CN103833730B

CN103833730B - Benzo five-membered Azacyclyl piperidine derivative, Its Preparation Method And Use

Info

Publication number: CN103833730B
Application number: CN201210486619.9A
Authority: CN
Inventors: 周延; 张丽荣; 周杰; 周欣
Original assignee: Shenyang Neptune Biotechnology 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: 2017-08-04
Anticipated expiration: 2032-11-26
Also published as: CN103833730A

Abstract

The present invention relates to a kind of benzo five-membered Azacyclyl piperidine derivative and its pharmaceutically acceptable salt, its preparation method, the pharmaceutical composition comprising the derivative and its purposes in vasodilator drug is prepared are further related toWherein R₁、R₂, Y, A, B be defined as in the description.

Description

Benzo five-membered azaheterocyclyl piperidine derivatives, process for their preparation and their use

Technical Field

The invention relates to a benzo five-membered nitrogen heterocyclic piperidine derivative, pharmaceutically acceptable salts thereof, a preparation method thereof, a pharmaceutical composition containing the derivative and application thereof in preparing vasodilation medicines.

Background

There are currently clinically available classes of vasodilating drugs, e.g., α₁Receptor blocker drugs, including prazosin, doxazosin, terazosin and the like, have obvious first dose effect or orthostatic hypotension, thereby limiting the wide application of the drugs in clinic; ca²⁺The channel blocker comprises the existing drugs of amlodipine, nifedipine, felodipine and the like, and the drugs are widely applied clinically at present, but the drugs also have the risk of inhibiting the heart.

Therefore, there is still a need to develop new vasodilating drugs to improve the efficacy, reduce drug resistance or minimize toxic side effects to meet the needs of different patients in clinical practice.

Disclosure of Invention

The invention provides a benzo five-membered azaheterocyclyl piperidine derivative of formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

R₁is represented by R₃A mono-or poly-substituted aromatic or aliphatic cyclic group, wherein

R₃Is H, halogen, CN, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, CHO, CO (C)₁-C₆Alkyl), COO (C)₁-C₆Alkyl), NO₂、NH₂、NH(C₁-C₆Alkyl), SH, S (C)₁-C₆Alkyl), -SO (C)₁-C₆Alkyl) or-SO₂(C₁-C₆Alkyl) in which the alkyl moiety is optionally substituted by one or more halogen atoms; when R is₃When it is a polysubstituent group, R₃Independently selected from H, halogen, CN, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, CHO, CO (C)₁-C₆Alkyl), COO (C)₁-C₆Alkyl), NO₂、NH₂、NH(C₁-C₆Alkyl), SH, S (C)₁-C₆Alkyl), -SO (C)₁-C₆Alkyl) or-SO₂(C₁-C₆Alkyl) in which the alkyl moiety is optionally substituted by one or more halogen atoms;

A. b independently represents CH or N;

R₂represents H, halogen, CN, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, CHO, CO (C)₁-C₆Alkyl), COO (C)₁-C₆Alkyl), NO₂、NH₂、NH(C₁-C₆Alkyl), SH, S (C)₁-C₆Alkyl), -SO (C)₁-C₆Alkyl) or-SO₂(C₁-C₆Alkyl) in which the alkyl moiety is optionally substituted by one or more halogen atoms; when R is₂When it is a polysubstituent group, R₂Independently selected from H, halogen, CN, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, CHO, CO (C)₁-C₆Alkyl), COO (C)₁-C₆Alkyl), NO₂、NH₂、NH(C₁-C₆Alkyl), SH, S (C)₁-C₆Alkyl), -SO (C)₁-C₆Alkyl) or-SO₂(C₁-C₆Alkyl) in which the alkyl moiety is optionally substituted by one or more halogen atoms;

y represents a saturated or unsaturated, linear or branched, hydrocarbyl chain containing 2 to 8 carbon atoms, optionally substituted with 1 to 3 halogen atoms, in which one or more carbons are optionally replaced by heteroatoms selected from oxygen, sulphur and nitrogen.

Detailed Description

wherein:

A. b independently represents CH or N;

Preferably, R in formula (I) according to the invention₂Is a mono-or polysubstituent group on the benzo five-membered nitrogen heterocycle, e.g. R₂Is a mono-substituted, di-substituted, tri-substituted group, etc.; r₂Is a radical attached to any carbon atom of a benzo-penta-nitrogen heterocycle, e.g. when A (or B) is C, then R₂Or may be connected thereto.

The term "aromatic group" as used herein is understood to mean C wherein at least one ring is aromatic_5-12A monocyclic hydrocarbon ring or a bicyclic hydrocarbon ring, wherein one or more carbons are optionally replaced by a heteroatom selected from oxygen, sulfur and nitrogen. Examples of aromatic groups include aryl and heteroaryl groups, such as phenyl, naphthyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzopyrazolyl, benzofuranyl, benzopyrimidinyl, benzopyridyl, quinoxalinyl, furanyl, pyridinyl, or pyrimidinyl.

The term "aliphatic cyclic group" as used herein is understood to mean C₄-₁₂Monocyclic saturated cycloalkyl or bicyclic saturated cycloalkyl wherein one or more carbons are optionally replaced by a heteroatom selected from oxygen, sulfur and nitrogen. Examples of aliphatic cyclic groups include cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuryl, piperidinyl, or piperazinyl, and the like.

The term "halogen" as used herein, unless otherwise specifically indicated, refers to fluorine, chlorine, bromine or iodine.

The term "alkyl" as used herein includes straight or branched chain alkyl groups. Said "C₁-C₆Examples of alkyl "groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl, isohexyl, and the like.

The term "alkoxy" as used herein refers to an-O-alkyl group, wherein alkyl includes straight or branched chain alkyl groups. Said "C₁-C₆Examples of alkoxy "groups include methoxy,Ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the like.

In one embodiment, the present invention provides a benzo five-membered azaheterocyclyl piperidine derivative of formula (I):

wherein:

The aromatic group is preferably phenyl, naphthyl, benzo five-membered heterocycle or six-membered heterocycle with heteroatom selected from N, S, O, or five-membered or six-membered unsaturated heterocycle; more preferably phenyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzpyrazolyl, benzofuranyl, benzopyrimidinyl, benzopyridyl, quinoxalinyl, furanyl, pyridinyl or pyrimidinyl; even more preferably phenyl, benzisoxazolyl, benzisothiazolyl, benzopyrazolyl, benzofuranyl, naphthyl, furanyl, pyridinyl, pyrimidinyl, or quinoxalinyl; particularly preferably phenyl, benzisoxazolyl; preferably, when the aromatic group is a benzisoxazolyl group, a is N;

the aliphatic cyclic group is preferably a five-membered or six-membered saturated cyclic hydrocarbon group, or a five-membered or six-membered saturated heterocyclic group with a heteroatom selected from N, S, O; more preferably cyclopentyl, cyclohexyl, tetrahydrofuryl, piperidinyl or piperazinyl; even more preferably cyclohexyl, piperidinyl or piperazinyl; particularly preferably cyclohexyl;

R₃is H, halogen, CN, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, CHO, CO (C)₁-C₆Alkyl), COO (C)₁-C₆Alkyl), NO₂、NH₂、NH(C₁-C₆Alkyl), SH, S (C)₁-C₆Alkyl), -SO (C)₁-C₆Alkyl) or-SO₂(C₁-C₆Alkyl) in which the alkyl moiety is optionally substituted by one or more halogen atoms; preferably, R₃Is H, F, Cl, Br, CN, C with alkyl moieties optionally substituted by 1-3 halogen atoms₁-C₆Alkyl or C₁-C₆Alkoxy, CHO, COCH₃Or COOCH₃(ii) a More preferably, R₃Is H, F, Cl, COCH₃C the alkyl part of which is optionally substituted by 1 to 3 halogen atoms₁-C₄Alkyl or C₁-C₄An alkoxy group; even more preferably, R₃Is H, F, Cl, CN, CF₃、CH₃、OCH₃Or COCH₃(ii) a When R is₃When it is a polysubstituent group, R₃Independently selected from the groups described above;

A. b independently represents CH or N; preferably, A, B each represent N;

R₂represents H, halogen, CN, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, CHO, CO (C)₁-C₆Alkyl), COO (C)₁-C₆Alkyl), NO₂、NH₂、NH(C₁-C₆Alkyl), SH, S (C)₁-C₆Alkyl), -SO (C)₁-C₆Alkyl) or-SO₂(C₁-C₆Alkyl) in which the alkyl moiety is optionally substituted by one or more halogen atoms; preferably, R₂Is H, F, Cl, Br, CN, C with alkyl moieties optionally substituted by 1-3 halogen atoms₁-C₆Alkyl or C₁-C₆Alkoxy, CHO, COCH₃Or COOCH₃(ii) a More preferably, R₂Is H, F, Cl, CN, CHO, COCH₃、COOCH₃Or C with alkyl moieties optionally substituted by 1 to 3 halogen atoms₁-C₄Alkyl or C₁-C₄An alkoxy group; even more preferably, R₂Is H, F, Cl, CN, CF₃、CH₃、OCH₃、CHO、COCH₃Or COOCH₃(ii) a When R is₂When it is a polysubstituent group, R₂Independently selected from the groups described above;

y represents a saturated or unsaturated, linear or branched, hydrocarbyl chain containing 2 to 8 carbon atoms, optionally substituted with 1 to 3 halogen atoms, in which one or more carbons are optionally replaced by heteroatoms selected from oxygen, sulphur and nitrogen; preferably, Y is an unsubstituted saturated hydrocarbon group containing 2 to 8 carbons, or an unsubstituted saturated hydrocarbon group containing 2 to 8 carbons in which 1 carbon atom is replaced by oxygen or sulfur, such as-C_1-7alkylene-O-; more preferably Y is methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, oxymethylene, oxyethylene, oxypropylene, oxybutylene, oxypentylene, oxyhexylene, oxyheptylene, methyleneoxy, ethyleneoxy, propyleneoxy, butyleneoxy, pentylene-oxy, hexylene-oxy or heptyleneoxy; even more preferably, Y is methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, methyleneoxy, ethyleneoxy, propyleneoxy, butyleneoxy, pentylene-oxy, hexylene-oxy, or heptyleneoxy; particularly preferred is ethylene, propylene, butylene, ethyleneoxy or propyleneoxy.

