CN106243003A - Cyclic hydrocarbon radical substituted methanesulfonylbenzamide derivant, its preparation method and purposes pharmaceutically - Google Patents

Abstract

The present invention relates to cyclic hydrocarbon radical substituted methanesulfonylbenzamide derivant, its preparation method and purposes pharmaceutically.Specifically, the invention discloses formula (I) compound or its pharmaceutically acceptable salt, stereoisomer, solvated compounds or prodrug, and its preparation method and application, in formula, the definition of each group refers to description.

Description

Cyclic hydrocarbon radical substituted methanesulfonylbenzamide derivant, its preparation method with pharmaceutically Purposes

Technical field

The invention belongs to pharmaceutical technology field.Specifically, the present invention be more particularly directed to a kind of substituted mesyl of cyclic hydrocarbon radical Heterocyclic carbamate derivatives and preparation method thereof and the application as sodium-ion channel (particularly Nav1.7) inhibitor, and by it The pharmaceutical composition of preparation and Pharmaceutical composition.

Background technology

Recently, the SCN9A gene of reported first coded voltage gate Nav1.7 passage on Nature such as the Cox of Britain Sudden change causes the unexpected result of study of the individual indifference to pain of heredity.The congenital pain sensation that loses of the individuality of this genetic mutation, but body Other function completely normal, in addition it has recently been demonstrated that express the valtage-gated Nav1.7 passage at DRG neuron and participate in The generation of signal play and control the function gate that pain sensation signal is incoming bitterly.This research prompting Nav1.7 passage may become choosing Selecting property treatment pain the drug target having no side effect.

Nav1.7 (PN1, SCN9A) VGSC is sensitive to the blocking-up of Fugu ocellatus toxin, and it is mainly expressed in tip sympathetic neuron And sensory neuron.SCN9A gene is replicated by multiple species (including the mankind, rat and rabbit), and shows people and rat base Aminoacid between Yin has the concordance of about 90%.

Increasing physical evidence shows that Nav1.7 (includes acute, chronic, inflammatory and/or god at multiple pain status Through property pain) in play the part of important role, in the mankind, Nav1.7 protein accumulation, in neuroma, particularly causes pain Neuroma.The sudden change (whether heritability or sporadic) that Nav1.7 function increases is considered to relate to constitutional erythromelalgia (a kind of causalgia being characterized as extremity and the disease of inflammation), and sudden extreme pain disease.Relevant non-selective sodium channel blocks Agent lignocaine and mexiletine can relax the symptom of heritability erythromelalgia, and carbamazepine can lower PEPD's effectively The number of times of invasion and attack and the report result of severity are consistent with above-mentioned observation.Nav1.7 is other cards of role in pain Phenotype according to the sudden change of the afunction being found in SCN9A gene.Follow-up research display can cause the function of SCN9A gene Lose the sudden change different from the many of CIP phenotype.

Due to Nav1.7 specifically DRG sensory neuron express and not myocardial cell and central nervous system etc. other Tissue expression, therefore researches and develops its specific blockage agent for treating chronic pain, it is not only possible to improve curative effect, and side effect also can be significantly Reduce, and the selective depressant of Nav1.7 ion channel may be used with nearly the treatment of various pain.

Additionally, Nav1.5 and Nav1.2 of one of member of this protein family is also an important class ion-type passage, NaV1.5 mainly expresses (Raymond, C.K. etc., op.cit.) in myocardial cell, including atrium, ventricle, sinuatrial node, chamber Knot and cardiac Purkinje fibers.The rapid ascending branch of heart action potential and by the rapid pulse conduction of heart tissue due to The unlatching of NaV1.5.The exception of NaV1.5 function may result in multiple ARR formation.The sudden change of human body NaV1.5 causes many Kind of arrhythmia syndrome, including, such as, long QT3 (LQT3), Brugada syndrome (BS), heritability cardiac conduction defect, Sudden sudden-death syndrome (SUNDS) and sudden infant death syndrome (SIDS) (Liu, H. etc., Am.J.Pharmacogenomics (2003),3(3):173-9).Sodium channel blockers treatment is widely used in treatment arrhythmia.Therefore Nav1.5 is suppressed Passage can produce cardiac toxicity.In addition NaV1.2 height in the brain expresses (Raymond, C.K. etc., J.Biol.Chem. (2004), 279 (44): 46234-41) and be important to normal brain function.Therefore suppression Nav1.2 passage can be to greatly Brain produces suppression toxicity.

Therefore, the effect limited in view of currently available medicament and unacceptable side effect, more pacify in the urgent need to exploitation Complete effective analgesic so that it is there is higher effect and less side effect.And Nav1.7 ion channel is that exploitation is without additive town The important target of medicine bitterly, exploitation has Nav1.7 ion channel high selectivity and has pressing down of good Pharmacokinetic Characteristics Preparation is the most necessary.

Summary of the invention

It is an object of the invention to provide a kind of Nav1.7 ion channel selective depressant and pharmaceutically applying.

First aspect present invention, it is provided that the compound shown in a kind of formula (I), or its pharmaceutically acceptable salt, solvation Thing, stereoisomer or prodrug:

In formula,

R₁For fluorine or chlorine；R₂For cyclopropyl or cyclohexenyl group；N is 0 or 1；Z is N or CR₇；

R₃、R₄、R₅、R₆、R₇It is each independently hydrogen, halogen, halo C_1-20Alkyl, C_1-20Alkoxyl, halo C_1-20Alcoxyl Base.

In another preference, R₁For fluorine；R₂For cyclopropyl.

In another preference, Z is CR₇, R₇Defined as described above.

In another preference, n is 1.

In another preference, R₃、R₄、R₅、R₆、R₇It is each independently hydrogen, fluorine, chlorine, trifluoromethyl, methoxyl group, ethoxy Base, propoxyl group, isopropoxy, trifluoromethoxy, trifluoro ethoxy.

In another preference, R₆For hydrogen.

In another preference, Z is CR₇；R₃、R₄、R₅、R₆、R₇It is each independently hydrogen, fluorine, chlorine, trifluoromethyl, methoxy Base, ethyoxyl, propoxyl group, isopropoxy, trifluoromethoxy, trifluoro ethoxy, trifluoromethyl；And R₃、R₄、R₅、R₆、R₇In three Individual for hydrogen.

In another preference, Z is CR₇；R₃、R₄、R₅、R₇Be each independently hydrogen, fluorine, chlorine, trifluoromethyl, methoxyl group, Ethyoxyl, propoxyl group, isopropoxy, trifluoromethoxy, trifluoro ethoxy, trifluoromethyl；R₆For hydrogen, and R₃、R₄、R₅、R₇In Two is hydrogen.

In another preference, Z is CR₇；R₃、R₅And R₆For hydrogen；And R₄And R₇Be each independently fluorine, chlorine, trifluoromethyl, Or trifluoromethoxy.

In another preference, Z is CR₇；R₃、R₅And R₆For hydrogen；And R₄For be each independently fluorine, chlorine, trifluoromethyl or Trifluoromethoxy, and R₇For chlorine.

In another preference, Z is N.

In another preference, Z is N；R₃、R₄、R₅、R₆It is each independently hydrogen, fluorine, chlorine, trifluoromethyl, methoxyl group, second Epoxide, propoxyl group, isopropoxy, trifluoromethoxy, trifluoro ethoxy, trifluoromethyl；And R₃、R₄、R₅、R₆In two be hydrogen.

In another preference, Z is N；R₃、R₆For hydrogen；R₄、R₅It is each independently hydrogen, fluorine, chlorine, trifluoromethyl, methoxy Base, ethyoxyl, propoxyl group, isopropoxy, trifluoromethoxy, trifluoro ethoxy, trifluoromethyl.

In another preference, described compound is the compound prepared by the embodiment of the present application:

Second aspect present invention provides a kind of pharmaceutical composition, and described compositions includes described in first aspect present invention Compound or its pharmaceutically acceptable salt, solvate, stereoisomer or prodrug；And pharmaceutically acceptable carrier.

Third aspect present invention provides compound as described in the first aspect of the invention or it is pharmaceutically acceptable Salt, solvate, stereoisomer or prodrug, or pharmaceutical composition described in second aspect present invention is in preparation treatment disease or disease Application in the medicine of disease.

In another preference, described disease or disease selected from pain, depression, cardiovascular disease, respiratory system disease, Mental sickness or a combination thereof.

In another preference, described disease or disease are selected from the pain relevant to HIV, the neuropathy of HIV therapy induction Change, trigeminal neuralgia, postherpetic neuralgia, acute pain, thermo-responsive, sarcoidosis, irritable bowel syndrome, sieve's g grace sick and The relevant pain of multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, Arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, paroxysmal dystonia, myasthenic syndrome, flesh are strong Directly, malignant hyperthermia, cystic fibrosis, pseudohyperaldosteronism, rhabdomyolysis, hypothyroidism, Bipolar Depression Disease, anxiety neurosis, schizophrenia, sodium channel toxin associated conditions, familial erythromelalgia, constitutional erythromelalgia Disease, familial rectal pain, cancer, epilepsy, locally and systemically tonic seizures, restless legs syndrome, arrhythmia, fiber flesh Bitterly, the neuroprotective under the ischemic diseases state caused by apoplexy or nerve injury, tachyarrhythmia, atrial fibrillation And ventricular fibrillation.

In another preference, described pain is selected from neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy Pain, trauma pain, operation pain, postoperative pain, production pain, labor pains, toothache, chronic pain, rest pain, The pain of periphery mediation, the pain of maincenter mediation, chronic headache, migraine, sinus headache, tension headache, phantom pain, surrounding Nerve injury, trigeminal neuralgia, postherpetic neuralgia, acute pain, familial erythromelalgia, constitutional are erythematous Erythroderma, familial rectal pain or fibromyalgia or a combination thereof.

