromide, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate or Isosorbide-5-Nitrae, and 7,10,13,16-hexaoxacyclooctadecane-6 (i.e. 18 hats 6) etc., are more preferably Tetrabutyl amonium bromide; It is solvent conventional in this area that the first step is reacted solvent used, is preferably water, N-Methyl pyrrolidone (NMP) or DMF (DMF) and composition thereof; The temperature of reaction of the first step is 10-150 DEG C, preferably 20-130 DEG C, more preferably 30-100 DEG C;

The second step of scheme () and scheme (two) reacts each comfortable organic bases, more preferably under the existence of organic bases and potassiumiodide, in solvent, carries out, described organic bases is preferably diisopropyl ethyl amine, diethylamine, triethylamine, pyridine, TERTIARY BUTYL AMINE, cyclopropylamine, Di-n-Butyl Amine, Diisopropylamine or 1,2-dimethyl propylamine is more preferably diisopropyl ethyl amine; It is solvent conventional in this area that second step reacts solvent used, is preferably acetonitrile, DMF, dimethyl sulfoxide (DMSO) (DMSO) or butanone and composition thereof;

The inventive method also preferably includes the step that makes product and corresponding acid-respons generate pharmacy acceptable salt.Wherein acid used can be hydrochloric acid, bromine hydracid, sulfuric acid, methylsulfonic acid, trifluoracetic acid, tartrate, oxysuccinic acid, succsinic acid, toxilic acid, citric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, fumaric acid, oxaloacetic acid, ethyl sulfonic acid, oxalic acid, Phenylsulfonic acid or isethionic acid, be more preferably hydrochloric acid, bromine hydracid, sulfuric acid or methylsulfonic acid, be most preferably hydrochloric acid.Described salify step is preferably carried out in solvent, solvent for use can be methyl alcohol, ethanol, propyl alcohol, methyl acetate, ethyl acetate, acetone, methyl ethyl ketone, methyl isopropyl Ketone, methyl iso-butyl ketone (MIBK), acetonitrile, propionitrile, dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, dimethyl sulfoxide (DMSO) or tetramethylene sulfone etc., ethyl acetate and/or ethanol.

Each embodiment that the application addresses, or other scheme of different priority except as otherwise noted all can arbitrary combination.

Compound of the present invention can adopt following method to synthesize:

Synthetic route 1:

Wherein, R ₁, R ₂, A, B, n be as definition above; M represents its pharmaceutically useful salt, for example HCl, HBr, H ₂sO ₄, CH ₃sO ₃h etc.

To replace benzo penta azacyclo as raw material, in aqueous sodium hydroxide solution, carry out condensation reaction with chloro alkyl bromide, preparation N-chlorine alkyl-benzo five-membered heterogeneous ring compound, again with the condensation reaction of 4-substituted piperidine, compound shown in preparation formula (I), optionally, prepares corresponding salt finally by acidifying salify.Adopt aforesaid method can prepare Compound I-1～I-9, I-12～I-23, I-26～I-34 and salt thereof.

Synthetic route 2:

Taking replace benzo five-membered nitrogen heterocyclic-1 alcohol as raw material, obtain corresponding sodium salt with sodium hydride exchange reactive hydrogen, obtain corresponding muriate with chloro alkyl bromine reaction again, again with the condensation reaction of 4-substituted piperidine, compound shown in preparation formula (I), finally optionally prepares corresponding salt through acidifying salify.Adopt aforesaid method can prepare Compound I-10～I-11, I-24～I-25 and salt thereof.

The preparation of synthetic logical method one: N-(3-chloropropyl)-replacement benzo penta azacyclo compound

1H-is replaced to benzo penta azacyclo (0.10mol) and be dissolved in 30 % by weight aqueous sodium hydroxide solution 100ml, add 3-chlorobromopropane (31.4g, 0.10mol), Tetrabutyl amonium bromide 0.8g, mix and blend 5 minutes.Reaction solution is slowly warming up to 60 DEG C, stirring reaction 2 hours.Be cooled to room temperature, add 100ml dichloromethane extraction, separatory, water adds methylene dichloride 100ml extraction, merges organic phase, through the washing of 100ml saturated brine, separatory, evaporate to dryness organic phase obtains oily matter.Oily matter is through neutral Al ₂o ₃chromatography or preparation HPLC separation and purification, obtain N-(3-chloropropyl)-replacement benzo penta azacyclo compound, yield 30.0～85.0%.

The preparation of synthetic logical method two: N-(3-(replacing benzo penta azacyclo) propyl group)-4-substituted piperidine

N-(3-chloropropyl)-replacement benzo penta azacyclo compound (0.06mol) is dissolved in 150ml acetonitrile, add respectively 4-substituted piperidine (0.05mol), diisopropyl ethyl amine (0.2mol), and potassiumiodide (0.05mol), stirring at room temperature 10 minutes, then temperature rising reflux reaction 10～20 hours.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al ₂o ₃chromatographic separation purifying, methylene chloride/methanol mixed solvent wash-out, obtains formula (I) compound, yield 65.0～72.0%.

The preparation of synthetic logical method three: N-(2-chloroethoxy)-replacement benzo penta azacyclo compound

To replace N-hydroxy benzo penta azacyclo compound (0.01mol) and be dissolved in 10ml NMP, add the solid paraffin mixture of 50 % by weight sodium hydrogen (0.01mol), stirring reaction 0.5h in batches.Meanwhile, by 3-chlorobromopropane (0.015mol), be dissolved in 5mlNMP, add in above-mentioned solution stirring reaction 12h under room temperature.Reaction solution is poured in 50ml water, and ethyl acetate extraction (3 × 50mL), merges organic phase, through 30ml water washing, adds anhydrous magnesium sulfate drying organic phase, filter, and solvent evaporated, oily matter is through neutral Al ₂o ₃chromatography or preparation HPLC separation and purification, obtain 1-(2-chloroethoxy)-replacement benzo penta azacyclo compound, yield 75.0～85.0%.

Embodiment 1

The preparation of N-(4-(1H-benzoglyoxaline-1-yl) butyl)-4-(3-chloro-phenyl-) piperidines (I-1)

1H-benzoglyoxaline (11.8g, 0.10mol) is dissolved in 20 % by weight aqueous sodium hydroxide solution 200ml, adds 4-chlorine n-butyl bromide (34.3g, 0.20mol), Tetrabutyl amonium bromide 1.0g, mix and blend 5 minutes, is warming up to 60 DEG C, stirring reaction 2 hours.Be cooled to room temperature, add 100ml dichloromethane extraction, separatory, water adds methylene dichloride 100ml extraction, merges organic phase, through the washing of 100ml saturated brine, separatory, evaporate to dryness organic phase obtains oily matter.Oily matter is through neutral Al ₂o ₃chromatographic separation purifying, obtains 1-(4-chlorobutyl)-1H-benzoglyoxaline 12.5g, yield 60.0%.

By 1-(4-chlorobutyl)-1H-benzoglyoxaline (7.51g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 3-chloro-phenyl-piperidines (5.9g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and potassiumiodide (5.0g, 0.03mol), stirring at room temperature 10 minutes, then temperature rising reflux reaction 15 hours.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al ₂o ₃chromatographic separation purifying, methylene chloride/methanol mixed solvent wash-out, obtains compound (I-1) 7.3g, yield 66.4%.ESI-MS[M+H] ⁺：m/z?368.2。

Embodiment 2

The preparation of N-(4-(1H-benzotriazole-1-yl) butyl)-4-(3-chloro-phenyl-) piperidines (I-2)

Benzotriazole (11.9g, 0.10mol) is dissolved in 30 % by weight aqueous sodium hydroxide solution 100ml, adds 4-chlorine n-butyl bromide (34.3g, 0.20mol), Tetrabutyl amonium bromide 0.8g, mix and blend 5 minutes.Reaction solution is slowly warming up to 60 DEG C, stirring reaction 2 hours.Be cooled to room temperature, add 100ml dichloromethane extraction, separatory, water adds methylene dichloride 100ml extraction again, merges organic phase, through the water washing of 100ml saturated common salt, separatory, evaporate to dryness organic phase obtains oily matter.Oily matter is through neutral Al ₂o ₃chromatographic separation purifying, methylene dichloride wash-out obtains 1-(4-chlorobutyl)-1H-benzotriazole 17.0g, yield 81.0%.