In another embodiment, the present invention provides a benzo five-membered azaheterocyclyl piperidine derivative of formula (I):

wherein:

R₁is represented by R₃A monosubstituted aromatic radical, wherein

The aromatic group is preferably phenyl or benzisoxazolyl; preferably, when the aromatic group is a benzisoxazolyl group, a is N;

R₃is H, F, Cl, CF₃、CH₃Or OCH₃；

A. B independently represents CH or N; preferably, A, B each represent N;

R₂represents H, F, Cl, CN, CH₃、OCH₃Or CHO;

y represents ethylene, propylene, butylene or propyleneoxy.

In yet another embodiment, the present invention provides a benzo five-membered azaheterocyclyl piperidine derivative of formula (I):

wherein:

R₁is represented by R₃A monosubstituted aromatic radical, wherein

R₃is H or CF₃；

A. B independently represents CH or N; preferably, A, B each represent N;

R₂represents H or OCH₃；

Y represents propylene or butylene.

wherein: when the A, B are all N, then,

R₁a benzisoxazolyl group which is not 6-fluoro substituted;

R₂is not H or Cl; and is

Y is not ethyleneoxy or propyleneoxy.

wherein: when the A, B are all C, the device will,

R₁a benzisoxazolyl group which is not 6-fluoro substituted;

R₂not being H, F, CN, COOCH₃Or Cl; and is

Y is not ethylene, propylene, butylene, pentylene, ethyleneoxy, or propyleneoxy.

wherein: when only one of A, B is C, the other is N,

R₁a benzisoxazolyl group which is not 6-fluoro substituted;

R₂is not H, F or CN; and is

Y is not propylene or butylene.

The benzo five-membered nitrogen heterocyclic piperidine compound comprises:

I-1N- (4- (1H-benzimidazol-1-yl) butyl) -4- (3-chlorophenyl) piperidine,

I-2N- (4- (1H-benzotriazole-1-yl) butyl) -4- (3-chlorphenyl) piperidine,

I-3N- (4- (1H-benzimidazol-1-yl) butyl) -4- (3-trifluoromethylphenyl) piperidine,

I-4N- (4- (1H-benzotriazole-1-yl) butyl) -4- (3-trifluoromethylphenyl) piperidine,

I-5N- (4- (1H-benzimidazol-1-yl) butyl) -4- (3-fluorophenyl) piperidine,

I-6N- (4- (1H-benzimidazol-1-yl) butyl) -4- (2-methoxyphenyl) piperidine,

I-7N- (4- (6-fluoro-1H-benzotriazole-1-yl) butyl) -4- (3-trifluoromethylphenyl) piperidine,

I-8N- (4- (6-methoxy-1H-benzotriazole-1-yl) butyl) -4- (3-trifluoromethylphenyl) piperidine,

I-9N- (4- (6-cyano-1H-benzotriazole-1-yl) butyl) -4- (3-trifluoromethylphenyl) piperidine,

I-10N- (4- (1H-benzotriazole-1-yl) propoxy) -4- (3-trifluoromethylphenyl) piperidine,

I-11N- (4- (1H-benzimidazol-1-yl) propoxy) -4- (3-trifluoromethylphenyl) piperidine,

I-12N- (3- (1H-benzotriazol-1-yl) propyl) -4- (3- (6-methylbenzisoxazole)) piperidine,

I-13N- (3- (1H-benzotriazol-1-yl) propyl) -4- (3- (6-methoxy benzisoxazole)) piperidine,

I-14N- (3- (6-fluoro-1H-benzotriazol-1-yl) propyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine,

I-15N- (3- (6-chloro-1H-benzotriazol-1-yl) propyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine,

I-16N- (3- (6-methyl-1H-benzotriazole-1-yl) propyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine,

I-17N- (3- (6-methoxy-1H-benzotriazol-1-yl) propyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine,

I-18N- (3- (6-formyl-1H-benzotriazole-1-yl) propyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine,

I-19N- (3- (6-methoxybenzotriazolyl) propyl) -4- (3-benzisoxazole) piperidine,

I-20N- (2- (1-benzotriazolyl) ethyl) -4- (3- (6-fluorobenzisoxazole)) piperidine,

I-21N- (4- (1-benzotriazolyl) butyl) -4- (3- (6-fluorobenzisoxazole)) piperidine,

I-22N- (4- (6-cyanobenzotriazolyl) butyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine,

I-23N- (4- (6-cyanobenzotriazolyl) butyl) -4- (3- (6-methoxybenzoisoxazole)) piperidine,

I-24N- (2- (6-methoxybenzotriazolyl) ethoxy) -4- (3-benzisoxazole) piperidine,

I-25N- (2- (1-benzotriazolyl) ethoxy) -4- (3-fluorobenzisoxazole) piperidine,

I-26N- (3- (6-methoxybenzotriazolyl) propyl) -4- (3- (6-fluorobenzoisothiazole)) piperidine,

I-27N- (3- (6-methoxybenzotriazolyl) propyl) -4- (3- (6-fluorobenzopyrazole)) piperidine,

I-28N- (3- (6-methoxybenzotriazolyl) propyl) -4- (3- (6-fluorobenzofuran)) piperidine,

I-29N- (4- (1H-benzimidazol-1-yl) butyl) -4- (2-furyl) piperidine,

I-30N- (4- (1H-benzimidazol-1-yl) butyl) -4- (4-pyridyl) piperidine,

I-31N- (4- (1H-benzimidazol-1-yl) butyl) -4- (2-pyrimidinyl) piperidine,

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

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

I-34N- (4- (1H-benzotriazole-1-yl) butyl) -4- (2-quinoxaline) piperidine.

The specific chemical structural formula is shown in the following table:

in a particular embodiment of the invention, the following compounds or pharmaceutically acceptable salts thereof are more preferred:

I-1N- (4- (1H-benzimidazol-1-yl) butyl) -4- (3-chlorophenyl) piperidine,

I-2N- (4- (1H-benzotriazole-1-yl) butyl) -4- (3-chlorphenyl) piperidine,

I-19N- (3- (6-methoxybenzotriazolyl) propyl) -4- (3-benzisoxazole) piperidine,

I-23N- (4- (6-cyanobenzotriazolyl) butyl) -4- (3- (6-methoxybenzoisoxazole)) piperidine.

In a particular embodiment of the invention, the following compounds or pharmaceutically acceptable salts thereof are particularly preferred:

I-19N- (3- (6-methoxybenzotriazolyl) propyl) -4- (3-benzisoxazole) piperidine.

The pharmaceutically acceptable salts of the compounds of formula (I) according to the invention are preferably the hydrochloride, hydrobromide, sulphate, trifluoroacetate, methanesulphonate, tartrate, malate, succinate, maleate, citrate, phosphate, lactate, pyruvate, acetate, fumarate, oxaloacetate, ethanesulphonate, oxalate, benzenesulphonate or isethionate salts. The pharmaceutically acceptable salt of the present invention preferably contains water of crystallization, more preferably 0.5 to 3 molecules of water of crystallization.

The invention also relates to the use of the compounds of formula (I) of the invention and their pharmaceutically acceptable salts for the prevention, alleviation or treatment of diseases or conditions associated with persistent pathological constriction or vasospasm of blood vessels in a subject. The compound of formula (I) and pharmaceutically acceptable salts thereof can be particularly used for preventing, alleviating or treating hypertension, heart failure, angina pectoris, coronary heart disease and the like; used for cerebral ischemic diseases, myocardial ischemic diseases, shock and the like caused by vasospasm; can be used for treating renal ischemia, renal hypofunction caused by renal vasospasm, and peripheral vasospastic diseases.

The subject described herein is preferably a mammal, particularly preferably a human.

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, particularly preferably for use in the prevention, alleviation or treatment of, for example, hypertension, angina pectoris, heart failure, coronary heart disease, cerebral ischemia and peripheral vasospastic diseases such as thromboangiitis obliterans, raynaud's disease and the like.

The invention also relates to pharmaceutical compositions comprising a compound of formula (I) according to the invention or a pharmaceutically acceptable salt thereof for oral, parenteral, administration by inhalation spray, rectal, intranasal, sublingual, buccal, transdermal or by implantation, including subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to the present invention is preferably administered orally, sublingually, intravenously, intramuscularly or subcutaneously. The pharmaceutical compositions may comprise one or more conventional pharmaceutically acceptable carriers, adjuvants or vehicles, such as: diluents, excipients such as water, etc.; binders such as cellulose derivatives, gelatin, polyvinylpyrrolidone, etc.; fillers such as starch and the like; disintegrating agents such as calcium carbonate, sodium bicarbonate; lubricants such as calcium stearate or magnesium stearate, etc.; and other adjuvants such as flavoring agents and sweetening agents.

The pharmaceutical compositions comprising a compound of formula (I) of the invention or a pharmaceutically acceptable salt thereof may be in the form of sterile injectable preparations, for example as sterile aqueous or oleaginous suspensions. The suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (e.g., Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic diluent or solvent which may be employed for parenteral administration, for example as a solution in 1, 3-butanediol. Usable media and solvents which can be used are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. The oil solution or suspension may also contain a long chain alcohol diluent or dispersant (such as those described in ph. helv) or similar alcohols.