Fourth aspect present invention provides a kind of method treating mammalian diseases or disease, and described method includes to needing The compound as described in first aspect present invention of object (such as mammal) the administering therapeutic effective dose wanted, or it pharmaceutically can connect Salt, solvate, stereoisomer or the prodrug being subject to, or the pharmaceutical composition described in second aspect present invention.

In should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and having in below (eg embodiment) Can be combined with each other between each technical characteristic that body describes, thus constitute new or preferred technical scheme.As space is limited, exist This tires out the most one by one states.

Accompanying drawing explanation

Fig. 1 is that rat crymodynia tests baseline chart.

Fig. 2 is the use one factor analysis of variance additional Dunnett multiple comparative test result figure of compound Z-2.

Detailed description of the invention

The present inventor is through extensively in-depth study, it has unexpectedly been found that the cyclic hydrocarbon radical of the present invention replaces (particularly ring Propyl group replace) methanesulfonylbenzamide derivant not only Nav1.7 is had higher inhibitory activity, simultaneously to Nav1.5 The most weak with the inhibitory activity of Nav1.2, have and significantly select inhibitory activity.Also show in pain model is tested simultaneously Go out obvious analgesic effect, pharmacokinetic have obvious medicine for assimilation effect and good bioavailability, And there is obvious metabolic stability.Therefore the series compound of the present invention can be developed into the medicine of the treatment for extensive pain Thing.On this basis, inventor completes the present invention.

Term defines

As used herein, " C_1-20Alkyl " refer to comprise the saturated aliphatic hydrocarbyl of the straight chain of 1 to 20 carbon atom and side chain, It is defined below being similar to；More preferably C_1-10Alkyl, nonrestrictive example includes: methyl, ethyl, n-pro-pyl, isopropyl, positive fourth Base, isobutyl group, the tert-butyl group, sec-butyl, n-pentyl, 1,1-dimethyl propyl, 1,2-dimethyl propyl, 2,2-dimethyl propyl, 1-ethyl propyl, 2-methyl butyl, 3-methyl butyl, n-hexyl, 1-Ethyl-2-Methyl propyl group, 1,1,2-thmethylpropyl, 1, 1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethyl-butyl, 2-methylpent Base, 3-methyl amyl, 4-methyl amyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methyl are own Base, 5-methylhexyl, 2,3-dimethyl amyl group, 2,4-dimethyl amyl group, 2,2-dimethyl amyl group, 3,3-dimethyl amyl group, 2- Ethyl pentyl group, 3-ethyl pentyl group, n-octyl, 2,3-dimethylhexanyl, 2,4-dimethylhexanyl, 2,5-dimethylhexanyl, 2,2- Dimethylhexanyl, 3,3-dimethylhexanyl, 4,4-dimethylhexanyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2- Methyl-2-ethyl pentyl group, 2-methyl-3-ethyl pentyl group, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethyl amyl groups, positive decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers etc.；More excellent Elect C as_1-6Alkyl, most preferably C_1-3Alkyl.

As used herein, " part is unsaturated " refers to containing one or more unsaturated bonds but does not have the π of total conjugated Electronic system.

As used herein, " C_1-20Alkoxyl " refer to-O-(C_1-20Alkyl), wherein alkyl is as defined above.Preferably C_1-10 Alkoxyl, more preferably C_1-6Alkoxyl, most preferably C_1-3Alkoxyl.Non-limiting example comprises methoxyl group, ethyoxyl, the third oxygen Base, isopropoxy, butoxy, tert-butoxy, isobutoxy, amoxy etc..

As used herein, " halogen " refers to fluorine, chlorine, bromine or iodine.

As used herein, " halo " refers to that one or more in group (such as 1,2,3,4 or 5) hydrogen is replaced by halogen.

Such as, " halo C_1-20Alkyl " refer to that alkyl is by one or more (such as 1,2,3,4 or 5) halogen substiuted, wherein alkane Base is as defined above.It is preferably halo C_1-10Alkyl, more preferably halo C_1-6Alkyl, most preferably halo C_1-3Alkyl. Halo C_1-20The example of alkyl includes, but is not limited to a chloroethyl, dichloromethyl, 1,2-Dichloroethyl, a bromoethyl, a fluorine Ethyl, a methyl fluoride, difluoromethyl, trifluoromethyl etc..

The most such as, " halo C_1-20Alkoxyl " refer to alkoxyl by one or more (such as 1,2,3,4 or 5) halogen substiuted, Wherein alkoxyl is as defined above.It is preferably halo C_1-10Alkoxyl, more preferably halo C_1-6Alkoxyl, most preferably Halo C_1-3Alkoxyl.Include, but is not limited to trifluoromethoxy, trifluoro ethoxy, a fluorine methoxyl group, a fluorine ethyoxyl, difluoro Methoxyl group, difluoroethoxy etc..

As used herein, " substituted " refers to the one or more hydrogen atoms in group, and preferably 1～5 hydrogen atom is each other Being replaced by the substituent group of respective number independently, more preferably 1～3 hydrogen atom is independently of one another by the substituent group of respective number Replace.Self-evident, substituent group is only in their possible chemical position, and those skilled in the art can not pay too much (by experiment or theoretical) possible or impossible replacement is determined in the case of effort.Such as, there is amino or the hydroxyl of free hydrogen Base is probably instability when the carbon atom with unsaturation (such as olefinic) key is combined.

Preparation method

The invention provides the preparation method of formula (I) compound, the compound in the present invention can be by multiple synthesis behaviour Easily preparing, these operations are that one of ordinary skill in the art skillfully grasp.The illustrative preparation method of these compounds Flow process hereinafter described can be included, but is not limited to.

Formula (I) compound of the present invention is referred to following synthetic route and is prepared, in specific operation process, and Ke Yigen Step in method is extended or merges according to needing.

Route 1

Step 1: in the presence of alkali systems, the reactive group of the nucleophilic character by being had in formula (I-b) compound (such as OH etc.) and formula (I-a) compound generation substitution reaction (such as nucleophilic substitution reaction etc.) production (I-c) compound, properly Alkali systems include being present in the potassium tert-butoxide of DMSO, the sodium hydride being present in DMF, be present in the potassium carbonate etc. of DMF, formula (I-a) Lev in is leaving group, includes, but is not limited to triflate；Chlorine, bromine, iodine；Sulfonate group, such as methanesulfonic acid Ester, tosylate, brosylate, p-toluenesulfonic esters etc.；Acyloxy, such as acetoxyl group, trifluoroacetyl epoxide etc..X For chlorine, bromine or iodine.

Step 2: formula (I-c) compound by group X and cyclic hydrocarbon radical borate or boric acid at a certain temperature, uses and closes Suitable catalyst and suitable solvent react, and generate compound I.Using Suzuki method, palladium catalyst used is permissible It is but not limited to PdCl₂(dppf), palladium, alkali used can be but not limited to potassium carbonate or cesium carbonate.Part used Tricyclohexyl phosphine can be but not limited to.

Route 2

Formula (I-a) compound can obtain formula (I-d) compound by Suzuki reaction, sends out with formula (I-b) compound subsequently Raw substitution reaction production I, the reaction condition of each step and group definition are with route 1.

In above-mentioned preparation method, formula (I-b) compound is commercially available or is prepared from known compounds by those skilled in the known methods. Formula (I-a) compound can be synthesized by following two exemplary method,

Method 1

With formula (I-a-1-1) compound as initiation material, pass sequentially through replacement, condensation, bromo, replace, hydrolyze and be acylated Reaction obtains formula (I-a-1) compound, the popular response that the most each step is well known to the skilled person.

Method 2

With formula (I-a-2-1) compound as initiation material, pass sequentially through replacement, condensation reaction obtains formula (I-a-2) chemical combination Thing, the popular response that the most each step is well known to the skilled person.

Reaction in the most each step is all popular response well known by persons skilled in the art.If no special instructions, synthesis Reagent used in route and starting compound is the most commercially available obtains, or those skilled in the art do not assimilate according to designed Laminate structures prepares with reference to known method.

Compared with prior art, main advantages of the present invention are:

Series compound of the present invention is high to the inhibitory activity of Nav1.7, relatively to the inhibitory activity of Nav1.5 and Nav1.2 simultaneously Weak, Nav1.5 and Nav1.2 is respectively provided with selection inhibitory activity.Series compound of the present invention is the suppression with statistical significance The effect of cold stimulation allodynia.Series compound of the present invention not only has obvious medicine for assimilation effect and good biological profit Expenditure, and there is obvious metabolic stability.

Below in conjunction with specific embodiment, the present invention is expanded on further.Should be understood that these embodiments are merely to illustrate the present invention Rather than restriction the scope of the present invention.The experimental technique of unreceipted actual conditions in the following example, generally according to conventional strip Part or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise percentage ratio and number are calculated by weight.Unless separately Definition, the same meaning that term used herein and one skilled in the art are familiar with.Additionally, it is any similar to described content Or equal method and material all can be applicable in the present invention.

As used herein, DMB is 2,4-dimethoxy-benzyl, and THF is oxolane, and EA is ethyl acetate, and PE is oil Ether, Ac₂O is acetic anhydride, and NBS is N-bromosuccinimide, and DCM is dichloromethane, and AIBN is azodiisobutyronitrile, Pd (dppf)Cl₂It is 1, double (diphenylphosphine) ferrocene of 1'-] palladium chloride, TFA is trifluoroacetic acid, and TBSCl is fert-butyidimethylsilyl Chlorosilane, NCS is N-chlorosuccinimide, and DHP is dihydropyran, LiAlH₄For lithium aluminium hydride reduction, PMB is to methoxybenzyl Base, LiHMDS is two (trimethyl is silica-based) Lithamide., Pd₂(dba)₃Being three (dibenzalacetone) two palladium, RuPhos is 2-bicyclo- Hexyl phosphorus-2', 6'-diisopropoxy-1,1'-biphenyl, DMAP is DMAP, and THP is Pentamethylene oxide., and n-BuLi is N-BuLi, TMsOTf is Trimethylsilyl trifluoromethanesulfonate, and TEBAC is triethyl benzyl ammonia chloride, and HATU is 2-(7-azo BTA)-N, N, N', N'-tetramethylurea hexafluorophosphoric acid ester, DMF is dimethylformamide, and DMSO is dimethyl sulfoxide, DIEA is DIPEA, and BINAP is (2R, 3S)-2, double diphenyl phosphine-1 of 2'-, 1'-dinaphthalene.