By 1-(4-chlorobutyl)-1H-benzotriazole (7.55g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 3-chloro-phenyl-piperidines (5.9g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and potassiumiodide (5.0g, 0.03mol), be uniformly mixed rear temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al ₂o ₃chromatographic separation purifying, methylene dichloride wash-out, obtains compound (I-2) 7.8g, yield 70.3%.ESI-MS[M+H] ⁺：m/z?369.2。

Compound (I-2) (5.55g, 0.015mol) is dissolved in 50ml ethyl acetate.Under ice-water bath cooling conditions, drip hydrogenchloride/ethyl acetate solution of concentration 3mol/L, to reaction soln pH=2, stir 10min, filter, dry, obtain compound (II-2) solid 5.4g, yield 88.0%.

Embodiment 3

The preparation of N-(4-(1H-benzoglyoxaline-1-yl) butyl)-4-(3-trifluoromethyl) piperidines (I-3)

Adopt the method in embodiment 1 to prepare 1-(4-chlorobutyl)-1H-benzoglyoxaline.

1-(4-chlorobutyl)-1H-benzoglyoxaline (0.06mol) is dissolved in 150ml acetonitrile, add respectively 4-(3-trifluoromethyl) piperidines (0.05mol), diisopropyl ethyl amine (0.2mol), and potassiumiodide (0.05mol), mix and blend 10 minutes under room temperature, then temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al ₂o ₃chromatographic separation purifying, methylene chloride/methanol mixed solvent wash-out, obtains N-(4-(1H-benzoglyoxaline-1-yl) butyl)-4-(3-trifluoromethyl) piperidines (I-3) 11.0g, yield 64.9%.ESI-MS[M+H] ⁺：m/z?402.2。

Compound (I-3) (6.02g, 0.015mol) is dissolved in 50ml ethyl acetate.Under ice-water bath cooling conditions, drip hydrogenchloride/ethyl acetate solution of concentration 3mol/L, to reaction soln pH=2, stir 10min, filter, dry, obtain compound (II-3) solid 5.4g, yield 89.0%.

Embodiment 4

The preparation of N-(4-(1H-benzotriazole-1-yl) butyl)-4-(3-trifluoromethyl) piperidines (I-4)

Adopt the method in embodiment 2 to prepare 1-(4-chlorobutyl)-1H-benzotriazole.

1-(4-chlorobutyl)-1H-benzotriazole (0.06mol) is dissolved in 150ml acetonitrile, add respectively 4-(3-trifluoromethyl) piperidines (0.05mol), diisopropyl ethyl amine (25.8g, 0.2mol), and potassiumiodide (0.05mol), mix and blend 10 minutes under room temperature, then temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al ₂o ₃chromatographic separation purifying, methylene chloride/methanol mixed solvent wash-out, obtains N-(4-(1H-benzotriazole-1-yl) butyl)-4-(3-trifluoromethyl) piperidines (I-4) 13.6g, yield 67.8%.ESI-MS[M+H] ⁺：m/z?403.2。

Embodiment 5

The preparation of N-(4-(1H-benzoglyoxaline-1-yl) butyl)-4-(3-fluorophenyl) piperidines (I-5)

By 1-(4-chlorobutyl)-1H-benzoglyoxaline (7.51g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 3-fluorophenyl piperidines (5.9g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and potassiumiodide (5.0g, 0.03mol), stirring at room temperature 10 minutes, then temperature rising reflux reaction 15 hours.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al ₂o ₃chromatographic separation purifying, methylene chloride/methanol mixed solvent wash-out, obtains compound (I-5) 7.1g, yield 67.2%.ESI-MS[M+H] ⁺：m/z?352.2。

Embodiment 6

The preparation of N-(4-(1H-benzoglyoxaline-1-yl) butyl)-4-(2-p-methoxy-phenyl) piperidines (I-6)

By 1-(4-chlorobutyl)-1H-benzoglyoxaline (7.51g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 2-anisole phenylpiperidines (5.7g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and potassiumiodide (5.0g, 0.03mol), stirring at room temperature 10 minutes, then temperature rising reflux reaction 15 hours.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al ₂o ₃chromatographic separation purifying, methylene chloride/methanol mixed solvent wash-out, obtains compound (I-6) 6.7g, yield 61.3%.ESI-MS[M+H] ⁺：m/z?364.2。

Embodiment 7

The preparation of N-(4-(the fluoro-1H-benzotriazole-1-of 6-yl) butyl)-4-(3-trifluoromethyl) piperidines (I-7)

Fluoro-6-benzotriazole (15.3g, 0.10mol) is dissolved in 30 % by weight aqueous sodium hydroxide solution 100ml, adds 4-chlorine n-butyl bromide (34.3g, 0.20mol), Tetrabutyl amonium bromide 0.8g, mix and blend 5 minutes.Reaction solution is slowly warming up to 60 DEG C, stirring reaction 2 hours.Be cooled to room temperature, add 100ml dichloromethane extraction, separatory, water adds methylene dichloride 100ml extraction again, merges organic phase, through the water washing of 100ml saturated common salt, separatory, evaporate to dryness organic phase obtains oily matter.Oily matter is through neutral Al ₂o ₃chromatographic separation purifying, methylene dichloride wash-out obtains the fluoro-1-of 6-(4-chlorobutyl)-1H-benzotriazole 17.0g, yield 77.0%.

Fluoro-6-1-(4-chlorobutyl)-1H-benzotriazole (0.06mol) is dissolved in 150ml acetonitrile, add respectively 4-(3-trifluoromethyl) piperidines (0.05mol), diisopropyl ethyl amine (0.2mol), and potassiumiodide (0.05mol), mix and blend 10 minutes under room temperature, then temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al ₂o ₃chromatographic separation purifying, methylene chloride/methanol mixed solvent wash-out, obtains N-(4-(1H-benzotriazole-1-yl) butyl)-4-(3-trifluoromethyl) piperidines (I-7) 13.5g, yield 64.1%.ESI-MS[M+H] ⁺：m/z?421.2。

Embodiment 8

The preparation of N-(4-(6-methoxyl group-1H-benzotriazole-1-yl) butyl)-4-(3-trifluoromethyl) piperidines (I-8)

6-methoxyl group-benzotriazole (14.9g, 0.10mol) is dissolved in 30 % by weight aqueous sodium hydroxide solution 100ml, adds 4-chlorine n-butyl bromide (34.3g, 0.20mol), Tetrabutyl amonium bromide 0.8g, mix and blend 5 minutes.Reaction solution is slowly warming up to 60 DEG C, stirring reaction 2 hours.Be cooled to room temperature, add 100ml dichloromethane extraction, separatory, water adds methylene dichloride 100ml extraction again, merges organic phase, through the water washing of 100ml saturated common salt, separatory, evaporate to dryness organic phase obtains oily matter.Oily matter is through neutral Al ₂o ₃chromatographic separation purifying, methylene dichloride wash-out obtains 6-methoxyl group-1-(4-chlorobutyl)-1H-benzotriazole 17.9g, yield 75.0%.

6-methoxyl group-1-(4-chlorobutyl)-1H-benzotriazole (0.06mol) is dissolved in 150ml acetonitrile, add respectively 4-(3-trifluoromethyl) piperidines (0.05mol), diisopropyl ethyl amine (0.2mol), and potassiumiodide (0.05mol), mix and blend 10 minutes under room temperature, then temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al ₂o ₃chromatographic separation purifying, methylene chloride/methanol mixed solvent wash-out, obtains N-(4-(1H-benzotriazole-1-yl) butyl)-4-(3-trifluoromethyl) piperidines (I-8) 14.0g, yield 64.6%.ESI-MS[M+H] ⁺：m/z?433.2。

Embodiment 9

The preparation of N-(4-(6-cyano group-1H-benzotriazole-1-yl) butyl)-4-(3-trifluoromethyl) piperidines (I-9)

6-cyano group-benzotriazole (14.4g, 0.10mol) is dissolved in 30 % by weight aqueous sodium hydroxide solution 100ml, adds 4-chlorine n-butyl bromide (34.3g, 0.20mol), Tetrabutyl amonium bromide 0.8g, mix and blend 5 minutes.Reaction solution is slowly warming up to 60 DEG C, stirring reaction 2 hours.Be cooled to room temperature, add 100ml dichloromethane extraction, separatory, water adds methylene dichloride 100ml extraction again, merges organic phase, through the water washing of 100ml saturated common salt, separatory, evaporate to dryness organic phase obtains oily matter.Oily matter is through neutral Al ₂o ₃chromatographic separation purifying, methylene dichloride wash-out obtains 6-cyano group-1-(4-chlorobutyl)-1H-benzotriazole 17.3g, yield 74.0%.