Pharmaceutical compositions comprising a compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof may be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, powders, granules, and aqueous suspensions and solutions. The dosage forms are prepared according to techniques well known in the art of pharmaceutical formulation. For tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents (e.g., magnesium stearate) are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient may be combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.

Pharmaceutical compositions comprising a compound of formula (I) of the invention or a pharmaceutically acceptable salt thereof may be administered by nasal aerosol or inhalation. Such compositions may be prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.

Pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the invention may also be administered in the form of suppositories for rectal administration of the drug. The compositions can be prepared by mixing a compound of the invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

As concluded from the results of the anesthetized rat test, the daily dose of the compound of formula (I) of the present invention should be smaller than the daily dose of amlodipine. The daily dose of amlodipine for vasodilation or hypertension is known in the art, e.g., 10 mg/day. The specific dosage of the compound of formula (I) according to the present invention can be determined by a physician according to the results of clinical trials and the condition, age, etc. of the patient.

Pharmaceutical compositions comprising a compound of formula (I) of the invention or a pharmaceutically acceptable salt thereof may be prepared by methods conventional in the medical arts, wherein the active ingredient is present in an amount of 0.1 to 99.5% by weight, depending on the condition to be treated or prevented and the nature of the subject to whom the compound is administered. Dosage regimens for a given compound can be readily determined by those skilled in the art using the disclosure herein.

In one embodiment, the compounds of the invention, compounds of formula (I) or pharmaceutically acceptable salts thereof, may be used in combination with one or more other active pharmaceutical ingredients. The combination may be in the form of a single composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and one or more other active pharmaceutical ingredients, or the combination may be in the form of a combination of two or more separate compositions, wherein a compound of the invention is included in one composition and one or more other active pharmaceutical ingredients are included in one or more separate compositions. Other active pharmaceutical ingredients which can be used in combination with a compound of formula (I) according to the invention or a pharmaceutically acceptable salt thereof for the prevention, alleviation or treatment of a disease or condition associated with persistent pathological constriction of blood vessels or vasospasm in a subject are for example other anti-smooth muscle spasm agents, preferably selected from sertraline, captopril, benazepril, valsartan, propranolol, diuretics.

In another aspect, the invention provides a process for the preparation of a benzo five-membered azaheterocyclyl piperidine compound of formula (I):

scheme I

Comprises that

At a temperature of 10-150 ℃ to react

And compounds

Reacting in a solvent in the presence of an inorganic base and a phase transfer catalyst to form a compound

Then under reflux, reacting it with the compound

In the presence of an organic base in a solvent to form a compound

Or

Scheme two

Comprises that

At a temperature of 10-150 ℃ to react

And compounds

Then under reflux, reacting it with the compound

In the presence of an organic base in a solvent to form a compound

Wherein,

A. b independently represents CH or N; preferably, A, B each represent N;

y represents a saturated or unsaturated, linear or branched, hydrocarbyl chain containing 2 to 8 carbon atoms, optionally substituted with 1 to 3 halogen atoms, in which one or more carbons are optionally replaced by heteroatoms selected from oxygen, sulphur and nitrogen; preferably, Y is an unsubstituted saturated hydrocarbon group containing 2 to 8 carbons, or an unsubstituted saturated hydrocarbon group containing 2 to 8 carbons in which 1 carbon atom is replaced by oxygen or sulfur, such as-C_1-7alkylene-O-; more preferably Y is methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, oxymethylene, oxyethylene, oxypropylene, oxybutylene, oxypentylene, oxyhexylene, oxyheptylene, methyleneoxy, ethyleneoxy, propyleneoxy, butyleneoxy, pentylene-oxy, hexylene-oxy or heptyleneoxy; even more preferably, Y is methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, methyleneoxy, ethyleneoxy, propyleneoxy, butyleneoxy, pentylene-oxy, hexylene-oxy, or heptyleneoxy; particularly preferably, Y is ethylene, propylene, butylene, ethyleneoxy or propyleneoxy;

the first-step reactions of the scheme (one) and the scheme (two) are each carried out in a solvent in the presence of an inorganic base, preferably sodium hydride, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, sodium bicarbonate, potassium hydride, potassium hydroxide, potassium methoxide, potassium ethoxide, potassium carbonate, or potassium bicarbonate, more preferably sodium hydride or sodium hydroxide, and a phase transfer catalyst; the phase transfer catalyst is preferably tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, or 1, 4, 7, 10, 13, 16-hexaoxacyclooctadecane (i.e., 18 crown 6), etc., more preferably tetrabutylammonium bromide; the solvent used in the first reaction step is a solvent commonly used in the art, preferably water, N-methylpyrrolidone (NMP) or N, N-Dimethylformamide (DMF), and a mixture thereof; the reaction temperature of the first step is 10-150 ℃, preferably 20-130 ℃, more preferably 30-100 ℃;

the second-step reactions of scheme (one) and scheme (two) are each carried out in a solvent in the presence of an organic base, more preferably an organic base and potassium iodide, the organic base preferably being diisopropylethylamine, diethylamine, triethylamine, pyridine, tert-butylamine, cyclopropylamine, di-n-butylamine, diisopropylamine or 1, 2-dimethylpropylamine, more preferably diisopropylethylamine; the solvent used in the second reaction step is a solvent commonly used in the art, preferably acetonitrile, DMF, dimethyl sulfoxide (DMSO), or butanone, and a mixture thereof;

the process of the invention also preferably comprises the step of reacting the product with the corresponding acid to form a pharmaceutically acceptable salt. Wherein the acid used may be hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, trifluoroacetic acid, tartaric acid, malic acid, succinic acid, maleic acid, citric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, fumaric acid, oxaloacetic acid, ethanesulphonic acid, oxalic acid, benzenesulphonic acid or isethionic acid, more preferably hydrochloric acid, hydrobromic acid, sulphuric acid or methanesulphonic acid, most preferably hydrochloric acid. The salt formation step is preferably carried out in a solvent which may be methanol, ethanol, propanol, methyl acetate, ethyl acetate, acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide or tetramethylene sulfone and the like, preferably ethyl acetate and/or ethanol.

The embodiments described herein, or different preferred grades, can be combined in any combination, unless otherwise indicated.

The compounds of the present invention can be synthesized by the following methods:

scheme 1:

wherein R is₁、R₂A, B, n are as defined above; m represents a pharmaceutically acceptable salt thereof, e.g. HCl, HBr, H₂SO₄、CH₃SO₃H, and the like.

Substituted benzo five-membered nitrogen heterocycle is used as a raw material, and is subjected to condensation reaction with chloroalkyl bromide in a sodium hydroxide aqueous solution to prepare an N-chloroalkyl-benzo five-membered heterocyclic compound, and is subjected to condensation reaction with 4-substituted piperidine to prepare a compound shown in a formula (I), and optionally, the compound is acidified to form salt to prepare corresponding salt. The compounds I-1 to I-9, I-12 to I-23, I-26 to I-34 and salts thereof can be prepared by the method.

Scheme 2:

Substituted benzo five-membered nitrogen heterocycle-1 alcohol is used as a raw material, exchanges active hydrogen with sodium hydride to obtain corresponding sodium salt, reacts with chloroalkyl bromide to obtain corresponding chloride, and then reacts with 4-substituted piperidine for condensation to prepare a compound shown in a formula (I), and finally, the compound is optionally acidified to form salt to prepare corresponding salt. The compounds I-10 to I-11, I-24 to I-25 and salts thereof can be prepared by the method.

The general synthesis method I comprises the following steps: preparation of N- (3-chloropropyl) -substituted benzo five-membered nitrogen heterocyclic compound

1H-substituted benzo pentaazacyclo (0.10mol) was dissolved in 100ml of 30% by weight aqueous sodium hydroxide solution, and 3-chlorobromopropane (31.4g, 0.10mol) and 0.8g of tetrabutylammonium bromide were added thereto, followed by mixing and stirring for 5 minutes. The reaction solution was slowly heated to 60 ℃ and stirred for 2 hours. Cooling to room temperature, adding 100ml dichloromethane for extraction, separating, adding 100ml dichloromethane for extraction to the water phase, combining the organic phases, washing with 100ml saturated saline, separating, and evaporating the organic phase to obtain oil. Neutral Al of oily matter₂O₃And (3) separating and purifying by chromatography or preparative HPLC to obtain the N- (3-chloropropyl) -substituted benzo five-membered nitrogen heterocyclic compound with the yield of 30.0-85.0%.

A second synthesis method: preparation of N- (3- (substituted benzo penta-nitrogen heterocycle) propyl) -4-substituted piperidine

Dissolving N- (3-chloropropyl) -substituted benzo five-membered nitrogen heterocyclic compound (0.06mol) in 150ml acetonitrile, respectively adding 4-substituted piperidine (0.05mol), diisopropylethylamine (0.2mol) and potassium iodide (0.05mol), stirring for 10 minutes at room temperature, and then heating and refluxing for 10-20 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al₂O₃And (3) carrying out chromatographic separation and purification, and eluting with a dichloromethane/methanol mixed solvent to obtain the compound shown in the formula (I), wherein the yield is 65.0-72.0%.