As used herein, room temperature refers to about 20-25 DEG C.

The preparation method of compound 1-a:

Step a: be partly dissolved in the solution of dichloromethane (500ml) to compound 1-a-1 (41.7g, 0.271mol) Add bromine (103.8g, 0.65mol), be under nitrogen guard mode and add iron powder (46.2g, 0.82mol) in batches, heating To 40 DEG C, stir 24 hours, be cooled to room temperature, sodium hydrosulfite aqueous solution (200ml*3) washing of 10%, separatory, aqueous phase EA (100ml*3) extraction, saturated aqueous common salt (50ml) washs, and sodium sulfate is dried, and filters, and filtrate is spin-dried for obtaining a black solid (45g), add ethyl acetate making beating and obtain compound 1-a-2 (45g, productivity: 71%) white solid；ESI-MS:233.0(M +H)⁺。

Step b: to equipped with compound 1-a-2 (26g, 0.112mmol), Methanesulfomide (16.34g, 0.172mol), EDCI (32.93g, 0.172mol), adds dichloromethane (270ml), N in the reaction bulb of DMAP (21g, 0.172mol)₂Protection, room temperature Overnight, water (100ml) cancellation, HCl (1M) adjusts pH=1～2, DCM (3*150ml), and saturated aqueous common salt (100ml) washs, sulphuric acid Sodium is dried, and filters, and filtrate is spin-dried for obtaining compound as white solid 1-a-3 (22.5g, productivity 65%).ESI-MS:310.7(M+H )⁺。

Step c: under nitrogen protection, to compound 1-a-3 (22.5g, 0.073mol), NBS (16.8g, 0.094mol) Mixture in add dichloroethanes (250ml), be warming up to 80 DEG C, reactant liquor is gradually clarified, will dissolve AIBN (238mg, 1.45*10^-3Mmol) dichloroethane solution is added drop-wise in above-mentioned reactant liquor, reaction overnight.Being cooled to room temperature, sodium hydrosulfite is water-soluble Liquid (10%, 100ml) cancellation, separatory, aqueous phase ethyl acetate (3*150ml) extracts, middle ammonia (150ml) and methanol (100ml) Mixed solution in add above-mentioned reactant liquor, it is allowed to reactant liquor is warmed to room temperature, and stirs 10 minutes, ethyl acetate (100ml*3) extract Taking, merge organic facies, saturated aqueous common salt (50ml) washs, and sodium sulfate is dried, and filtering and concentrating obtains 27g crude product, and ethyl acetate is beaten Slurry obtains compound 1-a-4 (5.2g, yield: 18%).ESI-MS:389.9 (M+H)⁺。

Step d: at N₂Protection, to compound 1-a-4 (5.2g, 1.34*10^-2Mol) potassium acetate (2.62g, 2.68*10^{- 2}Mol) mixture adds DMF (25ml), is heated to 80 DEG C, is stirred overnight.Being cooled to room temperature, ethyl acetate (200ml) is dilute Releasing, water (10ml*7) washs, and saturated aqueous common salt (10ml) washs, and sodium sulfate is dried, and filtering and concentrating obtains compound 1-a-5 (3.0g, yield: 61%), is a white solid.ESI-MS:363.0 (M+Na)⁺。

Step e: at N₂Under protection, to compound 1-a-5 (3.68g, 10mmol) and cyclopropylboronic acid (1.28g, Toluene (40ml) suspension 15mmol) adds water (10ml) suspension of potassium phosphate (9.5g, 45mmol), stir about 3～4 points Clock, then tricyclohexyl phosphine borofluoride (3.68g, 10mmol) and palladium (225mg, 1mmol) are sequentially added into above-mentioned reaction In liquid, being heated to 110 DEG C, be stirred overnight, be down to room temperature, water (50ml) cancellation reactant liquor, ethyl acetate (100ml) dilutes, silicon Diatomaceous earth filters, separatory, and hydrochloric acid (1mol/L) is acidified to pH=2, and ethyl acetate (4*50ml) extracts, and saturated aqueous common salt (20ml) is washed Washing, sodium sulfate is dried, and filtering and concentrating obtains grease, and preparation HPLC purification obtains compound 1-a (430mg, yield 14%). ESI-MS:288.1 (M+Na)⁺,¹H NMR (400MHz, DMSO) δ: 12.15 (s, 1H), 7.28 (d, J=11.6Hz, 1H), 7.22 (d, J=6.8Hz, 1H), 5.5 (s, 1H), 4.27 (s, 2H), 3.36 (s, 3H), 1.84 (m, 1H), 0.9 (m, 2H), 0.67 (m, 2H)。

The preparation method of compound 2-a:

Step a: under nitrogen protection, adds tetrahydrochysene in the reaction bulb equipped with NaH (6.4g, 0.167mol) by 0～5 DEG C Furan (165ml) solution；At 0～5 DEG C, dripping isopropanol (12.8ml, 0.167mol) in above-mentioned turbid solution, time for adding is about 1 hour, after finishing, reactant liquor allowed to be warming up to room temperature, stirs 1 hour.The four of compound 2-a-1 (15.57g, 0.105mol) Hydrogen furan (50ml) solution adds in above-mentioned turbid solution, is heated to 60 DEG C, is stirred overnight, at 30 DEG C, and saturated ammonium chloride (50ml) With water (60ml) cancellation, separatory, ethyl acetate (3x50ml) extracts, and saturated aqueous common salt (20ml) washs, and sodium sulfate is dried, and concentrates Obtain black liquor compound 2-a-2 (20.0g, yield 71%)；ESI-MS:172.0(M+H)⁺。

Step b: add sodium acetate in ethyl acetate (30ml) solution of compound 2-a-2 (6g, 0.035mol) (3.2g, 0.039mol), under stirring, less than 7 DEG C, drips bromine (10.6g, 0.042mol) in above-mentioned turbid solution, Allow to rise room temperature, be stirred overnight.Below 5 DEG C, by the aqueous solution (20ml) of sodium hydroxide (4.6g) and sodium thiosulfate (2g) Dropping to (during dropping, pH is less than 8) in reactant liquor, separatory, aqueous phase ethyl acetate (2x40ml) extracts, and merges organic facies, saturated Saline solution (30ml) washs, and sodium sulfate is dried, and filters, is concentrated to give grease, column chromatography (silica gel: 300-400 mesh, eluant: stone Oil ether) purification obtains compound 2-a-3 (5.1g, yield: 58%), for liquid.ESI-MS:249.8(M+H)⁺。

Step c: to connection boric acid pinacol ester (6.7g, 2.65x10^-3Mol), potassium acetate (7g, 7.13x10^-2Mol) and PdCl₂(dppf) .DCM (831mg, 1.02x10^-3Mol) mixture adds compound 2-a-3 (5.1g, 2.04x10^-3Mol) DMF (60ml) solution, reactant liquor nitrogen displacement 3 times, it is heated to 65 DEG C, is stirred overnight, diluted ethyl acetate (400ml), washing (6x30ml), saturated aqueous common salt (50ml) wash, sodium sulfate is dried, filter, be concentrated to give a compound 2-a-4 (6.0g, crude product, Yield: 100%), it is a slurry.ESI-MS:298.0(M+H)⁺。

Step d: at 15 DEG C, adds water (19ml), acetic acid in the reaction bulb of compound 2-a-4 (6.0g, 0.02mol) (38ml), peracetic acid (1.8g, 0.0236mol), it is allowed to be warmed to room temperature, stirred under nitrogen atmosphere is overnight.By remaining acetic acid Spinning off with oil pump, residue ethyl acetate (250ml) dilutes, and water (2x30ml) is washed, and saturated aqueous common salt (20ml) washs, mistake Filter, sodium sulfate is dried, and is concentrated to give a dark oil thing, column chromatography (silica gel: 200-300 mesh；Eluant-petroleum ether: ethyl acetate =15:1) purification obtains compound 2-a (5.1g, yield: 58%), is a liquid.ESI-MS:188.0(M+H)⁺。

The preparation method of compound 3-a:

The preparation method of compound 4-a:

Step a: add compound 4-a-1 (23.4g, 0.148mol) in cold concentrated sulphuric acid (120ml), treat that substrate is molten Xie Hou, maintains the temperature at less than 5 DEG C, is dividedly in some parts N-N-iodosuccinimide (33g, 0.148mol), maintains this temperature after finishing Degree, stirs 5 hours.Reactant liquor is poured in the frozen water (20ml) being stirred vigorously, and filters, and filter cake uses ethanol: water (1:1) is pulled an oar, Filter, obtain compound 4-a-2 (8.0g, yield: 20%), be a pink solid.ESI-MS:285.0(M+H)⁺。

Step b: Bis(tert-butoxycarbonyl)oxide (21g, 0.0962mol), DMAP (1g, 8x10^-3Mol) add successively Enter to obtain compound 4-a-2 (7.2g, 2.54x10^-2Mol), in the tert-butyl alcohol (40ml) solution, under nitrogen protection, it is heated to 60 DEG C, It is stirred overnight.Diluted ethyl acetate (300ml), dilute hydrochloric acid washes (1M, 30ml), saturated sodium bicarbonate aqueous solution (30ml), saturated Saline solution (20ml) washs, and sodium sulfate is dried, and filters, is concentrated to give to obtain compound 4-a-3 (8.0g, yield: 93%), is a brown Solid.ESI-MS:362.8(M+H)⁺。