6-cyano group-1-(4-chlorobutyl)-1H-benzotriazole (0.06mol) is dissolved in 150ml acetonitrile, add respectively 4-(3-trifluoromethyl) piperidines (0.05mol), diisopropyl ethyl amine (0.2mol), and potassiumiodide (0.05mol), mix and blend 10 minutes under room temperature, then temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al ₂o ₃chromatographic separation purifying, methylene chloride/methanol mixed solvent wash-out, obtains N-(4-(1H-benzotriazole-1-yl) butyl)-4-(3-trifluoromethyl) piperidines (I-9) 13.5g, yield 63.1%.ESI-MS[M+H] ⁺：m/z?427.2。

Embodiment 10

The preparation of N-(4-(1H-benzotriazole-1-yl) propoxy-)-4-(3-trifluoromethyl) piperidines (I-10)

The preparation of N-(2-chlorine propoxy-)-benzotriazole

1-hydroxy benzo triazole (0.01mol) is dissolved in 10ml NMP, adds the solid paraffin mixture of the sodium hydrogen (0.01mol) of 50% weight ratio, stirring reaction 0.5h in batches.Meanwhile, by 3-chlorobromopropane (0.015mol), be dissolved in 5mlNMP, add in above-mentioned solution stirring reaction 12h under room temperature.Reaction solution is poured in 50ml water, and ethyl acetate extraction (3 × 50mL), merges organic phase, through 30ml water washing, adds anhydrous magnesium sulfate drying organic phase, filter, and solvent evaporated, oily matter is through neutral Al ₂o ₃chromatography or preparation HPLC separation and purification, obtain 1-(3-chlorine propoxy-) benzotriazole, yield 75.0～85.0%.

1-(3-chlorine propoxy-) benzotriazole (0.06mol) is dissolved in 150ml acetonitrile, add respectively 4-(3-(the fluoro-benzoisoxazole base of 6-)) piperidines (0.05mol), diisopropyl ethyl amine (0.2mol), and potassiumiodide (0.05mol), mix and blend 10 minutes under room temperature, then temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al ₂o ₃chromatographic separation purifying, methylene chloride/methanol mixed solvent wash-out, obtains N-(4-(1H-benzotriazole-1-yl) propoxy-)-4-(3-trifluoromethyl) piperidines (I-10) 13.2g, yield 65.3%.ESI-MS[M+H] ⁺：m/z?405.2。

Embodiment 11

The preparation of N-(4-(1H-benzoglyoxaline-1-yl) propoxy-)-4-(3-trifluoromethyl) piperidines (I-11)

The preparation of N-(2-chlorine propoxy-)-benzoglyoxaline

1-hydroxy benzo imidazoles (0.01mol) is dissolved in 10ml NMP, adds the solid paraffin mixture of the sodium hydrogen (0.01mol) of 50% weight ratio, stirring reaction 0.5h in batches.Meanwhile, by 3-chlorobromopropane (0.015mol), be dissolved in 5mlNMP, add in above-mentioned solution stirring reaction 12h under room temperature.Reaction solution is poured in 50ml water, and ethyl acetate extraction (3 × 50mL), merges organic phase, through 30ml water washing, adds anhydrous magnesium sulfate drying organic phase, filter, and solvent evaporated, oily matter is through neutral Al ₂o ₃chromatography or preparation HPLC separation and purification, obtain 1-(3-chlorine propoxy-) benzoglyoxaline, yield 75.0%.

1-(3-chlorine propoxy-) benzoglyoxaline (0.06mol) is dissolved in 150ml acetonitrile, add respectively 4-(3-(6-fluorobenzene Bing isoxazolyl)) piperidines (0.05mol), diisopropyl ethyl amine (0.2mol), and potassiumiodide (0.05mol), mix and blend 10 minutes under room temperature, then temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al ₂o ₃chromatographic separation purifying, methylene chloride/methanol mixed solvent wash-out, obtains N-(4-(1H-benzoglyoxaline-1-yl) propoxy-)-4-(3-trifluoromethyl) piperidines (I-11) 13.6g, yield 67.1%.ESI-MS[M+H] ⁺：m/z?404.2。

Embodiment 12

The preparation of N-(3-(1H-benzotriazole-1-yl) propyl group)-4-(3-(6-methyl benzoisoxazole)) piperidines (I-12)

By 1-(3-chloropropyl)-1H-benzotriazole (11.7g, 0.06mol) be dissolved in 150ml acetonitrile, add 6-methyl-3-(piperidin-4-yl) benzoisoxazole (10.8g, 0.05mol), diisopropyl ethyl amine (25.8g, 0.2mol) and potassiumiodide (8.3g, 0.05mol), mix and blend 10 minutes under room temperature, then temperature rising reflux reaction 15h.Carry out post-processing operation by synthetic logical method two, obtain (I-12) 12.4g, yield 66.1%.ESI-MS[M+H] ⁺：m/z?376.2。

Embodiment 13

The preparation of N-(3-(1H-benzotriazole-1-yl) propyl group)-4-(3-(6-methoxyl group benzo isoxazole)) piperidines (I-13)

By 1-(3-chloropropyl)-1H-benzotriazole (11.7g, 0.06mol) be dissolved in 150ml acetonitrile, add 6-methoxyl group-3-(piperidin-4-yl) benzoisoxazole (11.6g, 0.05mol), diisopropyl ethyl amine (25.8g, 0.2mol) and potassiumiodide (8.3g, 0.05mol), mix and blend 10 minutes under room temperature, then temperature rising reflux reaction 15h.Carry out post-processing operation by synthetic logical method two, obtain (I-13) 13.3g, yield 67.7%.ESI-MS[M+H] ⁺：m/z?392.2。

Embodiment 14

The preparation of N-(3-(the fluoro-1H-benzotriazole-1-of 6-yl) propyl group)-4-(3-(6-fluorine benzoisoxazole)) piperidines (I-14)

The preparation of the fluoro-1H-benzotriazole of 1-(3-chloropropyl)-6-

Fluoro-6-1H-benzotriazole (13.7g, 0.10mol) is dissolved in 100ml 30 % by weight aqueous sodium hydroxide solutions, adds 3-chlorobromopropane (31.4g, 0.10mol), Tetrabutyl amonium bromide 0.8g, mix and blend 5 minutes.Reaction solution is slowly warming up to 60 DEG C, stirring reaction 2 hours.Carry out post-processing operation by synthetic logical method one, through preparation HPLC separation and purification, obtain the fluoro-1H-benzotriazole of 1-(3-chloropropyl)-6-6.9g, yield 32.3%.

The preparation of N-(3-(the fluoro-1H-benzotriazole-1-of 6-yl) propyl group)-4-(3-(6-fluorine benzoisoxazole)) piperidines (I-5)

By the fluoro-1H-benzotriazole of 1-(3-chloropropyl)-6-(6.41g, 0.03mol) be dissolved in 150ml acetonitrile, the fluoro-3-of 6-(piperidin-4-yl) benzoisoxazole (5.5g, 0.025mol), diisopropyl ethyl amine (12.9g, 0.1mol), and potassiumiodide (4.15g, 0.025mol), mix and blend 10 minutes under room temperature, then temperature rising reflux reaction 16h.Carry out post-processing operation by synthetic logical method two, obtain (I-14) 8.3g, yield 69.6%.ESI-MS[M+H] ⁺：m/z?398.2。

Embodiment 15

The preparation of N-(3-(the chloro-1H-benzotriazole-1-of 6-yl) propyl group)-4-(3-(6-fluorine benzoisoxazole)) piperidines (I-15)

The preparation of the chloro-1H-benzotriazole of 1-(3-chloropropyl)-6-

Chloro-6-1H-benzotriazole (15.4g, 0.10mol) is dissolved in 30 % by weight aqueous sodium hydroxide solution 100ml, adds 3-chlorobromopropane (31.4g, 0.10mol), Tetrabutyl amonium bromide 0.8g, mix and blend 5 minutes.Reaction solution is slowly warming up to 60 DEG C, stirring reaction 2 hours.Carry out post-processing operation by synthetic logical method one, through preparation HPLC separation and purification, obtain the chloro-1H-benzotriazole of 1-(3-chloropropyl)-6-7.3g, yield 31.7%.