A third synthesis method: preparation of N- (2-chloroethoxy) -substituted benzo five-membered nitrogen heterocyclic compound

Dissolving substituted N-hydroxybenzene five-membered nitrogen heterocyclic compound (0.01mol) in 10mL of NMP, adding a solid paraffin mixture of 50 weight percent of sodium hydrogen (0.01mol) in batches, stirring for reaction for 0.5h, simultaneously dissolving 3-chlorobromopropane (0.015mol) in 5mL of NMP, adding the solution into the solution, stirring for reaction for 12h at room temperature, pouring the reaction solution into 50mL of water, extracting with ethyl acetate (3 × 50mL), combining organic phases, washing with 30mL of water, adding anhydrous magnesium sulfate to dry the organic phase, filtering, evaporating the solvent to dryness, and passing oily matter through neutral Al₂O₃Separating and purifying by chromatography or preparative HPLC to obtain 1- (2-chloroethoxy) -substituted benzo five-membered nitrogen heterocycleThe yield of the compound is 75.0-85.0%.

Example 1

Preparation of N- (4- (1H-benzimidazol-1-yl) butyl) -4- (3-chlorophenyl) piperidine (I-1)

1H-benzimidazole (11.8g, 0.10mol) was dissolved in 200ml of 20 wt% aqueous sodium hydroxide solution, 4-chlorobromobutane (34.3g, 0.20mol) and 1.0g of tetrabutylammonium bromide were added, and the mixture was stirred for 5 minutes, warmed to 60 ℃ and stirred for reaction for 2 hours. Cooling to room temperature, adding 100ml dichloromethane for extraction, separating, adding 100ml dichloromethane for extraction to the water phase, combining the organic phases, washing with 100ml saturated saline, separating, and evaporating the organic phase to obtain oil. Neutral Al of oily matter₂O₃Chromatographic separation and purification to obtain 12.5g of 1- (4-chlorobutyl) -1H-benzimidazole with the yield of 60.0 percent.

1- (4-chlorobutyl) -1H-benzimidazole (7.51g, 0.036mol) was dissolved in 100ml of acetonitrile, and 3-chlorophenylpiperidine (5.9g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, and stirred at room temperature for 10 minutes, followed by heating under reflux for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al₂O₃Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 7.3g of compound (I-1) with yield of 66.4%. ESI-MS [ M + H ]]⁺：m/z 368.2。

Example 2

Preparation of N- (4- (1H-benzotriazole-1-yl) butyl) -4- (3-chlorophenyl) piperidine (I-2)

Benzotriazole (11.9g, 0.10mol) was dissolved in 100ml of a 30 wt% aqueous solution of sodium hydroxide, 4-chlorobromobutane (34.3g, 0.20mol) and 0.8g of tetrabutylammonium bromide were added, and the mixture was stirred for 5 minutes. The reaction solution was slowly heated to 60 ℃ and stirred for 2 hours. Cooling to room temperature, adding 100ml dichloromethane, extracting, separating, collecting water phase100ml of dichloromethane is added for extraction, organic phases are combined, the mixture is washed by 100ml of saturated saline solution, liquid is separated, and the organic phase is evaporated to dryness to obtain oily matter. Neutral Al of oily matter₂O₃Carrying out chromatographic separation and purification, eluting with dichloromethane to obtain 17.0g of 1- (4-chlorobutyl) -1H-benzotriazole, wherein the yield is 81.0%.

1- (4-chlorobutyl) -1H-benzotriazole (7.55g, 0.036mol) was dissolved in 100ml of acetonitrile, and 3-chlorophenylpiperidine (5.9g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added thereto, followed by stirring, mixing, and reflux reaction at elevated temperature for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al₂O₃Separating and purifying by chromatography, eluting with dichloromethane to obtain 7.8g of compound (I-2), with a yield of 70.3%. ESI-MS [ M + H ]]⁺：m/z369.2。

Compound (I-2) (5.55g, 0.015mol) was dissolved in 50ml of ethyl acetate. Under the cooling condition of an ice-water bath, a hydrogen chloride/ethyl acetate solution with the concentration of 3mol/L is dropwise added until the pH of the reaction solution is 2, the reaction solution is stirred for 10min, and the mixture is filtered and dried to obtain 5.4g of a compound (II-2) solid, wherein the yield is 88.0%.

Example 3

Preparation of N- (4- (1H-benzimidazol-1-yl) butyl) -4- (3-trifluoromethylphenyl) piperidine (I-3)

1- (4-chlorobutyl) -1H-benzimidazole was prepared by the method of example 1.

1- (4-chlorobutyl) -1H-benzimidazole (0.06mol) was dissolved in 150ml of acetonitrile, and 4- (3-trifluoromethylphenyl) piperidine (0.05mol), diisopropylethylamine (0.2mol), and potassium iodide (0.05mol) were added, respectively, and mixed and stirred at room temperature for 10 minutes, followed by heating under reflux for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al₂O₃Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain N- (4- (1H-benzimidazole-1-yl) butyl) -4- (3-trifluoromethylphenyl) piperidine (I-3)11.0g, with the yield of 64.9%. ESI-MS [ M + H ]]⁺：m/z 402.2。

Compound (I-3) (6.02g, 0.015mol) was dissolved in 50ml of ethyl acetate. Under the cooling condition of an ice-water bath, a hydrogen chloride/ethyl acetate solution with the concentration of 3mol/L is dropwise added until the pH of the reaction solution is 2, the reaction solution is stirred for 10min, and the mixture is filtered and dried to obtain 5.4g of a compound (II-3) solid, wherein the yield is 89.0%.

Example 4

Preparation of N- (4- (1H-benzotriazole-1-yl) butyl) -4- (3-trifluoromethylphenyl) piperidine (I-4)

1- (4-chlorobutyl) -1H-benzotriazole was prepared by the method of example 2.

1- (4-chlorobutyl) -1H-benzotriazole (0.06mol) was dissolved in 150ml of acetonitrile, and 4- (3-trifluoromethylphenyl) piperidine (0.05mol), diisopropylethylamine (25.8g, 0.2mol), and potassium iodide (0.05mol) were added thereto, respectively, followed by mixing and stirring at room temperature for 10 minutes, followed by heating under reflux for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al₂O₃Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 13.6g of N- (4- (1H-benzotriazole-1-yl) butyl) -4- (3-trifluoromethylphenyl) piperidine (I-4) with the yield of 67.8%. ESI-MS [ M + H ]]⁺：m/z 403.2。

Example 5

Preparation of N- (4- (1H-benzimidazol-1-yl) butyl) -4- (3-fluorophenyl) piperidine (I-5)

1- (4-chlorobutyl) -1H-benzimidazole was prepared by the method of example 1.

1- (4-chlorobutyl) -1H-benzimidazole (7.51g, 0.036mol) was dissolved in 100ml of acetonitrile, 3-fluorophenylpiperidine (5.9g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, and the mixture was stirred at room temperature for 10 minutes, followed by heating under reflux for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al₂O₃Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 7.1g of compound (I-5), with yield of 67.2%. ESI-MS [ M + H ]]⁺：m/z 352.2。

Example 6

Preparation of N- (4- (1H-benzimidazol-1-yl) butyl) -4- (2-methoxyphenyl) piperidine (I-6)

1- (4-chlorobutyl) -1H-benzimidazole was prepared by the method of example 1.

1- (4-chlorobutyl) -1H-benzimidazole (7.51g, 0.036mol) was dissolved in 100ml of acetonitrile, and 2-methoxyphenylpiperidine (5.7g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, and stirred at room temperature for 10 minutes, followed by heating under reflux for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al₂O₃Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 6.7g of compound (I-6) with yield of 61.3%. ESI-MS [ M + H ]]⁺：m/z 364.2。

Example 7

Preparation of N- (4- (6-fluoro-1H-benzotriazole-1-yl) butyl) -4- (3-trifluoromethylphenyl) piperidine (I-7)

6-fluoro-benzotriazole (15.3g, 0.10mol) was dissolved in 100ml of a 30 wt% aqueous solution of sodium hydroxide, 4-chlorobromobutane (34.3g, 0.20mol) and 0.8g of tetrabutylammonium bromide were added, and the mixture was stirred for 5 minutes. The reaction solution was slowly heated to 60 ℃ and stirred for 2 hours. Cooling to room temperature, adding 100ml dichloromethane for extraction, separating, adding 100ml dichloromethane into the water phase for extraction, combining the organic phases, washing with 100ml saturated saline solution, separating, and evaporating the organic phase to obtain oily substance. Neutral Al of oily matter₂O₃Separating and purifying by chromatography, eluting with dichloromethane to obtain 6-fluoro-1- (C)17.0g of 4-chlorobutyl) -1H-benzotriazole and the yield is 77.0%.

6-fluoro-1- (4-chlorobutyl) -1H-benzotriazole (0.06mol) is dissolved in 150ml of acetonitrile, 4- (3-trifluoromethylphenyl) piperidine (0.05mol), diisopropylethylamine (0.2mol) and potassium iodide (0.05mol) are added respectively, and the mixture is mixed and stirred at room temperature for 10 minutes and then heated to reflux for reaction for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al₂O₃Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 13.5g of N- (4- (1H-benzotriazole-1-yl) butyl) -4- (3-trifluoromethylphenyl) piperidine (I-7) with a yield of 64.1%. ESI-MS [ M + H ]]⁺：m/z 421.2。

Example 8

Preparation of N- (4- (6-methoxy-1H-benzotriazole-1-yl) butyl) -4- (3-trifluoromethylphenyl) piperidine (I-8)

6-methoxy-benzotriazole (14.9g, 0.10mol) was dissolved in 100ml of a 30% by weight aqueous solution of sodium hydroxide, 4-chlorobromobutane (34.3g, 0.20mol) and 0.8g of tetrabutylammonium bromide were added, and the mixture was stirred for 5 minutes. The reaction solution was slowly heated to 60 ℃ and stirred for 2 hours. Cooling to room temperature, adding 100ml dichloromethane for extraction, separating, adding 100ml dichloromethane into the water phase for extraction, combining the organic phases, washing with 100ml saturated saline solution, separating, and evaporating the organic phase to obtain oily substance. Neutral Al of oily matter₂O₃Carrying out chromatographic separation and purification, eluting by dichloromethane to obtain 17.9g of 6-methoxy-1- (4-chlorobutyl) -1H-benzotriazole, wherein the yield is 75.0%.