Step c: to compound 2-a (3.4g, 1.8x10^-2Mol), compound 4-a-3 (6.18g, 1.82x10^-2Mol), carbon Acid potassium (5.0g, 3.64x10^-2Mol) adding dimethyl sulfoxide (30ml) in, the lower stirred overnight at room temperature of nitrogen protection, ethyl acetate is dilute Releasing (300ml), water (3x30ml) washs, and saturated aqueous common salt (20ml) washs, and sodium sulfate is dried, and filtering and concentrating obtains compound 4- A-4 (8.91g, yield: 89.8%), is a brown solid.ESI-MS:508.0(M+H)⁺。

Step d: to compound 4-a-4 (150mg, 2.95x10^-4Mol), cyclopropylboronic acid (76mg, 8.86x10^-4Mol), Potassium phosphate (250mg, 1.18x10^-3Mol), tetra-triphenylphosphine palladium (30mg, 2.95x10^-5Mol) 1,4-dioxane is added in (1.5ml), nitrogen is replaced three times, is heated to 150 DEG C, microwave reaction 45 minutes.It is in product that LCMS shows part by-product Chlorine also replaced by ring third class.Diluted ethyl acetate, kieselguhr filters, is concentrated to give 1.7g yellow oil, Pre-HPLC purification, It is concentrated to give compound 4-a-5 (0.06g, yield: 50%), is a white slurry thing.ESI-MS:421.9(M+H)⁺。

Step e: at 0 DEG C, to compound 4-a-5 (0.5g, 1.85x10^-3Mol), in dichloromethane (15ml) solution, add Enter trifluoroacetic acid (0.5ml), it is allowed to be warmed to room temperature, stir 24 hours under condition of nitrogen gas.Concentration of reaction solution obtains white solid, molten In ethyl acetate, purified obtain compound 4-a (0.32g, yield: 73%).ESI-MS:365.9(M+H)⁺,¹H NMR (400MHz, DMSO) δ: 13.12 (s, 1H), 8.04 (d, J=2.4Hz, 1H), 7.90 (s, J=2.8Hz, 1H), 7.45 (d, J= 8Hz, 1H), 6.73 (d, J=11.6Hz, 1H), 5.28 (quint, J=6Hz, 1H), 2.10 (m, 1H), 1.37 (s, 3H), 1.33 (s, 3H), 0.95 (m, 2H), 0.71 (m, 2H).

The preparation method of compound 5-a:

Compound 5-a is with compound 4-a-1 as initiation material, and the method for reference compound 4-a is prepared, except for the difference that Change compound 2-a in step c into compound 3-a.

Embodiment 1 4-((3-chloro-4-(trifluoromethyl) phenoxy group) methyl)-5-cyclopropyl-2-fluoro-N-(sulfonyloxy methyl Base) preparation of Benzoylamide (Z-1)

Step 1: to compound 1-a (150mg, 0.522mmol) and the 5ml dichloro of triethylamine (106mg, 1.044mmol) Dichloromethane adds methylsufonyl chloride (60mg, 0.522mmol) at zero degrees celsius, is stirred at room temperature 2 hours.Reaction terminates, instead Answering liquid to pour in frozen water, dichloromethane extracts, and organic facies saturated common salt is washed, and anhydrous sodium sulfate is dried, and filters, filtrate decompression It is concentrated to give pale yellowish oil crude Compound 1-b (147mg).It is directly used in next step reaction.

Step 2: compound 1-b (117mg, 0.32mmol), 3-chloro-4-(trifluoromethyl) phenol (68mg, 0.32mmol), Potassium carbonate (89mg, 0.64mmol) adds in 5ml acetonitrile solution, and 60 degrees Celsius are stirred 2 hours.Reaction terminates, and is cooled to room temperature, Reactant liquor concentrating under reduced pressure, adds 10ml water, and regulation pH is 7, dichloromethane extraction (2 × 10ml), organic facies saturated aqueous common salt Washing, anhydrous sodium sulfate is dried, and filters, and filtrate reduced in volume obtains crude product.White solid chemical combination is obtained after purification through preparation liquid phase separation Thing Z-1 (60.3mg), productivity: 39.2%, MS m/z (ESI): 481.9 [M+H]⁺。¹H NMR(DMSO-d₆,400MHz):δ 12.23 (br.s., 1H), 7.54 (dd, J=9.2,1.2Hz, 1H), 7.49 (d, J=3.2Hz, 1H), 7.43 (d, J= 10.8Hz, 1H), 7.29 (d, J=6.8Hz, 1H), 7.19 (dd, J=9.2,2.8Hz, 1H), 5.37 (s, 2H), 3.37 (s, 3H),2.00-2.06(m,1H),0.92-1.00(m,2H),0.73-0.79(m,2H)。

Embodiment 2-3

Compound Z-2 and Z-3 is with compound 1-a as initiation material, and the method with reference to embodiment 1 is prepared, different It is that chloro-for the 3-in step 2 4-(trifluoromethyl) phenol is changed into respectively 3,4-chlorophenesic acid, 3,5-chlorophenesic acids.

Embodiment 4 4-(5-chloro-6-isopropyl pyridine-3-base epoxide)-5-cyclopropyl-2-fluoro-N-(methyl sulphonyl) benzene The preparation of Methanamide (Z-4)

Compound 4-a (100mg, 0.273mmol), compound 6-a (52mg, 0.546mmol), HATU (2-(7-diphenyl diimide And triazole)-N, N, N', N'-tetramethylurea hexafluorophosphoric acid ester) (104mg, 0.273mmol), DIPEA (N, N-diisopropyl second Amine) (71mg, 0.546mmol), DMAP (DMAP) (4mg, 0.027mmol) adds in 5ml dichloromethane solution, It is stirred at room temperature 3 hours.Reaction terminates, and reactant liquor is washed, and saturated common salt is washed, and anhydrous sodium sulfate is dried, and filters, and filtrate decompression is dense Contract to obtain crude product.Yellow solid compound Z-4 (21mg), MS m/z (ESI): 443.1 [M+H] is obtained after purification through TLC⁺。¹H NMR (400MHz,DMSO-d₆): δ 12.09 (s, 1H), 8.04 (d, J=2.8Hz, 1H), 7.87 (d, J=2.4Hz, 1H), 7.28 (d, J=8.0Hz, 1H), 6.82 (d, J=11.6HZ, 1H), 5.31-5.25 (m, 1H), 3.35 (s, 3H), 2.15-2.10 (m, 1H), 1.34 (d, J=6.4Hz, 6H), 0.98-0.93 (m, 2H), 0.83-0.79 (m, 2H).

Embodiment 5

Compound Z-5 is with compound 6-a as initiation material, and the method with reference to embodiment 4 is prepared, except for the difference that will step Compound 4-a in Zhou changes compound 5-a into.

Embodiment 6 5-cyclohexenyl group-4-((3,4-dichlorophenoxy) ethyl)-2-fluoro-N-(methyl sulphonyl) benzoyl The preparation of amine (Z-7)

With the synthetic method that compound 6-b (471mg) is raw material reference example 6 step 2, except for the difference that by 4-in step (4,4,5,5-tetramethyl-1,3,2-dioxy boron penta ring-2-base)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester changes 2-ring into Hexyl-4,4,5,5-tetramethyl-1,3,2-dioxy boron penta ring.Obtain yellow compound z-7 (36.8mg), productivity 42%, MS m/ z(ESI):472.0[M+H]⁺。¹H NMR(DMSO-d₆, 400MHz): δ 7.54 (d, J=8.8Hz, 1H), 7.47 (d, J= 7.2Hz, 1H), 7.25-7.34 (m, 2H), 7.01 (dd, J=8.8,2.8Hz, 1H), 5.60 (br.s., 1H), 5.07 (s, 2H), 3.04(s,3H),2.17-2.24(m,2H),2.04-2.12(m,2H),1.64-1.74(m,2H),1.49-1.64(m,2H)。

Embodiment 7 4-((5-chloro-6-isopropyl pyridine-3-base epoxide) methyl)-5-cyclopropyl-2-fluoro-N-(methyl sulphur Acyl group) preparation of Benzoylamide (Z-8)

Step 1: in the 8ml acetonitrile solution of compound 2-a (86mg, 0.46mmol) add compound 1-a-4 (178mg, 0.46mmol), potassium carbonate (128mg, 0.92mmol), 80 DEG C are stirred 4 hours.Reaction terminates, and is cooled to room temperature, filters, filter cake Adding hydrochloric acid (3N, 5ml), ethyl acetate extracts, and organic facies concentrating under reduced pressure obtains yellow solid compound 8-b (130mg).MS m/z (ESI):495.0[M+H]⁺.It is directly used in next step reaction.

Step 2: in the toluene and water of compound 8-b (117mg, 0.32mmol) add cyclopropylboronic acid (68mg, 0.32mmol), tricyclohexyl phosphine (89mg, 0.64mmol), potassium carbonate (89mg, 0.64mmol), palladium (89mg, 0.64mmol), argon shield, 100 DEG C are stirred 1 hour.Reaction terminates, and is cooled to room temperature, and ethyl acetate extracts, and organic facies is with full Washing with sodium bicarbonate, anhydrous sodium sulfate is dried, and filters, and filtrate reduced in volume obtains crude product.Through preparation liquid phase separation after purification in vain Color solid chemical compound Z-8 (18mg), productivity: 18%, MS m/z (ESI): 457.1 [M+H]⁺。1H NMR(500MHz,DMSO- D6): δ 7.97 (d, J=2.5Hz, 1H), 7.81 (d, J=2.5Hz, 1H), 7.31 (d, J=7.5Hz, 1H), 7.17 (d, J= 11.5Hz, 1H), 5.27 (s, 2H), 5.23-5.18 (m, 1H), 2.83 (s, 3H), 2.01-1.96 (m, 1H), 1.30 (d, J= 6.0Hz,6H),0.94-0.91(m,2H),0.62-0.60(m,2H).