N-(3-(the chloro-1H-benzotriazole-1-of 6-yl) propyl group)-4-(3-(6-fluorine benzoisoxazole)) piperidines (I-6)) preparation

By the chloro-1H-benzotriazole of 1-(3-chloropropyl)-6-(6.90g, 0.03mol) be dissolved in 150ml acetonitrile, the fluoro-3-of 6-(piperidin-4-yl) benzoisoxazole (5.5g, 0.025mol), diisopropyl ethyl amine (12.9g, 0.1mol), and potassiumiodide (4.15g, 0.025mol), mix and blend 10 minutes under room temperature, then temperature rising reflux reaction 16h.Carry out post-processing operation by synthetic logical method two, obtain (I-15) 8.1g, yield 65.2%.ESI-MS[M+H] ⁺：m/z?414.1。

Embodiment 16

The preparation of N-(3-(6-methyl isophthalic acid H-benzotriazole-1-yl) propyl group)-4-(3-(6-fluorine benzoisoxazole)) piperidines (I-16)

The preparation of 1-(3-chloropropyl)-6-methyl isophthalic acid H-benzotriazole

6-methyl isophthalic acid H-benzotriazole (13.3g, 0.10mol) is dissolved in 30 % by weight aqueous sodium hydroxide solution 100ml, adds 3-chlorobromopropane (31.4g, 0.10mol), Tetrabutyl amonium bromide 0.8g, mix and blend 5 minutes.Reaction solution is slowly warming up to 60 DEG C, stirring reaction 2 hours.Carry out post-processing operation by synthetic logical method one, through preparation HPLC separation and purification, obtain 1-(3-chloropropyl)-6-methyl isophthalic acid H-benzotriazole 7.2g, yield 34.3%.

The preparation of N-(3-(6-methyl isophthalic acid H-benzotriazole-1-yl) propyl group)-4-(3-(6-fluorine benzoisoxazole)) piperidines (I-7)

By 1-(3-chloropropyl)-6-methyl isophthalic acid H-benzotriazole (6.29g, 0.03mol) be dissolved in 150ml acetonitrile, the fluoro-3-of 6-(piperidin-4-yl) benzoisoxazole (5.5g, 0.025mol), diisopropyl ethyl amine (12.9g, 0.1mol) and potassiumiodide (4.15g, 0.025mol), mix and blend 10 minutes under room temperature, then temperature rising reflux reaction 16h.Carry out post-processing operation by synthetic logical method two, obtain (I-16) 8.5g, yield 71.9%.ESI-MS[M+H] ⁺：m/z?394.2。

Embodiment 17

The preparation of N-(3-(6-methoxyl group-1H-benzotriazole-1-yl) propyl group)-4-(3-(6-fluorine benzoisoxazole)) piperidines (I-17)

The preparation of N-(3-chloropropyl)-6-methoxyl group benzo triazole

6-methoxyl group-1H-benzotriazole (14.9g, 0.10mol) is dissolved in 30 % by weight aqueous sodium hydroxide solution 100ml, adds 3-chlorobromopropane (31.4g, 0.10mol), Tetrabutyl amonium bromide 0.8g, mix and blend 5 minutes.Reaction solution is slowly warming up to 60 DEG C, stirring reaction 2 hours.Carry out post-processing operation by synthetic logical method one, through preparation HPLC separation and purification, obtain N-(3-chloropropyl)-6-methoxyl group benzo triazole 7.7g, yield 34.1%.

The preparation of N-(3-(6-methoxyl group-1H-benzotriazole-1-yl) propyl group)-4-(3-(6-fluorine benzoisoxazole)) piperidines (I-8)

By 1-(3-chloropropyl)-6-methoxyl group-1H-benzotriazole (6.77g, 0.03mol) be dissolved in 150ml acetonitrile, the fluoro-3-of 6-(piperidin-4-yl) benzoisoxazole (5.5g, 0.025mol), diisopropyl ethyl amine (12.9g, 0.1mol) and potassiumiodide (4.15g, 0.025mol), mix and blend 10 minutes under room temperature, then temperature rising reflux reaction 16h.Carry out post-processing operation by synthetic logical method two, obtain (I-17) 8.6g, yield 70%.ESI-MS[M+H] ⁺：m/z?410.2。

Embodiment 18

The preparation of N-(3-(6-formyl radical-1H-benzotriazole-1-yl) propyl group)-4-(3-(6-fluorine benzoisoxazole)) piperidines (I-18)

The preparation of 1-(3-chloropropyl)-6-formyl radical-1H-benzotriazole

6-formyl radical-1H-benzotriazole (16.2g, 0.10mol) is dissolved in 100ml 30 % by weight aqueous sodium hydroxide solutions, adds 3-chlorobromopropane (31.4g, 0.10mol), Tetrabutyl amonium bromide 0.8g, mix and blend 5 minutes.Reaction solution is slowly warming up to 60 DEG C, stirring reaction 2 hours.Carry out post-processing operation by synthetic logical method one, through preparation HPLC separation and purification, obtain 1-(3-chloropropyl)-6-formyl radical-1H-benzotriazole 7.9g, yield 33.2%.

By 1-(3-chloropropyl)-6-formyl radical-1H-benzotriazole (7.13g; 0.03mol) be dissolved in 150ml acetonitrile; the fluoro-3-of 6-(piperidin-4-yl) benzoisoxazole (5.5g; 0.025mol), diisopropyl ethyl amine (12.9g; 0.1mol) and potassiumiodide (4.15g; 0.025mol), mix and blend 10 minutes under room temperature, then temperature rising reflux reaction 15h.Carry out post-processing operation by synthetic logical method two, obtain (I-18) 7.5g, yield 73.6%.ESI-MS[M+H] ⁺：m/z?408.2。

Embodiment 19

The preparation of N-(3-(6-methoxyl group benzo triazol radical) propyl group)-4-(3-benzoisoxazole) piperidines (I-19)

Adopt the method in embodiment 17 to prepare N-(3-chloropropyl)-6-methoxyl group benzo triazole.

N-(3-chloropropyl)-6-methoxyl group benzo triazole (0.06mol) is dissolved in 150ml acetonitrile, add respectively 4-(3-benzoisoxazole) piperidines (0.05mol), diisopropyl ethyl amine (0.2mol), and potassiumiodide (0.05mol), mix and blend 10 minutes under room temperature, then temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al ₂o ₃chromatographic separation purifying, methylene chloride/methanol mixed solvent wash-out, obtains N-(3-(6-methoxyl group benzo triazol radical) propyl group)-4-(3-benzoisoxazole) piperidines (I-19) 13.14g, yield 67.2%.ESI-MS[M+H] ⁺：m/z?391.2。

Embodiment 20

The preparation of N-(2-(1-benzotriazole base) ethyl)-4-(3-(6-fluorine benzoisoxazole)) piperidines (I-20)

Benzotriazole (11.9g, 0.10mol) is dissolved in 100ml 30 % by weight aqueous sodium hydroxide solutions, adds 3-chlorobromopropane (31.4g, 0.10mol), Tetrabutyl amonium bromide 0.8g, mix and blend 5 minutes.Reaction solution is slowly warming up to 60 DEG C, stirring reaction 2 hours.Be cooled to room temperature, add 100ml dichloromethane extraction, separatory, water adds 100ml dichloromethane extraction again, merges organic phase, through the water washing of 100ml saturated common salt, separatory, evaporate to dryness organic phase obtains oily matter.Oily matter is through column chromatography (neutral Al ₂o ₃) separation and purification, methylene dichloride wash-out separates, and obtains 1-(3-chloropropyl)-1H-benzotriazole 16.0g, yield 82.0%.