6-methoxy-1- (4-chlorobutyl) -1H-benzotriazole (0.06mol) was dissolved in 150ml of acetonitrile, and 4- (3-trifluoromethylphenyl) piperidine (0.05mol), diisopropylethylamine (0.2mol), and potassium iodide (0.05mol) were added thereto, respectively, and mixed and stirred at room temperature for 10 minutes, followed by heating under reflux for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al₂O₃Separating and purifying by chromatography, mixing dichloromethane/methanolEluting with solvent to obtain 14.0g of N- (4- (1H-benzotriazole-1-yl) butyl) -4- (3-trifluoromethylphenyl) piperidine (I-8) with a yield of 64.6%. ESI-MS [ M + H ]]⁺：m/z433.2。

Example 9

Preparation of N- (4- (6-cyano-1H-benzotriazole-1-yl) butyl) -4- (3-trifluoromethylphenyl) piperidine (I-9)

6-cyano-benzotriazole (14.4g, 0.10mol) was dissolved in 100ml of a 30 wt% aqueous solution of sodium hydroxide, 4-chlorobromobutane (34.3g, 0.20mol) and 0.8g of tetrabutylammonium bromide were added, and the mixture was stirred for 5 minutes. The reaction solution was slowly heated to 60 ℃ and stirred for 2 hours. Cooling to room temperature, adding 100ml dichloromethane for extraction, separating, adding 100ml dichloromethane into the water phase for extraction, combining the organic phases, washing with 100ml saturated saline solution, separating, and evaporating the organic phase to obtain oily substance. Neutral Al of oily matter₂O₃Carrying out chromatographic separation and purification, eluting with dichloromethane to obtain 17.3g of 6-cyano-1- (4-chlorobutyl) -1H-benzotriazole, wherein the yield is 74.0%.

6-cyano-1- (4-chlorobutyl) -1H-benzotriazole (0.06mol) was dissolved in 150ml of acetonitrile, and 4- (3-trifluoromethylphenyl) piperidine (0.05mol), diisopropylethylamine (0.2mol), and potassium iodide (0.05mol) were added thereto, respectively, and mixed and stirred at room temperature for 10 minutes, followed by heating under reflux for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al₂O₃Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 13.5g of N- (4- (1H-benzotriazole-1-yl) butyl) -4- (3-trifluoromethylphenyl) piperidine (I-9) with a yield of 63.1%. ESI-MS [ M + H ]]⁺：m/z 427.2。

Example 10

Preparation of N- (4- (1H-benzotriazole-1-yl) propoxy) -4- (3-trifluoromethylphenyl) piperidine (I-10)

Preparation of N- (2-chloropropoxy) -benzotriazole

Dissolving 1-hydroxybenzotriazole (0.01mol) in 10mL NMP, adding a solid paraffin mixture of sodium hydrogen (0.01mol) with the weight ratio of 50% in batches, stirring for reaction for 0.5h, simultaneously dissolving 3-chlorobromopropane (0.015mol) in 5mL NMP, adding the solution, stirring for reaction for 12h at room temperature, pouring the reaction solution into 50mL water, extracting with ethyl acetate (3 × 50mL), combining organic phases, washing with 30mL water, adding anhydrous magnesium sulfate, drying the organic phases, filtering, evaporating the solvent to dryness, and passing the oily substance through neutral Al₂O₃And (3) separating and purifying by chromatography or preparative HPLC to obtain the 1- (3-chloropropoxy) benzotriazole with the yield of 75.0-85.0%.

1- (3-chloropropyloxy) benzotriazole (0.06mol) was dissolved in 150ml of acetonitrile, and 4- (3- (6-fluoro-benzisoxazolyl)) piperidine (0.05mol), diisopropylethylamine (0.2mol), and potassium iodide (0.05mol) were added thereto, respectively, and the mixture was stirred at room temperature for 10 minutes, followed by heating and refluxing for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al₂O₃Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 13.2g of N- (4- (1H-benzotriazole-1-yl) propoxy) -4- (3-trifluoromethylphenyl) piperidine (I-10), with the yield of 65.3%. ESI-MS [ M + H ]]⁺：m/z 405.2。

Example 11

Preparation of N- (4- (1H-benzimidazol-1-yl) propoxy) -4- (3-trifluoromethylphenyl) piperidine (I-11)

Preparation of N- (2-chloropropyloxy) -benzimidazole

Dissolving 1-hydroxybenzimidazole (0.01mol) in 10mL NMP, adding 50 wt% of solid paraffin mixture of sodium hydrogen (0.01mol) in batches, stirring and reacting for 0.5h, simultaneously dissolving 3-chlorobromopropane (0.015mol) in 5mL NMP, adding the solution, stirring and reacting for 12h at room temperature, pouring the reaction liquid into 50mL water, extracting with ethyl acetate (3 × 50mL), combining organic phases, washing with 30mL water, adding anhydrous sulfurMagnesium acid drying organic phase, filtering, evaporating solvent, and passing oily substance through neutral Al₂O₃Separating and purifying by chromatography or preparative HPLC to obtain 1- (3-chloropropoxy) benzimidazole with yield of 75.0%.

1- (3-Chloropropoxy) benzimidazole (0.06mol) was dissolved in 150ml of acetonitrile, and 4- (3- (6-fluorophenylisoxazolyl)) piperidine (0.05mol), diisopropylethylamine (0.2mol), and potassium iodide (0.05mol) were added, respectively, and mixed and stirred at room temperature for 10 minutes, followed by heating under reflux for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al₂O₃Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 13.6g of N- (4- (1H-benzimidazole-1-yl) propoxy) -4- (3-trifluoromethylphenyl) piperidine (I-11), with the yield of 67.1%. ESI-MS [ M + H ]]⁺：m/z 404.2。

Example 12

Preparation of N- (3- (1H-benzotriazol-1-yl) propyl) -4- (3- (6-methylbenzisoxazole)) piperidine (I-12)

1- (3-chloropropyl) -1H-benzotriazole (11.7g, 0.06mol) was dissolved in 150ml of acetonitrile, and 6-methyl-3- (piperidin-4-yl) benzisoxazole (10.8g, 0.05mol), diisopropylethylamine (25.8g, 0.2mol), and potassium iodide (8.3g, 0.05mol) were added thereto, and mixed and stirred at room temperature for 10 minutes, followed by heating and refluxing for 15 hours. The work-up was carried out according to general method two to give 12.4g of (I-12) in 66.1% yield. ESI-MS [ M + H ]]⁺：m/z 376.2。

Example 13

Preparation of N- (3- (1H-benzotriazol-1-yl) propyl) -4- (3- (6-methoxy benzisoxazole)) piperidine (I-13)

1- (3-chloropropyl) -1H-benzotriazole (11.7g, 0.06mol) was dissolved in 150ml of acetonitrile, 6-methoxy-3- (piperidin-4-yl) benzisoxazole (11.6g, 0.05mol) and diisopropylethylamine (25.8g,0.2mol), and potassium iodide (8.3g, 0.05mol), stirred at room temperature for 10 minutes, and then heated to reflux for 15 hours. Working up was carried out according to general method II to give 13.3g of (I-13) in 67.7% yield. ESI-MS [ M + H ]]⁺：m/z 392.2。

Example 14

Preparation of N- (3- (6-fluoro-1H-benzotriazol-1-yl) propyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine (I-14)

Preparation of 1- (3-chloropropyl) -6-fluoro-1H-benzotriazole

6-fluoro-1H-benzotriazole (13.7g, 0.10mol) was dissolved in 100ml of a 30% by weight aqueous solution of sodium hydroxide, and 3-chlorobromopropane (31.4g, 0.10mol) and 0.8g of tetrabutylammonium bromide were added thereto, followed by mixing and stirring for 5 minutes. The reaction solution was slowly heated to 60 ℃ and stirred for 2 hours. Post-treatment operation is carried out according to the general synthesis method I, and 6.9g of 1- (3-chloropropyl) -6-fluoro-1H-benzotriazole is obtained through separation and purification by preparative HPLC, with the yield of 32.3%.

Preparation of N- (3- (6-fluoro-1H-benzotriazol-1-yl) propyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine (I-5)

1- (3-chloropropyl) -6-fluoro-1H-benzotriazole (6.41g, 0.03mol) was dissolved in 150ml of acetonitrile, and 6-fluoro-3- (piperidin-4-yl) benzisoxazole (5.5g, 0.025mol), diisopropylethylamine (12.9g, 0.1mol), and potassium iodide (4.15g, 0.025mol) were mixed and stirred at room temperature for 10 minutes, followed by heating and refluxing for 16 hours. The work-up was carried out according to general method two to give 8.3g of (I-14) in 69.6% yield. ESI-MS [ M + H ]]⁺：m/z 398.2。

Example 15

Preparation of N- (3- (6-chloro-1H-benzotriazol-1-yl) propyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine (I-15)

Preparation of 1- (3-chloropropyl) -6-chloro-1H-benzotriazole

6-chloro-1H-benzotriazole (15.4g, 0.10mol) was dissolved in 100ml of a 30% by weight aqueous solution of sodium hydroxide, and 3-chlorobromopropane (31.4g, 0.10mol) and 0.8g of tetrabutylammonium bromide were added thereto, followed by mixing and stirring for 5 minutes. The reaction solution was slowly heated to 60 ℃ and stirred for 2 hours. After-treatment operation is carried out according to the general synthesis method I, and the 1- (3-chloropropyl) -6-chloro-1H-benzotriazole is separated and purified by preparative HPLC to obtain 7.3g of 1- (3-chloropropyl) -6-chloro-1H-benzotriazole with the yield of 31.7 percent.