Embodiment 8 4-((3-chloro-4-(trifluoromethyl) phenoxy group) methyl)-5-cyclopropyl-2-fluoro-N-(sulfonyloxy methyl Base) preparation of Benzoylamide (Z-9)

Step 1: compound 3-chlorin-4-(trifluoromethyl) phenol (200mg, 1.017mmol), compound 1-a-4 (395mg, 1.017mmol), potassium carbonate (218mg, 2.035mmol) adds in 10ml acetonitrile solution, and 80 degrees Celsius are stirred overnight.Reaction knot Bundle, is cooled to room temperature, is poured into water, and ethyl acetate extracts, and saturated common salt is washed, and anhydrous sodium sulfate is dried, and filters, and filtrate concentrates Obtain yellow solid compound 9-b (0.647g).MS m/z(ESI):503.9[M-H]^-.It is directly used in next step reaction.

Step 2: compound 9-b (300mg, 0.594mmol), cyclopropylboronic acid (103mg, 1.189mmol), Pd (dppf) Cl₂(44mg, 0.059mmol), cesium carbonate (388mg, 1.189mmol) adds in 10ml dioxane solution, argon shield, and 80 DEG C it is stirred overnight.Reaction terminates, and is cooled to room temperature, and kieselguhr filters, and filtrate reduced in volume is pure through Combi-flash column chromatography Change and obtain crude product, add that proper amount of methanol is ultrasonic washes, filter to obtain compound as white solid z-9 (37mg).Productivity: 12%, MS m/z (ESI):464.0[M-H]^-。¹H NMR(500MHz,DMSO-d₆): δ 12.26 (s, 1H), 7.82 (d, J=9.0Hz, 1H), 7.52 (d, J=2.5Hz, 1H), 7.45 (d, J=11.5Hz, 1H), 7.30 (d, J=7.0Hz, 1H), 7.25 (dd, J=2.0, 9.0Hz,1H),5.44(s,2H),3.37(s,3H),2.05-2.01(m,1H),0.98-0.94(m,2H),0.78-0.74(m, 2H).

Embodiment 9-11

Compound Z-10, Z-11, Z-12 are with compound 1-a-4 as initiation material, with reference to the method system of embodiment 9 Standby, except for the difference that change chloro-for the 3-in step 1 4-(trifluoromethyl) phenol into 4-chlorophenol respectively, 3-chloro-4-fluorophenol, 2- Chloro-4-(trifluoromethyl) phenol.

Embodiment 12 4-((3-chloro-4-cumene epoxide) methyl)-5-cyclopropyl-2-fluoro-N-(methyl sulphonyl) benzene The preparation of Methanamide (Z-13)

Step 1: to hydroquinone (2g, 0.018mol) and the 20ml of compound 2-iodopropane (3.072g, 0.018mol) Adding the 10ml aqueous solution of potassium hydroxide (1.070g, 0.019mol) in alcohol reflux solution, return stirring is overnight.Reaction knot Bundle, is cooled to room temperature, concentrating under reduced pressure, adds 2N hydrochloric acid, and ethyl acetate extracts, and saturated common salt is washed, and anhydrous sodium sulfate is dried, mistake Filter, filtrate is concentrated to give crude product, obtains yellow oily compound 13-b (1.031g) through Combi-flash column chromatography purification.Purity: 89.84%, productivity: 37%, it is directly used in next step reaction.

Step 2: be added dropwise over chloroacetic chloride in the 5ml chloroform soln of compound 13-b (330mg, 2.168mmol) (189mg, 2.602mmol), is stirred at room temperature 6 hours.Reaction terminates, and is added dropwise over appropriate sodium bicarbonate solution, separates organic facies, Anhydrous sodium sulfate is dried, and filters, and filtrate is concentrated to give yellow oily crude Compound 13-c (400mg).Productivity: 95%, directly uses React in next step.

Step 3: be added dropwise over N-chloro fourth two in the 10ml acetonitrile solution of compound 13-c (300mg, 1.544mmol) Acid imide (309mg, 2.317mmol), stirred overnight at room temperature.Reaction terminates, and adds saturated common salt washing, separates organic facies, nothing Aqueous sodium persulfate is dried, and filters, and filtrate is concentrated to give yellow oily crude Compound 13-d (435mg).It is directly used in next step reaction.

Step 4: in the 5ml methanol solution of compound 13-d (378mg, 1.653mmol) add potassium hydroxide (92mg, 1ml aqueous solution 1.818mmol), is stirred at room temperature 3 hours.Reaction terminates, and adds appropriate 1M hydrochloric acid solution, and ethyl acetate extracts, Saturated common salt is washed, and anhydrous sodium sulfate is dried, and filters, and filtrate is concentrated to give brown oil crude Compound 13-e (283mg).Produce Rate: 91%, is directly used in next step reaction.

Step 5: compound 13-e (180mg, 0.964mmol), compound 1-a-4 (375mg, 0.964mmol), potassium carbonate (267mg, 1.929mmol) adds in 5ml acetonitrile solution, and 80 degrees Celsius are stirred overnight.Reaction terminates, and is cooled to room temperature, adds Appropriate 1M hydrochloric acid solution, ethyl acetate extracts, and saturated common salt is washed, and anhydrous sodium sulfate is dried, and filters, and it is solid that filtrate is concentrated to give yellow Body crude Compound 13-f (382mg).Productivity: 80%, MS m/z (ESI): 494.0 [M-H]^-.It is directly used in next step reaction.

Step 6: compound 13-f (382mg, 0.772mmol), cyclopropylboronic acid (221mg, 1.544mmol), palladium (29mg, 0.077mmol), tricyclohexyl phosphine (72mg, 0.154mmol), potassium carbonate (355mg, 1.544mmol) addition toluene/ In water (5ml/0.2ml) solution, argon shield, 90 DEG C are stirred overnight.Reaction terminates, and is cooled to room temperature, and kieselguhr filters, filtrate Concentrating under reduced pressure obtains crude product, obtains crude product through Combi-flash column chromatography purification, then through preparation liquid phase separation after purification white solid Body compound Z-13 (33.54mg), productivity: 5%, MS m/z (ESI): 454.1 [M-H]^-。¹H NMR(500MHz,DMSO-d₆): δ 7.31 (d, J=7.0Hz, 1H), 7.19 (d, J=3.0Hz, 1H), 7.16 (d, J=11.0Hz, 1H), 7.12 (d, J= 9.5Hz, 1H), 7.09 (brs, 4H), 6.98 (dd, J=3.0,9.0Hz, 1H), 5.21 (s, 2H), 4.53-4.46 (m, 1H), 2.87 (s, 3H), 2.02-1.95 (m, 1H), 1.26 (d, J=6.0Hz, 6H), 0.95-0.90 (m, 2H), 0.64-0.60 (m, 2H).

The preparation of compound Z-0

Step 1: compound Z-0-1 (20.0g, 155mmol) is dissolved in the tert-butyl alcohol (150mL), is cooled to 0 DEG C, nitrogen Diphenyl phosphate azide (47g, 170mmol), triethylamine (17.3g, 170mmol) is added under gas shielded.Mixture return stirring After 18h, it is spin-dried for Rotary Evaporators.Residue is dissolved in dichloromethane (400mL), with water (200mL x 2), saline solution (200mL) wash.Anhydrous sodium sulfate is dried, sucking filtration.Filtrate is spin-dried for Rotary Evaporators, and residue is with column chromatography (PE:EA=3:1) After purification light yellow solid Z-0-2 (15.2g, yield: 49%) .ESI-MS (M-55)+: 145, purity=97% (UV214) 。¹H NMR(400MHz,CDCl₃) δ: 8.85 (brs, 1H), 8.61 (d, 1H), 7.32 (s, 1H), 1.55 (s, 9H).

Step 2: at N₂Under protection, being dissolved in anhydrous THF (80ml) by Z-0-2 (8.0g, 0.04mol), mixture is cold But-78 DEG C are arrived, the THF solution of dropping LiHMDS (1M, 48ml, 0.048mol).After being added dropwise to complete, mixture, at-78 DEG C, stirs 0.5h.Reactant liquor is slowly ramped to room temperature, stirs 1h, be then cooled to-78 DEG C, by chloro-for 5-2,4 difluorobenzene sulfonic acid chloride THF (50ml) solution of (11.11g, 0.048mol) is added drop-wise to above-mentioned reactant liquor.Mixture, at-78 DEG C, rises to room after stirring 1h Temperature, and 16h is stirred at room temperature.Add in reactant liquor in saturated aqueous ammonium chloride (250ml), with ethyl acetate (3x 100ml) extraction, merges organic facies, washes with saturated aqueous common salt (200ml), is dried, and 40 DEG C are spin-dried for.Crude product crosses post (100-200 mesh Silica gel), leacheate is petroleum ether: ethyl acetate=(4:1), and obtaining Z-0-3 (5.11g, productivity: 31.8%) is white solid. ESI-MS (M+Na)+: 434.0, purity: 95.9% (UV214).