1-(3-chloropropyl)-1H-benzotriazole (0.06mol) is dissolved in 150ml acetonitrile, add respectively 4-(3-(6-fluorine benzoisoxazole)) piperidines (0.05mol), diisopropyl ethyl amine (0.2mol), and potassiumiodide (0.05mol), mix and blend 10 minutes under room temperature, then temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al ₂o ₃chromatographic separation purifying, methylene chloride/methanol mixed solvent wash-out, obtain N-(2-(1-benzotriazole base) ethyl)-4-(3-(6-fluorine benzoisoxazole)) piperidines (I-20) 12.67g, yield 69.4%.ESI-MS[M+H] ⁺：m/z?365.2。

Embodiment 21

The preparation of N-(4-(1-benzotriazole base) butyl)-4-(3-(6-fluorine benzoisoxazole)) piperidines (I-21)

Prepare 1-(4-chlorobutyl)-1H-benzotriazole with reference to the method in embodiment 2.

1-(4-chlorobutyl)-1H-benzotriazole (0.06mol) is dissolved in 150ml acetonitrile, add respectively 4-(3-(6-fluorine benzoisoxazole)) piperidines (0.05mol), diisopropyl ethyl amine (0.2mol), and potassiumiodide (0.05mol), mix and blend 10 minutes under room temperature, then temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al ₂o ₃chromatographic separation purifying, methylene chloride/methanol mixed solvent wash-out, obtain N-(4-(1-benzotriazole base) butyl)-4-(3-(6-fluorine benzoisoxazole)) piperidines (I-21) 13.96g, yield 71.0%.ESI-MS[M+H] ⁺：m/z?393.2。

Embodiment 22

The preparation of N-(4-(6-cyano group benzotriazole base) butyl)-4-(3-(6-fluorine benzoisoxazole)) piperidines (I-22)

The preparation of 1-(3 chlorobutyl)-6-cyano group-1H-benzotriazole

6-cyano group-1H-benzotriazole (15.9g, 0.10mol) is dissolved in 30 % by weight aqueous sodium hydroxide solution 100ml, adds 3-chlorine n-butyl bromide (32.6g, 0.10mol), Tetrabutyl amonium bromide 0.8g, mix and blend 5 minutes.Reaction solution is slowly warming up to 60 DEG C, stirring reaction 2 hours.Carry out post-processing operation by synthetic logical method one, through preparation HPLC separation and purification, obtain 1-(3 chlorobutyl)-6-cyano group-1H-benzotriazole 9.1g, yield 32.6%.

1-(3-chlorobutyl)-6-cyano group benzotriazole (0.06mol) is dissolved in 150ml acetonitrile, add respectively 4-(3-(6-fluorine benzoisoxazole)) piperidines (0.05mol), diisopropyl ethyl amine (0.2mol), and potassiumiodide (0.05mol), mix and blend 10 minutes under room temperature, then temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al ₂o ₃chromatographic separation purifying, methylene chloride/methanol mixed solvent wash-out, obtain N-(4-(6-cyano group benzotriazole base) butyl)-4-(3-(6-fluorine benzoisoxazole)) piperidines (I-22) 15.07g, yield 72.1%.ESI-MS[M+H] ⁺：m/z?418.2。

Embodiment 23

The preparation of N-(4-(6-cyano group benzotriazole base) butyl)-4-(3-(6-methoxyl group benzo isoxazole)) piperidines (I-23)

Adopt the method in embodiment 22 to prepare 1-(3-chlorobutyl)-6-cyano group benzotriazole.

1-(3-chlorobutyl)-6-cyano group benzotriazole (0.06mol) is dissolved in 150ml acetonitrile, add respectively 4-(3-(6-methoxyl group benzo isoxazole)) piperidines (0.05mol), diisopropyl ethyl amine (0.2mol), and potassiumiodide (0.05mol), mix and blend 10 minutes under room temperature, then temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al ₂o ₃chromatographic separation purifying, methylene chloride/methanol mixed solvent wash-out, obtain N-(4-(6-cyano group benzotriazole base) butyl)-4-(3-(6-methoxyl group benzo isoxazole)) piperidines (I-23) 15.01g, yield 69.8%.ESI-MS[M+H] ⁺：m/z?430.2。

Embodiment 24

The preparation of N-(2-(6-methoxyl group benzo triazol radical) oxyethyl group)-4-(3-benzoisoxazole) piperidines (I-24)

Adopt the method in logical method three to prepare N-hydroxyl-6-methoxyl group benzo triazole.

Be raw material by N-hydroxyl-6-methoxyl group benzo triazole, (2-chloroethoxy-6-methoxyl group benzo triazole (0.06mol) is dissolved in 150ml acetonitrile to prepare N-by the synthetic and post-treating method in logical method one, add respectively 4-(3-benzoisoxazole base) piperidines (0.05mol), diisopropyl ethyl amine (0.2mol), and potassiumiodide (0.05mol), mix and blend 10 minutes under room temperature, then temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al ₂o ₃chromatographic separation purifying, methylene chloride/methanol mixed solvent wash-out, obtains N-(2-(6-methoxyl group benzo triazol radical) oxyethyl group)-4-(3-benzoisoxazole) piperidines (I-24) 14.21g, yield 69.1%.ESI-MS[M+H] ⁺：m/z?394.2。

Embodiment 25

The preparation of N-(2-(1-benzotriazole base) oxyethyl group)-4-(3-fluorine benzoisoxazole) piperidines (I-25)

Adopt the method in logical method three to prepare N-hydroxy benzo triazole.

Be raw material by N-hydroxy benzo triazole, (2-chloroethoxy benzotriazole (0.06mol) is dissolved in 150ml acetonitrile to prepare N-by the synthetic and post-treating method in logical method one, add respectively 4-(3-benzoisoxazole) piperidines (0.05mol), diisopropyl ethyl amine (0.2mol), and potassiumiodide (0.05mol), mix and blend 10 minutes under room temperature, then temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al ₂o ₃chromatographic separation purifying, methylene chloride/methanol mixed solvent wash-out, obtains N-(2-(1-benzotriazole base) oxyethyl group)-4-(3-fluorine benzoisoxazole) piperidines (I-25) 12.88g, yield 67.6%.ESI-MS[M+H] ⁺：m/z?364.2。

Embodiment 26

The preparation of N-(3-(6-methoxyl group benzo triazol radical) propyl group)-4-(3-(6-fluorine benzisothiazole)) piperidines (I-26)

N-(3-chloropropyl)-6-methoxyl group benzo triazole (0.06mol) is dissolved in 150ml acetonitrile, add respectively 4-(3-(6-fluorine benzisothiazole)) piperidines (0.05mol), diisopropyl ethyl amine (0.2mol), and potassiumiodide (0.05mol), mix and blend 10 minutes under room temperature, then temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al ₂o ₃chromatographic separation purifying, methylene chloride/methanol mixed solvent wash-out, obtain N-(3-(6-methoxyl group benzo triazol radical) propyl group)-4-(3-(6-fluorine benzisothiazole)) piperidines (I-26) 13.17g, yield 69.1%.ESI-MS[M+H] ⁺：m/z?426.1。

Embodiment 27

The preparation of N-(3-(6-methoxyl group benzo triazol radical) propyl group)-4-(3-(6-fluorine benzopyrazoles)) piperidines (I-27)

N-(3-chloropropyl)-6-methoxyl group benzo triazole (0.06mol) is dissolved in 150ml acetonitrile, add respectively 4-(3-(6-fluorine benzisothiazole)) (0.05mol), diisopropyl ethyl amine (0.2mol), and potassiumiodide (0.05mol), mix and blend 10 minutes under room temperature, then temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al ₂o ₃chromatographic separation purifying, methylene chloride/methanol mixed solvent wash-out, obtain N-(3-(6-methoxyl group benzo triazol radical) propyl group)-4-(3-(6-fluorine benzopyrazoles)) piperidines (I-27) 12.11g, yield 66.5%.ESI-MS[M+H] ⁺：m/z?409.2。