Preparation of N- (3- (6-chloro-1H-benzotriazol-1-yl) propyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine (I-6))

1- (3-chloropropyl) -6-chloro-1H-benzotriazole (6.90g, 0.03mol) was dissolved in 150ml of acetonitrile, and 6-fluoro-3- (piperidin-4-yl) benzisoxazole (5.5g, 0.025mol), diisopropylethylamine (12.9g, 0.1mol), and potassium iodide (4.15g, 0.025mol) were mixed and stirred at room temperature for 10 minutes, followed by heating and refluxing for 16 hours. The work-up was carried out according to general method two to give 8.1g of (I-15) in 65.2% yield. ESI-MS [ M + H ]]⁺：m/z 414.1。

Example 16

Preparation of N- (3- (6-methyl-1H-benzotriazole-1-yl) propyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine (I-16)

Preparation of 1- (3-chloropropyl) -6-methyl-1H-benzotriazole

6-methyl-1H-benzotriazole (13.3g, 0.10mol) was dissolved in 100ml of a 30% by weight aqueous solution of sodium hydroxide, and 3-chlorobromopropane (31.4g, 0.10mol) and 0.8g of tetrabutylammonium bromide were added thereto, followed by mixing and stirring for 5 minutes. The reaction solution was slowly heated to 60 ℃ and stirred for 2 hours. After-treatment operation is carried out according to the general synthesis method I, and 7.2g of 1- (3-chloropropyl) -6-methyl-1H-benzotriazole is obtained through separation and purification by preparative HPLC, with the yield of 34.3%.

Preparation of N- (3- (6-methyl-1H-benzotriazole-1-yl) propyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine (I-7)

1- (3-chloropropyl) -6-methyl-1H-benzotriazole (6.29g, 0.03mol) was dissolved in 150ml of acetonitrile, and 6-fluoro-3- (piperidin-4-yl) benzisoxazole (5.5g, 0.025mol), diisopropylethylamine (12.9g, 0.1mol), and potassium iodide (4.15g, 0.025mol) were mixed and stirred at room temperature for 10 minutes, followed by heating and refluxing for 16 hours. The work-up was carried out according to general method two to give 8.5g of (I-16) with a yield of 71.9%. ESI-MS [ M + H ]]⁺：m/z 394.2。

Example 17

Preparation of N- (3- (6-methoxy-1H-benzotriazole-1-yl) propyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine (I-17)

Preparation of N- (3-chloropropyl) -6-methoxy benzotriazole

6-methoxy-1H-benzotriazole (14.9g, 0.10mol) was dissolved in 100ml of a 30% by weight aqueous solution of sodium hydroxide, and 3-chlorobromopropane (31.4g, 0.10mol) and 0.8g of tetrabutylammonium bromide were added thereto, followed by mixing and stirring for 5 minutes. The reaction solution was slowly heated to 60 ℃ and stirred for 2 hours. After-treatment operation is carried out according to the general synthesis method I, and the N- (3-chloropropyl) -6-methoxy benzotriazole is separated and purified by preparative HPLC to obtain 7.7g of N- (3-chloropropyl) -6-methoxy benzotriazole with the yield of 34.1 percent.

Preparation of N- (3- (6-methoxy-1H-benzotriazole-1-yl) propyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine (I-8)

1- (3-chloropropyl) -6-methoxy-1H-benzotriazole (6.77g, 0.03mol) was dissolved in 150ml of acetonitrile, and 6-fluoro-3- (piperidin-4-yl) benzisoxazole (5.5g, 0.025mol), diisopropylethylamine (12.9g, 0.1mol), and potassium iodide (4.15g, 0.025mol) were mixed and stirred at room temperature for 10 minutes, followed by heating and refluxing for 16 hours. The work-up was carried out according to general method two to give 8.6g of (I-17) in 70% yield. ESI-MS [ M + H ]]⁺：m/z 410.2。

Example 18

Preparation of N- (3- (6-formyl-1H-benzotriazole-1-yl) propyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine (I-18)

Preparation of 1- (3-chloropropyl) -6-formyl-1H-benzotriazole

6-formyl-1H-benzotriazole (16.2g, 0.10mol) was dissolved in 100ml of a 30% by weight aqueous solution of sodium hydroxide, and 3-chlorobromopropane (31.4g, 0.10mol) and 0.8g of tetrabutylammonium bromide were added thereto, followed by mixing and stirring for 5 minutes. The reaction solution was slowly heated to 60 ℃ and stirred for 2 hours. After-treatment operation is carried out according to the general synthesis method I, and 7.9g of 1- (3-chloropropyl) -6-formyl-1H-benzotriazole is obtained through separation and purification by preparative HPLC, with the yield of 33.2%.

1- (3-chloropropyl) -6-formyl-1H-benzotriazole (7.13g, 0.03mol) was dissolved in 150ml of acetonitrile, and 6-fluoro-3- (piperidin-4-yl) benzisoxazole (5.5g, 0.025mol), diisopropylethylamine (12.9g, 0.1mol), and potassium iodide (4.15g, 0.025mol) were mixed and stirred at room temperature for 10 minutes, followed by heating and refluxing for 15 hours. After-treatment according to general method II to obtain 7.5g of (I-18) with 73.6% yield. ESI-MS [ M + H ]]⁺：m/z 408.2。

Example 19

Preparation of N- (3- (6-methoxybenzotriazolyl) propyl) -4- (3-benzisoxazole) piperidine (I-19)

N- (3-chloropropyl) -6-methoxybenzotriazole is prepared as described in example 17.

Dissolving N- (3-chloropropyl) -6-methoxy benzotriazole (0.06mol) in 150ml of acetonitrile, adding 4- (3-benzisoxazole) piperidine (0.05mol), diisopropylethylamine (0.2mol) and potassium iodide (0.05mol) respectively, mixing and stirring for 10 minutes at room temperature, and then heating and refluxing for 15 hours. Cooling to the chamberWarming, filtering, concentrating the filtrate to obtain oil, and adding neutral Al₂O₃Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 13.14g of N- (3- (6-methoxybenzotriazolyl) propyl) -4- (3-benzisoxazole) piperidine (I-19) with yield of 67.2%. ESI-MS [ M + H ]]⁺：m/z 391.2。

Example 20

Preparation of N- (2- (1-benzotriazolyl) ethyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine (I-20)

Benzotriazole (11.9g, 0.10mol) was dissolved in 100ml of a 30 wt% aqueous solution of sodium hydroxide, and 3-chlorobromopropane (31.4g, 0.10mol) and 0.8g of tetrabutylammonium bromide were added thereto, followed by mixing and stirring for 5 minutes. The reaction solution was slowly heated to 60 ℃ and stirred for 2 hours. Cooling to room temperature, adding 100ml dichloromethane for extraction, separating, adding 100ml dichloromethane for extraction to the water phase, combining the organic phases, washing with 100ml saturated saline solution, separating, and evaporating the organic phase to obtain oil. The oil is subjected to column chromatography (neutral Al)₂O₃) Separating and purifying, eluting and separating by dichloromethane to obtain 16.0g of 1- (3-chloropropyl) -1H-benzotriazole with the yield of 82.0 percent.

1- (3-chloropropyl) -1H-benzotriazole (0.06mol) is dissolved in 150ml of acetonitrile, 4- (3- (6-fluorobenzoisoxazole)) piperidine (0.05mol), diisopropylethylamine (0.2mol) and potassium iodide (0.05mol) are added respectively, and the mixture is mixed and stirred at room temperature for 10 minutes and then heated to reflux for reaction for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al₂O₃Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain N- (2- (1-benzotriazolyl) ethyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine (I-20)12.67g with 69.4% yield. ESI-MS [ M + H ]]⁺：m/z 365.2。

Example 21

Preparation of N- (4- (1-benzotriazolyl) butyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine (I-21)

1- (4-chlorobutyl) -1H-benzotriazole was prepared according to the method in example 2.

1- (4-chlorobutyl) -1H-benzotriazole (0.06mol) was dissolved in 150ml of acetonitrile, and 4- (3- (6-fluorobenzoisoxazole)) piperidine (0.05mol), diisopropylethylamine (0.2mol), and potassium iodide (0.05mol) were added, respectively, and mixed and stirred at room temperature for 10 minutes, followed by heating and refluxing for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al₂O₃Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 13.96g of N- (4- (1-benzotriazolyl) butyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine (I-21) with the yield of 71.0%. ESI-MS [ M + H ]]⁺：m/z 393.2。

Example 22

Preparation of N- (4- (6-cyanobenzotriazolyl) butyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine (I-22)

Preparation of 1- (3 chlorobutyl) -6-cyano-1H-benzotriazole

6-cyano-1H-benzotriazole (15.9g, 0.10mol) was dissolved in 100ml of a 30% by weight aqueous solution of sodium hydroxide, and 3-chlorobromobutane (32.6g, 0.10mol) and 0.8g of tetrabutylammonium bromide were added thereto, followed by mixing and stirring for 5 minutes. The reaction solution was slowly heated to 60 ℃ and stirred for 2 hours. After-treatment operation is carried out according to the general synthesis method I, and the 1- (3 chlorobutyl) -6-cyano-1H-benzotriazole is separated and purified by preparative HPLC, so that 9.1g of 1- (3 chlorobutyl) -6-cyano-1H-benzotriazole is obtained with the yield of 32.6%.