Step 3: compound Z-0-4 (50.8g, 254mmol) is dissolved in THF (600mL), is cooled to 0 in ice bath DEG C stirring, be dividedly in some parts lithium aluminium hydride (8.4g, 220mmol).Mixture is after 0 DEG C of stirring 2h, and the cancellation that adds water is reacted, and adds hydrochloric acid (6N) regulation PH=3, separates aqueous phase, and organic facies anhydrous sodium sulfate is dried, sucking filtration.Filtrate is spin-dried for Rotary Evaporators, obtains white Solid Z-0-5 (32.0g, yield: 73.5%).¹H NMR(400MHz,CDCl₃) δ 7.22 7.16 (m, 1H), 6.77 (d, J= 8.7Hz, 1H), 4.61 (d, J=3.7Hz, 2H), 3.82 (s, 3H), 2.63 (s, 1H).

Step 4: compound Z-0-5 (32.0g, 190mmol) is dissolved in dichloromethane (400mL), is subsequently adding chlorine Change sulfoxide (50mL).Mixture under nitrogen protection, is heated to return stirring 3h.Mixture is down to room temperature, and add water (200mL) quenches Going out reaction, separate organic facies, aqueous phase dichloromethane extracts (200x 2mL).Merge organic facies brine It, anhydrous sulfur Acid sodium is dried, sucking filtration.Filtrate is spin-dried for Rotary Evaporators, obtains red solid Z-0-6 (33.0g, yield: 92.2%).¹H NMR (400MHz,CDCl₃) δ 7.34 (d, J=2.6Hz, 1H), 7.25 (dd, J=8.7,2.7Hz, 1H), 6.81 (d, J=8.8Hz, 1H),4.59(s,2H),3.86(s,3H).

Step 5: compound Z-0-6 (32g, 168mmol) is dissolved in DMSO (200mL), addition Cyanogran. (29g, 606mmol).Mixture under nitrogen protection, is heated to 80 DEG C of stirring 3h.Reactant mixture is cooled to room temperature, adds water-dispersible, takes out Filter.Filter cake is washed with a small amount.Air-dry to obtain orange red solid Z-0-7 (31g, yield: 98.3%).¹H NMR(400MHz, CDCl₃) δ 7.35 (d, J=2.5Hz, 1H), 7.28 (dd, J=8.5,2.3Hz, 1H), 6.82 (d, J=8.7Hz, 1H), 3.86 (s,3H),3.66(s,2H).

Step 6: compound Z-0-7 (32g, 177mmol) is dissolved in methyl formate (400mL), addition sodium (8.14g, 354mmol).Mixture under nitrogen protection, is heated to reflux stirring 24h.Reactant mixture is cooled to room temperature, and the cancellation that adds water is anti- Should, ethyl acetate extracts (400x 2mL), merges organic facies washing (200x 2mL), and anhydrous sodium sulfate is dried, sucking filtration.Decompression is steamed Do to obtain yellow solid Z-0-8 (10.5g, yield: 28.4%).¹H NMR(400MHz,DMSO)δ11.91(s,1H),7.71(d,J =93.3Hz, 1H), 7.40 7.32 (m, 1H), 7.29 (dd, J=12.2,2.6Hz, 1H), 7.08 (dd, J=8.7,3.1Hz, 1H),3.82(s,3H)。

Step 7: be dissolved in ethanol (150mL) by compound Z-0-8 (10.5g, 50.2mmol), adds tertiary butyl hydrazine (7.5g,60.3mmol).Mixture under nitrogen protection, is heated to reflux stirring 3.5h.Reactant mixture is cooled to room temperature, decompression Being evaporated to obtain yellow solid (15g), rapid column chromatography obtains yellow solid Z-0-9 (14.0g, yield: 99.9%).

Step 8: compound Z-0-9 (13.5g, 48.4mmol) is dissolved in dichloromethane (300mL), cold in ice bath But to 0 DEG C, trifluoroacetic anhydride (30.5g, 145.2mmol), triethylamine (14.7g, 145.2mmol) are added.Mixture is at nitrogen Under protection, it is warmed to room temperature stirring 4h.It is the most neutral that reactant mixture adds sodium carbonate cancellation reaction, separates aqueous phase, and organic facies is with full With brine It (100x 2mL), anhydrous sodium sulfate is dried, sucking filtration.Evaporated under reduced pressure obtains brown solid Z-0-10, and (12.0g receives Rate: 66.1%).ESI-MS (M-H): 376, purity=89.23% (UV254).

Step 9: compound Z-0-10 (11.0g, 29.3mmol) is dissolved in dichloromethane (200mL), in ice bath It is cooled to 0 DEG C, adds Boron tribromide (36.7g, 146.6mmol).Mixture under nitrogen protection, is warmed to room temperature stirring 4h.Instead Answering mixture to be slowly added into frozen water (100mL), separate aqueous phase, organic facies saturated aqueous common salt washs (100x 2mL), anhydrous sulfur Acid sodium is dried, sucking filtration.Evaporated under reduced pressure obtains brown solid Z-0-11 (6.3g, yield: 68.9%).ESI-MS (M-H): 362, purity =80.83% (UV254).

Step 10: being dissolved in methanol (100mL) by compound Z-0-11 (25.0g, 69mmol), hydrochloric acid dioxane is molten Liquid (4M/L, 100mL).Mixture stirs 18h at 70 DEG C.After being cooled to room temperature, it is spin-dried for.By methanol (50mL) solution of ammonia slowly Joining residue (100mL), 40 DEG C are spin-dried for.Crude product crosses post (100-200 mesh silica gel), and leacheate is dichloromethane: methanol (10:1) gray solid Z-0-12 (8.0g, yield: 38%), is obtained.ESI-MS (M-H): 210.1, purity=90% (UV214)。

Step 11: by compound Z-0-12 (4.18g, 20mmol), Z-0-3 (8.20g, 20mmol), potassium carbonate (8.28g, 60mmol) being dissolved in DMF (100mL), mixture under nitrogen protection, is heated to 40 DEG C of stirring 18h.Reactant mixture adds Water (500mL), dichloromethane extraction (200mL x 3), merge organic phases washed with water (100mL x 2), saturated aqueous common salt washs (100x 2mL), anhydrous sodium sulfate is dried, sucking filtration.Evaporated under reduced pressure obtain red solid Z-0-13 (15.1g, yield: > 100%). ESI-MS (M+H)+: 600.1, purity=28% (UV254).

Step 12: be dissolved in dichloromethane (40mL) by compound Z-0-13 (12.0g, 20mmol), adds trifluoro second Acid (20mL).Mixture under nitrogen protection, stirs 24h under room temperature.It is yellow solid that evaporated under reduced pressure obtains crude product, through HPLC system For obtaining off-white color pressed powder Z-0 (3.04mg, yield: 31%).ESI-MS (M+H)+: 499.8, purity=100% (UV254)。¹H NMR (400MHz, DMSO) δ 11.56 (s, 2H), 8.91 (d, J=2.4Hz, 1H), 7.90 (d, J=6.8Hz, 1H), 7.69 (s, 1H), 7.43 (s, 1H), 7.32 (dd, J=8.8,2.4Hz, 1H), 7.22 (dd, J=8.4Hz, 1H), 7.07 (d, J=2.0Hz, 1H), 6.73 (d, J=10.8Hz, 1H), 4.92 (s, 2H).

Electrophysiology measures

The manual patch clamp experiments of test case 1hNav1.7, hNav1.5 and hNav1.2 passage

Diaphragm voltage clamp electrophysiology can directly be measured and the current blocking of fixed rate voltage gated sodium channel (various Nav) And time of blocking-up can be measured and voltage relies on, it has been interpreted the knot of the tranquillization to sodium channel, opening and inactivated state Close difference and reflect suppression or activation effect (Hille, B., the Journal of General Physiology of compound (1977),69:497-515)。

The representational compound of the present invention uses manual patch clamp experiments to carry out, and object of this investigation is to apply manual diaphragm The method of pincers tests the compound effect to this ion channel current on the stable cell line of transfection specific ion passage.It makes Stable cell line CHO-hNav1.7 and HEK-hNav1.5 respectively from Genionics company and WuXi Apptec (on Sea) company.

Manual patch clamp experiments scheme is as follows:

(1) solution and the preparation of compound: use whole-cell patch-clamp recording technique record hNav1.7 and hNav1.5 electric current. In experiment, the constituent (mM) of extracellular fluid: HEPES:5, NaCl:40, KCl:3, CaCl₂: 1, MgCl₂: 1, CdCl₂: 0.1, TEA-Cl:20.With NaOH regulation pH value to 7.3, it is depressed into 310-320mOsm with sucrose regulation infiltration simultaneously, filters rear 4 DEG C of guarantors Deposit.The constituent (mM) of intracellular fluid: HEPES:10, NaCl:10, CsOH:5, CsF:140, EGTA:1.PH is regulated with CsOH Value, to 7.3, is depressed into 280-290mOsm with sucrose regulation infiltration ,-20 DEG C of preservations after filtration simultaneously.

Positive control drug and testing compound are first dissolved in 100%DMSO, and (Sigma-Aldrich, D2650 are configured to certain The stock solution of concentration (100nM, 1000nM).Test front DMSO and above-mentioned stock solution is carried out serial dilution, use the most again Extracellular fluid dilutes the test solution obtaining desired concn further.In extracellular fluid, DMSO ultimate density is less than 0.30%.

(2) manual patch clamp experiments: obtained cell suspension is added in the culture dish of 35mm, is placed in inverted microscope object stage On.After cell attachment, using extracellular fluid perfusion, flow velocity is 1 2mL/min.Glass microelectrode is drawn instrument two step by microelectrode and draws System, it enters water power resistance is 2-5M Ω.By Digidata 1440 (Molecular Devices) and pCLAMP software (10.2 Version, Molecular Devices) A/D D/A digital-to-analogue conversion, carry out stimulating and provide and signals collecting；Patch clamp amplifier (Multiclamp 700B, Molecular Devices) amplifies signal, is filtered into 4KHz.