Embodiment 28

The preparation of N-(3-(6-methoxyl group benzo triazol radical) propyl group)-4-(3-(6-fluorine cumarone)) piperidines (I-28)

N-(3-chloropropyl)-6-methoxyl group benzo triazole (0.06mol) is dissolved in 150ml acetonitrile, add respectively 4-(3-(6-fluorine benzisothiazole)) (0.05mol), diisopropyl ethyl amine (0.2mol), and potassiumiodide (0.05mol), mix and blend 10 minutes under room temperature, then temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al ₂o ₃chromatographic separation purifying, methylene chloride/methanol mixed solvent wash-out, obtain N-(3-(6-methoxyl group benzo triazol radical) propyl group)-4-(3-(6-fluorine cumarone)) piperidines (I-28) 12.40g, yield 68.1%.ESI-MS[M+H] ⁺：m/z?409.2。

Embodiment 29

The preparation of N-(4-(1H-benzimidazolyl--1-yl) butyl)-4-(2-furyl) piperidines (I-29)

By 1-(4-chlorobutyl)-1H-benzoglyoxaline (7.51g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 4-(2-furyl) piperidines (4.6g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and potassiumiodide (5.0g, 0.03mol), stirring at room temperature 10 minutes, then temperature rising reflux reaction 20 hours.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al ₂o ₃chromatographic separation purifying, methylene chloride/methanol mixed solvent wash-out, obtains compound (I-29) 6.0g, yield 61.6%.ESI-MS[M+H] ⁺：m/z?324.2。

Embodiment 30

The preparation of N-(4-(1H-benzimidazolyl--1-yl) butyl)-4-(4-pyridyl) piperidines (I-30)

By 1-(4-chlorobutyl)-1H-benzoglyoxaline (7.51g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 4-(4-pyridyl) piperidines (4.9g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and potassiumiodide (5.0g, 0.03mol), stirring at room temperature 10 minutes, then temperature rising reflux reaction 20 hours.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al ₂o ₃chromatographic separation purifying, methylene chloride/methanol mixed solvent wash-out, obtains compound (I-30) 6.3g, yield 62.1%.ESI-MS[M+H] ⁺：m/z?335.2。

Embodiment 31

The preparation of N-(4-(1H-benzimidazolyl--1-yl) butyl)-4-(2-pyrimidyl) piperidines (I-31)

By 1-(4-chlorobutyl)-1H-benzoglyoxaline (7.51g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 4-(2-pyrimidyl) piperidines (4.9g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and potassiumiodide (5.0g, 0.03mol), stirring at room temperature 10 minutes, then temperature rising reflux reaction 20 hours.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al ₂o ₃chromatographic separation purifying, methylene chloride/methanol mixed solvent wash-out, obtains compound (I-31) 6.1g, yield 60.1%.ESI-MS[M+H] ⁺：m/z?336.2。

Embodiment 32

The preparation of N-(4-(1H-benzotriazole-1-yl) butyl)-4-cyclohexyl piperidines (I-32)

Adopt the method in embodiment 2 to prepare 1-(4-chlorobutyl)-1H-benzotriazole.

By 1-(4-chlorobutyl)-1H-benzotriazole (7.55g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 4-(1-cyclohexyl) piperidines (5.1g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and potassiumiodide (5.0g, 0.03mol), be uniformly mixed rear temperature rising reflux reaction 20h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al ₂o ₃chromatographic separation purifying, methylene dichloride wash-out, obtains compound (I-32) 6.5g, yield 63.7%.ESI-MS[M+H] ⁺：m/z?341.3。

Embodiment 33

The preparation of N-(4-(1H-benzotriazole-1-yl) butyl)-4-(1-naphthyl) piperidines (I-33)

Adopt the method in embodiment 2 to prepare 1-(4-chlorobutyl)-1H-benzotriazole.

By 1-(4-chlorobutyl)-1H-benzotriazole (7.55g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 4-(1-naphthyl) piperidines (6.4g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and potassiumiodide (5.0g, 0.03mol), be uniformly mixed rear temperature rising reflux reaction 20h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al ₂o ₃chromatographic separation purifying, methylene dichloride wash-out, obtains compound (I-33) 6.9g, yield 60.1%.ESI-MS[M+H] ⁺：m/z?385.3。

Embodiment 34

The preparation of N-(4-(1H-benzotriazole-1-yl) butyl)-4-(2-quinoxalinyl) piperidines (I-34)

Adopt the method in embodiment 2 to prepare 1-(4-chlorobutyl)-1H-benzotriazole.

By 1-(4-chlorobutyl)-1H-benzotriazole (7.55g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 4-(2-quinoxalinyl) piperidines (6.4g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and potassiumiodide (5.0g, 0.03mol), be uniformly mixed rear temperature rising reflux reaction 20h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al ₂o ₃chromatographic separation purifying, methylene dichloride wash-out, obtains compound (I-34) 7.3g, yield 62.7%.ESI-MS[M+H] ⁺：m/z?387.2。

Embodiment 35

The diastole effect of Compound I I-1 to II-34 to rabbit myocardium vessel unstriated muscle

1. experimental animal:

Rabbit, male and female dual-purpose, body weight 2.0～3.0kg, is provided by Chinese Medical Sciences University's Experimental Animal Center.

2. medicine and reagent:

Compound I I-1 to II-34, Compound I-1 is to the hydrochloride of I-34, adopts the method preparation of embodiment, and the salt (hydrochloride) that can prepare them according to embodiment 2 (or 3) is for following test;

Sodium-chlor (NaCl): be purchased from Tianjin great Mao chemical reagent factory, lot number: 20120413;

Repone K (KCl): be purchased from Tianjin great Mao chemical reagent factory, lot number: 20111123;

Anhydrous magnesium sulfate (MgSO ₄): be purchased from Tianjin great Mao chemical reagent factory, lot number: 20101029;

Calcium Chloride Powder Anhydrous (CaCl ₂): be purchased from Tianjin great Mao chemical reagent factory, lot number: 20110314;

Sodium bicarbonate (NaHCO ₃): be purchased from Tianjin great Mao chemical reagent factory, lot number: 20120507;

Glucose (Glucose): be purchased from Tianjin great Mao chemical reagent factory, lot number: 20120512;

Potassium primary phosphate (KH ₂pO ₄): be purchased from Tianjin great Mao chemical reagent factory product, lot number: 20110928;

Sodium chloride injection (NaCl): be purchased from Zhiying Pharmaceutical Factory, Shenyang, lot number: 12021001;

Adrenalin hydrochloride injection liquid (Epinephrine Hydrochloride Injection) specification: 1mg/1ml, is purchased from Grandpharma (China) Co., Ltd., lot number 120105;

Noradrenaline bitartrate (Norepinephrine Bitartrate Injection) specification 2mg/1ml, Grandpharma (China) Co., Ltd., lot number 120304;

3. laboratory apparatus:

HSS-1 (B) type thermostatic bath: Chengdu Instruement Factory;

RM6240B type multi-path physiology signal acquiring processing system: Chengdu Instruement Factory;

JZJ01 type muscle tone transverter: Chengdu Instruement Factory;

YPJ01 type pressure transducer: Chengdu Instruement Factory;

TG-328A photoelectric analytical balance: Shanghai balance equipment factory;

T-500 type electronic balance: Changshu Shuan Jie testing tool factory;

Micropipet: Shanghai Rong Tai biochemical engineering company limited;

Electric-heated thermostatic water bath: Tianjin Stettlen Instrument Ltd..

4. the preparation of nutritive medium:

Krebs-Henseleit (K-H) physiological solution: NaCl 6.92 (concentration units), KCl 0.35, MgSO ₄0.29, KH ₂pO ₄0.16, CaCl ₂0.28, NaHCO ₃2.1, Glucose 2.0 (g/L), pH 7.2.

High potassium solution: will add KCl to be mixed with containing K after the NaCl of the mole numbers such as removal in K-H liquid ⁺the improvement K-H liquid of 60mmol/L.