1- (3-chlorobutyl) -6-cyanobenzotriazole (0.06mol) was dissolved in 150ml of acetonitrile, and 4- (3- (6-fluorobenzoisoxazole)) piperidine (0.05mol), diisopropylethylamine (0.2mol), and potassium iodide (0.05mol) were added, respectively, and mixed and stirred at room temperature for 10 minutes, followed by heating and refluxing for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al₂O₃Chromatographic separation and purification, dichloromethane/methanol mixtureEluting with mixed solvent to obtain 15.07g of N- (4- (6-cyanobenzotriazolyl) butyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine (I-22) with yield of 72.1%. ESI-MS [ M + H ]]⁺：m/z418.2。

Example 23

Preparation of N- (4- (6-cyanobenzotriazolyl) butyl) -4- (3- (6-methoxybenzoisoxazole)) piperidine (I-23)

1- (3-chlorobutyl) -6-cyanobenzotriazole was prepared as in example 22.

1- (3-chlorobutyl) -6-cyanobenzotriazole (0.06mol) was dissolved in 150ml of acetonitrile, and 4- (3- (6-methoxybenzoisoxazole)) piperidine (0.05mol), diisopropylethylamine (0.2mol), and potassium iodide (0.05mol) were added, respectively, and mixed and stirred at room temperature for 10 minutes, followed by heating and refluxing for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al₂O₃Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 15.01g of N- (4- (6-cyanobenzotriazolyl) butyl) -4- (3- (6-methoxybenzoisoxazole)) piperidine (I-23) with the yield of 69.8%. ESI-MS [ M + H ]]⁺：m/z 430.2。

Example 24

Preparation of N- (2- (6-methoxybenzotriazolyl) ethoxy) -4- (3-benzisoxazole) piperidine (I-24)

The N-hydroxy-6-methoxy benzotriazole is prepared by the method in the general method III.

Dissolving N- (2-chloroethoxy-6-methoxy benzotriazole (0.06mol) prepared by a synthesis and post-treatment method in the general method I into 150ml of acetonitrile, respectively adding 4- (3-benzisoxazolyl) piperidine (0.05mol), diisopropylethylamine (0.2mol) and potassium iodide (0.05mol), mixing and stirring at room temperature for 10 minutes, heating for reflux reaction for 15 hours, and cooling to the temperatureFiltering at room temperature, concentrating the filtrate to obtain oil, and purifying with neutral Al₂O₃Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain N- (2- (6-methoxybenzotriazolyl) ethoxy) -4- (3-benzisoxazole) piperidine (I-24)14.21g with 69.1% yield. ESI-MS [ M + H ]]⁺：m/z 394.2。

Example 25

Preparation of N- (2- (1-benzotriazolyl) ethoxy) -4- (3-fluorobenzoisoxazole) piperidine (I-25)

The N-hydroxybenzotriazole is prepared by the method in the general method III.

Dissolving N- (2-chloroethoxy benzotriazole (0.06mol) prepared by using N-hydroxy benzotriazole as a raw material according to a synthesis and post-treatment method in the general method I in 150ml of acetonitrile, respectively adding 4- (3-benzisoxazole) piperidine (0.05mol), diisopropylethylamine (0.2mol) and potassium iodide (0.05mol), mixing and stirring for 10 minutes at room temperature, then heating up for reflux reaction for 15 hours, cooling to room temperature, filtering, concentrating the filtrate to obtain an oily substance, and performing neutral Al treatment on the oily substance₂O₃Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain N- (2- (1-benzotriazolyl) ethoxy) -4- (3-fluorobenzoisoxazole) piperidine (I-25)12.88g, with the yield of 67.6%. ESI-MS [ M + H ]]⁺：m/z 364.2。

Example 26

Preparation of N- (3- (6-methoxybenzotriazolyl) propyl) -4- (3- (6-fluorobenzoisothiazole)) piperidine (I-26)

Dissolving N- (3-chloropropyl) -6-methoxybenzotriazole (0.06mol) in 150ml of acetonitrile, and adding 4- (3- (6-fluorobenzoisothiazole)) piperidine (0.05mol), diisopropylethylamine (0.2mol) and potassium iodide (0.05mol) respectively at room temperatureThe mixture was stirred for 10 minutes, and then heated to reflux for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al₂O₃Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 13.17g of N- (3- (6-methoxybenzotriazolyl) propyl) -4- (3- (6-fluorobenzoisothiazole)) piperidine (I-26), with the yield of 69.1%. ESI-MS [ M + H ]]⁺：m/z 426.1。

Example 27

Preparation of N- (3- (6-methoxybenzotriazolyl) propyl) -4- (3- (6-fluorobenzopyrazole)) piperidine (I-27)

N- (3-chloropropyl) -6-methoxybenzotriazole (0.06mol) is dissolved in 150ml of acetonitrile, 4- (3- (6-fluorobenzoisothiazole)) (0.05mol), diisopropylethylamine (0.2mol) and potassium iodide (0.05mol) are added respectively, and the mixture is mixed and stirred at room temperature for 10 minutes, and then heated to reflux for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al₂O₃Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 12.11g of N- (3- (6-methoxybenzotriazolyl) propyl) -4- (3- (6-fluorobenzopyrazole)) piperidine (I-27) with the yield of 66.5%. ESI-MS [ M + H ]]⁺：m/z 409.2。

Example 28

Preparation of N- (3- (6-methoxybenzotriazolyl) propyl) -4- (3- (6-fluorobenzofuran)) piperidine (I-28)

Dissolving N- (3-chloropropyl) -6-methoxybenzotriazole (0.06mol) in 150ml of acetonitrile, and adding 4- (3- (6-fluorobenzoisothiazole)) (0.05mol), diisopropylethylamine (0.2mol) and iodine respectivelyPotassium chloride (0.05mol) was mixed and stirred at room temperature for 10 minutes, followed by heating and refluxing for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al₂O₃Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain N- (3- (6-methoxybenzotriazolyl) propyl) -4- (3- (6-fluorobenzofuran)) piperidine (I-28)12.40g with yield of 68.1%. ESI-MS [ M + H ]]⁺：m/z 409.2。

Example 29

Preparation of N- (4- (1H-benzimidazolyl-1-yl) butyl) -4- (2-furyl) piperidine (I-29)

1- (4-chlorobutyl) -1H-benzimidazole was prepared by the method of example 1.

1- (4-chlorobutyl) -1H-benzimidazole (7.51g, 0.036mol) was dissolved in 100ml of acetonitrile, and 4- (2-furyl) piperidine (4.6g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, stirred at room temperature for 10 minutes, and then heated under reflux for 20 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al₂O₃Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 6.0g of compound (I-29) with yield of 61.6%. ESI-MS [ M + H ]]⁺：m/z 324.2。

Example 30

Preparation of N- (4- (1H-benzimidazolyl-1-yl) butyl) -4- (4-pyridyl) piperidine (I-30)

1- (4-chlorobutyl) -1H-benzimidazole was prepared by the method of example 1.

1- (4-chlorobutyl) -1H-benzimidazole (7.51g, 0.036mol) was dissolved in 100ml of acetonitrile, and 4- (4-pyridyl) piperidine (4.9g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, stirred at room temperature for 10 minutes, and then heated under reflux for 20 hours.Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al₂O₃Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 6.3g of compound (I-30) with yield of 62.1%. ESI-MS [ M + H ]]⁺：m/z 335.2。

Example 31

Preparation of N- (4- (1H-benzimidazolyl-1-yl) butyl) -4- (2-pyrimidinyl) piperidine (I-31)

1- (4-chlorobutyl) -1H-benzimidazole was prepared by the method of example 1.

1- (4-chlorobutyl) -1H-benzimidazole (7.51g, 0.036mol) was dissolved in 100ml of acetonitrile, and 4- (2-pyrimidinyl) piperidine (4.9g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, stirred at room temperature for 10 minutes, and then heated under reflux for 20 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al₂O₃Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 6.1g of compound (I-31) with yield of 60.1%. ESI-MS [ M + H ]]⁺：m/z 336.2。

Example 32

Preparation of N- (4- (1H-benzotriazole-1-yl) butyl) -4-cyclohexylpiperidine (I-32)

1- (4-chlorobutyl) -1H-benzotriazole was prepared by the method of example 2.

1- (4-chlorobutyl) -1H-benzotriazole (7.55g, 0.036mol) was dissolved in 100ml of acetonitrile, and 4- (1-cyclohexyl) piperidine (5.1g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added thereto, followed by stirring, mixing, and reflux reaction at elevated temperature for 20 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al₂O₃Separating and purifying by chromatography, eluting with dichloromethane to obtain compound (I-32)6.5g, with yield63.7％。ESI-MS[M+H]⁺：m/z 341.3。

Example 33

Preparation of N- (4- (1H-benzotriazol-1-yl) butyl) -4- (1-naphthyl) piperidine (I-33)

1- (4-chlorobutyl) -1H-benzotriazole was prepared by the method of example 2.

1- (4-chlorobutyl) -1H-benzotriazole (7.55g, 0.036mol) was dissolved in 100ml of acetonitrile, and 4- (1-naphthyl) piperidine (6.4g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added thereto, followed by stirring, mixing, and reflux reaction at elevated temperature for 20 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al₂O₃Chromatographic separation and purification, and eluting with dichloromethane to obtain 6.9g of the compound (I-33) with the yield of 60.1%. ESI-MS [ M + H ]]⁺：m/z385.3。

Example 34

Preparation of N- (4- (1H-benzotriazole-1-yl) butyl) -4- (2-quinoxaline) piperidine (I-34)

1- (4-chlorobutyl) -1H-benzotriazole was prepared by the method of example 2.