Two kinds of different voltage stimulation programs are used in the manual patch clamp experiments of hNav1.7 with hNav1.5.

One is inactivation stimulation programs, and command potential is arranged on the V of corresponding passage_1/2, the passage of the most about 50% is in Inactivated state.Then give voltage extremely-120mV, continue 50ms.Then depolarization is to-10mV, continues 20ms and draws sodium current, Eventually pass back to command potential.This stimulation programs can also be referred to as the voltage stimulation programs that channel status relies on.

Another kind is non-inactivation stimulation programs, keeps command potential at-120mV, and giving voltage stimulates to-10mV, continues 20ms draws sodium current, eventually passes back to command potential.That is, under the conditions of this kind of stimulation programs, all of passage does not all have Live through inactivated state, but directly activate from quiescent condition.

The time interval of above two voltage stimulation programs is 10s.The depression effect of compound is by before and after dosing Curent change calculates, and IC₅₀Numerical value is fitted gained by Hill equation.If compound is different in above two Voltage demonstrates, under stimulating, the difference having certain multiple to channelling effect, then this compound is to have State-dependence to this passage Property.

Data analysis

By the electric current after each drug level effect and blank current standard (compound peaks tail currents/right According to thing peak tail currents), then calculate suppression ratio corresponding to each drug level (1-(compound peaks tail currents/tester Peak tail currents)).Each concentration is calculated average and standard error, and with following Equation for Calculating every kind compound 503nhibiting concentration:

Suppression ratio=1/ (1+ (IC₅₀/c)^h)

By above equation, dose-dependent effect being carried out nonlinear fitting, wherein c represents drug level, IC₅₀For partly press down Concentration processed, h represents hill coefficient.Curve matching and IC₅₀Calculating utilize IGOR software to complete.Result is shown in Table 1 and table respectively 2。

Table 1 representative compound of the present invention suppression ratio to Nav1.7 under two kinds of concentration

The table 2 representative compound of the present invention IC to Nav1.7 and Nav1.5₅₀Value

Compound	Nav1.7(IC50/nM)	Nav1.5(IC50/nM)	Nav1.5/Nav 1.7
				Z-1	4.2	200	47.6
Z-2	8.47	810	95.6

The manual patch clamp experiments of hNav1.2

Cell prepares:

NaV1.2 gene information: people's voltage-gated sodium channel hypotype 1.2 is stably expressed by recombinant HEK 293 cell system (hNaV1.2) .cDNA follows strictly GenBank serial number: NM_001040142.1.

Stably express the HEK293 cell line of Nav1.2 passage containing 10% hyclone and 1.2mg/ml G418 Cultivating in DMEM culture medium, cultivation temperature is 37 DEG C, and gas concentration lwevel is 5%.

Passage: remove old culture medium and wash once with PBS, being subsequently adding 1ml TrypLE^TMExpress solution, 37 DEG C hatch 1 minute.When cell departs from from the bottom of ware, add the complete medium of 5ml 37 DEG C preheating.By light for cell suspension suction pipe The cell separation making gathering is beaten in featheriness.Being transferred to by cell suspension in aseptic centrifuge tube, 1000rmp is centrifuged 5 minutes and collects carefully Born of the same parents.Amplification or maintenance are cultivated, and cell is inoculated in 10 cm cell culture dishs, each Tissue Culture Dish, and inoculating cell amount is 3.5*10⁵(final volume: 10ml).

For maintaining the electrophysiologic activity of cell, cell density must not can exceed that 80%.

Patch-clamp detects, cell TrypLE before experiment^TMExpress separates, and is taped against on coverslip by 3*103 cell, In 24 orifice plates, cultivate (final volume: 500 μ l), after 18 hours, enter experiment detection.

Patch clamp experiments method:

Instrument (P97, Sutter Instruments) is drawn by glass capillary (BF150-86-10, Sutter with microelectrode Instruments) it is drawn into recording electrode.Instrument is handled at inverted microscope (IX71, Olympus) lower-pilot microelectrode Recording electrode is touched on cell by (MP285, Sutter Instruments), gives negative pressure-pumping, forms G Ω sealing-in.Shape Carry out flying capacitance compensation after becoming G Ω sealing-in, then proceed to give negative pressure, inhale broken cell film, form whole-cell recording technique pattern.So After carry out the compensation of electric capacity at a slow speed recording film electric capacity and series resistance, and give series resistance compensation, do not give electric leakage and compensate. When starting record after the current stabilization of whole-cell recording technique.Experimental data is acquired by EPC-10 amplifier (HEKA) and is stored in In PatchMaster (HEKA) software.

When starting to be administered after the current stabilization of whole-cell recording technique, to 5 minutes, (or electric current was to surely in each drug level effect Fixed), each tests compound test 1000nM concentration value.The coverslip being covered with cell is placed in be inverted micro-in record bath In groove, test compound and the outer liquid without compound utilize the method for gravity perfusion to flow through successively from low concentration to high concentration Record cell thus act on cell, utilize vacuum pump to carry out fluid exchange in record.Each cell is without compound Outer liquid in the electric current that detects as oneself matched group.3 cells of independent duplicate detection.All electro physiology are tested in room temperature Under carry out.

Liquid used by sodium-ion channel record:

Extracellular fluid: 140mM NaCl, 4mM KCl, 1mM MgCl₂、2mM CaCl₂, 5mM D-Dextrose Monohydrate, 10mM HEPES (pH=7.4 NaOH regulation).

Intracellular fluid liquid: 145mM CsCl, 0.1mM CaCl₂、2mM MgCl₂、10mM NaCl、0.5mM Na₂-GTP、 2mM Mg-ATP, 1.1mM EGTA, 10mM HEPES (pH 7.2 CsOH regulation).

The stimulation protocol of sodium-ion channel:

First the transmembrane potential of cell is maintained-90mV, is then spaced with the step of 5mv, by cell membrane potential step to- 120mV to 100mV.

Suppression ratio result is calculated as shown in table a by above-mentioned formula.

Under table a concentration of the same race, the suppression ratio of Nav1.7 and Nav1.2 compares

Compound (Z-2)	1000nM (%)
		Nav1.7	98.20
Nav1.2	35.00

From table 1, table 2 and table a it can be seen that representative compound of the present invention has higher inhibitory activity to Nav1.7, The most weak to the inhibitory activity of Nav1.5 and Nav1.2, representative compound the most of the present invention not only to Nav1.5 and also right Nav1.2 is respectively provided with selectivity.

Test case 2 cold stimulation allodynia method

Laboratory animal is male Sprague-Dawley rat, body weight 140-150g when experiment starts.Animal for research is equal Purchase in Si Lai g company, use the mode of free choice feeding to carry out food and water supply, sub-cage rearing after purchase, 4/cage, use Animal trailer label method l carries out animal marking.

Detection compound and packet:

Solvent control thing (Vehicle): 5% dimethyl acetylamide (traditional Chinese medicines science and technology), 5% Polyethylene Glycol-15 hydroxy stearate Acid esters (solutol) (Sigma) and 90% normal saline

Positive control: compound Z-0；

Medicine to be measured: compound Z-2；

The solvent composition of positive control and medicine to be measured is 5% dimethyl acetylamide, and 5% Polyethylene Glycol-15 hydroxyl is hard Fat acid ester and 90% normal saline.

After oral 2 hours, the crymodynia of Z-2 100mg/kg dosage suppression Rat Spinal Nerve Tissue ligation induction is super quick.Z-0 The crymodynia of 75mg/kg and 100mg/kg dosage suppression Rat Spinal Nerve Tissue ligation induction is super quick.As shown in table 3.

Table 3 compound is efficacy testing packet in spinal nerve ligated rats

Experimental technique:

1.1. Spinal Nerve Ligation Model

Operation process performs sterile working.

Operating theater instruments (shears, tweezers, scalpel, operation cotton, stitching thread, dilator) is sterilized the most.

Use that (50mg/kg, lumbar injection) anesthetized animal of pentobarbital.Extruding animal toe is to confirm animal surgery Before holonarcosis.Ophthalmic ointment is smeared to prevent animal corneal to be dried at animal eye.

Shave off animal lower part of the body operative region hair, use povidone iodine and 70% ethanol to operation area skin sterilization three Time.Operation is started after xerosis cutis.

Scalpel is used to open a longitudinal cut at animal waist sacrum rear portion, paraspinal muscle on the left of exposure, use dilator Separating muscle tissue is to expose vertebrae.

Spinal nerves L5 and L6 on the left of separation, uses the ligation of 6-0 silk thread.

Sew up a wound.

Sterile surgery apparatus, uses hot pearl steriliser sterilizing.

Animal is placed on electric blanket by Post operation, and subcutaneous injection 5mL normal saline is in case anti-avulsion water.Complete Deng animal After reviving, animal is put back in cage by (can be freely movable).

1.2. the test of crymodynia super quick baseline and packet

It is administered a few days ago, rat is carried out the test of crymodynia super quick baseline, use pipettor that 100 μ l acetone are coated in animal Art rear flank pedal skin.Record was patted in one minute by animal, contracting foot, and foot-up licks the time licking art parapodum portion.Acetone test is altogether Carry out twice, two minor ticks 10 minutes.Twice time sum is recorded as the rat crymodynia allergy time.Previous according to being administered It crymodynia allergy test result is by animal random packet.

1.3. the super quick test of crymodynia

After being administered two hours, use pipettor that 100 μ l acetone are coated in animal art rear flank toe section skin.Record animal exists Pat in one minute, contracting foot, foot-up, lick the time licking affected foot.Acetone test is carried out twice altogether, two minor ticks 10 points Clock.Twice time sum is recorded as the rat crymodynia allergy time.