Without calcium K-H liquid: by the CaCl in K-H liquid ₂remove, the KCl of mole number such as add, and add EDTA ^-2na ⁺0.1mmol/L, other components unchanged.

Without the high potassium liquid of calcium: by the CaCl in high potassium liquid ₂remove, the KCl of mole number such as add, and add EDTA ^-2na ⁺0.1mmol/L, other components unchanged.

The preparation of Compound I I-1 to II-34 solution: take certain mass Compound I I-1～II-34 sample, taking distilled water as solvent cut to series concentration (10 ^-10～10 ^-3mol/L), for subsequent use.

5. the preparation of rabbit myocardium vessel unstriated muscle sample

Rabbit, animal is hit after dizzy and cuts rapidly thoracic cavity open, separate descending aorta, (if carry out Serotonin receptor antagonistic experiment, also should use smooth stainless steel rod iron remove endotheliocyte) by reticular tissue and after fatty tissue is removed around, be cut into 3-5mm vascular circle, then steel wire hook is through vascular circle, and one end is fixed on ventilation hook, and the other end is connected on tonotransducer, be placed in the bath pipe that fills 20ml nutritive medium, record tension variation by registering instrument.Bathe 37 ± 0.5 DEG C of the interior maintenance of pipe temperature, and pass into mixed gas (95%O with the speed of 1～2 bubble per second ₂+ 5%CO ₂).Sample initial load 1.5g, every 20min changes one time of nutrition liquid, and balance 2 hours starts experiment after baseline stability.

6. concrete test operation and test-results

6.1 Compound I I-1 to II-34 shrink the diastole effect of rabbit myocardium vessel unstriated muscle to suprarenin (AD)

After sample tension stability, record one section of waveform, add adrenalin hydrochloride (AD) (10 to bathing in pipe ^-5mol/L) induction is shunk, and when reaching after maximum collapse, fully rinses sample, and every 20min changes K-H liquid one time, and balance 60min, after baseline restorer is steady, again uses same concentration to cause convulsion agent induction and shrinks.When after once shrink maximum reaction with front when once basically identical, accumulation adds the Compound I I-1～II-34 solution (1 × 10 preparing ^-10～1 × 10 ^-3mol/L), wave recording.The diastole effect of Compound I I-1 to II-34 is as shown in table 1.

Table 1 compound (II-1 to II-34) shrinks the diastole effect of rabbit myocardium vessel unstriated muscle to AD

Compound	-logEC ₅₀	Compound	-logEC ₅₀
				II-1	5.03±0.02	II-18	5.56±0.04
II-2	5.16±0.03	II-19	6.11±0.07
				II-3	6.21±0.04	II-20	5.92±0.05
II-4	6.36±0.03	II-21	5.96±0.04
				II-5	4.89±0.02	II-22	5.53±0.07
II-6	4.76±0.03	II-23	5.23±0.06
				II-7	5.31±0.04	II-24	4.03±0.05

II-8	4.86±0.03	II-25	4.26±0.04
				II-9	4.79±0.02	II-26	4.01±0.03
II-10	5.56±0.05	II-27	4.13±0.05
				II-11	5.31±0.06	II-28	4.26±0.06
II-12	5.45±0.04	II-29	4.43±0.05
				II-13	5.34±0.03	II-30	4.86±0.04
II-14	5.61±0.05	II-31	4.72±0.03
				II-15	5.42±0.04	II-32	4.39±0.05
II-16	5.38±0.03	II-33	4.22±0.06
				II-17	5.23±0.05	II-34	4.83±0.05

6.2 Compound I I-1 to II-34 shrink the diastole effect of rabbit myocardium vessel unstriated muscle to norepinephrine (NA)

After sample tension stability, record one section of waveform, add adrenalin hydrochloride (AD) (10 to bathing in pipe ^-5mol/L) induction is shunk, and when reaching after maximum collapse, fully rinses sample, and every 20min changes K-H liquid one time, and balance 60min, after baseline restorer is steady, with noradrenaline bitartrate (NA) (10 ^-5mol/L) induction is shunk.When after once shrink maximum reaction with front when once basically identical, accumulation adds Compound I I-1 to the II-34 solution 1 × 10 preparing ^-10～1 × 10 ^-3mol/L), wave recording.The diastole effect of Compound I I-1 to II-34 is as shown in table 2.

Table 2 Compound I I-1 to II-34 shrinks the diastole effect of rabbit myocardium vessel unstriated muscle to NA

Compound	-logEC ₅₀	Compound	-logEC ₅₀
				II-1	5.11±0.02	II-18	5.73±0.04
II-2	5.27±0.03	II-19	6.07±0.04
				II-3	6.32±0.04	II-20	5.81±0.03
II-4	6.45±0.03	II-21	5.73±0.04
				II-5	4.67±0.02	II-22	5.31±0.06
II-6	4.55±0.03	II-23	5.09±0.04
				II-7	5.21±0.04	II-24	4.31±0.05
II-8	4.77±0.03	II-25	4.04±0.07
				II-9	4.53±0.02	II-26	4.19±0.03
II-10	5.36±0.05	II-27	4.43±0.04
				II-11	5.15±0.06	II-28	4.06±0.06
II-12	5.26±0.04	II-29	4.23±0.03
				II-13	5.04±0.03	II-30	4.66±0.02
II-14	5.73±0.05	II-31	4.52±0.04
				II-15	5.22±0.04	II-32	4.44±0.05
II-16	5.35±0.03	II-33	4.34±0.04
				II-17	5.31±0.05	II-34	4.53±0.05

6.3 Compound I I-1 to II-34 shrink the diastole effect of rabbit myocardium vessel unstriated muscle to High potassium solution

After sample tension stability, record one section of waveform, add adrenalin hydrochloride (AD) (10 to bathing in pipe ^-5mol/L) induction is shunk, and when reaching after maximum collapse, fully rinses sample, and every 20min changes K-H liquid one time, and balance 60min, after baseline restorer is steady, changes K-H liquid in bath pipe into high potassium liquid induction and shrinks.When after once shrink maximum reaction with front when once basically identical, accumulation adds Compound I I-1 to the II-34 solution (1 × 10 preparing ^-10～1 × 10 ^-3mol/L), Compound I I-1 to II-34 diastole effect is as shown in table 3.

Table 3 Compound I I-1～II-34 shrinks the diastole effect of rabbit myocardium vessel unstriated muscle to High potassium solution

Compound	-logEC ₅₀	Compound	-logEC ₅₀
				II-1	4.69±0.02	II-18	5.32±0.04
II-2	4.82±0.03	II-19	5.11±0.03
				II-3	6.01±0.04	II-20	3.92±0.02
II-4	6.12±0.03	II-21	3.96±0.03
				II-5	4.44±0.02	II-22	3.53±0.02
II-6	4.38±0.03	II-23	4.23±0.04
				II-7	5.03±0.04	II-24	3.53±0.03
II-8	4.56±0.03	II-25	4.26±0.04
				II-9	4.23±0.02	II-26	3.31±0.03
II-10	5.22±0.05	II-27	3.63±0.04
				II-11	5.17±0.06	II-28	3.46±0.03
II-12	5.09±0.04	II-29	4.53±0.03
				II-13	5.12±0.03	II-30	4.26±0.04
II-14	5.72±0.05	II-31	4.32±0.02
				II-15	5.12±0.04	II-32	4.14±0.05
II-16	5.28±0.03	II-33	4.04±0.03
				II-17	5.02±0.05	II-34	4.13±0.04

Claims

1. the benzo five-membered Azacyclyl piperidine derivative of formula (I) or its pharmacy acceptable salt:

Wherein:

A, B independently represent respectively CH or N;

2. the compound of claim 1, wherein said pharmacy acceptable salt is hydrochloride, hydrogen bromide salt, vitriol, trifluoroacetate, mesylate, tartrate, malate, succinate, maleate, Citrate trianion, phosphoric acid salt, lactic acid salt, pyruvate salt, acetate, fumarate, oxaloacetate, esilate, oxalate, benzene sulfonate or isethionate; Preferably, described salt contains crystal water, is preferably the crystal water of 0.5-3 molecule.