1- (4-chlorobutyl) -1H-benzotriazole (7.55g, 0.036mol) was dissolved in 100ml of acetonitrile, and 4- (2-quinoxalinyl) piperidine (6.4g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, followed by stirring, mixing, and reflux reaction at elevated temperature for 20 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al₂O₃The product was separated and purified by chromatography, and eluted with methylene chloride to give 7.3g of Compound (I-34) in 62.7% yield. ESI-MS [ M + H ]]⁺：m/z 387.2。

Example 35

Relaxation of isolated vascular smooth muscle of rabbit by Compounds II-1 to II-34

1. Test animals:

the rabbit can be used for both male and female, has the weight of 2.0-3.0 kg and is provided by the experimental animal center of Chinese medical university.

2. Drugs and reagents:

compounds II-1 to II-34, i.e., hydrochloride salts of compounds I-1 to I-34, were prepared using the methods of the examples, and their salts (hydrochloride salts) were prepared according to example 2 (or 3) for the following experiments;

sodium chloride (NaCl): purchased from mao chemical reagents factory, Tianjin, lot number: 20120413, respectively;

potassium chloride (KCl): purchased from mao chemical reagents factory, Tianjin, lot number: 20111123, respectively;

anhydrous magnesium sulfate (MgSO)₄): purchased from mao chemical reagents factory, Tianjin, lot number: 20101029, respectively;

anhydrous calcium chloride (CaCl)₂): purchased from mao chemical reagents factory, Tianjin, lot number: 20110314, respectively;

sodium bicarbonate (NaHCO)₃): purchased from mao chemical reagents factory, Tianjin, lot number: 20120507, respectively;

glucose (Glucose): purchased from mao chemical reagents factory, Tianjin, lot number: 20120512, respectively;

potassium dihydrogen phosphate (KH)₂PO₄): product purchased from the mao chemical reagent plant, Tianjin, lot number: 20110928, respectively;

sodium chloride injection (NaCl): purchased from Shenyang Zhiying pharmaceutical factory, lot number: 12021001, respectively;

specification of Epinephrine Hydrochloride Injection (Epinephrine Hydrochloride Injection): 1mg/1ml, available from Yuanda pharmaceutical (China) Co., Ltd., lot number 120105;

noradrenaline Bitartrate Injection (Norepepinephrine Bitartrate Injection) specification 2mg/1ml, Dai medicine (China) Co., Ltd., lot number 120304;

3. an experimental instrument:

HSS-1(B) type constant temperature bath: chengdu instrument factories;

RM6240B multichannel physiological signal acquisition processing system: chengdu instrument factories;

model JZJ01 muscle tension transducer: chengdu instrument factories;

YPJ01 type pressure transducer: chengdu instrument factories;

TG-328A electro-optical analytical balance: shanghai balance instrumentation works;

model T-500 electronic balance: a well-done Shuangjie test instrumentation factory;

a micropipette: shanghai Rongtai Biochemical engineering Co., Ltd;

electric heating constant temperature water bath: tester instruments, Inc., Tianjin.

4. Preparing a nutrient solution:

Krebs-Henseleit (K-H) physiological solution: NaCl 6.92 (concentration unit), KCl 0.35, MgSO₄0.29、KH₂PO₄0.16、CaCl₂0.28，NaHCO₃2.1，Glucose 2.0(g/L)，pH 7.2。

High potassium solution: removing equimolar NaCl from K-H solution, adding KCl to prepare K-containing solution⁺60mmol/L modified K-H solution.

Calcium-free K-H solution: adding CaCl in K-H solution₂Removing, adding KCl in equal molar number, and adding EDTA^-2Na⁺0.1mmol/L, and the other components were unchanged.

Calcium-free high-potassium solution: adding CaCl in the high potassium solution₂Removing, adding KCl in equal molar number, and adding EDTA^-2Na⁺0.1mmol/L, and the other components are unchanged.

Preparation of solutions of Compounds II-1 to II-34: weighing a certain mass of compound II-1-II-34 samples, and diluting the samples to a series of concentrations (10) by using distilled water as a solvent^-10～10^-3mol/L) for standby.

5. Preparation of rabbit isolated blood vessel smooth muscle specimen

The rabbit, after stunning the animal, dissect the thorax rapidly, strip the descending aorta, after removing connective tissue and surrounding adipose tissue (if carrying on the antagonist experiment of serotonin receptor, should also use the smooth stainless steel rod to remove the endothelial cell), cut into the blood vessel ring of 3-5mm, then the steel wire hook crosses the blood vessel ring, one end is fixed on ventilating the hook, another end connects to the tension transducer, put into bath tube containing 20ml nutrient solution, record the change of tension through the recorder. Keeping the temperature in the bath tube at 37 +/-0.5 ℃, and introducing mixed gas (95% O) at the speed of 1-2 bubbles per second₂+5％CO₂). The initial load of the specimen is 1.5g, the nutrient solution is changed every 20min, the balance is carried out for 2 hours, and the experiment is started after the base line is stable.

6. Specific test operation and test result

6.1 relaxation of Compounds II-1 to II-34 on vascular smooth muscle in vitro of Epinephrine (AD) contractile rabbits

After the specimen tension was stabilized, a waveform was recorded and epinephrine hydrochloride (AD) (10) was added to the bath tube^-5mol/L) induced contraction, fully washing the specimen after the maximum contraction is reached, changing K-H liquid every 20min, balancing for 60min, inducing contraction again by using spasmolytic with the same concentration after the baseline is recovered to be stable, and cumulatively adding the prepared compound II-1-II-34 solution (1 × 10) when the maximum reaction of the next contraction is basically consistent with that of the previous one^-10～1×10^-3mol/L), the waveform is recorded. The relaxation effect of compounds II-1 to II-34 is shown in Table 1.

TABLE 1 relaxation of isolated vascular smooth muscle of AD-contracted rabbits by Compounds (II-1 to II-34)

Compound (I)	-logEC₅₀	Compound (I)	-logEC₅₀
				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 relaxation of Noradrenaline (NA) contracting isolated vascular smooth muscle in rabbits with Compounds II-1 to II-34

After the specimen tension was stabilized, a waveform was recorded and epinephrine hydrochloride (AD) (10) was added to the bath tube^-5mol/L) induced shrinkageAfter maximum contraction is reached, the specimen is fully washed, K-H solution is changed every 20min, the balance is 60min, and Norepinephrine (NA) bitartrate (10) is used after the baseline is recovered to be stable^-5mol/L) induced shrinkage when the maximum response of the latter shrinkage is substantially identical to that of the former shrinkage, the prepared compounds II-1 to II-34 solution 1 × 10 are added cumulatively^-10～1×10^-3mol/L), the waveform is recorded. The relaxation effect of compounds II-1 to II-34 is shown in Table 2.

TABLE 2 relaxation of NA contracting rabbit Ex vivo vascular smooth muscle by Compounds II-1 to II-34

Compound (I)	-logEC₅₀	Compound (I)	-logEC₅₀
				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 relaxation of Compounds II-1 to II-34 on isolated vascular smooth muscle of rabbits contracted with high Potassium solution

After the specimen tension was stabilized, a waveform was recorded and epinephrine hydrochloride (AD) (10) was added to the bath tube^-5mol/L), fully washing the specimen after the maximum contraction is reached, changing K-H liquid once every 20min, balancing for 60min, changing the K-H liquid in the bath tube into high-potassium liquid to induce contraction after the base line is recovered to be stable, and cumulatively adding the prepared compound II-1 to II-34 solution (1 × 10) when the maximum reaction of the latter contraction is basically consistent with the former one^-10～1×10^-3mol/L), compound II-1 to II-34 relaxation effects are shown in Table 3.

TABLE 3 relaxation of isolated vascular smooth muscle of rabbits by Compounds II-1 to II-34 in high Potassium solution

Compound (I)	-logEC₅₀	Compound (I)	-logEC₅₀
				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. A benzo five-membered azaheterocyclyl piperidine derivative of formula (I):

wherein:

R₁is represented by R₃A monosubstituted aromatic radical, wherein

The aromatic group is phenyl;

R₃is CF₃；

A. B independently represents CH or N;

R₂represents H;

y represents butylene.

2. The compound of claim 1, wherein the pharmaceutically acceptable salt is a hydrochloride, hydrobromide, sulfate, trifluoroacetate, methanesulfonate, tartrate, malate, succinate, maleate, citrate, phosphate, lactate, pyruvate, acetate, fumarate, oxaloacetate, ethanesulfonate, oxalate, benzenesulfonate or isethionate salt.

3. The compound of claim 2, wherein the pharmaceutically acceptable salt comprises water of crystallization.

4. The compound of claim 3, wherein said pharmaceutically acceptable salt comprises 0.5 to 3 molecules of water of crystallization.

5. A compound according to claim 1 wherein A, B all represent N.

6. A process for the preparation of a compound according to any one of claims 1 to 5:

scheme I

Comprises that

At a temperature of 10-150 ℃ to react

And compounds

Then under reflux, reacting it with the compound

In the presence of an organic base in a solvent to form a compound

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, optionally together with one or more pharmaceutically acceptable excipients or other vascular smooth muscle spasm activity ingredients.

8. Use of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof or a composition according to claim 7 in the manufacture of a vasodilating medicament.

9. The use according to claim 8, wherein the medicament is for the prevention, alleviation or treatment of a disease or condition associated with persistent hypertension of blood vessels, pathological constriction of blood vessels or vasospasm in a subject.

10. The use according to claim 8, wherein the medicament is for the treatment of hypertension, heart failure, angina pectoris, coronary heart disease, cerebral ischemic disease caused by vasospasm, myocardial ischemic disease, shock, renal ischemia, renal dysfunction caused by renal vasospasm or peripheral vasospastic disease.

11. The use of claim 8, wherein the medicament has α receptor antagonism and Ca²⁺The channel blocks the dual role.

12. The use of claim 11, wherein said α receptor antagonist is selective α₁Receptor antagonism.