1.4. be administered

The cold stimulation pain sensation tests oral administration before 2 hours.Wherein it is administered record and the weight of animals is as shown in table 4:

Table 4 is administered record and the weight of animals

The super quick test result of table 5 rat crymodynia

1.5. data collection and analysis

Excel software is used to collect data.Use Prism software analysis data.

As depicted in figs. 1 and 2, result shows that example compound Z-2 of the present invention is at spinal nerve ligated rats mould to experimental result Type has suppression cold stimulation allodynia effect, is statistically significant suppression effect in rat nerves within the body pain model Really.

In Fig. 2, compare with solvent control thing, use one factor analysis of variance additional Dunnett multiple comparative test, * * * p < 0.001, oral administration of compound Z-2 and compound Z-0 (100mg/kg and 75mg/kg) suppress Rat Spinal Nerve Tissue after two hours respectively The crymodynia of ligation induction is super quick.

Test case 3: rat in vivo test

Application LC/MS/MS method determines rat gavage respectively and intravenous gives after embodiment compound blood plasma the most in the same time In drug level, study the compounds of this invention pharmacokinetics behavior in rat body, evaluate its characteristics of pharmacokinetics.

Experimental program:

Experimental animal: healthy adult male SD rat (body weight 215-225g, 6, fasting), this Leco Corp. provide；

Administering mode and dosage: give SD rat dorsalis pedis vein and be administered (1mg/kg, 1mL/kg, 5%DMAC (dimethyl second Amide), 5%Solutol HS 15 (Polyethylene Glycol-15 hydroxy stearic acid ester) and 90% saline and gastric infusion (2mg/kg, 2mL/kg, 0.5%CMC-Na aqueous solution)

Blood specimen collection: first to selecting the animal meeting requirement of experiment, labelling of weighing before being administered.Before gathering blood sample, binding Rat, each rat being administered predetermined blood sampling time point (intravenously administrable: before being administered, after administration 0.083, 0.25,0.5,1,2,4,8,24h blood sampling, totally 9 time points；Gastric infusion: respectively at be administered before, after administration 0.083, 0.25,0.5,1,2,4,8,24h blood sampling, totally 9 time points), by tail vein blood, or through Culling heart blood (end blood sampling eventually) about 150μL.Taken a blood sample by eye socket, or through Culling heart blood (end blood sampling eventually) about 150 μ L.Blood is transferred to be previously added K₂EDTA's In 1.5mL test tube.The blood sample adopted be placed on wet on ice, centrifugal 5min (2000g, 4 DEG C), take out blood plasma, whole process is in blood sampling Complete in rear 15min.All of sample is required for depositing in-70 DEG C of refrigerators until sample analysis.

Application LC/MS/MS method measures drug level, and section Example compound of the present invention is at same dose and administering mode Under, the pharmacokinetic property parameter in rat body is as shown in table 6:

Table 6 compound is in Pharmacokinetics in Rat parameter

As can be seen from Table 6, the medicine of example compound of the present invention, for good absorbing, has obvious medicine for assimilation effect, with Time show good bioavailability.

Test case 4: metabolic stability is tested

1. the preparation of buffer

Buffer A: preparation 1L contains 1mM EDTA (Sigma, V900157-100G), the potassium dihydrogen phosphate of 100mM.

Buffer B: preparation 1L contains the dipotassium hydrogen phosphate solution of 1mM EDTA, 100mM.

Buffer C: take 700mL buffer B, titrates by buffer A, and being adjusted to PH is 7.4.

2. testing compound and the preparation of positive control drug (ketanserin (Sigma S006-10MG))

2.1 take 10mM testing compound and each 10uL of 10mM ketanserin, respectively add the pure acetonitrile of 190uL, are made into respectively 500uM testing compound and ketanserin solution.

2.2 take 20uL (20mg/mL) hepatomicrosome (Corning Lot.452161) and rat liver microsomes (Corning Lot.452501) store liquid and be added separately to the buffer C of 513.4uL, operate on ice wet.Preparation obtains 0.75mg/mL liver Microsome solution.

2.3 respectively take the above-mentioned testing compound of 1.5uL and ketanserin solution, are added separately to 498.5uL's (0.75mg/mL) In hepatomicrosome solution, operate on ice wet.Preparation obtains 1.5uM testing compound mixed liquor and ketanserin mixed liquor.

2.4 according to time point 0,5,15,30,45,60min, every hole 30uL, respectively by testing compound mixed liquor and ketone color Woods mixed liquor is dispensed on Sptting plate, operates on ice wet.

2.5 weigh 5mg NADPH (Roche, 10621706001), are dissolved in 1mL buffer C.It is configured to 6mM NADPH solution.NADPH solution is dispensed in Sptting plate.

2.6 by the solution of imipramine melt into 10mM, takes 100mL blank acetonitrile, adds 10uL imipramine solution.In being made into Mark.

2.7 at 0min, and every hole adds 135uL and contains interior target ice acetonitrile (Merck (Lot.1778229518)), adds 15uL buffer C.

Sptting plate is put into 37 degree of constant temperature water box by 2.8 preheats 5min.In Sptting plate, it is auxiliary that every hole adds 15uL reduced form Enzyme II solution starts reaction timing.5,15,30,45,60min time point, every hole adds 135uL and contains interior target ice acetonitrile Terminate reaction.

Sptting plate aluminum film is sealed by 2.9, is placed on shaking mixer, 500rpm, 5min.Again Sptting plate is placed on centrifugal Machine is centrifuged, 15min, 3750rpm.

2.10 take sample and pure water detects according to 1:1 dilution proportion, LC/MS.By the numerical value that obtains according to below equation meter Calculate and obtain half-life as shown in table 7 and clearance rate.

Half-life: 0.693/K (slope that brooding time and log concentration value map out)

Clearance rate: (0.693/ half-life) * (1/ protein concentration (0.5mg mL)) * (scale factor)

Wherein K value and scale factor are that those skilled in the art are according to existing method and hepatomicrosome description of product secretary The method carried is calculated.

Table 7 rat and people's hepatomicrosome metabolic stability experimental result

As can be seen from Table 7, the difference of structure has significantly impact to metabolic stability, by R₂Cyclopropyl change ring into After hexenyl, the metabolic stability of rat and people substantially reduces, after the group being joined directly together with oxygen in addition changes pyridine radicals into, and metabolism Stability is significantly reduced.

The all documents mentioned in the present invention are incorporated as reference the most in this application, just as each document by individually It is incorporated as with reference to like that.In addition, it is to be understood that after the above-mentioned teachings having read the present invention, those skilled in the art can To make various changes or modifications the present invention, these equivalent form of values fall within the model that the application appended claims is limited equally Enclose.

Claims (11)

1. the compound shown in formula (I), or its pharmaceutically acceptable salt, solvate, stereoisomer or prodrug:

In formula,

R₁For fluorine or chlorine；R₂For cyclopropyl or cyclohexenyl group；N is 0 or 1；Z is N or CR₇；

R₃、R₄、R₅、R₆、R₇It is each independently hydrogen, halogen, halo C_1-20Alkyl, C_1-20Alkoxyl, halo C_1-20Alkoxyl.

2. compound as claimed in claim 1 or its pharmaceutically acceptable salt, solvate, stereoisomer or prodrug, It is characterized in that, R₁For fluorine；R₂For cyclopropyl.

3. compound as claimed in claim 1 or its pharmaceutically acceptable salt, solvate, stereoisomer or prodrug, It is characterized in that, Z is CR₇, R₇Definition as claimed in claim 1.

4. compound as claimed in claim 1 or its pharmaceutically acceptable salt, solvate, stereoisomer or prodrug, It is characterized in that, n is 1.

5. compound as claimed in claim 1 or its pharmaceutically acceptable salt, solvate, stereoisomer or prodrug, It is characterized in that, R₃、R₄、R₅、R₆、R₇It is each independently hydrogen, fluorine, chlorine, trifluoromethyl, methoxyl group, ethyoxyl, propoxyl group, different Propoxyl group, trifluoromethoxy, trifluoro ethoxy.

6. compound as claimed in claim 1 or its pharmaceutically acceptable salt, solvate, stereoisomer or prodrug, It is characterized in that, R₆For hydrogen.

7. compound as claimed in claim 1 or its pharmaceutically acceptable salt, solvate, stereoisomer or prodrug, It is characterized in that, Z is CR₇；R₃、R₄、R₅、R₆、R₇Be each independently hydrogen, fluorine, chlorine, trifluoromethyl, methoxyl group, ethyoxyl, third Epoxide, isopropoxy, trifluoromethoxy, trifluoro ethoxy, trifluoromethyl；And R₃、R₄、R₅、R₆、R₇In three be hydrogen.

8. compound as claimed in claim 1 or its pharmaceutically acceptable salt, solvate, stereoisomer or prodrug, It is characterized in that, Z is CR₇；R₃、R₄、R₅、R₇It is each independently hydrogen, fluorine, chlorine, trifluoromethyl, methoxyl group, ethyoxyl, the third oxygen Base, isopropoxy, trifluoromethoxy, trifluoro ethoxy, trifluoromethyl；R₆For hydrogen, and R₃、R₄、R₅、R₇In two be hydrogen.

9. compound as claimed in claim 1 or its pharmaceutically acceptable salt or its solvate or its stereoisomerism Body or its prodrug, it is characterised in that described compound is selected from lower group:

10. a pharmaceutical composition, described compositions includes the compound according to any one of claim 1 to 9 or its pharmacy Upper acceptable salt, solvate, stereoisomer or prodrug；And pharmaceutically acceptable carrier.

11. compound as claimed in any one of claims 1-9 wherein or its pharmaceutically acceptable salt, solvate, solids Isomer or prodrug, or pharmaceutical composition application in the medicine of preparation treatment disease or disease as claimed in claim 10, Described disease or disease are selected from pain, depression, cardiovascular disease, respiratory system disease, mental sickness or a combination thereof.