3. the compound of claim 1, wherein said aromatic group is benzo five-membered heterocycle or the hexa-member heterocycle that phenyl, naphthyl, heteroatoms are selected from N, S, O, or five yuan or hexa-atomic unsaturated heterocycle; Be preferably phenyl, benzothiazolyl, benzisothiazole base, benzoxazolyl, benzoisoxazole base, benzimidazolyl-, benzopyrazoles base, benzofuryl, benzo pyrimidyl, benzo pyridyl, quinoxalinyl, furyl, pyridyl or pyrimidyl; More preferably phenyl, benzoisoxazole base, benzisothiazole base, benzopyrazoles base, benzofuryl, naphthyl, furyl, pyridyl, pyrimidyl Huo quinoxalinyl; Be particularly preferably phenyl, benzoisoxazole base; Preferably, in the time that described aromatic group is benzoisoxazole base, A is N; Or

Described aliphatics cyclic group is five yuan or hexa-atomic saturated cyclic, or heteroatoms is selected from five yuan or the hexa-atomic saturated heterocyclyl of N, S, O; Be preferably cyclopentyl, cyclohexyl, tetrahydrofuran base, piperidyl or piperazinyl; More preferably cyclohexyl, piperidyl or piperazinyl; Be particularly preferably cyclohexyl.

4. the compound of claim 1, wherein R ₃for H, F, Cl, Br, CN, moieties are optionally by the C of 1-3 halogen atom replacement ₁-C ₆alkyl or C ₁-C ₆alkoxyl group, CHO, COCH ₃or COOCH ₃; More preferably, R ₃for H, F, Cl, COCH ₃, the C that optionally replaced by 1-3 halogen atom of moieties ₁-C ₄alkyl or C ₁-C ₄alkoxyl group; Again more preferably, R ₃for H, F, Cl, CN, CF ₃, CH ₃, OCH ₃or COCH ₃; Particularly preferably, H, F, Cl, CF ₃, CH ₃or OCH ₃; Most preferably, R ₃for H or CF ₃; Work as R ₃during for polysubstituted group, R ₃independently selected from H, halogen, CN, C ₁-C ₆alkyl, C ₁-C ₆alkoxyl group, CHO, CO (C ₁-C ₆alkyl), COO (C ₁-C ₆alkyl), NO ₂, NH ₂, NH (C ₁-C ₆alkyl), SH, S (C ₁-C ₆alkyl) ,-SO (C ₁-C ₆alkyl) or-SO ₂(C ₁-C ₆alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms.

5. the compound of claim 1, wherein R ₂for H, F, Cl, Br, CN, moieties are optionally by the C of 1-3 halogen atom replacement ₁-C ₆alkyl or C ₁-C ₆alkoxyl group, CHO, COCH ₃or COOCH ₃; More preferably, R ₂for H, F, Cl, CN, CHO, COCH ₃, COOCH ₃or the C that moieties is optionally replaced by 1-3 halogen atom ₁-C ₄alkyl or C ₁-C ₄alkoxyl group; Again more preferably, R ₂for H, F, Cl, CN, CF ₃, CH ₃, OCH ₃, CHO, COCH ₃or COOCH ₃; Particularly preferably, R ₂for H, F, Cl, CN, CH ₃, OCH ₃or CHO; Most preferably, R ₂for H or OCH ₃; Work as R ₂during for polysubstituted group, R ₂independently selected from H, halogen, CN, C ₁-C ₆alkyl, C ₁-C ₆alkoxyl group, CHO, CO (C ₁-C ₆alkyl), COO (C ₁-C ₆alkyl), NO ₂, NH ₂, NH (C ₁-C ₆alkyl), SH, S (C ₁-C ₆alkyl) ,-SO (C ₁-C ₆alkyl) or-SO ₂(C ₁-C ₆alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms.

6. the compound of claim 1, wherein Y is the unsubstituted saturated hydrocarbyl containing 2-8 carbon, or wherein 1 carbon atom for example, by oxygen or the alternative unsubstituted saturated hydrocarbyl containing 2-8 carbon of sulphur ,-C _1-7alkyl-O-; Preferably Y is methylene radical, ethylidene, propylidene, butylidene, pentylidene, hexylidene, sub-heptyl, octylene, oxygen methylene, oxygen base ethylidene, oxygen base propylidene, oxygen base butylidene, oxygen base pentylidene, oxygen base hexylidene, the sub-heptyl of oxygen base, methylene radical oxygen base, ethyleneoxy group, propylidene oxygen base, butylene oxide base, pentylidene oxygen base, hexylidene oxygen base or sub-heptyl oxygen base; More preferably, Y is methylene radical, ethylidene, propylidene, butylidene, pentylidene, hexylidene, sub-heptyl, octylene, methylene radical oxygen base, ethyleneoxy group, propylidene oxygen base, butylene oxide base, pentylidene oxygen base, hexylidene oxygen base or sub-heptyl oxygen base; Again more preferably, Y is ethylidene, propylidene, butylidene, ethyleneoxy group or propylidene oxygen base; Particularly preferably, Y is ethylidene, propylidene, butylidene or propylidene oxygen base; Most preferably, Y is propylidene or butylidene.

7. the compound of claim 1, wherein

R ₁representative is by R ₃mono-substituted aromatic group, wherein

R ₃for H or CF ₃;

R ₂represent H or OCH ₃;

Y represents propylidene or butylidene.

8. the preparation method of the compound of claim 1-7:

Scheme (one)

Comprise

At the temperature of 10-150 DEG C, make compound

With compound

Then under refluxing, make itself and compound

Under the existence of organic bases in solvent reacting generating compound

Or

Scheme two

Comprise

At the temperature of 10-150 DEG C, make compound

With compound

Then under refluxing, make itself and compound

Under the existence of organic bases in solvent reacting generating compound

Wherein,

Saturated or the undersaturated straight or branched hydrocarbyl chain that contains 2-8 carbon atom that Y representative is optionally replaced by 1-3 halogen atom, the heteroatoms that wherein one or more carbon are optionally selected from oxygen, sulphur and nitrogen substitutes; Preferably, Y is the unsubstituted saturated hydrocarbyl containing 2-8 carbon, or wherein 1 carbon atom for example, by oxygen or the alternative unsubstituted saturated hydrocarbyl containing 2-8 carbon of sulphur ,-C _1-7alkylidene group-O-; More preferably Y is methylene radical, ethylidene, propylidene, butylidene, pentylidene, hexylidene, sub-heptyl, octylene, oxygen methylene, oxygen base ethylidene, oxygen base propylidene, oxygen base butylidene, oxygen base pentylidene, oxygen base hexylidene, the sub-heptyl of oxygen base, methylene radical oxygen base, ethyleneoxy group, propylidene oxygen base, butylene oxide base, pentylidene oxygen base, hexylidene oxygen base or sub-heptyl oxygen base; Again more preferably, Y is methylene radical, ethylidene, propylidene, butylidene, pentylidene, hexylidene, sub-heptyl, octylene, methylene radical oxygen base, ethyleneoxy group, propylidene oxygen base, butylene oxide base, pentylidene oxygen base, hexylidene oxygen base or sub-heptyl oxygen base; Particularly preferably, Y is ethylidene, propylidene, butylidene, ethyleneoxy group or propylidene oxygen base.

9. the optionally pharmaceutical composition together with one or more pharmaceutically acceptable vehicle or other vascular smooth muscle spasm active ingredients of a compound that comprises any one in claim 1-7 or its pharmacy acceptable salt.

10. the composition of the compound of claim 1-7 any one or its pharmacy acceptable salt or claim 9 is in the purposes of preparing in vasodilator drug, preferably in preparation prevention, alleviate or treatment experimenter and continuous vessel high pressure, purposes in the disease that vascular disease rationality is shunk or vasospasm is relevant or the medicine of illness, more preferably in preparation treatment hypertension, in heart failure, stenocardia, coronary heart disease, the cerebral ischemia diseases being caused by vasospasm, myocardial ischemia disease, shock, renal ischaemia, purposes in the poor kidney being caused by kidney vasospasm and the medicine of periperal vascular spasm, more preferably there is α receptor antagonist (particularly selectivity α in preparation one ₁receptor antagonist) and Ca ²⁺purposes in the medicine of carrier frequency channel break dual function.